Iron-catalyzed aerobic oxidative aromatization of 1,3,5-trisubstituted pyrazolines

Article abstract of DOI:10.1016/j.catcom.2013.09.002

A simple and high yielding method for the synthesis of tri-substituted pyrazoles via iron(III) catalyzed aerobic oxidative aromatization of pyrazolines has been reported. The process demonstrates a variety of functional group tolerance.

Full text of DOI:10.1016/j.catcom.2013.09.002

CATCOM-03633; No of Pages 4
Catalysis Communications xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Iron-catalyzed aerobic oxidative aromatization of 1,3,5-trisubstituted pyrazolines
⁎
Guddekoppa S. Ananthnag, Adithya Adhikari, Maravanji S. Balakrishna
Phosphorus Laboratory, Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 June 2013
Received in revised form 29 August 2013
Accepted 2 September 2013
Available online xxxx
A simple and high yielding method for the synthesis of tri-substituted pyrazoles via iron(III) catalyzed aerobic
oxidative aromatization of pyrazolines has been reported. The process demonstrates a variety of functional
group tolerance.
© 2013 Elsevier B.V. All rights reserved.
Keywords:
Pyrazoles
Iron(III) catalyst
Aerobic oxidation
Aromatization
1. Introduction
Transition metal catalysts offer an alternative and green way for
stoichiometric oxidants in oxidative aromatization and catalytic dehy-
Pyrazoles are an important class of nitrogen heterocycles because of
their relevance to pharmaceutical industries and materials.[1–3] The
substituted 1H-pyrazoles show a broad spectrum of pharmacological
activities such as antibacterial, antihyperglycemic, anti-inflammatory,
analgesic and hypoglycemic and sedative–hypnotic activities.[4] Several
methods have been reported for the synthesis of pyrazoles which
include the 1,3-dipolar addition,[5] cyclocondensation of hydrazine
derivatives with 1,3-dicarbonyl compounds[6,7] or α,β-unsaturated
carbonyl compounds,[8,9] metal-catalyzed intramolecular nucleophilic
addition of nitrogen to alkynes[10] and others.[11–15]
drogenation reactions.[31–34] High price and toxic nature of heavy
and precious metal catalysts have initiated search for alternative and
greener catalytic systems. Because of less cost, high abundance and
low toxic nature of iron, iron compounds are found to be ideal candi-
dates for efficient, greener and large scale industrial applications.
Indeed, use of iron catalysts is accomplishing significance in many or-
ganic transformations in recent years.[35] Herein, we report the ferric
chloride catalyzed oxidation of several trisubstituted pyrazolines.
2. Experimental section
Oxidation of pyrazolines is one of the easier methods employed in
the preparation of a range of pyrazoles due to its simplicity and versatil-
ity. It is well established that the treatment of α,β-unsaturated ketones
with hydrazines, in the absence of any metal catalyst, leads to the
formation of pyrazolines with regioselectivity.[16,17] These reactions
proceed through the formation of hydrazone followed by cyclization
to yield 1,3,5-substituted pyrazolines. The oxidation of pyrazolines
using reagents such as, lead tetraacetate,[18] manganese dioxide,[19]
trichloroisocyanuric acid,[20] iodic acid/iodine pentoxide,[21] silver ni-
trate,[22] mercury oxide,[23] potassium permanganate,[24] p-chloranil,
[25] activated carbon/O2,[26] iodobenzenediacetate,[27] Zr(NO3)2[28]
and DDQ[29] effectively yields pyrazoles. The major disadvantage with
most of these methods is the use of stoichiometric or an excess of
oxidizing agents. Off late, Hayashi and co-workers have reported the
catalytic oxidation of pyrazolines by Pd/C under aerobic condition.[30]
2.1. General procedure for the synthesis of 1,3-diaryl-2-propen-1-ones
A mixture of appropriate derivatives of both ketone (1.0 equiv.) and
aldehyde (1.0 equiv.) was taken in a 100 mL round-bottomed flask in
95% ethanol (25 mL). The mixture was then stirred magnetically and
heated gently if necessary until a clear solution is formed. Then a
NaOH (1.1 equiv., 10% in EtOH) solution (10 mL) was added slowly. In
most of the cases, a yellow precipitate was formed immediately.
The solid was collected by filtration, washed with cold water, dried
and recrystallized from ethanol. Compounds were characterised using
GC-MS and NMR spectroscopy.
2.2. General procedure for the synthesis of pyrazolines
Method A: A mixture of appropriate derivatives of both 1,3-diaryl-2-
propen-1-ones (1.0 equiv.) and aryl hydrazine (1.1 equiv.) was taken in
a 100 mL round-bottomed flask in 95% ethanol (25 mL). Addition of a
drop of H2SO4 initiated the precipitation. The reaction mixture was
refluxed for 3 to 5 h and cooled to room temperature to form precipitate
⁎
Corresponding author. Fax: +91 22 5172 3480, +91 22 2576 7152.
E-mail addresses: krishna@chem.iitb.ac.in, msb_krishna@iitb.ac.in (M.S. Balakrishna).
1566-7367/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2013.09.002
Please cite this article as: G.S. Ananthnag, et al., Iron-catalyzed aerobic oxidative aromatization of 1,3,5-trisubstituted pyrazolines, Catal. Commun.
(2013), http://dx.doi.org/10.1016/j.catcom.2013.09.002

