Multi-component reactions (MCRs) have emerged as a powerful tool for the synthesis of novel and complex molecular structures because they exhibit several distinct advantages over conventional multi-step reactions including lower costs, shorter reaction times, and higher atom-economy [1]. Furthermore, MCRs are generally much more environmentally friendly and provide rapid access to large compound libraries with diverse functionalities [2, 3].
There has always been considerable interest in the development of new methods for the synthesis of heterocyclic compounds because of their wide range of potentially interesting biological properties and applications [4]. Amongst the large variety of heterocyclic compounds, those containing a phthalazine moiety have attracted increasing attention mainly because this unit is an important structural motif found in numerous biologically active organic compounds [5]. For example, phthalazine derivatives have been reported to possess anticonvulsant [6], cardiotonic [7], and vasorelaxant [8] activities, and significant research efforts have been directed towards the development of new methods for the synthesis of these compounds and their derivatives.
Although a variety of different catalysts have been used for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones, the scope of these methods can be limited by the requirement for harsh and strongly acidic conditions [9], expensive catalysts [10], toxic organic solvents [11, 12], long reaction times [13] and their tendency to produce low yields of the desired products [14]. Some of these issues can be overcome by using a metal complex as a catalyst. Transition metal complexes have attracted increasing levels of attention from a variety of different fields because of the ease with which they can be prepared, as well as their biological activity [15, 16], variety of structure [17], and potential catalytic activities [18]. Although the catalytic activities of several different transition metal complexes towards MCRs have been reported extensively elsewhere in the literature [19], there have been no studies pertaining to the use of these catalysts for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones.
With this in mind, we have prepared a series of Ni(II), Co(II), and Cu(II) complexes incorporating 2-pyrazine carboxylic acid, and the resulting three complexes were fully characterized using a variety of different physicochemical and spectroscopic methods. These complexes have also been evaluated as catalysts in an environmentally friendly and efficient protocol for the four-component synthesis of 2H-indazolo[2,1-b]phthalazine-triones (Scheme 1).
2-Pyrazinecarboxylic acid, Ni(NO3)2·6H2O, Co(NO3)2·6H2O, and Cu(NO3)2·3H2O, as well as all of the solvents used in the current study were purchased from Merck (Darmstadt, Germany) and used without further purification. All of the other chemicals used in this study were either prepared in our laboratory or purchased from Sigma Aldrich or Fluka. Microanalyses for C, H, and N were determined on a ThermoFinnigan Flash Elemental Analyzer 1112EA (Bremen, Germany). The melting points (M.P.) of the products were measured on an Electrothermal-9100 apparatus (Electrothermal Engineering Ltd., Essex, UK) and have been reported as the uncorrected values. All of the reactions were monitored by thin layer chromatography (TLC) using a 3:1 (v/v) mixture of petroleum ether and ethyl acetate as the developing solvent. Fourier transform infrared (FT-IR) spectra were recorded on a Tensor 27 FT-IR spectrophotometer (Bruker Optics Inc. Billerica, MA, USA). 1H and 13C NMR spectra were recorded on a Bruker 300-MHz spectrometer using CDCl3 as a solvent with TMS as an internal reference standard. Conductance measurements were recorded on a Metrohm 712 conductometer (Herisau, Switzerland) using DMSO as the solvent
[Co(pzca)2(H2O)2], [Ni(pzca)2(H2O)2], and [Cu(pzca)2(H2O)2] were synthesized separately according to the procedure described below. A solution of metal nitrate salt (1 mmol) in 3 mL of ethanol (96%) was placed in the main arm of a branched tube, followed by 2-pyrazinecarboxylic acid (0.025 g, 2 mmol). Ethanol was then carefully added to fill the arms, and the tube was sealed. The ligand-containing arm was subsequently immersed in an oil bath and heated at 60 °C, while the other arm was kept at ambient temperature. Single crystals formed in the branched arm after 1 d under these conditions, which were collected by filtration and dried in a desiccator at ambient temperature over silica gel.
[Ni(pzca)2(H2O)2] (1). Yield: 0.237 g, 69%. M.P. 248 °C (decomp.). Molar conductivity (1 mmol/L, DMSO): 6.2 Ω-1 cm2 mol-1. Anal. Calcd for C10H10N4NiO6 (340.90 g/mol): C, 35.2; H, 2.9; N, 16.4; found: C, 35.5; H, 2.8; N, 16.1%. FT-IR (KBr) cm-1: ν(OH) 3247, ν(NH) 3074, νasy(COO-) 1624, νsy(COO-) 1357, ν(C=N) 1585, ν(C=C) 1470, ν(C-O) 1288, ν(Ni-O) 636, ν(Ni-N) 467.
