Amino acids as selective acylating agents

Abstract

The acylation of bioactive primaquine-based imidazolidin-4-ones was studied using N-chi-Boc-protected glycine as acylating agent. Two synthesis routes, eight different coupling methods and seven distinct solvents were compared. Mild carbodiimide-based couplings on high dielectric constant solvents such as DMF or MeCN increased acylation yields, whereas alcohols inhibited carbodiimide-mediated acylations to take place. Achievement of the synthetic goals was limited by the size of the imidazolidin-4-one ring substituents R-1, R-2 and R-3, but resort to MW-assisted synthesis allowed overcoming such obstacle, though with very modest reaction yields. All reactions involving a Boc-protected amino acid were regioselective, independent of reaction conditions employed. In contrast, regioselective acetylation of the imidazolidin-4-ones could only be achieved by resort to very mild coupling procedures. (C) 2008 Elsevier Ltd. All rights reserved.. - Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) ; PTDC/QUI [65142/ 2006]; SFRH/BD [17754/2004]; CIQUP ; CECF ; CEM Corporation (USA) ; QLabo (Portugal) ; CEM DiscoverSUPTM/SUP system. - Thanks are due to Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) for financial Support through Project PTDC/QUI/65142/ 2006. N.V. thanks FCT for Ph.D.grant SFRH/BD/17754/2004. P.G. and R.M. thank FCT for financial support to CIQUP and CECF, respectively. Thanks are also due to CEM Corporation (USA) and QLabo (Portugal) for providing a CEM DiscoverSUPTM/SUP system for a trial period.