One-pot tandem synthesis of tetrasubstituted pyrazoles via 1,3-dipolar cycloaddition between aryl hydrazones and ethyl but-2-ynoate

Article abstract of DOI:10.1080/00397911.2014.891744

1,3,4,5-Tetrasubstituted pyrazoles are rapidly and regioselectively synthesized in a one-pot, three-step sequence consisting of condensation, nitrilimine generation, and cycloaddition using mercuric acetate. Newly synthesized compounds were characterized by spectral studies. Regiochemistry of compounds 6a and 8a was determined as 1,4- and 1,5-regioisomers respectively by X-ray crystallography. Copyright

Full text of DOI:10.1080/00397911.2014.891744

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One-Pot Tandem Synthesis of
Tetrasubstituted Pyrazoles via 1,3-
Dipolar Cycloaddition Between Aryl
Hydrazones and Ethyl But-2-ynoate
Srikantamurthy Ningaiah a , Shridevi D. Doddaramappa b , Chandra c
, Mahendra Madegowda c , Shubakara Keshavamurthy a & Umesha K.
Bhadraiah a
a Department of Chemistry, Yuvaraja's College , University of
Mysore , Mysore , India
b Department of Studies in Chemistry , Manasagangotri, University of
Mysore , Mysore , India
c Department of Studies in Physics , Manasagangotri, University of
Mysore , Mysore , India
Accepted author version posted online: 15 Apr 2014.Published
online: 06 Jun 2014.
To cite this article: Srikantamurthy Ningaiah , Shridevi D. Doddaramappa , Chandra , Mahendra
Madegowda , Shubakara Keshavamurthy & Umesha K. Bhadraiah (2014) One-Pot Tandem Synthesis of
Tetrasubstituted Pyrazoles via 1,3-Dipolar Cycloaddition Between Aryl Hydrazones and Ethyl But-2-
ynoate, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 44:15, 2222-2231, DOI: 10.1080/00397911.2014.891744
To link to this article: http://dx.doi.org/10.1080/00397911.2014.891744
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Synthetic Communications1, 44: 2222–2231, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.891744
ONE-POT TANDEM SYNTHESIS OF
TETRASUBSTITUTED PYRAZOLES VIA 1,3-DIPOLAR
CYCLOADDITION BETWEEN ARYL HYDRAZONES AND
ETHYL BUT-2-YNOATE
Srikantamurthy Ningaiah,1 Shridevi D. Doddaramappa,2
Chandra,3 Mahendra Madegowda,3
Shubakara Keshavamurthy,1 and Umesha K. Bhadraiah1
1Department of Chemistry, Yuvaraja’s College, University of Mysore,
Mysore, India
2Department of Studies in Chemistry, Manasagangotri,
University of Mysore, Mysore, India
3Department of Studies in Physics, Manasagangotri, University of Mysore,
Mysore, India
GRAPHICAL ABSTRACT
Abstract 1,3,4,5-Tetrasubstituted pyrazoles are rapidly and regioselectively synthesized
in a one-pot, three-step sequence consisting of condensation, nitrilimine generation, and
cycloaddition using mercuric acetate. Newly synthesized compounds were characterized
by spectral studies. Regiochemistry of compounds 6a and 8a was determined as 1,4- and
1,5-regioisomers respectively by X-ray crystallography.
Keywords 1,3-Dipolar cycloaddition; ethyl but-2-ynoate; regioselective; tetrasubstituted
pyrazoles; X-ray crystallography
Received November 4, 2013.
Address correspondence to Umesha K. Bhadraiah, Department of Chemistry, Yuvaraja’s College,
University of Mysore, Mysore 570005, India. E-mail: kbu68umesha@rediffmail.com
Color versions of one or more of the figures in the article can be found online at www. tandfonline.
com/lsyc.
2222

