Facile synthesis of pyrazoles by iron-catalyzed regioselective cyclization of hydrazone and 1,2-diol under ligand-free conditions

Article abstract of DOI:10.1016/j.jorganchem.2018.02.043

A facile synthesis of pyrazoles by the cyclization of hydrazones and 1,2-diols was described. In the presence of ferric nitrate, the reaction occurs under neat conditions and makes the use of potassium persulfate to oxidize the diol to α-hydroxy carbaldehyde for the reaction with hydrazones to produce 1,3- and 1,3,5-substituted pyrazoles selectively. The overall regioselective transformation occurs in one-pot under ligand-free, mild conditions even in the presence of air.

Full text of DOI:10.1016/j.jorganchem.2018.02.043

Accepted Manuscript
Facile synthesis of pyrazoles by iron-catalyzed regioselective cyclization of hydrazone
and 1,2-diol under ligand-free conditions
Niranjan Panda, Subhadra Ojha
PII:
S0022-328X(18)30143-8
10.1016/j.jorganchem.2018.02.043
JOM 20342
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 16 January 2018
Revised Date: 19 February 2018
Accepted Date: 24 February 2018
Please cite this article as: N. Panda, S. Ojha, Facile synthesis of pyrazoles by iron-catalyzed
regioselective cyclization of hydrazone and 1,2-diol under ligand-free conditions, Journal of
Organometallic Chemistry (2018), doi: 10.1016/j.jorganchem.2018.02.043.
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ACCEPTED MANUSCRIPT
Facile Synthesis of Pyrazoles by Iron-catalyzed
Regioselective Cyclization of Hydrazone and 1,2-
diol under Ligand-free Conditions
Niranjan Panda* and Subhadra Ojha
Department of Chemistry, National Institute of Technology Rourkela, Odisha-769008, India
Email: npanda@nitrkl.ac.in; niranjanpanda@gmail.com; ORCID: 0000-0002-7431-8826
KEYWORDS: Pyrazoles, Iron-catalysis, 1,2-diol, hydrazones, ligand-free condition
ABSTRACT: A facile synthesis of pyrazoles by the cyclization of hydrazones and 1,2-diols was
described. In the presence of ferric nitrate, the reaction occurs under neat conditions and makes
the use of potassium persulfate to oxidize the diol to α-hydroxy carbaldehyde for the reaction
with hydrazones to produce 1,3- and 1,3,5-substituted pyrazoles selectively. The overall
regioselective transformation occurs in one-pot under ligand-free, mild conditions even in the
presence of air.
Graphical Abstract
1

ACCEPTED MANUSCRIPT
Highlights
•
An iron-catalyzed protocol for the synthesis of N-aryl pyrazoles starting from hydrazone
and 1,2-diol was described.
•
•
This reaction proceeds under mild reaction conditions in the absence of any ligand
This protocol eliminates the regioselective issue that usually associated with 1,3,5-
trisubstituted pyrazoles.
2

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1.1 Introduction
Pyrazoles are privileged structural motifs abundant in numerous agrochemicals and
pharmaceuticals.1 Substituted pyrazoles show a broad spectrum of biological activities, including
anti-inflammatory, antipyretic, analgesic, sedative, and hypnotic properties.2 They are also often
realized as optical brighteners,3 ultraviolet stabilizers,4 and building blocks in supramolecular
assemblies.5 Of the many methods developed, acid-catalyzed cyclocondensation of hydrazines
with 1, 3- dicarbonyl compounds (known as Knorr pyrazole synthesis) has been adapted as the
standard method to achieve pyrazoles.6,7 However, multistep access to appropriately substituted
dicarbonyl compounds and lack of regiospecificity of the product greatly reduce the
attractiveness of this method.8 1,3-dipolar cycloaddition of diazoalkanes or nitrile imines with
olefins or alkynes is another increasingly used method to synthesize pyrazoles.7,9 Notably,
though the later method somewhat overcomes the regioselectivity problem; difficulty in
preparation and explosive nature of diazonium salt vitiate the large scale use.10 As a result,
development of other alternative synthetic methods has been received considerable attention.
Indeed, several prevalent miscellaneous methods, including transition-metal-catalyzed
cyclocondensation and functionalization of pyrazole core-structure leading to the target molecule
have been emerged. For this purpose, several transition metal catalysts including Pd, Cu, Rh, Ru
and Co have been employed.11 Moreover, these catalysts are expensive and have their inherent
toxicity. Thus, the use of an efficient, environmentally benign and less expensive commercially
viable catalysts, such Fe for the construction of pyrazole structure is stimulating.12 Evidently,
there appear scattered precedents on the Fe-catalyzed synthesis of pyrazole derivatives.13 For
instance, iron(II) bromide catalyzed reaction of azides with methyl oxime substituents led to
pyrazoles through the formation of an N-O or N-N bond was developed by Driver and co-
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workers (Scheme 1a).13a In 2011, Bi et al. reported an iron-catalyzed method for the aminolysis
of β-carbonyl 1,3-dithianes with hydrazine hydrate to produce 3,4-disubstituted pyrazoles in
good yields (Scheme 1b).13b Zhang and Bao reported FeBr3/O2 mediated facile synthesis of
substituted pyrazoles from arylhydrazones via C−H activation/C−N bond formation reactions
(Scheme 1c).13c Very recently, Zhao and co-workers developed an iron(III) phthalocyanine
chloride-catalyzed oxidation–aromatization protocol for the synthesis of 3,5-disubstituted 1H-
pyrazoles by the reaction of α, β-unsaturated ketones with hydrazine hydrate (Scheme 1d).13d
Besides, previously, we have developed a strategically different, ligand-mediated FeCl3/O2-
catalyzed method for the regioselective synthesis of 1,3- and 1,3,5-substituted pyrazoles from the
reaction of diarylhydrazones and vicinal diols under neat conditions (Scheme 1e).14 Although our
method merits over complete regioselectivity control, necessities for stoichiometric excess
amounts of diol (liquid) and optimal ligand (i.e., acetylacetone, 2 equiv), which is quite wasteful,
are striking shortcomings. Within this context, in continuation of our earlier work15 here we
report a more simple iron-catalyzed outcompeted method for the synthesis of 3- and 3,5-
substituted N-arylpyrazoles from the reaction of diaryl hydrazones and diols under ligand-free
conditions using less expensive oxidant.
In our earlier report,14 we have proposed that the ligand-mediated selective oxidation of
vicinal diol by Fe+3/TBHP produces α-hydroxy carbonyl compound; which subsequently reacts
with hydrazone of carbaldehyde affords pyrazole in-situ. Evidently, in the absence of ligand (i.e.
acetyl acetone) the reaction produces only 13% of the required pyrazole, while the use of the
stoichiometric excess of ligand (2 equiv.) improves the yield. Indeed, the excess of ligand is not
only wasteful but also somewhat poses difficulty in purification. Therefore, development of a
simple and economical method for the regioselective synthesis of pyrazoles seems to be worthy.
4

