Selective O-deallylation of dihydropyrazoles by molecular iodine in the presence of active N-allyl and formyl groups

Article abstract of DOI:10.1007/s11164-012-0581-2

Selective O-deallylation of dihydropyrazoles has been achieved by use of iodine (10 mol%) in PEG-400 as ecofriendly solvent. Iodine (10 mol%) in dimethyl sulfoxide at 100 C also afforded O-deallylation with aromatization compatible with highly reactive N-

Full text of DOI:10.1007/s11164-012-0581-2

Res Chem Intermed (2013) 39:585–595
DOI 10.1007/s11164-012-0581-2
Selective O-deallylation of dihydropyrazoles
by molecular iodine in the presence of active
N-allyl and formyl groups
•
Vivek T. Humne Kamal Hasanzadeh
Pradeep D. Lokhande
•
Received: 3 March 2012 / Accepted: 26 April 2012 / Published online: 16 May 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Selective O-deallylation of dihydropyrazoles has been achieved by use
of iodine (10 mol%) in PEG-400 as ecofriendly solvent. Iodine (10 mol%) in
dimethyl sulfoxide at 100 °C also afforded O-deallylation with aromatization
compatible with highly reactive N-allyl and formyl groups. The function of iodine in
the synthesis of substituted pyrazoles under different conditions is described.
Keywords Iodine ꢀ Dihydropyrazole ꢀ Deallylation ꢀ PEG-400
Introduction
The design of new strategies for synthesis of N-containing heterocyclic compounds
is essential in organic chemistry from a biological and pharmacological perspective.
4,5-Dihydropyrazoles and their corresponding aromatic pyrazoles are important
heterocyclic compounds with a wide range of biological activity, for example anti-
inflammatory [1], analgesic [2], antimicrobial [3], and insecticidal [4]. 20-Hydroxy
dihydropyrazoles are also widely used intermediates capable of undergoing a
variety of transformations affording flavanone [5] and coumarin [6]-like natural
products and organometallic complexes [7] with biological activity [8–11].
A variety of methods have been reported for synthesis of substituted pyrazoles
[12–16]. Recently, transition-metal-catalyzed coupling of functionalized allenes
with organic halides, leading to pyrazoles, has been reported [17]. The most
practical method for obtaining substituted pyrazoles with favored regioselectivity is,
V. T. Humne (&) ꢀ K. Hasanzadeh ꢀ P. D. Lokhande
Center for Advance Studies, Department of Chemistry, University of Pune, Pune 411 007, India
e-mail: vivekhumne@rediffmail.com
P. D. Lokhande
e-mail: pdlokhande@chem.unipune.ac.in
123

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V. T. Humne et al.
however, treatment of substituted chalcones with hydrazine hydrate or phen-
ylhydrazine [18, 19].
A literature survey revealed that the free hydroxyl group of 20-hydroxy
dihydropyrazoles is of crucial importance in the synthesis of heterocyclic groups.
Appropriate selection of an efficient protecting group and selective deprotection are
challenging tasks in organic chemistry. Use of allyl groups to protect the nitrogen
and oxygen is becoming increasingly popular because of its less hindered nature and
the ease of protection. Thus protection and deprotection of these groups is necessary
and important. The deprotection of allyl ethers by use of transition metal catalysts,
for example palladium [20–26], ruthenium(II) [27], iridium(I) [28, 29], titanium
[30], and zirconium [31] has been reported.
R1
R2
R3
OH
OH
R
N
N
N
N
S
N
O
O
R1
O
S
HN
R2
MAO - inhibitor
Bioorg. Med. Chem. Lett., 2010, 20 132
Analgesic & Anti-inflammatory activities
Bioorg. Med. Chem. Lett.,2010, 20, 3721
OH
N
Ar
N
O
S
O
NH2
Anticancer drug
Bioorg. Med. Chem. Lett., 2011, 21, 4301
Previous procedures have limited scope, are expensive, and loading of the
catalyst is difficult. Oxidation of the resulting dihydropyrazoles is also a significant
intellectual task [32–42]. Therefore, development of a method for deprotection
under mild conditions with high selectivity is desirable.
