Organocatalysed three-component domino synthesis of 1,4-dihydropyridines under solvent free conditions

Article abstract of DOI:10.1016/j.tet.2008.02.022

An organocatalysed protocol for one-pot synthesis of 1,4-dihydropyridines via three-component coupling of cinnamaldehyde, aniline and β-keto esters under solvent free conditions at ambient temperature is reported. The reaction is generally very fast and the products are obtained in high yield. The catalytic activity of small organic molecules like amino acids (acidic, basic and neutral), ephedrine and cinchona alkaloids was studied.

Full text of DOI:10.1016/j.tet.2008.02.022

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3477e3482
www.elsevier.com/locate/tet
Organocatalysed three-component domino synthesis of 1,4-
dihydropyridines under solvent free conditions
*
Atul Kumar , Ram Awatar Maurya
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 14 September 2007; received in revised form 21 January 2008; accepted 7 February 2008
Available online 9 February 2008
Abstract
An organocatalysed protocol for one-pot synthesis of 1,4-dihydropyridines via three-component coupling of cinnamaldehyde, aniline and b-
keto esters under solvent free conditions at ambient temperature is reported. The reaction is generally very fast and the products are obtained in
high yield. The catalytic activity of small organic molecules like amino acids (acidic, basic and neutral), ephedrine and cinchona alkaloids was
studied.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Organocatalyst; Multi-component; 1,4-Dihydropyridines; Domino synthesis; Solvent free
1. Introduction
dihydropyridyl compounds effective in the treatment of hyper-
tension. 1,4-Dihydropyridine derivatives possess a variety of
biological activities such as HIV protease inhibition,8,9 MDR
reversal,10e12 radioprotection,13 vasodilator,14 antitumour,
bronchodilator and hepatoprotective activity.15 These exam-
ples clearly indicate the remarkable potential of novel dihy-
dropyridine derivatives as a source of valuable drug candidate.
Due to the potential importance of 1,4-dihydropyridyl com-
pounds from a pharmaceutical, industrial and synthetic point
of view, various methods for their preparation has been repor-
ted.16e26 Hantzsch reaction is very useful in dihydropyridine
synthesis but N-substituted, 5-unsubstituted or 5,6-unsubsti-
tuted dihydropyridines cannot be synthesised by Hantzsch
reaction protocol. Ishar et al. have synthesised some N-aryl-
5,6-unsubstituted-1,4-dihydropyridines via a regioselective
[4þ2] cycloaddition of 1-aryl-4-phenyl-1-azadienes with al-
The rapid assembly of molecular diversity is an important
goal of synthetic organic chemistry and one of key paradigms
of modern drug discovery. One approach to address this chal-
lenge involves the use of multi-component reactions (MCRs),
in which three or more reactants are combined together in
a single reaction flask to generate a product incorporating
most of the atoms contained in the starting material. Due to in-
trinsic atom economy, selectivity underlying such reaction,
simpler procedure, equipment, time and energy saving as
well as environmental friendliness MCRs are gaining much
importance in both academia and industry.1e4
1,4-Dihydropyridines (1,4-DHPs) and their derivatives are
important class of bioactive molecules in the field of drug
and pharmaceuticals. These compounds are well known as cal-
cium channel modulators and have emerged as one of the most
important classes of drugs for the treatment of hypertension.5
Various clinically used cardiovascular agents6,7 such as nifed-
ipine, nicardipine, amlodipine and other related derivatives are
lenic esters.27 Recently, Menendez et al. synthesised 5,6-unsub-
´
stituted dihydropyridines28 but even using inert/anhydrous
conditions the products were isolated in moderate yields (61e
74%). Similar multi-component reactions for the synthesis of
substituted piperidines, dihydropyridones and tetrahydropyrans
were also recently reported.29,30
Nowadays there is an increasing awareness of urgent neces-
sity to limit, as far as possible, any source of pollution. Facing
* Corresponding author. Tel.: þ91 522 2612411; fax: þ91 522 2623405/938.
E-mail address: dratulsax@gmail.com (A. Kumar).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.022

3478
A. Kumar, R.A. Maurya / Tetrahedron 64 (2008) 3477e3482
Table 1
Screening of organocatalysts for coupling of aniline, cinnamaldehyde and
ethyl acetoacetatea
up to these facts, chemists have to dedicate numerous efforts
to the development of clean technologies. This new challenge
has led to a growing interest in the displacement of organic re-
action in aqueous media31e33 and solvent free conditions.34e40
The catalytic property of small organic molecules like cin-
chona alkaloids and amino acids is well known (aldol,41,42
Mannich,43,44 Michael,45,46 DielseAlder,47,48 a-amination re-
actions and Knoevenagel type reactions49,50). Small organic
molecules have been shown as quite promising and highly ef-
ficient organocatalysts for multi-component reactions.51e54
Recently, we reported an organocatalysed multi-component
reaction of an aldehyde, acetoacetate ester, cyclic 1,3-diketone
and ammonium acetate to form polyhydroquinoline deriva-
tives.55 Thus, we decided to use the organocatalysts for the
multi-component reaction of acetoacetate ester, cinnamalde-
hyde and anilines to yield N-aryl 5-unsubstituted or 5,6-unsub-
stituted 1,4-dihydropyridines (Scheme 1).
