Thioalkylation with Sulfur as the Electrophile

Mechanism + Description

Attack of a carbon nucleophile on a sulfur atom activated by a suitable leaving group generating the thioether.

General comments

Essentially an umpolung of the classical Williamson-type ether synthesis where the sulfur atom is the electrophile and the carbon synthon a nucleophile. Typically the leaving group will be electron withdrawing thus activating sulfur towards nucleophilic attack. A number of leaving groups have been described: symmetrical disulfides, unsymmetrical disulfides where attack at the required S atom can be directed, S-Cl, S-CN, Bunte salts and thiosulfonates. The nucleophile can be an organometallic species, e.g., Li, MgX or an electron-rich arene/heteroarene. In the case of electron-rich aromatics, Lewis acidic metals are often used as catalysts. Recently, disulfides have been described as coupling partners in Pd-catalyzed synthesis of aryl thiol ethers.

Key references

Reeves, J. T.; Camara, K.; Han, Z. S.; Xu, Y.; Lee, H.; Busacca, C. A.; Senanayake, C. H. The Reaction of Grignard Reagents with Bunte Salts: A Thiol-Free Synthesis of Sulfides. Org. Lett. 2014, 16, 1196–1199.

Pakulski, Z.; Pierożyński, D.; Zamojski, A. Reaction of sugar thiocyanates with Grignard reagents. New synthesis of thioglycosides. Tetrahedron, 1994, 50, 2975–2992. 

Iwasaki, M.; Iyanaga, M.; Tsuchiya, Y.; Nishimura, Y.; Li, W.; Li, Z.; Nishihara, Y. Palladium‐Catalyzed Direct Thiolation of Aryl C–H Bonds with Disulfides. Chem. Eur. J. 2014, 20, 2459–2462.

Relevant scale up examples

Org. Process Res. Dev. 2005, 9, 555–569
60 kg scale

Org. Process Res. Dev. 2010, 14, 787–798.
2 kg scale

Org. Process Res. Dev. 2012, 16,1746−1753.
60 kg scale

Org. Process Res. Dev. 2011, 15, 1040–1045.
200 g scale