New and convenient route for the synthesis of some new pyrazol-5-yl-1H- imidazole derivatives

Article abstract of DOI:10.3987/COM-10-11984

A simple and efficient method for the synthesis of some new pyrazol-5-yl-1H-imidazoles 4a-h is described. In this method oxazolones 5a-h were produced as minor products. The X-ray analysis confirmed the structures of 4 and 5. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-11984

HETEROCYCLES, Vol. 81, No. 9, 2010
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HETEROCYCLES, Vol. 81, No. 9, 2010, pp. 2131 - 2138. © The Japan Institute of Heterocyclic Chemistry
Received, 26th May, 2010, Accepted, 6th July, 2010, Published online, 7th July, 2010
DOI: 10.3987/COM-10-11984
NEW AND CONVENIENT ROUTE FOR THE SYNTHESIS OF SOME
NEW PYRAZOL-5-YL-1H-IMIDAZOLE DERIVATIVES
Afsaneh Zonouzi,a Roghieh Mirzazadeh,a Marzieh Talebi,a Razieh
Jafarypoor,a Azadeh Peivandi,a and Seik Weng Ngb
aSchool of Chemistry, University College of Science, University of Tehran,
Tehran, Iran. E-mail:zonouzi@khayam.ut.ac.ir
bDepartment of Chemistry, University of Malaya, 50603 Kuala Lumpour,
Malaysia
Abstract - A simple and efficient method for the synthesis of some new pyrazol-
5-yl-1H-imidazoles 4a-h is described. In this method oxazolones 5a-h were
produced as minor products. The X-ray analysis confirmed the structures of 4 and
5.
The pyrazole derivatives are well known for their wide range of biological and pharmacological activities,
such as antibacterial, fungicidal, herbicidal, insecticidal, anti-HIV, antitumor and other biological
activities.1-8 Various methods have been reported for the synthesis of pyrazole derivatives.9-13 On the
other hand imidazole derivatives are frequently found in biological active natural products or
pharmaceutically important drugs. Some of them are useful as antitumor, antifungal, antimicrobial.14-16
There are some reports for the synthesis of imidazole derivatives.17-24 Imidazole derivatives were used
also as ligands in organomethalic compounds.25- 27
There are few reports on the synthesis of systems which contain the imidazole and pyrazole rings.5, 28
Here we wish to report a new and convenient route for the synthesis of pyrazol-5-yl-1H-imidazole
derivatives 4a-h under a one-pot and solvent-free conditions in 78-89 % yields. In this procedure
oxazolones 5a-h are produced as by-products in 8-15 % yields (Scheme 1, Table 1).
We have already reported one-pot and multicomponent synthetic procedures for the synthesis of some
heterocyclic compounds.29-33 In continuation of our request for developing one-pot procedure
heterocyclic frameworks, we here report a novel one-pot, multicomponent reaction of acetyl or
benzoylglycine 1 and benzaldehyde derivatives 2 and 1,3-diphenyl-1H-pyrazol-5-amine 334 in the

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HETEROCYCLES, Vol. 81, No. 9, 2010
presence of sodium acetate and acetic anhydride. It is well known that the reaction of acetyl or benzoyl
glycine 1, and benzaldehyde 2 in the presence of sodium acetate, acetic anhydride and heat afforded the
oxazolones 5.35,36 In this multicomponent reaction, the compounds 5a-h were produced as by-products in
8-15 % yields (their spectroscopic data have already been published36-43) and the pyrazol-5-yl-1H-
imidazoles 4a-h as the main products in 78 - 88% yields.
O
Ph
CHO
NaOAc, Ac2O
NH2
R1
N
CO2H
N
+
+
R2
H
N
, 24h
Ph
1
2
3
Ph
O
O
N
N
N
O
+
N
Ph
R2
N
R2
R1
R1
4
5
R1 = Me, Ph,
R2 = H, Cl, Br, NO2, Me, OMe
Scheme 1
Table 1. Yields of products 4 and 5.
Comp.
Entry 4, 5
R1
R2
Yield %
4
Yields %
5
a
b
c
d
e
f
Me
Me
Me
Me
Ph
H
85
82
83
78
84
85
89
85
1036,37
1038
839
1540
1036,41
1236,41
842
Cl
Br
NO2
H
Ph
Me
Br
g
h
Ph
Ph
OMe
843
Recrystalization of 4a in ethanol and 5a (4-benzylidine-2-methyloxazol-5-(4H)-one) in acetone gave the
single crystals suitable for X-ray analysis. X-ray crystal structures of 4a, 5a were performed to confirm
unambiguously their structures44 (Figures 1, 2).

