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.

テトラヒドロカルバゾールヒドロペルオキシドの1の合成<ol><li>テトラヒドロカルバゾールが非常に着色されている場合は、ヒドロペルオキシドの形成が遅くなる。この場合、無色の出発物質を得るために、トルエン/ペンタンを用いて再結晶により、またはカラムクロマトグラフィーによりそれを精製する。カラムクロマトグラフィーによる精製は、シリカゲル及びアルミナの上部層の下層でカラムを詰める。カラムの上部にテトラヒドロカルバゾールを入れて、トルエンで溶出する。すべての不要な黄色と黒色の副生成物は、カラムに吸着され、無色のテトラヒドロカルバゾールを溶出している。すぐに溶媒を蒸発し、暗所でアルゴン雰囲気下で精製された白色の生成物を保管してください。 </li><li> 250mlフラスコ中に、（1、報告された方法16に従って合成）のテトラヒドロカルバゾール又は置換されたテトラヒドロカルバゾール1gを秤量。このフラスコに100mLのトルエンを追加します。 </li><li> 2（ローズベンガルを量るmg）及び上記反応混合物に追加します。 </li><li>攪拌棒を加え、セプタムでフラスコをカバーしています。 </li><li>隔壁を通して酸素バルーンを追加します。これは、反応に酸素雰囲気の正圧を保持します。 </li><li> 23ワットランプで反応混合物を照射する。 </li><li> （70:30の比率でヘキサン/酢酸エチルの混合物を使用して、TLC、本明細書に記載のヒドロペルオキシドのR f値は、0.2と0.3の間である）薄層クロマトグラフィーにより反応の進行状況を確認から、または1 H NMRによってサンプル撮影（ロータリーエバポレーターで溶剤を蒸発させ、DMSO-d6中の残留物を溶解させる）。反応時間は1.1部で述べたように、光源と、出発物質の純度に依存して変化し得る。一般的には、テトラヒドロカルバゾール1の完全な変換は、3時間かかります。 </li><li>出発物質の完全な変換後に析出した固体を濾過する。固体の洗浄のほとんどを除去するためにペンタンを用いて行うことができるトルエンが、精製のために必要ではない。 </li><li>減圧下で単離した固体を乾燥させます。 </li></ol>注意：私たち一緒に働くのか、この作品に記載されている化合物の処理にも問題を経験したことはありませんが、過酸化物を処理する場合、予防措置を講じなければならない。特に、加熱するか、金属または金属塩とそれらを混合するためにニート過酸化物を露出させるために、可能な限り避けるべきである。ブラストシールドの背後にあるこのような反応を行うことは推奨されます。 図2カップリング反応 - メタノール中の10モル％トリフルオロ酢酸を用いた方法A <ol><li> （ステップ1から。0.49ミリモル、1.0当量）のヒドロペルオキシドを計量し、所望のアニリンの求核（0.49ミリモル、1.0当量）を12ミリリットルバイアルまたは適切な丸底フラスコに。 </li><li>トリフルオロ酢酸10ミリリットルのメタノールを追加し、その後に3.74μL（TFAを、0.049ミリモル、0.1当量）をバイアルまたは丸底フラスコに。 </li><li>キャップ付きの容器を閉め、4時間室温で反応混合物を撹拌する。 （反応の過程で沈殿する製品のための） 後処理変種A1： </li><li>所望の生成物を得るために、沈殿した固形物をろ過する。メタノール（3×0.5ml）で生成物を洗浄。 </li><li>製品の第二画分を得るために、ろ液からメタノールを蒸発させる。室温に冷却し、次いで、40℃で酢酸エチル5mlの粗生成物を溶解し、純粋な生成物が沈殿する3〜5mlのペンタンを加える。 </li><li>製品の異なる画分を組み合わせて、高真空下に乾燥させます。 （沈殿しない製品のための） 後処理変種A2： </li><li>直接ロータリーエバポレーターを用いて反応後、溶媒を蒸発させて、所望の生成物を得た（シリカゲル、ヘキサン/酢酸エチル/トリエチルアミン）で指定されたカラムクロマトグラフィーにより残渣を精製する。 </li></ol> 3カップリング反応 - 。方法B酢酸を用いて<ol><li> （ステップ1から。0.49ミリモル、1.0当量）のヒドロペルオキシドを計量し、所望のアニリンの求核（0.49ミリモル、1.0当量）を12ミリリットルバイアルまたは適切な丸底フラスコに。 </li><li>バイアルまたは丸底フラスコにに10ミリリットルの酢酸（AcOH中）を追加します。 </li><li>キャップ付きの容器を閉め、4時間室温で反応混合物を攪拌する。 （反応の過程で沈殿する製品のための） 後処理変種B1： </li><li>所望の生成物を得るために、沈殿した固形物をろ過する。のAcOH（3×0.5ml）で生成物を洗浄。 </li><li>製品の第二画分を得るために、ろ液から酢酸を蒸発させる。室温に冷却し、次いで、40℃で酢酸エチル5mlの粗生成物を溶解し、純粋な生成物が沈殿する3〜5mlのペンタンを加える。 </li><li>製品の異なる画分を組み合わせて、高真空下に乾燥させます。 後処理変種B2 </strオング&gt;（沈殿しない製品の場合）： </li><li>直接ロータリーエバポレーターを用いて反応後、溶媒を蒸発させて、所望の生成物を得た（シリカゲル、ヘキサン/酢酸エチル/トリエチルアミン）で指定されたカラムクロマトグラフィーにより残渣を精製する。 </li></ol>

