Novel synthetic route to 1,4-dihydropyridines from β-amino acrylates by using titanium(IV) chloride under facile conditions

Article abstract of DOI:10.1016/j.tet.2010.04.102

The reactions of Boc-β-amido- and β-amino acrylates, in which the C=C possesses both nucleophilic and electrophilic sites, were investigated under acidic conditions. The trifluoroacetic-acid induced cyclization of the β-amido acrylates to the corresponding oxazolidin-2-ones involves a rarely seen nucleophilic attack of the carbamate carbonyl group. The cyclotrimerization of 13-amino acrylates to N-substituted 1,4- dihydropyridines was observed in the presence of a Lewis acid. High yields of 1,4-dihydropyridines (7083%) were readily obtained by using substoichiometric amount TiCl₄ under mild condition. The cyclotrimerization is presumably occurring via a Hantzsch related mechanism involving three addition/ elimination reactions of the amphiphilically reactive C=C.

Full text of DOI:10.1016/j.tet.2010.04.102

Tetrahedron 66 (2010) 5161e5167
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel synthetic route to 1,4-dihydropyridines from
titanium(IV) chloride under facile conditions
b-amino acrylates by using
Thirawat Sirijindalert a, Kunlayanee Hansuthirakul b, Paitoon Rashatasakhon a,
,
Mongkol Sukwattanasinitt a, Anawat Ajavakom a
*
a Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
b Petrochemistry and Polymer Science, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of Boc-b-amido- and b-amino acrylates, in which the C]C possesses both nucleophilic and
Received 6 January 2010
Received in revised form 9 April 2010
Accepted 26 April 2010
electrophilic sites, were investigated under acidic conditions. The trifluoroacetic-acid induced cyclization
of the -amido acrylates to the corresponding oxazolidin-2-ones involves a rarely seen nucleophilic
attack of the carbamate carbonyl group. The cyclotrimerization of -amino acrylates to N-substituted 1,4-
dihydropyridines was observed in the presence of a Lewis acid. High yields of 1,4-dihydropyridines
(70e83%) were readily obtained by using substoichiometric amount TiCl4 under mild condition. The
cyclotrimerization is presumably occurring via a Hantzsch related mechanism involving three addition/
elimination reactions of the amphiphilically reactive C]C.
b
b
Available online 25 May 2010
Keywords:
Beta-Amino acrylate
1,4-Dihydropyridine
Oxazolidin-2-one
Titanium(IV) chloride
Acid-induced cyclization
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Enamines are often used as important intermediates for CeC
bond formation in total synthesis of many natural products and
drug candidates.1e6 Due to their high reactivity, they are rarely
isolated and often generated in situ. One of the most classic ex-
amples of enamine reaction is the Mannich reaction in which the
enamines are generated from carbonyl compounds and amines.7
Enamines can be used for the cyclization to allow an efficient
synthesis of various vital building blocks in natural products, such
as pyrrole.8 In most cases, enamines are utilized as nucleophiles
due to the electron donating nature of the nitrogen lone pair
electrons. Incorporation of an electron-withdrawing group on the
other terminus can lead to interesting amphiphilic reactivity of the
enamine. In order to gain a better understanding for designing the
amphiphilic synthons, the preparation of isolable enamines is es-
sential that should lead to greater application of this class of
In order to synthesize
lates 2, the experiments were easily undertaken following Mac-
donald’s method (Scheme 1).9
-Amino acrylates were
synthesized by addition reaction of a primary amine to alkyl pro-
piolate in CH2Cl2 at 0 ꢀC. The products were simply obtained by
solvent evaporation in excellent yields and purities as witnessed by
1H NMR spectroscopy. However, the products existed as a mixture
of cis and trans isomers. We initially protected the amino group
b-amino acrylates 1 and b-amido acry-
b
1
with tert-butoxycarbonyl (Boc) group to obtain the more stable b-
amido acrylates 2 in fair to good yields. It should be noted that the
cis enamine was observed by 1H NMR as the major adduct from the
first step, probably due to the preferred intramolecular hydrogen
bonding between the carbonyl oxygen and the amino proton.10
However, only the trans isomer of the Boc-protected product was
RO
RO
RO
RO
HC CCO2R'
CH2Cl2, 0 o
compounds. In this work, we synthesized and isolated
b-amino
H
N
NH2
acrylates, which are the enamines bearing an electron-withdraw-
ing group that possess both nucleophilic and electrophilic sites. Our
study of these enamines lead to novel synthetic methods for oxa-
zolidinones and 1,4-dihydropyridines.
CO2R'
C
1
O
Ot-Bu
1a, 2a (R = Me, R' = Me)
1b, 2b (R = Me, R' = Et)
1c, 2c (R = Et, R' = Me)
1d, 2d (R = Et, R' = Et)
RO
RO
(Boc)2O
N
Et3N, DMAP
CO2R'
(35 - 70%
2
in 2 steps)
* Corresponding author. Tel.: þ66 22187623; fax: þ66 22187598; e-mail address:
Scheme 1. Synthesis of substrates 1 and 2.
anawat77@hotmail.com (A. Ajavakom).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.102

5162
T. Sirijindalert et al. / Tetrahedron 66 (2010) 5161e5167
Table 2
isolated from the second step, indicating the geometrical isomeri-
zation to the less sterically strained form under the reaction
condition.
Optimization for 1,4-dihydropyridine 6 formation
OMe
OMe
Treatment of 2 with trifluoroacetic acid (TFA) in CH2Cl2 gave rise
to oxazolidin-2-one 3 in high yields (Scheme 2) without the simple
Boc protecting group. Apparently, Boc-enamide 2 underwent a 5-
exo-trig cyclization, presumably via the attack of the carbamate
carbonyl oxygen to the oxonium carbon to form an oxazolidinone
ring. A similar cyclization involving Au-catalyzed nucleophilic at-
tack onto an activated alkyne has recently been reported.11
N
MeO
H
Lewis acid
N
MeO
CO2Et
EtO2C
CO2Et
CO2Et
0 °C to rt
1b
6
Entry
Acid
Amount (equiv)
Solvent
Time
1b (%)
6 (%)
1
2
3
4
BF3OEt2
AlCl3
Me2AlCl
TiCl4
0.3
0.3
0.5
0.2
THF
THF
THF
DCM
10 h
3 h
10 h
10 h
d
d
98
d
17
<10
d
O
OtBu
O
RO
2 eq. TFA
33
O
N
CO2R'
N
CH2Cl2,
CO2R'
reflux 2 h
RO
RO
2
3
3a
3b
3c
3d
(R=Me, R'=Me, 94%)
(R=Me, R'=Et, 81%)
(R=Et, R'=Me, 97%)
(R=Et, R'=Et, 99%)
A number of related b-amino acrylates (7) without acetal moiety
were prepared and used as the cyclization substrates. According to
the yields presented in Table 2, TiCl4 was selected for reaction op-
timization on these b-amino acrylate substrates. Treatment of b-
amino acrylates 7 with a substoichiometric amount of TiCl4 resul-
ted in the formation of dyhydropyridine 8 containing various N-
Scheme 2. TFA-induced intramolecular cyclization of 2.
To demonstrate the generality of the cyclization, the reactionwas
further investigated using related Boc-protected secondary amines.
