Carbocyclic functionalization of quinoxalines, their chalcogen congeners 2,1,3-benzothia/selenadiazoles, and related 1,2-diaminobenzenes based on nucleophilic substitution of fluorine

Abstract Previously unknown mono-, di- and in some cases tri- and tetra- carbocycle-substituted quinoxalines ( 2 – 8 ), 2,1,3-benzothiadiazoles ( 11 , 12 , 14 – 17 ) and 2,1,3-benzoselenadiazoles ( 20 - 25 ) were synthesized by nucleophilic substitution of fluorine in 5,6,7,8-tetrafluoroquinoxaline ( 1 ) and 4,5,6,7-tetrafluoro-2,1,3-benzothia/selenadiazoles ( 10 and 19 , respectively) with methoxide and dimethylamine. In the 1:1 reactions, the nucleophiles attacked selectively the position 6 of 1 or the position 5 of 10 and 19 . The regioselective nature of the 1:1 reactions was confirmed by the DFT calculations at the M06-2X/6-31+G(d,p) level of theory. Disubstituted quinoxaline ( 28 ), thia- ( 29 ) and selena- ( 30 ) diazoles bearing two different substituents, i.e. MeO- and Me 2 N-, were synthesized in a similar way. New substituted 1,2-diaminobenzenes ( 31 – 33 ) were prepared by reduction of corresponding thiadiazoles ( 12 , 14 , 15 ) and isolated in the form of hydrochlorides. Compound 33 was converted into a new quinoxaline ( 34 ) by reaction with (PhCO) 2 . Compounds 5 , 7 and 14 were studied for cytotoxicity toward the human cancer cells and effects on the cytochrome P450 mRNA expression. They did not cause any significant modulations in the expression of several cytochrome P450 genes, and 7 was weakly toxic for the Hep2 (carcinoma) and U937 (leukemia) cells, particularly, apoptosis was observed.