Synthesis of some new 1,4-dihydropyridine derivatives through a facile one-pot Hantzsch condensation catalyzed by triethylamine

Article abstract of DOI:10.1002/cjoc.201280006

A facile and efficient synthesis of new 1,4-dihydropyridine derivatives was reported via Hantzsch three-component condensation reaction of aldehydes or formylphenylboronic acids, ethyl acetoacetate, and ammonium acetate in the presence of a catalytic amount of triethylamine under solvent-free conditions. The method described here offers several advantages including high yields, short reaction times, and simple work-up procedure.

Full text of DOI:10.1002/cjoc.201280006

FULL PAPER
DOI: 10.1002/cjoc.201280006
Synthesis of Some New 1,4-Dihydropyridine Derivatives
through a Facile One-pot Hantzsch Condensation Catalyzed by
Triethylamine
Ghalem, Wassima
Boulcina, Raouf
Debache, Abdelmadjid*
Laboratoire de Synthèse des Molécules d'Intérêt Biologique, Département de Chimie,
Faculté des Sciences Exactes, Université Mentouri de Constantine, 25000 Constantine, Algérie
A facile and efficient synthesis of new 1,4-dihydropyridine derivatives was reported via Hantzsch three-com-
ponent condensation reaction of aldehydes or formylphenylboronic acids, ethyl acetoacetate, and ammonium acetate
in the presence of a catalytic amount of triethylamine under solvent-free conditions. The method described here of-
fers several advantages including high yields, short reaction times, and simple work-up procedure.
Keywords 1,4-dihydropyridine, triethylamine, formylphenylboronic acid, Hantzsch reaction, solvent-free condi-
tion
Introduction
Realizing the importance of 1,4-DHP derivatives in
the synthesis of various drug sources, reported in many
classical methods such as conventional heating,[18] the
progress in this field is remarkable for microwave irra-
diation and ultrasound.[19] Also, HCl generated in situ
for the synthesis of new DHP glycoconjugates[20] and
various other catalysts such as I2,[21] TMSCl,[22] ionic
liquid,[23] HClO4-SiO2,[24] HY-Zeolite,[25] montmorillo-
nite K-10 clay,[26] cerium(IV) ammonium nitrate,[27]
iron(III) trifluoroacetate,[28] heteropoly acids,[29] metal
triflates,[30] p-TSA,[31] microwaves,[32] TMSCl-NaI,[33]
polymers,[34] and organo-catalysts have been described
in the litterature.[35]
Although most of these processes offer distinct ad-
vantages, they suffer from certain drawbacks such as
longer reaction times, unsatisfactory yields, high costs,
harsh reaction conditions, and the use of a large quantity
of volatile organic solvents. Thus, the possibility of
performing multicomponent reactions under solvent free
conditions could enhance their efficiency from an eco-
nomic as well as a green point of view. Therefore, a
new efficient method for the preparation of 1,4-DHPs is
desired.
Recently, much attention has been directed toward
the multicomponent synthesis of 1,4-dihydropyridine
compounds (1,4-DHPs) because of a variety of biologi-
cal activities as calcium antagonists or agonists.[1] The
1,4-DHPs cause vaso-relaxation by blocking volt-
age-operated calcium channel in smooth muscle cells
and also by increasing NO release from the intact endo-
thelium.[2] Moreover, they also have common features
of various bioactive compounds such as antitumor,[3]
bronchodilating,[4] antidiabetic,[5] antiviral[6] and anti-
anginal.[7] The 1,4-DHPs have also been extensively
used as analogs of NAD(P)H coenzymes to study the
mechanism and synthetic potential of various redox
processes.[8] The current studies reveal that 1,4-dihydro-
pyridine exhibits several medicinal applications which
include neuroprotectant,[9] platelet anti-aggregatory ac-
tivity,[10] cerebral anti-ischemic activity in the treatment
of Alzheimer’s disease,[11] and chemo sensitizer acting
in tumor therapy.[12] These examples clearly demon-
strate the remarkable potential of 1,4-DHP derivatives
as a source of valuable drugs. The aromatization of
1,4-DHPs is one of main metabolic pathway of these
drugs in biological systems,[13] as well as provides a fac-
ile access to the corresponding pyridine derivatives,[14]
which show anti-hypoxic and anti-ischemic activities.[15]
It has been reported also that 1,4-DHPs offer great op-
portunities for a wide range of applications in organic
synthesis and chemical processes including the hydro-
genation of olefins and quinolines,[16] and the reductive
amination of aldehydes and ketones.[17]
Results and Discussion
As part of an ongoing research program dealing with
the synthesis of heterocyclic compounds via multicom-
ponent condensation,[36] we have been investigating the
Hantzsch cycloaddition condensation reaction using
triethylamine as Lewis base. To the best of our knowl-
edge, there have been no examples of the use of triethyl-
*
E-mail: a_debache@yahoo.fr; Tel./Fax: 00 213 31818862
Received March 17, 2011; accepted October 25, 2011.
