On one hand, due to the unique properties of the fluorine atom, organofluorinated compounds play an important role in various fields including drug development, crop protection, and material science. On the other hand, Michael addition reaction (MAR) has been wildly used in contemporary synthesis to access multifarious functionalized products owing to its significant atom economy for the diastereo-and enantioselective bond formation. The combination of MAR and fluorine chemistry to afford organofluorinated compounds through the building-block strategy appears as an attractive strategy, but little attention has been paid in this area (see Chapter 1).

Therefore, in my Ph.D. thesis, we mainly focused on the synthesis of organofluorinated compounds by organocatalytic MAR to α-fluorinated α,βunsaturated carbonyl substrates.

In the first part of this thesis (Chapter 2), we described a sulfa-Michael addition to polysubstituted α-fluoroacrylates in both non-enantioselective and enantioselective versions. Furthermore, two fluorinated analogues of Diltiazem and Tiazesim were successfully synthesized. In the second part of this thesis (Chapter 3), we developed a highly diastereoselective phospha-Michael addition to α-trifluoromethylacrylates for the first time, and this method was also applied to α-fluoromethylacrylates. In the last part of this thesis (Chapter 4), we discussed the various reactions attempted to enlarge the scope of Michael addition reaction with our α-fluorinated Michael acceptors including fluorinated ester, ketone, and aldehyde.

Acknowledgment

Firstly, I would like to thank Prof. Thierry Brigaud, Dr. Sami Lakhdar, Dr. Xavier Guinchard, and Prof. Philippe Jubault for taking the time to evaluate my thesis.

My sincere gratitude to my two supervisors: Dr. Samuel Couve-Bonnaire and Dr.

Tatiana Besset. I truly appreciate that I have studied under your supervision in the past three years. Not only for your careful guidance, the warm encouragement, and the effective advice when I got stuck in trouble during my entire doctoral studies but also for the kindly help for my daily life.

I would like to thank Dr. Emilie David for her contribution to my first part work.

I want to thank the people who help me with the analysis: Lӕtitia Bailly and Emilie Petit for their help with the HPLC, GC-MS, and LC-MS analysis; Elisabeth Roger (Babette) for the IR analysis; Dr. Albert Marcual for the HRMS analysis; Dr. Morgane Sanselme for the X-ray analysis.

I feel very grateful to all the members of the "Synthesis of fluorinated biomolecules" group. As a foreign student, I feel like in a big family. At work, we are good partners and we help each other. In daily life, we are friends and we spend a lot of happy times together.

I would like to thank my family and my girlfriend Xing WANG, thanks for their selfless love and constant support.

Finally, I also would like to thank the China Scholarship Council (CSC) for its financial support.

Résumé

Les composés organofluorés, en raison des propriétés uniques de l'atome de fluor, sont largement utilisés dans divers domaines comme les matériaux, la chimie General Introduction

Abbreviations and Acronyms

General Introduction 1.1 Introduction of organofluorine chemistry

Fluorine is a chemical element with the symbol F and atomic number 9. It is the 13 th most abundant element in earth's crust and the 24 th most abundant element in the universe. 1 The inorganic minerals CaF2 and Na3AlF6 are the main sources of fluorine in nature, whereas the organic fluorine-containing compounds are rare (less than 20). 2 As the second smallest and the most electronegative element of the periodic table (Table 1), 3 fluorine atom generally exhibits unique properties and effects in organofluorine compounds.4

Mimic effect

Fluorine atom has a van der Waals radius that is only larger than hydrogen atom and very close to oxygen atom (rH = 1.20 Å, rO = 1.52 Å, rF = 1.47 Å). Thus, it is possible to replace hydrogen or oxygen with fluorine retaining the original spatial structure of a molecule. However, because of the highest electronegativity of fluorine among all the elements, this replacement often implies a great change for the electronic environment of the new fluorinated molecule.

Blocking effect in metabolic transformation

Owing to the high energy of the C-F bond (bond dissociation energy = 105.4 kcal mol - 1 ), the introduction of a fluorine atom or a fluorinated moiety in a defined position of a biomolecule, known to be highly sensitive to metabolism, usually allows developing an obvious resistance in metabolic transformations. In this way, the oxidative metabolism of fluorinated compounds can be selectively prevented, thus increasing their metabolic stability.

Electronic effect

The C-F bond is the strongest C-heteroatom bond and one of the strongest single bonds in chemistry. This bond is very short, highly polarized with the fluorine atom having a partial negative charge. So, the inductive electronic effect of fluorine makes implies an electron-withdrawing property in general, but sometimes fluorine could exhibit electron-donating characteristic in resonance structure by mesomeric effect (Figure 1

Some other physical effects

The low polarizability of the fluorine atom directly affects the intermolecular force and influences macrophysical properties of organofluorine compounds, such as boiling point, lipophilicity, surface tension, and so on. Generally, the organofluorine compound has a lower boiling point and a weaker surface tension compared to its non-fluorinated analogue. Introducing fluorine or fluorinated moiety into a molecule will change its lipophilicity. Usually, the introduction of F or CF3 on a sp 2 carbon will increase the molecular lipophilicity of a molecule whereas their introduction on a sp 3 carbon will do the opposite.

Applications of organofluorinated compounds

By virtue of the unique properties of fluorine atom (Figure 2) 5 , organofluorinated compounds are widely used in various fields including material science, pharmaceutical, and agrochemical industries. 6 Figure 2 Fluorine effects in biologically active agents and materials Indeed, since the advent of Freon (CCl2F2) in the early 1930s, organofluorine chemistry has been developed vigorously, fluorinated compounds are present in almost every aspect of human daily life. In material, for example, perfluorobutane (C4F10) is used as an extinguishing agent. PTFE (Teflon) and ETFE (Figure 3) are two very important polymer materials with excellent physical and chemical properties: PTFE is widely used in various applications requiring acid, alkali, and organic solvents, like making non-stick pans and dry transformers. Also due to its soft texture, PTFE is often used as a coating; ETFE has a high melting temperature and excellent electrical, chemical, and high-energy radiation resistance properties.

Thus, it has been used in many famous buildings and designs, like the National Space Centre in the UK, the football stadium called Allianz Arena in Germany, and so on. In medicine, it has been reported that about 20% of commercial pharmaceuticals containing at least one fluorine atom (Figure 4, a), 7 for example, an important pharmaceutical application is the use of fluorinated compounds as anesthetics such as sevoflurane or desflurane (Figure 4, b). In agrochemical industries, about 30% of agrochemicals contain fluorine (Figure 5). Similar to fluorinated pharmaceuticals, fluorine substitutions in agrochemicals can increase their biological stay time, the membrane crossing as well as their molecular recognition. 8

Access to organofluorinated compounds

There are two major strategies to introduce fluorine atom(s) or fluorinated moieties into an organic molecule (Figure 6) 5,9 : a) the direct introduction of one or several fluorine atom(s) into organic molecules by fluorination, using nucleophilic, electrophilic, or radical fluorinating reagents. 10 b) the use and the transformation of already fluorinated building-block. This method starts from fluorine-containing raw materials, converts functional groups and form C-C or C-heteroatom bonds to access more complex fluorinated molecules. 11 As the organofluorinated compounds draw more and more attention, it is still worthwhile to explore mild and efficient methods to access new fluorinated scaffolds. Among them, Michael addition reaction appears as a relevant tool to design new organofluorinated products and enlarge their structural diversity.

A brief introduction of Michael addition reaction

Michael addition reaction was originally defined by Arthur Michael in the late 1880s, 9 Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214-8264. 10 Champagne, P. A.; Desroches, J.; Hamel, J. D.; Vandamme, M.; Paquin, J. F. Chem. Rev. 2015, 115, 9073-9174. 11 (a) Percy, J. M. Organofluorine Chemistry 1997, 131-195. (b) Konev, A. S.; Khlebnikov, A. F. Collect. Czech. Chem. Commun. 2008, 73, 1553-1611. thus called Michael addition or Michael addition reaction (MAR). 12 Basically, MAR is the nucleophilic addition of a carbanion or another nucleophile to an α,βunsaturated carbonyl compound containing an electron-withdrawing group (EWG). 13 It is one of the most useful methods for mild formation of the C-C bond. A typical MAR is shown in Scheme 1, the R and R' on the nucleophile (Michael donor) are

EWGs such as acyl group and nitrile. These EWGs make the methylene hydrogen acidic, thus, in the presence of a base (B), it is easy to convert into a stable and reactive carbanion. Commonly, the alkene (Michael acceptor) activated by the presence of an EWG group (R'') reacts with a nucleophile, to form the corresponding adduct.

Scheme 1 General process of MAR More usually, MAR is also called "1,4-addition" to α,β-unsaturated carbonyl compounds. However, "1,2-addition" can also be observed competitively (Scheme 2). 14

Scheme 2

The competition between 1,2-and 1,4-addition Since its discovery, MAR has received much attention from organic chemists, the use of different Michael donors allows to enlarge the scope of the reaction and to exceed the only formation of C-C bond by the constructions of C-N, C-S, C-O, C-P, and other C-X bonds. These derived aza-, 15 sulfa-, 16 oxa-, 17 phospha- 18 reactions are also known as hetero-Michael addition reactions. Due to its significant atom economy for diastereoselective and enantioselective bond formation in asymmetric synthesis, MARs are widely used alone or in tandem with other reactions in contemporary organic synthesis to afford various functionalized products starting from the inexpensive and simple starting materials. In the following paragraph, we will concentrate only on fluorinated Michael acceptors, which are the core of my Ph.D. work, and their various uses in MAR reported to date.

Fluorinated Michael acceptors

Considering the power of MAR emerged in organic synthesis as well as the importance of fluorine-containing molecules, the combination of both fields, MAR and fluorine chemistry, to synthesize fluorinated compounds through the buildingblock strategy, appears as an appealing strategy, but little attention has been paid in this area. 19 In most reported MARs to access fluorine-containing compounds, the fluorine or fluorinated moieties are located in Michael donors. 20 Although the examples of using the fluorinated substrates as Michael acceptors is far less than as Michael donors, this approach to access the fluorinated compounds is evolving. In the past years, many conjugated fluorinated compounds have been synthesized by simple and efficient methods, like fluorinated α,β-unsaturated carbonyl compounds 21 , fluorinated nitroalkenes 22 and fluorinated α,β-unsaturated sulfoxide/sulfone 23 (Figure 7), these types of molecules could serve as the Michael acceptors. The progress of fluorinated substrates as Michael acceptors in MARs is summarized below. γ-fluoroglutamic acid can be traced back to the 60s. In 1960, Hudlický used the ethyl 2-fluoroacrylate as Michael acceptor in the presence of EtONa and diethyl Nacetylaminomalonate as a nucleophile. Hydrolysis of the corresponding Michael adduct gave the desired γ-fluoroglutamic acid in 50-60% yield (Scheme 3). 24 In 1988, Tsushima and co-workers reported the same reaction in 70% yield. 25

Scheme 3

The synthesis of γ-fluoroglutamic acid

The α-fluoro-α,β-unsaturated ketone and aldehyde also could be applied to MARs. In an early report, Normant and co-workers studied the addition of lithium dimethylcuprate to α-fluoro-α,β-unsaturated carbonyl compounds (Scheme 4). 26 The use of these fluorinated Michael acceptors with cuprates could form both 1,2-and 1,4-adducts, the ratio of 1,2-and 1,4-adducts being affected by the steric hindrance at β-position of the Michael acceptor. Surprisingly, in the case of fluorinated ester (R 1 R 2 = Cy and R 1 = n Pr, R 2 = H), the enolate from 1,4-addition immediately underwent a Claisen reaction to form a dimeric product with loss of the fluorine atom instead of forming the desired 1,4-adduct. 24 Hudlický, M. Tetrahedron Lett. 1960, 1, 21-22. 25

Scheme 8

The addition of aryl thiols to α-fluoro-α,β-unsaturated esters

F2-containing Michael acceptors

In 1990, Archibald and co-workers described an oxa-Michael addition of βnitroalcohols to β,β-difluoroacrylates or β,β-difluorovinyl ketones. 30 The electronegatively substituted alcohols generally affording the corresponding fluoro nitro ethers in moderate to high yields. Moreover, when the glycol, 2-fluoro-2-nitro-1,3-propanediol was used, a bis-adduct was obtained in 85% yield (Scheme 9).

Scheme 9

The addition of β-nitroalcohols to β,β-difluoroolefins

CHF2-containing Michael acceptors

There were very few reports of MAR specific with CHF2-containing Michael acceptors.

Normally, the CHF2-containing Michael acceptor comes up as a single substrate in the method which was developed for other fluorinated Michael acceptors. To our knowledge, only one example of MAR with CHF2-containing Michael acceptor has been reported in 2005 by Kitazume and co-worders. They employed a β-CHF2acrylate as a Michael acceptor for the synthesis of difluoromethylated materials 30 Archibald, T. G.; Baum, K. J. Org. Chem. 1990, 55, 3562-3565. using a microreactor. 31 In the presence of DBU, the 3-CHF2-acrylate with nitroalkanes proceeded smoothly to afford the corresponding 1,4-adducts in the microreactor without any detectable formation of polymeric products (Scheme 10). The comparison of the pz orbital coefficient of LUMO and the electron density between the CF3-acrylates and their nonfluorinated congeners showed similar characteristics at the β-position (Figure 9). 35 Nevertheless, the electron-withdrawing trifluoromethyl moiety lowered the LUMO energy levels which should increase the reactivity of the CF3-acrylates compared to non-fluorinated ones. The MAR strategy has thus been used to access CF3-containing compounds by the addition of lithium enolates to CF3-acrylates.

Figure 9

The pz orbital coefficient of LUMO and electron density of CF3-acrylates

In 1991, Yamazaki and co-workers reported the MARs of lithium enolates to (E)-β-CF3-acrylate, these reactions were found to proceed smoothly in moderate to excellent yields as well as with high diastereoselectivities (Scheme 12, Eq. a). 36 The same year, they described the addition of lithium enolates derived from chiral acylated oxazolidinones to the same Michael acceptor. Enantiomerically pure adducts were obtained in good to excellent yields with a high level of diastereoselectivity (Scheme 12, Eq. b). 37 There was a special case when R = H, which furnished the cyclic product possibly via a nucleophilic attack of the resulting ester enolate to the carbonyl moiety of oxazolidinone ring. 36 Yamazaki, T.; Haga, J.; Kitazume, T.; Nakamura, S. Chem. Lett. 1991, 20, 2171-2174. 37 Yamazaki, T.; Haga, J.; Kitazume, T. Chem. Lett. 1991, 20, 2175-2178.

Scheme 12

The addition of enolates to (E)-β-CF3-acrylates

For MAR of various types of lithium enolates to (E)-β-CF3-acrylate, the intramolecular Li-F interaction with both fluorine atoms played an important role to stabilize the intermediate and allowed the Michael addition reaction to occur (Scheme 13, Eq. a). 36 In 1994, the same authors proposed that the formation of Michael adducts of lithium enolates from α-CF3-acrylates may go through a similar six-membered intermediate. Nevertheless, instead of the expected 1,4-adduct (B), only polymerized products, coming from the polymerization of substrates and/or byproduct (C), obtained from the LiF elimination (Scheme 13, Eq. b), occurred from metallic enolates. Taking into account the high reactivity of such α-CF3-acrylates, the authors suggested that the employment of much weaker nonmetallic nucleophiles could limit or avoid the polymerization reaction as well as the formation of defluorinated byproducts (C). In this context, they described the MAR of enamines, imines, and active methylenes to benzyl-α-CF3-acrylate (Scheme 14). 35

Scheme 13

The possible formations of Michael adducts of lithium enolates from CF3-acrylates Scheme 14 Addition of nucleophiles to benzyl α-CF3-acrylate

One year later, building on their previous work, Yamazaki and co-workers extended the range of lithium donors, employing some cyclic enolates, enolates derived from β-carbonyl, β-hydroxyl ester, acyloxazolidinones and the lithium donor with anionstabilizing functionalities to react with the ethyl (E)-β-CF3-acrylate (Scheme 15). 38 Interestingly, In their subsequent work on sequential Michael addition-Ireland

Claisen reactions, the key intermediates of lithium enolate Michael addition reaction 38 Shinohara, N.; Haga, J.; Yamazaki, T.; Kitazume, T.; Nakamura, S. J. Org. Chem. 1995, 60, 4363-4374. were trapped with TMSCl (Scheme 16). 39

Scheme 15

The addition of lithium donors to (E)-β-CF3-acrylate

Scheme 16

The key intermediates were trapped with TMSCl

In 2003, Kitazume and co-workers employed a β-CF3-acrylate as a Michael acceptor for the synthesis of trifluoromethylated materials using a microreactor (Scheme 17). 40 Compared to the additions to β-CHF2-acrylate in the microreactor (see Scheme 10), better NMR yields were obtained. 39 Yamazaki, T.; Shinohara, N.; Kitazume, T.; Sato, S. J. Org. Chem. 1995, 60, 8140-8141. 40 Miyake, N.; Kitazume, T. J. Fluorine Chem. 2003, 122, 243-246.

Scheme 17

The addition of nitroalkanes to (E)-β-CF3-acrylate in the microreactor

In 2004, Pellacani and co-workers reported an aza-Michael Addition of nosyloxycarbamates to four α-trifluoromethylacrylates, including both containing chiral auxiliary. 41 The use of different bases led to two products: A weaker base as CaO led to the β-amino ester (a) by immediate protonation, whereas with the NaH, the absence of water might favor the ring closure reaction forming the aziridine (b).

The equip of (-)-8-phenylmenthol (A) to the α-CF3-acrylate induced a low diastereoselectivity, gave 12% and 18% of de to β-amino ester (a) and aziridine (b) respectively, better results were obtained by using the bulkier Helmchen's auxiliary (B), giving 70% and 72% of de respectively (Scheme 18).

Scheme 18

The addition of nosyloxycarbamates to α-CF3-acrylate

Gröger and co-workers described a one-pot process to synthesize the short-chain aliphatic β-amino acid esters in 2009. 42 The desired chiral amino acid ester was obtained in a two-step, one-pot process. Firstly, a non-enantioselective aza-Michael addition of benzylamine to enoates occurred to form the 1,4-adduct. Then, an 41 Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Org. Lett. 2004, 6, 197-200. 42 The same year, Shibata and co-workers constructed nonadjacent quaternary stereocenters by the organocatalyzed Michael addition of cyclic β-ketoesters to tertbutyl α-trifluoromethylacrylate. 44 Several commercially available cinchona alkaloids were tested and among them, cinchonine, gave the best results, furnishing the corresponding adducts in moderate to excellent yields as well as in moderate to very good diastereo-and enantioselectivities (Scheme 20).

Scheme 20

The addition of β-ketoesters to α-CF3-acrylate formation was reported by Röschenthaler and co-workers. 48 The authors synthesized γ-ketophosphonate by the reaction between β-CF3-enone and trimethyl phosphite. A

[4+1] cycloaddition reaction, where the initial attack of phosphorus occurred at the β-position of the enone followed by ring closure, produced 1,2λ

Scheme 24

The addition of trimethyl phosphite to β-CF3-enone

In 2008, a rhodium-catalyzed Michael addition reaction of arylboronic acids to trifluoromethylated-α,β-unsaturated ketones has been reported by Konno and coworkers. The adducts were obtained in good to excellent yields as well as the enantioselectivities (Scheme 25, Eq. a). 49 Some other CF3-containing Michael acceptors such as acrylate, acrylamide, nitroalkene, sulfone, and phosphonate were also employed, albeit showing less reactivity and enantioselectivity. Later, the addition of arylstannanes was described by the same research group. Unlike the previous work, these reactions occurred without ligand, and the authors did not provide the enantioselectivity (Scheme 25, Eq. b). 50 More recently, a transition metal-free asymmetric addition reaction of (E)-styrylboronic acids to β-CF3-enones was described by Chai and co-workers in 2019. 51 The reaction was carried out in the presence of a chiral organocatalyst, Mg(O t Bu)2 and 4 Å molecular sieves as additives.

The adducts were obtained in moderate to high yields with excellent enantiomeric ratios (up to 99:1) (Scheme 25, Eq. c). 49

Scheme 25

The addition of boronic acids/arylstannanes to β-CF3-enones

In 2011, Langlois and co-workers reported a Michael addition reaction of various electron-rich N-and O-containing heterocycles such as furans, benzofurans, pyrroles, and indoles to β-CF3-enones affording the heterocycle products bearing a CF3 group (Scheme 26, Eq. a). 52 They used different lewis acid catalysts involving TiCl4, BF3.Et2O

and Cu(OTf)2 with the different types of Michael donors to favor the reaction. In the addition of furan, the use of 2 equivalents of TiCl4 and β-CF3-enone could form the bis-adduct. For furan, benzofuran, and pyrrole, the addition occurred at C2 position whereas it occurred at C3 position with indoles. Also, with the similar β-CF3-enones

Michael acceptors, the organocatalytic asymmetric addition of pyrazol-5-ones was described by Zhu and Chang in 2019. 53 A urea-amide-tertiary amine organocatalyst was used and the asymmetric addition took place at the C3 position of pyrazolone and at the β-position of the enone, generating two adjacent chiral centers. The desired products were obtained in good yields and enantio-as well as diastereoselectivities (Scheme 26, Eq. b). 52

Scheme 26

The addition of electron-rich heterocycles to β-CF3-enones

In 2012, Konno and co-workers reported a 1,4-conjugate addition of organozinc reagents to β-CF3-enone which gave the corresponding alkylated 1,4-adducts in moderate yields without using either transition metals or Lewis acids (Scheme 27). 54 With Et2Zn, some other CF3-containing Michael acceptors such as phosphate, sulfone and a CHF2-containing enone were applied, giving moderate to good isolated yields.

Scheme 27

The addition of organozinc reagents to β-CF3-enone β-CF3-enones were also employed in sulfa-Michael addition reactions, to construct the stereogenic carbon center bearing a sulfur atom and a CF3 group. In 2018, Yuan and co-workers described an asymmetric sulfa-Michael addition of NaHSO3 to β-CF3enones for the preparation of optically active CF3-containing sulfonic acids. 55 A plausible transition state showed a dual hydrogen-bonding interaction between the N-H of cinchona alkaloid-derived squaramide and the carbonyl oxygen atom thus enhancing the electrophilicity of the β-position. Then, the addition of the activated bisulfate occurred from the Re-face to give the 1,4-adducts in (R)-configuration (Scheme 28, Eq. a). One year later, they used the same organocatalyst with thiocarboxylic acids as the sulfur-sources, to give the desired 1,4-adducts in quantitative yields and good to high enantioselectivities. In addition, the developed method could also be applied to (Z)-β-CF3-enones offering the corresponding adducts in (S)-configuration (Scheme 28, Eq. b). 56

1.4.1.4.c CF3-containing acrylamides

Trifluoromethylated acrylamides Michael acceptors also caught the attention of chemists and especially for the asymmetric synthesis. Indeed, in 1991, Ojima and coworkers described the preparation of fluorinated captopril analogues by conjugate addition of thiolacetic acid to a chiral α-CF3-acrylamide Michael acceptor (Scheme 29). 57 The diastereomeric adducts were obtained with a ratio of 1:2 (R,S:S,S) and were separated by medium pressure liquid chromatography. Then, subsequent reactions (removal of tert-butyl and thioacetyl groups) gave (R,S)-and (S,S)trifluoromethyl captoprils.

Scheme 29

The addition of thiolacetic to α-CF3-acrylamide

In 1996, Yamazaki and co-workers also employed the chiral β-CF3-acrylamides as Michael acceptors with a series of organocopper reagents. The optically active molecules bearing a CF3 group at the chiral center were obtained in good yields and high levels of diastereoselectivity (Scheme 30). 58 The stereochemical results of the reaction showed that organocopper approached the β-position of the Michael acceptor from the less hindered Si-face of alkene moiety.

Scheme 30 Addition of organocopper to chiral β-CF3-acrylamides

The use of peptides in drug development is limited due to their rapid degradation 57 Ojima, I.;Jameison, F. A. Bioorg. Med. Chem. Lett. 1991, 1, 581-584. 58 Yamazaki, T.; Shinohara, N.; Kitazume, T.; Sato, S. J. Fluorine Chem. 1999, 97, 91-96. and poor bioavailability. 59 The modification of peptide backbone appeared as an attractive strategy to overcome these disadvantages. The group of Fustero and Zanda described a methodology for the synthesis of partially modified retro [NHCH2]-peptides containing a chemically stable and stereo-defined trifluoroalanine unit. The key reaction was a stereo-controlled aza-Michael addition of α-amino ester to α-CF3-acrylamides (Scheme 31). 60 They also developed the stereo-controlled solid 61 and fluorous-phase 62 syntheses of partially modified retropeptides by using Wang resin-supported Michael acceptors(Figure 10, A) and F TMSE tagged Michael acceptors (Figure 10, B) respectively. A mechanistic study showed that this type of reaction is a two-step process. Firstly, the amide enol intermediate was generated by the initial aza-Michael addition of α-amino esters to α-CF3-acrylamide acceptors; then, an intramolecular hydrogen transfer stereoselectively occurred to give the final products. 63 The highly efficient aza- . 66 Later, this strategy was applied to the design of a novel matrix metalloprotease (MMP) inhibitor (Figure 11).

Scheme 32

The addition of α-amino esters to β-CF3-acrylamide acceptor Zanda and co-workers also reported the addition of amines and amino alcohols to the chiral β-CF3-acrylamide in 2007. 68 The reactions occurred in good to excellent yields, but with a low diastereocontrol. (Scheme 33).

Scheme 33 The addition of amines and amino alcohols to β-CF3-acrylamide

In 2012, Wang and co-workers reported an efficient sulfa-Michael addition on the β- CF3-acrylamide to access the chiral CF3-building blocks. Excellent yields and good to excellent enantioselectivities of products were obtained in a very short time with a low catalyst loading (Scheme 34). 69 Another feature of this protocol is that all the products are solid due to the incorporation of pyrazole moiety, and could be easily obtained in enantioenriched form by simple crystallization of the crude.

Scheme 34

The addition of thiols to β-CF3-acrylamide

In 2013, an enantioselective organocatalytic Michael addition of nitroalkanes to β-CF3 acrylamides was described by Lu and co-workers. 70 Different β-CF3-acrylamides were chosen as the Michael acceptors, under the catalysis of Cinchona-alkaloidthiourea, affording the corresponding adducts in moderate to excellent yields, diastereoselectivities, and enantioselectivities (Scheme 35).

Scheme 35 The addition of nitroalkanes to β-CF3-acrylamide

Perfluorinated Michael acceptors

In 1994, Portella and coworkers reported a reaction using a β-perfluorinated αfluoro, β-fluoro-unsaturated ketone to prepare heterocycles by reaction with bis- nucleophiles. 71 For this type of Michael acceptor, the bis-nucleophiles initial attack occurred at the β-carbon atom of the ketone with the formation of a carbanion at the α-position, subsequently followed by the elimination of the fluoride ion present at the β-position. Then the intramolecular nucleophilic cyclization can take place in two directions, at the β-carbon (path a: Michael-type addition) or at the carbonyl carbon atom (path b: condensation). The use of a more rigid bis-nucleophile will inhibit the formation of the Michael-type product (path a) and favor the formation of condensation product (path b) (Scheme 36, Eq. a). This regioselectivity of cyclization has also been observed later when they reported the use of constrained

Scheme 36

The addition of bis-nucleophiles to α,β-difluoro-β-perfluorinated ketones

In 2011, Yamazaki and co-workers described the addition of hydrazines to βperfluorinated methylene malonate. 73 This type of substrate was expected to be an excellent Michael acceptor due to three EWG substituents installed on the ethylene unit. The conjugate addition of hydrazine was very quick in CH2Cl2. The normal 1,4adduct and the product of intramolecular cyclization after the initial 1,4-addition were obtained depending on the nature of hydrazines. The use of less nucleophilic phenylhydrazine only producing Michael adduct (Scheme 37).

Scheme 37 The addition of hydrazines to β-perfluorinated dicarbonyl Michael acceptor

In the work described by Langlois and co-workers in 2011 that we already discussed, the Michael addition of various electron-rich O-and N-containing heterocycles has already been done to β-CF2Cl and β-C2F5 enone. 52 The corresponding adducts have been obtained in moderate to good yields (Scheme 38).

