Synthesis of sulfoxides and sulfones via oxidation of thioethers

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General Overview

Sulfoxides and sulfones are common structural motifs found in pharmaceuticals and agrochemicals. Occasionally these groups are introduced and later removed or modified, being used as handles for further synthetic manipulations, but in the majority of cases, they remain as an integral part of the final product.

The most common routes to sulfoxides and sulfones is via oxidation of dialkyl and aryl sulfides. Historically this was carried out with toxic and environmentally detrimental high valent metal reagents. These have largely been replaced by more benign reagents such as stoichiometric oxidants and catalytic methods using reagents like air/O2 and H2O2 as the terminal oxidants.

Most common oxidants will convert sulfides to sulfoxides and sulfones. Kinetically slow/less reactive oxidants are often employed with metal/bio catalysts to give an acceptable reaction rate. To maximize reaction efficiency when sulfoxides are the desired product then the following can minimize over reaction to sulfone:

  • Careful control of reaction stoichiometry
  • Mode of addition – add oxidant to reaction
  • Careful monitoring to avoid over-oxidation/li>
  • Acidic conditions can sometimes suppress sulfone formation/li>
  • Use of catalytic methods with lower reactivity terminal oxidants

Unsymmetrically substituted sulfoxides derived from prochiral sulfides exist as enantiomeric mixtures. Methodology to produce single enantiomer sulfoxides in high ee is important for the pharmaceutical industry, and various methods exist such as chiral stoichiometric oxidants, chiral metal complexes (catalytic and stoichiometric) and biocatalysis using enzymes such as Baeyer-Villiger monooxygenases.

General literature reviews on sulfoxides and sulfones via oxidation of thioethers

Adams, J. P.; Alder,C. M.; Andrews, I.; Bullion, A. M.; Campbell-Crawford, M.; Darcy, M. G.; Hayler, J. D.; Henderson, R. K.; Oare, C. A.; Pendrak, I.; Redman, A. M.; Shuster,L. E.; Sneddon, H. F.; Walker, M. D. Development of GSK's reagent guides – embedding sustainability into reagent selection. Green Chem., 2013,15, 1542-1549.

Rayner, C. M. Thiols, sulfides, sulfoxides, and sulfones. Contemp. Org. Synth. 1994, 1, 191-203.

O'Mahony, G. E.; Ford, A.; Maguire, A. R. Asymmetric oxidation of sulfides.  J. Sulfur Chem. 2013, 34, 301-341.

Kinen, C. O.; Rossi, L. I.; Hoyos de Ross, L. The development of an environmentally benign sulphide oxidation procedure and its assessment by green chemistry metrics. Green Chem. 2009, 11, 223-228.

Fernández, I.; Khiar, N. Recent Developments in the Synthesis and Utilization of Chiral Sulfoxides Chem. Rev. 2003, 103, 3651-3705.

 Caron, S.; Dugger, R. W.; Gut, S.; Ruggeri, Ragan, J. A.; Brown Ripin, D. H. Large-Scale Oxidations in the Pharmaceutical Industry. Chem. Rev. 2006, 106, 2943-2989.

 Li, Y.; Jiang, X. Green Oxidation of Sulfide to Sulfoxide and Sulfone. Green Oxidation in Organic Synthesis 2019, 329-360.

Kupwade, R. V. A Concise Review on Synthesis of Sulfoxides and Sulfones with Special Reference to Oxidation of Sulfides.  J. Chem. Rev. 2019, 1(2), 99-113

Drabowicz, J.; Mikołajczyk, M. Synthesis of sulphoxides. A review Org. Prep. Proc. Int. 1982, 14, 45-89. 

Matavos-Aramyan, S.; Soukhakian, S.; Jazebizadeh, M. H. Selected methods for the synthesis of sulfoxides and sulfones with emphasis on oxidative protocols. J. Phosphorus, Sulfur, and Silicon and the Related Elements 2020, 195, 181-193.

Ciriminna, R.; Albanese, L.;  Meneguzzo, F.; Pagliaro, M. Hydrogen Peroxide: A Key Chemical for Today's Sustainable Development. ChemSusChem, 2016, 9, 3374-3381.

Liu, N-W.; Shuai Liang, S.; Manolikakes, G. Recent Advances in the Synthesis of Sulfones. Synthesis 2016, 48, 1939-1973.

Further web-based resources

Green Criteria for oxidation of thioethers

  1. Large molar excesses of reagents should be avoided if possible.
  2. Solvents with CMR properties/alerts should be avoided
  3. Oxidants with lower mass intensity should be used if possible -O2, H2O2 preferred.
  4. High impact oxidants like heavy metals (Ce, Cr, Mn), and hypervalent iodine materials should be avoided.
  5. Consideration needs to be given to safe operating procedures and avoiding formation of hazardous mixtures with solvents with known incompatibility to specific oxidants. The process should have no major safety issues with uncontrolled exotherms and the generation of hazardous waste is minimized and controlled.
  6. Large molar excesses of oxidants should be avoided if possible.
  7. Any excess oxidant should be safely destroyed at the end of the reaction.
  8. Reaction stoichiometry needs careful optimization if sulfoxides are the desired product to avoid lowering yields due to over oxidation.
  9. Consider using catalysis to allow the use of O2/H2O2 as terminal oxidants.
  10. Base metals are preferred to Platinum group metals (PGM) for catalytic reactions.
© 2015 Green Chemistry Institute Pharmaceutical Roundtable. All rights reserved.