Metal-catalyzed oxidative transformations of carbonyl compounds: domino reactions, rearrangements, and continuous flow applications

Abstract

The metal-catalyzed reactions have pivotal importance in chemical synthesis, which can be utilized to construct challenging organic scaffold of biological importance with improved sustainability and atom economy. In particular, the oxidation reactions are profoundly important in chemical/biological synthesis, and it provides a breakthrough for the synthesis of building blocks/precursors towards natural/unnatural targets. Accordingly, the metal-catalyzed oxidative C-H functionalization offers a direct route to construct the C-C, C-O and C-N bond formation and gives access to novel bioactive compounds, commercial drugs, natural products, household products, petrochemicals, etc. The present investigation of this thesis describes C-C bond formation by α-alkylation of unactivated amides, C-O bond formation via sp3-C-H peroxidation in batch/continuous-flow, hydroxylation of carbonyl compounds and novel rearrangement of peroxides using Lewis or Brønsted acid to afford the biologically important scaffolds. This thesis describes research findings in the development of “Metal-Catalyzed Oxidative Transformations of Carbonyl Compounds: Domino Reactions, Rearrangements, and Continuous Flow Applications,” and which comprises of four chapters. Chapter 1: Introduction to Oxidative C-H Functionalization At the outset, the brief introduction of metal catalysis is described concerning the field of chemistry. Later, the fundamental of oxidation reactions, along with an overview of C-H functionalization is discussed. Then, the aim and rationale of the thesis are described.

Chapter 2: Ruthenium-Catalyzed Direct α-Alkylation of Amides Using Alcohols and C-H Hydroxylation of Carbonyl Compounds. In this chapter, we present a ruthenium-catalyzed direct α-alkylation of unactivated amides and 2-oxindoles, using alcohol as an alkylating agent and transition-metal-free C-H hydroxylation of carbonyl compounds. Chapter 2 is subdivided into two sections. Section A describes a highly efficient protocol for ruthenium-pincer catalyzed direct α-alkylation of amides using alcohol with an astonishing turnover number. A variety of pincer catalysts were screened for this transformation, and out of that, Ru-PNN catalyst was found to be the best. In section B, we describe transition-metal-free C-H hydroxylation of carbonyl derivatives using atmospheric oxygen and inexpensive base. Both the section includes a literature background, the rationale for work, optimization studies, substrate scope, and mechanistic studies.

Chapter 3: Metal-Catalyzed Batch/Continuous Flow Synthesis of Peroxides and Evaluation of Biological Properties This chapter describes the simple and efficient method for the synthesis of quaternary peroxides using homogeneous as well as a heterogeneous catalyst in batch/flow and evaluation of biological properties. This chapter is also subdivided into two sections, A and B. In section A, the use of homogeneous Fe-catalyst is demonstrated for the C-H peroxidation of derivatives of 2-oxindole, coumarin and barbituric acid. The peroxidation is accomplished using continuous flow with a shorter reaction time. At the outset, the introduction to continuous flow chemistry and literature precedence for the metal-catalyzed peroxidation reactions is described. Then, the optimization of reaction conditions in batch/flow and broad substrate scope is demonstrated. Subsequently, the mechanistic studies (EPR and radical quenching experiments) on the peroxidation reaction are shown. Finally, in biological studies, the anticancer activity of the synthesized peroxides is demonstrated. In section B, the synthesis and characterization of supported magnetic iron oxide nanoparticles and its catalytic property for the C-H peroxidation reaction using batch/flow are described. The extensive optimization and substrate scope using batch/flow is demonstrated. Eventually, the antimalarial property of the quaternary peroxides is evaluated against the malarial parasite.

Chapter 4: The Novel Rearrangements of Peroxide on Electron Deficient Oxygen The present chapter showcase the discovery of two novel rearrangements in peroxyoxindole derivatives to afford 1,4-Benzoxazin-3-one derivatives and substituted-2H-benzo[b][1,4]oxazin-3(4H)-one. This chapter is also subdivided into two sections. In the first section, highly selective synthesis of (Z)-2-arylidene and alkylidene-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives using Sn-catalyst is discussed. The results on FeCl3 catalyzed Hock fragmentation products via C−C bond cleavage are also described. In the second section, novel rearrangement of in situ generated peresters is presented. This reaction utilizes the feedstocks chemicals such as esters for the synthesis of perester intermediate as a key step for the skeletal rearrangement. In the beginning, the introduction and literature background delineates the variety of reported rearrangements in the peroxide scaffold. Next, the optimization and substrate scope for the novel rearrangement is described. To gain mechanistic insights, the isotope labeling experiments were performed. Furthermore, 2-oxindole hydroperoxide or perester intermediate was prepared separately, and their reactions were investigated. Finally, based on the preliminary experimental shreds of evidence, the plausible reaction mechanism is depicted for molecular rearrangement reactions.