HETEROCYCLES, Vol. 81, No. 9, 2010
2133
Figure 1: X-Ray crystal structure of 4a
Figure 2: X-Ray crystal structure of 5a
This procedure is optimized as following: To a mixture of acetyl- or benzoylglycine 1 and benzaldehydes
2, anhydrous sodium acetate in acetic anhydride were added gently at 0 °C and heated for 5-7 h. Then
1,3-diphenyl-1H-pyrazol-5-amine 3 was added to the reaction mixture and heated for 16-18 h. The
product 4 was purified by column chromatography and recrystalized from ethyl acetate or ethanol.
1
13
Structures 4 were assigned on the basis of their elemental analysis, IR, H, C NMR and MS data. The
MS of compounds 4a-h displayed molecular ion peaks at appropriate m/z values. For pyrazol-5-yl-1H-
imidazole derivatives 4, initial fragmentation involved the loss of the phenyls also pyrazole and imidazole
1
13
ring side groups. H NMR and C NMR spectra of 4a-h displayed resonances in agreement with their
structures.
In summary, we report an efficient multicomponent reaction for synthesis of some new pyrazol-5-yl-1H-
imidazole derivatives under a one-pot and solvent-free conditions. In this method novel extended π-
conjugated heterocyclic system with a pyrazole and imidazole rings were produced in fairly high yields.
Further investigations of this method are currently in progress to establish its scope and utility.
EXPERIMENTAL
Chemicals and solvents were obtained from Merck (Germany) and Fluka (Switzerland) and were used
without further purification. Compound 3 was synthesized according to the procedure.34 Isolation and
determination of the by-products 5a-h were according to references.36-43 Columns chromatography were
performed on silica Gel (0.015-0.04 mm, mesh-size) and TLC on precoated plastic sheets (25 DCUV-254
)
respectively. Melting points were measured on Barnstead Electrothermal melting point apparatus and
were not corrected. Elemental analyses for C, H and N were performed using a Thermo Finnigan Flash
EA1112 instrument. IR spectra were measured on a Bruker EQUINOX 55 spectrophotometer by ATR
1
13
method. H NMR and C NMR spectra were determined in CDCl3 on a Brucker 500 spectrophotometer

