The overall goal of this report is to demonstrate an efficient methodology for accessing N-2-alkoxy vinyl sulfonamides, a synthetically versatile functional group, and to illustrate several reactions that convert this group into valuable heterocycles, such as phthalans and phenethylamines. This method illustrates some general techniques for handling unstable synthetic intermediates, such as acid-sensitive organic compounds. The main feature of our technique is the efficient generation of N-2-alkoxy vinyl sulfonamides, which enables chemists to explore the synthetic potential of this valuable nitrogen and oxygen containing synthon.

Demonstrating this procedure will be Giovanny Dominguez, an undergraduate student from my laboratory. First, add 139 milligrams of 2-ethynylbenzyl alcohol, and 20 milligrams of copper-thiophene-carboxylate to an oven-dried microwave vial containing a magnetic stir bar. Seal the vial securely with a septum cap and crimper.

Remove air from the vial under vacuum, and refill with argon gas three times. Then, add four milliliters of anhydrous chloroform via syringe, and commence magnetic stirring. Next, add 0.15 milliliters of p-Toluenesulfonyl azide drop-wise via syringe.

Heat the sealed microwave vial in a microwave reactor at 100 degrees Celsius for 15 minutes. Once the reaction is complete, rapidly cool the vial to room temperature using a stream of compressed air, and transfer the reaction mixture to a 100 milliliter round-bottomed flask. Add approximately 1.5 grams of silica gel to the round-bottomed flask, and remove the solvent using a rotary evaporator.

Following this, tightly pack the silica gel adsorbed with the crude product into a solid load cartridge and attach to a 12 gram pre-packed silica gel column for automated flash chromatography. Run the column using a continuous gradient of zero to 100%ethyl acetate in hexanes over 15 minutes by beginning with pure hexanes, and ending with pure ethyl acetate. After the purification is complete, collect the major peak as indicated by UV absorbance at 254 nanometers, then concentrate the combined fractions in vacuo using a rotary evaporator to obtain the purified triazole product as an off-white solid.

Under argon atmosphere, dissolve 152 milligrams of the purified triazole in one milliliter of anhydrous chloroform, and transfer the resulting solution to a sealed microwave vial containing rhodium acetate dimer and a magnetic stir bar. Rinse the flask containing residual triazole two times with two milliliters of chloroform and transfer to the microwave vial to ensure that all starting material is transferred. Following this, heat the sealed microwave vial in a microwave reactor at 100 degrees Celsius for one hour.

Once the reaction is complete, rapidly cool the reaction vial to room temperature using a stream of compressed air. Then filter the cooled reaction mixture through a short plug of silica gel, eluting with ethyl acetate. Concentrate the filtrate in vacuo using a rotary evaporator with a warm water bath to obtain the phthalan product in sufficient purity to be used immediately for subsequent reactions.

Under argon atmosphere, dissolve 211 milligrams of the freshly prepared phthalan in 15 milliliters of absolute ethanol in a 25 milliliter round-bottomed flask containing a magnetic stir bar. Add 149 milligrams of 10 weight percent palladium on carbon to the flask, taking care to minimize exposure to air. Next, fill a standard latex balloon securely attached to a syringe with hydrogen gas, taking care not to exceed the recommended capacity of the balloon.

Attach the balloon and syringe to the reaction vessel using a needle to penetrate the septum. To replace the argon atmosphere with hydrogen, apply a weak vacuum to the reaction flask while pinching off the balloon. Stop the vacuum and refill the flask with hydrogen gas.

After stirring the reaction mixture for 24 hours, remove the balloon. Purge the flask with argon gas and filter the solution through a silica gel plug, eluting with ethyl acetate. Then, concentrate the filtrate in vacuo to provide the phthalan product.

Under argon atmosphere, dissolve 169 milligrams of the freshly prepared phthalan in five milliliters of diethyl ether in a 10 milliliter round-bottomed flask containing a magnetic stir bar. Cool the reaction mixture to zero degrees Celsius using an ice water bath, and slowly add 0.52 milliliters of a 60 weight percent solution of sodium bis 2-methoxyethoxy aluminumhydride in toluene. Stir the reaction for 18 hours at room temperature.

Once the reaction is complete, cool the reaction mixture to zero degrees Celsius with an ice water bath, and carefully add 0.5 milliliters of methanol drop-wise over two minutes. After stirring for two minutes at zero degrees Celsius, add 0.6 milliliters of saturated aqueous ammonium chloride. Remove the ice water bath, and stir for five minutes at room temperature.

Following this, pour the resulting solution into a separatory funnel containing 90 milliliters of one molar hydrochloric acid. Extract the aqueous layer three times with 60 milliliters of ethyl acetate. Wash the combined organic layers with 30 milliliters of water and 30 milliliters of brine.

Then, add sodium sulfate to remove residual water from the solution. Filter off the sodium sulfate using a Buchner funnel. After washing the sodium sulfate to remove residual product, concentrate the filtrate in vacuo using a rotary evaporator to obtain the phenethylamine product.

Under air atmosphere, dissolve 211 milligrams of the freshly prepared phthalan in two milliliters of ethylene glycol in a 10 milliliter round-bottomed flask containing a magnetic stir bar, and commence stirring. Using a one milliliter syringe equipped with an 18 gauge needle, add one drop of trimethylsilyl chloride to the stirring solution. After stirring the reaction mixture for 18 hours at room temperature, perform the workup and purification steps as indicated in the text protocol to obtain the purified ketal product as an off-white solid.

In the proton NMR spectrum of triazole 2a, the characteristic C5 proton appears at 8.45 ppm as a singlet. The mass spectrum generally shows both the mass plus proton peak, and the peak corresponding to the loss of dinitrogen. The proton NMR spectrum of phthalan 3a shows two doublets at 6.07, 6.25 ppm, corresponding to the vinyl and NH protons respectively.

In the carbon NMR spectrum, a key resonance is observed at 94.9 ppm that corresponds to the exocyclic final carbon. The proton NMR spectrum of compound four, which maintains the bicyclic phthalan substructure, shows signals at 3.49 and 3.14 ppm corresponding to the diastereotopic methylene protons. The proton NMR spectrum of phenethylamine-5 displays the same methylene as a quartet at 3.27 ppm due to free rotation in the ring opened product resulting in first-order splitting patterns.

For compound 6a through 6e, a characteristic carbon NMR signal corresponding to the ketal, hemiketal, or thioketal carbon is found between 95 and 110 ppm, such as the peak at 110 ppm observed in the carbon NMR spectrum of 6c. The mass spectra typically show a relatively small mass plus proton peak and a larger alkoxy or thioalkyl elimination fragment peak. After watching this video, you should have a good understanding how to generate N-2-alkoxy vinyl sulfonamides from readily accessible N-sulfonyl 1-2-3 triazoles.

When preparing end to N-2-alkoxy vinyl sulfonamides, it is important to budget enough time following synthesis and isolation of these compounds for use in subsequent reactions due to potential instability. We encourage researchers to expand upon the synthetic versatility of this functional group toward production of valuable nitrogen and oxygen containing compounds.