AISF: A Stable, Solid Alternative to Sulfuryl Fluoride Gas

Fluorosulfates and sulfamoyl fluorides have applications ranging from chemical biology to polymer chemistry in addition to being valuable synthetic precursors to diaryl sulfates, sulfamides and sulfamates. Synthetic methods to construct fluorosulfates and sulfamoyl fluorides have typically relied on the use of sulfuryl fluoride gas. However, the specialized equipment and additional safety precautions required for working with a toxic gas, in addition to challenges with procurement, have precluded the broad usage of sulfuryl fluoride gas.

Sulfurylation of Phenols and Amines

A solid and bench-stable alternative to sulfuryl fluoride gas has been developed by Pfizer and BioDuro chemists, 4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF, 901243). AISF is a shelf-stable, crystalline reagent for the installation of the valuable SO2F functional group.

AISF - [4-(Acetylamino)phenyl]ImidodiSulfuryl

Advantages

  • Bench stable, crystalline solid reagent used to synthesize fluorosulfates and sulfamoyl fluorides
  • Non-hygroscopic
  • No specialized equipment required – avoids the use of toxic sulfuryl fluoride gas
  • Mild, room temperature conditions
  • Excellent substrate scope
Fluorosulfates

Representative Procedure: To a one-dram vial containing the phenol or amine substrate (0.4 mmol) and AISF (901243; 134 mg, 0.48 mmol, 1.2 equiv.) was added tetrahydrofuran (2 mL) followed by 1,8-diazabicyclo [5.4.0]undec-7-ene (132 µL, 0.88 mmol, 2.2 equiv.) over a period of 30 seconds. The reaction mixture was stirred at room temperature for 10 minutes and then diluted with ethyl acetate or ether and washed with either 0.5 N KHSO4 or 0.5 N HCl (2x) and brine (1x). The combined organic fraction was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography.

Additional base and solvent combinations have also proved effective:

Additional base and solvent combinations

Application to single-flask transformations of phenols:

Application to single-flask transformations of phenols

AISF can be applied to peptide functionalization under aqueous conditions:

AISF can be applied to peptide functionalization

Special thanks to Chris am Ende (Pfizer) and the BioDuro Team for contributing this technology spotlight!

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References

1.
Zhou H, Mukherjee P, Liu R, Evrard E, Wang D, Humphrey JM, Butler TW, Hoth LR, Sperry JB, Sakata SK, et al. 2018. Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides. Org. Lett.. 20(3):812-815. http://dx.doi.org/10.1021/acs.orglett.7b03950

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