Firstly I would like to sincerely thank Dr. Emmanuel Magnier, Dr. Julien Pytkowicz and Dr. Alejandro Perez-Luna for accepting to review my thesis and be part of my jury.

I am truly grateful to my PhD director, Prof. Janine Cossy for giving me the opportunity to work in this laboratory. Over the past three years, you have trusted me with this work, you have afforded me great freedom to explore the project, always offering useful advice and suggestions.

I would also want to thank Dr. Domingo Gomez-Pardo, for his support and his patience during these three years. Thank you for your guidance, your optimism and for always being available in case of a problem.

I would then like to thank the DGP team:

First the oldest member of the group: Gael! Thank you for being patient with me, for answering all my questions and of course for having shared your project with me.

Thomas! Thank you for welcoming me in the lab, for showing me around and for allowing me to work next to you for three years. Also thank you for being there for me, whenever I asked for your help either to correct my reports, be there when I used Br2 or just when I needed to talk. Lastly, thank you (or not) for kindly making fun of my accent (English and French), and for teaching me all these french expressions (which I have already forgotten).

Thank you Sarah, the only girl in the lab when I arrived. It has been a pleasure working with you, laughing with you and of course sharing numerous reagents (Tf2O, proton sponge, TMSCF3) for three years!! Zeina, thank you for always being in a good mood and for always finding the time to make new playlists. Also thank you for feeding me from time to time with all these chocolates you have in your drawer. Good luck for next year! Guillaume, the new arrival in our group! Although we worked together for only a year, it was a pleasure to have you as my "work neighbour". Thank you for all the discussions we had, for all the times I've complained to you (and there were a lot!!!!) and of course for all the (weird) french words you had to explain to me over the year.

Of course I could not forget "le petit Gregory"! His love for grapefruits and ducks, as well as his animated drawings, always made my day! Johan a "half-member" of the team, thank you for all your advice and suggestions and for the time you took to help me each time.

I should also thank all former members of the DGP group who I had the pleasure to meet: Qi, Alexandre, Simon et Thomas. I would also like to thank all the other members of the lab: First of all, the permanent members: Christophe thank you for all the chemistry-concerning conversations we had during these three years, which encouraged me (almost) every time. Stellios the only greek person in the lab apart from me, thank you for all the times you offered to help me. I also thank Veronique, who welcomed me in her lab during the first months of my PhD! Amandine thank you for always giving me good advice and of course for organizing all the conferences. Thomas, I think a thank you is not enough for the times you helped me with my NMR spectra and for always finding time to repair the GC/MS machine!! Andrei, thank you for your advice and for handling the solvent orders.

Thank you to "les Meyers": Ernouf for all the cat-concerning conversations, Boiss, for being in a good mood and of course Florence for all her delicacy and subtlety, being the only girl in this manly group! Also thank you Alexandre, Aziz and Khalil, the new members of the team.

Next I want to thank the group of Stellios: Morgan.. I really don't know whether to say thank you or not.. For your (black) humour, for all the mean things we said together (and laughed about them) and most importantly for all the times you made me say "iiiiiouuu"!!! Thank you, it was fun! I will not forget Marllon, one of THE most stylish people I have ever met, good luck for the future, and of course Tao who came from far way and has managed to integrate perfectly into the group. I would also like to thank les "Guérinots": Baptiste, THE most energetic person I have ever met.

Laurine, THE most effective person I have ever met, our conversations about trips and holidays were a nice break to our lab routine. Of course, Etienne thank you for the 1,5 years we had lunch together, for all our conversations and more importantly for saying ouuuiiiiii every time you saw me!! Thibault and Morgan, I am grateful for all the advice you gave me, It was so nice meeting you, Claire another cat owner in the lab good luck on your PhD.

Last but not least, I thank the "Bellosta" group: Julien for always being so calm and "zen" and for showing me around when I worked in his lab, Tatiana and Pierrik it was a pleasure to meet you both and hope you are doing well.

A special thank you to Isabelle, Hélène and Arthur for all the administrative and IT help. It would have been impossible to manage all this without you. I will not forget to thank all the former members of the lab, who I had the chance to meet: Simon, Erica, Paolo, Amandine, Laurent, Baba, Jérémy, Damien, Elodie, Romaine, Jean-Philippe, Cyril, Johan, Kévin, Nisha, Mélanie, Pierre-Antoine et Parth. I hope I didn't forget anyone.

Thank you to all my friends in Paris: Sabrina, Fabiana, I had the pleasure to meet you during the M2 and I am grateful for all the moments we spent together. Alexis, Cédric, Simon and Brendan. I will miss our "apero" listening kiss.gr that did me good for these three years. Guillaume, Adrien, Ali, Florian, Sonia, Christian, Doriane, Paul, Lucie, Céline, Sébastien, Paulin, Marlène and Paul, thank you for all the ''soirées'' we had, all the birthdays we celebrated and for all the good times he had!!

The biggest thank you should go to Guillaume, who had the courage and the patience to put up with me, during three years and especially these last months. Thank you for believing in me even when I didn't.

I should also thank my friends in Greece. Antigoni, Nora, Alexandra, Mairi, Eleni, Georgia and JP, we did not see each other often during these years but I always consider you my best friends.

Last but not least, I would like to thank my family: especially my parents and my sister who always supported me in what I did even from far away. Thank you for giving me the chance to come to Paris and do my PhD, for encouraging me and of course for always asking questions and trying to understand what I do.

Table of Contents

Résumé

Ce manuscrit est divisé en trois chapitres.

Le premier chapitre présente l'intérêt du fluor en chimie médicinale. Son influence sur les propriétés chimiques et physico-chimiques des molécules sera discutée.

Le deuxième chapitre présente la réaction de contraction de cycle de (trifluorométhyl)pipéridines ainsi que de (trifluorométhyl)azépanes via un intermédiaire aziridinium, afin d'obtenir des Une autre propriété qui dérive de l'électronégativité élevée du fluor, est que ses trois paires

Schéma 5

La pipéridine 3 a été facilement obtenue à partir de la N-Boc-pipéridin-3-one 1. Lorsque la pipéridinone 1 a été soumise à une réaction de trifluorométhylation en présence du réactif de Ruppert-Prakash (TMSCF3), la (trifluorométhyl)pipéridine 2 a été obtenue avec 77% de rendement.

La déprotection de l'amine de 2 en présence d'acide triflluoroacétique (TFA), suivie de la protection par un groupement benzyle (BnBr, K2CO3, TBAI) a permis la formation de la N-benzyl-3-hydroxy-3-(trifluorométhyl)pipéridine 3 avec un rendement quantitatif pour les 2 étapes (Schéma 6). Signalons que le remplacement du groupement Boc par un groupement benzyle est nécessaire pour permettre, grâce à l'assistance anchimérique de l'azote, la formation de l'aziridinium intermédiaire B1 après activation de l'alcool tertiaire.

Schéma 6

Afin d'étudier si la formation de l'aziridinium ainsi que la contraction de la pipéridine 3 était possible, la réactivité de la pipéridine 3 a d'abord été examinée avec du chlorure de thionyle (SOCl2) dans du CH2Cl2 en présence d'un excès de triéthylamine (Et3N). Cependant, dans ces conditions, le produit désiré 4a n'a pas été obtenu (Tableau 2, entrée 1). La pipéridine 3 a ensuite été mise en réaction avec de la Et3N (4.0 équiv) et du chlorure de méthane sulfonyle (MsCl) (3.1 équiv), et dans ces nouvelles conditions, la pyrrolidine chlorée 4a a été isolée avec néanmoins un rendement faible de 7% et une conversion de 10% de 3 (Tableau 2, entrée 2). Etant donné la faible réactivité de l'alcool tertiaire du composé 3, cet alcool a été activé par un mélange de triphénylphosphine et de diiode en présence d'imidazole. Le composé souhaité 4b a été isolé avec un rendement de 25% pour une conversion totale de 3 (Tableau 2, entrée 3). Suite à ce résultat, le composé 3 a été traité par un réactif électrophile plus puissant, à savoir le trifluorure de diéthylaminosuflure (DAST). Le produit fluoré de contraction de cycle 4c a été obtenu avec un rendement de 71% (Tableau 2, entrée 4). Après avoir vérifié que la contraction de cycle de la (trifluorométhyl)pipéridine 3 était possible, il nous restait à trouver un mode d'activation de 3 compatible avec l'utilisation d'autres nucléophiles comme des amines, des alcools et dérivés, ainsi que des nucléophiles carbonés. Pour cela, la pipéridine 3 a été traitée par de l'anhydride triflique (Tf2O) en présence de l'éponge à proton D au reflux de CH2Cl2.

Après 5 h de réaction, de la benzylamine a été ajoutée au milieu réactionnel et dans ces conditions, la pyrrolidine désirée 4d a été isolée avec un rendement de 75% (Tableau 2, entrée 5). L'obtention de la pyrrolidine 4d en fin de réaction, peut s'expliquer par la formation successive des intermédiaires 5 et 6. Lorsque la pipéridine 3 est traitée par le Tf2O, le triflate 5 formé est déplacé par l'atome d'azote de la pipéridine 5, grâce à une assistance anchimérique et provoque la formation de l'aziridinium intermédiaire 6. Le nucléophile ajouté dans le milieu peut alors attaquer régiosélectivement cet aziridinium 6 en position C2' pour conduire à la pyrrolidine 4e (Schéma 7).

Signalons que le rôle de l'éponge à proton D est de piéger les protons présents dans le milieu réactionnel, afin que le doublet de l'azote reste disponible pour réaliser une attaque nucléophile intramoléculaire et transformer l'intermédiaire 5 en aziridinium 6.

Schéma 7

Après avoir établi les conditions optimales pour la contraction de cycle de la pipéridine 3, d'autres nucléophiles ont été impliqués dans la réaction afin d'établir le champ d'application de cette réaction de contraction de cycle. Lorsque l'aniline a été utilisée comme nucléophile, la pyrrolidine 7 a été obtenue avec 71% de rendement. L'utilisation des amines secondaires telles que la N-méthylaniline, la diéthylamine, la diallylamine, la dibenzylamine et la morpholine, ont permis d'isoler les pyrrolidines correspondantes 812 avec des rendements compris entre 60% et 83% (Schéma 8).

Schéma 8

Suite à ces résultats, l'utilisation de nucléophiles oxygénés a été envisagée. Lorsque des alcools et des alcoolates ont été utilisés, les produits de contraction de cycle 1319 ont été isolés avec des rendements moyens à bons (51%77%). Soulignons que l'eau peut être également utilisée comme nucléophile, pour conduire à la pyrrolidine 17 avec 61% de rendement. De plus, le phénolate de sodium ainsi que l'acétate de tétrabutylammonium permettent aussi la formation des produits de contraction de cycle 18 (75%) et 19 (72%) (Schéma 9).

Schéma 9

Des nucléophiles soufrés, sous forme de thiols ou de thiolates, peuvent également être engagés dans cette réaction de contraction et les pyrrolidines 2022 ont été obtenues avec des bons rendements.

De plus, lorsque la pipéridine 3 a été traitée par de l'anhydride triflique, en présence de l'éponge à proton D, suivi par l'addition du fluorure ou chlorure de tétrabutylammonium, les pyrrolidines 23 et 24 ont été isolées avec des rendements de 30% et 49% respectivement. Enfin, l'addition des nucléophiles carbonés est possible. Lorsqu'un cyanure ou l'anion du malonate de méthyle ont été utilisés comme nucléophiles, les pyrrolidines 25 et 26 ont été isolées avec des bons rendements (Schéma 10).

Schéma 10

Après avoir étudié le champ d'application de la contraction de cycle de la pipéridine 3 avec divers nucléophiles, nous avons voulu déterminer si au cours de cette réaction, un transfert de chiralité était possible. Pour cela, les deux énantiomères de 3 ont été séparés par SFC (Supercritical Fluid Chromatography) et ils ont ensuite été traités par de l'anhydride triflique en présence de l'éponge à proton D. Après 5 h au reflux du CH2Cl2, du méthanol a été ajouté au milieu réactionnel. Les composés (+)-13 et ()-13 ont été obtenus avec des pouvoirs rotatoires opposés, indiquant un transfert de chiralité pendant la contraction de cycle. Cependant, la détermination des excès énantiomériques de (+)-13 et ()-13 n'a pas été possible, une autre méthode a donc dû être mise au point pour vérifier ce transfert de chiralité.

Schéma 11

Ainsi, dans un premier temps, la pipéridine 3 a été traitée par de l'anhydride triflique, en présence de l'éponge à proton D, suivi par l'addition d'une amine chirale comme nucléophile, la (S)-α-méthylbenzylamine. Dans ce cas, la pyrrolidine 27 a été obtenue sous la forme d'un mélange de diastéréoisomères dans un rapport 1:1 (Schéma 12).

Schéma 12

Chacun des deux énantiomères de 3 a été traité dans les mêmes conditions (Tf2O/éponge à proton D/(S)-α-méthylbenzylamine) pour conduire cette fois-ci aux pyrrolidines 27a et 27b avec une diastéréosélectivité supérieure à 95>5 pour chaque composé (Schéma 13). Ce résultat, confirme que la contraction de cycle de pipéridines en pyrrolidines procède via un transfert total de chiralité.

Schéma 13

Afin de connaitre l'influence du groupement CF3 sur le processus de contraction de cycle, la pipéridine

Schéma 30

La réactivité des alcynes terminaux substitués par des groupements alkyles a été également étudiée.

Les pyridazines 8991, possédant des groupements alkyles en position C3, ont été obtenues avec des rendements plus modestes de 20%39% comparés à ceux obtenus avec des alcynes substitués par des groupements aryles (Schéma 31).

Schéma 31

Des alcynes terminaux substitués par des chaînes alkyles portant une fonction amine protégée ont ensuite été engagés dans la séquence de cycloadditions

General Introduction

Our quality of life is closely linked to the discovery of new drugs and biologically active molecules.

Among others, heterocycles represent an important family for the pharmaceutical and agrochemical industry, with 70% of pharmaceuticals and agrochemicals containing a heterocyclic motif. 1 Indeed, the insertion of such motif in a drug candidate can not only influence its physico-chemical properties but can also act as a bioisoster of other heterocycles.

However, the development of such bioactive molecules, which have no secondary effects for humans is often complicated. In order to modulate the physico-chemical and pharmacokinetical properties of a compound, medicinal chemists have turned their attention to the introduction of one or more fluorine atoms. This modification allows the improvement of a variety of properties such as a molecules lipophilicity, selectivity or bioavailability.

Consequently, the research for novel synthetic methods, which would allow access to fluorinated heterocycles, is imperative. Our work is focused on this purpose.

This manuscript is divided in three chapters.

The first chapter deals with fluorine in medicinal chemistry. The influence of fluorine on molecules chemical and physico-chemical properties will be discussed.

The second chapter is devoted to the ring contraction of (trifluoromethyl)piperidines and Bibliographic data concerning the chemistry of α-(trifluoromethyl)pyridazines will be presented.

The molecules, figures, schemes and tables will be numbered according to their order of apparition in the manuscript. For the presentation of bibliographic data, the number of each molecule will be proceeded by L2 (for chapter 2) and L3 (for chapter 3). For the presentation of our results, the molecules will be numbered starting from 1 for each chapter.

CHAPTER 1

Fluorine in medicinal chemistry

Introduction

Since the isolation of fluorine in 1886 by Henri Moissan, who was awarded the Nobel Prize in 1906, fluorinated compounds have opened new opportunities due to their interesting properties. Indeed, before 1950, the idea that the incorporation of a fluorine atom in a natural compound could have a beneficial effect on its biological properties was inconceivable, especially given that the first fluorinated natural product was toxic (Figure 1). 2

Figure 1

However, since 1955 and after the approval of the first fluorine-containing drug, around 150 fluorinated molecules have reached the market. Indeed, to date around 25% of all marketed drugs contain a fluorine atom. 3 2. Fluorine properties and its influence on the chemical and physico-chemical properties of molecules

CF bond generalities

Fluorine is a small atom with a Van der Waals radius close to the Van der Waals radius of oxygen (Table 1). 4 It is the most electronegative element in the periodic table, and as a result, the CF bond is highly polarized, with the fluorine atom bearing the partial negative charge and the carbon atom bearing the partial positive charge. 4,5 Due to the attraction between these two charges, the CF bond has a less covalent and a more significant ionic character, it is very short and very strong (105 kcal/mol).

Atom (A) H F O N C Cl Br
Van der Waals radius (Å) 1.20 Another consequence of the high electronegativity of the fluorine atom, is that its three lone pairs are strongly attracted by the nucleus, making this atom inert and unreactive. The high polarization of the CF bond, can also result in a low-energy σ* antibonding orbital, located behind the carbon atom in the plane of the CF bond (Figure 2). This orbital, can accept the electrons of a nearby electron-donating group such as a σ bond or a lone pair. 4,5 The importance of these orbitals will be discussed in Section 2.5.

Figure 2

Even if the replacement of a CH or a COH by a CF bond does not influence the size of the molecule, it can surely induce modifications in properties such as the pKa, the lipophilicity or the conformation of a molecule.

Influence of a fluorine atom on the pKa

Due to the high electronegativity of the fluorine atom, the modulation of the pKa of proximal functional groups can be achieved, depending on the number of fluorine atoms, as well as their position in the molecule. For example, the replacement of a hydrogen atom by one fluorine atom in acetic acid, can lead to a decrease of the pKa by 2.2 units, while the replacement of three hydrogens by three fluorine atoms, can induce a decrease of 4.6 units (Figure 3). 6

Figure 3

Similarly, the basicity of ethylamine decreases linearly due to the presence of one, two and three fluorine atoms (Figure 4). The lipophilicity of the drugs is normally measured as the logarithmic partition coefficient (log P)

between n-octanol and water, the higher the log P is, the higher is the lipophilicity of the compound. 8 When a fluorine atom is proximal to an amino group, the amine is less protonated and exists mostly in its neutral form, due to the decreased basicity of the amino group, caused by the presence of fluorine. This implies that the concentration of the compound is increased in octanol. Therefore by increasing the log P, the lipophilicity of the fluorinated compound is also increased compared to the non-fluorinated one. 9

Influence of a fluorine atom on the metabolic stability and bioavailability of molecules

A recurring problem in medicinal chemistry, is the oxidation and the metabolism of a drug prior to its elimination, by enzymes such as cytochrome P450 monooxygenases. In order to prevent this oxidation, the metabolically labile sites can be blocked with a fluorine substituent. 8 Due to the strength of the CF bond and its oxidative stability, this bond is highly stable towards chemical and metabolic transformations.

An example of the influence of fluorine on drugs metabolic stability, is illustrated in Figure 5. Blockage of the metabolically labile sites of SCH-48461 by the incorporation of a fluorine atom, can prevent the oxidation of the phenyl ring and the dealkylation of the methoxy group, leading to the discovery of the cholesterol-absorption inhibitor ezetimibe, which is 400 times more potent than SCH-48461. 7 Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 83158359. 8 Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320330. 9 Reddy, V. P. in Organofluorine Compounds in Biology and Medicine, Elsevier: Oxford, UK, 2015.

Figure 5

In addition, by modulating the lipophilicity and the metabolic stability of a drug, one can influence its absorption as well as its distribution. Indeed, due to the fact that the enzymes active site has a low polarity, the more lipophilic the drug candidate is, the higher its effective concentration is in the active site. As a result, smaller doses are required for an optimal efficacy. 9

Influence of a fluorine atom on molecular conformation

Due to its small size and high electronegativity, a fluorine atom plays an important role on the conformation of a molecule. Indeed, the CF bond can not only interact with its environment through electrostatic (dipole-dipole and charge-dipole) interactions, but due to its low-energy CF σ* antibonding orbital, it can also participate in a hyperconjugation effect. However, given its high electronegativity, which holds strongly its three lone pairs, fluorine is only a poor donor and hydrogen bonding acceptor unlike oxygen or nitrogen. The participation of fluorine in such interactions (dipoledipole, charge-dipole, hyperconjugation) might contribute to an enhanced affinity of fluorinecontaining compounds with an enzyme active site.

A) Dipole-dipole interactions

The ionic nature of the CF bond, confers to this bond a high dipolar moment, which is responsible for any electrostatic interactions. For example, Müller et al. studied the spatial conformation of fluorine containing drugs in their protein targets, and proved the existence of an interaction between the fluorine atom and the amide carbon of the protein receptor as it is shown in Figure 6a. 6,[START_REF] Müller | [END_REF] Another example indicating the influence of fluorine on the conformation of a molecule is illustrated in Figure 6b, where in α-fluorocarbonyls, the CF bond is aligned antiparallel to the C=O bond, with the CF dipole opposed to the carbonyl dipole. It is worth mentioning, that this effect decreases with the decrease of the dipole moment of the carbonyl group. 5 Furthermore, these interactions were also observed in the case of the 2-fluoroethylammonium and the protonated 2-fluoroethanol, where the gauche conformation is privileged (Figure 8). This enhanced gauche effect, can be attributed to the increased polarization of the CN + or the CO + bond due to the nitrogen or the oxygen positive charge, and to an interaction between the partially negative fluorine atom and the formally positively-charged nitrogen or oxygen atom. 12 It is worth mentioning, that intramolecular F-H interactions probably contribute to this stability, although the magnitude of this contribution is not clear. The gauche conformation is also preferred when X is a pyridine, even though the system cannot accommodate hydrogen bonding. 13 The fact that the gauche conformation is favored even when hydrogen bonding is not possible, proves that charge-dipole interaction is more important than any hydrogen bonding. The hyperconjugation effect, which is observed in the case of fluorine-containing molecules, is closely related to its low-energy σ* antibonding orbital. For example, for 1,2-difluoroethane there are two possible conformers (gauche and anti) (Figure 9). 4,5 Although one might predict that the anti conformation is privileged due to the repulsion of the two fluorine atoms, surprisingly, it is the gauche conformation that is favored. Indeed, in the gauche conformer, the two σ*CF orbitals receive electrons in the form of electron rich bonds (CH bond), thus stabilizing the conformation, whereas in the anti conformation, each σ*CF orbital is aligned with an adjacent electron-deficient CF bond.

As a result in the case of the anti conformation, the hyperconjugation cannot occur.

3. Biologically active CF 3 -containing molecules Among a variety of fluorinated groups, the trifluoromethyl group has received much attention over the last decades. 7,14 In 1928, Lehmann was the first to report that compounds containing a trifluoromethyl group, have interesting biological activities. More specifically, he found that m-nitrobenzotrifluoride and m-trifluoromethylbenzoic acid, were potent stimulants and that m-aminobenzotrifluoride had a narcotic effect, the three of them affecting the central nervous system of frogs (Figure 10). It was not until the 1950's that the trifluoromethyl group was widely recognized as a substituent of distinctive properties. 16 In 1987, the antidepressant fluoxetine, more commonly known as Prozac®, was approved by the Food and Drug Administration (FDA) and became the most prescribed antidepressant drug worldwide (Figure 11). 8

Figure 11

Since then, a large number of trifluoromethylated drugs were approved by the FDA, some of them being in the top 200 of the most successful drugs on the market and each of them treating a different type of disease. For example efavirenz, sold under the name Sustiva® and Stocrin®, is used to treat and prevent HIV/AIDS and sitagliptin, marketed under the trade name Januvia® is an antihyperglycemic drug. Other examples include celecoxib, an anti-inflammatory drug, nilotinib used for the treatment of chronic myelogenous leukemia, and siponimod which is an investigational drug used to treat multiple sclerosis (Figure 12). 17 Therefore, the introduction of fluorine-containing groups into bioactive molecules, resulted in a positive effect for the compounds, such as rendering them more selective or potent. Indeed, the trifluoromethyl group can be used as a bioisoster for an ethyl group, an isopropyl group or even a carbonyl. [START_REF] Müller | [END_REF]18 For instance, in an inhibitor of cathepsin K I, a trifluoroethylamino group was introduced as an amide isoster (Figure 13). 19 It is worth mentioning, that cathepsin K (CTSK) is a lysosomal cysteine protease which might be the enzyme responsible for the degradation of type I collagen. Therefore, CTSK inhibitor I might be effective for the treatment of osteoporosis. Replacement, of the C=O bond by a CCF3 bond, led to a more potent and more selective inhibitor II towards cathepsin K, without influencing the basicity of the amide. 18 Hangmann, W. K. J. Med. Chem. 2008, 51, 43594369. 19

Figure 13

Another example demonstrating the importance of the trifluoromethyl group, is illustrated in Figure 14. Piperidine III is an antagonist of the gonadotropin releasing hormone (GnRH), which is a peptide released by the hypothalamus. GnRH can activate its own receptor, that causes the release of luteinizing hormone, therefore regulating gonadal steroid hormone production. As a result, GnRH is implicated in several hormone diseases such as prostate cancer, and its suppression by an inhibitor is the key for the treatment of these disorders. By introducing a CF3 group at the α position of the piperidine and in spite of a small reduction of the inhibition, piperidine IV showed an increased oral bioavailability in dogs. 20 Figure 14

Thus, the introduction of a CF3 group into biologically active molecules, can have a significant impact on drug development due to the fluorine impact on chemical and physico-chemical properties. Given that for a large number of biologically active molecules, a CF3 group is present on saturated or unsaturated heterocycles, we have focused on the development of synthetic methods to obtain trifluoromethylated heterocycles.

1. Generalities, Biological activity and synthesis of pyrrolidines and piperidines

Generalities

Pyrrolidines and piperidines belong to the family of cyclic secondary amines and can also be classified as saturated heterocycles. Pyrrolidines are 5-membered rings containing one nitrogen atom, and piperidines are 6-membered rings also containing one nitrogen atom (Figure 15).

Figure 15

Both heterocycles can be found in numerous natural and non-natural compounds, presenting a diversity of biological activities, with both of them being in the top 10 of the most frequently used ring systems in FDA approved small molecule drugs. 21 As an evidence of their importance it may be noted that by the end of the year 2000, there were over 12.000 compounds possessing a piperidine or a pyrrolidine core, mentioned in clinical or preclinical studies. 22 Due to the interesting properties induced by a fluorine atom or by a CF3 group, we became interested in the synthesis of pyrrolidines and piperidines containing a CF3 group at the C2 position.

Biological activity of 2-substituted, 2-(trifluoromethyl) pyrrolidines

As already mentioned, pyrrolidine alkaloids are enormously ubiquitous in a variety of natural and non-natural compounds. There are around 80 pyrrolidine alkaloids known, which are mainly extracted from plants belonging to the Colanaceae, Convolvulaceae and Erythroxylaceae families.

In 1889, Carl Liebermann was one of the first to isolate one of the most simple pyrrolidine alkaloids, hygrine, along with a related compound called cuscohygrine, both found in coca leaves (Figure 16). 23 21

Figure 16

Other simple and well-known pyrrolidine alkaloids, are the amino acids proline and hydroxyproline, both isolated in 1901 by Hermann Emil Louis Fischer from casein (Figure 17). [START_REF] Plimmer | Monographs on biochemistry; The chemical constitution of the proteins, Part I. Analysis[END_REF] One of the simplest alkaloids, proline, can be used as a precursor for the synthesis of more complex alkaloids. [START_REF] Bhat | [END_REF]

Figure 17

Since then, a large number of natural products and drugs containing a pyrrolidine ring has been discovered, all of them endowed with a variety of biological activities and pharmacological behaviors and some of them are illustrated in Figure 18. 26 For example, kaitocephalin 27 is a glutamate receptor antagonist, that may be useful for the treatment of neurological disorders such as Alzheimer's disease. Radicamine A, 28 which was isolated from a plant mainly found in China, Korea and Japan, presents a potential inhibitory activity against α-glucosidases, closely linked to diabetes. In addition, spirotryptostatin A, 29 isolated from the Aspergillus fumigatus fungus, is a potent anti-cancer drug due to its anti-mitotic properties. Other examples, include marketed drugs such as captopril (hypertension treatment), which was later replaced by enalapril due to its undesired side-effects, and ramipril which is used for the treatment of high blood pressure and congestive heart failure. [START_REF] Plimmer | Monographs on biochemistry; The chemical constitution of the proteins, Part I. Analysis[END_REF]

Figure 18

Given the great abundance of pyrrolidines in natural alkaloids as well as pharmaceuticals, their trifluoromethylated analogues represent potential biologically interesting compounds.

Fluoroquinolones have been used as antibacterial agents in antiinfective chemotherapy. However, their frequent clinical use has rendered them ineffective towards the quinolone and methicillin-resistant Staphylococcus aureus. It has been reported that the introduction of a CF3 group onto the pyrrolidine A, increases their potency towards Staphylococcus aureus, while maintaining low side effects (Figure 19). 30

Figure 19

Another example that demonstrates the influence of the CF3 group on the biological profile of a pyrrolidinic compound, is illustrated in Figure 20. MIF-1, a melanocyte-stimulating hormone release 30 The piperidine ring is an important structural feature, present in many natural products and pharmaceuticals. Their structure can vary from very simple alkaloids to more complicated ones. One of the simplest piperidine-containing natural products, is the poisonous alkaloid coniine isolated from the poison Hemlock (Conium maculatum), along with ()--conhydrine. They both cause muscular paralysis leading to death (Figure 21). 32

Figure 21

Other piperidine alkaloids, include (-)-allosedamine and lobeline, both isolated from Lobelia inflata (also known as Indian tobacco). The first one is used for the treatment of respiratory illnesses such asthma, bronchitis and pneumonia, 33 and the second one has been used as a substitution therapy for tobacco smoking cessation and is reported to have many nicotine-like effects, including 31 cardiovascular and central nervous effects. 34 A third example includes micropine, 35 isolated from Microcos philippinensis, a plant whose ethanol extracts show antimicrobial activity (Figure 22).

As far as pharmaceutically active piperidine-containing molecules are concerned, among others we can cite naratriptan, which is a triptan drug marketed by GlaxoSmithKline and is used for the treatment of migraine headaches. Ritalin, also called methylphenidate, is a drug owned by Novartis and used for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. We can also cite miglitol, an oral anti-diabetic drug, that inhibits the ability of the patient to break down complex carbohydrates into glucose (Figure 22). 36

Figure 22

Taking into account the importance of the presence of a piperidine ring in biologically active compounds, whether it is natural alkaloids or pharmaceutical drugs, it is logical, that their trifluoromethylated analogues were also studied.

Indeed, some examples of biologically active piperidines containing a CF3 group have been reported.

For instance, mTORC1 is a protein complex that controls protein synthesis and therefore the mTORC1 inhibitor, containing a α-(trifluoromethyl)piperidine, can modulate the cellular proliferation (Figure 23). 37 34 Wieland, H. Ber. Dtsch. Chem. Ges. 1921, 54, 17841788. 35 α-Trifluoromethylated piperidines can also have an inhibitory effect towards Janus kinases 1 (JAK 1) and 2 (JAK 2), which are implicated in the proliferation and survival of the cells. As a result, these inhibitors, could eventually be used for the treatment of asthma, cancer or even rheumatoid arthritis (Figure 24). 38 Recently, a review was published by our laboratory, presenting the synthetic methods used to access substituted α-(trifluoromethyl)piperidines. 39 These methods were also applied to the synthesis of substituted α-(trifluoromethyl)pyrrolidines. Therefore, we will first summarize these methods which can be found in the recently-published review and we will then present in detail the synthetic methods reported to access only 2-substituted, 2-(trifluoromethyl)pyrrolidines. The most common method to access 2-substituted, 2-(trifluoromethyl)piperidines B is from (trifluoromethyl)imines C. Nenajdenko et al. showed that these imines, which could be formed from the corresponding lactams, reacted with a variety of nucleophiles to afford the desired (trifluoromethyl)piperidines B. 40 Alternatively, piperidines B, could be accessed from imines D. Indeed, imines D, which were obtained from the corresponding lactams, could react with the 39 The majority of the synthetic routes mentioned above, have been used to access 2-substituted, 2-(trifluoromethyl)pyrrolidines L. Therefore treatment of (trifluoromethyl)imines M with different nucleophiles, 40 or treatment of imines N with TMSCF3, 41a,49 led to a variety of functionalized pyrrolidines L. Moreover, the electrophilic-induced cyclization of aminoalkynes O was successfully applied to the synthesis of (trifluoromethyl)pyrrolidines L in the presence of a silver salt. 42 The regioselective ring-opening of aziridines P, followed by a ring-closure, also allowed the formation of pyrrolidines L. 43 Similarly, the optically pure aziridine Q, could be opened in the presence of the dimethyl malonate anion, to afford a ring-opening product which after an intramolecular nucleophilic

Scheme 6

The removal of the chiral auxiliary of (R,S)-L2.20 and (R,R)-L2.20 after hydrogenolysis, afforded the (trifluoromethyl)prolines (S)-L2.21 and (R)-L2.21. After treatment of (S)-L2.21 with LAH, α-(trifluoromethyl)prolinol (S)-L2.22 was isolated in 84% yield (Scheme 7). 53 53

Scheme 7

Alternatively, when the diastereomeric mixture of L2.19a and L2.19b was oxidized by the Jones reagent, a cyclization took place to afford the bicyclic lactams (R,S)-L2.23 and (R,R)-L2.23 in 61% and 20% yield respectively, conveniently separated by silica gel chromatography. After saponification of the lactone of (R,S)-L2.23 and (R,R)-L2.23 with LiOH and cleavage of the benzylic bond using Li/NH3, α-(trifluoromethyl)pyroglutamic acids (S)-L2.24 and (R)-L2.24 were isolated in 49% and 69% yield respectively (Scheme 8). 54

Scheme 8

Brigaud et al. reported an alternative pathway to access α-(trifluoromethyl)proline derivatives by an iodocyclization of the morpholinone mixture L2.18 induced by I2. After the dehydroiodination of L2.25, compounds (R,S)-L2.26 and (R,R)-L2.26 were obtained. At this stage (R,S)-L2.26 and (R,R)-L2.26 were easily separated by silica gel chromatography (Scheme 9). 55 54 Chaume, G.; Van Severen M. -C.; Ricard, L.; Brigaud, T. J. Fluorine Chem. 2008, 129, 11041109. 55

Scheme 9

Dihydroxylation of (R,S)-L2.26 and (R,R)-L2.26 followed by cleavage of the chiral auxiliary, led to α-(trifluoromethyl)dihydroxyprolines (S)-L2.27 and (R)-L2.27 in 68% and 73% yield respectively (Scheme 10). The dihydroxylation afforded the two compounds with complete diastereoselectivity in favour of the compounds possessing the two hydroxyl groups in a trans relationship with the CF3 group, indicating that the CF3 moiety directs the dihydroxylation and not the chiral auxiliary. 55

Scheme 10

In 2013, Zhang et al. reported an alternative synthetic route to access (trifluoromethyl)proline (R)-L2.21 by the enantioselective alkynylation of imine L2.28 catalyzed by the complex zinc/ligand L*.

The obtained acetylenic compound L2.29 was hydrogenated (H2, Pd/C), and the TBS group was then cleaved, to afford L2.30. This compound was cyclized after treatment with mesyl chloride, to give the protected (R)-proline L2.31. Deprotection of the amine led to the (trifluoromethyl)proline (R)-L2.21 in 66% yield (Scheme 11). 56 56 Huang, G.; Yin, Z.; Zhang, X. Chem. Eur. J. 2013, 19, 1199211998.

Scheme 11

In 2013 Osipov et al. reported the intramolecular cyclization of homopropargylamines L2.32a and L2.32b, to access the α-CF3-dehydroproline derivatives L2.34a and L2.34b. 57 When the N-Boc-protected homopropargylamines L2.32a were treated with TFA, a mixture of the deprotected compound L2.33a and the cyclized product L2.34a was obtained, which after treatment with the silver salt Ag(OTf), gave the dehydroprolines L2.34a, possessing a quaternary center at the C2 substituted by an ester and a CF3 group (Scheme 12, eq 1). However, when the N-Cbz-protected propargylamino-phosphonates L2.32b, were treated with a mixture of TFA/TsOH, the deprotected amines L2.33b were not observed. In this case, a spontaneous cyclization took place, to afford dehydroprolines L2.34b, while the addition of a silver salt was not necessary. This reaction therefore represents the first example of an intramolecular cyclization of amines containing a propargyl group without the use of a metal as an activator (Scheme 12, eq 2).

Scheme 12 57 Zotova, M. A.; Vasil'eva, T. P.; Osipov, S. N. Russ. Chem. Bull., Int. Ed. 2013, 62, 792796.

Scheme 15

It is worth mentioning that examples of ring contractions are scarce in the literature. 60 Before we start discussing our results, we will briefly present the regioselective ring-opening of the 2-(trifluoromethyl)aziridirines via the formation of an aziridinium intermediate. This regioselective attack can be induced due to the presence of the CF3 group on the aziridinium.

Regioselective ring-opening of 2-(trifluoromethyl) aziridinium intermediates

The regioselective ring-opening of 2-(trifluoromethyl)aziridines IV, has been the subject of many publications. However, (trifluoromethyl)aziridines whose nitrogen is substituted by an alkyl group, are unreactive towards nucleophilic attack, therefore their prior activation is necessary. Here, we will Interestingly, when aziridine L2.50 was treated with PhSH, without the presence of a strong acid, the ring-opening product L2.52 was isolated in a lower yield of 40%, along with 50% recovery of L2.50.

report
Another interesting point, is that nitrogen-containing nucleophiles, could not promote the ring-opening of aziridines, due to the nitrogen protonation under these acidic conditions.

Scheme 19

The regioselective ring-opening of other enantiopure aziridines was studied. For example, when the optically pure trans-aziridine L2.53 was activated by trifluoroacetic acid, the aziridinium intermediate L2.54 was formed. The regioselective and stereoselective attack of the counter-ion on the aziridinium L2.54 at the C3 position, allowed the ring-opening and therefore the access to the anti-(trifluoromethyl)amine L2.55 (Scheme 20). 64 63 Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.; Uneyama, K. J. Org. Chem. 1999, 64, 73237329. 64 Davoli, P.; Forni, A.; Franciosi, C.; Moretti, I.; Prati, F. Tetrahedron: Assymetry 1999, 10, 23612371.

Scheme 20

Furthermore, (trifluoromethyl)aziridines L2.56 can be either activated by a strong acid (HCl or CF3CO2H) to form the aziridinium salt L2.57a, where the resulting counter-ion can then serve as a nucleophile, or activated by CF3SO2H to form the aziridinium L2.57b which can then be attacked by an external nucleophile. In both cases, the corresponding amines L2.58 were obtained in moderate to excellent yields. The authors highlighted that the attack took place at the C3 position, indicating that the presence of the CF3 group and not the presence of the ester group, is responsible for the regioselective and diastereoselective ring-opening of the aziridinium (Scheme 21). 65

Scheme 21

In 2014, De Kimpe and D'hooghe reported the acid-promoted regio-and stereoselective ring-opening of cisand trans-(trifluoromethyl)aziridines L2.59a and L2.59b, to afford a range of α-(trifluoromethyl)amines L2.61a and L2.61b via the corresponding aziridinium intermediates L2.60a and L2.60b. After the activation of the aziridines L2.59a and L2.59b with sulfuric acid, and after treatment with water and methanol, the regioselective ring-opening of the aziridiniums L2.60a and L3.60b took place (Scheme 22). 66 The synand anti-products were obtained in good to excellent yields from the cisand trans-aziridines respectively. 65 Crousse, B.; Narizuka, S.; Bonnet-Delpon, D.; Bégué, J. -P. Synlett 2001, 679681. 66 Moens, M.; De Kimpe, N.; D'hooghe, M. J. Org. Chem. 2014, 79, 55585568.

Scheme 22

It is worth mentioning that when bromic acid was utilized, the activation of aziridines L2.59a and L2.59b occurred by HBr itself, and the ring-opened products L2.63a and L2.63b, were obtained in good yields without the addition of sulfuric acid, after the attack of the bromine anion to the C3 position of the aziridinium L2.62a and L2.62b (Scheme 23).

