L-Proline-catalyzed synthesis of highly functionalized multisubstituted 1,4-dihydropyridines

Article abstract of DOI:10.1039/b914659h

Highly functionalized multisubstituted 1,4-dihydropyridines 5 have been concisely synthesized in moderate to good yields vial-proline-catalyzed one-pot multicomponent reactions (MCRs) of alkynoates or alkynones 1, amines 2, β-dicarbonyl compounds 3 and aldehydes 4 under mild conditions. The MCR process involves hydroamination/Knoevenagel condensation/Michael-type addition/intramolecular cyclization processes and leads to the formation of 1,4-dihydropyridines 5. The molecular structure of 5ckaa was confirmed by single-crystal X-ray diffraction. This method is energy saving and environmentally friendly, providing easy access to diverse multisubstituted polyfunctional 1,4-dihydropyridines. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b914659h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
L-Proline-catalyzed synthesis of highly functionalized multisubstituted
1,4-dihydropyridines†
Huanfeng Jiang,* Ronghuan Mai, Hua Cao, Qiuhua Zhu and Xiaohang Liu
Received 20th July 2009, Accepted 8th September 2009
First published as an Advance Article on the web 5th October 2009
DOI: 10.1039/b914659h
Highly functionalized multisubstituted 1,4-dihydropyridines 5 have been concisely synthesized in
moderate to good yields via L-proline-catalyzed one-pot multicomponent reactions (MCRs) of
alkynoates or alkynones 1, amines 2, b-dicarbonyl compounds 3 and aldehydes 4 under mild
conditions. The MCR process involves hydroamination/Knoevenagel condensation/Michael-type
addition/intramolecular cyclization processes and leads to the formation of 1,4-dihydropyridines 5.
The molecular structure of 5ckaa was confirmed by single-crystal X-ray diffraction. This method is
energy saving and environmentally friendly, providing easy access to diverse multisubstituted
polyfunctional 1,4-dihydropyridines.
Introduction
Multicomponent reactions (MCRs) have been steadily gaining im-
portance in synthetic organic chemistry.1 They offer the advantage
of simplicity and synthetic efficiency over conventional chemical
reactions, and have emerged as powerful efficient tools for the
construction of complex and diverse organic molecules.2
On the other hand, dihydropyridines (DHPs) have exhibited a
broad range of biological activities3 and potential pharmaceutical
applications.4 They have also been recognized as versatile synthetic
intermediates5 and widely employed as a hydride source for
reductive amination.6 Since Hantzsch’s pioneering work more than
one century ago,7 the construction of multisubstituted dihydropy-
ridines has attracted considerable attention in synthetic organic
chemistry. Many efficient synthetic methods for the preparation
of these compounds have been reported for decades,8-18 however,
they are restricted to the use of expensive metal precursors,
Scheme 1 Divergent pathways for multicomponent domino reactions.
catalysts that are harmful to the environment, high reaction
temperatures and long reaction times. Thus, it is an important and
challenging goal of synthetic chemistry to develop new MCRs that
construct highly functionalized multisubstituted dihydropyridines
from easily available starting materials under mild conditions.19
Previously, we have reported the preparation of multisubsti-
tuted tetrahydropyrimidines,20 1,3-oxazine-6-ones,21 3,6-dihydro-
2H-1,3-oxazines22 and polyfunctional dihydropyrroles23 through
multicomponent domino reactions of alkynoates, amines, and
aldehydes (Scheme 1). These inspiring results prompted us
to search for a facile route for novel nitrogenous heterocycle
tetrahydropyridines 8 (Scheme 2). It was unexpected that the
1,4-dihydropyridine compound instead of 8 was obtained after
our considerable efforts to develop efficient protocols for 8. In
this paper, we present this efficient access to highly functionalized
Scheme 2 Hypothetical route for the synthesis of 8.
