Novel and efficient synthesis of 4-indazolyl-1,3,4-trisubstituted pyrazole derivatives

Article abstract of DOI:10.1080/00397911.2013.862724

In the present study, 1-(4,5-dihydro-3,6-dimethyl-4-(1,3-diphenyl-1H- pyrazol-4-yl)-3aH-indazol-5-yl)methanone derivatives (9-12) and isoxazoleyl (13-16) have been synthesized by the condensation of 1,3-diphenyl-1H-pyrazole-4- carbaldehyde (1-4) with acetyl acetone via Knoevenagel/Michael/aldol reactions in a sequential manner to yield intermediate cyclohexanone (5-8). The intermediates (5-8) treated with NH₂NH₂·H ₂O/NH₂OH·HCl afforded 4-indazolyl-1,3,4- trisubstituted pyrazole and isoxazoleyl derivatives. All of these compounds are reported for the first time, and the structures of these compounds were confirmed by means of infrared, ¹H NMR, ¹³C NMR, and mass spectroscopy.

Full text of DOI:10.1080/00397911.2013.862724

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Novel and Efficient Synthesis of 4-
Indazolyl-1,3,4-trisubstituted Pyrazole
Derivatives
Baliram S. Hote a & Pradeep D. Lokhande a
a Organic Chemistry Laboratory, Department of Chemistry ,
University of Pune , India
Accepted author version posted online: 10 Feb 2014.Published
online: 29 Apr 2014.
To cite this article: Baliram S. Hote & Pradeep D. Lokhande (2014) Novel and Efficient Synthesis of
4-Indazolyl-1,3,4-trisubstituted Pyrazole Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:10, 1492-1500, DOI:
10.1080/00397911.2013.862724
To link to this article: http://dx.doi.org/10.1080/00397911.2013.862724
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Synthetic Communications1, 44: 1492–1500, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.862724
NOVEL AND EFFICIENT SYNTHESIS OF
4-INDAZOLYL-1,3,4-TRISUBSTITUTED PYRAZOLE
DERIVATIVES
Baliram S. Hote and Pradeep D. Lokhande
Organic Chemistry Laboratory, Department of Chemistry,
University of Pune, India
GRAPHICAL ABSTRACT
Abstract In the present study, 1-(4,5-dihydro-3,6-dimethyl-4-(1,3-diphenyl-1H-pyrazol-
4-yl)-3aH-indazol-5-yl)methanone derivatives (9–12) and isoxazoleyl (13–16) have been
synthesized by the condensation of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde (1–4) with
acetyl acetone via Knoevenagel=Michael=aldol reactions in a sequential manner to yield inter-
mediate cyclohexanone (5–8). The intermediates (5–8) treated with NH2NH2 ꢀ H2O=
NH2OH ꢀ HCl afforded 4-indazolyl-1,3,4-trisubstituted pyrazole and isoxazoleyl derivatives.
All of these compounds are reported for the first time, and the structures of these compounds
were confirmed by means of infrared, 1H NMR, 13C NMR, and mass spectroscopy.
Keywords Acetyl acetone; cyclohexanone; indazolyl; isoxazoleyl
INTRODUCTION
Development of rapid access to N-heterocycles with complexity and diversity
stemming from their wide occurrence in nature and broad applications in chemistry,
biology, and material sciences has attracted considerable attention in the studies of
chemical genetics.[1] In this respect, pyrazoles and indazoles are important synthetic
Received August 26, 2013.
Address correspondence to Baliram S. Hote, Organic Chemistry Laboratory, Department of
Chemistry, University of Pune, Pune, India. E-mail: balwanthote7@rediffmail.com
1492

