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.

1. Synthese von Tetrahydrocarbazol Hydroperoxide <ol><li> Die Bildung des Hydroperoxids wird verlangsamt, wenn die tetrahydrocarbazol sehr gefärbt. In diesem Fall reinigt es durch Umkristallisation unter Verwendung von Toluol / Pentan oder durch Säulenchromatographie, um eine farblose Ausgangsmaterial zu erhalten. Zur Reinigung durch Säulenchromatographie Packung eine Säule mit einer unteren Schicht von Kieselgel und einer oberen Schicht aus Aluminiumoxid. Setzen Sie den tetrahydrocarbazol oben auf der Säule und Elution mit Toluol. Alle unerwünschten gelb und schwarz gefärbte Nebenprodukte werden auf der Säule und farblos ist tetrahydrocarbazol eluting adsorbiert. Sofort das Lösungsmittel verdampft und zu speichern, die das gereinigte weiße Produkt unter einer Argonatmosphäre im Dunkeln. </li><li> Man wiegt 1 g tetrahydrocarbazol oder eines substituierten tetrahydrocarbazol (1, synthetisiert gemäß berichteten Verfahren 16) in einen 250 ml-Kolben. 100 ml Toluol zu diesen Kolben. </li><li> Abwiegen Rose Bengal (2mg) hinzugefügt, und es in dem obigen Reaktionsgemisch. </li><li> Fügen Sie einen Rührstab und die Flasche mit Septum zu decken. </li><li> In einer Sauerstoffballon durch die Scheidewand; Das hält einen Überdruck von Sauerstoffatmosphäre auf die Reaktion. </li><li> Bestrahlen der Reaktionsmischung mit einer 23-Watt-Lampe. </li><li> Überprüfen Sie den Fortschritt der Reaktion durch Dünnschichtchromatographie (TLC unter Verwendung eines Gemischs von Hexan / Ethylacetat im Verhältnis 70:30, das R f-Wert der hier beschriebenen Hydroperoxide zwischen 0,2 und 0,3) oder 1 H-NMR von A Probe entnommen (dampfe das Lösungsmittel am Rotationsverdampfer entfernt und der Rückstand in DMSO-d6 auflösen). Reaktionszeiten können in Abhängigkeit von der Lichtquelle und der Reinheit des Ausgangsmaterials variieren kann, wie in Teil 1.1 erwähnt. Generell vollständigen Wandlung der Tetrahydrocarbazolen 1 dauert 3 Stunden. </li><li> Filtern Sie die ausgefallene Feststoff nach der vollständigen Umwandlung des Ausgangsmaterials. Waschen des Feststoff kann mit Pentan, um die meisten entfernen getan werdendas Toluol, ist aber nicht für die Reinigung erforderlich. </li><li> Trocknen unter reduziertem Druck die isolierte Feststoff. </li></ol> ACHTUNG: Obwohl wir nie ein Problem im Umgang mit oder den Umgang mit den in dieser Arbeit beschriebenen Verbindungen erfahren, sollten Vorsichtsmaßnahmen beim Umgang mit Peroxiden genommen werden. Insbesondere sollte sie so weit wie möglich, saubere Peroxide zu erwärmen oder um sie mit Metallen oder Metallsalzen zu mischen aussetzen vermieden werden. Die Durchführung solcher Reaktionen hinter einem Schutzschild wird empfohlen. . 