HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 6, 2013, pp. 1327-1336
Received, 25th March, 2013, Accepted, 7th May, 2013, Published online, 13th May, 2013.
DOI: 10.3987/COM-13-12719

■ Microwave-Assisted Synthesis of 3-Methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones under Solvent-Free Conditions

Guo-Yu Yang, Jing-Tian Yang, Cai-Xia Wang, Su-Fang Fan, Pu-Hui Xie, and Cui-Lian Xu*

College of Science, Henan Agricultural University, Zhengzhou 450002, China

Abstract

A novel microwave-assisted method for the synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones by the cyclization of 3-[1-(phenylhydrazono)ethyl]chromen-2-ones with CuO/SBA-15 under solvent-free conditions is described. The reaction gave the corresponding chromenopyrazole products in good to excellent yields in short reaction times.

Pyrazoles are heterocyclic compounds with a five membered ring containing three carbons and two nitrogens. Such heterocyclic systems are widely distributed in nature. Pyrazoles have a wide range of applications as agro and pharma chemicals due to their biological activities such as antibacterial, antidepressant, antiamoebic, anti-inflammatory and antinociceptive activities.1-4
Coumarin derivatives have been widely reported to possess various biological activities, such as antimicrobial activity5 and antifungal activity.6 Chromenopyrazoles are heterocyclic compounds containing a rigid six-six-five tricyclic ring system. They have found application as ligands for the central benzodiazepine receptor (BZR). For example, 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones are commonly used to synthesize immunomodulatory drugs which can interact with the benzodiazepine central receptor.7
One of the early synthetic methods for chromeno-pyrazoles which has been reported utilizes the cyclization of 1-(phenylhydrazono)chromen-2-ones 4-substituted with –OH and –Cl in xylene with p-toluenesulfonic acid as catalyst.8 Recently, a new method was reported for the preparation of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones using the oxidative cyclization of 3-[1-(phenylhydrazono)ethyl]chromen-2-ones with copper acetate as catalyst.9 However this method suffers from drawbacks such as difficult separation and recycling of the homogeneous catalyst, low efficiency, solvent use, etc. In order to overcome these shortcomings, we decided to explore a catalyst-supported system, using CuO as the catalyst under solvent-free microwave-assisted conditions. SBA-15 was chosen as the carrier because of its relatively large specific surface area and uniform pore diameter distribution.4,10-12 The supported catalyst CuO/SBA-15 has been used in many chemical reaction and has been found to have high activity and selectivity.13,14 With the development of green chemistry, microwave synthesis and solventless synthesis have been attracting more and more attention in organic chemistry.15-17
In this paper, we report on the development of a novel microwave-assisted method for the synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones (2) by the cyclization of 3-[1-(phenylhydrazono)ethyl]chromen-2-ones (1) with supported Cu(II) (CuO/SBA-15) as the catalyst under solvent-free conditions (Scheme 1).

Under solvent-free conditions, two controlled trials were done to determine the influence of the catalyst and microwave. In one, an oil bath was used and compound 1a was heated for 3 hours at 120 °C with CuO/SBA-15 as the catalyst (Table 1, entry 1, Conv: 85%). The other was run without the use of the catalyst and compound 1a was heated for half an hour under microwave irradiation of 567 W (Table 1, entry 2, Conv: 46%). we were pleased to find that in the presence of catalyst CuO/SBA-15 the conversion of the compound 1a was 97% when the reaction was done for half an hour under microwave irradiation of 567 W (Table 1, entry 5). These results show that the influence of the catalyst and microwave are significant.
This reaction was investigated for various reaction parameters such as time, microwave power and catalyst loading. The effect of time on the conversion of the reactant was monitored from 10 to 30 min (Table 1, entries 3-5). The conversion of compound 1a reached 97% when the time was 30 min. When the microwave power was increased from 406 to 567 W (Table 1, entries 5, 6), the conversion of compound 1a increased from 10% to 97%. When the microwave power was increased from 567 to 700 W (Table 1, entries 5, 7), the yield of product 2a decreased from 92% to 86%. When the molar ratio of the catalyst and the reactant 1a was varied from 0.35 to 1.4 ×10-2 (Table 1, entries 7-9), the conversion of compound 1a increased from 52% to 100%, and the time required for completing the reaction decreased from 30 to 20 minutes. This fully indicates that microwave power and catalyst amount are the key parameters affecting the reaction rate. We also found that when the molar ratio of the catalyst and the reactant 1a increased from 0.7 to 1.4 ×10-2 (Table 1, entries 5, 9), there was little decrease in the selectivity of the product 2a. In comprehensive consideration of the reaction rate and product selectivity, 0.7×10-2 molar ratio of the catalyst and the reactant 1a was optimum formulation.
Various chromenopyrazoles were efficiently synthesized with this green method. It was observed that the coumarin hydrazones were easily converted into the expected products in excellent yields (Table 2). We found that compounds containing electron withdrawing groups in the coumarin ring showed lower yields (Table 2, entries 6, 8). Similarly, compounds containing electron withdrawing groups in the N-benzene ring also showed lower yields (Table 2, entries 13, 14). These results show that electron withdrawing groups are unfavorable for the cyclization of 3-[1-(phenylhydrazono)ethyl]chromen-2-ones.

