Copper-Catalyzed Coupling between ortho-Haloanilines and Lactams/Amides: Synthesis of Benzimidazoles and Telmisartan.

An efficient copper-catalyzed synthesis of (annelated) benzimidazoles is reported. This transformation is based on a simple and straightforward one-pot sequence involving a copper-catalyzed cross coupling between o-haloanilines and lactams/amides followed by a subsequent cyclization under acidic conditions. A variety of (annelated) benzimidazoles could be easily obtained in high yields from readily available starting materials, and this procedure could be further applied to the synthesis of the antihypertensive blockbuster drug telmisartan.

Direct Access to Highly Enantioenriched α-Branched Acrylonitriles through a One-Pot Sequential Asymmetric Michael Addition/Retro-Dieckmann/Retro-Michael Fragmentation Cascade.

A highly enantioselective synthesis of α-branched acrylonitriles is reported featuring a one-pot sequential asymmetric Michael addition/retro-Dieckmann/retro-Michael fragmentation cascade. The method, which relies on a solid, bench-stable, and commercially available acrylonitrile surrogate, is practical, scalable, and highly versatile and provides a direct access to a wide range of enantioenriched nitrile-containing building blocks. Most importantly, the method offers a new tool to incorporate an acrylonitrile moiety in an asymmetric fashion.

Copper-Catalyzed Cross-Coupling between Alkyl (Pseudo)halides and Bicyclopentyl Grignard Reagents.

The development of a copper-catalyzed cross-coupling between primary and secondary (pseudo)halides and bicyclopentyl Grignard reagents is reported. Highly strained bicyclopentanes can be cross-coupled with a large panel of primary alkyl mesylates and secondary alkyl iodides. The catalytic system is simple and cheap, and the reaction is general and chemoselective.

Visible-Light-Driven CarboxyLic Amine Protocol (CLAP) for the Synthesis of 2-Substituted Piperazines under Batch and Flow Conditions.

Piperazines are privileged scaffolds in medicinal chemistry. Disclosed herein is a visible-light-promoted decarboxylative annulation protocol between a glycine-based diamine and various aldehydes to access 2-aryl, 2-heteroaryl, as well as 2-alkyl piperazines. The iridium-based complex [Ir(ppy)2(dtbpy)]PF6 and carbazolyl dicyanobenzene 4CzIPN were found to be the photocatalysts of choice to efficiently perform the transformation under mild conditions, whether in batch or in continuous mode.

A Unified Strategy for the Synthesis of Difluoromethyl- and Vinylfluoride-Containing Scaffolds.

Here, we report a general method for the synthesis of quaternary and tertiary difluoromethylated compounds and their vinylfluoride analogues. The strategy, which relies on a two-step sequence featuring a C-selective electrophilic difluoromethylation and either a palladium-catalyzed decarboxylative protonation or a Krapcho decarboxylation, is practical, scalable, and high yielding. Considering the generality of the method and the attractive properties offered by the difluoromethyl group, this approach provides a valuable tool for late-stage functionalization and drug development.

Introduction of Cyclopropyl and Cyclobutyl Ring on Alkyl Iodides through Cobalt-Catalyzed Cross-Coupling.

A cobalt-catalyzed cross-coupling between alkyl iodides and cyclopropyl, cyclobutyl, and alkenyl Grignard reagents is disclosed. The reaction allows the introduction of strained rings on a large panel of primary and secondary alkyl iodides. The catalytic system is simple and nonexpensive, and the reaction is general, chemoselective, and diastereoconvergent. The alkene resulting from the cross-coupling can be transformed to substituted cyclopropanes using a Simmons-Smith reaction. The formation of radical intermediates during the coupling is hypothesized.

Nickel-Catalyzed System for the Cross-Coupling of Alkenyl Methyl Ethers with Grignard Reagents under Mild Conditions.

A nickel-catalyzed cross-coupling of alkenyl methyl ethers with Grignard reagents, under mild conditions, is described. These conditions allowed access to various stilbenes and heterocyclic stilbenic derivatives as well as to a potential anticancer agent DMU-212.

Nickel-Catalyzed α-Allylation of Aldehydes and Tandem Aldol Condensation/Allylation Reaction with Allylic Alcohols.

An additive-free nickel-catalyzed α-allylation of aldehydes with allyl alcohol is reported. The reaction is promoted by 1 mol % of in situ formed nickel complex in methanol, and water is the sole by-product of the reaction. The experimental conditions allow the conversion of various α-branched aldehydes and α,ß-unsaturated aldehydes as nucleophiles. The same catalyst and reaction conditions enabled a tandem aldol condensation of aldehyde/α-allylation reaction.

TFA-promoted direct C-H sulfenylation at the C2 position of non-protected indoles.

A simple, efficient and practical metal-free C-H sulfenylation process at the C2 position of non-protected indoles has been developed. 2-Thioindoles were obtained in moderate to high yields using stable and readily available N-(thio)succinimides at room temperature in the presence of TFA.

Synthesis of Aryl Sulfides: Metal-Free C-H Sulfenylation of Electron-Rich Arenes.

A simple, efficient, and practical metal-free C-H sulfenylation of substituted electron-rich arenes has been developed. This method is highly regioselective, and the corresponding aryl sulfides were obtained in moderate to excellent yields from stable and readily accessible N-(alkylthio)- and N-(arylthio)succinimides at room temperature in the presence of TFA.

Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors.

Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.