2-Kupplung - Methode A mit 10 Mol-% Trifluoressigsäure in Methanol <ol><li> Wiegen Sie das Hydroperoxid (0,49 mmol, 1,0 Äquiv. Aus Schritt 1) ​​und das gewünschte Anilin Nucleophil (0.49 mmol, 1.0 Äquiv.) In ein 12 ml Fläschchen oder eine geeignete Rundkolben. </li><li> 10 ml MeOH und anschließend 3,74 ul Trifluoressigsäure (TFA, 0.049 mmol, 0.1 Äquiv.) In das Fläschchen oder Rundkolben. </li><li> Schließen Sie den Behälter mit einer Kappe undrührt man bei Raumtemperatur für 4 Stunden. Aufarbeitung Variante A1 (für Produkte, die über den Verlauf der Reaktion ausfallen): </li><li> Filtern des ausgefällten Feststoff, um das gewünschte Produkt zu erhalten. Mit Methanol (3 x 0,5 ml) waschen Sie das Produkt. </li><li> Um eine zweite Produktfraktion erhalten, dampft das Methanol aus dem Filtrat. Löse das Rohprodukt in 5 ml Ethylacetat bei 40 ° C, dann auf Raumtemperatur abkühlen, und fügen Sie 3-5 ml Pentan Das reine Produkt ausfällt. </li><li> Kombinieren der verschiedenen Fraktionen des Produkts und trocknen im Hochvakuum. Aufarbeitung Variante A2 (für Produkte, die nicht ausfallen müssen): </li><li> Dampfe das Lösungsmittel direkt nach der Reaktion durch Verwendung eines Rotationsverdampfers und der Rückstand wird durch Säulenchromatographie wie angegeben (Kieselgel, Hexan / Essigsäureethylester / Triethylamin), um das gewünschte Produkt zu erhalten. </li></ol> 3-Kupplung -. Verfahren BMit Essigsäure <ol><li> Wiegen Sie das Hydroperoxid (0,49 mmol, 1,0 Äquiv. Aus Schritt 1) ​​und das gewünschte Anilin Nucleophil (0.49 mmol, 1.0 Äquiv.) In ein 12 ml Fläschchen oder eine geeignete Rundkolben. </li><li> 10 ml Essigsäure (AcOH), um die in das Fläschchen oder Rundkolben. </li><li> Der Behälter ist mit einem Deckel gegeben und das Reaktionsgemisch bei Raumtemperatur für 4 Stunden. Aufarbeitung Variante B1 (für Produkte, die über den Verlauf der Reaktion ausfallen): </li><li> Filtern des ausgefällten Feststoff, um das gewünschte Produkt zu erhalten. Mit AcOH (3 x 0,5 ml) waschen Sie das Produkt. </li><li> Um eine zweite Fraktion des Produkts zu erhalten, verdampfen die Essigsäure aus dem Filtrat. Löse das Rohprodukt in 5 ml Ethylacetat bei 40 ° C, dann auf Raumtemperatur abkühlen, und fügen Sie 3-5 ml Pentan Das reine Produkt ausfällt. </li><li> Kombinieren der verschiedenen Fraktionen des Produkts und trocknen im Hochvakuum. Aufarbeitung Variante B2 </strong&gt; (für Produkte, die nicht ausfallen müssen): </li><li> Dampfe das Lösungsmittel direkt nach der Reaktion durch Verwendung eines Rotationsverdampfers und der Rückstand wird durch Säulenchromatographie wie angegeben (Kieselgel, Hexan / Essigsäureethylester / Triethylamin), um das gewünschte Produkt zu erhalten. </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>