A proposed mechanism for the synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones is shown in Scheme 2, which includes the Michael addition of an amino group to the enone, and then oxidation to give the product.
To confirm their structures, monocrystals of chromenopyrazole 2d suitable for X-ray crystal diffraction measurements were obtained by slow evaporation in acetic acid. X-Ray data for crystals of 2d were collected by graphite monochromatized Mo Kα radiation at 293K. Crystal data and experimental details for compound 2d are summarized in Table 3. The crystal structure and molecular packing of compound 2d are shown in Figure 1 and Figure 2, respectively. It can be seen that the benzopyran ring and the pyrazole ring are essentially coplanar. The other benzene ring is at an approximately 90° angle to the plane. Molecules of compound 2d are packed through weak interaction to form layered stacks.

The reusability of the CuO/SBA-15 catalyst was studied under microwave conditions. After the completion of the reaction for the first run, the reaction mixture was thoroughly washed with methylene chloride until the products were completely removed from the catalyst. Then the catalyst was washed with ethyl alcohol, filtered and dried in an oven at 120 °C for 4 h. The dried catalyst was used for the next runs and the same procedure was adopted for all the recyclability studies. The conversion of compound 1a for the various runs are listed in Table 4. The result shows that the catalytic activity of the CuO/SBA-15 could be kept at a constant high level.
In conclusion, a novel green, and atom economical method was developed for the synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones (2) by the cyclization of 3-[1-(phenylhydrazono)- ethyl]chromen-2-ones (1) in the presence of CuO/SBA-15 under solvent-free and microwave irradiation conditions. Compared with existing methods, the current protocol gives the targeted products in higher yields and in shorter reaction times owing to the use of microwave. Moreover, making use of the recoverable Cu catalyst under solvent-free conditions rendered this protocol advantageous, although solvents are necessary for the isolation of the products as well as catalyst recovery in the work-up step.

