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.     

Preparation of new gem-difluoro heterocyclic-fused 1,2,3-triazole derivatives

Starting from easily accessible gem-difluoropropargylic derivatives a cascade nucleophilic substitution by N₃^–, followed by an intramolecular 1,3 dipolar cycloaddition, afforded in fair to good yields new 1,2,3-triazoles fused to pyrrolidines or piperidines. These molecules, with a gem-difluoro group vicinal to the triazoles, are fluorinated analogues of bioactive heterocycles. In parallel, a few open chain analogues have been prepared in order to evaluate the possible role of the bicyclic core on the biological properties of such molecules.     

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.     

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.     

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.     

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.     

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.     

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.     

Synthesis of optically active gem-difluorocyclopropanes through a chemo-enzymatic reaction strategy

The synthesis of a chiral difluorocyclopropane building block has been accomplished using lipase-catalyzed reaction; the prochiral diacetate of cis-1,3-bishydroxymethyl-2,2-difluorocyclopropane was converted to the corresponding chiral monoacetate by the Alcaligenes lipase (lipase QL)-catalyzed hydrolysis with >99% enantiomeric excess. Enantiomerically pure trans-1,3-bishydroxymethyl-2,2-difluorocyclopropane was also obtained through the Pseudomonas cepacia SL-25 lipase (lipase SL)-catalyzed reaction. The synthesis of the chiral trans,trans-bis-gem-difluorocyclopropane derivatives has been accomplished using the same lipase technology; trans,trans-1,6-bishydroxymethyl-2,2,5,5-tetrafluorobicyclopropane was obtained in optically active form using the lipase SL-catalyzed hydrolysis of the corresponding diacetate.     

Synthesis of gem-difluoromethylenated massoialactone by ring-closing metathesis

4,4-Difluoromassoialactone has been synthesized for the first time via a very short sequence, where the ring-closing metathesis (RCM) was employed as a key step. The efficient procedure can easily be extended to the synthesis of other gem-difluoromethylenated α,β-unsaturated-δ-lactone moiety. In addition, the viability of RCM of high electron-deficient olefins has been demonstrated.     

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.     

A simple, efficient and versatile synthesis of primary gem-dihydroperoxides from aldehydes and hydrogen peroxide

Aldehydes were efficiently converted directly into the corresponding gem-dihydroperoxides (DHPs) on treatment with aqueous 70% H₂O₂ in a biphasic system with ether catalyzed by camphorsulfonic acid. The synthesis represents the most versatile access to this class of compounds.     

One-pot approach for the synthesis of 2-aryl benzothiazoles via a two-component coupling of gem-dibromomethylarenes and o-aminothiophenols

One-pot synthesis of 2-aryl benzothiazoles from gem-dibromomethylarenes using 2-aminoarylthiols is described. Benzothiazoles were obtained in high chemical yields under mild conditions. This transformation would facilitate synthesis by short reaction times, large-scale synthesis, easy and quick isolation of the products, which are the main advantages of this procedure.     

A new strategy for the synthesis of fluorinated 3,4-dihydropyrimidinones

A new family of 3,4-dihydropyrimidinones (DHPMs) bearing fluorinated substituents at C6 have been prepared from gem-difluorinated nitriles, alkyl 3-butenoates and iso(thio)cyanates. This novel Biginelli-type process relies on the γ-addition of the ester-derived enolate to fluorinated nitriles. A tandem nucleophilic addition aza-Michael reaction sequence completes the synthetic process.     

Non-catalytic conversion of C-F bonds of gem-difluoromethylene derivatives to C-H bonds with lithium aluminum hydride under room temperature

An unexpected hydrodefluorination of unactivated aliphatic C-F bonds of CF₂ derivatives with LiAlH₄ at room temperature without any added metal catalyst was reported. Deuterium-labeling experiments suggested that the hydrogens introduced into the products originated from LiAlH₄.     

Carbenoid rearrangement of gem-dihalogenospiropentanes

A skeletal rearrangement of dihalogenospiropentanes in the presence of alkyllithium reagents has been systematically studied using a number of gem-dibromospiropentanes. The scope and limitations of this carbenoid rearrangement are outlined and its mechanism is discussed.     

gem-Bromochlorospiropentane reactivity toward methyllithium: an unusual carbenoid rearrangement

A skeletal carbenoid rearrangement of the gem-bromochlorospiropentanes in the presence of methyllithium has been studied. The synthetic and mechanistic aspects of this rearrangement as well as the influence of the halogen atom nature on the reaction pathway are discussed.     

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.     

Synthesis of gem-difluoromethylenated biflavonoid via the Suzuki coupling reaction

gem-Difluoromethylenated biflavonoid 1 was synthesized via the Suzuki coupling reaction. The key intermediate 6-iodonated flavone 4 was regioselectively synthesized by the use of AgOAc/I₂ under mild conditions without handling of a strongly toxic reagent. The key step was the formation of a flavone 3′-boronate 3 using a palladium-catalyzed exchange of the corresponding 3′-iodonated flavone with a diboron reagent.     

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.