Name: synthesis of antiviral tetrahydrocarbazole derivatives by photochemical and acid-catalyzed c-h functionalization via intermediate peroxides (chips)
Uploaded: 2014-06-20T14:00:00
Description: 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

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 ...

<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. -. 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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="Figure 1" fo:content-width="5in" src="/files/ftp_upload/51504/51504fig1highres.jpg" width="500" /> 
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 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.

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): &#948; 10.90 (s, 1H), 7.97 (dd...

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.

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 ...

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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.

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

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.

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.

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.

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.

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.

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.

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.

&#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.

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.

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