<ol>
	<li>Bergman, R. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Organometallic+chemistry+-+C-H+activation.">Organometallic chemistry - C-H activation.</a> Nature. 446, 391-393 (2007).</li><li>Anastas, P., Green Eghbali, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Green+Chemistry:+Principles+and+Practice.">Green Chemistry: Principles and Practice.</a> Chem. Soc. Rev. 39, 301-312 (2010).</li><li>Yeung, C. S., Dong, V. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Catalytic+Dehydrogenative+Cross-Coupling:+Forming+Carbon&#8722;Carbon+Bonds+by+Oxidizing+Two+Carbon&#8722;Hydrogen+Bonds.">Catalytic Dehydrogenative Cross-Coupling: Forming Carbon&#8722;Carbon Bonds by Oxidizing Two Carbon&#8722;Hydrogen Bonds.</a> Chem. Rev. 111, 1215-1292 (2011).</li><li>Liu, C., Zhang, H., Shi, W., Lei, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Bond+Formations+between+Two+Nucleophiles:+Transition+Metal+Catalyzed+Oxidative+Cross-Coupling+Reactions.">Bond Formations between Two Nucleophiles: Transition Metal Catalyzed Oxidative Cross-Coupling Reactions.</a> Chem. Rev. 111, 1780-1824 (2011).</li><li>Klussmann, M., Sureshkumar, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Catalytic+Oxidative+Coupling+Reactions+for+the+Formation+of+C&#8211;C+Bonds+Without+Carbon-Metal+Intermediates.">Catalytic Oxidative Coupling Reactions for the Formation of C&#8211;C Bonds Without Carbon-Metal Intermediates.</a> Synthesis. 3, 353-369 (2011).</li><li>Yoo, W. -. J., Li, C. -. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cross-Dehydrogenative+Coupling+Reactions+of+sp3-Hybridized+C&#8211;H+Bonds.">Cross-Dehydrogenative Coupling Reactions of sp3-Hybridized C&#8211;H Bonds.</a> Top. Curr. Chem. 292, 281-302 (2010).</li><li>Dick, A. R., Sanford, M. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transition+metal+catalyzed+oxidative+functionalization+of+carbon-hydrogen+bonds.">Transition metal catalyzed oxidative functionalization of carbon-hydrogen bonds.</a> Tetrahedron. 62, 2439-2463 (2006).</li><li>Collet, F., Dodd, R. H., Dauban, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Catalytic+C&#8211;H+amination:+recent+progress+and+future+directions.">Catalytic C&#8211;H amination: recent progress and future directions.</a> Chem. Commun. 34, 5061-5064 (2009).</li><li>Rohlmann, R., Manche&#241;o, O. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metal-Free+Oxidative+C(sp3)-H+Bond+Couplings+as+Valuable+Synthetic+Tools+for+C-C+Bond+Formations.">Metal-Free Oxidative C(sp3)-H Bond Couplings as Valuable Synthetic Tools for C-C Bond Formations.</a> Synlett. 24, 6-10 (2013).</li><li>Wendlandt, A. E., Suess, A. M., Stahl, S. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Copper-Catalyzed+Aerobic+Oxidative+C-H+Functionalizations:+Trends+and+Mechanistic+Insights.">Copper-Catalyzed Aerobic Oxidative C-H Functionalizations: Trends and Mechanistic Insights.</a> Angew. Chem. Int. Ed. 50, 11062-11087 (2011).</li><li>Hermans, I., Peeters, J., Jacobs, P. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Autoxidation+of+Hydrocarbons:+From+Chemistry+to+Catalysis.">Autoxidation of Hydrocarbons: From Chemistry to Catalysis.</a> Top. Catal. 50, 124-132 (2008).</li><li>Milas, N. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Auto-oxidation.">Auto-oxidation.</a> Chem. Rev. 10, 295-364 (1932).</li><li>Pint&#233;r, &. #. 1. 9. 3. ;., Sud, A., Sureshkumar, D., Klussmann, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Autoxidative+Carbon-Carbon+Bond+Formation+from+Carbon-Hydrogen+Bonds.">Autoxidative Carbon-Carbon Bond Formation from Carbon-Hydrogen Bonds.</a> Angew. Chem. Int. Ed. 49, 5004-5007 (2010).</li><li>Pint&#233;r, &. #. 1. 9. 