Reviews and Accounts ARKIVOC 2012 (i) 66-133
NHNHEtOOCMeO2 Hantzsch pyridines Biginelli compound (Dihydropyridine) (Dihydropyrimidine)
He apparently did this reaction in a multicomponent way, and currently the development of multicomponent reactions (MCRs) is an integral part of numerous research efforts around the world involved in the drug development programs to achieve synthetic targets in expeditious way. It seems old discoveries are new fashions of the present times. Subsequent investigators have tried to understand the course of reaction and they invoke the participation of the Knoevenagel reaction.
In the initial years there was not much synthetic activity in this reaction but during last 100 years or so this reaction received much attention and as a result there were nearly five hundred research publications, mostly involving catalyst changes. During these years from its discovery emphasis was on understanding the course of reaction, with some emphasis on structural variants. Subsequent to these academic developments the Biginelli scaffold was shown to be of great value from a pharmaceutical point of view; because of this importance, investigations were very fast, and virtually every major journal was flooded with papers on the Biginelli reaction.6 Major emphasis being on process streamlining mainly Lewis acid catalyst etc. In this account, update on catalyst variations, asymmetric synthesis, scaffold variations and Biginelli like reactions aspect of this reaction is presented. During the past decade or so publications have been so fast and numerous, some of these may get missed incidently so authors feel sorry for that if it happens.
2. Discovery Historically, Italian chemist Pietro Biginelli (University of Florence) reported this reaction for the first time which is taken as the birth of this reaction; it is popularly named after him i.e. Biginelli Reaction.3 Classically, he did it as acid-catalyzed condensation of ethyl acetoacetate, benzaldehyde, and urea in ethanol by refluxing the mixture and on cooling he obtained a solid crystalline product 3,4-dihydropyrimidin-2(1H)-one which apparently was a three component reaction (Scheme 1), the acid used here was hydrochloric acid. Though it is more than 100 years acidic catalysts continue to be used though the number of variation done in this catalysts system
Page 68 ©ARKAT-USA, Inc.