Chin. J. Chem. 2012, 30, 733—737
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
733

Ghalem, Boulcina & Debache
FULL PAPER
amine as catalyst for the synthesis of dihydropyridines.
Herein, we would like to report the studies of a facile
Hantzsch condensation in the presence of triethylamine
using substituted aldehyde 1, ethyl acetoacetate 2, and
ammonium acetate 3 to produce dihydropyridine de-
rivatives 4 in high yields (Scheme 1). We examined this
condensation under different sets of reaction conditions.
In a typical experimental procedure using traditional
conditions, a mixture of benzaldehyde, ethyl acetoace-
tate, and ammonium acetate under solvent-free condi-
tions at 80 ℃ was stirred in the presence of catalytic
amount of triethylamine (10 mol%) for a certain period
of time required to complete the reaction (TLC), result-
ing in the formation of dihydropyridine 4a. The reaction
mixture was then poured into brine and extracted with
ethyl acetate. The organic layer was dried over anhy-
drous sodium sulfate and evaporated to give crude
product. The pure product was obtained by recrystalli-
zation from ethanol. We also carried out reactions
without any catalyst but the corresponding DHP was
isolated in poor yields.
benzaldehyde, ethyl acetoacetate, and ammonium ace-
tate at different concentrations of Et3N such as 5 mol%,
10 mol%, 20 mol% and 50 mol%. We found the product
in 60%, 74%, 90%, and 90% yields, respectively. This
indicates that 20 mol% of Et3N produces the best results
with respect to product yield.
We next investigated solvents in the reaction using
Et3N (20 mol%) and the results show that product 4a
was hardly obtained in DCM and THF. When EtOH and
CH3CN were used as solvents, the reactions could pro-
ceed but the yields of 4a were lower than that under
solvent free conditions. In addition, we studied the in-
fluence of temperature on the reaction yield. Increasing
the temperature above 80 ℃ neither improved the
yield nor reduced the reaction time whereas; lowering
the temperature is detrimental to the reaction resulting
in lower yields. When the reaction was conducted at
different temperatures using Et3N under solvent free
conditions, the reaction yield decreased steadily from
90% at 80 ℃ to 59% at 65 ℃ and 35% at ambient
temperature. We usually carried out the reactions with-
out any solvent at 80 ℃ and the results are shown bel-
low.
Scheme 1
With this initial success, the scope of this protocol
was examined for other substrates. Typical results are
summarized in Table 1. It is seen that the present pro-
cedure affords a very clean and efficient approach for a
variety of aldehydes. Both aromatic (Entries 1—10) and
heteroaromatic aldehydes (Entries 11 and 12) afforded
the desired products in excellent yields.
As shown in Table 1, it is evident that electron-rich
and electron-deficient aldehydes containing different
functional groups at different positions worked well and
did not show differences in the yield of products. In ad-
dition, heterocyclic systems such as thiophene-2-
carboxaldehyde and furan-2-carboxaldehyde reacted
O
OEt
Me
Ar
NH4OAc
+
+
3
H
O
O
2
1
O
Ar
O
EtO
OEt
Me
Et3N, 20 mol%
Solvent free, 80 oC, 1.5 - 4 h
Me
N
H
4
To determine the appropriate concentration of the
catalyst, we have investigated the model reaction of
Table 1 Et3N-mediated hantzsch synthesis of dihydropyridines 4a—4o under optimized conditions
m.p./℃
Entry
DHP
Ar
Time/h
Yielda/%
Measured
157—159
122—124
136—138
171—173
130—132
128—130
230—232
163—165
158—160
157—159
173—175
160—162
148—150
128—130
Reported
1
4a
4b
4c
4d
4e
4f
C6H5-
1.5
3
90
74
59
86
63
52
79
66
87
70
83
68
70
45
158—160[37]
122—124[36a]
135—137[38]
141—143[37]
133—135[39]
128—130[36a]
229—232[39]
162—164[37]
161—163[37]
140—142[39]
171—173[37]
160—161[37]
148—150[39]
—
2
3-(CH3)-C6H4-
4-(CH3)-C6H4-
3-(Cl)-C6H4-
2.6-(Cl)2-C6H3-
3.5-(Cl)2-C6H3-
4-(OH)-C6H4-
3-(NO2)-C6H4-
4-(OCH3)-C6H4-
2-(OCH3)-C6H4-
2-thienyl
3
3.5
2.5
1.5
2
4
5
6
7
4g
4h
4i
1.5
2.5
3
8
9
10
11
12
13
14
4j
2
4k
4l
3
2-furyl
2
4m
styryl
4
4n
2.3-dioxymethylene
4
a Isolated yields.
