A new three-component domino synthesis of 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tet.2007.03.092

Cerium ammonium nitrate (CAN) catalyzed the three-component domino reaction between aromatic amines, α,β-unsaturated aldehydes, and ethyl acetoacetate, providing an efficient new entry into 1,4-dihydropyridines. This new reaction requires very mild reaction conditions, has water as the only side product and is complementary to the classical Hantzsch synthesis in that it is well suited to the preparation of N-aryl-5,6-unsubstituted dihydropyridines. Experiments in the presence of a radical trap suggest that a one-electron oxidative mechanism can be excluded and that CAN acts as a Lewis acid.

Full text of DOI:10.1016/j.tet.2007.03.092

Tetrahedron 63 (2007) 4407–4413
A new three-component domino synthesis of 1,4-dihydropyridines
y
*
Vellaisamy Sridharan, Paramasivan T. Perumal, Carmen Avenda n˜ o and J. Carlos Men ꢀe ndez
Departamento de Qu ꢀı mica Org aꢀ nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, Ciudad Universitaria,
2
8040 Madrid, Spain
Received 9 February 2007; revised 9 March 2007; accepted 15 March 2007
Available online 18 March 2007
Abstract—Cerium ammonium nitrate (CAN) catalyzed the three-component domino reaction between aromatic amines, a,b-unsaturated
aldehydes, and ethyl acetoacetate, providing an efficient new entry into 1,4-dihydropyridines. This new reaction requires very mild reaction
conditions, has water as the only side product and is complementary to the classical Hantzsch synthesis in that it is well suited to the prep-
aration of N-aryl-5,6-unsubstituted dihydropyridines. Experiments in the presence of a radical trap suggest that a one-electron oxidative mech-
anism can be excluded and that CAN acts as a Lewis acid.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
important types of derivatives, including N-aryl-1,4-dihydro-
pyridines and C –C -unsubstituted 1,4-dihydropyridines.
1
4
5
6
1
2
Multicomponent and domino reactions allow the creation
of several bonds in a single operation and are attracting
increasing attention as one of the most powerful emerging
synthetic tools for the creation of molecular diversity and
complexity. They also have considerable advantages in
terms of user and environmental friendliness because of the
step reduction and atom economy associated to their use.
The development of efficient routes to these compounds is
important to allow the systematic study of their biological
activities and also from a synthetic point of view, since
the presence of a C –C -unsubstituted bond enables the use
5
6
3
of dihydropyridines as enamine-like reagents, allowing the
preparation of a variety of complex heterocyclic frame-
works.
1
5
1,4-Dihydropyridines are among the most widely used drugs
for the management of cardiovascular disease, have a broad
range of other pharmacological activities and play a cru-
(
a) Hantzsch reaction:
4
R4
CHO
5
–9
R4
1
0
3
cial role in CNS-targeted chemical delivery systems. Also,
in spite of initial, largely unfounded, misgivings about their
stability, 1,4-dihydropyridines have also proven to be very
important synthetic intermediates, finding application in
R3O C
2
CO R3
R3O C
2
CO R
2
2
R2
N
H
R2
R2
O
O
R2
NH3
1
1
the preparation of a large number of nitrogen alkaloids.
The synthesis of 1,4-dihydropyridines is often achieved by
nucleophilic addition to pyridinium salts, available from
(b) This work:
3
CO R
2
R4
1
2
the corresponding pyridine derivatives. The best known
procedure for the de novo preparation of 1,4-dihydropyri-
dines is the classical Hantzsch synthesis, a multicomponent
condensation involving, in its original version (Scheme 1a),
two molecules of a b-ketoester, one molecule of an alde-
hyde, and one molecule of ammonia. In spite of their wide-
spread use, neither the Hantzsch method nor related
3
CO R
2
R2
O
R2
R4
N
R4
N
R1
NH
2
1
O
R
1
R
1
3
reactions can be considered as general dihydropyridine
syntheses as they do not allow the preparation of some
Scheme 1.
With these precedents in mind, we set as our goal the devel-
opment of a new multicomponent procedure for the synthe-
sis of dihydropyridines that is designed to overcome the
above mentioned limitations and hence to be complementary
*
Corresponding author. Tel.: +34 91 3941840; fax: +34 91 3941822;
e-mail: josecm@farm.ucm.es
Permanent address: Organic Chemistry Division, Central Leather Re-
search Institute, Chennai 600 020, Tamil Nadu, India.
y
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.092

4408
V. Sridharan et al. / Tetrahedron 63 (2007) 4407–4413
to the Hantzsch reaction. Our strategy (Scheme 1b) is based
on a domino imine formation–Michael addition–condensa-
tion sequence, and is different from a recently introduced
one that involves Michael-initiated multicomponent reac-
Table 1. Catalyst scan for the reaction between m-toluidine, cinnamalde-
hyde, and ethyl acetoacetate
Entry
Catalyst
InCl
PPh $HClO
KHSO4
CAN
Mol %
Yield (%)
a
1
2
3
4
3
20
20
40
5
45
50
1
6
tions starting from b-dicarbonyl compounds. In spite of
the existence of an early paper claiming the development
of a two-component dihydropyridine synthesis by reaction
between neat a,b-unsaturated imines and b-dicarbonyl com-
a
3
4
a
45
71
b
a
1
Yields estimated from the H NMR spectra of the crude reaction mixtures.
Isolated yield.
