Name: preparation of n-(2-alkoxyvinyl)sulfonamides from n-tosyl-1,2,3-triazoles and subsequent conversion to substituted phthalans and phenethylamines
Uploaded: 2018-01-03T15:00:00.000+00:00
Duration: 10 min 42 s
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 vial under vacuum and refill with argon gas three times.</li>
	<li>Add 4 mL of anhydrous chloroform via syringe and commence magnetic stirring.</li>
	<li>Add 0.15 mL of p-toluenesulfonyl azide (TsN3) dropwise via syringe. CAUTION! p-Toluenesulfonyl azide is potentially explosive28 and must be handled using appropriate personal protective equipment.</li>
	<li>Heat the sealed microwave vial at 100 &#176;C in a microwave reactor for 15 min. CAUTION! Do not use a standard microwave oven or a unit unauthorized for chemical synthesis. 
	NOTE: A commercial microwave reactor was used in this protocol. The absorption level was set to &#34;normal&#34; and the stirring rate was kept at 600 rotations per minute (RPM). It is likely that other microwave reactors designed for chemical synthesis will also work for this protocol, although the ideal time, temperature, and other parameters may vary.</li>
	<li>Cool the reaction vessel to room temperature quickly (~2 - 3 min) using a stream of compressed air and transfer the reaction mixture to a 100 mL round-bottomed flask. Wash the reaction vial with an additional 2 x 10 mL of dichloromethane to transfer any residual crude product into the 100 mL round-bottomed flask.</li>
	<li>Add ~1.5 g of silica gel to the same round-bottomed flask and remove the solvents using a rotary evaporator.</li>
	<li>Tightly pack the silica gel adsorbed with the crude product into a solid load cartridge and attach to a 12 g pre-packed silica gel column for automated flash chromatography. 
	NOTE: An automated purification system, solid load cartridge, and 12 g silica gel column was used in this protocol. Solvent flow rates were maintained at approximately 30 mL/min. Automated flash chromatography is not required for purification; conventional flash chromatography can also be used. However, we favor automation since it typically enables one to isolate compound 2a as quickly as possible before significant decomposition occurs.</li>
	<li>Run the column using a continuous gradient of 0 - 100% ethyl acetate in hexanes over 15 min by beginning with pure hexanes and ending with pure ethyl acetate. Collect the major peak as indicated by UV absorbance at 254 nm and concentrate the combined, corresponding fractions on a rotary evaporator to obtain the purified product 2a as an off-white solid. 
	NOTE: Triazole 2a was typically found to be stable when stored as a solid under argon at 2 - 5 &#176;C for 1 - 2 weeks. However, certain batches of product degraded faster than others, possibly due to DCl contamination from CDCl3. Therefore, we recommend analyzing the purity of product by NMR using CDCl3 neutralized with K2CO3 and using it immediately in subsequent reactions for the best results.</li>
</ol>
2. Synthesis of N-(2-alkoxyvinyl)sulfonamide phthalan 3a: (Z)-N-(isobenzofuran-1(3H)-ylidenemethyl)-4-methylbenzenesulfonamide
<ol>
	<li>Add a 3 x 10 mm PTFE magnetic stir bar and 4.6 mg of rhodium(II) acetate dimer to an oven-dried 0.5 - 2 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 vial under vacuum and refill with argon gas three times.</li>
	<li>Under an argon atmosphere, dissolve 152 mg of triazole 2a in 1 mL of anhydrous chloroform and transfer the resulting solution to the microwave vessel via syringe. Rinse the flask containing residual triazole two times with an additional 2 mL of chloroform and transfer to the same microwave vessel to ensure that all starting material is transferred.</li>
	<li>Heat the sealed microwave vial at 100 &#176;C in a microwave reactor for 1 h. CAUTION! Do not use a standard microwave oven or a unit unauthorized for chemical synthesis. 
	NOTE: A commercial microwave reactor was used in this protocol. The absorption level was set to &#34;normal&#34; and the stirring rate was kept at 600 rotations per minute (RPM). It is likely that other microwave reactors designed for chemical synthesis will also work for this protocol, although the ideal time, temperature, and other parameters may vary.</li>
	<li>Cool the reaction vessel to room temperature quickly (~2 - 3 min) using a stream of compressed air and filter through a short plug of silica gel, eluting with ethyl acetate.</li>
	<li>Concentrate the filtrate in vacuo using a rotary evaporator with a warm (~30 &#176;C) water bath to obtain the product in sufficient purity to be used immediately for subsequent reactions. 
	Note that the product decomposes quickly (within 1h) under mildly acidic conditions such as in CDCl3 containing residual DCl, and gradually (within 1 - 3d) when stored neat under argon at 3 - 5 &#176;C. Therefore, we recommend analyzing the purity of product by NMR using CDCl3 neutralized with K2CO3 and using it immediately in subsequent reactions for the best results.</li>
	<li>If necessary, purify the product via column chromatography on silica gel using a 0 - 75% gradient of ethyl acetate in hexanes over 15 min by beginning with pure hexanes and ending with 75% ethyl acetate in hexanes. 
	NOTE: An automated purification system, solid load cartridge, and 12 g silica gel column was used in this protocol. Solvent flow rates were maintained at approximately 30 mL/min. Automated flash chromatography is not required for purification; conventional flash chromatography can also be used. However, we favor automation since it typically enables one to isolate compound 3a as quickly as possible before significant decomposition occurs.</li>
</ol>
3. Synthesis of Phthalan 4: N-((1,3-dihydroisobenzofuran-1-yl)methyl)-4-methylbenzenesulfonamide
<ol>
