Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow
Author(s)Seo, Hyowon; Bedard, Anne Catherine; Chen, Willie P.; Hicklin II, Robert William; Alabugin, Alexander; Jamison, Timothy F.; ... Show more Show less
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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
DepartmentMassachusetts Institute of Technology. Department of Chemistry
Seo, Hyowon et al. "Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow." Tetrahedron, 74, 25 (June 2018): 3124-3128.
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