Name: Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS) (Video) | JoVE Journal
Uploaded: 2014-06-20T14:00:00.000+00:00
Duration: 6 min 34 s
Description: Learn a two-step photochemical synthesis method for antiviral tetrahydrocarbazole derivatives using visible light, oxygen, and Brønsted acid catalysis. This environmentally friendly approach replaces expensive metal catalysts.

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5 minutes

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. Synthesis of Tetrahydrocarbazole Hydroperoxides
<ol>
	<li>The formation of the hydroperoxide is slowed down if the tetrahydrocarbazole is very colored. In this case, purify it by recrystallization using toluene/pentane or by column chromatography to get a colorless starting material. For purification by column chromatography, pack a column with a lower layer of silica gel and an upper layer of alumina. Put the tetrahydrocarbazole on top of the column and elute with toluene. All the unwanted yellow and black colored byproducts are adsorbed on the column and colorless tetrahydrocarbazole is eluting. Immediately evaporate the solvent and store the purified white product under an atmosphere of argon in the dark.</li>
	<li>Weigh out 1 g of tetrahydrocarbazole or of a substituted tetrahydrocarbazole (1, synthesized according to reported methods16) into a 250 ml flask. Add 100 ml toluene to this flask.</li>
	<li>Weigh out Rose Bengal (2 mg) and add it into the above reaction mixture.</li>
	<li>Add a stir bar and cover the flask with septa.</li>
	<li>Add an oxygen balloon through the septum; this keeps a positive pressure of oxygen atmosphere on the reaction.</li>
	<li>Irradiate the reaction mixture with a 23 watt lamp.</li>
	<li>Check the progress of the reaction by thin-layer chromatography (TLC, using a mixture of hexane/ethyl acetate in 70:30 ratio; the Rf value of the hydroperoxides described herein is between 0.2 and 0.3) or by 1H NMR from a sample taken (evaporate the solvent on a rotary evaporator and dissolve the residue in DMSO-d6). Reaction times can vary depending on the light source and the purity of the starting material, as mentioned in part 1.1. Generally, full conversion of tetrahydrocarbazoles 1 takes 3 hr.</li>
	<li>Filter the precipitated solid after full conversion of starting material. Washing of the solid can be done with pentane in order to remove most of the toluene, but is not necessary for purification.</li>
	<li>Dry the isolated solid under reduced pressure.</li>
</ol>
CAUTION: Although we never experienced any problem in working with or handling the compounds described in this work, precautions should be taken when working with peroxides. In particular, it should be avoided as much as possible to expose neat peroxides to heat or to mix them with metals or metal salts. Performing such reactions behind a blast shield is recommended.
2. Coupling Reaction &#8211; Method A Using 10 mol% Trifluoroacetic Acid in Methanol
<ol>
	<li>Weigh out the hydroperoxide (0.49 mmol, 1.0 equiv. from step 1) and the desired aniline nucleophile (0.49 mmol, 1.0 equiv.) into a 12 ml vial or a suitable round bottom flask.</li>
	<li>Add 10 ml MeOH and subsequently 3.74 &#181;l trifluoroacetic acid (TFA, 0.049 mmol, 0.1 equiv.) to the vial or round bottom flask.</li>
	<li>Close the container with a cap and stir the reaction mixture at room temperature for 4 hr. 
	Workup variant A1 (for products which precipitate over the course of the reaction):</li>
	<li>Filter the precipitated solid to get the desired product. Wash the product with methanol (3 x 0.5 ml).</li>
	<li>To obtain a second fraction of product, evaporate the methanol from the filtrate. Dissolve the crude product in 5 ml of ethyl acetate at 40 &#176;C, then cool to room temperature and add 3-5 ml of pentane The pure product precipitates.</li>
	<li>Combine the different fractions of the product and dry them under high vacuum. 
	Workup variant A2 (for products which do not precipitate):</li>
	<li>Evaporate the solvent directly after the reaction by using a rotary evaporator and purify the residue by column chromatography as specified (silica gel, hexane / ethyl acetate / triethylamine) to obtain the desired product.</li>
</ol>
3. Coupling Reaction &#8211; Method B Using&#160;Acetic Acid&#160;
<ol>
	<li>Weigh out the hydroperoxide (0.49 mmol, 1.0 equiv. from step 1) and the desired aniline nucleophile (0.49 mmol, 1.0 equiv.) into a 12 ml vial or a suitable round bottom flask.</li>
	<li>Add 10 ml acetic acid (AcOH) to the to the vial or round bottom flask.</li>
	<li>Close the container with a cap and stir the reaction mixture at room temperature for 4 hr. 
	Workup variant B1 (for products which precipitate over the course of the reaction):</li>
	<li>Filter the precipitated solid to get the desired product. Wash the product with AcOH (3 x 0.5 ml).</li>
	<li>To obtain a second fraction of product, evaporate the acetic acid from the filtrate. &#160;Dissolve the crude product in 5 ml of ethyl acetate at 40 &#176;C, then cool to room temperature and add 3-5 ml of pentane The pure product precipitates.</li>
	<li>Combine the different fractions of the product and dry them under high vacuum. 
	Workup variant B2 (for products which do not precipitate):</li>
	<li>Evaporate the solvent directly after the reaction by using a rotary evaporator and purify the residue by column chromatography as specified (silica gel, hexane / ethyl acetate / triethylamine) to obtain the desired product.</li>
</ol>