734
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 733—737

Synthesis of Some New 1,4-Dihydropyridine Derivatives
smoothly to produce high yields of products. The reac-
tion with styrylaldehyde 4m and 2.3-dioxymethylene-
benzaldehyde also preceded smoothly giving the corre-
sponding DHPs in good to moderate yields (Entries 13
and 14); although a relatively longer reaction time was
needed to complete the reaction. On the other side, even
if reaction time was prolonged (8h), aliphatic aldehydes
such as formaldehyde and isobutyraldehyde afforded
relatively lower yields (17% and 23%, respectively).
Under similar conditions, formylphenylboronic acids
also underwent the present protocol, in these cases,
1,4-DHP products were obtained selectively and no
other products were observed. Typical results are sum-
marized in Table 2. The procedure worked well on
2-formylphenylboronic acid, 3-formylphenylboronic
acid, and 4-formylphenylboronic acid (Entries 1—3).
The method was also successfully extended to 3-formyl-
furylboronic acid (Entry 4). In all cases, the corre-
sponding products were isolated in very good yields
within 1—1.5 h.
easy, efficient and versatile method for the synthesis of
dihydropyridine and other new dihydropyridinylboronic
acid derivatives from the reaction of aldehydes, ethyl
acetoacetate, and ammonium acetate catalyzed by
triethylamine under solvent free conditions. The process
does not require the use of any volatile organic solvent,
harmful metal catalyst and thus, is a simple, environ-
mentally friendly, and high yielding reaction for the
synthesis of 1,4-dihydropyridines via one-pot three-
component Hantzsch reaction.
Experimental
Typical experimental procedure for the synthesis of
dihydropyridines 4
A mixture of aldehyde (1 mmol), ammonium acetate
(2 mmol), ethyl acetoacetate (2 mmol) and Et3N (20
mol%), was magnetically stirred under solvent free
condition at 80 ℃ for the appropriate time indicated in
Tables 1 and 2. After complete conversion as indicated
by TLC, the reaction mixture was cooled then poured
onto cold water. The product was extracted with ethyl
acetate (15 mL×2) and the combined extracts were
dried over anhydrous Na2SO4 and concentrated in vac-
uum. The resulting product was purified by recrystalli-
zation from ethanol.
Scheme 2
HO
OH
B
O
OEt
Me
+
+
NH4OAc
3
O
Spectroscopic data for all synthesized compounds
Ethyl 4-(phenyl)-2,6-dimethyl-1,4-dihydropy-
ridine-3,5-dicarboxylate (4a) m.p. 157—159 ℃; H
H
O
1q
2
1
HO
OH
B
NMR (CDCl3, 250 MHz) δ: 1.23 (t, J＝7.1 Hz, 6H),
2.32 (s, 6H, 2CH3), 4.11 (q, J＝7.1 Hz, 4H), 5.00 (s,
1H), 6.07 (brs, 1H, NH), 7.11—7.32 (m, 5H); 13C
(CDCl3, 63 MHz) δ: 14.2, 19.4, 39.5, 59.7, 103.9, 125.7,
126.1, 127.8, 128.2, 128.8, 144.1, 147.8, 167.7; IR (KBr)
Et3N, 20 mol%
Solvent free, 80 oC, 1 - 1.5 h
O
O
EtO
Me
OEt
Me
－
1
N
H
ν: 3334, 1690, 1654, 1494, 1243, 1127, 721 cm .
Ethyl 4-(3-methylphenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4b) m.p.
4q
1
122—124 ℃; H NMR (CDCl3, 250 MHz) δ: 1.24 (t,
The structures of all compounds were confirmed by
their melting points and spectroscopic data. The H
NMR of DHPs displayed a singlet at δ 4.97 (H-4) and a
broad singlet due to NH at δ 6.83. Signals at δ 39 (C-4)
and δ 167 (C-2) in the 13C spectrum confirmed also the
formation of the desired products.
1
J＝7.1 Hz, 6H), 2.30 (s, 6H), 4.13 (q, J＝7.1 Hz, 4H),
4.98 (s, 1H), 6.44 (brs, 1H, NH), 7.04 (s, 1H),
7.11—7.17 (m, 3H); 13C NMR (CDCl3, 63 MHz) δ:
14.2, 19.2, 21.4, 39.5, 59.7, 103.7, 125.0, 126.8, 128.4,
128.7, 137.1, 144.4, 147.8, 167.8; IR (KBr) ν: 3344,
－
1
1692, 1648, 1490, 1212, 1130, 723 cm .
