N-Heterocyclic Carbene-Catalyzed Enantioselective Synthesis of Dihydrothiopyranones, Functionalized Benzofurans and Extending Michael Acceptor Aldimine Umpolung

Abstract

Carbenes exhibit high reactivity as divalent species with six electrons in their valence shell. Their electrophilic nature arises from an incomplete octet. However, when a heteroatom is introduced adjacent to the carbene carbon, it transforms into a nucleophilic species, known as N-heterocyclic carbenes. The presence of an adjacent heteroatom stabilizes this carbene through -electron withdrawal (inductomeric effect) and -electron donation (mesomeric effect). This exceptional behavior allows NHCs to function as excellent ligands in metal catalysis and as novel organocatalysts. Organocatalysis utilizing NHCs has emerged as an efficient and powerful synthetic tool for rapidly constructing complex architectures from readily available starting materials. Among the various reactivity modes of NHCs, their ability to reverse the polarity (umpolung) of aldehydes, Michael acceptors, alkyl halides, and imines stands out as particularly significant. Additionally, carbenes are known to catalyze reactions through the conventional pathway by generating acylazoliums and α,β- unsaturated acylazoliums, which can act as bis-electrophiles. Enolate and dienolate intermediates also play crucial roles in the normal mode of NHC catalysis. Recent advancements in NHC organocatalysis have focused on utilizing radical intermediates. By employing NHC-bound to ketyl radicals and conjugated ketyl radicals, various biologically important compounds can be synthesized. This chapter provides a summary of the different modes of action observed in NHC organocatalysis. The focal theme of the thesis is also included in this chapter. Chapter 2 summarizes the enantioselective synthesis of functionalized dihydrothiopyranone derivatives using the NHC-catalyzed [3+3] annulation of β-oxodithioester with modified enals. The reaction commences with the Michael addition to catalytically generated α,β-unsaturated acylazolium intermediates derived from 2-bromoenals, followed by intramolecular cyclization. This efficient and rapid process allows for the facile preparation of regioselective dihydrothiopyranone compounds with high yields and excellent enantioselectivities. Furthermore, comprehensive mechanistic investigations are provided to elucidate the reaction pathway. The broad substrate scope, mild reaction conditions, and compatibility with various functional groups highlight the notable features of this transformation. The regioselective formation of dihydrothiopyranones over the competing dihydropyranones is noteworthy. Given the prevalence of heterocycles containing sulfur in numerous medicines and natural products, the synthesis of dihydrothiopyranones in enantiopure form presented in this chapter are likely to find potential applications for the synthesis of sulfur heterocycles. In Chapter 3 the NHC-catalyzed enantioselective functionalization of 3-aminobenzofurans at the C2-position has been realized using 2-bromoenals as the coupling partner. The reaction proceeds via the generation of chiral -unsaturated ac-ylazoliums and follows an aza-Claisen rearrangement. The initially formed dihydropyridinone undergoes ring-opening catalyzed by Mg to afford the -amino acid derivatives. The reaction worked with 3-aminobenzothiophenes as well, and the C2-alkylated products were formed in moderate to high yields and selectivity. Overall, the process involves the directed C-H functionalization of benzofuran and benzothiophene derivatives using catalytically generated chiral α,β-unsaturated acylazoliums. Notably, the dihydropyridinone derivatives are also isolable. This transformation demonstrates a broad substrate scope and compatibility with various functional groups, and proceeds under mild conditions. Chapter 4 describes the NHC-catalyzed cross-coupling of activated olefins with ketones for the synthesis of functionalized oxindole derivatives. The catalytically generated deoxy-Breslow intermediate participates in nucleophilic addition to activated ketone derivatives, resulting in the formation of oxindole derivatives with good to excellent yields. The key deoxy-Breslow intermediates are isolated and characterized using X-ray analysis. Furthermore, comprehensive mechanistic studies are presented. Control experiments and detailed mechanistic investigations reveal that the reaction proceeds through the umpolung of cyclopent-4-ene-1,3-diones. This cross-coupling strategy offers a versatile and practical approach for synthesizing valuable oxindole derivatives. In Chapter 5 we also investigated the synthesis of various oxindole derivatives through the cross-coupling reaction between aldimines and isatins, utilizing NHC-catalyzed umpolung reactivity. Although carbene-catalyzed umpolung of imines has been well-documented in the literature, but is limited to intramolecular reactions mostly. However, there is only one report available regarding the intermolecular reactivity involving the addition of aza-Breslow to activated alkenes. To extend the scope of intermolecular imine umpolung strategy, cross-coupling of imines and isatins was envisioned. Overall, the present findings demonstrate the successful application of NHC-catalyzed umpolung reactivity in the cross-coupling reaction between imines and isatin, leading to the synthesis of oxindole derivatives. This research contributes to expanding the knowledge and understanding of intermolecular reactivity involving aza-Breslow intermediates and likely provides a foundation for further investigations in this field