The treatment of 4 with TFA cleanly produced oxazolidin-2-ones 5
in high yields (Table 1) comparable to other methods starting from
amino alcohols12, aziridines13 or epoxides14 precursors.
substituents in excellent yield (Table 3). In the case of N-aromatic b-
amino acrylates (entries 5e11), the higher amount of TiCl4 is re-
quired for the high percent yield (compare entries 7 to 6 and 9 to 8).
Although the synthesis of 1,4-dihydropyridines can be previously
achieved by several methods such as Michael condensation,17 re-
duction of pyridines18 and others,19 harsh conditions are generally
required and low yields are often obtained due to the competitive
formation of 1,2-regioisomer. The high yields and mild condition of
this Lewis acid-induced cyclization of enamines can thus be an
attractive alternative method for 1,4-dihydropyridine synthesis.
Table 1
Cyclization yields of 4 to oxazolidin-2-one 5
Table 3
Syntheses of a series of 1,4-dihydropyridine derivatives 8 at 0 ꢀC to room temper-
ature for overnight
Entry
Substrate
R0
Product
Yield (%)
1
2
3
4
2b
4a
4b
4c
CH]CHCO2Et
Bn
4-Nitrobenzyl
Naphthalenyl methyl
3b
5a
5b
5c
81 (95)a
84
92
84
a
Yield obtained from GC.
In the formation of oxazolidinone ring, the C]C in enamides 2
did not participate in the cyclization neither did it decompose under
the strongly acidic TFA treatment. The relatively unreactive C]C is
attributed to the presence of the electron-withdrawing Boc group.
Entry
Substrate
R
Amount (equiv)
Product
Yield (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
n-Bu
n-C18H37
Bn
HOCH2CH2
Ph
p-MeOePh
0.2
0.2
0.2
0.2
0.5
0.2
0.5
0.2
0.5
0.5
0.5
8a
8b
8c
8d
8e
8f
81
83
79
81
82
52
76
58
79
70
76
We thus turned our attention back to the unprotected b-amino ac-
rylates 1, which contain both nucleophilic and electrophilic sites on
their double bond. As the utilization of enamine intermediates are
usually performed under basic conditions due to their unstability,15
8f
7g
p-IePh
8g
8g
8h
8i
9
10
11
it would be of general interest to examine if the C]C in
acrylates can take part in any cyclization under acidic conditions.
Unfortunately, the initial attempt to isolate -amino acrylate 1 was
b-amino
7h
7i
p-FePh
m-ClePh
b
not successful due to its decomposition on a silica gel column.
However, with preelution of the silica gel with 1% triethylamine
(Et3N) in hexane,
b
-amino acrylate 1 could be isolated and found to
A few modified Hantzsch reactions using Lewis acid have re-
cently been reported. Vohra et al. reported the Lewis acid-catalyzed
synthesis of dihydropyridines from the condensation of enamines
be reasonably stable at room temperature for a week. By treating 1b
with TFA in CH2Cl2 at 0 ꢀC or at reflux failed to give any character-
izable products. When Lewis acids, such as BF3$OEt2, AlCl3, and TiCl4
were used in place of TFA,1,4-dihydropyridine 6 was obtained in low
yields while the use of AlMe2Cl gave no reaction (Table 2). Although
the formation of 1,4-dihydropyridine observed here is closely re-
lated to Hantzsch reaction,16 the reaction was noted to proceed at
a significantly lower temperature. However, the product yields
obtained from these initial results are not satisfactory, which is
and a,b
-unsaturated aldehydes.20 Kikuchi et al. have noted a for-
mation of 1,4-dihydropyridine derivatives from the reaction be-
tween aniline and ethyl propiolate in the presence of Sc(OTf)3.21 We
believe that this reaction should also proceed through the enamine
intermediate similar to our observation.
We also isolated dimer 9 (R¼Ph) as a minor product during
condition optimization suggesting that the cyclotrimerization oc-
curs via the formation of a dimeric intermediate according to the
proposed mechanism shown in Scheme 3.
likely due to the decomposition of the acetal group in b-amino ac-
rylate 1b under the acidic conditions.

T. Sirijindalert et al. / Tetrahedron 66 (2010) 5161e5167
5163
were dried and distilled according to standard procedures. Re-
actions progress and purity of compounds were monitored by thin
layer chromatography using silica plates (Merck F245). Silica gel 60
(SiO2, Merck 70e230 mesh ASTM, no. 7734) was used for flash
column chromatography.
H
N
H
N
O
O
R
L.A.
1st Michael
addition
R
RHN
L.A.
OEt
H
OEt
N
CO2Et
R
CO2Et
H
R
HN
- NH2R
CO2Et
RHN
4.2. Preparation of 5-alkoxy-2-oxazolidinones (3)
RHN
RHN
2
nd Michael
addition
9
EtO2C
CO2Et
OEt
L.A.
To the solution of enamide 2 (1 equiv) in CH2Cl2 (14 mM), TFA
(2 equiv) was slowly added and the reaction mixture was refluxed
for 5 h. The mixture was quenched by 0.2 M NaHCO3 (20 mL). The
aqueous layer was extracted with CH2Cl2 (3ꢂ20 mL). The collected
organic extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. The crude oil was purified by flash chromatography, eluting
with EtOAc/petroleum ether (1:7 to 1:3 v/v), to provide the corre-
sponding oxaolidin-2-one 3.
H
O
OEt
CO2Et
O
L.A.
R
N
R
N
H
RHN
EtO
O
cyclisation
- NH2R
CO2Et
EtO2C
CO2Et
L.A. CO2Et
CO2Et
8
4.2.1. (E)-Methyl-3-(5-methoxy-2-oxooxazolidin-3-yl)acrylate (3a).
Synthesized according to above procedure 4.2 from enamide 2a
(300 mg, 0.31 mmol) as a yellow oil (293 mg, 94%); Rf (25% EtOAc/
hexane) 0.05; dH (400 MHz, CDCl3): 7.93 (1H, d, J 14.2 Hz, NCH]
CH), 5.55 (1H, dd, J 2.4, 6.4 Hz, CHOMe), 5.14 (1H, d, J 14.1 Hz, NCH]
CH), 3.84 (1H, dd, J 6.4, 10.7 Hz, NCHAHBCH), 3.74 (3H, s, CO2Me),
3.57 (3H, s, OMe), 3.52 (1H, dd, J 2.4, 10.7 Hz, NCHAHBCH); dH
(100 MHz, CDCl3): 166.8, 153.1, 137.8, 100.3, 98.9, 56.9, 51.5, 48.8;
HRMS (ESI): MHþ, found 224.0529. C8H11NNaOþ5 requires 224.0529.
Scheme 3. Purposed mechanism of 1,4-dihydropyridine 8 formation.
The reaction presumably started with Lewis acid-catalyzed
Michael addition followed by amine elimination to give the dimer.
Owing to the amphiphilic reactivities of the C]C in the b-amino
acrylate, one C]C can play a role of nucleophile while another
plays an electrophilic role in the addition step. The dimer un-
dergoes the second addition/elimination series to form the trimer.
The final intramolecular addition/elimination results in the dihy-
dropyridine 8. In total, the dihydropyridine ring is derived from
4.2.2. (E)-Ethyl-3-(5-methoxy-2-oxooxazolidin-3-yl)acrylate (3b).
