Water mediated construction of trisubstituted pyrazoles/isoxazoles library using ketene dithioacetals

Article abstract of DOI:10.1021/cc900148q

A small molecule library of alkyl, sulfone, and carboxamide functionalized pyrazoles and isoxazoles has been developed via a rapid sequential condensation of various a-acylketene dithioacetals (la-o) with hydrazine hydrate or hydroxylamine hydrochloride, followed by oxidation of sulfide to sulfone using water as the reaction medium. An efficient and safe oxidation of sulfides (4/5a-o) to the corresponding sulfones (6/7a-o) using sodium per borate system in aqueous medium is reported. The concise and two step synthesis of trisubstituted pyrazoles and isoxazoles was investigated under variety of reaction condition. The newly developed methodology has the advantage of excellent yield and chemical purity with short reaction time using water as a solvent.

Full text of DOI:10.1021/cc900148q

176
J. Comb. Chem. 2010, 12, 176–180
Water Mediated Construction of Trisubstituted Pyrazoles/Isoxazoles
Library Using Ketene Dithioacetals
Mahesh M. Savant, Akshay M. Pansuriya, Chirag V. Bhuva, Naval Kapuriya,
Anil S. Patel, Vipul B. Audichya, Piyush V. Pipaliya, and Yogesh T. Naliapara*
Department of Chemistry, Chemical Research Laboratory, Saurashtra UniVersity, Rajkot 360005, India
ReceiVed September 24, 2009
A small molecule library of alkyl, sulfone, and carboxamide functionalized pyrazoles and isoxazoles has
been developed via a rapid sequential condensation of various R-acylketene dithioacetals (1a-o) with
hydrazine hydrate or hydroxylamine hydrochloride, followed by oxidation of sulfide to sulfone using water
as the reaction medium. An efficient and safe oxidation of sulfides (4/5a-o) to the corresponding sulfones
(6/7a-o) using sodium per borate system in aqueous medium is reported. The concise and two step synthesis
of trisubstituted pyrazoles and isoxazoles was investigated under variety of reaction condition. The newly
developed methodology has the advantage of excellent yield and chemical purity with short reaction time
using water as a solvent.
Introduction
activity with reduced gastrointestinal side effects. Oxacillin
and its derivatives are useful compounds because of their
narrow spectrum anti biotic properties10 (Figure 1, 4).
Recently, pyrrolyl aryl sulfones have been reported by
Silvestri et al.11 and Artico et al.12 as a new class of human
immunodeficiency virus type 1 (HIV-1) RT inhibitors acting
at the non-nucleoside binding site of this enzyme. Haruna
et al.,13 have synthesized the propargylic sulfones with
various planar molecules and evaluated their DNA binding
properties and DNA cleavage activity. Moreover, the 1-(4-
methylsulfonyl)benzene and 4-(4-methylsulfonyl)benzene
substituted pyrazole compounds containing a nitric oxide
donating group at the 3-position of the pyrazole ring,
respectively, have been synthesized and evaluated for their
ability to inhibit COX isoenzymes in human whole blood.14
Pyrazoles containing a sulfone group at N position have been
exhibited promising antimicrobial activity.15 Furthermore,
amide groups linked with isoxazole derivatives are found to
In recent decades, combinatorial chemistry tools have
enabled the rapid synthesis of a large number of heterocyclic
small molecule libraries and it is recognized now as a key
element of early drug discovery.1 The main advantage of
the combinatorial technique is the speed at which diverse
types of organic compounds can be synthesized, formulated,
and tested for a particular application. Moreover, in com-
binatorial study the quantity of required material is less in
comparison to conventional methods, which makes it more
suitable when the materials are expensive.2
The development of new methods for the synthesis of five
member heterocyclic compound libraries, both in solution
and in solid phase, is an ever-expanding area in combinatorial
chemistry. Specifically, those containing the pyrazole and
isoxazole nucleus have been widely used as key building
blocks for pharmaceutical agents. Its derivatives are endowed
with high pharmacological properties, for example, hypogly-
cemic, analgesic, anti-inflammatory, antibacterial, anti-HIV,
and anticancer activity,3 as well as useful activities in
conditions like schizophrenia, hypertension, and Alzheimer’s
disease.4 In addition, they also have agrochemical properties
including herbicidal and soil fungicidal activity; thus, they
have been used as pesticides and insecticides.5 Recently,
pyrazoles containing aryl substituted emerged as p38 Kinase
inhibitors, antiparasitic activities.6
Among these, pyrazoles and isoxazoles bearing sulfone
and carboxamide moieties demonstrated to have significant
pharmacological applications. For examples, cyclooxyge-
nase-2 (COX-2) selective inhibitors, celecoxib (1),7 rofecoxib
(2),8 and valdecoxib (3)9 are currently prescribed for the
treatment of arthritis and inflammatory diseases (Figure 1,
1-3). These COX-2 inhibitors exhibited anti-inflammatory
Figure 1. Biologically active pyrazoles and isoxazoles containing
alkyl, sulfone, and carboxamide groups (1-5).