Scheme 41

The addition of Ph3PCHCO2Et to fluorinated β-ketoaldehyde derivatives

In 2013, an organocatalytic asymmetric sulfa-Michael addition reaction on hexafluoroisopropyl α,β-unsaturated esters has been developed by Wang and coworkers. Introducing the two-CF3 group on the ester moiety is crucial to increase the electrophilicity of α,β-unsaturated ester as Michael acceptor as well as to hinder the carbonyl moiety. The catalytic system performed well over a broad substrate scope with excellent yields and enantioselectivities (Scheme 42, Eq. a). 75 In the same year, Duan and co-workers described an asymmetric phospha-Michael addition reaction of diphenylphosphine to the similar substrates. 76 Under the catalysis of a chiral palladium complex catalyst, the reaction of 2,2,2-trifluoroethyl cinnamate furnished the adduct with good yield and enantioselectivity. More electrophilic Michael acceptor 1,1,1,3,3,3-hexafluoroisopropyl cinnamate gave better yield and enantioselectivity (Scheme 42, Eq. b). 75

Fluorinated nitroalkene Michael acceptors

The fluorinated nitroalkene represents a highly reactive, easily handled fluorinated building block, which is very promising in the synthesis of functionalized organofluorinated compounds. 78 The (E)-3,3,3-trifluoro-1-nitropropene is the most common substrate having a structure of a double bond bearing both CF3-and NO2groups with (E)-configuration. The fluorinated nitroalkenes have been used in Diels-Alder, 79 1,3-dipolar, 80 Friedel-Crafts 81 reactions. There were also some reports, discussed hereafter, using this substrate as Michael acceptor.

In 2003 and 2009, Zanda and co-workers described the modification of the peptide backbone with a stereogenic [CH(CF3)NH] unit. 82 The key step was an aza-Michael reaction between (E)-3,3,3-trifluoro-1-nitropropene and a series of chiral α-amino acid esters delivering two diastereoisomers which could be separated in pure form by flash chromatography. The stereoselectivity was strongly dependent on several experimental parameters, like the solvent, the bulkiness of the nucleophile, and the base (Scheme 44, Eq. a). Later, Zanda and co-workers also synthesized new peptide mimics featuring [CH(RF)NH] units as peptide-bond surrogates, with different degrees of fluorination. 83 The diastereoselectivity of this process was more influenced by the electronegativity, rather than by the bulkiness of RF group of the fluorinated nitroalkenes (Scheme 44, Eq. b). A possible transition state for the formation of the major diastereomers was proposed (Figure 12). The (E)nitroalkenes reacted from Re face of the α-amino acid ester and a dual hydrogen bonding exists between the upward hydrogen of amino group with carbonyl oxygen and the nitro oxygen respectively, transferring the hydrogen from the amino group to the α-position of nitroalkene with the assistance of the DIPEA.

Scheme 44

The addition of chiral α-amino acid esters to fluorinated nitroalkenes

Figure 12

The possible transition state leading to the major diastereomers Then, the same authors reported Michael addition reactions of ketone-derived enamines, methylene active compounds, and methylated pyrroles/indoles to (E)fluorinated nitroalkenes, providing the corresponding adducts in moderate to good yields (Scheme 45, Eq. a). 84 In 2014, Liu and co-workers also investigated a Michael addition reaction of 1,3-dicarbonyl compounds to similar substrates. 85 The cinchona alkaloid catalytic system showed high efficiency with a broad scope substrate and the desired products were generally obtained in good to high yields, high diastereo-

Scheme 46

The addition of oxindoles to trifluoromethylated nitroolefins Some additional reactions of other nucleophiles to trifluoromethylated nitroolefins have also been reported. For example, in 2014, Xiao and co-workers developed a cinchona alkaloid-based thiourea catalyzed oxa-Michael addition of oximes to β-CF3β-disubstituted nitroalkenes. 88 A variety of oxime ethers with a trifluoromethylated chiral center were obtained in good yields and high enantioselectivities (Scheme 47).

Scheme 47 The addition of oximes to β-CF3-β-disubstituted nitroalkenes

In 2015, a chiral N-heterocyclic carbene (NHC) promoted aza-Michael reaction 88 Liu, F. L.; Chen, J. R.; Feng, B.; Hu, X. Q.; Ye, L. H.; Lu, L. Q.; Xiao, W. J. Org. Biomol. Chem. 2014, 12, 1057-1060. between primary alkyl amines and β-CF3-β-aryl nitroalkenes has been developed (Scheme 48). 89 In this reaction, a dual role of the NHC was proposed: the alkyl amines cannot be deprotonated by NHC due to their high pKa values, thus enhancing the nucleophilicity of N atom through the concurrent H-bonding between amines with NHC and HFIP. Meanwhile, a weak π-π interaction between the β-aryl substituent and positively charged NHC heterocycle was suggested by linear freeenergy relationship (LFER) study, which might be an explanation for the poor enantioselectivities when R 1 = H or Bn.

Scheme 48

The addition of primary alkyl amines to β-CF3-β-aryl nitroalkenes

Fluorinated sulfoxide and sulfone Michael acceptors

Because of the strong inductive electron-withdrawing effect of the sulfonyl or sulfinyl, a double bond with such moieties could be considered as a suitable Michael acceptor. 90 Meanwhile, some fluorinated Michael acceptors containing the sulfoxide or sulfone group have been investigated, providing a straightforward route to many building blocks bearing both the sulfur atom and a fluorinated moiety.

In 2009, Lequeux and co-workers described the synthesis of a fluorovinylsulfone by elimination or HWE reactions. This fluorovinyl sulfone could be functionalized by the 89 aza-Michael addition reaction of aliphatic, aromatic amines, and amino acid alkyl esters. Additionally, some fluoroalkylsulfones were prepared from alkyl iodides in the presence of Zn/CuI (Scheme 49, Eq. a). 91 In another report, the same authors described an aza-Michael addition reaction of 1-benzylpiperidin-4-amine to fluorovinylsulfone to prepare DPP-II inhibitor (II), they also investigated the conjugate addition of nucleic bases onto this fluorovinylsulfone (Scheme 49, Eq. b). 92

Scheme 49 The addition of nucleophiles to fluorovinylsulfone

In early reports from Ichikawa and co-workers, β-trifluoromethyl vinyl sulfoxide has been treated with a variety of lithium enolates and produced the corresponding adducts in high yields with excellent diastereoselectivities (Scheme 50, Eq. a and b). 93 Then, in 1997, Eguchi and co-workers reported a similar addition of enolates to chiral β-trifluoromethyl vinyl sulfonamides. 94 The corresponding products were obtained in moderate diastereoselectivities except for the one obtained with tetrasubstituted bulky pyrrolidine sulfonamide (b) (>98% de). Based on these results, the reaction of some other enolates with chiral sulfonamide b was performed and all the products were obtained in good to high yields with excellent diastereoselectivities (Scheme 50, Eq. c). sulfone. 96 Due to the powerful electronegative inductive effect of the CF3SO2, the nucleophiles occurred double addition or triple addition in the presence of KF and 18-crown-6-ether, furnished the corresponding products in good yields (Scheme 52).

Scheme 52

The double or triple addition to trifluoromethyl vinyl sulfone More recently, in the Michael addition of amines to perfluoroalkylated sulfoxides and sulfones developed by Magnier and co-workers, some examples of double addition were also described. 97 The secondary amines only occurred mono addition, affording the corresponding product in good to high yields. When the primary 95 amines were used as the nucleophile, there were some different results. Poor nucleophilic aniline only produced monoadduct regardless of the equivalent of Michael acceptor, whereas more nucleophilic benzyl amine and (R)-1-phenylethan-1amine produced bis-adducts when the reaction was carried out with an excess of perfluoroalkylated sulfoxide and sulfone (Scheme 53).

Scheme 53 The addition of amines to perfluoroalkylated sulfoxides and sulfones

In 2010, Sokolenko and co-workers reported a novel efficient approach to synthesize trifluoromethyl vinyl sulfoxide from 2-mercaptoethanol and trifluoromethyl iodide. only the trans-adduct (Scheme 55, Eq. a). 99 Then, this kind of substrates has been further studied in 2008 by the same group. Surprisingly, instead of the expected βfluoro-adduct, two inseparable diastereoisomers in a 70 :30 ratio were obtained in good yield when the substrate was reacted in the presence of TBAF. The same reaction occurred starting from hexacyclic trifluoromethyl sulfone, albeit in a low yield. Owing to the fact that the -SO2CF3 is a strong EWG as well as a good leaving group and the fluoride anion can behave as a base, a feasible mechanism was proposed (Scheme 55, Eq. b). 100

Scheme 55

The addition to cyclic trifluoromethyl sulfones

Objectives

In summary, some fluorinated substrates were used as Michael acceptors and showed a great potential to access more complex fluorinated compounds from simple and readily available starting materials.

In my Ph.D. thesis, we aimed at developing new methodologies for the construction of highly diastereoselective (enantioselective) fluorinated compounds by the 99 Meanwhile, as mentioned at the beginning of the thesis, the incorporation of one or several fluorine atoms into an organic molecular structure can modulate lipophilicity, metabolic stability, and acidity, for instance, 4 which are very important properties in drug design. 6d Thus, with the goal of designing potential new drugs, introducing fluorine atom or fluorinated moiety into sulfur-containing compounds might be feasible. As expected, numerous biologically active compounds contain both a sulfur atom and a fluorine atom (Figure 13). 102 Therefore, the development of simple and convenient strategies for the incorporation of both a sulfur atom and a fluorine atom into molecules is highly valuable. Among the various approaches to access the C-S bond, the sulfa-Michael addition (SMA) reaction represents a typical and convenient method. Similar to all other Michael addition reactions, the SMA reaction has the potential to construct two adjacent stereogenic carbon centers in one synthetic step, with an appropriate acceptor under suitable conditions. efficiency were established involving catalysis by chiral metal complex, organic molecules, enzymes, supramolecular structures, and polymeric compounds. 16 Some selected examples of organocatalytic asymmetric SMA reaction on α,β-unsaturated carbonyl substrates were summarized in this section, classified by different chiral catalysts involving alkaloid-, proline-and urea-based catalysts.

Alkaloid-based catalysts

In 1977, Pracejus and co-workers studied an enantioselective SMA reaction of benzylthiol with α-phthalimidomethacrylate. 103 In the screening of chiral catalysts, the targeting cysteine derivatives were obtained in low to moderate enantioselectivities, among the different chiral catalysts, the cinchona alkaloids provided the best enantioselectivity. Worth mentioning that no yield was reported for these reactions (Scheme 57).

Scheme 57 SMA reaction catalyzed by alkaloid-based catalysts

In the same year, Wynberg and co-workers exploited the catalytic potential of natural cinchona alkaloids for enantioselective SMAs of aromatic thiols to cyclic enones for the first time. 104 Quinine at a low catalyst loading (1 mol%) promoted the SMA of thiols to various cyclic enones, providing β-thioketones with good to excellent yields albeit with low to moderate enantioselectivities (Scheme 58, Eq. a).

Under the optimized reaction conditions, the authors found that various thiophenols could be added to five-and six-membered enones (Scheme 58, Eq. b). To date, (DHQD)2PYR which is a dimer of cinchona derivatives with a pyrimidine core, was found to be more effective than natural cinchona alkaloids as the chiral catalyst for asymmetric SMA reactions. In 2002, Deng and co-workers described a highly enantioselective SMA of thiols to cyclic enones under the catalysis of (DHQD)2PYR. 105 At room temperature, they studied the addition of different thiols (e.g. In 2005, Skarżewski and co-workers investigated the SMA reaction of thiols to acyclic α,β-unsaturated ketones. 106 In the presence of cinchonine as the catalyst, the sulfa- More recently, Tanyeli and co-workers reported a highly enantioselective SMA reaction of methyl thioglycolate to trans-chalcones, in the presence of quinine derived 2-adamantyl squaramide organocatalyst, the corresponding adducts were obtained in quantitative yields and moderate to excellent enantioselectivities. They proposed a transition state model to explain the control of the enantioselectivity.

The methyl thioglycolate was activated by the two hydrogens on squaramide via hydrogen bonding, the chalcone was activated and stabilized by quinuclidine ion.

Then, the nucleophilic attack occurred from the Re face of the complex, giving the (R)-product (Scheme 60). 107

Scheme 60 SMA reaction catalyzed by quinine derivative

Proline-based catalysts

In 2005, Jørgensen and co-workers reported a highly enantioselective SMA reaction on α,β-unsaturated aldehydes under the catalysis of trimethylsilyl (TMS) protected prolinol catalyst. 108 The alcohol products were obtained after a subsequent reduction of the sulfa-Michael adducts in good yields with excellent

Thiourea-based catalysts

The thiourea-based catalysts contain two sites to activate the α,β-unsaturated carbonyl Michael acceptor, through the cooperative activation of their two functionalities, the transition state can be specifically controlled and give the product in good yield with high stereocontrol (Scheme 64). This type of catalyst has also been wildly used in asymmetric SMA reactions.

Scheme 64 General transition state of thiourea-based catalyst reaction.

In 2005, Chen and co-workers have used Takemoto's catalyst 113 in the asymmetric SMA on unsaturated imides. The corresponding adducts were obtained in excellent yields and moderate to good enantioselectivities. Based on the obtained (R)products, a possible transition state was suggested. The imide was activated by the dual hydrogen-bonding interactions between its two carbonyls and the thiourea moiety. The sulfur nucleophile activated by tertiary amine had a Si-face attack on the complex. This catalytic system was also found to be efficient for promoting the SMA of thiophenols to cyclic enones (Scheme 65, Eq. a). 114 Later, with the same catalyst, Wang and co-workers have also performed the SMA reaction of thioacetic acid to α,β-unsaturated ketones. 115 The reactions proceeded smoothly at room temperature, affording the products in excellent yields whereas with poor enantioselectivities (Scheme 65, Eq. b). 113 Bifunctional iminophosphorane catalysts (BIMP) were firstly designed and used in nitro-Mannich reactions and conjugate addition reactions. 116 More recently, these catalysts were found to be highly efficient and selective in asymmetric SMA reactions.

In 2015, Dixon and co-workers described a highly enantioselective SMA of aliphatic thiols to α-substituted acrylates catalyzed by a BIMP under mild conditions. 117 The aliphatic thiols cloud be deprotonated by the BIMP catalyst due to its high basicity from the iminophosphorane moiety, meanwhile, the original chiral thiourea structure can activate the unreactive acylates and achieve the enantioselective control. As a consequence, the sulfa-Michael adducts were obtained in excellent yields and enantioselectivities and could be scaled up to a gram-scale with a catalyst loading as low as 0.05 mol% (Scheme 66, Eq. a). Inspired by these results, they also studied the asymmetric SMA of alkyl thiols to β-substituted acrylates catalyzed by 116 the BIMP catalyst. 118 In this case, the corresponding sulfa-Michael adducts were also obtained in excellent yields and enantioselectivities and the reaction was efficient even using a low 1 mol% catalyst loading (Scheme 66, Eq. b). In the addition of sulfur-nucleophiles, both 4-methylthiophenol, boc-cysteine methyl ester, and benzothiazole-thiol were tested, whereas only the first two sulfur nucleophiles could react, giving the products in moderate to good yields. In all cases of Boc-cysteine methyl ester, the 1,4-adducts were detected by 19 F NMR with diastereomeric ratio 1:1 (Scheme 67, Eq. b). 29

Scheme 67 SMA reaction on α-fluoro-α,β-unsaturated carbonyl substrates

Objectives

As all mentioned above, the asymmetric SMA reaction has indeed made great progress. However, the asymmetric SMA reaction on α-fluoro-α,β-unsaturated carbonyl substrates remains a challenge and no attempt has been made to our knowledge.

In this context, we aimed at developing new methodologies of organocatalytic SMA of thiols to α-fluoro-α,β-unsaturated carbonyl substrates in both nonenantioselective and, for the first time, in enantioselective versions (Scheme 68).

Scheme 68 SMA of thiophenols to α-fluoroacrylates

Non-enantioselective version

The first investigations were carried out in non-enantioselective conditions. To begin with the SMA reaction of thiophenols to α-fluoro-α,β-unsaturated carbonyl substrates, the (Z)-ethyl 2-fluoro-5-phenylpent-2-enoate (1a) was chosen as the Michael acceptor and the thiophenol (2a) as the nucleophile in a model reaction. It is worth to mention whatever precaution is taken, during the SMA reactions, the oxidation of thiophenols always occurred as a side-reaction, making difficult the purification of 1,4-adducts. So, to minimize the production of disulfide by-products, all the following reactions were performed in degassed solvents under argon.

Optimization of the reaction conditions

Herein, we discussed several parameters which have been tested with the model SMA reaction, including the equivalent of 2a, the nature of catalyst, the catalyst loading, the solvent, and the temperature (Table 2).

In the first attempts, Lewis acids were used as a catalyst in CH2Cl2. The use of BF3•Et2O and Me2AlCl3 to a full recovery of 1a, even in the refluxing CH2Cl2 (Table 2, entries 1-2). Considering that the SMA reactions have been generally carried out under basic conditions 16 and 2a has a low pKa value, a weak base Et3N was used as the catalyst. When Et3N was employed in CH2Cl2, traces of 1,4-adducts (3a) were observed in 19 F NMR (-195.7 ppm, dd, J = 48.0, 22.6 Hz; -197.0 ppm, dd, J = 48.0, 28.2 Hz), and there is no actual improvement of conversion when the reaction mixture was heated to reflux (Table 2, entry 3). In order to perform the reaction at a higher temperature, another solvent was tested. To our surprise, the use of MeCN showed an obvious improvement for the conversion even at room temperature (Table 2, entry 4). Heating the reaction to reflux, 75% conversion and 73:27 dr were obtained.

Nevertheless, 3a was isolated in only 37% yield due to difficulties to separate 3a from the remaining starting material and disulfide byproduct (Table 2,entry 5). The reaction did not occur in the absence of base or when PhSNa was used instead of the combination of two reactants base/PhSH (

Substrates scope of the reaction

With the optimized conditions in hand, we started the investigation of the scope on SMA reaction of various thiols to some α-fluoroacrylates under non-enantioselective conditions (Table 3). Under the reaction conditions, this SMA reaction showed good tolerance with both α-fluoroacrylates and aryl thiols. With the (Z)-ethyl 2-fluoro-5-phenylpent-2-enoate (1a), thiophenol could bear some common substituents, such as bromo, methoxy, amino, and methyl, and successfully provided the desired products in good to excellent yields with good diastereoselectivities (3b-g). Thiophenol with a methyl group substituted at the ortho-, meta-, and para-position furnished the desired products in similar diastereoselectivities, but higher yields were obtained when the methyl at ortho-and meta-position (3e-g). The aryl thiol could be extended to 2thiophenethiol and 2-naphthalenethiol giving the 1,4-adducts in the good yields and moderate diastereoselectivities (2h-i). Additions of 4-bromothiophenol and 2naphthalenethiol to a fluorinated Michael acceptor bearing a nitro-aryl substituent occurred also in good yields and moderate diastereoselectivities (3j-k). Cyclohexyl αfluoroacrylates were also tested, giving moderate to good yields and moderate diastereoselectivities (3l-q). At the end, we studied this SMA addition on different aryl α-fluoroacrylates, which generally afforded the 1,4-adducts with similar diastereoselectivities but in lower yields compared to alkyl α-fluoroacrylates. α-Fluorocinnamates bearing a cyano group at the ortho-, meta-, and para-positions of the arene moiety were tested and showed no significant substituent effects (3v-x).

To be briefly summarized in the non-enantioselective process, the sulfa-Michael adducts were obtained in moderate to excellent yields (40-98%) with the ratio of two diastereoisomers from 71:29 to 92:8. The substituent in thiols or fluoroacrylates did not show significant effects on the yield or diastereoselectivity. The fair yields of products 3o (43%), 3s (46%), 3y (40%) were due to the purification issues between the desired products and disulfide by-products. The major diastereoisomer in synconfiguration was confirmed by X-ray analysis of the crystals obtained from 3k (Figure 14).

Enantioselective version

After completing the substrates scope under non-enantioselective conditions, we turned our attention to the development of the corresponding asymmetric SMA reactions.

Optimization of the reaction conditions

Based on the previous optimizations, all the following reactions were performed in neat thiophenol (2a). Hereafter we explored the effects of temperature and different chiral organocatalysts including cinchona alkaloids, bis-cinchona alkaloids, urea derivatives, and chiral amines (Table 4). All the structures of catalysts were shown in the following Scheme 69.

We started the investigation with cinchona alkaloids (I-III) which have proven to be effective bases for the asymmetric SMA of thiols to non-fluorinated substrates [103][104]106 (Table 4, entries 1-3). Whereas the conversions and diastereoselectivities were pretty good, we were disappointed to see that the best ee was only 15% (Table 4, entry 1). Using the quinidine (II) led to the same kind of results with a reverse ee as low as 13% (Table 4, entry 2). Surprisingly, the use of the cinchonine (III) led to racemic 1,4-adducts (Table 4, entry 3). Increasing the catalyst loading to 20 mol% did not have a positive effect on the ee values (Table 4, entries 4-5). However, when biscinchona alkaloids (DHQ)2PYR, (DHQ)2AQN, and (DHQD)2PHAL (IV, VI, and VII) were used, comparable results in terms of dr with full conversions and better ee values were obtained (Table 4, entries 6, 9-10). Lowering the catalyst loading to 5 mol% decreased both conversion and ee value (Table 4,entry 7). The use of (DHQD)2PYR (V) afforded the expected product 3a with 72% ee but with only 63% conversion (Table 4, entry 8). We also tested the thiourea derivatives (VIII and IX), which showed high selectivity in SMA reactions, [114][115] but no better results were observed (

Scheme 69 Structures of chiral catalysts

In order to further improve the enantioselectivity, we also investigated the influence of different solvents on this model reaction at room temperature for 3 days (Table 5).

Various solvents were tested including Et2O, CH2Cl2, MeCN, toluene, and MeOH ( In addition, some further studies on this reaction have been explored concerning the nature of the ester group of the Michael acceptor. The use of bulkier esters such as iso-propyl and tert-butyl than methyl or ethyl group slightly increased the dr but led to lower yields and ee values (Table 6). A kinetic study showed that during the reaction, the ratio of the two diastereoisomers stays the same as well as the ee value of the major diastereoisomer (Table 7). The stability of 3a in the catalytic system proved that no retro-Michael addition occurred (Table 8).

Substrates scope of the reaction

After having the optimized conditions for the enantioselective process, we investigated the scope on SMA reaction of various thiols to α-fluoroacrylates (Table 9). Cyclohexyl α-fluoroacrylate (1c) was also used, the corresponding adducts were given in fair yields (34-77%), moderate to excellent dr (69:31 to 100:0) and moderate to good ee values (26-87%) (3l-q). The use of thiophenol and thiophene-2-thiol led to the formation of a single diastereoisomer (3l, 3o). The product 3p was obtained in the best enantiomeric excess 87%, and its X-ray crystal revealed that two stereogenic centers are both in S absolute configurations (Figure 15). Then, we studied the asymmetric SMA reaction on some aryl α-fluoroacrylates (1d-i).

Generally, aryl α-fluoroacrylates have lower reactivity compared to alkyl αfluoroacrylates as a higher temperature was required and lower yields were obtained for the 1,4-adducts (22-78%). However, they did not show much difference in the diastereoselectivity (87:13 to 100:0) and enantioselectivity (51-73%). α-Fluorocinnamates bearing a cyano group at the ortho-, meta-, and para-position of arene moiety gave the desired products in similar results showing no significant substituent effects (3v-x). The asymmetric SMA reaction could be easily scaled up under the optimized conditions. The reaction of 1a on a larger scale (1.5 mmol) succeeded in producing the desired products 3a in 73% isolated yield, 87:13 dr and 72% ee value for the major diastereoisomer giving the same results that in 0.3 mmol scale (82% yield, 84:16 dr, 71% ee). The reaction of 1c on 1.0 mmol scale produced 3p in 51% isolated yield, 91:9 dr and 85% ee value for the major diastereoisomer which is quite equivalent to the results obtained in 0.3 mmol scale (55% yield, 90:10 dr, 87% ee). Throughout all the products, we could notice that the low enantioselectivities (2-38% ee) were generally obtained with para-substituted aryl thiols and 2-naphthalenethiol (3b, 3c, 3i, 3j, 3k, 3m, 3n). This might be due to the para-substituent or the bulky naphthalen-2-yl hindering the approach of the aryl thiols in the catalyst "pocket".

The mechanism of bis-cinchona alkaloids derivatives catalyzed Michael addition reaction 105,119 is still not clear, essentially because of the lack of hydrogen-donor sites of these catalysts which generally exist in natural cinchona alkaloids and thioureabased catalysts. Referring to the X-ray of (DHQ)2PYR (Figure 16)120 , hereafter, we proposed a transition state model to explain the low ee values obtained for parasubstituted aryl thiols and 2-naphthalenethiol in our SMA reaction (Figure 17). We hypothesized that the thiophenolate enter into the pocket-like of the catalyst after deprotonation by the tertiary amine. Checking the X-ray of (DHQ)2PYR, we could find that the inward phenyl of pyrimidine is not a planar and could imply steric hindrance for the entered thiophenolate. This might explain why we obtained very low ee values with para-substituted thiol and 2-naphthalenethiol whereas relatively higher ee values were obtained with meta-and ortho-substituted thiols. Then, the αfluoroacrylate came from the si-face to minimize the steric interaction and allowed the conjugate addition.

Influence of the double bond geometry

As the reaction scope was all explored with (Z)-α-fluoroacrylates. To get insight into the influence of double bond geometry on this reaction, substrates (E)-1a and (E)-1d

have been synthesized and used in the SMA reaction (Table 10). The results showed that the replacement of (Z)-substrates by corresponding (E)-isomers gave similar yields and enantiomeric excess for the major diastereoisomer but with reversed diastereoisomer ratios. It has to be noted that for the reaction of (E)-1d, the starting material contained a small amount of (Z)-1d (E/Z = 90/10), explaining the lower dr obtained (Table 10, entries 6 and 8). All these results point out the face attack does not vary with the geometry of the double bond. Ninomiya and co-workers reported the same observations when they studied the SMA reaction between thiophenol and α,β-trisubstituted acrylates in the presence of a catalytic amount of base, and a concerted process was proposed to explain their results. 121 In our case, we may have

Synthesis of bioactive molecules

With our methodologies, two fluorinated analogues of bioactive compounds 5a and 5b have been synthesized. 5a is an analogue of the diltiazem, a calcium channel blocker, which has been clinically used since 1974 as an antianginal and antihypertensive agent. 122 5b is an analogue of the tiazesim, an antidepressant agent (Scheme 71). 122 Starting from the asymmetric adducts 3s and 3y respectively, a twostep synthesis, 123 a cyclization under acid catalysis followed by an alkylation reaction afforded the desired products 5a and 5b without any loss in enantiomeric excess. 122

Limitations of the reaction

Although we built the organocatalytic routes to access fluorine-containing molecules with α-fluoroacrylates in both non-enantioselective and enantioselective versions, some limitations cannot be ignored.

Specifically, in the asymmetric process, a long reaction time (5-8 days) was required, some products (3b, 3c, 3n, 3q) were obtained with minimal enantioselectivities (≤38% ee) including three no enantioselectivity products (3j, 3k, 3m) (≤11% ee). The use of other sulfur-nucleophiles such as benzyl mercaptan and thioacetic acid showed very poor 19 F NMR yields (Table 11). In addition, two commercially available gem-α-fluorinated acrylates were employed, which gave unsatisfactory results (Table 12).

Conclusion

In summary, we have developed a simple and efficient SMA reaction on βsubstituted-α-fluoroacrylates in both non-enantioselective and, for the first time, in the enantioselective versions (Scheme 72). 124 This strategy showed great tolerance of various substrates and substituents, providing moderate to excellent yields (40-98%), and moderate to good diastereoselectivities (dr = 3/1 to 12/1) in a nonenantioselective way. In the enantioselective way we developed, good levels of reactivity, fair to excellent yields and moderate to good enantioselectivities were achieved by using commercially available (DHQ)2PYR as a catalyst (22-95% yields, dr = 2/1 to >99/1, ee up to 87%). Two fluorinated analogues of therapeutic agents were successfully synthesized using this SMA strategy. Organophosphorus compounds were found in a wide range of applications in many fields including industrial chemistry and life science. 125 The quest for simple and efficient methods to access these compounds is highly valuable. The conjugate addition of phosphorus nucleophiles to an acceptor-substituted unsaturated bond, which is also known as the phospha-Michael addition (PMA), has been considered as an attractive approach. In many reported PMA reactions, α,β-unsaturated carbonyl compounds (enones, enals and acrylamides), nitroalkenes and olefins bearing sulfones, sulfoxides, phosphonates or phosphane oxides could serve as typical and suitable acceptors for the PMA reactions. 18 Hereafter, we have selected some examples of PMA reactions with acrylates, these reactions are summarized and classified according to the different phosphorus-based nucleophiles. BTSP was in situ generated by heating the ammonium phosphinate with NH(TMS)2.

