The use of magnesium nitride for the synthesis of enantiomerically pure 1,4-dihydropyridines via the hantzsch reaction

Article abstract of DOI:10.1055/s-0030-1258462

Enantiomerically pure 1,4-dihydropyridines are prepared taking advantage of magnesium nitride as a useful and convenient source of solid ammonia'. The products possess various substituents at carbons 3, 4 and 5 of the dihydropyridine moiety. Georg Thieme

Full text of DOI:10.1055/s-0030-1258462

PAPER
1071
The Use of Magnesium Nitride for the Synthesis of Enantiomerically Pure
1,4-Dihydropyridines via the Hantzsch Reaction
Synthesis of
E
h
nantiomeric
a
a
lly
P
ure 1,4-Dihy
L
dropyridines ong,a Mauro Panunzio,*a Alessandra Petroli,a Wenling Qin,b Zhining Xia*b
a
ISOF-CNR, Dipartimento di Chimica ‘G. Ciamician’, Via Selmi 2, 40126 Bologna, Italy
Fax +39(051)2099456; E-mail: mauro.panunzio@unibo.it
b
Department of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400044, P. R. of China
Received 3 January 2011; revised 1 February 2011
keto ester, takes place thereby allowing the use of stoichi-
ometric amounts of magnesium nitride, the b-keto ester
and the aldehyde.
Abstract: Enantiomerically pure 1,4-dihydropyridines are pre-
pared taking advantage of magnesium nitride as a useful and conve-
nient source of ‘solid ammonia’. The products possess various
substituents at carbons 3, 4 and 5 of the dihydropyridine moiety.
A series of 1,4-dihydropyridines was synthesized via the
Key words: 1,4-dihydropyridines, magnesium nitride, multicom- one-pot condensation of an aldehyde, a b-keto ester and
ponent reaction, Hantzsch esters, one-pot condensation
magnesium nitride in 1,4-dioxane (Scheme 1 and
Significant attention has been devoted to 1,4-dihydropyri-
dine derivatives due to their wide spectrum of biological
Cl
NO2
activity. Compounds containing the 1,4-dihydropyridine
moiety have been found to act as calcium modulators,1
BACE-1 inhibitors,2 drugs for the treatment of vasodila-
tion,3 a mineral corticoid receptor antagonist,4 hepatopro-
MeOOC
COOEt
MeOOC
COOMe
O
NH2
N
N
H
H
2
tection,
neuromodulatory,
antiatherosclerosis,
amlodipine
nifedipine
antidiabetes, antioxidant, antimutagenic and antitumor
agents,5 and also have an effect on the accumulation of
tau.6 1,4-Dihydropyridines such as nifedipine, (Adalat®,
Procardia®), amlodipine and nimodipine (Figure 1) are
widely prescribed as antihypertensive drugs.7 In addition,
the dihydropyridine moiety has found application as an
NADH analogue.8 The classic method to prepare dihydro-
pyridines was discovered by Hantzsch in 18829 and con-
sists of a multicomponent reaction (MCR) between an
aldehyde, a b-keto ester and a 30% aqueous ammonia so-
NO2
MeOH2CH2COOC
COOi-Pr
N
H
nimodipine
Figure 1 Some typical antihypertensive drugs based on the 1,4-di-
lution as the nitrogen source.4–7 Magnesium nitride hydropyridine scaffold
(Mg3N2), a commercially available bench-stable solid, has
been utilized by the Ley group, as an ammonia-releasing
OH
O
O
O
O
agent in the presence of proton sources.10 In order to dem-
onstrate the feasibility and utility of this reagent for the
preparation of highly functionalized molecules, with spe-
cial emphasis on those containing one or more stereo-
centers, we report herein our results on the synthesis of
enantiomerically pure Hantzsch esters in good to satisfac-
tory yields. In fact, the need for enantiomerically pure 1,4-
dihydropyridines for biological testing4,11 is well ac-
knowledged, and hence research on their synthesis and
bioactivity is highly warranted. Besides the preparation of
enantiomerically pure compounds, it should be noted that,
from a synthetic point of view, this work is based on the
use of aprotic 1,4-dioxane as the solvent, instead of protic
ethanol as reported by Ley.10 In this way, slow decompo-
sition of magnesium nitride, via the enolic form of the b-
+
Mg3N2
2
R1
R1
1
O
Mg
+
3
2 NH3
2
R1
R2
O
R2
O
O
H
R1
R1
3
1,4-dioxane, 80 °C, 24 h
N
H
4
O
R1
=
O
COOEt
;
1a
SYNTHESIS 2011, No. 7, pp 1071–1078
x
x
.
x
x
.2
0
1
1
1b
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1258462; Art ID: Z08811SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Preparation of 1,4-dihydropyridines 4a–p in 1,4-dioxane

1072
S. Long et al.
PAPER
Table 1). The starting optically active b-keto esters 1a and the yields were lower than those obtained by convective
1b were prepared in good yield by microwave-assisted heating, whereas the time needed to complete the reaction
transesterification in the absence of any catalyst.12 At- was similar under both microwave and convective heating
tempts to obtain the dihydropyridines 4a–p under micro- conditions. In summary, we have reported a simple proto-
wave-assisted organic synthesis (MAOS) conditions were col for the preparation of optically active 1,4-dihydropy-
not completely successful. In fact, even in the best cases, ridines in satisfactory yields.
