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In This Article

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

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 agrochemicals1,2. Initially employed for antibacterial purposes3,4, the application of this motif in drug discovery has been extended to numerous diseases including cancer, CNS disorders, diabetes, dementia and HIV5,6,7,8,9,10,11. Sulfonamides stand out as metabolically stable bioisosteres of carboxylic acids and carboxamides, with the N-H pKa being tunable by varying substitution patterns12,13,14,15.

Traditionally, sulfonamides are synthesized by substitution of a sulfonyl chloride with an amine16,17. The synthesis of sulfonyl chlorides often relies on a multi-step procedure employing harsh conditions, such as strong oxidants. Whilst milder one-step protocols for the installation of sulfonyl chloride intermediates have been developed18,19, the design of a single-step transformation to access sulfonamides is highly desirable.

In the last decades, powerful strategies have been developed for the synthesis of (hetero)aryl sulfonamides, using transition metals, photoredox catalysis or organic catalysts20,21,22,23,24,25,26,27,28,29,30,31,32,33,34. Nevertheless, the one-step synthesis of aliphatic analogues remains underexplored35,36,37,38,39,40. A notable exception is the electrochemical oxidative coupling of amines and thiols, reported by Noël and co-workers41. We were interested in a complementary late-stage functionalization strategy, allowing the direct attachment of commercially available sulfamoyl chlorides onto inexpensive olefins to afford products of net hydrosulfamoylation under visible light activation. Specifically, this process requires an in situ generated sulfamoyl radical, and a suitable hydrogen atom donor.

Preliminary studies indicated that the direct single electron reduction of N,N-dimethylsulfamoyl chloride (Ered = -1.59 V versus saturated calomel electrode (SCE) in MeCN)42 is more challenging than for methanesulfonyl chloride (Ered = -1.30 V versus SCE in MeCN)43, an observation encouraging the identification of an alternative mode of activation to generate sulfamoyl radicals. Inspired by Chatgilialoglu’s work in 198844, we believed that tris(trimethylsilyl)silane can act both as a silyl radical source capable of activating sulfamoyl chlorides, and as the hydrogen atom donor. Blue light irradiation is essential for this reaction to proceed, while Eosin Y is beneficial but not essential.

This practical and cost-effective one-step method tolerates numerous functional groups, thereby allowing access to a broad range of novel alkylsulfonamides including complex sulfonamide-containing cyclobutyl-spirooxindoles that are all valuable building blocks for drug discovery. As part of the challenges faced by industries aiming at avoiding operationally complex, over-engineered, and costly processes, this transformation is not sensitive to oxygen or moisture, uses a metal free photocatalyst, and is operationally simple. Furthermore, the use of blue light as an initiator for this chemical transformation makes this protocol green and sustainable.

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 protective equipment (PPE), including lab coat, safety glasses, and nitrile gloves is compulsory.

1. Hydrosulfamoylation of electron-deficient alkenes

  1. Add a magnetic stir bar to a 7 mL vial.
  2. Weigh out 73.5 mg of N-phenylacrylamide (0.50 mmol, 1.0 equiv) and 1.7 mg of photocatalyst Eosin Y (0.0025 mmol, 0.5 mol%) and add both to the same vial.
  3. Sequentially add 3.0 mL of MeCN, 309 µL of (TMS)3SiH (1.0 mmol, 2.0 equiv) and 134 µL of N,N-dimethylsulfamoyl chloride (1.25 mmol, 2.5 equiv) with a syringe. Cap the vial with a screw cap.
  4. Place the vial in the photobox equipped with an 18 W blue LED lamp (λ = 450 nm) and a fan.
  5. Stir the emulsion vigorously at 1,000 rpm for 4 h.

