I have thoroughly enjoyed the last three years working in the Maco team, it's been a wonderful experience on both a personal and professional level.

Firstly I am truly grateful to both my PhD directors; Marc (The Cobalt King). Firstly I want to thank you for giving me the chance to work on the project, the last three years have been an absolutely amazing. You found the perfect balance of giving me the freedom I needed to grow and mature as a researcher while always been there to help and support me. I loved the way we could easily discuss chemistry and bounce ideas of each other, in my opinion this is how research should be done. We have done 5 publications together which I am so pleased and proud about. Chemistry aside, I think we share a similar sense of humor and this only added to the atmosphere of the lab and made working together even more of pleasure. I look forward to drinking many pints of Beamish together in Cork!!!! Alejandro, I also want to thank you the opportunity to work on this project, but also for your support, guidance and patience over the last three years. While it's true that we didn't always work together, I knew you were there when I had questions or needed advice. I want to thank you for your availability and allowing me the possibility to grow as a researcher. I have matured significantly over the last three years both as a person and a scientist and I thank you both for your contribution to my personal and professional development. I wish you nothing but success for your future research.

I also want to thank the other members of the ''cobalt team'' Muriel and Corinne and Etienne (yes Etienne you are now part of the team). I would like to thank Muriel for being so approachable and friendly but also for your contribution to my work. You were always available to offer suggestions and correct my experimental sections (I still have nightmares of getting my exp section back from you and seeing all the red pen marks everywhere). Corinne, despite being the director of the IPCM you still always had time to chat and made me feel very welcome. Your good humor and attitude mean you are always the life-and-soul of the party. I would also like to thank you for taking the time to correct my thesis and for your suggestions on my PowerPoint for my defense. Etienne, we have worked together on almost all my projects over the last three years. It's been a real pleasure to work and learn from you and I thank you for all your advice. Chemistry aside, I have always enjoyed our chats and your witty humor. All the best for the future!! I would next like to thank all the other permanent members of the Maco team. Louis, for your Kich Lorraine jokes but also for your questions and suggestions during seminars. Virginie for putting up with me in the lab for three years, but also for your friendly nature and warmness. Marion and Marine for your good humor and contribution to the atmosphere of the team. Also I would like to wish Marion good luck having to share an office with Marc and Gilles. Cyril, I would like to thank you for the organization of Friday seminars but also for your availability to discuss chemistry. Gilles, the newest permanent member, I want to thank you for all the suggestions and discussions about my work, especially for teaching me about Torquoselectivity. I also enjoyed the many jokes and laughs we shared over the last year. I want to also wish you good luck as the new boss of the solvent machines, hopefully one day you will get it set up ;).

Having thanked all the permanents in our team, I would now like to give a mention to all the students who I have worked with and who have made these last three years so memorable.

Simon, le beau gosse de l'été. The first person I went for a pint with when I arrived in France, we have spent many great times together both in and out of the lab (Too many to mention). We were also the two starts of the team septentrion, I was more of a brut whereas you provided the finesse in front of goal. I look forward to having you visit me in Cork, if Tiffany allows you. VIEUX MEC!!!! Je rigole ;) Anthony, le deuxième beau gosse. My gym (ohhhhh c'est bon ca) and darts (pwoooomm) buddy. I my only wish for you is that someday you will be able to lift 20 kg x 2 in the bench press like me. I always want to thank you for organizing my pot. Comme Simon tu es aussi un vieux mec mais bon je vous aime quand meme!!! A bientot a Cork!! Jérémy dit Djédjé, I look forward to your marriage in Ireland with Chaton (now that its allowed). I thoroughly enjoyed our ''interesting'' chats in the lab, luckly nobody else heard us. I will miss you bo gosse!!!! Thomas, the resident geek of the Maco team, I'm sure I still owe you some pan au chocolates for all your help with word!!! At least I have the book now ;) Best of luck with the rest of your thesis and remember the day of your defense to not use a microphone!!!! Its been a pleasure working with you over the last 3 years and I would also like to thank you and Anne for all the help organizing my defense party.

Laura (Lolo), Always the last one to leave a party, its been great working and spending the last three years with you in the lab!! I hope you will make it over to Ireland to visit me!! In the meantime I hope that no stray darts will end up in your leg!! Caleb, the bodybuilder of the lab. Keep up the good work on your arms and someday they will be as big as mine!! Help Anthony also he needs it!! Good luck also in your new adventure in Canada!! Christopher, the raccoon man. We might not always have seen eye-to-eye but you are a good guy when you are not been chiant!! Good luck for the future!! Laura H, we worked in the same lab together when you first arrived, you were unfortunate enough to get stuck with me and Anthony!! Best of luck for the future, I wish you every success and happiness.

Zhonghua. Our first Chiness PhD student, the best of luck for your thesis and French classes. Your biggest challenge is probably trying to keep Virgine happy!! Vincent, we first met in Dublin, then we ended up working together in paris, it's a small world. Thanks for your help and advice throughout the last three years.

Finally, I would like to mention all the new first year students; Thibaut, although you haven't been in the lab along time you have fitted in seamlessly. Best of luck for you thesis, I'm sure you'll do a great job!! Ye, we haven't had much time to get to know each other but It's been a pleasure sharing my office with you since you arrived! Good luck with your French classes and I hope Anthony and Thibaut will look after you. I also want to thank you for all the chiness snacks you bought me for my defense party.

Of course there have been many students that have left the lab since I arrived… Gone but not forgotten!! Cédric, Mon petit Dric Dric, '''All the crazy shit I did tonight, those will be the best memories, I just wanna let it go for the night, that would be the best therapy for me''' Thanks for teaching me so many useful French phrases, even if Mindy might not have liked them. Avassaya, ma petite ploy, thanks for the two great years we spent together in the lab, I still miss you and look forward to seeing you again soon . Good luck for your post-doc, soon you will Prof. Ploy!!! Elise, the big boss in the lab when I arrived, you christened me fluffy, it's now Dr. Fluffy. I'll be sure to get my haircut regularly!! Frida, thanks for your good nature and kindness in the lab, best of luck in your career with goodyear!! Coralie aka Coco, the most reserved member of the team but it was a pleasure to work with you during the first two years of my PhD, best of luck in career!! Sandrine, you were the one how thought me how to get gold-fingers!!! Thank you for your kindness in the lab when I arrived and best of luck in the future. Ludwig, you also just make it onto the past-students having finished just before me.

Thanks for all you help and advice leading up to my defense and also for making punch at every lab party…. It's thanks to you I've woke up with many headaches!! Throughout the past three years, many master's and internship students have passed through the lab. I have to start with Mr Jean-Baptiste Garsi…. We shared many good times in the lab even if there was moments when I wanted to strangle you!! I will always associate you with the song '' there's a big tree in my garden''. Joking aside, you did a great job on the dihydropyridines proect and I was delighted to do a publication with you. Best of luck for your PhD in Canada. Quentin, I will always remember our week camping with fond memories, especially us two beating Simon in la Pétanque. Best of luck for your thesis! Also a mention to Pauline (Popo) and Cecilia, for their good humour and contribution to the team during their 6 month stay. Claire, thanks to Cedric being clumsy and cutting his hand we ended up working together, good luck for you PhD in the Cossy lab, I wish you every success in the future.

Of course during my time here at UPMC I made friends with students in other lab, notably the Rocs and Gobs. Valentin, we spent a great week together during the SECO, enjoy your holidays and all the best for your future career. Fares, one of the bubbliest and happy people I know, also my neighbor at Rue Bellier Dedouvre. Best of luck for the rest of your PhD and I'm sure you and Anthony will have time to share a whiskey or two on Friday evenings.

Xiaolei, I will miss talking with you and spending time together. Thank you for the food you prepared for my party and for your humour and warmness over the last three years. I wish you all the best for the last year of your thesis I'm sure you will do a great job. You are always welcome to visit me in Ireland  I would also like to thank Omar and Geoffry for all the analysis they did for me throughout the three years. I want to also mention Alexandra and Alexis, we have spent many wonderful evenings together. Best of luck for the future and I hope to see you both soon.

A quick mention also to the members of my football team, Pierre, Max, Mous, Flo and Jouve, thanks for all the good times we spent together!! Next I want to thank my fiancée Mindy, our relationship started in England, then we moved to France and now to Ireland. You have stuck by me through thick and thin and always supported me. I can't thank you enough for all that you have done. I am now excited to move onto the next chapter of our lives together. Je t'aime!!!! I also want to thank your parents, brothers and sister for being so kind to me over the last three years, I now consider them to be my second family.

Finally I want to thank my family for all the love and support they have shown me. I want to mention especially my mam, you thought me the value of hard work and have made many sacrifices in order for me to be where I am today. I appreciate everything you have done for me; you really are one in a million. I love you. I want to also mention my two sister Emer and Fiona who are always there to support me and keep me in my place. The final family member I want to mention is my cousin Gary (Big Schan), a great man to drink whiskey but also my big brother and best friend!! I can't thank him enough for all he has done for me.

IMes

1,3-Bis (2,4,6-trimethylphenyl)

Résumé

Cette thèse se divise en trois chapitres.

Le premier chapitre introduit dans un premier temps la bibliographie sur l'activation et la fonctionnalisation de la liaison C-H par les complexes de cobalt. Nous présenterons tout d'abord les résultats pionniers en version stoichiométrique de Klein sur l'activation de la liaison C-H. Puis, après les premiers résultats en version catalytique de Murahashi, nous exposerons les résultats décrit dans la littérature sur l'activation et la fonctionnalisation de liaisons C-H en utilisant des complexes de cobalt basse valence (Co(I) ou Co( 0)). Nous terminerons cette partie bibliographique sur l'utilisation des complexes de cobalt haute-valence de cobalt (Co(III)) pour le même type de réaction. Dans un deuxième temps dans ce premier chapitre nous décrirons les objectifs de notre projet basé sur les premiers résulats obtenus dans notre groupe dans le domaine de l'activation de liaisons C-H. Enfin, nous exposerons nos résultats en trois souspartie : Le deuxième chapitre présente l'état de l'art sur les complexes de cobalt ainsi que leur application pour l'hydrosilylation des alcènes et alcynes. Ensuite les résultats obtenus dans notre équipe seront présentés. D'abord, nous avons exploré l'utilisation d'une variété d'hydrosilanes pour l'hydrosilylation du diphenylacetylene. Ensuite, nous avons choisi le triphenylsilane et le triethoxysilane pour continuer l'étude avec une variété d'alcynes dissymétriques. Egalement, pour étudier le mécanisme de cette réaction nous avons réalisé des calculs théoriques, qui seront présentés à la fin de ce chapitre Le troisième chapitre présente la bibliographie sur les réactions de couplage avec des complexes et des sels de cobalt. Pendant nos études précedentes (Chapitre 1 et 2) nous avons découvert qu'il était possible de faire une réaction d'homocouplage avec le bromures et chlorures du benzyle, dont nous présenterons les résultats.

Chapitre 1

Fonctionnalisations de liaisons C-H catalysées par des complexes de cobalt.

a. L'hydroarylation d'alcynes avec des aryl cétimines

Tout d'abord, nous avons étudié la réactivité d'une variété de complexes de cobalt pour effectuer l'hydroarylation du diphénylacétylène 19 avec l'aryl cétimine 24a (Table R 1). À la suite de cette étude, il a été constaté que les conditions optimales pour cette réaction sont un chauffage à 170 °C pendant une heure au micro-ondes (entry 12). Avec ces conditions de réaction nous pouvons isoler le produit souhaité 25a avec un excellent rendement de 90%.

Table R 1 Optimisation des conditions réactionnelles

Avec les conditions optimales en main, nous avons commencé à explorer l'étendue d'application de cette réaction. Ainsi, nous avons montré que la réaction était possible avec une large gamme de substrats. Il a été possible d'utiliser de nombreux variété d'alcynes avec des substituants tels que phényle, alkyle et silyle. Dans tous les cas, nous avons obtenu une sélectivité anti, ce qui est à l'opposé de celle précédemment rapporté et en général les rendements sont bons allant de 45 à 96%.

Scheme R 1 Résultats de l'hydroarylation d'alcynes par des aryle-cétimines

Par la suite nous nous sommes attaché à comprendre le mécanisme de la réaction. Nous avons réalisé une série d'expériences avec du marquage au deutérium (Scheme R 2). Nous avons fait trois expériences : a) Une expérience de type <<Crossover>>.

b) Une expérience de type compétition. c) Une expérience en présence d'hydrure de cobalt.

Scheme R 2 Expériences de marquage au deutérium

Les conclusions principales de cette étude de marquage au deutérium sont que la réaction se déroule via un mécanisme concerté. Nous avons également obtenu des informations sur la cinétique de la réaction, une valeur de 1,4 pour le KIE nous laisse suggérer que l'addition n'est pas l'étape limitante. Enfin, une expérience en présence d'hydrure de cobalt montre que l'addition oxydante semble se faire par un mécanisme concerté. Suite à ces travaux nous avons effectué une série de calculs DFT pour une meilleure compréhension du mécanisme de la réaction (Figure R 1,Figure R 2). Cette étude a montré que les réactions menées en presence des deux catalyseurs ont des états de transition similaires. Avec Co(PMe 3 ) 4 la barrière est légèrement inférieure, ce qui correspond à nos résultats expérimentaux (meilleur rendements avec le Co(0)). Des études ELF ont également confirmé notre hypothèse que transfert d'hydrogène se déroule via un mécanisme concerté. En effet, l'électron impliqué reste associé à l'hydrogène pendant le transfert et n'est pas impliqué dans la liaison. En utilisant les conditions de réaction déjà optimisées de notre étude précédente, nous avons commencé à explorer la synthèse des 1,2-dihydropyridines (Scheme R 4). Nous avons été heureux de constater que la réaction fonctions avec un grand nombre d'imines et d'alcynes. Comme dans notre étude précédente, nous avons pu incorporer des alcynes portant des groupements phényles, alkyles, silyles et des hétéroatomes. De façon intéressante, nous avons pu également inclure des groupes chimiquement sensibles tels que les esters et cyano avec d'excellents rendements obtenus dans les deux cas.

Scheme R 4 Résultats de la synthèse de 1,2-dihydropyridines

En effectuant une étape de désilylation dans le même pot, nous avons également pu accéder à des dihydropyridines non substituées en position 2 (Scheme R 5), qui n'avaient jamais été décrites dans la littérature.

Scheme R 5 Désilylation des dihydropyridines

Nous avons effectué des calculs DFT afin de mieux comprendre le mécanisme de la réaction (Figure R 3). Il a été déterminé que la réaction se déroule d'une manière similaire à celle que nous avons précédemment rapportée.

c. C2-alkylation et alcénylation intra et intermoléculaires des indoles

Nous voulions par la suite étendre cette méthode d'hydroarylation des alcynes. Nous avons choisi d'utiliser un groupe fonctionnel indole car il est intéressant d'un point de vue de la chimie médicinale. Tout d'abord, nous avons examiné la réactivité des alcynes et comme avant, nous avons observé une sélectivité anti (Table R 2).

Table R 2 C2-alkylation de l'indole 81a avec des alcynes

Suite à cela, nous avons examiné un autre partenaire que les alcynes en nous orientant vers les alcènes. Nous avons obtenu une bibliothèque de composés en utilisant des styrènes, des alcènes simples et des silanes vinyliques avec de bons rendements (Scheme R 7).

Scheme R 7 Résultats des C2-alkylation avec différentes oléfines

Nous avons pu étendre cette réaction en version intramoléculaire. Ainsi, nous avons été capable d'isoler une variété de dihydropyrroloindoles avec de bons rendements (Scheme R 8).

Scheme R 8 Synthèses de dihydropyrroloindoles

Dans le cadre de nos expériences mécanistiques, nous avons effectué une étude de marquage au deutérium (Scheme R 9). Cette étude a montré que la première étape de la réaction (l'addition oxydante) est réversible, puisque nous avons observé une distribution du deutérium sur le composé obtenu.

Scheme R 9 Des expériences avec du marquage deutérium

Nous avons effectué des calculs DFT pour le styrène et le diphénylacétylène comme indiqué ci-dessous (Figure R 4). Les deux états de transition suggèrent un mécanisme similaire pour les deux type d'insaturations (Scheme R 10). Ceci est également le même type de mécanisme que nous avons précédemment raportés dans nos deux études antérieures. Comme nous l'avons constaté dans la partie bibliographique sur les hydrosilylations d'alcynes catalysées par des complexes du cobalt, celles-ci souffrent de plusieurs problèmes :

1) Une mauvaise compatibilité avec les hydrosilanes tertiaires est souvent observée, ou alors seul un ou deux silanes sont réactifs avec un complexe donné.

2) Les régio-et stéréosélectivités observées sont souvent modestes et fortement dépendantes d'une fonctionnalisation particulière de l'alcyne (groupement thiol ou CF 3 …) Nous avons commencé le screening des hydrosilanes en présence du diphénylacétylène qui a souvent été un très bon partenaire dans nos réactions. Nous avons trouvé des conditions optimales pour cette réaction en utilisant 5 % molaire de HCo(PMe 3 ) 4 dans le toluène à 110 o C pendant 24 heures. Nous avons été heureux de constater que la réaction était compatible avec une grande variété d'hydrosilanes que ce soit des aryle, alkoxy ou alkyle silanes (Table R 3). Nous avons aussi constaté que pour l'hydrosilylation, cette fois, le catalyseur de cobalt(I) donne de meilleurs résulats que le cobalt(0) ( Entrées 2,4 et 6).

Table R 3 Hydrosilylation de diphénylacétylène avec hydrosilanes

Sur la base de ces résultats initiaux, nous avons choisi de poursuivre notre étude avec le triphénylsilane et le triéthoxysilane en utilisant une grande variété d'alcynes dissymétriques. Nous avons du toutefois modifier légèrement les conditions réactionnelles par rapport à celles développées en présence de diphénylacétylène. En effet, certains alcynes dissymétriques étant moins réactifs, il a été nécessaire d'augmenter la température à 160 °C dans le toluène pendant 2 heures. Les alcynes utilisés sont substitués par différents groupes fonctionnels en fonction de l'encombrement stérique, R S (smaller group) and R L (larger group) (Figure R 5). La réaction fonctionne bien pour une large gamme d'alcynes en présence de triphénylsilane (Table R 4). Nous avons observé une excellente stéréosélectivité, et la régiosélectivité semble dirigée par l'encombrement stérique des substituants de l'alcyne. Nous avons montré que l'utilisation d'alcynes dissymétriques non stériquement différenciés mais portant des substituants électroniquement distincts a donné un mélange de régioisomères 50/50 suggérant que la réaction est sous contrôle stérique de l'alcyne (entrées [START_REF][END_REF][14][15].

Table R 4 Hydrosilylation d'alcynes dissymétriques avec Ph 3 SiH

Suite à cela, nous avons examiné l'utilisation de triéthoxysilane avec une variété d'alcynes (Table R 5). Nous avons observé les mêmes régioselctivité que pour le triphénylsilane, bien que les stéréosélectivités soient plus plus faibles.

Table R 5 Hydrosilylation d'alcynes dissymétriques avec (EtO) 3 SiH

Pour commencer nos investigations mécanistiques, nous avons d'abord synthétisé le cobalt (III) intermédiaire 98 que nous pensons être un intermédiaire important dans le mécanisme de la réaction (Scheme R 11).

Scheme R 11 Formation du complexe H 2 CoSiPh 3 (PMe 3 ) 3

Nous avons ensuite testé l'activité catalytique de ce complexe 98 dans notre réaction modèle avec le diphénylacétylène et le triphénylsilane. Nous avons observé une réactivité similaire à celle de HCo(PMe 3 ) 4 confirmant que ce complexe joue un role important dans la réaction.

Scheme R 12 Réaction catalytique du complexe H 2 CoSiPh 3 (PMe 3 ) 3 , en présence de diphénylacétylène et triphénylsilane

Pour avoir une idée plus précise du mécanisme, des calculs DFT ont été effectués sur un système basé sur le complexe 98 en conjonction avec le 1-phénylpropyne. La principale question posée est de savoir si l'insertion de l'alcyne se produit d'abord dans la liaison Co-H (hydrocobaltation) ou dans la liaison Co-Si (silacobaltation). D'après les résultats, la barrière pour l'hydrocobaltation est de 3,18 kcal / mol alors que celle pour la silacobaltation est de 19,42 kcal / mole. Il semble donc que notre catalyseur au cobalt suive le mécanisme de Chalk-Harrod classique (Figure R 6) par un processus d'hydrocobaltation.

Figure R 6 Surface d'énergie potentielle calculée par DFT pour l'hydrocobaltation et silacobaltation

Une autre question importante à étudier par des calculs DFT est que, malgré l'utilisation d'un catalyseur hydrido-cobalt avec un silane, aucune évolution de H 2 n'a été observée expérimentalement. Nous avons calculé que l'élimination réductrice de H 2 est une réaction endothermique avec un état de transition qui réside au-dessus de 3,36 kcal / mol, tandis que la barrière inverse (par exemple l'addition de H 2 sur le centre de cobalt) est très faible (0,47 kcal / mol). Ainsi, même si H 2 est produit au cours du processus catalytique, il va rapidement réagir et s'additionner sur le centre du cobalt pour régénérer les espèces actives (Figure R 7).

H 2 reductive elimination

Sur la base des données expérimentales et théoriques, nous avons pu proposer une voie mécanistique pour notre système catalytique illustré ci-dessous (Scheme R 13) Scheme R 13 Cycle catalytique Chapitre 3

Cobalt-catalyzed coupling reactions of benzyl halides

Dans ce dernier chapitre, nous rapportons l'homocouplage des halogénures de benzyle, en présence d'un catalyseur au cobalt et du diméthyl zinc. L'exploration des conditions de réaction a montré que la réaction se déroule dans des conditions de réaction modérées (40 ° C à 66 ° C), avec des charges catalytiques faibles (0,5 à 5 mol %) et un temps de réaction trés court (10-60 minutes) (Scheme R 14).

Scheme R 14 Conditions optimales pour l'homocouplage des halogénures de benzyle

Les bromures de benzyle substitués en position para sont dimérisés dans des conditions optimales. Des groupements donneurs d'électrons, comme par exemple 4-Me, 4-iPr, 4-OMe et les substituants attracteurs d'électrons, comme par exemple 4-CO 2 Me, 4-NO 2 , ont donné les produits désirés avec de bons rendements dans tous les cas (Scheme R 15).

Scheme R 15 Résultats de la réaction d'homocouplage

Les halogénures de benzyle portant des substituants encombrants (3, peuvent aussi participer à la réaction d'homocouplage. De plus, les groupes fonctionnels potentiellement sensibles (halogeure) peuvent être introduits en position ortho et méta des halogénures de benzyle pour donner le produit de dimérisation avec de bons à excellents rendements (Scheme R 16).

Scheme R 16 Résultats de la réaction d'homocouplage

Enfin, d'autres substitutions ont été étudiées, tel que les bromures de pentafluorobenzyle, de naphtalène et de pyridine (Scheme R 17). Encore une fois, les rendements obtenus sont très bons.

Scheme R 17 Résultats de la réaction d'homocouplage

Enfin, les chlorures de benzyle ont montré qu'ils pouvaient participer à la réaction l'homocouplage, avec toute fois une charge de catalyseur légèrement plus élevée et un temps de réaction plus long (Scheme R 18).

Scheme R 18 résultats de la réaction d'homocouplage

Nous avons étudié le mécanisme de réaction en essayant de comprendre le rôle du diméthylzinc et le mode d'activation de l'halogénure de benzyle. Les résultats de cette étude sont résumés ci-dessous (Table R 6). Nous avons constaté que le rôle du zinc était uniquement pour régénérer les espèces actives de cobalt. Nous avons également montré que le cobalt(0) était capable d'effectuer deux transfert monoélectronique et que le cobalt(I) pourrait faire un transfert monoélectronique.

General Introduction

Transition metal catalysis has seen exponential growth over the last few decades. Its applications extend to a myriad of research areas such as petroleum, environmental, chemicals and pharmaceuticals. 1 A great deal of the early work in this area focused on the development of late transition metals, largely due to their advantages in terms of the diversity, tunability and robustness. However, increasing prices of precious metals coupled with low natural abundance and toxicity issues somewhat limit their application particularly for future development. Despite showing excellent early potential for the direct C-H functionalization due to their low cost, high abundance and unique reactivity, first row transition metals have been greatly underutilized (Table 1). However, of late there has been a considerable upswing in momentum to develop the catalytic potential of 3d transition metals, and in particular cobalt. 3 Given that cobalt shares a group with rhodium and iridium and transition metals in the same group often exhibit similar reactivity, it's not surprising that cobalt has been the focus of much attention. Yet, a considerable challenge is the fact that the electronic properties of 3d transition metals are significantly different to their 4d and 5d analogs in terms of electronegativity, spin orbit couplings among others (Figure 1). 4 These differences in electronic properties do however offer the possibility to discover new and interesting reactivity. Within the field of transition metal catalysis, C-C bond forming reactions have attracted particular attention, specifically cross coupling reactions. 5 However, a pertinent issue with this reaction type is the formation of stoichiometric amounts of potentially harmful salts and the necessity to start from pre-functionalized molecules (Scheme 1). Thus it is desirable to develop more atom and step economic synthetic strategies. To this end, direct functionalization of otherwise inert C-H bonds has become an increasingly popular strategy 6 .

Scheme 1 Traditional cross-coupling reactions versus direct C-H bond activation

Indeed a quick search of the literature reveals the rapid growth in the area of the past 20 years as determined by the number of publications directly related to C-H bond functionalization (Figure 2).7

Figure 2 Number of publications per year on C-H bond activation from a sample of top chemistry journals

Therefore, it was the aim of this project to explore the use of cobalt complexes for a variety of reactions, with particular emphasis on C-H bond functionalization. This thesis will be divided into three chapters dealing with three broad areas; 1. C-H functionalization 2. Hydrosilylation of alkynes 3. Homocoupling of benzyl halides. Each chapter will commence with a literature review of the topic being discussed followed by the project aims and then the results obtained. Finally, future perspectives and the experimental data will be reported.

Chapter 1: Cobalt-catalyzed C-H bond functionalization

Chapter 1: Cobalt-catalyzed C-H bond functionalization 1 Stoichiometric C-H activation

The group of Klein has extensively explored the application of well-defined low-valent cobalt complexes towards C-H activation. Klein and co-workers described the first example of a well-defined cyclometalation reaction using MeCo(PMe 3 ) 4 and azobenzene 1 which occurred at a staggeringly low temperature (-70 to 20 o C). 8 The reaction was proposed to proceed via nitrogen-assisted oxidative addition into the ortho C-H bond by the Co(I) species, followed by reductive elimination of methane gas. They also demonstrated that the same complex was capable of promoting the cyclometalation of various arenes containing phosphorous, 9nitrogen,10 oxygen11 and sulphur. 12 The formation of such cyclocobaltated complexes was also possible with six (12), and even sterically constraint four-membered complexes (14) (Scheme 2). It is worth noting the reaction of MeCo(PMe 3 ) 4 with 2-fluorobenzophenone afforded exclusively the product of ortho-C-F cleavage indicating that C-F bond cleavage is favorable over C -H metalation. 11 While the formation of these metalated complexes demonstrated the undoubted potential of this class of complex to perform bond activation, further functionalization has remained rare by comparison. One exception was the formation of complex 17 through the treatment of the strained 4-membered cyclocobaltated complex 14 under an atmosphere of CO. CO insertion into the C-Co bond afforded the acyl complex 17 in low yield (Scheme 3). 9a cyclometalation followed by CO insertion. Further exploration and applications were somewhat limited due the rather harsh reaction conditions (Scheme 4). 13 Scheme 4 Cobalt catalyzed carbonylative cyclization

Addition reactions

Hydroarylation reactions

Despite the seminal work by Murahashi in 1955, further reports of cobalt catalyzed C-H functionalization remained largely sporadic. However, in 1994 the group of Kisch disclosed the first cobalt-catalyzed hydroarylation of alkynes using a cobalt(I) complex bearing a labile N 2 ligand CoH(N 2 )(PPh 3 ) 3 (Scheme 5). 14 The generation of the active catalytic species was achieved through ligand substitution of the N 2 by azobenzene, the reaction was also amenable with CoH(H 2 )(PPh 3 ) 3 as a precatalyst. Despite this considerable advancement, the present reaction suffers many drawbacks: I) high catalytic loading, II) narrow substrate scope, i.e. only diazobenzene and diphenylacetylene derivatives and, III) regioselectivity issues i.e. uncontrolled double addition of diphenylacetylene.

The last six years has seen an explosion in reports on the application of low-valent cobalt catalyzed C-H functionalization primarily from the group of Yoshikai. 15 Based on the earlier works by Murahashi, Klein and Kisch, Yoshikai and co-workers have developed a ternary 13 (a) Murahashi, S. J. Am. Chem. Soc. 1955, 77, 6403-6404. (b) Murahashi, S.; Horiie, S. J. Am. Chem. Soc. 1956, 78, 4816-4817. 14 Halbritter, G.; Knoch, F.; Wolski, A.; Kisch, H. Angew. Chem. Int. Ed. 1994, 33, 1603-1605. 15 Gao, K.; Yoshikai, N. Acc. Chem. Res. 2014, 47, 1208-1219.

Scheme 5 Cobalt-catalyzed hydroarylation of azobenzene

catalytic system consisting of a cobalt salt, ligand, stoichiometric reductant and in some cases additional additives such as pyridine which efficiently catalyze the hydroarylation of alkynes with a variety of aryl C-H bonds. Thus, in 2010 Yoshikai employed CoBr 2 , PMePh 2 (as ligand) and MeMgCl (as reductant) which afforded the 2-fold syn-alkenylation of 2-arylpyridines with a variety of alkynes (Scheme 6). 16

Scheme 6 Hydroarylation of alkynes with 2-arylpyridines

Building on his initial finding, the scope was expanded to include aryl ketimines 17 and aldimines 18 (Scheme 7).

Scheme 7 Hydroarylation of alkynes with aryl ketimines and aldimines

In the case of ketimines it was necessary to add pyridine as an additive, presumably to stabilize the in situ generated low valent cobalt species. It is noteworthy that the temperature could be significantly reduced in comparison to the early case with 2-arylpyridines and previous reports with rhodium. 19 In addition, hydroarylation of unsymmetrical alkynes proceeded with synthetically acceptable levels of regioselectivity with C-C bond formation occurring at the less 16 Gao, K.; Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2010, 132, 12249-12251. 17 Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133, 17283-17295. 18 Yamakawa, T.; Yoshikai, N. Tetrahedron 2013, 69, 4459-4465. 19 Lim, S.-G.; Lee, J. H.;Moon, C. W.;Hong, J.-B.;Jun, C.-H. Org. Lett. 2003, 5, 2759-2761. hindered acetylenic carbon. However, on switching from ketimines to aldimines, it was necessary to reoptimize the reaction conditions. Interestingly, imines bearing meta-methoxy, cyano and halogens yielded products with addition proximal to these groups i.e. in the more sterically hindered position (Figure 3). This curiosity can be attributed to the secondary directing group effect of these functional groups as also reported for ruthenium and iridium.20

Figure 3 Hydroarylation of alkynes with aryl ketimines substituted in the 3-position

The catalytic cycle is proposed to proceed via the formation of a low-valent cobalt species generated from the cobalt (II) precatalyst and excess of t-BuCH 2 MgBr (Scheme 8). Coordination of the alkyne to the cobalt center generates intermediate I followed by oxidative addition into the ortho-C-H bond to form complex II. A KIE (kinetic isotope effect) value of ca. 5 strongly suggests the oxidative addition is the turnover limiting step. Following this, a migratory insertion of the alkyne into the Co-H bond and finally a reductive elimination to afford the desired product and regenerate the initial cobalt species close the catalytic cycle. The observed regioselectivity for unsymmetrical alkynes can be explained by the preference of the larger substituent to avoid the steric repulsion around the cobalt center in the migratory insertion step.

Scheme 8 Proposed catalytic cycle for the cobalt-catalyzed hydroarylation of internal alkynes

Imines proved to be a versatile directing group and also allowed for the activation of an olefinic C-H bond. Thus the group of Yoshikai showed that α,β-unsaturated imine 31 undergoes an annulation reaction with diphenylacetylene 19 in the presence of an optimized bimetallic cobalt catalytic system to afford 1,2 dihydropyridines. The reaction presumably involves olefinic C-H activation/alkenylation followed by a subsequent 6π electrocyclization (Scheme 9). 21 The scope of the present hydroarylation reaction was also expanded to include indoles bearing a removable N-pyrimidyl directing group, (benzo)azoles and thiazoles (Scheme 10) .22

Scheme 9 Annulation of α,β-unsaturated imine and internal alkyne Scheme 10 Addition to indoles (A), (benzo)azoles (B) and thiazoles (C)

Given the success of cobalt-catalyzed alkyne hydroarylation it was naturally extended to incorporate alkenes. Generally speaking, addition of aromatic compounds to alkenes, for example styrene, can be classified into two reaction types I) Friedel-Crafts type in the presence of a Lewis or Brønsted acid23 or II) hydroarylation mediated by transition metal catalyzed C-H activation. While Friedel-Crafts reactions work well for electron-rich arenes and generally afford branched products, the C-H activation approach often requires the incorporation of directing groups or electron poor arenes and tends to give linear products. 24 Thus, there was a need to develop a branched selective hydroarylation via a C-H activation pathway thereby complementing the limitations for the Friedel-Crafts approach. Indeed, a protocol for selective preparation of branched products is arguably more valuable in terms of stereoselectivity.

To this end the group of Nakamura reported the hydroarylation of alkenes with benzamides using an in situ generated low-valent cobalt catalyst. However, for simple alkenes the linear product was obtained as the sole regioisomer in good yields and in the case of styrene a mixture of approximately 2:1 in favor of the linear product was achieved (Scheme 11). 25

Scheme 11 Cobalt catalyzed alkene hydroarylation with benzamides.

Inspired by this earlier work, Yoshikai and co-workers reported the reaction of 2phenylpyridine with styrene. Interestingly in this case, it was found that careful tuning of the ligand allowed a reasonable level of control in terms of regioselectivity. Thus, the reaction of CoBr 2 , PCy 3 and Me 3 SiCH 2 MgCl facilitated the generation of a branched product while switching the ligand from PCy 3 to an NHC ligand allowed for reversal of the regioselectivity to give the linear product. The selectivity also depended on the electronic properties of the substrates, for example, 2-arylpyridine bearing a trifluoromethyl group afforded the branched product as the major isomer regardless of the ligand employed. Sterics of the substrate were also important, for example using the linear selective catalyst Co-IMes with 2-vinylnaphthalene lead to significant deterioration in selectivity for the linear product (Scheme 12). 26

Scheme 12 Regiodivergent addition of 2-arylpyridines to styrenes

Deuterium labelling experiments revealed H/D scrambling in the ortho position of the 2phenylpyridine and the α and β positions of styrene before C-C bond formation under both catalytic systems. This result suggests a reversible insertion of the styrene following the initial oxidative addition. Finally, reductive elimination would yield either the 1,1-or 1,2-diarylethanes products. It is proposed that the two insertion paths compete with each other and that the regioselectivity is governed by the reductive elimination. The branched selective Co-PCy 3 55 catalysis would result from the preference to form a benzylcobalt species whereas the linear selectivity of the Co-IMes catalysis could be rationalized by the preference of the sterically bulky IMes ligand to avoid steric congestion. 24a A computational study by the group of Fu was performed to examine the observed regio-outcome of the reaction by Yoshikai. Indeed, ligand bulkiness alone does not account for the experimentally observed switch in regioselectivity as PCy 3 in fact occupies a greater volume than IMes (Table 2). 27

Table 2 Volume comparison of phosphine and NHC ligands

It was shown that the phosphine ligand adopts an ''umbrella-down'' shape with the groups on the phosphorus atom directed away from the metal center. In contrast, the NHC ligand adopts a more ''umbrella-up'' position with the phenyl groups on the nitrogen atom directed towards the metal center. Interestingly it was also shown that neither ligand size nor ligand shape when considered alone would adequately explain the regioselectivity rather a combination of the two factors. The proposed mechanism is shown below (Scheme 13) Scheme 13 Proposed catalytic cycle for the regiodivergent hydroarylation of styrene and 2-phenylpyridine 27 Yang, Z.; Yu, H.; Fu, Y. Chem. Eur. J. 2013, 19, 12093-12103. The group of Yoshikai has also extended this methodology to the branched-selective hydroarylation of aromatic aldimines and ketimines. 28 However, as seen previously and a reoccurring feature of these ternary catalytic systems, there is a need to optimize reaction conditions for each particular substrate. Thus, the catalytic system of CoBr 2 , P(p-Tol) 3 , and Me 3 SiCH 2 MgCl which was effective for aldimines proved ineffective for ketimines. Following a further reoptimization of reaction conditions, a system employing P(4-FC 6 H 4 ) 3 and cyclohexylmagnesium bromide allowed the branched-selective addition of styrene to ketimines. Styrene's aside, vinylsilanes and aliphatic olefins also participate in cobalt-catalyzed imine directed hydroarylation giving linear products (Scheme 14). 29 Based on earlier work by Bergman and Ellman, 30 Yoshikai and co-workers reported the first example of an intramolecular cobalt-catalyzed hydroarylation of alkenes via a C-H activation at the C-2 position of indoles (Scheme 15). 31 Thus, N-substituted indoles bearing homoallyl or bishomoallyl tethers cyclized to give a variety of fused tricyclic dihydropyrroloindoles and tetrahydropyridoindoles. It is interesting to note that the size of the ring formed depended on both the length of the tether and the ligand employed. In both cases a cobalt-NHC catalytic system was used. However, a cobalt-IPr system promoted the formation of tetrahydropyridoindoles, while a cobalt-SiMes catalyst exhibited selectivity towards the 28 (a) Lee, P.-S.;Yoshikai, N. Angew. Chem. Int. Ed. 2013, 52, 1240-1244. (b) Dong, J.; Lee, P.-S.; Yoshikai, N. Chem. Lett. 2013, 42, 1140-1142. 29 (a) Gao, K.; Yoshikai, N. Angew. Chem. Int. Ed. 2011, 50, 6888-6892. (b) Ding, Z.; Yoshikai, N. Beilstein J. Org. Chem. 2012, 8, 1536-1542. 30 Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814-825. 31 Ding, Z.;Yoshikai, N. Angew. Chem. Int. Ed. 2013, 52, 8574-8578. Scheme 14 Imine directed hydroarylation of vinylsilanes and alkyl olefins 57 formation of dihydropyrroloindole. Another point of interest is that a similar rhodium catalyzed reaction reported by Bergman and Ellman is believed to proceed through a 5-endo-type cyclization whereas the corresponding cobalt system appears to operate via a 5-exo-type cyclization.

To conclude the section on cobalt-catalyzed hydroarylation reactions, we will examine a recent report from the Yoshikai group where they disclose the first enantioselective hydroarylation of styrenes. A chiral phosphoramidate ligand yielded the branched products in moderate to good yields and enantioselectivity. Yields and enantioselectivities were highly dependent on the substitution on the nitrogen; methyl, tosyl and acetyl groups gave poor yields and low enantioselectivity, while a Boc group delivered optimal results (Scheme 16). 32

Scheme 16 Enantioselective hydroarylation of alkenes 32 Lee, P.-S.; Yoshikai, N. Org. Lett. 2015, 17, 22-25. Scheme 15 Cyclization of indoles bearing olefin tethers 58

Hydroacylation Reactions

The first report of a cobalt-catalyzed hydroacylation reaction came from Vinogradov (Scheme 17a) 33 and then later by Brookhart (Scheme 17b). 34 In the case of the intermolecular version reported by Brookhart, excellent yields were achieved under mild conditions and low catalytic loadings. However, efforts to extend the methodology beyond vinyl silanes proved fruitless. Despite the obvious potential for future development of this reaction, reports were sparse until the recently reported works by Dong and Yoshikai. 35 Thus Dong, and co-workers reported the hydroacylations of aromatic and aliphatic aldehydes with 1,3 dienes. This transformation is challenging in terms of regio-and diasteroselectivity. Firstly, depending on the regioselectivity, the hydroacylation could occur at the C3 or C1 position as demonstrated by Krische and Ryu under ruthenium catalysis. 36 Secondly, depending on the final position of the double bond, both β,γ and γ,δ unsaturated ketones could be obtained. Finally, in the case of β,γ ketones, the final configuration of the double bond needs to be controlled. After extensive optimization of reaction conditions, a catalytic system consisting of a cobalt (II) salt bearing a modified dppp ligand, In and InBr 3 33 Vinogradov, M. G.; Tuzikov, A. B.; Nikishin, G. I.; Shelimov, B. N.; Kazansky, V. B. J. Organomet. Chem. 1988, 348, 123-134. 34 (a) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1997, 119, 3165-3166. (b) Lenges, C. P.; Brookhart, M.; Grant, B. E. J. Organomet. Chem. 1997, 528, 199-203. 35 (a) Chen, Q. A.; Kim, D. K.; Dong, V. M. J. Am. Chem. Soc. 2014, 136, 3772-3775. (b) Yang, J.; Yoshikai, N. J. Am. Chem. Soc. 2014, 136, 16748-16751. (c) Yang, J.; Seto, Y. W.; Yoshikai, N. ACS Catal. 2015, 5, 3054-3057. 36 (a) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14120-14122. (b) Omura, S.; Fukuyama, T.; Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130, 14094-14095.

Scheme 17 Intramolecular and intermolecular hydroacylation

allowed for the generation of the catalytically active Co(I) species enabling the C-1-selective hydroacylation of aromatic aldehydes with 1,3 dienes, in a highly selective 1,4-addition manner, with good trans selectivity (Scheme 18). Mechanistic experiments tend to disfavor a traditional C-H oxidation pathway over a less common oxidative cyclization. Firstly a KIE of 2.7 was obtained. Thus, assuming a traditional C-H activation mechanism, either oxidative addition to the aldehyde or diene insertion would be rate limiting. However, kinetic studies show zeroorder dependence for both the aldehyde and the diene concentrations thus precluding a C-H activation pathway. Hence, following a proposed oxidative cyclization, two pathways are possible: isomerization via a 1,2 (path 2) or 1,4 (path 1) addition to give 5 or 7 membered cobaltacycle. Reductive elimination affords either the β,γ or γ,δ unsaturated ketones. The Z selectivity can be explained by the requirement of a cis geometry for the 1,4 addition (Scheme 19).