<ol><li>Bergman, R. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Organometallic+chemistry+-+C-H+activation%5BTitle%5D)+AND+%22Nature%22%5BJournal%5D)">Organometallic chemistry - C-H activation.</a> Nature. 446, 391-393 (2007).</li>
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<li>Collet, F., Dodd, R. H., Dauban, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Catalytic+C%E2%80%93H+amination%3A+recent+progress+and+future+directions%5BTitle%5D)+AND+%22Chem.+Commun%22%5BJournal%5D)">Catalytic C–H amination: recent progress and future directions.</a> Chem. Commun. 34, 5061-5064 (2009).</li>
<li>Rohlmann, R., Mancheño, O. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Metal-Free+Oxidative+C%28sp3%29-H+Bond+Couplings+as+Valuable+Synthetic+Tools+for+C-C+Bond+Formations%5BTitle%5D)+AND+%22Synlett%22%5BJournal%5D)">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/pubmed?term=((Copper-Catalyzed+Aerobic+Oxidative+C-H+Functionalizations%3A+Trends+and+Mechanistic+Insights%5BTitle%5D)+AND+%22Angew.+Chem.+Int.+Ed%22%5BJournal%5D)">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/pubmed?term=((Autoxidation+of+Hydrocarbons%3A+From+Chemistry+to+Catalysis%5BTitle%5D)+AND+%22Top.+Catal%22%5BJournal%5D)">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/pubmed?term=((Auto-oxidation%5BTitle%5D)+AND+%22Chem.+Rev%22%5BJournal%5D)">Auto-oxidation.</a> Chem. Rev. 10, 295-364 (1932).</li>
<li>Pintér, Á, Sud, A., Sureshkumar, D., Klussmann, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Autoxidative+Carbon-Carbon+Bond+Formation+from+Carbon-Hydrogen+Bonds%5BTitle%5D)+AND+%22Angew.+Chem.+Int.+Ed%22%5BJournal%5D)">Autoxidative Carbon-Carbon Bond Formation from Carbon-Hydrogen Bonds.</a> Angew. Chem. Int. Ed. 49, 5004-5007 (2010).</li>
<li>Pintér, Á, Klussmann, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Sulfonic+Acid+Catalyzed+Autoxidative+Carbon-Carbon+Coupling+Reaction+under+Elevated+Partial+Pressure+of+Oxygen%5BTitle%5D)+AND+%22Adv.+Synth.+Catal%22%5BJournal%5D)">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/pubmed?term=((Synergistic+Effect+of+Ketone+and+Hydroperoxide+in+Br%C3%B8nsted+Acid+Catalyzed+Oxidative+Coupling+Reactions%5BTitle%5D)+AND+%22Angew.