ONE-POT SYNTHESIS OF TETRASUBSTITUTED PYRAZOLES
2223
INTRODUCTION
Pyrazoles are important heterocycles with two adjacent nitrogen atoms in the
ring, and they have extensive uses in the pharmaceutical industry.[1] Pyrazole and its
derivatives show a broad spectrum of biological activities such as anti-inflammatory,
analgesic, antihypertensive, antipyretic, antibacterial, and sedative[2,3] activities.
To date, a number of pyrazole-containing compounds have been successfully
commercialized, such as Celebrex, Viagra, Fipronil, Lonazolac, and Rimonabant.[4]
1,3-Dipolar cycloaddition reaction has been employed as one of the most
powerful synthetic tools to provide substituted pyrazoles.[5] These reactions are
staggeringly useful also because they are stereospecific, diastereoselective, and
regioselective.[6,7]
Although they provide a multitude of choices to contrive substituted pyrazoles,
the existing synthetic methods[8–11] suffer from lack of regiospecificity, longer
reaction time, exhaustive workup, poor yield, and multistep procedures, which have
limited the exploitation of these methods in high-throughput synthesis. Thus an
improved, efficient, rapid, and regioselective approach to tetrasubstituted pyrazoles
is of current interest to organic chemists.
To the best of our knowledge, there are only very few reports on the regio-
selective synthesis of tetrasubstituted pyrazoles from substituted alkynes.[12] Thus
we were interested in a mild one-pot conversion of various aldehyde, phenyl hydra-
zine, and ethyl but-2-ynoate to the corresponding 1,3,4,5-tetrasubstituted pyrazoles
with good to excellent yields. Such transformation would be particularly useful for
medicinal chemists because it would give them direct access to useful pyrazoles in
a single chemical transformation.
RESULTS AND DISCUSSION
Our initial studies were focused on the stepwise strategy for the synthesis of
target pyrazole (6), which involves the formation of benzaldehyde phenyl hydrazine
(3) from respective benzaldehydes (1) and phenyl hydrazine (2), in situ generation of
nitrilimine (4) using chloramine-T (CAT),[13,14] and an addition of ethyl but-2-ynoate
(5) to nitrilimine (Scheme 1). The sequential transformation was monitored with
thin-layer chromatography (TLC), and each step requires a minimum of 1–2 h, except
for the last step, which requires heating to 120–150 ꢀC for about 48 h. Unfortunately
with these conditions we end up with the poor yield of 27%. This might be because
of the poor reactivity of alkynes toward cycloaddition and formation of undesired
cycloadduct (7) from nitrilimines generated in situ as they were very reactive
species.[15] (See Table 1 for reaction conditions and various reagents employed for
nitrilimine generation). In all the reactions we have used absolute EtOH as a solvent,
because the solvent polarity has less impact on the yield and rate of the reaction.[16]
The methods of generating nitrilimine from hydrazonoyl chlorides, tetrazole, or
its precursors would require strong background reaction and suffer from lower
yields and=or require high temperature.[17–21] Hence we have employed mild oxidizing
agents like CAT,[22] PhI(OAc)2,[23] Pb(OAc)2,[24] and Hg(OAc)2[25] for the generation
of nitrilimine. Gratifyingly, it was found that the reaction gave promising results in the
presence of Hg(OAc)2 at room temperature (Table 1, entry 12). Although, Hg(OAc)2

2224
S. NINGAIAH ET AL.
Scheme 1. 1,3-Dipolar cycloaddition strategy: Sequential steps to pyrazole synthesis.
was employed for the synthesis of trisubstituted pyrazolines,[25] here we have studied
the use of Hg(OAc)2 for the cycloaddition between an alkyne and nitrilimines, which
give direct access to the tetrasubstituted pyrazoles with a good tolerable substituent
scope and which can be utilized as building blocks for further study.
Prompted by these observations we next probed the concatenation of the three
individual steps to a consecutive one-pot reaction. The subsequent condensation–
imine generation–cycloaddition reaction of various benzaldehydes 1(aꢁl), phenyl
Table 1. Reaction condition for stepwise synthesis of 6a
Entry
Oxidant
CAT
CAT
Equiv
Temp. (ꢀC)
Time (h)
Yielda of 6a (%)
1
2
1.0
1.0
1.0
2.0
1.0
1.0
1.0
1.0
2.0
1.0
rt
80
24
24
24
48
24
24
24
24
24
1
NR
Trace
27
3
CAT
CAT
120
150
rt
4
29
5
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
Pb(OAc)2
Pb(OAc)2
Hg(OAc)2
NR
Trace
Trace
NR
32
6
80
7
120
rt
8
11
12
120
rt
67
aIsolated yields; NR, no reaction.
Note. All reactions were carried out in 1-mmol scale of reactants in 5 mL of EtOH.