Monosubstituted phosphinic acids could be formed under mild conditions after an acidic work-up. Interestingly, disubstituted phosphinic acids could be also obtained in a one-pot reaction, by adding another equivalent of NH(TMS)2 followed by a second Michael acceptor to the reaction mixture (Scheme 76).

Scheme 76 Bis(trimethylsilyl)phosphonite as the nucleophile

In 1995, Minami and co-workers described the synthesis of optically active 129 Boyd, E. A.; Regan, A. C.; James, K. Tetrahedron Lett. 1992, 33, 813-816. phosphinocarboxylic acids by PMA reaction of Ph2PH to α,β-unsaturated ester. 130 1,4-Addition of Ph2PLi to α,β-unsaturated esters followed by the subsequent treatment with p-toluenesulfonic acid (PTSA) led to the racemic phosphinocarboxylic acids in almost quantitative yields. The racemic acids were treated with (+)-or (-)-αmethylbenzylamine (PEA) respectively, giving the optically pure salts after recrystallizations, then the enantiomerically pure acids were obtained by treating the salts with diluted HCl (Scheme 77, Eq. a). In the phospha-Michael addition reaction of Ph2PH, the use of palladium-complex as the catalyst has already been successful with some electron-poor alkenes, such as α,β-unsaturated aldehydes, 131 α,β-unsaturated ketones, 132 and α,β-unsaturated N-acylpyrroles. 133 Later, the palladium complex catalyst has also been used with α,β-unsaturated esters. In 2012,

Leung and co-workers developed a method for asymmetric PMA of Ph2PH to methylidenemalonate esters under Pd-catalysis. 134 In that case, a palladacycle derived from the corresponding chloro-bridged dimeric palladium compound with silver perchlorate in acetonitrile was the active catalytic species. This protocol gave straightforwardly access to functionalized tertiary phosphines in high conversions and enantioselectivities (Scheme 77, Eq. b). In 2013, Duan and co-workers used a chiral palladium complex as the catalyst for the asymmetric PMA reaction of Ph2PH to α,β-unsaturated carbonyl esters. 76 Under these reaction conditions, various cinnamic acid aryl esters substituted with electron-rich and electron-poor groups were treated with diarylphosphine, providing the oxidative 1,4-adducts in excellent yields and moderate to excellent enantioselectivities (Scheme 77, Eq. c). reported a titanium iso-propoxide catalyzed PMA on acrylate-type alkenes. 139 With diphenyl phosphite, the 1,4-adducts were generally obtained in moderate to good yields ((Scheme 79, Eq. a). Acrylates with a bulky ester group or with methyl or phenyl substituted-double bond retarded the reaction. Under the catalytic system, when diethyl phosphite was applied as the nucleophile, the corresponding 1,4adduct was also detected in 31 Swamy and co-workers. 142 In the presence of TBAF in [BMIM] + [PF6] -, the Morita-Baylis-Hillman adducts furnished the corresponding γ-hydroxyphosphonates in good yields. With the α-bromomethyl-cinnamate, the final products formed by the initial 1,4-addition of cyclic phosphites followed by the elimination of HBr were also obtained in good yields (Scheme 80, Eq. b). Scheme 81 diaryl phosphine oxides as the nucleophile

Phosphine-borane nucleophiles

Phosphine-boranes (R3-nHnPBH3) are Lewis acid-Lewis base adducts derived from phosphines and borane. 147 As they are air-stable, they could be considered as a borane-protected form of the corresponding phosphines (R3-nHnP). Thus, they are used as phosphorus-nucleophiles in some Michael addition reactions. In 1990, Imamoto and co-workers developed a method for the synthesis of phosphineboranes in a one-pot process. 148 The resulting diphenylphosphine-borane could undergo a 1,4-addition with ethyl acrylate in the presence of KOH, affording the phospha-Michael adduct in 73% yield (Scheme 82, Eq. a). In 1994, Corre and coworkers described a PMA reaction of the same phosphine-borane to a chiral bis- In 2007, Kondratov and co-workers described the reaction between the Ph3PCHCO2Et ylide and fluorinated β-ketoaldehyde derivatives. 74 The unusual products were formed by the initial ylide attack at the β-position of the enone followed by subsequent EtO -elimination (Scheme 83, Eq. b). In 2013, Duan and coworkers used a chiral palladium complex as the catalyst for the asymmetric phospha-Michael addition reaction of diphenylphosphine to α,β-unsaturated carboxylic esters. 76 Two fluorinated cinnamate esters, for which the fluorinated substituent was located on the ester group, furnished the corresponding adducts in good yields and excellent enantioselectivities (Scheme 83, Eq. c).

Scheme 83 PMA reactions on fluorinated Michael acceptor

Objectives

Phospha-Michael addition reaction is an attractive strategy for the C-P bond formation. Indeed, various phosphorus-containing compounds could be treated as suitable phosphorus-nucleophiles and the electrophiles are also diverse. However, the α,β-unsaturated ester Michael acceptors are not widely used in the literature and to our knowledge, no α-fluorinated acrylate has been used in such reactions.

Regarding all the described PMA reactions on α,β-unsaturated esters, most of them performed with unsubstituted acrylates or monosubstituted acrylates. Therefore, in this chapter, our goal was to develop the first phospha-Michael addition on βsubstituted-α-trifluoromethylacrylates to synthesize original scaffolds bearing both phosphorus and fluorinated moieties (Scheme 84).

Scheme 84 The first PMA reaction on trifluoromethylated acrylates

Optimization of the reaction conditions

Preliminary results

At the beginning of our investigation, when the α-fluoroacrylates (1) and αtrifluoromethylacrylates ( 6) reacted with diphenylphosphine oxide (7a) in PMA reactions, different behaviors were observed (Table 13). In the presence of TMG, αfluoroacrylates (Table 13, entries 1-3), especially those with a β-substituent barely react with 7a (Table 13, entries 2-3), were less reactive than αtrifluoromethylacrylates (Table 13, entries 4-5). Both α-trifluoromethylacrylates gave full conversions and the desired 1,4-adducts were isolated in 68% and 84% (dr = 66:34) yields respectively (Table 13, entries 4-5). Considering these results, we decided to continue our investigations with α-trifluoromethylacrylates as substrates for the PMA reaction.

Screening of the base and the equivalents of Ph 2 P(O)H

Based on the preliminary results, we decided to choose methyl (Z)-3-phenyl-2-(trifluoromethyl)acrylate (6b) as the Michael acceptor and diphenylphosphine oxide (7a) as the phosphorus-nucleophile to optimize this PMA reaction. As the use of TMG led to a full conversion and 84% of isolated yield, but moderate diastereoselectivity (Table 14, entry 1), we screened some other bases which all have the potential to promote this reaction. An inorganic base K2CO3 led to a lower 19 F NMR yield (39%) with a reversed low diastereomeric ratio (Table 14, entry 2). The primary amine, isopropylamine (IPA) was inefficient in both yield and diastereoselectivity (Table 14, entry 3). Even though IPA and diisopropylamine (DIPA)

have very close pKa values, the latter gave a much better result, the 1,4-adduct (8a)

was obtained in 79% 19 F NMR yield as a mixture of diastereoisomers with a 18:82 dr (Table 14, entry 4). The use of tertiary amines led to good to high 19 F NMR yields (80-95%) for 8a except for DBU (47%) (Table 14, entries 5-8). Worth mentioning, with triethylamine and DABCO, 8a was isolated in 94% and 91% respectively, whereas a better but reversed diastereomeric ratio was afforded by DABCO (Table 14, entries 5 and8). The equivalents of 7a only affect the yield of 8a, decreasing the equivalent of 7a led to lower yields (Table 14, entries 9-10). The use of 2 equivalents of 7a did not give a better yield compared to 1.5 equivalents (Table 14, entries 8 and 11).

Additionally, we tested the reaction at 0 °C and 50 °C (Table 14, entries 12-13), the 19 F NMR yields were close to the one obtained when the reaction was carried out at room temperature (Table 14, entry 8). The lower temperature did not give a positive effect on diastereoselectivity lowering the dr (dr = 83:17) whereas the higher temperature furnished the same dr compared to the one obtained at room temperature. Finally, we confirmed that the best results were obtained when this reaction was performed with 1.5 equivalents of 7a under the catalysis of DABCO at room temperature.

Screening of the solvents and the DABCO loading

Herein, the effect of solvent and the loading of DABCO on this PMA reaction were explored. The use of CH2Cl2 as solvent lowered both 19 F NMR yield and diastereomeric ratio (Table 15, entry 1). Compared to MeCN, when THF or Et2O was used as the solvent, comparable 19 F NMR yields were obtained, with obvious decrease in diastereoselectivities (Table 15, entries 2-4). Based on these results, MeCN was chosen as the solvent to study the DABCO loading. A small amount of 8a with a reversed diastereomeric ratio was observed in the absence of DABCO (Table 15, entry 5). Increasing the loading of DABCO improved the 19 F NMR yields as well as the diastereoselectivities (Table 15, entries 4-7). The improvement in 19 F NMR yields was particularly obvious when the loading of DABCO was increased from 5 mol% to 10 mol% (Table 15, entries 6-7). In the end, we decided to perform this reaction with 20 mol% of DABCO in MeCN (Table 15,entry 4). a Reaction conditions: 6b (0.3 mmol, 1.0 equiv), 7a (0.45 mmol, 1.5 equiv), DABCO (y mol%), room temperature, 16 h, in solvent (0.5 mL). b19 F NMR yields were obtained by using PhCOCF3 as an internal standard. c Determined by the 19 F NMR of the reaction crude.

Thus, the optimal experimental conditions were defined as 1.5 equivalent of diphenylphosphine oxide with 20 mol% of DABCO in MeCN at room temperature overnight for 16 h.

Enlarge the scope of fluorinated Michael acceptors

As we defined the suitable conditions for the Michael addition of diphenylphosphine oxide (7a) to methyl (Z)-3-phenyl-2-(trifluoromethyl)acrylate (6b), we decided not only to use α-trifluoromethylacrylates as Michael acceptors in this PMA reaction.

Hereafter, another fluorinated acrylate was tested, and some further experiments have been done to optimize the reaction (Table 16).

The methyl (Z)-2-(fluoromethyl)-3-phenylacrylate (9a) was employed in PMA reaction, the optimized conditions used with α-trifluoromethylacrylate were not suitable for 9a, because only trace of products were observed in 19 F NMR ( Worthy to note that we also wanted to use the (Z)-2-(difluoromethyl)-3phenylacrylate as substrates to have a complete picture of the α-fluorinated methyl acrylate family, but the synthesis of these substrates was rather difficult and, for lack of time, we had to abandon this part.

Substrate scope of the reaction

With the optimized conditions in hand, we investigated the scope of DABCO-promoted phospha-Michael addition reaction of diarylphosphine oxides to αtrifluoromethylacrylates and α-fluoromethylacrylates respectively.

with α-trifluoromethylacrylates

The investigations showed various α-trifluoromethylacrylates (6) and diarylphosphine oxides (7) were tolerated in this PMA reaction. The corresponding phospha-Michael adducts (8) were obtained in moderate to excellent yields (55-95%) with moderate to excellent diastereoselectivities (dr = 70:30 to 99:1) (Table 17). With diphenylphosphine oxide (7a) as the nucleophile, the use of commercially available methyl 2-(trifluoromethyl)acrylate smoothly afforded the 1,4-adduct (8a) in 74% yield. The use of β-phenyl-α-trifluoromethylacrylate (6b) gave the product (8b) in 91% yield with a 92:8 dr ratio. On a larger scale (2.0 mmol), 6b also performed well, 8b was obtained in 84% yield with a 91:9 dr ratio. The phenyl moiety at βposition of these α-trifluoromethylacrylates could bear electron-donating groups, such as methoxy (6c, 6p), hydroxyl (6d), dimethylamino (6e), tert-butyl (6f), and methyl (at para-, meta-, and ortho-position) (6g-i). It could also bear electronwithdrawing groups, such as trifluoromethyl (6j), cyano (6k), and halogens (6l-o,6s).

Those substrates with a para-substituted arene usually furnished the products (8c-g, 8j-m, 8o) in good to high yields with high dr ratios (71-95% yield, dr = 81:19 to 99:1), except for 8e (52% yield). The substrates with a meta-or ortho-substituted arene lowered both the yields and diastereomeric ratios. The use of substrate beared a meta-substituted methylphenyl slightly decreased the yield and dr ratio (8h, 81% yield, 93:7 dr), whereas the ortho-substituted one led to a significant drop on both yield and dr ratio (8i, 61% yield, 70:30 dr), probably because of the steric hindrance.

The same phenomenon was observed for ortho-chloro 8n (55% yield, 74:26 dr).

When electron-withdrawing groups and halogens were presented at para-position of the phenyl moiety, the desired products (8j-m, 8o) were obtained in 80-95% yield with excellent diastereoselectivities (dr = 97:3 to 99:1). Additionally, the substrate 6p containing a disubstituted phenyl (3,5-dimethoxyphenyl) at β-position was also tested and the corresponding product 8p was obtained in 94% yield with a 90:10 dr ratio. The β-substituents of trifluoromethylacrylate could be extended to naphthalen-2-yl and thiophen-2-yl, furnishing the products in good yields with excellent dr ratios (8q, 83% yield, 94:6 dr; 8r, 75% yield, 96:4 dr). The product 8m could be obtained from both (Z) and (E)-trifluoromethylacrylates, the (E)-substrate (6s) led to a lower yield and lower dr ratio (70% yield, 85:15 dr). We were not surprised that the reaction did not occur with 6t due to its strong steric hindrance (8s). In the end, with 6b, we tested some other phosphorus-nucleophiles. The reactions proceeded smoothly when two other diarylphosphine oxides (7b-c) were employed (8t-u). However, the use of diethyl phosphite (7d) only led to the recovery of the two starting materials. The X-ray analysis of the crystal obtained from 8j confirmed that the major diastereoisomer was in anti-configuration (Figure 19).

Figure 19 X-ray of the major diastereoisomer of 8j

with α-fluoromethylacrylates

In this DABCO-promoted PMA reaction, α-fluoromethylacrylates (9) behaved less reactive compared to α-trifluoromethylacrylates (6). The phospha-Michael adducts (10) were obtained in low to moderate yields (29-70%) under long reaction time conditions at 40 °C, fortunately, with excellent diastereoselectivities (dr>94:6) (Table 18). By using methyl (Z)-2-(fluoromethyl)-3-phenylacrylate (9a), the desired 1,4-adduct was obtained in 64% yield with a 95:5 dr ratio (10a). The phenyl moiety at β-position could bear methoxy group (9b), chlorine (9c), and cyano group (9d). It did not affect the diastereoselectivitites but decreased the yields (10b -d, 29-51%, dr>96:4).

Highlighting that an electron-withdrawing substituent disrupted the reactivity of the substrate, the phenyl moiety bearing a cyano group led to the formation of the desired product in only 29% yield (10d) alongside with two major fluorine-free byproducts 10d' (22%) and 10d'' (16%) (isolated by preparative TLC, structures were identified by NMR and LC-MS). In that case, the presence of electron-withdrawing cyano group seemed to favor the elimination of a fluoride prior to reprotonation leading to compound 10d', then a second addition of diphenylphosphine oxide furnished the second byproduct 10d'' (Scheme 85). The use of substrate containing a para-nitrophenyl led to more complex unseparated products without forming desired product (10e). We were disappointed to see that furan-2-yl and n pentyl substituted substrates did not work at all in this reaction (10f-g). Some other diarylphosphine oxides were employed as the nucleophile, the corresponding 1,4adducts of bis(4-methoxyphenyl)phosphine oxide and bis(4-methylphenyl)phosphine oxide were obtained in 70% and 53% yield, respectively (10h-i). whereas, the use of bis(4-chlorophenyl)phosphine oxide as the nucleophile also led to complex byproducts without forming the desired product 10j. The major diastereoisomer for this PMA reaction was determined by X-ray analysis of the crystal obtained from 10a and proved to be in syn-configuration (Figure 20).

Conclusion

In conclusion, we built the first PMA reaction of diarylphosphine oxides to αtrifluoromethylacrylates under mild conditions. This reaction provided efficient and highly diastereoselective access to tertiary phosphine oxides among various βsubstituted-α-trifluoromethylacrylates. The corresponding products were generally obtained in moderate to excellent yields (52-95%) and good to high diastereoselectivities towards the anti-diastereoisomer (dr = 70:30 to 99:1) (Scheme 88, Eq. a). We also demonstrated that this method could also be applicable to βsubstituted-α-fluoromethylacrylates, producing the desired products in low to moderate yields (29-70%) but with excellent diastereoselectivities in each case towards the syn-diastereoisomer (dr >94:6) (Scheme 88, Eq. b).

Scheme 88 PMA reaction of diarylphosphine oxides to β-substituted-α-trifluoromethylacrylates

In this PMA reaction, we made some efforts for the enantioselective formation of C-P bond by using chiral catalysts or introducing chiral moiety to the Michael acceptor.

These results including various reactions attempted to enlarge the scope of Michael addition reactions with our α-fluorinated Michael acceptors will be discussed in the next chapter.

Chapter 4

Other Michael Addition Reactions on Fluorinated Substrates

α-Fluoroacrylates

We first tested the nucleophiles mentioned above with some α-fluoroacrylates 1 (Table 19). Although we knew that these α-fluoroacrylates were poorly reactive in Michael addition reactions, we were disappointed to see there was no reaction, when the nitromethane and diethyl malonate were applied as the nucleophiles (Table 19, entries 1-2). Two lithium cuprates, namely lithium dimethylcuprate and lithium cyano(methyl)cuprate, which are known as very soft nucleophiles, generally having 1,4-rather than 1,2-regioselectivity, 157 also were used in the Michael addition reaction on α-fluoroacrylates. However, we only observed the starting material even when we slightly increased the temperature or extended the reaction time (Table 19, entries 3-4). In the described Michael addition reactions of phenylboronic acid, βalkyl-substituted Michael acceptors were generally used. 156a-b Thus, besides βphenyl-α-fluoroacrylate, three β-alkyl-α-fluoroacrylates were also tested (Table 19, entries 5-8). Only the methyl 2-fluoroacrylate allowed the formation of the suspected product ddd,J = 48.8,28.7,24.1 Hz). We failed to confirm the structure of that product due to an unseparated non-fluorine byproduct (Table 19, entry 8). As only the unsubstituted α-fluoroacrylate gave traces of product, we did not search to improve this result. Since we did not get satisfactory results using α-fluoroacrylates as the Michael acceptors, we turned our attention to more reactive α-trifluoromethylacrylates.

α-Trifluoromethylacrylates

Enantioselective PMA reaction on α-trifluoromethylacrylate 6b

Even if the α-position of α-trifluoromethylacrylate is highly epimerizable, we wanted to test our PMA reaction in an enantioselective way as the experimental conditions used are soft. So, we studied the PMA reaction of diphenylphosphine oxide (7a) to methyl (Z)-3-phenyl-2-(trifluoromethyl)acrylate (6b) in an asymmetric process with several organocatalysts (I-IX) (for the structures, see Scheme 69) (Table 20). The use of cinchona alkaloids (I-III) did not have diastereocontrol for the formation of 8b (Table 20, entries 1-3). The use of bis-cinchona alkaloids (IV-VII) slightly increased the yields and diastereoselectivities (Table 20, entries 5-8). Among these biscinchona alkaloids catalysts, (DHQ)2PYR (IV) gave the best ee value, albeit still low for the major diastereoisomer (Table 20,entry 5). Thiourea-based catalyst (VIII) was not efficient for this reaction (Table 20,entry 9). Thiourea-based catalyst (IX) afforded a reversed dr ratio and ee value compared to (DHQ)2PYR (IV) (Table 20,entry 10). With (DHQ)2PYR (IV) as the catalyst, we carried out the reaction at a lower temperature to improve both diastereo-and enantioselectivity (Table 20, entries 11-13). In the same reaction time, as the temperature decreased to -20 °C, the yield reduced obviously but a 25:75 dr ratio and 39% ee value were obtained ( In this asymmetric process, we also tried metal/chiral ligand strategy based on the work of Ishihara and co-workers (Scheme 81, Eq. b). 144 A chiral magnesium complex catalyst was formed by MgBu2 with (R)-H8-binol, exhibiting excellent catalytic efficiency and enantioselectivity for non-fluorinated analogue of (Z)-3-phenyl-2-(trifluoromethyl)acrylate (6b), was not suitable for 6b (Scheme 89).

Scheme 89 PMA reaction under the catalysis of chiral magnesium complex

Enantioselective SMA reaction on α-trifluoromethylacrylate 6b

As we knew that arylthiols are good nucleophiles in Michael addition reaction on αfluoroacrylates (see Chapter 2), herein, we studied the behavior of (Z)-3-phenyl-2-(trifluoromethyl)acrylate (6b) with thiophenol (2a) in Michael addition reaction (Table 21). With all the selected catalysts, the corresponding products were generally obtained in high 19 F NMR yields (83-97%). This reaction occurred even in the absence of catalyst albeit losing diastereocontrol in this case (Table 21, entry 6).

In general, we found that the use of different catalysts whether it was achiral or chiral, did not affect the diastereoselectivities, except for the thiourea-based catalyst (IX). Among all the tested chiral catalysts, the thiourea-based catalyst (IX) was the only one afforded enantiomeric excess for the major diastereoisomer (Table 21, entry 11). So far, we did not further investigate this reaction.

Michael addition of other nucleophiles on αtrifluoromethylacrylates

Owning to the higher reactivity of α-trifluoromethylacrylates compare to α-fluoroacrylates, selected common nucleophiles (see in Table 19) were also tested on 6b, and some preliminary results were obtained (Table 22). The use of nitromethane as the nucleophile led to the full recovery of starting material 6b (Table 22, entry 1).

We were happy to see that the diethyl malonate, which did not react with αfluoroacrylates, furnished the corresponding adducts in 34% 19 F NMR yield with a 22:78 dr ratio under the catalysis of DABCO (Table 22,entry 2). Moreover, with lithium dimethyl cuprate, we obtained 41% 19 F NMR yield of two peaks of suspected 1,4-adducts ( 19 F NMR: -69.1 ppm, s; -73.9 ppm, s) (Table 22,entry 3). With phenylboronic acid as the nucleophile, we could form the desired product in 34% isolated yield only when we used the unsubstituted trifluoromethylacrylate (Table 22, entry 6), thus we did not study it any further.

Michael addition reaction of different nucleophiles to αfluorinated enal and enone

In the literature, Michael addition reaction on α,β-unsaturated aldehydes and ketones were also largely described. [15][16][17][18] Thus, the α-fluorinated enal (12a) and enone (13a) derived from α-fluoroacrylate (1d) were synthesized and used as the Michael acceptors. In the described Michael addition reactions on enals, the iminium ion activation strategy is well-known. 158 This strategy was also used in our investigation on Michael addition reaction of different nucleophiles to 12a (Table 23).

Among all the selected nucleophiles (S-, C-, O-, N-, and P-nucleophiles), thiophenol was the only one that could give the desired 1,4-adduct but with two other unseparated byproducts (Table 23,entry 1). In all reactions with catalyst a, the unknown product A was always formed, the same phenomenon was observed with the use of catalyst b. We assumed that unknown products A and B were somehow produced during the activation of 12a by the two catalysts, which was preliminarily verified in the reactions without nucleophile (Table 23, entries 10-11). When nitromethane was used as the nucleophile, under the catalysis of b, the nitro-alkene C resulting from the 1,2-addition was formed (Table 23,entry 3). With the aid of NMR, LC-MS and X-ray, the structure of C was determined and shown in Figure 21. With the α-fluorinated enone (13a), we studied the Michael addition of diethyl malonate. The only attempt was under the reported conditions for the non-fluorine analogue of 13a. 159 Under the catalysis of (R)-proline, with 1 equivalent of piperidine as an additive, the addition of diethyl malonate to 4-phenyl-3-buten-2-one furnished 82% conversion and desired 1,4-adduct obtained in 57% ee value. However, in our case, we only observed trace of product as a mixture of two diastereoisomers with a 68:32 dr ratio (Scheme 90).

Scheme 90 Michael addition of diethyl malonate to α-fluorinated enone

Conclusions

In summary, we studied the Michael addition reaction of various nucleophiles on different α-fluorinated Michael acceptors in this chapter. Due to the unique properties of the fluorine atom, the fluorinated substrates showed different reactivities compared to their non-fluorinated analogues. Some undesired products were obtained when the α-fluorinated enal (12a) was used (unknown A, unknown B, and byproduct C). At the same time, in the addition of diethyl malonate and lithium dimethylcuprate to α-trifluoromethylacrylate (6b), some preliminary results were obtained and deserved to be further explored. Under the catalysis of Et3N, a broad range of sulfa-Michael adducts were obtained in moderate to excellent yields with moderate to good diastereoselectivities. Under the catalysis of (DHQ)2PYR, the corresponding products were obtained in low to excellent yields and diastereoselectivities with moderate to good enantioselectivities.

Moreover, two fluorinated analogues of therapeutic agents were successfully synthesized using this SMA strategy (Scheme 91). 124

Scheme 91 SMA of aryl thiols to β-substituted-α-fluoroacrylates

Then, the first PMA reaction on α-trifluoromethylacrylates under mild conditions has been developed. It provided efficient and highly diastereoselective access to tertiary phosphine oxides among various β-substituted-α-trifluoromethylacrylates. The corresponding products were generally obtained in moderate to excellent yields and good to high diastereoselectivities. This methodology was applied to β-substitutedα-fluoromethylacrylates, producing the desired products in low to moderate yields but excellent diastereoselectivities in each case (Scheme 92).

Scheme 92 PMA reaction of diarylphosphine oxides to β-substituted-α-trifluoromethylacrylates

In the end, to expand the application of Michael addition reaction on fluorinated substrates, a series of attempts have been made with our fluorinated substrates. The fluorinated Michael acceptors showed different behaviors compared to their nonfluorinated analogues and some preliminary results have been obtained (Scheme 93).

Scheme 93 Preliminary results

Perspectives

In our developed SMA reaction, the mechanism of the asymmetric process is not clear. Although we proposed a transition state to explain the low enantioselectivities obtained from para-substituted thiophenols, more decisive proof was needed (get a crystal from the complex between the catalyst and thiol, if it is possible). Similarly, more evidence was needed to support the mechanism we proposed in the PMA reaction. For example, in the optimization of PMA reaction, Et3N and DABCO are both tertiary amines, but the use of Et3N as the base reversed the diastereomeric ratio compared to DABCO. It is worth doing some further studies, such as performing the reaction on (E)-trifluoromethylacrylates with Et3N, to figure out the role of the base in the diastereocontrol. We should also develop the synthesis of (E)-αfluoromethylacrylate to study, as in the SMA reaction, the influence of configuration of the the double bond, which will be a valuable clue for the mechanism we proposed (Scheme 94, Eq. a). It will also be interesting to synthesize the αdifluoromethylacrylates or α-perfluorinated acrylates family to have a complete picture of the reactivity of such fluorinated Michael acceptors (Scheme 94, Eq. b).

Additionally, as we did not obtain good results in enantioselective sulfa-and phospha-Michael addition reactions on α-trifluoromethylacrylates, we can study the use of chiral auxiliary into our α-fluorinated substrates to achieve the asymmetric construction of the C-S bond, the C-P bond and some other C-heteroatom bonds (Figure 22), or use some metal-catalyzed approach. 160 The study of Michael addition reaction on α-fluorinated substrates based on the preliminary results obtained in chapter 4 could also be further investigated, especially the addition of cuprate as a chiral ligand could be used in such reaction and induced enantioselectivity. Higherorder cuprates could also be studied for such reactions.