* To whom correspondence should be addressed. E-mail: naliaparachem@
yahoo.co.in. Phone: +91 9428036310. Fax: +91 281 2576802.
10.1021/cc900148q  2010 American Chemical Society
Published on Web 12/01/2009

Library of Trisubstituted Pyrazoles/Isoxazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 177
Scheme 1. Synthesis of Trisubstituted Pyrazoles and
Isoxazoles in Aqueous Medium
have combined R2-adrenoceptor antagonistic and serotonine
reuptake inhibiting activities.16 The isoxazoles containing aryl
and carboxamide (Figure 1, 5) were also shown to have
potent in vivo antithrombotic efficacy.17
As described above, the tremendous biological potential
of the sulfone group and carboxamide group bearing pyrazole
and isoxazole scaffolds have attracted many chemists to
synthesize this class of molecules. The classical methods to
synthesized pyrazoles and isoxazoles involves the condensa-
tion of a 1,3-dicarbonyl compound or its synthetic equivalent
with hydrazine in appropriate organic solvent.18 On the other
hand, functionalized ketene dithioacetals are versatile inter-
mediates in organic synthesis for the construction of sub-
stituted heterocycles such as pyrazoles and isoxazole. The
nucleophilic displacement of one of the alkylthio groups from
ketene dithioacetals either in an organic solvents or using
microwave irradiation which followed by cyclization to
afforded the heterocycles.19 The sulfone group containing
synthesis of pyrazoles and isoxazoles library from 2-sulfo-
nylacetonitriles using solid-phase strategy is reported. How-
ever, it required a long reaction time, 40 h, and a lengthy
workup process.20 Thus, the practical synthesis of structurally
diverse isoxazole/pyrazole based small molecules is of great
significance.
Table 1. Synthesis of 3-Methyl-5-(methylthio)-N-phenyl-1H-
pyrazole-4-carboxamide 4a Using Variety of Solvents
entrya
solvents
time, h
yieldb
%
1
2
3
4
5
6
7
iPrOH
MeOH
EtOH
2.8
4.0
3.5
4.5
4.0
3.5
3.0
85
81
83
79
75
80
97
THF
CH3CN
dioxane
water
a All solution-phase reactions were conducted at reflux temperature of
the solvent used. b Isolated yield after purification.
The condensation reaction was clean in water, and the
yield of desired product was higher (Entry 7, Table 1). On
the other hand, the reaction was relatively fast when iPrOH
was used as a solvent with 12% lower yield (Entry 1, Table
1). The yield of desired product was reasonable when MeOH,
EtOH, and dioxane were used as a solvent (Entry 2,3,6, Table
1). The other solvents, tetrahydrofuran (THF) and acetoni-
trile, gave lower yield with higher reaction time (Entry 4,5,
Table 1). Thus, it is clear from the aforementioned experi-
ments that the best yield of pyrazoles 4a could be obtained
by employing water as a solvent without using any phase
transfer catalyst.