Molecular iodine is convenient for pharmaceutical synthesis owing to its
inexpensive, non-toxic, and environmentally benign characteristics. Iodine can also
be easily removed from reaction systems [43–46] and is insensitive to air and
moisture. We have successfully performed deallylation with oxidative ring
closure in the synthesis of substituted flavones [47]. As part of a continuing study
123

Selective O-deallylation of dihydropyrazoles
587
of iodine-mediated transformations in our laboratory [48–51], we became interested
in the possibility of developing an easy and efficient method of deallylation of
substituted dihydropyrazoles and isoxazoles. To the best of our knowledge, this
paper is the first report of deallylation with aromatization of dihydropyrazoles and
isoxazoles by use of catalytic amount of iodine (10 mol%) in dimethyl sulfoxide
(DMSO) at ambient temperature. Selective O-deallylation, in the presence of N-allyl
groups, has also been achieved by use of iodine (10 mol%) in poly(ethylene glycol)
400 (PEG-400) at room temperature, with good yield.
Results and discussion
The dihydropyrazoles were conveniently prepared by treatment of a variety of
substituted 20-hydroxy chalcones with hydrazine hydrate or phenyl hydrazine in
methanol. To achieve the required substrate (Scheme 1, 1a–j), it was stirred with
stoichiometric amounts of allyl bromide and potassium carbonate in dimethylform-
amide at room temperature. In the course of our investigation of the effect of the
solvent used for deallylation, we found the reaction did not proceed in methanol,
acetonitrile, dimethylformamide, dichloromethane, of diphenyl ether. However,
DMSO was found to be efficient solvent. Thereafter, we investigated the amount of
iodine required to catalyze the reaction. First, we used 5 mol% and then 1.5 mol
iodine. No significant changes were observed at room temperature. On increasing
the temperature to 60 °C, the O-deallylated product was isolated in excellent yield.
It was observed that the time required for completion of the reaction was longer
when 5 mol% iodine was used. However, 20 mol% iodine was found adequate for
deallylation (Table 1, entry 2a–j). Use of 100 mol% iodine gave the deallylated
(yield 51 %) and aromatized (yield 37 %) mixed product.
To optimize the reaction conditions, the temperature was increased to 100 °C.
Under these conditions, uniquely, the deallylated, aromatized product was obtained
in good yield by use of 20 mol% iodine (Table 1, entry 3a–j).
To check the utility of iodine in DMSO, a variety of substituted dihydropyrazoles
and isaxozolines were used (Scheme 2). All aromatized product were isolated in
good yields. Even in the presence of the formyl group in dihydropyrazole [51]
(Table 1, entry 1f–j), deallylation with aromatization was achieved successfully by
R1
R1
R1
O
OH
N
OH
N
Allyl
R2
R2
R2
+
°
I2, H , DMSO, 60 C
or
N
I2, H+, DMSO
°
N
N
N
100
C
I2, PEG-400, rt
R4
R4
R4
R3
R3
R3
2a-j
1a-j
3a-j
Scheme 1
123

588
V. T. Humne et al.
Table 1 Selective deallylation and aromatization of substituted dihydropyrazoles
Entry Substrate 1
R1 R2
Product 2
Product 3
R3
R4
Timea (min) Yield (%) Timeb (min) Yield (%) Yield (%)
a
b
c
d
e
f
H
Cl
H
H
H
H
H
H
10
10
25
10
10
92a
90a
88a
92a
90a
92
35
30
40
25
25
30
35
35
30
25
74
76
80
78
71
83
84
81
89
86
87b
84b
84b
83b
82b
85
Cl Cl
H
H
H
Me
Cl
H
Cl
Cl
Cl Cl
H
H
H
H
H
Cl
H
CHO OMe 15
CHO 10
CHO OMe 15
g
h
i
H
90
82
H
90
77
H
CHO Cl
CHO Cl
10
10
89
81
j
Cl
93
76
a
Reaction conducted in DMSO at 60 °C
Reaction conducted in PEG-400 at room temperature
b
use of iodine in DMSO at 100 °C. Remarkably, the easily oxidizable formyl and
highly active N-allyl groups remained unchanged in aromatization process.
