通过中级过氧化物的抗病毒四氢咔唑衍生物的合成光化学和酸催化CH官能（筹）
Summary
A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Brønsted acid catalysis.
Abstract
The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Brønsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.
Introduction
CH键的直接官能是在有机化学1一项重要而长期的目标。这种转变可以是非常强大的，以便通过节省步骤，时间和材料相比，需要激活或指挥团的导入和去除传统的方法来简化合成。因此，CH键的功能化也是绿色化学2的吸引力。下的氧化的条件下，2 CH键或1 CH和一个杂原子-H键可以转换到CC和C-杂原子键，分别为（ 图1）3-9。通常，这些氧化偶联反应需要合成氧化剂，昂贵的催化剂或高温。因此，很多次尝试，开发使用廉价的催化剂，良性的条件和氧气或空气作为氧化剂终端10个方法。
<img alt="图1" fo:content-widþ="“5英寸”SRC" >
图1。氧化偶联反应。 请点击此处查看该图的放大版本。
许多有机化合物反应缓慢与氧从空气中自动氧化反应，这可以通过有效地插入O 2，形成氢过氧化物基团功能化11,12 CH键。自氧化过程是用在工业规模上，以从烃原料生成的含氧化合物，但是自氧化也是不希望的过程，如果它导致了有价值的化合物或材料分解。在某些情况下，例如乙醚，在空气中形成过氧化氢也可以是爆炸性的。近来，我们发现了一种反应，利用一个自动氧化，形成由CH键的新的C-C键，而不需要氧化还原活性的催化剂13,14的</SUP>。简单地在酸催化剂的存在下搅拌氧基板导致新产品的形成。键的反应是容易形成中间氢过氧化物，其通过酸催化15被取代的与第二基板的。该反应，但是，仅限于呫吨及被轻易氧和产品的气氛下被氧化的几个相关化合物具有迄今未发现的应用程序。这一发现启发然而，我们开发，利用CH功能化的原则通过中级过氧化物（CHIPS），合成药物活性吲哚衍生物16与氧化偶联方法。
吲哚类化合物，特别是四氢咔唑1，可以很容易地被氧化成氢过氧化物2中的单线态氧17〜19，可以使用增感剂和可见光20产生的存在。一个HYDRoperoxide部分原则上可以作为是否通过酸催化活性，并允许引入亲核试剂21,22离去基团。过氧化氢 也是已知的经过酸催化重排反应，如在工业合成苯酚的从异丙苯，Hock方法23利用。通过仔细的优化研究，我们可以找到条件有利于与N-亲核试剂像苯胺3在不需要的分解途径被重排16所希望的取代反应。在这里，我们描述了这两个步骤的CHIPS过程详细地说，只使用可见光，敏化剂，氧和酸。其中所选择的产品是吲哚衍生物4，它显示出高的抗病毒活性或抑制血管内皮生长因子（VGF），这可能是重要的肿瘤治疗24-26。
Protocol
Representative Results
Discussion
综上所述，我们能够证明在四氢咔唑CH键可以方便地官能化，以产生CN-偶联产物的两步骤程序中。
第一步是四氢咔唑（1）或其与元素氧17,19衍生物的公知的光催化氧化反应，使氢过氧化物2。如果在甲苯中进行的，氢过氧化物产物沉淀，并且可以很方便地通过过滤分离。进一步纯化不是必要的。
第二个步骤是酸催化的亲核…
Declarações
The authors have nothing to disclose.
Acknowledgements
Financial support from the DFG (Heisenberg scholarship to M.K., KL 2221/4-1; KL 2221/3-1) and the Max-Planck-Institut fuer Kohlenforschung is gratefully acknowledged.
Materials
| 1,2,3,4-Tetrahydrocarbazole | Sigma Aldrich | T12408 | If coloured, purification may be necessary. See Protocol 1.1 |
| Methanol | Sigma Aldrich | 322415 | 99.8% purity |
| 4-Nitroaniline | Acros Organics | 128371000 | 99% purity |
| Trifluoroacetic acid | Sigma Aldrich | T6508 | 99% purity |
| Acetic acid | J. T. Baker | JTB RS 426960101 | 99-100% purity |
| Aniline | Merck | 8222560100 | |
| 4-Aminobenzonitrile | Sigma Aldrich | 147753 | 98% purity |
Referências
- Bergman, R. G. Organometallic chemistry – C-H activation. Nature. 446, 391-393 (2007).
- Anastas, P., Green Eghbali, N. Green Chemistry: Principles and Practice. Chem. Soc. Rev. 39, 301-312 (2010).
- Yeung, C. S., Dong, V. M. Catalytic Dehydrogenative Cross-Coupling: Forming Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen Bonds. Chem. Rev. 111, 1215-1292 (2011).
