Modified reaction conditions to achieve high regioselectivity in the two component synthesis of 1,5-diarylpyrazoles

Article abstract of DOI:10.1016/j.tetlet.2004.08.100

The factors affecting regioselectivity during the formation of 1,5-diarylpyrazoles from aryl hydrazines and 1,3-diketones are identified and the regioisomers were characterized by 1D NOESY, LC-NMR and X-ray analyses. A simple alteration in the usual react

Full text of DOI:10.1016/j.tetlet.2004.08.100

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7679–7682
Modified reaction conditions to achieve high regioselectivity in
the two component synthesis of 1,5-diarylpyrazolesq
Sunil K. Singh,a,* M. Srinivasa Reddy,a S. Shivaramakrishna,a D. Kavitha,a R. Vasudev,b
J. Moses Babu,b A. Sivalakshmidevib and Y. Koteswar Raoa,*
aDiscovery Chemistry, Discovery Research––Dr. Reddyꢀs Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
bAnalytical Division, Discovery Research––Dr. Reddyꢀs Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
Received 21 June 2004; revised 13 August 2004; accepted 17 August 2004
Abstract—The factors affecting regioselectivity during the formation of 1,5-diarylpyrazoles from aryl hydrazines and 1,3-diketones
are identified and the regioisomers were characterized by 1D NOESY, LC–NMR and X-ray analyses. A simple alteration in the
usual reaction conditions is reported, which allows the exclusive formation of 1,5-diarylpyrazoles.
Ó 2004 Elsevier Ltd. All rights reserved.
R2
The pyrazole ring is present in many pharmacologically
O
O
important compounds.1 Although many methods are
known for the construction of this ring system,2 the
search for novel synthetic methodology addressing the
necessity for a particular regioisomer is always desira-
ble.3,4 Recently, 1,5-diarylpyrazoles gained further
importance after the introduction of celecoxib 1 (Fig.
1), a COX-2 inhibitor for the treatment of chronic
inflammatory diseases like rheumatoid and osteoarthri-
tis.4 The widely accepted synthetic method for this class
of compounds comprises of the coupling of an appropri-
ate phenylhydrazine hydrochloride with a suitable 1-
phenyl-1,3-diketone in hot ethanol.5 Although it is an
excellent method in terms of yield, it suffers from poor
regioselectivity in many cases depending on the nature
of the 1,3-diketone.6
R1
S
H2N
2
1
N
N
N
N
3
R3
CF3
Ar
O
1
2
Me
O
O
O
R1
,
, H, halo, alkoxy.
=
S
S
NH2
Me
R2 = CH2OH, CH2NHAc, H, halo, alkoxy
R3 = Alkyl, haloalkyl, heteroaryl
Figure 1.
Previously, the two component synthesis has been con-
ducted in acidic medium and the suitability of the 1,3-
diketone has generally been emphasized for the synthesis
of 1,5-diarylpyrazoles,3–6 but, to our knowledge, no sys-
tematic study has correlated the control of regiochemis-
try with reaction conditions and the electronic/steric
factors of the 1,3-diketone and phenylhydrazine. We
present here the outcome of our study of the effect of
substituents on both of the components on the forma-
tion of regioisomers. We found that by employing sim-
ple methods we could achieve excellent regioisomeric
excesses.
In a discovery project,7 we were interested in the practi-
cal synthesis of 1,5-diarylpyrazoles 2 (Fig. 1) with alkyl
and heteroaryl groups at C-3. While the reported regio-
specific syntheses of this class of compounds involves
4,8
lowyielding steps,
it was anticipated that the high
yielding coupling method described above would yield
a mixture of regioisomers.
Keywords: Regioselectivity; 1,5-Diarylpyrazoles; 1D NOESY; LC–
NMR.
q DRL Publication No 387 A.
Heating arylhydrazine hydrochlorides with 1-aryl-1,3-
diketones 3 (CF3) in ethanol afforded 1,5-diarylpyr-
azoles as the major products with small quantities of
*
Corresponding authors. Tel.: +91 40 2304 5439; fax: +91 40 2304
5438/5007; e-mail: sunilkumarsingh@drreddys.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.100

