148 RESEARCH PAPER
VOL. 39
MARCH, 148–153
JOURNAL OF CHEMICAL RESEARCH 2015
Synthesis of [1,2,4]triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4]pyridazino[1,6-d] [1,2,4]triazine; a novel tetracyclic system† Ayla Hazrathoseyni, Seyed Mohammad Seyedi, Ali Shiri* and Hossein Eshghi Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran. The condensation reaction of 6‑acetyl-3-amino-5-aryl-2-phenyl-2,5-dihydropyridazine-4-carbonitrile with triethyl orthoformate and then with hydrazine hydrate to obtain the new fused bicyclic 4‑aryl-5-hydrazinyl-3-(1-hydrazonoethyl)-1-phenyl-1,4dihydropyrimido[4,5-c]pyridazines via the Dimroth rearrangement is reported. Further cyclisation was achieved by the treatment of latter compounds with triethyl orthoformate to afford several derivatives of a novel tetracyclic fused system [1,2,4] triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4]pyridazino[1,6-d ][1,2,4]triazine. Keywords: triazolopyrimidines, pyrimidopyridazines, pyridazinotriazines, triazolopyrimidopyridazinotriazine Triazolopyrimidines, pyrimidopyridazines and pyridazinotriazines are important heterocyclic systems that can be found in many areas of chemistry. They are biological, pharmacological and industrially important compounds. For example, adsorption and inhibitive properties of triazolopyrimidine derivatives in acid corrosion of mild steel have been reported,1 while pyrimidopyridazines are useful as AKT,2 p38R,3 phosphodiesterase 5 (PDE5)4,5 and monoamine oxidase6 inhibitors. Pyridazinotriazines have shown broad spectrum herbicidal activities against several weeds7 and have antimicrobial, antiviral and antihypertensive properties;8 their activities as photosynthesis inhibitors have also been evaluated by an oxygen electrode method.9 Few literature data are available on the syntheses of tricyclic ring systems comprising triazole, pyrimidine and pyridazine rings.10,11 One of the synthesised structures is pyrimidotriazolopyridazine which is prepared either by ring closure of 6-(3-hydroxypropylamino)-1,2,4triazolo[4,3-b]pyridazine in polyphosphoric acid or by treatment of ethyl 2-[2-(3-methyl-4-oxo-4H-pyrimido[1,2-b] pyridazin-7-yl)hydrazono]acetate with bromine.12 In addition, triazolopyrimidopyridazine derivatives are obtained from heating of 5,6-dihydro-7-hydrazino-5-imino-3,4,6triphenylpyrimido[4,5-c]pyridazine with CS2, triethylorthoformate in acetic acid or condensation with aromatic aldehydes.13,14 As part of our ongoing studies dealing with the synthesis of new biologically active heterocyclic compounds,15–17 we now report the synthesis and structural elucidations of various pyrimido[4,5-c]pyridazines as precursors for the synthesis of the novel [1,2,4]triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4] pyridazino[1,6-d][1,2,4]triazine system and its derivatives. Results and discussion
1-(2-Phenylhydrazono)propan-2-one 1 as one of the starting materials was prepared from the reaction of benzenediazonium salt with ethyl 3‑oxobutanoate.18 2‑Benzylidenemalonitriles 2a–g were obtained from treatment of various substituted benzaldehydes with malononitrile.19 According to Scheme 1, the preparation of precursors 3a–g commenced from the reaction of compound 1 with each of compounds 2a–g in the presence of pyridine in EtOH according to the reported procedure.20–22 The structures of the newly synthesised derivatives, summarised in the experimental section, have been confirmed according to their spectral and microanalytical data. * Correspondent. E‑mail:
[email protected] † In memory of Prof. Mohammad Rahimizadeh
In order to obtain compounds 4a–g, the o‑amino nitriles 3a–g were refluxed with excess triethyl orthoformate in the presence of a few drops of acetic anhydride. The 1H NMR spectrum of compound 4a showed a triplet and a quartet signal at δ 1.15 and δ 4.15 belonging to the CH3 and CH2 of the ethyl group, respectively, and a distinct singlet signal at δ 7.91 due to the imine proton. Furthermore, the broad singlet signal at δ 4.35 due to NH2 group of the precursor 3a was absent. In the IR spectrum, the disappearance of stretching vibration bands for the NH2 group at 3412 and 3309 cm–1 as well as the appearance of the vibrational band of C–O at 1198 cm–1 confirmed the synthesised structure 4a. In an attempt to prepare new derivatives of pyrimidopyridazine ring system, the imidates 4a–g were treated with hydrazine hydrate. Surprisingly, it was observed that only compounds 4a–e were converted into the corresponding bicyclic compounds 5a–e while the two other derivatives, namely, 4f and 4g did not afford similar reaction products and instead gave compounds 5f and 5g, respectively. The facility with which hydrazine substitution as well as the Dimroth rearrangement occurred on compounds 4a–e was previously confirmed in analogueous heterocyclic compounds like pyrolopyrimidines-and pyrazolopyrimidines.23–27 The treatment of compounds 5a–e with triethyl orthoformate afforded the new derivatives of [1,2,4]triazolo[4′′,3′′:1′,6′] pyrimido[4′,5′:3,4]pyridazino[1,6-d][1,2,4]triazine as a novel heterocyclic system. The structural elucidations of the newly synthesised compounds were fully supported by their spectral and microanalytical data. For instance, the comparison of the 1 H NMR spectra of compounds 5a with 6a showed that there are three singlet signals in the spectrum of precursor 5a at δ 5.75, 6.60 and 6.90 due to NH2, NH and NH2 groups, respectively, which were removed when the cyclisation occurred and gave the corresponding tetracyclic product 6a. The CH signal of the pyridazine ring in the 1H NMR spectrum of compound 5a had also disappeared and instead, two singlet signals at δ 6.35 and δ 8.30 from the CH moieties of the newly formed triazine and triazole rings respectively were observed in the spectrum of compound 6a. In addition, a literature search revealed that the chemical shifts of protons in similar triazolopyrimidines are about 8.24–8.88 ppm for the triazole ring proton and 9.00–9.23 ppm for that from the pyrimidine ring.24,25,28,29 As in an analogueous triazine,30 we deduced that the signals at δ 6.35–6.41 belong to the hydrogen from the triazine rings in compounds 6a–e. Comparison of the mass spectra as well as the elemental analyses data of the synthesised compounds 5a and 6a clearly confirmed the one-pot formation of two new rings.
