Development of Bifunctional Ligands and Their Applications in Iridium-Catalyzed Remote Regio- and Enantioselective C(sp²)–H Borylation

Aditya, Netai (2026) Development of Bifunctional Ligands and Their Applications in Iridium-Catalyzed Remote Regio- and Enantioselective C(sp²)–H Borylation. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Netai Aditya (19RS044)) 19RS044.pdf - Submitted Version Restricted to Repository staff only Download (41MB)

Abstract

Catalytic functionalization of C−H bonds is a powerful strategy for the synthesis and diversification of organic compounds. Selective functionalization of C-H bonds enables the generation of molecular complexity from simple substrates. Iridium-catalyzed C-H borylation of arenes provides widely functionalizable arylboronate esters under mild reaction conditions. Over the last couple of decades, multiple elegant approaches have emerged for regioselective C-H borylation. While the proximal enantioselectivity could be achieved in multiple cases,simultaneous control over remote site- and enantioselectivity has remained rare. Chapter -1. Bifunctional Catalysis for Selective C–H Functionalization. This chapter outlines the progress in the field of C–H functionalization reactions, including iridium-catalyzed arene borylation. It discusses the challenges associated with the selective functionalization of organic molecules having a pool of C–H bonds of similar types. The emergence of bifunctional catalytic systems in regulating the selectivity of such processes has been discussed emphatically. Consequently, the development of bifunctional bipyridine ligands with the purpose of selective C(sp²)–H borylation has been thoroughly discussed, highlighting the lack of efficient catalytic systems for controlling both remote regio- and enantioselectivity. Chapter -2. Development of Chiral Bifunctional N,N’-Ligands. This chapter includes the prior works on chiral N,N’-ligands and the development of bifunctional chiral ligands. A library of chiral ligands having a planar ligand core has been synthesized and characterized. The modular synthetic route to the ligands offers high tunability of the ligands. The chiral sidearm, 2,2’-binaphthol (BINOL), can hold a Lewis acid aluminum center and interact with Lewis basic substrates to bring it in proximity to the bipyridine part for the iridium-catalyzed remote-selective borylation reaction. Chapter -3. Regioselective Meta-C−H Borylation Enabled by Iridium-Aluminum Bifunctional Catalysts. This chapter reports site-selective borylation of remote C(sp²)-H bonds of arylacetamides occurred with excellent meta/para selectivity up to >99:1. Despite being conformationally more flexible, longer arylcarboxamides provided good to excellent regioselectivity using a modified ligand containing the Lewis acidic side-arm at the C4-position of bipyridine. The strong recognising ability of the catalyst enabled unprecedented remote selectivity for the substrates of minimal rigidity. Chapter -4. Regio- and Enantioselective C(sp²)–H Meta-Borylation of α,α- Diarylcarboxamides This chapter presents iridium-catalyzed regio- and enantioselective meta-borylation of α,α- diarylcarboxamides, generating an all-carbon quaternary stereocenter in high yields and excellent regio- and enantioselectivities. The prochiral substrates were desymmetrized with up to an excellent 99% ee. An unprecedented kinetic resolution for such transformation has also been disclosed with moderate to good selectivity (s-factor up to 19.5). The synthetic utility was demonstrated through a successful scale-up experiment and subsequent transformation of the boronate ester to various functional groups. Further, mechanistic studies indicate that the catalyst primarily governs the enantioselectivity of the desymmetrization reaction, while the kinetic resolution of the mono-borylated product plays a secondary role in further enhancing the product’s enantioselectivity. Chapter -5. Synthesis of S-Stereogenic Sulfoximines via Enantioselective Meta- Borylation. Sulfur-stereogenic chiral molecules are of great synthetic interest owing to their promising bioactivities. The generation of S(VI)-stereogenic molecules via meta-selective borylation of diarylsulfoximines has been demonstrated in this chapter. Good to excellent enantioselectivity (up to 94% ee) was obtained for achiral substrates, while the racemic substrate was kinetically resoluted with a good s-factor of 19.3. The success of the protocol with ortho-substituted substrates showcased its robustness.

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