Microwave-assisted oxidative aromatization of Hantzsch 1,4-dihydropyridines using manganese dioxide

Article abstract of DOI:10.1055/s-2006-926407

4-Aryl- and 4-alkyl-1,4-dihydropyridines, prepared by microwave-assisted Hantzsch reaction, are readily and efficiently aromatized in only one minute using commercial manganese dioxide in the absence of an inorganic support at 100 °C under microwave irradiation. This rapid procedure is more efficient than microwave-assisted aromatization using Pd/C, iodine or o-iodoxybenzoic acid (IBX) and gives the dehydrogenated or 4-dealkylated product in 91-100% yield (13 examples). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926407

PAPER
1283
Microwave-Assisted Oxidative Aromatization of Hantzsch 1,4-Dihydro-
pyridines using Manganese Dioxide
Oxidative Aromatizati
a
H
antz
r
sch 1,4-D
k
ihydropyridines C. Bagley,* M. Caterina Lubinu
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20874030; E-mail: Bagleymc@cardiff.ac.uk
Received 14 October 2005
R1
Abstract: 4-Aryl- and 4-alkyl-1,4-dihydropyridines, prepared by
microwave-assisted Hantzsch reaction, are readily and efficiently
aromatized in only one minute using commercial manganese diox-
Cl
NO2
MeO2C
Me
CO2Et
MeO2C
Me
CO2Me
ide in the absence of an inorganic support at 100 °C under micro-
wave irradiation. This rapid procedure is more efficient than
microwave-assisted aromatization using Pd/C, iodine or o-iodoxy-
benzoic acid (IBX) and gives the dehydrogenated or 4-dealkylated
product in 91–100% yield (13 examples).
N
CH2R2
N
Me
H
H
amlodipine 1:
R
nifedipine 3
1 = H, R2 = OCH2CH2NH2;
felodipine 2: R1 = Cl, R2 = H
Key words: aromatization, Hantzsch dihydropyridines, heterocy-
cles, microwave synthesis, oxidation
NO2
nicardipine 4:
1 = Me, R2 = CH2CH2N(Me)CH2Ph;
nimodipine 5:
1 = i-Pr, R2 = CH2CH2OMe;
nitrendipine 6: R1 = Me, R2 = Et
Since its discovery by Hantzsch in 1881,1 the preparation
of 1,4-dihydropyridine-3,5-dicarboxylate (1,4-DHP) de-
rivatives by condensation of an aldehyde, b-keto ester and
ammonia has attracted substantial interest as a multicom-
ponent condensation reaction that provides heterocycles
of pharmacological importance.2 The 1,4-DHP motif is
found in a number of chemotherapeutic agents for the
treatment of cardiovascular disease such as hypertension
and angina pectoris,3 including the 4-(2-chlorophenyl) de-
rivatives amlodipine (1) and felodipine (2), 4-(2-nitrophe-
nyl)DHP derivative nifedipine (3) and 4-(3-nitrophenyl)
derivatives nicardipine (4), nimodipine (5) and nitren-
dipine (6), amongst others2 (Figure 1). This important
class of calcium channel antagonists relaxes the cardiac
muscle by decreasing the transmembrane calcium current
on binding4 and so considerable effort has been devoted to
establish efficient methods for their synthesis.
R
R1O2C
Me
CO2R2
Me
R
N
H
Figure 1 Some chemotherapeutic agents based upon 1,4-DHP deri-
vatives for the treatment of cardiovascular disease.
and cupric nitrate,8 ceric ammonium nitrate,9 pyridinium
chlorochromate (PCC),10 BrCCl3/hn,11 nitric acid,12 nitric
oxide,13,14 N-methyl-N-nitroso-p-toluenesulfonamide,14
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ),15
Bi(NO3)3,16 Zr(NO3)4,17 Mn(OAc)3,18 Pd/C,19 I2/MeOH,20
KMnO4,19b,21 tert-butyl hydroperoxide,22 Co(II)-catalyzed
auto oxidation,23 CrO3,24 and nitrous acid,25 amongst oth-
ers,24,26 all with varying degrees of success.