[Co(pzca)2(H2O)2] (2). Yield: 0.289 g, 85%. M.P. > 300 °C. Molar conductivity (1 mmol/L, DMSO): 8.4 Ω-1 cm2 mol-1. Anal. Calcd for C10H10CoN4O6 (341.14 g/mol): C, 35.2; H, 2.9; N, 16.4; found: C, 35.0; H, 2.8; N, 16.3%. FT-IR (KBr) cm-1: ν(OH) 3251, ν(NH) 3070, νasy(COO-) 1639, νsy(COO-) 1357, ν(C=N) 1584, ν(C=C) 1470, ν(C-O) 1289, ν(Co-O) 636, ν(Co-N) 466.
[Cu(pzca)2(H2O)2] (3). Yield: 0.253 g, 73%. M.P. > 300 °C. Molar conductivity (1 mmol/L, DMSO): 4.7 Ω-1 cm2 mol-1. Anal. Calcd for C10H10CuN4O6 (345.76 g/mol): C, 34.7; H, 2.9; N, 16.2; found: C, 34.5; H, 2.8; N, 16.4%. FT-IR (KBr) cm-1: ν(OH) 3250, ν(NH) 3068, νasy(COO-) 1621, νsy(COO-) 1358, ν(C=N) 1585, ν(C=C) 1470, ν(C-O) 1286, ν(Cu-O) 625, ν(Cu-N) 452.
Crystals of complexes 1-3 suitable for analysis were mounted on MitegenÔ loops and placed in the cold nitrogen stream of the Bruker D8 Venture Photon 100 CMOS diffractometer. Hemispheres of data were collected using the APEX2 software [20] and the raw data reduced to Fo2 values using the SAINT software [20], which was also used to achieve the global refinement of the unit cell parameters. Corrections for the absorption and merging of equivalent reflections were carried out using SADABS [20] and the structures were solved using a combination of Patterson and direct methods (SHELXT [20]). Full-matrix least-squares refinement of the structures was achieved using SHELXL-2013 [21]. All of the hydrogen atoms attached to carbon were placed in their calculated positions and those attached to oxygen were placed in positions derived from difference maps after, and their coordinates were adjusted to give O-H = 0.84 Å. All of these atoms were included as riding contributions with isotropic displacement parameters tied to those of the attached atoms. The details of crystallographic analysis are shown in Table 1.
A mixture of hydrazinium hydrate (1.2 mmol), phthalic anhydride (1 mmol), dimedone (1 mmol), an aryl aldehyde (1 mmol) and [Co(pzca)2(H2O)2] (20 mol%), [Ni(pzca)2(H2O)2] (25 mol%) or [Cu(pzca)2(H2O)2] (20 mol%)) in 5 mL of acetic acid was heated at 50 °C to give the corresponding 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivative. Upon completion of the reaction, as determined by TLC, the solvent was evaporated to give a residue, which was mixed with 5 mL of EtOH. The catalyst was removed by centrifugation and the crude product was recrystallized from a mixture of ethanol and water.
The scope and efficiency of this reaction for the synthesis of a wide variety of substituted 2H-indazolo[2,1-b]phthalazine-triones were evaluated under the optimized conditions using the title metal complexes. All of the products obtained from these reactions were identified through a comparison of their spectral data and melting points with those of the authentic samples. The compounds were also characterized by IR spectroscopy, as well as 1H and 13C NMR analysis. The spectral data for selected compounds are as follows.
3,4-Dihydro-3,3-dimethyl-13-phenyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (2a). M.P. = 207-209 °C. FT-IR (KBr) (υmax, cm-1): 2957, 1663, 1575. 1H NMR (300 MHz, CDCl3, 25 °C, ppm) δ = 1.21 (s, 6H), 2.35 (d, J = 6.03 Hz, 1H), 2.47 (d, J = 5.7 Hz, 1H), 3.24 (1H, dd, J = 19.03, 2.07 Hz), 3.41 (d, 1H, J = 19.03 H), 6.45 (s, 1H), 7.21-7.43 (m, 4H, arom), 7.84-7.86 (m, 2H, arom), 8.26-8.36 (m, 2H, arom). 13C NMR (125 MHz, CDCl3, 25 °C, ppm) δ = 28.4, 29.62, 35.8, 39.19, 42.00, 51.88, 119.73, 127.50, 128.28, 128.86, 129.12, 129.19, 129.52, 129.87, 130.12, 130.22, 134.69, 135.67, 137.55, 145.24, 152.01, 155.42, 157.18, 192.5.