Scheme 23

Interestingly, when the enantiopure aziridine L2.64, substituted by a phenyl and a CF3 group at the C2 position, was treated with a mixture of perchloric acid and water, two products were formed. The first one L2.66, obtained in 78% yield, is the result of the attack of the nucleophile to the aziridinium L2.65 at C3 and the second one L2.67, obtained in 3% yield, corresponds to the attack of the nucleophile at the benzylic C2 position of the aziridinium intermediate L2.65 (Scheme 24). 67 It is worth 67 noting, that when the N-benzyl group was replaced by a N-tosyl group, the amino alcohol L2.67 was the only isolated product.

Scheme 24

Formation of an aziridinium by N-alkylation

An alternative method to activate an aziridine is by alkylation of the nitrogen, to form an aziridinium intermediate. Katagiri et al. reported in 1999 the successful N-methylation of (trifluoromethyl)aziridine L2.50 using the Meerwein's reagent (Me3OBF4), to obtain the aziridinium L2.68. In order for an external nucleophile to attack the aziridinium L2.68, the presence of a non-reactive counter-ion (BF4  ) is necessary. In the presence of different nucleophiles, the aziridinium L2.68 underwent a regioselective attack of the nucleophile at C3, to afford a variety of α-(trifluoromethyl)amines L2.69 (Scheme 25). 63 It should be noted that under these conditions, the ring-opening of aziridines by carbanions as well as amines, is possible. This ring-opening, was not possible by the acid-promoted ring-opening of aziridines (see Section 3.1.1.).

Scheme 25

Due to the difficulty to cleave the N-methyl group, the authors have also examined the N-allylation of aziridine L2.50. Treatment of the aziridine L2.50 with allyl iodide in the presence of AgBF4, led to the formation of the activated aziridinium L2.70, which after the addition of n-butylamine, afforded the ring-opened product L2.71 in a regioselective manner (Scheme 26). 63

Scheme 26

Furthermore, primary -iodoamines L2.74 were obtained in very good yields, from aziridines L2.72.

Treatment of aziridines L2.72 with methyl iodide or benzyl iodide, afforded the aziridiniums L2.73, which, in the presence of iodide as a counter-ion, resulted in the regioselective attack of the anion at the C3 position and the formation of 2-iodo-1-(trifluoromethyl)amines L2.74 (Scheme 27). 68 It is worth mentioning that when alkyl iodides were used for the ring-opening of non-activated alkylaziridines, the attack of the nucleophile, took place at the substituted aziridine carbon C2, under thermodynamic conditions. 69 This indicates that due to the electron-withdrawing nature of the CF3 group, the recyclization of L2.74 towards the aziridinium L2.73 was not possible, pointing out that the reaction proceeds under kinetic control.

Scheme 27

The group of De Kimpe and D'hooghe reported the regioselective and stereoselective ring-opening of cisand trans-aziridines L2.59a and L2.59b by N-methylation of the aziridines in the presence of Me3OBF4. When the aziridiniums L2.75a and L2.75b were treated with thiophenol or benzylamine, the corresponding ring-opened products L2.76a and L2.76b, were obtained in poor to moderate yields. When thiophenol was used, one unexpected side-product was also isolated, the corresponding non-methylated amines L2.77a and L2.77b (Scheme 28). 66 The authors do not propose any explanation for the formation of L2.77a and L2.77b.

Scheme 28

In summary, the presence of a CF3 group can influence the regioselectivity of the ring-opening of an aziridinium intermediate, by directing the attack of the nucleophile, to the carbon which does not possess the trifluoromethyl group.

Results and discussion

As previously mentioned, our goal is to access 2-substituted, 2-(trifluoromethyl)pyrrolidines (n=1) Having the (trifluoromethyl)piperidine 1 in hand, this latter was treated with thionyl chloride in the presence of triethylamine (Et3N) in dichloromethane (CH2Cl2), however under these conditions, the desired pyrrolidine 4 was not observed (Scheme 32).

Scheme 32

On the contrary, when piperidine 1 was treated with mesyl chloride and Et3N, the conversion of 1 was low (10%), but the ring contraction product 4 was isolated in a 7% yield. The formation of 4 can be explained by the formation of intermediate 5 which led to aziridinium 6, due to the anchimeric assistance of the nitrogen. The chlorine anion present in the reaction mixture, can attack the aziridinium 6 at the C2' position to afford (trifluoromethyl)pyrrolidine 4 (Scheme 33).

Scheme 33

Due to the low yield and the poor reactivity of the tertiary alcohol of 1 towards mesyl chloride, the activation of the alcohol was achieved with a mixture of triphenylphosphine and iodine in the presence of imidazole. After the formation of intermediate 7 and due to the anchimeric assistance of the nitrogen, the aziridinium intermediate 8 was formed, which after the attack of the iodine anion to the C2' position, led to the desired iodomethyl-pyrrolidine 9 in 25% yield and a total conversion of 1 (Scheme 34).

Scheme 34

A more powerful electrophilic activator, such as diethylaminosulfur trifluoride (DAST) was then utilized to activate the tertiary alcohol of 1. By using DAST, the fluorinated pyrrolidine 12, corresponding to the ring contracted product, was selectively obtained in a good yield of 71%. The formation of pyrrolidine 12 is the result of the attack of a fluorine anion coming from DAST, to the aziridinium intermediate 11 (Scheme 35).

Scheme 35

The DAST reagent, allowed us to verify that the ring contraction of N-benzyl-3-hydroxy-3-(trifluoromethyl)piperidine 1 is an efficient process when the appropriate activator of the hydroxy group is used. In addition, the reaction proved to be regioselecive given that the attack takes place only at the C2' position. However, the inconvenience of the DAST reagent is that other external nucleophiles cannot be used and in consequence the access to a diversity of substituted (trifluoromethyl)pyrrolidines is impossible. As a result, alternative reaction conditions allowing the activation of the hydroxy group by other electrophilic reagents must be found, in order to introduce nucleophiles different from a fluorine atom on the (trifluoromethyl)pyrrolidines.

In

Scheme 36

Thus, when 3-hydroxy-piperidine 1 was treated with triflic anhydride (1.5 equiv), in the presence of the proton sponge VII (2.0 equiv) in CH2Cl2 at reflux, and after 5 h, benzylamine (2.5 equiv) was added to the reaction mixture, the ring contraction product, pyrrolidine 15 was isolated in 75% yield. This product is the result of the regioselective nucleophilic attack of the benzylamine to the aziridinium intermediate 14 (Scheme 37).

Scheme 37

As these conditions, successfully led to the desired pyrrolidine 15 and as they may allow the use of different nucleophiles, the scope of this reaction was then studied.

Scope of the reaction

Utilizing the conditions previously developed (Tf2O/Proton sponge VII/nucleophile), different primary and secondary amines were examined as nucleophiles. By adding aniline to the reaction mixture, the desired compound 16 was isolated in 71% yield (Table 2, entry 2). Five secondary amines were also tested, such as methylphenylamine, diethylamine, diallylamine, dibenzylamine and morpholine. In each case, the ring contraction products 1721 were obtained in good yields (Table 2, entries 37).

The best results were obtained with dibenzylamine and morpholine, where the 2-(trifluoromethyl)pyrrolidines 20 and 21 were isolated in 83% and 80% yield respectively (Table 2, entries 6 and 7). It is worth mentioning that when ammonia was involved in the ring contraction process, compound 23 was formed instead of the desired pyrrolidine 22 (Table 2, entry 8). 71 This product is the result of the addition of the amine to the aziridinium 14, which is followed by a second nucleophilic attack of the formed amino-pyrrolidine 22 on a second aziridinium intermediate 14. Furthermore, pyrrolidines 2430 were obtained in good yields when oxygenated nucleophiles were used. By using methanol and ethanol, the desired products 24 and 25 were isolated in 51% and 77% yield respectively (Table 3, entries 1 and 2). When allyl and benzyl alcohol were utilized, piperidine 1 was transformed to the corresponding pyrrolidines 26 and 27, in 57% and 65% yield respectively (Table 3, entries 3 and 4). Even water can be used as a nucleophile, leading to prolinol 28 in 61% yield, although 14.0 equiv of H2O were required (Table 3, entry 5). In addition, when piperidine 1 was treated with an oxygenated anion such as sodium phenolate and tetrabutylammonium acetate, the desired pyrrolidines 29 and 30 were isolated in 75% and 72% yield respectively (

Table 3

Other nucleophiles, such as sulfur-containing nucleophiles can undergo the ring contraction, either in the form of thiols or thiolates. Even if sodium ethanethiolate was able to induce the ring-opening of the aziridinium to produce 31 in 60% yield, thiols, which are soft nucleophiles were also able to produce the ring contraction products, given that pyrrolidine 31 was obtained in 54% yield when ethanethiol was used as a nucleophile. (Table 4, entry 1). Pyrrolidines 32 and 33, were isolated in 89% and 61% yield when benzyl thiol and thiophenol were utilized respectively (Table 4, entries 2 and 3). Piperidine 1 was also transformed to the corresponding fluoromethyl-and chloromethyl-pyrrolidines 12 and 4 in moderate yields (3049%), after the addition of tetrabutylammonium fluoride and tetrabutylammonium chloride respectively (Scheme 38). It is worth noting that fluoromethyl-pyrrolidine 12 was obtained in a better yield of 71% when piperidine 1 was treated with DAST (see Scheme 35).

Entry

Scheme 38

tetrabutylammonium cyanide and sodium dimethylmalonate, (trifluoromethyl)pyrrolidines 34 and 35

were isolated in 75% and 70% yield respectively (Scheme 39).

Scheme 39

4.1.1.4. Use of a chiral nucleophile: Chirality transfer Our next objective was to define whether a chirality transfer was induced or not, during the ring contraction process. Consequently, the two enantiomers of 1 were separated by Supercritical Fluid Chromatography (SFC). The two enantio-enriched piperidines (+)-1 and ()-1, were treated with triflic anhydride, in the presence of the proton sponge VII and methanol. Compounds (+)-24 and ()-24, were obtained in moderate yields and with opposite optical rotations, which could mean that the chirality was transferred during the reaction. However, the determination of the enantiomeric excess of (+)-24 and ()-24 by SFC was not possible, implying that another way had to be found, to prove the chirality transfer (Scheme 40).

Scheme 40

Therefore the racemic piperidine ()-1 was treated with triflic anhydride and the proton sponge VII, using a chiral amine, (S)-()-α-methylbenzylamine as a nucleophile. The desired pyrrolidine 36 was obtained in 75% yield as a mixture of two diastereoisomers (dr=50:50) (Scheme 41).

Scheme 41

The two enantio-enriched piperidines (+)-1 and ()-1 were then treated with the conditions developed above (Tf2O/proton sponge VII/(S)-()-α-methylbenzylamine), to afford the ring contraction products 36a and 36b in good yields and with diastereoselectivities superior to 95:5 in both cases (Scheme 42). This latter experiment, indicates that the ring contraction of piperidine (+)-1 and ()-1 proceeds with a chirality transfer.

Scheme 42

Comparison of the reactivity of 3-hydroxy-3-(trifluoromethyl)piperidine with 3-hydroxy-3-methylpiperidine

To study the influence of the CF3 group on the ring contraction process, the N-benzyl-3-hydroxy-3-methylpiperidine 37 was prepared and its reactivity under the conditions developed previously (Tf2O/proton sponge VII/nucleophile) was studied. The attack of the nucleophile on the aziridinium 38, can either take place at the C2 position to produce the ring-expansion product 39 (route a), or at the C2' position to produce the ring contraction product 40

(route b) (Scheme 43).

Scheme 43

Piperidine 37 was synthesized by addition of methylmagnesium bromide to piperidone 1 (THF, rt, 16 h). The N-Boc-3-hydroxy-3-methylpiperidine 41 was isolated in 50% yield, which after a deprotection/protection sequence (TFA/CH2Cl2 then BnBr/K2CO3/TBAI/MeCN) led to the desired 3-hydroxy-piperidine 37 in 78% yield (for the two steps) (Scheme 44).

Scheme 44

Piperidine 37, was then treated with triflic anhydride in the presence of the proton sponge VII and after 5 h at reflux, TBAF was added to the reaction mixture. Under these conditions, only the 6-membered ring 43 was observed (Scheme 45), indicating that without the CF3 group, the attack takes place at the C2 position of the aziridinium 38. 72 Therefore, this last experiment confirms the role of the CF3 group as a directing group for the regioselective attack of the nucleophile at the C2' position of the aziridinium, allowing a ring contraction process versus a ring-expansion. chloroacetaldehyde 47, by addition of an allyl metal, followed by treatment with allylamine (Scheme 47). 73 Scheme 47

After treatment of chloroacetaldehyde 47 with allyl bromide, in the presence of indium in H2O, compound 48 was formed in 80% yield and was then reacted with allylamine, to give after 5 days at

Scope of the ring contraction process

Having the 3-hydroxy-3-(trifluoromethyl)azepane 44 in hand, the ring contraction conditions previously developed (Tf2O/proton sponge VII/nucleophile) were applied to this azepane, in order to access the corresponding α-(trifluoromethyl)piperidines. The reaction was successful and no further optimization was needed, as the corresponding piperidines were obtained in very good to excellent yields.

Primary amines such as benzylamine and aniline, produced the corresponding piperidines 54 and 55 in very good to excellent yields from azepane 44 (Table 5, entries 1 and 2). When secondary amines such as diethylamine and diallylamine were used, even better yields in the piperidines were obtained as the desired compounds 56 and 57 were isolated in 92% and 85% yield respectively (Table 5, entries 3 and 4). By utilizing dibenzylamine and morpholine, piperidines 58 and 59 were afforded in quantitative yields (Table 5, entries 5 and 6). Several oxygenated nucleophiles were also tested. When methanol and ethanol were used, the corresponding substituted piperidines 60 and 61, were isolated in 93% and 95% yield respectively (Table 6, entries 1 and 2), while allyl alcohol and benzyl alcohol led to piperidines 62 and 63 in 93% and 82% yield respectively (Table 6, entries 3 and 4). Treatment of 44 with H2O, led to compound 64 in 93% yield (Table 6, entry 5). Moreover, piperidines 65 and 66 were obtained in quantitative yields, when charged nucleophiles such as phenolate and acetate were added to the reaction media (Table 6, entries 6 and 7). Furthermore, treatment of azepane 44 with Tf2O in the presence of the proton sponge VII, followed by the addition of reagents such as sodium ethanethiolate and sodium thiophenolate, led to piperidines 67 (92%) and 68 (85%) (Scheme 49).

Scheme 49

2-Methylhalogen piperidines were also obtained when tetrabutylammonium fluoride, chloride, bromide and iodide were added to the reaction media. The corresponding 2-substituted, 2-(trifluoromethyl)piperidines 6972 were afforded in good to very good yields from 61%89% (Scheme 50).

Scheme 50

It is interesting to mention, that when azepane 44 was treated with DAST in THF, the fluoromethyl-piperidine 69 was obtained in a better yield than by using Tf2O/proton sponge VII/TBAF (71% versus 61%) (Scheme 50 and Scheme 51).

Scheme 51

In addition, azepane 44 was transformed to (trifluoromethyl)piperidines 73 and 74 in excellent yields, by using a cyanide (94%) and a malonate anion (quantitative yield) (Scheme 52).

Scheme 52

The addition of a methyl group to the aziridinium 53 to produce 75 (Scheme 53) was then considered.

Therefore, azepane 44 was treated with triflic anhydride, in the presence of the proton sponge VII and then methyllithium was added to the reaction media. Under these conditions, only traces of the desired product 75 were detected by GC/MS analysis of the crude mixture, as well as the chlorinated piperidine 70 as the major product (Scheme 53). This result indicates that a reaction between methyllithium and dichloromethane takes place, by releasing a chlorine anion, which attacks the aziridinium. To avoid this secondary reaction, methylcyanocuprate was prepared from methyllithium and copper cyanide in THF, and then added to the reaction mixture. Here again, only traces of piperidine 75 were detected by GC/MS analysis, while piperidine 70 was still detected as the major product. Finally, the replacement of the organocuprolithium complex by organocupromagnesium chloride, afforded the desired piperidine 75 in 50% yield. It is worth noting that the presence of the undesired compound 70 was detected, although this latter was not isolated (Scheme 53).

Scheme 53

Interestingly, when sodium borohydride was utilized as a hydride source, the ring contraction product 76 was successfully obtained in 73% yield (Scheme 54).

Scheme 55

Azepane 77 was obtained from azepanone 51, previously synthesized (see Scheme 48). Treatment of 51 with methylmagnesium bromide in THF, afforded the N-Boc-azepane 81 in 72% yield. Treatment of azepane 81 with trifluoroacetic acid, led to the deprotected ammonium salt, which was then treated with benzyl bromide, in the presence of potassium carbonate and tetrabutylammonium iodide. The desired azepane 77 was isolated with a quantitative yield (Scheme 56).

Scheme 56

After treatment of azepane 77 with triflic anhydride, proton sponge VII and tetrabutylammonium fluoride, the ring contraction product 82 was not isolated, but compound 83 was obtained instead.

This latter, results from the attack of the nucleophile at the C2 position of the aziridinium intermediate 78 (Scheme 57). 72 As before, we can deduce that the presence of the CF3 group on the azepane, is important and necessary for the regioselective attack of the nucleophile on the aziridinium at the C2' position, to afford only the ring contraction products.

Scheme 57

Conclusion

Scheme 58

It was also demonstrated that the role of the CF3 group was crucial for the regioselectivity of the reaction. Our hypothesis according to which, the CF3 acts as a directing group to afford uniquely the ring contraction products, is therefore validated.

Finally, it is important to mention that the chirality transfer during the ring contraction was confirmed, proving that enantio-enriched pyrrolidines and piperidines can be obtained. 74 Infrared (IR) were recorded with a Bruker TENSORTM 27 (IRFT), wave-numbers are indicated in cm -1 .

Mass spectra with electronic impact (MS-EI) were recorded from a Shimadzu GCMS-QP 2010S.

High Resolution Mass Spectra (HRMS) were performed by the Centre Regional de Microanalyse (Université Pierre et Marie Curie, Paris VI, France).

Optical rotations were measured with a Perkin Elmer 343 polarimeter in a 10-cm cell. The concentrations indicated are in g/100 mL.

2. Synthesis and spectroscopic data of N-benzyl-3-hydroxy-

3-(trifluoromethyl)piperidine (1)

tert-Butyl 3-trifluoromethyl-3-hydroxypiperidin-1-carboxylate (2) 75 To a stirred solution of N-Boc- 3. Synthesis and spectroscopic data of 2-substituted,

2-(trifluoromethyl) pyrrolidines

General Protocol for the synthesis of 2-(trifluoromethyl)pyrrolidines

To a stirred solution of N-benzyl-3-hydroxy-3-(trifluoromethyl)piperidine 1 (1.0 equiv) and proton sponge VII (2.0 equiv) in CH2Cl2 (0.047 M) at 15°C was added triflic anhydride (1.5 equiv). After 5 h

of stirring at reflux, the solution was cooled to rt, the nucleophile (2.5 equiv) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with H2O, extracted with CH2Cl2 and the combined extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography.

N-Benzyl-2-chloromethyl-2-(trifluoromethyl)pyrrolidine (4)
1) Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = tetrabutylammonium chloride (268 mg, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (PE=100%) to afford 4 (53 mg, 0.19 mmol, 49%) as colorless oil.

2) To a stirred solution of N-benzyl-3-hydroxy-3-(trifluoromethyl)piperidine 1 (250 mg, 0.96 mmol, 1.0 equiv) in CH2Cl2 (6 mL) at 0 °C were added Et3N (0.54 mL, 3.9 mmol, 4.0 equiv) and MsCl (0.23 mL, 2.9 mmol, 3.1 equiv). The resulting mixture was stirred at reflux for 48 h. The reaction mixture was quenched with a H2O, extracted with CH2Cl2 and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (PE=100%) to afford 4 (20 mg, 0.07 mmol, 7%) as a colorless oil. MS m/z (relative intensity): 369 (M +• , 3), 300 (18), 228 (15), 173 (10), 91 (100), 65 (11).

N-Benzyl-2-fluoromethyl-2-(trifluoromethyl)pyrrolidine (12)
1) Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = tetrabutylammonium fluoride (1.0 M in THF, 261 mg, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (Pentane=100%) to afford 12 (30 mg, 0.11 mmol, 30%) as colorless oil.

2) To a stirred solution of N-benzyl-3-hydroxy-3-(trifluoromethyl)piperidine 1 (100 mg, 0.39 mmol, 1.0 equiv) in THF (4 mL) at 0 °C was added DAST (66 L, 0.54 mmol, 1.4 equiv). The resulting mixture was stirred at 0 °C for 1 h and at rt for 3 h. The reaction mixture was quenched with a saturated aqueous solution of Na2CO3, extracted with EtOAc and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. MS m/z (relative intensity): 314 (M +• , 0.1), 227 (10), 91 (76), 86 (100), 65 (12), 58 (7).

HRMS: calcd for C17H26F3N2 (M+H + ): 315.2043. Found 315.2043.

N-Benzyl-2-{[(N,N-diallyl)amino]methyl}-2-(trifluoromethyl)pyrrolidine (19)
Following the general protocol: 1 (71 mg, 0.27 mmol, 1.0 equiv), proton sponge (117. 2) Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165. Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165. MS m/z (relative intensity): 373 (M +• , 1), 304 (24), 242 (7), 228 (10), 91 (100), 65 (7).

HRMS: calcd for C18H23F3NO4 (M+H + ): 374.1574. Found 374.1581.

(+)-N-Benzyl-2-{[(S)-N-(1-methylbenzyl)amino]methyl}-2-(trifluoromethyl)pyrrolidine (+)-(36a)
Following the general protocol: (+)-1 (28 mg, 0.11 mmol, 1.0 equiv), proton sponge (46.3 []D 20 38 (c 1.0, CHCl3) MS m/z (relative intensity): 215 (M +• , 2), 159 (9), 142 (7), 101 (9), 85 (8), 58 (8), 57 (100), 56 (5).

N-Benzyl-3-hydroxy-3-methylpiperidine (37)

To a stirred solution of tert-butyl 3-methyl-3-hydroxypiperidin-1-carboxylate 41 (607 mg, 2.82 mmol, 1.0 equiv) in CH2Cl2 (16 mL) at rt, was added TFA (1.47 mL, 19.74 mmol, 7.0 equiv). The reaction mixture was stirred at rt for 15 h and then concentrated under reduced pressure.

To a stirred solution of the crude material previously obtained in MeCN (29 mL) at rt were added successively BnBr (0.34 mL, 2.82 mmol, 1.0 equiv), K2CO3 (1.9 g, 14.1 mmol, 5.0 equiv) and TBAI (0.52 mg, 1.41 mmol, 0.5 equiv). The reaction mixture was heated at 75 °C for 4 h and then allowed to cool to rt. The reaction mixture was quenched with H2O and extracted with CH2Cl2 (twice). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (EtOAc/PE=50:50) to afford 37 MS m/z (relative intensity): 213 (M +• , 2.7), 157 (9), 140 (7), 113 (5), 84 (32), 70 (4), 57 (100).

(
tert-Butyl 3-hydroxy-3-(trifluoromethyl)azepane-1-carboxylate (52)

To a stirred solution of tert-butyl 3-oxoazepane-1-carboxylate 51 (1.54 g, 7.22 mmol, 1.0 equiv) in THF (30 mL) at 0 °C was added TMSCF3 (2.16 mL, 14.44 mmol, 2.0 equiv). A solution of TBAF (1.0 M in THF, 14.44 mL, 14.44 mmol, 2.0 equiv) was added dropwise and the resulting mixture was stirred at rt for 5 days. The solution was quenched with an aqueous and saturated solution of NH4Cl and stirred for another 20 min. The solution was then concentrated under reduced pressure and diluted in CH2Cl2. The organic layer was separated and washed with H2O (twice), dried over anhydrous MgSO4, 78 To a stirred solution of tert-butyl 3-hydroxy-3-(trifluoromethyl)azepane-1-carboxylate 52 (1.9 g, 6.71 mmol, 1.0 equiv) in CH2Cl2 (37 mL) at rt, was added TFA (3.49 mL, 46.95 mmol, 7.0 equiv). The reaction mixture was stirred at rt for 18 h and then concentrated under reduced pressure.

To a stirred solution of the crude material previously obtained in MeCN (68 mL) at rt were added successively BnBr (0.80 mL, 6.71 mmol, 1.0 equiv), K2CO3 (4.6 g, 33.5 mmol, 5.0 equiv) and TBAI (1.24 g, 3.35 mmol, 0.5 equiv). The reaction mixture was heated at 75 °C for 4 h and then allowed to cool to rt. The reaction mixture was quenched with H2O and extracted with CH2Cl2 (twice). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (EtOAc/PE=5:95) to afford 44 (1. 56 7. Synthesis and spectroscopic data of 2-substituted,

2-(trifluoromethyl)piperidines

General Protocol for the synthesis of 2-(trifluoromethyl)piperidines

To a stirred solution of N-benzyl-3-hydroxy-3-(trifluoromethyl)azepane 44 (1.0 equiv) and proton sponge VII (2.0 equiv) in CH2Cl2 (0.047 M) at 15 °C, was added triflic anhydride (1.5 equiv). After 5 h of stirring at reflux, the solution was cooled to rt, the nucleophile (2.5 equiv) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with H2O, extracted with CH2Cl2 and the combined extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography.

N-Benzyl-2-{[(N-benzyl)amino]methyl}-2-(trifluoromethyl)piperidine (54)

Following the general protocol: 44 (150 mg, 0.55 mmol, 1.0 equiv), proton sponge (235.2 mg, 1.10 mmol, 2.0 equiv) and triflic anhydride (0.14 mL, 0.82 mmol, 1.5 equiv). Nucleophile = benzylamine (151 L, 1.37 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography MS m/z (relative intensity): 293 (M +• , 0.4), 291(M +• , 1.3), 242 (19), 222 (10), 208 (7), 91 (100), 65 Following the general protocol: 44 (70.8 mg, 0.26 mmol, 1.0 equiv), proton sponge (111 mg, 0.52 mmol, 2.0 equiv) and triflic anhydride (64 L, 0.39 mmol, 1.5 equiv); the organocuprate was added.

(
The crude mixture was purified by flash chromatography (PE=100%) to afford 75 (35 mg, 0.13 mmol, 50%) as a colorless oil.

To a stirred solution of coppercarbonitrile (93.7 mg, 1.04 mmol, 4.0 equiv) in THF (9.95 mL) at 78°C

under Ar atmosphere, was added methylmagnesium chloride (3 M, 0.43 mL, 1.3 mmol, 5.0 equiv) and the reaction mixture was stirred at rt for 1h. MS m/z (relative intensity): 229 (M +• , 1.5), 173 (9), 156 (8), 114 (7), 99 (18), 88 (10), 86 (22), 70 (7), 59 (15), 57 (100).

IR (neat

HRMS: calcd for C12H23NO3Na (M+Na + ): 252.1570. Found 252.1572.

N-Benzyl-3-hydroxy-3-methylazepane (77)

To a stirred solution of tert-butyl 3-hydroxy-3-methylazepane-1-carboxylate 81 (224 mg, 0.98 mmol, 1.0 equiv) in CH2Cl2 (5.4 mL) at rt was added TFA (0.51 mL, 6.84 mmol, 7.0 equiv). The reaction mixture was stirred at rt for 18 h and then concentrated under reduced pressure.

To a stirred solution of the crude material previously obtained in MeCN (10 mL) at rt were added successively BnBr (0.12 mL, 0.98 mmol, 1.0 equiv), K2CO3 (675 mg, 4.88 mmol, 5.0 equiv) and TBAI (180 mg, 0.49 mmol, 0.5 equiv). The reaction mixture was heated at 75 °C for 4 h and then allowed to cool to rt. The reaction mixture was quenched with H2O and extracted with CH2Cl2 (twice). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure.

The crude mixture was purified by flash chromatography (Et2O/PE=40: MS m/z (relative intensity): 219 (M +• , 7), 176 (7), 160 (11), 146 (2), 134 (69), 129 (11), 120 (10), 99 (7), 91 (100), 70 (7), 65 (12), 55 (11).

HRMS: calcd for C14H22NO (M+H + ): 220.1696. Found 220.1698.

9. Synthesis and spectroscopic data of N-benzyl-3-fluoro-3methylpiperidine ( 83)

N-Benzyl-2-fluoro-2-methylazepane (83)
Following the general protocol: N-benzyl-3-hydroxy-3-methylazepane 77 (85 mg, 0.39 mmol, 1.0 equiv), proton sponge (166 mg, 0.78 mmol, 2.0 equiv) and triflic anhydride (96 L, 0.59 mmol, 1.5 equiv). Nucleophile = tetrabutylammonium fluoride (1.0 M in THF, 0.97 mL, 0.97 mmol, 2.5 equiv).

The crude mixture was purified by flash chromatography (EtOAc/PE=5:95 and 10:90) to afford 83 (27 mg, 0.12 mmol, 31%) as a yellow oil. MS m/z (relative intensity): 221 (M +• , 28), 220 (11), 174 (8), 160 (33), 146 (11), 144 (11), 135 (18), 130 (25), 91 (100), 84 (15), 70 (10), 65 (16), 55 (9).

HRMS: calcd for C14H21FN (M+H + ): 222.1653. Found 222.1653.

1. Structure, biological activity and synthesis of pyridazines 1.1. Structure [START_REF] Cabal | Six-Membered Heterocycles: 1,2-, 1,3-, 1,4-Diazines and Related Systems[END_REF][START_REF] Haider | In Product Class 8: Pyridazines[END_REF] Pyridazines (1,2-diazines) are aromatic six-membered heterocycles, containing two sp 2 hybridized adjacent nitrogen atoms. They belong to the family of diazines along with pyrimidines (1,3-diazines) and pyrazines (1,4-diazines). Pyridazines are planar molecules with a slightly distorted hexagonal geometry, whose bond lengths are similar to those of benzene (1.39 Å). Although pyridazines are aromatic compounds, their resonance energy (100 kJ/mol) is considerably lower than the resonance energy of benzene (150 kJ/mol) and pyridine (117 kJ/mol) and thus, their aromaticity is lower (Figure 26).

Figure 26

Due to the nitrogen inductive effect, pyridazines are electron-deficient compounds with a partially positive charge on the carbon atoms and a partially negative charge on the nitrogen atoms.

Pyridazines are also molecules of low basicity with a pKa of 2.3, which is lower than the pKa of pyridine (pKa=5.2) and are therefore not easily protonated.

Two resonance structures contribute to the structure of pyridazine. According to calculations, structure B contributes more to the resonance hybrid than structure A, as the N-N bond has a significant single bond character (Figure 27).

1

.2. Biological activity

Until now, only nine natural compounds, containing a pyridazine ring, are reported in the literature, presenting a variety of biological activities (Figure 28). For example, pyridazomycin, which was the first pyridazine-containing natural product, was isolated from Streptomyces violaceoniger in 1988, [START_REF] Cabal | Six-Membered Heterocycles: 1,2-, 1,3-, 1,4-Diazines and Related Systems[END_REF] Cabal, M. -P. Six-Membered Heterocycles: 1,2-, 1,3-, 1,4-Diazines and Related Systems. In Modern Heterocyclic Chemistry, Vol. 2; Alvarez-Builla, J.; Vaquero, J. J.; Barluenga, J., Eds.; Wiley-VCH: Weinheim, 2011, 16831776. [START_REF] Haider | In Product Class 8: Pyridazines[END_REF] Haider, N.; Holzer, W. In Product Class 8: Pyridazines, Science of Synthesis, 2004, 16, 125249.

and has shown antifungal and antibiotic properties 81 while liguducimine A, isolated from the plant Ligularia duciformis, has antitussive properties. 82 In addition, cinnoline 4849F, isolated in 2007, has shown some cytotoxic activity towards human breast cancer and ovarian cancer cells 83 (Figure 28).

Figure 28

For a long time, pyridazines have been considered as dangerous heterocycles due to the potential toxicity of the hydrazine motif present on the pyridazine ring and, until 1950, only two drugs possessing a pyridazine moiety were on the market: hydralazine which is a vasodilator and sulfamethoxypyridazine which is an antibacterial agent (Figure 29). 84

Figure 29

However, over the last years, pyridazines have been considered as privileged structures 84 and one of the "most developable" heteroaromatic rings for drug design according to GlaxoSmithKline researchers. 85 Therefore, the increasing interest in pyridazine-containing compounds, has led to the 81 development of minaprine which is an antidepressant drug, SR 41378, a potent candidate for the treatment of seizures, and pyridate which is a herbicide (Figure 30).

Figure 30

Nowadays, numerous synthetic biologically-active pyridazines, with various therapeutic properties, are developed. For example, compound I was found to have an inhibitory activity towards picornavirus, a virus that is responsible for several human diseases such as acute hepatitis, myocarditis and poliomyelitis. 86 Compound II, seems to show an inhibitory activity towards acyl CoA:

DiacylGlycerol AcylTransferase (DGAT1), an enzyme that catalyzes the formation of triglycerides.

With the discovery of compound II, it seems that the formation of triglycerides could be modulated, offering a treatment for numerous diseases such as type II diabetes and obesity 87 (Figure 31).

Figure 31

Due to the increasing interest in pyridazine derivatives over the last years, as well as an interest in introducing fluorine atoms in molecules as mentioned before, the development of trifluoromethylated pyridazines has become increasingly popular.

A first example demonstrating the importance of (trifluoromethyl)pyridazines, is illustrated in Figure 32. Due to the lack of efficient drugs and/or with low side-effects, a new class of agents e.g. triple reuptake inhibitors, has been developed to inhibit serotonin, norepinephrine, and dopamine transporters. This inhibition provokes an increase in the extracellular concentration of these transporters and therefore an increase in the neurotransmission. Thus, these agents can be used for the treatment of depression. For example, BMS-911278, possessing a (trifluoromethyl)pyridazine ring, was presented as a potent triple reuptake inhibitor which could possibly treat depression. 88

Figure 32

Another example indicating the importance of (trifluoromethyl)pyridazines is illustrated in Figure 33.

In an attempt to develop new anti-HIV agents, due to the increasing resistance to already marketed drugs, a series of functionalized α-(trifluoromethyl)pyridazinones has been recently synthesized. The pyridazinone ring can act as a bioisoster of the pyrimidinone ring of raltegravir, an antiretroviral drug that targets integrase, an HIV-enzyme which integrates viral DNA into the host cell genome. Among a variety of synthesized pyridazinones, compounds III and IV exhibited high anti-HIV activity, while compound V and raltegravir showed a similar in-vitro and in-vivo anti-viral activity against the tobacco mosaic virus (TMV). 89 Figure 33 88

Main synthetic methods to access pyridazines

The first pyridazine synthesis was reported in 1886 by Emil Fischer. 90 However, it is not until the 1950's that the synthesis and reactivity of pyridazines were studied. Nowadays, numerous methods exist to access the pyridazine ring. Among them, we can cite:

 the condensation of hydrazine with 1,4-diketones (route a)

 a Diels-Alder/retro Diels-Alder reaction between tetrazines and alkynes (route b)

 a [1,3]-dipolar cycloaddition between a cyclopropene and a diazo compound (route c)

 the ring-contraction of diazepines (route d) (Scheme 59).

Scheme 59

As our goal was to access pyridazines possessing a CF3 group to the α position of one of the two nitrogens, we will focus only on the synthetic methods developed to obtain α-(trifluoromethyl)pyridazines as well as their derivatives. It should be mentioned that we have decided to number the pyridazine atoms as indicated in Figure 34, whatever the substituents on the pyridazine ring.

Figure 34 90 Fischer, E. Justus Liebigs Ann. Chem. 1886, 236, 126151.

Scheme 60

Treatment of L3.5 with ammonia in ether, followed by treatment with dinitrogen tetroxide (N2O4), led to the tetrakis-(trifluoromethyl)pyridazine L3.7 (Scheme 61).

Scheme 61

Beside the method presented above, a few synthetic methods are reported, to access specifically α-(trifluoromethyl)pyridazines and their derivatives. We have divided these methods according to the 91 number of CF3 groups present on the pyridazine ring (one or two) and then according to the reaction type.

Pyridazines possessing one CF3 group

Pyridazines possessing one CF3 group can be obtained either by:

Scheme 62

In 1993, Takahashi et al. reported the synthesis of (trifluoromethyl)pyridazines L3.12a and L3.12b from compound L3.8 and hydrazine. Indeed, condensation of L3.8 with hydrazine gave access to hydrazone L3.9 (85% yield), which after reaction with dibenzoyl L3.10 in the presence of p-toluenesulfonic acid, afforded azine L3.11 in 75% yield. Azine L3.11 was then converted to pyridazine L3.12a (15%) after treatment with LDA, and to pyridazine L3.12b (58%) when treated with sodium methoxide due to the release of a hydroxy anion during the condensation step (Scheme 63). 92 92 Takahashi, M.; Kotashima, H.; Saitoh, T. Heterocycles 1993, 35, 909914.

Scheme 69

In 2009, the synthesis of (trifluoromethyl)pyridazinones L3.34 was reported by the condensation of hydrazine derivatives with ketoester L3.31, under acidic conditions. After protonation of L3.31 with p-toluenesulfonic acid, intermediate L3.32 was attacked by the hydrazine derivatives to form intermediates L3.33. A condensation can then take place to afford compounds L3.34 in very good yields (80%94%) (Scheme 70). It is worth noting that the 1 to 1 ratio of ketoester L3.31 and hydrazine derivatives is important for the completion of the reaction. When this ratio is 1 to 2, the cyclization of L3.33 does not take place. The same result was obtained when the hydrazine is substituted by an aromatic ring possessing electron-withdrawing groups, such as two nitro groups, given that the reaction stops after the formation of compound L3.33 independently of the ratio of ketoester L3.31

and hydrazine derivatives. 95 Scheme 70 95 Over the years, the Diels-Alder reaction with inverse electron demand, has found application in the synthesis of substituted pyridazines and derivatives, which could act as a bioisoster of other heteroaromatic rings.

For example, the group of Seitz, has envisioned to replace the pyridine ring of ()-anabasine, which Furocoumarins are photoreactive molecules that can covalently link to DNA. Cross-linking problems are common during the furocoumarins mode of action, and could be limited and eventually eliminated by the insertion of nitrogen-containing rings in the furocoumarin system, that would improve the interactions with DNA. Therefore, the group of Uriarte,111 reported the synthesis of bis-(trifluoromethyl)pyridazine-containing furocoumarins, which could eventually limit cross-linking problems. For example L3.127 can be obtained by an inverse electron demand Diels-Alder reaction between tetrazine L3.73 and the enolized form of furocoumarin L3.124, L3.125. The reaction proceeded smoothly, to afford after elimination of H2O and N2, the desired polycyclic compound L3.127 in 54% yield (Scheme 95). 111b

Scheme 95

Therefore, the Diels-Alder reaction with inverse electron demand of the electron-poor tetrazine L3.73 with a variety of electron-rich dienophiles, constitutes an important method to access pyridazines substituted by two CF3 groups at the α position of each nitrogen.

Context of the study and objective

Over the years, the pyridazine core has been present in several commercial drugs and drug candidates (see Section 1.2). In addition, the biological significance of pyridazines trifluoromethylated analogues has recently become a new trend, therefore the search for new efficient methods for the synthesis of (trifluoromethyl)pyridazines has become a challenge. Our goal was to replace the commercially available diazoacetate compounds by the non-commercially available (trifluoromethyl)diazomethane, to access 6-(trifluoromethyl)pyridazines O. As this method is limited to pyridazines possessing a fluorine substituent at the C4 position, the replacement of the fluorine atom by other nucleophiles using a nucleophilic aromatic substitution (SNAr) was envisaged to access 3,4,6-functionalized pyridazines P (Scheme 98).