Table 2 Et3N-mediated Hantzsch synthesis of dihydropyridi-
nylboronic acids 4o—4r
Ethyl 4-(4-methylphenyl)-2,6-dimethyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (4c) m.p. 135—137
1
Aldehyde:
ArCHO
4o
℃; H NMR (CDCl3, 250 MHz) δ: 1.25 (t, J＝7.1 Hz,
Entry
Ar
Time/hYielda/% m.p./℃
6H), 2.29 (s, 9H), 4.08 (q, J＝7.1 Hz, 4H), 5.00 (s, 1H),
6.93 (brs, 1H, NH), 7.05 (d, J＝7.8 Hz, 2H), 7.23 (d,
J＝7.8 Hz); 13C NMR (CDCl3, 63 MHz) δ: 14.2, 19.4,
20.9, 39.1, 59.5, 103.6, 126.3, 127.8, 128.5, 135.4,
144.9, 168.1; IR (KBr) ν: 3343, 1690, 1651, 1491, 1213,
1
2
3
4
2-(B(OH)2)-C6H4-
3-(B(OH)2)-C6H4-
4-(B(OH)2)-C6H4-
3-(B(OH)2)-furyl
1.5
1.5
1.5
1
90 190—192
64 300—302
91 298—300
80 148—150
4p
4q
4r
－
1
1122, 772 cm .
a Isolated yields.
Ethyl 4-(3-chlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4d) m.p.
Conclusions
1
171—173 ℃; H NMR (CDCl3, 250 MHz) δ: 1.23 (t,
In conclusion, we have successfully developed an
J＝7.1 Hz, 6H), 2.31 (s, 6H), 4.11 (q, J＝7.1 Hz), 4.97
Chin. J. Chem. 2012, 30, 733—737
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
735

Ghalem, Boulcina & Debache
FULL PAPER
(s, 1H), 6.28 (brs, 1H, NH), 7.10—7.21 (m, 3H), 7.24 (s,
1H); 13C NMR (CDCl3, 63 MHz) δ: 14.2, 19.3, 39.6,
59.8, 103.3, 126.2, 126.5, 128.2, 129.0, 133.5, 144.6,
149.8, 167.5; IR (KBr) ν: 3323, 1703, 1649, 1491, 1215,
14.2, 18.9, 35.1, 55.1, 59.4, 102.6, 110.5, 119.5, 127.1,
130.5, 135.6, 144.4, 156.9, 168.3; FT-IR (KBr) ν: 3332,
－
1
2978, 1682, 1646, 1496, 1284, 1211, 1114, 744 cm .
Ethyl 4-(2-thienyl)-2,6-dimethyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (4k) m.p. 141—143
－
1
1124, 802 cm .
1
Ethyl 4-(2,6-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4e) m.p.
℃; H NMR (CDCl3, 250 MHz) δ: 1.28 (t, J＝7.1 Hz,
6H), 2.32 (s, 6H), 4.16 (q, J＝7.1 Hz, 4H), 5.36 (s, 1H),
6.29 (brs, 1H, NH), 6.81 (d, J＝3.4 Hz, 1H), 6.86 (dd,
J＝4.9, 3.4 Hz, 1H), 7.06 (d, J＝4.9 Hz, 1H); 13C NMR
(CDCl3, 63 MHz) δ: 14.3, 19.4, 34.3, 60.0, 103.3, 123.1,
123.2, 126.3, 144.8, 151.6, 167.5; IR (KBr) ν: 3344,
1
130—132 ℃; H NMR (CDCl3, 250 MHz) δ: 1.24 (t,
J＝7.1Hz, 6H), 2.30 (s, 6H), 4.10 (q, J＝7.1 Hz), 5.02
(s, 1H), 6.37 (brs, 1H, NH), 7.15 (d, J＝7.0 Hz, 1H),
7.22 (dd, J＝7.0, 7.5 Hz, 1H), 7.31 (d, J＝7.5 Hz, 1H);
13C NMR (CDCl3, 63 MHz) δ: 14.3, 19.3, 34.4, 59.9,
103.2, 123.0, 123.1, 124.8, 126.3, 145.0, 151.6, 167.5;
IR (KBr) ν: 3335, 2980, 1687, 1646, 1487, 1211, 1127,
－
1
1696, 1652, 1487, 1367, 1211, 1132, 723 cm .
Ethyl 4-(2-furyl)-2,6-dimethyl-1,4-dihydropyri-
1
dine-3,5-dicarboxylate (4l) m.p. 160—162 ℃; H
－
1
759 cm .