School of Chemistry and Chemical Engineering, South China University
of Technology, Guangzhou 510640, P.R. of China. E-mail: jianghf@
scut.edu.cn; Fax: (+86)20-8711-2906
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. CCDC reference number 744016.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b914659h
multisubstituted 1,4-dihydropyridines via the successful L-proline-
catalyzed MCRs of alkynoates or alkynones, amines, b-dicarbonyl
compounds and aldehydes under mild conditions.
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Table 1 The MCR for the synthesis of 5aaaa with different catalystsa
Yieldb (%)
Entry
Catalyst
Time (h)
5aaaa
6
7
1
2
3
4
5
6
7
8
5 mol% HCl
5 mol% HOAc
5 mol% ZnCl2
5 mol% AlCl3
5 mol% FeCl3
5 mol% FeCl2
5 mol% Iron(III) 2,4-pentanedionate
5 mol% SnCl2
5 mol% Boron trifluoride etherate
5 mol% L-Proline
10 mol% L-Proline
10 mol% L-phenylalanine
10 mol% L-Valine
10 mol% L-Leucine
10 mol% L-Serine
0.5
0.5
3
3
3
3
3
3
3
19
37
43
34
25
18
41
16
13
52
75
52
58
53
42
36
41
33
43
52
63
45
62
72
3
37
13
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
9
10
11
12
13
14
15
6
12
12
12
12
12
4
31
27
27
43
a Reaction conditions: diethyl butynedioate 1a (1.0 mmol), aniline 2a (1.0 mmol), acetylacetone 3a (1.0 mmol), formaldehyde 4a (1.0 mmol), ethanol
(3 mL), RT. b Determined by GC.
Table 2 Further optimization of the MCR for the synthesis of 5aaaaa
Results and discussion
Optimization of reaction conditions for the synthesis of 5aaaa
In our initial studies, diethyl butynedioate 1a (1.0 mmol), aniline
2a (1.0 mmol), acetylacetone 3a (1.0 mmol), and formaldehyde
4a (1.0 mmol) were reacted in the presence of Brønsted acids
in ethanol to test the hypothesis (Table 1, entries 1 and 2).
The resulting mixtures afforded diethyl 5-acetyl-1,4-dihydro-
6-methyl-1-phenylpyridine-2,3-dicarboxylate 5aaaa, diethyl 3,6-
dihydro-3-phenyl-2H-1,3-oxazine-4,5-dicarboxylate 6 and diethyl
1,3-diphenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate 7 in
different yields respectively. No trace of the hypothetical product
8 was found.
1a:2a:3a:4a
Entry
Solvent
[mole ratio]
Yieldb(%)
1
2
3
4
5
6
7
8
EtOH
CH2Cl2
MeCN
THF
1,4-Dioxane
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:2
1:1:1:4
1:1:2:2
1:1:2:1
1:1:1.5:1
1:1:1.5:1.2
1:1:1.5:1.2
75
61
57
38
64
67
72
66
74
77
77
79
41
As the result of further screening of the reaction conditions for
the new target product 5aaaa, a series of Lewis acids were found
to vary the ratio of 5aaaa and 6 (Table 1, entries 3–9), indicating
competitive reactions in this catalytic system. We had to turn our
attention to finding a new catalyst for the synthesis of 5aaaa.
Due to two functional groups in one molecule, L-proline has been
found to be very effective in direct catalytic asymmetric reactions,24
including the synthesis of 1,4-dihydropyridines.25 Fortunately,
when we used L-proline was as a catalyst, the reaction gave 5aaaa
in up to 52% yield (Table 1, entry 10). Further study indicated that
increasing the amount of L-proline and prolonging the reaction
time gave a good yield (Table 1, entry 11). Other amino acids such
as L-phenylalanine, L-valine, L-leucine and L-serine gave relatively
lower yields (Table 1, entries 12–15).
9
10
11
12
13c
a All reactions were carried out using the substrates according to the
indicated ratio in the mmol scale, solvent (3 mL), L-proline (10 mol%),
RT, 12 h. b Determined by GC. c 50 ◦C, 2 h.