Scheme 18 Hydroacylation of aldehydes with 1,3 -dienes

Scheme 19 Proposed catalytic cycle for the hydroacylation by oxidative cyclization

More recently, Yoshikai reported an enantioselective intramolecular hydroacylation with a chiral diphosphine which was successfully applied to 2-acetoxybenzaldehydes as well as 2-vinyl benzaldehydes (Scheme 20). The reaction worked well for a broad range of substrates giving good yields and enantioselectivities. Based on deuterium labelling experiments, the mechanism is believed to operate via a classical C-H activation with the reductive elimination proposed to be the rate-limiting step. 37

Scheme 20 Enantioselective intramolecular hydroacylation

C-H Arylations

Until rather recently the use of low-valent cobalt catalysis was restricted to addition reactions such as the previously discussed hydroarylation and hydroacylation reactions. In 2012 Ackermann and co-workers reported the first cobalt-catalyzed arylation reaction to proceed via a C-H/C-O bond cleavage mechanism. 20,38 Thus, a catalytic system composed of Co(acac) 2 , IMesHCl as a NHC precursor and cyclohexylmagnesium chloride, allowed for the arylation of arylpyridines with aryl carbamates, sulfamates and chlorides (Scheme 21).

Scheme 21 C-H arylation with aryl carbamates, sulfamates and chlorides

Related to the initial work by Ackermann, the group of Yoshikai disclosed a similar reaction using aryl ketimines as directing groups. 39 The reaction showed ample substrate scope 37 (a) Yang, J.; Yoshikai, N. J. Am. Chem. Soc. 2014, 136, 16748-16751. 38 (a) Song, W.; Ackermann, L. Angew. Chem. Int. Ed. 2012, 51, 8251-8254. 39 Gao, K.; Lee, P.-S.;Long, C.;Yoshikai, N. Org. Lett. 2012, 14, 4234-4237. with moderate to good yields. Further efforts by the Ackermann group have extended the methodology to now include amides and tetrazoles. 40 While mechanistic details remain somewhat vague, Ackermann has proposed a mechanism that involves the formation of an in situ cobalt(I) species, which then undergoes a cyclocobaltation (Scheme 22). After this, it is presumed that a single electron transfer (SET) type mechanism is operational, followed by a reductive elimination and transmetalation to regenerate the catalytically active species. Preliminary radical scavenger experiments using stoichiometric amounts of TEMPO led to a reduction in yield of about 30-40 % providing evidence to support a SET mechanism, however failure to completely shut down the catalytic cycle even in the presence of stoichiometric amounts of TEMPO would suggest that perhaps a competitive pathway may be operational or at least feasible.

C-H Alkenylations

Up until recently the most common route to access alkenylated arenes was through hydroarylation reactions of alkynes as previously discussed. While this is a broadly applicable process covering a wide variety of substrates and directing groups, it does have certain limitations. First, this methodology is not suitable for the preparation of cycloalkenylated derivatives and second, the regioselectivity is purely sterically controlled. Hence, internal alkynes bearing unsymmetrical difficult-to-distinguish groups generally give a complicated mixture of regioisomeric products. To overcome some of these pertinent issues, Ackermann and co-workers reported a procedure for the direct alkenylation of heteroarenes (indoles, 2phenylpyridines) by enol esters, phosphates, carbamates and carbonates (Scheme 23). 41 A combination of CoI 2 , IPrHCl as a NHC precursor and CyMgCl gave the optimum results and interestingly the catalytic system was also applicable to acyclic enol acetates affording exclusively the E product.

Scheme 23 Cobalt-catalyzed alkenylation with cyclic acetates, phosphates, carbamates and carbonates

Competition experiments showed that acetates and carbamates display close reactivities while phosphates were inherently less reactive. Radical trapping experiments failed to completely exclude a radical pathway, however it is proposed that the mechanism proceeds through the formation of a cyclocobaltated complex followed by coordination of the enol derivative and subsequent migratory insertion. β-elimination yields the final product and a reductive elimination via transmetalation regenerates the active catalytic species (Scheme 24). It is worth noting that before this report the direct alkenylations of 2-phenylpyridine with enol acetates had only been achieved under ruthenium catalysis using considerably harsher conditions. 42 41 Moselage, M.; Sauermann, N.; Richter, S. C.; Ackermann, L. Angew. Chem. Int. Ed. 2015, 54, 6352-6355. 42 (a) Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858-9859. (b) Ogiwara, Y.; Tamura, M.; Kochi, T.; Matsuura, Y.; Chatani, N.; Kakiuchi, F. Organometallics, 2014, 33, 402-420.

C-H Alkylations

Analogues to C-H alkenylations, previously the most common way to access alkylated products was through hydroarylation with alkenes. Therefore, a general procedure which would allow the direct alkylation with organic electrophiles such as alkyl halides would be desirable. Thus, the group of Nakamura disclosed the alkylation of benzamides with a variety of alkyl chlorides using an in situ generated low-valent cobalt species (Scheme 25). 43 The active catalytic species was generated through the reduction of Co(acac) 2 by cyclohexylmagnesium chloride in situ. Interestingly there was no requirement for the use of σ-donating ligand such as NHC or phosphine. A problem encountered with this reaction was over alkylation. However, this could be circumvented by the introduction of substitution in the ortho or meta postions. It was also shown that the N-H proton of the benzamide was critical for the success of the reaction as tertiary benzamides were not compatible. Another interesting point was that the reaction was compatible with a variety of cobalt salts, thus replacing Co(acac) 2 by Co(acac) 3 or CoCl 2 did not significantly affect the outcome of the reaction suggesting all precatalysts were converted to a similar active species.

Following this initial study, the groups of Ackermann and Yoshikai have further explored the transformation. Ackermann reported a protocol for the site and chemoselective alkylation of arylpyridines as well as N-pyridyl and pyrimidyl indoles with alkyl chlorides. 20 Following a screening of reaction conditions, a mixture of IPr-HCl, along with Co(acac) 2 and CyMgCl, provided the best results. Notably in this case, the use of NHC ligand was required which is in contrast to the earlier report by Nakamura. Indoles were selectively alkylated at the C-2 position over the intrinsically more nucleophilic C-3 position. Competition experiments between indoles and aryl-pyridines clearly indicated a preference for indoles, likely due to the increased acidity of the C-H bond. Yoshikai and co-workers also established the direct alkylation of ketimines with primary and secondary alkyl halides. 44 Primary alkyl halides gave significantly higher yields even with sterically hindered substrates.

Mechanistic studies by both the Ackermann and Yoshikai group led to similar conclusions about the potential mechanism in operation. A facile electrophilic type C-H activation mode was ruled out due to the fact that electron poor arenes reacted preferentially over electron-rich arenes which would tend to suggest a deprotonation-type C-H metalation pathway. A potential pathway by β-elimination followed by hydroarylation was also ruled out due to the fact that cyclic alkyl substrates participated equally well as acyclic. In the presence of a radical scavenger (TEMPO) a significant decrease in catalytically activity was noted, and when enantiomerically pure secondary alkyl halides were employed, a large degree of racemization was observed. Based on these observations the catalytic cycle show below is was proposed (Scheme 26), which is essentially identical to that put forward for cobalt catalyzed C-H arylation. First, a cyclometalation of the arene followed by a SET-type process and radical recombination. Second, a reductive elimination and transmetalation releases the final product and regenerates the catalyst. Until recently the field of cobalt C-H functionalization was dominated by the use of lowvalent complexes. These transformations were highly dependent on the use of excess Grignard reagents which limits functional group tolerance. An early example from Brookhart 34 on the use of Cp*Co(I) complexes for the hydroacylation of vinyl silanes demonstrated the potential of the Cp* ligands for C-H functionalization. Thus, a range of high-valent cobalt(III) complexes have been developed which bear a resemblance to related rhodium(III) analogues (Figure 4). 45 As with the corresponding low-valent cobalt complexes, these new Cp*Co(III) complexes have been applied to a variety of reaction types, namely hydroarylation, C-H amidations and oxidative annulations.

Hydroarylation reactions

The group of Kanai has been at the forefront of this development and in 2013 reported the direct addition of 2 aryl-pyridines to imines using complex 65 (Scheme 27). 46 Scheme 27 Cobalt (III)-catalyzed hydroarylation of aldimines 1,2-dichloroethane was found to be the optimum solvent and interestingly no further additives such as silver salts or σ-donating ligands were necessary. It is worth noting also that the use of simple cobalt salts such as CoCl 2 were ineffective for the current reaction. A variety of Co(III) complexes were examined and it was shown that the substitution pattern on the Cp ring was important for reactivity with sterically bulky groups drastically affecting the yield. The reaction showed good substrate compatibility and best yields were obtained with electron poor imines. The present reaction was also extended to synthetically more attractive indoles. 47 It was found that the inclusion of a catalytic amount of KOAc improved the overall performance of the 46 Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M. Angew. Chem. Int. Ed. 2013, 52, 2207-2211. 47 Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M. Chem. Eur. J. 2013, 19, 9142-9146. catalytic system. This increase in activity was explained by a carboxylate-assisted C-H activation mechanism48 via the in situ generation of a cobalt acetate complex [Cp*Co(OAc) 2 ].

Kanai and co-workers also extended the methodology to triple bonds based on a previous rhodium based system reported by Fagnou. 49 Thus, employing a cobalt(III) catalyst with a catalytic amount of KOAc allowed for the hydroarylation of a variety of symmetrical and unsymmetrical alkynes with N-carbamoylindoles (Scheme 28). 50 The reaction tolerated a wide variety of electron-donating and withdrawing substituents on the indole, while alkynes bearing both alkyl and aryl participated without problem. Even normally challenging terminal alkynes proved amenable to the current catalytic system. Limitations were found in the case of sterically demanding alkynes and, regioselectivities were low in the case of alkynes bearing difficult-to-distinguish groups.

Scheme 28 Cobalt(III)-catalyzed hydroarylation of alkynes

C-H Amidations

The scope of cobalt(III) catalysis was further extended to include the amidation of arenes. 51 In 2014 Kanai and co-workers reported the cobalt(III)-catalyzed amidation of pyrimidyl-substituted indoles with sulfonyl azides (Scheme 29). Interestingly, the sandwich complex 65 was poorly active for this reaction however, complex 66 proved to be the optimal catalyst. Thus a combination of complex 66, AgSbF 6 , and KOAc was found to be the optimal catalytic mixture. The reaction showed good functional group tolerance in terms of both the indole and the sulfonyl azide. In further studies, this strategy has been extended to include phosphoryl for the phosphoramidation of indoles. Indeed the reaction was not limited to azides, the group of Chang reported the amidation of arylpyridines with carbamates using a similar system to that reported previously by Kanai. 51c

Scheme 29 Cobalt(III)-catalyzed amidation with sulfonyl azides

The mechanism for this transformation is believed to commence by the action of a cationic Cp*Co(III) species. This species carries out a C-H cobaltation via concerted metalation deprotonation (CMD) or electrophilic type mechanism to yield intermediate I. Next coordination and insertion of the azide delievers complex III and finally a protodemetalation releases the product and regenerates the active catalytic species (Scheme 30).

Scheme 30 Proposed mechanism for the Cp*Co(III) catalyzed amidation

Oxidative C-H Functionalization and Annulations

Since the initial concept devised by Daugulis on the use of 8-aminoquinoline (Q) as a directing group for palladium-catalyzed functionalization of C-H bonds, 52 this versatile directing 52 Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154-13155. group has seen applications in ruthenium, iron and nickel catalysis among others. 53 Hence, given the ability of cobalt(III) complexes to participate in C-H functionalization, it was naturally extended to this bidentate directing group. Daugulis and co-workers reported the annulation of 8-aminoquinoline with alkynes (Scheme 31). 54 A catalytic system comprising of Co(OAc) 2 •4H 2 O, sodium pivalate and Mn(OAc) 2 was found to be optimal. A broad scope of benzamides as well as internal and terminal alkynes were efficiently converted to the desired products.

Scheme 31 Cobalt catalyzed oxidative alkyne annulation

Based on the fact that aminoquinoline ligands stabilize transition metals in high oxidation states, it is proposed that the reaction proceeds through the formation of cobalt(III) intermediate 75, which is formed through the oxidation of Co(OAc) 2 in the presence of the aminoquinoline amide ligand (Scheme 32). Insertion of the alkyne would give intermediate 76. However, it is possible to envisage an alternative mechanism though formation of a cobalt acetylide intermediate, this alternative mechanism was ruled out for two reasons: I) the reaction works for terminal and internal alkynes and II) terminal alkynes give an isomeric mixture of products suggesting coordination of the alkyne occurs after the initial C-H activation. Intermediate 76 could directly undergo reductive elimination to yield the desired product 78 or the cobalt (III) intermediate could be protonated to give intermediate 77 which could then oxidatively cyclize. This latter pathway was not considered viable as when intermediate 77 was subjected to the present reaction conditions no desired product was observed.

53 (a) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 898-901. (b) Asako, S.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 17755-17757. (c) Rouquet, G.;Chatani, N. Chem. Sci. 2013, 4, 2201-2208. (d)

Project objectives and aims

Our group originally became interested in the use of cobalt complexes for [2+2+2] cycloaddition reactions. 55 While several transition-metal catalysts have proved effective in this process, cobalt complexes of the form [Co(Cp)(L) 2 ] (Cp=cyclopentadienyl) type have remained catalysts of choice for decades. Although their catalytic efficiency is well established, this family of catalysts suffers from several drawbacks. Indeed, the non-commercially available [Co(C 2 H 4 ) 2 (Cp)], which has the advantage of being reactive at low temperature is tedious to prepare and thus often neglected. To be active, the commercially available dicarbonyl analogue [Co(CO) 2 (Cp)] requires heat and/or visible light that may lead to the isomerization of the final compound. But the major disadvantage for all those [Co(Cp)(L) 2 ] complexes is that, in most cases, a stoichiometric amount of cobalt is required due to the tendency for Co(I) or Co (0) to coordinate the final diene to form a very stable ɳ 4 -(1,3-cyclohexadiene) and, therefore, block the catalytic cycle.

Scheme 33 Coordination of cobalt by Ƞ 4 -(1,3-cyclohexadiene)

To overcome the practical limitations of the [Co(Cp)(L) 2 ] catalyst family, we sought to develop a catalytic procedure that would proceed under milder conditions (no activation and lower temperature) relative to the above-mentioned stoichiometric processes. It was hypothesized that a low-valent cobalt catalyst bearing electron-donating phosphine ligands could be an ideal candidate to prevent the undesired trapping of the cyclohexadiene formed during the reaction. Moreover, these ligands are easily exchangeable and external activation might not be required. To this end the group became interested in further exploration of welldefined low-valent cobalt complexes previously studied by Klein and Kisch. 8,9,10,11,12,14 In 1970 Klein described a convenient one-step synthesis of the hydridotetrakis(trimethylphosphine)cobalt(I) HCo(PMe 3 ) 4 but at this time no catalytic application of this complex had been reported. To examine its catalytic activity, our group initially explored the well-known cycloaddition of triynes. 56 The reaction proceeded smoothly at ambient temperature with a low catalytic loading (Scheme 34).

Scheme 34 HCo(PMe 3 ) 4 -catalyzed cycloaddition of triynes

The more challenging cycloaddition of yne-yne-enes was next examined, and pleasingly it was found that using the same reaction conditions as before allowed for the efficient synthesis of a variety of 1,3-cyclohexadienes (Scheme 35).

Scheme 35 HCo(PMe 3 ) 4 -catalyzed cycloaddition of yne-yne-enes

Our group continued to further explore the use of this low-valent cobalt complex towards the intermolecular version of a [2+2+2] cycloaddition reaction with terminal alkynes. Interestingly in this case the corresponding cycloaddition product was not observed rather the highly selective formation of the (E)-head-to-head enynes (Scheme 36). 57

Scheme 36 (E)-Selective cobalt-catalyzed dimerisation of arylacetylene derivatives

DFT calculations revealed that the reaction proceeds through a C-H activation/hydrocobaltation pathway (Scheme 37).

57 Ventre, S.; Derat, E.; Amatore, M.; Aubert, C.; Petit, M. Adv. Synth. Catal. 2013, 355, 2584-2590.

Scheme 37 Proposed mechanism for the Co-catalyzed dimerization of aryl alkynes

As we have already seen, there have been considerable advancements made within the field of cobalt catalysis over the past few decades and it is now considered a viable tool for the efficient and economical functionalization of organic molecules. Thus, low-valent cobalt catalysis laid the foundation for a variety of reactions including hydroarylations, hydroacylations among others. More recently high-valent systems have gained a lot of attention, the different electronic properties versus iridium and rhodium allow for in some cases improved selectivity and in other the unearthing of completely new reactivities. A key advantage for high-valent complexes versus their low-valent counterparts is their inherent air stability.

However there still are a number of pertinent issues that need to be addressed for the continued development of the field. Focusing our attention now to low-valent systems, in recent reviews by Ackermann and Wencel-Delord they bemoaned the lack of mechanistic insight in particular for the low-valent bimetallic systems developed by Yoshikai and others. 58,7a Indeed they highlight the use of an omnipresent use of Grignard as one of the main drawbacks of these systems. The use of stoichiometric Grignard reagents to generate the catalytically active species is not ideal for a number of reasons: 1) it leads to the generation of a difficult to identify (Co(I) or Co(0)) catalytic species in-situ, 2) Substrate scope is often limited, chemically 58 Moselage, M.; Li, J.; Ackermann, L. ACS Catal. 2016, 6, 498-525. susceptible groups such as esters may not be compatible and, 3) the precise reason why in many cases such an excess of Grignard is needed remains unclear. Another key issue with the use of bimetallic systems in general is the need to carry out extensive screening of reaction conditions i.e. ligands, Grignard reagents, additives and bases. All of these factors limit the synthetic utility of these systems and the generation of stoichiometric amounts of salts at the end of the reaction is seen as undesirable for industrial application.

Based on our results on the use of HCo(PMe 3 ) 4 and the earlier studies of Klein 8,9,10 , Kisch 14 and Li, 59 it seemed feasible that we could apply these catalysts to the other systems. Therefore it was our goal to develop a well-defined low-valent cobalt system which was capable of performing a variety of C-H functionalization in the absence of reductant or additives. Our approach versus that of Klein is summarized below (Scheme 38). We hypothesized that replacing MeCo(PMe 3 ) 4 with HCo(PMe 3 ) 4 or Co(PMe 3 ) 4 would prevent the reductive elimination of methane and that we could potentially use the hypothetical hydrido-cobalt(III) or (II) intermediate for interesting hydroarylation reactions. This would provide us with a simple, versatile catalyst that would be practically simple to use and avoid the necessity for laborious optimization studies. In addition, a simple catalytic system would allow us to perform more detailed mechanistic studies than previously reported. If successful in this approach we should in theory be able to perform the alkenylation and alkylation of a variety of sp 2 hybridized carbon-hydrogen bonds using a variety of alkene and alkyne coupling partners. A summary of the type of product which could be obtained is provided below (Scheme 39).

Scheme 39 Summary of project aims 5 Results and Discussion

Catalyst and ligand choice

We began our study using the previously described complexes by Klein, all of which bear trimethylphosphine ligands. Tertiary phosphines (PR 3 ), are important because they constitute one of the few series of ligands in which electronic and steric properties can be altered in a systematic and predictable way over a wide range by varying R. They also stabilize an exceptionally wide variety of metals of interest to the organometallic chemist. 60Trimethylphosphine is the sterically least demanding of the triorganophosphanes. It forms stable metal complexes and side reactions of the coordinated ligand are essentially unknown. Tolman has defined the steric requirements of phosphine ligands by the vertex angle θ of a cone with its vertex at the metal which encloses the van der Waals boundaries of the substituents at the phosphorus atom. 61 This sterically least demanding, basic trimethylphosphine is able to make backbonding to electron rich metal centers and able to stabilize low oxidation states. All these properties make it a suitable ligand, in addition due to its volatile nature excess ligand can be easily removed during the preparation of complexes.

Hydroarylation of alkynes by aryl ketimines

Optimization studies

Based on previous results obtained from the group on the dimerization of terminal alkynes via a C-H activation/hydroalkynylation pathway using Co(PMe 3 ) 4 and HCo(PMe 3 ) 4 , we postulated these catalysts could have the potential to participate in the C-H activation/functionalization of aromatic imines. 57 To begin the study we chose the aromatic ketimine 24a previously studied by Yoshikai and diphenylacetylene. 17 The results of this initial screening are summarized in Table 3. No conversion was observed at room temerature for Co(PMe 3 ) 4 , HCo(PMe 3 ) 4 , or HCo(N 2 )(PPh 3 ) 3 (entries 1-3). Heating the reaction to 80 °C using HCo(PMe 3 ) 4 and Co(PMe 3 ) 4 , product 25a could be isolated in 50 and 60% yield, respectively (entries [4][START_REF]E)-1-(5-Fluoro-1-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (81h) According to the general procedure (H[END_REF]. Much to our surprise, however, and in sharp contrast with Yoshikai's results, 25a was isolated exclusively as the (Z)-isomer, as determined by X-ray crystallography (see experimental). Increasing the reaction temperature to 110 °C in toluene showed no significant improvement in yield (entry 6). On switching from thermal to microwave conditions a reduction of the reaction time was observed (entry 7). Using the catalyst previously reported by Kish (entry 9), a very low yield of 10% was achieved further emphasizing the specificity of this catalyst to hydroarylation of azobenzenes. Further exploration of solvents and reaction temperature led to the optimal conditions of 1 h at 170 °C (MW) with Co(PMe 3 ) 4 (entry 10). Only a small decrease in yield was observed on switching to thermal conditions in a sealed tube, showing no significant microwave effect (entry 12). 62

Scope and limitations

With our optimal conditions in hand, we sought to explore the potential scope of the hydroarylation reaction on a variety of imines and internal alkynes (Scheme 40)

Scheme 40 Hydroarylation of internal alkynes by aryl ketimines

We began the present scope by introducing various substituents on the phenyl ring of the aryl ketimine (Figure 5). The reaction proceeded in good yields for para-substituted imines (25a-25e). Electron-donating (e.g., OMe), neutral, and electron-withdrawing groups (e.g., F) were all tolerated. The reaction ran smoothly on gram-scale with an identical yield to the standard reaction conditions for compound 24d. Interestingly the aryl aldimine (26) was not compatible with the current catalytic system presumably due to interaction of the catalyst with the aldimine C-H bond. Substrates bearing a methoxy, fluoro, and cyano group in the meta position reacted preferentially at the more hindered ortho position. Presumably this is due to the secondary directing effect previously reported for cobalt, ruthenium, and iridium catalysis. 17,20 While a substrate bearing a methyl group in meta position (25i) showed complete selectivity for the less hindered ortho position, which could be expected based on sterics, while similar secondary group effect was observed for the methylenedioxy product (25j). The imine derived from 2-acetonaphthone also participated in the reaction to afford the desired product (25k) in good yield and reasonable regioselectivity of (75/25). Imines derived from propiophenone and tetralone also yielded the desired compound (25l-25m). Note that the stereochemistry of addition in the case of the propiophenone was slightly reduced to (96/4) still in favor of the trans addition product (Figure 6). Having explored the scope of the reaction in terms of imine variation, we then focused on other alkynes. Interestingly, nondiarylic acetylenes proved to be much more active, thus lower catalyst loadings and shorter reaction times were possible. Thus, the following reactions were carried out using 5 mol % of catalyst and the reaction time was reduced to 30 min. The reaction of TMS-protected phenylacetylene with a variety of para-substituted imines proceeded in moderate to good yields (25n-25q). The insertion showed complete antistereoselectivity and the regioselectivty which was proven by 1 H NMR after removal of the TMS protecting group by TBAF. As seen previously with the addition of diphenylacetylene, metafluoro substituted imines preferentially reacted in the more hindered position (25r). We chose the imine bearing a tert-butyl substituent as the model substrate for the proceeding reactions due to the ease at which we could follow the reaction by 1 H NMR. The para-and metasubstituted TMS-protected phenylacetylene reacted in moderate to good yields with the same regio-and stereoselectivity as seen before (25s-25v). In the case of product (25t) the stereochemistry was slightly reduced to (85/15) (Figure 7). The bis-methyl substituted diphenylacetylene was shown to efficiently undergo addition (25w). TMS-protected pentyne (25x) produced a modest yield of 45% with reasonable stereoselectivity of addition (89/11). Due to stability issues, the product (25y) of 1-phenyl-1pentyne addition could not be isolated pure as the imine derivative but instead was hydrolyzed by 3M HCl to afford the corresponding ketone in 50% yield with a lower regioselectivity (86/14) of the addition. Next the reactivity of 4-octyne was explored (25z). It proved to be the most active of all substrates, but the regioselectivity of the C-H activation was difficult to control. The C-H functionalized product was isolated in 96% yield as a (70/30) mixture of mono and dialkenylated compounds (Figure 8). It is worth mentioning that using the cobalt(I) complex HCo(PMe 3 ) 4 as catalyst facilitated the formation of the same the compounds in slightly lower yields.

Figure 8 Reaction scope for the hydroarylation of internal alkynes by aryl ketimines

As demonstrated the reaction is compatible with a broad variety of imines and internal alkynes. However as mentioned previously, the reaction was not compatible with aryl aldimines. Through the course of the study it was also found that certain alkynes were not amenable under the current system (Scheme 41). Both 1,2-di(thiophen-2-yl)ethyne and trimethyl(thiophen-2-ylethynyl)silane gave poor conversions of about 10 % presumably due to the catalyst poisoning. 1,2-bis(trimethylsilyl)ethyne also failed to yield the desired product due to the intrinsically low reactivity of this compound. Due to the use of toluene as reaction medium there were also some issues with the solubility of certain compounds, thus a bis-keto substituted and bis-bromo did not participate under the present reaction conditions. Finally the bis-alcohol, but-2-yne-1,4-diol gave no conversion to the desired product, we can hypothesize that this was due to a strong coordination to the cobalt center or degradation at the elevated reaction temperature.

Scheme 41 Unsuccessful substrates for the present hydroarylation reaction

Mechanistic considerations

As mentioned in the project objectives, a key feature of starting from a well-defined catalyst in the absence of stoichiometric reductants or additives was that gaining mechanistic insight is greatly simplified. To this end a series of deuterium labelling experiments were performed using deuterium-labeled imine 24a-d 5 . Firstly, combining an equimolar mixture of 24a-d 5 and 24d no evidence of H/D crossover in the final products was observed. This unambiguously proves that the olefinic hydrogen atom in the final product is a result of intramolecular hydrogen transfer excluding any deprotonation step (Scheme 42).

Scheme 42 Deuterium crossover experiment

Secondly, competition experiment between an excess of 24a-d 5 and 24a compared to 19 was ran to determine the kinetic isotope effect. Values of 1.4 and 1.7 were obtained respectively for Co(PMe 3 ) 4 and HCo(PMe 3 ) 4 in agreement with the KIE (1.05 and 1.65) of the transition states calculated using the Bell kinetic theory. However, these values are not significant enough to suggest that the C-H activation is the rate limiting step (Scheme 43).

Scheme 43 Deuterium KIE experiments

Thirdly, combining imine 24a-d 5 with two equivalents of diphenylacetylene in the presence of 50 mol% of HCo(PMe 3 ) 4 under standard reaction conditions, we saw no incorporation of hydrogen in the final product with 25a-d 5 isolated in a 20% yield as the sole compound. Moreover, no evidence of oxidative addition was observed by 1 H NMR when heating HCo(PMe 3 ) 4 in the presence of the imine and absence of the alkyne partner. From these observations we postulated that the C-H bond activation and functionalization proceed in a concerted manner. (Scheme 44).

Scheme 44 Hydrido competition experiment

To further investigate this claim, a number of computational studies namely, DFT calculations were performed by Dr Etienne Derat on the key step of the catalytic process (the C-H activation). In order to find a relevant transition state, it was necessary to remove three phosphines from the metallic centre in order to accommodate simultaneously imine and alkyne. The two catalysts Co(PMe 3 ) 4 and HCo(PMe 3 ) 4 were investigated and led to globally similar transition state (TS) structures (Figure 9). It is noteworthy to mention the following observations. Firstly, the barrier with Co(PMe 3 ) 4 is found to be smaller than with HCo(PMe 3 ) 4 which is in line with the experimental observations. Secondly, the structural similarity between the two transition states can be explained by the fact that the orbital involving the unpaired electron (namely d z 2) in the Co(0) species shows no interaction with the migrating hydrogen. Nevertheless, the cobalt-hydrogen distance is shorter in the Co(0) species. Thirdly, to understand the mechanism of C-H activation, topological analyses were performed, specifically using AIM and ELF schemes (Figure 10, Figure 11) AIM analysis seem to suggest that there is a bonding between cobalt and hydrogen during the transfer. According to ELF methodology, one electron is always associated to the proton during hydrogen transfer. Thus, this C-H activation pattern can be designated as a metal-assisted (σ) bond metathesis, also known in a more general way as ligand-to-ligand hydrogen transfer (LLHT) previously coined by Eisenstein and Hall.63 A subsequent isomerization would account for the observed anti selectivity. Indeed, we calculated that at 170 °C anti-25a is 2.27 kcal more stable than syn-25a, high enough to achieve complete isomerization. Two mechanistic pathways can be envisioned. One possibility is a postisomerization after the reductive elimination step. Indeed, the ability of cobalt to participate in the isomerization of double bonds is well known. 64 In order to access the imine with synstereochemistry as reported by Yoshikai we attempted to repeat his protocol, however in our hands, attempts to reproduce this reaction were unsuccessful. Fortunately, Shibata reported a simple cationic iridium-catalyzed addition of aryl ketones to alkynes which allowed us access the ketone with syn-stereochemistry. 65 Introduction of this ketone into our catalytic system (MW 170 o C, 1h, Co(PMe 3 ) 4 10 mol%) resulted in an isomerization of 50 % to our observed anti product suggesting that the post-isomerization is a feasible pathway. Complete isomerization was not observed in this case presumably due to the weaker anchoring group effect of ketones compared to imines (Figure 12). 66 It was also found that for certain substrates such as 25t, increasing the reaction time lead to an increase in the trans/cis ratio in the final product despite the fact the isolated yield remained unchanged. Such an experimental proof strongly suggests a post-isomerization is operational in our system. The second possibility which cannot totally be ruled out is an isomerization of the intermediate (II) shown in the reaction mechanism, before the reductive elimination as previously shown for palladium. 67 Chem. Int. Ed. 2014, 54, 801-804. 65 Tsuchikama, K.; Kasagawa, M.; Hashimoto, Y.-K.; Endo, K.; Shibata, T. J. Organomet. Chem. 2008, 693, 3939-3942. 66 Zheng, T.; Sun, H.; Ding, J.; Zhang, Z.; Li, X. J. Organomet. Chem. 2010, 695, 1873-1877. 67 Aziz, J.; Frison, G.; Le Menez, P.; Brion, J-D.; Hamze, A.; Alami, M. Adv. Synth. Catal. 2013, 355, 3425-3436. 86

Non-innocent directing groups (importance of directing groups)

As discussed earlier we investigated the post-isomerization of the alkene bond in our final products. To access syn-addition products we employed the use of a simple cationic iridium-catalyzed addition of aryl ketones to alkynes previously reported by Shibata (Scheme 46). 65

Scheme 46 Syn-selective iridium-catalyzed addition of aryl ketones to alkynes

Interestingly when we applied the same conditions to imines we isolated exclusively the products of anti-addition (Scheme 47).

Scheme 47 iridium catalyzed addition of aryl ketimines to alkynes

While the exact reason behind the change in stereochemistry is not understood presently, it remains an interesting facet of directed C-H activation not commonly discussed i.e. the influence of the directing group on the stereochemical outcome of the final product. One possible explanation is the stronger coordinating ability of the imine directing group compared to the ketone permits the coordination of the metal center to the final product resulting in a post-isomerization. This is a topic that will be further investigated by our group.

Conclusion

In this first study we have demonstrated the utility of simple well-defined low-valent cobalt catalysts to carry out C-H functionalization without the need for reducing agents or additives. 68 Our system is practically easier to perfrom than that reported by Yoshikai and also much cheaper than other systems based on rhodium or iridium (Scheme 48). 49,69 Moreover, for a wide scope of substrates anti-selectivity was observed for this hydroarylation process. Additionally, deuterium-labelling studies and computational studies of our simple catalysts have allowed us to gain greater mechanistic insight than previously reported for cobaltcatalyzed C-H hydroarylation reaction.

Scheme 48 Hydroarylation of alkynes via directed C-H activation

Synthesis of 1,2-dihydropyridines

68 Fallon, B. J.; Derat, E.; Amatore, M.; Aubert, C.; Chemla, F.; Ferreira, F.; Perez-Luna, A.; Petit, M. J. Am. Chem. Soc. 2015, 137, 2448-2451. 69 Lett. 2009, 38, 118-119. As highlighted earlier, a key drawback of the bimetallic systems developed by Yoshikai was the need to carry out extensive optimization of reaction conditions on changing from one substrate to another. This is undesirable from both an economically and efficiency point of view. From our initial study on the use of Co(PMe 3 ) 4 and HCo(PMe 3 ) 4 for the hydroarylation of aryl ketimines we were confident that this methodology could be transferred to other systems without any need to optimize reaction conditions or make any alterations to the catalyst. Due to the prevalence of N-heterocycles in drugs and natural products, we became interested in applying our simple methodology towards this goal. 70 A common approach to access these structures is via a C-H alkenylation/cyclization pathway based predominately on the use of a second-row transition metal such as rhodium and ruthenium. 71, 72 However as discussed previously it is desirable to develop the potential of cheaper more earth abundant first row transition metals. Thus, based on the previous work by Bergman and Ellman, 71a-c Yoshikai reported C-H bond alkenylation/cyclization approach to access a variety of 1,2 dihydropyridines 21

Scope and limitations

Hence, taking the previously optimized conditions (Co(PMe 3 ) 4 , 170 o C, MW, 60 min) for the hydroarylation of alkynes with aryl ketimines we were able to efficiently catalyze the annulation of α,β-unsaturated imine 31a to the corresponding 1,2 dihydropyridine (Scheme 49).

Scheme 49 Annulation reaction between α,β-unsaturated imines and internal alkynes

On switching from microwave to thermal conditions, no decrease in yield was observed therefore the following scope was performed using sealed tube under standard thermal conditions. Initially, various α,β-unsaturated imines were examined in the presence of diphenylacetylene 19 (Figure 13). A variety of benzylidenacetone imines were smoothly converted to the desired dihydropyridine products, 32a-32m. Electron-donating groups (e.g.,Me, t-Bu and MeO) and electron-withdrawing groups (e.g., Cl, F, CF 3 , CN, CO 2 Me) were well tolerated. To examine the robustness of the system the reaction was performed on gramscale for product 32a with no decrease in yield observed. We could also synthesize product 32a using the cobalt(I) complex HCo(PMe 3 ) 4 albeit in slightly lower yield 94%, this result was consistent with our previous study where HCo(PMe 3 ) 4 consistently gave reduced yields compared to Co(PMe 3 ) 4 due to the higher energy of activation. It is worth highlighting that an ester substituent is compatible with our reaction conditions (no Grignard or reducing reagent) leading to the desired dihydropyridine 32i without side reactions. Interestingly the sterically hindered product 32j could be isolated in 62% yield under our reaction conditions, which is in contrast to the similar reaction reported by Yoshikai where the cyclized product was not obtained but rather just the dienone product (i.e. just the product of initial C-H bond activation). We can speculate the elevated reaction temperature in our case is sufficient to overcome the steric repulsion between the 1-naphthyl and the neighboring phenyl groups facilitating the 6π-electrocyclization. 73 The use of a phenyl-ketimine or aldimine was also possible and almost quantitative yields were obtained in both cases 32k, 32l. In our previous study, aryl aldimines were not compatible however the increased propensity of cobalt to undergo oxidative addition in the olefinic C-H bond versus an aromatic C-H might explain this discrepancy.

Figure 13 Scope of the annulation reaction between α,β-unsaturated imines and internal alkynes

Next, we examined the reactivity of a variety of symmetrical and unsymmetrical alkynes, commencing with TMS-substituted alkynes (Figure 14). All TMS-substituted alkynes examined exhibited excellent reactivity and in all but one case furnished the dihydropyridine product as a single regioisomer with the TMS substituent proximal to the dihydropyridine's nitrogen 32n-32t. In the case of product 32n a respectable regioisomeric ratio of (91/9) was obtained. The same trends in regioselectivity have been reported in our previous study. 68 It is also worth noting that TMS-substituted alkynes were not suitable for the bimetallic system reported by Yoshikai. In addition to the excellent regioselectivity observed, chemical susceptible alkynes bearing heteroatoms which often suppress the activity of transition metal-catalyzed processes participated in the annulation reaction without issue to furnish compounds 32s-32u. As was the case for TMS-substituted alkynes, the inclusion of alkynes bearing heteroatoms was not possible in previous reports with cobalt. 21

Figure 14 Scope of the annulation reaction between α,β-unsaturated imines and internal alkynes

1-Phenyl-1-pentyne reacted with imine 31a to afford product 32v in good yield and regioselectivity (75%, 95/5) (Figure 15). To gain a better understanding of the factors governing the regioselectivity, 1-phenyl-propyne and 1-phenyl-butyne were also examined. We observed a decrease in the regioselectivity for product 32w (80/20) and 32x (52/48). These results strongly suggest that regioselectivity is under steric control. Finally for the present scope, dihydropyridines 32y and 32z were obtained from the reaction of oct-4-yne with the corresponding imines in excellent yields.

Figure 15 Scope of the annulation reaction between α,β-unsaturated imines and internal alkynes

As demonstrated, the present annulation reaction is broadly applicable to a range of α,β-unsaturated imines and alkynes. However, in the presence of terminal alkynes, a commonly encountered limitation of cobalt-and rhodium-catalyzed processes is a competitive dimerization reaction. 57,74 We could circumvent this problem by developing a simple one-pot annulation/desilylation sequence of TMS-substituted alkynes (Scheme 50). Thus after the annulation reaction the crude reaction material was passed through a plug of celite and the filtrate evaporated. Treatment of the crude reaction material with a solution of TBAF in THF allowed us to isolate the corresponding desilylated products in moderate to good yields. This simple approach allowed us to benefit from the highly regioselective annulation of TMSsubstituted alkynes to access to the best of our knowledge the first example of 1,2dihydropyridines lacking substitution in the 2 position 32m'-32q'.

Scheme 50 One-pot desilylation of dihydropyridines

As was the case for the hydroarylation of alkynes with aryl ketimines during the course of the present study certain limitations were uncovered (Scheme 51). Imines bearing cyclohexene and ester moieties as shown below were unsuccessful in the annulation reaction. We can surmise that in the case of the cyclohexene this was due to the fixed orientation of the double bond. After examining the crude reaction mixture from the imine substituted with an ester it appears it wasn't stable at the elevated reaction temperature. Another plausible reason for the failure of this substrate would be due to a strong chelating effect between the ester and the cobalt catalyst. Ethyl hex-2-ynoate and diethyl but-2-ynedioate were also not successfully incorporated, in both cases the stability of the ester in the reaction conditions was an issue with degradation observed in both cases. In line with our previous report 1,2-di(thiophen-2yl)ethyne, trimethyl(thiophen-2-ylethynyl)silane and 1,2-bis(trimethylsilyl)ethyne were also not compatible in our current reaction. Finally, efforts to use an alkyne substituted with a boronic ester were also not possible using our catalytic system.

Scheme 51 Unsuccessful substrates for the annulation reaction of α,β-unsaturated imines and internal alkynes

Mechanistic considerations

To begin our mechanistic investigation and eliminate the possibility of a reaction pathway through a thermal [4 + 2] cycloaddition, compounds 31a and 19 were subjected to the reaction condition in absence of catalyst, and no dihydropyridine product was observed (Scheme 52).

Scheme 52 Control experiment in the absence of catlayst

When imine 81a was subjected to our reaction we did not observe the dihydropyridine product rather almost quantitative conversion to product 82a as a result of C2-alkenylation (Scheme 53). 75 We can surmise that the thermodynamic penalty incurred to facilitate the 6πelectrocyclization through loss of aromaticity is too great in this case, and thus, the reaction is arrested at the C-H alkenylation step. From this result, we can postulate that the present annulation reaction proceeds in a two-step fashion (i.e, olefinic C-H alkenylation to form an azatriene derivative followed by 6π-electrocyclization).

Scheme 53 C-H alkenylation of indole 81a

75 Wong, M. Y.; Yamakawa, T.; Yoshikai, N. Org. Lett. 2015, 17, 442-445. To examine the relative reactivity between olefinic C-H alkenylation versus aromatic sp 2 -hydroarylation, an intermolecular competition experiment was carried out between imines 24a and 31a. In the presence of a limiting amount of diphenylacetylene, a ratio of 80/20 in favor of the dihydropyridine compound 32a was observed, suggesting that the activation of olefinic C-H bond is favorable compared to the aromatic C-H bond (Scheme 54).