4-INDAZOLYL-1,3,4-TRISUBSTITUTED PYRAZOLE
1493
targets in biologically active molecules, synthetic drugs, and drug candidates, and in
addition, they can be used as ligands for generating metallic complexes.[2,3] The
importance of these heterocyclic moieties has prompted the development of many
practical synthetic routes to construct their derivatives.[4,5]
Substituted pyrazoles are rarely found in nature but serve as important
synthetic targets in medicinal chemistry and pharmaceutical industries.[6] Both
1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazoles constitute the useful structure of sev-
eral commercial drugs such as celebrex,[7] Viagra,[8] acomplia, and the insecticide
fipronil as well as numerous other compounds that exhibit a wide spectrum of
biological and pharmacological properties such as antifungal,[9] antimicrobial,[10]
antidiabetic,[11] herbicidal,[12,13] antitumor[14] and antianxiety,[15] activities and serve
as active pharmacophores in celecoxib (COX-2 inhibitor)[16] and slidenafil citrate[17]
(cGMP specific phosphodiesterase type 5) inhibitors. Substituted pyrazole deriva-
tives play essential roles in biologically active compounds and therefore are an
interesting template for medicinal chemistry.
There are several reactions reported for the preparation of pyrazole derivatives.
Among them, the Knorr pyrazole synthesis is considered one of the standard meth-
ods because of its generality. The reaction leads to the pyrazole derivatives via
the condensation of substituted hydrazine with 1,3-dicarbonyl compounds or their
derivatives.[18–21] The other method is the 1,3-dipolar cycloaddition of diazoalkanes
or nitrile imines with olefins or alkynes.[19] Recently, a novel regioselective synthesis
of 1,3,4-trisubstituted pyrazoles has been successfully employed.[22] As successful as
these two methods are in preparing pyrazoles with various substitution patterns,
both are not particularly suitable for the regioselective synthesis of 1,3,4-trisubsti-
tuted pyrazole in neutral condition.
The 4-substituted pyrazoles are pharmaceutically important, yet less repre-
sented in the literature, probably because of synthetic difficulties.[23] Recently, Liu
et al. reported moderate antitumor activity of 1-aryl-5-amino-4-pyrazolecarboxylate
derivatives.[24,25] Lange et al. synthesized novel 3,4-diarylpyrazolines and evaluated
cannabinoid (hCB1 and hCB2) receptors.[26] Liu et al. reported 2-ethoxyethyl-5-
amino-3-methyl-1-phenyl-1H-pyrazol-4-carboxylate derivatives and found antican-
cer, fungicidal, and herbicidal activity.[27] Furthermore, no reports were found on
the synthesis of 4-substituted indazolyl and isoxazoleyl derivatives of 1,3-diphenyl-1-
H-pyrazole compounds.
Keeping in view these points, we were prompted to synthesize functionalized
4-indazolyl substituted 1-(4,5-dihydro-3,6-dimethyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-
3aH-indazol-5-yl)methanone and 1,3-diphenyl-1H-pyrazole derivatives 1-(4,5-dihydro-
3,6-dimethyl-4-(1,3-diphenyl-1-phenyl-1H-pyrazol-4-yl)benzo[c]isoxazole-5-yl)ethanone
derivatives. To the best of our knowledge, this is the first time that this transformation
has ever been documented. The reaction scope is quite broad on a range of substrates,
and the functional group compatibility is excellent. Our method of preparation is simple,
economical, and devoid of any toxic by-products during the reaction.
RESULTS AND DISCUSSION
The synthesis of target derivatives 1-(4,5-dihydro-3,6-dimethyl-4-(1,3-
diphenyl-1H-pyrazol-4-yl)-3aH-indazol-5-yl)methanone 9–12 and 1-(4,5-dihydro-3,

1494
B. S. HOTE AND P. D. LOKHANDE
6-dimethyl-4-(1,3-diphenyl-1-phenyl-1H-pyrazol-4-yl)benzo[c]isoxazole-5-yl)ethanone
13–16 were synthesized as illustrated in Scheme 1. The key starting intermediates
containing various substituted 1, 3-diphenyl-1H-pyrazole-4-carbaldehyde 1–4 was
prepared from two steps. The first one was the reaction between various substituted
acetophenones with phenylhydrazine to afford hydrazone derivatves, which with
Vilsmeier–Haack reagent (DMF-POCl3) lead to the corresponding substituted
1,3-diphenyl-1H-pyrazole-4-carbaldehyde 1–4 functionalized pyrazole heterocyclic
ring in mild operating conditions.[28] Subsequently, acetyl acetone on condensation
with 1,3-diphenyl-1H-pyrazole-4-carbaldehyde via Knoevenagel, Michael, and intra-
molecular aldol reactions in solvent dimethylsulfoxide (DMSO) using piperidine
(10 mol%) with stirring for 10 h in a sequential manner afforded 2,4-diacetyl-
5-hydroxy-5-methyl-3-(1,3-diphenyl-1H-pyrazol-4-yl)cyclohexanone intermediates
5–8 with yields in the range of 79–66%.[29]
To synthesize the derivatives 9–12, condensation reactions of 2,4-diacetyl-5-
hydroxy-5-methyl-3-(1,3-diphenyl-1H-pyrazol-4-yl) cyclohexanone derivatives 5–8
refluxed with NH2NH2 ꢀ H2O in methanol for 7 h obtained 1-(4,5-dihydro-3,6-
dimethyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-3aH-indazol-5-yl)methanone derivatives
9–12.[30] In an extension of this methodology, 1-(4,5-dihydro-3,6-dimethyl-4-
(1,3-diphenyl-1-phenyl-1H-pyrazol-4-yl)benzo[c]isoxazole-5-yl)ethanone derivatives
13 were prepared in 66–71% yields by treatment of 5–8 with NH2NH2 ꢀ H2O in the
same manner, and the structures of 13–16 were examined by infrared (IR), 1H
NMR, 13C NMR, and mass spectral data.
Scheme 1. Synthesis of 4-indazolyl-1,3,4-trisubstituted pyrazole and isoxazolyl derivatives.