Scheme 94

Figure 22 Chiral α-fluorinated substrates

Experimental Section General Information

All the reactions were performed in oven-dried glassware with a magnetic stirring under the air or argon atmosphere unless otherwise stated. The reaction temperature was reported refers to the temperature of the oil bath around the glassware. Thin-layer chromatography (TLC) analyses were carried out on the silica gel (60 F254 from Merck) supported on an aluminum sheet. Flash column chromatography was done with Silicaflash P60 silica gel (40-60 μm). 1 H, 13 C, 19 F and 31 P NMR spectra were recorded using a Bruker Avance-300 spectrometer operating at 300 MHz

Materials

Unless otherwise specified, all the catalysts and reagents were purchased from commericial sources (Alfa Aesar, Fisher Chemical, Fluorochem, and Acros Organics) and used without further purification. Anhydrous solvents were purchased from heated to 90 °C for 4 h. The crude was filtrated over celite, washed with EtOAc (3×30 mL), then solvents were evaporated. The crude was then purified by flash silica gel column chromatography (eluent: petroleum ether/EtOAc). The analytic data of 1d-i were in agreement with those reported in literature. 21a In an oven-dried sealed tube, α-fluoro-α,β-unsaturated ester 1 (0.3 mmol, 1 equiv), arylthiol 2 (1.5 mmol, 5 equiv) followed by Et3N (0.03 mmol 10 mol%) were introduced, the tube was sealed and then freezed by liquid nitrogen, removed the air under high vacuum and introduced argon. The reaction mixture was stirred at 80 °C or room temperature for 16 hours and then was cooled to room temperature. The reaction mixture was purified by silica gel column chromatography (eluent: petroleum ether/EtOAc or petroleum ether/CH2Cl2).

General procedure (IV): enantioselective pathway

In an oven-dried sealed tube, α-fluoro-α,β-unsaturated ester 1 (0.3 mmol, 1 equiv), arylthiol 2 (1.5 mmol, 5 equiv) followed by (DHQ)2PYR (0.03 mmol 10 mol%) were introduced, the tube was sealed and then freezed by liquid nitrogen, removed the air under high vacuum and introduced argon. The reaction mixture was stirred at 0 °C or room temperature for 5-8 days and then the reaction mixture was purified by silica gel column chromatography (eluent: petroleum ether/EtOAc or petroleum ether/CH2Cl2).

Ethyl 2-fluoro-5-phenyl-3-(phenylthio)pentanoate (3a):

The syn-3a was obtained following the general procedure (III). 19 F NMR of the reaction crude showed dr = 76:24. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 20/1 to 15/1, v/v) affording two diastereoisomers in 91% yield (major: 80 mg as a colorless oil; minor: 11 mg as a colorless oil).

The (2S,3S)-3a was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 84:16. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 20/1 to 15/1, v/v) affording two diastereoisomers in 82% yield (major: 67 mg as a colorless oil; minor: 14 mg as a colorless oil). 71% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 6.810 min, t (major) = 7.507 min.]. 75MHz, CDCl3): δ 167.9 (d, JC-F = 22.5 Hz), 140.7, 133.8, 132.9, 129.0, 128.5, 128.5, 127.6, 126.2, 90.5 (d, JC-F = 195.0 Hz), 61.7, 50.5 (d, JC-F = 22.5 Hz), 33.4, 33.2, 14.0. IR: 2980, 1761, 1737, 1475, 1266, 1212, 1103, 1024, 745, 692, 557, 491 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C19H22FO2S: 333.1325, found: 333.1319.

Ethyl 2-fluoro-5-phenyl-3-(phenylthio)pentanoate (3a):

The anti-3a was obtained following the general procedure (III) starting from the (E)-1a. 19 F NMR of the reaction crude showed dr = 26:74. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 20/1 to 15/1, v/v) affording two diastereoisomers in 93% yield (major: 72 mg as a colorless oil; minor:

21 mg as a colorless oil).

The (2S,3R)-3a was obtained following the general procedure (IV) starting from the (E)-1a. 19 F NMR of the reaction crude showed dr = 14:86. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 20/1 to 15/1, v/v) affording two diastereoisomers in 86% yield (major: 39 mg as a colorless oil; major and minor mixture: 47 mg). 74% ee was obtained for the major diastereoisomer 8, 133.2, 132.9, 129.2, 128.5, 127.9, 126.2, 90.3 (d, JC-F = 195.0 Hz), 61.8, 49.5 (d, JC-F = 15.0 Hz), 32.8, 30.6, 14.1. The syn-3d was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 80:20. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 91% yield (major: 61 mg as a yellow oil; major and minor mixture: 34 mg).

The (2S,3S)-3d was obtained following the general procedure (IV). 19 2, 140.7, 137.3, 130.5, 128.5, 128.4, 126.2, 118.4, 115.1, 114.9, 89.8 (d, JC-F = 187.5 Hz), 61.8, 49.6 (d, JC-F = 15.0 Hz), 33.2, 32.9, 14.0. IR: 3468, 3371, 2925, 1754, 1607, 1479, 1216, 1103, 1022, 857, 747, 699, 454 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C19H23FNO2S: 348.1434, found: 348.1426.

Ethyl 2-fluoro-5-phenyl-3-(o-tolylthio)pentanoate (3e):

The syn-3e was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 73:27. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 91% yield (major: 68 mg as a colorless oil; major and minor mixture: 26 mg).

The (2S,3S)-3e was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 95:5. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 91% yield (major: 78 mg as a colorless oil; major and minor mixture: 16 mg). 78% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 5.793 min, t (major) = 6.470 min.].

[α]D 20 6, 140.1, 133.3, 132.3, 130.4, 128.5, 128.5, 127.4, 126.5, 126.2, 90.0 (d, JC-F = 187.5 Hz), 61.7, 49.7 (d, JC-F = 22.5 Hz), 33.5, 33.2, 20.9, 13.9. IR: 2935, 1761, 1736, 1454, 1299, 1212, 1025, 747, 699, 558, 438 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C20H24FO2S: 347.1481, found: 347.1480.

Ethyl 2-fluoro-5-phenyl-3-(m-tolylthio)pentanoate (3f):

The syn-3f was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 72:28. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 84% yield (major: 66 mg as a colorless oil; major and minor mixture: 21 mg).

The (2S,3S)-3f was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 94:6. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 95% yield (major: 86 mg as a colorless oil; major and minor mixture: 13 mg). 80% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 6.873 min, t (major) = 7.530 min.].

[α]D 20 = -18.8 (c 0.89, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.23 -6.97 (m, 9H), 7, 138.7, 133.5, 133.3, 129.7, 128.8, 128.5, 128.4, 126.2, 90.5 (d, JC-F = 187.5 Hz), 61.7, 50.4 (d, JC-F = 22.5 Hz), 33.4, 33.1, 21.3, 14.0. IR: 2933, 1762, 1737, 1454, 1299, 1212, 1025, 749, 698, 557, 432 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C20H24FO2S: 347.1481, found: 347.1479.

Ethyl 2-fluoro-5-phenyl-3-(p-tolylthio)pentanoate (3g):

The syn-3g was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 74:26. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 67% yield (major: 31 mg as a colorless oil; minor: 9 mg as a colorless oil; major and minor mixture: 30 mg).

The (2S,3S)-3g was obtained following the general procedure (IV). 19 8, 137.9, 133.5, 129.7, 129.7, 128.5, 128.5, 126.2, 90.6 (d, JC-F = 187.5 Hz), 61.7, 50.7 (d, JC-F = 15.0 Hz), 33.2, 33.2, 21.1, 14.0. IR: 2920, 1762, 1737, 1493, 1300, 1211, 1104, 1020, 811, 749, 699, 556, 496 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C20H24FO2S: 347.1481, found: 347.1481.

Ethyl 2-fluoro-5-phenyl-3-(thiophen-2-ylthio)pentanoate (3h):

The syn-3h was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 83:17. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 83% yield (major: 60 mg as a yellow oil; major and minor mixture: 24 mg)

The (2S,3S)-3g was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 88:12. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 73% yield (major: 41 mg as a yellow oil; major and minor mixture: 33 mg ). 67% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 167.9 (d, JC-F = 22.5 Hz), 140.7, 136.5, 130.8, 130.6, 128.6, 128.5, 127.6, 126.2, 90.4 (d, JC-F = 195.0 Hz), 61.8, 52.4 (d, JC-F = 15.0 Hz), 33.1, 32.5, 32.4, 14.1. IR: 2940, 1760, 1737, 1216, 1023, 847, 749, 698, 493 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C17H20FO2S2: 339.0889, found: 339.0899.

Ethyl 2-fluoro-3-(naphthalen-2-ylthio)-5-phenylpentanoate (3i):

The syn-3i was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 80:20. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 84% yield (major: 80 mg as a colorless oil; major and minor mixture: 16 mg).

The (2S,3S)-3i was obtained following the general procedure (IV). 19 75MHz, CDCl3): δ 167.9 (d, JC-F = 22.5 Hz), 140.8, 133.5, 132.4, 131.6, 131.1, 129.8, 128.6, 128.5, 127.7, 127.4, 126.6, 126.4, 126.3, 90.5 (d, JC-F = 187.5 Hz), 61.7, 50.3 (d, JC-F = 22.5 Hz), 33.4, 33.2, 14.0. IR: 2933, 1760, 1736, 1497, 1454, 1212, 1103, 1023, 858, 814, 744, 699, 475 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C23H24FO2S:

383.1481, found: 383.1477. The syn-3j was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 82:18. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 73% yield (major: 75 mg as a yellow oil; major and minor mixture: 24 mg)

The (2S,3S)-3j was obtained following the general procedure (IV). 19 (d, JC-F = 30.0 Hz), 148.3, 146.7, 134.7, 132.3, 132.2, 129.2, 123.9, 122.4, 90.5 (d, JC-F, = 187.5 Hz), 62.0, 50.6 (d, JC-F = 22.5 Hz), 33.0, 32.9, 14.1. IR: 2940, 1759, 1737[START_REF]64.5 Hz). 31 P{ 1 H} NMR (121 MHz[END_REF], 1516, 1343, 1068, 852, 817, 698, 479 cm -1 . HRMS (API -) m/z: [M] + calcd for C19H19BrFNO4S: 455.0202, found: 455.0193. The syn-3k was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 87:13. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 75% yield (major: 71 mg as a yellow oil; major and minor mixture: 25 mg).

The (2S,3S)-3k was obtained following the general procedure (IV). 19 5, 146.6, 133.5, 132.6, 131.9, 130.6, 129.8, 129.8, 129.3, 128.8, 127.7, 127.4, 126.9, 126.7, 123.8, 90.5 (d, JC-F = 187.5 Hz), 61.9, 50.4 (d, JC-F = 22.5 Hz), 33.1, 33.0, 14.0. IR: 2925, 1764, 1490, 1222, 1109, 1027, 830, 523, 468cm -1 .

HRMS (API -) m/z: [M] + calcd for C23H22FNO4S: 427.1254, found: 427.1254.

Ethyl 3-cyclohexyl-2-fluoro-3-(phenylthio)propanoate (3l):

The syn-3l was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 82:18. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 86% yield (major: 61 mg as a colorless oil; major and minor mixture: 19 mg).

The (2S,3S)-3l was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 100:0. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording an only diastereoisomer in 34% yield (32 mg as a colorless oil). 65% ee was obtained for it 7, 132.0, 128.9, 127.1, 89.3 (d, JC-F = 187.5 Hz), 61.6, 57.9 (d, JC-F = 15.0 Hz), 40.7, 31.1, 30.8, 26.2, 26.1, 13.9. IR: 2925, 1763, 1735, 1440, 1214, 1102, 1024, 746, 691, 537, 481 cm -1 . The syn-3n was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 78:22. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 20/1 to 15/1, v/v) affording two diastereoisomers in 65% yield (major: 47 mg as a white solid; major and minor mixture: 19 mg).

HRMS (API

The (2S,3S)-3n was obtained following the general procedure (IV). 19 4, 135.2, 125.5, 114.4, 89.4 (d, JC-F = 187.5 Hz), 61.6, 58.7 (d, JC-F = 15.0 Hz), 55.3, 40.2, 31.1, 30.7, 26.2, 26.2, 14.0. IR: 2926, 1763, 1590, 1490, 1222, 1026, 830, 594, 522, 473 cm -1 .

HRMS (API + ) m/z: [M+H] + calcd for C18H26FO3S: 341.1587, found: 341.1581.

Ethyl 3-cyclohexyl-2-fluoro-3-(thiophen-2-ylthio)propanoate (3o):

The syn-3o was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 82:18. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 43% yield (major: 30 mg as a yellow oil; major and minor mixture: 11 mg).

The (2S,3S)-3o was obtained following the general procedure (IV). 19 (d, JC-F = 22.5 Hz), 135.4, 133.2, 130.0, 127.3, 89.1 (d, JC-F = 195.0 Hz), 61.7, 60.4 (d, JC-F = 15.0 Hz), 39.8, 31.1, 30.5, 26.2, 26.1, 14.1. IR: 2925, 1762, 1736, 1448, 1216, 1024, 847, 700, 533, 495 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C15H22FO2S2: 317.1045, found: 317.1051.

Ethyl 3-((2-aminophenyl)thio)-3-cyclohexyl-2-fluoropropanoate (3p):

The syn-3p was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 80:20. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 75% yield (major: 38 mg as a yellow solid; minor: 11 mg as a yellow solid; major and minor mixture: 19 mg).

The (2S,3S)-3p was obtained following the general procedure (IV). 19 7, 136.5, 129.8, 118.4, 116.7, 115.0, 88.7 (d, JC-F = 187.5 Hz), 61.6, 56.7 (d, JC-F = 15.0 Hz), 40.9, 31.0, 30.5, 30.5, 26.4, 26.3, 26.2, 13.9. IR: 3445, 3351, 2925, 1748, 1613, 1480, 1233, 737, 602, 454 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C17H25FNO2S: 326.1590, found: 326.1594.

Ethyl 3-cyclohexyl-2-fluoro-3-(m-tolylthio)propanoate (3q):

The syn-3q was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 80:20. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 67% yield (major: 54 mg as a colorless oil; major and minor mixture: 11 mg).

The (2S,3S)-3q was obtained following the general procedure (IV). 19 (d, JC-F = 22.5 Hz), 138.6, 135.5, 132.4, 128.9, 128.7, 127.9, 89.3 (d, JC-F = 187.5 Hz), 61.6, 57.8 (d, JC-F = 22.5 Hz), 40.8, 31.1, 30.8, 26.2, 26.1, 21.3, 13.9. IR: 2925, 1764, 1735, 1600, 1449, 1213, 1102, 1025, 856, 776, 690, 541, 436 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C18H26FO2S:

325.1638, found: 325.1647.

Methyl 2-fluoro-3-phenyl-3-(phenylthio)propanoate (3r):

The syn-3r was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 83:17. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 61% yield (major: 42 mg as a white solid, major and minor mixture: 11 mg).

The (2S,3S)-3r was obtained following the general procedure (IV). 19 75MHz, CDCl3): δ 168.0 (d, JC-F = 22.5 Hz), 135.5, 133.5, 132.9, 129.2, 128.9, 128.8, 128.6, 128.4, 128.4, 89.2 (d, JC-F = 195.0 Hz), 54.6 (d, JC-F = 15.0 Hz), 52.4.

Methyl 3-((2-aminophenyl)thio)-2-fluoro-3-phenylpropanoate (3s):

The syn-3s was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 87:13. The crude was purified by silica gel column chromatography (petroleum ethe/CH2Cl2, from 5/1 to 2/1, v/v) affording two diastereoisomers in 46% yield (major: 34 mg as a yellow solid, major and minor mixture: 8 mg).

The (2S,3S)-3s was obtained following the general procedure (IV). 19 2, 138.1, 137.5, 130.8, 128.6, 128.3, 128.3, 128.1, 118.3, 115.0, 89.5 (d, JC-F = 195.0 Hz), 54.0 (d, JC-F = 22.5 Hz), 52.5. IR: 3432, 3327, 2951, 1755, 1609, 1217, 1101, 751, 698, 530, 457 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C16H17FNO2S: 306.0964, found: 306.0964. The syn-3t was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 85:15. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 89% yield (major: 45 mg as a colorless oil, major and minor mixture: 37 mg).

The (2S,3S)-3t was obtained following the general procedure (IV). 19 138.7, 138.0, 133.5, 133.3, 129.8, 128.8, 128.7, 128.6, 128.4, 128.4, 128.1, 91.3 (d, JC-F = 187.5 Hz), 55.7 (d, JC-F = 22.5 Hz), 52.5, 21.2. IR: 2960, 1765[START_REF]1481. Methyl 3-(4-chlorophenyl)-3-(diphenylphosphoryl)-2-(fluoromethyl)propanoate (10c): Following the general procedure (XI): 10c was obtained as a mixture of two diastereoisomers, dr = 96:4; white solid[END_REF], 1437, 1219, 1101, 774, 692, 544, 436 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C17H18FO2S:

305.1012, found: 305.1024.

Methyl 2-fluoro-3-(phenylthio)-3-(p-tolyl)propanoate (3u):

The syn-3u was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 77:23. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 75% yield (major: 51 mg as a white solid; major and minor mixture: 17 mg).

The (2S,3S)-3u was obtained following the general procedure (IV). 19 0, 134.8, 133.8, 132.8, 129.4, 128.9, 128.3, 128.2, 127.8, 91.5 (d, JC-F = 195.0 Hz), 55.5 (d, JC-F = 22.5 Hz), 52.6, 21.2. IR: 2927, 1739[START_REF](Z)-3-(3,5-dimethoxyphenyl)-2-(trifluoromethyl)acrylic acid (6'p): Following the general procedure (V): 6'p was obtained as a white[END_REF][START_REF]1611. Methyl 2-((4-(tert-butyl)phenyl)(diphenylphosphoryl)methyl)-3,3,3trifluoropropanoate (8f): Following the general procedure (X): 8f was obtained as a mixture of two diastereoisomers[END_REF], 1085, 1008, 741, 570, 413 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C17H18FO2S: 305.1012, found: 305.1009.

Methyl 3-(2-cyanophenyl)-2-fluoro-3-(phenylthio)propanoate (3v):

The syn-3v was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 89:11. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 62% yield (major: 43 mg as a white solid; major and minor mixture: 16 mg).

The (2S,3S)-3v was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 87:13. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 78% yield (major: 56 mg as a white solid, major and minor mixture: 14 mg). 52% ee was obtained for the major diastereoisomer 4, 133.4, 133.2, 132.8, 132.1, 130.0, 129.9, 129.2, 128.6, 128.5, 117.0, 112.1, 89.9 (d, JC-F = 195.0 Hz), 53.0 (d, JC-F = 15.0 Hz), 52.8. IR: 294752.8. IR: , 222452.8. IR: , 173252.8. IR: , 143852.8. IR: , 128352.8. IR: , 110652.8. IR: , 1016, 743, 692, 555, 491 cm -1 , 743, 692, 555, 491 cm -1 .

HRMS (API + ) m/z: [M+H] + calcd for C17H15FNO2S: 316.0808, found: 316.0814.

Methyl 3-(3-cyanophenyl)-2-fluoro-3-(phenylthio)propanoate (3w):

The syn-3w was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 92:8. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 62% yield (major: 54 mg as a colorless oil; major and minor mixture: 5 mg).

The (2S,3S)-3w was obtained following the general procedure (IV). 7, 133.4, 133.0, 132.9, 132.4, 132.0, 131.8, 129.5, 129.2, 128.5, 118.4, 112.8, 90.7 (d, JC-F = 195.0 Hz), 55.2 (d, JC-F = 15.0 Hz), 52.8. IR: 2953, 2231, 1763, 1438, 1221, 1102, 1008, 801, 739, 690, 528, 479 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C17H15FNO2S: 316.0808, found: 316.0808.

Methyl 3-(4-cyanophenyl)-2-fluoro-3-(phenylthio)propanoate (3x):

The syn-3x was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 81:19. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 64% yield (major: 51 mg as a white solid; major and minor mixture: 9 mg).

The (2S,3S)-3x was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 100:0. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording an only diastereoisomer in 70% yield (66 mg as a white solid). 68% ee was obtained for the it 130.8, 130.1, 129.5, 129.5, 118.3, 115.2, 115.0, 113.9, 91.0 (d, JC-F = 195.0 Hz), 55.3, 53.4 (d, JC-F = 22.5 Hz), 52.5. IR: 3354, 2953, 1754, 1605, 1511, 1480, 1243, 1102, 1023, 827, 743, 534, 435 cm -1 . HRMS (ESI + ) m/z: [M+H] + calcd for C17H19FNO3S:

336.1070, found: 336.1062. 3, 135.3, 135.3, 134.8, 130.6, 129.3, 128.8, 128.5, 126.7, 126.5, 123.1, 88.8 (d, JC-F = 195.0 Hz), 56.3 (d, JC-F = 15.0 Hz). IR: 3188, 3072, 2961, 2903, 1687, 1474, 1306, 1075, 768, 736, 717, 696, 524, 463 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C15H13FNOS: 274.0702, found: 274.0707. 0, 140.3, 134.8, 130.5, 130.5, 126.8, 123.1, 113.9, 88.4 (d, JC-F = 195.0 Hz), 55.6 (d, JC-F = 22.5 Hz), 55.3. IR: 3189, 3076, 2923, 2856, 1684, 1513, 1475, 1306, 1250, 1083, 1027, 785, 764, 652, 490, 410 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for To a solution of 4a (0.25 mmol, 68.5 mg) 1, 135.5, 131.1, 129.9, 128.9, 128.5, 128.4, 128.2, 128.1, 127.6, 124.7, 86.2 (d, JC-F = 187.5 Hz), 56.7, 55.0 (d, JC-F = 22.5 Hz), 47.8, 45.6. IR: 3064, 2939, 2765, 1681, 1441, 1179, 1088, 856, 766, 602, 591, 428 cm -1 . HRMS (ESI + ) m/z: [M+H] + calcd for C19H22FN2OS: 0, 145.0, 135.4, 131.0, 129.4, 128.2, 127.6, 124.6, 113.9, 86.1 (d, JC-F = 187.5 Hz), 56.6, 55.3, 54.5 (d, JC-F = 22.5 Hz), 47.7, 45.5. IR: 3058, 2938, 2770, 1676, 1609, 1511, 1251, 1178, 1092, 1029, 732, 602, 407 cm -1 . HRMS (ESI + ) m/z: [M+H] + calcd for C20H24FN2O2S: 375.1543, found: 375.1532.

The HPLC chromatograms

The organic layer was dried over anhydrous Na2SO4 followed by concentration under reduced pressure. The obtained residue was purified by flash silica gel column chromatography (eluent: petroleum ether/EtOAc) to give the corresponding αtrifluoromethyl acrylate (6). : 3304, 1686, 1235, 1124, 1106, 1016, 811, 698, 522, 420 cm -1 . HRMS (ES-) m/z: 6, 163.5, 158.5, 133.0 (q, JC-F = 6.2 Hz), 123.1 (q, JC-F = 270.8 Hz), 121.9 (q, JC-F = 29.9 Hz), 104.3, 90.4, 55.7, 55.5, 51.8. IR: 3023, 2950104.3, 90.4, 55.7, 55.5, 51.8. IR: 3023, , 2853104.3, 90.4, 55.7, 55.5, 51.8. IR: 3023, , 2124104.3, 90.4, 55.7, 55.5, 51.8. IR: 3023, , 1729104.3, 90.4, 55.7, 55.5, 51.8. IR: 3023, , 1649104.3, 90.4, 55.7, 55.5, 51.8. IR: 3023, , 1457104.3, 90.4, 55.7, 55.5, 51.8. IR: 3023, , 1287104.3, 90.4, 55.7, 55.5, 51.8. IR: 3023, , 1217104.3, 90.4, 55.7, 55.5, 51.8. IR: 3023, , 1123, 968, 819, 520, 495 cm -1 , 968, 819, 520, 495 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C14H16F3O5: 321.0944, found: 321.0951.

IR

Preparation of α-fluoromethylacrylates 9

The α-fluoromethylacrylates were prepared following the methodology developed by Kim in 2013 (Scheme 98). 168 General procedure (VII) for the synthesis of MBH adduct (9'a-g): In a round bottom flask charged with a stir bar was added aldehyde (5 mmol), followed by methyl acrylate (15 mmol, 3 equiv) and DABCO (1 equiv). The reaction mixture stirred at room temperature until judged complete by TLC, then water (10 mL) was added into the reaction mixture. The resulting solution was extracted with CH2Cl2 (3×15 mL), the combined organic layer was dried over with Na2SO4, then concentrated and purified by flash silica gel column chromatography (petroleum ether/EtOAc) to give 9'.

General procedure (VIII) for the synthesis of α-bromomethylacrylates (9"a-g): In a round bottom flask charged with a stir bar was added the MBH adduct (3 mmol, 1 equiv), followed by HBr (33 wt% in HOAc, 10.5 mmol, 3.5 equiv) stirred at room temperature for 2 h or followed PBr3 (3 mmol, 1 equiv) at 0 °C for 0.5 h then room temperature for 1.5 h. The reaction mixture quenched by adding water (10 mL), then extracted with CH2Cl2 (3×15 mL). The organic layer was concentrated under reduced pressure and purified by flash silica gel column chromatography (petroleum ether/EtOAc) to give 9".

General procedure (IX) for the synthesis of α-fluoromethylacrylates (9a-g): To a stirred solution of α-bromomethylacrylates 9" (1 mmol, 1 equiv) in t BuOH (2 mL) was 2959, 1750, 1438, 1176, 1116, 820, 759, 695, 530, 510, 420 cm -1 . HRMS (CI+) m/z: 3058, 2927, 2234, 1747, 1438, 1180, 1158, 1115, 863, 717, 700, 567, 530, 428 cm -1 . Following the general procedure (X): 8l was obtained as a mixture of two diastereoisomers, dr = 98:2; white solid, 95% yield (128 mg); M.P. 230 -232 °C.

HRMS (ES+

anti-8l: 3059, 2956, 1749, 1437, 1365, 1146, 1113, 752, 714, 697, 544, 510, 495, 425 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C23H20ClF3O3P: 467.0785, found: 467.0789. Following the general procedure (X): 8o was obtained as a mixture of two diastereoisomers, dr = 99:1; white solid, 88% yield (135 mg); M.P. 242 -243 °C.

anti-8o: 1 H NMR (300 MHz, CDCl3): δ 7. 99 -7.92 (m, 2H), 7.59 -7.46 (m, 5H), 7.36 -7.21 (m, 7H), 4.31 -4.12 (m, 2H), 3.14 (s, 3H). Hz). IR: 3059, 2926, 1748, 1590, 1438, 1238, 1181, 1153, 1116, 716, 697, 542, 513, 446 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C23H20BrF3O3P: 511.0280, found: 511.0302. 3059, 2932, 2841, 1755, 1608, 1591, 1436, 1197, 1143, 1070, 720, 700, 543, 510, 441 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C25H25F3O5P: 493.1386, found: 493.1370. 3059, 2956, 1750, 1437, 1272, 1177, 1111, 743, 701, 555, 478, 422 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C27H23F3O3P: 483.1331, found: 483.1343. 3060, 2944, 1750, 1439, 1174, 721, 700, 545, 525, 480 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C23H23FO3P: 397.1363, found: 397.1359. syn-10b: 1 H NMR (300 MHz, CDCl3): δ 7. 99 -7.92 (m, 2H), 7.57 -7.50 (m, 3H), 7.45 -1438, 1221, 837, 722, 698, 545, 518, 413 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C23H22ClFO3P: 431.0974, found: 431.0966. 3055, 2929, 2238, 1747, 1438, 1160, 1138, 1107, 863, 720, 567, 530, 428 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C24H22FNO3P: 422.1316, found: 422.1320. 3005, 2962, 2846, 1736, 1597, 1501, 1257, 1167, 1120, 827, 801, 704, 548, 450 cm -1 . [M+H] + calcd for C25H27FO5P: 457.1575, found: 457.1573.

HRMS (ES+) m/z:

Methyl 3-(di-p-tolylphosphoryl)-2-(fluoromethyl)-3-phenylpropanoate (10i):

Following the general procedure (XI): 10i was obtained as a mixture of two diastereoisomers, dr = 94:6; white solid, 53% yield (67 mg); M.P. 172 -173 °C.

syn-10i: 1 H NMR (300 MHz, CDCl3): δ 7. 88 -7.82 (m, 2H), 7.38 -7.32 (m, 3H), 7.30 -7.24 (m, 3H), 7.16 -7.12 (m, 3H), 7.01 -6.97 (m, 2H), 4.67 -4.36 (m, 2H), 3.97 -3.72 (m, 2H), 3.42 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H). 3036, 2950, 2920, 1741, 1602, 1456, 1170, 846, 807, 659, 537, 499, 474 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C25H27FO3P: 425.1676, found: 425.1687.

Other Michael addition reactions on fluorinated substrates

Preparation of α-fluorinated enal 12a

To an oven-dried flask equipped with a stir bar and flushed with argon, the dry THF (5 mL) solution of α-fluoroacrylate 1d (2 mmol) was added and cooled down to 0 °C.