EXPERIMENTAL
All solvents and reagents were purchased from commercial sources and were used without additional purification. Melting points were determined with a X-5 digital microscopic melting-point apparatus (Beijing Tech Instruments Co., Beijing, China) and are uncorrected. 1H and 13C NMR spectra were recorded on a Bruker DPX-400 (400MHz) instrument in CDCl3 with TMS as the internal standard. HRMS measurements were performed on a Waters Q-Tof MicroTM instrument. HPLC analysis was performed on an Agilent 1200 HPLC (Chromatographic Column: XDB-C18 column with MeOH–H2O as eluent) equipped with an Agilent 1200 UV detector. ICP were measured on an inductively coupled plasmas atomic emission spectrometer from the American Thermo Electron company.
CCDC-929647 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data-request/cif.
The preparation of the catalyst CuO/SBA-15
0.48 g (2.4 mmol) of Cu(MeCOO)2·H2O was dissolved in 75 mL of 1.6 mol/L HCl, and 2 g of p123 (EO20PO70EO20, Aldrich) was added to the above solution with stirring. The mixture was stirred until the p123 dissolved. Then, 5 mL of TEOS as the silica source was added dropwise to the aqueous solution with vigorous stirring. After the mixture was stirred for 24 h at 40 °C and aged for 24 h at 100 °C, the solid obtained was filtered off, dried at 120 °C for 8 h, and calcined at 550 °C for 4 h. The sample thus obtained is denoted as CuO/SBA-15 (0.16% by ICP).
Typical procedure for the preparation of compounds 2a-p.
3-[1-(Phenylhydrazono)ethyl]chromen-2-ones 1 (0.72 mmol), CuO/SBA-15 (0.7 mol%) and 4 g silica as media were thoroughly grinded in a mortar. The silica supported mixture was heated with a microwave at 567 W. The sample was monitored by HPLC. After completion of the reaction, the resulting mixture was extracted with CH2Cl2 (20 mL×3). The solvent was removed by reduced pressure distillation. The crude product was recrystallized from EtOH to give compounds 2.
6-Ethoxy-3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-one (2e): yield 198 mg (86%); white powder; mp 204-206 °C; 1H NMR (400 MHz, CDCl3): δ = 1.52 (t, J = 7.2 Hz, 3H, CH3), 2.70 (s, 3H, CH3), 4.17-7.54 (m, 2H, CH2), 6.64-6.66 (m, 1H, ArH), 6.92-6.96 (m, 1H, ArH), 6.99-7.02 (m, 1H, ArH), 6.99-7.02 (m, 1H, ArH), 7.53-7.55 (m, 2H, ArH), 7.59-7.61 (m, 3H, ArH); 13C NMR (100MHz, CDCl3): δ = 12.93, 14.75, 65.05, 106.38, 112.61, 113.88, 114.24, 123.69, 127.01, 129.79, 130.10, 139.49, 141.94, 147.52, 150.75, 157.49 ppm; HRMS (ESI+): m/z calcd for [C19H17N2O3]+: (M + H+) 321.1239; found: 321.1238.
6,8-Dibromo-3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-one (2g): yield 188 mg (60%); yellow powder; mp 246-250 °C; 1H NMR (400 MHz, CDCl3): δ = 2.69 (s, 3H, CH3), 7.12 (d, J = 2 Hz, 1H, ArH), 7.51-7.54 (m, 2H, ArH), 7.64-7.66 (m, 3H, ArH), 7.81 (d, J = 2 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ = 12.83, 106.68, 112.67, 114.23, 116.33, 124.21, 126.70, 130.09, 130.68, 136.68, 138.63, 139.85, 149.04, 150.97, 156.02 ppm; HRMS (ESI+): m/z calcd for [C17H11Br2N2O2]+: (M + H+) 432.9187; found: 432.9191.
1-(4-Bromophenyl)-3-methylchromeno[4,3-c]pyrazol-4(1H)-one (2k): yield 179 mg (70%); white powder; mp 225-227 °C; 1H NMR (400 MHz, CDCl3): δ = 2.69 (s, 3H, CH3), 7.07-7.11(m, 1H, ArH), 7.15-7.17 (m, 1H, ArH), 7.43-7.49 (m, 4H, ArH), 7.74-7.77 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ = 12.86, 106.64, 111.59, 118.20, 122.26, 123.99, 124.17, 128.39, 131.29, 133.09, 138.35, 141.74, 151.16, 153.27, 157.77 ppm; HRMS (ESI+): m/z calcd for [C17H12BrN2O2]+: (M + H+) 355.0082; found: 355.0083.
1-(2,4-Dichlorophenyl)-3-methylchromeno[4,3-c]pyrazol-4(1H)-one (2n): yield 124 mg (50%); light yellow powder; mp 262-264 °C; 1H NMR (400 MHz, CDCl3): δ = 2.68 (s, 3H, CH3), 7.15 (t, J = 7 Hz, ArH), 7.23 (d, J = 8 Hz, 1H, ArH), 7.46 (d, J = 8 Hz, 1H, ArH), 7.50-7.54 (m, 3H, ArH), 7.61(s, 1H, ArH). 13C NMR (100MHz, CDCl3): δ = 12.83, 106.98, 111.27, 118.34, 122.16, 124.20, 125.52, 130.33, 131.58, 136.13, 140.88, 141.88, 151.57, 153.32, 157.53 ppm. HRMS (ESI+): m/z calcd for [C17H11Cl2N2O2]+: (M + H+) 345.0198; found: 345.0199.
1-(2,4-Dimethylphenyl)-3-methylchromeno[4,3-c]pyrazol-4(1H)-one (2o): yield 170 mg (78%); yellow powder; mp 176-179 °C; 1H NMR (400 MHz, CDCl3): δ = 2.00 (s, 3H, CH3), 2.69 (s, 3H, CH3), 6.83 (d, J = 8 Hz, 1H, ArH), 7.00-7.04 (m, 1H, ArH), 7.20-7.29 (m, 3H, ArH), 7.42-7.44 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ = 13.01, 17.19, 21.40, 105.66, 112.01, 117.93, 121.83, 124.19, 127.50, 28.12, 130.99, 132.15, 135.71, 135.80, 140.84, 142.16, 150.65, 153.24, 158.11 ppm. HRMS (ESI+): m/z calcd for [C19H17N2O2]+: (M + H+) 305.1290; found: 305.1288.

ACKNOWLEDGMENTS
This work was supported by the Education Foundation of Henan Province (2006150011), the National Natural Science Foundation (NSFC21102037) and Key Science and Technology Foundation of Henan Province (112101110200).

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