	<li>In a 25 mL round-bottomed flask with a magnetic stir bar, dissolve 211 mg of freshly prepared phthalan 3a in 15 mL of absolute ethanol under an argon atmosphere.</li>
	<li>Add 149 mg of 10 wt% palladium on carbon to the flask, taking care to minimize exposure to air. CAUTION! It is very important to ensure that the reaction mixture is under an argon or nitrogen atmosphere. Palladium on carbon can ignite in the presence of air, hydrogen gas, and/or a flammable solvent. Wear all appropriate personal protective equipment and proactively keep a flame extinguisher and/or bucket of sand nearby to extinguish any flames.</li>
	<li>Fill a standard latex balloon securely attached to a syringe with hydrogen gas. Do not exceed the recommended capacity of the balloon.</li>
	<li>Attach the balloon and syringe to the reaction vessel using a needle to penetrate the septum. Check to ensure that there are no leaks in the balloon and/or septum.</li>
	<li>To replace the argon atmosphere with hydrogen, apply a weak vacuum to the reaction vessel while pinching off the balloon, then after stopping the vacuum, refill the vessel with hydrogen gas. Repeat two additional times.</li>
	<li>Stir the reaction for 24 h and then remove the balloon.</li>
	<li>Purge the flask with argon gas and then filter the solution through a silica gel plug eluting with ethyl acetate. Carefully discard the silica gel containing palladium by dampening the mixture with water and placing in a sealed solid waste container.</li>
	<li>Remove the solvent in vacuo to provide the product.</li>
</ol>
4. Synthesis of phenethylamine 5: N-(2-(hydroxymethyl)phenethyl)-4-methylbenzenesulfonamide
<ol>
	<li>In a 10 mL round-bottomed flask, dissolve 169 mg of freshly prepared phthalan 3a with 5 mL of diethyl ether under an argon atmosphere.</li>
	<li>Cool the reaction mixture to 0 &#176;C using an ice-bath and then slowly add 0.52 mL of a ~60 wt% solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene. CAUTION! Sodium bis(2-methoxyethoxy)aluminum hydride reacts violently with water. Only use this reagent in a moisture-free, inert atmosphere.</li>
	<li>Stir the reaction mixture for 18 h at room temperature.</li>
	<li>Cool the reaction mixture to 0 &#176;C and then carefully add 0.5 mL of methanol dropwise over 2 min. Stir for an additional 2 min at 0 &#176;C. CAUTION! Addition of methanol to sodium bis(2-methoxyethoxy)aluminum hydride is exothermic. Ensure that the solution is sufficiently cold and take care to avoid adding the methanol all at once.</li>
	<li>At 0 &#176;C, add 0.6 mL of saturated aqueous ammonium chloride, remove the ice bath, and stir for 5 min at room temperature.</li>
	<li>Pour the resulting solution into a separatory funnel containing 90 mL of 1M hydrochloric acid and extract the aqueous layer with 60 mL of ethyl acetate three times.</li>
	<li>Wash the combined organic layers with 30 mL of water and then 30 mL of brine before drying over sodium sulfate.</li>
	<li>Filter off the sodium sulfate using a Buchner funnel and concentrate the filtrate in vacuo to obtain the crude phenethylamine product. 
	NOTE: Typically, the product is sufficiently pure after this step, but occasionally contaminants from decomposition of N-(2-alkoxyvinyl)sulfonamide phthalan 3a may be present.</li>
	<li>If necessary, purify the product via column chromatography on silica gel using a 0 - 100% gradient of ethyl acetate in hexanes over 15 min by beginning with pure hexanes and ending with pure ethyl acetate. 
	NOTE: A purification system, solid load cartridge, and 12 g silica gel column was used in this protocol. Solvent flow rates were maintained at approximately 30 mL/min. Automated flash chromatography is not required for purification; conventional flash chromatography can also be used.</li>
</ol>
5. Synthesis of ketal 6c: N-((1-(2-hydroxyethoxy)-1,3-dihydroisobenzofuran-1-yl)methyl)-4-methylbenzenesulfonamide
<ol>
	<li>In a 10 mL round-bottomed flask with a stir bar, dissolve 211 mg of freshly synthesized phthalan 3a in 2 mL of ethylene glycol under an air atmosphere and commence stirring.</li>
	<li>Using a 1 mL syringe equipped with an 18 gauge needle, add 1 drop of trimethylsilyl chloride to the stirring solution.</li>
	<li>Place a rubber septum on the flask with a venting needle open to air and stir the reaction mixture for 18 h at room temperature.</li>
	<li>Transfer the reaction mixture to a 125 mL separatory funnel, rinsing with 50 mL of dichloromethane and then add 10 mL of saturated aqueous sodium bicarbonate and 40 mL of deionized water.</li>
	<li>Mix vigorously, venting often, and separate the organic layer into a clean flask. Extract the aqueous layer an additional three times with 30 mL of dichloromethane each time.</li>
	<li>Combine the organic layers and dry over sodium sulfate.</li>
	<li>Filter off the sodium sulfate using a Buchner funnel and concentrate the filtrate on a rotary evaporator.</li>
	<li>Dissolve the crude product in 10 mL of dichloromethane, add ~750 mg of silica gel to the mixture, and remove the solvent using a rotary evaporator.</li>
	<li>Tightly pack the silica gel adsorbed with the crude product into a solid load cartridge and attach to a 12 g pre-packed silica gel column for automated flash chromatography. 
	NOTE: A purification system, solid load cartridge, and 12 g silica gel column was used in this protocol. Solvent flow rates were maintained at approximately 30 mL/min. Automated flash chromatography is not required for purification; conventional flash chromatography can also be used.</li>
	<li>Run the column using a continuous gradient of 0 - 70% ethyl acetate in hexanes over 15 min by beginning with pure hexanes and ending with pure ethyl acetate. Collect the major peak as indicated by UV absorbance at 254 nm and concentrate the combined, corresponding fractions on a rotary evaporator to obtain the purified product 6c as an off-white solid.</li>
</ol>

