Developing Methodologies for the Synthesis of Heterocyclic Libraries: Parallel Synthesis of Flavours, Maleimides, alpha-beta-Unsaturated-gamma-Butryrolactams and Isoquinolines

Abstract

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, α-β-unsaturated-γ-butyrolactams and isoquinolines are described. A Pd2(dba)3.CHCl3 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. Synthetic strategies that led to the generation of libraries of bisaryl-maleirnides, anilinoaryl-maleimides and bisanilino-maleimides as well as bisaryl substituted α-β-unsaturated-γ-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 α-β-Unsaturated-γ-Butyrolactams from 3,4-dibromo-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-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 α-β-unsaturated-γ-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 cyclizations. 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 α-arylation of active methylene compounds using the palladium complex of 1,3,5,7-tetramethyl-6-(isobutyl)-2,4,8-trioxa-6-phosphaadamantane (P A-iBu) to generate products that served as precursors for a diverse collection of substituted isoquinolines is also described.