Hydride Shuttle Catalysis: From Conventional to Inverse Mode

Abstract

Hydride shuttle catalysis has emerged as a powerful synthetic platform, enabling the selective formation of C-C bonds to yield sp³-rich structures. By virtue of the compelling reactivity of sterically encumbered Lewis acids from the frustrated Lewis pair regime, hydride shuttle catalysis enables the regioselective functionalization of alkyl amines at either the α- or β-position. In contrast to classical Lewis acid reactivity, the increased steric hindrance prevents interaction with the Lewis basic amine itself, instead leading to reversible abstraction of a hydride from the amine α-carbon. The created positive charge facilitates the occurrence of transformations before hydride rebound or a similar capture event happen. In this Perspective, we outline a broad selection of transformations featuring hydride shuttle catalysis, as well as the recently developed approach of inverse hydride shuttle catalysis. Both strategies give rise to a wide array of functionalized amines and offer elegant approaches to otherwise elusive bond formations.

Figure 1

General concepts of (a) shuttle catalysis, (b) hydride shuttle catalysis, and (c) inverse hydride shuttle catalysis.

Figure 2

FLP enables HSC for the α- and β-functionalization of N-alkylamines.

Scheme 1. α-Functionalization of Amines by Wasa et al.

Scheme 2. Synthesis of δ-Aminocarbonyls by Wasa et al.

Scheme 3. HSC-Enabled Synthesis of Tetrahydroquinolines by (a) Grimme, Paradies et al. and (b) Wang et al.

Scheme 4. External-Oxidant-Free HSC-Enabled Synthesis of Mannich-Type Products by Wasa et al.

Scheme 5. Synthesis of α-Alkynyl Amines by Wasa et al.

Scheme 6. Alkylation of Indoles and Oxindoles with Amines by Melen, Morril, Pulis et al.

Scheme 7. (a) Formation of Lewis Acid Adduct 50 and (b) β-Alkylation of Trialkylamines by Yang, Zhao, Ma et al.

Scheme 8. β-Deuteration of Amines by Wasa et al.

Scheme 9. β-Functionalization with Isatins by Yang, Ma, et al.

Scheme 10. Enantioselective β-Functionalization by Wasa et al.

Scheme 11. Isomerization and [2 + 2]-Cycloaddition by Wang et al.

Scheme 12. Borane/Gold(I)-Catalyzed C–H Functionalizations by Wang et al.

Scheme 13. β-Functionalizations by (a) He, Fan et al. and (b) He, Zhao et al.

Scheme 14. β-C–H Allylation of Trialkylamines by Wang et al.

Scheme 15. β-C–H Functionalizations with Michael Acceptors by Xue, Wang et al.

Scheme 16. Inverse Hydride Shuttle Catalysis by Maulide et al.

Scheme 17. Enantioselective Inverse Hydride Shuttle Catalysis

Scheme 18. Lewis Acid-Driven Inverse Hydride Shuttle Catalysis by Maulide et al.

Scheme 19. Alternative Strategy for Lewis Acid-Driven Inverse Hydride Shuttle Catalysis by Maulide et al.