- Liu, C., Zhang, H., Shi, W., Lei, A. Bond Formations between Two Nucleophiles: Transition Metal Catalyzed Oxidative Cross-Coupling Reactions. Chem. Rev. 111, 1780-1824 (2011).
- Klussmann, M., Sureshkumar, D. Catalytic Oxidative Coupling Reactions for the Formation of C–C Bonds Without Carbon-Metal Intermediates. Synthesis. 3, 353-369 (2011).
- Yoo, W. -. J., Li, C. -. J. Cross-Dehydrogenative Coupling Reactions of sp3-Hybridized C–H Bonds. Top. Curr. Chem. 292, 281-302 (2010).
- Dick, A. R., Sanford, M. S. Transition metal catalyzed oxidative functionalization of carbon-hydrogen bonds. Tetrahedron. 62, 2439-2463 (2006).
- Collet, F., Dodd, R. H., Dauban, P. Catalytic C–H amination: recent progress and future directions. Chem. Commun. 34, 5061-5064 (2009).
- Rohlmann, R., Mancheño, O. G. Metal-Free Oxidative C(sp3)-H Bond Couplings as Valuable Synthetic Tools for C-C Bond Formations. Synlett. 24, 6-10 (2013).
- Wendlandt, A. E., Suess, A. M., Stahl, S. S. Copper-Catalyzed Aerobic Oxidative C-H Functionalizations: Trends and Mechanistic Insights. Angew. Chem. Int. Ed. 50, 11062-11087 (2011).
- Hermans, I., Peeters, J., Jacobs, P. A. Autoxidation of Hydrocarbons: From Chemistry to Catalysis. Top. Catal. 50, 124-132 (2008).
- Milas, N. A. Auto-oxidation. Chem. Rev. 10, 295-364 (1932).
- Pintér, &. #. 1. 9. 3. ;., Sud, A., Sureshkumar, D., Klussmann, M. Autoxidative Carbon-Carbon Bond Formation from Carbon-Hydrogen Bonds. Angew. Chem. Int. Ed. 49, 5004-5007 (2010).
- Pintér, &. #. 1. 9. 3. ;., Klussmann, M. Sulfonic Acid Catalyzed Autoxidative Carbon-Carbon Coupling Reaction under Elevated Partial Pressure of Oxygen. Adv. Synth. Catal. 354, 701-711 (2012).
- Schweitzer-Chaput, B., et al. Synergistic Effect of Ketone and Hydroperoxide in Brønsted Acid Catalyzed Oxidative Coupling Reactions. Angew. Chem. Int. Ed. 52, 13228-13232 (2013).
- Gulzar, N., Klussmann, M. Aerobic C-H Amination of Tetrahydrocarbazole Derivatives via Photochemically Generated Hydroperoxides. Org. Biomol. Chem. 11, 4516-4520 (2013).
- Beer, R. J. S., McGrath, L., Robertson, A., Woodier, A. B. Tetrahydrocarbazole Peroxides. Nature. 164, 362-363 (1949).
- Iesce, M. R., Cermola, F., Temussi, F. . Photooxygenation of Heterocycles. Curr. Org. Chem. 9, 109-139 (2005).
- Mateo, C. A., Urrutia, A., Rodríguez, J. G., Fonseca, I., Cano, F. H. Photooxygenation of 1,2,3,4-Tetrahydrocarbazole: Synthesis of Spiro[cyclopentane-1,2′-indolin-3′-one]. J. Org. Chem. 61, 810-812 (1996).
- Wasserman, H. H., Ives, J. L. Singlet oxygen in organic synthesis. Tetrahedron. 37, 1825-1852 (1981).
- Liguori, L., et al. Electrophilic Aromatic Alkylation by Hydroperoxides. Competition between Ionic and Radical Mechanisms with Phenols. J. Org. Chem. 64, 8812-8815 (1999).
- Dussault, P. H., Lee, H. -. J., Liu, X. Selectivity in Lewis acid-mediated fragmentations of peroxides and ozonides: application to the synthesis of alkenes, homoallyl ethers, and 1,2-dioxolanes. J. Chem. Soc., Perkin Trans. , 3006-3013 (2000).
- Hock, H., Lang, S. Autoxydation von Kohlenwasserstoffen IX. Mitteil.: Über Peroxyde von Benzol-Derivaten. Ber. 77, 257-264 (1944).
- Boggs, S. D., Gudmundsson, K. S., Richardson, L. D. A., Sebahar, P. R. Tetrahydrocarbazole derivatives and their pharmaceutical use. USA patent WO. 2004/110999 A1. , (2004).
- Gudmundsson, K. S. HCV Inhibitors. USA patent WO 2006/ 121467 A2. , (2006).
- Lennox, W. J., Qi, H., Lee, D. -. H., Choi, S., Moon, Y. -. C. Tetrahydrocarbazoles as active agents for inhibiting VEGF production by translational control. USA patent WO 2006/ 065480 A2. , (2006).
