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Article

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

by
Davood Azarifar
* and
Hassan Ghasemnejad
Department of Chemistry, Faculty of Science, Bu Ali- Sina University, Zip Code 65174, Hamadan, Iran
*
Author to whom correspondence should be addressed.
Molecules 2003, 8(8), 642-648; https://doi.org/10.3390/80800642
Submission received: 21 February 2003 / Revised: 28 July 2003 / Accepted: 30 July 2003 / Published: 31 July 2003
Browse Figure
Versions Notes

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.

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).
Molecules 08 00642 g001 550
Scheme 1.
Scheme 1.
Molecules 08 00642 g001

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
Table 1. Microwave synthesis of 3,5-arylated 2-pyrazolines (5af-eh) (power = 300 W)
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)
CHN
5afC22H20ON2785175-17680.49 (80.71)6.10 (6.29)8.54 (8.59)
5agC26H22N21.498167-16886.19 (86.35)6.08 (6.04)7.73 (7.82)
5ahC21H19ON3788182-18376.60 (76.74)5.77 (5.84)12.76 (12.72)
5bfC22H19ON2Cl2.396172-17372.83 (72.70)5.24 (5.29)7.72 (7.54)
5bgC26H21N2Cl1.798131-13278.69 (78.99)5.30 (5.43)7.06 (6.83)
5bhC21H18ON3 Cl6.482162-16469.32 (69.38)4.95 (4.82)11.55 (11.54)
5cfC21H17ON2Cl1.599177-17872.31 (72.34)4.88 (4.85)8.03 (8.16)
5cgC25H19N2Cl1.498129-13078.43 (78.58)4.97 (5.12)7.32 (7.52)
5chC20H16ON3Cl1185180-18268.67 (68.87)4.58 (4.67)12.02 (11.88)
5dfC22H20O2N21.398186-18776.74 (76.93)5.81 (5.59)8.14 (8.54)
5dgC26H22ON21.298135-13682.54 (82.51)5.82 (5.72)7.41 (7.48)
5dhC21H19 O2N37.586173-17573.04 (73.12)5.51 (5.46)12.17 (12.21)
5efC23H23ON34.585183-18477.31 (77.42)6.44 (6.48)11.76 (11.79)
5egC27H25N32.299185-18682.86 (82.83)6.39 (6.41)10.74 (10.78)
5ehC22H22ON46.886192-19373.74(73.87)6.14(6.34)15.64(15.28)
a Yields of isolated products, calculated on the basis of the chalcones 3a-e.
Table
Table 2. IR, 1H-NMR and MS (EI) spectral data of the 2-pyrazoline products
Table 2. IR, 1H-NMR and MS (EI) spectral data of the 2-pyrazoline products
CompoundIR (cm-1)1H-NMR (ppm)MS (m/z)
5af3068, 2975, 1660, 1620, 1580, 1484, 1337, 1638, 8062.38 (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
5ag3178, 2938, 2813,1600, 1500, 1100, 870, 820, 7502.40 (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
5ah3500, 3350, 3115, 2985, 1675, 1580, 1500, 1160, 855, 7602.23 (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
5bf3065, 2915, 1670, 1590, 1470, 1450, 1330, 1150, 975, 865, 745, 6302.42 (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
5bg3058, 2883, 1594, 1500, 1460, 1325, 1120, 1050, 865, 745, 7002.38 (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
5bh3450, 3250, 3085, 2965, 1680, 1580, 1478, 1240, 1075, 820, 7502.28 (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
5cf3048, 2980, 1665, 1600, 1500, 1475, 1452, 1195, 986, 735, 6402.42 (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
5cg3072, 2918, 1600, 1500, 1360, 1135, 825, 7303.18 (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
5ch3420, 3300, 3120, 2900, 1675, 1582, 1487, 1500, 1220, 1085, 820, 7453.25 (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
5df3068, 2887, 2838, 1670, 1600, 1495, 1448, 1120, 1095, 954, 7402.45 (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
5dg3150, 2880, 1600, 1495, 1410, 1350, 1240, 1115, 1035, 820, 7403.29 (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
5dh3480, 3375, 3150, 2900, 1685, 1580, 1520, 1490, 1250, 1070, 865, 7503.27 (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
5ef3087, 2983, 2810, 1657, 1648, 1615, 1595, 1340, 1075, 8152.43 (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
5eg3134, 3006, 2871, 1616, 1594, 1523, 1453, 1117, 865, 826, 7472.79 (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
5eh3120, 2818, 1660, 1635, 1600, 1589, 1348, 1150, 845, 6502.81 (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

Acknowledgements

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

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MDPI and ACS Style

Azarifar, D.; Ghasemnejad, H. Microwave-Assisted Synthesis of Some 3,5-Arylated 2-Pyrazolines. Molecules 2003, 8, 642-648. https://doi.org/10.3390/80800642

AMA Style

Azarifar D, Ghasemnejad H. Microwave-Assisted Synthesis of Some 3,5-Arylated 2-Pyrazolines. Molecules. 2003; 8(8):642-648. https://doi.org/10.3390/80800642

Chicago/Turabian Style

Azarifar, Davood, and Hassan Ghasemnejad. 2003. "Microwave-Assisted Synthesis of Some 3,5-Arylated 2-Pyrazolines" Molecules 8, no. 8: 642-648. https://doi.org/10.3390/80800642

APA Style

Azarifar, D., & Ghasemnejad, H. (2003). Microwave-Assisted Synthesis of Some 3,5-Arylated 2-Pyrazolines. Molecules, 8(8), 642-648. https://doi.org/10.3390/80800642

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