Table 1 Synthesis of Optically Active 1,4-Dihydropyridines 4a–p
Entry
R1
Product
Yield (%)
O
O
1
95
EtOOC
O
O
COOEt
N
H
4a
NO2
NO2
O
O
2
66
EtOOC
O
O
COOEt
N
H
4b
NO2
O
NO2
O
3
4
5
6
66
46
41
43
EtOOC
O
O
COOEt
N
H
4c
NO2
O
O
EtOOC
O
O
COOEt
NO2
N
H
4d
MeO
OMe
MeO
OMe
O
O
O
O
EtOOC
COOEt
N
H
4e
OMe
O
O
O
EtOOC
O
COOEt
OMe
N
H
4f
Synthesis 2011, No. 7, 1071–1078 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 1,4-Dihydropyridines
1073
Table 1 Synthesis of Optically Active 1,4-Dihydropyridines 4a–p (continued)
Entry
R1
Product
Yield (%)
O
O
7
65
EtOOC
O
O
COOEt
N
H
4g
O
O
8
9
58
28
73
Me(CH2)6
EtOOC
O
O
COOEt
N
H
4h
S
O
O
S
EtOOC
O
O
COOEt
N
H
4i
S
O
O
S
10
EtOOC
O
O
COOEt
N
H
4j
N
O
O
N
11
58
EtOOC
O
O
COOEt
N
H
4k
O
O
12
52
EtOOC
O
O
COOEt
N
H
4l
OMe
OMe
13
26
O
O
EtOOC
O
O
COOEt
N
H
4m
Synthesis 2011, No. 7, 1071–1078 © Thieme Stuttgart · New York

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Table 1 Synthesis of Optically Active 1,4-Dihydropyridines 4a–p (continued)
Entry
14
R1
Product
Yield (%)
Boc
N
O
O
22
50
25
EtOOC
O
O
COOEt
N
Boc
N
H
4n
NO2
O
NO2
O
15
O
O
N
H
4o
NO2
O
O
16
O
O
NO2
N
H
4p
All starting materials, unless otherwise stated, were purchased and
used without any further purification. Solvents were distilled and
dried according to standard procedures. All the reactions were run
in a sealed tube under a nitrogen atmosphere. Column chromatog-
raphy was performed using Merck KGaA Silicagel 60 (230-400
Mesh-ASTM). Melting points were obtained using a Stuart Scien-
tific SMP3 Melting Point apparatus and are not corrected. Optical
rotations were obtained using a Perkin Elmer 343 polarimeter. IR
spectra were recorded on a Nicolet 380 FT-IR infrared spectrome-
ter. NMR spectroscopy was performed on a Varian-Mercury 400
spectrometer using the residual signal of the solvent as the internal
standard. The chemical shifts are reported in ppm and coupling con-
stants (J) are reported in Hz. GC–MS spectra were recorded using
Agilent Technologies 6850 and 5975 GC-Mass instrumentation.
LC–MS spectra were obtained using an Agilent Technologies
MSD1100 single-quadrupole mass spectrometer. Elemental analy-
sis were performed at CNR-ISMAR, Bologna, Italy.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-phenyl-
1,4-dihydropyridine-3,5-dicarboxylate (4a); Typical Procedure
A mixture of benzaldehyde (3a) (0.203 mL, 2 mmol), b-keto ester
1a (0.836 g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol) in anhyd 1,4-
dioxane (3 mL) in a 5 mL sealed tube was stirred for 24 h at 80 °C.
The mixture was cooled, dissolved in ice-cold H2O (10 mL), and ex-
tracted with CH2Cl2 (3 × 15 mL). The combined organic layer was
dried over MgSO4, the solvent removed in vacuo and the product
purified by flash chromatography on silica gel (EtOAc–cyclohex-
ane, 35:65).
Yellow oil; yield: 0.896 g (95%); [a]D20 +133.43 (c 0.7, CHCl3).
IR (film): 1740, 1695 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.14 (t, J = 7.1 Hz, 3 H), 1.25 (t,
J = 7.1 Hz, 3 H), 1.42 (d, J = 6.9 Hz, 3 H), 1.46 (d, J = 6.9 Hz, 3 H),
2.34 (s, 3 H), 2.35 (s, 3 H), 4.07 (m, 2 H), 4.18 (m, 2 H), 4.96 (q,
J = 7.1 Hz, 1 H), 5.03 (q, J = 6.9 Hz, 1 H), 5.07 (s, 1 H), 5.97 (s, 1
H, NH), 7.13–7.31 (m, 5 H, Ar).
(2S)-1-Ethoxy-1-oxopropan-2-yl 3-Oxobutanoate (1a)
(S)-(–)-Ethyl lactate (0.3 mol, 35 mL) and ethyl acetoacetate (0.15
mol, 19.5 mL), in a 50 mL flask, were heated at reflux temperature
in a microwave oven (Milestone/MicroSynth) at 500 W for 3 h.
