The Development of a Stereoselective Method for the Synthesis of Tetrasubstituted Derivatives of α,β‐Unsaturated Carboxylic Acids

Alkenes possessing four different carbon-linked substituents are the main structural motif of many biologically active compounds. The derivatives of (2E)-3-(3-methoxyphenyl)-2-methylpent-2-enoic acid ((E)-2c) are suitable precursors for the synthesis of Tapentadol, a novel centrally acting analgesic. It was found that the Ni-carbometallation reaction of disubstituted alkyne 8 with CO2 and an Et2Zn allows for efficient and practical preparation of (E)-2c as a single (E)-regioisomer in 89% of isolated yield. The influence of the size of the aliphatic substituent of alkyne and the steric hindrance of the organozinc reagent on stereochemical course of the carbometallation reaction was evaluated. Finally, air stable Ni(dme)Cl2 was proposed as an alternative to widely used Ni(cod)2 catalyst. This article is protected by copyright. All rights reserved.