Synthesis and Characterization of Newly Fused 1,2-Dihydropyrido[3,4-b], Bridged Oxadiazol-2-yl, 4-Substituted-benzylidene Hydrazide and Arylidene 6-Chloroquinoxaline 1,4-Dioxides

Samy B. Said Fawzia Z. El-Ablack Hani M. Elbeheiry About the authors

Abstract

Some simple reactions using commercially available chemicals were used in the preparation of new biologically remarkable quinoxaline 1,4-dioxide derivatives. Several steps performed on 4-chloro-2-nitroaniline resulted in a quinoxaline 1,4-dioxide derivative, which reacted with dimethylformamide dimethylacetal (DMF-DMA) to produce an enamine. Transamination of this enamine with anilines gave the fused 1,2-dihydropyrido[3,4-b]quinoxaline 5,10-dioxide derivatives via an addition-elimination mechanism. Basic condensation reaction of quinoxaline active methyl afforded unexpected decarboxylated arylidene derivatives by using different aromatic aldehydes. Bridged oxadiazol-2-yl derivatives were obtained from the reaction of a hydrazide derivative with carbon disulfide and p-nitrobenzoic acid respectively. Whereas, acidic condensation of that hydrazide with aromatic aldehydes afforded the arylidene hydrazides.

Keywords:
quinoxaline 1,4-dioxide; transamination; enamine; arylidene; hydrazide


Introduction

Among the heterocyclic compounds, quinoxaline 1,4-dioxide (QdNO) and its derivatives proved an enormous scale of biological activities. These manifold biological properties include antimicrobial, antiprotozoal, antitumoral, antioxidant and anti-inflammatory activities. As antimicrobial, QdNOs can act as antibacterial,11 Carta, A.; Corona, P.; Loriga, M.; Curr. Med. Chem. 2005, 12, 2259.,22 Liu, J.; Ouyang, M.; Jiang, J.; Mu, P.; Wu, J.; Yang, Q.; Zhang, C.; Xu, W.; Wang, L.; Huen, M. S. Y.; Deng, Y.; Mutat. Res., Genet. Toxicol. Environ. Mutagen. 2012, 741, 70. antimycobacterial33 Vicente, E.; Villar, R.; Pérez-Silanes, S.; Aldana, I.; Goldman, R. C.; Mong, A.; Infect. Disord.: Drug Targets 2011, 11, 196.

4 Zanetti, S.; Sechi, L. A.; Molicotti, P.; Cannas, S.; Carta, A.; Bua, A.; Deriu, A.; Paglietti, G.; Int. J. Antimicrob. Agents 2005, 25, 179.
-55 dos Santos Fernandes, G. F.; Moreno-Viguri, E.; Santivañez-Veliz, M.; Paucar, R.; Chin, C. M.; Pérez-Silanes, S.; dos Santos, J. L.; J. Heterocycl. Chem. 2017, 54, 2380. and antifungal66 Carta, A.; Loriga, M.; Paglietti, G.; Mattana, A.; Fiori, P. L.; Mollicotti, P.; Sechi, L.; Zanetti, S.; Eur. J. Med. Chem. 2004, 39, 195.,77 Lakshmi, Y.; Murthy, N.; Mani, P.; Govindh, B.; Res. J. Pharm., Biol. Chem. Sci. 2011, 2, 553. agents. Antitrypanosomal,88 Torres, E.; Moreno-Viguri, E.; Galiano, S.; Devarapally, G.; Crawford, P. W.; Azqueta, A.; Arbillaga, L.; Varela, J.; Birriel, E.; Di Maio, R.; Cerecetto, H.; González, M.; Aldana, I.; Monge, A.; Pérez-Silanes, S.; Eur. J. Med. Chem. 2013, 66, 324.,99 Benitez, D.; Cabrera, M.; Hernandez, P.; Boiani, L.; Lavaggi, M. L.; Di Maio, R.; Yaluff, G.; Serna, E.; Torres, S.; Ferreira, M. E.; de Bilbao, N. V.; Torres, E.; Perez-Silanes, S.; Solano, B.; Moreno, E.; Aldana, I.; de Cerain, A. L.; Cerecetto, H.; Gonzalez, M.; Monge, A.; J. Med. Chem. 2011, 54, 3624. antimalarial,1010 Zarranz, B.; Jaso, A.; Aldana, I.; Monge, A.; Maurel, S.; Deharo, E.; Jullian, V.; Sauvain, M.; Drug Res. 2005, 55, 754.,1111 Vicente, E.; Charnaud, S.; Bongard, E.; Villar, R.; Burguete, A.; Solano, B.; Ancizu, S.; Pérez-Silanes, S.; Aldana, I.; Vivas, L.; Monge, A.; Molecules 2008, 13, 69. antitrichomonas66 Carta, A.; Loriga, M.; Paglietti, G.; Mattana, A.; Fiori, P. L.; Mollicotti, P.; Sechi, L.; Zanetti, S.; Eur. J. Med. Chem. 2004, 39, 195.,1212 Glazer, E. A.; Chappel, L. R.; J. Med. Chem. 1982, 25, 868. and antiamoebic1313 Duque-Montaño, B. E.; Gómez-Caro, L. C.; Sanchez-Sanchez, M.; Monge, A.; Hernández-Baltazar, E.; Rivera, G.; Torres-Angeles, O.; Bioorg. Med. Chem. 2013, 21, 4550. activities are proved as types of the antiprotozoal activities of QdNOs. QdNOs are pivotal in the anticancer chemotherapy because they have a selective toxicity toward hypoxic cells.1414 Monge, A.; Palop, J. A.; de Cerain, A. L.; Senador, V.; Martinez, F. J.; Sainz, Y.; Narro, S.; Garcia, E.; de Miguel, C.; J. Med. Chem. 1995, 38, 1786.

15 Monge, A.; Martinez-Crespo, F. J.; de Cerain, A. L.; Palop, J. A.; Narro, S.; Senador, V.; Marin, A.; Sainz, Y.; Gonzalez, M.; J. Med. Chem. 1995, 38, 4488.

16 Solano, B.; Junnotula, V.; Marín, A.; Villar, R.; Burguete, A.; Vicente, E.; Pérez-Silanes, S.; Aldana, I.; Monge, A.; Dutta, S.; Sarkar, U.; Gates, K. S.; J. Med. Chem. 2007, 50, 5485.
-1717 Das, U.; Pati, H. N.; Panda, A. K.; De Clercq, E.; Balzarini, J.; Molnár, J.; Baráth, Z.; Ocsovszki, I.; Kawase, M.; Zhou, L.; Sakagami, H.; Dimmock, J. R.; Bioorg. Med. Chem. 2009, 17, 3909. Also, antioxidant and anti-inflammatory activities have been studied in vitro and in vivo.1818 Burguete, A.; Pontiki, E.; Hadjipavlou-Litina, D.; Villar, R.; Vicente, E.; Solano, B.; Ancizu, S.; Pérez-Silanes, S.; Aldana, I.; Monge, A.; Bioorg. Med. Chem. Lett. 2007, 17, 6439.,1919 Burguete, A.; Pontiki, E.; Hadjipavlou-Litina, D.; Ancizu, S.; Villar, R.; Solano, B.; Moreno, E.; Torres, E.; Pérez, S.; Aldana, I.; Monge, A.; Chem. Biol. Drug Des. 2011, 77, 255.