Despite a plethora of methods for this transformation, pro-
longed reaction times, poor yields and the competing oxi-
dative dealkylation of 4-benzyl- and sec-alkyl-substituted
DHP substrates25 has led to the investigation of many al-
ternative procedures,2,27 such as solvent free condi-
tions,12,16,26h the use of sonication8,15 and microwave
(MW) heating,2,7,12,15,16,26e,26h,28 in particular with MnO2 as
oxidant.29,30 The first microwave-assisted method utilized
MnO2 supported on Mexican bentonite clay in a domestic
oven, giving the corresponding pyridines in a very short
time (10 min) and reasonable yield (47–100%).29 A recent
modification gave further improvements by immobilizing
the MnO2 on HZSM-5 zeolite,30 but found that in the ab-
sence of an inorganic solid support incomplete reactions
and alternative products were obtained. We now wish to
report our own findings on new methods for the oxidative
aromatization of 1,4-DHP derivatives that overcame these
difficulties and prioritized the need for excellent yields us-
ing cheap, commercially available reagents coupled with
The metabolism of these drugs is catalyzed in the liver by
cytochrome P-4505 and commences by oxidative aromati-
zation to give the corresponding 1,4-dehydro derivatives,
which are largely devoid of pharmacological activity. No-
tably, the 1,4-DHP motif also features in hydride transfer
biotransformations from the reduced nicotinamide ade-
nine dinucleotide (NADH and NADPH) coenzymes, and
analogues thereof, that mediate hydrogen transfer reac-
tions in biological systems.6 In order to understand and
model these biological processes, and as a useful synthetic
approach to polysubstituted pyridines, the oxidative aro-
matization of 1,4-DHP derivatives has received consider-
able attention from synthetic chemists. A wide variety of
oxidants have been studied in the reaction, including urea
nitrate,7 peroxydisulfate-Co(II),7 clay-supported ferric
SYNTHESIS 2006, No. 8, pp 1283–1288
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.03.2006
DOI: 10.1055/s-2006-926407; Art ID: P16805SS
© Georg Thieme Verlag Stuttgart · New York

1284
M. C. Bagley, M. C. Lubinu
PAPER
microwave irradiation, to dramatically reduce reaction
times.31
Table 1 Microwave-Assisted Synthesis of 1,4-DHP Derivatives
7a–m
The 1,4-DHP derivatives required for this study were ob-
tained by microwave-assisted Hantzsch synthesis,2,32 in a
single-mode microwave cavity synthesizer according to
the conditions of Öhberg.32d A mixture of the aldehyde, b-
keto ester and aqueous ammonia was irradiated at 140 °C
to give the pure 1,4-DHP derivatives 7a–m in poor to av-
erage yields following recrystallization (Scheme 1,
Table 1). Although the yields for these transformations
were disappointing (15–68%) next to Öhberg’s report,32d
they did compare reasonably with those obtained using
equivalent conductive heating procedures and gave the
product in high purity, on the basis of a comparison of
physical and spectroscopic properties with literature data.
Interestingly, the irradiation of ethyl acetoacetate, formal-
dehyde and aqueous ammonia (entry 9) gave a mixture of
1,4-DHP 7i and the corresponding pyridine 8i, in a ratio
of 3.5:1, respectively, indicating that for this substrate
spontaneous oxidative aromatization occurs at least in
part under the reaction conditions.
Entry
1
Product
7a
R
R¢
Yield (%)a
Me
Me
Me
Me
Et
Ph
47
15
45
27
39
36
45
23
54b
21
68
21
25
2
7b
7c
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
Ph
3
4
7d
7e
5
6
7f
Et
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
H
7
7g
Et
8
7h
7i
Et
9
Et
10
11
12
13
7j
Et
Me
7k
7l
Et
Et
Et
i-Pr
O
7m
Et
PhCH2
R'
NH4OH
MW, 140 °C
R'
H
a Isolated yield of pure 7 after recrystallization.
RO2C
Me
CO2R
Me
+
b A 3.5:1 crude mixture of 1,4-DHP 7i (42%) and pyridine 8i (12%)
was obtained by 1H NMR spectroscopic analysis, which was used di-
rectly without purification.