JOURNAL OF CHEMICAL RESEARCH 2015 149 R
R O H3C
R N
NH Ph
CN
+
1
O
O Py/EtOH
CN
H3C
N
CN 2a-g
N Ph
R
N N
N N
N Ph 6a-e
6a) 6b) 6c) 6d) 6e)
N
R=H R = 2-Cl R = 4-Cl R = 3-NO2 R = 4-NO2
HN
CH3
N N CH(OEt)3 reflux
N NH2 N
HC(OEt)3
CN N
N Ph
N CHOEt
4a-g
3a-g
R CH3
NH2
H3C
NH2
N2H4,EtOH heat
N N Ph
N
5a-e R CH3 N NH2 N
N Ph 5f ,g
CN NH2 HN N CH
5f) R = 4-Me 5g) R = 4-OMe Scheme 1
A plausible mechanism for these transformations can be explained as depicted in Scheme 2. Similar results relating to this rearrangement are in agreement with the reported results for analogueous compounds.25–27 In our attempts to prepare various derivatives of the novel [1,2,4]triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4]pyridazino[1,6-d] [1,2,4]triazine heterocyclic ring system, we encountered that compounds 4f and 4g did not react in an analogueous manner to compounds 4a–e. In the IR spectra of compounds 5f and 5g in contrast to compounds 5a–e, the stretching vibration band of CN group was still present and, on the basis of the other spectral and microanalytical analyses, it seems that the cyclisation has not occurred as with the similar analogues 5a–e. We are now exploring the effect of substituents on the aryl moiety on the nature of the two groups of products and these studies will be reported later. In summary the first members of the novel tetracyclic fused system [1,2,4]triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4] pyridazino[1,6-d][1,2,4]triazine have been reported using two successive cyclocondensation reactions. Experimental Melting points were recorded on an Electrothermal type 9100 melting point apparatus. The IR spectra were obtained on Avatar 370 FTIR
Thermo Nicolet instrument and only noteworthy absorptions are listed. The 1H NMR (400 MHz) and the 13C NMR (100 MHz) spectra were recorded on a Bruker Avance DRX-400 spectrometer. Chemical shifts are reported in ppm downfield from TMS as internal standard. The mass spectra were scanned on a Varian Mat CH‑7 at 70 eV. Elemental analyses were performed on a Thermo Finnigan Flash EA microanalyser. Synthesis of compounds 3a–g; general procedure Pyridine (0.5 mL) was added to a mixture of 1-(2-phenylhydrazono) propan-2-one 1 (10 mmol, 1.62 g) and the appropriate benzylidenemalononitrile derivative 2a–g (10 mmol) in ethanol (20 mL). The mixture was refluxed for 1.5 h and monitored by TLC using n‑hexane : ethyl acetate (2 : 1). After the completion of the reaction, the solvent was evaporated under reduced pressure and the resulting crude product was washed with water (2 × 20 mL) and recrystallised from ethanol. 6 -Acet yl-3 - amino -2,5 - diphe nyl-2,5 - dihydrop yr ida z ine - 4 carbonitrile (3a): Yield 78%; m.p. 229–231 °C; (lit.31 228–230 °C). 6-Acet yl-3-amino-5-(2-chlorophenyl)-2-phenyl-2,5-dihydropyridazine-4-carbonitrile (3b): Yellow crystals, yield 81%; m.p. 158–160 °C; 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H, CH3–CO), 4.37 (s, 2H, NH2, D2O exchangeable), 5.19 (s, 1H, H‑5), 7.21–7.66 (m, 9H, phenyl groups); 13C NMR (100 MHz, CDCl3) δ 25.8, 31.6, 91.3, 115.6, 122.1, 122.2, 128.1, 128.4, 128.7, 129.8, 131.2, 131.4, 131.5, 132.7, 136.9, 141.0, 147.4, 159.4, 191.6. MS (m/z) = 350(M+), 273 (M+ –77); IR (KBr)
150 JOURNAL OF CHEMICAL RESEARCH 2015 R
R
O Me N NH2NH2
NH2NH2
C N
H2NN
N
N CHOEt
N Ph
NH
Me
CN
N Ph
N
NH2
N
N C NHNH2 H
4a-g R Me H2NN
HN
NH2
N
N Ph
N
NH
N N
NH2
NH
N
N
NH2
NH N
rotation
N
NH2
N
5a-e HC(OEt)3 R
R Me N N
HN
H
N
OEt
N N
N OEt Ph
N
N N
Me N N
N N
N Ph
N
6a-e
Scheme 2 Suggested mechanisms for the formation of compounds 5a–e and 6a–e.
