Fe-catalyzed one-pot synthesis of 1,3-Di- and 1,3,5-trisubstituted pyrazoles from hydrazones and vicinal diols

Article abstract of DOI:10.1021/jo301770k

An iron-catalyzed route for the regioselective synthesis of 1,3- and 1,3,5-substituted pyrazoles from the reaction of diarylhydrazones and vicinal diols has been developed. This method was found to be practical with wide substrate scope.

Full text of DOI:10.1021/jo301770k

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Note
Fe-catalyzed one-pot Synthesis of 1,3- and 1,3,4-
substituted pyrazoles from hydrazones and vicinal diols
Niranjan Panda, and Ashis Kumar Jena
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Sep 2012
Downloaded from http://pubs.acs.org on September 22, 2012
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Fe-catalyzed one-pot Synthesis of 1,3- and 1,3,4-substituted
pyrazoles from hydrazones and vicinal diols
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Niranjan Panda,* and Ashis Kumar Jena
Department of Chemistry
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National Institute of Technology, Rourkela-769008
Odisha, India
npanda@nitrkl.ac.in
Abstract
R
Ar
Ar
HO
R
FeCl3, acac
+
N
H
N
TBHP, O2 balloon
r.t. - 120 C
N
HO
N
Ar'
Ar'
R = H, CH3; 24 examples; 51-85 % yield
An iron-catalyzed route for the regioselective synthesis of 1,3- and 1,3,4-substituted pyrazoles
from the reaction of diarylhydrazones and vicinal diols has been developed. This method was
found to be practical with wide substrate scope.
Keywords: Pyrazoles; oxidation; hydrazone; vicinal diol.
The presence of pyrazole motif in several blockbuster drugs and pesticides including
sildenafil (Viagra), celecoxib (Celebrex), rimonabant (Acomplia), Fipronil and Pyracolfos made
this heterocycle a popular synthetic target to pharmaceutical and agrochemical industries.1
Furthermore, substituted pyrazoles are privileged structural units in many functional materials
including optical brightener,2 ultraviolet stabilizer3 etc. The rising usage of pyrazoles stimulates
the development of new and complementary methods for their synthesis. The most powerful
tool is undoubtedly the Knorr reaction of hydrazine derivatives with 1,3-dicarbonyl compounds
or their derivatives.4 However, the multistep access of appropriately functionalized 1,3-
dicarbonyl compounds and the formation of regioisomeric mixture are the inevitable drawbacks
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of this reaction.5 The replacement of 1,3-diketones with acetylenic or olefinic ketones somewhat
improves the selectivity of the synthesis.6 In recent years, 1,3-dipolar cycloaddition of
diazoalkanes or nitrile imines with olefins or alkynes has been emerged as a complementary
approach towards the regioselective synthesis of substituted pyrazoles.7 Moreover, in this
method the question of regioselectivity is transferred to the preparation and handling of 1,3-
dipoles.8 Intriguingly, transition metal-catalyzed C-C/C-N/N-N bond formation reactions using
Pd- and Cu-based catalysts are efficiently used for the synthesis of 1,3- 1,3,4-, 1,3,5- and 1,3,4,5-
substituted pyrazoles.9 However, the high cost and toxicity of these catalysts often vitiate their
synthetic utility. Thus, development of efficient, less expensive and environmental friendly
catalysts has been found to be attractive for regioselective synthesis of pyrazoles. Undeniably,
among the myriad of important transition metal catalysts, iron catalysts are particularly attractive
in modern organic synthesis in terms of economical and ecological point of view.10 As such, a
number of iron-catalyzed Friedel-Crafts reactions,11 Aldol condensation reactions,12
carbometalation reactions,13 cycloaddition reactions14 have been disclosed. Fe-catalysts are also
successfully used for the oxidation of alcohols to the corresponding carbonyl compounds in
presence of peroxide as an oxidant.15-17 However, the use of iron catalysts in heterocycle
synthesis particularly substituted pyrazoles with controlled selectivity has been less literature
precedent.18 In turn, here we report a simple and efficient FeIII-catalyzed one-pot route to access
1,3- and 1,3,4-substituted pyrazoles regioselectively. To the best of our knowledge this is the
first report on the regioselective synthesis of substituted pyrazoles from the one-pot reaction of
simple vicinal diols and diarylhydrazones.
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Our strategy towards the synthesis of pyrazoles is outlined in Scheme 1. This involves the
condensation of α-hydroxy carbonyl compounds (5) with diarylhydrazones (3) to give 2; the
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latter may undergo transition-metal-catalyzed reductive coupling to afford the desired pyrazoles
(1). We envisioned that the intermediate α-hydroxy carbonyl compounds (5) can be achieved in-
situ by the oxidation of vicinal diols (7). Indeed, our anticipation to access 5 from 7 is based on
the pioneering work of Bolm,15 Beller16 and Repo.17 They used nontoxic and inexpensive iron-
based catalysts for the oxidation of alcohols to carbonyl compounds by peroxide oxidants.
