康 · 学术 | Reaction of the Day No. 1710

Deprotection of Benzyl Ethers via Solvent Anion-mediated EDA Complex

Cole Stenftenagel, AthulJoshy, Charles D. Irving, Micheal G. Esdon, Taylor E. Casey and Sébastien Laulhé

Department of Chemistry & Chemical Biology, Indiana University Indianapolis, USA

Recommended by Bing Han_MC3

KEY WORDS: photo chemistry, debenzylation (反应类型), benzyl ethers (原料), phenols, alcohols (产物), KOtBu, catalyst free,electron donor–acceptor (EDA) complexes (其它)

ABSTRACT: Benzyl ethers are among the most robust and indispensable protecting groups in the synthesis of complex natural products and pharmaceuticals, providing effective neutralization of the reactive hydroxy group in phenols and alcohols. However, their cleavage necessitates the use of expensive catalysts, hazardous conditions, or excessive organic additives. Herein, we report a catalyst-free, photoinduced debenzylation protocol of phenolic and aliphatic ethers. By leveraging in situ generated solvent-anions as the reductant, the protocol achieves chemoselective debenzylation in the presence of alkenes, amides, carbamates, alcohols, and boronic esters in high yields under mild conditions. This strategy circumvents the need for costly hydrogenation catalysts or toxic reagents, providing a sustainable and economically viable alternative for debenzylation.

Background

Optimization of Reaction Conditions

Substrate Scope (selected examples)

Proposed Mechanism

Summary and Comments

Prof. Sébastien Laulhéa and his co-workers reported a mild and metal-free photochemical protocol for the deprotection of phenols and aliphatic alcohols. The method exhibits broad functional group tolerance and orthogonality with the N-Boc protecting group as well as alkenes, while also being scalable. Importantly, this method enables selective deprotection of electronically differentiated benzyl groups, thereby providing potential synthetic utility in complex scaffolds containing multiple benzyl-protected alcohols and phenols. Lastly, by eliminating the need for hazardous reagents and expensive transition metals, this approach offers a more sustainable and atom economical manifold for the debenzylation of complex organic molecules.