3. ;., Klussmann, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sulfonic+Acid+Catalyzed+Autoxidative+Carbon-Carbon+Coupling+Reaction+under+Elevated+Partial+Pressure+of+Oxygen.">Sulfonic Acid Catalyzed Autoxidative Carbon-Carbon Coupling Reaction under Elevated Partial Pressure of Oxygen.</a> Adv. Synth. Catal. 354, 701-711 (2012).</li><li>Schweitzer-Chaput, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synergistic+Effect+of+Ketone+and+Hydroperoxide+in+Br&#248;nsted+Acid+Catalyzed+Oxidative+Coupling+Reactions.">Synergistic Effect of Ketone and Hydroperoxide in Br&#248;nsted Acid Catalyzed Oxidative Coupling Reactions.</a> Angew. Chem. Int. Ed. 52, 13228-13232 (2013).</li><li>Gulzar, N., Klussmann, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Aerobic+C-H+Amination+of+Tetrahydrocarbazole+Derivatives+via+Photochemically+Generated+Hydroperoxides.">Aerobic C-H Amination of Tetrahydrocarbazole Derivatives via Photochemically Generated Hydroperoxides.</a> Org. Biomol. Chem. 11, 4516-4520 (2013).</li><li>Beer, R. J. S., McGrath, L., Robertson, A., Woodier, A. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tetrahydrocarbazole+Peroxides.">Tetrahydrocarbazole Peroxides.</a> Nature. 164, 362-363 (1949).</li><li>Iesce, M. R., Cermola, F., Temussi, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Photooxygenation of Heterocycles. Curr. Org. Chem. 9, 109-139 (2005).</li><li>Mateo, C. A., Urrutia, A., Rodr&#237;guez, J. G., Fonseca, I., Cano, F. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Photooxygenation+of+1,2,3,4-Tetrahydrocarbazole:+Synthesis+of+Spiro[cyclopentane-1,2'-indolin-3'-one].">Photooxygenation of 1,2,3,4-Tetrahydrocarbazole: Synthesis of Spiro[cyclopentane-1,2'-indolin-3'-one].</a> J. Org. Chem. 61, 810-812 (1996).</li><li>Wasserman, H. H., Ives, J. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Singlet+oxygen+in+organic+synthesis.">Singlet oxygen in organic synthesis.</a> Tetrahedron. 37, 1825-1852 (1981).</li><li>Liguori, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electrophilic+Aromatic+Alkylation+by+Hydroperoxides.+Competition+between+Ionic+and+Radical+Mechanisms+with+Phenols.">Electrophilic Aromatic Alkylation by Hydroperoxides. Competition between Ionic and Radical Mechanisms with Phenols.</a> J. Org. Chem. 64, 8812-8815 (1999).</li><li>Dussault, P. H., Lee, H. -. J., Liu, X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selectivity+in+Lewis+acid-mediated+fragmentations+of+peroxides+and+ozonides:+application+to+the+synthesis+of+alkenes,+homoallyl+ethers,+and+1,2-dioxolanes.">Selectivity in Lewis acid-mediated fragmentations of peroxides and ozonides: application to the synthesis of alkenes, homoallyl ethers, and 1,2-dioxolanes.</a> J. Chem. Soc., Perkin Trans. , 3006-3013 (2000).</li><li>Hock, H., Lang, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Autoxydation+von+Kohlenwasserstoffen+IX.+Mitteil.:+&#220;ber+Peroxyde+von+Benzol-Derivaten.">Autoxydation von Kohlenwasserstoffen IX. Mitteil.: &#220;ber Peroxyde von Benzol-Derivaten.</a> Ber. 77, 257-264 (1944).</li><li>Boggs, S. D., Gudmundsson, K. S., Richardson, L. D. A., Sebahar, P. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tetrahydrocarbazole+derivatives+and+their+pharmaceutical+use.">Tetrahydrocarbazole derivatives and their pharmaceutical use.</a> USA patent WO. 2004/110999 A1. , (2004).</li><li>Gudmundsson, K. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=HCV+Inhibitors.">HCV Inhibitors.</a> USA patent WO 2006/ 121467 A2. , (2006).</li><li>Lennox, W. J., Qi, H., Lee, D. -. H., Choi, S., Moon, Y. -. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tetrahydrocarbazoles+as+active+agents+for+inhibiting+VEGF+production+by+translational+control.">Tetrahydrocarbazoles as active agents for inhibiting VEGF production by translational control.</a> USA patent WO 2006/ 065480 A2. , (2006).</li></ol>

