摘要：Yu Zhang,3†XinyuHan,3†Dong Li,1†DinggangWang,3JinxinWang,3Xin Luan,3Shao-FeiNi,1*ShoubhikDas,2*and Wei-Dong Zhang3*

转自：康龙化成

Facile Access to Hindered Ethers via Photoinduced O-H Bond Insertions

Yu Zhang,3†Xinyu Han,3† Dong Li,1†Dinggang Wang,3Jinxin Wang,3 Xin Luan,3 Shao-FeiNi,1*Shoubhik Das,2* and Wei-Dong Zhang3*

1 Department of Chemistry, Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University, Shantou 515063, China;

2 Department of Chemistry, University of Bayreuth, Bayreuth 95447, Germany;

3 Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Chemistry and Chemical Engineering, Henan NormalUniversity, Xinxiang, Henan 453007, People’s Republic of China; School of Pharmacy, Second Military Medical University, Shanghai 200433, China

—ACS Cent. Sci., 2025, org/10.1021/acscentsci.5c00099.

Recommended by Bingbing Chang _ MC5

KEY WORDS:photo chemistry,O-H insertion (反应类型), C(sp3)-O (成键类型), alcohols, N-tosylhydrazones (原料),polyfluorinated ether (产物), singlet carbenes (其他)

ABSTRACT:The synthesis of the hindered and polyfluorinated dialkyl ethers poses challenges owing to the bulkiness of tertiary alcohols and the low nucleophilicity of polyfluorinated alcohols. Additionally, associated competitive side reactions always provide poor reactivities. Although certain strategies, such as electrocatalytic decarboxylation and hydroalkoxylation, have been explored, a straightforward method for obtaining ethers with structural diversity remains elusive. Wei-Dong Zhang et al have exploited the photoinduced approach that involves the in situ formation of singlet carbenes followed by O-H insertionsto access the hindered and polyfluorinated ethers with congested or polyfluorinated alcohols. Moreover, other nucleophiles such as phenols, H2O, thiols, silanols, tributyltin hydride, etc., are also tolerable to obtain valuable products. The gram-scale synthesis of marketed drugs and the modification of complex molecules demonstrate the practicality of this approach. The detailed mechanistic studies have elucidated the key intermediates and reaction mechanism, which were distinct from traditional metal-carbenoid O-H insertions.

Background

Wei-Dong Zhang et al demonstrated the light-induced synthesis of hindered and polyfluorinated dialkylethers using congested tertiary alcohols and polyfluorinated alcohols. A wide range of tertiary alcohols bearing active groups or bulky structures were successfully accommodated in this system. Moreover, other nucleophilic coupling partners, including water, benzoic acids, thiols, silanols, and tributyltin hydride, were compatible, highlighting the broad tolerance of this strategy. The gram-scale synthesis and effective incorporation of challenging ether motifs into drug analogues underscore the practical utility of this approach. Moreover, the rapid and modular derivatization of a marketed drug exhibited its potential in expanding chemical diversity to aid drug discovery efforts. Finally, mechanistic investigations and DFT studies revealed that the major process involved the photoinduced formation of singlet carbenes followed by metal-free O-H insertion.

来源：新浪财经