Scheme 98

Before the presentation of our results, we will briefly describe the properties of (trifluoromethyl)diazomethane, along with its preparation and its use in organic chemistry.

(Trifluoromethyl)diazomethane is a yellow gas, first reported by Gilman and Jones in 1943. 113 The boiling point of this diazo compound is 13 °C. In addition, (trifluoromethyl)diazomethane is suspected to be toxic and is considered to be an explosive molecule, with 50100% of the energy released by the same weight of TNT. 114 Two resonance structures contribute to its structure and properties (Scheme 99).

Scheme 99

(Trifluoromethyl)diazomethane L3.138 can be prepared by the diazotization of the commercially available 2,2,2-trifluoroethylamine hydrochloride L3.134 with sodium nitrite (NaNO2) in H2O, with or without the presence of an acid. HNO2 is the active agent formed in situ that carries out the diazotization. Therefore, the reaction of HNO2 with trifluoroethylamine L3.134 leads to the N-nitroso intermediate L3.135, which after dehydration, affords the diazonium intermediate L3.137.

Elimination of the acidic proton leads to (trifluoromethyl)diazomethane L3.138 (Scheme 100). 113 Gilman, H.; Jones, R. G. J. Am. Chem. Soc. 1943, 65, 14581460. 114 Fields, R.; Tomlinson, J. P. J. Fluorine Chem. 1979, 13, 147158.

Results and discussion

For our part, we were interested in the synthesis of pyridazines O, possessing a CF3 group at the C6 position. We envisaged to form these pyridazines by the [2+1]-cycloaddition of difluorocarbene with terminal alkynes M, followed a [3+2]-cycloaddition between the formed difluorocyclopropene intermediates N and (trifluoromethyl)diazomethane (Scheme 103).

Scheme 103

We therefore initiated our study by synthesizing the starting materials e.g. different terminal alkynes, which would be used for the scope of the reaction.

Synthesis of the starting materials

As most of the terminal alkynes are either very expensive or not commercially available, their preparation is necessary. Most of these alkynes were easily accessible by a Sonogashira cross-coupling reaction between an aryl halide and trimethylsilylacetylene using PdCl2(PPh3)2 (510 mol %), CuI (510 mol %) and Et3N (3.0 equiv) in THF, followed by the cleavage of the trimethylsilyl group by treatment with K2CO3 in MeOH. The results are summarized in Table 7. Terminal alkynes 6 and 7, possessing an aromatic ring substituted by a nitro group or an ester at the para-position, were isolated in 76% and 57% yield respectively from the corresponding aryl iodides 1 and 2 (Table 7, entries 1 and 2). The Sonogashira cross-coupling of trimethylsilylacetylene with bromo-pyridines 3 and 4, followed by the cleavage of the TMS group, led to the desired alkynes 8 and 9 in 61% and 53% yield respectively (Table 7, entries 3 and 4). Treatment of 5-bromo-2-methylbenzoxazole 5 with trimethylsilylacetylene under the Sonogashira cross-coupling conditions, gave the corresponding alkyne 10 in 87% yield (Table 7, entry 5).

Scheme 107 3.2. Synthesis of α-(trifluoromethyl)pyridazines

Optimization of the reaction conditions

To access α-(trifluoromethyl)pyridazines, the optimization of the reaction conditions was carried out with phenylacetylene 22. To form the difluorocyclopropene 23 from 22, the difluorocarbene was generated according to the reaction conditions reported by Hu and Prakash et al. (TMSCF3, NaI, THF, 110 °C, 2 h). 116 When the Ruppert-Prakash reagent (TMSCF3) was treated with sodium iodide, the CF3 anion was generated, and under high temperature (110 °C), the difluorocarbene was formed along with a fluorine anion. A [2+1]-cycloaddition could then take place, between the difluorocarbene and phenylacetylene 22, to produce the difluorocyclopropene 23. This compound was not isolated, but was directly treated with (trifluoromethyl)diazomethane. This latter, was generated by using the conditions developed by Carreira et al. 115 Thus, when 2,2,2-trifluoroethylamine hydrochloride (2.05 equiv) was treated with sodium nitrite (2.4 equiv), in a mixture of 0.3 M CH2Cl2/H2O (30:1) at 0 °C for 1 h, (trifluoromethyl)diazomethane was formed. This solution was then cooled to 78 °C and transferred to the difluorocyclopropene solution. After 46 h at rt, the desired (trifluoromethyl)pyridazine 24 was obtained in 78% yield (Scheme 108). 116 Wang, F.; Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.; Ganesh, S. K.; Prakash, G. K. S.; Olah, G. A. Angew. Chem. Int. Ed. 2011, 50, 71537157.

pyridazine 24 was isolated in 87% yield from phenylacetylene 22 after a [2+1]/[3+2]-cycloaddition sequence utilizing TMSCF3 and NaI in THF at 110 °C for 2 h, followed by the addition of 0.6 M solution of (trifluoromethyl)diazomethane in CH2Cl2 at rt.

Scope of the reaction

Terminal alkynes substituted by an aryl group

To study the scope of the reaction, we first examined the reactivity of terminal alkynes possessing aromatic rings substituted by electron-donating groups. When alkyne 25, possessing an aromatic group substituted by a methyl group at the para-position, was engaged in the cycloaddition sequence, the corresponding compound 31 was isolated in 75% yield although the reaction time was long ( 6days) (Table 9, entry 2). The reaction time was increased to 3 weeks, when the terminal alkyne was substituted by an aromatic ring possessing a p-MeO or a o-MeO group, however, the cycloadducts 32 and 33 were respectively isolated in good yields of 83% and 73% (Table 9, entries 3 and 4). When the alkyne possessed a trisubstituted aryl group such as in 28, this latter underwent the cycloaddition sequence successfully, leading to (trifluoromethyl)pyridazine 34 in 76% yield (Table 9, entry 5). It is worth noting that it took one month as well as 2.0 equiv of (trifluoromethyl)diazomethane to obtain a total conversion of the difluorocyclopropene. Nevertheless, when the same reaction was carried out at 55 °C, pyridazine 34 was obtained in 83% yield after 12 days (see footnote b). On the contrary, when 4-ethynyl-N,N-dimethylaniline 29 was engaged in the cycloaddition sequence, neither product 35 nor the difluorocyclopropene were observed (Table 9, entry 6). A possible explanation might be that the nucleophilic character of the dimethylaniline (pKa=5.2), can interact with the electrophilic difluorocarbene leading to the deactivation of the difluorocarbene and to the degradation of the product. Furthermore, when alkyne 30, substituted with a methoxy naphthalene, was involved in the [2+1]/[3+2]-cycloaddition sequence, pyridazine 36 was formed in a good yield of 79% after 40 h (Table 9, entry 7).

Entry Time Product (%)

Table 9

The reactivity of terminal alkynes substituted by aryl groups possessing electron-withdrawing substituents was then examined. We noticed that the reaction times were in most cases shorter than the reaction times required for alkynes possessing aryl groups substituted with electron-donating substituents. When 1-ethynyl-2-trifluoromethylbenzene 37 was treated with TMSCF3/NaI in THF at 110 °C for 2 h, followed by the addition of (trifluoromethyl)diazomethane in CH2Cl2, pyridazine 41 was formed in 66% yield after 48 h (Table 10, entry 1). Alkynes 14 and 7, possessing an ester group at the metaand para-position of the aromatic ring respectively, were transformed to (trifluoromethyl)pyridazines 42 and 43 in good yields, 76% and 67% respectively (Table 10, entries 2 and 3). A decrease in the yield of pyridazines was observed when alkynes 12 and 6, substituted by an aryl possessing a p-PO(OEt)2 or a p-NO2 group underwent the [2+1]/[3+2]-cycloaddition sequence, as the corresponding pyridazines 44 and 45 were isolated in low yields, 27% and 34% respectively (Table 10, entries 4 and 5). It is worth noting that the presence of a weak electron-withdrawing substituent such as a bromine or a fluorine atom at the para-position of the aromatic ring, allowed an increase in the yield of pyridazines, as 46 and 47 were isolated in 85% and 57% yield respectively. However, longer reaction times of 5 to 7 days were necessary for the complete conversion of the difluorocyclopropene intermediate (Table 10, entries 6 and 7). Alkyne 40, possessing an aromatic ring substituted by a fluorine atom and a methyl group, afforded pyridazine 48 in a very good yield of 89% after 72 h of reaction (Table 10, entry 8).

In summary, terminal alkynes possessing aromatic rings substituted by electron-donating groups and terminal alkynes possessing aromatic rings substituted by electron-withdrawing groups, underwent the [2+1]/[3+2]-cycloaddition sequence successfully, to produce 6-(trifluoromethyl)pyridazines. In the case of alkynes possessing an aryl group substituted by electron-donating groups, long reaction times were required for the total conversion of difluorocyclopropenes to the corresponding pyridazines. In the case of alkynes possessing an aryl group substituted by an electron-withdrawing group, lower yields than those obtained with alkynes substituted by an aryl possessing electron-donating groups, were observed. The presence of electron-withdrawing substituents on the aryl group can be detrimental to the yields of difluorocyclopropenes, as these latter can be prone to For the formation of the difluorocarbene using TFDA, a slow addition of this latter in the reaction media at high temperature is needed, therefore the reaction was carried out in diglyme (b.p.=162 °C) at 120 °C.

Scheme 109

As these conditions do not involve the presence of strong nucleophiles in the reaction mixture, terminal alkynes substituted by an aryl group possessing an electron-withdrawing substituent could lead to the corresponding pyridazines in higher yields than those obtained previously with TMSCF3/NaI (see Table 10). However, when 1-ethynyl-2-trifluoromethylbenzene 37 was treated with TFDA, in the presence of a catalytic amount of NaF in diglyme at 120 °C, followed by the addition of (trifluoromethyl)diazomethane in CH2Cl2, pyridazine 41 was obtained in a lower yield of 43% than the

Table 11

The same observations were made when alkyne 27, possessing an aromatic ring substituted by an electron-donating group, was submitted to the TFDA procedure. Although the corresponding pyridazine 33 was obtained in a slightly lower yield compared to the one obtained with the TMSCF3 procedure (68% versus 73%), the reaction time was significantly improved from 15 days to 4 days (Scheme 110).

Scheme 110

Therefore, compared to the TMSCF3/NaI procedure, although the TFDA procedure was not able to improve the yields in pyridazines from alkynes possessing an aryl group substituted by electron-withdrawing groups, it remains a useful method to access pyridazines from alkynes substituted by aryl groups with electron-withdrawing or electron-donating substituents, as the [2+1]/[3+2]-cycloaddition products were obtained in shorter reaction times compared to the reaction times needed for the TMSCF3 procedure.

Terminal alkynes substituted by heterocycles

Terminal alkynes substituted by heteroaromatic rings were also involved in the

[2+1]/[3+2]-cycloaddition sequence. When 2-ethynylpyridine 51 was submitted to the TMSCF3 procedure (TMSCF3/NaI, THF, 110 °C, 2 h), pyridazine 53 was obtained in a low yield of 12%, possibly due to the nucleophilicity of the pyridine nitrogen (pKa=5.25) which can react with the difluorocarbene. When the same alkyne was submitted to the TFDA procedure (TFDA/NaF, diglyme, 120 °C, 2 h), only the degradation of the starting material was observed (Table 12, entry 1). However, when 2-chloro-6-ethynylpyridine 8 was treated with the system TMSCF3/NaI, the corresponding (trifluoromethyl)pyridazine 54 was isolated in a 25% yield, possibly due to a decrease in the nucleophilic character of the nitrogen of the pyridine. It is worth mentioning that treatment of 2-chloro-6-ethynylpyridine 8 with the TFDA/NaF system, gave pyridazine 54 in 30% yield (Table 12, entry 2). In addition, treatment of 2-chloro-5-ethynylpyridazine 9 with TMSCF3/NaI led to the cycloaddition product 55 in 37% yield, while its treatment with TFDA/NaF led to the degradation of 9

(Table 12, entry 3). The cycloaddition sequence applied to 3-ethynylthiophene 52, using the two procedures, led to pyridazine 56 in 76% yield when TMSCF3/NaI was used and in 52% when TFDA/NaF was utilized (Table 12, entry 4). Treatment of alkyne 10, substituted by a benzoxazole group, with TMSCF3/NaI, followed by the addition of (trifluoromethyl)diazomethane in CH2Cl2, afforded pyridazine 57 in 75% yield (Table 12, entry 5).

Entry

Conditions Time Product (%) a) 1.0 more equiv of TMSCF3 was necessary for a total conversion of the alkyne. b) 2.0 more equiv of TMSCF3 were necessary for a total conversion of the alkyne. c) 2.0 more equiv of TFDA were necessary for a total conversion of the alkyne. d) 4.0 more equiv of TMSCF3 were necessary for a total conversion of the alkyne.

1 a TMSCF3 TFDA

Table 12

It is worth mentioning that when 2-chloro-6-ethynylpyridine 8 was treated with TMSCF3, beside pyridazine 54, the presence of two more products was observed by GC/MS analysis, compounds 58 and 59. Compound 58 could be the result of the deprotonation of alkyne 8 by the CF3 anion generated in the reaction media followed by a trimethylsilylation of 60. In the case of compound 59, this latter could be formed either by attack of the difluorocarbene on 58, or by deprotonation of the difluorocyclopropene 61 followed by a trimethylsilylation (Scheme 111).

Scheme 111

Terminal alkynes substituted by alkyl groups

To further expand the scope of the reaction, terminal alkynes substituted by alkyl groups were engaged in the [2+1]/[3+2]-cycloaddition sequence. Treatment of alkynes 6264 with TMSCF3/NaI, followed by treatment with (trifluoromethyl)diazomethane in CH2Cl2, allowed the formation of the corresponding pyridazines 6567, although in moderate yields. For example, alkyne 62, substituted by a cyclohexyl group, gave the desired pyridazine 65 in 38% yield after 12 days (Table 13, entry 1).

Alkynes 63 and 64, substituted by a benzyl or a methoxymethyl group, were transformed to the corresponding cycloadducts 66 and 67 in 39% and 20% yield respectively (Table 13, entries 2 and 3).

Table 14

Thus, the reaction scope could be expanded not only to alkynes substituted by aromatic rings possessing electron-donating and electron-withdrawing groups but also to alkynes substituted by heterocycles and alkyl groups. Even though problems were encountered when a basic nitrogen is present on the heterocyclic rings, a variety of (trifluoromethyl)pyridazines were obtained, with the TMSCF3/NaI and/or the TFDA/NaF procedure.

Other fluorinated diazo compounds

To increase the diversity of substituted pyridazines possessing different fluorinated groups at the C6 position, other non-commercially available fluorinated diazo compounds were prepared and involved in the [2+1]/[3+2]-cycloaddition sequence.

When 1.5 equiv of (pentafluoroethyl)diazomethane, prepared according to the literature 118 from 2,2,3,3,3-pentafluoropropanamine hydrochloride and sodium nitrite (NaNO2), reacted with Scheme 112

In addition, the (difluoromethyl)diazomethane was prepared according to the literature, 119 starting from 2,2-difluoroethylamine and tert-butyl nitrite in CH2Cl2, in the presence of a catalytic amount of acetic acid. It is worth noting that heating the reaction mixture at 70 °C for 10 min was necessary to form the (difluoromethyl)diazomethane. When 2.0 equiv of this diazo compound were added to the difluorocyclopropene 23, the desired pyridazine 72 was obtained in a low yield of 13% and only 65% conversion of 23 was observed after 9 days (Scheme 113).

Scheme 113

To achieve a total conversion of 23 as well as to obtain a higher yield in 72, 4.0 equiv of (difluoromethyl)diazomethane were necessary to carry out the [3+2]-cycloaddition. Under these conditions, the corresponding pyridazine 72 was isolated with an improved yield of 44% after 8 days (Scheme 114). 15. When pyridazine 24 reacted with a secondary amine such as morpholine or dibenzylamine in acetonitrile at 100 °C, the corresponding pyridazines 73 and 74, were obtained in 85% and 83% yield respectively (Table 15, entries 1 and 2). When a primary amine was used as the nucleophile such as allylamine, the desired compound 75 was isolated in a quantitative yield (Table 15, entry 3). Treatment of pyridazine 24 with sodium methoxide in acetonitrile, led to pyridazine 76 in 69% yield (Table 15, entry 4). Interestingly, pyridazine 76 was obtained in a higher yield of 76% when 24 was treated with methanol in the presence of DBU in DMSO (Table 15, entry 5). When the allyl alcohol was used as a nucleophile, the corresponding pyridazine 77 was isolated in 71% yield (Table 15, entry 6). In addition, sulfur containing nucleophiles can be used such as sodium ethanethiolate, leading to pyridazine 78 in 94% yield (Table 15, entry 7). By using carbon nucleophiles such as a malonate anion, the corresponding product 79 was obtained with an excellent yield (92%) (Table 15, entry 8) however, when a nitromethane anion or a cuprate were used, the desired pyridazines 80 and 81 were isolated in low yields of 52% and 12% respectively (Table 15, entries 9 and 10). Pyridazine 24 is an excellent substrate for an SNAr reaction, allowing the introduction of different nucleophiles such as amines, alkoxy and sulfur derivatives as well as carbanions, to access highly functionalized pyridazines.

Variation of the substituent at the C3 position

The influence of the substituent at the C3 position of the (trifluoromethyl)pyridazines was investigated on the nucleophilic aromatic substitution, using morpholine as a nucleophile. As reported previously, when pyridazine 24, substituted by a simple phenyl group at the C3 position was treated with morpholine in acetonitrile, the SNAr product 73 was obtained in 85% yield (Table 16,

Table 16

From the obtained results, we notice that all the products resulting from the SNAr were obtained in very good to excellent yields independently of the nature and the position of the substituent at the C3 position of the α-(trifluoromethyl)pyridazines. However, the best yields were obtained when the aromatic ring is substituted by an electron-donating or a weak electron-withdrawing group at the para-position, indicating a small influence of the stereoelectronic effects of the substituents of the aromatic ring on the SNAr reaction.

Variation of the substituent at the C6 position

The SNAr was also carried out with 4-fluoro-pyridazines 71 and 72, substituted by different fluorinated groups at the C6 position. When pyridazine 71, substituted by a pentafluoroethyl group at the C6 position, was treated with allylamine and sodium ethanethiolate in acetonitrile at 100 °C, pyridazines 86 and 87 were isolated in 90% and 84% yield respectively (Scheme 116).

Scheme 116

The nucleophilic aromatic substitution applied to the 4-fluoro-pyridazine 72 also proceeded uneventfully when this pyridazine was treated with allylamine and sodium ethanethiolate, as the desired products 88 and 89 were obtained in very good yields of 92% and 87% respectively (Scheme 117).

Scheme 118

Moreover, pyridazines O', could be further functionalized by a nucleophilic aromatic substitution (SNAr), which rapidly and efficiently led to pyridazines P' in 12%99% yield, with no significant influence of the substituents at the C3 and C6 positions (Scheme 119).

Scheme 119

It is worth mentioning that during my PhD, a Master student (Gregory Fredj) worked on the synthesis of pyridazines S, possessing a hydrogen in the place of the CF3 group. When (trifluoromethyl)diazomethane was replaced by (trimethylsilyl)diazomethane, fluoropyridazines S were obtained. These fluoropyridazines could also be functionalized at the C4 position, when treated with different nucleophiles, to access a variety of 3,4-substituted pyridazines T (Scheme 120).120

General experimental methods

All reactions were carried out under an argon atmosphere unless otherwise specified. Infrared (IR) were recorded with a Bruker TENSORTM 27 (IRFT), wave-numbers are indicated in cm -1 .

Mass spectra with electronic impact (MS-EI) were recorded from a Shimadzu GCMS-QP 2010S.

High Resolution Mass Spectra (HRMS) were performed by the Centre Regional de Microanalyse (Université Pierre et Marie Curie, Paris VI, France).

Synthesis and experimental data of terminal alkynes

.

2-Chloro-6-pyridine (8) 112

In a pressure vial were introduced 6-bromo-2-chloropyridine 3 (361 mg, 1.9 mmol, 1.0 equiv), CuI (18.1 mg, 0.09 mmol, 5 mol %) and PdCl2(PPh3)2 (66.1 mg, 0.09 mmol, 5 mol %). The vial was flushed with argon and dry and degassed THF (4.4 mL) was added, followed by Et3N (0.8 mL, 5.7 mmol, 3.0 equiv) and ethynyltrimethylsilane (222 mg, 0.32 mL, 2.26 mmol, 1.2 equiv). The mixture was then sealed with a teflon-lined cap and stirred at rt for 2 h. The reaction mixture was filtered over a thin bed of silica gel (AcOEt washings), then an aqueous saturated NaHCO3 solution was added to the filtrate and the aqueous phase was extracted twice with AcOEt. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=2:98) to afford the desired product (355 mg, 1.69 mmol, 90%) as a brown solid.

, 63 (11).

To a solution of 2-chloro-5-[(trimethylsilyl)ethynyl]pyridine (600 mg, 2.86 mmol, 1.0 equiv) in MeOH (6 mL) was added K2CO3 (39 mg, 0.29 mmol, 0.1 equiv) in one portion. The resulting suspension was stirred under air at rt for 30 min. The reaction mixture was then concentrated under reduced pressure, an aqueous saturated NaHCO3 solution was added and the aqueous phase was extracted three times with AcOEt. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (Et2O/PE=5:95) to afford the desired product 9 (290 mg, 2.11 mmol, 74%) as a white solid.

.

5-Ethynyl-2-methyl-1,3-benzoxazole (10) 112

In a pressure vial were introduced 5-bromo-2-methyl-1,3-benzoxazole 5 (1.0 g, 4.72 mmol, 1.0 equiv), CuI (89.8 mg, 0.47 mmol, 10 mol %) and PdCl2(PPh3)2 (331 mg, 0.47 mmol, 10 mol %). The vial was flushed with argon and dry and degassed THF (12 mL) was added, followed by Et3N (2.0 mL, 14.2 mmol, 3.0 equiv) and trimethylsilylacetylene (2.0 mL, 13.7 mmol, 2.9 equiv). The mixture was then sealed with a teflon-lined cap and stirred at rt for 2 h. The reaction mixture was filtered over a thin bed of silica gel (AcOEt washings), then an aqueous saturated NaHCO3 solution was added to the filtrate and the aqueous phase was extracted twice with AcOEt. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was directly engaged without purification and MeOH (11 mL) and K2CO3 (1.96 g, 14.15 mmol, 3.0 equiv) were added. The resulting suspension was stirred under air at rt for 4 h. The reaction mixture was then concentrated under reduced pressure, an aqueous saturated NaHCO3 solution was added and the aqueous phase was extracted three times with AcOEt. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure.

, 158 (4), 119 (9), 118 (9), 109 (3), 107 (4), 79 (10).

In a pressure vial were weighted [(4-bromophenyl)ethynyl]trimethylsilane (1.2 g, 4.7 mmol, 1.0 equiv), Pd(PPh3)4 (274 mg, 0.24 mmol, 5 mol %) and PPh3 (6.2 mg, 0.024 mmol, 0.5 mol %). The vial was flushed with argon, then dry toluene (25 mL) was added, followed by Et3N (0.72 mL, 5.2 mmol, 1.1 equiv). The vial was sealed with a teflon-lined cap, the reaction mixture was stirred at 110 °C for 5 min, then diethyl phosphite (0.78 mL, 5.7 mmol, 1.2 equiv) was added through the septum. The MS m/z (relative intensity): 310 (M +• , 21), 296 (19), 295 (100), 282 (18), 267 (28), 237 (8), 221 (36), 158 (9), 120 (15). MS m/z (relative intensity): 238 (M +• , 23), 210 (19), 183 (13), 182 (100), 166 (31), 165 (39), 129 (46), 128 (14), 118 (43), 102 (53), 101 (37), 89 (8), 75 (27), 65 (8), 51 (12).

Methyl 3-ethynylbenzoate (14) 126

To a solution of 3-ethynylbenzoic acid 13 (927 mg, 6.34 mmol, 1.0 equiv) in DMF (30 mL), were added K2CO3 (1.3 g, 9.41 mmol, 1.5 equiv) and MeI (1.5 g, 0.64 mL, 10.2 mmol, 1.6 equiv). The solution was stirred at rt for 16 h. The reaction mixture was then filtrated and concentrated under reduced pressure and an aqueous saturated NaHCO3 solution was added. The aqueous phase was extracted three times with Et2O. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (Et2O/PE=20: MS m/z (relative intensity): 199 (M +• , 28), 160 (100), 133 (21), 104 (12), 77 (20), 50 (9). This solid was suspended in MeCN (7 mL), and Boc2O (8.4 mL, 39.4 mmol, 2.5 equiv) was added, followed by Et3N (6.60 mL, 47.3 mmol, 3.0 equiv) and DMAP (1.93 g, 15.8 mmol, 1.0 equiv). The resulting suspension was stirred at rt for 20 h. An aqueous saturated solution of NaHCO3 was added, followed by AcOEt. The aqueous phase was extracted twice with AcOEt. The combined organic phases were washed once with an aqueous 0.5 M HCl solution, twice with H2O, once with brine, dried over Na2SO4, and concentrated under reduced pressure to afford a white solid (1.9 g). GCMS analysis showed that the solid was not 21 but the monoprotected product 20.

To a solution of this crude solid (1.90 g, 11.2 mmol, 1.0 equiv) in MeCN (6 mL) was added Boc2O (3.60 g, 16.9 mmol, 1.5 equiv), followed by DMAP (1.37 g, 11.2 mmol, 1.0 equiv). The resulting solution was stirred at rt for 16 h. After concentration under reduced pressure, purification by flash column chromatography on silica gel (Et2O/PE=20:

, 169 (24), 138 (6), 75 (12), 69 (13).

HRMS: calcd for C12H6F7N2 (M+H + ): 311.0414. Found 311.0415.

4-Fluoro-3-(3-carbomethoxyphenyl)-6-(trifluoromethyl)pyridazine (42)

Prepared according to procedure A from methyl 3-ethynylbenzoate 14 (70 mg, 0.44 mmol, 1.0 equiv).

After the addition of (trifluoromethyl)diazomethane, 72 h were necessary to reach complete consumption of the gem-difluorocyclopropene. Formation of (pentafluoroethyl)diazomethane in situ: In an oven-dried vial were introduced 2,2,3,3,3-pentafluoropropan-1-amine hydrochloride (1.5 equiv compared to the alkyne) and NaNO2

(1.8 equiv compared to the alkyne). The vial was then flushed with argon, CH2Cl2 (c = 0.6 M) and H2O (CH2Cl2/H2O=30:1) were added. The reaction was then stirred at 0 °C for 1 h and at 78 °C for 10 min.

The solution was then added to the difluorocyclopropene solution via a syringe.

Prepared according to procedure A from phenylacetylene 22 (70 mg, 0.69 mmol, 1.0 equiv). After the addition of (pentafluoroethyl)diazomethane, 72 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=2:98) to afford 71 (142 mg, 0.48 mmol, 71%) as a light yellow solid. (5), 120 (22), 100 (5), 98 (6), 75 (10), 69 (5), 51 (9).

HRMS: calcd for C12H6F6N2Na (M+Na + ): 315.0327. Found 315.0328. MS m/z (relative intensity): 224 (M +• , 100), 195 (43), 177 (11), 175 (7), 151 (8), 146 (31), 125 (7), 120 (22), 102 (6), 94 (7), 75 (8), 51 (16).

HRMS: calcd for C11H7F3N2Na (M+Na + ): 247.0454. Found 247.0454. MS m/z (relative intensity): 279 (M +• , 92), 278 (100), 251 (21), 237 (13), 202 (22), 183 (37), 126 (10), 115 (8), 102 (21), 89 (16), 77 (16), 56 (24). MS m/z (relative intensity): 280 (M +• , 100), 279 (90), 251 (95), 249 (63), 239 (24), 224 (35), 203 (10), 196 (18), 170 (9), 144 (10), 142 (10), 133 (12), 128 (17), 126 (20), 115 (16), 108 (99), 102 (42), 89 (27), 77 (36), 69 (78), 63 (33), 51 (22).

HRMS: calcd for C14H12F3N2O (M+H + ): 281.0896. Found 281.0893.

4-Ethylthio-3-phenyl-6-(trifluoromethyl)pyridazine (78)

To a stirred solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (50 mg, 0.207 mmol, 1.0 equiv) in MeCN (0.2 mL) was added sodium ethanethiolate (28.9 mg, 0.31 mmol, 1.5 equiv) and the reaction mixture was stirred at 100 °C for 4 h. An aqueous saturated NaHCO3 solution was added to the mixture and the aqueous phase was extracted with AcOEt. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. MS m/z (relative intensity): 284 (M +• , 36), 255 (100), 207 (28), 183 (6), 158 (5), 134 (18), 126 (9), 120 (12), 89 (9), 77 (7), 69 (7).

HRMS: calcd for C13H12F3N2S (M+H + ): 285.0668. Found 285.0671. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=20: MS m/z (relative intensity): 283 (M +• , 28), 237 (100), 217 (8), 188 (64), 168 (20), 159 (12), 139 (19), 115 (18), 89 (14), 77 (15), 69 (14), 51 (12).

HRMS: calcd for C12H8F3N3O2Na (M+Na + ): 306.0461. Found 306.0462. MS m/z (relative intensity): 327 (M +• , 100), 296 (81), 282 (9), 269 (35), 268 (67), 220 (12), 201 (12), 200 (28), 162 (7), 144 (13), 120 (17), 86 (15), 75 (5), 57 (9). (CH, q, J = 2.4 Hz, C2), 65.9 (2xCH2, C7), 52.5 (CH3, C13), 49.5 (2xCH2, C6).

4-Methyl

MS m/z (relative intensity): 367 (M +• , 100), 352 (14), 336 (17), 309 (37), 308 (62), 250 (31), 240 (18), 202 (12), 139 (17), 125 (24), 86 (14), 59 (20). MS m/z (relative intensity): 339 (M +• , 100), 338 (60), 324 (22), 308 (29), 296 (17), 281 (20), 280 (35), 266 (10), 250 (11), 238 (11), 213 (12), 144 (9), 132 (11), 113 (6), 89 (10), 86 (24).

HRMS: calcd for C16H16F3N3O2Na (M+Na + ): 362.1087. Found 362.1086. MS m/z (relative intensity): 339 (M +• , 71), 308 (16), 280 (13), 266 (10), 253 (100), 225 (10), 219 (10), 182 (9), 155 (8), 131 (9), 118 (12), 102 (13), 91 (18), 86 (48), 77 (10), 57 (12). MS m/z (relative intensity): 334 (M +• , 34), 305 (100), 257 (7), 236 (5), 234 (5), 207 (9), 158 (8), 134 (20), 126 (8), 121 (15), 89 (8).

HRMS

HRMS: calcd for C14H12F5N2S (M+H + ): 335.0636. Found 335.0638. MS m/z (relative intensity): 261 (M +• , 100), 260 (98), 233 (17), 219 (11), 184 (29), 183 (40), 165 (5), 126 (8), 115 (10), 102 (18), 89 (15), 77 (14), 63 (6), 56 (17), 51 (11).

HRMS: calcd for C14H14F2N3 (M+H + ): 262.1150. Found 262.1148.

4-Ethylthio-3-phenyl-6-(difluoromethyl)pyridazine (89)

To a stirred solution of 4-fluoro-3-phenyl-6-(difluoromethyl)pyridazine 72 (26 mg, 0.12 mmol, 1.0 equiv) in MeCN (0.11 mL) was added sodium ethanethiolate (16 mg, 0.14 mmol, 2.0 equiv) and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=5:95) to afford 80 MS m/z (relative intensity): 266 (M +• , 39), 237 (100), 189 (24), 158 (5), 134 (16), 121 (11), 89 (7), 77 (6), 51 (7).

(
HRMS: calcd for C13H13F2N2S (M+H + ): 267.0762. Found 267.0760.

Synthesis of trifluoromethylated nitrogen-containing heterocycles

  Abbreviations ................................................................................................

3. 1 . 1 .

 11 Formation of an aziridinium under acidic conditions .......................................................... 3.1.2. Formation of an aziridinium by N-alkylation ....................................................................... 4. Results and discussion ............................................................................... 4.1.1. Synthesis of 2-substituted, 2-(trifluoromethyl)pyrrolidines ............................................... 4.1.1.1. Synthesis of the starting material ................................................................................ 4.1.1.2. Optimization of the conditions for the ring contraction .............................................. 4.1.1.3. Scope of the reaction ................................................................................................... 4.1.1.4. Use of a chiral nucleophile: Chirality transfer .............................................................. 4.1.1.1. Comparison of the reactivity of 3-hydroxy-3-(trifluoromethyl)piperidine with 3-hydroxy-3-methylpiperidine .................................................................................................. 4.1.2. Synthesis of 2-substituted, 2-(trifluoromethyl)piperidines ................................................. 4.1.2.1. Synthesis of the starting material ................................................................................ 4.1.2.2. Scope of the ring contraction process .......................................................................... 4.1.2.3. Comparison of the reactivity of 3-hydroxy-3-(trifluoromethyl)azepane with 3-hydroxy-3-methylazepane ..................................................................................................................... 5. Conclusion ............................................................................................... CHAPTER 2: Experimental Part .................................................................... 1. General experimental methods ............................................................... 3. General procedures for the [2+1]/[3+2]-cycloaddition sequence ............. 4. Synthesis and spectroscopic data of 6-(trifluoromethyl)pyridazines ........ 5. Synthesis and spectroscopic data of 4-fluoro-3-phenyl-6-(perfluoroethyl)pyridazine (71) ................................................................... 6. Synthesis and spectroscopic data of 4-fluoro-3-phenyl-6-(difluoromethyl)pyridazine (72) .................................................................. 7. Post-functionalization of 6-(trifluoromethyl) pyridazines: Synthesis and spectroscopic data of pyridazines 7389 ..................................................... General Conclusion ..................................................................................... Bibliography ................................................................................................

Abbreviations

  Abbreviations

2 - 1 2 3 Chapitre 1 :

 21231 (trifluorométhyl)pyrrolidines (Schéma 1, éq 1) et des 2-(trifluorométhyl)pipéridines fonctionnalisées (Schéma 1, éq 2). Schéma Le troisième chapitre présente une séquence de cycloadditions [2+1]/[3+2] impliquant un alcyne terminal, un difluorocarbène et le (trifluorométhyl)diazométhane, afin d'obtenir des 4-fluoro-6-(trifluorométhyl)pyridazines substituées en position C3 (Schéma 2). Schéma Ces pyridazines ont ensuite été fonctionnalisées en position C4 par une substitution nucléophile aromatique (SNAr) pour conduire aux pyridazines 3,4,6-substituées (Schéma 3). Schéma Le fluor en chimie médicinale L'atome de fluor est un atome petit possédant un rayon de Van der Waals de 1.47 Å, intermédiaire entre celui de l'hydrogène et celui de l'oxygène, tout en étant proche de celui de l'oxygène. Le fluor étant l'élément le plus électronégatif de la classification périodique, induit la polarisation de la liaison C-F avec une charge négative partielle sur l'atome de fluor et une charge positive partielle sur l'atome de carbone, ce qui confère à la liaison C-F un caractère ionique significatif. Ainsi, la liaison C-F est courte (1.40 Å) et forte (l'énergie de liaison est de 105 kcal/mol) (Tableau 1).

Chapitre 2 :

 2 d'électrons libres sont fortement attirées par le noyau ce qui rend cet atome relativement inerte. D'autre part, une orbitale antiliante σ* de faible énergie, orientée dans le plan de la liaison C-F, peut accepter les électrons d'un groupement donneur proche, tel qu'une paire d'électrons libres ou les électrons d'une liaison σ. Le remplacement d'une liaison C-H par une liaison C-F est très utilisé en chimie médicinale, car si l'introduction d'un atome de fluor, ne modifie pas la taille de la molécule, en revanche, électroniquement parlant, ce remplacement n'est pas négligeable et peut avoir une influence sur la stabilité métabolique, sur les interactions protéine-ligand et sur les propriétés physico-chimiques telles que le pKa ou la lipophilie des molécules. Contraction de cycle : synthèse de 2-(trifluorométhyl)pyrrolidines et de 2-(trifluorométhyl)pipéridines fonctionnalisées Les pyrrolidines et les pipéridines sont des cycles azotés à cinq et six chaînons respectivement, qui appartiennent à la famille des amines cycliques secondaires. Les motifs pyrrolidine et pipéridine sont présents dans de nombreux alcaloïdes possédant des activités biologiques intéressantes. De plus, ils représentent des motifs que nous pouvons retrouver dans certains médicaments présents sur le marché. Du fait des propriétés intéressantes du fluor, nous nous sommes intéressés à la synthèse des α-(trifluorométhyl)pyrrolidines et α-(trifluorométhyl)pipéridines A par contraction de cycle, à partir de (trifluorométhyl)pipéridines et de (trifluorométhyl)azépanes C respectivement via des intermédiaires aziridiniums B. Nous supposons que dû à la présence du groupement CF3, l'attaque d'un nucléophile devrait se faire de manière régioséléctive sur la position C2' de l'aziridinium B pour conduire au produit de contraction de cycle A (Schéma 4). Schéma 4 A) Synthèse de 2-(trifluorométhyl)pyrrolidines, 2-substituées Dans un premier temps, nous avons étudié la réaction de contraction de cycle de 3-hydroxy-3-(trifluorométhyl)pipéridine C1 pour obtenir des α-(trifluorométhyl)pyrrolidines A1 (Schéma 5).