During this time the EtOH produced during the transesterification
was removed by side-arm distillation. The excess (S)-(–)-ethyl lac-
tate was removed by rotary evaporation. The residue was found to
consist of 24.2 g (80% conversion) of the target compound. The an-
alytical data (including the optical rotation) was analogous with the
literature.12
13C NMR (100 MHz, CDCl3): d = 13.96, 14.06, 16.87, 17.04, 19.51,
19.85, 39.45, 60.94, 61.13, 68.24, 68.44, 103.15, 103.88, 126.11,
127.73, 128.14, 145.27, 147.45, 166.65, 166.70, 171.20, 171.47.
MS (ESI): m/z = 474 [M + H]+.
Anal. Calcd for C25H31NO8: C, 63.41; H, 6.60; N, 2.96. Found: C,
63.60; H, 6.62.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-(4-nitro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4b)
The product was prepared according to the typical procedure from
4-nitrobenzaldehyde (3b) (0.302 g, 2 mmol), b-keto ester 1a (0.836
g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The crude mixture
was extracted with EtOAc (3 × 10 mL), dried over Na2SO4 and pu-
rified by flash chromatography (EtOAc–cyclohexane, 35:65).
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 3-Oxobutanoate
(1b)
The title product was prepared using the previously reported micro-
wave-assisted organic synthesis technique.12
Yellow solid; yield: 0.681 g (66%); mp 55 °C; [a]D20 +63.64 (c 1.1,
CHCl3).
Synthesis 2011, No. 7, 1071–1078 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 1,4-Dihydropyridines
1075
IR (film): 1735, 1701 cm–1.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 4-(3,5-Dimethoxyphenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4e)
The product was prepared according to the typical procedure from
3,5-dimethoxybenzaldehyde (3e) (0.332 g, 2 mmol), b-keto ester 1a
(0.836 g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The crude mix-
ture was extracted with EtOAc (3 × 10 mL), dried over Na2SO4 and
purified by flash chromatography (EtOAc–cyclohexane, 35:65).
1H NMR (400 MHz, CDCl3): d = 1.13 (t, J = 7.2 Hz, 3 H), 1.25 (t,
J = 7.2 Hz, 3 H), 1.42 (d, J = 6.8 Hz, 3 H), 1.48 (d, J = 6.8 Hz, 3 H),
2.26 (s, 3 H), 2.38 (s, 3 H), 4.05 (m, 2 H), 4.20 (m, 2 H), 4.96 (q,
J = 6.8 Hz, 1 H), 5.00 (q, J = 6.8 Hz, 1 H), 5.15 (s, 1 H), 6.43 (s, 1
H), 7.47 (d, J = 9.6 Hz, 2 H), 8.07 (d, J = 9.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.94, 14.03, 16.90, 17.01, 19.34,
19.56, 39.83, 61.02, 61.37, 68.33, 68.55, 101.83, 102.61, 123.17,
129.08, 145.64, 146.55, 154.79, 166.10, 166.15, 170.95, 171.46.
Yellow oil; yield: 0.441 g (41%); [a]D20 +40.0 (c 1.1, CHCl3).
IR (film): 1740, 1698 cm–1.
MS (ESI): m/z = 519 [M + H]+.
1H NMR (400 MHz, CDCl3): d = 1.17 (t, J = 7.0 Hz, 3 H), 1.25 (t,
J = 7.2 Hz, 3 H), 1.44 (d, J = 6.8 Hz, 3 H), 1.49 (d, J = 7.6 Hz, 3 H),
2.34 (s, 3 H), 2.35 (s, 3 H), 3.75 (s, 6 H), 4.14 (m, 4 H), 5.00 (q,
J = 7.2 Hz, 1 H), 5.06 (q, J = 7.2 Hz, 1 H), 5.07 (s, 1 H), 5.84 (s, 1
H, NH), 6.27 (s, 1 H), 6.50 (s, 1 H), 6.51 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.74, 13.89, 16.82, 16.93, 18.88,
19.20, 39.31, 54.94, 60.82, 61.08, 68.02, 68.29, 97.51, 102.13,
102.98, 106.47, 145.04, 146.08, 149.92, 160.05, 166.66, 170.01,
171.59.
Anal. Calcd for C25H30N2O10: C, 57.91; H, 5.83; N, 5.40. Found: C,
58.03; H, 5.84.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-(3-nitro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4c)
The product was prepared according to the typical procedure from
3-nitrobenzaldehyde (3c) (0.302 g, 2 mmol), b-keto ester 1a (0.836
g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The crude mixture
was extracted with EtOAc (3 × 10 mL), dried over Na2SO4 and pu-
rified by flash chromatography (EtOAc–cyclohexane, 35:65).
MS (ESI): m/z = 534 [M + H]+.
Anal. Calcd for C27H35NO10: C, 60.78; H, 6.61; N, 2.63. Found: C,
60.96; H, 6.63.
Yellow oil; yield: 0.684 g (66%); [a]D20 +60.9 (c 1.1, CHCl3).