10 min
15–68%
N
H
O
O
OR
7a–m
Scheme 1 Microwave-assisted Hantzsch 1,4-DHP synthesis using a
monomodal microwave synthesizer.
wave-assisted procedure compares very favorably to tra-
ditional heating methods and demonstrates that no
inorganic support is required for efficient conversion, de-
spite previous reports.29,30
In the search for a rapid procedure for oxidative aromati-
zation, 1,4-DHP 7a was submitted to a range of conditions
with a number of different oxidants, coupled with micro-
wave irradiation (Table 2). Irradiating 7a in a methanolic
solution of iodine at 100 °C for 20 minutes failed to gen-
erate the product (entry 1), whereas the use of conductive
heating at reflux for 24 hours gave pyridine 8a.20 Similar-
ly irradiation over Pd/C in acetic acid at 120 °C for 10
minutes gave only a trace of product (entry 2), in contrast
to conductive heating methods.19 Conversion to the pyri-
dine 8a under microwave-assisted conditions was howev-
er facilitated using Pd/C by increasing the temperature to
180 °C (entry 3) but at these high temperatures a small
amount of oxidative dealkylation also occurred, giving a
mixture of products. The irradiation of a mixture of o-io-
doxybenzoic acid (IBX) and 7a in DMSO was also inves-
tigated, but at 180 °C a mixture of products was obtained
(entry 4). Carrying out the reaction at a lower temperature
in the ionic liquid 1-butyl-3-methylimidazolium tetrafluo-
roborate ([Bmim]BF4) did overcome some of these diffi-
culties (entry 5), but failed to effect complete conversion
to pyridine 8a. However, either heating a mixture of 7a
and manganese dioxide in dichloromethane at reflux over-
night with conductive heating (entry 6) or at 100 °C for 1
minute in a monomodal microwave synthesizer (entry 7),
gave pyridine 8a in quantitative yield without the need for
further purification. The facility and rapidity of the micro-
The scope of this rapid microwave-assisted oxidative aro-
matization was explored using 1,4-DHP derivatives 7a–m
Table 2 Exploring Microwave-Assisted Methods for the Oxidative
Aromatization of 1,4-DHP 7a
Entry
Conditionsa
Results
1
2
3
4
5
6
7
I2, MeOH, MW, 100 °C, 20 min
Pd/C, AcOH, MW, 120 °C, 10 min
Pd/C, AcOH, MW, 180 °C, 10 min
IBX, DMSO, MW, 180 °C, 1 min
IBX, [Bmim]BF4, MW, 120 °C, 1 min
MnO2, CH2Cl2, reflux, 18 h
7a, 8a (trace)
7a, 8a (trace)
8ab
8ac
7a:8a (1:17)
8a (ca. 100%)
8a (ca. 100%)
MnO2, CH2Cl2, MW, 100 °C, 1 min
a Initial MW irradiation power of 150 W was moderated throughout
the course of the reaction in order to maintain the required tempera-
ture.
b Compound 8a was contaminated with 4-dealkylated pyridine (R =
Me, R¢ = H), as shown by 1H NMR spectroscopic analysis.
c Compound 8a was contaminated with unidentified side products, as
shown by 1H NMR spectroscopic analysis.
Synthesis 2006, No. 8, 1283–1288 © Thieme Stuttgart · New York

PAPER
Oxidative Aromatization of Hantzsch 1,4-Dihydropyridines
1285
(Scheme 2, Table 3) under the same reaction conditions. or 4-benzyl substrates. This extremely facile and rapid
In all cases excellent yields of pyridines 8 were obtained. process provides the target pyridines without the need for
4-Aryl substrates 7a–h (entries 1–8) and 4-alkyl-1,4-DHP further purification and in excellent yield.
derivatives, where R¢ = H, Me or Et, 7i–k respectively
(entries 9–11), gave the products of oxidative aromatiza-
Commercially available reagents were used without further purifi-
tion 8a–k, whereas 4-i-Pr and 4-benzyl derivatives, 7l and
7m respectively, gave the product of oxidative dealkyla-
tion 8i (entries 12 and 13). This observation is in accord
with the reported behavior of these derivatives under oxi-
dative conditions.2 In the case of DHP derivative 7i,
which was generated in the Hantzsch reaction along with
the corresponding pyridine 8i, irradiating the crude mix-
ture in the presence of MnO2 completed conversion to tet-
rasubstituted pyridine 8i, which was isolated in 51%
overall yield over the two steps.
cation; solvents were dried by standard procedures. Light petroleum
refers to the fraction with bp 40–60 °C. Flash chromatography was
carried out using Merck Kieselgel 60 H silica or Matrex silica 60.
