An efficient regioselective copper catalyzed multi-component synthesis of 1,3-disubstituted pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2014.03.125

An efficient synthesis of unsymmetrically substituted 1,3-pyrazole derivatives has been developed via three-component coupling reaction involving 3-(dimethylamino)-1-phenylprop-2-en-1-one, hydrazine, and aryl halides in one pot process exhibiting high regioselectivity. The pyrazole synthesis proceeds via a sequential series of reactions such as Michael addition, heterocyclization, dehydration, and Ullmann cross-coupling.

Full text of DOI:10.1016/j.tetlet.2014.03.125

Accepted Manuscript
An efficient regioselective copper catalyzed multi-component synthesis of 1, 3-
disubstituted pyrazoles
Akula Raghunadh, Suresh Babu Meruva, Ramamohan Mekala, K. Raghavendra
Rao, Thalishetti Krishna, R. Gangadhara chary, L. Vaikunta Rao, U.K. Syam
Kumar
PII:
S0040-4039(14)00557-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.125
TETL 44447
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 February 2014
26 March 2014
28 March 2014
Please cite this article as: Raghunadh, A., Meruva, S.B., Mekala, R., Raghavendra Rao, K., Krishna, T., Gangadhara
chary, R., Vaikunta Rao, L., Syam Kumar, U.K., An efficient regioselective copper catalyzed multi-component
synthesis of 1, 3- disubstituted pyrazoles, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.03.125
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An efficient regioselective copper
catalyzed multi-component synthesis of 1, 3- disubstituted pyrazoles
Akula Raghunadh,*a Suresh Babu Meruva,a Ramamohan Mekala,a K. Raghavendra Rao,a Thalishetti
Krishna,a R. Gangadhara chary,a L. Vaikunta Rao,b U. K. Syam Kumar*c

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An efficient regioselective copper catalyzed multi-component synthesis of 1, 3-
disubstituted pyrazoles
Akula Raghunadh,*a Suresh Babu Meruva,a Ramamohan Mekala,a K. Raghavendra Rao,a Thalishetti
Krishna,a R. Gangadhara chary,a L. Vaikunta Rao,b U. K. Syam Kumar*c
b
aTechnology Development Centre, Custom Pharmaceutical Services, DR. Reddy’s Laboratories Ltd., Miyapur, Hyderabad - 500049, India. Department of
c
Chemistry, GIS, Gitam University, Visakhapatnam, India. Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Batchupally,
Hyderabad, 500 049. India.
E-mail: raghunadha@drreddys.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient synthesis of unsymmetrically substituted 1,3-pyrazole derivatives has been
developed via three-component coupling reaction involving 3-(dimethylamino)-1-phenylprop-
2-en-1-one, hydrazine and aryl halides in one pot process exhibiting high regioselectivity. The
pyrazole synthesis proceeds via a sequential series of reactions such as Michael addition,
heterocyclization, dehydration and Ullmann cross-coupling.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazoles, Multicomponent reaction, Michael
addition, Cu catalyst and Ullmann cross-coupling
reaction.
Considerable efforts have been made in the recent past
both in academia as well as industry for the development of
small molecule based drug discovery program. In this small
molecule based drug development program, N-aryl pyrazole
derivatives have been continuously evaluated for their
biological properties and thus found wide spread utilization
in pharmaceutical and agrochemical industries.1 Many
substituted pyrazole derivatives have found applications in
antibacterial, anticonvulsant, analgesic, antimicrobial,2 anti-
inflammatory,3 anti-diabetic, sedative, antirheumatic,
anticancer, and antitubercular drugs,4 either available or
different stages of clinical development . In addition to
these, 1,5-diarylpyrazole derivatives exhibit non-nucleoside
HIV-1 reverse transcriptase inhibitor activity5 as well as
COX-2 inhibitor activity.6 Celecoxib (1), Sulfaphenazole
(2), CDPPB (3), Linazolac (4), Mepiprazole (5),
Rimonabant (6)7 are some of the pyrazole based drugs
available today in the market (Fig.1).
cyclocondensation of aryl hydrazines with either α-
oxoketene dithioacetals or β-oxodithioesters for the
regioselective synthesis of 1-aryl-3,4-substituted/annulated-
5-(methylthio)-pyrazoles and 1-aryl-3-(methylthio)-4,5-
substituted/annulated pyrazoles.12 The tandem amine-
exchange/heterocyclization of enaminones is also
successfully utilized for the regioselective synthesis of 1,5-
diarylpyrazole derivatives.13 Other notable methodologies
employed for the synthesis of N-arylpyrazole derivatives
include the 1,3-dipolar cycloaddition of (phenylsulfiny1)-
and (phenylsulfonyl)alkenes with l-(chlorobenzal)-2-
phenylhydrazine,14 N-arylation in presence of copper and
iron, as well as Cu(OAc)2.H2O mediated conditions.15
Because of varied biological properties of 1,3-disubstituted
pyrazole derivatives, number of methodologies have been
exmplified in literature for their synthesis.8 Most of the
syntheses
of
N-arylpyrazole
derivatives
utilize
cyclocondensation of 1,3-dicarbonyl compound and
propargylic ketones with N-aryl hydrazines.9 Harrity and co-
workers reported the cycloaddition of 4-iodosydnones with
terminal alkynes
that proceeds with
excellent
regiochemistry to provide 5-iodopyrazoles.10 Odom et al
reported a multicomponent coupling of alkynes with
isonitriles, and mono aryl hydrazines catalyzed by
Ti(NMe2)2(pypyr)2 to provide pyrazoles in excellent
yields.11 Junjappa and co-workers reported the
Fig. 1 Biologically active pyrazole derivatives

