D J C Constable

P J Dunn

J D Hayler

G R Humphrey

J L Leazer

R J Linderman

K Lorenz

J Manley

B A Pearlman

A Wells

C Bryan

D Entwistle

F Gallou

S G Koenig

Je tiens tout d'abord à remercier les Professeur Belmont Philippe, Docteur Bour Christophe et Docteur Gulea Mihaela d'avoir accepté d'évaluer mon travail, ainsi que la région Grand-Est et LabEx pour le financement de ma thèse. Je tiens tout particulièrement à remercier Joseph Moran de m'avoir accepté dans son laboratoire et ainsi d'avoir rendu mes objectifs d'études possibles à savoir mener à son terme un doctorat en chimie. Ces trois années à l'ISIS ont été l'opportunité fantastique pour moi d'améliorer mes compétences en chimie tout en m'immergeant dans la langue anglaise, outil indispensable de nos jours dans l'environnement scientifique. En dépit des multiples responsabilités inhérentes à la charge de directeur de laboratoire (gérer plusieurs projets en même temps, trouver des financements, les cours magistraux …) Joseph a toujours pris le temps de discuter des difficultés rencontrées lors mes recherches à chaque fois que j'en faisais la demande. C'est pour toutes ces raisons que je remercie Joseph. D'autre personnes ont eu une part importante dans ma formation : un grand merci à David Leboeuf, arrivé au laboratoire durant ma troisièmes année, qui m'a beaucoup aidé pour la rédaction de ma thèse. Je regrette parfois de ne pas avoir pu bénéficier plus tôt de ses conseils avisés et de son intarissable source d'idées. Je tiens aussi à remercier Edward Richmond qui m'a pris sous son aile au début de ma thèse, et quand bien même le projet sur lequel nous avons bataillé de concert n'a peut-être pas abouti, il reste que travailler ensemble m'a beaucoup appris. Je tiens à remercier énormément Vuk Vuković qui m'a encadré en stage de master alors-même qu'il avait parallèlement à assumer tout le travail inhérent à l'approche de sa thèse. Je tiens aussi à remercier Jing Yi qui a travaillé avec moi sur le projet d'activation d'alcool propargylique. Merci aussi à Nicolas Zeidan de m'avoir aidé à la correction de la troisième partie de ma thèse. Je remercie aussi tous mes autres collègues, Shaofei, qui a commencé en même temps que moi son doctorat, pour toutes ces épreuves traversées ensemble. Sa bonne humeur et son esprit pratique m'ont été d'une grande aide durant ces 3 ans. Kamilla et Sreejith pour leurs énergies et leurs précieux conseils. Paul, pour nos discussions de métaphysique avancée. Lucas pour être … Lucas, il n'y a pas d'autres mots, son originalité débordante a été essentielle à la bonne ambiance au labo. Elodie, je ne te remercierai jamais assez de m'avoir fait découvrir le cross-fit. Le grand chevalier du bit-box, maître de l'analytique, pourfendeur de comètes, Robin, bien qu'arrivé sur le tard, ma thèse n'aurait pas été la même sans toi. Sophia pour son implication active dans la vie du Labo. Bien que pour toi tout doit être carré et que tu n'aimes Schéma 3. Champ d'application pour la formation d'allènes. a réaction à 50 °C. b temps de réaction de 24 h. c temps de réaction de 3 h. d temps de réaction de 5 min. f réaction à 80 °C.

De façon intéressante, en prolongeant le temps de réaction et en augmentant la température, un autre produit a été obtenu, à savoir un indène (Schéma 5). Ce composé est obtenu par une réaction de Friedel-Crafts intramoléculaire à partir de l'allène, ce que nous avons confirmé en conduisant la réaction à partir de l'allène pur dans des conditions réactionnelles identiques.

pas trop la ''French way'', je tiens à te remercier, pour l'immense travail de labelling que tu as fait avec la bibliothèque de composés du labo. Abhijit, Ankita, Harpreet, Elodie (master student) et Martin d'avoir participé à l'ambiance du laboratoire. Jan et Anton pour leur passage au laboratoire, certes bref, mais intense. Sans oublier mes masters students préférés Loui et Joris, (bien qu'ils soient PHD student maintenant). Et je souhaite bon courage aux nouveaux arrivants, Cyprien et Émilie.

Merci aussi à Annia et Nathalie, nos secrétaires, pour leur gentillesse, leurs sourires et pour leur implication dans leurs travails. Merci aussi à toutes ces personnes qui nous aident au quotidien, Jean-Louis et Cyrile pour la RMN et la GC à l'ISIS, Maurice du service RMN, Arthur qui s'occupe de la maintenance et bien d'autres… J'aimerais aussi remercier ma famille, mon père, ma mère et ma soeur Marc, Brigitte et Elsa pour leurs encouragements et leurs soutiens. Mes autres frère et soeur Vincent et Delphine, qui m'ont servi d'exemple même si on ne se voit pas beaucoup. J'espère qu'avec ce présent manuscrit, tous comme vous, je rejoindrai les rangs des docteurs. Merci aussi au reste de la famille, les autres Noël, les Bonazzi, les Sarah et les Lebeau… Et le meilleur pour la fin, un énorme merci à ma copine Anaëlle qui m'a encouragé pendant toutes mes études supérieures, même durant les moments difficiles. Je n'y serais jamais arrivé sans toi. Merci aussi à la famille Muno, Régis, Michelle et Florien pour tous les moments passés ensemble.

D'autre part, j'aimerais remercier mes amis, Clément et Shehrazade, Charles, Elodie, Florent (Grenier) et tous mes autres amis de Strasbourg, de l'île d'Oléron et de la Réunion, même si on s'est perdu de vue pour la plupart. Et surtout mes potes de Cross-Fit Strasbourg, les meilleurs, ceux qui viennent suer avec moi dès 7 h du matin, Marie, Valentin, Audrey, Denis, Amandine, Julien… Et les super coachs qui nous donnent la pêche tous les matins, Florian, Julien, Geoffroy et Yoann.

Table des matières

Résumé en Français 1) Introduction Le 1,1,1,3,3, est un solvant aux propriétés atypiques que l'on ne retrouve pas avec des solvants plus classiques (Schéma 1). 1 Par exemple :

(1) La présence de deux groupements trifluorométhyle confère au HFIP un fort effet inductif négatif, de sorte qu'il est k>10 7 fois plus acide (pKa = 9.3) que l'isopropanol (pKa = 17.1). Le HFIP a une plage d'acidité (les acidités accessibles dans un solvant donné) du même ordre de grandeur que l'eau. Cependant, en raison de sa basicité réduite, cette gamme est déplacée vers un régime beaucoup plus acide, comparable à celui de l'acide formique. Sa faible nucléophilie (N OTs = 4.23) permet également d'éviter de rentrer en compétition avec d'autres nucléophiles, limitant ainsi les réactions secondaires indésirables. En fait, le paramètre de nucléophilie du solvant rapporté par le groupe de Mayr pour le mélange HFIP/eau [99:1] est la valeur la plus faible que l'on puisse trouver pour un solvant classique (N 1 = 1.93).

(2) Il possède une forte capacité à donner des liaisons hydrogène (HBD = 1.96) qui est renforcée par la formation d'un réseau de liaisons H entre les molécules de HFIP. Les calculs DFT confirment cette observation, car l'énergie de l'orbitale LUMO de HFIP diminue de moitié lors de sa dimérisation, ce qui en fait, en principe, un excellent solvant pour l'activation électrophile d'une base de Lewis.

(3) La haute polarité de HFIP (ε=15.7) associée à sa faible nucléophilie en font également un solvant de choix pour la génération et l'étude d'espèces cationiques. La question reste cependant de savoir si HFIP stabilise les cations (phénomène thermodynamique) ou s'il les laisse simplement persister suffisamment longtemps pour réagir (phénomène cinétique), ce qui fait actuellement l'objet de nombreuses discussions.

(4) Bien que cela ne soit pas important pour nos études, le HFIP est stable en conditions redox, ce qui en fait un solvant idéal pour les processus électrochimiques, la photocatalyse ainsi que pour les transformations nécessitant des conditions très oxydantes. Ce solvant a ainsi récemment attiré l'attention des chimistes de synthèse pour le développement de nouveaux outils synthétiques, tout particulièrement lorsqu'il est combiné avec des acides de Lewis ou des acides de Brønsted comme catalyseurs. Pendant longtemps, l'efficacité catalytique de HFIP a été essentiellement attribuée à sa faculté de stabiliser des intermédiaires cationiques grâce à son fort pouvoir ionisant et sa faible nucléophilie. 1 Cependant, des études mécanistiques plus poussées ont récemment mis en évidence un fonctionnement beaucoup plus complexe qui impliquerait un effet coopératif entre le catalyseur et HFIP. 2 Ainsi, au cours des dernières années, plusieurs systèmes catalytiques utilisant un acide de Lewis ou de Brønsted en combinaison avec HFIP ont prouvé leur versatilité dans de nombreuses réactions, 3 comme par exemple des réactions de Friedel-Crafts, d'hydroarylation, d'hydrofunctionalisation et de cyclisation. Un des champs de recherche qui a particulièrement bénéficié de ce type d'associations est la substitution nucléophile directe d'alcools que l'on considère désactivés (typiquement des alcools possédant des groupements fortement électro-attracteurs en position a) en utilisant seulement une quantité catalytique d'activateur. En revanche, l'activation d'alcools aliphatiques primaires ne possédant pas de groupements fonctionnels comme des aryles, vinyles ou propargyles susceptibles de stabiliser un carbocation intermédiaire est extrêmement rare en raison de la faible propension de la fonction hydroxyle à agir comme un groupe partant. 4 Ces réactions restent pourtant hautement attractives car elles génèrent uniquement de l'eau comme sous-produit. De plus, les alcools sont des substrats très répandus et généralement peu coûteux. Le développement de méthodes de substitution directe d'alcools a par ailleurs été signalé comme étant un thème de recherche prioritaire par l'ACS Green Chemistry Institute Pharmaceutical Roundtable. 5 Pour ces raisons, le développement de méthodes d'activation directe d'alcools qui utilisent un système acide de Lewis ou acide de Brønsted/HFIP constitue pour nous un domaine de recherche majeur.

Cette thèse visait à étendre le champ d'application de la catalyse acide dans HFIP, notamment dans des réactions d'alkylation d'alcools désactivés de type Friedel-Crafts.

Ce projet était constitué de deux axes de recherche, l'un sur l'activation d'alcools propargyliques substitués par des groupements trifluorométhyles, et le second sur l'activation de substrats très faiblement réactifs, à savoir des alcools aliphatiques primaires. Inspirés par les précédents travaux effectués par notre groupe sur l'activation d'alcools benzyliques hautement désactivés (Schéma 2), 6 nous avons cherché à étendre ce type de réactivité à des alcools propargyliques portant un groupement CF 3 pour accéder dans un premier temps à des allènes trifluorométhylés en utilisant un système acide de Lewis (ou de Brønsted)/HFIP. Les alcools propargyliques constituent des briques moléculaires particulièrement attractives en synthèse grâce aux nombreuses transformations qu'ils peuvent engendrer. Par exemple, la substitution directe d'un alcool propargylique par un nucléophile peut conduire à deux types de produit, soit un alcyne α-substitué soit un allène, suivant les substituants présents sur le précurseur de départ (Schéma 3).

2) Résultats

Schéma 2. Réactivité des alcools propargyliques dans des réactions de substitution nucléophile Notre étude s'est concentrée sur les substrats portant un groupement CF 3 car celui-ci est connu pour être un bioisostère des substituants méthyles ou chlorures, pour augmenter la lipophilie et jouer sur la stabilité métabolique. Ce type de fonctionnalité est très populaire en chimie médicinale (Prozac, Celebrex, sustiva, etc.).

La première étape de ce projet était de tester différents acides en combinaison avec HFIP pour la synthèse d'allènes à partir d'alcools tertiaires. Les meilleurs résultats ont été obtenu avec FeCl 3 et une large variété d'allènes a pu être préparée avec jusqu'à 96% de rendement (Schéma 4). Des expériences de contrôle ont permis de mettre en évidence que FeCl 3 active en réalité HFIP qui est donc la véritable espèce active pour la réaction, celui-ci agissant comme un acide de Brønsted. a temps de réaction de 24 h. b réaction à 80 °C. c réaction à 50 °C. d temps de réaction de 1 h. e Isolé sous forme d'une mixture de régioisomères. f réaction à 120 °C Dans un second temps, nous avons décidé d'introduire un groupement hydroxyle en position ortho du cycle A, dans le but de générer des composés de type chromène via un mécanisme de piégeage intramoléculaire (Schéma 6). Nous avons pu noter que lorsque les substrats de départ étaient protégés par un groupement TBS, la réaction conduisait aux mêmes produits.

En revanche, les alcools propargyliques secondaires ont présenté une réactivité différente de celle des alcools propargyliques tertiaires. A cause de leur encombrement stérique plus limité, le nucléophile présent dans le milieu peut s'additionner deux fois, ce qui a conduit à la formation de divers alcènes (Schéma 7). Il a pu être observé par RMN et par cristallographie aux rayons X qu'il y avait un phénomène de p-stacking entre les deux cycles aromatiques.

b) Alkylations de Friedel-Crafts d'alcools aliphatiques primaires dans l'HFIP

Après l'activation d'alcools benzyliques et propargyliques hautement désactivés, les recherches de notre laboratoire se sont orientées vers une transformation plus complexe, la substitution nucléophile directe d'alcools aliphatiques primaires. En raison de la difficulté inhérente à leur activation et l'instabilité liée à la potentielle formation d'un carbocation primaire, seules deux méthodes substitution directe utilisant la catalyse hétérogène (montmorillonite, zéolite) ont été rapportées dans la litérature. 7 Cependant, ces méthodes conduisent à un mélange de produits linéaires (addition du nucleophile en position terminale) et de produits branchés (addition du nucléophile à une autre position de la chaine aliphatique).

Dans ce contexte, nous pensions que l'utilisation de HFIP combinée avec un acide de Brønsted fort, comme l'acide triflique, pourrait permettre l'activation de ce type d'alcools. Même si les rendements ne sont pas toujours excellents à cause de formation d'oligomères en produits secondaires, cette approche est tout de même très sélective pour la formation de produits linéaires (Schéma 8). Comme attendu, les produits branchés ont été observés lorsque la réaction était conduite à des concentrations plus élevées (1 M contre 0.25 M). Des calculs DFT effectués par le Dr. Chris Rowley supportent un mécanisme de type S N 2 pour l'activation de ces alcools primaires.

Schéma 7. Champ d'application pour l'activation d'alcools primaires

La combinaison TfOH/HFIP s'est révélée être également hautement efficace pour l'activation de dérivés 2-phényléthanols (Schéma 9). Cette différence de réactivité peut être attribuée à la formation d'un intermédiaire réactionel stable de type arénium qui a souvent été décrit dans la litérature. 8 Schéma 8. Champ d'application pour l'activation de 2-phényléthanols

3) Conclusion générale

Ainsi, nous avons pu démontrer la versatilité de la combinaison de HFIP avec un acide de Brønsted ou de Lewis dans plusieurs réactions inédites, laissant entrevoir le potentiel de cette méthode pour son exploitation dans de nouvelles transformations. Dans le cas d'alcools peu réactifs (alcools aliphatiques primaires ou alcools substitués en position a par un groupement électro-attracteur), l'utilisation de la combinaison TfOH/HFIP s'est généralement avérée être la solution la plus efficace pour résoudre les problèmes de réactivités.

En résumé, une méthode efficace pour la synthèse d'allènes, d'indènes, de chromènes et d'alcènes portant un groupement CF 3 à partir d'alcools propargyliques a pu être développée. En utilisant un système similaire, l'activation d'alcool primaire a également été rendue possible mais reste encore à optimiser. Cette méthode s'est montrée particulièrement sélective pour la formation du produit linéaire, ce qui n'avait jamais été rapporté auparavant dans la littérature.

4) Références

Introduction 1.1. HFIP: a solvent with atypical properties Hexafluoroisopropanol or 1,1,1,3,3, is a versatile solvent with a wide range of applications in organic chemistry, material science and biology, without forgetting to mention its fundamental theoretical interest. 1 The aim of this section is to present the key physical and chemical properties of HFIP and explain why this solvent stands apart from other fluorinated and non-fluorinated solvents. 2 1. 1.1. Generalities about HFIP HFIP is an alcohol solvent that is miscible with water and most of the common organic solvents. 1 Due to its low boiling point (59 °C), HFIP can be easily recovered by distillation once the reaction is complete. As an example, some industrial processes began to emerge, relying on its co-distillation with heptanes. 3 HFIP is also thermally stable, which allows its use in reactions at high temperatures.

However, what makes HFIP a unique solvent is the combination of a variety of properties that cannot be found all at once in other traditional solvents. Among them, we can cite:

(1) the presence of the two trifluoromethyl groups that generate a strong negative inductive effect, which in turn makes HFIP 10 7 times more acidic than isopropanol (pK a of 9.3 and 17.1, respectively). Besides its low pK a , HFIP has a range of acidity achievable in a given solvent that is comparable to that of water, though it is closer to formic acid in terms of absolute values (Figure 1). (2) Another important feature of HFIP is its low nucleophilicity, which is critical to prevent side reactions that could occur in transformations involving other nucleophilic species.

To continue the comparison with iPrOH, the value of the nucleophilic parameter of Hamamoto, H. Amii, RSC Adv. 2015, 5, 17269;(d) J. Wencel-Delord, F. Colobert, Org. Chem. Front. 2016, 3, 394;(e) HFIP is N OTs = -4.23, while N OTs = 0.2 for iPrOH (Scheme 1). N OTS is a nucleophilicity scale developed by Schleyer to describe the nucleophilic strength of a solvent. 4 In the equation below, 0.3 is a nucleophile-specific parameter linked to methyl tosylate. Thus, the higher the N OTS parameter, the higher the nucleophilicity of a given solvent.

Scheme 1: Nucleophilicity parameter N OTs (3) Due to its high dielectric constant (ε= 15.7) and low nucleophilicity, HFIP is an excellent solvent to form and study cationic species. 1,5 (4) Due to its redox stability, its use in electrochemical processes and transformations involving highly oxidizing reaction conditions is extremely widespread. 6Nevertheless, the most important property of HFIP remains probably its strong H-bond donating ability, which will be a recurrent thread in this manuscript. However, before examining it in more detail, let us first compare HFIP to other alcohol solvents.

1. 1.2 H-bond donating ability, polarity and acidity of HFIP vs fluorinated and non-fluorinated solvents

The H-bond donating ability (HBD), polarity and acidity of a molecule are intimately linked to each other. Nevertheless, differences can be observed between related classes of molecules.

For instance, the acidity and polarity of compounds do not always correlate, and the same is true for H-bond donating ability. The work of Bonnet-Delpon and co-workers emphasized that those variations are important in the case of fluorinated and non-fluorinated alcohols. 7 With respect to trifluoromethylated solvents, the pK a will be dependent on the number of CF 3 groups present at the a-position of the alcohol (Table 1). While the pK a will be around 12 in the case of one CF 3 , a pK a will be around 9 with two CF 3 .

76, 1126. Bonnet-Delpon and co-workers compared the properties of several fluorinated and nonfluorinated alcohols using three different methods (Figure 2):

Regarding the H-bond acceptance (HBA), they used the Kamlet-Taft scale (β parameter). This parameter is obtained by measuring the solvatochromic shift of 4-nitrophenol 3 compared to that of 4-nitroanisole 4 in the presence of a given alcohol. The closer that parameter is to 0, the lower the HBA of the molecule.

Two other methods were used to compare the H-bond donating ability. The first one is the use of E T (30), which is the solvatochromic shift of Reichardt's "betaine 30" 5. This parameter is employed to measure the polarity of a solvent and is sensitive to the bulkiness of the solvent. The second one is the acceptor number (AN) parameter, which is obtained by analyzing the 31 P chemical shift of triethylphosphine oxide 6 (TEPO), known as the Gutmann-Becket method. As TEPO is a smaller molecule than Reichardt's betaine 30, the AN parameter is less sensitive to steric hindrance. In both cases, the higher the value of AN, the more polar the solvent. Using a plot of E T (30) versus AN (Figure 3), a correlation could be observed between all the non-fluorinated alcohols, with the exception of t BuOH. Most of the studied trifluoromethylated alcohols (PhCF 3 CHOH, Ph(CF 3 ) 2 COH, All(CF 3 ) 2 COH and Pr(CF 3 ) 2 COH) have a better AN than E T (30). In other words, they are less efficient at stabilizing bulky molecules.

Yet, TFE and HFIP do not suffer from this downside.

Figure 3: Plot of E T (30) VS AN (E T (30) = 0.614 x AN + 29.28) In summary, HFIP is a highly polar solvent able to stabilize cations regardless of their bulkiness.

Most of the stabilizing effects of HFIP are due to its HBD because of its very low β parameter.

The pK a of a trifluoromethylated alcohol depends on how many CF 3 groups it has. However, the ability of HFIP to form aggregates plays a major role in its H-bond donating ability.

`Boosting' effect of HFIP aggregates

Olefin epoxidation by hydrogen peroxide is an appealing reaction, since water is the only byproduct of this reaction and the process is rather user-friendly. 8,9,10,11 This reaction is one of the best examples of the boosting effect of HFIP on chemical reactivity, as, in HFIP, this reaction is 10 5 time faster when compared to other polar solvent such 1,4-dioxane (Scheme 2). Several computational studies have been carried out on this reaction. In their initial studies, Shaik and co-workers considered that the mode of action of HFIP was monomolecular. 12 However, recent studies leaned towards the involvement of higher aggregates. Indeed, kinetic studies on the epoxidation of cyclooctene by Berkessel and Adrio indicated a first order kinetic dependence in cyclooctene and a kinetic dependence on HFIP between 2 and 3, depending on the co-solvent used. 10 Furthermore, the ΔS calculated for the ratedetermining step using an Eyring plot is higher than the one for traditional epoxidation by peracids (ΔS = -39 cal.mol -1 .K -1 and ΔS = -18 to -30 cal.mol -1 .K -1 , respectively). 13 From prior investigations, the authors deduced that 2 to 3 molecules of HFIP were involved in the rate determining step, but only 1 molecule of olefin and 1 molecule of peroxide. The highly negative entropy, obtained by using an Eyring plot, compared with more traditional epoxidation is consistent with the involvement of higher-order HFIP aggregates in the transition state of the RDS. A concerted mechanism involving a spiro-bicyclic intermediate has also been proposed as a transition state for the oxygen transfer from H 2 O 2 to the olefin (Scheme 3). Complementary in-silico studies by Kirchner and co-workers confirmed the involvement of such aggregates, with hydrogen peroxide interacting with 3 molecules of HFIP and ethylene (Figure 4). 11 Considerable efforts have been dedicated to the analyses of those aggregate. Berkessel, and co-workers combined DFT, NMR, kinetic and X-ray data with this aim. 9 Titration experiments monitored by 1 H NMR between HFIP and an electron acceptor, 1,4-dioxane, showed only one signal for the OH proton with a significant downfield shift. Consequently, those two observations led the authors to the conclusion that HFIP aggregates are dynamic. In other words, HFIP aggregates are not fixed in solution. They are involved in a dynamic hydrogen bonding interaction with 1,4 dioxane but are disrupted so rapidly that they could not be observed by NMR.

As a monomer, in gas phase, the hydroxyl group of HFIP adopts an antiperiplanar (ap) conformation as the synclinal (sc) conformation is around 1 kcal.mol -1 higher in energy than the (ap) one (Scheme 4). In agreement with quantum-chemical investigations and X-ray studies (Figure 5), the HFIP hydroxyl group adopts a (sc) to synperiplanar (sp) conformation in the liquid phase. This phenomenon reaches its maximum intensity for dimers or trimers of HFIP.

All the torsion angles are given between the CH bound and the OH bound of HFIP along the CO bound: sp: synperiplanar 0° to 30° sc: synclinal 30° to 90° ap: antiperiplanar 150° to 180°

Overall, the authors emphasized that the conformation along the hydroxyl bond in HFIP is critical for the H-bond donating ability. At the electronic level, the closer the conformation is to (sp), the lower is the σ*OH and the higher the dielectric constant.

In summary, the HBD of HFIP is directly related to its ability to generate aggregates in the liquid phase. Those aggregates induce a specific conformation along the CO bond, a synclinal conformation, which is different from that of the monomer in the gas phase. HFIP dimers and trimers have been identified as responsible for the reactivity of HFIP. Moreover, molecular orbital studies on HFIP by Leboeuf and co-workers demonstrated that the energy of the LUMO of HFIP decreased by half upon dimerization. Therefore, HFIP might not only be considered as an efficient H-bond donating solvent, but also as a Lewis base acceptor. 14

Use of HFIP as a solvent in organic synthesis

The objective of this section is to provide an overview of reactions that can be performed in HFIP. This part will focus on reactions that could not be achieved without HFIP or that required stoichiometric amounts of activating agent in the absence of HFIP. To stay consistent with the previous chapter, a first sub-part will be dedicated to transformations involving HFIP as sole promoter. A second sub-part will be devoted to the combination of Brønsted or Lewis acid catalysts with HFIP. To facilitate the reading and give a general view toward the progress in the area, the reactions will be described in chronological order.

HFIP as Sole Promoter

From the past 20 years, many reports have been published on the remarkable reactivity of HFIP (as well as TFE) as sole promoter (Scheme 5). Interestingly, the scope of reactions promoted by HFIP as a solvent is not limited to epoxidation; in 2000, the group of Neumann reported the Baeyer-Villiger oxidation of ketones with hydrogen peroxide. 15 Later on, the group of Berkessel demonstrated that this version of the Baeyer-Villiger oxidation was going through a completely different mechanism from the classic peracid-induced reaction. 16 In 2003, the group of Bonnet-Delpon developed a method for the aza-Diels-Alder reaction between N-arylimines, starting from arylimine 13 and enol ether 12 (Povarov reaction). 17 In 2010, the group of Qu accomplished the intramolecular Friedel-Crafts cycloalkylation of arene epoxide 15. 18 This reaction could be conducted in both HFIP and TFE, although HFIP proved to be much more efficient. More recently, Aubé and co-workers described an intermolecular Friedel-Crafts acylation under similar reaction conditions. 19 In 2014, the group of Qu reported that tetrahydro-β-carbolines could be synthesized via a Pictet-Spengler reaction between tryptamine 20 and aldehydes such as 21. 20

Scheme 5: Examples of reactions with HFIP as sole promoter

Aside from those examples, manifold examples have been depicted in the literature regarding reactions using HFIP as sole promoter. The next set of reactions will be more detailed, as they are representative of what could be accomplished in HFIP without any additional catalyst.

In 2012, the group of Nájera discovered that substitution of allylic alcohols could be directly achieved in HFIP (Scheme 6). 21 A large range of nucleophiles was tolerated, including amines, silyl enol ethers and arenes. Surprisingly, even more basic aliphatic amines worked with this method. This reaction proved to be particularly efficient for aromatic allylic alcohols as substrates. The key challenge of the process is to avoid the dimerization of the starting material or the trapping of the intermediate by the solvent.

Regarding the mechanism, three pathways have been identified: one involves a direct substitution and two involve indirect substitution. In the case of the direct substitution 21 P. Trillo, A. Baeza, C. Nájera, J. Org. Chem. 2012, 77, 7344 pathway, the aromatic allylic alcohol 23 reacts directly with tosylamide to form the allylic adduct 25 via a postulated carbocationic intermediate. The indirect pathways go through the formation of two carbocation reservoirs, the HFIP product 27 and the ether 28 formed by dimerization of the starting material. Owing to its Lewis acidic character and its strong H-bond donating ability, the formation of those byproducts is reversible. For every substrate studied, HFIP proved to be more active than its analog TFE.

Scheme 6: Substitution of allylic alcohols with HFIP as a sole promoter

The group of Aubé 22 investigated a catalyst-free version of the intramolecular Friedel-Crafts acylation using HFIP as sole promoter (Scheme 7). Original versions of this reaction required the use of stoichiometric amounts of acid catalyst because of the coordination of the ketone product to the acid catalyst. Surprisingly, the reaction worked well with other polar HBA-free solvent such as DCM in the presence of a catalytic amount of HFIP. On the other hand, the use of a solvent with a strong H-bond acceptance such as 1,4-dioxane in combination with HFIP shut down the reaction, which highlights the importance of the HBD ability of HFIP in this reaction.

