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

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• -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

• potential in the synthesis of various tyrosine kinase inhibitors, including hesperadin and the approved drug nintedanib. The key step of the synthesis involves the Eschenmoser coupling reaction (ECR) between a substituted 3-bromooxindole 1 and appropriate primary, secondary or tertiary thioamides which

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction

• Lukáš Marek,
• Lukáš Kolman,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2021, 17, 527–539, doi:10.3762/bjoc.17.47

• inhibiting activity, was prepared in yields varying mostly from 70 to 97% and always surpassing those obtained by other published methods. The method includes an Eschenmoser coupling reaction, which is very feasible (even without using a thiophile except tertiary amides) and scalable. The (Z)-configuration

• of all products was confirmed by NMR techniques. Keywords: 3-bromooxindoles; Eschenmoser coupling reaction; thioamides; tyrosin kinase inhibitors; (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones; Introduction 3-(Aminomethylidene)-1,3-dihydro-2H-indol-2-ones (3-(aminomethylidene

• desired Eschenmoser coupling reaction (route b). Therefore, the nucleophilicity of the conjugated base of the nitrogen (benzenecarbimidothioate or thioimidate) is exerted towards the oxindole carbonyl to give the thiazole. Moreover, if both benzene rings contain electron-withdrawing groups, enhancing

The Eschenmoser coupling reaction under continuous-flow conditions

• Sukhdeep Singh,
• J. Michael Köhler,
• Andreas Schober and
• G. Alexander Groß

Beilstein J. Org. Chem. 2011, 7, 1164–1172, doi:10.3762/bjoc.7.135

• [13], were prepared by utilization of the Eschenmoser coupling reaction. Recently, we explored the Eschenmoser coupling in order to produce Biginelli type dihydropyrimidine (DHPM) derivatives as screening candidates for pharmaceutical and crop science research [14]. Moreover, the Eschenmoser coupling

• agent, the mechanism of extraction via intermediate ionic states also seems plausible. Nevertheless, the Eschenmoser coupling reaction requires the addition of a base and a thiophilic agent in the most cases. Here, triphenylphosphine- or trialkyl-phosphite-derivatives are usually employed to promote the

• . Capillary reactor with jacketed cover removed, and the process controller. Eschenmoser coupling reaction with secondary S-alkylated thioamide derivatives of type 3. Eschenmoser coupling sequence of S-alkylated ternary thioamides of type 7. Exclusive formation of thiazol 13 with dihydropyrimidine derivatives