ꢀ
17
pounds in the presence of sodium ethoxide at 150 C, the
evidence provided for the proposed structures is insufficient
b
(
only mp, IR data, and analyses) and there is a considerable
discrepancy between the description of the reaction products
crystalline solids, some with high melting points) and the
isolated yield after 1 h at room temperature and requiring
only 5% of the catalyst. Although Ce(IV) derivatives are nor-
mally employed as one-electron oxidants, the use of the
commercially available, inexpensive, and easily handled
CAN in carbon–carbon and carbon–heteroatom bond form-
(
fact that some compounds 4 recently obtained by alternative
means have been reported to be non-crystallizable semi-
1
8
2
4
solids. Indeed, in our hands the base-catalyzed reaction
failed to give dihydropyridine systems, as shown by the
NMR spectra of the crude reaction products. Reliable litera-
ture precedent exists, however, for the key step in our pro-
posed reaction, namely a Michael reaction followed by
cyclization between a b-dicarbonyl compound and a a,b-un-
saturated imine in the presence of lithium iodide to give 1,4-
dihydropyridines. However, besides being a two-component
protocol, this method has serious limitations because it re-
quires long reaction times (3 days), it is limited to the prep-
aration of N-benzyl derivatives and it often gives low yields
ing reactions has recently attracted much attention, al-
though these studies are still in their early stages. As stated
2
4c
in a recent review on the subject, the main current goal
in this area is the development of reactions that allow the
2
5
use of catalytic amounts of CAN. In this light, the result
in entry 4 of Table 1 becomes particularly interesting.
The conditions developed for the model case were then
applied to a range of substrates. As shown in Scheme 3
and Table 2, the reaction proceeds normally in good yields,
and tolerates several types of electron-releasing and elec-
tron-withdrawing groups at all positions of the nitrogen
aryl substituent, including alkyl (entries 2, 5, 6, 9, and 12),
alkoxy (entry 10), bromo (entry 8), chloro (entries 4 and
7), and fluoro (entry 3). The aryl substituent at the a,b-unsat-
urated aldehyde component can also bear substituents, as
shown by the result in entry 11, although in the chosen exam-
ple the ortho-substitution leads to a lowered yield. When
tert-butyl esters were employed, a longer time (2 h) was
required and the yields were slightly lower than with their
ethyl counterparts (entries 13–15). The reaction could also
be extended to include the use of tert-butyl b-ketothioesters
as the dicarbonyl component, in yields similar to those found
for tert-butyl esters (entries 16–19). This possibility is inter-
esting because it potentially allows exploiting the high reac-
tivity of the thioester group toward alcohols and amines in
1
9
because of the formation of a transimination side product.
Hetero Diels–Alder reactions of 1-azadienes can also
generate dihydropyridines, including some N-aryl- and
2
0
1
8
C –C -unsubstituted systems, but these are two-compo-
5
6
nent procedures that require unusual starting materials
e.g., allenic esters), toxic solvents, and drastic reaction con-
(
1
8
ditions (e.g., 55–85 h reflux in benzene). In this context,
we present here the practical realization of the synthetic
method proposed in Scheme 1b.
2
. Results and discussion
We carried out an initial study in search for the optimal cat-
alyst and solvent for the proposed transformation using as
a model the reaction involving cinnamaldehyde, m-tolui-
dine, and ethyl acetoacetate, and the most significant data
obtained are summarized in Scheme 2 and Table 1. We first
2
6
the presence of thiophilic metals. On the other hand,
aliphatic amines (e.g., benzylamine) gave complex reaction
mixtures containing only small amounts of the desired prod-
ucts, and attempts to use a,b-unsaturated aldehydes other
than cinnamaldehyde derivatives were also unsuccessful.
2
1
assayed indium trichloride, triphenylphosphonium per-
chlorate, and potassium hydrogen sulfate as catalysts,
2
2
23
which have been successfully employed in related condensa-
tion reactions, but the yields obtained were only moderate,
even with high catalyst loadings. The best results were
obtained with cerium ammonium nitrate (CAN) in ethanol,
which gave the desired dihydropyridine derivative in 71%
R1
O
R1
O
+
Z
5
mol % CAN
Z
O
1
O
CH3
3
EtOH, r.t., 1h
N
CH
3
NH2
5
R
R5
R4
O
O
EtOH,
R2
R4
OC H
2 5
R2
+
OC H
2
5
r.t., 1 h
R3
O
R3
2
N
CH3
O
CH3
4
NH2
Scheme 3.
CH3
CH3
In order to confirm that our reaction follows the pathway
outlined in Scheme 1b, we carried out two additional
Scheme 2.

V. Sridharan et al. / Tetrahedron 63 (2007) 4407–4413
Table 2. Scope and yields of the CAN-catalyzed synthesis of 1,4-dihydropyridines
4409
1
R
2
3
4
R
5
Entry
Compound
Z
R
R
R
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
OC
OC
OC
OC
OC
OC
OC
OC
OC
OC
OC
OC
O–C(CH
O–C(CH
O–C(CH
S–C(CH
S–C(CH
S–C(CH
S–C(CH
2
2
2
2
2
2
2
2
2
2
2
2
H
H
H
H
H
H
H
H
H
H
H
H
5
5
5
5
5
5
5
5
5
5
5
5
H
H
H
H
H
H
H
H
H
H
NO
H
H
H
H
H
H
H
H
H
H
H
H
CH
CH
Cl
H
CH
OCH
H
H
H
H
H
H
H
H
H
H
CH
F
Cl
H
CH
H
Br
H
H
H
CH
H
CH
Cl
H
F
Cl
CH
H
H
H
H
H
H
H
H
CH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH
H
H
H
H
H
H
CH
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
1
1
1
1
74
70
76
74
71
70
72
74
71
65
50
72
52
61
65
61
62
63
61
3
3
3
3
3
3
10
11
12
13
14
15
16
17
18
19
4j
4k
3
2
a
4l
3
3
3
4m
4n
4o
4p
4q
4r
3
3
3
)
)
)
3
3
3
3
)
3
3
3
3
)
3
)
3
)
3
4s
3
3
a
Isolated as an 1.1:1 rotamer mixture.