+Chem.+Int.+Ed%22%5BJournal%5D)">Synergistic Effect of Ketone and Hydroperoxide in Brønsted 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/pubmed?term=((Aerobic+C-H+Amination+of+Tetrahydrocarbazole+Derivatives+via+Photochemically+Generated+Hydroperoxides%5BTitle%5D)+AND+%22Org.+Biomol.+Chem%22%5BJournal%5D)">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/pubmed?term=((Tetrahydrocarbazole+Peroxides%5BTitle%5D)+AND+%22Nature%22%5BJournal%5D)">Tetrahydrocarbazole Peroxides.</a> Nature. 164, 362-363 (1949).</li>
<li>Iesce, M. R., Cermola, F., Temussi, F. Photooxygenation of Heterocycles. Curr. Org. Chem. 9, 109-139 (2005).</li>
<li>Mateo, C. A., Urrutia, A., Rodríguez, J. G., Fonseca, I., Cano, F. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Photooxygenation+of+1%2C2%2C3%2C4-Tetrahydrocarbazole%3A+Synthesis+of+Spiro%5Bcyclopentane-1%2C2%27-indolin-3%27-one%5D%5BTitle%5D)+AND+%22J.+Org.+Chem%22%5BJournal%5D)">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/pubmed?term=((Singlet+oxygen+in+organic+synthesis%5BTitle%5D)+AND+%22Tetrahedron%22%5BJournal%5D)">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/pubmed?term=((Electrophilic+Aromatic+Alkylation+by+Hydroperoxides.+Competition+between+Ionic+and+Radical+Mechanisms+with+Phenols%5BTitle%5D)+AND+%22J.+Org.+Chem%22%5BJournal%5D)">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/pubmed?term=((Selectivity+in+Lewis+acid-mediated+fragmentations+of+peroxides+and+ozonides%3A+application+to+the+synthesis+of+alkenes%2C+homoallyl+ethers%2C+and+1%2C2-dioxolanes%5BTitle%5D)+AND+%22J.+Chem.+Soc.%2C+Perkin+Trans%22%5BJournal%5D)">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/pubmed?term=((Autoxydation+von+Kohlenwasserstoffen+IX.+Mitteil.%3A+%C3%9Cber+Peroxyde+von+Benzol-Derivaten%5BTitle%5D)+AND+%22Ber%22%5BJournal%5D)">Autoxydation von Kohlenwasserstoffen IX. Mitteil.: Über 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. Tetrahydrocarbazole derivatives and their pharmaceutical use. USA patent WO. 2004/110999 A1. , (2004).</li>
<li>Gudmundsson, K. S. HCV Inhibitors. USA patent WO 2006/ 121467 A2. , (2006).</li>
<li>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).</li>
</ol>

