A new protocol to synthesize 1,4-dihydropyridines by using 3,4,5-trifluorobenzeneboronic acid as a catalyst in ionic liquid: Synthesis of novel 4-(3-carboxyl-1H-pyrazol-4-yl)-1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tet.2005.01.008

3,4,5-Trifluorobenzeneboronic acid catalysed, ionic liquid mediated facile synthesis of 4-pyrazolyl 1,4-dihydropyridines at room temperature by the cyclocondensation of ethyl 3-aminocrotonate, pyrazole aldehyde and a β-keto ester is reported. The procedur

Full text of DOI:10.1016/j.tet.2005.01.008

Tetrahedron 61 (2005) 2465–2470
A new protocol to synthesize 1,4-dihydropyridines by using
3,4,5-trifluorobenzeneboronic acid as a catalyst in ionic liquid:
synthesis of novel
4-(3-carboxyl-1H-pyrazol-4-yl)-1,4-dihydropyridines
*
Radhakrishnan Sridhar and Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Received 21 September 2004; revised 22 November 2004; accepted 5 January 2005
Available online 26 January 2005
Abstract—3,4,5-Trifluorobenzeneboronic acid catalysed, ionic liquid mediated facile synthesis of 4-pyrazolyl 1,4-dihydropyridines at room
temperature by the cyclocondensation of ethyl 3-aminocrotonate, pyrazole aldehyde and a b-keto ester is reported. The procedure adopted
was found to be eco-benign, facile at room temperature and better than the conventional, [bmim]Cl mediated and InCl3 catalysed, [bmim]Cl
mediated 1,4-dihydropyridine syntheses.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
on the calcium antagonist activity revealed that pyrazolyl
and imidazolyl 1,4-dihydropyridines exhibit weak calcium
antagonist activity.16 Manfredini et al.17 have shown
pyrazole nucleosides as potential analogues of ribavirin18
in antitumor activity.
4-Aryl-l,4-dihydropyridines form a major class of drugs
used in the management of cardiovascular diseases.1,2
Baraldi et al. have explored the less common hetero aryl
dihydropyridines for the calcium channel activity.3,4
Development of drug resistance, both intrinsic drug
resistance and acquired drug resistance, remains a clinical
obstacle in the chemotherapy of many cancers.5,6 Among
the possible resistance modifiers, the dihydropyridines
(DHPs), calcium antagonists, have been studied extensively
as the analogue of verapamil (VP) 1.7 The finding that the
enantiomer of verapamil and nigludipine lacks calcium
antagonistic activity but still has MDR reversal activity
indicated that the MDR reversal activity is independent of
the calcium antagonistic activity.8,9 It was proposed by
Tanabe et al. that NIK-250, 2 which possess a heterocyclic
ring at the 4-postion can overcome MDR and has moderate
calcium antagonistic activity in vitro without optical
resolution.10–14 Further, it was observed that imidazothia-
zole derivatives could potentiate the MDR reversal activity
without significant side effects observed for 1,4-dihydro-
pyridine derivatives.15 Baraldi et al. during their exploration
Our interest was to synthesize 4-[3-ethoxycarbonyl-1H-
pyrazol-4-yl]-1,4-dihydro-pyridine dicarboxylates in which
the pyrazole-3-ester moiety mimic the one in pyrazole
nucleoside reported by Manfredini et al. We expect these
compounds to show weak calcium antagonist but high MDR
Keywords: 1,4-Dihydropyridines; 3,4,5-Trifluorobenzeneboronic acid;
Ionic liquid; 4-(3-Carboxyl-1H-pyrazol-4-yl)-1,4-dihydropyridines;
Vilsmeier reagent.
* Corresponding author. Tel.: C91 44 24913289; fax: C91 44 24911589;
e-mail: ptperumal2002@yahoo.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.008

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R. Sridhar, P. T. Perumal / Tetrahedron 61 (2005) 2465–2470
Scheme 1. Synthesis of alkyl-1(2,4-dinitrophenyl)-4-formyl-1H-pyrazole-3-carboxylate.
