Copper-catalyzed aryldifluoromethylenation of N-arylacrylamides to synthesis of the diheterocyclic compounds linked by gem-difluoromethylene moiety

An efficient method of copper-catalyzed aryldifluoromethylenation of N-arylacrylamides is described to step-economic synthesis of the various biologically important biheterocyclic compounds linked by gem-difluoromethylene moiety through addition of benzo-1,3-azolic (oxa- or thia-)difluoromethyl radicals generated in situ to terminal of C–C double bond of N-arylacrylamides then cyclization cascade. This protocol has demonstrated to have broad substrate scope and excellent functional-group tolerance under mild reaction conditions.     

1-tert-Butyl-1H-tetrazol-5-yl fluoromethyl sulfone (TBTSO2CH2F): a versatile fluoromethylidene synthon and its use in the synthesis of monofluorinated alkenes via Julia–Kocienski olefination

1-tert-Butyl-1H-tetrazol-5-yl fluoromethyl sulfone (TBTSO₂CH₂F) has been developed as a new and efficient fluoromethylidene synthon for the synthesis of both terminal and internal monofluoroalkenes via Julia–Kocienski olefination reaction. The base-mediated reaction between TBTSO₂CH₂F and carbonyl compounds (aldehydes and ketones) provided terminal monofluoroalkenes in good yields with moderate E/Z selectivity. The dominance of E- or Z-fluoroalkenes could be controlled by selection of proper reaction solvent and temperature. TBTSO₂CH₂F reagent was also found to be readily α-alkylated, acylated, and phenylsulfonylated to give corresponding α-functionalized fluorosulfones, which could be used in the synthesis of alkyl-, acyl-, and phenylsulfonyl-substituted internal monofluoroalkenes via Julia–Kocienski olefination reactions.     

Facile synthesis of 2-bromoindoles by ligand-free CuI-catalyzed intramolecular cross-coupling of gem-dibromoolefins

A mild and efficient synthesis of 2-bromoindoles by ligand-free CuI-catalyzed intramolecular cross-coupling of gem-dibromoolefins was developed. Reactions were carried out in toluene at room temperature and the corresponding 2-bromoindoles were obtained in excellent 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.     

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.     

A rapid and convenient synthesis of gem-bis(dithiocarbamate) derivatives from primary aliphatic amines,carbon disulfide,and aromatic aldehydes using boron trifluoride-diethyl etherate

An efficient route for the synthesis of gem-bis(dithiocarbamate) derivatives is developed using dithiocarbamic acid salts generated from primary aliphatic amines and CS₂. The method offers high yields, employs mild reaction conditions, and demonstrates excellent functional group compatibility. The structures of the products were confirmed spectroscopically and by X-ray analysis.     

Diastereoselective Synthesis of Monofluorocyclohexenes through Photocatalyzed Cascade Cyclization of gem-Difluoroalkenes and α,β-Unsaturated Carbonyl Compounds

Monofluoroalkenes are nonhydrolyzable mimetics of amides. Previous work focused on the synthesis of non-cyclic monofluoroalkenes. However, diastereoselective synthesis of monofluorocyclohexenes from non-cyclic substrates is challenging. Herein, we report the first photocatalyzed cascade cyclization reactions of readily available α,β-unsaturated carbonyl compounds and gem-difluoroalkenes for the synthesis of highly functionalized monofluorocyclohexenes. The reaction shows broad substrate scope with high diastereoselectivity (>30 examples, up to 86 % yield, >20 : 1 dr). The post-reaction transformations of the products demonstrate the synthetic potential of this methodology.     

Convenient and efficient access to tri- and tetra-substituted 4-fluoropyridines via a [3 + 2]/[2 + 1] cyclization reaction

A [3 + 2]/[2 + 1] cycloaddition reaction of gem?difluorocyclopropenes is presented, offering a mild and efficient approach to accessing tri- and tetra-substituted 4-fluoropyridines in moderate to good yields with excellent regioselectivity. Multiple synthetic applications, including process-scale reactions, modification of bioactive molecules, derivatization reactions and synthesis of the analogue of the PKM2 modulator, are subsequently described.     

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-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.     

Preparation of Chitosan-Composite-Film-Supported Copper Nanoparticles and Their Application in 1,6-Hydroboration Reactions of p-Quinone Methides

Here, we describe the preparation of copper nanoparticles that are stabilized on a chitosan composite film (CP@Cu). This material could catalyze the 1,6-hydroboration reactions of p-quinone methides with B₂pin₂ as a boron source under mild conditions. This reaction exhibited very good functional group compatibility, and the organoboron compounds that were formed could easily be converted into corresponding hydroxyl products with good to excellent yields. This newly developed methodology provides an efficient and sequential pathway for the synthesis of gem-disubstituted methanols.     