The lithium borohydride (6 mmol, 3 equiv) was added into the solution slowly, then the mixture was allowed to warm to room temperature and stir until no detection of 1d by TLC. The resulting mixture was quenched by NH4Cl(aq) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine, and dried over Na2SO4. Then, removed the solvents under the reduced pressure affording a white solid. The resulting solid without further purification was dissolved in dry CH2Cl2 (10 mL) followed by adding the DMP (2372.4 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 24 h then quenched by adding Na2S2O3(aq) and extracted with CH2Cl2 (3×15 mL). The organic layer was dried over anhydrous Na2SO4 then concentrated under reduced pressure and purified by flash silica gel column chromatography (eluent: petroleum ether/EtOAc). 12a was isolated as a white solid in 83% yield (249 mg) and its analytic data were in agreement with those reported in the literature. 173

Preparation of α-fluorinated enone 13a

To an oven-dried flask were added α-fluoroacrylate 1d (2 mmol), LiOH (8 mmol, 4 equiv), THF/H2O (6 mL, v/v = 1/1). The reaction mixture was stirred at room temperature until no detection of 1d by TLC, then adjusting the pH of the reaction mixture to ≤7 by adding 1 M HCl(aq). The mixture was extracted EtOAc (3×15 mL), the organic layers were combined, dried over Na2SO4 and concentrated under the reduced pressure affording a white solid. This white solid without further purification was dissolved in dry Et2O (5 mL). Then, the MeLi (1.6 M in Et2O, 2 equiv) was added dropwise to the reaction mixture over 30 min at 0 °C. The reaction mixture was stirred at room temperature for an additional 2.5 h then quenched by adding 0.1 M HCl(aq) and the resulting mixture was extracted with Et2O (3×15 mL). The organic layer was dried over anhydrous Na2SO4 then concentrated under reduced pressure and purified by flash silica gel column chromatography (eluent: petroleum ether/EtOAc). 13a was isolated as a yellow solid in 39% yield (128 mg) and its analytic data were in agreement with those reported in the literature.

X-ray analysis

X-ray analysis of syn-3k

Crystal preparation: The syn-3k (15 mg) was added into a 2 mL glass vial and dissolved in CHCl3 (0.3 mL), then n-hexane (1 mL) was added slowly into the vial to form two phases. The solvents were evaporated slowly at 3-5 °C and the crystal was then formed.

Crystallographic data: The crystal data of syn-3k are collected in Table 24.

X-ray analysis of (2S, 3S)-3p

Crystal preparation: The (2S, 3S)-3p (22 mg) was added into a 2 mL glass vial and dissolved in CHCl3 (0.5 mL), then n-hexane (1.2 mL) was added slowly into the vial to form two phases. The solvents were evaporated slowly at 3-5 °C and the crystal was then formed.

Crystallographic data: The crystal data of (2S, 3S)-3p are collected in Table 25. Structural description: The asymmetric unit is composed of one molecule of [C17H24FNO2S] (Figure 30). The stereogenic centers C7 and C14 are both in S absolute configuration. Molecules establish hydrogen bonds (Table 26, Figure 31) that generate molecular chains spreading along a axis. The cohesion between these molecular chains is ensured by vdW interactions. (Figure 32, Figure 33).

X-ray analysis of anti-8j

Crystal preparation: The anti-8j (14 mg) was added into a 2 mL glass vial and dissolved in CH2Cl2 (0.5 mL). The solvent was evaporated slowly at 3-5 °C and the crystal was then formed.

Crystallographic data: The crystal data of anti-8j are collected in Table 27.

X-ray analysis of syn-10a

Crystal preparation: The syn-10a (17 mg) was added into a 2 mL glass vial and dissolved in CH2Cl2 (0.5 mL). The solvent was allowed to evaporate at room temperature and the crystal was then formed.

Crystallographic data: The crystal data of syn-10a are collected in Table 28. Structural description: The asymmetric unit is composed of one molecule of C23H21FO3P (Figure 36, Figure 37). The compound crystallized in a centrosymmetric space group so that both enantiomers are present. Crystallographic data: The crystal data of (1Z, 3E)-byproduct C are collected in Table 29.

Table 29 Crystal data of (1Z, 3E)-byproduct C

Chemical Formula C10H8FNO2

Molecular Weight / g.mol -1 193.17

  pharmaceutique ou encore l'agrochimie. Parmi les modes d'obtention de ces molécules fluorées, la Réaction d'Addition de Michael (RAM) a été très peu utilisée alors qu'elle apparait comme une stratégie très intéressante pour accéder à de nouveaux motifs fluorés d'intérêt. En effet, la RAM est connue depuis longtemps comme une voie d'accès dia-et énantio-sélective à de multiples composés polyfoinctionnalisés. Néanmoins, cette réaction a été très peu appliquée aux accepteurs de Michael fluorés (voir chapitre 1 bibliographique). Dans cette thèse, nous avons donc développé de nouvelles methodologies de synthèse pour construire de manière diastéréosélective (voire énantiosélective) des produits fluorés originaux par réaction d'addition de Michael organocatalysée. Différents nucléophiles ont été utilisés en addition conjuguée sur des dérivés carbonylés α-fluorés α,β-insaturés et plus particulièrement sur les acrylates α-fluorés. Dans la première partie de cette thèse (chapitre 2), nous avons développé une réaction d'addition de Michael de thiophenols (sulfa-Michael addition) surdes acrylates fluorés polysubstitués dans des versions racémiques et énantiosélectives. De plus, deux analogues fluorés du Diltiazem et du Tiazesim, des biomolécules d'intérêt pharmaceutique, ont été synthétisés avec succès. Dans la deuxième partie de cette thèse (chapitre 3), nous avons pour la première fois mis au point une addition de Michael hautement diastéréosélective d'oxyde de phosphine (phospha-Michael addition) sur des trifluorométhylacrylates polyfonctionnalisés; cette méthode a également été appliquée à des fluorométhylacrylates polyfonctionnalisés. Dans la dernière partie de cette thèse (chapitre 4), nous présentons d'autres réactions d'addition de Michael que nous avons étudié avec nos accepteurs fluorés incluant des esters, cétones et aldéhydes α-fluorés, α,β-insaturés.

3 .

 3 Phospha-Michael addition (PMA) on α-trifluoromethyl-α,β-unsaturated esters ... 3.1 Phospha-Michael addition reaction on non-fluorinated α,β-unsaturated carbonyl esters ..................................................................................................... 3.1.1 Trivalent phosphorus-nucleophiles .................................................... 3.1.2 Pentavalent phosphorus-nucleophiles ............................................. 3.1.3 PMA reaction on fluorinated Michael acceptors: State of the art ... 3.2 Objectives ..................................................................................................... 3.3 Optimization of the reaction conditions ...................................................... 3.3.1 Preliminary results ............................................................................ 3.3.2 Screening of the base and the equivalents of Ph2P(O)H .................. 3.3.3 Screening of the solvents and the DABCO loading ........................... 3.3.4 Enlarge the scope of fluorinated Michael acceptors ........................ 3.5 Substrate scope of the reaction ................................................................... 3.5.1 with α-trifluoromethylacrylates........................................................ 3.5.2 with α-fluoromethylacrylates ........................................................... 3.6 Proposed reaction mechanism .................................................................... 3.7 Conclusion .................................................................................................... 4. Other Michael addition reactions on fluorinated substrates ................................ 4.1 Michael addition reaction of different nucleophiles to α-fluorinated acrylates. ............................................................................................................ 4.1.1 α-Fluoroacrylates .............................................................................. 127 4.1.2 α-Trifluoromethylacrylates ............................................................... 129 4.2 Michael addition reaction of different nucleophiles to α-fluorinated enal and enone ................................................................................................................. 133 4.3 Conclusions .................................................................................................. 135 5 Conclusion and perspectives .................................................................................. 139 5.1 Conclusion .................................................................................................... 139 5.2 Perspectives ................................................................................................. 140 Experimental Section ................................................................................................. 145 General Information .......................................................................................... 145 Materials ............................................................................................................ 145 1 Sulfa-Michael addition (SMA) of thiophenols to α-fluoro-α,β-unsaturated esters .................................................................................................................. 146 1.1 Preparation of α-fluoro-α,β-unsaturated esters ................................. 146 1.2 General procedure for the Sulfa-Michael addition (SMA) of thiophenols to α-fluoro-α,β-unsaturated esters ........................................................... 147 1.3 Synthesis of bioactive molecules ......................................................... 172 1.4 The HPLC chromatograms.................................................................... 176 2 Phospha-Michael addition (PMA) on α-trifluoromethyl-α,β-unsaturated esters ............................................................................................................................ 207 2.1 Preparation of α-trifluoromethyl-α,β-unsaturated esters and αfluoromethyl-α,β-unsaturated esters ........................................................ 207 2.2 General procedure for the Phospha-Michael addition (PMA) on αtrifluoromethyl-α,β-unsaturated esters .................................................... 218 3. Other Michael addition reactions on fluorinated substrates ........................ 237 3.1 Preparation of α-fluorinated enal 12a ................................................. 237 3.2 Preparation of α-fluorinated enone 13a ............................................. 238 3.3 Byproduct C .......................................................................................... 238 Chapter 1

  , a). Besides, the lone pairs of fluorine could serve as a weak hydrogen bond acceptor. Additionally, due to the strong electron-withdrawing effect of fluorine, the fluorinated substituent remarkably enhances the acidity of vicinal acidic moieties in organic molecules (Figure 1, b).

Figure 1

 1 Figure 1 Electronic effects of fluorine

Figure 3

 3 Figure 3The molecular structure of PTFE and ETFE

Figure 4

 4 Figure 4 Structure of some fluorinated pharmaceutical agents

Figure 5

 5 Figure 5 Structure of some fluorinated agrochemicals

Figure 6

 6 Figure 6 Strategies to access fluorinated compounds

Figure 7 Figure 8 .

 78 Figure 7 Selected examples of conjugated fluorinated compounds

Figure 8 1 . 4 . 1 . 1 F

 81411 Figure 8The electrophilic character transfer of α,β-unsaturated carbonyls

Scheme 4

 4 Scheme 4 Addition of Me2CuLi to α-fluoro-α,β-unsaturated Michael acceptorsIn 1981, Elkik and co-workers described the reaction between the 2-fluorohex-1-en-3-one and the 2-methylcyclohexane-1,3-dione. The new fluorinated cyclic product was formed by the Michael addition and a subsequent aldol reaction, but there was no characterization offered for this product (Scheme 5).27

Scheme 6 Scheme 7

 67 Scheme 6 The addition of thiophenols to 2-fluoro-3-methoxyacrylate More recently, Haufe and co-workers investigated the Michael addition of various nucleophiles (carbon, nitrogen, sulfur, and oxygen) to α-fluoro-α,β-unsaturated ketones and observed their behavior in the formation of C-C and C-heteroatom bonds (Scheme 7). 29 In the constructions of C-C, C-N, and C-S bond, all the selected fluorinated ketones were successfully converted into the desired β-substituted-αfluoro ketones which could be separated in moderate to good yields. The formation of C-O bond was possible with MeOH or EtOH. The use of other bulky alcohols or starting from fluorinated ketones with Cy or Ph substituent, led to complex inseparable product mixtures.

Scheme 10

 10 Scheme 10The addition of nitroalkanes to ethyl (E)-4,4-difluorobut-2-enoate

Scheme 11

 11 Scheme 11 Biocatalytic Michael addition to α-CF3-acrylic acid and α-/β-CF3-acrylatesSince 1984, the Michael addition reactions of lithium enolates as a tool for the diastereoselective construction of a new C-C bond came into chemists' view.34

43 Scheme 19

 4319 Scheme 19The addition of benzylamine and Boc-protected carbazate to (E)-β-CF3-acrylate

45 Scheme 21 Scheme 22 47 Scheme 23

 4521224723 Scheme 21The addition of thiols to (Z)-ethyl4,4,4-trifluorocrotonate The trifluoromethyl acrylic acid derivatives are easily accessible and have been used in Michael addition as presented in this section. Nevertheless, we can point out that most of the reactions have been done on unsubstituted α-or β-trifluoromethyl acrylates whereas two adjacent stereogenic centers could be obtained directly from α,β-disubstituted trifluoromethyl acrylate. Moreover, most of the reactions led to the formation of C-C bond, with few examples of C-N or C-S bond formation. To our knowledge, there is no example of C-P bond formation with this kind of substrates so far. During my Ph.D., we developed a phospha-Michael addition on trifluoromethyl acrylic acid derivatives, and the results will be presented in Chapter 3 (Scheme 22).Hereafter, we will continue to describe the different MAR with other CF3-containing Michael acceptors.

64 Scheme 31 Figure 10

 643110 Scheme 31The addition of α-amino ester to α-CF3-acrylamides

Figure 11

 11 Figure 11 Structure of (MMP) inhibitor

Scheme 45

 45 Scheme45 The addition of C-nucleophiles to (E)-3-RF-1-nitropropenesIn 2014, a highly enantioselective Michael addition of oxindole derivatives to fluorinated nitroalkenes has been described by Wang and co-workers.86 A series of biologically important chiral oxindoles, bearing a CF3 group at the newly formed quaternary chiral center, were obtained in good yields with excellent enantioselectivities (Scheme 46, Eq. a). The same year, Shi and co-workers described a similar Michael addition between 3-substituted oxindoles and trifluoromethylated nitroolefins catalyzed by a quinine-derived squaramide. The corresponding adducts beared a trifluoromethylated chiral carbon center and an adjacent quaternary stereocenter at the C3 position of the oxindoles (Scheme 46, Eq. b).87

Scheme 50 95 Scheme 51

 509551 Scheme 50The addition of enolates to fluorinated sulfone derivatives Furthermore, in 2013, Wang and co-workers reported the first asymmetric sulfa-Michael addition of thiols to trans-3,3,3-trifluoropropenyl phenyl sulfone. This

Furthermore 98 Scheme 54

 9854 Scheme 54 The addition of different nucleophiles to trifluoromethyl vinyl sulfoxideThe carbocycles bearing a trifluoromethyl sulfone are also constituted potentially valuable building blocks for further syntheses. In 1999, Billard and co-workers reported a Michael addition of n-hexylamine to a pentacyclic trifluoromethyl vinylsulfone, which occurred in a completely diastereoselective fashion and affording

organocatalyticScheme 56

 56 Scheme 56 General objectivesIn the following second chapter, we will describe the sulfa-Michael addition to polysubstituted α-fluoroacrylates. The latter is easily accessible and only very few Michael addition has been developed with it. In the third chapter, we will present the first phospha-Michael addition on α-trifluoromethylacrylates. Finally, our last chapter will present the various reactions attempted to enlarge the scope of Michael addition reactions with our α-fluorinated Michael acceptors.

Figure 13 2 . 1 . 1

 13211 Figure 13 Biologically active compounds containing a sulfur atom and a fluorine atom at two

  Scheme 61 SMA catalyzed by the proline-based catalyst Later on, they developed a tandem sulfa-Michael/aldol reaction leading to tetrahydrothiophenes with the same proline-based catalyst. 109 The reaction of various α,β-unsaturated aldehydes with 2-thioacetophenone was found to give the tetrahydrothiophenes in moderate to good yields and excellent enantioselectivities. This reaction can be considered as a two-step process: Firstly, the iminium ion A was formed between the proline-based catalyst and the α,β-unsaturated aldehyde, the SMA reaction of thiol to the iminium A generated sulfa-Michael adduct B which underwent an intramolecular aldol reaction to form the intermediate C, then hydrolysis of C providing the desired tetrahydrothiophene D (Scheme 62).

Scheme 66

 66 Scheme 66 SMA catalyzed by BIMP catalyst

Figure 14 X

 14 Figure 14 X-ray of major diastereoisomer of 3k

a

  Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a (1.5 mmol, 5 equiv), (DHQ)2PYR (0.03 mmol, 10 mol%), solvent (0.5 mL), room temperature, 3 days, under argon. b Determined by the 19 F NMR of the reaction mixture. c Determined by the 19 F NMR of the reaction crude. d Determined for the major diastereoisomer by HPLC.

Figure 15 X

 15 Figure 15 X-ray of the major enantiomer of 3p

Figure 16 XFigure 17

 1617 Figure 16 X-ray of (DHQ)2PYR

a

  stepwise mechanism with the thiol addition in favor of the Si-face attack of βposition and a concurrent protonation on the Re-face of the α-position (Scheme 70).

124

  Scheme 72 SMA of aryl thiols to β-substituted-α-fluoroacrylatesIn our quest for the development of new Michael addition with fluorinated acrylates, we will present in the next chapter the phospha-Michael addition with these substrates.

Scheme 73

 73 Scheme 73 Triphenylphosphine m-trisulfonate (TPPTS) as the nucleophileIn 1996, Boyd and co-workers described the synthesis of phenylphosphinic acid derivatives by Michael-type addition between bis(trimethylsilyl)phenylphosphonite and several electrophiles.127 In the case of α,β-unsaturated carbonyl esters, good to excellent yields of the corresponding products were obtained. Substitution of the double bond slightly lowered the yield probably because of the steric and electronic effects (Scheme 74).

  Scheme 77 Diarylphosphine as the nucleophile

Scheme 79

 79 Scheme 79 Diphenyl phosphite as the nucleophileCyclic phosphites were also used as nucleophiles in PMA reactions. In 2001, a chiral cyclic phosphite was used in PMA reaction to synthesize β-phosphono malonates.140 The 1,4-adducts were obtained in moderate to good yields and good diastereoselectivities by using Fe2O3 supported KOH as a solid base, which led to optically active β-phosphono malonates after easy cleavage of the chiral auxiliary (Scheme 80, Eq. a). Ionic liquids are often considered as green chemistry solvents both in laboratory research and industrial practice.141 In 2009, a PMA reaction of cyclic phosphite to Morita-Baylis-Hillman type substrates was described by Kumara

Figure 18

 18 Figure 18 The pz orbital coefficient of LUMO However, in the examples of trifluoromethylated Michael acceptors introduced in chapter 1, we can point out that a very few examples led to the C-P formation even including other fluorinated Michael acceptors. In 2000, Röschenthaler and coworkers described a protocol for the synthesis of γ-ketophosphonate. 48 A [4+1] cycloaddition reaction between (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one and trimethyl phosphite, where the initial attack of phosphorus occurred at the βposition of the enone followed by ring closure, produced 1,2λ 5 -oxaphospholene as a sole product which upon hydrolysis furnished γ-ketophosphonate (Scheme 83, Eq. a).

a

  Reaction conditions: 9 (0.3 mmol, 1.0 equiv), 7 (0.45 mmol, 1.5 equiv), DABCO (0.06 mmol, 20 mol%), 40 °C, 72 h, in MeCN (0.5 mL). b Isolated yield of 10 as a mixture of two diastereoisomers. c Determined by the 19 F NMR of the reaction crude. d Reaction was performed on 1.0 mmol scale. e NR = No Reaction. f Reaction was performed under 50 °C for 5 days.

Scheme 85 Figure 20 X 3 . 6 Scheme 86

 85203686 Scheme 85The formation of byproducts 10d' and 10d''

4 . 4 . 1

 441 Other Michael addition reactions on fluorinated substrates In our previous work, we demonstrated a SMA reaction of arylthiols to αfluoroacrylates and a PMA reaction of diarylphosphine oxides to αtrifluoromethylacrylates and α-fluoromethylacrylates respectively. These results proved that Michael addition reactions with such substrates were feasible and constituted a nice access to more complex fluorine-containing compounds. Therefore, we used our α-fluorinated acrylates in hand as well as some newly synthesized α-fluorinated α,β-unsaturated carbonyl compounds, to explore more possibilities of those substrates as Michael acceptors. Some nucleophiles besides thiols and diarylphosphine oxides, which were commonly used in Michael addition reaction on non-fluorinated analogues, have been tested, including nitromethane, 153 diethyl malonate, 154 lithium dimethylcuprate, 155 and phenylboronic acid. 156 Michael addition reaction of different nucleophiles to αfluorinated acrylates.

a

  Reaction condition: 12a (0.3 mmol, 1 equiv), nucleophile (0.6 mmol, 2 equiv), catalyst (0.03 mmol, 10 mol%), PhCO2H (0.03 mol, 10 mol%), toluene or MeOH (0.5 mL), 0 °C or rt, under argon. b Conversion were obtained by using PhF as an internal standard.

Figure 21

 21 Figure 21 Structure of byproduct C

  In my Ph.D. thesis, we mainly explored the possibilities of α-fluorinated substrates used as Michael acceptors.Firstly, we developed a simple and efficient sulfa-Michael addition on β-substitutedα-fluoroacrylates in both non-enantioselective and enantioselective versions. A common Et3N and a commercially available chiral catalyst (DHQ)2PYR were used.

  ( 1 H), 75 MHz ( 13 C), 282 MHz ( 19 F) and 121 MHz ( 31 P). The chemical shifts (δ) of 1 H and 13 C were calibrated on residual proton and carbon resonances of CDCl3 ( 1 H, δ = 7.26 ppm and 13 C, δ = 77.2 ppm) or CD3OD ( 1 H, δ = 3.31 ppm and 13 C, δ = 49.00 ppm) or (CD3)2SO ( 1 H, δ = 2.50 ppm and 13 C, δ = 39.52 ppm). The 19 F chemical shifts (δ) were determined relative to external CFCl3 ( 19 F, δ = 0.0 ppm). The multiplicity signals were indicated with the common abbreviations: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet) and br (broad) and the combinations of them. Melting points (M.P.) were determined on a Fisher Scientific hot stage melting point apparatus and are uncorrected. High Resolution Mass Spectra (HRMS) were recorded on a JEOL AccuTof 4G spectrometer coupled to a GC HP Agilent 7890 in chemical ionization mode (CI). Enantiomeric excesses (ee) were determined by using a SpectraSYSTEM TM HPLC equipped with a P1000XR pump, a UV1000 detector and a Rheodyne injector. See specific conditions detailed for each compound.

Scheme 96 1 . 2

 9612 Scheme 96 Synthesis of aryl α-fluoro-α,β-unsaturated esters

  (m, 8H), 4.97 (dd, JH-F = 48.0 Hz, JH-H = 3.0 Hz, 1H), 4.13 -3.89 (m, 2H), 3.49 -3.33 (m, 1H), 2.92 -2.68 (m, 2H), 2.09 -1.91 (m, 2H), 1.12 (t, JH-H = 9.0 Hz, 3H). 19 F NMR (282 MHz, CDCl3): δ -197.0 (dd, JF-H = 48.0 Hz, JF-H = 28.2 Hz). 13 C{ 1 H} NMR (

[

  determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 5.340 min, t (major) = 5.803 min.]. 1 H NMR (300 MHz, CDCl3): δ 7.40 -7.37 (m, 2H), 7.25 -7.09 (m, 8H), 4.80 (dd, JH-F = 48.0 Hz, JH-H = 6.0 Hz, 1H), 4.07 (q, JH-H = 6.0 Hz, 2H), 3.42 -3.31 (m, 1H), 2.94 -2.70 (m, 2H), 1.94 -1.87 (m, 2H), 1.13 (t, JH-H = 9.0 Hz, 3H). 19 F NMR (282 MHz, CDCl3): δ -195.7 (dd, JF-H = 48.0 Hz, JF-H = 22.6 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 168.1 (d, JC-F = 22.5 Hz), 140.

  F NMR of the reaction crude showed dr = 90:10. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 95% yield (major: 89 mg as a yellow oil; major and minor mixture: 11 mg). 84% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 230 nm, t (minor) = 11.380 min, t (major) = 15.850 min.]. [α]D 20 = +13.4 (c 1.08, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.30 -7.02 (m, 7H), 6.63 -6.56 (m, 2H), 4.92 (d, JH-F = 48.0 Hz, 1H), 4.32 (s, 2H), 4.10 -3.95 (m, 2H), 3.36 (d, J = 27 Hz, 1H), 2.85 -2.75 (m, 2H), 2.07 -1.91 (m, 2H), 1.15 (t, JH-H = 6.0 Hz, 3H). 19 F NMR (282 MHz, CDCl3): δ -196.0 (dd, JF-H = 48.0 Hz, JF-H = 25.4 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 168.1 (d, JC-F = 22.5 Hz), 149.

  = +29.4 (c 0.68, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.24 -7.06 (m, 9H), 4.98 (d, JH-F = 48.0 Hz, 1H), 4.08 -3.83 (m, 2H), 3.57 -3.45 (m, 1H), 2.84 -2.75 (m, 2H), 2.34 (s, 3H), 2.15 -1.97 (m, 2H), 1.10 (t, JH-H = 9.0 Hz, 3H). 19 F NMR (282 MHz, CDCl3): δ -196.5 (dd, JF-H = 48.0 Hz, JF-H = 28.2 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 167.8 (d, JC-F = 22.5 Hz), 140.

  , JH-F = 48.0 Hz, JH-H 3.0 Hz, 1H), 4.12 -3.93 (m, 2H), 3.47 -3.34 (m, 1H), 2.91 -2.69 (m, 2H), 2.23 (s, 3H), 2.06 -1.89 (m, 2H), 1.13 (t, JH-H = 9.0 Hz, 3H). 19 F NMR (282 MHz, CDCl3): δ -196.8 (dd, JF-H = 48.0 Hz, JF-H = 28.2 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 168.0 (d, JC-F = 22.5 Hz), 140.

F

  NMR of the reaction crude showed dr = 85:15. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 82% yield (major: 77 mg as a colorless oil; minor: 8 mg as a colorless oil). 54% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow =1 mL/min, λ = 254 nm, t (minor) = 7.347 min, t (major) = 8.143 min.]. [α]D 20 = -14.0 (c 0.84, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.28 -7.00 (m, 9H), 4.94 (d, JH-F = 48.0 Hz, 1H), 4.13 -3.97 (m, 2H), 3.40 -3.25 (m, 1H), 2.92 -2.68 (m, 2H), 2.24 (s, 3H), 2.03 -1.91 (m, 2H), 1.15 (t, JH-H = 6.0 Hz, 3H). 19 F NMR (282 MHz, CDCl3): δ -196.8 (dd, JF-H = 48.0 Hz, JF-H = 28.2 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 168.0 (d, JC-F = 22.5 Hz), 140.

6 .

 6 183 min, t (major) = 7.050 min.].[α]D CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.33 -7.31 (m, 1H), 7.24 - 7.10 (m, 6H), 6.92 -6.89 (m, 1H), 4.91 (dd, JH-F = 48.0 Hz, JH-H = 6.0 Hz, 1H), 4.20 -4.08 (m, 2H), 3.21 -3.14 (m, 1H), 2.95 -2.73 (m, 2H), 1.99 -1.91 (m, 2H), 1.21 (t, JH-H = 6.0 Hz, 3H). 19 F NMR (282 MHz, CDCl3): δ -196.5 (dd, JF-H = 48.0 Hz, JF-H = 25.4 Hz).

Ethyl 2 -

 2 fluoro-3-(naphthalen-2-ylthio)-5-(4-nitrophenyl)pentanoate (3k):

F

  NMR of the reaction crude showed dr = 84:16. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 10/1 to 8/1, v/v) affording two diastereoisomers in 55% yield (major: 47 mg as a yellow solid; major and minor mixture: 23 mg). 8% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 35.240 min, t (major) = 45.267 min.]. [α]D 20 = -2.2 (c 0.68, CDCl3); M.P. 86 -88 °C; 1 H NMR (300 MHz, CDCl3): δ 8.00 (d, JH-H = 9.0 Hz, 2H), 7.84 (s, 1H), 7.76 -7.65 (m, 3H), 7.45 -7.40 (m, 3H), 7.20 -7.18 (m, 2H), 5.02 (dd, JH-F = 48.0 Hz, JH-H = 3.0 Hz, 1H), 4.16 -3.93 (m, 2H), 3.59 -3.44 (m, 1H), 3.07 -2.82 (m, 2H), 2.19 -1.97 (m, 2H), 1.13 (t, JH-H = 6.0 Hz, 3H). 19 F NMR (282 MHz, CDCl3): δ -196.0 (dd, JF-H = 48.0 Hz, JF-H = 28.2 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 167.7 (d, JC-F = 30.0 Hz), 148.

[

  determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 6.607 min, t (major) = 7.450 min.]. [α]D 20 = -5.6 (c 0.32, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.39 -7.36 (m, 2H), 7.22 -7.13 (m, 3H), 5.20 (dd, JH-F = 48.0 Hz, JH-H = 3.0 Hz, 1H), 4.10 -3.81 (m, 2H), 3.34 -3.19 (m, 1H), 2.14 (d, JH-H = 15.0 Hz, 1H), 1.84 -1.53 (m, 5H), 1.21 -1.13 (m, 5H), 1.07 (t, JH-H = 6.0 Hz, 3H). 19 F NMR (282 MHz, CDCl3): δ -197.9 (dd, JF-H = 48.0 Hz, JF-H = 36.7 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 168.6 (d, JC-F = 30.0 Hz), 135.