ONE-POT SYNTHESIS OF TETRASUBSTITUTED PYRAZOLES
2225
hydrazine 2(aꢁl), and an alkyne (ethyl but-2-ynoate) 5 with Hg(OAc)2 furnished the
tetrasubstituted pyrazole 6(aꢁl) within a time period of 0.5–2 h in good to excellent
yields (Table 2).
With the optimized one-pot procedure in hand, we investigated the scope
for the synthesis of pyrazole 6 with commercially available arylaldehyde 1 and aryl-
hydrazines 2. The R1 and R2 in the aromatic rings of the aldehyde and hydrazines
respectively were substituted with groups of atoms with various electronic properties
as shown in Table 3. As is evident from Table 3, the electronic effect of the
substituted groups on the aromatic rings was not apparent. Both the electron-rich
and electron-deficient aldehydes and hydrazines provided the desired product in
good to excellent yields.
Good yield and shorter reaction time was attributed to the catalytic effect of
metal ion that would alter the orbital coefficient of reacting atoms as well as frontier
molecular orbitals (FMOs) of either the 1,3-dipole or the dipolarophile, when
coordinated to metal. This principle of activation can be applied to the 1,3-dipolar
cycloaddition reaction of nitrilimine and (1,3-dipole) and ethyl but-2-ynoate
(dipolarophile). Compared to sequential reaction, the yield was greater in the
one-pot condition because the (-complex formed during the course of the reaction
was readily available for cyclization with nitrilimine generated in situ, thereby
decreasing the formation of undesired cycloadduct.
Table 2. Optimization of reaction conditions for the one-pot synthesis of 6aa
Entry
Equiv
Temp. (ꢀC)
Time (h)
Yieldb of 6a (%)
1
2
0.5
0.5
0.5
1.0
1.0
1.5
1.5
1.5
1.5
2.0
2.5
2.5
2.5
2.5
rt
rt
rt
rt
rt
rt
rt
rt
80
rt
rt
rt
rt
80
0.5
1.0
2.0
0.5
1.0
0.5
1.0
2.0
1.0
0.5
0.5
1.0
2.0
0.5
52
55
56
72
80
88
98
90
86
88
84
80
78
82
3
4
5
6
7
8
9
10
11
12
13
14
aReaction conditions: benzaldehyde 1 1.0 mmol, phenylhydrazine 2 1.1 mmol,
ethyl but-2-ynoate 5 1.5 mmol, and EtOH 5 mL.
bIsolated yield.

2226
S. NINGAIAH ET AL.
Table 3. One-pot synthesis of tetrasubstituted pyrazoles 6(a–l) and 8aa
No.
R1
R2
Product
Time (h)
Ratio of (6:8)b
Yieldc (%)
1
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
6a
6b
6c
6d
6e
6f
0.5
1.5
0.5
2
1:0.2
1:trace
Nod
No
98
92
98
79
90
74
88
98
83
87
91
90
4-Cl-C6H4
4-CH3O-C6H4
4-NO2-C6H4
4-Br-C6H4
3-NO2-C6H4
3-Cl-C6H4
2-OH-C6H4
C6H5
3
4
5
1
No
No
6
2
7
6g
6h
6i
1.5
0.5
1.5
2
1:trace
No
No
8
9
4-CH3-C6H4
2,4-CH3-C6H3
4-Cl-C6H4
10
11
12
C6H5
C6H5
4-Cl-C6H4
6j
No
1:trace
No
6k
6l
1.5
2
2,4-Cl-C6H3
aReaction conditions: benzaldehyde 1 1.0 mmol, phenylhydrazine 2 1.1 mmol, ethyl but-2-ynoate 5
1.5 mmol, and EtOH 5 mL.
bThe ratio of 6:8 was determined by the isolated yields of 6 and 8.
cIsolated yields.
dNo isomer observed.
According to the previous work on the mechanism of 1,3-dipolar
cycloaddition,[26] the Huisgen cycloaddition occurs by a concerted process. In the
case of nitrilimine and ethyl but-2-ynoate, the regiochemistry can be interpreted
by the dominant interaction between the highest occupied molecular orbital
(HOMOdipole) and lowest unoccupied molecular orbital (LUMOdipolarophile), and
thus coordinating with metal ion would decrease the energy gap between the
interacting FMO, which leads to faster reaction rates.[27] Compounds 6a and 8a were
determined to be 1,4- and 1,5-regioisomers, respectively, by X-ray crystallography[28]
(see Fig. 1 for ORTEP diagrams of both the isomers).
On the basis of this information and earlier reports,[25] a possible mechanism is
proposed as shown in Scheme 2.
EXPERIMENTAL
General One-Pot Procedure for the Preparation of Ethyl
5-Methyl-1,3-diaryl-1H-pyrazole-4-carboxylates 6
Phenyl hydrazine (0.119 g, 1.00 mmol, 1.1 equiv) was added to a stirred
solution of benzaldehyde (0.106 g, 1.00 mmol) in EtOH (5 mL). After stirring at
room temperature for 15 min, the benzaldehyde phenyl hydrazone was formed

ONE-POT SYNTHESIS OF TETRASUBSTITUTED PYRAZOLES
2227
Figure 1. ORTEP diagram of the molecules at 50% probability.

