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首页> 外文期刊>Chemistry: A European journal >Direct Synthesis of a Trifluoromethyl Copper Reagent from Trifluoromethyl Ketones: Application to Trifluoromethylation
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Direct Synthesis of a Trifluoromethyl Copper Reagent from Trifluoromethyl Ketones: Application to Trifluoromethylation

机译：由三氟甲基酮直接合成三氟甲基铜试剂：在三氟甲基化中的应用

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Trifluoromethyl compounds have attracted much attention in the pharmaceutical and agrochemical industries due to the unique properties of the trifluoromethyl group. Various synthetic methods for such compounds have so far been developed by the use of trifluoromethyl organometallic (MCF_3) reagents. However, hard lithium and magnesium cations cannot be employed for such reagents, because these MCF_3 reagents are unstable even at low temperature and readily decompose to metal fluoride (MF) and singlet difluoromethylene (:CF_2) by means of a-fluoride elimination. In sharp contrast to hard metal cations, soft counterparts are useful as MCF_3 reagents for many types of trifluo-romethylation. Among the soft MCF_3 reagents, CuCF_3 reagents are relatively stable, but maintain their high reactivity. Intensive studies have thus been focused on efficient synthetic protocols for CuCF_3 reagents and their application to various trifluoromethylations. In particular, the Ruppert– Prakash reagents (CF_3SiR_3) are highly versatile as a stable CF_3~- source, and can readily generate CuCF_3 reagents by treatment with a CuI salt and metal fluoride; however, this process is still cost-prohibitive for large scale operations (Scheme 1a).[6] Therefore, fluoroform (CF_3H), a large-volume by-product of Teflon- (DuPont) manufacturing, as the cheapest and atom-economical CF_3~- source was utilized with the aim of preparing CuCF_3 reagents. Normant reported the preparation of CuCF_3 by adding a CuI salt to trifluoromethylated hemiaminolate [CF_3CH(O)NMe_2]~-, which can be produced by the deprotonation of fluoroform using a strong base followed by the addition to dimethylformamide (DMF); however, the yield of CuCF_3 was insufficient. Recently, Grushin succeeded in achieving a highly efficient preparation of CuCF_3 by direct cupration of fluoroform (Scheme 1b). The fundamental drawback of these methods is that fluoroform, a low boiling point gas (-83℃) is hard to handle in many synthetic laboratories. Therefore, a more practical synthetic method for the preparation of CuCF_3 reagents using low-cost and operationally easy CF_3~-sources in addition to fluoroform is strongly desired. Herein, we describe the practical synthesis of a CuCF_3 reagent from one of the most economical and efficient CF_3~-sources, that is, trifluoromethyl ketone derivatives, which are low-cost liquid and easy to handle (Scheme 1c). Moreover, the CuCF_3 reagent thus prepared in excellent yield can be utilized to a variety of trifluoromethylations with terminal alkynes, arylbronic acids, and aryl iodides under mild reaction conditions, and thus in late-stage functionalizations.
机译：由于三氟甲基的独特性质，三氟甲基化合物已在制药和农业化学工业中引起了广泛关注。迄今为止，已经通过使用三氟甲基有机金属（MCF_3）试剂开发了用于此类化合物的各种合成方法。但是，由于这些MCF_3试剂即使在低温下也不稳定，并且容易通过a-氟化物消除而分解为金属氟化物（MF）和单线二氟亚甲基（：CF_2），因此不能将硬锂和镁阳离子用于此类试剂。与硬金属阳离子形成鲜明对比的是，软对应物可用作MCF_3试剂，可用于许多类型的三氟甲基化。在软MCF_3试剂中，CuCF_3试剂相对稳定，但仍保持高反应活性。因此，深入的研究集中在CuCF_3试剂的有效合成方案及其在各种三氟甲基化中的应用。特别是，Ruppert–Prakash试剂（CF_3SiR_3）作为稳定的CF_3〜源具有很高的通用性，并且可以通过用CuI盐和金属氟化物处理而轻易生成CuCF_3试剂。但是，此过程对于大规模操作仍然是成本高昂的（方案1a）。[6]因此，为了制备CuCF_3试剂，利用了氟仿（CF_3H）作为最便宜，最经济的CF_3〜源，它是特氟隆（DuPont）生产中的大批量副产品。 Normant报道了通过向三氟甲基化的半氨基酸盐[CF_3CH（O）NMe_2]〜中加入CuI盐来制备CuCF_3的方法，这可以通过使用强碱对氟仿进行质子化然后再加入二甲基甲酰胺（DMF）来制备。然而，CuCF_3的产量不足。最近，Grushin通过直接杯化氟仿成功实现了高效制备CuCF_3的方法（方案1b）。这些方法的根本缺点是在许多合成实验室中难以处理低沸点气体（-83℃）氟仿。因此，迫切需要一种更实用的合成方法，该方法除了使用氟仿外，还使用低成本且易于操作的CF_3_来源制备CuCF_3试剂。在这里，我们描述了从最经济，最有效的CF_3〜来源之一，即三氟甲基酮衍生物中合成出CuCF_3试剂的实际方法，该衍生物为低成本液体且易于处理（方案1c）。此外，如此制得的CuCF_3试剂可在温和的反应条件下用于末端炔烃，芳基溴​​酸和芳基碘化物的各种三氟甲基化反应，从而可用于后期官能化。

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