NMR (CDCl3, 250 MHz) δ: 1.25 (t, J＝7.1 Hz, 6H),
2.29 (s, 6H), 4.15 (q, J＝7.1 Hz, 4H), 5.19 (s, 1H, CH),
5.92 (d, J＝3.1 Hz, 1H), 6.19 (d, J＝3.1, 1.8 Hz, 1H),
6.62 (brs, 1H, NH), 7.19 (d, J＝1.8 Hz, 1H); 13C NMR
(CDCl3, 63 MHz) δ: 14.2, 19.1, 33.3, 59.8, 100.3, 104.3,
110.0, 140.7, 145.6, 158.8, 167.7; IR (KBr) ν: 3342,
Ethyl 4-(3,5-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4f) m.p.
128—130 ℃; 1H NMR (CDCl3, 250 MHz) δ: 1.25 (t,
J＝7.1Hz, 6H), 2.34 (s, 6H), 4.13 (q, J＝7.1 Hz, 4H),
4.95 (s, 1H), 6.18 (brs, 1H, NH), 7.06 (d, J＝1.7 Hz,
1H), 7.09 (d, J＝1.8 Hz, 1H), 7.37 (d, J＝1.8 Hz, 1H);
13C NMR (CDCl3, 63 MHz) δ: 14.2, 19.5, 39.8, 60.0,
103.0, 126.2, 126.8, 134.1, 144.8, 151.0, 167.2; IR (KBr)
－
1
1697, 1648, 1480, 1361, 1211, 1132, 750 cm .
Ethyl 4-styryl-2,6-dimethyl-1,4-dihydropyridine-
1
3,5-dicarboxylate (4m) m.p. 148—150 ℃; H NMR
－
1
ν: 3315, 1701, 1645, 1492, 1217, 1124, 785 cm .
Ethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (4g) m.p. 230—232
(CDCl3, 250 MHz) δ: 1.31 (t, J＝7.1 Hz, 6H), 2.34 (s,
6H), 4.21 (q, J＝7.1 Hz, 4H), 4.65 (d, J＝5.9 Hz, 1H),
6.10 (brs, 1H, NH), 6.18—6.23 (m, 2H), 7.15—7.35 (m,
5H); 13C NMR (CDCl3, 63 MHz) δ: 14.4, 19.4, 36.5,
59.8, 103.1, 118.1, 123.5, 126.2, 126.8, 128.3, 131.8,
133.7, 137.7, 145.1, 167.7; IR (KBr) ν: 3335, 2980,
1
℃; H NMR (CDCl3, 250 MHz) δ: 1.79 (t, J＝7.1 Hz,
6H), 2.84 (s, 6H), 4.57 (q, J＝7.1 Hz, 4H), 5.37 (s, 1H),
6.03 (brs, 1H, NH), 7.19 (d, J＝8.2 Hz, 2H), 7.58 (d,
J＝8.2 Hz, 2H); 13C NMR (CDCl3, 63 MHz) δ: 14.1,
19.3, 39.5, 59.8, 103.9, 127.9, 130.9, 130.4, 142.3,
148.5, 167.8; IR (KBr) ν: 3331, 1689, 1656, 1490, 1244,
－
1
1687, 1646, 1487, 1211, 1127, 759 cm .
Ethyl 4-(benzo-1,3-dioxy-5-yl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4n) m.p.
－
1
1
1126, 720 cm .
128—130 ℃; H NMR (CDCl3, 250 MHz) δ: 1.22 (t,
Ethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (4h) m.p. 163—165
℃; H NMR (CDCl3, 250 MHz) δ: 1.28 (t, J＝7.1 Hz,
J＝7.1 Hz, 3H), 1.30 (t, J＝7.1 Hz, 3H), 2.21 (s, 3H),
2.39 (s, 3H), 4.29—4.08 (m, 4H), 5.52 (s, 1H), 5.87 (brs,
1H, NH), 5.91 (s, 2H), 6.76—6.68 (m, 2H), 6.83 (s, 1H);
13C NMR (CDCl3, 63 MHz) δ: 14.3, 19.6, 21.2, 54.8,
59.6, 60.0, 100.9, 107.1, 108.0, 110.4, 119.6, 137.4,
146.1, 147.1, 147.7, 154.3, 166.9, 167.9; IR (KBr) ν:
3440, 3294, 2916, 1689, 1643, 1585, 1497, 1203, 1037
cm－1; HRMS calcd for C20H23NO6 (M＋) 373.1525,
found 373.1864.
