Mitsunobu reaction, hydrazoic acid

Diphenylphosphoryl azide reacts with alcohols in the presence of triphenylphosphine and DEAD.76 Hydrazoic acid, HN3, can also serve as the azide ion source under these conditions.77 These reactions are examples of the Mitsunobu reaction. 

Alcohols can be converted to alkyl halides, which then react with amines (10-43). Alcohols react with various amine reagents that give products convertible to the amine. The conversion ROH RNH2 can be accomplished for primary and secondary alcohols by treatment with hydrazoic acid (HN3), diisopropyl azo-dicarboxylate (iPr—OOCN=NCOO—/Pr), and excess PhsP in THF, followed by water or aqueous acid. This is a type of Mitsunobu reaction (see 10-17). Other... 

The nature of the nucleophile is critical when considering the Mitsunobu reaction as a means of introducing amine functionalities. Because of the proton transfer components illustrated in the reaction mechanism, only acidic nitrogens can be introduced. The most common nitrogen nucleophiles include phthahmide, hydrazoic acid and zinc azide [62]. Once placed, phthahmides are easily converted to amines utihzing hydrazine [6]. Moreover, azides are easily reduced to amines under numerous conditions [32]. Schemes 6.32 and 6.33 illustrate the application of this chemistry to nucleosides [63] and pyranosides [64], respectively. 

The Mitsunobu reaction is also the basic step in the synthesis of 65. The starting homochiral hydroxy ester 62 is readily available by yeast-mediated reduction of ethyl 2-oxocyclopentanecarboxylate. Treatment of 62 with hydrazoic acid under Mitsunobu conditions resulted in inversion to the azide 63, which was hydrogenated in the presence of di-ter/-butyl... 

Finally, the Eschenmoser-Claisen rearrangement has found appUcations in drug synthesis. Mulzer s synthesis of the antidepressant (J )-rolipram serves as an example (Scheme 7.36) [84]. Rearrangement of chiral cinnamyl alcohol 104 gave unsaturated amide 105 with Uttle erosion of optical purity. Ozonolysis and reduction afforded alcohol 106 and set the stage for a subsequent Mitsunobu reaction with hydrazoic acid. Reduction of the azide function followed by intramolecular transamidation gave y-lactam 107, which was converted into (R)-rolipram in two straightforward steps. 

The use of these reagents in the synthesis of enantiomeiicaUy enriched labeled derivatives is illustrated by the following examples. CBS reduction of 3 -bromo- and 3 -methoxy[carbonyl- " C]acetophenones (33) with BH3 THF in the presence of 0.3 equivalents of iy>-30b furnished (/ )-carbinols 34 in chemical yields of 75% and e.e.s of 97%. Subsequent Mitsunobu reaction with hydrazoic acid and reduction of the resulting... 

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