Microwave-assisted synthesis of some 3,5-arylated 2-pyrazolines

Article abstract of DOI:10.3390/80800642

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,

Full text of DOI:10.3390/80800642

Molecules 2003, 8, 642-648
molecules
ISSN 1420-3049
http://www.mdpi.org
Microwave-Assisted Synthesis of Some 3,5-Arylated
2-Pyrazolines
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; e-mail azarifar@basu.ac.ir
Received: 21 February 2003; in revised form: 28 July 2003 / Accepted: 30 July 2003/ Published: 31
July 2003
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
[2-10]. Some of these compounds have also anti-inflammatory, anti-diabetic, anaesthetic and analgesic
properties [11-14]. 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 [15-19]. A
classical synthesis of these compounds involves the base-catalyzed aldol condensation reaction of

Molecules 2003, 8
643
aromatic ketones and aldehydes to give α,β-unsaturated ketones (chalcones), which undergo a
subsequent cyclization reaction with hydrazines affording 2-pyrazolines [11, 20-22]. 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 [25-33].
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
º
undergo a rapid cyclization with hydrazines 4f-h under microwave irradiation at 80 C 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
CHO
R
1
COCH
3
KOEt/EtOH
MWI
+
R
2
1
2
R
3
N
N
O
C
H
AcOH
MWI,
CH CH
R
R NHNH
2
+
3
2
o
80 C
4f - h
R
R
H
1
R
H
1
2
3a - e
*f R3 = H
g R3 = Ph
h R3 = CONH2
a R1 = H, R2 = Me
b R1 = Cl, R2 = Me
c R1 = H, R2 =Cl
5af - eh
d R1 = H, R2 = OMe
e R1 = H, R2 = NMe2
*
Acetylation, in situ, occurs in the presence of AcOH to convert the initially formed 2-pyrazolines (R = H) mainly into
3
their acetylated derivatives (R = COCH ).
3
3

Molecules 2003, 8
644
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.
Acknowledgements
The authors wish to acknowledge the financial support of the Bu-Ali Sina University, Chemistry
Department, to carry out this research.
Experimental
General
All melting points were determined on a Büchi 530 melting point apparatus, and are uncorrected.
1
The H-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.

Molecules 2003, 8
645
Table 1. Microwave synthesis of 3,5-arylated 2-pyrazolines (5af-eh) (power = 300 W)
Irradiation
Time
Elemental Analysis
Calcd (found)
Molecular
Formula
Yielda M.P.
Compound
(%)
(ºC)
(min)
7
C
H
N
5af
5ag
5ah
5bf
5bg
5bh
5cf
C22H20ON2
C26H22N2
85
175-
176
80.49
6.10
8.54
(80.71) (6.29)
86.19 6.08
(86.35) (6.04)
76.60 5.77
(8.59)
7.73
1.4
7
98
88
96
98
82
99
98
85
98
98
86
85
99
86
167-
168
(7.82)
12.76
C21H19ON3
C22H19ON2Cl
C26H21N2Cl
182-
183
(76.74) (5.84) (12.72)
2.3
1.7
6.4
1.5
1.4
11
172-
173
72.83
(72.70) (5.29)
78.69 5.30
(78.99) (5.43)
69.32 4.95
5.24
7.72
(7.54)
7.06
131-
132
(6.83)
11.55
C21H18ON3
Cl
162-
164
(69.38) (4.82) (11.54)
C21H17ON2Cl
177-
178
72.31
(72.34) (4.85)
78.43 4.97
(78.58) (5.12)
68.67 4.58
4.88
8.03
(8.16)
7.32
5cg
5ch
5df
5dg
5dh
5ef
C25H19N2Cl
C20H16ON3Cl
C22H20O2N2
C26H22ON2
C21H19 O2N3
C23H23ON3
C27H25N3
129-
130
(7.52)
12.02
180-
182
(68.87) (4.67) (11.88)
1.3
1.2
7.5
4.5
2.2
6.8
186-
187
76.74
(76.93) (5.59)
82.54 5.82
(82.51) (5.72)
73.04 5.51
5.81
8.14
(8.54)
7.41
135-
136
(7.48)
12.17
173-
175
(73.12) (5.46) (12.21)
77.31 6.44 11.76
(77.42) (6.48) (11.79)
82.86 6.39 10.74
(82.83) (6.41) (10.78)
73.74 6.14 15.64
(73.87) (6.34) (15.28)
183-
184
5eg
5eh
185-
186
C22H22ON4
192-
193
a Yields of isolated products, calculated on the basis of the chalcones 3a-e.