Die Autoren haben nichts zu offenbaren.

Zusammenfassend konnten wir zeigen, dass eine CH-Bindung in Tetrahydrocarbazolen bequem funktionalisiert werden, um CN-Kupplungsprodukte in einem zweistufigen Verfahren zu erzeugen. Der erste Schritt ist eine bekannte photokatalysierte Oxidation tetrahydrocarbazol (1) oder seinen Derivaten mit elementarem Sauerstoff 17,19, was eine 2-hydroperoxid. Wenn in Toluol durchgeführt wird, das Hydroperoxid Produkte aus und können in geeigneter Weise durc...

Die direkte Funktionalisierung von CH-Bindungen ist eine wichtige und langjährige Ziel in der organischen Chemie ein. Solche Transformationen können, um durch Einsparung von Syntheseschritten, Zeit und Material im Vergleich zu herkömmlichen Methoden, die die Einführung und Entfernung zu aktivieren oder zu dirigierende Gruppen erfordern rationalisieren sehr mächtig sein. Daher ist auch die Funktionalisierung von CH-Bindungen attraktiv für grüne Chemie 2. Unter oxidativen Bedingungen, zwei CH-Bindungen oder eine CH-und einem Heteroatom-Bindung für CC und C-Heteroatom-Bindungen, die jeweils (1) 3-9 umgewandelt werden. Oft sind diese oxidative Kupplung erfordern synthetische Antioxidantien, teure Katalysatoren oder hohen Temperaturen. Daher sind viele Versuche unternommen, um Methoden, die billige Katalysatoren, gutartige Bedingungen und Sauerstoff oder Luft als Oxidationsmittel verwenden 10 zu entwickeln. <img alt="Figur 1" fo:content-width = &quot;5in&quot; src = &quot;/ files/ftp_upload/51504/51504fig1highres.jpg&quot; width = &quot;500&quot; /&gt; Abbildung 1. Oxidative Kupplungsreaktionen. <a href="https://www.jove.com/files/ftp_upload/51504/51504fig1highres.jpg" target="_blank">Bitte klicken Sie hier, um eine größere Version dieser Figur zu sehen.</a> Viele organische Verbindungen langsam mit Sauerstoff aus der Luft in Autoxidationsreaktionen die CH-Bindungen durch die effektive Einsetzen O 2, bilden eine Einheit Hydroperoxid 11,12 funktionalisieren kann. Autoxidation Prozesse im industriellen Maßstab erzeugt sauerstoffhaltigen Verbindungen aus Kohlenwasserstoff-Ausgangsmaterialien verwendet, aber Autoxidation ist auch ein unerwünschter Prozess, wenn es um die Zersetzung des wertvollen Verbindungen oder Materialien führt. In einigen Fällen, beispielsweise Diethylether, Hydroperoxide in Luft gebildet werden, können auch explosiv sein. Kürzlich entdeckten wir eine Reaktion, die eine Autoxidation nutzt, um eine neue CC-Bindung von CH-Bindungen, ohne der Notwendigkeit einer redox-aktive Katalysator 13,14 bilden </sup&gt;. Einfaches Verrühren der Substrate unter Sauerstoff in Gegenwart eines Säurekatalysators zur Bildung der neuen Produkte. Schlüssel für die Reaktion ist die leichte Bildung von Zwischen Hydroperoxide, die mit dem zweiten Substrat durch Säure-Katalyse 15 substituiert sind. Die Reaktion ist jedoch beschränkt auf Xanthen und einige verwandte Verbindungen, die sich leicht unter einer Atmosphäre von Sauerstoff und die Produkte oxidiert werden bisher nicht gefunden Anwendungen. Trotzdem durch diese Entdeckung inspiriert, bezogen oxidative Kupplung Methode, die das Prinzip der CH-Funktionalisierung nutzt über Zwischen Peroxide (CHIPS), pharmazeutisch wirksame Indol-Derivate synthetisieren 16 entwickelten wir. Indole, Tetrahydrocarbazolen insbesondere 1, können leicht oxidiert werden, um 2 in Gegenwart von Singulett-Sauerstoff 17-19, die Verwendung eines Sensibilisators für sichtbares Licht und 20 erzeugt werden kann, Hydroperoxide. Ein hydroperoxide Einheit kann im Prinzip wirken als Abgangsgruppe, wenn durch Säurekatalyse aktiviert und damit für die Einführung eines Nucleophils 21,22. Hydroperoxide sind auch bekannt, unterzogen säurekatalysierte Umlagerung Reaktionen im industriellen Synthese von Phenol aus Cumol, dem Hock-Verfahren 23 verwendet. Durch sorgfältige Optimierung Studien haben wir Bedingungen, um die gewünschte Substitutionsreaktion mit N-Nucleophilen wie Aniline 3 über die unerwünschten Zersetzungswege durch Umlagerung 16 begünstigen finden konnte. Hier beschreiben wir dieses Zwei-Schritt-Verfahren im Detail CHIPS mit nur sichtbares Licht, einen Sensibilisator, Sauerstoff und Säure. Unter den ausgewählten Produkte sind Indolderivate 4, die eine hohe antivirale Aktivität zeigen oder Hemmung des vaskulären endothelialen Wachstumsfaktor (VGF), die für die Tumortherapie 24-26 wichtig sein kann.

