Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

• Main Authors: Seo, Hyowon (Author), Bedard, Anne Catherine (Author), Chen, Willie P. (Author), Hicklin II, Robert William (Author), Alabugin, Alexander (Author), Jamison, Timothy F. (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Chemistry (Contributor)
• Format: Article
• Language: English
• Published: Elsevier BV, 2020-03-03T20:27:29Z.
• Subjects: Article
• Online Access: Get fulltext

Selective N-monomethylation of anilines has been achieved under continuous flow conditions using dimethyl carbonate as a green methylating agent in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. Our methodology takes advantage of the expanded process windows available in the continuous flow regime to safely induce monomethylation in superheated solvents at high pressure. We propose selective N-monomethylation is achieved via an in situ protection-deprotection pathway, which is supported by the observed reactivities of several putative reaction intermediates. The robust and scalable method was applicable to a broad range of primary aniline substrates including ortho-, meta-, and para-substituted anilines, as well as electron-rich and electron-deficient anilines. The synthetic precursor of diazepam, 5-chloro-2-(methylamino)benzophenone, was selectively synthesized under our optimized conditions. Keywords: Monomethylation of anilines; Continuous flow chemistry; Green chemistry; Dimethyl carbonate; In situ protection-deprotection
United States. Defense Advanced Research Projects Agency (Contract W911NF-16-0023)