Skip to main content

Thioether Formation

The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures and local laws regarding handling chemicals

*CMR = Carcinogenic, mutagenic, reprotoxic

**Simple ligand = Ph3P, o-Toly3P
Complex ligand = one requiring multi-step(3 -8 RXN) synthesis. Exact positioning on grid will depend on catalytic efficacy for any Individual reaction (TON/TOF)

General Overview

The synthesis of carbon-heteroatom (C-N/O/S) bonds is one of the most common synthetic operations in the pharma industry. While C-N and C-O reactions predominate, C-S bond formation to create thioethers accounts for 5-10% of total carbon-heteroatom reactions. The thioether bond may be an integral part of the API molecule, or oxidised to sulfoxide /sulfone or sulfonyl halide (occasionally sulfonic acid). Sometimes the thioether may be introduced and later removed as a synthetic handle, e.g. leaving group (mesylate, tosylate, sulfone).

The most widely employed disconnections parallel those used in ether synthesis – SN2, SNAr and metal-catalyzed thiolation of aromatics/heteroaromatics where sulfur is a neutral or anionic nucleophile partnered with a carbon-based electrophile. Other disconnections available for thioether formation include conjugate addition to activated alkenes, radical processes – thio-ene/yne reactions, and reactions where sulfur acts as the electrophilic component with carbon-based nucleophiles.

In most cases, free thiol or thiolate anion generated in situ is used as the nucleophilic component in thioether formation. In certain cases, especially if the thiol is prone to oxidation, or is volatile and malodorous, a protected thiol (e.g., SiR3) can be used and deprotected in situ, or the disulfide used is reduced to the thiol in situ before reaction. In other cases, sulfur compounds are used essentially as a thiol equivalent and the thiol ether constructed in situ e.g., thiourea, alkylisothiouronium salts, and even elemental sulfur.

In general, as with many popular synthetic transformations, there is currently a lot of research interest in finding novel transformations and new or better catalytic routes to prepare thioethers, e.g., redox photocatalysis, C-H activation and hydrogen-borrowing chemistry. While thioether containing compounds are often further manipulated to more complex thioethers, this guide focuses solely on the synthetic techniques used to create the carbon-sulfur bond.

Green Criteria for Thioether Formation

  1. Solvents should be chosen to minimise any potential safety and environmental impact.
  2. If possible H340/H341/H360/H361 labelled dipolar aprotic or ethereal solvents should be avoided/substituted.
  3. Newer/neoteric replacements for older dipolar aprotic solvents may have insufficient data to truly evaluate vs. older solvents.
  4. If a dipolar aprotic solvent has to be used, minimize amounts used or see if the dipolar aprotic can be diluted with a more benign solvent.
  5. Reagents should be selected to minimize safety issues. Large molar excesses of reagents should be avoided if possible.
  6. Care should be taken to assess the ability of fluoride anions or HF to damage reactors and other process equipment.
  7. Many low molecular weight thiols and thioethers are highly malodorous and off-gases from reactions should be appropriately treated (scrubbed with NaOCl or other oxidizing agent).
  8. If H2S is used as a reagent, this gas is very toxic and highly flammable—appropriate engineering controls need to be in place. Look for possible H2S surrogates.
  9. SN2 – Leaving group MW <100 to maximize atom economy; Cl, Br, MeSO3 preferred.
  10. Catalytic method if applicable and substrates available.
  11. Inorganic base in preference to organic amine or organometallic reagent.
  12. Optimized stoichiometry to avoid excess of reagents.

General literature reviews on thioether formation

Feng, M.; Tang, B.; Liang, S.; Jiang X. Sulfur Containing Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry Curr. Top. Med. Chem., 2016, 16(11), 1200–1216.

Landelle, G.; Panossian, A.; Leroux, F. R. Trifluoromethyl Ethers and -Thioethers as Tools for Medicinal Chemistry and Drug Discovery. Curr. Top. Med. Chem. 2014, 14(7), 941-951.

Vlasov, V. M. Nucleophilic substitution of the nitro group, fluorine and chlorine in aromatic compounds. Russ. Chem. Rev. 2003, 72(8), 681-703.

Li, L.; Ding, Y. Recent Advances in the Synthesis of Thioether Mini Rev. Org. Chem. 2017, 14, 407-431.

Kazemi, M.; Shiri, L.; Kohzadi, H. Recent Advances in Aryl Alkyl and Dialkyl Sulfide Synthesis. Phosphorus Sulfur Silicon Relat. Elem., 2015, 190(7), 978-1003.    

Boiko, V. N. Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation. Beilstein J. Org. Chem. 2010, 6, 880–921.