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m.p. 196-200ºC; Yield: 78-80%; IR (KBr): 2926. (CH), 1674 (CO), 1595, 1516, 1431, 1271, 1220,. 1131, 1057 cm-1; 1H NMR (DMSO-d6, 300 MHz): δ. 2.45 (s ...
Indian Journal of Chemistry Vol. 52B, October 2013, pp 1352-1356

Synthesis of some novel 3,5-diarylpyrazole derivatives of dibenzo-18-crown-6- ether S D Jagadale, A G Mulik, D R Chandam, P P Patil, D R Patil, S A Sankpal, A D Sawant & M B Deshmukh* Department of Chemistry, Shivaji University, Kolhapur, India 416 004 Email: [email protected] Received 25 July 2012; accepted (revised) 27 June 2013 Novel pyrazole derivatives of dizenzo-18-crown-6-ether are obtained via three step protocol involving acylation of dibenzo-18-crown-6 1 followed by the condensation with various aromatic aldehydes to form the corresponding chalcones 3, which on heterocyclisation with hydrazine hydrate give the target molecule 4. These new molecules have been characterized on the basis of IR, 1H NMR, 13C NMR and elemental analysis. Keywords: Dibenzo-18-crown-6, acylation, chalcone, iodine, pyrazole

Recently, the pyrazole ring system has proven to be an increasingly popular heterocyclic compound because of interesting properties exhibited by large number of pyrazole derivatives. Their applications in the synthesis of pharmaceutically active compounds1 are of special importance. Many pyrazole derivatives are known to exhibit a wide range of biological properties such as anti-hyperglycemic, analgesic, antiinflammatory, anti-pyretic, anti-bacterial, hypoglycemic, hypnotic activity and anti-coagulant activity2-4. Substituted pyrazoles and condensed pyrazoles are important as pharmaceutical5,6 and biodegradable agrochemicals7,8. Recently, researchers have reported synthesis of some pyrazole derivatives exhibiting potential pharmacological activities such as analogues of the combretastatins9, cytotoxic agents10 or inhibitors of monoamine-oxidase-A11. Moreover, some pyrazoles are used in supramolecular and polymer chemistry, in the food industry, and as cosmetic coloring agents and UV stabilizers, while some have liquid crystal properties12-14. Because of wide spectrum of applications of pyrazoles, chemists have always been fascinated to develop new pyrazole derivatives. There are several conventional approaches to the synthesis of pyrazole derivatives viz. condensation of hydrazines with 1-3 dielectrophiles15,16, [3+2] cycloaddition of 1-3 dipoles to dipolarophiles17,18. In all these methods the substitutents are introduced before cyclization. A recent approach developed in last decade involves cross coupling of aryl electrophiles with substituted

pyrazoles19-21. Herein, we report efficient synthesis of pyrazole derivatives of dibenzo-18-crown-6 ether. The approach of condensation of hydrazine with chalcone derivatives of crown ether. Results and Discussion The 3,5-diaryl pyrazole 4 was synthesized as a novel compound for first time. The first step involves acylation of dibenzo-18-crown-6 1 by using sodium acetate in polyphosphoric acid (PPA) as the solvent and catalyst22. Earlier 4,4′-diacetyl dibenzo-18-crown-6 2 was prepared by acylation with acetic anhydride in orthophpshoric acid. But this method has some lacunas such as use of hazardous chemicals (acetic anhydride), tedious work up procedure (sticky product) and low yield23. Taking into account these aspects the procedure we modified. In the present work 4,4′-diacetyl dibenzo18-crown-6 2 was obtained in high yield (78-80%). The diacetyl derivative of dibenzo-18-crown-6 2 on Claisen-Schmidth condensation with aryl aldehydes in the second step gives corresponding chalcones 3. The chalcones 3 obtained in good yields (70-72%) in alkaline media with methanol as solvent (Table I). After literature review, it was decided to adapt conventional approach of condensation of hydrazine hydrate with 1-3-dielectrophiles. In the next step, the chalcone on treatment with hydrazine hydrate in the presence of elemental iodine gives 3,5-diarylpyrazole 4 (Scheme I)24. The structures of the synthesized compounds were confirmed by IR, 1H and 13C NMR spectra.

