The focus of this proposal is the further development of a concise and versatile route for the preparation of differentially substituted heteroaromatics based on the regioselective one-pot polycoupling of polyhalogenated heteroaromatics. The basic advantage of such an approach is that the starting polyhalogenated compounds can be readily prepared by a single halogenation reaction. Then, by applying coupling reactions 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 of the preparation of any regioisomer of a polysubstituted heteroaromatic. Previous work has already indicated that both regioselectivity and double couplings can be accomplished in one pot for a wide range of heteroaromatic systems. Additionally, a guide for predicting the regioselectivity of each coupling has been developed, which uses the 1H NMR chemical shift information for the parent, non-halogenated heteroaromatic to predict the order of coupling. One remaining limitation is that broadly universal coupling conditions have not been yet identified. Very recent results on cross-couplings using boronate salts display promise in overcoming this limitation. As a result, the first step in future work is to study the scope of applicability of these boronate salt couplings in terms of both the polyhaloheteroaromatic substrate and also the boronate salt substrate. The other broad area of effort will be the study of """"""""mixed"""""""" couplings in which the two (or more) coupling reactions are of different types. This will enable the installation of not only carbon-carbon bonds, but also carbon-nitrogen and carbon-oxygen bonds in a single pot. As a result, a enormous range of medicinally interesting compounds (such as the thiopeptide antibiotics and indolocarbazoles) can be prepared in a very concise fashion, which will in turn facilitate the study of their potential as new pharmaceutical agents.
Substituted heteroaromatics serve as the core of many existing and potential pharmaceutical agents. The regioselective polycoupling approach provides a new, more flexible and more efficient route for the synthesis of these compounds and will enable the timelier discovery of new pharmaceuticals.
| 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 |