Use of DMSO at higher temperatures for the reaction resulted in decomposition.
To avoid the requirement of high temperatures and to achieve selective
O-deallylation, we investigated use of different solvents for the deallylation
process. However, in ethylene glycol, the isolated product was obtained in low
yield, with recovery of starting substrate at room temperature. Increasing the
viscosity of solvent by using PEG-400 resulted in isolation of the selectively
deallylated product in excellent yield. Use of 10 mol% iodine in PEG-400 as
solvent afforded the O-deallylated product at room temperature (Scheme 1)
(Table 2). Use of one equivalent of iodine resulted in almost the same yield and
reaction time without formation of side products.
To investigate the generality and versatility of this new method of iodine-
catalyzed deallylation, we studied the selective deallylation of N-allyl-substituted
dihydropyrazoles in the presence of using iodine in PEG-400 as green reaction
solvent (Scheme 2, 5g–j). It was observed that N-allyl groups were not affected
whereas selective O-deallylation was achieved cleanly and smoothly for entries 4g–j
(Table 3) by use of iodine in PEG-400 at room temperature. The O-deallylated
product was obtained with excellent yield. The time required for completion of
reaction was longer for isoxazoline (Table 3, entry 5a–f).
Table 2 Recycling of PEG-400 for deallylation of 1a with 10 mol% iodine as catalyst at room
temperature
Run
1
2
3
4
5
Yielda
92
90
88
83
83
a
All reactions were conducted with 1 mmol substrate
123

Selective O-deallylation of dihydropyrazoles
589
R1
R1
R1
OH
OH
X
O
Allyl
R2
+
R2
°
I2, H , DMSO, 60 C
or
R2
I2, H+, DMSO
N
N
N
X
°
100 C
X
I2, PEG-400, rt
R3
R3
R3
5a-j
4a-j
6a-j
Scheme 2
Table 3 Selective deallylation and aromatization of substituted N-allyl dihydropyrazoles and isoxazoles
Entry Substrate 4
R1 R2
Product 5
Product 6
R3
X
Timea (min) Yield (%) Timeb (min) Yield (%) Yield (%)
a
b
c
d
e
f
H
Cl
H
H
H
H
H
H
O
O
O
O
O
O
30
25
15
25
30
20
95
96
95
91
90
94
89
90
91
85
10
10
20
15
15
20
10
10
10
20
91
95
88
92
91
85
92
90
91
86
91
93
87
89
93
85
79
77
77
74
Cl Cl
H
H
Me
Cl
Cl Cl
H
H
Me
Cl
g
h
i
Cl N-Allyl 30
Cl N-Allyl 35
Cl N-Allyl 35
Cl Cl
Br Cl
j
H
Me Cl N-Allyl 30
a
Reaction conducted in PEG-400 at room temperature
b
Reaction conducted in DMSO at 60 °C
To study the reusability of the solvent, the reaction mixture was extracted with
ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate
and the solvent was evaporated. The remaining mother liquor was subjected to
vacuum distillation to remove water, leaving PEG behind in the container. The
recovered PEG used five times without loss of its activity (Table 2).
