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

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 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.

Ketone Synthesis by a Nickel-Catalyzed Dehydrogenative Cross-Coupling of Primary Alcohols

“…Different alcohols were used to make benzophenone derivatives that were electron-neutral (4,5), electron-rich (6−8), and electron poor (9, 10), along with double coupling to provide bis-ketone 11. Similar tolerance was observed for variation of the organotriflate, with electronneutral (12,13), electron-rich (14,15), electron-poor (16,17), and sterically hindered (18) substrates readily participating. High yields were also observed in the presence of an aryl chloride ( 19), unprotected amide (20), and estrone backbone (21).…”

B(C6F5)3‐Catalyzed Tandem Friedel‐Crafts and C−H/C−O Coupling Reactions of Dialkylanilines

“…It is worth noticing that the reported catalysts of the C−H/C−O couplings are quite different from those of FC reactions due to the difference of their reaction mechanisms and the specifity of the catalysts. Besides, comparing with the abundant achievements on metal‐catalyzed C−C bond formation, processes promoted by metal‐free catalyst are still rare and full of challenges…”

“…Many famous reactions have been developed for the C−C bond formation . Among them, C−H/C−O coupling and Friedel‐Crafts (FC) reactions are two effective strategies …”

“…Hence, the C−H/C−O coupling to produce C−C bond is full of challenges. Until now, effectively accessing this coupling reaction still requires metal‐based catalysts, such as compounds containing Ni, Fe, Co, Mn, Rh, Ir, or Pd . It is worth noticing that, besides the use of highly active metal‐based catalysts, some of these reported C−H/C−O coupling reactions also require pre‐active substrates, such as Grignard reagent, organolithium reagent, or organoboron compound …”

Intermolecular and Intramolecular Friedel‐Crafts Acylation of Carboxylic Acids using Binary Ionic Liquids: An Experimental and Computational Study

“…Friedel‐Crafts acylation has received much attention due to its valuable utility in organic transformation [1–6] . The intrinsic drawbacks of the traditional procedure involved toxic acid chloride as the acylating agent and stoichiometric amounts of Lewis acid catalysts such as AlCl 3 , FeCl 3 , ZnCl 2, and TiCl 4 , [7–10] which could cause serious environmental problems.…”