Chapitre 3 : 25 L

 325 28, substituée en position C3 par un groupement méthyle à la place du groupement trifluorométhyle, a été traitée par Tf2O/éponge à proton D, suivi de l'ajout du fluorure de tétrabutylammonium. Le composé 30 a été obtenu avec un rendement de 36% tandis que le produit attendu de contraction 29 n'a pas été observé. Cela confirme donc l'hypothèse selon laquelle, le groupement CF3 agit comme un groupement directeur qui oriente le réarrangement de l'aziridinium intermédiaire vers le produit de contraction de cycle (Schéma 14). Schéma 14 B) Synthèse de 2-(trifluorométhyl)pipéridines, 2-substituées Suite à ces travaux, nous avons voulu appliquer les conditions précédemment développées (Tf2O/éponge à proton D/nucléophile) au 3,3-hydroxy-(trifluorométhyl)azépane C2 afin d'accéder à des α-(trifluorométhyl)pipéridines A2 (Schéma 15).Schéma 15Le N-benzylazépane 39 a été synthétisé à partir du chloroacétaldehyde 31 en 9 étapes. Le chloroacétaldehyde 31 a été mis en réaction avec de la poudre d'indium et du bromure d'allyle dans l'eau pour donner, après 3 h, le composé 32 avec 80% de rendement. Le composé 32, a ensuite été mis en réaction avec de l'allylamine pour former l'amino-alcool 33 avec un rendement de 96%, puis cet amino-alcool a été protégé par un groupement Boc pour conduire au composé 34 avec un rendement de 93%. Après la métathèse cyclisante de 34 en présence du catalyseur de Grubbs de première génération (Grubbs-I), l'azépane 35 a été obtenu avec 69% de rendement. Cet azépane a ensuite été hydrogéné en présence d'une quantité catalytique de PtO2 dans l'éthanol, pour donner le produit réduit 36 avec un rendement quantitatif. L'oxydation du composé 36 en présence du réactif de Dess-Martin, a permis la formation de l'azépanone 37 (86% de rendement). Après trifluorométhylation de 37 pendant 5 jours, à l'aide du TMSCF3, le (trifluorométhyl)azépane 38 a été isolé avec 93% de rendement. Les deux dernières étapes de la synthèse de 39 consistent en la déprotection de la fonction amine de 38 suivie de sa protection par un groupement benzyle, pour conduire au 3,3-hydroxy-(trifluorométhyl)azépane 39 (85%, 2 étapes) (Schéma 16).Schéma 16Ayant synthétisé le substrat de départ 39, ce dernier a été traité par de l'anhydride triflique, en présence de l'éponge à proton D au reflux du CH2Cl2 et après5 h, différents nucléophiles ont été ajoutés au milieu réactionnel. Lorsque des amines primaires comme la benzylamine ou l'aniline ont été utilisées, les pipéridines 40 et 41 ont été isolées respectivement avec un rendement de 62% et un rendement quantitatif. De plus, les α-(trifluorométhyl)pipéridines 4245 ont été obtenues avec de très bons rendements, lorsque des amines secondaires, telles que la diéthylamine, la diallylamine, la benzylamine et la morpholine, ont été utilisées comme nucléophiles (Schéma 17). Schéma 17 Après avoir étudié la réactivité de l'aziridinium B2 vis-à-vis de nucléophiles azotés, des nucléophiles oxygénés, sous forme d'alcools ou d'alcoolates, ont été examinés. Ainsi, les pipéridines 4652 ont été synthétisées avec de très bons rendements (82%quant). Soulignons que les meilleurs résultats ont été obtenus lorsque le nucléophile est sous la forme d'alcoolate (PhO  ) et d'acétate (AcO  ) puisque les pipéridines 51 et 52 ont été isolées avec des rendements quantitatifs (Schéma 18). Schéma 18 Deux nucléophiles soufrés sous la forme de thiolates ont été utilisés pour réaliser la contraction de cycle. Les α-(trifluorométhyl)pipéridines désirées 53 et 54 ont été isolées avec des bons rendements. Les sels d'halogénures tels que le fluorure, le chlorure, le bromure et l'iodure de tétrabutylammonium ont aussi été utilisés, afin d'obtenir les pipéridines halogénées 5558 avec des rendements allant de 69% à 89%. De plus, les pipéridines 59 et 60 ont été isolées avec des rendements excellents, lorsque le cyanure ou l'anion du malonate de méthyle ont été impliqués dans le processus de contraction de cycle. Signalons que le traitement de l'azépane 39, par l'anhydride triflique, suivi de l'addition du borohydrure de sodium, a permis l'obtention du composé 61 avec 73% de rendement (Schéma 19).Schéma 19 Il est intéressant de noter que la fluorométhyl-pipéridine 55 a été obtenue avec un rendement amélioré de 71% versus 61% lorsque l'azépane 39 a été traité par du DAST dans le THF (Schéma 20 versus Schéma 18). Schéma 20 La synthèse d'α-(trifluorométhyl)pipéridines substituées par un groupement alkyle a ensuite été envisagée. Pour cela, le (trifluorométhyl)azépane 39 a été traité par Tf2O/éponge à proton D, suivi de l'addition d'un organocupromagnésien. Le composé désiré 62 a été obtenu avec 50% de rendement. Parallèlement à la formation de 62, la formation du composé 56 a été observée par analyse GC/MS, indiquant une réaction entre l'ion chlorure de l'organocupromagnésien et l'aziridinium intermédiaire (Schéma 21). Schéma 21 Afin d'étudier l'influence du groupement CF3 sur la régiosélectivité de la réaction, nous avons remplacé le groupement CF3 de l'azépane 39, par un groupement CH3, comme nous l'avons fait pour la contraction de la pipéridine 3. Lors du traitement de l'azépane 63 par Tf2O/éponge à proton D suivi par l'addition de fluorure de tétrabutylammonium, la pipéridine 64 n'a pas été observée. Le seul produit isolé a été l'azépane 65 (31%), confirmant encore une fois le rôle important du CF3 comme groupement directeur pendant la contraction de cycle (Schéma 22). Schéma 22 Pour résumer, la synthèse d'α-(trifluorométhyl)pyrrolidines et d'α-(trifluorométhyl)pipéridines, possédant un centre quaternaire en position C2, a été réalisée par contraction de cycle de pipéridines et d'azépanes trifluorométhylées. La réaction est compatible avec une variété de nucléophiles tels que des amines, des alcools, des halogènes ou mêmes des nucléophiles soufrés et carbonés. De plus, il a été démontré que les contractions de cycle s'effectuaient via un transfert de chiralité. Enfin, notre hypothèse selon laquelle le pôle d'attaque du nucléophile sur l'intermédiaire bicyclique aziridinium était dirigé par le groupement trifluorométhyle a été validée. Synthèse d' α-(trifluorométhyl)pyridazines par une séquence de cycloadditions [2+1]/[3+2] Les pyridazines sont des hétérocycles aromatiques à six chaînons comportant deux atomes d'azote adjacents. Depuis leur découverte dans certains produits naturels ainsi qu'à la lumière des activités biologiques variées que ces produits possèdent, un grand intérêt synthétique pour le motif pyridazine est apparu ces dernières années. Au vu de l'importance pour le noyau pyridazine ainsi que les bénéfices apportés par le fluor en chimie médicinale, la mise au point d'une méthode de synthèse d'α-(trifluorométhyl)pyridazines est donc intéressante. En se basant sur des travaux précédemment effectués au laboratoire, nous avons envisagé d'accéder aux 6-(trifluorométhyl)pyridazines I par une séquence de cycloadditions [2+1]/[3+2] impliquant un alcyne terminal, un difluorocarbène et un composé diazo. En effet, le difluorocyclopropène F pourrait être formé lorsque l'alcyne E serait mis en réaction avec le difluorocarbène. Ce difluorocyclopropène, pourrait ensuite réagir avec le (trifluorométhyl)diazométhane pour conduire à une cyclopropanopyrazoline G. Suite au réarrangement de G suivie d'une aromatisation de H, les (trifluorométhyl)pyridazines I pourraient être obtenues (Schéma 23).Schéma 23 Le (trifluorométhyl)diazométhane 67, peut être formé à partir du chlorure de la trifluoroéthylamine 66, en présence du nitrite de sodium dans un mélange CH2Cl2/H2O à 0 °C. De l'acide nitreux (HNO2), généré in situ, réagit avec la trifluoroéthylamine 66 pour former l'intermédiaire nitroso qui, après une déshydratation, conduit au (trifluorométhyl)diazométhane 67 (Schéma 24). Schéma 24 Afin de vérifier si la réaction de cycloaddition entre un alcyne, un difluorocarbène et le (trifluorométhyl)diazométhane serait possible, le phénylacétylène a été mis en réaction avec le réactif de Ruppert-Prakash (TMSCF3) et d'iodure de sodium (NaI) dans le THF à 110 °C pendant 2 h. Dans ces conditions, l'ion iodure attaque le silicium du TMSCF3 pour former l'anion CF3, qui grâce à la haute température, peut se décomposer en ion F  et en difluorocarbène. Une fois le difluorocarbène formé, celui-ci peut subir une cycloaddition [2+1] en présence de phénylacétylène, afin de former un difluorocyclopropène. En présence du (trifluorométhyl)diazométhane (0.6 M dans le CH2Cl2), ce difluorocyclopropène peut subir une deuxième cycloaddition [3+2] pour mener à la pyridazine désirée 68 avec 87% de rendement (Schéma 25). Schéma 'étude du champ d'application de la séquence de cycloadditions [2+1]/[3+2] a été ensuite réalisée sur des alcynes terminaux, substitués par des groupements aryles possédant des groupements riches en électrons. Lorsque le noyau aromatique porte un substituant électro-donneur en position ortho ou para, les pyridazines correspondantes 6971 ont été isolées avec de très bons rendements (73%83%). La pyridazine 72, fonctionnalisée par un noyau benzénique tri-substitué, a été isolée avec un bon rendement de 76%. Cependant, la pyridazine 73, dont le noyau aromatique est substitué par un groupement N,N-diméthylaniline, n'a pas été obtenue, probablement à cause d'une incompatibilité entre le caractère nucléophile de l'azote de l'aniline et le caractère électrophile du difluorocarbène. Signalons qu'un alcyne terminal substitué par un groupement naphtyle peut aussi être engagé dans la séquence de cycloadditions pour donner la (trifluorométhyl)pyridazine 74 avec 79% de rendement. (Schéma 26). Schéma 26 Nous nous sommes par la suite intéressés à des alcynes terminaux portant des aryles qui possèdent des groupements électro-attracteurs. Lorsque le groupement aryle est substitué par un groupement CF3 en position ortho, ou un groupement ester en position méta et para, les pyridazines 75, 76 et 77 ont été isolées avec des bons rendements de 66% à 76%. Cependant, la présence d'un groupement phosphonate, ainsi qu'un groupement nitro sur le noyau aromatique a conduit aux pyridazines 78 et 79 avec des rendements plus faibles de 27% et 34% respectivement. Des aryles substitués par des halogènes peuvent aussi être engagés dans la séquence de cycloadditions [2+1]/[3+2], puisque les pyridazines 80, 81 et 82 ont été formées avec des rendements qui varient de moyens à bons (Schéma 27). Schéma 27 Devant les faibles rendements des pyridazines 78 et 79, un autre protocole a été mis en place afin d'accéder à ces composés avec des meilleurs rendements. Ainsi, le difluorocarbène peut être généré par réaction du fluorosulfonyldifluoroacétate de triméthylsilyle (TFDA) avec du fluorure de sodium (NaF) dans le diglyme à 120 °C. En effet, le TFDA est décomposé en difluorocarbène à 120 °C par une quantité catalytique de NaF, générant un équivalent de TMSF, du CO2, du SO2 ainsi qu'un ion F  . Il s'agit donc d'un procédé qui ne génère pas de nucléophiles tels que CF3  ou l'ion I  dans le milieu réactionnel (Schéma 28). Schéma 28 Après traitement des alcynes possédant des groupements aryles appauvris en électrons, avec du TFDA en présence de NaF dans le diglyme, les pyridazines correspondantes ont toutefois été obtenues avec des rendements similaires à ceux obtenus avec le protocole TMSCF3/NaI. Seule la pyridazine 79, possédant un aryle avec un groupement nitro en position para, a été isolée avec un rendement supérieur de 56% versus 34% obtenu avec TMSCF3/NaI. De plus, la pyridazine 83, possédant un aryle substitué par un cyanure en position méta a été obtenue avec 60% de rendement (Schéma 29).Schéma 29 Après avoir étudié la réactivité de divers alcynes terminaux substitués par des aryles dans la séquence de cycloadditions [2+1]/[3+2], la réactivité d'alcynes terminaux substitués par des hétérocycles aromatiques a été examinée. Plus précisément, des alcynes substitués par une pyridine, un thiophène ainsi qu'un groupement benzoxazole ont été traités dans les deux conditions réactionnelles (TMSCF3/NaI ou/et TFDA/NaF), et les pyridazines 8488 ont été isolées avec des rendements qui varient de faibles à très bons. Signalons que dans le cas des pyridazines 84 et 86, l'utilisation du protocole TFDA/NaF a mené à la dégradation du produit (Schéma 30).

(

  trifluoromethyl)azepanes via an aziridinium intermediate to obtain 2-substituted, 2-(trifluoromethyl)pyrrolidines (eq 1) and 2-substituted, 2-(trifluoromethyl)piperidines (eq 2trifluoromethyl)pyrrolidines and 2-substituted, 2-(trifluoromethyl)piperidines will be presented. The third chapter deals with the synthesis of α-(trifluoromethyl)pyridazines by a [2+1]/[3+2]-cycloaddition sequence between a terminal alkyne, a difluorocarbene and (trifluoromethyl)diazomethane. These (trifluoromethyl)pyridazines could be further functionalized at the C4 position to lead to a diversity of 3,4,6-substituted pyridazines.

7

 7

Figure 4 2. 3 .

 43 Figure 4

For a drug candidate

  to cross the membrane, it has to be sufficiently lipophilic. At the same time, high lipophilicity can often result in reduced solubility, which can then lead to several undesired properties for the compound, such as incomplete absorption after administration. To find a balance between lipophilicity and minimal polarity, fluorine is often used as a modulator.

Figure 6 B

 6 Figure 6

Figure 7

 7 Figure 7

Figure 8 C

 8 Figure 8

Figure 10

 10 Figure 10

Figure 12

 12 Figure 12

Figure 20 1. 3 .

 203 Figure 20

Figure 23

 23 Figure 23

1. 4 .

 4 Main synthetic methods to access 2-substituted, 2-(trifluoromethyl)pyrrolidines and 2-substituted, 2-(trifluoromethyl)piperidines Several synthetic methods have been reported in the literature, to obtain α-(trifluoromethyl)pyrrolidines and α-(trifluoromethyl)piperidines. As our goal is to synthesize 2-(trifluoromethyl)pyrrolidines and 2-(trifluoromethyl)piperidines possessing a quaternary center at the C2 position, we will only focus on methods developed to obtain 2-substituted, 2-(trifluoromethyl)pyrrolidines and 2-substituted, 2-(trifluoromethyl)piperidines (Figure 25).

Figure 25

 25 Figure 25

Scheme 5

 5 Scheme 5

and 2 -

 2 Scheme 29

4. 1 . 1 .

 11 Scheme 30

2 .. Scheme 46 4. 1 . 2 . 1 .

 246121 Scheme 45

Scheme 54 4. 1 . 2 . 3 .

 54123 Scheme 54

  -3-(trifluoromethyl)piperidine 1 and 3-hydroxy-3-(trifluoromethyl)azepane 44 was accomplished, to afford the corresponding pyrrolidines 74 1536 and piperidines 5476 respectively, possessing a quaternary center at the C2 position. A variety of nucleophiles such as amines, alcohols, thiols, carbanions and halides, can be used to obtain a diversity of 2-substituted, 2-(trifluoromethyl)pyrrolidines and 2-substituted, 2-(trifluoromethyl)piperidines in good to excellent yields (Scheme 58).

1 H 13 C

 113 NMR spectra were recorded on a Bruker AVANCE 400 at 400 MHz and data are reported as follows: chemical shift in ppm, with the solvent as internal standard (CDCl3, δ 7.26 ppm, DMSO-d6, δ 2.50 ppm). The multiplicity and shape of signals are designated by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br = broad, app = apparent. Coupling constants J were measured in Hertz. NMR spectra were recorded on a Bruker AVANCE 400 at 100 MHz and data are reported as follows: chemical shift in ppm, with the solvent as internal standard (CDCl3, δ 77.16 ppm, DMSO-d6, δ 39.52 ppm). The multiplicity and shape of signals are designated by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quadruplet, br = broad, m = multiplet. Coupling constants J were measured in Hertz.

13 C 1 )

 131 NMR (CDCl3, 100 MHz): δ 170.7 (C, C7), 140.0 (C, C11), 128.4 (2xCH, C12 or C13), 128.1 (2xCH, C12 or C13), 127.5 (C, q, J = 288.3 Hz, C9), 127.0 (CH, C14), 67.0 (C, q, J = 24.9 Hz, C5), 63.4 (CH2, C6), 53.0 (CH2, C10), 52.5 (CH2, C2), 31.4 (CH2, C4), 22.7 (CH2, C3), 21.0 (CH3, C8). MS m/z (relative intensity): 301 (M +• , 1), 228(25), 91 (100), 65(8).HRMS: calcd for C15H19F3NO2 (M+H + ): 302.1362. Found 302.1364.N-Benzyl-2-[(ethylsulfanyl)methyl]-2-(trifluoromethyl)pyrrolidine (31)Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = sodium ethanethiolate (81.1 mg, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=1:99) to afford 31 (70 mg, 0.23 mmol, 60%) as a colorless oil.

13 C 3 ( 6 (

 1336 NMR (CDCl3, 100 MHz): δ 138.8 (C, C10), 128.5 (2xCH, C11 or C12), 128.0 (2xCH, C11 or C12), 127.CH, C13), 127.1 (C, q, J = 290.6 Hz, C8), 116.4 (C, C7), 66.2 (C, q, J = 25.6 Hz, C5), 52.0 (CH2, C9), 51.CH2, C2), 33.4 (CH2, C4), 22.2 (CH2, C6), 22.0 (CH2, C3). MS m/z (relative intensity): 268 (M +• , 1), 228 (8), 199 (3), 91 (100), 65 (11), 54 (5). HRMS: calcd for C14H16F3N2 (M+H + ): 269.1260. Found 269.1259. N-Benzyl-2-[(1,3-dimethyl-propanedioate)methyl]-2-(trifluoromethyl)pyrrolidine (35)

1 H

 1 NMR (CDCl3, 400 MHz): δ 7.367.21 (m, 10Η, Har), 4.06 (d, J = 13.8 Hz, 1H, H14), 3.763.71 (m, 2H, H7 and H14), 2.90 (m, 1H, H2), 2.80 (d, J = 11.7 Hz, 1H, H6), 2.73 (m, 1H, H2), 2.54 (d, J = 11.7 Hz, 1H, H6), 2.40 (m, 1H, H4), 2.01 (m, 1H, H4), 1.791.76 (m, 2H, H3), 1.62 (br s, NH), 1.36 (d, J = 6.6 Hz, 3H, H8).

13 C 4 . 1 H

 1341 NMR (CDCl3, 100 MHz): δ 145.8 (C, C9 or C15), 140.3 (C, C9 or C15), 128.6 (4xCH, Car), 128.6 (C, q, J = 292.8 Hz, C13), 128.1 (2xCH, Car), 127.1 (CH, C12 or C18), 127.0 (CH, C12 or C18), 126.7 (2xCH, Car), 68.4 (C, q, J = 23.0 Hz, C5), 59.0 (CH, C7), 52.0 (2xCH2, C2 and C14), 47.0 (CH2, C6), 30.5 (CH2, C4), 25.6 (CH3, C8), 22.3 (CH2, C3). MS m/z (relative intensity): 362 (M +• , 0.04), 228 (8), 209 (49), 208 (29), 134 (12), 105 (69), 91 (100), 79 (8), 77 (8), 65 (10), 51 (3).HRMS: calcd for C21H26F3N2 (M+H + ): 363.2043. Found: 363.2045. Synthesis and spectroscopic data of N-benzyl-3-hydroxy-3-methylpiperidine(37) tert-Butyl 3-methyl-3-hydroxypiperidin-1-carboxylate (41)76 To a stirred solution of N-Boc-3-piperidone 3 (1.48 g, 7.43 mmol, 1.0 equiv) in THF (37 mL) at 0 °C was added MeMgBr (3.0 M in Et2O, 9.9 mL, 29.7 mmol, 4.0 equiv) and the resulting mixture was stirred at rt for 16 h. The solution was quenched with an aqueous and saturated solution of NH4Cl and extracted with EtOAc (twice). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (Et2O/PE=30:70) to afford 41 (800 mg, 3.72 mmol, 50%) as a colorless oil. IR (neat): 3393, 2930, 1684, 1422, 1365, 1274, 1247, 1158, 1049, 1025, 1001 cm -1 . NMR (DMSO-d6, 400 MHz at 122 o C): δ 3.81 (br s, OH), 3.323.22 (m, 2H, H2), 3.19 (d, J = 12.8 Hz, 1H, H6), 3.13 (d, J = 12.9 Hz, 1H, H6), 1.67 (m, 1H, H3), 1.541.50 (m, 2H, H4), 1.38 (m, 1H, H3), 1.42 (s, 9H, H10), 1.11 (s, 3H, H7).

13 C 9 (

 139 NMR (DMSO-d6, 400 MHz at 122 o C): δ 153.8 (C, C8), 77.6 (C, C9), 66.2 (C, C5), 54.2 (CH2, C6), 42.CH2, C2), 37.2 (CH2, C4), 27.6 (3xCH3, C10), 25.4 (CH3, C7), 21.1 (CH2, C3).

5 . 1 H

 51 Synthesis and spectroscopic data of N-benzyl-3-fluoro-3methyl piperidine(43) N-Benzyl-3-fluoro-3-methylpiperidine(43) Following the general protocol: N-benzyl-3-hydroxy-3-methylpiperidine 37 (50 mg, 0.24 mmol, 1.0 equiv), proton sponge (104 mg, 0.49 mmol, 2.0 equiv), triflic anhydride (61 L, 0.37 mmol, 1.5 equiv). Nucleophile = tetrabutylammonium fluoride (1.0 M in THF, 0.61 mL, 0.61 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=5:95 and 10:90) to afford 43 (18 mg, 0.09 mmol, 36%) as a yellow oil. IR (neat): 2935, 2859, 2801, 1732, 1679, 1604, 1495, 1453, 1376, 1304, 1284, 1204, 1166, 1130, 1028, 920, 881 cm -1 . NMR (CDCl3, 400 MHz): δ 7.337.23 (m, 5Η, H10, H11 and H12), 3.55 (s, 2H, H8), 2.652.53 (m, 2H, H2 and H6), 2.272.17 (m, 2H, H2 and H6), 1.851.76 (m, 2H, H3 and H4), 1.571.45 (m, 2H, H3 and H4), 1.34 (d, J = 21.7 Hz, 3H, H7).

13 C

 13 NMR (CDCl3, 100 MHz): δ 138.1 (C, C9), 129.2 (2xCH, C10 or C11), 128.3 (2xCH, C10 or C11), 127.1 (CH, C12), 92.7 (C, d, J = 169.7 Hz, C5), 62.9 (CH2, C8), 62.0 (CH2, d, J = 22.9 Hz, C6), 53.0 (CH2, C2), 35.4 (CH2, d, J = 22.4 Hz, C4), 25.2 (CH3, d, J = 24.1 Hz, C7), 22.3 (CH2, d, J = 4.7 Hz, C3). MS m/z (relative intensity): 207 (M

1 H

 1 NMR (CDCl3, 400 MHz): δ 5.81 (ddt, J = 17.3, 10.2 and 7.1 Hz, 1H, H4), 5.185.11 (m, 2H, H5), 3.88 (m, 1H, H2), 3.61 (dd, J = 11.2 and 4.0 Hz, 1H, H1), 3.51 (d, J = 11.2 and 6.3 Hz, 1H, H1), 3.29 (br s, OH), 2.392.31 (m, 2H, H3).

13 C 1 H

 131 NMR (CDCl3, 100 MHz): δ 133.3 (CH, C4), 118.2 (CH2, C5), 70.5 (CH, C2), 49.0 (CH2, C1), 38.5 (CH2, C3). N-(Allylamino)pent-7-en-5-ol (46) 73 1-chloropent-4-en-2-ol 48 (3.73 g, 30.9 mmol, 1.0 equiv) was treated with allylamine (11.6 mL, 154 mmol, 5.0 equiv) and the reaction mixture was stirred at 86 °C for 5 days. The solution was concentrated under reduced pressure to remove the excess of allylamine. The crude mixture was purified by flash chromatography (MeOH/CH2Cl2=2:98 and 10:90) to afford 46 (4.2 g, 29.4 mmol, 96%) as an orange oil. IR (neat): 3301, 3076, 2978, 2911, 2825, 1642, 1441, 1341, 1078, 993, 913 cm -1 . NMR (CDCl3, 400 MHz): δ 5.975.79 (m, 2H, H2 and H7), 5.285.07 (m, 4H, H1 and H8), 4.38 (s, 2H, OH and NH), 3.85 (m, 1H, H4), 3.373.35 (m, 2H, H6), 2.78 (dd, J = 12.2 and 3.0 Hz, 1H, H5), 2.59 (dd, J = 12.2 and 9.5 Hz, 1H, H5), 2.272.23 (m, 2H, H3).

13 C

 13 NMR (CDCl3, 400 MHz) mixture of rotamers: δ 212.2 (C, C6), 155.2 (C, C8), 154.3 (C, C8'), 80.5 (C, C9), 80.3 (C, C9'), 58.5 (CH2, C7), 57.7 (CH2, C7'), 49.9 (CH2, C2), 49.7 (CH2, C2'), 42.8 (CH2, C5), 42.5 (CH2, C5'), 29.2 (CH2, C3), 28.3 (CH2, C3'), 28.4 (3xCH3, C10), 28.3 (3xCH3, C10'), 23.9 (CH2, C4), 23.7 (CH2, C4').

13 C 3 (

 133 NMR (CDCl3, 100 MHz): δ 139.8 (C, C10), 128.6 (C, q, J = 299.5 Hz, C8), 128.4 (2xCH, C11 or C12), 128.2xCH, C11 or C12), 127.0 (CH, C13), 62.9 (C, q, J = 21.2 Hz, C6), 54.0 (CH2, C9), 46.2 (CH2, C2), 45.0 (CH2, C7), 28.6 (CH2, C5), 25.0 (CH2, C3), 20.0 (CH2, C4).

1 H

 1 ): 2945, 2852, 1453,1243, 1132, 1117 cm -1 . NMR (CDCl3, 400 MHz): δ 7.357.20 (m, 5H, H12, H13 and H14), 4.16 (d, J = 15.2 Hz, 1H, H10), 3.48 (ddapp, J = 15.2 and 2.4 Hz, 1H, H10), 2.642.59 (m, 2H, H2), 1.96 (dq, J = 15.0 and 7.5 Hz, 1H, H7), 1.841.45 (m, 7H, H3, H4, H5 and H7), 0.98 (t, J = 7.5 Hz, 3H, H8).

13 C

 13 NMR (CDCl3, 100 MHz): δ 140.6 (C, C11), 130.1 (C, q, J = 299.7 Hz, C9), 128.4 (2xCH, C12 or C13), 127.7 (2xCH, C12 or C13), 126.7 (CH, C14), 61.8 (C, q, J = 20.2 Hz, C6), 53.7 (CH2, C10), 46.3 (CH2, C2), 29.0 (CH2, C5), 25.5 (CH2, C3 or C7), 25.3 (CH2, C3 or C7), 20.5 (CH2, C4), 7.3 (CH3, C8). MS m/z (relative intensity): 272 (M

13 C 3 (

 133 NMR (CDCl3, 400 MHz): δ 158.2 (C, C9), 80.3 (C, C10), 74.5 (C, C6), 58.6 (CH2, C7), 49.6 (CH2, C2), 42.CH2, C5), 29.4 (CH2, C3 or C4), 28.5 (3xCH3, C11), 27.5 (CH3, C8), 21.9 (CH2, C3 or C4).

1 H

 1 IR (neat): 2931, 2862, 1494, 1375, 1350, 1263, 1228, 1188, 1117, 1042, 1029, 965, 910 cm -1 . NMR (CDCl3, 400 MHz): δ 7.357.21 (m, 5H, H11, H12 and H13), 3.71 (d, J = 13.5 Hz, 1H, H9), 3.66 (d, J = 13.5 Hz, 1H, H9), 2.87 (m, 1H, H7), 2.732.59 (m, 3H, H2 and H7), 1.98 (m, 1H, H5), 1.861.64 (m, 3H, H3, H4, and H5 ), 1.58 (m, 1H, H3), 1.42 (m, 1H, H4), 1.25 (d, J = 21.7 Hz, 3H, H8).

13 C 1 (

 131 NMR (CDCl3, 100 MHz): δ 139.9 (C, C10), 129.0 (2xCH, C11 or C12), 128.3 (2xCH, C11 or C12), 127.CH, C13), 98.3 (C, d, J = 166.4 Hz, C6), 65.4 (CH2, d, J = 28.9 Hz, C7), 63.9 (CH2, C9), 57.5 (CH2, C2), 40.0 (CH2, d, J = 23.4 Hz, C5), 30.8 (CH2, C3), 26.6 (CH3, d, J = 25.0 Hz, C8), 21.8 (CH2, d, J = 6.0 Hz, C4).

1. 4 .

 4 Main synthetic methods to access α-(trifluoromethyl) pyridazines and derivatives One of the first synthesis of a α-(trifluoromethyl)pyridazine, was reported by Kobayashi et al. in 1980. 91 When triazoline L3.1 was activated with triphenylphosphine, intermediate L3.3 was formed. This intermediate could then react with cyclopropene L3.2 to afford intermediate L3.4 which, after the release of triphenylphosphine oxide, produced the polycyclic compound L3.5 possessing four CF3 groups (38% yield) (Scheme 60).

  a) the condensation of hydrazine with a carbonyl compound or b) a Staudinger/intramolecular diaza-Wittig sequence. 1.4.1.1. Condensation of hydrazine with carbonyl compounds Condensation of hydrazine with a variety of carbonyl compounds is a typical method to access α-(trifluoromethyl)pyridazines. Generally, the mechanism involves the reaction of hydrazine with a dicarbonyl compound C, to afford intermediate D by elimination of one molecule of H2O. Reaction of the second nitrogen of the hydrazine with the second carbonyl group and elimination of another molecule of H2O, leads to the desired pyridazines E (Scheme 62).

catalyst. A [ 1 , 3 ] 77 1. 4 . 1 . 2 . 79 1. 4 . 2 .

 13774127942 Scheme 77

  Scheme 92

Recently, a [ 96 Pyridazines

 a96 Scheme 96

  of (trifluoromethyl)diazomethane were necessary for a total conversion of the cyclopropene. b) When the reaction was carried out at 55 °C, the reaction time decreased in 12 days and the product was obtained in 83% yield.

a

  nucleophilic attack by the anions present in the reaction mixture (CF3  and I  ) when treated with the Hu and Prakash conditions. To solve this problem, another source of difluorocarbene was envisaged, based on the work of Chen et al. 117 Thus, TMSCF3 was replaced by trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) and NaI by a catalytic amount of NaF. After the attack of the fluorine to the trimethylsilyl group of TFDA, a difluorocarbene is formed, along with CO2, SO2 and fluorine. This fluorine can then attack another molecule of TFDA, in consequence a catalytic amount of NaF is necessary (Scheme 109).

  117 a) Tian, F.; Kruger, V.; Bautista, O.; Duan, J. -X.; Li, A. -R.; Dolbier, Jr. W. R.; Chen, Q. -Y. Org. Lett. 2000, 2, 563564; b) Xu, W.; Chen, Q. -Y. J. Org. Chem. 2002, 67, 94219427. equiv of TFDA were necessary for a total conversion of the alkyne.

  equiv of TMSCF3 were necessary for a total conversion of the alkyne. b) 3.0 more equiv of TFDA were necessary for a total conversion of the alkyne. c) 1.0 more equiv of TMSCF3 were necessary for a total conversion of the alkyne.

  118 a) Mykhailiuk, P. K. Chem. Eur. J. 2014, 20, 49424947; b) Mykhailiuk, P. K. Beilstein J. Org. Chem. 2015, 11, 1624; c) Mykhailiuk, P. K.; Ishchenko, A. Y.; Stepanenko, V.; Cossy, J. Eur. J. Org. Chem. 2016, 54855493. difluorocyclopropene 23, the cycloaddition product 71 was isolated in 71% yield (Scheme 112). It should be mentioned that difluorocyclopropene 23 was formed after a [2+1]-cycloaddition between the difluorocarbene generated from TMSCF3/NaI and phenylacetylene 22.

  Scheme 114

3. 3 . 3 . 3 . 1 .

 3331 Scheme 115

entry 1 )

 1 . The replacement of the phenyl ring at C3 by 4-fluorobenzene (the fluorine atom being a weak electron-withdrawing group), led to the corresponding α-(trifluoromethyl)pyridazine 82 in an excellent yield (quant) (

  reaction was carried out at 100 °C.

  Scheme 117

1 H 13 C

 113 NMR spectra were recorded on a Bruker AVANCE 400 at 400 MHz and data are reported as follows: chemical shift in ppm, with the solvent as internal standard (CDCl3, δ 7.26 ppm). The multiplicity and shape of signals are designated by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br = broad, app = apparent. Coupling constants J were measured in Hertz. NMR spectra were recorded on a Bruker AVANCE 400 at 100 MHz and data are reported as follows: chemical shift in ppm, with the solvent as internal standard (CDCl3, δ 77.16 ppm). The multiplicity and shape of signals are designated by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quadruplet, br = broad, m = multiplet. Coupling constants J were measured in Hertz.

13 C

 13 NMR (CDCl3, 100 MHz): δ 133.5 (CH, C5), 131.6 (CH, C6), 122.9 (C, C4 or C7), 122.3 (C, C4 or C7), 104.0 (C, C3), 95.5 (C, C2), 0.0 (3xCH3, C1). MS m/z (relative intensity): 254 (M +• , 22), 252 (M +• , 22), 239 (100), 237 (100), 220 (14), 209 (5), 207

1 H

 1 reaction mixture was then stirred at 110 °C for 4 h. An aqueous saturated NaHCO3 solution was added to the reaction mixture, and the aqueous phase was extracted 2 times with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a black oil. The crude mixture was purified by flash chromatography (AcOEt/PE=50:50) to give the desired product (1.19 g, 3.80 mmol, 81%) as a pale yellow oil. Diethyl {4-[(trimethylsilyl)ethynyl]phenyl}phosphonate 124 IR (neat): 2981, 1560, 1392, 1249, 1128, 1051, 1019, 964 cm -1 . NMR (CDCl3, 400 MHz): δ 7.757.70 (m, 2H, H6), 7.547.51 (m, 2H, H5), 4.154.02 (m, 4H, H8), 1.30 (t, J = 7.1 Hz, 6H, H9), 0.25 (d, J = 3.4 Hz, 9H, H1).

13 C

 13 NMR (CDCl3, 100 MHz): δ 131.9 (2xCH, d, J = 15.2 Hz, C5), 131.7 (2xCH, d, J = 10.0 Hz, C6), 128.4 (C, d, J = 189.0 Hz, C7), 127.4 (C, d, J = 3.4 Hz, C4), 104.0 (C, C3), 97.6 (C, C2), 62.3 (2xCH2, d, J = 5.4 Hz, C8), 16.4 (2xCH3, d, J = 6.4 Hz, C9), 0.0 (3xCH3, C1).

To a solution of 1 H

 1 diethyl {4-[(trimethylsilyl)ethynyl]phenyl}phosphonate (1.18 g, 3.8 mmol, 1.0 equiv) in THF (59 mL) was added TBAF (1.0 M in THF, 13.0 mL, 3.4 mmol, 3.4 equiv). The resulting solution was stirred at 0 °C for 2 h. This solution was then filtered over a short pad of silica gel (EtOAc washings), and the filtrate was concentrated under reduced pressure to give an orange oil. The crude mixture was purified by flash chromatography (AcOEt/PE=50:50) to afford 12 (799 mg, 3.35 mmol, 88%) as a yellow oil.Diethyl (4-ethynylphenyl)phosphonate (12) IR (neat): 3200, 2983, 1560, 1392, 1240, 1125, 1049, 1016, 962 cm -1 . NMR (400 MHz, CDCl3): δ 7.807.74 (m, 2H, H5), 7.597.56 (m, 2H, H4), 4.194.05 (m, 4H, H7), 3.22 (s, 1H, H1), 1.32 (td, J = 7.1 and 0.6 Hz, 6H, H8).

13 C

 13 NMR (CDCl3, 100 MHz): δ 132.1 (2xCH, d, J = 15.2 Hz, C4), 131.8 (2xCH, d, J = 10.0 Hz, C5), 129.0 (C, d, J = 189.1 Hz, C6), 126.4 (C, d, J = 3.5 Hz, C3), 82.7 (C, d, J = 1.5 Hz, C2), 79.9 (CH, C1), 62.4 (2xCH2, d, J = 5.4 Hz, C7), 16.4 (2xCH3, d, J = 6.4 Hz, C8).

13 C

 13 NMR (CDCl3, 100 MHz): δ 168.1 (2xC, C5), 134.1 (2xCH, C7), 132.0 (2xC, C6), 123.4 (2xCH, C8), 80.4 (C, C2), 70.4 (CH, C1), 36.6 (CH2, C4), 18.4 (CH2, C3).

N

  ,N-Bis[(tert-butoxy)carbonyl]-N-(but-3-yn-1-yl)carbamate (21) 112 To a solution of N-homopropargyl phthalimide 19 (3.14 g, 15.8 mmol, 1.0 equiv) in absolute ethanol (70 mL) was added hydrazine hydrate (1.20 mL, 31.5 mmol, 2.0 equiv) and the solution was refluxed for 1 h. The resulting suspension was poured onto 20 mL of a 1 M aqueous solution of HCl, and filtered over a fritted glass. The filtrate was concentrated under reduced pressure to give a yellow solid.

13 C

 13 NMR (CDCl3, 100 MHz): δ 160.4 (C, d, J = 281.5 Hz, C3), 153.6 (C, d, J = 4.7 Hz, C4), 151.9 (C, qd, J = 35.6 and 3.3 Hz, C1), 131.4 (CH, C9), 130.9 (C, d, J = 4.7 Hz, C6), 129.4 (2xCH, d, J = 5.2 Hz, C7), 129.0 (2xCH, C8), 120.8 (C, qd, J = 274.6 and 2.8 Hz, C5), 111.8 (CH, dq, J = 18.1 and 2.4 Hz, C2).

13 C

 13 NMR (CDCl3, 100 MHz): δ 162.3 (C, C9), 160.1 (C, d, J = 280.8 Hz, C3), 153.1 (C, d, J = 4.2 Hz, C4), 151.1 (C, qd, J = 35.5 and 3.3 Hz, C1), 131.1 (2xCH, d, J = 6.0 Hz, C7), 123.3 (C, d, J = 5.0 Hz, C6), 120.9 (C, qd, J = 274.6 and 2.8 Hz, C5), 114.5 (2xCH, C8), 111.5 (CH, dq, J = 18.2 and 2.4 Hz, C2), 55.5 (CH3, C10).MS m/z (relative intensity): 272 (M

13 C

 13 NMR (CDCl3, 100 MHz): δ 160.7 (C, d, J = 280.8 Hz, C3), 157.6 (C, C7), 154.1 (C, d, J = 10.3 Hz, C4), 152.3 (C, qd, J = 35.5 and 3.5 Hz, C1), 132.5 (CH, C9), 131.4 (CH, C11), 121.1 (CH, C10), 120.9 (C, qd, J = 274.7 and 2.9 Hz, C5), 120.6 (C, d, J = 3.6 Hz, C6), 111.

13 C

 13 NMR (CDCl3, 100 MHz): δ 160.2 (C, d, J = 279.7 Hz, C3), 154.9 (C, d, J = 10.8 Hz, C4), 153.3 (C, qd, J = 35.8 and 3.1 Hz, C1), 132.2 (CH, C9), 131.5 (CH, C7), 130.9 (CH, C8), 129.7 (C, q, J = 31.5 Hz, C11), 129.2 (C, m, C6), 127.2 (CH, q, J = 4.7 Hz, C10), 123.7 (C, q, J = 273.8 Hz, C12), 120.7 (C, qd, J = 275.1 and 3.0 Hz, C5), 111.0 (CH, dq, J = 17.1 and 2.4 Hz, C2).MS m/z (relative intensity): 310 (M +• , 100), 291(11), 263(9), 232(30), 213(89), 193 (14), 187 (14), 182

13 C

 13 NMR (CDCl3, 100 MHz): δ 168.1 (2xC, C8), 161.2 (C, d, J = 278.4 Hz, C3), 155.0 (C, d, J = 10.4 Hz, C4), 152.6 (C, qd, J = 35.4 and 3.0 Hz, C1), 134.3 (2xCH, C10 or C11), 131.9 (2xC, C9), 123.5 (2xCH, C10 or C11), 120.7 (C, qd, J = 274.8 and 3.0 Hz, C5), 110.4 (CH, dq, J = 16.4 and 2.4 Hz, C2), 35.7 (CH2, C7), 29.5 (CH2, d, J = 2.0 Hz, C6

5 .

