Regioselectivity in the multi-component synthesis of indolizinoquinoline-5,12-dione derivatives

The one-pot cyclisation to form the indolizinoquinoline-5,12-dione ring system has been investigated starting from 6,7-dichloroquinoline-5,8-dione by reaction with pyridine and ethyl acetoacetate. Both the N,N-syn and the N,N-anti products have been fully characterised by mass spectrometry and NMR analysis, and the regio selectivity of their formation is discussed in terms of solvent polarity and/or the nature of the metal ion. We demonstrate here that, among a wide series of polar and apolar solvents, tert-butyl alcohol is the best choice to enhance the yield of the N,N-syn regioisomer, while the N,N-anti regioisomer can be obtained with a very high selectivity when the reaction is carried out with scandium triflate. In the presence of metal chelation, semi-empirical ZINDO calculations offer an appropriate tool to explain the regioselectivity observed when different metal ions are used. The study of the regioselectivity is also supported by the data for the corresponding two-step reactions with reversed addition of the nucleophilic reagents, and it has been extended to the cases involving 4-methylpyridine and 6,7-dichloroisoquinoline-5,8-dione as reagents. (c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006.