4-INDAZOLYL-1,3,4-TRISUBSTITUTED PYRAZOLE
1495
The 2,4-diacetyl-5-hydroxy-5-methyl-3-(1,3-diphenyl-1H-pyrazol-4-yl)cyclo-
hexanone 5 exhibited strong intensity OH broad stretching bands ꢁin1 the region
3440 cmꢁ1 and strong C O stretching bands in the region 1713 cm due to the
=
CH3CO group, and weak stretching bands in the region 1692 cmꢁ1 shows the C O
=
in cyclohexanone moiety. The weak bands in the region 1069 cmꢁ1 show the C-N
=
stretching vibrations in pyrazol ring. The C O stretching bands appeared at
1741 cmꢁ1 in 4-substituted indazolyl 9 and 1720 cmꢁ1 in isoxazolyl derivatives 13.
1
The H NMR spectra of 2,4-diacetyl-5-hydroxy-5-methyl-3-(1,3-diphenyl-1H-
pyrazol-4-yl)cyclohexanone (5) has the 60-H proton at d 3.782, dd, J ¼ 2.4 Hz,
coupled with 20-H and hydroxyl proton. The 20-H proton at d 3.570, J ¼ 12–
13.8 Hz appears coupled with 30-H proton whereas in target compound 9, the 90-H
proton doublet at d 1.897 with coupling constant J ¼ 9.9 Hz is coupled with 40-H
proton. We concluded that there is formation of a five-member ring.
The 70-H proton in 4-substituted indazolyl derivatives appears as a singlet at d
4.913, but in isoxazolyl derivatives, the same proton appears as a singlet at d 6.126,
with formation of olefinic double bond due to dehydration. In isoxazoleyl derivatives
13, 40-H proton shows a doublet at d 4.462, J ¼ 11.1 Hz, coupled with 50-H. It is a
useful tool to confirm that there is no 90-H proton.
In 13C NMR spectrum of the cyclohexanone intermediates 5–8, C-2 appears
=
downfield at d 71.0 ppm due to CH3CO and C O substitution, whereas in indazolyl
and isoxazoleyl it shows upfield at d 40.2 ppm. It is important to notice the absence
=
of C O group. The C-5 in 5–8 appears to peak in the range of d 60.8–60.4 ppm, and
in C-7 derivatives 9–16 appears as a signal at d 121.9–107.0. This deshielding effect is
due to the conjugation between five-membered heterocyclic and cyclohexene rings.
Considering first the cyclohexanone derivatives, the large coupling constants
J2–3 (J ¼ 12.3 Hz) and J3–4 (J ¼ 12.3 Hz) are clearly indicative of trans diaxial pro-
tons. The large substituents at the neighboring carbon C-3 then must occupy the pre-
ferred equatorial positions. The hydroxyl proton was observed to be a doublet,
J ¼ 2.4 Hz, coupled to the axial proton 6Ha, the resonance of which appeared as a
doublet of doublets. This is one of the few instances known of long-range coupling
to hydroxyl group (Fig. 1).[31] Addition of deuterium oxide caused the disappearance
of the hydroxyl doublet and concurrent simplification of the 6Ha pattern. It is sug-
gested that strong hydrogen bonding of the hydroxyl proton with the neighboring
6Ha and carbomethoxy function holds the hydroxyl proton in a conformation favor-
able for long-range coupling.
The plausible mechanism of target molecules for the formation of cyclohexa-
none derivatives D during the reaction of aldehyde and b-keto ester or ketone has
already been reported by Enders et al.[32] It involves the Knoevenagel condensation
of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde with acetyl acetone to give a Knoevenagel
product A, which undergoes a Michael addition of an active methylene compound
via its enol form B to give an intermediate C. The latter undergoes intramolecular
aldol condensation in the presence of a base to give an intermediate cyclized
2,4-diacetyl-5-hydroxy-5-methyl-3-(1,3-diphenyl-1H-pyrazol-4-yl)cyclohexanone D,
which on treatment with NH2NH2 ꢀ H2O=NH2OH ꢀ HCl afforded 1-(4,5-dihydro-
3,6-dimethyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-3aH-indazol-5-yl)methanone E and 1-(4,
5-dihydro-3,6-dimethyl-4-(1,3-diphenyl-1-phenyl-1H-pyrazol-4-yl)benzo[c]isoxazole-
5-yl) ethanone F derivatives.