Table 1. Synthesis of 1H-pyrazole-3-carboxylic acid esters
Entry
X
R
Time (h)
Yield (%)
4a
4b
4c
4d
H
NO2
H
CH3
CH3
C2H5
C2H5
4
4
4
4
85
79
88
80
NO2
reversal activity. The original Hantzsch19 dihydropyridine
synthesis consisted of the reaction of ethyl acetoacetate
(2 equiv) with an aldehyde and ammonia. This method has
been widely used for the preparation of the 1,4-dihydro-
pyridine where the substitution at the fourth position is an
aliphatic,20 aromatic21 or heterocyclic22 residue. Enamines
could replace ethyl acetoacetate and could serve as an
ammonia source paving way to a series of 1,4-dihydro-
pyridines of medicinal interest.23 Microwave-assisted
synthesis of dihydropyridines24 was reported advantageous
since it accelerates the reaction rate. A solid-phase synthesis
of dihydropyridines was also demonstrated.25 Conventional
Hantzsch dihydropyridine syntheses generally involve
organic solvents like methanol and acetic acid. Ionic liquid
because of its polarity, negligible vapor pressure, recycl-
ability, high thermal stability and immiscibility with a
number of organic solvents has attracted much interest from
synthetic chemists.26 In continuation of our work on the
synthesis of 1H-Pyrazole-4-carboxylates27 using Vilsmeier
methodology, we synthesized 4-formyl-1H-pyrazole-3-car-
boxylates17b 4(a–d) (Scheme 1) from alkyl pyruvate 4-nitro
or 2,4-dinitro phenyl hydrazones 3(a–d) upon treatment
with 8 equiv of DMF/POCl3 (Table 1).
During the earlier attempts28 to synthesise dihydropyridines
by condensing an aldehyde, b-ketoester and methyl
3-aminocrotonate using [bmim]PF6 and [bmim]BF4 as the
reaction media, it was observed that [bmim]Cl was
unsuccessful. When we attempted the synthesis of 4-[3-
ethoxycarbonyl-1H-pyrazol-4-yl]-1,4-dihydro-pyridine
dicarboxylates in [bmim]Cl the reaction was facile with
ethyl 3-aminocrotonate, pyrazole aldehydes and a b-keto
ester. The reason may be attributed to the substrate effect
that can contribute to the formation of the product
dihydropyridine in moderate to good yields. The remaining
ionic liquid was thoroughly washed with ethyl acetate after
completion of the reaction (monitored by TLC) and
recycled in subsequent reactions. Second and third reactions
using recovered ionic liquid afforded similar yields to those
obtained in the first run. In the fourth and fifth runs, the
yields steadily decreased. That is in the case of pyrazole
aldehyde 4d, ethyl acetoacetate and ethyl 3-aminocrotonate
in [bmim]Cl, the yields of 7e obtained were 51, 50, 50, 48,
47 in five successive runs. However, the activity of ionic
liquid was consistent and no decrease in yield was observed
when the recycled ionic liquid was activated at 80 8C under
vacuum in each cycle. In order to increase the yield of the
dihydropyridine obtained through [bmim]Cl mediated
synthesis we added 5 mol% of InCl3 or 5 mol% of 3,4,5-
trifluorobenzeneboronic acid (Scheme 2) to the reaction
We have attempted the pyrazolyl dihydropyridines syn-
thesis by using ionic liquid medium at room temperature.
Scheme 2. Synthesis of pyrazolyl dihydropyridines.

