Difunctionalizations of Alkynes in the Domino Synthesis of Heterocycles

The Lautens group has investigated the use of metal catalysts for the domino synthesis of heterocycles. These strategies aim at generating products with high atom economy and minimal generation of waste. This thesis consists of three chapters describing the synthesis of various heterocycles in this fashion using both metal- and non-metal-catalyzed methodologies. Chapter 1 describes a palladium-catalyzed cycloisomerization of 1,6-diynes for the synthesis of silylated 2-azafluorenes. This reaction occurs via a palladium-hydride addition and C–H bond functionalization cascade. Originally, we desired to generate carbohalogenation products via the reductive elimination of a C–Pd(II)–X species, however, the corresponding intermediates demonstrated higher aptitudes for C–H activation. The synthetic utility of the products was investigated, and several mechanistic experiments were performed. Chapter 2 focuses on a palladium-catalyzed synthesis of dihydrobenzoindolones via an ortho C–H bond functionalization and alkyne insertion process. The reaction forms three new C–C bonds and generates products in high yields and excellent regioselectivities using unsymmetrically substituted alkynes. Chapter 3 describes the intramolecular chloroacylation of alkyne-tethered carbamoyl chlorides for the synthesis of E-3-(chloromethylene)oxindoles. Initial attempts to synthesize methylene oxindoles using nickel catalysts revealed that fluorinated alcohols promote this process in the absence of a metals or other additives. The products were obtained in high yields and excellent E-selectivity, and their synthetic versatility was demonstrated via a series of derivatizations, including the synthesis of nintedanib. Isomerization and halide-exchange experiments were performed to gain further insight into the reaction mechanism. Furthermore, analogous reactivity was extended towards the synthesis of chlorinated methylene pyrrolidones and 2-quinolinones. Chapter 4 describes future directions of the previous chapters. Mechanistic experiments, new substrate classes, asymmetric variants, among other related and unexplored areas of research are discussed.Ph.D