 5 Synthesis and spectroscopic data of 4-fluoro-3-phenyl-6-(perfluoroethyl)pyridazine (71) 4-Fluoro-3-phenyl-6-(perfluoroethyl)pyridazine (71)

Mp: 52 1 H

 521 °C. IR (neat): 1591, 1550, 1411, 1393, 1334, 1320, 1194, 1145, 1099, 1040, 1019, 906 cm -1 . NMR (CDCl3, 400 MHz): δ 8.138.10 (m, 2H, H8), 7.66 (d, J = 10.7 Hz, 1H, H2), 7.597.54 (m, 3H, H9 and H10).

13 C

 13 NMR (CDCl3, 100 MHz): δ 160.5 (C, d, J = 281.8 Hz, C3), 153.6 (C, d, J = 5.2 Hz, C4), 151.7 (C, td, J = 26.3 and 3.1 Hz, C1), 131.6 (CH, C10), 130.9 (C, d, J = 4.8 Hz, C7), 129.5 (2xCH, d, J = 5.3 Hz, C8), 129.1 (2xCH, C9), 118.7 (C, qt, J = 286.5 and 36.5 Hz, C6), 113.0 (CH, dt, J = 18.1 and 4.1 Hz, C2), 110.7 (C, tqd, J = 255.0, 39.0 and 2.0 Hz, C5). MS m/z (relative intensity): 292 (M +• , 100), 273 (5), 245 (2), 195 (74), 175 (12), 169 (6), 151 (6), 125

6 .9 1 H

 61 Synthesis and spectroscopic data of 4-fluoro-3-phenyl-6-(difluoromethyl)pyridazine(72) 4-Fluoro-3-phenyl-6-(difluoromethyl)pyridazine(72) Formation of (difluoromethyl)diazomethane in situ: In an oven-dried vial was introduced 2,2-difluoroethan-1-amine (4.0 equiv compared to the alkyne) and CH2Cl2 (c = 0.6 M) was added. t-BuONO (4.8 equiv compared to the alkyne) and AcOH (0.8 equiv compared to the alkyne) were added.The reaction was then stirred at 70 °C for 10 min and was then allowed to cool down to rt. The solution was then added to the difluorocyclopropene solution via a syringe.Prepared according to procedure A from phenylacetylene 22 (50 mg, 0.49 mmol, 1.0 equiv). After the addition of (difluoromethyl)diazomethane, 8 days were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=3:97) to afford 72 (48 mg, 0.21 mmol, 44%) as a yellow oil. IR (neat): 3065, 1601, 1551, 1399, 1350, 1166, 1087, 1051, 990, 898 cm -1 . NMR (CDCl3, 400 MHz): δ 8.098.06 (m, 2H, H7), 7.61 (d, J = 10.6 Hz, 1H, H2), 7.597.55 (m, 3H, H8 and H9), 7.01 (td, J = 54.4 and 1.4 Hz, 1H, H5).

13 C

 13 NMR (CDCl3, 100 MHz): δ 160.9 (C, d, J = 280.6 Hz, C3), 156.4 (C, td, J = 27.6 and 3.2 Hz, C1), 153.4 (C, d, J = 5.8 Hz, C4), 131.3 (C, d, J = 4.6 Hz, C6), 131.2 (CH, C9), 129.4 (2xCH, d, J = 5.0 Hz, C7), 129.0 (2xCH, C8), 112.8 (C, td, J = 240.9 and 1.4 Hz, C5), 111.1 (CH, dt, J = 16.9 and 2.0 Hz, C2).

7 . 1 H

 71 Post-functionalization of 6-(trifluoromethyl) pyridazines: Synthesis and spectroscopic data of pyridazines 7389 4-Morpholino-3-phenyl-6-(trifluoromethyl)pyridazine (73) To a stirred solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (50 mg, 0.21 mmol, 1.0 equiv) in MeCN (0.2 mL) was added morpholine (0.036 mL, 0.41 mmol, 2.0 equiv) and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=30:70) to afford 73 (54 mg, 0.17 mmol, 85%) as a white solid. Mp: 149 °C. IR (neat): 2960, 2859, 1582, 1568, 1426, 1374, 1313, 1291, 1274, 1253, 1179, 1133, 1098, 1071,1055, 1010, 968 cm -1 . NMR (CDCl3, 400 MHz): δ 7.887.86 (m, 2H, H9 or H10), 7.507.46 (m, 3H, H9 or H10 and H11), 7.16 (s, 1H, H2), 3.673.70 (m, 4H, H7), 3.063.03 (m, 4H, H6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 155.7 (C, C3), 150.2 (C, q, J = 33.8 Hz, C1), 149.2 (C, C4), 137.0 (C, C8), 130.0 (CH, C11), 129.0 (2xCH, C9 or C10), 128.0 (2xCH, C9 or C10), 121.7 (C, q, J = 274.9 Hz, C5), 109.6 (CH, q, J = 2.2 Hz, C2), 65.9 (2xCH2, C7), 49.3 (2xCH2, C6). MS m/z (relative intensity): 309 (M +• , 100), 308(50), 282(22), 251 (41), 250(77), 202(18), 182(34), 155(9), 126 (14), 102(23), 86(17),77 (14).HRMS: calcd for C15H15F3N3O (M+H + ): 310.1162. Found 310.1161.4-Dibenzylamino-3-phenyl-6-(trifluoromethyl)pyridazine (74)To a stirred solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (50 mg, 0.21 mmol, 1.0 equiv) in MeCN (0.2 mL) was added N,N-dibenzylamine (0.

1 H

 1 HRMS: calcd for C25H21F3N3 (M+H + ): 420.1682. Found 420.1681.4-Allylamino-3-phenyl-6-(trifluoromethyl)pyridazine (75)To a stirred solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (60 mg, 0.25 mmol, 1.0 equiv) in MeCN (0.24 mL) was added allylamine (0.037 mL, 0.50 mmol, 2.0 equiv) and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure.The crude mixture was purified by flash chromatography (AcOEt/PE=20:80) to afford 75 (70 mg, 0.25 mmol, quant) as a white solid. Mp: 132 °C. IR (neat): 3267, 1590, 1548, 1507, 1427, 1387, 1290, 1180, 1142, 1096, 1011, 929 cm -1 . NMR (CDCl3, 400 MHz): δ 7.537.51 (m, 2H, H10 or H11), 7.457.40 (m, 3H, H10 or H11 and H12), 6.73 (s, 1H, H2), 5.74 (m, 1H, H7), 5.205.13 (m, 3H, NH and H8). 3.793.76 (m, 2H, H6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 152.2 (C, C3), 150.2 (C, q, J = 33.3 Hz, C1), 144.1 (C, C4), 133.9 (C, C9), 131.8 (CH, C7), 130.0 (CH, C12), 129.5 (2xCH, C10 or C11), 128.7 (2xCH, C10 or C11), 121.8 (C, q, J = 274.8 Hz, C5), 117.0 (CH2, C8), 101.8 (CH, q, J = 2.6 Hz, C2), 44.9 (CH2, C6).

HRMS: 1 ) 1 H

 11 calcd for C14H13F3N3 (M+H + ): 280.1056. Found 280.1055. 4-Methoxy-3-phenyl-6-(trifluoromethyl)pyridazine (76) To a stirred solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (50 mg, 0.21 mmol, 1.0 equiv) in MeCN (0.2 mL) was added sodium methoxide (33.5 mg, 0.62 mmol, 3.0 equiv) and the reaction mixture was stirred at 100 °C for 48 h. The reaction mixture was then concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=20:80) to afford 76 (36 mg, 0.14 mmol, 69%) as a pale brown oil. 2) To a stirred solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (50 mg, 0.21 mmol, 1.0 equiv) in DMSO (0.2 mL) was added MeOH (0.025 mL, 0.62 mmol, 3.0 equiv) and DBU (0.093 mL, 0.62 mmol, 3.0 equiv) and the reaction mixture was stirred at 80 °C for 3 h. An aqueous saturated NH4Cl solution was added to the mixture and the aqueous phase was extracted with AcOEt. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=20:80) to afford 76 (40 mg, 0.16 mmol, 76%) as a pale brown oil. IR (neat): 2927, 1586, 1571, 1468, 1388, 1321, 1297, 1265, 1178, 1139, 1091, 1021, 918 cm -1 . NMR (CDCl3, 400 MHz): δ 7.907.87 (m, 2H, H8 or H9), 7.427.40 (m, 3H, H8 or H9 and H10), 7.18 (s, 1H, H2), 3.93 (s, 3H, H6).

13 C 1 H

 131 NMR (CDCl3, 100 MHz): δ 157.1 (C, C3), 154.9 (C, C4), 151.0 (C, q, J = 34.3 Hz, C1), 133.3 (C, C7), 130.3 (CH, C10), 129.8 (2xCH, C8 or C9), 128.4 (2xCH, C8 or C9), 121.4 (C, q, J = 274.8 Hz, C5), 104.9 (CH, q, J = 2.4 Hz, C2), 56.1 (CH3, C6). MS m/z (relative intensity): 254 (M +• , 46), 253 (100), 225(5), 205(6), 183(9), 133 (14), 102(26), 89(23), 77(8), 69(8), 63(10), 51(7).HRMS: calcd for C12H10F3N2O (M+H + ): 255.0740. Found 255.0738.4-Allyloxy-3-phenyl-6-(trifluoromethyl)pyridazine (77)To a stirred solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (50 mg, 0.21 mmol, 1.0 equiv) in DMSO (0.2 mL) was added allylic alcohol (0.042 mL, 0.62 mmol, 3.0 equiv) and DBU (0.093 mL, 0.62 mmol, 3.0 equiv) and the reaction mixture was stirred at 80 °C for 3 h. An aqueous saturated NH4Cl solution was added to the mixture and the aqueous phase was extracted with AcOEt.The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=10:90) to afford 77 (41 mg, 0.15 mmol, 71%) as a colorless oil. IR (neat): 1584, 1409, 1357, 1321, 1267, 1178, 1140, 1092, 1014, 988, 926 cm -1 . NMR (CDCl3, 400 MHz): δ 8.027.99 (m, 2H, H10 or H11), 7.527.48 (m, 3H, H10 or H11 and H12), 7.25 (s, 1H, H2), 6.02 (m, 1H, H7), 5.475.39 (m, 2H, H8), 4.76 (dtapp, J = 5.1 and 1.5 Hz, 2H, H6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 156.0 (C, C3), 155.0 (C, C4), 150.9 (C, q, J = 34.3 Hz, C1), 133.3 (C, C9), 130.3 (CH, C7), 130.2 (CH, C12), 129.9 (2xCH, C10 or C11), 128.4 (2xCH, C10 or C11), 121.4 (C, q, J = 274.9 Hz, C5), 119.8 (CH2, C8), 105.9 (CH, q, J = 2.4 Hz, C2), 69.8 (CH2, C6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 161.0 (C, C3), 149.1 (C, q, J = 34.2 Hz, C1), 144.6 (C, C4), 135.3 (C, C8), 130.3 (CH, C11), 129.1 (2xCH, C9 or C10), 128.6 (2xCH, C9 or C10), 121.6 (C, q, J = 274.9 Hz, C5), 117.8 (CH, q, J = 2.3 Hz, C2), 25.6 (CH2, C6), 12.5 (CH3, C7).

4 -

 4 Dimethyl malonate-3-phenyl-6-(trifluoromethyl)pyridazine(79) To a stirred solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (50 mg, 0.207 mmol, 1.0 equiv) in DMSO (0.5 mL) was added dimethyl malonate (0.071 mL, 0.62 mmol, 3.0 equiv) and DBU (0.093 mL, 0.62 mmol, 3.0 equiv) and the reaction mixture was stirred at 80 °C for 3 h. An aqueous saturated NH4Cl solution was added to the mixture and the aqueous phase was extracted with AcOEt.

13 C 1 H

 131 NMR (CDCl3, 100 MHz): δ 166.6 (2xC, C7), 163.8 (C, C4), 150.4 (C, q, J = 34.9 Hz, C1), 134.7 (C, C3 or C9), 132.2 (C, C3 or C9), 130.2 (CH, C12), 129.5 (2xCH, C10 or C11), 129.1 (2xCH, C10 or C11), 125.1 (CH, q, J = 2.4 Hz, C2), 121.5 (C, q, J = 274.6 Hz, C5), 53.9 (2xCH3, C8), 52.7 (CH, C6).HRMS: calcd for C16H14F3N2O4 (M+H + ): 355.0900. Found 355.0900.4-Nitromethyl-3-phenyl-6-(trifluoromethyl)pyridazine (80)To a stirred solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (150 mg, 0.62 mmol, 1.0 equiv) in DMSO (1.8 mL) was added nitromethane (0.1 mL, 1.89 mmol, 3.0 equiv) and DBU (0.28 mL, 1.89 mmol, 3.0 equiv) and the reaction mixture was stirred at 80 °C for 3 h. An aqueous saturated NH4Cl solution was added to the mixture and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude mixture was purified by flash chromatography (MeOH/CH2Cl2=2:98) to afford 80 (91 mg, 0.32 mmol, 52%) as a yellow oil. IR (neat): 2925, 2854, 1561, 1398, 1364, 1292, 1266, 1194, 1148, 1085, 1036, 1015, 908 cm -1 . NMR (CDCl3, 400 MHz): δ 7.93 (br s, 1H, H2), 7.527.42 (m, 5H, H8, H9 or H10), 5.54 (s, 2H, H6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 163.8 (C, C4), 150.9 (C, q, J = 35.6 Hz, C1), 134.0 (C, C3 or C7), 130.8 (CH, C10), 129.4 (2xCH, C8 or C9), 129.2 (2xCH, C8 or C9), 128.3 (C, C3 or C7), 125.9 (CH, q, J = 2.4 Hz, C2), 121.2 (C, q, J = 274.7 Hz, C5), 75.3 (CH2, C6).

1 H

 1 -3-phenyl-6-(trifluoromethyl)pyridazine(81) To a stirred solution of CuI (433 mg, 2.27 mmol, 5.5 equiv) in Et2O (7.1 mL) at 30 °C was added dropwise MeLi (2.58 mL, 4.13 mmol, 10.0 equiv, 1.6 M in Et2O) and the reaction mixture was stirred at 30 °C for 5 min. A solution of 4-fluoro-3-phenyl-6-(trifluoromethyl)pyridazine 24 (100 mg, 0.41 mmol, 1.0 equiv) in Et2O (3.6 mL) was added to the mixture and the solution was stirred at 0 °C for 48 h. An aqueous saturated NH4Cl solution was added to the mixture and the aqueous phase was extracted with Et2O. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=5:95 and 10:90) to afford 81 (12 mg, 0.05 mmol, 12%) as a yellow oil. IR (neat): 2920, 1448, 1397, 1318, 1293, 1269, 1197, 1169, 1128, 1092, 761, 702 cm -1 . NMR (CDCl3, 400 MHz): δ 7.71 (q, J = 0.8 Hz, 1H, H2), 7.637.61 (m, 2H, H8 or H9), 7.557.53 (m, 3H, H8 or H9 and H10), 2.49 (d, J = 0.7 Hz, 3H, H6).

13 C 1 H

 131 NMR (CDCl3, 100 MHz): δ 164.3 (C, C4), 150.1 (C, q, J = 34.6 Hz, C1), 137.5 (C, C3 or C7), 136.0 (C, C3 or C7), 129.8 (CH, C10), 129.4 (2xCH, C8 or C9), 128.8 (2xCH, C8 or C9), 125.5 (CH, q, J = 2.2 Hz, C2), 121.7 (C, q, J = 274.4 Hz, C5), 20.1 (CH3, C6). MS m/z (relative intensity): 238 (M +• , 35), 237 (100), 188(8), 170(6), 116(30), 115(95), 89(8), 63(18), 51(22). HRMS: calcd for C12H9F3N2Na (M+Na + ): 261.0610. Found 261.0608. 4-Morpholino-3-(4-fluorophenyl)-6-(trifluoromethyl)pyridazine (82) To a stirred solution of 4-fluoro-3-(4-fluoro-phenyl)-6-(trifluoromethyl)pyridazine 47 (50 mg, 0.19 mmol, 1.0 equiv) in MeCN (0.19 mL) was added morpholine (0.034 mL, 0.38 mmol, 2.0 equiv) and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography (Et2O/PE=20:80 and 30:70) to afford 82 (62 mg, 0.19 mmol, quant) as a white solid. Mp: 166 °C. IR (neat): 2960, 2858, 1602, 1570, 1508, 1433, 1402, 1320, 1299, 1228, 1134, 1117, 1054, 970 cm -1 . NMR (CDCl3, 400 MHz): δ 7.947.90 (m, 2H, H9), 7.227.17 (m, 3H, H2 and H10), 3.733.70 (m, 4H, H7), 3.06-3.03 (m, 4H, H6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 163.7 (C, d, J = 250.6 Hz, C11), 154.8 (C, C3), 150.3 (C, q, J = 33.8 Hz, C1), 149.2 (C, C4), 133.0 (C, d, J = 3.4 Hz, C8), 130.1 (2xCH, d, J = 8.3 Hz, C9), 121.6 (C, q, J = 274.9 Hz, C5), 116.1 (2xCH, d, J = 21.7 Hz, C10), 109.9 (CH, q, J = 2.4 Hz, C2), 65.9 (2xCH2, C7), 49.3 (2xCH2, C6).

HRMS:

  calcd for C15H14F4N3O (M+H + ): 328.1068. Found 328.1068.4-Morpholino-3-(4-carbomethoxyphenyl)-6-(trifluoromethyl)pyridazine (83)To a stirred solution of 4-fluoro-3-(4-methylbenzoate)-6-(trifluoromethyl)pyridazine 43 (50 mg, 0.17 mmol, 1.0 equiv) in MeCN (0.16 mL) was added morpholine (0.029 mL, 0.33 mmol, 2.0 equiv) and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography (Et2O/PE=70:30) to afford

13 C

 13 NMR (CDCl3, 100 MHz): δ 166.5 (C, C12), 154.7 (C, C3), 150.6 (C, q, J = 33.9 Hz, C1), 149.3 (C, C4), 141.3 (C, C11), 131.5 (C, C8), 130.3 (2xCH, C10), 128.1 (2xCH, C9), 121.6 (C, q, J = 274.9 Hz, C5), 109.9

HRMS: 1 H

 1 calcd for C17H17F3N3O3 (M+H + ): 368.1217. Found 368.1216. 4-Morpholino-3-(4-methoxyphenyl)-6-(trifluoromethyl)pyridazine (84) To a stirred solution of 4-fluoro-3-(4-methoxyphenyl)-6-(trifluoromethyl)pyridazine 32 (55 mg, 0.20 mmol, 1.0 equiv) in MeCN (0.20 mL) was added morpholine (0.036 mL, 0.40 mmol, 2.0 equiv) and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=35:65) to afford 84 (70 mg, 0.20 mmol, quant) as a pale yellow solid. Mp: 119 °C. IR (neat): 2863, 1431, 1300, 1252, 1174, 1135, 1113, 1035, 1001, 968, 905, 724 cm -1 . NMR (CDCl3, 400 MHz): δ 7.80 (d, J = 8.9 Hz, 2H, H9), 7.05 (s, 1H, H2), 6.93 (d, J = 8.9 Hz, 2H, H10), 3.79 (s, 3H, H12), 3.653.62 (m, 4H, H7), 2.972.94 (m, 4H, H6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 161.0 (C, C11), 155.4 (C, C3), 149.8 (C, q, J = 33.6 Hz, C1), 149.1 (C, C4), 129.5 (2xCH, C9), 129.1 (C, C8), 121.7 (C, q, J = 274.7 Hz, C5), 114.3 (2xCH, C10), 109.7 (CH, q, J = 2.2 Hz, C2), 66.0 (2xCH2, C7), 55.4 (CH3, C12), 49.2 (2xCH2, C6).

4 - 1 H

 41 Morpholino-3-(2-methoxyphenyl)-6-(trifluoromethyl)pyridazine (85) To a stirred solution of 4-fluoro-3-(2-methoxyphenyl)-6-(trifluoromethyl)pyridazine 33 (72 mg, 0.26 mmol, 1.0 equiv) in MeCN (0.26 mL) was added morpholine (0.047 mL, 0.53 mmol, 2.0 equiv) and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=35:65) to afford 85 (70 mg, 0.21 mmol, 78%) as a white mousse. IR (neat): 2856, 1576, 1493, 1460, 1434, 1321, 1295, 1259, 1179, 1135, 1117, 1051, 1024, 1007, 970, 910 cm -1 . NMR (CDCl3, 400 MHz): δ 7.487.42 (m, 2H, H9 and H11), 7.09 (m, 1H, H10), 7.09 (br s, 1H, H2), 7.00 (d, J = 8.3 Hz, 1H, H12), 3.80 (s, 3H, H14), 3.57 (t, J = 4.8 Hz, 4H, H7), 3.05 (br s, 4H, H6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 156.5 (C, C13), 154.1 (C, C3), 150.1 (C, q, J = 33.4 Hz, C1), 149.1 (C, C4), 131.1 (CH, C11), 130.5 (CH, C9), 126.7 (C, C8), 121.8 (C, q, J = 274.8 Hz, C5), 121.3 (CH, C10), 111.3 (CH, C12), 108.6 (CH, q, J = 2.5 Hz, C2), 66.2 (2xCH2, C7), 55.6 (CH3, C14), 48.5 (2xCH2, C6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 160.9 (C, C3), 148.8 (C, t, J = 25.3 Hz, C1), 144.4 (C, C4), 135.2 (C, C9), 130.4 (CH, C12), 129.2 (2xCH, C10 or C11), 128.6 (2xCH, C10 or C11), 119.0 (CH, t, J = 4.1 Hz, C2), 118.8 (C, qt, J = 286.8 and 36.9 Hz, C6), 111.4 (C, tq, J = 256.3 and 39.1 Hz, C5), 25.6 (CH2, C7), 12.5 (CH3, C8).

5 - 1 H

 51 Allylamino-3-phenyl-6-(difluoromethyl)pyridazine(88) To a stirred solution of 4-fluoro-3-phenyl-6-(difluoromethyl)pyridazine 72 (26 mg, 0.12 mmol, 1.0 equiv) in MeCN (0.11 mL) was added allylamine (0.017 mL, 0.23 mmol, 2.0 equiv) and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure.The crude mixture was purified by flash chromatography (AcOEt/PE=40:60) to afford 88 (28 mg, 0.11 mmol, 92%) as a white solid. Mp: 127 °C. IR (neat): 3248, 1585, 1546, 1504, 1424, 1357, 1299, 1240, 1193, 1148, 1085, 1035, 1008, 995, 920 cm -1 . NMR (CDCl3, 400 MHz): δ 7.647.61 (m, 2H, H10 or H11), 7.567.50 (m, 3H, H10 or H11 and H12), 6.83 (s, 1H, H2), 6.79 (t, J = 55.0 Hz, 1H, H5), 5.84 (m, 1H, H7), 5.265.22 (m, 2H, H8), 5.08 (br s, NH), 3.873.83 (m, 2H, H6).

13 C 1 (

 131 NMR (CDCl3, 100 MHz): δ 154.3 (C, t, J = 26.0 Hz, C1), 152.2 (C, C3), 144.2 (C, C4), 134.3 (C, C9), 132.0 (CH, C7), 129.9 (CH, C12), 129.5 (2xCH, C10 or C11), 128.7 (2xCH, C10 or C11), 117.8 (CH2, C8), 114.CH, t, J = 240.2 Hz, C5), 101.3 (CH, t, J = 2.0 Hz, C2), 44.9 (CH2, C6).

13 C

 13 NMR (CDCl3, 100 MHz): δ 160.8 (C, C3), 153.0 (C, t, J = 26.8 Hz, C1), 144.4 (C, C4), 135.6 (C, C8), 130.1 (CH, C11), 129.2 (2xCH, C9 or C10), 128.6 (2xCH, C9 or C10), 117.6 (CH, t, J = 1.7 Hz, C2), 113.9 (CH, t, J = 240.5 Hz, C5), 25.5 (CH2, C6), 12.6 (CH3, C7).

L

  'introduction d'un atome de fluor sur un composé organique peut avoir une influence importante sur les propriétés chimiques et physico-chimiques de ce composé, ainsi que sur son activité biologique. Par ailleurs, les hétérocycles représentent une famille de composés intéressante pour l'industrie pharmaceutique et agrochimique avec 70% de nouvelles molécules bioactifs possédant un motif hétérocyclique. Ainsi, le développement des méthodes de synthèse permettant la formation des hétérocycles trifluorométhylés, représente un défi en chimie organique. Dans le cadre de nos travaux, nous avons dans un premier temps développé une méthode afin d'accéder aux α-(trifluorométhyl)pyrrolidines et α-(trifluorométhyl)pipéridines substituées, par contraction de cycle de (trifluorométhyl)pipéridines et (trifluorométhyl)azépanes respectivement via un intermédiaire aziridinium. L'attaque régiosélective du nucléophile sur l'aziridinium est induite par le groupement CF3 présent sur cet intermédiaire. Dans un deuxième temps, nous avons développé une séquence de cycloadditions [2+1]/[3+2] entre un alcyne terminal, un difluorocarbène et le (trifluorométhyl)diazométhane, afin d'accéder aux α-(trifluorométhyl)pyridazines fonctionnalisées. Mots clés: contraction de cycle, α-(trifluorométhyl)pyrrolidines, α-(trifluorométhyl)pipéridines, aziridinium, cycloaddition, α-(trifluorométhyl)pyridazines.The introduction of a fluorine atom in an organic compound can have major impact on the compounds chemical and physico-chemical properties, therefore influencing its biological activity. Moreover, heterocycles represent an important class of compounds for the pharmaceutical and agrochemical industry, given that 70% of the biologically-active molecules possess a heterocyclic moiety. Therefore, the development of synthetic methods which allow access to trifluoromethylated heterocycles represent a challenge in organic chemistry. The work presented in this manuscript is focused on the synthesis of nitrogen containing heterocycles possessing a CF3 group at the α position to the nitrogen. More specifically, a variety of substituted α-(trifluomethyl)pyrrolidines and substituted α-(trifluomethyl)piperidines were obtained by the ring contraction of (trifluoromethyl)piperidines and (trifluoromethyl)azepanes respectively via an aziridinium intermediate. The regioselective attack of the nucleophile on the aziridinium is induced by the CF3 group present on the intermediate. Furthermore, a diversity of functionalized α-(trifluoromethyl)pyridazines were obtained by a [2+1]/[3+2]-cycloaddition sequence between a terminal alkyne, a difluorocarbene and (trifluoromethyl)diazomethane. Key words: ring contraction, α-(trifluoromethyl)pyrrolidines, α-(trifluoromethyl)piperidines, aziridinium, cycloaddition, α-(trifluoromethyl)pyridazines.

Table 1

 1

	1.47 1.52 1.55	1.70 1.75 1.85

  According to the proposed mechanism, isoxazole L2.6 could undergo a Michael addition in the presence of the enolized ketoester L2.7, to form intermediate L2.9. Then, the product

	In 2016, multi-substituted α-(trifluoromethyl)piperidines L2.11 were obtained via a one-pot,
	multicomponent reaction between isoxazole L2.6, ketoester L2.7, ammonium acetate and aryl
	aldehydes L2.8. obtained from the condensation of aldehyde L2.8 with ammonium acetate, could react with L2.9 to
	obtain compound L2.10, which after an intramolecular cyclization led to the desired spiropiperidines
	L2.11 (Scheme 3). 48
	Scheme 1
	In addition to the above methods, two more particular synthetic routes exist, allowing the formation
	of 2-substituted, 2-(trifluoromethyl)piperidines of type B. In 2012, Fustero et al. reported the one-pot
	iodocyclization of oxazinone L2.2, followed by a [1,2]-shift of the CF3 group of the intermediate L2.3
	to afford (trifluoromethyl)lactone L2.4, which could then be transformed to a variety of Scheme 3
	α-(trifluoromethyl)pipecolic acid derivatives L2.5 (Scheme 2). 47 1.4.2. Synthetic methods to	access	2-substituted,
	2-(trifluoromethyl)pyrrolidines
	Rioton, S.; Gomez Pardo, D.; Cossy, J. Molecules 2017, 22, 483505.
	40 a) Gulevich, A. V.; Shevchenko, N. E.; Balenkova, E. S.; Röschenthaler, G. -V.; Nenajdenko, V. G. Synlett 2009,
	403406; b) Odinets, I. L.; Artyushin, O. I.; Lyssenko, K. A.; Shevchenko, N. E.; Nenajdenko, V. G.; Röschenthaler, G. -V. J. Fluorine Chem. 2009, 130, 662666; c) Shevchenko, N. E.; Balenkova, E. S.; Röschenthaler, G. -V.; Scheme 2
	Nenajdenko, V. G. Synthesis 2010, 120126; d) Shmatova, O. I.; Nenajdenko, V. G. Eur. J. Org. Chem. 2013,
	63976403; e) Shmatova, O. I.; Shevchenko, N. E.; Balenkova, E. S.; Röschenthaler, G. -V.; Nenajdenko, V. G.
	Eur. J. Org. Chem. 2013, 30493058; f) Shmatova, O. I.; Shevchenko, N. E.; Balenkova, E. S.; Röschenthaler,
	G. -V.; Nenajdenko, V. G. Mendeleev Commun. 2013, 23, 9293; g) Shevchenko, N. E.; Shmatova, O. I.;
	Balenkova, E. S.; Röschenthaler, G. -V.; Nenajdenko, V. G. Eur. J. Org. Chem. 2013, 22372245; h) Shmatova, O. 47 a) Fustero, S.; Albert, L.; Aceña, J. L.; Sanz-Cervera, J. F.; Asensio, A. Org. Lett. 2008, 10, 605608; b) Fustero,
	I.; Khrustalev, V. N.; Nenajdenko, V. G. Org. Lett. 2016, 18, 44944497. S.; Albert, L.; Mateu, N.; Chiva, G.; Miró, J.; González, J.; Aceña, J. L. Chem. Eur. J. 2012, 18, 37533764.

  Chaume, G.; Van Severen M. -C.; Marinkovic, S.; Brigaud, T. Org. Lett. 2006, 8, 61236126.

  Caupène, C.; Chaume, G.; Ricard, L.; Brigaud, T. Org. Lett. 2009, 11, 209212.

Table 3

 3

	, entries 6 and

a) 14.0 equiv of water were used.

  All reactions were carried out under an argon atmosphere unless otherwise specified. Flasks were oven-dried at 120 °C and cooled down under argon prior to use. Without any specification, all commercially available products were used directly without any purification. THF and Et2O were distilled over sodium/benzophenone and Et3N and CH2Cl2 were distilled over CaH2 before their use.MeCN and DMSO were bought dry from Aldrich and used as received. All others reagents were used as obtained from Aldrich, without further purification unless otherwise specified.

	1. General experimental methods
	Purification by flash column chromatography was carried out by using silica gel (pore size 60 Å, 230
	mesh). TLC were performed on silica gel plate (Merck 60F254) and visualized either with a UV lamp
	(254 nm) or by treatment with an aqueous potassium permanganate solution (KMnO4/K2CO3/AcOH)
	and subsequent heating.
	CHAPTER 2
	Experimental Part

Feraldi-Xypolia, A.; Gomez Pardo, D.; Cossy, J. Chem. Eur. J. 2015, 21, 1287612880. Melting points (Mp) were recorded using a Wagner & Munz Kofler bench and a Büchi Melting Point M-560 apparatus with open capillaries.

  3-piperidone 3 (2.0 g, 9.74 mmol, 1.0 equiv) in THF (40 mL) at 0 °C was

	N-Benzyl-3-hydroxy-3-(trifluoromethyl)piperidine (1)
	To a stirred solution of tert-butyl 3-trifluoromethyl-3-hydroxypiperidin-1-carboxylate 2 (2.03 g, 7.52
	mmol, 1.0 equiv) in CH2Cl2 (42 mL) at rt was added TFA (3.91 mL, 52.64 mmol, 7.0 equiv). The reaction
	mixture was stirred at rt for 15 h and then concentrated under reduced pressure.
	To a stirred solution of the crude material previously obtained in MeCN (77 mL) at rt were added
	successively BnBr (0.90 mL, 7.52 mmol, 1.0 equiv), K2CO3 (5.2 g, 37.6 mmol, 5.0 equiv) and TBAI (1.39
	HRMS: calcd for C13H17F3NO (M+H + ): 260.1257. Found 260.1260.
	Separation of the two enantiomers by SFC: RegisPack 4.4*250 mm, 5µm, Pressure=137 bar,
	CO2/MeOH=95:5, Flow rate=40 mL/min, UV=210 nm, tR=1.8 min and tR=2.8 min.

added TMSCF3 (2.94 mL, 19.47 mmol, 2.0 equiv). A solution of TBAF (1.0 M in THF, 19.5 mL, 19.47 mmol, 2.0 equiv) was added dropwise and the resulting mixture was stirred at rt for 19 h. The solution was quenched with an aqueous and saturated solution of NH4Cl (40 mL) and stirred for another 20 min. The solution was then concentrated under reduced pressure and diluted in CH2Cl2. The organic layer was separated and washed with H2O (twice), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (EtOAc/PE=10:90 to 20:80) to afford 2 (2.03 g, 7.52 mmol, 77%) as a white solid. IR (neat): 3407, 2978, 1740, 1672, 1432, 1368, 1278, 1247, 1145, 1045, 1010 cm -1 . 1 H NMR (DMSO-d6, 400 MHz at 122 o C): δ 5.48 (br s, OH), 3.69 (d, J = 13.2 Hz, 1H, H6), 3.68 (m, 1H, H2), 3.27 (d, J = 13.5 Hz, 1H, H6), 3.03 (m, 1H, H2), 1.801.73 (m, 3H, H3 and H4), 1.55 (m, 1H, H4), 1.44 (s, 9H, H10).

13 C NMR (DMSO-d6, 400 MHz at 122 o C): δ 153.7 (C, C8), 125.8 (C, q, J = 286.5 Hz, C7), 78.3 (CH2, C6), 69.3 (C, q, J = 26.6 Hz, C5), 46.6 (C, C9), 42.3 (CH2, C2), 28.3 (CH2, C4), 27.5 (3xCH3, C10), 18.8 (CH2, C3).

MS m/z (relative intensity): 269 (M +• , 0.7), 210 (2), 196

(10)

, 85

(8)

, 57 (100).

75

Ryu, J. H.; Kim, S. A.; Ryu, K. H.; Kim, J. S.; Kim, N. H.; Han, H. Y.; Kim, Y. H.; Youn, W. -N.; Lee, Y. -J.; Son, H. J.; Lee, B. -Y.; Park, S. H.; Lee, J. -Y.; Lee, H. J.; Jung, H. C.; Shin, Y. A.; Lee, J. A.; Lee, B. R.; Sa, J. H. 2011 (WO 2011/139107).

g, 3.76 mmol, 0.5 equiv). The reaction mixture was heated at 75 °C for 4 h and then allowed to cool to rt. The reaction mixture was quenched with H2O and extracted with CH2Cl2 (twice). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (EtOAc/PE=10:90) to afford 1 (1.

93

g, 7.44 mmol, quant) as a colorless oil. IR (neat): 3458, 3030, 2953, 2817, 1496, 1454, 1368, 1284, 1181, 1149, 1103, 1029, 1009, 943 cm -1 .

1 H NMR (CDCl3, 400 MHz): δ 7.357.23 (m, 5Η, H10, H11 and H12), 3.55 (s, 2H, H8), 3.47 (br s, OH), 2.862.83 (m, 2H, H2 and H6), 2.20 (d, J = 11.2 Hz, 1H, H6), 1.97 (m, 1H, H2), 1.861.79 (m, 2H, H3 and H4), 1.62 (m, 1H, H3), 1.48 (m, 1H, H4).

13 C NMR (CDCl3, 100 MHz): δ 137.3 (C, C9), 129.1 (2xCH, C10 or C11), 128.6 (2xCH, C10 or C11), 127.6 (CH, C12), 125.5 (C, q, J = 282.4 Hz, C7), 71.3 (C, q, J = 28.6 Hz, C5), 62.7 (CH2, C8), 57.1 (CH2, dapp, J = 2.0 Hz, C6), 52.9 (CH2, C2), 28.2 (CH2, C4), 20.3 (CH2, C3).

MS m/z (relative intensity): 259 (M +• , 20), 182 (14), 168

(23)

, 146

(17)

, 134

(12)

, 91 (100), 65

(12)

.

  2H, H7), 3.78 (d, J = 12.4 Hz, 1H, H11), 3.75 (d, J= 9.6 Hz, 1H, H6), 3.60 (d, J = 9.8 Hz, 1H, H6), 2.82 (m, 1H, H2), 2.63 (dd, J = 15.3 and 8.4 Hz, 1H, H2), 2.142.12 (m, 2H, H4), 1.781.71 (m, 2H, H3). CDCl3, 400 MHz): δ 7.347.19 (m, 7Η, Har), 7,01-6.94 (m, 3Η, H8 and H10), 4.29 (d, J = 9.6 Hz, 1H, H6), 4.18 (d, J = 13.7 Hz, 1H H12), 4.13 (d, J = 9.8 Hz, 1H, H6), 3.80 (d, J = 13.6 Hz, 1H, H12), 2.89 (m, 1H, H2), 2.78 (qapp, J = 7.8 Hz, 1H, H2), 2.252.23 (m, 2H, H4), 1.871.81 (m, 2H, H3).