3,4-Dihydro-3,3-dimethyl-13-(4-methylphenyl)-2H-indazolo[2,1-b] phthalazine-1,6,11(13H)-trione (2b). M.P. = 225-227 °C. FT-IR (KBr) (υmax, cm-1): 2958, 1668, 1630. 1H NMR (300 MHz, CDCl3, 25 °C, ppm) δ = 1.17 (s, 6H), 2.25 (s, 3H), 2.28 (s, 2H), 3.18 and 3.37 (AB system, s, 2H, J = 18.85 Hz), 6.36 (s, 1H), 7.08-7.2 (m, 4H), 7.8 (m, 2H), 8.2-8.3 (m, 2H). 13C NMR (125 MHz, CDCl3, 25 °C, ppm) δ = 21.6, 28.8, 29.1, 35.0, 38.4, 51.3, 65.1, 118.9, 127.4, 128.0, 128.3, 129.3, 129.5, 129.7, 133.8, 134.8, 138.8, 151.1, 154.6, 156.3, 192.5.
All three complexes were synthesized according to the reaction shown in Scheme 2, with pyrazine carboxylic acid being reacted with the appropriate metal salt in a 2:1 molar ratio. The resulting complexes were found to be stable in air and soluble in several organic solvents, including DMSO and DMF. However, the complexes were found to be insoluble in methanol, n-hexane, and diethyl ether. The molar conductivities of these complexes were found to be in agreement with their non-electrolytic nature.
The ORTEP representations of the asymmetric unit of complexes 1-3 are shown in Fig. 1. These drawings show that all three complexes have similar structural features, including a trans-[diaquabis(pyrazine-2-carboxylato)M(II)] (M = Ni, Co, Cu) moiety with crystallographically-imposed centrosymmetry. They have all been structurally characterized previously [22, 23, 24], and all of the metrical parameters observed in the current study are quite comparable to those in prior reports, although the su’s are slightly smaller due to the low temperature of the data collection (100 K).
For the FT-IR studies, the most prominent peaks detected in the IR spectra of complexes 1-3 in the 400-4000 cm-1 region are listed in the Experimental section. These data show that individual molecules of 2-pyrazine carboxylic acid (in deprotonated form) were binding to the metal center through one of their ring nitrogen atoms and one of their carboxylate oxygen atoms. The IR spectra also contained stretching frequency bands where the asymmetric-symmetric separations [νasy(COO-)-νsy(COO-)] were greater than 200 cm-1 (i.e., 267, 282, and 263 cm-1 for compounds 1-3, respectively), which indicated that the COO- moiety of 2-pyrazine carboxylic acid unit was coordinated to the metal centers as a monodentate ligand [25]. The IR spectra of all three complexes contained a band at 1470 cm-1, which was assigned to the ν(C=C) stretching vibrations of the aromatic rings [26, 27]. Broad peaks were also observed in the range of 3251-3247 cm-1 for all three complexes, which were attributed to the OH stretching vibrations of water molecules [28, 29].
Cyclic voltammograms were recorded in a 1 mmol/L solutions of each complex in DMSO containing 0.1 mol/L tetrabutylammonium perchlorate (TBAP) as a supporting electrolyte by scanning the potential from -1 to 1 V. A three-electrode assembly was employed using an Ag/AgCl electrode as a reference electrode, a platinum wire as a counter electrode and a glassy carbon electrode as the working electrode. The voltammogram obtained for the Cu(II) complex is shown in Fig. 2.
As shown in Fig. 2, the cyclic voltammogram the Cu(II) complex was characterized by a pair of well defined oxidation and reduction peaks at -281 and -352 mV, which had peak currents of 85.6 and -25.9 µA, respectively. The peak-to-peak potential separation (ΔEp) of this complex was found to be 71 mV, and the half-wave potential was 316.5 mV. Irreversible redox peaks were also observed at 691 and 254 mV. The ratios of the anodic to cathodic peak currents correspond to the chemical changes that occur during the electron transfer processes of Cu(II) → Cu(I) → Cu(0).
Redox peaks were observed at 52 and -292 mV for the Co(II) complex, and -110 and -215 mV for the Ni(II) complex. The peaks observed in all three complexes with potentials more positive than 500 mV were attributed to the oxidation of the pyrazine ring of the ligand.
