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. 2021 Feb 23:17:527-539.
doi: 10.3762/bjoc.17.47. eCollection 2021.

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

Lukáš Marek  1 , Lukáš Kolman  1 , Jiří Váňa  1 , Jan Svoboda  1 , Jiří Hanusek  1
Affiliations

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

Lukáš Marek et al. Beilstein J Org Chem. .

Abstract

A highly modular method for the synthesis of (Z)-3-[amino(phenyl/methyl)methylidene]-1,3-dihydro-2H-indol-2-ones starting from easily available 3-bromooxindoles or (2-oxoindolin-3-yl)triflate and thioacetamides or thiobenzamides is described. A series of 49 compounds, several of which have previously been shown to possess significant tyrosin kinase 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: (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones; 3-bromooxindoles; Eschenmoser coupling reaction; thioamides; tyrosin kinase inhibitors.

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Figures

Figure 1
Figure 1
Nintedanib ethanesulfonate.
Scheme 1
Scheme 1
The known synthetic strategies leading to 3-(aminomethylidene)oxindoles.
Scheme 2
Scheme 2
The possible intermediates and products occurring in the reactions of 3-bromooxindoles with thiobenzamides.
Figure 2
Figure 2
The R1 and R2 substitution influence on the isolated yields of products 5aa–ed.
Scheme 3
Scheme 3
The Eschenmoser coupling reaction of 3-bromooxindole (1a) with thioacetamides.
Scheme 4
Scheme 4
The synthesis of alternative 3-substituted oxindoles and their Eschenmoser coupling reaction with thiobenzamide (2a).
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References

    1. Howard H R Jr, Sarges R, inventors. Heteroylidene indolone compounds. US 4,476,307. U.S. Patent. 1984 Oct 9;
    1. Sarges R, Howard H R, Koe B K, Weissman A. J Med Chem. 1989;32:437–444. doi: 10.1021/jm00122a025. - DOI - PubMed
    1. Davis S T, Dickerson S H, Frye S V, Harris P A, Hunter R N, Kuyper L F, Lackney K E, Lackney M J, Veal J M, Walker D H, inventors. Substituted oxindole derivatives as protein tyrosine kinase and as protein serine/threonine kinase inhibitors. WO 99/15500 A1. WO Pat. Appl. 1999 Apr 1;
    1. Grell W, Wittneben H, van Meel J C A, Redemann N, Walter R, Himmelsbach F, Haigh R, inventors. Indolinones having kinase-inhibiting activity. US 6,043,254 A. U.S. Pat. Appl. 2000 Mar 28;
    1. Bramson H N, Corona J, Davis S T, Dickerson S H, Edelstein M, Frye S V, Gampe R T, Harris P A, Hassell A, Holmes W D, et al. J Med Chem. 2001;44(25):4339–4358. doi: 10.1021/jm010117d. - DOI - PubMed