Evolution of functional cyclohexadiene-based synthetic reagents: the importance of becoming aromatic.

Suites of new precursors designed around a cyclohexadiene core and intended to mediate "clean" radical chain syntheses have been prepared and tested. 1-Functionalized cyclohexa-2,5-dienes were found to readily donate H-atoms, and the resulting cyclohexadienyl radicals rapidly extruded their functional group as a free radical, because this beta-scission restored aromaticity to the ring. This concept was employed to generate designer radicals from esters of the corresponding alcohols with 1-methyl- or 1-phenylcyclohexa-2,5-diene-1-carboxylic acids. In a similar way, pre-adapted carbamoyl radicals were obtained from cyclohexadienyl-amides and proved advantageous for syntheses of alpha- and beta-lactams. Oxime ether substituted carbamoyl radicals cyclized successfully in convenient syntheses of dihydroindolin-2-ones with N-functionality at the 3-position. Similarly, silicon-centered radicals were obtained from 1-silylated cyclohexadienes, and these reagents proved to be very efficient, environmentally benign organotin hydride substitutes. Radical reactions including reductions, cyclizations, intermolecular additions, and hydrosilylations were carried out in high yields with this reagent. Other heteroatom-centered radicals, especially N-centered radicals, were obtained from appropriate cyclohexadienes enabling chain hydroaminations to be conducted. Several of the cyclohexadiene precursors proved to be useful for electron paramagnetic resonance (EPR) spectroscopic purposes, and this enabled rate constants for fragmentations of the cyclohexadienyl radicals to be obtained. Kinetic data for H-atom abstraction from cyclohexadienes, the second propagation step of the chain processes, was derived from customized radical clocks and from EPR measurements. In this way, conceptual tools were developed for improving future synthetic methodology based around these reagents.