There are two main strategies for the preparation of QdNOs. The first one, known as direct oxidation, is an old and non-specific method which produces a mixture of N-monoxides and N,N-dioxides. This method can be achieved via the oxidation of a quinoxaline derivative. Different oxidizing agents were used as m-chloroperoxybenzoic acid,2020 Figdor, S. K.; Hobbs, D. C.; Can. J. Chem. 1980, 58, 1957. peroxyformic acid2121 Loriga, M.; Nuvole, A.; Paglietti, G.; Fadda, G.; Zanetti, S.; Eur. J. Med. Chem. 1990, 25, 527. and peroxyacetic acid.2222 Lanquist, J. K.; Stacey, G. J.; J. Chem. Soc. 1953, 1, 2822.

The second strategy, called Beirut reaction,2323 Haddadin, M. J.; Issidorides, C. H.; Tetrahedron Lett. 1965, 6, 3253. is a relatively new reaction and more commonly used. Depending on its ability to perform a cycloaddition reaction, benzofuroxan (1) (Figure 1) reacts with different reagents producing QdNOs. These different reagents include simple alkenes,2424 Lia, J.; Jia, M.; Hua, W.; Hua, H.; Indian J. Chem. 2001, 408, 1230. simple ketones,2525 Heyns, K.; Behse, E.; Francke, W.; Eur. J. Inorg. Chem. 1981, 114, 240. b-diketones,2626 Takabatake, T.; Hasegawa, M.; J. Heterocycl. Chem. 1987, 24, 529.,2727 Chupakhin, O. N.; Kotovskaya, S. K.; Perova, N. M.; Baskakova, Z. M.; Charushin, V. N.; Chem. Heterocycl. Compd. 1999, 35, 459. b-ketoesters,2828 Vega, A. O.; Gil, M. J.; Fernández-Alvarez, E.; J. Heterocycl. Chem. 1984, 21, 1271. b-ketoamides,2929 Stumm, G.; Niclas, H.-J.; J. Prakt. Chem. 1989, 331, 736. a-enamines3030 Zarranz, B.; Jaso, A.; Aldana, I.; Monge, A.; Bioorg. Med. Chem. 2003, 11, 2149. and malononitrile.3131 Monge, A.; Palop, J. A.; González, M.; Martínez-Crespo, F. J.; de Ceráin, A. L.; Sáinz, Y.; Narro, S.; Barker, A. J.; Hamilton, E.; J. Heterocycl. Chem. 1995, 32, 1213.

Figure 1
Benzofuroxan and 6-chlorobenzofuroxan.

Herein, we utilized Beirut reaction to synthesize some new 6-chloroquinoxaline 1,4-dioxide derivatives from the reaction of 6-chlorobenzofuroxan (2) (Figure 1) with ethyl acetoacetate. These compounds covers some 2-arylidene-6-chloro-3-(ethoxycarbonyl)quinoxaline 1,4-dioxides, 8-chloro-1-oxo-2-substituted-1,2-dihydropyrido[3,4-b]quinoxaline 5,10-dioxide derivatives and some derivatives of 6-chloro-3-(hydrazinecarbonyl)-2-methylquinoxaline 1,4-dioxide. Biological activities of this set of compounds will be screened in a next study.

Results and Discussion

This study describes the design, synthesis and characterization of some novel 6-chloroquinoxaline 1,4-dioxide derivatives. The starting material 6-chloro-3-(ethoxycarbonyl)-2-methylquinoxaline 1,4-dioxide (7) was prepared in four steps as shown in Scheme 1. Diazotization of 4-chloro-2-nitroaniline (3) produced 1-chloro-2-(4-chloro-2-nitrophenyl)diazene (4), which further reacted with sodium azide to yield 1-azido-4-chloro-2-nitrobenzene (5).1515 Monge, A.; Martinez-Crespo, F. J.; de Cerain, A. L.; Palop, J. A.; Narro, S.; Senador, V.; Marin, A.; Sainz, Y.; Gonzalez, M.; J. Med. Chem. 1995, 38, 4488. Then under the effect of heat, the azide 5 gave off nitrogen gas forming 5-chlorobenzofuroxan (6) which tautomerizes in solutions to the major form 6-chlorobenzofuroxan (2).3232 Gasco, A.; Ermondi, G.; Fruttero, R.; Gasco, A.; Eur. J. Med. Chem. 1996, 31, 3. Ultimately and using Beirut reaction, we modified a previous method3333 Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A.; J. Med. Chem. 2005, 48, 2019. via reacting 2 with ethyl acetoacetate by using morpholine as a base instead of triethylamine. A promotion in yield from 26 to 42% was achieved by this modification to obtain the derivative 7.

Scheme 1

Due to the presence of the ester group and the N-oxide bond in the quinoxaline (7), the methyl group at carbon-2 becomes activated and we exploited the active methyl group to prepare some novel quinoxaline derivatives via condensation reactions. The condensation of 7 with dimethylformamide dimethylacetal (DMF-DMA) gave (E)-6-chloro-2-(2-(dimethylamino)vinyl)-3-(ethoxycarbonyl)quinoxaline 1,4-dioxide (8) in an excellent yield (Scheme 2). From the 1H nuclear magnetic resonance (NMR) data, the configuration of the olefinic double bond in the enamine 8 is trans. The two protons Ha and Hb have two doublet peaks of a chemical shift (d) 4.7 and 9.5 ppm, respectively, with a coupling constant (J) of 12.5 Hz. The low value of J is due to the electronegative nitrogen atom, which withdraws electrons from the C-H bond and weakens communication through the bonds.3434 Clayden, J.; Greeves, N.; Warren, S. G.; Organic Chemistry, 2nd ed.; Oxford University Press: New York, 2012. The high value of δ for Hb is due to the anisotropic effect of the quinoxaline 1,4-dioxide scaffold. Furthermore, Hb is shielded by the electron delocalization (mesomeric effect coming from the non bonding electrons of nitrogen atom) as shown in Scheme 3.

Scheme 2

Scheme 3

Transamination3535 Lyubchanskaya, V. M.; Alekseeva, L. M.; Granik, V. G.; Chem. Heterocycl. Compd. 1992, 28, 34. of the enamine 8 with primary aromatic amines (aniline, p-toluidine and p-nitroaniline) in the presence of p-toluenesulfonic acid as a catalyst afforded the cyclized 8-chloro-1-oxo-2-substituted-1,2-dihydropyrido[3,4-b]quinoxaline 5,10-dioxide derivatives (10a-c) (Scheme 4). The 1,2-dihydropyrido[3,4-b]quinoxaline structures are confirmed from the spectral data where infrared (IR) spectra showed a shifting in the absorption of the carbonyl of the ester group from 1735 to 1670-1680 cm-1 due to the newly formed amide group. Additionally, the disappearance of the ethyl group protons in the 1H NMR and the drop of J of the protons Ha and Hb from 12.5 to around 9.5 Hz (turned to cis configuration) confirmed the cyclization process.

