Synthesis and Reactivity of N-Alkyl Carbamoylimidazoles: Development of N-Methyl Carbamoylimidazole as a Methyl Isocyanate Equivalent

Abstract

A high-yielding synthesis of N-methyl carbamoylimidazole from 1,1-carbonyldiimidazole (CDI) and MeNH(3)Cl is described. The product is a crystalline, readily storable, water-stable compound that reacts as a methyl isocyanate (MIC) substitute. Reaction of N-methyl carbamoylimidazole in the presence of a base such as triethylamine occurs with nucleophiles such as amines, protected and unprotected amino acids, thiols and alcohols. The product N-methylureas, carbamates and thiocarbamates are obtained in good to excellent yields, with reactions occurring in either organic solvents or water. The protocol for the synthesis of N-methyl carbamoylimidazole is both scalable and general, occurring in quantitative yield at scales ranging from 300 mg to 20 g. The success of this method relies upon the reaction of CDI with the ammonium salt rather than the free amine, resulting in a significant improvement in the yield of N-methyl carbamoylimidazole. The reaction presumably involves a proton transfer from MeNH(3)Cl to the CDI, which results in the release of MeNH(2) with simultaneous activation of the CDI as its protonated form. Other primary ammonium hydrochloride salts, including protected α-amino acid salts, give excellent yields of the corresponding N-alkyl carbamoylimidazoles and serve as alkyl isocyanate surrogates. The resultant N-alkyl carbamoylimidazoles can be converted to ureas in high yields without the formation of intermediary isocyanates.

Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens

“…For the subsequent installation of the N4 carbamoyl group, aminolysis of N 4-phenoxycarbonyl 37 did not take place due to the steric hindrance of the N3 methyl group. Inspired by the N -PMB carbamoylimidazole urea formation reported by Batey et al 38 , we developed a scalable and efficient protocol to prepare 22b . In the presence of Et 3 N, 20 was allowed to react with 21 under reflux, giving rise to 22b in 96% yield.…”

Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins

“…Indeed, the symmetrical urea of the starting amino ester – obtained from the corresponding N- carbamoyl imidazole amino ester A – was not observed, as shown by the LC–MS analyses of the crude mixture. An approach complementing similar strategies was already described to avoid the formation of symmetrical ureas in solution [13]. …”

Total Synthesis of (−)‐Spiroleucettadine

“…Following neutralization of the HCl salt 15,t reatment with N-methyl carbamoylimidazole [14] yielded 16 (Scheme 3). Following neutralization of the HCl salt 15,t reatment with N-methyl carbamoylimidazole [14] yielded 16 (Scheme 3).…”