Facile nucleophilic fluorination reactions using tert-alcohols as a reaction medium: Significantly enhanced reactivity of alkali metal fluorides and improved selectivity
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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DOI：
10.1021/jo7021229
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发表时间：
2008-02-01
影响因子：
3.6
通讯作者：
Chi, Dae Yoon
中科院分区：
文献类型：
--
作者：
Kim, Dong Wook;Jeong, Hwan-Jeong;Chi, Dae Yoon
虽然质子溶剂通常不优选用于亲核置换反应，因为它们的部分正电荷和氢键能力使亲核试剂溶剂化并降低其反应性，但我们最近报道了使用叔醇作为与碱金属氟化物亲核置换的反应介质的显著有益效果，以及用[F-18]氟离子进行氟-18放射性标记以制备PET放射性药物。在这项工作中，我们进一步调查的叔醇反应介质的影响，通过研究叔醇，碱金属氟化物（CsF），和磺酰氧基底物之间的各种相互作用与碱金属氟化物的亲核取代。CsF与叔醇溶剂之间的氢键、叔醇溶剂化氟化物的形成以及磺酸酯离去基团与叔醇之间的氢键等因素似乎有助于在不存在任何种类的催化剂的情况下亲核取代反应的速率的显著增加。我们发现1-（2-甲磺酰氧基乙基）萘（5）和N-5-溴戊酰基-3，4-二甲氧基苯胺（8）在叔醇中与Bu 4 N +F-反应得到相应的氟代产物，产率比使用偶极非质子溶剂的常规方法高得多。质子介质还抑制副产物如烯烃、醚和环状加合物的形成。
[GRAPHICS]Although protic solvents are generally not preferred for nucleophilic displacement reactions because of their partial positive charge and hydrogen-bonding capacity that solvate the nucleophile and reduce its reactivity, we, recently reported a remarkably beneficial effect of using tertiary alcohols as a reaction media for nucleophilic fluorination with alkali metal fluorides, as well as fluorine-18 radiolabeling with [F-18]fluoride ion for the preparation of PET radiopharmaceuticals. In this work, we investigate further the influence of the tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluorides by studying various interactions among tert-alcohols, the alkali metal fluoride (CsF), and the sulfonyloxy substrate. Factors such as hydrogen bonding between CsF and the tert-alcohol solvent, the formation of a 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 reaction in 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 dipolar aprotic solvents. The protic medium also suppresses formation of byproducts, such as alkenes, ethers, and cyclic adducts.