Best Synthetic Methods: Construction of Aromatic and Heteroaromatic Rings

Aromatic and heteroaromatic rings are the heart of pharmaceutical design. Several useful methods for monocyclic and polycyclic aromatic ring construction have recently been reported.

Aaron L. Odom of Michigan State University has described (Org. Lett. 2004, 6, 2957. DOI: 10.1021/ol0489088) a new approach to dialkyl pyrroles. Ti-catalyzed hydroamination of a 1,4-diyne such as 1 leads smoothly to 2. Similarly, Ti-catalyzed hydroamination of a 1,5-diyne such as 3 delivers 4. An inherent limitation of this approach is that it only allows substitution at the 2 and the 5 positions of the pyrrole.

A more flexible approach to pyrroles has been developed (Tetrahedron Lett. 2004, 45, 9315. DOI: 10.1016/j.tetlet.2004.10.126) by Keiji Maruoka of Kyoto University. Rearrangement of 5 by the Al complex 6 leads, by preferential benzyl migration, to the trisubstituted pyrrole 7.

Martin Banwell of the Australian National University has devised (Org. Lett. 2004, 6, 2741. DOI: 10.1021/ol0490375) a Pd-mediated approach to fused quinolines. Coupling of 8 with the bromo aldehyde 9 leads to 10, which on reduction cyclizes to 11.

Substituted naphthalenes can be prepared by adding an aromatic ring onto an existing benzene derivative. Rai-Shung Liu of the National Tsing-Hua University, Taiwan, has found (J. Am. Chem. Soc. 2004, 126, 6895. DOI: 10.1021/ja049943c) that exposure of an epoxy alkyne such as 12 to a catalytic amount of TpRuPPh₃(CH₃CN)₂PF₆ leads to the β-naphthol 15. The reaction is thought to be proceeding by initial rearrangement to the vinylidene complex 13. O-atom transfer converts 13 to the ketene 14, which undergoes cycloaddition to the newly-liberated alkene to give 15. The facile conversion of 12 to the TpRu-vinylidene complex 13 will have many other applications in organic synthesis.