Nitrene-mediated aminative N-N-N coupling: facile access to triazene 1-oxides

Abstract

Significant progress has been made in metal-catalyzed cross-coupling reactions over the past few decades. However, the development of innovative aminative coupling strategies remains highly desirable. Herein, we report a nitrene-mediated aminative N-N-N coupling reaction that leverages an anomeric amide as a key reagent to bridge amines with nitrosoarenes. This strategy enables the in situ generation of an aminonitrene intermediate, which is efficiently intercepted by nitrosoarenes, providing a direct, mild, and highly efficient route to triazene 1-oxides. Mechanistic investigations reveal that the N-substituents of the amine play a crucial role in modulating the reactivity of the aminonitrene intermediate. Complementary computational studies further indicate that aminonitrene acts as a nucleophile, while nitrosobenzene serves as an electrophile. Notably, aminonitrene-nitrosoarene coupling is significantly favored due to a substantial reduction in distortion energy, effectively outcompeting the nitrene dimerization pathway.

Fig. 1. A summary of transition-metal catalyzed coupling reactions and nitrene-mediated aminative N–N–N coupling. (A) State-of-the-art in coupling reaction. (B) Our aminative coupling hypothesis. (C) Established reactivity of amines with anomeric amides. (D) Nitrene-mediated aminative N–N–N coupling (this work).

Fig. 2. ^a All reactions were conducted at a 0.3 mmol scale with amine 1 (0.3 mmol), anomeric amide 2 (0.36 mmol), nitrosobenzene 3 (0.45 mmol), and base (0.6 mmol) in 6.0 mL solvent. Yields were determined by NMR analysis of the reaction mixture using 1,1,2,2-tetrachloroethane as an internal standard. ^b Isolated yield. ^c Accompanied by the formation of azoxybenzene. N.D. = not detected. DABCO = 1,4-diazabicyclo[2.2.2]octane. ^d The neat condition was highly exothermic, leading to vigorous gas evolution and resulting in a messy reaction mixture.

Fig. 3. Substrate scope of aminative N–N–N coupling. ^a Reactions were conducted at a 0.3 mmol scale, isolated yield. ^b Condition B: without DABCO.

Fig. 4. The gram scale synthesis and synthetic applications. (a) Gram-scale synthesis of 4. (b) Comparison of our method with conventional synthesis. (c) Synthetic application.

Fig. 5. Radical trapping and N-substituent effects studies. (a) Radical trapping experiments. (b) N-Substituent effects.

Fig. 6. Mechanistic studies. (a) Proposed reaction mechanism. (b) Computational studies of nitrene dimerization (red line) and nitrene transfer (blue line). (c) Frontier molecular orbital (FMO) analysis (isovalue = 0.05). (d) Distortion/interaction activation strain analysis.