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In this context, we speculated that if the overall oxidation of diol can be achieved by any other
oxidant under ligand-free conditions in-situ, then the desired pyrazoles could be obtained
regioselectively from the reaction of hydrazone in the presence of less expensive eco-friendly
Fe-catalyst.
Scheme 1. Fe-catalyzed pyrazole synthesis
Previous works
R1
R1
OMe
N
FeBr2
N
OMe
a)
b)
N3
N
Driver, 2010
N
NH
O
S
FeCl3
R1
R1
S
NH2.NH2. H2O
R2
R2
Bi et al. 2011
Ar
Ar
N
NH
FeBr3, O2
N
N
R2
c)
d)
R1
R2
R1
Zhang and Bao 2013
H
N
O
Fe(III)Cl-Pc,air
N
N2H4. H2O
R2
+
R1
R2
Zhao et al. 2016
R1
Ar
Ar
HO
R2
NH
N
FeCl3/TBHP, O2
N
N
+
R2
e)
acac (2 equiv.)
R1
H
HO
R1
Panda et al. 2012
40 equiv.
Present work
Ar
N
Ar
Fe(NO3)3. 9H2O
(5 mol%)
HO
R2
NH
N
N
+
R2
K2S2O8
HO
R1
R1
H
(2 equiv.)
No ligand
functional group tolerant
Mild reaction conditions
1.2 Results and Discussion
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We, therefore, began our study with the screening of various oxidants in the presence of Fe-
catalysts for the reaction of phenyl hydrazone of benzaldehyde (1) and 1,2-propane diol (2)
(Table 1). To our dismay when the reactions were conducted with the oxidants such as CAN,
BQ, H2O2 in the presence Fe(NO3)3.9H2O (5 mol%) catalyst, desired pyrazole 3a was not formed
rather hydrazone (1a) decomposed completely (entries 1-3). Moreover, similar reactions in the
presence of other oxidants such as TBHP, MnO2, DDQ, Ag2CO3, Ag2O, AgOAc, oxone and
(NH4)2S2O8 produce 3a in 13-44% yield (entries 4-11) under neat conditions (hydrazone 1
equiv., diol 15 equiv. and oxidant 1 equiv. at 60°C). Moreover, an improved yield of 47% was
achieved when 1 equiv. of potassium persulfate (K2S2O8) was used as the terminal oxidant (entry
12). Notably, lowering the temperature to room temperature and decreasing the concentration of
diol to 2 equiv. increases the yield of the reaction further to 52% (entry 13). Additionally, the
optimum yield of 68% was obtained when hydrazone (1a) was treated with propane diol (2) (2
equiv.) in the presence of 2 equiv. of potassium persulfate at room temperature for 12 h (entry
14). Further rise in the concentration of K2S2O8 or prolonged stirring for 24h did not afford better
yield. To test the catalytic efficiency of other iron salts such as FeCl2, FeBr3, Fe(acac)2, FeCl3,
FeSO4, the similar reaction was performed (entries 15-21). However, Fe(NO3)3 furnished the
best yield. Addition of acetyl acetone (2 equiv.) as ligand14 did not improve the yield of 3a,
rather detrimental effect (39% yield) was observed. Under controlled experimental condition
when the reaction was carried out in the absence of any oxidant, i.e., treatment of 1a with 2 in
the presence of ferric nitrate did not produce any pyrazole 3a with complete recovery of starting
material (entry 22). While similar reaction in the absence of iron salt and the presence
peroxosulfate afforded 3a in 13% yield (entry 23). Surprisingly, in the presence of any polar as
well as non-polar solvents no or trace amount of product forms with the decomposition of
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ACCEPTED MANUSCRIPT
hydrazone 1a. Additionally, we have not identified any 3, 4-substituted N-aryl pyrazole (3a’)
from the reaction mixture.
Table 1. Optimization of reaction conditionsa
Me
Ph
Ph
OH
Me
Ph
[Fe]-catalyst
oxidant, 12 h
+
HO
and/or
N
N
N
Me
NH
N
N
Ph
Ph
3a,
Ph
3a
2
1a
Entry Oxidant
Catalyst
Yield (%)b
1
2
3
4
5
6
7
8
9
CAN
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
0
BQ
0
H2O2
0
TBHP
MnO2
DDQ
Ag2CO3
AgOAc
Ag2O
21
13
44
23
41
49
47
33
47
52c
68d
36 d
51d
10 Oxone
11 (NH4)2S2O8 Fe(NO3)3.9H2O
12 K2S2O8
13 K2S2O8
14 K2S2O8
15 K2S2O8
16 K2S2O8
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
Fe(NO3)3.9H2O
FeCl2
FeBr3
7