Scheme 1. Retrosynthetic analysis
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Ar
R
Ar
Ar
Y
N
R
X
R
+
N
H
N
N
N
N
HO
Ar'
Ar'
Ar'
4
3
2
1
HO
HO
R
X
R
X
R
HO
O
5
6
7
X = Br or I
To test the viability of our strategy, we took diphenylhydrazone (8) and ethylene glycol (9) as
model substrates. To synthesize 2, when the reaction was carried out in presence of FeCl3, TBHP
and pyridine no desired product was formed even at elevated temperature (120°C). Interestingly
on addition of ligand such as acetylacetone (acac) resulted 1,3-disubstituted pyrazole directly
(Table 1, entry 6). From the systematic screening of a range of iron sources, ligands and solvents
at different temperature, we found that tandem oxidation and cyclization occurred at 120 °C in
the presence of 5 mol % FeCl3 and provided 1,3-disubstituted pyrazole (10a) in 75% yield
within 6 h (Table 1). Among the tested ligands, acetylacetone (acac) was found to be more
effective to afford 10a in good yield. Notably, the reaction was sluggish in N2 as well as in air
and led to 10a in 10 and 25 % yield respectively whereas under O2 atmosphere reaction proceeds
rapidly and resulted 10a in 75% yield. The reaction did not lead to any pyrazole in absence
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TBHP or FeCl3. Moreover, optimum yield of 1,2-disubstituted pyrazole (10a) was obtained
when diphenylhydrazone and ethylene glycol were heated at 120 °C in presence of 5 mol% of
FeCl3, 2 equiv. of acac and 1 equiv. of TBHP under O2 atmosphere. In line with the pioneering
work of Barton19 and Bolm,12c it may be hypothesized that in presence of FeCl3/TBHP/O2, acac
initially oxidized in an analogous manner to an intermediate that oxidizes the diol to α-hydroxy
aldehyde. Subsequently, FeCl3 activates the in-situ generated aldehyde through coordination of
the carbonyl oxygen to the iron (III) center20 to form activated intermediate which then reacts
with hydrazone and leads to 10a.
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Table 1. Optimization of reaction conditionsa
Ph
Ph
HO
5 mol% catalyst,
N
H
N
N
Ligand, TBHP,
120 C, 6 h
O2 balloon
N
Ph
10a
HO
Ph
8
9
Entry Catalyst
Ligand
Yield (%)
1
2
3
4
5
6
7
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
--
EAA
13
10
0
DMEDA
TMEDA
1,10-phen
DEM
acac
0
≤5
75
0
acac
8
9
10
11
FeCl3
--
acac
acac
acac
13
40
≤5
20
FeCl2.2H2O
Fe(acac)3
Fe3O4
aReaction conditions: diphenylhydrazone (100 mg, 0.51 mmol), ethylene glycol (2 mL), catalyst
(5 mol %), ligand (1 mmol), TBHP (0.51 mmol), heated at 120 °C, 6 h, O2 balloon.
Next we exploited the scope of the reaction with varieties of hydrazones. A number of
substituted hydrazones were synthesized by the reaction of corresponding aldehydes and
hydrazines following the standard protocol. When diarylhydrazones were treated with ethylene
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glycol under optimum reaction conditions, 1,3-disubstituted pyrazoles (10a-q) were obtained
selectively in good yield (Table 2). Notably, the presence of electron donating substituents to N-
Table 2. Synthesis of 1,3-diaryl pyrazolesa
H
OH
HO
N
N
Ar
Ar'
Ar
N
Ar'
N
FeCl3, acac
10a-r
TBHP, 80-120 C
O2 balloon
Entry Hydrazone
Product Yield (%)b Entry Hydrazone
Product
Yield (%)
CH3
H
N
CH3
1
75
62
68
N
N
N
Ph
N
Ph
H
Ph
Ph
N
10
N
N
N
65
N
N
N
Ph
N
Ph
Ph
10a
Ph
Cl
Cl
10j
2
H
N
21
22
23
24
25
26
N NH
N
Ph
N
N
Ph
Cl
Ph
Cl
11
77
85
Cl
N
Ph
10b
Cl
10k
H
3
Cl
Cl
N
N
N
N
N
N NH
N
N
Ph
12
13
Cl
Cl
10c
Ph
Cl
Cl
Cl
10l
4
H
N
27
62
73
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35
36
N
N
O2N
Cl
N NH2
N
N
N
Ph
O2N
O2N
10d
O2N
O2N
71
74
H
10m
N
5
O2N
N
N
14
N NH
N
Ph
N
Cl
Ph
10e
O2N
10n
NO2
6
H
Cl
MeO
MeO
70
N
15
N
N
N NH
Ph
N
N
Ph
N
61
58
60
CH3
10f
10o
H
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N
CH3
Me
63
Ph
N
16
N NH
Ph
N
N
N
N
N
OH
Me
OH
OH
10g
OH
10p
H
OH
N
N
OH
65
8
9
17
18
N
N
N
Me
Ph
N
NO2
10q
O2N
Me
H
HN Ph
N
10h
10i
N
N
N
10r
S
S
H
NO2
N
00
NO2
N
68
Ph
N
N
Ph
aReaction conditions: diarylhydrazone (100 mg), ethylene glycol (2 mL), anhyd. FeCl3 (5 mol
%), acac (2 equiv.), TBHP (1 equiv.), 6 h, O2 balloon.
aryl group increases the reactivity of the hydrazone by increasing the nucleophilicity of the
nitrogen and hence the reaction completes at lower temperature (< 120°C). However, the
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presence of electron-withdrawing groups such as –NO2 to the N-phenyl ring retards the reaction
and desired pyrazole was not formed even at elevated temperature (entry 18). Furthermore, this
protocol was found to be tolerant to both electron-donating and –withdrawing groups at the C3-
aryl ring and afforded the pyrazoles in moderate to good yield.
