Synthesis of Some New Heterocyclic Nitrogen Compounds Starting from Pyromellitic Dianhydride

Introduction

Owing to the wide spread applications of pyromellitic dianhydride (PMDA) in several fields, such as synthesis of polyimides ^[1-3], epoxy resins ^[4] and Metal Carboxylate ^[5,6] Complexes. In addition, pyrrole, benzoxazine and phthalazine derivatives exhibit wide range of pharmacological and biological applications, such as analgesic ^[7-9], antifungal ^[10-12], antitoxic ^[13], anticancer ^[14-17], alkaloids, agro-chemicals ^[18,19] and dyes applications ^[20], this encourage us to synthesize new derivatives of condensed dipyrrole, dibenzoxazine and dipyridazine starting with pyromellitic dianhydride which may posses a greater certain pharmacological activity.

Results and discussion

During the last few years our research group has been interested in the chemistry of anhydrides with the objective of finding new routes for the synthesis of new heterocyclic derivatives with expected biological activities ^[21-24].

E.V.Ganin et al ^[25], were able to fined a synthetic procedure for the preparation of pyromellitic diimide 2 by the reaction of PMDA 1 with formamide. In our work, we have investigated the action of other amides such as urea, thiourea, and thiosemicarbazide on the anhydride 1 in order to synthesize new diimide derivatives which may undergo cyclization or further polymerization, the only product isolated from these reactions was pyromellitic diimide 2 in good yield (cf. Scheme 1).

Scheme 1 Click here to View scheme

When compound 1 was allowed to react with benzylamine in dry toluene, 2,5-di[(benzylamino)carbonyl]terephthalic acid 3 was formed through cross linked nucleophilic attack. The presence of electron withdrawing carbonyl group in para position to the anhydride carbonyl carbones facilitates the cross nucleophilic attack ^[26]. Fusion of compound 3 gave the corresponding cyclic diimide assigned as 2,6-dibenzylpyrroloisoindole-1,3,5,7-tetrone 4 (cf.Scheme 2).

Scheme 2 Click here to View scheme

PMDA was reacted with 2-aminothiophenol in glacial acetic acid as a proteic solvent to give 2,5-di(benz-1,3-thiazol-2-yl)terephthalic acid 5 through cross nucleophilic ring opening of PMDA followed by intramolecular nucleophilic cyclization to give benzothiazole moiety. Repeating the reaction in non-polar solvent namely, toluene gave 2,5-di(benz-1,3-thiazol-2-yl)benzoic acid 6 which on thermal decarboxylation at 320^oC  gave 1,4-di(benz-1,3-thiazole)benzene 7 via losses of CO₂ (cf. Scheme3).

Scheme 3 Click here to View scheme

The reaction of 1 to give compound 6 may proceed via losses of CO₂ through the following intermediate shown in

Scheme 4 Click here to View scheme

 

The molecular ion peak of compound 6 indicated (M⁺·) at m/z = 388 (9.2%) corresponding to the formula  C₂₁H₁₂N₂O₂S_2, and the following fragents observed in the mass spectrum of the compound 6 confirms its assigned structure (Scheme 5): The peaks at 387, 344, 343, 311, and 235 are characteristic peaks corresponding to the fragments. Thus the structure of compound 6 is in agreement with the observed spectral data.

Scheme 5 Click here to View scheme

 

On the other hand, the Friedel-Crafts reaction of pyromellitic dianhydride with benzene to give 2,5-dibenzoylterephthalic acid 8a and its isomer 4,6-dibenzoyl- isophtalic acid 9a was previously described ^[27]. In our work, the same reaction was intensively investigated using more reactive aromatic substrates namely anisol, toluene in addition to chlorobenzene.

The two isomeric structures formed in each reaction were separated by fractional crystallization to give 2,5-diaroylterephthalic acid 8a-d and 2,6-diaroylisophthalic acid 9a-d (Scheme 6). The configuration assigned to these proposed structures was based on the IR spectroscopic evidence. ¹H-NMR for terephthalic isomers 8a-dindicates the presence of a singlet for the two identical benzene protons at δ 7.88-7.92, while for isophthalic isomers 9a-d showed two different benzene protons at  δ7.31-7.95 and at δ 8.55-8.77 respectively.

2,5-diaroylterephthalic acids 8a-d and/or 2,6-diaroylisophthalic acids 9a-d were reacted with hydroxylamine hydrochloride in pyridine under reflux, compounds 10a-d identified as 4,9-diaryl-1H,6H[1,2]oxazino[5,4-g][2,3]benzoxazine-1,6-diones and/or 11a-d identified as 4,6-diaryl-1H,9H[1,2]oxazino[4,5-g][2,3]benzoxazine-1,9-diones were obtained respectively (Scheme 6).

