An efficient, three-component one-pot preparation of 1,4-dihydropyridines containing novel substituted pyrazole under sulfamic acid catalysis

Article abstract of DOI:10.1002/cjoc.201190114

An efficient approach to 1,4-dihydropyridines containing novel substituted pyrazole is achieved via threecomponent reaction of pyrazolyl aldehyde, β-ketoester, and ammonium acetate in one-pot under sulfamic acid catalysis.

Full text of DOI:10.1002/cjoc.201190114

FULL PAPER
An Efficient, Three-component One-pot Preparation of
1,4-Dihydropyridines Containing Novel Substituted
Pyrazole under Sulfamic Acid Catalysis
Li, Jianping*(李建平)
Li, Huijuan(李会娟)
Qiu, Jikuan(仇记宽)
Zhang, Guisheng(张贵生)
College of Chemistry and Environmental Science, Key Labaratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, China
An efficient approach to 1,4-dihydropyridines containing novel substituted pyrazole is achieved via three-
component reaction of pyrazolyl aldehyde, β-ketoester, and ammonium acetate in one-pot under sulfamic acid ca-
talysis.
Keywords Hantzsch reaction, 1,4-dihydropyridines, pyrazole, sulfamic acid, catalysis, synthesis
Introduction
most of these catalysts such as TMSCl-NaI, Yb(OTf)3,
InCl3, and some organocatalysts are costly or require
additional efforts to prepare. Although FeCl3•6H2O and
CAN were inexpensive catalysts, the reaction only af-
forded the desired product in moderate yields (Table 1,
Entries 8 and 9). Herein, we report that sulfamic acid is
an extremely efficient and inexpensive catalyst for the
synthesis of 1,4-DPHs by one-pot, three-component
reaction of pyrazolyl aldehyde, β-ketoester, and ammo-
nium acetate (Scheme 1).
4-Substituted 1,4-dihydropyridines (1,4-DHPs) con-
stitute an important class of calcium channel blockers1-3
and are used most frequently as cardiovascular agents
for treatment of hypertension.4 1,4-Dihydropyridines
possess a variety of biological activities,5 such as bron-
chodilator, antiatherosclerotic, antitumor and antidia-
betic agents. They also function as neuroprotectants, as
anti-platelet treatment of aggregators and are important
in Alzheimer’s disease as antiischaemic agents.6-8
Among 1,4-DPHs, there are also examples of
drug-resistance modifiers,9 antioxidabts10 and a durg for
the treatment of urinary urge incontinence.11 Therefore,
the development of synthetic methods for 4-substituted
1,4-dihydropyridines is very significant to both hetero-
cycle chemistry and medicinal chemistry.
Scheme 1 SA-catalyzed synthesis of 1,4-dihydropyridines con-
taining pyrazole
Nowadays, the pyrazole derivatives were paid much
attention for their various biological activities, such as
antitumor,12,13 selective COX-2 inhibitory.14 Besides,
they can be used as cytokine inhibitors,15 potent catalytic
activity inhibitor of human telomerase.16 Consequently,
we may obtain some compounds with higher biological
activities by putting the pyrazole group into the
1,4-DPHs. This might help us to develop new chemo-
therapeutic agents.
1,4-DPHs are generally synthesized using the
Hantzsch methods,17 which involve cyclocondensation
of an aldehyde, active methylene compounds and am-
monia either in acetic acid or under reflux in alcohols
for long reaction time which typically leads to low
yields.18,19 Other procedures comprise the use of
TMSCl-NaI,20 InCl3,21 Yb(OTf)3,22 I2,23 SiO2/NaHSO4,24
CAN,25 FeCl3•6H2O and organocatalysts.26 However,
Results and discussion
To obtain the best experimental conditions, treatment
of one equivalent of 4-substituted pyrazolyl aldehyde 1b
and ammonium acetate 3 with two equiv. of ethyl ace-
toacetate 2a in the presence of 10 mol% of SA in etha-
*
E-mail: jplig@163.com
Received September 5, 2010; revised November 2, 2010; accepted November 23, 2010.
Project supported by the National Natural Sciences Foundation of China (No. 20872029).
Chin. J. Chem. 2011, 29, 511— 514
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
511

Li et al.
