1,3,4-Thiadiazino[5,6-b]quinoxaline

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(1)Journal of the Korean Chemical Society 2003, Vol. 47, No. 3 Printed in the Republic of Korea. . 1,3,4-Thiadiazino[5,6-b]quinoxaline * Yoshihisa Kurasawa

(2) (2003. 4. 7 ). †. †. Synthesis of 1,3,4-Thiadiazino[5,6-b]quinoxalines with Antimicrobial Activity Ho Sik Kim*, Tong Eun Kim, Kyong Hwan Lee, and Yoshihisa Kurasawa† Department of Chemistry, Catholic University of Daegu, Gyongsan 712-702, Korea † School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan (Received April 7, 2003). :. , . 1,3,4-Thiadiazino[5,6-b]quinoxaline ,. Keywords: 1,3,4-Thiadiazino[5,6-b]quinoxalines, Antimicrobial Activity, Algicidal Activity. . @, .8A@B(Chart 2), 5 CD@, . E ./ 3 C -Me F C -Ph! G !, HI 8! 9J! KLM " NMO 2P QRM HI 5 ST 4H-1,3,4-thiadiazino[5,6-b]quinoxline% . T U (. VWO " MO 1,3,4-thiadiazino[5,6-b]quinoxaline % .T XY3 !>@, 2,3-dihydroxyquinoxaline (10) 2,6-dichloroquinoxaline(11)3 Z[/\, ]^ ^_ & à >?`b quinoxaline '-M 1,3,4thiadiazine '- .E c,d 1,3,4-thiadiazino[5,6b]quinoxaline% .]e@f, .T ./M T 3 g]e. 5,6. 4H-1,3,4-Thiadiazine(1) quinoxaline(2) !"#$ % &' ((Chart 1). ) *+,'- ./0 1/23 & 45 6' 7'89 (. :& 4H-1,3,4thiadiazino[5,6-b]quinoxaline(3) 2,3-dichloroquinoxaline(4) thioacylhydrazine(5); Smiles -<=>? 1-3. 4. 2. 2. 7-9.

(3) . Chart 1.. " NYMO ghT à ijk3 lm]& n' gh]e@f, ho EPj3 p, gh]e. Z[/ \, ghT 2,3-dihydroxyquinoxaline(10) 2,6LqM rst CD@, dichloroquinoxaline(11) .]e. u-' vw Haake Buchlerg; x& y vw zl{H,| }A', 7l ]& n~. 10. 11,12. Chart 2.. 301.

(4) Yoshihisa Kurasawa. 302. Mattson Polaris FT-IR % g h]^ }A', H NMR Varian Gemini200(200 MHz) % gh]^ }A. u-' Mass Shimadzu GC/MS QP-5000 % gh ]^ }A. IR. 1. 2-Substitutedamino-4H-1,3,4-thiadiazino[5,6-b]quinoxaline. (14) . I! E 100 mL W M ./ 13(1 g, 5 mmol), methyl isothiocyanate(0.56 g, 7.7 mmol), u-' N,N-x 30 mL% ' !MO 2` I`. >?/3 N@, ` 1E '% ^ T N,N-x /MQ, ¡l]^ ¢ £ ¡l$ 2methylamino-4H-1,3,4-thiadiazino[5,6-b]quinoxaline. ¤¥ 46%)3 }A. mp: 240-241 C; o. (14a) 0.53 g(. 1238; MS(m/z): 325(M+), 327(M ++2); 1H NMR(DMSOd6, δ): 11.48(s, 1H, NH), 9.83(s, 1H, NH), 7.94-7.55(m, 4H, aromatic H), 4.25(q, J=7.0 Hz, 2H, CH2), 1.28(t, J=7.0 Hz, 3H, CH3). 6-Chloro-2-[2-(N-substituted thiocarbamoyl)-. (.