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Catal. 358 (7), 1078-1087 (2016).</li><li>Miura, T., Nakamuro, T., Kiraga, K., 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=The+stereoselective+synthesis+of+&#945;-amino+aldols+starting+from+terminal+alkynes.">The stereoselective synthesis of &#945;-amino aldols starting from terminal alkynes.</a> Chem. Commun. 50 (72), 10474-10477 (2014).</li><li>Hazen, G. G., Weinstock, L. M., Connell, R., Bollinger, F. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Safer+Diazotransfer+Reagent.">A Safer Diazotransfer Reagent.</a> Synth. Commun. 11 (12), 947-956 (1981).</li><li>Easton, N. R., Bartron, L. R., Meinhofer, F. L., Fish, V. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+Some+Substituted+3-Piperidones.">Synthesis of Some Substituted 3-Piperidones.</a> J. Am. Chem. Soc. 75 (9), 2086-2089 (1953).</li><li>Van den Branden, S., Compernolle, F., Hoornaert, G. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+lactam+and+ketone+precursors+of+2,7-substituted+octahydro-pyrrolo[1,2-a]pyrazines+and+octahydro-2H-pyrido[1,2-a]pyrazines.">Synthesis of lactam and ketone precursors of 2,7-substituted octahydro-pyrrolo[1,2-a]pyrazines and octahydro-2H-pyrido[1,2-a]pyrazines.</a> J. Chem. Soc., Perkin Trans 1. 1 (8), 1035-1042 (1992).</li><li>Aszodi, J., Rowlands, D. A., Mauvais, P., Collette, P., Bonnefoy, A., Lampilas, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Design+and+synthesis+of+bridged+&#947;-lactams+as+analogues+of+&#946;-lactam+antibiotics.">Design and synthesis of bridged &#947;-lactams as analogues of &#946;-lactam antibiotics.</a> Bioorg. Med. Chem. Lett. 14 (10), 2489-2492 (2004).</li><li>D&#8217;hooghe, M., Baele, J., Contreras, J., Boelens, M., De Kimpe, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reduction+of+5-(bromomethyl)-1-pyrrolinium+bromides+to+2-(bromomethyl)pyrrolidines+and+their+transformation+into+piperidin-3-ones+through+an+unprecedented+ring+expansion-oxidation+protocol.">Reduction of 5-(bromomethyl)-1-pyrrolinium bromides to 2-(bromomethyl)pyrrolidines and their transformation into piperidin-3-ones through an unprecedented ring expansion-oxidation protocol.</a> Tetrahedron Lett. 49 (42), 6039-6042 (2008).</li></ol>