R. Sridhar, P. T. Perumal / Tetrahedron 61 (2005) 2465–2470
2467
Table 2. Ionic liquid mediated synthesis of symmetrical and unsymmetrical dihydropyridines catalysed by 3,4,5-trifluorobenzene boronic acid
Ester (R0)
Entry
Aldehyde (Z-CHO)
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
4a
4a
4c
4c
4d
4c
–CH3
–CH2 CH3
–CH3
–CH2 CH3
–CH2 CH3
–CH2 C6H5
–CH2 CH3
–CH2 CH3
7a
7b31
7c
7d
7e
7f
7g
7h
6
5
4
4
5
4
4
5
92
86
87
91
85
87
90
93
Benzaldehyde
m-Nitro-benzaldehyde
The compounds gave satisfactory spectral and elemental analysis value. Furthermore the structure of compound 7b was confirmed by X-ray crystallographic
study (Fig. 1).31
indicates the versatility of 3,4,5-trifluorobenzeneboronic
acid catalysed [bmim]Cl mediated synthesis over the other
methods adopted for the synthesis of dihydropyridines.
In summary, we have developed a mild, simple and
environmentally benign protocol for the synthesis of
dihydropyridines in ionic liquid media using 3,4,5-trifluoro-
benzeneboronic acid as catalyst. We hope the pyrazolyl
dihydropyidines we have synthesized to show MDR
reversal activity, exploration of which would be our
ultimate goal.
2. Experimental
2.1. General procedure for the preparation 1H-pyrazole-
3-carboxylates
Figure 1. The ORTEP31 view of 4-[3-methoxycarbonyl-1-(4-nitrophenyl)-
1H-pyrazol-4-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
diethyl ester, 7b showing 30% probability displacement ellipsoids and
the atom numbering scheme.
1.4 g of POCl3 (0.008 mol) was added drop wise to an ice-
cold stirred solution of ethyl pyruvate 2,4-dinitrophenyl
hydrazone (0.001 mol) in 10 mL dry DMF. The reaction
mixture was allowed to attain room temperature and then
refluxed at 70–80 8C for about 4 h. The resulting mixture
was poured onto crushed ice, neutralized with sodium
acetate and left standing overnight. The pale yellow
precipitate obtained was purified by silica gel (60–120
mesh) column chromatography with ethyl acetate–
petroleum ether mixture (15:85) to yield the product.
mixture and found that the yield obtained increased
considerably (Table 2).
The stability of boronic acids to air and moisture and their
relatively low toxicity (benzeneboronic acid:29 LD50, oral-
ratZ740 mg/kg), have enthused us to employ 3,4,5-
trifluorobenzeneboronic acid30 as a catalyst in dihydro-
pyridine synthesis.
2.1.1. Methyl-1(4-nitrophenyl)-4-formyl-1H-pyrazole-3-
carboxylate, 4a. Yellow crystals (15% ethyl acetate:
petroleum ether); mp 214 8C; IR (KBr) cmK1: 3123, 2919,
1
The increase in yield might be due to increase in the acidity
of the reaction mixture, which contributes to the product
yield. Both the catalyst and [bmim]Cl recovered after the
reaction are recyclable. The yield decreases during
successive runs with the recovered ionic liquid-catalyst
mixture but further addition of 5 mol% of catalyst to the
reaction mixture ensures excellent yield of the product.
Further we found that the formation of dihydropyridine in
exceptional yields was feasible with other aromatic
aldehydes also. The following comparison (Table 3) clearly
2882, 1716, 1677, 1595, 1529, 1340, 1262, 857; H NMR
(500 MHz, CDCl3) d: 10.46 (s, 1H, formyl –CH), 8.62 (s,
1H Pyrazole –CH), 8.40–8.42 (d, JZ9.2 Hz, 2H), 7.99–8.01
(d, JZ9.2 Hz, 2H), 4.06 (s, 3H); 13C NMR (125 MHz,
CDCl3, ppm): d 186.2, 161.5, 147.4, 145.1, 142.8, 130.5,
126.6, 125.6, 120.6, 53.1; MS (m/z): 275 (MC); Anal. Calcd
for C12H9N3O5: C, 52.37; H, 3.30; N, 15.27; Found: C,
52.42; H, 3.28; N, 15.38.