著者らは、開示することは何もありません。

要約すると、我々は、テトラヒドロカルバゾールにおけるCH結合は都合の二段階の方法でCN-カップリング生成物を生成するために官能化され得ることを実証できた。 最初のステップは、ヒドロペルオキシド2を与え、テトラヒドロカルバゾール（1）又は酸素元素17,19とその誘導体の周知の光触媒酸化である。トルエン中で実行した場合、?...

C-H結合の直接官能化は、有機化学1で重要と長年の目標である。このような変換は、グループの活性化や演出の導入および除去を必要とする従来の方法に比べて、ステップ、時間と材料を保存することで、合成を合理化するために、非常に強力なことができます。そのため、C-H結合の官能もグリーンケミストリー2のための魅力的である。酸化条件下で、2個のCH結合または1つのヘテロ原子及びCH-H結合は、それぞれ、（ 図1）3-9 CCに変換され、C-ヘテロ原子結合することができる。多くの場合、これらの酸化的カップリング反応は、合成酸化剤、高価な触媒や高温度を必要とする。したがって、多くの試みが端末酸化剤10として安価な触媒は、良性状態及び酸素又は空気を使用する方法を開発するために行われる。 <img alt="図1" fo:content-wIDTH = &quot;5インチ&quot; SRC = &quot;/ files/ftp_upload/51504/51504fig1highres.jpg&quot;幅= &quot;500&quot; /&gt; 図1。酸化的カップリング反応。 <a href="https://www.jove.com/files/ftp_upload/51504/51504fig1highres.jpg" target="_blank">この図の拡大版を表示するには、こちらをクリックしてください。</a> 多くの有機化合物はヒドロペルオキシド部分11,12を形成し 、効果的にO 2を挿入することにより、C-H結合を官能することができます自動酸化反応で空気中の酸素とゆっくり反応する。自動酸化プロセスは、炭化水素原料から生成された含酸素化合物を工業的規模で使用されるが、それは、貴重な化合物または材料の分解をもたらす場合には自動酸化はまた、望ましくないプロセスであるている。いくつかの場合において、例えばジエチルエーテル、大気中で形成されたヒドロペルオキシドも爆発することができる。最近では、酸化還元活性触媒13,14を必要とせずにC-H結合から新しいC-C結合を形成するための自動酸化を利用して反応を発見</SUP&gt;。単に、酸触媒の存在下で、酸素の下で基板を撹拌し、新製品の形成につながる。反応の鍵は、酸触媒15によって、第2の基板で置換されている中間ヒドロペルオキシド、の容易な形成である。この反応は、しかしながら、キサンテンに制限し、容易に酸素と生成物の雰囲気下で酸化されているいくつかの関連化合物は、これまでに見つかっていないアプリケーションを有している。それにもかかわらず、この発見に触発され、私たちは、薬学的に活性なインドール誘導体16を合成するための中間過酸化物（チップ）を経由して、CH官能の原理を利用し、関連する酸化カップリング法を開発した。 インドール類、特に1テトラヒドロカルバゾール、容易に可視光増感剤20を用いて生成することができる一重項酸素17-19の存在下で2クメンに酸化することができる。 hydroperoxide部分は、脱離基として、原則として同法に酸触媒により活性化されている場合と求核21,22の導入を可能にすることができる。またクメンヒドロペルオキシド、ホック法23からのフェノールの工業的合成に利用される酸は転位触媒反応を受けることが知られている。慎重な最適化研究によって、我々は再配列16による不要な分解経路上のアニリン3様N-求核試薬で所望の置換反応を支持するための条件を見つけることができる。ここでは、可視光のみ、増感剤、酸素および酸を用いて、詳細には、この二段階のCHIPSの手順が記載されている。選択された商品の中でも、高い抗ウイルス活性を示すまたは腫瘍治療のための重要な24〜26であることができる血管内皮増殖因子（VGF）を阻害するインドール誘導体4である。

