Integrating Metal-Catalyzed C-H and C-O Functionalization to Achieve Sterically Controlled Regioselectivity in Arene Acylation

Nicholas A. Serratore, Constance B. Anderson, Grant B. Frost, Truong Giang Hoang, Steven Underwood, Philipp Gemmel, Melissa A. Hardy, Christopher J Douglas

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

One 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 the 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 anti-cancer agent hydroxyphenstatin.

Original languageEnglish (US)
Pages (from-to)10025-10033
Number of pages9
JournalJournal of the American Chemical Society
Volume140
Issue number31
DOIs
StatePublished - Aug 8 2018

PubMed: MeSH publication types

  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.

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