Thermally Stable Cation-Pools in C-X (X = Halogen) and C-C Bond Formation

Abstract

The cationic intermediates are valuable electrophiles with broad applications in organic synthesis. Various strategies have been established for cationic intermediate generation. However, the transient and unstable nature of cations in conventional reaction media necessitates their formation in the presence of nucleophiles. Further, the nucleophiles that are unstable or inert to the reaction media cannot be used for trapping the cationic species. Yoshida and co-workers established the "Cation Pool" method to address the limitations of the conventional methods. The "Cation pool" strategy facilitates the generation and accumulation of carbocations and onium ions in an appropriate solvent through an electrochemical redox process at lower temperatures. However, the accumulation of halogen and chalcogen cations in the solution as "cation pools" found to be challenging due to their instability. Besides, the electrochemical oxidation method employed for the generation of cation intermediates and their accumulation as cation pools at very low temperature is a sophisticated process and is expensive for large scale production. So development of new methods for the preparation and stabilization of cationic species is demanding. The current thesis entitled “Thermally Stable Cation-Pools in C-X (X = Halogen) and C-C Bond Formation” mainly describes the development of a new protocol for the generation and accumulation of halonium ions and methyl(methylene)sulfonium ion cation pools, and their further application in organic synthesis, particularly, in carbon-halogen and carbon-carbon bond formation reactions. The current thesis contains 7 chapters which are summarised as follows: Chapter 1: A brief review on generation of cation pools and their synthetic applications This chapter briefly describes different methods for the generation and accumulation of cationic intermediates involving carbocations and heteroatom cations as a cation pool in the appropriate solvent. Additionally, various applications of the cation pool method are also described in this chapter. In addition, a critical overview and objective of the present work are also presented. Chapter 2: Generation of dimethyl sulfoxide coordinated thermally stable halogen cation pools for C-H halogenation In this chapter, we discussed our effort in generating halogen cation pools from the reaction of 1,2-dihaloethanes (hal= Br, I) and dimethyl sulfoxide (DMSO) to facilitate C-H halogenation of both arenes and heteroarenes. The initial reaction between DMSO and 1,2- dihaloethane produces the sulfur ylide, which undergoes pyrolytic elimination of ethylene, resulting in halonium ions. These ions are accumulated and stabilized by DMSO through coordination, leading to halogen cation pools for subsequent halogenation reactions. This protocol demonstrates selective electrophilic monohalogenation of arenes at room temperature. However, when the reaction temperature was increased, polyhalogenated products are formed. The late-stage halogenation of heteroarenes and certain commonly marketed drugs further signifies the synthetic utility of this protocol in pharmaceutical chemistry. Chapter 3. Synthesis of oxazoles from enamides using thermally generated bromonium cation-pool This chapter describes the utilization of thermally generated bromine cation pool from the reaction of 1,2-dibromoethane and DMSO in the synthesis of substituted oxazoles from enamides. The reaction proceeds through initial bromination of enamides followed by tandem annulation to afford substituted oxazoles. Chapter 4. Benzannulation and N-annulation of β-ketoenamines for synthesizing aniline and pyridine derivatives using DMSO as a methine source This chapter describes the benzannulation and N-annulation of β-ketoenamines by the in-situ generated methyl(methylene)sulfonium ion from the reaction of dimethyl sulfoxide (DMSO) and 1,2-dibromoethane (DBE). The β ketoenamines underwent N-annulation to pyridine derivatives, while the N-alkylated enamines were benzannulated to afford substituted anilines. Based on the control experiments a reasonable mechanism was depicted for the said transformations. Chapter 5. Synthesis of bis-1,3-dicarbonyl compounds using DMSO as methylene source This chapter deals with the application of the in situ generated methyl(methylene)- sulfonium cation pool from the reaction of DMSO and DBE for the synthesis of methylenexv bridged bis-1,3-dicarbonyl compounds from the 1,3-dicarbonyl compounds. A plausible mechanism for the above transformation was also presented. Chapter 6: DMSO-DCE triggered chemodivergent C-methylenation of electron rich arenes: An easy access to diarylmethanes In this chapter, we exploited the chemodivergent property of dimethyl sulfoxide (DMSO) in combination with 1,2-dichloroethane (DCE) to incorporate a methylene group. The methyl(methylene)sulfonium ion pool is generated by heating commonly used solvents like DMSO and DCE. Subsequently, this cation pool is trapped by electron-rich arenes and heteroarenes through a dearomatization/rearomatization process, resulting in the formation of both symmetrical and unsymmetrical diarylmethanes. This protocol is further extended to produce N-methylenamides by reacting 2-naphthol with amides or nitriles in the presence of DMSO and DCE. Chapter 7: Conclusion and future scope In the last chapter, the overall summary and future scopes of the present work have been described.