7680
S. K. Singh et al. / Tetrahedron Letters 45 (2004) 7679–7682
Ar1
Ar1
R
undesired 1,3-diarylpyrazoles, which were discarded by
triturating the products, after column purification, with
a mixture of ethyl acetate and toluene (Scheme 1 and
Table 1). However, this selectivity was limited to those
examples where electron-withdrawing groups such as
CF3, CHF2, CH2F etc. were attached to C-3 of the
1,3-diketone.7b,9 In the cases of simple alkyl substituents
such as CH3, C2H5 and n-C3H7, a ꢀ 60:40 a nonsepara-
ble mixture of the regioisomers was obtained, which
could be quantified by integration of the 1H NMR spec-
trum of the mixture and by HPLC analysis (Table 1).9b
The identities of this nonseparable two component mix-
ture was established by a 1D NOESY experiment, and
N
N
N
N
+
Ar2
Ar2
OH
R
b
40%
a
5-9
60%
O:
i
H
O
H+
H+
O
Ar2
R
Ar2
R
3a
3b
R = EWG (CF3, Py)
Ar1
R = EDG (Me, n-Pr)
i-iii/ii-iii
Ar1
N
N
N
N
1
+
Ar2
R
Ar2
confirmed by the H NMR spectra of the pure compo-
nents obtained from LC–NMR analysis.
R
a
b
96-99%
minor/not detected
4, 10-12 (i-iii) and 5-9 (ii-iii)
Various arylhydrazine hydrochlorides were reacted with
1-aryl-hexane-1,3-diones under acidic conditions to
study the regioselectivity. While arylhydrazines having
electron-donating and weakly electron-withdrawing
Scheme 1. Reagents and conditions: (i) Ar1NHNH2ÆHCl, absolute
ethanol, 50–60°C, 4–5h; (ii) Ar1NHNH2ÆHCl, TEA, absolute ethanol,
50–60°C, 4–5h; (iii) Ar1NHNH2, absolute ethanol, 50–60°C, 4–5h.
Table 1. Regioselectivity achieved in the synthesis of 1,5-diarylpyrazoles
Compound
Ar1
Ar2
R
Reaction conditionsa
a (%)b
b (%)b
4
5
5
5
6
6
6
7
7
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-O2N–C6H4–
4-O2N–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
CF3
CH3
ic
i
99
71
0
29
0
CH3
CH3
ii
iii
i
100
100
62
0
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
38
3
ii
iii
i
96
99
1
21
99
79
0
ii
O
O
S
H2N
8
8
4-MeO–C6H4–
4-MeO–C6H4–
n-C3H7
n-C3H7
i
67
98
32
0
O
O
S
H2N
ii
O
O
O
O
S
Me
9
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
4-MeO–C6H4–
n-C3H7
n-C3H7
n-C3H7
i
52
99
48
1
HOH2C
O
S
Me
9
ii
iii
ic
ic
ic
HOH2C
O
S
Me
9
98
1
HOH2C
O
O
O
O
S
H2N
10
11
99
1
N
HOH2C
O
S
H2N
99
0
N
N
HOH2C
O
S
Me
12
100
0
HOH2C
a See Scheme 1.
b By 1H NMR and HPLC.
c Reaction conditions (ii)–(iii) also provided similar results.

S. K. Singh et al. / Tetrahedron Letters 45 (2004) 7679–7682
7681
Figure 2. X-ray crystal structure of the O-propanoate of 3-(4-pyridyl)-1,5-diarylpyrazole 10.
groups afforded ꢀ50–65% of the 1,5-diarylpyrazoles 8
and 9, those with strongly electron-withdrawing groups
such as a nitro group afforded ꢀ80% of the 1,3-diarylpyr-
azole 7. But, with these diketones we never achieved
formation of a single regioisomer. However, the dike-
tones with pyridyl rings exclusively afforded 3-pyridyl
analogues 10–12. Apart from the spectroscopic evidence,
the structures of these 3-pyridyl derivatives were con-
firmed by a single crystal X-ray diffraction study of the
O-propanoate of 3-(4-pyridyl)pyrazole 10 (Fig. 2).10
at ꢀ6.2ppm for the desired 1,5-diarylpyrazoles whereas
the undesired 1,3-diarylpyrazoles could be recognized by
the appearance of the C-4 proton at ꢀ6.5ppm. The regio-
isomers were neither distinguishable on TLC nor separa-
ble by column chromatography and thus had to be
1
detected by H NMR and HPLC analysis.
The first step in the regioselective synthesis of the 1,5-
diarylpyrazole is reported to be the formation of a
hydrazone through the C-3 carbonyl group of the 1-
aryl-1,3-diketone.6 Presumably, the 1-aryl-1,3-diketones
having electron-withdrawing groups exclusively exist in
the enolic form 3a (R = CF3, Py) under all the condi-
tions tested and afforded 1,5-diarylpyrazoles 4 and 10–
12 whereas those having electron-donating groups
existed as enolate 3a (R = CH3, n-C3H7) only in TEA
and neutral media to afford the desired 1,5-diarylpyr-
azoles 5–9 (Scheme 1).
We explored alternative reaction conditions, hoping to
enhance the selectivity for 3-alkylated 1,5-diarylpyr-
azoles. A fewpyrazoles had been prepared using an org-
anic base,11 but there was no systematic study
reported regarding their regiochemistry. In the synthesis
of 6, changing to basic conditions using TEA, exclu-
sively afforded 96% of the 1,5-diarylpyrazole with the
n-C3H7 group at C-3. We performed another reaction
by heating the mixture of the arylhydrazine and 1,3-
diketone in absolute ethanol without TEA. This experi-
ment produced even better regioselectivity (99%). To
demonstrate the generality of this methodology, a vari-
ety of arylhydrazines and 1,3-diketones were used for
the exclusive synthesis of several 1,5-diarylpyrazoles
(Scheme 1 and Table 1). The regioselectivity of com-
pounds 4 and 10–12 was retained even under these
newconditions.
In summary, we have described the factors affecting the
regioisomeric formation of 1,5-diarylpyrazoles during
the two component synthesis, their identification
through 1D NOESY, LC–NMR and X-ray analyses,
and simple reaction conditions providing excellent reg-
ioselectivity and high yields in the synthesis of this phar-
maceutically important scaffold.
Acknowledgements
12
In our newmethod, an ethanolic solution of the aryl-
The authors gratefully acknowledge the constant
support and encouragement received from Dr. K. Anji
Reddy and Prof. J. Iqbal.
hydrazine hydrochloride was basified (pH ꢀ 11.0) using
3–5equiv of TEA under an argon atmosphere and an
ethanolic solution of the 1,3-diketone (0.95equiv) was
added. The reaction mixture was heated at 50–60°C
for 4–5h to afford 1,5-diarylpyrazoles with excellent reg-
ioselectivity and in very high yields (70–80%). Alterna-
tively, an ethanolic solution of the arylhydrazine was
mixed with the diketone (0.95equiv) under an argon
atmosphere and heated at the same temperature for
the same period of time to afford 1,5-diarylpyrazoles
(e.g., compound 6) with improved regioselectivity and
yield. In the 1H NMR spectra, the C-4 proton appeared
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.08.100. The procedure for the preparation of
1,3-diketones 3 and the O-propanoate derivative of
compound 10, the spectral data/charts including 1H
NMR, 1D NOESY and LC–NMR for the identification