	N-Benzyl-2-{[(N,N-dibenzyl)amino]methyl}-2-(trifluoromethyl)pyrrolidine (20) 1 H NMR (CDCl3, 400 MHz): δ 7.377.21 (m, 5Η, H12, H13 and H14), 4.14 (d, J = 13.8 Hz, 1H, H10), 3.74 N-Benzyl-2-ethoxymethyl-2-(trifluoromethyl)pyrrolidine (25) N-Benzyl-2-[(hydroxy)methyl]-2-(trifluoromethyl)pyrrolidine (28)
	(dq, J = 13.8 and 1.8 Hz, 1H, H10), 3.68 (tapp, J = 4.6 Hz, 4H, H8), 2.802.69 (m, 4H, H2, H6 and H7),
	2.662.50 (m, 4H, H2, H6 and H7), 2.27 (m, 1H, H4), 2.07 (m, 1H, H4), 1.791.72 (m, 2H, H3). 13 C NMR (CDCl3, 100 MHz): δ 140.8 (C, C12), 134.6 (CH, C8), 128.3 (2xCH, C13 or C14), 128.2 (2xCH, C13
	13 C NMR (CDCl3, 100 MHz): δ 140.1 (C, C11), 128.7 (C, q, J = 293.6 Hz, C9), 128.4 (2xCH, C12 or C13), or C14), 127.8 (C, q, J = 287.5 Hz, C10), 126.8 (CH, C15), 117.2 (CH2, C9), 72.6 (CH2, C7), 69.8 (CH2, C6), 13 C NMR (CDCl3, 100 MHz): δ 158.5 (C, C13), 140.5 (C, C7), 129.7 (2xCH, Car), 128.4 (2xCH, Car), 128.1
	128.2 (2xCH, C12 or C13), 126.9 (CH, C14), 68.8 (C, q, J = 21.6 Hz, C5), 67.4 (2xCH2, C8), 58.7 (CH2, C6), 67.8 (C, q, J = 24.6 Hz, C5), 53.4 (CH2, C11), 53.1 (CH2, C2), 31.2 (CH2, C4), 23.0 (CH2, C3). (2xCH, Car), 127.6 (C, q, J = 286.8 Hz, C11), 126.9 (CH, C16), 121.5 (CH, C10), 114.7 (2xCH, C8), 67.7 (C, q,
	55.9 (2xCH2, C7), 52.5 (CH2, C10), 51.6 (CH2, C2), 30.9 (CH2, C4), 22.3 (CH2, C3). MS m/z (relative intensity): 299 (M +• , 0.6), 228 (21), 91 (100), 65 (8). J = 25.0Hz, C5), 67.5 (CH2, C6), 53.3 (CH2, C2 or C12), 53.3 (CH2, C2 or C12), 31.3 (CH2, C4), 23.1 (CH2, C3).
	MS m/z (relative intensity): 328 (M +• , 0.2), 228 (8), 100 (100), 91 (54), 65 (5). Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 HRMS: calcd for C16H21F3NO (M+H + ): 300.1570. Found 300.1570. Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 MS m/z (relative intensity): 335 (M +• , 0.3), 228 (22), 91 (100), 77 (5), 65 (8).
	Following the general protocol: 1 (79 mg, 0.31 mmol, 1.0 equiv), proton sponge (131.1 mg, 0.6 mmol, 2.0 equiv), triflic anhydride (76 L, 0.46 mmol, 1.5 equiv). Nucleophile = dibenzylamine (0.15 mL, 0.16 HRMS: calcd for C17H24F3N2O (M+H + ): 329.1835. Found 329.1837. mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = ethanol (56 L, 0.96 mmol, 14.0 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=5:95 to mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=2:98) to afford N-Benzyl-2-[(benzyloxy)methyl]-2-(trifluoromethyl)pyrrolidine (27) mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = H2O (0.1 mL, 5.55 HRMS: calcd for C19H21F3NO (M+H + ): 336.1570. Found 336.1569.
	mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=2:98 to 10:90) N-Benzyl-2-methoxymethyl-2-(trifluoromethyl)pyrrolidine (24) 25 (85.6 mg, 0.30 mmol, 77%) as a colorless oil. 10:90) to afford 28 (62 mg, 0.24 mmol, 61%) as a brown oil. N-Benzyl-2[(acetyl)methyl]-2-(trifluoromethyl)pyrrolidine (30)
	to afford 20 (111 mg, 0.25 mmol, 83%) as a white solid.
	IR (neat): 2976, 2875, 1495, 1454, 1379, 1360, 1139, 1122, 1103, 1030, 949 cm -1 . IR (neat): 3445, 3030, 2927, 2852, 1496, 1454, 1366, 1287, 1138, 1109, 1058, 943 cm -1 .
	Mp: 6871 °C
	IR (neat): 3031, 2922, 2848, 2361, 1159, 1119, 1099, 752 cm -1 .
	q, J = 21.3 Hz, C5), 60.2 (2xCH2, C7), 52.6 (CH2, C13), 52.3 (CH2, C6), 51.3 (CH2, C2), 29.9 (CH2, C4), 22.2
	(CH2, C3).
	13 C NMR (CDCl3, 100 MHz): δ 140.8 (C, C10), 128.3 (2xCH, C11 or C12), 128.2 (2xCH, C11 or C12), 127.8 (C,
	13 C NMR (CDCl3, 100 MHz): δ 140.0 (C, C12), 135.9 (2xCH, C8), 128.9 (C, q, J = 294.2 Hz, C10), 128.4 q, J = 287.1 Hz, C8), 126.8 (CH, C13), 72.5 (CH2, C6), 67.7 (C, q, J = 24.5 Hz, C5), 59.6 (CH3, C7), 53.3 (CH2, C11 or C17), 73.7 (CH2, C7), 69.9 (CH2, C6), 67.9 (C, q, J = 24.6 Hz, C5), 53.4 (CH2, C13), 53.2 (CH2, C2), 31.2
	(2xCH, C13 or C14), 128.2 (2xCH, C13 or C14), 126.9 (CH, C15), 117.4 (2xCH2, C9), 69.4 (C, q, J = 21.0 Hz, C9), 53.1 (CH2, C2), 31.0 (CH2, C4), 23.0 (CH2, C3). (CH2, C4), 23.0 (CH2, C3). Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77
	C5), 58.5 (2xCH2, C7), 52.8 (CH2, C6), 52.3 (CH2, C11), 51.4 (CH2, C2), 30.4 (CH2, C4), 22.2 (CH2, C3). MS m/z (relative intensity): 273 (M +• , 1), 228 (24), 91 (100), 65 (9). Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 MS m/z (relative intensity): 349 (M +• , 0.1), 243 (3), 228 (20), 91 (100), 77 (5), 65 (9). mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = sodium phenoxy
	MS m/z (relative intensity): 338 (M +• , 0.04), 225 (8), 110 (100), 91 (97), 81 (3), 65 (15). HRMS: calcd for C14H19F3NO (M+H + ): 274.1413. Found 274.1416. mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = allyl alcohol (66 L, HRMS: calcd for C20H23F3NO (M+H + ): 350.1726. Found 350.1727. trihydrate (164.1 mg, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography
	HRMS: calcd for C19H26F3N2 (M+H + ): 339.2043. Found 339.2041. Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (PE=100% to (EtOAc/PE=2:98) to afford 29 (98 mg, 0.29 mmol, 75%) as a colorless oil.
	mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = morpholine (85 L, EtOAc/PE=1:99) to afford 26 (66 mg, 0.22 mmol, 57%) as a colorless oil. IR (neat): 3030, 2955, 2814, 1600, 1589, 1497, 1474, 1455, 1367, 1331, 1288, 1238, 1139, 1077, 1055, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=5:95 to 947 cm -1 .

4 mg, 0.55 mmol, 2.0 equiv), triflic anhydride (68 L, 0.41 mmol, 1.5 equiv). Nucleophile = diallylamine (84 L, 0.68 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=1:99) to afford 19 (56 mg, 0.17 mmol, 60%) as a colorless oil. IR (neat): 3077, 2977, 2814, 1643, 1496, 1454, 1376, 1282, 1137, 1100, 995, 919 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.297.21 (m, 5H, H13, H14 and H15), 5.905.80 (m, 2H, H8), 5.175.11 (m, 4H, H9), 4.15 (d, J = 13.8 Hz, 1H, H11), 3.68 (d, J = 13.8 Hz, 1H, H11), 3.43 (dd, J = 14.3 and 4.7 Hz, 2H, H7), 3.09 (dd, J = 12.0 and 4.0 Hz, 2H, H7), 2.82 (m, 1H, H2), 2.77 (d, J = 16.0 Hz, 1H, H6), 2.72 (d, J = 16.0 Hz, 1H, H6), 2.60 (qapp, J = 7.9 Hz, 1H, H2), 2.39 (m, 1H, H4), 2.00 (m, 1H, H4), 1.751.71 (m, 2H, H3).

1 H NMR (CDCl3, 400 MHz): δ 7.387.19 (m, 15H, Har), 4.11 (d, J = 12.0 Hz, 1H, H6), 4.10 (d, J = 12.0 Hz, 2H, H7), 3.64 (d, J = 13.7 Hz, 1H, H6), 3.43 (d, J = 13.7 Hz, 2H, H7), 2.862.77 (m, 3H, H2 and H13), 2.57 (m, 1H, H2), 2.47 (m, 1H, H4), 1.88 (m, 1H, H4), 1.741.69 (m, 2H, H3).

13 C NMR (CDCl3, 100 MHz): δ 139.8 (C, C14), 139.5 (2xC, C8), 129.1 (4xCH, Car), 128.8 (C, q, J = 294.8 Hz, C12), 128.4 (4xCH, Car), 128.4 (2xCH, Car), 128.3 (2xCH, Car), 127.1 (2xCH, Car), 126.9 (CH, Car), 69.4 (C, MS m/z (relative intensity): 347 (M +• -Bn • , 0.3), 210 (59), 181 (4), 91 (100), 65 (7). HRMS: calcd for C27H30F3N2 (M+H + ): 439.2356. Found 439.2359. N-Benzyl-2-[(morpholino)methyl]-2-(trifluoromethyl)pyrrolidine (21) 10:90) to afford 21 (101 mg, 0.31 mmol, 80%) as a brown oil. IR (neat): 2957, 2851, 2808, 1496, 1455, 1397, 1371, 1287, 1135, 1118, 1036, 967 cm -1 .

Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = methanol (39 L, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=2:98) to afford 24 (53.6 mg, 0.20 mmol, 51%) as a colorless oil. IR (neat): 2893, 2816, 1495, 1453, 1366, 1331, 1139, 1102, 1030 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.307.16 (m, 5H, H11, H12 and H13), 4.11 (d, J = 13.7 Hz, 1H, H9), 3.74 (d, J = 13.7 Hz, 1H, H9), 3.67 (d, J = 9.8 Hz, 1H, H6), 3.52 (d, J = 9.8 Hz, 1H, H6), 3.38 (s, 3H, H7), 2.77 (tdapp, J = 7.4 and 2.9 Hz, 1H, H2), 2.58 (dd, J = 15.5 and 8.0 Hz, 1H, H2), 2.102.07 (m, 2H, H4), 1.741.67 (m, 2H, H3).

1 H NMR (CDCl3, 400 MHz): δ 7.347.21 (m, 5Η, H12, H13 and H14), 4.16 (d, J = 13.6 Hz, 1H, H10), 3.77 (d, J = 13.9 Hz, 1H, H10), 3.74 (d, J = 9.6 Hz, 1H, H6), 3.593.51 (m, 3H, H6 and H7), 2.81 (tdapp, J = 7.4 and 2.9 Hz, 1H, H2), 2.63 (dd, J = 15.1 and 8.2 Hz, 1H, H2), 2.152.11 (m, 2H, H4), 1.771.70 (m, 2H, H3), 1.24 (t, J = 7.0 Hz, 3H, H8).

13 C NMR (CDCl3, 100 MHz): δ 141.0 (C, C11), 128.3 (2xCH, C12 or C13), 128.2 (2xCH, C12 or C13), 127.8 (C, q, J = 286.9 Hz, C9), 126.8 (CH, C14), 70.0 (CH2, C6), 67.8 (C, q, J = 24.4 Hz, C5), 67.2 (CH2, C7), 53.3 (CH2, C10), 53.2 (CH2, C2), 31.1 (CH2, C4), 23.0 (CH2, C3), 15.4 (CH3, C8). MS m/z (relative intensity): 287 (M +• , 0.5), 228 (17), 91 (100), 65 (7). HRMS: calcd for C15H21F3NO (M+H + ): 288.1570. Found 288.1572. N-Benzyl-2-[(prop-2-en-1-yloxy)methyl]-2-(trifluoromethyl)pyrrolidine (26) IR (neat): 2833, 1495, 1454, 1366, 1330, 1139, 1090, 1020, 989, 926 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.347.19 (m, 5H, H13, H14 and H15), 5.92 (m, 1H, H8), 5.32 (dqapp, J = 17.2 and 1.7 Hz, 1H, H9), 5.21 (dqapp, J = 10.5 and 1.5 Hz, 1H, H9), 4.15 (d, J = 13.7 Hz, 1H, H11), 4.064.04 (m, Following the general protocol: 1 (79 mg, 0.30 mmol, 1.0 equiv), proton sponge (130.6 mg, 0.61 mmol, 2.0 equiv), triflic anhydride (76 L, 0.46 mmol, 1.5 equiv). Nucleophile = benzyl alcohol (79 L, 0.76 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=1:99) to afford 27 (69 mg, 0.20 mmol, 65%) as a colorless oil. IR (neat): 3030, 2874, 1496, 1454, 1366, 1330, 1139, 1096, 1028, 926 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.387.21 (m, 10Η, Har), 4.62 (d, J = 11.8 Hz, 1H, H7), 4.57 (d, J = 12.1 Hz, 1H, H7), 4.15 (d, J = 13.6 Hz, 1H, H13), 3.79 (d, J = 9.9 Hz, 1H, H6), 3.78 (d, J = 13.1 Hz, 1H, H13), 3.64 (d, J = 9.9 Hz, 1H, H6), 2.83 (tdapp, J = 7.4 and 3.0 Hz, 1H, H2), 2.65 (qapp, J = 8.0 Hz, 1H, H2), 2.162.13 (m, 2H, H4), 1.781.72 (m, 2H, H3).

13 C NMR (CDCl3, 100 MHz): δ 140.8 (C, C8 or C14), 138.1 (C, C8 or C14), 128.6 (2xCH, Car), 128.3 (2xCH, Car), 128.2 (2xCH, Car), 127.9 (CH, C11 or C17), 127.7 (C, q, J = 286.8 Hz, C12), 127.6 (2xCH, Car), 126.8 (CH, 1 H NMR (CDCl3, 400 MHz): δ 7.357.25 (m, 5Η, H10, H11 and H12), 4.09 (d, J = 13.3 Hz, 1H, H8), 3.84 (d, J = 10.9 Hz, 1H, H6), 3.68 (dq, J = 13.3 and 1.8 Hz, 1H, H8), 3.61 (m, 1H, H6), 2.90 (m, 1H, H2), 2.75 (qapp, J = 17.3 Hz, 1H, H2), 2.53 (br s, OH), 2.192.15 (m, 2H, H4), 1.80 (m, 1H, H3), 1.71 (m, 1H, H3).

13 C NMR (CDCl3, 100 MHz): δ 139.3 (C, C9), 128.7 (2xCH, C10 or C11), 128.5 (2xCH, C10 or C11), 128.0 (C, q, J = 291.6 Hz, C7), 127.4 (CH, C12), 69.2 (C, q, J = 23.3 Hz, C5), 59.5 (CH2, C6), 52.2 (CH2, C8), 51.9 (CH2, C2), 30.1 (CH2, C4), 22.1 (CH2, C3). MS m/z (relative intensity): 259 (M +• , 0.6), 228 (17), 91 (100), 65 (8). HRMS: calcd for C13H17F3NO (M+H + ): 260.1257. Found 260.1260. N-Benzyl-2-phenoxymethyl-2-(trifluoromethyl)pyrrolidine (29) 1 H NMR (Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = tetrabutylammonium acetate (290.7 mg, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=5:95 to 10:90) to afford 30 (84 mg, 0.28 mmol, 72%) as a yellow oil. IR (neat): 3030, 2973, 2813, 1749, 1496, 1454, 1367, 1226, 1141, 1050, 955, 907 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.317.22 (m, 5H, H12, H13 and H14), 4.39 (d, J = 11.8 Hz, 1H, H6), 4.32 (d, J = 11.8 Hz, 1H, H6), 4.06 (d, J = 13.6 Hz, 1H, H10), 3.81 (d, J = 13.6 Hz, 1H, H10), 2.82 (m, 1H, H2), 2.67 (qapp, J = 7.5 Hz, 1H, H2), 2.21 (m, 1H, H3), 2.13 (s, 3H, H8), 1.99 (m, 1H, H3), 1.821.74 (m, 2H, H4).

  3 mg, 0.77 mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = ethyl mercaptan (72 L, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (EtOAc/PE=1:99) to afford 31 (64 mg, 0.21 mmol, 54%) as a colorless oil. L, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (PE=100%) to afford 32 (126 mg, 0.34 mmol, 89%) as a colorless oil.HRMS: calcd for C19H21F3NS (M+H + ): 352.1341. Found 352.1341.

	N-Benzyl-2-cyanomethyl-2-(trifluoromethyl)pyrrolidine (34)
	IR (neat): 3063, 3028, 2954, 2821, 1602, 1494, 1454, 1369, 1315, 1257, 1145, 1100, 1073, 1029, 997,
	944 cm -1 .
	1 H NMR (CDCl3, 400 MHz): δ 7.367.22 (m, 10Η, Har), 3.94 (d, J = 13.7 Hz, 1H, H13), 3.74 (s, 2H, H7),
	3.73 (d, J = 16.0 Hz, 1H, H13), 3.15 (d, J = 12.7 Hz, 1H, H6), 2.762.65 (m, 3H, H2 and H6) 2.16 (m, 1H,
	H4), 2.05 (m, 1H, H4), 1.771.70 (m, 2H, H3).
	13 C NMR (CDCl3, 100 MHz): δ 140.1 (C, C8 or C14), 138.2 (C, C8 or C14), 129.0 (2xCH, Car), 128.7 (2xCH, Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77
	Car), 128.3 (2xCH, Car), 128.3 (2xCH, Car), 128.2 (C, q, J = 291.8 Hz, C12), 127.3 (CH, C11 or C17), 126.9 (CH, mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = tetrabutylammonium
	C11 or C17), 67.9 (C, q, J = 23.9 Hz, C5), 52.2 (CH2, C13), 51.8 (CH2, C2), 37.9 (CH2, C7), 34.6 (CH2, C6), 31.7 cyanide (273 mg, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography
	(CH2, C4), 22.3 (CH2, C3). (EtOAc/PE=4:96) to afford 34 (78 mg, 0.29 mmol, 75%) as a yellow oil.
	IR (neat): 3031, 2962, 2839, 2359, 2252, 1454, 1373, 1349, 1278, 1141, 1105, 1076, 1029, 979, 914
	cm -1 .
	13 C NMR (CDCl3, 100 MHz): δ 140.2 (C, C11), 128.3 (2xCH, C12 or C13), 128.3 (C, q, J = 291.6 Hz, C9),
	128.2 (2xCH, C12 or C13), 126.9 (CH, C14), 68.0 (q, J = 23.8 Hz, C5), 52.3 (CH2, C10), 51.9 (CH2, C2), 35.2
	(CH2, C6), 31.7 (CH2, C4), 27.9 (CH2, C7), 22.4 (CH2, C3), 15.1 (CH3, C8).
	IR (neat): 3062, 3028, 2955, 2834, 1584, 1495, 1480, 1454, 1438, 1372, 1314, 1252, 1137, 1100, 1026,
	997, 943 cm -1 .
	1 H NMR (CDCl3, 400 MHz): δ 7.407.18 (m, 10Η, Har), 4.07 (d, J = 13.6 Hz, 1H, H12), 3.80 (ddapp, J = 13.6
	and 1.4 Hz, 1H, H12), 3.67 (d, J = 12.6 Hz, 1H, H6), 3.21 (d, J = 12.6 Hz, 1H, H6), 2.85 (m, 1H, H2), 2.75
	(qapp, J = 7.2 Hz, 1H, H2), 2.38 (m, 1H, H4), 2.19 (m, 1H, H4), 1.851.78 (m, 2H, H3).
	13 C NMR (CDCl3, 100 MHz): δ 139.9 (C, C7 or C13), 137.2 (C, C7 or C13), 129.5 (2xCH, Car), 129.2 (2xCH,
	Car), 128.4 (2xCH, Car), 128.3 (2xCH, Car), 128.2 (C, q, J = 292.4 Hz, 1C, C11), 127.0 (CH, C10 or C16), 126.4

IR (neat): 2968, 2928, 2831, 1495, 1454, 1373, 1330, 1315, 1266, 1137, 1100, 1075, 1029, 943 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.387.36 (m, 2Η, Har), 7.327.28 (m, 2Η, Har), 7.257.20 (m, 1Η, Har), 4.00 (d, J = 13.6 Hz, 1H, H10), 3.84 (d, J = 13.6 Hz, 1H, H10), 3.27 (d, J = 12.9 Hz, 1H, H6), 2.772.71 (m, 2H, H2), 2.73 (d, J = 12.6 Hz, 1H, H6), 2.59 (q, J = 8.0 Hz, 2H, H7), 2.33 (m, 1H, H4), 2.15 (m, 1H, H4), 1.821.75 (m, 2H, H3), 1.30 (t, J = 7.4 Hz, 3H, H8).

MS m/z (relative intensity): 303 (M +• , 0.1), 228

(22)

, 91 (100), 65

(7)

.

HRMS: calcd for C15H21F3NS (M+H + ): 304.1341. Found 304.1342.

N-Benzyl-2-[(benzylsulfanyl)methyl]-2-(trifluoromethyl)pyrrolidine (32)

Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = benzyl mercaptan (113 MS m/z (relative intensity): 365 (M +• , 0.5), 228

(42)

, 91 (100), 65

(10)

.

HRMS: calcd for C20H23F3NS (M+H + ): 366.1498. Found 366.1499.

N-Benzyl-2-[(phenylsulfanyl)methyl]-2-(trifluoromethyl)pyrrolidine (33)

Following the general protocol: 1 (100 mg, 0.39 mmol, 1.0 equiv), proton sponge (165.3 mg, 0.77 mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleopile = sodium thiophenolate (127 mg, 0.96 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (PE=100%) to afford 33 (83 mg, 0.24 mmol, 61%) as a colorless oil.

(CH, C10 or C16), 68.1 (C, q, J = 23.8 Hz, C5), 52.3 (CH2, C12), 51.7 (CH2, C2), 37.5 (CH2, C6), 31.8 (CH2, C4),

22.4 (CH2, C3).

MS m/z (relative intensity): 351 (M +• , 0.3), 228

(43)

, 123 (2), 91 (100), 77 (3), 65

(9)

. 1 H NMR (CDCl3, 400 MHz): δ 7.377.23 (m, 5Η, H11, H12 and H13), 4.03 (d, J = 13.5 Hz, 1H, H9), 3.86 (d, J = 13.5 Hz, 1H, H9), 2.89 (m, 1H, H2), 2.89 (d, J = 16.0 Hz, 1H, H6), 2.76 (m, 1H, H2), 2.74 (d, J = 16.0 Hz, 1H, H6), 2.36 (m, 1H, H4), 2.20 (m, 1H, H4), 1.931.84 (m, 2H, H3).

  For the sodium dimethylmalonate: To a stirred suspension of NaH (60% wt oil dispersion, 40 mg, 1.00 mg, 2.6 equiv) in THF (3 mL) at 15°C was added dropwise dimethylmalonate (0.35 mL, 1.35 mmol, 3.5 equiv) and the solution was stirred at rt for 30 min.

	IR (neat): 2956, 2845, 1736, 1455, 1436, 1366, 1268, 1137 1104, 1038 cm -1 .
	1 H NMR (CDCl3, 400 MHz): δ 7.327.22 (m, 5H, H13, H14 and H15), 4.10 (d, J = 13.5 Hz, 1H, H11), 3.78 (s,
	3H, H9 or H9'), 3.77 (m, 1H, H7), 3.68 (s, 3H, H9 or H9'), 3.57 (dq, J = 13.5 and 2.3 Hz, 1H, H11), 2.86 (m,
	1H, H2), 2.64-2.59 (m, 2H, H2 and H6), 2.38 (dd, J = 15.0 Hz and 6.1 Hz, 1H, H6), 2.13 (m, 1H, H4),
	1.821.66 (m, 3H, H3 and H4).
	13 C NMR (CDCl3, 100 MHz): δ 170.6 (C, C8 or C8'), 170.2 (C, C8 or C8'), 139.4 (C, C12), 128.6 (C, q, J =
	294.3 Hz, C10), 128.4 (2xCH, C13 or C14), 128.3 (2xCH, C13 or C14), 127.0 (CH, C15), 67.6 (C, q, J = 23.2 Hz,
	C5), 53.1 (CH3, C9 or C9'), 53.0 (CH3, C9 or C9'), 51.9 (CH2, C11), 51.1 (CH2, C2), 46.7 (CH, C7), 31.2 (CH2,
	C4), 29.2 (CH2, C6), 21.9 (CH2, C3).
	3 mg, 0.77
	mmol, 2.0 equiv), triflic anhydride (96 L, 0.58 mmol, 1.5 equiv). Nucleophile = sodium
	dimethylmalonate. The crude mixture was purified by flash chromatography (EtOAc/PE=10:90) to

afford 35 (101 mg, 0.27 mmol, 70%) as a yellow oil.

  solution of allyl bromide (5.48 mL, 63 mmol, 1.6 equiv) and In (5.88 g, 51.2 mmol, 1.3 equiv) in H2O (99 mL) was stirred for 15 min and then 2-chloroacetaldehyde 47 (5 mL, 39.4 mmol, 1.0 equiv) was added to the gray heterogeneous mixture. After 3 h at rt, the reaction mixture was extracted with Et2O and the combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced presssure to afford 48 (3.7 g, 30.9 mmol, 80%) as a colorless oil. IR (neat): 3382, 3079, 2956, 2917, 1642, 1432, 1047, 996, 919 cm -1 .

	6. Synthesis	and	spectroscopic	data	of
	N-benzyl-3-hydroxy-3-(trifluoromethyl)azepane (44)
	1-Chloropent-4-en-2-ol (48) 77
		+• , 24), 206 (17), 146 (8), 134 (9), 130 (34), 116 (39), 92 (15), 91
	(100), 65 (14).
	HRMS: calcd for C13H19FN (M+H + ): 208.1496. Found 208.1497.

A

  CDCl3, 100 MHz): δ 134.4 (CH, C2 or C7), 134.3 (CH, C2 or C7), 118.2 (CH2, C1 or C8), 117.6 (CH2, C1 or C8), 68.3 (CH, C4), 53.5 (CH2, C5), 51.6 (CH2, C6), 39.8 (CH2, C3). tert-Butyl allyl(2-hydroxypent-4-en-1-yl)carbamate (49)73 To a stirred solution of N-(allylamino)pent-7-en-5-ol 46 (1.2 g, 8.5 mmol, 1.0 equiv) in CH2Cl2 (16.3 mL) was added Et3N (1.77 mL, 12.7 mmol, 1.5 equiv) and Boc2O (2.09 mL, 9.77 mmol, 1.15 equiv) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was evaporated under reduced pressure, diluted in EtOAc and treated with HCl 1M and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (EtOAc/PE=15:85 and 20:80) to afford 49 (1.9 g, 7.9 mmol, 93%) as a colorless oil. CDCl3, 400 MHz) mixture of rotamers: δ 5.745.64 (m, 2H, H3 and H4), 4.14 (dapp, J = 17.5 Hz, 1H, H2), 4.01 (m, 1H, H6), 3.77 (dapp, J = 16.7 Hz, 2H, H2 and H7), 3.60 (m, 1H, H7), 2.38 (m, 2H, H5), 1.47 (s, 9H, H10).

	tert-Butyl 3-oxoazepane-1-carboxylate (51) 78
	13 C NMR (CDCl3, 100 MHz) mixture of rotamers: δ 156.8 (C, C8), 155.3 (C, C8'), 130.0 (CH, C3' or C4'),
	129.4 (CH, C3 or C4), 126.3 (CH, C3 or C4), 125.9 (CH, C3' or C4'), 80.3 (C, C9), 70.0 (CH, C6), 69.4 (CH, C6'),
	54.3 (CH2, C7), 54.1 (CH2, C7'), 48.2 (CH2, C2), 47.2 (CH2, C2'), 34.4 (CH2, C5), 33.8 (CH2, C5'), 28.4 (3xCH3, To a solution of tert-butyl 3-(hydroxy)azepane-1-carboxylate 50 (2.24 g, 10.4 mmol, 1.0 equiv) in
	C10). CH2Cl2 (52 mL) was added Dess-Martin periodinane (4.85 g, 3.56 mL, 11.4 mmol, 1.1 equiv) and the
	MS m/z (relative intensity): 213 (M +• , 0.05), 157 (6), 139 (11), 11 (5), 94 (11), 83 (5), 68 (10), 57 (100), reaction mixture was stirred at rt for 2.5 h. The mixture was then quenched with a saturated aqueous
	55 (18). solution of Na2S2O3, followed by an aqueous solution of NaOH 1M. The resulting mixture was
	tert-Butyl 3-(hydroxy)azepane-1-carboxylate (50) 73 extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated under reduced pressure. The
	crude product was purified by flash chromatography (Et2O/PE=20:80 to 30:70) to give 51 (1.9 g, 8.91
	mmol, 86%) as a colorless oil.
	IR (neat): 2975, 2933, 2864, 1700, 1458, 1415, 1366, 1251, 1158, 1094, 889 cm -1 .
	13 C NMR (CDCl3, 100 MHz): δ 157.4 (C, C9), 134.4 (CH, C2 or C7), 133.9 (CH, C2 or C7), 117.8 (CH2, C1 or
	C8), 116.4 (CH2, C1 or C8), 80.3 (C, C10), 70.9 (CH, C4), 53.0 (CH2, C5), 51.6 (CH2, C6), 39.8 (CH2, C3), 28.4
	(3xCH3, C11).
	tert-Butyl 3-hydroxy-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (45) 73
	13 C NMR (DMSO-d6, 400 MHz) mixture of rotamers: δ 154.7 (C, C8), 154.4 (C, C8'), 78.3 (C, C9), 78.2
	(C, C9'), 68.8 (CH, C6), 53.3 (CH2, C7), 53.0 (CH2, C7'), 47.1 (CH2, C2), 46.8 (CH2, C2'), 36.2 (CH2, C5), 35.6
	(CH2, C5'), 28.1 (3xCH3, C10), 27.3 (CH2, C3), 27.3 (CH2, C3'), 20.8 (CH2, C4), 20.6 (CH2, C4').
	To a stirred solution of tert-butyl allyl(2-hydroxypent-4-en-1-yl)carbamate 49 (4.7 g, 19.5 mmol, 1.0 MS m/z (relative intensity): 215 (M +• , 0.49), 159 (5), 141 (16), 114 (6), 84 (7), 70 (22), 57 (100).
	equiv) in CH2Cl2 (106 mL) was added Grubbs-I catalyst (2.48 g, 2.92 mmol, 15 mol %) and the reaction
	mixture was stirred for 48 h at rt and concentrated under reduced pressure. The crude mixture was
	purified by flash chromatography (EtOAc/PE=25:75) to afford 45 (2.86 g, 13.4 mmol, 69%) as a brown
	oil.

77

Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem. 2001, 66, 46794686. 13 C NMR (IR (neat): 3433, 3079, 2978, 2931, 2248, 1669, 1461, 1409, 1366, 1247, 1168, 1097, 993, 913 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 5.895.75 (m, 2H, H2 and H7), 5.145.09 (m, 4H, H1 and H8), 3.85 (m 3H, H4 and H6), 3.55 (s, 1H, OH), 3.25 (m, 2H, H5), 2.242.22 (m, 2H, H3), 1.46 (s, 9H, H11). IR (neat): 3428, 2976, 2930, 1668, 1415, 1366, 1246, 1161, 1057, 880 cm -1 . 1 H NMR (To a stirred solution of tert-Butyl 3-hydroxy-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate 45 (2.86 g, 13.4 mmol, 1.4 equiv) in EtOH (224 mL) was added PtO2 (305 mg, 1.34 mmol, 10 mol %) and the reaction mixture was stirred under H2 atmosphere for 16 h. The solution was then filtered over Celite, washed with EtOAc and concentrated under reduced pressure to afford 50 (2.84 g, 13.2 mmol, quant) as a brown oil. IR (neat): 3425, 2975, 2929, 2863, 1692, 1666, 1478, 1415, 1365, 1250, 1160, 1053 cm -1 . 1 H NMR (CDCl3, 400 MHz) mixture of rotamers: δ 3.94 (m, 1H, H6), 3.683.56 (m, 2H, H2 and H7), 3.37 (dd, J = 14.8 and 4.2 Hz, 1H, H7), 3.10 (m, 1H, H2), 1.88 (m, 1H, H5), 1.781.64 (m, 3H, H3 and H4), 1.50 (m, 1H, H5), 1.47 (s, 9H, H10), 1.35 (m, 1H, H4).

1 H NMR (CDCl3, 400 MHz) mixture of rotamers: δ 4.03 (m, 2H, H7), 3.96 (m, 2H, H7'), 3.45 (m, 2H, H2), 3.38 (m, 2H, H2'), 2.53 (dd, J = 7.6 and 4.1 Hz, 2H, H5), 1.851.72 (m, 4H, H3 and H4), 1.51 (s, 9H, H10), 1.46 (s, 9H, H10').

  and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (EtOAc/PE=5:95) to afford 52 (1.90 g, 6.71 mmol, 93%) as a colorless oil. IR (neat): 3392, 2935, 1659, 1423, 1368, 1287, 1152, 1119, 868 cm -1 .

	1 H NMR (CDCl3, 400 MHz): δ 4.91 (br s, OH), 4.21 (d, J = 15.0 Hz, 1H, H7), 3.84 (m, 1H, H2), 3.07 (d, J =
	15.0 Hz, 1H, H7), 2.99 (d, J = 13.5 and 5.9 Hz, 1H, H2), 1.941.53 (m, 6H, H3, H4 and H5), 1.48 (s, 9H,
	H11).
	13 C NMR (CDCl3, 400 MHz): δ 159.0 (C, C9), 126.1 (C, q, J = 286.4 Hz, C8), 81.4 (C, C10), 76.7 (C, q, J =
	26.3 Hz, C6), 49.5 (CH2, C7), 47.7 (CH2, C2), 34.1 (CH2, C3 or C4 or C5), 28.4 (3xCH3, C11), 28.3 (CH2, C3 or
	C4 or C5), 20.1 (CH2, C3 or C4 or C5).
	MS m/z (relative intensity): 283 (M +• , 0.19), 228 (4), 210 (5), 182 (5), 70 (19), 57 (100).

Mangion, I. K.; Nwamba, I. K.; Shevlin, M.; Huffman, M. A. Org. Lett. 2009, 11, 35663569. filtered HRMS: calcd for C12H20F3NO3Na (M+Na + ): 306.1288. Found 306.1288. N-Benzyl-3-hydroxy-3-(trifluoromethyl)azepane (44)

  IR (neat): 2954, 2852, 1736,1436, 1237, 1140, 1115 cm -1 .

	IR (neat): 2946, 2853, 1453, 1141, 1070 cm -1 . N-Benzyl-2-cyanomethyl-2-(trifluoromethyl)piperidine (73)
	1 H NMR (CDCl3, 400 MHz): δ 7.457.23 (m, 5Η, H11, H12 and H13), 4.07 (d, J = 14.4 Hz, 1H, H9), 3.85 (d, 1 H NMR (CDCl3, 400 MHz): δ 7.317.19 (m, 5H, H14, H15 and H16), 4.25 (d, J = 15.2 Hz, 1H, H12), 3.95
	J = 11.5 Hz, 1H, H7), 3.52 (m, 1H, H9), 3.48 (d, J = 11.5 Hz, 1H, H7), 2.652.62 (m, 2H, H2), 2.09 (m, 1H, (dd, J = 6.2 and 3.2 Hz, 1H, H8), 3.78 (s, 3H, H10 or H10'), 3.45 (s, 3H, H10 or H10'), 3.44 (dd, J = 15.1 and
	H5), 1.92 (dtdapp, J = 14.1, 4.1 and 1.3 Hz, 1H, H5), 1.691.62 (m, 2H, H4), 1.581.47 (m, 2H, H3). 2.4 Hz, 1H, H12), 2.81 (dd, J = 15.5 and 3.2 Hz, 1H, H7), 2.70 (m, 1H, H2), 2.61 (m, 1H, H2), 2.20 (dd, J =
	13 C NMR (CDCl3, 100 MHz): δ 139.6 (C, C10), 128.4 (2xCH, C11 or C12), 128.3 (2xCH, C11 or C12), 127.8 (C, 15.6 Hz and 6.3 Hz, 1H, H7), 1.90 (dd, J = 14.1 Hz and 2.1 Hz, 1H, H5), 1.601.43 (m, 5H, H3, H4 and H5).
	q, J = 299.8 Hz, C8), 127.0 (CH, C13), 62.2 (C, q, J = 21.1 Hz, C6), 54.0 (CH2, C9), 46.1 (CH2, C2), 34.2 (CH2, 13 C NMR (CDCl3, 100 MHz): δ 170.8 (C, C9 or C9'), 169.9 (C, C9 or C9'), 139.6 (C, C13), 129.2 (C, q, J =
	C7), 29.7 (CH2, C5), 25.0 (CH2, C3), 20.0 (CH2, C4). Following the general protocol: 44 (94 mg, 0.34 mmol, 1.0 equiv), proton sponge (147.4 mg, 0.69 299.6 Hz, C11), 128.4 (2xCH, C14 or C15), 127.3 (2xCH, C14 or C15), 126.6 (CH, C16), 62.1 (C, q, J = 21.0 Hz,
	MS m/z (relative intensity): 337 (M +• , 0.7), 335 (M +• , 0.7), 268 (8), 266 (8), 242 (12), 91 (100), 65 (8). mmol, 2.0 equiv) and triflic anhydride (86 L, 0.52 mmol, 1.5 equiv). Nucleophile = C6), 53.8 (CH2, C12), 53.0 (CH3, C10 or C10'), 52.8 (CH3, C10 or C10'), 46.5 (CH2, C2), 46.0 (CH, C8), 30.9 (CH2,
	HRMS: calcd for C14H18BrF3N (M+H + ): 336.0569 and 338.0549. Found 336.0572 and 338.0546. tetrabutylammonium cyanide (231 mg, 0.86 mmol, 2.5 equiv). The crude mixture was purified by C7), 30.2 (CH2, C5), 25.1 (CH2, C3), 20.2 (CH2, C4).
	flash chromatography (EtOAc/PE=5:95) to afford 73 (92 mg, 0.32 mmol, 94%) as a yellow oil. MS m/z (relative intensity): 387 (M +• , 1.8), 318 (34), 242 (11), 91 (100), 65 (6), 55 (4).
	N-Benzyl-2-iodomethyl-2-(trifluoromethyl)piperidine (72) IR (neat): 2951, 2853, 1453, 1240, 1142, 1117 cm -1 . HRMS: calcd for C19H25F3NO4 (M+H + ): 388.1730. Found 388.1730.
	1 H NMR (CDCl3, 400 MHz): δ 7.447.22 (m, 5Η, H12, H13 and H14), 4.12 (d, J = 14.4 Hz, 1H, H10), 3.50
	(dq, J = 14.4 and 2.2 Hz, 1H, H10), 3.06 (d, J = 17.2 Hz, 1H, H7), 2.64 (d, J = 17.2 Hz, 1H, H7), 2.672.56
	(m, 2H, H2), 2.11 (dtdapp, J = 14.1, 3.8 and 1.4 Hz, 1H, H5), 2.00 (m, 1H, H5), 1.691.51 (m, 4H, H3 and
	H4).
	3 (CH2,
	C2), 31.4 (CH2, C5), 24.8 (CH2, C7), 24.4 (CH2, C3), 20.1 (CH2, C4).
	MS m/z (relative intensity): 282 (M +• , 1.6), 242 (14), 213 (7), 91 (100), 65 (10), 54 (3).
	N-Benzyl-2-bromomethyl-2-(trifluoromethyl)piperidine (71) 13 C NMR (CDCl3, 100 MHz): δ 139.2 (C, C10), 128.5 (2xCH, C11 or C12), 128.3 (2xCH, C11 or C12), 127.0
	(CH, C13), 125.7 (C, q, J = 300.6 Hz, C8), 61.1 (C, q, J = 20.9 Hz, C6), 53.9 (CH2, C9), 46.0 (CH2, C2), 31.9
	(CH2, C5), 25.0 (CH2, C3), 20.1 (CH2, C4), 10.3 (CH2, C7).
	MS m/z (relative intensity): 383(M +• , 1.9), 314 (28), 256 (3), 242 (19), 187 (10), 186 (11), 91 (100), 65 Following the general protocol: 44 (81.3 mg, 0.30 mmol, 1.0 equiv), proton sponge (127.5 mg, 0.60
	(14). mmol, 2.0 equiv) and triflic anhydride (74 L, 0.45 mmol, 1.5 equiv). Nucleophile = sodium
	HRMS: calcd for C14H18F3IN (M+H + ): 384.0431. Found 384.0439. dimethylmalonate. The crude mixture was purified by flash chromatography (Et2O/PE=10:90) to
	Following the general protocol: 44 (251 mg, 0.92 mmol, 1.0 equiv), proton sponge (393.6 mg, 1.84 afford 74 (115 mg, 0.30 mmol, quant) as a colorless oil.

.

HRMS: calcd for C14H18ClF3N (M+H + ): 292.1074 and 294.1043. Found 292.1076 and 294.1045. mmol, 2.0 equiv) and triflic anhydride (229 L, 1.38 mmol, 1.5 equiv). Nucleophile = tetrabutylammonium bromide (740.2 mg, 2.30 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (PE=100%) to afford 71 (250 mg, 0.74 mmol, 81%) as colorless oil.

