Theoretical insights into the mechanism and origin of chemoselectivity in the catalyst- and directing group-dependent oxidative cyclization of diynes with pyridine N-oxides

The transition-metal-catalyzed oxidative cyclization of diynes can be exploited to synthesize N-heterocycles, which are important structural motifs found in drug candidates and biologically active compounds. Herein, the mechanisms and origin of the chemoselectivity of Cu(I)- and Au(I)-catalyzed oxidation of diynes for the divergent syntheses of two different N-heterocycles, substituted pyrroles and dihydroindeno[1,2-c]pyrrol-3(2H)-ones, respectively, were elucidated using density functional theory (DFT). The DFT results reveal that the active catalytic species of the Cu(CH3CN)(4)BF4 catalyst in the developed Cu(I)-catalysis system is Likely to be a cationic Cu(I) complex, which preferentially simultaneously coordinates to the two C C bonds and the nitrogen atom of the amide directing group of the diyne to generate a precursor. In contrast, the Au(I) species preferentially binds to the electron-rich amide-tethered C C bond of the diyne, and thus produces a precursor sufficiently different from that of the Cu(I)-catalyzed pathway that two discrete reaction pathways result, Leading to different products. Both catalyses involve the following steps: substrate activation, N-oxidant attack, N-O bond cleavage, five-membered cyclization, carbene migration, H-shift, and substrate exchange. The difference between the two systems is that the Au(I)-catalysis can undergo another intramolecular five-membered cyclization, whereas the Cu(I)-catalysis cannot. This research provides a detailed mechanism and information on the chemoselectivity of the transition metal-catalyzed oxidative cyclization of diynes, which will be useful for understanding and designing novel transition metal-catalyzed reactions of diynes.