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

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 stra....

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.
....

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.......

Materials

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