The authors have nothing to disclose.

In summary, we could demonstrate that a C-H bond in tetrahydrocarbazoles can be conveniently functionalized to generate C-N-coupling products in a two-step procedure.
The first step is a well-known photocatalyzed oxidation of tetrahydrocarbazole (1) or its derivatives with elemental oxygen17,19, giving a hydroperoxide 2. If performed in toluene, the hydroperoxide products precipitate and can be conveniently isolated by filtration. Further purificati...

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry1. 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 chemistry2. 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 (Figure 1)3-9. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Therefore, many attempts are made to develop methods that use cheap catalysts, benign conditions and oxygen or air as terminal oxidant10.
<img alt="Catalytic hydrogen transfer process; R-H + H-R' to R-R'; chemical reaction diagram." fo:content-width="5in" src="/files/ftp_upload/51504/51504fig1highres.jpg" width="500" data-altupdatedat="1787630408000" data-alt="Figure 1"> 
Figure 1. Oxidative coupling reactions. <a href="https://www.jove.com/files/ftp_upload/51504/51504fig1highres.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Many organic compounds react slowly with oxygen from air in autoxidation reactions which can functionalize C-H bonds by effectively inserting O2, forming a hydroperoxide moiety11,12. Autoxidation processes are used on industrial scale to generated oxygenated compounds from hydrocarbon feedstocks, but autoxidation is also an unwanted process if it leads to decomposition of valuable compounds or materials. In some cases, for example diethyl ether, hydroperoxides formed in air can also be explosive. Recently, we discovered a reaction that utilizes an autoxidation to form a new C-C bond from C-H bonds without need of a redox-active catalyst13,14. Simply stirring the substrates under oxygen in the presence of an acid catalyst leads to the formation of the new products. Key to the reaction is the facile formation of intermediate hydroperoxides, which are substituted with the second substrate by acid catalysis15. The reaction, however, is restricted to xanthene and a few related compounds that are easily oxidized under an atmosphere of oxygen and the products have so far not found applications. Nevertheless inspired by this discovery, we developed a related oxidative coupling method that utilizes the principle of C-H functionalization via Intermediate PeroxideS (CHIPS) to synthesize pharmaceutically active indole derivatives16.
Indoles, especially tetrahydrocarbazoles 1, can be easily oxidized to hydroperoxides 2 in the presence of singlet oxygen17-19, which can be generated using a sensitizer and visible light20. A hydroperoxide moiety can in principle act as a leaving group if activated by acid catalysis and allow for the introduction of a nucleophile21,22. Hydroperoxides are also known to undergo acid catalyzed rearrangement reactions as utilized in the industrial synthesis of phenol from cumene, the Hock process23. By careful optimization studies, we could find conditions to favor the desired substitution reaction with N-nucleophiles like anilines 3 over the unwanted decomposition pathways by rearrangement16. Here, we describe this two-step CHIPS procedure in detail, using only visible light, a sensitizer, oxygen and acid. Amongst the selected products are indole derivatives 4, which show high antiviral activity or inhibit the vascular endothelial growth factor (VGF), which can be important for tumor therapy24-26.

<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)

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.

Synthesis of 1-(5-nitroindolin-1-yl)-2,3,4,9-tetrahydro-1H-carbazole (4a):
Synthesized according to Method A, Rf = 0.63 (hexane/ethyl acetate 70:30).
Purification: Purify the product by using Method A, workup variant A1 (steps 2.4, 2.5, 2.6). Orange solid, Yield: 95%.
1H NMR (500 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.97 (dd, <em...

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.

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 ...