Following the general protocol: 44 (107.6 mg, 0.39 mmol, 1.0 equiv), proton sponge (168.8 mg, 0.79 mmol, 2.0 equiv) and triflic anhydride (98 L, 0.59 mmol, 1.5 equiv). Nucleophile = tetrabutylammonium iodide (363.6 mg, 0.98 mmol, 2.5 equiv). The crude mixture was purified by flash chromatography (PE=100%) to afford 72 (135 mg, 0.35 mmol, 89%) as colorless oil. IR (neat): 2944, 2853, 1450, 1139, 1112, 1064 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.497.20 (m, 5Η, H11, H12 and H13), 4.02 (d, J = 14.3 Hz, 1H, H9), 3.72 (d, J = 11.4 Hz, 1H, H7), 3.47 (dq, J = 14.3 and 2.5 Hz, 1H, H9), 3.33 (d, J = 11.4 Hz, 1H, H7), 2.632.58 (m, 2H, H2), 2.00 (m, 1H, H5), 1.89 (dtdapp, J = 14.2, 3.8 and 0.9 Hz, 1H, H5), 1.701.46 (m, 4H, H3 and H4).

13 C NMR (CDCl3, 100 MHz): δ 138.9 (C, C11), 128.6 (2xCH, C12 or C13), 128.2 (2xCH, C12 or C13), 128.0 (C, q, J = 298.7 Hz, C9), 127.3 (CH, C14), 116.0 (C, C8), 60.9 (C, q, J = 22.2 Hz, C6), 54.4 (CH2, C10), 46.HRMS: calcd for C15H18F3N2 (M+H + ): 283.1417. Found 283.1419. N-Benzyl-2-[(1,3-dimethyl-propanedioate)methyl]-2-(trifluoromethyl)piperidine (74)

For the sodium dimethylmalonate: To a stirred suspension of NaH (60% wt oil dispersion, 31 mg, 0.77 mmol, 2.6 equiv) in THF (3 mL) at 15 °C was added dropwise dimethylmalonate (0.12 mL, 1.04 mmol, 3.5 equiv) and the reaction mixture was stirred at rt for 30 min.

N-Benzyl-2-ethyl-2-(trifluoromethyl)piperidine

(75)

  .4.2.2. Intramolecular diaza-Wittig reactionIn 2011, the synthesis of bis-(trifluoromethyl)pyridazines L3.72 was reported by using a diaza-Wittig reaction. When diazo-oxo-trifluorobutanoates L3.67 reacted with the dicarbonyl compound L3.68, in Scheme 81).103 It is worth mentioning that when the reaction was carried out in the presence of triphenylphosphine instead of tris(dimethylamino)phosphine, the pyridazines were obtained in moderate yields. These moderate yields can be explained by the presence of H2O released during the intramolecular condensation, which can hydrolyze the diazoketoesters L3.67 and phosphazines L3.69 valence tautomerism was reported in 1995. 105k More specifically, when tetrazine L3.73 reacted with the tautomeric system cylclooctatetraene L3.78/bicyclo[4.2.0]octatriene L3.79, the non-isolable cycloadduct L3.80 was formed. Elimination of N2, afforded L3.81 which rapidly tautomerized to the more stable compound L3.82 (Scheme 84). The authors pointed out that the equilibrium cylclooctatetraene L3.78/bicyclo[4.2.0]octatriene L3.79 is constant in refluxing dichloromethane (b.p.=39.6 °C), therefore it is the cyclooctatetraene L3.78 that acts as the dienophile rather than the bicyclo[4.2.0]octatriene L3.79. They also specified that even if the formation of the tautomers L3.83 and L3.84 can be envisaged, chromatographic and spectroscopic analysis did not reveal the presence of such intermediates. However, during the Diels-Alder reaction, the side product L3.85 was isolated in 5% yield, indicating that a small amount of L3.83 can react with another molecule of tetrazine L3.73 to form the cycloadduct L3.85. Oxidation with silver oxide, promotes a [2+2]-cycloreversion to afford pyridazines L3.86 (61%) and L3.87 (64%) (Scheme 84).

	the	presence	of	tris(dimethylamino)phosphine,	the	desired	tetrasubstituted
	bis-(trifluoromethyl)pyridazines L3.72 were isolated. In this process, diazoketoesters L3.67
	underwent a Staudinger reaction in the presence of tris(dimethylamino)phosphine, to form
	phosphazines L3.69 in excellent yields (up to 97%). A diaza-Wittig reaction then took place when
	L3.69 was treated with ketoester L3.68, to produce intermediate L3.70, which released
	tris(dimethylamino)phosphine oxide to afford compound L3.71. An intramolecular condensation of
	L3.71 led to the desired bis-(trifluoromethyl)pyridazines L3.72 in 44% (R=Me) and 50% (R=Et) yield
	Scheme 84 Scheme 89 An unexpected double inverse electron demand Diels-Alder reaction was reported in 1999, when dienamine L3.106 reacted with 2.0 equiv of tetrazine L3.73, as two unexpected monocyclic (Scheme 81 cycloadducts, L3.107 and L3.108 were obtained in 38% and 44% yield respectively (Scheme 90). 107
		1.4.2.3. Diels-Alder reaction with inverse electron demand involving tetrazines

1.4.2.1. Condensation of hydrazine with carbonyl compounds In 1985, Tamborski et al. reported the condensation of hydrazine with diketone L3.64 in pyridine, to afford the bis-(trifluoromethyl)pyridazine L3.66, insisting on the fact that the expected intermediate L3.65 was not observed but instead product L3.66 was isolated in 73% yield (Scheme 80). 102 Scheme 80 101 Mao, H.; Lin, A.; Tang, Z.; Hu, H.; Zhu, C.; Cheng, Y. Chem. Eur. J. 2014, 20, 24542458. 102 Tamborski, C.; Prabhu, U. D. G.; Eapen, K. C. J. Fluorine Chem. 1985, 28, 139150.

1(Ph instead of NMe2). In addition, these moderate yields can also come from the dissociation of phosphazines L3.69 into the initial diazoketoesters L3.67 and triphenylphosphine. The inverse electron demand Diels-Alder reaction of a tetrazine with a dienophile, followed by a retro Diels-Alder reaction, releasing N2, represents one of the most common methods to obtain dienophiles displaying U.; Seitz, G. Arch. Pharm. 1993, 326, 2932; j) Frenzen, G.; Massa, W.; Reimers, U.; Seitz, G. Chem. Ber. 1993, 126, 441445; k) Baumann, L.; Folkerts, A.; Imming, P.; Klindert, T.; Massa, W.; Seitz, G.; Wocadlo, S. Liebigs Ann. 1995, 661666; l) Klindert, T.; Seitz, G. Synth. Comm. 1996, 26, 25872596; m) Klindert, T.; Stroetmann, I.; Seitz, G.; Hofner, G.; Wanner, K. T.; Frenzen, G.; Eckhoff, B. Arch. Pharm. Pharm. Med. Chem. 1997, 330, 163168; n) Klindert, T.; Von Hagel, P.; Baumann, L.; Seitz, G. J. Prakt. Chem. 1997, 339, 623632. Scheme 88 However, when indole L3.103, possessing a N-mesyl group, without a leaving group at the C3 position, was treated in refluxing toluene, a ring-opening took place slowly to produce the substituted bis-(trifluoromethyl)pyridazine L3.105 instead of the expected aromatization compound L3.102, showing that, in this case the ring-opening step is more favorable than the aromatization of the indole as L3.102 was not formed (Scheme 89). 106 107 Kotschy, A.; Novak, Z.; Vincze, Z.; Smith, D. M.; Hajos, G. Tetrahedron Lett. 1999, 40, 63136316.

  Table 16, entry 2). Treatment of pyridazine 43, possessing an aromatic ring substituted by a p-CO2Me group, led to the desired compound 83 in a good yield of 82% (Table16, entry 3). In addition, when pyridazine 32, substituted by an aromatic ring possessing an electron-donating group at the para-position, was submitted to the same conditions, pyridazine 84 was isolated in a quantitative yield (Table16, entry 4). Replacement of the p-OMe by o-OMe substituent, induced a slight decrease of the yield as pyridazine 85 was obtained in 78% yield instead of a quantitative yield (Table16, entry 5).

	Entry	Substrate	Product (%)

  Flasks were oven-dried at 120 °C and cooled down under argon prior to use. THF and Et2O were distilled over sodium/benzophenone. Et3N, CH2Cl2 and diglyme were distilled over CaH2. NaI and NaF were dried at 120 °C for 24 h and cooled down under Ar atmosphere. MeCN and DMSO were bought dry from Aldrich and used as received. All others reagents were used as obtained from Aldrich without further purification unless otherwise specified.

	Purification by flash column chromatography was carried out by using silica gel (pore size 60 Å, 230
	mesh). TLC were performed on silica gel plate (Merck 60F254) and visualized either with a UV lamp
	(254 nm) or by treatment with an aqueous potassium permanganate solution (KMnO4/K2CO3/AcOH)
	and subsequent heating.
	Melting points (Mp) were recorded using a Wagner & Munz Kofler bench and a Büchi Melting Point
	M-560 apparatus with open capillaries.

  lined cap and stirred at rt for 2 h. The reaction mixture was filtered over a thin bed of silica gel (AcOEt washings), then an aqueous saturated NaHCO3 solution was added to the filtrate and the aqueous phase was extracted twice with AcOEt. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was directly engaged without purification and MeOH (15 mL) and K2CO3 (650 mg, 0.36 mmol, 0.1 equiv) were added. The resulting suspension was stirred under air at rt for 2 h. The reaction mixture was then concentrated under reduced pressure, an aqueous saturated NaHCO3 solution was added and the aqueous phase was extracted three times with AcOEt. The combined organic phases were dried over The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (Et2O/PE=5:95) to afford the desired product 7 (468 mg, 2.92 mmol, 57%) as a white solid.

	Methyl 4-ethynylbenzoate (7) 122
	1-Ethynyl-4-nitrobenzene (6) 121
	In a pressure vial were introduced the methyl 4-iodobenzoate 2 (1.36 g, 5.19 mmol, 1.0 equiv), CuI
	In a pressure vial were introduced the 1-iodo-4-nitrobenzene 1 (1.00 g, 4.0 mmol, 1.0 equiv), CuI (38.7 mg, 0.20 mmol, 5 mol %) and PdCl2(PPh3)2 (141.5 mg, 0.20 mmol, 5 mol %). The vial was flushed with argon and dry and degassed THF (10 mL) was added, followed by Et3N (1.7 mL, 3.1 mmol, 3.0 equiv) and ethynyltrimethylsilane (0.7 mL, 4.89 mmol, 1.2 equiv). The mixture was then sealed with a teflon-Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (Et2O/PE=5:95) to afford 6 (304 mg, 2.21 mmol, 76%) as a beige solid. Mp: 148 °C. IR (neat): 3254, 1594, 1509, 1351, 1311, 1288, 1107 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 8.20 (d, J = 8.9 Hz, 2H, H5), 7.64 (d, J = 9.0 Hz, 2H, H4), 3.36 (s, 1H, H1). 13 C NMR (CDCl3, 100 MHz): δ 17.7 (C, C3), 133.1 (CH, C5), 129.1 (C, C6), 123.7 (CH, C4), 82.5 (C, C2), 81.6 (CH, C1). MS m/z (relative intensity): 147 (M +• , 100), 117 (52), 101 (84), 89 (41), 75 (92), 74 (32), 63 (16), 51 (43), 50 (18). (50 mg, 0.26 mmol, 5 mol %) and PdCl2(PPh3)2 (183 mg, 0.26 mmol, 5 mol %). The vial was flushed with argon and dry and degassed THF (13 mL) was added, followed by Et3N (1.6 g, 2.2 mL, 15.8 mmol, 3.0 equiv) and ethynyltrimethylsilane (621 mg, 0.9 mL, 6.32 mmol, 1.2 equiv). The mixture was then sealed with a teflon-lined cap and stirred at rt for 2 h. The reaction mixture was filtered over a thin bed of silica gel (AcOEt washings), then an aqueous saturated NaHCO3 solution was added to the filtrate and the aqueous phase was extracted twice with AcOEt. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=2:98) to afford the desired product (1.20 g, 5.16 mmol, quant) as a white solid. Methyl 4-[2-(trimethylsilyl)ethynyl]benzoate 122 Mp: 57 °C. IR (neat): 2956, 1719, 1604, 1441, 1406, 1274, 1248, 1172, 1108, 1018, 840 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.97 (d, J = 8.6 Hz, 2H, H6), 7.52 (d, J = 8.6 Hz, 2H, H5), 3.91 (s, 3H, H9), 0.26 (s, 9H, H1). 13 C NMR (CDCl3, 100 MHz): δ 166.7 (C, C8), 132.0 (2xCH, C6), 129.8 (C, C4), 129.5 (2xCH, C5), 127.9 (C, C7), 104.2 (C, C2), 97.8 (C, C3), 52.4 (CH3, C9), 0.0 (3xCH3, C1). MS m/z (relative intensity): 232 (M +• , 20), 218 (18), 217 (100), 201 (5), 158 (5), 143 (7), 93 (9), 86 (5), 79 (8). To a solution of methyl 4-[2-(trimethylsilyl)ethynyl]benzoate (1.2 g, 5.16 mmol, 1.0 equiv) in MeOH (10 mL) was added K2CO3 (2.1 g, 15.49 mmol, 3.0 equiv) in one portion. The resulting suspension was stirred under air at rt for 1 h. The reaction mixture was then concentrated under reduced pressure, an aqueous saturated NaHCO3 solution was added and the aqueous phase was extracted three times Mp: 94 °C. IR (neat): 3241, 1702, 1607, 1434, 1403, 1310, 1278, 1193, 1175, 1109, 1017, 959 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.99 (d, J = 8.7 Hz, 2H, H5), 7.55 (d, J = 8.6 Hz, 2H, H4), 3.92 (s, 3H, H8), 3.23 (s, 1H, H1). 13 C NMR (CDCl3, 100 MHz): δ 166.5 (C, C7), 132.2 (2xCH, C5), 130.2 (C, C3), 129.6 (2xCH, C4), 126.9 (C, C6), 82.9 (CH, C1), 80.2 (C, C2), 52.4 (CH3, C8). with AcOEt. Methyl 4-ethynylbenzoate (7) MS m/z (relative intensity): 160 (M +• , 46), 130 (10), 129 (100), 101 (49), 75 (20), 74 (8), 51 (10), 50

  -lined cap and heated in a Biotage Initiator microwave oven at 90 °C for 2 h. The reaction mixture was cooled down to rt, filtered over a thin bed of silica gel (AcOEt washings), then an aqueous saturated NaHCO3 solution was added to the filtrate and the aqueous phase was extracted twice with AcOEt. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (PE=100% and Et2O/PE=2:98) to afford the desired product (790 mg, 3.77 mmol, 72%) as a white solid.

	2-Chloro-5-ethynylpyridine (9) 112
	2-Chloro-6-[(trimethylsilyl)ethynyl]pyridine 112
	Mp: 48 °C. In a pressure vial were introduced 5-bromo-2-chloropyridine 4 (1.0 g, 5.2 mmol, 1.0 equiv), CuI
	IR (neat): 2960, 1569, 1555, 1429, 1250, 1158, 1140 cm -1 . (50 mg, 0.26 mmol, 5 mol %) and PdCl2(PPh3)2 (183 mg, 0.26 mmol, 5 mol %). The vial was flushed
	1 H NMR (CDCl3, 400 MHz): δ 7.60 (m, 1H, H6), 7.37 (dd, J = 7.6 and 0.9 Hz, 1H, H7), 7.26 (dd, J = 8.0 with argon and dry and degassed THF (13 mL) was added, followed by Et3N (1.6 g, 2.2 mL, 15.8 mmol,
	and 0.9 Hz, 1H, H5), 0.26 (s, 9H, H1). 3.0 equiv) and ethynyltrimethylsilane (614 mg, 0.89 mL, 6.25 mmol, 1.2 equiv). The mixture was then
	13 C NMR (CDCl3, 100 MHz): δ 151.3 (C, C8), 143.2 (C, C4), 138.7 (CH, C6), 126.0 (CH, C7), 124.1 (CH, C5), 102.4 (C, C3), 96.8 (C, C2), 0.29 (3xCH3, C1). MS m/z (relative intensity): 210 (M +• , 8), 208 (M +• , 16), 196 (33), 194 (100), 166 (4), 164 (5), 97 (7), 79 (17), 65 (8), 63 (16). To a solution of 2-chloro-6-[(trimethylsilyl)ethynyl]pyridine (355 mg, 1.69 mmol, 1.0 equiv) in MeOH (3.6 mL) was added K2CO3 (23.7 mg, 0.17 mmol, 0.1 equiv) in one portion. The resulting suspension was stirred under air at rt for 2 h. The reaction mixture was then concentrated under reduced pressure, an aqueous saturated NaHCO3 solution was added and the aqueous phase was extracted three times with AcOEt. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (Et2O/PE=5:95) to sealed with a teflon2-Chloro-5-[(trimethylsilyl)ethynyl]pyridine 123
	afford 8 (159 mg, 1.16 mmol, 68%) as a white solid. Mp: 58 °C.
	IR (neat): 2961, 1579, 1548, 1454, 1356, 1251, 1226, 1133, 1106, 1021 cm -1 .
	1 H NMR (CDCl3, 400 MHz): δ 8.18 (dd, J = 2.3 and 0.7 Hz, 1H, H8), 7.41 (dd, J = 8.3 and 2.4 Hz, 1H, H5),
	6.99 (dd, J = 8.3 and 0.7 Hz, 1H, H6), 0.00 (s, 9H, H1).
	2-Chloro-6-pyridine (8) C NMR (CDCl3, 100 MHz): δ 152.1 (CH, C8), 150.3 (C, C7), 141.0 (CH, C5), 123.5 (CH, C6), 118.9 (C, C4), 13
	99.9 (C, C2 or C3), 99.3 (C, C2 or C3), 0.5 (3xCH3, C1).
	Mp: 37 °C. IR (neat): 3295, 1573, 1428, 1159, 1136, 987 cm -1 . MS m/z (relative intensity): 211 (M +• , 7), 209 (M +• , 19), 196 (35), 194 (100), 166 (5), 164 (5), 89 (7),
	H NMR (CDCl3, 400 MHz): δ 7.64 (tapp, J = 7.6 Hz, 1H, H5), 7.41 (d, J = 7.6 Hz, 1H, H6), 7.32 (d, J = 8.0 Hz, 1 80
	1H, H4), 3.21 (s, 1H, H1).
	13 C NMR (CDCl3, 100 MHz): δ 151.5 (C, C7), 142.4 (C, C3), 138.9 (CH, C5), 126.1 (CH, C6), 124.6 (CH, C4),
	81.6 (C, C2), 78.7 (CH, C1).
	MS m/z (relative intensity): 139 (M +• , 33), 137 (M +• , 100), 102 (77), 74 (10), 62(4), 51 (23), 50 (24).

  The crude product was purified by flash column chromatography (Et2O/PE=10:90) to give 10 (645 mg, 4.10 mmol, 87%) as a brown solid.

	Mp: 71 °C.
	IR (neat): 3291, 2108, 1623, 1575, 1469, 1428, 1382, 1260, 1180 cm -1 .
	1 H NMR (CDCl3, 400 MHz): δ 7.79 (s, 1H, H4), 7.457.39 (m, 2H, H9 and H10), 3.06 (s, 1H, H1), 2.64 (s,
	3H, H7).
	13 C NMR (CDCl3, 100 MHz): δ 165.1 (C, C6), 151.3 (C, C8), 141.7 (C, C5), 129.0 (CH, C10), 123.5 (CH, C4),
	118.2 (C, C3), 110.4 (CH, C9), 83.5 (CH, C1), 76.6 (C, C2), 14.6 (CH3, C7).
	MS m/z (relative intensity): 157 (M +• , 100), 128 (9), 116 (8), 102 (16), 88 (38), 87 (12), 79 (6), 62 (31).
	Diethyl (4-ethynylphenyl)phosphonate (12) 124
	1-Bromo-4-iodobenzene 11 (2.00 g, 7.07 mmol, 1.0 equiv), CuI (34 mg, 0.18 mmol, 2.5 mol %),
	PdCl2(PPh3)2 (20 mg, 0.028 mmol, 0.4 mol %), and PPh3 (28 mg, 0.11 mmol, 1.5 mol %) were
	introduced in a round bottom flask, which was then flushed with argon. Et3N (23 mL) was then added,
	the resulting solution was stirred at rt for 10 min, and trimethylsilylacetylene (1.00 mL, 7.07 mmol,
	1.0 equiv) was then added. The resulting solution was stirred at rt for 6 h, before being filtered over
	a glass frit. The filtrate was concentrated under reduced pressure to give a yellow oil, which was then
	filtered over a short pad of silica gel (PE washings). The filtrate was concentrated under reduced
	pressure to give the desired product (1.8 g, 7.1 mmol, quant) as a white solid.
	[(4-Bromophenyl)ethynyl]trimethylsilane 125
	Mp: 58 °C.
	IR (neat): 2959, 1486, 1394, 1250, 1214, 1071, 1011 cm -1 .
	1 H NMR (CDCl3, 400 MHz): δ 7.447.38 (m, 2H, H6), 7.337.26 (m, 2H, H5), 0.24 (s, 9H, H1).

  Prepared according to procedure A from phenylacetylene 22 (70 mg, 0.69 mmol, 1.0 equiv). After the addition of (trifluoromethyl)diazomethane, 40 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=2:98) to afford 24 (145 mg, 0.60 mmol, 87%) as a light yellow solid.

	4. Synthesis	and	spectroscopic	data	of
	6-(trifluoromethyl)pyridazines
	4-Fluoro-3-phenyl-6-(trifluoromethyl)pyridazine (24)
	Mp: 75 °C.

IR (neat): 3081, 2928, 2856, 1598, 1555, 1453, 1407, 1320, 1296, 1248, 1145, 1078, 1036 942 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 8.088.05 (m, 2H, H7), 7.63 (d, J = 10.5 Hz, 1H, H2), 7.567.52 (m, 3H, H8 and H9).

  CDCl3, 400 MHz): δ 7.99 (dd, J = 8.3 and 1.8 Hz, 2H, H7), 7.59 (d, J = 10.7 Hz, 1H, H2), 7.35 (br d, J = 8.0 Hz, 2H, H8), 2.44 (s, 3H, H10).

	IR (neat): 3050, 2927, 1587, 1427, 1393, 1317, 1295, 1267, 1251, 1151, 1080, 943 cm -1 .
	13 C NMR (CDCl3, 100 MHz): δ 160.4 (C, d, J = 281.2 Hz, C3), 153.6 (C, d, J = 5.1 Hz, C4), 151.6 (C, qd, J =
	35.6 and 3.3 Hz, C1), 142.0 (C, C9), 129.8 (2xCH, C8), 129.3 (2xCH, d, J = 5.5 Hz, C7), 128.1 (C, d, J =
	4.8 Hz, C6), 120.8 (C, qd, J = 274.4 and 2.7 Hz, C5), 111.6 (CH, dq, J = 18.2 and 2.4 Hz, C2), 21.5 (CH3,
	C10).
	MS m/z (relative intensity): 256 (M +• , 100), 228 (14), 213 (4), 177 (4), 159 (8), 134 (13), 133 (30), 115
	(11), 107 (4).
	HRMS: calcd for C12H9F4N2 (M+H + ): 257.0696. Found 257.0696.
	4-Fluoro-3-(4-methoxyphenyl)-6-(trifluoromethyl)pyridazine (32)
	IR (neat): 2847, 1656, 1592, 1511, 1463, 1433, 1397, 1315, 1253, 1172, 1149, 1078, 1030, 980,
	MS m/z (relative intensity): 242 (M +• , 100), 214 (22), 213 (17), 195 (13), 170 (10), 164 (24), 120 (34), 940 cm -1 .
	102 (14). 1 H NMR (CDCl3, 400 MHz): δ 8.128.09 (m, 2H, H7), 7.58 (d, J = 10.9 Hz, 1H, H2), 7.077.03 (m, 2H,
	HRMS: calcd for C11H7F4N2 (M+H + ): 243.0540. Found 243.0542. H8), 3.88 (s, 3H, H10).
	4-Fluoro-3-(p-tolyl)-6-(trifluoromethyl)pyridazine (31)
	Prepared according to procedure A from 4-ethynyltoluene 25 (60 mg, 0.52 mmol, 1.0 equiv). After
	the addition of (trifluoromethyl)diazomethane, 6 days were necessary to reach complete
	consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash
	Mp: 86 °C.

19

F NMR (CDCl3, 470 MHz): δ 66.7 (s, F, CF3), 113.5 (s, 1F, F). chromatography (AcOEt/PE=2:98) to afford 31 (99 mg, 0.39 mmol, 75%) as a light yellow solid.

1 H NMR (

Prepared according to procedure A from 4-ethynylanisole 26 (70 mg, 0.53 mmol, 1.0 equiv). After the addition of (trifluoromethyl)diazomethane, 3 weeks were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=5:95) to afford 32 (120 mg, 0.44 mmol, 83%) as a light yellow oil.

  IR (neat): 1613, 1550, 1446, 1401, 1279, 1246, 1148, 1069, 1010, 954, 934 cm -1 . CDCl3, 100 MHz): δ 160.2 (C, d, J = 276.8 Hz, C3), 156.7 (C, d, J = 11.3 Hz, C4), 152.5 (C, qd, J

	4-Fluoro-3-[2-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyridazine (41)
	1 H NMR (CDCl3, 400 MHz): δ 7.64 (d, J = 8.4 Hz, 1H, H2), 7.02 (s, 2H, H8), 2.36 (s, 3H, H11), 2.03 (s, 6H,
	H10).
	= 35.6 and 3.0 Hz, C1), 140.1 (C, C9), 136.7 (2xC, C7), 128.9 (2xCH, C8), 127.2 (C, d, J = 2.7 Hz, C6), 120.8
	(C, qd, J = 274.9 and 3.0 Hz, C5), 110.9 (CH, dq, J = 17.6 and 2.3 Hz, C2), 21.2 (CH3, C11), 19.8 (2xCH3, Prepared according to procedure A from 1-ethynyl-2-(trifluoromethyl)benzene 37 (70 mg,
	C10). 0.41 mmol, 1.0 equiv). After the addition of (trifluoromethyl)diazomethane, 48 h were necessary to
	MS m/z (relative intensity): 284 (M +• , 33), 283 (10), 269 (25), 267 (16), 265 (100), 250 (11), 215 (25), reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by
	200 (9), 171 (6), 146 (19), 133 (7), 115 (9), 77 (10). flash chromatography (Et2O/PE=10:90) to afford 41 (84 mg, 0.27 mmol, 66%) as a yellow oil.
	HRMS: calcd for C14H13F4N2 (M+H + ): 285.1009. Found 285.1009.
	Prepared according to procedure B from 1-ethynyl-2-(trifluoromethyl)benzene 37 (80 mg,
	4-Fluoro-3-(6-methoxynaphthalene)-6-(trifluoromethyl)pyridazine (36) 0.47 mmol, 1.0 equiv). After the addition of (trifluoromethyl)diazomethane, 16 h were necessary to
	reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by
	flash chromatography (Et2O/PE=10:90) to afford 41 (66 mg, 0.20 mmol, 43%) as a yellow oil.
	Prepared according to procedure A from 2-ethynyl-6-methoxynaphthalene 30 (100 mg, 0.55 mmol,
	1.0 equiv). After the addition of (trifluoromethyl)diazomethane, 40 h were necessary to reach
	complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash
	3 (CH, C8), 110.7 (CH, dq, J = 17.5 and 2.2 Hz, C2), chromatography (AcOEt/PE=4:96 and 6:94) to afford 36 (139 mg, 0.43 mmol, 79%) as a yellow solid.
	55.7 (CH3, C12).
	MS m/z (relative intensity): 272 (M +• , 99), 253 (61), 244 (53), 213 (21), 203 (100), 164 (30), 154 (32), Mp: 119 °C.
	151 (34), 120 (29), 107 (43). IR (neat): 1629, 1487, 1426, 1386, 1255, 1203, 1164, 1076, 904 cm -1 .
	HRMS: calcd for C12H9F4N2O (M+H + ): 273.0646. Found 273.0649. 1 H NMR (CDCl3, 400 MHz): δ 8.48 (s, 1H, H7), 8.15 (dtapp, J = 8.7 and 1.7 Hz, 1H, H15), 7.82 (d, J = 7.2 Hz,
	1H, H9 or H14), 7.80 (d, J = 7.4 Hz, 1H, H9 or H14), 7.55 (d, J = 10.9 Hz, 1H, H2), 7.17 (dd, J = 8.9 and
	4-Fluoro-3-mesityl-6-(trifluoromethyl)pyridazine (34) 2.5 Hz, 1H, H10), 7.12 (dapp, J = 2.4 Hz, 1H, H12), 3.91 (s, 3H, H16).
	13 C NMR (CDCl3, 100 MHz): δ 160.5 (C, d, J = 281.5 Hz, C3), 159.5 (C, C11), 153.4 (C, d, J = 4.3 Hz, C4),
	151.3 (C, qd, J = 35.4 and 3.3 Hz, C1), 136.1 (C, C6), 130.8 (CH, C10 or C14), 130.1 (CH, d, J = 7.3 Hz, C7),
	128.4 (C, C13), 127.6 (CH, C10 or C14), 126.0 (CH, d, J = 4.4 Hz, C15), 126.0 (C, d, J = 4.9 Hz, C8), 120.8 (C,
	Prepared according to procedure A from 2-ethynyl-1,3,5-trimethylbenzene 28 (70 mg, 0.49 mmol, 1.0 qd, J = 274.4 and 2.6 Hz, C5), 119.8 (CH, C9), 111.6 (CH, dq, J = 18.3 and 2.4 Hz, C2), 105.7 (CH, C12),
	55.4 (CH3, C16). equiv). After the addition of (trifluoromethyl)diazomethane (2.0 equiv), 1 month was necessary to MS m/z (relative intensity): 322 (M +• , 100), 294 (7), 279 (16), 251 (21), 250 (11), 201 (9), 200 (11),
	157 (23), 147 (5).

reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=2:98) to afford 34 (105 mg, 0.37 mmol, 76%) as an orange solid.

Mp: 95 °C. 13 C NMR (HRMS: calcd for C16H11F4N2O (M+H + ): 323.0802. Found 323.0804. IR (neat): 1413, 1315, 1281, 1167, 1132, 1087, 1059, 1036, 942 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 7.88 (m, 1H, H10), 7.777.71 (m, 2H, H8 and H9), 7.68 (d, J = 8.4 Hz, 1H, H2), 7.51 (m, 1H, H7).

  consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=2:98) to afford 46 (105 mg, 0.33 mmol, 85%) as a white solid. CDCl3, 100 MHz): δ 160.7 (C, d, J = 282.3 Hz, C3), 152.9 (C, qd, J = 35.8 and 3.4 Hz, C1), 151.5 (C, d, J = 4.7 Hz, C4), 134.7 (CH, C9), 133.5 (CH, d, J = 5.2 Hz, C7 or C11), 132.9 (CH, d, J = 5.9 Hz, C7 or reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=10:90) to afford 55 (52 mg, 0.19 mmol, 37%) as an orange solid. C7), 126.7 (CH, d, J = 0.9 Hz, C8), 121.2 (C, qd, J = 274.5 and 3.0 Hz, C5), 111.5 (CH, dq, J = 17.7 and The crude mixture was purified by flash chromatography (AcOEt/PE=2:98) to afford 65 (53 mg, 0.21 mmol, 38%) as a yellow oil. IR (neat): 2933, 2857, 1604, 1554, 1451, 1411, 1370, 1319, 1284, 1242, 1182, 1151, 1060, 950 cm -1 .