IR (film): 1738, 1701 cm–1.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 4-(2-Methoxyphenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4f)
The product was prepared according to the typical procedure from
2-methoxybenzaldehyde (3f) (0.272 g, 2 mmol), b-keto ester 1a
(0.808 g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The crude mix-
ture was extracted with EtOAc (3 × 10 mL), dried over MgSO4 and
purified by flash chromatography (EtOAc–cyclohexane, 35:65).
1H NMR (400 MHz, CDCl3): d = 1.12 (t, J = 6.8 Hz, 3 H), 1.24 (t,
J = 6.8 Hz, 3 H), 1.44 (d, J = 6.8 Hz, 3 H), 1.49 (d, J = 6.8 Hz, 3 H),
2.37 (s, 3 H), 2.41 (s, 3 H), 4.04 (m, 2 H), 4.20 (m, 2 H), 4.97 (q,
J = 6.8 Hz, 1 H), 5.00 (q, J = 7.2 Hz, 1 H), 5.16 (s, 1 H), 6.17 (s, 1
H, NH), 7.39 (t, J = 7.8 Hz, 1 H), 7.68 (dt, J = 1.4 Hz, J = 7.7 Hz, 1
H), 8.01 (ddd, J = 1.0 Hz, J = 1.4 Hz, J = 8.2 Hz, 1 H), 8.14 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.88, 14.02, 16.82, 16.95, 19.13,
19.37, 39.85, 60.90, 61.45, 68.23, 68.53, 101.83, 102.73, 121.25,
123.44, 128.58, 134.80, 145.71, 146.78, 147.83, 149.81, 166.09,
166.22, 170.91, 171.74.
Yellow oil; yield: 0.431 g (43%); [a]D20 +55.56 (c 0.9, CHCl3).
IR (film): 1740, 1691 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.03 (t, J = 7.1 Hz, 3 H), 1.25 (t,
J = 7.1 Hz, 3 H), 1.40 (d, J = 6.9 Hz, 3 H), 1.45 (d, J = 6.9 Hz, 3 H),
2.21 (s, 3 H), 2.32 (s, 3 H), 3.72 (s, 3 H), 3.95 (m, 2 H), 4.19 (m, 2
H), 4.87 (q, J = 7.1 Hz, 1 H), 4.98 (q, J = 7.1 Hz, 1 H), 5.28 (s, 1 H),
6.65 (br s, 1 H, NH), 6.78 (m, 2 H), 7.08 (dt, J = 1.8 Hz, J = 7.4 Hz,
1 H), 7.21 (dd, J = 1.8 Hz , J = 7.5 Hz , 1 H).
13C NMR (100 MHz, CDCl3): d = 13.79, 13.99, 16.76, 16.80, 18.86,
19.23, 35.36, 55.08, 60.64, 61.10, 67.80, 67.99, 101.31, 102.13,
110.51, 119.67, 127.16, 131.26, 135.37, 145.04, 146.08, 157.24,
167.05, 167.27, 171.36, 172.11.
MS (ESI): m/z = 541 [M + 23]+.
Anal. Calcd for C25H30N2O10: C, 57.91; H, 5.83; N, 5.40. Found: C,
59.59; H, 5.99.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-(2-nitro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4d)
The product was prepared according to the typical procedure from
2-nitrobenzaldehyde (3d) (0.151 g, 1 mmol), b-keto ester 1a (0.404
g, 2 mmol) and Mg3N2 (2) (0.50 g, 0.5 mmol). The crude mixture
was extracted with EtOAc (3 × 10 mL), dried over Na2SO4 and pu-
rified by flash chromatography (EtOAc–cyclohexane, 35:65).
MS (ESI): m/z = 504 [M + H]+.
Anal. Calcd for C26H33NO9: C, 62.02; H, 6.61; N, 2.78. Found: C,
62.20; H, 6.63.
Yellow oil; yield: 0.236 g (46%); [a]D20 +55.0 (c 1.0, CHCl3).
IR (film): 1735, 1701 cm–1.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-styryl-1,4-
dihydropyridine-3,5-dicarboxylate (4g)
The product was prepared according to the typical procedure from
trans-cinnamaldehyde (3g) (0.264 g, 2 mmol), b-keto ester 1a
(0.836 g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The crude mix-
ture was extracted with EtOAc (3 × 10 mL), dried over Na2SO4 and
purified by flash chromatography (EtOAc–cyclohexane, 35:65).
Yellow oil; yield: 0.645 g (65%); [a]D20 +44.55 (c 0.9, CHCl3).
IR (film): 1741, 1698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.19 (t, J = 6.8 Hz, 3 H), 1.26 (t,
J = 6.8 Hz, 3 H), 1.51 (d, J = 6.4 Hz, 3 H), 1.53 (d, J = 6.4 Hz, 3 H),
2.32 (s, 3 H), 2.33 (s, 3 H), 4.16 (m, 4 H), 4.69 (d, J = 6.0 Hz, 1 H),
5.08 (q, J = 6.8 Hz, 1 H), 5.12 (q, J = 7.2 Hz, 1 H), 5.99 (s, 1 H,
NH), 6.36 (m, 2 H), 7.14–7.31 (m, 5 H, Ar).
