The focus of this proposal is the development of a concise and versatile route for the preparation of differentially substituted hetero aromatics, based on the regioselective one-pot coupling of polyhalogenated heteroaromatics.The basic advantages of such an approach is that the starting polyhalogenated compounds can be readily prepared by a single halogenation reaction. Then, by applying a coupling reaction in the second step a wide range of functionalized substituents can be installed regioselectively in a single step. The end result is a two step method for the preparation of any regioisomer of a polysubstituted heteroaromatic. Preliminary results have already indicated that both regioselectivity and double couplings can be accomplished in one pot. To further application of this method, a hypothesis has been developed using the 1H NMR chemical shift information for the parent, non-halogenated heteroaromatic to predict the order of coupling as well as what reaction conditions will work with which substrates. Further, two sets of coupling conditions have been developed based on the structure of the starting heteroaromatic. One set works for substrates that lack strongly coordinating Lewis basic sites, while the other set works for coordinating and potentially weakly coordinating but bidentate systems. Most of the preliminary studies have focused on pyrrole and pyridine, but the efforts outlined in this proposal will expand this scope to include a wide range of other classes of heteroaromatics in an effort to demonstrate that the same reaction conditions can be expanded to the preparation of a wide range of heteroaromatic compounds of medicinal interest. Further, some trihalogenated heteroaromatics will be studied in an effort to extend the polycoupling method to even more complex systems and thereby reap the benefit of greater reduction to the overall length of the synthesis of these types of compounds. On the basis of these studies, future research will be able to both synthesize compounds of biological interest (such as the lamellarins and pyridine-based antibiotics) as well as extend this method to other types of coupling reactions. ? ?
| Piala, Alexander; Mayi, Diyar; Handy, Scott T (2011) Studies of one-pot double couplings on dibromoquinolines. Tetrahedron 67:4147-4154 |
| Anderson, Samantha C; Handy, Scott T (2010) One-pot Double Suzuki Couplings of Dichloropyrimidines. Synthesis (Stuttg) 2010:2721-2724 |
| Varello, Samantha; Handy, Scott T (2009) Double Couplings of Dibromothiophenes using Boronic Acids and Boronates. Synthesis (Stuttg) 40: |
| Handy, Scott T; Mayi, Diyar (2007) Regioselective double Suzuki couplings of 4,5-dibromothiophene-2-carboxaldehyde. Tetrahedron Lett 48:8108-8110 |
| Handy, Scott T; Wilson, Thomas; Muth, Aaron (2007) Disubstituted pyridines: the double-coupling approach. J Org Chem 72:8496-500 |