	Mp: 121 °C. 1 H NMR (CDCl3, 400 MHz): δ 8.328.28 (m, 2H, H7 and H11), 7.79 (m, 1H, H9), 7.67 (d, J = 10.5 Hz, 1H, Mp: 138 °C.
	IR (neat): 1723, 1602, 1552, 1425, 1395, 1278, 1261, 1145, 1109, 1077, 1012, 945 cm -1 . H2), 7.65 (tdapp, J = 7.8 and 0.7 Hz, 1H, H10). 2.4 Hz, C2), IR (neat): 2927, 1776, 1720, 1607, 1411, 1394, 1365, 1281, 1189, 1167, 1113, 1057, 947, 905 cm -1 .
	1 H NMR (CDCl3, 400 MHz): δ 8.238.16 (m, 4H, H7 and H8), 7.71 (d, J = 10.5 Hz, 1H, H2), 3.98 (s, 3H, Mp: 106 °C. Mp: 112 °C. MS m/z (relative intensity): 248 (M +• , 100), 220 (16), 201 (17), 176 (9), 170 (14), 157 (3), 126 (29), 108 1 H NMR (CDCl3, 400 MHz): δ 7.917.87 (m, 2H, H9 or H10), 7.797.75 (m, 2H, H9 or H10), 7.60 (d, J =
	H11). 13 C NMR (CDCl3, 100 MHz): δ 166.3 (C, C10), 160.7 (C, d, J = 282.3 Hz, C3), 152.7 (C, d, J = 5.1 Hz, C4), IR (neat): 2971, 1591, 1423, 1386, 1308, 1286, 1253, 1155, 1080, 1009, 943 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 8.017.98 (m, 2H, H7), 7.927.69 (m, 2H, H8), 7.65 (d, J = 10.6 Hz, 1H, C11), 132.3 (C, d, J = 4.8 Hz, C6), 130.2 (CH, C10), 120.6 (C, qd, J = 275.0 and 3.0 Hz, C5), 118.0 (C, C12), IR (neat): 1586, 1546, 1468, 1423, 1411, 1367, 1281, 1259, 1238, 1174, 1142, 1110, 1081, 1005, 942 cm -1 . (11), 107 (8), 81 (9), 69 (17). HRMS: calcd for C9H5F4N2S (M+H + ): 249.0104. Found 249.0103. 1 9.1 Hz, 1H, H2), 5.34 (s, 2H, H6). H NMR (CDCl3, 400 MHz): δ 7.38 (d, J = 9.4 Hz, 1H, H2), 3.18 (m, 1H, H6), 1.89-1.72 (m, 7H, H7, H8 and H9), 1.45-1.23 (m, 3H, H8 and H9). 13 C NMR (CDCl3, 100 MHz): δ 167.7 (2xC, C7), 160.5 (C, d, J = 279.9 Hz, C3), 153.4 (C, qd, J = 35.9 and
	152.4 (C, qd, J = 35.6 and 3.4 Hz, C1), 134.9 (C, d, J = 4.8 Hz, C6), 132.6 (C, C9), 130.1 (2xCH, C8), 129.4 (2xCH, d, J = 5.3 Hz, C7), 120.7 (C, qd, J = 274.6 and 2.7 Hz, C5), 112.0 (CH, dq, J = 18.0 and 2.4 Hz, C2), 52.5 (CH3, C11). MS m/z (relative intensity): 300 (M +• , 36), 269 (100), 241 (42), 193 (9), 144 (20), 119 (11), 99 (11), 75 (12), 69 (13). H2). 13 C NMR (CDCl3, 100 MHz): δ 160.4 (C, d, J = 281.8 Hz, C3), 152.7 (C, d, J = 4.5 Hz, C4), 152.2 (C, qd, J = 35.7 and 3.3 Hz, C1), 132.4 (2xCH, C8), 130.9 (2xCH, d, J = 5.6 Hz, C7), 129.8 (C, d, J = 4.9 Hz, C6), 126.5 (C, C9), 120.7 (C, qd, J = 274.7 and 2.9 Hz, C5), 111.9 (CH, dq, J = 18.0 and 2.4 Hz, C2). MS m/z (relative intensity): 322 (M +• , 98), 320 (M +• , 100), 294 (17), 292 (17), 248 (9), 250 (9), 213 113.7 (C, C8), 112.3 (CH, dq, J = 17.9 and 2.4 Hz, C2). 1 H NMR (CDCl3, 400 MHz): δ 9.13 (m, 1H, H10), 8.47 (ddd, J = 8.4, 2.5 and 1.1 Hz, 1H, H7), 7.74 (d, J = 4-Fluoro-3-(2-methylbenzo[d]oxazole)-6-(trifluoromethyl)pyridazine (57) 13 2.9 Hz, C1), 160.0 (C, d, J = 9.8 Hz, C4), 134.4 (2xCH, C9 or C10), 132.1 (2xC, C8), 123.8 (2xCH, C9 or C10), C NMR (CDCl3, 100 MHz): δ 161.4 (C, d, J = 9.2 Hz, C4), 160.4 (C, d, J = 277.8 Hz, C3), 151.8 (C, qd, J = MS m/z (relative intensity): 267 (M +• , 100), 239 (20), 238 (17), 220 (14), 189 (28), 145 (23), 127 (9), 118 (9), 75 (12), 69 (9). 10.5 Hz, 1H, H2), 7.58 (dd, J = 8.4 and 0.7 Hz, 1H, H8). 13 C NMR (CDCl3, 100 MHz): δ 160.6 (C, d, J = 282.2 Hz, C3), 154.6 (C, d, J = 1.0 Hz, C9), 152.8 (C, qd, J = 120.5 (C, qd, J = 275.0 and 3.0 Hz, C5), 110.8 (CH, dq, J = 15.5 and 2.3 Hz, C2), 36.1 (CH2, C6). 35.2 and 3.2 Hz, C1), 120.9 (C, qd, J = 274.7 and 3.1 Hz, C5), 110.3 (CH, dq, J = 17.5 and 2.4 Hz, C2), 39.2 MS m/z (relative intensity): 325 (M +• , 100), 213 (12), 212 (82), 161 (81), 133 (11), 105 (13), 104 (78), (C, d, J = 2.1 Hz, C6), 31.0 (2xCH2, C7), 26.4 (2xCH2, C8), 25.8 (CH2, C9). HRMS: calcd for C12H5F4N3Na (M+Na + ): 290.0312. Found 290.0313. 4-Fluoro-3-(6-pyridin-2-yl)-6-(trifluoromethyl)pyridazine (53) 36.0 and 3.3 Hz, C1), 150.4 (C, d, J = 5.4 Hz, C4), 150.1 (CH, d, J = 8.4 Hz, C10), 139.1 (CH, d, J = 4.4 Hz, C7), 126.2 (C, d, J = 5.3 Hz, C6), 125.0 (CH, C8), 120.6 (C, qd, J = 274.8 and 2.8 Hz, C5), 112.2 (CH, dq, J = 77 (25), 76 (49), 75 (11), 50 (18). MS m/z (relative intensity): 248 (M +• , 6), 233 (8), 219 (20), 207 (15), 193 (100), 180 (86), 145 (9), 95 HRMS: calcd for C14H7F4N3NaO2 (M+Na + ): 348.0367. Found 348.0366. (6), 81 (6), 67 (6). HRMS: calcd for C13H9F4N2O2 (M+H + ): 301.0595. Found 301.0596. (34), 144 (18), 119 (22), 99 (17), 75 (16), 69 (10). 17.6 and 2.4 Hz, C2). HRMS: calcd for C11H13F4N2 (M+H + ): 249.1009. Found 249.1009. 4-Fluoro-3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-6-(trifluoromethyl)pyridazine (69)
	4-Fluoro-3-[4-(diethoxyphosphoryl)phenyl]-6-(trifluoromethyl)pyridazine (44) MS m/z (relative intensity): 279 (M +• , 34), 277 (M +• , 100), 242 (9), 214 (15), 194 (14), 155 (15), 120 Prepared according to procedure A from 5-ethynyl-2-methyl-1,3-benzoxazole 10 (70 mg, 0.45 mmol, HRMS: calcd for C11H6BrF4N2 (M+H + ): 320.9645 and 322.9625. Found 320.9646 and 322.9625. 4-Fluoro-3-benzyl-6-(trifluoromethyl)pyridazine (66)
	(20), 93 (9), 69 (14). 1.0 equiv). Supplementary amounts of TMSCF3 (0.13 mL, 2.0 equiv) were necessary to reach complete
	4-Fluoro-3-(4-flluorophenyl)-6-(trifluoromethyl)pyridazine (47) HRMS: calcd for C10H5ClF4N3 (M+H + ): 278.0103 and 280.0073. Found 278.0105 and 280.0073. consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 48 h were necessary
	4-Fluoro-3-(2-thiophen-3-yl)-6-(trifluoromethyl)pyridazine (56)
	Prepared according to procedure A from diethyl (4-ethynylphenyl)phosphonate 12 (80 mg, Mp: 151 °C. Prepared according to procedure A from 3-phenyl-1-propyne 63 (60 mg, 0.52 mmol, 1.0 equiv). After
	0.34 mmol, 1.0 equiv). After the addition of (trifluoromethyl)diazomethane, 48 h were necessary to Prepared according to procedure A from 1-ethynyl-4-fluorobenzene 39 (60 mg, 0.50 mmol, 1.0 IR (neat): 2922, 1594, 1402, 1382, 1333, 1269, 1254, 1139, 1071, 947 cm -1 . the addition of (trifluoromethyl)diazomethane, 20 days were necessary to reach complete
	reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by equiv). After the addition of (trifluoromethyl)diazomethane, 5 days were necessary to reach H NMR (CDCl3, 400 MHz): δ 8.37 (tapp, J = 1.5 Hz, 1H, H7), 8.11 (dtapp, J = 8.6 and 1.5 Hz, 1H, H12), 7.68 1 consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash
	flash chromatography (MeOH/CH2Cl2=2:98) to afford 44 (34 mg, 0.09 mmol, 27%) as a colorless oil. complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash IR (neat): 3061, 2926, 2855, 1723, 1590, 1474, 1443, 1409, 1304, 1256, 1178, 1154, 1085, 946 cm -1 . Prepared according to procedure A from 3-ethynylthiophene 52 (60 mg, 0.55 mmol, 1.0 equiv). After (d, J = 10.6 Hz, 1H, H2), 7.65 (dd, J = 8.6 and 0.4 Hz, 1H, H11), 2.70 (s, 3H, H13). chromatography (AcOEt/PE=2:98) to afford 66 (51 mg, 0.20 mmol, 39%) as a light yellow oil.
	chromatography (AcOEt/PE=5:95) to afford 47 (74 mg, 0.28 mmol, 57%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz): δ 8.83 (br d, J = 4.7 Hz, 1H, H10), 8.30 (dd, J = 7.9 and 0.6 Hz, 1H, H7), 7.97 the addition of (trifluoromethyl)diazomethane, 72 h were necessary to reach complete consumption 13 C NMR (CDCl3, 100 MHz): δ 165.4 (C, C9), 160.4 (C, d, J = 281.3 Hz, C3), 153.4 (C, d, J = 4.7 Hz, C4), IR (neat): 3066, 1602, 1559, 1496, 1455, 1415, 1304, 1281, 1242, 1183, 1144, 1056, 956 cm -1 . Prepared according to procedure B from diethyl (4-ethynylphenyl)phosphonate 12 (90 mg, 0.38 mmol, 1.0 equiv). Supplementary amounts of TFDA (0.15 mL, 2.0 equiv) were necessary to reach (tdapp, J = 7.8 and 1.8 Hz, 1H, H8), 7.71 (d, J = 10.0 Hz, 1H, H2), 7.51 (m, 1H, H9). of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography 152.9 (C, C10), 151.8 (C, qd, J = 35.7 and 3.4 Hz, C1), 142.2 (C, C8), 127.1 (C, d, J = 4.8 Hz, C6), 126.2 (CH, 1 H NMR (CDCl3, 400 MHz): δ 7.46 (d, J = 9.0 Hz, 1H, H2), 7.36-7.22 (m, 5H, H8, H9 and H10), 4.49 (d, J = Mp: 102 °C. IR (neat): 3084, 2927, 1603, 1511, 1421, 1392, 1310, 1298, 1274, 1255, 1234, 1170, 1143, 1102, 1079, 13 C NMR (CDCl3, 100 MHz): δ 161.2 (C, d, J = 287.5 Hz, C3), 153.0 (C, qd, J = 35.6 and 3.9 Hz, C1), 152.9 (Et2O/PE=3:97) to afford 56 (104 mg, 0.42 mmol, 76%) as a yellow solid. d, J = 4.6 Hz, C12), 121.1 (CH, d, J = 6.6 Hz, C7), 120.7 (C, qd, J = 274.6 and 2.8 Hz, C5), 111.8 (CH, dq, J 1.9 Hz, 2H, H6). complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 16 h were 944 cm -1 . (C, d, J = 3.8 Hz, C4), 151.2 (C, d, J = 6.4 Hz, C6), 149.9 (CH, C10), 137.4 (CH, C8), 125.4 (CH, C9), 124.7 Prepared according to procedure B from 3-ethynylthiophene 52 (60 mg, 0.55 mmol, 1.0 equiv). After = 18.2 and 2.4 Hz, C2), 111.0 (CH, C11), 14.6 (CH3, C13). 13 C NMR (CDCl3, 100 MHz): δ 160.8 (C, d, J = 278.9 Hz, C3), 156.9 (C, d, J = 9.5 Hz, C4), 152.5 (C, qd, J = necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was 1 H NMR (CDCl3, 400 MHz): δ 8.178.12 (m, 2H, H7), 7.65 (d, J = 10.7 Hz, 1H, H2), 7.287.23 (m, 2H, (CH, C7), 120.7 (C, qd, J = 274.8 and 2.7 Hz, C5), 112.6 (CH, dq, J = 17.4 and 2.4 Hz, C2). the addition of (trifluoromethyl)diazomethane, 24 h were necessary to reach complete consumption MS m/z (relative intensity): 297 (M +• , 100), 269 (13), 225 (12), 200 (26), 175 (18), 157 (7), 150 (7), 35.7 and 3.2 Hz, C1), 135.8 (C, C7), 129.2 (2xCH, C8 or C9), 129.0 (2xCH, C8 or C9), 127.5 (CH, C10), 120.7 Mp: 143 °C. purified by flash chromatography (Et2O=100%) to afford 44 (36 mg, 0.10 mmol, 25%) as a colorless H8). MS m/z (relative intensity): 243 (M +• , 100), 196 (8), 165 (20), 146 (15), 94 (9), 78 (10), 51 (11). of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography 106 (14), 81 (7), 63 (6). (C, qd, J = 274.9 and 3.1 Hz, C5), 110.9 (CH, dq, J = 16.4 and 2.4 Hz, C2), 36.8 (CH2, d, J = 1.9 Hz, C6). IR (neat): 2925, 2854, 1720, 1700, 1430, 1410, 1304, 1250, 1171, 1153, 1132, 1058, 997, 948 cm -1 . oil. 13 C NMR (CDCl3, 100 MHz): δ 164.8 (C, d, J = 253.8 Hz, C3 or C9), 160.4 (C, d, J = 281.3 Hz, C3 or C9), HRMS: calcd for C10H5F4N3Na (M+Na + ): 266.0312. Found 266.0334. (Et2O/PE=3:97) to afford 56 (72 mg, 0.29 mmol, 52%) as a yellow solid. HRMS: calcd for C13H8F4N3O (M+H + ): 298.0598. Found 298.0598. MS m/z (relative intensity): 256 (M +• , 31), 255 (100), 235 (10), 215 (5), 133 (8), 118 (5), 91 (9), 65 (6), 1 H NMR (CDCl3, 400 MHz): δ 7.817.79 (m, 2H, H10 or H11), 7.747.71 (m, 2H, H10 or H11), 7.52 (d, J =
	IR (neat): 2927, 1421, 1389, 1314, 1252, 1175, 1156, 1078, 1053, 1024, 967, 943 cm -1 . 1 H NMR (CDCl3, 400 MHz): δ 8.238.19 (m, 2H, H8), 8.058.00 (m, 2H, H7), 7.71 (d, J = 10.4 Hz, 1H, 13 10.9 Hz, 1H, H2), 7.50 (ddd, J = 5.2, 3.0 and 0.4 Hz, 1H, H8). MS m/z (relative intensity): 260 (M +• , 100), 232 (21), 213 (12), 188 (10), 182 (17), 138 (34), 120 (13), C NMR (CDCl3, 100 MHz): δ 160.7 (C, d, J = 282.3 Hz, C3), 152.8 (C, d, J = 6.3 Hz, C4), 152.6 (C, qd, J = J = 21.9 Hz, C8), 111.9 (CH, dq, J = 18.1 and 2.4 Hz, C2). H NMR (CDCl3, 400 MHz): δ 8.30 (m, 1H, H9), 8.02 (dtapp, J = 5.2 and 1.3 Hz, 1H, H7), 7.61 (d, J = 1 H2), 4.254.12 (m, 4H, H10), 1.37 (td, J = 7.1 and 0.4 Hz, 6H, H11). 152.6 (C, d, J = 5.0 Hz, C4), 152.0 (C, qd, J = 35.7 and 3.3 Hz, C1), 131.7 (2xCH, dd, J = 8.8 and 5.7 Hz, C7), 127.1 (C, dd, J = 4.7 and 3.5 Hz, C6), 120.6 (C, qd, J = 274.6 and 2.8 Hz, C5), 116.4 (2xCH, d, Mp: 76 °C. IR (neat): 1602, 1560, 1522, 1435, 1422, 1357, 1267, 1193, 1148, 1116, 1075, 1034, 950 cm -1 . HRMS: calcd for C12H9F4N2 (M+H + ): 257.0696. Found 257.0695. 4-Fluoro-3-cyclohexyl-6-(trifluoromethyl)pyridazine (65) 51 (6). 9.0 Hz, 1H, H2), 4.25 (t, J = 6.7 Hz, 2H, H7), 3.54 (td, J = 6.7 and 1.4 Hz, 2H, H6).
	75 (8), 69 (7).

The crude mixture was purified by flash chromatography (Et2O/PE=15:85) to afford 42 (100 mg, 0.33 mmol, 76%) as a white solid.

36

.0 and 3.5 Hz, C1), 134.6 (C, m, C6), 132.4 (2xCH, d, J = 10.0 Hz, C8), 131.8 (C, d, J = 187.9 Hz, C9), 129.4 (2xCH, dd, J = 14.9 and 5.2 Hz, C7), 120.7 (C, qd, J = 274.6 and 2.9 Hz, C5), 112.1 (CH, dq, J = 17.9 and 2.3 Hz, C2), 62.6 (2xCH2, d, J = 5.5 Hz, C10), 16.5 (2xCH3, d, J = 6.4 Hz, C11). complete HRMS: calcd for C11H6F5N2 (M+H + ): 261.0446. Found 261.0444.

13 C NMR (Prepared according to procedure A from 6-ethynylpyridine 51 (80 mg, 0.78 mmol, 1.0 equiv).

Supplementary amounts of TMSCF3 (0.11 mL, 1.0 equiv) were necessary to reach complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 24 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=25:75) to afford 53 (22 mg, 0.09 mmol, 12%) as a brown oil. to 13 C NMR (CDCl3, 100 MHz): δ 159.9 (C, d, J = 281.1 Hz, C3), 151.5 (C, qd, J = 35.6 and 3.3 Hz, C1), 149.8 (C, d J = 5.3 Hz, C4), 132.8 (C, d, J = 5.4 Hz, C6), 130.5 (CH, d, J = 10.3 Hz, C9), 127.5 (CH, d, J = 3.8 Hz, to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (CH2Cl2/Et2O=2:98) to afford 57 (99 mg, 0.33 mmol, 75%) as a light yellow solid.

Prepared according to procedure A from cyclohexylacetylene 62 (60 mg, 0.55 mmol, 1.0 equiv). After the addition of (trifluoromethyl)diazomethane, 12 days were necessary to reach complete consumption of the gem-difluorocyclopropene.

Prepared according to procedure A from N-homopropargyl phthalimide 19 (100 mg, 0.50 mmol, 1.0 equiv). Supplementary amounts of TMSCF3 (0.15 mL, 2.0 equiv) were necessary to reach complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 48 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=20:80) to afford 69 (50 mg, 0.15 mmol, 29%) as a pale yellow solid.

Prepared according to procedure B from N-homopropargyl phthalimide 19 (100 mg, 0.50 mmol, 1.0 equiv). After the addition of (trifluoromethyl)diazomethane, 16 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=20:80) to afford 69 (68 mg, 0.20 mmol, 40%) as a pale yellow solid.

  ).

	MS m/z (relative intensity): 339 (M +• , 49), 252 (7), 192 (16), 175 (14), 161 (11), 160 (100), 133 (17),
	105 (16), 104 (25), 77 (26), 76 (19), 50 (7).
	HRMS: calcd for C15H9F4N3NaO2 (M+Na + ): 362.0523. Found 362.0529.
	4-Fluoro-3-(2-{bis[(tert-butoxy)carbonyl]amino}ethyl)-6-(trifluoromethyl)pyridazine (70)
	Prepared according to procedure A from N,N-bis[(tert-butoxy)carbonyl]-N-(but-3-yn-1-yl)carbamate
	21 (106 mg, 0.39 mmol, 1.0 equiv). Supplementary amounts of TMSCF3 (0.06 mL, 1.0 equiv) were
	necessary to reach complete consumption of the alkyne. After the addition of
	(trifluoromethyl)diazomethane, 40 h were necessary to reach complete consumption of the
	purified by flash chromatography (AcOEt/PE=5:95) to afford 70 (55 mg, 0.13 mmol, 36%) as a yellow
	oil.
	IR (neat): 2982, 1790, 1731, 1692, 1415, 1398, 1367, 1346, 1316, 1232, 1129, 1106, 1059, 963 cm -1 .
	1 H NMR (CDCl3, 400 MHz): δ 7.50 (d, J = 9.0 Hz, 1H, H2), 4.11 (t, J = 6.6 Hz, 2H, H7), 3.46 (td, J = 6.5 and
	1.6 Hz, 2H, H6), 1.44 (s, 18H, H10).
	13 C NMR (CDCl3, 100 MHz): δ 161.3 (C, d, J = 278.1 Hz, C3), 155.8 (C, d, J = 10.2 Hz, C4), 152.3 (2xC, C8),
	152.3 (C, qd, J = 35.5 and 3.1 Hz, C1), 120.7 (C, qd, J = 274.6 and 3.1 Hz, C5), 110.0 (CH, dq, J = 16.6 and
	2.4 Hz, C2), 82.9 (2xC, C9), 44.2 (CH2, C7), 29.9 (CH2, d, J = 2.1 Hz, C6), 28.0 (6xCH3, C10).
	HRMS: calcd for C17H23F4N3NaO4 (M+Na + ): 432.1517. Found 432.1536.

gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=5:95) to afford 70 (102 mg, 0.25 mmol, 64%) as a yellow oil.

Prepared according to procedure B from N,N-bis[(tert-butoxy)carbonyl]-N-(but-3-yn-1-yl)carbamate 21 (100 mg, 0.37 mmol, 1.0 equiv). After the addition of (trifluoromethyl)diazomethane, 16 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was

  080 mL, 0.41 mmol, 2.0 equiv) and the reaction mixture was stirred at 100 °C for 72 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography (AcOEt/PE=15:85) to afford 74 (72 mg, 0.17 mmol, 83%) as a white solid. IR (neat): 1564, 1495, 1452, 1418, 1358, 1288, 1176, 1140, 1102, 1028, 1011, 953 908 cm -1 . CDCl3, 100 MHz): δ 155.6 (C, C3), 149.7 (C, q, J = 33.5 Hz, C1), 148.2 (C, C4), 137.7 (C, C11), 135.6 (2xC, C7), 129.6 (CH, C14), 129.1 (2xCH, C12 or C13), 128.9 (4xCH, C8 or C9), 128.3 (2xCH, C12 or C13),128.1 (2xCH, C10), 128.1 (4xCH, C8 or C9), 121.7 (C, q, J = 274.9 Hz, C5), 110.9 (CH, q, J = 2.6 Hz, C2), 54.7 (2xCH2, C6). MS m/z (relative intensity): 419 (M +• , 15), 418(8), 328(18), 250(6), 126 (1), 92(9), 91 (100), 65(11).

	Mp: 127 °C.
	1 H NMR (CDCl3, 400 MHz): δ 7.857.82 (m, 2H, H12 or H13), 7.527.44 (m, 3H, H12 or H13 and H14),
	7.327.24 (m, 6H, H9 and H10), 7.11 (s, 1H, H2), 7.037.01 (m, 4H, H8), 4.18 (s, 4H, H6).

13

C NMR (

  The crude mixture was purified by flash chromatography (AcOEt/PE=10:90) to afford 78 (55 mg, 0.19 mmol, 94%) as a yellow oil. IR (neat): 3061, 2932, 1551, 1447, 1353, 1315, 1292, 1255, 1177, 1139, 1110, 1073, 1009, 1034 cm - CDCl3, 400 MHz): δ 7.717.69 (m, 2H, H9 or H10), 7.537.51 (m, 4H, H2, H9 or H10 and H11), 2.99 (q, J = 7.4 Hz, 2H, H6), 1.39 (t, J = 7.4 Hz, 3H, H7).

1

.

1 H NMR (

  80) to afford 79 (67 mg, 0.19 mmol, 92%) as a white solid. IR (neat): 2959, 2850, 1739, 1437, 1392, 1263, 1218, 1193, 1144, 1083, 1017, 913 cm -1 .

	Mp: 118 °C.
	1 H NMR (CDCl3, 400 MHz): δ 8.11 (s, 1H, H2), 7.49 (br s, 5H, H10, H11 and H12), 4.91 (s, 1H, H6), 3.71 (s,
	6H, H8).

  83 (50 mg, 0.14 mmol, 82%) as a white solid. IR (neat): 2956, 2856, 1719, 1578, 1564, 1434, 1402, 1275, 1179, 1135, 1113, 1009, 969, 911 cm -1 . CDCl3, 400 MHz): δ 8.198.17 (m, 2H, H10), 8.007.98 (m, 2H, H9), 7.20 (s, 1H, H2), 3.97 (s, 3H, H13), 3.713.69 (m, 4H, H7), 3.063.04 (m, 4H, H6).

	Mp: 186 °C.

1 H NMR (

  : calcd for C16H17F3N3O2 (M+H + ): 340.1267. Found 340.1266. IR (neat): 2934, 1549, 1446, 1403, 1329, 1311, 1199, 1152, 1113, 1092, 1013, 993 cm -1 . CDCl3, 400 MHz): δ 7.667.64 (m, 2H, H10 or H11), 7.457.43 (m, 4H, H2, H10 or H11 and H12), 2.91 (q, J = 7.4 Hz, 2H, H7), 1.31 (t, J = 7.4 Hz, 3H, H8).

1 H NMR (

  27 mg, 0.10 mmol, 87%) as a white solid. CDCl3, 400 MHz): δ 7.717.68 (m, 2H, H9 or H10), 7.537.50 (m, 4H, H2, H9 or H10 and H11), 6.92 (t, J = 54.7 Hz, 1H, H5), 2.99 (q, J = 7.4 Hz, 2H, H6), 1.39 (t, J = 7.4 Hz, 3H, H7).

	Mp: 107 °C.
	IR (neat): 2932, 1553, 1520, 1493, 1443, 1364, 1344, 1262, 1145, 1106, 1070, 1021, 1010, 918, 891
	cm -1 .

1 H NMR (

Bioactive Heterocyclic Compound Classes : Pharmaceuticals and Agrochemicals; Lamberth, C.; Dinges, J., Eds.; Wiley-VCH : Weinheim,

Böhm, H. -J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637643.

Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 18811886.

Jiang, J.; DeVita, R. J.; Goulet, M. T.; Wyvratt, M. J.; Lo, J. -L.; Ren, N.; Yudkovitz, J. B.; Cui, J.; Yang, Y. T.; Cheng, K.; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2004, 14, 17951798.

Shi, W.; Wang, Y.; Zhu, Y.; Zhang, M.; Song, L.; Deng, H. Synthesis 2016, 48, 35273536.

a) Levin, V. V.; Kozlov, M. A.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A. Russ. Chem. Bull., Int. Ed. 2009, 58, 484486; b) Huang, W.; Ni, C.; Zhao, Y.; Zhang, W.; Dilman, A. D.; Hu, J. Tetrahedron 2012, 68, 51375144.

Wenthur, C. J.; Morrison, R.; Felts, A. S.; Smith, K. A.; Engers, J. L.; Byers, F. W.; Daniels, J. S.; Emmitte, K. A.; Conn, P. J.; Lindsley, C. W. J. Med. Chem. 2013, 56, 52085212.

Hamdouchi, C.; Sanchez-Martinez, C.; Gruber, J.; Del Prado, M.; Lopez, J.; Rubio, A.; Heinz, B. A. J. Med. Chem. 2003, 46, 43334341.

Fox, B. M.; Iio K.; Li, K.; Choi, R.; Inaba, T.; Jackson, S.; Sagawa, S.; Shan, B.; Tanaka, M.; Yoshida, A.; Kayser, F. Bioorg. Med. Chem. Lett. 2010, 20, 60306033.

The authors underline that when AgOTf was replaced by Rh(Oct)4, the[1,3]-shift could not take place and therefore a pyrazole derivative was obtained instead of the pyridazine derivative.

Supurgibekov, M. B.; Yanyuk, N . S.; Nikolaev, V. A. Russ. J. Org. Chem. 2011, 47, 12521255.

a) Gonzalez-Gomez, J. C.; Dedola, T.; Santana, L.; Uriarte, E.; Begala, M.; Copez, D.; Podda, G. J. Heterocycl. Chem. 2000, 37, 907910; b) Gonzalez-Gomez, J. C.; Santana, L.; Uriarte, E. Synthesis 2002, 4346; c) Gonzalez, J. C.; Lobo-Antunes, J.; Pérez-Lourido, P.; Santana, L.; Uriarte, E. Synthesis 2002, 475478.

Feraldi-Xypolia, A.; Fredj, G.; Tran, G.; Tsuchiya, T.; Vors, J. -P.; Mykhailiuk, P.; Gomez Pardo, D.; Cossy, J. Asian J. Org. Chem. 2017, 6, 927935.

Schmidt, B.; Riemer, M.; Schilde, U. Eur. J. Org. Chem. 2015, 76027611.

Pearson, A. J.; Kim, J. B. Tetrahedron Lett. 2003, 44, 85258527.

Hapuarachchige, S.; Montano, G.; Ramesh, C.; Rodriguez, D.; Henson, L. H.; Williams, C. C.; Kadavakkollu, S.; Johnson, D. L.; Shuster, C. B.; Arterburn, J. B. J. Am. Chem. Soc. 2011, 133, 67806790.

Onouchi, H.; Maeda, K.; Yashima, E. J. Am. Chem. Soc. 2001, 123, 74417442.

Shigeta, M.; Watanabe, J.; Konishi, G. Tetrahedron 2013, 54, 17611764.

Gao, M.; Duan, L.; Luo, J.; Zhang, L.; Lu, X.; Zhang, Y.; Zhang, Z.; Tu, Z.; Xu, Y.; Ren, X.; Ding, K. J. Med. Chem. 2013, 56, 32813295.

Iyer, S.; Liebeskind, L. S. J. Am. Chem. Soc. 1987, 109, 27592770.

Acknowledgements

CHAPTER 2

Ring contraction: Synthesis of 2-substituted, 2-(trifluoromethyl) pyrrolidines and 2-substituted, 2-(trifluoromethyl) piperidines CHAPTER 3

Synthesis of 6-(trifluoromethyl)pyridazines by a [2+1]/[3+2]-cycloaddition sequence Scheme 63

Another interesting application of this method, was reported the same year by the group of Hegde. 93 Surprisingly, condensation of aryl and alkyl hydrazines with compound L3. 13, synthesized according to the literature ( , TFAA, iPrNH2), 94 did not lead to the expected product L3.14, but to the unexpected pyridazine carboxylate derivatives L3. 15. Furthermore, treatment of pyridazinone L3.15

(R=Ph) with HCl in H2O, produced hydroxypyridazinone L3.16. Finally, compound L3.16 was converted to different trifluoromethyl alkoxy-pyridazine derivatives L3.17 by alkylation of the hydroxy group with alkyl iodides in the presence of potassium carbonate (Scheme 64). 93 93 Hegde, S. G.; Jones, C. R. J. Heterocycl. Chem. 1993, 30, 15011508. 94

Scheme 64

To explain the formation of L3.15, a mechanism was proposed by the authors, where the carbonyl that possesses the CF3 group in L3. 13

Scheme 65

In 2012, this method was applied to the synthesis of a diversity of pyridazinones L3. 22, following the same procedure as illustrated in Scheme 64. 93 These pyridazinones could be further functionalized by the addition of neat 4-fluorobenzylamine, to give a diversity of 6-(trifluoromethyl)pyridazinones L3.23 which after treatment under acidic conditions led to pyridazinones L3.24 (Scheme 66). 89 Scheme 66

The formation of (trifluoromethyl)pyridazinones L3. 24, can be rationalized by the formation of intermediate L3. 25 after treatment of pyridazinones L3.23 under acidic conditions. An allylic rearrangement can then take place to produce L3.26, which after elimination of benzylamine, leads to pyridazinones L3.24 (Scheme 67).

Scheme 67

Furthermore, when R is an isopropyl group, treatment of L3. bis-(trifluoromethyl)pyridazines as well as their derivatives. This reaction, under orbital control (LUMOdiene/HOMOdienophile), is favored by the presence of electron-withdrawing groups on the tetrazine and electron-donating groups on the dienophile. Therefore, an extremely electron-poor diene such as bis-(trifluoromethyl)tetrazine L3.73 is an excellent substrate for this reaction. Generally, after a [4+2]-cycloaddition between tetrazine L3.73 and an alkene, intermediate J is formed which after the release of N2 by a retro-Diels Alder reaction can lead to compound K. After oxidation of K, the desired bis-(trifluoromethyl)pyridazines L are obtained (Scheme 82).

Scheme 82

At this point, it is important to mention that this reaction was mostly used for the synthesis of pyridazines polycyclic derivatives and it was not until recently, that it was applied to the synthesis of monocyclic bis-(trifluoromethyl)pyridazines.

In 1987, a Diels-Alder reaction with inverse electron demand was reported by the group of Seitz.

When tetrazine

Scheme 83

The same group applied this method to access a diversity of bis-(trifluoromethyl)pyridazine derivatives. 105 For example, an inverse electron demand Diels-Alder reaction using -system

Scheme 102

In summary, (trifluoromethyl)diazomethane L3.138 is a versatile reagent which can be considered as a 1,1,1-trifluoroethyl carbene unit. However, this compound has to be handled with great care.

Entry

Ar-X Conditions

Table 7

Alkyne 12, possessing an aryl group substituted by a phosphonate at the para-position, was synthesized from the aryl iodide 11. The Sonogashira coupling of 11 with trimethylsilylacetylene, followed by a second coupling catalyzed by palladium (0) was used to introduce a diethyl phosphite substituent [Pd(PPh3)4 (5 mol %), PPh3 (0.5 mol %) and Et3N in toluene at 110 °C for 4 h]. After the cleavage of the TMS group (TBAF in THF at 0 °C for 2 h), the terminal alkyne 12 was isolated with an overall yield of 71% (Scheme 104).

Scheme 104

Alkyne 14, possessing an aromatic ring substituted by a methyl ester at the meta-position, was easily obtained from 3-ethynylbenzoic acid 13. When alkyne 13 was treated with methyl iodide (1.6 equiv) in the presence of K2CO3 (1.5 equiv), in DMF at rt for 16 h, alkyne 14 was isolated in 90% yield (Scheme 105).

Scheme 105

To access propargylamino derivatives, a Mitsunobu reaction was carried out. Thus, N-propargyl phthalimide 17 was synthesized in 87% yield from propargylic alcohol 15 and phthalimide 16, using PPh3 and DIAD (Scheme 106).

Scheme 106

By using the same Mitsunobu conditions (PPh3, DIAD), N-homopropargyl phthalimide 19 was isolated in 91% yield, starting from homopropargylic alcohol 18 and phthalimide 16. After treatment of 19 with hydrazine (EtOH, reflux, 1 h) followed by treatment with Boc2O (2.5 equiv), DMAP (1.0 equiv) and Et3N (3.0 equiv), the protected homopropargylamine 20 was formed. Given that our goal was to obtain alkyne 21, the monoprotected alkyne 20 was not isolated but directly treated with Boc2O in the presence of DMAP, to afford the desired alkyne 21 in 20% yield from 19 (Scheme 107).

Scheme 108

To optimize the reaction conditions, we first decided to carry out the [3+2]-cycloaddition at 80°C instead of rt in order to decrease the reaction time. However at 80 °C, the corresponding pyridazine 24 was only obtained in 66% yield, while the reaction time remained the same (46 h) (Table 8, entry 2 versus entry 1). As the yield in 24 was better at rt than at 80 °C, we then turned our attention to the influence of the concentration of the diazo compound (2.05 equiv) on the yield of 24. Instead of 0.3 M solution, a 0.6 M solution of (trifluoromethyl)diazomethane in CH2Cl2/H2O (30:1) was used. Under these conditions, pyridazine 24 was still obtained in a moderate yield of 60% after 40 h (Table 8, entry 3). When 1.5 equiv of (trifluoromethyl)diazomethane were used instead of 2.05 equiv, at a concentration of 0.6 M in CH2Cl2/H2O (30:1), the desired compound 24 was isolated in 87% yield after 40 h at rt (

Table 13

Alkynes substituted by alkyl chains with protected nitrogen groups, were also involved in the

[2+1]/[3+2]-cycloaddition sequence, by using both procedures, TMSCF3/NaI and TFDA/NaF. When N-propargyl phthalimide 17 was treated with TMSCF3/NaI in THF, at 110 °C for 2 h, followed by the addition of (trifluoromethyl)diazomethane, (trifluoromethyl)pyridazine 68 was isolated in 17% yield after 48 h. The yield in 68, as well as the reaction time were improved, when TMSCF3/NaI was replaced by TFDA/NaF, as the (trifluoromethyl)pyridazine was isolated in 57% yield after 16 h (Table 14, entry 1). Similarly, treatment of N-homopropargyl phthalimide 19 with the TMSCF3/NaI system, led to pyridazine 69 in 29% yield after 48 h, whereas treatment of 19 with the TFDA/NaF system afforded 69 in 40% yield after 16 h (Table 14, entry 2). This improvement of the reaction time when using the TFDA/NaF procedure, was also observed in the case of alkyne 21. However, for this compound, a higher yield in pyridazine 70 was obtained with the TMSCF3 procedure than with the TFDA procedure (Table 14, entry 3).

Scheme 120

Due to this efficient approach, a diversity of substituted 6-(trifluoromethyl)pyridazines can be obtained and can potentially lead to interesting biologically active compounds.

CHAPTER 3

Experimental Part

General procedures for the [2+1]/[3+2]-cycloaddition sequence

Procedure A: TMSCF3 as the carbene CF2 source.

In an oven-dried vial were introduced NaI (2.2 equiv) and the alkyne (1.0 equiv). The vial was then flushed with argon, and THF (c = 0.375 M) was added, followed by the addition of neat TMSCF3 (2.0 equiv). The vial was then immerged in a pre-heated oil bath at 110 °C. Vigorous stirring was then applied for 2 h and completion of the reaction was monitored by TLC or GC/MS. If necessary, supplementary amounts of TMSCF3 were added until complete consumption of the alkyne. The reaction mixture was allowed to cool down to rt and to this solution was added Et3N (1.5 equiv), followed by the addition of (trifluoromethyl)diazomethane (0.6 M in CH2Cl2, 1.5 equiv). The resulting solution was stirred at rt under argon, until complete consumption of the gem-difluorocyclopropene, as assessed by TLC or GC/MS. The reaction mixture was then carefully concentrated under reduced pressure and purified by flash column chromatography on silica gel.

Procedure B: TFDA as the carbene CF2 source.

In an oven-dried vial were introduced NaF (0.2 equiv) and the alkyne (1.0 equiv). The vial was then flushed with argon and diglyme (c = 2.0 M) was added. The reaction mixture was then heated in a pre-equilibrated oil bath at 120 °C and neat TFDA (3.0 equiv) was added dropwise over 1 h using a syringe pump. At the end of the addition, the reaction mixture was stirred for 1 h and completion of the reaction was assessed by TLC or GC/MS. The reaction mixture was allowed to cool down to rt and to this solution was added Et3N (1.5 equiv), followed by the addition of (trifluoromethyl)diazomethane (0.6 M in CH2Cl2, 1.5 equiv). The resulting solution was stirred, under argon until complete consumption of the gem-difluorocyclopropene, as assessed by TLC or GC/MS.

The reaction mixture was then carefully concentrated under reduced pressure and purified by flash column chromatography on silica gel.

Formation of (trifluoromethyl)diazomethane in CH2Cl2

In an oven-dried vial were introduced 2,2,2-trifluoroethylamine hydrochloride (1.5 equiv compared to the alkyne) and NaNO2 (1.8 equiv compared to the alkyne). The vial was then flushed with argon, CH2Cl2 (c = 0.6 M) and H2O (CH2Cl2/H2O=30:1) were added and the solution was stirred at 0 °C for 1 h and at 78 °C for 10 min. The solution was then added to the difluorocyclopropene solution via a syringe.

Prepared according to procedure B from methyl 3-ethynylbenzoate 14 (60 mg, 0.37 mmol, 1.0 equiv).

After the addition of (trifluoromethyl)diazomethane, 16 h were necessary to reach complete consumption of the gem-difluorocyclopropene.

4-Fluoro-3-(4-carbomethoxyphenyl)-6-(trifluoromethyl)pyridazine (43)

Prepared according to procedure A from methyl 3-ethynylbenzoate 7 (70 mg, 0.44 mmol, 1.0 equiv).

After the addition of (trifluoromethyl)diazomethane, 24 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (Et2O/PE=15:85) to afford 43 (88 mg, 0.29 mmol, 67%) as a yellow solid.

Prepared according to procedure B from methyl 4-ethynylbenzoate 7 (90 mg, 0.56 mmol, 1.0 equiv).

Supplementary amounts of TFDA (0.22 mL, 2.0 equiv) were necessary to reach complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 24 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (Et2O/PE=15:85) to afford 43 (115 mg, 0.38 mmol, 68%) as a yellow solid.

MS m/z (relative intensity): 378 (M +• , 20), 350 (14), 349 (11), 322 (100), 305 (40), 269 (51), 258 (26), 242 (49), 193 (12), 144 (15), 136 (6), 120 (7), 99 (7), 81 (8), 65 (18).

HRMS: calcd for C15H15F4N2O3PNa (M+Na + ): 401.0649. Found 401.0649.

4-Fluoro-3-(4-nitrophenyl)-6-(trifluoromethyl)pyridazine (45)

Prepared according to procedure A from 1-ethynyl-4-nitrobenzene 6 (60 mg, 0.41 mmol, 1.0 equiv).

Supplementary amounts of TMSCF3 (0.13 mL, 2.0 equiv) were necessary to reach complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 24 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (Et2O/PE=15:85) to afford 45 (40 mg, 0.14 mmol, 34%) as a light yellow solid.

Prepared according to procedure B from 1-ethynyl-4-nitrobenzene 6 (60 mg, 0.41 mmol, 1.0 equiv).

After the addition of (trifluoromethyl)diazomethane, 16 h were necessary to reach complete consumption of the gem-difluorocyclopropene. 1H, H2), 7.17 (tapp, J = 8.9 Hz, 1H, H10), 2.37 (d, J = 1.9 Hz, 3H, H12). MS m/z (relative intensity): 274 (M +• , 100), 246 (20), 202 (10), 177 (11), 152 (17), 151 (33), 133 (15), 134 (11), 83 (5), 57 (5).

HRMS: calcd for C12H8F5N2 (M+H + ): 275.0602. Found 275.0603.

4-Fluoro-3-(3-benzonitrile)-6-(trifluoromethyl)pyridazine (50)

Prepared according to procedure B from 3-ethynyl-benzonitrile 49 (60 mg, 0.47 mmol, 1.0 equiv).

Supplementary amounts of TFDA (0.19 mL, 2.0 equiv) were necessary to reach complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 16 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (Et2O/PE=30:70) to afford 50 (76 mg, 0.28 mmol, 60%) as a white solid.

Mp: 85 °C.

IR (neat): 2233, 1595, 1557, 1416, 1441, 1393, 1299, 1254, 1145, 1082, 948 cm -1 .

4-Fluoro-3-(6-chloropyridin-2-yl)-6-(trifluoromethyl)pyridazine (54)

Prepared according to procedure A from 2-chloro-6-ethynylpyridine 8 (70 mg, 0.51 mmol, 1.0 equiv).

Supplementary amounts of TMSCF3 (0.15 mL, 2.0 equiv) were necessary to reach complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 40 h were necessary to reach complete consumption of the gem-difluorocyclopropene. MS m/z (relative intensity): 279 (M +• , 30), 277 (M +• , 100), 242 (7), 230 (8), 214 (32), 194 (26), 164 (8),155 (8), 145 (8), 120 (17), 112 (7), 100 (7), 76 (12), 69 (13), 50 (7).

HRMS: calcd for C10H4ClF4N3Na (M+Na + ): 299.9922 and 301.9893. Found 299.9923 and 301.9892. Supplementary amounts of TMSCF3 (0.30 mL, 4.0 equiv) were necessary to reach complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 48 h were necessary 4-Fluoro-3-methoxymethyl-6-(trifluoromethyl)pyridazine (67) Prepared according to procedure A from methyl propargyl ether 64 (60 mg, 0.86 mmol, 1.0 equiv).

After the addition of (trifluoromethyl)diazomethane, 72 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=20: Prepared according to procedure A from N-propargyl phthalimide 17 (100 mg, 0.54 mmol, 1.0 equiv).

Supplementary amounts of TMSCF3 (0.16 mL, 2.0 equiv) were necessary to reach complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 48 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=20:80) to afford 68 (30 mg, 0.09 mmol, 17%) as a white solid.

Prepared according to procedure B from N-propargyl phthalimide 17 (100 mg, 0.54 mmol, 1.0 equiv).

Supplementary amounts of TFDA (0.32 mL, 3.0 equiv) were necessary to reach complete consumption of the alkyne. After the addition of (trifluoromethyl)diazomethane, 16 h were necessary to reach complete consumption of the gem-difluorocyclopropene. The crude mixture was purified by flash chromatography (AcOEt/PE=20:80) to afford 68 (100 mg, 0.31 mmol, 57%) as a white solid.

4-Allylamino-3-phenyl-6-(pentafluoroethyl)pyridazine (86)

To a stirred solution of 4-fluoro-3-phenyl-6-(pentafluoroethyl)pyridazine 71 (75 mg, 0.26 mmol, 1.0 equiv) in MeCN (0.25 mL) was added allylamine (0.038 mL, 0.51 mmol, 2.0 equiv) and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure.

The crude mixture was purified by flash chromatography (AcOEt/PE=20: MS m/z (relative intensity): 329 (M +• , 87), 328 (100), 301 (22), 287 (14), 252 (27), 233 (7), 183 (30), 141 (7), 126 (10), 102 (20), 89 (18), 77 (15), 56 (24). (58 mg, 0.17 mmol, 84%) as a yellow oil.

General Conclusion

The aim of this project was to access three different families of nitrogen-containing heterocycles: