Simple and efficient synthesis of 2,6-dialkyl-3,5-dialkoxycarbonyl-4-(3- aryl-1-phenyl-pyrazol-4-yl)pyridines using TPAP/NMO as a catalyst under mild conditions

Article abstract of DOI:10.1016/j.tet.2011.02.040

Biologically important pyrazolylpyridines were synthesized in excellent yield by the oxidation of pyrazolyl 1,4-dihydropyridines (pyrazolyl 1,4-DHPs) using tetrapropylammonium perruthenate/N-methylmorpholine-N-oxide (TPAP/NMO) under mild conditions at 0 °C.

Full text of DOI:10.1016/j.tet.2011.02.040

Tetrahedron 67 (2011) 2998e3002
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Simple and efficient synthesis of 2,6-dialkyl-3,5-dialkoxycarbonyl-4-
(3-aryl-1-phenyl-pyrazol-4-yl)pyridines using TPAP/NMO
as a catalyst under mild conditions
,
a
a
a,b,c
R. Murugan a , K. Ramamoorthy , S. Sundarrajan , S. Ramakrishna
*
a HEM Laboratory, NUSNNI, National University of Singapore, 2 Engineering Drive 3, Singapore 117576, Singapore
b Institute of Material Research and Engineering, Singapore 117602, Singapore
c King Saud University, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Biologically important pyrazolylpyridines were synthesized in excellent yield by the oxidation of pyr-
azolyl 1,4-dihydropyridines (pyrazolyl 1,4-DHPs) using tetrapropylammonium perruthenate/N-methyl-
morpholine-N-oxide (TPAP/NMO) under mild conditions at 0 ꢀC.
Received 30 September 2010
Received in revised form 23 January 2011
Accepted 14 February 2011
Available online 19 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazolylpyridines
TPAP/NMO
Oxidation
Pyrazolyl 1,4-dihydropyridines
1. Introduction
pyrazolylpyridines from pyrazolyl 1,4-DHPs. We report the rapid and
efficient catalytic oxidation of pyrazolyl 1,4-DHP derivatives at 0 ꢀC
Pyrazoles form an integral part of many natural products of
therapeutic importance and possess potentially reactive sites
for a variety of chemical reactions to generate molecular diversity.
(S)-3-Pyrazolylalanine,1 lonazolac,2 difenamizole,3 mepirizole,4
metamizol,5 phenidone,6 pyrazomycine, fezolamin, 4,5-dihydro-
3-phenyl-6H-pyrrolo[1,2-b]pyrazole are some of the examples of
biologically active compounds endowed with antimicrobial,7 anti-
inflammatory,8 analgesic,9 hypoglycaemic,10 and non nucleoside
HIV-1 reverse transcriptase inhibitor properties.11 Pyrazolyl 1,4-
DHPs have pronounced pharmacological applications as anti-
inflammatory agents, and also possess calcium channel activity,12
including control of arthropod pests,13 and also pyrazolylpyridine
ligands exhibit efficient lanthanide sensors.14
Oxidation of 1,4-DHP has received considerable attention because
DHP based calcium channel blockers are oxidatively converted to
pyridine derivatives by the action of cytochrome P450 in the liver.15
Efforts on the synthesis of heteroaryl DHP chemistry mimicking
NADH coenzyme is recentlyexpanding to explore the mechanisms and
utilizing them for a variety of synthetic reactions. Therefore, the syn-
thesis of these moieties has become of interest to synthetic chemists
and biologists. This manuscript describes ourefforts on the synthesis of
in DCM/acetonitrile (Scheme 1). Several groups have reported
the oxidation of 1,4-DHPs with metal based catalysts,16 I2/UHP,17 N-
nitroso-2-aryl-1,3-oxazolidines,18 magtroneÔ,19 9-phenyl-10-meth-
ylacridinium/O2,20 IBX,21 NO gas,22 claycop,23 S-nitrosoglutathione,24
4-phenyl-1,2,4-triazol-3,5-dione,25 electrochemical,26 and photooxi-
dation,27 and chloranil28 promote these type of reactions including
ones at room temperature. Although some of these reactions are per-
formed under mild conditions, most of them require a long period for
completion, high temperature, freshly prepared reagents, tedious
work-up, include the formation of side products, and give only modest
yields of the products. Therefore, development and introduction of a
convenient, milder and efficient method for the oxidation of hetero-
cyclic 1,4-DHPs to the corresponding pyridines is of practical impor-
tance and is still in demand.
