Radical Cyclization onto Polar Unsaturated Bonds. A New Method for the Synthesis of Nitrogen-Heterocycles

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The aim of this work is to develop a new class of radical cyclization reactions available for the synthesis of nitrogen-heterocycles. We investigated radical cyclization which employs a system that both attacking radical and accepting unsaturation have a polarity, under the hypothesis that the polarity-matching would boost the desired cyclization mode. Acyl radicals generally behave as nucleophilic radical, however the carbonyl carbon should have an electrophilic nature. Thus, we examined the reaction of ω-imino alkyl radicals with CO in detail and observed that the complete exo-mode cyclization leading to lactam rings. Ab initio and DFT MO calculations revealed the transition state of the cyclization is akin to that of nucleophilic attack of imine-nitrogen to aldehyde, supporting that polar interaction between attacking radical site and accepting N-C double bond is crucial. Having a strong support from the calculation, we then embarked on the work to find powerful radical cyclization systems boosted by polarity-matching, and found that stannylcarbonylation reaction of azaenynes is particularly useful reaction in its unusual breath in the cyclization modes covering 4-exo, 5-exo, 6-exo, 7-exo, and even 8-exo. With this novel cyclization method in hand, four to eight membered ring lactarns having an α-stannylmethylene group can be prepared conveniently. The resulting Sn-C bond was successfully converted to the corresponding H-C, I-C, and C-C bonds by the subsequent protonation, iodination, and Stille coupling reaction. The carbonylative cyclization of enynes was further extended to include those with (TMS)_3SiH and alkane thiols as radical mediators. Thus, we have established a new concept of polarity-governed radical cyclization with convincing results available for α-methylene lactam synthesis, whose basic principle would have a general applications in radical reactions.