ν max/cm –1 3441, 3346, 2184, 1676, 745. Anal. calcd for C19H15ClN4O: C, 65.05; H, 4.31; N, 15.97; found: C, 64.97; H, 4.30; N, 15.75%. 6-Acet yl-3-amino-5-(4-chlorophenyl)-2-phenyl-2,5-dihydropyridazine-4-carbonitrile (3c): Yellow crystals, yield 88%; m.p. 197–199 °C; 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H, CH3–CO), 4.35 (s, 2H, NH2, D2O exchangeable), 5.00 (s, 1H, H‑5), 7.20–7.63 (m, 9H, phenyl groups);13C NMR (100 MHz, CDCl3) δ 25.7, 34.2, 90.7, 115.6, 122.1, 122.2, 128.3, 128.4, 129.8, 130.4, 130.6, 131.4, 131.5, 132.7, 139.9, 141.0, 146.3, 159.4, 191.6; MS (m/z) = 350(M+), 273 (M+ –77); IR (KBr) ν max/cm –1 3403, 3313, 3218, 2191, 1647, 1596, 1418, 1146. Anal. calcd for C19H15ClN4O: C, 65.05; H, 4.31; N, 15.97; found: C, 64.91; H, 4.28; N, 15.86%. 6 -Acet yl-3- amino-5-(3-nitrophenyl)-2-phenyl-2,5- dihydropyridazine-4-carbonitrile (3d): Yellow crystals, yield 80%; m.p. 228–230 °C; 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H, CH3–CO), 4.35 (s, 2H, NH2, D2O exchangeable), 5.41 (s, 1H, H‑5),7.13–7.30 (m, 5H, phenyl group), 7.50–7.58 (m, 2H, phenyl group), 8.02–8.08 (m, 2H, phenyl group);13C NMR (100 MHz, CDCl3) δ 25.7, 33.7, 90.7, 115.6, 121.3, 122.0, 122.2, 126.0, 129.8, 131.3, 131.5, 131.8, 133.7, 140.6, 141.0, 146.3, 149.5, 159.4, 191.6; MS (m/z) = 361(M+), 284(M+ –77); IR (KBr) ν max/cm –1 3408, 3310, 3218, 2193, 1678, 1646, 1528, 1349, 1142, 737, 689. Anal. calcd for C19H15N5O3: C, 63.15; H, 4.18; N, 19.38; found: C, 63.20; H, 4.11; N, 19.35%. 6 -Acet yl-3- amino-5-(4-nitrophenyl)-2-phenyl-2,5- dihydropyridazine-4-carbonitrile (3e): Yellow crystals, yield 83%; m.p. 176–179 °C; 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H, CH3–CO), 4.35 (s, 2H, NH2, D2O exchangeable), 5.00 (s, 1H, H‑5), 7.13–7.30 (m, 5H, phenyl group), 7.45–7.49 (m, 2H, phenyl group), 7.99–8.03 (m, 2H, phenyl group); 13C NMR (100 MHz, CDCl3) δ 191.6, 159.4, 146.8, 146.3,
145.3, 141.0, 131.5, 131.4, 129.8, 128.6, 128.4, 125.7, 125.5, 122.2, 122.0, 115.6, 90.7, 34.2, 25.7; MS (m/z) = 361(M+), 285(M+ –77); IR (KBr) ν max/ cm–1 3476, 3365, 2185, 1681, 1228, 746, 578. Anal. calcd for C19H15N5O3: C, 63.15; H, 4.18; N, 19.38; found: C, 63.11; H, 4.15; N, 19.30%. 6-Acetyl-3-amino-2-phenyl-5-(p-tolyl)-2,5-dihydropyridazine4-carbonitrile (3f): Yellow crystals, yield 85%; m.p. 121–123 °C; 1 H NMR (400 MHz, CDCl3) δ 1.99 (s, 3H, CH3), 2.33 (s, 3H, CH3–CO), 4.35 (br, 2H, NH 2, D2O exchangeable), 5.00(s, 1H, H‑5), 7.08–7.60 (m, 9H, phenyl groups); 13C NMR (100 MHz, CDCl3) δ 22.5, 25.7, 34.2, 90.7, 115.5, 122.2, 122.3, 126.1, 126.2, 129.8, 131.0, 131.1, 131.4, 131.5, 136.6, 139.4, 140.9, 146.3, 159.4, 191.6; MS (m/z) = 330(M+), 253 (M+ –77); IR (KBr) ν max/cm –1 3411, 3313, 2193, 1678. Anal. calcd for C20H18N4O: C, 72.71; H, 5.49; N, 16.96; found: C, 72.70; H, 5.41; N, 17.05%. 6-Acetyl-3-amino-5-(4-methoxyphenyl)-2-phenyl-2,5-dihydropyridazine-4-carbonitrile (3g): Yellow crystals, yield 84%; m.p. 99–101 °C; 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H, CH3–CO), 3.06 (s, 3H, OCH3), 4.35 (br, 2H, NH2, D2O exchangeable), 5.00 (s, 1H, H‑5), 6.92–6.94 (m, 2H, phenyl group), 7.15 (m, 2H, phenyl group), 7.23–7.30 (m, 5H, phenyl group); 13C NMR (100 MHz, CDCl3) δ 25.7, 34.1, 55.1, 90.7, 113.1, 113.2, 115.5, 122.2, 122.3, 126.0, 126.1, 129.8, 131.4, 131.4, 134.1, 140.9, 146.3, 157.7, 159.3, 191.5; MS (m/z) = 346(M+), 269(M+ –77); IR (KBr) ν max/cm –1 3449, 3403, 3331, 3222, 2217, 1607, 1506, 1183. Anal. calcd for C20H18N4O2: C, 69.35; H, 5.24; N, 16.17; found: C, 69.30; H, 5.21; N, 16.15%. Synthesis of ethyl N-(6-acetyl-5-aryl-4-cyano-2-phenyl-2,5-dihydropyridazin-3-yl)formimidates 4a–g; general procedure A solution of each of compounds 3a–e (10 mmol) and an excess amount of triethyl orthoformate (20 mL) in acetic anhydride (5 mL)