(5) ). I! E 100 mL WM . / 17(1 g, 5 mmol), methyl isothiocyanate(0.73 g, 10 mmol), u-' tetrahydrofuran 30 mL% ' /M O 3` I`. ho% °[m± ` /3 ² 1³ ¡l3 ^ ]^ £ ¡l$ 6-chlorohydrazino]quinoxaline 4-Oxide (18). 2-[2-(N-methylthiocarbamoyl)hydrazino]quinoxaline. ¤¥ 69%)3 }A. mp: 223-. 4-oxide(18a) 0.98 g(. 224 oC; IR(KBr, cm−1): 3273, 1576, 1561, 1498, 1391,. IR(KBr, cm−1): 3365, 1639, 1410; MS(m/z): 231(M +);. 1223; MS(m/z): 283(M+), 285(M ++2); 1H NMR(DMSO-. H NMR(DMSO-d6, δ): 10.11(s, 1H, NH), 7.65-7.24. d6, δ): 9.52(s, 1H, NH), 9.48(s, 1H, NH), 8.26(s, 1H,. (m, 4H, aromatic H), 6.63(brs, 1H, NH), 2.70(d, J=4.6. C3-H), 7.90(s, 1H, C5-H), 7.80-7.70(m, 2H, aromatic C7-. Hz, 3H, CH3).. H and C8-H), 2.87(d, J=4.3 Hz, 3H, CH3).. carbonyl isothiocyanate. hydrazino]quinoxaline 4-Oxide(18b). 1. u-', ./ 133 phenyl isothiocyanate F ethoxy >?`b ./ 14b,c% .¦ X§M ./ 14a ¨©ª, ]e@ B, ho MQ3 gh]e. 2-Phenylamino-4H-1,3,4-thiadiazino[5,6-b]quinoxaline (14b). '«£ ¡l@, 0.90 g(¤¥ 61%)3 }A. −1. o. 6-Chloro-2-[2-(N-ethoxycarbonylthiocarbamoyl)-. ´£ ¡l@,. ¤¥ 74%)3 }A. mp: 176-177 C; IR(KBr, o. 1.26 g( −1. cm ): 3210, 1719, 1541, 1478, 1233; MS(m/z): 341(M+), 343(M++2); 1H NMR(DMSO-d6, δ): 11.63(s, 1H, NH), 11.40(s, 1H, NH), 10.52(s, 1H, NH), 8.63(s, 1H, C3-H),. mp: 300 C(dec.); IR(KBr, cm ): 3230, 1637, 1409, 748,. 7.93(s, 1H, C5-H), 7.80-7.40(m, 2H, aromatic C7-H and C8-. 689; MS(m/z): 293(M+); 1H NMR(DMSO-d6, δ): 10.35. H), 4.24(q, J=7.0 Hz, 2H, CH2), 1.28(t, J=7.0 Hz, 3H, CH3).. (s, 1H, NH), 9.05(s, 1H, NH), 7.70-6.87(m, 9H, aromatic H).. . I! E 100 mL WM ./ 17(1 g, 5 mmol), phenyl isothiocyanate (2 g, 14.2 mmol), u-' tetrahydrofuran 30 mL% ' /MO 6` I`. hµ3 N@, ` ¡l3 ^ ]^ p´£ ¡l$ ./ 19(0.72 g, ¤¥ 44%)% }A. mp: 218-219 C;. 2-Ethoxycarbonylamino-4H-1,3,4-thiadiazino[5,6b]quinoxaline(14c). ¬£ ¡l@, 0.79 g(¤¥. 3 }A. mp: 242-243 C; IR(KBr, cm o. 55%). −1. ): 3226,. 1695, 1406; MS(m/z): 289(M ); H NMR(DMSO-d6, δ): +. 1. 10.73(s, 1H, NH), 10.58(s, 1H, NH), 7.64-7.30(m, 4H, aromatic H), 4.12(q, J=7.0 Hz, 2H, CH2), 1.22(t, J=7.0 Hz, 3H, CH3). 1-(3-Chloroquinoxalinyl)-4-ethoxycarbonyl-2-. . I! E 250 mL WM ./ 13(1 g, 5 mmol), ethoxycarbonyl isothiocyanate(1 g, 7.5 mmol), u-' ®,,¯ 50 mL % ' /MO 2` I`. >?/3 N @, ` 1E '% ^ ]^ ¢ £ ¡l$ ./ 15c(0.82 g, ¤¥ 50%)% }A. mp: thiosemicarbazate(15c). 192-193 oC; IR(KBr, cm−1): 3289, 1716, 1544, 1450,. 8-Chloro-2-phenylamino-4H-1,3,4-thiadiazino[5,6-. b]quinoxaline(19). o. −1. IR(KBr, cm ): 3205, 1551, 1345, 1276; MS(m/z): 327(M+), 329(M++2); 1H NMR(DMSO-d6, δ): 10.37(s, 1H, NH), 9.85(s, 1H, NH), 9.15(s, 1H, NH), 8.05(d, J=2.7 Hz, 1H, C9-H), 7.85-6.88(m, 7H, C6-H, C7-H and aromatic H). 7-Chloro-1,2,4-triazolo[4,3-a]quinoxalin-3-ium-1-. thiolate(20) . I! E 100 mL WM ./ 17(0.5 g, 2.4 mmol), phenyl isothiocyanate (1.01 g, 7.1 mmol), u-' N,N-x 20 mL% ' !MO 2` I`. ho% ° Journal of the Korean Chemical Society.