Regarding the mechanism, the possibility that the transformation of the acyl chloride 29 into the ketone 30 goes through an HFIP ester was ruled out, as the adduct of 28 and HFIP proved to be inefficient to furnish the product 30 in HFIP. The authors suggested that the reactivity might be explained by the intrinsic acidity of HFIP acidity. As anticipated, the addition of a base precluded the reaction. However, the reaction of 29 in DCM in the presence of 1 equivalent of HFIP was far more efficient than the one in DCM in the presence 1 equivalent of HCl, which is produced during the reaction. Yet, as pK a (HCl) < pK a (HFIP), the HBD of HFIP might play a major role in this reaction aside from its acidity. Based on those data, the authors proposed two plausible intermediates. First, an in-situ ionization of 29 could occur to form an acyl cation 31 that could be in equilibrium with a protosolvated cation 32. Their second idea was the possibility that the aryl ring directly attacked the acyl chloride to generate a 22 H. tetrahedral adduct 33. Such activated species could exist owing to the strong HBD of HFIP and its Lewis acids character.

Scheme 7: Intramolecular Friedel-Crafts acylation with HFIP as a sole promoter

Challenging reactions could thus be achieved with simple reaction conditions. Xiao and coworkers reported an elegant one-pot reaction using HFIP. In this reaction, a cascade dearomative cyclization occured between phenol 34 and o-aminobenzaldehyde 35 to form nitrogen-containing compound 36 (Scheme 8). 23 Such densely functionalized cyclic amines are of high interest for the pharmaceutical industry. Although this reaction involves several chemical events, the use of mild conditions featuring HFIP as a solvent prevented the formation of any side product.

Regarding the mechanism, KIE experiment indicated that the [1,5]-hydride shift was not the rate determining step. Thus, the authors deduced that the driving force for this reaction was the ability of the ortho-quinone methide 39 formed in-situ to trigger the [1,5]-hydride shift by a rearomatization process (step 3). The authors suggested that HFIP assisted the formation of the ortho-quinone methide due to its HBD ability through the aggregates 37 and 38. 23 S.-S. Li, X. Lv, D. Ren, C.-L. Shao, Q. Liu, J. Xiao, Chem. Sci. 2018, 9, 8253

MeO MeO MeO

Scheme 8: Synthesis of nitrogen-containing polycyclic compound using HFIP as a sole promoter 1.3. HFIP in combination with Brønsted and Lewis acids This part aims to present a global view on the state of the art in the field of Brønsted and Lewis acid catalysis in HFIP, focusing on the different types of reactions.

Friedel-Crafts reaction

The Friedel-Crafts reaction was first reported in 1887 by Charles Friedel and James Manson Crafts. 24,25 They started their investigations by mixing alkyl chlorides and AlCl 3 . A large acid chloride release was observed. From this observation, they concluded that `the organic chlorides are attacked by aluminum chlorides' and assumed that it would be of interest in organic synthesis. Indeed, based on this discovery, they developed two famous reactions (Scheme 9): the Friedel-Crafts alkylation, which is the reaction between an alkyl halide and an aromatic nucleophile, and the Friedel-Crafts acylation, which is the addition/elimination of an acyl halide with an aromatic nucleophile.

24 C. Friedel, J.-M. Crafts, Compt. Rend. Acad. Sci. Paris, 1877, 84, 1392. 25 C. Friedel, J.-M. Crafts, Compt. Rend. Acad. Sci. Paris, 1877, 84, 1450. One of the first reports of Friedel-Crafts reaction using HFIP as solvent was published in 2004 by the group of Ichikawa. 26 This study described the defluorinative Friedel-Crafts cyclization of 1,1-difluoroalkene (Scheme 10). Original Friedel-Crafts reactions required the use of chloride, bromide or iodide as a leaving group. Fluoride was usually let aside as the strength of the C-F bond is much higher than that of other carbon-halogen bonds. Surprisingly, the authors found that the reaction was quicker and furnished better yields with fluorinated substrates than with chlorinated or brominated substrates, although 2 carbon-halide bonds had to be broken during the reaction. This difference of reactivity was attributed to the ability of fluorine to stabilize carbocations in the a-position by injecting electron density on the πvacant orbital (hyperconjugation effect) and its ability to be stable in its anionic form owing to its electronegativity. Once again, HFIP proved to be superior to other fluorinated and nonfluorinated solvents for this reaction due to its high ionizing power and low nucleophilicity.

Scheme 10: Friedel-Crafts defluorinative cyclization of 1,1-difluoroalkenes

Then, in 2008 and 2015, the group of Ichikawa extended the scope of the Friedel-Crafts defluorinative cyclization of 1,1-difluoroalkene to the synthesis of ortho-condensed polycyclic helicenes. 27 These compounds exhibit interesting optical activity and great potential in molecular recognition, asymmetric synthesis, dyes and material science. In 2015, they described that, under similar reaction conditions, dibenzo [g,p]chrysenes that are π-twisted polycyclic unsaturated molecules could be prepared. 28 Such molecules have application as semiconductors for thin-film transistors or organic light-emitting diodes.

In the same vein, in 2019, the group of Shibata developed a cascade Friedel-Crafts cyclization of fluorinated arylalkanes catalyzed by B(C 6 F 5 ) 3 for the synthesis of spirobiindanes (Scheme 11). 29 This method overcame two major challenges, namely the activation of inert Csp 3 -F bond and avoiding the formation of competing elimination E 1 product. Indeed, the use of another solvent such 1,4-difluorobenzene led to the elimination product. This product was also observed when more basic leaving groups such as bromide were used.

Herein, HFIP served a dual purpose. It reduced the Brønsted basicity of the fluoride anion, therefore suppressing the elimination process, and it stabilize the numerous carbocationic intermediates involved in this reaction. Similar effects on the basicity of fluorides have been observed for CsF 30 and TBAF 31 regarding tertiary alcohols.

Scheme 11: Defluorinative Friedel-Crafts cyclization of fluorinated arylalkanes into spirobiindanes

To conclude the discussion on defluorinative Friedel-Crafts reactions in HFIP, this reactivity is not limited to intramolecular cyclizations. The group of Paquin reported the Friedel-Crafts aromatic propargylation of secondary propargylic fluorides in 2017 (Scheme 12). 32 As for all defluorinative Friedel-Crafts, up to one equivalent of HF is produced during the process. As HF pK a (HF) is lower than pK a (TFA), the authors suggested that the generation of HF becomes the true active species during the reaction. The group of Paquin group also reported that even fluorobenzylic substrates could undergo the Friedel-Crafts reaction with arene nucleophiles in a mixture of solvents HFIP/DCM (Scheme 13). 33 In that case, no acid catalyst was required. However, employing TFA as a catalyst drastically improved the rate conversion. In 2015, the Hall group was the first to report a catalytic version of the Friedel-Crafts reaction with benzylic alcohols in HFIP, using ferroceniumboronic acid hexafluoroantimonate as a catalyst (Scheme 14). 34 Regarding the mechanism, the authors suggested that the catalyst was involved in the stabilization of the benzylic carbocation. In their proposal, the benzylic alcohol reacted with the boron moiety, while the ferrocenium ion and the hexafluoroantimonate counterion stabilized the formation of the benzylic cation by forming a tetra-ion.

Scheme 14: Friedel-Crafts reaction of benzylic alcohols catalyzed by ferroceniumboronic acid hexafluoroantimonate 33 P. A. Champagne, Y. Benhassine, J. Desroches, J.-F. Paquin, Angew. C hem. Int. Ed. 2014, 53, 13835. 34 X. Mo, J. Yakiwchuk, J. Dansereau, J. A. McCubbin, D. G. Hall, J. Am. Chem. Soc. 2015, 137, 9694 Nevertheless, this interpretation was recently questioned by our group as the involvement of HFIP would make this process more complex. 35 We reported a series of control experiments with boronic and Brønsted acids and analyzed their reactivity, kinetics, and their acidity by the Gutmann-Beckett method. In several examples, strong Brønsted acids or simple H-bond donors showed a similar reactivity to boronic acids (Scheme 15). In most cases, it was concluded that the true mode of catalysis might involve either dual H-bond catalysis or Brønsted acid catalysis, in which HFIP would be the active species.

Scheme 15:Comparison of boronic and Brønsted acids as catalysts in the presence of HFIP

One additional catalytic effect in the Friedel-Crafts reaction with benzylic alcohol could be the in-situ formation of hexafluoroantimonic acid, a strong Brønsted acid. With this possibility in mind, our lab wondered whether this reaction could be achieved with simple Brønsted acid in HFIP (Scheme 16). 36 Interestingly, the utilization of triflic acid as a catalyst not only allowed the Friedel-Crafts reaction but was also compatible with highly deactivated substrates that could not be employed under the reaction conditions developed by the group of Hall.

35 S. Zhang, D. Leboeuf, J. Moran, Chem. Eur. J. 2020, 26, 9883. 36 V. D. Vuković, E. Richmond, E. Wolf, J. Moran, Angew. Chem. Int. Ed. 2017, 56, 3085 To probe the role of HFIP, the reaction was monitored by 1 H NMR titration using benzylic alcohol 75 and HFIP with increasing amount of triflic acid (Figure 6). It was noteworthy that the H m proton of 75 did not shift with increasing amount of TfOH while the HFIP signals H y and H z shifted downfield. Thus, the TfOH acidic proton preferentially interacts with HFIP over the benzylic alcohol 75. In other words, TfOH is likely not the true catalyst of this reaction, which would be instead an HFIP/TfOH aggregate. This is consistent with the results of kinetic experiments. Indeed, a first order dependence in concentration of TfOH and benzylic alcohol was observed, while a fifth order dependence in HFIP concentration was found, highlighting the involvement of HFIP aggregates. Finally, a S N 1 -type mechanism was proposed based on a racemization experiment (Scheme 17). In 2018, the group of Antonchick reported a similar reaction using NOBF 4 as a catalyst in a HFIP/DCE mixture. 37 In addition to be the first report of Friedel-Crafts reaction using an inexpensive nitrosonium salt, this reaction could be achieved with benzyl ether instead of benzyl alcohols. In that case, the reaction occurred in an intramolecular fashion. It is noteworthy that they achieved the synthesis of phenprocoumon, an oral anticoagulant drug using NOBF 4 in HFIP/DCE (Scheme 18). Regarding the mechanism, a S N 1 process was also proposed as enantiopure starting materials led to racemic products and the use of radical scavengers did not affect the reactivity. However, Lewis acid catalysis seemed to be involved in this reaction as neither HCl nor nitromethane promoted the reaction, ruling out the hypothesis of hidden Brønsted catalysis.

Scheme 18: Synthesis of phenprocoumon by Friedel-Crafts reaction using nitrosonium salt in HFIP/DCE

While investigating a boronic acid-catalyzed Beckmann rearrangement, 38 the group of Hall discovered that the use of perfluoropinacol as an additive could improve the reactivity by forming an electrophilic boronic ester. Based on this result, they transposed this idea to the Friedel-Crafts process (Scheme 19). Indeed, a significant improvement of the reactivity of highly deactivated benzylic alcohol was observed. 39 Regarding the mechanism, the authors suggested the involvement of a tetracoordinate boron species as a critical intermediate for the reaction. Indeed, when water was added, products 86 and 88 were experimentally observed by 11 B NMR and by mass spectrometry. Addition of water or HFIP on the boron catalyst did not occur in the absence of perfluoropinacol. Moreover, no target product was obtained without the presence of perfluoropinacol. The authors identified the hydronium boronate 86 formed as a key player in the reactivity as no product was obtained in strictly anhydrous conditions. In addition, the use of a proton scavenger, the sterically hindered amine 2,6-di-tert-butylpyridine, completely inhibited the formation of the desired product. Yet, the authors emphasized that it does not mean that a strictly Brønsted acid system is at work as they experimentally observed by 11 B NMR that boronate 86 formed a complex with 2,6-di-tert-butylpyridine that is not an efficient catalyst for this reaction. Therefore, they proposed three different pathways for the alcohol activation:

(1) a strictly Lewis acid catalysis where the benzylic alcohol is directly coordinated to the Lewis acidic tetracoordinate boron ester, (2) a Brønsted acid catalysis where the acidic water of the hydronium borate salt 84 protonates the benzylic alcohol, and (3) a Lewis acid-assisted Brønsted acid catalysis where the acidity of HFIP is enhanced upon coordination to the borate species in order to transfer its proton to the benzylic alcohol. 37 L. Bering, K. Jeyakumar, A. P. Antonchick, Org. Lett. 2018, 20, 3911. 38 X. Mo, T. D. R. Morgan, H. T. Ang, D. G. Hall, J. Am. Chem. Soc. 2018, 140, 5264. 39 H. T. Ang, J. P. Ryugus, D. G. Hall, Org. Biomol. Chem. 2019,17, 6007 1.3.2. Hydroarylation Donor-acceptor cyclopropanes are useful building blocks for the synthesis of acyclic, alicyclic and heterocyclic compounds. 40 Due to its unique properties, HFIP proved to be a solvent of choice for the acidic catalytic activation of donor-acceptor cyclopropanes (Scheme 20). In 2017, the group of Xu developed an intramolecular cascade ring-opening of donor-acceptor cyclopropanes by using Hf(OTf) 4 and 3,4,eq. 1). 41 This elegant cascade reaction is one of the rare examples with the use of a phenol derivative as an organocatalyst. On the other hand, addition of a hindered Brønsted base such as 2,6-ditert-butylpyridine completely prevented the reactions. The authors concluded that formation of TfOH during the reaction might be critical for the reactivity. Unfortunately, no control experiments with TfOH were carried out to support this claim. In the same vein, the group of Xu developed a [4+2] annulation between electron-rich phenols and donor-acceptor cyclopropanes by using Sc(OTf) 3 as a catalyst (Scheme 20, eq. 2). 42 More recently, the group of Li developed a method for the synthesis of 9H-fluorenes through an intramolecular arylative ring-opening of donor-acceptor cyclopropanes (Scheme 20,eq. 3). 43 This reaction could be also conducted in DCM with good yields. On the other hand, in that case, the reaction required 6 equiv. of TfOH compared to only 0.1 equiv. in HFIP. Prior to Li's report, our group made several breakthroughs in the arylative ring-opening of cyclopropanes. 44,45 Our initial goal was to determine whether a combination of a Brønsted acid with HFIP could efficiently promote the hydroarylation of donor-acceptor cyclopropanes (Scheme 21, eq. 1). In a similar fashion to the Friedel-Crafts alkylation, TfOH provided the best results as a catalyst. Furthermore, those conditions allowed even the activation of weaklypolarized cyclopropanes bearing a single electron-withdrawing group and those bearing electron-deficient aryl groups. Regarding the nucleophiles, the reaction tolerates a wide range of nucleophile including arenes, azides, diketones and alcohols (Scheme 21, eq. 2). Nevertheless, heteroaromatic substrates such as indole required a milder acid, B(C 6 F 5 ) 3

. H 2 O.

Scheme 21: Hydroarylation of DA cyclopropanes and monosubstituted cyclopropanes

To account for the reactivity, mechanistic studies relying on kinetic experiments (Hammet plot) and DFT calculations were performed (Scheme 22). The formation of the arenium ion 108 was identified as the RDS for this reaction. The racemization of the product from an enantiopure donor-acceptor cyclopropane combined with 1 H NMR monitored kinetic experiments supported a homo-conjugate addition pathway (S N 2 -like mechanism). Indeed, by plotting the reaction rates of several para-substituted cyclopropanes vs Hammett substituent parameter the authors observed (1) that a positive charge was generated in the RDS as a negative slope with a strong relationship was observed with most data (2) that the magnitude of this slope is consistent with a S N 2 -like mechanism.

44 E. Richmond, V. D. Vuković, J. Moran, Org. Lett. 2018, 20, 574. 45 To probe the role of HFIP in the hydroarylative ring-opening of donor-acceptor and monosubstituted cyclopropanes under HFIP/TfOH reaction conditions, a series of computational studies were carried out by Zhang and Feng. 46 In their report, the authors emphasized the importance of considering the explicit solvation effect while conducting DFT calculations. Regarding the rate determining step, two models were studied (Scheme 23). One without explicit solvation effect (Scheme 23, eq.1) and one involving the solvation with three HFIP molecules (Scheme 23, eq.2). An energy barrier of 29.5 kcal/mol was calculated for the solvent-excluded model, which would require roughly 100 °C for the reaction to take place.

On the other hand, regarding the model including explicit solvation effect, an energy barrier of 20.5 1 H NMR titration of TfOH into a solution of cyclopropyl ketone, HFIP and 1,3,5trimethoxybenzene conducted by our group revealed a preferential protonation of the nucleophile 1,3,5-trimethoxybenzene. Taking this information into account, the groups of Zhang and Feng proposed two alternative modes of activation for the ring-opening of donoracceptor cyclopropanes and cyclopropyl ketone (Scheme 24), in which either the nucleophile or TfOH induced the activation. In summary, the activation pathway will likely change between those two depending on the pair nucleophile/cyclopropane. In the case of DA cyclopropanes and cyclopropyl ketones, the rate determining step is the formation of the arenium ion that occurs through a homo-conjugate (S N 2 -like) addition pathway.

OTf

Interestingly, aryl-substituted cyclopropanes exhibited a different reactivity, leading to branched products (Scheme 25). A S N 1 -type mechanism was proposed by our group as, in the absence of nucleophile, aryl cyclopropanes decomposed under HFIP/TfOH reaction conditions, which is consistent with the formation of carbocationic species.

Scheme 25: Ring-opening of aryl cyclopropanes

In another vein, Leboeuf and co-workers succeeded to report the first hydroarylation of highly deactivated styrene by using a Ca(II)/HFIP system (Scheme 26). 47 DFT calculation supported a mechanism in which an efficient cooperative effect occurred between HFIP and calcium(II) triflimide. Not surprisingly, the protonation of the styrene derivative was identified as the RDS followed by the addition of the aryl nucleophile to the benzylic cation to form an arenium ion. The resulting Wheland-type intermediate should then rotate so that the NTf 2 is spatially close enough to capture the proton. Since the addition of the arene creates a new stereogenic center, and the calcium complex is chiral, both directions of rotation do not have the same energetic requirements. One of the diastereoisomers is however significantly more stable than the other one (ΔG (123) = 16.5 kcal/mol < ΔG (123') = 23.9 kcal/mol). Then, the arenium ion undergoes a rearomatization that leads to the product 125. 47 C. Qi, V. Gandon, D. Leboeuf, Angew. Chem. Int. Ed. 2018, 57, 14245. In 2019, Magre and Rueping found out that magnesium (II) triflimide salt was also efficient for the selective ortho-C alkylation of anilines with alkynes (Scheme 27). 48 Mechanistic investigations using deuterium labeling and NMR experiments suggested a similar mechanism to the system with Ca(NTf 2 ) 2 , involving first protonation of the π system with HFIP. Indeed, when deuterated hexafluoroisopropanol HFIP-OD was used, complete incorporation of deuterium was observed at the alkene moiety. acids, the addition of the proton scavenger 2,6-tert-butylpyridine did not affect the reactivity, which is consistent with the Lewis acid mechanism proposed.

Scheme 27: HFIP-assisted magnesium(II)-catalyzed hydroarylation of alkynes with anilines

Regarding alkyne activation, the group of Ichikawa recently depicted a biphasic system, using HFIP/cyclohexane and TsOH . H 2 O as a catalyst for the Brønsted acid-catalyzed hydroarylation of unactivated alkynes to synthesize phenanthrene frameworks (Scheme 28). 49 In this reaction, the apolar alkyne is essentially located in the cyclohexane phase, while the toluenesulfonic acid monohydrate resides in the HFIP phase. At the interface, the alkyne can be protonated by the TsOH . H 2 O to form a vinyl cation that will migrate in the HFIP phase due to the stabilizing properties of the latter. The separation of the vinyl cation species from the starting material via this biphasic system precludes the formation of side-products and proved to be critical for the success of the reaction when compared to the sole use of HFIP as a solvent. Moreover, the author emphasized that the phase containing the catalyst as well as HFIP could be reused several times. 49 Takahashi, T. Fujita, N. Shoji, J. Ichikawa, Chem. Commun. 2019, 55, 9267. Scheme 28: Intramolecular hydroarylation of alkynes in the biphasic HFIP-cyclohexane system 1.3.3. Hydrofunctionalizations In the past 5 years, numerous studies have been dedicated to the use of fluorinated alcohols for hydrofunctionalization reactions. In 2016, the group of Li developed a Markovnikov-type hydration protocol using triflic acid in combination with TFE or HFIP (Scheme 29, eq.1). 50 In 2018, the group of Wang developed a ring-opening hydroamination of 3,4-epoxy alcohols using a boronic acid in HFIP (Scheme 29, eq.2). 51 The amination proved to be regioselective owing to the alcohol group, which acts as a directing group enabling access to enantioenriched amino alcohols. Later, they reported that ring-opening of 3,4-epoxy alcohols was also possible with thiols and thiophenols under similar reaction conditions (Scheme 29, eq.3). In 2018, Leboeuf and co-workers reported an HFIP assisted calcium(II)-catalyzed hydroamidation of unactivated alkene (Scheme 30). 53 One key parameter on this system is the HBD abilities of HFIP that facilitate the release of Lewis acids from off-cycle binding with the substrate or the product. Thanks to this ability, their promoter system overcame several limitations regarding the hydroamination of unactivated alkenes, as no rare metal was required and a large range of basic nucleophile such as urea, amides and carbamates were well-tolerated. On the other hand, substrates substituted with electron-rich functional groups on the aryl moiety furnished lower yield due to oligomerization.

Concerning the mechanism of the reaction, the role of the ammonium salt is to promote the formation of [CaNTf 2 ] + [PF 6 ] -, which is more Lewis acidic than CaNTf 2 . Based on DFT calculations, the authors proposed the [(NTf 2 )Ca(HFIP) n ] + complex 146 as the active species for the protonation (RDS). Herein, HFIP serves a dual purpose: it rigidifies the substrate conformation, therefore inducing a good diastereoselectivity, and protonates the alkene to trigger the cyclization. The authors emphasized that the coordination of HFIP to the calcium center is critical for the reaction, as it drastically increases the acidity of HFIP.

53 C. Qi, F. Hasenmaile, V. Gandon, D. In the continuity of those studies, they demonstrated that this system was also efficient for the intramolecular hydroacyloxylation of unactivated alkenes (Scheme 31). 54 At that time, this reaction was still highly challenging because of the tendency of carboxylic acid functionalities to strongly coordinate to transition metals or Lewis acids, thus preventing the transformation.

Scheme 31: Calcium (II)-catalyzed intramolecular hydroacyloxylation of unactivated alkenes in HFIP

More recently, the group of Li developed a straightforward process for the synthesis of cis-2,5-disubstituted pyrrolidines via N,O-acetals, which were formed following an intramolecular hydroamination of alkynes and a subsequent addition of HFIP (Scheme 32). HFIP plays multiple role in this reaction: it acts as a solvent, an acid, an additive, a leaving group and more surprisingly a nucleophile. 55 Remarkably, reactions with enantiopure precursors led to the formation of enantioenriched product along with a high diastereoselectivity. To probe the mechanism the authors carried out a series of control experiments and DFT calculations. (1) The first step is the classic coordination of the Ag complex to the π-system to form the complex 151.

(2) The second step is the intramolecular hydroamination to form the complex 152. This step has been identified as the RDS. Indeed, according to their DFT studies (with explicit inclusion of 2 HFIP molecules), the energy barrier for the cyclization step is 25.8 kcal/mol. ( 3) The third step is the deprotonation of the quaternary ammonium by the HFIP aggregate to generate 153. (4) In the fourth step, a proto-demetalation occurred to give the intermediate 154. (5) In the fifth step, a protonation of the enamide moiety takes place to form iminium 155, which dictated the addition of HFIP as the cis HFIP/intermediate/Ag cluster was calculated to be 1.6 kcal/mol lower than a trans aggregate. ( 6) Finally, the nucleophilic addition of HFIP to the iminium led to the target product. Experimental evidence showed that intermediate 154 could undergo nucleophilic addition of HFIP in the absence of AgOAc (Scheme 33). In that case, however, the reaction is much slower.

The authors concluded that the reaction of the homopropargylic sulfonamide in HFIP occurred via dihydropyrrole intermediate 155 and HFIP served as a hydroalkoxylative reagent in the addition reaction without requiring AgOAc. In addition, control experiments with intermediate 156 in the presence of indole under standard conditions showed a preferential addition of HFIP rather than that of indole, even if the bulk nucleophilicity of HFIP is lower than that of indole. This observation might be explained by the formation of a HFIP/Ag cluster that would enhance the nucleophilicity of HFIP.

Scheme 33: Mechanistic control experiments for pyrrolidine synthesis in HFIP 1.3.4. Cyclization In the past 20 years, several cyclization reactions have been investigated in HFIP, including Nazarov cyclizations, 56 Diels-Alder cycloadditions, 57 intramolecular cyclizations 58 and a range of polycyclic cascade reactions. 59 .

The Nazarov cyclization is a 4π conrotatory electrocyclization usually involving divinyl ketones for the synthesis of cyclopentenones (Scheme 34). The original version involved the use of stoichiometric amounts of Lewis or Brønsted acid, suffering from a lack of control of the selectivity regarding the position of the double bond. 60 In particular, a variant featuring TMSOTf in HFIP was developed by Minami in 1995 and enabled the use of fluorinated divinyl ketone owing to the H-bonding/cationic charge stabilizing properties of

+ 2.6:1 R R R R O R R R R OH OH O O R R R R R R R R R R R R Nu H Nu β-H Elim.

n-Bu

(2)

164 165 (3)
(4)

1-halocyclopentenes from a substrate bearing a halogen functionality instead of a ketone (eq.

3). 63 More recently, they extended the scope of halo-Nazarov cyclization to aryl substrates (Scheme 34, eq.4). 64 DFT computations carried out indicated that 3-halo-cationic intermediates are more kinetically accessible and thermodynamically favorable than their 3oxy-Nazarov analogs, allowing therefore a lower catalyst loading.

Concerning polycyclic reactions, the potential of HFIP was further illustrated in the synthesis of polycyclic terpenoids by Qu and co-workers (Scheme 35). 65 They reported the epoxideinitiated polycyclization of up to 4 double bonds in one pot, under air conditions, within 5 min.

The downside of this reaction is that super-stoichiometric quantity of Ph 4 PBF 4 was required.

Scheme 35: Polycyclization of terpenes in HFIP

An interesting variant of the Nazarov reaction is the aza-Piancatelli cyclization, which is a useful method for the synthesis of 4-aminocyclopentenone derivatives. Over the past five years, Leboeuf and co-workers investigated the potential of HFIP with respect to the aza-Piancatelli reaction (Scheme 36). 66 In their initial studies, they devised an efficient catalytic system featuring Ca(NTf 2 ) 2 /nBu 4 NPF 6 in nitromethane to promote this transformation. 67 However, they became aware that many substrates could lead to side reactions at the carbinol position, including Friedel-Crafts and deoxyamination reactions, or could decompose at high temperatures. It notably concerned 2-furylcarbinols incorporating alkene and cyclopropyl moieties or sterically hindered 2-furylcarbinols and secondary anilines. 66 Additionally, they noticed that anilines bearing strong electron-donating groups were less reactive as they could entrap the catalyst to generate an "off-cycle" species. Thus, they hypothesized that employing HFIP would favor the dissociation of the "off-cycle" species, therefore improving the reactivity of aniline derivatives such as p-anisidine.