2228
S. NINGAIAH ET AL.
Scheme 2. Possible mechanism.
(based on thin-layer chromatographic, TLC, analysis). Hg(OAc)2 (0.478 g, 1.5 mmol,
1.5 equiv) in 5 ml EtOH and ethyl but-2-ynoate (0.224 g, 2.00 mmol, 2.0 equiv) were
added simultaneously to the reaction mixture from two separate droppers. The
contents were then allowed to stir at room temperature for 30 min (1.0 h total).
On completion of the reaction, the reaction mixture was extracted with ethyl acetate
(3 ꢂ 5 mL). The combined organic layer was washed with 1M KBr solution (to remove
mercury salts) and with brine, dried over anhydrous Na2SO4, and then concentrated
under reduced pressure. The crude product was purified by column chromatography
(n-hexane=EtOAc 95=05) to give two fractions. On evaporation, 6a was obtained as
a white solid (0.277 g, 96%) and 8a as an off-white solid (0.057 g, 2%).
Compound 6a
White solid; mp 102–104 ꢀC; 1H NMR (400 MHz, CDCl3) d 1.15 (t, J ¼ 7.2 Hz,
3H), 2.41 (s, 3H), 4.13 (q, J ¼ 7.2 Hz, 2H), 7.29–7.36 (m, 4H), 7.41–7.45 (m, 4H),
7.49–7.57 (m, 2H); 13C NMR (100 MHz, CDCl3) d 12.75, 14.10, 60.10, 110.63,
125.85, 127.65, 128.23, 128.68, 129.25, 129.48, 133.18, 138.84, 144.79, 153.62,
164.21; LC-MS m=z 307.6 (MþH)þ. Anal. calcd. for C19H18N2O2: C, 74.50; H,
5.90; N, 9.14. Found: C, 74.56; H, 5.91; N, 9.10.
Compound 8a
White solid; mp 100–102 ꢀC; 1H NMR (400 MHz, CDCl3) d 1.14 (t, J ¼ 7.2 Hz,
3H), 2.51 (s, 3H), 4.13–4.19 (q, J ¼ 7.0 Hz, 2H), 7.38–7.42 (m, 3H), 7.49–7.53 (m, 1H),
7.55–7.61 (m, 6H); 13C NMR (100 MHz, CDCl3) d 11.40, 14.30, 61.10, 110.01,
124.35, 126.70, 127.53, 127.80, 128.20, 129.00, 132.48, 141.10, 141.20, 149.50,
163.10; LC-MS m=z 307.1 (MþH)þ. Anal. calcd. for C19H18N2O2: C, 74.42; H,
5.88; N, 9.20. Found: C, 74.45; H, 5.90; N, 9.15.

ONE-POT SYNTHESIS OF TETRASUBSTITUTED PYRAZOLES
2229
CONCLUSIONS
In conclusion, we have developed a rapid, one-pot, regioselective synthesis of
tetrasubstituted pyrazoles with a highly flexible substitution pattern in good yields
by utilizing easily available and economical chemicals as starting materials. This
reaction is quite broad in scope, generating a diverse set of pyrazole products in
moderate to excellent yields. The effectiveness of this protocol can be attributed to
the easy access of the starting materials, shortened reaction time, and simple and
clean reaction profiles. Finally, this method gives a facile approach to N-substituted
pyrazole carboxylates, which can be utilized as building blocks for further reactions.
The arguments on the type of mechanism involved remain unresolved to date.
A via media conclusion is that the reactions are concerted but not synchronous.[26]
Thus density functional theory (DFT) and kinetic studies of the reaction and the uti-
lization of other disubstituted alkynes are in progress and will be reported in due
course.
ACKNOWLEDGMENTS
The authors are thankful to K. Yeshoda Nanjappa, assistant professor of
English, Yuvaraja’s College, University of Mysore (UOM), Mysore, for proofread-
ing the article and to the principal, Yuvaraja’s College, UOM, Mysore, for providing
necessary facilities and constant encouragement.
SUPPLEMENTARY DATA
Full experimental details and 1H and 13C NMR spectra can be accessed on the
publisher’s website.
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