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Having the proved efficiency of our catalytic protocol with ethylene glycol, the scope of the
reaction was subsequently extended towards the regioselective synthesis of 1,3,4-trisubstituted
pyrazoles. Thus, when diarylhyrazones were reacted with 1,2-propane diol, 1,3,4-trisubstituted
pyrazoles were resulted in moderate to good yield (Table 3). Interestingly, these reactions
proceed at room temperature in absence of any solvent although excess of diol is required.
Several 1,3,4-trisubstituted pyrazoles (11a-g) have been prepared by varying the substituents to
the aromatic ring of diarylhydrazone.
Table 3. Synthesis of 1,3,4-substituted pyrazolesa
CH3
H3C
OH
H
HO
N
Ar
N
N
FeCl3-acac,
TBHP, r. t.,
Ar'
Ar
Ar'
N
1h, O2 balloon
Me
Me
Me
Me
Cl
Ph
Ph
N
MeO
Ph
N
N
N
N
N
N
HO
Ph
N
Cl
11b; 52%
11a;55%
11d; 52%
11c; 58%
Me
Me
Me
S
N
N
N
N
MeO
N
Ph
N
Cl
Ph
OH
11f; 51%
11e; 56%
11g; 60%
aReaction conditions: diarylhydrazone (100 mg), 1,2-propanediol (2 mL), anhyd. FeCl3 (5 mol
%), acac (2 equiv.), TBHP (1 equiv.), 1 h, O2 balloon.
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In summary, we first developed iron-catalyzed one-pot synthesis of substituted pyrazoles
from the reaction of simple vicinal diols and diarylhydrazones. This protocol was found to be
tolerant to varieties electron-donating and -withdrawing substitutions to the aromatic rings. This
reaction is simple and affords a new route for the regioselective synthesis of 1,3- and 1,3,4-
substituted pyrazoles.
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Experimental
General Procedure for the synthesis of substituted 1,3-disubstituted pyrazoles (method A)
A mixture of diarylhydrazones (100 mg), FeCl3 (5 mol %) and ethylene glycol 9 (2 mL) was
stirred under O2 atmosphere at RT. To the resulting mixture acetyl acetone (2 equiv.) followed
by TBHP (1 equiv.) was added dropwise and the temperature was slowly increased to 80-120 0C.
After stirring at appropriate temperature for 6 h (completion of the reaction was monitored by
TLC), the reaction mixture was cooled to room temperature. Dichloromethane was added. The
organic layer was washed with water, dried over Na2SO4 and then evaporated under reduced
pressure. The crude product was purified by flash column chromatography using ethyl acetate
and petroleum ether as eluent to afford 10a-q.
General procedure for the synthesis of 1,3,4-trisubstituted pyrazoles 11a-g (method B)
A mixture of diaryl hydrazones 8 (100 mg) and FeCl3 (5 mol %) in propane1,2-diol (2 mL) was
stirred under O2 atmosphere. To the resulting mixture acetyl acetone (2 equiv.) followed by
TBHP (1 equiv.) was added dropwise at room temperature. After stirring for 1 h at r. t.
dichloromethane was added. The organic layer was washed with water, dried over Na2SO4 and
evaporated under reduced pressure. The crude product was purified by column chromatography
using ethyl acetate and petroleum ether as eluent to afford 1,3,4-trisubstituted pyrazoles 11a-g.
1,3-Diphenyl-1H-pyrazole (10a)21
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Following method A, the reaction was carried out at 120 °C to give 83 mg (75 %) of 10a as a
white solid. M. P.: 80-82 °C. IR (KBr): 1597, 1527, 1504, 1456, 1361 cm-1. 1H NMR (400 MHz,
CDCl3): δ 7.96-7.90 (m, 3H), 7.80-7.76 (m, 2H), 7.51-7.40 (m, 4H), 7.38-7.26 (m, 2H), 6.79 (d,
1H, J = 2.4 Hz). 13C NMR (100 MHz, CDCl3): δ 152.9 (s), 140.2 (s), 133.1 (s), 129.4 (d), 128.6
(d), 128.0 (d), 128.0 (d), 126.3 (d), 125.8 (d), 119.0 (d), 105.0 (d). MS (ESI): m/z (relative
intensity) 243 ([M+Na]+ , 100 %), 221 ([M+H]+ , 37 %).
