Synthesis and characterization of some novel 4-aryloxy substituted pyrazoles

Article abstract of DOI:10.14233/ajchem.2014.17172

The synthesis of some novel 4-aryloxy substituted pyrazoles was performed in two steps. The synthetic route involves the synthesis of 3-aryloxy substituted 1,3-dicarbonyl compounds (3a-e) in first step by the condensation of 3-chloro-pentan-2,4-dione (1)

Full text of DOI:10.14233/ajchem.2014.17172

Asian Journal of Chemistry; Vol. 26, No. 21 (2014), 7435-7438
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17172
Synthesis and Characterization of Some Novel 4-Aryloxy Substituted Pyrazoles
1
1
1
1
2,*
2
1
3
MUHAMMAD SHER , PERVAIZ ALI , ZAMAN ASHRAF , MUHAMMAD AAMIR , EJAZ AHMED ,AHSAN SHARIF , NADIA RIAZ and SHAHID IQBAL
1Department of Chemistry, AllamaIqbal Open University, Islamabad-44000, Pakistan
2Institute of Chemistry, University of the Punjab, Quaid-e-Azam Campus, Lahore-54590, Pakistan
3Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan
*Corresponding author: Fax: +92 42 99231269; Tel: +92 42 99230463; E-mail: dr.ejaz.ahmed@gmail.com
Received: 6 February 2014;
Accepted: 6 May 2014;
Published online: 30 September 2014;
AJC-16155
The synthesis of some novel 4-aryloxy substituted pyrazoles was performed in two steps. The synthetic route involves the synthesis of
3-aryloxy substituted 1,3-dicarbonyl compounds (3a-e) in first step by the condensation of 3-chloro-pentan-2,4-dione (1) and substituted
phenols (2a-e). The hydrazine monohydrate/substituted aromatic hydrazides (4a-e) in the second step were then treated with compounds
3a-e to afford the target pyrazoles (5a-e). The interesting feature of this reaction is the isolation of the intermediate pyrazoline. The
structure of this intermediate was also confirmed by the X-ray single crystal. The structures of the synthesized compounds 5a-e were
assigned on the basis of FT-IR, 1H NMR, 13C NMR and mass spectroscopic data.
Keywords: Hydrazides, 4-Aryloxy pyrazoles, 5-Hydoxy-2-pyrazoline.
substituted 1,3-dicarbonyl compounds and their condensation
in the latter step with hydrazine hydrate and substituted
hydrazides to afford the target molecules. The method adopted
for the synthesis of pyrazoles also employed for the synthesis
of stable 5-hydroxy pyrazolines which can act as bidentate
chelating agents25.
INTRODUCTION
Pyrazoles and their substituted analogues are important
class of five membered heterocyclic systems that find extensive
use in pharmaceutical and agrochemical industries1. The growing
interest in bioactive N-arylpyrazoles has led to an increasing
demand for efficient syntheses of this class of heterocyclic
compounds. Several reports have found diverse applications
for N-arylpyrazoles in medicine such as antitumor2-12, anti-
viral13, antiinflammatory14 agents, or kinase inhibitors for the
treatment of type 2 diabetes, hyperlipidemia and obesity15.
Moreover, these compounds have remarkable potential in
nanomedicine applications against malignant gliomas16. 1-(4-
Chlorophenyl)-4-hydroxy-3-substituted-1H-pyrazoles were
reported by the U.S. National Cancer Institute (NCI) to have
EXPERIMENTAL
Melting points were recorded using a digital Gallenkamp
(SANYO) model MPD.BM 3.5 apparatus and are uncorrected.
13
1H and C NMR spectra were determined in CDCl3 at 300
MHz and 75 MHz, respectively using a BrukerAMX spectro-
photometer. FTIR spectra were recorded on 1310 FT-IR
spectrometer with KBr pellets. All chemicals were purchased
from Merck andAldrich and were used without further purifi-
cation. Mass spectra were recorded on SHIMADZU GCQP-
2010 and API 4000 by ion trap system.
pronounced anticancer activity17,18
.
1,3-Dicarbonyl compounds are most widely used pre-
cursors for the preparation of pyrazoles. The various strategies
employed for the synthesis of pyrazoles include 1,3-dipolar
cycloaddition of diazo compounds onto triple bond19, cyclo-
addition of 6-nitroquinoline with aromatic hydrazones20, biaryl
coupling21 and addition of hydrazines to 1,3-dicarbonyl com-
pounds and α,β-unsaturated compounds22-24. Among these,
addition of hydrazine to 1,3-dicarbonyl compounds is the most
easily accessible route for the synthesis of pyrazoles.