A plausible mechanism of deallylation of substituted pyrazolines is depicted
in Scheme 3. Gunduz et al. [52] reported that iodine and DMSO under acidic
O
O
I
I
O
O
O
OH
H
OH
I2
+
+
N
Ar
N
N
Ar
N
R
R
1
2
Scheme 3 Plausible mechanism of deallylation of O-allyl dihydropyrazoles
123

590
V. T. Humne et al.
conditions effectively produced the iodonium ion. Floyd et al. [53] regenerated the
halogen from the combination of a halo acid and DMSO. On the basis of to this
hypothesis, we believe molecular iodine in a polarized state in DMSO promoted the
deallylation and aromatization process. The function of PEG is possibly to form a
complex with the cation, much like a crown ether, and these complexes cause the
anion to be activated. In addition, there is no need for any external phase transfer
catalyst (PTC) or acidic medium to activate the oxygen atom of the ally ether.
Initially, we assumed the deallylation mechanism was based on the iodine cation,
which is stabilized by interaction with the oxygen of PEG. However, when
potassium iodide or sodium iodide was used in the reaction, the deallylation product
was not observed.
Similarly, tetraalkylammonium iodide did not give the expected product. On the
basis of our results and the literature, a tentative mechanism for deallylation is
proposed. As soon as iodine is added it activates the C=C bond and forms a three-
membered iodonium intermediate, it is stabilized by interaction with the oxygen
atom of PEG. The color of the solution remains unchanged, which suggest
regeneration of the iodine. Formation of allyl alcohol in the reaction could not be
traced. Finally, we believe PEG is not only acting as an efficient solvent but also as
a PTC, causing the anion to be activated.
In conclusion, we have developed the sequential procedure for selective
O-deallylation and aromatization of substituted pyrazolines and isoxozolines by
using a catalytic amount of iodine either in PEG-400 at room temperature or in
DMSO at different temperatures, in good yield and with easy workup. The
attractiveness of this method is its tolerance of N-allyl and formyl groups of
pyrazolines. The operational simplicity and economic viability of this method
justify further study of this reaction.
Experimental
Allylic substrates were prepared by the conventional method. Analytical TLC was
performed on Merck aluminium foil plates precoated with silica gel 60 F254. IR
spectra were recorded (in KBr pallets) on a Shimadzu spectrophotometer. 1H NMR
spectra were recorded (in CDCl3) on a Varian Mercury 300 MHz spectrometer
using TMS as internal standard. Mass spectra were recorded on Shimadzu-QP 5050
GC–MS spectrometer.
General procedure for synthesis of compounds 2a–j and 5a–j
To a solution of 1 (10 mmol) in PEG-400, iodine (10 mol%) was added and the
reaction mixture was stirred at room temperature. After completion of the reaction
(progress was monitored by TLC) the reaction mixture was poured into a saturated
solution of sodium thiosulfate. The precipitate was isolated by filtration and washed
with cold water. The crude product was crystallized from methanol.
123

Selective O-deallylation of dihydropyrazoles
591
Alternative procedure
To solution of 1 (10 mmol) in DMSO, iodine (10 mol%) was added and the reaction
mixture was heated at 120 °C for 25–50 min (progress was monitored by TLC).
After cooling, the reaction mixture was poured on to crushed ice. The precipitate
was isolated by filtration and washed with methanol to remove excess iodine. The
crude product was crystallized from methanol.
4-(3-(5-Chloro-2-hydroxyphenyl)-4,5-dihydro-5-(4-methoxyphenyl)pyrazol-1-
yl)benzaldehyde (2f): mp 174–175 °C
IR (KBr) m cm-1: 3,144, 3,063, 2,931, 2,835, 2,742, 1,685, 1,595. 1H NMR
(300 MHz, TMS, CDCl3): d 3.29 (dd, 1H, J1 = 17.4 Hz, J2 = 5.7 Hz), 3.78 (s,
3H), 3.96 (dd, 1H, J1 = 17.4 Hz, J2 = 12.3 Hz), 5.38 (dd, 1H, J1 = 12.3 Hz,
J2 = 5.7 Hz), 6.87 (d, 2H, J = 8.7 Hz), 6.99–7.03 (m, 3H), 7.11 (d, 1H,
J = 2.7 Hz), 7.17 (d, 2H, J = 8.4 Hz), 7.23–7.35 (m, 1H), 7.71 (d, 2H,
J = 8.7 Hz), 9.76 (s, 1H), 10.46 (s, 1H). 13C NMR (75 MHz, TMS, CDCl3):
d 44.1, 59.4, 61.9, 112.7, 114.2, 117.8, 119.9, 126.1, 127.0, 127.8, 130.2, 130.7,
132.5, 134.3, 147.1, 149.3, 157.6, 159.4, 190.8. MS m/z (%): 406 (M?) (100), 299
(91).
