Name: preparation of n-(2-alkoxyvinyl)sulfonamides from n-tosyl-1,2,3-triazoles and subsequent conversion to substituted phthalans and phenethylamines
Uploaded: 2018-01-03T15:00:00
Description: Watch this Scientific Journal Video about Preparation of N-2-alkoxyvinylsulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines at JoVE.com

This work was funded by Hamilton College and the Edward and Virginia Taylor Fund for Student/Faculty Research in Chemistry.

1. Synthesis of N-Tosyl Triazole 2a: (2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)methanol
<ol>
	<li>Add a 3 x 10 mm PTFE magnetic stir bar, 139 mg of 2-ethynylbenzyl alcohol, and 20 mg of copper(I) thiophenecarboxylate (CuTC) to an oven-dried 2 - 5 mL microwave vial and seal the vial securely with a septum cap and crimper. Due to the rapid heating of the microwave, always use a new vial and cap that are free of any defects and make sure the cap is secure and properly fitted.</li>
	<li>Remove air from the...

<ol>
	<li>Horneff, T., Chuprakov, S., Chernyak, N., Gevorgyan, V., Fokin, V. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rhodium-Catalyzed+Transannulation+of+1,2,3-Triazoles+with+Nitriles.">Rhodium-Catalyzed Transannulation of 1,2,3-Triazoles with Nitriles.</a> J. Am. Chem. Soc. 130 (45), 14972-14974 (2008).</li><li>Cuprakov, S., Kwok, S. W., Zhang, L., Lercher, L., Fokin, V. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rhodium-Catalyzed+Enantioselective+Cyclopropanation+of+Olefins+with+N-Sulfonyl+1,2,3-Triazoles.">Rhodium-Catalyzed Enantioselective Cyclopropanation of Olefins with N-Sulfonyl 1,2,3-Triazoles.</a> J. Am. Chem. Soc. 131 (50), 18034-18035 (2009).</li><li>Grimster, N., Zhang, L., Fokin, V. 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S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reactions+of+metallocarbenes+derived+from+N-sulfonyl-1,2,3-triazoles.">Reactions of metallocarbenes derived from N-sulfonyl-1,2,3-triazoles.</a> Chem. Soc. Rev. 43 (15), 5151-5162 (2014).</li><li>Anbarasan, P., Yadagiri, D., Rajasekar, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+Advances+in+Transition-Metal-Catalyzed+Denitrogenative+Transformations+of+1,2,3-Triazoles+and+Related+Compounds.">Recent Advances in Transition-Metal-Catalyzed Denitrogenative Transformations of 1,2,3-Triazoles and Related Compounds.</a> Synthesis. 46 (22), 3004-3023 (2014).</li><li>Hockey, S. C., Henderson, L. 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A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=1-Sulfonyl-1,2,3-triazoles+as+promising+reagents+in+the+synthesis+of+nitrogen-containing+linear+and+heterocyclic+structures.">1-Sulfonyl-1,2,3-triazoles as promising reagents in the synthesis of nitrogen-containing linear and heterocyclic structures.</a> Chem. Heterocylc. Compd. 52 (4), 216-218 (2016).</li><li>Jiang, Y., Sun, R., Tang, X. -. Y., Shi, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+Advances+in+the+Synthesis+of+Heterocycles+and+Related+Substances+Based+on+&#945;-Imino+Rhodium+Carbene+Complexes+Derived+from+N-Sulfonyl-1,2,3-triazoles.">Recent Advances in the Synthesis of Heterocycles and Related Substances Based on &#945;-Imino Rhodium Carbene Complexes Derived from N-Sulfonyl-1,2,3-triazoles.</a> Chem Eur. 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Soc. 134 (1), 194-196 (2012).</li><li>Chuprakov, S., Worrell, B. T., Selander, N., Sit, R. K., Fokin, V. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereoselective+1,3-Insertions+of+Rhodium(II)+Azavinyl+Carbenes.">Stereoselective 1,3-Insertions of Rhodium(II) Azavinyl Carbenes.</a> J. Am. Chem. Soc. 136 (1), 195-202 (2014).</li><li>Shen, H., Fu, J., Gong, J., Yang, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tunable+and+Chemoselective+Syntheses+of+Dihydroisobenzofurans+and+Indanones+via+Rhodium-Catalyzed+Tandem+Reactions+of+2-Triazole-benzaldehydes+and+2-Triazole-alkylaryl+Ketones.">Tunable and Chemoselective Syntheses of Dihydroisobenzofurans and Indanones via Rhodium-Catalyzed Tandem Reactions of 2-Triazole-benzaldehydes and 2-Triazole-alkylaryl Ketones.