Deoxygenated Alkylation of Heteroarenes with Alcohols
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Date
2016-05
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The Ohio State University
Abstract
The synthesis and functionalization of pharmaceutically useful compounds has long been a major focus in organic/medicinal chemistry. Post-synthetic alkylation of target compounds is a topic of strong interest to the pharmaceutical community. In light of this, the project focus is on designing metal-free conditions to alkylate heteroarenes using readily available alcohols. In the classic Minisci reaction, alcohol addition to heteroarenes results in a remaining alcohol within the product. Alternatively, a gamma radiation-based procedure allows for a spin-center shift mechanism that provides the alcohol free alkylation product. Recently, a photoredox approach using an iridium catalyst has also been developed to carry out this alkylation. The requirement of an iridium photocatalyst and the need for removal of the toxic iridium metal before biological testing, establishes a need for metal-free versions of this transformation. In this project, we have invented a new, alkylation reaction of heteroarenes with alcohols, under metal-free conditions via a peroxide-mediated radical mechanism. Importantly, we have demonstrated that our new method can alkylate isoquinoline, quinoline, 2,6-lutidine and 4-tButylpyridine derivatives without metal catalysts and with a variety of alcohols. In conclusion, our protocol enables access to diverse alkylated drug derivatives under mild conditions, with the promise for divergent functionalizations of heteroarenes with important pharmaceutical applications.
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Keywords
Alkylation, Spin-Center Shift, Minisci reaction, Radical Chemistry, Pharmaceuticals, Heteroarenes