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Integrating Metal-Catalyzed C–H and C–O Functionalization To Achieve Sterically Controlled Regioselectivity in Arene Acylation
journal contribution
posted on 2018-07-10, 00:00 authored by Nicholas A. Serratore, Constance B. Anderson, Grant B. Frost, Truong-Giang Hoang, Steven J. Underwood, Philipp M. Gemmel, Melissa A. Hardy, Christopher J. DouglasOne
major goal of organometallic chemists is the direct functionalization
of the bonds most recurrent in organic molecules: C–H, C–C,
C–O, and C–N. An even grander challenge is C–C
bond formation when both precursors are of this category. Parallel
to this is the synthetic goal of achieving reaction selectivity that
contrasts with conventional methods. Electrophilic aromatic substitution
(EAS) via Friedel–Crafts acylation is the most renowned method
for the synthesis of aryl ketones, a common structural motif of many
pharmaceuticals, agrochemicals, fragrances, dyes, and other commodity
chemicals. However, an EAS synthetic strategy is only effective if
the desired site for acylation is in accordance with the electronic-controlled
regioselectivity of the reaction. Herein we report steric-controlled
regioselective arene acylation with salicylate esters via iridium
catalysis to access distinctly substituted benzophenones. Experimental
and computational data indicate a unique reaction mechanism that integrates
C–O activation and C–H activation with a single iridium
catalyst without an exogenous oxidant or base. We disclose an extensive
exploration of the synthetic scope of both the arene and the ester
components, culminating in the concise synthesis of the potent anticancer
agent hydroxyphenstatin.
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activationAchieve Sterically Controlled Regioselectivitybondexogenous oxidantorganometallic chemistsArene Acylationmethodelectronic-controlled regioselectivitysalicylate estersreaction mechanismreport steric-controlled regioselective arene acylationcommodity chemicalsiridium catalystsynthesisester componentsiridium catalysisanticancer agent hydroxyphenstatinaryl ketonesreaction selectivityEAS
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