Scheme 6 Click here to View scheme

The H-C COSY technique (Carbon-13 detection and proton decoupling) is attractive because it efficient and provides unequivocal results; it allows the shift of two nuclei (¹H and ¹³C) to be measured in a single experiment. Figures (1) and (2) showed H-C COSY for the two isomers 8d and 9d in which the shifts of the ¹H and ¹³C nuclei are bonded to one another are read as coordinates of the cross signal. In (Fig. 1), for example, the protons with shifts 7.6 and 7.96 are bonded to the carbon atoms at 128.91 and 128.82 respectively for compound 8d. On the other hand, compound 9d, the protons with shifts 7.58 and 7.95 are bonded to the carbon atoms C-2 and C-9 at 128.84, while the protons with shifts 7.74 and 8.54 are bonded to the carbon atoms C-3 and C-10 at 130.67 and 131.38 respectively (cf. Fig. 2).

Figure 1: 1H-13C correlation spectrum of 8d          Click here to View figure

Figure 2: 1H-13C correlation spectrum of 9d Click here to View figure

                     

13C-NMR data were also useful to differentiate between the two isomers  8d and 9d in which compound 8d showed nine different signals for nine non identical carbon atoms, while for 9d showed ten different carbon atoms.

Through another synthetic route, the two isomeric structures 10b and 11b were also obtained by the reaction of 2,6-dihydroxypyromellitimide ^[28] 14 with anisole in presence of anhydrous aluminum chloride (Scheme 6). The chemical structures of 10b and 11b were established on the basis of NMR spectrocopy, which were found to be completely fit with the proposed structures. ¹³C-NMR data were found to be ideal technique for the differentiation between the two isomers 10b and 11b. Compound 10b revealed the presence of ten different carbon signals, while 11b showed eleven different carbon signals, which were in good agreement with the proposed structures.

The reaction of 14 to give the two isomers 10b and 11b may proceed according to the mechanism shown in (Scheme 7).

Scheme 7  Click here to View scheme

Also, treatment of the acids 8a-d and/or 9a-d with hydrazine hydrate and/or phenylhydrazine gave the corresponding pyridazino[4,5-g]phthalazine-1,6-diones 12a-h and/or pyridazino[4,5-g]phthalazine-1,9-diones 13a-f respectively (Scheme 8).

Scheme 8 Click here to View scheme

The structure of compounds 12a-h and 13a-f were characterized by elemental analysis, IR and MS data.

¹H-NMR  spectra were not available because of  low solubility of these compounds in organic solvents.

Conclusions

In summary, we have found that pyromellitic dianhydride is extremely useful for the synthesis of biologically relevant heterocyclic compounds such as dipyrroles, dibenzoxazines, dipyridazines and isophthalic and terephthalic derivatives in good yields after short reaction times.

Acknowledgement

Special thanks to Prof. Dr. T. Throll and Dr. Burgemeister (Regensburg University, Germany) for the IR help in the determenation of 13C-NMR, H-C COSY and elemental analysis.

Experimental

Melting points were uncorrected determined on an electric melting point apparatus (Kofler). The IR spectra (KBr) were recorded on a Shimadzu 408 spectrometer. The 1H-NMR spectra were recorded by 400 MHz Varian EM 390 spectrometer. The 13C-NMR spectra and The 1H-13C-NMR (H-C COSY) were measured on Avance 600 spectrometer; chemical shifts are reported in ppm with TMS as an internal standard and are given in δ units. Electron impact mass spectra were obtained at 70 ev using a GCMS sp.1000 Shimadzu. Elemental analyses were carried out at Microanalysis Unit at RegensburgUniversity.

Pyromellitic diimide  2.

 A mixture of pyromellitic dianhydride 1 (1.09 g, 5 mmol) and the appropriate amide, namely, urea, thiourea and/ or thiosemicarbazide (20 mmol) was fused in an oil bath at 180^o until the odour of ammonia was stopped (15 min). The residue was washed with water and crystallized from ethanol/DMF (2:1), as greenish white crystals in 93% yield; mp >360⁰_;IR (KBr): ν 3250 cm^-1 (NH) 1780 ; 1700 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 8.05 (s, 2H, two identical benzene protons) 11.82 (s, 2H, 2NH);; MS: m/z 216(M).  Anal. Calcd. For C₁₀ H₄ N₂ O₄: C, 55.57; H, 1.87; N, 12.96; Found; C, 55.60; H, 1.77; N, 13.03%.

2,5-di[(benzylamino)carbonyl]terephthalic acid 3.

