Hydrazine Mitsunobu conditions

A second non-selective addition of vinyl Grignard to 661 produces a mixture of alcohols 662 and 665. The hydroxyl center is inverted with phthalimide under Mitsunobu conditions, after which the phthaloyl group is cleaved with hydrazine and the resulting amine acylated to give 664 and 667 (separable by HPLC). Compound 667 is then debenzylated, the acetonide group is hydrolyzed, and the olefin is ozonolyzed to give 668 as a crystalline solid. Likewise, 664 is converted to 669. By a parallel sequence of reactions, 660 is transformed to 670 and 671. Ozonolysis as the last step is a critical feature of these syntheses, because the A-acetyl-hexosamines are generated very cleanly, and such compounds are notoriously difficult to purify. 

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. 

More recently, the Mitsunobu protocol (Chapter 8, Scheme 8.32) has been widely used to effect the substitution as, under the proper conditions, diethyl azodicarboxylate can be shown to react with, for example, secondary alcohols, to form products with inverted absolute stereochemistry. Thus, as shown in Scheme 10.23 (and the details of Scheme 8.32), treatment of (5)-(+)-2-octanol, [ajo = +14.3 (heptane) with diethyl azodicarboxylate, triphenylphosphine, and phthalimide in THF at room temperature for several hours produced the corresponding N-1-octylphthalimide in high yield. Then, treatment of the latter with hydrazine hydrate yielded the desired, optically pure, (/ )-(-)-2-octylamine in about 50% overall yield (and with complete inversion of configuration). 

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