JAGADALE et al.: NOVEL 3,5-DIARYLPYRAZOLE DERIVATIVES

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Table I ― Synthesis of pyrazole derivatives of dibenzo-18-crown-6 Compd 3

R

Time (hr)

A B C D E F

H p-Cl o-Cl p-F p-Nme2 m-NO2

4 2.5 4 3.5 4 3

a

Yield (%)

Compd 4

R

Time (hr)

70 72 71 70 69 71

A B C D E F

H p-Cl o-Cl p-F p-NMe2 m-NO2

4 3 3.5 4 4 3

b

Yield(%) 60 63 62 61 60 62

Yields are isolated yields, areaction at RT, breaction at 60°C.

It was observed that, the aromatic aldehydes possessing electron withdrawing groups gave excellent yields while aromatic aldehydes possessing electron donating group gave relatively low yields. Hence, we have used aromatic aldehydes possessing electron withdrawing group for the reaction. Materials and Methods Crown ether and aldehydes were purchased from Sigma-Aldrich and used as received. All other chemicals and solvents were AR grade and used as purchased without any further purification. The progress of reaction was monitored by TLC (Silica gel 60 F254). IR spectra were recorded on PerkinElmer spectrometer. The 1H and 13C NMR were recorded on Bruker 300 Avance II with CDCl3/DMSO-d6 as solvent and TMS as internal standard. Melting points were determined in open capillary tube and are uncorrected. Experimental Section Procedure for the synthesis of 4,4′-diacetyl dibenzo-18-crown-6 and 4,5′-diacetyl dibenzo 18crown-6, 2. The dibenzo-18-crown-6 1 (1 mmol) and sodium acetate (2.5 mmol) was added to polyphosphoric acid (8 g). The mechanically stirred mixture was heated for 7 hr at 70°C. After completion of the reaction, 10 mL water was added and neutralized with dilute NaOH. The white precipitate was filtered, dried and recrystallized from ethanol. 4,4′-diacetyl dibenzo-18-crown-6, 2. White solid; m.p. 196-200ºC; Yield: 78-80%; IR (KBr): 2926 (CH), 1674 (CO), 1595, 1516, 1431, 1271, 1220, 1131, 1057 cm-1; 1H NMR (DMSO-d6, 300 MHz): δ 2.45 (s, 6H), 3.7-4 (m, 8H), 4-4.30 (m, 8H), 6.67-7.5 (m, 6H); 13C NMR (DMSO-d6): δ 194, 153, 146, 141, 139, 128, 122, 118, 117, 113, 78, 67, 65, 64, 62, 42, 38, 25; Anal. Calcd. C24H28O8: C, 64.85; H, 6.35. Found: C, 64.78; H, 6.31%.

