NICKEL-CATALYZED SUSTAINABLE ORGANIC TRANSFORMATIONS: DIRECT ACCESS TO AMINES, PYRROLES, PYRIDINES, QUINOLINES AND GEM-BISSUBSTITUTED KETONES

Abstract

The work carried out in the research tenure has been accumulated in the form of a thesis entitled as “NICKEL-CATALYZED SUSTAINABLE ORGANIC TRANSFORMATIONS: DIRECT ACCESS TO AMINES, PYRROLES, PYRIDINES, QUINOLINES AND GEM-BIS-SUBSTITUTED KETONES”. The thesis has been divided into four chapters, as follows: CHAPTER-1: Metal-Catalyzed Sustainable Synthesis of C-C and C-N Bonds: A Brief Literature Summary CHAPTER-2: Ni-Catalyzed Direct N-Alkylation of Anilines with Alcohols. CHAPTER-3: SECTION-A: Nickel-Catalyzed Intermolecular Cyclization for the Synthesis of Five and Six Membered N-heterocycles. CHAPTER-3: SECTION-B: Nickel-Catalyzed Synthesis of Pyrroles from Unsaturated Diols and Amines. CHAPTER-4: Nickel-Catalyzed Synthesis of gem-Bis-Alkylkated Ketones. Chapter-1: Metal catalyzed sustainable synthesis of C-C and C-N Bonds: A brief literature Summary This chapter deals with the brief literature summary for transition metal catalyzed activation and functionalization of small molecules. Recent studies have attracted great attention towards sustainable development of new catalytic protocols for C-C and C-N bonds. This simple and straightforward method can be applied for the synthesis of bioactive natural product, drug molecules, agrochemicals and important pharmaceuticals. Thus, homogeneous catalysis using more abundant and inexpensive first row transition metals has become a widespread research theme. In this direction, cobalt, iron, nickel and manganese catalysis are mainly desirable because of their earth abundant, readily available, inexpensive and nontoxic nature. The constructions of C-C and C-N bonds are the most important tasks in organic synthesis. Classical methods for these bond formations occur through electrophilic alkylation of an alkyl halide or pseudo-halide, reductive alkylation and amination of aryl halide. However, these conventional methods suffer with drawbacks such as pre-functionalization of starting materials, use of hazardous reagents and stoichiometric amount of waste production. In modern organic chemistry, chemists are concerned about the more efficient synthetic methodology which mainly involves environmental benign processes and thereby vi contributing to atom economy. This strategy generates only water as a byproduct and avoids the use of multi-step production of dangerous alkylating agents. Compared to other synthetic methodologies for the synthesis of C-C and C-N bond, these transformation is highly attractive because often alcohols are readily available starting materials and most of them are available in a large scale from renewable sources. Further, application of hydrogen borrowing methodology using alcohols in combination with non-noble metal-catalysts are prime goal here described in the present thesis. Chapter-2: Ni-catalyzed direct N-alkylation of anilines with alcohols (ACS Catal. 2017, 7, 8152-8158). This chapter of thesis describe the development of a general and inexpensive nickel-nitrogen ligated system for selective alkylation of alcohols with amines to secondary amines derivatives. vii More specifically, herein, we developed an efficient and selective nickel catalyzed monoalkylation of a series of primary alcohols with aryl and hetero(aryl) amines together with diols and amino alcohol derivatives. Notably, the catalytic protocol consisting of earth abundant and non-precious NiBr2/1,10-phenanthroline system enable the transformations in presence of hydroxyl, alkenes, nitrile and nitro-functionalities. As a special highlight, we have demonstrated the alkylation of di-aniline, intramolecular cyclization to N-heterocycles, and functionalization of complex vitamin E, (±) α-tocopherol derivative. Preliminary mechanistic studies including synthesis of defined Ni-catalysts, defined Ni-H species and a series of deuterium labeling experiments revealed the participation of benzylic C-H bond in the rate determining step. Chapter-3 Section-A: Nickel-catalyzed intermolecular cyclisation for the synthesis of five and six membered N-heterocycles (Green Chem. 2018, 20, 2250- 2256). viii The prime objective of this chapter is to develop a general and efficient nickel-catalyzed system for the synthesis of five and six-member N-heterocycles. Owing to the great demand for synthesis of N-heterocycles, development of new reactions that utilize renewable resources and convert them into key chemicals using non-precious base metal-catalysts is highly desirable. Here we demonstrated a sustainable Ni-catalyzed dehydrogenative approach for pyrroles, pyridines and quinolines synthesis employing β- and γ-amino alcohols with ketones via C-N and C-C bond formations in a tandem fashion. A variety of aryl, hetero-aryl and alkyl ketones having free amine, halides, alkyl, alkoxy, alkenes, activated benzyl and pyridine moiety converted into synthetically interesting 2,3 and 2,3,5 substituted bicyclic as well as tricyclic N-heterocycles in up to 90% yields. As a special highlights, we demonstrated an interesting pyrrole derivative employing intermolecular cyclisation of steroid hormone with phenylalaninol. Chapter-3 Section-B: Nickel-catalyzed synthesis of pyrroles from unsaturated diols and amines (J. Org. Chem., 2018, 83,15406-15414). ix The main objective of this study is to develop an operational simple and inexpensive catalytic system that utilize renewable resources and convert them into key chemicals using base metal-catalysts is highly desirable. Herein, we reported the Ni-catalyzed dehydrogenative strategy for pyrroles formations using butene-1,4-diols and butyne-1,4-diols with a series of aryl, alkyl and hetero-aryl amines. The catalytic protocol is tolerant to free alcohol, halides, alkyl, alkoxy, oxygen heterocycles, activated benzyl and pyridines moieties and resulted in up to 90% yield. Initial mechanistic studies using defined Ni-catalyst, isolation of intermediate species as well as deuterium labeling experiments were performed to establish the hydrogen-borrowing strategy for pyrrole synthesis. Chapter-4: Nickel-catalyzed synthesis of gem-bis-alkylkated ketones (Org. Lett. 2018, 20, 5587-5591). The work presented in this Chapter has recently been published in Org. Lett. 2018, 20, 5587- 5591. This work has been contributed equally by another author. Therefore, in this chapter we will only discuss those part of the work mainly contributed by me. In this section we report the α-alkylation of methylene ketones using an earth-abundant and non-precious NiBr2/N-ligand system that enables the transformations to a range of branched x gem-bis(alkyl) ketones using renewable primary alcohols. This nickel catalyzed system could be performed in gram scale and successfully applied in the synthesis of donepezil (Alzheimer’s drug), functionalization of steroid hormone, and fatty acid derivatives. Green synthesis to N-heterocycles, α-methylation of ketones using methanol and one pot double alkylation to bis-hetero aryl ketones using two different alcohols with a single catalyst broaden the scope of the catalytic protocol. A detailed mechanistic studies involving isolation of defined Ni-intermediate species, Ni-H species, Ni-alkoxy complex, determination of rate and order of the reaction, competition reactions of electronically different alcohols and a series of deuterium labelling experiments established the participation of borrowinghydrogen strategy for nickel-catalyzed α-alkylation of methylene ketones with alcohols