R3
R2
R3
R2
N
N
N
N
R4
R4
TPAP/NMO
CO2R1
Me
R1O2C
R1O2C
CO2R1
Me
DCM:Acetonitrile, 0oC
Me
N
Me
N
H
1a - 1j
2a - 2i
* Corresponding author. Tel.: þ65 6516 6593; fax: þ65 6773 0339; e-mail
Scheme 1. TPAP/NMO catalyzed synthesis of pyrazolylpyridines 2aei.
address: mperajen@nus.edu.sg (R. Murugan).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.040

R. Murugan et al. / Tetrahedron 67 (2011) 2998e3002
2999
Recently, the TPAP/NMO combination has received considerable
attention as a mild catalyst for oxidation reactions at lower
temperature.29 Here, TPAP/NMO is introduced as a mild and highly
efficient catalyst for the preparation of pyrazolylpyridine de-
rivatives under mild conditions.
2. Results and discussion
The experimental procedure is simple and clean. 1,4-DHPs were
prepared using the appropriate aldehyde, ammonium acetate, and
alkyl acetoacetate under reflux conditions using reported litera-
ture.30 Pyrazolylpyridines have been synthesized by TPAP/NMO
catalyzed oxidation of pyrazolyl 1,4-DHPs under mild conditions. In
our method, including RuCl3, MnO2, and TPAP/NMO were screened
initially for catalytic activity and the compared studies results are
summarized in Table 1.
Table 1
Screening of oxidants for the conversion of 3c to 4ca
Fig. 2. Effect of catalyst loading on the synthesis of pyridines 2a, 2d, and 4e. Reaction
conditions: 1,4-DHP (1 equiv), NMO (0.1 equiv), solvent (10 mL), 0 ꢀC. aIsolated yields.
Entry Catalyst
Amount Conditions
Time
Yield (%)
a
b
c
Fe(ClO4)3
VOCl3
V2O5
2 mol % AcOH, rt
2.1 equiv DCM, rt
2.1 equiv AcOH, rt
50 mol % UHP (2 equiv),
AcOEt, rt
1.5 h
60 h
9116d
9716u
Table 2
168 h 8416u
25 min 8917
Synthesis of pyridines 4aeea
d
I2
R2
R2
R1O2C
Me
CO2R1
Me
e
f
RuCl3
5 mol % O2, AcOH, rt
53 h
6 h
5516y
9629
CO2R1
Me
R1O2C
Me
TPAP/NMO
NeNO Oxazolidine 10 mol % DCM, rt
g
h
i
MnO2
Mn(OAc)3
BiCl3
5 equiv DCM, rt
2 equiv AcOH, rt
30 mol % PhCH2Ph3PHSO5,
acetonitrile, rt
30 min 8716g
35 min 9816h
DCM:Acetonitrile, 0°C
N
H
N
2 h
8916p
4a - 4e
3a - 3e
Entry
Reactant
Product
Time
(min)
Yieldb
(%)
i
TPAP
5 mol % NMO (0.1 equiv),
30 min
97
DCM/acetonitrile, 0 ꢀC
a
Isolated yields.
The oxidation of 1a using TPAP/NMO as a catalyst was chosen as
a
30
30
91
a model for optimization of the solvent. Initially, the reaction of
pyrazolyl 1,4-DHP1awas carriedout in thepresence ofTPAP/NMOin
different solvents at 0 ꢀC. The catalytic activity of TPAP/NMO is found
to vary with different solvents (Fig.1). Dichloromethane/acetonitrile
were found to give maximum yield followed by acetonitrile alone.
