One-pot synthesis of trisubstituted pyrazoles via multicomponent approach

Article abstract of DOI:10.1007/s10593-011-0779-z

An efficient one-pot multicomponent reaction for the synthesis of 1-aryl-or 1-heteryl-substituted 3,5-dimethylpyrazoles with excellent yields has been described. Reaction of 3-(2-bromoacetyl)coumarins or phenacyl bromides with acetylacetone and hydrazine

Full text of DOI:10.1007/s10593-011-0779-z

Chemistry of Heterocyclic Compounds, Vol. 47, No. 4, July 2011 (Russian original Vol. 47, No. 4, April, 2011)
ONE-POT SYNTHESIS OF TRISUBSTITUTED
PYRAZOLES VIA MULTICOMPONENT APPROACH
P. Santhosh1, V. S. R. Chunduru1, V. Rajeswar Rao1*
An efficient one-pot multicomponent reaction for the synthesis of 1-aryl- or 1-heteryl-substituted 3,5-di-
methylpyrazoles with excellent yields has been described. Reaction of 3-(2-bromoacetyl)coumarins or
phenacyl bromides with acetylacetone and hydrazine hydrate in ethanol afforded the corresponding
3,5-dimethylpyrazoles in good yields. All the synthesized compounds were characterized by their ana-
lytical and spectral data.
Keywords: acetylacetone, 3-(2-bromoacetyl)coumarins, hydrazine hydrate, phenacyl bromides, pyra-
zole, one-pot, multicomponent reactions.
A multicomponent reaction, offering a straightforward route to generate complexity and diversity in a
single operation, is an extremely powerful tool in combinatorial chemistry and drug discovery. Multicomponent
reactions play an important role in modern organic chemistry because they generally exhibit higher atom
economy and selectivity, as well as produce fewer by-products compared to classical multistep synthesis. In
many cases, multicomponent reactions are easy to perform, inexpensive, and quick, consume less energy, and
involve simple experimental procedures [1].
Pyrazoles are well-known and important nitrogen-containing heterocyclic compounds, and various
methods have been developed for their synthesis [2]. Due to the interesting biological activity of substituted
pyrazoles, considerable attention has been focused on this class of compounds.
Pyrazole derivatives have been found to possess antimicrobial [3], analgesic [4], immunosuppressive
[5], anticancer [6], antidiabetic [7], and anti-inflammatory [8] activity. On the other hand, coumarin and its
derivatives are biologically active compounds widely occurring in nature and are known to possess anti-
inflammatory activity [9].
In view of the various biological activities of coumarins and pyrazoles, we became interested in new
synthetic routes to pyrazoles incorporating the coumarin moiety.
As a part of our continuing work on the synthesis of novel heterocyclic systems [10–12], we have develo-
ped a novel one-pot reaction for the synthesis of 3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-2H-chromen-2-one
and 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-phenylethanone derivatives via a three-component reaction.
_____________
*To whom correspondence should be addressed; e-mail: vrajesw@yahoo.com.
1 Department of Chemistry, National Institute of Technology, Warangal-506 004, A.P, India.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 547–551, April, 2011. Original
article submitted December 28, 2010.
0009-3122/11/4704-0448©2011 Springer Science+Business Media, Inc.
448