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(7) 1,3,4-Thiadiazino[5,6-b]quinoxaline . 303. [m±` MQ3 ² 1³ ¡l3 ^ ] ^ ¶·£ ¡l$ ./ 20(0.46 g, ¤¥ 81%)3 } A. mp: 250-251 C; IR(KBr, cm ): 3241, 1630, 1560, −1. o. +. 1253, 1193; MS(m/z): 236(M ), 238(M++2); 1H NMR (DMSO-d6, δ): 15.05(brs, 1H, NH), 10.34(d, J=9.0 Hz, 1H, C9-H), 9.15(s, 1H, C4-H), 8.07(d, J=2.4 Hz, 1H, C6H), 7.82(dd, J=2.4, 9.0 Hz, 1H, C8-H).. ¸7 MO 4H-1,3,4-oxadiazino[5,6-b]quinoxaline; .M ]^ 7']e¹, .T ./ MO 3 gT ¡ ./ 6, 7; {º²(Growth Inhibition, %) 500 ppb; » MO Selenastrum capricornutumM ]^ 92.0%, 45.1%, B¼½@f,. ./ 8, 9 Nitzschia closteriumM ]^ 41.0%, 43.2%, 3 B¼¾A(Chart 3). " MO ¸7 MO .T 1,3,4-oxadiazino[5,6b]quinoxaline; oxadiazine '-M ( ¿R À ÁM ´ À HIE 1,3,4-thiadiazino[5,6-b]quinoxaline % .]' 50 ./; 3 g]e. Â, o-ÃÄÅxÆ oxalic acid dihydrate% >?`b } 2,3-dihydroxyquinoxaline(10), u-' 6-chloro-2quinoxalinone3 phosphoryl chloride, ÇR >?`b } 2,6-dichloroquinoxaline(11)3 Z[/\, ]^ 5 03 ^_ & à >?`b 1/# 25 ! 8 1,3,4-thiadiazino[5,6-b]quinoxaline; .3 ` ]e¹, 50; .X, .. ./ 103 phosphorous pentachloride, ÇR > ?`b ¡È3 t 2,3-dichloroquinoxaline(12)3 .T , hydrazine hydrate, hydrazinolysis` b 2-chloro-3-hydrazinoquinoxaline(13)3 .]e. 543 isothiocyanate N,N-x É 13. 13. 14-16. 17. Scheme 1.. MQ ho]MO >?`b 2-methylamino-4H-1,3,4thiadiazino[5,6-b]quinoxaline(14a), 2-phenylamino-4H1,3,4-thiadiazino[5,6-b]quinoxaline(14b). 3 .]e(Scheme 1). uÊ¹, ./ 133®,,¯ ho]MO ethoxycarbonyl isothiocyanate >?`ËÌ ÍlT ./$ 1-(3(14c). chloroquinoxalinyl)-4-ethoxycarbonyl-2-thiosemi-. carbazate(15c) 18A',543 MQ ho]MO I`ËÌ ¾ '- >?M ;² ./ 14c 1 8A. u_B ./ 133 methyl isothiocyanate É phenyl isothiocyanate ®,,¯ ho]MO >? `ËÎ ./ 15b,c -8& n' 50; % ±Ï ¾ '- >?5 Ð9BO ./ 14b,c 1 8A. ./ 14; Ñ$ ./ 13; H NMR MO B¼½Ò 4.69-4.62 ppmMO; ¬! ; Ó5 B¼B& n 4 IR F MS Ô@, Ñ$]e@f, ./ 15c IR MO 1716 cm MO B¼Õ Ö×7Ä!; ØÙ H NMR F MS Ô@, Ñ$]e. 5PM 57' ECD@, 2,6-dichloroquinoxaline(11)3 Z[/\, ]^ m-chloroperbenzoic acid (MCPBA) >?`b 2,6-dichloroquinoxaline 4-oxide (16)% .T hydrazinolysis`b 6-chloro-2hydrazinoquinoxaline 4-oxide(17)% .]e. ./ 173 isothiocyanate >?`b 6-chloro-2-[2-(N1. −1. 1. 11,12,18. Chart 3. 2003, Vol. 47, No. 3. F 2-ethoxycar-. bonylamino-4H-1,3,4-thiadiazino[5,6-b]quinoxaline.