The catalyst was found to be only mildly effective in toluene.
The effect of an ionic liquid on the TPAP/NMO catalyzed reaction
was also examined. The method reported is favorable and gave
good yields (89e94%).
b
90
We decided to find out the optimal amount of catalyst (TPAP) to
reach complete conversion at 0 ꢀC. The results are presented in
Fig. 2. The incremental amount of catalyst drastically accelerates
the reaction with the same level of selectivity. From the results
outlined in Fig. 2 and 5 mol % of catalyst was chosen for further
experiments. The simple methyl and phenyl substituted 1,4-DHPs
also worked well without the formation of side products (Table 2).
c
30
97
d
30
94
e
30
94
a
Reaction conditions: 1,4-DHP (1 equiv), TPAP/NMO (5 mol%:0.1 equiv), DCM/
acetonitrile (5 mL), 0 ꢀC.
Fig. 1. Effect of solvent on the conversion of 1d to 2d. Reaction conditions: pyrazolyl
1,4-DHP (1 equiv), TPAP/NMO (5 mol%:0.1 equiv), Solvent (10 mL), 0 ꢀC. *Ionic liquids
(3 mL), rt. aIsolated yields.
b
Isolated yields.

3000
R. Murugan et al. / Tetrahedron 67 (2011) 2998e3002
Table 3 (continued)
Pyrazolyl 1,4-DHP 1e reacted in the presence of TPAP/NMO to
give 2e in good yield (89%; Scheme 1). The reaction did not proceed
to good extent in the presence of TPAP alone in DCM/acetonitrile
(1:1). This result confirmed the need for a catalytic amount of NMO.
We found that TPAP/NMO promoted reactions were clean and
afforded higher yields of product. For an illustrative example, 1a in
DCM/acetonitrile mixture was stirred at ambient temperature un-
der N2 at 0 ꢀC. To the stirring reaction mixture was added 5 mol% of
TPAP, 0.1 equiv of NMO and the total consumption of 1a after
30 min as monitored by TLC was an indication of completion of the
reaction (Scheme 1). However, the reaction when conducted
without the addition of TPAP/NMO did not afford any appreciable
amount of 2a. Furthermore, no aqueous work-up was required after
completion of the reaction. The reaction mixture was directly
charged into a column after removing the solvent under vacuum.
The maximum yield observed was 94% for 2f. All the pyrazolyl 1,4-
DHPs oxidized to give pyrazolylpyridines 2aei in high yields
(Scheme 1). The results are summarized in Table 3. In the case of 1c,
both DHP and 4-substituted methylsufanyl groups are get oxidized
Entry
Reactant
Product
Time Yieldb
(min) (%)
e
30
30
45
30
45
90
94
92
89
90
f
Table 3
Synthesis of pyrazolylpyridines 2aeia
R3
R2
R3
R2
g
h
i
N
N
N
N
R4
R4
TPAP/NMO
R1O2C
CO2R1
Me
R1O2C
CO2R1
Me
DCM:Acetonitrile, 0oC
Me
N
Me
N
H
2a - 2i
1a - 1j
Entry
Reactant
Product
Time Yieldb
(min) (%)
a
b
c
30
30
30
91
90
90
j
45
93
a
Reactionconditions:pyrazolyl1,4-DHP(1 equiv),TPAP(5 mol %), NMO(0.1 equiv),
DCM/acetonitrile [1:1] (10 mL), 0 ꢀC.
b
Isolated yields, and all the compounds were characterized by spectroscopic
techniques.
under the identical reaction conditions, yielding 2c with good yield
(Table 1, entry c). Pyrazolyl 1,4-DHPs 1c and 1i, in both cases the
product was found to be pyrazolylpyridine 2c (Scheme 2).
