Stereodivergent Hydrohalogenation of SCF Alkynes and Cross- Coupling Reactions.

SCF-substituted internal alkynes undergo regio- and stereoselective hydrohalogenation to provide the corresponding β-halo-α-SCF-alkenes. The regioselectivity is ensured by the strong polarization of the C≡C triple bond in SCF-alkynes, while the stereoselectivity is governed by the strength of the proton donor and/or by the solvent polarity. The potential of β-iodo-α-SCF-alkenes was illustrated in several cross-coupling, protodeiodination, and cyanation reactions.

Photocatalyzed Cascade Hydrogen Atom Transfers for Assembly of Multi-Substituted α-SCF and α-SCFH Cyclopentanones.

A photocatalyzed formal (3+2) cycloaddition has been developed to construct original polysubstituted α-SCF cyclopentanones in a regio- and diastereoselective manner. This building block approach leverages trifluoromethylthio alkynes and branched/linear aldehydes, as readily available reaction partners, in consecutive hydrogen atom transfers and C-C bond formations. Difluoromethylthio alkynes are also compatible substrates.

10-Phenylphenothiazine-Organophotocatalyzed Bromo-Perfluoroalkylation of Unactivated Olefins.

In this study, we have developed a smooth metal-free visible-light-induced bromo-perfluoroalkylation of unactivated olefins with the aid of 10-phenylphenothiazine (PTH) as an organic photoredox catalyst. The reaction is 100% atom-economic redox-neutral and proceeds with stoichiometric amounts of olefin and perfluoroalkyl bromide. To show the potential of these unexplored motifs, we carried out various postfunctionalizations taking advantage of the bromine atom, including gram-scale experiments.

Stereoselective Nucleophilic Halogenation at CF-Substituted Nonclassical Carbocation.

CF-substituted cyclopropyl carbinol derivatives undergo regioselective and diastereoselective nucleophilic halogenation at the quaternary carbon center to provide acyclic products as a single diastereomer. The selectivity of the substitution is rationalized by the formation of a nonclassical cyclopropylcarbinyl cation intermediate, reacting at the most-substituted carbon center. Tertiary alkyl chlorides, bromides, and fluorides adjacent to a stereogenic C-CF-motif are diastereomerically pure and can be obtained in few catalytic steps from commercially available alkynes.

Expanding Radical Chloropentafluorosulfanylation of Alkynes.

The chloropentafluorosulfanylation of alkynes is a delicate but crucial operation for accessing SF-alkynes that serve as substrates in numerous transformations. Dolbier's procedure using EtB/O was the most efficient approach, while recent efforts make use of other initiators and light activation. We found that THF, as a single stimulus, is sufficient to trigger the reaction of SFCl with alkynes.

Tracking SF I in the Iodopentafluorosulfanylation of Alkynes.

In the vibrant field of SF chemistry, SF X reagents (X=F, Cl, Br) are at the heart of current investigations in radical pentafluorosulfanylation reactions. SF I is the missing link whose existence has not been reported despite its potential as SF donor. This study reports the formal addition of the hitherto unknown SF I reagent to alkynes by means of a combination of SF Cl/KI/18-crown-6 ether.

Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens.

We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor , in complex with GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound showed low nanomolar inhibition of DNA gyrase (IC < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.

Structure-property relationships of fluorinated carboxylic acid bioisosteres.

Fluorinated alcohols and phenols are potentially useful as bioisosteres of the carboxylic acid functional group. To enable a direct comparison of the properties of fluorinated carboxylic acid surrogates with those of other commonly used, non-fluorinated bioisosteres, we conducted a structure-property relationship (SPR) study based on matched molecular pair (MMP) analyses. A series of representative examples have been characterized by experimentally determining physicochemical properties, such as acidity (pK), lipophilicity (logD), and permeability (PAMPA).

N-Fluoro Ammonium Salts of Cinchona Alkaloids in Enantioselective Electrophilic Fluorination.

From 2000, our two research groups independently and simultaneously designed and developed a novel family of electrophilic fluorinating reagents based on the use of Cinchona alkaloids. The chiral N-fluoro ammonium salts demonstrated the highest efficiency compared to prior art in enantioselective electrophilic fluorination for a wide range of substrates. In this account, we tell our respective stories, how the same idea germinated in our laboratories, the characterization of the chiral reagents, the use in stoichiometric quantity then the development of a catalytic version, the application to the synthesis of chiral fluorinated molecules of pharmaceutical interest, and finally the exploitation of our reagents by other teams and for other applications.

