ABSTRACTTELESCOPING C–H BORYLATIONS WITH PHOTOREDOX AND IMIDAZOLYLSULFONATE CHEMISTRY: A WAY TO AVOID HALOAROMATICS AND POTENTIALLY GENOTOXIC IMPURITIES IN SUZUKI REACTIONSByDamith PereraCross-coupling reactions are a mainstay of drug candidate synthesis. Owing to this prominence, the American Chemical Society’s Green Chemistry Institute's Pharmaceutical Roundtable deemed cross-couplings that avoid halogenated aromatics (C–H activation) as their top aspirational reaction. To meet this aspiration, we have worked to develop iridium-catalyzed C–H borylations as a practical approach for directly converting arenes and heterocycles into nucleophilic cross-coupling partners. This chemistry not only obviates the need for halogens in the preparation of aryl and heteroarylboronic esters, but with hydrogen gas as the only stoichiometric byproduct of these chemoselective reactions, we and others have shown that Ir catalyzed borylations can be combined with other chemical events enabling a multitude of one-pot processes. Among these telescoped reaction sequences, we established C–H borylation/oxidations as a novel route to phenols, including phenols that often bear otherwise difficult to access contra-electronic substitution patterns. Herein we discuss the development and further advancement of the scope and green features of this chemistry by performing in situ oxidation of the boron under photoredox conditions. Furthermore, as phenols can be readily converted to sulfonates, we have expanded the reach of iridium-catalyzed borylations and use C–H activation to eliminate the need for halogenated cross-coupling electrophiles. Thus we have developed a one-pot C–H borylation/ photoredox oxidation/ sulfonation sequence. In recognition of the potential safety-genotoxicity issues related to triflates, mesylates and tosylates this sequence was built so as to enable the generation of imidazolylsulfonates (ArOSO2Im) as the final cross-coupling electrophile. We also telescoped sequence that does not conclude with the imidazolylsulfonate formation. Rather the final aim was the establishment of a one-pot sequence that joins the efficiency of C–H borylation with the environmentally friendly aspects of photoredox chemistry and the safety features of imidazolylsulfonates. Namely we have established a one-pot C–H borylation/photoredox oxidation/imidazolylsulfonation/Suzuki coupling sequence.In the second part of this dissertation, the use of high-throughput experimentation for the discovery of cheap, readily available catalytic systems, namely bismuth(III) acetate and silver oxide for selective deborylation of polyborylated substrates will be discussed. Bismuth (III) acetate is a safe, inexpensive, and selective facilitator of sequential protodeboronations, which when used in conjunction with Ir-catalyzed borylations allows access to a diversity of borylated indoles. The versatility of combining Ir-catalyzed borylations with Bi(III)-catalyzed protodeboronation is demonstrated by selectively converting 6-fluoroindole into products with Bpin groups at the 4-, 5-, 7-, 2,7-, 4,7-, 3,5-, and 2,4,7- positions and the late-stage functionalization of sumatriptan. Further elaboration of the reactivity of Bi(OAc)3 for heteroarene substrates and Ag2O for arene substrates including deborylation/deuteration studies are discussed. Ir-catalyzed C–H borylations of aromatic compounds often allowed achieving the kinetically favored product. Herein a procedure to achieve reversibility in the catalytic borylation was studied with excess borylating agents and higher catalyst loads to obtain a novel thermodynamic borylated product, which cannot be obtained under usual Ir-catalyzed borylation methods.
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