d
30
92
3. Conclusions
Insummary, wehavefound TPAP/NMOtobeavaluableaddition to
the existing methods available for the oxidation of pyrazolyl 1,4-DHPs
with the added advantage of mild reaction conditions, operational

R. Murugan et al. / Tetrahedron 67 (2011) 2998e3002
3001
(300 MHz, CDCl3) 7.92 (1H, s, pyrazole C]CH), 7.58 (2H, d, J 7.34 Hz,
Ph), 7.48 (2H, t, J 8.1 Hz, Ph), 7.34 (1H, d, J 7.5 Hz, Ph), 7.20 (1H, d, J
7.8 Hz, Ph), 7.12e7.08 (2H, m, Ph), 6.89 (1H, d, J 7.5 Hz, Ph),
4.07e3.92 (4H, m, CO2CH2Me), 3.71 (3H, s, PhOMe), 2.60 (6H, s, Me),
0.93 (6H, t, J 7.1 Hz, CO2CH2Me); dC (75 MHz, CDCl3) 167.3, 159.4,
155.6, 150.4, 139.5, 138.1, 133.3, 129.4, 129.3, 127.9, 127.8, 126.7,
119.9, 115.8, 114.3, 112.2, 61.4, 55.0, 23.0, 13.4.
Scheme 2. TPAP/NMO catalyzed synthesis of pyrazolylpyridines 2c.
simplicity, fast, and cleaner reaction profiles, and high yields all of
which make it an attractive strategy for the preparation of pyr-
azolylpyridines. Furthermore, therangeofusefulness ofTPAP/NMOin
organic synthetic application has also been extended. This simple
experimental procedure, offers an alternative route to synthesis of
biologically active pyrazole derivatives.
4.2.3. 2,6-Dimethyl-3,5-diethoxycarbonyl-4-(3-(4-methyl
sulfonyl
phenyl)-1-phenyl-pyrazol-4-yl)pyridine (2c). Yield (190 mg, 90%) as
a off white solid; mp 158e159 ꢀC; [found: C, 63.52; H, 5.40; N, 7.74;
S, 5.82. C29H29N3O6S requires C, 63.60; H, 5.34; N, 7.67; S, 5.86%]
m/z 548.2 (M); nmax (neat) 2983, 2922, 2852, 1722, 1596, 1561, 1500,
1442, 1406, 1379, 1340, 1306, 1235, 1206, 1146, 1111, 1089, 1067,
1035, 1006, 958, 906, 854, 777, 755, 730, 687, 656, 625, 559 cmꢁ1
;
4. Experimental section
4.1. General
dH (400 MHz, CDCl3) 7.94 (1H, s, pyrazole C]CH), 7.89 (2H, d, J
8.5 Hz, Ph), 7.76e7.74 (4H, m, Ph), 7.51 (2H, t, J 8.3 Hz, Ph), 7.37 (1H,
t, J 7.5 Hz, Ph), 4.07e3.91 (4H, m, CO2CH2Me), 2.93 (3H, s, O2SMe),
2.62 (6H, s, Me), 0.91 (6H, t, J 7.1 Hz, CO2CH2Me); dC (100 MHz,
CDCl3) 167.1, 155.9, 148.5, 139.6, 137.8, 137.3, 129.6, 128.4, 127.9,
127.8, 127.4, 127.2, 119.0, 116.3, 61.4, 44.4, 23.0, 13.5.
Melting points were recorded on a Concord melting point ap-
paratus and are uncorrected. Analytical TLC was performed on
precoated sheets of silica gel G of 0.25 mm thickness containing
PF254 indicator (Merck, Darmstadt). Catalyst was purchased from
Aldrich and used as such. All the Hantzsch 1,4-DHPs needed for
oxidation were using a reported procedure30 and purified by col-
umn chromatography before subjecting to dehydrogenation.
Known pyridine derivatives were analyzed by spectroscopic tech-
niques and compared with reported methods. Column chroma-
tography was performed with silica gel (100e200 mesh, Merck).