General procedure for the synthesis of 4,4′(acrylphenonyl) dibenzo-18-crown-6, 3a-3f. To 0.3 g of KOH in 5 mL methanol (0.5 mmol), 4,4′-diacetyl dibenzo-18-crown-6 2 was added and the reaction mixture was stirred at RT for 5 min. Then 1 mmol of aldehyde was added and mixture was stirred for 4-5 hr. The reaction was monitored by TLC. After completion of the reaction, reaction mixture was poured into ice cold water and neutralized with dil. HCl. Then precipitate was filtered, dried and recrystallized from ethanol. 4,4′-Di (acrylphenonyl) dibenzo-18-crown-6, 3a. Pale yellow solid; m.p. 210°C; Yield: 70%, IR (KBr): 2930 (CH), 1668 (CO), 1587, 1515, 1428, 1359, 1270, 1134, 1057 cm-1; 1H NMR (DMSO-d6, 300 MHz): δ 3.4-4 (m, 8H), 4-4.4 (m, 8H), 6.7-7.5 (m, 16H), 7.6 (dd, 2H), 7.9 (dd, 2H); 13C NMR (DMSOd6): δ 194, 153, 146, 141, 139, 128, 122, 118, 117, 113, 78, 67, 65, 64, 62, 42, 38, 25; Anal. Calcd. C38H36O8: C, 73.52; H, 5.85. Found: C, 73.60; H, 5.90%. 4,4′-Di (acrylphenonyl) dibenzo-18-crown-6 (4chloro benzaldehyde), 3b. Pale yellow solid; m.p. 212°C; Yield: 72%, IR (KBr): 2927 (CH), 1655 (CO), 1593, 1514, 1430, 1321, 1220, 1133, 1056 cm-1; 1H NMR (DMSO-d6, 300 MHz): δ 3.7-4.0 (m, 8H), 4.14.4 (m, 8H), 6.6-7.4 (m, 14H), 7.9 (dd, 2H), 8.0 (dd, 2H); 13C NMR (DMSO-d6): δ 188.07, 148.36, 142.28, 133.48, 129.56, 129.12, 122.04, 111.52, 110.81, 77.81, 77.38, 76.93, 69.18, 68.12, 40.57, 40.29, 40.01, 39.73, 39.45. Anal. Calcd. C38H34O8Cl2: C, 66.20; H, 4.98. Found: C, 66.00; H, 4.90%. 4,4′-Di (acrylphenonyl) dibenzo-18-crown-6 (2chloro benzaldehyde), 3c. Yellow solid; m.p. 197°C; Yield: 71%, IR (KBr): 2925 (CH), 1654(CO), 1595, 1508, 1430, 1321, 1220, 1133, 1056 cm-1; 1H NMR (DMSO-d6 300 MHz): δ 3.8-4.1 (m, 8H), 4.2-4.4 (m, 8H), 6.6-7.7 (m, 14H), 7.8 (dd, 2H), 7.9 (dd, 2H); 13C NMR (DMSO-d6): δ 188.52, 148.41, 139.71,