<table><tbody><tr><td>1,2,3,4-Tetrahydrocarbazole</td><td>Sigma Aldrich</td><td>T12408</td><td>If coloured, purification may be necessary. See Protocol 1.1</td></tr><tr><td>Methanol</td><td>Sigma Aldrich</td><td>322415</td><td>99.8% purity</td></tr><tr><td>4-Nitroaniline</td><td>Acros Organics</td><td>128371000</td><td>99% purity</td></tr><tr><td>Trifluoroacetic acid</td><td>Sigma Aldrich</td><td>T6508</td><td>99% purity</td></tr><tr><td>Acetic acid</td><td>J. T. Baker</td><td>JTB RS 426960101</td><td>99-100% purity</td></tr><tr><td>Aniline</td><td>Merck</td><td>8222560100</td><td></td></tr><tr><td>4-Aminobenzonitrile</td><td>Sigma Aldrich</td><td>147753</td><td>98% purity</td></tr></tbody></table>

synthesis of antiviral tetrahydrocarbazole derivatives by photochemical and acid-catalyzed c-h functionalization via intermediate peroxides (chips)

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 Br&#248;nsted-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.

1 - （5 -ニトロインドリン-1 -イル）-2,3,4,9 -テトラヒドロ-1H-カルバゾール（図4a）。 方法A は、R f = 0.63（ヘキサン/酢酸エチル70:30）に従って合成。 精製 ：方法A、精密検査変種A1（2.4、2.5、2.6ステップ）を使用して生成物を精製する。オレンジ色の固体、収率：95％。 1</sup...

Watch this Scientific Journal Video about Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS at JoVE.com

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Br&#248;nsted acid catalysis.

中間過酸化物を介した光化学および酸触媒CH機能化による抗ウイルステトラヒドロカルバゾール誘導体の合成（チップ）

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 ...

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Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

Unit 1

Acids and Bases

SCIENTISTS IN ACTION

13.8K ビュー.  Max-Planck-Institut fuer Kohlenforschung. 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.

ビデオ: Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 &deg;C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates. 
The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene.

Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.

生成Cyanocarbenesの適用のための超原子価ヨードニウムアルキニルトリフラートの合成

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent ...