<table border="0" cellpadding="0" cellspacing="0" width="797">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">1,2,3,4-Tetrahydrocarbazole</td>
			<td style="width:139px;">Sigma Aldrich</td>
			<td style="width:151px;">T12408</td>
			<td style="width:291px;">If coloured, purification may be necessary. See Protocol 1.1</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Methanol</td>
			<td style="width:139px;">Sigma Aldrich</td>
			<td>322415</td>
			<td>99.8% purity</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">4-Nitroaniline</td>
			<td style="width:139px;">Acros Organics</td>
			<td>128371000</td>
			<td>99% purity</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Trifluoroacetic acid</td>
			<td style="width:139px;">Sigma Aldrich</td>
			<td>T6508</td>
			<td>99% purity</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Acetic acid</td>
			<td style="width:139px;">J. T. Baker</td>
			<td style="width:151px;">JTB RS 426960101</td>
			<td>99-100% purity</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Aniline</td>
			<td style="width:139px;">Merck</td>
			<td>8222560100</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">4-Aminobenzonitrile</td>
			<td style="width:139px;">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.

Synthese von 1 - (5-nitroindolin-1-yl) -2,3,4,9-tetrahydro-1H-carbazol (4a): Nach Verfahren A, R f = 0,63 (Hexan / Ethylacetat 70:30) synthetisiert. Reinigung: Reinigen Sie das Produkt nach Methode A, Aufarbeitung Variante A1 (Schritte 2.4, 2.5, 2.6). Orangefarbenen Feststoff, Ausbeute: 95%. 1 H-NMR (500 MHz, DMSO-d6): δ 10.90 (s, 1H), ...

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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.

Synthese von Antivirale Tetrahydrocarbazolderivate durch photochemische und Säure-katalysierten CH-Funktionalisierung über Zwischen Peroxide (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 ...

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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

13.7K Aufrufe.  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.

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

Anticancer Metal Complexes: Synthesis and Cytotoxicity Evaluation by the MTT Assay

Titanium (IV) and vanadium (V) complexes are highly potent anticancer agents. A challenge in their synthesis refers to their hydrolytic instability; therefore their preparation should be conducted under an inert atmosphere. Evaluation of the anticancer activity of these complexes can be achieved by the MTT assay.
The MTT assay is a colorimetric viability assay based on enzymatic reduction of the MTT molecule to formazan when it is exposed to viable cells. The outcome of the reduction is a color change of the MTT molecule. Absorbance measurements relative to a control determine the percentage of remaining viable cancer cells following their treatment with varying concentrations of a tested compound, which is translated to the compound anticancer activity and its IC50 values. The MTT assay is widely common in cytotoxicity studies due to its accuracy, rapidity, and relative simplicity.
Herein we present a detailed protocol for the synthesis of air sensitive metal based drugs and cell viability measurements, including preparation of the cell plates, incubation of the compounds with the cells, viability measurements using the MTT assay, and determination of IC50 values.

A method for synthesis of air-sensitive titanium and vanadium anticancer agents is described, along with the evaluation of their cytotoxic activity towards human cancer cell line by the MTT Assay.

Anti-Krebs-Metall-Komplexe: Synthese und Zytotoxizität Bewertung durch die MTT-Assay

Titanium (IV) and vanadium (V) complexes are highly potent anticancer agents. A challenge in their synthesis refers to their hydrolytic instability; ...

Forschung

Chemie

Synthesis, Characterization, and Functionalization of Hybrid Au/CdS and Au/ZnS Core/Shell Nanoparticles

Plasmonic nanoparticles are an attractive material for light harvesting applications due to their easily modified surface, high surface area and large extinction coefficients which can be tuned across the visible spectrum. Research into the plasmonic enhancement of optical transitions has become popular, due to the possibility of altering and in some cases improving photo-absorption or emission properties of nearby chromophores such as molecular dyes or quantum dots. The electric field of the plasmon can couple with the excitation dipole of a chromophore, perturbing the electronic states involved in the transition and leading to increased absorption and emission rates. These enhancements can also be negated at close distances by energy transfer mechanism, making the spatial arrangement of the two species critical. Ultimately, enhancement of light harvesting efficiency in plasmonic solar cells could lead to thinner and, therefore, lower cost devices. The development of hybrid core/shell particles could offer a solution to this issue. The addition of a dielectric spacer between a gold nanoparticles and a chromophore is the proposed method to control the exciton plasmon coupling strength and thereby balance losses with the plasmonic gains. A detailed procedure for the coating of gold nanoparticles with CdS and ZnS semiconductor shells is presented. The nanoparticles show high uniformity with size control in both the core gold particles and shell species allowing for a more accurate investigation into the plasmonic enhancement of external chromophores.

