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Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation
其他题名稳定的亲电三氟甲硫基化试剂
Shao XX(邵欣欣); Xu CF(徐春发); Lv L(吕龙); Shen QL(沈其龙)
2015
发表期刊Accounts Chem. Res.
卷号48期号:5页码:1227-1236
摘要Fluorine, which is the most electronegative element and has a small atomic radius, plays a key role in pharmaceutical, agrochemical,. and materials sciences. One of the fluoroalkyl groups, the trifluoromethylthio group (CF3S-), has been well-recognized as an important structural motif in the design of lead compounds for new drug discovery because of its high lipophilicity (Hansch lipophilicity parameter pi = 1.44) and strong electron-withdrawing properties, which could improve the drug molecule's cell-membrane permeability and enhance its chemical and metabolic stability. While classic methods for the preparation of trifluoromethylthiolated compounds typically involve halogen fluorine exchange reactions of polyhalogenomethyl thioethers or trifluoromethylation of sulfur-containing compounds under harsh reaction conditions, an alternative but more attractive strategy is direct trifluoromethylthiolation of the substrate at a late stage by employing an electrophilic trifluoromethylthiolating reagent. Although several electrophilic trifluoromethylthiolating reagents have been reported previously, these reagents either require a strong Lewis acid/Bronsted acid as an activator or suffer from a toxic nature or limited substrate scope. To address these problems, in late 2011 we initiated a project with the aim to develop new, shelf-stable, and highly reactive electrophilic trifluoromethylthiolating reagents that could easily install the trifluoromethylthio group at the desired positions of the drug molecule at a late stage of drug development. Inspired by the broad reactivity of the hypervalent iodine reagent, we initially discovered a highly reactive trifluoromethylthiolating reagent, trifluoromethanesulfenate 1a. Structure reactivity studies disclosed that the iodine atom of reagent 1a does not play an important role in this reagent's reactivity. Consequently, a simplified second-generation electrophilic reagent, trifluoromethanesulfenate 1b, was developed. In parallel, we developed another shelf-stable, highly reactive electrophilic reagent with a broad substrate scope, N-trifluoromethylthiosaccharin (2). In this Account, we mainly describe our discovery of these two different types of electrophilic trifluoromethylthiolating reagents, trifluoromethanesulfenates 1a and 1b and N-trifluoromethylthiosaccharin 2. Systematic studies showed that both types of reagents are highly reactive toward a wide range of nucleophiles, yet the substrate scopes of thee two different types of reagents are complementary. In particular, reagents la and 1b are more reliable in transition-metal-catalyzed reactions such as copper-catalyzed trifluoromethylthiolation of aryl/vinyl/alkylboronic acids and silver-catalyzed decarboxylative trifluoromethylthiolation of aliphatic carboxylic acids as well as in the organocatalytic asymmetric trifluoromethylthiolation of beta-keto esters and oxindoles. Reagent 2 is more electrophilic than reagents 1a and 1b, and 2 very attractive as ...
文章类型论文
学科领域氟化学
DOI10.1021/acs.accounts.5b00047
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收录类别SCI
语种英语
WOS记录号WOS:000355055700004
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文献类型期刊论文
条目标识符http://ir.sioc.ac.cn/handle/331003/39724
专题中科院有机氟化学重点实验室
通讯作者Shen QL(沈其龙)
作者单位中科院上海有机化学研究所, 有机氟化学重点实验室
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GB/T 7714
Shao XX,Xu CF,Lv L,et al. Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation[J]. Accounts Chem. Res.,2015,48(5):1227-1236.
APA 邵欣欣,徐春发,吕龙,&沈其龙.(2015).Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation.Accounts Chem. Res.,48(5),1227-1236.
MLA 邵欣欣,et al."Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation".Accounts Chem. Res. 48.5(2015):1227-1236.
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