A simple conversion of amines into monosubstituted ureas in organic and aqueous solvents

A versatile and highly efficient synthesis of monosubstituted ureas is described. The reaction of an amine with 4-nitrophenyl-N-benzylcarbamate, followed by hydrogenolysis, provides the corresponding urea in high yield and purity. This carbamate can also be employed for the derivatization of water-soluble polyamines (e.g. aminoglycoside antibiotics), while other reagents (e.g. benzylisocyanate) fail to give the desired products in any significant yield. © 2001 Elsevier Science Ltd. All rights reserved. Substituted ureas are found in natural products, pharmaceutical and agricultural preparations, as well as in numerous artificial receptors and self-assembled supramolecules. During our investigation of small organic molecules as RNA binders, we have become interested in monosubstituted urea functionalities as uncharged, isostructural analogs of guanidinium groups. A general approach for the synthesis of such derivatives that can tolerate amines of various structure and complexity, as well as reaction media (i.e. organic or water-containing), has become a necessity. Most synthetic approaches to ureas utilize phosgene or its tamed analogs. Commercially available reagents, such as benzylisocyanate, also effectively convert amines into easily deprotected disubstituted ureas. We have suspected, however, that such reagents might not withstand aqueous conditions or react efficiently with complex starting materials. Indeed, reactions of aminoglycoside antibiotics with benzylisocyanate in dioxane/ water mixtures failed to yield the desired products in any significant yield. We have therefore sought to develop a simple reagent that is electrophilic enough to effectively react with amines of various structures, yet reasonably stable in aqueous environments. Here we report on a highly versatile and efficient two-step synthesis of monosubstituted ureas using 4-nitrophenyl-Nbenzylcarbamate 1 (Scheme 1). The reaction of amines with 1, followed by hydrogenolysis, provides the corresponding ureas in high yield and purity (Scheme 1). Importantly, excellent transformations are obtained when 1 reacts with more sophisticated amines (such as aminoglycoside antibiotics) in aqueous solvents (Scheme 2). 4-Nitrophenyl-N-benzylcarbamate 1 was obtained in high yield by condensing benzylamine with 4-nitrophenyl-chloroformate. The colorless, crystalline material 1 effectively reacts with various amines to give the corresponding N-benzyl ureas in excellent yields (Table 1). Thus, reaction of cyclohexanemethylamine with 1 in dichloromethane in the presence of triethylamine for 30 min, followed by a basic aqueous workup gives the disubstituted urea 2 in 92% yield and in pure form (Scheme 1). No additional chromatography or recrystallizations are needed. Medium pressure (30–50 psi) hydrogenolysis in acetic acid, in the presence of Pd black, yields the desired monosubstituted urea 3 in Scheme 1. The reaction of cyclohexanemethylamine with 1 provides urea 3 in 92% overall yield after hydrogenolysis. * Corresponding author. Tel.: (858) 534-6401; fax: (858) 534-5383; e-mail: [email protected] 0040-4039/01/$ see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0040 -4039 (00 )02289 -9