Scheme 54 Competition experiment

As previously demonstrated, one of the great advantages of using a well-defined catalytic species bearing a simple ligand is the ease at which computational studies can be performed. Thus we turned to DFT calculations to aid with elucidation of the reaction mechanism (Figure 16). Using Turbomole (v6.4), at the B3LYPD3/def2-SV(P) level, investigations on the key step (namely, the C-H activation) were undertaken because several pathways were possible depending on the number of coordinating phosphines. It appears that the mechanism is similar in the case of α,β-unsaturated imines to the one previously reported for aromatic imines. A barrier of 16.85 kcal/mol (11.17 kcal/mol with entropy included) was found for the C-H activation leading to product 32a. The C-H activation is concomitant with a direct hydrogen transfer to the alkyne, the transition state being late because the C-H bond broken in this process was found to have a distance of 1.73 Å. The alkyne is mandatory in this process, because without it, the reaction was calculated to be endothermic (by 5.10 kcal/mol or by 4.97 kcal/mol with entropy included). Inclusion of solvent effect (by using the implicit COSMO scheme) did not modify these conclusions. Thus, it is necessary to exchange three phosphines with an imine and an alkyne before the C-H activation step. The calculated transition states for intermediates containing one and two coordinating phosphine are shown below (Figure 17, Figure 18). This C-H activation pattern can be designated as a metal-assisted σ bond metathesis as we previously disclosed, which is also termed ligand-to-ligand hydrogen transfer (LLHT). Attempts to observe or isolate the product at direct C-H activation were unsuccessful, which is in-keeping with the DFT calculations which indicate that both the alkyne and imine are required simultaneously and that the C-H transfer proceeds in a concerted manner (Scheme 55).

Scheme 55 Attempts to isolate dihydro-cobalt species

Combining our experimental data from this study and our previous work on the use of well-defined cobalt species for C-H functionalization, we can propose the following catalytic cycle (Scheme 56). Ligand exchange between three trimethylphosphines, the α,β-unsaturated imine, and alkyne leads to the generation of intermediate (I). A concerted hydrogen transfer via an oxidative pathway furnishes intermediate (II). Intermediate (II) undergoes reductive elimination leading to the formation of intermediate (III). Exchange with the starting materials liberates the intermediate (IV), which readily undergoes a subsequent 6π-electrocyclization to yield the desired dihydropyridine product 32. It is worth noting that due to the elevated temperature, at which the present reaction is carried out, we never managed to isolate or observe the expected azatriene intermediates with the exception of product 82aa as previously discussed.

Conclusion

In conclusion, we have developed a cobalt-catalyzed C-H bond activation/alkenylation/6π-electrocyclization cascade to provide access to a diverse range of dihydropyridines up to gram scale in excellent yields (Scheme 57). 76 Given the fact the reactions proceed in good yield in the absence of side-products, we could successfully include a desilylation step which has allowed us unprecedented access to 2-unsubstituted 1,2dihydropyridines in a one-pot manner. Through a combination of computational and experimental studies, we have been able to decipher the C-H activation mechanism. It is worth highlighting that no modification of the catalyst or reaction conditions was required from our previous study emphasizing the versatility of this family of catalysts.

Scheme 57 Summary of study on the synthesis of 1,2-dihydropyridines 76 Fallon, B. J.; Garsi, J.-B.; Derat, E.; Amatore, M.; Aubert, C.; Petit, M. ACS Catal. 2015, 5, 7493-7497.

Intra and intermolecular C2-alkylation and alkenylation of indoles

We have now demonstrated the ability of well-defined low-valent cobalt complexes to carry out the hydroarylation of alkynes in a catalytic fashion without the need for stoichiometric Grignard reagents. In addition, this reaction is applicable to both aromatic and olefinic sp 2 bonds. In this next section we will turn our attention primarily to the more challenging hydroarylation of alkenes. As previously discussed, the group of Yoshikai disclosed several reports on the hydroarylation of alkenes however these reactions were largely limited to the use of styrenes and as before it was necessary to perform lengthy optimization studies on switching from alkynes to alkenes. Thus, it was our aim to examine the reactivity of theses well-defined low-valent cobalt complexes [HCo(PMe 3 ) 4 and Co(PMe 3 ) 4 ] towards the hydroarylation of a variety of alkenes.

Optimization studies

Having already explored the use of aryl ketimines and α,β-unsaturated imine it seemed logical to explore the use of both these substrates for the hydroarylation of alkenes. However to our disappointment neither substrate offered satisfactory results (Scheme 58).

Scheme 58 Initial exploration into hydroarylation of alkenes

We initially examined aryl ketimine 24 in the presence of styrene however despite trying a variety of reaction conditions and solvents the best result obtained yielded only 20 % of the desired product, which was isolated as an 85/15 mixture of branched and linear isomers. This result was obtained using 10 mol % Co(PMe 3 ) 4 in toluene at 170 o C. Next we submitted the α,βunsaturated imine 31 to the same reaction conditions, however in this case no conversion to the desired product was observed. This was a strange result considering we had previously demonstrated the olefinic bond was more reactive than the aromatic C-H bond for the hydroarylation of alkynes. We can propose that the reversibility of the C-H activation/hydrogen transfer step via β-hydride elimination is more favorable in this case. This will be discussed in the latter during the mechanistic.

Disappointed but not discouraged by these initial results we began to explore alternative substrates. Based on the previously observed high reactivity of indole 81a towards the hydroarylation of diphenylacetylene we chose to examine this substrate next. Indeed, the use of indoles has been a popular choice of substrate and has been the subject of many C-H functionalization reactions. 22b,31,32,77 The inclusion of an N-heteroatom increases the acidity thus activity of the C-2 position towards oxidative addition. In addition, the indole core structure is found in many natural products and pharmaceutical compounds consequently having efficient and selective reactions to synthesize and modify these structures is desirable (Scheme 59). 78

Scheme 59 Biologically active compounds containing an indole moiety

Therefore we examined the use of substrate 81 for the hydroarylation of styrene (Scheme 60). To our delight, the previously optimized conditions yielded the desired product in quantitative yield and with complete selectivity for the branched isomer. It is worth noting that the catalytic system used by Yoshikai to promote the hydroarylation of alkynes with aryl ketimine 24 and α,β-unsaturated imine 31 were ineffective for the C-2 alkylation of styrene. This further emphasizes the generality and broad applicability of these well-defined low-valent cobalt complexes to perform catalytic C-H functionalization.

Scope and limitations

With this initial positive result we then began to explore the scope and limitations of the present reaction. Having previously demonstrated the hydroarylation of indole 81a with diphenylacetylene we were initially intrigued to see how the reaction would perform with other internal alkynes (Table 4).

Table 4 C2-Alkenylation of Indole 81a with Alkynes

As already mentioned product 82aa was isolated in quantitative yield with complete anti-selectivity in line with our previous work and in contrast to the syn-selective system previously reported. 22b During the course of this study it was found that lowering the catalyst loading to 5 mol% showed no adverse effect on the isolated yield. As before it was also possible to perform the reaction using HCo(PMe 3 ) 4 albeit with marginally lower yields (86 vs 99 %). The reaction of TMS protected phenylacetylene also took place regioselectively, with the new C-C bond being formed at the position distal to the silyl group 82ab. The product 82ac from 1phenyl-1-hexyne addition was isolated in moderate yield and good stereoselectivity. The inclusion of alkynes bearing heteroatoms was also feasible with adduct 82ad obtained in excellent yield and with complete regio-and stereoselectivity. To conclude the present scope on the alkenylation of internal alkynes, oct-4-yne and dec-5-yne were shown to participate smoothly and provide 82ae and 82af albeit with lower stereoselectivity. The lower stereoselectivity in this case compared to our previous study with aryl ketimines can possibly be explained by the absence of the methyl group on the aldimine.

We then turned our attention to the C2-alkylation of indoles (Scheme 61).

Scheme 61 Scope of C2-Alkylation with Various Olefins

To this end, we initially screened a variety of substituted styrenes (Figure 19). The reaction showed good generality affording the desired products 82ag-82al in excellent yields. In all cases the branched isomer was obtained exclusively with the exception of 82aj presumably due to the steric impingement of the methoxy group in the 2-position. 27 The reaction could also be performed on gram scale without any noticeable decrease in yield for product 82ag, while using HCo(PMe 3 ) 4 as catalyst the yield was slightly lower than that for Co(PMe 3 ) 4 . Trans-β-methylstyrene was also converted to the desired product 82am in moderate yield. 75 The present system showed excellent tolerance to the inclusion of Nheteroatoms with product 82an isolated in quantitative yield.

Figure 19 Scope of C2-Alkylation with various vinyl aromatics

An indole substrate bearing a N-benzyl protecting group reacted smoothly to afford the adduct 82bg. The addition of styrene to indoles substituted in the 5-7 positions yielded the desired alkylated products 82cg-82hg in good to excellent yields. In addition a chemically susceptible ester group provided no issues with adduct 82fg isolated in quantitative yields (Figure 20).

Figure 20 Scope of C2-alkylation of substituted indoles with various vinyl aromatics

Next we explored the addition of simple alkenes that often have a very low or no reactivity in C-H alkylation reactions. 79 Various C2-substituted indoles 82ao-82ar were isolated in good to excellent yields with complete selectivity for the linear regioisomers (Figure 21).

Figure 21 Scope of C2-alkylation with various simple olefins

Finally, for the present scope, we explored a variety of vinyl silanes which proved to be amenable to the addition reaction with products 82as-82au isolated in excellent yields and exclusively as the linear regioisomers. Of particular note is product 82au because triethoxysilane is intrinsically prone to polymerization (via the sol-gel process) and not compatible with previously reported hydroarylation reactions in the presence of Grignard derivatives. 29b As previously shown for styrene, the reaction of various indole derivatives with vinyltrimethylsilane yielded the desired alkylated products 82cs-82is in high yields (Figure 22).

79 Yamakawa, T.; Yoshikai, N. Chem. -Asian J. 2014, 9, 1242-1246.

Figure 22 Scope of C2-alkylation with various vinyl silanes

As with our previous study there were certain limitations (Scheme 62). Styrene's substituted in the α position were not viable, styrenes with a phenyl and methyl in the α position were examined and neither gave the desired hydroarylation product. This is believed to be due to steric effects during the insertion step. While the use of 4-vinylpyridine posed no issues yielding product 82an in quantitative yield, 2-vinylpyridine was not compatible for the C-2 alkylation of indoles under our system. This is believed to be due to the known ability of lowvalent cobalt catalysts to form 5-membered metallacycles with this compound through oxidative addition into the olefinic bond and stabilization through coordination with the nitrogen atom of the pyridine. 10 The electron-poor pentafluorostyrene also failed to perform satisfactorily under our reaction conditions. Simple long chain alkyl-alkenes such as 1-octene also were not amenable; it's believed that the elevated reaction temperature lead to degradation of the alkene as crude NMR analysis failed to show any remaining alkene despite no indication of the desired product. Unsurprisingly, 2-allylcyclopentan-1-one didn't participate either, we can envisage a complexation between the cobalt center the alkene and the ketone moiety of the substrate in a pincer fashion which is probably sufficiently strong to shut the reactions down. We also tested t-butyl vinyl ether however no conversion to the desired product was obtained. As with 1-octene, the alkene was not stable to our reaction conditions with significant degradation observed. Efforts to lower the reaction temperature also failed to yield the desired product.

Scheme 62 Unsuccessful substrates for the C2 alkylation of indoles

As a natural extension of this work we became curious about the possibility of applying the current methodology to the synthesis of fused tricyclic indoles with dihydropyrroloindole skeletons. It seemed feasible that an indole bearing a N-homoallylic tether would cyclize to give the desired product through selective C-H activation at the C2-position. 31 To this end indole 47a was subjected to the reaction conditions described below which afforded the fivemembered cyclization product 83a as the sole regioisomer in quantitative yield (Scheme 63). Notably, the reaction temperature and catalytic loading could be significantly lowered compared to the intermolecular variant. Also worthy of mention is that no modulation of the catalyst [Co(PMe 3 ) 4 ] was necessary, a feature not observed under the cobalt ternary catalytic system reported. Consistent with all other results the use of HCo(PMe 3 ) 4 also delivered the desired product in a reduced yield of 70 %. The use of a ketimine directing group was also possible allowing the formation of product 83b in good yield. Indole 47c, bearing a substituted homoallylic terminal position, cyclized to give the five-membered tricycle 83c as the sole product. Interestingly under our reaction conditions, substrate 47d bearing a methyl substituent in the allylic position gave the dihydropyrroloindole 83d in high diasteroselectivity (86:14 trans/cis) while the same substrate gave exclusively the six-membered ring using Yoshikai's conditions. 31 This result strongly confirms the important role of the ligand in the regioselectivity of the final product. Indoles presenting electron-donating (OMe) and electronwithdrawing (CO 2 Me) groups 47e and 47f respectively were also amenable with the current cyclization reaction. In line with earlier reports with cobalt and in contrast to rhodium catalysis N-allylindole derivatives did not cyclize to the corresponding five-membered ring products. This result suggests that ring formation takes places directly through a 5-exo-type cyclization.

Scheme 63 Cyclization of indoles bearing tethered alkenes

As shown above, the cyclization of indoles bearing N-homoallylic tethers is efficiently catalyzed by our low-valent cobalt complexes to form a variety of dihydropyrroloindole 83a-83f. However, the present reaction was somewhat limited in terms of the length of the tether (Scheme 64). Only tethers which cyclized in a 5-exo manner were possible. As shown below indole 47g bearing an N-allyl tether was not cyclized to the corresponding dihydropyrroloindole. In addition, the formation of tetrahydropyridoindoles was also not possible as seen by the failure of substrate 47h to furnish the desired cyclized product. The synthesis of tetrahydropyridoindoles was possible in the previous report by Yoshikai, this suggests that the ligand on the cobalt plays an important role in determining regioselectivity.

Scheme 64 Substrates not successfully cyclized

Mechanistic Considerations

To probe the reaction mechanism, we initially carried out a series of experiments using deuterium-labeled imine 81a-d. The reaction of 81a-d with 3-methoxystyrene was quenched after 1 min, affording the hydroarylation product 82ai-d in 22% yield along with recovery of both starting materials 81a-d 66% and 38i 63% (Scheme 65). The deuterium content at the C2position of 81a-d was significantly reduced (by 75%), and a similar degree of deuterium incorporation was observed in the recovered alkene 38i (≈ 66%). Consistent with these observations we observed deuterium incorporation into both the methyl group and the methine moiety of 82ai-d. These results suggest the initial steps are reversible through β-H elimination. 32

Scheme 65 Deuterium labelling exeriment

To further examine this hypothesis, 81a-d was reacted with 50 mol% of HCo(PMe 3 ) 4 for 60 min at 110 o C. The recovered imine showed a decrease in deuterium content which reinforces the notion that the oxidative addition step is reversible (Scheme 66).

Scheme 66 Probing the reversibility of the oxidative addition

To gain further insight into the mechanism, 81a-d was reacted with diphenylacetylene in the presence of 50 mol % HCo(PMe 3 ) 4 to afford 82aa-d with complete deuterium transfer. This observation was consistent with our previous study on the hydroarylation of aryl ketimines with alkynes and was strongly suggestive that the C-H bond activation proceeds in a concerted manner also termed Ligand-to-Ligand Hydrogen Transfer (LLHT) (Scheme 67). 68,76 Scheme 67 Deuterium labelling experiment A value of 1.4 was obtained for the KIE, from a competition experiment between 81a-d and 81a in the presence of limiting amount of diphenylacetylene. This value suggests that cleavage of the C-H bond is not turnover-limiting. 80 Rather, this value is consistent with reversible cleavage of the C-H bond before an irreversible step (Scheme 68).

Scheme 68 KIE determination

As with our previous studies, we turned to DFT calculations to complete the mechanistic study. Results are summarized in (Figure 23). The barriers for C-H activation of indole 81a with diphenylacetylene and styrene were found to be respectively 12.46 and 8.02 kcal/mol. These values are consistent with a C-H activation which is not the rate determining step. Analyzing the electronic structure of the transition state reveals that the unpaired electron remains on cobalt and that the activation occurs through an LLHT mechanism, similar to that previously reported in our two earlier studies. The origin of the branched selectivity for the styrene product was not studied as the group of Fu preformed an extensive DFT study on the topic in relation to the work of Yoshikai. 27 It was found that regardless of the ligand used the branched product is energetically favorable compared to the linear regioisomer. To understand why this was so a number of relevant factors were considered during this study, it was determined that ligand size and shape were both significant contributors to the final regioselectivity however alone neither size nor shape was enough to completely influence the regioselectivity rather a combination of the two. In our case the branched product obtained with the use of styrene can be attributed to the increased stabilization of the intermediate due to a π benzyl type interaction while the tendency of alkyl olefins to give linear products can be explained by the tendency of the alkylycobalt species to avoid steric repulsion.81

Conclusion

In summary, we disclose the use of a well-defined low-valent cobalt complex for the functionalization of indoles in the absence of an external reductant or additives. 82 The versatility of this catalyst allows performance of the imine-directed C2-alkenylation and alkylation of indoles with a large family of alkenes (bearing styryl, silyl, and alkyl groups) without any tuning of the catalytic system for the first time. Deuterium labeling studies and DFT calculations confirm that [Co(PMe 3 ) 4 ] operates through an LLHT mechanism for the hydroarylation of both alkenes and alkynes. A summary of this study is provided below which highlights the differences between our systems on the use of well-defined low-valent cobalt species versus the in situ generated low-valent systems reported by Yoshikai (Scheme 70). Although it was previously mentioned it is worth reiterating the versatility shown by this family of well-defined cobalt complexes is in stark contrast to the bimetallic systems reported by Yoshikai. We can see in the scheme below that even on switiching from intra-to intermolecular functionalization it was necessary to alter the reaction conditions. We therefore believe the results disclosed in this section provide evidence that this family of complexes offer a credible alternative to expensive rhodium based catalysts and the complicated bimetallic systems reported by Yoshikai.

Scheme 70 Summary of our study on the cobalt-catalyzed functionalization of indoles

6

Preliminary results

C(sp 3 )-H bond functionalization

While there has been undoubted success in the field of low valent and high valent cobalt catalyzed C-H functionalization there still remains a number of challenges. It will not have escaped the readers attention that the all examples presented thus far involve the activation of C(sp 2 )-H bonds. Activation of C(sp 3 )-H bonds catalyzed by first-row transition metals is at its infancy stage, especially with cobalt. Cenini and Zhang reported the functionalization of C(sp 3 )-H bonds intramolecularly proceeded through an outer-sphere mechanism, using a Co(I) catalyst. 83 Very recently, Ge et al. and the group of Zhang independently reported the functionalization of an unactivated C(sp 3 )-H bond under oxidative conditions, using 8-aminoquinoline as a bidentate chelating group for amidation and cyclization with terminal alkynes at 150 °C. 84 A very recent report by the group of Sundararaju documented the highly regioselective C(sp 3 )-H bond alkenylation of 8-methylquinoline catalyzed by a (Cp*)Co(III) complex (Scheme 71).85

Scheme 71 Cp*Co(III)-Catalyzed C(sp3)-H Bond Activation

The group of Li also demonstrated the potential of well-defined low-valent cobalt complexes to perform the stoichiometric C-H activation of C(sp3 )-H hybridized bonds. When a solution of (Ph 2 POCH 2 ) 2 CH 2 was treated with a one equivalent of MeCo(PMe 3 ) 4 in diethyl ether, the desired cyclometalated product was isolated in good yield. The reaction is believed to begin with the coordination of the cobalt to the phosphorus atom in ligand (Ph 2 POCH 2 ) 2 CH 2 by substituting two of the trimethylphosphines, which brings the metal closer to the central C(sp 3 )-H bond. This precoordination facilitates the interaction between C-H bonds and the metal center and results in an easier and highly selective C-H bond cleavage. This results in the 113 reductive elimination of methane and renders the reaction irreversible and affords a Co(Ι) with two five-membered cobaltocycles in high yield (Scheme 72). 59 Encouraged by these initial results in particular the report by Li we began to explore possibility of performing similar hydroarylation reactions using the same low-valent welldefined cobalt complexes previously discussed i.e. Co(PMe 3 ) 4 and HCo(PMe 3 ) 4 (Scheme 73). However, as shown below our initial attempts have so far been met with failure. Using a similar PCP ligand to Li we were unable to perform the desired C-H functionalization reaction. Similarly the use of pyridine or imine directing groups also failed to be effective. Despite these initially unsuccessful attempts this remains an attractive area for further research and is sure to attract considerable attention in the future.

Scheme 73 Attempts towards C(sp

Enantioselective C-H addition reactions

As seen in our previous discussion, transition-metal-catalyzed, directing group-assisted addition of aromatic and vinylic C-H bonds across alkenes has gained considerable attention as a straightforward and atom-economical approach for the regioselective alkylation of arenes and alkenes. However, enantioselective variants remain comparatively rare particularly for first row transition metals. The group of Bergman and Ellman extensively explored the enantioselectively C-H addition reactions in an intramolecular setting under rhodium catalysis. 86 On the other hand, intermolecular directed hydroarylation of alkenes has rarely been performed enantioselectively, mainly because the reaction typically shows anti-Markovnikov selectivity with terminal olefins and thus precludes the formation of a new stereogenic center. One notable exception is the previously discussed cobalt-catalyzed enantioselective C-H alkylation of indole with styrenes reported by Yoshikai. 32 Inspired by these previous results and our success with well-defined low-valent cobalt complexes, we began to explore the possibility of carrying out an intermolecular enantioselective C-H alkylation of indole with styrenes through the in situ formation of a chiral amine species (Scheme 74).

Scheme 74 Attempts towards the enantioselective C-H alkylation of indoles with styrene

As shown below a wide variety of amines were examined but in all cases only formation of the imine product was observed, with none of the desired alkylated product detected (Table 5). In addition to N-metylated indoles N-benzyl and Boc groups were also explored but as before failed to deliver the desired product of C-H functionalization. One hypothesis to explain the failure of this reaction was the generation of water during the reaction through in situ formation of the imine. Indeed, the inclusion of water was shown to drastically hinder the reaction reducing the yield from 99% to 25%. However, rather surprisingly the inclusion of molecular sieves in the reaction mixture still failed to yield the alkylated product.

Table 5 Chiral amines examined for the enantioselective C-H alkylation of indoles with styrene

Despite this unsuccessful approach there is still an undoubted need to further explore the potential of cobalt to perform enantioselective C-H functionalization. Other possible options are to perform the reaction with a preformed chiral imine or to synthesis a well-defined cobalt complex bearing chiral ligands. Both of these possibilities will be explored further by our group.

Scheme 75 C-H alkylation of indole with styrene in the presence of water

Conclusions

To conclude this section we have seen that our initial attempts to perform enantioselective C-H functionalization and C(sp 3 )-H bond activation have so far been unsuccessful. However, both of these remain areas of interest. We intend to explore the possibility of synthesizing a chiral cobalt complex through substitution of the PMe 3 ligand with an alternative electron rich chiral ligand. Regarding C(sp 3 )-H bond functionalization we remain confident that it is possible based on the results of Klein, future efforts will be directed towards the use of alternative directing groups such as 8-methylquinoline.

Experimental Section Chapter 1 7.1 General remarks

All reactions were carried out in dry glassware under an argon atmosphere or using standard Schlenk techniques under an argon atmosphere. All solvents were purified prior to use following the guidelines of Perrin and Armarego. 87 THF was distilled under dry nitrogen atmosphere on benzophenone/sodium ketyl and subsequently degassed by argon bubbling or freeze pump. Toluene was degassed by argon bubbling or freeze pump. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporatory. Deuterated NMR solvents were dried over molecular sieves. Reactions were monitored by thin layer chromatography (TLC) carried out on Merk 60 F254 silica gel plates using UV light (λ = 254 nm) as visualizing agent and para-anisaldehyde solution. Chromatographic purification of products were accomplished using force-flow chromatography on Merk Geduran SI 60 Å (35 -70 µm) silica gel according to the method of Still. 88 Filtration through alumina were performed using aluminum oxide activated, neutral Brockmann I from Sigma-Aldrich. NMR spectra were recorded on Bruker 400 AVANCE or Bruker 300 AVANCE spectrometers and calibrated using deuterated chloroform (δ H = 7.26 ppm and δ C = 77.16 ppm) as internal references. The following abbreviations are used to designate multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, quint = quintet, br = broad signal. IR spectra were recorded on a Tensor 27 (ATR diamond) Bruker spectrometer and are reported in terms of frequency of absorption (cm -1 ). High Resolution Mass Spectra were recorded on Bruker micrTOF. 87

Preparation of low-valent well-defined cobalt complexes

Tetrakis(trimethylphosphine)hydridocobalt. 89Under argon atmosphere, Co(acac) 2 (2.57 g, 10 mmol, 1 equiv.) was introduced to a Schlenk flask attached to a vacuum manifold. Commercial trimethylphosphine solution (1 M THF, 40 mL, 40 mmol, 4 equiv.) was added and the resulting mixture was stirred at room temperature. After 15 minutes, NaBH 4 (0.772 g, 20 mmol, 2 equiv.) was added and the reaction mixture was stirred for 3h at room temperature. The solvent was removed under vacuum. Degassed pentane was added (60 mL), the yellow solution was cool down to -78 °C and filtered via cannula. Pentane was removed under vacuum to give HCo(PMe 3 ) 4 as a yellow solid (1.6 g, 44%) which was subsequently dried and stored in a glove box. Methyl-tetrakis(trimethylphosphine)cobalt. 90 Under an argon atmosphere, chloro-tris(trimethylphosphine)cobalt (1.5 g, 4.65 mmol, 1 equiv.) was introduced to a Schlenk flask attached to a vacuum manifold. Commercial trimethylphosphine solution (1 M THF, 5.6 mL, 5.58 mmol, 1.2 equiv.) was added and the resulting mixture was cooled down to -78 °C before addition of methyllithium (1.6M THF, 3.2 mL, 5.11 mmol, 1.1 equiv.). The orange-red mixture was allowed to slowly warm up to room temperature and stirred overnight. The solvent was removed under reduced pressure, the resulting solid was dissolved in degassed pentane at -78 °C and filtrated via cannula. The filtrate was then concentrated to furnish the methyl-tetrakis(trimethylphosphine)cobalt as a red solid 1.5 g (85%) and stored in a glove box. Tetrakis(trimethylphosphine)cobalt. 91In a Schlenk flask attached to a vacuum manifold, CoCl 2 (2 g, 15.4 mmol, 1 equiv.) and trimethylphosphine (1 M solution in THF, 73.7 mL, 73.7 mmol, 4.8 equiv.) were added under an argon atmosphere, to a suspension of magnesium (600 mg, 24.7 mmol, 1.6 equiv.) activated by a mixture of anthracene (50 mg, 0.39 mmol, 0.025 equiv.) and 1,2-dibromoethane (4 drops) in THF (1 mL). The dark black/golden solution was stirred at room temperature for 24 h and the solvent were removed under reduced pressure. The resulting dark brown solid was dissolved twice in degassed pentane allowing separation of impurities by filtration via cannula. The resulting brown solution was concentrated under reduced pressure and the tetrakis(trimethylphosphine)cobalt was obtained as a brown solid 5.4 g (97%) and stored in a glove box. This catalyst has already been fully characterized in the literature. 91

Chloro-tris(trimethylphosphine)cobalt. 92Under an argon atmosphere, in a Schlenk flask tetrakis(trimethylphosphine)cobalt (856 mg, 2.35 mmol, 1 equiv.) was added to a solution of dichloro-tris(trimethylphosphine)cobalt (841 mg, 2.35 mmol, 1 equiv) in degassed diethyl ether (15 mL) for a comproportination reaction. The resulting mixture was stirred for 2h at room temperature, by which time a blue precipitate had formed. The blue solid was washed three times with degassed diethyl ether and the solvent was removed by filtration via cannula. The resulting solid was dried under reduced pressure and the chloro-tris(trimethylphosphine)cobalt was obtained as blue-violet solid 720 mg (95%) and stored in a glove box. This catalyst has already been fully characterized in the literature. 92 Dichloro-tris(trimethylphosphine)cobalt. 93Under an argon atmosphere, anhydrous CoCl 2 (2 g, 15.4 mmol, 1 equiv.) was introduced in a schlenk flash attached to a vacuum manifold followed by trimethylphosphine (46.2 mL, 46.2 mmol, 3 equiv.). The resulting blue mixture was stirred overnight and concentrated under reduced pressure. The dichloro-tris(trimethylphosphine)cobalt was obtained as a dark bluegreen solid 5.2 g (99%) which was stored in a glove box. This catalyst has already been fully characterized in the literature. 93 Hydridodinitrogentris(tripheny1phosphine)cobalt. 94 Under an argon atmosphere, in a Schlenk flask was added triphenylphosphine 2.65 g (10.5 mmol) and cobalt(III) tris(acety1acetonate) 1.0 g (3.0 mmol) which were suspended in 30 ml of diethyl ether. Diethylaluminum monoethoxide 3.0 ml (12.0 mmol) was added to the suspension which was subsequently cooled to -50 o C under a nitrogen atmosphere. The reaction mixture was stirred and the temperature was raised gradually to room temperature, with nitrogen passing through the reaction mixture. After the reaction had proceeded for 3h at room temperature, orange crystals deposited from the dark red solution. The crystals were filtered, washed several times with hexane, and dried in vacuo. This catalyst has already been fully characterized in the literature. To an argon purged round bottom flask were added the carbonyl compound (50 mmol), paraanisidine (60 mmol) in toluene (30 ml) followed by MS 4Å (20 g). The reaction was stirred at rt until TLC analysis showed complete conversion of starting material. The reaction mixture was filtered to remove the molecular sieves and then concentrated under reduced pressure. The crude product was purified by recrystallization or distillation under reduced pressure. The 1 H NMR spectrum of all compounds showed good agreement with the literature data.

(E)-1-(4-(tert-butyl)phenyl)-N-(4-methoxyphenyl)ethan-1-imine (24a) 95

According to the general procedure (A). Light yellow solid (70%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.03 -7.96 (m, 2H), 7. 52 -7.43 (m, 3H), 6.98 -6.91 (m, 2H), 6.83 -6.75 (m, 2H), 3.85 (s, 3H), 2.29 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165. 7, 155.9, 144.8, 139.7, 130.3, 128.3, 127.1, 120.7 (2C), 116.4, 114.8, 114.2 (2C), 55.4, 17.3. 94 Yamamoto, A.; Kitazume, S.; Pu, L. S.; Ikeda, S. J. Am. Chem. Soc. 1971, 93, 371-380. 95 Imamoto, T.; Iwadate, N.; Yoshida, K. Org. Lett. 2006Lett. , 8, 2289Lett. -2292.

(E)-N-(4-methoxyphenyl)-1-(phenyl-d5)ethan-1-imine (24a-d 5 ) 17

According to the general procedure (A). Light yellow solid (75%). 1 H NMR (400 MHz, CDCl 3 ): δ 6.97 -6.91 (m, 2H), 6.80 -6.75 (m, 2H), 3.85 (s, 3H), 2.28 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165. 7, 155.9, 144.7, 139.5, 130.3, 128.4, 127.7 120.7 (2C), 116.7, 114.9, 114.2 (2C), 55.4, 17.3. 95 According to the general procedure (A). Brown solid (75%). 9, 155.9, 144.9, 139.7, 138.0, 131.0, 128.2, 127.6, 124.3, 120.7 (2C), 114.9 (2C), 55. 4, 21.4, 17.3.

(E)-N-(4-methoxyphenyl)-1-(p-tolyl)ethan-1-imine (24b)

(E)-N,1-bis(4-methoxyphenyl)ethan-1-imine (24c) 96

According to the general procedure (A). Yellow solid (62%).

(E)-1-(4-fluorophenyl)-N-(4-methoxyphenyl)ethan-1-imine (24e) 29a

According to the general procedure (A). Bright yellow solid (80%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.08 -7.93 (m, 2H), 7.18 -7.07 (m, 2H), 7.00 -6.88 (m, 2H), 6.85 -6.72 (m, 2H), 3.84 (s, 3H), 2.26 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165. 4,163.0 (d,J = 249.3 Hz),156.0,144.6,136.1,135.9,129.2 (d,J = 7.9 Hz), 120.7 (2C), 115.3 (d, J = 24,5 Hz, 2C), 114.2 (2C), 55. 4, 17.2.

(E)-1-(3-methoxyphenyl)-N-(4-methoxyphenyl)ethan-1-imine (24f) 97

According to the general procedure (A). Pale yellow solid (80%).

(E)-3-(1-((4-methoxyphenyl)imino)ethyl)benzonitrile (24g) 29a

According to the general procedure (A). Pale orange solid (53%). 3, 156.4, 143.8, 140.7, 133.3, 131.2, 130.9, 129.2, 120.7 (2C), 118.5, 114.3 (2C), 112.6, 55.5, 17.1.

(E)-1-(3-fluorophenyl)-N-(4-methoxyphenyl)ethan-1-imine (24h) 17

According to the general procedure (A). Bright yellow solid (61%).

(E)-4-Methoxy-N-(1-m-tolylethylidene)aniline (24i) 98

According to the general procedure (A). White solid (61%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (m, 1H), 7.76 (m, 1H), 7.42 -7.25 (m, 2H), 6.99 -6.91 (m, 2H), 6.83 -6.75 (m, 2H), 3.85 (s, 3H), 2.46 (s, 3H), 2.27 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165. 9, 155.9, 144.9, 139.7, 138.0, 131.0, 128.2, 127.6, 124.3, 120.7 (2C), 114.2 (2C), 55.4, 21.4, 17.3.

(E)-1-(benzo[d][1,3]dioxol-5-yl)-N-(4-methoxyphenyl)ethan-1-imine.
(24j) 97 According to the general procedure (A). White solid (81%). 4, 155.3, 148.3, 148.1, 144.7, 122.1, 121.0 (2C), 116.3, 114.3 (2C), 108.1, 107.2, 101.8, 55.0, 17.1.

(E)-N-(4-methoxyphenyl)-1-(naphthalen-2-yl)ethan-1-imine. (24k) 96

According to the general procedure (A). Yellow solid (63%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, J = 1.7 Hz, 1H), 8.24 (dd, J = 8.7, 1.9 Hz, 1H), 7.92 (m, 3H), 7.55 (m, 2H), 7.04 -6.90 (m, 2H), 6.91 -6.76 (m, 2H), 3.86 (s, 3H), 2.40 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 165. 5, 156.0, 144.8, 137.1, 134.4, 132.9, 128.9, 128.0, 127.5, 127.1, 126.3, 124.2, 120.8 (2C), 116.4, 114.8 (2C), 55.5, 17.3.

(E)-N-(4-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-imine (24l) 99

According to the general procedure (A). White solid (59%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (ddd, J = 7.8, 1.5, 0.5 Hz, 1H), 7.38 (m, 1H), 7.31 (m, 1H), 7.22 (m, 1H), δ 7.00 -6.88 (m, 2H), 6.83 -6.74 (m, 2H). 3.84 (s, 3H), 2.93 (t, J = 6.1 Hz, 2H), 2.61 -2.53 (m, 2H), 1.99 -1.90 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ 165. 9, 155.8, 144.6, 141.2, 134.0, 130.5, 128.7, 126.4, 126.2, 120.8 (2C), 114.2 (2C), 55. 5, 29.9, 29.8, 23.

(E)-N-(4-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-imine (24m) 99

According to the general procedure (A). Yellow solid (44%). E:Z = 90:10; 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 -7.90 (m, 2H), 7.51 -7.43 (m, 3H), 6.97 -6.90 (m, 2H), 6.81 -6.74 (m, 2H), 3.85 (s, 3H), 2.72 (q, J = 7.7 Hz, 2H), 1.11 (t, J = 7.7 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 172. 0, 155.9, 145.0, 138.3, 129.9, 128.6 (2C), 127.9 (2C), 120.2 (2C), 114.2 (2C), 55.4, 23.2, 13.0.

General Procedure B: Addition of Aryl Imines to diphenylacetylene

To a microwave vial under argon were added imine (0.5 mmol, 1 equiv.), alkyne (1.0 mmol, 2equiv.) and Co(PMe 3 ) 4 (0.05 mmol, 10 mol%). The microwave vial was then sealed followed by the addition of degassed toluene (toluene was degassed via purging with argon for a period of 30 mins). The reaction was heated in the microwave at 170 o C for 1h (normal absorption level). The reaction mixture was then filtered through a plug of celite and washed with ethyl acetate (3 x 10 mL). The crude product was purified by silica chromatography to afford the title compound.

(E)-1-(2-((Z)-1,2-diphenylvinyl)-4-methoxyphenyl)-N-(4-methoxyphenyl)ethan-1-imine (25a)

The general procedure (B) was applied to (E)-N-(4-methoxyphenyl)-1phenylethan-1-imine (24a, 112.5 mg, 0.5 mmol) diphenylacetylene (178.1 mg, 1 mmol) and Co(PMe 3 ) 4 (18 mg, 0.05 mmol). Silica chromatography (eluent pentane/diethyl ether 90/10) afforded the title compound as a yellow oil which was subsequently crystallised from pentane/DCM to give bright yellow crystals (181.4 mg, 90% yield) mp: 125 o C. The anti-addition of the olefin moiety was confirmed by X-ray crystallography. 1 H NMR (400 MHz) δ 7.65 (ddd, J = 7.7, 1.5, 0.5 Hz, 1H), 7.47 (m, 1H), 7.42 -7.30 (m, 6H), 7.28 -7.13 (m, 6H), 7.08 (s, 1H), 6.80 -6.75 (m, 2H), 6.29 -6.15 (m, 2H), 3.78 (s, 3H), 1.92 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 169. 4, 155.6, 144.3, 142.6, 142.6, 141.9, 138.0, 137.2, 131.8, 129.6 (2C), 129.3, 128.7, 128.5, 128.3 (2C), 128.1 (2C), 128.1, 127.6, 127.6 (2C), 127.0, 120.2 (2C), 113.8 (2C), 55.3, 19.9. IR (neat, cm-1): ν max 3057,3020,2833,1502,1293,1180,1050,910,765,716

(E)-1-(2-((Z)-1,2-diphenylvinyl)-4-methylphenyl)-N-(4-methoxyphenyl)ethan-1-imine (25b)

The general procedure (B) was applied to (E)-N-(4-methoxyphenyl)-1-(ptolyl)ethan-1-imine (24b, 119.5 mg, 0.5 mmol) and diphenylacetylene ( 178.1 mg, 1 mmol). Silica gel chromatography (eluent pentane/diethyl ether 85/15) afforded the title compound as a yellow oil (171 mg, 82% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (d,J = 7.8 Hz,1H),5H),.04 (m, 7H), 7.02 (s, 1H), 6.77 -6.70 (m, 2H), 6.24 -6.16 (m, 2H), 3.75 (s, 3H), 2.32 (s, 3H), 1.86 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 169. 1, 155.5, 144.5, 142.8, 142.0, 139.8, 139.2, 138.0, 137.2, 132.1, 129.5(2C)

(E)-1-(2-((Z)-1,2-diphenylvinyl)-4-methoxyphenyl)-N-(4-methoxyphenyl)ethan-1-imine (25c)

The general procedure (B) was applied to (E)-N,1-bis(4methoxyphenyl)ethan-1-imine (24c, 127.5 mg, 0.5 mmol) and diphenylacetylene (178.1 mg, 1 mmol). Silica gel chromatography (eluent pentane/diethyl ether 85/15) afforded the title compound as a yellow oil which was subsequently crystallised from pentane/DCM to give yellow crystals (194.94 mg, 90% yield) mp: 90 o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d,J = 8.5 Hz,1H),5H),5H), 7.03 (s, 1H), 6.96 (dd,J = 8.6,2.7 Hz,1H),3H),2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.87 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 168. 6, 160.2, 155.5, 144.5, 142.4, 141.9, 139.7, 137.1, 135.3, 130.4, 129.5 (2C), 128.3, 128.3 (2C), 128.1 (2C), 127.6, 127.5 (2C), 127.0, 120.2 (2C), 116. 6, 113.8 (2C), 113.6, 55.4, 55.3, 19.9. IR (neat, cm-1): ν max 3055,2998,2833,1633,1502,1237,1203,1030,765,693. HRMS (ESI) Calcd for C 30 H 28 NO 2 [M+H]+ 434.2115, found 434.2123.

(E)-1-(4-(tert-butyl)-2-((Z)-1,2-diphenylvinyl)phenyl)-N-(4-methoxyphenyl)ethan-imine (25d)

The general procedure (B) was applied to (E)-1-(4-(tert-butyl)phenyl)-N-(4-methoxyphenyl)ethan-1-imine (24d, 140.5 mg, 0.5 mmol) and diphenylacetylene (178.1 mg, 1 mmol). Silica gel chromatography (eluent pentane/diethyl ether 90/10) afforded the title compound as a yellow oil subsequently crystallised from pentane/DCM to give bright yellow crystals (181.4 mg, 90% yield) mp: 105 o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d,J = 8.1 Hz,1H),7.46 (dd,J = 8.1,2.1 Hz,1H),5H),1H),12 (m, 5H), 7.09 (s, 1H), 6.80 -6.73 (m, 2H), 6.24 -6.17 (m, 2H), 3.77 (s, 3H), 1.93 (s, 3H), 1.22 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 169. 4, 155.6, 152.2, 144.5, 142.8, 142.6, 139.8, 137.4, 137.3, 129.6, 129.6(2C), 128.5, 128.4, 128.3(2C), 128.0(2C), 127.6, 127.5(2C), 126.8, 124.8, 120.3(2C), 113.8(2C), 55.3, 34.5, 31.1(3C), 20.0. IR (neat, cm-1): ν max 3022,2963,1633,1502,1240,1209,1050,9794,750,696 3058,3024,2833,1639,1602,1502,1217,1033,830,751,695. HRMS (ESI) Calcd for C 29 H 24 FNNaO + [M+Na + ] 444.1734, found 444.1752.