</a> Org. Lett. 16 (21), 5588-5591 (2014).</li><li>Yuan, H., Gong, J., Yang, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereoselective+Synthesis+of+Oxabicyclo[2.2.1]heptenes+via+a+Tandem+Dirhodium(II)-Catalyzed+Triazole+Denitrogenation+and+[3+++2]+Cycloaddition.">Stereoselective Synthesis of Oxabicyclo[2.2.1]heptenes via a Tandem Dirhodium(II)-Catalyzed Triazole Denitrogenation and [3 + 2] Cycloaddition.</a> Org. Lett. 18 (21), 5500-5503 (2016).</li><li>Yu, Y., Zhu, L., Liao, Y., Mao, Z., Huang, X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rhodium(II)-Catalysed+Skeletal+Rearrangement+of+Ether+Tethered+N-Sulfonyl+1,2,3-Triazoles:+a+Rapid+Approach+to+2-Aminoindanone+and+Dihydroisoquinoline+Derivatives.">Rhodium(II)-Catalysed Skeletal Rearrangement of Ether Tethered N-Sulfonyl 1,2,3-Triazoles: a Rapid Approach to 2-Aminoindanone and Dihydroisoquinoline Derivatives.</a> Adv. Synth. Catal. 358 (7), 1059-1064 (2016).</li><li>Sun, R., Jiang, Y., Tang, X. -. Y., Shi, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=RhII-Catalyzed+Cyclization+of+Ester/Thioester-Containing+N-Sulfonyl-1,2,3-triazoles:+Facile+Synthesis+of+Alkylidenephthalans+and+Alkylidenethiophthalans.">RhII-Catalyzed Cyclization of Ester/Thioester-Containing N-Sulfonyl-1,2,3-triazoles: Facile Synthesis of Alkylidenephthalans and Alkylidenethiophthalans.</a> Asian J. Org. Chem. 6 (1), 83-87 (2017).</li><li>Miura, T., Tanaka, T., Biyajima, T., Yada, A., Murakami, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-Pot+Procedure+for+the+Introduction+of+Three+Different+Bonds+onto+Terminal+Alkynes+through+N-Sulfonyl-1,2,3-Triazole+Intermediates.">One-Pot Procedure for the Introduction of Three Different Bonds onto Terminal Alkynes through N-Sulfonyl-1,2,3-Triazole Intermediates.</a> Angew. Chem. Int. Ed. 52 (14), 3883-3886 (2013).</li><li>Medina, F., Besnard, C., Lacour, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-Step+Synthesis+of+Nitrogen-Containing+Medium-Sized+Rings+via+&#945;-Imino+Diazo+Intermediates.">One-Step Synthesis of Nitrogen-Containing Medium-Sized Rings via &#945;-Imino Diazo Intermediates.</a> Org. Lett. 16 (12), 3232-3235 (2014).</li><li>Alford, J. S., Davies, H. M. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mild+Aminoacylation+of+Indoles+and+Pyrroles+through+a+Three-Component+Reaction+with+Ynol+Ethers+and+Sulfonyl+Azides.">Mild Aminoacylation of Indoles and Pyrroles through a Three-Component Reaction with Ynol Ethers and Sulfonyl Azides.</a> J. Am. Chem. 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K., Liao, P., Bi, X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tandem+O-H+Insertion/[1,3]-Alkyl+Shift+of+Rhodium+Azavinyl+Carbenoids+with+Benzylic+Alcohols:+A+Route+To+Convert+C-OH+Bonds+into+C-C+Bonds.">Tandem O-H Insertion/[1,3]-Alkyl Shift of Rhodium Azavinyl Carbenoids with Benzylic Alcohols: A Route To Convert C-OH Bonds into C-C Bonds.</a> Org. Lett. 18 (19), 4998-5001 (2016).</li><li>Seo, 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=Sequential+Functionalization+of+the+O-H+and+C(sp2)-O+Bonds+of+Tropolones+by+Alkynes+and+N-Sulfonyl+Azides.">Sequential Functionalization of the O-H and C(sp2)-O Bonds of Tropolones by Alkynes and N-Sulfonyl Azides.</a> Adv. Synth. 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Triazoles 2a-b can be cleanly obtained via a Cu(I)-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC) using CuTC as catalyst. Notably, triazole 2a is most efficiently generated at high temperature via a standard reflux in chloroform for 3h or heating to 100 &#176;C for 15 min in a microwave reactor (note that time may vary depending on microwave efficiency); however, triazole 2b is most efficiently prepared via a CuAAC at room temperature. Therefore, effort must be taken...