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HETEROCYCLES, Vol. 81, No. 9, 2010
and chemical shifts were expressed in ppm downfield from tetramethylsilane. Mass spectra were recorded
on a Finnigan-MAT 8430 spectrometer at an ionization potential of 70 ev.
General Procedure:
To a magnetically stirred mixture of acetyl- or benzoylglycine 1 (2mmol) and benzaldehyde derivatives 2
(2.5 mmol), anhydrous sodium acetate (3 mmol) in acetic anhydride (3 mmol) were added and heated for
5-7 h. Then 1, 3-diphenyl-1H-pyrazol-5-amine 3 (2 mmol) was added to the above mixture and was
heated for 16-18 h. The brown residue was purified by column chromatography using silica gel and
EtOAc: n-hexane (1:4) as co-solvent. The products 4a-h were recrystalized from EtOAc or EtOH.
4-Benzylidine-2-methyl-1-(1,3-diphenyl-1H-pyrazol-5-yl)-1H-imidazol-5(4H)-one (4a).
Light yellow crystals; mp 145 °C; νmax: 1724 (C=O), 1643, 1623 (C=N), 1524, 1500 (C-N) cm-1; δH (500
MHz, CDCl3): 2.14 (3H, s, CH3), 6.86 (1H, s, olefinic), 7.41-7.44, 7.47-7.49, 7.52-7.53, 7.94-7.96, 8.18-
8.20 (16H, 5m, aromatic and pyrazole); δC (125 MHz): 16.22 (CH3), 104.28 (olefinic), 124.28, 126.12,
128.97, 129.01, 129.20, 129.27, 130.05, 130.09, 131.21, 132.49, 132.81, 132.84, 134.10, 137.42, 138.39
(aromatic), 152.58, 160.60 (C=N), 170.01 (C=O); MS: m/z: 404, 327, 260, 116, 77; Anal. Calcd for
C26H20N4O: C, 77.21; H, 4.98; N, 13.85. Found: C, 77.20; H, 4.96; N, 13.88.
4-(4-Chlorobenzylidine)-2-methyl-1-(1,3-diphenyl-1H-pyrazol-5-yl)-1H-imidazol-5(4H)-one (4b).
Light yellow crystals; mp 157 °C; νmax: 1726 (C=O), 1648, 1621 (C=N), 1529, 1503 (C-N), 904 (C-Cl)
cm-1; δH (500 MHz, CDCl3): 2.12 (3H, s, CH3), 6.85 (1H, s, olefinic), 7.31-7.32, 7.42-7.44, 7.45-7.47,
7.48-7.50, 7.93-7.95, 8.12-8.14 (15H, 6m, aromatic and pyrazole); δC (125 MHz): 16.24 (CH3), 104.27
(olefinic CH), 124.29, 126.11, 128.37, 129.01, 129.20, 129.55, 130.10, 132.59, 132.74, 133.95, 134.08,
137.28, 137.69, 138.35 (aromatic), 152.60, 161.04 (C=N), 169.82 (C=O); MS: m/z: 440, 438, 363, 361,
286, 284, 219, 77; Anal. Calcd for C26H19ClN4O: C, 71.15; H, 4.36; N, 12.77. Found: C, 71.14; H, 4.37;
N, 12.80.
4-(4-Bromobenzylidine)-2-methyl-1-(1,3-diphenyl-1H-pyrazol-5-yl)-1H-imidazol-5(4H)-one (4c).
Yellow crystals; mp 178 °C; νmax: 1738 (C=O), 1645, 1616 (C=N), 1552, 1510 (C-N), 826, 765 (C-Br)
cm-1; δH (500 MHz, CDCl3): 2.11 (3H, s, CH3), 6.84 (1H, s, olefinic), 7.14-7.15, 7.28-7.29, 7.40-7.42,
7.43-7.48, 7.49-7.51, 7.58-7.60, 7.92-7.94, 8.03-8.05 (15H, 8m, aromatic and pyrazole); δC (125 MHz):
16.25 (CH3), 104.26 (olefinic CH), 124.28, 125.86, 126.11, 128.41, 129.00, 129.06, 129.20, 130.10,
132.31, 132.53, 132.74, 132.98, 134.10, 137.82, 138.34 (aromatic), 152.61, 161.11 (C=N), 169.82 (C=O);
MS: m/z: 482, 484, 327, 260, 116, 77; Anal. Calcd for C26H19BrN4O: C, 64.61; H, 3.96; N, 11.59. Found:
C, 64.59; H, 3.97; N, 11.62.
4-(4-Nitrobenzylidine)-2-methyl-1-(1,3-diphenyl-1H-pyrazol-5-yl)-1H-imidazol-5(4H)-one (4d).
Yellow crystals; mp 174 °C; νmax: 1737 (C=O), 1650, 1627 (C=N), 1526, 1512 (C-N), 1563, 1311 (NO2)