化学

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of trifluoromethoxylated aromatic compounds remains a formidable challenge in organic synthesis. Conventional approaches often suffer from poor substrate scope, or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Herein, we report a user-friendly protocol for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II). Treating methyl 4-(N-hydroxyacetamido)benzoate (1a) with Togni reagent II in the presence of a catalytic amount of cesium carbonate (Cs2CO3) in chloroform at RT afforded methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a). This intermediate was then converted to the final product methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) in nitromethane at 120 &#176;C. This procedure is general and can be applied to the synthesis of a broad spectrum of ortho-trifluoromethoxylated aniline derivatives, which could serve as useful synthetic building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and functional materials.

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.

の合成のためのプロトコル<em&gt;オルソ</em&gt; -trifluoromethoxylatedアニリン誘導体

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of ...

Chemoselective Modification of Viral Surfaces via Bioorthogonal Click Chemistry

The modification of virus particles has received a significant amount of attention for its tremendous potential for impacting gene therapy, oncolytic applications and vaccine development.1,2,3 Current approaches to modifying viral surfaces, which are mostly genetics-based, often suffer from attenuation of virus production, infectivity and cellular transduction.4,5 Using chemoselective click chemistry, we have developed a straightforward alternative approach which sidesteps these issues while remaining both highly flexible and accessible.1,2
The goal of this protocol is to demonstrate the effectiveness of using bioorthogonal click chemistry to modify the surface of adenovirus type 5 particles. This two-step process can be used both therapeutically1 or analytically,2,6 as it allows for chemoselective ligation of targeting molecules, dyes or other molecules of interest onto proteins pre-labeled with azide tags. The three major advantages of this method are that (1) metabolic labeling demonstrates little to no impact on viral fitness,1,7 (2) a wide array of effector ligands can be utilized, and (3) it is remarkably fast, reliable and easy to access.1,2,7
In the first step of this procedure, adenovirus particles are produced bearing either azidohomoalanine (Aha, a methionine surrogate) or the unnatural sugar O-linked N-azidoacetylglucosamine (O-GlcNAz), both of which contain the azide (-N3) functional group. After purification of the azide-modified virus particles, an alkyne probe containing the fluorescent TAMRA moiety is ligated in a chemoselective manner to the pre-labeled proteins or glycoproteins. Finally, an SDS-PAGE analysis is performed to demonstrate the successful ligation of the probe onto the viral capsid proteins. Aha incorporation is shown to label all viral capsid proteins (Hexon, Penton and Fiber), while O-GlcNAz incorporation results in labeling of Fiber only.
In this evolving field, multiple methods for azide-alkyne ligation have been successfully developed; however only the two we have found to be most convenient are demonstrated herein &#x2013; strain-promoted azide-alkyne cycloaddition (SPAAC) and copper-catalyzed azide-alkyne cycloaddition (CuAAC) under deoxygenated atmosphere.

Adenovirus particles are engineered to contain either the unnatural amino acid analogue azidohomoalanine or the azido sugar O-GlcNAz. The azide group of each is chemoselectively ligated via "click" chemistry reactions as a means of viral surface modification.

Bioorthogonalクリックケミストリーを介したウイルス表面の化学選択的修飾

The modification of virus particles has received a significant amount of attention for its tremendous potential for impacting gene therapy, oncolytic ...

免疫・感染学

Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile N-(2-alkoxyvinyl)sulfonamides, which react under a variety of conditions to afford useful N- and O-containing compounds. Acid-catalyzed addition of alcohols or thiols to N-(2-alkoxyvinyl)sulfonamide-containing phthalans provides access to ketals and thioketals, respectively. Selective reduction of the vinyl group in N-(2-alkoxyvinyl)sulfonamide-containing phthalans via hydrogenation yields the corresponding phthalan in good yield, whereas reduction with sodium bis(2-methoxyethoxy)aluminumhydride generates a ring-opened phenethylamine analogue. Because the N-(2-alkoxyvinyl)sulfonamide functional group is synthetically versatile, but often hydrolytically unstable, this protocol emphasizes key techniques in preparing, handling, and reacting these pivotal substrates in several useful transformations.

Preparation of N-2-alkoxyvinylsulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Representative experimental procedures for the synthesis of N-(2-alkoxyvinyl)sulfonamides and subsequent conversion to phthalan and phenethylamine derivatives are presented in detail.