JOURNAL OF CHEMICAL RESEARCH 2015 151 was refluxed for about 5 h. After the completion of the reaction which was monitored by TLC using chloroform : methanol (9 : 1), the solvent was removed under reduced pressure. The resulting crude product was washed with water (2 × 20 mL), dried and recrystallised from ethanol. Ethyl N-(6-acetyl-4-cyano-2,5-diphenyl-2,5-dihydropyridazin-3-yl)formimidate (4a): Yellow crystals, yield 90%; m.p. 137–135 °C; 1 H NMR (400 MHz, CDCl3) δ 1.15 (t, 3H, CH2CH3), 2.45 (s, 3H, CH3–CO), 4.15 (q, 2H, O–CH2–), 5.05 (s, 1H, H‑5), 7.20–7.60 (m, 10H, phenyl groups), 7.91 (s, 1H, N=CH–O); 13C NMR (100 MHz, CDCl3) δ 14.2, 25.8, 38.8, 61.7, 105.8, 116.3, 122.4, 122.5, 125.2, 126.9, 127.0, 127.6, 127.7, 130.5, 132.8, 132.9, 141.3, 142.2, 149.3, 152.0, 166.9, 191.6; MS (m/z) = 372 (M+); IR (KBr) ν max/cm –1 3068, 2982, 2202, 1686, 1637, 1198, 759, 702. Anal. calcd for C22H20N4O2: C, 70.95; H, 5.41; N, 15.04; found: C, 70.90; H, 5.39; N, 15.02%. Ethyl N-(6-acetyl-5-(2-chlorophenyl)-4-cyano-2-phenyl-2,5-dihydropyridazin-3-yl)formimidate (4b): Yellow crystals, yield 89%; m.p. 138–141 °C; 1H NMR (400 MHz, CDCl3) δ 1.16 (t, 3H, CH2CH3),2.45 (s, 3H, CH3–CO), 4.17 (q, 2H, –O–CH2–), 5.25 (s, 1H, H‑5), 7.21–7.58 (m, 9H, phenyl groups), 7.92 (s, 1H, N=CH–O);13C NMR (100 MHz, CDCl3) δ 14.2, 25.8, 38.8, 61.7, 105.8, 116.3, 122.4, 122.5, 125.2, 126.8, 126.9, 127.4, 127.6, 130.5, 132.6, 132.8, 141.3, 142.2, 149.3, 152.0, 166.9, 191.6; MS (m/z) = 406(M+), 359(M+ –47); IR (KBr) ν max/ cm –1 3060, 2987, 2201, 1687, 1632, 1198, 757, 699. Anal. calcd for C22H19ClN4O2: C, 64.94; H, 4.71; N, 13.77; found: C, 64.90; H, 4.69; N, 13.69%. Ethyl N-(6-acetyl-5-(4-chlorophenyl)-4-cyano-2-phenyl-2,5-dihydropyridazin-3-yl)formimidate (4c): Cream-coloured crystals, yield 86%; m.p. 140–142 °C;1H NMR (400 MHz, CDCl3) δ 1.16 (t, 3H, CH2CH3), 2.45(s, 3H, CH3–CO), 4.17 (q, 2H, –O–CH2–), 5.25(s, 1H, H‑5), 7.21–7.58 (m, 9H, phenyl groups), 7.92 (s, 1H, N=CH–O);13C NMR (100 MHz, CDCl3) δ 14.2, 25.8, 38.8, 61.7, 105.8, 116.3, 122.3, 122.4, 125.2, 126.8, 126.9, 127.4, 127.6, 130.5, 132.7, 132.8, 141.3, 142.2, 149.3, 152.0, 166.9, 191.6; MS (m/z) = 406(M+), 359(M+ –47); IR (KBr) ν max/cm –1 3056, 2978, 2198, 1692, 1635, 1197, 763, 697. Anal. calcd for C22H19ClN4O2: C, 64.94; H, 4.71; N, 13.77; found: C, 64.89; H, 4.70; N, 13.74%. Ethyl N-(6-acetyl-4-cyano-5-(3-nitrophenyl)-2-phenyl-2,5-dihydropyridazin-3-yl)formimidate (4d): Yellow crystals, yield 79%; m.p. 154–156 °C;1H NMR (400 MHz, CDCl3) δ 1.16 (t, 3H, CH2CH3), 2.45(s, 3H, CH3–CO), 4.17 (q, 2H, –O–CH2–), 5.25(s, 1H, H‑5), 7.21–7.58 (m, 9H, phenyl groups), 7.92 (s, 1H, N=CH–O);13C NMR (100 MHz, CDCl3) δ 14.2, 25.8, 38.8, 61.7, 105.8, 116.3, 122.3, 122.4, 125.2, 126.7, 126.9, 127.5, 127.6, 130.5, 132.7, 132.8, 141.3, 142.2, 149.3, 152.0, 166.9, 191.6; MS (m/z) = 417(M+), 340(M+ –77); IR (KBr) ν max/cm –1 3109, 3060, 2982, 2198, 1696, 1636, 1594, 1571, 1350, 1198, 751, 694. Anal. calcd for C22H19N5O4: C, 63.30; H, 4.59; N, 16.78; found: C, 63.28; H, 4.50; N, 16.74%. Ethyl N-(6-acetyl-4-cyano-5-(4-nitrophenyl)-2-phenyl-2,5-dihydropyridazin-3-yl)formimidate (4e): Cream-coloured crystals, yield 84%; m.p. 140–142 °C;1H NMR (400 MHz, CDCl3) δ 1.16 (t, 3H, CH2CH3),2.45 (s, 3H, CH3–CO), 4.17 (q, 2H, –O–CH 2–), 5.06 (s, 1H, H‑5),7.16 (m, 1H, phenyl group), 7.44 (m, 2H, phenyl group), 7.61 (m, 2H, phenyl group), 7.71 (m, 2H, phenyl group), 8.09(m, 2H, phenyl group), 7.92 (s, 1H, N=CH–O); 13C NMR (100 MHz, CDCl3): 14.2, 25.8, 38.8, 61.7, 105.8, 116.3, 122.3, 122.4, 126.2, 126.4, 129.6, 129.8, 130.5, 132.6, 132.8, 142.2, 145.6, 146.9, 149.3, 152.0, 166.9, 191.6; MS (m/z) = 417(M+), 340(M+ –77); IR (KBr) ν max/cm –1 3117, 3060, 2974, 2194, 1696, 1635, 1524, 1356, 1197, 698. Anal. calcd for C22H19N5O4: C, 63.30; H, 4.59; N, 16.78; found: C, 63.27; H, 4.54; N, 16.75%. Ethyl N-(6-acetyl-4-cyano-2-phenyl-5-(p-tolyl)-2,5-dihydro-pyridazin3-yl)formimidate (4f): Yellow crystals, yield 75%; m.p. 127–129 °C; 1 H NMR (400 MHz, CDCl3) δ 1.14 (t, 3H, OCH2CH3), 1.74 (s, 3H, aromatic-CH3), 2.45 (s, 3H, CH3–CO), 4.15 (q, 2H, –O–CH2–), 5.04(s, 1H, H‑5), 7.16–7.44 (m, 7H, phenyl groups), 7.70 (m, 2H, phenyl group), 7.92 (s, 1H, N=CH–O); 13C NMR (100 MHz, CDCl3): 14.2, 22.4, 25.7, 38.7, 61.6, 105.8, 116.3, 122.4, 122.5, 127.4, 127.5, 130.4, 131.7, 131.8, 132.7, 132.8, 136.5, 139.6, 142.1, 149.2, 152.0, 166.8, 191.5; MS (m/z) = 386(M+); IR (KBr) ν max/cm –1 3035, 2222, 1708, 1604, 1588,
