°c

Keywords:

A Ac Acetyl Ar Aryl atm Atmosphere B Boc tert-Butyloxycarbonyl BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl Bn Benzyl Bu Butyl C cat. Catalyst °C Degree Celsius cod 1,

This thesis was conducted under the direction of Doctor Virginie Vidal, Professor Véronique Michelet and Doctor Mansour Haddad (co-advisor) at Chimie ParisTech in the "Catalysis, Synthesis of Biomolecules and Sustainable Development" team (CSB2D team) at the Institut de Recherche de Chimie Paris (IRCP laboratory).

I have been working in Paris since October 2014, I have thoroughly enjoyed the wonderful three years in this beautiful city. I am deeply touched by the people who support me warmly to complete this thesis, and I would like to thank them sincerely.

I would like to express my sincere gratitude to Doctor Corinne Gosmini, Professor Jean Rodriguez and Professor Max Malacria for accepting to read and review my thesis and to be part of my defense committee.

First and foremost, I wish to thank my PhD advisors, Virginie and Véronique. I want to say they are the lucky stars in my life since they gave me the opportunity to start my PhD program in their wonderful team, my life has become more bright since then. They take care very much of me and were always thoughtful in my life, my work and my future. They always give me a power to move forward. I remember they used to say something like "you have done a very good job", "excellent", "super" to encourage me, even if I didn't make the things perfect.

I am very grateful that they can be so patient with me. Although they are very busy, they never hesitate to spend plenty of time to guide me to make things better. In such circumstances, over these three years, my personal and professional abilities have been greatly improved. In chemistry, we have many full discussions in each project, I have enjoyed so much working with them. We have done three papers together. It makes me more confident in this area. Thanks to them with all my heart! I am also grateful to Mansour. He is like a teacher and a friend all in one. He taught me a lot of professional experience and good habits in chemistry. He is always willing to help me and never said no to me. Thanks for his good humor and optimistic attitude, it makes me so comfortable working in his lab over these three years. I will never forget it. I wish him will be very happy and good health in his retired life, although there are some years to work yet.

I also want thank the other permanents in CSB2D team. Phannarath Phansavath, called Pocki, who was enthusiastic to me. I thank her for the responsiblility of each commercial order (forgive me for all the mistakes I have made with the "commandes" ). Sylvain Darses, for his good spirit, and also for his jokes. He had fun with everyone. Thanks to Tahar Ayad and Patrick Toullec, for few chemistry discussions and good humors. Big thanks also to Maxime Vitale, who combines not only chemical skills, but also computing skills as well.

I would like to give a special thanks to our dear Chachaaaaaa, Charlène. As she said, she is everywhere. A special thanks to her for the responsibility of the lab's security, allowing us to work in a safer environment, that's very important for a chemist. Thanks also for giving me a special right to take all the staffs (needles, syringe, vials, caps, septum…) in any day of the week. I will miss this period.

Next, it's time to give my thanks to all the former and present ATER, Postdoc and PhD students.

Let's start from the ATER. Aurélie, her positive and optimistic attitude towards all the things makes me admiring. Congratulations for her permanent position in ICSN. Fatma, thanks for her work on the [2+2+2] project. I hope she will enjoy her next ATER position in Versailles.

The former postdoc, Adrien, thank him for showing me the first Chinese restaurant Bambou in Paris, I am the VIP of the restaurant now . Amandine, I still remember her sweet smile and beautiful window's painting, it's one of my seldom updated image in my Facebook.

Eder, to me he is like a master (师父 Shi Fu in Chinese), thank him for teaching me the professional experience on crystallization, that's amazing. I wish him to have a good future in academic research, and I hope to see him again. Sudipta, he is an awesome guy, he is always the first one in and the last one out working in the lab, I believe that the hardest work he did will one day bring him the biggest benefits. Clément, he is always doing a big column when I saw him. Thanks for his kindness.

The former PhD students. Pierre-George, PG, he is my "idol". He always makes everything to be the best :))))). Gaëtan, we haven't had much time to get to know each other, in my mind, he is very optimistic and kind, I liked to chat with him. Marc, he helped me a lot when I started my work in the lab, he was always available and patient to explain me everything.

Fabien, thanks for his good humour and jokes especially with the montage pictures, he made a lot of fun in the lab. Next one is our Miss Panda, dear Charlotte, I've never seen a girl who loves so much panda. It is sure that wherever I see a panda, I will think about her. And thank her for taking me running in Luxembourg Park. However, it is a pity that we have never run again since she left to Germany. I hope her to have good life in the future.

A special acknowledgement goes to the best other three graduating PhD students, Benjamin, Maxime and Quentin. Thanks to the king of battery, BenBen. It was my honor to work with him in the same lab. Thanks to him for teaching me a lot of interesting French words and jokes. I also thank him for organizing wonderful outdoor activities, picnic in Fontainebleau, barbecues in his warmly house, accro-branches afternoon, etc. I wish him a bright future in his carrier. Big thanks to Maxime L, he is definitively a nice guy in the lab. I don't remember how many administrative works he helped me to do, registration files, comité de suivi, application of defense. Wish him to enjoy his future research in pharmaceutical company, congratulations! Thanks to sunshine Quentin, he was also warm-hearted and enthusiastic. I am envious of his ability to carry out recreational activities and chemistry at the same time. I wonder if he can play the trumpet in his defense day, that will be awesome. I also thank him for inviting me for the Raclette Party in his house. I enjoyed the typical French tradition very much. Hope him to enjoy the oncoming work in fine chemical company.

I next want to thank the present PhD students. Longsheng, my brother, I can't thank him enough. He takes care of me so much since we met six years ago. We have so many things worth remembering, all the things converge into a word "no brother no game, no brother no chemistry". Yue, he is an artist, chemist and scholar. I always call him Dr. Tang, because he knows everything in heaven above and the earth underneath. I also thank him for giving me the first defense gift. Aymane, I enjoyed the cooperation with him for the passeur NMR, thanks to him for not complaining to Marie-Noëlle for my all the times absent. And also I believe that his hard work can provide him a good return, sooner or later, Bon courage! Johanne, congratulations for her success to get a grant and being a doctoral student in this laboratory.

And thank to her for bring the homemade Lemon Tarte in her ending internship pot, I could eat the whole of it.

I next want to thank all the staffs working in Chimie ParisTech for support me to finish my PhD thesis. Particularly, I would like to thank Marie-Noëlle for her hard work and careful explanation in NMR spectrometry. Thanks to Céline and Claudine for their incredible work in mass spectrometry. Thanks to Frédéric for some measurement of melting points. Thanks to Franck for bringing all the experimental consumables from upstairs to downstairs every day. I also thank Suzanne and Marjorie for the administrative work.

I would like also to thank Lise-Marie Chamoreau and Geoffrey Gontard for the Xray analysis (IPMC, UPMC).

I also want to thank my two tutors of "Comité de suivi de thèse", Doctor Muriel Amatore and Doctor Christophe Meyer, for their comments on my work during my PhD study.

I would like also to thank all my friends in France and China who helped and supported me, I would like to name those who were closer to me over these three years: Lu, Jie, Tao, Tongwei, Sen, Wenbin, Shaoyi, Dandan, Kunyun, Jingwen, Jun, Xiaohan, Conghui.

Last, my thanks would go to my beloved family, my parents and my sister, for their thorough concern and great confidence in me all through these years. Particularly, I want to thank my lover for accompanying me during these lovely and memorable three years.

Finally, I would like to give a special acknowledgement to China Scholarship Council for giving me a three years's fellowship in Paris. I also thank all the support of various platforms and institutions for CSB2D team.

D

Résumé

Ce manuscrit présente le développement de nouveaux systèmes catalytiques à base de ruthénium et de rhodium pour des réactions de cyclisation [2+2+2].

Chapitre 1. Réactions de cycloaddition [2+2+2]: bibliographie

Au cours de ce chapitre nous examinerons les différents types de cycloaddition en fonction de la nature des fonctions alcynes impliquées dans la cycloaddition (Schéma R1).

Schéma R1

Pour chaque cas, des exemples seront donnés afin d'illustrer les résultats de la littérature.

Dans une seconde partie, nous détaillerons les différents métaux de transition utilisés pour mettre en oeuvre les réactions. Parmi les complexes de métaux de transition, on verra que ceux qui sont le plus couramment utilisés sont des complexes au cobalt avec le complexe CpCo(CO)2; au rhodium (par exemple le complexe de Wilkinson RhCl(PPh3)3 ou encore au rhodium sous forme cationique tel Rh(cod)2BF4 associé à un ligand phosphine type BINAP); le nickel a aussi été utilisé sous forme Ni(dppe)Br2 par exemple ou bien Ni(CO)2(PPh3)2; ensuite on peut citer l'iridium dont le complexe dimère [Ir(cod)Cl]2 a été souvent employé; pour finir nous citerons le ruthénium, dont le complexe le plus connu est le catalyseur de Grubbs de 1ère ge ńe ŕation.

+

(1) Intermoléculaire:

(2) Partiellement intramoléculaire:

+ (3)Totalement intramoléculaire: M [ ] M [ ] M [ ]
Chapitre 2. Vers un nouvel accès aux dérivés fluorénones via une cycloaddition [2+2+2] catalysée par le trichlorure de ruthenium hydraté.

Au cours de notre étude sur la synthèse de carbocycles et d'hétérocycles, catalysée par les métaux de transition, nous avons mis en évidence la possibilité d'accéder relativement facilement à des fluorénones substituées ainsi qu'à des analogues, à partir de diynes- augmente la réactivité par rapport à un groupe alkyle (n-butyle). L'introduction de groupements donneur ou accepteur conduit à peu de changement, les rendements restant du même ordre. Un groupement silyle à la place du groupe phényle apporte peu de modifications, et conduit aussi au produit attendu (Schéma R2). Ce résultat est intéressant car il permet d'envisager une postfonctionnalisation. Le groupement protecteur des alcools a aussi été examiné et les groupes benzyle ou tert-butyle sont compatibles avec les conditions reactionnelles, et conduisent ainsi aux produits 76 et 77 (80 et 81%). La structure de la fluorénone 77 a pu être établie sans ambiguïté par une analyse de diffraction des rayons X (Schéma R3).

Schéma R2 nBu nBu O O R 3 R 1 R 2 R 2 R 1 O R 3

Schéma R3

Le pont reliant les deux fonctions diynes a ensuite été modifié: le groupe phenyle a ainsi été remplacé par un hétérocycle (furanyle, thiényle, cycle azoté); la cycloaddition se fait également pour conduire à des hétéro-fluorénones variées 83-87, 89 et 90 avec des rendements allant de 30 à 78 % (Schéma R4).

Schéma R4

Cette réaction de cycloaddition ne se limite pas aux diynes symétriques internes, puisqu'une série de diynes terminaux a éte utilisée. La réaction de ces derniers avec le diyne 17

Schéma R5

Pour valider l'intérêt synthétique de cette méthode catalytique, la réaction a été conduite sur une échelle d'un gramme dans les conditions pré-établies. La fluorénone 65 a pu être isolée avec un rendement de 71% (Schéma R6).

Schéma R6

Après avoir synthétisé une gamme de dérivés fluorénones, nous nous sommes tournés vers l'étude de la post-fonctionnalisation des composés 65, 69 et 76. En utilisant des protocoles décrits dans la littérature, nous avons pu accéder aux composés dihydrobenzo [b]

Schéma R7

La fluorénone silylée 69 s'est également avérée un bon intermédiaire pour accéder, après iodation au composé 97, lui même précurseur de dérivés fonctionnalisés par un alcyne ou un ester boronique par des réactions de couplage de Sonogashira ou .

Schéma R8

La fluorénone bromée 73 s'est également révélée un bon adduit, puisque après couplage de Suzuki-Miyaura, elle a été transformée en ester boronique 100 avec un rendement de 85% (Schéma R9).

Schéma R9

Une nouvelle approche directe et éco-compatible vers la synthèse de fluorénones hautement substituées ainsi que des analogues a été mise au point. Cette méthode fait intervenir une cycloaddition [2+2+2] semi-intramoléculaire de cétones possédant un motif 1,6-diyne avec un alcyne, initié par le complexe RuCl3•nH2O. Ce procédé économique est conduit sans solvant, ni aucun ligand ou additif, et ce dans des conditions douces. Cette réaction a permis l'obtention de fluorénones polycycliques complexes, d'aza-fluorénones, des benzo [b]furanones et également des thiophénones polycycliques, avec de bons rendements. Des études ultérieures ont montré que les fluorénones ainsi obtenues pouvaient être converties en molécules plus complexes.

Chapitre 3. Utilisation de la catalyse au ruthénium pour des cycloadditions [2+2+2] de diynes avec des cyanamides électroniquement enrichis: un accès facile aux dérivés 2aminopyridines

Dans la continuité de notre précédent travail relatif aux cycloadditions [2+2+2] catalysées par un métal de transition, nous avons décidé d'explorer, la réaction de cycloaddition [2+2+2] de -diynes et cyanamides dans le but de synthétiser des dérivés 2-aminopyridines.

a. Cycloaddition [2+2+2] d'-diynes avec des cyanamides catalysée par RuCl3•nH2O

Différent diynes et cyanamides ont été efficacement préparés. La diyne 101 et le diméthyl cyanamide 154 ont été choisis comme substrats modèles pour optimiser les conditions réactionnelles. Nous avons commencé l'étude avec 5% molaire de RuCl3•nH2O, dans des conditions sans solvant. Un examen plus approfondi a montré qu'il fallait opérer à 110 °C pour une durée de 18 heures. Après avoir mis au point les conditions pour réactionnelles, nous avons évalué la réactivité de divers diynes et cyanamides. Les résultats sont regroupés dans le Schéma R10.

Une série de cyanamides obtenus à partir d'amines secondaires ont été soumis à la réaction de cycloaddition pour conduire aux 2-aminopyridines correspondantes avec de bons rendements.

Par exemple, des diynes symétriques portant diverses fonctions telles que des esters, cétones ou amides sont compatibles.

Schéma R10

La régiosélectivité de la réaction de cycloaddition de diynes-1,6 non symétriques a aussi été étudiée, comme indiqué dans le Schéma R11. Les diynes-1,6 portant un substituant méthyle ou phényle ont été mis en réaction avec la 4-carbonitrile morpholine et ont conduit à 2 régioisomères avec une sélectivité réduite et un rendement global plus faible. Le ratio des deux régioisomères a été déterminé par analyse RMN 1 H du brut réactionnel.

Schéma R11

Un exemple de nitrile électro-déficient a également été considéré, plus précisement le malononitrile qui a été soumis à la cycloaddition avec le diyne 108 comportant un pont azoté, dans les conditions usuelles de 110 °C en présence de RuCl3•nH2O. Dans ce cas, le cycloadduit 195 est obtenu avec une conversion de 22%, malgré un taux de catalyseur de 10% molaire (Schéma R12). Ce résultat est nettement inférieur à ceux obtenus avec des nitriles enrichis. 2) 5 min 188 >99 82 a 0.6 mmol de cyanamide 155 et 0.5 mL de dichlorométhane utilisés. b échelle d'un gramme Dans un second temps et comme précédemment, ayant établi les conditions optimales de la réaction, nous nous sommes intéressés à la généralisation de cette reaction en faisant intervenir divers diynes substitués et le cyanamide 155 comme partenaire (Schéma R13). Une grande variété de diynes symétriques, pontés avec un carbone quaternaire, un oxygène ou encore un azote protégé ont été soumis au cyanamide 155 pour donner les 2-aminopyridines correspondantes. L'introduction de groupements volumineux tels que le groupe tert-butyle ou iso-propyle conduit également à d'excellents rendements. De même, des groupes fonctionnels portés par le carbone quaternaire, tels que des diols, des nitriles, des diones ont également été utilisés avec succès. La formation des composés 186 et 187 montre aussi que la réaction est compatible avec des diynes internes (Schéma R13).

Schéma

Schéma R13

Par la suite, dans le but d'examiner les limites de la réaction, un certain nombre d'amines secondaires portées sur le cyanamide a été testé. Comme indiqué dans le Schéma R14, les résultats se sont avérés très probants avec l'obtention d'un grand nombre de 2-aminopyridines.

Schéma R14

Comme dans le cas du ruthénium neutre (RuCl3•nH2O), la régiosélectivité a été examinée. Dans ce cas, il a été observé que la régiosélectivité ainsi que le rendement étaient plus élevés. Notamment, le régioisomère ortho était formé majoritairement (Schéma R15). De plus la réaction tolère un grand nombre de fonctions avec l'obtention des halopyridines, diaminopyridines, et vinylpyridines avec des rendements allant de 65 à 93%. La structure du produit 220 a été confirmée sans ambiguïté par une étude de diffraction des rayons X (Schéma R15).

Schéma R15

Une étude ultérieure a par ailleurs montré que la réaction était possible avec les diynes-1,7 138 (lien oxygéné) et 139 (lien azoté). En présence de 5% molaire de Cp*Ru(CH3CN)3PF6, ils conduisent aux pyridines bicycliques à 6 chaînons 230-233 avec des rendements de 34 à 86% et une excellente régiosélectivité (Schéma R16).

Schéma R16

Le composé spirocyclique 237 a été isolé à partir d'un dérivé du mestranol avec 58% de rendement et une haute régiosélectivité. La structure de ce dernier a été précisément établie par diffraction des rayons X (Schéma R17).

Schéma R18

En se basant sur les résultats obtenus, ainsi que sur ceux décrits dans la littérature, nous proposons le mécanisme ci-dessous afin d'expliquer la régiosélectivité observée (Schéma R19).

La réaction passerait par un intermédiaire ruthénacyclopentadiène Ru-II, dont la formation serait suivie par l'insertion du cyanamide et l'élimination de l'espèce ruthénium, conduisant majoritairement à la pyridine ortho-substituée la moins encombrée.

Schéma R19

La synthèse de composés à motif 2-aminopyridine hautement substitués par cycloaddition [2+2+2] de -diynes avec des cyanamides via une catalyse en présence de complexes de ruthénium aussi bien sous forme neutre (RuCl3•nH2O) que cationique (Cp*Ru(CH3CN)3PF6), a donc été réalisée. Le complexe RuCl3•nH2O peu onéreux s'est révélé très efficace en tant que catalyseur pour la préparation de 2-aminopyridines substituées. La réaction se déroule en présence de 5% molaire de RuCl3•nH2O sans l'ajout de ligand ou autre additif, et en l'absence de solvant. Le ruthénium complexe cationique (Cp*Ru(CH3CN)3PF6) s'est avéré très efficace pour ce type de cycloaddition aussi bien dans le cas des diynes-1,6 ou -1,7, en présence de cyanamides et dans des dans des conditions douces. Diverses diynes, terminaux ou internes possédant des groupes fonctionnels variés se sont révélés compatibles avec ce système catalytique. Une excellente régiosélectivité a été obtenue dans le cas de diynes dissymétriques. L'utilité de ce protocole a ensuite été démontrée avec la synthèse de molécules à haute valeur ajoutée telles que des halopyridines, des diaminopyridines ou encore des vinylpyridines en une seule étape. Cette réaction a pu conduire à des pyridines polycycliques incluant des hétéroatomes, à partir de diynes-1,7 et cyanamides. La fonctionnalisation du mestranol, molécule biologiquement active, a pu aussi valider le potentiel de cette méthodologie. Une famille d'aza-fluorénones et aza-fluorénols a également été préparée efficacement selon cette méthode éco-compatible et directe.

Chapitre 4. Synthèse asymétrique de 1,3-dihydroisobenzofuranes 1,1-disubstitués à partir de triynes prochiraux et des alcynes internes catalysée par des complexes de rhodium

Les 1,3-dihydroisobenzofuranes sont une classe de composés hétérocycliques oxygénés très présents dans les composés naturels biologiquement actifs 172 ainsi que dans un certain nombre de médicaments. 173 Plusieurs méthodes permettent d'accèder à ces structures, parmi lesquelles on peut citer la cyclotrimérisation [2+2+2] d'alcynes, 7 les réactions de Diels-Alder, 175 ou encore la transformation de phtalides 176 . Parmi ces méthodes, la cycloaddition [2+2+2] catalysée par les métaux de transition constitue l'une des plus efficaces comme indiqué dans le chapitre I.

Concernant la préparation de 1,3-dihydroisobenzofuranes contenant un centre chiral en position , peu d'exemples ont été rapportés, c'est pourquoi leur accès constitue un défi. 177 La réaction de désymétrisation de composés prochiraux constitue un moyen efficace pour accéder à des molécules complexes possédant un centre stéréogène. C'est pourquoi nous avons envisagé que la construction de 1,3-dihydroisobenzofuranes optiquement actifs pouvait être accomplie via une cycloaddition [2+2+2] de triynes oxygénés avec un alcyne interne catalysée par un métal de transition comme indiqué dans le Schéma R20.

Schéma R20

Les triynes de départs peuvent être facilement obtenus à partir de produits commerciaux selon la rétrosynthèse décrite dans le schéma R21.

Schéma R21

Dans un premier temps, nous nous sommes intéressés à la préparation des produits de départ. Les triynes ont été préparés en deux étapes. Une condensation d'un acétylure sur un chlorure d'acide conduit à un alcool quaternaire, qui peut ensuite être condensé sur le bromure de propargyle ou le 1-bromo-but-2-yne pour conduire au triyne. Les alcynes internes ont été obtenus à partir du 2-butyl-1,4-diol dont les fonctions alcools ont été protégées par différents groupements (OAc, OMe, …).

a. Optimisation des conditions de la réaction

L'étude de la réaction de cycloaddition [2+2+2] a pu ainsi être menée, en utilisant le triyne 255 et le

General introduction

General introduction

Heterocycles represent by far the largest of classical divisions in organic chemistry and are of great importance biologically and industrially. The majority of pharmaceuticals and biologically active agrochemicals are heterocyclic while several additives and modifiers used in industrial applications in the field of cosmetics, reprography, information storage and plastics are heterocyclic in nature. Over the past century, heterocycles have constituted one of the largest areas of research in organic chemistry. They have contributed to the development of humanity from a biological and industrial point of view as well as to the understanding of life processes and to the improvement of the quality of life.

In this context in the field of chemistry, efficient clean methods to access functionalized heterocycles are highly suitable. One of the key principles of "Green Chemistry"1 (Figure 1) is to limit the use of organic solvents in industrial processes. Indeed, these solvents are often toxic, expensive and generate difficulties in disposal and reprocessing. A major research effort in recent years is to develop new more environmentally friendly synthetic methods. Even if water seems to be the best choice because of its abundance and non-toxicity,2 the development of solvent-free processes during the reaction and purification, is undeniably the ideal solution. 3 A solvent-free system is not only environmentally friendly but also provides effective, safer and more economical solutions for industrial partners (temperature and reaction time decreased, reducing the size of the reactors, process intensification, no extra costs incurred relating to the purchase and processing of solvents).

Figure 1

Functionalization of aromatic or heteroaromatic compounds has been a major topic of study among organic chemists, and has been used both in industrial 4 and academic laboratories.

One of the best known and traditional methods to functionalize aromatic rings involves the stepwise addition of electrophilic substituents, using Friedel-Crafts alkylation 5 or acylation 6 .

This method is very useful for the synthesis of polysubstituted benzene derivatives, but may cause problems in terms of regioselectivity (and therefore yield), which requires special attention in the choice of reagents and synthesis plan of the target compound (Scheme 1).

Another method, transition-metal-catalyzed [2+2+2] cycloaddition reactions, 7 involves the In 1973, Yamazaki and Wakatsuki discovered that the substituted pyridines can be stepwise assembled from two acetylenes and one nitrile by using a catalytic amount of πcyclopentadienyl(triphenylphosphine)cobalt complex (Scheme 3). 10,11

Scheme 3

Apart from the synthesis of benzenes and pyridines via cyclotrimerization of three alkynes or two alkynes with one nitrile, other unsaturated carbocyclic and heterocyclic compounds such as

4 R R R R + R' R" O S C S O C O N C O R' N R' • R' R" R' N C S R' R' R" R' N R" R R R' R" R R R R R R R" R' N R R R' R R O R R R" R R R' N R R R R R' R" S R R R R S O R R R R O N R R R R O R' N R R R R S R' R R R R R'
Chapter I: Bibliography

Chapter I: Bibliography

The first chapter will present selected literature data concerning the formation of benzene via transition-metal-catalyzed [2+2+2] cycloaddition reactions. In each section, we will deliver the works based on three types of cycloaddition reactions (intermolecular, partially intramolecular, and totally intramolecular, Scheme 5). Practical and general catalyst, construction of novel scaffolds, recent advances in mechanistic insight, regioselectivity and chemoselectivity issues will also be described.

Scheme 5

Intermolecular reactions

The intermolecular [2+2+2] alkyne cyclotrimerization is considered as one of the most efficient synthetic method to access benzene skeleton. Various types of transition metal complexes have been used for this transformation. However, the reaction is limited because of the low chemo-and regioselectivity. For example, as shown in Scheme 6, the homocyclotrimerization of a single symmetrical alkyne gives hexa-substituted benzenes (Eq. 1), the cycloaddition of unsymmetrical alkynes produces two regioisomers (Eq. 2), and the combination of two or three different alkynes leads to the formation of complex mixtures (Eq.

3).

+

(1) Intermolecular:

(2) Partially intramolecular:

+ (3) Totally intramolecular: M [ ] M [ ] M [ ] Scheme 6

Cyclotrimerization of one alkyne

In 1993, Rothwell and co-workers reported the first regioselective transition-metalcatalyzed [2+2+2] cycloaddition reactions, which selectively produced the symmetrical 1,3,5and unsymmetrical 1,2,4-substituted benzene derivatives using a catalytic amount of titanium complex. 12 It was demonstrated that the steric effects controlled the regioselectivity. For instance, in the presence of 0.004 mol % titanium catalyst, cyclotrimerization of phenylacetylene led to trisubstituted benzenes in quantitative yield, with 1,2,4-substituted regioisomer as the major product (ratio = 7:93). The more sterically hindered alkynes, such as trimethylsilyl acetylene and tert-butyl acetylene, afforded the 1,3,5-substituted products in high yields (ratio > 95:5), albeit with higher catalyst loading and prolonged reaction time (Scheme 7).

12 Hill, J. E.; Balaich, G.; Fanwick, P. E.; Rothwell, I. P. Organometallics 1993, 12, 2911.

R R R R R R R R hexa-substituted benzenes R R R R 1,2,4-isomer R R R + 1,3,5-isomer R 1 R 2 R 3 R 4
(3) + +

Scheme 7

After this pioneering work, many late transition metals have been used for the regioselective synthesis of benzene derivatives. The most common employed metals were cobalt, rhodium, ruthenium, iridium, nickel, and iron. An interesting example was reported by Hess and co-workers, who described a solvent-dependent regioselective [2+2+2] cyclotrimerization of phenylacetylene using a cobalt complex catalyst containing a disulfide ligand (Scheme 8). 13 Optimization of different disulfide ligands in various solvents was also studied in this reaction. The result indicates that the coordination ability of the solvent greatly influenced the regioselectivity of the cyclotrimerizations.

Scheme 8

Sivasankar and co-workers reported a series of highly efficient pincer ligands stabilized Ni(II) complexes as catalyst to promote the regioselective [2+2+2] cyclotrimerization of various alkynes. The complex bearing di-tert-butyl groups on the phosphine ligand acts as the best catalyst in this reaction. 14 They observed that the selectivity correlated well with the electronic feature of the alkynes, the electron-rich alkynes were trimerized to give 1,3,5-

DCM

MeCN

substituted benzenes as the major products, whereas the electron-deficient alkynes afforded the 1,2,4-substituted benzenes as the major products (Scheme 9).

Scheme 9

Transition-metal-catalyzed [2+2+2] cyclotrimerization of disubstituted acetylene is considered as an elegant and efficient method to access hexa-substituted benzene derivatives in a single synthetic operation. Many groups have reported such reactions, including Fréchet and co-workers for the convergent synthesis of dendrimers using a cobalt-catalyzed [2+2+2] cyclotrimerization of bisdendritic alkynes, affording the corresponding benzene-cored dendrimers in 36-83% yields (Scheme 10). 15

Scheme 10

Zhao and co-workers reported a facile and efficient method for the regioselective synthesis of polysubstituted benzenes via nickel-catalyzed [2+2+2] cyclotrimerization of simple unactivated alkyl(aryl)acetylenes and diarylacetylenes (Scheme 11). 16 They found that the combination of Ni(acac)2, imidazonium salt (IBz•HBr) and Grignard reagent (nBuMgCl) at 15 Hecht, S.; Fréchet, J. M. J. Am. Chem. Soc. 1999, 121, 4084. 16 Xue, F.; Loh, Y. K.; Song, X.; Teo, W. J.; Chua, J. Y. D. Zhao, J.; Hor, T. S. A. Chem. Asian J. 2017, 12, 168. 60 °C led exclusively to the formation of 1,2,4-substituted isomer in up to 98% yield. This method was also utilized to access hexa-substituted benzenes by using IBz•HCl as the imidazolium salt partner providing a convenient synthetic route to various -conjugated systems.

Scheme 11

Cycloaddition between two different alkynes.

Takeuchi and Nakaya 17 described the chemoselective iridium-catalyzed [2+2+2] cyclotrimerization of electron-deficient alkynes with electron-rich internal alkynes (Scheme 12). It was demonstrated that the chemoselectivity was controlled by the nature of the phosphine ligands. When 1,2-bis(diphenylphosphino)ethane (dppe) was used as a ligand, the electron-rich iridium/dppe complex coordinates with two electron-deficient alkynes to form iridacyclopentadiene Ir-I which undergoes coordination and insertion of another electron-rich alkyne to furnish the dicarbomethoxyl-substituted product as a major product. On the other hand, when electron-deficient 1,2-bis(dipentafluorophenylphosphino)ethane (fdppe) was employed, the reaction proceeded via iridacyclopentadiene Ir-II as the intermediate, affording the tetracarbomethoxyl-substituted compound as a major product. This reaction provided a useful and practical method for the synthesis of polycyclic substituted benzene derivatives.

Scheme 12

The same group also described in 2008 an iridium-catalyzed chemo-and regioselective synthesis of 1,3,5-substituted benzene derivatives via [2+2+2] cyclotrimerization of two different terminal alkynes. 18 In the presence of Ir/fdppe catalyst system, a variety of 1,3,5substituted benzenes was obtained as a single regioisomer in 58-96% yields. However, this strategy required the combination of one strong electron-deficient alkyne and one electron-rich alkyne (Scheme 13).

Scheme 13

18 Onodera, G.; Matsuzawa, M.; Aizawa, T.; Kitahara, T.; Shimizu, Y.; Kezuka, S.; Takeuchi, R.

Cycloaddition of three different alkynes

The intermolecular [2+2+2] cyclotrimerization of three different alkynes is difficult to control. Early transition metals such as zirconium 19 and titanium 20 were used for such transformation. However, the use of stoichiometric catalyst and harsh reaction conditions were required in some cases.

In 2004, Yamamoto and co-workers developed a chemo-and regioselective intermolecular cyclotrimerization of three different unsymmetrical alkynes using Cp*Ru(cod)Cl as the catalyst. 21 The reaction is initiated by the oxidative cyclization of an alkynylboronate and a propagyl alcohol to form the key ruthenacycle intermediate Ru-I, which undergoes insertion of the third alkyne to afford the intermediate arylboronate. The subsequent one-pot functionalization of these arylboronates could further be converted into several substituted aromatic compounds such as biaryls, boraphthalides, phthalides, and imidates (Scheme 14).

Scheme 14

19 (a) Takahashi, T.; Kotora, M.; Xi, Z. J. Chem. Soc. Chem. Commun. 1995, 361. (b) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 1999, 121, 11093. 20 (a) Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123, 7925. (b) Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2002, 124, 9682. 21 (a) Yamamoto, Y.; Ishii, J.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2004, 126, 3712. (b) In 2005, Mitsudo and co-workers developed a ruthenium-catalyzed chemoselective [2+2+2] cycloaddition to form polysubstituted o-phthalates (Scheme 15). 22 It was demonstrated that a high chemoselectivity and regioselectivity could be attained by controlling the molar ratio of the three substrates. The reaction is also influenced by the bulkiness of the two substituents on the internal and terminal alkynes. Mitsudo's group proposed a plausible mechanism for the [2+2+2] cycloaddition. At the first step, the internal alkyne and DMAD react with the ruthenium to form the ruthenacyclopentadiene Ru-I intermediate, followed by an insertion of the terminal alkyne into the formed ruthenacycle. A subsequent reductive elimination would afford the final regioisomers and regenerate the ruthenium catalytic species. However, a large excess of internal alkyne was required to avoid the formation of side-products.

Scheme 15

Cyclotrimerization of two alkynes with another unsaturated substrate

Tanaka and co-workers described a cationic rhodium-catalyzed intermolecular [2+2+2] cycloaddition reaction of a terminal alkyne, a dialkyl acetylenedicarboxylate, and an enol ester. 23 A variety of tri-and tetra-substituted benzenes was obtained in 35-80% yields with complete regioselectivity. The proposed mechanism features the regioselective formation of the rhodacyclopentadiene Rh-I followed by the regioselective insertion of an enol acetate leading to the intermediate Rh-II, which is stabilized by the coordination of the carbonyl group with the cationic rhodium through a five-membered chelation. Finally, a subsequent reductive elimination affords the corresponding substituted benzenes and one equivalent of acetic acid (Scheme 16).

Scheme 16

Cheng and co-workers described a new and efficient Ni(dppe)Br2/Zn catalytic system for the cross intermolecular [2+2+2] cyclotrimerization of two alkynes with an allene. 24 A 23 (a) Hara, H.; Hirano, M.; Tanaka, K. Org. Lett. 2008, 10, 2537. (b) Hara, H.; Hirano, M.; Tanaka, K. Tetrahedron 2009, 65, 5093. 24 Shanmugasundaram, M.; Wu, M.-S.; Cheng, C.-H. Org. Lett. 2001, 3, 4233.

R 1 E E [Rh(cod) 2 ]BF 4 / (rac)-BINAP 5 mol % DCM, rt, 16 h R 2 E E + + 5 equiv 1.1 equiv E = CO 2 Me, CO 2 tBu R 1 = alkyl, alkenyl, aryl, SiMe 3 R 2 = H, Me OAc R 2 R 1 18 examples single isomer 35-80% PPh 2 PPh 2 (rac)-BINAP Rh + R 1 E E Rh + R 2 O O Me E R 1 Rh + R 1 E E Rh(I) + R 1 E E + R 2 E E R 1 + HOAc Rh-I Rh-II Me O O Me O R 2

Partially intramolecular reactions

Cobalt-catalyzed partially intramolecular [2+2+2] cycloadditions

In 2006, Okamoto and co-workers reported the first partially intramolecular cobaltcatalyzed [2+2+2] cycloaddition reaction of -diynes with alkynes by using a catalytic system based on the combination of 2- (2,6-diisopropylphenyl)iminomethylpyridine (dipimp), CoCl2•6H2O, and Zn powder. 25 This method is efficient with a variety of functional terminal or internal alkynes, such as alcohols, esters, alkenes and silyl-substituted alkynes (Scheme 18). The use of Zn powder was required to promote the catalytic cycles, and the reaction was incompatible with aryl bromides, iodides, and nitro compounds because of the interaction with zinc and/or cobalt. Okamoto's team also demonstrated that the addition of a silver salt, such as silver triflate (AgOTf) or silver hexafluoroantimonate (AgSbF6), could accelerate the reaction to furnish sterically demanding benzene derivatives starting from unactivated simple internal alkynes. 26

Scheme 18

Doszczak and Tacke accomplished a one-step synthesis of hydroxyalkyl-substituted 1,1,and 1, cycloaddition of silicon-containing diynes and unprotected propargyl alcohols under mild conditions (Scheme 19). 27 25 Saino, N.; Amemiya, F.; Tanabe, E.; Kase, K.; Okamoto, S. Org. Lett. 2006, 8, 1439. 26 Goswami, A.; Ito, T.; Okamoto, S. Adv. Synth. Catal. 2007, 349, 2368. 27

X R 3 R 4 R 3 R 4 X = C(CO 2 Et) 2 , O, NBn R 1 = H, nBu, SiMe 3 , Ph R 2 = H, nBu, SiMe 3 , Ph R 3 = CH 2 OH, CH 2 OMe, CO 2 Et, CH 2 CCSiMe 3 , CCnBu R 4 = CH 2 OH, nBu, SiMe 3 , CH 2 CH=CH 2 , Ph, 4-MeOC 6 H 4 R 1 R 2 R 1 R 2

Scheme 19

In 2011, Aubert, Gandon, and Malacria engaged a series of halogenated diynes with alkynes in the presence of CpCo(CO)(dimethylfumarate) and Cp*Ru(cod)Cl catalyst via [2+2+2] cycloaddition reactions. 28 The studies confirmed that the ruthenium complex remains the best choice for the cycloaddition of all kind of alkynyl halides. The air-stable CpCo(CO)(dmfu) complex proved to be efficient with alkynyl bromides (Scheme 20).

Scheme 20

Rhodium-catalyzed partially intramolecular [2+2+2] cycloadditions

Since the first examples of partially intramolecular [2+2+2] cycloadditions of diynes and alkynes using a stoichiometric amount of Wilkinson's catalyst (RhCl(PPh3)3)

28 Iannazzo, L.; Kotera, N.; Malacria, M.; Aubert, C.; Gandon, V. J. Organomet. Chem. 2011, 696, 3906

Wilkinson's catalyst:

Grigg and co-workers described the first catalytic [2+2+2] cycloaddition of 1,6-diynes with alkynes under mild conditions in the presence of a catalytic amount of RhCl(PPh3)3 catalyst. 30 Various tethered diynes and monoalkynes could be employed under these reaction conditions to afford the cycloadducts in 3-99% yields (Scheme 21). 31

Scheme 21

The Wilkinson's catalyst could also be used in the regioselective cycloaddition of unsymmetrical diynes with alkynes. In 1995, McDonald and co-workers reported the RhCl(PPh3)3-catalyzed [2+2+2] cycloaddition of different substituted diynes with simple monosubstituted alkynes to afford functionalized dihydroisobenzofuran products in 35-61% yields. 32 In most cases, the meta-substituted aromatic products were formed as major products because of the steric hindrance of the alkyne substituents (Scheme 22).

Scheme 22

In contrast to the formation of five or six-membered bicyclic benzene derivatives, the [2+2+2] cycloadditions to form medium-sized ring systems remain a challenge. Wu and coworkers developed a Rh-catalyzed [2+2+2] cycloaddition reaction for the preparation of trifluoromethylated benzo-fused eight-membered rings. The Wilkinson's catalyst was chosen for the reaction to deliver the expected products in 46-90% yields with good functional group tolerance (Scheme 23). 33

Scheme 23

Cationic Rh(I)-biaryl bisphosphine complexes:

The cationic rhodium/biaryl bisphosphine catalysts are the most efficient catalysts and have been widely studied in partially intramolecular [2+2+2] cycloaddition reactions. In 2006, Tanaka and co-workers successfully employed a Rh(cod)2BF4/(S)-Xylyl-BINAP complex for the enantioselective [2+2+2] cycloaddition of -diynes with trimethylsilylynamides to furnish axially chiral anilides. 34 The authors demonstrated that the substituted groups on the ynamides greatly influenced the yield of anilides. Indeed, the phenyl-and methoxycarbonylsubstituted trimethylsilylynamides showed high reactivity. According to the mechanism, the high enantioselectivity of the anilides could be explained by the formation of the key intermediate Rh-I, in which the rhodium center is coordinated to the carbonyl group of trimethylsilylynamide and the bulky PAr2 group of (S)-Xylyl-BINAP which sterically interacts with the R 3 of the trimethylsilylynamide (Scheme 24).

Scheme 24

The same group applied the cationic rhodium(I)/H8-BINAP catalyst for the synthesis of substituted benzopicenes via [2+2+2] cycloaddition of binaphthyl-linked diynes with alkynes (Scheme 25). 35 This method was further applied for the benzopicene-based long ladder and helical molecules synthesis.

Scheme 25

35 Murayama, K.; Shibata, Y.; Sugiyama, H.; Uekusa, H.; Tanaka, K. J. Org. Chem. 2017, 82, 1136.

R 1 [Rh(cod) 2 ]BF 4 /(S)-Xylyl-BINAP 10 mol % DCM, rt, 15-42 h + X R 1 X R 1 R 1 N N SiMe 3 R 3 R 2 O R 3 R 2 O X = C(CH 2 OMe) 2 , C(CO 2 Me) 2 , NTs, NSO 2 (4-BrC 4 H 6 ), O R 1 = Me, Et R 2 = Me, MeO, Ph R 3 = nBu,
+ R 2 R 1 R 1 R 2 R 1 R 1

Nickel-catalyzed partially intramolecular [2+2+2] cycloadditions

Since the first examples of cyclotrimerization of alkynes to form benzene derivatives reported by Reppe, 9 the nickel-catalyzed [2+2+2] cycloaddition reactions have been well studied because of several advantages such as a high reactivity, a broad functional groups tolerance, relatively cheaper price compared to other late transition metals.

Cheng and co-workers developed an efficient protocol for the synthesis of polysubstituted arylalkynes based on the nickel-catalyzed [2+2+2] cycloaddition of nonconjugated diynes with 1,3-diynes in a single transformation (Scheme 26). 36 The results showed that the electron-withdrawing ester groups substituted diynes are more reactive compared to the terminal diynes.

Scheme 26

Under the optimized conditions, the reaction of unsymmetrical 1,6-diynes with symmetrical 1,3-diynes afforded the products in 58-79% yields with excellent chemo-and regioselectivity. Phenyl-, n-butyl-, and trimethylsilyl-substituted 1,3-diynes reacted with 1,6diynes to afford highly functionalized arylalkynes. Interestingly, unsymmetrical 1,3-diynes reacted with di-ester-substituted symmetrical diynes at room temperature to give the cycloadduct with high regioselectivity (ratio = 19:1). The cycloaddition mainly occurred with the triple bond adjacent to the n-butyl group of the 1,3-diyne (Scheme 27).

36 Jeevanandam, A.; Korivi, R. P.; Huang, I.; Cheng, C.-H. Org. Lett. 2002, 4, 807.

Scheme 27

Kotora and co-workers reported a nickel-catalyzed [2+2+2] cycloaddition of 6alkynylpurines with -diynes to access biologically active 6-arylpurines. 37 A variety of terminal diynes and substituted 6-alkynylpurines was examined to afford various functionalized 6-arylpurines. Several catalysts have been evaluated in this reaction, such as CoBr(PPh3)3, RhCl(PPh3)3, NiBr2(dppe)/Zn, NiI2(PPh3)/Zn, and Ni(cod)2/PPh3. The results showed that Ni/phosphine complexes were the best catalysts for the cyclotrimerization of alkynes. For example, in the presence of 20 mol % of Ni(cod)2/2PPh3, different 1,6-diynes smoothly reacted with 6-alkynylpurine nucleosides at 20 °C to deliver the 6-arylpurine nucleosides in 48-81% yields (Scheme 28). 38

Scheme 28

37 Turek, P.; Kotora, M.; Hocek, M.; Císařová, I. Tetrahedron lett. 2003, 44, 785 38 (a) Turek, P.; Kotora, M.; Tišlerová, I.; Hocek, M.; Votruba, I.; Císařová, I. J. Org. Chem. 2004, 69, 9224. (b) Turek, P.; Novak, P.; Pohl, R.; Hocek, M.; Kotora, M. J. Org. Chem. 2006, 71, 8978. Deiters and co-workers described the microwave irradiation assisted nickel-catalyzed [2+2+2] cyclotrimerization reactions to quickly access highly substituted aromatic compounds. 39 The application of microwave irradiation highly enhanced the reactivity of Ni(CO)2(PPh3)2 catalyst, and enabled the reaction to produce highly substituted benzene derivatives in a short reaction time. A variety of diynes and alkynes were tolerated to afford various substituted indanes, isoindolines, and tetraline core structures in 50-98% yields.

Notably, the developed protocols were used as a key step for the total synthesis of natural product Illudinine (Scheme 29).

Scheme 29

Iridium-catalyzed partially intramolecular [2+2+2] cycloadditions

In 2001, Takeuchi and co-workers described a simple and convenient protocol for the synthesis of polysubstituted benzene derivatives by using [Ir(cod)Cl]2/dppe complex as a catalyst. 40 A broad range of functional groups such as alcohols, amines, alkenes, ethers, halogens, and nitriles were tolerated to give various functionalized benzene derivatives. 41 It was proposed that the reaction formed an iridacyclopentadiene intermediate Ir-I by the oxidative cyclization of -diynes. The coordination of a monoyne would facilitate a Diels-Alder type 39 Teske, J. A.; Deiters, A. J. Org. Chem. 2008, 73, 342. 40 Takeuchi, R.; Tanaka, S.; Nakaya, Y. Tetrahedron Lett. 2001, 42, 2991. 41 Kezuka, S.; Tanaka, S.; Ohe, T.; Nakaya, Y.; Takeuchi, R. J. Org. Chem. 2006, 71, 543. Ni(CO) 2 (PPh 3 ) 2 10 mol % mW (300 w) To luene, 82 °C, 2 min

X X R 2 + R 2 nBu BocN CH 2 NHBoc 79% 0% (conventional heating) 80% 84% EtO 2 C EtO 2 C Me Me N Boc PMB Me Me N CO 2 H OMe Illudinine 5 steps R 1 R 1 R 1 R 1 CO 2 Et CO 2 Et X = CO 2 Et, NBoc, C(Me) 2 R 1 = H, CO 2 Et R 2 = nBu, CH 2 NHBoc, CH 2 CH 2 N(PMB)Boc Selected examples: 21 examples 50-98%
process to form an intermediate Ir-II, followed by reductive elimination to deliver the cycloadduct (Scheme 30).