(E)-1-(2-((Z)-1,2-diphenylvinyl)-3-methoxyphenyl)-N-(4methoxyphenyl)ethan-1-imine (25f)

The general procedure (B) was applied to (E)-1-(3-methoxyphenyl)-N-(4-methoxyphenyl)ethan-1-imine (24f, 127.5 mg, 0.5 mmol) and diphenylacetylene (106.86 mg, 0.6 mmol). Silica gel chromatography (eluent pentane/diethyl ether 85/15) afforded the title compound and its imine (Z)-isomer as a yellow oil (130.0 mg, 60% yield, 80/20 (E/Z) as determined by 1 H NMR). 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 -7.39 (m, 3H), 7.35 -7.27 (m, 3H), 7.20 -7.09 (m, 7H), 7.02 -6.97 (m, 1H), 6.78 -6.71 (m, 2H), 6.30 -6.23 (m, 2H), 3.75 (s, 3H), 3.55 (s, 3H), 1.81 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 169. 3, 157.3, 130 155.6, 144.2, 143.9, 142.3, 137.7, 136.6, 129.6, 129.5, 129.2, 128.6 (2C), 128.2 (2C), 128.0 (2C), 127. 2, 127.0, 126.8 (2C), 120.8, 120.2 (2C), 113.9 (2C), 111.9, 55.9, 55.3, 20.0.IR (neat, cm-1): ν max 3020,2997,2834,1641,1570,1463,1209,1033,798,742 (m, 6H), 7.23 -7.16 (m, 3H), 7.12 -7.07 (m, 2H), 6.81 -6.72 (m, 2H), 6.29 -6.18 (m, 2H), 3.76 (s, 3H), 1.88 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 167. 3, 159.2, 156.1, 144.0, 143.4, 141.9, 140.9, 137.2, 136.4, 133.9, 132.8, 131.7, 129.3(2C), 128.5(2C), 128.5, 128.3(2C), 128.0, 127.7, 127.2(2C), 120.2(2C), 114.0(2C), 55. 4, 30.3, 19.6. IR (neat, cm-1): ν max 3023,2957,2833,2229,1641,1465,1208,967,750,695 The general procedure (B) was applied to (E)-1-(3-fluorophenyl)-N-(4methoxyphenyl)ethan-1-imine (24h, 121.5 mg, 0.5 mmol) and diphenylacetylene (106.86 mg, 0.6 mmol). Silica gel chromatography (eluent pentane/diethyl ether 95/5) afforded the title compound as a yellow oil which was subsequently crystallised from pentane/DCM to give yellow crystals (179 mg, 85% yield) mp: 116 o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 -7.37 (m, 4H), 7.36 -7.28 (m, 3H), 7.23 -7.10 (m, 7H), 6.81 -6.71 (m, 2H), 6.33 -6.20 (m, 2H), 3.76 (s, 3H), 1.84 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 167.9, 162.4 (d,J = 274 Hz),158.8,155.8,144.6 (d,J = 2.7 Hz),143.9,141.8,137.2,134.1,130.8,129.5,129.6,128.7 (2C),128.4 (2C),128.2 (2C),127.6,127.4,126.9 (2C),125.8 (d,J = 17.3 Hz), 124.1 (d, J = 3.2 Hz), 120.2, 116.3 (d, J = 23.2 Hz), 113.9, 55.3, 19.7. 19 F NMR (376 MHz, CDCl 3 ) δ -115.1. IR (neat, cm-1): ν max 3021,2951,2833,1695,1640,1501,1441,1239,1032,842,760,693. HRMS (ESI) Calcd for C 29 H 25 FNO [M+H]+ 422.1915, found 422.1930.

(E)-1-(2-((Z)-1,2-diphenylvinyl)-5-methylphenyl)-N-(4-methoxyphenyl)ethan-1-imine (25i)

The general procedure (B) was applied to (E)-4-methoxy-N-(1-mtolylethylidene)aniline (24i, 119.5 mg, 0.5 mmol) and diphenylacetylene (106.86 mg, 0.6 mmol). Silica gel chromatography (eluent pentane/diethyl ether 85/15) afforded the title compound as a yellow oil (127.2 mg, 61% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (dd, J = 1.7, 0.8 Hz, 1H), 7.37 -7.30 (m, 4H), 7.23 -7.13 (m, 8H), 7.05 (s, 1H), 6.82 -6.71 (m, 2H), 6.27 -6.18 (m, 2H), 3.76 (s, 3H), 2.47 (s, 3H), 1.92 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 169. 7, 155.7, 144.4, 142.9, 142.5, 141.9, 137.9, 137.3, 135.0, 131.8, 130.0, 129.5(2C), 129.3, 128.4, 128.3(2C), 128.1(2C), 127.6(2C), 127.6, 126.9, 120.2(2C), 113.9(2C), 55. 3, 21.2, 19.9. IR (neat, cm-1): ν max 3021,2950,2832,1602,1502,1239,1209,1034,818,727,694. HRMS (ESI) Calcd for C 30 H 28 NO [M+H]+ 418.2165, found 418.2155.

(E)-1-(4-((Z)-1,2-diphenylvinyl)benzo[d][1,3]dioxol-5-yl)-N-(4-methoxyphenyl)ethan-1-imine (25j)

The general procedure (B) was applied to (E)-1-(benzo [d][1,3]dioxol-5-yl)-N-(4-methoxyphenyl)ethan-1-imine (1j, 134.5 mg, 0.5 mmol) and diphenylacetylene (2a, 106.86 mg, 0.6 mmol). Silica gel chromatography (eluent pentane/diethyl ether 95/5) afforded the title compound as a yellow solid which was subsequently crystallised from pentane/DCM to give yellow crystals (156.5 mg, 70% yield) mp 145 o C. 1 H NMR (400 MHz, CDCl 3 ) 2H),3H),6H),7.13 (s,1H),1H),2H),2H),5.84 (d,J = 1.4 Hz,1H),5.54 (d,J = 1.3 Hz,1H), 3.75 (s, 3H), 1.86 (s, 3H). 13 C NMR (100 MHz, CDCl 3 )δ 168. 1, 155.5, 148.0, 145.9, 144.3, 141.4, 137.6, 136.7, 135.0, 130.1, 128.7 (2C)

(E)-1-(1-((Z)-1,2-diphenylvinyl)naphthalen-2-yl)-N-(4-methoxyphenyl)ethan-1-imine ( 25k
Major)

The general procedure (B) was applied to (E)-N-(4-methoxyphenyl)-1-(naphthalen-2-yl)ethan-1-imine (24k, 125.5 mg, 0.5 mmol) and diphenylacetylene (106.86 mg, 0.6 mmol). NMR analysis showed a mixture

(Z)-1-(2-(1,2-diphenylvinyl)phenyl)propan-1-one (25m)

A modified version of the general procedure (B) was applied to (E)-N-(4methoxyphenyl)-1-phenylpropan-1-imine (24m, 119.5 mg, 0.5 mmol) and diphenylacetylene (178.1 mg, 1 mmol). The crude product was filtered through a plug of celite using ethyl acetate (3 x 10mL) and concentrated under reduced pressure to yield a brown oil. Ethyl acetate (5 mL) was added followed by 3M HCl (1mL) and the reaction stirred for 1h at rt and then extracted with EtOAc (10 mL x 3). The combined organic layer was dried over with MgSO 4 and concentrated under reduced pressure. The crude product was purified by silica chromatography (eluent pentane/diethyl ether 95/5) to afford the title and the product of (E) insertion as a yellow oil (95 mg, 61% yield, 96/4 (Z/E) as determined by 1 H NMR). Only peaks for major isomer are assigned. To a microwave vial under argon were added imine (0.5 mmol), alkyne (0.6 mmol) and Co(PMe 3 ) 4 (0.025 mmol). The microwave vial was then sealed followed by the addition of degassed toluene (toluene was degassed via purging with argon for a period of 30 mins). The reaction was heated in the microwave at 170 o C for 1h (normal absorption level). The reaction mixture was then filtered through a plug of celite and washed with ethyl acetate (3 x 10 mL). The crude product was purified by silica chromatography to afford the title compound

(E)-N-(4-methoxyphenyl)-1-(2-((Z)-1-phenyl-2-(trimethylsilyl)vinyl)phenyl)ethan-1-imine (25n)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1phenylethan-1-imine (24a, 112.5 mg, 0.5 mmol), 7, 157.1, 155.6, 144.5, 142.5, 139.8, 139.0, 138.3, 132.6, 130.0, 128.8, 128.2, 128.1 (2C), 127.7, 127.4 (2C), 120.2 (2C), 113.9 (2C), 55.

(E)-1-(4-methoxy-2-((Z)-1-phenyl-2-(trimethylsilyl)vinyl)phenyl)-N-(4-methoxyphenyl)ethan-1imine (25p)

The general procedure (C) was applied to (E)-N,1-bis(4methoxyphenyl)ethan-1-imine. (24c, 127.5 mg, 0.5 mmol) and 1phenyl-2-trimethylsilylacetylene (118 µL, 0.6 mmol). Silica gel chromatography (eluent pentane/diethyl ether 90/10) afforded the title compound as a yellow oil (118 mg, 55% yield). 6, 157.1, 155.6, 151.5, 144.4, 142.6, 139.4, 138.9, 129.8, 128.5, 128

(E)-1-(4-(tert-butyl)-2-(1-phenylvinyl)phenyl)-N-(4-methoxyphenyl)ethan-1-imine (25q')

The compound 25q (100 mg, 0.22 mmol) was dissolved in THF (5 mL) and added to a solution of TBAF (1.0 M, 0.53 mL, 0.53 mmol). The reaction mixture was heated at 60 °C for 8 h, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent: pentane/diethyl ether 90/10) to afford the title compound as a pale yellow oil (51 mg, 60% yield).

(E)-1-(3-fluoro-2-((Z)-1-phenyl-2-(trimethylsilyl)vinyl)phenyl)-N-(4-methoxyphenyl)ethan-1imine (25r)

The general procedure (C) was applied to (E)-1-(3-fluorophenyl)-N-(4methoxyphenyl)ethan-1-imine (24h, 121.5 mg, 0.5 mmol) and

(E)-1-(2-((Z)-1,2-bis(4-butylphenyl)vinyl)-4-(tert-butyl)phenyl)-N-(4-methoxyphenyl)ethan-1imine (25w)

The general procedure (B) was applied to (E)-

(E)-1-(4-(tert-butyl)-2-((Z)-1-(trimethylsilyl)pent-1-en-2-yl)phenyl)-N-(4methoxyphenyl)ethan-1-imine (25x)

A modified version of procedure (C) was applied to (E)-1-(4-(tertbutyl)phenyl)-N-(4-methoxyphenyl)ethan-1-imine (24d, 140.5 mg, 0.5 mmol), trimethyl(pent-1-yn-1-yl)silane (110 µL, 0.6 mmol). The reaction was heated in the microwave at 170 o C for 60 mins. The crude product was purified by silica chromatography (eluent pentane/diethyl ether 90/10) to afford a mixture of the title compound and the product of syn-addition as a yellow oil (95 mg, 45% yield, anti/syn addition 89/11 as determined by 1 1, 159.2, 155.6, 151.3, 144.4, 142.8, 137.6, 130.5, 127.6, 125.2, 123.7, 120.3 (2C)

(Z)-1-(4-(tert-butyl)-2-(1-phenylpent-1-en-1-yl)phenyl)ethan-1-one (25y)

A modified version of procedure (C) was applied to (E)-1-(4-(tertbutyl)phenyl)-N-(4-methoxyphenyl)ethan-1-imine (24d, 140.5 mg, 0.5 mmol),1-phenyl-1-pentyne (96 µL, 0.6 mmol). The reaction was heated in the microwave at 170 o C for 30 mins. The crude product was filtered through a plug of celite using ethyl acetate (3 x 10mL) and concentrated under reduced pressure to yield a brown oil. Ethyl acetate (5 mL) was added followed by 3M HCl (1mL) and the reaction stirred for 1h at rt and then extracted with EtOAc (10 mL x 3). The combined organic layer was dried over with MgSO 4 and concentrated under reduced pressure. The crude product was purified by silica chromatography (eluent pentane/diethyl ether 90/10) to afford the title and the product of (E) insertion as a yellow oil (80 mg, 50% yield, 86/14 (Z/E) as determined by 1

(E)-1-(4-(tert-butyl)-2-((Z)-oct-4-en-4-yl)phenyl)-N-(4-methoxyphenyl)ethan-1-imine (25z)

A modified version of the general procedure (C) was applied to (E)-1-(4-(tert-butyl)phenyl)-N-(4-methoxyphenyl)ethan-1-imine (24d, 140.5 mg, 0.5 mmol) and oct-4-yne (146 µL 1 mmol). Silica gel chromatography (eluent pentane/diethyl ether 90/10) afforded the title compound as a mixture of mono and dialkylated products (70/30) (189 mg, 96% yield). The mono-alkylated product was isolated as a (87/13) mixture of anti/syninsertion as determined by 1 H NMR. The dialkylated product was isolated as (77/23) mixture anti/syn-insertion as determined by 1 H NMR. Characterisation of the major isomer of mono-addition shown below. (Note: spectra of dialkylated product not shown due to difficulty of interpreting the overlapping signals, however mass spectra is provided) 6, 155.8, 151.2, 144.7, 141.4, 139.1, 138.5, 127.6, 127.6, 127.2, 123.6, 120.5(2C), 114.2(2C), 55. 4, 41.3, 34.5, 31.4, 31.3, 31.2(3C), 22.9, 21.1, 20.3, 13.8. IR (neat, cm-1): 2956, 2929, 2869, 1633, 1402, 1240, 1208, 1102, 748. ν General X-Ray information:

1=25a, 2=25k' minor, 3=25d, 4=25j, 5=25h, 6=25g, 7=25h, 8=25c, 9=3l

Intensity data was collected with a Bruker Kappa-APEX2 system using Cu-Ka micro-source (1,2,[START_REF]E)-1-(5-Fluoro-1-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (81h) According to the general procedure (H[END_REF]8,9) and Mo-Ka fine-focus sealed tube (3,4,6,7) radiations. Unit-cell parameters determination, data collection strategy and integration were carried out with the Bruker APEX2 suite of programs. Multi-scan absorption correction was applied. 100 The structures were solved using SIR92101 (1,2,4,6,7), SHELXS86102 (3,[START_REF]E)-1-(5-Fluoro-1-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (81h) According to the general procedure (H[END_REF] or SUPERFLIP103 (8) and refined anisotropically by full-matrix least-squares methods using SHELXL-2013 101 (1,2,4,6,7) or CRYSTALS104 (3,[START_REF]E)-1-(5-Fluoro-1-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (81h) According to the general procedure (H[END_REF]8). Crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre with no's CCDC-1038980 through CCDC-1038987. This data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.

Identification code 25a

Empirical formula C29 H25 N O Formula weight 403.50 The alkynes were prepared via Sonogashira cross coupling or silylation of terminal alkynes.

Sonogashira cross-coupling (D):

To a dried round-bottomed flask under argon were added the alkyne, iodine derivative, copper iodide and DIPA. Then Pd(PPh 3 ) 2 Cl 2 was added and the solution was stirred at rt until TLC analysis indicated that the reaction had gone to completion (3 h). The reaction was filtered over Celite, eluting with AcOEt, and a saturated aqueous NH 4 Cl (50 mL) was added. The aqueous layer was extracted twice with CH 2 Cl 2 (50 mL), dried over MgSO 4 , filtered and concentrated. The crude products were purified by column chromatography with silica gel.

Silylation (E):

To a dried round-bottomed flask under argon was added the alkyne in distilled THF. The solution was cooled to -78 °C and n-BuLi was added dropwise. The solution was stirred for 1 h while being kept at -78 °C then TMSCl was added dropwise. The solution was stirred for 1 h more at -78 °C and then allowed to reach rt. The reaction was stirred until TLC analysis indicated that the reaction had gone to completion. The reaction was quenched with a saturated aqueous solution of NH 4 Cl (50 mL) and the aqueous layer was extracted twice with CH 2 Cl 2 (50 mL). The resulting organic layer was dried over MgSO 4 , filtered and concentrated.

((3,5-Dimethoxyphenyl)ethynyl)trimethylsilane

The general procedure (E) was applied to 1-ethynyl-3,5dimethoxybenzene (672.7 mg, 4.15 mmol, 1.0 eq.), n-BuLi (2.0 mL, 0.5 M in hexane, 4.98 mmol, 1.2 eq. ) and TMSCl (636.5 µL, 4.98 mmol, 1.2 eq.) in distilled THF (25 mL), provided the title compound as a beige solid (843.0 mg, 87 %).

(2E,3E)-4-(4-(tert-butyl)phenyl)-N-(4 methoxyphenyl)but-3-en-2-imine (31a) 109

According to the general procedure (A). Light yellow solid (65%).

(E)-4-methoxy-N-((E)-4-(p-tolyl)but-3-en-2-ylidene)aniline (31b) 21

According to the general procedure (A). Yellow solid (71%). To a sealed tube under argon were added Co(PMe 3 ) 4 (0.05 mmol, 0,018 mg), imine (0.5 mmol) and alkyne (0.5 -0.6 mmol). Degassed toluene (1 mL) was added and the resulting solution was heated in an oil bath at 170 °C for 1 h. The reaction mixture was then filtered through a plug of celite and washed with ethyl acetate (3 x 10 mL). The crude product was purified by silica chromatography (pre-treated with NEt 3 10% in pentane overnight) to yield the desired dihydropyridine product.

1-(4-Methoxyphenyl)-6-methyl-2,3,4-triphenyl-1,2-dihydropyridine (32a) 21

The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4phenylbut-3-en-2-ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and diphenylacetylene (82.6 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound (32a) as a yellow solid (179.9 mg, 99 %). mp: 74-76 °C.

1-(4-Methoxyphenyl)-6-methyl-2,3-diphenyl-4-(p-tolyl)-1,2-dihydropyridine (32b) 21

The general procedure (F) was applied to (E)- The general procedure (F) was applied to (2E,3E)-N,4-bis(4methoxyphenyl)but-3-en-2-imine (140.0 mg, 0.50 mmol, 1.0 eq.) and diphenylacetylene (82.6 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3, 156.7, 143.4, 141.1, 139.1, 138.7, 133.5, 133.4, 130.5 (2C)

4-(4-Chlorophenyl)-1-(4-methoxyphenyl)-6-methyl-2,3-diphenyl-1,2-dihydropyridine (32e) 21

The general procedure (F) was applied to (E)-N-((E)-4-(4chlorophenyl)but-3-en-2-ylidene)-4-methoxyaniline (142.9 mg, 0.50 mmol, 1.0 eq.) and diphenylacetylene (103.3 mg, 0.60 mmol, 1.2 eq.).

Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound (32e) as a yellow solid, (188.8 mg, 80 %). mp 64-66 °C. 143.2, 140.6, 140.0, 139.3, 138.8, 132.7, 131.8, 130.9 (2C), 129.4 (2C), 128.2 (2C), 128.1 (2C), 128.0 (2C), 127. 5, 127.0 (2C), 126.7 (2C), 125.9, 119.2, 114.3 (2C), 107.7, 69.9, 55.1, 19.5.

4-(4-Fluorophenyl)-1-(4-methoxyphenyl)-6-methyl-2,3-diphenyl-1,2-dihydropyridine (32f)

The general procedure (F) was applied to (2E,3E)-4-(4-fluorophenyl)-N-( 4-methoxyphenyl)but-3-en-2-imine (134.0 mg, 0.50 mmol, 1.0 eq.) and diphenylacetylene (82.6 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound (32f) as a yellow solid (207.6 mg, 93 %). mp 55-57 °C. (d,J = 245.4 Hz),156.9,143.2,140.7,139.1,138.9,137.1 (d,J = 3.2 Hz),132.9,131.4,130.9 (d,J = 8.0 Hz),129.5 (2C),128.1 (2C),127.8 (2C),127.4,127.0 (2C),126.9 (2C),126.5,125.6,118.7,114.8 (d,J = 21.2 Hz),114.1 (2C),107.6,69.7,55.4,20 0,143.0,142.0,140.2,139.8,138.8,132.9 (d,J = 1.5 Hz),132.5,131.4,130.5,130.1,129.5 (2C), 128.2 (2C), 128.2, 127.9 (2C), 127.5, 127.4 (q, J = 151.1 Hz), 127.0 (2C), 126.9 (2C), 123.1 (q, J = 3.9 Hz), 119.9, 114.1 (2C), 106. 5, 69.8, 55.4, 20.1. 19

4-(1-(4-Methoxyphenyl)-6-methyl-2,3-diphenyl-1,2-dihydropyridin-4-yl)benzonitrile (32h) 21

The general procedure (F) was applied to 4-((1E,3E)-3-((4methoxyphenyl)imino)but-1-en-1-yl)benzonitrile (138.0 mg, 0.50 mmol, 1.0 eq.) and diphenylacetylene (82.6 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound (32h) as an orange solid (224.4 mg, 99 %). mp 81-83 °C. 2, 120.2, 119.1, 114.1 (2C), 109.9, 105.8, 69.8, 55.4, 20.1.

Methyl 4-(1-(4-methoxyphenyl)-6-methyl-2,3-diphenyl-1,2-dihydropyridin-4-yl)benzoate (32i)

The general procedure (F) was applied to methyl 4-((1E,3E)-3-((4methoxyphenyl)imino)but-1-en-1-yl)benzoate (154.0 mg, 0.50 mmol, 1.0 eq.) and diphenylacetylene (82.6 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 90/10) afforded the title compound (32i) as a yellow solid (218.4 mg, 90 %). mp 162-164 °C. 1, 156.9, 146.3, 143.0, 140.3, 139.4, 138.8, 133.1, 129.5 (2C), 129.4 (2C), 129.3 (2C), 128.2 (2C), 128.0, 127.9 (2C), 127.4, 126.9 (2C), 126.8 (2C), 125.9, 119.7, 114.1 (2C), 106.9, 69.7, 55.4, 51.9, 20.0. IR (thin film): 3056,2950,1719,1507,1276,1242,1103,860,776,732

 max =

1-(4-Methoxyphenyl)-6-methyl-4-(naphthalen-1-yl)-2,3-diphenyl-1,2-dihydropyridine (32j)

The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4-(naphthalen-1-yl)but-3-en-2-ylidene)aniline (150.8 mg, 0.50 mmol, 1.0 eq.) and diphenylacetylene (103.3 mg, 0.60 mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound, (32j) as an orange solid and mixture of rotamers (150.4 mg, 0.31 mmol, 62 %). mp 80-82 °C, 1 H NMR (400 MHz, Acetone-d 6 ) 1H),8.00 (ddd,J = 10.4,2.7,1.9 Hz,1H),1H),1H),1H),2H),2H),2H),6H),6H),2H),2H) 4, 158.3, 145.0, 144.7, 142.3, 141.8, 140.9, 140.5, 140.3, 139.9, 139.9, 139.2, 135.2, 135.1, 133.9, 133.7, 133.0, 129.9, 129.7, 129.5 (2C), 129.4 (2C), 129.4 (2C), 129.3 (2C), 129.0 (2C), 128.8 (2C), 128.6, 128.5, 128.3, 128.3 (2C), 128.1, 128.0, 127.9, 127.7 (2C), 127.6 (2C), 127.5, 127.4 (2C), 127.1, 127.0, 126.9, 126.9, 126.9, 126.8, 126.8, 126.7, 126.7, 124.8, 123.0, 122.8, 115.7 (2C), 115.5 (2C), 115.5, 112.3, 109.9, 71.0, 70.5, 56.1, 20.6, 20.4

4-(Benzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)-6-methyl-2,3-diphenyl-1,2-dihydropyridine (32k)

The general procedure (F) was applied to (E)-N-((E)-4-(benzo [d][1,3]dioxol-5-yl)but-3-en-2-ylidene)-4-methoxyaniline (147.6 mg, 0.50 mmol, 1.0 eq.) and diphenylacetylene (103. 0, 148.3, 147.4, 144.3, 141.9, 139.9, 139.7, 136.1, 134.5, 130.2 (2C), 129.0 (2C), 128.7 (2C), 128.3, 128.0 (2C), 127.4 (2C), 126.6, 123.6, 119.1, 115.1 (2C), 110.6, 109.8, 108.8, 101.9, 70.9, 55.8, 20.2.

1-(4-Methoxyphenyl)-2,3,4,6-tetraphenyl-1,2-dihydropyridine (32l)

The general procedure (F) was applied to (Z)-N-((E)-1,3diphenylallylidene)-4-methoxyaniline (156.7 mg, 0.50 mmol, 1.0 eq.) and diphenylacetylene (82.6 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 98/2) afforded the title compound (32l) as a yellow solid (179.9 mg, 99 %). mp 89-91 °C. 0, 142.6, 140.7, 140.5, 140.4, 137.0, 134.4, 129.7 (2C) 1, 142.0, 140.8, 140.7, 139.7, 132.8, 129.8 (2C), 129.4, 129.1 (2C), 128.2 (2C), 127.9 (4C), 127. 4, 126.5 (2C), 126.4, 125.9, 121.6, 118.9 (2C), 114.6 (2C), 106.5, 65.4, 55.6.

1-(4-Methoxyphenyl)-6-methyl-3,4-diphenyl-2-(trimethylsilyl)-1,2-dihydropyridine (3ab)

The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4-phenylbut-3-en-2ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and trimethyl(phenylethynyl)silane (98.2 µL, 0.50 mmol, 1.0 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound 32n as an orange oil and mixture of regioisomers (91/9 as determined by 1 H NMR), (159.6 mg, 62 %). Characteristic signals for each isomer have been attributed where possible.

1 H NMR (400 MHz, CDCl 3 ) Major Isomer 32n: 2H),7.11 (app. d,J = 1.8 Hz,2H),7.09 (m,2H),4H),2H),2H), 5.76 (q, J = 1.0 Hz, 1H), 4.31 (s, 1H), 3.83 (s, 3H), 1.88 (d, J = 1.1 Hz, 3H), 0.08 (s, 9H).

Characteristic Peaks for Minor Isomer: 5.32 (s, 1H), 5.24 (q, J = 0.9 Hz, 1H), 3.82 (s, 3H), 0.18 (s, 9H).

13 C NMR (100 MHz, CDCl 3 ) Major Isomer 32n: δ 157. 0, 143.1, 142.5, 142.2, 142.0, 132.5, 130.7 (2C), 130.3 (2C), 129.4 (2C), 129.0 (2C), 127.4, 126.8, 126.0 (2C), 125.3, 117.8, 115.5 (2C), 65.1, 56.9, 20.9, -0.01 (3C) 3, 145.7, 141.8, 141.0, 140.3, 133.5, 129.5 (2C), 128.9, 127.8, 128.7 (2C), 127.5, 126.9, 125.8, 124.9 (2C), 124.5 (q, J = 3.7 Hz), 123. 1, 121.1, 115.9, 114.2 (2C), 63.4, 54.8, 18.8, -2.11 (3C). The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4phenylbut-3-en-2-ylidene)aniline (92.9 mg, 0.37 mmol, 1.0 eq.) and ((3,5-dimethoxyphenyl)ethynyl)trimethylsilane (91.6 mg, 0.37 mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 90/10) afforded the title compound (32p) as an orange oil (154.0 mg, 83 %). Note: other regioisomer not detected. 2, 144.1, 142.6, 142.4, 142.0, 132.9, 129.9 (2C), 129.3 (2C), 127.3, 125.7 (2C), 124.2, 117.7, 115.4 (2C), 108.5 (2C), 98.9, 64.5, 56.1, 55.6 (2C), 20.1, -0.6 (3C). IR (thin film):  max = 2998, 2897, 1598, 1504, 1243, 1204, 1178, 836 6, 156.9, 142.5, 141.9, 141.5, 137.3, 134.0, 132.4, 130.0, 129.9 (2C), 129.8, 129.5, 129.1 (2C), 128.2, 127.0, 126.9, 125.4 (2C), 124.9, 119.5, 117.6, 115.2 (2C), 106.6, 64.4, 55.9, 55.7, 19.9, -0.91 (3C)

1,3-Bis(4-methoxyphenyl)-6-methyl-4-phenyl-2-(trimethylsilyl)-1,2-dihydropyridine (32r)

The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4phenylbut-3-en-2-ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and ((4-methoxyphenyl)ethynyl)trimethylsilane (128.2 µL, 0.60 mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pretreated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 90/10) afforded the title compound (32r) as an orange oil (147.9 mg, 65%). Note: other regioisomer not detected. 1 H NMR (400 MHz, Acetoned 6 ) δ 7.20 -7.16 (m, 2H), 7.13 -7.07 (m, 4H), 6.94 -6.88 (m, 3H), 6.81 -6.75 (m, 2H), 6.65 -6.58 (m, 2H) 0, 157.0, 142.8, 142.3, 141.3, 134.2, 131.6, 131.4 (2C), 130.0 (2C), 129.2 (2C), 127. 1, 125.4 (2C), 125.0, 118.0, 115.4 168 (2C), 114.4 (2C), 64.7, 56.1, 55.6, 20.0, -0.7 (3C) 2, 151.2, 147.3, 142.7, 142.1, 141.3, 137.8, 136.7, 134.3, 129.8 (2C), 129.3 (2C), 127.4, 125.7 (2C), 123.6, 120.3, 117.1, 115.2 (2C), 64.2, 55.8, 19.9, -1.06 (3C). IR (thin film): The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4phenylbut-3-en-2-ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and 0, 155.4, 148.6, 142.3, 141.4, 140.9, 134.4, 134.0, 129.4, 128.9 (2C), 128.3 (2C), 126.6, 124.8 (2C), 122.9, 121.0, 119.5, 113.9 (2C), 59.9, 55.5, 19.6, -1.0 The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4phenylbut-3-en-2-ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and 1,2-di(pyridin-4-yl)ethyne (86.7 mg, 0.60 mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 80/20) afforded the title compound (32u) as a yellow oil (187.7 mg, 87 %). 7, 151.4, 150.6 (2C), 150.0, 149.6, 148.2, 141.4, 139.9, 138.1, 130.6 (2C), 129.0 (2C), 128.6 (2C), 127.6, 126.9 (2C), 123.7, 121.7, 114.6 (2C), 113.8, 108.4, 77.3, 68.1, 55.6, 20

 max = 3024,

1-(4-Methoxyphenyl)-6-methyl-3,4-diphenyl-2-propyl-1,2-dihydropyridine (32v)

The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4phenylbut-3-en-2-ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and pent-1-yn-1-ylbenzene (79.6 µL, 0.60 mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound (3aj) as a yellow oil and mixture of regioisomers (95/5 as determined by 1 8, 127.7, 126.0, 125.8 (2C), 125.4, 123.2, 114.1 (2C), 111.2, 68.1, 54.4, 34.0, 20.5, 19.3, 19.3, 14

2-Ethyl-1-(4-methoxyphenyl)-6-methyl-3,4-diphenyl-1,2-dihydropyridine (32w) 21

The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4-phenylbut-3-en-2ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and but-1-yn-1-ylbenzene (85.4 µL, 0.60 mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound (32w) and its minor isomer as a yellow oil and mixture of regioisomers (80/20 as determined by 1 H NMR), (100 mg, 52 %). Characteristic signals for each isomer have been attributed where possible. 13 C NMR (100 MHz, CDCl 3 ) δ 156. 6, 156.1, 144.0, 141.4, 141.1, 141.0, 140.1, 139.4, 137.3, 137.2, 131.9, 129.2, 129.1, 128.6, 128.1, 127.9, 127.8, 127.6, 127.3, 127.2, 127.0, 126.3, 126.1, 125.8, 125.3, 123.3, 122.6, 114.0, 113.9, 110.7, 105.7, 69.0, 67.6, 55.5, 55.4, 24.3, 20.1, 19.7, 13.4, 10.7. Note signals for the major and minor isomer could not be distinguished.

1-(4-Methoxyphenyl)-3,6-dimethyl-2,4-diphenyl-1,2-dihydropyridine (32x) 21

The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4-phenylbut-3-en-2ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and prop-1-yn-1-ylbenzene (75.3 µL, 0.60 mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound (32x) and its minor isomer as a yellow oil and mixture of regioisomers (52/48 as determined by 1 H NMR), (83 mg, 45 %). Characteristic signals for each isomer have been attributed where possible.

1 H NMR (400 MHz, CDCl 3 ) Major isomer (32x): δ 7.50 -7.46 (m, 2H), 7.38 -7.28 (m, 3H), 7.20 -6.94 (m, 5H), 6.88 -6.83 (m, 2H), 6.82 -6.78 (m, 2H), 5.45 (q, J = 1.0 Hz, 1H), 4.58 (q, J = 6.4 Hz, 1H), 3.81 (s, 3H), 1.92 (s, 3H), 1.44 (d,J = 6.5 Hz,3H).

Characteristic peaks for minor Isomer (32x): 5.14 (s, 1H), 5.00 (s, 1H), 1.80 (s, 3H), 1.71 (s, 3H).

13 C NMR (100 MHz, CDCl 3 ) δ 156. 6, 156.4, 144.0, 141.3, 141.2, 140.6, 139.4, 139., 137.4, 137.3, 132.1, 131.2, 129.2, 128.8, 128.3, 127.9, 127.8, 127.6, 127.3, 127.2, 126.8, 126.3, 126.2, 126.1, 125.3, 121.2, 117.7, 114.0, 113.8, 107.0, 104.2, 71.3, 62.7, 55.5, 20.2, 19.9, 18.7, 17.4. Note signals for the major and minor isomer could not be distinguished.

1-(4-Methoxyphenyl)-6-methyl-4-phenyl-2,3-dipropyl-1,2-dihydropyridine (32y)

The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4phenylbut-3-en-2-ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and 4octyne (88.0 µL, 0.60 mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 98/2) afforded the title compound (32y) as a brown oil (180.1 mg, 99 %). 4, 141.3, 140.4, 134.7, 130.4, 128.8 (2C), 127.6 (2C), 125.9, 125.0 (2C), 123.4, 113.7 (2C), 110.7, 64.6, 55.2, 33.4, 32.8, 21.9, 19.3, 19.0, 14.2, 13.5. The general procedure (F) was applied to (E)-N-((E)-4-(benzo [d][1,3]dioxol-5-yl)but-3-en-2-ylidene)-4-methoxyaniline (147.6 mg, 0.50 mmol, 1.0 eq.) and 4-octyne (88.0 µL, 0.60 mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 90/10) afforded the title compound (32z) as a yellow powder (151.9 mg, 75 %). mp: 75-78 °C. 2, 148.6, 147.3, 141.5, 136.5, 136.1, 131.7, 126.3 (2C), 124.2, 123.2, 115.2 (2C), 112.2, 110.4, 108.9, 102.1, 66.03, 56.0, 34.7, 34.0, 23.0, 20.2, 20.1, 15.1, 14.4 . IR (thin film):  max = 2956, 2931, 1506, 1485, 1297, 1103, 832 cm -1 . HRMS (ESI): calculated for C 26 H 30 NO 3 [M-H] + : 404.2283; found 404.2220.

4-(Benzo

General procedure G: Desilylation of α-silyl dihydropyridines

Following procedure (F), the crude reaction material was transferred to a dried roundbottomed flask. Distilled THF was added and the solution was cooled to 0 °C. TBAF was added dropwise and the solution was stirred until TLC analysis indicated that the reaction has gone to completion. The solution was quenched with saturated NH 4 Cl aqueous solution, extracted twice with AcOEt. The resulting organic phase was washed with saturated NaCl aqueous solution, dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by silica chromatography (pre-treated with NEt 3 10% in pentane overnight) to yield the desired product.

1-(4-Methoxyphenyl)-6-methyl-3,4-diphenyl-1,2-dihydropyridine (32n')

The general procedure (G) was applied to 1-(4-methoxyphenyl)-6methyl-3,4-diphenyl-2-(trimethylsilyl)-1,2-dihydropyridine (32n). The crude product was concentrated and transferred, then THF (5 mL) was added. TBAF (1.0 M in THF, 0.55 mL, 1.1 eq) was added dropwise. Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 95/5) afforded the title compound (32n') as a red oil (80 mg, 45 %). 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.28 -7.25 (m, 2H), 7.16 (m, 2H), 7.14 -7.08 (m, 4H), 6.99 -6.94 (m, 3H), 6.87 -6.83 (m, 3H), 6.81 (s, 1H), 4.63 -4.54 (m, 2H), 3.68 (s, 3H), 1.43 (s, 3H). 13 C NMR (100 MHz, Acetone-d 6 ) δ, 159. 3, 149.2, 140.5, 138.1, 133.4, 131.6, 129.5 (2C), 129.3 (2C), 128.9 (2C), 128.2 (2C), 126. 6, 125.8, 125.2 (2C), 115.2 (2C), 111.5, 104.4, 55.8, 43.4, 19.7

1-(4-Methoxyphenyl)-6-methyl-4-phenyl-3-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine (32o')

The general procedure (G) was applied 1-(4-methoxyphenyl)-6-methyl-4-phenyl-3-(4-(trifluoromethyl)phenyl)-2-(trimethylsilyl)-1,2-dihydropyridine (32o). The crude product was concentrated and transferred, then THF (5 mL) was added. TBAF (1.0 M in THF, 0.55 mL, 1.1 eq) was added dropwise. Silica gel chromatography on buffered silica (pretreated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 90/10) afforded the title compound (32o') as a red oil (147 mg, 70 %). 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 -7.18 (m, 8H), 7.13 -7.07 (m, 3H), 6.89 (s, 1H), 6.87 -6.81 (m, 2H), 4.74 -4.55 (m, 2H), 3.74 (s, 3H), 1.50 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158. 4,147.6,143.1 (d,J = 1.5 Hz),136.9,132.6,132.4,128.8 (2C),128.7 (2C),127.1 (2C),126.8,126.3,126.2,125.0 (q, J = 3.8 Hz), 124.1 (2C), 122.7, 114.4 (2C), 109.1, 103.9, 55.5 (d,J = 4.6 Hz),42.5,19.6 (d,J = 3.6 Hz). 19 F NMR (376 MHz, CDCl 3 ) δ -62.9. IR (thin film):  max = 2924, 2838, 1678, 1598, 1508, 1320, 1226, 1111, 1068, 758, 734 cm -1 HRMS (ESI): calculated for C 26 H 22 F 3 NO [M-H] + : 420.1470; found 420.1560.

1-(4-Methoxyphenyl)-6-methyl-3,4-diphenyl-1,2-dihydropyridine (32p')

The general procedure (G) was applied to 3-(3,5dimethoxyphenyl)-1-(4-methoxyphenyl)-6-methyl-4-phenyl-2-(trimethylsilyl)-1,2-dihydropyridine (32p). The crude product was concentrated and transferred, then THF (5 mL) was added. TBAF (1.0 M in THF, 0.55 mL, 1.1 eq) was added dropwise. Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 90/10) afforded the title compound (32p') as a red oil as a red oil (128.2 mg, 62 %). 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.45 -7.41 (m, 2H), 7.30 -7.23 (m, 4H), 7.15 -7.10 (m, 1H), 7.00 -6.97 (m, 3H), 6.50 (t, J = 2.1 Hz, 2H), 6.19 -6.16 (m, 1H), 4.71 (d, J = 5.5 Hz, 2H), 3.83 (s, 3H), 3.64 (s, 6H), 1.58 (s, 3H). 13 C NMR (100 MHz, Acetone-d 6 ) δ 161. 7, 159.4, 149.6, 142.8, 138.1, 133.5, 132.0, 129.7 (2C), 129.4 (2C), 128.3 (2C), 126.8, 115.3 (2C), 111.6, 104.7, 103.7 (2C), 98.2, 55.9, 55.7, 55.4 (2C), 43.8, 19.9. IR (thin film):  max = 2999, 2837, 1952, 1510, 1246, 1154 cm -1 . HRMS (ESI): calculated for C 27 H 27 NO 3 [M-H] + : 412.1907; found 412.1927.

3-(6-Methoxynaphthalen-2-yl)-1-(4-methoxyphenyl)-6-methyl-4-phenyl-1,2-dihydropyridine (32q')

The general procedure (G) was applied to 3-(6methoxynaphthalen-2-yl)-1-(4-methoxyphenyl)-6-methyl-4phenyl-2-(trimethylsilyl)-1,2-dihydropyridine (32q). The crude product was concentrated and transferred, then THF (5 mL) was added. TBAF (1.0 M in THF, 0.55 mL, 1.1 eq) was added dropwise. Silica gel chromatography on buffered silica (pretreated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 90/10) afforded the title compound (32q') as a red oil (166.9 mg, 77 %). 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.63 (s, 1H), 7.59 -7.46 (m, 5H), 7.31 -7.23 (m, 4H), 7.11 (dd, J = 9.4, 2.0 Hz, 3H), 7.04 -6.98 (m, 3H), 4.90 (d, J = 4.9 Hz, 1H), 4.76 (dd, J = 5.0, 1.1 Hz, 1H), 3.83 (s, 6H), 1.60 (s, 3H). 13 C NMR (100 MHz, Acetone-d 6 ) δ 159. 4, 158.1, 149.4, 138.2, 135.7, 133.8, 133.5, 131.6, 130.2, 129.9, 129.7 (2C), 129.4 (2C), 128.4 (2C), 127.4, 126.7, 124.8, 123.2, 119.3, 115.3 (2C), 111.7, 106.6, 104.5, 55.9, 55.6, 43.5, 19.9. IR (thin film):  max = 3060, 2960, 1629, 1510, 1245, 1030 cm -1 . HRMS (ESI): calculated for C 30 H 26 NO 2 [M-H] + : 432.1958; found 432.2071.

1,3-Bis(4-methoxyphenyl)-6-methyl-4-phenyl-1,2-dihydropyridine (32r')

The general procedure (G) was applied to 1,3-bis(4methoxyphenyl)-6-methyl-4-phenyl-2-(trimethylsilyl)-1,2dihydropyridine (32r). The crude product was concentrated and transferred, then THF (5 mL) was added. TBAF (1.0 M in THF, 0.55 mL, 1.1 eq) was added dropwise. Silica gel chromatography on buffered silica (pre-treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc 90/10) afforded the title compound (32r') as a red oil (86 mg, 40 %). 1 H NMR (400 MHz, CDCl 3 ) δ 7.40 -7.36 (m, 2H), 7.33 -7.27 (m, 2H), 7.16 (m, 5H), 6.94 -6.89 (m, 2H), 6.77 (s, 1H), 6.72 -6.67 (m, 2H), 4.75 -4.59 (m, 2H), 3.83 (s, 3H), 3.71 (s, 3H), 1.59 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158. 0, 157.4, 148.2, 137.4, 132.7, 132.2, 129.6, 128.6 (2C), 128.6 (2C), 127.2 (2C), 125.9, 125.7 (2C), 114.2 (2C), 113.5 (2C), 110.5, 103.0, 55.5, 55.1, 43.1, 19.6. IR (thin film):  max = 3000, 2955, 2923, 1608, 1508, 1246, 1179, 1033, 836, 755 cm -1 . HRMS (ESI): calculated for C 26 H 25 NO 2 [M-H] + : 382.1802; found 382.1797.