Elemental analyses were done in VarioMicro analyzer. The Fourier-
transform infrared (FT-IR) spectra of the products were recorded on
a Thermo NICOLET AVATAR 360 spectrometer. NMR spectra were
obtained on a JEOL 300 and 400 MHz spectrometer. NMR was
4.2.4. 2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(3-(4-chloro-3-nitro-
phenyl)-1-phenyl-pyrazol-4-yl)pyridine (2d). Yield (183 mg, 92%) as
a white solid; mp 150e151 ꢀC; [found: C, 59.98; H, 4.15; N, 10.62.
C26H21ClN4O6 requires 59.95; H, 4.06; N, 10.76%]; m/z 521.2 (M);
nmax (neat) 2923, 1731, 1597, 1540, 1500, 1435, 1361, 1278, 1232,
1204, 1105, 1034, 960, 909, 859, 830, 800, 747, 688, 549 cmꢁ1
; dH
(400 MHz, CDCl3) 8.20 (1H, d, J 1.7 Hz, Ph), 7.94 (1H, s, pyrazole C]
CH), 7.76 (2H, d, J 8.2 Hz, Ph), 7.52 (3H, t, J 8.1 Hz, Ph), 7.45 (1H, d, J
8.4 Hz,Ph), 7.40e7.38(1H,m,Ph),3.55(6H,s,CO2Me), 2.61(6H, s,Me);
dC (75 MHz, CDCl3) 167.6, 156.1, 147.9, 147.3, 139.0, 136.9, 132.5, 131.7,
131.3, 129.6, 128.0, 127.6, 127.3, 126.0, 123.9, 118.9, 115.6, 52.3, 23.0.
recorded in CDCl3, DMSO-d6, and the chemical shifts are given in d.
4.2.5. 2,6-Dimethyl-3,5-diethoxycarbonyl-4-(3-(4-chloro-3-nitro
phenyl)-1-phenyl-pyrazol-4-yl)pyridine (2e). Yield (179 mg, 90%) as
a off white solid; mp 126e128 ꢀC; [found: C, 61.18; H, 4.54; N, 10.27.
C28H25ClN4O6 requires C, 61.26; H, 4.59; N, 10.21%]; m/z 549.2 (M);
nmax (neat) 2977, 2929, 1737, 1716, 1596, 1579, 1540, 1500, 1463,
1435, 1409, 1369, 1347, 1276, 1227, 1100, 1035, 960, 908, 860, 838,
4.2. General procedure for the synthesis of pyrazolylpyridines
2aei
To a solution of pyrazolyl 1,4-DHPs (1a, 200 mg, 0.422 mmol,
1 equiv) in DCM/acetonitrile [1:1] (10 mL), TPAP (8 mg,
0.021 mmol), and NMO (5 mg, 0.04 mmol) were added at 0 ꢀC. The
reaction mixture was stirred at 0 ꢀC for the time indicated in Table 1.
After complete conversion, as indicated by TLC, the solvent evap-
orated in vacuo. Purification of the crude product by flash chro-
matography (30% EtOAc/hexane) gave the title compound 2a. All the
products were characterized by spectroscopic techniques.
752, 723, 687, 600 cmꢁ1
; dH (400 MHz, CDCl3) 8.24 (1H, d, J 2.4 Hz,
Ph), 7.94 (1H, s, pyrazole C]CH), 7.53 (2H, d, J 7.8 Hz, Ph), 7.57e7.49
(3H, m, Ph), 7.46 (1H, d, J 8.4 Hz, Ph), 7.38 (1H, t, J 7.3 Hz, Ph),
4.08e3.98 (4H, m, CO2CH2Me), 2.62 (6H, s, Me), 0.94 (6H, t, J 7.1 Hz,
CO2CH2Me); dC (100 MHz, CDCl3) 167.1, 156.1, 148.1, 147.3, 139.2,
136.8, 132.6, 131.7, 131.2, 129.6, 128.4, 127.9, 127.4, 126.1, 123.9, 119.1,
116.0, 61.5, 23.0, 13.5.
