Construction of functionalized bicyclic nitrogen heterocycles via a novel variation of the Heck reaction

A novel variation of the Heck reaction has been developed in which sequential C-C and C-N bond-forming operations are performed in an efficient one-pot procedure on readily available acyclic compounds to produce diverse, functionalized bicyclic nitrogen heterocycles in good yields. Vinyl bromides are intramolecularly coupled with simple olefins in the presence of a palladium catalyst to form {dollar}pi{dollar}-allylpalladium complexes regioselectively, which then undergo further regioselective intramolecular addition by internal nitrogen nucleophiles to yield the bicyclic products. The fact that no crossover products were found in the cyclizations of regioisomers 181 and 226 confirms that it is possible to generate and trap {dollar}pi{dollar}-allylpalladium complexes by Heck reactions of vinyl halides and simple alkenes in a completely predictable manner.; While most of the vinyl bromide olefins cyclized regiospecifically in the 5- or 6-exo-trig fashion to give a single {dollar}pi{dollar}-allylpalladium intermediate, the minor product 193 in the reaction of 181 was the result of an anomalous 6-endo-trig cyclization. The major product 192 in the cyclization of 181 demonstrates that quaternary centers are easily formed by this methodology. In addition, two other substrates, 253 and 260, cyclized smoothly to form compounds containing quaternary centers.; Vinyl bromide olefin 253 cyclized in a regiospecific manner to generate {dollar}pi{dollar}-allylpalladium complex 254. However, a slight variation (15{dollar}spcirc{dollar}C) in reaction temperature dramatically altered the regiochemistry of the intramolecular nucleophilic addition in the intermediate 254. The kinetic product 256 was favored when the reaction was run at 60{dollar}spcirc{dollar}C, whereas the thermodynamic product 255 was formed exclusively at 75{dollar}spcirc{dollar}C. The kinetic product 256 isomerized to the thermodynamic product 255 upon subjection to the Heck reaction conditions at 75{dollar}spcirc{dollar}C, presumably via the {dollar}pi{dollar}-allylpalladium intermediate 254.; This novel methodology can be applied to terminal Z-vinyl bromides as well as internal vinyl bromides. While Z-vinyl bromide 278 cyclized to afford exclusively spirocyclic allylic sulfonamide 287 in poor yield, Z-vinyl bromide 269 cyclized to yield cis-fused hexahydroindole derivative 274 in good yield.