63 G. Alachouzos, A. J. Frontier, Angew. Chem. Int. Ed. 2017, 56, 15030. 64 C. Holt, G. Alachouzos, A. J. Frontier, J. Am. Chem. Soc. 2019, 141, 5461. 65 Y. Tian, X. Xu, L. Zhang, J. Qu, Org. Lett. 2016, 18, 268. 66 In order to understand the mode of activation of Ca(II)/nBu 4 NPF 6 in HFIP, the authors used the Childs' method to measure the acidity of their system (Table 3). From those results, the authors deduced that the activation of furylcarbinol was triggered by an HFIP-calcium cooperative effect. In the case of some nucleophiles such as indole, the acidity of HFIP was sufficient to promote the reaction and the authors hypothesized that the role of calcium was not to directly promote the reaction as a classic Lewis acid but, instead, to increase the inherent acidity of HFIP, which was confirmed by DFT calculations. In 2017, the same group pushed the boundaries of the aza-Piancatelly reaction by combining this reaction with an intramolecular hydroamination in a one-pot fashion to synthetize

R = H R = (F 3 C) 2 CH R = iPr
densely functionalized cyclopenta [b]pyrroles (Scheme 37). 68 When the reaction was performed in 1,2-DCE, cyclopenta [b]pyrrole 176 was generated following a hydroamination/isomerization process. While the use of HFIP as a solvent delivered the same compound, albeit at a lower temperature, they noticed that a prolonged reaction time led to the complete dearomatization of the product to give cyclopenta [b]pyrroline 177 through the activation of the carbonyl moiety by HFIP. Scheme 37: Synthesis of cyclopentane [b]pyrroles in HFIP 1.3.5. Other reactions HFIP attractive properties have been used in a large variety of reactions, notably to overcome a lack of reactivity of a given substrate, to reduce side reactions or sometimes to achieve unprecedented reactivity. Komiya and co-workers discovered, for instance, an unprecedented reactivity in their attempts to synthesize vitamin K3 and K1. 69 Indeed, the precursor 178 underwent an intramolecular cyclization to furnish the benzoquinone 179 in HFIP using BF 3 •Et 2 O as a catalyst, while p-toluquinone 180 was obtained in other solvents such as DCM (Scheme 38). The authors attributed this effect to HFIP's ability to stabilizes cationic intermediate during the rearrangement. The properties of HFIP have also been used to efficiently conduct the Petasis reaction, the Schmidt reaction and the Pictet-Spengler reaction. 70 68 (a) L. Marin, V. Gandon, E. Schulz, D. Leboeuf, Adv. Synth. Catal. 2017, 359, 1157;(b)

L. Marin, R. Guillot, V.
Gandon, E. Schulz, D. Leboeuf, Org. Chem. Front. 2018, 5, 640. 69 S.-I. Murahashi, A. Fujii, Y. Inubushi, N. Komiya, Tetrahedron. Lett. 2010, 51, 2339. 70 The Petasis reaction (Boronic Acid Mannich BAM reaction) is a one-step multicomponent reaction involving an organoboronic acid, an amine and a carbonyl derivative (Scheme 39). In 2017, the group of Tehrani discovered that the use of HFIP as a cosolvent could accelerate this reaction and, therefore, reduce the formation of side products. 71 The authors supposed that this acceleration was due to the ability of HFIP to stabilize/accelerate the formation of the iminium species. In a similar fashion, the group of Ware found that cyclic amines could undergo [1,5]-H nitro-Mannich reaction using HFIP as sole promoter, which was in line with Teharani assumption. The intramolecular Schmidt reaction is a method to synthesize lactams from azidoalkyl ketones. Classical methods required super-stoichiometric amount of acid to assist the transformation. 73 In 2013, the group of Aubé suggested that this lack of reactivity might be caused by a catalyst inhibition, resulting from the trapping of the catalyst by the lactam formed. Thus, they believed that the strong hydrogen bond donor ability displayed by HFIP would favor the release of the catalyst and, thus, the turn-over of the process. 74 Indeed, excellent reactivity was observed with a low catalyst loading of TiCl 4 in HFIP (Scheme 40).

O N H R R N R R OH (HO) 2 B R 1 N R R B(OH) 3 R 1 N R R R 1

Petasis (Boronic Acid Mannich

Scheme 40: Intramolecular Schmidt reaction in HFIP

In 2016, while studying the intermolecular Schmidt reaction, Aubé and co-workers found out that ketones could lead to the formation of a ring extended tetrazole using TMSN 3 and TfOH in HFIP (Scheme 41). 75 Interestingly, they observed another product resulting from the triple addition of trimethylsilyl azide. Concerning the role of HFIP, the authors hypothesized that HFIP might stabilize or promote the formation of the nitrilium ion 192, which was not the case in other solvents that gave a lactam as a major product. Nevertheless, this assessment was not supported by experimental or computational evidence. 73 (a) G. L. Milligan, C. J. Mossman, J. Aubé, J. Am. Chem. Soc. 1995, 117, 10449 (b) In summary, the combination of HFIP/Brønsted acid and HFIP/Lewis acid is a useful tool to overcome reactivity problems that can be met in other acid/polar solvent systems. In the different reactions described, HFIP can enhance the reactivity in different ways and often plays multiples role at the same time, including (1) stabilizing cationic intermediates, ( 2) preventing catalyst inhibition (off-cycle species) (3) assisting bond cleavage and ( 4) sometimes completely changing the reaction pathway. Recent computational studies and experimental evidence revealed that the formation of clusters between HFIP and Brønsted or Lewis acid was critical for the reactivity, in which HFIP is often the true active species, limiting the need to use expensive Lewis and Brønsted acids. Alcohols are interesting targets for substitution as they are widely available, straightforward to prepare and tractable compounds. 76 Moreover, water is the only stoichiometric byproduct of alcohol substitution reactions. For those reasons, the ACS Green Chemistry Pharmaceutical Roundtable Institute® identified the direct substitution of alcohols as a top priority. 77 Nevertheless, due to the poor leaving group ability of the hydroxyl group, the classical approach was to convert the alcohol to a better leaving group such as a halide or to use stoichiometric amounts of acid or even using strong Brønsted acids as solvent. Nowadays, considerable advances have been made in the field of direct alcohol substitution using sub-stoichiometric amounts of catalyst. 79 Four approaches dominate, the classic S N 1 and S N 2 substitution (Scheme 42, A and B). The third pathway is the borrowing hydrogen method (Scheme 42, C). This approach is so named because a metal center borrows two hydrogens from the alcohol and then gives them back after addition of the nucleophile to form the final product. The overall mechanism is a nucleophilic substitution. The fourth mechanism is allylic substitution; this method takes advantage of the reactive π-allyl system to promote the substitution (Scheme 42, D).

Scheme 42: General mechanism for catalytic dehydrative substitution

Only few examples of catalytic S N 2 reactions on alcohols exist in the literature. In 2015, Samec and coworkers developed a Brønsted acid catalyzed intramolecular reaction that promotes the substitution of the hydroxyl group to yield enantioenriched tetrahydrofuran, pyrrolidine and tetrahydrothiophene derivatives using phosphinic acid catalysis (Scheme 43). DFT

CAT CAT O H H H O H R Nu Nu H R O CAT H R OH CAT CAT O H H H O H R Nu Nu H R O CAT H R OH R O CAT H M M H H R OH R O R Nu R Nu NuH2 H 2 O M O H H H O H Nu Nu H R R OH R M M OH A) S N 2 type substitution B) S N 1 type substitution C) Borrowing hydrogen D) Allylic substitution
calculations supported an S N 2 mechanism in which the phosphinic acid acted as a directing group. 80Scheme 43: Intramolecular cyclisation using phosphoric acid as a directing group

In 2019, the group of Denton report an impressive fully catalytic Mitsunobu reaction. 81 The original Mitsunobu reaction required a stoichiometric amount of an oxidant, DEAD, and a stoichiometric amount of reductant, triphenylphosphine (Scheme 44). By using an already oxidized phosphine, they succeeded to decrease the amount of phosphine required to 10%. In addition, the oxidation state of the phosphorus (V) catalyst does not change during the course of the reaction, therefore no oxidant is required. Concerning the mechanism:

(1) The nucleophile protonates the phenol group of the organocatalyst, which then undergo an intramolecular cyclization to form an oxyphosphonium salt. As the nucleophile also acts as an acid, no additional acid is required for this reaction. The downside is that the scope of nucleophile tolerated is limited to highly acidic carboxylic acids and sulfonate-bearing nucleophiles such p-toluene sulfonic acid.

(2) The second step is an S N 2 reaction, where the alcohol induces a ring-opening of the oxyphosphonium salt. This step breaks the strong P-O bond, which explain the high temperature required for this reaction.

(3) The subsequent addition of a nucleophile on the alkoxyphosphonium salt leads to the formation of the S N 2 product and regenerates the catalyst. 81 An example from our group of a catalytic S N 1 reaction of highly deactivated alcohols was described in depth in the Friedel-Crafts part of this manuscript. 36 In a S N 1 reaction, the stabilization of the carbocation is critical, as this carbocation needs to exist long enough for the nucleophilic attack to occur. Thus, S N 1 reactions require substrates bearing carbocationstabilizing groups such as phenyl and/or a stabilizing effect from the solvent or from an additive. Recently, in 2019, Böld and Fleischer reported two S N 1 catalytic dehydrative reactions involving a Brønsted acid and a Lewis base for the homo-coupling of benzylic alcohol (Scheme 45). 82 According to the authors the role of PPh 3 is to avoid oligomerization. The previous methods aimed at increasing the reactivity of the hydroxyl group. An alternative approach is the hydrogen borrowing strategy. 83 This method consists of using a catalytic amount of metal catalyst to remove two hydrogens from the alcohol to oxidize it into a more reactive carbonyl group. Then, the carbonyl can react with an amine nucleophile to form an imine and water. The oxidized metal species can then reduce the imine to form the amine product, thus closing the catalytic cycle. An evident downside of this reaction is that tertiary alcohols cannot be used under this strategy. Furthermore, the hydrogen borrowing strategy generally requires late transition metals such ruthenium and iridium, which restrains its application for industrial processes. As an example of a hydrogen borrowing system, the group of Williams reported an efficient [Ru(p-cymene)Cl 2 ] 2 system to convert primary amines into secondary amines and secondary amines into tertiary amines using primary and secondary alcohols, respectively (Scheme 46). 84 Scheme 46: Hydrogen borrowing strategy Due to their reactive π-allyl system, allylic alcohols have been widely used for direct catalytic alcohol substitution using diverse metal salts such as copper 85 , calcium 86 and later metals such as palladium 87 and platinum 88 complexes. Those metals furnish usually a better selectivity toward the nucleophilic substitution. Nevertheless, the allylic alcohol substitution is not limited to Lewis acids; in some cases, similar reactivity was obtained with Brønsted acids (Scheme 47). 89 Scheme 47: Amination of allylic alcohols 1.4.2. Carbocation stability and alcohol reactivity.

Which electrophiles react with which nucleophiles? Mayr and co-workers have tackled this difficult issue. 90 Based on experimental data, they developed a tool for predicting the rate of a reaction between a nucleophile and an electrophile [log K 20°C = s(E+N)], in which the electrophile is characterized by a parameter (E) and the nucleophile by two parameters (N, S) (Table 4). They also developed a rule of thumb to predict whether a nucleophile/electrophile pair can react together within a realistic experimental time: if [E+N > -5] the reaction could be expected at room temperature. 87 (a) M. As an example of easy application of Mayr's scale:

As the scale is logarithmic, if a nucleophile reacts with A (electrophile on the top of the scale) within a minute, it will take 20 billion years for the same nucleophile to react with B (electrophile on the bottom of the scale) in the same conditions.

Scheme 48: Application of Mayr's scale

Although this method is applicable for numerous electrophile/nucleophile combinations, this method does not account for two important parameters, the ease of the carbocation formation and the possible interactions between the catalyst and the nucleophile. Furthermore, this approach considers the reaction of a nucleophile and a carbocation. Therefore, its application concerns S N 1 type reactions and important deviations might be observed with S N 2 reactions. Ten years later, in 2013 Biswas and Samec reported a study aiming to map the reactivity of alcohols toward S N 1 reactions. 91 They conclude that, in the case of alcohols, the reactivity and the selectivity of the reaction is more related to "the ease" of the carbocation formation rather than the electrophilic character of the carbocation. Thus, the reactivity of alcohols starting from the less reactive to more reactive is the following: benzylic alcohols, allylic alcohols, propargylic alcohols, and then aliphatic alcohols (Scheme 49).

Scheme 49: Biswas and Samec map of alcohol reactivity

Benzylic alcohols are the most reactive thanks to the stabilization of the carbocation by the large π system of the aromatic ring (Scheme 50). The case of allylic alcohol is more complicated as two different mechanisms are possible depending if the activation occurs though coordination of a metal center on the allylic system or if a true carbocation is formed. Furthermore, if the substitution of the allylic alcohol is pseudo-symmetric (R 1 = R 2 ) the nucleophilic substitution leads to only one product, while in the opposite regioselectivity of the nucleophilic substitution must be considered. Propargylic alcohols are even more versatile. Dehydration reactions on propargylic alcohols leads to two possible ions, the propargylium ion and the allenylium ion, leading to allene and indene products, respectively. The ease of carbocation generation for aliphatic alcohols depends only on the hyperconjugation effect, and thus to the substitution pattern of the alcohol. Although direct alcohol substitution on aliphatic tertiary and secondary alcohols though a S N 1 mechanism is relatively easy, primary carbocation generation is not favorable thermodynamically. Therefore, no report of S N 1 reactions on primary aliphatic alcohols have been reported and this mechanism is highly unlikely for that class of substrates. 91

Thesis project

As detailed in the above subchapters, HFIP in combination with Brønsted and Lewis acids have demonstrated their versatility in a variety of reactions and possess a great potential to be exploited for quite a long time in the future. On the other hand, our group turned to the utilization of Brønsted or Lewis acid system a few years ago and commenced to benefit from the TfOH/HFIP combination for the activation of highly deactivated benzylic alcohols and mono-substituted cyclopropanes. This association proved to be efficient for conducting reactions with more versatile substrates and for the activation of less activated molecules.

To further exploit Brønsted or Lewis acids for alcohol substitution in HFIP, in the following chapters I will present my work regarding the activation of propargylic alcohols for the synthesis of allenes, indenes, chromenes and alkenes, followed by my current progress on the direct substitution of primary aliphatic alcohols.

OH R 2 R 1 R 2 R 1 Nu R 2 R 1 R 2 R 1 Nu S N 1 S N 1' OH R 2 R 1 R 2 R 1 Nu R 2 R 1 R 2 R 1 Nu S N 1 S N 1' ML x R OH R R Nu S N 1 R 2 R 1 OH R 2 R 1 R 1 R 2 S N 1 S N 1' R 2 R 1 Nu Nu R 1 R 2 R 1 R 3 OH R 1 R 3 R 1 R 3 Nu S N 1 R 2 R 2 R 2

Benzylic alcohols

Allylic alcohols

Aliphatic alcohols

Propargylic alcohols

Part 2: Catalytic activation of trifluoromethylated propargylic alcohols

In comparison with the direct nucleophilic substitution of benzyl alcohols, that of propargylic alcohols offers a more versatile reactivity as it can give rise to two types of products, either an α-substituted alkyne or an allene (Scheme 51). Numerous examples regarding the direct substitution of this class of alcohol have been reported, using transition metal-based catalysts (ruthenium, gold, copper, etc.) as well as Brønsted acids such as TfOH. 92 On the other hand, there are only a few examples of the formation of allenes from propargylic alcohols via a carbocationic intermediate. 93 Scheme 51: S N 1 and S N

' reaction of propargylic alcohols

Following previous studies in our group on the Friedel-Crafts alkylation of a-trifluoromethyl benzyl alcohols in HFIP, we wondered whether this type of reactivity could be extended to their propargyl alcohol analogs. The idea of adding fluorine functional groups to a molecule is now a well-established approach in order to modulate its physiochemical and pharmaceutical properties. 94 Nearly 20-25% of drugs in the pharmaceutical pipeline contain at least one fluorine atom. Fluorine is the most electronegative element and the addition of a CF 3 group to a molecule can (1) increase its local polarity and, therefore, enhance the propensity of a molecule to bind to a host such as an enzyme center in comparison with a non-fluorinated analog, (2) decrease the size of the electron cloud of an electron-rich heteroatom or a π system, hence increasing its lipophilicity and, thus, its ability to cross biological barriers, (3) increase its biological stability owing to the strength of the C-F bound. Indeed, the CF 3 group can be used as a bioisostere of methyl or chloride to protect a molecule against biological metabolizing by enzymes such the P450 cytochrome. 95 With respect to this project, we anticipated that the presence of a CF 3 group at the α-position of the propargylic alcohol would favor the isomerization of the propargylium cation to the allenylium cation, leading to the formation of an allene product. Interestingly, allene moieties

R 1 CF 3 CF 3 OH R 1 R 1 CF 3

State of the art for the synthesis of trifluoromethylated allenes

Few examples for the preparation of trifluoromethylated allenes have been reported in the literature. The first example dates from 1974. 97 The standard method relied on the use of a stoichiometric amount of trifluoromethyl copper with a propargyl halide (Scheme 52). This method proved to be also efficient with other perfluoroalkyl copper reagents. The group of Hsu noticed that the choice of the leaving group was critical as a tosylate group furnished better yields with short perfluoroalkyl chains (CF 3 to n-C 3 F 7 ), while chloride worked better for n-C 6 F 13 to n-C 8 F 17 perfluoroalkyls.

Scheme 52: Seminal example of the synthesis of CF 3 -bearing allenes

In 2012, Zhao and Szabó described a copper-mediated trifluoromethylation of propargylic halides and propargylic trifluoroacetate for the synthesis of CF 3 -bearing allenes (Scheme 53). 98 Control experiments conducted in the presence of a radical scavenger (TEMPO) did not affect the reactivity. Thus, the authors deduced that the reaction occurred through an ionic mechanism involving a nucleophilic transfer of the CF 3 group from the copper complex to the propargylic substrate. Additional experiments starting from an enantiomerically enriched substrate led to the formation of an enantio-enriched allene, which suggest a concerted mechanism (S N 2'-type mechanism). Nevertheless, the authors stated that a further in-depth study would be required to understand in details this transformation.

Scheme 53: Copper-mediated trifluoromethylation of propargylic halides for the synthesis of CF 3 allenes

In 2015, the group of Altman reported a ligand-controlled regioselective copper-catalyzed trifluoromethylation of propargyl acetates to generate CF 3 -bearing allenes (Scheme 54). 99 The selectivity of the reaction is based on the ability of the bipyridyl ligand to control the regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation. As the trifluoromethyl source is not on the Copper, Altman's method is a good alternative to methods that required stoichiometric amount of Cu-CF 3 catalyst. 96 A. Hoffmann-Röder, N. Krause. Angew. Chem. Int. Ed. 2004, 43, 1196. 97 Tetrahedron Lett. 1990, 31, 3699;(c) M.-H. Hung, Tetrahedron Lett. 1990, 31, 3703;(d) In 2016, Gagosz and co-workers described a method to access CF 3 -bearing allenes through gold-catalyzed rearrangement of propargylic benzyl ethers (Scheme 55). 100 This reaction had the advantage of controlling the axial chirality of the allene product. In a mechanistic proposal, the authors explained that (1) the alkyne is first activated upon coordination to the gold complex and, then, ( 2) the metal induces a 1,5-hydride shift of the activated propargylic benzyl ether, which leads to an oxocarbenium intermediate. (3) The subsequent elimination of benzaldehyde delivers the allene product and the regeneration of the catalyst.

Scheme 55: Gold-catalyzed rearrangement of propargylic benzyl ethers for the synthesis of CF 3 -bearing allenes

Unlike the above examples, the transformation that we envisioned does not require preactivation of propargylic alcohols and has the advantage to generate water as the sole stoichiometric byproduct.

Synthesis of starting materials

Synthesis of tertiary propargylic alcohols

Tertiary propargylic alcohols were synthetized according to a copper-catalyzed direct alkynylation of trifluoromethyl ketones developed by the group of Shi (Scheme 56). 101 While Cu(I) and Cu(II) catalysts could efficiently promote this reaction, the role of copper seems to go further than that of a simple Lewis acid as all other Lewis acid tested by the authors failed to trigger the reaction. Thus, they suggested that the true catalyst for this reaction might be Cu(I) as, even when a Cu(II) catalyst was used, a reductive homo-coupling of phenylacetylene was observed either in presence or absence of trifluoromethyl ketone.

However, the mechanism remains still unclear. A plausible mechanism would involve the activation of the carbonyl group of the trifluoromethyl ketone to increase its electrophilicity, combined with the activation of the alkyne by copper to lower the pK a of the terminal hydrogen. On the other hand, conducting the reaction in the absence of phenylacetylene led Secondary propargylic alcohols were prepared via a two-step method (Scheme 58). 103 The first step is the addition of lithium acetylide to ethyl trifluoroacetate promoted by boron trifluoride etherate to provide ketone 233. In a second step, the ketone was reduced with NaBH 4 to furnish the corresponding secondary propargylic alcohol.

Scheme 58: Synthesis of CF 3 -bearing secondary propargylic alcohols 2.4. Synthesis of CF 3 -bearing allenes 2. 4

.1. Reaction discovery and optimization

We began our investigation with a simple propargylic alcohol 225 using mesitylene as a nucleophile, which has shown excellent reactivity in the nucleophilic substitution of highly deactivated benzylic alcohols reported by our group. A series of Brønsted and Lewis acid were screened in HFIP (Table 5). Gratifyingly, triflic acid afforded the allene 235 in 85% yield at room temperature (entry 1). On the other hand, increasing the temperature to 50 °C did not only lead to the targeted allene (entry 2) but also to indene 236. When the reaction was conducted in the presence of weaker Brønsted acids (entries 3-5), the product was either not obtained or was delivered in a lower yield due to a lack of reactivity. Stronger Brønsted acid HSbF 6 •6H 2 O (entry 6) led to a slightly improved reactivity, while several Lewis acids tested provided 235 in moderate yields (entries 7-11).

Regarding this reaction, the best result was obtained using FeCl 3 as a catalyst, yielding 235 in 93% at room temperature within 10 minutes (entry 12). Increasing the temperature to 80 °C furnished the indene 236 in 94% yield (entry 13). The use of HFIP was critical to the success of the reaction as another fluorinated solvent such as TFE only furnished the allene in 39% yield, and no reaction took place in the non-fluorinated analog of HFIP (iPrOH) (entries 14-15). Replacing FeCl 3 by FeCl 2 significantly decreased the efficacy of the reaction (entry 17). trace amounts of the allenic product. On the other hand, carrying out the reaction in the presence of a proton scavenger, 2,6-di-tert-butylpyridine, which does not coordinate most metal ions, 104 completely shut down the transformation. Based on previous findings from different groups, we believed that ferric ions could enhance Brønsted acidity of HFIP by forming higher order aggregates, which would act as the active catalytic species (hidden Brønsted acid catalysis). The first step of the proposed mechanism involves the classical formation of a propargylic cation that can then isomerize into the allenylium cation (Scheme 59). A subsequent trapping of this intermediate by an arene nucleophile gives the allenic product.

Scheme 59: Mechanism for the formation of the allene

Scope of allenes

The scope of CF 3 -bearing allenes was then explored (Scheme 60). As mentioned above, our model substrate, propargylic alcohol 225, with no substituent on phenyl rings A and B, afforded the corresponding allene 235 in 93% yield. Replacing aromatic ring A by a cyclohexyl moiety group still delivered the target product, albeit in a lower yield (240, 51%) while requiring a higher reaction temperature (50 °C). The same applied to a biphenyl substituent (241). The moderate yields obtained in both cases might be explained by the fact that the absence of a stabilizing π-system (ring A) disfavored the formation of allenylium (240), while the biphenyl group made the cationic intermediates more stable and thus less reactive (241).

On the other hand, the introduction of a p-tolyl and o-tolyl group was well tolerated (242 and 243). The presence of moderately electron-withdrawing groups (Br or F) tended to deactivate the substrate, slowing down the reaction (reaction time increased from 1 h to 3 h). The effect of electron-donating substituents, such as methoxy, was highly dependent on its position. Located on ring B, the reaction provided the allene 248 in a good yield (82%), while, on ring A, the product 249 was obtained in a moderate yield (27%) as the allenic product was rapidly converted into indene, even after 5 min. Attempts to shorten the reaction time and lower the temperature did not improve the yields because the subsequent cyclization into indene proved to be faster than the initial formation of the allene. Lastly, the use of a sterically hindered nucleophile such as 1,4-diisopropylbenzene (250-253) or nucleophiles incorporating electron-withdrawing groups (254-256) were also less reactive with respect to the transformation. CF 3 -bearing indenes are not readily available compounds and only a few reports regarding their synthesis have been described in the literature. 105 Yet, CF 3 -bearing indenes are interesting scaffolds for drug discovery. Indeed, the group of Vasilyev discovered that indene 259 displayed inhibitory activity towards fatty acid amide hydrolase (FAAH) and the machinery responsible for arachidonyl ethanol-amine (AEA) uptake (Scheme 61). 106 Concerning indene synthesis, Vasilyev's method required super-stoichiometric amounts of triflic acid, which might be a limitation for industrial scale-up. The same group recently reported another method to access CF 3 -bearing indenes using, in this case, a heterogeneous catalyst featuring a zeolite. 107 Although the use of zeolites is typically considered as "green chemistry", this reaction displayed a few major disadvantages for industrial scale-up: (1) high temperature (100 °C), ( 2) the zeolite catalyst must be preactivated at 550 °C for 4 h and ( 3) there is a lack of selectivity regarding the cyclization of the indene. The authors rationalized the good yields obtained with this method compared to classic Brønsted acid catalysis by the ability of the zeolite to act as a cage for carbocationic intermediates, therefore preventing the formation of oligomers. at rt for a short reaction time led to the allene product. However, interestingly, a prolonged heating at a higher temperature (80 °C) enabled the formation of another product, an indene derivative (Scheme 62). To determine whether phenyl ring A or ring B underwent the cyclization, we prepared deuterated substrate 225-D 5 , which was subjected to the standard reaction conditions. Analysis of the resulting 1 H and 2 H NMR spectra as well as the HRMS of the resulting product was consistent with the formation of 236-D 4 indene, thereby implying that phenyl ring A was involved in the cyclization. Of note, subjecting the isolated allene product to the standard reaction conditions also led to the indene, confirming its role as intermediate in the formation of the indene.

Scheme 62: Allene vs indene

Based on these results, we proposed the following mechanism (Scheme 63): after formation of the allenic product, the electron-rich π-system of the allene can be protonated to generate an allyl cation. A Nazarov-type electrocyclization would then occur to form 267 before a subsequent rearomatization, finally furnishing the indene.

Scheme 63: Mechanistic proposal for the formation of the indene

Scope of indenes

The scope of indenes was then investigated (Scheme 64). Propargylic alcohols with no substituent at the phenyl ring A and ring B furnished the corresponding indenes in high yields (up to 94%) when mesitylene, 1,4-diisopropylbenzene and even bulkier 1,3,5-triethylbenzene were used as nucleophiles. In addition, the reaction was compatible with the presence of electron-donating groups (Ph, Me and MeO) at the para-position of phenyl ring A to furnish the target products in good to high yields (up to 91%). In the same vein, introducing electrondonating and -withdrawing groups at the para-position of phenyl ring B did not prevent the reaction, providing compounds 262 and 275 in 90% and 77% yields, respectively. Of note, increasing the temperature to 120 °C was necessary with the more nucleophilic 1,3,5trimethoxybenzene 278, giving the indene in high yield (95%). Indeed, as mentioned in the introduction for the reactivity of cyclopropanes, this nucleophile can be easily protonated under the reaction conditions to form an off-cycle species, which might slow down the reaction. Unfortunately, chloro-bearing nucleophiles such as 276 were less efficient in this transformation. In general, our efforts to prepare indenes from propargylic alcohols using weaker arene nucleophiles were ineffective (allenes 254), due both to the reduced ability of the nucleophile to capture the propargylic carbocation and the subsequent deactivating effect of the electron-poor arene on the cyclization of the allene intermediate (Scheme 65). Even under harsher reaction conditions, propargylic alcohols bearing a bromide or fluoride functionality on the phenyl ring A or ring B did not give access to the desired indenes, stopping at the allene intermediates (245, 246, 247, 253 and 256) previously described in Scheme 10.

. Formation of chromenes and mechanistic proposal

Inspired by the results obtained with the formation of indenes, we hypothesized that propargylic alcohols bearing an additional nucleophile at the ortho-position of phenyl ring could undergo an intramolecular cyclization to afford a bicyclic derivative (Scheme 66). Indeed, propargylic alcohols substituted with an o-hydroxyl group on ring A led to the formation of chromene 285. In the studied case, better results were obtained with TfOH as a catalyst rather than with FeCl 3 , affording compound 285 in nearly quantitative yield. Chromenes are an attractive class of molecules as they exhibit important biological activities.

In particular, CF 3 -bearing chromenes have been used for the development of non-steroidal anti-inflammatory agents (NSAIDs) (Scheme 67). 108 Indeed, they have been found to be efficient for the specific inhibition of COX-2, one of the two isoforms of cyclooxygenase that is an enzyme expressed in response to inflammatory stimuli. Inhibition of one of those isoforms of the cyclooxygenase is sufficient to generate an efficient anti-inflammatory response. Nevertheless, the gastrointestinal tissue needs a basal level of expression of COX-1 for its homeostasis and platelet clotting ability. Thus, a specific inhibition of COX-2 is required to avoid detrimental effects on the gastrointestinal system.

