Fukuyama amine synthesis

What is Fukuyama amine synthesis?

In 1995, Fukuyama and colleagues first reported a reaction known as the Fukuyama amine synthesis also known as the Fukuyama-Mitsunobu N-alkylation, Fukuyama-Mitsunobu alkylation, Fukuyama-Mitsunobu condition, Fukuyama-Mitsunobu procedure, or Fukuyama- Mitsunobu reaction.

This two-step process converts primary amines to secondary amines through orthonitrobenzenesulfonation in combination with the Mitsunobu reaction, followed by removal of the o-nitrobenzenesulfonyl group using thiophenol.

Fukuyama amine synthesis - general reaction scheme
Fukuyama amine synthesis

The protected amine is alkylated with alcohol using PPh3 and either diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and the deprotection is carried out under mild conditions (nearly neutral). The o-nitrobenzenesulfonyl group is referred to as the Fukuyama sulfonamide protecting group. This reaction has proven to be a versatile method for synthesizing secondary amines, polyamines, and even tertiary amines on a solid-support, with DIAD being preferred over DEAD.

The reaction described is particularly valuable in the production of secondary amines, particularly when using solid support synthesis.

References

Fukuyama, T., Jow, C.-K., and Cheung, M. (1995). 2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines. Tetrahedron Letters, 36(36), 6373-6374.
DOI: 10.1016/0040-4039(95)01316-A

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