Nowadays, a great deal of effort has been focused on the
field of green chemistry in adopting methods and processes.
As a part of this “green” concept, toxic and/or flammable
organic solvents are replaced by alternative non-toxic and
nonflammable media. In this context, many efforts have been
made to use aqueous media. Among alternative green
solvents, water has been the solvent of choice for a variety
of transformations.21 Given the importance of sulfone and
carboxamide group containing pyrazoles and isoxazoles, we
set out to prepare a small molecule library of 3-methyl-5-
(methylsulfonyl)-N-aryl-1H-pyrazole/isoxazole-4-carboxam-
ide derivatives using ketene dithioacetals in aqueous medium
(Figure 1, 6/7a-o).
Herein, we wish to report a novel synthesis of alkyl,
methylsulfonyl, and carboxamide functionalized pyrazole or
isoxazole heterocyles via condensation of R-acylketene
dithioacetals (R-AKDTAs) with hydrazine hydrate or hy-
droxyl amine hydrochloride and followed by oxidation of
sulfide to sulfone using sodium per borate (SPB) in aqueous
medium. To our knowledge, this is the first attempt to
construct 3-methyl-5-(methylsulfonyl)-N-aryl-1H-pyrazole/
isoxazole-4-carboxamide in solution phase.19a,22
To test the generality of the condensation and to realize
the synthesis of a small combinatorial library of substituted
pyrazoles and isoxazoles, 15 R-AKDTAs 1a-o were reacted
with hydrazine hydrate 2 or hydroxyl amine hydrochloride
3 and potassium hydroxide to furnish pyrazoles 4a-o and
isoxazoles 5a-o in excellent yield using water as a solvent
(Scheme 1, Table 2). The synthesized compounds were
1
characterized by spectral data. The H NMR spectra of
compound 4c displayed characteristic singlet for methyl,
mehtylthio, and methoxy hydrogen, respectively, at δ 2.54,
2.64, and 3.92. The two singlets appeared for pyrazole NH
at δ 10.12 and amide hydrogen at δ 9.62 which revealed
1
the formation of pyrazole ring. However, in H NMR of
isoxazole 5b a characteristic singlet for amide proton
appeared at δ 9.19 and hydrogen of methylthio group
displayed a singlet at δ 2.63.
Results and Discussions
Because of the remarkable utility of sulfone group in
pharmaceuticals and to develop a library of pyrazole and
isoxazole functionalized with alkyl, carboxamide, and sul-
fone, we next planned to oxidize the sulfides to sulfones.
Although sulfides can be easily oxidized by a wide variety
of oxidizing reagents, unfortunately some of these reagents
are not satisfactory for the oxidation of sulfide to sulfone
because of low yields of products, toxicity, and expensive
reagents or catalysts.24 The reaction condition for oxidation
of sulfide to sulfone was optimized with a variety of
oxidizing agent in various solvent (Table 3, Scheme 2).
A series of various R-AKDTAs 1a-o was prepared by
some modification in reported procedure.23 Initially, con-
densation of R-AKDTA 1a with hydrazine hydrate 2 took
place smoothly in isopropyl alcohol reflux to afford the
3-methyl-5-(methylsulfonyl)-N-phenyl-1H-pyrazole-4-car-
boxamide 4a in good yield (Scheme 1; Entry 1, Table 1).
The condensation of 1a with 2 to generate pyrazole 4a was
investigated using a variety of solvents, as a part of the “green
chemistry” concept and to optimize the yield, and the results
are summarized in Table 1.

178 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Savant et al.