Scheme 4

The transamination mechanism was not clear and proceeded via the cis isomer and not the trans as mentioned in a previous work.3636 El-Gogary, S. R.; Waly, M. A.; Ibrahim, I. T.; El-Sepelgy, O. Z.; Monatsh. Chem. 2010, 141, 1253. We suggested that the formation of the cyclized product (10) took place via an addition-elimination mechanism. In order to support our point of view, the transamination was performed using a secondary amine (morpholine) and the produced morpholino derivative (9) have the trans configuration and the J value of the protons Ha and Hb is 12.5 Hz. From this observation, there are two possible products formed from the transamination reaction and the more stable one is produced as a major product. In case of the secondary amine, the major is the trans isomer, while the cis is the major in case of the primary amine. In fact, the formation of the pyrido derivatives (10a-c) is accomplished via two sequential reactions. Transamination followed by intramolecular amidation get the task done. A plausible mechanism for the synthesis of 10 is shown in Scheme 5. The olefinic double bond in 8 abstract proton from p-toluenesulfonic acid to form a, which is directly attacked by a primary amine to form b. The newly formed intermediate b undergoes proton transfer followed by dimethylamine elimination to form c and a stereoisomer mixture of δ and e. Only the cis isomer e completes the amidation process through an intramolecular nucleophilic attack of the alkylated nitrogen on the carbonyl ester to form f, which can eliminate a molecule of ethanol to form the cyclized product 10.

Scheme 5

In the same manner, condensation of the quinoxaline 7 with different aromatic aldehydes gave the corresponding 2-arylidene-6-chloro-3-(ethoxycarbonyl)quinoxaline 1,4-dioxide (11) or the unexpected 2-arylidene-6-chloroquinoxaline 1,4-dioxide (12) (Scheme 6). An excess amount of the aldehyde in the presence of piperidine as a catalyst was refluxed with the compound 7 for 2 h to obtain the desired arylidene derivative 11 or 12.

Scheme 6

The structures of the obtained products (11a-f) were confirmed by their spectral data and elemental analysis. Thus, the 1H NMR spectra showed that the vinylic protons (Ha and Hb) are also trans as the value of J is around 16 Hz. The IR spectra showed bands in the region of 1610 to 1587 cm-1 assignable to the double bonds in combination with aromatic absorptions. The mass spectrum of each compound manifested a molecular ion peak. The derivatives (12a-b) have the same previous spectra except that of the ester group. Protons Ha, H2, H4 and H6 in (12a) are shielded by the mesomeric effect as shown in Scheme 7. Also the HD proton is deshielded by the mesomeric effect in both 12a and 12b, where it is shifted to δ 9.2 and 9.16 ppm, respectively. The higher downfield hydrogen absorption in 12b at δ 10.42 ppm is attributed to the hydroxyl group of the phenol moiety. This is because of the hydrogen bonding formation with one of the N-oxide group as shown in Scheme 7b. To explain this unexpected result, we focused on the aromatic aldehydes as the reaction conditions are the same. We noted that in the case of using m-nitrobenzaldehyde or o-hydroxybenzaldehyde, the aldehyde group is activated toward the condensation reaction by the electron withdrawing nitro group or by the hydrogen bond of the hydroxyl group, respectively. Thus the condensation rate in these cases is faster than that of the other aldehydes. Now, the formed water (by-product of the condensation), the basic medium, the high temperature and the time, are all perfect conditions for hydrolysis and decarboxylation of the ester group. This explanation was established by the complete characterization data of both 12a and 12b, which prove the decarboxylation reaction.

Scheme 7

Heating of compound 7 with hydrazine hydrate under reflux on a steam bath for an hour afforded 6-chloro-3-(hydrazinecarbonyl)-2-methylquinoxaline 1,4-dioxide (13) in good yield (Scheme 8). The hydrazide 13 structure is confirmed by the spectral data and elemental analysis. The higher downfield hydrogen absorption in 13 at δ 9.97 ppm is attributed to the NH group of the hydrazinecarbonyl moiety. This is because of the hydrogen bonding formation with one of the N-oxide group.

Scheme 8

When the hydrazide 13 was refluxed for 24 h with excess carbon disulfide (CS2) in ethanol as a solvent and potassium hydroxide as a base then acidified using (1 M) HCl, 6-chloro-2-methyl-3-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)quinoxaline 1,4-dioxide (14) was produced in 68% yield (Scheme 9). Also when the hydrazide 13 was heated at 70 °C with p-nitrobenzoic acid in the presence of phosphorous oxychloride as a catalyst, the hydrazide group was converted into the 1,3,4-oxadiazole ring (Scheme 9). The produced 6-chloro-2-methyl-3-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)quinoxaline 1,4-dioxide (15) is confirmed by spectral data. Condensation of 13 with different aldehydes in the presence of acetic acid as a catalyst yielded the para substituted benzylidene hydrazide (16a-e) in very good yield (Scheme 9). The derivatives 16a-e showed characteristic absorption peaks around 3300 and 1685 cm-1 for N-H and carbonyl group, respectively. In 1H NMR there is a peak of N-H proton around 12 ppm, which exchanges with D2O.

Scheme 9

Conclusions

The synthesis of some new bioactive quinoxaline 1,4-dioxides was described. During our work we discovered that a basic condensation reaction can result in a hydrolysis recation followed by decarboxylation of an existing ester group. Also, the mechanism of transamination of enamines proved as an addition-elimination mechanism.

Experimental

All chemicals (AR graded) were commercially available and used without further purification. All liquid aldehydes were purified by extraction with a diluted solution of sodium carbonate, washed with water then dried over anhydrous sodium sulfate. Analytical thin-layer chromatography (TLC) was carried out using 0.2 mm precoated plates of silica gel G60 F254 (Merck). Visualization on TLC was achieved by UV light (254 and 366 nm) or with an iodine vapor. Plate chromatography was performed using precoated 20 × 20 cm plates of silica gel G60 F254 (Merck). Melting points are uncorrected and were determined in an open capillary with a Griffin melting point apparatus. IR spectra were obtained for KBr pellets on JASCO 410 spectrometer with only selected absorptions being recorded in the range of 4000-400 cm-1. Ultraviolet absorption spectra were recorded in DMSO on a double beam JASCO V630 spectrophotometer in the wavelength range 300-900 nm in 1 cm quartz cuvettes.1H and 13C NMR spectra were recorded on a Bruker Avance III 400 MHz NMR spectrometer and Jeol ECA-II 500 MHz NMR specrometer in CDCl3 and DMSO-d6. Chemical shifts are expressed in δ ppm downfield from tetramethylsilane (TMS) as an internal reference. The mass spectra were recorded on Direct Inlet part to mass analyzer in Thermo Scientific GCMS model ISQ. Elemental analysis for C, H, and N was performed on FLASH 2000 CHNS/O analyzer, Thermo Scientific analyzer.

Synthesis of 6-chloro-3-(ethoxycarbonyl)-2-methyl quinoxaline 1,4-dioxide (7)

To a solution of 4-chloro-2-nitroaniline 3 (8.63 g, 50 mmol) in water (20 mL) and concentrated HCl (12 mL), a solution of NaNO2 (3.63 g, 52 mmol) in water (13 mL) was added dropwise at 0 °C. After an hour of stirring, the formed yellow solution 4 was filtered off to remove the insoluble impurities. With stirring at 0 °C, a solution of NaN3 (3.25 g, 50 mmol) in water (13 mL) was added dropwise to the previous solution. Immediately, the azide 5 began to precipitate, which was filtered off after finishing the addition. The azide 5 was refluxed in acetic acid (50 mL) till nitrogen gas ceased and was poured into crashed ice, the product 6 was filtered off, washed with cold water then it was dried. To a solution of 6 (1.70 g, 10 mmol) in ethyl acetoacetate (1.30 g, 10 mmol) at 0 °C, morpholine (1.74 g, 20 mmol) was added slowly. The ice bath was removed after an hour then the mixture was stirred for 12 h at room temperature in darkness. The produced precipitate was filtered off and washed with diethyl ether then recrystallized from methanol to form yellow needle-like crystals. Yield 1.2 g (42%); mp 174-176 °C; IR (KBr) n / cm-1 3093 (Ar-H), 2983 (C-H saturated), 1741 (C=O ester), 1599 (C=C aromatic), 1327 (N-O), 1276 (C-O), 821 (C-Cl); UV (DMSO) lmax / nm 406; 1H NMR (500 MHz, DMSO-d6) δ 1.35 (t, J 7.2 Hz, 3H, OCH2CH3), 2.42 (s, 3H, CH3), 4.50 (q, J 7.2 Hz, 2H, OCH2CH3), 8.02 (dd, Jortho 9.2, JW 2.3 Hz, 1H, HB), 8.40 (d, JW 2.3 Hz, 1H, HA), 8.46 (d, Jortho 9.2 Hz, 1H, HC); 13C NMR (500 MHz, DMSO-d6) δ 13.80, 14.13, 63.39, 118.87, 122.07, 133.08, 135.56, 136.67, 136.98, 138.78, 159.46; MS (m/z) 282 (60) [M]+, 284 (20) [M + 2]+, 193 (100). Anal. calcd. for C12H11ClN2O4: C, 50.99; H, 3.92; N, 9.91. Found: C, 50.79; H, 3.89; N, 9.93.