HETEROCYCLES, Vol. 81, No. 9, 2010
2135
cm-1; δH (500 MHz, CDCl3): 2.15 (3H, s, CH3), 6.85 (1H, s, olefinic), 7.20-7.21, 7.40-7.41, 7.42-7.44,
7.47-7.50, 7.93-7.94, 8.29-8.34 (15H, 6m, aromatic and pyrazole); δC (125 MHz): 16.38 (CH3), 104.29
(olefinic CH), 124.24, 124.31, 126.03, 126.11, 129.09, 129.20, 129.23, 130.16, 133.22, 138.26, 140.12,
148.58 (aromatic), 152.70, 163.41 (C=N), 169.51 (C=O) ; MS: m/z: 449, 434, 372, 295, 237, 135, 116,
77; Anal. Calcd for C26H19N5O3: C, 69.48; H, 4.26; N, 15.58. Found: C, 69.47; H, 4.24; N, 15.61.
4-Benzylidine-2-phenyl-1-(1,3-diphenyl-1H-pyrazol-5-yl)-1H-imidazol-5(4H)-one (4e).
Light yellow crystals; mp 167 °C; νmax: 1736 (C=O), 1654, 1630 (C=N), 1531, 1511 (C-N) cm-1; δH (500
MHz, CDCl3): 6.95 (1H, s, olefinic), 7.20-7.22, 7.29-7.34, 7.41-7.42, 7.47-7.53, 7.95-7.98, 8.31-8.32
(21H, 6m, aromatic and pyrazole); δC (125 MHz): 103.96 (olefinic CH), 124.38, 126.15, 128.51, 128.56,
128.61, 128.91, 129.02, 129.15, 129.30, 129.68, 131.13, 131.40, 132.22, 132.92, 133.27, 133.72, 134.39,
137.70, 138.29 (aromatic), 152.48, 158.83 (C=N), 170.59 (C=O) ; MS: m/z: 466, 389, 312, 247, 116, 77;
Anal. Calcd for C31H22N4O: C, 79.81; H, 4.75; N, 12.01. Found: C, 79.79; H, 4.75; N, 12.04.
4-(4-Methylbenzylidine)-2-phenyl-1-(1,3-diphenyl-1H-pyrazol-5-yl)-1H-imidazol-5(4H)-one (4f).
Light yellow crystals; mp 173 °C; νmax: 1724 (C=O), 1647, 1621 (C=N), 1559, 1510 (C-N) cm-1; δH (500
MHz, CDCl3): 2.46 (3H, s, CH3), 6.94 (1H, s, olefinic), 7.20-7.22, 7.28-7.32, 7.39-7.50, 7.95-7.97, 8.19-
8.21 (20H, 5m, aromatic and pyrazole); δC (125 MHz): 22.24 (CH3), 103.96 (olefinic CH), 124.38,
126.16, 128.47, 128.57, 128.69, 128.89, 129.00, 129.15, 129.67, 130.13, 131.40, 131.76, 132.07, 132.76,
132.97, 133.34, 133.84, 136.99, 138.34, 140.27 (aromatic), 152.45, 158.21 (C=N), 170.62 (C=O); MS:
m/z: 480, 326, 203, 116, 100, 98, 57; Anal. Calcd for C32H24N4O: C, 79.98; H, 5.03; N, 11.66. Found: C,
79.99; H, 5.02; N, 11.68.
4-(4-Bromobenzylidine)-2-phenyl-1-(1,3-diphenyl-1H-pyrazol-5-yl)-1H-imidazol-5(4H)-one (4g).
Yellow crystals; mp 186 °C; νmax: 1729 (C=O), 1638, 1611 (C=N), 1560, 1492 (C-N), 817, 762 (C-Br)
cm-1; δH (500 MHz, CDCl3): 6.94 (1H, s, olefinic), 7.18-7.20, 7.29-7.30, 7.31-7.33, 7.39-7.41, 7.48-7.50,
7.94-7.96, 8.15-8.17 (20H, 7m, aromatic and pyrazole); δC (125 MHz): 16.70 (CH3), 103.96 (olefinic
CH), 124.37, 126.15, 128.12, 128.41, 128.53, 128.66, 128.94, 129.07, 129.16, 129.42, 129.70, 132.40,
132.58, 132.87, 133.27, 133.56, 134.46, 138.10, 138.26 (aromatic), 152.50, 159.27 (C=N), 170.40 (C=O);
MS: m/z: 544, 546, 467, 469, 390, 392, 168, 116, 118, 77; Anal. Calcd for C31H21BrN4O: C, 68.26; H,
3.88; N, 10.27. Found: C, 68.25; H, 3.87; N, 10.30.
4-(4-Methoxybenzylidine)-2-phenyl-1-(1,3-diphenyl-1H-pyrazol-5-yl)-1H-imidazol-5(4H)-one (4h).
Light yellow crystals; mp 188 °C; νmax: 1727 (C=O), 1635, 1614 (C=N), 1563, 1508 (C-N) cm-1; δH (500
MHz, CDCl3): 3.91 (1H, s, OCH3), 6.92 (1H, s, olefinic), 7.03-7.05, 7.26-7.29, 7.50-7.57, 7.61-7.66,
8.14-8.16, 8.19-8.24 (20H, 6m, aromatic and pyrazole); δC (125 MHz): 55.18 (OCH3), 103.91 (olefinic
CH), 124.29, 126.10, 127.17, 128.39, 128.50, 128.62, 128.84, 129.03, 129.26, 129.72, 130.11, 130.81,
131.38, 132.44, 133.44, 133.88, 134.19, 135.85, 137.53 (aromatic), 152.53, 159.16 (C=N), 170.11 (C=O);

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MS: m/z: 496, 464, 419, 387, 167, 105, 77, 57; Anal. Calcd for C32H24N4O2: C, 77.40; H, 4.87; N, 11.28.
Found: C, 77.41; H, 4.86; N, 11.30.
ACKNOWLEDGEMENTS
We wish to thank Research Council of University of Tehran for the financial support.
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These
data
can
be
obtained
free
of
charge
via
www.ccdc.com.ac.uk/data_request/cif.