Exploring Molecular Intricacy: Development of Facile Carbon- Heteroatom Bonds via Oxidative Dearomatization Reactions (ODRs)

Abstract

In the last few decades, oxidative dearomatization has been widely recognized as an attractive and straightforward transformation for the development of a high level of molecular complexity, as it provides an efficient method to derive three dimensional architectures from simple planar achiral substrates. Attempts to dearomatize arenols employing non-metallic reagents have been confined mostly to hypervalent iodine reagents, being to generate mostly spiro-lactones, spiro- ethers, and spiro-amines. In this context, our group with the continued interest in dearomative transformations, we started our journey through the exploration of an oxidative dearomative methodology by employing quaternary ammonium tribromides. It has been envisaged that spiro[4.5] and [5.5]trienones, the core structures of many naturally occurring compounds, can be directly accessed from dearomative spiro-annulation of ynones, biaryl ynones and appropriately substituted phenols bearing a pendant side chain. The thesis chapters highlight spiro-annulation via energetically demanding dearomatization reactions promoted by either visible-light or Lewis acid or quaternary ammonium tribromides for the formation of structurally complex spirocyles along with several carbon-heteratom bond generations. The thesis presently divided into the following six chapters. Chapter 1. Bromine induced spirocyclization of biaryl ynones facilitated the synthesis of spiro[5.5]trienones suitable for extended functionality at the C(3´) position. Herein, a step- economic photo-oxidative brominative carbannulation of biaryl ynones employing ammonium bromide and riboflavin tetraacetate (RFTA) have been developed. The reactivity between distal phenyl C-H activated ortho-annulation and dearomative ipso-annulation are well exemplified. The eminent features of the methodology include metal-free, external additive free, low-loading photocatalyst (0.1 mol%) and use of simple precursor. Chapter 2. In chapter 2, we conceptualized an efficient radical cyclization approach for the synthesis of SCF3, SAr, SO2Ar and COAr featured spirocyclic [4.5] and [5.5] trienones between biaryls and ArSO2H or ArCOCO2H in presence of RFTA as a photocatalyst and ArSSAr or AgSCF3 without photocatalyst via energetically demanding dearomatization pathway under visible-light catalysis. The unprecedented photo-excited charge transfer complex with biaryl tethered ynone provides a way to promote S-centered radical generation. Success of this approach was the wide range of sulfur centered radical generation/addition to the organic molecules/consecutive cyclization under mild conditions. Chapter 3. Sulfinyls are valuable structural moieties in the development of new pharmaceuticals and agrochemicals. In this chapter 3 of the thesis, we disclose a straightforward synthesis of functionalized spirotrienones proceeding via an unprecedented BF3.Et2O promoted spirocyclization of biaryl ynones in presence of aryl sulfinic acid. The economic availability of the BF3.Et2O to carry out transformations in bulk scale along with its further application towards the synthesis of dibenzocyclohepten-5-ones delivers a unique opportunity to utilize it in various synthetic directions. Chapter 4. An extended period of rapid growth in annulated arene heterocyles via radical route has occurred in the last few decades, leading to the synthesis of several naturally occurring compounds or biologically significant building blocks. Herein, we discover a smooth interface for the synthesis of spiro[4.5] and [5.5]trienones, a simple brominative (PART I) and thiolative (PART II) addition of alkynoates by oxidative spirocyclization. A simple protocol which leads to exclusive formation of C(3´)bromo spiro[4.5]trienones and C(3´)thiomethyl spiro[5.5]trienones from biaryl substrate, where it endures a regio-selective spirocyclization in presence of corresponding electrophiles. The methodology features a broad scope of biaryl substrates into challenging spirocyclic cores with good functional group tolerance and operates under mild metal-free conditions. Chapter 4.1. In this sub-chapter, a convenient and generalized method for in situ tribromide generation was studied and with this strategy we developed a wide variety of brominative spiro[4.5] and [5.5]trienones. Figure 4. Graphical abstract for chapter 4.1 Chapter 4.2. In this sub-chapter, an efficient and metal-free dearomative cationic approach is achieved for the synthesis of thiomethylated spiro[5.5]trienones from biaryl ynones and 1,1,2- trimethyldisulfan-1-ium as a source of thiomethyl cation. Chapter 5. A wide range of spirolactams were synthesized with good yields and regio-selectivity through a step-up oxidative dearomatization of readily available arenols tethered to ester and primary amines in presence of less explored quaternary ammonium tribromides (QATBs). The probable reaction mechanism associated with tribromide triggered dearomatization reaction has been forecasted with a series of control experiments, time-dependent HRMS and DFT studies to establish the reaction mechanism 6. In this chapter, biologically valuable isocoumarins were synthesized with broad substrate scope in high yields and excellent regio-selectivity through oxidative dearomatization of easily prepared o-alkynylbenzoates and o-alkynylbenzamides employing quaternary ammonium tribromides under metal-free conditions. Besides halocyclization, this intramolecular cyclization proceeds smoothly with several chalcogen-based electrophiles for the generation of C-S, C-Se and C-Te bonds. Interestingly, under certain condition, isochromenones were obtained in presence of diorganyl disulfides with PTATB.