Synthesis of (E)-6-chloro-2-(2-(dimethylamino)vinyl)-3-(ethoxycarbonyl)quinoxaline 1,4-dioxide (8)

A solution of 6-chloro-3-(ethoxycarbonyl)-2-methyl quinoxaline 1,4-dioxide (7, 1.41 g, 5 mmol) and DMF-DMA (0.90 g, 7.5 mmol) in dry benzene (10 mL) was refluxed for 12 h. Solvent was evaporated under reduced pressure and the precipitate was titurated with diethyl ether to obtain solid product as red crystals. Yield 1.48 g (88%); mp 162-163 °C; IR (KBr) n / cm-1 3100 (Ar-H), 2979 (C-H saturated), 1737 (C=O ester), 1616 (C=C aliphatic), 1591 (C=C aromatic), 1358 (N-O), 1282 (C-O), 756 (C-Cl); UV (DMSO) lmax / nm 370; 1H NMR (500 MHz, CDCl3) δ 1.45 (t, J 7.0 Hz, 3H, OCH2CH3), 2.88 (s, 3H, NCH3), 3.14 (s, 3H, NCH3), 4.55 (q, J 7.0 Hz, 2H, OCH2CH3), 4.71 (d, Jtrans 12.5 Hz, 1H, Hb), 7.69 (dd, Jortho 9.2, JW 2.2 Hz, 1H, HB), 8.38 (d, Jortho 9.2 Hz, 1H, HC), 8.42 (d, JW 2.2 Hz, 1H, HA), 9.53 (d, Jtrans 12.5 Hz, 1H, Ha); 13C NMR (500 MHz, CDCl3) δ 14.00, 63.25, 83.89, 119.37, 120.13, 121.79, 133.00, 133.03, 134.37, 136.61, 137.94, 151.69, 160.51; MS (m/z) 337 (10) [M]+, 339 (7) [M + 2]+, 73 (100). Anal. calcd. for C15H16ClN3O4: C, 53.34; H, 4.77; N, 12.44. Found: C, 53.44; H, 4.77; N, 12.70.

Synthesis of (E)-6-chloro-3-(ethoxycarbonyl)-2-(2-morpholinovinyl)quinoxaline 1,4-dioxide (9) and 8-chloro-1-oxo-2-substituted-1,2-dihydropyrido[3,4-b]quinoxaline 5,10-dioxide derivatives (10a-c)

A solution of (E)-6-chloro-2-(2-(dimethylamino)vinyl)-3-(ethoxycarbonyl)quinoxaline 1,4-dioxide (8, 0.34 g, 1 mmol), p-toluenesulfonic acid (0.12 g, 1 mmol), the primary aromatic amine (1 mmol), chloroform (10 mL) and isopropanol (10 mL) was refluxed for 4-8 h. The solvent was evaporated under reduced pressure and the precipitate formed was filtered off, washed with Na2CO3 solution (50 mL, 30%), water (50 mL), HCl solution (50 mL, 30%) then water (50 mL).

(E)-6-Chloro-3-(ethoxycarbonyl)-2-(2-morpholinovinyl)quinoxaline 1,4-dioxide (9)

Yield 0.26 g (68%); mp 156-158 °C; IR (KBr) n / cm-1 3093 (Ar-H), 2985 (C-H saturated), 1743 (C=O ester), 1597 (C=C aliphatic), 1520 (C=C aromatic), 1362 (N-O), 1230 (C-O), 764 (C-Cl); UV (DMSO) lmax / nm 370; 1H NMR (500 MHz, CDCl3) δ 1.45 (t, J 7.2 Hz, 3H, OCH2CH3), 3.34 (t, J 4.9 Hz, 4H, (CH2)2N), 3.75 (t, J 4.9 Hz, 4H, (CH2)2O), 4.56 (q, J 7.2 Hz, 2H, OCH2CH3), 4.72 (d, Jtrans 12.5 Hz, 1H, Hb), 7.69 (dd, Jortho 9.1, JW 2.3 Hz, 1H, HB), 8.39 (d, Jortho 9.1 Hz, 1H, HC), 8.43 (m, 1H, HA), 9.53 (d, Jtrans 12.5 Hz, 1H, Ha); 13C NMR (500 MHz, CDCl3) δ 14.05, 63.30, 63.83, 83.98, 84.47, 119.45, 120.17, 133.10, 133.22, 134.47, 136.66, 138.03, 151.76, 160.56; MS (m/z) 379 (59) [M]+, 381 (25) [M + 2]+, 362 (100). Anal. calcd. for C17H18ClN3O5: C, 53.76; H, 4.78; N, 11.06. Found: C, 53.79; H, 4.08; N, 11.01.

8-Chloro-1-oxo-2-phenyl-1,2-dihydropyrido[3,4-b]quinoxaline 5,10-dioxide (10a)

Dark red crystals (methanol); yield 0.16 g (47%); mp 246-248 °C; IR (KBr) n / cm-1 3074 (Ar-H), 1674 (C=O amide), 1623 (C=C aliphatic), 1500 (C=C aromatic), 1312 (N-O), 1273 (C-O), 763 (C-Cl); UV (DMSO) lmax / nm 353; 1H NMR (500 MHz, DMSO-d6) δ 7.46 (d, Jcis 8.0 Hz, 1H, Hb), 7.49-7.62 (m, 5H, Ar), 7.82 (dd, Jcis 8.0, J5 4.7 Hz, 1H, Ha), 7.99 (dd, Jortho 9.3, JW 2.3 Hz, 1H, HB), 8.5 (d, Jortho 9.3 Hz, 1H, HC), 8.52 (d, JW 2.3 Hz, 1H, HA); MS (m/z) 339 (26) [M]+, 341 (11) [M + 2]+, 323 (100). Anal. calcd. for C17H10ClN3O3: C, 60.10; H, 2.97; N, 12.37. Found: C, 59.97; H, 2.93; N, 12.25.