1191, 815, 615. Anal. calcd for C23H22N4O2: C, 71.48; H, 5.74; N, 14.50; found: C, 71.27; H, 5.64; N, 14.45%. Ethyl N-(6-acetyl-4-cyano-5-(4-methoxyphenyl)-2-phenyl-2,5-dihydropyridazin-3-yl)formimidate (4g): Yellow crystals, yield 79%; m.p. 102–104 °C; 1H NMR (400 MHz, CDCl3) δ 1.15 (t, 3H, OCH2CH3), 2.45 (s, 3H, CH3–CO), 3.72 (s, 3H, OCH3), 4.15 (q, 2H, –O–CH2–), 5.04 (s, 1H, H‑5), 7.06–7.44 (m, 7H, phenyl groups), 7.72 (m, 2H, phenyl group), 7.92 (s, 1H, N=CH–O); 13C NMR (100 MHz, CDCl3): 14.2, 25.7, 38.7, 55.1, 61.6, 105.8, 116.3, 122.4, 122.5, 127.3, 127.5, 130.4, 132.7, 132.8, 134.3, 142.1, 149.2, 152.0, 157.7, 166.8, 191.5; MS (m/z) = 402(M+); IR (KBr) ν max/cm –1 3027, 2223, 1605, 1571, 1513, 1278, 1183, 1025, 833, 612. Anal. calcd for C23H22N4O3: C, 68.64; H, 5.51; N, 13.92; found: C, 68.60; H, 5.48; N, 13.85%. Synthesis of 4‑aryl-5-hydrazinyl-3-(1-hydrazonoethyl)-1-phenyl-1,4dihydropyrimido[4,5-c]pyridazine 5a–e; general procedure To a solution of each of the compounds 4a–e (10 mmol) in absolute ethanol (20 mL), an excess amount of hydrazine hydrate (60 mmol, 1.50 g) was added and the solution was refluxed for 3–5 h. After the completion of the reaction which was monitored by TLC using chloroform–methanol (9 : 1), the resulting solid was filtered off, washed with water, dried and recrystallised from ethanol. 5-Hydrazinyl-3-(1-hydrazonoethyl)-1,4-diphenyl-1,4-dihydropyrimido[4,5-c]pyridazine (5a): Yellow crystals, yield 85%; m.p. 266–269 °C; 1H NMR (400 MHz, DMSO-d6):δ 1.95 (s, 3H, CH3), 5.65 (s, 1H, H‑4), 5.75 (br s, 2H, NH 2, D2O exchangeable), 6.60 (br s, 1H, NH, D2O exchangeable), 6.90 (s, 2H, NH2, D2O exchangeable), 7.11–7.60 (m, 10H, phenyl groups), 7.85 (s, 1H, H‑7); 13C NMR (100 MHz, DMSO-d6) δ 10.3, 36.2, 97.5, 114.7, 114.8, 125.9, 128.6, 128.8, 128.9, 129.1, 129.2, 129.3, 129.4, 136.3, 139.9, 141.9, 146.2, 153.9, 159.4, 166.1; MS (m/z) = 372 (M+), 356(M+ –16), 341(M+ –31), 281(M+ –91), 77(M+ –295), 57(M+ –315); IR (KBr) ν max/cm –1 3403, 3321, 3272, 1633, 1594, 745, 695. Anal. calcd for C20H20N8: C, 64.50; H, 5.41; N, 30.09; found: C, 64.49; H, 5.38; N, 30.05%. 4-(2-Chlorophenyl)-5-hydrazinyl-3-(1-hydrazonoethyl)-1-phenyl1,4-dihydropyrimido[4,5-c]pyridazine (5b): Cream-coloured crystals, yield 35%; m.p. 253–255 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.95(s, 3H, CH3), 5.66(s, 1H, H‑4), 5.76 (br s, 2H, NH2, D2O exchangeable), 6.61 (br s, 1H, NH, D2O exchangeable), 6.91 (brs, 2H, NH 2, D2O exchangeable), 7.20–7.64 (m, 9H, phenyl groups), 7.90 (s, 1H, H‑7);13C NMR (100 MHz, DMSO-d6) δ 9.7, 33.7, 91.2, 114.7, 114.8, 125.9, 127.0, 129.1, 129.2, 129.4, 129.8, 132.0, 135.9, 139.9, 140.0, 141.9, 147.3, 153.9, 159.3, 166.0; MS (m/z) = 406(M+), 351(M+ –55), 319(M+ –87), 293(M+ –113), 210(M+ –196), 76(M+ –330), 57(M+ –349); IR (KBr) ν max/cm –1 3428, 3387, 3313, 3224, 1591, 1495, 1447, 751. Anal. calcd for C20H19ClN8: C, 59.04; H, 4.71; N, 27.54; found: C, 59.01; H, 4.57; N, 27.52%. 