Analytical TLC was carried out using aluminum-backed plates
coated with Merck Kieselgel 60 GF254 that were visualized under
UV light (at 254 and/or 360 nm). Melting points were determined
on a Kofler hot stage apparatus and are uncorrected. IR spectra were
recorded, as a Nujol mull for solid samples or as a thin film between
NaCl plates for liquid samples, in the range 4000–600 cm–1 on a
Perkin-Elmer 1600 series FTIR spectrometer and peaks are reported
1
in cm–1. H NMR spectra were recorded at 400 MHz in CDCl3 at
25 °C using a Bruker DPX 400 instrument and were reported in
ppm. In vacuo refers to evaporation at reduced pressure using a ro-
tary evaporator and diaphragm pump, followed by the removal of
trace volatiles using a vacuum (oil) pump.
R'
R'
MnO2, CH2Cl2
MW, 100 °C
RO2C
Me
CO2R
Me
RO2C
Me
CO2R
Me
1 min
91–100%
N
H
N
Microwave-Assisted Hantzsch 1,4-DHP Synthesis; Diethyl 2,6-
Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate
(7e); Typical Procedure
7a–m
8a–k
According to the method of Öhberg,32d a mixture of benzaldehyde
(0.27 g, 2.5 mmol), ethyl acetoacetate (1.63 g, 12.5 mmol), and 35%
aq NH4OH (0.17 g, 10.0 mmol) was irradiated for 10 min at 140 °C
in a CEM Discover monomodal microwave synthesizer at an initial
power of 150 W. The mixture was allowed to cool and concentrated
in vacuo. Purification by column chromatography on silica, eluting
with light petroleum–EtOAc (7:3), followed by recrystallization (aq
EtOH) gave 1,4-DHP 7e (0.294 g, 39%) as a pale-yellow solid; mp
158–160 °C (Lit.33 mp 156–157 °C).
Scheme 2 Oxidative aromatization of 1,4-DHP derivatives 7a–m
using MnO2.
Table 3 Synthesis of Pyridines 8a–k by Oxidative Aromatization or
Oxidative Dealkylation of 1,4-DHP Derivatives 7a–m
Entry
1
Substrate Product
R
R¢
Yield (%)a
ca. 100
99
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
Me
Me
Me
Me
Et
Ph
IR (Nujol): 3340, 1688, 1650, 1298, 1212, 1124, 1090, 1018, 827
cm–1.
1H NMR: d = 7.20–7.02 (5 H), 5.74 (br s, 1 H), 4.92 (s, 1 H), 4.03
(m, 4 H), 2.25 (s, 6 H), 1.18 (t, 6 H, J = 7.1 Hz).
2
4-NO2C6H4
4-ClC6H4
3
97
4
4-MeOC6H4 96
Dimethyl 2,6-Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-di-
carboxylate (7a)
5
Ph
99
93
94
Pale-yellow solid; mp 199–200 °C (Lit.34 mp 198–199 °C).
6
Et
4-NO2C6H4
4-ClC6H4
IR (Nujol): 3341, 1700, 1648, 1433, 1344, 1300, 1222, 1121, 1101,
1053, 1018, 764, 700 cm–1.
1H NMR: d = 7.26 (m, 2 H), 7.22 (m, 2 H), 7.13 (m, 1 H), 5.74 (br
s, 1 H), 5.04 (s, 1 H), 3.67 (s, 6 H), 2.35 (s, 6 H).
7
7g
7h
7ib
7j
8g
8h
8i
Et
8
Et
4-MeOC6H4 99
9
Et
H
94b
Dimethyl 2,6-Dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylate (7b)
10
11
12
13
8j
Et
Me
Et
H
97
98
91
98
Yellow solid; mp 198–200 °C (Lit.34 mp 198–199 °C).
7k
7l
8k
8i
Et
IR (Nujol): 3341, 1704, 1650, 1519, 1345, 1216, 1123, 1097, 1016,
830 cm–1.
1H NMR: d = 8.03 (d, J = 8.8 Hz, 2 H), 7.36 (d, J = 8.8 Hz, 2 H),
5.68 (br s, 1 H), 5.03 (s, 1 H), 3.58 (s, 6 H), 2.29 (s, 6 H).
Et
7m
8i
Et
H
a Isolated yield of pure 8.
b A mixture of 7i and 8i was used (51% overall yield over 2 steps).
Dimethyl 4-(4-Chlorophenyl)-2,6-dimethyl-1,4-dihydropyri-
dine-3,5-dicarboxylate (7c)
Pale-yellow solid; mp 198 °C (Lit.34 mp 194–196 °C).
