Conjugate Addition of Thiols

Mechanism + Description

1,4-Michael addition of a neutral or anionic thiol to an activated alkene or alkyne.

General comments

A highly atom efficient process to construct thioethers. Thiols or thiolate anions add easily to activated alkenes or alkynes—regioselectivity is predictably 1,4 addition. Typical electron-withdrawing activating groups are keto, ester, nitrile, etc. Sometimes base or organocatalysis is employed. In some cases, chirality can be induced by using chiral organocatalysts as additives.

Key references

Nair, D. P.; Podgórski, M.; Chatani, S.; Gong, T.; Xi, W.; Fenoli, C. R.; Bowman, C. N. The Thiol-Michael Addition Click Reaction: A Powerful and Widely Used Tool in Materials Chemistry. Chem. Mater. 2014, 26, 724–744.

Choudary, B.; Giles, R. G.; Jovic, F.; Lewis, N.; Moore, S.; Urquhart, M. Synthesis of the Pleuromutilin Antibiotic SB-268091: A New Practical and Efficient Synthesis of Quinuclidine-4-thiol. Org. Process Res. Dev. 2012, 16, 1927−1939.

Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Catalyst-Free Conjugated Addition of Thiols to α,β-Unsaturated Carbonyl Compounds in Water. Org. Lett. 2006, 8, 2433–2436.

Sun, Y.; Liu, H.; Cheng, L.; Zhu, S.; Cai, C.; Yang, T.; Yang, L.; Ding, P. Thiol Michael addition reaction: a facile tool for introducing peptides into polymer-based gene delivery systems. Polymer Int. 2018, 67,  25–31.

Azizi, N.; Khajeh-Amiri, A.; Ghafuri, H.; Bolourtchian, M. A highly efficient, operationally simple and selective thia-Michael addition under solvent-free condition. Green Chem. Lett. Rev. 2009, 2, 43–46.

Enders, D.; Lüttgen, K.; Narine, A. Asymmetric Sulfa-Michael Additions. Synthesis 2007, 959–980.   

Relevant scale up examples

None found.