1H NMR (400 MHz, CDCl3): d = 1.03 (t, J = 6.8 Hz, 3 H), 1.26 (t,
J = 6.8 Hz, 3 H), 1.41 (d, J = 7.2 Hz, 3 H), 1.45 (d, J = 7.6 Hz, 3 H),
2.26 (s, 3 H), 2.41 (s, 3 H), 3.96 (m, 2 H), 4.19 (m, 2 H), 4.92 (q,
J = 6.8 Hz, 1 H), 5.01 (q, J = 7.2 Hz, 1 H), 6.09 (s, 1 H), 6.77 (br s,
1 H, NH), 7.25 (t, J = 8.4 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.56
(d, J = 7.6 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.00, 13.05, 14.96, 15.26, 15.46,
33.34, 59.73, 60.37, 67.47, 67.55, 101.48, 102.00, 123.19, 125.98,
131.05, 132.02, 142.16, 145.20, 145.63, 146.10, 165.37, 165.89,
170.09, 171.16.
MS (ESI): m/z = 519 [M + H]+.
Anal. Calcd for C25H30N2O10: C, 57.91; H, 5.83; N, 5.40. Found: C,
59.71; H, 6.01.
13C NMR (100 MHz, CDCl3): d = 14.02, 14.08, 17.05, 17.11, 19.46,
19.60, 36.33, 61.05, 61.15, 68.25, 68.36, 100.54, 101.23, 126.25,
Synthesis 2011, No. 7, 1071–1078 © Thieme Stuttgart · New York

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S. Long et al.
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126.78, 128.28, 128.37, 128.73, 131.76, 137.83, 145.49, 146.18,
166.63, 166.74, 171.33, 171.49.
MS (ESI): m/z = 500 [M + H]+.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 7.0 Hz, 3 H), 1.26 (t,
J = 6.6 Hz, 3 H), 1.45 (d, J = 7.2 Hz, 3 H), 1.50 (d, J = 7.2 Hz, 3 H),
2.32 (s, 3 H), 2.33 (s, 3 H), 4.17 (m, 4 H), 5.03 (q, J = 6.8 Hz, 1 H),
5.06 (q, J = 7.2 Hz, 1 H), 5.20 (s, 1 H), 6.15 (br s, 1 H, NH), 6.98
(m, 1 H), 7.06 (dd, J = 1.2 Hz, J = 5.0 Hz,1 H), 7.12 (dd, J = 3.0 Hz,
J = 4.9 Hz, 1 H).
Anal. Calcd for C27H33NO8: C, 64.92; H, 6.66; N, 2.80. Found: C,
65.18; H, 6.69.
13C NMR (100 MHz, CDCl3): d = 14.05, 14.07, 16.96, 17.08, 19.43,
19.63, 34.33, 61.07, 61.20, 68.30, 68.46, 102.43, 103.00, 120.55,
124.49, 127.69, 145.22, 145.81, 147.50, 166.66, 166.72, 171.35,
171.49.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 4-Heptyl-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate (4h)
The product was prepared according to the typical procedure from
octanal (3h) (0.256 g, 2 mmol), b-keto ester 1a (0.836 g, 4 mmol)
and Mg3N2 (2) (0.100 g, 1 mmol). The crude mixture was extracted
with EtOAc (3 × 10 mL), dried over Na2SO4 and purified by flash
chromatography (EtOAc–cyclohexane, 35:65).
Yellow oil; yield: 0.572 g (58%); [a]D20 +52.00 (c 0.9, CHCl3).
IR (film): 1741, 1696 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.83 (t, J = 7.0 Hz, 3 H), 1.19–1.41
(complex pattern, 18 H), 1.48 (d, J = 7.2 Hz, 3 H), 1.49 (d, J = 6.8
Hz, 3 H), 2.23 (s, 3 H), 2.26 (s, 3 H), 3.95 (t, J = 5.6 Hz, 1 H), 4.18
(m, 4 H), 5.05 (q, J = 7.2 Hz, 1 H), 5.06 (q, J = 6.8 Hz, 1 H), 6.32
(s, 1 H, NH).
MS (ESI): m/z = 480 [M + H]+.
Anal. Calcd for C23H29NO8S: C, 57.61; H, 6.10; N, 2.92. Found: C,
57.80; H, 6.30.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-(pyridin-
3-yl)-1,4-dihydropyridine-3,5-dicarboxylate (4k)
The product was prepared according to the typical procedure from
pyridine-3-carbaldehyde (3k) (0.332 g, 2 mmol), b-keto ester 1a
(0.836 g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The crude mix-
ture was extracted with EtOAc (3 × 10 mL), dried over Na2SO4 and
purified by flash chromatography (EtOAc–cyclohexane, 9:1).
13C NMR (100 MHz, CDCl3): d = 14.03, 14.06, 16.95, 16.98, 19.12,
19.16, 22.62, 24.70, 29.39, 29.92, 31.92, 32.70, 36.95, 60.94, 61.12,
68.05, 68.09, 101.93, 102.47, 146.00, 146.39, 167.11, 167.41,
171.58, 171.71.
