Reduction of Biginelli compounds by LiAlH4: a rapid access to molecular diversity?

RSC Advances Pub Date: 2016-11-28 DOI: 10.1039/C6RA24535H

Abstract

Herein, the reduction of Biginelli compounds by LiAlH4 was investigated for the first time. The reduction of urea-derived dihydropyrimidinones yielded 80–95% of hydrogenolysis products (4-aryl-5-(m)ethyl-6-methyl-3,4-dihydropyrimidin-2(1H)-ones; 11 examples), while the reduction of N-1-methylated Biginelli compounds gave the corresponding alcohols (4-aryl-5-((1-)hydroxy(m)ethyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-ones; 4 examples) in 70–80% yield. The obtained alcohols could be readily dehydrated to vicinal bis(exo-methylene) derivatives (4-aryl-1-methyl-5-(m)ethylene-6-methylene-tetrahydropyrimidin-2(1H)-ones; 4 examples) or isomerized to acyclic compounds (1-methyl-3-(1-aryl-2-methylene-3-oxobutyl)ureas; 2 examples) under mildly acidic conditions. The outcome of the reduction also depended on other structural features and reaction conditions such as: urea/thiourea and the type of 1,3-dicarbonyl compound, order of reagent addition, etc. LiAlH4-reduction of Biginelli compounds affords a rapid approach to a library of diverse compounds of apparent synthetic utility and possible biological interest. The mechanism of this reduction was discussed and additionally elucidated through deuteration experiments and pKa measurements.

Graphical abstract: Reduction of Biginelli compounds by LiAlH4: a rapid access to molecular diversity
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