Entry
Organocatalyst
Catalyst
(mol %)
Reaction
time (h)
Yieldb
(%)
1
2
3
4
5
6
7
8
9
10
a
(ꢀ)-Cinchonidine
(ꢀ)-Ephedrine
L-Lysine
5a
5b
5c
5d
5e
5f
10
10
10
10
10
10
10
10
20
5
2
2
2
2
2
2
1
1
1
1
45
48
50
55
68
71
90
85
90
70
L-Histidine
L-Glutamic acid
L-Asparatic acid
L-Proline
5g
5h
5g
5g
L-Pipecolic acid
L-Proline
L-Proline
Reaction conditions: aniline (1 mmol), cinnamaldehyde (1 mmol), ethyl
acetoacetate (1 mmol), catalyst 5 (10 mol %), solvent free.
b
Isolated yield.
stepwise addition. We further tested the catalytic activity of
other amino acids and alkaloids.
R
Alkaloids like cinchonidine and ephedrine were found not
very good as the product 4a and were isolated in low yields
(45 and 48%). Basic amino acids like L-lysine and L-histidine
also resulted in poor conversion of 4a. Acidic amino acids
were found somewhat better but best results were obtained
with neutral amino acids like L-proline (90%) and L-pipecolic
acid (85%). Catalyst of 10 mol % was sufficient to push the
reaction forward and increasing the amount of catalyst did
not result to any significant improvement in the yield (entry 9,
Table 1). Reducing the amount of catalyst below 10 mol % re-
sulted in a lower yield (entry 10, Table 1). Thus, reactions
were carried out with 10 mol % of the catalyst. The results
of this study are shown in Table 1.
R
R1
R2
O
R6
NH2
O
R3
R4
R1
R2
Organocatalyst 5
R6
N
+
+
r.t. solvent free
1 hr
R3
O
CHO
1
R5
3
2
R4
R5
4
Scheme 1. Organocatalysed synthesis of 1,4-dihydropyridines.
2. Results and discussion
In order to study the solvent effect over the reaction and
comparison of efficiency of catalysts, we carried out the reac-
tions in different solvents. With 5g and 5h in less polar sol-
vents like CH2Cl2 and THF, poor yields were obtained. In
more polar solvents like methanol and ethanol better yields
were obtained. However, the best results were obtained with
5g under solvent free conditions. The results of this study
are shown in Table 2.
We were also interested to study the enantioselectivity of
the reaction. Unfortunately, in L-proline catalysed reactions,
poor enantioselectivity (<20%) was observed under solvent
free conditions, however, when the reaction was carried out
Initially, we tried this reaction with simple secondary
amines as catalyst but the reaction gave a complex mixture
and the desired product was isolated in low yield. Then we
screened a number of organocatalysts 5ae5h for efficient cou-
pling of anilines, b-keto esters and cinnamaldehydes. Amino
acids have the advantage of having both the amine (which
could catalyse the reaction via nucleophilic enamine forma-
tion) and carboxylic acid (which could catalyse the reaction
via protonation of substrate) functional groups. So we
screened acidic, basic and neutral amino acids to optimise
the reaction conditions. We also studied the catalytic activity
of ephedrine and cinchona alkaloids over the reaction. The re-
action of aniline, cinnamaldehyde and ethyl acetoacetate was
taken as model to optimise the reaction conditions and
catalyst.
In our initial experiments, aniline (1 mmol), cinnamalde-
hyde (1 mmol), and L-proline (10 mol %) were stirred for
20 min at room temperature under solvent free conditions.
Then ethyl acetoacetate (1 mmol) was added to it and further
stirred for 1 h. In the other experiment aniline, cinnamalde-
hyde, ethyl acetoacetate and L-proline were all added together
and the mixture was stirred for 1 h. In both cases 4a was iso-
lated in same yield (90%). Thus it was concluded that simul-
taneous addition of three components was equally well as
Table 2
Comparative study of solvent effect over organocatalysed reactiona
Entry
Solvent
Yield of 4ab (%)
L-Proline 5g
L-Pipecolic acid 5h
1
2
3
4
5
6
a
CH2Cl2
THF
38
46
60
75
78
90
32
40
58
74
75
85
CH3CN
MeOH
EtOH
None
Reaction conditions: aniline (1 mmol), cinnamaldehyde (1 mmol), ethyl
acetoacetate (1 mmol), catalyst 5g/5h (10 mol %), rt.
b
Isolated yield.