experiments. In the first of them, the purified imine derived
from aniline and cinnamaldehyde was treated at room tem-
perature for 1 h with ethyl acetoacetate in ethanol containing
3. Conclusion
In conclusion, we have developed a new strategy that
provides an efficient entry into 1-aryl-5,6-disubstituted
1,4-dihydropyridines and is therefore complementary to
existing procedures, particularly the Hantzsch synthesis. Our
method involves mild reaction conditions, uses very simple
and accessible starting materials and solvents, as well as an
inexpensive and non-toxic catalyst. It also has the additional
advantage of proceeding with high atom economy and
having water as the only side product.
5
% CAN, and was found to give identical results to the three-
component protocol. In a second experiment designed to dis-
card an alternative Michael-initiated sequence similar to the
1
6
one described by Rodriguez, we have found that CAN
does not catalyze the Michael reaction between ethyl aceto-
acetate and cinnamaldehyde in ethanol under our conditions,
the crude reaction product being composed of unreacted
starting materials and a small amount of cinnamaldehyde
diethylacetal.
Most of the synthetic applications of CAN are based on
radical mechanisms, as expected from a powerful one-
electron oxidant. In an effort to clarify whether CAN exerts
its role in our dihydropyridine synthesis through such an
oxidative pathway, we have performed the reaction between
cinnamaldehyde, aniline, and ethyl acetoacetate (entry 1 in
Table 2) in the presence of a large amount of a radical
trap, namely 1,1-diphenylethylene, and found no noticeable
loss in yield, which indicates that a radical mechanism is not
in operation under our conditions. In this regard, it is relevant
to note that some literature results can be interpreted by
assuming that CAN may behave as a Lewis acid, although
this role has not been systematically studied. Some examples
are our own results on the deviation of the [4+2] cyclo-
addition of 1-dimethylamino-1-azadienes and quinoline-
quinones toward the formation of furo[3,2-f]quinoline
4. Experimental
4.1. General
All reagents were of commercial quality (Aldrich, Fluka,
SDS, Probus) and were used as received. Solvents (from
SDS) were dried and purified using standard techniques.
Reactions were monitored by thin layer chromatography,
on aluminum plates coated with silica gel with fluorescent
indicator (SDS CCM221254). Separations by flash chroma-
tography were performed on silica gel (SDS 60 ACC, 230–
40 mesh). Melting points were measured with a Reichert 723
hot stage microscope, and are uncorrected. Infrared spectra
were recorded on a Perkin–Elmer Paragon 1000 FTIR spec-
trophotometer, with all compounds examined as films on
a NaCl disk. NMR spectra were obtained on a Bruker
2
7
1
systems in the presence of CAN, and its use as a catalyst
for the ring-opening of aziridines by water and Michael
Avance instrument (250 MHz for H NMR, 62.9 MHz for
C NMR), maintained by the Servicio de RMN, Universi-
2
8
13
2
9
additions in indoles. The clearest example can be found
in a study about the use of CAN as a catalyst for acetal
and ketal deprotection, where it has been proved by cyclic
voltammetry that cerium remains in the Ce(IV) oxidation
dad Complutense, with CDCl as solvent. Combustion ele-
3
mental analyses were determined by the Servicio de
Microan ꢀa lisis Elemental, Universidad Complutense, using
a Leco 932 CHNS microanalyzer.
3
0,31
state, strongly suggesting that it acts as a Lewis acid.
Regarding the order of the steps of the three-component
reaction, the imine formation step must occur first, as
indicated in Scheme 1b, because treatment of isolated
imines with b-dicarbonyl compounds under our conditions
gave results identical to those of the three-component
protocol.
4.2. General procedure for the CAN-catalyzed synthesis
of ethyl 1,4-dihydro-2-methyl-1,4-diarylpyridine-3-
carboxylates (4)
To a solution of the suitable cinnamaldehyde 1 (2 mmol) and
arylamine 2 (2 mmol) in 30 mL of absolute ethanol were

4410
V. Sridharan et al. / Tetrahedron 63 (2007) 4407–4413
added ethyl acetoacetate 3 (2 mmol) and ceric ammonium
nitrate, CAN (5 mol %). The mixture was stirred at room
temperature under argon atmosphere for 60 min. After com-
pletion of the reaction, the solvent was evaporated under re-
duced pressure and extracted with ethyl ether (2ꢁ20 mL).