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3-(2-chlorophenyl)-1-phenyl-1H-pyrazole (10b)22
Following method A, the reaction was stirred at 120 °C to give 68 mg (62 %) of 10b as a white
1
solid. M. P.: 134-136 °C. IR (KBr): 3050, 1597, 1503, 1448, 1386, 1348 cm-1. H NMR (400
MHz, CDCl3): δ 8.00 (d, 1H, J = 2.4 Hz), 7.99-7.95 (m, 1H), 7.80 (d, 2H, J = 8 Hz), 7.49 (t, 3H,
J = 7.6 Hz), 7.39-7.29 (m, 3H), 7.03 (d, 1H, J = 2.0 Hz). 13C NMR (100 MHz, CDCl3): δ 150.6
(s), 140.1 (s), 132.4 (s), 132.1 (s), 130.7 (d), 130.3 (d), 129.4 (d), 129.0 (d), 127.1 (d), 126.8 (d),
126.5 (d), 119.1 (d), 109.0 (d). MS (ESI): m/z (relative intensity) 277 ([M+Na]+ , 100 %), 255
([M+H]+ , 45 %).
3-(4-chlorophenyl)-1-phenyl-1H-pyrazole (10c)21
Following method A, the reaction was stirred at 120 °C to give 75 mg (68 %) of 10c as a white
1
solid. M. P.: 118 °C. IR (KBr) : 3052, 2924, 1596, 1507, 1442, 1410, 1262 cm-1. H NMR (400
MHz, CDCl3): δ 7.98 (d, 1H, J = 2.8 Hz), 7.87 (d, 2H, J = 8.4 Hz), 7.78 (d, 2H, J = 7.6 Hz),
13
7.52-7.46 (m, 2H), 7.42 (d, 2H, J = 8.4 Hz), 7.35-7.30 (m, 1H), 6.77 (d, 1H, J = 2.4 Hz). C
NMR (100 MHz, CDCl3): δ 151.8 (s), 140.1 (s), 133.7 (s), 131.6 (s), 129.4 (d), 128.8 (d), 128.1
(d), 127.0 (d), 126.5 (d), 119.0 (d), 104.9 (d). MS (ESI): m/z (relative intensity) 277 ([M+Na]+ ,
100 %), 255 ([M+H]+ , 39 %).
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3-(3-nitrophenyl)-1-phenyl-1H-pyrazole (10d)
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Following method A, the reaction was stirred at 100 °C to give 68 mg (62 %) of 10d as a yellow
solid. M. P.: 110-112 °C. IR (KBr) : 1596, 1518, 1455, 1345 cm-1. 1H NMR (400 MHz, CDCl3):
δ 8.27 (d, 1H, J = 0.8 Hz), 8.22-8.18 (m, 2H), 8.03 (d, 1H, J = 2.8 Hz), 7.80 (d, 2H, J = 7.6 Hz),
7.64-7.48 (m, 3H), 7.38-7.32 (m, 1H), 6.88 (d, 1H, J = 2.4 Hz). 13C NMR (100 MHz, CDCl3): δ
150.5 (s), 148.7 (s), 139.9 (s), 135.0 (s), 131.4 (d), 129.5 (d), 128.5 (d), 126.8 (d), 122.4 (d),
120.6 (d), 119.1 (d), 105.2 (d). MS (ESI): m/z (relative intensity) 288 ([M+Na]+ , 100 %), 266
([M+H]+ , 23 %).
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Anal. Calcd for C15H11N3O2: C, 67.92; H, 4.18; N, 15.84. Found: C, 67.89; H, 3.99; N, 15.74.
3-(4-nitrophenyl)-1-phenyl-1H-pyrazole (10e)22
Following method A, the reaction was stirred at 120 °C to give 80 mg (73 %) of 10e as a yellow
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solid. M. P.: 138-140 °C. IR (KBr): 1597, 1557, 1506, 1457, 1418, 1334 cm-1. H NMR (400
MHz, CDCl3): δ 8.31 (d, 2H, J = 8.8 Hz), 8.09 (d, 2H, J = 8.8 Hz), 8.03 (d, 1H, J = 2.4 Hz), 7.80
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(d, 2H, J = 7.6 Hz), 7.55-7.49 (m, 2H), 7.39-7.34 (m, 1H), 6.89 (d, 1H, J = 2.4 Hz). C NMR
(100 MHz, CDCl3): δ 150.5 (s), 147.3 (s), 139.9 (s), 139.4 (s), 129.5 (d), 128.6 (d), 127.0 (d),
126.2 (d), 124.0 (d), 119.2 (d), 105.8 (d). MS (ESI): m/z (relative intensity) 288 ([M+Na]+ , 100
%), 266 ([M+H]+ , 24 %).
3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole (10f)21
Following method A, the reaction was stirred at 120 °C to give 77 mg (70 %) of 10f as a white
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solid. M. P.: 102-104 °C. IR (KBr): 3141, 3059, 2959, 1596, 1510, 1452, 1389, 1358 cm-1. H
NMR (400 MHz, CDCl3): δ 7.95 (d, 1H, J = 2.4 Hz), 7.89-7.85 (m, 2H), 7.80-7.76 (m, 2H),
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7.51-7.45 (m, 2H), 7.32-7.30 (m, 1H), 7.01-6.97 (m, 2H), 6.72 (d, 1H, J = 2.4 Hz), 3.87 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 159.6 (s), 152.7 (s), 140.3 (s), 129.3 (d), 127.8 (d), 127.1 (d),
126.1 (d), 125.9 (s), 118.9 (d), 114.0 (d), 104.5 (d), 55.3 (q). MS (ESI): m/z (relative intensity)
273 ([M+Na]+ , 100 %), 251 ([M+H]+, 70 %).
