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Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor
Author(s) -
Fuse Shinichiro,
Komuro Keiji,
Otake Yuma,
Masui Hisashi,
Nakamura Hiroyuki
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202100059
Subject(s) - triphosgene , electrophile , reagent , combinatorial chemistry , substrate (aquarium) , chemistry , organic chemistry , catalysis , biology , phosgene , ecology
Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid‐mediated and coupling‐agent‐mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less‐wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5–10 s), mild, inexpensive, and less‐wasteful lactamization are described. Methods A and B, which use N ‐methylmorpholine and N ‐methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid‐ and/or heat‐labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.