The Generation of Dihydropyrimidine Libraries Utilizing Biginelli Multicomponent Chemistry

Abstract

With the emergence of high-throughput screening in the pharmaceutical industry over a decade ago, synthetic chemists were faced with the challenge of preparing large collections of molecules to satisfy the demand for new screening compounds. The unique exploratory power of multicomponent reactions such as the Ugi four-component reaction was soon recognized to be extremely valuable to produce compound libraries in a time-and cost effective manner. The present review article summarizes strategies for the construction of libraries through another multicomponent reaction, the Biginelli dihydropyrimidine synthesis. In this three-component condensation dating back to 1893, CH-acidic carbonyl compounds, aldehydes and urea-type building blocks combine to assemble a multifunctionalized dihydropyrimidine scaffold. Due to the interesting pharmacological properties associated with the privileged DHPM structures, the Biginelli reaction and related procedures have received increasing attention in recent years. This review details synthetic advances for the construction of Biginelli libraries via solution phase and solid-phase strategies that are amenable to a highthroughput or combinatorial format.

Controlled Microwave Heating in Modern Organic Synthesis

“…[157] Under conventional conditions this MCR typically requires several hours of heating under reflux conditions (ca. 80 8C) in a solvent such as ethanol.…”

Catalysis of Salicylaldehydes and Two Different CH Acids with Electricity: First Example of an Efficient Multicomponent Approach to the Design of Functionalized Medicinally Privileged 2‐Amino‐4H‐Chromene Scaffold

“…[5] The rapid assembly of molecular diversity utilizing MCRs has received a great deal of attention, especially for the design and construction of elaborate heterocyclic frameworks possessing enhanced "drug-like" properties. [6] For example, the Hantzsch, [6c] Ugi, [6e, f] and Biginelli [7] multicomponent reactions are the methods of choice to prepare func-tionalized 1,4-dihydropyridine, benzodiazepinedione, and dihydropyrimidine privileged scaffolds, respectively.…”

N‐acyliminium intermediates in solid‐phase synthesis

“…The multicomponent Biginelli reaction, with its variants, are well-established methods for the synthesis of dihydropyrimidine-type structures. 40,41 The mechanism of the reaction presumably involves the formation of an N-acyliminium (N-carbamoyliminium) intermediate stemming from the condensation of a urea-derivative and an aldehyde under acidic reaction conditions. 42 The capture of this intermediate by the enol form of a b-keto ester and final cyclization allows the formation of the Biginelli product.…”