A mixture of pyromellitic dianhydride 1 (2.18 g, 10 mmol) and benzylamine (2.14 ml, 20 mmol) in toluene (50 ml) was refluxed for 1 hrs. After cooling, the solid crystals was filtered off and crystallized from acetic acid, as white crystals in 88% yield; mp 298-300⁰; IR (KBr): ν 3300 cm^-1 (NH) 1710 ; 1660 cm^-1 (C=O’s); ¹H-NMR (DMSO-d6): δ 4.43 (s, 4H, 2CH₂), 7.22-7.43(m, 10H, arom.H), 7.77(s, 2H, two identical benzene protons), 9.17(s, 2H, 2COOH). Anal. Calcd. For C₂₄H₂₀N₂O₆: C, 66.66; H, 4.66; N, 6.48; Found; C, 66.71; H, 4.57; N, 6.52%.

2,6-dibenzylpyrrolo[3,4-f]isoindole-1,3,5,7(2H,6H)tetrone 4.

1.08 g (2.5 mmol) of 3 was fused at 310 ^o for 15 min. The solid formed was washed with water then ethanol and crystallized from DMF, as white crystals in  81% yield; mp 308-9^o; IR (KBr): ν 1740 ; 1700 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 4.85 (s, 4H, 2CH₂), 7.34 (m, 10H, arom.H), 8.22 (s, 2H, two identical benzene protons). Anal. Calcd. For C₂₄H₁₆N₂O₄: C, 72.72; H, 4.07; N, 7.07; Found; C, 72.69; H, 4.13; N, 7.04 %.

2,5-di(benz-1,3-thiazol-2-yl)terephthalic acid 5.

A mixture of pyromellitic dianhydride 1 (2.18 g, 10 mmol) and 2-aminothiophenol (2.5 g, 20 mmol) in glacial acetic acid (50 ml) was refluxed for 5 hrs. After cooling, the solid precipitated was filtered off and crystallized from DMF/ acetic acid (4:1), as white crystals in  83% yield; mp 335-37^o; IR (KBr): ν 3600-3250 cm^-1 (COOH), 1779, 1726 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.51-8.25 (m, 10H, arom.H), 13.8 (s, 2H, 2COOH); MS: m/z =432(M).  Anal. Calcd. For C₂₂ H₁₂ N₂O₄S₂: C, 61.10; H, 2.80; N, 6.48; S, 14.82; Found; C, 61.21; H, 2.84; N, 6.42; S, 14.73 %.

2,5-di(benz-1,3-thiazol-2-yl)benzoic acid 6.

Pyromellitic dianhydride 1 (2.18 g, 10 mmol) and 2-aminothiophenol (2.5 g, 20 mmol) in toluene (50 ml) were refluxed for 10 hrs. After cooling, the solid precipitated was filtered off and crystallized from ethanol, as green crystals in 77% yield; mp 323-25⁰; IR (KBr): ν 3600-3250 cm^-1 (COOH), 1707cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.36-8.25 (m, 11H, arom.H), 13.65 (s,1H, COOH); MS: m/z 388(M). Anal. Calcd. For C₂₁ H₁₂ N₂O₂S₂: C, 64.92; H, 3.11; N, 7.21; S, 16.51; Found; C, 64.96; H, 3.18; N, 7.14; S, 16.47 %.

1,4-di(benz-1,3-thiazol-2-yl)benzene 7.

1 g (2.6 mmol) of 6 was fused at 320^oC for 5 min. The solid formed was washed with water then sodium bicarbonate solution and crystallized from benzene, as brown crystals in  68% yield; mp 160-62⁰; MS: m/z 344(M).  Anal. Calcd. For C₂₀ H₁₂ N₂S₂: C, 69.74; H, 3.51; N, 8.13; S, 18.62; Found; C, 69.80; H, 3.47; N, 8.20; S, 18.53 %.

2,5-diaroylterephthalic acid 8a-d and 2,6-diaroylisophthalic acid 9a-d.

 General procedure

Anhydrous aluminium chloride (8 g, 60 mmol) was added gradually while stirring to pyromellitic dianhydride (2.18 g, 10 mmol) in dry aromatic substrate, namely, benzene, anisole, toluene and/or chlorobenzene (30 ml). The reaction mixture was refluxed for 2 hrs. and then left overnight. The complex formed was decomposed with ice-cold dilute hydrochloric acid (1:1). The solvent was steam distilled, and after cooling, the solid isomers precipitated (83-94% yield) and were separated by column chromatography (30 cm height, 3 cm diameter) using benzene/ethanol (4:1) as an eluent to give 8a-d and 9a-d as white crystals.