The overall goal of the following experiment is to show the usefulness of a new concept called chips, using only visible light oxygen and catalysis to functionalize carbon hydrogen bonds via intermediate high hydro peroxides. This is achieved by irradiating a solution of a tetro hydro Carole, with visible light in the presence of catalytic amounts of a photo initiator to form a hydroperoxide by reaction with singlet oxygen as a second step, the hydroperoxide is treated with catalytic amounts of an acid, which facilitates the substitution of the hydro peroxide group by an added nucleo file. Next chromatography of the reaction mixture is needed, or as is often the case, simply filtration of the precipitate in order to isolate the pure product.The results show how pharmaceutically active compounds can be synthesized by the concept of chips requiring only catalysts, visible light and oxygen. The main advantage of this technique over existing methods requiring expensive metal catalysts are statue metric. More sub synthetic oxygen is that we use environmentally friendly oxygen and visible light.Although we never experienced any problems with these compounds, don't forget that peroxides are potentially explosive. Take precautions, for example, never hit the need peroxides or never expose them to pure asset catalysts. Prior to starting this procedure, purify the desired tetra hydro Carole if it is colored using rech crystallization or column chromatography to obtain a colorless starting material, weigh out one gram of the tetra hydro Carole into a 250 milliliter flask.Then add 100 milliliters of toluene to the flask. Add two milligrams of rose bengal to the reaction mixture. After adding a stir bar, cover the flask with a septum.Next, insert an oxygen balloon through the septum to keep a positive pressure of oxygen atmosphere on the reaction. Irradiate the reaction mixture with LEDs or a 23 watt lamp for one to three hours. Check the progress of the reaction by proton NMR using derated dimethyl sulfoxide.Once the reaction is complete, filter the precipitated solid. Wash the solid with pentane in order to remove most of the toluene. After transferring the solid to a round bottom flask, dry it under reduced pressure.At this point, weigh out 0.49 millimoles of the isolated hydroperoxide and 0.49 millimoles of the desired analy nucleo file into a 12 milliliter vial. Add 10 milliliters of methanol, 3.74 microliters of tri fluoro acidic acid and stir bar to the vial. Then close the container with a cap and stir the reaction mixture at room temperature for four hours.For products that precipitate over the course of the reaction, filter the precipitated solid to obtain the desired product. Wash the product three times with 0.5 milliliters of methanol to obtain a second fraction of product. Evaporate the methanol from the filtrate when finished.Dissolved the crude product in five milliliters of ethyl acetate. If necessary, heat gently at 40 degrees Celsius until the solution becomes homogenous. After that, at three to five milliliters of pentane to precipitate the pure product following filtration of the pure product, combine the different fractions of the product and dry them under high vacuum.For an alternative coupling procedure, weigh out 0.49 millimoles of the synthesized hydro peroxide into a 12 milliliter vial. Add 10 milliliters of acetic acid and stir bar to the vial. Add the alion nucleo vial last if it is a liquid.After closing the container with a cap, stir the reaction mixture at room temperature for four hours. For products that do not precipitate, evaporate the solvent directly by using a rotary evaporator. Following this, purify the residue by silica gel column chromatography using a 95 to five to five ratio of hexanes ethyl acetate and triethyl amine to obtain the desired product.This protocol demonstrates how tetra hydro carbazoles can be conveniently functionalized by chips. This method utilizes ly nucleo files to synthesize coupling products including pharmaceutically active compounds. In a two step procedure, the first step is a photo catalyzed oxidation of tetro hydro Carole one, or its derivatives with elemental oxygen giving hydroperoxide two if performed in toluene, the hydroperoxide products precipitate and can be conveniently isolated by filtration in the second step.Hydroperoxide two is treated with alion three to furnish product four by acid catalyzed substitution. Either a catalytic amount of tri fluoro, acetic acid, and methanol is used, or the reaction is performed in acetic acid without any catalyst products. Four A through C precipitate from the reaction and can be isolated by filtration with no additional purification.For products such as four D that do not precipitate column chromatography is used for purification and isolation. This technique can be performed in a single day, including two chemical steps work up and Drank. The implications of this technique extend to what the application to other substrate classes.A goal we are currently pursuing.

synthesis-antiviral-tetrahydrocarbazole-derivatives-photochemical

Research

JoVE Journal

Chemistry

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.

Chemoselective Modification of Viral Surfaces via Bioorthogonal Click Chemistry

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.

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

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.

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Scale-up synthesis of highly efficient thermally activated delayed fluorescence emitters is described in the presented article.

Scale-up Chemical Synthesis of Thermally-activated Delayed Fluorescence Emitters Based on the Dibenzothiophene-S,S-Dioxide Core

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

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

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

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

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.

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

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

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

Here, we describe a bioassay using 3-(4′,5′-dimethylthiazol-2′-yl)-2,5- diphenyltetrazolium bromide (MTT) to test previously synthesized spirocyclic oximes.

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay

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.

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

Learn a two-step photochemical synthesis method for antiviral tetrahydrocarbazole derivatives using visible light, oxygen, and Brønsted acid catalysis. This environmentally friendly approach replaces expensive metal catalysts.

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

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

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