8-Chloro-1-oxo-2-(p-tolyl)-1,2-dihydropyrido[3,4-b]quinoxaline 5,10-dioxide (10b)

Dark red crystals (ethanol); yield 0.25 g (71%); mp > 300 °C; IR (KBr) n / cm-1 3089 (Ar-H), 2916 (C-H saturated), 1676 (C=O amide), 1612 (C=C aliphatic), 1510 (C=C aromatic), 1315 (N-O), 1261 (C-O), 819 (C-Cl); UV (DMSO) lmax / nm 353; 1H NMR (500 MHz, CDCl3) δ 2.42 (s, 3H, CH3), 7.29-7.33 (m, 4H, Ar), 7.48 (d, Jcis 8.0 Hz, 1H, Hb), 7.84 (dd, Jortho 9.3, JW 2.3 Hz, 1H, HB), 8.56 (d, Jortho 9.3 Hz, 1H, HC), 8.60 (d, Jcis 8.0 Hz, 1H, Ha), 8.68 (d, JW 2.3 Hz, 1H, HA); 13C NMR (500 MHz, CDCl3) δ 21.22, 95.27, 95.83, 120.16, 120.56, 121.75, 126.07, 126.37, 130.26, 130.46, 133.29, 134.79, 136.79, 138.95, 139.44, 154.82; MS (m/z) 353 (13) [M]+, 306 (100). Anal. calcd. for C18H12ClN3O3: C, 61.11; H, 3.42; N, 11.88. Found: C, 60.95; H, 3.13; N, 12.20.

8-Chloro-2-(4-nitrophenyl)-1-oxo-1,2-dihydropyrido[3,4-b]quinoxaline 5,10-dioxide (10c)

Dark red crystals (washed with boiling ethanol); yield 0.28 g (73%); mp 264-265 °C; IR (KBr) n / cm-1 3109 (Ar-H), 1674 (C=O amide), 1631 (C=C aliphatic), 1529 (C=C aromatic), 1319 (N-O), 1269 (C-O), 831 (C-Cl); UV (DMSO) lmax / nm 352; 1H NMR (500 MHz, DMSO-d6) δ 7.83-8.03 (m, 4H, Ar), 8.06 (dd, Jortho 9.3, JW 2.3 Hz, 1H, HB), 8.33-8.48 (m, 3H, HA, Ha, Hb), 8.53 (d, Jortho 9.3 Hz, 1H, HC); MS (m/z) 384 (18) [M]+, 386 (2) [M + 2]+, 383 (100). Anal. calcd. for C17H9ClN4O5: C, 53.07; H, 2.36; N, 14.56. Found: C, 53.39; H, 2.14; N, 14.94.

Synthesis of 6-chloro-2-arylidene-3-(ethoxycarbonyl)quinoxaline 1,4-dioxide (11a-f) and 6-chloro-2-aryli denequinoxaline 1,4-dioxide (12a-b)

To a solution of 6-chloro-3-(ethoxycarbonyl)-2-methylquinoxaline 1,4-dioxide (7, 0.28 g, 1 mmol) and the corresponding aromatic aldehyde (3 mmol) in ethanol (2 mL), two drops of piperidine were added as a basic catalyst. The reaction mixture was heated under reflux for 2 h in an oil bath at 110 °C, left to cool then ethanol (3 mL) was added. The obtained precipitate was filtered off, washed with diethyl ether, purified via plate chromatography and recrystalized from the proper solvent.

(E)-6-Chloro-3-(ethoxycarbonyl)-2-styrylquinoxaline 1,4-dioxide (11a)

Fluffy yellowish orange solid (methanol); yield 0.10 g (27%); mp 198-200 °C; IR (KBr) n / cm-1 3081 (Ar-H), 2979 (C-H saturated), 1733 (C=O ester), 1606 (C=C aliphatic), 1498 (C=C aromatic), 1360 (N-O), 1238 (C-O), 754 (C-Cl); UV (DMSO) lmax / nm 330; 1H NMR (500 MHz, CDCl3) δ 1.44 (t, J 7.2 Hz, 3H, OCH2CH3), 4.59 (q, J 7.2 Hz, 2H, OCH2CH3), 7.07 (d, Jtrans 16.5 Hz, 1H, Hb), 7.40 (m, 3H, Ar), 7.55 (dd, Jortho 7.5, JW 2.3 Hz, 2H, Ar), 7.80 (dd, Jortho 9.0, JW 2.3 Hz, 1H, HB), 8.35 (d, Jtrans 16.5 Hz, 1H, Ha), 8.56 (m, 2H, HA, HC); 13C NMR (500 MHz, CDCl3) δ 14.06, 63.96, 114.81, 119.92, 122.99, 128.93, 129.35, 133.59, 134.19, 135.74, 136.21, 136.32, 136.86, 136.89, 138.71, 140.05, 159.63; MS (m/z) 370 (17) [M]+, 105 (100). Anal. calcd. for C19H15ClN2O4: C, 61.55; H, 4.08; N, 7.56. Found: C, 61.78; H, 3.92; N, 7.72.

(E)-6-Chloro-2-(4-chlorostyryl)-3-(ethoxycarbonyl)quinoxaline 1,4-dioxide (11b)

Fluffy yellow solid; yield 0.12 g (30%); mp 191-192 °C; IR (KBr) n / cm-1 3100 (Ar-H), 2983 (C-H saturated), 1739 (C=O ester), 1606 (C=C aliphatic), 1506 (C=C aromatic), 1361 (N-O), 1274 (C-O), 806 (C-Cl); UV (DMSO) lmax / nm 333; 1H NMR (500 MHz, CDCl3) δ 1.38 (t, J 7.2 Hz, 3H, OCH2CH3), 4.53 (q, J 7.2 Hz, 2H, OCH2CH3), 6.95 (d, Jtrans 16.3 Hz, 1H, Hb), 7.31 (d, Jortho 8.4 Hz, 2H, Ar), 7.41 (d, Jortho 8.4 Hz, 2H, Ar), 7.75 (dd, Jortho 9.3, JW 2 Hz, 1H, HB), 8.27 (d, Jtrans 16.3 Hz, 1H, Ha), 8.50 (m, 2H, HA, HC); 13C NMR (500 MHz, CDCl3) δ 14.03, 63.92, 114.28, 119.86, 121.96, 127.82, 128.95, 129.05, 130.28, 133.55, 135.64, 136.21, 136.85, 137.17, 138.56, 141.56, 159.66; MS (m/z) 404 (86) [M]+, 406 (53) [M + 2]+, 139 (100). Anal. calcd. for C19H14Cl2N2O4: C, 56.32; H, 3.48; N, 6.91. Found: C, 56.42; H, 3.29; N, 6.91.

(E)-6-Chloro-2-(4-(dimethylamino)styryl)-3-(ethoxy carbonyl)quinoxaline 1,4-dioxide (11c)

Dark red solid; yield 0.12 g (29%); mp 218-220 °C; IR (KBr) n / cm-1 3074 (Ar-H), 2965 (C-H saturated), 1743 (C=O ester), 1625 (C=C aliphatic), 1587 (C=C aromatic), 1357 (N-O), 1269 (C-O), 798 (C-Cl); UV (DMSO) lmax / nm 403; 1H NMR (400 MHz, CDCl3) δ 1.50 (t, J 7.0 Hz, 3H, OCH2CH3), 3.08 (s, 6H, N(CH3)2), 4.64 (q, J 7.0 Hz, 2H, OCH2CH3), 6.72 (d, Jortho 8.5 Hz, 2H, Ar), 6.87 (d, Jtrans 16.0 Hz, 1H, Hb), 7.49 (d, Jortho 8.5 Hz, 2H, Ar), 7.81 (dd, Jortho 9.2, JW 2.2 Hz, 1H, HB), 8.53 (d, Jtrans 16.0 Hz, 1H, Ha), 8.58 (m, 2H, HA, HC); 13C NMR (400 MHz, CDCl3) δ 14.07, 29.68, 40.13, 63.73, 108.69, 111.97, 119.71, 119.75, 121.69, 126.41, 129.75, 133.34, 142.40, 151.83, 151.87, 160.00; MS (m/z) 413 (16) [M]+, 415 (6) [M + 2]+, 397 (100). Anal. calcd. for C21H20ClN3O4: C, 60.95; H, 4.87; N, 10.15. Found: C, 60.93; H, 4.84; N, 10.13.

