Harnessing electroorganic synthesis for generation of valuable intermediates towards construction of diverse cyclic and acyclic scaffolds

Abstract

Chapter 1: Introduction to Electroorganic Chemistry and Reactivity of Various Intermediates The development of diverse cyclic and acyclic scaffolds in a sustainable and step-economic manner has always been a paramount interest for the synthetic community. In the modern times, the organic chemists have successfully designed and implemented various notable sustainable strategies for accessing the valuable molecular architectures. The adoption of technologies like electrosynthesis has blessed the scientific community to perform many such sustainable transformations in an environmentally benign and step-economic manner. This chapter describes the striking features of this modern sustainable technology, i.e., electroorganic chemistry in details. To have a clear understanding of the concept, a brief discussion on the historical advancements of the electroorganic chemistry has been documented. Discovered and pioneered by Kolbe and Faraday, the field of electrosynthesis has witnessed several path pointing achievements. In the last decade, this field has gained a considerable attention from the traditional synthetic chemists and various notable transformations has been documented in this domain. However, for adoption of this technology a detailed knowledge about the components and the basics of the electrochemistry is highly desirable. Therefore, a thorough literature survey has been conducted to realize every aspect of electrosynthesis. This section of the thesis focuses on all the basics associated with electroorganic chemistry like types of electrolysis, various modes of electrolysis etc. Moreover, some discussions of phenomenal accomplishments by the eminent organic chemists like Prof. Phil Baran, Prof. S.R. Waldvogel, Prof. Song Lin etc. is also described in this chapter. Furthermore, the rationale behind establishing this chemistry in our laboratory was to generate various intermediates like isocyanates, endoperoxides, N-centered radicals (NCRs) that have gained a cardinal position in the synthesis of various cyclic and acyclic scaffolds. This segment of the dissertation reviews the detailed study of these intermediates and their accomplishments in synthesizing several molecules. This comprehensive study of the electrosynthesis and these intermediates has inspired and encouraged us to understand the necessity of designing 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 Access to Benzimidazolone and Quinazolinone Derivatives via in situ Generation of Isocyanates Isocyanates are the key intermediates for several organic transformations towards the synthesis of diverse pharmaceutical targets. At present, the global market of isocyanates has blossomed a lot with a market surge of more than 5% every year. This underlines the importance of this ubiquitous intermediate as it has been employed for the synthesis of several structural scaffolds like polyurethanes, biurets, allophanate etc. Discovered in 1848 by Wurtz, the synthesis of isocyanates majorly requires the reaction between toxic phosgene and amines. The problems associated with handling phosgene, hazardous to health, difficult to store has compelled the synthetic community to think about the alternatives for accessing the isocyanates. Next, conducting the detailed literature survey revealed that, in 2018, Rousseaux and co-workers turned up with a phosgene and metal free synthesis of unsymmetrical ureas and carbamates where they employed isocyanate as an intermediate. Despite several such reports and developments isocyanates intermediates still suffer from several challenges like sensitivity towards moisture etc. To resolve such issues, blocked isocyanates or protected isocyanates are introduced. Further, utilizing these them several notable transformations have been documented for the synthesis of various heterocycles which are biologically active. However, at present the chemists are most interested in their in situ generation. For instance, Beauchemin et al engaged an N-substituted isocyanate for the cascade synthesis of aminohydantoins. With the vision to establish electrosynthesis in our lab, we inspired and motivated ourself to design an electrochemical strategy for in situ generation of these isocyanates. Further, we envisaged that once these isocyanates are generated, they can be further utilized to synthesize valuable structural candidates like benzimidazolone, quinazolinone etc. Our investigation commenced with set of protocols and after rigorous optimization, we could obtain the desired product in good yields of upto 60%. Several attempts were made to improve the yield of the protocol, but none of the variations could render the desired product in more than 60% yield. So, we started evaluating the substrate scope for the protocol with carbon electrodes, tetrabutylammonium tetrafluororborate as the supporting electrolyte under constant current of 3 mA. Interestingly, several examples of benzimidazolone, quinazolinone could be accessed with the desired conditions. Fascinated by these results, we anticipated the synthesis of two more valuable analogs oxazinone and perimidinone. To our delight, both were successfully achieved under standard conditions in moderate yields. Next, to prove that protocol involves isocyanate pathway, detailed mechanistic studies were performed. Among which the most interesting was trapping of the isocyanate intermediate and its detection by high resolution mass spectroscopy. Based on these experiments, a comprehensive pathway for the formation was proposed. At last, the obtained product was also employed for the synthesis of drug like molecule that bears an anticancer activity with low IC50 values. Chapter 3: Electricity Driven 1,3-oxohydroxylation of Donor-Acceptor Cyclopropanes: A Mild and Straightforward Access to β-hydroxy ketones The chemistry of strained rings especially cyclopropanes have enabled the scientific community to exploit them for the construction of complex molecular architectures. Bearing the ring strain of 115 KJ mol-1 with an inefficient orbital overlap induces a significant amount of π-character in the bent C-C bonds of cyclopropanes. Further, the introduction of donor and the acceptor group at the vicinal position induces a push pull effect which polarizes the C-C bond of the cyclopropanes. However, most of the documented protocols rely on the concept of transition metal-based Lewis acids or Bronsted acids catalysis which cleaves the C-C bond in heterolytic fashion to render the zwitter-ionic species. These species are further employed for carrying out various cycloadditions, rearrangement and ring opening reactions. Also, these species can be seized with various functional groups like phenols, amines, azides, thiols etc. affording the 1,3-bifunctionalised products. In 2011, Sparr and Gilmour manifested the enantioselective 1,3-dichlorination of cyclopropane carbaldehyde in an organocatalytic fashion. Later, in 2014, Werz and coworkers disclosed the ring-opening 1,3-dichlorination in the presence of iodobenzene dichloride. Our group has been working in the area of donor-acceptor cyclopropanes since last one decade. With our several affirmative experiences in the area of donor-acceptor cyclopropanes and with our desire to merge electrosynthesis with donor-acceptor cyclopropanes, we envisioned the activation followed by functionalization of these cyclopropanes under electrochemical conditions. This chapter of this thesis describes a new arena in the area of donor-acceptor cyclopropanes which led us to document an electrochemical protocol for accessing the βhydroxy ketones. Our investigation commenced with a set of protocols and after varying several conditions, we successfully obtained the desired β-hydroxy ketones in good yields of upto 85%. Further, several deviations from the standard conditions were attempted. However, none of the deviations improve the yield of the protocol. With the standard conditions that involved the carbon electrodes, tetrabutylammonium hexafluorophosphate as supporting electrolyte, at a constant current of 1 mA in acetonitrile solvent, substrate scope of the protocol was evaluated. Delightfully, various variations of β-hydroxy ketones were successfully synthesized in good yields. To understand the mechanistic pathway of the protocol various control experiments were carried out. From these mechanistic insights and our experiences with donor-acceptor cyclopropane, a plausible mechanism of the protocol was proposed. The designed protocol was scalable and several downstream modification of the obtained product rendered the pyridazine derivatives. Chapter 4: Electricity Mediated [3+2]-cycloaddition of N-sulfonylcyclopropanes with Olefins via N-centered Radical Intermediates: Access to Cyclopentane Analogs Recent times has witnessed enormous surge in the protocols that encounter N-centered Radical (NCRs) intermediates by the employment of several sustainable strategies like photoredox chemistry and electroorganic synthesis. Being a versatile intermediate, N-centered radicals have been employed for synthesizing several nitrogen containing molecular frameworks. In this direction, various notable transformations have been documented that involves the reaction of N-centered radical intermediates with various π-systems or aromatic rings etc. In this context, several notable transformations have been documented, wherein the N-H precursor undergoes proton/electron or electron/proton transfer to generate the NCRs. In 2012, Zheng et al. disclosed a photoredox mediated intermolecular [3+2] cycloaddition of cyclopropylamines with olefins. Later, in 2014, the same group further extended the protocol to alkynes affording the cyclic allylic amines. In continuation to this endeavor, Jiang and Huang et al. revealed the photoredox based generation of all-carbon quaternary stereocenters via radical-based asymmetric reaction of cyclopropylamines with alkenes. Encouraged by the utility of N-centered radical intermediates, we envisaged that nitrogen atom can be used as a handle to activate the cyclopropane ring for the β-scission of C-C bond. Hence, we employed the commercially available cyclopropylamines for this job. In the initial stages, cyclopropylamine was treated with p-toluenesulfonyl chloride to access the N-tosyl cyclopropylamines that was used as the active substrate for our protocol. Therefore, this chapter of the thesis describes a novel electrochemical way of cleaving the C-C bond of cyclopropanes by employing the concept of NCRs. After meticulously screening the various conditions, we established our standard condition that employ the carbon anode, nickel cathode, tetrabutylammonium tetrafluororborate as supporting electrolyte, with ferrocene mediator, potassium carbonate as base at a current of 1.5 mA in 1,2-dichloroethane solvent. After establishing the optimized conditions, explorations regarding the substrate scope were carried out. To our delight, a diverse substrate scope was synthesized. The methodology provided access to all carbon quaternary stereogenic centers, several di- and tri-substituted cyclopentane analogs. Next, a detailed mechanistic study was carried out with cyclic voltammetry experiments suggesting the role of ferrocene and base in the transformations. Moreover, the intermediate detection experiments revealed the importance of paired electrolysis in the transformation. At last, the obtained product was further subjected to late-stage derivatization to render the alcohol and acid analog of the product.