4-(4,5-Dihydro-3-(2-hydroxyphenyl)-5-phenylpyrazol-1-yl)benzaldehyde (2g):
mp 164–165 °C
1
IR (KBr) m cm-1: 3,333, 3,163, 3,086, 2,924, 2,829, 2,750, 1,685, 1,595. H NMR
(300 MHz, TMS, CDCl3): d 3.35 (dd, 1H, J1 = 17.4 Hz, J2 = 5.7 Hz), 4.03 (dd,
1H, J1 = 17.25 Hz, J2 = 12.3 Hz), 5.38 (dd, 1H, J1 = 12.15 Hz, J2 = 5.4 Hz),
6.90 (t, 1H, J = 7.8 Hz), 6.99 (d, 2H, 8.7 Hz), 7.07 (d, 1H, J = 8.4 Hz), 7.14 (d,
1H, J = 7.8 Hz), 7.28–7.38 (m, 6H), 7.70 (d, 2H, J = 8.7 Hz), 9.75 (s, 1H), 10.49
(s, 1H). 13C NMR (75 MHz, TMS, CDCl3): d 43.4, 58.6, 112.3, 116.8, 117.1, 120.4,
126.4, 126.6, 126.9, 128.3, 129.8, 130.8, 131.3, 143.9, 149.5, 152.3, 159.2, 190.9.
MS m/z (%): 342 (M?) (100), 265 (95).
4-(4,5-Dihydro-3-(2-hydroxyphenyl)-5-(4-methoxyphenyl)pyrazol-1-ylbenzaldehyde
(2h): mp 178–179 °C
1
IR (KBr) m cm-1: 3,338, 3,005, 2,808, 2,727, 1,680, 1,584, 1,514 cm-1. H NMR
(300 MHz, TMS, CDCl3): d 3.33 (dd, 1H, J1 = 17.55 Hz, J2 = 5.7 Hz), 3.75 (s,
3H), 4.00 (dd, 1H, J1 = 17.25 Hz, J2 = 12.3 Hz), 5.35 (dd, 1H, J1 = 11.7 Hz,
J2 = 5.7 Hz), 6.86–6.94 (m, 3H), 7.01 (d, 2H, J = 8.7 Hz), 7.09 (d, 1H,
J = 8.4 Hz), 7.15–7.21 (m, 3H), 7.32 (t, 1H, J = 7.2 Hz), 7.71 (d, 2H,
J = 8.7 Hz), 9.76 (s, 1H), 10.52 (s, 1H). 13C NMR (75 MHz, TMS, CDCl3): d
43.9, 55.2, 61.5, 112.4, 114.7, 115.6, 116.7, 119.6, 126.7, 127.6, 128.0, 131.3,
131.6, 132.5, 147.4, 152.4, 157.2, 159.3, 190.3. MS m/z (%): 372(M?) (100), 265
(94).
123

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V. T. Humne et al.