  + ) m/z:[M+H] + calcd for C17H24FO2S: 311.1481, found: 311.1491.

F

  NMR of the reaction crude showed dr = 91:9. The crude was purified by silica gel column chromatography (petroleum ether/CH2Cl2, from 5/1 to 2/1, v/v) affording two diastereoisomers in 22% yield (major: 16 mg as a yellow solid, major and minor mixture: 4 mg). 51% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 11.947 min, t (major) = 14.737 min.]. [α]D 20 = +111.2 (c 1.02, CDCl3); M.P. 77 -79 °C; 1 H NMR (300 MHz, CDCl3): δ 7.24 -7.21 (m, 5H), 7.10 -7.00 (m, 2H), 6.62 -6.47 (m, 2H), 5.13 (dd, JH-F = 48.0, JH-H = 3.0 Hz, 1H), 4.48 (dd, JH-F = 28.0 Hz, JH-H = 3.0 Hz, 1H), 4.23 (s, 2H), 3.56 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -194.2 (dd, JF-H = 48.0 Hz, JF-H = 28.0 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 168.1 (d, JC-F = 30.0 Hz), 149.

  F NMR of the reaction crude showed dr = 87:13. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 72% yield (major: 50 mg as a colorless oil, major and minor mixture: 16 mg). 62% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 6.750 min, t (major) = 7.183 min.].[α]D20 = +113.0 (c 0.70, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.31 -7.20 (m, 5H), 7.07 -6.94 (m, 4H), 5.15 (dd, JH-F = 48.0 Hz, JH-H = 3.0 Hz, 1H), 4.59 (dd, JH-F = 28.0 Hz, JH-H = 3.0 Hz, 1H), 3.60 (s, 3H), 2.18 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -194.1 (dd, JF-H = 48.0 Hz, JF-H = 28.0 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 168.0 (d, JC-F = 22.5 Hz),

  -7.13 (m, 4H), 7.05 -7.03 (m, 2H), 5.12 (dd, JH-F = 48.0 Hz, JH-H = 6.0 Hz, 1H), 4.57 (dd, JH-F = 28.0 Hz, JH-H = 6.0 Hz, 1H), 3.60 (s, 3H), 2.24 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -194.0 (dd, JF-H = 48.0 Hz, JF-H = 28.0 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 168.0 (d, JC-F = 22.5 Hz), 138.

  [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 12.513 min, t (major) = 13.350 min.]. [α]D 20 = +3.0 (c 1.03, CDCl3); M.P. 71 -72 °C; 1 H NMR (300 MHz, CDCl3): δ 7.74 -7.71 (m, 1H), 7.56 -7.51 (m, 2H), 7.35 -7.29 (m, 3H), 7.20 -7.18 (m, 3H), 5.20 (dd, JH-F = 48.0 Hz, JH-H = 3.0 Hz, 1H), 5.12 (dd, JH-F = 28.0 Hz, JH-H = 3.0 Hz, 1H), 3.64 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -195.8 (dd, JF-H = 48.0 Hz, JF-H = 28.0 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 167.0 (d, JC-F = 22.5 Hz), 141.

[α]D 20 =

 20 +85.8 (c 1.15, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.56 -7.48 (m, 3H), 7.37 - 7.32 (m, 1H), 7.23 -7.16 (m, 5H), 5.16 (dd, JH-F = 48.0 Hz, JH-H = 3.0 Hz, 1H), 4.60 (dd, JH-F = 28.0 Hz, JH-H = 3.0 Hz, 1H), 3.69 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -195.4 (dd, JF-H = 48.0 Hz, JF-H = 28.0 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 167.5 (d, JC-F = 22.5 Hz), 139.

[

  determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 21.380 min, t (major) = 23.313 min.]. [α]D 20 = +168.8 (c 0.32, CDCl3); M.P. 79 -80 °C; 1 H NMR (300 MHz, CDCl3): δ 7.54 -

  ,3S)-3c(0.35 mmol, 106.8 mg) with p-TsOH (0.07 mmol, 6.9 mg) were added into xylene (2 mL) and the resulting mixture was heated to reflux overnight. After completion of the reaction, the solvent was removed in vacuo and the crude mixture was purified by column chromatography (petroleum ether/EtOAc, from5/1 to 4/1, v/v) to give the desired product 4a in 85% yield (81 mg, white solid) with 51% ee [determined by HPLC, AD-H column, Hept/ i PrOH: 80/20, flow = 1 mL/min, λ = 254 nm, t (minor) = 10.467 min, t (major) = 14.543 min.].[α]D23 = +126.1 (c 0.80, CDCl3); M.P. 161 -163 °C; 1 H NMR (300 MHz, CDCl3): δ 9.39 (s, 1H), 7.74(d, JH-H = 6.0 Hz, 1H), 7.59 -7.58 (m, 2H), 7.45 -7.35 (m, 4H), 7.27 -7.21 (m, 2H), 5.36 -5.18 (m, 2H). 19 F NMR (282 MHz, CDCl3): δ -190.5 (dd, JF-H = 47.9 Hz, JF-H = 8.5 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 169.6 (d, JC-F = 22.5 Hz), 140.

  ,3S)-3y (0.2 mmol, 67.0 mg) with p-TsOH (0.04 mmol, 3.9 mg) were added into xylene (1.2 mL) and the resulting mixture was heated to reflux overnight. After completion of the reaction, the solvent was removed in vacuo and the crude mixture was purified by column chromatography (petroleum ether/EtOAc, from 5/1 to 3/1, v/v) to give the desired product 4b in 76% yield (46 mg, white solid) with 73% ee [determined by HPLC, AD-H column, Hept/ i PrOH: 80/20, flow = 1 mL/min, λ = 254 nm, t (minor) = 13.940 min, t (major) = 21.507 min.]. [α]D 23 = +122.2 (c 0.54, CDCl3); M.P. 165 -166 °C; 1 H NMR (300 MHz, CDCl3): δ 9.00 (s, 1H), 7.63 (d, JH-H = 9.0 Hz, 1H), 7.41 -7.30 (m, 3H), 7.18 -7.11 (m, 2H), 6.81 -6.75 (m, 2H), 5.22 -5.04 (m, 2H), 3.71 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -190.4 (ddd, JF-H = 47.9 Hz, JF-H = 8.5 Hz, JF-H = 2.8 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 169.3 (d, JC-F = 22.5 Hz), 160.

C16H15FNO2S

13 C{ 1

 1 H} NMR (75 MHz, CD3OD): δ 166.7 (d, JC-F = 1.5 Hz), 161.4, 149.6 (d, JC-F = 2.3 Hz), 133.7 (q, JC-F = 2.3 Hz), 125.8, 124.0 (q, JC-F = 271.5 Hz), 120.0 (q, JC-F = 31.5 Hz), 116.3.

2. 2

 2 General procedure for the Phospha-Michael addition (PMA) on α-trifluoromethyl-α,β-unsaturated esters General procedure (X): To an oven-dried tube were added α-trifluoromethylacrylate 6 (0.3 mmol, 1 equiv), diarylphosphine oxide 7(0.45 mmol, 1.5 equiv), DABCO (0.06 mmol, 20 mol%), and MeCN (0.5 mL). The tube was then sealed. The reaction mixture was stirred at room temperature for 16 h. After removing solvents under reduced pressure, the residue was purified by silica gel column chromatography (eluent: petroleum ether/EtOAc) to give the desired 8.General procedure (XI):To an oven-dried tube were added α-fluoromethylacrylate 9 (0.3 mmol, 1 equiv), diarylphosphine oxide 7 (0.45 mmol, 1.5 equiv), DABCO (0.06 mmol, 20 mol%), and MeCN (0.5 mL). The tube was then sealed. The reaction mixture was stirred at 40 °C for 72 h and was then cooled down to room temperature. After removing solvents under reduced pressure, the residue was purified by silica gel column chromatography (eluent: petroleum ether/EtOAc) to give the desired 10.Methyl 2-((diphenylphosphoryl)methyl)-3,3,3-trifluoropropanoate (8a):Following the general procedure (X): 8a was obtained as a white solid, 74% yield (79mg); M.P. 91 -92 °C. 1 H NMR (300 MHz, CDCl3): δ 7.78 -7.69 (m, 4H), 7.55 -7.43 (m, 6H), 3.68 -3.58 (m, 1H), 3.44 (s, 3H), 3.09 -2.97 (m, 1H), 2.64 -2.54 (m, 1H). 19 F NMR (282 MHz, CDCl3): δ -69.7 (d, JF-H = 8.5 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 166.7, 132.5 (d, JC-P = 2.3 Hz), 132.4 (d, JC-P = 3.0 Hz), 131.8 (d, JC-P = 102.8 Hz), 131.3 (d, JC-P = 101.3 Hz), 131.1 (d, JC-P = 9.8 Hz), 130.7 (d, JC-P = 9.0 Hz), 129.1 (d, JC-P = 12.0 Hz), 128.8 (d, JC-P = 12.0 Hz), 124.5 (qd, JC-F = 279.0 Hz, JC-P = 16.5 Hz), 53.0, 44.2(q, JC-F = 29.3 Hz), 26.6 (d, JC-P = 70.5 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 27.9 (s). IR: 3059,

  13 C{ 1 H} NMR (75 MHz, (CD3)2SO): δ 165.9 (d, JC-F = 1.9 Hz), 156.5 (d, JC-P = 2.1 Hz), 132.5 (d, JC-P = 100.5 Hz), 132.3 (d, JC-P = 90.0 Hz), 131.8 (d, JC-P = 2.3 Hz), 131.4 (d, JC-P = 9.0 Hz), 131.0 (d, JC-P = 3.0 Hz), 130.5 (d, JC-P = 9.0 Hz), 128.3 (d, JC-P = 11.3 Hz), 127.9 (d, JC-P = 11.3 Hz), 124.6 (qd, JC-F = 281.3 Hz, JC-P = 18.8 Hz), 122.6 (d, JC-P = 6.0 Hz), 114.8, 52.1, 50.4 (q, JC-F = 25.5 Hz), 41.5 (d, JC-P = 64.5 Hz). 31 P{ 1 H} NMR (121 MHz, (CD3)2SO): δ 28.9 (d, JP-F = 1.4 Hz

  δ -63.2 (d, JF-P = 1.8 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 166.3 (d, JC-F = 1.5 Hz), 138.1 (d, JC-P = 5.3 Hz),132.6 (d, JC-P = 3.0 Hz), 132.0 (d, JC-P = 3.0 Hz), 131.9, 131.8 (d, JC-P = 10.5 Hz), 131.3, 130.6 (d, JC-P = 8.3 Hz) 130.5 (d, JC-P = 103.5 Hz), 130.2 (d, JC-P = 94.5 Hz), 128.7 (d, JC-P = 12.0 Hz), 128.4 (d, JC-P = 12.0 Hz), 124.1 (qd, JC-F = 281.3 Hz, JC-P = 17.3 Hz), 118.5 (d, JC-P = 1.5 Hz), 111.8 (d, JC-P = 2.3 Hz) 52.7, 50.3 (q, JC-F = 26.3 Hz), 44.9 (d, JC-P = 62.3 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 28.6 (s). IR:

  ) m/z:[M+H] + calcd for C24H20F3NO3P: 458.1127, found: 458.1122.

  δ 166.8 (d, JC-F = 1.5 Hz), 162.4 (dd, JC-F = 246.0 Hz, JC-P = 3.0 Hz), 132.4 (d, JC-P = 3.0 Hz), 132.2 (d, JC-F = 6.8 Hz), 131.9 (d, JC-P = 9.0 Hz), 131.7 (d, JC-P = 2.3 Hz), 131.2 (d, JC-P = 102.0 Hz), 130.9 (d, JC-P = 9.0 Hz), 130.9 (d, JC-P = 93.0 Hz), 128.6 (d, JC-P = 12.0 Hz), 128.3 (d, JC-P = 12.0 Hz), 128.0 (d, JC-F = 5.3 Hz), 127.9 (d, JC-F = 6.0 Hz), 124.2 (qd, JC-F = 282.0 Hz, JC-P = 18.0 Hz), 115.4 (dd, JC-F = 21.0 Hz, JC-P = 1.5 Hz), 52.6, 50.7 (q, JC-F = 26.3 Following the general procedure (X): 8n was obtained as a mixture of two diastereoisomers, dr = 74:26; white solid, 55% yield (77 mg); M.P. 119 -122 °C. anti-8n: 1 H NMR (300 MHz, CDCl3): δ 8.02 -8.01 (m, 2H, syn + 2H, anti), 7.74 -7.68 (m, 1H, syn + 1H, anti ), 7.51 -7.39 (m, 5H, syn + 5H, anti), 5.05 (dd, JH-H = 7.2 Hz, JH-P = 11.7 Hz, 1H, anti), 4.94 (dd, JH-H = 6.6 Hz, JH-P = 8.4 Hz, 1H, syn), 4.33 -4.14 (m, 1H, syn+1H, anti), 3.41 (s, 3H, syn), 3.03 (s, 3H, anti). 19 F NMR (282 MHz, CDCl3): δ -63.4 (dd, JF-H = 7.6 Hz, JF-P = 2.1 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 166.0 (d, JC-F = 1.5 Hz), 134.3 (d, JC-P = 7.5 Hz), 131.4 (d, JC-P = 7.5 Hz), 131.4 (d, JC-P = 9.0 Hz), 131.0 (d, JC-P = 3.8 Hz), 130.8 (d, JC-P = 8.3 Hz), 130.6 (d, JC-P = 5.3 Hz), 130.4 (d, JC-P = 9.0 Hz), 129.4 (d, JC-P = 95.3 Hz), 129.3 (d, JC-P = 99.0 Hz), 129.3 (d, JC-P = 1.5 Hz), 128.9 (d, JC-P = 2.3 Hz), 128.4 (d, JC-P = 12.0 Hz), 127.7 (d, JC-P = 12.0 Hz), 126.6 (d, JC-P = 2.3 Hz), 124.1 (qd, JC-F = 281.3 Hz, JC-P = 17.3 Hz), 52.3, 50.6 (q, JC-F = 26.3 Hz), 39.5 (d, JC-P = 63.8 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 30.5 (s). IR:

19 F

 19 NMR (282 MHz, CDCl3): δ -63.2 (dd, JF-H = 7.0 Hz, JF-P = 2.1 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 166.7 (d, JC-F = 2.3 Hz), 132.4 (d, JC-P = 2.3 Hz), 132.2 (d, JC-P = 5.3 Hz), 131.9 (d, JC-P = 9.0 Hz), 131.8 (d, JC-P = 3.0 Hz), 131.5 (d, JC-P = 1.5 Hz), 131.3 (d, JC-P = 5.3 Hz), 130.9 (d, JC-P = 103.5 Hz), 130.9 (d, JC-P = 9.0 Hz), 130.7 (d, JC-P = 93.8 Hz), 128.6 (d, JC-P = 12.0 Hz), 128.3 (d, JC-P = 12.0 Hz), 124.2 (qd, JC-F = 281.3 Hz, JC-P = 17.3 Hz), 122.2 (d, JC-P = 3.0 Hz),52.7, 50.5 (q, JC-F = 26.3 Hz), 44.3 (d, JC-P = 63.8 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 28.9(d, JP-F = 1.9

  Following the general procedure (X): 8p was obtained as a mixture of two diastereoisomers, dr = 90:10; white solid, 94% yield (139 mg); M.P. 181 -182 °C.anti-8p: 1 H NMR (300 MHz, CDCl3): δ 7.99 -7.91 (m, 2H), 7.56 -7.51 (m, 5H), 7.32 - 7.20 (m, 3H), 6.48 (s, 3H), 6.23 -6.21 (m, 1H), 4.29 -4.20 (m, 2H), 3.66 (s, 6H), 3.21 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -63.5 (dd, JF-H = 6.6 Hz, JF-P = 2.1 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 166.6 (d, JC-F = 1.5 Hz), 160.4 (d, JC-P = 2.3 Hz), 134.2 (d, JC-P = 5.3 Hz), 132.1 (d, JC-P = 3.0 Hz), 131.7 (d, JC-P = 9.0 Hz), 131.5 (d, JC-P = 3.0 Hz), 131.2 (d, JC-P = 95.3 Hz), 131.1 (d, JC-P = 101.3 Hz), 131.0 (d, JC-P = 9.0 Hz), 128.5 (d, JC-P = 11.3 Hz), 128.0 (d, JC-P = 12.0 Hz), 124.2 (qd, JC-F = 281.3 Hz, JC-P = 18.0 Hz), 108.6, 100.4 (d, JC-P = 2.3 Hz), 55.3, 52.5, 50.8 (q, JC-F = 26.3 Hz), 45.1 (d, JC-P = 63.8 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 29.4 (d, JP-F = 2.0 Hz). IR:

  Following the general procedure (X): 8q was obtained as a mixture of two diastereoisomers, dr = 94:6; white solid, 83% yield (120 mg); M.P. 246 -247 °C.anti-8q: 1 H NMR (300 MHz, CDCl3): δ 8.00-7.93 (m, 2H), 7.74 -7.66 (m, 3H), 7.62 - 7.59 (m, 1H), 7.54 -7.38 (m, 8H), 4.53 -4.27 (m, 2H), 3.21 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -63.3 (d, JF-H = 4.9 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 166.9 (d, JC-F = 1.5 Hz), 133.0 (d, JC-P = 1.5 Hz), 132.7 (d, JC-P = 1.5 Hz), 132.2 (d, JC-P = 3.0 Hz), 131.9 (d, JC-P = 9.0 Hz), 131.5 (d, JC-P = 3.0 Hz), 131.3 (d, JC-P = 93.0 Hz), 131.1 (d, JC-P = 102.8 Hz), 131.0 (d, JC-P = 9.0 Hz), 130.5 (d, JC-P = 18.8 Hz), 130.3 (d, JC-P = 6.8 Hz), 129.7 (d, JC-P = 6.0 Hz), 128.6 (d, JC-P = 11.3 Hz), 128.0 (d, JC-P = 13.5 Hz), 127.9 (d, JC-P = 3.0 Hz), 127.6 (d, JC-P = 0.8 Hz), 126.3 (d, JC-P = 8.3 Hz), 124.3 (qd, JC-F = 281.3 Hz, JC-P = 18.0 Hz), 52.7, 50.9 (q, JC-F = 27.0 Hz), 45.2 (d, JC-P = 63.8 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 29.3 (d, JP-F = 2.0 Hz). IR:

  Following the general procedure (X): 8r was obtained as a mixture of two diastereoisomers, dr = 96:4; white solid, 75% yield (99 mg); M.P. 244 -245 °C. Following the general procedure (XI): 10a was obtained as a mixture of two diastereoisomers, dr = 95:5; white solid, 64% yield (76 mg); M.P. 177 -178 °C . syn-10a: 1 H NMR (300 MHz, CDCl3): δ 8.02 -7.95 (m, 2H), 7.61 -7.51 (m, 3H), 7.43 -7.36 (m, 2H), 7.28 -7.08 (m, 8H), 4.64 -4.34 (m, 2H), 4.01 -3.96 (m, 1H), 3.86 -3.70 (m, 1H), 3.41 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -219.5 (td, JF-H = 46.4 Hz, JF-H = 18.3 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 171.6 (dd, JC-P = 3.8 Hz, JC-F = 12.8 Hz), 134.4 (d, JC-P = 5.3 Hz), 132.7 (d, JC-P = 93.0 Hz), 132.3 (d, JC-P = 2.3 Hz), 132.0 (d, JC-P = 102.0 Hz), 131.3 (d, JC-P = 3.0 Hz), 131.1 (d, JC-P = 9.0 Hz), 130.9 (d, JC-P = 8.3 Hz), 130.1 (d, JC-P = 6.0 Hz), 129.0 (d, JC-P = 11.3 Hz), 128.4 (d, JC-P = 1.5 Hz), 128.1 (d, JC-P = 12.0 Hz), 127.6 (d, JC-P = 2.3 Hz), 82.2 (dd, JC-P = 3.0 Hz, JC-F = 171.8 Hz), 52.1, 48.5 (d, JC-F = 20.3 Hz), 45.0 (dd, JC-F = 5.3 Hz, JC-P = 66.0 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 29.9 (s). IR:

  Following the general procedure (XI): 10b was obtained as a mixture of two diastereoisomers, dr = 96:4; white solid, 51% yield (65 mg); M.P. 181 -182 °C .

  Following the general procedure (XI): 10d was obtained as a mixture of two diastereoisomers, dr = 97:3; white solid, 29% yield (37 mg); M.P. 169 -170 °C.syn-10d: 1 H NMR (300 MHz, CDCl3): δ 8.05 -7.98 (m, 2H), 7.63 -7.55 (m, 3H), 7.42 - 7.27 (m, 7H), 7.22 -7.16 (m, 2H), 4.58 -4.32 (m, 2H), 4.13 -3.68 (m, 2H), 3.47 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -221.1 (td, JF-H = 46.4 Hz, JF-H = 21.5 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 171.1 (dd, JC-P = 3.8 Hz, JC-F = 12.8 Hz), 140.6 (d, JC-P = 5.3 Hz), 132.7 (d, JC-P = 3.0 Hz), 132.0 (d, JC-P = 1.5 Hz), 131.9 (d, JC-P = 93.8 Hz), 131.8 (d, JC-P = 2.3 Hz), 131.5 (d, JC-P = 102.0 Hz), 130.9 (d, JC-P = 15.8 Hz), 130.8 (d, JC-P = 1.5 Hz), 130.6 (d, JC-P = 9.0 Hz), 129.3 (d, JC-P = 12.0 Hz), 128.4 (d, JC-P = 11.3 Hz), 118.6 (d, JC-P = 0.75 Hz), 111.4 (d, JC-P = 2.3 Hz) 81.7 (dd, JC-P = 3.0 Hz, JC-F = 172.5 Hz), 52.4, 48.1 (d, JC-F = 19.5 Hz), 44.8 (dd, JC-F = 4.5 Hz, JC-P = 64.5 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 29.2 (s). IR:

Methyl 3 -

 3 (bis(4-methoxyphenyl)phosphoryl)-2-(fluoromethyl)-3-phenylpropanoate (10h): Following the general procedure (XI): 10h was obtained as a mixture of two diastereoisomers, dr = 95:5; white solid, 70% yield (96 mg); M.P. 154 -155 °C. syn-10h: 1 H NMR (300 MHz, CDCl3): δ 7.86 -7.80 (m, 2H), 7.29 -7.10 (m, 7H), 7.05 -6.99 (m, 2H), 6.69 -6.64 (m, 2H), 4.68 -4.34 (m, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 3.39 (s, 3H). 19 F NMR (282 MHz, CDCl3): δ -218.9 (td, JF-H = 46.5 Hz, JF-H = 16.8 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 171.8 (dd, JC-P = 3.8 Hz, JC-F = 12.8 Hz), 162.7 (d, JC-P = 3.0 Hz), 161.8 (d, JC-P = 3.0 Hz), 134.7 (d, JC-P = 5.3 Hz), 132.9 (d, JC-P = 9.8 Hz), 132.8 (d, JC-P = 10.5 Hz), 130.1 (d, JC-P = 5.3 Hz), 128.3 (d, JC-P = 1.5 Hz), 127.5 (d, JC-P = 2.3 Hz), 123.7 (d, JC-P = 99.8 Hz), 123.4 (d, JC-P = 108.0 Hz), 114.5 (d, JC-P = 12.0 Hz), 113.6 (d, JC-P = 12.8 Hz), 82.3 (dd, JC-P = 3.0 Hz, JC-F = 171.0 Hz), 55.5, 55.3, 52.0, 48.5 (d, JC-F = 20.3 Hz), 45.6 (dd, JC-F = 5.3 Hz, JC-P = 66.0 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 30.2 (s). IR:

19 F

 19 NMR (282 MHz, CDCl3): δ -219.0 (td, JF-H = 46.4 Hz, JF-H = 16.9 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 171.7 (dd, JC-P = 3.8 Hz, JC-F = 13.5 Hz), 142.7 (d, JC-P = 3.0 Hz), 141.6 (d, JC-P = 3.0 Hz), 135.1 (d, JC-P = 5.3 Hz), 131.0 (d, JC-P = 9.0 Hz), 130.9 (d, JC-P = 9.0 Hz), 130.1 (d, JC-P = 5.3 Hz), 129.7 (d, JC-P = 11.3 Hz), 129.5 (d, JC-P = 96.8 Hz), 128.8 (d, JC-P = 104.3 Hz), 128.8 (d, JC-P = 12.8 Hz), 128.3 (d, JC-P = 2.3 Hz), 127.5 (d, JC-P = 2.3 Hz), 82.3 (dd, JC-P = 3.0 Hz, JC-F = 171.0 Hz), 52.0, 48.5 (d, JC-F = 20.3 Hz), 45.2 (dd, JC-F = 5.3 Hz, JC-P = 66.0 Hz), 21.7 (d, JC-P = 0.8 Hz), 21.5 (d, JC-P = 0.8 Hz). 31 P{ 1 H} NMR (121 MHz, CDCl3): δ 30.3 (s). IR:

  174

  To an oven-dried tube were added (Z)-2-fluoro-3-phenylacrylaldehyde 12a (0.3 mmol, 1 equiv), nitromethane (0.9 mmol, 3 equiv), benzoic acid (0.03 mmol, 10 mol%), (S)-2-(Diphenyl-trimethylsilanyloxy-methyl)-pyrrolidine (Catalyst b) (0.03 mmol, 10 mol%) and methanol (0.5 mL). The tube was sealed and stirred at room temperature for 24 h. After removing solvents under reduced pressure, the residue was purified by silica gel column chromatography (eluent: petroleum ether/EtOAc) to give the byproduct C as a yellow solid in 43% (25 mg). M.P. 139 -140 °C .1 H NMR (300 MHz, CDCl3): δ 7.86 -7.84 (m, 2H), 7.77 -7.53 (m, 5H), 6.45 (d, JH-F = 36.3 Hz, 1H).19 F NMR (282 MHz, CDCl3): δ -117.2 (ddd, JF-H = 36.3, 26.4, 1.5 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 151.6 (d, JC-F = 259.3 Hz), 137.0 (d, JC-F = 2.3 Hz), 131.9 (d, JC-F = 3.9 Hz), 131.3 (d, JC-F = 21.3 Hz), 130.3 (d, JC-F = 8.0 Hz), 130.1 (d, JC-F = 2.6 Hz), 129.0, 122.2 (d, JC-F = 7.7 Hz).

  Structural description: The asymmetric unit is composed of two molecules of C23H22FNO4S (Figure25), labelled Mol A (Figure23) and Mol O (Figure24). These two molecules are the same diastereoisomer. They differ by the relative orientation of the naphthyl moiety. In the packing, two identical molecules (Mol A /Mol A or Mol O/Mol O) establish some π-π interactions that leads to dimers (Figure26). The cohesion between the dimers is ensured by vdW interactions and some long-range π interactions (Figure27, Figure28, and Figure29).

Figure 23 Figure 24 Figure 25 Figure 26

 23242526 Figure 23 Mol A from the asymmetric unit in thermal ellipsoidal representation

Figure 27 Figure 28

 2728 Figure 27 Projection along a

Figure 29

 29 Figure 29 Projection along c

Figure 30

 30 Figure 30 Asymmetric unit in thermal ellipsoidal representation.

Figure 31 Figure 32 Figure 33

 313233 Figure 31 Molecular bond chain, the hydrogen bonds are displayed in dashed pink lines

Figure 34 Figure 35

 3435 Figure 34 Asymmetric unit in thermal ellipsoidal representation

Figure 36 Figure 37

 3637 Figure 36 Asymmetric unit in thermal ellipsoidal representation

F

  (000) / e - 200 Absorption coefficient µ (MoK1) / mm -1 0.110 Structural description: The asymmetric unit is composed of one molecule of C10H8FNO2 (Figure 38).

Figure 38 Figure 39 Figure 40

 383940 Figure 38 Asymmetric unit in thermal ellipsoidal representation

  Substrates scope of the reaction ........................................................ 2.4 Enantioselective version ................................................................................ 2.4.1 Optimization of the reaction conditions ............................................. 2.4.2 Substrates scope of the reaction ........................................................ 2.5 Influence of the double bond geometry ........................................................ 2.6 Synthesis of bioactive molecules ................................................................... 2.7 Limitations of the reaction ............................................................................. 2.8 Conclusion ......................................................................................................