The effects of solvent and the mole ratio of reactants for
the multicomponent reaction were also investigated. Among the
various solvents, ethanol was the most effective (Table 2, entry 1).
Other solvents such as CH2Cl2, MeCN, THF, 1,4-dioxane and
DMF gave 5aaaa in 38–67% yields (Table 2, entries 2–6). After
screening the mole ratio of reactants, a 79% yield was obtained
4944 | Org. Biomol. Chem., 2009, 7, 4943–4953
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in the mole ratio of 1a/2a/3a/4a = 1:1:1.5:1.2 (Table 2, entry
12). However, when we used ethanol as the solvent and heated the
reaction to 50 ◦C, it promoted the formation of 6 and only 41% of
5aaaa was obtained (Table 2, entry 13).
Possible mechanism for the formation of 5
According to the experimental results mentioned above, a plausi-
ble reaction mechanism was proposed as shown in Scheme 3. The
MCRs underwent the following sequences: the proline-catalyzed
Knoevenagel condensation of 3 and 4, the proline-catalyzed
Michael-type addition of intermediates D to C, the tautomeriza-
tion of E and F, and intramolecular cyclization of intermediate F.
In the Knoevenagel condensation, the carboxyl group of proline
activates the carbonyl acceptors 4 by hydrogen bonding. Then
the nitrogen of proline attacks the carbonyl group with higher
activity in 4, followed by the formation of adduct B, and then the
Knoevenagel product C with the regeneration of L-proline.25c,27
The p (C–C) bond electrons instead of lone pair electrons on the
nitrogen in the Z- and E-isomers D,20c,23 which were obtained
via the hydramination of 1 with 2, attack the active carbon in
intermediate C under the catalysis of bifunctional L-proline and
give the intermediate E. This is followed by the tautomerization
of E and F, and then the intermolecular cyclization of F to give
the target products 5.
Scope of the MCRs for the synthesis of 1,4-dihydropyridines
On the basis of the above optimization, we examined the scope
of the multicomponent reaction (Table 3). We were pleased
to find that the reaction proceeded smoothly, and the desired
products were afforded in moderate to good yields. The electronic
effects of the substituents on the aromatic ring of the aromatic
amines had a slight influence on the reaction: the electron-
donating groups (Table 3, entries 5–6) gave higher yields than
the electron-withdrawing groups (Table 3, entries 2–4). Sterically
hindered amines such as o-toluidine and naphthalen-1-amine also
performed well (Table 3, entries 7–8). The results indicated that
the activity of aliphatic primary amines was higher than that of
the aromatic ones (Table 3, entries 9–10).
Alkynones with aryl- or alkyl-substituted groups were also
employed as substrates for the multicomponent reaction and
afforded moderate to good yields (Table 3, entries 11–18). The
electronic effects of the substituents on the aromatic ring of
the alkynones (Table 3, entries 14–15) did not significantly
influence the yields. But the heterocyclic alkynone (Table 3,
entry 16) and the cyclohexyl alkynone (Table 3, entry 17)
gave slightly reduced yields. Other b-dicarbonyl compounds
such as ethyl acetoacetate (Table 3, entries 19–22) and benzoyl
acetone (Table 3, entry 23) were also tolerated under similar
conditions, although it was necessary to increase the amount of
ethyl acetoacetate (2 equiv.) and afforded the product in lower
yields.
Conclusions
In conclusion, we have described a convenient and efficient
one-pot synthesis of highly functionalized multisubstituted
1,4-dihydropyridines via multicomponent domino reactions. The
notable advantages of this method are mild reaction conditions
and the use of inexpensive, non-toxic ethanol and L-proline. This
method is energy saving and environmentally friendly. Moreover,
due to the easy availability of the starting materials, solvent and
catalyst, this reaction may find applications in organic synthesis.
Further studies and applications of this multicomponent reaction
are ongoing in our laboratory and will be published in due course.