2
G.S. Ananthnag et al. / Catalysis Communications xxx (2013) xxx–xxx
in most of the cases. The residue was filtered, washed with water
and dried under vacuum. In some cases where precipitate was not
observed after cooling to room temperature, water was added to obtain
precipitate.
a model substrate to optimize the reaction conditions. The reaction
was completed within 4 h when Pd(OAc)2 (2 mol%) was used as cata-
lyst (Table 1, entry 1), in refluxing acetic acid under aerobic conditions.
On decreasing the catalyst loading to 1 mol% under similar reaction con-
ditions also led to complete conversion but in 6 h (Table 1, entry 2). In
order to explore a better and economic catalytic system, catalysts such
as Ag2CO3, [Ru(η6-p-cymene)Cl2]2, Ni(OAc)2 · 4H2O, NiCl2 · 6H2O,
FeCl2, and anhydrous FeCl3 (Table 1, entries 5–13) were also tested
under similar reaction conditions. The conversions were excellent
when FeCl3 (10 mol%) was used as a catalyst (Table 1, entry 13)
(Scheme 1). The degree of hydration of FeCl3 did not show any substan-
tial effect on the reaction (Table 1, entry 16). The reactions carried out
using high purity FeCl3 (N99.9%) also did not show any significant
change in the conversion rates or yields (Table 1, entries 14 and 15).
This confirms that the trace metal impurities often found in iron salts
have no effect on aromatization reactions carried out in the present in-
vestigation. It was observed that the acetic acid is necessary for the reac-
tion to proceed.[30] The yield was lowered considerably when other
solvents were used (Table 1, entry 17). Air was used as an effective ox-
idant and in its absence yields were lowered significantly (Table 1, en-
tries 18 and 20).
Under these optimized reaction conditions (Table 1, entry 13 with
FeCl3 (N98%)), various substituted pyrazolines were subjected to oxida-
tive aromatization reaction, and the results obtained are summarized in
Charts 1 and 2. The electron donating, electron withdrawing and hetero
aromatic substituents on pyrazolines were effective substrates in
this catalytic system. The reaction time was usually 6–7 h in case of
electron donating substituents. Interestingly, electron withdrawing
nitro- (Chart 1, 8, 17 and Chart 2, 25) and halo- (Chart 1, 7, 9–14 and
Chart 2, 20, 22) substituted pyrazolines also gave good to excellent
yield, but took longer time for the completion of reaction (8–10 h).
The electronic effects of the substituents on pyrazolines are not
pronounced under these conditions. It is noteworthy that, alkene
(Chart 1, 15–18) and methoxy (Chart 1, 5, 6 and Chart 2, 23, 24) func-
tionalities were also tolerated and the corresponding products were
isolated in excellent yield. The generality of the reaction was further
established by investigating the reactivity of hetero-aromatic substitu-
ents like furan and thiophene on pyrazolines (Chart 2). For example,
1-phenyl-3,5-di(thiophen-2-yl)-1H-pyrazole (19) was obtained in 96%
yield from 1-phenyl-3,5-di(thiophen-2-yl)-1H-pyrazoline. Various com-
binations of heteroaromatic with methoxy-, nitro-, and halo-substituted
pyrazolines were also successfully tested under the reaction conditions
(Chart 2, 20–27).
Method B: A mixture of appropriate derivatives of both 1,3-diaryl-2-
propen-1-ones (1.0 equiv.) and hydrazine (1.1 equiv.) was taken in a
100 mL round-bottomed flask along with acetic acid. A drop of H2SO4
was added to this mixture, immediate precipitate was observed. The
reaction mixture was refluxed for 3 h and cooled to room temperature
to give precipitate. The precipitate was filtered, washed consecutively
with water and petroleum ether (bp range: 60–85 °C) and the residue
was dried under vacuum. In some cases where precipitate was not
observed after cooling to room temperature, water was added to obtain
precipitate. Compounds were characterised using GC-MS and NMR
spectroscopy.
2.3. General procedure for the synthesis of pyrazoles
A 10 mL screw capped tube was charged with pyrazoline (1 equiv.),
acetic acid (2 mL), and FeCl3 (10 mol%). The mixture was stirred at
120 °C for 6–10 h. After confirmation of the complete consumption of
pyrazoline by GC-MS analysis, the reaction mixture was cooled to
room temperature, neutralized with saturated aqueous Na2CO3 and
extracted with ethyl acetate (10 mL × 3). After usual work-up (see
Supporting data), the residue obtained was passed through a small
pad of silica gel using ethyl acetate to give analytically pure substituted
pyrazoles.
3. Results and discussion
Our initial efforts were focused on identifying a suitable catalytic sys-
tem for the aromatization of substituted pyrazolines into substituted
pyrazoles. Initially 3-methyl-1,5-diphenyl-1H-pyrazoline was used as
Table 1
Optimization of reaction conditions.
4. Conclusions
Entry Catalyst
Solvent
Time (h) Conva (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (2 mol%)
AcOH
AcOH
Acetone
AcOH:H2O (1:1)
AcOH
4
6
6
6
4
4
6
6
6
6
6
6
6
6
6
6
6
6
6
6
100 (98b)
99
36
48
96
100
75
90
55
99
In conclusion, we have developed an easy and greener process for
the preparation of pyrazoles via Fe(III) catalyzed oxidative aromatiza-
tion reaction. Current method utilizes FeCl3 as a catalyst, which makes
the reaction more economical and productive (Scheme 2). All the prod-
ucts are obtained in pure form without the use of column chromatogra-
phy. The method is high yielding and shows variety of functional group
tolerance.
Pd(OAc)2 (1 mol%)
Pd(OAc)2 (2 mol%)
Pd(OAc)2 (2 mol%)
Ag2CO3 (2 mol%)
[Ru(η6-p-cymene)Cl2]2 (2 mol%) AcOH
Ni(OAc)2 · 4H2O (5 mol%)
NiCl2 · 6H2O (5 mol%)
NiCl2 · 2H2O (5 mol%)
Ni(OAc)2 · 4H2O (10 mol%)
FeCl3 (5 mol%)
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
Acetone
AcOH
AcOH
AcOH
9
10
11
12
13
14
15
16
17
18
19
20
75
98
FeCl2 (N99.8%) (10 mol%)
FeCl3 (N98%)(10 mol%)
FeCl3 (N99.9% pure) (5 mol%)
FeCl3 (N99.9% pure) (10 mol%)
FeCl3 · 6H2O (10 mol%)
FeCl3 (10 mol%)
100 (98b)
72
100
97
39
61
46
FeCl3 (10 mol%)c
No catalyst
No catalystc
34
a
Conversion based on GC analysis with dodecane as internal standard.
Isolated yields.
The reactions were carried out under nitrogen atmosphere.
b
c
Scheme 1. Synthesis of pyrazole via iron catalyzed oxidation of pyrazoline.
Please cite this article as: G.S. Ananthnag, et al., Iron-catalyzed aerobic oxidative aromatization of 1,3,5-trisubstituted pyrazolines, Catal. Commun.
(2013), http://dx.doi.org/10.1016/j.catcom.2013.09.002

