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. 2003 Jul 31;8(8):642–648. doi: 10.3390/80800642

Microwave-Assisted Synthesis of Some 3,5-Arylated 2-Pyrazolines

Davood Azarifar 1,*, Hassan Ghasemnejad 1
PMCID: PMC6146882

Abstract

Condensation of 2-acetylnaphthalene with benzaldehydes under microwave irradiation affords chalcones which undergo facile and clean cyclizations with hydrazines RNHNH2 (R= H, Ph, Ac) to afford 3,5-arylated 2-pyrazolines in quantitative yields, also under microwave irradiation and in the presence of dry AcOH as cyclizing agent. The results obtained indicate that, unlike classical heating, microwave irradiation results in higher yields, shorter reaction times (2-12 min.) and cleaner reactions.

Keywords: Microwave irradiation; chalcones; 3,5-arylated-2-pyrazolines; pyrazolines; heterocyclic synthesis

Introduction

Variously substituted pyrazolines and their derivatives are important biological agents and a significant amount of research activity has been directed towards this class. In particular, they are used as antitumor [1], antibacterial, antifungal, antiviral, antiparasitic, anti-tubercular and insecticidal agents [2,3,4,5,6,7,8,9,10]. Some of these compounds have also anti-inflammatory, anti-diabetic, anaesthetic and analgesic properties [11,12,13,14]. Moreover, pyrazolines have played a crucial part in the development of theory in heterocyclic chemistry and also used extensively as useful synthons in organic synthesis [15,16,17,18,19]. A classical synthesis of these compounds involves the base-catalyzed aldol condensation reaction of aromatic ketones and aldehydes to give α,β-unsaturated ketones (chalcones), which undergo a subsequent cyclization reaction with hydrazines affording 2-pyrazolines [11,20,21,22]. In this method, hydrazones are formed as intermediates, which can be subsequently cyclized to 2-pyrazolines in the presence of a suitable cyclizing reagent like acetic acid [23,24].

In recent years, a significant portion of research in heterocyclic chemistry has been devoted to 2-pyrazolines containing different aryl groups as substituents, as evident from the literature [25,26,27,28,29,30,31,32,33]. We have recently reported on the synthesis of some newly 3,5-naphthylated 2-pyrazolines which exhibit efficient antimicrobial activity against a variety of test organisms [8].

Results and Discussion

As a result of our studies related to the development of synthetic protocols using microwave irradiation, we now report a novel and easy access to 3,5-arylated 2-pyrazolines using a one-pot procedure and demonstrate its superiority over our previously reported classical heating method [8]. We report in this paper some aldol condensation reactions between 2-acetylnaphthalene (1) and benzaldehydes 2a-e in the presence of KOC2H5/C2H5OH to give intermediate chalcones 3a-e which undergo a rapid cyclization with hydrazines 4f-h under microwave irradiation at 80 ºC to yield 2-pyrazolines 5af-eh quantitatively in 2-12 minutes (Scheme 1). The heterocyclic products were characterized on the basis of their IR, 1H-NMR, 13C-NMR, MS spectral and elemental analysis (Table 2).

Scheme 1.

Scheme 1

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Table 2.