2.1.2. Methyl-1(2,4-dinitrophenyl)-4-formyl-1H-pyra-
zole-3-carboxylate, 4b. Yellow crystals (15% ethyl acetate:
petroleum ether); mp 138 8C; IR (KBr) cmK1: 3120, 2958,
Table 3. Comparison of dihydropyridine syntheses (synthesis of 7e)
1
2888, 1727, 1684, 1611, 1541, 1348, 1257, 836, 743; H
Reaction condition
Time (h)
Yield (%)
NMR (500 MHz, CDCl3) d: 10.43 (s, 1H, formyl –CH),
8.87–8.88 (d, J1Z2.3 Hz, 1H), 8.61–8.63 (dd, J1Z2.3 Hz,
J2Z8.6 Hz, 1H), 8.39 (s, 1H, Pyrazole –CH), 7.92–7.93 (d,
J2Z8.6 Hz, 1H), 4.01 (s, 3H); 13C NMR (125 MHz, CDCl3,
ppm): d 185.9, 161.1, 144.3, 147.8, 145.7, 136.5, 134.1,
Reflux in ethanol (D)
[bmim]Cl (rt)
[bmim]ClCboronic acid
[bmim]ClCInCl3
8
6
5
6
48
51
85
80

2468
R. Sridhar, P. T. Perumal / Tetrahedron 61 (2005) 2465–2470
128.7, 128.4, 126.5, 121.6, 53.1; MS (m/z): 320 (MC); Anal.
Calcd for C12H8N4O7: C, 45.01; H, 2.52; N, 17.50; Found:
C, 44.92; H, 2.58; N, 17.56.
51.1, 29.7, 19.7, 19.6, 14.3; MS (m/z): 484 (MC); Anal.
Calcd for C23H24N4O8: C, 57.02; H, 4.99; N, 11.56; Found:
C, 57.12; H, 5.04; N, 11.58.
2.1.3. Ethyl-1(4-nitrophenyl)-4-formyl-1H-pyrazole-3-
carboxylate, 4c. Yellow crystals (15% ethyl acetate:
petroleum ether); mp 148 8C; IR (KBr) cmK1: 3130, 2992,
2.2.2. 4-[3-Methoxycarbonyl-1-(4-nitrophenyl)-1H-
pyrazol-4-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylic acid diethyl ester, 7b. Yellow crystals (15%
1
2889, 1714, 1681, 1596, 1528, 1342, 1258, 856, 750; H
ethyl acetate:petroleum ether); mp 212 8C; IR (KBr) cmK1
:
NMR (500 MHz, CDCl3) d: 10.45 (s, 1H, formyl –CH), 8.62
(s, 1H, Pyrazole –CH), 8.39–8.41 (d, JZ9.2 Hz, 2H), 8.00–
8.01 (d, JZ9.2 Hz, 2H), 4.51–4.55 (q, JZ7.5 Hz, 2H),
1.46–1.49 (t, JZ7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3,
ppm): d 186.3, 161.1, 147.3, 145.5, 142.8, 130.5, 126.5,
125.6, 120.6, 62.4, 14.4; MS (m/z): 289 (MC); Anal. Calcd
for C13H11N3O5: C, 53.98; H, 3.83; N, 14.53; Found: C,
53.92; H, 3.81; N, 14.64.
3338, 3093, 2982, 1728, 1689, 1494, 1339, 1216, 1099, 854,
750; 1H NMR (500 MHz, CDCl3, ppm): d 8.27–8.29 (d, JZ
9.2 Hz, 2H), 7.86–7.88 (d, JZ9.2 Hz, 2H), 7.86 (s, 1H,
pyrazole –CH), 5.83 (brs, 1H), 5.61 (s, 1H), 4.03–4.09 (m,
4H), 3.97 (s, 3H), 2.31 (s, 6H), 1.16–1.19 (t, JZ7.5 Hz, 6H);
13C NMR (125 MHz, CDCl3, ppm): d 167.5, 162.5, 146.0,
143.9, 143.8, 143.3, 135.3, 128.7, 125.3, 119.4, 104.3, 60.0,
52.1, 29.7, 19.7, 14.3; MS (m/z): 498 (MC); Anal. Calcd for
C24H26N4O8: C, 57.83; H, 5.26; N, 11.24; Found: C, 57.94;
H, 5.31; N, 11.13.