Synthesis of 4-aryloxy substituted pyrazoles (5a-j): The
3-aryloxy substituted pentan-2,4-diones (3a-e) have been
synthesized according to reported procedure26. The 3-chloro
pentan-2,4-dione (1) dissolved in acetone was treated with
substituted phenols (2a-e) in the presence of potassium carbo-
nate to afford the compounds 3a-e . Then 3-aryloxy pentan-
2,4-dione (3a-e) were condensed in ethanol with hydrazine
monohydrate/substituted aromatic hydrazides (4a-e) in equi-
molar ratio. The reaction mixture was refluxed for 4-8 h in the
presence of catalytic amount of conc. H2SO4. The reaction
We report herein the two-step synthesis of 4-aryloxy subs-
tituted pyrazoles. The first step involves synthesis of 3-aryloxy

7436 Sher et al.
Asian J. Chem.
was monitored by thin layer chromatography. After the
completion of reaction solvent was removed under reduced
pressure and residue was recrystallized from 70 % ethanol to
afford the pyrazoles (5a-j).
4-(4-Bromo-phenoxy)-3,5-dimethyl-1H-pyrazole (5f):
1
Redish oil (yield, 40 %), H NMR (300 MHz, CDCl3): δ =
9.53 (s, 1H, NH), 7.34 (d, J = 7.5 Hz, 2H, ArH), 6.65 (d, J =
7.3 Hz, 2H, ArH), 2.43 (s, 1H, CH3), 2.26 (s, 3H, CH3), 13C
NMR (75 MHz, CDCl3): δ = 154.8, 144.9, 137.6, 124, 120.4,
110.4, 11.1, 9.5. IR (KBr, νmax, cm-1) 3115 (sp2CH), 2955
(sp3CH), 1569 (C=N), 1595-1495 (C=C), 1070 (C-O). GC-
MS (EI, 70 eV): m/z (%): 267 (M+, 81Br, 49), 265 (M+, 79Br,
48), 156 (7), 136 (100) 111 (10), 91 (30), 65 (25), 51 (10).
3,5-Dimethyl-4-(4-nitrophenoxy)-1H-pyrazole (5g):
Pink oil (yield, 58 %),1H-NMR (300 MHz, CDCl3): δ = 9.33
(s, 1H, NH), 8.02 (d, J = 7.5 Hz, 2H,ArH), 7.08 (d, J = 7.3 Hz,
2H), 2.41 (s, 1H, CH3), 2.24 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3): δ = 155.8, 143.9, 139.6, 137.6, 134.2, 123.05, 120.4,
10.1, 8.5. IR (NaCl Cell, νmax, cm-1) 3115 (sp2CH), 2955 (sp3CH),
1569 (C=N), 1595 (C=C), 1070 (C-O). GC-MS (EI, 70 eV): m/z
(%): 233 (M+, 100), 138 (7), 111 (10), 91 (30), 65 (25), 51 (10).
4-(4-Methoxy-phenoxy)-3,5-dimethyl-1H-pyrazole
(5h): Pink oil (yield, 38 %), 1H NMR (300 MHz, CDCl3): δ =
9.28 (s, 1H, NH), 7 (d, J = 7.5 Hz, 2H, ArH), 6.70 (d, J = 7.5
Hz, 2H, ArH) 3.41 (s, 1H, OCH3), 2.33 (s, 3H, CH3), 2.21 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3): δ = 153.1, 139.6, 137.6,
135.4, 134.2, 128.9, 120.3, 61.1, 10.1, 8.5. IR (KBr, νmax, cm-1):
3125 (sp2CH), 2935 (sp3CH), 1577 (C=N), 1600-1485 (C=C),
1053 (C-O). GC-MS (EI, 70 eV) m/z (%): 218 (M+, 100), 123
(7), 111 (35), 107 (6), 91 (30), 65 (25), 51 (10).
4-Chlorophenyl-(3,5-dimethyl-4-(p-tolyloxy)-1H-
pyrazol-1-yl)-methanone (5a): Yellow solid (yield, 37 %),
m.p. 155 °C. 1H NMR (300 MHz, CDCl3) δ = 7.71 (d, J = 7.5
Hz, 2H, ArH), 7.44 (d, J = 7.5 Hz, 2H, ArH ), 6.97 (d, J = 7.5
Hz, 2H, ArH), 6.72 (d, J = 7.5 Hz, 2H, ArH), 2.52 (s, 3H,
CH3), 2.42 (s, 1H, CH3), 2.32 (s, 3H, CH3).13C NMR (75 MHz,
CDCl3)δ: 166.3, 153.7, 141.9, 140.6, 139.7, 134.2, 132.8,
129.8, 129.2, 128.6, 125, 119.9, 21.1, 10.2, 9.1. IR (KBr, νmax
,
cm-1): 3095 (CH), 2919 (CH), 1586 (C=N), 1640 (C=O), 1567-
1488 (C=C), 1070 (C-O). GC-MS (EI, 70 eV): m/z (%): 340
(M+,37Cl, 24), 238 (M+, 35Cl, 54), 207 (26), 164 (15), 139
(100), 111 (45), 91 (15).