Experimental section for the intra-intermolecular C2-Alkylation and alkenylation of indoles

General procedure (H): Preparation of indole precursors:

Indole precursors were prepared through N-alkylation of indole-3-carboxaldehyde with methyl iodide, benzyl bromide or alkyl bromide with NaH as base in DMF. The corresponding carbonyl compounds were condensed with para-anisidine in toluene with MS 4Å to afford the corresponding indole substrates which were purified by precipitation from pentane/Et 2 O. The 1 H NMR spectrum of all compounds showed good agreement with the literature data.

(E)-N-(4-Methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine (47a) 31

According to the general procedure (H). Yellow Solid (64%). 3, 152.8, 146.6, 136.9, 134.0, 133.0, 126.1, 123.1, 122.2, 121.8, 121.4 (2C), 118.0, 115.1, 114.8 (2C), 109.6, 55.7, 46.3, 34.2.

(E)-1-(1-(But-3-en-1-yl)-1H-indol-3-yl)-N-(4-methoxyphenyl)ethan-1-imine (47b)

According to the general procedure (H). Orange solid (53%). mp: 69-71 °C. 8, 155.4, 145.4, 137.0, 134.2, 131.0, 123.5, 122.7, 121.3 (2C), 117.8, 117.1, 116.6, 114.1 (2C), 109.4, 60.4, 55.5, 46.2, 34.3, 17.9

(E)-1-(1-((E)-Hex-3-en-1-yl)-1H-indol-3-yl)-N-(4methoxyphenyl)methanimine (47c) 31

According to the general procedure (H). Pale yellow solid (51%). 1, 153.0, 146.8, 136.9, 136.0, 132.9, 126.2, 124.3, 123.4, 122.6, 122.0, 121.4 (2C), 115.0, 114.3 (2C), 109.8, 55.5, 47.0, 33.6, 25.6, 13.4.

(E)-1-(1-((E)-Hex-3-en-1-yl)-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (47d) 31

According to the general procedure (H). Yellow solid (49%). 3, 128.1, 127.3 (2C), 126.5, 126.4, 122.5, 122.2 (2C), 121.9, 115.6, 114.4 (2C), 110.4, 55.6, 50.7.

(E)-1-(1,7-Dimethyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (81c)

According to the general procedure (H). Pale yellow solid (53%). mp: 142-144 °C.

(E)-N-(4-Methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine

(81d) 79 According to the general procedure (H). White solid (33%). 0, 155.7, 153.2, 146.9, 134.2, 133.2, 126.5, 122.1 (2C), 114.6, 114.3, 113.9 (2C), 110.6, 104.0, 56.3, 55.5, 33.5.

(E)-1-(5-(Benzyloxy)-1-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (81e)

According to the general procedure (H). White solid (44%). mp: 157-159 °C. 2, 154.8, 152.7, 146.7, 137.5, 134.3, 133.1, 128.5 (2C), 127.8 (2C), 127.7, 126.5, 121.8 (2C), 114.7, 114.3 (2C), 114.0, 110.2, 105.4, 70.7, 55.5, 33.4 The characteristic peaks for the minor isomer as determined by 1 H NMR are as follows: δ 6.23 (s, 1H), 3.83 (s, 3H), 3.41 (s, 3H).

(Z)-1-Methyl-2-(1-phenylhex-1-en-1-yl)-1H-indole-3-carbaldehyde (82ac)
A modified version of procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine (81a, 132.0 mg, 0.50 mmol, 1.0 eq.) and hex-1-yn-1-ylbenzene (95 mg, 0.60 mmol, 1.2 eq.). The resulting mixture was quenched with 3M HCl (1.0 mL). The resulting mixture was stirred at room temperature for 1 h, and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over MgSO 4 and concentrated under reduced pressure. Silica gel chromatography (eluent pentane/EtOAc 80/20) afforded the title compound (82ac) as a yellow oil (218.7 mg, 65 %) as a mixture of stereoisomers 88/12 anti/syn as determined by 1 1, 149.3, 138.9, 138.0, 129.1, 128.8, 128.6, 128.0 (2C), 127.9, 125.9 (2C), 125. 1, 123.6, 123.1, 122.2, 115.8, 109.7, 31.3, 30.3, 22.3, 13.8 The characteristic peaks for the minor isomer as determined by 1 H NMR are as follows: δ 9.89 (s, 1H), 6.06 (t, J = 7. 5 Hz,1H).

(E)-N-(4-Methoxyphenyl)-1-(1-methyl-2-((Z)-1-(pyridin-3-yl)-2-(trimethylsilyl)vinyl)-1H-indol-

3-yl)methanimine (82ad)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine (81a, 132.0 mg, 0.50 mmol, 1.0 eq.) and 3-((trimethylsilyl)ethynyl)pyridine (105.1 mg, 0.60 mmol, 1.2 eq.). Silica gel chromatography (eluent pentane/EtOAc 75/25) afforded the title compound (82ad) as a yellow oil (217.3 mg, 99 %). 3, 154.3, 150.4, 148.3, 147.6, 1.68 -1.19 (m, 7H), 1.06 (m, 1H), 0.97 -0.90 (m, 3H), 0.90 -0.82 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 157. 1, 154.0, 147.3, 146.2, 137.6, 136.0, 130.1, 125.6, 122.7, 122.6, 121.8 (2C), 121.6, 114.3 (2C), 112.1, 109.2, 55.5, 38.6, 31.5, 30.4, 30.3, 29.5, 22.5, 22.3, 13.9, 13.8. IR (thin film): 2926,1614,1498,1463,1436,1240,1103,747 The characteristic peaks for the minor isomer as determined by 1 H NMR are as follows: δ 8.63 (s, 1H), 5.76 (s, 1H).

 max =

General procedure (C) : Intermolecular hydroarylation of alkenes: (E)-N-(4-Methoxyphenyl)-1-(1-methyl-2-(1-phenylethyl)-1H-indol-3-yl)methanimine (82ag)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1methyl-1H-indol-3-yl)methanimine (81a, 132 mg, 0.50 mmol, 1.0 eq.) and styrene (62 mg, 0.6 mmol, 1.2 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound (82ag) as a yellow foam (182 mg, 99 %). mp: 59-61 °C. 2, 153.0, 148.2, 147.1, 141.9, 137.6, 128.6 (2C), 127.1 (2C), 126.5, 125.9, 122.7, 122.2, 121.8 (2C), 121.6, 114.2 (2C), 111.8, 108.8, 55.5, 34.5, 30.9, 18.6

(E)-N-(4-Methoxyphenyl)-1-(1-methyl-2-(1-(p-tolyl)ethyl)-1H-indol-3-yl)methanimine (82ah)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine (81a, 132 mg, 0.50 mmol, 1.0 eq.) and 1-methyl-4-vinylbenzene (70 mg, 0.6 mmol, 1.2 eq.).

Silica gel chromatography on silica (eluent pentane/EtOAc 90/10) afforded the title compound (82ah) as a yellow oil (182 mg, 99 %). 7.27 (m, 3H), 7.20 -7.12 (m, 6H), 6.95 -6.89 (m, 2H), 5.10 (q, J = 8 Hz, 1H), 3.83 (s, 3H), 3.49 (s, 3H), 2.35 (d, J = 0.7 Hz, 3H), 1.85 (d, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 157. 2, 153.1, 148.5, 147.2, 138.9, 137.6, 136.1, 129.3 (2C), 127.0 (2C), 125. 9, 122.6, 122.3, 121.8 (2C), 121.6, 114.2 (2C), 111.8, 108.8, 55.5, 34.2, 30.9, 20.9, 18.7

(E)-N-(4-Methoxyphenyl)-1-(2-(1-(3-methoxyphenyl)ethyl)-1-methyl-1H-indol-3-

yl)methanimine (82ai)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine (82a, 132 mg, 0.50 mmol, 1.0 eq.) and 1-methoxy-3-vinylbenzene (68 mg, 0.6 mmol, 1.2 eq.).

Silica gel chromatography on silica (eluent pentane/EtOAc 85/15) afforded the title compound (82ai) as a yellow oil (179.6 mg, 90 %). 0, 157.2, 152.9, 148.0, 147.2, 143.7, 137.6, 129.7, 125.9, 122.7 (2C), 122.2, 121.8, 121.6, 119.6, 114.3 (2C), 113.5, 111.8, 111.3, 108.8, 55.5, 55.2, 34.5, 31.0, 18.6

(E)-N-(4-Methoxyphenyl)-1-(2-(1-(2-methoxyphenyl)ethyl)-1-methyl-1H-indol-3yl)methanimine (82aj)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3yl)methanimine (81a, 132 mg, 0.50 mmol, 1.0 eq.) and 1-methoxy-2-vinylbenzene (83 mg, 0.6 mmol, 1.2 eq.). Silica gel chromatography on silica (eluent pentane/EtOAc 90/10) afforded a mixture of the title compound (82aj) and the product of linear addition as a yellow foam (169 mg, 85 %). The branched/linear ratio was determined to be 76/24 by 1 2, 157.0, 154.0, 149.1, 147.3, 137.1, 130.8, 128.1, 127.2, 126.0, 122.8, 122.2, 121.9 (2C), 121.8, 121.4, 120.4, 114.1 (2C), 111.0, 110.8, 108.7, 55.4, 31.0, 30.1, 19.8

(E)-1-(2-(1-(4-Fluorophenyl)ethyl)-1-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (82ak)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine (81a, 132 mg, 0.50 mmol, 1.0 eq.) and 1-fluoro-4-vinylbenzene (73 mg, 0.6 mmol, 1.2 eq.). Silica gel chromatography on silica (eluent pentane/EtOAc 90/10) afforded the title compound (82ak) as a yellow oil (162.6 mg, 84 %). 3, 152.7, 147.7, 147.1, 137.7 (d, J = 3.2 Hz), 137.6, 130.0 (d, J = 7.9 Hz), 128.6 (d, J = 8.0 Hz), 125.9, 122.8, 122.2, 121.8 (2C), 121.7, 115.6, 115.3, 114.3 (2C), 111.8, 108.8, 55.5, 33.9, 30.9, 18.8. 19

(E)-N-(4-Methoxyphenyl)-1-(1-methyl-2-(1-(naphthalen-2-yl)ethyl)-1H-indol-3yl)methanimine (82al)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine (81a, 132 mg, 0.50 mmol, 1.0 eq.) and 2-vinylnaphthalene (93 mg, 0.6 mmol, 1.2 eq.). Silica gel chromatography on silica (eluent pentane/EtOAc 90/10) afforded the title compound (82al) as a yellow oil (136.0 mg, 65 %).

(E)-1-(1-Benzyl-2-(1-phenylethyl)-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (82bg)

The general procedure (C) was applied to

(E)-1-(1-benzyl-1H-indol-3- yl)-N-(4-

(E)-1-(1,7-Dimethyl-2-(1-phenylethyl)-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (82cg)

The general procedure (C) was applied (E)-1- (1,7-dimethyl-1H-indol-3yl)-N-(4-methoxyphenyl)methanimine (81c, 139 mg, 0.50 mmol, 1.0 eq.) and styrene (62 mg, 0.6 mmol, 1.2 eq.). Silica gel chromatography (eluent pentane/EtOAc 80/20) afforded the title compound (82cg) as a yellow oil (96 mg, 50 %). 126.4, 126.9, 126.2, 121.8 (2C), 121.6, 120.6, 120.1, 114.2 (2C), 111.7, 55.5, 34.3, 34.1, 20.7, 18.3

(E)-1-(2-(3-Cyclohexylpropyl)-1-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (82ar)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1methyl-1H-indol-3-yl)methanimine (81a, 132 mg, 0.50 mmol, 1.0 eq.) and allylcyclohexane (124.0 mg, 1.00 mmol, 2.0 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound (82ar) as a yellow oil (117 mg, 61 %). 1, 152.8, 147.4, 146.6, 137.3, 125.9, 122.3, 121.9, 121.8 (2C), 121.5, 114.3 (2C), 111.2, 108.8, 55.5, 37.4, 37.1, 33.3 (2C), 29.7, 27.4, 26.6, 26.3 (2C)

(E)-N-(4-Methoxyphenyl)-1-(1-methyl-2-(2-(trimethylsilyl)ethyl)-1H-indol-3-yl)methanimine (82as)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine (81a, 132 mg, 0.50 mmol, 1.0 eq.) and trimethylvinylsilane (60 mg, 0.6 mmol, 1.2 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound (82as) as a yellow solid (180 mg, 99 %). mp 119-121 °C. 9, 154.2, 150.7, 149.2, 139.0, 127.9, 124.1, 123.6 (2C), 123.4, 123.3, 116.1 (2C), 111.7, 110.6, 57.3, 31.4, 20.8, 19.6, 0.0 (3C)

(E)-1-(6-Chloro-1-methyl-2-(2-(trimethylsilyl)ethyl)-1H-indol-3-yl)-N-(4methoxyphenyl)methanimine (82is)

The general procedure (C) was applied to (E)-1-(6-chloro-1methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (81i, 149 mg, 0.50 mmol, 1.0 eq.) and trimethylvinylsilane (0.6 mg, 0.6 mmol, 1.2 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound (82is) as a yellow oil (109 mg, 55 %). 2, 151.9, 149.3, 147.0, 137.7, 128.2, 124.5, 122.7, 121.9, 121.7 (2C), 114.3 (2C), 110.0, 109.0, 55.5, 29.6, 18.9, 17.8, -1.8 (3C). IR (thin film):  max = 2950, 1615, 1568, 1377, 1104, 912 cm -1 . HRMS (ESI): calculated for C 22 H 28 N 2 OSiCl [M+ H] + : 399.1654; found 399.1668.

General procedure (I): Intramolecular hydroarylation of alkenes:

To a sealed tube under argon were added Co(PMe 3 ) 4 (1 mol %) and imine (0.5mmol). Degassed toluene (1 ml) was added and the resulting solution was heated at 110 °C for 1 h in the microwave (absorption level normal). The reaction mixture was then filtered through a plug of celite washing with ethyl acetate (3 x 10 mL). The crude product was purified by silica chromatography to yield the desired product.

(E)-N-(4-Methoxyphenyl)-1-(1-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)methanimine (83a)

The general procedure (I) was applied to (E)-1-(1-(but-3-en-1yl)-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (47a, 152 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound (83a) as a yellow oil (189 mg, 95 %). 1 H NMR (400 MHz, CDCl 3 ) δ 8.75 (s, 1H), 8.56 -8.43 (m, 1H), 7.34 -7.17 (m, 5H), 7.03 -6.90 (m, 2H), 4.19 (m, 1H), 4.07 (m, 1H), 3.87 (s, 3H), 3.70 (m, 1H), 2.89 (m, 1H), 2.35 -2.24 (m, 1H), 1.54 (d, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 157. 1, 154.1, 152.1, 147.3, 132.9, 130.5, 122.1, 122.0, 121.8 (2C), 121.3, 114.3 (2C), 109.6, 106.8, 55.5, 43.3, 36.0, 32.7, 20.1. IR (thin film):  max = 3050, 1600, 1565, 1475, 1457, 750 cm -1 . HRMS (ESI): calculated for C 20 H 21 N 2 O [M+ H] + : 305.1648; found 305.1657. -2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)ethan-1-one (83b) A modified version of general procedure (I) was applied to 4-methoxyphenyl)ethan-1-imine (47b, 160 mg, 0.50 mmol, 1.0 eq.). After the reaction the resulting mixture was quenched with 3M HCl (1.0 mL). The resulting mixture was then stirred at room temperature for 1 h, and then extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over MgSO 4 and concentrated under reduced pressure. Silica gel chromatography (eluent pentane/EtOAc 80/20) afforded the title compound (83b) as a yellow oil (91 mg, 85 %). 1 H NMR (400 MHz, CDCl 3 ) δ 8.25 -8.10 (m, 1H), 7.40 -7.17 (m, 3H), 4.16 (m, 2H), 3.80 (m, 1H), 2.89 (m, 1H), 2.63 (s, 3H), 2.40 -2.29 (m, 1H), 1.44 (d, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 156. 8, 132.4, 130.5, 122.2, 122.1 (2C), 121.7, 109.9 (2C), 42.9, 35.2, 34.1, 29.7, 19

1-(1-Methyl

(E)-1-(1- (but-3-en-1-yl)-1H-indol-3-yl)-N-(

(E)-N-(4-Methoxyphenyl)-1-(1-propyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)methanimine (83c)

The general procedure (I) was applied to 4-methoxyphenyl)methanimine (47c, 166 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound (83c) as a yellow oil (164 mg, 99 %). 1 H NMR (400 MHz, CDCl 3 ) δ 8.60 (s, 1H), 8.42 -8.31 (m, 1H), 7.18 -7.10 (m, 5H), 6.91 -6.79 (m, 2H), 4.10 -3.94 (m, 2H), 3.75 (s, 3H), 3.56 -3.46 (m, 1H), 2.80 -2.67 (m, 1H), 2.34 -2.25 (m, 1H), 1.93 -1.82 (m, 1H), 1.59 (m, 1H), 1.38 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 157. 0, 153.3, 152.3, 147.3, 133.0, 130.5, 122.2, 122.0, 121.7 (2C), 121.3, 114.3 (2C), 109.5, 107.0, 55.5, 43.4, 37.7, 36.7, 33.5, 20.5, 14.1. IR (thin film):  max = 2953, 1615, 1459, 1329, 1206, 1035, 743 cm -1 . HRMS (ESI): 333.1961; found 333.1968.

(E)-1-(1-((Z)-hex-3-en-1- yl)-1H-indol-3-yl)-N-(
calculated for C 22 H 25 N 2 O [M+ H] + :

Methyl (E)-9-(((4-methoxyphenyl)imino)methyl)-1-methyl-2,3-dihydro-1H-pyrrolo[1,2a]indole-6-carboxylate (83f)

The general procedure (I) was applied methyl to (E)-1-(but-3-en-1yl)-3-(((4-methoxyphenyl)imino)methyl)-1H-indole-6-carboxylate (47f, 182 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane/EtOAc 80/20) afforded the title compound (83f) as a yellow oil (180 mg, 99 %). 9, 157.3, 156.7, 151.4, 146.8, 134.2, 132.2, 123.6, 122.4, 121.7 (2C), 121.5, 114.3 (2C), 111.8, 107.2, 55.5, 51.9, 43.6, 35.9, 32.9, 19.8

Chapter 2: Cobalt-catalyzed hydrosilylation reactions 1 Background and significance

The hydrosilylation reaction, which allows for the addition of silicon hydrides across multiple bonds, is an efficient method for the formation of organosilicon compounds and represents one of the most important reactions in silicon chemistry. The process is widely used in industry in the fields of organic synthesis, polymer chemistry and material sciences. 112 Given the fact that hydrosilanes are generally unreactive toward common unsaturated bonds, UV light-irradiation, heat, or a catalyst must be present to promote the addition reaction. The latter method, which is called catalytic hydrosilylation, is the most commonly used method in laboratories and industry, because of its high selectivity and applicability under relatively mild reaction conditions.

The first example of a hydrosilylation reaction was disclosed by Whitmore in 1947, in which trichlorosilane and 1-octene reacted in the presence of peroxide in a free-radical mechanism, although the reaction's selectivity was quite poor. 113 In the late 1950s hexachloroplatinic acid [H 2 PtCl 6 ].H 2 O (Speier's catalyst) was shown to be an effective homogeneous transition metal catalyst which offered improved selectivity. 114 A significant advancement in the field came when Karstedt reported the use of a platinum (0) complex bearing vinyl-siloxane ligands Figure 24. This catalyst exhibited high levels of activity and selectivity and is still regarded as benchmark for other hydrosilylation catalysts. Currently platinum complexes remain the metal of choice in industry for hydrosilylation reactions. Thus, given the large scale production of organosilicon compounds the uptake of platinum is significant. Indeed, it was estimated that the silicon industry alone depleted 5.6 tons of platinum in 2007. Thus there is a clear need to explore and develop cheaper and more abundant alternatives among the late 3d transition metals.

Similar to the previously discussed developments in C-H activation, iron, cobalt and nickel have gained considerable attention in the context of Si -H activation. 116 This is primarily due to their higher abundancy, low-cost and low-toxicity. Iron catalyzed hydrosilylation reactions have been met with a good deal of success even compared to platinum catalysis. Recent explorations into the field of cobalt catalyzed hydrosilylation of alkenes and alkynes have also proved to be fruitful with considerable strides made in the field. For the rest of this chapter we will only focus on cobalt-catalyzed hydrosilylation reactions.

Cobalt-catalyzed alkene hydrosilylation

Pioneering work by Chalk and Harrod in the 1960s demonstrated the ability of Co 2 (CO) 8 to perform the hydrosilylation of terminal alkenes. 117 This initial report sparked an interest in the field which remains to this day. While these early studies did not produce highly efficient catalysts, they did result in the disclosure of two important mechanisms for the late transitionmetal-catalyzed hydrosilylation of alkenes; the Chalk-Harrod mechanism and the modified Chalk-Harrod mechanism. As mentioned Chalk and Harrod reported the hydrosilylation of alkylsubstituted terminal alkenes (1-octene, 1-hexene, and 1-pentene) with tertiary silanes (HSiEt 3 , HSi(OMe) 3 , and HSiPhCl 2 ) to selectively produce the anti-Markovnikov addition products n-alkyl silanes in excellent yields (Scheme 76). The reaction was performed at ambient temperature and under solvent free conditions. It is worthy to mention that the reaction could be performed at very low catalytic loadings between (0.6-0.06 mol %). A limitation of these reaction was however the need to use a large excess of alkene (3 equiv, relative to the hydrosilanes), this was due to the parallel cobalt-catalyzed isomerization of the terminal alkenes to internal alkenes. Indeed, it was found that this side reaction was in fact faster than the hydrosilylation reaction which was not the case for the corresponding platinum and rhodium catalyzed reactions.

Scheme 76 Chalk-Harrod study on the Co 2 (CO) 8 -catalyzed hydrosilylation of alkyl-substituted alkenes

As an extension of this initial study, the group of Kalinin reported on the Co 2 (CO) 8 catalyzed hydrosilylation of styrene, vinyltrimethylsilane, 1-vinyl-o-carborane, and allyl di(triethoxysilyl)amine with HSi(OEt) 3 (Scheme 77).118

Scheme 77 Co 2 (CO) 8 -catalyzed hydrosilylation of a variety of alkenes

Excellent yields were obtained for styrene and vinyltrimethylsilane however, for 1-vinylo-carborane, and allyl di(triethoxysilyl)amine yields were significantly reduced presumably due the coordinating carbonyl and amine groups. A study to compare the reactions of vinyltrimethylsilane with HSi(OEt) 3 using Co 2 (CO) 8 (0.023 M) and Rh 4 (CO) 12 (0.0011 M) as catalysts showed that both reactions can yield the anti-Markovnikov addition product in comparable yields. However, in the case of the cobalt-catalyzed reaction the rate is slower. Later, Seki, Murai and their co-workers reported the Co 2 (CO) 8 -catalyzed reaction of α,βunsaturated esters with hydrosilanes. 119 Thus in the presence of 4 mol % Co 2 (CO) 8 , the reaction of the hydrosilanes, HSiEt 2 Me, HSiMe 3 , HSiMe 2 Ph, and HSi(OEt) 3 , with 5 equiv of H 2 C=CHCOOR (R = Me, Et) in benzene at 25 °C gave the dehydrogenative silylation products (E)-3-silyl acrylates in 43%-86% yields, β-silylesters in only trace amounts, and the alkene hydrogenation products in good yields (Scheme 78). As already mentioned the mechanistic details for the Co 2 (CO) 8 -catalyzed hydrosilylation of alkenes was studied in detail by Chalk and Harrod (Scheme 79). They showed that Co 2 (CO) 8 reacts with hydrosilanes to form R 3 SiCo(CO) 4 and HCo(CO) 4 in the presence of hydrosilanes. It was also shown that the hydride complex can be converted to R 3 SiCo(CO) 4 and H 2 . 117b It was also demonstrated that Co 2 (CO) 8 and HSi(OEt) 3 were capable of performing the isomerization of alkenes as demonstrated by the deuterium scrambling observed with 1-heptene-3-d 2 . In addition, it was shown via infrared spectroscopy that as the reaction proceeds the concentration of Et 3 SiCo(CO) 4 increases while Scheme 78 Co 2 (CO) 8 -catalyzed reaction of α,β-unsaturated esters with hydrosilanes -the rate of the hydrosilylation reaction decreases. Taking into account the above observations they put forward a mechanism based on the generation of a cobalt hydride species. Thus the Chalk-Harrod mechanism suggests that the precatalyst Co 2 (CO) 8 initially reacts with HSiR 3 to furnish a cobalt silyl complex and a cobalt hydride species I. The alkene coordinates and then inserts into the cobalt hydride complex to generate alkylcobalt carbonyl intermediate II. This intermediate can then undergo an oxidative addition with HSiR 3 to produce the addition product (R 3 Si)(H)-(R′CH 2 CH 2 )Co(CO) n III that then undergoes a reductive elimination to form the hydrosilylation product and the cobalt hydride species, or the hydrogenation product and cobalt silyl species. The Chalk-Harrod mechanism also explains the formation of the alkene isomerization product.

Scheme 79 Chalk-Harrod mechanism

Wrighton and co-workers performed a series of experiments to support a modified Chalk-Harrod mechanism (Scheme 80). The main difference being that, whereas it was initially proposed that Et 3 SiCo(CO) 4 is catalytically irrelevant, Wrighton showed that with a catalyst loading of 0.05 mol% Et 3 SiCo(CO) 4 , the reaction of 1-pentene with 1 equiv of HSiEt 3 under the irradiation of 355 nm light for 39 h at 25 °C afforded the desired product n-C 5 H 11 SiEt 3 in 60% yield. 120a Later the same group established the conversion of Et 3 SiCo(CO) 4 to Et 3 SiCo(CO) 3 via photolyis using cryogenic infrared spectroscopy. They also observed the coordination of Et 3 SiCo(CO) 3 with ethylene to form Et 3 SiCo(CO) 3 (CH 2 =CH 2 ), the conversion of the alkenecomplex to HCo(CO) 3 and CH 2 =CHSiEt 3 at elevated temperature, and the reaction of MeCo(CO) 3 with HSiMe 3 liberating methane and forming the complex Me 3 SiCo(CO) 3 . These observations lead to the formulation of the modified Chalk-Harrod mechanism. Thus following the generation of the species R 3 SiCo(CO) 3 I a migratory insertion of an alkene into the Co-Si bond (silacobaltation) leads to the formation of β-silylalkyl species II. An oxidative addition of the alkyl species with a hydrosilane generates complex III that following a reductive elimination yields the desired product and regenerates the active catalytic species. 120b The formation of alkenylsilanes was explained by the β-hydride elimination of the cobalt-silyl complex II as shown below.

Scheme 80 Modified Chalk-Harrod mechanism

Cobalt carbonyl catalysts aside, cobalt catalysts bearing a variety of other common ligands such as phosphines, cyclopentadienyl and N-heterocyclic carbenes have also been reported. The group of Parish reported the use of phosphine-cobalt-hydride complexes [(CoH(N 2 )(PPh 3 ) 3 ] and [CoH 3 (PPh 3 ) 3 ] for the hydrosilylation of 1-hexene with HSi(OEt) 3 (Scheme 81 ) . 121 It was shown that the these cobalt complexes can react reversibly with HSi(OEt) 3 to form a cobalt (III) silyl complex CoH 2 (Si(OEt) 3 )(PPh 3 ) 3 which was also shown to be an active catalyst. It was shown that for these particular class of catalysts the rate of alkene isomerization was half that for the hydrosilylation reaction. The group of Hilt also reported the use of an in situ generated low valent cobalt species for the hydrosilylation of isoprene with HSi(OEt) 3 . The catalytically active species was generated through the interaction of CoBr 2 , PBu 3 , Bu 4 NBH 4 , and ZnI 2 . 122 Scheme 81 Cobalt-phosphine complex catalyzed hydrosilylation of 1-hexene A considerable contribution to the field of non-precious metal-catalyzed hydrosilylation reactions was reported by the group of Chirik. Thus Chirik and co-workers disclosed the use of 2,6-iminopyridine-cobalt-dinitrogen complexes that display a similar level of activity in alkene hydrosilylation reactions to that of traditional platinum catalysts (Scheme 82). 123 Further studies on the use of 2,6-iminopyridine-cobalt-dinitrogen complexes led to the development of new systems for dehydrogenative silylation of alkenes. The reaction was amenable with a variety of hydrosilanes (HSi(OSiMe 3 ) 2 Me, HSi(OEt) 3 , HSiEt 3 , H 2 SiPh 2 , H 3 SiPh) and linear terminal alkenes giving E/Z ratios in the region of 3:1. It's important to note that the outcome of the reaction of the cobalt-catalyzed dehydrogenative silylation reaction is substrate-dependent as the majority of the alkenes subjected to study were converted to allyl silanes while the reactions of 3,3-dimethylbutene and isobutene (i.e. substrates lacking allylic hydrogens generate vinylsilanes as the major products.

Scheme 82 Cobalt-catalyzed dehydrogenative silylation of alkenes 121 (a) Archer, N. J.; Haszeldine, R. N.; Parish, R. V. J. Chem. Soc. D 1971, 524-525. (b) Archer, N. J.; Haszeldine, R. N.; Parish, R. V. J. Chem. Soc., Dalton Trans. 1979, 695-702. 122 Hilt, G.; Lü ers, S.; Schmidt, F. Synthesis 2004, 634-638. 123 Atienza, C. C. H.; Diao, T.; Weller, K. J.; Nye, S. A.; Lewis, K. M.; Delis, J. G. P.; Boyer, J. L.; Roy, A. K.; Chirik, P. J. J. Am. Chem. Soc. 2014, 136, 12108-12118. Based on the observed experimental results and deuterium labelling studies, a mechanism similar to that proposed for the Co 2 (CO) 8 -catalyzed dehydrogenative silylation of α,β-unsaturated esters by Seki and Murai was proposed (Scheme 83). 124 The sequence begins with activation of (MesPDI)CoCH 3 with the tertiary silane to form methane and the silyl cobalt I. After the formation of the silyl cobalt, the first equivalent of the terminal alkene undergoes 2,1insertion, forming a secondary bis(imino)pyridine cobalt alkyl complex II, which explains the anti-Markovnikov selectivity in the dehydrogenative silylation. Following on from this fast βhydrogen elimination furnishes the observed allylsilane. The observed formation of allyl-rather than vinylsilane is explained by the preferential β-hydrogen elimination distal the large tertiary silane substituent to form the cobalt hydride, (MesPDI)CoH. Insertion of another equivalent of alkene, followed by oxidative addition of a hydrosilane, and reductive elimination generates one equivalent of alkane and regenerates the active cobalt (II)-silyl complex.

Scheme 83 Proposed mechanism for bis(imino)pyridine cobalt-catalyzed dehydrogenative silylation of α-olefins 124 Takeshita, K.; Seki, Y.; Kawamoto, K.; Murai, S.; Sonoda, N. J. Org. Chem. 1987, 52, 4864-4868. In another recent report by Chirik, he demonstrated that careful modulation of the cobalt complex allowed for the effective hydrosilylation of alkenes. 125 In contrast to the aforementioned N-mesityl 2,6-diiminopyridine-cobalt methyl complex that promotes the dehydrogenative silylation reaction, the N-methyl 2,6-diiminopyridine-cobalt alkyl complex (PDIMe)Co(CH 2 SiMe 3 ) turns out to be an effective catalyst for the hydrosilylation of alkenes with HSi(OEt) 3 . It was shown that alkenes such as 1-octene and allyl(poly)ether gave exclusively the anti-Markovnikov in whereas vinyl silanes gave a mixture of products (Scheme 84).

Scheme 84 Cobalt-catalyzed hydrosilylation of terminal alkenes 3 Cobalt-catalyzed alkyne hydrosilylation

On the surface it would appear that the transition-metal catalyzed hydrosilylation of alkynes would be a practical route to access vinylsilanes which are useful reagents in organic synthesis. 126 However, in practice, this reaction is hampered by the difficulty in achieving regiocontrol and stereocontrol. This difficulty can be better understood by considering that even the hydrosilylation of a terminal alkyne might result in three vinylsilanes, namely, the β-(Z), β- (E), and α-isomers (Scheme 85). While the regio and stereoselective hydrosilylation of alkynes catalyzed by noble metals has been met with success, 112 reports with late 3d metalbased catalysts is comparatively rare. 127,128 Scheme 85 Hydrosilylation of terminal alkynes It is well known that Co 2 (CO) 8 can readily react with alkynes to form Co 2 (CO) 6 (C 2 R 2 ). It was during the course of an investigation into the reductive decomplexation of alkyne dicobalt hexacarbonyl species that Isobe et al. found that tertiary hydrosilanes reacted with acetylene biscobalt hexacarbonyl complexes to afford vinylsilanes, albeit with poor regioselectivity. 129 Further studies revealed that Co 2 (CO) 8 and (2-methylbut-3-yn-2-ol)-biscobalthexacarbonyls (shown below), which is relatively more air-stable than Co 2 (CO) 8 , can serve as effective catalysts for the hydrosilylation of alkynes with tertiary hydrosilanes, although the cobalt-catalyzed reactions require higher catalyst loadings than the Na 2 PtCl 6 -catalyzed reaction. 130 For the hydrosilylation of phenylthio alkynes with HSiEt 3 or HSiPhMe 2 the reaction proceeded in both high regio-and stereoselectivity in favor of the cis α-phenylthio-α-silyl alkenes (Scheme 86). The high syn-α selectivity observed for this reaction was attributed to the directing groups, phenylthio and hydroxyl groups on the alkyne moiety. Notably the reaction was only successful for phenylthio substituted alkynes, thus its application in synthesis is rather limited.

Scheme 86 Cobalt-catalyzed hydrosilylation of phenylthio alkynes

Konno and co-workers also reported the Co 2 (CO) 8 catalyzed hydrosilylation of fluoroalkylated alkynes. 131 Using F 3 CC≡CC 6 H 4 -Cl-p as a model substrate with a variety of different tertiary hydrosilanes revealed that the reaction with HSiEt 3 affords α-trifluoromethylα-silyl alkene as the major product, whereas the reactions with HSiPhMe 2 and HSi(OEt) 3 have αtrifluoromethyl-β-silyl alkenes being the major products. Having examined the reaction of various hydrosilanes they then explored the reaction of HSiEt 3 with a series of fluoroalkylated alkynes containing different fluoroalkyl groups (CF 3 , CF 2 H, and CF 2 CF 2 CF 2 H) and/or aryl, benzyl, propargyl alcohol groups. The cis-addition products were obtained as the major isomers in good yields with the α/ β ratio varying from 71:29 to 100:0 (Scheme 87). Konno postulates the formation of a mononuclear cobalt carbonyl species that parallels the previously modified Chalk-Harrod mechanism for alkene hydrosilylation (Scheme 88). However, a key limitation of this system is the need to have an alkyne bearing a CF 3 group, which somewhat limits the synthetic utility of this approach. Butenchön et al. also reported the use of an interesting cyclopentadienylcobalt(I) ethylene complex bearing a phosphine tether for the hydrosilylation of alkynes. 132 The same group also demonstrated the ability of this complex to perform the oxidative addition of hydrosilanes to furnish cobalt(III) hydrido silyl complexes. 133 Thus, using a catalytic loading of 5 132 Yong, L.; Kirleis, K.; Butenschö n, H. Adv. Synth. Catal. 2006, 348, 833-836. 133 Yong, L.; Hofer, E.; Wartchow, R.; Butenschö n, H. Organometallics 2003, 22, 5463-5467. mol% the hydrosilylation of symmetrical internal alkynes with HSiEt 3 selectively yielded cisaddition products in moderate-to-good yields (Scheme 89). Interestingly, when the authors employed HSi(OEt) 3 , a complete switch in stereoselectivity was observed and the anti-addition product was the major isomer. While this switch in regioselectivity is not completely understood, it is believed to originate from an initial syn-addition followed by a subsequent isomerization. 134 An alternative explanation is via a concerted oxidative addition-hydride insertion step as proposed in ruthenium-catalyzed alkyne hydrosilylation reactions. 135 Under this catalytic system, the hydrosilylation of unsymmetrical internal alkynes and terminal alkynes suffered from poor regioselectivity. In the case of the former, the use of HSiEt 3 and HSi(OEt) 3 gave exclusively the cis-addition products as mixtures of two regioisomers in moderate yields. For terminal alkynes, the reaction of HSiEt 3 gave 1:1 mixtures of β-(E) and α-isomers, while the use of HSi(OEt) 3 failed to yield the desired hydrosilylation product and rather led to alkyne trimerization. The authors postulate that the reaction proceeds through a typical Chalk-Harrod or modified Chalk-Harrod mechanism. It is believed that the hemilabile phosphine ligand plays an important role in creating an open coordination site and aiding the reductive elimination process.

Scheme 89 Cyclopentadienylcobalt(I) complex-catalyzed hydrosilylation of alkynes

A very recent report from Deng et al. revealed interesting low-coordinate cobalt(I) catalysts that are capable of the hydrosilylation of terminal and internal alkynes with high stereoselectivity and regioselectivity. 136 It was shown that bulky NHCs were capable of stabilizing three-and two coordinate cobalt(I) complexes in the form of (NHC) 2 CoCl and [(NHC) 2 Co][BAr 4 ]. 137 Further studies on the use of these complexes led to the discovery of the three coordinate cobalt(I) alkyl complex (IAd)(Ph 3 P)Co(CH 2 SiMe 3 ) which was synthesized from the reaction of (Ph 3 P) 3 CoCl with IAd, followed by alkylation with LiCH 2 SiMe 3 . It was shown that with 2 mol% catalyst in the presence of 1-octyne and 1.2 equiv of H 2 SiPh 2 at room temperature it was possible to isolate (E)-octenyldiphenylsilane selectively in 96% yield. Indeed the lower yields and selectivity observed with Rh(PPh 3 ) 3 Cl, Pt 2 (dvtms) 3 , and other cobalt complexes emphasize the high catalytic activity of the present complex (Table 6).

Table 6 Catalytic performance of some metal complexes in hydrosilylation of 1-octyne

Further exploration of substrate scope showed that good regioselectivity and stereoselectivity could be obtained for a broad range of phenyl-and alkyl-substituted terminal alkynes in the presence of H 2 SiPh 2 . The β-(E)-adducts were obtained as the sole products in high yields and the functional group tolerance was broad with tertiary amine, ester, chloro groups all tolerated. Indeed it was also possible to perform the catalytic hydrosilylation of 1,6-dialkynes with H 2 SiPh 2 to produce the silylated 1,2-dialkylidenecyclopentanes in moderate yields with high selectivity. The catalytic system could also be transferred to the hydrosilylation of internal symmetrical alkynes, yielding the syn-adducts in more than 80% yields. In the case of unsymmetrical alkynes, the syn-adducts were exclusively formed and the regioselectivity was dependent on the steric nature of the substituents. Through careful tuning of the steric properties of the substituents, it was possible to achieve the regioselective and stereoselective hydrosilylation of unsymmetrical internal alkynes bearing a trimethylsilyl group. For these alkynes the (Z)-α,α-disilylalkenes were formed exclusively in good to excellent yield (Table 7). Despite these excellent results, a key limitation of this system is that it requires of H 2 SiPh 2 as hydrosilane. Indeed switching to other hydrosilanes led to a complete loss of catalytic activity. A detailed mechanistic study was undertaken to elucidate the reaction pathway. To this end stoichiometric reactions of (IAd)(PPh 3 )Co(CH 2 SiMe 3 ) with PhC≡CPh and H 2 SiPh 2 were performed. They were able to isolate a low-coordinate alkyne complex (IAd)(η 2 -PhC≡CPh)Co-(CH 2 SiMe 3 ) and the silyl complex (IAd)(PPh 3 )Co(SiHPh 2 ), respectively (Scheme 90). The catalytic activity of both these complexes was examined, thus with the silyl complex as catalyst in the presence in 1-octyne and H 2 SiPh 2 , very similar reactivity and selectivity was

Project Aims and Objectives

Given the economic concern about the use of precious metals for metal-catalyzed hydrosilylation reactions, it is unsurprising that the chemical community has begun to explore their nonprecious metal alternatives. The aforementioned advances have undoubtedly demonstrated the ability of cobalt complexes to perform the hydrosilylation of alkenes and alkynes. However, despite this progress, the application of cobalt complexes for the production of organosilanes in fine chemicals synthesis is dwarfed by traditional noble-metal catalysts. 138 The main reason behind the reluctance of industries to adopt the use of cobalt complexes are the limited substrate scope and also the difficulty in achieving good regio-and stereo control. For example, in the case of cobalt catalyzed hydrosilylation of alkenes there is generally a large excess of alkene partner in the reaction to compensate for unwanted and uncontrolled side reactions. In addition, there are few cobalt catalysts that allow for the hydrosilylation of disubstituted and polysubstituted alkenes. The lesser explored hydrosilylation of alkynes also suffers from many limitations, primarily selectively control, which still remains a challenge. Another issue is the narrow scope of hydrosilanes, which in many cases is constrained to primary hydrosilanes. To date, the results of hydrosilylation of alkynes with tertiary hydrosilanes is far from ideal.