Nの準備-(2-alkoxyvinyl) N- トシル-1,2,3-トリアゾールと置換 Phthalans とフェネチルアミンに後続の変換からサルファ剤

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile ...

Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and 1-methyl-4-(1,2,2-triiodovinyl)benzene as representative examples for the practical chemoselective preparation of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes from the chemoselective iodination of terminal alkynes mediated by hypervalent-iodine reagents. The chemoselectivity was confirmed by using p-tolylethyne as a model substrate to screen a variety of iodine sources and/or the hypervalent-iodine reagents. A combination of tetrabutylammonium iodide (TBAI) and (diacetoxyiodo)benzene (PIDA) selectively generates 1-iodoalkynes, while a combination of KI and PIDA generates 1,2-diiodoalkenes. A one-pot synthesis based on both TBAI-PIDA and KI-PIDA yields the corresponding 1,1,2-triiodoalkenes. These protocols were subsequently applied to the synthesis of synthetically important aromatic and aliphatic 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes, which were obtained in good yield with excellent chemoselectivity.

Herein, detailed protocols for the oxidative iodination of terminal alkynes using hypervalent-iodine reagents are presented, which chemoselectively afford 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes.

1-Iodoalkynes、1, 2-Diiodoalkenes、末端アルキンの酸化ヨウ素化に基づく 1,1,2 Triiodoalkenes の化学選択的準備

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and ...

Isolating Free Carbenes, their Mixed Dimers and Organic Radicals

Protocols for the isolation of the commonly employed cyclic (alkyl)(amino) carbene (CAAC) and N-heterocyclic carbene (NHC) are reported. Furthermore, the synthesis of their mixed CAAC&#8211;NHC &#8220;Wanzlick&#8221; dimer and the synthesis of the related stable organic &#8220;olefin&#8221; radical are presented. The main goal of this manuscript is to give a detailed and general protocol for the synthetic chemist of any skill level on how to prepare free heterocyclic carbenes by deprotonation using filter cannulas. Due to the air-sensitivity of the synthesized compounds, all experiments are performed under inert atmosphere using either Schlenk technique or a dinitrogen filled glovebox. Controlling Wanzlick&#8217;s equilibrium (i.e., the dimerization of free carbenes), is a crucial requirement for the application of free carbenes in coordination chemistry or organic synthesis. Thus, we elaborate on the specific electronic and steric requirements favoring the formation of dimers, heterodimers, or monomers. We will show how proton catalysis allows for the formation of dimers, and how the electronic structure of carbenes and their dimers affects the reactivity with either moisture or air. The structural identity of the reported compounds is discussed based on their NMR spectra.

We present protocols for the isolation of stable heterocyclic carbenes. The synthesis of a cyclic (alkyl)(amino) carbene (CAAC) and an N-heterocyclic carbene (NHC) is demonstrated using filter cannulas and Schlenk technique. We furthermore present the synthesis of the related oxygen-sensitive, electron-rich mixed &#8220;Wanzlick dimer&#8221; and the reduced stable organic radical.

無料カルベン、混合二量体および有機ラジカルを分離します。

Protocols for the isolation of the commonly employed cyclic (alkyl)(amino) carbene (CAAC) and N-heterocyclic carbene (NHC) are reported. Furthermore, the ...

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

官能化 Monoorganozinc 臭化物の共役添加による全炭素4級センターの効率的な合成

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products and notably to generate chiral carbon centers. The crucial first step consists in the selective double hydroboration of CO2 catalyzed by an iron hydride complex. The product obtained with this 4 e- reduction is a rare bis(boryl)acetal, compound 1, which is subjected in situ to three different reactions in a second step. The first reaction concerns a condensation reaction with (diisopropyl)phenylamine affording the corresponding imine 2. In the second and third reaction, intermediate 1 reacts with triazol-5-ylidene (Enders&#39; carbene) to afford compounds 3 or 4, depending on the reaction conditions. In both compounds, C-C bonds are formed, and chiral centers are generated from CO2 as the only source of carbon. Compound 4 exhibits two chiral centers obtained in a diastereoselective manner in a formose-type mechanism. We proved that the remaining boryl fragment plays a key role in this unprecedented stereocontrol. The interest of the method stands on the reactive and versatile nature of 1, giving rise to various complex molecules from a single intermediate. The complexity of a two-step method is compensated by the overall short reaction time (2 h for the larger reaction time), and mild reaction conditions (25 &#176;C to 80 &#176;C and 1 to 3 atm of CO2).

