Light Driven Pd-catalyzed Regioselective C─H Halogenation of Benzo[b][1,4]oxazin-2-ones Using DXDMH

Area of Science:

• Organic Chemistry
• Photocatalysis
• Medicinal Chemistry

Background:

• C-H functionalization is crucial for drug discovery.
• Developing sustainable and efficient halogenation methods is essential.
• Palladium catalysis and photoredox catalysis offer powerful synthetic tools.

Purpose of the Study:

• To develop a mild, visible-light-driven protocol for regioselective ortho-C-H halogenation.
• To utilize a synergistic metallaphotoredox strategy for efficient C-H functionalization.
• To provide a sustainable method for late-stage diversification of benzo[b][1,4]oxazin-2-one scaffolds.

Main Methods:

• Synergistic palladium/photoredox catalysis using Pd(OAc)2 and eosin Y.
• Visible-light irradiation (blue LED) of 3-aryl-2H-benzo[b][1,4]oxazin-2-ones.
• Use of N-halo-5,5-dimethylhydantoins as sustainable halogen sources in DCE with p-toluenesulfonic acid.

Main Results:

• High isolated yields (75%-97%) of ortho-halogenated products (Cl, Br, I) with excellent regioselectivity.
• Broad substrate scope, tolerating diverse substituents on the 3-aryl ring.
• Mechanistic studies support a cooperative pathway involving Pd(II)-directed C-H activation and photoredox catalysis.

Conclusions:

• The developed protocol is operationally simple, mild, and sustainable.
• This dual catalytic approach is efficient for late-stage diversification of pharmaceutically relevant scaffolds.
• The study advances sustainable photocatalytic C-H halogenation strategies.