Gribble reductive amination

What is Gribble reductive amination?

The Gribble reductive amination, first reported in 1974 by Gribble et al., involves the direct acidic reduction of indoles using NaBH4 or NaBH3CN in acetic acid AcOH or trifluoroacetic acid (TFA) to synthesize indolines or N-alkylated indolines.

Gribble reductive amination - general reaction scheme
Gribble reductive amination

This method is unique in that it prevents polymerization that can occur in other reduction methods. Reduction using NaBH4 in formic acid leads to the formation of an indole dimer and other side products, while reduction in TFA results in the exclusive formation of indoline without N-alkylation. Protonation at the 3-position, followed by the reduction of the formed indolenium intermediate, has been shown to be involved in this reaction.

The Gribble reductive amination has been extended to the reduction of primary and secondary aromatic amines and the direct synthesis of unsymmetrical tertiary amines from primary amines. Other heterocycles, such as quinoxaline, quinazoline, and pyrazine, can also be reduced using this method. Additionally, aryl alcohols can be directly converted to their corresponding arylalkanes.

The Gribble reductive amination has broad applicability for reducing not only indoles but also other nitrogenous heterocycles. Furthermore, it can be selectively utilized for the preparation of unsymmetrical tertiary amines.

References

Reactions of sodium borohydride in acidic media. I. Reduction of indoles and alkylation of aromatic amines with carboxylic acids
Gordon W. Gribble, Pierre D. Lord, Jerauld Skotnicki, Stephen E. Dietz, Jefferson T. Eaton, and Jerry Johnson
Journal of the American Chemical Society 1974 96 (25), 7812-7814
DOI: 10.1021/ja00832a035

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