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Abstract:
Aryl sulfonium salts, in particular aryl thianthrenium salts, have been demonstrated to be valuable synthetic handles, which not only can be incorporated into complex molecules with high site-selectivity, but also engage well in transition metal catalysis and photoredox catalysis. Building on those recent discoveries, this work consists of three parts dealing with (1) the synthesis of aryl sulfonamides, sulfones, and sulfonyl fluorides from aryl thianthrenium salts, (2) the discovery / development of new reactivity modes of (hetero)aryl sulfonium salts, such as cine-substitution, redox activation with α-amino alkyl radicals, and (3) the extension of the exquisite cross coupling chemistry of aryl thianthrenium salts to bicyclo[1.1.1]pentane thianthrenium salt (TT-BCPCF3+BF4-), a novel compound class first demonstrated in this work.
The sulfonyl functionality has become relevant in the pharmaceutical industry and well-defined strategies to access sulfonamides, sulfones, and sulfonyl fluorides are desired. The typically low functional group tolerance and the formation of constitutional isomers by electrophilic aromatic substitution with chlorosulfuric acid have prevented the modification of small complex molecules at a late-stage. Thus, the first part of this thesis reports the use of inexpensive industrial reagent sodium hydroxymethanesulfinate (Rongalite), as a nucleophilic coupling partner in the palladium-catalyzed sulfination of highly site-selectively functionalized aryl thianthrenium salts. The access of an aryl sulfinate salt precursor and the unique reactivity of aryl sufinates in presence of electrophiles leads to the functional group diversification of aryl sulfinates towards the synthesis of sulfonamides, sulfones and sulfonyl fluorides.
The second part of this thesis describes a methodology to access new substitution patterns (cine-and tele-substitution) by using heteroaryl sulfonium salts as pseudo-Michael acceptors. The synthetic transformation is exemplified with the broad scope of nitrogen-nucleophiles and cyanide leading to synthetically difficult-to-access molecules. Findings during the cine-substitution project led to the development of a new mode of C—S bond activation of aryl sulfonium salts, namely using α-amino alkyl radicals as single-electron reductants. The methodology consists of the generation of a strong reductant (α-amino alkyl radicals) from a weak reductant (amine) through oxidation and deprotonation, a process known as reductant upconversion. The reductant upconversion concept can be strategically used to generate aryl radicals from aryl sulfonium salts and conduct aryl radical addition to electronically diverse heteroarenes in a late-stage process. The protocol proceeds without the need for a catalyst, irradiation, or inert atmosphere.
Finally, an operationally simple protocol to achieve the synthesis of a novel tertiary alkyl thianthrenium salt is disclosed through strain-release trifluoromethylthianthrenation of [1.1.1]propellane. Despite the fact that tertiary sulfonium salts are generally of low stability towards dissociation into carbocations, the lacking stability of bicyclo[1.1.1]pentyl cations, although tertiary, prevents such decomposition pathways, and thus the trifluoromethyl bicyclo[1.1.1]pentane thianthrenium salt (TT-BCPCF3+BF4-) was found to be a stable salt. The first example of a previously elusive class of BCP sulfonium salts, TT-BCPCF3+BF4- bears the advantages of being a bioisostere of aryl thianthrenium salts and carrying a reactive thianthrene-based group. The exquisite cross coupling chemistry of aryl thianthrenium salts can be translated to TT-BCPCF3+BF4- to enable rapid access to drug-like BCP targets and valuable trifluoromethyl bicyclo[1.1.1]pentane derivatives, through the manipulation of the synthetic sulfonium-based linchpin for challenging C–N, C–C, and elusive C–O bond formation. The access of a novel bicyclo[1.1.1]pentane derivative with desirable features such as storage and reactivity profile may successfully cover a versatile platform to accomplish useful synthetic transformations.
