Supporting information

Synthesis of dihydropyrano[2,3-c]pyrazolesusing Ca9.5Mg0.5(PO4)5.5(SiO4)0.5F1.5 as a new nano cooperative catalyst

Leila Khazdooz,* Amin Zarei, TahminehAhmadi, HamidrezaAghaei,NasrinNazempour,LalehGolestanifar, NafisehsadatSheikhan

Department of Science, Khorasgan (Isfahan) Branch, Islamic Azad University, Isfahan 81595-158, Iran.
Email:

Experimental

All reagents were purchased from Merck and Aldrich and usedwithout further purification. All yields refer to isolated productsafter purification. The products were characterized by comparison of physical data with those of known compounds and by spectroscopic data (FTIR, 1HNMR and 13CNMR spectra).1HNMRspectrawere recorded with a BrukerAvance 400 (400 MHz) in DMSO-d6 as the solvent. Apatite derivatives nanopowders were synthesized by a high energy planetary ball mill (FretchPulversette 5) with a 125 mL zirconia vial and four 20 mm diameter zirconia balls at room temperature. The morphology and particle size of the catalyst were measured by using transmission electron microscopy (TEM, Philips CM-FG120) at 200KV.The BET surface area and pore volume were measured by using a KELVIN sorptometer 1042 with nitrogen adsorption and desorption isotherms at 77 K. All samples were degassed at 100 °C for 130 min. pH of all samples were measured by using a suspension of 1.00 g of milled apatite derivative in 200 ml of distilled water with a magnetic stirrer. Pyridine adsorption was studied by employing 0.2 g of catalyst (pre-activated at 350 °C for 2 h) exposed to dry pyridine vapors in a vacuum desiccator. Phase structure analyses were determined by X-ray diffractometer (XRD, Philips Xpert) using the Ni-filtered CuKα (λCuKα=0.1542 nm, radiation at 40 kV and 30 mA). The data were collected over the 2θ range of 10–70°, time per step was 2.5 s and step size was 0.021°.

Preparation of Ca9.5Mg0.5(PO4)5.5(SiO4)0.5F1.5

A mixtureof calcium hydroxide (2.594 g, 35 mmol), diphosphorouspentoxide(1.562 g, 11 mmol),calcium fluoride (0.234 g, 3 mmol), magnesiumhydroxide (0.117 g, 2 mmol)andsilicon dioxide (0.120 g, 2 mmol) wasmechanochemically activated by usingahighenergyplanetaryballmill(FretchPulverisette5)witha125mlzirconiavialandfour20mmdiameter zirconia balls.The rotation speed was 250 rpm and the ball milling process was carried out at ambient temperaturefor 12 h.

General procedure for the synthesis of dihydropyrano[2,3-c]pyrazoles

An aldehyde (2 mmol), malononitrile (2 mmol) and Ca9.5Mg0.5(PO4)5.5(SiO4)0.5F1.5 (0.04 g, 2 mol%) were added to a stirred mixture of ethyl acetoacetate (2 mmol) and hydrazine hydrate (2 mmol) in 8 mL of EtOH/H2O (1:1). The resulting mixture was heated at 70 °C for the specified time. After completion of the reaction, monitored by TLC, ethanol (2×20 mL) was added to the reaction mixture and heated to dissolve the product. Then, the reaction mixture was filtered to separate the catalyst. The collected EtOH was evaporated under reduced pressure to give the crude product. The further purification was followed by recrystallization in EtOH/H2O (9:1).

Spectral data of some representative compounds

6-amino-4-(4-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4a).

Melting point: 236-237°C(Lit: 234-235°C [48]). IR (KBr, cm-1): 3480, 3410, 3290, 3173, 2973, 2187, 1645, 1599, 1491, 1402, 1294, 1162, 1088, 1046, 897, 873, 797.1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.78 (3 H, s, CH3), 4.62 (1 H, s, CH), 6.92 (2 H, s, NH2), 7.18 (2 H, d, J = 8.0 Hz, ArH), 7.36 (2 H, d, J = 8.0 Hz, ArH), 12.12 (1 H, s, NH). 13C NMR (100 MHz, DMSO-d6), δ (ppm): 9.71, 35.50, 56.66, 97.15, 120.65, 128.43, 129.34, 131.19, 135.64, 143.46, 154.66, 160.87.

6-amino-4-(2-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4b).

Melting point: 246-247°C(Lit: 245-246°C [48]).IR (KBr, cm-1): 3390, 3352, 3313, 3164, 2189, 1654, 1609, 1595, 1489, 1407, 1049, 760.1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.80 (3 H, s, CH3), 5.16 (1 H, s, CH), 7.05 (2 H, s, NH2), 7.27 (1 H, d, J = 7.3 Hz, ArH), 7.33-7.43 (2 H, m, ArH), 7.50 (1 H, dd, J1 = 7.8 Hz, J2 = 1.3 Hz, ArH), 12.24 (1 H, s, NH). 13C NMR (100MHz, DMSO-d6), δ (ppm): 9.45, 33.1, 55.64, 96.81, 120.35, 127.74, 128.59, 129.47, 130.69, 131.92, 135.36, 140.86, 154.84, 161.28.

