( E )‐,( Z )‐Stereodefined α‐Chloro‐β‐tosyloxy‐α,β‐unsaturated Esters: Sequential Cross‐Couplings for ( E )‐,( Z )‐Stereo Complementary Synthesis of Fully‐Substituted α,β‐Unsaturated Esters

An ( E )‐, ( Z )‐stereocomplementary synthesis of fully‐substituted α,β‐unsaturated esters has been developed. The present method involves sequential cross‐coupling reactions of readily available ( E )‐, ( Z )‐stereodefined α‐chloro‐β‐tosyloxy‐α,β‐unsaturated esters, which were obtained by ( Z )‐ and ( E )‐stereocomplementary enol tosylation of methyl α‐chloro‐β‐oxoesters using novel reagents, TsCl−NaH−TMEDA(−LiCl) for Z and TsCl− i Pr 2 NEt− N ‐methylimidazole for E . The first highly chemoselective and stereoretentive Suzuki‐Miyaura cross‐couplings proceeded smoothly at the β‐TsO‐position of ( E )‐ and ( Z )‐α‐chloro‐β‐tosyloxy‐α,β‐unsaturated esters to afford ( Z )‐ and ( E )‐β‐aryl(Ar)‐α‐chloroacrylates, respectively by an accessible [Pd(OAc) 2 −PPh 3 −K 2 CO 3 ] catalysis (4 examples: 89–94% yield). Subsequent highly stereoretentive Suzuki‐Miyaura cross‐couplings using the obtained ( Z )‐ and ( E )‐acrylates were successfully performed by a reactive [Pd(OAc) 2 −SPhos−K 2 CO 3 ] catalysis to produce a number of ( E )‐ and ( Z )‐ β‐aryl(Ar)‐α‐aryl’(Ar 1 ) and β‐aryl(Ar)‐α‐ n ‐hexyl acrylates (24 examples, 62–94 %). As a distinct extension, ( Z )‐ and ( E )‐β‐( p ‐tolyl)‐α‐chloroacrylate served as appropriate partners for ( E )‐ and ( Z )‐stereoretentive Sonogashira, Mizoroki‐Heck, and Buchwald‐Hartwig cross‐couplings, which afforded the corresponding enyne, diene, and α‐aminoolefin types of fully‐substituted α,β‐unsaturated esters (6 examples: 52–75% yield).