IR, 1H-NMR and MS (EI) spectral data of the 2-pyrazoline products

Compound IR (cm-1) 1H-NMR (ppm) MS (m/z)
5af 3068, 2975, 1660, 1620, 1580, 1484, 1337, 1638, 806 2.38 (s, 3H, Me), 2.46 (s, 3H, COMe), 3.16 (dd, J = 18.2, 5.1 Hz, 1H, CH2(Pyraz) ), 3.80 (dd, J = 18.2, 11.8 Hz, 1H, CH(Pyraz) ), 5.91 (dd, J = 11.8, 5.1 Hz, 1H, CH2(Pyraz) ), 7.12 (s, 4H, Ph ), 7.25-8.00 (m, 7H, Naph) 57, 71, 77, 91, 127, 153, 255, 285, 286, 328, 329
5ag 3178, 2938, 2813,1600, 1500, 1100, 870, 820, 750 2.40 (s, 3H, Me), 3.05 (dd, J = 16.9, 8.4 Hz, 1H, CH2(Pyraz) ), 3.82 (dd, J = 16.9, 12.0 Hz, 1H, CHPyraz), 5.29 (dd, J = 12.0, 8.4 Hz, 1H, CH2(Pyraz) ), 6.60 - 8.20 (m, 16H, Ar) 42, 77, 91, 101, 118, 125, 127, 153, 167, 244, 271, 362
5ah 3500, 3350, 3115, 2985, 1675, 1580, 1500, 1160, 855, 760 2.23 (s, 3H, Me), 3.26 (dd, J = 18.3, 5.8 Hz, 1H, CH2(Pyraz) ), 3.77 (dd, J = 18.3, 12.4 Hz, 1H, CHPyraz), 5.33 (bs, 2H, NH2), 5.50 (dd, J = 12.4, 5.8 Hz, 1H, CH2(Pyraz) ), 7.08 (s, 4H, Ph ), 7.20 - 8.00 (m, 7H, Naph ) 42, 77, 91, 101, 127, 169, 153, 118, 195, 238, 285, 313, 329
5bf 3065, 2915, 1670, 1590, 1470, 1450, 1330, 1150, 975, 865, 745, 630 2.42 (s, 3H, Me), 2.52 (s, 3H, COMe), 3.16 (dd, J = 18.0, 5.2 Hz, 1H, CH2(Pyraz) ), 3.83 (dd, J =18.0, 12.0 Hz, 1H, CHPyraz), 5.92 (dd, J = 12.0, 5.20 Hz, 1H, CH2(Pyraz) ), 7.10-8.10 (m, 10H, Ar) 57, 71, 77, 112, 127, 138, 154, 271, 237, 277, 279, 294, 292, 305, 307, 308, 348, 350
5bg 3058, 2883, 1594, 1500, 1460, 1325, 1120, 1050, 865, 745, 700 2.38 (s, 3H, Me), 3.14 (dd, J = 16.6, 8.1 Hz, 1H, CH2(Pyraz) ), 4.11 (dd, J = 16.6, 11.6 Hz, 1H, CHPyraz), 5.58 (dd, J = 11.6, 8.1 Hz, 1H, CH2(Pyraz) ), 6.50 - 8.20 (m, 15H, Ar) 77, 91, 101, 113, 111, 127, 138, 140, 153, 167, 244, 271, 382, 384
5bh 3450, 3250, 3085, 2965, 1680, 1580, 1478, 1240, 1075, 820, 750 2.28 (s, 3H, Me), 3.33 (dd, J = 16.6, 5.8 Hz, 1H, CH2(Pyraz) ), 3.89 (dd, J = 16.6, 12.2 Hz, 1H, CHPyraz), 5.38 (bs, 2H, NH2), 5.60 (dd, J = 12.2, 5.8 Hz, 1H, CH2(Pyraz) ), 7.26 (s, 3H, Ph ), 7.38 - 8.20 (m, 7H, Naph) 42, 91, 115,127, 153, 169, 196, 195, 249, 305, 307, 349, 351
5cf 3048, 2980, 1665, 1600, 1500, 1475, 1452, 1195, 986, 735, 640 2.42 (s, 3H, COMe), 3.12 (dd, J = 18.0, 6.20 Hz, 1H, CH2(Pyraz) ), 3.78 (dd, J = 18.0, 12.6 Hz, 1H, CHPyraz ), 5.95 (dd, J = 18.0, 6.2 Hz, 1H, CH2(Pyraz) ), 7.20 (s, 4H, Ph ), 7.32 - 8.30 (m, 7H, Naph) 57, 77, 114, 127, 138, 153, 271, 237, 277, 276, 294, 292, 306, 307, 308, 348, 349, 350
5cg 3072, 2918, 1600, 1500, 1360, 1135, 825, 730 3.18 (dd, J = 16.6, 8.5 Hz, 1H, CH2(Pyraz) ), 3.83
(dd, J = 16.6, 11.4 Hz, 1H, CHPyraz ), 5.18 (dd, J = 11.4, 8.5 Hz, 1H, CH2(Pyraz) ), 6.60 - 8.20 (m, 16H, Ar)		 77, 91, 101, 113, 127, 139, 140, 153, 168, 244, 271, 382, 383, 384