Scheme 1
R
R
Me
Me
.
NH2NH2 H2O,
O
O
O
O
O
O
O
O
O
O
O
O
EtOH
+
+
Reflux
N
R1
R1
Br
N
Me
Me
Me
Me
1a–f
Me
.
NH2NH2 H2O,
O
O
O
EtOH
N
N
Reflux
Br
O
Me
1g
1 a R = R1 = H; b R = Br, R1 = H; c R = R1 = Br; d R = Cl, R1 = H; e R = R1 = Cl; f R = H, R1 = OMe
Scheme 2
Me
Me
.
NH2NH2 H2O,
R
R
O
O
EtOH
+
N
Reflux
N
Br
Me
O
O
Me
2a–e
2 a R = H; b R = Cl; c R = Br; d R = OMe; e R = NO2
TABLE 1. Analytical Data of Compounds 1a–g, 2a–e
Found, %
Calculated, %
Compound Empirical formula
mp, °C
Yield, %
C
H
N
1a
1b
1c
1d
1e
1f
C16H14N2O3
C16H13BrN2O3
C16H12Br2N2O3
C16H13ClN2O3
C16H12Cl2N2O3
C17H16N2O4
67.12
68.07
4.91
5.00
9.67
9.92
295
274
252
270
265
210
288
274
291
270
186
186
87
85
81
79
76
85
82
76
81
85
81
78
53.15
53.21
3.56
3.63
7.67
7.76
43.60
43.67
2.68
2.75
6.39
6.37
60.61
60.67
54.74
54.72
4.10
4.14
3.38
3.44
8.81
8.84
7.91
7.98
68.31
65.38
5.10
5.16
8.91
8.97
1g
2a
2b
2c
2d
2e
C20H16N2O3
72.21
72.28
4.80
4.85
8.38
8.43
C13H14N2O
72.81
72.87
6.51
6.59
12.96
13.07
C13H13ClN2O
C13H13BrN2O
C14H16N2O2
62.71
62.78
5.21
5.27
14.12
14.25
53.21
53.26
68.80
68.83
4.41
4.47
6.56
6.60
9.51
9.56
11.41
11.47
C13H13N3O3
60.18
60.22
4.97
5.05
16.16
16.21
449

TABLE 2. 1H and 13C* NMR Spectra of Compounds 1a–g, 2a–e
Compound
Chemical shift (CDCl3) δ, ppm (J, Hz)
1a
2.30 (3H, s, CH3); 2.39 (3H, s, CH3); 4.75 (2H, s, CH2); 6.20 (1H, s, H pyrazole);
7.60 (1H, d, J = 8.0, H Ar); 7.65–7.78 (2H, m, H Ar); 7.79 (1H, d, J = 8.0, H Ar);
8.65 (1H, s, H-4 coumarin)
1b
1c
1d
1e
1f
2.32 (3H, s, CH3); 2.39 (3H, s, CH3); 4.76 (2H, s, CH2); 5.96 (1H, s, H pyrazole);
8.21–8.32 (1H, m, H Ar); 8.43–8.51 (2H, m, H Ar); 8.65 (1H, s, H-4 coumarin)
2.28 (3H, s, CH3); 2.36 (3H, s, CH3); 4.71 (2H, s, CH2); 5.90 (1H, s, H pyrazole);
7.98 (1H, d, J = 2.0, H Ar); 8.15 (1H, d, J = 2.0, H Ar); 8.48 (1H, s, H-4 coumarin)
2.30 (3H, s, CH3); 2.37 (3H, s, CH3); 4.78 (2H, s, CH2); 5.92 (1H, s, H pyrazole);
7.40–7.56 (2H, m, H Ar); 7.92–8.00 (1H, m, H Ar); 8.21 (1H, s, H-4 coumarin)
2.30 (3H, s, CH3); 2.37 (3H, s, CH3); 4.75 (2H, s, CH2); 5.92 (1H, s, H pyrazole);
7.92 (1H, d, J = 2.0, H Ar); 8.22 (1H, d, J = 2.0, H Ar); 8.68 (1H, s, H-4 coumarin)
2.19 (3H, s, CH3); 2.22 (3H, s, CH3); 4.00 (3H, s, OCH3); 5.56 (2H, s, CH2);
5.90 (1H, s, H pyrazole); 7.22–7.30 (3H, m, H Ar); 8.57 (1H, s, H-4 coumarin)
1g
2a
2b
2c
2d
2e
2.30 (3H, s, CH3); 2.38 (3H, s, CH3); 4.78 (2H, s, CH2); 5.94 (1H, s, H pyrazole);
7.42–8.07 (5H, m, H Ar); 8.41–8.49 (1H, m, H Ar); 9.10 (1H, s, H-4 coumarin)
2.16 (3H, s, CH3); 2.24 (3H, s, CH3); 5.47 (2H, s, CH2); 5.92 (1H, s, H pyrazole);
7.49–7.53 (2H, m, H Ar); 7.61–7.65 (1H, m, H Ar); 7.97–7.99 (2H, m, H Ar)
2.08 (3H, s, CH3); 2.09 (3H, s, CH3); 5.67 (2H, s, CH2); 5.86 (1H, s, H pyrazole);
7.66 (2H, d, J = 8.0, H Ar); 8.05 (2H, d, J = 8.4, H Ar)
2.16 (3H, s, CH3); 2.23 (3H, s, CH3); 5.42 (2H, s, CH2); 5.91 (1H, s, H pyrazole);
7.64 (2H, d, J = 8.4, H Ar); 7.84 (2H, d, J = 8.4, H Ar)
2.16 (3H, s, CH3 ); 2.23 (3H, s, CH3); 3.88 (3H, s, OCH3); 5.40 (2H, s, CH2);
5.91 (1H, s, H pyrazole); 6.96 (2H, d, J = 8.8, H Ar); 7.96 (2H, d, J = 8.8, H Ar)
2.16 (3H, s, CH3); 2.23 (3H, s, CH3); 5.72 (2H, s, CH2); 6.41 (1H, s, H pyrazole);
8.22 (2H, d, J = 8.8, H Ar); 8.29 (2H, d, J = 8.8, H Ar)
__________________
13
* C NMR, δ, ppm: compound 1a (in CDCl3) – 10.8, 13.4, 103.7, 105.4,
116.1, 119.5, 120.9, 124.5, 128.1, 131.1, 136.7, 138.0, 139.1, 147.0, 152.6,
158.8; compound 2a (in DMSO-d6) – 10.5, 13.2, 55.1, 104.9, 128.1, 128.9,
133.9, 134.5, 140.1, 146.1, 193.9; compound 2b (in DMSO-d6) – 10.5,
13.3, 55.1, 105.0, 129.1, 130.1, 133.3, 138.9, 140.2, 146.4, 193.1.
TABLE 3. IR Spectra of Compounds 1a–g, 2a–e
, cm–1
Compound
C=C
CN
C=O
lactone C=O
1a*
1544
1546
1556
1558
1549
1566
1562
1582
1576
1587
1563
1554
1598
1600
1603
1609
1603
1606
1612
1617
1602
1607
1594
1602
1692
1687
1687
1679
1692
1691
1688
1690
1713
1691
1690
1718
1741
1731
1713
1728
1733
1722
1726
1b
1c
1d
1e
1f
1g
2a
2b
2c
2d*
2e
________
* Mass spectrum, m/z: compound 1a – [M+H]+ 283; compound 2a –
[M+H]+ 249.
450

