Design, green synthesis and reactions of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6 sulfonohydrazide derivatives

2,3-Dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonohydrazide and its derivatives were synthesized and characterize by IR, 1 H-NMR, 13 C-NMR and mass spectrometry analytical methods. The 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl hydrazide (compound 1), was synthesized from the reaction of o-phenylenediamine with oxalic acid to obtain quinoxaline-2,3-dione, which was subjected to chlorosulfonation with chlorosulfonic acid to give 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride. The 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride was reacted with hydrazine hydrate to afford 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl hydrazide (compound 1). The quinoxaline-6-sulfonohydrazone derivatives were synthesized by reacting compound 1 with substituted benzaldehydes or aromatic ketones. The chemical structures of the compounds prepared were confirmed by spectral data. The synthetic methodology was efficient and environmentally friendly; this was due to the fact that the work-up stage was carried out in water.

Microwave-assisted reactions have been intensely investigated since the earliest publication of Gedye et al. (1986) and Giguerre et al. (1986). It is fast becoming unavoidable technique for the accelerated synthesis of both organic compounds (Sha et al., 2001) and inorganic (Vanetsev et al., 2005), most importantly in the synthesis of different biologically active heterocycles (Abdellatif et al., 2008;Qingqing et al., 2008;Rodrigo et al., 2008;Outirite et al., 2008;Tinh and Stadlbauer, 2008;Muscia et al., 2008). Chemists have discovered that, microwave enhanced chemical reaction time and can be faster than those of conventional heating methods by as much as a thousand-fold (Hayes, 2004). This present work was designed to develop a series of novel 2,3-dioxo-1,2,3,4tetrahydroquinoxaline-6-sulfonyl hydrazone using microwave irradiation technique and also compare it with traditional method of conventional heating approach.

General
Melting points were determined with open capillary tube on a Gallenkamp (variable heater) melting point apparatus and were uncorrected. Infrared spectra were recorded as KBr pellets on a Buck Spectrometer. The 1 H and 13 C NMR were run on a Bruker 600 MHz spectrometer (δ in ppm relative to Me 4 Si). Mass spectra were taken on a high-resolution (m/∆m = 30 000). Thermo Scientific LTQ-Orbitrap Discovery mass spectrometer (San Jose, CA) equipped with an electrospray ionization source at the Department of Chemistry, Portland State University, Portland U.S.A. The purity of the compounds were routinely checked by TLC on silica gel G plates using n-hexane/ethyl acetate (1:1, v/v) solvent system and the developed plates were visualized by UV light. All reagents used were obtained from Sigma-Aldrich Chemical Ltd, except glacial acetic acid, ethanol, oxalic acid and vanillin which were obtained from BDH Chemical Limited.

General procedure for the reaction of quinoxaline-6sulfonohydrazide with substituted benzaldehydes and aromatic ketones
Quinoxaline-6-sulfonohydrazide (1.0 g, 39 mmol) and substituted benzaldehydes or aromatic ketones (39 mmol) were added to glacial acetic acid (25 ml) in a round bottom flask and refluxed at 120°C for 3 h. The reaction mixture was cooled and poured into crushed ice with continuous stirring to obtain a solid product which was filtered and dried. Recrystallization from DMF/water afforded N-(E)-(phenylideneamino)-6-(quinoxaline-2,3-(1H,4H)dione)sulfonamide compounds 2 to 13. Completion of the reaction was monitored by TLC.
Generally, the infrared spectra of the compounds showed absorption bands due to the stretching vibrations of N-H and OH between 3135 and 3390 cm -1 , C=O