The authors have nothing to disclose.

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

preparation-n-2-alkoxyvinyl-sulfonamides-from-n-tosyl-123-triazoles

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Amines

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9.6K Views.  Hamilton College. Representative experimental procedures for the synthesis of N-(2-alkoxyvinyl)sulfonamides and subsequent conversion to phthalan and phenethylamine derivatives are presented in detail.

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

Modification and Functionalization of the Guanidine Group by Tailor-made Precursors

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. In this article, an easy method for the modification of the guanidine group in peptidic ligands is provided, with an example of RGD-binding integrin ligands. It was recently demonstrated that the distinct modification of the guanidine group in these ligands allows for the selective modulation of the subtype (e.g., between the subtypes &#945;v and &#945;5). Moreover, a formerly unknown strategy for the functionalization via the guanidine group was demonstrated, and the synthetic approach is reviewed in this document. The modifications described here involve terminally (N&#969;) alkylated and acetylated guanidine groups. For the synthesis, tailor-made precursor molecules are synthesized, which are then subjected to a reaction with an orthogonally deprotected amine to transfer the pre-modified guanidine group. For the synthesis of alkylated guanidines, precursors based on N,N&#8242;-Di-Boc-1H-pyrazole-1-carboxamidine are used to synthesize acylated compounds, the precursor of choice being a correspondingly acylated derivative of N-Boc-S-methylisothiourea, which can be obtained in one- and two-step reactions.

A protocol for the synthesis of alkyl-modified guanidines based on the use of the corresponding precursors is presented.

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. ...

Biochemistry

Facile Preparation of 4-Substituted Quinazoline Derivatives

Reported in this paper is a very simple method for direct preparation of 4-substituted quinazoline derivatives from a reaction between substituted 2-aminobenzophenones and thiourea in the presence of dimethyl sulfoxide (DMSO). This is a unique complementary reaction system in which thiourea undergoes thermal decomposition to form carbodiimide and hydrogen sulfide, where the former reacts with 2-aminobenzophenone to form 4-phenylquinazolin-2(1H)-imine intermediate, whilst hydrogen sulfide reacts with DMSO to give methanethiol or other sulfur-containing molecule which then functions as a complementary reducing agent to reduce 4-phenylquinazolin-2(1H)-imine intermediate into 4-phenyl-1,2-dihydroquinazolin-2-amine. Subsequently, the elimination of ammonia from 4-phenyl-1,2-dihydroquinazolin-2-amine affords substituted quinazoline derivative. This reaction usually gives quinazoline derivative as a single product arising from 2-aminobenzophenone as monitored by GC/MS analysis, along with small amount of sulfur-containing molecules such as dimethyl disulfide, dimethyl trisulfide, etc. The reaction usually completes in 4-6 hr at 160 &#186;C in small scale but may last over 24 hr when carried out in large scale. The reaction product can be easily purified by means of washing off DMSO with water followed by column chromatography or thin layer chromatography.

A protocol for facile preparation of 4-substituted quinazoline derivatives from 2-aminobenzophenones, thiourea and dimethyl sulfoxide is presented.

Reported in this paper is a very simple method for direct preparation of 4-substituted quinazoline derivatives from a reaction between substituted ...