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17 K2S2O8
18 K2S2O8
19 K2S2O8
20 K2S2O8
21 K2S2O8
22 --
Fe3O4
49d
47d
38d
Fe(acac)3
FeCl3
FeCl3.6H2O
FeSO4.7H2O
Fe(NO3)3.9H2O
-
32d
27d
N.R.
13
23
K2S2O8
a
Reaction conditions: Hydrazone 1a (100 mg, 0.51 mmol), diol 2 (15 equiv), oxidant ( 0.51
mmol, 1 equiv), catalyst (5 mol%), 60°C. bGC yield. c Hydrazone 1a (100 mg, 0.51 mmol), diol 2
d
(2 equiv), oxidant (0.51 mmol, 1 equiv), catalyst (5 mol%), rt. Hydrazone 1a (100 mg, 0.51
mmol), diol 2 (2 equiv), oxidant (1.02 mmol, 2 equiv), catalyst (5 mol%), rt.
To explain the reaction pathway and regioselectivity, some experiments were performed. For
instance when benzyl alcohol (0.51 mmol) was treated with 1 equiv. of K2S2O8 in the presence of
Fe(NO3)3.9H2O, benzaldehyde was produced (50% yield) with complete consumption of the
starting material at room temperature. While the similar reaction of 1-phenylethane-1,2-diol
(0.36 mmol) afforded 2-hydroxy-1-phenylethanone16 (24% yield) along with some other
unidentified impurities; which indicates that the catalytic protocol initially oxidizes the
secondary alcoholic group preferentially than the primary alcoholic –OH group though the exact
reason is not known yet.17 A plausible mechanism for overall transformation is described in
Scheme 2. Thus, in the presence of K2S2O8 and Fe(NO3)3.9H2O, 1,2-propane diol (2) oxidized to
1-hydroxypropan-2-one (I), which subsequently reacts with hydrazone 1a to produce the enol II
via the iminium ion intermediate. II might be tautomerized to the corresponding carbonyl
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compound III. Co-ordination of iron to the carbonyl group and subsequent intramolecular
annulation leads to the intermediate V. Removal of water as well aromatization produces the
desired pyrazole 3a.
Scheme 2. Plausible mechanism
Me
HO
2
OH
2-
S2O8
Fe+3
Me
Ph
OH
Ph
H
OH
Me
HO
Ph
Ph
OH
Me
Ph
O
OH
Me
O
N
N
I
N
N
N
N
N
NH
Ph
N
N
Me
Ph
Ph
Ph
Ph
III
1a
II
Ph
O Fe+3
Me
H
Ph
OH
Me
Fe+3
Ph
-H2O
N
Me
N
N
N
N
N
Ph
Ph
Ph
3a
V
IV
With the optimum condition in hand, scope and limitation of the reaction were investigated
(Table 2). Thus, when phenyl hydrazones of differently substituted aryl carbaldehyde react with
the 1,2-propane diol, the corresponding 1,3,5-trisubstituted pyrazoles were produced smoothly in
moderate yield. Hydrazones having both electron-donating and -withdrawing groups attached to
hydrazones (1a-1e) afforded the desired pyrazoles 3a-3e in moderate yield. Hydrazones derived
from thiophene 2-carbaldehyde produces the substituted pyrazoles (3f), while the similar reaction
of furfural failed with the complete decomposition of starting material (3g). Besides, hydrazones
derived from the differently substituted aryl hydrazines (i.e., -Me, –Cl, -Br) produces the
corresponding 1,3,5-substituted pyrazoles in appreciable yield. However, hydrazones with the
corresponding electron-withdrawing groups (1l, 1m) were failed to give pyrazole (i.e., 3l and
3m) probably due to the poor nucleophilicity of nitrogen (e.g., 1 II).
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Table 2. Synthesis of 1,3,5-substituted pyrazoles
Me
Me
Ar'
OH
Ar
HO
2
H
N
N
N
Ar
N
Ar'
Fe(NO3)3.9H2O
(0.005 mmol, 5 mol%)
K2S2O8 (2 equiv.) rt-60°C
3
1
(0.1 mmol)
substrate
Entry
product
yield (%)
H
N
Me
N
Ph
Ph
N
N
68
32
1
2
Ph
1a
3a
Cl
H
N
Me
N
N
N
N
Cl
Ph
Me
Ph
3b
1b
H
N
NO2
Ph
Ph
3
4
b
45
N
N
NO2
1c
3c
H
N
Me
N
Cl
66
N
Cl
N
Ph
1d
3d
3e
H
Me
b
N
N
Ph
39
O2N
5
N
N
O2N
Ph
1e
H
N
Me
N
N
Ph
Ph
38
0
6
7
N
N
S
S
N
N
Ph
3f
1f
H
N
Me
O
O
Ph
3g
1g
10

