Synthesis of Dihydroimidazoles and Quinazolinones via C–H Amination

Significance

Selective amination of aliphatic C–H bonds is an attractive strategy in the transition-metal-catalyzed synthesis of heterocycles and alkaloids (see Reviews below). This work describes the synthesis of dihydroimidazoles 2 and quinazolinones 4 through copper-catalyzed radical 1,5-hydrogen shift (see Reviews below) and subsequent C–N bond formation. The strategy provides a non-obvious disconnection towards dihydroimidazoles, and is a redox neutral variation of ­Chiba’s earlier reports on the construction of ­dihydroimidazoles (Org. Lett. 2013, 15, 212).

Reviews

For reviews on amination of C–H bonds, see: J. DuBois Org. Process Res. Dev. 2011, 15, 758–762; T. A. Ramirez, B. Zhao, Y. Schi Chem. Soc. Rev. 2012, 41, 931–942. For reviews on 1,5-hydrogen shift, see: C. P. Jaspers, D. P. Curran, T. L. Fevig Chem. Rev. 1991, 91, 1237–1286; J. Robertson, J. Pillai, R. K. Lush Chem. Soc. Rev. 2001, 30, 94–103.

Comment

The reaction is thought to proceed through a copper-promoted reduction of amidoxime 1, forming an amidinyl radical A, which then undergoes a 1,5-hydrogen shift to give radical B. Oxidation of B to the carbocation C and amination completes the catalytic cycle. An aryl substituent (R³ or R⁴) was essential for the reaction to give high yields, likely because of added stability of the intermediate radical/carbocation. Substrates bearing secondary methylene groups (R³ or R⁴ = H) were also challenging, giving lower yields of the desired imidazoles. N-Benzoyl amidoximes 3 delivered quinazolinones 4 following radical reaction with the π-system of the aromatic ring. Variation of the substitution pattern on the aryl ring revealed amidinyl radical addition to both ortho- (4, major) and ipso- (5, minor) carbon atoms.