2.1.4. Ethyl-1(2,4-dinitrophenyl)-4-formyl-1H-pyrazole-
3-carboxylate, 4d. Yellow crystals (15% ethyl acetate:
petroleum ether); mp 130 8C; IR (KBr) cmK1: 3330, 3122,
3079, 2999, 2890, 1734, 1686, 1610, 1551, 1351, 1268,
1242, 1109, 742, 629; 1H NMR (500 MHz, CDCl3) d: 10.45
(s, 1H, formyl –CH), 8.87–8.88 (d, J1Z2.3 Hz, 1H), 8.61–
8.63 (dd, J1Z2.3 Hz, J2Z8.6 Hz, 1H), 8.36 (s, 1H Pyrazole
–CH), 7.91–7.93 (d, J2Z8.6 Hz, 1H), 4.47–4.51 (q, JZ
7.5 Hz, 2H), 1.42–1.45 (t, JZ7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3, ppm): d 186.0, 160.6, 147.7, 146.1,
144.3, 136.6, 134.0, 128.7, 128.3, 126.5, 121.6, 62.6, 14.3; MS
(m/z): 334 (MC); Anal. Calcd for C13H10N4O7: C, 46.70; H,
3.02; N, 16.77; Found: C, 46.75; H, 3.06; N, 16.58.
2.2.3.
4-[3-Ethoxycarbonyl-1-(4-nitrophenyl)-1H-
pyrazol-4-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylic acid 3-ethyl ester 5-methyl ester, 7c. Yellow
crystals (15% ethyl acetate:petroleum ether); mp 202 8C; IR
(KBr) cmK1: 3336, 3094, 2982, 1720, 1690, 1495, 1339,
1217, 1098, 855, 750; 1H NMR (500 MHz, CDCl3, ppm): d
8.27–8.29 (d, JZ9.2 Hz, 2H), 7.86–7.88 (d, JZ9.2 Hz, 2H),
7.82 (s, 1H, pyrazole –CH), 5.79 (brs, 1H), 5.59 (s, 1H),
4.44–4.48 (q, JZ7.5 Hz, 2H), 4.05–4.09 (q, JZ7.5 Hz, 2H),
3.59 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H), 1.44–1.47 (t, JZ
7.5 Hz, 3H), 1.15–1.18 (t, JZ7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3, ppm): d 167.9, 167.5, 162.3, 146.0,
144.0, 143.8, 143.7, 143.6, 135.1, 128.5, 125.3, 119.4,
104.4, 104.2, 61.2, 60.0, 51.1, 29.7, 19.7, 19.6, 14.5, 14.4;
MS (m/z): 498 (MC); Anal. Calcd for C24H26N4O8: C,
57.83; H, 5.26; N, 11.24; Found: C, 57.88; H, 5.11; N,
11.29.
2.2. General procedure for InCl3 or 3,4,5-trifluoro-
benzeneboronic acid catalyzed synthesis of symmetrical
and unsymmetrical dihydropyridines in ionic liquid at
room temperature
0.72 g (2.5 mmol, 1 equiv) of pyrazole aldehyde 4c, 0.33 g
(2.5 mmol, 1 equiv) of ethyl acetoacetate, 0.32 g (2.5 mmol,
1 equiv) of ethyl 3-aminocrotonate were mixed with
2 grams of bmimCl and stirred after adding 5 mol% of
InCl3 or 5 mol% 3,4,5-trifluorobenzeneboronic acid for
about six hours. Then the mixture was extracted with ethyl
acetate and column chromatographed with 15% ethyl
acetate–petroleum ether (bp. 60–80 8C) mixture to get
pure yellow colored 4-[3-ethoxycarbonyl-1-(4-nitro-
phenyl)-1H-pyrazol-4-yl]-2,6-dimethyl-1,4-dihydropyri-
dine-3,5-dicarboxylic acid diethyl ester 7d in excellent
yield. The remaining ionic liquid-catalyst mix was
thoroughly washed with ethyl acetate and recycled for
subsequent reactions.