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Entry
substrate
product
yield (%)
Me
Br
Me
N
Ph
Ph
N
N
H
1h
8
b
b
Me
42
48
Ph
N
3h
Me
N
N
H
N
Br
9
Ph
N
1i
3i
Me
N
Cl
b
Cl
10
68
m-O2NC6H4
N
M-O2NC6H4
N
N
H
3j
1j
Me
Me
b
65
p-MeC6H4
N
11
N
Me
N
p-MeC6H4
N
H
3k
1k
Me
Ph
Ph
N
Ts
12
13
N
H
N
Ts
0
0
Ph
Ph
N
3l
Me
1l
N
COPh
N
H
N
COPh
N
1m
3m
a Reaction conditions: 1 (0.51 mmol), 2 (1.02 mmol, 2 equiv), oxidant (1.02 mmol, 2.0 equiv),
Fe(NO3)3.9H2O (5 mol %), rt, 12h. b similar condition but heated at 60oC.
Next, we surveyed the suitability of this protocol for the synthesis of 1,3-substituted
pyrazoles (Scheme 3) from the reaction of hydrazone from the carbaldehyde (1) and ethylene
glycol (4). Interestingly, under similar reaction conditions, various 1,3-disubstituted pyrazoles
(5-18) were produced readily even at room temperature in moderate to good yield.
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Scheme 3. Synthesis of 1,3-diaryl pyrazoles
OH
HO
4
H
(2 equiv.)
N
Ar
Ar
N
Ar'
N
N
Ar'
Fe(NO3)3.9H2O (0.5 mol%)
K2S2O8 (2 equiv.), rt - 60°C
1
Cl
NO2
N
N
N
N
N
N
N
Ph
Ph
N
Ph
7 (45%)b
5 (87 %)
6 (76%)
Cl
O2N
N
N
N
Ph
N
Ph
Ph
O2N
10 (73%)
9 (65%)
8 (69%)
OH
MeO
Me
N
N
N
N
N
Ph
Ph
N
Ph
11 (66%)
12 (44%)
13 (69%)
OH
Ph
N
N
N
N
N
S
N
Ph
Cl
15 (65%)
16 (82%)b
14 (62%)
Cl
Br
Ph
N
N
N
N
Br
18 (89%)b
17 (79%)b
aReaction conditions: 1 (0.51 mmol), 4 (1.02 mmol, 2 equiv), K2S2O8 (1.02 mmol , 2.0 equiv),
Fe(NO3 )3.9H2O (5 mol %), rt, 12h. b similar condition but heated at 60oC.
In conclusion, we have developed a simple and economical method for the regioselective
synthesis of 1,3,5-trisubstituted pyrazoles from the reaction of hydrazones of aryl carbaldehyde
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and 1,2-propane diol. Low concentration of inexpensive ferric nitrate salt was employed as the
catalyst along with oxidant potassium persulfate to catalyze the reaction. It is expected that in the
presence of Fe+3 peroxosulfate oxidizes the diol to 1-hydroxypropan-2-one, which subsequently
reacts with hydrazone to produce the required pyrazoles. Additionally, when ethylene glycol was
employed instead of 1,2-propane diol, 1,3-disubstituted pyrazoles are generated efficiently.
Application of this strategy to the synthesis of natural products is going on in our laboratory.
Experimental
General Information: Unless otherwise noted, the reagents (chemicals) were purchased from
commercial sources and used without further purification. Hydrazones were prepared by
following the literature procedure from the reaction of carbaldehyde and hydrazine in methanol
at room temperature. The reactions were monitored by TLC, and the residue was
chromatographed on a pad of silica gel (mesh 80-120) (Merck, India), using an ethyl acetate-
petroleum ether (60-80 °C) mixture as eluent. All NMR spectra were recorded on a 400 MHz
1
(for H NMR) and 100 MHz (for 13C NMR) NMR spectrometer (Bruker, Avance III), and
chemical shifts were expressed in δ units (ppm). Multiplicities are indicated as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet, when multiplicity is complex) for 1H NMR.
Coupling constants, J were reported in Hz. High-resolution mass spectrometry (ESI-HRMS)
(Agilent 6520 Q-TOF) was used to determine the elemental composition.
General procedure for the Synthesis of substituted Pyrazoles
Method A: A mixture of diaryl hydrazones (0.51 mmol), K2S2O8 (2 equiv.), Fe(NO3)3.9H2O (5
mol%) and diol (1.02 mmol, 2 equiv.) was stirred at room temperature for 12h. After complete
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consumption of hydrazone, the reaction mixture was poured into water (20 mL) and extracted
with dichloromethane (3 x 20 mL). The combined organic layer was washed with water (50 mL),
dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by
column chromatography using ethyl acetate and petroleum ether as eluent to afford the desired
pyrazoles.
Method B: Similar to method A, but the reaction mixture was stirred at room temperature
instead of heating at 60°C for 12h stirring.
Synthesis and Analytical Data
5-Methyl-1,3-diphenyl-1H-pyrazole14 (3a). Following method A, the reaction was carried out at
rt to give 75 mg (68% yield) of 3a as a yellow liquid. IR: 3060, 2924, 1597, 1549, 1500, 1456,
1412, 1365 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.91-7.85 (m, 2H), 7.58-7.47 (m, 5H), 7.46-7.37
13
(m, 4H), 6.55 (s, 1H); C NMR (100 MHz, CDCl3): δ 151.5, 140.1, 139.9, 133.3, 129.1, 128.5,
127.7, 127.6, 125.7, 125.0, 104.3, 12.6.
3-(2-Chlorophenyl)-5-methyl-1-phenyl-1H-pyrazole (3b). Following method A, the reaction was
carried out at rt to give 35 mg (32% yield) of 3b as a yellow liquid. IR: 3063, 2925, 1598, 1547,
1503, 1459, 1349 cm-1 .1H NMR (400 MHz, CDCl3): δ 7.94-7.88 (m, 1H), 7.59-7.44 (m, 5H),
7.45-7.39 (m, 1H), 7.36-7.25 (m, 3H), 6.78 (s, 1H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3); δ
149.1, 139.6, 139.1, 132.2, 132.1, 130.5, 130.1, 128.9, 128.6, 127.6, 126.7, 124.8, 108.1, 12.5.
+
HRMS (ESI) calcd for C16H14ClN2 [M+H] + 269.0846; found 269.0840.
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5-Methyl-3-(2-nitrophenyl)-1-phenyl-1H-pyrazole (3c). Following method B, the reaction
mixture was heated at 60°C to give 56 mg (45% yield) of 3c as a red liquid. IR: 2983, 2355,
1511, 1541, 1370, 1237 cm1 .1H NMR (400 MHz, CDCl3): δ 7.7.86-7.80 (m, 1H), 7.76-7.70 (m,
1H), 7.7.64-7.56 (m, 1H), 7.53-7.38 (m, 5H), 6.36 (s, 1H); 13C NMR (100 MHz, CDCl3): δ
146.8, 140.1, 139.5, 131.8, 130.7, 129.1, 128.4, 127.8, 127.5, 124.8, 123.5, 106.2, 12.5. HRMS
+
(ESI) calcd for C16H14N3O2 [M+H]+ 280.1086.
14
5-Methyl-3-(4-chlorophenyl)-1-phenyl-1H-pyrazole
(3d). Following method A, the reaction
was carried out at rt to give 69 mg (66% yield) of 3d as a colorless liquid. IR: 3059, 2920, 1597,
1547, 1501, 1453, 1431, 1397, 1360 cm-1 .1H NMR (400 MHz, CDCl3): δ 7.80 (t, 2H, J = 2 Hz),
7.55-7.48 (m, 4H), 7.45-7.36 (m, 3H), 6.51 (s, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
150.4, 140.4, 139.7, 133.4, 131.8, 129.1, 128.7, 127.8, 126.9, 125.0, 104.2, 12.5.
5-Methyl-3-(4-nitrophenyl)-1-phenyl-1H-pyrazole 18 (3e). Following method A, the reaction was
carried out at rt to give 45 mg (39% yield) of 3e as a white crystalline solid. M.P.: 130°C .IR:
2928, 1594, 1502, 1416, 1320, 1261 cm-1 .1H NMR (400 MHz, CDCl3): δ 8.27 (d, 2H, J = 1.6
Hz), 8.02 (dd, 2H, J1 = 2 Hz, J2 = 7.2 Hz), 7.54 (d, 4H, J = 4 Hz), 7.49-7.44 (m, 1H), 6.64 (s,
1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 149.0, 139.6, 129.4, 129.1, 128.0, 125.9,
124.9, 124.0, 123.9, 118.9, 105.0, 12.4.
14
5-Methyl-1-phenyl-3-(thiophene-2-yl)-1H-pyrazole (3f). Following method A, the reaction
was carried out at rt to give 46 mg (38% yield) of 3f as a colorless liquid. IR: 3067, 2962, 1596,
1
1565, 1532, 1500, 1424, 1375, 1327 cm-1. H NMR (400 MHz, CDCl3): δ 7.53-7.47 (m, 4H),
15