A. Kumar, R.A. Maurya / Tetrahedron 64 (2008) 3477e3482
3479
Table 3
Organocatalysed domino synthesis of 1,4-dihydropyridinesa
Entry
R
R1
R2
R3
R4
R5
R6
Product
Yieldb (%)
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OtBu
4a
4b
4c
4d
4e
4f
90
88
89
85
88
90
89
88
92
87
91
90
81
80
2
H
H
H
CH3
F
3
H
H
H
H
4
H
H
H
H
Cl
Br
H
5
H
H
H
H
6
H
NO2
H
H
H
7
H
H
H
H
4g
4h
4i
8
H
H
H
H
OCH3
H
9
H
H
CH3
H
H
10
11
12
13
14
a
OCH3
H
H
H
H
4j
H
CH3
CH3
H
H
H
4k
4l
H
H
CH3
H
H
H
H
H
Cl
4m
4n
H
H
H
H
OtBu
Reaction conditions: aniline (1 mmol), cinnamaldehyde (1 mmol), acetoacetate ester (1 mmol), L-proline (10 mol %), solvent free, rt.
Isolated yield.
b
in polar solvents like MeOH or EtOH, improved enantioselec-
tivities (40%) were observed.
catalysed 1,4-conjugate addition with acetoacetate ester fol-
lowed by cyclisationedehydration to give 4a; (b) initial for-
mation of enamine with acetoacetate ester and aniline,
which then undergoes a 1,4-conjugate addition with cinnamal-
dehyde followed by cyclisationedehydration to give 4a
(Scheme 2).
In order to study the generality of this procedure a number
of 1,4-dihydropyridines using 5g as catalyst under solvent free
conditions were synthesised. The reaction generally gave high
yields of products. The electron donating as well as electron
withdrawing groups in aniline are well tolerated.
We also attempted to carry out the reaction with aliphatic
primary amines. But the reaction was unsuccessful and gave
a complex mixture. Ethyl and methyl acetoacetate gave high
yields but in case tert-butyl acetoacetate yields were somewhat
lower. 4-Methoxy-cinnamaldehyde and 2-nitro-cinnamalde-
hyde both gave reasonably high yields of products. a-Methyl
cinnamaldehyde yielded better yields in comparison to cinna-
maldehyde. The results of this study are shown in Table 3.
In order to study the mechanism of the reaction, we carried
out the following two experiments. In the first experiment,
Schiff base 6a was prepared by stirring aniline, cinnamalde-
hyde and L-proline for 20 min. Then it was treated with ethyl
acetoacetate in the presence of L-proline. In another experi-
ment aniline and ethyl acetoacetate were heated at 100 ꢁC to
form an enamine 7a, which was then treated with cinnamalde-
hyde in the presence of L-proline (10 mol %) at rt. In the first
experiment 4a was isolated in 88% and in second experiment
in 69% yield. Thus, It appears that the reaction follows any or
both of the following possible pathways: (a) initial formation
of an a,b-unsaturated imine, which then undergoes proline
3. Conclusion
In conclusion, we have developed a high yielding reaction
protocol for the synthesis of a variety of 1,4-dihydropyridines
via organocatalysed three-component coupling of cinnamalde-
hyde, anilines and alkyl acetoacetates under solvent free con-
ditions. The reaction does not require the use of any volatile
organic solvents as well as harmful metal catalysts. Thus
this is an ecofriendly and environmentally friendly procedure
for the synthesis of N-substituted and 5-unsubstituted or 5,6-
unsubstituted 1,4-dihydropyridines.
4. Experimental
4.1. Materials and general
All the reactions were carried out at room temperature, that
is, 28e32 ꢁC. All the reagents were purchased from Sigma-Al-
drich Chemical Company and Lancaster. NMR spectra were
obtained using the Brucker DRX 200 and 300 MHz
OH
O
O
O
R
R
CHO
Ph
O
O
O
NPh
Ph
L-proline
L-proline
(a)
NHPh
Ph
Ph
6a
NH2
Ph
COOR
-H2O
O
O
Ph
N
Ph
4a
NH
CHO
L-proline
NH
O
R
Ph
O
R
O
CHO
R
O
L-proline
(b)
7a
Ph
Scheme 2. Proposed mechanism for organocatalysed coupling of aniline, cinnamaldehyde and ethyl acetoacetate.

3480
A. Kumar, R.A. Maurya / Tetrahedron 64 (2008) 3477e3482
spectrometer. Chemical shifts (d) are given in parts per million
relative to TMS, coupling constants (J) in hertz. Mass spectra
were obtained using JEOL SX-102 (ESI) instrument. IR spec-
tra were taken on VARIAN FT-IR spectrometer. Elemental
analysis was preformed using a Perkin Elmer Autosystem
XL Analyzer. All compounds isolated (4ae4n) were oily. Re-
actions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm silica gel plates visualised with UV
light.