2,5-dibenzoylterephthalic acid 8a.

Compound 8a was obtained in 56% yield, crystallized from ethanol/benzene (3:2); mp 320-22⁰; IR (KBr) ν 3400-2550 cm^-1 (COOH), 1750; 1680 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.52-7.75 (m, 10H, arom.H), 7.92 (s, 2H, two identical benzene protons) and disappearance of COOH protons. Anal. Calcd. For C₂₂H₁₄O₆: C, 70.59; H, 3.77. Found; C, 70.56; H, 3.80%.

2,5-di(4-methoxybenzoyl)terephthalic acid 8b.

Compound 8b was obtained in 49% yield, crystallized from ethanol/benzene (2:1); mp 325-27⁰; IR (KBr) ν 3200-2500cm^-1 (COOH), 1700;1660 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ = 3.81 (s, 6H, 2 OCH₃), 7.04-7.72 (dd, A₂B₂ system, 8H arom.), 7.85 (s, 2H, two identical benzene protons) and disappearance of COOH protons; MS: m/z 434. Anal. Calcd. For C₂₄H₁₈O₈: C, 66.36; H, 4.18. Found; C, 66.40; H, 4.14 %.

2,5-di(4-methylbenzoyl)terephthalic acid 8c.

Compound 8c was obtained in 52% yield, crystallized from ethanol/benzene (3:2); mp 310-12⁰; IR (KBr) ν 3400-2800 cm^-1 (COOH), 1720;1680 cm^-1 (C=O’s); ¹H-NMR (DMSO-d6): δ 2.37 (s, 6H, 2 CH₃), 7.32-7.65 (dd, A₂B₂ system, 8H arom.), 7.88 (s, 2H, two identical benzene protons) and disappearance of COOH protons. Anal. Calcd. For C₂₄H₁₈O₆: C, 71.64; H, 4.51. Found; C, 71.62; H, 4.52%.

2,5-di(4-chlorobenzoyl)terephthalic acid 8d.

Compound 8d was obtained in 55% yield, crystallized from ethanol/benzene (3:1); mp 320-23⁰; IR (KBr) ν 3400-2800cm^-1 (COOH), 1720;1680cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.55-7.79 (dd, A₂B₂ system, 8H arom.), 7.85 (s, 2H, two identical benzene protons) and disappearance of COOH protons; ¹³C-NMR (DMSO-d₆): 128.82, d, C-2; 128.91, d, C-9; 130.90, d, C-3;    133.40 , s, C-4; 135.16, s, C-1;  138.40, s, C-6; 141.82, s, C-7; 165.63, s, C-5; 194.05, s, C-8. Anal. Calcd. For C₂₂H₁₂Cl₂O₆: C, 59.62; H, 2.73; Cl, 15.99. Found; C, 59.65; H, 2.74; Cl, 15.95 %.

4,6-dibenzoylisophthalic acid 9a.

Compound 9a was obtained in 38% yield, crystallized from ethanol/benzene (1:3); mp 278-79⁰; IR (KBr) ν 3300-2800 cm^-1 (COOH), 1720;1670 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.78-7.76 (m, 11H, arom.H + H-5), δ 8.85 (s, 1H, H-2) and disappearance of COOH signal. Anal. Calcd. For C₂₂H₁₄O₆: C, 70.59; H, 3.77. Found; C, 70.61; H, 3.75 %.

4,6-di(4-methoxybenzoyl)isophthalic acid 9b.

Compound 9b was obtained in a 34% yield, crystallized from ethanol/benzene (1:3); mp 215-17⁰; IR (KBr) ν 3300-2500 cm^-1 (COOH), 1730; 1680 cm^-1 (C=O’s); ¹H-NMR (CDCl₃):  δ 33.85 (s, 6H, 2OCH₃), 7.10-7.65 (dd, A₂B₂ system, 8H arom.), 7.40 (s, 1H, H-5), ) 8.55 (s, 1H, H-2), 13.85 (s, 2H, 2COOH); ¹³C-NMR (CDCl₃): 55.59, q; 114.04, d; 126.41, d; 129.29, s; 130.50, s; 131.39, d; 131.44, d; 144.95, s; 163.36, s; 165.63, s; 193.56, s.; MS: m/z 434 (M). Anal. Calcd. For C₂₄H₁₈O₈: C, 66.36; H, 4.18. Found; C, 66.39; H, 4.15 %.

4,6-di(4-methylbenzoyl)isophthalic acid 9c.