4-(4-Chlorophenyl)-5-hydrazinyl-3-(1-hydrazonoethyl)-1-phenyl1,4-dihydropyrimido[4,5-c]pyridazine (5c): Yellow crystals, yield 38%; m.p. 265–267 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.95 (s, 3H, CH3), 5.65 (s, 1H, H‑4), 5.76 (br s, 2H, NH2, D2O exchangeable), 6.61 (br s, 1H, NH, D2O exchangeable), 6.91 (br s, 2H, NH 2, D2O exchangeable), 7.21–7.65 (m, 9H, phenyl groups), 8.03 (s, 1H, H‑7);13C NMR (100 MHz, DMSO-d6) δ 9.3, 36.2, 97.3, 114.7, 114.8, 125.9, 129.0, 129.1, 129.2, 129.3, 131.4, 131.3, 134.1, 136.4, 139.9, 141.9, 146.2, 153.9, 159.4, 166.1; MS (m/z) = 406(M+), 388(M+ –18), 319(M+ –87), 292(M+ –114), 57(M+ –349); IR (KBr) ν max/cm –1 3409, 3297, 3223, 3109, 1592, 1489, 1440, 1303, 898. Anal. calcd for C20H19ClN8: C, 59.04; H, 4.71; N, 27.54; found: C, 58.99; H, 4.62; N, 27.50%. 5-Hydrazinyl-3-(1-hydrazonoethyl)-4-(3-nitrophenyl)-1-phenyl-1,4dihydropyrimido[4,5-c]pyridazine (5d): Orange crystals, yield 30%; m.p. 242–245 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.94(s, 3H, CH3), 4.43 (br s, 2H, NH 2, D2O exchangeable), 6.01 (s, 1H, H‑4), 6.94 (br s, 2H, NH2, D2O exchangeable), 7.23–7.69 (m, 9H, phenyl groups), 8.11 (s, 1H, H‑7), 8.69 (s, 1H, NH, D2O exchangeable);13C NMR (100 MHz, DMSO-d6) δ 9.7, 33.9, 91.6, 123.8, 124.0, 125.2, 125.3, 125.7, 128.6, 128.7, 129.1, 129.3, 139.5, 142.9, 146.5, 146.7, 149.8, 153.1, 156.0,
152 JOURNAL OF CHEMICAL RESEARCH 2015 161.1; MS (m/z) = 417(M+), 402(M+ –15), 385(M+ –32), 369(M+ –48), 322(M+ –95), 227(M+ –190), 57(M+ –360); IR (KBr) ν max/cm –1 3293, 3194, 1593, 1527, 1494, 1348, 1102, 1045, 865, 693. Anal. calcd for C20H19N9O2: C, 57.55; H, 4.59; N, 30.20; found: C, 57.49; H, 4.48; N, 30.15%. 5-Hydrazinyl-3-(1-hydrazonoethyl)-4-(4-nitrophenyl)-1-phenyl1,4-dihydropyrimido[4,5-c]pyridazine (5e): Orange crystals, yield 31%; m.p. 229–231 °C;1H NMR (400 MHz, DMSO-d6) δ 1.94 (s, 3H, CH3), 4.48 (br s, 2H, NH 2, D2O exchangeable), 6.02 (s, 1H, H‑4), 6.96 (br s, 2H, NH2, D2O exchangeable), 7.23–7.61(m, 7H, phenyl and 4‑NO2 phenyl groups), 8.11 (s, 2H, 4‑NO2phenyl group), 8.13 (s, 1H, H‑7), 8.71 (s, 1H, NH, D2O exchangeable); 13C NMR (100 MHz, DMSO-d6) δ 9.7, 34.0, 91.7, 123.9, 124.0, 125.2, 125.3, 125.8, 128.6, 128.7, 129.2, 129.3, 139.5, 142.9, 146.5, 146.7, 149.8, 153.1, 156.0, 161.1; MS (m/z) = 417(M+); IR (KBr) ν max/cm –1 3399, 3289, 3183, 3056, 1592, 1519, 1352, 1103, 890, 694, 608. Anal. calcd for C20H19N9O2: C, 57.55; H, 4.59; N, 30.20; found: C, 57.43; H, 4.42; N, 30.18%. N′′-(4-Cyano-6-(1-hydrazonoethyl)-2-phenyl-5-(p-tolyl)-2,5-dihydropyridazin-3-yl)formimidohydrazide (5f): Yellow crystals, yield 40%; m.p. 265–267 °C;1H NMR (400 MHz DMSO-d6) δ 1.81 (s, 3H, CH3), 2.08 (s, 3H, CH3), 5.11 (s, 1H, H‑4), 4.81 (br s, 2H, NH2, D2O exchangeable), 6.51 (s, 1H, NH, D2O exchangeable), 6.82 (br. s, 2H, NH2, D2O exchangeable), 7.22–7.81 (m, 9H, phenyl and p‑tolyl groups), 7.93 (s, 1H, =CH); 13C NMR (100 MHz DMSO-d6) δ 22.6, 22.8, 38.9, 105.9, 122.7, 122.8, 123.1, 127.3, 127.4, 130.5, 132.4, 132.5, 133.1, 133.6, 137.2, 139.9, 140.1, 142.6, 148.8, 149.1, 159.4; MS (m/z) = 386(M+); IR (KBr) ν max/cm –1 3444, 3390, 3312, 3215, 2177 (CN), 1588. Anal. calcd for C21H22N8: C, 65.27; H, 5.74; N, 29.00; found: C, 65.16; H, 5.67; N, 28.98%. N′′-(4-Cyano-6-(1-hydrazonoethyl)-5-(4-methoxyphenyl)-2-phenyl2,5-dihydropyridazin-3-yl)formimidohydrazide (5g): Yellow crystals, yield 43%; m.p. > 300 °C;1H NMR (400 MHz DMSO-d6) δ 2.12 (s, 3H, CH3), 3.85 (s, 3H, –OCH3), 5.13 (s, 1H, H‑4), 4.75 (br. s, 2H, NH2, D2O exchangeable), 6.55 (s, 1H, NH, D2O exchangeable), 6.84 (br. s, 2H, NH2, D2O exchangeable), 7.23–7.84(m, 9H, phenyl and 4‑MeOC6H4 groups), 7.90 (s, 1H, =CH); 13C NMR (100 MHz DMSO-d6) δ 22.7, 39.0, 55.1, 105.5, 113.9, 114.1, 122.9, 127.3, 127.3, 130.4, 132.3, 132.4, 133.1, 133.6, 137.4, 139.8, 140.3, 142.5, 148.9, 149.0, 159.5; MS (m/z) = 402(M+); IR (KBr) ν max/cm –1 3452, 3325, 3223, 2207 (CN), 1603, 1251, 831. Anal. calcd for C21H22N8O: C, 62.67; H, 5.51; N, 27.84; found: C, 62.53; H, 5.45; N, 27.78%. Synthesis of substituted 13‑aryl-12-methyl-7-phenyl-7H-[1,2,4] triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4]pyridazino[1,6-d][1,2,4]triazine 6a–e; general procedure A mixture of each