Table 2. 3-Methyl, 5-Methylthio, 4-Carboxamide Substituted
Pyrazoles and Isoxazoles
Table 4. 3-Methyl, 5-Sulfone, 4-Carboxamide Functionalized
Library of Pyrazoles and Isoxazoles
entry
R
time, h
yielda
%
mp, °C
entry
R
time, min
yielda
%
mp, °C
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
3.0
3.5
3.0
2.8
2.9
3.2
3.8
3.5
2.5
3.2
3.0
3.4
3.2
2.9
3.2
2.5
2.8
3.0
3.2
2.6
3.0
2.9
3.3
2.5
3.4
3.6
2.8
2.9
3.0
3.2
97
95
96
94
92
93
94
95
91
90
93
89
91
94
93
94
92
92
90
88
87
89
90
87
88
90
89
98
87
91
120-122
125-127
118-120
132-134
126-128
122-124
128-130
130-132
135-137
128-130
136-138
126-128
122-124
121-123
130-132
135-137
141-142
128-130
142-144
136-138
133-135
145-147
147-148
149-151
134-136
151-153
142-144
136-138
137-139
146-148
6a
6b
6c
6d
6e
6f
6g
6h
6i
Ph
60
45
55
50
60
50
55
65
55
50
50
65
60
55
50
60
50
60
55
65
55
60
65
60
55
55
60
55
50
65
91
92
89
88
90
94
89
92
92
91
93
88
87
89
85
94
95
93
91
94
96
92
95
93
92
91
90
91
88
89
168-170
172-174
166-168
175-177
170-172
165-167
173-175
177-179
181-183
176-178
186-188
176-178
170-172
171-173
181-183
186-188
192-194
188-190
191-193
184-186
179-181
185-187
192-194
196-198
188-190
195-197
188-190
181-183
187-189
189-191
4-CH3Ph
4-CH3OPh
4-FPh
2-CH3OPh
2-CH3
4-CH3Ph
4-CH3OPh
4-FPh
2-CH3OPh
2-CH3
4-ClPh
4-EtPh
4-ClPh
4-EtPh
4-NO2Ph
3-Cl,4-FPh
5-Cl,2-CH3OPh
2,5-diClPh
2,5-diCH3Ph
4-Cl,2-CH3Ph
3,4-diFPh
Ph
4-CH3Ph
4-CH3OPh
4-FPh
2-CH3OPh
2-CH3
4-NO2Ph
3-Cl,4-FPh
5-Cl,2-CH3OPh
2,5-diClPh
2,5-diCH3Ph
4-Cl,2-CH3Ph
3,4-diFPh
Ph
4-CH3Ph
4-CH3OPh
4-FPh
2-CH3OPh
2-CH3
4j
4k
4l
6j
6k
6l
4m
4n
4o
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
6m
6n
6o
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
4-ClPh
4-EtPh
4-ClPh
4-EtPh
4-NO2Ph
3-Cl,4-FPh
5-Cl,2-CH3OPh
2,5-diClPh
2,5-diCH3Ph
4-Cl,2-CH3Ph
3,4-diFPh
4-NO2Ph
3-Cl,4-FPh
5-Cl,2-CH3OPh
2,5-diClPh
2,5-diCH3Ph
4-Cl,2-CH3Ph
3,4-diFPh
5m
5n
5o
7m
7n
7o
a Isolated yield after purification.
a Isolated yield after purification.