Synthesized according to above procedure 4.2 from enamide 2b
(98 mg, 0.32 mmol) as a yellow oil (58 mg, 81%); Rf (25% EtOAc/
hexane) 0.08; dH (400 MHz, CDCl3): 7.93 (1H, d, J 14.2 Hz, NCH]
CH), 5.55 (1H, dd, J 2.5, 6.4 Hz, CHOMe), 5.13 (1H, d, J 14.1 Hz, NCH]
CH), 4.20 (2H, q, CO2CH2), 3.84 (1H, dd, J 6.4, 10.6 Hz, NCHAHBCH),
3.57 (3H, s, OMe), 3.53 (1H, dd, J 2.5, 10.6 Hz, NCHAHBCH), 1.26 (3H,
t, J 7.1 Hz CH2CH3); dC (100 MHz, CDCl3): 166.9, 153.2, 137.9, 100.2,
97.8, 65.7, 51.2, 48.9, 14.8; Elem. Anal. Found C, 50.44%; H, 6.12%; N,
6.51% (calcd for C9H13NO5; C, 50.23%; H, 6.09%; N, 6.51%).
three addition/elimination steps involving three molecules of
amino acrylate.
b-
3. Conclusion
In conclusion, b-amino acrylates containing both nucleophilic
and electrophilic sites were synthesized and their reactions under
acidic conditions were investigated. With Boc protecting group, the
C]C in the
b-amido acrylates is unreactive and the cyclization
using TFA involves the attack of the carbamate carbonyl group to an
electrophilic site to give oxazolidin-2-one in high yield. Without
the protecting group, the C]C in b-amino acrylates functions as
both nucleophile and electrophile in series of addition/elimination
leading to the efficient formation of 1,4-dihydropyridine ring when
treated with TiCl4 at 0 ꢀC to room temperature.
4.2.3. (E)-Methyl-3-(5-ethoxy-2-oxooxazolidin-3-yl)acrylate (3c).
Synthesized according to above procedure 4.2 from enamide 2c
(98 mg, 0.31 mmol) as a pale yellow oil (65 mg, 97%); Rf (25% EtOAc/
hexane) 0.11; dH (400 MHz, CDCl3): 7.93 (1H, d, J 14.2, NCH]CH),
5.65 (1H, dd, J 2.5, 6.4 Hz, CHOEt), 5.13 (1H, d, J 14.2 Hz, NCH]CH),
3.99e3.91 (1H, m, OCHAHBCH3), 3.84 (1H, dd, J 6.4, 10.6 Hz,
NCHAHBCH), 3.73 (3H, s, CO2CH3), 3.72e3.64 (1H, m, OCHAHBCH3),
3.53 (1H, dd, J 2.5, 10.6 Hz, NCHAHBCH), 1.26 (3H, t, J 7.1 Hz,
CH2CH3); dC (100 MHz, CDCl3): 166.9, 153.2, 137.9, 100.2, 97.8, 65.7,
51.2, 48.9,14.8; Elem. Anal. Found C, 50.44%; H, 6.12%; N, 6.51%
(calcd for C9H13NO5; C, 50.23%; H, 6.09%; N, 6.51%).
4. Experimental
4.1. General
The NMR spectra were recorded with a Varian Mercury YH400
NMR spectrometer at 400 MHz for 1H NMR and at 100 MHz for 13
NMR using solutions in CDCl3. Chemical shifts (d) are shown in part
C
4.2.4. (E)-Ethyl-3-(5-ethoxy-2-oxooxazolidin-3-yl)acrylate (3d). Syn-
thesized according to above procedure 4.2 from enamide 2d
(107 mg, 0.32 mmol) as a pale yellow oil (74 mg, 99%); Rf (25%
EtOAc/hexane) 0.14; dH (400 MHz, CDCl3): 7.93 (1H, d, J 14.1 Hz,
NCH]CH), 5.65 (1H, dd, J 2.3, 6.4 Hz, OCHCH2), 5.12 (1H, d, J 14.1 Hz,
NCH]CH), 4.19 (2H, q, J 7.2 Hz, CO2CH2CH3), 3.99e3.91 (1H, m,
OCHAHBCH3), 3.84 (1H, dd, J 6.4, 10.6 Hz, NCHAHBCH), 3.72e3.64
(1H, m, OCHAHBCH3), 3.52 (1H, dd, J 2.3, 10.6 Hz, NCHAHBCH), 1.28
(3H, t, J 7.2 Hz, CO2CH2CH3), 1.26 (3H, t, J 7.2 Hz, OCH2CH3); dC
(100 MHz, CDCl3): 166.4, 153.2, 137.6, 100.6, 97.8, 65.6, 60.2, 48.9,
14.7, 14.2; Elem. Anal. Found C, 52.31%; H, 6.68%; N, 6.16% (calcd for
C10H15NO5; C, 52.40%; H, 6.60%; N, 6.11%).
per million relative to the residual proton resonance of CHCl3 at
7.26 ppm and solvent carbon resonance of CDCl3 77.0 ppm for 1H
and 13C, respectively. Coupling constants values (J) are shown in
hertz (Hz). The IR spectra were collected with the Nicolet 6700 FT-
IR spectrometer equipped with a global source and DTGS detector
in region 4000e400 cmꢁ1. The HRMS spectra were measured on an
electrospray ionization mass spectrometer (micrOTOF, Bruker
Daltomics). Elemental (C, H, N) analysis was performed on PE 2400
Series II elemental analyzer (Perkin-Elmer, USA). Gas chromato-
graphic analyzes were conducted on a Shimadzu GC-14A chro-
matograph. Reagents were purchased from commercial suppliers
and used freshly. Dichloromethane (CH2Cl2) was dried over CaH2
and distilled prior to use. Tetrahydrofuran (THF) was dried over
sodium/benzophenone and distilled just before use. Other solvents
4.2.5. 3-Benzyl-5-methoxyoxazolidin-2-one (5a). Synthesized acc-
ording to above procedure 4.2 from enamide 4a (500 mg,
1.69 mmol) as a pale yellow oil (295 mg, 84%); dH (400 MHz, CDCl3):

5164
T. Sirijindalert et al. / Tetrahedron 66 (2010) 5161e5167
7.37e7.25 (5H, m, C6H5), 5.34 (1H, dd, J 6.4, 2.3 Hz, CHOMe), 4.48
(1H, d, J 15.0 Hz ArCHAHB) 4.42 (1H, d, J 15.0 Hz, ArCHAHB),
3.90e3.45 (4H, m, Me, and NCHaHb), 3.21 (1H, dd, J 10.0, 2.3 Hz,
NCHaHb); dC (100 MHz, CDCl3): 156.3, 135.1, 128.4, 127.6, 127.5 97.8,
55.8, 49.8, 47.3; HRMS (ESI): MHþ, found 208.0973. C11H14NOþ3
requires 208.0968.
J 14.6, 7.2 Hz, N(CH2)2CH2), 1.21 (3H, t, J 7.1 Hz, OCH2CH3), 0.88 (3H,
t, J 7.3 Hz, N(CH2)3CH3); dC (100 MHz, CDCl3): 170.8 (cis), 169.6
(trans), 152.3, 85.1 (trans), 81.2 (cis), 58.8 (trans), 58.4 (cis), 48.2,
33.2, 19.6, 14.5, 13.6; HRMS (ESI): MNaþ, found 194.1159.
C9H17NNaOþ2 requires 194.1151.
