Studies Of Palladium-Catalyzed Direct C-3Alkynylation Of Indolizines And Synthesis Of Tricyclic Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Transition-metal-catalyzed C—H bond activations have become an important method to construct carbon-carbon and carbon-heteroatom bond in organic synthesis. Compared with conventional coupling reactions (such as Suzuki-Miyaura coupling reaction, Kumada coupling reaction and Sonogashira coupling reaction), these strategy do not require prefunctionalization of the substrates (usually halogenation or metallation). The C-H bonds could be directly involved in series of transformations, therefore being more effective and green. Consequently, transition-metal-catalyzed C-H activation transformations have aroused considerable interests in recent years.C-H bond activations can generally be divided into two parts:the directing group assisted reactions and the direct functionalizations. The former one requires the participation of directing groups (usually containing nitrogen, oxygen and sulfur atom), and the C-H bonds are activated through the formation of metal ring complexes intermediates. The latter one usually takes advantage of some special properties of the substrate to achieve the activation process. However, the directing groups can not be easily removed in some cases, hence compromising the practicality of the reactions.Indolizines serving as an available substrate for direct C-H functionalization have received much attention duo to their widespread presence in bioactive natural products and pharmaceuticals. Herein we provide an approach for C-3direct alkynylation of indolizines by employing (2,2-dibromovinyl)arenes as reaction partners which can be easily prepared from corresponding aldehydes by Corey-Fuchs reaction. The direct C-3alkynylation of Indolizines with (2,2-dibromovinyl)arenes efficiently proceeded through the test of various catalysts, ligands, bases, additives and solvents. This novel protocol showed wide substrate scope with respect to both indolizines and dibromoalkenes and was characterized with excellent functional group tolerance. Based on the relevant work, a plausible mechanism was proposed.