The synthesis of uniform gold nanoparticles coated with semiconductor shells of CdS or ZnS is performed. The semiconductor coating is conducted by first depositing a silver sulfide shell and exchanging the silver cations for zinc or cadmium cations.

Synthese, Charakterisierung und Funktionalisierung von Hybrid Au / CdS und Au / ZnS Kern / Schale-Nanopartikel

Plasmonic nanoparticles are an attractive material for light harvesting applications due to their easily modified surface, high surface area and large ...

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.

Protokoll für die Synthese von<em&gt; Ortho</em&gt; -trifluoromethoxylated Anilin-Derivate

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

Functionalization of Single-walled Carbon Nanotubes with Thermo-reversible Block Copolymers and Characterization by Small-angle Neutron Scattering

We demonstrate a protocol for single-walled carbon nanotube functionalization using thermo-sensitive PEO-PPO-PEO triblock copolymers in an aqueous solution. In a carbon nanotube/PEO105-PPO70-PEO105 (poloxamer 407) aqueous solution, the amphiphilic poloxamer 407 adsorbs onto the carbon nanotube surfaces and self-assembles into continuous layers, driven by intermolecular interactions between constituent molecules. The addition of 5-methylsalicylic acid changes the self-assembled structure from spherical-micellar to a cylindrical morphology. The fabricated poloxamer 407/carbon nanotube hybrid particles exhibit thermo-responsive structural features so that the density and thickness of poloxamer 407 layers are also reversibly controllable by varying temperature. The detailed structural properties of the poloxamer 407/carbon nanotube particles in suspension can be characterized by small-angle neutron scattering experiments and model fit analyses. The distinct curve shapes of the scattering intensities depending on temperature control or addition of aromatic additives are well described by a modified core-shell cylinder model consisting of a carbon nanotube core cylinder, a hydrophobic shell, and a hydrated polymer layer. This method can provide a simple but efficient way for the fabrication and in-situ characterization of carbon nanotube-based nano particles with a structure-tunable encapsulation.

A method for the functionalization of carbon nanotubes with structure-tunable polymeric encapsulation layers and structural characterization using small-angle neutron scattering is presented.

Funktionalisierung von einwandigen Kohlenstoff-Nanoröhrchen mit Thermo-reversible Blockcopolymere und Charakterisierung durch Kleinwinkelneutronenstreuung

We demonstrate a protocol for single-walled carbon nanotube functionalization using thermo-sensitive PEO-PPO-PEO triblock copolymers in an aqueous ...

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the development of antibody drug conjugates (ADCs) and nanomedicine, fluorescent microscopy and systems chemistry. For many of these applications, specificity of the bioconjugation method used is of prime concern. The Michael addition of maleimides with cysteine(s) on the target proteins is highly selective and proceeds rapidly under mild conditions, making it one of the most popular methods for protein bioconjugation.
We demonstrate here the modification of the only surface-accessible cysteine residue on yeast cytochrome c with a ruthenium(II) bisterpyridine maleimide. The protein bioconjugation is verified by gel electrophoresis and purified by aqueous-based fast protein liquid chromatography in 27% yield of isolated protein material. Structural characterization with MALDI-TOF MS and UV-Vis is then used to verify that the bioconjugation is successful. The protocol shown here is easily applicable to other cysteine - maleimide coupling of proteins to other proteins, dyes, drugs or polymers.

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

This protocol details the important steps required for the bioconjugation of a cysteine containing protein to a maleimide, including reagent purification, reaction conditions, bioconjugate purification and bioconjugate characterization.

Synthese von Protein Biokonjugate<em&gt; über</em&gt; Cystein-maleimid Chemie

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the ...