2. Monitoring of the starting material conversion by thin-layer chromatography (TLC)

  1. Dissolve 1 mg of N-phenylacrylamide in 1 mL of dichloromethane (DCM). Sample this solution on the TLC plate (left and middle spot).
  2. Sample a 50 μL aliquot of the reaction mixture and transfer it to a 1.5 mL vial containing 50 μL of DCM. Sample this solution on the TLC plate (middle and right spot).
  3. Add a solvent mixture of pentane and ethyl acetate (eluent: 80/20 pentane/ethyl acetate) to a TLC chamber.
  4. Run the TLC plate in the chamber until the solvent front is at 0.5 cm distance of the top of the plate.
  5. Remove the plate from the chamber, dry it under air and expose the plate to UV light (λ = 254 nm) under a lamp (Rf values: Starting material = 0.4; Product = 0.2).

3. Workup and purification

  1. Transfer the reaction mixture to a 25 mL round-bottom flask and concentrate the mixture under reduced pressure using a rotary evaporator (150 rpm; until 20 mbar) equipped with a water bath, heated to 40 °C to obtain a crude oil.
  2. Condition a silica column (pore size 60 Å, 230–400 mesh particle size, 12 g) by passing 60 mL of pentane through the column via a syringe.
  3. Dilute the crude oil in 2 mL of DCM and transfer the solution onto the column.
  4. Run a gradient elution on the automated column (EtOAc in pentane 0/100 to 100/0 over 20 min) and monitor by UV-VIS (254 nm) to elute the compounds.
  5. Collect the fractions in test tubes and monitor the collected fractions by TLC (see section 2).
  6. Sample aliquots of the collected fractions on a TLC plate.
  7. Run the TLC plate in the chamber until the solvent front has almost reached the top of the plate and compare the Rf values (see step 2.5).
  8. Collect the desired fractions as determined by TLC analysis and concentrate the solution under reduced pressure on a rotary evaporator (150 rpm; less than 20 mbar) equipped with a water bath heated to 40 °C.
  9. Dissolve 5 mg of the product in 0.6 mL CDCl3 and add this solution to a nuclear magnetic resonance spectroscopy (NMR) tube.
  10. Run a 1H NMR and a 13C NMR and compare the spectra with the information listed below.

תוצאות

The sequence produced the desired hydrosulfamoylated product with 83% yield (106 mg, 0.41 mmol) as an off-white solid. The structure and purity can be assessed by 1H and 13C NMR spectra (Figure 1, Figure 2). More specifically, in the 1H and 13C NMR, disappearance of two characteristic alkene peaks and appearance of two aliphatic peaks, are characteristic for the addition of N,N-dimethylsulfamoyl chloride to th...

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...

Disclosures

The authors have nothing to disclose.

Acknowledgements

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 721902.

Materials

NameCompanyCatalog NumberComments
AcetonitrileSigma Aldrich34851for HPLC, ≥99.9%
Biotage#
Black Polypropylene Screw CapsFisherbrand15394789-
Blue LEDHepatoChemP201-18-2 450 nm 18W-
Capillary tubeSigma AldrichZ114960volume 5-25 µL
Eosin YSigma AldrichE4009Dye content ~99 %
EtOAcSigma Aldrich34858for HPLC, ≥99.7%
GraceResolv LOK flash cartridgeGrace5171343
Magnetic stirring barBiotage355543-
N,N-Dimethylsulfamoyl chlorideSigma AldrichD186252-
N-PhenylacrylamideHomemade--
PentaneSigma Aldrich34956for HPLC, ≥99.0%
Photoredox BoxHepatoChemHCK1006-01-016-
TLC Silica gel 60 F254Merck105554aluminium sheets 20 x 20 cm
Tris(trimethylsilyl)silaneCombi-BlocksQF-2110-
Vial holderHepatoChemHCK1006-01-020-
Vial screw glass 7mlSamcoT101/V3-

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SulfonamidesSulfamoyl ChloridesVisible Light ActivationElectron deficient AlkenesRadical PrecursorsEosin YPhotocatalystHydrosulfamoylationMethodologyPharmaceutical IndustryFunctional Group ToleranceLate stage FunctionalizationScalable ReactionPractical Method

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