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2-(1-phenyl-1H-pyrazol-3-yl)phenol (10g)22
Following method A, the reaction was stirred at 120 °C to give 70 mg (63 %) of 10g as a white
solid. M. P.: 102 °C. IR (KBr) : 3142, 3050, 2951, 2920, 2854, 1621, 1599, 1523, 1506, 1451,
1403, 1362, cm-1. 1H NMR (400 MHz, CDCl3): δ 10.87 (s), 7.99 (d, 1H, J = 2.8 Hz), 7.70 (d, 1H,
J = 8 Hz), 7.64 (d, 1H, J = 8 Hz), 7.54-7.48 (m, 2H), 7.38-7.26 (m, 2H), 7.10 (d, 1H, J = 8 Hz),
6.99-6.94 (m, 1H), 6.88 (d, 1H, J = 2.4 Hz). 13C NMR (100 MHz, CDCl3): δ 156.0 (s), 152.9 (s),
139.2 (s), 129.6 (d), 129.6 (d), 127.7 (d), 126.8 (d), 126.5 (d), 119.3 (d), 118.8 (d), 117.2 (d),
116.2 (s), 104.5 (d). MS (ESI): m/z (relative intensity) 259 ([M+Na]+ , 100 %), 237 ([M+H]+ , 55
%).
1-(1-phenyl-1H-pyrazol-3-yl)naphthalen-2-ol (10h)
Following method A, the reaction was stirred at 120 °C to give 71 mg (65 %) of 10h as a white
solid. M. P.: 74-76 °C. IR (KBr) : 3145, 3048, 2912, 1598, 1547, 1528, 1509, 1464, 1391, 1368,
1336 cm-1. 1H NMR (400 MHz, CDCl3): δ 10.53 (s, 1H), 8.33 (d, 1H, J = 8.8 Hz), 8.15 (d, 1H, J
= 2.4 Hz), 7.86-7.77 (m, 4H), 7.56-7.48 (m, 3H), 7.41-7.31 (m, 3H), 7.04 (d, 1H, J = 2.4 Hz). 13C
NMR (100 MHz, CDCl3): δ 153.7 (s), 150.4 (s), 139.4 (s), 132.0 (s), 130.4 (d), 129.6 (d), 129.0
(s), 128.7 (d), 127.9 (d), 126.8 (d), 126.7 (d), 123.8 (d), 123.0 (d), 118.9 (d), 118.8 (d), 109.8 (s),
109.5 (d). MS (ESI): m/z (relative intensity) 309 ([M+Na]+ , 100 %), 287 ([M+H]+ , 30 %). Anal.
Calcd for C19H14N2O : C, 79.70; H, 4.93; N, 9.78. Found: C, 79.80; H, 4.82; N, 9.80.
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1-phenyl(3-thiophen-2-yl)-1H-pyrazole (10i)23
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Following method A, the reaction was stirred at 120 °C to give 75 mg (68 %) of 10i as a white
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solid. M. P.: 65 °C. IR (KBr) : 3066, 2920, 1597, 1559, 1506, 1460, 1375 cm-1. H NMR (400
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MHz, CDCl3): δ 7.93 (s, 1H), 7.76 (d, 2H, J = 8 Hz), 7.51-7.44 (m, 3H), 7.34-7.29 (m, 2H), 7.13-
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7.10 (m, 1H), 6.70 (d, 1H, J = 2.4 Hz). C NMR (100 MHz, CDCl3): δ 148.2 (s), 139.9 (s),
136.3 (s), 129.4 (d), 128.0 (d), 127.4 (d), 126.4 (d), 124.9 (d), 124.2 (d), 119.0 (d), 105.0 (d). MS
(ESI): m/z (relative intensity) 249 ([M+Na]+ , 100 %), 227 ([M+H]+ , 56 %).
3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenyl-1H-pyrazole (10j)
Following method A, the reaction was stirred at 100 °C to give 70 mg (65 %) of 10j as a white
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solid. M. P.: 110-112 °C. IR (KBr) : 3048, 2922, 1595, 1506, 1450, 1408, 1378, 1337 cm-1. H
NMR (400 MHz, CDCl3): δ 8.03 (d, 1H, J = 2.4 Hz), 7.82-7.78 (m, 2H), 7.63-7.59 (m, 2H),
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7.55-7.42 (m, 5H), 7.34-7.29 (m, 1H), 6.87 (d, 1H, J = 2.8 Hz), 2.65 (s, 3H). C NMR (100
MHz, CDCl3): δ 148.9 (s), 144.9 (s), 140.1 (s), 138.2 (s), 129.4 (d), 129.2 (s), 129.0 (d), 128.1
(d), 126.9 (d), 126.2 (d), 125.2 (d), 118.7 (d), 112.2 (s), 106.6 (d), 14.6 (q). MS (ESI) m/z
(relative intensity) 357 ([M+Na]+ , 100 %), 335 ([M+H]+ , 68 %). Anal. Calcd for C19H15ClN4:
C, 68.16; H, 4.52; N, 16.73. Found: C, 68.32; H, 4.41; N, 16.75.