Scheme 30

The authors also studied the regioselective cycloaddition of unsymmetrical diynes with terminal alkynes. The regioselectivity was controlled by the ligands. A plausible mechanism was shown in Scheme 31. When dppe is employed as the ligand, the reaction goes through a

[4+2] Diels-Alder type mechanism forming intermediate Ir-III, and affords meta selective product as the major product. When dppf is used as ligand, the reaction proceeds via an insertion mechanism forming intermediate Ir-IV and provides selectively the ortho product as the major product.

Scheme 31

In 2014, Takeuchi's group expanded the scope of this reaction to the synthesis of carbonyl group functionalized benzene derivatives. Upon screening several iridium complexes and ligands, they found that the [Ir(cod)Cl]2/(rac)-BINAP was the best catalytic system for the reaction. 42 A broad range of 2,7-diynes reacted with alkynyl ketones and alkynyl esters in the presence of [Ir(cod)Cl]2/(rac)-BINAP catalyst to provide the corresponding functionalized benzenes in 22-91% yields (Scheme 32).

Scheme 32

42 Hashimoto, T.; Okabe, A.; Mizuno, T.; Izawa, M.; Takeuchi, R. Taking advantage of the triply iodo-bridged iridium(III) complexes, [{Ir(H)[racbinap]}2(-I)3]I, 43 our group developed in 2012 a convenient and efficient protocol for the preparation of fused arenes. Isoindolines, indanes, and dihydroisobenzofurans bearing a wide range of substitution groups could be achieved through an iridium(III)-catalyzed [2+2+2] cycloaddition of -diynes with alkynes. The reaction proceeds with symmetrical and unsymmetrical diynes, which affords highly substituted benzene derivatives in up to 97% yields. This methodology can be applied to alkynylboronates, which is a convenient means to generate the challenging, highly functionalized borylated fused arenes that present great potential for further elaboration. Notably, these processes are extremely robust and simple to perform. The catalyst system is compatible with commercial grade non-degassed solvents, whereas the alkynes herein do not necessitate purification before use (Scheme 33). The regioselectivity of the ruthenium-catalyzed cycloadditions was also studied by using unsymmetrical monosubstituted diynes. Treatment of the unsymmetrical diynes, bearing methyl, phenyl, and trimethylsilyl terminal substituents, with the Cp*Ru(cod)Cl catalyst, gave the corresponding cycloadducts in high yields with high regioselectivities, the meta selective product being formed as the major product. According to the mechanism, the coordination and oxidative coupling of diyne with ruthenium complex led to the ruthenacyclopentadiene intermediate Ru-I, followed by the selective insertion of the monoalkyne into the less substituted Ru-C single bond leading to the formation of the ruthenacycloheptatriene intermediates Ru-II or Ru-II'. The reductive elimination from Ru-II afforded meta-selective product, whereas Ru-II' furnished ortho-selective isomer (Scheme 36).

Scheme 36

In 2004, Yamamoto's group described the cycloaddition of unsymmetrical terminal diynes bearing amide, ester and ketone carbonyl tethered groups with terminal alkynes to afford the corresponding cycloadducts with unexpected regioselectivities. 48 The observed results

showed that the regioselectivity was directed by the electron effects of the internal conjugated carbonyl groups, and increased in the order of amide tether (X = NBn) ≈ ester tether (X = O) < ketone (X = CH2). The stronger electron-withdrawing ability of the carbonyl group allowed the highest regioselectivity (Scheme 37).

Scheme 37

During the investigation of partially intramolecular [2+2+2] cycloaddition reactions, a bicyclic ruthenacyclopentatriene complex Ru-I was isolated by Yamamoto's group. 47 The internal diyne bearing two phenyl substituents slowly reacts with Cp*Ru(cod)Cl complex in CDCl3 at room temperature to give the bis-carbene ruthenium complex in 51% yield, which could react in a stoichiometric way with acetylene to afford [2+2+2] cycloadduct. Another example of naphthoquinone-fused ruthenacyclopentatriene complex Ru-II was prepared from

Totally intramolecular reactions

Totally intramolecular cycloaddition reactions are considered as the most efficient method to solve the problem of the control of the chemo-and regioselectivity to access highly substituted benzenes. Three alkynes linked with two or three carbo-or hetero-tethers form a triyne which can be assembled via a cyclotrimerization to give a polycyclic aromatic compound with complete selectivity. Malacria and Aubert reported in 2004 the first totally chemo-and regioselective formal intermolecular [2+2+2] cycloaddition of three different alkynes by using the CpCo(CO)2 catalyst. 52 A series of easily prepared silicon-tethered triynes 53 successfully reacted with cobalt catalyst to furnish various benzene derivatives. Selective deprotection of the silylated group, 52 Chouraqui, G.; Petit, M.; Aubert, C.; Malacria, M. Org. Lett. 2004, 6, 1519. 53 resulted in the formation of functionalized arenes. This synthetically useful method avoided the formation of unexpected regioisomers in such cycloaddition reactions (Scheme 42).

Scheme 42

In 2009, Aubert, Gandon, and Malacria applied the new designed and synthesized CpCo(CO)dmfu catalyst for totally intramolecular [2+2+2] cycloaddition reactions. 54 The airstable cobalt catalyst efficiently catalyzed the cyclotrimerization of carbo-and hetero-tethered triynes, forming a variety of fused tricycle benzenes in 69-92% yields (Scheme 43). Notably, these reactions can be performed under both conventional heating and microwave irradiation heating conditions. 54 Geny, A.; Agenet, N.; Iannazzo, L.; Malacria, M.; Aubert, C.; Gandon, V. Angew. Chem. Int. Ed. 2009, 48, 1810.

Co X X R 2 R 1 CpCo(CO)dmfu 5 mol % X X R 1 R 2

Scheme 43

In contrast to the linear triynes, the macrocyclic triynes can also be employed in [2+2+2] cycloaddition reactions. In 2004, Roglans and co-workers reported a totally intramolecular rhodium-catalyzed [2+2+2] cycloaddition reaction of nitrogen-containing 15-membered triacetylenic macrocycles. 55 The nitrogen-tethered macrocyclic triynes smoothly reacted with 1-5 mol % of RhCl(CO)(PPh3)2 in toluene to afford various multiple ring compounds in 80-96% yields (Scheme 44). Notably, this was the first example of [2+2+2] cycloaddition reactions of macrocyclic triynes.

Scheme 44

Taking advantage of this strategy, Witulski and co-workers reported the first total synthesis of the sesquiterpenoid alcyopterosin E from simple starting materials. In this multistep synthesis, the formation of the key precursor indeno [4,5-c] Chapter II: Access toward fluorenone derivatives through solvent-free ruthenium trichloride mediated [2+2+2] cycloadditions Over the past few years, fluoren-9-one and its derivatives have attracted much attention from academia and industry regarding their frequent application in various fields. 57 The fluorenone scaffolds and related chemicals are important structural moiety that constitute the central core of a variety of compounds, which are found in many natural products and bioactive molecules encompassing a wide range of biological properties (Scheme 46). 58 For example, Dengibsin A and Dengibsinin B were the first natural fluorenone derivatives isolated from the Indian orchid Dendrobium gibsonii Lindl, 58a 2,7-disubstituted amidofluorenone derivatives D exhibited a range of human telomerase inhibitory activities, 58d

tilorone dihydrochloride E has great potential for inducing interferon against pathogenic infection, 58e indenone F showed anti-HIV-1 activity, 58f dicationic 2-fluorenonylcarbapenems G were potent anti-MRS agents. 58g

Scheme 46

Additionally, because of their attractive luminescent properties, fluorenones could also be employed as organic and polymer light-emitting diodes, bulk heterojunction solar cells and photochemical sensitizers (Scheme 47). 59 For examples, bisindenofluorene H represented a novel building block class for n-type electronic materials, 59a compounds I formed ferroelectric liquid crystals, 59b 2,7-poly(9-fluorenone) J was a suitable candidate as an electron-injection material in multilayer LEDs, 59i and compound K was a stable fluorenone-based sensitizer dye for solar cell.

Transition-metal-catalyzed synthesis of fluorenones

Over recent years, transition-metal-catalyzed functionalization has been recognized as a novel and efficient method to synthesize complex fluorenone derivatives that are not accessible by conventional methods. Palladium, rhodium, silver and copper complexes have been reported as catalysts to access fluorenones and derivatives. Synthetic methods for the preparation of fluorenone derivatives are summarized below and classified according to the metal.

Palladium-catalyzed synthesis of fluorenones

C-H functionalization of 2-haloarylketones

In 1984, Ames and Opalko disclosed a novel palladium-catalyzed dehydrohalogenation of 2-iodobenzophenone to provide fluorenone (Scheme 49). 64 Various bases and solvents employed with Pd(OAc)2 have been used in this reaction. When 2-iodobenzophenone was heated in N-methylimidazole in the presence of Pd(OAc)2 at 190 °C, fluorenone product was obtained in 100% yield.

64 Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919.

Oxidation X Diels-Alder reaction O Friedel-Crafts acylation Remote metalation O R 2 R 1 X = H or OH O X X = H, OH, OR, NR 2 O X M X = OH, NR 2 R 1 = Ar or R 2 = Ar

Scheme 49

Based on the previous results reported by Ames and Opalko, Jones and co-workers further optimized the reaction conditions, involving high-temperature with PdCl2(PPh3)2 and sodium acetate in dimethylacetamide (DMA) under microwave irradiation (Scheme 50). 65 They successfully synthesized benzo [b]fluorenone in 53% yield, this derivative being considered as a key intermediate to access the natural products stealthin C 66 and prekinamycin 67 . Scheme 50

Directing-group-assisted C-H activation

In 2007, Larock's research group reported an efficient synthesis of fluorenones using a Pd-catalyzed intramolecular C-H activation strategy involving an aryl to imidoyl palladium migration process (Scheme 51). 68 Treatment of imines with 5 mol % of Pd(OAc)2, 5 mol % of bis(diphenylphosphino)methane (dppm), and 2 equivalents of CsO2CCMe3 (CsPiv) in DMF at 100 °C, followed by hydrolysis using aqueous HCl, afforded the desired fluorenones in 56-100% yields. Subsequent deuterium labeling experiments showed that the reaction involved both a palladium migration and a C-H activation process through an unprecedented organopalladium hydride intermediate Pd-I.

65 Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65, 7187. 66 Koyama, H.; Kamikawa, T. Tetrahedron. Lett. 1997, 38, 3973. 67 Gore, M. P.; Gould, S. J.; Weller, D. D. J. Org. Chem.1992, 57, 2774. 68 cyclization of benzophenones. 78 This process provided a wide range of fluorenones in 36-94% yields (Scheme 61). A mechanistic study demonstrated that the first step was the coordination between the ketone group and Pd(II) followed by the consecutive ortho-C-H activation to form a palladacycle Pd-I, which was expected to be in equilibrium with its palladium aryl -complex Pd-II. Then the palladium complex Pd-II underwent the second C-H activation, lead to the sixmembered palladium complex Pd-III and subsequent reductive elimination to produce the fluorenone product and Pd(0) species. Independently,

.5-1 h R 1 R = cyclohexyl R 1 = H, 3-Me, 3-Br, 2-Cl R 2 = 3,5-diMe, 4-CO 2 Et, 3-Cl, 4-Cl, 4-CF 3 , 3-OCF 3 R = propyl R 1 = 3-Me, 2-MeO, 4-tBu R 2 =

Scheme 67

A rapid approach to access fluorenone derivatives via domino reactions using microwave as heating source has been reported by Lautens and co-workers. 87 The arylpalladium intermediate generated by a sequence of norbornene mediated C-H activation and subsequent ortho-arylation, underwent ester addition providing the corresponding fluorenone in 46-93% yields (Scheme 68). Several aldehydes were also subjected to this method affording the 9H-fluoren-9-one products in good yields. In the case of aldehydes, the reaction proceeded with triphenylphosphine as ligand under conventional heating at 90 °C for 24 h. In 2010, Ray and co-workers disclosed an efficient method for the preparation of fluorenones through a palladium-catalyzed one-pot Suzuki-Miyaura coupling reaction followed by an intramolecular arylpalladation of 2-bromophenyl boronic acid with 2bromocarboxaldehyde (Scheme 69). 88 Various fluorenones and condensed fluorenone derivatives have been synthesized in 51-80% yields from readily available starting materials.

Scheme 69

The Dharmaraj's group described in 2016 an efficient palladium-catalyzed domino reaction of benzoyl chloride with arylboronic acid to synthesize substituted fluorenones (Scheme 70). 89 A newly synthesized ONO pincer-type Pd II complex has been used in this reaction and exhibited high catalytic efficiency (0.1 mol % catalyst-loading). Compared to other systems the catalyst could be reused over six consecutive runs.

Cl O R 2 R 1 + R 1 R 2 25 examples 62-93% MeO N N O O Pd PPh 3 S Pd complex 0.1 mol % Pd complex R 1 = H, 4-Me, 4-MeO, 4-F R 2 = H, 2-Me, 2-MeO, 3-OH, 3-Cl, 3-Br, 3-CHO, 3-NMe 2 , 3-COCH 3 , 4-Me, 4-MeO, 4-tBu, 4-CF 3 1 2 3 4 1 2 3
Scheme 72

Intramolecular acylation

Ryu and co-workers disclosed in 2014 the first catalytic preparation of fluorenone derivatives through Rh-catalyzed intramolecular acylation of biarylcarboxylic acids (Scheme 73). 93 Screening of several reaction conditions led to the selection of [Rh(cod)Cl]2/dppe system and potassium iodide/pivalic anhydride as catalyst and additives. Notably, the microwave irradiation promoted the reaction in a shorter reaction time.

Scheme 73

93 Fukuyama, T.; Maetani, S.; Miyagawa, K. Ryu, I. Org. Lett. 2014, 16, 3216.

Objectives

As we detailed above, various fluorenones have been synthesized through transitionmetal-catalyzed reactions. However, there are still important challenges to solve considering current limitations of these methods. Because of special structural features, the construction of the three single C-C bonds between the two six-membered rings has been generally privileged (Scheme 77). In contrast, only few examples focused on the construction of one of the two sixmembered rings.

Scheme 77

Considering the results described in the literature, we envisioned that highly substituted fluorenones and related derivatives, such as azafluorenones, indenothiophenones, and benzo [b]furanones, could be successfully accessed using [2+2+2] cycloaddition of suitably substituted arylcarbamoyl bridged -diynes and monoalkynes. The retrosynthetic analysis is shown in Scheme 78. The synthesis of benzoyl bridged diynes could be accessed from the commercially available 2-bromobenzaldehydes via Sonogashira cross-coupling followed by condensation of the corresponding alkyl or phenyl substituted terminal alkyne to the carbonyl group, and final oxidation of the resulting secondary alcohol to ketone.

Scheme 78

O R 1 R 2 O R 1 R 2 Previous work This work O R 2 R 1 O Br R 2 R 1 [2+2+2] cycloaddition Sonogashira coupling & condensation & oxidation
First, the substituted monoalkyne benzaldehyde derivatives 1-7 were prepared by a Sonogashira cross-coupling reaction. Under classical conditions, the reactions were conducted with 1.2 to 1.5 equivalents of the corresponding terminal alkynes and 2-bromobenzaldehyde in the presence of 5 mol % PdCl2(PPh3)2 and 2.5 mol % CuI in a mixture of triethylamine and tetrahydrofuran (5.0 M, v/v = 1/1) at 50 °C. As shown in Scheme 79, various commercial substituted acetylenes were used, such as phenylacetylene, 1-hexyne, and trimethylsilylacetylene. In order to study the influence of the substituents on the phenyl ring at C7 position, electron-donating groups such as methyl ( 4) or tert-butyl (5) were introduced by using 4-ethynyltoluene or 4-(tert-butyl)phenylacetylene. In order to evaluate the effect on the tethered phenyl ring, the 2-bromoarylaldehydes having both electron-donating and electronwithdrawing substituents, such as methylenedioxy [START_REF]ESI + ): calcd. for C20H29N2O5[END_REF] and fluoride (7), were used for the crosscoupling reaction. All the desired compounds 1-7 were obtained in 70-87% yields (Scheme 79).

Scheme 79

In the second step, derivatives 8-16 were synthesized by a lithium mediated nucleophilic addition of terminal alkynes with benzaldehyde derivatives 1-7, as shown in Scheme 80. The anion of terminal alkynes was formed by reacting n-butyl lithium with terminal alkyne at low

Scheme 83

Next, aldehydes 30-36 reacted with terminal alkynes in the presence of nBuLi to provide the corresponding diynes 37-43 in yields ranging from 71% to 90% (Scheme 84). Scheme 85

Synthesis of internal alkynes

Alkynes 51-64 that were used in this chapter are shown in Scheme 86. Symmetrical alkynes 51-54 and unsymmetrical alkynes 58-64 were purchased, while ether-substituted monoalkynes 55, 97 56, 98 and 57 99 were synthesized in agreement with the methods described in the literature.

Scheme 86

Alkyne 55 was prepared by reacting 2-butyne-1,4-diol 52 with a large excess of tertbutyl methyl ether (as solvent). The reaction was performed in the presence of two equivalents of sulfuric acid and molecular sieves at room temperature, providing The nucleophilic substitution of 2-butyne-1,4-diol 52 with 2.2 equivalents of benzyl bromide in the presence of sodium hydride, afforded 1,4-dibenzyloxy-2-butyne 56 in 75% isolated yield (Scheme 88).

Scheme 88

Internal alkyne 57 was synthesized through the nucleophilic substitution of 2-butyne-

Interest of RuCl3•nH2O complex

Since we synthesized a series of benzoyl bridged -diynes and internal alkynes, we therefore attempted to find a suitable catalytic system for the [2+2+2] cycloaddition reactions.

In this context, ruthenium trichloride is a stable salt which can be easily oxidized or reduced, and most commonly used in hydrated form (RuCl3 As the most commonly available ruthenium source, ruthenium trichloride was reported to be the best starting material for the synthesis of various ruthenium complexes (Scheme 91), 101 with a wide range of oxidation states present in these complexes (Ru VIII to Ru II).

Scheme 91

Ruthenium trichloride was also reported as an efficient catalyst to promote C-C, C-H, C-O and C-N bond formations. 102 Notable examples include many types of cyclization reactions. For example, as shown in Scheme 92, Sames and co-workers demonstrated that RuCl3/AgOTf was a mild and efficient catalyst for the intramolecular hydroarylation cyclization of a range of arene-ene substrates (Eq. a). 102c Liu and co-workers reported that the thermal cyclization of various 3,5-dien-1-ynes can be greatly enhanced by using RuCl3 as catalyst (Eq. b). 102d The group of Jia developed a series of RuCl3-catalyzed intramolecular C-H amination reactions of organic azides, affording the corresponding indoles (Eq. c). 102l

Rostamnia and co-workers described a RuCl3-catalyzed solvent-free Ugi-type Groebke-Blackburn condensations of aldehydes and 2-aminopyridines with isocyanides in the presence of 5 mol % RuCl3•nH2O without any ligand or additive leading to the formation of aminoimidazole heterocycles (Eq. d). 102t

Scheme 92

In the context of RuCl3-catalyzed cycloaddition reactions, our group previously reported the first RuCl3•nH2O-promoted [2+2+2] cycloaddition reaction of-diynes and alkynes to access highly substituted benzene derivatives (Scheme 93). 103 We demonstrated that the costeffectively available RuCl3•nH2O was an efficient catalyst to promote the cycloaddition reaction under solvent-free conditions affording fused functionalized arenes including dihydrobenzofurans, isoindolines, and indanes in 48-97% yields. Notably, this practical method used neither additional ligand nor additive.

Scheme 93

Encouraged by these results, we assumed that the RuCl3•nH2O complex might also be an efficient catalyst for solvent-free [2+2+2] cycloaddition of arylcarbamoyl bridged diynes and monoalkynes to access fluorenone derivatives.

RuCl3•nH2O-mediated [2+2+2] cycloaddition of benzoyl bridged diynes with symmetrical internal alkynes

With a series of diynes and alkynes in hand, we began our study by investigating the reaction of arylcarbamoyl bridged diyne 17 with 1,4-dimethoxy-2-butyne 51 which has often been reported as a good partner in transition-metal-catalyzed [2+2+2] cycloaddition reactions.

The reaction was therefore initially performed in the presence of 5 mol % RuCl3•nH2O at 110 °C under previously described solvent-free conditions. 103 Fortunately, the reaction gave the corresponding fluorenone 65 in complete conversion and isolated yield up to 86% (Entry 1, Table 1). It is noteworthy that the desired product could be isolated on silica column chromatography without any treatment after complete conversion (determined by TLC and crude 1 H NMR). This result confirmed that RuCl3•nH2O is an efficient catalyst in [2+2+2] cycloaddition of -diynes with alkynes under solvent-free conditions. Based on such 103 Jacquet, J.; Auvinet, A.-L.; Mandadapu, A. K.; Haddad, M.; Ratovelomanana-Vidal, V.; Michelet, V. Adv. Synth. Catal. 2015, 357, 1387. encouraging result, we further optimized the reaction conditions. First, we studied the consumption of the monoalkyne 51, we were pleased to observe that when the amount of alkyne 51 was decreased from 6 to 2 equivalents, the reaction still provided the desired product 65 in satisfactory yields (Entries 2-6). In addition, decreasing the reaction temperature to 50 °C provided the cycloadduct in a similar yield (Entry 3, 73% and Entry 5, 75%, respectively).

Lowering the catalyst loading from 5 to 2 mol %, led to a decrease of the conversion and isolated yield was observed in 18 hours at 80 °C (Entry 4, 60% conv. and 40% yield, respectively).

Furthermore, we found that the reaction could be accomplished in 2 hours at 50 °C affording the desired cycloadduct 65 in satisfactory yield of 72% (Entries 6-8). When the reaction was placed under open-air condition, the conversion decreased significantly (Entry 9). To investigate the synthetic utility of this catalytic method, the reaction was performed on one gram-scale under optimized conditions. Fluorenone 65 was efficiently isolated in 71% yield (Scheme 94).

Scheme 94

Having established a set of optimal conditions, we examined the scope and limitations of the solvent-free RuCl3•nH2O-catalyzed [2+2+2] cycloaddition between diynes 18-27 and alkyne 51, as shown in Scheme 95. Initially, we observed that diyne 18 having two identical alkyl substituents at the C1 and C7 positions was less reactive compared to the unsymmetrical substituted diynes having a phenyl group at C7 position, the corresponding product 66 was obtained in 38% yield. The use of diyne 19 gave the desired product 67 in 43% yield. This result suggested that the unsymmetrical substituted diynes having a phenyl group at C7 positions was necessary. On the other hand, the reaction of diyne 20 with a cyclopropyl moiety delivered the cyclic product 68 in 63% yield. Interestingly, the cyclization of silyl-substituted diyne 21 with alkyne 51 provided the desired compounds 69 with 58% yield, which was used for further functionalization. Further experiments showed that diynes 22, 23, 26 and 27, having electron-donating or electron-withdrawing substituent on para position of phenyl ring at C7 could be successfully used in this reaction, leading to the targeted products 70-73 in 56-71% yields. To evaluate the influence of the tethered phenyl group, cycloaddition using diynes 24

and 25, bearing electron-donating or electron-withdrawing group, were accomplished smoothly to yield the desired products 74 and 75 in similar yields (68% and 65%, respectively). It is worth mentioning that these reactions were based on complete conversion even at elevated temperatures or prolonged reaction times.

Scheme 95

To further investigate the generality of the [2+2+2] cyclization, the reactivity of various alkynes was examined (Scheme 96). Switching the methyl group to a bulkier group, such as tert-butyl and benzyl, allowed to access the corresponding functionalized fluorenones 76 and 77 in 80% and 81% yields, respectively. The structure of fluorenone 77 was unambiguously confirmed by single crystal X-ray diffraction as shown in Scheme 96. Furthermore, when the cycloaddition of diyne 17 with 3-hexyne 53 was carried out under the same conditions, cycloadduct 78 was obtained in 11% isolated yield. However, we did not observe the cyclized products 79 and 80 when the alkynes 54 and 57 were used in the reactions, these results could be explained by the steric effects and poor reactivity of these alkynes.

Scheme 96

During our ongoing investigation on the scope of different substituted diynes and alkynes, we found that the reaction of diyne 8 with alkyne 51 did not afford cyclic product 81, most of starting material being decomposed under the reaction conditions (Eq. a, Scheme 97).

To further evaluate the influence of free hydroxyl substituent, the reaction of diyne 17 with 2butyne-1,4-diol 51 was studied. Unfortunately, we did not observe any desired product 82 (Eq. b, Scheme 97). This result suggested that free hydroxyl groups from both diyne or monoalkyne would greatly influence the formation of cycloadduct in this reaction.

RuCl3•nH2O-mediated [2+2+2] cycloaddition of heteroaromatic carbonyl bridged -diynes with internal alkynes

Once the heteroaromatic carbonyl bridged diynes 44-50 were obtained, we examined their partially intramolecular [2+2+2] cycloaddition to provide the corresponding hetero-based fluorenones. A series of hetero-aromatic tethered diynes has been studied.

First, the cycloaddition of furan-bridged diyne 44 with alkyne 51 in the presence of RuCl3•nH2O under the optimal conditions delivered the corresponding benzo [b]furanones 83 in 55% yield. Then, the thienyl-based fluorenones 84 and 85 were obtained in 71% and 62% isolated yields, respectively. Moreover, the cyclization of diyne 46, having a benzo [b]thiophene moiety as tether, produced the expected fused fluorenone 86 in 78% yield. When diyne 47 was used in the cycloaddition, the corresponding cyclic product 87 was obtained in 30% yield (Scheme 98).

Scheme 98

On the other hand, it was found that the use of diyne 49 only gave the corresponding cycloadduct 89 in 6% yield, while cyclization of diyne 48 with alkyne 51 did not provide cyclized product 88. To explain these results, we speculate that the position of the nitrogen atom in pyridine would influence the course of the reaction toward the formation of an unactivated intermediate where the ruthenium is coordinated to the nitrogen atom. This could be confirmed by the preparation of aza-fluorenone 90, starting from the pyridine tethered diynes 50 and alkyne 51, 60% yield was obtained and a chlorine atom was compatible with this reaction.

(Scheme 99). Scheme 99

Regioselective RuCl3•nH2O-mediated [2+2+2] cycloaddition of benzoyl bridged-diynes with unsymmetrical terminal and internal alkynes

The cycloaddition reaction was not limited to symmetrical internal alkynes, since a series of unsymmetrical terminal alkynes, such as cyclopropylacetylene 58, phenylacetylene 59, and 5-chloro-1-pentyne 60, were successfully reacted with phenylcarbamoyl bridged diyne 17 under optimized reaction conditions. The [2+2+2] cycloaddition reactions led to unseparable mixtures of regioisomers 91, 92, and 93 in 61-84% yields with regioselectivities from 55:45 to 73:27 ratio (Scheme 100).

Scheme 100

Next, we turned our attention to the examination of unsymmetrical internal alkynes. First, we focused on the functionalization of cycloadducts 65 and 76, as shown in Scheme 102. When the dimethyl ether substituted fluorenone 65 was refluxed in the presence of concentrated trifluoroacetic acid, the reaction did not lead to the expected deprotected diol 95: the substituted cyclized product dihydrobenzo [b]furan 94 was isolated as the main product in 85% yield. To achieve the deprotection of di-tert-butyl ether substituted fluorenone 76, the latter was subjected to classical deprotection conditions, yielding 75% of diol 95. On the other hand, the direct dibromination of compound 76 in the presence of refluxing mixture of HBr and Bu4NBr in chloroform provided the dibrominated 96 in 90% yield. The diol and dibrominated products were reported as key building blocks for the synthesis of OLEDs materials. 59d

Scheme 102

The silyl-based fluorenone adduct 69 has been considered as a suitable substrate, since the reactivity of the substituted silyl group is expected to enable functionalization reactions, such as iodination reaction. 104 The iodinated product could further allow the introduction of a variety of substituents using metal-catalyzed cross-coupling reactions. 105 Starting from compound 69, the iodination by means of iodine monochloride afforded the iodinated product 97 in 84% yield. Consequently, a single Sonogashira cross-coupling reaction of compound 97 with phenylacetylene led to the desired alkyne 98 in 98% yield. Additionally, adduct 97 was subjected to Suzuki-Miyaura cross-coupling reaction, leading to boronic ester 99 in 65% yield (scheme 103).

Scheme 103

To extend the applications of the functionalized fluorenones, additional Suzuki-Miyaura cross-coupling reaction was performed with bromo-substituted fluorenone 73. Boronic ester derivative 100 was obtained in 85% yield (Scheme 104).

Scheme 104

Conclusion

In summary, we have developed a novel and eco-friendly straightforward access to highly substituted fluorenones and related analogues using RuCl3•nH2O-promoted partially intramolecular [2+2+2] cycloaddition of carbonyl bridged -diynes with alkynes. This economical process was performed without solvent, additional ligands or additives, and allowed the construction of complex polycyclic fluorenones, aza-fluorenones, benzo [b]furanones and indenothiophenones. This protocol offers several advantages: i) the stability and cost-effective RuCl3•nH2O used as catalyst, ii) prevention of pollution with no elimination of toxic or volatile solvents, iii) practical protocol without work up to access the targeted products.

A wide range of carbonyl bridged -diynes and alkynes containing different substituents was evaluated in this reaction. Unsymmetrical diynes bearing alkyl and phenyl substituents proved to be more active in the ruthenium-catalyzed [2+2+2] cycloaddition reaction. Both electron-donating and electron-withdrawing substituents on the phenyl ring and tether phenyl ring were tolerated in this reaction. Furthemore, heteroarene tethered carbonyl diynes, such as furanyl-, thienyl-and aza-based moieties, have been shown to be active in this cyclization and their cycloaddition proceeded efficiently to give the expected cycloadducts in 30-78% yields. With regards to the scope of the alkynes, a wide range of substituted alkynes has been used for the [2+2+2] cycloaddition. It was found that symmetrical dialkoxy-substituted alkynes, such as methoxy, benzyloxy and tert-butoxy, could be engaged in the cyclization to deliver the desired product in 6-81% yields. Unsymmetrical terminal alkynes also converted well to the expected cycloadducts, although 55:45 to73:27 regioselectivities were obtained.

Chapter III: Ruthenium-catalyzed [2+2+2] cycloaddition of diynes with electron-rich cyanamides: an easy access to 2-aminopyridine derivatives

Chapter III: Ruthenium-catalyzed [2+2+2] cycloaddition of diynes with electron-rich cyanamides: an easy access to 2aminopyridine derivatives 1. Interest of 2-Aminopyridines

A recent report demonstrated that pyridine is the second most commonly used nitrogen heterocycle among all U.S. FDA approved pharmaceuticals (Figure 2). 106 As analogues of pyridines, 2-aminopyridines represent one of the most important skeleton motifs which are widely present in many biologically active molecules as well as pharmaceuticals.

Figure 2 106

106 Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257. aldol reaction. 115 Pyrido [2,3-b]azepine H, a pH sensitive fluorescence dye, can be an ideal candidate for fluorescence label 116 (Scheme 105).

Scheme 105

Amino-aza-fluorenones, containing 2-aminopyridine structural motif, have received increasing interest in recent years. Many of the synthetic and natural amino-aza-fluorenones displayed interesting properties and are present in a variety of pharmacophores 117 and chromophores. 118 As depicted in Scheme 106, 2-azafluorenone I is an antagonist of the 115 Daka, P.; Xu, Z.; Alexa, A.; Wang, H. Chem. Commun. 2011, 47, 224. 116 Schramm, O. G.; Dediu, N.; Oeser, T.; Müller, T. J. J. J. Org. Chem. 2006, 71, 3494. 117 Adenosine A2a receptor; 117a piperazinyl derived compound J which exhibits inhibitory effect on topoisomerase I would be a potent anti-breast cancer candidate; 117b 2-azafluorenone K with typical aggregation-induced emission (AIE) properties can be used for lipid droplet-specific live cell imaging. 118b Scheme 106

Synthetic methods for the preparation of 2aminopyridines 2.1 Traditional methods

The preparation of 2-aminopyridines has been reported with numerous strategies. For example, Chichibabin reactions start from pyridine and sodium amide, 119 Buchwald-Hartwig amination 120 and Ullmann coupling reactions 121 of halopyridines with primary or secondary amines, one-pot three-component cascade reaction 116 using N-tosyl propargyl amines, aryl halides, and N,S-ketene acetals, formal [2+2+1+1] cycloaddition reaction 122 of aldehydes with ketones, and malononitrile (Scheme 107). However, these methods were efficient to access simple 2-aminopyridines, but for more complex substitution patterns, additional synthetic manipulations were required. In addition, these reactions suffered more or less from some shortcomings such as harsh reaction conditions, multistep procedures, limited functionalities tolerance, etc. Scheme 107

Transition-metal-catalyzed [2+2+2] cycloadditions of alkynes with cyanamides

Cyanamide derivatives moiety are widely present in pharmaceutical molecules and bioactive compounds. 123 Owing to the high reactivity of the electron-rich nitrile triple bonds, bearing an amine group at the-position of nitrile (R2N-CN), these privileged structures serve as versatile building blocks and have been widely used for the synthesis of various nitrogencontaining heterocycles, 124 as shown in Scheme 108.

Scheme 108

Particularly, cyanamides also proved to be good partners for the transition-metalcatalyzed [2+2+2] cycloaddition which has been reported as a powerful and atom-economical method for the construction of highly substituted 2-aminopyridines. The following discussion will focus on the [2+2+2] cycloaddition reactions involving the most common used cobalt, rhodium, nickel, iron, iridium and ruthenium complexes.

Cobalt-catalyzed [2+2+2] cycloadditions

In 1984, Bönnemann and co-workers disclosed the first cobalt-catalyzed [2+2+2] cycloaddition of acetylene and cyanamide to form 2-aminopyridine containing a free amino group using ( 6 -boranato)cobalt as catalyst. The reaction was successfully performed at 130 °C under 40 bar to afford 2-aminopyridine in 54% yield (Scheme 109). 125

Scheme 109

125 Bönnemann, H.; Brijoux, W.; Brinkmann, R.; Meurers, W. Helv. Chim. Acta 1984, 67, 1616. After the pioneer work reported by Bönnemann, Heller and co-workers described the co-trimerization of acetylene with dimethyl-, pyrrolidinyl-, piperidinyl-substituted cyanamides in the presence of CpCo(cod) catalyst under photo-irradiation conditions at room temperature (Scheme 110). 126 The reaction afforded the corresponding 2-aminopyridines respectively in 46%, 68%, and 75% yields. Notably, in this case, the acetylene gas was delivered at constant normal pressure.

Scheme 110

In 2000, Eaton and co-workers reported one example of cyclotrimerization of 2-butyne-1,4-diol with N-cyanopyrrolidine to afford a highly functionalized pyridine in 71% yield. 127 This reaction presented many advantages including the use of a water-soluble cobalt(I) complex as catalyst, without the need of photochemical activation, only a stoichiometric amount of nitrile (alkyne:nitrile = 2:1) was required (Scheme 111).

Scheme 111

In 2004, Maryanoff's group described the preparation of bicyclic 2-aminopyridine derivatives starting from -diynes and cyanamides. 128 A variety of diynes and N-substituted cyanamides underwent cycloadditions in the presence of 15 mol % of CpCo(CO)2 catalyst in 126 (a) Heller, B.; Reihsig, J.; Schulz, W.; Oehme, G. Appl. Organomet. Chem. 1993, 7, 641. (b) refluxing dioxane, providing the corresponding bicyclic 2-aminopyridines in a range of 16% to 88% yield. Cyanamides disubstituted with alkyl, allyl, and aryl groups furnished the annulated compounds in 19-88% yields. The cyanamides possessing a large dibenzazepinyl group showed lower reactivity, and gave the cycloadduct in 19% yield. The cycloaddition of a bulky adamantyl-substituted cyanamide led to the corresponding 2-aminopyridine with a secondary amine group in 32% yield (Scheme 112).

Scheme 112

The same group also investigated in 2005 the formation of macrocycles from long-chain diynes and cyanamides in cobalt-mediated [2+2+2] cycloaddition reactions. 129 The reaction of 1,15-diynes with cyanamides provided mainly the corresponding 16-membered parapyridinophanes in 32-80% yields, whereas the reaction of 1,17-diyne furnished a mixture of both 17-membered meta-and 18-membered para-pyridinophanes in 64% yield. These results indicated that the regioselectivity of the reactions was affected by the length and the type of linker unit between the alkyne groups (Scheme 113).

Scheme 113

In 2007, Maryanoff and co-workers applied this method employing CpCo(CO)2 catalyst system for the synthesis of macrocyclic (17-20 members) bis(indolyl)maleimide pyridinophanes, although lower isolated yields (9-15%) were observed (Scheme 114). The biological results indicated that these macrocyclic heterophanes were potent and selective inhibitors of glycogen synthase kinase-3. 130 Scheme 114 130 Zhang, H.-C.; Boñaga, L. V. R.; Ye, H.; Derian, C. K.; Damiano, B. P.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2007, 17, 2863. One example of the synthesis of axially chiral biaryl containing 2-aminopyridine moiety was achieved. 131 The use of chiral cobalt(I) catalyst for the enantioselective [2+2+2] cycloaddition of naphthyl-substituted 1,7-diyne with N-cyanopiperidine gave the expected biaryl cycloadduct in 89% yield with 87% enantioselectivity (Scheme 115).

Scheme 115

A quick access to allocolchicine analogues was developed by Schmalz and Nicolaus. 132 In the presence of 20 mol % CpCo(CO)2 under microwave conditions at 150 °C, the 3,4,5trimethoxybenzaldehyde and 3,4,5-trimethoxyacetophenone derived diynes reacted with morpholine-4-carbonitrile to generate the desired products in a short reaction time with 27% and 35% yields, and regioselectivities up to >99:1 were obtained (Scheme 116).

Scheme 116

Malacria, Aubert, Gandon and co-workers reported the CpCo(CO)(dmfu) complexcatalyzed [2+2+2] cycloaddition of yne-ynamides with cyanamides to provide 2,5- diaminopyridine derivatives. 133 Five-, six-, and seven-membered bicyclic compounds were synthesized in 20-85% yields with perfect regioselectivities (Scheme 117).

Scheme 117

Rhodium-catalyzed [2+2+2] cycloadditions

As described in the first chapter, the cationic rhodium/bisphosphine complex is an efficient catalyst for [2+2+2] cycloaddition reactions (Schemes 24 and 25). However, only a single example was described for the synthesis of annulated

Nickel-catalyzed [2+2+2] cycloadditions

Louie and co-workers reported the nickel-catalyzed [2+2+2] cycloaddition of diynes with cyanamides to form 2-aminopyridines. 135 A variety of diynes reacted with different substituted cyanamides in the presence of Ni(cod)2 catalyst in combination with a Nheterocyclic carbene (NHC) at room temperature. Various 2-aminopyridines were successfully obtained in 76-99% yields (Scheme 119). However, the nickel catalyst and NHC ligands required a pre-treatment in a glove box for at least 4 hours before introducing the two reactants.

Scheme 119

This Ni/NHC catalytic system was also applied for the totally intermolecular cyclotrimerization of two alkynes with cyanamides. 136 Treatment of terminal alkynes and cyanamides with Ni(cod)2/SIPr (1:2) complex catalyst in toluene at room temperature for 4 h, provided the 3,5-disubstituted-2-aminopyridines as the major products (Scheme 120). However, this protocol was limited to the use of alkyl-alkynes, whereas the reaction of aryl-, ester-, or chloride-substituted alkynes failed to afford the desired 2-aminopyridines.

X R 1 N X R 1 R 2 N N N + (1.0 equiv) R 4 R 3 R 4 R 3 21 examples 76-99% X = C(CO 2 Me) 2 , NTs, O, (CH 2 ) 2 , (CH 2 ) 3 R 1 = H, Me, Et, tBu R 2 = H, Me, Et R 3 = R 4 = Me, Et, nPr, Bn, N R 4 R 3 = N N IMes or N Ph Me N PMB Me N Ac nBu N nBu N O N CO 2 Me , , ,

Scheme 120

The same group also disclosed in 2011 the Ni/Xantphos-mediated cycloaddition of

+ X R 1 N X R 1 R 2 N N N (1.5 equiv) N Me Me N EtO 2 C EtO 2 C EtO 2 C EtO 2 C >99% N Me Me N 76% N N 86% MeO 2 C MeO 2 C Me O PPh 2 PPh 2 Xantphos R 3 R 3 N N EtO 2 C EtO 2 C EtO 2 C EtO 2 C 75% O Me Me NiL n N Me N MeO 2 C CO 2 Me Me Me NiL n N MeO 2 C MeO 2 C Me N Me Me via: EtO 2 C EtO 2 C EtO 2 C EtO 2 C X = C(CO 2 Me) 2 , [C(CO 2 Et) 2 ] 2 R 1 = H, Me and/or R 2 = H, Me N R 3 R 3 = N N O N , , N Me Me , R 3 R 3
Liu and co-workers successfully developed in 2017 the synthesis of -carbolines via nickel-catalyzed [2+2+2] cycloaddition of functionalized alkyne-cyanamides with alkynes. 138 Both internal and terminal alkynes successfully reacted with aryl-or alkyl substituted alkynecyanamides in the presence of NiCl2(DME)/dppp/Zn catalytic system to provide -carboline derivatives in 67-81% yields with moderate regioselectivities (Scheme 122). Interestingly, when phenyl-and TMS-substituted acetylenes were employed as the alkyne partners, the reaction resulted in the opposite regioselective formation of the cycloadduct, probably because of the difference of electronic effects between the two terminal alkynes.

Scheme 122

Iron-catalyzed [2+2+2] cycloadditions

Iron, the earth abundant and low cost metal, has rarely been used for the pyridines synthesis via [2+2+2] cycloadditions. 139 Louie's group described in 2012 the iron-catalyzed [2+2+2] cycloaddition of diynes with electron-rich cyanamides to form highly substituted 2aminopyridines. 140 The reaction proceeded in the presence of 5 mol % FeCl2 in combination with 10 mol % Mes PDAI and Zn dust in benzene at 70 °C, various 2-aminopyridines were synthesized in 35-97% yields. The group of Wan reported in 2013 a similar work by using FeI2/dppp/Zn catalytic system. 141 When comparing these works, Wan's group used less toxic THF as solvent instead of benzene, and lower reaction temperature (Scheme 123). However, both conditions suffered from the moisture-sensitive iron salts as well as a slow-addition technique which was required in Louie's work.

Scheme 123

With regard to the regioselectivity, the two reactions gave rise to an opposite selectivity of the regioisomers. In the case of Louie's conditions, the reaction provided the sterically less demanding compound as the major product whereas the small substituent was placed in ortho to the nitrile substituent. In the case of Wan's conditions, the regioselectivity trends led to the 2-aminopyridines with the small substituent placed in ortho to the nitrogen atom in the pyridine ring (Scheme 124). These two iron systems suggested that the regioselectivity may be controlled by the choice of the ligand. Mes PDAI

X R 1 R 2 + FeX 2 5 mol % Ligand 10 mol % Zn dust 10 mol % Solvent, T, t CN N R 3 R 4 N N R 4 R 3 X R 1 R 2 N N N FeCl 2 5 mol % Zn dust 10 mol % Benzene, 70 °C, 4-22 h R 1 = R
X = CH 2 , C(CO 2 Me) 2 , [C(CO 2 Me) 2 ] 2 , NTs, O R 1 = R 2 = H, Me, Et CN N R 3 R 4 = N CN N CN N CN O N CN Me Me , , , N CN Et Et , N CN X = CH 2 , C(CO 2 Me) 2 , NTs, O R 1 = R 2 = H, Me, Ph CN N R 3 R 4 = N CN N CN N CN O N CN Me Me

Scheme 124

Furthermore, Louie and co-workers also reported the totally intermolecular ironcatalyzed [2+2+2] cycloaddition of two alkynes with cyanamides. 142 In contrast to the Ni(cod)2/SIPr system (Scheme 120), in this case, the 2,4-disubstituted-2-aminopyridines were formed as major products with complete regioselectivity (Scheme 125).

Scheme 125 2.2.5. Iridium-catalyzed [2+2+2] cycloadditions

In 2015, Takeuchi and co-workers developed an efficient [Ir(cod)Cl]2/dppf or BINAP catalyst system that was able to promote the [2+2+2] cycloaddition of -diynes and cyanamides in refluxing benzene. 143 A wide range of secondary amines derived cyanamides was tolerated under these reaction conditions. Several examples have been studied by using 142 Spahn, N. A.; Nguyen, M. H.; Renner, J.; Lane, T. K.; Louie, J. J. Org. Chem. 2017, 82, 234. 143 Hashimoto, T.; Ishii, S.; Yano, R.; Miura, H.; Sakata, K.; Takeuchi, R. Adv. Synth. Catal. 2015, 357, 3901. symmetrical diynes with cyanamides to provide various 2-aminopyridines in 31-99% yields (Scheme 126). However, toxic and refluxing benzene was used as solvent.

Scheme 126

For the regioselectivity, as shown in Scheme 127, the methyl-/phenyl-or methyl-/2pyridyl-substituted diynes reacted with N-cyanomorpholine, leading to the formation of less hindered product as a single product in which the phenyl and pyridyl groups were substituted at the-position. Interestingly, the methyl/TMS-substituted diyne underwent cycloaddition reaction and gave exclusively the more sterically hindered product in which the TMS group was substituted at the -position. The authors therefore demonstrated that the regioselectivity was mainly controlled by the electronic effect of the substituent on the terminus of alkynes.