(8) Yoshihisa Kurasawa. 304. Scheme 3. Scheme 2.. methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide(18a), 6chloro-2-[2-(N-ethoxycarbonylthiocarbamoyl)-hydrazino]-. F 8-chloro-2-phenylamino4H-1,3,4-thiadiazino[5,6-b]quinoxaline(19)3 .]e quinoxaline 4-oxide(18b) (Scheme 2).. ./ 173 methyl isothiocyanate É ethoxycarbonyl isothiocyanate tetrahydrofuran ho]MO >?`Ë Î ./ 18a,b 18A. u_B ./ 173 phenyl isothiocyanate tetrahydrofuran ho]MO > ?`ËÎ ./ 19 18A. quinoxaline N-oxide ; α-QR N-oxide moietyM N >?5 Ð9Õ ÚÈ ÛÜ5 ÝÞ Ð9B¹, " MO u_T ß5 à¹ ./ 19 18A. u' ho% N,N-x% gh]Ì ./ 185 -8& n' A, B% ±Ï R 5á. ./ $ 7-chloro-1,2,4-triazolo[4,5-a]quinoxalin3-ium-1-thiolate(20) 18A. 54 ho; â KLM triazole '- 1E 4@, ã (. u' phenyl isothiocyanate y¿Rm ,O y¿R Ö ÎäM å^ ]e¹, >? ÖÎä 3,7,9. 9,19-22. 23. (Scheme 3).. .T ./ MO ./ 15c Bacillus subtilisM ]^æR[çº&» (Minimum Inhibitory Concentration: MIC, ppm) >10 ppm@, 3 B¼¾A', . / 19 Bacillus subtilis, Rhodotorula mucilaginosa, Trichophyton mentagrophytesM ]^ MIC >10 ppm@, F t3 B¼¾A. u' ./ 14a, 15c; {º²(Growth Inhibition, %). 500 ppb; » MO Selenastrum carpricornutumM ]^ 93.2%, 42.1%, B¼½@f, ./ 14c Selenastrum capricornutum, Nitzschia closteriumM ]^ 93.0%, 86.5%, 3 B¼¾A. " 2003è ª & ÀM ;]^ é8A@f, M T screening test