1-(4-chlorophenyl)-3-phenyl-1H-pyrazole (10k)24
Following method A, the reaction was stirred at 100 °C to give 85 mg (77 %) of 10k as a white
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solid. M. P. : 132-133 °C. IR (KBr) : 3059, 1594, 1530, 1505, 1491, 1451, 1385 cm-1. H NMR
(400 MHz, CDCl3): δ 7.96-7.90 (m, 3H), 7.76-7.72 (m, 2H,), 7.48-7.44 (m, 4H), 7.40-7.34 (m,
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1H), 6.80 (d, 1H, J = 2.4 Hz). C NMR (100 MHz, CDCl3): δ 153.2 (s), 138.7 (s), 132.8 (s),
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131.7 (s), 129.4 (d), 128.7 (d), 128.2 (d), 127.9 (d), 125.8 (d), 120.0 (d), 105.4 (d). MS (ESI) m/z
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(relative intensity) 277 ([M+Na]+ , 54 %), 255 ([M+H]+ , 30 %).
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1,3-bis(4-chlorophenyl)-1H-pyrazole (10l)
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Following method A, the reaction was stirred at 100 °C to give 92 mg (85 %) of 10l as a white
solid. M. P.: 136 °C. IR (KBr) : 3145, 3048, 1594, 1565, 1501, 1443, 1419, 1381 cm-1. 1H NMR
(400 MHz, CDCl3): δ 7.93 (d, 1H, J = 2.4 Hz), 7.88-7.82 (m, 2H), 7.75-7.69 (m, 2H), 7.48-7.40
(m, 4H), 6.76 (d, 1H, J = 2.4 Hz). 13C NMR (100 MHz, CDCl3): δ 152.0 (s), 138.6 (s), 133.9 (s),
131.9 (s), 131.4 (s), 129.5 (d), 128.8 (d), 128.0 (d), 127.0 (d), 120.1 (d), 105.3 (d). MS (ESI) m/z
relative intensity 289 ([M+H]+, 40%). Anal. Calcd for C15H10Cl2N2: C, 62.30; H, 3.49; Cl, 24.52;
N, 9.69. Found: C, 62.33; H, 3.35; N, 9.65.
1-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazole (10m)25
Following method A, the reaction was stirred at 80 °C to give 77 mg (71 %) of the 1,3-
diarylpyrazole 10m as a yellow solid. M. P.: 168-170 °C. IR (KBr) : 2920, 1598, 1555, 1511,
1449, 1422, 1343 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.33-8.29 (d, 2H, J = 8.8 Hz), 8.10-8.06
(d, 2H, J = 8.8 Hz), 8.00 (d, 1H, J = 2.4 Hz), 7.77-7.73 (d, 2H, J = 8.4 Hz), 7.51-7.46 (d, 2H, J =
8.8 Hz), 6.90 (d, 1H, J = 2.4 Hz). 13C NMR (100 MHz, CDCl3): δ 150.8 (s), 147.4 (s), 139.1 (s),
138.4 (s), 132.5 (s), 129.6 (d), 128.5 (d), 126.2 (d), 124.1 (d), 120.3 (d), 106.2 (d).
1-(4-chlorophenyl)-3-(3-nitrophenyl)-1H-pyrazole (10n)
Following method A, the reaction was stirred at 90 °C to give 80 mg (74 %) of 10n as a yellow
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solid. M. P.: 144-146 °C. IR (KBr) : 3083, 1594, 1519, 1501, 1433, 1416, 1346, 1308 cm-1. H
NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.28-8.18 (m, 2H), 8.00 (d, 1H, J = 2.8 Hz), 7.77-7.72
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(m, 2H), 7.62 (t, 1H, J = 8 Hz), 7.51-7.45 (m, 2H), 6.89 (d, 1H, J = 2.4 Hz). C NMR (100
MHz, CDCl3): δ 150.8 (s), 148.7 (s), 138.4 (s), 134.7 (s), 132.3 (s), 131.5 (d), 129.6 (d), 128.4
(d), 122.6 (d), 120.6 (d), 120.2 (d), 105.6 (d). MS (ESI): m/z (relative intensity) 300 ([M+H]+ ,
48 %). Anal. Calcd for C15H10ClN3O2: C, 60.11; H, 3.36; Cl, 11.83; N, 14.02. Found: C, 60.21;
H, 3.21; N, 14.25.
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3-phenyl-1-p-tolyl-1H-pyrazole (10o)21
Following method A, the reaction was stirred at 90 °C to give 67 mg (61 %) of 10o as a white
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solid. M. P.: 110-111 °C. IR (KBr) : 3145, 3029, 1605, 1521, 1453, 1389, 1364 cm-1. H NMR
(400 MHz, CDCl3): δ 7.95-7.91 (m, 3H), 7.69-7.64 (m, 2H,), 7.48-7.42 (m, 2H), 7.38-7.32 (m,
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1H), 7.30-7.26 (m, 2H), 6.78 (d, 1H, J = 2.8 Hz), 2.41 (s, 3H). C NMR (100 MHz, CDCl3): δ
152.6 (s), 138.0 (s), 136.1 (s), 133.2 (s), 129.9 (d), 128.6 (d), 127.9 (d), 125.8 (d), 119.0 (d),
104.7 (d), 20.9 (q). MS (ESI): m/z (relative intensity) 257 ([M+Na]+ , 69 %), 235 ([M+H]+ , 100
%).