	LDA 2.3.2	lithium diisopropylamide
	LiHMDS	lithium bis(trimethylsilyl)amide
	Ac LUMO	acetyl lowest unoccupied molecular orbital
	aq M.P.	aqueous melting point
	Bn Me	benzyl methyl
	Boc MS	tert-butoxycarbonyl molecular sieves
	Cbz MTBE	benzyloxycarbonyl methyl tert-butyl ether
	Cy MWI	cyclohexyl microwave irradiation
	DABCO n Bu	1,4-diazabicyclo[2.2.2]octane normal butyl
	DBU NMR	1,8-diazabicyclo[5.4.0]undec-7-ene nuclear magnetic resonance
	DCE n Pr	1,2-dichloroethane normal propyl
	de Ns	diastereomeric excess nosyl
	DIPA Nu	diisopropylamine nucleophile
	DIPEA PG	N,N-diisopropylethylamine protecting group
	DMP Ph	Dess-Martin periodinane phenyl
	dr PTFE	diastereoisomeric ratio polytetrafluoroethylene
	ee (R)-H8-BINOL	enantiomeric excess (R)-(+)-5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol
	Equiv rt	equivalent room temperature
	er (S)-BINAP	enantiomeric ratio (S)-(-)-(1,1'-Binaphthalene-2,2'-diyl)bis(diphenylphosphine)
	Et s Bu	ethyl secondary butyl
	ETFE T	poly(1,1,2,2-tetrafluorobutane-1,4-diyl) temperature
	EWG TBAF	electron-withdrawing group tetra-n-butylammonium fluoride
	h t Bu	hour tertiary butyl
	HFIP Tf	1,1,1,3,3,3-hexafluoro-2-propanol trifluoromethanesulfonyl
	HMPA TFA	hexamethylphosphoramide trifluoroacetate
	HPLC THF	high performance liquid chromatography tetrahydrofuran
	HRMS i Bu TMG	high resolution mass spectroscopy isobutyl 1,1,3,3-tetramethylguanidine
	Int	intermediate
	IPA	isopropyl alcohol
	i Pr	isopropyl
	IR	infrared
	J	spin-spin coupling constant
	LCMS	liquid chromatography-mass spectrometry

Table 1

 1 A comparison of atomic properties

				X
	Property
		H	N	O	F	Cl
	Bond length C-X (Å)	1.09	1.47	1.43	1.35	1.77
	Bond dissociation energy C-X (kcal mol -1 )	98.8	69.7	84.0	105.4	78.5
	Electronegativity (Pauling scale)	2.20	3.04	3.44	3.98	3.16
	Van der Waals radius (Å)	1.20	1.55	1.52	1.47	1.75
	Atom polarizability, α (10 -24 cm -3 )	0.667	1.100	0.802	0.557	2.180

  33

.1.6 Other Fluorinated α,β-unsaturated carbonyl Michael acceptors

	Scheme 39 The adducts obtained from β-C2F5-acrylamides
	1.4Another type of fluorinated α,β-unsaturated carbonyl compound where the
	fluorinated moieties were located in carbonyl group, instead of in the α-or β-
	position of the alkene, was also used in Michael addition reaction. As early as 1993,
	in the work of Suzuki and co-workers, the addition of alkenyldiisopropoxyboranes to
	these substrates could occur smoothly, and the desired products were obtained in
	good yields without the formation of 1,2-adducts (
	Scheme 38 The addition of electron-rich heterocycles to β-perfluorinated enones
	Similarly, in the Michael addition to β-CF3-acrylamide reported by Lu in 2013 (see
	Scheme 35), the β-C2F5-acrylamide could also serve as a good Michael acceptor.
	Under the optimized conditions, the adducts were obtained as good as those from β-
	CF3-acrylamide, i.e. in good yields with high diastereo-and enantioselectivities
	(Scheme 39). 70

Scheme 40). 47 Scheme 40 The addition of boranes

	In 2007, Kondratov and co-workers reported the reaction between the ethyl
	triphenylphosphoranylideneacetate (Ph3PCHCO2Et) and β-alkoxyvinyl polyfluoroalkyl
	ketones (fluorinated β-ketoaldehyde derivatives). The reaction offered a mixture of
	two products, which can be easily separated, in high overall yields. 74 Surprisingly, the
	unusual major process is an initial ylide addition to β-carbon (intermediate B),
	instead of ylide addition to carbonyl moiety (intermediate A) of the enone, with the
	subsequent EtO -elimination to form Michael adducts (Scheme 41). Worthy of note
	that the increase of RF group bulkiness favored the formation of the Michael adduct.

74

Kondratov, I. S.; Gerus, I. I.; Furmanova, M. V.; Vdovenko, S. I.; Kukhar, V. P. Tetrahedron 2007,

63, 7246-7255.

43).

	Scheme 42 The addition of thiols to hexafluoroisopropyl α,β-unsaturated esters
	In 2018, a protocol for the synthesis of O, S-containing heterocycles has been
	reported. The desired products were obtained by the sequentially sulfa-Michael
	addition and heterocyclization starting from the β-fluorinated α-bromo enones
	(Scheme 43). 77 A proposed mechanism showed that the initial step of this reaction
	sequence was a sulfa-Michael addition to give A, which easily underwent
	intramolecular nucleophilic substitution to give sulfonium intermediate B. Then, the
	intermediate B underwent deprotonation and ring-opening to give the intermediate
	C which could form the desired heterocycle product by an intramolecular
	acetalization (Scheme Scheme 43 The addition of β-Mercaptoalcohols to fluorinated α-bromoenones
	Fang, X.; Li, J.; Wang, C. J. Org. Lett. 2013, 15, 3448-3451. 77 Obijalska, E.; Pawelec, M.; Mlostoń, G.; Capperucci, A.; Tanini, D.; Heimgartner, H. Eur. J. Org. Chem. 2018,
	76 Du, D.; Lin, Z. Q.; Lu, J. Z.; Li, C.; Duan, W. L. Asian J. Org. Chem. 2013, 2, 392-394. 2018, 3716-3723.

  87

86

Chen, Q.; Wang, G.; Jiang, X.; Xu, Z.; Lin, L.; Wang, R. Org. Lett. 2014, 16, 1394-1397.

87

Zhao, M. X.; Ji, F. H.; Zhao, X. L.; Han, Z. Z.;

Shi, M. Eur. J. Org. Chem. 2014, 2014, 644-653.

Table 2 ,

 2 entries 6-7). Increasing the amount of 2a led to 84% isolated yield of 3a (Table2, entry 8). The amount of Et3N could be reduced to 0.1 equivalent giving a similar yield and dr (Table2, entry 9). We

finally found this reaction could be performed in neat 2a, and the use of 5 equivalent of 2a could give a full conversion of 1a and 3a was isolated in 89% yield as a mixture of two diastereoisomers in a 76:24 ratio (Table

2

, entries 10-12). Some other tertiary amines were tested, the use of DIPEA and DBU slightly improved the dr ratio with lower yields whereas the use of DABCO gave a lower yield with a similar dr ratio (Table

2

, entries

13-15)

.

Table 2

 2 Optimization of non-enantioselective SMA reaction

	Entry Equiv of PhSH	Catalyst (Equiv)	Solvent	T (°C)	Conversion b (Yield) c %	Dr d
	1	1.1	BF3•Et2O (1.5)	CH2Cl2	rt or 45	0	-
	2	1.1	Me2AlCl3 (1.5)	CH2Cl2	rt or 45	0	-
	3	1.1	Et3N (0.14)	CH2Cl2	rt or 45	Trace	-
	4	1.1	Et3N (0.14)	MeCN	rt	50	-
	5	1.1	Et3N (0.14)	MeCN	80	75 (37)	73:27
	6	1.1	-	MeCN	80	0	-
	7	PhSNa (2.0)	MeCN	80	0	-
	8	2	Et3N (0.14)	MeCN	80	98 (84)	77:23
	9	2	Et3N (0.10)	MeCN	80	94 (81)	76:24
	10	3	Et3N (0.10)	-	80	91 (77)	74:26

b Determined by the 19 F NMR of the reaction mixture. c Isolated yield of the diastereoisomers mixture (3a). d Determined by the 19 F NMR of the reaction crude

Table 3

 3 Substrate scope in the non-enantioselective process

Table 4 ,

 4 entries11-12). The use of chiral amines (X and XI) only provided racemic products (

Table 4 ,

 4 entries 13-14). In comprehensive consideration of conversion, dr and ee

	value, (DHQ)2PYR (IV) was selected as it gave the best results: 100% conversion,

89:11 dr, 68% ee (Table

4

, entry 4). On the basis of choosing (DHQ)2PYR (IV) as the catalyst, we studied the influence of temperature. The reaction performed at 80 °C was complete after 16 h but gave only 37% ee (Table

4, entry 17

). Decreasing the temperature allowed the obtention of better ee values but lower conversions (

Table 4 ,

 4 entries 15-16). Extended the reaction time to 5 days provided the full conversion with 71% ee (Table4, entry 18).

Table 4

 4 Screening of chiral catalysts and temperature for the asymmetric SMA Determined by the 19 F NMR of the reaction mixture. c Isolated yield of the diastereoisomers mixture (3a). d Determined by the 19 F NMR of the reaction crude.

	Entry	Catalyst	x (mol%)	T (°C)	Conversion b (Yield) c %	Dr d	Ee(%) e
	1	Quinine I	10	rt	90	83:17	15
	2	Quinidine II	10	rt	85	85:15	-13
	3	Cinchonine III	10	rt	98	86:14	0
	4	Quinine I	20	rt	96	80:20	15
	5	Quinidine II	20	rt	87	83:17	-11
	6	(DHQ)2PYR IV	10	rt	100	89:11	68
	7	(DHQ)2PYR IV	5	rt	98	87:13	60
	8	(DHQD)2PYR V	10	rt	63	88:12	-72
	9	(DHQ)2AQN VI	10	rt	100	85:15	51
	10	(DHQD)2PHAL VII	10	rt	100	92:8	-53
	11	VIII	10	rt	60	60:40	50
	12	IX	10	rt	69	61:39	22
	13	X	10	rt	88	72:28	0
	14	XI	10	rt	72	84:16	0
	15	(DHQ)2PYR IV	10	-20	42	81:19	73
	16	(DHQ)2PYR IV	10	0	89 (73)	85:15	70
	17	(DHQ)2PYR IV	10	80	100 (91)	85:15	37
	18	(DHQ)2PYR IV	10	0	100 (82)	84:16	71
	a Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a (1.5 mmol, 5 equiv), catalyst (0.05-0.20 equiv), the given
	temperature, under argon, 3 days.

b e

Determined for the major diastereoisomer by HPLC. f Reaction time = 16 h. g Reaction time = 5 days.

Table 5

 5

, entries 1-5). Et2O and toluene gave relatively good ee values, 60% and 64% respectively (Table

5, entry 1, 4

). Accordingly, two other solvents MTBE and mxylene were tested, both of them furnished excellent dr but unfortunately gave lower conversions and ee values (Table

5, entries 6-7

). Carrying out the reaction in neat thiophenol still provided the best results in terms of conversion, dr and ee value (Table

5

, entry 8).

Table 5

 5 Influence of solvents

	Entry	Solvent (0.5 mL)	Conversion (%) b	Dr c	Ee d
	1	Et2O	76	88:12	60
	2	CH2Cl2	32	85:15	48
	3	MeCN	47	91:9	49
	4	Toluene	58	85:15	64
	5	MeOH	62	83:17	36
	6	MTBE	62	96:4	56
	7	m-Xylene	18	97:3	59
	8	-	100	89:11	68

Table 6

 6 Effects of the ester group

	Entry	R	isolated yield (%) b	Dr c	Ee (%) d
	1	Me	75	86:14	49
	2	Et	82	84:16	71
	3	i Pr	41	95:5	43
	4	t Bu	19	92:8	55

a Reaction conditions: 1a' (0.3 mmol, 1.0 equiv), 2a (1.5 mmol, 5 equiv), (DHQ)2PYR (0.03 mmol, 10 mol%), 0 °C, 5 days, under argon. b Isolated yield of the diastereoisomers mixture (3a'). c Determined by the

19

F NMR of the reaction crude. d Determined for the major diastereoisomer by HPLC.

Table 7

 7

	kinetic study

a Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a

(1.5 mmol, 5 equiv)

, (DHQ)2PYR (0.03 mmol, 10 mol%), 0 °C, 6 days, under argon. b Determined by the 19 F NMR of the reaction mixture. c Determined by the 19 F NMR of the reaction crude. d Determined for the major diastereoisomer by HPLC.

Table 8

 8 Stability of products Reaction conditions: Racemic-3a (0.2 mmol, 1.0 equiv), 2a (1.0 mmol, 5 equiv), (DHQ)2PYR (0.02 mmol, 10 mol%), 0 °C, 5 days, under argon. b S.M. = starting material, only 3a were detected in19 F NMR.

				Kinetic study
	100%					100%	100%
	90%			89%	94%
	70% 80%	76% 71%	74% 71%	72% 70%	74% 70%	68% 71%	72% 71%
	60%
	40% 50%		46%
	30%	29%
	20%
	10%
	0%
		1 day	2 days	3 days	4 days	5 days	6 days
			De (%)	Ee (%)	Conversion (%)

a c

Determined for 3a by HPLC.

Table 9

 9 Substrate scope of the reaction obtained by the 2-thiophenethiol (3h-i). Additions of 4-bromothiophenol and 2-naphthalenethiol to a fluorinated Michael acceptor bearing a nitro substituent (1b) occurred in moderate yields and dr but without enantioselectivities (3j-k).

	In the asymmetric process, with the (Z)-ethyl 2-fluoro-5-phenylpent-2-enoate (1a),
	aryl thiols substituted with a halogen (3b) and some common electron-donating
	groups like methoxy (3c), amino-(3d), and methyl (at ortho-, meta-and para-
	positions) (3e-g) groups were suitable substrates and the desired products were
	obtained in moderate to excellent yields (38-95%), dr (67:33 to 95:5) and moderate
	to good ee values (23-84%). Thiophenol with a substituent at the ortho-or the meta-
	position offered good results in both yields, dr and ee values (3d-f). However,

thiophenol with a substituent in para-position, 3b (p-Br), 3c (p-OMe), and 3g (p-Me), gave relatively low ee values, 23%, 38%, and 54% respectively. 2-Thiophenethiol and 2-naphthalenethiol furnished the products in moderate dr, but higher yield and ee value were

Table 10

 10 Influence of the double bond geometry

	Entry	Substrates	Conditions	Yield (%) b	Dr c	Ee (%) d
	1	(Z)-1a	A	91	76:24	-
	2	(E)-1a	A	93	26:74	-
	3	(Z)-1a	B	82	84:16	71
	4	(E)-1a	B	86	14:86	74
	5	(Z)-1d	A	61	87:13	-
	6	(E)-1d e	A	74	33:67	-
	7	(Z)-1d	B	54	88:12	63
	8	(E)-1d e	B	56	24:76	51

a Reaction conditions A : Et3N (0.03 mmol, 10 mol%), 80 °C, 16 h, under argon. conditions B : (DHQ)2PYR (0.03 mmol, 10 mol%), 0 °C, 5 or 8 days, under argon. b Isolated yield of diastereoisomers. c Determined by the 19 F NMR of the reaction crude. d Determined for the major diastereoisomer by HPLC. e Contaminated with 10 % of (Z)-1d. Scheme 70 Proposed mechanism

Table 11

 11 The use of other S-nucleophiles

	Entry	R-SH	Conversion (%) b	19 F NMR yield (%) c	Dr d
	1	BnSH	57	43	66:34
	2	MeC(O)SH	70	8	-

a Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2 (1.5 mmol, 5 equiv), Et3N (0.03 mmol, 10 mol%),

80 °C, 16 h,

Table 12

 12 The use of gem-α-fluorinated acrylates

a Reaction conditions A: Et3N (0.03 mmol, 10 mol%), 80 °C, 16 h, under argon. Conditions B: (DHQ)2PYR (0.03 mmol, 10 mol%), 0 °C, 5 days, under argon. b Isolated yield. c Determined by HPLC.

  synthesis of phosphonate inhibitors.136 A key intermediate of this process was obtained in good yield by a PMA reaction of diethyl phosphite to methyl acrylate under the catalysis of DBU (Scheme 78, Eq. b). In 2010, a CaO promoted PMA of diethyl phosphite to α,β-unsaturated esters was described by Petrini and co-workers.137 At room temperature, without solvent, the inexpensive CaO showed high efficiency for methyl acrylate and methyl (2-bromomethyl)acrylate (Scheme 78, a basic promoter for this reaction under solvent-free conditions. The substituent on the double bond of Michael acceptor has a significant effect on the 1,4-adduct yield (Scheme 78, Eq. d).

	Eq. c). In 2016, Vaccaro and co-workers reported a PMA reaction of dialkyl phosphite
	to acrylates using a polymer-supported catalyst. 138 The polystyrene supported 2-tert-
	butylimino-2-diethylmanio-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP)
	was used as Scheme 78 Dialkyl phosphite as the nucleophile
	In PMA reactions, diaryl phosphites are also used as nucleophiles. In 2007, Yao

135

Simoni, D.; Invidiata, F. P.; Manferdini, M.; Lampronti, I.; Rondanin, R.; Roberti, M.; Pollini, G. P. Tetrahedron

Lett. 1998, 39, 7615-

7618. 136 Fonvielle, M.; Mariano, S.; Therisod, M. Bioorg. Med. Chem. Lett. 2005, 15, 2906-2909. reaction 137 Martínez-Castro, E.; López, Ó .; Maya, I.; Fernández-Bolaños, J. G.; Petrini, M. Green Chem. 2010, 12, 1171-1174. 138

Strappaveccia, G.; Bianchi, L.; Ziarelli, S.; Santoro, S.; Lanari, D.; Pizzo, F.; Vaccaro, L. Org. Biomol. Chem. 2016, 14, 3521-3525.

Scheme 80 Cyclic phosphite as the nucleophile 3.1.2.2 Nucleophiles such as R2P(O)H

	phospha-Michael adducts in high yields (Scheme 81, Eq. a). Later, Ishihara and co-
	workers described the enantioselective PMA reaction of diaryl phosphine oxides to
	α,β-unsaturated carbonyl esters. 144 The chiral magnesium complex catalyst was
	formed by MgBu2 with (R)-H8-binol and the presence of water, which the magnesium
	center providing a strong Brønsted/Lewis acidity to activate the Michael acceptor
	and the oxygen atom of the (R)-H8-binol moiety providing a strong Brønsted/Lewis
	basicity to activate R2P(O)H. Under the optimized conditions, the 1,4-adducts were
	obtained in good to excellent yields with a high level of enantioselectivity (Scheme
	81, Eq. b). In 2018, Salin and co-workers reported a tributylphosphine (PBu3)
	Diarylphosphine oxides are typical phosphorus-nucleophiles with the general
	structure R2P(O)H. In 2012, Stockland and co-workers developed a protocol for the
	PMA reaction on substituted acrylates in a microwave reactor without catalyst. 143
	Under a high temperature, by using ditolyphosphine oxide as the nucleophile, this
	method was successfully applied on various substituted acrylates, giving the

catalyzed PMA reaction on α,β-unsaturated carbonyl esters.

145

This methodology afforded a series of tertiary phosphine oxides in good to excellent yields under mild conditions and performed well on a gram-scale (Scheme 81, Eq. c). In 2020, Guo and co-workers reported a weak base promoted PMA reaction on several acrylates.

146

With diphenyl phosphine oxide as the nucleophile source, K2CO3 promoted the reaction furnishing the corresponding phospha-Michael adducts in moderate to excellent yields (Scheme 81, Eq. d).

144 Hatano, M.; Horibe, T.; Ishihara, K. Angew.

Chem. Int. Ed. 2013, 52, 4549-4553. 145

Salin, A. V.; Il'in, A. V.; Faskhutdinov, R. I.; Galkin, V. I.; Islamov, D. R.; Kataeva, O. N. Tetrahedron Lett. 2018,

59, 163059, -1634. 146 Guo, S.;. 146 Guo, S.;Huang, Z.; Liu, W.; Li, S.;Yang, Y.; Cai, H. Synlett 2020, 31, 1295-1297.

  .149 Interestingly, this reaction gave a single diastereoisomer in 79% yield, even if the bis-acrylate was initially obtained as a (Z)/(E) mixture (Scheme 82, Eq. b).

147

Staubitz, A.; Robertson, A. P. M.; Sloan,

M. E.; Manners, I. Chem. Rev. 2010, 110, 4023-4078.

148 Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K. J. Am. Chem.

Soc. 1990, 112, 5244-5252.

acrylateScheme 82 phosphine-borane as the nucleophile

3.1.3 PMA reaction on fluorinated Michael acceptors: State of the art

The trifluoromethyl (CF3) group represents an important fluorine-containing substituent. 150 CF3-containing compounds are very popular due to the effect of CF3 group on modulating physical, chemical and biological properties like lipophilicity, acidity, steric hindrance and so on.

Table 13

 13 PMA reaction of different fluorinated acrylates

	Entry	R 1	R 2	RF	Conversion% b	19 F NMR yield b (isolated yield c )%	Dr d
	1	H	Me	F	83	78 (38)	-
	2	Ph(CH2)2	Et	F	5	Trace	50:50
	3	Ph	Me	F	7	Trace	20:80
	4	H	Me	CF3	100	89 (68)	-
	5	Ph	Me	CF3	100	93 (84)	66:34

a Reaction conditions: 1 or 6 (0.3 mmol, 1 equiv), 7a

(0.45 mmol, 1.5 equiv)

, TMG (0.06 mmol, 20 mol%), room temperature, 16 h, in MeCN (0.5 mL). b Conversion and

19

F NMR yield were obtained by using PhF or PhCOCF3 as an internal standard. c Isolated yield of (

8

) as a mixture of two diastereoisomers. d Determined by the

19

F NMR of the reaction crude.

Table 14

 14 Screening of the base and the equivalents of Ph2P(O)H

	Entry	Base	x equiv of Ph2P(O)H	19 F NMR yield b (isolated yield c )%	Dr d
	1	TMG	1.5	93 (84)	66:34
	2	K2CO3	1.5	39	41:59
	3	IPA	1.5	13	32:68
	4	DIPA	1.5	79	18:82
	5	Et3N	1.5	92 (94)	17:83
	6	DIPEA	1.5	80	27:73
	7	DBU	1.5	47	75:25
	8	DABCO	1.5	95 (91)	92:8
	9	DABCO	1.0	59	92:8
	10	DABCO	1.2	64	92:8
	11	DABCO	2.0	94	91:9
	12 e	DABCO	1.5	94	83:17
	13 f	DABCO	1.5	96	91:9

a Reaction conditions: 6b (0.3 mmol, 1 equiv), 7a (x equiv), base (0.06 mmol, 20 mol%), room temperature, 16 h, in MeCN (0.5 mL). b19 F NMR yields were obtained by using PhCOCF3 as an internal standard. c Isolated yield of 8a as a mixture of two diastereoisomers. d Determined by the

19

F NMR of the reaction crude. e Reaction carried out at 0 °C. f Reaction carried out at 50 °C.

Table 15

 15 Screening of the solvents and the DABCO loading

	Entry	DABCO (y mol%)	Solvent (0.5 mL)	19 F NMR yield b	Dr c
	1	20	CH2Cl2	50	56:44
	2	20	THF	90	74:26
	3	20	Et2O	94	77:23
	4	20	MeCN	96	92:8
	5	0	MeCN	14	23:77
	6	5	MeCN	42	82:18
	7	10	MeCN	83	89:11

Table 16 ,

 16 entry 1). Extending the reaction time to 40 h, afforded the corresponding 1,4-adduct in 16%19 F NMR yield as a mixture of diastereoisomers with a 96:4 dr ratio (

Table 16 ,

 16 entry 2). Carrying out the reaction at 40 °C led to a better NMR yield, with the same dr ratio (Table16, entries 1, 3). Increasing the temperature to 80 °C had no positive effect on NMR yield and reduced the diastereoselectivity (Table16, entry 4). So we decided to perform this reaction at 40 °C and to increase the reaction time to enhance the reaction yield (Table16, entries 2, 5-6). Finally, 72 h of reaction time led to a full conversion of 9a, and 10a was isolated in 64% yield with a 95:5 dr ratio

(Table

16, entry 6

).

Table 16

 16 Optimization of α-fluoromethylacrylate

	Entry	T (°C)	Reaction time (h)	19 F NMR yield b (isolated yield c )%	Dr d	Identities of products
	1	rt	16	Trace	-
	2	rt	40	16	96:4	Major: -218.6 ppm
	3	40	16	35 (21)	96:4	(td, J = 46.2, 16.9 Hz)
	4	80	16	38	90:10	Minor: -222.3 ppm
	5	40	40	55	95:5	(td, J = 46.7, 17.8 Hz)
	6	40	72	79 (64)	95:5

a Reaction conditions: 9a (0.3 mmol, 1.0 equiv), 7a (0.45 mmol, 1.5 equiv), DABCO (0.06 mmol, 20 mol%), in MeCN (0.5 mL). b19 F NMR yields were obtained by using PhF as an internal standard. c Isolated yield of 10a as a mixture of two diastereoisomers. d Determined by the

19

F NMR of the reaction crude.

Table 17

 17 Substrate scope on α-trifluoromethylacrylates

	Entry	R 1	6	R 2	8	Isolated yield (%) b	Dr c
	1	H	6a	Ph	8a	74	-
	2	Ph	6b	Ph	8b	91 (84 d )	92:8 (91:9 d )
	3	4-OMe-C6H4	6c	Ph	8c	84	93:7
	4	4-OH-C6H4	6d	Ph	8d	71	85:15
	5	4-NMe2-C6H4	6e	Ph	8e	52	93:7
	6	4-t Bu-C6H4	6f	Ph	8f	77	81:19
	7	4-Me-C6H4	6g	Ph	8g	91	97:3
	8	3-Me-C6H4	6h	Ph	8h	81	93:7
	9	2-Me-C6H4	6i	Ph	8i	61	70:30
	10	4-CF3-C6H4	6j	Ph	8j	88	99:1
	11	4-CN-C6H4	6k	Ph	8k	80	97:3
	12	4-F-C6H4	6l	Ph	8l	95	98:2
	13	4-Cl-C6H4	6m	Ph	8m	94	97:3
	14	2-Cl-C6H4	6n	Ph	8n	55	74:26
	15	4-Br-C6H4	6o	Ph	8o	88	99:1
	16	3,5-di-OMe-C6H3	6p	Ph	8p	94	90:10
	17	Naphthalen-2-yl	6q	Ph	8q	83	94:6
	18	Thiophen-2-yl	6r	Ph	8r	75	96:4
	19	(E)-4-Cl-C6H4	6s	Ph	8m	70	85:15

b Isolated yield of 8 as a mixture of two diastereoisomers. c Determined by the 19 F NMR of the reaction crude. d Reaction was performed on 2.0 mmol scale. e NR = No Reaction.

Table 18

 18 Substrates scope on α-fluoromethylacrylates

	Entry	R 1	9	R 2	10	Isolated yield (%) b	Dr c
	1	Ph	9a	Ph	10a	64 (52 d )	95:5 (95:5 d )
	2	4-OMe-C6H4	9b	Ph	10b	51	96 :4
	3 f	4-Cl-C6H4	9c	Ph	10c	44	96 :4
	4 f	4-CN-C6H4	9d	Ph	10d	29	97 :3
	5 f	4-NO2-C6H4	9e	Ph	10e	0	-
	6	Furan-2-yl	9f	Ph	10f	NR	-
	7	n Pentyl	9g	Ph	10g	NR	-
	8	Ph	9a	4-OMe-C6H4	10h	70	95 :5
	9	Ph	9a	4-Me-C6H4	10i	53	94 :6
	10	Ph	9a	4-Cl-C6H4	10j	0	-

Table 19 α

 19 -Fluoroacrylates with different nucleophiles Reaction condition: 1 (0.3 mmol, 1 equiv), nucleophile (0.6 mmol, 2 equiv), specific conditions indicated in the table. b NR = No Reaction.

	Entry	R 1	R 2	H-Nu	Conditions a	Results b
	1	Ph	Me	MeNO2	DIPEA or Et3N or DBU (20 mol%)	NR
	2	Ph	Me	CH2(CO2Et)2	MeCN, reflux, 16 h	NR
	3	Ph	Me	CuMe2Li	Et2O, -78 or -40 °C, 2-6 h	NR
	4	Ph	Me	Cu(CN)MeLi	Et2O, -78 or -40 °C, 2-6 h	NR
	5	Ph	Me			NR
	6 7	Ph(CH2)2 Cyclohexyl	Et Et	PhB(OH)2	[Rh(cod)Cl2] (4.5 mol%) (±)-binap (4.5 mol%) dioxane/H2O = 3 mL (6/1)	NR NR
	8	H	Me		100 °C, Ar, 16 h	-190.7 ppm (ddd, J = 48.8,

a

Table 20 ,

 20 entry 12). So far, the best results to afford 8b were obtained under -20 °C for 48 h (40%19 F NMR yield, dr = 24:76, 47% ee) (Table20, entry 13).

