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In This Article

  • Summary
  • Abstract
  • Introduction
  • Protocol
  • Results
  • Discussion
  • Disclosures
  • Acknowledgements
  • Materials
  • References
  • Reprints and Permissions

Summary

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

Abstract

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.

Introduction

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 → 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.

Protocol

1. Synthesis of N-Tosyl Triazole 2a: (2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)methanol

  1. 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.
  2. Remove air from the vial under vacuum and refill with argon gas three times.
  3. Add 4 mL of anhydrous chloroform via syringe and commence magnetic stirring.
  4. 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.
  5. Heat the sealed microwave vial at 100 °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 "normal" 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.
  6. 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.
  7. Add ~1.5 g of silica gel to the same round-bottomed flask and remove the solvents using a rotary evaporator.
  8. 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.
  9. 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 °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.

2. Synthesis of N-(2-alkoxyvinyl)sulfonamide phthalan 3a: (Z)-N-(isobenzofuran-1(3H)-ylidenemethyl)-4-methylbenzenesulfonamide

  1. 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.
  2. Remove air from the vial under vacuum and refill with argon gas three times.
  3. 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.
  4. Heat the sealed microwave vial at 100 °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 "normal" 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.
  5. 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.
  6. Concentrate the filtrate in vacuo using a rotary evaporator with a warm (~30 °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 °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.
  7. 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.

3. Synthesis of Phthalan 4: N-((1,3-dihydroisobenzofuran-1-yl)methyl)-4-methylbenzenesulfonamide

  1. 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.
  2. 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.
  3. Fill a standard latex balloon securely attached to a syringe with hydrogen gas. Do not exceed the recommended capacity of the balloon.
  4. 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.
  5. 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.
  6. Stir the reaction for 24 h and then remove the balloon.
  7. 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.
  8. Remove the solvent in vacuo to provide the product.

4. Synthesis of phenethylamine 5: N-(2-(hydroxymethyl)phenethyl)-4-methylbenzenesulfonamide

  1. 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.
  2. Cool the reaction mixture to 0 °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.
  3. Stir the reaction mixture for 18 h at room temperature.
  4. Cool the reaction mixture to 0 °C and then carefully add 0.5 mL of methanol dropwise over 2 min. Stir for an additional 2 min at 0 °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.
  5. At 0 °C, add 0.6 mL of saturated aqueous ammonium chloride, remove the ice bath, and stir for 5 min at room temperature.
  6. 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.
  7. Wash the combined organic layers with 30 mL of water and then 30 mL of brine before drying over sodium sulfate.
  8. 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.
  9. 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.

5. Synthesis of ketal 6c: N-((1-(2-hydroxyethoxy)-1,3-dihydroisobenzofuran-1-yl)methyl)-4-methylbenzenesulfonamide

  1. 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.
  2. Using a 1 mL syringe equipped with an 18 gauge needle, add 1 drop of trimethylsilyl chloride to the stirring solution.
  3. 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.
  4. 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.
  5. 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.
  6. Combine the organic layers and dry over sodium sulfate.
  7. Filter off the sodium sulfate using a Buchner funnel and concentrate the filtrate on a rotary evaporator.
  8. 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.
  9. 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.
  10. 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.

Results

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...

Discussion

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 °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...

Disclosures

The authors have nothing to disclose.

Acknowledgements

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

Materials

NameCompanyCatalog NumberComments
2-Ethynylbenzyl alcohol, 95%Sigma Aldrich520039
Copper (I) thiophene-2-carboxylateSigma Aldrich682500
Chloroform, ≥99%Sigma Aldrich372978
Toluenesulfonylazide, 99.24%Chem-Impex International26107Potentially explosive
Dichloromethane, ≥99.5%Sigma Aldrich320269
Rhodium (II) acetate dimer, 99%Strem Chemicals45-1730
Silica Gel, 32-63, 60AMP Biomedicals Inc.2826For silica gel plugs
HexanesSigma Aldrich178918
Ethyl acetateSigma Aldrich439169
Chlorofom-DSigma Aldrich151823
Ethylene glycolSigma Aldrich293237
Chlorotrimethylsilane, 98%Acros11012
Sodium bicarbonateSigma AldrichS6014Dissolved in deionized water to prepare a saturated aqueous solution
Sodium sulfateFisher ScientificS429
Ethyl alcohol, absolute - 200 proofAaper Alcohol and Chemical Co.82304
10 wt% Palladium on carbonSigma Aldrich520888Can ignite in the presence of air, hydrogen gas, and/or a flammable solvent
Hydrogen gasPraxairUN1049
Diethyl etherSigma Aldrich309966
60 wt% sodium bis(2-methoxyethoxy)aluminum hydride solution in tolueneSigma Aldrich196193Reacts violently with water
MethanolSigma Aldrich34966
Ammonium chlorideFisher ScientificA661Dissolved in deionized water to prepare a saturated aqueous solution
Hydrochloric acid, 37%Sigma Aldrich258148Dissolved in deionized water to prepare a 1M solution
Sodium ChlorideSigma AldrichS25541Dissolved in deionized water to prepare a saturated aqueous solution
2-5 mL Microwave vialsBiotage355630
Microwave vial capsBiotage352298
RediSep Rf Gold Normal Phase, Silica Columns, 20 – 40 micronTeledyne Isco69-2203-345For column chromatography
BalloonsCTI Industries Corp.912100For hydrogenation
Biotage Initiator+ Microwave ReactorBiotage356007

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Keyword Extraction N 2 alkoxyvinyl sulfonamidesN tosyl 123 triazolesPhthalansPhenethylamines2 ethynylbenzyl AlcoholCopper thiophene carboxylateP Toluenesulfonyl AzideMicrowave ReactorSilica GelFlash ChromatographyTriazole Product

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