Hydrazides as tunable reagents for alkene hydroamination and aminocarbonylation

Abstract

Intramolecular hydroamination and aminocarbonylation of alkenes are highly desirable synthetic transformations providing access to structures frequently used in medicinal chemistry. Most research efforts currently focus on achieving this reactivity through transition metal catalysis. Our approach involves using hydrazides under thermal (metal-free) conditions to achieve hydroamination or aminocarbonylation upon selection of the appropriate hydrazide substituent (R). Upon substitution when R=Ph, various different compounds were synthesized and isolated in moderate to excellent yields (39 to 98%). Primary and secondary hydrazides pyrrolidines were cyclized and terminal or internal substituted double bonds were tolerated. Morpholine, piperazine, piperidine and azepane moieties were also cyclised with increased heat. This methodology was also consistent with hydroamination on a benzylic olefin. Aminocarbonylation products were obtained in good to excellent yields (52--86%), when R=NH2 and O-tBu. Substituted terminal bonds are obtained with retention of alkene stereochemistry, suggesting a novel concerted reaction pathway. Such reactions are very practical: the starting materials are accessed readily, and both starting materials and products are easy to handle and purify. Such products are also remarkably stable at high temperatures.* *Please refer to dissertation for diagrams.