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations are conducted in a one-pot two-step procedure for the synthesis of complex molecules. The selective 4 e- reduction of CO2 with a hydroborane reductant affords a reactive and versatile bis(boryl)acetal intermediate which is subsequently involved in condensation reaction or carbene-mediated C-C coupling generation.

多彩なCO2の複雑な製品への変革:ワンポット2段階戦略

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products ...

Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions

The interest on nitrogen-containing heterocycles has expanded rapidly in the synthetic community since they are important motifs for new drugs. Traditionally, they were synthesized through thermal cycloaddition reactions, whereas today, photocatalysis is preferred due to the mild and efficient conditions. With this focus, a new photocatalytic method for the synthesis of nitrogen-containing heterocycles is highly desired. Here, we report a protocol for the biosynthesis of cercosporin, which could function as a metal-free photocatalyst. We then illustrate cercosporin-photocatalyzed protocols for the synthesis of nitrogen-containing heterocycles 1,2,3-thiadiazoles through annulation of azoalkenes with KSCN, and synthesis of 1,4,5,6-tetrahydropyridazines [4+2] through cyclodimerization of azoalkenes under mild conditions, respectively. As a result, there is a new bridge between the microbial fermentation method and organic synthesis in a mild, cost-effective, environmentally friendly and sustainable manner.

New routes for the synthesis of nitrogen-containing heterocycles utilizing cercosporin as a metal-free photocatalyst were developed.

セルコスポリン-フォトカタ分解[4+1]-および[4+2]-軽度の条件下でのアゾアルケンのアゾアルケンのアヌレーション

The interest on nitrogen-containing heterocycles has expanded rapidly in the synthetic community since they are important motifs for new drugs. ...

トリアゾールおよびテトラゾール官能化Zr-MOFの合成と特性評価

Synthesis of Triazole and Tetrazole-Functionalized Zr-Based Metal-Organic Frameworks Through Post-Synthetic Ligand Exchange

Metal-organic frameworks (MOFs) are a class of porous materials that are formed through coordination bonds between metal clusters and organic ligands. Given their coordinative nature, the organic ligands and strut framework can be readily removed from the MOF and/or exchanged with other coordinative molecules. By introducing target ligands to MOF-containing solutions, functionalized MOFs can be obtained with new chemical tags via a process called post-synthetic ligand exchange (PSE). PSE is a straightforward and practical approach that enables the preparation of a wide range of MOFs with new chemical tags via a solid-solution equilibrium process. Furthermore, PSE can be performed at room temperature, allowing the incorporation of thermally unstable ligands into MOFs. In this work, we demonstrate the practicality of PSE by using heterocyclic triazole- and tetrazole-containing ligands to functionalize a Zr-based MOF (UiO-66; UiO = University of Oslo). After digestion, the functionalized MOFs are characterized via various techniques, including powder X-ray diffraction and nuclear magnetic resonance spectroscopy.

著者スポットライト:Functionalizing Metal-Organic Frameworks: Advancements, Challenges, and the Power of Post-Synthetic Ligand Exchange 

Post-synthetic ligand exchange (PSE) is a versatile and powerful tool for installing functional groups into metal-organic frameworks (MOFs). Exposing MOFs to solutions containing triazole- and tetrazole-functionalized ligands can incorporate these heterocyclic moieties into Zr-MOFs through PSE processes.

合成後配位子交換によるトリアゾールおよびテトラゾール官能化Zr系金属有機構造体の合成

Metal-organic frameworks (MOFs) are a class of porous materials that are formed through coordination bonds between metal clusters and organic ligands. ...

中間過酸化物を介した光化学および酸触媒CH機能化による抗ウイルステトラヒドロカルバゾール誘導体の合成（チップ）

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