Rapid Bergman cyclization of 1,2-diethynylheteroarenes

The synthesis and cyclization of acyclic quinoxaline, pyridine, and pyrimidine enediynes (1-3) are described. These compounds were prepared using palladium(0) coupling of trimethylsilyl acetylene to o-dihalo- or o-halotriflic heteroarenes. All compounds were prepared in modest to good yields. The enediynes prepared were shown to undergo Bergman cyclization. Kinetics over a minimum of 3 half-lives were used to construct Arrhenius plots. Pyrimidine 3 was found to have an activation energy of 16.1 kcal/mol. Cyclization of the closest known aromatic analogue, o-diethynylbenzene (15), has E-a = 25.1 kcal/mol (Grissom, J. W.; Calkins, T. L.;McMillen, H. A.; Jiang, Y. J. Org. Chem. 1994, 59, 5833-5835). Pyridine 2 and quinoxaline 1 gave activation energies of 21.5 and 33.6 kcal/mol, respectively. The results illustrate that heteroarenes can be used to activate Bergman cyclization. We expect these compounds to play an important role in furthering the understanding of Bergman cyclization and in aiding the development of new biologically significant enediynes.