7.24e7.33 (m, 4H, ArH). 13C NMR (50 MHz, CDCl3) d:
14.7, 19.0, 40.6, 59.9, 102.3, 108.0, 116.9 (d, J¼22.6 Hz),
126.6, 128.0, 128.8, 129.8 (d, J¼8.2 Hz), 129.9, 140.1 (d,
J¼3.8 Hz), 148.2, 148.8, 161.9 (d, J¼247.2 Hz), 169.1. Anal-
ysis calculated for C21H20FNO2: C, 74.76; H, 5.97; N, 4.15.
Found: C, 74.61; H, 5.82; N, 4.07.
4.3.4. 1-(4-Chlorophenyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid ethyl ester (4d)27
MS (ESI) m/z¼355 (MþH). IR (neat, cmꢀ1): 1693, 1568,
1
4.2. Typical experimental procedure for the synthesis
of 1,4-dihydropyridines (4)
1222. H NMR (CDCl3, 200 MHz) d: 1.18 (t, 3H, J¼7.1 Hz,
CH3), 2.19 (s, 3H, CH3), 4.07 (q, 2H, J¼7.1 Hz, OCH2),
4.73 (d, 1H, J¼5.4 Hz, CH), 5.07 (dd, 1H, J¼5.4 and
7.6 Hz, CH); 6.16 (d, 1H, J¼7.6 Hz, CH), 7.16e7.44 (m,
9H, ArH). 13C NMR (50 MHz, CDCl3) d: 14.6, 19.1, 40.6,
59.9, 102.9, 108.2, 126.7, 127.9, 128.8, 129.2, 129.5, 130.2,
133.4, 142.6, 147.7, 148.6, 169.1. Analysis calculated for
C21H20ClNO2: C, 71.28; H, 5.70; N, 3.96. Found: C, 71.11;
H, 5.85; N, 3.87.
Cinnamaldehyde (1 mmol), aniline (1 mmol), acetoacetate
ester (1 mmol) and L-proline (10 mol %) were taken in 25 ml
RB flask and stirred for 1 h. After completion the reaction mix-
ture was diluted with water and extracted with ethyl acetate. The
ethyl acetate layer was dried over anhydrous sodium sulfate and
concentrated to give a crude product, which after purification
from silica gel column chromatography yielded 4a (90%).
4.3.5. 1-(4-Bromophenyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid ethyl ester (4e)28
4.3. Analytical and spectral data
MS (ESI) m/z¼399 (MþH). IR (neat, cmꢀ1): 1691, 1565,
1
4.3.1. 2-Methyl-1,4-diphenyl-1,4-dihydro-pyridine-3-
carboxylic acid ethyl ester (4a)27
1221. H NMR (CDCl3, 200 MHz) d: 1.18 (t, 3H, J¼7.1 Hz,
CH3), 2.20 (s, 3H, CH3), 4.08 (q, 2H, J¼7.1 Hz, OCH2),
4.74 (d, 1H, J¼5.5 Hz, CH), 5.07 (dd, 1H, J¼5.5 and
7.6 Hz, CH); 6.17(d, 1H, J¼7.6 Hz, CH), 7.12 (d, 2H,
J¼8.1 Hz, ArH), 7.23e7.38 (m, 5H, ArH), 7.58 (d, 2H,
J¼8.1 Hz, ArH). 13C NMR (50 MHz, CDCl3) d: 4.7, 19.2,
40.6, 60.1, 103.0, 108.3, 121.3, 126.7, 128.0, 128.8, 29.5,
129.6, 135.2, 143.1, 147.6, 148.6, 169.0. Analysis calculated
for C21H20BrNO2: C, 63.33; H, 5.06; N, 3.52. Found: C,
63.22; H, 5.05; N, 3.37.
MS (ESI) m/z¼320 (MþH). IR (neat, cmꢀ1): 1691, 1568,
1
1221. H NMR (CDCl3, 200 MHz) d: 1.19 (t, 3H, J¼7.1 Hz,
CH3), 2.21 (s, 3H, CH3), 4.08 (q, 2H, J¼7.1 Hz, OCH2),
4.75 (d, 1H, J¼5.5 Hz, CH), 5.07 (dd, 1H, J¼5.5 and
7.6 Hz, CH), 6.23 (d, 1H, J¼7.6 Hz, CH), 7.24e7.47 (m,
10H, ArH). 13C NMR (50 MHz, CDCl3) d: 14.7, 19.2, 40.6,
59.9, 102.1, 107.9, 126.6, 127.8, 127.9, 128.0, 128.8, 129.9,
130.0, 144.1, 148.4, 148.9, 169.2. Analysis calculated for
C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.82; H,
6.50; N, 4.27.