compound 5a–e (1 mmol) and triethyl orthoformate (12 mL) heated under reflux for 12 h. The progress of the reaction was monitored by TLC using chloroform-methanol (9 : 1). After the completion of the reaction, the mixture was cooled and the resulting solid was filtered off, washed with water (2 × 30 mL) and recrystallised from acetic acid. 12-Methyl-7,13-diphenyl-7H-[1,2,4]triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4]pyridazino[1,6-d][1,2,4]triazine (6a): Yellow crystals, yield 51%; m.p. 148–150 °C;1H NMR (400 MHz, CDCl3) δ 2.24 (s, 3H, CH3), 6.35(s, 1H, H‑9),7.20–7.70 (m, 10H, phenyl groups), 8.30 (s, 1H, H‑3), 9.01 (s, 1H, H‑5);13C NMR (100 MHz, CDCl3) δ 13.9, 98.1, 123.9, 124.0, 126.5, 127.4, 127.5, 129.3, 129.7, 129.8, 130.4, 130.5, 131.9, 135.4, 135.5, 139.4, 141.2, 146.3, 147.4, 149.2, 156.4, 165.7; MS (m/z) = 392(M+), 365(M+ –27), 347(M+ –45), 322(M+ –70), 294(M+ –98); IR (KBr) ν max/ cm –1 3063, 1698, 1628, 1276, 693 cm–1. Anal. calcd for C22H16N8: C, 67.34; H, 4.11; N, 28.55; found: C, 67.31; H, 4.09; N, 28.50%. 13-(2-Chlorophenyl)-12-methyl-7-phenyl-7 H-[1,2,4]triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4]pyridazino[1,6-d][1,2,4]triazine (6b): Yellow crystals, yield 54%; m.p. 115–117 °C; 1H NMR (400 MHz, CDCl3) δ 2.24 (s, 3H, CH3), 6.35(s, 1H, H‑9),6.83–7.58 (m, 9H, phenyl groups), 8.30 (s, 1H, H‑3), 9.01 (s, 1H, H‑5);13C NMR (100 MHz, CDCl3) δ 14.0, 98.1, 124.0, 124.2, 127.3, 127.4, 127.5, 129.2, 129.3, 129.4, 131.2, 131.9, 133.5, 135.4, 135.5, 138.3, 141.2, 146.3, 147.4, 150.0, 156.4, 165.7; MS (m/z) = 426(M+); IR (KBr) ν max/cm –1 1704, 1625, 1493,
1253, 747. Anal. calcd for C22H15ClN8: C, 61.90; H, 3.54; N, 26.25; found: C, 61.81; H, 3.50; N, 26.21%. 13-(4-Chlorophenyl)-12-methyl-7-phenyl-7 H-[1,2,4]triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4]pyridazino[1,6-d][1,2,4]triazine (6c): Yellow crystals, yield 56%; m.p. 216–218 °C;1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H, CH3), 6.35(s, 1H, H‑9),7.09–7.62 (m, 9H, phenyl groups), 8.31(s, 1H, H‑3), 9.02 (s, 1H, H‑5);13C NMR (100 MHz, DMSO-d6) δ 14.0, 98.1, 123.9, 124.1, 124.6, 124.8, 125.0, 127.0, 128.2, 128.3, 128.6, 128.7, 138.4, 141.2, 142.0, 144.6, 147.0, 147.3, 147.7, 149.9, 156.2, 165.6; MS (m/z) = 426(M+); IR (KBr) ν max/cm –1 1704, 1626, 1594, 1491, 1252, 690. Anal. calcd for C22H15ClN8: C, 61.90; H, 3.54; N, 26.25; found: C, 61.80; H, 3.52; N, 26.24%. 12-Methyl-13-(3-nitrophenyl)-7-phenyl-7 H-[1,2,4]triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4]pyridazino[1,6-d][1,2,4]triazine (6d): Yellow crystals, yield 52%; m.p. 210–213 °C; 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H, CH3), 6.40 (s, 1H, H‑9),7.14–7.65 (m, 9H, phenyl groups), 8.30 (s, 1H, H‑3), 9.02 (s, 1H, H‑5);13C NMR (100 MHz, DMSO-d6) δ 14.0, 98.8, 124.2, 124.3, 124.8, 124.9, 125.0, 127.1, 128.3, 128.4, 128.7, 128.8, 138.5, 141.3, 142.0, 144.8, 147.1, 147.4, 147.8, 151.7, 156.4, 165.6; MS (m/z) = 437 (M+); IR (KBr) ν max/ cm –1 1690, 1627, 1532, 1350, 1253, 698. Anal. calcd for C22H15N9O2: C, 60.41; H, 3.46; N, 28.82; found: C, 60.35; H, 3.42; N, 28.74%. 12-Methyl-13-(4-nitrophenyl)-7-phenyl-7 H-[1,2,4]triazolo[4′′,3′′:1′,6′]pyrimido[4′,5′:3,4]pyridazino[1,6-d][1,2,4]triazine (6e): Orange crystals, yield 50%; m.p. 112–114 °C;1H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H, CH3), 6.41 (s, 1H, H‑9),7.28 (s, 1H, phenyl), 7.41–7.67 (m, 6H, phenyl), 8.12 (s, 1H, 4‑NO2 phenyl), 8.15 (s, 1H, 4‑NO2 phenyl), 8.32 (s, 1H, H‑3), 9.04 (s, 1H, H‑5);13C NMR (100 MHz, CDCl3) δ 14.1, 98.8, 124.2, 124.3, 124.8, 124.9, 125.0, 127.2, 128.4, 128.5, 128.8, 128.9, 138.6, 141.5, 142.1, 144.9, 147.2, 147.6, 147.9, 151.7, 156.4, 165.7; MS (m/z) = 437 (M+); IR (KBr) ν max/cm –1 1709, 1672, 1629, 1343, 1245, 1122, 697. Anal. calcd for C22H15N9O2: C, 60.41; H, 3.46; N, 28.82; found: C, 60.38; H, 3.44; N, 28.79%.
