Practical Synthesis of Terminal Vinyl Fluorides.

The synthesis of di- and trisubstituted vinyl fluorides with high isomeric purity remains a challenge for organic synthesis. While many methods exist to access these compounds, the separation of the desired isomer from the minor isomer and/or starting materials often is difficult. Herein, we report a practical method to access di- and trisubstituted vinyl fluorides via a selective Horner-Wadsworth-Emmons olefination/hydrolysis, which provides crystalline 2-fluoroacrylic acids in high (>98%) E-isomeric purity. A subsequent silver-catalyzed stereoretentive decarboxylation provides the title substances with high isomeric purity and without the need for tedious chromatography to remove the minor isomer. The process was amenable to a variety of aldehydes and ketones and provided a diverse array of di- and trisubstituted vinyl fluorides. The sequence was applied to the synthesis of antibacterial and anti-inflammatory compounds.

Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes.

Selective carbon-carbon (C-C) bond formation in chemical synthesis generally requires prefunctionalized building blocks. However, the requisite prefunctionalization steps undermine the overall efficiency of synthetic sequences that rely on such reactions, which is particularly problematic in large-scale applications, such as in the commercial production of pharmaceuticals. Herein, we describe a selective and catalytic method for synthesizing 1,3-enynes without prefunctionalized building blocks. In this transformation several classes of unactivated internal acceptor alkynes can be coupled with terminal donor alkynes to deliver 1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols, (homo)propargyl amine derivatives, and (homo)propargyl carboxamides. This method is facilitated by a tailored P,N-ligand that enables regioselective addition and suppresses secondary E/Z-isomerization of the product. The reaction is scalable and can operate effectively with as low as 0.5 mol % catalyst loading. The products are versatile intermediates that can participate in various downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II) catalytic cycle.

Copper-catalyzed asymmetric hydrogenation of 2-substituted ketones via dynamic kinetic resolution.

A new class of tunable heterophosphole dimeric ligands have been designed and synthesized. These ligands have enabled the first examples of Cu-catalyzed hydrogenation of 2-substituted-1-tetralones and related heteroaryl ketones via dynamic kinetic resolution, simultaneously creating two contiguous stereogenic centers with up to >99 : 1 dr and 98 : 2 er. The ligand-Cu complexes were isolated and characterized by single crystal X-ray, and DFT calculations revealed a novel heteroligated dimeric copper hydride transition state.

BABIPhos Family of Biaryl Dihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation.

Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP.

Enantioselective Synthesis of α-(Hetero)aryl Piperidines through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights.

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.

Construction of Quaternary Stereocenters by Nickel-Catalyzed Heck Cyclization Reactions.

A nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters is reported. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in numerous biologically active molecules. The method shows broad scope, proceeds in synthetically useful yields, and provides a rare means to construct stereochemically complex frameworks by nonprecious-metal catalysis.

Carboxylate switch between hydro- and carbopalladation pathways in regiodivergent dimerization of alkynes.

Experimental and theoretical investigation of the regiodivergent palladium-catalyzed dimerization of terminal alkynes is presented. Employment of N-heterocyclic carbene-based palladium catalyst in the presence of phosphine ligand allows for highly regio- and stereoselective head-to-head dimerization reaction. Alternatively, addition of carboxylate anion to the reaction mixture triggers selective head-to-tail coupling. Computational studies suggest that reaction proceeds via the hydropalladation pathway favoring head-to-head dimerization under neutral reaction conditions. The origin of the regioselectivity switch can be explained by the dual role of carboxylate anion. Thus, the removal of hydrogen atom by the carboxylate directs reaction from the hydropalladation to the carbopalladation pathway. Additionally, in the presence of the carboxylate anion intermediate, palladium complexes involved in the head-to-tail dimerization display higher stability compared to their analogues for the head-to-head reaction.

Synthesis of fluoro- and perfluoroalkyl arenes via palladium-catalyzed [4 + 2] benzannulation reaction.

An efficient entry into densely substituted fluorinated and perfluoroalkylated benzene derivatives via chemo- and regioselective Pd-catalyzed [4 + 2] cross-benzannulation is presented. The synthetic utility of these products for the synthesis of various aromatic and heteroaromatic compounds is also demonstrated. This strategy offers a viable and quite general alternative to existing fluorination and perfluoroalkylation methods for securing these valuable molecules.

General and selective head-to-head dimerization of terminal alkynes proceeding via hydropalladation pathway.

A general highly regio- and stereoselective palladium-catalyzed head-to-head dimerization reaction of terminal acetylenes is presented. This methodology allows for the efficient synthesis of a variety of 1,4-enynes as single E stereoisomers. Computational studies reveal that this dimerization reaction proceeds via the hydropalladation pathway.