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%).