ACCEPTED MANUSCRIPT
13
7.41-7.36 (m, 2H), 7.29-7.24 (m, 1H), 8.01-7.05 (m, 1H), 6.45 (s, 1H), 2.37 (s, 3H); C NMR
(100 MHz, CDCl3): δ 146.7, 140.1, 139.5, 128.9, 127.6, 127.2, 124.9, 124.4, 123.6, 104.2, 12.3.
19
5-Methyl-3-Phenyl-1-(p-tolyl)-1H-pyrazole
(3h). Following method B, the reaction mixture
was heated at 60°C to give 47 mg (42% yield) of 3h as a white gummy liquid. IR: 2968, 1518,
1
1466, 1372, 248 cm-1. H NMR (400 MHz, CDCl3): δ 8.00-7.84 (m, 2H), 7.45-7.38 (m, 4H),
13
7.36-7.27 (m, 3H), 6.53 (s, 1H), 2.44 (s, 3H), 2.38 (s, 3H); C NMR (100 MHz, CDCl3): δ
151.2, 140.2, 137.7, 133.3, 129.6, 128.5, 127.6, 125.7, 124.9, 122.2, 104.0, 21.1, 12.5.
20
1-(4-Bromo-phenyl)-5-methyl-3 -phenyl-1H-pyrazole (3i). Following method B, the reaction
mixture was heated at 60°C to give 54 mg (48%) of 3i as a yellow gummy liquid. IR: 3063,
2917, 1583, 1554, 1488, 1364 cm-1 .1H NMR (400 MHz, CDCl3): δ 7.89-7.83 (m, 2H), 7.66-7.60
(m, 2H), 7.47-7.39 (m, 4H), 7.35 (d, 1H, J = 7.6 Hz), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 151.8, 140.1, 138.9, 133.0, 132.2, 128.6, 127.9, 126.3, 125.7, 121.1, 104.8, 12.6.
1-(4-Chloro-phenyl)-5-methyl-3-(3-nitro-phenyl)-1H-pyrazole (3j). Following method B, the
reaction was heated at 60°C to give 77 mg (68%) of 3j as a white crystalline solid. M.P.: 130-
132°C. IR: 3092, 1882, 1590, 1496, 1394, 1350 cm-1 .1H NMR (400 MHz, CDCl3): δ 8.69-8.64
(m, 1H), 8.23-8.14 (m, 2H), 7.62-7.54 (m, 1H), 7.50 (s, 3H), 6.63 (s, 1H), 2.42 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 149.4, 148.6, 140.9, 138.0, 134.9, 133.8, 131.4, 129.5, 129.4, 126.0, 122.4,
120.5, 104.9, 12.6. HRMS (ESI) calcd for C16H13ClN3O2 [M+H] + 314.0696; found 314.0692.
5-Methyl-1,3-di-p-tolyl-1H-pyrazole (3k). Following method B, the reaction mixture was heated
at 60°C to give 74 mg (65%) of 3k as a yellow liquid. IR: 3569, 1560, 1456, 1436, 1363 cm-1.1H
NMR (400 MHz, CDCl3): δ 7.76 (d, 2H, J = 8 Hz), 7.41 (d, 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.4
16