Condensation of various 3-(2-bromoacetyl)coumarins and phenacyl bromides with hydrazine hydrate
and acetylacetone resulted in the formation of the cyclic products 1 and 2, respectively. We believe that in the
formation of the title products hydrazine hydrate first reacts with an α-halo carbonyl compound to give a
phenacyl hydrazine intermediate which further undergoes cyclocondensation with acetylacetone to close the
pyrazole ring. The pyrazoles of both series were obtained in good yields, which were not influenced by
substituents in coumarin or benzene rings. The structures of the newly prepared compounds have been
established on the basis of elemental analysis (Table 1) and spectral data (Table 2 and 3).
EXPERIMENTAL
Melting points were determined in open capillaries with a Cintex melting point apparatus and were un-
1
corrected. IR spectra (KBr) were recorded on a Thermo Nicolet Nexus 670 spectrometer. H and 13C NMR
spectra were recorded on a Bruker WM-400 spectrometer (400 and 100 MHz, respectively) using TMS as
internal standard. Mass spectra (EI-MS) were recorded on a Perkin-Elmer (SCIEX API-2000) at 12.5 eV.
Elemental analysis was done on a Carlo Erba EA 1108 automatic elemental analyzer. The purity of the
compounds was checked on TLC plates (E. Merck, Mumbai, India). All the reagents and solvents were
purchased from commercial sources and used without further purification. 3-(2-Bromoacetyl)coumarins were
prepared using literature procedure [13].
Synthesis of Compounds 1a–g and 2a–e (General Method). A solution containing an equimolar amount
of the appropriate 3-(2-bromoacetyl)coumarin or phenacyl bromide (1 mmol), hydrazine hydrate (0.048 ml,
1 mmol), and acetyl acetone (0.1 ml, 1 mmol) in ethanol (10 ml) was stirred at room temperature for 1 h and then
refluxed for 4 h. The reaction mixture was cooled to room temperature. The product was separated by filtration,
washed with water, and recrystallized from ethanol (compounds 1a–g) or methanol (compounds 2a–e).
The authors are thankful to the Director of the National Institute of Technology, Warangal, A. P., India,
for providing financial support and facilities.
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