4.3.3. Ethyl-3-(octadecylamino)acrylate (7b). Synthesized accord-
ing to above general procedure 4.3 from octadecylamine (200 mg,
0.74 mmol) as a yellow solid (254 mg, 93%) as a cis-isomer; mp
59e63 ꢀC; Rf (25% EtOAc/hexane) 0.75; nmax (neat) 3332, 2920,
4.2.6. 5-Methoxy-3-(4-nitrobenzyl)oxazolidin-2-one (5b). Synthe-
sized according to above procedure 4.2 from enamide 4b (66 mg,
0.19 mmol) as a colorless oil (45 mg, 92%); Rf (50% EtOAc/hexane)
0.13; nmax(neat) 3099, 3073, 2916, 2845, 1746, 1525, 1345 cmꢁ1
;
dH
2851, 1665, 1614, 1466, 1194, 1149, 1039 cmꢁ1
; dH (400 MHz, CDCl3):
(400 MHz, CDCl3): 8.21 (2H, d, J 8.6 Hz, 3-ArH), 7.44 (2H, d, J 8.4 Hz,
2-ArH), 5.39 (1H, dd, J 6.3, 2.1 Hz, CHOMe), 4.61 (1H, d, J 15.9 Hz,
AreCHAHB), 4.48 (1H, d, J 15.9 Hz, AreCHAHB), 3.60 (1H, dd, J 9.9,
6.3 Hz, NCHaHb), 3.52 (3H, s, Me), 3.25 (1H, dd, J 9.9, 2.1 Hz,
NCHaHb); dC (100 MHz, CDCl3): 156.6, 147.6, 142.9, 128.4 (2C), 124.0
(2C), 98.1, 56.3, 50.4, 47.0; HRMS (ESI): MNaþ, found 275.0664.
C11H12N2NaOþ5 requires 275.0638.
7.90e7.75 (1H, m, NH), 6.61 (1H, dd, J 13.2, 8.0 Hz, ]CHN), 4.43 (1H,
d, J 8.0 Hz, CH]CHN), 4.10 (2H, td, J 14.2, 5.0 Hz, CH2N), 3.13 (2H, q, J
6.7 Hz, OCH2CH3), 1.51 (2H, td, J 14.1, 7.0 Hz, NCH2CH2), 1.35e1.13
(33H, m, OCH2CH3 and N(CH2)2(CH2)15), 0.87 (3H, t, J 6.8 Hz, N
(CH2)17CH3); dC (100 MHz, CDCl3): 152.4, 81.2, 58.6, 48.7, 31.9, 31.3,
29.7e29.6 (10C, br), 29.5, 29.4, 29.3, 26.5, 22.7, 14.6, 14.1; HRMS
(ESI): MHþ, found 368.3523. C23H46NOþ2 requires 368.3523.
4.2.7. 5-Methoxy-3-(naphthalen-1-ylmethyl)oxazolidin-2-one (5c).
Synthesized according to above procedure 4.2 from enamide 4c
(45 mg, 0.13 mmol) as a colorless oil (28 mg, 84%); Rf (50% EtOAc/
hexane) 0.50; nmax (neat) 3049, 3001, 2933, 2837, 1745, 1481,
4.3.4. Ethyl-3-(benzylamino)acrylate (7c). Synthesized according to
above general procedure 4.3 from benzyl amine (500 mg,
4.67 mmol) as a pale yellow oil (862 mg, 90%) as a 1:2 mixture of
trans- and cis-isomers; Rf (25% EtOAc/hexane) 0.35; nmax (neat)
3333, 3056, 3023, 2977, 2937, 2900, 1668, 1612, 1483, 1452, 1191,
1217 cmꢁ1
; dH (400 MHz, CDCl3): 8.12 (1H, d, J 8.3 Hz, ArH), 7.86
(2H, dd, J 16.2, 7.8 Hz, ArH), 7.62e7.49 (2H, m, ArH), 7.48e7.35 (2H,
m, ArH), 5.32e5.24 (1H, m, CHOMe), 5.00 (1H, d, J 14.8 Hz,
AreCHACHB), 4.80 (1H, d, J 14.8 Hz, AreCHACHB), 3.47 (3H, s, Me),
3.39 (1H, dd, J 10.1, 6.5 Hz, NCHAHB), 3.15 (1H, dd, J 10.1, 2.4 Hz,
NCHAHB); dC (100 MHz, CDCl3): 156.2, 133.8, 131.4, 130.9, 129.1,
128.7, 127.2, 126.9, 126.2, 125.1, 123.4, 98.0, 56.1, 50.2, 46.1; HRMS
(ESI): MNaþ, found 280.0970. C15H15NNaOþ3 requires 280.0944.
1142, 1055 cmꢁ1
; dH (400 MHz, CDCl3): 8.20e8.00 (0.67H, br, NH
(cis)), 7.58 (0.33H, dd, J 13.2, 8.0 Hz, ]CHN (trans)), 7.40e7.19 (5H,
m, Ph), 6.69 (0.67H, dd, J 13.0, 8.1 Hz, ]CHN (cis)), 4.90e4.70
(0.66H, d (br), J 13.3 Hz, NH (trans) and CH]CHN (trans)), 4.54
(0.67H, d, J 8.1 Hz, CH]CHN (cis)), 4.34 (0.67H, d, J 6.0 Hz, NCH2
(cis)), 4.21 (0.33H, d, J 5.3 Hz, NCH2 (trans)), 4.12 (2H, q, J 7.1 Hz,
OCH2), 1.25 (3H, dt, J 7.1, 3.3 Hz, OCH2CH3); dC (100 MHz, CDCl3):
170.8 (cis), 169.5 (trans), 152.0, 138.5, 128.8 (trans), 128.7 (cis), 127.8
(trans), 127.5 (cis), 127.1, 86.8 (trans), 82.8 (cis), 59.0 (trans), 58.7
(cis), 52.1, 14.5; HRMS (ESI): MNaþ, found 228.0993. C12H15NNaOþ2
requires 228.0995.
4.3. Preparation of aliphatic enamine substrates (1b, 7aed)
To the solution of aliphatic amine (1 equiv) in CH2Cl2 (0.2 M),
ethyl propiolate (1.2 equiv) was slowly added and the reaction
mixture was stirred overnight at room temperature under nitrogen
atmosphere. The mixture was evaporated in vacuo and condensed
residue was purified by column chromatography (EtOAc/
4.3.5. Ethyl-3-(2-hydroxyethylamino)acrylate
(7d). Synthesized
according to above general procedure 4.3 from 2-hydroxyethyl-
amine (200 mg, 3.27 mmol) as a pale yellow solid (494 mg, 95%) as
a 1:1 mixture of trans- and cis-isomers; mp 36e38 ꢀC; Rf (50%
EtOAc/hexane) 0.20; nmax (neat) 3346, 2976, 2930, 1666, 1606, 1162,
hexane¼1:10) to provide the corresponding ethyl
b-amino acrylate
(7aed).