4.3.6. 2-Methyl-4-(2-nitrophenyl)-1-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid ethyl ester (4f)28
4.3.2. 2-Methyl-4-phenyl-1-(4-methylphenyl)-1,4-dihydro-
pyridine-3-carboxylic acid ethyl ester (4b)27
MS (ESI) m/z¼365 (MþH). IR (neat, cmꢀ1): 1694, 1568,
1
1524, 1355, 1222. H NMR (200 MHz, CDCl3) d: 0.95 (t,
MS (ESI) m/z¼334 (MþH). IR (neat, cmꢀ1): 1691, 1568,
3H, J¼7.1 Hz, CH3), 2.24 (s, 3H, CH3), 3.90 (q, 2H,
J¼7.1 Hz, OCH2), 5.21e5.25 (m, 2H, CH), 6.14e6.16 (m,
1H, CH), 7.22e7.50 (m, 6H, ArH), 7.62e7.65 (m, 1H,
ArH), 7.75 (dd, 2H, J¼8.1 and 1.5 Hz, ArH). 13C NMR
(50 MHz, CDCl3) d: 14.3, 19.0, 36.6, 59.9, 100.6, 106.6,
123.6, 127.1, 128.0, 128.1, 130.1, 130.4, 131.6, 133.6,
143.7, 143.8, 148.2, 150.3, 168.3. Analysis calculated for
C21H20N2O4: C, 69.22; H, 5.53; N, 7.69. Found: C, 69.17;
H, 5.40; N, 7.54.
1
1222. H NMR (CDCl3, 200 MHz) d: 1.19 (t, 3H, J¼7.1 Hz,
CH3), 2.21 (s, 3H, CH3), 2.43 (s, 3H, CH3), 4.08 (q, 2H,
J¼7.1 Hz, OCH2), 4.75 (d, 1H, J¼5.4 Hz, CH), 5.05 (dd,
1H, J¼5.4 and 7.6 Hz, CH), 6.19 (d, 1H, J¼7.6 Hz, CH),
7.14 (d, 2H, J¼8.2 Hz, ArH), 7.25e7.44 (m, 7H, ArH). 13C
NMR (50 MHz, CDCl3) d: 14.6, 19.1, 23.1, 40.7, 59.8,
101.7, 107.7, 126.6, 127.8, 128.0, 128.7, 130.0, 130.6,
137.7, 141.5, 148.7, 149.1, 169.3. Analysis calculated for
C22H23NO2: C, 79.25; H, 6.95; N, 4.20. Found: C, 79.12; H,
6.80; N, 4.27.
4.3.7. 2-Methyl-1,4-diphenyl-1,4-dihydro-pyridine-3-
carboxylic acid methyl ester (4g)
4.3.3. 1-(4-Fluorophenyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid ethyl ester (4c)27
MS (ESI) m/z¼306 (MþH). IR (neat, cmꢀ1): 3062, 2943,
1
1688, 1570, 1225. H NMR (CDCl3, 200 MHz) d: 2.07 (s,
MS (ESI) m/z¼338 (MþH). IR (neat, cmꢀ1): 1693, 1569,
3H, CH3), 3.50 (s, 3H, OCH3), 4.58 (d, J¼5.6 Hz, 1H, CH),
4.61 (dd, J¼5.6 and 7.6 Hz, 1H, CH), 6.08 (d, J¼7.8 Hz,
1H, CH), 7.07e7.37 (m, 10H, ArH). 13C NMR (CDCl3,
50 MHz) d: 19.1, 40.4, 51.1, 101.8, 107.8, 126.5, 126.9,
127.4, 127.7, 127.9, 128.1, 128.2, 128.9, 129.0, 129.5,
1
1216. H NMR (CDCl3, 200 MHz) d: 1.19 (t, 3H, J¼7.1 Hz,
CH3), 2.20 (s, 3H, CH3), 4.09 (q, 2H, J¼7.1 Hz, OCH2),
4.75 (d, 1H, J¼5.4 Hz, CH), 5.06 (dd, 1H, J¼5.4, 7.6 Hz,
CH), 6.14 (d, 1H, J¼7.6 Hz, CH), 7.11e7.20 (m, 5H, ArH),

A. Kumar, R.A. Maurya / Tetrahedron 64 (2008) 3477e3482
3481
1
129.9, 144.0, 148.6, 148.7, 169.6. Analysis calculated for
C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.60; H,
6.22; N, 4.48.
(MþH). IR (neat, cmꢀ1): 2938, 1690, 1566, 1385, 1231. H
NMR (CDCl3, 300 MHz) d: 1.58 (s, 3H, CH3), 2.09 (s, 3H,
CH3), 2.19 and 2.25 (2s, 4la and 4lb, 3H, CH3), 2.36 (s, 3H,
CH3), 3.60 and 3.61 (2s, 4la and 4lb, 3H, OCH3), 4.52 and
4.61 (2s, 4la and 4lb, 1H, CH), 5.78 and 5.87 (2d,
J¼1.0 Hz, 4la and 4lb, 1H, CH), 7.00e7.57 (m, 8H, ArH).