The ethereal solution was washed twice with saturated
sodium bicarbonate solution (30 mL), dried with anhydrous
sodium sulfate, evaporated, and the resultant crude product
was purified by flash silica column chromatography using
petroleum ether–ethyl acetate as eluant (96:4). Yields are
given in Table 2, and characterization data follow. With
the exceptions of 4i and 4p–s, all compounds 4 were semi-
solid and could not be crystallized. Compounds 4a–d were
4.2.5. Ethyl 2-methyl-4-phenyl-1-(3-methylphenyl)-1,4-
dihydropyridine-3-carboxylate (4e). IR (NaCl) n: 1693.0,
1568.0, 1226.4 cm . H NMR (250 MHz, CDCl ) d: 1.20
3
ꢂ1
1
(t, 3H, J¼7.1 Hz); 2.24 (s, 3H); 2.44 (s, 3H); 4.10 (q, 2H,
J¼7.1 Hz); 4.77 (d, 1H, J¼5.5 Hz); 5.06 (dd, 1H, J¼5.5,
7.6 Hz); 6.22 (d, 1H, J¼7.6 Hz); 7.05–7.08 (m, 2H); 7.17–
1
3
7.46 (m, 7H). C NMR (63 MHz, CDCl ) d: 14.7, 19.2,
3
21.8, 40.7, 59.8, 101.9, 107.8, 125.0, 126.6, 128.0, 128.5,
128.6, 128.8, 129.8, 129.9, 140.1, 144.0, 148.6, 149.0,
169.3. Anal. Calcd for C H NO , M¼333.4: C, 79.25;
2
2
23
2
H, 6.95; N, 4.20. Found: C, 79.03; H, 6.84; N, 4.23.
4.2.6. Ethyl 2-methyl-1-(3,4-dimethylphenyl)-4-phenyl-
1,4-dihydropyridine-3-carboxylate (4f). IR (NaCl) n:
1
8
13
previously known, and our C NMR data are substantially
identical to those found in the literature.
ꢂ1
1
1693.5, 1567.9, 1228.6 cm . H NMR (250 MHz, CDCl )
3
d: 1.19 (t, 3H, J¼7.1 Hz); 2.21 (s, 3H); 2.33 (s, 6H); 4.08 (q,
4
3
1
.2.1. Ethyl 2-methyl-1,4-diphenyl-1,4-dihydropyridine-
-carboxylate (4a). IR (NaCl) n: 1690.9, 1568.0,
221.0 cm . H NMR (CDCl , 250 MHz) d: 1.19 (t, 3H,
2H, J¼7.1 Hz); 4.74 (d, 1H, J¼5.5 Hz); 5.04 (dd, 1H, J¼5.5,
13
1
8
7.6 Hz); 6.18 (d, 1H, J¼7.6 Hz); 6.95–7.02 (m, 2H); 7.19–
ꢂ1
1
7.31 (m, 6H). C NMR (63 MHz, CDCl ) d: 14.7, 19.1,
3
3
J¼7.1 Hz); 2.21 (s, 3H); 4.08 (q, 2H, J¼7.1 Hz); 4.75 (d,
19.8, 20.3, 40.7, 59.8, 101.5, 107.6, 125.2, 126.5, 128.0,
128.7, 129.0, 130.1, 131.0, 136.4, 138.5, 141.8, 148.9,
149.2, 169.3. Anal. Calcd for C H NO , M¼347.5: C,
1
H, J¼5.5 Hz); 5.07 (dd, 1H, J¼5.5 and 7.6 Hz); 6.23 (d,
1
3
1
CDCl ) d: 14.7, 19.2, 40.6, 59.9, 102.1, 107.9, 126.6,
H, J¼7.6 Hz); 7.24–7.47 (m, 10H). C NMR (63 MHz,
2
3
25
2
79.51; H, 7.25; N, 4.03. Found: C, 79.06; H, 6.92; N, 4.23.
3
1
1
7
27.8, 127.9, 128.0, 128.8, 129.9, 130.0, 144.1, 148.4,
48.9, 169.2. Anal. Calcd for C H NO , M¼319.4: C,
4.2.7. Ethyl 1-(3-chlorophenyl)-2-methyl-4-phenyl-1,4-
2
1
21
2
8.97; H, 6.63; N, 4.39. Found: C, 78.85; H, 6.39; N, 4.50.
dihydropyridine-3-carboxylate (4g). IR (NaCl) n:
ꢂ1
694.0, 1590.9, 1222.0 cm . H NMR (250 MHz, CDCl )
3
1
1
4.2.2. Ethyl 2-methyl-4-phenyl-1-(4-methylphenyl)-1,4-
dihydropyridine-3-carboxylate (4b).
d: 1.18 (t, 3H, J¼7.1 Hz); 2.20 (s, 3H); 4.07 (q, 2H,
13
1
8
IR (NaCl) n:
691.1, 1567.8, 1222.2 cm . H NMR (250 MHz, CDCl )
J¼7.1 Hz); 4.73 (d, 1H, J¼5.5 Hz); 5.07 (dd, 1H, J¼5.5,
ꢂ1
1
1
7.6 Hz); 6.19 (d, 1H, J¼7.6 Hz); 7.12–7.40 (m, 9H).
C
NMR (63 MHz, CDCl ) d: 14.6, 19.2, 40.6, 60.0, 103.3,
3
d: 1.19 (t, 3H, J¼7.1 Hz); 2.21 (s, 3H); 2.43 (s, 3H); 4.08
q, 2H, J¼7.1 Hz); 4.75 (d, 1H, J¼5.4 Hz); 5.05 (dd, 1H,
J¼5.4 and 7.6 Hz); 6.19 (d, 1H, J¼7.6 Hz); 7.14 (d, 2H,
3
(
108.4, 126.2, 126.7, 127.9, 128.0, 128.1, 128.8, 129.4,
130.9, 135.4, 145.2, 147.5, 148.5, 169.1. Anal. Calcd for
C H ClNO , M¼353.8: C, 71.28; H, 5.70; N, 3.96. Found:
1
3
J¼8.2 Hz); 7.25–7.44 (m, 7H).