1050 cmꢁ1
; dH (400 MHz, CDCl3): 8.00e7.80 (0.5H, br, NH (cis)), 7.53
4.3.1. Ethyl-3-(2,2-dimethoxyethylamino)acrylate (1b). Synthesized
according to above procedure 4.3 from aminoacetaldehyde dime-
thylacetal (500 mg, 4.76 mmol) as a pale yellow oil (880 mg, 91%) as
a cis-isomer; Rf (25% EtOAc/hexane) 0.25; nmax (neat) 3350, 2986,
(0.5H, dd, J 13.3, 8.3 Hz, ]CHN (trans)), 6.66 (0.5H, dd, J 13.1, 8.0 Hz,
]CHN (cis)), 5.10e5.00 (0.5H, br, NH (trans)), 4.74 (0.5H, d, J
13.3 Hz, CH]CHN (trans)), 4.50 (0.5H, d, J 8.0 Hz, CH]CHN (cis)),
4.11 (2H, 2q, J 7.1 Hz, OCH2), 3.77 (1H, t, J 5.0 Hz, NCH2 (cis)), 3.69
(1H, t, J 4.7 Hz, NCH2 (trans)), 3.30 (1H, dd, J 11.2, 5.5 Hz, HOCH2
(cis)), 3.20 (1H, dd, J 10.5, 5.3 Hz, HOCH2 (trans)), 2.43e2.32 (0.5H,
br, OH (cis)), 2.32e2.20 (0.5H, br, OH (trans)), 1.25 (3H, dt, J 7.1,
2.5 Hz, OCH2CH3); dC (100 MHz, CDCl3): 171.0 (cis), 169.9 (trans),
152.6, 86.1 (trans), 82.6 (cis), 62.6, 59.1 (cis), 58.8 (trans), 50.7, 14.5;
HRMS (ESI): MNaþ, found 182.0798. C7H13NNaOþ3 requires
182.0788.
2937, 2837, 1663, 1618, 1476, 1372, 1194, 1125, 1070 cmꢁ1
; dH
(400 MHz, CDCl3): 7.79 (1H, s (br), NH), 6.57 (1H, ddd, J 13.0, 8.1,
1.4 Hz, ]CHN), 4.46 (1H, dd, J 8.1, 1.7 Hz, CH]CHN), 4.30 (1H, dt, J
5.3, 1.6 Hz, CH(OMe)2), 4.08 (2H, dq, J 7.1, 1.7 Hz, OCH2CH3), 3.38
(6H, 2s, OMe), 3.21 (2H, t, J 5.8 Hz, NCH2), 1.23 (3H, dt, J 7.1, 1.7 Hz,
OCH2CH3); dC (100 MHz, CDCl3): 170.6, 152.3, 103.9, 82.8, 58.6, 54.6
(2C), 50.3, 14.5; HRMS (ESI): MNaþ, found 226.1042. C9H17NNaOþ4
requires 226.1050.
4.4. Preparation of aromatic enamine substrates (7eei)
4.3.2. Ethyl-3-(butylamino)acrylate (7a). Synthesized according to
above general procedure 4.3 from n-butylamine (450 mg,
6.15 mmol) as a pale yellow oil (917 mg, 87%) as a 1:3 mixture of
trans- and cis-isomers; Rf (25% EtOAc/hexane) 0.45; nmax (neat)
To the solution of ethyl propiolate (1.2 equiv) in ClCH2CH2Cl
(20 mM), copper(I) iodide (0.5 equiv) and aromatic amine (1 equiv)
were dispersed and the reaction mixture was stirred for 10 min.
The reaction mixture was then heated at 60 ꢀC overnight. The re-
action products were filtered, evaporated, and condensed residue
was purified by column chromatography (EtOAc/hexane¼1:10 v/v)
to provide the corresponding aromatic enamine (7eei).
3332, 2960, 2929, 2873, 1667, 1625, 1479, 1198, 1149, 1052 cmꢁ1
; dH
(400 MHz, CDCl3): 7.94e7.64 (0.75H, br, NH (cis)), 7.46 (0.25H, dd, J
13.1, 8.1 Hz, ]CHN (trans)), 6.58 (0.75H, dd, J 13.2, 8.0 Hz, ]CHN
(cis)), 4.67 (0.50H, d (br), J 13.2 Hz, NH (trans) and CH]CHN (trans)),
4.39 (0.75H, d, J 8.0 Hz, CH]CHN (cis)), 4.11e4.00 (2H, m, CH2eN),
3.11 (1.50H, dd, J 13.2, 6.6 Hz, OCH2CH3 (cis)), 2.99 (0.50H, dd, J 12.6,
6.7 Hz, OCH2CH3 (trans)), 1.59e1.39 (2H, m, NCH2CH2), 1.32 (2H, dq,
4.4.1. Ethyl-3-(phenylamino)acrylate (7e). Synthesized according to
above procedure 4.4 from aniline (500 mg, 5.37 mmol) as

T. Sirijindalert et al. / Tetrahedron 66 (2010) 5161e5167
5165
a colorless oil (564 mg, 55%) as a cis-isomer; Rf (10% EtOAc/hexane)
0.50; nmax (neat) 3307, 3054, 3031, 2982, 1667, 1628, 1598, 1488,
mixture was stirred overnight at room temperature under nitrogen
atmosphere. After the solution was quenched with ice, distilled
deionized water (25 mL) was added and the mixture was extracted
with CH2Cl2 (25 mL). The organic potions were combined and neu-
tralized by addition of 0.1 M aq NaHCO3 solution. The organic phase
was washed three times with deionized water (3ꢂ25 mL), dried over
Na2SO4, and evaporated under reduced pressure. The crude product
was purified by column chromatography (EtOAc/hexane¼1:50 to
1:3) to provide the corresponding dihydropyridines 6, 8aed.
1453, 1242, 1190 cmꢁ1
; dH (400 MHz, CDCl3): 9.92 (1H, d (br), J
11.7 Hz, NH), 7.36e7.18 (3H, m, ]CHN and ortho-C6H5), 7.05e6.88
(3H, m, meta-C6H5 and para-C6H5), 4.85 (1H, d, J 8.3 Hz, CH]CHN),
4.19 (2H, q, J 7.1 Hz, OCH2), 1.31 (3H, t, J 7.1 Hz, OCH2CH3); dC
(100 MHz, CDCl3): 170.3, 142.9, 140.6, 129.6 (2C), 122.4, 115.2 (2C),
87.3, 59.2, 14.4; HRMS (ESI): MNaþ, found 214.0715. C11H13NNaOþ2
requires 214.0838.
4.4.2. Ethyl-3-(4-methoxyphenylamino)acrylate (7f). Synthesized
according to above procedure 4.4 from 4-methoxyaniline (500 mg,
4.05 mmol) as a yellow oil (296 mg, 33%) as a cis-isomer; Rf (17%
EtOAc/hexane) 0.38; nmax (neat) 3274, 3073, 3037, 2976, 2950, 1615,
4.5.1. Diethyl-1-(2,2-dimethoxyethyl)-4-(2-ethoxy-2-oxoethyl)-1,4-
dihydropyridine-3,5-dicarboxylate (6). Synthesized according to
above general procedure 4.5 from ethyl-3-(2,2-dimethox-
yethylamino)acrylate 1b (577 mg, 2.84 mmol) as a pale yellow oil
(33 mg, 81%); Rf (25% EtOAc/hexane) 0.38; nmax (neat) 2981, 2934,
1589, 1508, 1482, 1277, 1164 cmꢁ1
; dH (400 MHz, CDCl3): 9.81 (1H,
d (br), J 12.6 Hz, NH), 7.15 (1H, dd, J 12.8, 8.3 Hz, ]CHN), 6.91 (2H, d,
J 9.0 Hz, meta-C6H4), 6.85 (2H, d, J 9.0 Hz, ortho-C6H4), 4.77 (1H, d, J
8.2 Hz, CH]CHN), 4.17 (2H, q, J 7.1 Hz, OCH2CH3), 3.78 (3H, s, OMe),
1.30 (3H, t, J 7.1 Hz, OCH2CH3); dC (100 MHz, CDCl3): 170.5, 155.4,
144.1, 134.4, 116.9 (2C), 114.9 (2C), 86.0, 59.1, 55.5, 14.5; HRMS (ESI):
MNaþ, found 244.0828. C12H15NNaOþ3 requires 244.0944.
