Substituted benzoquinazolinones. Part 2: Synthesis of amino-, and sulfanyl-derivatives of benzo[f]- and benzo[h]quinazolinones

• Published in: Tetrahedron Vol. 71; no. 50; pp. 9463 - 9473
• Main Authors: Nowak, Monika, Malinowski, Zbigniew, Fornal, Emilia, Jóźwiak, Andrzej, Parfieniuk, Ewa, Gajek, Gabriela, Kontek, Renata
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 16.12.2015; Elsevier
• Subjects: Anticancer activity; aza-Fries rearrangement; Beznoquinazolinones; Bromine–lithium exchange; Buchwald–Hartwig reaction; Chemistry; Chemistry, Organic; Palladium coupling; Physical Sciences; Science & Technology; aza-Fries rearrangement; Buchwald–Hartwig reaction; Beznoquinazolinones; Palladium coupling; Anticancer activity; Bromine–lithium exchange; OXIDATION; Bromine-lithium exchange; ANALOGS; ACIDS; THYMIDYLATE SYNTHASE; DISCOVERY; Buchwald Hartwig reaction; N-BROMOSUCCINIMIDE; KINETICS; INHIBITORS; DUOCARMYCIN
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2015.10.049

Amino- and sulfanyl-derivatives of benzoquinazolinones 16a–c, 20a–c and 21a–c were prepared under palladium-catalyzed Buchwald–Hartwig coupling reaction using bromobenzoquinazolinones 15, 19a, 19b and 1-substituted piperazines or mercaptans. The combination of Pd(OAc)2 with XantPhos proved to be the best for these conversions in the presence of KOt-Bu, in 1,4-dioxane as a solvent, at 90–100 °C. The 8-bromobenzo[f]quinazolin-1(2H)-one 15 was synthesized via condensation of the ethyl or tert-butyl 2-amino-8-bromonaphthalene-1-carboxylate 6, 10 with formamide, followed by reaction with 3,4-dimethoxybenzyl bromide. However, the 6-bromobenzo[h]quinazolin-4(3H)-ones 19a, 19b were prepared from ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]naphthalene-2-carboxylate (17). Biological screening of the potential cytotoxicity of compounds 16a, 20a, 20c on HT29 and HCT116 cell lines, has shown that compound 20a has a significant anticancer activity. [Display omitted]