DISCUSSION
1,2,3,4-Tetrahydroquinoxaline-2,3-dione was prepared by the modified procedure of Obafemi and Pfleiderer (1994) by reacting o-phenylenediarnine with oxalic acid dehydrate thermally or by microwave irradiation in acidified water (Scheme 1). The mechanism of the reaction between oxalic acid and the 1, 2-diaminobenzene is acid catalyzed condensation reaction involving the protonation of the carbonyl oxygen atom of the oxalic acid by the acid used as the catalyst. This makes the carbonyl carbon more electrophilic and this can easily be attacked by the nucleophile. In this case the nucleophile is the amino group of the 1, 2-diaminobenzene. The acid is regenerated during the cyclization stage which is effected by the heat supplied into the system (Scheme 2). 1,2,3,4tetrahydroquinoxaline-2,3-dione was allowed to react with excess of chlorosulfonic acid under reflux to obtain 2,3dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride (Scheme 1). The proposed mechanism for the synthesis of 2,3-dioxo-1,2, 3, 4-tetrahydroquinoxaline-6-sulfonyl chloride is given in Scheme 3. The reaction of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride with hydrazine hydrate in absolute methanol afford afforded 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6sulfonylhydrazide, 1 (Scheme 1). The mechanism of the synthesis of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6sulfonyl hydrazide is outlined in Scheme 4. The treatment of equimolar amount of 1 with some aromatic aldehydes under refluxing condition in glacial acetic acid afforded the hydrazones 2 to 11 (Scheme 5). The proposed general mechanism for the reactions of 2,3-dioxo-1,2,3,4tetrahydro quinoxaline-6-sulfonyl hydrazide, 1 ‫׳‬ with different benzaldehydes are given in Scheme 5. The mechanism of the reaction involves the protonation of the carbonyl carbon of the substituted benzaldehydes. This makes the carbon to be electron deficient and enables the centre to be more susceptible to Nucleophilic attack by the amino end of the hydrazide. The heat supplied serves as the driving force for the loose of water molecules to afford the hydrazones Scheme 6. Treatment of equimolar amount of compound 1 and isatin in glacial acetic acid led to the formation of N-(E)-(2-oxoindole-3ylideneamino)-6-(quinoxaline-2,3-(1H,4H)-dione) sulfonamide 12. The proposed mechanism for the reaction of 2, 3-dioxo-1, 2, 3, 4-tetrahydroquinoxaline-6sulfonyl hydrazide, 1 with isatin is highlighted in Scheme 5. The mechanism of the reaction involves the protonation of the ketonic carbonyl carbon of the isatin. This makes the carbon to be electron deficient and enables the centre to be more susceptible to nucleophilic attack by the amino end of the hydrazide. The heat supplied serves as the driving force for the loose of water molecules to afford the expected hydrazone Scheme 7. The synthesis of N-(E)-(phenylideneamino)-6-(quinoxaline-2-(1H,4H)-dione)sulfonamide 13 was achieved by the condensation of compound 1 and equimolar amount of acetophenone in glacial acetic acid. The mechanism of the reaction involves the protonation of the carbonyl carbon of the acetophenone. This makes the carbon to be electron deficient and enables the centre to be more susceptible to nucleophilic attack by the amino end of the hydrazide. The heat supplied serves as the driving force for the loose of water molecules to afford the hydrazone Scheme 8.
The evidences from 1 H-NMR and 13 C-NMR spectra of compound 3 showed that the hydrazine NH proton was observed at a downfield region in the NMR spectrum. This characteristic broad singlet was observed at 11.61 ppm. This downfield position of the NH peak suggests that the proton is involved in strong intra-molecular hydrogen bonds. The quinoxaline (-NH-C=O) protons were observed in the NMR spectrum at a further downfield region as broad singlet between 12.18 and 12.12 ppm (integrating for 2 protons). This two singlet signals look like a doublet but a closer look at the expanded spectral shows they are two singlet that are very close to one another that makes them look like a doublet. The down field shift of this signal is characteristic for the formation of an intra-molecular hydrogen bond of the NH proton. On observing the expanded spectra a strong singlet at 8.72 δppm was observed which was Table 2. The Infrared Spectral Data of the 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl hydrazones 1-13. assigned to the hydrazono proton (N=C-H). This hydrazono proton (N=C-H) is a single proton not surrounded by any other proton in its vicinity hence a singlet was observed for it, moreover as its carbon is directly attached to electronegative nitrogen moiety or more particularly the C-N-N system and aromatic ring hence it is extremely deshielded and thus found in the downfield region. On further studying the expanded NMR spectrum in the aromatic region, it was observed that there was a mutiplet signal accounting for 1 proton between 7.45 and 7.47 δppm (J=1.7 Hz). This multiplet was assigned to proton at C-5. A doublet of doublet signal accounting for 1 proton between 7.89 and 7.91 δppm (J=8.5 Hz, J=2.4 Hz) was observed, this signal was assigned to proton at C-7. The doublet signal accounting for 1 proton between 7.24 ppm and 7.25 δppm (J=8.5 Hz) was assigned to proton at C-8. This splitting was observed because of one adjacent proton at C-7. A multiplet between 7.66 and 7.65 δppm (J=1.9

