Developing new synthetic methodologies via direct oxidative manner by employing electroorganic chemistry

Abstract

Chapter 1: Introduction to Electroorganic Chemistry and its Utilization via Direct Anodic Oxidation The concept of electroorganic chemistry is discovered by Faraday and Kolbe with the introduction of Faraday’s law of electrolysis and Kolbe’s electrolysis in the 19th century. However, the field has not gained much attention till the mid of 20th century. After the discovery of potentiostat in 1942, several advancements have been achieved employing this sustainable approach and some notable transformations have been discovered. This chapter describes the basic concepts and requirements of electroorganic chemistry. A brief discussion of historical advancements from 1800 to end of 20th century have been documented. Moreover, remarkable achievements in the 21st century by the eminent organic chemists like Prof. Phil Baran, Prof. S.R. Waldvogel, Prof. Song Lin etc. have also been discussed. The development of diverse cyclic and acyclic scaffolds in a sustainable and stepeconomic manner has always been a subject of continual interest among the synthetic community. This thesis also describes the anodic oxidation-based synthesis of various cyclic and acyclic scaffolds from oxidation of amines, phenols, and alkenes. Their oxidation led to the generation of intermediate species like iminium ion, phenonium cation and alkene derived radical cation. This section of the thesis reviews the detailed study of these moieties and their accomplishments based on their oxidation in synthesizing several molecules. This comprehensive study of the electrosynthesis based on anodic oxidation encouraged us to engage ourselves towards the designing of the sustainable route for the synthesis of various carbo- and heterocycles. The aim of the thesis and the investigations carried out during the doctoral training are outlined in the form of different chapter as follows: Chapter 2: Electrochemical Generation of a Nonstabilized Azomethine Ylide: Access to Substituted N‑Heterocycles The anodic oxidation of amines and amides led to the generation of N-centered radical cation which undergoes α- fragmentation to afford iminium ion. If a carbanion is present adjacent to iminium ion it refers to a 1,3 dipolar species which is azomethine ylide and they undergo 1,3-dipolar cycloaddition reaction with various dipolarophiles to afford cyclic N-heterocycles such as pyrrolidines, pyrrolines, and pyrroles. Based on substitution at the termini of the ylide, they can be classified as stabilized or nonstabilized ylide. Mostly, the azomethine ylides are generated in-situ and immediately reacted with dipolarophiles; however, in some case they can be isolated. Generation of the nonstabilized azomethine ylides and their 1,3-dipolar cycloaddition reactions with various dipolarophiles is a reliable and efficient protocol for the synthesis of N-heterocycles like pyrrolidines, oxazolidine and imidazolidines etc. Consequently, various traditional methods have been developed towards the construction of these Nheterocyclic ring system via generation of nonstabilized azomethine ylide. A few of the important methodologies include the fluoride ion initiated desilylation of cyanoamino silanes or trimethyl silyliminium salts and thermal ring opening of aziridines. However, most of these protocols rely on either metal-based activation or require high temperature. However, at the end of the 20th century, Pandey and coworkers reported a novel methodology for the generation of nonstabilized azomethine ylide from N-benzyl-1-(trimethylsilyl)-N-((trimethylsilyl)methyl) methanamine. In continuation with this endeavour, other groups, have also devised protocols for the generation of the nonstabilized azomethine ylide by employing visible-light, metal fluoride, and trifluoroacetic acid. However, all these conventional methods for the generation of nonstabilized azomethine ylides and their cycloaddition necessitate external oxidants or photocatalyst towards the generation of 1,3-dipoles. Therefore, we have developed a metal and oxidant free protocol towards the in-situ generation of nonstabilized azomethine ylide under electrochemical conditions which undergoes 3+2 cycloaddition with ethyl acrylate as dipolarophile and the pyrrolidine product was obtained in 55% of yield after a comprehensive study of optimization. With this the substrate scope were evaluated w.r.t both the azomethine ylide precursors and dipolarophiles and a class of pyrrolidine derivatives were synthesised. Interestingly, the benzaldehyde derivatives as dipolarophiles were also found compatible with the protocol and afford oxazolidine derivatives in good yield. The protocol was also scalable to gram scale synthesis. Chapter 3: Electrochemical sulfinylation of phenols with sulfides: a metal- and oxidantfree cross-coupling for the synthesis of aromatic sulfoxides The C-H functionalization of arenes is an illustrious transformation in organic chemistry. It has been extensively exploited over the past few decades to manipulate the molecules to directly approach the target scaffolds. However, the analogous sulfinylation has largely remained unexplored despite having societal importance as medicines (antihypertensive, antibacterial, antifungal, antiulcer) and herbicide. These structures are also featured in a plethora of natural products. In addition, these sulfinates (existing in the SIV-oxidation state) are well-established