Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

Abstract

Reactions of thiobenzamide or thioacetamide with 4-bromo-1,1-dimethyl-1,4-dihydroisoquinoline-3(2H)-one, 4-bromoisoquinoline-1,3(2H,4H)-dione and two α-bromo(phenyl)acetamides were examined under various conditions (base, solvent, thiophile, temperature) and structure/medium features that influence product distribution (Eschenmoser coupling reaction, Hantzsch thiazole synthesis and elimination to nitriles) were identified. The key factor that enables the successful Eschenmoser coupling reaction involves the optimum balance in acidity of nitrogen and carbon atoms of the intermediary α-thioiminium salts.

Keywords: Eschenmoser coupling reaction; Hantzsch thiazole synthesis; isoquinolin-4-ones; primary thioamides; structure–reactivity relationships.

Scheme 1

Eschenmoser coupling reaction between 3-substituted oxindoles and thioamides.

Scheme 2

Possible reactions of α-haloketones, esters and amides with primary thioamides.

Figure 1

Studied α-bromoamides and α-bromolactams.

Scheme 3

Reaction of 4-bromo-1,1-dimethyl-1,4-dihydroisoquinolin-3(2H)-one (2b) with thiobenzamide and thioacetamide.

Scheme 4

Reaction of 4-bromo-1,1-dimethyl-1,4-dihydroisoquinolin-3(2H)-one (2b) with 4’-substituted thiobenzanilides and thioacetanilide.

Scheme 5

Reaction of 4-bromoisoquinoline-1,3(2H,4H)-dione (3) with thiobenzamide, thioacetamide, and thiobenzanilide.

Scheme 6

Reaction of N-phenyl- and N-methyl-2-bromo(phenyl)acetamide (4a,b) with thiobenzamide in acetonitrile.

Scheme 7

Transformation of salt 15 under kinetic and thermodynamic control conditions [1].

Figure 2

Comparison of energy profiles (relative Gibbs energies at 298 K in kJ·mol⁻¹ for the ECR (right) and Hantzsch (left) pathways for salts 6a, 10a, 12a, and 15 calculated at the B3LYP-D3/6-311++G(d,p) level of theory in N,N-dimethylformamide (SMD). Extended version of Figure 2 involving energies of final products can be found in Supporting Information File 1.