1731, 1705, 1583, 1415, 1250, 1184, 1079 cmꢁ1
; dH (400 MHz, CDCl3):
7.15 (2H, s, CH]C), 4.39 (1H, t, J 5.1 Hz, CH(OMe)2), 4.23e4.16 (5H,
m, DHPeCO2CH2CH3 and CHCH2CO2Et), 4.03 (2H, q, J 7.1 Hz,
CH2CO2CH2CH3), 3.43 (6H, s, OMe), 3.37 (2H, d, J 5.1 Hz, NCH2), 2.47
(2H, d, J 5.0 Hz, CH2CO2Et), 1.29 (6H, t, J 7.1 Hz, DHPeCO2CH2CH3),
1.21 (3H, t, J 7.1 Hz, CH2CO2CH2CH3); dC (100 MHz, CDCl3): 171.7,
166.9 (2C), 139.8 (2C), 106.1 (2C), 103.4, 60.1 (2C), 59.9, 56.4, 55.1
(2C), 40.7, 29.2, 14.4 (2C), 14.1; HRMS (ESI): MHþ, found 400.1971.
C19H30NOþ8 requires 400.1967.
4.4.3. (Z)-Ethyl-3-(4-iodophenylamino)acrylate (7g). In this case,
synthesized according to above procedure 4.4 from 4-iodoaniline
(1.01 g, 4.61 mmol) in CH2Cl2 solution at room temperature as
a white solid (1.21 g, 83%) as a cis-isomer; mp 90e95 ꢀC; Rf (20%
EtOAc/hexane) 0.50; nmax (neat) 3294, 3084, 2971, 1666, 1625, 1584,
4.5.2. Diethyl-1-butyl-4-(2-ethoxy-2-oxoethyl)-1,4-dihydropyridine-
3,5-dicarboxylate (8a). Synthesized according to above general
procedure 4.5 from ethyl-3-(butylamino)acrylate 7a (450 mg,
2.63 mmol) as a pale yellow oil (262 mg, 81%); Rf (25% EtOAc/hex-
ane) 0.28; nmax (neat) 2975, 2957, 2932, 1731, 1699, 1580, 1196,
1470, 1196 cmꢁ1
; dH (400 MHz, CDCl3): 9.89 (1H, d (br), J 11.6 Hz,
NH), 7.57 (2H, d, J 8.7 Hz, meta-C6H4), 7.17 (1H, dd, J 12.5, 8.4 Hz, ]
CHN), 6.73 (2H, d, J 8.7 Hz, ortho-C6H4), 4.87 (1H, d, J 8.4 Hz, CH]
CHN), 4.17 (2H, q, J 7.1 Hz, OCH2), 1.30 (3H, t, J 7.1 Hz, OCH2CH3); dC
(100 MHz, CDCl3): 170.2, 142.2, 140.4, 138.4(2C), 117.2(2C), 88.4,
84.6, 59.4, 14.4; HRMS (ESI): MHþ, found 317.9985. C12H15NNaOþ3
requires 317.9986.
1081 cmꢁ1
; dH (400 MHz, CDCl3): 7.12 (2H, s, CH]C), 4.23e4.15 (5H,
m, DHPeCO2CH2CH3 and CHCH2CO2Et), 4.03 (2H, q, J 7.1 Hz,
CH2CO2CH2CH3), 3.30 (2H, t, J 7.2 Hz, NCH2), 2.45 (2H, d, J 5.0 Hz,
CH2CO2Et), 1.66e1.53 (2H, m, NCH2CH2), 1.41e1.31 (2H, m,
NCH2CH2CH2), 1.29 (6H, t, J 7.1 Hz, DHPeCO2CH2CH3), 1.20 (3H, t, J
7.2 Hz, CH2CO2CH2CH3), 0.95 (3H, t, J 7.3 Hz, N(CH2)3CH3); dC
(100 MHz, CDCl3): 171.7, 166.9 (2C), 139.3 (2C), 105.7 (2C), 60.0 (2C),
59.9, 54.7, 40.9, 32.3, 29.5, 19.5, 14.4 (2C), 14.1, 13.6; HRMS (ESI):
MNaþ, found 390.1887. C19H29NNaOþ6 requires 390.1887.
4.4.4. Ethyl-3-(4-fluorophenylamino)acrylate
(7h). Synthesized
according to above procedure 4.4 from 4-fluoroaniline (500 mg,
4.50 mmol) as a yellow solid (556 mg, 59%) as a cis-isomer; mp
35e38 ꢀC; Rf (10% EtOAc/hexane) 0.50; nmax (neat) 3305, 3275,
3071, 3948, 2980, 1665, 1624, 1600, 1509, 1478, 1197 cmꢁ1
; dH
(400 MHz, CDCl3): 9.87 (1H, d (br), J 11.5 Hz, NH), 7.15 (1H, dd, J 12.6,
8.3 Hz, ]CHN), 7.06e6.95 (2H, m, meta-C6H4), 6.95e6.85 (2H, m,
ortho-C6H4), 4.82 (1H, d, J 8.3 Hz, CH]CHN), 4.17 (2H, q, J 7.1 Hz,
OCH2CH3),1.34e1.27 (3H, m, OCH2CH3); dC (100 MHz, CDCl3): 170.4,
158.5 (d, J 241.3 Hz, CF), 143.4, 137.0, 116.7 (2C, d, J 7.9 Hz, CFCHCH),
116.3 (2C, d, J 23.0 Hz, CFCH), 87.3, 59.3, 14.4; HRMS (ESI): MNaþ,
found 232.0663. C11H12FNNaOþ2 requires 232.0744.
4.5.3. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-octadecyl-1,4-dihydropyr-
idine-3,5dicarboxylate (8b). Synthesized according to above gen-
eral procedure 4.5 from ethyl-3-(octadecylamino)acrylate 7b
(318 mg, 0.87 mmol) as a pale yellow oil (134 mg, 83%); Rf (25%
EtOAc/hexane) 0.20; nmax (neat) 2929, 2850, 1736, 1697, 1211, 1175,
1072 cmꢁ1
; dH (400 MHz, CDCl3): 7.12 (2H, s, CH]C), 4.23e4.15 (5H,
m, DHPeCO2CH2CH3, and CHCH2CO2Et), 4.02 (2H, q, J 7.1 Hz,
CH2CO2CH2CH3), 3.28 (2H, t, J 7.3 Hz, NCH2), 2.45 (2H, d, J 5.0 Hz,
CH2CO2Et), 1.65e1.55 (2H, m, NCH2CH2), 1.43e1.11 (39H, m,
DHPeCO2CH2CH3, and CH2CO2CH2CH3 and N-(CH2)2(CH2)15CH3),
0.87 (3H, t, J 6.8 Hz, N(CH2)17CH3); dC (100 MHz, CDCl3): 171.7, 166.9
(2C), 139.3 (2C), 105.7 (2C), 60.0 (2C), 59.9, 54.9, 40.9, 31.9, 30.3,
29.8e29.6 (11C, br), 29.5, 29.3, 26.2, 22.7, 14.4 (2C), 14.2, 14.1; HRMS
(ESI): MHþ, found 564.4259. C33H58NOþ6 requires 564.4259.
