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Practical One‐Pot Multistep Synthesis of 2H‐1,3‐Benzoxazines Using Copper, Hydrogen Peroxide, and Triethylamine
Author(s) -
Trammell Rachel,
Cordova Alexandra,
Zhang Shuming,
Goswami Sunipa,
Murata Richel,
Siegler Maxime A.,
GarciaBosch Isaac
Publication year - 2021
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202100783
Subject(s) - chemistry , triethylamine , deprotonation , intramolecular force , benzophenone , medicinal chemistry , hydroxylation , hydrogen peroxide , combinatorial chemistry , functional group , stereochemistry , organic chemistry , ion , enzyme , polymer
In this article, we describe simple one‐pot syntheses of 2H‐1,3‐benzoxazines from ketones utilizing an imino‐pyridine directing group (R 1 R 2 ‐C=N−CH 2 ‐Pyr), which promotes a Cu‐directed sp 2 hydroxylation using H 2 O 2 as oxidant and followed by an oxidative intramolecular C−O bond formation upon addition of NEt 3 . This synthetic protocol is utilized in the gram scale synthesis of the 2H‐1,3‐benzoxazine derived from benzophenone. Mechanistic studies reveal that the cyclization occurs via deprotonation of the benzylic position of the directing group to produce a 2‐azallyl anion intermediate, which is oxidized to the corresponding 2‐azaallyl radical before the C−O bond formation event. Understanding of the cyclization mechanism also allowed us to develop reaction conditions that utilize catalytic amounts of Cu.