In conclusion, microwave irradiation of 1,4-DHP deriva-
tives at 100 °C in CH2Cl2 provides tetra- or pentasubsti-
tuted pyridines in only one minute without the use of an
inorganic solid support. The reaction proceeds by either
oxidative aromatization, for 4-aryl or linear primary 4-
alkyl substrates, or oxidative dealkylation for 4-sec-alkyl
IR (Nujol): 3333, 1697, 1650, 1345, 1306, 1210, 1121, 1020, 842
cm–1.
1H NMR: d = 7.23 (m, 4 H), 5.70 (br s, 1 H), 5.00 (s, 1 H), 3.68 (s,
6 H), 2.37 (s, 6 H).
Synthesis 2006, No. 8, 1283–1288 © Thieme Stuttgart · New York

1286
M. C. Bagley, M. C. Lubinu
PAPER
Dimethyl 4-(4-Methoxyphenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (7d)
1H NMR: d = 5.42 (br s, 1 H), 4.12 (m, 4 H), 3.85 (d, J = 5.4 Hz, 1
H), 2.24 (s, 6 H), 1.53 (m, 1 H), 1.24 (t, J = 7.2 Hz, 6 H), 0.67 (d,
J = 6.8 Hz, 6 H).
Pale-yellow solid; mp 184–185 °C (Lit.35 mp 181–183 °C).
IR (Nujol): 3345, 1694, 1650, 1303, 1271, 1212, 1174, 1121, 1094,
1049, 1026, 820 cm–1.
1H NMR: d = 7.11 (d, J = 8.7 Hz, 2 H), 6.69 (d, J = 8.7 Hz, 2 H),
5.61 (br s, 1 H), 4.88 (s, 1 H), 3.69 (s, 3 H), 3.58 (s, 6 H), 2.27 (s, 6
H).
Diethyl 4-Benzyl-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (7m)
Pale-yellow solid; mp 112–114 °C (Lit.15 mp 114–116 °C).
IR (Nujol): 3330, 1694, 1656, 1299, 1241, 1214, 1099, 1054, 750,
699 cm–1.
Diethyl 2,6-Dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylate (7f)
1H NMR: d = 7.07 (3 H), 6.93 (m, 2 H), 5.15 (br s, 1 H), 4.12 (d,
J = 5.5 Hz, 1 H), 3.99 (m, 4 H), 2.51 (d, J = 5.5 Hz, 2 H), 2.11 (s, 6
H), 1.18 (t, J = 7.2 Hz, 6 H).
Yellow solid; mp 131–132 °C (Lit.36 mp 129–130 °C).
IR (Nujol): 3315, 1702, 1646, 1517, 1348, 1302, 1212, 1119, 1094,
1019, 824 cm–1.
1H NMR: d = 8.01 (d, J = 8.8 Hz, 2 H), 7.38 (d, J = 8.8 Hz, 2 H),
5.65 (br s, 1 H), 5.04 (s, 1 H), 4.03 (m, 4 H), 2.30 (s, 6 H), 1.17 (t,
J = 7.1 Hz, 6 H).
Microwave-Assisted Synthesis of Pyridines Using MnO2;
Diethyl 2,6-Dimethyl-4-phenylpyridine-3,5-dicarboxylate (8e);
Typical Procedure
A mixture of 7e (0.12 g, 0.36 mmol) and MnO2 (0.32 g, 3.6 mmol)
in CH2Cl2 (2 mL) was irradiated for 1 min at 100 °C in a CEM Dis-
cover monomodal microwave synthesizer at an initial power of
150 W. The mixture was allowed to cool, filtered though Celite and
concentrated in vacuo to give pyridine 8e (0.118 g, 99%) as a color-
less solid; mp 63 °C (Lit.25 mp 63–64 °C).
Diethyl 4-(4-Chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (7g)
Pale-yellow solid; mp 147–148 °C (Lit.15 mp 144–146 °C).
IR (Nujol): 1730, 1556, 1289, 1229, 1098, 1041, 754, 704 cm–1.
1H NMR: d = 7.30–7.18 (m, 5 H), 3.94 (q, J = 7.1 Hz, 4 H), 2.53 (s,
6 H), 0.82 (t, J = 7.1 Hz, 6 H).
IR (Nujol): 3354, 1695, 1650, 1334, 1298, 1213, 1169, 1086, 1015,
830 cm–1.
1H NMR: d = 7.16 (d, J = 8.6 Hz, 2 H), 7.11 (d, J = 8.6 Hz, 2 H),
5.55 (br s, 1 H), 4.89 (s, 1 H), 4.03 (m, 4 H), 2.26 (s, 6 H), 1.15 (t,
J = 7.1 Hz, 6 H).