Scheme 67: CF 3 -bearing chromenes as anti-inflammatory agents

Concerning the mechanism, as for the synthesis of the indene, once the allene intermediate is formed and then protonated (Scheme 68), a S N 2' nucleophilic addition of the hydroxyl group takes place to lead to the chromene.

Scope of CF3-bearing chromenes

With respect to the scope, bulky nucleophiles such as durene and pentamethylbenzene are well-tolerated under the reaction conditions (Scheme 69). As for the case with indenes, the use of 1,3,5-trimethoxybenzene slowed down the reaction but still afforded the corresponding chromene 293 (43%). Additionally, the reaction proved to be compatible with the presence of electron-donating and -withdrawing groups at the para-position of the phenyl ring B. Importantly, the presence of an aromatic ring at the α-position of the CF 3 group was not necessary as substrate 296 incorporating an alkyl group (ethyl) underwent the cyclization to give the target product in 77% yield. Propargylic alcohol with a o-hydroxyl protected with a tert-butyl-dimethylsilyl group showed a similar reactivity as its non-protected analog, which might be explained by the highly acidic reaction conditions that could favor the in situ deprotection of the phenol.

Scheme 69: Scope of CF 3 -bearing chromenes a Reaction performed on 1 mmol scale.

On the other hand, further attempts with propargylic alcohols bearing amine functionalities failed to give efficiently the desired cyclic products (Scheme 70). Precursor 297 substituted with an o-NH 2 did not provide the corresponding cyclic product under the standard conditions used for the synthesis of chromenes. 1 H NMR and TLC showed a rapid degradation of the starting material. An N-tosyl-protected substrate did not furnish either product at rt.

Br

Nevertheless, 23% of deprotected cyclic product was isolated by increasing the temperature to 80 °C. In order to improve the reactivity, another protecting group (carboxybenzyl) was tested at 80 °C but neither the protected nor unprotected product was detected. This reaction will require more optimizations to obtain the desired reactivity.

Scheme 70: Attempts towards the cyclization o-amine substituted tertiary propargylic alcohols 2.7. Synthesis of CF 3 -bearing alkenes

Formation of alkenes and mechanistic proposal

Lastly, we investigated the reactivity of secondary propargylic alcohols. Due to their lower steric hindrance, we observed a different reactivity than tertiary propargylic alcohols as they underwent a double addition of aromatic nucleophiles to give access to bis-arylated alkenes under identical reaction conditions (Scheme 71). Regarding the mechanism, we assumed that, following the formation of the allene and its subsequent protonation, a second addition of nucleophile occurred to provide the corresponding alkene (Scheme 72). The structure as well as the Z geometry were probed by X-ray crystallography. We noticed that the preferred conformation was the one in which the two mesityl groups were aligned. Interestingly, in solution it was possible to distinguish two different rotamers in the reaction product by 1 H NMR when p-xylene was used as a nucleophile. We first explored the influence of the para-substitution on the phenyl ring (Scheme 73). The reaction could be achieved in good yields in the case of electron-donating groups (Me and MeO, 77% and 81%, respectively). However, in the case of electron-withdrawing groups (Br and CN), a significant decrease of the reactivity was observed. A plausible explanation might be the destabilization of the carbocation intermediate after the protonation. Additionally, due to its Lewis base character, the cyano group could also buffer the Brønsted acid catalyst and prevent the reaction. The electron-rich 1,3,5-trimethoxybenzene (311) also afforded the desired alkene in 73% yield. Other methyl-substituted arenes nucleophiles such as p-xylene (312), pentamethylbenzene (313-314) and durene (315) were also tested and led to the corresponding alkenes in good to high yields (up to 95%).

Conclusion

In summary, we have described a method for straightforward access to trifluoromethylated compounds such as allenes and indenes from tertiary propargylic alcohols, chromenes from o-hydroxyl substituted tertiary propargylic alcohols and alkenes from secondary propargylic alcohols (Scheme 74). Mechanistic experiments suggest that the role of FeCl 3 is to activate HFIP upon coordination to generate a Brønsted acid, which would be the true catalytic species. Moreover, it had been determined that the formation of indenes resulted from an intramolecular rearrangement of allenes. Regarding the reactivity of o-hydroxyl substituted tertiary propargylic alcohols, an intramolecular cyclization was observed, leading to the corresponding chromenes. Attempts to use o-amine and o-tosylamine as nucleophile were unfortunately not successful to obtain the nitrogen-bearing analog. The use of other osubstituted tertiary propargylic alcohols such o-sulfide-bearing substrate could be an interesting alternative to extend the scope of the transformation. Finally, we can change the

Experimental Section

General information

All Friedel-Crafts reactions were performed in 10 mL glass pressure tubes under an atmosphere of air. Elevated temperatures were achieved by way of a stirrer-hotplate, metal heating block and thermocouple. Purification of reaction products was carried out by flash column chromatography using Merck silica gel (40-63 μm). Analytical thin layer chromatography (TLC) was performed on aluminum sheets precoated with silica gel 60 F254 (Merck), cut to size. Visualization was accomplished with UV light. 1 H NMR spectra were recorded on a Bruker UltraShield Plus 400 (400 MHz) spectrometer at ambient temperature and are reported in ppm using solvent as internal standard (residual CHCl 3 at 7.26 ppm). 13 C{ 1 H} NMR spectra were recorded on a Bruker UltraShield Plus 400 (100 MHz) spectrometer at ambient temperature and are reported in ppm using solvent as internal standard (CDCl 3 at 77.16 ppm). 19 F NMR spectra were recorded on a Bruker UltraShield Plus 400 (376.5 MHz) spectrometer at ambient temperature and are reported in ppm using trifluoroacetic acid as external standard (peak at -76.55 ppm). Data are reported as: multiplicity (ap = apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dddd = doublet of doublet of doublet of doublets, qd = quartet of doublets, dt = doublet of triplets, dm = doublet of multiplets, td = triplet of doublets, quintd = quintet of doublets), coupling constants (in Hz) and integration. In cases where compounds were isolated as mixtures of regioisomers, signals corresponding to protons of the major regioisomer were integrated as integer values matching the number of protons in the molecule. Non-integer integration values correspond to signals of protons of minor regioisomers or to overlapping signals of regioisomers. GC/MS analysis was conducted on a GC System 7820A (G4320) connected to a MSD block 5977E (G7036A) using Agilent High Resolution Gas Chromatography Column HP-5MS UI, 30 m×0.250 mm×0.25 µm. High resolution mass spectrometry (HRMS) analysis was performed on instruments GCT 1er Waters (EI and CI), MicroTOF-Q Bruker (ESI), and a GC Thermo Scientific Trace 1300 GC unit coupled to an APPI MasCom source mounted on a Thermo Scientific Exactive Plus EMR mass unit (Orbitrap FT-HRMS analyzer). Materials: All commercial materials were purchased from Sigma-Aldrich, Alfa Aesar and FluoroChem, and were used as received, without further purification.

Preparation of tertiary propargylic alcohols

General procedure A for tertiary propargylic alcohols synthesis: Trifluoromethyl phenyl ketone (5.0-10 mmol, 1.0 equiv) and phenyl acetylene (1.5 equiv) were diluted in 10-15 mL DMSO. CuI (0.10 equiv) and K 2 CO 3 (0.20 equiv) were added and the reaction mixture was heated at 50-70 o C for 24 h. The reaction mixture was then treated with brine, extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate and concentrated at reduced pressure. The product was then purified by silica gel column chromatography.

HO CF 3 32.3 Hz), 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH -ext. st.): d (ppm) -80.9 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M+H-H 2 O] + : Calcd for C 22 H 15 F 3 O 335.1042;Found 335.1054 (3.5 ppm). )-1,1,1-trifluoro-2-phenylbut-3-yn-2-ol 320 was prepared according to general procedure A and isolated as a yellow oil. Spectral data are in agreement with the literature. 13 Isolated 2.70 g, 90% yield. R f = 0.43 (petroleum ether/EtOAc 9:1). 1 H NMR (500 MHz, CDCl 3 ): d (ppm) 7.68 (d, J = 8.6 Hz, 2H), 7.58-7.50 (m, 4H), 7.44-7.35 (m, 3H), 3.26 (s, 1H).

4-(4-Bromophenyl

4-(4-Bromophenyl

)-1,1,1-trifluoro-2-phenylbut-3-yn-2-ol 321 was prepared according to general procedure A and isolated as a yellow oil. Spectral data are in agreement with the literature. 13 Isolated 1.56 g, 52% yield. R f = 0.44 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): d (ppm) 7.75-7.69 (m, 2H), 7.46-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.34-7.28 (m, 2H), 3.09 (s, 1H).

1,1,1-Trifluoro-2-(4-methoxyphenyl)-4-phenylbut-3-yn-2-ol 322 was prepared according to

general procedure A and isolated as pale yellow solid. Spectral data are in agreement with the literature. 113 Isolated 1.92 g, 64% yield. 1 H NMR (400 MHz, CDCl 3 ): d (ppm) 7.73 (d, J = 8.8 Hz, 2H), 7.57-7.50 (m, 2H), 7.43-7.32 (m, 3H), 6.96 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 3.10 (s, 1H).

1,1,1-Trifluoro-2-(4-methoxy-phenyl)-4-phenylbut-3-yn-2-ol 323 was prepared according to general procedure A and isolated as a yellow oil. Spectral data are in agreement with the literature. 15 Isolated 2.73 g, 91% yield. R f = 0.36 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): d (ppm) 7.73 (dt, J = 8.8 Hz, 3.0 Hz, 2H), 7.56-7.51 (m, 2H), 7.45-7.33 (m, 3H), 6.93-6.10 (m, 2H), 3.84 (s, 3H), 3.10 (s, 1H).

1,1,1-Trifluoro-2-(4-fluorophenyl)-4-phenylbut-3-yn-2-ol 324 was prepared according to

general procedure A and isolated as a yellow oil. Spectral data are in agreement with the literature. 13 Isolated 2.85 g, 95% yield. R f = 0.40 (petroleum ether/EtOAc 9:1). 1 H NMR (400 113 (a) T. Kitazume, T. Sato, J. Fluorine Chem. 1985, 30, 189. (b) 7.83-7.76 (m, 2H), 7.56-7.50 (m, 2H), 7.45-7.34 (m, 3H), 7.16-7.08 (m, 2H), 3.29 (s, 1H).

Preparation of allenes

General procedure B: To a 10 mL reaction tube was added the catalyst (10 mol%), HFIP (0.50 M relative to propargylic alcohol), propargylic alcohol (0.17-0.40 mmol, 1.0 equiv), followed by the arene nucleophile (5.0 equiv). The mixture was allowed to stir at 25 °C until judged complete by TLC (9:1 Petroleum ether:EtOAc), typically after 10 min. The reactions typically turn an opaque black. The crude reaction mixture was directly transferred for silica gel chromatography.

General procedure C: To a 10 mL reaction tube was added the catalyst (10 mol%), HFIP (0.5-1.0 M relative to propargylic alcohol), and propargylic alcohol (0.17-0.40 mmol, 1.0 equiv), followed by the arene nucleophile (5.0 equiv). The reactions typically turn an opaque black. After completion of the reaction as judged by TLC, the crude reaction mixture was directly transferred for silica gel chromatography.

Characterization data for allenes 4,butadiene 231 was prepared according to general procedure B from 1,1,1-trifluoro-2,4-diphenylbut-3-yn-2-ol (100 mg, 0.363 mmol) and mesitylene (253 µL, 1.82 mmol, 5.0 equiv) with 5.9 mg (0.036 mmol) of FeCl 3 in 0.73 mL of HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether) gave 128 mg (93% yield) of white solid. R f = 0.83 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.49 (d, J = 7.5 Hz, 2H), 7.43-7.12 (m, 8H), 6.94 (s, 2H), 2.32 (s, 3H), 2.17 (s, 6H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 205.1 (q, J = 3.5 Hz), 138.1, 137.1, 133.3, 130.2, 129.9, 129.2, 128.9, 128.7, 128.6, 128.5, 127.6, 126.7, 123.7 (q, J = 275.1 Hz), 114.1, 104.0 (q, J = 34.3 Hz), 21.2, 20.4. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH -ext. st.): d (ppm) - 62.5 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 25 H 21 F 3 378.1590;Found 378.1596 (1.5

ppm).

1-Cyclohexyl- 1-mesityl-3-phenyl-4,4,4-trifluoro-1,2-butadiene 240 was prepared according to general procedure B from 4-cyclohexyl-1,1,1-trifluoro-2-phenylbut-3yn-2-ol (49 mg, 0.17 mmol) and mesitylene (70 µL, 0.50 mmol, 3.0 equiv) with 2.7 mg (0.017 mmol) of FeCl 3 , in 0.33 mL of HFIP. The reaction mixture was stirred at 50 o C for 24 h. Purification by flash column chromatography over silica (petroleum ether) gave 33 mg (51% yield) of the product. 1 (400 MHz, CDCl 3 ): δ (ppm) 7.48 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 6.89 (s, 2H), 2.41-2.15 (m, 10H), 2.03-1.91 (m, 2H), 1.87-1.75 (m, 2H), 1.75-1.66 (m, 1H), 1.43-1.18 (m, 5H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 201.5 (q, J = 4.0 Hz), 137.2, 131.9, 130.9, 128.7, 128.0, 127.32, 127.31, 124.1 (q, J = 272.7 Hz), 118.1, 102.2 (q, J = 33.8 Hz), 43.4, 32.1, 31.9, 26.7, 26.7, 26.2, 21.1. 19 F NMR (376.5 MHz, CDCl 3 ): d (ppm) -58.1 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 25 H 27 F 3 384.2059;Found 384.2059 (-0.1 ppm). -4,4,4-trifluoro-3-phenyl-1,2-butadiene 241 was prepared according to general procedure B from 4-((1,1'-biphenyl)-4-yl)-1,1,1-trifluoro-2-phenylbut-3yn-2-ol (59 mg, 0.17 mmol) and mesitylene (71 µL, 0.51 mmol, 3.0 equiv) with 2.7 mg (0.017 mmol) of FeCl 3 , in 0.34 mL of HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether) gave 31 mg (40% yield) of the product with 95% purity (the rest is the corresponding indene that started to form quickly). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.67-7.56 (m, 4H), 7.54 (d, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.43-7.30 (m, 6H), 6.99 (s, 2H), 2.36 (s, 3H), 2.23 (s, 6H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 205.3 (q, J = 3.9 Hz), 141.5, 140.6, 138.1, 137.2, 132.2, 130.2, 129.9, 129.0, 128.9, 128.8, 128.6, 127.9, 127.7, 127.7, 127.2, 127.1, 123.7 (q, J = 273.3 Hz), 113.9, 104.1 (q, J = 34.1 Hz), 21.2, 20.4. 19 F NMR (376.5 MHz, CDCl 3 ): d (ppm) -58.1 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 31 H 25 F 3 454.1903;Found 454.1903 (0.1 ppm).

H NMR

1-Mesityl-1-(1,1'-biphenyl-4-yl)

1-Mesityl-4,4,4-trifluoro-1-(p-toluyl)-3-phenyl-1,2-butadiene 242

was prepared according to general procedure B from 1,1,1-trifluoro-2-phenyl-4-(p-tolulyl)but-3-yn-2-ol (85 mg, 0.29 mmol) and mesitylene (117 µL, 0.84 mmol, 5.0 equiv) with 4.6 mg (0.028 mmol) of FeCl 3 , in 0.57 mL of HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether) gave 84 mg (74% yield) of the product. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.63 (d, J = 7.6 Hz, 2H), 7.50-7.31 (m, 3H), 7.33-7.22 (m, 4H), 7.07 (s, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 2.32 (6H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 205.0 (q, J = 4.0 Hz), 138.7,138.0,137.1,130.4,130.3,130.0,128.9,128.7,128.5,127.6,127.1,126.1,123.8 (q,J = 273.5 Hz),114.1,103.9 (q, J = 34.2 Hz), 21.4, 21.2, 20.4. 19 F NMR (376.5 MHz, CDCl 3 ): d (ppm) - 59.2 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 26 H 23 F 3 392.1746;Found 392.1750 (1.0 ppm). mmol) of FeCl 3 , in 0.5 mL of HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether) gave 78 mg (70% yield) of a colorless oil. 1 H NMR (400 MHz, CDCl 3 ): d (ppm) 7.52-7.41 (m, 4H), 7.41-7.29 (m, 3H), 7.10 (d, J = 8.6 Hz, 2H), 6.95 (s, 2H), 2.32 (s, 3H), 2.15 (s, 6H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): d (ppm) 204.9 (q, J = 3.8 Hz), 138.3, 137.0, 132.3, 129.8, 129.3, 128.9, 128.8, 128.7, 128.1, 127.6, 127.6, 123.5 (q, J = 273.5 Hz), 122.7, 113.3, 104.3 (q, J = 34.3 Hz), 21.1, 20.3. 19 F NMR (376.5 MHz, CDCl 3 , C 6 F 6 -ext. st.): d (ppm) - 62.5 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 25 H 20 79 BrF 3 456.0695;Found 456.0700 (1.1 ppm).

3-(4-Bromophenyl

)- 1-mesityl-1,3-diphenyl-4,4,4-trifluoro-1,2- HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether) gave 118 mg (90% yield) of a colorless oil. R f = 0.82 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.49 (d, J = 8.6 Hz, 2H), 7.38-7.28 (m, 5H), 7.25-7.18 (m, 2H), 6.95 (s, 2H), 2.33 (s, 3H), 2.16 (s, 6H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 205.0 (q, J = 3.8 Hz), 138.2, 137.0, 132.9, 132.1, 129.6, 129.3, 129.2, 129.2, 128.8, 127.1, 126.7, 123.5 (q, J = 275.0 Hz), 122.7, 114.6, 103.2 (q, J = 34.6 Hz), 21.2, 20.4. 19 F NMR (376.5 MHz, CDCl 3 , C 6 F 6 -ext. st.): d (ppm) - 62.5 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 25 H 20 79 BrF 3 456.0695; Found 456.0699 (0.9 ppm). -1-phenyl-4,4,4-trifluoro-1,2-butadiene 247 was prepared according to modified general procedure B from 1,1,1-trifluoro-2-(p-fluorophenyl)-4-phenylbut-3-yn-2-ol (72 mg, 0.21 mmol) and mesitylene (146 µL, 1.05 mmol, 5.0 equiv) with 3.4 mg (0.021 mmol) of FeCl 3 , in 0.42 mL of HFIP. The reaction mixture was stirred at ambient temperature for 1 h. Purification by flash column chromatography over silica (petroleum ether) gave 50 mg (52% yield) of white solid. 1 H NMR (400 MHz, CDCl 3 ): d (ppm) 7.56-7.48 (m, 2H), 7.44-7.33 (m, 3H), 7.33-7.27 (m, 2H), 7.16-7.07 (m, 2H), 7.02 (s, 2H), 2.39 (s, 3H), 2.23 (s, 6H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): d (ppm) 204.8 (q, J = 3.6 Hz), 162.9 (d, J = 246.9 Hz), 138.2, 137.0, 133.1, 129.7, 129.5 (d, J = 8.1 Hz), 129.2, 128.8, 128.7, 126.6, 126.2 (d, J = 3.3 Hz), 123.6 (q, J = 273.3 Hz), 116.1 (d, J = 21.7 Hz), 114.3, 103.1 (q, J = 34.6 Hz), 21.3, 20.3. 19 F NMR (376.5 MHz, CDCl 3 , C 6 F 6 -ext. st.): d (ppm) - 62.8 (s, 3F), -116.0 (m, 1F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 25 H 20 F 4 396.1496;Found 396.1500 (1.0 ppm). HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether/EtOAc 40:1 to 30:1) gave 79 mg (82% yield) of colorless oil. R f = 0.81 (petroleum ether/EtOAc 9:1). 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 7.42 (d, J = 8.5 Hz, 2H), 7.38-7.21 (m, 5H), 6.96 (s, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.34 (s, 3H), 2.18 (s, 6H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): δ (ppm) 204.5 (q, J = 3.5 Hz), 159.8, 138.0, 137.1, 133.5, 130.1, 129.1, 128.9, 128.7, 128.5, 126.6, 123.8 (q, J = 275.0 Hz), 122.2, 114.3, 113.8, 103.6 (q, J = 34.5 Hz), 55.4, 21.2, 20.4. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) -59.1 (s, 3F). HRMS (APPI + -Orbitrap): m/z [M] +. Calcd for C 26 H 23 F 3 O 408.1696;Found 408.1708 (2.9 ppm). 4,butadiene 249 was prepared according to modified general procedure B from 1,1,1-trifluoro-4-(4-metoxyphenyl)-2phenylbut-3-yn-2-ol ol (73 mg, 0.24 mmol) and mesitylene (84 µL, 0.74 mmol, 2.5 equiv) with 3.9 mg (0.024 mmol) of FeCl 3 , in 0.48 mL of HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica gave 26 mg (27% yield) of the product. 1 H NMR (400 MHz, CDCl 3 ): d (ppm) 7.50 (d, J = 7.6 Hz, 2H), 7.41-7.29 (m, 3H), 7.20 (d, J = 8.8 Hz, 2H), 6.95 (s, 2H), 6.88 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.33 (s, 3H), 2.19 (s, 6H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): d (ppm) 204.8 (q, J = 3.9 Hz), 160.0,137.9,137.1,130.5,130.1,128.8,128.7,128.4,128.0,127.6,127.6,125.3,123.7 (q,J = 273.3 Hz),114.6,113.7,103.8 (q, J = 34.1 Hz), 55.5, 21.2, 20.3. 19 F NMR (376.5 MHz, CDCl 3 ): d (ppm) - 59.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M+H] +. calculated for C 26 H 24 F 3 O 409.1774; found 409.1768 (-1.5

3-(4-Fluorophenyl)-1-mesityl

ppm).

1- (2,4,butadiene 250 was prepared according to general procedure B from 1,1,1-trifluoro-2,4-diphenylbut-3-yn-2-ol (104 mg, 0.376 mmol) and diizopropyl benzene (356 µL, 1.88 mmol, 5.0 equiv) with 6.1 mg (0.038 mmol) of FeCl 3 , in 0.75 mL of HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether) gave 103 mg (65% yield) of a colorless oil. R f = 0.82 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.45 (d, J = 7.9 Hz, 2H), 7.35-7.27 (m, 2H), 7.25-7.14 (m, 8H), 7.20-7.12 (m, 1H), 2.94 (sept, J = 6.8 Hz, 1H), 2.83 (sept, J = 6.9 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H), 1.04 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.9 Hz, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): d (ppm) 205.5 (q, J = 3.6 Hz), 146.7,145.0,134.7,132.0,130.1,128.9,128.9,128.5,128.5,128.3,127.3,127.3,127.2,126.2,123.6 (q,J = 273.6 Hz),116.4,103.9 (q, J = 34.1 Hz), 33.7, 30.4, 24.4, 24.1, 24.1, 24.1. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) - 58.7 (s, 3F). HRMS (APPI + -Orbitrap) m/z [M] +. Calcd for C 28 H 27 F 3 420.2059;Found 420.2062 (0.7 ppm).

1- (2,4, 251 was prepared according to modified general procedure B from 1,1,1-trifluoro-4-phenyl-2-(otolulyl)but-3-yn-2-ol (63 mg, 0.22 mmol) and diisopropylbenzene (123 µL, 0.647 mmol, 3.0 equiv) with 3.5 mg (0.022 mmol) of FeCl 3 , in 0.86 mL of HFIP. The reaction mixture was stirred at ambient temperature for 3 h. Purification by flash column chromatography over silica (petroleum ether) gave 63 mg (58% yield) of colorless oil. R f = 0.84 (petroleum ether/EtOAc 9:1). 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 7.49 (d, J = 7.7 Hz, 2H), 7.41-7.34 (m, 2H), 7.34-7.28 (m, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.21 (d,J = 4.0 Hz,2H) 7.18-7.13 (m, 1H), 7.11 (d, J = 1.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 3.00 (sept, J = 6.8 Hz, 1H), 2.87 (sept, J = 6.9 Hz, 1H) 2.30 (s, 3H), 1.30-1.16 (d, J = 7.0 Hz, 6H), 1.04 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): δ (ppm) 205.7 (q, J = 3.6 Hz), 146.6, 144.8, 137.0, 134.7, 134.0, 131.3, 130.6, 129.7, 128.8, 128.3, 128.3, 128.2, 127.4 (q, J = 1.1 Hz), 127.0, 126.3, 126.2, 123.8 (q, J = 274.8 Hz), 115.2, 101.4 (q, J = 34.1 Hz), 33.6, 30.0, 24.2, 24.1, 21.5. 19 F NMR (282 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) - 60.5 (s, 3F). HRMS (APPI + -Obitrap) m/z: [M] +. Calcd for C 29 H 29 F 3 434.2216;Found 434.2226 (2.3 ppm). (2,5-diisopropylphenyl)-3-phenyl-4,4,4-trifluoro-1,2-butadiene 252 was prepared according to general procedure B from 4-(4-bromophenyl)-1,1,1-trifluoro-2,4diphenylbut-3-yn-2-ol (10.2 mg, 0.28 mmol) and diisopropylbenzene (267 µL, 1.411 mmol, 5.0 equiv) with 4.5 mg (0.028 mmol) of FeCl 3 , in 0.56 mL of HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether) gave 56 mg (40% yield) of yellow solid. R f = 0.87 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.55-7.47 (m, 2H), 7.44-7.28 (m, 7H), 7.25-7.19 (m, 2H), 7.14-7.08 (m, 1H), 2.98 (sept, J = 6.8 Hz, 1H), 2.90 (sept, J = 6.9 Hz, 1H), 1.25 (d, J = 6.9 Hz, 6H), 1.12 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): δ (ppm) 205.4 (q, J = 4.2 Hz), 146.8,145.0,134.3,132.1,131.7,129.1,129.0,128.8,128.7,128.2,127.4,127.3,126.3,123.3 (q,J = 275.0 Hz),122.7,117.0,103.1 (q,J = 34.8 Hz),33.7,30.4,24.4,24.1.

1-(4-Bromophenyl)-1-

CF 3 CF 3
Br 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) - 58.8 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 28 H 26 79 BrF 3 498.1165;Found 498.1168 (0.6 ppm).

1-(4-Bromophenyl)-1- (2,5-diisopropylphenyl)-3-phenyl-4,4,4-trifluoro-1,2- 7.52 (d, J = 7.7 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.42-7.36 (m, 2H), 7.36-7.31 (m, 2H), 7.31-7.27 (m, 1H), 7.15-7.10 (m, 3H), 2.98 (sept, J = 6.9 Hz, 1H), 2.92 (sept, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H), 1.13 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): δ (ppm) 206.3 (q, J = 3.9 Hz), 146.9, 145.0, 133.8, 132.1, 131.6, 129.7, 129.0, 128.8, 128.7, 128.2, 127.5, 127.3, 126.3, 123.4 (q, J = 273.5 Hz), 122.7, 115.7, 104.3 (q, J = 34.2 Hz), 33.7, 30.4, 24.4, 24.1, 24.1, 24.1. 19 498.1165;Found 498.1175 (2.0 ppm).