Compound 9c was obtained in 40% yield, crystallized from ethanol/benzene (2:3); mp 248-50⁰; IR (KBr) ν 3250-2500 cm^-1 (COOH), 1700,1670 cm^-1 (C=O’s); ¹H-NMR (CDCl₃): δ 2.40 (s, 6H, 2CH₃), 7.22-7.37 (dd, A₂B₂ system, 8H arom.), 7.31 (s, 1H, H-5), 8.77 (s, 1H, H-2), 9.49 (s, 2H, 2COOH); MS: m/z 402(M). Anal. Calcd. For C₂₄H₁₈O₆. C, 71.64; H, 4.51. Found; C, 71.61; H, 4.53%.

4,6-di(4-chlorobenzoyl)isophthalic acid 9d.

Compound 9d was obtained in 33% yield, recrystallized from ethanol/benzene (1:2); mp 240-42⁰; IR (KBr) ν 3400-2270 cm^-1 (COOH), 1740,1700 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.56-7.72 (dd, A₂B₂ system, 8H arom.), 7.95 (s, 1H, H-5), 8.55 (s, 1H, H-2) and disappearance of COOH protons; ¹³C-NMR (DMSO-d6): 128.84, d, C-2, C-9; 130.67, d, C-3; 131.38, d, C-10; 135.03, s, C-1; 138.30, s, C-4; 141.73, s, C-6; 144.41, s, C-7; 165.56, s, C-5; 193.91, s, C-8; MS: m/z 442(M). Anal. Calcd. For C₂₂H₁₂C_l2O₆: C, 59.62; H, 2.73; Cl, 15.99. Found; C, 59.66; H, 2.74; Cl, 15.94%.

Synthesis of diaryl-[1,2]oxazinobenzoxazines 10a-d and 11a-d.

 General procedure

To a solution of 2,5-diaroylterephthalic acid 8a-d and/or 4,6-diaroylisophthalic acid 9a-d (5 mmol) in dry pyridine (10 ml), hydroxylamine hydrochloride (1.38 g, 20 mmol) was added, then the reaction mixture was refluxed for 1 hr. After cooling, the reaction mixture was poured onto ice-dilute hydrochloric acid, the solid precipitated was filtered off and crystallized from appropriate solvent to give  10a-d and/or 11a-d white crystals.

4,9-diphenyl-1H,6H[1,2]oxazino[5,4-g][2,3]benzoxazine-1,6-dione 10a.

 Compound 10a was obtained in 60% yield, crystallized from Ethanol/DMF (6:1); mp >360⁰; IR (KBr) ν 1740 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.69(m, 10H , arom. H), 8.15 (s, 2H, two identical benzene protons). Anal. Calcd. For C₂₂H₁₂N₂O₄: C, 71.74; H, 3.28; N, 7.61. Found; C, 71.71; H, 3.27; N, 7.65 %.

4,9-di(4-methoxyphenyl)-1H,6H[1,2]oxazino[5,4-g][2,3]benzoxazine-1,6-dione10b.

Compound 10b was obtained in 57% yield, recrystallized from acetic acid; mp 355-58⁰; IR (KBr) ν 1750 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 3.72 (s, 6H, 2OCH₃), 6.89-7.13 (dd, A₂B₂ system, 8 H arom.), 7.72 (s, 2H, two identical benzene protons); MS: m/z 428(M). Anal. Calcd. For C₂₄H₁₆N₂O₆: C, 67.29; H, 3.76; N, 6.54. Found; C, 67.32; H, 3.71; N, 6.56 %.

4,9-di(4-methylphenyl)-1H,6H[1,2]oxazino[5,4-g][2,3]benzoxazine-1,6-dione 10c.

Compound 10c was obtained in 66% yield, crystallized from DMF; mp 350-52⁰; IR (KBr) ν 1750 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 2.45 (s, 6H, 2CH₃), 7.48-7.57 (dd, A₂B₂ system, 8 H arom.), 8.17 (s, 2H, two identical benzene protons); MS: m/z 396(M). Anal. Calcd. For C₂₄H₁₆N₂O₄: C, 72.72; H, 4.07; N, 7.07. Found; C, 72.77; H, 4.05; N, 7.04%.

4,9-di(4-chlorophenyl)-1H,6H[1,2]oxazino[5,4-g][2,3]benzoxazine-1,6-dione 10d.

Compound 10d was obtained in 70% yield, crystallized from methanol; mp 358-59⁰; IR (KBr) ν 1750; 1740 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.71-7.79 (dd, A₂B₂ system, 8 H arom.), 8.13 (s, 2H, two identical benzene protons); MS: m/z 436(M). Anal. Calcd. For C₂₂H₁₀Cl₂N₂O: C, 60.43; H, 2.31; N, 6.41; Cl, 16.22. Found; C, 60.39; H, 2.35; N, 6.46; Cl, 16.16%.