White solid; yield: 0.549 g (58%); mp 127 °C; [a]D20 +74.00 (c 1.0,
CHCl3).
IR (film): 1741, 1699 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.11 (t, J = 7.0 Hz, 3 H), 1.24 (t,
J = 6.8 Hz, 3 H), 1.43 (d, J = 7.1 Hz, 3 H), 1.48 (d, J = 7.1 Hz, 3 H),
2.33 (s, 3 H), 2.36 (s, 3 H), 4.04 (m, 2 H), 4.18 (m, 2 H), 4.95 (q,
J = 7.1 Hz, 1 H), 5.00 (q, J = 7.1 Hz, 1 H), 5.04 (s, 1 H), 6.90 (s, 1
H, NH), 7.16 (dd, J = 4.7 Hz, J = 7.7 Hz, 1 H), 7.64 (m, 1 H), 8.36
(m, 1 H), 8.52 (d, J = 2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.95, 14.05, 16.89, 17.02, 19.19,
19.41, 37.55, 60.97, 61.29, 68.26, 68.48, 101.99, 102.74, 123.04,
135.92, 143.19, 145.69, 146.59, 147.14, 149.65, 166.28, 166.29,
171.02, 171.51.
MS (ESI): m/z = 496 [M + H]+.
Anal. Calcd for C26H41NO8: C, 63.01; H, 8.34; N, 2.83. Found: C,
63.17; H, 8.36.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-(thien-2-
yl)-1,4-dihydropyridine-3,5-dicarboxylate (4i)
The product was prepared according to the typical procedure from
thiophene-2-carbaldehyde (3i) (0.332 g, 2 mmol), b-keto ester 1a
(0.836 g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The crude mix-
ture was extracted with EtOAc (3 × 10 mL), dried over Na2SO4 and
purified by flash chromatography (EtOAc–cyclohexane, 35:65).
MS (ESI): m/z = 475 [M + H]+.
Yellow oil; yield: 0.268 g (28%); [a]D20 +33.08 (c 1.3, CHCl3).
IR (Nujol): 1737, 1697 cm–1.
Anal. Calcd for C24H30N2O8: C, 60.75; H, 6.37; N, 5.90. Found: C,
60.91; H, 6.39.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 7.6 Hz, 3 H), 1.26 (t,
J = 7.1 Hz, 3 H), 1.48 (d, J = 7.1 Hz, 3 H), 1.50 (d, J = 7.1 Hz, 3 H),
2.36 (s, 3 H), 4.19 (m, 4 H), 5.06 (q, J = 7.1 Hz, 1 H), 5.10 (q,
J = 7.1 Hz, 1 H), 5.42 (s, 1 H), 6.01 (s, 1 H, NH), 6.86 (m, 2 H), 7.05
(dd, J = 1.4 Hz, J = 5.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.04, 14.08, 16.96, 17.07, 19.52,
19.79, 34.25, 61.06, 61.17, 68.45, 68.59, 102.89, 103.31, 123.13,
123.46, 126.41, 144.96, 145.64, 151.34, 166.38, 166.44, 171.23,
171.37.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-(naphtha-
len-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate (4l)
The product was prepared according to the typical procedure from
naphthalene-2-carbaldehyde (3l) (0.312 g, 2 mmol), b-keto ester 1a
(0.808 g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The crude mix-
ture was extracted with EtOAc (3 × 10 mL), dried over MgSO4 and
purified by flash chromatography (EtOAc–cyclohexane, 35:65).
Yellow oil; yield: 0.543 g (52%); [a]D20 +49.60 (c 1.0, CHCl3).
IR (film): 1744, 1699 cm–1
1H NMR (400 MHz, CDCl3): d = 0.95 (t, J = 7.1 Hz, 3 H), 1.20 (t,
J = 7.1 Hz, 3 H), 1.39 (d, J = 7.1 Hz, 3 H), 1.44 (d, J = 7.1 Hz, 3 H),
2.36 (s, 6 H), 3.95 (m, 2 H), 4.16 (m, 2 H), 4.90 (q, J = 7.1 Hz, 1 H),
5.02 (q, J = 7.1 Hz, 1 H), 5.23 (s, 1 H), 5.87 (s, 1 H, NH), 7.36 (m,
2 H), 7.49 (dd, J = 1.8 Hz, J = 8.7 Hz, 1 H), 7.68–7.77 (complex
pattern, 4 H).
MS (ESI): m/z = 480 [M + H]+.
Anal. Calcd for C23H29NO8S: C, 57.61; H, 6.10; N, 2.92. Found: C,
57.80; H, 6.30.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-(thien-3-
yl)-1,4-dihydropyridine-3,5-dicarboxylate (4j)
The product was prepared according to the typical procedure from
thiophen-3-carbaldehyde (3j) (0.332 g, 2 mmol), b-keto ester 1a
(0.836 g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The crude mix-
ture was extracted with EtOAc (3 × 10 mL), dried over Na2SO4 and
purified by flash chromatography (EtOAc–cyclohexane, 35:65).
