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.     

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.     

A novel type of donor–acceptor cyclopropane with fluorine as the donor: (3 + 2)-cycloadditions with carbonyls

gem-Difluorocyclopropane diester is disclosed as a new type of donor–acceptor cyclopropane, which smoothly participates in (3 + 2)-cycloadditions with various aldehydes and ketones. This work represents the first application of gem-difluorine substituents as an unconventional donor group for activating cyclopropane substrates in catalytic cycloaddition reactions. With this method, a wide variety of densely functionalized gem-difluorotetrahydrofuran skeletons, which are otherwise difficult to prepare, could be readily assembled in high yields under mild reaction conditions. Computational studies show that the cleavage of the C–C bond between the difluorine and diester moieties occurs upon a S_N2-type attack of the carbonyl oxygen.

A new type of donor–acceptor cyclopropane with gem-difluorine as an unconventional donor group undergoes (3 + 2)-cycloadditions with various aldehydes/ketones, affording densely functionalized gem-difluorotetrahydrofurans.     

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.     

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-Dihalocyclopropane formation by iron/copper activation of tetrahalomethanes in the presence of nucleophilic olefins. Evidence for a carbene pathway

The activation of CBr₄ and CCl₄ by a bimetallic iron/copper couple in acetonitrile is a new, inexpensive, nontoxic and efficient procedure for gem-dibromo- and gem-dichloromethylenation of nucleophilic alkenes. This new route to gem-dihalocyclopropanes involves dihalocarbene species.     

Chiral ligands derived from abrine. Part 5: Substituent effects on asymmetric induction in enantioselective addition of diethylzinc to benzaldehyde catalyzed by chiral oxazolidines possessing an indole moiety

A number of the indole-containing chiral oxazolidines possessing the gem-di-p-tolyl and gem-di-o-tolyl groups at C₅ were synthesized from abrine and the effects of the C₅ and C₂ substituents on the asymmetric induction in catalytic enantioselective addition of diethylzinc to benzaldehyde were examined. A working model is proposed to rationalize the asymmetric catalysis by these chiral oxazolidines.     

Synthetic exploitation of halogenated alkenes containing an electron-withdrawing group: synthesis of α-chlorohydrazones and ketene aminals by regiospecific reactions of in situ generated imide chlorides

A concise approach for the construction of ketene aminals and α-chlorohydrazones has been developed. It involves reactions of the regiodefined gem-dihalo nitrovinyl compound of in situ generated imide chlorides in different media with primary arylamines being dependent on the aryl groups. A range of ketene aminals and α-chlorohydrazones are obtained in good to high yields. In addition, α-aminohydrazones are prepared by using α-chlorohydrazones as the precursors.     

Synthesis of γ,γ-difluoro-β-hydroxy-δ-lactones as new precursors of HMG-CoA reductase inhibitor

A series of γ,γ-difluoro-β-hydroxy-δ-lactones 1 were efficiently synthesized as new precursors of HMG-CoA reductase inhibitor in one pot by treatment of readily prepared gem-difluoromethylenated acetonides 3 with trifluoroacetic acid. Contrarily, acetonides 3 could be transformed to the γ,γ-gem-difluoromethylenated α,β-unsaturated δ-lactones 2 through hydrolyzation and lactonization in refluxing toluene.     

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.     

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.     

Dibromocarbene and bromofluorocarbene addition to substituted allylsilanes

The dibromocarbene or bromofluorocarbene addition to substituted allyldisilanes afforded instable gem-dibromocyclopropanes or a gem-bromofluorocyclopropane, respectively. These gem-bromohalogenocyclopropanes undergo a spontaneous ring opening at room temperature to give halogenated dienylsilanes or bromo dienes or dibromotetraenes.     

Recent advances in the synthesis and CF functionalization of gem-difluoroalkenes

The gem-difluoroalkenes and related compounds have gained much attention from the organic synthetic community due to their widespread applications as versatile fluorinated building blocks for the synthesis of pharmaceuticals, agrochemicals and functional materials. In the past two decades, significant progress has been made to the development of efficient methods for the construction of gem-difluoroalkenes and useful reactions involving the cleavage of CF bond in gem-difluoroalkenes. In this Digest review, these advances in the synthesis and reaction chemistry of gem-difluoroalkenes are summarized, with special emphasis placed on novel synthetic applications of them in recent ten years.     

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.     

Regio-selective hydroxylation of gem-difluorinated octanes by alkane hydroxylase (AlkB)

gem-Difluoromethylene substituted molecules constitute a distinct class of fluorinated compounds. In this study, special chemistry has been developed for their preparation based on the highly selective terminal hydroxylation of these gem-difluorinated octanes by AlkB (alkane hydroxylase) from Pseudomonas putida Gpo1 to form gem-difluorinated octan-1-ols. The hydroxylation reaction is performed by whole-cell catalysis. Identification of the distal- and proximal-hydroxylation products was made by ¹H, ¹³C, and ¹⁹F NMR; GC and GC/MSD; and/or by comparison with authentic standards in GC. To the best of our knowledge, we have obtained the first synthesis of 2,2-, 3,3- and 4,4-difluorooctan-1-ols, from simple and inexpensive starting materials.     

Synthesis of β-nitramino derivatives ofgem-dinitroalkanes

A method for the synthesis of β-nitramino derivatives ofgem-dinitroalkanes by nitration of the products of condensation of sulfamic acid derivatives with the correspondinggem-dinitroalkanes was proposed.     

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.     

Transition-metal-free coupling reactions involving gem‑diborylalkanes

Due to the increasing demand for the sustainability of modern organic chemistry, the development of green and powerful methods for C-C and C-B bond formation is highly desired. Among them, the transition-metal-free coupling reactions of gem‑diborylalkanes emerge as one valuable tool for organic chemists in the last decade. The review covers selected representative examples. A comparison of these reactions with transition-metal-catalyzed reactions is provided. The recent example of α-boryl radical formation from gem‑diborylalkanes is also briefly discussed.     

Copper-catalyzed synthesis of gem-difluoroallylboronates from α-trifluoromethyl alkenes and B2pin2

A novel and efficient method for the synthesis of gem-difluoroallylboronates via copper-catalyzed defluorinative borylation of α-trifluoromethyl alkenes with B₂pin₂ using Xantphos as ligand and NaOtBu as base was developed.     

Lanthanum metal-assisted cyclopropanation of alkenes with gem-dihaloalkanes

It was confirmed that lanthanum metal was an efficient reagent for the reductive dehalogenation of gem-dihaloalkanes. When gem-dihaloalkanes were allowed to react with lanthanum metal in the presence of alkenes, cyclopropanation of the alkenes occurred under mild conditions giving the corresponding cyclopropanes in moderate to good yields.