G.S. Ananthnag et al. / Catalysis Communications xxx (2013) xxx–xxx
3
Chart 1. Substrate scope for the aromatization of pyrazolines.
Acknowledgments
SR/S1/IC-17/2010. GSA (SRF) and AA (RA) thank CSIR, New Delhi,
for Research Fellowships. We also thank the Department of Chemis-
try Instrumentation Facilities, IIT Bombay, for spectral and analytical
data.
We are grateful to the Department of Science and Technology
(DST), New Delhi, for financial support of this work through grant
Please cite this article as: G.S. Ananthnag, et al., Iron-catalyzed aerobic oxidative aromatization of 1,3,5-trisubstituted pyrazolines, Catal. Commun.
(2013), http://dx.doi.org/10.1016/j.catcom.2013.09.002

4
G.S. Ananthnag et al. / Catalysis Communications xxx (2013) xxx–xxx
Chart 2. Aromatization of hetero-aromatic substituted pyrazolines.
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Scheme 2. Comparisons of previous reports and our methodology for the synthesis of
trisubstituted pyrazoles.
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Please cite this article as: G.S. Ananthnag, et al., Iron-catalyzed aerobic oxidative aromatization of 1,3,5-trisubstituted pyrazolines, Catal. Commun.
(2013), http://dx.doi.org/10.1016/j.catcom.2013.09.002