Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations

Abstract

Monothiomalonates (MTMs) are surrogates of thioester enolates that allow for stereoselective C–C bond formations under mild conditions and thereby afford access to synthetically versatile thioester derivatives. Here we present a straightforward synthetic route to MTMs that proceeds through nucleophilic ring‐opening of Meldrum's acid derivatives followed by O‐alkylation of the resulting malonic acid half thioesters with alkyl triflates or acetimidates as electrophiles. The method affords MTMs in overall yields of 34 – 92% and allows for variations of the oxo‐ and thioester moieties as well as the substituent at the C(α) position.

Decarboxylative Organocatalyzed Aldol-Type Addition Reaction of Chloroacetate Surrogates

“…For the synthesis of 3, we first prepared chloro-Meldrum's acid 5 in three steps from Meldrum's acid. 13 Upon addition of a slight excess of trimethylsilyl-protected p-methoxythiophenol 3 formed in 94% yield (Scheme 1). Here, the use of a silylprotected thiol and an acidic workup were crucial for preventing decarboxylation of Cl-MAHT.…”

“…For the synthesis of 3 , we first prepared chloro-Meldrum’s acid 5 in three steps from Meldrum’s acid . Upon addition of a slight excess of trimethylsilyl-protected p -methoxythiophenol 3 formed in 94% yield (Scheme ).…”

Dichloromeldrum’s Acid (DiCMA): A Practical and Green Amine Dichloroacetylation Reagent

“…Hence, we focused on the discovery of a safer and more benign dichloroacetylation reagent than those previously used in the traditional approaches. While Meldrum’s acid itself reacts readily with electrophiles to produce alkylated or acylated scaffolds, we hypothesized that the dichlorinated derivative should accept nucleophiles now that the α-protons have been removed and the electrophilicity of the carbonyl has been enhanced . The subsequent loss of acetone and CO 2 would not only provide easily separable byproducts, but provide a driving force that should facilitate rapid and room temperature reactivity.…”