ACCEPTED MANUSCRIPT
13
Hz), 7.22 (d, 2H, J = 8 Hz), 6.50 (s, 1H); C NMR (100 MHz, CDCl3): δ 151.3, 140.0, 137.5,
137.3, 130.6, 129.6, 129.2, 128.9, 128.8, 125.5, 124.9, 103.9, 21.3, 21.1, 12.5. HRMS (ESI)
calcd for C18H19N2 [M+H]+ 263.1548; found 263.1539.
1,3-Diphenyl-1H-pyrazole 14 (5). Following method A, the reaction was carried out at rt to give
97 mg (87% yield ) of 5 as a white crystalline solid. M. P: 80-82°C. IR: 1597, 1527, 1504, 1456,
1361 cm 1 .1H NMR (400 MHz, CDCl3): δ 7.96 (d, 1H, J = 2.4 Hz), 7.86-7.76 (m, 4H), 7.52-7.44
13
(m, 2H), 7.34-7.23 (m, 4H), 6.77 (d, 1H, J = 2.8 Hz); C NMR (100 MHz, CDCl3): δ 152.9,
140.2, 133.1, 129.4, 128.6, 128.0, 128.0, 126.3, 125.8, 119.0, 105.0.
3-(2-Chlorophenyl)-1-phenyl-1H-pyrazole 14 (6). Following method A, the reaction was carried
out at rt to give 84 mg (76% yield) of 6 as a colorless crystalline solid. M.P: 134-136°C. IR:
3050, 1597, 1503, 1448, 1386, 1348 cm-1 .1H NMR (400 MHz, CDCl3): δ 8.02 (t, 2H, J = 1.6
Hz), 7.82 (t, 2H, J = 8 Hz), 7.56-7.46 (m, 3H), 7.41-7.04 (m, 3H), 7.05 (d, 1H, J = 2.4 Hz); 13C
NMR (100 MHz, CDCl3): δ 150.6, 140.0, 132.4, 132.1, 130.8, 130.4, 129.4, 129.1, 127.2, 126.9,
126.5, 119.1, 109.0.
3-(2-Nitrophenyl)-1-phenyl-1H-pyrazole 21 (7). Following method B, the reaction mixture was
heated at 60°C to give 84 mg (76% yield) of 7 as a red crystalline solid. M.P.: 80-82°C. IR:
1599, 1503, 1343, 1271, 1038 cm-1.1H NMR (400 MHz, CDCl3): δ 7.98 (d, 1H, J = 2.8 Hz), 7.88
- 7.82 (m, 1H), 7.78 - 7.70 (m, 3H), 7.62 (t, 1H, J = 6.8 Hz), 7.53 - 7.43 (m, 3H), 7.32 - 7.29 (m,
1H), 6.63 (d, 1H, J = 2.4Hz); 13C NMR (100 MHz, CDCl3): δ 148.2, 139.8, 131.8, 130.7, 129.4,
128.7, 127.9, 126.7, 124.4, 123.7, 119.1, 106.9, 65.3.
17