Dimethyl 2,6-Dimethyl-4-phenylpyridine-3,5-dicarboxylate
(8a)
Colorless solid; mp 137 °C (Lit.5 mp 135–136 °C).
Diethyl 4-(4-Methoxyphenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (7h)
IR (Nujol): 1732, 1556, 1288, 1113, 1036, 825 cm–1.
1H NMR: d = 7.30 (3 H), 7.18 (m, 2 H), 3.46 (s, 6 H), 2.52 (s, 6 H).
Pale-yellow solid; mp 159–161 °C (Lit.37 mp 159 °C).
IR (Nujol): 3339, 1690, 1649, 1301, 1253, 1213, 1121, 1088, 1030,
834 cm–1.
1H NMR: d = 7.12 (d, J = 8.7 Hz, 2 H), 6.68 (d, J = 8.7 Hz, 2 H),
5.48 (br s, 1 H), 4.87 (s, 1 H), 4.03 (m, 4 H), 3.69 (s, 3 H), 2.26 (s,
6 H), 1.15 (t, J = 7.1 Hz, 6 H).
Dimethyl 2,6-Dimethyl-4-(4-nitrophenyl)pyridine-3,5-
dicarboxylate (8b)
Pale-yellow solid; mp 150–152 °C (Lit.23 mp 148 °C).
IR (Nujol): 1721, 1602, 1558, 1516, 1346, 1303, 1231, 1099, 1048,
834 cm–1.
1H NMR: d = 8.19 (d, J = 8.8 Hz, 2 H), 7.35 (d, J = 8.8 Hz, 2 H),
3.50 (s, 6 H), 2.56 (s, 6 H).
Diethyl 2,6-Dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(7i)38
Pale-yellow solid, as a mixture of 7i and 8i (3.5:1), which was used
without separation.
Dimethyl 4-(4-Chlorophenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate (8c)
1H NMR: d= 5.18 (br s, 1 H), 4.24 (q, J = 7.1 Hz, 4 H), 3.35 (s, 2
H), 2.27 (s, 6 H), 1.37 (t, J = 7.1 Hz, 6 H).
Colorless solid; mp 138–140 °C (Lit.23 137–139 °C).
Diethyl 4-Methyl-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (7j)
IR (Nujol): 1731, 1556, 1241, 1211, 1098, 1039, 1019, 832 cm–1.
1H NMR: d = 7.28 (d, J = 8.9 Hz, 2 H), 7.12 (d, J = 8.9 Hz, 2 H),
3.50 (s, 6 H), 2.53 (s, 6 H).
Colorless solid; mp 130–131 °C (Lit.38 mp 131 °C).
IR (Nujol): 3343, 1697, 1641, 1493, 1299, 1224, 1099, 1061 cm–1.
Dimethyl 4-(4-Methoxyphenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate (8d)
1H NMR: d = 5.41 (br s, 1 H), 4.13 (m, 4 H), 3.75 (q, J = 6.5 Hz, 1
H), 2.21 (s, 6 H), 1.24 (t, J = 6.9 Hz, 6 H), 0.90 (d, J = 6.5 Hz, 3 H).
Pale-yellow solid; mp 115–117 °C (Lit.23 mp 115 °C).
Diethyl 4-Ethyl-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (7k)
IR (Nujol): 1731, 1609, 1562, 1513, 1292, 1245, 1180, 1111, 1030,
829 cm–1.
1H NMR: d = 7.09 (d, J = 8.7 Hz, 2 H), 6.83 (d, J = 8.7 Hz, 2 H),
3.77 (s, 3 H), 3.51 (s, 6 H), 2.51 (s, 6 H).
Pale-yellow solid; mp 111–112 °C (Lit.39 mp 110 °C).
IR (Nujol): 3312, 1699, 1651, 1302, 1211, 1133, 1072, 999 cm–1.
1H NMR: d = 5.48 (br s, 1 H), 4.11 (m, 4 H), 3.86 (t, J = 5.5 Hz, 1
H), 2.10 (s, 6 H), 1.29 (m, 2 H), 1.22 (t, J = 7.2 Hz, 6 H), 0.67 (d,
J = 7.5 Hz, 3 H).