13C NMR (CDCl3, 75 MHz) d: 12.8, 12.9, 16.1, 16.3, 17.2,
17.3, 19.1, 19.2, 44.3, 44.5, 49.2, 97.3, 97.4, 98.7, 113.6,
114.2, 123.3, 123.9, 124.7, 124.8, 124.9, 125.1, 125.2,
125.3, 126.5, 126.7, 126.8, 127.4, 128.1, 128.2, 128.3,
133.8, 133.9, 134.0, 137.1, 137.5, 137.6, 141.1, 141.5,
145.6, 145.9, 146.9, 147.0, 148.5, 168.1, 168.2. Analysis cal-
culated for C23H25NO2: C, 79.51; H, 7.25; N, 4.03. Found: C,
79.42; H, 7.16; N, 3.97.
4.3.8. 1-(4-Methoxy-phenyl)-2,5-dimethyl-4-phenyl-1,4-
dihydro-pyridine-3-carboxylic acid methyl ester (4h)
MS (ESI) m/z¼350 (MþH). IR (neat, cmꢀ1): 2947, 1690,
1
1567, 1508, 1439. H NMR (CDCl3, 300 MHz) d: 1.59 (s,
3H, CH3), 2.18 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 3.84 (s,
3H, OCH3), 4.51 (s, 1H, CH), 6.00 (d, J¼1.3 Hz, 1H, CH),
6.94e6.99 (m, 2H, ArH), 7.13e7.42 (m, 7H, ArH). 13C
NMR (CDCl3, 75 MHz) d: 12.8, 12.9, 44.0, 48.8, 54.2, 98.6,
113.4, 114.1, 124.4, 124.5, 124.9, 126.4, 126.6, 126.7,
126.8, 127.5, 127.6, 127.7, 135.4, 145.6, 146.8, 157.3,
168.0. Analysis calculated for C22H23NO3: C, 75.62; H,
6.63; N, 4.01. Found: C, 76.54; H, 6.57; N, 3.98.
4.3.13. 2-Methyl-1,4-diphenyl-1,4-dihydro-pyridine-3-
carboxylic acid tert-butyl ester (4m)28
MS (ESI) m/z¼348 (MþH). IR (neat, cmꢀ1): 2956, 1690,
1571, 1235. 1H NMR (200 MHz, CDCl3) d: 1.34 (s, 9H,
3CH3), 2.16 (s, 3H, CH3), 4.71 (d, 1H, J¼5.1 Hz, CH), 5.00
(dd, 1H, J¼5.1 and 7.7 Hz, CH), 6.16 (d, 1H, J¼7.7 Hz,
CH), 7.22e7.47 (m, 10H, ArH). 13C NMR (50 MHz,
CDCl3) d: 19.1, 28.6, 41.3, 79.6, 103.7, 107.6, 126.5, 127.6,
128.0, 128.7, 129.7, 129.9, 144.2, 147.2, 149.2, 168.0. Analy-
sis calculated for C23H25NO2: C, 79.51; H, 7.25; N, 4.03.
Found: C, 79.40; H, 7.12; N, 3.90.
4.3.9. 2,5-Dimethyl-1,4-diphenyl-1,4-dihydro-pyridine-3-
carboxylic acid methyl ester (4i)
MS (ESI): m/z¼320 (MþH). IR (neat, cmꢀ1): 2945, 1690,
1
1
1567, 1493, 1382, 1226. H NMR (CDCl3, 300 MHz) d: H
NMR (CDCl3, 200 MHz) d: 1.48 (s, 3H, CH3), 2.06 (s, 3H,
CH3), 3.50 (s, 3H, OCH3), 4.39 (s, 1H, CH), 5.96 (d,
J¼1.3 Hz, 1H, CH), 7.09e7.37 (m, 10H, ArH). 13C NMR
(CDCl3, 50 MHz) d: 17.3, 17.4, 44.5, 50.5, 99.7, 114.7,
124.4, 125.1, 126.1, 126.5, 126.7, 127.1, 128.5, 142.7,
145.6, 146.5, 168.2. Analysis calculated for C21H21NO2: C,
78.97; H, 6.63; N, 4.39. Found: C, 78.82; H, 6.58; N, 4.31.