6-amino-4-(2,6-dichlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4c).

Melting point: 246-248°C(Lit: 249-250°C [36]).IR (KBr, cm-1): 3405, 3151, 2183, 1654, 1600, 1492, 1405, 1153, 1042, 787, 743.1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.79 (3 H, s, CH3), 5.59 (3 H, s, CH), 7.03 (2 H, s, NH2), 7.33 (1 H, t, J = 8.0 Hz, ArH), 7.40 (1 H, dd, J1 = 8.0 Hz, J2 = 1.6 Hz, ArH), 7.55 (1 H, dd, J1 = 8.0 Hz, J2 = 1.6 Hz, ArH), 12.12 (1 H, s, NH). 13C NMR (100MHz, DMSO-d6), δ (ppm): 9.75, 32.96, 53.30, 95.28, 120.65, 128.94, 130.08, 131.33, 134.93, 135.27, 135.63, 136.37, 156.02, 162.52.

6-amino-3-methyl-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4g).

Melting point: 242-243°C(Lit: 243-244°C [48]).IR (KBr, cm-1): 3372, 33172, 2186, 1655, 1596, 1528, 1413, 1349, 1046, 791, 740. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.77 (3 H, s, CH3), 5.10 (1 H, s, CH), 7.05 (2 H, s, NH2),7.33 (1 H, d, J = 7.7 Hz, ArH), 7.50 (1 H, t, J = 7.8 Hz, ArH), 7.66 (1 H, t, J = 7.6 Hz, ArH), 7.85, (1 H, d, J = 8.1 Hz, ArH), 12.23 (1 H, s, NH). 13C NMR (100 MHz, DMSO-d6), δ (ppm): 9.43, 31.32, 55.92, 96.31, 120.15, 123.54, 128.29, 131.22, 133.32, 135.50, 137.51, 149.08, 154.83, 161.07.

6-amino-3-methyl-4-(3-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4h).

Melting point: 234-236°C(Lit: 232-234°C [45]).IR (KBr, cm-1): 3474, 3225, 3119, 2883, 2195, 1655, 1598, 1518, 1492, 1402, 1350, 1166, 1076, 805.1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.82 (3 H, s, CH3), 4.89 (1 H, s, CH), 7.07 (2 H, s, NH2), 7.64-7.70 (2 H, m, ArH), 8.03 (1 H, s, ArH), 8.14 (1 H, m, ArH), 12.23 (1 H, s, NH). 13C NMR (100 MHz, DMSO-d6), δ (ppm): 10.19, 36.1, 56.61, 97.15, 120.98, 122.33, 122.49, 130.75, 134.88, 136.23, 147.29, 148.37, 155.12, 161.59.

6-amino-4-(4-methoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4j).

Melting point: 211-213°C(Lit: 210-212°C [48]).IR (KBr, cm-1): 3484, 3256, 3111, 2192, 1600, 1513, 1493, 1392, 1260, 1030, 804.

1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.87 (3 H, s, CH3), 3.82 (3 H, s, OCH3), 4.63 (1 H, s, CH), 6.92 (2 H, NH2), 6.96 (2 H, d, J = 8.6 Hz, ArH), 7.17 (2 H, d, J = 8.6 Hz, ArH), 12.18 (1 H, s, NH). 13C NMR (100 MHz, DMSO-d6), δ (ppm): 9.67, 35.35, 54.95, 57.50, 97.84, 113.72, 120.77, 128.46, 135.Melting point: 211-213°C(Lit: 210-212°C [48]).34, 136.42, 154.63, 157.91, 160.56.

6-amino-4-(3,4-dimethoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4k).

Melting point: 194-195°C(Lit: 192-194°C [41]).IR (KBr, cm-1): 3253, 3120, 2191, 1638, 1599, 1515, 1490, 1397, 1261, 1230, 1140, 1023, 752.1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.84 (3 H, s, CH3), 3.71 (3 H, s, OCH3), 3.84 (3 H, s, OCH3), 4.57 (1 H, s, CH), 6.70 (1 H, dd, J1 = 8.2 Hz, J2 = 2 Hz, ArH), 6.77 (1 H, d, J = 2.0 Hz, ArH), 6.85 (2 H, s, NH2), 6.92, (1 H, d, J = 8.4 Hz, ArH), 12.10 (1 H, s, NH).

13C NMR(100MHz, DMSO-d6), δ (ppm): 10.28, 36.30, 55.91, 55.94, 57.91, 98.19, 111.66, 112.19, 119.97, 121.34, 135.95, 137.36, 148.03, 149.01, 155.15, 161.20.

6-amino-4-(4-methoxycarbonylphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4l).