4,6-diphenyl-1H,9H[1,2]oxazino[4,5-g][2,3]benzoxazine-1,9-dione 11a.

Compound 11a was obtained in 56% yield, crystallized from DMF; mp 305-8⁰; IR (KBr): ν 1760 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.52-7.69(m, 11H, arom. H + H-5), 8.96 (s, 1H, H-10). Anal. Calcd. For C₂₂H₁₂N₂O₄: C, 71.74; H, 3.28; N, 7.61. Found; C, 71.78; H, 3.30; N, 7.55%.

4,6-di(4-methoxyphenyl)-1H,9H[1,2]oxazino[4,5-g][2,3]benzoxazine-1,9-dione11b.

Compound 11b was obtained in 69% yield, crystallized from chloroform, mp 278-79⁰; IR (KBr) ν = 2932-2832 cm^-1 (CH₃), 1703 cm^-1 (C=O’s); ¹H-NMR (DMSO): δ 3.72 (s, 6H, 2OCH₃), 6.83-7.10 (dd, A₂B₂ system, 8 H arom.), 7.62 (s, 1H, H-5), 7.97 (s, 1H, H-10). Anal. Calcd. For C₂₄H₁₆N₂O₆: C, 67.29; H, 3.76; N, 6.54. Found; C, 67.30; H, 3.74; N, 6.55%.

4,6-di(4-methylphenyl)-1H,9H[1,2]oxazino[4,5-g][2,3]benzoxazine-1,9-dione 11c.

Compound 11c was obtained in 72% yield, crystallized from DMF; mp 292-94 ⁰C; IR (KBr) ν 1755 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 2.39 (s, 6H, 2CH₃), 7.39-7.48 (dd, A₂B₂ system, 9 H, arom. H+ H-5), 8.97 (s, 1H, H-10). Anal. Calcd. For C₂₄H₁₆N₂O₄: C, 72.72; H, 4.07; N, 7.07. Found; C, 72.75; H, 4.09; N, 7.02%.

4,6-di(4-chlorophenyl)-1H,9H[1,2]oxazino[4,5-g][2,3]benzoxazine-1,9-dione 11d.

Compound 11d was obtained in 76% yield, crystallized from acetic acid; mp 310-12⁰; IR (KBr) ν 1760, 1730 cm^-1 (C=O’s); ¹H-NMR (CDCl₃): δ 7.24-7.50 (dd, A₂B₂ system, 9 H arom. H+ H-5) , 7.62 (s, 1H, H-10). Anal. Calcd. For C₂₂H₁₀Cl₂N₂O: C, 60.43; H, 2.31; N, 6.41; Cl, 16.22. Found; C, 60.46; H, 2.33; N, 6.40; Cl, 16.17%.

4,9-di(4-methoxyphenyl)-1H,6H[1,2]oxazino[5,4-g][2,3]benzoxazine-1,6-dione 10b and 4,6-di(4-methoxyphenyl)-1H,9H[1,2]oxazino[4,5-g][2,3]benzoxazine-1,9-dione 11b.

Anhydrous aluminum chloride (8 g, 60 mmol) was added gradually while stirring to 2,6-dihydroxypyrrolo[3,4-f]isoindolo-1,3,5,7(2H,6H)tetrone 14 (2.48g, 10 mmol) in dry anisole (20 ml). The reaction mixture was stirred for 1.5 hrs. left overnight and the complex formed was decomposed with ice-cold dilute hydrochloric acid (1:1). The solvent was steam distilled, the crude solid formed was filtered off and the two isomers were separated using hot ethanol. The insoluble isomer was filtered off and crystallized from acetic acid to give 10b. The soluble isomer was isolated and crystallized from chloroform to give 11b.

4,9-di(4-methoxyphenyl)-1H,6H[1,2]oxazino[5,4-g][2,3]benzoxazine-1,6-dione10b.

Compound 10b was obtained in 45% yield; mp 355-58⁰; IR (KBr) ν 1690 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 3.75 (s, 6H, 2OCH₃), 6.85-7.13 (dd, A₂B₂ system, 8H, arom. H), 7.72 (s, 2H, two identical benzene protons); ¹³C-NMR (DMSO-d₆): 55.08, q, C-1; 158.95, s, C-2; 113.76, d, C-3; 129.27, d, C-4; 74.00, s, C-5; 146.98, s, C-6; 161.03, s, C-7; 132.29, s, C-8; 131.56, s, C-9; 118.43, d, C-10. Anal. Calcd. For C₂₄H₁₆N₂O₆: C, 67.29; H, 3.76; N, 6.54. Found; C, 67.33; H, 3.74; N, 6.52%.

