Mitsunobu reaction Fukuyama amine synthesis

Despite the broad scope of the Fukuyama amine synthesis, there are possible complications that may arise. Common to any Mitsunobu reaction, there is the issue of purification that is often required in order to remove the copious amounts of Ph3P=0 that are generated. This can be difficult, but modifications to the phosphine base employed can mitigate this problem (vida infra). The Mitsunobu alkylation also oftentimes... 

This reaction was initially reported by Fukuyama and co-workers in 1995. It is a two-step conversion of primary amines into secondary amines via ortho-nitrobenzenesulfonation in conjunction with the Mitsunobu Reaction and subsequent removal of the o-nitrobenzenesulfonyl group by thiophenol. Therefore, this reaction is generally known as the Fukuyama amine synthesis. In addition, it is also referred to as the Fukuyama-Mitsunobu A -alkylation," Fukuyama-Mitsunobu alkylation, Fukuyama-Mitsunobu condition, Fukuyama-Mitsunobu procedure, or Fukuyama-Mitsunobu Reaction. In this reaction, the o-nitrobenzenesulfonyl-protected amine is alkylated with alcohol in the presence of PPhs and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and the deprotection occurs in a very mild condition (almost neutral ). The o-nitrobenzenesulfonyl group is simply called the Fukuyama sulfonamide protecting groupThis reaction has become a versatile method... 

Synthesis of Amines, Amides, Ureas, Thioamides, and Thioureas. The Fukuyama-Mitsunobu reaction is the best method to synthesize secondary amines from primary amines, avoiding formation of undesired tertiary amines and/or the quaternary ammonium salts (eq 1). ... 

Activated amines tethered to solid supports have found ready application in the preparation of primary amines or Boc-protected amines. These approaches usually rely on doubly activated amines or a Fukuyama style approach. The figure below lists two amine synthesis precursors (186, 187) after Mitsunobu reaction, appropriate deprotection conditions yield the desired amines. Additional examples for the synthesis of Fmoc-iV-methyl amino acids are also known. ... 

Scheme 17.1 Bidirectional solid-phase total synthesis of AigTX-636. The monoprotected diamine was anchored to the resin by reduced amination, followed by adding the amino acid linker and aromatic head group under the standard coupling condition. The polyamine backbone was prolonged by repeated Fukuyama-Mitsunobu reactions. After adding the terminal arginine to the intermediate, the protected resin-bound molecule was released from the resin, and then the protecting group was removed to obtain the nature ArgTX-636...

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