2.2.4. 4-[3-Ethoxycarbonyl-1-(4-nitrophenyl)-1H-
pyrazol-4-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylic acid diethyl ester, 7d. Yellow crystals (15%
:
ethyl acetate:petroleum ether); mp 224 8C; IR (KBr) cmK1
1
3334, 3090, 2990, 1722, 1693, 1492; H NMR (500 MHz,
CDCl3, ppm): d 8.26–8.28 (d, JZ9.2 Hz, 2H), 7.86–7.88 (d,
JZ9.2 Hz, 2H), 7.85 (s, 1H, pyrazole –CH), 5.83 (brs, 1H),
5.61 (s, 1H), 4.42–4.47 (q, JZ7.5 Hz, 2H), 4.04–4.09 (q,
JZ7.5 Hz, 4H), 2.30 (s, 6H), 1.43–1.46 (t, JZ7.5 Hz, 3H),
1.15–1.18 (t, JZ7.5 Hz, 6H); 13C NMR (125 MHz, CDCl3,
ppm): d 167.6, 162.2, 146.0, 143.9, 143.7, 143.7, 135.2,
128.6, 125.3, 119.4, 104.3, 61.1, 60.0, 29.7, 19.7, 14.4, 14.4;
MS (m/z): 513 (MC); Anal. Calcd for C25H28N4O8: C, 58.59;
H, 5.51; N, 10.93; Found: C, 58.54; H, 5.48; N, 11.02.
2.2.1. 4-[3-Methoxycarbonyl-1-(4-nitrophenyl)-1H-
pyrazol-4-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylic acid 3-ethyl ester 5-methyl ester, 7a. Yellow
crystals (15% ethyl acetate:petroleum ether); mp 228 8C; IR
(KBr) cmK1: 3318, 2986, 1707, 1650, 1494, 1340, 1221,
2.2.5. 4-[3-Ethoxycarbonyl-1-(2,4-dinitrophenyl)-1H-
pyrazol-4-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylic acid diethyl ester, 7e. Yellow crystals (15%
ethyl acetate:petroleum ether); mp 88 8C; IR (KBr) cmK1
:
3344, 3092, 2984, 1726, 1690, 1545, 1348, 1216, 1098, 912,
1
855, 749; H NMR (500 MHz, CDCl3, ppm): d 8.28–8.30
1
739; H NMR (500 MHz, CDCl3, ppm): d 8.63–8.64 (d,
(d, JZ9.2 Hz, 2H), 7.86–7.87 (d, JZ9.2 Hz, 2H), 7.83 (s,
1H, pyrazole –CH), 5.83 (brs, 1H), 5.58 (s, 1H), 4.03–4.09
(m, 2H), 3.98 (s, 3H), 3.59 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H),
1.16–1.19 (t, JZ8.0 Hz, 3H); 13C NMR (125 MHz, CDCl3,
ppm): d 167.9, 167.5, 162.6, 146.1, 144.0, 143.9, 143.8,
143.3, 135.2, 128.6, 125.3, 119.5, 104.3, 104.1, 60.1, 52.1,
J1Z2.3 Hz, 1H), 8.43–8.45 (dd, J1Z2.3 Hz, J2Z8.6 Hz,
1H), 7.86–7.88 (d, J2Z8.6 Hz, 1H), 7.60 (s, 1H, pyrazole
–CH), 6.32 (brs, 1H), 5.49 (s, 1H), 4.35–4.39 (q, JZ7.5 Hz,
2H), 3.98–4.09 (m, 4H), 2.22 (s, 6H), 1.36–1.39 (t, JZ7.5 Hz,
3H), 1.12–1.15 (t, JZ7.5 Hz, 6H); 13C NMR (125 MHz,

