Applications of Radical Carbonylation and Amine Addition Chemistry: 1,4-Hydrogen Transfer of 1-Hydroxylallyl Radicals

CONSPECTUS: 1,4-Hydrogen transfer from the 1-hydroxyallyl radical to give the enoxyl (alpha-keto) radical is an exothermic process with a high activation energy based on DFT calculations. The lack of experimental examples of such 1,4-H shift reactions lies in the difficulty of generating the 1-hydroxyallyl radical. We have shown that radical carbonylation of alkenyl radicals with CO followed by nucleophilic trapping of the carbonyl portion of the resulting radical by amines gives rise to 1-amino-substituted 1-hydroxyallyl radicals in situ. At the outset of this chemistry, we examined intramolecular trapping reactions via radical carbonylation of alkynylamines mediated by tributyltin hydride. Consequently, alpha-methylene lactams were obtained, for which the initially formed 1-amino-substituted 1-hydroxyallyl radical underwent a 1,4-H shift followed by subsequent beta-scission, which led to the expulsion of a tributyltin radical. A competing pathway of the 1,4-H shift of 1-amino-substituted 1-hydroxyallyl radicals involving hydrogen abstraction was observed, which led to the formation of alpha-stannylmethylene lactams as a major byproduct. However, in contrast, when intermolecular trapping of alpha-ketenyl radicals by amines was carried out, the 1,4-H shift from the 1-amino-substituted 1-hydroxyallyl radical became the major pathway, which gave good yields of alpha,beta-unsaturated amides. Thus, we were able to develop three-component reactions comprising terminal alkynes, CO, and amines that led to alpha,beta-unsaturated amides via the 1,4-H shift reaction. DFT calculations support the observation that the 1,4-H shift is more facile when 1-hydroxyallyl radicals have both 1-amino and 3-tin substituents. The choice of substituents on the amine nitrogen is also important, since N-C bond cleavage via an S(H)2-type reaction can become a competing pathway. Such an unusual S(H)2-type reaction at the amine nitrogen is favored when the leaving alkyl radicals are stable, such as PhC(center dot)H(CH3) and t-Bu center dot. Interestingly, even nucleophilic attack of tertiary amines onto alpha-ketenyl radicals causes cleavage of the CN bond. For this reaction, DFT calculations predict an indirect homolytic substitution mechanism involving expulsion of alkyl radicals through the zwitterionic radical intermediate arising from nucleophilic amine addition onto the alpha-ketenyl radical. In contrast, the carbonylation of aryl radicals, generated from aryl iodides, in the presence of amines gave aromatic carboxylic amides in good yields. It is proposed that radical anions originating from acyl radicals and amines undergo electron transfer to aryl iodides to give aminocarbonylation products.