Compounds Infrared spectral
Hz) which accounts for 2 protons was observed in the NMR spectrum, this multiplet was assigned to proton at C-2 ΄ and C-6 ΄ . On further investigation of the NMR specrum, a doublet of doublet was observed, accounting for 2 protons. The characteristic doublet of doublet between 7.56 and 7.6 1 ppm (J=1.86 Hz, J=9 Hz) can be assigned to proton at C-2 ΄ and C-5 ΄ .
The 13 C NMR spectrum of compound 3 shows signals at 160.58 and 155.18 δppm which are due to amide carbon (C=O) of the quinoxaline ring. The azomethine carbon (C=N) has appeared at 154.78 δppm. The spectrum shows the aromatic carbons in the region between 114.19 and 134.54 δppm. The NMR spectral data are listed in Tables  3 and 4.
The mass spectrum of the compound 3 showed molecular ion peak at m/z 378 (M + ). Other peaks at m/z 254, 123.04, 130.16 which was the base peak, support the structure of compound 3 (Scheme 9). The mass spectrum of the compound 4 showed peak at m/z 342.43 ([M -NO 2 ] + . Other peaks at m/z 324. 43, 287.22, 185.04, 116.98, and 107.04 which was the base peak, support the structure of compound 4 (Scheme 10). 1 H-NMR and 13 C-NMR spectra of compound 12 showed that the hydrazine NH proton was observed at a down field region in the NMR spectrum. This characteristic broad singlet was seen at 10.73 δppm. This downfield position of the NH peak suggests that the proton is involved in strong intra-molecular hydrogen bonds. The quinoxaline (-NH-C=O) protons are observed in the NMR spectrum at a further downfield region as a broad singlet between 12.21 and 12. 17 δppm (integrating for 2 protons). This two singlet signals look like a doublet but a closer look at the expanded spectral shows they are two singlet that are very close to one another that makes them look like a doublet. The downfield shift of this signal is characteristic for the formation of an intra-molecular hydrogen bond of the NH proton. On studying the expanded NMR spectrum in the aromatic region it was observed that there is a   doublet signal accounting for 1 proton at 8.87 δppm. This doublet was assigned to proton at C-5. A doublet of doublet between 7.63-7.65 δppm (J = 8.64 Hz) (integrating for 1 proton) was assigned to proton at C-7. A doublet signal accounting for 1 proton at 7.22 δppm was assigned to proton sat C-8. On studying the aromatic region a doublet of doublet between 6.85 and 6.86 δppm (J = 8 Hz) which accounts for 1 proton was observed. This signal is assigned to proton at C-4 ΄ . The triplet signal accounting for 1 proton at 7.37 δppm was assigned to proton at C-5 ΄ . A triplet at 7.06 δppm which accounts for 1 proton was assigned to proton at C-6 ΄ . The doublet signal accounting for 1 proton between 7. 27 and 7.29 δppm (J = 8 Hz) was assigned to proton at C-7 ΄ . The 13 C NMR spectrum of compound 12 shows signals between 155.16 and 163.61 δppm which are due to amide carbon (C=O) on the quinoxaline ring. The azomethine carbon (C=N) has appeared at 154.86 δppm. The spectrum shows the aromatic carbons in the region of 110.50 and 143.84 δppm.
The mass spectrum of the compound 12 showed peak at m/z 254.01. Other peaks at m/z 160.04, 148.04 (which was the base peak) and 132.04 support the structure of compound 12 (Scheme 11). The mass spectrum of the compound 13 showed peak at m/z 243.03. Other peaks at m/z 243.03, 163.06, 129.13 and 111.12 (which was the base peak) support the structure of compound 13 (Scheme 12).

Conclusion
This work is in the areas of research related to heterocyclic chemistry.. It aims at the synthesis and characterization of new heterocyclic systems, using 2,3dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonohydrazide as starting material.
It can be concluded that the synthesis of some new 2,3-Dioxo-1,2,3,4-tetrahydroquinoxaline-6sulfonohydrazide derivatives were successful. The synthetic methodology was efficient and environmentally friendly, this was due to the fact that the work-up stages were carried out in water.