(9) êëìíîïðñ(Ð")M ;]^ é8A!M g; òó3 ôÎ.. 1. (a) Smalley, R. K. Comprehensive Heterocyclic Chemistry II; Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pregamon Press : Oxford, U. K., 1996; Vol. 6, pp 737-781. (b) Sato, N. Comprehensive Heterocyclic Chemistry II; Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pregamon Press: Oxford, U. K., 1996; Vol. 6, pp 234-278. (c) Cheeseman, G. W. H.; Cookson, R. F. The Chemistry of Heterocyclic Compounds. Condensed Pyrazines; Weissberger, A., Taylor, E. C., Eds.; John Wiley & Sons: New York, U. S. A., 1979; pp 1-290. 2. Kurasawa, Y.; Takada, A.; Kim, H. S. J. Heterocyclic Chem. 1995, 32, 1085. 3. Kim, H. S.; Kurasawa, Y. Heterocycles 1998, 49, 557. 4. Elliott, A. J.; Gibson, M. S.; Kayser, M. M.; Pawelchak, G. A. Can. J. Chem. 1973, 51, 4115. 5. Elliott, A. J. J. Heterocyclic Chem. 1981, 18, 799. 6. Elliott, A. J. U. S. Patent 1997, 4025510 ; Chem. Abstr. 1997, 87, 153420h. 7. Kurasawa, Y.; Sekine, M.; Kim, H. S.; Okamoto, Y. J. Heterocyclic Chem. 1996, 33, 1859. 8. Kim, H. S.; Okamoto, Y.; Kurasawa, Y. J. Heterocyclic Journal of the Korean Chemical Society.

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(11) 1,3,4-Thiadiazino[5,6-b]quinoxaline Chem. 1997, 34, 1029. 9. Kim, H. S.; Kim, T. E.; Kwag, S. T.; Park, Y. T.; Hong, Y. S.; Okamoto, Y.; Kurasawa, Y. J. Heterocyclic Chem. 1997, 34, 1539. 10. Mager, H. I. X.; Berends, W. Rec. Trav. Chim. PaysBas 1958, 77, 842. 11. Sakata, G.; Makino, K. Chem. Lett. 1984, 323. 12. Makino, K.; Sakata, G.; Morimoto, K.; Ochiai, Y. Heterocycles 1985, 23, 2025. 13. Kim, T. E.; Kim, H. S. J. Korean Chem. Soc. 1998, 42, 449. 14. Cheeseman, G. W. H. J. Chem. Soc. 1962, 1170. 15. Tomoda, H.; Saito, S.; Ohishi, M.; Shiraishi, S. Nippon Kagaku Kaishi 1989, 2059. 16. Asano, K. Yakugaku Zasshi 1958, 78, 729. 17. Reddy Sastry, C. V.; Krishman, V. S. H.; Narayan, G.. 2003, Vol. 47, No. 3. 305. K. A. S. S.; Vemana, K. Ind. J. Chem. 1991, 30B, 936. 18. Kim, H. S.; Kurasawa, Y.; Yoshii, C.; Masuyama, M.; Takada, A.; Okamoto, Y. J. Heterocyclic Chem. 1990, 27, 1111. 19. Newton, C. G.; Ramsden, C. A. Tetrahedron 1982, 38, 2965. 20. Friedrichsen, W.; Kappe, T.; Bottcher, A. Heterocycles 1982, 19, 1083. 21. Kurasawa, Y.; Kawano, T.; Katoh, A.; Takada, A.; Kim, H. S.; Okamoto, Y. J. Heterocyclic Chem. 1992, 29, 1337. 22. Buccheri, F.; Cusmano, G.; Gruttadauria, M.; Noto, R.; Werber, G. J. Heterocyclic Chem. 1997, 34, 1447. 23. Kurasawa, Y.; Yoshishiba, N.; Kureyama, T.; Okano, T.; Takada, A.; Kim, H. S.; Okamoto, Y. J. Heterocylic Chem. 1992, 29, 1653..

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  1,3,4-Thiadiazino[5,6-b]quinoxaline

1,3,4-Thiadiazino[5,6-b]quinoxaline