NON-PRECIOUS METAL CATALYSED C-C BOND FORMATION USING ALCOHOL AS ALKYLATING REAGENT

Abstract

The work accomplished during the research period has been collated in the form of a thesis with the title “NON-PRECIOUS METAL CATALYSED C-C BOND FORMATION USING ALCOHOL AS ALKYLATING REAGENT”. The thesis has been divided into five chapters. Chapter-1: Transition Metal-Catalyzed Sustainable Approaches for the Construction of C-C Bonds using primary alcohol. Chapter-2: Mn (II)-Catalysed Alkylation of Methylene Ketones with Alcohols: Direct Access to Functionalised Branched Products. Chapter-3: Direct Synthesis of gem-β,β’-Bis(alkyl) Alcohols using Nickel Catalysis via Sequential DCR-Approach. Chapter-4: Iron-Catalysed Alkylation of 2-Methyl and 4-Methyl Azaarenes with Alcohols via C-H Bond Activation. Chapter-5: Ni-catalyzed synthesis of CF3-Embedded 1,5 Diketones: Access to 4-Perfluoro Methyl Pyridines Using Perfluoro Alcohols CHAPTER 1: Transition Metal-Catalyzed Sustainable Approaches for the Construction of C-C Bonds using primary alcohol. This chapter deals with a general introduction and newer approaches for the construction of C-C bonds. A brief literature survey summarized the synthesis of numerous pharmaceutically important and biologically active compounds. Classical approaches for C-C bond constructions are not only associated with many challenges but lower the value of synthesis using a series of protection de-protection chemistry, including the generation of stoichiometric waste. Notably, herein, we have demonstrated the application of hydrogen borrowing catalysis using alcohols as a sustainable reagent and the potential role of 3d-metal-based catalysis for the construction of C-C bonds.CHAPTER 2: Mn (II)-Catalysed Alkylation of Methylene Ketones with Alcohols: Direct Access to Functionalised Branched Products. (Chem. Commun. 2018, 54, 14069-14072) Branched α,α-di-substituted ketones are ubiquitous in natural products and pharmaceuticals and are broadly used as valuable intermediates in multi-step organic synthesis. In this direction, Herein, we explored an inexpensive and earth-abundant Mn/1,10-phenanthroline catalytic system that enables the alkylation of methylene ketones with primary alcohols to access a series of functionalized branched ketones. Further, the protocol was extended to onepot sequential double alkylation and Alzheimer’s drug donepezil. Preliminary mechanistic investigation, determination of the rate, order of reactions, and deuterium labeling experiments support the participation of the hydrogen-borrowing strategy for the ketone alkylation.CHAPTER 3: Direct Synthesis of gem-β,β’-Bis(alkyl) Alcohols using Nickel Catalysis via Sequential DCR-Approach. (ACS Catal. 2024, 14, 4018-4029). Chemoselective synthesis of functionalized gem- β,β′-bis(alkyl)alcohols by coupling of a β- alkylated secondary alcohol with a primary alcohol is reported using nickel via sequential DCR (dehydrogenation-condensation-rehydrogenation) approach. Using our method, 1- arylethanol and benzyl alcohols undergo a one-pot successive double alkylation reaction to form functionalized alcohols. Methanol, C2-C12 alcohols, citronellol, and fatty acid-derived oleic alcohols are tolerated, including late-stage functionalization of steroid hormones (cholesterol and testosterone) and 5-pregnen-3β-ol-20-one. The catalytic transformations enabled the synthesis of donepezil drug, N-heteroarenes, including chromane and intermediate flavan derivatives. Hammett kinetic plot analysis indicated a negative ρ value (- 0.60) strongly signify the formation of the positive charge on benzyl alcohol. Preliminary mechanistic investigation revealed that the dehydrogenation of alcohol to aldehyde is the rate determining step as it involves the C-H/D bond breaking of the alcohol, and a PH/PD value of 6.0 was calculated. Reaction profile studies, EPR experiments, Hammett-plot studies, cyclic voltammetry, and UV-visible experiments, including XPS analysis, indicated the structural and electronic changes at the Ni-center as well as the behavior of the catalysts and alcohols during the progress of the reactions.CHAPTER 4: Iron-Catalysed Alkylation of 2-Methyl and 4-Methyl Azaarenes with Alcohols via C-H Bond Activation. (Chem. Comm. 2020, 56, 4777-4780). We have reported an operationally simple and cost-efficient iron-catalyzed system for the alkylation of 2-methyl and 4-methylazaarenes with alcohols. A series of substituted N-heteroarenes could efficiently react with various cyclic and acyclic alkyl alcohols and hetero-aryl alcohols having allylic and terminal olefin functionalities (<39 examples and up to 95% yield). Multi-functionalization of pyrazines and synthesis of the anti-malarial drug (±) Angustureine significantly broaden the scope of this methodology. Preliminary mechanistic investigation, deuterium labeling, and kinetic experiments, including trapping of the enamine intermediate, are of special importance.CHAPTER 5: Ni-Catalysed Synthesis of CF3 Embedded 1, 5 Diketone: Access to 4- Perfluromethyl Pyridine using Perfluoro Alcohols. (Manuscript submitted 2024) Herein, we report an inexpensive NiCl2/phen-based catalytic system to synthesize CF3- embedded 1,5 diketone and extend the protocol to develop a method for 4-CF3 pyridine in a one-pot manner. Polyfluorinated alcohols have been used as a fluorinating reagent without pre-functionalization. The protocol can tolerate a range of functional groups bearing acetophenone and is compatible with trifluoroethanol and other perfluoro alcohols. H2 and H2O are the only sole by-products formed during the reaction. Deuterium scrambling experiments revealed that the PC-H/PC-D is approximately 2.12. Preliminary mechanistic studies, radical quenching experiment, and EPR analyses indicated a radical pathway.