Fluorinated Ylides/Carbenes and Related Intermediates from Phosphonium/Sulfonium Salts
Fluorinated Ylides/Carbenes and Related Intermediates from Phosphonium/Sulfonium Salts
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来自磷/锍盐的氟化叶立德/卡宾和相关中间体
DOI：
10.1021/acs.accounts.0c00244
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发表时间：
2020-08-18
影响因子：
18.3
通讯作者：
Xiao, Ji-Chang
中科院分区：
文献类型：
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作者：
Lin, Jin-Hong;Xiao, Ji-Chang
由于氟元素的特殊效应，包括高电负性和小原子半径，在有机分子中引入氟化基团可以改变其物理、化学和生物性质。含氟化合物在许多领域得到了广泛的应用，因此，开发高效的试剂和方法来掺入含氟基团已成为人们非常感兴趣的课题。本文介绍了我们在含氟叶立德/卡宾和由膦/硫盐生成的相关中间体的化学方面的最新发现。最初，我们得到了(三苯基膦)二氟乙酸酯，ph3p+CF2CO2-(PDFA)，它被认为是一种反应中间体，但从未成功合成过。PDFA不仅是一种温和的叶立德(ph3p+CF2-)试剂，而且货架稳定，易于制备，也是一种有效的二氟卡宾来源。它可以通过第一代叶立德ph3p+CF2-在升温条件下直接生成二氟卡宾，而不需要任何添加剂。有趣的是，后来用PDFA作为试剂发现了二氟卡宾化学。二氟卡宾能被氧化成CF2=O，能与单质硫反应生成CF2=S，能被NaNH2或NH3捕获生成CN-。将这些过程发展成合成工具，使我们能够实现各种反应，包括具有挑战性的F-18-三氟甲硫基化和氰基二氟甲基化。研究发现，尽管阳离子具有很高的亲电性，但阳离子上的取代基可以作为亲核试剂直接转移。这一转移过程就像是阳离子的一个“Upolung”，这可能会为膦盐的合成利用提供更多的机会。对这一转移过程的研究使我们发现，易生成的活性中间体碘膦盐可以有效地促进醛和醇的脱氧官能化。通过该协议对醇的脱羟基取代允许使用具有较高pK值的无保护的胺作为亲核试剂，这是与Mitsunobu反应相比的一个吸引人的特征。在叶立德-卡宾工艺(ph3p+CF2->；：CF2)的基础上，我们进一步开发了硫盐作为氟化叶立德和氟甲基卡宾的前体。特别是对二氟甲基卡宾的研究，大部分仍未被探索，可能值得更多的关注。这些发现可能会在合成具有生物活性的含氟分子方面发挥作用。
Owing to the special effects of the fluorine element, induding high electronegativity and small atomic radius, the incorporation of a fluorinated group into organic molecules may modify their physical, chemical, and biological properties. Fluorine-containing compounds have found widespread application in a variety of areas, and thus, the development of efficient reagents and methods for the incorporation of fluorinated groups has become a subject of significant interest. Described in this Account are our recent discoveries in the chemistry of fluorinated ylides/carbenes and related intermediates generated from phosphonium/sulfonium salts. Initially, we obtained the (triphenylphosphonio) difluoroacetate, Ph3P+CF2CO2- (PDFA), which was proposed as a reactive intermediate but had never been successfully synthesized. PDFA, shelf-stable and easy to prepare, is not only a mild ylide (Ph3P+CF2-) reagent, but also an efficient difluorocarbene source. It can directly generate difluorocarbene, via the first generation of ylide Ph3P+CF2-, simply under warming conditions without the need for any additive. Interestingly, difluorocarbene chemistry was then discovered by using PDFA as a reagent. Difluorocarbene can be oxidized to CF2=O, can react with elemental sulfur to afford CF2=S, and can be trapped by NaNH2 or NH3 to give CN-. The development of these processes into synthetic tools allowed us to achieve various reactions, including the challenging F-18-trifluoromethylthiolation and cyanodifluoromethylation. It was found that a substituent on the cation of a phosphonium salt can be directly transferred as a nucleophile despite the cation's high electrophilicity. This transfer process is like an "umpolung" of the cation, which may provide more opportunities for the synthetic utilities of phosphonium salts. The investigation of this transfer process led us to find that iodophosphonium salts, active intermediates which can be easily generated, may efficiently promote deoxygenative functionalizations of aldehydes and alcohols. Dehydroxylative substitution of alcohols by this protocol permits the use of unprotected amines with higher pK, values as nucleophiles, which is an attractive feature compared with the Mitsunobu reaction. On the basis of the ylide-tocarbene process (Ph3P+CF2- -> :CF2), we further developed sulfonium salts as precursors of fluorinated ylides and fluorinated methyl carbenes. In particular, the studies on difluoromethylcarbene, remaining largely unexplored, may deserve more attention. The discoveries may find utility in the synthesis of biologically active fluorine-containing molecules.