4-Aminophenyl[3,5-dimethyl-4-(p-tolyloxy)-1H-
pyrazol-1-yl]methanone (5b): Red solid (yield, 35 %), m.p.
160 °C. 1H NMR (300 MHz, CDCl3) δ: 7.57 (d, J = 7.5 Hz,
2H, ArH), 6.97 (d, J = 7.5 Hz, 2H, ArH ), 6.76-6.67 (m, 4H,
ArH), 3.82 (s, 2H, NH2), 2.52 (s, 1H, CH3), 2.43 (s, 3H, CH3),
2.32 (s, 3H, CH3).13C NMR (75 MHz, CDCl3)δ: 166.3, 153.7,
152.7, 141.9, 140.6, 134.2, 131.8, 128.6, 125, 122.8, 119.9,
112.3, 21.1, 10.2, 9.1. IR (KBr, νmax, cm-1): 3127 (CH), 2952
(CH), 1573 (C=N), 1670 (C=O), 1592-1498 (C=C), 1060
(C-O). GC-MS (EI, 70 eV): m/z (%): 238 (M+, 100), 209 (7),
119 (35), 91(30), 65 (25) , 51 (10).
3,5-Dimethyl-4-(2,4,6-trinitro-phenoxy)-1H-pyrazole
(5i):Yellow oil (yield, 40 %), 1H NMR (300 MHz, CDCl3): δ
= 9.34 (s, 1H, NH), 8 (d, J = 7.5 Hz, 2H, ArH), 2.41 (s, 3H,
CH3), 2.33 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): δ = 152.1,
4-Aminophenyl[3,5-dimethyl-4-(4-nitro-phenoxy)-
pyrazol-1-yl]methanone (5c): Light yellow oil (yield, 45 %),
1H NMR (300 MHz, CDCl3): δ = 8.02 (d, J = 7.5 Hz, 2H,
ArH), 7.68 (d, J = 7.3 Hz, 2H, ArH), 6.76-6.67 (m, 4H, ArH),
148.6, 145.6, 138.4, 128.9, 107.3, 10.1, 8.5. IR (KBr, νmax
,
13
3.82 (s, 2H, NH2), 2.43 (s, 3H, CH3), 2.32 (s, 3H, CH3). C
cm-1): 3125 (sp2CH), 2935 (sp3CH), 1579 (C=N), 1600-1485
(C=C), 1053 (C-O). GC-MS (EI, 70 eV) m/z (%): 323 (M+,
100), 212 (30), 111 (9), 105 (6), 65 (25), 51 (10).
NMR (75 MHz, CDCl3): δ = 178.3, 158.7, 152.7, 141.9, 140.6,
134.2, 131.8, 128.6, 125, 122.8, 119.9, 112.3, 21.1, 10.2. IR
(KBr, νmax, cm-1) 3437 (NH), 3115 (CH), 2955 (CH), 1569
(C=N), 1595-1495 (C=C), 1070 (C-O). GC-MS (EI, 70 eV)
m/z (%): 352 (M+, 52), 232 (7), 120 (100), 91 (30), 65 (25) ,
51 (10).
4-(3,4-Dimethoxy-phenoxy)-3,5-dimethyl-1H-pyrazole
(5j): Pink solid (yield, 45 %), m.p. 85 °C, 1H NMR (300 MHz,
CDCl3): δ = 9.32 (s, 1H, NH), 6.75 (d, J = 8.7 Hz, 1H, ArH),
6.55 (d, J = 2.8 Hz, 1H, ArH), 6.31 (dd, J = 8.7 Hz, 2.8 Hz,
1H, ArH), 3.83 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 2.41 (s,
3H, CH3), 2.33 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): δ =
152.1, 148.6, 145.6, 145.7, 145.6, 122.9, 120.9, 109.3, 107.3,
56.5, 53.5, 10.1, 8.5. IR (KBr, νmax, cm-1): 3125 (sp2CH), 2935
(sp3CH), 1577 (C=N), 1600-1485 (C=C), 1053 (C-O). GC-MS
(EI,70 eV) m/z (%): 248 (M+, 100), 137 (30), 111 (9), 105 (6),
65 (25), 51 (10).