Synthesis of Substrate-Bound Au Nanowires Via an Active Surface Growth Mechanism

Advancing synthetic capabilities is important for the development of nanoscience and nanotechnology. The synthesis of nanowires has always been a challenge, as it requires asymmetric growth of symmetric crystals. Here, we report a distinctive synthesis of substrate-bound Au nanowires. This template-free synthesis employs thiolated ligands and substrate adsorption to achieve the continuous asymmetric deposition of Au in solution at ambient conditions. The thiolated ligand prevented the Au deposition on the exposed surface of the seeds, so the Au deposition only occurs at the interface between the Au seeds and the substrate. The side of the newly deposited Au nanowires is immediately covered with the thiolated ligand, while the bottom facing the substrate remains ligand-free and active for the next round of Au deposition. We further demonstrate that this Au nanowire growth can be induced on various substrates, and different thiolated ligands can be used to regulate the surface chemistry of the nanowires. The diameter of the nanowires can also be controlled with mixed ligands, in which another &#34;bad&#34; ligand could turn on the lateral growth. With the understanding of the mechanism, Au nanowire-based nanostructures can be designed and synthesized.

We report a solution-based method to synthesize substrate-bound Au nanowires. By tuning the molecular ligands used during the synthesis, the Au nanowires can be grown from various substrates with different surface properties. Au nanowire-based nanostructures can also be synthesized by adjusting the reaction parameters.

Synthese von Substrat-gebundenen Au Nanodrähten über eine aktive Oberfläche Wachstumsmechanismus

Advancing synthetic capabilities is important for the development of nanoscience and nanotechnology. The synthesis of nanowires has always been a ...

Regioselective O-Glycosylation of Nucleosides via the Temporary 2',3'-Diol Protection by a Boronic Ester for the Synthesis of Disaccharide Nucleosides

Disaccharide nucleosides, which consist of disaccharide and nucleobase moieties, have been known as a valuable group of natural products having multifarious bioactivities. Although chemical O-glycosylation is a commonly beneficial strategy to synthesize disaccharide nucleosides, the preparation of substrates such as glycosyl donors and acceptors requires&#160;tedious protecting&#160;group manipulations and a purification at each synthetic step. Meanwhile, several research groups have reported that boronic and borinic esters serve as a protecting or activating group of carbohydrate derivatives to achieve the regio- and/or stereoselective acylation, alkylation, silylation, and glycosylation. In this article, we demonstrate the procedure for the regioselective O-glycosylation of unprotected ribonucleosides utilizing boronic acid. The esterification of 2&#39;,3&#39;-diol of ribonucleosides with boronic acid makes the temporary protection of diol, and, following O-glycosylation with a glycosyl donor in the presence of p-toluenesulfenyl chloride and silver triflate, permits the regioselective reaction of the 5&#39;-hydroxyl group to afford the disaccharide nucleosides. This method could be applied to various nucleosides, such as guanosine, adenosine, cytidine, uridine, 5-metyluridine, and 5-fluorouridine. This article and the accompanying video represent&#160;useful (visual) information for the O-glycosylation of unprotected nucleosides and their analogs for the synthesis of not only disaccharide nucleosides, but also a variety of biologically relevant derivatives.

Regioselective O-Glycosylation of Nucleosides via the Temporary 2&#039;,3&#039;-Diol Protection by a Boronic Ester for the Synthesis of Disaccharide Nucleosides

Here, we present protocols for the synthesis of disaccharide nucleosides by the regioselective O-glycosylation of ribonucleosides via a temporary protection of their 2&#39;,3&#39;-diol moieties utilizing a cyclic boronic ester. This method applies to several unprotected nucleosides such as adenosine, guanosine, cytidine, uridine, 5-methyluridine, and 5-fluorouridine to give corresponding disaccharide nucleosides.

Regioselective O- Glykosylierung Nukleoside über die temporäre 2', 3'-Diol Schutz durch eine Boronic Ester für die Synthese von Disaccharid Nukleosiden

Disaccharide nucleosides, which consist of disaccharide and nucleobase moieties, have been known as a valuable group of natural products having ...