1- ) -1,3-diphenyl-4,4,4-trifluoro-1,2-butadiene 254 was prepared according to modified general procedure B from 1,1,1-trifluoro-2,4-diphenylbut-3-yn-2-ol (104 mg, 0.376 mmol) and 5-fluoro-m-xylene (142 µL, 1.13 mmol, 3.0 equiv) with 6.1 mg (0.038 mmol) of FeCl 3 , in 1.50 mL of HFIP. The reaction mixture was heated at 80 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether) gave 37 mg (25% yield) of colorless oil. R f = 0.84 (petroleum ether/EtOAc 9:1). 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 7.48 (d, J = 7.4 Hz, 2H), 7.40-7.29 (m, 6H), 7.25-7.20 (m, 2H), 6.84 (d, J = 9.4 Hz, 2H), 2.20 (s, 6H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): δ (ppm) 205.1 (q, J = 3.8 Hz), 162.4 (d, J = 244.7 Hz), 139.7 (d, J = 7.2 Hz), 132.9, 129.9, 129.3, 129.0, 128.8, 128.7, 128.6 (d, J = 2.0 Hz), 127.6 (q, J = 1.1 Hz), 126.6,123.6 (q,J = 273.5 Hz),114.6 (d,J = 21.0 Hz),113.5,104.3 (q,J = 34.3 Hz), 20.6. 19 F NMR (282 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) -60.1 (s, 3F), -115.9 (s, 1H). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 24 H 18 F 4 382.1339;Found 382.1348 (2.4 ppm). Cl (1)(2)4, 255 was prepared according to modified general procedure B from 1,1,1-trifluoro-2,4-diphenylbut-3yn-2-ol (108 mg, 0.392 mmol) and 3,5-dichlorotoluene (190 mg, 1.18 mmol, 3.0 equiv) with 6.4 mg (0.039 mmol) of FeCl 3 , in 1.57 mL of HFIP. The reaction mixture was heated at 80 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether) gave 31 mg (23% yield) of white solid. 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 7.56 (d,J = 7.1 Hz,2H), 7.41-7.30 (m, 7H), 7.24-7.19 (m, 3H), 2.27 (s, 3H). 7.56 (d,J = 7.1 Hz,2H), 7.41-7.30 (m, 7H), 7.24-7.19 (m, 3H), 2.27 (s, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): δ (ppm) 205.3 (q, J = 3.9 Hz), 141.1, 135.3, 134.7, 132.1, 131.0, 129.3, 129.1, 129.0, 128.9, 127.7(q, J = 1.2 Hz), 127.3, 126.5, 123.4 (q, J = 273.9 Hz), 112.8, 106.6 (q, J = 34.2 Hz), 20.6. 19 (1- (2,4, 256 was prepared according to modified general procedure B from 1,1,1-trifluoro-2,4-diphenylbut-3yn-2-ol (108 mg, 0.392 mmol) and 3,5-dichlorotoluene (190 mg, 1.18 mmol, 3.0 equiv) with 6.4 mg (0.039 mmol) of FeCl 3 , in 1.57 mL of HFIP. The reaction mixture was heated at 80 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether) gave 17 mg (10% yield) of white solid 1 H NMR (500 MHz, CDCl3) δ (ppm) 7.57 (d,J = 7.1 Hz,2H), 7.43 -7.31 (m, 7H), 7.25 -7.20 (m, 3H), 2.27 (s, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): δ (ppm) 205.3 (q, J = 3.9 Hz), 141.1, 135.3, 134.7, 132.1, 131.0, 129.3, 129.1, 129.0, 128.9, 127.7(q, J = 1.2 Hz), 127.3, 126.5, 123.4 (q, J = 273.9 Hz), 112.8, 106.6 (q, J = 34.2 Hz), 20.6. 19 F NMR (282 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) - 60.8 (s, 3F). HRMS (APPI + -Orbitrap) m/z [M] +. Calcd for C 23 H 15 Cl 2 F 3 418.0497; Found 418.0500 (0.7 ppm). -1,3-diphenyl-4,4,4-trifluoro-1,2-butadiene 257 was prepared according to modified general procedure B 4-(4-bromophenyl)-1,1,1-trifluoro-2,4diphenylbut-3-yn-2-ol (101 mg, 0.284 mmol) and durene (114 mg, 0.85 mmol, 3.0 equiv.) with 2.9 mg (0.028 mmol) of FeCl 3 , in 1.13 mL of HFIP. The reaction mixture was heated at 80 °C for 3 h. Purification by flash column chromatography over silica (petroleum ether) gave 125 mg (93% yield) of white solid. R f = 0,90 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.49 (dd,J = 8.8,2.0 Hz,2H), 7.39-7.30 (m, 5H), 7.24-7.17 (m, 2H), 7.03 (s, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H), 2.06 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 205.0 (q, J = 3.6 Hz), 134.6, 134.2, 133.2, 132.6, 132.5, 132.1, 131.7, 129.4, 129.2, 128.8, 126.9,

3-(4-Bromophenyl)-1-durenyl

CF 3 Cl CF 3
Br 123.6 (q,J = 275.2 Hz),122.7,115.8,103.2 (q,J = 34.8 Hz), 20.2 (2C), 17.5, 16.7. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) -59.0 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 26 H 22 79 BrF 3 470.0851;Found 470.0862 (2.3 ppm).

Preparation of Indenes

Characterization data for indenes 3-Mesityl-1-phenyl-1-(trifluoro-methyl)-1H-indene 235 was prepared according to general procedure C from 1,1,1-trifluoro-2,4-diphenylbut-3-yn-2-ol (106 mg, 0.382 mmol) and mesitylene (160 µL, 1.15 mmol, 3.0 equiv) with 6.2 mg (0.038 mmol) of FeCl 3 , in 1.50 mL of HFIP. The reaction mixture was heated at 80 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether) gave 137 mg (94% yield) of a colorless oil. R f = 0.80 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.68-7.61 (m, 1H), 7.61-7.55 (m, 2H), 7.38-7.29 (m, 5H), 6.98 (s, 1H), 6.94 (s, 1H), 6.93-6.90 (m, 1H), 6.44 (s, 1H), 2.35 (s, 3H), 2.15 (s, 3H), 2.05 (s, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): d (ppm) 147.1, 145.0, 143.5, 137.6, 136.9, 136.5, 135.0, 133.4, 130.5, 128.9, 128.8, 128.4, 128.2, 128.1, 127.8, 126.9 (q, J = 280.6 Hz), 126.7, 125.4, 121.4, 64.8 (q, J = 26.6 Hz), 21.3, 20.3, 20.0. 19 4,5,[START_REF]HRMS (APPI-Orbitrap): m/z for C 17 H 18 18 F[END_REF]-1H-indene 235-D 4 was prepared according to general procedure C from 1,1,1-trifluoro-2-phenyl-4-pentadeuterophenyl-but-3yn-2-ol (68.4 mg, 0.243 mmol) and mesitylene (102 µL, 0.73 mmol, 3.0 equiv) with 3.9 mg (0.024 mmol) of FeCl 3 in 0.97 mL of HFIP. The reaction mixture was heated at 80 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether) gave 37 mg (39% yield) of a colorless oil. R f = 0.80 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.62-7.56 (m, 2H), 7.41-7.29 (m, 3H), 6.99 (s, 1H), 6.95 (s, 1H), 6.45 (s, 1H), 2.36 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H). 2 H NMR (600 MHz, CH 2 Cl 2 ): δ (ppm) 7.71 (br. s, 1D), 7.38 (br. s, 2D), 6.94 (br. s, 1D). HRMS (ESI-TOF) m/z: [M+H] + Calcd for C 25 H 18 D 4 F 3 383.1919;Found 383.1918 (0.3 ppm). The reaction mixture was heated at 50 °C for 6 h. Purification by flash column chromatography over silica (petroleum ether) gave 82 mg (91% yield) of the product (in 90% purity). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.84 (s, 1H), 7.68-7.57 (m, 4H), 7.54 (dd, J = 7.9, 1.6 Hz, 1H), 7.47-7.40 (m, 2H), 7.38-7.30 (m, 4H), 7.03-6.93 (m, 3H), 6.46 (s, 1H), 2.35 (s, 3H), 2.18 (s, 3H), 2.09 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): d (ppm) 146.9, 144.4, 144.2, 144.1, 140.1, 137.7, 136.9, 136.5, 135.0, 133.7, 130.5, 129.0, 128.9, 128.5, 128.3, 128.2, 128.0, 127.8, 127.5, 127.4, 126.9 (q, J = 280.8 Hz), 124.4, 121.6, 65.4 (q, J = 26.6 Hz), 21.3, 20.4, 20.1. 19 F NMR (376.5 MHz, CDCl 3 ): d (ppm) -65.9 (s, 3F). HRMS (APPI + -Orbitrap) m/z [M] +. Calcd for C 31 H 25 F 3 454.1903;Found 454.1904 (0.2 ppm).

3-Mesityl-6-methyl-1-phenyl-1-(trifluoromethyl)-1H-indene 270 was prepared according to modified general procedure C from 1,1,1-trifluoro-2-phenyl-4-(p-toluyl)but-3-yn-2-ol (80 mg, 0.28 mmol) and mesitylene (117 µL, 0.84 mmol, 3.0 equiv) with 4.5 mg (0.028 mmol) of FeCl 3 , in 0.55 mL of HFIP. The reaction mixture was heated at 50 °C for 6 h. Purification by flash column chromatography over silica (petroleum ether) gave 98 mg (91% yield) of the product. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.65 (d, J = 7.3 Hz, 2H), 7.52 (s, 1H), 7.44-7.33 (m, 3H), 7.19 (d, J = 7.7 Hz, 1H), 7.04 (s, 1H), 7.00 (s, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.43 (s, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): d (ppm) 147.0, 143.9, 142.4, 137.5, 136.9, 136.7, 136.5, 135.3, 132.5, 130.7, 129.6, 128.8, 128.4, 128.2, 128.0, 127.8, 127.0 (q, J = 280.9 Hz), 126.3, 121.1, 64.7 (q, J = 26.3 Hz), 21.8, 21.2, 20.3, 20.0. 19 F NMR (376.5 MHz, CDCl The reaction mixture was stirred at ambient temperature for 3 h. Purification by flash column chromatography over silica (petroleum ether) gave 120 mg (96% yield) of colorless oil. R f = 0.83 (petroleum ether/EtOAc 9:1). 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 7.67-7.64 (m, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.34-7.28 (m, 2H), 7.16 (d, J = 8.1 Hz, 2H), 6.99 (s, 1H), 6.95 (s, 1H), 6.93-6.90 (m, 1H), 6.44 (s, 1H), 2.35 (s, 3H), 2.34 (s, 3H), 2.16 (s, 3H), 2.06 (s, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ (ppm) 146.9, 144.9, 143.6, 137.9, 137.6, 136.9, 136.5, 133.5, 131.9, 130.6, 129.5, 128.8, 128.4, 128.2, 127.7, 126.9 (q, J = 282.5 Hz), 126.6, 125.4, 121.3, 64.5 (q, J = 26.7 Hz), 21.2, 21.1, 20.3, 20.0. 19 Purification by flash column chromatography over silica (petroleum ether/EtOAc 40:1 to 30:1) gave 131 mg (90% yield) of yellow oil. R f = 0.58 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.69-7.63 (m, 1H), 7.54-7.48 (d, J = 8.8 Hz, 2H), 7.31 (dd, J = 5.5, 3.1 Hz, 2H), 6.98 (s, 1H), 6.94 (s, 1H), 6.91 (dd, J = 5.5, 3.2 Hz, 1H), 6.87 (d, J = 8.9 Hz, 2H), 6.43 (s, 1H), 3.80 (s, 3H), 2.35 (s, 3H), 2.15 (s, 3H), 2.04 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ (ppm) 159.3, 146.8, 144.9, 143.6, 137.6, 136.9, 136.5, 133.5, 130.6, 129.1, 128.8, 128.4, 128.2, 126.7, 126.9 (q, J = 282.5 Hz), 126.6, 125.4, 121.4, 114.1, 64.2 (q, J = 26.8 Hz), 55.4, 21.2, 20.3, 20.0. 19 3-Mesityl-5-methoxy-1-phenyl-1-(trifluoromethyl)-1H-indene 273 was prepared according to general procedure C from 1,1,1-trifluoro-4-metoxyphenyl-2-phenylbut-3-yn-2-ol (106 mg, 0.345 mmol) and mesitylene (144 µL, 1.03 mmol, 3.0 equiv) with 5.6 mg (0.035 mmol) of FeCl 3 , in 1.03 mL of HFIP. The reaction mixture was heated at 80 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether/EtOAc 40:1 to 30:1) gave 84 mg (60% yield) of acolorless oil. R f = 0.74 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 7.8 Hz, 2H), 7.35-7.25 (m, 3H), 7.19 (s, 1H), 6.95 (s, 1H), 6.91 (s, 1H), 6.80 (s, 2H), 6.28 (s, 1H), 3.78 (s, 3H), 2.31 (s, 3H), 2.14 (s, 3H), 2.06 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 159.1, 146.7, 145.4, 137.8, 137.5, 136.9, 136.5, 135.2, 131.4, 130.8, 128.8, 128.4, 128.2, 128.1, 127.7, 126.9 (q, J = 282.5 Hz), 121.8, 113.5, 112.7, 64.7 (q, J = 26.7 Hz), 55.7, 21.2, 20.3, 20.0. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) -74.9 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 26 H 23 F 3 O 408.1696;Found 408.1695 (-0.2 ppm).

F 3 C OMe F 3 C MeO

3-(2,5-Diisopropylphenyl)-1-phenyl-1-(trifluoromethyl)-1H-indene

274 was prepared according to general procedure C from 1,1,1-trifluoro-2,4-diphenylbut-3-yn-2-ol (104 mg, 0.375 mmol) and diizopropyl benzene (213 µL, 1.13 mmol, 3.00 equiv) with 6.1 mg (0.038 mmol) of FeCl 3 , in 0.75 mL of HFIP. The reaction mixture was stirred at ambient temperature for 3 h. Purification by flash column chromatography over silica (petroleum ether) gave 142 mg (90% yield) of a white solid. R f = 0.91 (petroleum ether/EtOAc 9:1). 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 7.37-7.20 (m, 11H), 7.17 (d, J = 8.3 Hz, 1H), 6.15 (s, 1H), 2.94-2.85 (m, 2H), 1.15 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 7.4 Hz, 3H), 0.98 (d, J = 7.4 Hz, 3H), 0.66 (d, J = 6.7 Hz, 3H). 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ (ppm) 148.5, 143.7, 141.8, 141.1, 141.0, 138.1, 136.4 (q, J = 2.1 Hz), 134.8, 131.9, 128.7 (q, J = 2.0 Hz), 128.2, 128.1, 127.9, 127.8, 126.7, 126.8 (q, J = 283.5 Hz), 126.1, 125.7, 121.5, 64.4 (q, J = 26.4 Hz), 29.3, 27.1, 24.3, 23.9, 23.6, 23.4. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH-ext. st.): δ (ppm) -63.7 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 28 H 27 F 3 420.2059;Found 420.2061 (1.9 ppm).

1-(4-Bromophenyl)-3-(2,5-diisopropylphenyl)-1-(trifluoromethyl)-1H-indene

275 was prepared according to modified general procedure C from 4-(4-bromophenyl)-1,1,1-trifluoro-2,4-diphenylbut-3-yn-2-ol (102 mg, 0.288 mmol) and diisopropylbenzene (164 µL, 0.87 mmol, 3.0 equiv) with 4.7 mg (0.029 mmol) of FeCl 3 , in 1.15 mL of HFIP. The reaction mixture was heated at 80 °C for 1 h. Purification by flash column chromatography over silica (with petroleum ether) gave 111 mg (77% yield) of yellow solid. R f = 0.88 (petroleum ether/EtOAc 9:1). 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 7.57-7.29 (m, 8H), 7.22-7.12 (m, 3H), 6.11 (s, 1H), 2.88 (sept, J = 6.4 Hz, 2H), 1.17 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H). 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ (ppm) 148.5, 143.7, 141.8, 141.1, 141.0, 138.1, 136.4 (q, J = 1.7 Hz), 134.8, 131.9, 128.7 (q, J = 1.7 Hz), 128.2, 128.1, 127.9, 127.8, 126.8 (q, J = 281.8 Hz), 126.7, 126.1, 125.7, 121.5, 64.4 (q, J = 26.4 Hz), 29.4, 27.1, 24.3, 23.9,

F 3 C F 3 C
Br 23.6, 23.4z. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) - 64.5 (s, 3F). HRMS (APPI + -Orbitrap): m/z for C 28 H 26 81 BrF 3 [M] +. : calculated 500.1150; found 500.1145 (-1.0 ppm).

3-(4-(1-Chloro-3,5-dimethylphenyl))-1-phenyl-1-(trifluoro-methyl)-1H-indene

276 was prepared according to a modification of general procedure B from 1,1,1-trifluoro-2,4diphenylbut-3-yn-2-ol (113 mg, 0.410 mmol) and 5-chloro-m-xylene (165 µL, 1.23 mmol, 3.0 equiv) with 6.1 mg (0.041 mmol) of FeCl 3 , in 1.6 mL of HFIP. The reaction mixture was heated at 80 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether) gave 31 mg (19 % yield) of a white solid. R f = 0.31 (petroleum ether). 1 H NMR (500 MHz, CDCl 3 ): δ (ppm): 7.64 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 6.8 Hz, 2H), 7.37-7.27 (m, 5H), 7.16 (s, 1H), 6.98 (s, 1H), 6.95-6.91 (m, 1H), 6.51 (s, 1H), 2.33 (s, 3H), 2.05 (s, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ): δ (ppm) 144.7, 144.4, 143.2, 139.3, 138.6, 134.8, 134.6, 133.8, 129.7, 129.3, 128.9, 128.8, 128.2, 127.8, 127.7, 126.7, 126.7 (q, J = 281.1 Hz), 125.5, 121.4, 65.0 (q, J = 26.8 Hz), 21.1, 20.6. 19 F NMR (282 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) -67.7 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. calculated for C 24 H 18 35 ClF 3 398.1044; found 398.1050 (1.5 ppm). 4,-1-(trifluoromethyl)-1H-indene 277 was prepared according to general procedure C from 1,1,1-trifluoro-2,4-diphenylbut-3-yn-2-ol (117 mg, 0.424 mmol) and 1,3,5-triethylbenzene (239 µL, 1.27 mmol, 3.0 equiv) with 6.9 mg (0.042 mmol) of FeCl 3 , in 1.69 mL of HFIP. The reaction mixture was heated at 80 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether) gave 127 mg (71% yield) of colorless oil. R f = 0.88 (petroleum ether/EtOAc 9:1). 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 7.67-7.62 (m, 1H), 7.57 (d, J = 6.9 Hz, 2H), 7.36-7.29 (m, 5H), 7.03 (s, 1H), 7.00 (s, 1H), 6.96-6.91 (m, 1H), 6.48 (s, 1H), 2.69 (q, J = 7.6 Hz, 2H), 2.57-2.27 (m, 4H), 1.30 (t, J = 7.6 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ (ppm) 146.4, 146.1, 144.3, 143.3, 143.3, 142.9, 134.9, 133.9, 129.4, 128.9, 128.8, 128.1, 127.8, 126.9 (q, J = 282.5 Hz), 126.7, 125.7, 125.5, 125.3, 121.6, 64.8 (q, J = 26.7 Hz), 28.9, 27.0, 26.9, 16.3, 16.2, 15.6. 19 F NMR (282 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) -67.9 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 28 H 27 F 3 420.2059;Found 420.2055 (-1.2 ppm). The reaction mixture was heated at 120 °C for 24 h in a high-pressure reaction tube. Purification by flash column chromatography over silica (petroleum ether/EtOAc 40:1 to 30:1) gave 364 mg (95% yield) of a yellow solid. R f = 0.21 (petroleum ether/EtOAc 9:1). 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 7.64-7.58 (m, 3H), 7.30 (td, J = 1.0, 7.5 Hz, 1H), 7.26 -7.22 (m, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.91 -6.84 (m, 2H), 6.58 (s, 1H), 6.26 (s, 2H), 3.89 (s, 3H), 3.79 (s, 3H), 3.76-3.70 (m, 6H). 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ (ppm) 161.5, 159.4, 159.3, 159.1, 145.4, 143.5, 139.8, 135.3 (q, J = 1.8 Hz), 129.1 (q, J = 1.8 Hz), 128.2,127.4,127.0 (q,J = 282.4 Hz),125.8,124.7,121.9,113.9,104.8,91.2,91.1,63.9 (q, J = 26.8 Hz), 56.2, 55.9, 55.5, 55.3. 19

Preparation of tertiary propargylic alcohols for synthesis of chromenes

General procedure D: 114 Step 1. To a 0.5 M solution of ethynyl magnesium bromide (10 mmol) in THF was slowly added aryl trifluoromethyl ketone (10 mmol) in THF (20 mL). After 3 h at ambient temperature the reaction mixture was quenched first with water and then with saturated NH 4 Cl(aq). The aqueous layer was extracted with Et 2 O. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford colored oil (2-aryl-1,1,1-trifluoro-3-butyn-2-ol -compound A) that was engaged in the next step without further purification.

Step 2. To a solution of 2-iodophenol (10 mmol) and imidazole (20 mmol) in dry THF (20 mL) was added tert-butyldimethylsilyl chloride (20 mmol) in one portion and the reaction mixture was stirred at ambient temperature for 1 h. The mixture was then diluted with CH 2 Cl 2 and filtered through celite. The residue was purified by flash column chromatography (petroleum ether) to provide the desired product (1-iodo-2-(tertbutyldimethylsilyloxy)benzene -compound B).

Step 3. To a stirred solution of compound B (10 mmol) in Et 3 N (20 mL) under argon were sequentially added Pd(PPh 3 ) 2 Cl 2 (1 mol %) and CuI (2 mol %) at ambient temperature. Then compound A (1.3 equiv) was added and the mixture was stirred overnight. The reaction was quenched with saturated NH 4 Cl (aq), extracted with Et 2 O, dried over Na 2 SO 4 , and was purified by flash column chromatography (petroleum ether/EtOAc 9:1). To the isolated product (10 mmol) in THF (20 mL) was added tetra-n-butyl ammonium fluoride (1.2 equiv) at room temperature for 30 min. The reaction was quenched by adding water and extracted with EtOAc, dried over Na 2 SO 4 . The crude material was purified by column chromatography (petroleum ether/EtOAc 10:1) to give the pure propargylic alcohol that was used for subsequent synthesis of chromenes. 2- (4,4,phenol 235 was prepared according to general procedure D using 2,2,2-trifluoro-1-phenylethan-1-one (1.4 mL, 10 mmol).

Purification by flash column chromatography over silica (petroleum ether/EtOAc 9:1) gave 263 mg (90% yield) of light yellow yellow solid. Mp: 92-93 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.85-7.76 (m, 2H), 7.47-7.44 (m, 3H), 7.42 (dd, J = 7.7, 1.6 Hz, 1H), 7.33 (ddd, J = 8.2, 7.5, 1.5 Hz, 1H), 6.98 (dd, J = 7.6, 0.7 Hz, 1H), 6.92 (td, J = 7.6, 1.1 Hz, 1H), 5.57 (s, 1H), 3.16 (s, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 157.4, 135.0, 132.5, 132.0, 129.9, 128.6, 127.2, 123.4 (q, J = 285.6 Hz), 120.8, 115.5, 107.4, 91.6, 82.9, 73.7 (q, J = 32.8 Hz). 19 F NMR (376. 2- (4,4,but-1-yn-1-yl)phenol 325 was prepared according to general procedure D using 2,2,2-trifluoro-1-(p-tolyl)ethan-1-one (1.5 mL, 10 mmol).

Purification by flash column chromatography over silica (petroleum ether/EtOAc 9:1) gave 110 mg (36% yield) of brown oil. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.68 (d, J = 8.2 Hz, 2H), 7.41 (dd, J = 7.7, 1.4 Hz, 1H), 7.36-7.30 (m, 1H), 7.22-7.25 (m, 2H), 6.97 (d, J = 8.3 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 5.61 (s, 1H), 3.19 (s, 1H), 2.40 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 157.4, 140.0, 132.4, 132.2, 131.9, 129.3, 127.1, 123.5 (q, J = 285.8 Hz), 120.8, 115.5, 107.5, 91.8, 82.7, 73.6 (q, J = 31.6 Hz), 21.3. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -81.1 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 17 H 13 O 2 F 3 306.0862; Found 305.0862 (-0.1 ppm).

2- pent-1-yn-1-yl)phenol 326 was prepared according to general procedure D using 1,1,1-trifluorobutan-2-one (1 g, 8 mmol). Purification by flash column chromatography over silica (petroleum ether/EtOAc 9:1) gave 54 mg (22% yield, 70% purity (remainder is 1,1,1-trifluorobutan-2-one) of brown oil. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.36 (dd, J = 7.7, 1.6 Hz, 1H), 7.33 (ddd, J = 8.2, 7.5, 1.5 Hz, 1H), 6.96 (d, J = 8.3 Hz, 2H), 6.90 (td, J = 7.6, 1.0 Hz, 1H), 5.57 (s, 1H), 2.70 (s, 1H), 1.98 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.4 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 157.0, 132.4, 131.7, 124.3 (q, J = 285.2 Hz), 120.7, 115.4, 107.6, 90.4, 82.2, 73.2 (q, J = 31.1 Hz), 28.4, 7.9. 19 F NMR (376.

4-(2-((Tert-butyldimethylsilyl)oxy)phenyl)-1,1,1-trifluoro-2-(p-tolyl

)but-3-yn-2-ol 327 was prepared according to general procedure D using 2,2,2-trifluoro-1-(p-tolyl)ethan-1-one (1.5 mL, 10 mmol), without deprotection step. Purification by flash column chromatography over silica (petroleum ether/EtOAc 9:1) gave 362 mg (86% yield) of brown oil. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.69 (d, J = 8.1 Hz, 2H), 7.45 (dd, J = 7.7, 1.7 Hz, 1H), 7.28-7.19 (m, 3H), 6.93 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 3.02 (s, 1H), 2.38 (s, 3H), 0.97 (s, 9H), 0.24 (s, 3H), 0.23 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 156.9, 139.3, 134.3, 132.5, 130.7, 128.9, 127.2, 123.1 (q, J = 285.3 Hz), 121.1, 119.2, 113.4, 87.8, 85.5, 73.3 (q, J = 31.9 Hz), 25.6, 21.3, 18.3, -4.2. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -78.9 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M+H] +. calculated for C 23 H 28 O 2 F 3 Si 421.1805; Found 421.1797 (-2.0 ppm).

2-(4-Bromophenyl)-4-(2-((tert-butyldimethylsilyl)oxy)phenyl)-1,1,1-trifluoro-but-3-yn-2-ol 328

was prepared according to general procedure D using 1-(4-bromophenyl)-2,2,2trifluoroethan-1-one (2.5 g, 10 mmol), without deprotection step. Purification by flash column chromatography over silica (petroleum ether/EtOAc 9:1) gave 427 mg (88% yield) of brown oil. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.68 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.44 (dd, J = 7.7, 1.7 Hz, 1H), 7.28-7.25 (m, 1H), 6.93 (td, J = 7.6, 1.0 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 3.09 (s, 1H), 0.95 (s, 9H), 0.23 (s, 3H), 0.22 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 157. 0, 134.9, 134.6, 131.7, 131.2, 129.4, 124.1, 123.4 (q, J = 286.4 Hz), 121.4, 119.8, 113.4, 87.4, 86.4, 73.4 (q, J = 32.8 Hz), 25.8, 18.5, -3.9. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -81.0 (s, 3F). HRMS (APPI + -Orbitrap) m/z [M] +. Calcd for C 22 H 25 O 2 79 BrF 3 Si 485.0754; Found 485.0756 (0.4 ppm).

Preparation of Chromenes

General procedure E for synthesis of CF 3 -chromenes and CF 3 -alkenes. To a solution of propargylic alcohol (0.25 mmol) in HFIP (125 μL), aryl nucleophile was added (0.75 mmol) and TfOH (2.2 μL, 10 mol%). The reaction was stirred at 50 o C for 16 h. The crude reaction mixture was directly transferred for silica gel chromatography.

Characterization data for chromenes. . 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.67 (d, J = 7.5 Hz, 2H), 7.41-7.33 (m, 3H), 7.20 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 10.0 Hz, 2H), 6.77 (t, J = 7.5 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.01 (s, 1H), 2.33 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 151.7, 137.9, 137.5, 136.9, 133.2, 130.6, 129.3, 128.7, 128.6, 128.5, 127.1, 125.7, 125.0 (q, J = 284.6 Hz), 122.5, 120.9, 118.3, 116.9, 80.4 (q, J = 30.1 Hz), 21.4, 20.1, 19.9. 19 F NMR (376. 2-Phenyl-4- (2,3,5,6-tetramethylphenyl)-2-(trifluoromethyl)-2H-chromene 291 was prepared according to general procedure E from 2-(4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-yn-1yl)phenol (73 mg, 0.25 mmol) and durene (102 mg, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 88 mg (86% yield) of white solid. Mp: 158-160 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.66 (d, J = 7.3 Hz, 2H), 7.42-7.33 (m, 3H), 7.22-7.18 (m, 1H), 7.12 (dd, J = 8.1, 0.9 Hz, 1H), 7.01 (s, 1H), 6.77 (td, J = 7.5, 1.1 Hz, 1H), 6.53 (dd, J = 7.6, 1.4 Hz, 1H), 5.99 (s, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H), 1.89 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 151.6, 139.0, 137.5, 136.2, 134.3, 134.1, 132.8, 132.6, 131.5, 130.5, 129.3, 128.6, 127.2, 126.0, 124.3 (q, J = 284.6 Hz), 122.4, 121.3, 118.0, 116.8, 80.4 (q, J = 30.5 Hz), 20.4, 20.3, 16.8, 16.6. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -80.3 (s, 3F). HRMS (APPI + -Obitrap) m/z: [M] +. Calcd for C 26 H 23 OF 3 408.1696;Found 408.1698 (0.6 ppm).

