Zeng Y.-F,
*,
Li Y.-N,
Zhou M.-X,
Han S,
Guo Y,
*,
Wang Z.
*
University of South China, Hunan, P. R. of China
Metal-Free Hydrogenation of
N-Heterocycles with Trimethylamine Borane and TFA in Aqueous Solution.
Adv. Synth. Catal. 2022;
364: 3664-3669
Key words
hydrogenation - metal-free - aromatic heterocycles - room temperature
Significance
Tetrahydroquinoxalines and indolines are important medicinal chemistry motifs that are currently being explored for treatment of a range of conditions, including cancer and diabetes (D. S. Millan et al. ACS Med. Chem. Lett.
2017, 8, 847). Synthetic strategies to access these groups from their quinoxaline and indole heteroaryl precursors, however, currently involve the use of flammable H2 gas and/or excessive use of expensive metal catalysts, often with a limited substrate scope. This report details a simple and convenient method for hydrogenation of quinoxalines and indoles using TFA and Me3N·BH3 in water at room temperature. The method offered a substantial substrate scope with wider functional group tolerance, including chloro and bromo groups that readily undergo hydrogenation in transition-metal-catalyzed hydrogenation, as well as sensitive cyano, ester and amino groups.
Comment
Optimized reaction conditions were found to be the following: 0.2 mmol of heteroaryl, one equivalent of Me3N·BH3 and five equivalents of TFA stirred in water for three hours in air at room temperature. The reaction was also scalable on multi-gram scale, as demonstrated with both quinoxaline and indole to give 1.21 g and 0.91 g of 2a and 4a, respectively. Preliminary mechanistic studies suggest that TFA furnished the proton, while Me3N·BH3 provided the hydride, with protonation occurring at the C3-position of the indole followed by C2-hydrogenation (
II.
). Structural motifs such as isoquinoline (2j), benzoxazole (4g), benzimidazole (4h), and benzothiazole (4i) were not well tolerated and gave 0% yields, setting guidelines to the applicability of this method. In summary, this method provides a safer and efficient alternative to the current hydrogenation strategies, with commercial reagents and mild reaction conditions, a wide substrate scope, and concrete scope limitations.