2
The development of new methodologies for the synthesis of
pyrazole derivatives is always in demand. Herein we
describe a straight forward novel transition-metal catalyzed
multi-component reaction strategy for the regioselective
synthesis of 1,3-disubstituted pyrazole derivatives in good
to excellent yields. The synthesis of 1,3-disubstituted
pyrazole derivatives utilizes enaminone 7,16 hydrazine 9, and
aryl halide 8, the reaction was conveniently carried out in
one pot in presence of Cs2CO3 and Cu catalyst in DMF at
elevated temperature (Scheme 1) .
reaction was attempted in polar aprotic solvents such as
DMSO, 1,4-dioxane, 2-MeTHF as well as CPME. However
the required product was obtained in diminished yields.
During further studies on reaction parameters, temperature
of the reaction was found to have high impact in this three-
component coupling reaction. The reactions conducted at
lower temperature (less than 70 °C) afforded the required
product in lower yields, and the reaction stopped at
pyrazole17 without proceeding for the required N-arylation
reaction. When the reaction was carried out at elevated
temperatures (80-90 °C) over a period of 14 h, N-arylation
reaction proceeded well, and nearly 80-85% of the required
product was formed along with 15% formation of pyrazole;
however when the reaction was conducted above 140 °C, N-
aryl pyrazole18 was obtained in more than 84% yields.
Table 1: Catalyst & solvent screening.
Scheme 1. Retrosynthesis of 10
Entry Catalyst
Solvent Base
Yield
%
The retrosynthetic strategy employed for the synthesis of
1,3-disubstituted pyrazoles is depicted in Scheme 1. The
pyrazole could be easily obtained by the reaction of
enaminone 7 with hydrazine 9 in polar aprotic solvents. The
so-formed pyrazole in situ reacts with aryl halide 8 in
presence of Cu(II) catalyst to afford the 1,3-disubstituted
pyrazole under Ullmann reaction conditions in a one pot
process.
1
CuI
DMF
Cs2CO3
30
2
3
4
CuBr2.2H2O
CuO
CuI +
DMF
DMF
DMF
Cs2CO3
Cs2CO3
Cs2CO3
40
55
65
[Cu(OAc)2]
5
6
7
8
9
10
11
12
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
1,4-
Cs2CO3
K2CO3
Na2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
84
54
35
40
0a
15b
68
43
dioxane
Scheme 2. One-pot three-component synthesis of 1,3-
Optimized reaction conditions: 0.1 eq. of Cu(OAc)2.H2O,
3.5 eq. of Cs2CO3, and DMF. a Reaction conducted at 30–35
°C . b Reaction conducted at 65 °C.
disubstituted pyrazole
The synthesis of 1,3-disubstituted pyrazole derivative was
initiated with enaminone 7, hydrazine hydrate (9), and
iodobenzene 8 in presence of copper catalyst and a base. For
the identification of suitable copper catalyst as well as base,
catalyst screening reactions were carried out in DMF
employing various bases. The best result was obtained when
the reaction was performed in presence of Cu(OAc)2.H2O
using Cs2CO3 as the base. Initially the reaction was carried
out with 1 equiv. of Cu(OAc)2.H2O; however during further
studies, the quantity of Cu(OAc)2.H2O for N-arylation
reaction was successfully optimized with 10 mol%. Further
reduction in the quantity of Cu(OAc)2.H2O resulted in
prolonged reaction time as well as incompletion of the N-
arylation reaction. In order to improve the yields further, the
Table 2.
With optimized reaction conditions in hand, we have further
elaborated the scope of this three-component coupling
reaction by reacting the enaminone 7a-7f, with substituted
aryl iodides 8a-8e and hydrazine hydrate. The reaction
resulted the 1,3-disubstituted pyrazoles in excellent yields,
and structure of the pyrazole derivatives were confirmed by
spectral and analytical methods (Table 2). The substituent
on both the aryl rings of the enaminone as well as aryl
halide doesn’t have any impact on either regioselectivity or
on yields, as the reaction conducted with both electron
releasing groups (7a-7f) as well as electron withdrawing
groups resulted substituted pyrazoles in comparable yields.
Entry
Enaminone
Aryl halide
Product
Yield (%)
1
84

