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

Summary

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

Abstract

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.

Introduction

Over the recent decades, sulfonamides featured in a broad range of biologically active molecules and are common motifs in pharmaceuticals and agrochemicals^1,2. Initially employed for antibacterial purposes^3,4, the application of this motif in drug discovery has been extended to numerous diseases including cancer, CNS disorders, diabetes, dementia and HIV^5,6,7,8,9,

Protocol

CAUTION: All chemicals used in this protocol must be handled with care. Please carefully read the material safety data sheets (MSDS) of solvents and reagents used in this protocol. (TMS)₃SiH, dimethylsulfamoyl chloride, MeCN, EtOAc and silica have been shown to be toxic, corrosive, irritant, cancerogenic and flammable. Standard lab safety measures are relevant for the handling of those chemicals. All manipulations must be performed in a ventilated laboratory fume hood and the use of appropriate personal protec.......

Discussion

This operationally simple protocol uses commercially available substrates. Nitrogen atmosphere as well as strict water-free conditions are not required for the reaction to proceed in high yields, demonstrating the ease of this protocol. These reactions are often complete within 4 h at room temperature, although some less reactive sulfamoyl chlorides required additional time.

The absence of work-up and the ease of the purification step by silica column chromatography, make this protocol operati.......

Materials

Name	Company	Catalog Number	Comments
Acetonitrile	Sigma Aldrich	34851	for HPLC, ≥99.9%
Biotage			#
Black Polypropylene Screw Caps	Fisherbrand	15394789	-
Blue LED	HepatoChem	P201-18-2 450 nm 18W	-
Capillary tube	Sigma Aldrich	Z114960	volume 5-25 µL
Eosin Y	Sigma Aldrich	E4009	Dye content ~99 %
EtOAc	Sigma Aldrich	34858	for HPLC, ≥99.7%
GraceResolv LOK flash cartridge	Grace	5171343
Magnetic stirring bar	Biotage	355543	-
N,N-Dimethylsulfamoyl chloride	Sigma Aldrich	D186252	-
N-Phenylacrylamide	Homemade	-	-
Pentane	Sigma Aldrich	34956	for HPLC, ≥99.0%
Photoredox Box	HepatoChem	HCK1006-01-016	-
TLC Silica gel 60 F254	Merck	105554	aluminium sheets 20 x 20 cm
Tris(trimethylsilyl)silane	Combi-Blocks	QF-2110	-
Vial holder	HepatoChem	HCK1006-01-020	-
Vial screw glass 7ml	Samco	T101/V3	-