4.2.1. 2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(3-(3-methoxy
phe-
nyl)-1-phenyl-pyrazol-4-yl)pyridine (2a). (181 mg, 91%) as a white
solid; mp 129e130 ꢀC; [found: C, 68.70; H, 5.29; N, 8.97.
C27H25N3O5 requires C, 68.78; H, 5.34; N, 8.91%]; m/z 472.2 (M);
nmax (neat) 2997, 2945, 2843, 1728, 1614, 1554, 1503, 1463, 1435,
1341, 1283, 1236, 1198, 1104, 1070, 1032, 957, 857, 793, 748, 721,
4.2.6. 2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(3-(2-nitro phenyl)-1-
phenyl-pyrazol-4-yl)pyridine (2f). Yield (187 mg, 94%) as a white
solid; mp 159e160 ꢀC; [found: C, 64.17; H, 4.50; N,11.57. C26H22N4O6
requires C, 64.19; H, 4.56; N,11.52%]; m/z 487.2 (M); nmax (neat) 2971,
2932, 2897, 2855,1724,1628,1558,1496,1449,1427,1369,1321,1296,
680 cmꢁ1
;
dH (400 MHz, CDCl3) 7.94 (1H, s, pyrazole C]CH), 7.77
1223,1172,1134,1099,1038,1013, 988, 877, 831, 741, 702, 602 cmꢁ1
;
(2H, d, J 7.9 Hz, Ph), 7.49 (2H, t, J 8.0 Hz, Ph), 7.34 (1H, d, J 7.3 Hz, Ph),
7.22e7.20 (1H, m, Ph), 7.08e7.06 (2H, m, Ph), 6.88 (1H, t, J 6.0 Hz,
Ph), 3.72 (3H, s, PhOMe), 3.51 (6H, s, CO2Me), 2.58 (6H, s, Me); dC
(75 MHz, CDCl3) 167.9, 159.4, 155.7, 150.5, 139.4, 138.2, 133.3, 129.4,
129.3, 127.5, 126.7, 120.0, 118.8, 115.6, 112.4, 55.0, 52.2, 23.1.
dH (400 MHz, DMSO-d6) 8.70 (1H, s, Ph), 7.93 (1H, s, pyrazole C]CH),
7.79 (2H, d, J 8.4 Hz, Ph), 7.58e7.52 (4H, m, Ph), 7.37 (1H, t, J 6.88 Hz,
Ph), 7.17e7.16 (1H, m, Ph), 3.55 (6H, s, CO2Me), 2.46 (6H, s, Me); dC
(100 MHz, DMSO-d6) 148.6, 145.6, 139.0, 136.4, 132.2, 129.8, 129.7,
129.5, 128.7, 127.6, 127.1, 124.6, 124.1, 118.1, 116.2, 52.4, 22.6.
4.2.2. 2,6-Dimethyl-3,5-diethoxycarbonyl-4-(3-(3-methoxy phenyl)
1-phenyl-pyrazol-4-yl)pyridine (2b). Yield (179 mg, 90%) as a white
solid; mp 98e99 ꢀC; [found: C, 69.76; H, 5.79; N, 8.48. C29H29N3O5
requires C, 69.72; H, 5.85; N, 8.41%]; m/z 500.2 (M); nmax (neat)
2975, 2926, 1722, 1613, 1572, 1503, 1463, 1437, 1375, 1341, 1284,
4.2.7. 2,6-Dimethyl-3,5-diethoxycarbonyl-4-(3-(2-nitrophenyl)-1-
phenyl-pyrazol-4-yl)pyridine (2g). Yield (183 mg, 92%) as an off
white solid; mp 127e128 ꢀC; [found: C, 65.29; H, 5.01; N, 10.94.
