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J Org Chem. 2012 Nov 16;77(22):10362-8. doi: 10.1021/jo302084a. Epub 2012 Oct 29.

Synthesis and reactivity of N-alkyl carbamoylimidazoles: development of N-methyl carbamoylimidazole as a methyl isocyanate equivalent.

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Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6.


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.

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