R. Sridhar, P. T. Perumal / Tetrahedron 61 (2005) 2465–2470
2469
2. Spedding, M.; Paoletti, R. Pharm. Rev. 1992, 44, 363.
CDCl3, ppm): d 167.6, 161.9, 146.1, 144.7, 144.3, 143.4,
137.2, 135.5, 131.3, 127.6, 127.1, 121.1, 103.7, 61.2, 59.9,
29.7, 19.3, 18.4, 14.3; MS (m/z): 558 (MC); Anal. Calcd for
C25H27N5O10: C, 53.86; H, 4.88; N, 12.56; Found: C, 53.80;
H, 4.92; N, 12.62.
3. Baraldi, P. G.; Chiarini, A.; Budriesi, R.; Roberti, M.; Casolari,
A.; Manfredini, S.; Simoni, D.; Zanirato, V.; Varani, K.;
Borea, P. A. Drug Des. Deliv. 1989, 5, 13.
4. Baraldi, P. G.; Budriesi, R.; Cacciari, B.; Chiarini, A.; Garuti,
L.; Giovanninetti, G.; Leoni, A.; Roberti, M. Collect. Czech.
Chem. Commun. 1992, 57, 169.
2.2.6. 4-[3-Ethoxycarbonyl-1-(4-nitrophenyl)-1H-pyra-
zol-4-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicar-
boxylic acid 3-benzyl ester 5-ethyl ester, 7f. Yellow
crystals (15% ethyl acetate:petroleum ether); mp 138 8C; IR
(KBr) cmK1: 3337, 3093, 2981, 1725, 1694, 1494, 1216,
1113, 855, 749; 1H NMR (500 MHz, CDCl3, ppm): d 8.26–
8.28 (d, JZ9.2 Hz, 2H), 7.77–7.79 (d, JZ9.2 Hz, 2H), 7.74
(s, 1H, pyrazole –CH), 7.21–7.27 (m, 5H), 5.80 (brs, 1H),
5.60 (s, 1H), 5.02–5.11 (q, JZ16.0 Hz, 2H), 4.35–4.26 (m,
2H), 4.03–4.07 (q, JZ7.5 Hz, 2H), 2.30 (s, 3H), 2.29 (s,
3H), 1.33–1.36 (t, JZ7.5 Hz, 3H), 1.14–1.17 (t, JZ7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3, ppm): d 167.5, 167.3,
162.2, 146.0, 144.6, 143.9, 143.6, 136.7, 134.3, 128.7,
128.5, 128.1, 127.9, 125.2, 119.4, 104.0, 103.3, 65.7, 61.1,
60.0, 30.2, 19.9, 19.8, 14.4; MS (m/z): 575 (MC); Anal.
Calcd for C30H30N4O8: C, 62.71; H, 5.26; N, 9.75; Found:
C, 62.63; H, 5.32; N, 9.65.
5. Davis, H. L.; Davis, T. E. Cancer Treat. Rep. 1979, 63, 809.
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Bioorg. Med. Chem. 1998, 6, 2219.
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Arzneim-Forschung. 1991, 41, 855.
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10. Kiue, A.; Sano, T.; Naito, A.; Inada, H.; Suzuki, K.; Okumura,
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11. Watanabe, Y.; Takano, H.; Kiue, A.; Kohno, K.; Kuwano, M.
Anti-Cancer Drug Des. 1991, 6, 47.
12. Kiue, A.; Sano, T.; Suzuki, K.; Inada, H.; Okumura, M.;
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1990, 50, 310.