4,6-di(4-methoxyphenyl)-1H,9H[1,2]oxazino[4,5-g][2,3]benzoxazine-1,9-dione11b.

Compound 11b was obtained in 25% yield; mp 278-89⁰; IR (KBr) ν 1680 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 3.73 (s, 6H, 2OCH₃), 6.87-7.08 (dd, A₂B₂ System, 8H, arom. H) and two non identical protons at 7.59 (s, 1H, H-5) and at 7.95 (s, 1H, H-10); ¹³C-NMR (DMSO-d₆): 55.12, q, C-1; 158.89, s, C-2; 113.60, d, C-3; 129.30, d, C-4; 74.02, s, C-5; 150.68, s, C-6; 161.01, s, C-7; 131.55, s, C-8, C-9 (Interfered); 117.06, d, C-10; 120.12, d, C-11. Anal. Calcd. For C₂₄H₁₆N₂O₆: C, 67.29; H, 3.76; N, 6.54. Found; C, 67.32; H, 3.75; N, 6.52%.

Synthesis of pyridazinophthalazines 12a-h and 13a-f.

General procedure

Hydrazine hydrate (20 mmol) and/or phenylhydrazine (10 mmol) was added to a solution of 2,5-diaroylterephthalic acid 8a-d and/or 4,6-diaroylisophthalic acid 9a-d in acetic acid (30 ml). The reaction mixture was refluxed for 2 hrs and after cooling the solid formed was filtered and washed with DMF to give 12a-h as white crystals and/or 13a-f as yellow crystals respectively.

4,9-diphenyl-pyridazino[4,5-g]phthalazine-1,6(2H,7H)dione 12a.

Compound 12a was obtained in 78% yield; mp >360⁰; IR (KBr) ν 3150 cm^-1 (NH) 1660 cm^-1 (C=O’s); MS: m/z 366(M). Anal. Calcd. For C₂₂H₁₄N₄O₂: C, 72.12; H, 3.85; N, 15.29. Found; C, 72.18; H, 3.81; N, 15.28%.

4,9-di(4-methoxyphenyl)-pyridazino[4,5-g]phthalazine-1,6(2H,7H)dione 12b.

Compound 12b was obtained in 81% yield; mp >360⁰; IR (KBr) ν 3200 cm^-1 (NH), 1665cm^-1 (C=O’s); MS: m/z 426(M). Anal. Calcd. For C₂₄H₁₈N₄O₄: C, 67.60; H, 4.25; N, 13.14. Found; C, 67.58; H, 2.29; N, 13.12%.

4,9-di(4-methylphenyl)-pyridazino[4,5-g]phthalazine-1,6(2H,7H)dione 12c.

Compound 12c was obtained in 73% yield; mp >360 ⁰C; IR (KBr) ν 3200 cm^-1 (NH), 1660cm^-1 (C=O’s); MS: m/z 394(M). Anal. Calcd. For C₂₄H₁₈N₄O₂: C, 73.08; H, 4.60; N, 14.20. Found; C, 73.11; H, 4.65; N, 14.13%.

4,9-di(4-chlorophenyl)-pyridazino[4,5-g]phthalazine-1,6(2H,7H)dione 12d.

Compound 12d was obtained in 84% yield; mp >360⁰; IR (KBr) ν 3200 cm^-1 (NH), 1680cm^-1 (C=O’s); MS: m/z 434(M). Anal. Calcd. For C₂₂H₁₂Cl₂N₄O₂: C, 60.71; H, 2.78; N, 12.87; Cl, 16.29. Found; C, 60.69; H, 2.81; N, 12.85; Cl, 16.30%.

4,9-diphenyl-2,7-diphenylpyridazino[4,5-g]phthalazine-1,6-dione 12e.

 Compound 12e was obtained in 83% yield, crystallized from xylene; mp >360 ⁰C; IR (KBr) ν 1670 cm^-1 (C=O’s); MS: m/z 518(M). Anal. Calcd. For C₃₄H₂₂N₄O₂: C, 78.75; H, 4.28; N, 10.80. Found; C, 78.79; H, 4.30; N, 10.74%.

4,9-di(4-methoxyphenyl)-2,7-diphenylpyridazino[4,5-g]phthalazine-1,6-dione 12f.

Compound 12f was obtained in 85% yield, crystallized from xylene; mp 357-59⁰; IR (KBr) ν 1670 cm^-1 (C=O’s); MS: m/z 578(M). Anal. Calcd. For C₃₆H₂₆N₄O₄: C, 74.73; H, 4.53;  N, 9.68. Found; C, 74.78; H, 4.57; N, 9.59%.

