“Tribromides in Oxidative Dearomatisation: A Toolbox to Solve Molecular Complexities”

Abstract

The immanent reactivity and functionality of aromatic compounds furnish numerous possibilities for the synthesis of three dimensional complex organic structures via dearomatization reactions. Under oxidizing conditions, the dearomatization of ortho- and para-substituted phenols delivers cyclohexadienones, and these products are found to be omnipresent in the chemical synthesis of natural products and pharmaceutically active compounds. With the continuation to the recent trends, the proposed research work was designed to synthesize biologically active core molecules employing oxidative dearomatisation and photo-catalysis. Many groups have been putting serious efforts on dearomatisation from years albeit, spiro-oxacycle synthesis has been a less explored direction. The thesis chapters highlight the transformation of planar arenol derivatives into multifunctionalised spiro molecules employing Tribromides (TBs) and photo-catalysis. Heterocyclic motifs have been important point of attraction due to their demanded biological activity and pharmaceutical importance. The thesis presently divided into the following four chapters. Chapter 1.1 A series of ammonium tribromides were screened for exploring the role of ammonium counterpart attached to tribromides on generation of stereoselective spiro-furans via oxidative dearomatisation of naphthols. The proposition enlightens a suitable combination of the ammonium tribromide and sol vent employed, deliver the best achieved diastereoselectivities. This in turn, has also envisioned the mechanistic aspects related to this category of reactions. The mentioned dearomative spirofurano naphthalones has also been successfully achieved on a large-scale. Chapter 1.2 It is well known that phenols are strongly prone to aromatic substitution at the ortho-and para- positions. Although, selectivity at those positions was difficult due to very small difference in electron density. Here, we overcome this problem with recall of umpolung chemistry and found a tribromide mediated chemical engineering process for the controlled generation of ortho- and para- quinomethide product via oxidative dearomatization reactions. Chapter 2 In chapter 2 of the thesis, we have discussed a catalytic strategy towards the tribromide catalyzed dearomative spiro-cyclization reaction is described using TBAB and V2O5/H2O2 or H2MoO4/HClO4/H2O2 or Oxone as an oxidising agent. This methodology leads to the exclusive formation of spirofurano dienone product without subsequent rearomatisation or halogenated side product. The oxidation of naphthols as well as phenols, which are hardly reactive, are readily proceed under this mild condition generating only inorganic wastes from the used oxidant. This is the first report on tribromide-catalyzed dearomative transformation, resulting high functional group tolerance and broad substrate scope with excellent yield (up to 98%) and good diastereoselectivity (de up to 88%). The reactive spiro furano dienone core was utilised further for the synthesis of Vitamin E core system and other synthetic functionalisation. Several control experiments, Raman analysis, UV Visible studies and IR-Spectroscopy are performed to figure out the reaction pathway, which revealed that in situ generated tribromide is the active species. Chapter 3 Achiral tribromides are well-known compounds and widely used as an alternative source of molecular bromine. Herein, we present the first synthesis of a new set of air- and moisture-stable chiral tribromides. Categorically, first we introduced proline-based chiral tribromides, followed by Cinchonine-based tribromides and Maruoka-based tribromides. NMR, IR and UV spectroscopy of chiral tribromides revealed the presence of tribromide. This strategy enables the synthesis of a variety of air-, moisture-, and benchtop- stable quaternary tribromide derivatives. Further studies showed that these reagents are optically pure and quite efficient for pursuing asymmetric transformation via oxidative dearomatization reactions. Chapter 4.1 In the past few decades, annulated arene heterocyles via radical initiated or cation initiated cascade reactions experienced a period of rapid development, and numerous biologically important building blocks or natural products have been synthesised. Till now, a significant number of transformations accomplished with metal-catalysis, non metal, electrocatalysis and so on. Among these methodologies, C-C, C-Si, C-S, C-P bond-forming cascade reactions are common. We found few reports on C-halogen bond-forming cascade reactions using oxidant, although it has great potential of post functionalization. In Figure 5, tribromide-catalyzed N-heterocyclic ynone dearomatization reactions are shown. Chapter 4.2 In this part of the chapter, we are presenting first visible light-catalyzed C halogen bond-forming dearomative ipso-cyclisation of N arylpropiolamide.