chromatography (Entry 2,5,8, Table 3). The best results were
obtained when water was used as solvent with the SPB, and
the sulfide underwent oxidation to the corresponding sulfone
in 45 min with excellent yield (Entry 6, Table 3). However,
an excess amount of SPC did not improve yield. When the
amount of SPB was reduced, the yield of desired product
was lower. The above results indicate, the cheap, environ-
mentally friendly and effective oxidizing agent in water was
SPB and gave quantitatively yield of product without use of
any activator. With this oxidizing system, all the synthesized
compounds 4/5a-o were oxidized to generate sulfone
containing pyrazoles and isoxazole based small molecule
library using solution phase synthesis, and the results are
gathered in Table 4. The chemical purity of all newly
synthesized compounds was examined using UPLC at 254
nm. Among all the final compounds, compounds 6k and 7l
shown less than 95% chemical purity and other showed more
than 95% chemical purity (Figure 2). The 1H NMR spectrum
of pyrazole 6j displayed two characteristic singlets for the
methyl and mehtylthio proton, respectively, at δ 2.53 and
3.64. However, two singlets appeared for pyrazole NH at δ
12.97 and amide hydrogen at δ 9.61. Compound 7a displayed
a characteristic singlet for amide proton at δ 9.88 and two
singlets for methyl and mehtylthio hydrogen, respectively,
at δ 2.69 and 3.33. The overall study indicates that this is
the simple and facile methodology to introduce sulfone and
caboxamide group to pyrazole and isoxazole scaffold in
excellent yield and chemical purity.
Table 3. Optimization of the Reaction Condition for Oxidation
of 4a and 5a to Its Sulfone
entrya
oxidantb
solvent
yieldc % 6a: 7a
time, min
1
2
3
4
5
6
7
8
9
mCPBA
mCPBA
mCPBA
SPB
SPB
SPB
SPC
SPC
SPC
CH2Cl2
acetone
water
CH2Cl2
acetone
water
CH2Cl2
acetone
water
74:76
56:60
65:64
79:82
62:64
91:94
59:60
52:55
75:77
125
95
75
110
95
60
120
90
60
a All solution phase reactions were heated at reflux temperature of the
solvent used. b Oxidant: mCPBA-2 equiv, SPB-3 equiv, and SPC-3
equiv. c Isolated yields after purification.
Scheme 2. Water Mediated Synthesis of Pyrazoles and
Isoxazoles Containing Methyl, Sulfone, and Carboxamide
Groups
The results gathered in Table 3 indicate that when
dichloromethane was used as a solvent the yield of sulfone
was higher with m-chloroperbenzoic acid (mCPBA) as
compared to sodium per carbonate (SPC) and SPB, but it
required high reaction time (Entry 1,4,7, Table 3). The yields
of desired products were very poor when acetone was used
as solvent, and the products were isolated using column
Conclusion
In summary, we have synthesized a solution-phase library
of pyrazoles and isoxazoles functionalized with methyl,

Library of Trisubstituted Pyrazoles/Isoxazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 179
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Figure 2. Chemical purity of trifunctionalized pyrazoles and
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oxidation of sulfide to sulfone in aqueous medium. This
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of pyrazoles and isoxazoles containing caboxamide and
sulfone in two steps. The present procedure is significant
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Acknowledgment. The authors are thankful to FIST-DST
(sanction No. SR/FST/CSI-072/2003, Dt. 24/12/2003) and
SAP-UGC (Sanction No. 540/6/DRS/2004, SAP-I, Dt. 26/
03/2004) for their generous financial and instrumentation
support. Special thanks are due to “National Facility for Drug
Discovery through NCE’s Development & Instrumentation
Support to Small Manufacturing Pharma Enterprises” Pro-
gramme under DPRS jointly funded by Department of
Science & Technology (DST, sanction letter no. VI/D&P/
188/06-07/, TDT, Dated 30/03/07) New Delhi, Government
of Gujarat Industries Commissionerate (Sanction Letter No.
IC/SSI/R&D/SU/07/3279/168, Dated 17/01/07) & Saurashtra
University (Sanction Letter No.PLG/UGC/MS/238/20006,
Dated 19/09/06), Rajkot. M. M. S. thanks to Prof. H.
Junjappa for helpful discussions. We are also thankful to
SAIF, CIL, Chandigarh, and NRC, IISc, Bangalore for
providing spectroscopic analysis.
Supporting Information Available. General experimental
procedures for the synthesis of 1-o, 4/5a-o, and 6/7a-o,
analytical and spectral characterization data along with IR,
Mass, UPLC purity, 1H and 13C NMR spectral copies. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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