Synthesis of (±)-Baclofen using Wittig Olefination–Claisen Rearrangement

Baclofen, a lipophilic derivative of GABA (gamma-Aminobutyric acid), which acts as an inhibitory neurotransmitter in CNS (central nervous system) was synthesized by Witting olefination-Claisen rearrangement protocol. ۴-Chlorobenzaldehyde was subjected to Wittig reaction with ((allyloxy)methylene)triphenyl-phosphane to give ۱-(۲-(allyloxy)vinyl)-۴-chlorobenzene which on heating under reflux condition in toluene underwent Claisen rearrangement to give ۲-(۴-chlorophenyl)pent-۴-enal. Aldehyde was reduced to corresponding alcohol ۲-(۴-chlorophenyl)pent-۴-en-۱-ol as an important precursor which can be used for the synthesis of Baclofen and different GABA derivatives. Further tosylation, formation-reduction of azide group and oxidative ozonolysis of terminal double bond yields ۴-amino-۳-(۴-chlorophenyl)butanoic acid in excellent yield. Therefore, an efficient method was developed for the synthesis of (±)-Baclofen in a simple seven step procedure. 

Keywords:

Wittig reaction , Claisen rearrangement , Ozonolysis , Azido acid , Neurotransmitter , Agonist