Alkali Carbonate Effects on N‐(2‐Hydroxyethyl)urea Cyclization: Application to a 2‐Imidazolidinone Scale‐Up

An imidazolidinone intermediate (3) used in the synthesis of novel HIV-entry inhibitors was prepared on multihundred gram scales in four steps and 40% overall yield. The penultimate step in the synthesis involved regioselective N-cyclization of N-(2-hydroxylethyl)urea (11) by in situ activation of the terminal hydroxyl group with p-TsCl in the presence of base. The ratio of N-cyclized to O-cyclized products followed a group IA periodic trend relative to the alkali carbonate base employed. The use of Cs2CO3 as base effected the desired N-cyclization with a high degree of regiocontrol (>98%).