1
6H), 2.30 (s, 6H), 4.13 (q, J＝7.1 Hz, 4H), 5.34 (s, 1H),
5.85 (brs, 1H, NH), 6.76—6.90 (m, 3H), 7.04 (dd, J＝
6.1, 1.1 Hz, 1H); 13C NMR (CDCl3, 63 MHz) δ: 14.3,
19.1, 34.3, 60.0, 103.1, 123.1, 123.4, 124.3, 126.3,
145.1, 145.3, 151.7, 167.6; IR (KBr) ν: 3337, 1693,
－
1
1645, 1527, 1487, 1215, 1123, 704 cm .
Ethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (4i) m.p. 158—160
℃; H NMR (CDCl3, 250 MHz) δ: 1.24 (t, J＝7.1 Hz,
2-(3,5-Diethoxycarbonyl-2,6-dimethyl-1,4-dihy-
dropyridin-4-yl)phenylboronic acid (4o) m.p.
190—192 ℃; H NMR (CDCl3, 250 MHz) δ: 1.14 (t,
1
1
6H), 2.31 (s, 6H), 3.76 (s, 3H), 4.08 (q, J＝7.1 Hz, 4H),
4.94 (s, 1H), 6.09 (brs, 1H, NH), 6.76 (d, J＝8.6 Hz,
2H), 7.34 (d, J＝8.6 Hz, 2H); 13C NMR (CDCl3, 62.9
MHz) δ: 14.2, 19.4, 38.7, 55.1, 59.7, 104.1, 113.1, 129.9,
140.4, 143.9, 157.8, 167.8; IR (KBr) ν: 3342, 1690,
J＝7.1 Hz, 6H), 2.26 (s, 6H), 4.02 (q, J＝7.1 Hz, 4H),
5.03 (s, 1H), 5.96 (brs, 1H, NH), 7.25—7.34 (m, 4H);
13C NMR (CDCl3, 63 MHz) δ: 14.6, 19.1, 38.8, 60.1,
103.7, 125.8, 128.6, 128.7, 130.1, 132.8, 145.9, 153.1,
168.7; IR (KBr) ν: 3398, 3336, 1705, 1651, 1477, 1377,
－
－
1
1
1651, 1491, 1211, 1124, 750 cm .
1222, 1099, 760 cm ; HRMS calcd for C19H24BNO6
Ethyl 4-(2-methoxyphenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4j) m.p.
(M＋) 373.1697, found 373.1707.
3-(3,5-Diethoxycarbonyl-2,6-dimethyl-1,4-dihy-
dropyridin-4-yl)phenylboronic acid (4p) m.p.
1
157—159 ℃; H NMR (CDCl3, 250 MHz) δ: 1.19 (t,
1
J＝7.1 Hz, 6H), 2.23 (s, 6H), 3.76 (s, 3H), 4.02 (q, J＝
7.1 Hz, 4H), 5.28 (s, 1H), 6.60 (brs, 1H, NH),
6.76—6.95 (m, 2H), 7.09 (dd, J＝8.7, 7.7 Hz, 1H), 7.24
(d, J＝8.7, Hz, 1H); 13C NMR (CDCl3, 62.9 MHz) δ:
300—302 ℃; H NMR (CDCl3, 250 MHz) δ: 1.06 (t,
J＝7.1 Hz, 6H), 2.31 (s, 6H), 4.01 (q, J＝7.1 Hz, 4H),
4.95 (s, 1H), 5.36 (brs, 1H, NH), 6.6—7.82 (m, 4H); 13C
NMR (CDCl3, 62.9 MHz) δ: 14.4, 19.0, 39.0, 69.7,
736
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 733—737

Synthesis of Some New 1,4-Dihydropyridine Derivatives
[16] (a) Liu, Q.; Li, J.; Shen, X.-X.; Xing, R.-G.; Yang, J.; Liu, Z.; Zhou,
B. Tetrahedron Lett. 2009, 50, 1026; (b) Babu, T. H.; Shanthi, G.;
Perumal, P. T. Tetrahedron Lett. 2009, 50, 2881.
[17] (a) Itoh, T.; Nagata, K.; Miyazaki, M.; Ishikawa, H.; Kurihara, A.;
Ohsawa, A. Tetrahedron 2004, 60, 6649; (b) Itoh, T.; Nagata, K.;
Kurihara, A.; Miyazaki, M.; Ishikawa, H.; Ohsawa, A. Tetrahedron
Lett. 2002, 50, 3105.
[18] (a) Sainani, J. B.; Shah, A. C. Indian J. Chem., Sect. B 1994, 33, 526;
(b) Sufirez, M.; Ochoa, E.; Verdecia, Y.; Verdecia, B.; Moran, L.;
Martin, N.; Quinteiro, M.; Seoane, C.; Soto, J. L.; Novoa, H.; Blaton,
N.; Peters, O. M. Tetrahedron 1999, 55, 875.