1496
B. S. HOTE AND P. D. LOKHANDE
Figure 1. Conformational studies of cyclohexanone derivatives.
CONCLUSIONS
In conclusion, we have demonstrated a simple, convenient, efficient method for
the preparation of functionalized 4-indazolyl and isoxazolyl substituted of 1,3,4-
trisubstituted pyrazole derivatives via domino Knoevenagel, Michael and intramol-
ecular aldol reactions to give cyclohexanone derivatives, followed by treatment with
NH2NH2 ꢀ H2O=NH2OH ꢀ HCl. The procedure offers several advantages such as easy
workup process, excellent yield of products, operational simplicity, and minimum
environmental impact, making the technology practical, easy to perform, and facile.
EXPERIMENTAL
All chemicals and reagents used in the current study were of analytical grade.
Melting points were determined with a digital thermometer and were uncorrected.
The IR absorption spectra were scanned on Perkin-Elmer Spectrum, BX II FTIR spec-
trometer using potassium bromide (KBr) pellets, and the wave numbers are given in
1
cmꢁ1. All the H NMR spectra were recorded on a Bruker DPX300 model spec-
trometer in CDCl3 using tetramethylsilane (TMS) as an internal standard, the chemical
shifts are reported in d units, and the coupling constants (J) are reported in hertz. Mul-
tiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, dd ¼ double
doublet) and mass spectra were recorded. Thin-layer chromatography (TLC) was per-
formed on silica-gel sheets (silica gel 60F254, Merck) and visualized in ultraviolet light
(254 nm). Column chromatography was performed using silica gel (100–200 mesh),
eluting with ethyl acetate and petroleum ether solvent.
Procedure for the Preparation of 2,4-Diacetyl-5-hydroxy-5-methyl-3-
(1,3-diphenyl-1H-pyrazol-4-yl)cyclohexanone (5–8)
To a magnetically stirred solution of acetyl acetone (2 mmol) and different sub-
stituted 1,3-diphenyl-1H-pyrazole-4-carbaldehyde (1 mmol) 1–4 in dimethylsulfoxide

4-INDAZOLYL-1,3,4-TRISUBSTITUTED PYRAZOLE
1497
Figure 2. Plausible mechanisms.
(10 mL), 20 mol% of piperidine was added to the reaction mixture and refluxed 10 h.
The progress of reaction checked by (TLC). After completion, the reaction mixture
was quenched with ice water, acidified with diluted. HCl, extracted with chloroform,
dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by column chromatography over SiO2 (100–200 mesh)
using ethylacetate–petroleum ether as an eluent to give the desired product.
2,4-Diacetyl-5-hydroxy-5-methyl-3-(1,3-diphenyl-1H-
4-yl)cyclohexanone (5)
Faint white; yield: 79%; mp ¼ 146–148 ꢂC; IR tmax (KBr, cmꢁ1) 3440, 3060,
1
2966, 2884, 1713, 1692, 1600, 1538, 1503, 1449, 1415, 1069, 964, 855, 776, 651; H
NMR (300 MHz, CDCl3) d (ppm): 7.706 (m, 10 H), 7.636 (s, 1H), 3.782 (dd,