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O O

O

O

O O 1

AcONa/PPA 70°C

O

O O

O

O

O

O

O 2 (cis & trans) CHO aq. KOH, MeOH rt

R

O

O

R

O

O

O

O

O

O 3

R

NH2NH2, AcOH, I2 60°C

HN

O

N

O

O

R

N

NH

O

O O

R 4

a b c

R H p-Cl o-Cl

d e f

R p-F p-NMe2 m-NO2

Scheme I

JAGADALE et al.: NOVEL 3,5-DIARYLPYRAZOLE DERIVATIVES

133.47, 129.72, 129.37, 129.22, 113.04, 103.13, 69.76, 69.43, 69.33, 68.52, 68.45, 68.22, 68.10, 36.48, 31.42. Anal. Calcd. C38H34O8Cl2: C, 66.20; H, 4.98. Found: C, 66.06; H, 4.92%. 4,4′-Di (acrylphenonyl) dibenzo-18-crown-6 (4fluro benzaldehyde), 3d. Pale yellow solid; m.p. 196°C; Yield: 70%, IR (KBr): 2926 (CH), 1659 (CO), 1597, 1505, 1454, 1430, 1326, 1254, 1127, 1060 cm-1, 1 H NMR (DMSO-d6, 300 MHz): δ 3.8-4.0 (m, 8H), 4.1-4.3 (m, 8H), 6.7-7.7 (m, 14H), 7.8 (dd, 2H), 7.9 (dd, 2H); 13C NMR (DMSO-d6): δ 187.01, 148.20, 141.28, 132.48, 129.56, 129.12, 122.04, 115.52, 110.81, 77.81, 77.38, 76.93, 69.18, 68.12, 40.57, 40.29, 40.01, 39.73, 39.45. Anal. Calcd. C38H34O8F2 : C, 69.44; H, 5.23. Found: C, 69.40; H, 5.20%. 4,4′-Di (acrylphenonyl) dibenzo-18-crown-6 (4N,N′-dimethyl benzaldehyde), 3e. Yellow solid; m.p. 230°C; Yield: 69%, IR (KBr): 2926 (CH), 1678 (CO), 1596, 1508, 1453, 1368, 1256, 1167, 1061 cm1 1 ; H NMR (DMSO-d6, 300 MHz): δ 3.0 (s, 12H), 3.84.0 (m, 8H), 4.1-4.2 (m, 8H), 6.5-7.3 (m, 14H), 7.5 (dd, 2H), 7.7 (dd, 2H); 13C NMR (DMSO-d6): δ 214.66, 190.35, 132.03, 121.29, 112.84, 112.47, 111.93, 110.06, 77.37, 77.05, 76.73, 69.42, 68.42, 40.68, 40.09, 33.71, 26.19, 24.37. Anal. Calcd. C42H46N2O8: C, 71.35; H, 6.56; N, 3.97. Found: C, 71.40; H, 6.60; N, 3.95%. 4,4′-Di (acrylphenonyl) dibenzo-18-crown-6 (3nitro benzaldehyde), 3f. Yellow solid; m.p. 210°C; Yield: 71%, IR (KBr): 2927 (CH), 1683 (CO), 1597, 1508, 1452, 1343, 1256, 1228, 1126, 1059 cm-1; 1H NMR (DMSO-d6, 300 MHz): δ 3.8-4.0 (m, 8H), 4.14.2 (m, 8H), 6.7-8.3(m, 14H), 8.4(dd, 2H), 8.6(dd, 2H); 13C NMR (DMSO-d6): δ 196.30, 151.80, 147.34, 131.61, 129.89, 129.65, 123.09, 120.72, 111.86, 110.31, 79.31, 79.13, 68.73, 67.09, 40.11, 39.91, 26.26. Anal. Calcd. C38H34N2O12: C, 64.24; H, 4.83; N, 3.94. Found: C, 64.20; H, 4.83; N, 3.91%. General procedure for the synthesis of 4a-f. A mixture of 4,4′-di (acrylophenonyl) dibenzo-18crown-6 3 (0.5 mmol) and hydrazine hydrate (1 mmol) in 5 mL methanol was mechanically stirred at 60°C for 3 hr. Iodine (0.5 mmol) was added to the reaction mixture and resulting mixture was poured into crushed ice and treated with sodium sulphite. The precipitate was filtered, dried and recrystallised from ethanol. 4,4′-Di [3-(5-phenyl)-1H pyrazole] dibenzo-18crown-6, 4a. Pale yellow solid; m.p. 130°C; Yield: 60%, IR (KBr): 2924 (CH), 1596, 1515, 1450, 1265, 1137, 1056 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.3

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(br s, 2H), 3.8-4.1 (m, 8H), 4.2-4.4 (m, 8H), 6.5-8.0 (m, 18H); 13C NMR (CDCl3): δ 200.70, 199.89, 199.39, 197.02, 148.36, 128.91, 128.82, 128.64, 126.95, 126.35, 125.76, 125.55, 113.10, 69.59, 68.28, 43.69, 39.76. Anal. Calcd. For C38H36N4O6: C, 70.69; H, 5.63; N, 8.68. Found: C, 70.64; H, 5.60; N 8.62%. 4,4′-Di [3-(5-(4-chloro-phenyl))-1H pyrazole] dibenzo-18-crown-6, 4b. Yellow solid; m.p. 135°C; Yield: 63%, IR (KBr): 2925 (CH), 1595, 1508, 1430, 1321, 1258, 1134, 1056 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.4 (br s, 2H), 3.9-4.0 (m, 8H), 4.1-4.2 (m, 8H), 6.6-7.9 (m, 16H); 13C NMR (CDCl3): δ 202.06, 182.14, 179.36, 153.38, 152.12, 148.84, 142.03, 138.49, 136.48, 133.70, 121.34, 113.27, 111.25, 92.33, 69.90, 69.57, 69.46, 68.57, 68.34, 68.25, 36.38, 31.16. Anal. Calcd. C38H34N4O6Cl2: C, 64.01; H, 4.81; N, 7.86. Found: C, 63.90; H, 4.79; N, 7.81%. 4,4′-Di [3-(5-(2-chloro-phenyl))-1H pyrazole] dibenzo-18-crown-6, 4c. Yellow solid; m.p. 134°C; Yield: 62%, IR (KBr): 2925 (CH), 1595, 1508, 1430, 1321, 1220, 1133, 1056 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.3 (br s, 2H), 3.9-4.0 (m, 8H), 4.1-4.2 (m, 8H), 6.6-7.6 (m, 16H); 13C NMR (CDCl3): δ 200.06, 181.10, 175.06, 152.83, 152.12, 147.84, 140.30, 138.49, 135.48, 133.01, 120.43, 111.27, 111.25, 92.33, 68.90, 68.50, 68.06. Anal. Calcd. C38H34N4O6Cl2: C, 64.01; H, 4.81; N, 7.86. Found: C, 64.00; H, 4.75; N 7.82%. 4,4′-Di [3-(5-(4-fluro-phenyl))-1H pyrazole] dibenzo-18-crown-6, 4d. Yellow solid; m.p. 130°C; Yield: 61%, IR (KBr): 2926 (CH), 1597, 1505, 1454, 1430, 1326, 1254, 1127, 1060 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.0 (br s, 2H), 3.8-4.0 (m, 8H), 4.1-4.2 (m, 8H), 6.7-7.8 (m, 16H); 13C NMR (CDCl3): δ 188.52, 148.55, 148.41, 135.16, 133.47, 130.98, 129.72, 128.64, 121.16, 112.06, 111.00, 69.76, 69.43, 69.33, 68.52, 68.45, 68.10, 36.48, 31.42. Anal. Calcd. C38H34N4O6F2: C, 67.01; H, 5.04; N, 8.23. Found: C, 66.98; H 4.99; N, 8.19%. 4,4′-Di [ 3-(5-(4-NN′-dimethyl phenyl))-1H pyrazole] dibenzo-18-crown-6, 4e. Yellow solid; m.p. 131°C; Yield: 60%; IR (KBr): 2923 (CH), 1596, 1523, 1433, 1364, 1257, 1181, 1130, 1058 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.0 (s, 12H),3.1 (br s, 2H), 3.9-4.1 (m, 8H), 4.1-4.3 (m, 8H), 6.6-7.9 (m, 16H); 13C NMR (CDCl3): δ 190.12, 186.08, 162.35, 157.52, 154.66, 148.14, 132.10, 128.84, 120.23, 113.71, 111.75, 110.97, 106.15, 77.94, 77.51, 77.08, 69.37, 67.29, 34.43, 29.47, 27.38, 26.08. Anal Calcd. C42H46N6O6: C, 68.94; H, 6.35; N,11.49. Found: C, 68.90; H, 6.31; N, 11.42%.

