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, NO(2), 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.

Iodine/DMSO-Promoted Selective Direct Arylthiation of Anilines with Thiols under Metal-Free Conditions

“…2-((2-Bromophenyl)thio)-4-methylaniline (5ah). 32 Light-yellow solid (petroleum ether/EtOAc = 50:1); 80% (47.1 mg); mp 82−84 °C; 1 H NMR (400 MHz, CDCl 3 ): δ 7.51 (d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.09 (t, J = 7.5 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 3.87 (s, 2H), 2.25 (s, 3H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ): δ 146.7, 138. 1, 137.8, 132.7, 132.6, 128.4, 127.7, 126.2, 126.1, 120.5, 115.6, 113.0, 20.2. 2-((2,3-Dichlorophenyl)thio)-4-methylaniline (5ai).…”