4.3.14. 1-(4-Chlorophenyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid tert-butyl ester (4n)28
4.3.10. 4-(4-Methoxy-phenyl)-2-methyl-1-phenyl-1,4-
dihydro-pyridine-3-carboxylic acid methyl ester (4j)
MS (ESI) m/z¼382 (MþH). IR (neat, cmꢀ1): 2966, 1691,
1570, 1236. 1H NMR (200 MHz, CDCl3) d: 1.33 (s, 9H,
3CH3), 2.14 (s, 3H, CH3), 4.69 (d, 1H, J¼5.1 Hz, CH), 4.99
(dd, 1H, J¼5.1 and 7.7 Hz, CH), 6.10 (d, 1H, J¼7.7 Hz,
CH), 7.14e7.41 (m, 9H, ArH). 13C NMR (50 MHz, CDCl3)
d: 19.1, 28.6, 41.3, 79.7, 104.5, 108.0, 126.6, 127.9, 128.8,
129.2, 129.3, 130.1, 133.2, 142.8, 146.5, 148.9, 168.6. Analy-
sis calculated for C23H24ClNO2: C, 72.34; H, 6.33; N, 3.67.
Found: C, 72.41; H, 6.23; N, 3.51.
MS (ESI) m/z¼336 (MþH). IR (neat, cmꢀ1): 2946, 1692,
1595, 1236. 1H NMR (CDCl3, 200 MHz) d: 2.15 (s, 3H,
CH3), 3.45 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.96e5.05
(m, 2H, CH), 5.91 (d, J¼7.4 Hz, 1H, CH), 6.77e6.86 (m,
2H, ArH), 7.07e7.31(m, 7H, ArH). 13C NMR (CDCl3,
50 MHz) d: 19.0, 33.9, 51.0, 55.7, 107.6, 110.7, 121.2,
121.4, 127.2, 127.5, 128.0, 128.3, 129.5, 129.8, 156.0,
168.0. Analysis calculated for C21H21NO3: C, 75.20; H,
6.31; N, 4.18. Found: C, 75.02; H, 6.18; N, 4.11.
Acknowledgements
4.3.11. 1-(3-Chloro-phenyl)-2,5-dimethyl-4-phenyl-1,4-
dihydro-pyridine-3-carboxylic acid methyl ester (4k)
MS (ESI) m/z¼354 (MþH). IR (neat, cmꢀ1): 2943, 1694,
R.A.M. is thankful to CSIR, New Delhi for the award of
a SRF. Authors also acknowledge SAIF-CDRI for providing
spectral and analytical data.
1
1577, 1478, 1227. H NMR (CDCl3, 200 MHz) d: 1.56 (s,
3H, CH3), 2.15 (s, 3H, CH3), 3.59 (s, 3H, OCH3), 4.46 (s,
1H, CH), 6.03 (d, J¼1.3 Hz, 1H, CH), 7.08e7.37 (m, 9H,
ArH). 13C NMR (CDCl3, 50 MHz) d: 18.7, 18.9, 45.9, 51.1,
102.3, 116.6, 125.4, 126.1, 126.7, 127.8, 128.1, 128.6,
130.8, 135.4, 145.3, 146.7, 147.1, 169.4. Analysis calculated
for C21H20ClNO2: C, 71.28; H, 5.70; N, 3.96. Found: C,
71.12; H, 5.60; N, 3.87.
References and notes
1. Ramon, D. J.; Miguel, Y. Angew. Chem., Int. Ed. 2005, 44, 1602.
2. Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
3. Ugi, I.; Heck, S. Comb. Chem. High Throughput Screening 2001, 4, 1.
4. Weber, L.; IIIgen, K.; Almstetter, M. Synlett 1999, 366.
5. Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; Dimarco, J. D.;
Gougoutas, J.; Hedberg, A.; Malley, M.; MaCarthy, J. P.; Zhang, R.;
Mereland, S. J. Med. Chem. 1995, 38, 119.
4.3.12. 1-(2,3-Dimethyl-phenyl)-2,5-dimethyl-4-phenyl-1,4-
dihydro-pyridine-3-carboxylic acid methyl ester (4l)
6. Kappe, C. O.; Fabian, W. M. F.; Semones, M. A. Tetrahedron 1997, 53,
2803.
The compound was isolated as 1.13:1 rotamer mixture (4la
major rotamer, 4lb minor rotamer). MS (ESI) m/z¼348
7. Aouam, K.; Berdeaux, A. Therapie 2003, 58, 333.
8. Hilgeroth, A. Mini-Rev. Med. Chem. 2002, 2, 235.

3482
A. Kumar, R.A. Maurya / Tetrahedron 64 (2008) 3477e3482
9. Hilgeroth, A.; Lilie, H. Eur. J. Med. Chem. 2003, 38, 495.
10. Avendano, C.; Menendez, J. C. Curr. Med. Chem. 2002, 9, 159.
11. Avendano, C.; Menendez, J. C. Med. Chem. Rev. Online 2004, 1, 419.
12. Boumendjel, A.; Baubichon-Cortay, H.; Trompier, D.; Perrotton, T.; Di
Pietro, A. Med. Res. Rev. 2005, 25, 453.