4- (2,3,4,5,-2-phenyl-2-(trifluoromethyl)-2H-chromene 292 was prepared according to general procedure E from 2-(4,4,4-trifluoro-3-hydroxy-3-phenylbut-1yn-1-yl)phenol (72.5 mg, 0.25 mmol) and pentamethyl-benzene (111 mg, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 132 mg (quantitative yield) of white solid. Mp: 92-94 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.65 (d, J = 7.3 Hz, 2H), 7.44-7.30 (m, 3H), 7.23-7.17 (m, 1H), 7.12 (dd, J = 8.1, 1.0 Hz, 1H), 6.77 (td, J = 7.5, 1.2 Hz, 1H), 6.56 (dd, J = 7.6, 1.5 Hz, 1H), 6.00 (s, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H), 2.11 (s, 3H), 1.95 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 151.6, 139.6, 137.5, 136.1, 133.8, 133.2, 132.9, 132.4, 132.2, 130.5, 129.3, 128.6, 127.2, 126.2, 124.4 (q, J = 284.6 Hz), 122.4, 121.6, 118.1, 116.8, 80.5 (q, J O CF 3

Ph

O CF 3 Ph = 30.5 Hz), 18.1, 17.8, 17.2, 16.9, 16.8. 19 F NMR (376. 7.74 (d, J = 7.4 Hz, 2H), 7.38-7.32 (m, 3H), 7.11 (t, J = 6.9 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.20 (d, J = 3.4 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 6.13 (s, 1H), 3.87 (s, 3H), 3.69 (s, 3H), 3.67 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 161.8,159.6,159.4,151.4,137.6,131.7,129.6,129.2,128.2,127.9,125.8,124.7 (q,J = 283.8 Hz),122.4,122.0,120.5,116.8,107.3,91.3,91.2,56.3,56.1,55.7 (quaternary carbon a displayed a very weak signal). 19 F NMR (376. 7.55 (d,J = 8.1 Hz,2H), 7.21-7.17 (m, 3H), 7.09 (dd, J = 8.1, 1.0 Hz, 1H), 6.95 (s, 1H), 6.93 (s, 1H), 6.76 (td, J = 7.5, 1.2 Hz, 1H), 6.54 (dd, J = 7.6, 1.5 Hz, 1H), 6.00 (s, 1H), 2.34 (s, 3H), 2.33 (s, 3H), 2.12 (s, 3H), 2.02 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 151.7, 139.2, 137.8, 137.7, 136.9, 134.5, 133.3, 130.5, 129.3, 128.7, 128.4, 127.1, 125.6, 124.2 (q, J = 284.6 Hz), 122.4, 121.0, 118.5, 116.9, 80.4 (q, J = 30.5 Hz), 24.5, 21.4, 20.1, 19.9. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) - 80.5 (s, 3F). HRMS (APPI + -Orbitrap) m/z:

[M] +. Calcd for C 26 H 23 OF 3 408.1698;Found 408.1696 (-0.7 ppm). . 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (s, 4H), 7.23-7.18 (m, 1H), 7.09 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 6.9 Hz, 2H), 6.79 (t, J = 7.4 Hz, 1H), 6.55 (dd, J = 1.2, 7.7 Hz, 1H), 5.97 (s, 1H), 2.33 (s, 3H), 2.11 (s, 3H), 2.00 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 151.4,138.4,138.0,136.8,136.7,136.5,133.0,131.9,130.8,128.9,128.7,128.5,125.8,124.1 (q,J = 284.6 Hz),123.8,122.7,120.8,117.7,116.9,80.1 (q,J = 30.5 Hz),21.4,20.1,19.9. 19 F NMR (376.5 (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 67 mg (77% yield) of colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.14 (td, J = 8.0, 1.6 Hz, 1H), 6.94 (s, 1H), 6.92 (s, 1H), 6.90 (dd, J = 8.1, 0.8 Hz, 1H), 6.73 (td, J = 7.5, 1.1 Hz, 1H), 6.52 (dd, J = 7.6, 1.6 Hz, 1H), 5.26 (s, 1H), 2.33 (s, 3H), 2.17-2.07 (m, 1H), 2.14 (s, 3H), 2.09 (s, 3H), 1.83 (dq,J = 14.2,7.3 Hz,1H), 1.11 (t, J = 7.4 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 153.4, 139.7, 137.7, 137.1, 136.3, 133.5, 130.4, 128.7, 128.4, 125.5, 125.0 (q, J = 284.6 Hz), 121.8, 119.8, 117.4, 115.8, 80.7 (q, J = 30.5 Hz), 27.9, 21.4, 20.2, 19.8, 7.8. 19 F NMR (376.

Et

trifluoride diethyl etherate (12 mmol), and anhydrous THF (20 mL) were added. After an additional 2 h of stirring, the reaction was quenched with brine, extracted with ethyl acetate, and dried over Na 2 SO 4 . The resulting ketone was purified by flash chromatography (petroleum ether/EtOAc 9:1). The ketone was dissolved in methanol (10 mL). To the solution was added NaBH 4 (10 mmol) slowly and the reaction solution was stirred for 30 min at room temperature.

The mixture was quenched by adding brine and extracted with ethyl acetate, dried over Na 2 SO 4 . Finally, purification by flash chromatography yielded the secondary propargylic alcohols.

1,1,1-Trifluoro-4-phenylbut-3-yn-2-ol 234 was prepared according to general procedure F using phenylacetylene (0.54 mL, 5.0 mmol). Purification by flash column chromatography over silica (petroleum ether/EtOAc 9:1) gave 88 mg (44% yield) of yellow oil. The experimental data are in agreement with the literature. 116 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.50-7.48 (m, 2H), 7.42-7.32 (m, 3H), 4.94-4.88 (m, 1H), 2.52 (d, J = 8.3 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 132.4, 129.9, 128.8, 123.2 (q, J = 281.9 Hz), 121.2, 88.4, 80.7, 63.3 (q, J = 36.5 Hz). 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -80.2 (s, 3F).

1 ,1,but-3-yn-2-ol 329 was prepared according to general procedure F using 1-ethynyl-4-methylbenzene (0.63 mL, 5.0 mmol). Purification by flash column chromatography over silica (petroleum ether/EtOAc 9:1) gave 98 mg (46% yield) of white solid. Mp: 69-71 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.40 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 4.95-4.89 (m, 1H), 2.47 (d, J = 6.7 Hz, 1H), 2.39 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 140.2,132.3,129.5,123.1 (q,J = 281.7 Hz),118.1,88.6,80.1,63.3 (q,J = 36.4 Hz), 21. [START_REF]HRMS (APPI-Orbitrap): m/z for C 17 H 18 18 F[END_REF]. 19 F NMR (376. 1,1,but-3-yn-2-ol 330 was prepared according to general procedure F using 1-ethynyl-4-methoxybenzene (0.65 mL, 5.0 mmol). Purification by flash column chromatography over silica (petroleum ether/EtOAc 85:15) gave 69 mg (30% yield) of yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.44-7.39 (m, 2H), 6.89-6.83 (m, 2H), 4.89 (dq, J = 5.7, 8.2 Hz, 1H), 3.82 (s, 3H), 2.47 (d, J = 8.3 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 160.8,133.9,123.3 (q,J = 282.0 Hz),114.4,113.2,88.4,79.5,63.3 (q,J = 36.7 Hz), 55. 7. 19 F NMR (376. 4,benzonitrile 331 was prepared according to general procedure F using 1-ethynyl-4-isocyanobenzene (0.64 g, 5.0 mmol). Purification by flash column chromatography over silica (petroleum ether/EtOAc 9:1) gave 56 mg (25% yield) of yellow solid. Mp: 90-92 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.65 (d,J = 8.1 Hz,2H), 7.58 (d, J = 8.4 Hz, 2H), 4.98-4.91 (m, 1H), 2.59 (d, J = 8.4 Hz, 1H). 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 132 .7, 132.3, 125.8, 122.7 (q, J = 282.0 Hz), 118.2, 113.1, 86.1, 84.6, 63.1 (q, J = 36.8 Hz). 19 F NMR (376. 4-(4-Bromophenyl)-1,1,1-trifluorobut-3-yn-2-ol 332 was prepared according to general procedure F using 1-ethynyl-4-bromobenzene (0.60 mL, 5.0 mmol). Purification by flash column chromatography over silica (petroleum ether/EtOAc 9:1) gave 167 mg (60% yield) of yellow/dark yellow solid. Mp: 62-63 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.49 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 4.91-4.88 (m, 1H), 2.50 (d, J = 7.0 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 133.8,132.2,124.4,123.1 (q,J = 282.4 Hz),120.1,87.2,81.8,62.3 (q,J = 36.6 Hz). 19 F NMR (376. (4,4,bis (1,3,5-trimethylbenzene) 303 was prepared according to general procedure E from 1,1,1-trifluoro-4-phenylbut-3-yn-2-ol (50 mg, 0.25 mmol) and mesitylene (105 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 80 mg (75% yield) of white solid. Mp: 135-136 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.27-7.21 (m, 5H), 6.95 (s, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.79 (s, 1H), 6.76 (s, 1H), 6.65 (d,J = 5.1 Hz,1H),1H), 2.51 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.14 (s, 3H). 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ 143.0, 139.2, 138.9, 137.6, 137.6, 137.3, 137.2, 135.3, 134.3, 130.9, 129.2, 128.7, 128.7, 128.6, 128.4, 127.9, 127.6 (q, J = 280.9 Hz) 125.9, 121.7, 45.8 (q, J = 27.8 Hz), 22.7 (q, J = 3.2 Hz), 21.2, 20.9, 19.9, 19.6, 18.4. 19 F +. Calcd for C 28 H 29 F 3 422.2216;Found 422.2217 (0.4

ppm).

(Z)-2,2'- (4,4,bis (1,3,5-trimethylbenzene) 307 was prepared according to general procedure E from 1,1,1-trifluoro-4-(p-tolyl)but-3-yn-2-ol (53 mg, 0.25 mmol) and mesitylene (105 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 84 mg (77% yield) of white solid. Mp: 90-91 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.16 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 6.95 (s, 1H), 6.87 (d, J = 8.7 Hz, 1H), 6.76 (s, 1H), 6.65 (d,J = 4.5 Hz,2H),1H), 2.50 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 1.39 (s, 3H), 1.13 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 142.8, 139.2, 137.8, 137.6, 137.5, 137.1, 136.0, 135.3, 134.5, 130.9, 129.4 (2C), 129.1, 128.6, 128.4, 127.6 (q, J = 281.2 Hz), 125.8 (2C),120.7,45.8 (q,J = 27.8 Hz),22.7 (q, J = 3.1 Hz), 21.3, 21.2, 20.9, 19.9, 19.6, 18.3. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) - 68.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 29 H 31 F 3 436.2372;Found 436.2377 (1.1 ppm).

(Z)-2,2'- (4,4,but-1-ene -1,3-diyl)bis (1,3,5-trimethylbenzene) 308 was prepared according to general procedure E from 1,1,1-trifluoro-4-(4methoxyphenyl)but-3-yn-2-ol (58 mg, 0.25 mmol) and mesitylene (105 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether/EtOAc 98:2) gave 91 mg (81% yield) of colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.22 (d, J = 8.8 Hz, 2H), 6.98 (s, 1H), 6.83 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 6.9 Hz, 2H), 6.68 (d,J = 5.2 Hz,2H),1H), 3.81 (s, 3H), 2.53 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H), 1.42 (s, 3H), 1.17 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 159.5, 142.4, 139.2, 137.6, 137.5, 137.1 (q, J = 2.6 Hz), 135.2, 134.6, 131.5, 130.9, 129.1, 128.6, 128.4, 127.7 (q, J = 281.1 Hz), 127.1 (2C), 119.6, 114.0 (2C), 55.4, 45.8 (q, J = 27.7 Hz), 21.2, 20.9, 19.9, 19.6, 18.3. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) - 67.4 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 29 H 31 OF 3 452.2322;Found 452.2323 (0.3 ppm).

CF 3 H

CF 3 H MeO

CF 3 H NC

(Z)-4- (4,4,benzonitrile 309 was prepared according to general procedure E from 4- (4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)benzonitrile (56 mg, 0.25 mmol) and mesitylene (105 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (88 h,100 °C). Purification by flash column chromatography over silica (petroleum ether/EtOAc 98:2) gave 25 mg (22% yield) of colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.56 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.77 (s, 1H), 6.67 (d, J = 8.6 Hz, 2H), 4.40-4.30 (m, 1H), 2.48 (s, 3H), 2.29 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 1.40 (s, 3H), 1.10 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ (ppm) 143.3,141.8,139.3,138.0,137.6,137.5,137.4,135.2,133.0,132.6,131.0,129.3,128.9,128.7,128.0,127.8 (q,J = 280.7 Hz),126.4,125.4,119.0,111.3,46.0 (q,J = 28.0 Hz),22.7 (q,J = 3.8 Hz), 21.2, 20.9, 19.8, 19.6, 18.3. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) - 67.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 29 H 28 NF 3 447.2168;Found 447.2172 (0.8 ppm).

(Z)-2,2'- 4,bis (1,3,5-trimethylbenzene) 310 was prepared according to general procedure E from 4-(4-bromophenyl)-1,1,1-trifluorobut-3yn-2-ol (70 mg, 0.25 mmol) and mesitylene (105 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 77 mg (61% yield) of colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.40 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.96 (s, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.77 (s, 1H), 6.67 (d,J = 6.1 Hz,2H),1H), 2.48 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H), 1.40 (s, 3H), 1.13 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 142.3, 139.4, 138.0, 137.8, 137.7, 137.5, 135.4, 134.5, 133.9, 132.0, 131.1, 129.4, 128.9, 128.7, 123.0 (q, J = 281.2 Hz), 127.7,126.0,123.1,122.2,46.1 (q,J = 27.8 Hz),22.9,21.5,21.0,20.1,19.8,18.5. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) - 67.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 28 H 28 79 BrF 3 500.1321;Found 500.1331 (1.9 ppm).

(Z)-2,2'- (4,4,but-1-ene-1,3-diyl)bis (1,3,5-trimethoxybenzene) 311 was prepared according to general procedure E from 1,1,1-trifluoro-4-(4methoxyphenyl)but-3-yn-2-ol (58 mg, 0.25 mmol) and 1,3,5-trimethoxybenzene (116 mg, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether/EtOAc 8:2) gave 100 mg (73% yield) of white solid. Mp: 128-129 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.24 (d, J = 8.9 Hz, 2H), 6.79 (dd, J = 21.3, 8.5 Hz, 3H), 6.20 (d,J = 2.1 Hz,1H), 6.08 (s, 1H), 5.90 (s, 1H), 5.87 (d,J = 2.1 Hz,1H),1H), 3.82 (s, 6H), 3.78 (s, 3H), 3.76 (s, 6H), 3.43 (s, 3H), 3.07 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 161.1, 160.8, 159.2, 159.0, 158.3, 135.5, 133.9, 127.8 (q, J = 280.9 Hz), 127.3, 123.2, 113.7, 109.5, 105.9, 91.6, 90.5, 90.4, 90.2, 56.4, 56.2, 55.7, 55.6 (2C), 55.5, 55.2, 30.2 (q, J = 27.8 Hz). 19 F NMR (376. (Z)-2,2'- (4,4,bis (1,4-dimethylbenzene) 312 was prepared according to general procedure E from 1,1,1-trifluoro-4-phenylbut-3-yn-2-ol (50 μL, 0.25 mmol) and p-xylene (92 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 48 mg (49% yield) of colorless oil which was isolated as a 6:4 mixture of stereoisomers as determined by 1 H NMR. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 6.69 (d, J = 9.7 Hz, 1H, major), 6.68 (d,J = 9.7 Hz,1H,minor),[START_REF]HRMS (APPI-Orbitrap): m/z for C 17 H 18 18 F[END_REF]36 (s,1H,minor), 4.39-4.22 (m, 1H, minor), 4.15-4.01 (m, 1H, major), 2.41 (s, 3H, minor), 2.34 (s, 6H, major), 2.16 (s, 3H, major), 2.06 (s, 3H, major), 1.78 (s, 3H, minor), 1.68 (s, 3H, minor), 1.45 (s, 3H, minor). 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 146.1,145.8,140.0,139.8,138.0,137.8,135.7,135.7,135.3,134.5,134.0,133.8,133.7,133.6,133.3,130.5,130.4,130.4,130.3,130.2,129.7,129.2,128.8,128.7,128.6,128.5,128.0,126.7,126.6,45.2 (q,J = 27.4 Hz),44.8 (q,J = 27.4 Hz),21.3,21.2,20.9,19.1,18.5,18.5. (mixture of two rotamers). 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -69.2 (s, 2.2F -minor), - 69.5 (s, 3F -major). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 26 H 25 F 3 394.1908;Found 394.1902 (-1.7

ppm).

(Z) 4,bis (1,2,3,4,5-pentamet-hylbenzene) 313 was prepared according to general procedure E from 1,1,1-trifluoro-4-phenylbut-3-yn-2-ol (50 μL, 0.25 mmol) and pentamethylbenzene (111 mg, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 114 mg (95% yield) of white solid. Mp: 183-185 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.31-7.24 (m, 5H), 6.94 (d,J = 7.4 Hz,1H),1H), 2.41 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 2.02 (s, 3H), 1.82 (s, 3H), 1.29 (s, 3H), 0.84 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 144.4, 140.0, 135.1, 134.8, 134.4, 134.0, 133.7, 133.4, 133.2, 132.9, 132.7, 132.4, 130.3, 129.7, 128.8, 127.8, 127.8 (q, J = 280.5 Hz), 126.2, 122.8, 46.2 (q, J = 27.9 Hz), 19.9, 19.8, 17.5, 17.4, 17.3, 17.1, 16.9, 16.8, 16.2, 15.9. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) - 66.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M+H] + Calcd for C 32 H 38 F 3 479.2920;Found 479.2923 (0.6 ppm).

(Z) 4,bis (1,2,3,4,5-pentamethylbenzene) 314 was prepared according to general procedure E from 1,1,1-trifluoro-4-(p-tolyl)but-3-yn-2-ol (53 mg, 0.25 mmol) and pentamethylbenzene (111 mg, 0.75 mmol), with 2.2 μL (0.025 mmol) CF 3

Ar = CF 3 H Ar Ar

Ar = CF 3 H Ar Ar

of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 108 mg (88% yield) of white solid. Mp: 206-209 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.19 (d, J = 8.2 Hz, 2H), 7.09 (d,J = 8.1 Hz,2H), 6.89 (d, J = 7.4 Hz, 1H), 4.52-4.41 (m, 1H), 2.39 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H), 1.82 (s, 3H), 1.29 (s, 3H), 0.84 (s, 3H), 0.09 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 144.2, 137.7, 137.2, 135.1, 134.9, 134.4, 133.9, 133.7, 133.4, 133.2, 132.8, 132.7, 132.0, 130.3, 129.8, 129.5, 127.8 (q, J = 281.1 Hz), 126.1,121.8,46.2 (q,J = 27.8 Hz),21.4,19.9,19.8,17.5,17.4,17.2,17.0,16.9,16.8,16.2,15.9. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) - 66.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 33 H 39 F 3 492.2998;Found 492.3005 (1.2 ppm).

(Z) [3][4]4,but-1-ene-1,3-diyl)bis (1,2,4,5tetramethyl benzene) 315 was prepared according to general procedure E from 1,1,1-trifluoro-4-(4methoxyphenyl)but-3-yn-2-ol (58 mg, 0.25 mmol) and durene (102 mg, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether/EtOAc 98:2) gave 65 mg (54% yield) of white solid. Mp: 144-146 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.19 (d, J = 8.8 Hz, 2H), 6.89 (s, 1H), 6.83 (d, J = 7.9 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 4.52-4.35 (m, 1H), 3.78 (s, 3H), 2.36 (s, 3H), 2.27 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 1.88 (s, 3H), 1.22 (s, 3H), 0.89 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 159.6, 143.4, 137.7, 135.7, 134.8, 134.4, 134.1, 133.9, 133.8, 133.4, 133.3, 131.9, 131.2, 130.6, 130.4, 127.5 (q, J = 281.1 Hz), 127.2, 119.9, 110.2, 55.4, 45.9 (q, J = 27.8 Hz), 21.4, 21.1, 20.5, 19.9, 19.7, 18.6, 16.1, 15.4, 14.9. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -66.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 31 H 35 OF 3 480.2635;Found 480.2636 (0.4

ppm).

Ar = CF 3 H Ar Ar

MeO

Part 3: Friedel-Crafts reaction of primary aliphatic alcohols in HFIP The first reaction that comes to mind when thinking about the alkylation of arenes is the Friedel-Crafts alkylation between an aryl nucleophile and an alkyl halide, alkyl triflate, or alkyl mesylate. These activated electrophilic species are usually synthesized from the corresponding alcohols and, thus, require an additional synthetic step which necessarily produces a stoichiometric amount of waste. All these factors make the whole process poorly atom-and step-economic. In addition, the Friedel-Crafts alkylation with linear alky halides generally leads to mixtures of branched and linear products (Scheme 75). Therefore, while this reaction is well described in undergraduate textbooks, efficient preparations of linear products remain scarce. 117 In this transformation, the formation of branched products results from a [1,2]-H shift, which generates a secondary carbocation rather than a primary one, which is too unstable to form.

Scheme 75: Example of a Friedel-Crafts reaction with a primary alkyl halide

Regarding the substitution of triflate esters and mesylate esters, the group of He developed a gold(III)-catalyzed functionalization of aromatic C-H bonds (Scheme 76). 118 Good yield and selectivity were obtained with the sterically hindered pentamethylbenzene (Scheme 76, eq. 1). On the other hand, lower selectivity was observed with the less sterically hindered pxylene, leading to the branched product as a major product (Scheme 76, eq. 2). The authors noticed the formation of 5 mol% of aryl chloride, resulting from the hydrolysis of an arylgold(III) complex upon treatment with brine. Therefore, they suggested that the role of the gold catalyst might be more complex than simply acting as a Lewis acid. Nevertheless, the authors did not consider the possible formation of triflic acid and hydrochloric acid following the hydrolysis of either the gold or silver catalyst. Phenylethyl mesylate also led to the corresponding product in an excellent yield (92%) with a complete selectivity in favor of the 117 Clayden-Organic Chemistry-2 nd Edition-p493 118 Z. Shi, C. He, J. Am. Chem. Soc. 2004, 126, 13596. 123 linear product (Scheme 76, eq. 3). However, we suspect a different mechanism in that case, which we will discuss later on.

Scheme 76: Functionalization of arenes with primary sulfonate esters

Another common method for the alkylation of arenes is the Kumada-Corriu cross-coupling reaction (Scheme 77). 119 This reaction involves an aryl Grignard and an alkyl halide. Crosscoupling reactions with alkyl halides have two significant barriers to overcome: the oxidative addition with relatively-electron rich alkyl electrophiles (compared to standard aryl and vinyl electrophiles) and the possibility of β-hydride elimination, which would lead to the formation of undesired byproducts. 120 The general mechanism starts by the oxidative addition of the metal into the carbon-halide bond, followed by a trans-metalation with the aryl Grignard. A subsequent trans-cis isomerization and a reductive elimination deliver the corresponding cross-coupling product, while regenerating the metal catalyst. Despite the strength of the carbon-fluoride bond, the group of Koga succeeded in preparing linear alkyl arenes in moderate yields from alkyl fluorides and an aryl Grignard (Scheme 79). 123 To probe the mechanism, the authors investigated whether the linear alkylarene 357 was produced from the alkyl chloride, which was formed in-situ. Although the reaction was possible with the alkyl chloride and the aryl Grignard, it was much slower, delivering the product in 7% yield. Hence, the authors ruled out the cross-coupling from the alkyl chloride as the major reaction pathway. The authors attributed this difference of reactivity to the Lewis acidic affinity of the magnesium for the fluoride of the fluoroalkanes. A first order radical mechanism was ruled out as the yield increased as the amount of reagent or reactant was increased (no S N 1 involved) and no n-hexadecane and n-octane were observed (no primary alkyl radical involved). Thus, the authors proposed a concerted mechanism. However, the addition of a radical scavenger, TEMPO, had a detrimental effect on the reaction, suggesting that a single electron transfer was involved in the reaction mechanism.

123 K. Matsubara, T. Ishibashi, Y. Koga, Org. Lett. 2009Lett. , 11, 1765. For its part, the group of Weix reported the first selective nickel-catalyzed cross-electrophile coupling of aryl chlorides with primary alkyl chlorides (Scheme 81). 125 The main challenge with the activation of C-Cl bonds in cross-coupling reactions is the need for a reactivity comparable with C-Br or C-I versions of the cross-coupling reaction, without compromising the selectivity.

Overcoming this dual reactivity-selectivity issue requires a catalyst that selectively reacts with the aryl chloride over the alkyl chloride and, yet, could slowly generate an alkyl radical from the alkyl chloride precursor. The authors circumvented this challenge by using salt additives in order to maintain a very low, steady-state concentration of an alkyl bromide or iodide and a uniquely selective pyridine-2,6-bis(N-cyanocarboxamide)-ligated nickel catalyst. The overall mechanism is still under investigation; nevertheless, the authors underlined that: (1) LiCl was essential for an efficient reduction of the nickel catalyst over the zinc surface, the role of LiCl being to prevent the formation of ZnCl 2 that is known for its inhibitory effect on reduction of nickel catalysts and, (2) halide exchange played a key role by increasing the reactivity of the alkyl chloride.

125 S. Kim, M. J. Goldfogel, M. M. Gilbert, D. J. Weix, J. Am. Chem. Soc. 2020, 142, 9902. In both cases, the direct alcohol substitution reaction yielding a linear product was in competition with elimination reactions, which led to the formation of branched products upon addition of benzene to the newly formed olefins. Aware of the current limitations of Friedel-Crafts reactions, we wondered whether the remarkable properties HFIP could enable Friedel-Crafts alkylations of primary aliphatic alcohols in order to exclusively provide the linear product.

Scheme 83: State of the art on direct alcohol substitution vs this work 3.2. Friedel-Crafts alkylation of primary aliphatic alcohols

Reaction discovery and optimization

We began our investigation with the HFIP/TfOH system, which has proven its effectiveness in the prior chapter. 1-Tetradecanol was used as a model substrate because of its high boiling point, while mesitylene was employed as a nucleophile. The ratios of branched and linear products were estimated by the relative integration of the secondary aromatic carbons in 13 DEPT NMR. This method is unusual but given that only one signal was observed for each branched product and that all these signals came from two secondary aromatic carbons, the relaxation time should be approximately similar. It was not possible to use 1 H NMR to quantify the ratio between the branched and the linear products as the characteristic signals were overlapping. In this reaction, we noticed that the concentration was critical to the process. At 140 °C, a 1 M concentration of alcohol led to a mixture of linear and branched products (Table 6, entry 1), while lowering the concentration to 0.25 M led only to the linear product (Table 6, entry 2). We then screened other Lewis and Brønsted acids. Neither FeCl 3 , which was an efficient catalyst for tertiary propargylic alcohols, nor the weak Brønsted acid TFA furnished the linear product or branched products (Table 6, entries 3 and 5). Bi(OTf) 3 provided a similar selectivity as triflic acid, albeit in a lower yield (Table 6, entry 4). We assumed that, under the reaction conditions, triflic acid might be easily formed in-situ via hydrolysis of Bi(OTf) 3 . In these circumstances, we limited our studies to triflic acid.

The influence of the solvent was then studied. When the reaction was conducted in isopropanol, no reaction was observed (Table 6, entry 6). The use of other fluorinated solvents such as trifluoroethanol and hexafluoro-2-methyl-2-propanol was also detrimental to both yield and selectivity (Table 6, entries 7 and8). Other solvents such as chloroform and nitromethane, the latter known for its H-bonding properties, did not improve the reactivity either (Table 6, entries 10 and 11). 130 When the nucleophile was used as a solvent, the target product was obtained in moderate yield and selectivity (Table 6, entry 9). Initial attempts to conduct the reaction at a lower temperature using the optimal conditions (HFIP/TfOH at 0.25 M) furnished a mixture of branched and linear product.

Entry

Catalyst b Ratio estimated by 13 C DEPT NMR from the isolated mixture. c Isolated yields after flash column chromatography.