[19] (a) Li, M.; Zuo, Z.; Wen, L.; Wang, S. J. Comb. Chem. 2008, 10,
436; (b) Tu, S. J.; Zhou, J. F.; Deng, X.; Cai, P. J.; Wang, H.; Feng,
J. C. Chin. J. Org. Chem. 2001, 21, 313.
103.3, 128.7, 129.1, 130.7, 131.9, 134.8, 142.2, 150.7,
167.2; IR (KBr) ν: 3335, 2980, 1687, 1646, 1487, 1211,
－
＋
1
1127, 759 cm ; HRMS calcd for C19H24BNO6 (M )
373.1697, found 373.1675.
4-(3,5-Diethoxycarbonyl-2,6-dimethyl-1,4-dihy-
dropyridin-4-yl)phenylboronic acid (4q) m.p.
1
298—300 ℃; H NMR (CDCl3, 250 MHz) δ: 1.11 (t,
J＝7.0 Hz, 6H), 2.50 (s, 6H), 3.96 (q, J＝7.0 Hz, 4H),
4.67 (s, 1H), 4.87 (brs, 1H, NH), 7.18 (d, J＝7.8 Hz,
2H), 7.59 (d, J＝7.8 Hz, 2H), 7.80 (s, 2H, OH); 13C
NMR (CDCl3, 63 MHz) δ: 14.2, 18.9, 39.5, 59.4, 102.9,
127.2, 133.7, 141.4, 145.1, 150.4, 167.8; IR (KBr) ν:
3398, 3336, 1705, 1651, 1442, 1373, 1223, 1099, 763
[20] Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Krishna, P. R.
Synthesis 2006, 55.
－
＋
1
cm ; HRMS calcd for C19H24BNO6 (M ) 373.1697,
[21] Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C.-F. Tetrahedron Lett. 2005,
46, 5771.
[22] Sabitha, G.; Reddy, G. S. K.; Reddy, C. S.; Yadav, J. S. Tetrahedron
Lett. 2003, 44, 4129.
[23] (a) Ji, S. J.; Jiang, Z. Q.; Lu, J.; Loa, T. P. Synlett 2004, 831; (b)
Sridhar, R.; Perumal, P. T. Tetrahedron 2005, 61, 2465; (c) Zhang,
X. Y.; Li, Y. Z.; Fan, X. S.; Qu, G. R.; Hu, X. Y.; Wang, J. J. Chin.
Chem. Lett. 2006, 17, 150.
[24] Maheswara, M.; Siddaiah, V.; Damu, G. L.; Venkata Rao, C.
Arkivoc 2006, 2, 201.
found 373.1712.
2-(3,5-Diethoxycarbonyl-2,6-dimethyl-1,4-dihy-
dropyridin-4-yl)furan-3-ylboronic acid (4r) m.p.
1
148—150 ℃; H NMR (CDCl3, 250 MHz) δ: 1.23 (t,
J＝7.1 Hz, 6H), 2.27 (s, 6H), 4.20 (q, J＝7.1 Hz, 4H),
5.18 (s, 1H), 5.90 (d, J＝3.0 Hz, 1H), 6.17 (d, J＝3.0
Hz, 1H), 6.78 (brs, 1H, NH), 7.16 (s, 2H, OH); 13C
NMR (CDCl3, 63 MHz) δ: 14.2, 19.1, 33.3, 1, 59.7,
100.1, 104.3, 109.9, 140.7, 145.8, 158.8, 167.7; IR (KBr)
ν: 3398, 3337, 1705, 1651, 1477, 1373, 1223, 1099, 764
[25] Das, B.; Ravikanth, B.; Ramu, R.; Vittal Rao, B. Chem. Pharm. Bull.
2006, 54, 1044.
[26] Song, G.; Wang, B.; Wu, X.; Kang, Y.; Yang, L. Synth. Commun.
2005, 35, 2875.
－
＋
1
cm ; HRMS calcd for C17H22BNO7 (M ) 363.1489;
found 363.1470.
[27] (a) Reddy, C. S.; Raghu, M. Chin. Chem. Lett. 2008, 19, 775; (b) Ko,
S.; Yao, C.-F. Tetrahedron 2006, 62, 7293.
[28] Adibi, H.; Samimi, H. A.; Beygzadeh, M. Catal. Commun. 2007, 8,
2119.
References
[1] Grün, G.; Fleckenstein, A. Arzneim. Forsch. (Drug Res.) 1972, 22,
334.
[2] Berkels, B.; Roesen, R.; Dhein, S.; Fricke, U.; Klaus, W. Cardiovasc.
Drug Rev. 1999, 17, 179.