C NMR (63 MHz,
2
1
20
2
CDCl ) d: 14.6, 19.1, 23.1, 40.7, 59.8, 101.7, 107.7, 126.6,
3
C, 70.99; H, 5.48; N, 3.72.
1
1
7
27.8, 128.0, 128.7, 130.0, 130.6, 137.7, 141.5, 148.7,
49.1, 169.3. Anal. Calcd for C H NO , M¼333.4: C,
4.2.8. Ethyl 1-(4-bromophenyl)-2-methyl-4-phenyl-1,4-
2
2
23
2
9.25; H, 6.95; N, 4.20. Found: C, 79.16; H, 6.85; N, 4.46.
dihydropyridine-3-carboxylate (4h). IR (NaCl) n: 1691.0,
ꢂ1
565.4, 1221.3 cm . H NMR (250 MHz, CDCl ) d: 1.18
3
1
1
4
.2.3. Ethyl 1-(4-fluorophenyl)-2-methyl-4-phenyl-1,4-di-
(t, 3H, J¼7.1 Hz); 2.20 (s, 3H); 4.08 (q, 2H, J¼7.1 Hz);
4.74 (d, 1H, J¼5.5 Hz); 5.07 (dd, 1H, J¼5.5, 7.6 Hz); 6.17
(d, 1H, J¼7.6 Hz); 7.12 (d, 2H, J¼8.1 Hz); 7.23–7.38 (m,
1
8
hydropyridine-3-carboxylate (4c). IR (NaCl) n: 1693.2,
ꢂ1
568.8, 1215.6 cm . H NMR (250 MHz, CDCl ) d: 1.19
3
1
1
1
3
(
4
t, 3H, J¼7.1 Hz); 2.20 (s, 3H); 4.09 (q, 2H, J¼7.1 Hz);
5H); 7.58 (d, 2H, J¼8.1 Hz). C NMR (63 MHz, CDCl )
3
.75 (d, 1H, J¼5.4 Hz); 5.06 (dd, 1H, J¼5.4, 7.6 Hz); 6.14
d: 14.7, 19.2, 40.6, 60.1, 103.0, 108.3, 121.3, 126.7, 128.0,
128.8, 129.5, 129.6, 135.2, 143.1, 147.6, 148.6, 169.0.
Anal. Calcd for C H BrNO , M¼398.3: C, 63.33; H,
(
d, 1H, J¼7.6 Hz); 7.11–7.20 (m, 5H); 7.24–7.33 (m, 4H).
1
3
C NMR (63 MHz, CDCl ) d: 14.7, 19.0, 40.6, 59.9,
3
21 20
2
1
1
1
02.3, 108.0, 116.9 (d, J¼22.6 Hz), 126.6, 128.0, 128.8,
29.8 (d, J¼8.2 Hz), 129.9, 140.1 (d, J¼3.8 Hz), 148.2,
48.8, 161.9 (d, J¼247.2 Hz), 169.1. Anal. Calcd for
5.06; N, 3.52. Found: C, 63.04; H, 5.15; N, 3.42.
4.2.9. Ethyl 2-methyl-1-(3,5-dimethylphenyl)-4-phenyl-
1,4-dihydropyridine-3-carboxylate (4i). Mp 96–97 C.
ꢀ
H NMR
C H FNO , M¼337.4: C, 74.76; H, 5.97; N, 4.15. Found:
2
1
20
2
ꢂ1
1
C, 74.51; H, 5.91; N, 4.18.
IR (NaCl) n: 1691.9, 1567.9, 1236.6 cm
.
(
250 MHz, CDCl ) d: 1.21 (t, 3H, J¼7.1 Hz); 2.24 (s, 3H);
3
4
.2.4. Ethyl 1-(4-chlorophenyl)-2-methyl-4-phenyl-1,4-
2.41 (s, 6H); 4.10 (q, 2H, J¼7.1 Hz); 4.77 (d, 1H,
J¼5.5 Hz); 5.06 (dd, 1H, J¼5.5 and 7.6 Hz); 6.21 (d, 1H,
J¼7.6 Hz); 6.89 (s, 2H); 7.02 (s, 1H); 7.25–7.47 (m, 5H).
1
8
dihydropyridine-3-carboxylate (4d).
1
IR (NaCl) n:
ꢂ1
692.6, 1567.7, 1222.1 cm . H NMR (250 MHz, CDCl )
3
1
1
3
d: 1.18 (t, 3H, J¼7.1 Hz); 2.19 (s, 3H); 4.07 (q, 2H,
C NMR (63 MHz, CDCl ) d: 14.7, 19.2, 21.7 (2 signals),
3
J¼7.1 Hz); 4.73 (d, 1H, J¼5.4 Hz); 5.07 (dd, 1H, J¼5.4,
40.7, 59.8, 101.7, 107.6, 125.6, 126.5, 128.0, 128.7, 129.4,
130.0, 139.8, 144.0, 148.7, 149.1, 169.3. Anal. Calcd for
C H NO , M¼347.5: C, 79.51; H, 7.25; N, 4.03. Found:
1
3
7
NMR (63 MHz, CDCl ) d: 14.6, 19.1, 40.6, 59.9, 102.9,
.6 Hz); 6.16 (d, 1H, J¼7.6 Hz); 7.16–7.44 (m, 9H).
C
3
23 25
2
1
1
08.2, 126.7, 127.9, 128.8, 129.2, 129.5, 130.2, 133.4,
42.6, 147.7, 148.6, 169.1. Anal. Calcd for C H ClNO ,
C, 79.29; H, 6.96; N, 3.98.
