Synthesis Of Dihydropyrrole Derivatives Via Palladium-catalyzed Heck/Suzuki Cross-coupling Cascade Reaction

The2,3-dihydropyrrole frameworks are an important structural motif, widely found in natural products, synthetic building blocks, materials, and biologically and therapeutically active compounds such as antitumour, anti-inflammatory, hypolipidemic and antimicrobial agents, retroviral reverse transcriptase inhibitors, insecticids, playing an important role in the discovery of drug molecules. Therefore, molecules containing this motif have attracted considerable attention and much effort has been focused on the development of efficient synthetic methods.Recent studies reveal that haloacetylenes can undergo addition by nitrogen nucleophiles to give halo-substituted olefins as valuable synthetic building blocks for nitrogen-containing heterocyclic compounds. Then an expedient protocol for the synthesis of5-aryl-2,3-dihydropyrroles, starting from N-Tos protected2-methylprop-2-en-l-amine, alkynyl bromides and arylboronic acids, is described. The sequentially accomplished reaction comprises the nucleophilic addition of sulfonamides to alkynyl bromides, then followed by Pd-catalyzed tandem intramolecular Heck/intermolecular Suzuki cross-coupling reaction of bromoalkene adducts. With Pd(OAc)2(5mol%) as the catalyst, PPh3(5mol%) as the ligand, PivOH (30mol%) as the additive and K2CO3as the base, sulfonamides could undergo tandem Heck/Suzuki C-C cross-coupling reaction in DMA at110℃for24hours to produce the corresponding target in moderate yield.Encouraged by the above result, the scope and generality of the present process were then explored. Our research shows that the target has good tolerance of substituents on the aryl boric acid, including electron-withdrawing group (F and Cl) and electron-donating group (Me and OMe). In addition, heteroaromatic rings, such as2-thiophenylboric acid are also applicable. Based on the experimental results, a mechanism for this transformation is proposed. Oxidative addition of the vinyl bromide to Pd(0) formed a key Csp2-Pd(Ⅱ) trimethylacetate, which strongly favored the migratory insertion of tethered olefin to form Csp3-Pd(Ⅱ) intermediate, and suppressed the transmetalation process of arylboronic acid to form Suzuki-type product. The transmetalation of arylboronic acid with the Csp3-Pd(Ⅱ) pivalate complex led to the formation of intermediate, which underwent C-C bond-forming reductive elimination to afford the desired2,3-dihydropyrroleand regenerate the active catalytic species.This thesis has developed a practical, simple and efficient method to synthesize2,3-dihydropyrrole derivatives. This protocol is not only a valuable addition to the tool box of the synthesis of2,3-dihydropyrroles, but also enriches the contents of palladium-catalyzed cascade cyclizations reactions, which should be of considerable interest of the valuable synthetic building blocks for medicinal and material science.