C28H26N4O6 requires C, 65.36; H, 5.09; N, 10.89%]; m/z 515.2 (M);
nmax (neat) 3076, 2947, 1730, 1598, 1559, 1503, 1455, 1432, 1396,
1306, 1277, 1227, 1103, 1067, 1035, 966, 958, 934, 892, 810, 749, 682,
1227, 1206, 1100, 1035, 955, 893, 859, 789, 754, 731, 692 cmꢁ1
; dH

3002
R. Murugan et al. / Tetrahedron 67 (2011) 2998e3002
7. (a) Rathna Durga, R. S. M.; Jayashankaran, J.; Ramesh, R.; Raghunathan, R. Tet-
575 cmꢁ1
;
dH (300 MHz, DMSO-d6) 7.98 (1H, s, pyrazole C]CH),
rahedron Lett. 2006, 47, 7571e7574; (b) Jayashankaran, J.; Rathna Durga, R. S.
M.; Raghunathan, R. Tetrahedron Lett. 2006, 47, 2265e2270; (c) Pimerova, E. V.;
Voronina, E. V. J. Pharm. Chem. 2001, 35, 18e21.
8. Gandhale, D. N.; Patil, A. S.; Awate, B. G.; Naik, L. M. Pesticides 1982, 16, 27e28.
9. Takagi, K.; Tanaka, M.; Murakami, Y.; Morita, H.; Aotsuka, T. Eur. J. Med. Chem.-
Chim. Ther. 1986, 21, 65e69.
7.78 (1H, d, J 15.0 Hz, Ph), 7.63 (2H, d, J 5.8 Hz, Ph), 7.52e7.40 (4H, m,
Ph), 7.39e7.28 (2H, m, Ph), 4.25e4.01 (4H, m, CO2CH2Me), 2.58 (6H,
s, Me), 1.01 (6H, t, J 7.1 Hz, CO2CH2Me); dC (75 MHz, CDCl3) 167.5,
149.2, 147.0, 144.0, 139.7, 132.8, 131.8, 129.6, 129.1, 128.4, 127.8,
126.5, 126.1, 123.8, 118.7, 102.7, 50.8, 29.7, 19.3.
10. Bauer, V. J.; Dalalian, H. P.; Fanshawe, S. R.; Safir, S. R.; Tocus, E. C.; Benedict, A. J.
Med. Chem. 1968, 11, 981e984.
11. Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.; Swaney, S. M.; Tarpley, W. G.;
Yagi, Y.; Romero, D. L. J. Med. Chem. 2000, 43, 1034e1040.
12. Baraldi, P. G.; Garuti, L.; Leoni, A.; Cacciari, B.; Budriesi, R.; Chiarini, A. Drug Des.
4.2.8. 2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(3-(4-chloro phenyl)-
1-phenyl-pyrazol-4-yl)pyridine (2h). Yield (179 mg, 90%) as a white
solid; [found: C, 65.68; H, 4.61; N, 8.87. C26H22ClN3O4 requires C,
65.62; H, 4.66; N, 8.83; mp 144e145 ꢀC; nmax (neat) 2950, 2924,
2851, 1730, 1598, 1579, 1558, 1498, 1435, 1402, 1371, 1336, 1278,
1229,1104,1064,1036, 958, 862, 833, 753, 730, 686 cmꢁ1; m/z 476.2
[M]; dH (300 MHz, CDCl3) 7.92 (1H, s, pyrazole C]CH), 7.75 (2H, d, J
7.8 Hz, Ph), 7.47e7.44 (4H, m, Ph), 7.29e7.27 (3H, m, Ph), 3.51 (6H, s,
CO2Me), 2.59 (6H, s, Me); dC (75 MHz, CDCl3) 167.8, 155.8, 149.5,
139.3, 137.8, 134.0, 130.7, 129.5, 129.4, 128.6, 128.5, 127.7, 126.8,
118.8, 115.5, 52.2, 23.1.
Discovery 1993, 10, 319e329.