(E)-6-Chloro-3-(ethoxycarbonyl)-2-(4-methoxystyryl)quinoxaline 1,4-dioxide (11d)

Orange solid; yield 0.10 g (25%); mp 214-215 °C; IR (KBr) n / cm-1 3072 (Ar-H), 2954 (C-H saturated), 1738 (C=O ester), 1602 (C=C aliphatic), 1506 (C=C aromatic), 1338 (N-O), 1250 (C-O), 814 (C-Cl); UV (DMSO) lmax / nm 339; 1H NMR (500 MHz, CDCl3) δ 1.49 (t, J 7.2 Hz, 3H, OCH2CH3), 3.88 (s, 3H, OCH3), 4.63 (q, J 7.2 Hz, 2H, OCH2CH3), 6.96 (d, Jortho 8.8 Hz, 2H, Ar), 7.11 (d, Jtrans 16.0 Hz, 1H, Hb), 7.54 (d, Jortho 8.8 Hz, 2H, Ar), 7.83 (dd, Jortho 9.2, JW 2.1 Hz, 1H, HB), 8.43 (d, Jtrans 16.0 Hz, 1H, Ha), 8.59 (m, 2H, HA, HC); 13C NMR (500 MHz, CDCl3) δ 14.07, 55.44, 63.84, 111.88, 114.55, 119.85, 121.89, 128.46, 129.54, 133.45, 135.69, 135.99, 136.90, 137.39, 138.19, 141.43, 159.80, 161.52; MS (m/z) 400 (56) [M]+, 402 (18) [M + 2]+, 135 (100). Anal. calcd. for C20H17ClN2O5: C, 59.93; H, 4.28; N, 6.99. Found: C, 59.78; H, 4.08; N, 6.91.

(E)-6-Chloro-3-(ethoxycarbonyl)-2-(4-methylstyryl)quinoxaline 1,4-dioxide (11e)

Orange solid; yield 0.12 g (32%); mp 202-204 °C; IR (KBr) n / cm-1 3072 (Ar-H), 2978 (C-H saturated), 1739 (C=O ester), 1599 (C=C aliphatic), 1502 (C=C aromatic), 1356 (N-O), 1236 (C-O), 802 (C-Cl); UV (DMSO) lmax / nm 333; 1H NMR (500 MHz, CDCl3) δ 1.44 (t, J 7.2 Hz, 3H, OCH2CH3), 2.36 (s, 3H, Ar-CH3), 4.58 (q, J 7.2 Hz, 2H, OCH2CH3), 7.00 (d, Jtrans 16.1 Hz, 1H, Hb), 7.18 (d, Jortho 7.5 Hz, 2H, Ar), 7.42 (d, Jortho 7.5 Hz, 2H, Ar), 7.78 (dd, Jortho 9.2, JW 2.2 Hz, 1H, HB), 8.32 (d, Jtrans 16.1 Hz, 1H, Ha), 8.54 (d, 2H, HA, HC); 13C NMR (500 MHz, CDCl3) δ 14.07, 21.47, 63.87, 113.71, 118.31, 199.79, 121.88, 127.78, 129.73, 132.85, 133.46, 136.02, 136.80, 137.28, 138.34, 140.81, 141.54, 159.67; MS (m/z) 384 (12) [M]+, 386 (14) [M + 2]+, 119 (100). Anal. calcd. for C20H17ClN2O4: C, 62.42; H, 4.45; N, 7.28. Found: C, 62.50; H, 4.22; N, 7.38.

(E)-2-(4-Bromostyryl)-6-chloro-3-(ethoxycarbonyl)quinoxaline 1,4-dioxide (11f)

Orange solid; yield 0.10 g (23%); mp 183-185 °C; IR (KBr) n / cm-1 3097 (Ar-H), 2925 (C-H saturated), 1734 (C=O ester), 1610 (C=C aliphatic), 1540 (C=C aromatic), 1354 (N-O), 1236 (C-O), 804 (C-Cl); UV (DMSO) lmax / nm 333; 1H NMR (500 MHz, CDCl3) δ 1.43 (t, J 7.2 Hz, 3H, OCH2CH3), 4.58 (q, J 7.2 Hz, 2H, OCH2CH3), 7.03 (d, Jtrans 16.1 Hz, 1H, Hb), 7.37 (d, Jortho 8.6 Hz, 2H, Ar), 7.53 (d, Jortho 8.6 Hz, 2H, Ar), 7.80 (dd, Jortho 9.3, JW 2.4 Hz, 1H, HB), 8.30 (d, Jtrans 16.1 Hz, 1H, Ha), 8.55 (m, 2H, HA, HC); 13C NMR (500 MHz, CDCl3) δ 14.05, 63.99, 114.83, 119.88, 121.95, 129.12, 129.21, 131.11, 132.16, 132.28, 133.65, 134.54, 136.83, 137.93, 138.73, 140.14, 159.61; MS (m/z) 448 (22) [M]+, 185 (100). Anal. calcd. for C19H14BrClN2O4: C, 50.75; H, 3.14; N, 6.23. Found: C, 50.55; H, 3.10; N, 6.11.

(E)-6-Chloro-2-(3-nitrostyryl)quinoxaline 1,4-dioxide (12a)

It was washed with boiling ethanol and obtained as a fluffy yellow solid; yield 0.10 g (29%); mp 242-244 °C; IR (KBr) n / cm-1 3070 (Ar-H), 1599 (C=C aliphatic), 1531 (C=C aromatic), 1367 (N-O), 767 (C-Cl); UV (DMSO) lmax / nm 326; 1H NMR (500 MHz, DMSO-d6) δ 7.71 (d, Jtrans 16.5 Hz, 1H, Ha), 7.80 (d, J 9.2 Hz, 1H, H6), 8.01 (dd, Jortho 9.2, JW 2.3 Hz, 1H, HB), 8.18 (d, Jortho 8.0 Hz, 1H, H4), 8.24 (dd, Jortho 8.0, JW 2.3 Hz, 1H, H2), 8.37 (d, Jtrans 16.5 Hz, 1H, Hb), 8.44 (d, JW 2.3 Hz, 1H, HA), 8.50 (m, 2H, H3, HC), 9.20 (s, 1H, HD); 13C NMR (500 MHz, DMSO-d6) δ 118.39, 119.11, 121.97, 122.35, 130.61, 130.67, 132.60, 133.59, 135.89, 136.39, 137.08, 137.22, 137.56, 139.37, 148.34; MS (m/z) 343 (99) [M]+, 345 (29) [M + 2]+, 327 (100). Anal. calcd. for C16H10ClN3O4: C, 55.91; H, 2.93; N, 12.23. Found: C, 56.11; H, 2.70; N, 12.56.

