NON-PRECIOUS METAL-CATALYZED SUSTAINABLE SYNTHESIS OF C-C AND C-N BONDS

Abstract

his thesis contains the research work carried out during the Ph.D. tenure and is entitled as “Non-precious Metal-Catalyzed Sustainable Synthesis of C-C and C-N Bonds”. The thesis has been divided into the following five chapters: CHAPTER-1: Transition-metal catalyzed synthesis of C-C and C-N bonds: A Concise Literature Survey. CHAPTER-2: Nickel-catalyzed direct N-alkylation of amides with alcohols. CHAPTER-3: Nickel-catalyzed α-alkylation of ketones with alcohols. CHAPTER-4: Nickel-catalyzed alkylation of methyl N-heteroaromatics with alcohols. CHAPTER-5: Section-A: Nickel-catalyzed dehydrogenative alkylation of methyl Nheteroaromatics with alcohols. CHAPTER-5: Section-B: Iron-catalyzed dehydrogenative alkylation of alkyl-substituted Nheteroaromatics with alcohols CHAPTER-1: Transition-metal catalyzed synthesis of C-C and C-N bonds: A Concise Literature Survey This chapter deals with a brief literature survey about the transition metal catalyzed C-C and C-N bond forming reactions. Metal-catalyzed synthesis of C-C and C-N bonds are extremely important reactions widely used for the synthesis of pharmaceuticals, agrochemicals, bioactive natural products and in material chemistry at laboratory scale as well as in industrial bulk-scale processes. Classical methodologies involve for these process are generally associated with stoichiometric side waste. Again, often, metal catalyzed synthesis of C-C and C-N bonds were also known to use activated derivatives, such as, alkyl halides, esters and anhydrides as alkylating agents. In this direction, application of renewable alcohols would be more sustainable and environmentally benign process, releasing only water as by product. Till last decades, applications of toxic and expensive noble metal-catalysts, such as, Ru, Ir, Pd, Rh, etc. were known for such processes following borrowing hydrogen approach. Recently, there is a potential drive for the applications of earth-abundant and inexpensive metals, such as, Fe-, Co-, Mn- and Ni-for such applications with equal efficiency. This vi chapter cover the applications of precious as well as non-precious metal-catalyzed synthesis of C-C and C-N bonds under hydrogen auto-transfer principle. CHAPTER-2: Nickel-catalyzed direct N-alkylation of amides with alcohols (Das, J.; Banerjee, D. J. Org. Chem. 2018, 83, 3378−3384) In the Chapter-2 we demonstrated the development of an operational simple, practical, and selective Ni-catalyzed synthesis of secondary amides. Application of renewable alcohols, earth-abundant and non-precious nickel catalyst facilitates the transformations, releasing water as byproduct. The catalytic system is tolerant to a variety of functional groups including nitrile, allylic ether, and alkene and could be extended to the synthesis of bisamide, antiemetic drug Tigan, and dopamine D2 receptor antagonist Itopride. Preliminary mechanistic studies revealed the participation of a benzylic C-H bond in the rate determining step. vii CHAPTER-3: Nickel-catalyzed α-alkylation of ketone enolates with alcohols (Das, J.; Vellakkaran, M.; Banerjee, D. J. Org. Chem. 2019, 84, 769-779) (Das, J.; Singh, K.; Vellakkaran, M.; Banerjee, D. Org. Lett. 2018, 20, 5587−5591.) Herein, we have demonstrated an inexpensive and operational simple base-metal catalyzed protocol for selective mon-alkylation of methyl-ketones as well as methylene ketones with alcohols using borrowing hydrogen approach. This Ni-catalyzed dehydrogenative coupling of alcohol could be performed in gram scale and extended to a range of aryl, alkyl and viii hetero-aryl derivatives (>40 examples) in up to 90% yield including green synthesis of Nheterocycles. For a synthetic application, functionalization of steroid hormone, unsaturated fatty acids and post synthetic modification of naproxen drug have shown. Also, this nickelcatalyzed reaction could be performed in gram scale and successfully applied in the synthesis of donepezil (Alzheimer’s drug) and functionalization of steroid hormones and fatty acid derivatives. The methylation of ketones using methanol, and one-pot double alkylation to bis-hetero aryl ketones using two different alcohols with a single catalyst broadens the scope of the catalytic protocol. Detailed mechanistic studies involving isolation of a Ni intermediate, defined Ni-H species, intermediate Ni-alkoxy species and determination of rate and order of reaction as well as a series of deuterium labeling experiments were crucial for preliminary mechanistic studies for selective alkylation of ketones. CHAPTER-4: Nickel-catalyzed alkylation of methyl N-heteroaromatics with alcohols (Vellakkaran, M.;# Das, J.;# Bera, S.; Banerjee, D. Chem. Commun. 2018, 54, 12369; #-Equal authorship) In this chapter, we have illustrated the first Ni-catalyzed functionalization of C(sp3)–H bonds in methyl N-heteroaromatics using primary alcohols. Easily available, inexpensive Nicatalysts and 1,10-phenanthroline ligands enable long chain C2-alkylated N-heteroaromatics in up to quantitative yields. The catalytic system allows transformations in the presence of reducible functional moieties, such as allylic ethers and alkenes, including unsaturated ix alcohols. Initial mechanistic studies strongly support the participation of a Ni–H species and the bi-functional nature of the Ni-catalyst. A series of deuterium labeling experiments revealed the involvement of H/D exchange during the progress of the reaction. CHAPTER-5: Section-A: Nickel-catalyzed dehydrogenative alkylation of methyl Nheteroaromatics with alcohols (Das, J.; Vellakkaran, M.; Banerjee, D. Chem. Commun. 2019, 55, 7530-7533) We have demonstrated catalytic α-olefination of 2-methylheteroarenes with primary alcohols via dehydrogenative coupling. A simple nickel catalyst system stabilized by readily available nitrogen ligand enables a series of interesting E-configured vinylarenes (X-ray crystalstructure analysis) in good to excellent yields with olefin/alkane selectivity of >20:1. Hydrogen and water are generated as byproducts and rendering the process environmentally benign. x CHAPTER-5: Section-B: Iron-catalyzed dehydrogenative alkylation of alkylsubstituted N-heteroaromatics with alcohols (Das, J.; Vellakkaran, M.; SK, M.; Banerjee, D. Org. Lett. 2019. DOI: 10.1021/acs.orglett.9b02793). This chapter describe the direct α-olefination of alkyl substituted N-heteroarenes with primary alcohols using an efficient Fe-catalyst ligated with nitrogen ligands. This dehydrogenated coupling involving alkyl N-heteroaromatics with a series of primary alcohols resulted a series of functionalized E-substituted olefins with very high olefin/alkane selectivity. A series of deuterium labeling experiments, kinetics studies and controlexperiments provide evidences for the participation of the benzylic C-H/D bond of alcohols and C(sp3)-H/D bond of 2-alkylheteroarenes following dehydrogenative couplings