可放大、绿色的烯丙位C-H键电化学氧化

Evan J. Horn, Brandon R. Rosen, Yong Chen, Jiaze Tang, Ke Chen, Martin D. Eastgate &Phil S. Baran. Scalable and sustainableelectrochemical allylic C–H oxidation.Nature, 2016(533):77–81.

烯丙醇和烯丙酮衍生物在合成中是很重要、多功能的一类中间体。烯丙醇可发生Sharpless反应，或衍生化后进行Cope重排、claisen重排转化成其它官能团。烯丙酮可作为Michael加成受体。现有通过活化C-H键制备烯丙醇或烯丙酮的方法多用到毒性试剂如铬或硒化合物，或者贵重金属如钯或铑，尚不能进行放大生产（figure1b）。有研究人员用电化学的方法制备，但收率较低，易产生其它副产物（figure1c）。

Scripps研究所的Baran等人对电化学方法进行了改进优化。首先筛选了一些列条件，如氧化剂、介导剂、溶剂、电极、碱，得到了最佳反应条件：20mol% Cl₄NHPI，吡啶(2.0equiv.)，t-BuOOH(1.5 equiv.),和LiClO4电极(0.1 M)，丙酮为溶剂。

对一些环烯烃和链状烯烃底物进行烯丙位糖基化反应，含有羟基、甲氧基、三甲基团硅氧基都能使反应进行，收率42~72%。如下图所示：

单萜类化合物、倍半萜类化合物和二萜类化合物亦能进行反应，羟基、三甲硅氧基、酯基、胺基、酰胺基在该条件下亦能耐受，收率41~91%。如下图所示：

甾体和三萜类化合物亦能进行，收率38~81%。如下图所示：

为考察反应的实用性，进行了放大，至百克级实验。如下图所示：

此外，还比较了现有方法与之前报道方法的PGSs(ProcessGreeness Scores，该值越大，表示工艺越绿色环保)，高于先前报道的方法。如下图所示：

提出了反应机理：Cl₄NHPI先在吡啶作用下脱去质子，形成负离子，随后在阴极失去一个电子，形成自由基。自由基提取烯丙基位的氢，形成烯丙基自由基。烯丙基自由基与过氧叔丁基自由基结合，脱去叔丁醇，得到烯丙酮。如下图所示：

在前人的基础上，作者对烯丙基位的电化学氧化反应在共氧剂、介导剂、反应的设备进行了改进，收率有较大提高，反应底物适应范围较广。进一步的放大反应证实了该方法的实用性。可作为后期药物分子官能团化手段。但正如作者文中所提到的，该方法也存在一些缺点：有些底物收率相对较低（反应不完全导致）。此外，电极需要自己制作，尚未商品化。

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1.     New methods and strategies for the direct functionalization of C-H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and materials.

2.     The oxidation of allylic systems has played a prominent role in thiscontext as possibly the most widely applied C-H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials.

3.     Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as “classics”. (ubiquitous)

4.     Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as Palladium or Rhodium).

5.     These requirements are problematic in industrial settings.

6.     This oxidation strategy is therefore rarely used for large scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists.

7.     Here we describe an electrochemical C-H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity.

8.     Electrochemical oxidation presents an attractive alternative to traditional chemical reagents for large scale applications, in a large part owing to the generation of less toxic waste than that produced by current chemical processes.

9.     Although these reactions are not useful in apreparative sense, they were a proofof concept that served as a foundation for our work.

10. precedent[ pri'si:dənt, 'presi- ]n.an example that is used to justify similar occurrences at a later time.先例；前例

In our own laboratory, systematic and extensive experimentation led to the identification of three modifications of the original precedent, which transformed this process into a synthetically useful electrochemical allylic C-H oxidation.

11.   From the outset of this work, we avoided the use of expensive electrodes such as precious metals, focusing our efforts exclusively on carbon.

12.   We considered that this might have partially been due to absorption of the substrate onto the graphite.

13.   reticulate[ri'tikjuleitid]adj.resembling or forming a network.网状的

vitreous['vitriəs]adj. (of ceramics) having the surface made shiny and nonporous by fusing a vitreous solution to it.有玻璃性质的；似玻璃的

Switching to reticulated vitreous carbon electrodes provedto be far more productive.

14.   Our hypothesis was that air was the oxygen-atom source in this transformation, which was qualitatively confirmed by bubbling O₂ gas in the reaction, resulting in an improved isolated yield of 18%.

15.   The use of acetone as solvent led to a slightly increased yield and was chosen as general solvent forthis reaction owing to its ability to solubilize a wide range of organic substrates.

16.   Voltammetry[vəul'tæmitri]n.Voltammetry is a category of electroanalytical methods used in analytical chemistry and various industrial processes.伏安法；伏安测量法(监测微量化学品的技术)

17.   The expectation of increased reactivity was supported by cyclic voltammetry.

18.   The final optimized conditions for oxidation of 4 to 5 are as follows.

19.   Our initial explorations into the tolerance focused on several cycloalkene-derived substrates relevant to drug discovery.

20.   Owing to their prevalence in the drug discovery, flavor and fragrance industries, our subsequent efforts focused on a variety of representative terpene classes.

21.   As such, we evaluated the efficiency with which the electrochemical allylic oxidation could be applied to these substances.

22.   as such adv. with respect to its inherent nature.就其本身而论；就这一点而论

23.   To put these results incontext, an extensive comparative survey of literature conditions and yields is included in supplementary information.

24.   Sesquiterpenoid and diterpenoid natural products, many of which are componentsof essential oils, have provided inspiration for many strategies and methods in synthesis, primarily owing to their complex and dense structures and their promising biological activities.

25.   obviate['ɔbvieit]vt.prevent the occurrence of;prevent from happening.防止；排除；消除（困难、不利因素等）

26.   We demonstrate the feasibility of adopting this technology in processsetting, using the described conditions.

27.   inset['inset, ,in'set]n.a small picture insertedwithin the bounds or a larger one.插入物；嵌入物

28.   The RuCl₃-catalysed oxidation had animproved, albeit still modest,PGS of 37.%.

29.   We were pleased to find that the electrochemical allylic oxidation showed a markedly improved PGS of 55.8%.

30.   testament['testəmənt]n. strong evidence for something.实证；证据

31.   As a further testament to its robustness, the electrochemical oxidation was carried outusing a 6-V lantern battery.

32.   Although this reaction is useful for the oxidation of numerous natural and unnatural carbon skeletons, it is not without its limitations.