1498
B. S. HOTE AND P. D. LOKHANDE
J ¼ 2.43 Hz, 2H), 3.778 (d, J ¼ 2.4 Hz, 1H), 3.570 (d, J ¼ 2.4 Hz, 1H), 3.216 (t, 1H),
2.036 (s, 3H), 2.018 (s, 1H), 1.909 (s, 3H), 1.233 (s, 3H); 13C NMR (75 MHz, CDCl3)
d (ppm) 209.8, 208.5, 203.2, 150.2, 139.7, 133.3, 129.6, 129.5, 128.8, 127.4, 126.3,
120.4, 117.7, 71.2, 60.9, 60.7, 53.3, 29.5, 28.8, 24.3, 9.4. Anal. calc. for
C27H30N2O4: C, 72.62; H, 6.77; N, 6.27; O, 14.33%. Found: C, 72.64; H, 6.79; N,
6.25; O, 14.31%
Procedure for the Preparation of Derivatives 9–16
The mixture of 2,4-diacetyl-5-hydroxy-5-methyl-3-(1,3-diphenyl-1H-pyrazol-
4-yl)cyclohexanone (1 mmol) 5–8 and the requisite NH2NH2 ꢀ H2O=NH2OH ꢀ HCl
(4 mmol) in methanol (15 mL) was refluxed for 7 h. The reaction was monitored
by TLC. After completion, the reaction mixture was quenched in ice water, extracted
with chloroform, dried over sodium sulfate (Na2SO4), and concentrated under
reduced pressure. The crude product was purified by column chromatography to
give the desired product.
1-(4,5-Dihydro-3,6-dimethyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-3aH-
indazol-5-yl) Methanone (9)
Faint white; yield: 73%; mp ¼ 100–102 ꢂC; IR tmax (KBr, cmꢁ1) 3622, 3058,
2924, 2854, 1741, 1696, 1643, 1598, 1500, 1448, 1062, 959, 758, 692; 1H NMR
(300 MHz, CDCl3) d (ppm): 7.710 (m, 10 H), 7.225 (s, 1H), 4.913 (s, 1H), 3.506 (d,
J ¼ 13.8 Hz, 1H), 3.013 (t, 1H), 2.223 (s, 3H), 2.060 (t, 3H), 1.951 (s, 3H), 1.897
(d, J ¼ 9.9 Hz, 1H);13C NMR (75 MHz, CDCl3) d (ppm) 203.5, 164.6, 150.3, 139.6,
133.4, 129.6, 129.3, 128.6, 127.5, 126.4, 123.3, 120.4, 117.8, 107.3, 58.4, 40.5, 29.6,
27.7, 20.8, 16.3. Anal. calc. for C26H26N4O2: C, 76.07; H, 6.38; N, 13.65; O,
3.90%. Found: C, 76.10; H, 6.40; N, 13.67; O, 3.87%.
1-(4,5-Dihydro-3,6-dimethyl-4-(1,3-diphenyl-1-phenyl-1H-
pyrazol-4-yl)benzo[c] isoxazole-5-yl) Ethanone (13)
Faint white; yield: 71%; mp ¼ 85–87 ꢂC; IR tmax (KBr, cmꢁ1) 2999, 2876, 1720,
1
1668, 1614, 1479, 1373, 1024, 991, 873, 778, 648; H NMR (300 MHz, CDCl3) d
(ppm): 7.708 (m, 10H), 7.612 (s, 1H), 6.126 (s, 1H), 4.462 (d, J ¼ 11.1 Hz, 1H),
3.345 (d, J ¼ 10.6 Hz, 1H), 2.185 (s, 3H), 2.047 (s, 3H), 1.873 (s, 3H); 13C NMR
(75 MHz, CDCl3) d (ppm) 203.5, 158.9, 150.4, 141.7, 139.8, 133.4, 129.7, 129.6,
128.8, 127.7, 126.5, 123.3, 121.9, 120.5, 117.6, 100.7, 74.3, 62.8, 29.7, 29.4, 20.5.
Anal. calc. for C27H27N3O2: C, 76.21; H, 6.40; N, 9.87; O, 7.52%. Found: C,76.23;
H, 6.42; N, 9.85; O, 7.50%.
FUNDING
B.S.H. is thankful for financial assistance through a Dr. D. S. Kothari
postdoctoral Fellowship, UGC, New Delhi, India.

4-INDAZOLYL-1,3,4-TRISUBSTITUTED PYRAZOLE
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SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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