FULL PAPER
nol at reflux afforded the corresponding 1,4-dihydro-
pyridine 4b in 84% yield (Table 1, Entry 5). Thus, the
reaction conditions were optimized. Ethanol proved to
be a much better solvent in terms of yield than all the
others tested including tetrahydrofuran (Entry 1), ace-
tonitrile (Entry 2) which afforded the desired product in
moderate yields (28%—47%). Neat conditions fur-
nished 1,4-DPHs 4b in 78% yield (Entry 3). Under the
similar conditions as Entry 5, reaction with 20 mol% of
SA in ethanol at reflux raised the yield to an excellent
90% (Entry 4). However, there was no improvement in
the reaction rates and yields on decreasing the amount of
SA to 10 or 5 mol%. To demonstrate the efficiency of
our catalyst, a blank reaction was carried out in the ab-
sence of SA. After 7 h at reflux in ethanol only a 30%
yield of 4b was obtained.
Table 2 SA-catalyzed Hantzsch synthesis of 1,4-dihydropyri-
dines containing pyrazole 4a—4ga
Entry
Ar
R1
R2
Time/h Product Yieldb/%
1
2
3
4
5
6
7
C6H5
CH3 CH2CH3
CH3 CH2CH3
5
4
4
5
4
7
7
4a
4b
4c
4d
4e
4f
73
90
86
80
84
70
78
4-Me-C6H4
4-MeO-C6H4 CH3 CH2CH3
4-Cl-C6H4 CH3 CH2CH3
4-O2N-C6H4 CH3 CH2CH3
4-Me-C6H4 CH3CH2 CH3
4-MeO-C6H4 CH3CH2 CH3
4g
a 4-Substituted pyrazolyl aldehyde/β-ketoester/ammonium acetate＝
1∶2∶1 (molar ratio), reflux, 4—7 h. b Isolated yield.
Experimental
General procedures
Table 1 SA-catalyzed Hantzsch synthesis of 1,4-dihydropyri-
dines containing pyrazole 4b under different conditionsa
Melting points were determined with an XRC-1 mi-
cromelting point apparatus and uncorrected. NMR spec-
tra were measured on a Bruker DPX 400 M, respec-
tively, using TMS as the internal standard and CDCl3 as
the solvent. Chemical shifts (δ) were expressed down-
field from the internal standand TMS and coupling con-
stants J were given in Hz. Elemental analysis was per-
formed on a PE-2400 Analyzer. Common reagents and
materials were purchased from commercial sources and
purified by recrystallization or distillation. The starting
material, 1-phenyl-3-aryl-1H-pyrazole-4-carbaldehyde
(1) was prepared according to Ref.27
General procedure for the synthesis of 4a— 4g
A mixture of pyrazolyl aldehyde 1 (1 mmol),
β-ketoester 2 (2 mmol), ammonium acetate 3 (1 mmol),
and SA (20 mol%) was heated at reflux in ethanol (5
mL) for the appropriate time (Table 2, monitored by
TLC). The reaction mixture, after being cooled to room
temperature was poured into cold water and extracted
with ethyl acetate. The organic layer was dried over so-
dium sulfate. Then the crude products were purified by
silica gel column chromatography [V(petroleum
ether)∶V(ethyl acetate)＝4∶1].
Entry Solvent
Catalyst (mol%)
SA (20)
Yieldb of 4b/%
1
2
3
4
5
6
7
8
9
THF
CH3CN
Nonec
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
28
47
78
90
84
72
30
62
56
SA (20)
SA (20)
SA (20)
SA (10)
SA (5)
Diethyl 1,4-dihydro-2,6-dimethyl-4-(1,3-diphenyl-
1H-pyrazol-4-yl)pyridine-3,5-dicarboxylate
(4a)
None
1
White crystal; m.p. 169—171 ℃; H NMR (CDCl3,
400 MHz) δ: 1.076 (t, J＝7.0 Hz, 6H, 2CH3), 2.230 (s,
6H, 2CH3), 3.761—3.824 (m, 2H, CH2), 3.981—4.043
(m, 2H, CH2), 5.298 (s, 1H, CH), 5.400 (s, 1H, NH),
7.229 (t, J＝7.0 Hz, 1H, ArH), 7.337 (t, J＝7.6 Hz, 1H,
ArH), 7.393—7.424 (m, 4H, ArH), 7.678 (d, J＝8.0 Hz,
2H, ArH), 7.746 (s, 1H, N＝CH), 7.829 (d, J＝6.4 Hz,
2H, ArH); 13C NMR (CDCl3, 100 MHz) δ: 14.28, 19.53,
29.67, 59.67, 104.35, 125.92, 127.01, 127.40, 127.84,
128.52, 128.96, 129.18, 134.84, 140.06, 143.24, 151.24,
167.51. Anal. calcd for C28H29N3O4: C 71.32, H 6.20, N
8.91; found C 71.62, H 6.37, N 9.18.
