ABSTRACT
Ketones were selectively synthesized from thioesters by using diarylcuprates(I) generated inâ situ from copper(I) salts and aryl Grignard reagents in a 1 : 1.3-1.5â ratio under ambient temperature. During the ketone synthesis, various functional groups, such as carbonyl (ketones, esters, and amides), O-protecting groups, halogens, and heteroarenes, were tolerated to afford multifunctionalized ketones in excellent yields. This copper-mediated ketone synthesis could be applied to the synthesis of not only gluconolactone-derived ketone 6, a synthetic intermediate in the transformation to the SGLT2 inhibitor canagliflozin, but also thiolactol 8, a valuable synthetic intermediate for (+)-biotin. Control experiments on an isolated diphenylcuprate(I), [CuPh2 ]- (12), and DFT calculations revealed that this ketone synthesis proceeded by oxidative addition of the C-S bond of thioesters to [CuPh2 ]- , while reductive elimination from the CuIII intermediate produced the corresponding ketone and an inactive species [(RS)CuPh]- , the latter reacted with [CuPh]4 (11) to regenerate the reactive diphenylcuprate(I).
Subject(s)
Copper , Ketones , Catalysis , Copper/chemistry , Esters/chemistry , Halogens , Ketones/chemistryABSTRACT
Nickel- and palladium-catalyzed Fukuyama coupling reactions of a d-gluconolactone-derived thioester with arylzinc reagents at ambient temperature provided the corresponding multifunctional aryl ketones in high yield. Ligand screening for the nickel-catalyzed Fukuyama coupling reactions indicated that 1,2-bis(dicyclohexylphosphino)ethane (dCype) served as a superior supporting ligand to improve the product yield. In addition, Pd/C was a practical alternative that enabled ligand-free Fukuyama coupling reactions and was efficiently applied to the key C-C bond-forming step to prepare canagliflozin and dapagliflozin, which are diabetic SGLT2 inhibitors of current interest.
Subject(s)
Palladium , Sodium-Glucose Transporter 2 Inhibitors , Catalysis , Ligands , NickelABSTRACT
A regio- and chemoselective cross-coupling study using 2,3-dibromobenzofurans and 2,3,5-tribromobenzofuran was achieved with sub-stoichiometric loadings of triarylbismuths as atom-economic reagents under Pd-catalyzed conditions. As part of this study, various 2,3-diaryl- and 2,3,5-triarylbenzofuran products were obtained in high yields, involving one-pot operations and short reaction times.