4-(5-(4-Chlorophenyl)-4,5-dihydro-3-(2-hydroxyphenyl) pyrazol-1-yl)benzaldehyde
(2i): mp 186–188 °C
IR (KBr) m cm-1: 3,155, 2,922, 1,678, 1,593. 1H NMR (300 MHz, TMS, CDCl3): d
3.32 (dd, 1H, J1 = 19.05 Hz, J2 = 5.4 Hz), 4.04 (dd, 1H, J1 = 17.1 Hz,
J2 = 12.3 Hz), 5.37 (dd, 1H, J1 = 12.15 Hz, J2 = 6 Hz), 6.92 (t, 1H,
J = 7.2 Hz), 6.98 (d, 2H, J = 8.7 Hz), 7.09 (d, 1H, J = 8.4 Hz), 7.15 (d, 1H,
J = 8.4 Hz), 7.22 (d, 2H, J = 8.4 Hz), 7.31–7.36 (m, 3H), 7.72 (d, 2H,
J = 9.9 Hz), 9.78 (s, 1H), 10.44 (s, 1H). 13C NMR (75 MHz, TMS, CDCl3): d
43.7, 59.1, 112.9, 113.1, 115.8, 119.5, 124.3, 128.6, 128.9, 130.6, 131.1, 132.0,
132.5, 141.4, 148.3, 150.0, 159.8, 189.9. MS m/z (%): 376 (M?) (100), 265 (94).
4-(3-(5-Chloro-2-hydroxyphenyl)-5-(4-chlorophenyl)-4,5-dihydropyrazol-1-yl)
benzaldehyde (2j): mp 190–192 °C
IR (KBr) m cm-1: 3,099, 3,033, 2,978, 2,815, 2,750, 1,687, 1,585. 1H NMR
(300 MHz, TMS, CDCl3): d 3.29 (dd, 1H, J1 = 17.4 Hz, J2 = 5.4 Hz), 4.00 (dd,
1H, J1 = 17.55 Hz, J2 = 12 Hz), 5.40 (dd, 1H, J1 = 12.15 Hz, J2 = 5.7 Hz),
6.98 (d, 1H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.7 Hz), 7.10 (d, 1H, J = 2.4 Hz),
7.19–7.28 (m, 3H), 7.35 (d, 2H, J = 8.4 Hz), 7.73 (d, 2H, J = 8.7 Hz), 9.79 (s, 1H),
10.39 (s, 1H). 13C NMR: 43.6, 61.5, 112.6, 116.6, 118.2, 124.3, 126.4 126.8, 128.6,
129.7, 131.0, 131.7, 134.2, 138.7, 146.9, 150.9, 155.7, 190.3. MS m/z (%): 410
(M?) (100), 299 (93).
2-(1-Allyl-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-chlorophenol (5g):
mp 156–158 °C
1
IR (KBr) m cm-1: 3,123, 2,971, 2,848, 1,701, 1,585, 1,510. H NMR (300 MHz,
TMS, CDCl3): d 3.27 (dd, 1H, J1 = 17.4 Hz, J2 = 5.4 Hz), 4.04 (dd, 1H,
J1 = 17.4 Hz, J2 = 12.3 Hz, 4.60 (m, 2H), 4.87 (dd, 1H, J1 = 17 Hz,
J2 = 1.5 Hz), 5.08 (dd, 1H, J1 = 17 Hz, J2 = 1.2 Hz), 5.37 (dd, 1H,
J1 = 12.3 Hz, J2 = 5.5 Hz), 5.83–5.90 (m, 1H), 6.71 (d, 1H, J = 8.2 Hz), 7.06
(d, 2H, J = 8.1 Hz), 7.11 (d, 1H, J = 8.2 Hz), 7.22 (d, 2H, J = 8.1 Hz), 7.54 (d,
1H, J = 2 Hz). MS m/z (%): 346 (M?) (100), 348 (66), 347 (20).
2-(1-Allyl-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4,6-dichlorophenol
(5h): mp 167–169 °C
1
IR (KBr) m cm-1: 3,103, 3,059, 2,839, 2,744, 1,693, 1,600, 1,581, 1,496. H NMR
(300 MHz, TMS, CDCl3): d 3.24 (dd, 1H, J1 = 17.1 Hz, J2 = 5.2 Hz), 4.05 (dd,
1H, J1 = 17.1 Hz, J2 = 13.1 Hz, 4.61 (m, 2H), 4.87 (dd, 1H, J1 = 17 Hz,
J2 = 1.5 Hz), 5.08 (dd, 1H, J1 = 17 Hz, J2 = 1.2 Hz), 5.37 (dd, 1H,
J1 = 12.3 Hz, J2 = 5.1 Hz), 5.83–5.90 (m, 1H), 7.0–7.08 (m, 3H), 7.22 (d, 2H,
J = 7.9 Hz), 7.34 (s, 1H). MS m/z (%): 380 (M?) (100), 382 (98).