Stereoselective Preparation of CF-Containing Cyclopropanes.

A regio- and diastereoselective carbometalation of easily accessible CF-substituted cyclopropenes is developed with a diastereoselectivity of the addition opposite to the CF group. This simple strategy allows the preparation of polysubstituted (up to penta-) cyclopropyl rings possessing two adjacent quaternary carbon stereocenters with excellent diastereoselectivities.

Amphiphilic Polyfluorinated Amino Ethers from Cyclic Sulfamidates.

Regioselective ring opening of cyclic sulfamidates was achieved by means of nucleophilic polyfluorinated alkoxides to access achiral and chiral β- and γ-OR amines and α-amino esters. Subsequent transformations provide free amines ready for incorporation into bioactive substances through amide bond formation or nucleophilic aromatic substitution.

KHMDS/Triglyme Cryptate as an Alternative to Phosphazene Base in Stereodivergent Pentafluoroethylation of -Sulfinylimines Using HFC-125.

A protocol for the stereodivergent pentafluoroethylation of -sulfinylimines using HFC-125 with KHMDS/triglyme has been developed. Both diastereomers of the pentafluoroethylated amines can be selectively synthesized based on the presence or absence of triglyme. This additive-controlled protocol allows the KHMDS/triglyme cryptate to be a straightforward and cheap alternative to previously reported base-controlled stereodivergent trifluoromethylation using potassium hexamethyldisilazide (KHMDS) versus P-Bu.

Catalytic Stereoconvergent Synthesis of Homochiral β-CF, β-SCF, and β-OCF Benzylic Alcohols.

We describe an efficient catalytic strategy for enantio- and diastereoselective synthesis of homochiral β-CF, β-SCF, and β-OCF benzylic alcohols. The approach is based on dynamic kinetic resolution (DKR) with Noyori-Ikariya asymmetric transfer hydrogenation leading to simultaneous construction of two contiguous stereogenic centers with up to 99.9% ee, up to 99.

Radical 1,5-Chloropentafluorosulfanylation of Unactivated Vinylcyclopropanes and Transformation into α-SF Ketones.

The radical 1,5-chloropentafluorosulfanylation of vinyl cyclopropanes (VCPs) initiated by EtB/O affords allylic pentafluorosulfanyl/homoallylic chloride products through the ring-strain release of the cyclopropane. The VCP substitution pattern was investigated. The utility of this reaction was illustrated in post-transformation of the C═C bond by ozonolysis, giving access to valuable α-SF carbonyl compounds.

Enantioselective catalytic synthesis of α-aryl-α-SCF-β-amino acids.

We herein report a novel entry towards chiral α-SCF3-β2,2-amino acids by carrying out the ammonium salt-catalyzed α-trifluoromethylthiolation of isoxazolidin-5-ones. This approach allowed for high enantioselectivities and high yields and the obtained heterocycles proved to be versatile platforms to access other targets of potential interest.

Asymmetric Electrophilic Difluoromethylthiolation of Indanone-Based β-Keto Esters Using Difluoromethanesulfonyl Hypervalent Iodonium Ylides.

The first electrophilic diastereoselective direct introduction of the difluoromethylthio group is described. We used a chiral auxiliary-based approach to illustrate the versatility of our recently developed difluoromethanesulfonyl hypervalent iodonium ylide reagents for the difluoromethylthiolation of indanone-based β-keto esters. Chiral SCF₂H-featuring compounds were obtained in up to 93% ee value.

CFSOX (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CFSOCl.

The recent progresses of the application of trifluoromethanesulfonyl chloride, CFSOCl, in the formation of C-CF, C-SCF, C-SOCF, and C-Cl bonds are summarised in this second part of a two-part review published back-to-back on both sodium trifluoromethanesulfinate, CFSONa, (Part 1) and trifluoromethanesulfonyl chloride, CFSOCl (Part 2). There are many reactions in common between these two reagents but it should be noted that CFSOCl reacts under reductive conditions while CFSONa requires oxidative conditions. Electrophilic chlorination is obviously the exclusive preserve of CFSOCl that has been exploited with emphasis in enantioselective chlorination.

CFSOX (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CFSONa.