Mechanistic proposal for the Friedel-Crafts alkylation of aliphatic alcohols

Primary aliphatic alcohols do not undergo nucleophilic substitution via an S N 1 pathway because of the extreme instability of primary carbocations. In addition to the difficulty of the carbocation formation, the C-O bond energy is more than 200 kJ/mol higher than that of the C-F bond, the least likely leaving group among the halogens. As the formation of the desired product was observed when the reaction was conducted in mesitylene, our first assumption was that the aryl nucleophile acts as an activating group and pre-activates the alcohol into a phenol-ether moiety (Scheme 84). We hypothesized that this phenol-ether moiety would be a better leaving group than the starting primary alcohol. Nevertheless, we did not observe by 1 H NMR or GC-MS the formation of the enol product 384 which should be formed as a byproduct of the reaction. As the enol ether byproduct could easily re-aromatize into mesitylene under acidic conditions, further computational studies would be required to rule out this mechanism.

Scheme 84: A plausible mechanism for the Friedel-Crafts alkylation of aliphatic alcohols

Other mechanisms have been considered using DFT calculations (carried out by Prof. Christopher Rowley):

(1) Under standard conditions, the beginnings of the formation of a primary aliphatic carbocation would presumably be accompanied by a nearly synchronous 1,2-proton shift to form a secondary carbocation, which would yield the standard branched product for a typical dissociative Friedel-Crafts mechanism. It was found by DFT that the primary carbocation could be stabilized by coordination of an explicit HFIP molecule (Scheme 85). This complex can react with the arene through a mechanism where the arene starts to form a bond from the opposite face, displacing the HFIP molecule and forming the Wheland intermediate. Modeling this reaction for butanol and mesitylene as substrates, it was found that the Gibbs energy of activation of this step is 50.7 kcal/mol, largely because the carbocation-HFIP complex is unstable relative to the alcohol, elevating the reaction barrier. (2) The ability of HFIP to facilitate proton transfer reactions through hydrogen bonding interactions presents an alternative mechanism, where proton transfer to the hydroxyl group and the formation of the bond with the arene occur simultaneously (Scheme 86). In this mechanistic model, a molecule of triflic acid, stabilized by hydrogen bonds from explicit HFIP molecules, transfers a proton to the hydroxyl group of butanol while mesitylene attacks from the opposite face of the alcohol centre. The proton transfer occurs early in this mechanism, such that the protonated hydroxyl group has begun to dissociate from the alcohol to form a water molecule in the transition state. The Gibbs energy of activation energy for this mechanism was calculated to be 20.6 kcal/mol.

Scheme 86: Concerted mechanism

(3) An alternative mechanism where a protonated cluster of HFIP transfers the proton was also considered. A similar transition state structure was identified, where a proton is transferred to the hydroxyl group of the alcohol from a protonated cluster of 4 HFIP molecules. The transition state geometry is otherwise similar to that of the concerted mechanism where triflic acid is the proton donor. The calculated activation energy is higher for this mechanism (48.6 kcal/mol), although the mixed continuum/explicit solvent model used to represent the HFIP may be underestimating the significance of HFIP-mediated proton transfer.

Stability of branched and linear products

To test the stability of linear and branched products under the standard reaction conditions, three control experiments were carried out with (1) the linear product, (2) the mixture of branched products and (3) the mixture of linear and branched products (Figure 7). We observed that only the linear product remained stable after 8 hours. From the above information, we deduced that, under the standard conditions, the arylation was reversible in the case of branched products, leading to the formation of oligomers over time, and irreversible in the case of the linear product (Scheme 87). Indeed, the retro-hydroarylation of branched products leads to a secondary carbocation, which is much more stable than the formation of a primary carbocation resulting from the retro-hydroarylation of a linear product. Thus, while only the linear product was isolated under the optimized reaction conditions, we cannot rule out that some branched products were not formed during the course of the reaction. We then explored the scope of the transformation with various primary aliphatic alcohols under the optimized reaction conditions (Scheme 88). As above, only the formation of the linear product was obtained. The longer the aliphatic chain, the better was the yield. For all reactions, complete conversion of the starting material was observed. During the reaction, the reaction mixture took on a yellow-brown color and a broad signal was observed by 1 H NMR in the aliphatic region suggesting the formation of oligomers. We assumed that dehydration (elimination reaction) of the starting primary alcohol and oligomerization competed with the direct substitution of the alcohol by the aryl nucleophile. It would be interesting to investigate further how to inhibit those side reactions to obtain better yields. Regarding the reactivity of 3-phenylpropan-1-ol 391, we hypothesized that the moderate yield was due to a competitive intramolecular cyclization. Thus, 3-phenylpropan-1-ol 391 was subjected to the standard reaction conditions in the absence of nucleophile (Scheme 89). However, the corresponding indane product was neither observed by NMR nor by GC-MS. Therefore, this moderate yield might be explained by an enhanced acidity of the hydrogens connected to the C-2 carbon due to the electron rich π system of the aromatic ring, which might trigger elimination reactions.

Scheme 89: Control experiment with 3-phenylpropan-1-ol

Primary alcohols with a short aliphatic chain displayed a different behavior than those with a long aliphatic chain (Scheme 90). As an example, a low yield was obtained with methanol. This might be due to a higher proportion of the alcohol residing in the gas phase with respect to the liquid phase inside the high-pressure reaction tube. Ethanol furnished relatively high yields; nevertheless, because of its limited steric hindrance, a mixture of bis-alkylated and mono-alkylated products was obtained. On the other hand, a lower selectivity was obtained with butanol with a 68:32 linear/branched ratio. An interesting feature of this transformation was the excellent efficiency of the combination TfOH/HFIP for the activation of phenyl ethanol substrates (Table 7). At a 1 M concentration, phenyl ethanol led to the arylated product 403 in 98% yield. Regarding the screening of other catalysts and solvents, the same trends as with 1-tetradecanol were observed in terms of reactivity. b Isolated yield after flash column chromatography.

Entry

Mechanistic proposal for the Friedel-Crafts alkylation of phenyl ethanol

The difference of reactivity, notably in terms of yields, between primary aliphatic alcohols bearing a long alkyl chain and phenyl ethanol might be explained by the formation of a well- established phenonium ion. 131 Back bonding effect from the LUMO of the phenyl cation moiety to the HOMO of the ethylene fragment is responsible for the orthogonal nature of the ipso-carbon (Figure 8). These orbital interactions make the phenonium ion more stable than a hypothetic primary carbocation. Once the phenonium ion is formed, a subsequent nucleophilic addition of mesitylene will generate a Wheland intermediate (Scheme 91).

Finally, re-aromatization of this species will lead to the corresponding linear adduct. When phenyl ethanol was used as a substrate, an alternative reaction pathway might be that the branched product underwent a retro-arylation leading to styrene 203, which subsequently undergoes an anti-Markovnikov hydroarylation to give a linear product. To definitively rule out this unlikely pathway, styrene was subjected to the standard reaction conditions (Scheme 92). Encouraged by this initial result, the scope of arenes and phenyl ethanol derivatives was explored (Scheme 93). The bulkier 1,3,5-triethylbenzene 407 was also well tolerated for this reaction. Other less nucleophilic arenes such as p-xylene 408 and 1,4-diethylbenzene 409 delivered the products in good yields. Not surprisingly, halogenated nucleophiles such as 3,5dimethyl-1-fluorobenzene 410, 3,5-dimethyl-1-chlorobenzene 411 and 3,5-dimethyl-1bromobenzene 412 furnished two regioisomers in moderate yields. Replacing the phenyl group by a naphthalene group 413 had no impact on the reactivity, providing the corresponding linear adduct in 95% yield. The reaction proved to be compatible with the introduction of electron-donating and moderately electron-withdrawing groups at the paraposition (yields up to 98%). On the other hand, a significant decrease of the reactivity was observed with bis-halogenated aryl substituents as dechlorination was observed during the course of the reaction.

Scheme 93: Scope of phenyl ethanol derivatives and arene nucleophiles a All reactions were conducted in the presence of 5 equivalents of mesitylene in a sealed Pyrex® high pressure reaction tube and all isolated yields were obtained after flash column chromatography.

Unfortunately, several nucleophiles were not compatible with this transformation (Scheme 94), either because they are not nucleophilic enough (benzene, 1,4-difluorobenzene, 1,4dichlorobenzene and 1,2-difluorobenzene), too sterically hindered (1,4-diisopropylbenzene) or unstable under the highly acidic reaction conditions (2,5-dimethylfurane, N-methylpyrrole and N-methylindole). In the case of 1,3,5-trimethoxybenzene, we suspect that, since this compound can be easily protonated (cf introduction on hydroarylation of cyclopropanes), the retro-Friedel-Crafts reaction could easily take place to re-generate the alcohol substrate. In the case of 3,5-dimethyl-1-iodobenzene, this compound underwent a dehalogenation under the reaction conditions as the reaction turned deep purple and iodide crystals were observed in the reaction media.

Scheme 94: Unsuccessful Friedel-Crafts alkylations

Other phenyl ethanol derivatives and substituted aliphatic alcohols were screened (Scheme 95). 3-Trifluoropropan-1-ol 430 did not lead to the expected product due to the depolarization of the C-OH bond owing to the proximity of an electron withdrawing group. Not surprisingly, pentafluoro-substituted phenyl ethanol 431-432 did not lead to the corresponding product as the nucleophilicity of the aromatic ring was lowered due to the presence of several electron withdrawing groups, thus reducing the propensity of this alcohol to form a stabilized phenonium ion to enable the reaction. Starting arylethanol derivatives substituted with methoxy and hydroxy group did not afford the corresponding product, likely because of their basicity and ability to interact with HFIP networks. Alcohols bearing either a nitrile and silyl moiety did not provide the target products as they readily transformed into the corresponding alkenes and oligomerize. In the case of adamantane derivative 437, a complex mixture of products was obtained. Our studies on the dehydrative Friedel-Crafts reactions of phenyl ethanol derivatives inspired us to develop an alternative way to access diaryl compounds, starting from the epoxide (Scheme 96). This one-pot reaction was achieved in two steps: (1) reduction of the epoxide using triethylsilane and, then, (2) a Friedel-Crafts alkylation of the silyl ether with mesitylene. Gratifyingly, the target compound was obtained in high yield (95%).

Scheme 96: Epoxide ring-opening and subsequent Friedel-Crafts alkylation 3.4. Summary In summary, we described a simple and highly selective method for the Friedel-Crafts alkylation of primary aliphatic alcohols, using a combination of TfOH and HFIP. Preliminary DFT calculations support a S N 2 mechanism. The combination of TfOH with HFIP was particularly effective for the substitution of phenylethanol derivatives, paving the way for more extensive access to diarylalkanes. The difference in reactivity between simple aliphatic alcohols and phenyl ethanol derivatives was attributed to the formation of a stable cyclopropenium ion in the latter case. To date, this report is the first example of a reliable Brønsted acid-catalyzed Friedel-Crafts alkylation of primary aliphatic alcohols, only leading to 3.5. Experimental data All Friedel-Crafts reactions were performed in 15 mL ACE pressure reaction tubes under an atmosphere of air. Elevated temperatures were achieved by way of a silicon oil bath and heating plates equipped with a thermocouple. Purification of reaction products was carried out by flash column chromatography using Merck silica gel (40-63 μm). Analytical thin layer chromatography (TLC) was performed on aluminum sheets precoated with silica gel 60 F254 (Merck), cut to size. 1 H NMR spectra were recorded on a Bruker UltraShield Plus 400 (400 MHz) spectrometer at ambient temperature and are reported in ppm using solvent as internal standard (residual CHCl 3 at 7.26 ppm). 13 C{ 1 H} NMR spectra were recorded on a Bruker UltraShield Plus 400 (100 MHz) spectrometer at ambient temperature and are reported in ppm using solvent as internal standard (CDCl 3 at 77.16 ppm). 19 F NMR spectra were recorded on a Bruker UltraShield Plus 400 (376.5 MHz) spectrometer at ambient temperature and are reported in ppm. Data are reported as: multiplicity (ap = apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dddd = doublet of doublet of doublet of doublets, qd = quartet of doublets, dt = doublet of triplets, dm = doublet of multiplets, td = triplet of doublets, quintd = quintet of doublets), coupling constants (in Hz) and integration. High resolution mass spectrometry (HRMS) analysis was performed on the instrument GC Thermo Scientific Trace 1300 GC unit coupled to an APPI MasCom source mounted on a Thermo Scientific Exactive Plus EMR mass unit (Orbitrap FT-HRMS analyzer). Materials: All commercial materials were purchased from Sigma-Aldrich and FluoroChem, and were used as received, without further purification.

General Procedure: A 15 mL ACE pressure reaction tube equipped with a stir bar was charged with the requisite alcohol (10 mmol), nucleophile (5 equiv) and HFIP. TfOH (10 mol%) was then added, the tube capped and heated at 140 o C for 24 h. After cooling to room temperature, the reaction mixture was evaporated then purified by chromatography column using (40-63 µm) silica gel and ethyl acetate/petroleum ether eluent system. The author states that the reproduction of these reactions may require small modifications depending on the thickness of the tube and the stability of the heating system. 1,3,5-Trimethyl-2-(3-phenylpropyl)benzene 391 was prepared according to General Procedure from 3-phenyl-1-propanol (264 µL, 1.94 mmol) and mesitylene (1.35 mL, 9.71 mmol, 5 equiv) with 17.2 µL (0.194 mmol) of TfOH, in 1.94 mL of HFIP. The reaction mixture was stirred at 140 °C during 24 h. Purification by flash column chromatography over silica (petroleum ether/EtOAc 10:0 to 9:1) gave 101 mg (21% yield) of colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.33-7.29 (m, 2H), 7.24-7.19 (m, 3H), 6.83 (s, 2H), 2.76 (t, J = 7.6 Hz, 2H), 1,4-Diethyl-2-phenethylbenzene 409 was prepared according to General Procedure from 2phenyl-1-ethanol (265 µL, 2.21 mmol) and 1,4-diethylbenzene (1.72 mL, 11.1 mmol, 5 equiv) with 19.6 µL (0.221 mmol) of TfOH in 2.2 mL of HFIP. The reaction mixture was stirred at 140 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether/EtOAc 10:0 to 9:1) gave 358.9 mg (68% yield) of colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 7.35-7.30 (m, 2H), 7.26-7.21 (m, 3H), 7.14 (d, J = 7.6 Hz, 1H), 7.0 -7.01 (m, 2H), 2.95-2.87 (m, 4H), 2.70-2.59 (m, 4H), 1.26-1.22 (m, 6H). 13 C NMR (126 MHz, CDCl 3 ) δ 142.3,141.8,139.3,139.2,128.9,128.5 (3C),126.1,125.9,37.9,35.1,28.6,25.3,15.8,: m/z for C 18 H 21 [M-H] + : calculated 237.1649; found 237.1639 (-4.1 ppm).

5-Fluoro-1,3-dimethyl-2-phenethylbenzene 410-p was prepared according to General Procedure from 2-phenyl-1-ethanol (265 µL, 2.21 mmol) and fluoro-m-xylene (1.39 mL, 11.1 mmol, 5 equiv) with 19.6 µL (0.221 mmol) of TfOH in 2.2 mL of HFIP. The reaction mixture was stirred at 140 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether/EtOAc 10:0 to 9:1) gave 124.4 mg (25% yield) of colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 7.34-7.30 (m, 2H), 7.24-7.20 (m, 3H), 6.74 (d, J = 9.5 Hz, 2H), 2.90-2.86 (m, 2H), 2.75-2.71 (m, 2H), 2.31 (s, 6H). 13 C NMR (ppm) (126 MHz, CDCl 3 ) δ 160.74 (d,J = 242.7 Hz),142.0,138.3 (d,J = 7.8 Hz),134.1 (d,J = 3.0 Hz),128.6,128.4,126.2,114.6 (d,J = 20.3 Hz),35.6 (d,J = 1.5 Hz), 31.5, 20.1 (d, J = 1.7 Hz). 19 F NMR (282 MHz, CDCl 3 ) δ (ppm) -118. [START_REF]HRMS (APPI-Orbitrap): m/z for C 17 H 18 18 F[END_REF]. HRMS (APPI-Orbitrap): m/z for C 16 H 16 F [M-H] + : calculated 227.1236; found 227.1230 (-2.7

ppm).

1-Fluoro-3,5-dimethyl-2-phenethylbenzene 410-o was prepared according to General Procedure from 2-phenyl- 1-ethanol (265 µL, 2.21 mmol) and fluoro-m-xylene (1.39 mL, 11.1 mmol, 5 equiv) with 19.6 µL (0.221 mmol) of TfOH, in 2.2 mL of HFIP. The reaction mixture was stirred at 140 °C for 24 h. Purification by flash column chromatography over silica (petroleum ether/EtOAc 10:0 to 9:1) gave 164.6 mg (33% yield) of colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 7.32-7.27 (m, 2H), 7.22 (dd, J = 3.2, 7.4 Hz, 3H), 6.75 (s, 1H), 6.72 (d, J = 10.5 Hz, 1H), 2.90-2.86 (m, 2H), 2.79 (dd,J = 5.9,10.3 Hz,2H), 2.29 (s, 3H), 2.22 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ (ppm) 161.5 (d,J = 243.0 Hz),142.1,138.2 (d,J = 5.1 Hz), 137.1 (d, J

General conclusion and perspectives

This doctoral thesis was devoted to the exploration and the application of Brønsted and Lewis acid catalysis in combination with HFIP for the activation of alcohols, particularly propargylic and primary alcohols. Over the last few years, our research group obtained some valuable results by employing the TfOH/HFIP system and FeCl 3 /HFIP system. In a second part, we have described a straightforward method to access triaryl CF 3 -bearing allenes, indenes, chromenes and alkene directly from α-CF 3 propargylic alcohols. Mechanistic experiments suggest the initial formation of a CF 3 -allene that could then be diverted into the given allene, chromene, or alkene depending on the substitution of the starting propargylic alcohol.

This work led to an article: F. Noël, V. D. Vuković, J. Yi, E. Richmond, P. Kravljanac, J. Moran. J. Org. Chem. 2019, 84, 15926. In a third part, we have described a simple and highly selective method for the dehydroarylation (Friedel-Crafts reaction) of primary aliphatic alcohols. Computational studies were consistent with an S N 2 mechanism. The developed method was especially effective for the substitution of phenylethanol derivatives. The difference of reactivity between simple aliphatic alcohols and phenylethanol derivatives was attributed to the latter's ability to form stable phenonium ion intermediates. To date, this report is the first example of a Brønsted acid catalyzed Friedel-Crafts reaction on primary aliphatic alcohols leading to the exclusive formation of the linear product.

Nevertheless, the work on the Friedel-Crafts reactions of primary aliphatic alcohols will not be published alone but will be part of a bigger project. As these discoveries paved the way for the one pot synthesis of diaryl and triaryl alkanes from cyclopropanes. At the current time, another PhD student, Shaofei Zhang, is actively working on this part. However, publication of this work would require 1) additional computational experiments to determine the energy of formation of the cyclopropenium intermediate. 2) additional experimental and computational research to better understand the selectivity in the case of the substitution of regular aliphatic propargylic alcohols. All of the above-mentioned work is ongoing at the time of the writing of this thesis.

  ethanol-amine AN: acceptor number obtained by analyzing the chemical shift of 31 P of triethylphosphine solvatochromic shift of 30 th Reichardt's betaine E 1 and E 2 : first order and second order elimination reaction FAAH: fatty acid amide hydrolase GC: gas chromatography GC-MS: gas chromatography coupled with mass HBA: H-bond acceptance HBD: H-bond donating ability HOMO: highest occupied molecular orbital HRMS: high resolution mass spectrometry HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol IC 50 : half maximal inhibitory concentration iPr: isopropyl LUMO: lowest unoccupied molecular orbital -steroidal anti-inflammatory agents NMP: N-methyl-2-pyrrolidone NMR: nuclear magnetic resonance N OTs : nucleophilicity scale developed by Schleyer to describe the nucleophilic strength of negative base -10 logarithm of the acid dissociation constant (Ka) of a solution RDS: rate determining step sc: synclinal 30° to 90° sp: synperiplanar 0° to 30°

Figure 1 .

 1 Figure 1. Propriétés de HFIP

Schéma 1 .

 1 Alkylation de Friedel-Crafts d'alcools benzyliques désactivés

Schéma 4 .

 4 Champ d'application pour la formation d'allènes.

Schéma 6 .

 6 Champ d'application pour la formation d'alcènes. a réaction à l'échelle du 1 mmol. b réaction à 100 °C pendant 88 h. Mes = 1,3,5-triméthylbenzène.

Figure 1 :

 1 Figure 1: Acidity scale (the acidities achievable in a given solvent). Reproduced from ref 1e.

1

  (a) J.-P. Bégué, D. Bonnet-Delpon, B. Crousse, Synlett 2004, 18; (b) I. A. Shuklov, N. V. Dubrovina, A. Börner, Synthesis 2007, 2925; (c) T. Sugiishi, M. Matsugi, H.

Figure 2 :

 2 Figure 2: Molecules used to determine HBA and HBD

Scheme 3 :Figure 4 :

 34 Scheme 3: Spiro-bicyclic intermediate in HFIP-assisted olefin epoxidation

  Scheme 4: HFIP conformers

  Scheme 9: Original Friedel-Crafts reactions

  Scheme 12: Friedel-Crafts alkylation of secondary fluoropropargylic alcohols

Scheme 13 :

 13 Scheme 13: Friedel-Craft alkylation of fluorobenzylic substrate

Figure 6 : 1 H

 61 Figure 6: 1 H titration of a mixture of HFIP (1 equiv) and 75 (0.05 equiv) with TfOH

  Scheme 23: Donor-acceptor cyclopropanes ring opening models from DFT calculations

Scheme 24 :

 24 Scheme 24: General modes of activation for the ring-opening reaction of donor-acceptor cyclopropanes and cyclopropyl ketones

  Scheme 26: Mechanistic proposal for hydroarylation of highly deactivated styrene

  54 C. Qi, S. Yang, V. Gandon, D. Leboeuf, Org.Lett. 2019, 21, 7405. 55 W. Wang, X. Cao, W. Xiao, X. Shi, X. Zuo, L. Liu, W. Chang, J. Li, J.Org. Chem. 2020, 85, 7045.

Scheme 32 :HFIP

 32 Scheme 32: Mechanism for the formation of pyrrolidine derivative in HFIP

  N. G. Voznesenskaia, O. I. Shmatova, V. G. Nenajdenko, Synthesis 2019, 52, 263.

  Scheme 38: Rearrangement in HFIP

  Scheme 41: Modified Schmidt reaction for tetrazole synthesis

1 .

 1 Catalytic dehydrative substitution of alcohols

  82 M. Böldl, I. Fleischer, Eur. J.Org. Chem. 2019, 5856.

  Scheme 45: Homo coupling of electron riche secondary Benzylic alcohols

  83 A. J. A. Watson, J. M. J. Williams, Science 2010, 329, 635. 84 M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C. Maytum, A. J. A. Watson, J. M. J. Williams, J. Am. Chem. Soc. 2009, 131, 1766. 85 (a) B. V. Rokade, K. Gadde, K. R. Prabhu, Eur. J. Org. Chem 2015, 2706; (b) K. Chen, H. J. Chen, J. Wong, J. Yang, S. A. Pullarkat, ChemCatChem 2013, 5, 3882. 86 (a) T. Stopka, M. Niggemann, Org. Lett. 2015, 17, 1437; (b) D. Leboeuf, M. Presset, B. Michelet, C. Bour, S.Bezzenine-Lafollée, V. Gandon, Chem.Eur. J. 2015, 21, 11001.

  (a) P. L. Coe, N. E. J. Milner, J.Organomet. Chem. 1974, 70, 147; (b) D. J. Burton, G. A. Hartgraves, J. Hsu,

  Scheme 54: Ligand-controlled regioselective copper-catalyzed trifluoromethylation for the synthesis of CF 3 -bearing allenes

3 .

 3 Synthesis of secondary propargylic alcohols.

Further

  investigations were conducted to shed light on the mode of activation of FeCl 3 , notably whether we are in the presence of a Lewis acid catalyst or a hidden Brønsted acid catalyst. First, we rule out the hypothesis of hydrolysis of FeCl 3 into HCl as HCl afforded only 103 (a) T. Kitazume, T.A. Sato, J. Fluorine Chem. 1985, 30, 189; (b) L. Xiao,T. Kitazume, Tetrahedron: Asymmetry 1997, 8, 3597.

F 2 .

 2 Mechanistic proposal for the formation of allenes

  Scheme 60: Scope of CF 3 -bearing allenes a Reaction conducted at 50 o C. b Reaction for 24 h. c Reaction for 3 h. d Reaction for 1 h. e Reaction for 5 min. f Reaction conducted at 80 o C.

1

 1 Formation of indenes and mechanistic proposal

Scheme 61 :

 61 Scheme 61: Synthesis of CF 3 -bearing indenesRegarding the standard protocol for the reaction between propargylic alcohol 225 and mesitylene in HFIP employing FeCl 3 as a catalyst, we emphasized that conducting the reaction

F

F

  Scheme 65: Unsuccessful propargylic alcohols for the formation of indenes

  Scheme 66: Activation of tertiary propargylic alcohols bearing an o-hydroxyl group at ring A

Scheme 68 :F

 68 Scheme 68: Mechanistic proposal for the formation of the chromene

F

  Scheme 71: Formation of CF 3 -bearing alkenes

Scheme 72 :

 72 Scheme 72: Mechanistic proposal for the formation of the alkene

  Scheme 73: Scope of CF 3 -bearing alkenes a Isolated yield after column chromatography.b Performed on 1 mmol scale.c Reaction heated at 100 °C for 88 h. Mes = mesityl.

  Scheme 74: Summary of the reactivity of CF 3 -bearing propargylic alcohols

F

  MHz, CDCl 3 ): d (ppm)

3 F 1 -

 31 -1-phenyl-trifluoro-1,2-butadiene 248 was prepared according to modified general procedure B from 1,1,1-trifluoro-2-(4-metoxyphenyl)-4-phenylbut-3-yn-2-ol ol (71 mg, 0.25 mmol) and mesitylene (102 µL, 0.735 mmol, 3.0 equiv) with 4.0 mg (0.025 mmol) of FeCl 3 , in 0.98 mL of

  F NMR (282 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) -60. (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 23 H 15 Cl 2 F 3 418.0497; Found 418.0500 (0.7 ppm).

  -1,6-diphenyl-1-(trifluoromethyl)-1H-indene 269 was prepared according to modified general procedure C from 4-((1,1'-biphenyl)-4-yl)-1,1,1-trifluoro-2-phenylbut-3-yn-2-ol (70 mg, 0.20 mmol) and mesitylene (84 µL, 0.60 mmol, 3.0 equiv) with 3.3 mg (0.020 mmol) of FeCl 3 , in 0.41 mL ofHFIP.

  3 ): d (ppm) -66.0 (s, 3F). HRMS (ESI-TOF) m/z: [M+H] + Calcd for C 26 H 24 F 3 393.1825; Found 393.1815 (2.5 ppm).

  -1-toluyl-1-(trifluoromethyl)-1H-indene 271 was prepared according to general procedure C from 1,1,1-trifluoro-4-phenyl-2-(p-tolulyl)but-3-yn-2-ol (93 mg, 0.32 mmol) and mesitylene (133 µL, 0.96 mmol, 3.0 equiv) with 5.1 mg (0.032 mmol) of FeCl 3 , in 1.27 mL ofHFIP.

3 -

 3 Mesityl-1-(4-methoxyphenyl)-1-(trifluoromethyl)-1H-indene 272 was prepared according to modified general procedure C from 1,1,1-trifluoro-2-(4-metoxyphenyl)-4-phenylbut-3-yn-2-ol (109 mg, 0.356 mmol) and mesitylene (149 µL, 1.07 mmol, 3.0 equiv) with 5.8 mg (0.036 mmol) of FeCl 3 , in 1.42 mL of HFIP. The reaction mixture was heated at 80 °C for 1 h.

6 -

 6 Trimethoxyphenyl)-1-(4-methoxyphenyl)-1-(trifluoromethyl)-1H-indene 278 was prepared according to a modification of general procedure C from 1,1,1-trifluoro-2-(4metoxyphenyl)-4-phenylbut-3-yn-2-ol (258 mg, 0.841 mmol) and 1,3,5-trimethoxybenzene (424 mg, 2.52 mmol, 3.0 equiv) with13.6 mg (0.084 mmol) of FeCl 3 , in 3.4 mL ofHFIP.