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 ...

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the aziridine ring. The utility of bicyclic aziridinium ions, specifically 1-azoniabicyclo[3.1.0]hexane and 1-azoniabicyclo[4.1.0]heptane tosylate highlighted in the aziridine ring openings by the nucleophile with the release of the ring strain to yield the corresponding ring-expanded azaheterocycles such as pyrrolidine, piperidine and azepane with diverse substituents on the ring in regio- and stereospecific manner. Herein, we report a simple and convenient method for the preparation of the stable 1-azabicyclo[4.1.0]heptane tosylate followed by selective ring opening via a nucleophilic attack either at the bridge or at the bridgehead carbon to yield piperidine and azepane rings, respectively. This synthetic strategy allowed us to prepare biologically active natural products containing piperidine and azepane motif including sedamine, allosedamine, fagomine and balanol in highly efficient manner.

Bicyclic aziridinium ions such as 1-azoniabicyclo[4.1.0]heptane tosylate were generated from 2-[4-tolenesulfonyloxybutyl]aziridine, which was utilized for the preparation of substituted piperidines and azepanes via regio- and stereospecific ring-expansion with various nucleophiles. This highly efficient protocol allowed us to prepare diverse azaheterocycles including natural products such as fagomine, febrifugine analogue and balanol.

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the ...

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. ...

Easy Access to Aliphatic Sulfonamides using Sulfamoyl Chlorides Under Visible Light Activation

Sulfonamides are prevalent motifs in marketed drugs and natural products. Their synthesis represents a great interest to the pharmaceutical industry, due to their unique biological properties. Recently, several methods for the synthesis of aryl sulfonamides have been developed, but little effort has focused on developing one-step methodologies to access sulfonamides flanked by two alkyl groups. This protocol describes a practical and facile method for the net hydrosulfamoylation of electron-deficient alkenes using sulfamoyl chlorides as radical precursors under blue-light activation. This practical and cost-effective methodology is performed in the presence of the metal-free photocatalyst Eosin Y and uses light as a clean and traceless energy source. The procedure is scalable, displays a broad functional group tolerance, and can be applied for late-stage functionalization. All reagents used in this protocol are commercially available. Simple reaction set-up, the absence of work-up and easy purification, demonstrate the convenience of this protocol. The reaction is best applied to electron-deficient alkenes.

Presented here is a protocol for the easy synthesis of aliphatic sulfonamides using sulfamoyl chlorides, (TMS)3SiH and Eosin Y under blue-light irradiation.

Sulfonamides are prevalent motifs in marketed drugs and natural products. Their synthesis represents a great interest to the pharmaceutical industry, due ...

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very difficult and laborious to make aziridines in optically pure forms on a large scale to apply asymmetric synthesis of aza compounds. Fortunately, we successfully achieved both enantiomers (2R)- and (2S)-aziridine-2-carboxylates with the electron-donating &#945;-methylbenzyl group at the ring nitrogen as non-activated aziridines. These starting aziridines have two distinct functional groups-highly reactive three-membered ring and versatile carboxylate. They are applicable in ring-opening or ring-transformation with aziridine and in functional group transformation to others from carboxylate. Both of these enantiomers were utilized in the preparation of biologically important amino acyclic and/or aza-heterocyclic compounds in an asymmetric manner. Specifically, this report describes the first expedient asymmetric synthesis of both enantiomers of 5, 6-dihydrouracil-type marine natural products biemamide B and D as potential TGF-&#946; inhibitors. This synthesis consisted of regio- and the stereoselective ring-opening reaction of aziridine-2-carboxylate and subsequent formation of 4-aminoteterahydropyrimidine-2,4-dione. One more example in this protocol dealt a highly stereoselective Mukaiyama reaction of aziridine-2-carboxylate and silyl enol ether, following intramolecular aziridine ring-opening to provide easy and facile access to (-)-epiallo-isomuscarine.

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

In this study, we prepare both enantiomers of aziridine-2-carboxylate, which are used in the asymmetric synthesis of alkaloids, including biemamide B and D, and (-)-epiallo-isomuscarine.

Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very ...

