An efficient palladium-catalyzed process has been developed for Negishi coupling of secondary alkylzinc halides and sterically and electronically demanding aryl bromides and activated aryl chlorides. The palladium catalyst composed of a new biaryldialkylphosphine ligand, CPhos, effectively promotes the reductive elimination step relative to the undesired β-hydride elimination pathway. The general substrate scope and excellent ratio of the desired secondary to the undesired primary coupling product make this method a powerful and reliable tool for C(sp 3 )-C(sp 2 ) bond formation.The transition-metal-catalyzed cross-coupling reactions involving sp 2 -hybridized carbon nucleophiles and aryl or vinyl halides have been extensively examined during the past three decades. 1 In contrast, few comprehensive studies have been published concerning the analogous cross-coupling of secondary C(sp 3 )-hybridized organometallics with aryl halides. 2 A simplified scheme of the course of the reaction for the coupling of an isopropyl metal with an aryl halide is shown (Scheme 1). 1 Oxidative addition followed by transmetallation would produce intermediate B, which can reductively eliminate to form the desired product i-PrAr with concomitant reformation of L n Pd(0). Competitive with this is the reversible β-hydride elimination to form C, from which reductive elimination can take place producing reduced arene. Additionally, C can undergo a migratory insertion reaction to produce D which can reductively eliminate to form the undesired product n-PrAr. Of obvious importance to developing a successful catalytic method is to have ligands that will facilitate the rate of reductive elimination from B relative to the rate of β-hydride elimination.Pioneering work by Kumada and Hayashi demonstrated, with a limited set of substrates, that dichloro[1,3-bis(diphenylphosphino)propane] nickel(II) (NiCl 2 (dpppk)) 2h and dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(II) (PdCl 2 (dppf)) 2i could be used for the coupling of secondary alkyl Grignard reagents with aryl and vinyl halides. Recently, Dreher and Molander reported an elegant and more comprehensive study of the Pd-catalyzed SuzukiMiyaura coupling of secondary alkyltrifluoroborates with aryl chlorides. 2g These publications describe the formation of good ratios of secondary to primary alkyl coupling products in a Correspondence to: Stephen L. Buchwald, sbuchwal@mit.edu. Supporting Information Available. Experimental procedures, structural proofs, and spectral data for all new compounds are provided (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. number of cases. However, the product ratios obtained when electron-deficient and/or orthosubstituted aryl halide substrates were used were poor to moderate and the substrate scope reported was somewhat limited in terms of the functional groups that were demonstrated to be tolerated. NIH Public AccessIn this communication, we report a general catalyst for the palladium-catalyzed Negishi cou...

A process for preparation of amides from unactivated esters and amines has been developed using a catalytic system comprised of group (IV) metal alkoxides in conjunction with additives including 1-hydroxy-7-azabenzotriazole (HOAt). In general, ester-amide exchange proceeds using a variety of structurally diverse esters and amines without azeotropic reflux to remove the alcohol byproduct. Initial mechanistic studies on the Zr(Ot-Bu) 4 -HOAt system revealed that the active catalyst is a novel, dimeric zirconium complex as determined by X-ray crystallography.

[reaction: see text] Copper(I)-mediated C-N bond formation has been employed to prepare both N-acyl vinylogous carbamic acids and ureas. The novel N-acyl vinylogous carbamic acid antibiotic, CJ-15,801, was synthesized using this methodology.

A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki–Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of Pd(OAc)2/RuPhos catalytic system. Both the enol tosylation and Suzuki–Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either E- or Z-olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki–Miyaura coupling. However, under the optimized cross-coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species.