Developing methodologies for the synthesis of heterocyclic libraries: Parallel synthesis of flavones, maleimides, alpha,beta-unsaturated-gamma-butyrolactams and isoquinolines

Parallel synthesis technologies that allow for rapid generation of compound collections that can be screened and quickly provide useful structure-activity relationships are needed to probe and understand biological systems. Synthetic strategies that are robust and allow the rapid access to a library of flavones, maleimides, alpha,beta-unsaturated-gamma-butyrolactams and isoquinolines are described.;Synthetic strategies that led to the generation of libraries of bisaryl-maleimides, anilinoaryl-maleimides and bisanilino-maleimides as well as bisaryl substituted alpha,beta-unsaturated-gamma-butyrolactams are described. The reaction protocol also takes advantage of Pd-cross-coupling reactions using the catalytic system mentioned above as well as Michael addition / elimination reactions. Reaction conditions that allow for the control necessary for the synthesis of a library of symmetrical and non-symmetrical 3,4-disubstituted maleimides from N-(p-methoxybenzyl)-3,4-dibromomaleimide as well as symmetrical and non-symmetrical 3,4-disubstituted alpha,beta-unsaturated-gamma-butyrolactams from 3,4-dibromo-1-(4-methoxybenzyl)-1H-pyrrol-2(5 H)-one are presented. Protocol for facile deprotection of the p-methoxybenzyl group to generate the final products of both 3,4-disubstituted maleimides and 3,4-substituted alpha,beta-unsaturated-gamma-butyrolactams is also described.;A robust parallel synthetic strategy that makes use of simple, cheap and readily available precursors is described for the preparation of a library of substituted isoquinolines. The approach involves microwave-assisted Pictet-Spengler and Bischler-Napieralski cyc1izations. In addition, a Pd-catalyzed cross-coupling reaction protocol using the Pd/PA-Ph provides access to a diverse collection of C1 and C4 substituted isoquinolines via the activation of an isoquinolin-1 (2H)-one scaffold.;A protocol for the Pd- catalyzed a-relation of active methylene compounds using the palladium complex of 1,3,5,7-tetramethyl-6-(isobutyl)-2,4,8-trioxa-6-phosphaadamantane (PA-iBu) to generate products that served as precursors for a diverse collection of substituted isoquinolines is also described.;A Pd2(dba)3CHCl3 catalyst system incorporating the 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane (PA-Ph) ligand permits the generation of a library of substituted flavones via sequential microwave-assisted copper free Sonogashira and carbonylation annulation reactions under mild conditions. Application of this protocol is described for several aryl iodides and bromides with TMS-acetylenes allowing for the "one pot" synthesis of a diverse collection of substituted flavones.