Development of alkyl-pyrazole-based phosphine ligands and their applications in palladium-catalyzed chemoselective cross-coupling reactions

Abstract

Palladium catalysts represent one of the most widely utilized classes of catalysts for cross-coupling reactions in contemporary organic synthesis. Rational design of the ligands can lead to the development of high-performance palladium catalysts, enabling the utilization of more challenging substrates, the enhancement of reactivity, as well as the implementation of milder and more environmentally benign reaction conditions. However, the challenging chemoselectivity of cross-coupling reactions, which utilize electrophiles featuring two or more potentially competitive reaction sites, have only seen a resurgence in recent years. Over the past few years, our group has been actively exploring palladium-catalyzed chemoselective cross-coupling reactions via a ligand control strategy, especially for electrophiles bearing Cl and OTf. Based on this, our group developed a novel alkyl-indole-based phosphine ligand and then achieved a series of Pd-catalyzed chemoselective cross-coupling reactions such as chemoselective Suzuki-Miyaura coupling, Sonogashira reaction, and α-arylation of carbonyl compounds, with the reactivity order of C–Cl > C–OTf. Nevertheless, the design of new ligands for chemoselectivity control, particularly for inverting traditional reactivity order (e.g., C–Cl > C–OTf), is still limited. This thesis focuses on the exploration of novel phosphine ligands and their subsequent application in underexplored palladium-catalyzed chemoselective cross-coupling reactions. In Chapter 1, a brief introduction of some palladium-catalyzed reaction including C–N bond formation via Buchwald-Hartwig amination, redox-neutral decarboxylative cross-coupling reaction and direct C–H bond arylation of heterocycles as well as corresponding chemoselective investigations. Then, we will discuss the chemoselective reactions with unconventional C–Cl > C–OTf reactivity order. Our investigation on exploring new skeleton phosphine ligands to finish Pd-catalyzed chemoselective cross-coupling reactions is depicted in the subsequent sections of this thesis (Chapters 2-5). In Chapter 2, the successful preparation of pyrazole-based phosphine ligands bearing two Cy groups at C3 and C5 positions of pyrazole enabled inter-, and intramolecular chemoselective amination with excellent chemoselectivity in a C–Cl > C–OTf reactivity order. The high-performance catalytic system showed good reactivity and good functional group tolerance toward a wide range of chloro(hetero)aryl triflates as well as various amines including aromatic, aliphatic, and heterocyclic amines. Late-stage functionalization of some drugs and the gram-scale reaction were also feasible. In Chapter 3, further modification on the alkyl groups attached to the pyrazole scaffold resulted in the achievement of regio-, and chemoselective C–H arylation of heterocyclic compounds with excellent α-regioselectivity and chemoselectivity at C–Cl bond. This approach enabled a series of heterocycles to be feasible substrates including benzo[b]thiophene, thiophene, furan, benzofuran, and thiazole. Gram-scale synthesis and synthetic application for the synthesis of optical materials were also demonstrated. Density functional theory (DFT) results revealed that the modification of the cycloalkyl ring size influences the angle and length of the Pd···H–C interaction, thereby inducing differential stabilizing effects on the critical intermediates of the reaction. Mechanistic investigations supported by both experimental and DFT results suggest that the alkyl-pyrazole-based phosphine ligands bearing optimal ring sizes (five-membered cycloalkyl ring) enable the reaction to proceed with a lower energy barrier through a concerted metalation-deprotonation (CMD) pathway. In Chapter 4, the further investigation of the alkyl-pyrazole phosphine ligand showed that it could lower the reaction temperature of the redox-neutral decarboxylative cross-coupling reaction. Compared to Buchwald-type ligands such as SPhos, pyrazole-based phosphine ligand bearing i-Pr group could lower the reaction temperature by 60–80 °C and enable a wide range of aryl chlorides couple well with a series of benzoates under relatively mild conditions. Moreover, we utilized the Hammett plot and Eyring plot to explore the mechanism of the reaction and determine the rate-determining step might be the decarboxylative step. In Chapter 5, considering that the Pd···H–C interaction provided by the newly developed pyrazole-based phosphine ligand bearing i-Pr group may also effectively control the chemoselectivity towards the C–Cl bond under mild conditions, we subsequently leveraged this ligand to achieve chemoselective decarboxylative cross-coupling reaction. Various chloroaryl triflates coupled well with 2,6-difluoro benzoates affording corresponding diaryl compounds remaining OTf group under mild conditions, which demonstrated the high-performance of our developed catalytic system. In summary, our research focuses on developing novel phosphine ligands for palladium-catalyzed chemoselective cross-coupling reactions. We successfully achieved various reactions, including amination, C–H arylation, and decarboxylative coupling, demonstrating improved chemoselectivity, reactivity, and functional group tolerance, highlighting the potential for milder and environmentally friendly conditions.