Molecules 2003, 8
Table 2. IR, 1H-NMR and MS (EI) spectral data of the 2-pyrazoline products
646
IR (cm-1)
1H-NMR (ppm)
MS (m/z)
57, 71, 77, 91, 127, 153,
Compound
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, 11.8 255, 285, 286, 328, 329
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)
5ag
5ah
3178, 2938,
2813,1600, 1500,
1100, 870, 820, 750
2.40 (s, 3H, Me), 3.05 (dd, J = 16.9, 8.4 Hz, 1H,
42, 77, 91, 101, 118, 125,
CH2(Pyraz) ), 3.82 (dd, J = 16.9, 12.0 Hz, 1H, CHPyraz), 127, 153, 167, 244, 271, 362
5.29 (dd, J = 12.0, 8.4 Hz, 1H, CH2(Pyraz) ), 6.60 -
8.20 (m, 16H, Ar)
3500, 3350, 3115,
2985, 1675, 1580,
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), 153, 118, 195, 238, 285,
42, 77, 91, 101, 127, 169,
1500, 1160, 855, 760 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 )
313, 329
5bf
5bg
5bh
3065, 2915, 1670,
1590, 1470, 1450,
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
57, 71, 77, 112, 127, 138,
154, 271, 237, 277, 279,
294, 292, 305, 307, 308,
348, 350
1330, 1150, 975, 865, Hz, 1H, CHPyraz), 5.92 (dd, J = 12.0, 5.20 Hz, 1H,
745, 630
3058, 2883, 1594,
1500, 1460, 1325,
CH2(Pyraz) ), 7.10-8.10 (m, 10H, Ar)
2.38 (s, 3H, Me), 3.14 (dd, J = 16.6, 8.1 Hz, 1H,
77, 91, 101, 113, 111, 127,
CH2(Pyraz) ), 4.11 (dd, J = 16.6, 11.6 Hz, 1H, CHPyraz), 138, 140, 153, 167, 244,
1120, 1050, 865, 745, 5.58 (dd, J = 11.6, 8.1 Hz, 1H, CH2(Pyraz) ), 6.50 -
271, 382, 384
700
8.20 (m, 15H, Ar)
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,
42, 91, 115,127, 153, 169,
CH2(Pyraz) ), 3.89 (dd, J = 16.6, 12.2 Hz, 1H, CHPyraz), 196, 195, 249, 305, 307,
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)
349, 351
5cf
5cg
5ch
5df
3048, 2980, 1665,
1600, 1500, 1475,
2.42 (s, 3H, COMe), 3.12 (dd, J = 18.0, 6.20 Hz, 1H, 57, 77, 114, 127, 138, 153,
CH2(Pyraz) ), 3.78 (dd, J = 18.0, 12.6 Hz, 1H, CHPyraz ), 271, 237, 277, 276, 294,
1452, 1195, 986, 735, 5.95 (dd, J = 18.0, 6.2 Hz, 1H, CH2(Pyraz) ), 7.20 (s,
292, 306, 307, 308, 348,
349, 350
640
4H, Ph ), 7.32 - 8.30 (m, 7H, Naph)
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
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 42, 77, 101, 115, 127, 153,
= 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 )
169, 196, 195, 228, 293,
305, 307, 349, 351
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, 344, 345
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,

Molecules 2003, 8
647
Table 2. Cont.
Compounds
5dg
IR (cm-1)
1H-NMR (ppm)
MS (m/z)
3150, 2880, 1600,
1495, 1410, 1350,
1240, 1115, 1035,
820, 740
3480, 3375, 3150,
2900, 1685, 1580,
1520, 1490, 1250,
1070, 865, 750
3.29 (dd, J = 17.8, 6.0 Hz, 1H, CH2(Pyraz)), 3.82 (dd, J 77, 107, 127, 134, 153, 154,
= 17.8, 12.0 Hz, 1H, CHPyraz), 3.70 (s, 3H, Me), 5.18 167, 244, 271, 378
(dd, J = 12.0, 6.0 Hz, 1H, CH2(Pyraz) ), 6.60 - 8.20 (m,
16H, Ar)
5dh
5ef
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 )
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)
2.79 (s, 6H, NMe2), 3.15 (dd, J = 15.5, 8.1 Hz, 1H,
77, 91, 121,134, 149,153,
169, 191, 195, 303, 302,
345, 346
3087, 2983, 2810,
1657, 1648, 1615,
1595, 1340, 1075,
815
44, 77, 101, 110, 127,
137, 153, 167, 195, 237,
313, 314, 342, 357
5eg
3134, 3006, 2871,
1616, 1594, 1523,
48, 64, 77, 91, 120, 121,
CH2(Pyraz) ), 3.71 (dd, J = 15.5, 11.2 Hz, 1H, CHPyraz ), 134, 147, 153, 171, 244,
1453, 1117, 865, 826, 5.09 (dd, J = 11.2, 8.1 Hz, 1H, CH2(Pyraz) ), 6.30 -
271, 389, 391, 392, 393
747
8.20 (m, 16H, Ar)
5eh
3120, 2818, 1660,
1635, 1600, 1589,
2.81 (s, 6H, NMe2), 3.26 (dd, J = 15.0, 8.2 Hz, 1H,
42, 77, 120, 127, 147, 153,
CH2(Pyraz) ), 3.82 (dd, J = 15.0, 12.2 Hz, 1H, CHPyraz), 154, 169, 191, 195, 314, 358
1348, 1150, 845, 650 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 )
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