5ch 3420, 3300, 3120, 2900, 1675, 1582, 1487, 1500, 1220, 1085, 820, 745 3.25 (dd, J= 17.4, 6.4 Hz, 1H, CH2(Pyraz) ), 3.81 (dd, J = 17.4, 12.2 Hz, 1H, CHPyraz ), 5.35 (bs, 2H, NH2), 5.48 (dd, J = 12.2, 6.4 Hz, 1H, CH2(Pyraz) ), 7.18 (s, 4H, Ph ), 7.30 - 8.10 (m, 7H, Naph ) 42, 77, 101, 115, 127, 153, 169, 196, 195, 228, 293, 305, 307, 349, 351
5df 3068, 2887, 2838, 1670, 1600, 1495, 1448, 1120, 1095, 954, 740 2.45 (s, 3H, COMe), 3.25 (dd, J = 18.1, 5.8 Hz, 1H, CH2(Pyraz) ), 3.75 (s, 3H, OMe), 3.82 (dd, J = 18.1, 12.2 Hz, 1H, CHPyraz), 5.54 (dd, J = 12.2, 5.8 Hz, 1H, CH2(Pyraz)), 6.82 (d, J = 9.5 Hz, 2H, 3-HPh), 7.20 (d, J = 9.5 Hz, 2H, 2-HPh ), 7.50 - 8.10 (m, 7H, Naph ) 57, 77, 101, 108, 127, 134, 153, 167, 274, 301, 329, 344, 345
5dg 3150, 2880, 1600, 1495, 1410, 1350, 1240, 1115, 1035, 820, 740 3.29 (dd, J = 17.8, 6.0 Hz, 1H, CH2(Pyraz)), 3.82 (dd, J = 17.8, 12.0 Hz, 1H, CHPyraz), 3.70 (s, 3H, Me), 5.18 (dd, J = 12.0, 6.0 Hz, 1H, CH2(Pyraz) ), 6.60 - 8.20 (m, 16H, Ar) 77, 107, 127, 134, 153, 154, 167, 244, 271, 378
5dh 3480, 3375, 3150, 2900, 1685, 1580, 1520, 1490, 1250, 1070, 865, 750 3.27 (dd, J = 18.1, 5.0 Hz, 1H, CH2(Pyraz)), 3.69 (s, 3H, Me), 3.78 (dd, J = 18.1, 11.2 Hz, 1H, CHPyraz), 5.40 (bs, 2H, NH2), 5.52 (dd, J = 11.2, 5.0 Hz, 1H, CH2(Pyraz) ), 6.77 (d, J = 9.8 Hz, 2H, 3-HPh ), 7.15 (d, J = 9.8 Hz, 2H, 2-HPh ), 7.30 - 8.00 (m, 7H, Naph ) 77, 91, 121,134, 149,153, 169, 191, 195, 303, 302, 345, 346
5ef 3087, 2983, 2810, 1657, 1648, 1615, 1595, 1340, 1075, 815 2.43 (s, 3H, COMe), 2.83 (s, 6H, NMe2), 3.12 (dd, J = 15.9, 7.9 Hz, 1H, CH2(Pyraz) ), 3.75 (dd, J = 15.9, 11.8 Hz, 1H, CHPyraz ), 5.85 (dd, J = 11.8, 7.9 Hz, 1H, CH2(Pyraz) ), 7.35 (d, J = 9.6 Hz, 2H, 3-HPh ), 7.63 (d, J = 9.6 Hz, 2H, 2-HPh ), 7.80 - 8.10 (m, 7H, Naph) 44, 77, 101, 110, 127,
137, 153, 167, 195, 237, 313, 314, 342, 357
5eg 3134, 3006, 2871, 1616, 1594, 1523, 1453, 1117, 865, 826, 747 2.79 (s, 6H, NMe2), 3.15 (dd, J = 15.5, 8.1 Hz, 1H, CH2(Pyraz) ), 3.71 (dd, J = 15.5, 11.2 Hz, 1H, CHPyraz ), 5.09 (dd, J = 11.2, 8.1 Hz, 1H, CH2(Pyraz) ), 6.30 - 8.20 (m, 16H, Ar) 48, 64, 77, 91, 120, 121, 134, 147, 153, 171, 244, 271, 389, 391, 392, 393
5eh 3120, 2818, 1660, 1635, 1600, 1589, 1348, 1150, 845, 650 2.81 (s, 6H, NMe2), 3.26 (dd, J = 15.0, 8.2 Hz, 1H, CH2(Pyraz) ), 3.82 (dd, J = 15.0, 12.2 Hz, 1H, CHPyraz), 5.36 (bs, 2H, NH2), 5.68 (dd, J = 12.2, 8.2 Hz, 1H, CH2(Pyraz) ), 7.21 (d, J = 10.3 Hz, 2H, 3-HPh ), 7.58 (d, J = 10.3 Hz, 2H, 2-HPh ), 7.70 - 8.10 (m, 7H, Naph ) 42, 77, 120, 127, 147, 153, 154, 169, 191, 195, 314, 358
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Conclusions

