Regioselective oxidative arylation of N-acetylindoles and N-alkylindoles

Shathaverdhan Potavathri, University of Rhode Island

Abstract

Direct C-H bond arylation holds a significant importance in the synthesis of small biologically active molecular as it eliminates the need for pre-functionalization of either of the coupling partners. The use of these pre-functionalized coupling partners is inherently wasteful and uneconomical in comparison to methods that might directly couple the arenes together through C-H bond activation. This dissertation is mainly focused on the regioselective oxidative arylation of indoles and the synthesis of next-generation inhibitors of botulinum neurotoxin by a direct catalytic cross-coupling strategy. The first manuscript entitled "Oxidant – Controlled Regioselectivity in the Oxidative Arylation of N-Acetylindoles" is focused on regioselective palladium catalyzed oxidative cross-coupling of N-acetylindole in the presence of stoichiometric oxidants like silver acetate and copper acetate. We have developed and optimized conditions for the selective C2/C3 arylation of N-acetylindoles in non-acidic media in the presence of an oxidant. We have demonstrated the kinetic isotope effects for both the major and minor products of reactions oxidized by both AgOAc and Cu(OAc)2, which were determined using GC/MS analysis of benzene/benzene-d6. The second manuscript "Regioselective Oxidative Arylation of Indoles Bearing N-Alkyl Protecting Groups: Dual C-H Functionalization via a Concerted Metallation-Deprotonation Mechanism", is focused on the selective C2-arylation of N-SEM protected indoles under buffered conditions. We have shown that both the activity and regioselectivity of these cross-coupling reactions are correlated to the acidity of the medium. Computational data indicates the mechanism for C-H palladation of both the indoles and simple arenes and is best described as concerted metallation-deprotanation (CMD), regardless of the substituition on the arenes. The third manuscript "Synthesis of Next-Generation Inhibitors of Botulinum Neurotoxin A via Double C-H Activation," is focused on the synthesis of small molecule inhibitors of Botulinum Neurotoxin A (BoNTA) by direct catalytic cross-coupling reaction involving double C-H activation reactions. We have designed and executed a novel synthetic route for the synthesis of a next-generation inhibitor of BoNTA. Our future studies in this field will include further exploration towards the substrate scope.

Subject Area

Biochemistry|Organic chemistry

Recommended Citation

Shathaverdhan Potavathri, "Regioselective oxidative arylation of N-acetylindoles and N-alkylindoles" (2010). Dissertations and Master's Theses (Campus Access). Paper AAI3451843.
https://digitalcommons.uri.edu/dissertations/AAI3451843

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