Scheme 127

Ruthenium-catalyzed [2+2+2] cycloadditions

During the publication process of our work, Goswami's group reported a rutheniumcatalyzed [2+2+2] cycloaddition of N-cyanoindoles with -diynes to provide 1-(2pyridyl)indole derivatives. 144 In this work, the reaction was performed under solvent-free or with small amount of EtOH conditions with Cp*Ru(cod)Cl catalyst for a short reaction time, providing the desired product in 86-93% yields. Three examples have been studied using monosubstituted unsymmetrical oxygen tethered diynes to evaluate the regioselectivity. The less sterically hindered products were obtained as a single regioisomer in 86-89% yields (Scheme 128). However, the scope of diynes and cyanamides were limited to eight diynes and three 3-carbonyl indoles derived cyanamides. Scheme 128

Objectives

Ruthenium complexes have been reported as highly efficient catalysts for the cycloaddition of -diynes with activated nitriles, 7u,7w such as electron-deficient nitriles, dicyanides, and -halogen nitriles. However, there was no ruthenium-catalyzed synthesis of functionalized pyridines with electron-rich nitriles such as cyanamides that have been reported when we started this project (Scheme 129).

Scheme 129

Considering the rare reports on the transition-metal-catalyzed [2+2+2] cycloadditions of alkynes with cyanamides to access 2-aminopyridines, as well as the limitations of current methodologies, we decided to investigate the ruthenium-catalyzed [2+2+2] cycloaddition reaction to access highly substituted 2-aminopyridines and its derivatives.

Results and discussion

Synthesis of starting materials: diynes and cyanamides

We first decided to study the partially intramolecular [2+2+2] cycloadditions to access 2-aminopyridine derivatives using -diynes and cyanamides. Most of the starting diynes and cyanamides were not commercially available and were synthesized.

Synthesis of symmetrical diynes

Scheme 131

Treatment of diyne 101 with 6 equivalents of LiAlH4 in THF solution afforded the dioldiyne 104 in 95% yield. The two hydroxyl groups of diyne 104 could be easily protected with acetyl and benzyl groups under basic conditions. In the presence of 4.4 equivalents of diisopropylethylamine in DCM, diyne 104 reacted with acetic anhydride to afford diacetylfunctionalized diyne 105 in 92% yield. The nucleophilic substitution of diol 105 with benzyl bromide using 2.5 equivalents of sodium hydride as base with 25 mol % n-tetrabutylammonium iodide as additive, gave dibenzyl protected diyne 106 in quantitative yield (Scheme 132).

Scheme 132

The reaction of diol 120, in the presence of 2 equivalents of phosphorus pentoxide in dry acetone at room temperature, allowed a rapid access to diyne 121 in 80% isolated yield (Scheme 133).

Scheme 133

The synthesis of nitrogen-tethered diynes 108 and 122 was based on the nucleophilic substitution of p-toluenesulfonamide with 1-bromo-2-butyne or propargyl bromide using 5 equivalents of potassium carbonate as base. The desired products could be easily synthesized in 70% and 91% yields, respectively (Scheme 134).

Scheme 134

The malonate derived diynes 110 and 124, bearing two functional groups on the terminal position of -diyne, have been synthesized (Scheme 135). Diyne 109 was treated with 2.2 equivalents of lithium bis(trimethylsilyl)amide in anhydrous THF at -78 °C, followed by the addition of an excess of trimethylsilyl chloride at the same temperature. After stirring for additional 1 h at room temperature, the reaction provided the disubstituted internal alkyne 110 in 45% yield (Eq. a). The low yield could be explained by the low reactivity of the terminal position of the alkyne as well as the formation of the monosubstituted side product. Dibromosubstituted diyne 124 was prepared through a classical bromination reaction using diyne 109 and NBS, in 98% yield (Eq. b).

Scheme 135

Synthesis of unsymmetrical diynes

To study the regioselective [2+2+2] cycloaddition reactions, we synthesized several unsymmetrical 1,6-, 1,7-and 1,8-diynes, as depicted in Scheme 136.

Scheme 136

The preparation of monosubstituted unsymmetrical diyne 125 started from malonate by stepwise alkylation reactions to introduce the internal and terminal alkyne motifs. Finally, the desired product was successfully isolated in 50% yield over two steps (Scheme 137).

Scheme 137

Compounds 138, 142, and 143 were prepared via nucleophilic substitution reactions.

Starting from commercially available alcohols 3-butyn-1-ol, 4-pentyn-1-ol and Mestranol, the oxygen tethered 1,6-143, 1,7-138 and 1,8-diynes 142 were respectively synthesized in 36%, 75%, and 79% yields (Scheme 138).

Scheme 138

To prepare the unsymmetrical oxygen tethered diynes 127, 131 and 140 containing a propargyl motif, the nucleophilic substitution reaction was performed using potassium hydroxide as the base in a mixed solution of water and DMSO, affording 127, 131 and 140 in respectively 79%, 50%, and 84% yields (Scheme 139).

Scheme 139

Upon treatment with N-bromosuccinimide (NBS) in the presence of 10 mol % AgNO3 in dry acetone at room temperature, the corresponding terminal alkynes were converted to bromo-substituted diynes 129, 130, 132 and 141 in 65-98% yields. The iodo-substituted diyne 133 was prepared via the silver-catalyzed Csp-H halogenation reaction using 10 mol % AgNO3 in N,N-dimethylformamide (DMF), with 98% yield. In addition, starting from propargyl alcohol, the useful intermediate bromo-substituted propargyl alcohol 145 was prepared in 65% yield (Scheme 140).

Scheme 140

The diyne 134 containing an ynamide moiety was obtained using a copper-catalyzed aerobic oxidative coupling reaction 146 of terminal alkyne 127 with 2-oxazolidinone. The reaction proceeded efficiently in the presence of 20 mol % CuCl2 and 2 equivalents of Na2CO3 and pyridine under 1 atm of O2, providing the corresponding ynamide in 60% yield (Scheme 141).

Scheme 141

To study the tolerance ability of the [2+2+2] cycloaddition reactions, other examples were evaluated. For this purpose, the synthesis of diyne 135 containing a vinyl group was envisaged. Starting from dimethyl malonate, a mono-alkylation with 0.85 equivalents of propargyl bromide followed by a Sonogashira cross-coupling reaction with 1.2 equivalents vinyl bromide provided the malonate-derived enyne 147. Subsequent nucleophilic substitution of the latter with 1.2 equivalents propargyl bromide in the presence of sodium hydride afforded the desired diyne 135 (Scheme 142).

146 Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833.

Scheme 142

The unsymmetrical diyne 137 was prepared through a Sonogashira reaction of diyne 125 with 1.2 equivalents of 2-bromopyridine using 2 mol % PdCl2(PPh3)2 and 1 mol % CuI, and was obtained in 60% yield (Scheme 143).

Scheme 143

Synthesis of benzoyl bridged -diynes

With the aim to synthesize amino-aza-fluorenones, the preparation of benzoyl or benzyl bridged -diynes 17, 28, 29, 149, 152, and 153 were envisaged, as shown in Scheme 144.

The synthesis of diynes 17, 28, and 29 has been described in chapter II. Diynes 149, 152, and 153 were synthesized in accordance with the previously described protocols for diyne 29.

Scheme 144

The preparation of diyne 149 followed a two-steps procedure. The previously prepared monoalkyne 2 was treated with a lithium TMS-acetylide, which was prepared in situ from trimethylsilylacetylene and n-butyllithium, affording the product 148 in 78% yield. The resulting silylated alcohol 148 was subjected to deprotection using 1 equivalent of TBAF. The desired compound 149 was isolated in 81% yield (Scheme 145).

Scheme 145

The synthetic methods for preparation of 2, 148, and 149 were used for the preparation cyanamides 157-159 and 161-167 were prepared according previously reported procedures, 147 most commonly via the electrophilic N-cyanation of amines using cyanogen bromide.

Scheme 147

The synthesis of cyanamides 157, 158, and 161-163 was achieved by the N-cyanation of piperidine, N-methylbenzylamine, N-methylaniline, and n-butylamine with cyanogen bromide in a mixture solution of diethyl ether and THF (1:1) at 0 °C. Two equivalents of amines were required to promote the reaction furnishing the desired compounds in 82-96% yields. In the case of n-butylamine, pure diethyl ether was used as solvent, the reaction was complete in 1 hour (Scheme 148).

Scheme 148

Another similar protocol was used for the preparation of cyanamides 159, 164, 166, and cyanogen bromide. After 3 hours stirring at room temperature, the reaction afforded the desired products in 86-99% yields. (Scheme 149).

Scheme 149

The cyanamide 164 containing a secondary amine group could easily undergo the acetylation by using 1.2 equivalents of sodium hydride and acetyl chloride to give the acetylprotected cyanamide 165 in 80% yield (Scheme 150). Firstly, we examined the reaction of diyne 101 with a large excess of cyanamide 154 (6 equivalents) in the presence of 5 mol % RuCl3•nH2O at 110 °C affording the highly substituted 2-aminopyridine 168 in 75% yield (Entry 1, Table 2). Subsequently, we decreased the amount of cyanamide from 6 to 3 equivalents. To our delight, the reaction gave almost the same isolated yield of product 168 (Entry 2). Attempt to decrease the catalyst loading to 2 mol % caused a significant decrease of the conversion (50%, Entry 3). We also evaluated the temperature effect on the reaction. Incomplete conversion of the benzannulation was observed when the reaction was carried out at 80 °C, 50 °C, 90 °C, 100 °C (Entries 4-8). Finally, we found that the diyne 101 was fully converted to pyridine 168 in 74% yield when the amount of cyanamide 154 was further reduced to 2 equivalents (Entry 9). 3). The reaction did not occur with both unprotected N-butylcyanamide 163 and acetyl-protected N-butyl-N-cyanoacetamide 165

(Entries 11 and 12). N,N-diallylcyanamide 166, containing two alkenes, was also evaluated and gave decomposed reaction mixtures (Entry 13), which could be explained by the competitive reaction between the activated alkenes and alkynes. N-methylpiperazine-derived cyanamide 167 was also employed but no reaction took place in these conditions (Entry 14).

Having evaluated the reactivity of several cyanamides, we then turned our attention to explore the scope and limitations of the reaction conditions by using the prepared symmetrical However, only the major isomer 194 was isolated in 16% yield, despite a 90:10 ratio of the two regioisomers detected by crude 1 H NMR.

Scheme 152

Compared to electron-rich cyanamides, the reaction of symmetrical diyne 108 with electron-deficient nitrile such as malononitrile was also performed in the presence of RuCl3•nH2O catalyst at 110 °C to afford cycloadduct 195 with 22% conversion, although with increased catalyst loading and prolonged reaction time (Scheme 153). This result indicated that the electron-rich nitriles are more suitable with the RuCl3•nH2O complex catalytic system.

Scheme 153

The neutral RuCl3•nH2O has therefore been successfully used for the synthesis of highly substituted 2-aminopyridine derivatives via [2+2+2] cycloaddition of ,-diynes with electron-rich cyanamides. A range of 2-aminopyridines has been successfully synthesized in 10-95% yields. However, the regioselective synthesis of 2-aminopyridines still remains a challenge. To address this issue, encouraged by our results with RuCl3•nH2O, we decided to investigate the ruthenium-catalyzed [2+2+2] cycloadditions by using cationic ruthenium complex as catalyst.

Cp*Ru(CH3CN)3PF6-catalyzed [2+2+2] cycloaddition of -diynes with cyanamides

Encouraged by the results obtained using the neutral RuCl3•nH2O complex for the [2+2+2] cycloaddition reaction of -diynes with cyanamides, and since the cationic ruthenium complex is known to be an efficient catalyst for [2+2+2] cycloaddition reactions, 46- 50 we anticipated that the cationic ruthenium complex would be a good alternative for conducting this reaction.

Initial studies were focused on the ruthenium-catalyzed [2+2+2] cycloaddition reactions between dimethyl substituted internal diyne 101 and cyanamide 155 using ruthenium complex catalyst under solvent-free conditions at room temperature. The reaction was optimized with respect to the different type of ruthenium complexes and catalyst loading, as shown in Table 4.

Several ruthenium complexes were evaluated. When Ru(PPh3)3Cl2 and [Ru(p-cymene)Cl2]2

were used as catalyst, no desired products were observed (Entries 1 and 2). We found that the presence of both pentamethylcyclopentadienyl (Cp*) complexes Cp*Ru(cod)Cl and Cp*Ru(CH3CN)3PF6, allowed to access the desired 2-aminopyridine 169 in respectively 85% and 93% yields in a short reaction time of 5 min (Entries 3 and4). The catalyst loading could be efficiently reduced to 2 mol % when using Cp*Ru(CH3CN)3PF6 as catalyst. The reaction effectively provided the cycloadduct in 91% yield within 5 min (Entry 5). We showed that the conversion of the benzannulation was significantly diminished by lowering the catalyst loading to 1 mol % (Entry 6). In addition to the internal diyne, terminal 1,6-diyne 109 was examined under these reaction conditions. Treatment of diyne 109 with cyanamide 155 in the presence of 2 mol % Cp*Ru(CH3CN)3PF6 under solvent-free conditions at room temperature provided the cycloadduct 188 in 94% yield (Entry 7). Interestingly, we found that when the reaction was conducted with a small amount of dichloromethane as solvent, the catalyst loading (1 mol %) and consumption of cyanamide (1.2 equivalents) were further reduced (Entries 7 and 8).

However, lowering the catalyst loading to 0.5 mol % led to lower conversion and yield, despite longer reaction time (Entry 9). Finally, to demonstrate the applicability of our method, we performed the Ru-catalyzed cycloaddition on one-gram of 1,6-diyne 109 (Entry 10). Under the optimized solvent-free conditions in the presence of 2 mol % of Cp*Ru(CH3CN)3PF6 catalyst, the corresponding 2-aminopyridine 188 was isolated in 82% yield. Similarly, as previously observed, no desired products 215 and 216 were obtained by using Nbutyl-N-cyanoacetamide 165 and N,N-diallylcyanamide 166.

Scheme 155

With respect to the regioselectivity, we previously studied the reaction of unsymmetrical diynes 125 with cyanamides 155 in the presence of neutral RuCl3•nH2O catalyst. However, moderate yield and regioselectivity (48%, 88:12) were obtained. In contrast, when the reaction was run using the cationic ruthenium complex, Cp*Ru(CH3CN)3PF6, the yield and regioselectivity were significantly increased (91%, 98:2) and the ortho-substituted regioisomer 193 was formed as the major product (Scheme 156). In addition, other unsymmetrical diynes were employed to explore the regioselectivity of the cycloaddition reactions. The reaction of phenyl-substituted diyne 126 exclusively furnished the biaryl compound 194 in excellent 96% yield. Unsymmetrical 1,6-diynes tethered by either oxygen or nitrogen atom, possessing a terminal alkyne and a methyl internal alkyne moieties, were compatible with the cycloadditions and afforded the corresponding bicyclic compounds 217 and 218 as a single regioisomer, in 86% and 90% yields. However, the methyl/2-pyridyl-substituted diyne 137 did not undergo the cycloaddition to give the bipyridine 219, although the reaction was heated at 50 °C for 2 hours.

Scheme 156

Encouraged by these promising results, we extended this study to develop a feasible synthetic route for the preparation of pyridine derivatives possessing various functional groups.

To our delight, the challenging halogen-substituted diynes were all tolerated to deliver the synthetic useful halopyridines in 65-85% yields with up to 99:1 regioselectivities (Scheme 157).

Treatment of malonate-derived bromodiyne 129 and cyanamide 155 under the standard solventfree conditions at room temperature, generated the less sterically hindered ortho-bromopyridine as the major product, in 80% yield and high regioselectivity (96:4). The structure of the product 220 was unambiguously determined by the basis of 2D-NMR analysis and X-ray crystallographic analysis. Bromodiynes 130-132 reacted nicely with cyanamide 155 to provide the corresponding bromopyridines 221-223 in 65-85% yields with 98:2 regioselectivities. The iodo-substituted 2-amimopyridine 224 was isolated as a single regioisomer in 83% yield.

Scheme 157

Inspired by the success of halogen substituted diynes to yield the halopyridines, we next examined whether the ynamide and enyne, could be suitable for the synthesis of the corresponding functionalized pyridines under the same conditions (Scheme 157). Gratifyingly, the cycloaddition of ynamide 134 with cyclic cyanamides 155 and 156 gave rise to pyridines 225 and 226 with excellent regioselectivities, in 79% and 93% yields, respectively. or DCM as solvent (B) rt or 50 °C, t We hypothesized that by using benzoyl bridged -diynes and cyanamides, it should be possible to access amino-aza-fluorenones via the regioselective ruthenium-catalyzed [2+2+2] cycloaddition reaction. A retrosynthesis was proposed in Scheme 161.

R 1 R 2 R 2 R 1 X N N R L R S R 1

Scheme 161

Therefore, the benzoyl bridged internal diyne 17 was reacted with dimethylcyanamide 154 under the optimized conditions using 5 mol % RuCl3•nH2O under solvent-free conditions at 80 °C. Unfortunately, no desired product 238 was obtained and only decomposition of diyne 17 was detected (Eq. a, Scheme 162). The same result was also observed by using

X R Ru + + Ru + R X N N R 1 R 2 R 2 N R 1 N + N Ru N R 1 R 2 X R X N R N R 1 R 2
Ru-III (favorable)

major Ru + Ru + X N N R 1 R 2 Ru-III' (less favorable) R + N Ru N R 1 R 2 X R X N N R 1 R 2 R minor Cp*Ru(CH 3 CN) 3 PF 6 + Ru + X R Ru X R Ru-I Ru-II Ru-IV Ru-IV' O R 2 R 1 [2+2+2] cycloaddition + N O R 2 R 1 N R 4 R 3 N N R 4 R 3 N O R 2 R 1 N R 4 R 3 or
Cp*Ru(CH3CN)3PF6 as catalyst for the cycloaddition of diyne 17 and cyanamide 155 (Eq. b, Scheme 162). The results could be explained by the lower reactivity of the diyne which bears both phenyl and n-butyl groups on the terminal positions.

Scheme 162

To address this issue, we reasoned that a less sterically demanding diynes possessing a terminal alkyne moiety would be more reactive in the presence of Cp*Ru(CH3CN)3PF6 catalytic system. Indeed, as shown in Scheme 163, when the benzoyl bridged diyne 29 was reacted with morpholine-4-carbonitrile 155 in the presence of 2 mol % Cp*Ru(CH3CN)3PF6 at room temperature under solvent-free conditions, the 2-azafluorenone 240 was formed as a single regioisomer in 92% yield. Different cyanamides were next screened, such as Ncyanopyrrolidine 156, N-cyanopiperidine 157 and N,N-methylbenzyl cyanamide 158, and the desired 2-azafluorenones 241-243 were synthesized as a single isomer in 78-87% yields. In addition, the reaction of benzyl-bridged diyne 28 bearing an unprotected hydroxyl group could also be performed smoothly and exclusively to give rise to 2-azafluorenols 244 and 245 in 84% and 81% yields, respectively. Interestingly, in parallel to the synthesis of 2-azafluorenol 245, exchanging the terminal position of the starting diyne, allowed the formation of the 3azafluorenol 247 in 71% yield with 99:1 regioselectivity. Moreover, switching to a cyclopropyl group instead of n-butyl group promoted the formation of 3-azafluorenol 247 in 78% yield with the same regioselectivity. The cycloaddition of benzoyl bridged diyne 153 was performed under the optimized reaction conditions, 3-azafluorenone 248 was formed as the major product in 89% isolated yield, with a decreased regioselectivity (94:6). The structure of 248 was unambiguously confirmed by single crystal X-ray diffraction (Scheme 163). These results illustrated that the regioselectivity allows the formation of less sterically hindered regioisomer.

It is important to highlight that all the reactions occurred in a short reaction time using traces of dichloromethane or solvent-free conditions.

Scheme 163

Conclusion

To conclude, we have demonstrated that highly substituted 2-aminopyridine derivatives can be efficiently synthesized by ruthenium-catalyzed [2+2+2] cycloaddition of 6-diynes and 1,7-diynes with cyanamides using both neutral RuCl3•nH2O and cationic Cp*Ru(CH3CN)3PF6 complex as catalyst.

N OH nBu N O N OH nBu N N O nBu N O N O nBu N N O nBu N N O nBu N Me Ph N O N N OH N X R 1 R 2 + R 3 N R 4
Cp*Ru(CH 3 CN) 3 PF 6 (2 or 5 mol%) solvent-free conditions (A) or DCM as solvent (B) rt, 5-30 min

N X R 1 N R 4 R 3 N 2-azafluorenone(ol) 240-245 N X R 2 N R 4
, X = CHOH, R 1 = nBu, R 2 = H 29, X = CO, R 1 = nBu, R 2 = H 149, X = CHOH, R 1 = H, R 2 = nBu 152, X = CHOH, R 1 = H, R 2 = cyclopropyl 153, X = CO, R 1 = H, R 2 = cyclopropyl
Firstly, the easy to handle and cost-effective RuCl3•nH2O complex has been successfully employed for the synthesis of highly substituted 2-aminopyridines. The reaction proceeded in the presence of 5 mol % RuCl3•nH2O, with neither additional ligands nor additives under solvent-free conditions, affording a range of different 2-aminopyridines in 10-95% yields.

Secondly, we established that a cationic Cp*Ru(CH3CN)3PF6 complex is a highly efficient catalyst for the cycloaddition of both 1,6-and 1,7-diynes with cyanamides under mild conditions. Various symmetrical terminal or internal diynes possessing different functional groups were compatible with the catalytic system. High regioselectivity was obtained when unsymmetrical diynes were employed. The practicability and utility of this protocol were demonstrated with the preparation of high valuable halopyridines, diaminopyridines, and vinylpyridines in one-step synthesis. The reaction also provided synthetic useful six-membered heteroatom-fused pyridines starting from unsymmetrical 1,7-diynes and cyanamides. The latestage functionalization of biologically active mestranol further improved the facile and usefulness of the present method. Chapter IV: Rhodium-catalyzed asymmetric synthesis of 1,1disubstituted 1,3-dihydroisobenzofurans from prochiral triynes and internal alkynes

Chapter IV: Rhodium-catalyzed asymmetric synthesis of 1,1-disubstituted 1,3-dihydroisobenzofurans from prochiral triynes and internal alkynes

The transition-metal-catalyzed enantioselective [2+2+2] cycloaddition reactions are extremely important tools in modern synthetic organic chemistry, because they serve as a powerful and atom-economical straightforward approach for the rapid construction of chiral polycyclic carbocycles and heterocycles in a single step. 7h,7j,7x Since the first example of enantioselective [2+2+2] cycloaddition discovered in 1994 with the work of Sato, Mori, and Nishimata, 151 catalytic asymmetric [2+2+2] cycloaddition reactions using a transition metal catalyst, such as rhodium, cobalt, nickel, and iridium, in the presence of a chiral ligand have been widely reported for the construction of various chiral molecules associated with central, axial, planar, helical chirality (Figure 3).

Enantioselective [2+2+2] cycloaddition reactions 1.Construction of central chirality

The transition-metal-catalyzed [2+2+2] cycloadditions of alkynes with unsaturated partners, such as olefins, imines, aldehydes, are of great interest given that they allow the construction of a six-membered ring containing one or more chiral carbon center. These processes proceed via a widely known reactive metallacyclopentene or metallacyclopentadiene intermediate, which is generated from the oxidative coupling of two unsaturated carbon-carbon bonds to the chiral metal catalytic species. The insertion and reductive elimination steps then provide the cyclic compound with chiral carbon center(s) on the six-membered ring (Scheme 164).

Scheme 164

In 2006, Shibata reported the first rhodium-catalyzed enantioselective [2+2+2] cycloaddition of diynes and alkenes. 152 In the presence of a preliminary isolated chiral rhodium(I) complex, various exo-methylene cyclic lactones and ketones could undergo the cycloaddition with 1,6-diynes to give a family of chiral spirocyclic compounds possessing a quaternary carbon stereocenter, with 62-94% yields and 80-99% enantioselectivities (Scheme 165).

152 Tsuchikama, K.; Kuwata, Y.; Shibata, T. J. Am. Chem. Soc. 2006, 128, 13686.

R 1 R 1 ML * ML* R 1 R 1 R 2 O R 2 X * * R 2 R 1 R 1 X=CH 2 , NR 3 , O metallocyclopentene or metallocyclopentadiene NR 3 R 2
or or

Scheme 165

The enantioselective [2+2+2] cycloaddition involving two alkene units allowed to introduce two new stereogenic centers in a single step in the resulting cycloadduct. The first report was described by Tanaka and co-workers in 2012. 153 They demonstrated that the successful construction of annulated cyclohexene relies on the use of reactive acrylamides as alkene partners (Scheme 166). The high regioselective and diastereoselective formation of the cycloadduct could be explained by the regioselective insertion of the acrylamide into a rhodacyclopentene intermediate.

Scheme 166

The unsaturated imine was also a good partner for these cycloadditions. The first asymmetric transition-metal-catalyzed [2+2+2] cycloaddition of diynes with sulfonimines was reported by Aubert, Gandon, Malacria and co-workers, 154

Construction of axial chirality

Axially chiral biaryl compounds are widely found as a key structural motif in many chiral ligands, catalysts as well as biologically active compounds. 155 The catalytic enantioselective synthesis of axially chiral biaryls via transition-metal-catalyzed [2+2+2] cycloadditions have been proved to be a straightforward and efficient method. The sterically demanding prochiral substrates and a chiral catalyst were commonly used for the formation of chiral biaryl compounds (Scheme 168).

R 3 R 1 R 3 R 1 R 2 R 2 R 3 R 2 R 1

ML* ML*

In 2004, Gutnov, Heller and co-workers reported the first example of direct synthesis of enantioenriched axially biaryls via a chiral cobalt(I) complex-catalyzed [2+2+2] cycloaddition of alkynes with nitriles. 156 The reaction was performed under mild conditions using visible light or sunlight as the energy source (Scheme 169).

Scheme 169

Shibata and co-workers reported the first example of iridium-catalyzed [2+2+2] cycloaddition of -diynes with alkynes. 157 The combination of [Ir(cod)Cl]2 and (S,S)-Me-Duphos promoted the high enantio-and diastereoselective synthesis of axially chiral 1,4teraryls (Scheme 170).

Scheme 170

Tanaka and co-workers also employed the cationic rhodium(I)/bisphosphine catalytic system to the asymmetric synthesis of axially chiral biaryls. 158 In the presence of cationic rhodium(I)/(S)-H8-BINAP complex, various unsymmetrical diynes and internal alkynes were converted to axially chiral phthalides. Functional groups, such as trifluoromethyl and chloride were tolerated using these conditions (Scheme 171).

) Me R 1 R 1 or R 1 R 1 + R 1 R 1 R 1 = C 3 H 7 , C 5 H 9 R 2 =
Scheme 171

Construction of planar chirality

The transition-metal-catalyzed intramolecular [2+2+2] cycloaddition of triynes, possessing a short ansa chain, could be possible to form a planar chirality cyclophanes in which the ansa chain cannot flip around the benzene ring (Scheme 172).

Scheme 172

In 2007, the group of Tanaka first reported that the planar-chiral metacyclophanes could be synthesized by transition-metal-catalyzed [2+2+2] cycloaddition reactions. 159 The intramolecular cyclotrimerization of linear triynes, bearing ester or ether-linked 1,6-diyne moieties, proceeded in the presence of rhodium(I)/(R)-H8-BINAP complex furnishing the [7]-

[10]metacyclophanes with high enantioselectivities (Scheme 173). This method opened a new way to synthesize these compounds. 159

R 2 R 1 L* M R 2 R 1 L* M R 1 R 2 R 2 R 1 R 1 R 2 achiral chiral ML*
Scheme 173

Construction of helical chirality

The combination of transition metals with chiral ligands to catalyze [2+2+2] cyclotrimerization of alkynes is considered as one of the most efficient method for the synthesis of helically chiral -electron systems, although most examples are diastereoselective cycloadditions (Scheme 174).

Scheme 174

Stará, Starý and co-workers reported a rapid approach for the synthesis of dibenzohelicenes based on a nickel-catalyzed cycloaddition reaction.

Desymmetric transition-metal-catalyzed [2+2+2] cycloaddition reactions

Although many methods have been developed on enantioselective transition-metalcatalyzed [2+2+2] cycloadditions for the synthesis of useful chiral compounds, new strategies to access challenging targets are still desirable.

The construction of all-carbon quaternary stereogenic centers via catalytic enantioselective desymmetrization 161 of prochiral substrate is an ideal method which exhibits many advantages over conventional strategies (Figure 4). For example, the quaternary carbon stereocenter is formed, no matter what kind of reaction occurred at one of the two identical functional groups attached to the quaternary carbon; the functional groups could previously be introduced to the quaternary carbon; the theoretical yield of the desymmetrization reaction is 100%, while the yield of the kinetic resolution reaction cannot exceed 50%.

R R (R)-Quinap R = tolyl N PPh 2

Figure 4

Taking advantage of the powerful and practical transition-metal-catalyzed [2+2+2] cycloadditions, and based on the principles of desymmetrization reactions, the synthesis of chiral compounds in term of desymmetric enantioselective [2+2+2] cycloaddition reactions were designed but scarely reported (Scheme 176).

Scheme 176

The first example was reported by Sato, Mori and Nishimata using a nickel(0)-catalyzed enantioselective [2+2+2] cycloaddition of prochiral triynes with gaseous acetylene in the presence of chiral phosphine ligands under mild conditions (Scheme 177). 151, 162 The combination of Ni(cod)2 and (R,S)-BPPFA promoted the reaction of prochiral triynes with acetylene affording the isoindoline derivatives in 52% yield and 73% enantioselectivity, 162 Sato, Y.; Nishimata, T.; Mori, M. Heterocycles 1997, 44, 443.

X R 2 R 3 R 4 R 4 R 1 R 1 ML* ML* R 1 R 1 R 1 R 1 X * * R 2 R 3 R 4 R 4 achiral chiral
whereas the cycloaddition of 1,7-diynes and acetylene by using (S)-MOP as ligand led to isoquinoline in 62% yield and 54% enantioselectivity. Notably, this new method opened a novel route for the construction of benzylic chiral carbon centers, although the enantioselectivities were moderate.

Scheme 177

Since this pioneering work, the desymmetric [2+2+2]

(R)-Xylyl-Solphos (Ar = 3,5-di-MeC 6 H 3 ) MeO 2 C MeO 2 C NC CN R Bn N MeO 2 C MeO 2 C Me Me * * R CN Bn R = H, (R)-Xylyl-Solphos 91% yield, 64% ee R = Me, (R)-BINAP 75% yield, 33% ee R = H (1.1 equiv) R = Me (2.0 equiv)
In 2007, the same group described the synthesis of enantioenriched tricyclic 3,3disubstituted phthalides involving a cationic rhodium-catalyzed desymmetric [2+2+2] cycloaddition reaction. 164 The reaction proceeded via an initial oxidative coupling of 1,6-diyne bearing a carbomethoxy group and simultaneously a transesterification with a symmetrical bispropargylic alcohol to form the rhodacyclopentadiene reactive species, followed by desymmetric insertion of one of the two alkynes to give the phthalide derivatives, which bear a chiral quaternary carbon center at the benzylic position (Scheme 179). The high regio-and enantioselectivity strongly relied on the presence of both methoxycarbonyl group and propargylic hydroxyl group.

Scheme 179

The C2-symmetric spirobipyridine structures were also prepared via the rhodium/bisphosphine-catalyzed enantioselective intramolecular double [2+2+2] cycloadditions of bis-diynenitriles. 165 A wide range of substrates were examined to produce various C2-symmetric spirobipyridine ligands in 70-99% yields with 18-71% enantioselectivities (Scheme 180). 164

Scheme 180

The aromatics containing a chiral center at -position are more challenging to synthesize.

Thus, Shibata and co-workers recently developed a rhodium-catalyzed intramolecular enantioselective [2+2+2] cycloaddition of amino-acid-tethered triynes for the preparation of the chiral center of tethered Aic derivatives (Scheme 181). 166

Scheme 181

166 Tahara, Y. K.; Obinata, S.; Kanyiva, K. S.; Shibata, T.; Mándi, A.; Taniguchi, T.; Monde, K. Eur. J. Org. Chem. 2016, 1405.

Aic

Not only quaternary-carbon-stereogenic centers but also other hetero-stereogenic centers, such as phosphorus and silicon, can be constructed through desymmetric enantioselective [2+2+2] cycloaddition reactions.

In 2008, Tanaka and co-workers successfully synthesized a family of phosphorusstereogenic alkynylphosphine oxides by using cationic rhodium(I)/bisphosphine complexcatalyzed [2+2+2] cycloadditions of symmetrical dialkynylphosphine oxides with 1,6diynes. 167 The desymmetric formation of a phosphorus-stereogenic center could be explained by the steric effect between the coordinated dialkynylphosphine oxide and the chiral phosphine ligand in the formed rhodium intermediate (Scheme 182).

Scheme 182

Nozaki and co-workers reported in 2015 a facile and efficient method for the preparation of silicon-stereogenic dibenzosiloles through enantioselective rhodium-catalyzed [2+2+2] cycloaddition of silicon-containing prochiral triynes with internal alkynes. 168 In the presence of [RhCl(C2H4)2]2/monophosphine catalytic system, by exchange of the different tethers and unsaturated partners, enantioenriched germanium-stereogenic dibenzogermoles, siliconstereogenic silicon-bridged arylpyridinones 169 and arylpyridines 170 were successfully obtained with good to high chemo-, regio-and enantioselectivities (Scheme 183). A drawback of this method was the difficult multiple-step synthesis of starting prochiral triynes.

167 Nishida, G.; Noguchi, K.; Hirano, M.;

Objectives

Considering the literature, the enantioselective synthesis of 1,3-dihydroisobenzofurans containing a stereogenic centerat the -position has rarely been reported and remains a challenge. 177 Desymmetrization of prochiral compounds serves as an efficient method to prepare complex molecules with a stereogenic chiral center. Therefore, we anticipated that the construction of 1,3-dihydroisobenzofurans could be achieved via the transition-metal-catalyzed The prochiral oxygen-tethered triynes having an -diyne motif could be prepared from commercially available reagents, the retrosynthesic route is depicted in Scheme 187.

Scheme 187

The symmetrical bispropargylic alcohols 249-253 were prepared through the lithium mediated nucleophilic addition of terminal alkynes with acyl chlorides. As shown in Scheme 188, a series of acyl chlorides reacted with 2 equivalents of lithium acetylide, prepared in situ from the corresponding alkynes and n-butyllithium, affording the bispropargylic alcohols 249-253 in 70-99% yields. Both aryl and alkyl groups could be introduced to the quaternary carbon atom by using different acyl chlorides.

Scheme 188

The oxygen-tethered triynes 254-259 were successfully synthesized via the nucleophilic substitution of the alcohols 249-253 with 1.3 equivalents of propargyl bromide or 1-bromo-but-2-yne. The reaction was performed in the presence 1.3 equivalents of sodium hydride in THF, and afforded the desired triynes 254-259 in 70-90% yields (Scheme 189).

Scheme 189

Treatment of terminal triyne 254 with 1.1 equivalents of nbutyllithium in THF at -70 °C, followed by subsequent silylation with 1.1 equivalents of trimethlylsilyl chloride, delivered the TMS-substituted triyne 260 in 93% yield (Scheme 190).

Scheme 190

Synthesis of internal monoalkynes

To study the steric influence of the alkynes, different internal alkynes were prepared (Scheme 191). Diynes 51, 53, 54 and 261 were purchased from commercial sources, diynes 262-265 were prepared in the laboratory following the procedures described in the literature. 178

Scheme 191

The reaction of 2-butyl-1,4-diol 52 with 3 equivalents of acyl chlorides, such as acetyl chloride and benzoyl chloride, in the presence of 2.5 equivalents of pyridine provided the corresponding alkynes 262 and 264 in 96% and 95% yields, respectively (Scheme 192).

Scheme 192

Alkyne 263 could be prepared by the reaction of 2-butyl-1,4-diol 52 with 3 equivalents of pivaloyl chloride using 5 mol % DMAP as catalyst and 4 equivalents of ethyldiisopropylamine as base, 98% of the desired product was obtained (Scheme 193). 3). The results showed that the use of Rh(cod)2BF4 in combination with (R)-BINAP was the best choice for the transformation. Using 5 mol % of cationic Rh(cod)2BF4/(R)-BINAP complex in dichloromethane at 40 °C lead to 50% yield and 50% ee of the desired product 266 by using 1:2 ratio of triyne 255 and alkyne 262 (Entry 1). Further evaluation of the ratio of [Rh]/ligand showed that an increase of the amount of (R)-BINAP (10 mol %, Entry 4) gave no improvement (yield and enantioselectivity). The reaction did not take place in the absence of phosphine ligand (Entry 5). Hydrogenation of the rhodium complex under 1 atm H2 for 1 hour to remove the cod ligand allowed the formation of cycloadduct 266 in 66% isolated yield, but with a lower enantiomeric excess of 43% (Entry 6). Moreover, slow-addition technique was used to introduce triyne 255 in 3 h to a DCM solution of alkyne 262 and Rh(cod)2BF4/(R)-BINAP complex using a syringe pump (Entry 7). However, the formation of unclear side products was observed, due to the homo-cyclization of triyne and totally intramolecular cycloaddition of triyne with alkyne. Determined by SFC analysis. d Ar F = 3,5-(CF3)2C6H3. e 10 mol % of (R)-BINAP was used. f No ligand. g [Rh]/(R)-BINAP complex with previous hydrogenation (H2, 1 atm, rt, 1 h). h Slow addition of triyne 255 in 3 hours using a syringe pump.

To further optimize the reaction conditions, a variety of bisphosphine and monophosphine ligands has been examined (Table 6). The influence of the chiral ligand was explored, (S)-Tol-BINAP, (R)-Xylyl-BINAP and (R)-H8-BINAP gave slight decreased enantiomeric excesses. The combination of Rh(cod)2BF4 with axially chiral monophosphine (R)-MOP, which previously demonstrated high reactivity and selectivity for the desymmetrization of silicon-containing prochiral triynes with internal alkynes, 168-170 afforded the cycloadduct in 70% yield with 7% ee. Oxygen fused electron-rich and electron-poor bidentate ligands, such as (R)-SegPhos, (R)-DifluorPhos, (R)-SynPhos and (R)-(4-CF3)-SynPhos, showed higher reactivity to access compound 266 (60-81% yields), but lower enantioselectivities were obtained (16-30% ee). Phosphine ligands bearing sterically hindered PAr2 moiety, such as (R)-dtbm-SegPhos and (R)-dtbm-MeOBiphep, did not provide the desired product. In contrast to the axially chiral phosphine ligands, (S)-Tol-BDP, (S)-PHANEPHOS, (R,S)-JosiPhos and (R,R)-Me-DuPhos, showed poor enantioselectivities and low reactivities under these reaction conditions.

Table 6 Screening of chiral phosphine ligands

a Toluene was used as solvent.

We also evaluated a series of monodentate phosphoramidite ligands. 179 However, no improvement of enantioselectivity of compound 267 was obtained (5-40%, Scheme 195).

Scheme 195

These results demonstrated that the chiral phosphine ligands play an important role to promote the desymmetric [2+2+2] cycloadditions, although moderate enantioselectivities were obtained. In this context, the Rh(cod)2BF4/(R)-BINAP complex was selected for the [2+2+2] cycloaddition reactions.

To improve the yield and enantiomeric excess, we next screened different organic solvents (Table 7). First, polar solvents were examined. The reaction was carried out in dichloroethane and tetrahydrofuran at 40 °C, in the presence of 5 mol % Rh(cod)2BF4/(R)-BINAP complex to deliver the desired 1,3-dihydroisobenzofuran 266 in 61% and 72% yields, respectively, with 37% and 47% ee, respectively (Entries 2 and 3). The non-polar solvents such as toluene, xylene, chlorobenzene have also been evaluated (Entries 4-6). Slight increased yields of cycloadducts were observed, with moderate enantioselectivity. Performing the cycloaddition in toluene at 100 °C did not significantly improve the course of the cycloaddition (70% yield, 50% ee, Entry 4). The reaction was performed in the presence of 5 mol % Rh(cod)2BF4/(R)-BINAP complex in 3 mL dichloromethane at 40 °C to evaluate the scope of the [2+2+2] With the optimized reaction conditions in hand, we then investigated the generality and limitations of the synthetic protocol. A series of symmetrical internal alkynes with different substituents were engaged with triyne 255 under the optimized reaction conditions (Scheme 196). Switching to the more sterically hindered 2,2-dimethylpropanoate 263 and benzoate 264 allowed to promote the reaction to form cycloadducts 267 and 268 in respective 20% and 28% yields, and 36% and 46% ee. The use of 3-hexyne 53 gave the desired product 269 in 79% yield and 21% ee. The reaction of more electron-rich alkyne such as 1,4-dimethoxy-2-butyne 51 with triyne 255 afforded the cycloadduct 270 in 63% yield with 32% ee. In addition, the electrondeficient alkyne dimethyl acetylenedicarboxylate 261 can also be employed to provide the corresponding cyclized product 271 in 51% yield and 47% ee. On the other hand, we observed that the reaction was not compatible with diphenylacetylene 54, probably because of the steric effect of the two phenyl groups. It was also found that no reaction occurred with the tosyl group protected 2-butyne 265.

Scheme 196

With respect to the prochiral triynes, different substituents on the triynes were evaluated (Scheme 197). Replacement of methyl group on the quaternary carbon atom by n-propyl group provided the corresponding product 274 with similar 46% yield and 51% enantiomeric excess.

The reaction of sterically demanding tert-butyl-and phenyl-substituted triynes 257 and 258

with internal alkyne 262 were inefficient for the enhancement of the enantioselectivity, leading to cycloadducts 275 and 276 with slightly lower 38% and 41% ee. The reaction also proceeded smoothly with the prochiral triyne 259 affording the cycloadduct 277 in 54% yield with 24% ee. The reaction was also applicable to the trimethylsilyl-substituted triyne 260, which successfully reacted with alkyne 262 to deliver the corresponding product 278 with 52% enantioselectivity in 26% yield. Finally, the reactivity of the triyne 254 having a terminal alkyne moiety was examined. However, no desired product 279 was formed under these reaction conditions, only the decomposition of the starting triyne was observed.

Scheme 197

To rationalize the moderate enantioselectivities, two plausible reaction pathways for the formation of chiral 1,3-dihydroisobenzofurans could be considered, A and B (Scheme 198).

Conclusion

In summary, we have developed a new route for the synthesis of enantioenriched 1,3dihydroisobenzofuran derivatives via an enantioselective rhodium-catalyzed [2+2+2] cycloaddition of prochiral triynes and monoalkynes. The reaction proceeded in the presence of a cationic Rh(cod)2BF4/(R)-BINAP complex in DCM. This desymmetrization strategy allowed the formation of 1,1-disubstituted 1,3-dihydroisobenzofurans containing a quaternary carbon stereocenter in up to 79% yield and up to 52% ee. Two plausible reaction pathways were proposed to rationalize the moderate enantioselectivities.

General conclusion

General conclusion

With the aim of the PhD project to develop environmentally friendly and atomeconomical processes to access biologically interesting polycyclic and heterocyclic aromatic compounds via transition-metal-catalyzed [2+2+2] cycloaddition reactions, we successfully accessed relevant building blocks including fluorenones, 2-aminopyridines and enantioenriched 1,3-dihydroisobenzofurans.

This work was first dedicated to the development of an efficient and practical route for the preparation of highly substituted fluorenones and analogues via solvent-free RuCl3•nH2Omediated [2+2+2] cycloaddition of -diynes and alkynes. 180 This green approach involves a solvent-free and atom-economical catalytic process to generate densely functionalized fluorenones and related derivatives of high synthetic utility (Scheme 199).

Scheme 199

We also developed a convenient access to functionalized 2-aminopyridines via a solvent-free RuCl3•nH2O-promoted [2+2+2] cycloaddition reaction of -diynes and cyanamides. 181 This transformation efficiently proceeds in the presence of a stable, easy to handle, and cost-effective RuCl3•nH2O complex, leading to various 2-aminopyridines in moderate to high yields following an eco-friendly straightforward approach. During the course of the studies, we found that the cationic ruthenium complex, Cp*Ru(CH3CN)3PF6, could also be an efficient catalyst to promote the [2+2+2] regioselectivities to access highly substituted pyridine derivatives of high synthetic utility (Scheme 200).

Scheme 200

Taking advantage of the cationic Cp*Ru(CH3CN)3PF6 catalytic system, we also synthesized a family of aza-fluorenones and aza-fluorenols with high regioselectivities (Scheme 201).

Scheme 201

Finally, we focused on the enantioselective synthesis of substituted 1,3dihydroisobenzofurans, containing a quaternary carbon stereogenic center, through a [2+2+2] cycloaddition of prochiral triynes with internal alkynes using a cationic rhodium complex incorporating BINAP ligand. Moderate yields and enantioselectivities were obtained (Scheme 202). Further investigations of this method are underway in the laboratory.

Scheme 202

Experimental part

Experimental part Enantiomeric excesses were determined by SFC using stationary phase columns: Daicel

Chiralpak OD-H.

Mass spectrometry analyses (direct introduction by chemical ionization with ammoniac

or electrospray) were performed at the Ecole Nationale Supérieure de Chimie de Paris (ENSCP). High resolution mass spectra were performed at the University Pierre and Marie Curie (Paris).

X-ray diffraction was made at Pierre et Marie Curie University (UPMC).

Chromatography

Sigma-Aldrich Silica gel (high-purity grade, pore size 60 Å, 230-400 mesh particle size, 40-63 μm particle size) was employed for flash column chromatography. Analytical thin layer chromatography (TLC) was carried out using commercial silica-gel plates (Merck 60 F254), spots were detected with UV light (254 nm) and revealed with a KMnO4 or para-anisaldehyde stain solution.

