Intermolecular Ritter-type C-H amination of unactivated sp3 carbons

Abstract

Intermolecular Ritter-type C-H amination of unactivated sp(3) carbons has been developed. This new reaction proceeds under mild conditions using readily available reagents and an inexpensive source of nitrogen (acetonitrile). A broad scope of substrates can be aminated with this method since many functional groups are tolerated. This reaction also allows for the direct, innate C-H amination of a variety of hydrocarbons such as cyclohexane without the need of prefunctionalization or installation of a directing group.

Figure 1

(A) Overview of C_sp3–H amination methods (B) Reported synthesis of dihydrooxazinium salt 2 derived from (−)-menthol (1) by Banks et al. and synthesis of hydroxymenthol 3 by Chen et al. (C) Reaction optimization with 2,6-dimethylheptan-4-ol (4) (1.0 equiv, 0.13 mmol).^a Number of equivalents^b Yields were determined by ¹H NMR with an internal standard.^c 16% of recovered starting material 4.

Figure 2

(A) A postulated mechanism for the reaction. (B) Kinetic isotope effect with cyclohexane and cyclohexane d₁₂.

Scheme 1

Hydrolysis of acetamide products: synthesis of aminomenthol 37