Byproducts formed During Thiol-Acrylate Reactions Promoted by Nucleophilic Aprotic Amines: Persistent or Reactive?

The nucleophile-initiated mechanism of thiol-Michael reactions naturally leads to the formation of undesired nucleophile byproducts. Three aza-Michael compounds representing nucleophile byproducts of thiol-acrylate reactions initiated by 4-dimethylaminopyridine (DMAP), 1-methylimidazole (MIM), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been synthesized and their reactivity in the presence of thiolate has been investigated. Spectroscopic analysis shows that each nucleophile byproduct reacts with thiolate to produce a desired thiol-acrylate product along with liberated aprotic amines DMAP, MIM, or DBU, thus demonstrating that these byproducts are reactive rather than persistent. Density functional theoretical computations support experimental observations and predict that a β-elimination mechanism is favored for converting each nucleophile byproduct into a desired thiol-acrylate product, though an SN 2 process can be competitive (i. e. within <2.5 kcal/mol) in less polar solvents.