31. Li, C.-J.; Chan, T.-H. Organic Reaction in Aqueous Media; John Wiley
and Sons: New York, NY, 1997.
32. Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic and
Professional: London, 1998.
33. Lindstrom, U. M. Chem. Rev. 2002, 102, 2751.
34. Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209.
35. Wang, Z.-X.; Qin, H.-L. Green Chem. 2004, 6, 90.
36. Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001,
2159.
13. Donkor, I. O.; Zhou, X.; Schmidt, J.; Agrawal, K. C.; Kishore, V. Bioorg.
Med. Chem. 1998, 6, 563.
14. Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Mereland, S.;
Hedberg, A.; O’Reilly, B. C. J. Med. Chem. 1991, 34, 806.
15. Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Mereland, S.;
Swanson, B. N.; Gougoutas, D. Z.; Schwartz, J.; Smillie, K. M.; Malley,
M. F. J. Med. Chem. 1990, 33, 2629.
37. Raston, C. L.; Scott, J. L. Green Chem. 2000, 2, 49.
38. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983.
39. Tanaka, K.; Sugino, T.; Toda, F. Green Chem. 2000, 2, 303.
40. Yoshizawa, K.; Toyota, S.; Toda, F. Green Chem. 2002, 4, 68.
41. Rasalkar, M. S.; Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. J. Mol.
Catal. A: Chem. 2005, 235, 267.
16. Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. J. Org. Chem.
1989, 54, 5898.
17. Snider, B. B.; Chen, J.; Patil, A. D.; Freyer, A. J. Tetrahedron Lett. 1996,
37, 6977.
18. Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.;
Brosse, C. D.; Mai, S.; Truneh, A.; Faulkner, D. J.; Carte, B.; Breen,
A. L.; Hertzberg, R. P.; Johnson, R. K.; Westley, J. W.; Potts, B. C. M.
J. Org. Chem. 1995, 60, 1182.
42. Alcaide, B.; Almendros, P.; Luna, A.; Torres, M. S. J. Org. Chem. 2006,
71, 4818.
43. Bogevig, A.; Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Jorgensen,
K. A. Angew. Chem., Int. Ed. 2002, 41, 1790.
44. Janey, J. M.; Hsiano, Y.; Armstrong, J. D., III. J. Org. Chem. 2006, 71,
390.
19. Barluenga, J.; Tomas, M.; Ballesteros, A.; Lopez, L. A. Tetrahedron Lett.
1989, 30, 4573.
45. Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.; Jorgensen,
K. A. J. Am. Chem. Soc. 2002, 124, 827.
46. Kotrusz, P.; Toma, S. Molecules 2006, 11, 197.
47. Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem.
2003, 115, 4365.
20. O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185.
21. Maiti, G.; Kundu, P.; Guin, C. Tetrahedron Lett. 2003, 44, 2757.
22. Su, W.; Li, J.; Zheng, Z.; Shen, Y. Tetrahedron Lett. 2005, 46, 6037.
23. Lu, J.; Ma, H. Synlett 2000, 63.
24. Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63, 3454.
25. Reddy, K. R.; Reddy, C. V.; Mahesh, M.; Raju, P. V. K.; Reddy, V. V. N.
Tetrahedron Lett. 2003, 44, 8173.
48. Kotrusz, P.; Toma, S. ARKIVOC 2006, 100.
49. Hossein, A. O.; Elham, R.; Majid, M. H. J. Chem. Res. 2006, 246.
50. Chandrasekhar, S.; Reddy, N. S.; Sultana, S. S.; Narsihmulu, C.; Reddy,
K. V. Tetrahedron 2006, 62, 338.
51. Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732.
52. Poulsen, T. B.; Bernardy, L.; Bell, M.; Jorgensen, K. A. Angew. Chem.,
Int. Ed. 2006, 45, 1.
26. Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B. Synlett 2001, 863.
27. Ishar, M. P. S.; Kumar, K.; Kaur, S.; Kumar, S.; Girdhar, N. K.; Sachar, S.;
Marwaha, A.; Kapoor, A. Org. Lett. 2001, 3, 2133.
28. Sridharan, V.; Perumal, P. T.; Avendano, C.; Menendez, J. C. Tetrahedron
2007, 63, 4407.
29. Devi, N. S.; Perumal, S. Tetrahedron Lett. 2007, 48, 5627.
30. Clarke, P. A.; Zaytzev, A. V.; Whitwood, A. C. Tetrahedron Lett. 2007, 48,
5209.
53. Yadav, J. S.; Kumar, S. P.; Kondaji, G.; Rao, R. S.; Nagaiah, K. Chem.
Lett. 2004, 33, 1168.
54. Mabry, J.; Ganem, B. Tetrahedron Lett. 2006, 47, 55.
55. Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946.