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4,4′-Di [3-(5-(3-Nitro-phenyl))-1H pyrazole] dibenzo-18-crown-6, 4f. Pale yellow solid; m.p. 134°C; Yield: 62%, IR (KBr): 2924 (CH), 1596, 1515, 1450, 1265, 1137, 1056 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.1 (br s, 2H), 3.8-4.0 (m, 8H), 4.1-4.3 (m, 8H), 6.7-8.9 (m, 16H); 13C NMR (CDCl3): δ 183.34, 175.61, 170.74, 168.41, 162.26, 159.93, 156.33, 154.50, 148.28, 140.37, 134.87, 131.90, 129.08, 112.14, 88.67, 83.87, 83.43, 83.00, 70.68, 60.77, 57.38, 54.25, 40.69, 39.12, 30.77, 24.52. Anal Calcd. C38H34N6O10: C, 62.12; H, 4.67; N, 11.44. Found: C, 62.09; H, 4.63; N, 11.39%. Conclusion In conclusion, an efficient synthesis of various novel pyrazole derivatives, important class of pharmaceuticals, was accomplished via condensation of hydrazine with 1,3 dielectrophile in the presence of iodine as an efficient oxidizing agent. Iodine is much less expensive than other oxidizing agents. This convenient approach shortened the reaction time and utilized readily available aromatic aldehydes and hydrazine to assemble C-N bond in a simple sequential heterocyclisation experimental protocol. Obtaining good yields, easy work up procedure and shorter reaction time to construct useful heterocycles, are some of the salient features of this approach. Acknowledgements One of the authors is thankful to DST-PURSE and UGC for fellowship. The authors are thankful to DST for FIST and UGC for SAP. References 1 Comrehensive Heterocyclic Chemistry, edited by A R Katritzky, C W Rees & E F V Scriven (Pergamon, Oxford), 1996, 5. 2 Cottineau B, Toto P & Pipaud C, J Bioorg Med Chem Lett, 12, 2002, 2105. 3 Lee K Y & Kim J N, Tetrahedron Lett, 44, 2003, 6737.

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