Practical One‐Pot Multistep Synthesis of 2H‐1,3‐Benzoxazines Using Copper, Hydrogen Peroxide, and Triethylamine

Abstract

In this article, we describe simple one‐pot syntheses of 2H‐1,3‐benzoxazines from ketones utilizing an imino‐pyridine directing group (R1R2‐C=N−CH2‐Pyr), which promotes a Cu‐directed sp2 hydroxylation using H2O2 as oxidant and followed by an oxidative intramolecular C−O bond formation upon addition of NEt3. 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.

Regioselective Hydroxylation of Unsymmetrical Ketones Using Cu, H2O2, and Imine Directing Groups via Formation of an Electrophilic Cupric Hydroperoxide Core

“…(A) Metal-promoted C–H functionalization of aldehydes and ketones using removable imine directing groups. − (B) Cu-directed hydroxylations using imino-pyridine directing groups. − …”

“…Inspired by the reactivity of Cu-dependent monooxygenase/peroxygenase enzymes, − our research laboratory has published a series of papers that describe the utilization of imine directing groups, Cu, and H 2 O 2 to perform the γ hydroxylation of sp 2 and sp 3 C–H bonds and the β hydroxylation of sp 3 C–H bonds (Figure B; Note: following literature precedents on Cu-directed hydroxylation reactions, we named the carbonyl of the ketone C α and the adjacent position C β ). − The selectivity of these Cu-promoted oxidations, which were initially developed by Schöenecker and co-workers for the selective oxidation of steroids and have been applied to the total synthesis of complex molecules, − also relies on the formation of only one of the imine isomers in unsymmetrical substrates (e.g., cyclohexyl phenyl ketone), an issue that can be avoided in the hydroxylation of symmetrical substrates (e.g., symmetrical benzophenones). In this paper, we studied the regioselectivity in the Cu-directed hydroxylation of unsymmetrical ketones (Figure B).…”

Methylene Insertion into Nitrogen‐Heteroatom Single Bonds of 1,2‐Azoles via a Zinc Carbenoid: An Alternative Tool for Skeletal Editing

“…Since the resulting 2H-1,3-oxazines are labile under acidic or heating conditions, their general synthetic methods have not been established. [16,17] www.advancedsciencenews.com www.advancedscience.com Scheme 1. Methylene insertion into nitrogen-heteroatom single bonds of 1,2-azoles.…”

“…Since the resulting 2 H ‐1,3‐oxazines are labile under acidic or heating conditions, their general synthetic methods have not been established. [ 16 , 17 ]…”