Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow |
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Authors: | Hyowon Seo Anne-Catherine Bédard Willie P Chen Robert W Hicklin Alexander Alabugin Timothy F Jamison |
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Institution: | Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA |
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Abstract: | 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-diazabicyclo5.4.0]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. |
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Keywords: | Monomethylation of anilines Continuous flow chemistry Green chemistry Dimethyl carbonate Corresponding author |
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