Nature 光和铜共催化的脱羧sp3 C-N键的构建

化学部落~~格格

本文作者无问西东

最近光催化领域的“大哥大”MacMillan课题组利用光和铜的双催化，从廉价、稳定、易得的烷基羧酸出发，在室温下高效地实现了其与一系列N-亲核试剂（包括药物分子中常见各类含氮杂环、芳香胺、磺酰胺、酰胺等）的交叉偶联，反应底物范围非常广谱，不仅适用于一级、二级底物，同时对极具挑战性的三级底物也能够适用，整个反应只需5分钟到1小时。

Decarboxylative sp³C–N coupling via dual copper and photoredox catalysis

Liang, Y.; Zhang, X.; MacMillan, D.Nature2018,559, 83.

DOI:https://doi.org/10.1038/s41586-018-0234-8

研究背景

C-N键的构建一直以来是有机化学中的热点领域，过去的六十年，sp²C-N键的构建已经取得了巨大的进展，发展了系列经典的反应：Buchwald–Hartwig胺化反应, Ullmann偶联反应以及Chan–Lam胺化等¹。然而sp³C-N键的有效构建仍然是一个巨大的挑战，目前合成化学家对于其构建依然依赖于传统的合成方法：N-亲核试剂和烷基卤代试剂间的亲核取代，还原偶联，烯烃的氢胺化反应等。虽然近年来，许多小组如Gregory Fu等陆续报道了过渡金属催化的烷基卤代物参与的sp³C-N键的构建方法²，但其只能实现几类特定的N-亲核试剂的烷基化，同时对于烷基卤代物也仅仅局限在了一级、二级底物，因此这些方法的底物范围比较局限，难以满足目前工业界和药化界的广大需求。

MacMillan小组近年来利用光和金属Ni双催化发展了一系列烷基羧酸脱羧形成C-C键的方法，因此，他们设想能否利用这样一个高效地产生烷基自由基的方法来开发出一种广谱的sp³C-N键的构建方法。然而金属Ni对于碳杂键的构建，由于其还原消除这一步较困难，故鲜有报道。而金属Cu催化的还原消除形成碳杂键这样一步基元反应，早已被诸多文献所例证。因此，他们设想是否能够利用Cu来捕捉光催化产生的烷基自由基实现sp³C-N偶联来解决上述挑战。作为MacMillan小组研究兴趣从金属Ni跨度到金属Cu的开篇大作，这篇文章报道了他们通过光和铜的共催化，利用醋酸碘苯对烷基羧酸进行简单活化，实现了底物范围非常广谱的烷基羧酸与一系列N-亲核试剂（超过15类的亲核底物）的交叉偶联。

细心的化学空间读者们可能已经留意到我们之前公开的一篇Nature Catalysis杂志上发表的Hu的文章³:

巧合的是，这篇文章与MacMillan的这篇nature文章的题目几乎一样，让人不禁想起“英雄所见略同”，两位教授都意识到了此研究领域的重要性。更为有趣的是文章的投稿与发表日期，我们发现Hu的发表日期是2月7日，而MacMillan的投稿日期是1月25日，那么MacMillan是不是应该庆幸自己早于Hu文章出来前两周将文章投出去了呢。然而这两篇文章的实质内容差别还是非常之大，待我们在文中再来进行比较。

最优反应条件优化

根据设想，作者探索了吲唑和环己酸活化物的反应。通过筛选诸如溶剂、配体和Cu催化剂等多个变量，作者发现以CuTC作为催化剂，二苯基菲罗啉作为配体，Ir(F-Meppy)₂(dtbbpyPF₆作为光催化剂，室温下1小时就可以以90%的产率得到预期产物（图1，entry 1），对照实验表明配体和Cu催化剂都是反应必需的（entries 2, 5）。有趣的是，在没有光和光催化剂的条件下仍然能得到86%的产物。作者接下来又探索了吲哚（11a）和氮杂吲哚（11b）的反应条件，发现在没有光和光催化剂的存在下，这两种底物仅得到了7%和47%的产率；然而当光和光催化剂的存在下，反应收率能够提高到60%和76%（图2）。因此，从底物的整体普适性角度，作者认为光和光催化剂的同时存在是反应高效进行的前提。

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图1 反应条件的筛选

图2对于不同类型亲核试剂反应条件的筛选

反应底物拓展

确定最优条件后，作者首先对烷基羧酸底物范围进行了研究。以吲唑为N-亲核底物，一级烷基羧酸都能以良好到优秀的产率得到产物（图3），且反应能够兼容双键、三键、硝基苯、酯、酮以及未保护的醇等官能团，同时该反应能够利用醋酸脱羧来充当甲基化试剂（13）。

图3一级羧酸底物范围

对于二级烷基羧酸底物，不同大小的环状底物和非环状底物均可高效地参与反应（图4）。羧酸底物中，最夺人耳目的应该是该反应实现了极具挑战的三级底物的C-N偶联，尤其是对于近年来药物开发中非常重要的bicyclo[1,1,1]pentane体系（36）⁴, 利用以往的方法往往需要多步繁琐的合成才能实现，这不得不说是合成上一个重大的突破。而反观之前介绍的Hu教授的文章中，很遗憾的是我们并没有看到三级底物的例子。

图4二级和三级羧酸底物范围

随后作者探索了N-亲核试剂的适用范围，从下面这张巨大的底物表中（图5），我们可以看到此反应几乎实现了药物分子中常见各类含氮杂环（吲唑、氮杂吲唑、吲哚、氮杂吲哚、吡唑。吡咯、三氮唑等）、芳香胺、磺酰胺、酰胺等的烷基化，并且该方法能够对各类复杂药物进行有效地后期修饰。最为重要的是对于含多个含氮亲核位点的底物（37,38,42,43,52,53,55,56,59），该反应表现出了高度的区域选择性；同时对于含潜在二次烷基化位点的底物（44,45,46,47,48），该反应表现出了单一烷基化选择性。对比Hu教授的文章，药物中常见的含氮杂环完全不能参与偶联，底物范围基本只局限在了芳香胺能够有效地参与偶联，因此，很大程度上的限制了Hu教授这项技术的应用前景。两篇文章底物范围相差如此之大，我们推测可能跟他们所采用的截然不同的脱羧机理有很大的关系。

图5N-亲核底物的范围

反应机理

作者提出了反应的可能机理（图6），在可见光辐射下，光催化剂（2）首先将Cu(I)和亲核试剂形成的金属Cu(I)配合物（3）氧化成Cu(II)配合物（4），同时形成一个低价态具有还原性的Ir物种（5），该Ir物种可以将经醋酸碘苯活化的羧酸碘苯（8）还原，经过脱羧形成烷基自由基（9），该自由基可被Cu(II)配合物（4）所捕获形成三价Cu(III)配合物（10），该高价态的Cu物种经过快速的还原消除得到产物（12）。

图6 可能的反应机理

结论

MacMillan小组报道的这样一个全新的脱羧参与的sp³C-N偶联反应，不仅突破了以往人们对于脱羧反应仅能参与实现C-C，C-F，C-Si，C-B键构建的认识，更为重要的是，该技术极大地拓展了sp³C-N的底物应用范围，相信该技术很快会在工业界和药化界得到应用。

参考文献

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