Rhodium(II)-azavinyl carbenoids have recently emerged as an exceptionally versatile reactive intermediate en route to numerous valuable products.1,2,3,4,5,6,7,8,9,10 In particular, many novel uses of these intermediates for production of heterocycles10 have provided chemists with new and efficient synthetic strategies. Toward this end, our group initiated development of a new protocol for the synthesis of phthalans11 that would capitalize on recent advancements in the inter- and intramolecular additions of oxygen-based nucleophiles to Rh(II)-azavinyl carbenoids derived from N-sulfonyl-1,2,3-triazoles.12,13,14,15,16,17 Our approach features a straightforward two-step protocol for converting terminal alkynes such as 1 into N-sulfonyl-1,2,3-triazoles 2 bearing a pendent alcohol (Figure 1). Subsequently, a Rh(II)-catalyzed denitrogenation / 1,3-OH insertion cascade from 2 provides phthalans 3 having a reactive N-(2-alkoxyvinyl)sulfonamide functional group.
Since the N-(2-alkoxyvinyl)sulfonamide moiety is a potentially versatile, but relatively underexplored N- and O-containing synthon,16,17,18,19,20,21,22,23,24,25,26,27 we became interested in studying the reactivity of its fused enol-ether/ene-sulfonamide system under a variety of conditions (Figure 2). After screening various reducing protocols, two methods were identified which led to stable phthalan and/or phenethylamine-containing products (Figure 2, 3 &#8594; 4/5). First, it was discovered that a standard hydrogenation of N-(2-alkoxyvinyl)sulfonamide 3a with catalytic palladium on carbon (Pd/C) selectively reduces the C=C bond to yield phthalan 4. Alternatively, treatment of 3a with sodium bis(2-methoxyethoxy)aluminum hydride in diethyl ether/toluene provides the uniquely substituted phenethylamine derivative 5. We believe that both of these transformations are valuable, as they lead to product classes with potential biological activity including neuroactive properties arising from the embedded phenethylamine, and in the case of 4, metal-chelation via the cis-oriented N- and O-atoms.
While investigating acid-promoted additions to exploit the electron-rich C=C bond of 3a, it was found that treatment of this compound with catalytic trimethylsilyl chloride in the presence of alcohols or a thiol yielded ketals 6a-c and thioketal 6e, respectively, while keeping the bicyclic phthalan framework intact. Alternatively, stirring 3a in a 1:1 acetic acid/water solution yields stable hemiketal 6d.