(E)-6-Chloro-2-(2-hydroxystyryl)quinoxaline 1,4-dioxide (12b)

It was washed with boiling methylene chloride and obtained as a yellow solid; yield 0.10 g (32%); mp 252-254 °C; IR (KBr) n / cm-1 3410 (O-H), 3075 (Ar-H), 1599 (C=C aliphatic), 1525 (C=C aromatic), 1369 (N-O), 764 (C-Cl); UV (DMSO) lmax / nm 320; 1H NMR (500 MHz, DMSO-d6) δ 6.87 (t, J 8.0 Hz, 1H, Ar), 6.94 (d, Jortho 8.1 Hz, 1H, Ar), 7.22 (t, J 8.0 Hz, 1H, Ar), 7.57 (d, Jortho 8.1 Hz, 1H, Ar), 7.73 (d, Jtrans 16.7 Hz, 1H, Ha), 7.98 (d, Jortho 9.2 Hz, 1H, HB), 8.30 (d, Jtrans 16.7 Hz, 1H, Hb), 8.42 (s, 1H, HA), 8.47 (d, Jortho 9.2 Hz, 1H, HC), 9.16 (s, 1H, HD), 10.42 (s, 1H, exchanges with D2O, Ar-O-H); 13C NMR (500 MHz, DMSO-d6) δ 116.03, 116.62, 119.44, 120.29, 122.63, 122.92, 129.62, 130.89, 131.72, 133.18, 135.64, 136.62, 136.93, 137.41, 141.11, 156.88; MS (m/z) 314 (33) [M]+, 60 (100). Anal. calcd. for C16H11ClN2O3: C, 61.06; H, 3.52; N, 8.90. Found: C, 60.90; H, 3.59; N, 8.98.

Synthesis of 6-chloro-3-(hydrazinecarbonyl)-2-methyl quinoxaline 1,4-dioxide (13)

A solution of 6-chloro-3-(ethoxycarbonyl)-2-methyl quinoxaline 1,4-dioxide (7, 1.13 g, 4 mmol), hydrazine hydrate (2 g, 40 mmol) and ethanol (20 mL) was refluxed on a steam bath for an hour. Then the product was filtered off and recrystallized from ethanol as pale yellow needle-like crystals. Yield 0.60 g (56%); mp 242-244 °C; IR (KBr) n / cm-1 NH2 3352, 3307, NH 3199, 3062 (Ar-H), 2962 (C-H saturated), 1674 (C=O hydrazide), 1570 (C=C aromatic), 1327 (N-O), 1273 (C-O), 648 (C-Cl); UV (DMSO) lmax / nm 326; 1H NMR (500 MHz, DMSO-d6) δ 2.59 (s, 3H, CH3), 4.71 (s, 2H, exchanges with D2O, NH2), 7.91 (dd, Jortho 9.2, JW 2.3 Hz, 1H, HB), 8.23 (d, JW 2.3 Hz, 1H, HA), 8.46 (d, Jortho 9.2 Hz, 1H, HC), 9.97 (s, 1H, exchanges with D2O, NH); 13C NMR (500 MHz, DMSO-d6) δ 14.02, 120.71, 128.83, 131.90, 135.30, 136.31, 139.72, 142.66, 151.52, 163.80; MS (m/z) 268 (19) [M]+, 151 (100). Anal. calcd. for C10H9ClN4O3: C, 44.71; H, 3.38; N, 20.85. Found: C, 44.63; H, 3.67; N, 20.82.

Synthesis of 6-chloro-2-methyl-3-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)quinoxaline 1,4-dioxide (14)

A solution of 6-chloro-3-(hydrazinecarbonyl)-2-methylquinoxaline 1,4-dioxide (13, 0.54 g, 2 mmol), potassium hydroxide (0.11 g, 2 mmol), excess carbon disulfide (2 mL) and ethanol (20 mL) was refluxed for 24 h. The resulting solution was acidified by HCl solution (10 mL, 1 M), the formed precipitate was filtered off, washed with HCl (10 mL, 0.1 M) and recrystalized from ethanol as yellow crystals. Yield 0.42 g (68%); mp 252-256 °C; IR (KBr) n / cm-1 3136 (NH), 3047 (Ar-H), 2947 (C-H saturated), 1570 (C=C aromatic), 1342 (N-O), 1307 (C=S), 1256 (C-O), 833 (C-Cl); UV (DMSO) lmax / nm 336; 1H NMR (500 MHz, DMSO-d6) δ 2.84 (s, 3H, CH3), 7.95 (dd, Jortho 9.2, JW 2.3 Hz, 1H, HB), 8.41 (d, JW 2.3 Hz, 1H, HA), 8.46 (d, Jortho 9.2 Hz, 1H, HC), 9.97 (s, 1H, exchanges with D2O, NH); 13C NMR (500 MHz, DMSO-d6) δ 14.09, 120.58, 128.93, 132.45, 135.06, 136.45, 140.31, 140.79, 142.50, 157.84, 177.70; MS (m/z): 310 (33) [M]+, 312 (61) [M + 2]+, 55 (100). Anal. calcd. for C11H7ClN4O3S: C, 42.52; H, 2.27; N, 18.03. Found: C, 42.49; H, 2.38; N, 18.35.

Synthesis of 6-chloro-2-methyl-3-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)quinoxaline 1,4-dioxide (15)

A mixture of 6-chloro-3-(hydrazinecarbonyl)-2-methylquinoxaline 1,4-dioxide 13 (0.27 g, 1 mmol), p-nitrobenzoic acid (0.17 g, 1 mmol) and phosphorus oxychloride (2 mL) was heated under reflux for 2 h at 70 °C in water bath then the produced solution was poured into ice-water. The formed precipitate was filtered off and recrystallized from ethanol-water as a gray powder. Yield 0.20 g (50%); mp 96-97 °C; IR (KBr) n / cm-1 3079 (Ar-H), 2990 (C-H saturated), 1602 (C=N), 1527 (C=C aromatic), 1346 (N-O), 1275 (C-O), 717 (C-Cl); 1H NMR (500 MHz, CDCl3) δ 1.77 (s, 3H, CH3), 8.07 (d, Jortho 8.4 Hz, 2H, Ar), 8.14 (d, Jortho 8.1 Hz, 1H, HC), 8.25-8.34 (m, 4H, HA, HB, 2 for Ar); 13C NMR (500 MHz, CDCl3) δ 24.08, 44.75, 65.65, 123.62, 124.10, 124.52, 128.08, 128.61, 130.56, 131.02, 133.91, 140.27, 141.42, 150.05, 164.59; MS (m/z) 399 (3) [M]+, 312 (100). Anal. calcd. for C17H10ClN5O5: C, 51.08; H, 2.52; N, 17.52. Found: C, 51.28; H, 2.59; N, 17.83.

Synthesis of (E)-6-chloro-2-methyl-3-(2-(4-substituted-benzylidene)hydrazine-1-carbonyl)quinoxaline 1,4-dioxide derivatives (16a-e)

A solution of 6-chloro-3-(hydrazinecarbonyl)-2-methylquinoxaline 1,4-dioxide (13, 0.27 g, 1 mmol), the crossponding aromatic aldehyde (1 mmol), 3 drops of glacial acetic acid and ethanol (10 mL) was refluxed for 8-12 h. The produced precipitate was filtered off and recrystallized from the proper solvent.