Purification of solvents and reagents

All reactions were performed under an atmosphere of argon. Toluene, THF, CH2H2, DMF, Et2O were dried over alumina columns in an Innovative Technologies apparatus.

Acetone was distilled over K2CO3, and water was distilled. All the solvents for catalysis were degassed prior to use.

All reagents were used as received from commercial sources, unless specified otherwise, or prepared as described in the literature. Every reagent was either purified following the methods described in the literature or used without further purification.

Formation of fluorenone and related derivatives 2.1. Synthesis of benzoyl bridged -diynes

General procedure A:

PdCl2(PPh3)2 (2-5 mol %) and CuI (1-2.5 mol %) were added to a NEt3/THF (1:1, 5.0 M) solution containing aryl halide (1.0 equiv), alkyne (1.2-1.5 equiv). The mixture was stirred at 50 °C for 3-5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to room temperature. A saturated aqueous solution of ammonium chloride was added and the mixture was stirred for 5 minutes. The organic layer was extracted with ethyl acetate (×3), washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the desire compound.

General procedure B:

To a THF solution of alkyne (1.2 equiv, 5.0 M) was added nBuLi (1.3 equiv) at -70 °C.

The mixture was warmed to 0 °C and stirred for 1 h. The resulting mixture was then cooled to -70 °C again and a solution of aldehyde (1.0 equiv) in THF was added over 10 min. Then the mixture was warmed to room temperature and stirred for 2-3 h before addition of a saturated aqueous ammonium chloride solution. The organic layer was extracted with ethyl acetate (×3), washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the desired compound.

General procedure C:

Dess-Martin periodinane (1.3 equiv) was added to a solution of corresponding alcohol

(1 equiv) in anhydrous CH2Cl2 (5 M) at 0 °C and the resulting mixture was stirred at room temperature for 4-12 h. When the reaction was complete (TLC monitoring), the reaction mixture was filtered through a pad of celite. A saturated aqueous solution of NaHCO3 was added to the organic layer and stirred for 20 minutes. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the desired compound.

General procedure D:

TBAF (1 M in THF, 1.0 equiv) was added to a solution of TMS-protected product (1 equiv) in THF (5 M) at 0 °C and the resulting mixture was stirred at room temperature for 1 h.

The reaction was quenched with water and the product was extracted with DCM (×3). The organic layer washed with saturated aqueous solution of NaHCO3, water and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product.

2-(Phenylethynyl)benzaldehyde (1)

This compound was prepared using procedure A. 8, 135.9, 133.9, 133.3, 131.8, 129.2, 128.7, 128.6, 127.4, 127.0, 122.4, 96.4, 85.0.

2-(Hex-1-yn-1-yl)-benzaldehyde (2)

This compound was prepared using procedure A. Starting from 2-bromobenzaldehyde (2.5 g, 13.5 mmol) and 1-hexyne (2.0 mL, 17.5 mmol, 1. 3, 136.2, 133.8, 133.4, 128.1, 128.0, 127.0, 98.3, 76.5, 30.7, 22.2, 19.4, 13.7.

MS (CI, NH3

): m/z = 187 [M + H] + .

2-((Trimethylsilyl)ethynyl)benzaldehyde (3)

This compound was prepared using procedure A.

2-(p-Tolylethynyl)benzaldehyde (4)

This compound was prepared using procedure A. 13 C NMR (75 MHz, CDCl3), δ 191.9, 139.5, 136.0, 133.9, 133. 3, 131.7, 129.4, 128.5, 127.4, 119.4, 96.8, 84.5, 21.7.

MS (CI, NH3): m/z = 221 [M + H] + .

2-((4-(tert-Butyl)phenyl)-ethynyl)-benzaldehyde (5)

This compound was prepared using procedure A. 152.7, 136.0, 133.9, 133.3, 131.6, 130.2, 128.6, 127.3, 125.7, 119.5, 96.8, 84.5, 35.1, 31.3.

6-(Phenylethynyl)benzo[d][1,3]dioxole-5-carbaldehyde (6)

184 Alfonsi, 13 C NMR (75 MHz, CDCl3) δ 190. 1, 152.5, 148.9, 132.3, 131.7, 129.1, 128.7, 123.8, 122.5, 112.2, 106.3, 102.5, 95.3, 84.9.

MS (CI, NH3

): m/z = 251 [M + H] + .

5-Fluoro-2-(phenylethynyl)benzaldehyde (7)

This compound was prepared using procedure A. 132.5, 131.7, 128.9, 128.7, 128.5, 128.2, 126.7, 123.0, 121.4, 94.9, 87.7, 86.8, 79.4, 63.5, 30.7, 22.1, 18.7, 13.7.

1-(2-(Hex-1-yn-1-yl)-phenyl)hept-2-yn-1-ol (9)

This compound was prepared using procedure B. Starting from 2-(hex-1-yn-1-yl)benzaldehyde 2 (0.91 g, 4.9 mmol) and 1-hexyne (0.73 mL, 6. 13 C NMR (75 MHz, CDCl3) δ 142.9, 132. 6, 128.2, 128.1, 126.7, 122.3, 96.3, 87.6, 79.4, 78.1, 63.7, 30.9, 30.8, 22.2, 22.1, 19.4, 18.7, 13.7.

MS (CI, NH3

): m/z = 251 [M + H -H2O] + .

1-(2-(Hex-1-yn-1-yl)phenyl)-3-phenylprop-2-yn-1-ol (10)

This compound was prepared using procedure B. Starting from 2-(hex-1-yn-1-yl)benzaldehyde 2 (1 g, 5.4 mmol) and phenylacetylene (0.77 mL, 7.0 mmol, 1.3 equiv).

Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 10 (1.25 g, 81%) as a pale yellow oil.

Rf = 0.4 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV). 13 C NMR (75 MHz, CDCl3) δ 142. 3, 132.7, 131.9, 128.6, 128.4, 128.3, 128.3, 126.8, 122.8, 122.4, 96.7, 88.5, 86.6, 78.1, 64.1, 30.9, 22.2, 19.5, 13.8.

MS (CI, NH3

): m/z = 271 [M + H -H2O] + .

3-Cyclopropyl-1-(2-(phenylethynyl)phenyl)prop-2-yn-1-ol (11)

This compound was prepared using procedure B. Starting from 2-(phenylethynyl)benzaldehyde 8, 132.3, 131.5, 129.2, 128.7, 128.1, 126.6, 121.6, 119.9, 95.1, 87.5, 86.2, 79.5, 63.5, 30.7, 22.0, 21.6, 18.6, 13.6.

1 (1.

MS (CI, NH3

): m/z = 285 [M + H -H2O] + .

1-(2-((4-(tert-Butyl)phenyl)-ethynyl)-phenyl)-hept-2-yn-1-ol (14)

This compound was prepared using procedure B. Starting from 2-((4-(tert-butyl)-phenyl)ethynyl)-benzaldehyde 5 (0.92 g, 3.5 mmol) and 1-hexyne (0.52 mL, 4.5 mmol, 1.3 equiv).

Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 14

(1.0 g, 83%) as a pale oil.

Rf = 0.42 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV). Hz, 3H).

13 C NMR (75 MHz, CDCl3) δ 152. 1, 143.0, 132.5, 131.5, 128.8, 128.2, 126.8, 125.6, 121.8, 120.0, 95.2, 87.8, 86.2, 79.5, 63.7, 35.0, 31.3, 30.8, 22.1, 18.7, 13.7.

MS (CI, NH3

): m/z = 327 [M + H -H2O] + . 13 C NMR (75 MHz, CDCl3) δ 148.5, 147. 4, 138.6, 131.6, 128.5, 123.2, 114.9, 111.7, 107.6, 101.8, 93.4, 87.7, 86.8, 79.5, 63.2, 30.8, 22.1, 18.7, 13.7.

1-(6-(Phenylethynyl)benzo[d][1,3]dioxol-5-yl)hept-2-yn-1-ol (15)

MS (CI, NH3

): m/z = 315 [M + H -H2O] + .

1-(5-Fluoro-2-(phenylethynyl)phenyl)hept-2-yn-1-ol (16)

This compound was prepared using procedure B. Starting from 5-fluoro-2-(phenylethynyl)benzaldehyde 7 (0.9 g, 4.1 mmol) and 1-hexyne (0.6 mL, 5.2 mmol, 1.3 equiv).

Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 16

(1.16 g, 92%) as a colorless oil.

Rf = 0.35 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV). 8, 138.4, 134.3, 132.4, 132.0, 131.8, 128.7, 128.4, 127.9, 123.4, 122.9, 97.2, 95.2, 88.4, 80.8, 29.9, 22.2, 19.1, 13.6. 191 Tang, J.-M.; Liu, T.-A.; Liu, R.-S. J. Org. Chem. 2008, 73, 8479.

1-(2-(hex-1-yn-1-yl)phenyl)-hept-2-yn-1-one (18)

This compound was prepared using procedure C. 13 C NMR (75 MHz, CDCl3) δ 178. 1, 138.6, 134.7, 132.2, 131.7, 127.2, 123.8, 97.0, 96.7, 81.0, 79.3, 30.8, 30.0, 22.2, 19.8, 19.1, 13.8, 13.7.

MS (ESI, NH3

): m/z = 267 [M + H] + .

1-(2-(Hex-1-yn-1-yl)phenyl)-3-phenylprop-2-yn-1-one (19)

This compound was prepared using procedure C. 138.7, 134.7, 133.2, 132.4, 131.3, 130.8, 128.7, 127.3, 124.1, 120.6, 97.6, 93.2, 88.4, 79.2, 30.8, 22.2, 19.8, 13.7. 13 C NMR (75 MHz, CDCl3),  177. 6, 138.8, 134.3, 132.2, 132.0, 131.5, 128.7, 128.4, 128.0, 123.5, 122.9, 101.6, 95.3, 88.4, 10.0, 0.3.

3-cyclopropyl

MS (ESI, NH3

): m/z = 271 [M + H] + .

1-(2-((Trimethylsilyl)ethynyl)phenyl)hept-2-yn-1-one (21)

This compound was prepared using procedure C. .5, 139.0, 135.1, 132.1, 131.7, 128.2, 122.6, 103.3, 100.9, 96.8, 80.7, 29.9, 22.2, 19.1, 13.6, -0.1.

MS (ESI, NH3

): m/z = 283 [M + H] + .

1-(2-(p-Tolylethynyl)phenyl)hept-2-yn-1-one (22)

This compound was prepared using procedure C. 1 H NMR (300 MHz, CDCl3) δ 8.14 -8.06 (m, 1H), 7.68 -7.58 (m, 1H), 7.56 -7.46 (m, 3H), 7.45 -7.37 (m, 1H), 7.20 -7.13 (m, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.62 -1.52 (m, 2H), 1.50 -1.38 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

13 C NMR (75 MHz, CDCl3) δ 177.9, 138.9, 138.5, 134.3, 132.3, 132.0, 131.8, 129.2, 127.8, 123.3, 120.4, 97.2, 95.6, 87.9, 81.0, 29.9, 22.2, 21.7, 19.2, 13.6.

Martin periodinane (2.07 g, 4.9 mmol, 1.3 equiv). Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 24 (0.9 g, 77%) as a pale yellow oil.

Rf = 0.31 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 7.61 -7.56 (m, 3H), 7.36 -7.31 (m, 3H), 7.05 (s, 1H), 6.09 (s, 2H), 2.43 (t, J = 7.1 Hz, 2H), 1.63 -1.53 (m, 2H), 1.46 -1.37 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

13 C NMR (75 MHz, CDCl3) δ 176.0, 151. 1, 147.8, 133.9, 132.0, 128.6, 128.4, 123.6, 119.0, 113.6, 111.4, 102.5, 96.8, 94.3, 88.6, 80.8, 30.0, 22.2, 19.2, 13.6.

MS (ESI, NH3

): m/z = 331 [M + H] + .

1-(5-Fluoro-2-(phenylethynyl)phenyl)hept-2-yn-1-one (25)

This compound was prepared using procedure C. 4,161.8 (d,J = 249.8 Hz),140.4 (d,J = 6.8 Hz),136.2 (d,J = 7.5 Hz),132.0,128.8,128.5,123.3,119.8 (d,J = 21.8 Hz),119.1,118.4 (d,J = 23.3 Hz),,98.2,95.0,87.4,80.6,29.9,22.2,19.2,13.6.

MS (ESI, NH3

): m/z = 305 [M + H] + .

1-(2-((4-(Trifluoromethyl)phenyl)ethynyl)phenyl)hept-2-yn-1-one (26)

This compound was prepared using procedure A. .5,138.7,134.5,132.5,132.2,132.2,150.33 (d,128.6,127.3,125.9,125.4,125.4,122.3,122.2,97.3,93.3,90.8,80.7,29.9,22.2,19.1,13.6.

19 F NMR (282 MHz, CDCl3) δ -63.8 (s).

MS (ESI, NH3

): m/z = 355 [M + H] + .

1-(2-((4-Bromophenyl)-ethynyl)-phenyl)-hept-2-yn-1-one (27)

This compound was prepared using procedure A. 6, 138.5, 134.3, 133.5, 132.4, 132.1, 131.8, 128.2, 123.1, 122.6, 122.5, 97.2, 93.9, 89.6, 80.8, 29.9, 22.2, 19.1, 13.6.

MS (CI, NH3

): m/z = 365 [M + H] + .

1-(2-Ethynylphenyl)hept-2-yn-1-ol (28)

This compound was prepared using procedure D. 7, 133.3, 129.5, 128.2, 126.9, 120.5, 88.0, 82.6, 81.3, 79.3, 63.3, 30.8, 22.1, 18.7, 13.7.

MS (CI, NH3

): m/z = 212 [M + NH4 -H2O] + .

1-(2-ethynylphenyl)hept-2-yn-1-one (29)

This compound was prepared using procedure C. .5, 139.2, 135.5, 132.3, 131.8, 128.6, 121.7, 97.4, 82.9, 82.1, 80.8, 29.9, 22.2, 19.1, 13.6.

MS (CI, NH3

): m/z = 211 [M + H] + .

3-(Phenylethynyl)furan-2-carbaldehyde (30)

This compound was prepared using procedure A. 3, 152.9, 147.7, 131.9, 129.6, 128.7, 122.0, 119.8, 115.3, 97.6, 78.4.

MS (ESI, NH3

): m/z = 197 [M + H] + .

3-(Phenylethynyl)thiophene-2-carbaldehyde (31)

This compound was prepared using procedure A. Starting from 3-bromothiophene-2carbaldehyde (1.0 g, 5.23 mmol) and phenylacetylene (0.64 g, 6.28 mmol, 1.2 equiv).

Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 98/2 to 95/5) afforded 31 (0.92 g, 83%) as a brown oil. The analytical data were identical to the literature. 193 Rf = 0.4 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV). 13 C NMR (75 MHz, CDCl3) δ 183. 1, 143.7, 134.0, 131.9, 131.7, 131.1, 129.4, 128.7, 122.2, 96.2, 81.7.

MS (CI, NH3): m/z = 213 [M + H] + .
192 Sagar, P.; Fröhlich, R.; Würthwein, E.-U. Angew. Chem. Int. Ed. 2004, 43, 5694. 193 Okamoto, N.; Sakurai, K.; Ishikura, M.; Takeda, K.; Yanada, R. Tetrahedron Lett. 2009, 50, 4167.

3-(Phenylethynyl)benzo[b]-thiophene-2-carbaldehyde (32)

This compound was prepared using procedure A. Starting from 3-bromobenzo [b] 13 C NMR (75 MHz, CDCl3) δ 184. 6, 143.6, 141.3, 139.6, 132.1, 129.7, 129.0, 128.8, 127.9, 125.8, 125.2, 123.5, 122.1, 99.2, 80.7.

MS (ESI, NH3

): m/z = 263 [M + H] + .

2-(Phenylethynyl)benzofuran-3-carbaldehyde (33)

This compound was prepared using procedure A. Starting from 2-chlorobenzofuran-3carbaldehyde (0.9 g, 5 mmol), phenylacetylene (0.61 g, 6 mmol, 1.2 equiv), PdCl2(PPh3) 7, 154.8, 148.2, 132.3, 130.5, 128.9, 127.3, 125.4, 124.0, 123.5, 122.6, 120.6, 111.4, 101.1.

MS (ESI, NH3): m/z = 247 [M + H] + .

2-(Phenylethynyl)nicotinaldehyde (34)

This compound was prepared using procedure A. (dd, J = 1.8, 7.9 Hz, 1H), 7.66-7.59 (m, 2H), 7.43-7.37 (m, 4H).

13 C NMR (75 MHz,CDCl3)  190.9,154.6,146.1,134.9,132.3,131.9,130.0,128.7,123.3,121.3,96.2,84.7.

MS (CI, NH3): m/z = 208 [M + H] + .
195 Tiano, M.; Belmont, P. J. Org. Chem. 2008, 73, 4101. 196 Verma, A. K.; Rustagi, V.; Aggarwal, T.; Singh, A. P. J. Org. Chem. 2010, 75, 7691.

2-((4-(tert-Butyl)phenyl)ethynyl)nicotinaldehyde (35)

This compound was prepared using procedure A. (dd, J = 1.8, 7.9 Hz, 1H), 7. 58-7.56 (m, 2H), 7.42-7.35 (m, 3H), 1.32 (s, 9H).

13 C NMR (75 MHz,CDCl3)  191.0,154.6,153.5,146.4,134.9,132.1,131.8,125.7,123.1,118.3,96.7,84.3,35.1,31.2.

2-Chloro-5-(phenylethynyl)isonicotinaldehyde (36)

This compound was prepared using procedure A. 4, 154.6, 151.6, 142.8, 132.0, 130.0, 128.8, 121.5, 120.8, 120.4, 100.1, 81.1. 13 C NMR (75 MHz, CDCl3) δ 155. 3, 142.3, 131.6, 128.5, 123.2, 113.4, 105.0, 93.6, 87.9, 79.9, 57.2, 30.6, 22.1, 18.7, 13.7.

MS (CI

MS (ESI, NH3

): m/z = 261 [M + H -H2O] + .

1-(3-(Phenylethynyl)thiophen-2-yl)hept-2-yn-1-ol (38)

This compound was prepared using procedure B. 4, 131.7, 130.1, 128.6, 128.5, 124.7, 123.1, 120.2, 93.5, 87.6, 82.8, 79.2, 59.4, 30.6, 22.1, 18.6, 13.7. 1 H NMR (300 MHz, CDCl3) δ 8.02 -7.91 (m, 1H), 7.87 -7.79 (m, 1H), 7.65 -7.55 (m, 2H), 7.49 -7.33 (m, 5H), 6.25 -6.14 (m, 1H), 2.54 (d, J = 5.1 Hz, 1H), 2.29 (td, J = 7.0, 2.0 Hz, 2H), 1.52 -1.36 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H).

MS

13 C NMR (101 MHz, CDCl3) δ 149. 3, 139.6, 138.1, 131.8, 128.8, 128.6, 125.6, 125.0, 123.4, 123.0, 122.8, 115.9, 96.4, 88.3, 81.4, 78.8, 60.1, 30.6, 22.1, 18.7, 13.7.

MS (ESI, NH3

): m/z = 327 [M + H -H2O] + .

1-(2-(Phenylethynyl)benzofuran-3-yl)hept-2-yn-1-ol (40)

This compound was prepared using procedure B. 2, 131.9, 129.5, 128.7, 126.2, 125.7, 124.8, 123.4, 121.7, 121.3, 111.5, 98.7, 87.6, 78.6, 78.1, 57.5, 30.6, 22.1, 18.7, 13.7.

MS (ESI, NH3

): m/z = 311 [M + H -H2O] + . 2, 141.2, 139.6, 134.5, 132.1, 129.3, 128.5, 123.3, 122.1, 94.7, 90.8, 86.2, 74.3, 62.0, 8.6, 8.4, -0.4.

3-Cyclopropyl-1-(2-(phenylethynyl)pyridin-3-yl)prop-2-yn-1-ol (41)

1-(2-((4-(tert-Butyl)phenyl)ethynyl)pyridin-3-yl)hept-2-yn-1-ol (42)

This compound was prepared using procedure B. 8, 149.3, 141.5, 139.4, 134.5, 131.9, 125.5, 123.1, 119.0, 95.0, 88.1, 85.7, 78.9, 62.2, 35.0, 31.2, 30.6, 22.1, 18.6, 13.7.

1-(2-Chloro-5-(phenylethynyl)pyridin-4-yl)hept-2-yn-1-ol (43)

This compound was prepared using procedure B. 8, 152.5, 151.3, 131.8, 129.4, 128.7, 122.3, 121.3, 117.4, 98.9, 89.0, 82.7, 62.2, 30.5, 22.1, 18.6, 13.6.

MS (CI, NH3

): m/z = 324 [M + H] + .

1-(3-(Phenylethynyl)furan-2-yl)hept-2-yn-1-one (44)

This compound was prepared using procedure C. 13 C NMR (101 MHz, CDCl3) δ 164. 1, 152.7, 146.4, 131.9, 129.2, 128.6, 122.7, 116.4, 116.3, 98.0, 97.8, 80.8, 79.7, 29.8, 22.2, 19.2, 13.6. 1 H NMR (300 MHz, CDCl3) δ 7.63 -7.52 (m, 3H), 7.42 -7.31 (m, 3H), 7.28 -7.19 (m, 1H), 2.36 (t, J = 7.1 Hz, 2H), 1.52 -1.45 (m, 2H), 1.41 -1.28 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H).

MS

13 C NMR (75 MHz, CDCl3) δ 169.0, 144. 3, 133.3, 132.5, 131.9, 129.1, 128.6, 126.9, 123.0, 97.5, 96.3, 84.4, 80.3, 29.9, 22.2, 19.2, 13.6.

MS (CI, NH3): m/z = 293 [M + H] + .

1-(3-(Phenylethynyl)benzo[b]thiophen-2-yl)hept-2-yn-1-one (46)

This compound was prepared using procedure C. .5, 144.3, 140.7, 140.5, 132.0, 129.3, 128.7, 128.6, 125.6, 123.3, 122.9, 99.7, 98.8, 83.1, 80.6, 77.5, 77.2, 76.8, 29.9, 22.2, 19.4, 13.6.

MS (ESI, NH3

): m/z = 343 [M + H] + .

1-(2-(Phenylethynyl)benzofuran-3-yl)hept-2-yn-1-one (47)

This compound was prepared using procedure C. 7, 154.3, 144.3, 132.2, 130.2, 128.8, 127.0, 125.0, 124.9, 124.0, 123.1, 121.4, 111.2, 101.2, 96.4, 81.1, 79.6, 30.0, 22.2, 19.2, 13.6.

MS (ESI, NH3

): m/z = 327 [M + H] + .

3-Cyclopropyl-1-(2-(phenylethynyl)pyridin-3-yl)prop-2-yn-1-one (48)

This compound was prepared using procedure C. 4, 151.7, 140.8, 137.5, 134.0, 131.5, 128.5, 127.4, 121.3, 102.4, 94.2, 87.0, 9.2, -0.73.

1-(2-((4-(tert-Butyl)phenyl)ethynyl)pyridin-3-yl)hept-2-yn-1-one (49)

This compound was prepared using procedure C. 8, 138.4, 134.3, 132.4, 132.0, 131.8, 128.7, 128.4, 127.9, 123.4, 122.9, 97.2, 95.2, 88.4, 80.8, 29.8, 22.2, 19.1, 13.6.

1-(2-chloro-5-(phenylethynyl)pyridin-4-yl)hept-2-yn-1-one (50)

This compound was prepared using procedure C. 2, 154.7, 150.8, 146.4, 132.1, 129.5, 128.6, 124.3, 122.5, 117.2, 100.5, 98.9, 84.1, 80.2, 29.7, 22.2, 19.3, 13.6.

MS (CI, NH3): m/z = 322 [M + H] + .

Preparation of internal alkynes

1,4-Bis(benzyloxy)but-2-yne (56)

In an oven-dried argon-filled round bottom flask, sodium hydride (0.88 g, 22 mmol, 2.2 equiv) was dissolved in dry THF (20 mL). A THF solution (10 mL) of 2-butyne-1,4-diol 52 (0.86 g, 1.0 equiv) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. The solution was cooled to 0 °C and benzyl bromide (2.6 mL, 2.2 equiv) was added.

The resulting mixture was allowed to warm to room temperature for 48 h. When the reaction was complete (TLC monitoring), water (20 mL) was added and the residue was extracted with diethyl ether (2×40 mL). The organic layer was separated and washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. 13 C NMR (75 MHz, CDCl3) δ 83.5, 52.0, 26.0, 18.5, -5.0.

RuCl3•nH2O-catalyzed [2+2+2] cycloadditions for the formation of fluoreone and related derivatives

General procedure E:

A sealed tube was equipped with RuCl3•nH2O (5 mol%) and diyne (1 equiv), followed by the addition of alkyne (2 equiv) under argon atmosphere. The tube was sealed and the reaction mixture was stirred for the required time at 50-80 °C. When the reaction was complete (TLC monitoring), the crude reaction mixture was directly purified by flash chromatography over silica gel to afforded cycloadducts.

1-Butyl-2,3-bis(methoxymethyl)-4-phenyl-9H-fluoren-9-one (65)

This compound was obtained following the general procedure E. 3.51 (s, 3H), 3.29 -3.20 (m, 2H), 3.18 (s, 3H), 1.67 -1.49 (m, 4H), 1.02 (t, J = 6.9 Hz, 3H).

13 C NMR (75 MHz,CDCl3) δ 194.6,144.8,143.6,142.9,142.4,138.3,137.6,137.0,135.2,134.1,130.8,129.6,128.9,128.5,128.1,123.6,123.2,68.5,67.4,58.9,58.6,33.6,27.3,23.5,14 6.9 Hz, 3H), 0.98 (t, J = 6.9 Hz, 3H).

13 C NMR (75 MHz,CDCl3) δ 194.9,144.0,143.1,142.9,142.8,137.8,137.5,135.4,134.6,131.3,128.4,124.0,123.5,68.1,67.5,59.0,58.8,33.6,32.3,29.2,27.2,23.4,14.1.

MS (CI, NH3): m/z = 349 [M + H -MeOH] + .

4-Butyl-2,3-bis(methoxymethyl)-1-phenyl-9H-fluoren-9-one (67)

This compound was obtained following the general procedure E. 1 H NMR (300 MHz, CDCl3) δ 7.67 (dt, J = 7.7, 0.9 Hz, 1H), 7. 59 -7.48 (m, 2H), 7.49 -7.42 (m, 3H), 7.32 -7.24 (m, 3H), 4.64 (s, 2H), 4.18 (s, 2H), 3.55 (s, 3H), 3.22 (s, 3H), 3.13 -3.02 (m, 2H), 1.80 -1.57 (m, 4H), 1.09 (t, J = 7.1 Hz, 3H).

13 C NMR (75 MHz,CDCl3) δ 192.9,143.9,142.9,142.8,140.6,139.4,137.6,136.9,135.2,134.6,131.3,129.2,128.6,127.8,127.6,124.1,123.6,68.2,68.1,59.1,58.4,32.2,29.3,23.5,14.1.

MS (CI, NH3

): m/z = 401 [M + H] + .

1-Cyclopropyl-2,3-bis(methoxymethyl)-4-phenyl-9H-fluoren-9-one (68)

This compound was obtained following the general procedure E. Starting from diyne 20 (100 mg, 0.37 mmol), 4, 143.8, 143.4, 142.9, 142.6, 139.5, 138.1, 137.8, 135.1, 134.0, 133.2, 129.5, 128.8, 128.5, 128.1, 123.6, 123.1, 68.4, 68.2, 59.0, 58.7, 10.9, 8.4. 13 C NMR (75 MHz,CDCl3) δ 195.0,152.9,151.9,145.5,144.6,135.4,135.3,133.2,130.7,128.5,125.9,123.5,71.9,67.3,58.5,57.7,33.5,27.0,23.4,14.1,2.8. 13 C NMR (75 MHz,CDCl3) δ 194.7,144.6,143.8,143.0,142.6,137.8,137.6,137.1,135.1,134.1,130.7,129.6,129.4,128.4,123.6,123.3,68.5,67.4,58.9,58.5,33.6,27.3,23.5,21.5,14.1.

HRMS (ESI

HRMS (ESI

HRMS (ESI + ): calcd. for C28H30O3Na [M+Na] + : 437.2087, found 437.2087.

1-Butyl-4-(4-(tert-butyl)-phenyl)-2,3-bis(methoxymethyl)-9H-fluoren-9-one (71)

This compound was obtained following the general procedure E. (s, 3H), 3.29 -3.21 (m, 2H), 3.19 (s, 3H), 1.64 -1.52 (m, 4H), 1.43 (s, 9H), 1.02 (t, J = 6.9 Hz, 3H).

13 C NMR (75 MHz,CDCl3) δ 194.7,151.3,144.7,143.8,143.1,142.6,137.6,137.1,135.2,134.1,130.7,129.2,128.4,125.7,123.6,123.2,68.6,67.5,58.9,58.6 34.9,33.7,31.6,27.3,23.5,14.1. 13 C NMR (75 MHz,CDCl3) δ 194.3,145.4,143.2,142.7,142.3,142.1,137.9,135.5,135.2,134.3,130.9,130.3,128.9,125.8,125.8,124.0,122.9,68.4,67.3,59.0,58.7,33.7,27.4,23.5,14.1. 19 F NMR (282 MHz, CDCl3) δ -63.4 (s). 4H), 1.01 (t, J = 6.9 Hz, 3H).

HRMS (ESI

13 C NMR (75 MHz,CDCl3) δ 194.4,145.2,143.3,142.8,142.3,137.8,137.2,135.6,135.1,134.3,132.1,131.5,130.9,128.8,123.9,123.1,122.4,68.5,67.4,59.0,58.7,33.7,27.3,23.5,14.1. 4H), 1.00 (t, J = 6.9 Hz, 3H).

HRMS (ESI

13 C NMR (75 MHz,CDCl3) δ 193.0,152.4,147.9,144.2,142.0,140.6,138.0,137.0,136.0,131.2,130.1,129.6,128.9,128.2,104.6,104.5,101.9,68.5,67.4,58.9,58.6,33.7,27.2,23.5,14.1. 3.50 (s, 3H), 3.26 -3.18 (m, 2H), 3.18 (s, 3H), 1.66 -1.51 (m, 4H), 1.01 (t, J = 6.9 Hz, 3H).

HRMS (ESI

13 C NMR (75 MHz, CDCl3) δ 193. 1,163.2 (d,J = 247.5 Hz),145.2,142.8,142.4,139.4 (d,J = 2.8 Hz),138.1,137.5,137.4,136.7,131.0 (d,J = 1.6 Hz),129.5,129.0,128.3,124.6 (d,J = 7.7 Hz), 120.2 (d, J = 22.5 Hz), 111.1 (d,J = 23.6 Hz),68.5,67.4,59.0,58.6,33.6,27.4,23.5 1 H NMR (300 MHz, CDCl3), δ 7. 58 -7.52 (m, 1H), 7.56 -7.44 (m, 3H), 7.39 -7.29 (m, 2H), 7.11 (td, J = 7.5, 0.9 Hz, 1H), 7.02 (td, J = 7.5, 1.2 Hz, 1H), 5.89 (d, J = 7.5 Hz, 1H), 4.55 (s, 2H), 4.19 (s, 2H), 3.28 -3.15 (m, 2H), 1.72 -1.51 (m, 4H), 1.36 (s, 9H), 1.03 (t, J = 6.9 Hz, 3H), 1.01 (s, 9H).

13 C NMR (75 MHz,CDCl3),δ 194.8,145.1,143.9,143.3,142.8,138.4,138.3,137.3,135.2,134.0,130.7,129.9,128.7,128.3,128.0,123.5,123.1,73.7,73.6,57.9,56.8,33.7,27.9,27.6,27.5,23.7,14.1. 1 H NMR (300 MHz, CDCl3), δ 7. 58 -7.53 (m, 1H), 7.53 -7.46 (m, 3H), 7.40 -7.27 (m, 10H), 7.22 -7.17 (m, 2H), 7.13 (td, J = 7.5, 0.9 Hz, 1H), 7.04 (td, J = 7.5, 1.2 Hz, 1H), 5.93 (d, J = 7.5 Hz, 1H), 4.53 (s, 2H), 4.50 (s, 2H), 4.16 (s, 2H), 4.15 (s, 2H), 3.23 -3.12 (m, 2H), 1.57 -1.41 (m, 4H), 0.97 (t, J = 6.9 Hz, 3H).

HRMS (ESI

13 C NMR (75 MHz,CDCl3),δ 194.7,144.9,143.7,143.0,142.6,138.2,138.0,137.7,137.1,135.2,134.1,130.8,129.7,128.9,128.7,128.6,128.5,128.3,128.1,127.9,123.7,123.2,73.6,73.3,66.2,64.7,33.7,27.4,23.5,14 1 H NMR (300 MHz, CDCl3) δ 7. 57 -7.41 (m, 4H), 7.38 -7.27 (m, 2H), 7.12 -7.03 (m, 1H), 7.03 -6.92 (m, 1H), 5.73 (d, J = 7.5 Hz, 1H), 3.23 -3.05 (m, 2H), 2.73 (q, J = 7.5 Hz, 2H), 2.48 (q, J = 7.5 Hz, 2H), 1.66 -1.49 (m, 4H), 1.23 (t, J = 7.7 Hz, 3H), 1.10 -0.89 (m, 6H).

13 C NMR (75 MHz, CDCl3) δ 195. 1, 147.8, 144.2, 143.2, 142.8, 140.8, 139.6, 136.0, 135.3, 133.8, 129.5, 129.0, 128.9, 127.9, 127.8, 123.4, 122.6, 33.6, 27.6, 23.7, 23.6, 21.5, 15.8, 15.5, 14.1.

7-Butyl-5,6-bis(methoxymethyl)-4-phenyl-8H-indeno[2,1-b]furan-8-one (83)

This compound was obtained following the general procedure E. 4H), 0.99 (t, J = 7.0 Hz, 3H).

13 C NMR (75 MHz, CDCl3) δ 179. 6, 154.6, 151.3, 145.0, 144.6, 140.9, 138.2, 137.7, 135.1, 134.8, 131.6, 129.7, 128.4, 128.0, 108.0, 68.8, 67.4, 58.9, 58.5, 33.7, 26.7, 23.4, 14.1. 13 C NMR (75 MHz, CDCl3), δ 186. 6, 157.2, 144.6, 141.2, 139.3, 138.5, 138.1, 137.3, 134.8, 133.7, 129.8, 128.5, 128.0, 122.3, 68.8, 67.4, 58.9, 58.5, 33.7, 26.9, 23.5, 14.1.

HRMS (ESI

HRMS (ESI

2H), 1.52 -1.38 (m, 4H), 0.95 (t, J = 6.9 Hz, 3H).

13 C NMR (75 MHz, CDCl3), δ 186. 6, 157.2, 144.6, 141.5, 139.3, 138.5, 138.0, 137.4, 137.3, 134.9, 133.7, 129.8, 128.6, 128.6, 128.5, 128.3, 128.1, 128.0, 127.9, 122.3, 73.5, 73.2, 66.4, 64.7, 33.7, 26.9, 23.4, 14.0. 13 C NMR (75 MHz, CDCl3) δ 188. 4, 151.6, 147.4, 144.6, 142.1, 141.3, 140.2, 139.9, 137.4, 135.0, 133.2, 132.6, 131.2, 128.7, 128.4, 126.6, 126.3, 125.1, 124.0, 68.9, 67.4, 59.0, 58.6, 33.6, 27.0, 23.5, 14.0. 2H), 1.68 -1.51 (m, 4H), 1.02 (t, J = 6.9 Hz, 3H).

HRMS (ESI

HRMS (ESI

13 C NMR (75 MHz, CDCl3) δ 186. 3, 177.5, 160.7, 144.3, 140.8, 140.3, 136.7, 134.2, 133.0, 129.8, 128.2, 128.1, 125.1, 124.8, 122.2, 120.7, 119.6, 112.7, 68.5, 67.4, 59.0, 58.5, 33.7, 27.0, 23.5, 14.1. (s, 3H), 1.60 -1.52 (m, 4H), 1.01 (t, J = 6.9 Hz, 3H).

6-Butyl

13 C NMR (75 MHz,CDCl3) δ 191.9,151.7,146.4,144.2,143.7,141.5,138.8,137.8,137.6,136.0,130.3,129.4,129.1,128.9,128.8,118.1,67.3,59.1,58.7,33.5,27.6,23.5,14.0. 13 C NMR (75 MHz,CDCl3) δ 194.5,149.6,144.2,144.1,142.6,138.9,136.0,133.8,129.7,129.1,128.3,127.9,125.3,123.5,123.1,33.1,31.5,22.9,14.1,12.5,10.2. Minor product: 2, 143.9, 143.4, 140.2, 139.4, 135.8, 135.2, 134.0, 133.3, 131.1, 129.1 128.8, 128.6, 128.2, 128.0, 123.7, 122.7, 32.6, 27.0, 23.5, 14.0, 12.5, 7.8. Major product: 1 H NMR (300 MHz, CDCl3)  7.66-7.58 (m, 1H), 7.34-7.30 (m, 3H), 7.20-7.05 (m, 10H), 6.22 -6.13 (m, 1H), 3.15 (t, J = 7.8 Hz, 2H), 1.75-1.65 (m, 2H), 1.55-1.46 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

HRMS (ESI

HRMS (ESI

13 C NMR (75 MHz,CDCl3)  194.7,148.0,144.1,143.8,143.1,140.4,138.3,135.3,134.6,134.1,132.8,130.4,130.0,129.6,128.6,128.5,127.8,127.7,127.1,123.6,123.3,33.1,31.2,23.0, 14.1.

Minor product: 194.9, 144.2, 143.7, 142.2, 141.2, 140.4, 139.7, 137.9, 135.7, 135.1, 134.1, 131.4, 129.4, 129.1, 129.0 128.8, 128.3, 128.1, 127.4, 123.8, 123.0, 33.3, 27.7, 23.1,13.8. Major product: 1 H NMR (300 MHz, CDCl3)  7. 57-7.50 (m, 4H), 7.30-7.27 (m, 2H), 7.19 -7.11 (m, 1H), 7.05 (dd, J = 7.5, 1.4 Hz, 1H), 7.01 (s, 1H), 5.95-5.92 (m, 1H), 3.40 (t, J = 6.6

HRMS (ESI

Hz, 2H), 3.08 (t, J = 7.7 Hz, 2H), 2.57-2.52 (m, 2H), 1.91-1.86 (m, 2H), 1.68-1.64 (m, 2H), 1.52-1.46 (m, 2H), 0.99 (t, J = 7.7 Hz, 3H).

13 C NMR (75 MHz,CDCl3)  194.7,146.3,144.1,144.0,143.1,138.2,135.4,135.2,134.0,131.6,129.4,129.3,129.0,128.4,128.2,123.6,123.0,44.4,33.6,33.1,31.2,30.6,22.9, 14.1.

Minor product 195.0, 143.8, 142.6, 140.9, 140.3, 139.9, 137.2, 136.0, 135.0, 134.7, 134.1, 131.5, 129.1, 128.8, 128.1, 123.8, 122.8, 44.6, 34.0, 33.3, 29.1, 26.9, 23.5, 14.1. 13 C NMR (75 MHz,CDCl3),δ 194.3,145.4,143.6,142.7,139.9,137.8,137.5,135.4,134.1,131.2,129.8,129.3,128.5,123.8,122.8,73.9,73.3,32.2,29.0,23.2,14.1.

HRMS (ESI

HRMS (ESI + ): calculated for C25H22O2Na + [M+Na + ]: 377.1512, found 377.1515.

1-Butyl-2,3-bis(hydroxymethyl)-4-phenyl-9H-fluoren-9-one (95).

To a solution of 76 (100 mg, 0.21 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL, large excess amount). The reacton mixture was stirred at room temperature for 36 h. When the reaction was complete (TLC monitoring), CH2Cl2 and the excess of trifluoroacetic acid were evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) to afford compound 95 (60 mg, 75%) as a yellow solid. m.p. 166 -168 °C.

Rf = 0.28 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3), δ 7.66 -7.60 (m, 1H), 7.58 -7.51 (m, 3H), 7.34 -7.27 (m, 2H), 7.22 (td, J = 7.5, 0.9 Hz, 1H), 7.11 (td, J = 7.5, 1.2 Hz, 1H), 5.96 (d, J = 7.5 Hz, 1H), 5.57 (s, 2H), 5.22 (s, 2H), 3.33 -3.22 (m, 2H), 1.63 -1.52 (m, 4H), 1.01 (t, J = 6.9 Hz, 3H).

13 C NMR (75 MHz,CDCl3),δ 193.7,145.4,144.9,142.7,138.2,138.0,136.5,134.9,134.7,133.1,132.1,129.6,129.6,129.2,124.2,123.6,63.7,62.7,33.8,27.4,23.4,13.9.

HRMS (ESI + ): calculated for C25H24O3Na + [M+Na + ]: 395.1618, found 395.1619.

2,3-Bis(bromomethyl)-1-butyl-4-phenyl-9H-fluoren-9-one (96)

To a solution of 76 (480 mg, 1.0 mmol) in CHCl3 (10 mL) were added nBu4NBr (0.16 g, 0.5 mmol), aq. HBr (48% in water, 3 mL) and conc. H2SO4 (0.3 mL). The resulting mixture was heated at 60 °C for 24 h. At the end of the reaction (TLC monitoring), the reaction mixture was poured into water (50 mL). The product was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Petroleum ether/Dichloromethane = 2/1) to afford compound 96 (444 mg, 90%) as a yellow solid. m.p.

132 -133 °C.

Rf = 0.52 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 7.62 -7.50 (m, 4H), 7.48 -7.35 (m, 2H), 7.17 (td, J = 7.5, 0.9 Hz, 1H), 7.07 (td, J = 7.6, 1.3 Hz, 1H), 5.88 (d, J = 7.5 Hz, 1H), 4.79 (s, 2H), 4.42 (s, 2H), 3.37 -3.13 (m, 2H), 1.75 -1.50 (m, 4H), 1.04 (t, J = 7.0 Hz, 3H).

13 C NMR (75 MHz,CDCl3) δ 194.0,144.5,143.8,143.1,142.1,137.0,136.9,136.8,135.0,134.4,131.2,129.4,129.3,129.1,128.9,123.9,123.4,33.3,27.5,27.3,26.3,23.5,14.0.

HRMS (ESI + ): calcd. for C25H22Br2OH [M+H] + : 497.0110, found 497.0109.

1-Butyl-4-iodo-2,3-bis(methoxymethyl)-9H-fluoren-9-one (97)

To a solution of 69 (0.56 g, 1.41 mmol) in CH2Cl2 (10 mL) was added a solution of iodine monochloride (240 mg, 1.5 mmol) in DCM (2 mL) at -78 °C and the mixture was allowed to warm to room temperature and stirred for additional 30 minutes. The reaction was quenched with aqueous saturated Na2S2O3 and extracted with CH2Cl2 (3×30 mL). The organic layer was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure.

The residue was purified by flash chromatography on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) to afford compound 97 (0.53 g, 84%) as a yellow solid. m. (s, 3H), 3.18 (t, J = 7.5 Hz, 2H), 1.55 -1.44 (m, 4H), 0.98 (t, J = 6.8 Hz, 3H).

13 C NMR (101 MHz, CDCl3) δ 193. 3, 147.8, 146.5, 145.3, 144.2, 138.9, 135.1, 133.8, 133.1, 129.6, 124.1, 122.9, 95.8, 75.2, 67.8, 59.0, 58.9, 33.5, 27.0, 23.4, 14.0. Hz, 2H), 1.68 -1.40 (m, 4H), 0.99 (t, J = 6.9 Hz, 3H).

HRMS (ESI

13 C NMR (75 MHz,CDCl3) δ 193.9,145.9,145.3,143.3,138.1,134.9,134.7,131.6,131.0,129.4,129.1,128.8,123.9,123.2,123.1,116.9,97.8,86.2,69.5,67.1,59.0,58.8,33.6,27.4,23.5,14.1. 13 C NMR (75 MHz,CDCl3) δ 194.9,150.5,148.7,145.2,144.9,135.2,135.0,134.0,129.8,128.8,123.7,122.7,84.1,71.2,66.7,58.3,57.5,33.6,27.0,25.9,23.3,14.1. 3.49 (s, 3H), 3.31 -3.18 (m, 2H), 3.17 (s, 3H), 1.66 -1.45 (m, 4H), 1.42 (s, 12H), 1.01 (t, J = 6.6 Hz, 3H).

HRMS (ESI

1-Butyl

13 C NMR (75 MHz, CDCl3) δ 194. 6, 144.9, 143.5, 142.7, 142.2, 141.3, 137.7, 136.9, 135.2, 135.1, 134.3, 130.8, 129.0, 128.5, 123.6, 123.4, 84.2, 68.5, 67.4, 58.9, 58.6, 33.6, 27.3, 25.1, 23.5, 14.1.

MS (ESI, NH3

): m/z = 549 [M + Na] + .

Formation of 2-aminopyridine and related derivatives

Synthesis of symmetrical diynes

General procedure F:

To a suspension of NaH (60% in mineral oil, 1.1-2.4 equiv) in THF was added dropwise a solution of nucleophile (1.0 equiv) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. A solution of 1-bromo-2-butyne or propargyl bromide (1.2 or 2.4 equiv) in THF was added to the mixture. The reaction was allowed to warm up to room temperature and stirred until completion. The mixture was finally quenched with saturated ammonium chloride and extracted with diethyl ether (×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography or distillation under vacuum to afford the desired product.

General procedure G:

To a round bottom flask p-toluenesulfonamide (1 equiv), 1-bromo-2-butyne or propargyl bromide (3.0 equiv), potassium carbonate (5 equiv) and acetonitrile (5 M) were employed. The resulting mixture was stirred at 80 °C for 14 h. When the reaction was complete (TLC monitoring), the reaction mixture was filtered, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product.