2-(1-p-tolyl-1H-pyrazol-3-yl)phenol (10p)
Following method A, the reaction was stirred at 90 °C to give 64 mg (58 %) of 10p as a white
solid. M. P.: 117-119 °C. IR (KBr) : 3152, 3044, 2955, 1619, 1584, 1519, 1454, 1402, 1365,
1299 cm-1. 1H NMR (400 MHz, CDCl3): δ 10.87 (s, 1H), 7.95 (d, 1H, J = 2.8 Hz), 7.66-7.56 (m,
3H), 7.32-7.24 (m, 4H), 7.08 (d, 1H, J = 8 Hz), 7.07-6.93 (m, 1H), 6.86 (d, 1H, J = 3.2 Hz), 2.42
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 155.9 (s), 152.6 (s), 137.1 (s), 136.7 (s), 130.1 (d), 129.5
(d), 127.6 (d), 126.5 (d), 119.3 (d), 118.8 (d), 117.1 (d), 116.3 (s), 104.2 (d), 20.9 (q). MS (ESI):
m/z (relative intensity) 273 ([M+Na]+ , 60 %), 250 ([M+H]+ , 100 %). Anal. Calcd for
C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.67; H, 5.48; N, 11.35.
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Following method A, the reaction was stirred at 80 °C to give 65 mg (60 %) of 10q as a yellow
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solid. M. P.: 113-115 °C. IR (KBr) : 3032, 2921, 2854, 1609, 1580, 1522, 1455, 1347 cm-1. H
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NMR (400 MHz, CDCl3): δ 8.76-8.74 (m, 1H), 8.26 (d, 1H, J = 8 Hz), 8.20-8.16 (m, 1H), 7.97
(d, 1H, J = 2.4 Hz),7.67 (d, 2H, J = 8.4 Hz), 7.59 (t, 1H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.4 Hz),
6.84 (d, 1H, J = 2.4 Hz), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 150.2 (s), 148.7 (s), 137.7
(s), 136.7 (s), 135.0 (s), 131.4 (d), 130.0 (d), 129.5 (d), 128.4 (d), 122.4 (d), 120.5 (d), 119.1 (d),
105.0 (d), 20.9 (q). MS (ESI) m/z (relative intensity) 302 ([M+Na]+ , 100 %), 280 ([M+H]+, 43
%). Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N, 15.05. Found: C, 68.75; H, 4.52; N,
15.14.
4-methyl-1,3-diphenyl-1H-pyrazole (11a)
Following method B, the reaction was stirred at r. t. to give 66 mg (55 %) of the 1,3-diaryl-4-
methylpyrazole 11a as a liquid. IR (neat): 3060, 2924, 1597, 1549, 1500, 1456, 1412, 1365 cm-1.
1H NMR (400 MHz, CDCl3): δ 7.91-7.86 (m, 2H), 7.57-7.48 (m, 4H), 7.45-7.39 (m, 3H), 7.36-
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7.32 (m, 1H), 6.55 (s, 1H), 2.41 (s, 3H). C NMR (100 MHz, CDCl3): δ 151.5 (s), 140.1 (s),
139.9 (s), 133.3 (s), 129.0 (d), 128.5 (d), 127.7 (d), 127.6 (d), 125.7 (d), 125.0 (d), 104.3 (d),
12.5 (q). MS (ESI): m/z (relative intensity) 257 ([M+Na]+ , 100 %), 235 ([M+H]+ , 88 %). Anal.
Calcd for C16H14N2: C, 82.02; H, 6.02; N, 11.96. Found: C, 82.21; H, 5.87; N, 11.87.
3-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole (11b)
Following method B, the reaction was stirred at r. t. to give 60 mg (52 %) of 11b as a white
crystaline solid. M. P.: 80 °C. IR (KBr) : 3059, 2920, 1597, 1547, 1501, 1453, 1431, 1397, 1360
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3H), 6.51 (s, 1H), 2.39 (s, 3H). C NMR (100 MHz, CDCl3): δ 150.4 (s), 140.4 (s), 139.8 (s),
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133.4 (s), 131.9 (s), 129.1 (d), 128.7 (d), 127.7 (d), 126.9 (d), 124.9 (d), 104.3 (d), 12.5 (q). MS
(ESI): m/z (relative intensity) 291 ([M+Na]+ , 97 %), 269 ([M+H]+ , 100 %). Anal. Calcd for
C16H13ClN2: C, 71.51; H, 4.88; N, 10.42. Found: C, 71.45; H, 4.69; N, 10.56.
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3-(4-methoxyphenyl)-4-methyl-1-phenyl-1H-pyrazole (11c)
Following method B, the reaction was stirred at r. t. and gave 68 mg (58 %) of 11c as a white
solid. M. P.: 102-104 °C. IR (KBr): 3059, 2956, 1597, 1523, 1500, 1453, 1432, 1404, 1362, 1292
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cm-1. H NMR (400 MHz, CDCl3): δ 7.82-7.78 (m, 2H), 7.56-7.47 (m, 4H), 7.42-7.37 (m, 1H),
6.98-6.93 (m, 2H), 6.47 (s, 1H), 3.85 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.4
(s), 151.3 (s), 140.0 (s), 139.9 (s), 129.0 (d), 127.4 (d), 126.9 (d), 126.1 (s), 124.9 (d), 113.9 (d),
103.9 (d), 55.2 (q), 12.5 (q). MS (ESI): m/z (relative intensity) 287 ([M+Na]+ , 100 %), 265
([M+H]+ , 85 %). Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.32; H,
5.97; N, 10.72.