Table 20

 20 Enantioselective PMA reaction on α-trifluoromethylacrylates

	Entry	Catalyst	T (°C)	19 F NMR yield (%) b	Dr c	Ee (%) d

a Reaction conditions: 6b (0.3 mmol, 1.0 equiv), 7a (0.45 mmol, 1.5 equiv), catalyst (0.03 mmol, 10 mol%), rt, 16 h. b19 F NMR yields were obtained by using PhCOCF3 as an internal standard. c Determined by the 19 F NMR of the reaction crude. d Determined for the major diastereoisomers by HPLC. e Reaction carried out at -20 °C for 48 h.

Table 21

 21 SMA reaction on α-trifluoromethylacrylates Determined by the19 F NMR of the reaction crude.

	Entry	Catalyst	x (mol%)	19 F NMR yield (%) b	Dr c	Ee (%) d
	1	Et3N	20	83	28:72	-
	2	DIPEA	20	87	28:72	-
	3	DABCO	20	85	28:72	-
	4	DBU	20	85	29:71	-
	5	K2CO3	20	87	28:72	-
	6	-	-	27	44:56	-
	7	Quinine I	10	93	28:72	0
	8	Cinchonine III	10	89	29:71	0
	9	(DHQ)2PYR IV	10	97	29:71	0
	10	(DHQ)2AQN VI	10	95	28:72	0
	11	IX	10	87	33:67	28
	a Reaction conditions: 6b (0.3 mmol, 1.0 equiv), 2a (0.9 mmol, 3 equiv), catalyst (0.03 or 0.06 mmol, 10 or 20
	mol%), MeCN (0.5 mL), rt, 16 h, under argon.

b19 F NMR yields were obtained by using PhCOCF3 as an internal standard.

c d

Determined for the major diastereoisomers by HPLC.

Table 22 α

 22 -Trifluoromethylacrylates with different nucleophiles

	Entry	H-Nu	Conditions a	Results
	1	MeNO2	DIPEA or Et3N or DBU (20 mol%) MeCN, rt or reflux, 16 h	NR b
	2	CH2(CO2Et)2	DABCO (20 mol%) MeCN, rt, 16 h	34% 19 F NMR yield c dr = 22:78 d
	3	CuMe2Li	Et2O, -78 to 0 °C, 6 h	41% 19 F NMR yield c dr = 49:51 d
	4	Cu(CN)MeLi	Et2O, -78 or -40 or -78 to 0 °C , 2-6 h	NR b
	5	PhB(OH)2	dioxane/H2O = 3 mL (6/1) [Rh(cod)Cl2] (4.5 mol%) (±)-binap (4.5 mol%)	NR b
			100 °C, Ar, 16 h
	6 e			34% isolated yield
	a Reaction condition: 1 (0.3 mmol, 1 equiv), nucleophile (0.6 mmol, 2 equiv), specific conditions indicated in the
	table.

b NR = No Reaction. c19 F NMR yields were obtained by using PhCOCF3 as an internal standard. d Determined by the 19 F NMR of the reaction crude. e Methyl 2-(trifluoromethyl)acrylate as the Michael acceptor.

Table 23

 23 Michael addition reaction on α-fluorinated enal

	Entry	H-Nu	Catalyst	Conversion (%) b	Results
	1	PhSH	a	96	-190.1 to -192.9 ppm, 4*ddd

  F NMR of the reaction crude showed dr = 90:10. The crude was purified by silica gel column

	chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two
	diastereoisomers in 55% yield (major: 45 mg as a yellow solid, major and minor
	mixture: 9 mg). 87% ee was obtained for the major diastereoisomer [determined by
	HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 16.160
	min, t (major) = 22.437 min.].
	[α]D 20 = +24.1 (c 0.22, CDCl3); M.P. 112 -113 °C; 1 H NMR (300 MHz, CDCl3): δ 7.28 (d,
	JH-H = 6.0 Hz, 1H), 7.03 -6.98 (m, 1H), 6.61 -6.56 (m, 2H), 5.09 (dd, JH-F = 48.0 Hz, JH-H
	= 3.0 Hz, 1H), 4.29 (s, 2H), 4.05 -3.94 (m, 1H), 3.80 -3.69 (m, 1H), 3.35 -3.21 (m,
	1H), 2.02 -1.88 (m, 2H), 1.74 -1.61 (m, 4H), 1.26 -1.04 (m, 8H). 19 F NMR (282 MHz,
	CDCl3): δ -196.1 (dd, JF-H = 48.0 Hz, JF-H = 33.8 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ
	168.7 (d, JC-F = 30.0 Hz), 148.

  F NMR of the reaction crude showed dr = 81:19. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 44% yield (major: 35 mg as a colorless oil, major and minor mixture: 8 mg). 26% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow =1 mL/min, λ = 254 nm, t (minor) = 7.013

	min, t (major) = 7.820 min.].
	[α]D 20 = -20.3 (c 0.10, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.19 -7.15 (m, 2H), 7.11 -
	7.05 (m, 1H), 6.96 -6.93 (m, 1H), 5.19 (dd, JH-F = 51.0 Hz, JH-H = 3.0 Hz, 1H), 4.11 -
	3.81 (m, 2H), 3.34 -3.19 (m, 1H), 2.24 (s, 3H), 2.13 (d, JH-H = 12.0 Hz, 1H), 1.71 -1.60
	(m, 5H), 1.20 -1.01 (m, 8H). 19 F NMR (282 MHz, CDCl3): δ -197.7 (dd, JF-H = 51.0 Hz,
	JF-H = 33.8 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ 168.6

13 C{ 1 H} NMR (

  JF-H = 48.0 Hz, JF-H = 26.0 Hz).

	NMR (282 MHz, CDCl3): δ -195.0 (dd,
	F NMR of the
	reaction crude showed dr = 88:12. The crude was purified by silica gel column
	chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two
	diastereoisomers in 54% yield (major: 40 mg as a white solid, major and minor
	mixture: 7 mg). 63% ee was obtained for the major diastereoisomer [determined by
	HPLC, IC column, Hept/ i PrOH: 90/10, flow =1 mL/min, λ = 254 nm, t (minor) = 6.530

  76% yield (major: 60 mg as a colorless oil, major and minor mixture: 8 mg). 52% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 50.573 min, t (major) = 54.183 min.].

19

F NMR of the reaction crude showed dr = 92:8. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in

  After the mixture was stirred for 24 h under reflux, it was cooled to room temperature. The mixture was dried over Na2SO4 then the crude mixture was purified by column chromatography (CH2Cl2/MeOH, 9/1 to 8/1, v/v) to give the desired product 5b in 32% yield(18 mg,

	colorless oil) with 73% ee [determined by HPLC, luxcell-2 column, Hept/ i PrOH: 80/20,
	flow = 1.2 mL/min, λ = 254 nm, t (minor) = 18.370 min, t (major) = 23.353 min.].
	[α]D 20 = +126.4 (c 0.47, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7.72 -7.64 (m, 1H), 7.43
	-7.35 (m, 3H), 7.23 -7.19 (m, 2H), 6.86 -6.75 (m, 2H), 5.28 -4.78 (m, 2H), 4.45 -
	4.17 (m, 1H), 3.74 (s, 3H), 3.71 -3.62 (m, 1H), 2.71 -2.32 (m, 2H), 2.21 (s, 6H). 19 F
	NMR (282 MHz, CDCl3): δ -189.2 (d, JF-H = 47.9 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl3): δ
	166.6 (d, JC-F = 22.5 Hz), 160.
	To a solution of 4b (0.15 mmol, 45.0 mg) in ethyl acetate (1.0 mL) was added 2-

dimethylaminoethyl chloride hydrochloride (43.2 mg, 0.30 mmol), followed by potassium carbonate

(82.8 mg, 0.6 mmol)

and H2O (10 L).

)-3-(4-hydroxyphenyl)-2-(trifluoromethyl)acrylic acid (6'd): Following

Scheme 97 Synthesis of α-trifluoromethylacrylates

All the analytic data of α-trifluoromethyl acrylic acid

(6'b-c, 6'f)

161 , 6'e 162 , (6'g-i, 6'l-m, 6'o, 6'q-r) 163 , (6'k, 6'n)

164

and α-trifluoromethyl acrylate 6b 165 , (6c, 6o) 166 , (6d, 6k, 6m)

167

were in agreement with those reported in literature.

(Zthe general procedure (V): 6'd was obtained as a pale-yellow solid, 45% yield (1566 mg); M.P.

194 -195 °C;

1 H NMR (300 MHz, CD3OD): δ

	8.03 (s, 1H), 7.35
	(d, JH-H = 8.4 Hz, 2H), 6.82 (d, JH-H= 8.7 Hz, 2H).

19

F NMR (282 MHz, CD3OD): δ -57.1 (s).

  Following the general procedure (X): 8k was obtained as a mixture of two diastereoisomers, dr = 97:3; white solid, 80% yield (110 mg); M.P. 242 -243 °C.

	anti-8k: 1 H NMR (300 MHz, CDCl3): δ 8.00 -7.93 (m, 2H), 7.59 -7.39 (m, 9H), 7.32 -
	7.27 (m, 1H), 7.23 -7.17 (m, 2H), 4.38 -4.19 (m, 2H), 3.08 (s, 3H).
		). IR: 3164, 2956, 2913, 1738, 1520, 1437,
	1269, 1176, 722, 697, 540, 439 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C23H21F3O4P:
	449.1124, found: 449.1131.
	Methyl	2-((4-(dimethylamino)phenyl)(diphenylphosphoryl)methyl)-3,3,3-
	trifluoropropanoate (8e): Following the general procedure (X): 8e was obtained as a

mixture of two diastereoisomers, dr = 93:7; pale yellow solid, 52% yield (74 mg); M.P.

Table 24

 24 Crystal data of syn-3k

	Chemical Formula	C23H22FNO4S
	Molecular Weight / g.mol -1	427.5
	Crystal System	Triclinic
	Space Group	P-1
	Z , Z' (asymmetric units per unit cell)	4, 2
	a / Å	10.866(1)
	b / Å	13.597(1)
	c / Å	16.769(1)
	 / °	103.930(2)
	 / °	103.924(2)
	 / °	109.759(2)
	V / Å 3	2117.8(3)
	dcalc / g.cm -3	1.341

Table 25

 25 Crystal data of (2S, 3S)-3p

	Chemical Formula	C17H24FNO2S
	Molecular Weight / g.mol -1	325.43
	Crystal System	orthorhombic
	Space Group	P 212121
	Z, Z' (asymmetric units per unit cell)	4, 1
	a / Å	8.1448(2)
	b / Å	9.6689(2)
	c / Å	21.6673(1)
	 / °	65.785(2)
	 / °	90
	 / °	90
	V / Å 3	90
	dcalc / g.cm -3	1.267

Table 26

 26

Hydrogen bond table D-H.

Table 27

 27 Crystal data of anti-8j

	Chemical Formula	C24H19F6O3P
	Molecular Weight / g.mol -1	500.36
	Crystal System	Monoclinic
	Space Group	P21/a
	Z , Z' (asymmetric units per unit cell)	4,2
	a / Å	11.374(3)
	b / Å	13.663(3)
	c / Å	14.832(4)
	 / °	90
	 / °	99.268(5)
	 / °	90
	V / Å 3	2274.9(1)
	dcalc / g.cm -3	1.461
	F(000) / e -	1024
	Absorption coefficient µ (MoK1) / mm -1	0.194

Structural description: The asymmetric unit is composed of one molecule of

Table 28

 28 Crystal data of syn-10a

	Chemical Formula	C23H21FO3P
	Molecular Weight / g.mol -1	395.37

F(000) / e - 1664 Absorption coefficient µ (MoK1) / mm -1 0.164

Cameron, A. G. W. Space Sci. Rev. 1973, 15, 121-146.

Harper, D. B.; O'Hagan, D. Nat. Prod. Rep. 1994, 11, 123-133.

(a) Sen, K. D.; Jorgensen, C. K. Electronegativity inStructure and Bonding, Vol. 66 (Springer-Verlag, New York, 1987). (b) Smart, B. E. Organofluorine Chemistry: Principles and Commercial Applications, Springer US, Boston, MA, 1994.

(a) O'Hagan, D. Chem. Soc. Rev. 2008, 37, 308-319. (b) Mikami, K.;Itoh, Y.; Yamanaka, M. Chem. Rev. 2004, 104, 1-16.

(a) Fang, X.; Dong, X.-Q.;Wang, C.-J. Tetrahedron Lett. 2014, 55, 5660-5662. (b) Calter, M. A.; Korotkov, A. Org. Lett. 2015, 17, 1385-1388. (c) Auria-Luna, F.; Marqués-López, E.; Gimeno, M. C.; Heiran, R.; Mohammadi, S.; Herrera, R. P. J.Org. Chem. 2017, 82, 5516-5523.

Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro,M. Angew. Chem. Int. Ed. 2008, 47, 4157-4161.

under argon. b Determined by19 F NMR of the reaction mixture. c Fluorobenzene as an internal standard.d Determined by19 F NMR of the reaction crude.

Balaraman, E.; Srinivas, V.; Kumara Swamy, K. C. Tetrahedron 2009,65, 7603-7610.

Lenker, H. K.; Richard, M. E.; Reese, K. P.; Carter, A. F.; Zawisky, J. D.; Winter, E. F.; Bergeron, T. W.; Guydon, K. S.; Stockland, R. A., Jr. J.Org. Chem. 2012, 77, 1378-1385.

Erkkila, A.;Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416-5470.

Conclusion and Perspectives 5 Conclusion and Perspectives

(a) Krause, N. Angew. Chem. Int. Ed. 1998, 37, 283-285. (b) Krause, N.;Hoffmann-Röder, A. Synthesis 2001, 2001, 0171-0196. (c) Wu, G.; Huang, M. Chem. Rev. 2006, 106, 2596-2616. (d) Gutnov, A. Eur. J. Org. Chem. 2008, 2008, 4547-4554. (e) Schmid, T. E.; Drissi-Amraoui, S.; Crevisy, C.; Basle, O.; Mauduit, M. Beilstein J.Org. Chem. 2015, 11, 2418-2434. (f) Hui, C.;Pu, F.; Xu, J. Chem. Eur. J. 2017, 23, 4023-4036.

Experimental SectionExperimental Section

Liu, Y.; Lai, H.; Rong, B.; Zhou, T.; Hong, J.; Yuan, C.; Zhao, S.; Zhao, X.; Jiang, B.;Fang, Q. Adv. Synth. Catal. 2011, 353, 3161-3165.

Acros Organics (in a sealed bottle with molecular sieves) except for CH2Cl2 (distilled from calcium hydride), THF and toluene (distilled from sodium with benzophenone).

1 Sulfa-Michael addition (SMA) of thiophenols to α-fluoroα,β-unsaturated esters

Preparation of α-fluoro-α,β-unsaturated esters

The alkyl α-fluoro-α,β-unsaturated esters (1a-c) were synthesized according to the literature in the following procedure (I) (Scheme 96) 21b : To an anhydrous CH2Cl2 solution (50 mL) of the appropriate aldehyde (5.0 mmol, 1 equiv) and ethyl dibromofluoroacetate (2 equiv) was added Et2Zn (1 M in hexane, 4 equiv) dropwise under argon. The reaction mixture was stirred for 3 h at room temperature. The resulting solution was then poured into saturated NH4Cl, CH2Cl2 was evaporated under vacuum, EtOAc was added, and the mixture was stirred for 15 min. The remaining zinc salts were filtered off through a Büchner funnel. The heterogeneous resulting solution was extracted twice with Et2O (2×20 mL), dried over MgSO4, and concentrated under reduced pressure and then purified by flash silica gel column chromatography (eluent: petroleum ether/EtOAc). The analytic data of 1a-c were in agreement with those reported in literature. 21a Scheme 95 Synthesis of alkyl α-fluoro-α,β-unsaturated esters

The aryl α-fluoro-α,β-unsaturated esters (1d-i) were synthesized according to the literature in the following procedure (II) (Scheme 96) 21a : In a vial was added iodoarene (5.0 mmol, 1 equiv), methyl 2-fluoroacrylate (1.5 equiv), Ag2CO3 (2 equiv) and Pd(TFA)2 (10 mol %). The vial was then filled with 1,4-dioxane (5 mL), then was The syn-3b was obtained following the general procedure (III). 19 F NMR of the reaction crude showed dr = 73:27. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 20/1 to 15/1, v/v) affording two diastereoisomers in 98% yield (major: 107 mg as a white solid; minor: 13 mg as a white solid).

The (2S,3S)-3b was obtained according to the general procedure (IV). 19 F NMR of the reaction crude showed dr = 67:33. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 38% yield (major: 38 mg as a white solid; minor: 9 mg as a white solid). 23% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 98/2, flow = 1 mL/min, λ = 254 nm, t (minor) = 9.810 min, t (major) = 11.183 min.].

[α]D 20 = -6.1 (c 1.09, CDCl3); M.P. 54-56 °C; 1 H NMR (300 MHz, CDCl3): δ 7. 34 -7.31 (m, 2H), 7.22 -7.06 (m, 7H), 4.97 (dd, JH-F = 51.0 Hz, JH-H = 3.0 Hz, 1H), 4.13 -4.02 (m, 2H), 3.41 -3.29 (m, 1H), 2.85 -2.73 (m, 2H), 2.07 -1.93 (m, 2H), 1.17 (t, JH-H = 6.0 Hz, 3H). (d, JC-F = 22.5 Hz), 140.4, 134.5, 132.8, 132.0, 128.6, 128.5, 126.3, 122.0, 90.6 (d, JC-F = 187.5 Hz), 61.8, 50.4 (d, JC-F = 15.0 Hz), 33.3, 33.1, 14.1. IR: 2920, 1757, 1474, 1209, 1091, 815, 695, 585, 478 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C19H21BrFO2S: 411.0430, found: 411.0429. The syn-3c was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 84:16. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 49/1 to 19/1, v/v) affording two diastereoisomers in 87% yield (major: 78 mg as a colorless oil; minor: 19 mg as a colorless oil).

The (2S,3S)-3c was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 81:19. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 49/1 to 19/1, v/v) affording two diastereoisomers in 74% yield (major: 71 mg as a colorless oil; minor: 9 mg as a colorless oil; major and minor mixture: 12 mg). 38% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 8.783 min, t (major) = 9.857 min.].

[α]D 20 = -10.4 (c 0.57, CDCl3); 1 H NMR (300 MHz, CDCl3): δ 7. 36 -7.33 (m, 2H), 7.19 -7.06 (m, 5H), 6.75 -6.73 (m, 2H), 4.92 (d, JH-F = 48.0 Hz, 1H), 4.16 -4.01 (m, 2H), 3.71 (s, 3H), 3.27 -3.17 (m, 1H), 2.89 -2.70 (m, 2H), 1.99 -1.88 (m, 2H) 9, 140.9, 136.2, 128.6, 128.5, 126.2, 123.4, 114.5, 90.8 (d, JC-F = 187.5 Hz), 61.7, 55.4, 51.1 (d, JC-F = 22.5 Hz), 33.2, 33.0, 14.1. IR: 2940, 1760, 1455, 1494, 1245, 1026, 829, 699, 525, 493 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C20H24FO3S: 363.1430, found: 363.1426. Ethyl 3-((4-bromophenyl)thio)-3-cyclohexyl-2-fluoropropanoate (3m): The syn-3m was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 71:29. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 10/1 to 8/1, v/v) affording two diastereoisomers in 76% yield (major: 62 mg as a white solid; major and minor mixture: 24 mg).

The (2S,3S)-3m was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 69:31. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 10/1 to 8/1, v/v) affording two diastereoisomers in 38% yield (major: 24 mg as a white solid; major and minor mixture: 20 mg). 11% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 5.987 min, t (major) = 6.587 min.].

[α]D 20 40.5, 31.0, 30.7, 26.1, 26.1, 14.0. IR: 292040.5, 31.0, 30.7, 26.1, 26.1, 14.0. IR: , 175340.5, 31.0, 30.7, 26.1, 26.1, 14.0. IR: , 147240.5, 31.0, 30.7, 26.1, 26.1, 14.0. IR: , 129940.5, 31.0, 30.7, 26.1, 26.1, 14.0. IR: , 1216, 817, 595, 466, 483 cm -1 , 817, 595, 466, 483 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C17H23BrFO2S: 137.8, 133.6, 132.9, 128.9, 128.7, 128.4, 128.4, 126.2, 127.7, 91.3 (d, JC-F = 187.5 Hz), 55.8 (d, JC-F = 22.5 Hz), 52.6. IR: 294752.6. IR: , 175552.6. IR: , 143852.6. IR: , 122552.6. IR: , 108752.6. IR: , 1001, 736, 701, 688, 540, 467 cm -1 , 736, 701, 688, 540, 467 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C16H16FO2S: 291.0855, found: 291.0859.

Methyl 2-fluoro-3-phenyl-3-(phenylthio)propanoate (3r):

The anti-3r was obtained following the procedure (III) starting from the (E)-1d. 19 F NMR of the reaction crude showed dr = 33:67. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 74% yield (major: 30 mg as a white solid, major and minor mixture: 34 mg).

The (2S,3R)-3r was obtained following the general procedure (IV) starting from the (E)-1d. 19 F NMR of the reaction crude showed dr = 24:76. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers in 56% yield (major and minor mixture: 49 mg). 51% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow =1 mL/min, λ = 254 nm, t (minor) = 6.773 min, t (major) = 143.3, 133.4, 132.4, 132.4, 129.3, 129.3, 129.2, 126.5, 118.4, 112.1, 90.6 (d, JC-F = 195.0 Hz), 55.6 (d, JC-F = 15.0 Hz), 52.9. IR: 2967, 2237, 1767, 1441, 1214, 1096, 1003, 836, 745, 570, 437 cm -1 . HRMS (API + ) m/z: [M+H] + calcd for C17H15FNO2S: 316.0808, found: 316.0790.

Methyl 3-(2-aminophenyl)thio)-2-fluoro-3-(4-methoxyphenyl)propanoate (3y):

The syn-3x was obtained following the procedure (III). 19 F NMR of the reaction crude showed dr = 87:13. The crude was purified by silica gel column chromatography (petroleum ether/CH2Cl2, from 5/1 to 2/1, v/v) affording two diastereoisomers in 40% yield (major: 35 mg as a yellow solid, major and minor mixture: 5 mg).

The (2S,3S)-3x was obtained following the general procedure (IV). 19 F NMR of the reaction crude showed dr = 94:6. The crude was purified by silica gel column chromatography (petroleum ether/CH2Cl2, from 5/1 to 2/1, v/v) affording two diastereoisomers in 37% yield (major: 30 mg as a yellow solid, major and minor mixture: 7 mg). 73% ee was obtained for the major diastereoisomer [determined by HPLC, IC column, Hept/ i PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 16.977 min, t (major) = 23.033 min.].

[α]D 20 = +183.2 (c 2.20, CDCl3); M.P. 80 -82 °C; 1 H NMR (300 MHz, CDCl3): δ 7. 18 -6.99 (m, 4H), 6.76 -6.73 (m, 2H), 6.62 -6.59 (m, 1H), 6.52 -6.47 (m, 1H) We first synthesized the (Z)-or (E)-α-trifluoromethyl acrylic acids (6'b-t)

following

Fang's protocol reported in 2011. 161 Then, these pure 6'b-t, obtained after further recrystallizations, followed the treatments with thionyl chloride in MeOH affording the corresponding (Z)-or (E)-α-trifluoromethylacrylates (6b-t) (Scheme 97).

General procedure (V) for the synthesis of α-trifluoromethyl acrylic acids (6'b-t):

To a stirred solution of aryl aldehyde (22.5 mmol, 1.5 equiv), 3,3,3-trifluoropropionic acid (15 mmol, 1 equiv) in dry THF (40 mL) was added TiCl4 (1 M in CH2Cl2, 30 mmol, 2 equiv) at room temperature. The mixture was stirred for 0.5 h, followed by adding dropwise Et3N (60 mmol, 4 equiv). After stirring for an additional 40 h, the reaction with quenched by adding water, then extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous Na2SO4 then concentrated under reduced pressure and purified by flash silica gel column chromatography (CH2Cl2/MeOH). The pure (Z)-or (E) α-trifluoromethyl acrylic acid (6') was obtained by further recrystallization from CH2Cl2/pentane mixed solvent.

General procedure (VI) for the synthesis of α-trifluoromethyl acrylates (6b-t):

The α-trifluoromethyl acrylic acid (6') (5 mmol, 1 equiv) was dissolved in anhydrous MeOH (20 mL). The resulting solution was cooled down to 0 °C, then the thionyl chloride (25 mmol, 5equiv) was added dropwise slowly. After the addition, keep the reaction mixture at 0 °C for 0.5 h and then warm to 60 °C for 6 h. The reaction was quenched by adding water and the mixture was extracted with CH2Cl2 (3×20 mL). JC-F = 271.5 Hz), 116.3 (q, JC-F = 33.0 Hz), 52.7. IR: 3113, 295652.7. IR: 3113, , 172052.7. IR: 3113, , 161352.7. IR: 3113, , 142252.7. IR: 3113, , 127052.7. IR: 3113, , 111952.7. IR: 3113, , 1039, 862, 714, 651, 614, 475, cm -1 , 862, 714, 651, 614, 475, cm -1 . HRMS (EI+) m/z: [M] + calcd for C11H6F6O2: 236.0113, found: 236.0127.

Methyl (Z)-3-(3,5-dimethoxyphenyl)-2-(trifluoromethyl)acrylate (6p):

Following the general procedure (VI): 6p was obtained as a white solid, 80% yield (1160 mg); M.P. 55 -56 °C; 1 H NMR (300 MHz, CDCl3): δ 8.01 (s, 1H), 6.49 -6.47 (m, 3H), 3.86 (s, 3H), 3.76 (s, 6H). 19 F NMR (282 MHz, CDCl3): δ -58.3 (s). 13 C{ 1 H} NMR ( 75MHz, CDCl3): δ 163.9 (d, JC-F = 1.9 Hz), 160.6, 148.5 (q, JC-F = 3.0 Hz ), 134.4, 123.1 (q, JC-F = 32.0 Hz), 121.8 (q, JC-F = 273.5 Hz), 107.1 (q, JC-F = 2. 5 Hz), 102.3, 55.5, 52.9. IR: 3004, 2974[START_REF]64.5 Hz). 31 P{ 1 H} NMR (121 MHz[END_REF], 1720, 1600, 1398, 1282, 1198[START_REF]) m/z: [M+H] + calcd for C23H20ClF3O3P: 467.0785, found: 467.0794. Methyl 2-((2-chlorophenyl)(diphenylphosphoryl)methyl)-3,3,3-trifluoropropanoate (8n): anti-8r: 1 H NMR (300 MHz, CDCl3): δ 7[END_REF], 1117, 1067, 1046, 834, 772, 630, 582 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C13H14F3O4: 291.0839, found: 291.0843.

Methyl (E)-2-(trifluoromethyl)-3-(2,4,6-trimethoxyphenyl)acrylate (6t):

JC-F = 161. 3 Hz), 55.3, 52.3. IR: 2956, 2840, 1706[START_REF]1115. Methyl 2-((4-chlorophenyl)(diphenylphosphoryl)methyl)-3,3,3-trifluoropropanoate (8m): Following the general procedure (X): 8m was obtained as a mixture of two diastereoisomers[END_REF], 1511, 1234, 1176, 949, 842, 522, 395 cm -1 . HRMS (EI+) m/z: [M + -F] calcd for C12H13O3: 205.0859, found: 205.0866. 52.8. IR: 296252.8. IR: , 170352.8. IR: , 151952.8. IR: , 134552.8. IR: , 1240, 980, 863, 715, 474, 384 cm -1 , 980, 863, 715, 474, 384 cm -1 . HRMS (EI+) m/z: [M] + calcd for C11H10FNO4: 239.0588, found: 239.0594. 2955, 1751, 1437, 1141, 1112, 881, 719, 699, 550, 536, 461, 423, 394 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C24H23F3O3P: 447.1331, found: 447.1327. 3058, 2927, 1749, 1439, 1322, 1182, 1154, 1130, 862, 716, 698, 608, 538, 513, 493 cm -1 . HRMS (ES+) m/z: [M+H] + calcd for C24H20F6O3P: 501.1049, found: 501.1048.

Methyl