General procedure H:

Silver nitrate (10 mol%) and N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS)

(1.2-2 equiv) were added to a solution of terminal alkyne (1 equiv) in dry acetone or DMF, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with Et2O and washed with water. The aqueous phase was extracted with Et2O (×3), the combined organic fractions were washed with water, saturated Na2S2O3 aqueous solution and brine. The solvent was dried over MgSO4, filtered and concentrated under reduced pressure.

The residue was purified by flash chromatography to afford the desired compound.

Dimethyl 2,2-di(but-2-yn-1-yl)malonate (101)

This compound was obtained following the general procedure F. Starting from dimethyl malonate (4.01 g, 30 mmol), 1-bromo-2-butyne (5.84 mL, 66 mmol, 2.2 equiv) and NaH (2.64 g, 66 mmol). The reaction mixture was stirred at room temperature for 14 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 101 (6.15 g, 87 %) as a white solid. The analytical data were identical to the literature. 154 Rf = 0.51 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 3.73 (s, 6H), 2.88 (q, J = 2.7 Hz, 4H), 2.05 (t, J = 2.7 Hz, 6H). 3, 151.4, 80.0, 72.4, 56.6, 28.8, 28.3, 3.4. 13 C NMR (75 MHz, CDCl3) δ 201.9, 142. 8, 135.6, 123.2, 79.5, 73.1, 56.6, 23.5, 3.2.

MS (CI

2,2-Di(but-2-yn-1-yl)propane-1,3-diol (104)

To a stirred mixture of LiAlH4 (2.89 g, 76.2 mmol, 6 equiv) in dry THF (50 mL) at 0 °C was added dropwise a solution of dimethyl 2,2-di(but-2-ynyl)malonate 101 (3.0 g, 12.7 mmol, 1 equiv) in THF (20 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched carefully with water (2.9 mL), followed by stirring at 0 °C for 10 min. Then a solution of NaOH (15%, 2.9 mL) was added and stirred for additional 10 min, followed by addition of water (8.7 mL) and stirred for additional 1 h. The resulting solution was dried over MgSO4, filtered through Celite, and concentrated to give the diol 104 (2.05 g, 95%) as a white solid. m.p. 85-87 °C. The analytical data were identical to the literature. 34 Rf = 0.1 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 3.68 (s, 4H), 2.46 (br, 2H), 2.24 (q, J = 2.4 Hz, 4H), 1.78 (s, 6H).

13 C NMR (75 MHz, CDCl3) δ 78.5, 75. 2, 67.1, 42.5, 22.5, 3.6.

2,2-Di(but-2-yn-1-yl)propane-1,3-diyl diacetate (105)
To a solution of diol 104 (0.72 g, 4 mmol) in DCM (20 mL) at 0 °C was added dropwise acetic anhydride (1.63 g, 16 mmol, 4 equiv) and diisopropylethylamine (2.27 g, 17.6 mmol, 4.4 equiv). The reaction mixture was stirred at room temperature for 24 h and then quenched with water. The aqueous layer was extracted with Et2O (2×50 mL), and the combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure.

The residue was purified by flash chromatography on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 105 (0.98 g, 92%) as a colorless oil. The analytical data were identical to the literature. 145b Rf = 0.48 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 4.07 (s, 4H), 2.30 (q, J = 2.6 Hz, 4H), 2.05 (s, 6H), 1.76 (t, J = 2.6 Hz, 6H).

13 C NMR (75 MHz, CDCl3) δ 170.9, 78. 8, 73.8, 65.6, 40.4, 22.6, 21.0, 3.7.

(((2,2-Di(but-2-yn-1-yl)propane-1,3-diyl)bis(oxy))bis(methylene))dibenzene (106)

To a suspension of NaH (60% in mineral oil, 2.5 equiv, 2.14 g) in THF (20 mL) was added dropwise diol 104 (0.9 g, 5 mmol) in THF (5 mL). The reaction mixture was stirred at 0 °C for 30 minutes before a solution of benzyl bromide (2.14 g, 12.5 mmol, 2.5 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 12 h and then quenched with water. The aqueous layer was extracted with Et2O (2×50 mL), and the combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 106 (1.8 g, 99%) as a colorless oil. The analytical data were identical to the literature. 145b Rf = 0.45 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV). 13 C NMR (75 MHz, CDCl3) δ 139.0, 128. 3, 127.5, 127.4, 75.6, 73.4, 71.7, 42.6, 22.5, 3.7.

1-(But-2-yn-1-yloxy)but-2-yne (107)

This compound was obtained following the general procedure F. Starting from 2-butyne-1-ol (1.05 g, 15 mmol), 1-bromo-2-butyne (1.6 mL, 18 mmol, 1.2 equiv) and NaH (1.32 g, 33 mmol, 2.2 equiv). The reaction mixture was stirred at room temperature for 4 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 99/1 to 80/20) afforded 107 (1.75 g, 96 %) as a colorless oil. The analytical data were identical to the literature. 154 Rf = 0.5 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 4.18 (q, J = 2.3 Hz, 4H), 1.85 (t, J = 2.3 Hz, 6H).

13 C NMR (75 MHz, CDCl3) δ 83.0, 74.7, 57.1, 3.7.

N,N-di(but-2-yn-1-yl)-4-methylbenzenesulfonamide (108)

This compound was obtained following the general procedure G. 4, 143.3, 129.2, 128.0, 81.7, 71.8, 36.8, 21.6, 3.5. 4, 79.9, 71.5, 66.0, 35.2, 23.9, 22.8.

4-Methyl-N,N-di(prop-2-yn-1-yl)benzenesulfonamide (122)

This compound was obtained following the general procedure G. 4, 56.5, 53.4, 42.3, 24.2.

MS (CI, NH3

): m/z = 384 [M + NH4] + .

Synthesis of unsymmetrical diynes

General procedure I:

To a solution of alcohol (1.0 equiv) in DMSO (1 M) was slowly added an aqueous solution of potassium hydroxide (1 M, 1.3 equiv) at 0 °C. After 10 mins, a solution of propargyl bromide (1.0 equiv) was added dorpwise. The reaction mixture was stirred at room temperature for 4 h.

The reaction was quenched with water, and the aqueous layer was extracted with Et2O (×3).

The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the desired compound. .5, 79.4, 78.8, 73.0, 71.6, 57.0, 53.1, 23.2, 22.9, 3.6.

1-(Prop-2-yn-1-yloxy)but-2-yne (127)

This compound was obtained following the general procedure I. 3, 79.3, 74.8, 74.3, 57.3, 56.4, 3.7. 4, 79.5, 74.8, 72.9, 56.9, 53.2, 41.7, 24.1, 23.3, 3.6.

1-((3-Bromoprop-2-yn-1-yl)oxy)but-2-yne (130)

This compound was obtained following the general procedure H. .5, 75.9, 74.3, 57.5, 57.4, 46.4, 3.7.

1-Bromo-3-(prop-2-yn-1-yloxy)prop-1-yne (131)

This compound was obtained following the general procedure I. 8, 75.5, 75.3, 57.6, 56.8, 46.9.

N-(3-bromoprop-2-yn-1-yl)-N-(but-2-yn-1-yl)-4-methylbenzenesulfonamide (132)

This compound was obtained following the general procedure H. 9, 135.3, 129.6, 128.1, 82.3, 73.0, 71.5, 45.2, 37.4, 37.2, 21.7, 3.5. Rf = 0.34 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

MS (CI

1 H NMR (300 MHz, CDCl3) δ 3.75 (s, 6H), 3.13 (s, 2H), 2.90 (q, J = 2.5 Hz, 2H), 1.75 (t, J = 2.5 Hz, 3H).

13 C NMR (75 MHz, CDCl3) δ 169. 4, 88.9, 79.5, 77.4, 72.9, 57.2, 53.2, 25.1, 23.3, 3.6. 2, 83.2, 76.5, 74.4, 67.6, 63.2, 57.2, 56.8, 46.8, 3.7. 13 C NMR (75 MHz, CDCl3) δ 169. 3, 127.1, 117.0, 84.3, 82.6, 78.6, 71.8, 56.9, 53.2, 23.7, 22.9. 6, 150.0, 136.1, 127.4, 122.8, 84.8, 83.3, 79.6, 73.0, 57.1, 53.2, 23.7, 23.5, 3.6.

3-(3-(But

MS

MS

4-(But-2-yn-1-yloxy)but-1-yne (138)

This compound was obtained following the general procedure F. 7, 77.0, 75.7, 74.6, 68.7, 58.3, 20.1, 3.6.

5-((3-Bromoprop-2-yn-1-yl)oxy)pent-2-yne (141)

This compound was obtained following the general procedure H. 1 H NMR (300 MHz, CDCl3) δ 4.19 (s, 2H), 3.57 (t, J = 6.9 Hz, 2H), 2.41 (ddt, J = 6.9, 4.4, 2.5 Hz, 2H), 1.76 (t, J = 2.6 Hz, 3H).

13 C NMR (75 MHz, CDCl3) δ 77.0, 76. 2, 75.6, 68.8, 59.2, 46.2, 20.0, 3.6.

5-(But-2-yn-1-yloxy)pent-1-yne (142)

This compound was obtained following the general procedure F. 4, 75.3, 68.5, 68.4, 58.8, 28.6, 15.4, 3.7. 6, 138.1, 132.7, 126.5, 113.9, 111.6, 85.9, 84.35, 81.76, 76.6, 76.1, 55.4, 54.5, 49.7, 47.8, 43.6, 39.4, 37.4, 34.3, 30.0, 27.4, 26.7, 22.9, 13.0, 3.9. .5, 126.8, 117.1, 86.0, 81.3, 52.9, 51.2, 19.5. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 98/2 to 95/5) afforded 150

(

MS

MS (CI

(2.1 g, 57%) as an orange oil.

1 H NMR (300 MHz, CDCl3) δ 10.48 (d,J = 0.6 Hz,1H),1H),2H),1H),1H), 0.98 -0.85 (m, 4H).

13 C NMR (75 MHz,CDCl3) δ 192.2,136.2,133.8,133.4,128.0,127.9,127.1,101.4,71.6,9.0, 0.5. 13 C NMR (75 MHz, CDCl3) δ 142. 1, 132.6, 128.3, 128.2, 126.8, 122.4, 104.5, 99.6, 91.4, 73.1, 63.9, 9.0, 8.9, 0.5, -0.01. 8, 132.7, 128.4, 128.2, 126.6, 122.2, 99.8, 83.1, 74.6, 73.0, 63.3, 9.0, 0.5. This compound was obtained following the general procedure C. 1H),2H),1H),3.41 (d,J = 0.3 Hz,1H),J = 6.6 Hz,1H), 0.91 (d,J = 6.6 Hz,4H).

MS (CI

13 C NMR (75 MHz,CDCl3) δ 175.7,136.3,133.6,131.9,131.2,126.2,123.2,99.9,80.3,79.6,73.6,8.0, -0.1.

MS (CI, NH3

): m/z = 195 [M + H] + .

Synthesis of cyanamides

General procedure J:

N-substituted amine (2 equiv) was added to a solution of cyanogen bromide (1 equiv) in Et2O/THF (1:1, 5 M) at 0 °C. The reaction mixture was stirred at room temperature for 3 h.

Hexane (5 mL) was added, and the mixture was stirred for an additional 10 min. It was then filtered through a pad of Celite, and the filtrate was washed with water (×3) and brine (×3).

The solution was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the desired product.

General procedure K:

A solution of sodium hydrogen carbonate (2 equiv) in H2O (2 M) was slowly added to a solution of N-substituted amine (1 equiv) in DCM (1 M) at 0 °C. Then, a solution of cyanogen bromide (1.05 equiv) in DCM (1 M) was added to the reaction mixture at 0 °C. The mixture was stirred at the same temperature for 30 min, and then allowed to warm to room temperature for an additional 2 h. The organic layers were separated and washed with saturated sodium hydrogen carbonate solution (×3) and brine (×3), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the desired product.

Piperidine-1-carbonitrile (157)

This compound was obtained following the general procedure J. .5, 129.1, 128.8, 128.5, 119.0, 57.3, 37.9. 203 .5, 129.0, 128.8, 128.7, 118.4, 54.4.

N,N-Dipropylcyanamide (161)

This compound was obtained following the general procedure J. Starting from dipropylamine (3 mL, 20 mmol, 2 equiv) and cyanogen bromide (1.06 g, 10 mmol, 1 equiv). The reaction provided the compound 161 (1.13 g, 90 %) as a colorless oil, pure enough to be used without purification. The analytical data were identical to the literature. 135a Rf = 0.6 (Cyclohexane/Ethyl acetate; 80/20, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 2.91 (t, J = 7.2 Hz, 4H), 1.69 -1.53 (m, 4H), 0.93 (t, J = 7.4

Hz, 6H).

13 C NMR (75 MHz, CDCl3) δ 117.9, 53. 3, 21.1, 11.1.

N-Methyl-N-phenylcyanamide (162)

This compound was obtained following the general procedure J. .5, 129.7, 123.5, 115.0, 114.2, 36.9.

N-Butylcyanamide (163)

This compound was obtained following the general procedure J. Starting from N-butylamine

(2.93 g, 40.0 mmol, 2 equiv) and cyanogen bromide (2.12 g, 20 mmol, 1 equiv). The reaction provided the compound 163 (1.9 g, 96 %) as a colorless oil, pure enough to be used without purification. The analytical data were identical to the literature.205 Rf = 0.2 (Cyclohexane/Ethyl acetate; 80/20, KMnO4, UV). 13 C NMR (75 MHz, CDCl3) δ 116. 4, 46.1, 31.8, 19.6, 13.7.

N-butyl-N-methylcyanamide (164)

This compound was obtained following the general procedure K. 8, 52.8, 38.9, 29.4, 19.8, 13.7.

N-butyl-N-cyanoacetamide (165)

To a suspension of NaH (0.77 g, 19. 4, 111.1, 46.1, 29.7, 22.3, 19.6, 13.6.

N,N-diallylcyanamide (166)

This compound was obtained following the general procedure K. 1 H NMR (300 MHz, CDCl3) δ 5.90 -5.75 (m, 2H), 5.41 -5.32 (m, 2H), 5.32 -5.24 (m, 2H), 3,65 -3,54 (m, 4H).

13 C NMR (75 MHz, CDCl3) δ 131. 1, 120.6, 117.7, 53.5.

4-Methylpiperazine-1-carbonitrile (167)

This compound was obtained following the general procedure K. Starting from N-methyl piperazine (2 g, 20 mmol, 1 equiv), cyanogen bromide (2.22 g, 21 mmol, 1.05 equiv) and sodium hydrogen carbonate (3.3 g, 4 mmol, 2 equiv). The reaction provided the compound 167

(1.45 g, 58 %) as a pale yellow oil, pure enough to be used without purification.

Rf = 0.24 (EA, KMnO4, UV).

Ruthenium-catalyzed [2+2+2] cycloaddition of-diynes with cyanamides

General procedure L:

A sealed tube was equipped with RuCl3•nH2O (5 mol %) and -diyne (1 mmol, 1 equiv), followed by the addition of cyanamide (2.0 mmol, 2.0 equiv) under argon atmosphere.

The tube was sealed and the reaction mixture was stirred vigorously at 80 °C or 110 °C. When the reaction was complete (TLC monitoring), the crude reaction mixture was directly purified by flash chromatography over silica gel to afford cycloadduct. In some cases, the excess of cyanamide was removed by bulb to bulb distillation.

General procedure M:

A sealed tube was equipped with Cp*Ru(CH3CN)3]PF6 (1-5 mol %) and diyne (1 equiv), followed by the addition of cyanamide (2 equiv) under argon atmosphere. The reaction mixture was stirred vigorously at room temperature or 50 °C. When the reaction was complete (TLC monitoring), the crude mixture was directly purified by flash chromatography over silica gel to afford cycloadduct. In some cases, the excess of cyanamide was removed by bulb to bulb distillation.

General procedure N: 2, 161.6, 150.3, 147.9, 127.2, 117.1, 59.9, 53.2, 42.5, 40.1, 38.7, 21.8, 14.9. 13 C NMR (75 MHz, CDCl3) δ 172. 1, 160.2, 150.5, 148.5, 128.3, 117.9, 67.4, 59.9, 53.2, 50.8, 40.0, 38.7, 21.7, 14.4. 3, 158.9, 150.3, 147.4, 124.6, 113.5, 60.0, 53.1, 50.3, 40.1, 38.6, 25.6, 21.7, 15.8. 2, 161.7, 150.1, 148.1, 127.5, 118.1, 59.8, 53.2, 51.6, 40.01, 38.7, 26.5, 24.8, 21.7, 14.4. 2, 161.4, 150.4, 148.1, 140.0, 128.4, 128.2, 127.7, 126.8, 117.8, 59.9, 58.4, 53.2, 40.1, 39.8, 38.8, 21.7, 14.8. 2, 159.9, 150.4, 148.2, 139.9, 128.6, 128.3, 128.2, 126.7, 118.9, 59.7, 55.4, 53.2, 40.1, 38.8, 21.6, 14.5. 2, 160.7, 151.4, 150.6, 148.3, 127.3, 117.8, 67.4, 55.8, 50.8, 44.0, 42.6, 29.3, 21.8, 14.5. 9, 160.6, 151.3, 148.4, 141.7, 136.2, 128.9, 123.9, 118.0, 67.4, 58.5, 50.8, 39.6, 21.8, 14.5. 8, 152.4, 149.1, 130.0, 118.6, 69.5, 67.4, 50.8, 48.7, 37.9, 36.6, 21.7, 14.4. 13 C NMR (75 MHz, CDCl3) δ 171. 1, 160.1, 151.4, 149.1, 129.2, 118.4, 67.4, 66.9, 50.8, 46.2, 38.1, 36.8, 21.7, 21.0, 14.4. 7, 152.9, 148.9, 138.8, 130.7, 128.5, 127.6, 118.5, 73.7, 73.4, 67.5, 50.9, 48.1, 38.5, 37.1, 21.7, 14.4. The analytical data were identical to the literature. 143 Rf = 0.13 (Petroleum ether/Ethyl acetate; 90/10, KMnO4, UV).

R 1 X R 2 + N N X R 1 R 2 N N R 4 R 3 R 4 R 3

MS

MS

MS

MS

MS

MS (CI

MS (CI

MS (CI

MS

MS

MS

1 H NMR (300 MHz, CDCl3) δ 5.05 (s, 2H), 5.00 (s, 2H), 3.86 -3.81 (m, 4H), 3.12 -3.07 (m, 4H), 2.32 (s, 3H), 2.12 (s, 3H).

13 C NMR (75 MHz, CDCl3) δ 160.5, 150. 1, 146.2, 127.6, 115.1, 73.2, 72.7, 67.3, 50.7, 21.9, 14.6. 8, 147.7, 146.8, 144.0, 134.1, 130.1, 127.8, 124.8, 116.4, 67.3, 53.5, 52.6, 50.69, 21.7, 14.5. 8, 159.4, 151.7, 143.1, 126.3, 102.8, 66.9, 60.7, 53.2, 46.3, 40.6, 37.6. 7, 159.7, 149.9, 143.5, 124.0, 120.1, 102.6, 66.8, 54.1, 47.6, 46.0, 42.9, 40.6. .5, 159.6, 152.5, 143.0, 141.5, 136.1, 126.7, 123.8, 102.7, 66.9, 59.1, 46.3, 39.7, 38.4. 7, 156.5, 143.8, 130.6, 105.7, 67.8, 66.2, 51.6, 47.9, 38.8, 35.3. 3, 153.3, 143.8, 127.8, 103.7, 98.2, 68.7, 66.9, 46.4, 42.8, 40.2, 36.4, 24.7, 23.2. .5, 147.8, 144.0, 142.1, 133.8, 130.0, 127.7, 122.5, 100.5, 66.8, 53.5, 51.4, 46.0, 21.7. (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 5 min. 6, 154.6, 148.7, 142.2, 124.1, 100.8, 80.1, 66.9, 52.0, 49.8, 46.4, 28.7. 4, 151.6, 143.1, 138.7, 128.7, 127.2, 127.0, 124.6, 101.2, 60.6, 53.1, 51.3, 40.6, 37.6. 1, 157.3, 151.1, 143.2, 123.0, 100.8, 60.7, 53.1, 42.8, 40.6, 37.6, 13.1. 13 C NMR (75 MHz, CDCl3) δ 172. 1, 157.8, 151.0, 143.1, 122.9, 100.8, 60.7, 53.1, 51.0, 40.6, 37.6, 20.9, 11.6. 4, 151.2, 143.0, 123.3, 101.0, 60.8, 53.1, 50.4, 40.6, 37.5, 36.7, 29.6, 20.4, 14.2. 9, 158.5, 150.8, 147.3, 142.8, 129.8, 126.3, 125.7, 125.3, 104.8, 60.7, 53.1, 40.4, 38.9, 37.6. Rf = 0.17 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV). 158.7, 151.5, 143.1, 139.1, 128.6, 127.2, 126.9, 124.1, 101.1, 60.7, 53.7, 53.1, 40.6, 37.6, 36.5. 2, 146.7, 143.9, 139.6, 134.0, 130.0, 128.4, 128.1, 127.7, 127.0, 124.0, 116.0, 58.1, 53.4, 52.5, 39.8, 21.7, 14.8. 13 C NMR (75 MHz, CDCl3) δ 159.0, 155. 1, 154.0, 140.1, 120.4, 114.5, 73.4, 72.5, 67.1, 62.9, 50.4, 44.9, 14.4. 8, 158.8, 152.3, 147.9, 134.0, 124.1, 118.6, 102.3, 67.0, 60.3, 53.2, 46.1, 40.5, 37.7. 13 C NMR (75 MHz, CDCl3) δ 172.0, 158. 1, 152.1, 147.7, 139.4, 134.2, 128.6, 127.4, 126.9, 122.1, 118.2, 100.9, 60.3, 53.5, 53.2, 40.5, 37.6, 36.3. 3, 147.3, 144.0, 133.8, 133.6, 130.0, 127.6, 120.1, 119.7, 99.9, 66.8, 53.4, 51.5, 45.9, 21.6. 1 H NMR (300 MHz, CDCl3) δ 6.23 (s, 1H), 4.63 (s, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.85 -3.75 (m, 4H), 3.48 -3.35 (m, 4H), 2.76 (dt, J = 5.8, 2.9 Hz, 2H), 2.22 (s, 3H).

MS

MS

MS

HRMS (ESI

HRMS (ESI

HRMS (ESI

HRMS (ESI

HRMS (ESI

HRMS (ESI

MS

HRMS (ESI

HRMS (ESI

MS

HRMS (ESI

HRMS (ESI

MS

HRMS (ESI

MS

MS

13 C NMR (75 MHz, CDCl3) δ 158.0, 152.0, 144. 1, 119.1, 104.0, 67.0, 65.8, 64.6, 46.2, 28.9, 21.1. 9, 151.9, 143.4, 115.9, 103.1, 66.0, 64.7, 46.8, 28.9, 25.7, 21.1. 2, 151.7, 143.8, 139.4, 128.5, 127.4, 126.9, 116.7, 102.3, 65.9, 64.7, 53.0, 36.0, 29.0, 21.2. 4.06 (s, 2H), 3.86 -3.72 (m, 4H), 3.48 -3.35 (m, 4H), 3.30 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 5.7

HRMS (ESI

MS (CI

MS

Hz, 2H), 2.42 (s, 3H), 2.27 (s, 3H).

13 C NMR (75 MHz, CDCl3) δ 157.9, 153. 4, 143.9, 143.8, 133.6, 129.9, 127.8, 116.1, 103.7, 66.9, 46.0, 45.0, 43.0, 29.5, 21.7. 8, 157.6, 156.9, 149.0, 137.9, 132.4, 126.4, 124.8, 114.0, 111.6, 98.9, 98.3, 69.9, 67.0, 55.3, 49.9, 48.3, 46.6, 43.9, 39.3, 36.3, 33.6, 30.0, 27.7, 26.4, 23.7, 22.2, 15.5. 1 H NMR (400 MHz, CDCl3) δ 7.70 -7.61 (m, 1H, H1), 7.58-7.52 (m, 1H, H4), 7.49 -7.43 (m, 1H, H3), 7.42-7.35 (m, 1H, H2), 6.37 (s, 1H, H10), 3.62 (br, 4H, H17), 3.07 (t, J = 7.6 Hz, 2H, H13), 2.03 (br, 4H, H18), 1.78 -1.65 (m, 2H, H14), 1.52 -1.36 (m, 2H, H15), 0.95 (t, J = 7.4

MS

MS (CI

Hz, 3H, H16). 1 H NMR (300 MHz, CDCl3) δ 7.67 (dt, J = 7.1, 1.1 Hz, 1H), 7. 58 -7.50 (m, 1H), 7.50 -7.38 (m, 2H), 7.38 -7.24 (m, 5H), 6.57 (s, 1H), 4.99 (s, 2H), 3.20 (s, 3H), 3.15 -3.04 (m, 2H), 1.80 -1.67 (m, 2H), 1.52 -1.40 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

13 C NMR (75 MHz,CDCl3) δ 191.2,163.2,161.1,154.0,140.9,138.1,137.2,133.0,130.6,128.8,127.5,127.4,123.5,120.7,115.6,95.1,53.5,36.5,34.1,30.8,22.8,14.2. 13 C NMR (75 MHz,CDCl3) δ 191.0,163.3,160.7,153.7,141.0,137.3,132.9,130.5,123.4,120.6,115.0,95.4,46.3,34.2,30.8,25.9,24.9,22.8,14.2. 1 H NMR (400 MHz, CDCl3) δ 7.67 -7.52 (m, 2H, H1,4), 7.46 -7.32 (m, 2H, H2,3) NOESY (400 MHz, CDCl3) H10 (6.58 ppm) correlates to H17 (3.52 -3.35 ppm). 1 H NMR (300 MHz, CDCl3) δ 7.68 -7.52 (m, 2H), 7.46 -7.29 (m, 2H), 6.26 (s, 1H), 5.58 (s, 1H), 3.45 -3.24 (m, 4H), 3.11 -2.63 (m, 2H), 2.42 (br, 1H), 1.95 -1.81 (m, 4H), 1.80 -1.67 (m, 2H), 1.49 -1.34 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).

HRMS (ESI

HRMS (ESI

HRMS (ESI

13 C NMR (75 MHz, CDCl3) δ 158. 6, 158.0, 149.4, 147.9, 138.8, 129.4, 128.7, 125.5, 124.7, 120.8, 94.7, 73.9, 46.9, 34.6, 31.4, 25.5, 23.0, 14.3. 3, 155.3, 144.7, 139.7, 129.0, 125.3, 125.2, 121.1, 100.4, 74.50, 46.7, 36.0, 30.4, 25.2, 22.9, 14.2. 13 C NMR (101 MHz, DMSO-d6) δ 157. 6, 155.6, 153.7, 145.3, 139.2, 128.4, 125.0, 124.9, 121.0, 120.7, 99.8, 73.0, 46.3, 25.0, 14.6, 8.4, 7.9. 8, 128.4, 122.3, 89.5, 83.7, 64.7, 46.3, 18.3, 14.1. 128.7, 128.4, 122.6, 88.9, 84.4, 71.8, 40.8, 25.1. .5, 131.8, 129.4, 129.1, 128.7, 128.6, 126.0, 121.9, 91.3, 83.8, 64.7. 2, 128.4, 125.9, 85.9, 81.3, 65.4, 30.6, 22.1, 18.7, 13.7. 13 C NMR (75 MHz,CDCl3) δ 132.0,128.9,128.4,122.1,87.3,85.0,80.3,74.3,67.3,54.3,31.1. This compound was obtained following the general procedure F. Starting from 3-methyl- 0, 128.9, 128.4, 122.2, 87.5, 84.8, 82.6, 75.4, 66.9, 54.9, 31.2, 4. 1 H NMR (300 MHz, CDCl3) δ 7. 57 -7.41 (m, 4H), 7.38 -7.28 (m, 6H), 4.53 (q, J = 2.4 Hz, 2H), 2.18 -2.06 (m, 2H), 1.87 (t, J = 2.4 Hz, 3H), 1.83 -1.71 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H).

HRMS (ESI

MS

HRMS (ESI

MS (CI

MS (CI

MS

MS

MS (CI

13 C NMR (75 MHz, CDCl3) δ 132. 0, 128.8, 128.4, 122.4, 87.0, 85.6, 82.4, 75.6, 70.8, 54.7, 45.4, 18.2, 14.1, 4. To a stirred mixture of 2-butyn-1,4-diol 52 (0.86 g, 10 mmol, 1 equiv) and iPr2NEt (6.7 mL, 40 mmol, 4 equiv) in DCM (20 mL) was cooled at 0 °C in an ice bath. DMAP (0.1 g, 0.5 mmol, 5 mol %) and pivaloyl chloride (3.69 mL, 30 mmol, 3 equiv) in DCM (20 mL) were then introduced. The reaction mixture was stirred at room temperature for 3 h until completion (TLC monitoring). The organic layer was washedwith water (3×30 mL) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Cyclohexane/Ethyl acetate; 80/20) to afford 263 (2.5 g, 98%) as a colorless oil.

Rf = 0.3 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 4.69 (s, 4H), 1.21 (s, 18H).

13 C NMR (75 MHz, CDCl3) δ 177. 8, 80.8, 52.3, 38.9, 27.2.

But-2-yne-1,4-diyl dibenzoate (264)

207 Muchow, G.; Brunel, J. M.; Maffei, M.; Buono, G. J. Org. Chem. 1995, 60, 852. This compound was obtained following the general procedure P. Starting from 2-butyne-1,4diol 52 (1.72 g, 20 mmol), benzoyl chloride (5.8 mL, 50 mmol, 2.5 equiv) and pyridine (4 mL, 50 mmol, 2.5 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate; 90/10) afforded 264

(5.6 g, 95%) as a white solid. m.p. 80 -82 °C.

Rf = 0.3 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 8. 13 -8.02 (m, 4H), 7.63 -7.51 (m, 2H), 7.51 -7.39 (m, 4H), 5.00 (s, 4H).

13 C NMR (75 MHz, CDCl3) δ 165.9, 133.5, 130.0, 129.6, 128.6, 81.1, 52.8. 8, 170.3, 140.6, 140.2, 136.8, 136.2, 134.1, 131.9, 131.6, 131.0, 129.6, 128.3, 128.1, 127.8, 127.7, 123.0, 91.1, 85.6, 71.3, 61.2, 60.5, 42.1, 21.0, 21.0, 17.2, 16.0, 13.9.

MS

SFC

  le Schéma R5. La faible régiosélectivité peut s'expliquer par un encombrement stérique proche des substituants présents.

  travail précédent faisant intervenir le ruthénium sous forme neutre (RuCl3•nH2O) pour la mise en oeuvre de cycloaddition [2+2+2] d'-diynes et cyanamides, nous avions démontré que le ruthénium sous forme cationique était également très efficace pour cette réaction. Les essais initiaux ont porté sur l'utilisation du diyne 101 et du cyanamide 155, dans des conditions sans solvant à température ambiante. La réaction a été optimisée en faisant varier différents paramètres. Nous avons ainsi montré que la réaction pouvait être conduite efficacement avec 2% molaire du complexe pentaméthylcyclopentadiényle (Cp*) Cp*Ru(CH3CN)3PF6 pour fournir la 2-aminopyridine 169 avec un excellent rendement et un temps de réaction de 5 min. Par ailleurs, nous avons également découvert que lorsque la réaction était réalisée avec un petit volume de dichlorométhane, avec le diyne 109 comme modèle, il était possible de réduire à la fois le taux catalytique à 1% molaire et le nombre d'équivalents de cyanamide à 1.2 équivalents (entrée 8). L'utilité de cette méthode a été démontrée en conduisant la réaction sur une échelle d'un gramme, avec le diyne 109 comme modèle. La 2-aminopyridine 188 a ainsi été obtenue avec 82% de rendement (entrée 10).

  méthode catalytique et éco-compatible, une famille d'aza-fluorénols et aza-fluorénones a été préparée. Le choix de la position du substituant sur le diyne permet de contrôler la régiosélectivité du substituant sur le cycle pyridine. La structure de l'azafluorénone 248 a été formellement établie par diffraction des rayons X (Schéma R18).

  Afin de rendre compte de la stéréosélectivité observée, nous nous sommes intéressés au cycle catalytique de la réaction. Un des mécanismes possible est développé dans le Schéma R24.La réaction pourrait débuter par le couplage oxydatif de deux fonctions alcynes issues du triyne et de l'alcyne avec l'espèce rhodium pour conduire à l'intermédiaire rhodacyclopentadiène Rh-I. Une coordination intramoléculaire ultérieure avec l'une des fonctions alcynes portée par le carbone quaternaire fournirait l'intermédiaire Rh-II. Ceci pourrait être considéré comme l'étape stéréo déterminante pour expliquer l'énantiosélectivité observée en raison de la gêne stérique entre le groupe alcyne et le ligand chiral. L'insertion intramoléculaire de l'alcyne sur le rhodium de Rh-II délivrerait alors l'intermédiaire à 7 chainons Rh-III, qui subirait une élimination réductrice pour donner le 1,3dihydroisobenzofurane avec un excès énantiomérique (Schéma R24).

  , nous avons donc démontré que la cycloaddition [2+2+2] conduite en présence d'un catalyseur au rhodium Rh(cod)2BF4, en présence d'une phosphine chirale, était un moyen d'accès rapide vers les 1,3-dihydroisobenzofuranes énantiomériquement enrichis. Bien que les rendements et l'énantiosélectivité restent à améliorer, cette méthode est prometteuse.

  Scheme 17

  59j

1

 1 Scheme 47

1 .

 1 Synthesis of benzoyl bridged -diynes

80 Compounds 8 - 2 .

 8082 Scheme 80

  Scheme 84

Catal. 2011 ,

 2011 353, 1045. (p) Kawatsura, M.; Uchida, K.; Terasaki, S.; Tsuji, H.; Minakawa, M.; Itoh, T. Org. Lett. 2014, 16, 1470. (q) Seki, M. ACS Catal. 2011, 1, 607. (r) Thirunavukkarasu V. S.; Ackermann, L. Org. Lett. 2012, 14, 6206. (s) Adrio, L. A.; Gimeno, J.; Vicent, C. Chem. Commun. 2013, 49, 8320. (t) Rostamnia, S.; Hassankhani, A. RSC Adv. 2013, 3, 18626. (u) Singh, M. K.; Akula, H. K.; Satishkumar, S.; Stahl, L.; Lakshman, M. K. ACS Catal. 2016, 6, 1921. (v) Tan, D.-W.; Li, H.-X.; Young, D. J.; Lang, J.-P. Tetrahedron 2016, 72, 4169. (w) Baruah, P. K.; Deb, M. L.; Borpatra, P. J.; Saikia, P. J. Org. Biomol. Chem. 2017, 15, 1435.

  Scheme 97

  Scheme 101

  (a) Heintzelman, G. R.; Bullington, J. L.; Rupert, K. C. PCT Int. Appl. WO 2005042500 A1 20050512, 2005. (b) Chen, T.-C.; Yu, D.-S.; Chen, S.-J.; Chen, C.-L.; Lee, C.-C.; Hsieh, Y.-Y.; Chang, L.-C.; Guh, J.-H.; Lin, J.-J.; Huang, H.-S. Arab. J. Chem. 2016. DOI: 10.1016/j.arabjc.2016.06.014. 118 (a) Landmesser, T.; Linden, A.; Hansen, H.-J. Helv. Chim. Acta 2008, 91, 265. (b) Gao, M.; Su, H.; Lin, Y.; Ling, X.; Li, S.;Qin, A.; Tang, B. Z. Chem. Sci. 2017, 8, 1763.

  123 (a) Kumar, R.; Rai, D.; Sharma, S. K.; Saffran, H. A.; Blush, R.; Tyrrell, D. L. J. J.Med. Chem. 2001, 44, 3531. (b) Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C.; Fensterbank, L.; Lacôte, E. Synthesis 2012, 44, 1279. (c) Carta, F.; Akdemir, A.; Scozzafava, A.; Masini, E.; Supuran, C. T. J. Med. Chem. 2013, 56, 4691. (d) Yu, J.-T.; Teng, F.; Cheng, J. Adv. Synth. Catal. 2017, 359, 26. 124(a) Pawlas, J.; Begtrup, M. Org. Lett. 2002, 4, 2687. (b) Köhn, U.; Klopfleisch, M.; Görls, H.; Anders, E. Tetrahedron Asymmetry 2006, 17, 811. (c) Jenkinson, S. F.; Jones, N. A.; Moussa, A.; Stewart, A. J.; Heinz, T.; Fleet, G. W. J. Tetrahedron Lett. 2007, 48, 4441. (d) Dornan, P.; Rowley, C. N.; Priem, J.; Barry, S. T.; Burchell, T. J.; Woo, T. K.; Richeson, D. S. Chem. Commun. 2008, 31, 3645. (e) Nasrollahzadeh, M.; Habibi, D.; Shahkarami, Z.; Bayat, Y. Tetrahedron 2009, 65, 10715. (f) Giles, R. L.; Nkansah, R. A.; Looper, R. E. J. Org. Chem. 2010, 75, 261. (g) Larraufie, M.-H.; Courillon, C.; Ollivier, C.; Lacôte, E.; Malacria, M.; Fensterbank, L. J. Am. Chem. Soc. 2010, 132, 4381. (h) Zhou, L.; Chen, J.; Zhou, J.; Yeung, Y.-Y. Org.Lett. 2011, 13, 5804.

N + NaNH 2 Formal

 2

Firstly, a

 a Scheme 130

4 .

 4 Scheme 146

167.

  Dibenzylamine, diallylamine, N-methylpiperazine and N-methylbutylamine were treated with cyanogen bromide in a mixture solution of water and dichloromethane (1:1) at 0 °C. In this case, 2 equivalents of sodium bicarbonate were used as the base, with 1.05 equivalents of 147 (a) For cyanamide 161-165, see: ref 130a. (b) For cyanamide 159, see: Goldberg, K.; Clarke, D. S.; Scott, J. S.Tetrahedron Lett. 2014, 55, 4433.

  Scheme 150

  The cyanamides 160-163 and 165-167 seemed incompatible with the RuCl3•nH2Omediated[2+2+2] cycloaddition reaction, despite a higher temperature in some cases. Low conversion of cycloadducts was observed in the case of N,N-diethylcyanamide 160, N,Ndipropylcyanamide 161, and N-methyl-N-phenylcyanamide 162, because of the lower reactivity of the alkyl substituted cyanamides (Entries 8-10, Table

  Scheme 151

  Scheme 158

  Scheme 160

Finally, a

 a family of aza-fluorenones and aza-fluorenols were synthesized via ecofriendly and straightforward approaches. Controlling the terminal position of the benzoyl-or benzyl-bridged diyne allowed the synthesis of 2-or 3-azafluorenone(ol) with high regioselectivities.

Figure 3 151

 3 Figure 3

  Scheme 167

[

  Scheme 186

  Scheme 198

  This compound was prepared using procedure C. Starting from 3-cyclopropyl-1-(2-(phenylethynyl)phenyl)prop-2-yn-1-ol 11(1.1 g, 4.0 mmol) and Dess-Martin periodinane (2.2 g, 5.2 mmol, 1.3 equiv). Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 99/1 to 98/2) afforded 20 (0.82 g, 75%) as a pale yellow oil. Rf = 0.55 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (300 MHz, CDCl3),  8.07 -8.02(m, 1H), 3H), 7.51 (td, J = 7.5, 1.5 Hz, 1H), 7.41 (td, J = 7.5, 1.5 Hz, 1H), 3H), 1H), 0.99 -0.93(m, 4H).

1 H

 1 NMR (300 MHz, CDCl3) δ 10.24 (d, J = 1.3 Hz, 1H), 7.70 (dd, J = 5.0, 1.3 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.45 -7.30 (m, 3H), 7.27 -7.23 (m, 1H).

  This compound was prepared using procedure B. Starting from 3-(phenylethynyl)furan-2carbaldehyde 30 (0.43 g, 2.2 mmol) and 1-hexyne (0.37 mL, 3.3 mmol, 1.5 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 37 (0.45 g, 74%) as a yellow oil. Rf = 0.28 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.50 (dd, J = 6.6, 3.0 Hz, 2H), 7.37 (d, J = 1.8 Hz, 1H), 7.37 -7.29 (m, 3H),6.48 (d, J = 1.8 Hz, 1H), 1H), 2.38 (d, J = 6.9 Hz, 1H), 2.25 (td, J = 7.0, 2.0 Hz, 2H),1.56 -1.44 (m, 2H), 1.44 -1.32 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

  (CI, NH3): m/z = 277 [M + H -H2O] + . benzo[b]thiophene-2-carbaldehyde 32 (0.4 g, 1.5 mmol) and 1-hexyne (0.26 mL, 2.25 mmol, 1.5 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 39 (0.46 g, 89%) as a yellow oil. Rf = 0.3 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

  This compound was prepared using procedure C. Starting from 1-(3-(phenylethynyl)thiophen-2-yl)hept-2-yn-1-ol 38 (1.12 g, 3.8 mmol) and Dess-Martin periodinane (2.1 g, 4.9 mmol, 1.3 equiv). Purification on silica gel (Petroleum ether/Ethyl acetate gradient 99/1 to 98/2) afforded 45 (0.6 g, 55%) as a yellow solid. m.p. 33 -35 °C. Rf = 0.33 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).

13 C

 13 NMR (75 MHz, CDCl3) δ 82.5, 74.2, 50.8, 27.5. MS (CI, NH3): m/z = 216 [M + NH4] + .

  + ): calcd. for C31H36O3Na [M+Na] + : 479.2557, found 479.2557. This compound was obtained following the general procedure E. Starting from diyne 26 (100.0 mg, 0.28 mmol), 1,4-dimethoxy-2-butyne 51 (80 mg, 0.56 mmol, 2.0 equiv) and RuCl3•nH2O (2.9 mg, 0.014 mmol). The reaction mixture was stirred at 50 °C for 14 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 98/2 to 95/5) afforded 72 (85 mg, 65%) as a brown solid. m.p. 113 -115 °C. Rf = 0.53 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.59 (dd, J = 7.3, 0.6 Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.17 (td, J = 7.5, 1.0 Hz, 1H), 7.08 (td, J = 7.6, 1.3 Hz, 1H), 5.91(d, J = 7.5 Hz, 1H), 4.55 (s, 2H), 4.11 (s, 2H), 3.51 (s, 3H), 3.30 -3.20 (m, 2H), 3.17 (s, 3H), 1.64 -1.50 (m, 4H), 1.02 (t, J = 7.0 Hz, 3H).

  This compound was obtained following the general procedure E. Starting from diyne 27 (127.0 mg, 0.35 mmol), 1,4-dimethoxy-2-butyne 51 (80 mg, 0.7 mmol, 2.0 equiv) and RuCl3•nH2O (3.6 mg, 0.0175 mmol). The reaction mixture was stirred at 50 °C for 14 h. Purification on silica gel (Petroleum ether/ Ethyl acetate gradient from 98/2 to 95/5) afforded 73 (94 mg, 56%) as a yellow oil. Rf = 0.43 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.71 -7.61(m, 2H), 7.61 -7.54 (m, 1H), 7.25 -7.20 (m, 2H), 7.20 -7.07 (m, 2H), 6.04 (d, J = 7.5 Hz, 1H), 4.54 (s, 2H), 4.13 (s, 2H),3.50 (s, 3H), 3.28 - 3.18 (m, 2H), 3.20 (s, 3H), 1.64 -1.51 (m,

  + ): calcd. for C28H28O5Na [M+Na] + : 467.1829, found 467.1830.

  + ): calculated for C39H36O3Na + [M+Na + ]: 575.2557, found 575.2551. This compound was obtained following the general procedure E. Starting from diyne 17 (100 mg, 0.35 mmol), 1,4-bis(benzyloxy)but-2-yne 56 (186 mg, 0.7 mmol, 2.0 equiv) and RuCl3•nH2O (3.6 mg, 0.0175 mmol). The reaction mixture was stirred at 50 °C for 14 h. The excess of alkyne was removed by bulb to bulb distillation (condition: 3.0x10 -3 mbar, 175℃ for 20 minutes). Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 77 (156 mg, 81%) as a yellow solid. m.p. 145 -147 °C. Rf = 0.25 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).

  + ): calculated for C25H26O4Na + [M+Na + ]: 413.1723, found 413.1723. This compound was obtained following the general procedure E. Starting from diyne 45 (102 mg, 0.35 mmol), 1,4-dimethoxy-2-butyne 51 (80 mg, 0.7 mmol, 2.0 equiv) and RuCl3•nH2O (3.6 mg, 0.0175 mmol). The reaction mixture was stirred at 50 °C for 14 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 84 (101 mg, 71%) as a yellow oil. Rf = 0.4 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (300 MHz, CDCl3), δ 7.49 -7.43 (m, 3H), 7.34 (d, J = 4.5 Hz, 1H), 7.33 -7.27 (m, 2H), 5.62 (d, J = 4.8 Hz, 1H), 4.51 (s, 2H), 4.16 (s, 2H), 3.49 (s, 3H), 3.19 (s, 3H), 3.17 -3.07 (m, 2H), 1.62 -1.47 (m, 4H), 1.00 (t, J = 7.2 Hz, 3H).

  + ): calcd. for C29H28O3SNa [M+Na] + : 479.1651, found 479.1650.

  This compound was obtained following the general procedure E. Starting from diyne 49 (100 mg, 0.29 mmol), 1,4-dimethoxy-2-butyne 51 (200 mg, 1.75 mmol, 6.0 equiv) and RuCl3•nH2O (3.0 mg, 0.0146 mmol). The reaction mixture was stirred at 80 °C for 18 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 89 (8 mg, 6%) as a brown oil. Rf = 0.65(Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 8.23 (dd, J = 5.0, 1.7 Hz, 1H), 7.76 (dd, J = 7.4, 1.7 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 6.99 (dd, J = 7.5obtained following the general procedure E. Starting from diyne 50 (112 mg, 0.35 mmol), 1,4-dimethoxy-2-butyne 51 (80 mg, 0.7 mmol, 2.0 equiv) and RuCl3•nH2O (3.6 mg, 0.0175 mmol). The reaction mixture was stirred at 80 °C for 2 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 90 (91 mg, 60%) as a yellow solid. m.p. 94 -96 °C. Rf = 0.31 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.55 -7.48 (m, 3H), 7.40 (d, J = 0.9 Hz, 1H), 7.32 -7.27 (m, 2H), 6.90 (d, J = 1.2 Hz, 1H), 4.57 (s, 2H), 4.22 (s, 2H),3.51 (s, 3H), 3.24 -3.15 (m, 2H), 3.20

  + ): calcd. for C26H26ClNO3Na [M+Na] + : 458.1493, found 458.1494.Thess compounds were obtained following the general procedure E. Starting from diyne 17 (200 mg, 0.7 mmol), cyclopropyl acetylene 58 (93 mg, 1.4 mmol, 2.0 equiv) and RuCl3•nH2O (7.2 mg, 0.035 mmol). The reaction mixture was stirred at 80 °C for 14 h. Purification on silica ether/Ethyl acetate 99/1) afforded the title regioisomers 91 (208 mg, 84%) in the ratio of 67/33 as an orange oil. Rf = 0.6 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).Major product: 1 H NMR (300 MHz, CDCl3) δ 7.60 -7.45(m, 4H), 2H), 2H), 6.56 (s, 1H), 1H), 3.05 (t, J = 7.8 Hz, 2H), 3H), 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.86 -0.74(m, 2H), 0.75 -0.64 (m, 2H).

  + ): calculated for C26H24OH + [M+H + ]:353.1900, found 353.1900. Thess compounds were obtained following the general procedure E. Starting from diyne 17 (200 mg, 0.7 mmol), phenyl acetylene 59 (93 mg, 1.4 mmol, 2.0 equiv) and RuCl3•nH2O (7.2 mg, 0.035 mmol). The reaction mixture was stirred at 80 °C for 14 h. Purification on silica gel (Petroleum ether/Ethyl acetate 99/1) afforded the title regioisomers 92(191 mg, 70%) in the ratio of 73/27 as an orange solid. Rf = 0.45 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).

  + ): calculated for C29H24ONa + [M+Na + ]: 411.1719, found 411.1722. This compound was obtained following the general procedure E. Starting from diyne 17 (200 mg, 0.7 mmol), 5-chloro-1-pentyne 60 (143 mg, 1.4 mmol, 2.0 equiv) and RuCl3•nH2O (7.2 mg, 0.035 mmol). The reaction mixture was stirred at 80 °C for 14 h. Purification on silica gel (Petroleum ether/Ethyl acetate 99/1) afforded the title regioisomers 93 (165 mg, 61%) in the ratio of 55/45 as an orange oil. Rf = 0.5 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).

  + ): calculated for C26H25ClONa + [M+Na + ]: 411.1486, found 411.1490. 65 (400 mg, 1.0 mmol) in trifluoroacetic acid (3 mL) was refluxed for 36 h. Evaporation of the excess of trifluoroacetic acid under reduced pressure gave a residue which was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) to afford compound 94 (300 mg, 85%) as a yellow solid. m.p. 109 -111 °C. Rf = 0.28 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

  + ): calcd. for C21H23IO3Na [M+Na] + : 473.0584, found 473.0580. , 19.6 mg) and CuI (5 mol%, 2.7 mg) were added to a NEt3/THF (1:1, 2 mL) solution containing iodo-substituted fluorenone 97 (250 mg, 0.56 mmol), phenylacetylene (86 mg, 0.84 mmol, 1.5 equiv). The mixture was stirred at 40 °C for 4 h under argon. When the reaction was complete (TLC monitoring), a saturated aqueous solution of ammonium chloride was added and the mixture was stirred for 5 minutes. The organic layer was extracted with ethyl acetate (3×20 mL), washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) to afford compound 98 (232 mg, 98%) as a yellow solid. m.p. 124 -126 °C. Rf = 0.28 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 8.43(d, J = 7.6 Hz, 1H), 3H), 4H), 1H), 4.86 (s, 2H), 4.57 (s, 2H), 3.52 (s, 3H), 3.48 (s, 3H), 3.21 (t, J = 7.5

  + ): calcd. for C29H28O3Na [M+Na] + :447.1931, found 447.1930. To a dry DMF solution (1 mL) of 97 (135 mg, 0.3 mmol) were added bis(pinacolato)diboron (114 mg, 0.45 mmol), PdCl2(dppf)•CH2Cl2 (11 mg, 0.015 mmol), and KOAc (60 mg, 0.6 mmol). The mixture was stirred at 80 °C for 18 h. After cooling, the DMF was removed under vacuum, and CH2Cl2 and water were added. The resulting mixture was extracted with dichloromethane (2×30 mL), and the organic layer was washed with water and brine, dried over anhydrous MgSO4. The organic solvent was concentrated in vacuo to yield a dark-black oil. The excess bis(pinacolato)diboron was removed under reduced pressure with heating. The residue was purified by flash chromatography on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 99 (88 mg, 65%) as a yellow oil. Rf = 0.23 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 8.07(d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.42 (td, J = 7.6, 1.3 Hz, 1H), 1H), 4.70 (s, 2H), 4.42 (s, 2H), 3.39 (s, 3H), 3.27 (s, 3H), 2H), 1.47 (s, 16H), 3H).

  To a dry DMF solution (1 mL) of 73 (150 mg, 0.313 mmol) were added bis(pinacolato)diboron (120 mg, 0.47 mmol), PdCl2(dppf)•CH2Cl2 (11.4 mg, 0.0156 mmol), and KOAc (61 mg, 0.626 mmol). The mixture was stirred at 80 °C for 18 h. After the solution was cooled, the DMF was removed under vacuum, and CH2Cl2 and water were added. The resulting mixture was extracted with dichloromethane (2×30 mL), and the organic layer was washed with water and brine, dried over anhydrous MgSO4. The solvent was concentrated in vacuo to yield a dark-black oil. The excess bis(pinacolato)diboron was removed under reduced pressure with heating. The residue was purified by flash chromatography on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 100 (140 mg, 85%) as a yellow oil. Rf = 0.2 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV). 1 H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 7.7 Hz, 2H), 7.56 (d, J = 7.0 Hz, 1H), 7.34 (d, J = 7.7 Hz, 2H), 7.09 (dt, J = 23.8, 7.2 Hz, 2H), 6.00 (d, J = 7.4 Hz, 1H), 4.55 (s, 2H), 4.14 (s, 2H),

  This compound was obtained following the general procedure F. Starting from 1,3dimethylbarbituric acid (0.94 g, 6 mmol), 1-bromo-2-butyne(1.26 mL, 14.4 mmol, 2.4 equiv) and NaH (0.58 g, 14.4 mmol, 2.4 equiv). The reaction mixture was stirred at room temperature for 12 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 85/15) afforded 102 (0.96 g, 62 %) as a white solid. m.p. 118-120 °C. Rf = 0.62 (Cyclohexane/Ethyl acetate; 80/20, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 3.40 -3.24(m, 6H), 2.78 -2.51 (m, 4H), 1.75 -1.50 (m, 6H).

13 C

 13 NMR (75 MHz, CDCl3) δ 170.

  To a solution of diol 120 (0.6 g, 4.0 mmol) in dry acetone (20 mL) was added phosphorus pentoxide(1.14 g, 8.0 mmol, 2 equiv) by one portion and the reaction mixture was stirred at room temperature for 20 mins. Then the resulting mixture was poured into a mixture of NaOH (2 g) and ice (30 g), and extracted with diethyl ether (3×30 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 and brine, dried with MgSO4, filtered and concentrated under reduced pressure. The residues was purified by flash chromatography on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 121 (0.61 g, 80%) as a slight yellow oil. The analytical data were identical to the literature. 145i Rf = 0.65 (Cyclohexane/Ethyl acetate; 80/20, KMnO4, UV).

Dimethyl 2 -

 2 (but-2-yn-1-yl)-2-(prop-2-yn-1-yl)malonate (125) This compound was obtained following the general procedure F. Starting from dimethyl 2-(but-

  This compound was obtained following the general procedure H. Starting from dimethyl 2-(but-2-yn-1-yl)-2-(prop-2-yn-1-yl)malonate 125 (0.67 g, 3 mmol), NIS (0.87 g, 3.6 mmol, 1.2 equiv) and silver nitrate (0.05 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 3 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 90/10 to 80/20) afforded 133 (1.02 g, 99 %) as a yellow solid. m.p. 68-70 °C. The analytical data were identical to the literature. 145l

  , 5 equiv) and sodium carbonate (2.12 g, 20 mmol, 2.0 equiv). The reaction flask was purged with oxygen for 15 min. A solution of pyridine(1.58 g, 20.0 mmol, 2.0 equiv) in dry toluene (40 mL) was added. A balloon filled with oxygen was connected to the reaction flask via a needle. The flask was placed in an oil-bath and heated at 70 °C. After 15 min, a solution of 1-(prop-2-yn-1-yloxy)but-2-yne 127 (1.08 g, 10.0 mmol, 1 equiv) in dry toluene (40 mL) was added over 4 h using syringe pump. After this addition, the mixture was allowed to stir at 70 °C for additional 16 h and was then cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Cyclohexane/Ethyl acetate gradient from 60/40 to 50/50) to afford 134 (1.15 g, 60%) as a slight yellow solid. m.p. 63 -65 °C. Rf = 0.11 (Cyclohexane/Ethyl acetate; 70/30, KMnO4, UV).

  (CI, NH3): m/z = 194 [M + H] + . This compound was obtained following the general procedure F. Starting from dimethyl 2-(pent-4-en-

  (CI, NH3): m/z = 235 [M + H] + . Dimethyl 2-(but-2-yn-1-yl)-2-(3-(pyridin-2-yl)prop-2-yn-1-yl)malonate (137) This compound was obtained following the general procedure A. Starting from dimethyl 2-(but-2-yn-1-yl)-2-(prop-2-yn-1-yl)malonate 125 (1.1 g, 5 mmol), 2-bromo pyridine (0.57 mL, 6 mmol, 1.2 equiv), PdCl2(PPh3)2 (70 mg, 2 mol %) and CuI (9.5 mg, 1 mol %). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 70/30) afforded 137 (0.9 g, 60%) as a pale yellow oil. The analytical data were identical to the literature. 198 Rf = 0.2 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

  This compound was obtained following the general procedure B. Starting from 2-(hex-1-yn-1yl)benzaldehyde 2 (1.0 g, 5.4 mmol), trimethylsilylacetylene (1.14 mL, 8 mmol, 1.5 equiv) and n-BuLi (3.5 mL, 1.85 M in hexane, 6.5 mmol, 1.2 equiv). Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 148 (1.2 g, 78%) as a pale yellow oil. This compound was obtained following the general procedure A. Starting from 2bromobenzoaldehyde (4.0 g, 21.7 mmol), cyclopropylacetylene (1.7 g, 26 mmol, 1.2 equiv), PdCl2(PPh3)2 (0.75mg, 1.09 mmol, 5 mol %) and CuI (0.1 g, 0.55 mmol, 2.5 mol %).

  This compound was obtained following the general procedure B. Starting from 2-(cyclopropylethynyl)benzaldehyde 150 (2.0 g, 11.8 mmol), trimethylsilylacetylene(3.25 mL, 23.5 mmol, 2 equiv) and n-BuLi (8.8 mL, 2.0 M in hexane, 17.6 mmol, 1.5 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 151(2.5 g, 80%) as a pale yellow oil.1 H NMR (300 MHz, CDCl3) δ 7.70 -7.55(m, 1H), 1H), 2H), 5.79 (d, J = 5.5 Hz, 1H), 2.70 (d, J = 5.7 Hz, 1H), 1H), 4H), 0.20 (s, 9H).

1 H

 1 NMR (300 MHz, CDCl3) δ 3.36 (br, 1H), 3.07 (t, J = 7.0 Hz, 2H), 1.67 -1.50 (m, 2H), 1.47 -1.25 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

A

  sealed tube was equipped with Cp*Ru(CH3CN)3]PF6 (1-5 mol %) and cyanamide (1.2 or 2.0 equiv), a solution of diyne (1 equiv) in DCM (1 or 2 M) was added under argon atmosphere. The reaction mixture was stirred vigorously at room temperature or 50 °C. When the reaction was complete (TLC monitoring), the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford cycloadduct. In some cases, the excess of cyanamide was removed by bulb to bulb distillation. This compound was obtained following the general procedure L. Starting from diyne 101 (236 mg, 1.0 mmol), N,N-dimethylcyanamide 154 (140 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O (10.4 mg, 0.05 mmol). The reaction mixture was stirred at 110 °C for 18 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 80/20 to 70/30) afforded 168 (225 mg, 74%) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions:1.0x10 -3 mbar, 70 °C for 10 minutes). The analytical data were identical to the literature. 135a Rf = 0.34 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

  compound was obtained following the general procedure L. Starting from diyne 101 (236 mg, 1.0 mmol

  This compound was obtained following the general procedure L. Starting from diyne 101 (236 mg, 1.0 mmol), piperidine-1-carbonitrile 157 (220 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O (10.4 mg, 0.05 mmol

  This compound was obtained following the general procedure L. Starting from diyne 101 (236 mg, 1.0 mmol), N-benzyl-N-methylcyanamide 158 (292 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O (10.4 mg, 0.05 mmol

  , NH3): m/z = 459 [M + H] + . 1,1',3',4-Tetramethyl-3-morpholino-5,7-dihydro-2'H-spiro[cyclopenta[c]pyridine-6,5'pyrimidine]-2',4',6'(1'H,3'H)-trione (181)

  This compound was obtained following the general procedure L. Starting from diyne 103 (250 mg, 1.0 mmol), 4-cyanomorpholine 155 (224 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O (10.4 mg, 0.05 mmol

  This compound was obtained following the general procedure L. Starting from diyne 104 (180 mg, 1.0 mmol), 4-cyanomorpholine 155 (224 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O (10.4 mg, 0.05 mmol). The reaction mixture was stirred at 80 °C for 18 h. Purification on silica gel (Cyclohexane/Ethyl acetate 80/20) afforded 183 (30 mg, 10%) as a pale yellow solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10

( 1 , 4 -

 14 (CI, NH3): m/z = 293 [M + H] + . Dimethyl-3-morpholino-6,7-dihydro-5H-cyclopenta[c]pyridine-6,6-diyl)bis (methylene) diacetate (184)

  compound was obtained following the general procedure L. Starting from diyne 107 (122 mg, 1.0 mmol), 4-cyanomorpholine 155 (224 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O (10.4 mg, 0.05 mmol). The reaction mixture was stirred at 80 °C for 18 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 186 (150 mg, 64%) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes). b) This compound was obtained following the general procedure M. Starting from diyne 107 (61 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 186 (94 mg, 80%) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes).

  compound was obtained following the general procedure L. Starting from diyne 108 (275 mg, 1.0 mmol), 4-cyanomorpholine 155 (224 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O (10.4 mg, 0.05 mmol). The reaction mixture was stirred at 110 °C for 18 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 187 (280 mg, 72%) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions:1.0x10 -3 mbar, 90 °C for 10 minutes). b) This compound was obtained following the general procedure N. Starting from diyne 108 (137.5 mg, 0.5 mmol), 4-cyanomorpholine 155 (67 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 5 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 187 (180 mg, 93%) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes).The analytical data were identical to the literature. 143 Rf = 0.15 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

  (CI, NH3): m/z = 321 [M + H] + . compound was obtained following the general procedure L. Starting from diyne 125 (222 mg, 1.0 mmol), 4-cyanomorpholine 155 (224 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O (10.4 mg, 0.05 mmol

( 3 -

 3 + ): calcd. for C20H19N2O3 [M+H] + : 335.1390, found 335.1392. Morpholino-6,7-dihydro-5H-cyclopenta[c]pyridine-6,6-diyl)dimethanol (202) This compound was obtained following the general procedure M. Starting from diyne 120 (76 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 5 min. Purification on silica gel (Pure ethyl acetate followed by DCM/MeOH 9/1) afforded 202 (115 mg, 87%) as a white solid. m.p. 158 -160 °C. Rf = 0.2 (Pure ethyl acetate, KMnO4, UV).

  + ): calcd. for C14H21N2O3 [M+H] + : 265.1547, found 265.1546. This compound was obtained following the general procedure M. Starting from diyne 121 (96 mg, 0.5 mmol), 4-cyanomorpholine 156 (112 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 10 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 80/20 to 60/40) afforded 203 (132 mg, 87%) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes). m.p. 125 -127 °C. Rf = 0.1 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

  + ): calcd. for C18H22N3O3S [M+H] + : 360.1376, found 360.1378. This compound was obtained following the general procedure N. Starting from diyne 123 (96.5 mg, 0.5 mmol), 4-cyanomorpholine 155 (67 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6

  This compound was obtained following the general procedure N. Starting from diyne 109 (104 mg, 0.5 mmol), N,N-diethylcyanamide 160 (59 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 10 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 209 (132 mg, 86%) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0 x 10 -3 mbar, 80 °C for 10 minutes). The analytical data were identical to the literature. 128 Rf = 0.22 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

  This compound was obtained following the general procedure N. Starting from diyne 109 (104 mg, 0.5 mmol), N,N-dipropylcyanamide 161 (76 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 5 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 210 (140 mg, 84%) as a pale yellow oil. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 5x10 -3 mbar, 100 °C for 10 minutes). Rf = 0.23 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H),6.27 (s, 1H), 3.74 (s, 6H), 4H), 4H), 4H), 0.91 (t, J = 7.4 Hz, 6H).

  This compound was obtained following the general procedure N. Starting from diyne 109 (104 mg, 0.5 mmol), N-benzyl-N-methylcyanamide 158 (88 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (2.5 mg, 0.005 mmol). The reaction mixture was stirred at room temperature for 2 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 80/20 to 70/30) afforded 213 (168 mg, 95%) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0 x 10 -3 mbar, 120 °C for 20 minutes). m.p.136 -138 °C.

  This compound was obtained following the general procedure M. Starting from diyne 129 (150 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 60 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 220 (161 mg, 78%, ratio = 96:4) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (condition: 1.0x10 -3 mbar, 90 °C for 10 minutes). m.p. 118 -120 °C. Rf = 0.36 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

1 H

 1 NMR (400 MHz, CDCl3) δ 3.85 -3.79 (m, 4H, H12), 3.77 (s, 6H, H1), 3.55 (s, 2H, H5), 3.54 (s, 2H, H4), 3.11 -3.06 (m, 4H, H11), 2.12 (s, 3H, H13).

  MHz, CDCl3) H13 (2.12 ppm) correlate to H4 (3.54 ppm) and H11(3.11 -3.06 ppm).

  This compound was obtained following the general procedure N. Starting from diyne 130 (93 mg, 0.5 mmol), 4-cyanomorpholine 155 (67 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6(5.0 mg, 0.01 mmol). The reaction mixture was stirred at 50 °C for 2 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 221 (124 mg, 83%, ratio = 98:2) as a pale yellow solid. The excess of cyanamide was removed by bulb to bulb distillation (condition: 1.0x10 -3 mbar, 90 °C for 10 minutes). m.p. 108 -110°C. Rf = 0.19 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

1 H

 1 NMR (400 MHz, CDCl3) δ 5.07 (s, 2H, H4), 5.03 -4.95 (m, 2H, H5), 3.88 -3.77 (m, 4H, H10), 3.18 -3.08 (m, 4H, H9), 2.10 (s, 3H, H1).

13 C 1 (

 131 NMR (101 MHz, CDCl3) δ 161.2 (C8), 152.4 (C3), 130.5 (C6), 129.0 (C7), 117.1 (C2), 73.9 (C4), 73.6 (C5), 67.0 (C10), 50.5 (C9), 14.8 (C1). NOESY (400 MHz, CDCl3) H1 (2.10 ppm) correlate to H4 (5.07 ppm) and H9(3.18 -3.08 ppm). HRMS (ESI + ): calcd. for C12H16BrN2O2 [M+H] + : 299.0390, found 299.0393. This compound was obtained following the general procedure N. Starting from diyne 131 (89 mg, 0.5 mmol), 4-cyanomorpholine 155 (67 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 2 h.Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 60/40) afforded 222 (95 mg, 65%, ratio = 98:2) as a pale yellow solid. The excess of cyanamide was removed by bulb to bulb distillation (condition: 1.0x10 -3 mbar, 90 °C for 10 minutes). m.p. Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).1 H NMR (400 MHz, CDCl3) δ 6.40 (s, 1H, H1), 5.06 (dd, J = 2.7, 1.8 Hz, 2H, H3), 4.94 (t, J = 1.8 Hz, 2H, H4),3.83 -3.75 (m, 4H, H9), 3.53 -3.41 (m, 4H, H8).

13 C

 13 NMR (101 MHz, CDCl3) δ 159.6 (C7), 153.1 (C2), 132.7 (C6), 126.0 (C5), 97.7 (C1), 74.1 (C3), 72.8 (C4), 66.7 (C9), 45.9 (C8). NOESY (400 MHz, CDCl3) H1 (6.40 ppm) correlate to H3 (5.06 ppm) and H8 (3.53 -3.41 ppm). HRMS (ESI + ): calcd. for C11H14BrN2O2 [M+H] + : 285.0233, found 285.0235. This compound was obtained following the general procedure N. Starting from diyne 132 (169.5 mg, 0.5 mmol), N-benzyl-N-methylcyanamide 158 (88 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at 50 °C for 2 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 85/15) afforded 223 (182 mg, 75%, ratio = 98:2) as a white solid. m.p. 138-140 °C. Rf = 0.46 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

  This compound was obtained following the general procedure N. Starting from diyne 133 (174 mg, 0.5 mmol), 4-cyanomorpholine 155 (67 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at 50 °C for 30 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 224 (190 mg, 83%, ratio > 99:1) as a brown solid. The excess of cyanamide was removed by bulb to bulb distillation (condition: 1.0x10 -3 mbar, 90 °C for 10 minutes). m.p. 126 -128°C. Rf = 0.14 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

1 H

 1 NMR (400 MHz, CDCl3) δ 3.84 -3.79 (m, 4H, H13), 3.77 (s, 6H, H1), 3.57 (s, 2H, H4), 3.49 (s, 2H, H5), 3.10 -3.03 (m, 4H, H12), 2.11 (s, 3H, H11).

  MHz, CDCl3) H11 (2.11 ppm) correlate to H4 (3.57 ppm) and H12 (3.10 -3.03 ppm).

  This compound was obtained following the general procedure N. Starting from diyne 134 (96.5 mg, 0.5 mmol), morpholine-4-carbonitrile 155 (67 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at 50 °C for 16 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 60/40 to 50/50) afforded 225 (120 mg, 79%, ratio > 99:1) as a white solid. m.p. 202 -204 °C. Rf = 0.21 (Petroleum ether/Ethyl acetate; 50/50, KMnO4, UV).

1 H

 1 NMR (300 MHz, CDCl3) δ 5.19 (s, 2H), 4.96 (s, 2H), 4.48 (t, J = 7.8 Hz, 2H), 4.22 (t, J = 7.9 Hz, 2H),3.89 -3.74 (m, 4H), 3.15 -3.01 (m, 4H), 2.12 (s, 3H).

  (CI, NH3): m/z = 306 [M + H] + . This compound was obtained following the general procedure M. Starting from diyne 134 (96.5 mg, 0.5 mmol), pyrrolidine-1-carbonitrile 156 (96.1 mg, 1.0 mmol, 2.0 equiv) and 13 C NMR (75 MHz, CDCl3) δ 171.

  + ): calcd. for C18H23N2O5 [M+H] + : 347.1601, found 347.1603. This compound was obtained following the general procedure N. Starting from diyne 135 (70 mg, 0.3 mmol), N-benzyl-N-methylcyanamide 158 (53 mg, 0.36 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (7.6 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 30 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 228 (105 mg, 92%, ratio > 99:1) as a white solid. m.p. 146 -148 °C. Rf = 0.33 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.35 -7.18 (m, 5H),6.72 (dd, J = 17.1, 10.6 Hz, 1H), 6.33 (s, 1H), 6.27 (dd, J = 17.1, 2.3 Hz, 1H), 5.39 (dd, J = 10.6, 2.3 Hz, 1H), 4.83 (s, 2H), 3.75 (s, 6H),3.56 (s, 2H), 3.47 (d, J = 1.1 Hz, 2H), 3.05 (s, 3H).

  This compound was obtained following the general procedure M. Starting from diyne 136 (136.5 mg, 0.5 mmol), morpholine-4-carbonitrile 155 (112 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 3 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 80/20 to 60/40) afforded 229 (145 mg, 75%, ratio > 99:1) as a white solid. m.p. 168 -170 °C. Rf = 0.1 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 6.52 (dd, J = 17.2, 10.7 Hz, 1H), 6.35 (s, 1H), 6.18 (dd, J = 17.2, 1.9 Hz, 1H), 5.46 (dd, J = 10.6, 1.9 Hz, 1H), 4.56 (s, 2H), 4.51 (s, 2H),3.85 -3.70 (m, 4H), 3.53 -3.40 (m, 4H), 2.40 (s, 3H).

13 C

 13 NMR (75 MHz, CDCl3) δ 159.0, 148.

Found

  (CI, NH3): m/z = 386 [M + H] + . Elemental Analysis: Anal. Calcd for C20H23N3O3S (385.15): C, 62.32; H, 6.01; N, 10.90. This compound was obtained following the general procedure N. Starting from diyne 138 (61 mg, 0.5 mmol), morpholine-4-carbonitrile 155 (112 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at 50 °C for 2 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 70/30) afforded 230 (95 mg, 81%, ratio > 99:1) as a white solid. m.p. 140 -142 °C. Rf = 0.2 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

  + ): calcd. for C13H19N2O2 [M+H] + : 235.1441, found 235.1440. This compound was obtained following the general procedure N. Starting from diyne 138 (61 mg, 0.5 mmol), pyrrolidine-1-carbonitrile 156 (96.1 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at 50 °C for 4 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 231 (50 mg, 46%, ratio > 99:1) as a white solid. m.p. 110 -112 °C. Rf = 0.28 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

1 H

 1 NMR (400 MHz, CDCl3) δ 5.96 (s, 1H), 4.64 (s, 2H), 3.89 (t, J = 5.7 Hz, 2H), 3.49 -3.33 (m, 4H), 2.75 (t, J = 5.7 Hz, 2H), 2.22 (s, 3H), 2.03 -1.91(m, 4H).

13 C

 13 NMR (101 MHz, CDCl3) δ 155.

  , NH3): m/z = 219 [M + H] + . This compound was obtained following the general procedure N. Starting from diyne 138 (61 mg, 0.5 mmol), N-benzyl-N-methylcyanamide 158 (146 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol

  (CI, NH3): m/z = 269 [M + H] + . 4-(1-Methyl-7-tosyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)morpholine (233) This compound was obtained following the general procedure N. Starting from diyne 139 (82.5 mg, 0.3 mmol), morpholine-4-carbonitrile 155 (67 mg, 0.6 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (7.6 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 2 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 80/20 to 60/40) afforded 233 (100 mg, 86%, ratio > 99:1) as a white solid. m.p. 136 -138 °C. Rf = 0.2 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

1 H

 1 NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.17 (s, 1H),

  This compound was obtained following the general procedure M. Starting from diyne 29 (105 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 10 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 240 (142 mg, 92%, ratio > 99:1) as a light yellow solid. m.p. 106 -108 °C. Rf = 0.12 (Petroleum ether/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (400 MHz, CDCl3) δ 7.69 -7.64 (m, 1H, H1), 7.54 (dd, J = 7.3, 0.9 Hz, 1H, H4), 7.47 (td, J = 7.4, 1.2 Hz, 1H, H3), 7.40 (td, J = 7.4, 1.1 Hz, 1H, H2),6.62 (s, 1H, H10), 4H, H18), 4H, H17), 2H, H13), 2H, H14), 2H, H15), 0.95 (t, J = 7.3 Hz, 3H, H16).

13 C

 13 NMR (101 MHz, CDCl3) δ 191.3 (C7), 163.0 (C12), 161.0 (C11), 154.1 (C9), 140.8 (C5), 136.9 (C6), 133.3 (C3), 130.8 (C2), 123.6 (C1), 120.7 (C4), 116.1 (C8), 95.5 (C10), 66.8 (C18), 45.3 (C17), 34.1 (C13), 30.9 (C14), 22.8 (C15), 14.2 (C16). NOESY (400 MHz, CDCl3) H10 (6.62 ppm) correlates to H17 (3.81 -3.73 ppm). HRMS (ESI + ): calcd. for C20H23N2O2 [M+H] + : 323.1754, found 323.1755. This compound was obtained following the general procedure M. Starting from diyne 29 (105 mg, 0.5 mmol), pyrrolidine-1-carbonitrile 156 (96.1 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 10 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 241 (133 mg, 87%, ratio > 99:1) as a light yellow solid. m.p. 90 -91 °C. Rf = 0.4 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

  This compound was obtained following the general procedure N. Starting from diyne 29 (105 mg, 0.5 mmol), N-benzyl-N-methylcyanamide 158 (88 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 30 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 98/2 to 95/5) afforded 242 (142 mg, 80%, ratio > 99:1) as a yellow solid. m.p. 106 -108 °C. Rf = 0.34 (Petroleum ether/Ethyl acetate; 90/10, KMnO4, UV).

  + ): calcd. for C24H25N2O1[M+H] + : 357.1961, found 357.1961. This compound was obtained following the general procedure N. Starting from diyne 29 (105 mg, 0.5 mmol), piperidine-1-carbonitrile 157 (66 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 5 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 99/1 to 98/2) afforded 243 (125 mg, 78%, ratio > 99:1) as a yellow solid. m.p. 100 -102 °C. Rf = 0.4 (Petroleum ether/Ethyl acetate; 90/10, KMnO4, UV).

1 H

 1 NMR (300 MHz, CDCl3) δ 7.65 (dt, J = 7.1, 1.0 Hz, 1H), 7.55 (dt, J = 7.5, 1.0 Hz, 1H), 7.46 (td, J = 7.4, 1.3 Hz, 1H), 7.38 (td, J = 7.3, 1.2 Hz, 1H), 6.64 (s, 1H), 3.86 -3.68 (m, 4H), 3.06 (t, J = 7.5 Hz, 2H), 1.78 -1.60 (m, 8H), 1.52 -1.31 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).

  + ): calcd. for C21H25N2O1[M+H] + : 321.1961, found 321.1962. This compound was obtained following the general procedure M. Starting from diyne 28 (106 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 5 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 244 (110 mg, 68%, ratio > 99:1) as a light yellow solid. m.p. 156 -158 °C. Rf = 0.18 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

  + ): calcd. for C20H25N2O2 [M+H] + :325.1911, found 325.1912. This compound was obtained following the general procedure N. Starting from diyne 28 (106 mg, 0.5 mmol), pyrrolidine-1-carbonitrile 156 (58 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 1 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 245 (124 mg, 81%, ratio > 99:1) as a yellow solid. m.p. 170 -171 °C. Rf = 0.23 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

  + ): calcd. for C20H25N2O1[M+H] + : 309.1961, found 309.1962. This compound was obtained following the general procedure N. Starting from diyne 149 (106 mg, 0.5 mmol), pyrrolidine-1-carbonitrile 156 (58 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 5 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 246 (110 mg, 71%, ratio = 99:1) as a slight pink solid. m.p. 140 -142 °C. Rf = 0.2 (Petroleum ether/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.66 -7.55(m, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), 7.19 (td, J = 7.4, 1.0 Hz, 1H),6.20 (s, 1H), 5.33 (s, 1H), 3.78 -3.50(br, 1H), 3

13 C

 13 NMR (75 MHz, CDCl3) δ 156.

  (CI, NH3): m/z = 309 [M + H] + . 1-Cyclopropyl-3-(pyrrolidin-1-yl)-5H-indeno[1,2-c]pyridin-5-ol (247) This compound was obtained following the general procedure N. Starting from diyne 152 (56 mg, 0.3 mmol), pyrrolidine-1-carbonitrile 156 (35 mg, 0.36 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (7.5 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 3 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 60/40 to 50/50) afforded 247 (68 mg, 78%, ratio > 99:1) as a white solid. m.p. 210 -212 °C. Rf = 0.23 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).

1 H 4 Hz

 14 NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 6.46 (s, 1H), 5.85(d, J = 7.4 Hz, 1H), 5.37(d, J = 7.

  + ): calcd. for C19H21N2O1 [M+H] + : 293.1648, found 293.1649.This compound was obtained following the general procedure N. Starting from diyne 153 (58.2 mg, 0.3 mmol), pyrrolidine-1-carbonitrile 156 (58 mg, 0.6 mmol, 2.0 equiv) and Cp*Ru(CH3CN)3PF6 (7.6 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 10 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from To a stirred mixture of 2-butyn-1,4-diol 52 (1 equiv) and pyridine (2.5 equiv) in DCM (0.5 M) was cooled at 0 °C in an ice bath. Acyl chloride (3 equiv) was then added in DCM (0.5 M). The reaction mixture was stirred at room temperature for 18 h until completion (TLC monitoring). The organic layer was washed with water (×3) and brine (×3), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the desired compound.3-Methyl-1,5-diphenylpenta-1,4-diyn-3-ol (249)This compound was obtained following the general procedure O. Starting from acetyl chloride (0.89 mL, 12.5 mmol), phenylacetylene (2.75 mL, 25 mmol, 2 equiv) and nBuLi (25 mmol, 2 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate; 90/10) afforded 249(2.2 g, 70%) as a white solid. m.p. 110 -112 °C. Rf = 0.4 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

  , NH3): m/z = 257 [M -H2O + H] + . 3-(tert-Butyl)-1,5-diphenylpenta-1,4-diyn-3-ol (251) This compound was obtained following the general procedure O. Starting from pivaloyl chloride (1.23 mL, 10 mmol), phenylacetylene (2.2 mL, 20 mmol, 2 equiv) and nBuLi (20 mmol, 2 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate; 95/5) afforded 251 (2.6 g, 90%) as a white solid. m.p. 83 -85 °C. Rf = 0.5 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

13 C

 13 NMR (75 MHz, CDCl3) δ 132.0,

  , NH3): m/z = 271 [M -H2O + H] + . 1,3,5-Triphenylpenta-1,4-diyn-3-ol (252)

  This compound was obtained following the general procedure F. Starting from 3-methyl-1,5diphenylpenta-1,4-diyn-3-ol 249 (1 g, 4.1 mmol), propargyl bromide (0.58 mL, 5.3 mmol, 1.3 equiv) and sodium hydride (0.22 g, 5.3 mmol, 1.3 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 254 (1 g, 87%) as a white solid. m.p. 50 -52 °C. Rf = 0.6 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.55 -7.44 (m, 4H), 7.39 -7.28 (m, 6H), 4.59 -4.53 (m, 2H), 2.52 -2.46 (m, 1H), 1.99 (s, 3H).

  0. MS (CI, NH3): m/z = 229 [M -C4H6O + H] + .This compound was obtained following the general procedure F. Starting from 1-phenyl-3-(phenylethynyl)hex-1-yn-3-ol 250 (0.27 g, 1 mmol), 1-bromo-2-butyne (0.1 mL, 1.2 mmol, 1.2 equiv) and sodium hydride (0.052 g, 1.3 mmol, 1.3 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 98/2 to 95/5) afforded 256 (0.24 g, 74%) as a pale yellow sticky oil. The melting point was difficult to determine. Rf = 0.65 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

  In a round bottom flask, 2-butyne-1,4-diol 52(2.15 g, 25.0 mmol) was dissolved in THF (50 mL) and combined with NaOH (3.5 g, 87 mmol, 3.5 equiv) in water (50 mL). The flask was cooled to 0 °C (ice bath), and a solution of p-toluenesulfonyl chloride (10.5 g, 55.0 mmol, 2.2 equiv) in THF (50 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 2 h until complete reaction. The product was then extracted with ethyl acetate (2×50 mL) and washed with saturated NaHCO3 (3×30 mL), water (2×50 mL), and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the product 265 as a grey solid (8.2 g, 83%). m.p. 98-100 °C. The analytical data were identical to the literature. 208 Rf = 0.21 (Cyclohexane/Ethyl acetate; 80/20, KMnO4, UV).1 H NMR (300 MHz, CDCl3) δ 7.81 -7.71 (m, 4H), 7.39 -7.30 (m, 4H), 4.58 (s, 4H), 2In a vacuum line, an oven-dried Schlenk tube was degassed and purged with argon three times. Rh(cod)2BF4 (5 mol %) and (R)-BINAP (5 mol%) were introduced under argon. The Schlenk flask was then degassed and purged with argon three additional times. Under argon, freshly distilled and degassed DCM (1.0 mL) was added and the mixture was allowed to stir at room temperature for 30 min. A solution of the corresponding alkyne (2 equiv) in distilled DCM (1.0 mL) was then introduced under argon. The Schlenk flask was tightly sealed and allowed to stir at room temperature for additional 10 minutes. A solution of the corresponding triyne (1 equiv) in distilled DCM (1.0 mL) was finally added dropwise at room temperature. The reaction mixture allowed to stir at 40 °C for 20-24 h, concentrated under reduced pressure, and the residue was purified by flash chromatography to afford the desired product.

  : ee = 51%, Chiralpak OD-H, scCO2/MeOH 95/5, P = 150 bar, flow = 4.0 mL/min, 215nm, tmajor = 4.91 min, tminor = 5.78 min. MS (CI, NH3): m/z = 514 [M + NH4] + . This compound was obtained following the general procedure Q. Starting from (3-(but-2-yn-1yloxy)-3-(tert-butyl)penta-1,4-diyne-1,5-diyl)dibenzene 257 (102 mg, 0.3 mmol), but-2-yne-1,4-diyl diacetate 262 (102 mg, 0.6 mmol, 2 equiv), Rh(cod)2BF4 (6.1 mg, 0.015 mmol, 5 mol %), and (R)-BINAP (9.3 mg, 0.015 mmol, 5 mol %). The reaction mixture was stirred at 40 °C for 24 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 275 (80 mg, 51%) as a pale yellow oil.

Table R1 . Optimisation des conditions de la réaction

 R1 1,6 pontés et d'alcynes, en présence de RuCl3•nH2O comme catalyseur. Nous avons étudié la cycloaddition [2+2+2] catalysée par le complexe RuCl3•nH2O, en utilisant le diyne 17, qui contient un pont benzoyle, avec le 1,4-diméthoxy-but-2-yne 51 comme substrat modèle. Nous avons examiné différents paramètres en vue d'optimiser les conditions de la réaction. Nous avons ainsi fait varier la température, le nombre d'équivalents d'alcyne, le pourcentage de RuCl3•nH2O et enfin le temps de réaction. Nous avons ainsi pu établir que les meilleures conditions étaient d'opérer avec 2 équivalents d'alcyne, 5% molaire de RuCl3•nH2O, à 50 °C pour une durée de deux heures. Dans ces conditions réactionnelles, le dérivé 65 a été isolé avec 72% de rendement.

	O	OMe	O	nBu
	Entrée 1 2 3 4 a 5 6 7 8 9 b 17 a 2% mol RuCl3•nH2O (0.007 mmol) utilisés. nBu 17/51 T (°C) t (h) 1:6 110 18 1:4 80 18 1:3 80 18 1:3 80 18 1:3 50 18 1:2 50 18 1:2 50 4 1:2 50 2 1:2 50 18 T, t OMe 51 RuCl 3 •nH 2 O 5% mol Conv. (%) b > 99 > 99 > 99 60 > 99 > 99 > 99 > 99 40 conditions sans-solvant +	65	Rdt (%) c 86 74 73 40 75 72 73 72 nd OMe OMe

b Sous atmosphère d'air.

Ayant établi les conditions optimales de la réaction, nous nous sommes intéressés à la généralisation, en particulier l'effet du substituant en position C7. Il ressort ainsi qu'un phényle

  furan 94, au diol 95, et au polycycle dibromé 96 avec de bons rendements (Schéma R7).

	O	OMe		O	nBu
	nBu	+	RuCl 3 •nH 2 O 5% mol conditions sans-solvant		OMe OMe
		OMe	80 °C, 20 h
	17, 1.0 g	51 (2 équiv)	65, 71%

Table R2 . Optimisation des conditions de la réaction

 R2

	Entrée	101/154	T (°C)	Conv. (%) b	Rdt (%) c
	1	1:6	110	>99	75
	2	1:3	110	>99	76
	3 a,b	1:3	110	50	nd
	4	1:3	80	90	72
	5	1:3	50	nr	nd
	6	1:2	80	30	nd
	7 b	1:2	90	70	nd
	8 b	1:2	100	93	70
	9	1:2	110	>99	74

a 0.02 mmol of RuCl3•nH2O (2% mol) utilisés.

b

24 heures de réaction.

Table R3 . Optimisation des conditions de la réaction

 R3

	Entrée Diyne	Catalyst (x% mol)	t	Produit Conv. (%)	Rdt (%)
	1	101	Ru(PPh3)3Cl2 (5)	8 h	169	nr	nd
	2	101	[Ru(p-cymene)Cl2]2 (2.5)	8 h	169	nr	nd
	3	101	Cp*Ru(cod)Cl (2)	5 min	169	>99	85
	4	101	Cp*Ru(CH3CN)3PF6 (5)	5 min	169	>99	93
	5	101	Cp*Ru(CH3CN)3PF6 (2)	5 min	169	>99	91
	6	101	Cp*Ru(CH3CN)3PF6 (1)	60 min	169	80	nd
	7	109	Cp*Ru(CH3CN)3PF6 (2)	3 min	188	>99	94
	8 a	109	Cp*Ru(CH3CN)3PF6 (1)	2 min	188	>99	95
	9 a	109	Cp*Ru(CH3CN)3PF6 (0.5)	18 h	188	90	82
	10 b	109	Cp*Ru(CH3CN)3PF6 (

Table R4 . Optimisation des conditions de la réaction

 R4 1,4-diacétoxy-but-2-yne 262 comme modèles pour conduire au 1,3-Ayant établi les conditions optimales pour mener la réaction de cycloaddition, nous avons examiné l'influence de différentes phosphines, comme le (R)-Xylyl-BINAP, le (R)-Difluorphos ou encore le (R)-MeOBiphep. Nous n'avons pas noté d'amélioration significative. De même, plusieurs solvants ont été testés, parmi lesquels le THF, le dichloroéthane, ou le xylène. Le toluène s'est avéré un bon candidat puisque il a donné un ee identique à celui obtenu avec le DCM, et avec un rendement supérieur (70%); toutefois cela nécessite d'opérer à une température de 100 °C.

				Schéma R22
	d	Entrée	[Rh] catalyseur	Additif (x% mol) Rendement (%) b ee (%)

dihydroisobenzofurane 266. Différents catalyseurs de rhodium ont été évalués, en opérant dans le dichlorométhane à une température de 40°C, en présence de (R)-BINAP comme ligand. Les résultats sont regroupés dans le tableau R4, et montrent que la combinaison du catalyseur Rh(cod)2BF4 et du (R)-BINAP est la plus efficace pour mener la cycloaddition. Il est à noter que la réaction n'a pas lieu en absence de phosphine.

c. Influence de l'alcyne interne symétrique

Par la suite, nous avons examiné l'influence de différents groupes protecteurs sur les fonctions alcools en utilisant les conditions mises au point, à savoir des groupements donneurs ou électroattracteurs. De même, les fonctions alcools ont été remplacées par des groupes alkyles ou esters. Il est à noter qu'aucune réaction n'a lieu avec deux groupements phényles (composé 272 voir Schéma R22). Les rendements varient entre 20% et 79%, tandis que les ee restent modérés à faibles (21-50%).

. Influence du substituant porté par le carbone quaternaire du triyne Pour

									Ph
	Ph	Me	O	Ph Me	+	R R	Rh(cod) 2 BF 4 5% mol (R)-BINAP 5% mol DCM, 40 °C, 20-24 h	O	Me	Ph	R R
			255	51, 53, 54, 261-265				Me
					(2 équiv)
	Ph				Ph				Ph
	Me	Ph			Me	Ph	Me	Ph
	O		OAc OAc		O		OCOtBu OCOtBu	O			OCOPh OCOPh
		Me				Me			Me
	266					267		268
	Rdt 50 %, 50% ee			Rdt 20%, 36% ee	Rdt 28 %, 46% ee
	Ph				Ph			Ph
	Me	Ph			Me	Ph		Me	Ph
	O		Et Et			O		OMe OMe	O			CO 2 Me CO 2 Me
			Me					Me			Me
	269					270		271
	Rdt 79%, 21% ee			Rdt 63%, 32% ee	Rdt 51%, 47% ee
			Ph					Ph
				Me	Ph		Me	Ph
				O		Ph Ph		O	OTs OTs
						Me			Me
			272, non observé		273, non observé

compléter cette étude, nous nous sommes intéressés à l'influence stérique engendrée sur les triynes, en remplaçant le groupe méthyle par un groupement plus volumineux, comme le n-propyle ou tert-butyle ou encore un phényle. L'augmentation de l'encombrement stérique en position R' ne conduit pas à une amélioration du rendement ni de l'excès énantiomérique (Schéma R23).

  Synlett 2008, 755.

	CO 2 Me CO 2 Me	+	OMe OMe	[Ir(cod)Cl] 2 2 mol % Ligand 4 mol % THF, 50 °C, 1-2 h	OMe OMe	OMe CO 2 Me CO 2 Me OMe	+	MeO 2 C MeO 2 C	CO 2 Me CO 2 Me	OMe OMe
								A			B
			dppe		Ph 2 P	PPh 2		Ligand	Yield (%)	A : B
			fdppe	(C 6 F 5 ) 2 P	P(C 6 F 5 ) 2	dppe fdppe		98 97	<5:95 >95:5
				E	E	Ph 2 P	R	R	Pf 2 P
					Ir			Ir
				E	E Cl	P Ph 2	R	R Cl	P Pf 2
					Ir-I			Ir-II
					E = CO 2 Me	R = CH 2 OMe, Pf = C 6 F 5

  Me, nBu, nC 5 H 11 , nC 10 H 21 , Ph, CO 2 Et, CH 2 OMe R 3 = H, nC 5 H 11 , CH 2 OH, CH 2 OMe, CO 2 Et

				PPh 2
				PPh 2
	R 1 = H, CO 2 nBu R 2 = R 3		R 3	(rac)-H 8 -BINAP
	Selected examples:
	Ph	Ph	n-C 12 H 25 n-C 12 H 25
			Me Me	Me Me
	6% (two steps)	46% (two steps)

  44

Scheme 34 2.5. Ruthenium-catalyzed partially intramolecular [2+2+2] cycloadditions Cp*Ru(cod)Cl catalyst:

  ChemCatChem 2013, 5, 2389.

	In 2003, this atom-economical process has also been successfully performed under
	solvent-free conditions to access various fused arenes in 43-85% yields (Scheme 34). 45
	[{Ir(H)[rac-binap]} 2 (m-I) 3 ]I 4 mol % iPrOH or To luene 80 or 110 °C, 17-48 h R 3 = nBu, cyclopropyl, CH 2 OH, CH(Me)OH, (CH 2 ) 2 OH, R 1 R 3 X + R 2 X = C(CO 2 Me) 2 , NTs, NBoc, O R 1 , R 2 = H, Me, Ph O B In 2000, Itoh and Yamamoto described the first example of ruthenium-catalyzed [2+2+2] R 1 R 3 X R 2 , 40 examples 30-97%
	(CH 2 ) 3 OH, (CH 2 ) 3 Cl, Ph, 4-Me-C 6 H 4 , 4-MeO-C 6 H 4 cycloaddition of -diynes with monoalkynes using Cp*Ru(cod)Cl catalyst. 46 Later, they O
	Ph 2 P H Ir extended the scope of this reaction, and found that a variety of tethered diynes including I I Ph 2 P Ir + H
	PPh 2 heteroatom tethered diynes, such as nitrogen, oxygen, sulfur, was compatible with these I Ph 2 P [I] -
	reaction conditions leading to the formation of the corresponding benzene derivatives in 64-
	[{Ir(H)[rac-binap]} 2 (m-I) 3 ]I 96% yields. A self-dimerization or trimerization of diynes product have been detected in some
	Selected examples: cases as a competitive process (Scheme 35). 47			Me
	BocN	OH	BocN		Cl	TsN	OH
	90%				61%			76% Me
	TsN		Ph	B O	O	O	B O	O
			Ph
			78%				62%
				Scheme 33 Scheme 35
	45 Auvinet, A.-L.; Michelet, V.; Ratovelomanana-Vidal, V. Synthesis 2013, 45, 2003.
	46 Yamamoto, Y.; Ogawa, R.; Itoh, K. Chem. Commun. 2000, 549.
	47 Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2003, 125, 12143.

43 Yamagata, T.; Tadaoka, H.; Nagata, M.; Hirao, Y.; Kataoka, Y.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Mashima, K. Organometallics 2006, 25, 2505. 44 (a) Auvinet, A.-L.; Ez-Zoubir, M.; Vitale, M. R.; Brown, J. A.; Michelet, V.; Ratovelomanana-Vidal, V. ChemSusChem 2012, 5, 1888. (b) Auvinet, A.-L.; Ez-Zoubir, M.; Bompard, S.; Vitale, M. R.; Brown, J. A.; Michelet, V.; Ratovelomanana-Vidal, V.

  Petit, M.; Chouraqui, G.; Aubert, C.; Malacria, M. Org. Lett. 2003, 5, 2037.

	TsN	Me	+	R 1	Grubbs-I 5 mol % DCM, 40 °C, 10-20 h	TsN	Me	R 1	+	TsN	Me	R 1
						PCy 3		meta				ortho
					Cl Cl	Ru	Ph	R 1		Yield %	meta:ortho
						PCy 3		Ph		82	5:1
					Grubbs-I	C 3 H 7	92	6:1
	X		Me	Cl 2 (PCy 3 ) 2 Ru	Ph				Me
											X
		preferred addition								R 1 meta selective
				Me			Me
		X		[Ru]				X			R 1
										Ru
		Ru-I	Ph							Ru-III
										Ph
							Me
							[Ru]		R 1
						X
						Ru-II	Ph

  Zhao, J.; Yue, D.-W.; Campo, M. A.; Larock, R. C. J. Am.Chem. Soc. 2007, 129, 5288.

						O						O
									Pd(OAc) 2 10 mol %
										NMI, 190	°C
						I			100%
									Scheme 51
													O
					O	OCH	OCH
							3
								PdCl	2 (PPh	3 )	2 20 mol %	H	3 C	OCH
		3 OCH In 2008, Daugulis and co-workers reported a one-pot synthetic method for ortho-NaOAc 2 equiv H 3 C
													3
									DMA, 140 °C, 1 min
	53% benzonitriles and fluorenone derivatives formation by the palladium-catalyzed C-H bond H 3 CO I
				OCH	3	OCH	3						H	3 CO
	functionalization of simple benzamide and aryl halides (Scheme 52). 69 Notably, the reaction
	could afford various desired products by tuning the alkyl substituent on the amide group. N-
	cyclohexyl benzamides led to the formation of benzonitrile derivatives, whereas N-propyl
	benzamides can be converted to fluorenones.
	R 1	CN H	R 2	1. Pd(OAc) 2 5 mol % Ag 2 O 1.3-2.3 equiv TFA , 120 °C 2. (CF 3 CO) 2 O 90-110 °C, 1-3 h	O	NHR H +	I H	R 2	1. Pd(OAc) 2 5 mol% AgOAc 1.3-2.3 equiv TFA , 120 °C 2. (CF 3 CO) 2 O 110 °C, 0	R 1	O	R 2
									Scheme 52
		Beside imines, oximes can be also considered as directing groups in Pd-catalyzed C-H
	activation to synthesize fluorenone derivatives. In 2008, Cheng and co-workers reported a Pd-
	catalyzed synthesis of fluorenones from substituted aromatic aldoxime ethers and aryl iodides
	through a dual C-H activation and oxidative Heck cyclization (Scheme 53). 70 A series of control
	69 Shabashov, D.; Maldonado, J. R. M.; Daugulis, O. J. Org. Chem. 2008, 73, 7818.
	70 Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem. Int. Ed. 2008, 47, 9462.

Scheme 60 2.2.1.3 Dehydrogenative cyclization

	experiments suggested that both palladium acetate and silver oxide are required for this
	transformation, allowing the facile synthesis of the desired fluorenones in 63-90% yields.
	Scheme 55
	Hsieh and co-workers developed in 2013 a method for the preparation of polysubstituted
	Scheme 59 fluorenones via a Pd-catalyzed nitrile directed remote C-H and dual C-H bond activation with Scheme 57 Scheme 53 intramolecular 1,2-insertion of nitrile (Scheme 56). 73 A wide range of functional groups were Sorensen's group reported in 2017 Pd-catalyzed C(sp 2 )-H functionalization cascade
	Shi and co-workers described in 2010 a one-pot Pd-catalyzed ortho-directed C-H arylation of aromatic aldoxime ether and arylboronic acids for the synthesis of fluorenone tolerated under the reaction conditions, providing various fluorenones in 17-91% yields. In 2014, Wang's group described a Pd-catalyzed intramolecular C-C coupling reaction reactions for the preparation of fluorenones from readily available benzaldehydes and aryl through a dual C-H bond activation directed by a removable carboxylate group. 75 The reaction iodides using anthranilic acid as transient directing group. 77 It is worthy to mention that the
	derivatives (Scheme 54). 71 proceeds in the presence of Pd(OAc)2 and Cu(OAc)2•nH2O under air atmosphere, to provide antiviral drug Tilorone was synthesized in 40% yield over three steps (Scheme 60).
	various substituted fluorenones in 31-91% yields. According to the proposed mechanism, the
	intramolecular carboxylate-directed dual C-H activation generates a 9H-fluorene-9-carboxylic NH 2
	acid (I) intermediate, a subsequent oxidative decarboxylation by the oxygen from the air in the presence of Pd(OAc)2 and Cu(OAc)2 and furnishes the cyclized product along with eliminating carbon dioxide and water (Scheme 58). Scheme 58 R 1 H R 2 H (9:1, 0.15 M) R 1 R 2 AcOH/HFIP + AgTFA 2.0 equiv H I Pd(OAc) 2 10 mol % O O
	120 °C, air, 36 h	33 examples
	Another interesting example involving Pd-catalyzed carboxylic acid directed ortho-14-72%
	Scheme 56 selective oxidative C-H/C-H cross-coupling of aromatic carboxylic acids with arenes followed
	3,5-diMe, 4-tBu, 4-CO 2 Et, 6 examples by subsequent intramolecular Friedel-Crafts acylation for the construction of poly-substituted 7 examples 54-84% 62-79% Scheme 54 In addition, a Pd-catalyzed ortho C-H activation of benzylamines with iodo arenes to fluorenones was reported by You and co-workers. (Scheme 59). 76 By following this strategy, a
	4-Cl, 4-Br, 4-CF 3 In 2011, the continuous work in Cheng's group demonstrated that a Pd-catalyzed ortho-provide fluoreonone derivatives has been explored. Satyanarayana and co-workers reported a variety of commercially available aromatic carboxylic acids and arenes were successfully
	directed multiple C-H activation of aromatic aldoxime ether with arenes could proceed one-pot domino Pd-catalyzed reaction proceeding through the formation of a five-membered converted to substituted fluorenones in 53-82% yields.
	smoothly to give the corresponding substituted fluorenone derivatives in 42-91% yields Pd(II)-cycle and subsequent ortho C-H activation with iodoarenes to give fluorenones in 42-
	(Scheme 55). 72 Notably, this synthetic method for the preparation of fluorenones showed a 88% yields with high regioselectivities (Scheme 57). 74 Notably, the reaction could further
	significant improvement since it avoided the use of aryl halides, aryl boronic acids, and activate C(sp 3 )-H and C(sp 2 )-H bonds to afford the fused fluorenone derivatives.
	expensive metal oxidants.
	In 2012, Cheng's group disclosed a novel synthetic method involving a dual C-H
	activation of diarylketones to form fluorenones by Pd-catalyzed oxidative dehydrogenative
	71 Sun, C.-L.; Liu, N.; Li, B.-J.; Yu, D.-G.; Wang, Y.; Shi, Z.-J. Org. Lett. 2010, 12, 184. 73 Wan, J.-C.; Huang, J.-M.; Jhan, Y.-H.; Hsieh, J.-C. Org. Lett. 2013, 15, 2742.
	72 Thirunavukkarasu, V. S.; Cheng, C.-H. Chem. Eur. J. 2011, 17, 14723. 74 Kumar, D. R.; Satyanarayana, G. Org. Lett. 2015, 17, 5894. 77 Chen, X.-Y.; Ozturk, S.; Sorensen, E. J. Org. Lett. 2017, 19, 1140.

.2.1.5 Decarboxylative cyclization

	(Scheme 62). 80 Fluorenones were formed in 50-85% yields in the presence of reusable Pd(II)/Mg-La catalyst under heterogeneous reaction conditions. smoothly under a carbon monoxide atmosphere, leading to the substituted fluorenones in 22-94% yields (Scheme 64). Notably, a series of more challenging fluorenones containing various substituents and -conjugated extended systems was achieved. 2With respect to carbonyl sources, several methods involving different carbonyl sources,
	such as carboxylic acids, nitriles, aldoximes, aldehydes, have been reported for the preparation
	of fluorenones. Jin and co-workers reported in 2016 a one-pot palladium-catalyzed
	decarboxylative cyclization of 2-phenylbenzoic acid to synthesize fluorenones by using tert-
	Shi's group reported similar conditions butyl isocyanide as a new carbonyl source (Scheme 66). 84 Subsequent C-H activation and
	to access fluorenone derivatives through palladium-catalyzed dehydrogenative cyclization decarboxylation insertion of the isocyanide into 2-phenylbenzoic acid provided a six-membered
	reactions. 79 intermediate that underwent elimination and hydrolysis to generate the cyclized product. Scheme 62
	2.2.1.4 Cyclocarbonylation
	The first practical method for the Pd-catalyzed cyclocarbonylation of ortho-halobiaryls
	to substituted fluorenone derivatives was developed by Larock's group in 2000. 81 Treatment of
	the ortho-halobiaryls with 5 mol % of Pd(PCy3)2 and 2 equivalents of anhydrous cesium
	pivalate in DMF solution under 1 atm of carbon monoxide atmosphere provided the expected
	fluorenones in 67-100% yield. This method has been successfully employed for the preparation
	of polycyclic and heterocyclic fluorenones (Scheme 63).
					Scheme 64
	Kakiuchi's group described in 2016 a Pd-catalyzed cyclocarbonylation of 2-
	bromobiphenyls with formaldehyde through the cleavage of a C-H bond to afford the desired
	fluorenones in 45-75% yields (Scheme 65). 83 The use of paraformaldehyde as a carbonyl
	surrogate resulted in a practical synthetic method and can be widely used.
	Br				Pd(OAc) 2 10 mol % PCy 3 •HBF 4 30 mol %	O
	1'	2'	4' R 3'	+ (CH 2 O) n (20 equiv)	Scheme 61 To luene, 110 °C, 20 h Na 2 CO 3 2 equiv, MgSO 4 PivOH 30 mol %	6 examples	R
	Scheme 63 R = 4'-H, 4'-MeO, 4'-Me, 4'-F, 4'-CF 3 , 2'-F	45-75%
	Kantam and co-workers reported in 2015 an efficient method for the synthesis of
	fluorenones A related study published in 2015 by Xie and co-workers 82 demonstrated that the Pd-by dehydrogenative cyclization of benzophenones using a Scheme 65
	palladium(II)/magnesium-lanthanum mixed oxide catalyst in TFA/H2O solution system catalyzed carbonylative cross-coupling of aryl dihalides with arylboronic acids proceeded
	80 Kishore, R.; Priya, S. S.; Sudhakar, M.; Venu, B.; Venugopal, A.; Yadav, J.; Kantam, M. L. Catal. Sci. Technol.
	2015, 5, 3363.
	78 Gandeepan, P.; Hung, C.-H.; Cheng, C.-H. Chem. Commun. 2012, 48, 9379. 81 Campo, M. A.; Larock, R. C. Org. Lett. 2000, 2, 3675.
	79 Li, H.; Zhu, R.-Y.; Shi, W.-J.; He, K.-H.; Shi, Z.-J. Org. Lett. 2012, 14, 4850. 82 Song, J.; Wei, F.-L.; Sun, W.; Li, K.; Tian, Y.-N; Liu, C.; Li, Y.-L; Xie, L.-H. Org. Lett. 2015, 17, 2106. 83 Furusawa, T.; Morimoto, T.; Oka, N.; Tanimoto, H.; Nishiyama, Y.; Kakiuchi, K. Chem. Lett. 2016, 45, 406.

Scheme 66 2.2.1.6 Other methods for the preparation of fluorenones

	In 2005, Larock's group reported the synthesis of fluorenone derivatives via a
	palladium-catalyzed annulation of arynes with o-halobenzaldehydes. 85 Later, they extended the
	scope of functionalized o-halobenzaldehydes and arynes. 86 A variety of o-halobenzaldehydes
	and arynes has been examined, affording the substituted fluorenones in 33-82% yields (Scheme
	67).
	84 Cai, Z.-Q.; Hou, X.; Hou, L.; Hu, Z.-Q.; Zhang, B.; Jin, Z.-S. Synlett 2016, 27, 395.
	85 Zhang, X.-X.; Larock, R. C. Org. Lett. 2005, 7, 3973.
	86 Waldo, J. P.; Zhang, X.-X.; Shi, F.; Larock, R. C. J. Org. Chem. 2008, 73, 6679.

.3 Silver-catalyzed synthesis of fluorenones 2.2.3.1 Intramolecular radical cyclization

	DCM, rt, 1-40 h Rh(cod) 2 BF 4 10 mol % (R)-Segphos or (R)-BINAP or (R)-H 8 -BINAP 10 mol % 2.2In 2011, Baran and co-workers developed a silver-catalyzed intramolecular radical 8 examples 26-61% yields, 10-47% ees O Me Me + O R O O O Me R R O O O R Me R 1 O cyclization of arylboronic acids and potassium aryltrifluoroborates, in the presence of silver O R = Me, nBu, Ph, CH 2 OMe nitrate and potassium persulfate, to access fluorenones through a 'borono-Pschorr' process
	R 1 (Scheme 74). 94 The reaction was carried out under mild conditions and tolerated various R 2 Rh(cod) 2 BF 4 R 2
	O functional groups, such as CO2Me, CN, CF3. The aza-fluorenones were synthesized as a + /(S)-Xylyl-Segphos 10-20 mol % O DCE, rt, 16 h mixture with moderate regioselectivity.
	R 1	R 2				R 2
					R 1
	R 1 = H, CO 2 nBu				10 examples
	R 2 = nBu, (CH 2 ) 9 CH 3 , (CH 2 ) 3 Ph, (CH 2 ) 3 OBn, (CH 2 ) 3 Cl			49-74% yields, 53-93% ees
			O		O
	PPh 2	PPh 2	O	PPh 2	O	PAr 2
	PPh 2	PPh 2	O	PPh 2	O	PAr 2
			O		O
	(R)-H 8 -BINAP	(R)-BINAP	(R)-Segphos	(S)-Xylyl-Segphos
					Ar = 3,5-Me 2 C 6 H 3

Scheme 74 2.2.3.2 Decarboxylative radical cyclization

	Greaney and co-workers reported in 2012 a similar study which involved Ag-catalyzed
	decarboxylative radical cyclization of arylbenzoic acids to afford fluorenones (Scheme 75). 95
	Notably, CD3CN was unconventionally chosen as solvent, because of the stronger C-D bond
	that decreased hydrogen atom abstraction from the solvent. In addition, deuterated
	decarboxylation product was obtained as a side product which confirmed that the solvent was
	acting as a hydrogen atom donor.
	94 Lockner, J. W.; Dixon, D. D.; Risgaard, R.; Baran, P. S. Org. Lett. 2011, 13, 5628.
	95 Seo, S.; Slater, M.; Greaney, M. F. Org. Lett. 2012, 14, 2650.

Scheme 75 2.2.4 Copper-catalyzed synthesis of fluorenones

	A Cu-catalyzed simple construction of methoxy-substituted fluorenones from
	substituted 2-iodobenzophenones was reported by Haggam (Scheme 76). 96 This study
	demonstrated that the intramolecular Cu-catalyzed cyclization of 2-iodobenzophenones
	afforded the corresponding fluorenones in 71-92% yields under conventional heating or under
	microwave conditions in a shorter reaction time.
	Scheme 76
	96 Haggam, R. A. Tetrahedron 2013, 69, 6488.

Table 1

 1 Optimization of the reaction conditions

	Entry a	17/51	T (°C)	t (h)	Conv. (%) b	Yield (%) c
	1	1:6	110	18	> 99	86
	2	1:4	80	18	> 99	74
	3	1:3	80	18	> 99	73
	4 d	1:3	80	18	60	40
	5	1:3	50	18	> 99	75
	6	1:2	50	18	> 99	72
	7	1:2	50	4	> 99	73
	8	1:2	50	2	> 99	72
	9 e	1:2	50	18	40	nd

a Reaction conditions: RuCl3•nH2O (0.0175 mmol), diyne 17 (0.35 mmol), alkyne 51 (0.7 mmol) were heated in a screw-capped tube under free-solvent conditions and argon atmosphere. b Determined by 1 H NMR. c Isolated yields. d 2 mol % RuCl3•nH2O (0.007 mmol) was used. e Under air atmosphere.

  Several examples have been described in 40-99% yields.

	138 Wang, G.; You, X.; Gan, Y.; Liu, Y. Org. Lett. 2017, 19, 110.
	139 (a) D'Souza, B. R.; Lane, T. K.; Louie, J. Org. Lett. 2011, 13, 2936. (b) Wang, C.; Li, X.; Wu, F.; Wan, B.

Angew. Chem. Int. Ed. 2011, 50, 7162. (c)

Richard, V.; Ipouck, M.; Mérel, D. S.; Gaillard, S.; Whitby, R. J.; Witulski, B.; Renaud, J.-L. Chem. Commun 2014, 50, 593. (d) Casitas, A.; Krause, H.; Goddard, R.; Fürstner, A. Angew. Chem. Int. Ed. 2015, 54, 1521. 140 Lane, T. K.; D'Souza, B. R.; Louie, J. J. Org. Chem. 2012, 77, 7555. 141 Wang, C.; Wang, D.; Xu, F.; Pan, B.; Wan, B. J. Org. Chem. 2013, 78, 3065.

Table 2 Optimization of reaction conditions

 2

	MeO 2 C MeO 2 C	Me Me	+	Me	N N	Me	solvent-free conditions T, 18 h RuCl 3 •nH 2 O 5 mol %	MeO 2 C MeO 2 C	Me N Me	Me Me N
	101				154				168
	Entry	101/154			T (°C)	Conv. (%) b	Yield (%) c
	1	1:6					110	>99		75
	2	1:3					110	>99		76
	3 d,e	1:3					110		50		nd
	4	1:3					80		90		72
	5	1:3					50		nr		nd
	6	1:2					80		30		nd
	7 e	1:2					90		70		nd
	8 e	1:2					100		93		70
	9	1:2					110	>99		74
	reaction being carried out at 80 °C under solvent-free conditions (Entry 1). However, attempts
	to further decrease the reaction temperature to 70 °C and 60 °C, led to a decreased conversion
	or no reaction (Entries 2 and 3). Cyclic cyanamides N-cyanopyrrolidine 156 and N-

a Reaction conditions: RuCl3•nH2O (0.05 mmol), diyne 101 (1.0 mmol), cyanamides 154 (2.0 mmol) were heated in a screw-capped tube under free-solvent conditions and an argon atmosphere.

b

Determined by crude 1 H NMR, nr = no reaction. c Isolated yields, nd = not detected. d 0.02 mmol of RuCl3•nH2O (2 mol %) was used.

e

The reaction was stirred for 24 hours.

With a set of optimized reaction conditions in hand, we next evaluated the reactivity of various secondary or primary amines derived cyanamides 155-163 and 165-167 with diyne 101, as shown in Table

3

. We found that the

[2+2+2]

cycloaddition of diyne 101 with morpholinefunctionalized cyanamide 155 furnished the desired pyridine 169 in excellent 95% yield, the cyanopiperidine 157 successfully reacted with diyne 101 to give the targeted heterocycles 170 and 171 in 86% and 78% yields, respectively (Entries 4 and 5). The N-methylbenzylcyanamide 158 reacted with diyne 101 at 80 °C to provide 2-aminopyridine 172 in 81% yield (Entry 6),

Table 3 Scope of different substituted cyanamides

 3

	Entry	Cyanamides	T (°C) Product Conv. (%) b Yield (%) c
	1		80	169	>99	95
	2	155	70	169	95	88
	3		60	169	nr	nd
	4	156	80	170	96	86
	5	157	110	171	>99	78
	6	158	80	172	>99	81
	7	159	110	173	90	75
	8	160	80	174	26	nd
	9	161	110	175	20	nd
	10	162	80	176	22	nd
	11	163	110	177	nr	nd
	12	165	110	178	nr	nd
	13	166	110	179	decomposed	nd
	14	167	110	180	nr	nd

a Reaction conditions: RuCl3•nH2O (0.05 mmol), diyne 101 (1.0 mmol), cyanamides 155-163 and 165-167 (2.0 mmol) were heated in a screw-capped tube under freesolvent conditions and an argon atmosphere.

b

Determined by crude 1 H NMR, nr = no reaction. c Isolated yields, nd = not detected.

Table 4 Optimization of reaction conditions

 4 The formation of compounds 186 and 187 demonstrated that the cycloaddition was not limited to terminal diynes but also worked well with internal diynes. However, more sterically hindered internal diynes, such as di-TMS, diaryl, and dibromo-substituted diynes (110, 113 and 124) did not afford the desired cycloadducts, despite increased reaction temperature (Scheme 154).

	Entry Diyne	Catalyst (x mol %)	t	Product	Conv. (%) b	Yield (%) c
	1	101	Ru(PPh3)3Cl2 (5)	8 h	169	nr	nd
	2	101	[Ru(p-cymene)Cl2]2 (2.5)	8 h	169	nr	nd
	3	101	Cp*Ru(cod)Cl (2)	5 min	169	>99	85
	4	101	Cp*Ru(CH3CN)3PF6 (5)	5 min	169	>99	93
	5	101	Cp*Ru(CH3CN)3PF6 (2)	5 min	169	>99	91
	6	101	Cp*Ru(CH3CN)3PF6 (1)	60 min	169	80	nd
	7	109	Cp*Ru(CH3CN)3PF6 (2)	3 min	188	>99	94
	8 d	109	Cp*Ru(CH3CN)3PF6 (1)	2 min	188	>99	95
	9 d	109	Cp*Ru(CH3CN)3PF6 (0.5)	18 h	188	90	82
	10 e	109	Cp*Ru(CH3CN)3PF6 (2)	5 min	188	>99	82

a Reaction conditions: Ru complex (0.5-5 mol %), diyne 101 or 109 (0.5 mmol), cyanamides 155 (1.0 mmol) were stirred in a screw-capped tube under solvent-free conditions and an argon atmosphere.

b

Determined by crude 1 H NMR, nr = no reaction. c Isolated yields, nd = not detected. d With 0.6 mmol of cyanamide 155 was used and 0.5 mL of dichloromethane as solvent. e One gramscale.

With a set of optimal conditions in hand, we investigated the scope and limitations of the cycloaddition using different substituted diynes and cyanamide 155 as partner (Scheme 154). A variety of symmetrical diynes with a quaternary-carbon tether reacted with cyanamide 155 to give various 2-aminopyridines in high yields. The 2-aminopyridine cycloadducts 196-199 bearing bulkier tert-butyl, isopropyl, and methyl ester moieties were obtained in 81-98% yields from the corresponding diynes. Notably, a nitrile group substituted on the quaternarycarbon of diyne 117 was compatible with the reaction conditions. However, the malononitrilederived diyne 118 provided the desired product 200 in relatively lower yield (The diyne 121 containing a ketal moiety was also reactive to afford the corresponding product 203 in 87% yield. The reaction was not limited to a quaternary-carbon tethered diyne since the heteroatom-tethered diynes were successfully used, leading to the formation of various pyridine-based fused heterocycles (186, 187, 204, and 205) within a range of 80-99% yields.

Next, an evaluation of the reactivity of the cyanamide substrates was examined. As shown in Scheme 155, various secondary amine derived cyanamides smoothly underwent the cycloaddition reactions to produce the corresponding 2-aminopyridines in 76-97% yields. The reaction of N-cyanopyrrolidine 156 with diynes 101 and 109 delivered the cycloadducts 170 and 207 in 81% and 90% yields, respectively. The cyanamides 159-161 and 164, bearing dibenzyl, diethyl, di-n-propyl, and methyl/n-butyl groups, were engaged in the cycloaddition to

  and provided a new and efficient

					Me
	BnO 2 C BnO 2 C	Me Me	X	O	[Rh(cod)(S)-Xylyl-BINAP]BF 4 5 mol % DCE, 80 °C, 30 min
					Me
					13 examples
					62-94% yield, 80-99% ee

153 Masutomi, K.; Sakiyama, N.; Noguchi, K.;

Tanaka, K. Angew. Chem. Int. Ed. 2012, 51 (52)

, 13031. 154 Amatore, M.; Leboeuf, D.; Malacria, M.; Gandon, V.; Aubert, C. J.

Am. Chem. Soc. 2013, 135, 4576.

  rise to various dibenzo[5]-, dibenzo[6]-, and dibenzo[7]helicenes. Notably, a high catalyst loading (20 mol %) was required to give a higher enantioselectivity (Scheme 175).

	Scheme 175
	160 A series of ortho-
	phenylene-tethered triynes were employed under the Ni(cod)2/(R)-Quinap catalytic system and

160 Jančařík, A.; Rybáček, J.; Cocq, K.; Chocholoušová, J. V.; Vacek, J.; Pohl, R.; Bednárová, L.; Fiedler, P.; Císařová, I.; Stará, I. G.; Starý, I. Angew.

Chem. Int. Ed. 2013, 52, 9970.

gave

  Treatment of the 2-butyl-1,4-diol 52 with 3.5 equivalents of sodium hydroxide in a mixture solution of water and THF at 0 °C with 2.2 equivalents of tosyl chloride furnished the tosyl protected internal alkyne 265 in 83% yield (Scheme 194).

	Scheme 194
	5.2 Rhodium-catalyzed desymmetric [2+2+2] cycloaddition of prochiral
	triynes with internal alkynes
	Scheme 193

178 (a) Muchow, G.; Brunel, J. M.; Maffei, M.; Buono, G. J.

Org. Chem. 1995, 60, 852. (b)

Hudiono, Y. C.; Miller, A. L.; Gibson, P. W.; LaFrate, A. L.; Noble, R. D.; Gin, D. L. Ind. Eng. Chem. Res. 2012, 51, 7453.

With a series of alkynes in hand, we then attempted to synthesize 1,3dihydroisobenzofuran 266 from prochiral triyne 255 and 1,4-diacetoxy-2-butyne 262 through an enantioselective rhodium-catalyzed

[2+2+2]

cycloaddition reaction. As shown in Table

5

, we began our studies by investigating the reactivity of different cationic rhodium catalysts, such as Rh(cod)2BF4,

163-167

[Rh(hexadiene)Cl]2/AgSbF6, 154 [Rh(ethylene)Cl]2/NaBAr F 4, 168-170 which proved to be efficient catalysts in related enantioselective

[2+2+2]

cycloadditions (Entries 1-

Table 5 Optimization of reaction conditions

 5

	Entry a	[Rh] catalyst	Additive (mol %) Yield (%) b	ee (%) c
	1	Rh(cod)2BF4	/	50	50
	2	[Rh(hexadiene)Cl]2	AgSbF6 (5)	74	20
	3 d	[Rh(ethylene)Cl]2	NaBAr F 4 (10)	72	49
	4 e	Rh(cod)2BF4	/	50	50
	5 f	Rh(cod)2BF4	/	nr	/
	6 g	Rh(cod)2BF4	/	66	43
	7 h	Rh(cod)2BF4	/	50	50

a Reaction conditions: [Rh] catalyst (5 mol %), (R)-BINAP (5 mol %), triyne 255 (0.3 mmol), alkyne 262 (0.6 mmol) were heated at 40 °C in a sealed Schlenk tube in DCM (3 mL) under an argon atmosphere for 20-24 h. b Isolated yield, nr = no reaction.

c

Table 7 The effect of solvent

 7

			Ph		Ph Ph			Ph Ph	Ph
	O O P NH	Ph	O O P N Ph	O O	Ph Ph O O	P N	O O	Ph Ph O O	Ph P N
	23%, 27% ee		51%, 40% ee		75%, 5% ee		23%, 5% ee

cycloaddition.

179

Grandclaudon C. (2016) Réactions d'halocarbocyclisation par activation électrophile de fonctions carbonées insaturées (alcènes, alcynes, allènes). Etude des versions racémiques et chirales catalysées par des bases de Lewis

(Doctoral dissertation). Retrieved from https://www.theses.fr/en/2016PA066228 a Reaction conditions: Rh(cod)2BF4 (5 mol %), (R)-BINAP (5 mol %), triyne 255 (0.3 mmol), alkyne 262 (0.6 mmol) were heated at 40 °C or 100 °C in a sealed Schlenk tube under an argon atmosphere for 20 h. b Isolated yield.

c

Determined by SFC analysis.

  Ethyl acetate gradient from 99/1 to 98/2) afforded 4 (2.3 g, 80%) as a white solid. m.p. 32 -34 °C. The analytical data were identical to the literature.184

	Rf = 0.62 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3), δ 10.66 (d, J = 0.9 Hz, 1H), 7.97 -7.92 (m, 1H), 7.68 -7.53 (m,
	2H), 7.49 -7.41 (m, 3H), 7.23-7.16 (m, 2H), 2.39 (s, 3H).

Starting from 2-bromobenzaldehyde (2.5 g, 13.5 mmol) and 4-ethynyltoluene

(1.88 mL, 16.2 mmol, 1.2 equiv)

. Purification on silica gel (Cyclohexane/

  Starting from 1-(2-ethynylphenyl)-hept-2-yn-1-one 29 (0.3 g, 1.42 mmol) and 1-Bromo-4-iodobenzene (0.48 g, 1.7 mmol, 1.2 equiv).

	Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded
	27 (0.25g, 48%) as a brown oil.
	Rf = 0.4 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 8.14 (dd, J = 7.7, 1.1 Hz, 1H), 7.65 -7.60 (m, 1H), 7.56 -7.41
	(m, 6H), 2.45 (t, J = 7.0 Hz, 2H), 1.65 -1.55 (m, 2H), 1.52 -1.38 (m, 2H), 0.92 (t, J = 7.3 Hz,
	3H).

13 C NMR (75 MHz, CDCl3) δ 177.

  Cyclohexane/Ethyl acetate gradient from 98/2 to 95/5) afforded 33(1.3 g, 82%) as a yellow solid. The analytical data were identical to the literature.195

	Rf = 0.4 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 10.37 (s, 1H), 8.24 -8.16 (m, 1H), 7.70 -7.61 (m, 2H), 7.55 -
	7.38 (m, 6H).
	3 (140
	mg, 0.2 mmol, 4 mol %) and CuI (19 mg, 0.1 mmol, 2 mol %). Purification on silica gel

194 Lyaskovskyy, V.; Fröhlich R.; Würthwein, E.-U. Synthesis 2007, 14, 2135.

(13 C NMR (101 MHz, CDCl3) δ 185.

  Starting from 3-(phenylethynyl)thiophene-2carbaldehyde 31 (0.92 g, 4.33 mmol) and 1-Hexyne (0.65 mL, 5.6 mmol, 1.3 equiv).

	Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 38
	(1.13 g, 89%) as a yellow oil.
	Rf = 0.28 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.59 -7.46 (m, 2H), 7.35 (dd, J = 6.5, 2.7 Hz, 3H), 7.23 (d, J =
	5.2 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.05 -5.88 (m, 1H), 2.48 (d, J = 5.1 Hz, 1H), 2.28 (td, J
	= 6.9, 2.0 Hz, 2H), 1.47 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H).

13 C NMR (75 MHz, CDCl3) δ 148.

  Starting from 1-(3- (phenylethynyl)benzo[b]thiophen-2-yl)hept-2-yn-1-ol 39 (0.46 g, 1.34 mmol) and Dess-Martin periodinane (0.74 g, 1.7 mmol, 1.3 equiv). Purification on silica gel (Petroleum ether/Ethyl acetate gradient 98/2 to 95/5) afforded 46 (0.34 g, 74%) as a yellow solid. m.p. 90 -92 °C.

	Rf = 0.62 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 8.19 -8.09 (m, 1H), 7.88 -7.62 (m, 1H), 7.72 -7.62 (m, 2H),
	7.58 -7.45 (m, 2H), 7.45 -7.34 (m, 3H), 2.41 (t, J = 7.2 Hz, 2H), 1.62 -1.48 (m, 2H), 1.45 -
	1.29 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H).

13 C NMR (101 MHz, CDCl3) δ 170

  The residue was purified by flash chromatography (Cyclohexane/Ethyl acetate gradient from 98/2 to 95/5) to afford compound 56 (2.0 g, 75%) as a colorless oil. The analytical data were identical to the

	literature. 98
	Rf = 0.52 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV)
	1 H NMR (300 MHz, CDCl3) δ 7.49 -7.24 (m, 10H), 4.62 (s, 4H), 4.26 (s, 4H).
	13 C NMR (75 MHz, CDCl3) δ 137.6, 128.6, 128.2, 128.0, 82.7, 71.8, 57.6.
	2,2,3,3,10,10,11,11-Octamethyl-4,9-dioxa-3,10-disiladodec-6-yne (57)
	1 H NMR (300 MHz, CDCl3) δ 4.34 (s, 4H), 0.90 (s, 18H), 0.11 (s, 12H).

2-Butyn-1,4-diol 52 (2.0 g, 23.2 mmol), imidazole

(3.8 g, 55.8 mmol)

, and N,N-4dimethylaminopyridine (0.28 g, 2.32 mmol) were introduced in an oven-dried 250 mL roundbottom flask with a stir bar containing dichloromethane (200 mL). Recrystallized chloro-tertbutyldimethylsilane

(8.4 g, 55.8 mmol)

was added. The resulting solution was stirred at room temperature for 3 h. Then the reaction mixture was poured into 40 mL 10% aqueous potassium carbonate. The resulting aqueous fraction was extracted with diethyl ether (2×40 mL). The combined organic fractions were washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Cyclohexane/Ethyl acetate gradient from 98/2 to 95/5) to afford compound 57 (5.85 g, 80%) as a colorless oil. The analytical data were identical to the literature. 99 Rf = 0.5(Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).

  .1.

	HRMS (ESI + ): calcd. for C27H28O3Na [M+Na] + : 423.1931, found 423.1928.
	1,4-Dibutyl-2,3-bis(methoxymethyl)-9H-fluoren-9-one (66)
	This compound was obtained following the general procedure E. Starting from diyne 18 (93
	mg, 0.35 mmol), 1,4-dimethoxy-2-butyne 51 (80 mg, 0.7 mmol, 2.0 equiv) and RuCl3•nH2O
	(3.6 mg, 0.0175 mmol). The reaction mixture was stirred at 80 °C for 14 h. Purification on silica
	nBu gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 66 (50 mg, 38%) as a O
	yellow solid. m.p. 76 -78 °C.
	OMe
	OMe
	Chemical Formula: C 27 H 28 O 3
	Exact Mass: 400.2038

Rf = 0.33 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 7.68 -7.62

(m, 1H), 7.62 -7.56 (m, 1H)

, 7.47 (td, J = 7.5, 1.2 Hz, 1H), 7.27 (td, J = 7.5, 1.2 Hz, 1H), 4.52 (s, 2H), 4.48 (s, 2H), 3.51 (s, 3H), 3.49 (s, 3H),

3.22 -3.12 (m, 2H), 3.01 -2.91 (m, 2H), 1.68 -1.56 (m, 4H), 1.55 -1.46 (m, 4H)

, 1.03 (t, J =

  + ): calcd. for C26H24O3Na [M+Na] + : 407.1618, found 407.1623.

	1-Butyl-2,3-bis(methoxymethyl)-4-(trimethylsilyl)-9H-fluoren-9-one (69)
	This compound was obtained following the general procedure E. Starting from diyne 21 (99.0
	mg, 0.35 mmol), 1,4-dimethoxy-2-butyne 51 (80 mg, 0.7 mmol, 2.0 equiv) and RuCl3•nH2O
	(3.6 mg, 0.0175 mmol). The reaction mixture was stirred at 50 °C for 14 h. Purification on silica
	gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 69 (81 mg, 58%) as a
	yellow oil.
	1 H NMR (300 MHz, CDCl3) δ 7.62 (t, J = 7.5 Hz, 2H), 7.42 (td, J = 7.5, 1.2 Hz, 1H), 7.30 -
	7.20 (m, 1H), 4.59 (s, 2H), 4.47 (s, 2H), 3.44 (s, 3H), 3.34 (s, 3H), 3.26 -3.15 (m, 2H), 1.58 -
	1.44 (m, 4H), 0.98 (t, J = 6.6 Hz, 3H), 0.46 (s, 9H).

Rf = 0.46 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

  + ): calcd. for C24H32O3SiNa [M+Na] + : 419.2013, found 419.2008.

	This compound was obtained following the general procedure E. Starting from diyne 22 (102
	mg, 0.35 mmol), 1,4-dimethoxy-2-butyne 51 (80 mg, 0.7 mmol, 2.0 equiv) and RuCl3•nH2O
	(3.6 mg, 0.0175 mmol). The reaction mixture was stirred at 50 °C for 2 h. Purification on silica
	gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 70 (101 mg, 71%) as a
	yellow solid. m.p. 86 -88 °C.
	O Rf = 0.4 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV). nBu
	OMe 1 H NMR (300 MHz, CDCl3) δ 7.56 (d, J = 7.5 Hz, 1H), 7.35 -7.27 (m, 2H), 7.24 -7.17 (m, OMe Me 3 Si 2H), 7.17 -7.02 (m, 2H), 6.02 (d, J = 7.5 Hz, 1H), 4.57 (s, 2H), 4.19 (s, 2H), 3.51 (s, 3H), 3.28
	Chemical Formula: C 24 H 32 O 3 Si
	Exact Mass: 396.2121 -3.18 (m, 2H), 3.20 (s, 3H), 2.49 (s, 3H), 1.66 -1.51 (m, 4H), 1.02 (t, J = 7.2 Hz, 3H).
	1-Butyl-2,3-bis(methoxymethyl)-4-(p-tolyl)-9H-fluoren-9-one (70)
	O
	nBu
	OMe
	OMe
	Me
	Chemical Formula: C 28 H 30 O 3
	Exact Mass: 414.2195

  + ): calcd. for C27H27BrO3Na [M+Na] + : 501.1036, found 501.1036. This compound was obtained following the general procedure E. Starting from diyne 24 (115.5 mg, 0.35 mmol), 1,4-dimethoxy-2-butyne 51 (80 mg, 0.7 mmol, 2.0 equiv) and RuCl3•nH2O (3.6 mg, 0.0175 mmol). The reaction mixture was stirred at 50 °C for 6 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 74 (105 mg, 68%) as a

	O	nBu
	yellow oil.
		OMe
		OMe
	Rf = 0.25 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	Br Chemical Formula: C 27 H 27 BrO 3 1 H NMR (300 MHz, CDCl3) δ 7.52 -7.46 (m, 3H), 7.33 -7.27 (m, 2H), 6.99 (s, 1H), 5.88 (s,
	Exact Mass: 478.1144 2H), 5.32 (s, 1H), 4.53 (s, 2H), 4.14 (s, 2H), 3.49 (s, 3H), 3.22 -3.15 (m, 2H), 3.16 (s, 3H),
	1.61 -1.49 (m,
	8-Butyl-6,7-bis(methoxymethyl)-5-phenyl-9H-fluoreno[2,3-d][1,3]dioxol-9-one (74)
	O	nBu
	O	OMe
	O	OMe
	Chemical Formula: C 28 H 28 O 5
	Exact Mass: 444.1937

  + ): calculated for C37H34O3SNa + [M+Na + ]: 581.2121, found 581.2115. This compound was obtained following the general procedure E. Starting from diyne 46 (120 mg, 0.35 mmol), 1,4-dimethoxy-2-butyne 51 (80 mg, 0.7 mmol, 2.0 equiv) and RuCl3•nH2O (3.6 mg, 0.0175 mmol). The reaction mixture was stirred at 60 °C for 14 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 86 (124 mg, 78 %) as a red solid. m.p. 135 -137 °C.

	O	nBu
	S
		OBn
		OBn
	Chemical Formula: C 37 H 34 O 3 S
	Exact Mass: 558.2229
	Rf = 0.32 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 1H), 7.51 -7.40 (m, 5H), 7.20 -7.10 (m,
	1H), 6.83 -6.72 (m, 1H), 5.19 (d, J = 8.6 Hz, 1H), 4.52 (s, 2H), 4.10 (s, 2H), 3.51 (s, 3H), 3.24
	-3.11 (m, 2H), 3.19 (s, 3H), 1.69 -1.52 (m, 4H), 1.03 (t, J = 7.0 Hz, 3H).
	7-Butyl-8,9-bis(methoxymethyl)-10-phenyl-6H-benzo[b]indeno[1,2-d]thiophen-6-one
		(86)
	O
		nBu
	S
		OMe
		OMe
	Chemical Formula: C 29 H 28 O 3 S
	Exact Mass: 456.1759

  NMR (300 MHz, 1H), 7.67 (dd, J = 7.3, 0.6 Hz, 1H), 7.56 (td, J = 7.7, 1.3 Hz, 1H), 7.35 (td, J = 7.4, 0.8 Hz, 1H), 4.74 (s, 2H), 4.55 (s, 2H), 3.54 (s, 3H), 3.48

	p. 93 -
	95 °C.

Rf = 0.3 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H

  This compound was obtained following the general procedure F. Starting from indene dione (0.84 g, 6 mmol), 1-bromo-2-butyne(1.26 mL, 14.4 mmol, 2.4 equiv) and NaH (0.58 g, 14.4 mmol, 2.4 equiv). The reaction mixture was stirred at room temperature for 3 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 103(1.15 g, 77 %) as a yellow solid. m.p. 97-99 °C. The analytical data were identical to the literature.

	1 H NMR (300 MHz, CDCl3) δ 8.06 -7.93 (m, 2H), 7.92 -7.76 (m, 2H), 2.63 -2.46 (m, 4H),
	1.39 (s, 6H).

145e Rf = 0.28 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

  Starting from ptoluenesulfonamide (2 g, 11.7 mmol), 1-bromo-2-butyne (4.66 g, 35.1 mmol, 3 equiv) and K2CO3(8 g, 58.5 mmol, 5 equiv). The reaction mixture was stirred at 80 °C for 14 h.