ACCEPTED MANUSCRIPT
1-(4-Chlorophenyl)-3-phenyl-1H-pyrazole 14 (8). Following method A, the reaction mixture was
stirred at rt for 12h to give 76 mg (69% yield) of 8 as colorless crystalline solid. M.P.: 118°C.
IR: 3052, 2924, 1596, 1507, 1442, 1410, 1262 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 1H,
J = 2.4 Hz), 7.88 (t, 2H, J = 6.8 Hz), 7.78 (d, 2H, J = 7.6 Hz), 7.49 (t, 2H, J = 8.4 Hz), 7.42 (d,
13
2H, J = 8.4 Hz), 7.38-7.28 (m, 1H), 6.77 (d, 1H, J = 2.4 Hz); C NMR (100 MHz, CDCl3): δ
151.8, 140.0, 133.7, 131.6, 129.4, 128.8, 128.2, 127.0, 126.5, 119.0, 104.9.
14
3-(4-Nitrophenyl)-1-phenyl-1H-pyrazole
(9). Following method A, the reaction was carried
out at rt to give 71 mg (65% yield) of 9 as a yellow crystalline solid. M.P.: 138-140°C. IR: 1597,
1557, 1506, 1457, 1418, 1334 cm-1.1H NMR (400 MHz, CDCl3): δ 8.31 (d, 2H, J = 8.8 Hz), 8.10
(t, 2H, J = 8.8 Hz), 8.04 (d, 1H, J = 2.4 Hz), 7.81 (t, 2H, J = 7.6 Hz), 7.52 (t, 2H, J = 8.4 Hz),
7.41-7.35 (m, 1H), 6.90 (d, 1H, J = 2.4 Hz); 13C NMR (100 MHz, CDCl3): δ 150.5, 147.2, 139.8,
139.3, 129.5, 128.6, 127.0, 126.2, 124.1, 119.2, 105.9.
3-(3-Nitrophenyl)-1-phenyl-1H-pyrazole 14 (10). Following method A, the reaction was carried
out at rt to give 86 mg (73% yield) of 10 as a yellow crystalline solid. M.P.: 110-11°C. IR: 1596,
1
1518, 1455, 1345 cm-1. H NMR (400 MHz, CDCl3): δ 8.76 (d, 1H, J = 1.6 Hz), 8.31-8.24 (m,
2H), 8.23-8.17 (m, 1H), 7.03 (d, 1H, J = 2.4 Hz), 7.84-7.78 (m, 2H), 7.62 (t, 1H, J = 8 Hz), 7.56-
7.48 (d, 2H), 7.39-7.32 (m, 1H), 6.88 (s, 1H, J = 2.8 Hz); 13C NMR (100 MHz, CDCl3): δ 150.5,
148.7, 139.9, 134.9, 131.5, 129.5, 129.5, 128.5, 126.8, 122.5, 120.6, 119.1, 105.3.
2-(1-Phenyl-1H-pyrazol-3-yl) phenol 14 (11). Following method A, the reaction was carried out
at rt to give 73 mg (66% yield) of 11 as a colorless crystalline solid. M.P.: 102°C. IR: 3142,
3050, 2951, 2920, 2854, 1621, 1599, 1523, 1506, 1451, 1403, 1362 cm-1.1H NMR (400 MHz,
18

ACCEPTED MANUSCRIPT
CDCl3): δ 10.86 (s, 1H), 8.01 (d, 1H, J = 2.4 Hz), 7.74-7.68 (m, 2H), 7.67-7.62 (m, 1H,), 7.55-
7.48 (m, 2H), 7.35 (t, 1H, J = 7.2 Hz), 7.33-7.24 (m, 2H), 7.10 (m, 1H), 7.01-6.93 (m, 1H), 6.89
13
(d, 1H, J = 2.4 Hz); C NMR (100 MHz, CDCl3): δ 155.9, 152.9, 139.2, 129.6, 127.7, 126.8,
126.5, 119.3, 118.8, 117.2, 116.2, 104.6.
14
3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole
(12). Following method A, the reaction was
carried out at rt to give 49 mg (44% yield) of 12 as a colorless crystalline solid. M.P.: 102-
104°C. IR: 3141, 3059, 2959, 1596, 1510, 1452, 1389, 1358 cm-1 .1H NMR (400 MHz, CDCl3): δ
7.96 (d, 1H, J = 2.4 Hz), 8.02-7.84 (m, 2H), 7.82-7.75 (m, 2H), 7.48. (t, 2H, J = 8 Hz), 7.30 (t,
2H, J = 7.6 Hz), 7.00 (t, 2H, J = 7.2 Hz), 6.73 (d, 1H, J = 2.4 Hz); 13C NMR (100 MHz, CDCl3):
δ 159.6, 152.7, 140.2, 129.4, 128.1, 127.9, 127.6, 127.1, 126.1, 125.9, 118.9, 114.0, 104.6, 55.3.
1-Phenyl-3-p-tolyl-1H-pyrazole 22(13). Following method A, the reaction was carried out at rt to
give 77 mg (69% yield) of 13 as a white crystalline solid. M.P.: 78°C. IR: 3036, 2926, 1599,
1511, 1446, 1387, 1351 cm-1 .1H NMR (400 MHz, CDCl3): δ 7.96 (d, 1H, J = 2.8 Hz), 7.85-7.73
(m, 4H), 7.50-7.42 (m, 2H), 7.32-7.21 (m, 3H), 6.75 (d, 1H, J = 2.4 Hz), 2.39 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 152.9, 140.1, 137.8, 130.2, 129.3, 129.3, 127.8, 126.1, 125.6, 118.9, 104.9,
104.8, 21.2.
14
1-(1-Phenyl-1H-pyrazol-3-yl)-naphthalen-2-ol (14). Following method A, the reaction was
carried out at rt to give 57 mg (62% yield) of 14 as a colorless crystalline solid. M.P.: 74-76°C.
IR: 3145, 3048, 2912, 1598, 1547, 1528, 1509, 1464, 1391, 1368, 1336 cm-1 .1H NMR (400
MHz, CDCl3): δ 12.09 (s, 1H), 8.79 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.84-7.74 (m, 2H), 7.65 (s,
1H), 7.53 (t, 1H, J = 8 Hz), 7.42-7.31 (m, 3H), 7.25(S, 1H), 7.07 (d, 2H, J = 8 Hz), 6.97 (t, 1H, J
19

