Issue 17, 2011

Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure

Abstract

Amino-substituted biphenyls were obtained by Suzuki cross-coupling of 2,6-dibromoaniline with a phenylboronic acid (substituted with Me, NO2, OH, OMe or Cl) preferably assisted by microwave irradiation. Conversion of the amino group into a thiol preceded a base-induced intramolecular substitution, also facilitated by microwave heating, to generate the second C–S bond of the target dibenzothiophene. The 1-, 2-, 3- or 4-substituted 6-halodibenzothiophenes obtained were subjected to a palladium-mediated coupling with 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one to give the respective 6-, 7-, 8- or 9-substituted dibenzothiophen-4-ylchromenones. These compounds were evaluated as inhibitors of DNA-dependent protein kinase (DNA-PK) and compared to the parent 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-chromen-4-one. Notably, derivatives bearing hydroxy or methoxy substituents at C-8 or C-9 retained activity, whereas substitution at C-7 lowered activity. Substitution with chloro at C-6 was not detrimental to activity, but a chloro group at C-7 or C-8 reduced potency. The data indicate permissive elaboration of hydroxyl at C-8 or C-9, enabling the possibility of improved pharmaceutical properties, whilst retaining potency against DNA-PK.

Graphical abstract: Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure

Supplementary files

Article information

Article type
Paper
Submitted
21 Feb 2011
Accepted
18 May 2011
First published
18 May 2011

Org. Biomol. Chem., 2011,9, 6066-6074

Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure

S. Rodriguez-Aristegui, K. M. Clapham, L. Barrett, C. Cano, M. Desage-El Murr, R. J. Griffin, I. R. Hardcastle, S. L. Payne, T. Rennison, C. Richardson and B. T. Golding, Org. Biomol. Chem., 2011, 9, 6066 DOI: 10.1039/C1OB05282A

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