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. Recently, we have developed a two-step strategy for ketone enolate umpolung that has enabled the development of methods for chlorination, azidation, and amination using azoles. In addition, we have developed C-C bond&#8211;forming arylation and allylation reactions. At the heart of these methods is the preparation of the intermediate and highly reactive enolonium species prior to addition of a reactive nucleophile. This strategy is thus reminiscent of the preparation and use of metal enolates in classical synthetic chemistry. This strategy allows the use of nucleophiles that would otherwise be incompatible with the strongly oxidizing hypervalent iodine reagents. In this paper we present a detailed protocol for chlorination, azidation, N-heteroarylation, arylation, and allylation. The products include motifs prevalent in medicinally active products. This article will greatly assist others in using these methods.

A two step one-pot protocol for the umpolung of ketone enolates to enolonium species and addition of a nucleophile to the &#945;-position is described. Nucleophiles include chloride, azide, azoles, allyl-silanes, and aromatic compounds.

Ein zweistufiges Protokoll für die Umpolung Funktionalisierung von Ketonen über Enolonium Arten

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. ...

Surface Functionalization of Metal-Organic Frameworks for Improved Moisture Resistance

Metal-organic frameworks (MOFs) are a class of porous inorganic materials with promising properties in gas storage and separation, catalysis and sensing. However, the main issue limiting their applicability is their poor stability in humid conditions. The common methods to overcome this problem involve the formation of strong metal-linker bonds by using highly charged metals, which is limited to a number of structures, the introduction of alkylic groups to the framework by post-synthetic modification (PSM) or chemical vapour deposition (CVD) to enhance overall hydrophobicity of the framework. These last two usually provoke a drastic reduction of the porosity of the material. These strategies do not permit to exploit the properties of the MOF already available and it is imperative to find new methods to enhance the stability of MOFs in water while keeping their properties intact. Herein, we report a novel method to enhance the water stability of MOF crystals featuring Cu2(O2C)4&#160;paddle-wheel units, such as HKUST (where HKUST stands for Hong Kong University of Science &#38; Technology), with the catechols functionalized with alkyl and fluoro-alkyl chains. By taking advantage of the unsaturated metal sites and the catalytic catecholase-like activity of CuII ions, we are able to create robust hydrophobic coatings through the oxidation and subsequent polymerization of the catechol units on the surface of the crystals under anaerobic and water-free conditions without disrupting the underlying structure of the framework. This approach not only affords the material with improved water stability but also provides control over the function of the protective coating, which enables the development of functional coatings for the adsorption and separations of volatile organic compounds. We are confident that this approach could also be extended to other unstable MOFs featuring open metal sites.

Robust functional catechol coatings were produced in one step by direct reaction of the material known as HKUST with synthetic catechols under anaerobic conditions. The formation of homogeneous coatings surrounding the entire crystal is ascribed to the biomimetic catalytic activity of Cu(II) dimers on the external surface of the crystals.

Oberfläche Funktionalisierung der Metall-organischen Frameworks für verbesserte Feuchtigkeitsbeständigkeit

Metal-organic frameworks (MOFs) are a class of porous inorganic materials with promising properties in gas storage and separation, catalysis and sensing. ...

Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the reaction is commonly performed using chlorinated or amide solvent systems, which are hazardous to human health and the environment. Our methodology utilizes acetonitrile as a greener and less hazardous solvent system. This protocol exhibits rates and yields that are comparable to traditional solvent systems and employs an extraction and wash sequence that eliminates the need for the purification of the ester product via column chromatography. This general method can be used to couple a variety of carboxylic acids with 1&#176; and 2&#176; aliphatic alcohols, benzylic and allylic alcohols, and phenols to obtain pure esters in high yields. The goal of the protocol detailed here is to provide a greener alternative to a common esterification reaction, which could serve useful for ester synthesis in both academic and industrial applications.

A modified Steglich esterification reaction was used to synthesize a small library of ester derivatives with primary and secondary alcohols. The methodology uses a non-halogenated and greener solvent, acetonitrile, and enables product isolation in high yields without the need for chromatographic purification.

Synthese von Estern über ein grüner Steglich-Veresterung in Acetonitril

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the ...