ACCEPTED MANUSCRIPT
= 7.6 Hz); 13C NMR (100 MHz, CDCl3): δ 156.8, 143.4, 137.8, 131.3, 131.2, 129.6, 129.1,
128.3, 127.1, 123.3, 120.9, 119.9, 118.9, 112.6, 108.9, 29.7.
1-Phenyl (3-thiophene-2-yl)-1H-pyrazole 14 (15). Following method A, the reaction was carried
out at rt to give 72 mg (65% yield) of 15 as a colorless crystalline solid. M.P: 64-66°C. IR: 3066,
1
2920, 1597, 1559, 1506, 1460, 1375 1351 cm-1. H NMR (400 MHz, CDCl3): δ 7.94 (d, 1H, J =
2.8 Hz), 7.76 (dd, 2H, J1 = 1.2 Hz, J2 = 8 Hz), 7.52-7.41 (m, 3H), 7.35-7.27 (m, 2H), 7.14-7.08
13
(m, 1H), 6.70 (d, 1H, J= 2.4 Hz); C NMR (100 MHz, CDCl3): δ 148.2, 139.9, 136.3, 129.4,
128.0, 127.4, 126.4, 124.9, 124.2, 119.0, 105.1.
14
1-(4-Chloro-phenyl)-3-phenyl-1H-pyrazole (16). Following method B, the reaction mixture
was heated at 60°C to give 91 mg (82% yield) of 16 as a colorless crystalline solid. M.P: 131-
133°C. IR: 3059, 1594, 1530, 1505, 1491, 1451, 1385 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.93
(d, 3H, J = 7.2 Hz), 7.74 (d, 2H, J = 8.8 Hz), 7.50-7.42 (m, 4H), 7.41-7.34 (m, 1H), 6.80 (d, 1H,
13
J = 1.6 Hz); C NMR (100 MHz, CDCl3): δ 153.2, 138.7, 132.8, 131.7, 129.5, 128.7, 128.2,
127.9, 125.8, 120.0, 105.4.
22
1-(4-Bromo-phenyl)-3-phenyl-1H-pyrazole
(17). Following method B, the reaction mixture
°
was heated at 60 C to give 73 mg (79% yield) of 17 as a white crystalline solid. M.P: 112-
123°C. IR: 3152, 3050, 2467, 1592, 1504, 1453, 1366, 1271 cm-1. 1H NMR (400 MHz, CDCl3): δ
7.97 (d, 1H, J = 2.4 Hz), 7.95-7.89 (m, 2H), 7.72-7.89 (m, 2H), 7.63-7.57 (m, 2H), 7.49-7.42 (m,
13
2H), 7.41-7.35 (m, 1H), 6.81 (d, 1H, J = 2.4 Hz); C NMR (100 MHz, CDCl3): δ 153.1, 139.0,
132.7, 132.3, 128.6, 128.1, 127.7, 125.7, 120.2, 119.3, 105.3.
20

ACCEPTED MANUSCRIPT
1-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-1H-pyrazole (18). Following method B, the reaction
°
mixture was heated at 60 C to give 96 mg (89% yield) of 18 as a white crystalline solid. M.P:
134-136°C. IR: 3152, 2314, 1592, 1497, 1417, 1387 cm-1 .1H NMR (400 MHz, CDCl3): δ 7.97 (d,
1H, J = 2.4 Hz), 7.88 - 7.82 (m, 2H), 7.70 - 7.64 (m, 2H), 7.64 - 7.57 (m, 2H), 7.45 - 7.39 (m,
2H), 6.77 (d, 1H, J = 2.4 Hz); 13C NMR (100 MHz, CDCl3): δ 152.0, 138.9, 133.8, 132.3, 131.2,
+
+
128.7, 127.9, 126.9, 120.2, 119.5, 105.3. HRMS (ESI) calcd for C15H11BrClN2 [M+H]
332.9794; found 332.9788.
ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR of unknown compounds.
AUTHOR INFORMATION
Corresponding Author
*Niranjan Panda
ORCID: 0000-0002-7431-8826
Email: npanda@nitrkl.ac.in
Acknowledgements
Authors like to thank SERB (Ref. No. SB/S1/ OC-21/2014) and CSIR (Ref. No.
02(0278)/16/EMR-II), Government of India for financial support.
Conflicts of interest
Authors ensure there is no conflict of interest.
21

ACCEPTED MANUSCRIPT
References
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Highlights
•
An iron-catalyzed protocol for the synthesis of pyrazoles starting from hydrazone and
1,2-diol was described.
•
•
This reaction proceeds under mild reaction conditions in the absence of any ligand
This protocol eliminates the regioselective issue that usually associated with 1,3,5-
trisubstituted pyrazoles.