3,5-Dimethyl-4-(naphthalen-2-yloxy)-1H-pyrazole
1
(5d): Pink solid (yield, 70 %), m.p. 120 °C. H NMR (300
MHz, CDCl3): δ = 9.20 (s, 1H, NH), 7.83-7.63 (m, 2H), 7.59
(qd, J = 7.5, 1.4 Hz, 2H, ArH), 7.40-7.29 (m, 3H, ArH), 2.41
(d, J = 11.5 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ = 156.5,
136.1, 134.2, 129.8, 129.6, 127.7, 126.9, 126.6, 124.2, 117.6,
108.9, 108.6, 106.2, 9.6. IR (KBr, νmax, cm-1): 3160 (sp2CH),
2899 (sp3CH), 1528 (C=N), 1597-1508 (C=C), 1053 (C-O).
GC-MS (EI, 70 eV) m/z (%): 238 (M+, 100), 209 (10), 155
(15), 127 (30), 115 (11) , 77 (10).
RESULTS AND DISCUSSION
The synthetic sequence leading to the 4-aryloxy substi-
tuted pyrazoles is outlined in Scheme-I. The 3-aryloxy substi-
tuted 1,3-dicarbonyl compounds (3a-e) were synthesized by
treating 3-chloropentan-1,3-dione with substituted phenols
(2a-e). The reaction involves nucleophilic substitution of chloro
functional from compound 1 by hydroxyl group of substituted
phenols (2a-e). The reaction was carried out according to the
reported procedure26. The resulting 1,3-dicarbonyl (3a-e) were
then condensed with hydrazine/substituted hydrazides in the
presence of catalytic amount of conc. H2SO4 to afford the target
4-aryloxy substituted pyrazoles (5a-j) in moderate to good yield.
3,5-Dimethyl-4-(p-tolyloxy)-1H-pyrazole (5e): Colorless
oil (yield, 65 %), m.p. 71 °C. 1H NMR (300 MHz, CDCl3): δ
= 9.28 (s, 1H, NH), 7 (d, J = 7.5 Hz, 2H, ArH), 6.76 (d, J = 7.5
Hz, 2H, ArH) 2.41 (s, 1H, CH3), 2.33 (s, 3H, CH3), 2.21 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3): δ =153.1, 139.6, 137.6,
135.4, 134.2, 128.9, 128.9, 120.3, 21.1, 10.1, 8.5. IR (KBr,
ν
max, cm-1): 3125 (sp2CH), 2935 (sp3CH), 1577 (C=N), 1600-
1485 (C=C), 1053 (C-O). GC-MS (EI, 70 eV) m/z (%): 202
(M+, 100), 132 (7), 119 (35), 111 (9), 105 (6), 91 (30), 65
(25), 51 (10).

Vol. 26, No. 21 (2014)
Synthesis and Characterization of Some Novel 4-Aryloxy Substituted Pyrazoles 7437
R1
CH3
O
O
O
O
O
H2SO4/C2H5OH
K2CO3/
∆
NHNH
R
2
2
H3C
CH3
+
N
H3C
CH3
∆
R1
OH
+
H3C
Acetone
N
O
R1
Cl
R2
(1)
(2a-e)
(3a-e)
(4a-e)
(5a-j)
Compound
R1
R2
Yield (%)
Compound
R1
R2
Yield (%)
O
37
5f
H
40
5a
C l
C H
Br
3
O
35
45
5g
5h
5i
58
46
35
45
5b
5c
5d
5e
H
H
N
H
N O 2
C H
2
3
O
N
H
N O
2
O C H
3
2
N o 2
N o 2
70
65
H
H
H
N o2
5j
O CH3
H
OCH3
C H
3
Scheme-I: Synthesis of pyrazoles (5a-j)
sation of 1,3-diketones with hydrazines proceed through the
formation of 5-hydroxy-2-pyrazoline intermediate. It was also
proposed that the presence of strongly electron with drawing
groups at position 5 of pyrazoline stabilize the intermediate27.
The present work depicted that when reaction of 1,3-diketone
(2a) with hydrazide (3a) was carried in the absence of catalyst
then 5-hydroxy-2-pyrazoline was stable enough can be isola-
ted. The structure of the said compound was also confirmed
by X-ray crystallography (Fig. 1).
Fig. 1. ORTEP plot of 5-hydoxy-2-pyrazoline
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