123

Selective O-deallylation of dihydropyrazoles
593
2-(1-Allyl-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-6-chloro-4-
methylphenol (5i):mp 161–163 °C
1
IR (KBr) m cm-1: 3,134, 2,920, 2,850, 1,693, 1,599, 1,510. H NMR (300 MHz,
TMS, CDCl3): d 2.56 (s, 3H), 3.21 (dd, 1H, J1 = 16.9 Hz, J2 = 4.7 Hz), 3.99 (dd,
1H, J1 = 17.0 Hz, J2 = 12.0 Hz), 4.56 (m, 2H), 4.91 (dd, 1H, J1 = 16.9 Hz,
J2 = 1.7 Hz), 5.1 (dd, 1H, J1 = 17 Hz, J2 = 1.2 Hz), 5.40 (dd, 1H, J1 = 12.5 Hz,
J2 = 5.2 Hz), 5.83–5.90 (m, 1H), 7.0–7.1 (m, 3H), 7.22–7.225 (m, 2H).MS m/z (%):
360 (M?) (100), 362 (66), 361 (21).
General procedure for synthesis of compounds 3a–j and 6a–j
To a solution of 1 (10 mmol) in DMSO, iodine (10 mol%) was added. The reaction
mixture was then heated at 120 °C for 25–50 min (monitored by TLC). After
cooling, the reaction mixture was poured on to crushed ice. The precipitate was
isolated by filtration and washed with methanol to remove excess iodine. The crude
product was then crystallized from methanol.
4-(3-(5-Chloro-2-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-
yl)benzaldehyde (3f): mp 218–220 °C
1
IR (KBr) m cm-1: 3,441, 3,134, 3,007, 2,837, 2,739, 1,701, 1,600, 1,508. H NMR
(300 MHz, TMS, CDCl3): d 3.85 (s, 3H), 6.85 (s, 1H), 6.92 (d, 2H, 8.4 Hz),
7.21–7.26 (m, 3H), 7.50 (d, 2H, J = 8.4 Hz), 7.61 (d, 1H, J = 7.5 Hz), 7.72 (d, 1H,
J = 2.7 Hz), 7.88 (d, 2H, J = 8.4 Hz), 10.03 (s, 1H), 11.76 (s, 1H). 13C NMR
(75 MHz, TMS, CDCl3): d 55.3, 105.3, 114.3, 117.0, 118.6, 121.3, 124.1, 124.6,
126.1, 129.5, 130.1, 130.4, 134.8, 143.6, 144.4, 151.6, 154.7, 160.3, 190.8. MS m/
z (%): 404 (M?) (100), 238 (31).
4-(3-(2-Hydroxyphenyl)-5-phenyl-1H-pyrazol-1-yl)benzaldehyde (3g): mp
189–191 °C
IR (KBr) m cm-1: 3,419, 3,123, 2,971, 2,848, 1,701, 1,585, 1,510. 1H NMR
(300 MHz, TMS, CDCl3): d 6.92 (s, 1H), 6.95 (t, 1H, J = 7.8 Hz), 7.07 (d, 1H,
J = 7.8 Hz), 7.24–7.31 (m, 3H), 7.35–7.42 (m, 3H),7.52 (d, 2H, J = 8.7 Hz), 7.61
(dd, 1H, J1 = 7.8 Hz, J2 = 1.8 Hz), 7.92 (d, 2H, J = 8.7 Hz), 10.11 (s, 1H), 10.43
(s, 1H). 13C NMR (75 MHz, TMS, CDCl3): d 105.7, 115.3, 118.5, 118.8, 120.8,
127.3, 127.9, 128.0, 128.7, 129.2, 129.7, 133.3, 133.8, 141.6, 142.1, 152.1, 158.3,