As already discussed our group has been recently interested in the application of welldefined low-valent cobalt complexes in particular HCo(PMe 3 ) 4 and Co(PMe 3 ) 4 towards C-H bond activation and [2+2+2] enediynes cycloadditions. 56,68,76,82 . During the course of our studies on the use of these low-valent cobalt complexes we found that they were capable of performing the hydrosilylation of ketimines (Scheme 92).

Scheme 92 Hydrosilylation of ketimines

138 Sun, J.; Deng, L. ACS Catal. 2016 , 6, 290-300.

Results and Discussions

Hydrosilylation of diphenylacetylene with a variety of hydrosilanes

Having found during the course of our previous studies that the use of toluene as solvent at elevated temperatures was an effective combination for the hydroarylation of internal alkynes we chose to explore similar reaction conditions for the hydrosilylation of alkynes. To this end we began to examine the reaction of triphenylsilane and diphenylacetylene in the presences of Co(PMe 3 ) 4 and HCo(PMe 3 ) 4 . Thus, it was found that the use of 5 mol% of HCo(PMe 3 ) 4 in toluene at 110 o C for 24 hours gave optimal results allowing us to isolate the corresponding vinyl silane in good yields. The results are summarized in (Table 8). Pleasingly, we encountered a reaction amenable with an ample variety of aryl/alkyl tertiary silanes and alkoxysilanes (Table 8, entries 1-7), achieving in many cases good yields (up to 94%). Notably, these reaction conditions successfully allow for the hydrosilylation of highly functionalized and sterically demanding hydrosilanes such as that shown in (entry 7). In general, the products of syn-hydrosilylation were observed as major isomers, with (E/Z) ratios up to 98%, using the both cobalt(0) and cobalt(I) complexes, and, in all cases, the hydrido complex HCo(PMe 3 ) 4 gave better results. Note yields in brackets refer to those obtained using Co(PMe 3 ) 4 as catalyst. It is interesting to mention that in our previous studies on the use of these cobalt complexes for the hydroarylation of alkynes and alkenes we found that the cobalt(0) complex Co(PMe 3 ) 4 consistently outperformed its cobalt(I) HCo(PMe 3 ) 4 counterpart. However, this trend in reactivity was reversed for the present hydrosilylation reaction. It is worth highlighting the unique ability of these complexes to carry out the hydrosilylation of alkynes with a wide variety of hydrosilanes which has not been previously described under cobalt catalysis.

Hydrosilylation of Internal Unsymmetrical Alkynes

Having demonstrated the ability of our catalysts to perform the hydrosilylation of diphenylacetylene with a variety of hydrosilanes, we then turned out attention to the more challenging hydrosilylation of internal unsymmetrical alkynes. Indeed, the hydrosilylation of internal unsymmetrical alkynes can in theory lead to four different products as shown in (Scheme 93). Therefore this represents a difficult reaction in terms of both regio-and stereoselectivity.

Scheme 93 Hydrosilylation of internal unsymmetrical alkynes

For our study we chose alkynes which were substituted by functional groups with varying degrees of steric hindrance, designated R S (smaller group) and R L (larger group). Products will be designated type 97 or type 97' based on the position of the silane (Figure 25). Based on the positive preliminary results, regarding the high yields and syn selectivity observed we chose to use complex HCo(PMe 3 ) 4 in combination with hydrosilanes HSi(OEt) 3 and HSiPh 3 for the following study. Using less reactive alkynes (compare to diphenylacetylene) new optimized reactions conditions were required. It was found that increasing the reaction temperature to 160 °C and decreasing the reaction time to 2 h provided optimal reaction conditions for the hydrosilylation of a variety of internal unsymmetrical alkynes. high yields and complete regioselectivity towards the adducts of type 97 ie. (E)-α,βdisilylalkenes. The catalytic system also allowed the use of heteroatoms with TMS-protected pyridylalkynes, isolating only the products of type 97 in moderate to good yields (entries 9-10). It is worth noting that the regioselectivity observed in our reaction with TMS-containing alkynes is opposite to the one previously reported by Deng. 136 It was shown that the introduction of two methyl groups in the ortho positions of the phenyl ring in the case for alkyne 1,3-dimethyl-2-(phenylethynyl)benzene generated sufficient steric hindrance to yield the corresponding vinyl silane with complete regioselectivity, i.e. with the bulky silyl group positioned alpha to the unsubstituted phenyl group (entry 11). Phenylpropyne followed the same trend of steric dependence of the alkyne substituents in the formation of the desired product (entry 12).

On the other hand, the reaction of non-sterically differentiated unsymmetrical alkynes but bearing electronically distinct substituents gave 50/50 mixtures of vinylsilanes of type 97 and 97'(entries [START_REF][END_REF][14][15]. These latter results imply that the regio-and stereocontrol of the reaction is predominantly governed by steric factors of the starting substrates, while electronic factors have no significant effect on the outcome of the reaction. Finally, the use of estersubstituted alkyne in the present hydrosilylation reaction with HSiPh 3 yields solely the product of type 97', presumably due to the chelating effect of the ester which appears to be sufficiently strong to overcome the steric control (entries 16-17).

Having explored the use of the hydrosilane HSiPh 3 with a broad variety of internal alkynes we turned our attention to the use of HSi(OEt) 3 (entries 18-27, Table 10). Unsurprisingly we obtained analogous results to those previously described with HSiPh 3 , obtaining almost exclusively the syn-adducts of type 3. When employing HSi(OEt) 3 as the source of hydrosilane in the presence of alkynes hex-1-yn-1-ylbenzene and 1-(hex-1-yn-1-yl)-4methoxybenzene complete regioselectivity was achieved (entries 18-19). This increase in regioselectivity compared to the corresponding reaction with HSiPh 3 can be attributed to the larger steric bulk provided by the triethoxy moieties in the silane. Further exploration into the scope of the current reaction showed identical results by employing TMS-protected arylacetylenes, with complete selectivity towards the corresponding (E)-α,β-disilylalkenes of type 97 and regardless of the aromatic group linked to the alkyne. Likewise, the use of sterically encumbered alkynes 1,3-dimethyl-2-(phenylethynyl)benzene and 1-methoxy-4-(phenylethynyl)benzene displayed the expected results in accordance with the steric dependence of the reaction (Table 2, entries 26-76).

Mechanistic considerations

Having investigated the scope and limitations of the current hydrosilylation reaction we then turned our focus to elucidating the reaction pathway. Assuming the reaction pathway proceeds through a classical oxidative addition of the cobalt complex with the hydrosilane we should in theory generate a cobalt(III) complex. To this end we explored the possibility of isolating this hypothetical intermediate. Pleasingly, we found that simply heating HCo(PMe 3 ) 4 and HSiPh 3 in toluene for 2 hours followed by precipitation from pentane allowed us isolate the desired cobalt(III) intermediate as a pale yellow solid (Scheme 94).

Scheme 94 Formation of H 2 CoSiPh 3 (PMe 3 ) 3

We were also able to monitor the formation of the cobalt(III) species by proton and phosphorous NMR as shown below (Figure 26, Figure 27). Examining the proton NMR we observed the disappearance of the mono-hydrido species at -17 ppm and the formation of the new di-hydrido species at -15 ppm. Similarly we observed the disappearance of the phosphorous peak at 0 ppm corresponding to the cobalt(I) complex and the formation of a new peak at 5 ppm in the new complex. produced during the catalytic process, it will quickly rebound and split on the cobalt center to regenerate the active species. Based on the experimental and theoretical information, we were able to propose a mechanistic pathway for our catalytic system, shown in the (Scheme 97). Initial oxidative addition of the silane to the cobalt catalyst, followed by coordination of the alkyne gives the dihydridocobalt(III) intermediate III, which undergoes alkyne insertion into a Co-H bond to furnish the vinyl organometallic IV. At this point the H atom is directed towards the more bulky substituent in order to place the cobalt moiety in the less hindered plane of the molecule. Direct reductive elimination releases the vinylsilane V as the major product with the observed regioselectivity and regenerates the catalytically active species I. To a much lesser extent, an opposite migratory insertion would yield the adduct isomer VI, which eventually results in the unfavored product VII.

Figure 29 Comparison between regioselectivity determining steps in cobalt-catalyzed hydrosilylation of alkynes

Conclusion

To conclude, the regioselective hydrosilylation of a wide variety of internal alkynes catalyzed by an inexpensive and versatile low-valent cobalt(I) complex HCo(PMe 3 ) 4 is reported (Scheme 98). The scope of silanes and alkynes successfully incorporated is unprecedented in the realm of cobalt catalysis. In addition the use of this simple well-defined low-valent cobalt complex gave good levels of stereo control. The analysis of data obtained from NMR and computational studies revealed the direct correlation of steric effects in the outcome of the hydrosilylation products, towards a syn-regioselective reaction. DFT calculations also reveal that alkyne insertion proceeds via a hydrocobaltation pathway rather than a silacobaltation mechanism. Further investigations regarding the application of these complexes towards other reactions are being currently explored. 6 Preliminary results, and background

Scheme 98 Summary of our group's results on the hydrosilylation of internal alkynes

Co L n-2 H H R 3 Si R L R S Co(III) Co SiHPh 2 IAd R L R S Co(I) Co L n-2

Cobalt-catalyzed hydroboration of carbon-carbon multiple bonds

Organoboron compounds play an important role in modern synthetic organic chemistry, being utilized as essential carbon nucleophiles for introduction of functional groups and a carbon-carbon bond-forming process such as Suzuki-Miyaura coupling. 143 Organoboranes specifically boronic esters have a number of characteristics that make them popular reagents compared to other organometallics and include bench stability and easy-to-handle properties arising from the inertness toward oxygen and moisture, low toxicity, moderate reactivities suitable for chemoselective transformations, high functional group compatibility, plus others. Given its atom economy, the metal-catalyzed hydroboration of alkenes is an attractive approach for the synthesis of secondary alkyl boronate esters. Rhodium and iridium complexes have proven to be effective catalysts for this reaction. However, the renewed interest in cheaper more earth abundant alternatives to these precious metals has led to the discovery of copper, 144 iron and cobalt catalysts for alkene hydroboration. 145 The group of Chirik has been at the forefront of much of this development and has shown that iron and cobalt catalysts offer the distinguishing feature of promoting alkene isomerization-hydroboration with high terminal selectivity. In many cases, no matter the starting position of the C=C bond, carbon-boron bond formation is highly selective for the terminal position of the alkyl chain (Scheme 99).

Scheme 99 Iron-and Cobalt-catalyzed alkene isomerization-hydroboration

In comparison to the cobalt catalyzed hydroboration of alkenes the corresponding reaction with alkynes remains largely unexplored. To date only two examples have been reported in the literature. 146,147 Thus, the group of Orpen reported the diboration of a diarylalkyne with bis(catecholato)diboron which proceeded in the presence of Co(PMe 3 ) 4 to afford syn-selective products. Unfortunately, the yield of the reaction was not described and no further studies on this topic were released by the group (Scheme 100).

Scheme 100 Cobalt-Catalyzed diboration of an internal alkyne

Thus, the group of Chirik has recently disclosed the regio-and stereoselective hydroboration of terminal alkynes with pinacolborane catalyzed by a methylcobalt complex coordinated by a bis(imino)pyridine ligand having a cyclohexyl substituent on both imine nitrogen's. The reaction of aliphatic or aromatic terminal alkynes provided linear (Z)alkenylboranes with high yield and selectivity (Scheme 101).

Scheme 101 Cobalt-catalyzed hydroboration of terminal alkynes

The reaction is proposed to proceed through an interesting mechanism which involves the formation of cobalt acetylide I which forms through the liberation of methane (Scheme 102). Subsequent oxidative addition of pinacolborane, followed by reductive elimination affords an alkynylborane and a cobalt hydride III. Syn-hydrocobaltation of the alkynylborane then takes place to give an alkenylcobalt species IV, which is finally transformed into an (Z)alkenylborane via protonation by an alkyne. Thus we began our study with HCo(PMe 3 ) 4 (5 mol%) in toluene at 110 o C, pleasingly under these unoptimized conditions we were able to isolate the corresponding vinyl boronate in 78% yield with complete syn-selectivity (Entry 1). On switching from HCo(PMe 3 ) 4 to Co(PMe 3 ) 4 the yield increased to 87% again with complete stereoselectivity (Entry 2). This was a surprising result considering that for the hydrosilylation of alkynes with variety of hydrosilanes HCo(PMe 3 ) 4 consistently gave higher yields. This may suggest the present hydroboration operates via a different mechanism to that postulated for the corresponding hydrosilylation reaction. Further exploration of the reaction scope revealed a variety of functional groups were tolerated under the present reaction conditions including TMS, Alkyl, and ester (Entry 3-11).

These preliminary results showcase the ability of these simple low valent complexes to perform the hydroboration of a variety of internal alkynes with excellent syn-selectivity and in good yields. Further efforts will involve extending the reaction scope in addition to elucidation of the reaction mechanism.

Preparation of dihydrido cobalt(III) complex 98.

Under argon atmosphere, an oven-dried Schlenk tube containing a magnetic stir bar was charged with cobalt(I) complex HCo(PMe 3 ) 4 (100 mg, 0.274 mmol) and triphenylsilane (71 mg, 0.274 mmol). The Schlenk tube was then capped with a rubber septum and then freshly distilled and degassed toluene (5 mL) was added via syringe through the septum. The reaction mixture was stirred in an oil bath at 80 °C for 2 h, after which time the solvent was removed in vacuo until dryness. Next, degassed pentane (5 mL) was added and the solution was filtered via cannula leaving behind a solid precipitate (this sequence was repeated three times). Finally, after complete removal of the solvent complex 98 is obtained as a yellow solid (90 mg, 60% yield). 1 H NMR (400 MHz, C 6 D 6 ) δ 7.94 (d,J = 7.3 Hz,6H),

Cobalt catalyzed hydrosilylation of internal alkynes

Triphenyl-[(E)-(1,2-diphenylvinyl)]silane (97aa) 148

The general procedure (J) was applied to diphenylacetylene (89 mg, 0.5 mmol) and triphenylsilane (143 mg, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97aa as a white solid (173 mg, 79% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7. 15H),6H),7.05 (s,1H,4H). 13 C NMR (100 MHz, CDCl 3 ) δ 143. 3, 141.8, 141.0, 137.1, 136.5, 133.8, 129.7, 129.5, 128.4, 128.3, 127.9, 127.7, 127.4, 125.9.

Diisopropyl[(trimethylsilyl)ethynyl][(E)-(1,2-diphenylvinyl)]silane (97ga)

The general procedure (J) was applied to diphenylacetylene (89 mg, 0.5 mmol) and diisopropyl[(trimethylsilyl)ethynyl]silane153 (117 mg, 0.55 mmol). Purification by silica gel flashchromatography afforded the title compound 97ga as a yellow oil (181 mg, 93% yield). 1 H NMR (400 MHz, CDCl 3 ) 11H,, 1.17 -1.09 (m, 2H), 1.10 (d, J = 6.7 Hz, 6H), 1.06 (d, J = 6.7 Hz, 6H), 0.23 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 142. 4, 141.9, 140.0, 137.3, 129.7, 128.5, 128.0, 127.8, 127.1, 125.9, 118.3, 108.5, 18.0, 17.9, 11.6, 0.0

Triphenyl-[(E)-(1-phenyl-2-butylvinyl)]silane (97ab)

The general procedure (K) was applied to 1-phenyl-1-hexyne (87 mg, 0.5 mmol) and triphenylsilane (143 mg, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97ab as a colorless oil (192 mg, 92% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.32-6.77 (m, Ar-H), 6.12 (t, J = 7.1 Hz, C=CH), 1.98 (q, J = 7.2 Hz, 2H, C=CH-CH 2 -), 1.20 (m, -CH 2 -CH 2 -), 0.72 (t, J = 7.1 Hz, 3H, CH 2 -CH 3 ). 13 C NMR (100 MHz, CDCl 3 ) δ 148. 5, 141.7, 138.6, 136.5, 136.4, 136.2, 135.8, 134.4, 129.3, 128.7, 128.0, 127.8, 127.8, 127.6, 125.5, 31.6, 30.1, 22.3, 13.9. IR (thin film):  max 3068.07, 3049. 52, 2956.03, 2923.23, 2359.54, 1427.87 The general procedure (K) was applied to (4-methoxyphenylethynyl)trimethylsilane (87 mg, 0.5 mmol) and triphenylsilane (102 mg, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97af as a white solid (200 mg, 86% yield).

Triphenyl-[(E)-(1-(4-trifluoromethyl)phenyl-2-(trimethylsilyl)vinyl)]silane (97ag)

The general procedure (K) was applied to 1-((trimethylsilyl)ethynyl)-4-(trifluoromethyl)benzene (121 mg, 0.5 mmol) and triphenylsilane (102 mg, 0.55 mmol). Purification by silica gel flashchromatography afforded the title compound 97ag as a yellow solid (203 mg, 81% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.62-7.44 (m, 17H), 7.09 (d, J = 8.0 Hz, 2H), 6.95 (s, 1H), 0.00 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 158. 5, 152.3, 136.4 (2C), 133.3, 129.6, 128.4, 127.8 (2C) The general procedure (K) was applied to 1-[(trimethylsilyl)ethynyl]-3,5-dimethoxybenzene (117 mg, 0.5 mmol) and triphenylsilane (102 mg, 0.55 mmol). Purification by silica gel flashchromatography afforded the title compound 97ah as a white solid (215 mg, 87% yield). 517.1990, found 517.1998.

Triphenyl-[(E)-(1-(6-methoxynaphthalen-2-yl)-2-(trimethylsilyl)vinyl)]silane (97ai)

The general procedure (K) was applied to (6-methoxynaphthalen-2-ylethynyl)trimethylsilane (127 mg, 0.5 mmol) and triphenylsilane (102 mg, 0.55 mmol). Purification by silica gel flashchromatography afforded the title compound 97ai as a white solid (193 mg, 75% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 -7.44 (m, 18H), 7.30 -7.25 (m, 2H), 7.15 (dd, J = 8.4, 1.7 Hz, 1H), 6.90 (s, 1H), 4.10 (s, 3H), 0.01 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 159. 4, 157.0, 151.9, 139.9, 136.4, 133.9, 132.8, 129.2, 129.1, 128.3, 127.6, 127.5, 126.2, 125.5, 118.4, 105.4, 55.1, 0. The general procedure (K) was applied to 1,3-dimethyl-2-(phenylethynyl)benzene 9 (103 mg, 0.5 mmol) and triphenylsilane (143 mg, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97al as a white solid (212 mg, 91% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.56-7.24 (m, 6H), 7.42-7.33 (m, 9H), 7.00-6.94 (m, 5H), 6.87-6.80 (m, 4H), 2.13 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 145. 4, 141.7, 141.3, 137.6, 136.5, 135.2, 134.4, 129.5, 128.2, 127.8, 127.6, 127.0, 126.6, 126.0, 20.8

Triphenyl-[(E)-(1-phenylprop-1-en-2-yl)]silane (97am) 154

The general procedure (K) (Note: reaction was heated at 60 °C for 24h) was applied to 1phenyl-1-propyne (0.06 mL, 0.5 mmol) and triphenylsilane (102 mg, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97am as a white solid (35 mg, 19% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 -7.64 (m, 6H), 7.48 -7.35 (m, 14H), 6.96 (q, J = 1.7 Hz, 1H), 2.14 (d, J = 1.8 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 143. 6, 138.1, 136.3 (2C), 135.7, 134.4, 134.0, 129.5, 129.1, 128.0, 127.8 (2C), 126.9, 18.2.

Triphenyl-[(E)-(1-(4-trifluoromethylphenyl)-2-phenylvinyl)]silane and triphenyl-[(E)-(1-phenyl-2-(4-trifluoromethylphenyl)vinyl)]silane (97ap)

The general procedure (K) was applied to 1-trifluoromethyl-4-(phenylethynyl)benzene (123 mg, 0.5 mmol) and triphenylsilane (143 mg, 0.55 mmol). Purification by silica gel flashchromatography (pentane/ethyl acetate 95:5) afforded a 52:48 mixture of the title compounds as a yellow solid (203 mg, 80 % yield). 1 H NMR (400 MHz, CDCl 3 ) 35H,minor and Major),6H,minor and major),7.16 (s,1H,major),2H,J = 8.1 Hz,minor),7.03 (s,1H,minor),2H,J = 8.1 Hz,major),2H,major),2H,minor). 13 C NMR (100 MHz, CDCl 3 ) δ 146. 0,144.5,144.0,141.6,141.2,140.5,139.9,136.5,136.5,135.2,133.3,133.1,129.7,129.7 (d,J = 3.1 Hz),128.8,128.6,128.1,128.1,127.8,127.8,127.7,126.3,125.3 (q,J = 3.7 Hz), 124.8 (q, J = 3.8 Hz). 19 F NMR (376 MHz, CDCl 3 ) δ -62.25 (Major), -62.63 (minor). IR (thin film):  max 3000,1650,1487,1430,1350,1166,837. HRMS (ESI) calculated for C 33 H 25 F 3 NaSi [M+Na]+ 529.6330, found 529.6318.

(E)-Ethyl 3-phenyl-2-(triphenylsilyl)acrylate (97'aq) 150

The general procedure (K) was applied to ethyl phenylpropiolate (0.08 mL, 0.5 mmol) and triphenylsilane (102 mg, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97'aq as a white solid (35 mg, 19% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 -7.65 (m, 6H), 7.46 -7.28 (m, 14H), 6.95 (s, 1H), 3.93 (q, J = 7.1 Hz, 2H), 0.91 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 171. 3, 147.4, 136.3 (2C), 133.7, 132.8, 129.8, 128.8, 128.5, 128.3, 127.8 (2C), 60.5, 13.6.

(E)-Methyl 2-(triphenylsilyl)-2-octenoate (97'ar)

The general procedure (K) was applied to methyl 2-octynoate (0.08 mL, 0.5 mmol) and triphenylsilane (102 mg, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97'ar as a white solid (85 mg, 50% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 -7.54 (m, 6H), 7.43 -7.34 (m, 9H), 6.30 (t, J = 7.3 Hz, 1H), 3.47 (s, 3H), 2.45 (q, J = 7.3 Hz, 2H), 1.41 (t, J = 7.3 Hz, 2H), 1.28 (m, 4H), (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 170. 5, 158.3, 136.1, 135.8, 135.3, 128.0, 127.7, 51.0, 32.0, 31.4, 28.5, 22.3, 13.9. IR (thin film):  max 3060,2969,2921,2360,2362,2125,1714,1428. HRMS (ESI) calculated for C 27 H 30 NaO 2 Si [M+Na] + 437.1907, found 437.1899.

Triethoxy-[(E)-(1-phenyl-2-butylvinyl)]silane (97bb) 155

The general procedure (K) was applied to 1-phenyl-1-hexyne (87 mg, 0.5 mmol) and triethoxysilane (0.1 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97bb as a colorless oil (148 mg, 92% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.23-7.03 (m, phenyl-H, 5H), 6.30 (t, J = 7.1 Hz, C=CH, 2H), 3.70 (q, J = 7 Hz, O-CH 2 -CH 3 ), 2.00 (q, J = 7.2 Hz, 2H), 1.19-1.10 (m, -CH 2 -CH 2 -), 1.09 (t, J = 7 Hz, O-CH 2 -CH 3 ) , 0.74 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 147. 6, 140.5, 135.2, 128.5, 127.8, 127.8, 127.7, 125.7, 58.6, 31.5, 29.5, 22.3, 18.1, 13.9.

Minor product: triethoxy-[(Z)-1-phenyl-2-butylvinyl)]silane relevant signal: 1 H NMR (400 MHz, CDCl 3 ) δ 2.39 (q, J = 7. 4 Hz). Other signals are overlapped with the E-isomer.

Triethoxy-[(E)-(1-(4-methoxyphenyl)-2-butylvinyl)]silane (97bc)

The general procedure (K) was applied to 1-(4-methoxyphenyl)-1-hexyne (94 mg, 0.5 mmol) and triethoxysilane (0.1 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97bc as a colorless oil (169 mg, 96% yield). 7, 147.4, 134.4, 132.6, 129.5, 113.3, 58.6, 55.1, 31.6, 29.4, 22.3, 18.1, 13.9 Minor product: triethoxy-[(Z)-1-(4-methoxyphenyl)-2-butylvinyl)]silane relevant signal: 1 H NMR (400 MHz, CDCl 3 ) δ 2.37 (q, J = 7. 4 Hz). Other signals are overlapped with the E-isomer.

Triethoxy-[(E)-(1-(4-(trifluoromethyl)phenyl)-2-butylvinyl)]silane (97bd)

The general procedure (K) was applied to 1-(4-(trifluoromethyl)phenyl)-1-hexyne (113 mg, 0.5 mmol) and triethoxysilane (0.1 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97bd as a colorless oil (183 mg, 96% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.3, 2H), 7.17 (d, J = 8.4, 2H), 6.34 (t, J = 7.2 Hz, C=CH), 3.71 (q, J = 7.0 Hz, O-CH 2 -CH 3 ), 1.96 (q, J = 7.2 Hz, 2H), 1.20-1.16 (m, -CH 2 -CH 2 -), 1.10 (t, J = 7 Hz, O-CH 2 -CH 3 ) , 0.75 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 153. 7, 148.4, 134.5, 128.7, 128.0, 124.8, 58.7, 31.4, 29.5, 22.3, 18.0, 13.8

Triethoxy-[(E)-(1-phenyl-2-(trimethylsilyl)vinyl)]silane (97be) 156

The general procedure (K) was applied to 1-phenyl-2-trimethylsilylacetylene (87 mg, 0.5 mmol) and triethoxysilane (0.1 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97be as a colorless oil (160 mg, 95% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.42-7.26 (m, phenyl-H), 6.85 (s, C=CH), 3.92 (q, J = 7 Hz, O-CH 2 -CH 3 ), 1.32 (t, J = 7 Hz, O-CH 2 -CH 3 ), 0.00 (s, TMS). 13 C NMR (100 MHz, CDCl 3 ) δ 156. 2, 154.6, 150.5, 128.5, 127.9, 127.8, 127.6, 126.4, 58.4, 18.1, 00.

Triethoxy-[(E)-(1-(4-methoxyphenyl)-2-(trimethylsilyl)vinyl)]silane (97bf)

The general procedure (K) was applied to (4-methoxyphenylethynyl)trimethylsilane (87 mg, 0.5 mmol) and triethoxysilane (0.1 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97bf as a yellow oil (175 mg, 95% yield). 2, 150.2, 136.2, 130.2, 128.7, 112.9, 58.6, 18.0, 0.0 The general procedure (K) was applied to 1-((trimethylsilyl)ethynyl)-4-(trifluoromethyl)benzene (121 mg, 0.5 mmol) and triethoxysilane (0.1 mL, 0.55 mmol). Purification by silica gel flashchromatography afforded the title compound 97bg as a yellow solid (183 mg, 95% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.68, 7.40 (dd, J = 8.3 Hz, 4H), 6.95 (s, C=CH, 1H), 3.94 (q, J = 7 Hz, O-CH 2 -CH 3 ), 1.32 (t, J = 7 Hz, O-CH 2 -CH 3 ), 0.00 (s, TMS). 13 C NMR (100 MHz, CDCl 3 ) δ 156. 7, 155.2, 150.9, 128.1, 125.8, 124.9, 124.6, 58.9, 18.1, 00. The general procedure (K) was applied to 2-[(triethylsilyl)ethynyl]pyridine (87 mg, 0.5 mmol) and triethoxysilane (0.1 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97bj as a yellow oil (51 mg, 30% yield). 1 H NMR (400 MHz, CDCl 3 ) 1H),7.59 (td,J = 7.7,1.8 Hz,1H),7.36 (d,J = 7.9 Hz,1H),7.10 (ddd,J = 7.4,4.8,1.2 Hz,1H),6.88 (s,1H,C=CH), 3.82 (q, J = 7.0 Hz, 6H), 1.18 (t, J = 7.0 Hz, 9H), -0.05 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 160. 1, 154.5, 153.1, 148.2, 135.3, 122.6, 121.1, 58.5, 17.8, 0.0

Triethoxy-[(E)-(1-(3-pyridyl)-2-(trimethylsilyl)vinyl)]silane (97bk)

The general procedure (K) was applied to 3-[(triethylsilyl)ethynyl]pyridine (87 mg, 0.5 mmol) and triethoxysilane (0.1 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97bk as a yellow oil (76 mg, 45% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (bs, 2H), 7.51 -7.43 (m, 1H), 7.21 (s, 1H), 6.80 (s, 1H, C=CH), 3.78 (q, J = 7.0 Hz, 6H), 1.17 (t, J = 7.0 Hz, 9H), -0.14 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 157. 1, 152.8 (2C), 152.3, 148.5, 147.6, 135.0, 58.8, 18.1, 0.0

Chapter 3 Cobalt-catalyzed coupling reactions of benzyl halides 1 Background and significance

Transition metal-catalyzed C-C or C-Heteroatom (F, N, S, P..) bond forming reactions are extremely important tools in organic chemistry, allowing the construction of complex molecular scaffolds from simple precursors. 157 Many of these processes have been successfully applied to natural products and pharmaceutical synthesis. 158 Palladium-catalyzed processes came to prominence in the early 1970's with the work of Neigishi, Kumada, Suzuki and Heck and have had an enormous impact on organic synthesis. 159 The generally accepted mechanisms for these palladium-catalyzed cross-coupling reactions are depicted in Scheme 103. Common to both types of coupling reaction is the oxidative addition of the aryl halide (or pseudohalide) to the catalytically active LnPd(0) species which initiates the catalytic cycle. It is at this point that two divergent pathways are possible. In the Mizoroki-Heck coupling, the reaction proceeds via the coordination of an alkene to the Pd(II) species, followed by a syn migratory insertion. The regioselectivity of this insertion depends on the nature of the alkene, the catalyst, and the reaction conditions employed. The newly generated organopalladium species then undergoes syn β-hydride elimination to form the alkene product. Subsequently, base-assisted elimination of HX from [LnPd(H)(X)] occurs to regenerate the LnPd(0) catalyst. Alternatively, in the Negishi and Stille reactions, the oxidative addition is followed by transmetallation of an organometallic species to generate a Pd(II) intermediate bearing the two organic coupling partner fragments. Reductive elimination results in the formation of the C-C bond with the simultaneous regeneration of the Pd(0) species which is then free to re-enter the catalytic cycle.

3 Cobalt-catalyzed Csp 2 -Csp 2 cross-coupling reactions

Alkenylation reactions

In 1943, Kharasch disclosed the first cobalt-catalyzed alkenylation of aromatic Grignards reagents. 171 The highly reactive vinyl halides gave moderate yields while sterically hindered or more substituted alkenyl halides gave very poor yields. A significant amount of homocoupling products from both the alkenyl halide and the Grignard derivative were observed. In addition, the synthetic utility of the reaction was somewhat limited by the need to have at least 2 equivalents of alkenyl halide.

Scheme 106 Cobalt-catalyzed alkenylation of aromatic Grignard reagents

The group of Cahiez showed that yields could be significantly improved by changing to a solvent system of THF/NMP. Thus a wide variety of alkenyl halides have been coupled stereospecifically in good to excellent yields. 172 More recently, the group of Perichon and Gosmini reported the cobalt-catalyzed coupling between aryl halides and alkenyl acetates (Table 12). 173 The reaction was performed in the presence of a large excess of manganese (10 equiv).

Table 12 Cobalt-catalyzed coupling between functionalized aryl halides and alkenyl acetates 171 Kharasch, M. S.; Fuchs, C. F. J. Am. Chem. Soc. 1943, 65, 504-507. 172 Cahiez, G.; Avedissian, H. Tetrahedron Lett. 1998, 39, 6159-6162 173 Amatore, M.; Gosmini, C.; Perichon, J. Eur. J. Org. Chem. 2005, 989-992. The reaction was amenable with aryl bromides and chlorides but in some cases aryl chlorides led to slightly better yields. The reaction could also be extended to halopyridines with good yields obtained. The mechanistic pathway proposed by the authors is shown in Scheme 107. In the first step, the Co(II) salt is reduced by manganese powder in the presence of pyridine either in Co(I) or in Co(0) I. In an earlier study, Perichon reported that Co(I) is stabilized by vinylic acetate in an acetonitrile/pyridine mixture. 174 The low-valent cobalt species formed is likely to be coordinated by the vinyl acetate. Oxidative addition of the aryl halide would give an "arylcobalt" species II. This species could then react with vinylic acetate via a six-membered transition state III. Following reductive elimination, reduction of the cobalt by the excess of Mn would regenerate the active cobalt species. In 2003, the groups of Knochel and Cahiez reported the cross-coupling between heteroaryl chlorides and aryl-or heteroarylmagnesium halides (Scheme 108). 175 The reaction showed good substrate tolerance and was not sensitive to steric hindrance with the mesitylmagnesium chloride and 1-chloroisoquinoline coupled in 85% yield.

Scheme 108 CoCl 2 -Catalyzed Cross-coupling between Heteroaryl Chlorides and Aromatic or Heteroaromatic

Grignard Reagents

While the above example provides a synthetically facile method to access biaryl products, it requires the use of heteroaromatic or activated aromatic halides. Thus Nakamura and co-workers developed a cobalt-catalyzed cross-coupling reaction of nonactivated aryl chlorides or heteroaryl bromides and aromatic Grignard reagents (Scheme 109). 176 The reaction proceeds in the presence of cobalt(II) fluoride and a NHC ligand affording a wide range of biaryl products in high yields.

Aryl-Aryl coupling from two aromatic halides

Gosmini and co-workers also reported the synthesis of unsymmetrical biaryl compounds from the coupling of two aromatic halides ArX and Ar'X in the presence of a cobalt salt (Scheme 110). 177 The reaction requires the use of 2 equivalents or more of the more reactive aryl halide to obtain satisfactory yields of the desired cross-coupling product. Similar yields were obtained with aryl iodides, bromides and chlorides. However, the synthetic utility of this reaction is somewhat limited by the significant amount of homocoupling product produced. From a practical view point the presence of the homocoupled product would greatly increase the difficulty of any column chromatography.

Scheme 110 Synthesis of unsymmetrical biaryl compounds by coupling two aryl halides under cobalt catalysis

The proposed mechanism is similar to that put forward for nickel catalysis when an excess of reductant is present (Scheme 111). 178 The first step is the formation of a low-valent cobalt species presumably cobalt(I) I. An oxidative addition of the aryl halide followed by reduction of the cobalt center generates a cobalt(I) aryl species III which undergoes a second oxidative addition and finally a reductive elimination to afford the desired cross-coupled product.

This methodology was extended by the groups of Cahiez and Knochel to incorporate alkylzinc halides. 180 These reagents are less reactive than the corresponding organomagnesium halides therefore required longer reaction times and elevated temperatures. In addition to this higher catalytic loadings (20-30 mol%) and a large excess of organozinc halides (3 equiv) was required (Scheme 113).

Scheme 113 Cobalt-catalyzed alkenylation of benzylzinc bromide

In 2006, Oshima reported the cobalt-catalyzed cross-coupling between a variety of alkyl halides and 1-(trimethylsilyl)ethenylmagnesium bromide in the presence of CoCl 2 and TMEDA (Table 13). 181 High yields were obtained from either primary or secondary alkyl halides, but a large excess of Grignard reagent was required (4 equiv) and the reaction was specific to the use of this particular reagent. Based on previous work by the group of Oshima they propose a mechanism based on a radical oxidative addition that begins with single electron transfer from a cobalt complex to alkyl halide. 182 Table 13 Cross-coupling between primary or secondary alkyl halides and 1-(trimethylsilyl)ethenylmagnesium bromide

Arylation

In 1969 Hey reported the first example of a cobalt-catalyzed arylation of a C-(sp 3 ) center. A significant improvement in yield was observed in the reaction of 2-bromopyridine and 180 Avedissian, H.; Berillon, L.; Cahiez, G.; Knochel, P. Tetrahedron Lett. 1998, 39, 6163-6166. 181 Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2006, 8, 3093-3096. 182 Tsuji, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006, 128, 1886-1889. 270 methylmagnesium iodide in the presence of a catalytic amount of cobalt(II) chloride (Scheme 114). 183

Scheme 114 First cobalt-catalyzed arylation of aliphatic Grignard reagents

Then in 2001, Oshima described the cobalt-catalyzed tandem radical cyclization and arylation reaction between a variety of halo acetals and a phenyl Grignard reagents. 184 The reaction can be applied to the synthesis of a range of heterocyclic compounds and yields are generally good. However, yields were shown to vary quite significantly depending on the position and number of substituents on the substrate (Table 14).

Table 14 Tandem radical cyclization and cross-coupling reaction from unsaturated haloacetals

It is worth mentioning that when the reaction is performed with starting substrates where the alkene is not terminal, the arylation product is not observed. In these cases a regioselective β-hydride elimination occurs to furnish the cyclized product (Scheme 115) 183 Davies, D. I.; Done, J. N.; Hey, D. H. J. Chem. Soc. C 1969, 2019-2021. 184 Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2001, 123, 5374-5375. The group of Cahiez also reported the cross coupling between functionalized alkyl halides and aliphatic Grignard reagents in the presence of the ate complex CoCl 2 •2LiI with TMEDA as a ligand.187 A good variety of substrates were examined, acyclic and secondary alkyl bromides gave moderate to good yields of the cross-coupled product. The absence of a significant steric hindrance was vital in determining the success of the reaction. Thus, 2bromopentane gave a better yield than 3-bromopentane, while tert-pentyl bromide was unreactive. In addition the reaction showed good tolerance with ester, nitriles and ketones groups possible.

Cobalt-Catalyzed Heck-type reactions

The Heck reaction is an incredible useful tool for the elaboration of C-C bonds.188 However as mentioned earlier, a limitation of the reaction of the decomposition of the alkylpalladium species through β-hydride elimination. The cobalt-catalyzed version is complementary to the classical palladium-catalyzed version since it avoids this particular drawback. The group of Branchaud was the first to report a cobalt-catalyzed Heck-type reaction between styrene and various alkyl halides using a stoichiometric amount of zinc as reductant. 189Oshima and co-workers later reported that excellent yields could be obtained using a catalytic system of CoCl 2 •dpph and trimethylsilylmethylmagnesium chloride as reductant (Scheme 120).190

Scheme 120 CoCl 2 (dpph)-catalyzed Heck-type reaction

Primary, secondary and tertiary alkyl halides were all smoothly converted to the desired product. It was observed that alkyl bromides generally gave better results than the corresponding iodides or chlorides. The use of functionalized styrene derivatives was also feasible with ortho, meta and para chloro-styrenes participating in the current reaction in yields above 80 %.

The mechanism proposed by Oshima is shown in (Scheme 121). At first, CoCl 2 •dpph reacts with Me 3 SiCH 2 MgCl to give Co(0)•dpph I, which is the active catalytic species. A single electon transfer to the alkyl halide leads to the Co(I) species II that reacts with Me 3 SiCH 2 MgCl to generate the intermediate III. This intermediate in turn reacts with the benzylic radical resulting from RX to produce the cobalt species IV. The Heck product is then obtained from this species via a β-hydrogen elimination. Finally, Co(0)•dpph is regenerated from the hydridocobalt species V by reductive elimination.

Project Aims and Goals

Encouraged by our earlier results on the use of low-valent cobalt complexes for the functionalization of C-H bonds, we became interested in the application of such complexes for the C-H coupling reaction. As previously discussed, the group of Klein has extensively explored the ability of low-valent cobalt complexes to perform C-H activation. In particular MeCo(PMe 3 ) 4 has proven to be particular effective for these cyclometallation reactions (Scheme 122). 8,9,10,11,12 Scheme 122 Cyclometallation reaction However, if we are to be successful in performing a C-H activation/coupling reaction with a halide partner we would need to find a suitable reagent to regenerate the cobalt catalyst. Inspired by previous results based on rhodium, the use of dialkylzinc reagents seemed like an attractive option.191 Indeed, a common feature of many coupling reactions is the need for an excess of organometallic reagents such as Grignard reagents to generate and reform the catalytically active species. It was previously shown by the group of Knochel that dialkyl zinc reagents are capable of transferring both alkyl groups to the cobalt center. Therefore a combination of both a well-defined low valent cobalt complex in the presence of a substoichiometric amount of dialkyl zinc reagent should in theory provide a simple catalytic system for a C-H coupling reaction.

The hypothetical catalytic cycle for this reaction is shown below (Scheme 123). An orthodirected C-H activation followed by reductive elimination of methane will furnish the cyclometallated product described by Klein. A subsequent SET or oxidative addition of the halide partner will lead to a cobalt(III) intermediate. A reductive elimination followed by a transmetallation with Me 2 Zn would regenerate the active cobalt(I) species MeCo(PMe 3 ) 4 . pharmaceuticals, agrochemicals and polymers. 193 Many of these homocoupling reactions have been carried out in the presence of both stoichiometric and catalytic amounts of metals such as nickel, 194 rhodium 195 and palladium 196 among others. Cobalt has also been used to promote benzyl halide dimerization, however to date, compared to oxidative coupling, 197 no catalytic turnover under reductive conditions has been achieved. 198

Scope and limitations

Upon further exploration of reaction conditions it was found that reaction proceeds under mild reaction conditions (40 °C to 66 o C), at low catalyst loadings (0.5 to 5 mol%) and in a short reaction time (10 to 60 min). In addition, the procedure is easily scalable to 10 mmol without any decrease in yield. It is worth noting the reaction proceeds at room temperature in 18 h with only a slight decrease in yield (75 %). Me 2 Zn, Et 2 Zn and Me 3 Al were all investigated as transmetallation reagents with Me 2 Zn proving as the most efficient. The dimerization is compatible with a variety of solvents. It proceeds most rapidly in toluene however direct substitution of the benzyl halide by Me 2 Zn was an issue. This problem could be completely eradicated on switching the reaction medium to THF.

