Continuous Flow Electrochemistry Enables Practical and Site‐Selective C−H Oxidation

Abstract

The selective oxygenation of ubiquitous C(sp3)–H bonds remains a highly sought‐after method in both academia and the chemical industry for constructing functionalized organic molecules. However, it is extremely challenging to selectively oxidize a certain C(sp3)–H bond to afford alcohols due to the presence of multiple C(sp3)–H bonds with similar strength and steric environment in organic molecules, and the alcohol products being prone to further oxidation. Herein, we present a practical and cost‐efficient electrochemical method for the highly selective monooxygenation of benzylic C(sp3)–H bonds using continuous flow reactors. The electrochemical reactions produce trifluoroacetate esters that are resistant to further oxidation but undergo facile hydrolysis during aqueous workup to form benzylic alcohols. The method exhibits a broad scope and exceptional site selectivity and requires no catalysts or chemical oxidants. Furthermore, the electrochemical method demonstrates excellent scalability by producing 115 g of one of the alcohol products. The high site selectivity of the electrochemical method originates from its unique mechanism to cleave benzylic C(sp3)–H bonds through sequential electron/proton transfer, rather than the commonly employed hydrogen atom transfer (HAT).

N-heterocyclic carbene and photocatalyst-catalyzed rapid access to indole ketones via radical C(sp3)–H acylation

“…Previously, numerous reports revealed that the benzylic C(sp 3 )–H on the phenyl ring of the indoles could be activated and participate in various functionalization reactions. 24 o ,25 Therefore, the more challenging substrates for our acylation reactions are those bearing alkyl groups at the phenyl ring and pyrrole ring of the indole skeleton simultaneously. To test the ability of our acylation reaction in distinguishing the above two types of benzylic C(sp 3 )–H bonds, N -protected 3,5- and 3,6-dimethyl-substituted indoles were subjected to the standard reactions.…”

Unlocking the Potential of Oxidative Asymmetric Catalysis with Continuous Flow Electrochemistry

“…A significant portion of our research endeavor is dedicated to the advancement of electro-oxidative synthetic methodologies, utilizing continuous flow single-pass microreactors. − Herein, we report that continuous flow electrochemistry serves as an enabling tool for promoting oxidative asymmetric catalysis, as evidenced through the development of distinct asymmetric reactions such as sulfenylation of 1,3-dicarbonyls, dehydrogenative C–C coupling, and dehydrogenative alkene annulation (Figure C). These diverse electrochemical asymmetric transformations are efficient and necessitate only minimal electrolyte concentrations.…”

Electrochemical-induced solvent-tuned selective C(sp3)–H bond activation towards the synthesis of C3-functionalized chromone derivatives

“…For example, Xu's group has disclosed the electrocatalytic allylic C(sp 3 )–H alkylation reaction and benzylic C(sp 3 )–H cyanation reaction. 35,36 Lei and co-workers used the electrophotocatalytic method to achieve oxidative azidation of C(sp 3 )–H bonds. 37 Despite the progress made, the development of efficient and green methods for constructing C3-functionalized chromones via the activation of the C(sp 3 )–H bond remains of great significance.…”