	Purification on silica gel (Petroleum ether/Ethyl acetate; 90/10) afforded 108 (2.8 g, 70 %) as a
	white solid. The analytical data were identical to the literature. 145d
	Rf = 0.76 (Cyclohexane/Ethyl acetate; 70/30, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 2H), 7.32 -7.20 (m, 2H), 4.07 (q, J = 2.2
	Hz, 4H), 2.41 (s, 3H), 1.64 (t, J = 2.2 Hz, 6H).

13 C NMR (75 MHz, CDCl3) δ 150.

Dimethyl 2,2-di(prop-2-yn-1-yl)malonate (109)

  To a solution of dimethyl 2,2-di(prop-2-yn-1-yl)malonate 109(1.04 g, 5 mmol) in THF (40 mL) was slowly added lithium hexamethyldisilazide (11 mmol, 11 mL, 1 M in THF) at -78 °C, and the solution was stirred at the same temperature for 1 h. To the resulting mixture was added at chlorotrimethylsilane (1.08 mL, 12.5 mmol, 2.5 equiv) at -78 °C, and the reaction mixture was allowed to warm to room temperature and stirred for additional 1 h. The reaction

	was quenched with water (10 mL). The aqueous layer was extracted with Et2O (2×30 mL),
	and the combined organic layer was washed with brine, dried with MgSO4, filtered and
	concentrated under reduced pressure. The residues was purified by flash chromatography on
	silica gel (Petroleum ether/Ethyl acetate gradient from 98/2 to 95/5) afforded 110 (0.8 g, 45%)
	as a colorless sticky oil. The analytical data were identical to the literature. 145a
	Rf = 0.65 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 3.74 (s, 6H), 2.97 (s, 4H), 0.12 (s, 18H).
	This compound was obtained following the general procedure F. Starting from dimethyl
	malonate (4.01 g, 30 mmol), propargyl bromide (7.12 mL, 67.5 mmol, 2.2 equiv) and NaH
	(2.64 g, 66 mmol). The reaction mixture was stirred at room temperature for 14 h. Purification
	on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 109 (5.7 g,
	91 %) as a white solid. The analytical data were identical to the literature. 41
	Rf = 0.3 (Cyclohexane/Ethyl acetate; 85/15, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 3.75 (s, 6H), 2.98 (d, J = 2.7 Hz, 4H), 2.03 (t, J = 2.6 Hz, 2H).
	13 C NMR (75 MHz, CDCl3) δ 169.0, 78.3, 71.8, 56.4, 53.2, 22.6.
	Dimethyl 2,2-bis(3-(trimethylsilyl)prop-2-yn-1-yl)malonate (110)

  Starting from p-

	Dimethyl 2,2-bis(3-bromoprop-2-yn-1-yl)malonate (124)
	This compound was obtained following the general procedure H. Starting from dimethyl 2,2-
	di(prop-2-yn-1-yl)malonate 109 (1.04 g, 5 mmol), NBS (1.78 g, 10 mmol, 2 equiv) and silver
	nitrate (85 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 3 h. toluenesulfonamide (6.84 g, 40 mmol), propargyl bromide (11.4 mL, 120 mmol, 3 equiv) and Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded K2CO3 (27.2 g, 200 mmol, 5 equiv). The reaction mixture was stirred at 80 °C for 14 h. 124 (5.7 g, 98 %) as a slight yellow solid. m.p. 60-62 °C. The analytical data were identical to Purification on silica gel (Petroleum ether/Ethyl acetate; 85/15) afforded 122 (9.2 g, 91 %) as a white solid. The analytical data were identical to the literature. 145j the literature. 145l
	Rf = 0.3 (Cyclohexane/Ethyl acetate; 85/15, KMnO4, UV). Rf = 0.38 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 4.16 (d, J = 1 H NMR (300 MHz, CDCl3) δ 3.76 (s, 6H), 2.99 (s, 4H).
	2.7 Hz, 4H), 2.42 (s, 3H), 2.14 (t, J = 2.7 Hz, 2H).
	13 C NMR (CDCl3, 75 MHz): δ 144.2, 136.9, 129.2, 128.2, 76.2, 74.4, 36.2, 21.6.
	tert-Butyl di(prop-2-yn-1-yl)carbamate (123)
	This compound was obtained following the general procedure F. Starting from Boc-protected
	propargylamine (3.45 g, 22.3 mmol), propargyl bromide (3.5 mL, 33.4 mmol, 1.5 equiv) and
	NaH (1.34 g, 33.4 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for
	14 h. Purification on silica gel (Petroleum ether/Ethyl acetate; 90/10) afforded 123 (3.13 g,
	73%) as pale yellow oil. The analytical data were identical to the literature. 145k
	Rf = 0.57 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 4.16 (br, 4H), 2.22 (t, J = 2.5 Hz, 2H), 1.47 (s, 9H).
	13 C NMR (CDCl3, 75 MHz): δ 154.4, 81.3, 79.0, 72.0, 35.3, 28.4.

13

C NMR (75 MHz, CDCl3) δ 169.0, 74.

Dimethyl 2-(3-bromoprop-2-yn-1-yl)-2-(but-2-yn-1-yl)malonate (129)

	This compound was obtained following the general procedure H. Starting from dimethyl 2-
	(but-2-yn-1-yl)-2-(prop-2-yn-1-yl)malonate 125 (0.89 g, 4 mmol), NBS (1 g, 5.5 mmol, 1.4
	equiv) and silver nitrate (0.1 g, 0.6 mmol). The reaction mixture was stirred at room temperature
	for 3 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10)
	afforded 129 (1.17 g, 98 %) as a white solid. m.p. 65-67 °C. The analytical data were identical
	to the literature. 145l
	Rf = 0.44 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 3.74 (s, 6H), 2.98 (s, 2H), 2.89 (q, J = 2.5 Hz, 2H), 1.74 (t, J =
	2.6 Hz, 3H).

13

C NMR (75 MHz, CDCl3) δ 169.

8R,9S,13S,14S,17R)-17-(But-2-yn-1-yloxy)-17-ethynyl-3-methoxy-13-methyl-7,8,9,11,12, 13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene (143)

  This compound was obtained following the general procedure F. Starting from Mestranol (0.31 g, 1 mmol), 1-bromo-2-butyne (0.16 g, 1.2 mmol, 1.2 equiv) and NaH (48 mg, 1.2 mmol, 1.2 equiv). The reaction mixture was stirred at 60 °C for 20 h. Purification on silica gel (Petroleum ether/Ethyl acetate gradient from 95/5 to 90/10) afforded 143 (0.13 g, 36%) as a white solid.

	m.p. 138-140 °C.
	Rf = 0.4 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.20 (d, J = 8.6 Hz, 1H), 6.71 (dd, J = 8.6, 2.8 Hz, 1H), 6.63 (d,
	J = 2.7 Hz, 1H), 4.33 -4.20 (m, 2H), 3.78 (s, 3H), 2.90 -2.76 (m, 2H), 2.65 (s, 1H), 2.39 -
	1.92 (m, 5H), 1.91 -1.66 (m, 7H), 1.53 -1.27 (m, 4H), 0.92 (s, 3H).

13 C NMR (75 MHz, CDCl3) δ 157.

  (CI, NH3): m/z = 380 [M + NH4] + .

	3-Bromoprop-2-yn-1-ol (145) 1 H NMR (300 MHz, CDCl3) δ 3.77 (s, 6H), 3.61 (t, J = 7.7 Hz, 1H), 2.79 (dd, J = 7.7, 2.7 Hz,
	2H), 2.02 (t, J = 2.7 Hz, 1H).
	13 C NMR (75 MHz, CDCl3) δ 168.6, 80.1, 70.8, 53.2, 51.2, 18.8.
	This compound was obtained following the general procedure H. Starting from propargyl Dimethyl 2-(pent-4-en-2-yn-1-yl)malonate (147)
	alcohol (2.8 g, 50 mmol), NBS (10 g, 55 mmol, 1.1 equiv) and silver nitrate (0.43 g, 5 mmol).
	The reaction mixture was stirred at room temperature for 3 h. Purification on silica gel
	(Petroleum ether/Ethyl acetate gradient from 90/10 to 80/20) afforded 145 (4.35 g, 65 %) as a
	colorless oil. The analytical data were identical to the literature. 201
	This compound was obtained following the general procedure A. Starting from dimethyl 2-Rf = 0.38 (Cyclohexane/Ethyl acetate; 80/20, KMnO4, UV). (prop-2-yn-1-yl)malonate (1.02 g, 6 mmol), vinyl bromide (7.2 mL, 7.2 mmol, 1.2 equiv),
	1 H NMR (300 MHz, CDCl3) δ 4.28 (s, 2H), 3.40 (br, 1H). PdCl2(PPh3)2 (84 mg, 2 mol %) and CuI (11 mg, 1 mol %). Purification on silica gel
	(Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 147 (0.5 g, 43%) as a
	13 C NMR (75 MHz, CDCl3) δ 78.4, 52.1, 46.1. colorless oil.
	Dimethyl 2-(but-2-yn-1-yl)malonate (144) Dimethyl 2-(prop-2-yn-1-yl)malonate (146) Rf = 0.2 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 5.79 -5.65 (m, 1H), 5.62 -5.50 (m, 1H), 5.48 -5.38 (m, 1H),
	3.77 (s, 6H), 3.61 (t, J = 7.7 Hz, 1H), 2.95 -2.84 (m, 2H).
	In a round bottom flask, dimethyl malonate (4.76 g, 36 mmol, 1.2 equiv), propargyl
	This compound was obtained following the general procedure F. Starting from dimethyl bromide (3.34 mL, 30 mmol, 1 equiv), potassium carbonate (9.95 g, 72 mmol, 2.4 equiv) and
	malonate (11.6 g, 87.5 mmol, 2.3 equiv), 1-bromo-2-butyne (3.3 mL, 37.5 mmol, 1 equiv) and acetone (60 mL) were placed. The resulting mixture was stirred at 50 °C for 24 h. After the
	NaH (1.65 g, 41.3 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for reaction was complete, the reaction mixture was filtered, and the organic layers were
	5 h. The residue was purified by distillation under vacuum (80 °C, 1.5 torr) to afford 144 (4.3 concentrated under reduced pressure. The residue was purified by distillation under vacuum g, 62%) as a colorless oil. The analytical data were identical to the literature. 200 (70 °C, 1.5 torr) to afford 146 (3.1 g, 60%) as a colorless oil. The analytical data were identical
	Rf = 0.29 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV). to the literature. 202
	1 H NMR (300 MHz, CDCl3) δ 3.76 (s, 6H), 3.55 (t, J = 7.7 Hz, 1H), 2.76-2.70 (m, 2H), 1.74 Rf = 0.25 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	(t, J = 2.5 Hz, 3H).
	13 C NMR (75 MHz, CDCl3) δ 168.7, 78.1, 74.7, 52.8, 51.6, 19.0, 3.6.

201

Karmakar, R.; Yun, S. Y.; Chen, J.;

Xia, Y.; Lee, D. Angew. Chem. Int. Ed. 2015, 54, 6582. 202

Iafe, R. G.; Kuo, J. L.; Hochstatter, D. G.; Saga, T.; Turner, J. W.; Merlic, C. A. Org. Lett. 2013, 15, 582. 13 C NMR (75 MHz, CDCl3) δ 168

  The excess of cyanamide was removed by bulb to bulb distillation (conditions:1.0x10 -3 mbar, 90 °C for 10 minutes). The analytical data were identical to the literature.

	Dimethyl 1,4-dimethyl-3-morpholino-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-
	dicarboxylate (169)
	a) This compound was obtained following the general procedure L. Starting from diyne 101
	(236 mg, 1.0 mmol), 4-cyanomorpholine 155 (224 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O
	(10.4 mg, 0.05 mmol). The reaction mixture was stirred at 80 °C for 18 h. Purification on silica
	gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 169 (330 mg, 95%) as
	a white solid. Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room
	temperature for 2 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from
	90/10 to 80/20) afforded 169 (158 mg, 91%) as a white solid. The excess of cyanamide was
	removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes).
	Rf = 0.24 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 3.86 -3.78 (m, 4H), 3.76 (s, 6H), 3.50 (s, 2H), 3.48 (s, 2H),
	3.12 -2.99 (m, 4H), 2.33 (s, 3H), 2.14 (s, 3H).

(CI, NH3): m/z = 307 [M + H] + . 135a b) This compound was obtained following the general procedure M. Starting from diyne 101 (118 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and

  ). The reaction mixture was stirred at 110 °C for 18 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 171 (251 mg, 73%) as a colorless oil. The excess of cyanamide was removed by bulb to bulb distillation (conditions:1.0x10 -3 mbar, 80 °C for 10 minutes). The analytical data were identical to the literature.143

	Rf = 0.33 (Petroleum ether/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 3.75 (s, 6H), 3.49 (s, 2H), 3.47 (s, 2H), 3.06 -2.91 (m, 4H), 2.32 (s, 3H), 2.13 (s, 3H),

1.73 -1.61 (m, 4H), 1.61 -1.50 (m, 2H)

.

13 C NMR (75 MHz, CDCl3) δ 172.

  ). The reaction mixture was stirred at 80 °C for 18 h.

	Rf = 0.26 (Petroleum ether/Ethyl acetate; 90/10, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.45 -7.38 (m, 2H), 7.32 (t, J = 7.3 Hz, 2H), 7.28 -7.16 (m,
	1H), 4.26 (s, 2H), 3.77 (s, 6H), 3.55 -3.45 (m, 4H), 2.67 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H).

Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 85/15) afforded 172 (306 mg, 81%) as a colorless oil. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 120 °C for 10 minutes). 13 C NMR (75 MHz, CDCl3) δ 172.

  (CI, NH3): m/z = 383 [M + H] + .

	Dimethyl 3-(dibenzylamino)-1,4-dimethyl-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-
	dicarboxylate (173)
	This compound was obtained following the general procedure L. Starting from diyne 101 (236
	mg, 1.0 mmol), dibenzylcyanamide 159 (444 mg, 2.0 mmol, 2.0 equiv) and RuCl3•nH2O (10.4
	mg, 0.05 mmol). The reaction mixture was stirred at 110 °C for 18 h. Purification on silica gel
	(Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 173 (344 mg, 75%) as a
	sticky yellow oil. The excess of cyanamide was removed by bulb to bulb distillation
	(conditions: 1.0x10 -3 mbar, 180 °C for 20 minutes).
	Rf = 0.17 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.39 -7.13 (m, 10H), 4.25 (s, 4H), 3.76 (s, 6H), 3.49 (s, 4H),
	2.29 (s, 3H), 2.24 (s, 3H).

13

C NMR (75 MHz, CDCl3) δ 172.

  ). The reaction mixture was stirred at 80 °C for 18 h. Purification on silica gel

	Rf = 0.21 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 8.08 -7.98 (m, 2H), 7.93 -7.85 (m, 2H), 3.89 -3.73 (m, 4H),
	3.23 (s, 2H), 3.22 (s, 2H), 3.14 -3.01 (m, 4H), 2.31 (s, 3H), 2.13 (s, 3H).

(Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 182 (268 mg, 74%) as a yellow solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions:

1.0x10 -3 mbar, 90 °C for 10 minutes). m.p. 206 -209 °C. 13 C NMR (75 MHz, CDCl3) δ 202.

Dimethyl 3-morpholino-1-phenyl-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6- dicarboxylate (194)

  ) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes). b) This compound was obtained following the general procedure M. Starting from diyne 125 (Petroleum ether/Ethyl acetate; 85/15, KMnO4, UV).

	gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 194 (32 mg, 16%, ratio
	= 90:10) as a white solid. The excess of cyanamide was removed by bulb to bulb distillation
	(conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes). 1 H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 6.53 (s, 1H), 3.85 (s, 3H), 3.83 -3.74 (m, 4H),
	3.65 -3.39 (m, 8H).
	(111 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and b) This compound was obtained following the general procedure M. Starting from diyne 126
	Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room (142 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and
	temperature for 10 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at 50 °C for 15
	95/5 to 90/10) afforded 193 (148 mg, 89%, ratio = 98:2) as a slight yellow solid. The excess of min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 80/20 to 70/30)
	cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 afforded 194 (190mg, 96%, ratio > 99:1) as a white solid. The excess of cyanamide was
	minutes). m.p. 110 -112 °C. removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes). m.p.
	166 -168 °C.
	Rf = 0.17 (Cyclohexane/Ethyl acetate; 85/15, KMnO4, UV).
	Rf = 0.2 (Petroleum ether/Ethyl acetate; 85/15, KMnO4, UV).
	1 H NMR (400 MHz, CDCl3) δ 6.33 (s, 1H, H8), 3.83 -3.78 (m, 4H, H13), 3.75 (s, 6H, H1), 3.49
	(s, 2H, H4), 3.47 -3.41 (m, 6H, H5,12), 2.32 (s, 3H, H11) 1 H NMR (400 MHz, CDCl3) δ 7.81 -7.78 (m, 2H, H12), 7.47 -7.41 (m, 2H, H13), 7.39 -7.35
	(m, 1H, H14), 6.52 (s, 1H, H8), 3.86 -3.80 (m, 4H, H16), 3.73 (s, 6H, H11), 3.72 (s, 2H, H5), 3.60
	13 C NMR (101 MHz, CDCl3) δ 172.0 (C2), 159.3 (C7), 151.7 (C9), 151.5 (C10), 124.3 (C6), -3.41 (m, 4H, H15), 3.54 (s, 2H, H4).
	100.1 (C8), 67.0 (C13), 60.0 (C3), 53.2 (C1), 46.4 (C12), 40.8 (C4), 38.0 (C5), 22.2 (C11).
	13 C NMR (75 MHz, CDCl3) δ 171.8 (C2), 159.0 (C9), 153.1 (C6), 151.2 (C10), 139.9 (C11), 128.4
	NOESY (400 MHz, CDCl3) H8 (6.33 ppm) correlates to H12 (3.47 -3.41 ppm), H5 (3.47 -3.41 (C12), 128.3 (C13), 128.3 (C14), 123.2 (C7), 101.5 (C8), 67.0 (C16), 60.5 (C3), 53.2 (C1), 46.0
	ppm) correlates to H11 (2.32 ppm). (C15), 40.5 (C4), 39.6 (C5).
	HRMS (ESI + ): calcd. for C17H23N2O5 [M+H] + : 335.1601, found 335.1603. NOESY (400 MHz, CDCl3) H12 (7.81 -7.78 ppm) correlates to H5 (3.72 ppm), H8 (6.52 ppm)
	correlate to H15 (3.60 -3.41 ppm) and H4 (3.54 ppm).
	HRMS (ESI + ): calcd. for C22H25N2O5 [M+H] + : 397.1758, found 397.1756.
	16 16
	1 1 MeO 2 C 2 2 MeO 2 C Di-tert-butyl 3-morpholino-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate 3 3 4 4 5 5 6 6 10 10 7 7 15 15 O 8 8 N 9 9 N (196)
	11 11
	12 12
	13 13
	14 14
	Chemical Formula: C 22 H 24 N 2 O 5
	Exact Mass: 396.1685

). The reaction mixture was stirred at 100 °C for 18 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 193 (71 mg, 43%, ratio = 87:13a) This compound was obtained following the general procedure L. Starting from diyne 126 (142 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and RuCl3•nH2O (5.2 mg, 0.025 mmol). The reaction mixture was stirred at 100 °C for 18 h. Purification on silica This compound was obtained following the general procedure M. Starting from diyne 114 (146 mg, 0.5 mmol), 4-cyanomorpholine 155 (112 mg, 1.0 mmol, 2.0 equiv) and Rf = 0.1 13 C NMR (75 MHz, CDCl3) δ 168.

  + ): calcd. for C15H18N3O3 [M+H] + : 288.1343, found 288.1343.

	This compound was obtained following the general procedure N. Starting from diyne 119 (111
	mg, 0.5 mmol), 4-cyanomorpholine 155 (67 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6
	(2.5 mg, 0.005 mmol). The reaction mixture was stirred at room temperature for 5 min.
	Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 80/20 to 50/50) afforded
	3-Morpholino-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarbonitrile (200) 201 (162 mg, 97%) as a pale yellow solid. The excess of cyanamide was removed by bulb to
	bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes). m.p. 194 -196 °C.
	Rf = 0.1 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 8.08 -7.95 (m, 3H), 7.93 -7.81 (m, 2H), 6.54 (s, 1H), 3.89 -
	This compound was obtained following the general procedure N. Starting from diyne 118 (71 3.72 (m, 4H), 3.54 -3.37 (m, 4H), 3.24 (s, 2H) , 3.23 (s, 2H).
	mg, 0.5 mmol), morpholine-4-carbonitrile 155 (67 mg, 0.6 mmol, 1.2 equiv) and
	Cp*Ru(CH3CN)3PF6 (5 mg, 0.01 mmol). The reaction mixture was stirred at room temperature
	for 2 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 80/20 to 50/50)
	afforded 200 (64 mg, 50%) as a white solid. m.p. 176 -178 °C.
	Rf = 0.4 (Petroleum ether/Ethyl acetate; 50/50, KMnO4, UV).
	1 H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 6.56 (s, 1H), 3.85 -3.76 (m, 4H), 3.65 (s, 2H),
	3.61 (s, 2H), 3.55 -3.40 (m, 4H).
	13 C NMR (75 MHz, CDCl3) δ 159.9, 147.7, 144.0, 121.8, 116.0, 102.6, 66.7, 45.9, 44.6, 42.0,
	34.0.
	MS (CI, NH3): m/z = 255 [M + H] + .
	3-Morpholino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,2'-indene]-1',3'-dione (201)

13 C NMR (75 MHz, CDCl3) δ 202

  + ): calcd. for C16H24N3O3 [M+H] + : 306.1812, found 306.1814.

	This compound was obtained following the general procedure N. Starting from diyne 109 (104
	mg, 0.5 mmol), N,N-dibenzylcyanamide 159 (133 mg, 0.6 mmol, 1.2 equiv) and
	Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room Dimethyl 3-(pyrrolidin-1-yl)-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate (207) temperature for 10 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from
	90/10 to 80/20) afforded 208 (163 mg, 76%) as a pale yellow oil. The excess of cyanamide was
	removed by bulb to bulb distillation (conditions: 5x10 -3 mbar, 150 °C for 30 minutes).
	Rf = 0.37 (Petroleum ether/Ethyl acetate; 85/15, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 7.35 -7.14 (m, 10H), 6.33 (s, 1H), 4.76 (s, 4H),
	3.74 (s, 6H), 3.50 (s, 2H), 3.42 (s, 2H).
	80/20 to 70/30) afforded 207 (144 mg, 90%) as a white solid. The excess of cyanamide was
	removed by bulb to bulb distillation (conditions: 3.0x10 -3 mbar, 80 °C for 10 minutes). The
	analytical data were identical to the literature. 128
	Rf = 0.42 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 6.22 (s, 1H), 3.74 (s, 6H), 3.47 (s, 4H), 3.44 -3.30
	(m , 4H), 2.07 -1.87 (m, 4H).
	13 C NMR (75 MHz, CDCl3) δ 172.0, 157.1, 151.0, 143.3, 123.3, 101.8, 60.8, 53.1, 47.0, 40.5,
	37.6, 25.7.
	MS (CI, NH3): m/z = 305 [M + H] + .
	Dimethyl 3-(dibenzylamino)-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate
	(208)

This compound was obtained following the general procedure N. Starting from diyne 109 (104 mg, 0.5 mmol), pyrrolidine-1-carbonitrile 156 (57 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 2 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 13 C NMR (75 MHz, CDCl3) δ 172.0, 158.

  + ): calcd. for C18H27N2O4 [M+H] + :335.1965, found 335.1967.

	This compound was obtained following the general procedure N. Starting from diyne 109 (104
	mg, 0.5 mmol), N-butyl-N-methylcyanamide 164 (67 mg, 0.6 mmol, 1.2 equiv) and
	Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room
	temperature for 5 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from
	90/10 to 70/30) afforded 211 (130 mg, 81%) as a colorless oil. The excess of cyanamide was
	removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes).
	Rf = 0.24 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 6.33 (s, 1H), 3.74 (s, 6H), 3.52 -3.38 (m, 6H),
	3.00 (s, 3H), 1.59 -1.48 (m, 2H), 1.42 -1.30 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).
	Dimethyl 3-(butyl(methyl)amino)-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-
	dicarboxylate (211)

13

C NMR (75 MHz, CDCl3) δ 172.0, 158.

4-Methyl-6-morpholino-1,3-dihydrofuro[3,4-c]pyridine (217)

	Rf = 0.17 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).
	1 H NMR (400 MHz, CDCl3) δ 6.33 (s, 1H, H1), 5.02 -4.97 (m, 4H, H3,4), 3.87 -3.77 (m, 4H,
	H10), 3.49 -3.42 (m, 4H, H9), 2.31 (s, 3H, H7).
	13 C NMR (101 MHz, CDCl3) δ 159.6 (C8), 151.0 (C2), 149.4 (C6), 123.8 (C5), 96.5 (C1), 73.5
	(C3), 71.8 (C4), 66.9 (C10), 46.4 (C9), 22.4 (C7).
	NOESY (400 MHz, CDCl3) H1 (6.33 ppm) correlate to H3 (5.02 -4.97 ppm) and H9 (3.49 -
	3.42 ppm), H4 (5.02 -4.97 ppm) correlates to H7 (2.31 ppm), H7 (6.33 ppm) does not correlates
	to H9 (3.49 -3.42 ppm).
	HRMS (ESI + ): calcd. for C12H17N2O2 [M+H] + : 221.1285, found 221.1285.
	4-(4
	This compound was obtained following the general procedure N. Starting from diyne 127 (54
	mg, 0.5 mmol), 4-cyanomorpholine 155 (67 mg, 0.6 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6
	(12.5 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 5 min.

+ ): calcd. for C24H28N3O2S [M+H] + : 422.1897, found 422.1890.

Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 80/20 to 60/40) afforded 217 (95 mg, 86%, ratio > 99:1) as a pale yellow solid. The excess of cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10 minutes). m.p. 90 -92 °C.

-Methyl-2-tosyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)morpholine (218)

	This compound was obtained following the general procedure N. Starting from diyne 128
	(130.5 mg, 0.5 mmol), 4-cyanomorpholine 155 (67 mg, 0.6 mmol, 1.2 equiv) and
	Cp*Ru(CH3CN)3PF6 (12.5 mg, 0.025 mmol). The reaction mixture was stirred at room
	temperature for 5 min. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from
	90/10 to 70/30) afforded 218 (168 mg, 90%, ratio > 99:1) as a white solid. The excess of
	cyanamide was removed by bulb to bulb distillation (conditions: 1.0x10 -3 mbar, 90 °C for 10
	minutes). m.p. 169 -172 °C.
	Rf = 0.13 (Petroleum ether/Ethyl acetate; 80/20, KMnO4, UV).
	1 H NMR (400 MHz, CDCl3) δ 7.78 -7.72 (m, 2H, H4), 7.34 -7.28 (m, 2H, H3), 6.24 (s, 1H,
	H13), 4.51 (s, 2H, H6), 4.45 (s, 2H, H7), 3.81 -3.75 (m, 4H, H15), 3.45 -3.39 (m, 4H, H14), 2.41
	(s, 3H, H1), 2.26 (s, 3H, H11).

  NMR (400 MHz, 2H, H4), 2H, H3), 4H, H17, 18), 7.29 -7.22 (m, 1H, H19),4.51 (s, 2H, H6), 4.53 -4.49 (m, 2H, H7), 4.29 (s, 2H, H15), 2.72 (s, 3H, H14), 2.43 (s, 3H, H1), 2.09 (s, 3H, H13).

	13 C NMR (101 MHz, CDCl3) δ 162.1 (C11), 148.8 (C8), 144.2 (C2), 138.6 (C16), 133.6 (C15),
	130.1 (C3, 10), 128.5 (C18), 128.0 (C17), 127.7 (C4), 127.2 (C19), 126.5 (C9), 117.4 (C12), 57.8
	(C15), 54.1 (C6), 53.7 (C7), 39.6 (C14), 21.7 (C1), 15.0 (C13).
	NOESY (400 MHz, CDCl3) H13 (2.09 ppm) correlate to H6 (4.51 ppm), H15 (4.29 ppm) and H14
	(2.72 ppm).

1 H

  ). The reaction mixture was stirred at 50 °C for 4 h.Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 232 (45 mg, 34%, ratio > 99:1) as a white solid m.p. 78 -79 °C.

	Rf = 0.47 (Petroleum ether/Ethyl acetate; 75/25, KMnO4, UV).
	1 H NMR (300 MHz, CDCl3) δ 7.37 -7.26 (m, 2H), 7.27 -7.15 (m, 3H), 6.11 (s, 1H), 4.81 (s,
	2H), 4.65 (s, 2H), 3.89 (t, J = 5.7 Hz, 2H), 3.00 (s, 3H), 2.85 -2.62 (m, 2H), 2.23 (s, 3H).

13

C NMR (101 MHz, CDCl3) δ 157.

9S,13S,14S,17S)-3-Methoxy-4',13-dimethyl-6'-morpholino-6,7,8,9,11,12,13,14,15,16- decahydro-3'H-spiro[cyclopenta[a]phenanthrene-17,1'-furo[3,4-c]pyridine (237)

  This compound was obtained following the general procedure N. Starting from diyne 143 (72.4 mg, 0.2 mmol), morpholine-4-carbonitrile 155 (27 mg, 0.24 mmol, 1.2 equiv) and Cp*Ru(CH3CN)3PF6 (5.0 mg, 0.01 mmol). The reaction mixture was stirred at 50 °C for 2 h.Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 90/10 to 80/20) afforded 237 (48.5 mg, 51%, ratio = 10:1) as a white solid. m.p. 208 -210 °C.

	J = 2.8 Hz, 1H), 6.30 (s, 1H), 4.93 -4.78 (m, 2H), 3.91 -3.80 (m, 4H), 3.77 (s, 3H), 3.61 -
	3.35 (m, 4H), 2.98 -2.78 (m, 2H), 2.31 (s, 3H), 2.28 -2.17 (m, 1H), 2.15 -1.94 (m, 4H), 1.87
	-1.78 (m, 1H), 1.74 -1.55 (m, 3H), 1.46 -1.26 (m, 4H), 1.06 (s, 3H).

(CI, NH3): m/z = 388 [M + H] + (8R,Rf = 0.14 (Petroleum ether/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 7.12 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.8 Hz, 1H), 6.62

(d, 13

C NMR (75 MHz, CDCl3) δ 159.

  NOESY (400 MHz, CDCl3) H10 (6.37 ppm) correlates to H17(3.62 ppm).HRMS (ESI+ ): calcd. for C20H23N2O1 [M+H] + : 307.1805, found 307.1805.

	13 C NMR (101 MHz, CDCl3) δ 191.3 (C7), 163.8 (C12), 159.2 (C11), 153.1 (C9), 140.8 (C5),
	137.4 (C6), 132.9 (C3), 130.5 (C2), 123.3 (C1), 120.7 (C4), 114.8 (C8), 96.2 (C10), 47.4 (C17),
	34.2 (C13), 31.0 (C14), 25.5(C17), 22.9 (C15), 14.2 (C16).

  , 6.58 (d, J = 1.5 Hz, 1H, H10), 5.58 (s, 1H, H7), 3.82 -3.70 (m, 4H, H18), 3.52 -3.35 (m, 4H, H17), 2.98 -2.75 (m, 2H, H13), 2.37 (br, 1H, OH), 1.80 -1.65 (m, 2H, H14), 1.50 -1.35 (m, 2H, H15), 0.96 (t, J = 7.3 Hz, 3H, H16).

	13 C NMR (101 MHz, CDCl3) δ 160.2 (C11), 158.2 (C12), 150. 1 (C9), 147.6 (C6), 138.4 (C5),
	129.8 (C3), 129.0 (C2), 127.7 (C8), 125.6 (C1), 120.9 (C4), 95.2 (C10), 73.8 (C7), 66.8 (C18), 46.0
	(C17), 34.5 (C13), 31.1 (C14), 22.9 (C15), 14.3 (C16).

  NMR (75 MHz, CDCl3) δ 132.0, 128.8, 128.4, 122.2, 90.2, 82.8, 61.0, 32.1. This compound was obtained following the general procedure O. Starting from butyl chloride (0.52 mL, 5 mmol), phenylacetylene (1.09 mL, 10 mmol, 2 equiv) and nBuLi (10 mmol, 2 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 250 (1.17 g, 85%) as a white solid. m.p. 73 -75 °C. NMR (300 MHz, CDCl3) δ 7.51 -7.44 (m, 4H), 7.36 -7.28 (m, 6H), 2.66 (s, 1H), 2.12 -2.03 (m, 2H), 1.82 -1.69 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H).

	Rf = 0.4 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).
	13 C NMR (75 MHz, CDCl3) δ 132.0, 128.
	1 H NMR (300 MHz, CDCl3) δ 7.54 -7.44 (m, 4H), 7.37 -7.28 (m, 6H), 2.80 -2.73 (m, 1H),
	1.97 (s, 3H).
	MS (CI, NH3): m/z = 229 [M -H2O + H] + .
	1-Phenyl-3-(phenylethynyl)hex-1-yn-3-ol (250)

13 C

1 H

  This compound was obtained following the general procedure O. Starting from benzoyl chloride(1.16 mL, 10 mmol), phenylacetylene (2.2 mL, 20 mmol, 2 equiv) and nBuLi (20 mmol, 2 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate; 90/10) afforded 252 (3.06 g, 99%) as a yellow oil. The analytical data were identical to the literature. 206 Rf = 0.33 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV). NMR (300 MHz, CDCl3) δ 8.01 -7.88(m, 2H), 7.60 -7.27 (m, 13H), 3.09 (br, 1H).

1 H 13 C NMR (75 MHz, CDCl3) δ 143

  This compound was obtained following the general procedure O. Starting from benzoyl chloride (1.16 mL, 10 mmol), 1-hexyne (2.3 mL, 20 mmol, 2 equiv) and nBuLi (20 mmol, 2 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 253 (2.45 g, 91%) as a colorless oil. NMR (300 MHz, CDCl3) δ 7.86 -7.72(m, 2H), 7.46 -7.27 (m, 3H), 2.73 (s, 1H), 2.29 (t, J = 7.0 Hz, 4H),1.59 -1.33 (m, 8H), 0.92 (t, J = 7.2 Hz, 6H).

	Rf = 0.3 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

206 Ram, B.; Lee, H.; Kang, S.; Jung, K.; Hyeon, G.; Kim, J.; Lee, S.; Yoon, Y. Tetrahedron 2013, 69, 10331. 1 H 13 C NMR (75 MHz, CDCl3) δ 143.

  1,5diphenylpenta-1,4-diyn-3-ol 249 (3.2 g, 13.1 mmol), 1-bromo-2-butyne(1.4 mL, 16 mmol, 1.2 equiv) and sodium hydride (0.64 g, 16 mmol, 1.2 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 255 (3 g, 76%) as a white solid. m.p. 110 -112 °C. H NMR (300 MHz, CDCl3) δ 7.52 -7.45(m, 4H), 7.37 -7.30 (m, 6H), 4.52 (q, J = 2.4 Hz, 2H), 1.98 (s, 3H), 1.88 (t, J = 2.4 Hz, 3H).

	Rf = 0.6 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 13 C NMR (75 MHz, CDCl3) δ 132.

  0.This compound was obtained following the general procedure P. Starting from 2-butyne-1,4diol 52(1.72 g, 20 mmol), acetyl chloride (4.3 mL, 60 mmol, 3 equiv) and pyridine (4 mL, 50 mmol, 2.5 equiv). Purification on silica gel (Cyclohexane/Ethyl acetate; 80/20) afforded 262(3.25 g, 96%) as a colorless oil. The analytical data were identical to the literature. 207 Rf = 0.4 (Cyclohexane/Ethyl acetate; 70/30, KMnO4, UV). C NMR (75 MHz, CDCl3) δ 170.2, 80.8, 52.1, 20.7.

	1 H NMR (300 MHz, CDCl3) δ 4.69 (s, 4H), 2.07 (s, 6H).
	But-2-yne-1,4-diyl bis(2,2-dimethylpropanoate) (263)

13

  diacetate 262 (102 mg, 0.6 mmol, 2 equiv), Rh(cod)2BF4 (6.1 mg, 0.015 mmol, 5 mol %), and (R)-BINAP (9.3 mg, 0.015 mmol, 5 mol %). The reaction mixture was stirred at 40 °C for 20 h. Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 80/20) afforded 274 (68 mg, 46%) as a colorless oil. NMR (300 MHz, CDCl3) δ 7.51 -7.22(m, 9H), 1H), 5.26 (d, J = 3.6 Hz, 2H), 5.16 (ABsys, J = 12.6 Hz, 2H), 4.91 (ABsys, J = 12.3 Hz, 2H), 2.33 (s, 3H), 2.09 (s, 3H),1.96 (s, 3H), 1.76 -1.60 (m, 1H), 1.46 -1.20 (m, 2H), 1.20 -1.01 (m, 1H), 0.73 (t, J = 7.0 Hz, 3H).

	Rf = 0.2 (Cyclohexane/Ethyl acetate; 85/15, KMnO4, UV).
							R 2
	R 2	R 1 O	R 2	R 3	+	R 4 R 4	Rh(cod) 2 BF 4 5 mol % (R)-Binap 5 mol % DCM, 40 °C, 20-24 h	O	R 1	R 2	R 4 R 4
										R 3

208 Maisonial, A.; Billaud, E. M. F.; Besse, S.; Rbah-Vidal, L.; Papon, J.; Audin, L.; Bayle, M.; Galmier, M. J.; Tarrit, S.; Borel, M.; Askienazy, S.; Madelmont, J. C.; Moins, N.; Auzeloux, P.; Miot-Noirault, E.; Chezal, J. M. Eur. J. Med. Chem. 2013, 63, 840. 1 H 13 C NMR (75 MHz, CDCl3) δ 170.

Anastas, P.T.; Warner, J. C. Green chemistry: Theory and Practice, Oxford University Press, New York, 1998, 30.

Reviews: (a) Li, C. J. Chem.Rev. 2005, 105,

(b) Pinault, N.; Bruce, D.W. Coord. Chem. Rev. 2003, 241, 1. (c) Lindström, U,M. Chem. Rev. 2002, 102, 2751. (d) Li, C. J. Chem. Rev. 1993, 93, 2023. (e) Li, C.-J.; Chan, T.H. Tetrahedron 1999, 55, 11149.3 a) Tanaka, K. Solvent-Free Organic Synthesis, Wiley-VCH, Weinheim, Germany, 2003. (b) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025. (c) Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975. (d) Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem. Comm. 2001, 2159. (e) Walsh, P. J.; Li H.; de Parrodi, C. A. Chem. Rev. 2007, 107, 2503. (f) Marvaniya, H. M.; Modi, K. N.; Sen, D. J. Greener reactions under solvent free conditions, Int J. Drug Dev. & Res. April-June 2011, 3, 34. (g) Varma, R. S. Green Chem. 1999, 1, 43. (h) Capello, C.; Fischer, U.; Hungerbühler, K. Green Chem. 2007, 9, 927. (h) Keith, L. H.; Gron, L. U.; Young, J. L.; Chem. Rev. 2007, 107, 2695.

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C NMR (75 MHz, CDCl3) δ 82.8, 81.2, 74.9, 69.5, 67.8, 58.9, 19.8, 3.7.

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Acknowledgments

MS (ESI, NH3

): m/z = 301 [M + H] + .

1-(2-((4-(tert-Butyl)phenyl)ethynyl)-phenyl)-hept-2-yn-1-one (23)

This compound was prepared using procedure C. Starting from 1- (2-((4-(tert-butyl)phenyl)ethynyl)-phenyl)--hept-2-yn-1-ol (0.36 g, 1.05 mmol) 14 and Dess-Martin periodinane (0.53 g, 1.25 mmol, 1.2 equiv). Purification on silica gel (Petroleum ether/ Ethyl acetate gradient from 99/1 to 98/2) afforded 23 (0.32 g, 89%) as a pale yellow oil. Rf = 0.55 (Cyclohexane/Ethyl acetate; 90/10, KMnO4, UV).

1 H NMR (300 MHz, CDCl3) δ 8.16 -8.06 (m, 1H), 7.65 -7.58 (m, 1H), 7. 2H),7.47 (td,J = 7.5,0.8 Hz,1H),3H), 2.41 (t, J = 7.1 Hz, 2H), 1.61 -1.50 (m, 2H), 1.46 -1.38 (m, 2H), 1.31 (s, 9H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (75 MHz, CDCl3) δ 177. 5, 151.9, 138.3, 134.1, 132.2, 131.6, 131.6, 127.6, 125.3, 123.1, 120.3, 96.9, 95.5, 87.8, 80.8, 34.8, 31.1, 29.8, 22.0, 19.0, 13.5.

MS (ESI, NH3

): m/z = 343 [M + H] + . [d] [1,3]dioxol-5-yl)hept-2-yn-1-one [START_REF]Purification on silica gel (Cyclohexane/Ethyl acetate gradient from 95/5 to 90/10) afforded 268 (50 mg, 28%) as a colorless oil. Rf = 0.5[END_REF] This compound was prepared using procedure C. Starting from 1- (6-(phenylethynyl)benzo [d][1,3]dioxol-5-yl)hept-2-yn-1-ol 15 (1.25 g, 3.8 mmol) and Dess-Rf = 0.33 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).

1-(6-(Phenylethynyl)benzo

1 H NMR (300 MHz, CDCl3) δ 7. 1H),1H),2H),5.84 (d,J = 5.7 Hz,1H),2.69 (dd,J = 5.7,0.4 Hz,1H),2.46 (t,J = 7.0 Hz,2H),2H),2H), 0.96 (t, J = 7.2 Hz, 3H), 0.20 (s, 9H).

13 C NMR (75 MHz,CDCl3) δ 141.9,132.6,128.3,128.2,126.8,122.6,104.5,96.5,91.5,78.0,63.9,30.9,22.2,19.4,13.8,0. 1 H NMR (400 MHz, CDCl3) δ 7.67 (dd,J = 7.5,1.6 Hz,1H),7.43 (dd,J = 7.1,1.9 Hz,1H),2H),5.85 (d,J = 2.3 Hz,1H), 2.64 (s, 1H), 2.64 (s, 1H), 2.48 (t, J = 7.0 Hz, 2H), 1.70 -1.57 (m, 2H), 1.57 -1.41 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H).

13 C NMR (101 MHz, CDCl3) δ 141. 6, 132.7, 128.4, 128.3, 126.6, 122.4, 96.7, 83.1, 77.9, 74.6, 63.3, 30.9, 22.2, 19.4, 13.7.

MS (CI, NH3

): m/z = 212 [M + NH4 -H2O] + .

2-(Cyclopropylethynyl)benzaldehyde (150)

Methyl 3-morpholino-6-phenyl-6,7-dihydro-5H-cyclopenta [c] 6, 159.4, 152.9, 142.9, 142.2, 128.7, 127.6, 127.4, 126.7, 103.1, 67.0, 60.0, 52.9, 46.3, 42.9, 39.5.

HRMS (ESI

Formation of enantioenriched 1,3-dihydroisobenzofuran derivatives

Synthesis of prochiral triynes

General procedure O:

In an oven-dried Argon-filled round bottom flask, n-butyl lithium (2 equiv) was added slowly to a solution of alkyne (2 equiv) in THF (5 M) at -50 °C, and the resulting mixture was stirred at -50 °C for 1 h. Acetyl chloride (1 equiv) was added at the same temperature, and the resulting mixture was allowed to warm to room temperature for 14-18 h. The reaction was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the desired compound. 13 C NMR (75 MHz, CDCl3) δ 140. 4, 132.1, 129.0, 128.5, 128.4, 127.0, 122.2, 87.4, 86.5, 82.7, 75.4, 72.2, 54.7, 4. 1 H NMR (300 MHz, CDCl3) δ 7.85 -7.70 (m, 2H), 7.42 -7.27 (m, 3H), 4.32 (q, J = 2.4 Hz, 2H), 2.30 (t, J = 7.0 Hz, 4H), 1.83 (t, J = 2.4 Hz, 3H), 1.61 -1.48 (m, 4H), 1.48 -1.35 (m, 4H), 0.92 (t, J = 7.2 Hz, 6H).

General

13 C NMR (75 MHz, CDCl3) δ 141. 2, 128.5, 128.2, 126.9, 87.9, 82.1, 78.4, 75.7, 71.5, 54.0, 30.6, 22.1, 18.7, 13.7, 3.9.

Trimethyl(3-((3-methyl-1,5-diphenylpenta-1,4-diyn-3-yl)oxy)prop-1-yn-1-yl)silane (260)

To a solution of (3-methyl-3-(prop-2-yn-1-yloxy)penta-1,4-diyne-1,5-diyl)dibenzene 254 (0.43 g, 1.5 mmol) in anhydrous THF (4 mL) was slowly added nBuLi (2.3 M in hexane, 0.72 mL, 1.65 mmol, 1.1 equiv) at -70 °C. The solution was stirred at the same temperature for 30 min. To the resulting mixture was added chlorotrimethylsilane (0.14 mL, 1.65 mmol, 1.1 equiv) at -70 °C, and the reaction mixture was allowed to warm to room temperature and stirred for additional 1.5 h. The reaction was quenched with saturated aqueous NH4Cl (1.0 mL), The aqueous layer was extracted with diethyl ether (3×20 mL), and the combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure.

The residue was purified by flash chromatography on silica gel (Cyclohexane/Ethyl acetate gradient from 98/2 to 95/5) to afford 260 (0.5 g, 93%) as a pale yellow solid. m.p. 70 -72 °C.

Rf = 0.3 (Cyclohexane/Ethyl acetate; 95/5, KMnO4, UV).