Electronic supplementary information
Copies of the 1H and 13C NMR spectra of derivatives of 5 and 6 are available through: stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data. The authors gratefully acknowledge Ferdowsi University of Mashhad for partial support of this project (3/19530). Received 26 August 2014; accepted 8 February 2015 Paper 1402853 doi: 10.3184/174751915X14241706062908 Published online: 18 March 2015 References 1 K. Parameswari, S. Chitra, S. Kavitha, J. Rajpriya and A. Selvaraj, Eur. J. Chem., 2011, 8, 1250. 2 J.G. Kettle, S. Brown, C. Crafter, B.R. Davies, P. Dudley, G. Fairley, P. et al., J. Med. Chem., 2012, 55, 1261. 3 J.P. Duffy, E.M. Harrington, F.G. Salituro, J.E. Cochran, J. Green, H. Gao, G. et al., ACS Med. Chem. Lett., 2011, 2, 758. 4 P.M. Giovannoni, C. Vergelli, C. Biancalani, N. Cesari, A. Graziano, P. Biagini, J. Gracia, A. Gavalda and V.D. Piaz, J. Med. Chem., 2006, 49, 5363. 5 M. Rimaz, J. Khalafy, N.N. Pesyan and R.H. Prager, Aust. J. Chem., 2010, 63, 507. 6 C. Altomare, S. Cellamare, L. Summo, M. Catto and A. Carotti, J. Med. Chem., 1998, 41, 3812. 7 E.S.H. Elashry, N. Rashed, A. Mousaad and E. Ramadan, Adv. Heterocycl. Chem., 1994, 61, 234. 8 R.A. Coburn and R.A. Carapellotti, J. Pharm. Sci., 1976, 65, 1505. 9 H. Oda, Y. Masaki and H. Nagashima, Ann. Proc. Gifu Pharm. Univ., 1987, 36, 42. 10 Y. Sato, Y. Shimoji, H. Fujita, H. Nishino, H. Mizuno, S. Kobayashi and S. Kamakura, J. Med. Chem.,1980, 23, 927. 11 Y. Kurasawa, K. Nagahara and A. Takada, Chem. Pharm. Bull., 1979, 27, 2143. 12 J. Kosary, E. Kasztreiner and M. Soti, Heterocycles, 1983, 20, 749.
JOURNAL OF CHEMICAL RESEARCH 2015 153 13 S. Nishigaki, M. Ichiba and K. Senga, J. Org. Chem., 1983, 48, 1628. 14 M.I.A. Moneam, Monat. Chem., 2004, 135, 45. 15 M. Bakavoli, G. Bagherzadeh, M. Vaseghifar, A. Shiri, M. Pordel, M. Mashreghi, P. Pordeli and M. Araghi, Eur. J. Med. Chem., 2010, 45, 647. 16 M. Rahimizadeh, A. Shiri, M. Ranaei and M. Bakavoli, Heterocycl. Commun., 2012, 18, 39. 17 M. Bakavoli, S.M. Seyedi, A. Shiri, S. Saberi, M. Gholami and H. Sadeghian, J. Chem. Res., 2013, 36, 48. 18 B.S. Furniss, A.J. Hannaford, P.W.G. Smith and A.R. Tatchell, Vogel’s textbook of practical organic chemistry, 5th edn. Longman Scientific & Technical, London, 1989, pp. 920–953. 19 S. Wang, Z. Ren, W. Cao and W. Tong, Synth. Commun., 2001, 31, 673. 20 N.A. Al‑Awadi, M.R. Ibrahim, A.M. Al‑Etaibi and M.H. Elnagdi, Arkivoc, 2011, 2, 310. 21 S.M. Al‑Mousawi, M.S. Mustafa and M.H. Elnagdi, Tetrahedron Lett., 2009, 50, 6411. 22 H. Sheibani, M.A. Amrollahi, Z. Esfandiarpoor, Mol. Divers., 2010, 14, 277.
23 A.E. Rashad, M.I. Hegab, R.E. Abdel-Megeid, N. Fathalla and F.M.E. Abdel-Megeid, Eur. J. Med. Chem., 2009, 44, 3285. 24 A.S. Shawali, H.M. Hassaneen and N. Kh. Shurrab, Tetrahedron, 2008, 64, 10339. 25 M.S. Mohamed, A.E. Rashad, M.E.A. Zaki, S.S. Fatahala, Acta Pharm., 2005, 55, 237. 26 A.E. Rashad, O.A. Heikal, A.O.H. El‑Nezhawy, F.M.E. Abdel-Megeid, Heteroatom Chem., 2005, 16, 226. 27 E.S.H. El‑Ashry, S. Nadeem, M.R. Shah, Y. El‑Kilany, Adv. Heterocycl. Chem., 2010, 101, 161. 28 N.A. Hassan, Molecules, 2000, 5, 826. 29 A. Guillot, H.G. Viehe, B. Tinnant and J.P. Declercq, Tetrahedron, 1990, 46, 3897. 30 D.N. Kozhevnikov, I.S. Kovalev, A.M. Prokhorov, V.L. Rusinov and O.N. Chupakhin, Russ. Chem. Bull., 2003, 52, 1588. 31 S.A.S. Ghozlan, I.A. Abdelhamid, H.M. Hassaneen and M.H. Elnagdi, J. Heterocycl. Chem., 2007, 44, 105.