[3] Tsuruo, T.; Iida, H.; Nojiri, M.; Tsukagoshi, S.; Sakurai, Y. Cancer
Research 1983, 43, 2905.
[4] Chapman, R. W.; Danko, G.; Siegels, M. I. Pharmacology 1984, 29,
282.
[5] Malaise, W. J.; Mathias, P. C. F. Diabetologia 1985, 28, 153.
[6] Krauze, A.; Germane, S.; Eberlins, O.; Sturms, I.; Klusa, V.; Duburs,
G. Eur. J. Med. Chem. 1999, 34, 301.
[7] Peri, R.; Padmanabhan, S.; Rutledge, A.; Singh, S.; Triggle, D. J. J.
Med. Chem. 2000, 43, 2906.
[29] Heravi, M. M.; Bakhtiri, K.; Javadi, N. M.; Bamoharram, F. F.;
Saeedi, M.; Oskooi, H. A. J. Mol. Catal. A: Chem. 2007, 264, 50.
[30] (a) Donelson, J. L.; Gibbs, A.; De, S. K. J. Mol. Catal. A: Chem.
2006, 256, 309; (b) Wang, L.-M.; Sheng, J.; Zhang, L.; Han, J.-W.;
Fan, Z.; Tian, H.; Qian, C.-T. Tetrahedron 2005, 61, 1539.
[31] Cherkupally, S. R.; Mekalan, R. Chem. Pharm. Bull. 2008, 56, 1002.
[32] (a) Ohberg, L.; Westman, J. Synlett 2001, 1296; (b) Agarwal, A.;
Chauhan, P. M. S. Tetrahedron Lett. 2005, 46, 1345; (c) Tu, S.;
Zhang, J.; Zhu, X.; Zhang, Y.; Wang, Q.; Xu, J.; Jiang, B.; Jia, R.;
Zhang, J.; Shi, F. J. Heterocycl. Chem. 2006, 43, 985.
[33] Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S. Tetrahe-
dron Lett. 2003, 44, 4129.
[8] Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223.
[9] Klusa, V. Drugs Future 1995, 20, 135.
[10] Bretzel, R. G.; Bollen, C. C.; Maeser, E.; Federlin, K. F. Am. J.
Kidney Dis. 1993, 21, 53.
[11] Bretzel, R. G.; Bollen, C. C.; Maeser, E.; Federlin, K. F. Drugs Fu-
ture 1992, 17, 465.
[12] Boer, R.; Gekeler, V. Drugs Future 1995, 20, 499.
[13] (a) Böcker, R. H.; Guengerich, F. P. J. Med. Chem. 1986, 29, 1596;
(b) Kudo, S.; Okumura, H.; Miyamoto, G.; Ishizaki, T. Drug Metab.
Dispos. 1999, 27, 303.
[14] De Paolis, O.; Baffoe, J.; Landge, S. M.; Török, B. Synthesis 2008,
3423.
[15] (a) Filipan-Litvić, M.; Litvić, M.; Vinković, V. Bioorg. Med. Chem.
2008, 16, 9276; (b) Shamim, T.; Gupta, M.; Paul, S. J. Mol. Catal. A:
Chem. 2009, 302 15; (c) Khadikar, B.; Borkat, S. Synth. Commun.
1998, 28, 207 and references cited therein.
[34] (a) Legeay, J. C.; Goujon, J. Y.; Eynde, J. J. V.; Toufet, L.;
Bazureau, J. P. J. Comb. Chem. 2006, 8, 829; (b) Dondoni, A.;
Massi, A.; Minghini, E.; Bertolasi, V. Tetrahedron 2004, 60, 2311.
[35] Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946.
[36] (a) Debache, A.; Boulcina, R.; Belfaitah, A.; Rhouati, S.; Carboni, B.
Synlett 2008, 509; (b) Debache, A.; Ghalem, W.; Boulcina, R.; Bel-
faitah, A.; Rhouati, S.; Carboni, B. Tetrahedron Lett. 2009, 50, 5248;
(c) Debache, A.; Ghalem, W.; Boulcina, R.; Belfaitah, A.; Rhouati,
S.; Carboni, B. Lett. Org. Chem. 2010, 7, 272.
[37] Eynde, J. J.; Delfosse, F.; Mayence, A.; Haverbeke, Y. V. Tetrahe-
dron 1995, 51, 6511.
[38] Khadikar, B. M.; Gaikar, V. G.; Chitnavis, A. A. Tetrahedron Lett.
1995, 36, 8083.
[39] Loev, B.; Goodman, M. M.; Snader, K. M.; Tedeschi, R.; Macko, E.
J. Med. Chem. 1974, 17, 956.
(Lu, Y.)
Chin. J. Chem. 2012, 30, 733—737
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
737