2
1
20
2
M¼353.8: C, 71.28; H, 5.70; N, 3.96. Found: C, 70.97; H,
4.2.10. Ethyl 2-methyl-1-(3-methoxyphenyl)-4-phenyl-
1,4-dihydropyridine-3-carboxylate (4j). IR (NaCl) n:
5
.79; N, 3.91.

V. Sridharan et al. / Tetrahedron 63 (2007) 4407–4413
4411
ꢂ1
1
1
690.5, 1569.0, 1213.7, 1199.9 cm . H NMR (250 MHz,
C H NO , M¼361.5: C, 79.74; H, 7.53; N, 3.87. Found:
2
4
27
2
CDCl ) d: 1.18 (t, 3H, J¼7.1 Hz); 2.22 (s, 3H); 3.86 (s,
C, 79.54; H, 7.52; N, 3.85.
3
3
(
H); 4.07 (q, 2H, J¼7.1 Hz); 4.73 (d, 1H, J¼5.5 Hz); 5.05
dd, 1H, J¼5.5 and 7.6 Hz); 6.22 (d, 1H, J¼7.6 Hz); 6.77–
4.2.15. tert-Butyl 1-(4-chlorophenyl)-1,4-dihydro-2-
methyl-4-phenylpyridine-3-carboxylate (4o). IR (NaCl)
1
3
6
CDCl ) d: 14.7, 19.1, 40.6, 55.9, 59.6, 102.2, 107.8, 113.2,
.83 (m, 3H); 6.91–7.42 (m, 6H). C NMR (63 MHz,
ꢂ1
1
n: 1690.5, 1569.5, 1235.6 cm
CDCl ) d: 1.33 (s, 9H); 2.14 (s, 3H); 4.69 (d, 1H,
.
H NMR (250 MHz,
3
1
1
13.7, 120.2, 126.6, 128.0, 128.8, 129.8, 130.6, 145.2,
48.3, 148.9, 160.9, 169.2. Anal. Calcd for C H NO ,
M¼349.4: C, 75.62; H, 6.63; N, 4.01. Found: C, 75.37; H,
3
J¼5.1 Hz); 4.99 (dd, 1H, J¼5.1, 7.7 Hz); 6.10 (d, 1H,
2
2
23
3
1
3
J¼7.7 Hz); 7.14–7.41 (m, 9H).
C NMR (63 MHz,
CDCl ) d: 19.1, 28.6, 41.3, 79.7, 104.5, 108.0, 126.6,
3
6
.51; N, 4.33.
127.9, 128.8, 129.2, 129.3, 130.1, 133.2, 142.8, 146.5,
4.2.11. Ethyl 2-methyl-4-(2-nitrophenyl)-1-phenyl-1,4-
dihydropyridine-3-carboxylate (4k). IR (NaCl) n:
148.9, 168.6. Anal. Calcd for C H ClNO , M¼381.9: C,
2
3
24
2
72.34; H, 6.33; N, 3.67. Found: C, 72.05; H, 6.10; N, 3.45.
ꢂ1
1
1
693.9, 1567.9, 1523.6, 1354.5, 1221.3 cm . H NMR
(
250 MHz, CDCl ) d: 0.95 (t, 3H, J¼7.1 Hz); 2.24 (s, 3H);
4.2.16. S-tert-Butyl 2-methyl-1,4-diphenyl-1,4-dihydro-
ꢀ
3
3
1
1
.90 (q, 2H, J¼7.1 Hz); 5.21–5.25 (m, 2H); 6.14–6.16 (m,
pyridine-3-carbothioate (4p). Mp 104–105 C. IR (NaCl)
ꢂ1
1
H); 7.22–7.50 (m, 6H); 7.62 (t, 1H, td, J¼8.1 and
n: 1673.6, 1628.5, 1533.4, 1155.9 cm
.
H NMR
(250 MHz, CDCl ) d: 1.45 (s, 9H); 2.12 (s, 3H); 4.86
1
3
.5 Hz); 7.75 (dd, 2H, J¼8.1 and 1.5 Hz). C NMR
3
(
63 MHz, CDCl ) d: 14.3, 19.0, 36.6, 59.9, 100.6, 106.6,
3
(d, 1H, J¼5.8 Hz); 5.13 (dd, 1H, J¼5.8, 7.5 Hz); 6.19 (d,
1
3
1
1
23.6, 127.1, 128.0, 128.1, 130.1, 130.4, 131.6, 133.6,
43.7, 143.8, 148.2, 150.3, 168.3. Anal. Calcd for
1H, J¼7.5 Hz); 7.19–7.48 (m, 10H). C NMR (63 MHz,
CDCl ) d: 19.5, 30.5, 41.2, 47.7, 107.8, 110.8, 126.7,
3
C H N O , M¼364.4: C, 69.22; H, 5.53; N, 7.69. Found:
127.7, 127.8, 127.9, 128.9, 129.8, 130.0, 143.8, 144.8,
147.7, 194.5. Anal. Calcd for C H NOS, M¼363.5: C,
2
1 20 2 4
C, 68.93; H, 5.33; N, 7.42.
2
3 23
7
5.99; H, 6.93; N, 3.85. Found: C, 75.93; H, 7.07; N, 3.90.