7682
S. K. Singh et al. / Tetrahedron Letters 45 (2004) 7679–7682
10. Tables of atomic coordinates, anisotropic thermal para-
meters and bond lengths etc. may be obtained free of
charge from The Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, on quoting the deposition
number CCDC 242156, the names of the authors and the
journal citation (fax: +44 1223 336 033; e-mail: deposit@
ccdc.cam.ac.uk; web site: http://www.ccdc.cam.ac.uk).
Single crystals suitable for X-ray diffraction were grown
from a mixture of MeOH and EtOAc. A half mole
equivalent of EtOAc is present in the crystal lattice. The
compound crystallized as colourless needles in monoclinic
space group Pna21 with cell dimensions a = 7.736 (2),
b = 18.365 (4), c = 20.742 (5), and V = 2946.9 (11) con-
taining four molecules in the unit cell. The intensity data
were collected on a Rigaku AFC-7S single crystal diffrac-
of 1,5-diarylpyrazoles 4–12 and a table of elemental
analysis are available.
References and notes
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12. Representative procedure: 1,5-di(4-methoxyphenyl)-3-n-
propyl-1H-pyrazole
6a.
4-Methoxyphenylhydrazine
hydrochloride (2.0g, 11.46mmol) was suspended in abso-
lute ethanol (30mL) under Ar and to the agitated reaction
mixture was slowly added TEA (2.89g, 28.65mmol) at
room temperature, which achieved a pH of ꢀ11.0. After
stirring for a further 15min, an ethanolic solution of 1-(4-
methoxyphenyl)-1,3-hexanedione 3 (2.39g, 10.88mmol)
was added, and the mixture was heated at 50–60°C for 4–
5h. The solvent was removed and the residue was stirred
with ice-cold water. After acidification with 6N HCl, the
solution was extracted with EtOAc and the combined
organic layers were washed with brine and water. The
dried organic layer after solvent evaporation left behind a
dark residue, which on column chromatographic purifica-
tion over 230–400mesh silica gel using ethyl acetate–
petroleum ether (15:85) and repeated trituration with
petroleum ether afforded the desired product (2.62g, 78%)
as an off-white low melting solid. Alternatively, the
mixture of 4-methoxyphenylhydrazine (2.0g, 14.49mmol)
and 1-(4-methoxyphenyl)-1,3-hexanedione (3.02g, 13.76
mmol), dissolved in absolute ethanol (30mL) which
attained a pH of ꢀ5, on heating under Ar at 50–60°C
for 4–5h, followed by a similar work-up and purification,
afforded the same product in almost the same yield. IR
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(neat) 2959, 1612, 1516, 1453, 1248cmÀ1 1H NMR
.
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unpublished results.
(CDCl3, 400MHz) d 7.19 (d, J = 8.8Hz, 2H), 7.13 (d,
J = 8.8Hz, 2H), 6.83 (d, J = 9.2Hz, 2H), 6.80 (d,
J = 9.2Hz, 2H), 6.23 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H),
2.67 (t, J = 7.6Hz, 2H), 1.85–1.65 (m, 2H), 1.03 (t,
J = 7.6Hz, 3H). MS (CI Method) 323 [(M+1)+, 100%],
294. HPLC 96.3% (in the presence of TEA) and 98.5%
(without TEA) [Hichrom RPB (250mm), mobile phase
0.01M KH2PO4/CH3CN–CH3OH (50:50), flowrate
1.0mL/min and UV detection at 210nm]. Anal. Calcd
(C20H22N2O2)C: 74.51; found, 74.68; H: calcd, 6.88;
found, 6.72; N: calcd, 8.69; found, 8.53.