(E)-3-(2-Benzylidenehydrazine-1-carbonyl)-6-chloro-2-methyl quinoxaline 1,4-dioxide (16a)

Yellow crystals obtained after washing with boiling ethanol. Yield 0.34 g (95%); mp 256-258 °C; IR (KBr) n / cm-1 3315 (NH), 3101 (Ar-H), 2990 (C-H saturated), 1660 (C=O hydrazide), 1600 (C=N), 1550 (C=C aromatic), 1334 (N-O), 1118 (C-O), 717 (C-Cl); UV (DMSO) lmax / nm 340; 1H NMR (500 MHz, DMSO-d6) δ 2.68 (s, 3H, CH3), 7.25-7.53 (m, 5H, Ar), 7.95 (d, Jortho 8.6 Hz, 1H, HC), 8.32 (s, 1H, HD), 8.45-8.54 (m, 2H, HA, HB), 12.30 (s, 1H, exchanges with D2O, NH); 13C NMR (500 MHz, DMSO-d6) δ 14.01, 120.82, 127.08, 127.73, 128.95, 129.17, 129.26, 130.98, 132.30, 134.00, 135.64, 136.48, 140.34, 142.47, 150.16, 150.26, 160.87; MS (m/z) 356 (34) [M]+, 306 (100). Anal. calcd. for C17H13ClN4O3: C, 57.23; H, 3.67; N, 15.70. Found: C, 57.22; H, 3.72; N, 15.66.

(E)-6-Chloro-3-(2-(4-methoxybenzylidene)hydrazine-1-carbonyl)-2-methylquinoxaline 1,4-dioxide (16b)

Bright yellow plates (ethanol); yield 0.34 g (89%); mp 245-250 °C; IR (KBr) n / cm-1 3305 (NH), 3074 (Ar-H), 2980 (C-H saturated), 1689 (C=O hydrazide), 1604 (C=N), 1500 (C=C aromatic), 1336 (N-O), 1101 (C-O), 829 (C-Cl); UV (DMSO) lmax / nm 340; 1H NMR (500 MHz, DMSO-d6) δ 2.67 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 7.04 (d, Jortho 8.6 Hz, 2H, Ar), 7.71 (d, Jortho 8.6 Hz, 2H, Ar), 7.95 (dd, Jortho 9.2, JW 2.3 Hz, 1H, HB), 8.31 (d, JW 2.3 Hz, 1H, HA), 8.39 (s, 1H, HD), 8.49 (d, J 9.2 Hz, 1H, HC), 12.16 (s, 1H, exchanges with D2O, NH); 13C NMR (500 MHz, DMSO-d6) δ 13.93, 55.55, 114.53, 114.62, 120.72, 126.50, 128.83, 129.33, 132.11, 135.50, 136.33, 140.16, 142.41, 149.85, 150.44, 161.43; MS (m/z) 386 (19) [M]+, 370 (100). Anal. calcd. for C18H15ClN4O4: C, 55.90; H, 3.91; N, 14.49. Found: C, 55.58; H, 4.11; N, 14.42.

(E)-6-Chloro-2-methyl-3-(2-(4-nitrobenzylidene)hydrazine-1-carbonyl)quinoxaline 1,4-dioxide (16c)

Yellow crystals obtained after washing with boiling ethanol. Yield 0.39 g (97%); mp 272-274 °C; IR (KBr) n / cm-1 3347 (NH), 3083 (Ar-H), 2960 (C-H saturated), 1680 (C=O hydrazide), 1593 (C=N), 1533 (C=C aromatic), 1342 (N-O), 1112 (C-O), 835 (C-Cl); UV (DMSO) lmax / nm 340; 1H NMR (500 MHz, DMSO-d6) δ 2.69 (s, 3H, CH3), 8.03 (d, Jortho 8.8 Hz, 2H, Ar), 8.13 (d, Jortho 9.1, JW 2.3 Hz, 1H, HB), 8.28-8.35 (m, 3H, HA, 2 for Ar), 8.50 (d, Jortho 9.1 Hz, 1H, HC), 8.58 (s, 1H, HD), 12.10 (s, 1H, exchanges with D2O, NH); 13C NMR (500 MHz, DMSO-d6) δ 13.97, 120.83, 124.40, 128.15, 128.67, 128.93, 132.40, 135.70, 136.49, 140.29, 140.50, 142.38, 147.71, 148.47, 161.14; MS (m/z) 401 (17) [M]+, 177 (100). Anal. calcd. for C17H12ClN5O5: C, 50.82; H, 3.01; N, 17.43. Found: C, 50.98; H, 2.99; N, 17.75.

(E)-3-(2-(4-Bromobenzylidene)hydrazine-1-carbonyl)-6-chloro-2-methylquinoxaline 1,4-dioxide (16d)

Yellow crystals obtained after washing with boiling ethanol. Yield 0.40 g (92%); mp 276-278 °C; IR (KBr) n / cm-1 3241 (NH), 3099 (Ar-H), 2919 (C-H saturated), 1687 (C=O hydrazide), 1595 (C=N), 1568 (C=C aromatic), 1338 (N-O), 1115 (C-O), 825 (C-Cl); UV (DMSO) lmax / nm 339; 1H NMR (500 MHz, DMSO-d6) δ 2.67 (s, 3H, CH3), 7.66-7.75 (m, 4H, Ar), 7.95 (dd, Jortho 9.1, JW 2.3 Hz, 1H, HB), 8.31 (d, JW 2.3, 1H, HA), 8.42 (s, 1H, HD), 8.49 (d, Jortho 9.1 Hz, 1H, HC), 12.42 (s, 1H, exchanges with D2O, NH); 13C NMR (500 MHz, DMSO-d6) δ 13.83, 120.65, 124.03, 128.73, 129.39, 132.05, 132.56, 133.15, 135.46, 136.26, 140.15, 142.26, 148.72, 149.99, 160.68; MS (m/z) 435 (9) [M + 1]+, 420 (100). Anal. calcd. for C17H12BrClN4O3: C, 46.87; H, 2.78; N, 12.86. Found: C, 46.96; H, 2.70; N, 12.54.

(E)-6-Chloro-3-(2-(4-(dimethylamino)benzylidene)hydrazine-1-carbonyl)-2-methylquinoxaline 1,4-dioxide (16e)

Orange crystals (ethanol); yield 0.35 g (88%); mp 245-249 °C; IR (KBr) n / cm-1 3209 (NH), 3091 (Ar-H), 2912 (C-H saturated), 1680 (C=O hydrazide), 1606 (C=N), 1522 (C=C aromatic), 1330 (N-O), 1112 (C-O), 820 (C-Cl); UV (DMSO) lmax / nm 340; 1H NMR (500 MHz, DMSO-d6) δ 2.65 (s, 3H, CH3), 2.97 (s, 6H, N(CH3)2), 6.76 (d, Jortho 8.6 Hz, 2H, Ar), 7.57 (d, Jortho 8.6 Hz, 2H, Ar), 7.93 (dd, Jortho 9.2, JW 2.3 Hz, 1H, HB), 8.25 (s, 1H, HD), 8.29 (d, JW 2.3 Hz, 1H, HA), 8.47 (d, Jortho 9.2 Hz, 1H, HC), 11.99 (s, 1H, exchanges with D2O, NH); 13C NMR (500 MHz, DMSO-d6) δ 14.27, 112.26, 120.95, 121.33, 128.63, 129.15, 129.41, 131.78, 132.35, 135.77, 136.67, 140.40, 142.77, 151.04, 152.37, 160.55; MS (m/z) 399 (3) [M]+, 401 (2) [M + 2]+, 43 (100). Anal. calcd. for C19H18ClN5O3: C, 57.08; H, 4.54; N, 17.52. Found: C, 57.29; H, 4.50; N, 17.42.

Supplementary Information

Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.

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Publication Dates

  • Publication in this collection
    Oct 2018

History

  • Received
    13 Mar 2018
  • Accepted
    16 Apr 2018
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