191.1. MS m/z (%): 340 (M?) (100), 208 (42).
4-(3-(2-Hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl)benzaldehyde (3h):
mp 196–198 °C
IR (KBr) m cm-1: 3,446, 3,103, 3,059, 2,839, 2,744, 1,693, 1,600, 1,581,
1
1,496 cm-1; H NMR (300 MHz, TMS, CDCl3): d 3.85 (s, 3H), 6.86(s, 1H), 6.91
(d, 2H, J = 8.7 Hz), 6.96 (t, 1H, J = 7.5 Hz) 7.07(d, 1H, J = 8.4 Hz), 7.24(d, 2H,
123

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V. T. Humne et al.
J = 8.4 Hz), 7.28–7.31(m, 1H), 7.51(d, 2H, J = 8.7 Hz), 7.64(dd, 1H, J1 = 7.8 Hz,
J2 = 1.5 Hz), 7.88 (d, 2H, J = 8,7 Hz), 10.02 (s, 1H), 10.68(s, 1H). 13C NMR
(75 MHz, TMS, CDCl3): d 55.3, 105.4, 114.3, 115.7, 117.2, 119.4, 121.6, 124.5,
126.6, 129.9, 130.2, 130.4, 134.6, 143.8, 144.2, 152.7, 156.1, 160.2, 190.9. MS m/z
(%): 370 (M?) (100), 238 (45).
4-(5-(4-Chlorophenyl)-3-(2-hydroxyphenyl)-1H-pyrazol-1-yl)benzaldehyde (3i):
mp 209–211 °C
IR (KBr) m cm-1: 3,437, 3,134, 2,920, 2,850, 1,693, 1,599, 1,510. 1H NMR
(300 MHz, TMS, CDCl3): 6.92 (s, 1H), 6.97 (t, 1H, J = 8.1 Hz), 7.07 (d, 1H,
J = 7.8 Hz), 7.24–7.31 (m, 3H), 7.37 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H,
J = 8.7 Hz), 7.63 (dd, 1H, J1 = 7.9 Hz, J2 = 1.5 Hz), 7.90 (d, 2H, J = 8.7 Hz),
10.03 (s, 1H), 10.56 (s, 1H). 13C NMR (75 MHz, TMS, CDCl3): 106.0, 115.5,
117.3, 119.5, 124.6, 126.6, 127.8, 129.2, 130.1, 130.5, 134.9, 135.5, 143.1, 143.4,
152.9, 156.12, 190.7. MS m/z (%): 374 (M?) (100), 242 (52).
4-(3-(5-Chloro-2-hydroxyphenyl)-5-(4-chlorophenyl)-1H-pyrazol-1-
yl)benzaldehyde (3j): mp 224–226 °C
IR (KBr) m cm-1: 3,423, 3,156, 2,994, 2,881, 1,756, 1,561, 1,497. 1H NMR
(300 MHz, TMS, CDCl3): d 6.90 (s, 1H), 7.01 (d, 1H, J = 9 Hz) 7.20–7.27 (m, 3H)
7.38 (d, 2H, J = 9 Hz) 7.48 (d, 2H, J = 8.7 Hz) 7.59 (d, 1H, J = 2.4 Hz) 7.91 (d,
2H, J = 8.7 Hz) 10.03 (s, 1H) 10.55 (s, 1H). 13C NMR (75 MHz, TMS, CDCl3):
d 106.0, 116.1, 118.6, 124.6, 124.8, 126.3, 127.5, 129.2, 129.7, 130.0, 135.1, 135.6,
138.2, 142.9, 143.6, 150.0, 154.6, 190.6. MS m/z (%): 408 (M?) (100), 242 (39).
Acknowledgment VTH thanks CSIR, New Delhi, India, for the award of a Senior Research Fellowship.
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