4
1
.2.12. Ethyl 2-methyl-4-(2,4-dimethylphenyl)-1-phenyl-
,4-dihydropyridine-3-carboxylate (4l). This compound
4.2.17. S-tert-Butyl 2-methyl-4-phenyl-1-(4-fluoro-
phenyl)-1,4-dihydropyridine-3-carbothioate (4q). Mp
was isolated as a 1.1:1 rotamer mixture (4la major rotamer,
4
ꢀ
1153.7 cm . H NMR (250 MHz, CDCl ) d: 1.43 (s, 9H);
lb minor rotamer). IR (NaCl) n: 1684.8, 1559.7,
210.4 cm . H NMR (250 MHz, CDCl ) d: 1.10–1.18
138–139 C. IR (NaCl) n: 1672.9, 1628.5, 1508.4,
ꢂ1
1
ꢂ1
1
1
3
3
(
m, 4la and 4lb, CO CH CH ); 2.10 and 2.12 (2s, 4la and
2
2.08 (s, 3H); 4.83 (d, 1H, J¼5.8 Hz); 5.10 (dd, 1H, J¼5.8,
2
3
1
3
4
2
4
4
4
4
1
1
1
1
1
7
lb, CH ); 2.25 and 2.28 (2s, 4la and 4lb, CH ); 2.38 and
3
7.5 Hz); 6.10 (d, 1H, J¼7.5 Hz); 7.12–7.38 (m, 9H).
C
NMR (63 MHz, CDCl ) d: 19.2, 30.4, 41.2, 47.8, 107.2,
3
.39 (2s, 4la and 4lb, CH ); 4.04 (q, J¼7.1 Hz, 4la and
3
3
lb); 4.72 (d, 1H, J¼5.5 Hz, 4lb); 4.79 (d, 1H, J¼5.5 Hz,
la); 4.98–5.04 (m, 4la and 4lb); 5.90 (d, 1H, J¼7.6 Hz,
lb); 5.96 (d, 1H, J¼7.6 Hz, 4la); 7.03–7.35 (m, 4la and
111.0, 116.9 (d, J¼22.6 Hz), 126.8, 127.7, 128.9, 129.6,
129.7 (d, J¼8.2 Hz), 139.8 (d, J¼3.8 Hz), 144.3, 147.5,
161.9 (d, J¼247.4 Hz), 194.7. Anal. Calcd for C H FNOS,
2
3 24
1
3
lb). C NMR (63 MHz, CDCl ) d: 14.6, 17.9, 18.0, 18.1,
M¼381.5: C, 72.41; H, 6.34; N, 3.67. Found: C, 72.31; H,
3
8.2, 21.5, 40.7, 40.8, 59.7, 100.0, 100.3, 107.7, 107.8,
26.4, 126.5, 128.0, 128.2, 128.4, 128.6, 128.7, 128.9,
29.2, 129.3, 129.6, 131.7, 132.1, 132.5, 136.5, 136.8,
38.4, 138.6, 140.0, 140.4, 149.2, 149.4, 149.5, 153.3,
69.3, 169.4. Anal. Calcd for C H NO , M¼347.5: C,
6.41; N, 3.74.
4.2.18. S-tert-Butyl 1-(4-chlorophenyl)-2-methyl-4-phe-
nyl-1,4-dihydropyridine-3-carbothioate (4r). Mp 119–
ꢀ
ꢂ1
120 C. IR (NaCl) n: 1670.3, 1635.9, 1540.2, 1155.5 cm
.
2
3
25
2
1
9.51; H, 7.25; N, 4.03. Found: C, 79.23; H, 7.03; N, 3.78.
H NMR (250 MHz, CDCl ) d: 1.42 (s, 9H); 2.07 (s, 3H);
3
4
.82 (d, 1H, J¼5.8 Hz); 5.11 (dd, 1H, J¼5.8, 7.5 Hz); 6.13
1
3
4.2.13. tert-Butyl 2-methyl-1,4-diphenyl-1,4-dihydropyr-
idine-3-carboxylate (4m). IR (NaCl) n: 1689.9, 1570.0,
(d, 1H, J¼7.5 Hz); 7.12–7.42 (m, 9H). C NMR (63 MHz,
CDCl ) d: 19.3, 30.4, 41.2, 47.8, 108.0, 111.6, 126.8, 127.7,
3
ꢂ1
1
1
2
7
234.3 cm . H NMR (250 MHz, CDCl ) d: 1.34 (s, 9H);
3
128.9, 129.1, 129.5, 130.2, 133.5, 142.3, 143.7, 147.3, 194.7.
Anal. Calcd for C H ClNOS, M¼397.9: C, 69.42; H, 6.08;
.16 (s, 3H); 4.71 (d, 1H, J¼5.1 Hz); 5.00 (dd, 1H, J¼5.1,
2
3 24
1
3
.7 Hz); 6.16 (d, 1H, J¼7.7 Hz); 7.22–7.47 (m, 10H).
C
N, 3.52. Found: C, 69.55; H, 6.15; N, 3.60.