Melting point: 242-244°C(Lit: 240-242°C [36]).IR (KBr, cm-1): 3484, 3281, 3231, 3117, 2187, 1725, 1641, 1595, 1492, 1409, 1277, 1116, 750.1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.79, (3 H, s, CH3), 3.85 (3 H, s, OCH3), 4.73 (1 H, s, CH), 7.00 (2 H, s, NH2), 7.34 (2 H, d, J = 6.6 Hz, ArH), 7.94 (2 H, d, J = 6.6 Hz, ArH), 12.18 (1 H, s, NH). 13C NMR (100 MHz, DMSO-d6), δ (ppm): 10.15, 36.58, 52.55, 56.87, 97.45, 121.05, 128.42, 128.67, 130.03, 136.07, 150.31, 155.13, 161.46, 166.55.

6-amino-4-(4-cyanophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4n).

Melting point: 215-216 °C(Lit: 212-214 °C [47]).IR (KBr, cm-1): 3482, 3236, 3118, 2227, 2189, 1643, 1597, 1492, 1411, 1056, 748.

1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.79, (3 H, s, CH3), 4.75, (1 H, s, CH), 7.03 (2 H, s, NH2), 7.39 (2 H, d, J = 8.1 Hz, ArH), 7.80 (2 H, d, J = 8.1 Hz, ArH), 12.18 (1 H, s, NH).

6-amino-4-(furan-2-yl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4o).

Melting point: 234-236°C(Lit: 232-234°C [45]).IR (KBr, cm-1): 3355, 3172, 2187, 1649, 1600, 1493, 1405, 1070, 751.1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.99 (3 H, s, CH3), 4.79 (1 H, s, CH), 6.19 (1 H, d, J = 3.2 Hz, ArH), 6.38 (1 H, dd, J1 = 4.8 Hz, J2 = 2.0 Hz, ArH), 6.98 (2 H, s, NH2), 7.54 (1 H, dd, J1 = 2.4 Hz, J2 = 0.8 Hz, ArH), 12.19 (1 H, s, NH). 13C NMR (100 MHz, DMSO-d6), δ (ppm): 10.01, 30.28, 54.48, 95.59, 106.14, 110.73, 121.06, 136.16, 142.74, 155.28, 156.17, 161.92.

Figure 1. FTIR of 6-amino-4-(4-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4a)..

Figure 2. 1HNMR of 6-amino-4-(4-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4a) in DMSO- d6.

Figure 3. 13CNMR of 6-amino-4-(4-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4a) in DMSO-d6.

Figure 4. FTIR of 6-amino-4-(2-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4b).

Figure 5. 1HNMR of 6-amino-4-(2-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4b) in DMSO- d6.

Figure 6. 13CNMR of 6-amino-4-(2-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4b) in DMSO- d6.

Figure 7. FTIR of 6-amino-4-(2,6-dichlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4c).

Figure 8.1HNMR of 6-amino-4-(2,6-dichlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4c)in DMSO-d6.

Figure 9.13CNMR of 6-amino-4-(2,6-dichlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4c) in DMSO-d6.

Figure 10. FTIR of 6-amino-3-methyl-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4g).

Figure 11. 1HNMR of 6-amino-3-methyl-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4g) in DMSO-d6.

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Figure 12. 13CNMR of 6-amino-3-methyl-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4g) in DMSO-d6.

Figure 13. FTIR of 6-amino-3-methyl-4-(3-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4h).

Figure 14. 1HNMR of 6-amino-3-methyl-4-(3-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4h) in DMSO-d6.

Figure 15. 13CNMR of 6-amino-3-methyl-4-(3-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4h) in DMSO-d6.

Figure 16. FTIR of 6-amino-4-(4-methoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4j).

Figure 17. 1HNMR of 6-amino-3-methyl-4-(4-methoxyphenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4j) in DMSO-d6.

Figure 18. 13CNMR of 6-amino-3-methyl-4-(4-methoxyphenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4j) in DMSO-d6.

Figure 19. FTIR of 6-amino-4-(3,4-dimethoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4k).

Figure 20. 1HNMR of 6-amino-3-methyl-4-(3,4-dimethoxyphenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4k) in DMSO-d6.

Figure 21. 13C.NMR of 6-amino-3-methyl-4-(3,4-dimethoxyphenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4k)in DMSO-d6.

Figure 22. FTIR of 6-amino-4-(4-methoxycarbonylphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4l).

Figure 23.1HNMR of 6-amino-4-(4-methoxycarbonylphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4l)in DMSO-d6.

Figure 24.13CNMR of 6-amino-4-(4-methoxycarbonylphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4l)in DMSO-d6.

Figure 25. FTIR of 6-amino-4-(furan-2-yl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4o).

Figure 26.1HNMR of 6-amino-4-(furan-2-yl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4o) in DMSO-d6.

Figure 27.13CNMR of 6-amino-4-(furan-2-yl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(4o)in DMSO-d6.

Figure 28. FTIR of 6-amino-4-(4-cyanophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4n) .

Figure 29.1HNMR of 6-amino-4-(4-cyanophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4n).in DMSO-d6.