FeCl3•6H2O (20)
CAN (20)
a
4-Substituted pyrazolyl aldehyde/ethyl acetoacetate/ammonium
acetate＝1∶2∶1 (molar ratio), reflux, 4h. b Isolated yield. c Re-
action at 80 ℃.
The reactions of various 4-substituted pyrazolyl al-
dehydes possessing either electrondonating or electron-
withdrawing substituents with β-ketoester and ammo-
nium acetate in the presence of a catalytic amount (20
mol%) of SA afforded good yields of the corresponding
1,4-DPHs (70%—90%) in short time. The results are
presented in Table 2.
Diethyl 1,4-dihydro-2,6-dimethyl-4-(1-phenyl-3-p-
tolyl-1H-pyrazol-4-yl)pyridine-3,5-dicarboxylate (4b)
512
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 511— 514

An Efficient, Three-component One-pot Preparation of 1,4-Dihydropyridines
1
White crystal; m.p. 194—195 ℃; H NMR (CDCl3,
400 MHz) δ: 1.075 (t, J＝7.0 Hz, 6H, 2CH3), 2.282 (s,
6H, 2CH3), 2.389 (s, 3H, CH3), 3.756—3.801 (m, 2H,
CH2), 4.005—4.049 (m, 2H, CH2), 5.288 (s, 1H, CH),
5.408 (s, 1H, NH), 7.217 (d, J＝7.6 Hz, 3H, ArH),
7.396 (t, J＝7.8 Hz, 2H, ArH), 7.671 (d, J＝8.4 Hz, 2H,
ArH), 7.708 (s, 1H, N＝CH), 7.728 (s, 2H, ArH); 13C
NMR (CDCl3, 100 MHz) δ: 14.23, 19.39, 21.24, 29.60,
59.65, 104.38, 118.73, 125.84, 127.00, 128.50, 128.63,
128.75, 129.15, 131.87, 136.96, 140.09, 143.33, 151.16,
167.58. Anal. calcd for C29H31N3O4: C 71.73, H 6.43, N
8.65; found C 72.01, H 6.58, N 8.89.
Faint yellow colloid; m.p. 68—70 ℃; 1H NMR (CDCl3,
400 MHz) δ: 1.190 (t, J＝7.4 Hz, 6H, 2CH3), 2.406 (s,
3H, CH3), 2.563—2.616 (m, 2H, CH2), 2.832—2.886
(m, 2H, CH2), 3.338 (s, 3H, CH3), 5.281 (s, 1H, CH),
5.675 (s, 1H, NH), 7.234 (d, J＝9.6 Hz, 2H, ArH),
7.399 (t, J＝8.0 Hz, 2H, ArH), 7.648 (d, J＝7.6 Hz, 2H,
ArH), 7.680 (s, 1H, N＝CH), 7.764 (d, J＝8.0 Hz, 2H,
ArH); 13C NMR (CDCl3, 100 MHz) δ: 12.66, 21.26,
25.76, 29.40, 50.58, 103.59, 118.77, 125.89, 126.93,
128.45, 128.67, 128.91, 129.18, 129.45, 131.95, 136.92,
140.10, 149.27, 150.92, 167.40. Anal. calcd for
C29H31N3O4: C 71.73, H 6.43, N 8.65; found C 72.15, H
6.69, N 8.91.
Diethyl 1,4-dihydro-4-[3-(4-methoxyphenyl)-1-
phenyl-1H-pyrazol-4-yl]-2,6-dimethylpyridine-3,5-
dicarboxylate (4c) White crystal; m.p. 128—130 ℃;
1H NMR (CDCl3, 400 MHz) δ: 1.088 (t, J＝7.0 Hz, 6H,
2CH3), 2.242 (s, 6H, 2CH3), 3.797—3.842 (m, 2H, CH2),
3.853 (s, 3H, OCH3), 3.991—4.054 (m, 2H, CH2), 5.270
(s, 1H, CH), 5.409 (s, 1H, NH), 6.957 (d, J＝8.4 Hz, 2H,
ArH), 7.219 (t, J＝7.2 Hz, 1H, ArH), 7.399 (t, J＝7.8
Hz, 2H, ArH), 7.669 (d, J＝7.6 Hz, 2H, ArH), 7.729 (s,
1H, N＝CH), 7.771 (d, J＝8.4 Hz, 2H, ArH); 13C NMR
(CDCl3, 100 MHz) δ: 14.28, 19.37, 29.65, 55.34, 59.68,
104.30, 113.33, 118.70, 125.85, 127.03, 127.45, 128.57,
129.17, 130.07, 140.05, 143.39, 150.90, 159.18, 167.62.