4.4.5. Ethyl-3-(3-chlorophenylamino)acrylate
(7i). Synthesized
according to above procedure 4.4 from 3-chloroaniline (411 mg,
3.22 mmol) as a yellow solid (392 mg, 54%) as a cis-isomer; mp
51e52 ꢀC; Rf (10% EtOAc/hexane) 0.48; nmax (neat) 3067, 2982, 2927,
2898, 1670, 1635, 1599, 1469, 1203 cmꢁ1
; dH (400 MHz, CDCl3): 9.91
(1H, d (br), J 11.8 Hz, NH), 7.19 (2H, td, J 12.5, 7.2 Hz, ]CHN and 2-
ArH), 6.95 (2H, d, J 6.7 Hz, 4-ArH and 6-ArH), 6.81 (1H, d, J 7.8 Hz, 5-
ArH), 4.88 (1H, d, J 8.4 Hz, CH]CHN), 4.18 (2H, q, J 7.1 Hz, OCH2),
1.30 (3H, t, J 7.1 Hz, OCH2CH3); dC (100 MHz, CDCl3): 170.2, 142.2,
141.9, 135.4, 130.6, 122.3, 115.1, 113.6, 88.7, 59.5, 14.4; HRMS (ESI):
MNaþ, found 248.0346. C11H1235ClNNaOþ2 requires 248.0449.
4.5.4. Diethyl-1-benzyl-4-(2-ethoxy-2-oxoethyl)-1,4-dihydropyr-
idine-3,5-dicarboxylate (8c). Synthesized according to above gen-
eral procedure 4.5 from ethyl-3-(benzylamino)acrylate 7c (401 mg,
1.95 mmol) as apaleyellowoil (207 mg, 79%); Rf (25%EtOAc/hexane)
0.25; nmax (neat) 3060, 3029, 2979, 2928,1731,1698,1582,1241,1186,
4.5. Preparation of 1,4-dihydropyridines (6, 8aei)
1077 cmꢁ1
; dH (400 MHz, CDCl3): 7.47e7.21 (5H, m, Ph), 7.19 (2H, s,
CH]C), 4.50 (2H, s, NCH2), 4.23e4.13 (5H, m, DHPeCO2CH2CH3, and
CHCH2CO2Et), 3.99 (2H, q, J 7.1 Hz, CH2CO2CH2CH3), 2.50 (2H, d, J
5.0 Hz, CH2CO2Et),1.27 (6H, t, J 7.1 Hz, DHPeCO2CH2CH3),1.16 (3H, t, J
7.1 Hz, CH2CO2CH2CH3); dC (100 MHz, CDCl3): 171.7,166.7 (2C),139.4
(2C), 129.0 (2C), 128.2 (2C), 127.1, 109.9, 106.4 (2C), 60.1 (2C), 59.9,
To a solution of N-substituted
dried CH2Cl2 (0.1 M) in an ice bath, TiCl4 (0.2 equiv in the case of N-
b-amino acrylates 7 (1 equiv) in
aliphatic
aromatic
b
b
-amino acrylates 1b and 7aed or 0.5 equiv in the case of N-
-amino acrylates 7eei) was added rapidlyand the reaction

5166
T. Sirijindalert et al. / Tetrahedron 66 (2010) 5161e5167
58.0, 40.8, 29.5, 14.3 (2C), 14.1; HRMS (ESI): MHþ, found 402.1916.
C22H28NOþ6 requires 402.1911.
7h (556 mg, 2.66 mmol) as a pale yellow solid (251 mg, 69%); mp
75e76 ꢀC; Rf (25% EtOAc/hexane) 0.38; nmax (neat) 3071, 2982,
2940, 1732, 1707, 1594, 1516, 1219, 1085 cmꢁ1
; dH (400 MHz, CDCl3):
4.5.5. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-(2-hydroxyethyl)-1,4-di-
hydropyridine-3,5-dicarboxylate (8d). Synthesized according to
above general procedure 4.5 from ethyl-3-(2-hydroxyethylamino)
acrylate 7d (500 mg, 31.4 mmol) as a pale yellow solid (303 mg,
81%); mp 73e75 ꢀC; Rf (50% EtOAc/hexane) 0.20; nmax (neat)
3625e3200 (br), 2981, 2940, 1724, 1699, 1579, 1229, 1185,
7.48 (2H, s, CH]C), 7.24e7.16 (2H, m, meta-C6H4), 7.11 (2H, t, J
8.5 Hz, ortho-C6H4), 4.28e4.18 (5H, m, DHPeCO2CH2CH3 and
CHCH2CO2Et), 4.03 (2H, q, J 7.1 Hz, CH2CO2CH2CH3), 2.59 (2H, d, J
4.8 Hz, CH2CO2Et),1.30 (6H, t, J 7.1 Hz, DHPeCO2CH2CH3),1.18 (3H, t,
J 7.1 Hz, CH2CO2CH2CH3); dC (100 MHz, CDCl3): 171.7, 166.6 (2C),
160.9 (d, J 246.7 Hz, CF), 139.4, 137.8 (2C), 123.1 (2C, d, J 8.4 Hz,
CFCHCH), 116.6 (2C, d, J 23.0 Hz, CFCH), 108.2 (2C), 60.4 (2C), 60.0,
40.4, 29.5, 14.4 (2C), 14.2; HRMS (ESI): MNaþ, found 428.1480.
C21H24FNNaOþ6 , requires 428.1480.
1069 cmꢁ1
; dH (400 MHz, CDCl3): 7.17 (2H, s, CH]C), 4.27e4.10 (4H,
m, DHPeCO2CH2CH3), 4.07 (1H, t, J 3.7 Hz,CHCH2CO2Et), 4.02 (2H, q,
J 7.1 Hz, CH2CO2CH2CH3), 3.88e3.81 (1H, m, OH), 3.78e3.70 (2H, m,
HOCH2), 3.49e3.37 (2H, m, CH2eN), 2.64 (2H, d, J 3.7 Hz, CH2CO2Et),
1.28 (6H, t, J 7.1 Hz, DHPeCO2CH2CH3), 1.18 (3H, t, J 7.1 Hz,
CH2CO2CH2CH3); dC (100 MHz, CDCl3): 173.9, 166.8 (2C), 140.3 (2C),
105.3 (2C), 61.7, 60.3 (2C), 60.1, 57.6, 39.1, 28.6, 14.4 (2C),14.0; HRMS
(ESI): MHþ, found 356.1704. C17H26NOþ7 requires 356.1704.
