Chemoselective and stereoselective synthesis of gem-difluoro-β-aminoesters or gem-difluoro-β-lactams from ethylbromodifluoroacetate and imines during Reformatsky reaction

The chemoselective and stereoselective synthesis of gem-difluoro-β-aminoesters or gem-difluoro-β-lactams was investigated from ethylbromodifluoroacetate and imines during Reformatsky reaction. Influence of various reaction parameters, such as nature of the amine part, nature of the chiral auxiliary, was evaluated. High levels of stereoselectivity (up to 98%) were obtained for gem-difluoro-β-aminoesters and gem-difluoro-β-lactams using either (R)-phenylglycinol or (R)-methoxyphenylglycinol.     

Practical synthesis of gem-difluorides from cyclohexanone: Synthesis of gem-bistrifluoroacetates and their reactions with fluoride nucleophiles

Formation of ketone acylals bearing trihaloacetoxy groups and their nucleophilic geminal disubstitution by fluoride ions were investigated. Cyclohexanone reacted with trifluoroacetic anhydride without catalyst to give gem-bistrifluoroacetates via a concerted bimolecular reaction. Treatment with hydrogen fluoride under mild conditions efficiently yielded the corresponding gem-difluorides. In this reaction process, trifluoroacetic acid was recovered and converted to trifluoroacetic anhydride using P₂O₅. Since gem-difluorides were derived from ketones, HF and P₂O₅, this constitutes a practical synthesis of gem-difluorides.     

Synthesis of gem-difluorides from aldehydes using DFMBA

Synthesis of gem-difluorides from aldehydes was effectively achieved using DFMBA and Et₃N-3HF under microwave irradiation or conventional thermal heating. Both aromatic and aliphatic aldehydes could be converted to the corresponding gem-difluorides in good yields.     

Synthesis of gem-diamino derivatives on solid support

Anchoring of an α-amino-acid amide residue by its amine function to a carbamate resin followed by primary amide Hofmann rearrangement led to a gem-diamino residue linked to the resin. The generated primary amine could be acylated with various carboxylic compounds offering a large variety of molecules. Furthermore, this new solid-phase strategy allowed a reliable synthesis of a gem-diamino monomeric residue which could not be easily obtained in solution due to the limited stability of monocarbamate-protected gem-diaminoalkyl derivatives.     

A new flexible strategy for the synthesis of gem-difluoro-bisarylic derivatives and heterocyclic analogues

A new strategy has been designed for the preparation of gem-difluoro-bisarylic derivatives. It starts from easily accessible and reactive gem-difluoro-propargylic intermediates and elaborates the aromatic rings by a Diels-Alder-aromatization sequence. Heterocyclic systems can be also obtained by 1,3 dipolar cycloadditions, affording mixed aromatic/heteroaromatic derivatives with CF₂ as a linker. Since this motif is a bioisostere of O and CO, corresponding bisarylic scaffolds could be of use to prepare chemical libraries of fluorinated analogues of bioactive natural products and/or drugs.     

α,α-Difluoro-α-phenylsulfanylmethyl carbanion equivalent: a novel gem-difluoromethylenation of carbonyl compounds

α,α-Difluoro-α-phenylsulfanyl-α-trimethylsilylmethane (PhSCF₂SiMe₃) has been demonstrated as an α,α-difluoro-α-phenylsulfanylmethyl carbanion equivalent. gem-Difluorophenylsulfanylmethylation of carbonyl compounds has been successfully achieved by using PhSCF₂SiMe₃ in the presence of TBAF in THF. The adducts have been converted to the corresponding gem-difluoroalkenes by a novel pyrolytic and/or FVP elimination of the β-hydroxy-α-phenylsufinyl derivatives under reduced pressure.     

Ring-opening reaction of methylenecyclopropanes with LiCl, LiBr or NaI in acetic acid

The methylenecyclopropanes 1 react with LiCl, LiBr or NaI at 80 °C to give the corresponding gem-disubstituted homoallylic halides 2 in good to excellent yields in acetic acid. In some cases, the ring-opening reaction can be completed within 5 min to give the corresponding gem-disubstituted homoallylic halides in high yields.     

Fritsch-Buttenberg-Wiechell rearrangement to alkynes from gem-dihaloalkenes with lanthanum metal

The first example of the FBW rearrangement using of lanthanum metal and a catalytic amount of iodine was disclosed. When gem-diiodo- and gem-dibromoalkenes were treated with lanthanum metal in the presence of a catalytic amount of iodine, the reductive dehalogenation of these compounds smoothly proceeded to produce the corresponding alkynes in moderate to good yields.     

gem-Difluoromethylation of α- and γ-ketoesters: preparation of gem-difluorinated α-hydroxyesters and γ-butyrolactones

PhSCF₂SiMe₃ has been demonstrated as difluoromethyl carbanion synthon (⁻CF₂H). It reacts chemoselectively with α- and γ-ketoesters at the keto group in the presence of a catalytic amount of TBAF in THF to give the corresponding α-hydroxy ester adducts as well as γ-gem-difluorophenylsulfanylmethylated-γ-butyrolactones in good yields. Reductive cleavage of the phenylsulfanyl group of these products employing Bu₃SnH/AIBN gives the corresponding gem-difluoromethylated α-hydroxyesters and γ-butyrolactones in good yields.     