Biological Assessment of Thiophenesulfonamides in Quorum Sensing Inhibition

Synthesis and Assay of Vibrio Quorum Sensing Inhibitors

Bacteria detect local population numbers using quorum sensing, a method of cell-cell communication broadly utilized to control bacterial behaviors. In Vibrio species, the master quorum sensing regulators LuxR/HapR control hundreds of quorum sensing genes, many of which influence virulence, metabolism, motility, and more. Thiophenesulfonamides are potent inhibitors of LuxR/HapR that bind the ligand pocket in these transcription factors and block downstream quorum sensing gene expression. This class of compounds served as the basis for the development of a set of simple, robust, and educational procedures for college students to assimilate their chemistry and biology skills using a CURE model: course-based undergraduate research experience. Optimized protocols are described that comprise three learning stages in an iterative and multi-disciplinary platform to engage students in a year-long CURE: (1) design and synthesize new small molecule inhibitors based on the thiophenesulfonamide core, (2) use structural modeling to predict binding affinity to the target, and (3) assay the compounds for efficacy in microbiological assays against specific Vibrio LuxR/HapR proteins. The described reporter assay performed in E. coli successfully predicts the efficacy of the compounds against target proteins in the native Vibrio species.

Author Spotlight: Advancing Therapeutics to Treat Vibriosis in Humans and Aquatic Organisms

Thiophenesulfonamide compounds are potent and specific inhibitors of Vibrio quorum sensing regulators LuxR/HapR that block their activity in vivo, thus preventing transcription of genes for virulence, motility, and biofilms. This protocol details how these compounds are synthesized, modeled in silico, and assayed in vivo for activity against LuxR/HapR.

Bacteria detect local population numbers using quorum sensing, a method of cell-cell communication broadly utilized to control bacterial behaviors. In ...

Biology

Preparation of 1&deg; Amines: Gabriel Synthesis

Direct alkylation is not a suitable method for synthesizing amines because it produces polyalkylated products. Gabriel synthesis is the most preferred method to exclusively make primary amines. The method uses phthalimide, which contains a protected form of nitrogen that participates in alkylation only once to predominantly give primary amines.
Strong bases like NaOH or KOH deprotonate the phthalimide to form the corresponding anion, which acts as a nucleophile. Further, the anion attacks an alkyl halide to give N-alkylphthalimide. This double-amide compound reacts with hydrazine under the influence of heat to produce primary amines. Alternatively, N-alkylphthalimide can also undergo hydrolysis in the presence of a base or an acid to produce primary amines.
<img alt="Figure1" src="/files/ftp_upload/12859/12859_PT_Figure_1.svg" style="text-align: center; height: 100px;" />
Unhindered primary and secondary alkyl halides are the preferred substrates for Gabriel synthesis, since the reaction uses the SN2 mechanism.
Gabriel&rsquo;s method is useful for synthesizing a stimulant drug&#8212;amphetamine, used during World War II as an appetite suppressant.

Preparation of 1&amp;deg; Amines: Gabriel Synthesis

Direct alkylation is not a suitable method for synthesizing amines because it produces polyalkylated products. Gabriel synthesis is the most preferred ...

KEY TERMS AND CONCEPTS

Preparation and Reactions of Sulfides

Sulfides are the sulfur analog of ethers, just as thiols are the sulfur analog of alcohol. Like ethers, sulfides also consist of two hydrocarbon groups bonded to the central sulfur atom. Depending upon the type of groups present, sulfides can be symmetrical or asymmetrical. Symmetrical sulfides can be prepared via an SN2 reaction between 2 equivalents of an alkyl halide and one equivalent of sodium sulfide.
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Asymmetrical sulfides can be synthesized by treating thiols with an alkyl halide and a base. The reaction follows an SN2 pathway and proceeds via the thiolate ion intermediate. This reaction is the sulfur analog of Williamson ether synthesis and prefers methyl, primary, and secondary alkyl halides but not tertiary alkyl halides. Sulfides can readily oxidize to sulfoxide and sulfones.
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Treatment of sulfide with one equivalent of hydrogen peroxide at room temperature yields sulfoxide, which upon further oxidation with a peroxy acid yields a sulfone. However, 2 equivalents of hydrogen peroxide oxidize sulfide directly to sulfone.
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Dimethyl sulfoxide (DMSO) and tetramethylene sulfone are common examples of sulfoxides and sulfones, respectively. They both are excellent dipolar aprotic solvents.

Sulfides: Preparations and Reactions

Sulfides are the sulfur analog of ethers, just as thiols are the sulfur analog of alcohol. Like ethers, sulfides also consist of two hydrocarbon groups ...

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