Diethyl 2,6-Dimethyl-4-(4-nitrophenyl)pyridine-3,5-
dicarboxylate (8f)
Pale-yellow solid; mp 115–117 °C (Lit.15 mp 114–116 °C).
Diethyl 4-Isopropyl-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (7l)
IR (Nujol): 1723, 1601, 1556, 1518, 1349, 1295, 1230, 1105, 1045,
842 cm–1.
1H NMR: d = 8.18 (d, J = 8.7 Hz, 2 H), 7.38 (d, J = 8.7 Hz, 2 H),
3.97 (q, J = 7.2 Hz, 4 H), 2.57 (s, 6 H), 0.92 (t, J = 7.2 Hz, 6 H).
Yellow solid; mp 95–97 °C (Lit.39 mp 97 °C).
IR (Nujol): 3342, 1694, 1650, 1298, 1216, 1089, 1049 cm–1.
Synthesis 2006, No. 8, 1283–1288 © Thieme Stuttgart · New York

PAPER
Oxidative Aromatization of Hantzsch 1,4-Dihydropyridines
1287
Diethyl 4-(4-Chlorophenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate (8g)
(10) Vanden Eynde, J.-J.; Mayence, A.; Maquestiau, A.
Tetrahedron 1992, 48, 463.
(11) Kurz, J. L.; Hutton, R.; Westheimer, F. H. J. Am. Chem. Soc.
1961, 83, 584.
(12) García, O.; Delgado, F.; Cano, A. C.; Alvarez, C.
Tetrahedron Lett. 1993, 34, 623.
(13) Itoh, T.; Nagata, K.; Matsuya, Y.; Miyazaki, M.; Ohsawa, A.
J. Org. Chem. 1997, 62, 3582.
Pale-yellow solid; mp 64–65 °C (Lit.15 mp 65–67 °C).
IR (Nujol): 1731, 1556, 1231, 1103, 1044, 835 cm–1.
1H NMR: d = 7.28 (d, J = 8.9 Hz, 2 H), 7.12 (d, J = 8.9 Hz, 2 H),
3.99 (q, J = 7.1 Hz, 4 H), 2.54 (s, 6 H), 0.91 (t, J = 7.1 Hz, 6 H).
Diethyl 4-(4-Methoxyphenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate (8h)
(14) Zhu, X.-Q.; Zhao, B.-J.; Cheng, J.-P. J. Org. Chem. 2000,
65, 8158.
Colorless solid; mp 49 °C (Lit.37 mp 51–53 °C).
(15) Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van
Haverbeke, Y. Tetrahedron 1995, 51, 6511.
(16) Tajbakhsh, M.; Heravi, M. M.; Hosseini, A.; Shahrezaiee, A.
Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 773.
(17) Sabitha, G.; Reddy, G. S. K. K.; Reddy, Ch. S.; Fatima, N.;
Yadav, J. S. Synthesis 2003, 1267.
(18) Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 21.
(19) (a) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett.
2002, 4, 3955. (b) Kamal, A.; Ahmad, M.; Mohd, N.;
Hamid, A. M. Bull. Chem. Soc. Jpn. 1964, 37, 610.
(20) Yadav, J. S.; Reddy, B. V. S.; Sabitha, G.; Reddy, G. S. K.
K. Synthesis 2000, 1532.
IR (Nujol): 1730, 1610, 1556, 1515, 1292, 1250, 1180, 1106, 1028,
832 cm–1.
1H NMR: d = 7.13 (d, J = 8.7 Hz, 2 H), 6.82 (d, J = 8.7 Hz, 2 H),
3.97 (q, J = 7.1 Hz, 4 H), 3.75 (s, 3 H), 2.52 (s, 6 H), 0.93 (t, J = 7.1
Hz, 6 H).
Diethyl 2,6-Dimethylpyridine-3,5-dicarboxylate (8i)
Colorless solid; mp 72–73 °C (Lit.18 mp 70–71 °C).
IR (Nujol): 1721, 1591, 1555, 1298, 1254, 1223, 1107, 1045, 772
cm–1.
(21) Vanden Eynde, J.-J.; D’Orazio, R.; Van Haverbeke, Y.
1H NMR: d = 8.60 (s, 1 H), 4.33 (q, J = 7.2 Hz, 4 H), 2.78 (s, 6 H),
1.34 (t, J = 7.2 Hz, 6 H).
Tetrahedron 1994, 50, 2479.
(22) Chavan, S. P.; Dantale, S. W.; Kalkote, U. R.; Jyothirmai, V.