NMR (63 MHz, CDCl ) d: 19.1, 28.6, 41.3, 79.6, 103.7,
3
1
1
07.6, 126.5, 127.6, 128.0, 128.7, 129.7, 129.9, 144.2,
47.2, 149.2, 168.8 (one aromatic carbon signal is merged
4.2.19. S-tert-Butyl 1-(2,4-dimethylphenyl)-2-methyl-4-
phenyl-1,4-dihydropyridine-3-carbothioate (4s). This
compound was isolated as a 1:0.75 rotamer mixture (4la
with others). Anal. Calcd for C H NO , M¼347.5: C,
2
3
25
2
ꢀ
7
9.51; H, 7.25; N, 4.03. Found: C, 79.28; H, 6.96; N, 3.94.
major rotamer, 4lb minor rotamer). Mp 132–133 C. IR
ꢂ1
1
(NaCl) n: 1672.6, 1627.6, 1525.8, 1152.4 cm . H NMR
(250 MHz, CDCl ) d: 1.42 and 1.43 (2s, 4sa and 4sb,
4.2.14. tert-Butyl 1,4-dihydro-2-methyl-1-(4-methyl-
phenyl)-4-phenylpyridine-3-carboxylate (4n). IR (NaCl)
3
C(CH ) ); 2.04 and 2.06 (2s, 4sa and 4sb, CH ); 2.17 and
3
3
3
ꢂ1
1
n: 1693.3, 1568.3, 1234.8 cm
CDCl ) d: 1.34 (s, 9H); 2.17 (s, 3H); 2.42 (s, 3H); 4.71 (d,
.
H NMR (250 MHz,
2.23 (2s, 4sa and 4sb, CH ); 2.37 and 2.38 (2s, 4sa and
3
4sb, CH ); 4.84 (d, 1H, J¼5.9 Hz, 4sb); 4.91 (d, 1H,
3
3
1
H, J¼5.2 Hz); 4.98 (dd, 1H, J¼5.2, 7.7 Hz); 6.13 (d, 1H,
J¼5.9 Hz, 4sa); 5.06–5.15 (m, 4sa and 4sb); 5.85 (d, 1H,
13
J¼7.7 Hz); 7.12 (d, 2H, J¼8.3 Hz); 7.23–7.43 (m, 7H).
J¼7.5 Hz, 4sb); 5.94 (d, 1H, J¼7.5 Hz, 4sa); 7.01–7.53
1
3
C NMR (63 MHz, CDCl ) d: 19.0, 21.5, 28.6, 41.3, 79.5,
3
03.3, 107.5, 126.4, 127.8, 128.0, 128.7, 129.8, 130.5,
37.5, 141.7, 147.6, 149.4, 168.8. Anal. Calcd for
(m, 4sa and 4sb). C NMR (63 MHz, CDCl ) d: 17.9,
18.1, 18.4, 18.6, 21.5, 30.5, 41.0, 41.1, 47.6, 107.8, 107.9,
108.5, 108.9, 126.5, 126.6, 127.7, 128.1, 128.4, 128.5,
3
1
1

4412
V. Sridharan et al. / Tetrahedron 63 (2007) 4407–4413
1
1
1
7
28.7, 128.8, 128.9, 129.1, 129.3, 132.1, 132.5, 136.3, 136.7,
38.5, 138.7, 139.7, 140.1, 146.0, 146.4, 148.0, 148.2, 194.2,
10. (a) Misra1, A.; Ganesh, S.; Shahiwala, A.; Shah, S. P. J. Pharm.
Sci. 2003, 6, 252; (b) Bodor, N.; Buchwald, P. Drug Discov.
Today 2002, 7, 766; (c) Prokai, L.; Prokai-Tatrai, K.; Bodor,
N. Med. Res. Rev. 2000, 20, 367.
94.3. Anal. Calcd for C H NOS, M¼391.6: C, 76.68; H,
2
5 29
.46; N, 3.58. Found: C, 76.59; H, 7.47; N, 3.68.
1
1. For reviews of the chemistry of 1,4-dihydropyridines, see: (a)
Comins, D. L.; O’Connor, S. Adv. Heterocycl. Chem. 1988,
Acknowledgements
4
2
2
4, 199; (b) Kumar, R.; Chandra, R. Adv. Heterocycl. Chem.
001, 78, 269; (c) Lavilla, R. J. Chem. Soc., Perkin Trans. 1
002, 1141.
The stay of P.T.P in Madrid was supported by a grant from
the Santander-UCM ‘‘Programa de Visitantes Distingui-
dos’’. Financial support from MEC (grant CTQ2006-10930/
BQU) and CAM-UCM (Grupos de Investigaci ꢀo n, grant
1
1
2. For a review of the synthesis of substituted pyridines, see:
Henry, G. D. Tetrahedron 2004, 60, 6043.
3. For a review of the use of 1,3-dicarbonyl compounds in multi-
component reactions, including the Hantzsch reaction, see:
Simon, C.; Constantieux, T.; Rodr ꢀı guez, J. Eur. J. Org. Chem.
9
20234) is also gratefully acknowledged.
2
004, 4957.
Supplementary data
1
4. Microwave irradiation under solvent-free conditions allows the
preparation of some N-substituted 1,4-dihydropyridines by
Hantzsch chemistry. See: Kidwai, M.; Mohan, R. Can. J.
Chem. 2004, 82, 427; For a review of the synthesis and aroma-
tization of Hantzsch 1,4-dihydropyridines under microwave
irradiation, see: Vanden Eynde, J. J.; Mayence, A. Molecules
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.03.092.
References and notes
2
003, 8, 381.
1
. For selected reviews and monographs on multicomponent reac-
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2
(
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4
5
36, 10777.
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949.
7
24. Some reviews on cerium ammonium nitrate-promoted syn-
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8
9
. MDR reversal: (a) Avenda n˜ o, C.; Men ꢀe ndez, J. C. Curr. Med.
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25. Some other CAN-catalyzed reactions have been described
very recently. For selected examples, see: (a) Zeng, X.-F.;

V. Sridharan et al. / Tetrahedron 63 (2007) 4407–4413
4413
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2
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