The reaction of benzaldehyde with hydrazine hydrate, dimedone, and phthalic anhydride was selected as a model reaction to optimize the conditions of the MCR for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones. The reaction was conducted in the presence of all three metal catalysts in a variety of different solvents, and the results are summarized in Table 2. Higher yields and shorter reaction times were obtained when the reaction was carried out in acetic acid.
In a separate screening study, the condensation of hydrazine hydrate with benzaldehyde, phthalic anhydride, and dimedone was conducted in acetic acid in the presence of different quantities of the catalysts (Table 3). Notably, the results of these experiments revealed that the model MCR gave a very low yield of the desired 3,4-dihydro-3,3-dimethyl-13-phenyl-2H-indazolo[1,2-b]phthalazine-1,6,11(13H)-trione product when it was conducted in the absence of the title metal complexes.
With the optimized conditions in hand, we proceeded to evaluate the scope of this method using a variety of different aromatic aldehydes in the presence of complexes 1-3, which were used as catalysts. Notably, a variety of different aromatic aldehydes, including ortho-, meta-, and para-substituted aryl aldehydes, all reacted smoothly under the optimized reaction conditions to give the corresponding products in good to excellent yields. As shown in Table 4, the aldehydes bearing both electron-donating and electron-withdrawing groups participated in the condensation reaction with equal efficiency. Thus, the nature and position of the substituents on the aromatic ring had no discernible impact on the success of the reaction.
Finally, to demonstrate the efficiency of our newly developed method, the performance of catalysts 1-3 was compared with those of several other catalysts that had been reported previously for the synthesis of 3,4-dihydro-3,3-dimethyl-13-phenyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives. As shown in Table 5, our newly developed method offers several significant advantages of the other existing methods, such as a cleaner reaction profile, easier handling of the catalyst, shorter reaction times, and environmental compatibility. Overall, the use of the complexes prepared in the current study allowed for the preparation of the desired products in satisfactory yields using lower temperatures over shorter reaction times, and without the need for expensive catalysts.
A mechanism was proposed for the current reaction using the metal catalysts and is shown in Scheme 3. An initial Knoevenagel condensation reaction between the aryl aldehyde and dimedone in the presence of a catalytic amount of the metal complex would afford intermediate (A). The condensation of hydrazine monohydrate with phthalic anhydride would afford phthalhydrazide (B) with the loss of water. The subsequent 1,4-conjugate addition of phthalhydrazide (B) to intermediate (A), followed by the sequential cyclization and tautomerization of the addition product would give the corresponding product (C). Kiasat et al. [37] previously performed density functional theory calculations on the nature of each step of this mechanism, which confirmed the accuracy of the proposed mechanism.
The recyclability properties of the three different catalysts were also investigated using the model reaction between hydrazine monohydrate, phthalicanhydride, benzaldehyde and dimedone for the preparation of 3,4-dihydro-3,3-dimethyl-13-phenyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (Table 4, entry 1). Upon completion of the reaction, the solvent was evaporated to give a residue, which was suspended in 5 mL EtOH. The catalyst was then removed by centrifugation and the crude product was recrystallized from a mixture of ethanol and water. The pure products were characterized by a comparison of their physical data with those of the known compounds. The recovered catalysts could be reused at least three times without any discernible loss in their activities (Fig. 3).
Three complexes of Ni(II), Co(II), and Cu(II) containing pyrazine carboxylic acid have been synthesized and structurally characterized. All these complexes were found to be octahedral in geometry, and their metal ions were surrounded by the nitrogen and oxygen atoms of 2-pyrazinecarboxylate (pzca-), as well as the oxygen atom of coordinated water molecules. These complexes performed as efficient catalysts for the one-pot, four-component synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives. The key advantages of this synthetic methodology include its high efficiency, generality, good to excellent yields of the desired products, short reaction time, simplicity, low reaction temperature, ease of product isolation, clean reaction profile, avoidance of hazardous catalysts and solvents, and general agreement with the principles of green chemistry, making it a useful and attractive process for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones.
Supplementary data
CCDC 1040555-1040557 contain the supplementary crystallographic data for complexes 1-3. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk
Acknowledgments
The authors gratefully acknowledge the financial support provided for this work by the Shahid Bahonar University of Kerman and PNU. The support of NSF-MRI Grant #1228232 for the purchase of the diffractometer and of Tulane University for the Tulane Crystallography Laboratory is gratefully acknowledged.
2015, Vol. 36 Issue (7): 1101-1108
PDF (1065 KB)
2015, Vol. 36 Issue (7): 1101-1108
PDF (1065 KB)