13C NMR (100 MHz, CDCl3): d = 13.53, 13.93, 16.82, 16.93, 18.98,
19.30, 39.70, 60.72, 61.18, 68.01, 68.35, 102.34, 103.26, 124.94,
125.37, 126.52, 127.12, 127.21, 127.28, 127.67, 132.19, 133.16,
144.98, 145.09, 146.07, 166.71, 171.19, 171.79.
MS (ESI): m/z = 524 [M + H]+.
Yellow oil; yield: 0.704 g (73%); [a]D20 +52.35 (c 1.7, CHCl3).
Anal. Calcd for C29H33NO8: C, 66.53; H, 6.35; N, 2.68. Found: C,
66.71; H, 6.37.
IR (film): 1740, 1698 cm–1.
Synthesis 2011, No. 7, 1071–1078 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 1,4-Dihydropyridines
1077
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 2,6-Dimethyl-4-(6-meth-
oxynaphthalen-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(4m)
The product was prepared according to the typical procedure from
6-methoxynaphthalene-2-carbaldehyde (3m) (0.300 g, 1.6 mmol),
b-keto ester 1a (0.649 g, 3.2 mmol) and Mg3N2 (2) (0.083 g, 0.8
mmol). The reaction mixture was stirred for 29 h at 90–100 °C, and
then at r.t. for an additional 48 h. The crude mixture was extracted
with CH2Cl2 (3 × 15 mL), dried over MgSO4 and purified by flash
chromatography (EtOAc–cyclohexane, 35:65).
CH2Cl2 (3 × 10 mL), dried over MgSO4 and purified by flash chro-
matography (Et2O–cyclohexane, 30:70).
Yellow solid; yield: 0.589 g (50%); mp 151 °C; [a]D20 –26.25 (c 0.8,
CHCl3).
IR (Nujol): 1700 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.49 (d, J = 7.1 Hz, 3 H), 0.58 (d,
J = 7.1 Hz, 3 H), 0.76 (d, J = 6.9 Hz, 3 H), 0.84 (d, J = 6.5 Hz, 3 H),
0.90 (d, J = 6.5 Hz, 3 H), 0.94 (d, J = 7.1 Hz, 3 H), 0.72–2.08 (com-
plex pattern, 18 H), 2.33 (s, 3 H), 2.43 (s, 3 H), 4.67 (dt, J = 4.3 Hz,
J = 11.2 Hz, 2 H), 5.10 (s, 1 H), 5.64 (br s, 1 H, NH), 7.38 (t, J = 8.1
Hz, 1 H), 7.62 (dt, J = 1.4 Hz, J = 8.1 Hz, 1 H), 8.01 (ddd, J = 1.0
Hz, J = 2.4 Hz, J = 5.9 Hz, 1 H), 8.14 (t, J = 2.2 Hz, 1 H).
Yellow oil; yield: 0.224 g (26%); [a]D20 +54.27 (c 1.0, CHCl3).
IR (film): 1740, 1691 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.97 (t, J = 7.1 Hz, 3 H), 1.23 (t,
J = 7.1 Hz, 3 H), 1.42 (d, J = 7.1 Hz, 3 H), 1.47 (d, J = 7.1 Hz, 3 H),
2.35 (s, 3 H), 2.38 (s, 3 H), 3.89 (s, 3 H), 3.94 (m, 2 H), 4.18 (m,
2H), 4.91 (q, J = 7.1 Hz, 1 H), 5.01 (q, J = 7.1 Hz, 1 H), 5.19 (s, 1
H), 6.16 (s, 1 H, NH), 7.01–7.13 (m, 2 H), 7.46 (dd, J = 1.8 Hz,
J = 8.5 Hz, 1 H), 7.61 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 15.64, 16.87, 19.61, 20.91, 22.06,
22.85, 23.91, 25.52, 31.46, 34.35, 39.96, 41.05, 41.58, 47.27, 47.54,
73.33, 74.10, 103.19, 104.10, 121.23, 123.39, 128.68, 134.60,
144.25, 145.37, 148.05, 150.13, 166.69.
MS (ESI): m/z = 595 [M + H]+.
13C NMR (100 MHz, CDCl3): d = 13.72, 14.03, 16.90, 17.03, 18.40,
19.74, 39.52, 55.23, 60.85, 61.16, 68.15, 68.42, 102.96, 103.81,
105.51, 118.17, 126.12, 126.41, 127.73, 128.74, 129.27, 133.18,
142.91, 144.38, 145.44, 157.11, 166.72, 166.78, 171.20, 171.61.
Anal. Calcd for C35H50N2O6: C, 70.68; H, 8.47; N, 4.71. Found: C,
70.93; H, 8.50.
Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] 2,6-Dimethyl-
4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4p)
The product was prepared according to the typical procedure from
2-nitrobenzaldehyde (3d) (0.302 g, 2 mmol), b-keto ester 1b (0.960
g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The mixture was
stirred for 24 h at 90–100 °C, then at 120 °C for 8 h, and then at r.t.
for an additional 48 h. The crude mixture was extracted with CH2Cl2
(3 × 10 mL), dried over MgSO4 and purified by flash chromatogra-
phy (Et2O–cyclohexane, 30:70).