S.; Kharul, R. K. Synth. Commun. 1998, 28, 2789.
(23) Chavan, S. P.; Kharul, R. K.; Kalkote, U. R.; Shivakumar, I.
Synth. Commun. 2003, 33, 1333.
Diethyl 2,6-Dimethyl-4-methylpyridine-3,5-dicarboxylate (8j)
Colorless oil.25
IR (film): 2981, 1727, 1567, 1446, 1285, 1220, 1106, 1042 cm–1.
(24) Sausinš, A.; Duburs, G. Heterocycles 1988, 27, 291.
(25) Love, B.; Snader, K. M. J. Org. Chem. 1965, 30, 1914.
(26) (a) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Synthesis
2004, 1015. (b) Heravi, M. M.; Behbahani, F. K.; Oskooie,
H. A.; Shoar, R. H. Tetrahedron Lett. 2005, 46, 2775.
(c) Mashraqui, S. H.; Karnik, M. A. Tetrahedron Lett. 1998,
39, 4895. (d) Litvić, M.; Cepanec, I.; Filipan, M.; Kos, K.;
Bartolinčić, A.; Druković, V.; Tibi, M. M.; Vinković, V.
Heterocycles 2005, 65, 23. (e) Tajbakhsh, M.; Lakouraj, M.
M.; Khojasteh, V. Phosphorus, Sulfur Silicon Relat. Elem.
2004, 179, 463. (f) Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Li,
W. Synth. Commun. 2001, 31, 2625. (g) Zeynizadeh, B.;
Dilmaghani, K. A.; Roozijoy, A. Synth. Commun. 2005, 35,
557. (h) Heravi, M. M.; Ghassemzadeh, M. Phosphorus,
Sulfur Silicon Relat. Elem. 2005, 180, 347.
1H NMR: d = 4.34 (q, J = 7.1 Hz, 4 H), 2.46 (s, 6 H), 2.19 (s, 3 H),
1.32 (t, J = 7.1 Hz, 6 H).
Diethyl 4-Ethyl-2,6-dimethylpyridine-3,5-dicarboxylate (8k)
Colorless oil.39
IR (film): 2979, 1729, 1568, 1447, 1414, 1384, 1278, 1236, 1208,
1106, 1040, 860 cm–1.
1H NMR: d = 4.34 (q, J = 7.1 Hz, 4 H), 2.52 (q, J = 7.6 Hz, 2 H),
2.45 (s, 6 H), 1.32 (t, J = 7.1 Hz, 6 H), 1.11 (t, J = 7.6 Hz, 3 H).
Acknowledgment
We thank the EPSRC for funding (GR/S41463 and GR/S25456)
and Robert L. Jenkins for technical assistance.
(27) Vanden Eynde, J. J.; Rutot, D. Tetrahedron 1999, 55, 2687.
(28) Torchy, S.; Cordonnier, G.; Barbry, D.; Vanden Eynde, J. J.
Molecules 2002, 7, 528.
(29) (a) Alvarez, C.; Delgado, F.; García, O.; Medina, S.;
Márquez, C. Synth. Commun. 1991, 21, 619. (b) Delgado,
F.; Alvarez, C.; García, O.; Penieres, G.; Márquez, C. Synth.
Commun. 1991, 21, 2137.
(30) Heravi, M. M.; Moosavi, F. S. Sh.; Beheshtiha, Y. Sh.;
Ghassemzadeh, M. Heterocycl. Commun. 2004, 10, 415.
(31) (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Microwaves in Organic Synthesis; Loupy, A., Ed.;
Wiley-VCH: Weinheim, 2002.
(32) (a) Alajarín, R.; Vaquero, J. J.; García Navío, J. L.; Alvarez-
Builla, J. Synlett 1992, 297. (b) Khadilkar, B. M.; Gaikar, V.
G.; Chitnavis, A. A. Tetrahedron Lett. 1995, 36, 8083.
(c) Anniyappan, M.; Muralidharan, D.; Perumal, P. T. Synth.
Commun. 2002, 32, 659. (d) Öhberg, L.; Westman, J.
Synlett 2001, 1296. (e) Sivamurugan, V.; Sureshkumar, R.;
Palanichamy, M.; Murugesan, V. J. Heterocycl. Chem.
2005, 42, 969.
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M. C. Bagley, M. C. Lubinu
PAPER
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Synthesis 2006, No. 8, 1283–1288 © Thieme Stuttgart · New York