Nanocrystalline magnesium oxide as a solid base catalyst promoted one pot synthesis of gem-dichloroaziridine derivatives under thermal conditions

In this study, efficient and mild synthesis of gem-dichloroaziridines from Schiff bases in the presence of nanocrystalline magnesium oxide/chloroform as a novel source of dichlorocarbene intermediate under thermal conditions have been described. The reaction is dramatically enhanced in the presence of nanocrystalline magnesium oxide, and any byproducts were detected during or after the reaction. The corresponding products have been obtained in excellent yields, high purity and short reaction times.     

One-Pot and Catalyst-Free Transformation of N-Protected 1-Amino-1-Ethoxyalkylphosphonates into Bisphosphonic Analogs of Protein and Non-Protein α-Amino Acids

Herein, we describe the development of one-pot transformation of α-ethoxy derivatives of phosphorus analogs of protein and non-protein α-amino acids into biologically important N-protected 1-aminobisphosphonates. The proposed strategy, based on the three-component reaction of 1-(N-acylamino)-1-ethoxyphosphonates with triphenylphosphonium tetrafluoroborate and triethyl phosphite, facilitates good to excellent yields under mild reaction conditions. The course of the reaction was monitored by ³¹P NMR spectroscopy, allowing the identification of probable intermediate species, thus making it possible to propose a reaction mechanism. In most cases, there is no need to use a catalyst to provide transformation efficiency, which increases its attractiveness both in economic and ecological terms. Furthermore, we demonstrate that the one-pot procedure can be successfully applied for the synthesis of structurally diverse N-protected bisphosphonic analogs of α-amino acids. As shown, the indirect formation of the corresponding phosphonium salt as a reactive intermediate during the conversion of 1-(N-acylamino)-1-ethoxyphosphonate into a 1-aminobisphosphonate derivative is a crucial component of the developed methodology.     

Rhodium-catalyzed formal [4 + 3] annulation reaction of N-methoxybenzamides with gem‑difluorocyclopropenes: A combination of experimental and theoretical studies

A rhodium-catalyzed [4 + 3] cycloaddition reaction between N-methoxybenzamides and gem?difluorocyclopropenes is described. The reaction offers a mild and efficient approach towards the synthesis of fluorinated 2H-azepin-2-ones with broad substrate scope. A consecutive HOAc-assisted CN bond formation and fluorine elimination are involved as key steps for success as illustrated by detailed DFT studies.     

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.     

New gem-difluoromethylene-containing isocyanide as a useful building block for the synthesis of difluorinated pseudopeptides via Ugi reaction

A new and efficient method was developed for the synthesis of novel gem-difluoromethylene-containing isocyanide, which can be used as a building block for the synthesis of difluorinated pseudopeptides via Ugi reaction.     

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.     

Rhodium-Catalyzed Regio- and Diastereoselective [3+2] Cycloaddition of gem-Difluorinated Cyclopropanes with Internal Olefins

Direct synthesis of gem-difluorinated carbocyclic molecules represents a longstanding challenge in organic chemistry. Herein, a Rh-catalyzed [3+2] cycloaddition reaction between readily available gem-difluorinated cyclopropanes (gem-DFCPs) and internal olefins has been developed, enabling the efficient synthesis of gem-difluorinated cyclopentanes with good functional group compatibility, excellent regioselectivity and good diastereoselectivity. The resulting gem-difluorinated products can undergo downstream transformations to access various mono-fluorinated cyclopentenes and cyclopentanes. This reaction demonstrates the use of gem-DFCPs as a type of “CF₂” C3 synthon for cycloaddition under transition metal catalysis, which provides potential strategy for synthesizing other gem-difluorinated carbocyclic molecules.     

A Convenient Synthesis of Diketopyrrolopyrrole Dyes

Diketopyrrolo[3,4-c]pyrroles (DPP) are high-performance organic optoelectronic materials. They have applications in solar cells, fluorescent probes, bioimaging, photodynamic/photothermal therapy, and in many other areas. This article reports a convenient two-step synthesis of various DPP dyes from Pigment Red 254, an inexpensive commercial pigment. The synthesis includes a Suzuki–Miyaura cross-coupling reaction of a bis(4-chlorophenyl)DPP derivative with aryl and hetaryl boronic acids under mild reaction conditions. The new dyes show large Stokes shifts and high fluorescence quantum yields, important features for their potential use in technical and biological applications.     

Solvent- and catalyst-free gem-bisallylation of carboxylic acid derivatives with allylzinc bromide

A rapid and efficient procedure for the solvent-free synthesis of gem-bisallylation products has been achieved by allylzinc bromide with carboxylic acid derivatives in the absence of any catalysts at room temperature.