Copper-Catalyzed C-C Bond Formation through C-H Functionalization: Synthesis of Multisubstituted Indoles from N-Aryl Enaminones
Copper-Catalyzed C-C Bond Formation through C-H Functionalization: Synthesis of Multisubstituted Indoles from N-Aryl Enaminones
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DOI：
10.1002/anie.200902440
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Cacchi, Sandro
中科院分区：
文献类型：
--
作者：
Bernini, Roberta;Fabrizi, Giancarlo;Cacchi, Sandro
由于铜催化方法的经济吸引力和良好的功能耐受性，因此它们在大规模应用中的潜力，在过去的几年中，在有机合成中使用铜催化已经取得了显着的进展。已经描述了从芳基卤化物和合适的试剂开始的大量Ullmann偶联反应。[1]最近的报道[2]表明，铜催化也可用于通过选择性催化活化芳基C13 H键来形成C13 H杂原子和C13 C键，这是一个当前非常感兴趣的主题，在大多数情况下，已经见证了钯-、铑-和铼-基催化剂的使用。[3]特别地，已经显示通过C13 N和C13 O键形成反应的分子内铜催化的邻C13 H官能化分别从脒和酰苯胺形成苯并咪唑[2c]和苯并恶唑[2d]。在此，我们公开了一种由N-芳基烯胺酮合成多取代吲哚的新方法，该方法涉及分子内铜催化的芳基C3 H通过C3 C键形成的官能化。[4]吲哚部分普遍存在于大量具有生物活性的天然和非天然化合物中。因此，尽管存在许多合成吲哚衍生物的方法，[5]开发新的，更有效的程序是一个非常重要的主题。N-芳基烯胺酮1通过末端炔与芳酰氯的Sonogashira交叉偶联容易地制备[6]，然后苯胺与所得的α，β-炔酮共轭加成。[7]我们通过检查烯胺酮1a是否可以转化为相应的吲哚2a来开始我们的研究。反应通常在空气气氛下进行。在初步筛选铜催化剂（CuSO_4、CuCl_2、CuI）之后，我们发现在二甲基乙酰胺（DMA）中使用CuI、Li_2CO_3和1，10-菲咯啉（phen）在48小时后可以以63%的产率分离2a（表1，条目1）。然后进行优化研究，改变溶剂，碱，温度和过量的phen的性质。这些研究表明，使用二甲基亚砜（DMSO）得到类似的产率，但时间为一半（表1，条目2），而1，4-二氧六环导致以几乎定量的产率回收起始烯胺酮（表1，条目3）。当使用二甲基甲酰胺（DMF）作为溶剂时，获得令人满意的结果：以80%产率分离2a（表1，条目4）。使用K2 CO 3（表1，条目5）或Cs2 CO 3（表1，条目6）导致较低的产率，降低反应温度（表1，条目7）或过量的phen（表1，条目8）也是如此。在省略CuI（表1，条目9）或phen时，甚至在将CuI的量增加到30mol%和反应温度增加到120 ℃（表1，条目10）之后，也没有观察到吲哚形成。有趣的是，当反应在氧气气氛下进行时，化合物2a仅以50%的产率分离（表1，条目11），并且在氩气气氛下以良好的产率形成（表1，条目12）。
Because of the economic attractiveness and good functional tolerance of copper-catalyzed methods and hence their potential in large-scale applications, during the past few years there have been remarkable advances in the use of copper catalysis in organic synthesis. An impressive number of Ullmann coupling reactions have been described starting from aryl halides and suitable reagents.[1] Recent reports [2] have shown that copper catalysis can also be used in the formation of CÀheteroatom and CÀC bonds through selective catalytic activation of aryl CÀH bonds, a topic of intense current interest that, for the most part, has witnessed the use of palladium-, rhodium-, and ruthenium-based catalysts.[3] In particular, intramolecular copper-catalyzed ortho CÀH functionalizations through CÀN and CÀO bond-forming reactions have been shown to form benzimidazoles [2c] and benzoxazoles [2d] from amidines and anilides, respectively. Herein, we disclose a new synthesis of multisubstituted indoles from N-aryl enaminones that involves an intramolecular coppercatalyzed aryl CÀH functionalization through CÀC bond formation.[4] The indole moiety is prevalent in a vast array of biologically active natural and nonnatural compounds. Consequently, despite the existence of numerous methods for the synthesis of indole derivatives,[5] the development of new, more efficient procedures is a subject of great importance. N-Aryl enaminones 1 were readily prepared through Sonogashira cross-coupling of terminal alkynes with aroyl chlorides,[6] followed by the conjugate addition of anilines with the resultant α, β-ynones.[7] We initiated our study by examining whether the enaminone 1a could be converted into the corresponding indole 2a. Reactions were usually carried out under an atmosphere of air. After an initial screen of copper catalysts (CuSO4, CuCl2, CuI), we found that 2a could be isolated in 63% yield by using CuI, Li2CO3, and 1, 10-phenanthroline (phen) in dimethyl acetamide (DMA) after 48h (Table1, entry1). Optimization studies were then performed that varied the nature of solvents, bases, temperature, and the excess phen. These investigations revealed that the utilization of dimethyl sulfoxide (DMSO) gave a similar yield but in half the time (Table 1, entry 2), whereas 1, 4-dioxane led to the recovery of the starting enaminone in almost quantitative yield (Table 1, entry 3). A satisfactory result was obtained when dimethylformamide (DMF) was used as solvent: 2a was isolated in 80% yield (Table 1, entry 4). The use of K2CO3 (Table 1, entry 5) or Cs2CO3 (Table 1, entry 6) resulted in lower yields, as did decreasing the reaction temperature (Table 1, entry 7) or the excess phen (Table 1, entry 8). No indole formation was observed upon omitting CuI (Table 1, entry 9) or phen even after increasing the amount of CuI to 30mol% and the reaction temperature to 1208C (Table 1, entry 10). Interestingly, compound 2a was isolated in only 50% yield when the reaction was carried out under an atmosphere of oxygen (Table 1, entry 11) and was formed in good yield under an argon atmosphere (Table 1, entry 12).