Synthesis of m-Alkylphenols via a Ruthenium-Catalyzed C–H Bond Functionalization of Phenol Derivatives

Abstract

The first example of the synthesis of m-alkylphenols via a ruthenium-catalyzed C-H bond functionalization of phenol derivatives with sec/tert-alkyl bromides is reported. Mechanistic studies indicated that the m-C-H bond alkylation may involve a radical process and that a six-membered ruthenacycle complex was the active catalyst. Moreover, this approach can provide an expedited strategy for the atom-/step-economical synthesis of many noteworthy pharmaceuticals and other functional molecules.

Jenseits von Friedel und Crafts: dirigierte Alkylierung von C‐H‐Bindungen in Arenen

“…Aufd er Grundlage der meta-Alkylierung von Aryloxazolinen [111] und N-(2-Pyrimidyl)anilinen [141] nach Ackermann et al erweiterte die Gruppe von Li diese Strategie auf die meta-Alkylierung von Phenolen mit einer integrierten dirigierenden Pyridingruppe (Schema 33). [153] Bei der Reaktion mit katalytischen Mengen an [RuCl 2 (p-Cymol)] 2 und 1-Adamantancarbonsäure in Gegenwart von Kaliumcarbonat konnte eine große Auswahl an O-(2-Pyridyl)phenolen regioselektiv mit sekundären und tertiären Alkylbromiden in ihren meta-Positionen alkyliert werden. Eine zweifache Alkylierung scheint kein Problem darzustellen, und mit einem ortho-Substituenten im Startmaterial erfolgt die Alkylierung,a us mechanistischen Gründen, in der Nähe dieses Substituenten.…”

Transition Metal‐Catalyzed Directing‐Group‐Assisted C−H Activation of Phenols

“…Ru‐catalyzed ortho ‐metalation‐triggered S E Ar provided an easy access to meta ‐substituted 2‐phenylpyridine derivatives . In 2017, Li and co‐workers reported a method for Ru‐catalyzed meta ‐C−H alkylation of pyridyl‐protected phenols with sec ‐ or tert ‐alkyl bromides (Scheme ) . The electronic properties significantly affected the efficiency of the reaction.…”

“…[59] In 2017, Li and co-workersr eported am ethod for Ru-catalyzed meta-CÀHa lkylation of pyridyl-protected phenols with sec-o r tert-alkyl bromides (Scheme 47). [60] The electronic properties significantly affected the efficiency of the reaction. Substrates with electron-donatingg roups were favorable for meta-alkylation, whereas those with weakly electron-withdrawing groups provided the desired meta-alkylated products in lower yields.…”

Ruthenium‐Mediated Distal C−H Activation

“…Li and co‐workers outline sequential meta ‐alkylation and meta ‐sulfonation reactions on an atypical 2‐phenoxypyridine template, which also serves as a removable handle, to yield meta ‐alkylated/ meta ‐sulfonated phenols. In this case, a radical mechanism is described for both regioselective functionalization reactions (Scheme ) …”

“…In this case, ar adical mechanism is described for both regioselective functionalization reactions (Scheme 10). [26,27] In an ensuing report, Zhang and co-workers report an improvement of their earlier meta-nitration strategy.B etter yields are secured by manipulating the directingm oiety to an oxime (a removable auxiliary) under milder reaction conditions. AgNO 3 is used as the nitratinga gent insteado fC u(NO 3 ) 2 ·3H 2 O in combination with PhI(TFA) 2 ([bis(trifluoroacetoxy)iodo]benzene) to generate the NO 2 radical, and O 2 acts as the oxidant.…”