Facile Nucleophilic Fluorination Reactions Using tert-Alcohols as a Reaction Medium: Significantly Enhanced Reactivity of Alkali Metal Fluorides and Improved Selectivity

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• 作者：Dong Wook Kim ; Hwan-Jeong Jeong ; Seok Tae Lim ; Myung-Hee Sohn ; John A. Katzenellenbogen ; Dae Yoon Chi
• 刊名：Journal of Organic Chemistry
• 出版年：2008
• 出版时间：February 1, 2008
• 年：2008
• 卷：73
• 期：3
• 页码：957 - 962
• 全文大小：244K
• 年卷期：v.73,no.3(February 1, 2008)
• ISSN：1520-6904

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Although protic solvents are generally not preferred for nucleophilic displacement reactions because oftheir partial positive charge and hydrogen-bonding capacity that solvate the nucleophile and reduce itsreactivity, we recently reported a remarkably beneficial effect of using tertiary alcohols as a reactionmedia for nucleophilic fluorination with alkali metal fluorides, as well as fluorine-18 radiolabeling with[¹⁸F]fluoride ion for the preparation of PET radiopharmaceuticals. In this work, we investigate furtherthe influence of the tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluoridesby studying various interactions among tert-alcohols, the alkali metal fluoride (CsF), and the sulfonyloxysubstrate. Factors such as hydrogen bonding between CsF and the tert-alcohol solvent, the formation ofa tert-alcohol solvated fluoride, and hydrogen bonding between the sulfonate leaving group and the tert-alcohol appear to contribute to the dramatic increase in the rate of the nucleophilic fluorination reactionin the absence of any kind of catalyst. We found that fluorination of 1-(2-mesyloxyethyl)naphthalene (5)and N-5-bromopentanoyl-3,4-dimethoxyaniline (8) with Bu₄N⁺F^- in a tert-alcohol afforded the corresponding fluoro products in much higher yield than obtained by the conventional methods using dipolaraprotic solvents. The protic medium also suppresses formation of byproducts, such as alkenes, ethers,and cyclic adducts.