and reliable precursors or intermediates to diverse structurally and biologically significant functionalities existing in either the SIV or SVI oxidation states such as sulfones, sulfoximine, sulfinamides, sulfonate esters, sulfinate esters, sulfonyl halides, and others. In spite of the tremendous importance, there are only a few trivial strategies disclosed so far to construct aromatic sulfoxides. Though the direct mono-oxidation of diaryl sulfides has been a straightforward approach, the palladium-catalyzed cross-coupling of sulfenate anions by Poli and Madec, Walsh, Nolan, and Perrio has emerged as the promising gateway to these aryl sulfoxides. The other approaches include a nucleophilic substitution of sulfinyl precursors with organometallic reagents and the Lewis acid-mediated Friedel- Craft-type electrophilic aromatic substitutions of sulfinyl chlorides. The oxidation protocols suffer from employing hazardous peracid or hypervalent iodine oxidants in stoichiometric amounts, and the other requires metals and elevated temperatures to accomplish the transformation. Moreover, the over-oxidation of sulfide to sulfone is also encountered in most cases. Consequently, the development of a practically green, oxidant-free, and sustainable strategy for the selective synthesis of sulfoxides remains in high demand. In this direction, several groups have devised protocols towards the synthesis of various sulfoxide derivative via cross coupling reactions. In 2022, Baran and coworkers reported Ni-catalyzed electrochemical sulfinylation of aryl halides with SO2. Motivated by our previous reports demonstrating the site-selective functionalization of phenol towards the direct synthesis of paracetamol and other arene oxidation-mediated functionalizations, we envisioned the direct synthesis of aryl sulfoxides via oxidative cross-coupling of phenols with sulfides and developed an electrochemical protocol towards the synthesis of aromatic sulfoxide via oxidative cross coupling of phenols and sulfides. The protocols afford 60% of yield after an extensive optimization studies. Further, the substrate scope w.r.t to both the phenols and sulfides have been tolerated well and procured the final compound up to 65% of the yield. Plausible mechanism is proposed after several control experiments. The practicality of the methodology was further demonstrated by gram scale synthesis and transformation of sulfoxide derivative to sulfone. Chapter 4: Electrochemical Oxidative C-C Bond Cleavage of Methylenecyclopropanes with Alcohols Cyclopropanes are the important building blocks, and their ring-opening via C-C bond cleavage driven by the release of ring strain has been widely applied in total synthesis. Methylenecyclopropanes (MCPs) are one of the important classes of small strained carbocycles which is having double bond directly attached to the cyclopropane ring. These are readily accessible and have been used very often in the construction of spiro-, hetero-, and polycyclic compounds. In general, the ring-opening reaction modes of MCPs are transition metal-catalyzed reactions, Lewis or Brønsted acid-catalyzed/mediated reactions, and thermal-induced cyclizations. At the same time, the MCPs have also been used as radical acceptors with a variety of radicals furnishing the ring-opening functionalized product. In 2019, Tang and coworkers reported silver-mediated oxidative C-C bond sulfonylation/ arylation of methylenecyclopropanes with sodium sulfinates initiated via radical addition. However, the reactivity of MCPs in other pathways, such as radical cation and singlet or triplet excited states, has rarely been explored. The first direct oxidation of MCPs by ozone was disclosed by Beck and coworkers in 2001 to afford cyclobutanone, peroxide, and ketone derivatives, illustrating the possibility of a single-electron oxidation pathway of MCPs. Later, direct photooxidation of MCPs to radical cationic species upon visible light irradiation has also been reported. However, all these conventional methods are concerned with the usage of stoichiometric oxidant, transition metal catalyst, or a photocatalyst towards the ring opening functionalization of MCPs. Organic electrochemistry has emerged as a sustainable alternative due to effortlessness of scalability, evasion of stoichiometric oxidants or reductants, and adaptable reaction tunability. The ring opening of MCPs via direct oxidation of double bonds followed by nucleophilic attack of has not been investigated so far. So, we developed an electricity-mediated C-C bond cleavage of MCPs towards the synthesis of methyl 4-methoxy-4-phenylbutanoate derivatives under oxidant and metal-free conditions via oxidation of double bond. After a comprehensive optimization, the carbon anode and nickel cathode in presence of tetrabutylammonium tetrafluoroborate as supporting at a constant current of 1 mA with methanol as solvent was found to be ideal condition for the transformation. The functional groups w.r.t methylenecyclopropanes were well tolerated and provide up to 80% of the yield. Different alcohol derivative was also used as nucleophiles to open the cyclopropane ring. Several mechanistic studies like radical scavenging experiment, D2O experiment and cyclic voltammetry were carried out to prove the proposed reaction mechanism. The methodology was scalable up to gram scale synthesis. Next, the product was subjected to various post functionalizations such as reduction of ester, amidation of ester, and base hydrolysis.