13. Bretschneider, T.; Franken, E.M.; Goergens, U.; Fuesslein, M.; Hense, A.; Kluth, J.;
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16. Na: (a) Liao, X.; Lin, W.; Lu, J.; Wanga, C. Tetrahedron Lett. 2010, 51, 3859e3861
K: (b) Eynde, J. V.; Orazio, R. D.; Van Haverbeke, Y. Tetrahedron 1994, 50,
2479e2484 Fe: (c) Liu, D.; Gui, J.; Wang, C.; Lu, F.; Yang, Y.; Sun, Z. Synth.
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Z.; Yang, B.; Li, W. Synth. Commun. 2001, 31, 2625e2630 Mn: (f) Moghadam, M.;
Nasr-Esfahani, M.; Tangestaninejad, S.; Mirkhani, V. Bioorg. Med. Chem. Lett.
2006, 16, 2026e2030; (g) Vanden Eynde, J.-J.; Delfosse, F.; Mayence, A.; Van
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Maquestiau, A. Tetrahedron 1992, 48, 463e468; (j) Sausins, A.; Duburs, G.
Heterocycles 1988, 27, 291e314; (k) Love, B.; Snader, K. M. J. Org. Chem. 1965, 30,
1914e1916 Pt: (l) Zhang, D.; Wu, L. Z.; Zhou, L.; Han, X.; Yang, Q. Z.; Zhang, L. P.;
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Synthesis 1990, 689e690 Bi: (o) Sabir, H.; Mashraqui, M.; Karnik, A. Synthesis
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1008e1012 Co: (q) Anniyappan, M.; Muralidharan, D.; Perumal, P. T. Tetrahe-
dron 2002, 58, 5069e5073; (r) Hashemi, M. M.; Ahmadibeni, Y.; Ghafuri, H.
Monatsh. Chem. 2003, 134, 107e110; (s) Wang, B.; Hu, Y.; Hu, H. Synth. Commun.
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20, 3664e3668 V: (u) Filipan-Litvic, M.; Litvic, M.; Vinkovic, V. Tetrahedron
2008, 64, 10912e10918; (v) Su, J.; Zhang, C.; Lin, D.; Duan, Y.; Fu, X.; Mu, R.
Synth. Commun. 2010, 40, 595e600 Zr: (w) Sabitha, G.; Reddy, G. S. K. K.; Reddy,
C. S.; Fatima, N.; Yadav, J. S. Synthesis 2003, 1267e1271 Sb: (x) Filipan-Litvic, M.;
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1586e1588.
4.2.9. 2,6-Dimethyl-3,5-diethoxycarbonyl-4-(3-(4-chloro phenyl)-1-
phenyl-pyrazol-4-yl)pyridine (2i). Yield (185 mg, 93%) as a white
solid; mp 101e102 ꢀC; [found: C, 66.67; H, 5.25; N, 8.27.
C28H26ClN3O4 requires C, 66.73; H, 5.20; N, 8.34%]; m/z 504.2 (M);
nmax (neat) 2982, 2899, 2361, 1716, 1559, 1502, 1441, 1413, 1379,
1339, 1296, 1238, 1205, 1091, 1039, 1007, 956, 863, 831, 754, 730,
691 cmꢁ1
; dH (300 MHz, DMSO-d6) 8.63 (1H, s, pyrazole C]CH),
7.90 (2H, d, J 7.9 Hz, Ph), 7.52 (2H, t, J 7.9 Hz, Ph), 7.44e7.41 (4H, m,
Ph), 7.35 (1H, t, J 7.2 Hz, Ph), 3.97e3.87 (4H, m, CO2CH2Me), 2.49
(6H, s, Me), 0.80 (6H, t, J 7.0 Hz, CO2CH2Me); dC (75 MHz, DMSO-d6)
166.9, 155.6, 148.9, 139.4, 138.1, 133.3, 131.3, 130.1, 129.0, 128.9,
128.0, 127.2, 118.6, 115.8, 61.6, 23.1, 13.6.
Acknowledgements
The authors gratefully acknowledge the funding support of the
Ministry of Education (MOE) Singapore, under the project grant
number 265-000-318-112.
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2006, 451e454.
Supplementary data
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Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.02.040.
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