In summary, this work demonstrates a rapid, efficient and environmentally friendly method of synthesis of 3,5-arylated 2-pyrazolines under microwave heating, and the results obtained confirm the superiority of the microwave irradiation method over the classical heating one.

Experimental

General

All melting points were determined on a Büchi 530 melting point apparatus, and are uncorrected. The 1H-NMR spectra were recorded for deuteriochloroform solutions using tetramethylsilane as the internal standard on Jeol FX (at 90 MHz) and Brüker AM (at 200 MHz) spectrometers at ambient temperature. IR spectra were recorded on a Shimadzu IR-435U-04 instrument using potassium bromide pellets. Elemental analyses were performed at the Iran Polymer Research Center, Karaj, Iran.

General procedure for microwave-assisted preparation of 3,5-diaryl-2-pyrazoline derivatives (5af-eh)

In the first step the chalcones 3a-e are prepared by the reaction between 2-acetylnaphthalene (1.70 g, 10 mmol), dissolved in 1M KOC2H5/C2H5OH solution (10 mL), and the corresponding benzaldehyde (10 mmol) under microwave irradiation (300 watt) for a few min. The resulting crude yellow solid is filtered, washed successively with dilute HCl solution and distilled water and finally recrystallized from ethanol (95%) to give the pure chalcones 3a-e in 80-95 % yield. In the second step, the hydrazine reagent (12 mmol) is then added dropwise to a stirring solution of the chalcones 3a-e (10 mmol) in glacial AcOH (10 mL). The mixture is subjected to microwave heating for several min. using a domestic microwave oven (300 watt) to afford 2-pyrazolines, which were recrystallized from ethanol (95%) to give pure compounds 5af-eh with a 82-99% yield. Analytical data for the prepared compounds is given in Table 1. Spectroscopic data is summarized in Table 2.

Table 1.

Microwave synthesis of 3,5-arylated 2-pyrazolines (5af-eh) (power = 300 W)

Compound Molecular
Formula 		Irradiation
Time (min)		 Yielda
(%)		 M.P.
(ºC)		 Elemental Analysis
Calcd (found)
C H N
5af C22H20ON2 7 85 175-176 80.49 (80.71) 6.10 (6.29) 8.54 (8.59)
5ag C26H22N2 1.4 98 167-168 86.19 (86.35) 6.08 (6.04) 7.73 (7.82)
5ah C21H19ON3 7 88 182-183 76.60 (76.74) 5.77 (5.84) 12.76 (12.72)
5bf C22H19ON2Cl 2.3 96 172-173 72.83 (72.70) 5.24 (5.29) 7.72 (7.54)
5bg C26H21N2Cl 1.7 98 131-132 78.69 (78.99) 5.30 (5.43) 7.06 (6.83)
5bh C21H18ON3 Cl 6.4 82 162-164 69.32 (69.38) 4.95 (4.82) 11.55 (11.54)
5cf C21H17ON2Cl 1.5 99 177-178 72.31 (72.34) 4.88 (4.85) 8.03 (8.16)
5cg C25H19N2Cl 1.4 98 129-130 78.43 (78.58) 4.97 (5.12) 7.32 (7.52)
5ch C20H16ON3Cl 11 85 180-182 68.67 (68.87) 4.58 (4.67) 12.02 (11.88)
5df C22H20O2N2 1.3 98 186-187 76.74 (76.93) 5.81 (5.59) 8.14 (8.54)
5dg C26H22ON2 1.2 98 135-136 82.54 (82.51) 5.82 (5.72) 7.41 (7.48)
5dh C21H19 O2N3 7.5 86 173-175 73.04 (73.12) 5.51 (5.46) 12.17 (12.21)
5ef C23H23ON3 4.5 85 183-184 77.31 (77.42) 6.44 (6.48) 11.76 (11.79)
5eg C27H25N3 2.2 99 185-186 82.86 (82.83) 6.39 (6.41) 10.74 (10.78)
5eh C22H22ON4 6.8 86 192-193 73.74(73.87) 6.14(6.34) 15.64(15.28)
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a Yields of isolated products, calculated on the basis of the chalcones 3a-e.

Acknowledgements

The authors wish to acknowledge the financial support of the Bu-Ali Sina University, Chemistry Department, to carry out this research.

Footnotes

Sample Availability: Available from the authors.

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