NON-PRECIOUS METAL-CATALYZED (DE)HYDROGENATION OF ALCOHOLS: SYNTHESIS OF OLEFINS, N-HETEROARENES AND 1,5-DIKETONES

Abstract

The work accomplished during the research period has been collated in the form of a thesis with the title “NON-PRECIOUS METAL-CATALYZED (DE)HYDROGENATION OF ALCOHOLS: SYNTHESIS OF OLEFINS, N-HETEROARENES AND 1,5-DIKETONES”. The thesis has been divided into six chapters, as follows: Chapter-1: Transition metal-catalyzed sustainable approaches for the construction of C-C and C-N bond. Chapter-2: A simple iron-catalyst for alkenylation of ketones using primary alcohols. Chapter-3: Nickel-catalyzed synthesis of C-3-substituted quinolines. Chapter-4: Nickel-catalyzed one-pot synthesis of 1,5 diketones, pyridines and -aminomethylation of ketones Chapter-5: Oxidative dehydrogenation of N-heterocycles using Ni-immobilized MOF catalyst Chapter-6: References CHAPTER 1: Transition metal-catalyzed sustainable approaches for the construction of C-C and C-N bond Chapter 1 of thesis illustrates a brief literature summary of transition metal-catalyzed sustainable construction of C-C and C-N bonds. Transition metal-catalyzed sustainable development of C-C and C-N bond has drawn a lot of attraction as a crucial domain at the forefront of organic synthetic chemistry. This plays a key role for the synthesis of a wide range of functional compounds such as pharmaceutically active compounds, natural products, agrochemicals and vital raw materials for industry. A broad spectrum of transition metal catalysts has been established to serve a crucial role for C-C and C-N bond production. In this direction, second and third-row transition metals has some limitation and shortcomings including inadequate resources, penurious stability and noxious in nature. Thus, there has been a great deal of interest in producing earth-abundant, non-toxic first row transition-metal catalysts including Mn, Co, Fe, and Ni for C-C and C-N bond formation CHAPTER 2: A simple iron-catalyst for alkenylation of ketones using primary alcohols (Molecules 2020, 25, 1590) The main objective of this chapter is to develop an inexpensive iron catalyst system for the synthesis of α, β-unsaturated ketones. A series of functionalized α, β-unsaturated ketones having aryl, heteroaryl, alkyl, halogen moieties were efficiently synthesized with excellent selectivity following this protocol and using a series of primary alcohols as well as a variety of ketones. Halogen moities (-F, -Cl) were well tolerated under the reaction condition and good yield was obtained without dehalogenated product. Notably, strong electron withdrawing groups such as –CF3, -CN and -NO2 also underwent reaction smoothly to deliver the desired product in up to 62% yield. Heteroaryl alcohols such as 1,3-dioxolone-substituted benzyl alcohol and 2-furfurylmethanol efficiently reacted with α-tetralone to provide product in excellent yield. More challenging alkyl alcohols such as cyclohexylmethanol, cyclopropylmethanol afforded the desired products in moderate to good yields. This was further extended for different cyclic and acyclic ketone derivatives to achieve higher yield as well as selectivity. Determination of rate and order, quantitative determination of H2 gas and deuterium labeling experiments are in agreement with ADC mechanism which produces only water and dihydrogen as byproduct. CHAPTER 3: Nickel-catalyzed synthesis of C-3-substituted quinolines (ChemCatChem, 2023, 15, e2023004). Herein, we have demonstrated a general and effective Ni-catalyzed technique for double dehydrogenative cyclization of two different alcohols to 3-substituted quinolines liberating water and dihydrogen as by products. A variety of aryl ethanol as well as alkyl alcohols smoothly reacted with 2-aminobenzyl alcohol to synthesize 3-substituted quinolines in up to 88% isolated yield. Different 2-aminobenzyl alcohols coupled with primary alcohols to deliver the desired product in up to 72% isolated yield. Particularly noteworthy were the reports of late-stage functionalization of cholesterol derivatives, which included chemoselective conversions of citronellol, oleyl alcohol produced from fatty acids, and long-chain C4–C14 alkyl alcohols (42-88% yield). We successfully synthesized 3-substituted quinolines using 2-nitrobenzyl alcohol with different primary alcohols (30-82%). Deuterium-labelling investigations and other preliminary mechanistic studies were carried out to confirm the dehydrogenative cyclization. CHAPTER 4: Nickel-catalyzed one-pot synthesis of 1,5 diketones, pyridines and - aminomethylation of ketones using methanol and ethanol. In this chapter, we established a highly efficient and convenient protocol for the synthesis of 1,5-diketones and substituted pyridine using ethanol and methanol in the presence of simple, earth abundant Ni catalyst in conjunction with bench stable nitrogen ligand. First, we explored the synthesis of 1,5 diketone by altering the nature of the substituent on the aromatic rings of acetophenones with ethanol. Electron donating as well as halogen substituted acetophenone reacted with ethanol to give the desired product up to 72% isolated yield. Pleasingly, sulphar containing heterocylic ring 1-(thiophen-2-yl)ethan-1-one responded well under our reaction condition which resulted with 62% isolated yield. Inspired by the result obtained for the synthesis of 1,5-diketones using EtOH, we next focused the diketones synthesis using MeOH as a C1 alkylating agent. Electron donating group substituted ketone and fused ring system delivered the desired product with good to excellent isolated yield (62- 89% yield). We upgraded our methodology for the sequential one-pot synthesis of substituted pyridines by using 1,5-diketones as effective precursors. We have successfully synthesized substituted pyridines with excellent yield. After that, we explored the -aminomethylation of ketones in one-pot two-step strategy using various N-nucleophiles. CHAPTER 5: Oxidative dehydrogenation of N-heterocycles using Ni-immobilized MOF catalyst. In this chapter, we have reported an oxidative dehydrogenation strategy for the synthesis of N-heterocycles using a recyclable Ni-immobilized metal-organic framework (MOF) catalyst is reported. Five as well as six-membered heterocycles with one or two nitrogens have been successfully synthesized with up to 98% isolated yield using our optimized reaction condition. This protocol could be applicable for the synthesis of ligand with admirable yield (bi and tridentate) and could be extended for the synthesis of -glucuronidase inhibitor, lifesaving drug such as antimalarial medicine Quinine, and the nonsteroidal anti-inflammatory drug (NSAID) Indomethacin with satisfactory yield. Control experiments and mechanistic investigation suggest that reaction proceeds via imine intermediate for step-by-step dehydrogenation.