4 -

 4 -2H-chromene 285 was prepared according to general procedure E from 2-(4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-yn-1-yl)phenol (73 mg, 0.25 mmol) and mesitylene (105 μL, 0.750 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP(16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 101 mg (quantitative yield) of white solid. Mp: 90-92 o C

  Bromophenyl)-4-mesityl-2-(trifluoromethyl)-2H-chromene 295 was prepared according to general procedure E from 2-(4-bromophenyl)-4-(2-((tert-butyldimethylsilyl)oxy)phenyl)-1,1,1-trifluoro-but-3-yn-2-ol (121 mg, 0.25 mmol) and mesitylene (105 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum ether) gave 89 mg (75% yield) white solid. Mp: 113-115 o C

  , CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -68.4 (s, 3F). HRMS (APPI + -Orbitrap) m/z:[M]

  Scheme 80: Catalytic benzylation and alkylation with subsequent hydrofluorination

  Scheme 81: Nickel-catalyzed cross-coupling of aryl chlorides with primary alkyl chlorides

Figure 7 :

 7 Figure 7: GC-experiment, stability of linear and branched products under standard reaction conditions

Scheme 88 :

 88 Scheme 88: Scope of primary aliphatic alcohols a All reactions were conducted in the presence of 5 equivalents of mesitylene in a sealed Pyrex® high pressure reaction tube.b Isolated yield after flash column chromatography. c Concentration = 1 M. d Concentration = 0.25 M.

Scheme 90 : 1 .

 901 Scheme 90: Substitution of primary alcohols with short alkyl chains a 1 H NMR yield with hexamethyldisiloxane as external standard.

Figure 8 :

 8 Figure 8: The orthogonal ipso-carbon in the phenonium ion

Scheme 92 : 3 .

 923 Scheme 92: Control experiment with styrene

  Scheme 95: Unsuccessful Friedel-Crafts alkylations

F

F

  I. Colomer, A. E. R. Chamberlain, M. B. Haughey, T. J.

Donohoe, Nat.

Rev. Chem. 2017, 1, 0088;

(f) S.

K. Sinha, T. Bhattacharya, D. Maiti, React. Chem. Engl. 2019, 4, 244;

(g) V. Pozhydaiev, M. Power, V. Gandon, J. Moran, D.

Leboeuf, Chem. Commun. 2020

, 56, 11548. 2 A. J. Phillips, e-EROS Encycl. Reagents Org. Synth. http://dx.doi. org/10.1002/047084289X.rn01164 (2010). 3 S. J. Brenek, S. Caron, E. Chisowa, M. P. Delude, M. T. Drexler, M. D. Ewing, R. E. Handfield, N. D. Ide, D. V. Nadkarni, J. D. Nelson, M. Olivier, H. H. Perfect, J. E. Phillips, J. J. Teixeira, R. M. Weekly, J. P. Zelina, Org. Process Res.

Dev. 2012Dev. , 16, 1348. .

k 0 ) MeOTs -0.3Y OTs k: rate constante of solvolysis of MeOTs k 0 : rate constant of solvolysis of MeOTs in aqueous EtOH (80%) Y: Solvent ionising power 1 2 solvent

	Me	O S O O N OTS = log (k/Solvent TFE PhCF 3 CHOH HFIP Ph(CF 3 ) 2 COH	NuH pK a (H 2 O) 12.4 11.9 9.3 8.8	Me Nu pK a (MeOH/H 2 O) HO S O O + 11.8 11.7 9.5 9.3

Table 1 :

 1 pK a of fluorinated alcohols

Table 2

 2

	).

Table 2 :

 2 b parameter of several alcohols

HFIP, rt, 20 h HFIP, rt, 7 h HFIP, 59 °C, 5 min HFIP, rt, 5 h HFIP, 59 °C, 5 min

					O		O
							O
					9		10
				Bayer-	91%
	NH 2					N		OEt
						OEt
		+		2x
	11				12	13	14	N H
							79%
	MeO	O	O	Ph			MeO	O
								OH
	OMe						OMe	Ph
	15						16
							99%
								O
	MeO	+		Cl	O	Ph	MeO	Ph
	OMe						OMe
	17				18		19
							66%
					CHO
		NH 2						NH
	N H						N H
					NO 2
	20				21		22
							99%	NO 2

villiger reaction aza-Diels-Alder Intramolecular Friedel-Crafts alkylation Intermolecular Friedel-Crafts acylation Pictet-Spengler reaction H 2 O 2

  .

HFIP, 50°C, 2 h TFA (5 mol%) Ph F Ph 58 60 65% + 59 HFIP, DCM (1:9) rt, 18 h + F tBu tBu

	62 (99%, 18 h, without TFA)
	(89%, 1 h, TFA (5 mol%))

61 59 HFIP, CH 3 NO 2 (4:1), 50°C, 24 h (10 mol%) OH + Fe(III) B(OH) 2 SbF 6 a b Fe(III) B(OH) 2 SbF 6 Fe(III) B(OH) 3 SbF 6 OH tetra-ion 66 63 65 87% a:b = 82:18 64 63

HFIP, 80 °C, 20 h Catalyst (10 mol %) HFIP/MeNO 2 (4:1), 50 °C, 24 h Catalyst (10 mol %) HFIP/MeNO 2 (4:1), 25 °C, 24 h Catalyst (10 mol %) Ph OMe Ph MeO + Br OH Br N Ph Ph OH N H

	69 (97%, TfOH)
	(96%, B3)
	+
	72 (98%, TfOH)
	(94%, B1)
	O
	Ph	Ph
	74 (96%, TfOH)
	(85%,

B3) 67 70 73 Fe(III) (HO) 2 B SbF 6 F F F F B HO OH B HO OH CO 2 Me OH F 3 C HO F 3 C CF 3 CF 3 + B1 B2 B3 68 71

	Scheme 16: Friedel-Crafts reaction of highly deactivated benzylic alcohols

HFIP, 100 °C, 24 h TfOH (10 mol%) OH + 75 76 94% F F F F F F F F F F 59 OH n 75 F F F F F OH y CF 3 F 3 C H Z H m

							TfOH x
	H x + H y		H m	H n	H z	f	110 mol%
		H x + H y	H m	H n	H z	e	43 mol%
		H x + H y	H m	H n	H z	d	10 mol%
		H x + H y + H m		H n	H z	c	5 mol%
				H m	H x + H y H n	H z	b	0.5 mol%
				H m		H x + H y	H z	a	0 mol%
	9	8	7	6		5	4.8 4.7 4.6 4.5
		(ppm)				(ppm)

HFIP, 100 °C, 24 h TfOH (10 mol%) OH + 77 78 61% (4% ee) CF 3 CF 3 59

  .

HFIP/DCE (1:1), 80 °C, 1 h NOBF 4 (5 mol%) OH + O 79 81 phenprocoumon 68% O OH O O OH 80 Scheme 19: Boronic acid/perfluoropinacol combination for the Friedel-Crafts alkylations of benzylic alcohols in HFIP HFIP/CH 3 NO 2 (4:1), 80 °C, 24 h + 82 83 80% F F F F B(OH) 2 (10 mol%) L (10 mol%) OH F 3 C OH CF 3

HFIP, 0 °C, 15 h HF(OTf) 4 (0.5 mol%) CO 2 Me O (20 mol%) OH -H 2 O CO 2 Me COMe Ph OH CO 2 Me OH CO 2 Me 90 94 98% HFIP, 0 °C to rt, 24 h Sc(OTf) 3 (0.5 mol%) CO 2 Me O OH -H 2 O CO 2 Me COMe Ph OH 90 OH Ph CO 2 Me 97 78% CO 2 Et CO 2 Et HFIP, 70 °C, 2 h TfOH (0.1 mol%) CO 2 Et CO 2 Et 99 92% 98 + 92 93 96 95 91

HFIP, rt, 3 h TfOH (10 mol%) Ph CO 2 Me CO 2 Me OMe OMe MeO CO 2 Me CO 2 Me Ph MeO OMe OMe + HFIP, rt, 3 h TfOH (10 mol%) Ph OMe OMe MeO Ph MeO OMe OMe + Ph O Ph O Donor-acceptor cyclopropane Monosubstituted cyclopropane 102 95% 104 98% 100 101 103 101

	Scheme 22: Mechanistic proposal for hydroarylation of cyclopropyl ketone in HFIP/TFOH conditions

  Unlike prior discussed reactions with boronic

48

A. Chatupheeraphat, M. Rueping, M. Magre, Org Lett 2019, 21, 9153.

HFIP, 80 °C, 2 h Ca(NTf 2 ) 2 (10 mol%) n-Bu 4 NPF 6 (10 mol%)

  52

	Ph
		Ph
	TsOH . H 2 O (5 mol%)
	HFIP, c-C 6 H 12 (1:2),
	rt, 9 h
	131	132
		77%
	Ph
		Ph
	131	132
	c-C 6 H 12
	HFIP phase	OTs
	131	Ph
	+	132
	TsOH
	133	TsOH

50 W. Liu, H.

Wang, C.-J. Li, Org Lett. 2016, 18, 2184. 51 J. Liu, H. Yao, C. Wang, ACS Catal. 2018, 8, 9376. 52

H. Yao, J. Liu, C. Wang, Org.

Biomol. Chem. 2019, 17, 1901.

phase Scheme 29: Hydrofunctionalization reactions in HFIP

Table 3 :

 3 Investigations on Ca(NTf 2 ) 2 /nBu 4 NPF 6 in HFIP

HFIP, rt, 30 min BF 3 •OEt 2 (20 mol%) O O t-BuOO t-Bu O 179 83% 178 O O 180 Other solvents

  78

76 M. Dryzhakov, E. Richmond, J. Moran, Synthesis 2016, 48, 935 77 (a) D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L. Leazer, Jr., R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007, 9, 411; (b) M. C. Brayan, P. J. Dunn, D. Entwistle, F. Gallou, S. G. Koenig, J. D. Hayler, M. R. Hickey, S. Hughes, M. E. Kopach, G. Moine, P. Richardson, F. Roschangar, A. Steven,

F. J. Weiberth, Green Chem. 2018, 20, 5082. 78

(a) V. N. Ipatieff, H. Pines, B. S. Friedman. J.

Am. Chem. Soc. 1938, 60, 2731; (b)

P. F. Oesper, C. P. Smyth, M. S. Kharasch, J. Am.

Chem. Soc. 1942, 64, 937;(c)

M. Ouertani, J. Collin, H. B. Kagan, Tetrahedron 1985, 41, 3689; (d)

J. Y. Gauthier, F. Bourdon, R.

N. Young, Tetrahedron Lett 1986, 27, 15.

p-TsOH . H 2 O (5 mol%) PPh 3 (2 mol%) DCE, 100 °C, 4 h

		OH
	2	Ph				Ph	Ph
		201				202
						80%
		+H + -2 H 2 O		-H +
				PPh 3		PPh 3
	Ph	+	Ph			Ph	Ph
	203		204		206
						OH	Oligomers
				Ph	201
		Ph	O	Ph
				205
	Ph	OH		H		Ph	H N tBu

2 NtBu + [Ru(p-cymene)Cl 2 ] 2 (2.5 mol %) dppf (5 mol%) Toluene, 110 °C, 24 h 209

	207	208
		94 %

212, 50 °C, FeCl 3 . 6H 2 O (5 mol%) yield = 90% 25 °C, TfOH (1 mol%) yield = 92% 210 211Table 4 :

 4 Mayr electrophilic and nucleophilic scales

		OH					NHTs
	ph	Me	+	Ts NH 2	1,4-dioxane, 24 h	ph	Me

mol%) NaO 2 CCF 2 Br (25 mol%) KF, DMF, 50 °C, 14 h H

  conversion of trifluoromethyl ketone 224 into diol following a dimerization process, suggesting it might be an important active intermediate.

	Ph H 11 C 5 to the full Scheme 57: Synthesis of CF 3 -bearing tertiary propargylic alcohols with an o-hydroxyl group CuI (10 mol%) Phen (1 Ph CF 3 H 217 71% (25 : 1) N N 218 Phen O CF 2 Br O 216 [LAu(NCCH 3 )]SbF 6 (4 mol%) CDCl 3 , 60 °C, 1 h H 11 C 5 H CF 3 220 85% P ArO OAr MeO MeO L CF 3 OBn H H 11 C 5 CF 3 O Ph H Au O Au C 5 H 11 H CF 3 H Ph 219 221 222 223	OMe

100

A. Boreux, G. Lonca, O. Riant, F. Gagosz, Org. Lett. 2016, 18, 5162. 101

L.

Wang, N. Liu, B. Dai, X. Ma, L. Shi, RSC Adv. 2015, 5, 10089.

Scheme 56: Synthesis of tertiary propargylic alcohols

2.3.2

. Synthesis of tertiary propargylic alcohols bearing an o-hydroxyl group

Tertiary propargylic alcohols bearing an o-hydroxyl group were synthetized according to a known three step protocol (Scheme 57).

102

The first step is a classic alkynylation of the trifluoroacetophenone 224 with a solution of ethynylmagnesium bromide to form alkyne 227, followed by a Sonogashira cross-coupling with aryl iodide 228 bearing a o-OTBS group. A subsequent desilylation of the phenol led to the targeted tertiary propargylic alcohols bearing an o-hydroxyl group. 102 Y.-F. Qiu, Y.-Y. Ye, X.-R. Song, X.-Y. Zhu, F. Yang, B. Song, J. Wang, H.-L. Hua, Y.-T. He, Y.-P. Han, X.-Y. Liu, Y.-M.

Liang, Chem.

Eur. J. 2015, 21, 3480.

Table 5 :

 5 Reaction optimization

a Reaction performed at 50

°C. b

Reaction conducted in the presence of 37% aq. HCl (w/w).

c

Reaction performed at 80 °C.

104 T. C. Wabnitz, J.-Q. Yu, J. B. Spencer, Chem.

Eur. J. 2004, 10, 484.

  F NMR (376.5 MHz, CDCl 3 , C 6 F 6 -ext. st.): d (ppm) -68.4 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 26 H 23 F 3 392.1746; Found 392.1747 (0.3 ppm).

  5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -81.1 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M+H] + Calcd for C 16 H 12 O 2 F 3 293.0784; Found 293.0783 (-0.2 ppm).

OH HO CF 3 OH Et HO CF 3 OH

  5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -82.1 (s, 3F). HRMS (APPI + -Orbitrap) [M] +. Calcd m/z: for C 12 H 11 O 2 F 3 244.0711; Found 244.0705 (-2.5 ppm).

	HO CF 3

  5 MHz, CDCl 3 CF 3 CO 2 H, -ext. st.): δ (ppm) -80.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M-H] + for C 25 H 20 OF 3 Calcd 393.1461; Found 393.1460 (-0.1 ppm).

  5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -80.2 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M]+. Calcd for C 27 H 25 OF 3422.1852; Found 422.1855 (0.7 ppm).

	2-Phenyl-2-(trifluoromethyl)-4-(2,4,6-trimethoxyphenyl)-2H-chromene 293 was prepared
	according to general procedure E from 2-(4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-yn-1-
	yl)phenol (73 mg, 0.25 mmol) and 1,3,5-trimethoxybenzene (116 mg, 0.75 mmol), with 2.2 μL
	(0.025 mmol) of triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column
	chromatography over silica (petroleum ether/EtOAc 97:3) gave 47 mg (43% yield) of white
	solid. Mp: 133-135 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm)

  5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -79.9 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M+H] + Calcd for C 25 H 22 O 4 F 3 443.1465; Found 443.1464 (-0.2 ppm).

	4-Mesityl-2-(p-tolyl)-2-(trifluoromethyl)-2H-chromene 294 was prepared according to general
	procedure E from 2-(4,4,4-trifluoro-3-hydroxy-3-(p-tolyl)but-1-yn-1-yl)phenol (77 mg, 0.25
	mmol) and mesitylene (105 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125
	mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over silica (petroleum
	ether) gave 55 mg (54% yield) of white solid. 294 was also prepared according to general
	procedure E from 4-(2-((tert-butyldimethylsilyl)oxy)phenyl)-1,1,1-trifluoro-2-(p-tolyl)but-3-
	yn-2-ol (105 mg, 0.25 mmol) and mesitylene (105 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of
	triflic acid, in 0.125 mL of HFIP (16 h, 50 °C). Purification by flash column chromatography over
	silica (petroleum ether) gave 290 mg (71% yield) of white solid. Mp: 110-113 o C. 1 H NMR (400
	MHz, CDCl 3 ): δ (ppm)

  MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -80.5 (s, 3F). HRMS (APPI + -Orbitrap) m/z [M]+. Calcd for C 25 H 21 OBrF 3473.0722;

	2-Ethyl-4-mesityl-2-(trifluoromethyl)-2H-chromene 296 was prepared according to general
	procedure E from 2-(3-hydroxy-3-(trifluoromethyl)pent-1-yn-1-yl)phenol (61 mg, 0.25 mmol)
	and mesitylene (105 μL, 0.75 mmol), with 2.2 μL (0.025 mmol) of triflic acid, in 0.125 mL of
	HFIP

  5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -83.0 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +.. Calcd for C 21 H 21 OF 3 346.1539; Found 346.1538 (-0.3 ppm).

			Br
	O	CF 3
		O	CF 3
	2.9.7. Preparation of secondary propargylic alcohols
	General procedure F for preparation of secondary propargylic alcohols. Secondary
	propargylic alcohols were prepared via two-step Kitazume/Sato sequence. 115 To a mixture of
	alkyne (10 mmol) and anhydrous THF (30 mL) at -78 o C was added n-BuLi (10 mmol, 2.5 M
	solution) for 5 min. After 20 min stirring at -78 o C, ethyl trifluoroacetate (10 mmol), boron

115

(a) T. Kitazume, T.

A. Sato, J. Fluorine Chem. 1985, 30, 189. (b)

L. Xiao, et al. Tetrahedron: Asymmetry 1997, 8, 3597.

  5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -80.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: for C 11 H 10 OF 3 [M+H] +. Calcd 215.0678; found 215.0678 (-0.0 ppm).

  5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -78.3 (s, 3F). HRMS (APPI + ): m/z for C 11 H 9 O 2 F 3 ([M] + ): calculated 230.0555; found 230.0551 (-1.7 ppm).

	OH
	CF 3
	OH
	CF 3
	OH
	CF 3
	MeO

116 S-J.

Ko. Tetrahedron: Asymmetry 2009, 20, 1109

  5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -80.0 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M+H] + Calcd for C 11 H 7 ONF 3 226.0480; Found 226.0475 (-2.3 ppm).

Characterization data for Friedel-Crafts reaction products of secondary propargylic alcohols

	5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): δ (ppm) -80.2 (s, 3F). HRMS (APPI + -
	Orbitrap) m/z: [M] +. Calcd for C 10 H 5 O 79 BrF 3 276.9470; found 276.9473 (0.8 ppm).
	2.9.8. Characterization of alkenes
	(Z)-2,2'-

  5 MHz, CDCl 3 , CF 3 CO 2 H -ext. st.): 3F). HRMS (ESI-Orbitrap) m/z: [M+H] + Calcd for C 29 H 32 O 7 F 3 549.2095; Found 549.2114 (3.6 ppm).

	δ (ppm) -68.2 (s,
			CF 3
		Br	H
		Ar Ar	OMe
		CF 3	Ar =
	MeO	H	MeO	OMe

  Owing to the stability of the carbon-oxygen bond in aliphatic alcohols, only a few examples of direct primary alcohol substitution have been reported in the literature. A common example of this type of reaction is the synthesis of diethyl ether from the dehydration of ethanol. The formation of diethyl ether from ethanol with sulfuric acid occurs at 130-140 °C and has been known for more than 150 years (Scheme 82).126 More recent industrial processes use catalytic amounts of metal salts such as Cs/Ge-Ɣ-Al 2 O 3 , Sn-Li-mordenite and Pt-Ɣ-Al 2 O 3 and require high temperatures (250-400 °C) and pressures(17-34 bar). 127

	Scheme 82: Diethyl ether synthesis from ethanol
	To the best of our knowledge, only two articles were published regarding the Friedel-Crafts
	alkylation of primary aliphatic alcohols. They both feature heterogeneous catalysis, using K10-
	montmorrillonite 128 and zeolite-Y 129 with benzene as the nucleophile and solvent (Scheme 83).

3.1.2. State of the art on direct alcohol substitution 126 A. W. Williamson, Phil. Mag. S. 1850, 37, 350. 127 C. Zhang, V. J. Johnston, Patent No. US 2014/0275636 A1. 128 O. Sieskind, P. Albrecht, Tetrahedron

Lett. 1993, 34, 1197. 129

A. R. A. S. Deshmukh, V. K. Gumaste, B. M. Bhawal, Catal.

Lett. 2000, 64, 247.

Ph to 3-Ph) 91% TfOH (10 mol%) OH Ar H Ar This work HFIP 368 371 357 369 370 372 373 374 368

  C

		Linear product
		(1-Ph)
		9%
	K10 Montmorillonite
	OH
	benzene, 80 °C, 16 h	Branched products
		(2-
		Linear product
		(1-Ph)
		9%
	Zeolite-Y (Re-Na-Y)
	OH
	benzene, 140 °C, 6 h	Branched products
		(2-Ph to 5-Ph)
		91%

Table 6 :

 6 Optimization studies for the alkylation of 1-tetradecanol with mesitylene

a All reactions were conducted in the presence of 5 equivalents of mesitylene in a sealed Pyrex® high pressure reaction tube.

Table 7 :

 7 Optimization studies for the alkylation of phenyl ethanol with mesitylene a All reactions were conducted in the presence of 5 equivalents of mesitylene in a sealed Pyrex® high pressure reaction tube.

; o, 33% Cl 411 p, 11% ; o, 36% p o Br 412 p,13% ; o, 45% p o 415 86% 414 62% Ar H (5 equiv) TfOH (10 mol%) HFIP (1 M), 140 °C, 16 h +

	Ar	OH		Ar	Ar
	403		407	408	409
	98%		82%	69%	68%
			F
		p	o
	410				413
	p, 25%				95%
				F	Cl
				416	417
				85%	93%
					Cl
	Br		I	MeO	Cl
	418		419	420	421
	98%		61%	82%	19%
	Cl
	Cl
	422
	39%

Schéma 5. Champ d'application pour la formation de chromènes.a temps de réaction de 24 h

F. L. Schadt, T. W. Bentley, P. v. R. Schleyer, J. Am.Chem. Soc. 1976, 98, 7667.

G. Hallett-Tapley, F. L. Cozens, N. P. Schepp, J.Phys. Org. Chem. 2009, 22, 343.

S. Ayata, A. Stefanova, S. Ernst, H. Baltruschat, J. Electro. Chem. 2013,

701,1. 7 D. Vuluga, J. Legros, B. Crousse, A. M. Z. Slawin, C. Laurence, P. Nicolet, D. Bonnet-Delpon, J.Org. Chem. 2011,

J. Ichikawa, H. Jyono, T. Kudo, M. Fujiwara, M. Yokota, Synthesis 2005, 39.

J. Ichikawa, M. Yokota, T, Kudo, S. Umezaki, Angew.Chem. Int. Ed. 2008, 47, 4870.

N. Suzuki, T. Fujita, J. Ichikawa, Org. Lett. 2015, 17, 4984.

J. E. Taylor, S. Estopiñá-Durán, Chem. Eur. J. 2020, DOI 10.1002/chem.202002106.

A. Bunrit, C. Dahlstrand, S. K. Olsson, P. Srifa, G. Huang, A.Orthaber, P. J. R. Sjöberg, S. Biswas, F. Himo, J. S. M. Samec, J. Am.Chem. Soc. 2015, 137, 4646.

M. Dryzhakov, M. Hellal, E. Wolf, F. C. Falk, J. Moran, J. Am.Chem. Soc. 2015, 137, 9555.

Remerciements

was prepared according to general procedure B from 1,1,1-trifluoro-4-phenyl-2-(o-tolulyl)but-3-yn-2-ol (91 mg, 0.31 mmol) and mesitylene (188 µL, 1.57 mmol, 5.0 equiv) with 5.1 mg (0.031 mmol) of FeCl 3 , in 0.63 mL of HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether) gave 118 mg (96% yield) of white solid. R f = 0.87 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.52 (d, J = 7.6 Hz, 2H), 7.46-7.33 (m, 3H), 7.33-7.23 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.00 (s, 2H), 6.91 (d, J = 7.8 Hz, 1H), 2.54 (s, 3H), 2.39 (s, 3H), 2.24 (s, 6H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 205.4 (q, J = 4.3 Hz), 137.8, 137.6, 136.9, 132.6, 132.3, 131.7, 130.7, 128.9, 128.8, 128.4, 128.3, 128.2, 128.0, 126.5, 123.8 (q, J = 274.6 Hz), 112.5, 101.5 (q, J = 34.5 Hz), 22.0, 21.2, 20.4. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) -58.2 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for C 26 H 23 F 3 392.1746; Found 392.1747 (0.2 ppm). -1-phenyl-3-toluyl-4,4,4-trifluoro-1,2-butadiene 244 was prepared according to general procedure B from 1,1,1-trifluoro-4-phenyl-2-(p-tolulyl)but-3-yn-2-ol (100 mg, 0.346 mmol) and mesitylene (241 µL, 1.73 mmol, 5.0 equiv) with 3.5 mg (0.022 mmol) of FeCl 3 , in 0.69 mL of HFIP. The reaction mixture was stirred at ambient temperature for 10 min. Purification by flash column chromatography over silica (petroleum ether) gave 122 mg (93% yield) of a colorless oil. R f = 0.93 (petroleum ether/EtOAc 9:1). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.43 (d, J = 8.0 Hz, 2H), 7.40-7.32 (m, 3H), 7.32-7.27 (m, 2H), 7.21 (d, J = 8.0, 2H), 7.00 (s, 2H), 2.39 (s, 3H), 2.37 (s, 3H), 2.23 (s, 6H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ (ppm) 204.8 (q, J = 3.8 Hz), 138.5, 138.0, 137.1, 133.4, 129.6, 129.1, 128.7, 128.5, 127.5, 127.1, 127.1, 126.7, 123.8 (q, J = 275.2 Hz), 113.9, 103.8 (q, J = 34.3 Hz), 21.3, 21.2, 20.4. 19 F NMR (376.5 MHz, CDCl 3 , CF 3 COOH-ext. st.): d (ppm) - 58.3 (s, 3F). HRMS (APPI + -Orbitrap) m/z: [M] +. Calcd for

1-Mesityl

Scheme 77: Kumada-Corriu cross-coupling reaction

More recently, several iron-catalyzed Kumada-Corriu reactions have been described (Scheme 78). 121 Among them, the group of Nakamura reported the use of a bulky bidentate phosphine ligand, 3,5-(t-Bu) 2 -SciOPP, for an efficient reaction (Scheme 78, eq. 1). 122 Previous methods required a large excess of ligand, such as TMEDA (tetramethylethylenediamine). The authors designed this ortho-phenylene-bisphosphine ligand with a peripheral steric bulk around the iron center such that the iron complex remains in a tetrahedral shape, which was believed to be the active form of the catalyst. In this way, it was possible to reduce the catalyst loading from 3 mol% to 0.5 mol%. Regarding the mechanism, the authors mentioned the plausible involvement of a radical intermediate as the reaction with iodomethylcyclopropane afforded the corresponding olefin under the standard conditions (Scheme 78, eq. 2), which might result from a radical ring-opening process. Int. Ed. 2014, 53, 1804;(b) M. Nakamura, K. Matsuo, S. Ito, E. Nakamura, J. Am. Chem. Soc. 2004, 126, 3686; (c) R. Martin, A. Fürstner, Angew. Chem. Int. Ed. 2004, 43, 3955;(d) The group of Stephan has also developed a method for accessing linear alkyl arenes from the alkylation of benzene with alkanes bearing trifluoromethyl group and subsequent hydrodefluorination (Scheme 80). 124 Regarding the mechanism, the reaction begins with the activation of the trifluoromethyl group by a fluorophosphonium cation to generate a difluoro carbocation, which undergoes a subsequent electrophilic aromatic substitution. Hydride reduction of the catalyst regenerates the catalyst, while hydrodefluorination at the benzylic position affords the linear alkyl-arene product. The proposed mechanism was further confirmed as mono-fluorinated alkyl fluoride provided a mixture of linear and branched products via a hydride migration from the carbocation intermediate. linear products. This selectivity has been attributed to a lack of stability of the branched products under the reaction conditions, rendering our method well-suited to isolate the linear products when compared to methods that furnish a mixture of linear and branched products.