MS (ESI): m/z = 554 [M + H]+.
Anal. Calcd for C30H35NO9: C, 65.09; H, 6.37; N, 2.53. Found: C,
65.30; H, 6.39.
Bis[(2S)-1-ethoxy-1-oxopropan-2-yl] 4-[1-(tert-Butoxycarbon-
yl)-1H-indol-3-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicar-
boxylate (4n)
The product was prepared according to the typical procedure from
tert-butyl-3-formyl-1H-indole-1-carboxylate (3n) (0.492, 2.0
mmol), b-keto ester 1a (0.808 g, 2.0 mmol) and Mg3N2 (2) (0.100
g, 1.0 mmol). The reaction mixture was stirred for 29 h at 90–100
°C, and then at r.t. for an additional 48 h. The crude mixture was ex-
tracted with CH2Cl2 (3 × 15 mL), dried over MgSO4 and purified by
flash chromatography (EtOAc–cyclohexane, 35:65).
Yellow solid; yield: 287 mg (25%); mp 93 °C; [a]D20 +20.87 (c 1.0,
CHCl3).
IR (CHCl3): 1687 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.46 (d, J = 7.1 Hz, 3 H), 0.51 (d,
J = 7.1 Hz, 3 H), 0.65 (d, J = 6.7 Hz, 3 H), 0.82 (d, J = 6.7 Hz, 6 H),
0.88 (d, J = 7.1 Hz, 9 H), 0.90–1.94 (complex pattern, 12 H), 2.27
(s, 3 H), 2.34 (s, 3 H), 4.64 (dq, J = 4.3 Hz, J = 9.8 Hz, 2 H), 5.78
(br s, 1 H, NH), 5.96 (s, 1 H), 7.23 (m, 1 H), 7.46 (dt, J = 1.2 Hz,
J = 7.1 Hz, 1 H), 7.56 (dd, J = 1.2 Hz, J = 7.9 Hz, 1 H), 7.81 (dd,
J = 1.2 Hz, J = 8.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 15.58, 16.34, 19.71, 19.99, 20.62,
20.99, 20.98, 22.84, 23.54, 25.24, 26.33, 31.42, 31.50, 34.08, 34.18,
39.68, 40.22, 40.72, 46.14, 46.40, 73.37–73.42, 74.16–74.21,
103.92, 104.45, 124.21, 126.61, 131.60, 132.76, 143.45, 143.76,
145.00, 147.42, 166.80, 166.97.
Yellow oil; yield: 0.272 g (22%); [a]D20 +38.34 (c 0.8, CHCl3).
IR (CH2Cl2): 1732, 1699 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.96 (t, J = 7.1 Hz, 3 H), 1.24 (t,
J = 7.1 Hz, 3 H), 1.36 (d, J = 7.1 Hz, 3 H), 1.43 (d, J = 7.1 Hz, 3 H),
1.64 (s, 9 H), 2.28 (s, 3 H), 2.35 (s, 3 H), 3.80–3.99 (complex pat-
tern, 2 H), 4.19 (m, 2 H), 4.91 (q, J = 7.1 Hz, 1 H), 5.00 (q, J = 7.1
Hz, 1 H), 5.34 (s, 1 H), 6.59 (br s, 1 H, NH), 7.02 (d, J = 2.4 Hz, 1
H), 7.15–7.24 (complex pattern, 2 H), 7.38 (s, 1 H), 7.67 (d, J = 7.9
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.60, 13.98, 16.82, 16.89, 19.07,
19.47, 28.13, 30.70, 60.76, 61.20, 68.11, 68.38, 83.24, 102.72,
110.87, 114.80, 120.44, 121.98, 123.55, 124.40, 129.66, 144.48,
145.69, 166.78, 171.14, 171.80.
MS (ESI): m/z = 595 [M + H]+.
Anal. Calcd for C35H50N2O6: C, 70.68; H, 8.47; N, 4.71. Found: C,
70.96; H, 8.80.
MS (ESI): m/z = 613 [M + H]+.
Acknowledgment
Anal. Calcd for C32H40N2O10: C, 62.73; H, 6.58; N, 4.57. Found: C,
62.91; H, 6.60.
S.L. thanks the China Scholarship Council (CSC) for a Scholarship
(2009–2012). We thank Glyconova (Colleretto Giacosa, Italy) for
financial support and Dr. S. Biondi for helpful discussions.
Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] 2,6-Dimethyl-
4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4o)
The product was prepared according to the typical procedure from
3-nitrobenzaldehyde (3c) (0.302 g, 2 mmol), b-keto ester 1b (0.960
g, 4 mmol) and Mg3N2 (2) (0.100 g, 1 mmol). The mixture was
stirred for 28 h at 90–100 °C. The crude mixture was extracted with
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Synthesis 2011, No. 7, 1071–1078 © Thieme Stuttgart · New York

1078
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PAPER
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Synthesis 2011, No. 7, 1071–1078 © Thieme Stuttgart · New York