4,9-di(4-methylphenyl)-2,7-diphenylpyridazino[4,5-g]phthalazine-1,6-dione 12g.

Compound 12g was obtained in 81% yield, crystallized from xylene; mp >360⁰; IR (KBr) ν 1670 cm^-1 (C=O’s); MS: m/z 546(M). Anal. Calcd. For C₃₆H₂₆N₄O₂: C, 79.10; H, 4.79;  N, 10.25. Found; C, 79.16; H, 4.81; N, 10.18%.

4,9-di(4-chlorophenyl)-2,7-diphenylpyridazino[4,5-g]phthalazine-1,6-dione 12h.

Compound 12h was obtained in 88% yield, crystallized from DMF; mp >360⁰; IR (KBr) ν 1680 cm^-1 (C=O’s); MS: m/z 586(M). Anal. Calcd. For C₃₄H₂₀Cl₂N₄O₂: C, 69.51; H, 3.43;  N, 9.54; Cl, 12.07. Found; C, 69.50; H, 3.45; N, 9.56; Cl, 12.04%.

4,6-diphenyl-pyridazino[4,5-g]phthalazine-1,9(2H,8H)dione 13a.

Compound 13a was obtained in 74% yield; mp >360⁰; IR (KBr) ν 3300-3200 cm^-1 (NH), 1700 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.47-7.63(m, 10H, arom. H ),  8.02 (S, 1H, H-5), 9.07 (s, 1H, H-10), 13.10 (s, 2H, 2NH). Anal. Calcd. For C₂₂H₁₄N₄O₂: C, 72.12; H, 3.85; N, 15.29. Found; C, 72.15; H, 3.88; N, 15.24%.

4,6-di(4-methoxyphenyl)-pyridazino[4,5-g]phthalazine-1,9(2H,8H)dione 13b.

Compound 13b was obtained in 75% yield; mp >360⁰; IR (KBr) ν 3494; 3447 cm^-1 (NH), 1688  cm^-1 (C=O’s); MS: m/z 426(M). Anal. Calcd. For C₂₄H₁₈N₄O₄: C, 67.60; H, 4.25; N, 13.14. Found; C, 67.62; H, 4.27; N, 13.10%.  

4,6-di(4-methylphenyl)-pyridazino[4,5-g]phthalazine-1,9(2H,8H)dione 13c.

Compound 13c was obtained in 82% yield; mp >360 ⁰C; IR (KBr) ν 3200 cm^-1 (NH), 1660 cm^-1 (C=O’s); MS: m/z 394(M). Anal. Calcd. For C₂₄H₁₈N₄O₂: C, 73.08; H, 4.60; N, 14.20. Found; C, 73.06; H, 4.64; N, 14.18%.

4,6-di(4-chlorophenyl)-pyridazino[4,5-g]phthalazine-1,9(2H,8H)dione 13d.

Compound 13d was obtained in 72% yield; mp >360⁰; IR (KBr) ν 3200 cm^-1 (NH), 1680cm^-1 (C=O’s); MS: m/z 434(M). Anal. Calcd. For C₂₂H₁₂Cl₂N₄O₂: C, 60.71; H, 2.78; N, 12.87; Cl, 16.29. Found; C, 60.76; H, 2.72; N, 12.82; Cl, 16.35%.

2,4,6,8-tetraphenyl-pyridazino[4,5-g]phthalazine-1,9-dione 13e.

 Compound 13e was obtained in 78% yield, crystallized from xylene; mp 324-26⁰. IR (KBr) ν 1680 cm^-1 (C=O’s); MS: m/z 518 (M). Anal. Calcd. For C₃₄H₂₂N₄O₂: C, 78.75; H, 4.28; N, 10.80. Found; C, 78.79; H, 4.25; N, 10.79%.

4,6-di(4-chlorophenyl)-2,8-diphenyl pyridazino[4,5-g]phthalazine-1,9-dione 13f.

Compound 13f was obtained in 64% yield, crystallized from Xylene / DMF; mp= 360⁰; IR (KBr) ν 1680 cm^-1 (C=O’s); ¹H-NMR (DMSO-d₆): δ 7.53-7.81 (m, 19H, 18 arom. H + H-5) 8.67 (s, 1H, H-10); MS: m/z 586 (M). Anal. Calcd. For C₃₄H₂₀Cl₂N₄O₂: C, 69.51; H, 3.43; N, 9.54; Cl, 12.07. Found; C, 69.53; H, 3.45; N, 9.56; Cl, 12.01%.

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