Homocoupling reactions mediated by a stoichiometric amount of ClCo(PPh 3 ) 3 have been reported to proceed through single electron transfer (SET) followed by dimerization of the produced benzylic radical. 198 Involvement of radicals in our system was confirmed using 1 equivalent of TEMPO as radical scavenger to form 115 as the sole product as confirmed by GC analysis (entry 4). The suggestion of a radical process was also reinforced by the absence of any -hydride elimination type product in the case of substituted starting material. We thus hypothesised that the aforementioned formation of Cl 2 Co(PMe 3 ) 3 would be the result of two consecutive SET reactions.

To further probe this hypothesis, we synthesised the postulated reaction intermediates i.e. ClCo(PMe 3 ) 3 and Cl 2 Co(PMe 3 ) 3. . To this end we examined the reaction of 10 mol% ClCo(PMe 3 ) 3 in the absence of Me 2 Zn. A conversion of 10 % of the starting material to the desired homocoupling product was observed, suggesting ClCo(PMe 3 ) 3 is capable of promoting the dimerization of 1 equivalent of benzyl halide (entry 5). With the addition of Me 2 Zn to the reaction mixture we were able to reactivate the active catalytic species leading to complete conversion to the desired product (entry 6). Finally we exposed Cl 2 Co(PMe 3 ) 3 to benzyl bromide under standard reaction conditions in the absence of zinc. No conversion to the homocoupling product was observed but as before we could regain catalytic activity through the addition of Me 2 Zn (entries 7 and 8). As previously reported the use of ClCo(PPh 3 ) 3 yielded the homocoupling product in quantitative yield (entry 9). However to our surprise using Me 2 Zn we could not achieve a catalytic turnover starting from ClCo(PPh 3 ) 3 (entry 10). We can suppose that the hypothetical methyl-cobalt intermediate bearing triphenylphosphine ligands undergoes internal rearrangement and thus degradation of the catalytic species. 199Putting together our control and radical trapping experiments in combination with our study on the precise role of zinc we can propose the following catalytic cycle (Scheme 131). First a single electron transfer would generate the cobalt(I) intermediate II and a benzylic radical that can undergo dimerization. Intermediate II also undergoes SET to furnish the cobalt(II) III species and a benzylic radical that again participates in a dimerization reaction. Intermediate III would then undergo transmetallation with dimethylzinc to lead to the formation of dimethyl cobalt(II) species IV. This intermediate would evolve rapidly through a reductive elimination of ethane (Note: bubbling is observed during the reaction) leading to the regeneration of the catalytically active cobalt(0) species Co(PMe 3 ) 4 I.

Conclusion

In summary, to the best of our knowledge we disclose a cobalt-catalyzed reductive homocoupling of benzyl halides (Scheme 132). Chemical susceptible motifs such as bromo-, chloro-, iodo-and nitro-substituted benzyl halides were all smoothly converted under our reaction conditions. In addition the use of well-defined low valent cobalt complexes has allowed us to gain a greater mechanistic insight than usually reported using cobalt salt. We also report a novel approach to the regeneration of the cobalt(0) species through a combination with Me 2 Zn. Further investigations are currently underway to understand why ClCo(PPh 3 ) 3 cannot be used catalytically in the presence of dimethylzinc.

Scheme 132 Homocoupling of benzyl halides with low-valent cobalt complexes

General Conclusion

The aim of this project was to explore the family of well-defined cobalt complexes RCo(PMe 3 ) 4 with particular emphasis on their application towards C-H bond functionalization. Our study began with the synthesis of this family of catalysts which have been previously described by the group of Klein. We successfully synthesized a variety of low-valent cobalt complexes for example Co(PMe 3 ) 4 , HCo(PMe 3 ) 4 , MeCo(PMe 3 ) 4 among others.

Based on the pioneering work on cobalt-catalyzed C-H bond functionalization from the groups of Kline, Kisch and Yoshikai we identified a number of areas we felt improvement could be achieved. Firstly, the ''catalytic cocktail'' of cobalt salt, excess Grignard reagent, ligand and sometimes additives employed by Yoshikai, make gaining mechanistic insight very difficult. The exact oxidation state of the active cobalt species and the precise role of the Grignard reagent still remain unknown. Secondly, the use of excess Grignard reagent somewhat limits substrate scope and chemical sensitive groups such as esters and generally not compatible. Thirdly, extensive optimization of reaction conditions is necessary on switching from one substrate to another, limiting the practicality of this approach.

We have demonstrated that the use of as Co(PMe 3 ) 4 and HCo(PMe 3 ) 4 in catalytic amounts are effective for the hydroarylation of alkenes and alkynes with a variety of substrates. We have successfully synthesized a variety of substituted aryl ketimines, 1,2-dihydropyridines and C-2 substituted indoles. We have shown that these reactions do not require the use of Grignard reagents and no reoptimization of reaction conditions was necessary on switching from one substrate to another. We also performed detailed mechanistic studies, comprising of deuterium-labelling experiments and DFT calculations. We disclosed an interesting ligand-toligand hydrogen transfer mechanism was operational, a pathway not previously proposed for cobalt-catalyzed C-H functionalization.

Given the success of our initial study with this family of catalysts we began to explore the possibility of applying them to other bond activations. It was noted that a combination of Co(PMe 3 ) 4 and a hydrosilane led to the reduction of aryl ketimines during our previous study. This observation led to explore the less studied hydrosilylation of alkynes. While there has been some success in the area, most notably by the group of Deng, the hydrosilylation of alkynes under cobalt catalysis still suffers from poor regio-and stereocontrol. In addition, the use of tertiary hydrosilanes remains problematic.

In this thesis we show that catalytic amounts of HCo(PMe 3 ) 4 is efficient for the hydrosilylation of a variety of internal unsymmetrical alkynes with good regio-and stereocontrol. Interestingly we observed the opposite regioselectivity than Deng in the case of TMS protected alkynes. In addition it was possible to perform the reaction with a large variety of hydrosilanes. From a mechanistic point of view, we isolated an interesting dihydrocobalt(III) intermediate which we believe to be a key component of the reaction mechanism.

Finally, the ability of these catalysts to perform the homocoupling of benzyl halides is discussed. The reaction ran smoothly for a variety of benzyl bromides and chlorides with excellent yields obtained in most cases. Our initial mechanistic studies suggest the reaction operates via a two SET and that dimethyl zinc acts just to regenerate the catalyst.

To conclude we have demonstrated that this family of low-valent cobalt complexes is very versatile and capable of a variety of bond functionalization. A summary of the result presented in the manuscript is shown in Figure 30. The study has opened up a variety of other interesting possibilities that will be further explored in the lab.

  a) L'hydroarylation d'alcynes par des aryl-cétimine via une activation de liaisons C-H. b) La synthèse de 1,2-dihydropyridines par une séquence activation de liaisons C-H / hydrovinylation d'alcynes / 6π-électrocyclisation. c) C2-alkylation et alcénylation intra-et intermoléculaires d'indoles.

Figure R 1 4 Figure R 2

 142 Figure R 1 DFT états de transition pour l'activation C-H avec les deux catalyseurs Co(PMe 3 ) 4 et HCo(PMe 3 ) 4

Figure R 3

 3 Figure R 3 État de transition Le mécanisme proposé est illustré ci-dessous (Scheme R 6). Comme pour notre mécanisme précédent l'étape clé est une étape concertée de C-H activation / transfert d'hydrogène.

Figure R 4

 4 Figure R 4 DFT calculée pour l'activation C-H (A) diphénylacétylène et (B) le styrène. L' isosurface de densité de spin est également indiquée (orange: densité de spin alpha; vert: densité de spin bêta).

Figure R 5

 5 Figure R 5 Produit de type 97 vs type 97'

Figure R 7

 7 Figure R 7 Surface d'énergie potentielle calculée par DFT pour H 2 élimination réductrice.

Figure 1

 1 Figure 1 Electronegativities and electronic configuration of group 8,9 and 10 elements

  Scheme 26 Proposed catalytic cycle for the cobalt catalyzed alkylation with organic electrophiles

Figure 4

 4 Figure 4 Representative high valent cobalt complexes

Figure 5

 5 Figure 5 Reaction scope for the hydroarylation of internal alkynes by aryl ketimines

Figure 6

 6 Figure 6 Reaction scope for the hydroarylation of internal alkynes by aryl ketimines

Figure 7

 7 Figure 7 Reaction scope for the hydroarylation of internal alkynes by aryl ketimines

Figure 9 4 Figure

 94 Figure 9 DFT transition states for the C-H activation for both Co(PMe 3 ) 4 & HCo(PMe 3 ) 4

Figure 12

 12 Figure 12 Syn/Anti isomerization

  (a) Lim, S.-G.; Lee, J. H.; Moon, C. W.; Hong, J.-B.; Jun, C.-H. Org. Lett. 2003, 15, 2759-2761 (b) Katagiri, T.; Mukai, T.; Satoh, T.; Hirano, K.; Miura, M. Chem.

  63

Figure 16

 16 Figure 16 DFT calculated transition state structure for the C-H activation, Spin density is also shown in yellow

  Scheme 60 C-2 alkylation of indole 81a with styrene

Figure 23

 23 Figure 23 DFT-calculated TS structures for the C-H activation, respectively with (A) diphenylacetylene and (B) styrene. The spin density isosurface is also shown (orange: alpha spin density ; green : beta spin density). Based on the results from the deuterium-labeling experiments and DFT calculations, we can propose a common catalytic cycle for both alkenylation and alkylation (Scheme 69). This cycle consists of a concerted C-H activation/hydrogen transfer to generate an intermediate (II). The H/D scrambling observed during the reaction of 81a-d with 38i suggests that this initial step is reversible for the alkene via β-hydride elimination. Intermediate II would then undergo a reductive elimination resulting in the formation of intermediate III. The anti-selectivity observed in the hydroarylation of alkynes can be explained by isomerization of the double bond. 68

  Scheme 72 C(sp 3 )-H bond activation in the presence of a stoichiometric low-valent cobalt species

  1 H NMR (C 6 D 6, 400 MHz): δ = 1.25 (s, 36 H), -17.35 (quint, J = 32.7 Hz, 1 H) ppm; 13 C NMR (C 6 D 6, 100 MHz): δ = 27 ppm; 31 P NMR (C 6 D 6, 160 MHz): δ = 0.09 (br s) ppm.

  1 H NMR (C 6 D 6, 400 MHz): δ = 1.14 (s, 36 H), -0.44 (s, 3 H) ppm; 13 C NMR (C 6 D 6, 100 MHz): δ = 23.7 (12 C), -6.0 ppm; 31 P NMR (C 6 D 6, 400 MHz): δ = -1.77 (br s) ppm.

  94

7. 3

 3 Experimental section for the hydroarylation of alkynes by aryl ketimines 7.3.1 General Procedure A: Preparation of Imines.

  δ 8.04 -7.90 (m, 2H), 7.04 -6.88 (m, 4H), 6.83 -6.73 (m, 2H),3.90 (s, 3H), 3.86 (s, 3H), 2.26 (s, 3H).13 C NMR (100 MHz, CDCl 3 ):164.2, 161.5, 155.5, 145.2, 137.4, 132.6, 128.3 (2C), 121.0 (2C), 114.2 (2C), 113.7, 55.6, 55.1, 17.0.(E)-1-(4-(tert-butyl)phenyl)-N-(4-methoxyphenyl)ethan-1-imine (24d)According to the general procedure (A). Light yellow solid (85%). mp: 105 o C, 1 H NMR (400 MHz, CDCl 3 ): 7.89 -7.94 (m, 2H), 7.45 -7.51 (m, 2H), 6.89 -6.94 (m, 2H), 6.72 -6.78 (m, 2H), 3.82 (s, 3H), 2.25 (s, 3H), 1.37 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 165.4, 155.8, 153.7, 145.0, 137.0, 126.9 (2C), 125.2 (2C), 120.7 (2C), 114.2 (2C), 55.5, 34.8, 31.2 (3C), 17.1. HRMS (ESI) Calcd for C 19 H 24 NO [M+H]+ 282.1852, found 282.1845. 96 Chen, F.; Ding, Z.; He, Y.; Qin, J.; Wang, T.; Fan, Q.-H. Tetrahedron, 2012, 68, 5248-5257.

  , CDCl 3 ): 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 6.96 (m, 2H), 6.80 (m, 2H), 3.86 (s, 3H), 2.31 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 163.

  , CDCl 3 )δ 7.83 -7.63 (m, 2H), 7.44 (m, 1H), 7.19 (m, 1H), 7.03 - 6.90 (m, 2H), 6.83 -6.73 (m, 2H), 3.86 (s, 3H), 2.28 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): 164.1, 163.0 (d, J = 274 Hz), 163.3, 156.2, 144.0, 142.1 (d, J = 7.7 Hz), 129.8 (d, J = 8.6 Hz), 122.2, 120.7 (2C), 117.2 (d, J = 22 Hz), 114.3, 114.0 (d, J = 23 Hz), 55.1, 17.0.97 Wu, J.; Barnard, J. H.; Zhang, Y.; Talwar, D.; Robertson, C. M.; Xiao,J. Chem.Commun. 2013, 49, 7052-7054.

  . HRMS (ESI) Calcd for C 33 H 34 NO [M+H]+ 460.2635, found 460.2639. The general procedure (B) was applied to (E)-1-(4-fluorophenyl)-N-(4methoxyphenyl)ethan-1-imine (24e 121.5 mg, 0.5 mmol) and diphenylacetylene (178.1 mg, 1 mmol). Silica gel chromatography (eluent pentane/diethyl ether 95/5) afforded the title compound as a yellow/orange oil which was subsequently crystallised from pentane/DCM to give yellow crystals (168.4 mg, 80% yield) mp: 112 o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.63 (dd, J = 8.6, 5.8 Hz, 1H), 7.38 -7.29 (m, 5H), 7.23 -7.09 (m, 6H), 7.06 (s, 1H), 6.95 (dd, J = 9.4, 2.7 Hz, 1H), 6.78 -6.71 (m, 2H), 6.23 -6.16 (m, 2H), 3.75 (s, 3H), 1.88 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 168.1, 163.07(d, J = 249.3 Hz)155.8, 144.1, 142.1, 140.8 (d, J = 1.5 Hz), 140.6 (d, J = 8.0 Hz), 138.9(d, J = 3.2 Hz), 136.7, 130.8 (d, J = 8.6 Hz), 129.5 (2C), 129.0, 128.4 (2C), 128.3 (2C), 127.8, 127.5 (2C), 127.3, 120.2 (2C), 118.5 (d, J = 21.4 Hz), 114.9 (d, J = 21.2 Hz), 113.9 (2C), 55.4, 19.8. 19 F NMR (376 MHz, CDCl 3 ) δ -112.4. IR (neat, cm-1): ν max

  . HRMS (ESI) Calcd for C 30 H 25 N 2 O [M+H]+ 429.1961, found 429.1944.

  The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(ptolyl)ethan-1-imine (24b, 119.5 mg, 0.5 mmol) and 1-phenyl-2trimethylsilylacetylene (118 µL, 0.6 mmol). Silica gel chromatography (eluent pentane/diethyl ether 90/10) afforded the title compound as a yellow oil (130.1 mg, 63% yield).

  The general procedure (C) was applied to (E)-1-(4-(tert-butyl)phenyl)-N-(4-methoxyphenyl)ethan-1-imine (24d, 140.5 mg, 0.5 mmol) and

  , 6.95 (m, 7H), 6.89 -6.82 (m, 8H), 5.87 (s, 1H), 5.76 (s, 1H), 5.41 (m, 1H), 5.35 (d, J = 1.0 Hz, 1H), 3.80 (s, 6H), 1.93 (m, 3H), 1.90 (d, J = 1.0 Hz, 3H). 13 C NMR (100 MHz, Acetone-d 6 ) δ 158.

  19 F NMR (376 MHz, Acetone-d 6 ) δ -62.7. IR (thin film):  max = 2955, 2360, 1505, 1324, 1245, 1123, 842 cm -1 . HRMS (ESI): calculated for C 26 H 21 F 3 NO [M-SiC 3 H 9 ] + : 420.1584; found 420.1582.

  , 5.79 (d, J = 1.0 Hz, 1H), 4.36 (s, 1H), 3.78 (s, 3H), 3.65 (s, 3H), 1.88 (d, J = 0.7 Hz, 3H), 0.09 (d, J = 5.1 Hz, 9H). 13 C NMR (100 MHz, Acetone-d 6 ) δ 159.

  2951, 1503, 1243, 1071, 833 cm -1 . HRMS (ESI): calculated for C 27 H 30 N 2 OSi [M-H] + : 427.2200; found 427.2212.

  m, 2H), 5.15 (q, J = 7.4 Hz, 1H), 3.85 (s, 3H), 3.50 (s, 3H), 1.89(d, J = 7.4 Hz, 3H).13 C NMR (100 MHz, CDCl 3 δ 157.

  85 -6.81 (m, 2H), 5.06 (q, J = 7.9 Hz, 1H), 3.38 (s, 3H), 1.77 (d, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 161.5(d, J = 245.5 Hz), 157.

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 8.68 (s, 1H), 8.44 (dd, J = 8.4, 0.5 Hz, 1H), 7.31 (dd, J = 1.8, 0.5 Hz, 1H), 7.25 -7.20 (m, 3H), 6.97 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.70 (s, 3H), 3.05 -2.96 (m, 2H), 0.97 -0.85 (m, 2H), 0.15 -0.08 (m, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 157.

  115

Figure

  Figure 24 Karstedt's catalyst

  Scheme 87 Co 2 (CO) 8 -catalyzed hydrosilylation of fluoro-containing alkynes

  Scheme 90 Reactions of (IAd)(PPh 3 )Co(CH 2 SiMe 3 ) with PhC≡CPh and H 2 SiPh 2

Figure 25

 25 Figure 25 Product type 97 vs type 97'

Figure

  Figure 26 Evolution of cobalt(III) species followed by 1 H NMR (Co-H peak)

Figure 28

 28 Figure 28 DFT calculated potential energy surface for the three main processes: hydrocobaltation, silacobaltation and H 2 reductive elimination

  (m, 9H), 0.95 (s, 27H), -14.72 (s, 2H). 13 C NMR (100 MHz, C 6 D 6 ) δ 150.1, 136.7, 127.0, 126.5, 23.8. 31 P NMR (162 MHz, C 6 D 6 ) δ 4.72. 29 Si NMR (119 MHz, C 6 D 6 ) δ 9.69 (J Si-P = 24,79 Hz).

  Minor product: triphenyl-[(E)-1-butylvinyl-2-phenyl)]silane relevant signal: 1 H NMR (400 MHz, CDCl 3 ) δ 2.35 (m, C=C(Si)-CH 2 -). Other signals are overlapped with the major product.

0 .

 0 IR (thin film):  max 3069, 2955, 2360, 2341, 1485. HRMS (ESI) calculated for C 30 H 29 F 3 NaSi 2 [M+Na] + 525.1652, found 525.1636.

0 .

 0 IR (thin film):  max 3067, 3050, 2952, 2360, 2341, 1601. HRMS (ESI) calculated for C 34 H 34 NaOSi 2 [M+Na] + 537.2040, found 537.2042.

0 .

 0 Minor product: triethoxy-[(Z)-(1-phenyl-2-(trimethylsilyl)vinyl)]silane relevant signals: 1 H NMR (400 MHz, CDCl 3 ) δ 6.94 (s, C=CH), 0.36 (s, TMS). 13 C NMR (100 MHz, CDCl 3 ) δ 57.9 (O-CH 2 -CH 3 ), 0.4 (TMS). Other signals are overlapped with the E-isomer.

   4H), 6.88 (s, C=CH, 1H), 3.91 (m, O-CH 2 -CH 3 and O-CH 3 ), 1.30 (t, J = 7 Hz, O-CH 2 -CH 3 ), 0.33 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.

  Minor product: Triethoxy-[(Z)-(1-(4-methoxyphenyl)-2-(trimethylsilyl)vinyl)]silane relevant signals: 1 H NMR (400 MHz, CDCl 3 ) δ 7.18, 6.94 (m, 4H), 6.79 (s, C=CH), 0.37 (s, TMS). 13 C NMR (100 MHz, CDCl 3 ) δ 58.3 (O-CH 2 -CH 3 ), 17.9 (O-CH 2 -CH 3 ), 0.4 (TMS). Other signals are overlapped with the E-isomer. Triethoxy-[(E)-(1-(4-trifluoromethyl)phenyl-2-(trimethylsilyl)vinyl)]silane (97bg)

0 .

 0 IR (thin film):  max 2975, 2928, 2358, 2340, 1614. HRMS (ESI) calculated for C 18 H 29 F 3 NaO 3 Si 2 [M+Na] + 429.1500, found 429.1498. Minor product: Triethoxy-[(Z)-(1-(4-trifluoromethyl)phenyl-2-(trimethylsilyl)vinyl)]silane relevant signals: 1 H NMR (400 MHz, CDCl 3 ) δ 7.68, 7.57 (dd, J = 8.2 Hz), 6.91 (s, C=CH), 0.37 (s, TMS). 13 C NMR (100 MHz, CDCl 3 ) δ 58.6 (O-CH 2 -CH 3 ), 18.0 (O-CH 2 -CH 3 ), 0.3 (TMS). Other signals are overlapped with the E-isomer.

Scheme 107

 107 Scheme 107 Mechanism proposal for the cobalt-catalyzed alkenylation of aryl halides by vinyl acetates

3. 2

 2 Aryl-Aryl cross-coupling 3.2.1 Aryl-Aryl cross-coupling from ArX and ArMgX

Figure 30

 30 Figure 30 Summary of PhD work

Table R 6 Etude mécanistique de la réaction d'homocouplage

 R Sur la base de notre étude mécanistique, nous proposons le mécanisme suivant(Scheme R 19)

  2

Table 1 Abundance of selected transition metals in earth's crust

 1

Scheme 22 Proposed catalytic cycle for the cobalt catalyzed C-H arylation

40 Li, J.; Ackermann, L. Chem.

Eur. J. 2015, 21, 5718-5722.

Scheme 38 Our approach versus that of Klein

	59 (a) Xu, G.; Sun, H.; Li, X. Organometallics 2009, 28, 6090-6095 (b) Wu, S.; Li, X.; Xiong, Z.; Xu, W.; Lu, Y.; Sun, H.
	Organometallics 2013, 32, 3227-3237.

Table 3 Optimization of reaction conditions 62

 3 Kappe, C. O.; Pieber, B.; Dallinger, D. Angew. Chem. Int. Ed. 2013, 52, 1088-1094 and references therein.

1 H NMR (400 MHz, CDCl 3 ): δ

  7.86 (m, 1H), 7.76 (m, 1H), 7.40 -7.26 (m, 2H), 7.00 -6.91 (m, 2H), 6.83 -6.75 (m, 2H), 3.85 (s, 3H), 2.46 (s, 3H), 2.27 (s, 3H).

13 C NMR (100 MHz, CDCl 3

): δ 165.

1 H NMR (400 MHz, CDCl 3 ): δ

  7.62 (dd, J = 2.7, 1.6 Hz, 1H), 7.54 (m, 1H), 7.38 (ddd, J = 8.2, 7.7, 0.4 Hz, 1H), 7.04 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H),6.99 -6.90 (m, 2H), 6.84 -6.74 (m, 2H), δ 3.90 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H).

13 C NMR (100 MHz, CDCl 3 ): 163

  .2, 162.1, 155.2, 145.2, 137.4, 132.6, 128.1 (2C), 122.0 (2C), 114.8 (2C), 113.7, 55.9, 55.6, 17.3

1 H NMR (400 MHz, CDCl 3 ) δ

  7.59 (d, J = 1.8 Hz, 1H), 7.46 (dd, J = 8.2, 1.8 Hz, 1H), 2H), 6.87 (d, J = 8.2 Hz, 1H), 2H), 6.04 (s, 2H), 3.84 (s, 3H), 2.22 (s, 3H).

13 C NMR (100 MHz, CDCl 3

):  164.

  0.

98

Moessner, C.; Bolm, C. Angew. Chem. Int. Ed. 2005, 44, 7564-7567. 99

Yoshikai, N.; Matsumoto, A.; Norinder, J.; Nakamura, E. Angew.

Chem. Int. Ed. 2009, 48, 2925[START_REF]] + 493.2146, found 493.2160. Triphenyl-[(E)-(1-phenyl-2-(trimethylsilyl)vinyl)]silane (97ae) The general procedure (K) was applied to 1-phenyl-2-trimethylsilylacetylene (87 mg, 0.5 mmol) and triphenylsilane[END_REF]

  . HRMS (ESI) Calcd for C 29 H 26 NO [M+H]+ 404.2009, found 404.2025.

IR (neat, cm-1): ν max 3056

  , 3021, 2832, 1633, 1502, 1239, 1033, 907, 766, 728. HRMS (ESI) Calcd for C 30 H 28 NO [M+H]+ 418.2165, found 418.2178.

	, 128.7
	(2C), 128.2 (2C), 128.2, 128.1 (2C), 127.5, 127.5 (2C), 126.9, 120.2 (2C), 113.8 (2C), 55.3, 21.2,
	19.8.

-1,2-diphenylvinyl)-3-((E)-1-((4-methoxyphenyl)imino)ethyl)benzonitrile (25g)

  . HRMS (ESI) Calcd for C 30 H 28 NO 2 [M+H]+ 434.2115, found 434.2009. .86 mg, 0.6 mmol). Silica gel chromatography (eluent pentane/diethyl ether 85/15) afforded the title compound as a yellow oil which was subsequently crystallised from pentane/DCM to give yellow crystals (179.8 mg, 84% yield) mp: 135 o C. 1

	2-((Z)The	general	procedure	(B)	was	applied	to	(E)-3-(1-
	((4methoxyphenyl)imino)ethyl)benzonitrile (24g, 125.5 mg, 0.5 mmol) and
	diphenylacetylene (106

H NMR (400 MHz, CDCl 3 ) δ

  7.82 (dd, J = 7.8, 1.4 Hz, 1H), 7.72 (dd, J = 7.8, 1.4 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H),

1 H NMR (400 MHz, CDCl 3 )

  Calcd for C 23 H 20 NaO + [M+Na + ] 335.1406, found 335.1411.

	δ 7.52 -7.47 (m, 1H), 7.34 (m, 2H), 7.21
	(m, 3H), 7.20 -7.15 (m, 3H), 7.06 -7.00 (m, 3H), 6.93 -6.87 (m, 3H), 2.57 -2.24 (m, 2H), 0.74
	(t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 204.4, 142.6, 141.9, 140.8, 139.3, 137.1, 132.1,
	131.1, 129.4 (2C), 128.2 (2C), 128.1 (2C), 128.0 (2C), 127.6 (2C), 127.5, 127.4, 126.8, 34.0, 7.9. IR

(neat, cm-1): ν max

3081, 3021, 2975, 1695, 1492, 1444, 1216, 951, 762, 695

. HRMS (ESI)

7.3.3 General Procedure C: Addition of Aryl Imines to Substituted Internal Alkynes

1 H NMR (400 MHz, CDCl 3 )

	δ 7.47 (d, J =
	7.8 Hz, 1H), 7.32 -7.22 (m, 6H), 7.17 -7.12 (m, 1H), 6.80 -6.67 (m, 2H),
	6.36 (s, 1H), 6.20 -6.09 (m, 2H), 3.75 (s, 3H), 2.44 (s, 3H), 1.87 (s, 3H), -
	0.04 (s, 9H).

13 C NMR (100 MHz, CDCl 3

) δ 169.

  Calcd for C 27 H 32 NOSi [M+H]+ 414.2248, found 414.2231.

	4, 21.2, 20.6,
	0.0 (3C).IR (neat, cm-1): ν max 3057, 2950, 2832, 2639, 1502, 1206, 951, 864, 825, 765. HRMS
	(ESI)

13 C NMR (100 MHz, CDCl 3

	1-
	phenyl-2-trimethylsilylacetylene (118 µL, 0.6 mmol). Silica gel
	chromatography (eluent pentane/diethyl ether 90/10) afforded the title
	compound as a yellow oil (193 mg, 85% yield). 1 H NMR (400 MHz,
	CDCl 3 ) δ 7.52 -7.44 (m, 2H), 7.33 (d, J = 1.8 Hz, 1H), 7.25 (m, 5H), 6.76 -
	6.69 (m, 2H), 6.37 (s, 1H), 6.22 -6.12 (m, 2H), 3.74 (s, 3H), 1.87 (s, 3H),
	1.39 (s, 9H), -0.06 (s, 9H).

) δ 169.

  Calcd for C 30 H 38 NOSi [M+H]+ 456.2717, found 456.2712.

	.1 (2C), 128.0, 127.7, 127.2 (2C), 125.1, 120.2 (2C), 113.8 (2C),
	55.3, 34.6, 31.3 (3), 20.4, -0.2 (3). IR (neat, cm-1): ν max 3044, 2964, 2827, 2645, 1524, 1227,
	948, 850 830, 760. HRMS (ESI)

1 H NMR (400 MHz, CDCl 3 ) δ

	1-phenyl-
	2-trimethylsilylacetylene (118 µL, 0.6 mmol). Silica gel chromatography
	(eluent pentane/diethyl ether 90/10) afforded the title compound as a
	yellow oil (184.2 mg, 81% yield). 7.51 -7.45
	(m, 2H), 7.42 -7.30 (m, 5H), 7.29 -7.23 (m, 1H), 6.90 -6.80 (m, 2H), 6.72
	(s, 1H), 6.47 -6.36 (m, 2H), 3.83 (s, 3H), 1.97 (s, 3H), -0.01 (s, 9H). 13 C
	NMR (100 MHz, CDCl 3 ) δ 169.4 , 162.4 (d, J = 272 Hz), 160.0, 156.9, 148.0, 145.1 (d, J = 2.7 Hz),
	144.9, 142.8, 134.1 (d, J = 1.6 Hz), 130.3 (d, J = 8.7 Hz), 129.4(2C), 128.9, 127.6(2C), 124.9 (d, J =
	3.2 Hz), 121.4 (2C), 116.9 (d, J = 23.7 Hz), 115.1 (2C), 56.4, 21.8, 0.0 (3C). 19 F NMR (376 MHz,
	CDCl 3 ) δ -114.2. IR (neat, cm-1): ν max 3056, 3021, 2952, 2832, 1639, 1502, 1240, 1077, 824,
	751. HRMS (ESI) Calcd for C 26 H 29 NOSi [M+H]+ 418.1997, found 418.2004.

NMR (100 MHz, CDCl 3

	1 H
	NMR (400 MHz, CDCl 3 ) δ 7.54 (m, 2H), 7.42 -7.30 (m, 3H), 7.24 (m,
	2H), 7.17 -7.01 (m, 5H), 7.02 -6.84 (m, 6H), 5.54 (s, 1H), 5.41 (s, 1H), 3.84 (s, 3H), 1.93 (s, 3H).

13 C ) δ 161.6

1 H NMR (400 MHz, CDCl 3 )

	δ 7.50 -7.45
	(m, 4H), 7.35 -7.31 (m, 5H), 7.11 -7.04 (m, 5H), 6.94 -6.89 (m, 2H), 6.87 -6.83 (m, 2H), 5.53
	(s, 1H), 5.32 (s, 1H), 3.81 (s, 3H), 1.91 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 157.1, 146.4, 142.8,
	140.0, 138.6, 132.4 (2C), 131.7 (2C), 130.1 (2C), 129.5 (2C), 128.3 (2C), 128.0 (2C), 127.6, 127.1
	(2C), 126.8 (2C), 126.

1 H NMR (400 MHz, Acetone-d 6 ) δ

	8.00 (dd, J = 10.4, 4.8 Hz, 2H), 7.65
	(dd, J = 8.2, 1.3 Hz, 2H), 7.49 (m, 2H), 7.44 (m, 2H), 7.31 (m, 6H), 7.25 -7.15 (m, 4H), 7.10 -7.03
	(m, 4H), 6.80 -6.75 (m, 2H), 6.40 (s, 1H), 5.93 (s, 1H), 3.61 (s, 3H). 13 C NMR (100 MHz, Acetone-
	d 6 ) δ 156.

  . IR (thin film):  max = 3054, 2951, 1505, 1243, 834 cm -1 . HRMS (ESI): calculated for C 25 H 22 NO [M-SiC 3 H 9 ] + : 352.1696; found 352.1694.

	1-(4-Methoxyphenyl)-6-methyl-4-phenyl-3-(4-(trifluoromethyl)phenyl)-2-(trimethylsilyl)-1,2-
	dihydropyridine (32o)
	The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4-
	phenylbut-3-en-2-ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and
	trimethyl((4-(trifluoromethyl)phenyl)ethynyl)silane (141.3 µL, 0.60
	mmol, 1.2 eq.). Silica gel chromatography on buffered silica (pre-
	treated with NEt 3 10% in pentane overnight) (eluent pentane/EtOAc
	98/2) afforded the title compound (32o) as an orange oil (184.4 mg,
	75 %). Note: other regioisomer not detected.

1

H NMR (400 MHz, Acetone-d 6 ) δ 7.37

(d, J = 8.2 Hz, 2H), 3H), 2H),

08 (m, 2H), 7.04 -7.00 (m, 2H), 6.95 -6.92 (m, 2H), 5.77 (d, J = 1.0 Hz, 1H), 4.42 (s, 1H), 3.80 (s, 3H), 1.89 (d, J = 0.9 Hz, 3H), 0.11 (s, 9H). 13 C NMR (100 MHz, Acetone-d 6 ) δ 156.

  cm -1 . HRMS (ESI): calculated for C 27 H 26 NO 3 [M-SiC 3 H 9 ] + : 412.1907; found 412.1971.

	3-(6-Methoxynaphthalen-2-yl)-1-(4-methoxyphenyl)-6-methyl-4-phenyl-2-(trimethylsilyl)-1,2-
	dihydropyridine (32q)
	The general procedure (F) was applied to (E)-4-methoxy-N-((E)-
	4-phenylbut-3-en-2-ylidene)aniline (125.6 mg, 0.50 mmol, 1.0
	eq.) and ((6-methoxynaphthalen-2-yl)ethynyl)trimethylsilane
	(127.2 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography on
	buffered silica (pre-treated with NEt 3 10% in pentane overnight)
	(eluent pentane/EtOAc 95/5) afforded the title compound (32q)

as an orange oil (252.6 mg, 95 %). Note: other regioisomer not detected 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.44 (dd, J = 15.9, 8.7 Hz, 2H), 7.31 (s, 1H), 7.12 (m, 8H), 6.99 (dd, J = 9.0, 2.5 Hz, 1H), 6.96 -6.91 (m, 2H), 6.89 (dd, J = 8.5, 1.8 Hz, 1H), 5.82 (s, 1H), 4.52 (s, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 1.90 (s, 3H), 0.07 (s, 9H). 13 C NMR (100 MHz, Acetone-d 6 ) δ 158.

  . IR (thin film):  max = 3006, 2893, 1606, 1506, 1246, 835 cm -1 HRMS (ESI): calculated for C 26 H 25 NO 2 [M-SiC 3 H 9 ] + : 382.1809; found 382.1802.

	1-(4-Methoxyphenyl)-6-methyl-4-phenyl-2-(trimethylsilyl)-1,2-dihydro-3,3'-bipyridine (32s)
	The general procedure (F) was applied to (E)-4-methoxy-N-((E)-4-
	phenylbut-3-en-2-ylidene)aniline (125.6 mg, 0.50 mmol, 1.0 eq.) and
	3-((trimethylsilyl)ethynyl)pyridine (105.2 mg, 0.60 mmol, 1.2 eq.).
	Silica gel chromatography on buffered silica (pre-treated with NEt 3
	10% in pentane overnight) (eluent pentane/EtOAc 80/20) afforded the
	title compound (32s) as a red oil (176.3 mg, 83%). Note: other
	regioisomer not detected. 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.19 (dd, J = 4.8, 1.5 Hz, 1H), 8.07
	(d, J = 1.8 Hz, 1H), 7.17 (m, 3H), 7.09 -7.04 (m, 4H), 7.03 -7.00 (m, 1H), 6.95 -6.89 (m, 1H),
	6.89 -6.84 (m, 2H), 5.72 (d, J = 0.9 Hz, 1H), 4.25 (s, 1H), 3.82 (s, 3H), 1.86 (d, J = 0.7 Hz, 3H),
	0.09 -0.07 (m, 9H).

13

C NMR (100 MHz, Acetone-d 6 ) δ 157.

4-Methoxyphenyl)-6'-methyl-4'-phenyl-1',2'-dihydro-4,2':3',4''-terpyridine (32u)

	(3C) IR (thin film):  max = 3053, 2955, 1631, 1509, 1243 cm -1 . HRMS (ESI):
	calculated for C 27 H 30 N

2 OSi [M-H] + : 427.2200; found 427.2251.

1'-(

1 H NMR (400 MHz, Toluene-d 8 ) δ

	7.26 -7.21 (m, 2H), 7.09 (m, 1H), 7.07 -6.94
	(m, 6H), 6.91 -6.85 (m, 2H), 6.84 -6.78 (m, 1H), 6.71 -6.65 (m, 2H), 5.75 (q, J = 1.0 Hz, 1H),
	4.57 (dd, J = 9.3, 4.0 Hz, 1H), 3.32 (s, 3H), 2.15 -2.04 (m, 1H), 1.85 (d, J = 1.0 Hz, 3H), 1.76 -1.62
	(m, 2H), 1.54 -1.41 (m, 1H), 0.93 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, Toluene-d 8 ) δ 156.5,
	141.2, 141.2, 140.1, 137.1, 129.2 (2C), 129.1 (2C), 128.7 (2C), 127.

H NMR), (148.3 mg, 75 %)

. Only peaks for major isomer assigned.

  2H), 1.16 -0.99 (m, 5H), 0.62(t, J = 7.3 Hz, 3H).

1

H NMR (400 MHz, CDCl 3 )

δ 7.36 -7.31 (m, 2H), 7.26 - 7.22 (m, 3H), 7.02 -6.98 (m, 2H), 6.87 -6.81 (m, 2H)

, 5.46 (s, 1H), 3.95 -3.90 (m, 1H), 3.80 (s, 3H), 2.17 -2.08 (m, 1H), 1.90 -1.77 (m, 5H), 1.67

(m, 1H), 1.56 -1.46 (m, 13

C NMR (100 MHz, CDCl 3 ) δ 155.

1 H NMR (400 MHz, Acetone-d 6 )

	δ
	7.06 -6.96 (m, 2H), 6.86 (m, 3H), 6.73 -6.65 (m, 2H), 5.98 (s, 2H), 5.42 (s, 1H), 4.02 -3.90 (m,

1H),

3.77 (s, 3H), 1H), 1.88 (ddd, J = 12.8, 8.4, 4.7 Hz, 1H)

, 1.83 -1.74 (m, 4H), 1.71 -1.41 (m, 3H), 1.22 -1.04 (m, 2H), 1.04 -0.95 (m, 3H), 0.59 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, Acetone-d 6 ) δ 157.

  . IR (thin film):  max = 2922, 1619, 1509, 1243 cm -1 HRMS (ESI): calculated for C 25 H 22 NO [M-H] + : 352.1696; found 352.1682

13 C NMR (100 MHz, CDCl 3

	1 H
	NMR (400 MHz, CDCl 3 ) 1H NMR δ 8.68 (s, 1H), 8.55 -8.47 (m, 1H), 7.57
	(s, 1H), 7.43 -7.29 (m, 2H), 7.28 -7.25 (m, 2H), 7.00 -6.94 (m, 2H),
	5.54 (m, 1H), 5.42 -5.31 (m, 1H), 4.19 (t, J = 7.1 Hz, 2H), 3.87 (s, 3H),
	2.70 -2.57 (m, 2H), 2.01 -1.89 (m, 3H), 0.92 (t, J = 7.6 Hz, 3H).

) δ 157.

1 H NMR (400 MHz, CDCl 3 )

	δ 8.63 (s, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.55
	(m, 2H), 7.48 -7.40 (m, 3H), 7.39 -7.33 (m, 1H), 7.30 -7.23 (m, 3H), 7.08
	(dd, J = 8.9, 2.5 Hz, 1H), 7.00 -6.94 (m, 2H), 5.21 (s, 2H), 3.87 (s, 3H), 3.82
	(s, 3H).

13

C NMR (100 MHz, CDCl 3 ) δ 157.

  cm -1 . HRMS (ESI): calculated for C 27 H 35 N 2 O [M+ H] + : 403.2744; found 403.2748.

  . IR (thin film):  max = 2936, 1612, 1574, 1497, 1240, 1061, 964, 777 cm -1 . HRMS (ESI): calculated for C 26 H 26 N 2 O [M+ H] + : 383.2122; found 383.2118.

  H NMR. Note: NMR signals are only assigned to the major isomer. mp: 68-79 °C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (s, 1H), 8.71 -8.67(m, 1H), 1H), 5H), 3H), 2H), 4.96 (q, J = 7.4 Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.68 (s, 3H), 1.84 (d, J = 7.4 Hz, 3H).

13

C NMR (100 MHz, CDCl 3 ) δ 157.

F NMR (376 MHz, CDCl 3

) δ -116.2. IR (thin film):  max = 2939, 1574, 1439, 1179, 1003, 831, 778 cm -1 . HRMS (ESI): calculated for C 25 H 23 N 2 OF [M+ H] + : 387.1868; found 387.1867.

1 H NMR (400 1612

  , 1440, 1241, 1061, 749, 730 cm -1 . HRMS (ESI): calculated for C 24 H 24 N 3 O [M+ H] + :370.1914; found 370.1920.

1 H NMR (400 MHz, CDCl 3 ) δ

	8.68 (s, 1H),
	8.46 (ddd, J = 8.0, 1.3, 0.7 Hz, 1H), 7.31 -7.15 (m, 5H), 7.11 -7.01 (m,
	3H), 6.90 (dt, J = 7.1, 1.2 Hz, 1H), 6.86 -6.78 (m, 2H), 5.11 (q, J = 7.4
	Hz, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 2.66 (s, 3H), 1.78 (d, J = 7.4 Hz, 3H).
	13 C NMR (100 MHz, CDCl 3 ) δ 157.1, 153.0, 148.5, 147.2, 142.1, 136.4, 128.7 (2C), 127.0 (2C),

  , 24.8. IR (thin film):  max = 3051, 2921, 1614, 1535, 1500, 1290, 1127, 829 cm -1 . HRMS (ESI): calculated for C 26 H 32 N 2 O [M+ H] + : 388.2598; found 388.2587.

