Cyclic ureas have recently gained much interest as human immunodeficiency virus (HIV) protease inhibitors 1 and 5HT 3 receptor antagonists 2 and are expected to have increased conformational rigidity relative to the corresponding linear ureas, which are incorporated in many pharmaceuticals. 3 5-Membered cyclic ureas, 2-imidazolidinones, are also used as useful chiral auxiliaries 4 in highly diastereoselective alkylation, aldol, and DielsAlder reactions. 2-Imidazolidinones are generally prepared by the cyclization reaction of 1,2-diamine with phosgene 5 or its derivatives, 2 and these methods cause the polymerization as a side reaction. 6 The intramolecular cyclization of N-(2-hydroxyethyl)urea 1 having an ambident nucleophile using PPh 3 /CCl 4 or dimethylaminosulfur trifluoride (DAST) generally leads to O-cyclized 2-oxazoline in preference to N-cyclized 2-imidazolidinone, 7 and there has been no report regarding N-cyclized 2-imidazolidinone formation with substrates 1. In this paper, we report the result of a new and general method that gives N-cyclized products, 2-imidazolidinones 2, as single isomers using N-(2-hydroxyethyl)urea 1 derived from 1,2-amino alcohol and phenyl isocyanate shown in Scheme 1.We chose N-(2-hydroxyethyl)ureas 1a and 1f as substrates to investigate the route shown in Scheme 2 in a variety of reaction conditions. These were readily prepared from the reaction of the corresponding 1,2-amino alcohols with phenyl isocyanate, and the regioselectivities in the cyclization reaction of 1a and 1f were investigated as follows: These reactions are expected to give three regioisomers, namely, two N-cyclized 2-imidazolidinone 2 and aziridine (in the case of R 1 d H) 3 and an O-cyclized 2-oxazoline 4 depending on the nucleophilicity of the substrate and reaction conditions. Upon the Mitsunobu reaction conditions (PPh 3 , EtOCONdNCOOEt), the cyclization of 1a gave the mixtures of N-cyclized product and O-cyclized product in a ratio of 52:48 due to the low nucleophilicity of the nitrogen atom of 1a. For activation of the hydroxyl group followed by the intramolecular reaction with some bases, we treated 1a and 1f with 1.2 equiv of p-toluenesulfonyl chloride (TsCl) in the presence of excess of Et 3 N to provide the tosylate product of 55% and 62% yields, respectively, and then the intramolecular reaction of tosylate of 1a with tert-butoxide (t-BuOK) gave no desired cyclized product while the tosylate of 1f resulted in the O-cyclized 2-oxazoline 4f of 84% good yield without the 2-imidazolidinone (Scheme 3). We turned to a one-pot reaction with TsCl (1.2 equiv) and t-BuOK (2.4 (1) (a) Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.; Chang, C.-H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R.; Erickson-Viitanen, S. Patel, M.; Bacheler, L. T.; Rayner, M. M.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1998, 8, 823. (2) Heidempergher, F.; Pillan, A.; Pinciroli, V.; Vaghi, F.; A...