Anal. calcd for C29H31N3O5: C 69.44, H 6.23, N 8.38;
found C 69.76, H 6.43, N 8.62.
Dimethyl 2,6-diethyl-1,4-dihydro-4-[3-(4-meth-
oxyphenyl)-1-phenyl-1H-pyrazol-4-yl]pyridine-3,5-
dicarboxylate (4g) Faint yellow colloid; m.p. 67—69
1
℃; H NMR (CDCl3, 400 MHz) δ: 1.192 (t, J＝7.6 Hz,
6H, 2CH3), 2.563—2.616 (m, 2H, CH2), 2.835—2.888
(m, 2H, CH2), 3.342 (s, 6H, 2CH3), 3.866 (s, 3H, OCH3),
5.266 (s, 1H, CH), 5.669 (s, 1H, NH), 6.995 (d, J＝8.8
Hz, 2H, ArH), 7.221 (t, J＝7.6 Hz, 1H, ArH), 7.399 (t,
J＝8.0 Hz, 2H, ArH), 7.645 (d, J＝7.6 Hz, 2H, ArH),
7.678 (s, 1H, N＝CH), 7.822 (d, J＝8.0 Hz, 2H, ArH);
13C NMR (CDCl3, 100 MHz) δ: 12.68, 25.76, 29.44,
50.66, 55.33, 103.57, 113.46, 118.73, 125.89, 126.95,
127.54, 128.84, 129.19, 129.76, 140.07, 149.30, 159.13,
167.42. Anal. calcd for C29H31N3O5: C 69.44, H 6.23, N
8.38; found C 69.88, H 6.47, N 8.75.
Diethyl 4-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-
4-yl]-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarb-
1
oxylate (4d) White crystal; m.p. 167—168 ℃; H
Conclusions
NMR (CDCl3, 400 MHz) δ: 1.077 (t, J＝7.0 Hz, 6H,
2CH3), 2.266 (s, 6H, 2CH3), 3.778—3.841 (m, 2H, CH2),
3.990—4.070 (m, 2H, CH2), 5.265 (s, 1H, CH), 5.482 (s,
1H, NH), 7.233 (d, J＝7.6 Hz, 1H, ArH), 7.412 (t, J＝
7.8 Hz, 4H, ArH), 7.663 (d, J＝8.0 Hz, 2H, ArH), 7.738
(s, 1H, N＝CH), 7.855 (d, J＝8.4 Hz, 2H, ArH); 13C
NMR (CDCl3, 100 MHz) δ: 14.26, 19.51, 29.63, 30.90,
59.75, 104.45, 118.82, 126.14, 127.34, 128.02, 128.86,
129.22, 130.19, 133.35, 139.93, 143.33, 167.44. Anal.
calcd for C28H28ClN3O4: C 66.46, H 5.58, N 8.30; found
C 66.86, H 6.04, N 8.62.
In summary, we have developed a simple and effi-
cient method for the synthsis of 1,4-dihydropyridines
containing novel substituted pyrazole under sulfamic
acid catalysis. The present method has many obvious
advantages compared to those reported in the previous
literatures, including the avoidance of discharging
harmful organic solvents, the simplicity of the method-
ology and the inexpensive catalyst.
References
Diethyl 1,4-dihydro-2,6-dimethyl-4-[3-(4-nitro-
phenyl)-1-phenyl-1H-pyrazol-4-yl]pyridine-3,5-
dicarboxylate (4e) Yellow crystal; m.p. 124—126 ℃;
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2CH3), 2.312 (s, 6H, 2CH3), 3.770—3.832 (m, 2H, CH2),
3.983—4.028 (m, 2H, CH2), 5.323 (s, 1H, CH), 5.572 (s,
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Chin. J. Chem. 2011, 29, 511— 514