1 H NMR (400 MHz, CDCl 3 ) δ

	8.60 (s, 1H), 8.48 -8.30 (m, 1H), 7.15
	(m, 5H), 6.84 (d, J = 8.3 Hz, 2H), 3.73 (s, 3H), 3.61 (s, 3H), 2.96 -2.86
	(m, 2H), 0.85 -0.72 (m, 2H), 0.00 (s, 9H).

13 C NMR (100 MHz, CDCl 3

) δ 158.

  . IR (thin film):  max = 2949, 1612, 1470, 1240, 939, 797 cm - 1 . HRMS (ESI): calculated for C 22 H 29 N 2 OSi [M+ H] + : 365.2033; found 365.2044.

  .1. IR (thin film):  max = 3050, 1636, 1571, 1459, 841 cm -1 . HRMS (ESI): calculated for C 14 H 16 NO [M+ H] + : 214.1190; found 214.1189.

Table 7 (IAd)(PPh 3 )Co(CH 2 SiMe 3 )-catalyzed hydrosilylation of alkynes

 7

Table 8 Hydrosilylation of diphenylacetylene with various hydrosilanes

 8

Table 10 Hydrosilylation of unsymmetrical alkynes with (EtO) 3 SiH

 10

Table 11 Cobalt-catalyzed hydroboration of internal alkynes

 11

  . IR (thin film):  max 2954, 2862, 1599, 1249. HRMS (ESI) calculated for C 25 H 34 NaSi 2 [M+Na] + 413.2091, found 413.2077.

  . HRMS (ESI) calculated for C 30 H 30 NaSi [M+Na] + 441.2009, found 441.2001.

1 H NMR (400 MHz, CDCl 3 ) δ

  7.56-7.41 (m, 15H), 6.91 (d, J = 8.7 Hz, 3H), 6.81 (d, J = 8.7 Hz, 3H), 6.75 (s, 1H), 3.91 (s, 3H), 0.00 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.0, 157.9, 151.6, 136.4 (2C), 134.1, 129.2, 129.1, 127.5 (2C), 112.8, 55.0, 0.0. IR (thin film):  max 3133, 3045, 2125, 1503. HRMS (ESI) calculated for C 30 H 32 NaOSi 2 [M+Na] + 487.1884, found 487.1892.

1 H NMR (400 MHz, CDCl 3 ) δ

  7.56-7.41 (m, 15H), 6.91 (d, J = 8.7 Hz, 3H), 6.81 (d, J = 8.7 Hz, 3H), 6.75 (s, 1H), 3.91 (s, 3H), 0.00 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.0, 157.9, 151.6, 136.4 (2C), 134.1, 129.2, 129.1, 127.5 (2C), 112.8, 55.0, 0.0. IR (thin film):  max 3068, 2953, 2359, 1588. HRMS (ESI) calculated for C 31 H 34 NaO 2 Si 2 [M+Na] +

  . IR (thin film):  max 3059, 2909, 2363, 1378. HRMS (ESI) calculated for C 34 H 30 NaSi [M+Na] + 489.2009, found 489.1994.

1 H NMR (400 MHz, CDCl 3 ) δ

  6.99(d, J = 8.6, 2H), 6.76 (d, J = 8.6, 2H), 6.27 (t, J = 7.1 Hz, C=CH), 3.71 (m, O-CH 2 -CH 3 and O-CH 3 ), 2.02 (q, J = 7.4 Hz, 2H), 1.26-1.16 (m, -CH 2 -CH 2 -), 1.09 (t, J = 7 Hz, 9H, O-CH 2 -CH 3 ), 0.75 (t, J = 7.1 Hz, 3H).

13 C NMR (100 MHz, CDCl 3

) δ 157.

  . IR (thin film):  max 2979, 2925, 2360, 2341, 1508. HRMS (ESI) calculated for C 19 H 32 NaO 4 Si [M+Na] +375.1962, found 375.1957.

NMR (400 MHz, CDCl 3 ) δ

  . IR (thin film):  max 2974, 2928, 2360, 2341, 1614. HRMS (ESI) calculated for C 19 H 29 F 3 NaO 3 Si [M+Na] + 413.1730, found 413.1714. 2.40 (q, J = 7.2 Hz). Other signals are overlapped with the E-isomer.

	Minor product: triethoxy-[(Z)-(1-(4-(trifluoromethyl)phenyl)-2-butylvinyl)]silane relevant signal:
	1 H

  . IR (thin film):  max 2973, 2836, 2360, 1506. HRMS (ESI) calculated for C 18 H 32 NaO 4 Si 2 [M+Na] + 391.1731, found 391.1743.

  . IR (thin film):  max 3030, 2952, 2897, 1076. HRMS (ESI) calculated for C 16 H 30 NO 3 Si 2 [M+H] + 340.1759, found 340.1748.

  . IR (thin film):  max 3028, 2972, 2360, 1077. HRMS (ESI) calculated for C 16 H 30 NO 3 Si 2 [M+H] + 340.1759, found 340.1754.

Scheme 109 Cobalt-catalyzed cross-coupling between nonactivated aryl halides or heteroaryl bromides and aromatic Grignard reagents

175 Korn, T. J.; Cahiez, G.;

Knochel, P. Synlett 2003, 12, 1892-1894. 176

Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M. J.

Am. Chem. Soc. 2009, 131, 11949-11693.

Table 16 Cobalt-catalyzed coupling between unactivated alkyl Cobalt-catalyzed Heck-type reactions

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Scheme 45 Proposed catalytic cycle

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Scheme 56 Proposed catalytic cycle

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Scheme 123 Hypothetical catalytic cycle

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Résumé: Dans cette these, nous nous concentrerons principalement sur l'utilisation de complexes basse-valence de cobalt bien définis de la famille des RCo(PMe 3 ) 4 pour l'activation de divers types de liaisons (C-H, Si-H, C-X). Notre but était de développer un système compétitif par rapport au système bimétallique de Yoshikai, mais aussi par rapport aux systèmes onéreux à base de rhodium. Nous avons démontré avec succès que les complexes isolés Co(PMe 3 ) 4 et HCo(PMe 3 ) 4 étaient des catalyseurs efficaces pour l'hydroarylation de différents alcynes et alcènes via une activation de liaisons C-H. De plus, nous avons fait une étude mécanistique en couplant des marquages au deutérium et des études de chimie théorique. Nous avons déterminé que la fonctionnalisation de liaisons C-H se faisait selon un mécanisme concerté appelé ''Ligand-to-Ligand Hydrogen Transfer'' (LLHT). A partir de ces études, nous avons pu aussi développer une hydrosilylation hautement régio-et stéréosélective d'alcynes permettant d'utiliser un grand nombre de silanes différents. Nous avons pu au cours de cette étude isoler un nouveau complexe de cobalt(III) bis-hydrure jouant un rôle important dans le mécanisme. Enfin, nous décrivons aussi que ces mêmes complexes de cobalt RCo(PMe 3 ) 4 sont capables de catalyser l'homocouplage de bromure et chlorure de benzyle en présence de dimethylzinc. Une étude mécanistique préliminaire suggère que la réaction procède par deux transferts mono-électroniques et que le diméthylzinc permet de régénérer le catalyseur.Mot-clés: Cobalt, activation de liaisons C-H, LLHT, Hydrosilylation, homocouplage.

Acknowledgments

This project was carried out at the Institut Parisien de Chimie Moléculaire which is directed by Doctor Corinne Aubert. I worked specifically in the MACO team directed by Professor Louis Fensterbank. I thank them both for accepting me into the laboratory and team I would like to sincerely thank Prof. Jean-Luc Renaud, Prof. Giovanni Poli, Dr. Jean-Baptiste Sortais and Dr. Joanna Wencel-Delord for accepting to review my thesis and be part of my Jury.

Experimental Section Chapter 1

118

Abbreviations

Early examples

Cobalt was in fact the first metal to be used for the so-called chelation-assisted functionalization of C-H bonds. In 1955 Murahashi reported the ortho-carbonylation of azobenzene using Co 2 (CO) 8 . The reaction is proposed to proceed via a cobalt-mediated Scheme 32 Mechanistic considerations for aminoquinoline-directed alkyne annulation ((6-Methoxynaphthalen-2-yl)ethynyl)trimethylsilane

The general procedure (E) was applied to 2-ethynyl-6methoxynaphthalene (628.0 mg, 3.34 mmol, 1.0 eq.), n-BuLi (1.6 mL, 0.5 M, 4.00 mmol, 1.2 eq.) and TMSCl (511.7 µL,4.00 mmol, 1.2 eq.) in distilled THF (25 mL) and provided the title compound as a beige solid (757.0 mg, 89 %) mp: 98 -102 °C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.65 (m,2H),7.46 (m,1H),2H),3.92 (d,J = 2.6 Hz,3H), 0.28 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 158. 4, 134.3, 131.9, 129.4, 129.3, 128.4, 126.7, 119.4, 118.1, 105.9, 105.8, 93.7, 55.4, 0.1 (3C). The values reported are in good accordance with those reported in literature. 106

3-((Trimethylsilyl)ethynyl)pyridine

The general procedure (D) was applied to 3-iodopyridine (500.0 mg, 2.44 mmol, 1.0 eq.), ethynyltrimethylsilane (405.0 µL, 2.920 mmol, 1.2 eq.), Pd(PPh 3 ) 2 Cl 2 (171.3 mg, 0.24 mmol, 0.1 eq.), CuI (45.5 mg, 0.24 mmol, 0.1 eq.) and DIPA (10 mL). Purification by column chromatography (buffered SiO 2 , 0  10% Et 2 O/n-pentane) provided the title compound as a red oil (215.0 mg, 50 %). 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (d, J = 1.1 Hz, 1H), 8.52 (dd, J = 4.9, 1.5 Hz, 1H), 7.73 (dt, J = 7.9, 1.8 Hz, 1H), 7.23 (dd, J = 7.9, 5.0 Hz, 1H), 0.26 (d,J = 3.4 Hz,9H). 13 C NMR (100 MHz, CDCl 3 ) δ 153. 1, 149.2, 139.2, 123.3, 120.7, 101.9, 98.7, 0.2 (3C). The values reported are in good accordance with those reported in literature. 107

2-((Trimethylsilyl)ethynyl)pyridine

The general procedure (D) was applied to 2-iodopyridine (500.0 mg, 2.44 mmol, 1.0 eq.), ethynyltrimethylsilane (405.0 µL, 2.92 mmol, 1.2 eq.), Pd(PPh 3 ) 2 Cl 2 (171.3 mg, 0.24 mmol, 0.1 eq.), CuI (45.5 mg, 0.24 mmol, 0.1 eq.) and DIPA (10 mL). Purification by column chromatography (buffered SiO 2 , 0  10% Et 2 O/n-pentane) provided the title compound as a brown oil (223.0 mg, 52 %). 1 H NMR (400 MHz, CDCl 3 ) 8.44 (d,J = 4.4 Hz,1H),7.53 (t,J = 7.2 Hz,1H),7.33 (d,J = 7.4 Hz,1H),7.11 (dd,J = 6.6,5.7 Hz,1H),0.15 (s,9H). 13 C NMR (100 MHz, CDCl 3 ) δ 149. 9, 136.0, 128.4, 127.2,

Methyl (E)-3-(((4-methoxyphenyl)imino)methyl)-1-methyl-2-(1-phenylethyl)-1H-indole-6-

carboxylate (82fg)

The general procedure (C) was applied to methyl (E) -3-(((4methoxyphenyl)imino)methyl)-1-methyl-1H-indole-6-carboxylate (81f, 161 mg, 0.50 mmol, 1.0 eq.) and styrene (62 mg, 0.6 mmol, 1.2 eq.). Silica gel chromatography (eluent pentane/EtOAc 85/15) afforded the title compound (82fg) as a yellow foam (209 mg, 99 %). mp: 68-79 °C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (s, 1H), 8.55 (d,J = 8.4 Hz,1H),1H),7.86 (dd,J = 8.4,1.5 Hz,1H),2H),12 (m, 3H), 7.08 -7.01 (m, 2H), 6.86 -6.77 (m, 2H), 5.03 (q, J = 7.4 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H), 3.44 (s, 3H), 1.77 (d,J = 7.3 Hz,3H). 13 C NMR (100 MHz, CDCl 3 ) δ 167. 9, 157.4, 152.4, 151.0, 146.7, 141.5, 137.1, 129.6, 128.8 (2C), 127.1, 126.8, 124.2, 122.7 (2C), 121.9 (2C), 121.8, 114.3 (2C), 112.1, 111.1, 55.5, 52.0, 34.8, 31.1, 18.5

(E)-3-(((4-Methoxyphenyl)imino)methyl)-1-methyl-2-(1-phenylethyl)-1H-indole-5-carbonitrile (82gg)

The general procedure (C) was applied to methyl (E)-3-(((4methoxyphenyl)imino)methyl)-1-methyl-1H-indole-5-carbonitrile (81g, 144 mg, 0.50 mmol, 1.0 eq.) and styrene (62 mg, 0.6 mmol, 1.2 eq.).

Silica gel chromatography (eluent pentane/EtOAc 85/15) afforded the title compound (82gg) as a yellow oil (162 mg, 82 %). 8.5,1.7 Hz,1H),6H),2H),2H), 5.10 (q, J = 7.9 Hz, 1H), 3.83 (s, 3H), 3.52 (s, 3H), 1.88 (d,J = 7.4 Hz,3H). 13 C NMR (100 MHz, CDCl 3 ) δ 157. 7, 151.6, 150.0, 146.1, 141.1, 139.2, 128.9 (2C), 128.1, 127.0 (2C), 126.9, 125.8, 125.7, 121.9 (2C), 120.7, 114.3 (2C), 112.5, 109.7, 104.6, 55.5, 34.8, 31.2, 18.7 394.1914; found 394.1909.

(E)-1-(5-Fluoro-1-methyl-2-(1-phenylethyl)-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (82hg)

The general procedure (C) was applied to (E)-1-(5-fluoro-1-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine (81h, 141 mg, 0.50 mmol, 1.0 eq.) and styrene (0.62 mg, 0.6 mmol, 1.2 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound (82hg) as a yellow foam (182 mg, 99 %). mp 63-65 °C. (d,J = 239.3 Hz),157.3,152.6,148.65 (d,J = 3.0 Hz),146.8,141.8,138.0 (d,J = 11.7 Hz),128.7 (2C),127.0 (2C),126.7,123.5 (d,J = 9.6 Hz),122.2,121.8 (2C),114.3 (2C),112.0,109.8 (d,J = 23.4 Hz),95.6 (d,J = 26.5 Hz),55.5,34.6,31.1,18.8.

(E)-1-(2-(2-Cyclopentylethyl)-1-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)methanimine

(82ao)

The general procedure (C) was applied to (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)methanimine (81a, 132 mg, 0.50 mmol, 1.0 eq.) and vinylcyclopentane (96 mg, 1.00 mmol, 2.0 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound (82ao) as a yellow solid (126 mg, 70 %). mp: 104-106 °C. 1, 152.6, 147.4, 146.8, 137.3, 125.9, 122.3, 121.8 (2C), 121.5, 114.9, 114.3 (2C), 111.0, 108.8, 55.5, 39.8, 36.6, 32.6 (2C), 29.7, 25.2 (2C), 23.9. IR (thin film): 3049, 2946, 1614, 1535, 1469, 1326, 1126, 832 cm -1

(E)-1-(1,7-Dimethyl-2-(2-(trimethylsilyl)ethyl)-1H-indol-3-yl)-N-(4methoxyphenyl)methanimine (82cs)

The general procedure (C) was applied to (E)-1- (1,-N-(4-methoxyphenyl)methanimine (81c, 139 mg, 0.50 mmol, 1.0 eq.) and trimethylvinylsilane (60 mg, 0.6 mmol, 1.2 eq.).

Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound (82cs) as a yellow oil (135 mg, 71 %). 9, 154.3, 151.1, 149.2, 137.8, 128.8, 127.4, 123.6 (2C), 123.2, 122.3, 121.3, 116.1 (2C), 111.5, 57.3, 34.5, 22.3, 20.7, 19.4, 0.0 (3C). IR (thin film):

Methyl (E)-3-(((4-methoxyphenyl)imino)methyl)-1-methyl-2-(2-(trimethylsilyl)ethyl)-1Hindole-6-carboxylate (82fs)

The general procedure (C) was applied to methyl (E)-3-(((4methoxyphenyl)imino)methyl)- 9, 159.2, 153.6, 153.5, 148.7, 138.5, 131.7, 125.5, 124.4, 123.6 (2C), 122.8, 116.2 (2C), 112.9, 112.0, 57.4, 53.8, 31.5, 21.0, 19.4, -0.0 (3C) Based on these experimental results a catalytic cycle is shown below, which is based on a modified Chalk-Harrod mechanism (Scheme 91). The interaction of (IAd)(Ph 3 P)Co(CH 2 SiMe 3 ) with H 2 SiPh 2 generated a three coordinate cobalt-silyl species I which further undergoes ligand substitution with an alkyne to form the alkyne-Co(I)-silyl species, Co(IAd)(η 2 -RC≡CR )(SiHPh 2 ) II. Once formed a migratory insertion of the alkyne into the silicon-cobalt bond (silacobaltation), which is likely triggered by the coordination of PPh 3 , will produce an alkenyl metal species III that could further react with H 2 SiPh 2 to yield the hydrosilylation product and regenerate the active catalytic species.

Scheme 91 Proposed mechanism for (IAd)(PPh 3 )Co(CH 2 TMS)-catalyzed hydrosilylation reactions

The regioselectivity and stereoselectivity observed in the catalytic reactions was proposed to be governed by the intricate balance of steric repulsion among the IAd ligand, the silyl group and the coordinated alkyne of the alkyne-cobalt(I)-silyl intermediate. Therefore, in the case of terminal alkynes, the alkyl and phenyl substituents are not bulky and could be positioned toward IAd. The following migratory insertion of the silyl group to the terminal carbon of the alkyne, which is less sterically hindered, will then readily happen and eventually lead to the formation of β-syn-adducts. For the TMS-substituted internal alkynes, to avoid severe steric repulsion between the TMS and IAd groups, the alkynes have to orient their small substituents above the imidazole plane, which, subsequently, will produce α,α-disilylalkenyl cobalt intermediates and lead to the formation of α,α-disilylalkenes. In line with this proposal the authors claim the failure of TMSC≡CTMS to participate in the hydrosilylation reaction is due to these previously discussed steric properties and that that the reaction of 1-octyne with H 3 SiPh exhibits poor selectivity.

We hypothesized that the reaction proceeded via an oxidative addition of the silane to the cobalt center, followed by a hydrocobaltation and finally reductive elimination to regenerate the catalyst. We were excited about this result and it seemed feasible that we could also perform the less studied hydrosilylation of carbon-carbon multiple bonds. 139 The two main issues we were hoping to address in this study was the poor regio-and stereo control often observed as well as the pertinent issue regarding the limitations associated with the application of tertiary hydrosilanes.

Having in hand the isolated and fully characterized dihydrocobalt(III) complex 98, we began to explore its catalytic activity. 121 To this end the reaction of diphenylacetylene and triphenylsilane in the presence of 5 mol% of 98 afforded the desired hydrosilylation product in good yields and same selectivity to that observed with HCo(PMe 3 ) 4 (Scheme 95). This result strongly suggests a crucial role of the dihydrodocobalt(III) complex in triggering the catalytic process.

Scheme 95 Catalytic reaction of H 2 CoSiPh 3 (PMe 3 ) 3 in the presence of diphenylacetylene and triphenylsilane

While not previously mentioned, It could also be possible that the reaction proceeds through an initial hydrocobaltation reaction between HCo(PMe 3 ) 4 and the corresponding alkyne followed by an oxidative addition of the hydrosilane. To examine this possibility a stoichiometric reaction between the two partners was performed, however only ligand exchange was observed with no evidence of hydrocobaltation (Scheme 96).

Scheme 96 Stoichiometric experiment between HCo(PMe 3 ) 4 and diphenylacetylene

To gain a deeper insight into the mechanistic details, DFT calculations were performed on a system based on complex 98 in conjunction with 1-phenylpropyne. For the sake of simplicity, the silane moiety was modeled by HSi(OMe) 3 . Following our previous studies with the same cobalt catalyst, 68,76,82 parameters were set as functional B3LYP and basis set SVP, while all the DFT calculations were performed with Gaussian09. After numerous calculations performed we present the conformation leading to the smallest activation barriers, showed in the (Figure 28). The main question addressed is whether the alkyne insertion initially occurs into the Co-H bond (hydrocobaltation) or into the Co-Si bond (silacobaltation). According to the results, the barrier for the hydrocobaltation process is 3.18 kcal/mol while the silacobaltation barrier is 19.42 kcal/mol. Thus, our cobalt catalyst would follow the classical Chalk-Harrod mechanism. 117 Another important question addressed by the DFT calculations was that, despite the use of a hydrido-cobalt catalyst with a silane, no H 2 evolution was experimentally observed. This could be explained since starting from the cobalt complex 98 bearing two hydrogen atoms, it was calculated that the reductive elimination of H 2 is an endothermic process with a transition state residing above by 3.36 kcal/mol, while the reverse barrier (i.e. H 2 addition on the cobalt center) is very small (0.47 kcal/mol). Thus, even if H 2 is Scheme 97 Proposed mechanism for the hydrosilylation of unsymmetrical internal alkynes catalyzed by HCo(PMe 3 ) 4

As previously mentioned, the results obtained for the hydrosilylation of TMS substituted alkynes under our system displayed opposite regioselectivity to the earlier report by the group of Deng. 136 Our rational for the discrepancy between the regioselectivity is shown in (Figure 29). In the model proposed by Deng, the silacobaltation step is controlled by the very bulky ligand IAd (1,3-diadamantylimidazol-2-ylidene) and this determines the regioselectivity of the reaction. For unsymmetrical internal alkynes this control based on a bulky ligand works well when the steric differentiation between the two substituents is significant. Otherwise, it leads to low selectivity as shown by Deng using 1-phenylpropyne which yielded a 50/50 mixture of regioisomers. In our catalytic system, the selectivity is controlled by the hydrocobaltation step. In this process the steric differentiation between the silylcobalt moiety and the hydrogen atom is very important. Thus, the regioselectivity is less affected by a change of the silane and by a small steric differentiation between R L and R S .

Scheme 102 Proposed catalytic cycle for the hydroboration of terminal alkynes

Based on the exciting results by the groups of Chirik and Orpen, and our own previous work on the use of the low valent cobalt complexes Co(PMe 3 ) 4 and HCo(PMe 3 ) 4 towards C-H functionalization and hydrosilylation we began to explore the possibility of performing the hydroboration of internal alkynes with the same complexes (Table 11). Under argon, a sealed tube (0.5-2 mL) was charged with diphenylacetylene (89 mg, 0.5 mmol) and the cobalt catalyst (9 mg, 0.025 mmol of Co(PMe 3 ) 4 or 9.1 mg, 0.025 mmol of HCo(PMe 3 ) 4 ). The vial was sealed followed by the addition of freshly distilled and degassed toluene (1mL) and the corresponding silane (0.55 mmol). The reaction was heated in an oil bath at 110 °C for 24h. The reaction mixture was diluted with ethyl acetate (2 mL), filtered through a plug of celite and washed with ethyl acetate (3 x 10 mL). The crude product was purified by silica chromatography (mixtures of pentane/ethyl acetate as eluent) to afford the final products.

General Procedure K: Hydrosilylation of Unsymmetrical Alkynes with Triphenylsilane and Triethoxysilane

Under argon, a glass vial (0.5-2 mL) was added HCo(PMe 3 ) 4 ) (9.1 mg, 0.025 mmol) and triphenylsilane or triehtoxysilane (0.55 mmol) and then sealed. Degassed toluene (1mL) and the corresponding alkyne (0.5 mmol) were then added. The reaction was then heated in an oil bath at 160 °C for 2h. The reaction mixture was diluted with ethyl acetate (2 mL), filtered through a plug of celite and washed with ethyl acetate (3 x 10 mL). The crude product was purified by silica chromatography (mixtures of pentane/ethyl acetate as eluent) to afford the final products.

Triethoxy-[(E)-(1,2-diphenylvinyl)]silane (97ba) 149 The general procedure (J) was applied to diphenylacetylene (89 mg, 0.5 mmol) and triethoxysilane (0.1 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97ba as a colorless oil (155 mg, 91% yield). 4, 140.7, 137.1, 136.9, 129.8, 128.4, 128.2, 127.8, 127.4, 126.0, 58.8, 18.1.

Triethyl-[(E)-(1,2-diphenylvinyl)]silane (97ca) 150

The general procedure (J) was applied to diphenylacetylene (89 mg, 0.5 mmol) and triethylsilane (0.09 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97ca as a colorless oil (85 mg, 58% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 -7.08 (m, 3H), 7.03 -6.84 (m, 7H), 6.70 (s, 1H, C=CH), 0.88 (t, J = 7.9 Hz, 9H), 0.57 (q, J = 7.8 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 144. 1, 143.1, 138.7, 137.4, 129.5, 128.6, 127.8, 127.3, 126.9, 125.5, 7.3, 2.8.

Dimethylphenyl-[(E)-(1,2-diphenylvinyl)]silane (97da) 151

The general procedure (J) was applied to diphenylacetylene (89 mg, 0.5 mmol) and dimethylphenylsilane (0.08 mL, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97da as a yellow oil (147 mg, 94% yield).

Triphenyl-[(E)-(1-(4-methoxyphenyl)-2-butylvinyl)]silane (97ac)

The general procedure (K) was applied to 1-(4-methoxyphenyl)-1-hexyne (94 mg, 0.5 mmol) and triphenylsilane (143 mg, 0.55 mmol). Purification by silica gel flash-chromatography afforded the title compound 97ac as a yellow solid (215 mg, 96% yield). 6, 148.7, 137.9, 136.5, 135.8, 134.5, 129.7, 129.2, 128.0, 127.7, 127.6, 113.3, 55.1, 31.6, 30.0, 22.4, 13.9

(E)-3-(2-(trimethylsilyl)-1-(triphenylsilyl)vinyl)pyridine (97ak)

The general procedure (K) was applied to 3-[(triethylsilyl)ethynyl]pyridine (87 mg, 0.5 mmol) and triphenylsilane (102 mg, 0.55 mmol) in degassed toluene (1ml) then heated in an oil bath at 160 °C for 2h. Purification by silica gel flash-chromatography (pentane/ethyl acetate 98:2) afforded the title compound 97ak as a white solid (122 mg, 56% yield).

Chapter 3 Cobalt-catalyzed coupling reactions of benzyl halides Scheme 103 General catalytic cycles for palladium-catalyzed cross-coupling reactions

Despite the undeniable success of the aforementioned palladium-catalyzed coupling reactions, there remains a need to explore the reactivity of cheaper, more earth abundant alternatives. Thus the last 15 years has seen an increased effort by the chemical community to examine the catalytic potential of Mn-, 160 Fe-, 161 Cu-, 162 Ni-, 163 and Co. 164 Indeed cobalt is an attractive alternative and has been the subject of much development. The use of cobalt for couplings involving alkyl halides is particularly interesting, since the decomposition by β-hydride elimination of the alkyl-cobalt intermediate is not a limitation as is the case for palladium. In the case of cobalt, the oxidative addition is achieved through a single electron transfer therefore as mentioned a major drawback of the palladium-catalyzed process is avoided. 164 Indeed this is an important consideration for the coupling of secondary or even tertiary alkyl halides, which remain quite difficult with the other metals. For the following discussion we will focus our attention solely on reactions involving cobalt. 160 Cahiez, G.; Duplais, C.; Buendia, J. Chem. Rev. 2009, 109, 1434-1476. 161 Czaplik, W. M.; Mayer, M.; Cvengroš, J.; von Wangelin, A. J. ChemSusChem 2009, 2, 396-417. 162 Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545-1554. 163 Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2010, 111, 1346-1416. 164 Cahiez, G.; Moyeux, A. Chem. Rev. 2010, 110, 1435-1462. In 1994, Kharasch reported the coupling between β-bromostyrene and methyl magnesium iodide, which took place in the presence of a catalytic amount of cobalt chloride (Scheme 112). 179 A drawback of this reaction was the requirement to use 2 equivalents of Grignard reagent and it was also limited to the very reactive β-bromostyrene.

Scheme 112 Cobalt-catalyzed coupling reaction between β-bromostyrene and methylmagnesium iodide

179 Kharasch, M. S.; Fuchs, C. F. J. Org. Chem. 1945, 10, 292-297.

Scheme 115 Heck-type reaction from unsaturated haloacetal

To gain an insight in the reaction mechanism a number of stoichiometric experiments were performed. Firstly treatment of the haloacetal used in entry 1, Table 14 with 1 equivalent of CoCl 2 (dppe) and 2 mmol of PhMgBr, provided a trace of the desired product. Most of starting material was recovered, and biphenyl was quantitatively obtained. Accordingly, Co(II)Ph 2 (dppe) was unstable under the reaction conditions and underwent reductive elimination. Based on these and other observations the authors postulate the catalytically active species for this reaction would be the 17-electron-ate complex [Co(0)Ph 2 (dppe)](MgBr) 2 , which would potentially exist as an equilibrium mixture of a mono-ate complex and the di-ate complex. Thus the proposed mechanism starts with reduction of CoCl 2 (dppe) with 4 equiv of PhMgBr gives [Co(0)Ph 2 (dppe)](MgBr) 2 I with concomitant production of 1 equiv of biphenyl (Scheme 116). The zero-valent-ate complex undergoes a single electron transfer to the substrate to yield the corresponding anion radical and cobalt(I) complex II. The immediate loss of bromide from the anion radical affords 5-hexenyl radical intermediate, which is transformed into a cyclopentylmethyl radical. Then, the cobalt species would recombine with the carbon centered radical to form a divalent cobalt species III. The following reductive elimination would provide the product and the Co(0) complex IV, which is reconverted into the active catalytic species by the action of the remaining PhMgBr.

Scheme 116 Proposed catalytic cycle for the tandem radical cyclization and cross-coupling reaction from unsaturated haloacetals

Alkylation

The group of Oshima has also disclosed the reaction between alkyl halides and trimethylsilyethynylmagnesium bromide in the presence of cobalt chloride (Scheme 117). 182 Moderate to good yields were obtained from primary or secondary alkyl halides but large excess of Grignard reagent was necessary. The same group also showed it was possible to extend this reaction to simple acetylenic Grignard reagents, although 4 equivalents of Grignard derivative was necessary in this case. 185

Scheme 117 Cobalt-catalyzed tandem radical cyclization and alkynylation reaction

185 Someya, H.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007Lett. , 9, 1565Lett. -1567. . 273 5 Cobalt-catalyzed Csp 3 -Csp 3 cross-coupling reactions

Allylation

The coupling of unactivated alkyl halides and allylic Grignard reagents under cobalt catalysis was reported by Oshima in 2002. 186 Thus, a combination of cobalt chloride and dppp as ligand afforded good yields under mild reaction conditions for primary, secondary and tertiary alkyl halides. The use of benzylic halides was also possible under the present reaction conditions (Table 15).

Table 15 Cobalt-catalyzed coupling between unactivated alkyl halides and allylmagnesium chloride

Using the same set of reaction conditions it was possible to perform the tandem radical cyclization followed by cross-coupling to prepare various cyclic compounds in high yields (Scheme 118).

Scheme 118 Cobalt-catalyzed tandem radical cyclization and alkylation of allylic Grignard reagents

Rather unexpectedly, on changing from THF to diethyl ether a cyclopropane derivative was formed (Scheme 119). The proposed mechanism is first the formation of a reduced cobalt species [Co n ] by action of the Grignard reagent. After the single electron transfer to the halide (formation of a radical anion) and then cleavage of the C-I bond, a radical is obtained. A sequential 5-exo radical cyclization and trapping of the resulting radical by the catalytic cobalt species then affords the cobalt intermediate. In diethyl ether, this intermediate undergoes rapid elimination of BuO-Metal (Co or Mg) to give the cyclopropane derivative. It is believed this elimination is aided by the complexation of the metallic center (Co or Mg) with the oxygen atom of the butoxy group (it would be more difficult to achieve such a complexation in THF). The resulting aldehyde then reacts with the allylmagnesium chloride to yield the final product containing an alcohol moiety.

Scheme 119 Mechanism of the cobalt-catalyzed reaction of iodoallylic acetal with allylmagnesium chloride

Alkylation

Scheme 121 Proposed mechanism of the CoCl 2 (dpph)-catalyzed Heck-type reaction

Cobalt-catalyzed activation of C-H bonds/C-C coupling

Transition metal-catalyzed activation and functionalization of C-H bonds is currently a very popular area of research. 58 Hydroarylation and hydroacylation reactions have been widely studied primarily by the groups of Yoshikai and Ackermann among others. However, it is only more recently that the chemical community has begun to address C-H coupling reactions. Thus the groups of Yoshikai and Ackermann have recently reported on the use of in situ generated low-valent cobalt salts for C-H arylation, C-H alkenylation and C-H alkylation. This topic was previously covered in Chapter 1 and will not be discussed further here.

Results and Discussion

Initial results: Homocoupling of benzyl halides

To begin the present study we chose to examine the coupling reaction between imine 24a and bromobenzene in the presence of 10 mol% MeCo(PMe 3 ) 4 and 50 mol% Me 2 Zn. A variety of reaction times and temperatures were examined however the desired coupling product was not observed (Scheme 124). We did however detect the presence of the biphenyl homocoupled product in low yield.

Scheme 124 Attempts towards cobalt-catalyzed cross coupling reaction

We began to examine other cobalt catalysts namely Co(PMe 3 ) 4 for the present coupling reaction however again we observed none of the desired cross-coupled rather the biphenyl homocoupled product. On switching to benzyl bromide we again saw none of the desired coupling product rather quantitative conversion to the homocoupled product (Scheme 125). It was hypothesized that the formation of the homocoupled product was as result of two oxidative additions or two SET of the benzyl bromide to the cobalt center followed by regeneration by dimethyl zinc. 191

Scheme 125 Attempts towards cobalt-catalyzed cross coupling reaction

Although not the desired result we became interested in the homocoupling reaction between two benzyl bromides. While C-C bond formation involving C(sp) and C(sp 2 ) has been extensively explored, homocoupling reactions between two Csp 3 -hybridized carbons remain comparatively rare. 192 Indeed dibenzyl derivatives are key intermediates in the synthesis of

Scheme 128 Scope of homocoupling reaction

Pentafluorobenzyl bromide also gave the desired product in a satisfactory yield. 3,4-Methylenedioxybenzyl bromide reacted in quantitative yield and could be used as a building block in synthesis. Naphthalene based derivative could also be isolated in good yield. Furthermore, products that have substituents in the benzylic position were obtained in moderate to good yields. Pleasingly we could also apply our methodology to the synthesis of pyridine containing compounds that could find use as ligands in organometallic chemistry or as pharmaceutical scaffolds (Scheme 129).

Scheme 129 Scope of homocoupling reaction

Finally, it was also possible to perform homocoupling reaction with benzyl chlorides, albeit with slightly higher catalytic loading (5 mol%) and longer reaction time (1h) than previously reported for benzyl bromides (Scheme 130).

Scheme 130 Homocoupling of benzyl chlorides

Mechanistic considerations

We then focused on the reaction mechanism and tried to shed light both on the role of dimethylzinc and on the activation mode of the benzyl halide. Toward this end, we initially carried out a series of blank experiments (Table 17).

Table 17 Mechanistic investigation of the homocoupling reaction

In the absence of cobalt no homocoupling product was observed rather quantitative conversion of 113 to ethylbenzene 116 through substitution of the benzyl bromide by Me 2 Zn. The use of 10 or 20 mol % Co(PMe 3 ) 4 without Me 2 Zn furnished the dimerised product in 20 and 40 % yield respectively (entries 1-2). These results suggested that the role of Me 2 Zn is purely regeneration of the catalyst and that Co(PMe 3 ) 4 can promote the dimerization of 2 equivalents of benzyl halide.

Experimental Section Chapter 3 10.1 General procedure M: homocoupling of benzyl bromides

To a solution of Co(PMe 3 ) 4 (0.5-5 mol %) in degassed THF (0.5 mL) was added 1.0 M Me 2 Zn in hexane (0.6 mL, 0.6 mmol) followed by benzyl halide (1; 0.5 mmol) at ambient temperature. The reaction was then transferred to an oil bath and heated to 90 o C for 10-60 mins. The resulting mixture was quenched with 10 % HCl, and extracted with AcOEt. The organic layer was washed with brine and dried over MgSO 4 . The solvent was removed in vacuo and the residue was purified by column chromatography on silica to give the desired product.

1,2-Diphenylethane 200

The general procedure (M) was applied to (bromomethyl)benzene ( 85 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane 100%) afforded the title compound as a colorless solid (90% yield); mp: 50.5-51.0 °C.

1,2-di-p-tolylethane 200

The general procedure (M) was applied to 1-(bromomethyl)-4methylbenzene (92 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane 100%) afforded the title compound as a colorless solid (95% yield); mp: 78.5-79.5 °C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.12 (s, 8H), 2.90 (s, 4H), 2.36 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 138.8 (2C), 135.2 (2C), 128.9 (4C), 128.2 (4C), 37.6 (2C), 21.0 (2C). IR (neat, cm-1): ν max 2901, 2839, 1498, 1412.

1,2-Bis-(4-bromophenyl)ethane 200

The general procedure (M) was applied to 1-bromo-4-(bromomethyl)benzene (124 mg, 0.50 mmol, 1.0 eq.). (Note reaction temperature for this reaction was reduced to 40 o C. Silica gel chromatography (eluent pentane 100%) afforded the title compound as a colorless solid (72% yield); mp: 117-118 °C. The general procedure (M) was applied to 1-(bromomethyl)-4nitrobenzene (107 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound as a yellow solid (80% yield); mp: 175-177 °C. The general procedure (M) was applied to methyl 4-(bromomethyl)benzoate (114 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound as a colorless solid (96% yield); mp: 120-121 °C.

1,2-Bis-(4-methoxyphenyl)ethane 202

The general procedure (M) was applied to 1-(bromomethyl)-4methoxybenzene (100 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane/EtOAc 95/5) afforded the title 1,2-Di-(naphthalen-2-yl)ethane 205 The general procedure (M) was applied to 2-(bromomethyl)naphthalene (107 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane 100%) afforded the title compound as a colorless solid (83% yield); mp: 181-183 °C. 1 H NMR (400 MHz, CDCl 3 ) 6H),2H),4H),7.38 (dd,J = 8.4,1.8 Hz,2H),3.20 (s,4H). 13 C NMR (100 MHz, CDCl 3 ) δ 139.2 (2C), 133.6 (2C), 132.0 (2C), 127.9 (2C), 127.6 (2C), 127.4 (2C), 127.3 (2C), 126.5 (2C), 125.9 (2C), 125.1 (2C), 38.0 (2C). IR (neat, cm-1): ν max 935, 2914, 1598, 1452, 862, 775.

2,3-Diphenylbutane 200

The general procedure (M) was applied to 2-(bromomethyl)naphthalene (92 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane 100%) afforded the title compound as a colorless solid (92% yield), isolated as a mixture of dl and meso compounds (48/52). 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 -7.34 (m, 5H,), 7.32 -7.12 (m, 12H), 7.10 -7.05 (m, 3H), 3.01 (m, 2H, dl isomer), 2.86 (m, 2H, meso isomer), 1.38 -1.31 (m, 6H, dl isomer), 1.12 -1.06 (m, 6H, meso isomer ). The general procedure (M) was applied to 3-(bromomethyl)pyridine (85 mg, 0.50 mmol, 1.0 eq.). Silica gel chromatography (eluent pentane/EtOAc 90/10) afforded the title compound as a yellow oil (90% yield),. 1 H NMR (400 MHz, CDCl 3 ) 4H),7.36 (dt,J = 7.8,2.0 Hz,2H),7.13 (ddd,J = 7.8,4.8,0.9 Hz,2H),2.87 (s,4H). 13 C NMR (100 MHz, CDCl 3 ) δ 149.9 (2C), 147.7 (2C), 135.9 (2C), 135.9 (2C), 123.3 (2C), 34.5 (2C). IR (neat, cm-1): ν max 2994, 2918, 1593, 1479, 1424, 1100, 808, 713. Brendan Fallon, Méthodes et Applications en Chimie Organique, IPCM, UMR 8232, UPMC

Cobalt-Catalyzed bond activation: C-H functionalization, hydrosilylation and coupling reactions

Abstract: This thesis has focused on the use of well-defined low-valent cobalt complexes of the family RCo(PMe 3 ) 4 for a variety of bond activation (C-H, Si-H, C-X). We aimed to develop a catalytic system that could compete with the previously reported bimetallic systems of Yoshikai and expensive rhodium catalysis. To this end, we successful demonstrated that Co(PMe 3 ) 4 and HCo(PMe 3 ) 4 are efficient catalysts for the hydroarylation of a broad variety of alkynes and alkenes. In addition, we carried out extensive mechanistic investigations using deuterium labelling experiments and theoretical studies namely DFT. The main finding of these studies was that the C-H bond activation proceeded via a ligand-to-ligand hydrogen transfer mechanism. Following on from this study we then showed that it was possible to carry out the regio-and stereoselective hydrosilylation of internal alkynes with a broad variety of hydrosilanes. During this study we successfully isolated an interesting cobalt(III) intermediate which we believe plays a crucial role in the reaction mechanism. Finally, we report on the ability of these catalysts to efficiently catalyze the homocoupling of benzyl halides in the presence of dimethylzinc. Initial mechanistic investigations suggest that the reaction takes via two single electron transfers and that dimethylzinc act to regenerate the catalyst.