Efficient partial hydrogenation of trichloromethyl to gem-dichloromethyl groups in platinum on carbon-catalyzed system

While gem-dichloromethyl groups can be directly synthesized by the mono-dechlorination of the corresponding trichloromethyl groups, the suppression control of the over-reduction to form chloromethyl or methyl functionalities is quite difficult. We have established the efficient and widely applicable mono-dechlorination method of the trichloromethyl groups to form the corresponding gem-dichloromethyl groups using platinum on carbon in dimethylacetamide as a specific solvent at 25 °C under a hydrogen atmosphere. The mono-dechlorination of the α,α,α-trichloromethylcarbonyl groups smoothly proceeded by the use of platinum on carbon as a catalyst in a highly chemoselective manner, while the efficient mono-dechlorination of the alkyl- and aryl-trichloromethyl groups required the combined use of Bu₃SnH.     

N-tert-Butyl-N-chlorocyanamide: a new reagent for the efficient preparation of gem-chloronitroso compounds

A new reagent for the efficient preparation of gem-chloronitroso compounds has been developed. The reaction of ketoximes with N-tert-butyl-N-chlorocyanamide takes place instantaneously in carbon tetrachloride at room temperature with excellent yields under mild conditions.     

One-pot synthesis of benzimidazoles from gem-dibromomethylarenes using o-diaminoarenes

A one-pot synthesis of benzimidazoles from gem-dibromomethylarenes is described. The reaction shows the method to prepare a variety of benzimidazole analogues with excellent yield.     

Synthesis of gem-difluoromethylenated analogues of anamarine

Practical synthesis of two gem-difluoromethylenated analogues of anamarine was described. The important synthetic steps included the preparation of the key intermediates 20-21 through the indium-mediated gem-difluoropropargylation of aldehyde 18 with the fluorine-containing building block 19 and efficient construction of α,β-unsaturated-δ-lactone scaffold via BAIB/TEMPO procedure.     

Highly efficient copper/palladium-catalyzed tandem Ullman reaction/arylation of azoles via C-H activation: synthesis of benzofuranyl and indolyl azoles from 2-(gem-dibromovinyl)phenols(anilines) with azoles

In this paper, a novel and highly efficient copper/palladium-catalyzed tandem intramolecular Ullman-type C-O(N) coupling reaction of 2-(gem-dibromovinyl)phenols(anilines) followed by an intermolecular arylation of azoles through C-H activation has been developed. In the presence of CuBr with Pd(PPh₃)₂Cl₂ used as co-catalyst, and LiO^tBu as a base, the one-pot reactions of 2-(gem-dibromovinyl)phenols and 2-(gem-dibromovinyl)anilines with a variety of azoles, including oxazoles, imidazoles, thiazoles, and oxadiazoles underwent smoothly in toluene at 100 °C to generate the corresponding biheteroaryl products in high yields. A tentative mechanism of copper/palladium-catalyzed tandem reaction was described.     

Recent advances in asymmetric fluorination and fluoroalkylation reactions via organocatalysis

The past decade has witnessed the significant advances of asymmetric organocatalytic fluorination, monofluoroalkylation, gem-difluoroalkylation, and trifluoromethylation. This digest summarizes the latest progress of these reactions. In the research area of asymmetric organocatalytic fluorination, a new catalysis concept, chiral anion phase-transfer catalysis strategy, has emerged and has proved to be highly efficient. Asymmetric organocatalytic monofluoroalkylation and gem-difluoroalkylation have been much less explored and the Lewis base/acid catalysis has been the most used strategy. Compared with electrophilic trifluoromethylation, nucleophilic trifluoromethylation has been intensively studied in the research field of asymmetric organocatalytic trifluoromethylation.     

Chemistry of difluorocarbene adducts: Stereospecific synthesis of conjugated fluoroolefins and 1,3-azabutadienes from gem-difluorocyclopropenyl ketones

Treatment of gem-difluorocyclopropenyl ketones with malonate anion, amine gave stereospecifically conjugated fluoroolefins and azabutadienes, respectively.     

Three-component reactions of polynitromethanes with alkynes. The first synthesis of gem-dinitroaziridines

Three-component one-pot reactions of tetranitro- and bromotrinitromethanes with alkoxyacetylenes, mediated by diazomethane or bicyclobutylidene, yielding gem-dinitroaziridines via sequential electrophile transfer followed by [3+2]-cycloaddition, have been studied. A series of novel N-alkoxy-2,2-dinitroaziridines have been prepared by these reactions.     

Synthesis of gem-dihaloenynes and butatrienes from gem-dihalovinyl derivatives

gem-Dihaloenynes were synthesized in high yields from 1,1,4,4-tetrahalo-1,3-butadienes through the Fritsch-Buttenberg-Wiechell (FBW) rearrangement mediated by an organolithium compound. Butatriene derivatives could be obtained efficiently via an organolithium-mediated reaction of o-halo-(2,2-dihalovinyl)benzenes.     

ZnCl2-catalyzed hydrodefluorination of gem-difluoromethylene derivatives with lithium aluminum hydride

Hydrodefluorination of gem-difluoromethylene derivatives with lithium aluminum hydride in the presence of a catalytic amount of ZnCl₂ in good to high yields was described. A possible mechanism is also suggested.     

A versatile method for the hydrolysis of gem-dibromomethylarenes bearing carboxylate or boronate group into aldehydes

Hydrolysis of gem-dibromomethylarenes bearing carboxylate or boronate group to corresponding aldehydes without affecting the ester group was successfully accomplished in high yields by subjecting them to refluxing pyridine. Both aromatic and heteroaromatic substrates gave the corresponding aldehydes in good yields. This method was efficiently adapted for the large scale synthesis of 2d and 2f.