4.5.10. Diethyl-1-(3-chlorophenyl)-4-(2-ethoxy-2-oxoethyl)-1,4-di-
hydropyridine-3,5-dicarboxylate (8i). Synthesized according to
above general procedure 4.5 from ethyl-3-(3-chlorophenylamino)
acrylate 7i (346 mg,1.53 mmol) as a pale yellow oil (164 mg, 76%); Rf
(25% EtOAc/hexane) 0.30; nmax (neat) 3072, 2976, 2935, 1729, 1707,
4.5.6. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-phenyl-1,4-dihydropyr-
idine-3,5-dicarboxylate (8e). Synthesized according to above gen-
eral procedure 4.5 from ethyl-3-(phenylamino)acrylate 7e (480 mg,
2.51 mmol) as a pale yellow oil (265 mg, 82%); Rf (17% EtOAc/hex-
ane) 0.25; nmax (neat) 3063, 2975, 2935, 1734, 1704, 1596, 1586,
1594, 1483, 1207, 1081 cmꢁ1
; dH (400 MHz, CDCl3): 7.54 (2H, s, CH]
C), 7.40e7.10(4H, m,C6H4), 4.29e4.20 (5H, m, DHPeCO2CH2CH3 and
CHCH2CO2Et), 4.03 (2H, q, J 7.1 Hz, CH2CO2CH2CH3), 2.60 (2H, d, J
4.8 Hz, CH2CO2Et),1.31 (6H, t, J 7.1 Hz, DHPeCO2CH2CH3),1.18 (3H, t, J
7.1 Hz, CH2CO2CH2CH3); dC (100 MHz, CDCl3): 171.5, 166.4 (2C),
143.9, 136.9 (2C), 135.5, 130.8, 126.3, 120.8, 118.6, 109.0 (2C), 60.4
1495, 1235,1204,1072 cmꢁ1
; dH (400 MHz, CDCl3): 7.58 (2H, s, CH]
C), 7.42 (2H, t, J 7.9 Hz, meta-C6H5), 7.30e7.19 (3H, m, ortho-C6H5,
and para-C6H5), 4.30e4.17 (5H, m, DHPeCO2CH2CH3, and
CHCH2CO2Et), 4.03 (2H, q, J 7.1 Hz, CH2CO2CH2CH3), 2.59 (2H, d, J
4.8 Hz, CH2CO2Et),1.30 (6H, t, J 7.1 Hz, DHPeCO2CH2CH3), 1.17 (3H, t,
J 7.1 Hz, CH2CO2CH2CH3); dC (100 MHz, CDCl3): 171.7, 166.7 (2C),
143.0, 137.6 (2C), 129.8 (2C), 126.4, 120.8 (2C), 108.2 (2C), 60.3 (2C),
60.1, 40.5, 29.6, 14.4 (2C), 14.2; All data are identical to that of the
literature compound.21
(2C), 60.0, 40.2, 29.5, 14.3 (2C), 14.1; HRMS (ESI): MNaþ, found
35
444.1184. C21
H
ClNNaOþ6 , requires 444.1184.
24
4.5.11. Synthesis of diethyl 4-((phenylamino)methylene)pent-2-ene-
dioate (9). To the solution of ethyl propiolate (651 mg, 6.64 mmol)
in dried ClCH2CH2Cl (20 mL) copper(I) iodide (409 mg, 2.15 mmol)
and aniline (265 mg, 2.15 mmol) were dispersed and the reaction
mixture was refluxed overnight. The reaction mixture was filtered
and evaporated under reduced pressure. The condensed residue
was purified by column chromatography (EtOAc/hexane¼1:50 to
1:3) to provide the corresponding dihydropyridine 9as a yellow oil
(261 mg, 42%); Rf (25% EtOAc/hexane) 0.50; nmax (neat) 3271, 3220,
4.5.7. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-(4-methoxyphenyl)-1,4-di-
hydropyridine-3,5-dicarboxylate (8f). Synthesized according to
above general procedure 4.5 from ethyl-3-(4-methoxyphenylamino)
acrylate 7f (356 mg, 1.61 mmol) as a pale yellow oil (170 mg, 76%), Rf
(25% EtOAc/hexane) 0.30; nmax (neat) 3079, 3039, 2977, 2934, 1738,
3047, 2981, 1659, 1597, 1582, 1278, 1179, 1157,1029 cmꢁ1
; dH
(400 MHz, CDCl3): 10.78 (1H, d, J 13.2 Hz, NH), 7.76 (1H, d, J 13.2 Hz,
C]CH), 7.48 (1H, d, J 15.7 Hz, CH]CHCO2Et), 7.36 (2H, t, J 7.6 Hz,
meta-C6H5), 7.19e7.00 (3H, m, para-C6H5 and ortho-C6H5), 6.18 (1H,
d, J 15.7 Hz, CH]CHCO2Et), 4.33 (1H, q, J 7.1 Hz, ]CCO2CH2CH3),
4.22 (1H, q, J 7.1 Hz, ]CHCO2CH2CH3), 1.40 (1H, t, J 7.1 Hz, ]
CCO2CH2CH3), 1.31 (1H, t, J 7.1 Hz, ]CHCO2CH2CH3); HRMS (ESI):
MNaþ, found 312.1205. C16H19NNaOþ4 , requires 312.1206. This data
are fully identical to that of compound isolated in trace amount
from the previous procedure 4.5.6.
1702, 1599, 1582, 1518, 1229, 1205, 1079 cmꢁ1
; dH (400 MHz, CDCl3):
7.46 (2H, s, CH]C), 7.15 (2H, d, J 9.0 Hz, meta-C6H4), 6.92 (2H, d, J
9.0 Hz, ortho-C6H4), 4.28e4.17 (5H, m, DHPeCO2CH2CH3 and
CHCH2CO2Et), 4.04 (2H, q, J 7.1 Hz, CH2CO2CH2CH3), 3.82 (3H, s, OMe),
2.57 (2H, d,
J
4.8 Hz, CH2CO2Et), 1.29 (6H, t,
J
7.1 Hz,
DHPeCO2CH2CH3),1.18 (3H, t, J 7.1 Hz, CH2CO2CH2CH3); dC (100 MHz,
CDCl3):171.7,166.8(2C),158.2,138.3(2C),136.6,122.9 (2C),114.8(2C),
107.5 (2C), 60.3 (2C), 60.0, 55.6, 40.6, 29.5,14.4 (2C),14.2; HRMS (ESI):
MHþ, found 418.1860. C22H28NOþ7, requires 418.1860.
Acknowledgements
4.5.8. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-(4-iodophenyl)-1,4-dihy-
dropyridine-3,5-dicarboxylate (8g). Synthesized according to above
general procedure 4.5 from ethyl-3-(4-iodophenylamino)acrylate
7g (928 mg, 2.93 mmol) as a pale yellow solid (396 mg, 79%); mp
61e66 ꢀC; Rf (20% EtOAc/hexane) 0.20; nmax (neat) 3083, 3063,
This work is financially supported by the Integration Project:
Innovations for the improvement of Food Safety and Food Quality
for New World Economy, Government Research Budget and Center
for Petroleum, Petrochemicals and Advanced Materials, Chula-
longkorn University.
2974, 2931, 1731, 1704, 1625,1582, 1494, 1229 cmꢁ1
; dH (400 MHz,
CDCl3): 7.72 (2H, d, J 8.4 Hz, meta-C6H4), 7.51 (2H, s, CH]C), 6.98
(2H, d, J 8.4 Hz, ortho-C6H4), 4.30e4.14 (5H, m, DHPeCO2CH2CH3,
and CHCH2CO2Et), 4.01 (2H, q, J 7.1 Hz, CH2CO2CH2CH3), 2.59 (2H, d,
J 4.7 Hz, CH2CO2Et), 1.30 (6H, t, J 7.1 Hz, DHPeCO2CH2CH3), 1.16 (3H,
t, J 7.1 Hz, CH2CO2CH2CH3); dC (100 MHz, CDCl3): 171.5, 166.5 (2C),
142.7, 138.8 (2C), 136.9 (2C), 122.4 (2C), 108.9 (2C), 90.2, 60.4 (2C),
60.1, 40.3, 29.5, 14.3 (2C), 14.2; HRMS (ESI): MNaþ, found 536.0541.
C21H24INNaOþ6 , requires 536.0540.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.102.
References and notes
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