2.2.7. 2,6-Dimethyl-3,5-dicarboethoxy-4-phenyl-1,4-
dihydropyridine,32 7g. Yellow crystals (15% ethyl acetate:
petroleum ether); mp 158 8C (lit. mp 158–159)32b; IR
(KBr) cmK1: 3322, 1676, 1633, 1595, 1529, 1102, 851; 1H
NMR (500 MHz, CDCl3, ppm): d 7.01–7.26 (m, 5H), 6.00
(brs, 1H), 4.98 (s, 1H), 4.08 (q, JZ8.2 Hz, 4H), 2.29 (s, 6H),
1.21 (t, JZ7.7 Hz, 6H); 13C NMR (125 MHz, CDCl3, ppm):
d 168.2, 152.2, 148.3, 144.9, 128.6, 126.2, 103.8, 59.6, 39.5,
19.3, 14.3; MS (m/z): 329 (MC); Anal. Calcd for
C19H23NO4: C, 69.28; H, 7.04; N, 4.25; Found: C, 69.21;
H, 7.07; N, 4.31.
13. Kiue, A.; Sano, T.; Naito, A.; Okumura, M.; Kohno, K.;
Kuawno, M. J. Br. Cancer 1991, 64, 221.
14. Nogae, I.; Kohno, K.; Kikuchi, J.; Kuwano, M.; Akiyama, S.;
Kiue, A.; Suzuki, K.; Yoshida, Y.; Cornwell, M. M.; Pastan, I.;
Gottesman, M. M. Biochem. Pharm. 1989, 38, 519.
15. Tasaka, S.; Tanabe, H.; Sasaki, Y.; Machida, T.; Iino, M.;
Kiue, A.; Naito, S.; Kuwano, M. J. Heterocyclic Chem. 1997,
34, 1763.
16. Baraldi, P. G.; Garuti, L.; Leoni, A.; Cacciari, B.; Budriesi, R.;
Chiarini, A. Drug Des. Discov. 1993, 10, 319.
17. (a) Manfredini, S.; Bazzanini, R.; Baraldi, P. G.; Guarneri, M.;
Simoni, D.; Marongiu, M. E.; Pani, A.; Tramontano, E.; Colla,
P. L. J. Med. Chem. 1992, 35, 917. (b) Manfredini, S.;
Bazzanini, R.; Baraldi, P. G.; Bonora, M.; Marangoni, M.;
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P. L. Anti-Cancer Drug Des. 1996, 11, 193.
2.2.8.
2,6-Dimethyl-3,5-dicarboethoxy-4-(3-nitro-
phenyl)-1,4-dihydropyridine,32 7h. Yellow crystals (15%
ethyl acetate:petroleum ether); mp 164 8C (lit. mp 162–
163);32b IR (KBr) cmK1: 3328, 1674, 1633, 1590, 1529,
1
1105, 857; H NMR (500 MHz, CDCl3, ppm): d 8.13 (s,
18. Riley, T. A.; Larson, S. B.; Avery, T. L.; Finch, R. A.; Robins,
R. K. J. Med. Chem. 1990, 33, 572.
1H), 8.02 (d, JZ7.5 Hz, 1H), 7.66 (d, JZ7.5 Hz, 1H), 7.38
(d, JZ8.6 Hz, 1H), 6.16 (brs, 1H), 5.10 (s, 1H), 4.10 (q, JZ
7.8 Hz, 4H), 2.36 (s, 6H), 1.24 (t, 6H); 13C NMR (125 MHz,
CDCl3, ppm): d 167.2, 150.0, 148.1, 145.0, 134.5, 128.6,
123.1, 121.3, 103.2, 60.0, 40.0, 19.5, 14.2; MS (m/z): 374
(MC); Anal. Calcd for C19H22N2O6: C, 60.95; H, 5.92; N,
7.48; Found: C, 60.81; H, 5.88; N, 7.62.
19. Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
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Acknowledgements
24. Alajarin, R.; Vaquero, J. J.; Garcia Navio, J. L.; Alvarez-
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One of the authors (R.S.) is grateful to Council of Scientific
and Industrial Research, New Delhi, India for financial
support.
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