Sodium trifluoromethanesulfinate, CFSONa, and trifluoromethanesulfonyl chloride, CFSOCl, are two popular reagents that are widely used for the direct trifluoromethylation of a large range of substrates. Further, these two reagents are employed for the direct trifluoromethylsulfenylation and trifluoromethylsulfinylation, the introduction of the SCF and the S(O)CF group, respectively. In addition to the aforementioned reactions, the versatility of these two reagents is presented in other reactions such as sulfonylation and chlorination.

Telescoping Reactions with Trifluorodiazoethane-Derived Aza-Wittig Reagents and Allenyl esters.

A telescoping process involving the consecutive addition of four reagents (trifluorodiazoethane, phosphine, allenyl ester, and acetic acid) into a single reactor was developed for the novel functionalization of allenyl esters. First, new phosphazenes derived from trifluorodiazoethane and phosphines were generated and reacted with allenyl esters to give unexpected α-iminophosphoranes through the creation of C=P, C=N, and C-H bonds at the α-, β-, and γ-carbon atoms, respectively, of the allenyl esters. The α-iminophosphoranes did not react with aldehydes in a classic Wittig reaction, but instead β-enamino esters were obtained.

Nucleophilic Trifluoromethylthiolation of Cyclic Sulfamidates: Access to Chiral β- and γ-SCF Amines and α-Amino Esters.

The regio- and stereoselective ring opening of 1,2- and 1,3-sulfamidates with trifluoromethanethiolate anion is reported. This direct introduction of the whole SCF motif is a straightforward synthetic route toward β- and γ-SCF amines and α-amino acid derivatives. The utility of this reaction was further illustrated by incorporation of Cys(S-CF) into di- and tripeptides.

Novel Use of CF3SO2Cl for the Metal-Free Electrophilic Trifluoromethylthiolation.

The regioselective trifluoromethylthiolation of indole derivatives was achieved under reductive conditions with trifluoromethanesulfonyl chloride as the readily available source of electrophilic SCF3 and a phosphine as the reducing agent. It is a straightforward process free from any metal and also applicable for the trifluoromethylthiolation of other azaarenes, enamines, and enoxysilanes.

Stereoarrayed CF3 -Substituted 1,3-Diols by Dynamic Kinetic Resolution: Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation.

CF3 -substituted 1,3-diols were stereoselectively prepared in excellent enantiopurity and high yield from CF3 -substituted diketones by using an ansa-ruthenium(II)-catalyzed asymmetric transfer hydrogenation in formic acid/triethylamine. The intermediate mono-reduced alcohol was also obtained in very high enantiopurity by applying milder reaction conditions. In particular, CF3 C(O)-substituted benzofused cyclic ketones underwent either a single or a double dynamic kinetic resolution during their reduction.

Enantiomerization of Allylic Trifluoromethyl Sulfoxides Studied by HPLC Analysis and DFT Calculations.

Enantiomerization of allylic trifluoromethyl sulfoxides occurs spontaneously at room temperature through the corresponding allylic trifluoromethanesulfenates via a [2,3]-sigmatropic rearrangement. Dynamic enantioselective high-performance liquid chromatography (HPLC) analysis revealed the stereodynamics of these sulfoxides ranging from chromatographic resolution to peak coalescence at temperatures between 5 and 53 °C. The rate constant of enantiomerization and activation parameters were determined and compared with Density Functional Theory (DFT) calculations.

Trifluoromethyl sulfoxides from allylic alcohols and electrophilic SCF3 donor by [2,3]-sigmatropic rearrangement.

An electrophilic trifluoromethylthiolation of allylic alcohols produces the corresponding allylic trifluoromethanesulfenates, which spontaneously rearrange into trifluoromethyl sulfoxides via a [2,3]-sigmatropic rearrangement. The reaction is straightforward and proceeds in good to high yields for the preparation of various allylic trifluoromethyl sulfoxides.

Palladium(II)-catalyzed directed trifluoromethylthiolation of unactivated C(sp³)-H bonds.

The synthesis of trifluoromethylthiolated aliphatic acid derivatives by Pd-catalyzed C(sp(3))-H bond functionalization was developed. Using a bidentate directing group, the direct and selective introduction of a SCF3 moiety was possible on a range of amides with remarkable selectivity for C(sp(3))-centers with an electrophilic SCF3 source and pivalic acid as an additive. This work constitutes an example of the unactivated C(sp(3))-SCF3 bond formation by C-H activation offering a new access to relevant molecules.