Phthalimide Mitsunobu reaction, alcohol-amine

MacDougall and Cashman et al. prepared a number of analogs of morphine-6-glucuronide. As such, the amine intermediate 111 was prepared using a phthalimide Mitsunobu reaction. The free phenol was protected as the acetate ester prior to the Mitsimobu reaction since the phenol is more reactive than the vinyl alcohol under the reaction conditions. Other diverse examples employing phthalimide are listed below as well (112-115). - ... 

A very interesting variant of the polymer-supported Mitsunobu reaction was recently disclosed by Gelb and Aronov (Scheme 14) [40]. Polymer-bound phthalimide 34 was designed which is able to trap alcohols such as nucleosides under Mitsunobu conditions. After purification by washing the loaded resin the corresponding amine was subsequently released into solution in high yield by hydrazinolysis. 

Treatment of 75 with lithium acetylide ethylenediamine complex afforded the acetylene derivative 78 (85%), which was transformed into the vinyl alcohol 79 by partial hydrogenation using Lindlar catalyst. Employing the Mitsunobu reaction, compound 79 was transformed into the phthalimide 80, which was converted into the benzamide 82 (64%) via the primary amine 81 by sequential deacylation and benzoylation. When the... 

Isomannide (80) was the core for a hexahydrofurofuran library." Primary amines were loaded onto solid-support by reductive amination and acylated with bromoacetic acid to give bromides 79 (Scheme 7.16). Alkylation of bromides 79 on solid-support with isomannide (80) gave the solid-supported alcohols 81. A Mitsunobu reaction with phthalimide (82) proceeded to furnish amines 83 in excellent yield and purity after removal of the protecting group." " Support-bound primary amines 83 were converted to secondary amines by stepwise imine formation with aldehydes 84 and reduction with sodium borohydride." The hindered secondary amines 85 were acylated with acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates to yield 87 after cleavage from solid-support. 

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. 

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