<table border="0" cellpadding="0" cellspacing="0" width="829">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">2-Ethynylbenzyl alcohol, 95%</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">520039</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Copper (I) thiophene-2-carboxylate</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">682500</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Chloroform, &#8805;99%</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">372978</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Toluenesulfonylazide, 99.24%</td>
			<td style="width:219px;">Chem-Impex International</td>
			<td style="width:119px;">26107</td>
			<td>Potentially explosive</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Dichloromethane, &#8805;99.5%</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">320269</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Rhodium (II) acetate dimer, 99%</td>
			<td style="width:219px;">Strem Chemicals</td>
			<td style="width:119px;">45-1730</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Silica Gel, 32-63, 60A</td>
			<td style="width:219px;">MP Biomedicals Inc.</td>
			<td style="width:119px;">2826</td>
			<td>For silica gel plugs</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Hexanes</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">178918</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Ethyl acetate</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">439169</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Chlorofom-D</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">151823</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Ethylene glycol</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">293237</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Chlorotrimethylsilane, 98%</td>
			<td style="width:219px;">Acros</td>
			<td style="width:119px;">11012</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Sodium bicarbonate</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">S6014</td>
			<td>Dissolved in deionized water to prepare a saturated aqueous solution</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Sodium sulfate</td>
			<td style="width:219px;">Fisher Scientific</td>
			<td style="width:119px;">S429</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Ethyl alcohol, absolute - 200 proof</td>
			<td style="width:219px;">Aaper Alcohol and Chemical Co.</td>
			<td style="width:119px;">82304</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">10 wt% Palladium on carbon</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">520888</td>
			<td>Can ignite in the presence of air, hydrogen gas, and/or a flammable solvent</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Hydrogen gas</td>
			<td style="width:219px;">Praxair</td>
			<td style="width:119px;">UN1049</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Diethyl ether</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">309966</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:324px;">60 wt% sodium bis(2-methoxyethoxy)aluminum hydride solution in toluene</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">196193</td>
			<td>Reacts violently with water</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Methanol</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">34966</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Ammonium chloride</td>
			<td style="width:219px;">Fisher Scientific</td>
			<td style="width:119px;">A661</td>
			<td>Dissolved in deionized water to prepare a saturated aqueous solution</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Hydrochloric acid, 37%</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">258148</td>
			<td>Dissolved in deionized water to prepare a 1M solution</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Sodium Chloride</td>
			<td style="width:219px;">Sigma Aldrich</td>
			<td style="width:119px;">S25541</td>
			<td>Dissolved in deionized water to prepare a saturated aqueous solution</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">2-5 mL Microwave vials</td>
			<td style="width:219px;">Biotage</td>
			<td style="width:119px;">355630</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Microwave vial caps</td>
			<td style="width:219px;">Biotage</td>
			<td style="width:119px;">352298</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:324px;">RediSep Rf Gold Normal Phase, Silica Columns, 20 &#8211; 40 micron</td>
			<td style="width:219px;">Teledyne Isco</td>
			<td style="width:119px;">69-2203-345</td>
			<td>For column chromatography</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Balloons</td>
			<td style="width:219px;">CTI Industries Corp.</td>
			<td style="width:119px;">912100</td>
			<td>For hydrogenation</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:324px;">Biotage Initiator+ Microwave Reactor</td>
			<td style="width:219px;">Biotage</td>
			<td style="width:119px;">356007</td>
			<td></td>
		</tr>
	</tbody>
</table>

preparation of n-(2-alkoxyvinyl)sulfonamides from n-tosyl-1,2,3-triazoles and subsequent conversion to substituted phthalans and phenethylamines

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

All compounds in this study were characterized by 1H and 13C NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS) to confirm the product structure and assess purity. Key data for representative compounds are described in this section.
Spectral data are in good agreement with the triazole structure of 2a (Figure 3). In the 1H NMR sp...

Watch this Scientific Journal Video about Preparation of N-2-alkoxyvinylsulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines at JoVE.com

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

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

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

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

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