4-(1-(4-chlorophenyl)-4-methyl-1H-pyrazol-3-yl)phenol (11d)
Following method B, the reaction was stirred at r. t. to give 61 mg (52 %) of 11d as a white
solid. M. P. : 176-178 °C. IR (KBr): 2984, 1611, 1551, 1524, 1496, 1466, 1435, 1404, 1362 cm-
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1. H NMR (400 MHz, CDCl3): δ 7.71-7.67 (m, 2H), 7.46 (m, 4H), 6.85-6.81 (m, 2H), 6.46 (s,
1H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 155.7 (s), 151.7 (s), 140.2 (s), 138.3 (s), 133.2
(s), 129.2 (d), 127.2 (d), 126.0 (d), 125.6 (s), 115.5 (d), 104.3 (d), 12.5 (q). MS (ESI): m/z
(relative intensity) 307 ([M+Na]+ , 51 %), 285 ([M+H]+ , 46 %). Anal. Calcd for C16H13ClN2O:
C, 67.49; H, 4.60; N, 9.84. Found: C, 67.32; H, 4.47; N, 10.02.
1-(4-chlorophenyl)-3-(4-methoxyphenyl)-4-methyl-1H-pyrazole (11e)
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Following method B, the reaction was stirred at r. t. to give 64 mg (56 %) of 11e as a colourless
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6.93 (m, 2H), 6.47 (s, 1H), 3.86 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.5 (s),
151.6 (s), 140.0 (s), 138.5 (s), 133.1 (s), 129.2 (d), 126.9 (d), 125.9 (s), 114.0 (d), 104.3 (d), 55.2
(q), 12.5 (q). MS (ESI): m/z (relative intensity) 321 ([M+Na]+ , 91 %), 299 ([M+H]+ , 100 %).
Anal. Calcd for C17H15ClN2O: C, 68.34; H, 5.06; Cl, 11.87; N, 9.38. Found: C, 68.44; H, 5.03;
N, 9.39.
2-(4-methyl-1-phenyl-1H-pyrazol-3-yl)phenol (11f)
Following method B, the reaction was stirred at r. t. to give 60 mg (51 %) of 11f as a colourless
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liquid. IR (neat): 3133, 3102, 3056, 1619, 1596, 1548, 1501, 1458, 1367, 1295 cm-1. H NMR
(400 MHz, CDCl3): δ 10.94 (s, 1H), 7.60 (d, 1H, J = 1.6 Hz), 7.59-7.49 (m, 4H), 7.47-7.41 (m,
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1H), 7.27-7.21 (m, 1H), 7.06-7.02 (m, 1H), 6.97-6.91 (m, 1H), 6.61 (s, 1H), 2.44 (s, 3H). C
NMR (100 MHz, CDCl3): δ 156.1 (s), 151.6 (s), 139.9 (s), 139.1 (s), 129.2 (d), 129.1 (d), 127.9
(d), 126.3 (d), 124.6 (d), 119.1 (d), 117.0 (d), 116.4 (s), 103.8 (d), 12.4 (q). MS (ESI): m/z
(relative intensity) 273 ([M+Na]+ , 91 %), 251 ([M+H]+ , 100 %). Anal. Calcd for C16H14N2O: C,
76.78; H, 5.64; N, 11.19. Found: C, 76.88; H, 5.58; N, 11.29.
4-methyl-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole (11g)
Following method B, the reaction was stirred at r. t. to give 71 mg (60 %) of 11g as a colourless
1
liquid. IR (neat): 3067, 2962, 1596, 1565, 1532, 1500, 1424, 1375, 1327 cm-1. H NMR (400
MHz, CDCl3): δ 7.54-7.46 (m, 4H), 7.43-7.37 (m, 2H), 7.28-7.26 (m, 1H), 7.10-7.06 (m, 1H),
13
6.45 (s, 1H), 2.37 (s, 3H). C NMR (100 MHz, CDCl3): δ 146.8 (s), 140.2 (s), 139.6 (s), 136.6
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(s), 129.1 (d), 127.7 (d), 127.4 (d), 125.0 (d), 124.5 (d), 123.8 (d), 104.3 (d), 12.5 (q). MS (ESI)
m/z (relative intensity) 263 ([M+Na]+ , 100 %), 241 ([M+H]+ , 55 %). Anal. Calcd for
C14H12N2S: C, 69.97; H, 5.03; N, 11.66; S, 13.34. Found: C, 70.00; H, 4.90; N, 11.56; S, 13.25.
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Acknowledgment. We thank DST, (Ref. No. SR-S1/OC-60/2011), New Delhi and BRNS (Ref.
No. 2012/37C/3/BRNS), DAE. Govt of India for financial support. DST, (Ref. No. SR/FST/CS1-
018/2010), New Delhi also thanked for providing MS facility at NIT Rourkela.
Supporting Information Available. NMR spectra of compounds 10a-q and 11a-g. This
material is available free of charge via the Internet at http://pubs.acs.org.
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