3
2
3
4
5
78
80
72
76
6
7
82
77
8
9
74
78
10
76

4
11
12
82
76
13
14
79
78
77
15
Table 2. All the pyrazoles were characterized by 1H NMR, 13C NMR, Mass, and HRMS.
Fig. 3 COSY of 10d and 10c.
Fig. 2 Proton interaction comparison of 10 and 11
The synthesis of 1,3-disubstituted pyrazoles under copper
catalyzed multicomponent coupling reaction conditions can
proceed in two mechanistic pathways. In path A, hydrazine can
react with enaminone 7, leading to the formation of pyrazole and
further N-arylation under Ullmann condition can result the N-
substituted pyrazole 10. In path B, the hydrazine can undergo
Ullmann coupling reaction to form N-aryl hydrazine 12, which
on further Michael addition and heterocycloannulation could lead
to the formation of N-aryl pyrazole 10. (Scheme 3).
To establish the position of N-aryl group in this regioselective N-
aryl pyarzole synthesis, detailed NMR studies were conducted.
The 2D NMR (Fig. 3) studies have clearly proved that the
substitution pattern in N-aryl pyarzole is 1,3- rather than 1,5. The
absence of NOE relation between the protons on the phenyl and
4-MeOPh groups further confirmed that both the aryl rings are
spatially apart.

5
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Scheme 3: Proposed mechanism for the synthesis of 1,3-
disubstituted pyrazoles.
To check the possibility of these two mechanistic pathways, N-
aryl hydrazine was further reacted with enaminone as reported in
the literature.19 This reaction exclusively yielded 1,5-
disubstituted pyrazole. The formation of 10 as the sole product in
this three-component coupling reaction clearly indicates that the
reaction proceeds only through mechanistic path A.
In conclusion, we have developed a novel multi-component
reaction for the synthesis of 1,3-disubstituted pyrazoles in
excellent yields from enaminone, hydrazine, and aryl halides
under copper(II) catalyzed conditions in a one pot process. The
synthesis of 1,3-disubstituted pyrazoles proceeded via a series of
reactions such as Michael addition, cyclization, dehydration and
copper catalyzed Ullmann cross-coupling reaction. This multi-
component reaction strategy offers several advantages like
shorter reaction time, high yields, operational convenience and
high regioselectivity.
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Acknowledgments
The authors are grateful to Dr Upadhya Timmanna and Dr Shiva
Kumar Kota Balaji for their constant encouragement, support,
and useful discussions. We also thank the analytical department
of Dr Reddy’s Laboratories for providing analytical support.
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