We also attempted to carry out the reaction with acetaldehyde 4b
(Table 3, entry 24). The reaction was successful but gave a racemic
product 5bka◦b in 84% yield. When the reaction temperature was
lowered to 5 C to perform the reaction, racemic 5bkab was still
obtained. More bulky 4c was used, but also without chirality
detected (Table 3, entry 25).
Experimental section
General
¨
Melting points were measured with a BUCHI B-545 melting point
instrument and were uncorrected. 1H and 13C NMR spectra were
recorded using a Bruker Avance 400 MHz NMR spectrometer.
The chemical shifts are referenced to signals at 7.24 and 77.0 ppm,
respectively, for chloroform solvent with TMS as the internal
standard. IR spectra were obtained either as potassium bromide
pellets or as liquid films between two potassium bromide pellets
with a Bruker Vector 22 spectrometer. Mass spectra were recorded
on a Shimadzu GCMS-QP5050A spectrometer at an ionization
voltage of 70 eV equipped with a DB-WAX capillary column
(internal diameter: 0.25 mm, length: 30 m). Elemental analyses
were performed with a Vario EL elemental analyzer. TLC was
performed by using commercially prepared 100–400 mesh silica
gel plates (GF254) and visualization was effected at 254 nm. The
alkynones were prepared by the Sonagashira couplings between
acyl chlorides and terminal alkynes. All the other chemicals were
purchased from Aldrich Chemicals.
The molecular structure of 5ckaa was determined by X-ray
crystallography (Fig. 1).26
General procedure for the synthesis of 1,4-dihydropyridine 5 (A).
Amine 2 (1.0 mmol) was added to a stirring solution of alkyne 1
(1.0 mmol) in ethanol (3 mL). After the mixture was stirred at room
temperature for 30 min, b-dicarbonyl compound 3 (1.5 mmol),
Fig. 1 X-Ray structure of 5ckaa. Ellipses are shown at the 30% probability
level.
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Table 3 Synthesis of multisubstituted polyfunctional 1,4-dihydropyridines via the MCRa
Entry
1
Alkynoate/Alkynone
Amine
b-Dicarbonyl compound
Aldehyde
Product
Yieldb(%)
1a
2a
3a
HCHO
4a
5aaaa 74
2
3
4
1a
1a
1a
2b
3a
3a
3a
4a
4a
4a
5abaa 70
5acaa 68
5adaa 71
2c
2d
5
1a
1a
2e
3a
3a
4a
4a
5aeaa 74
6
2f
5afaa 72
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Table 3 (Contd.)
Entry
7
Alkynoate/Alkynone
Amine
b-Dicarbonyl compound
Aldehyde
Product
Yieldb(%)
1a
1a
1a
1a
2g
3a
4a
5agaa 71
8
9
2h 3a
4a
4a
5ahaa 65
2i
3a
5aiaa 79
10
11
2j
3a
3a
4a
4a
5ajaa 78
5baaa 76
1b
2a
12
1b
2i
3a
4a
5biaa 83
13
1b
2k
3a
4a
5bkaa 85
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Table 3 (Contd.)
Entry
14
Alkynoate/Alkynone
Amine
1c 2k
b-Dicarbonyl compound
Aldehyde
Product
Yieldb(%)
82
3a
4a
5ckaa
15
1d 2k
3a
4a
5dkaa
86
16
17
1e
2k
2k
3a
3a
4a
4a
5ekaa
5fkaa
76
78
1f
18
1g 2k
3a
4a
5gkaa
62
19
20
1a
1a
2a
2c
3bc
4a
4a
5aaba
5acba
65
64
3bc
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Table 3 (Contd.)
Entry
21
Alkynoate/Alkynone
Amine
b-Dicarbonyl compound
Aldehyde
Product
Yieldb(%)
67
1a
2l
3bc
4a
5alba
22
23
1b
1b
2k
2k
3bc
4a
4a
5bkba
5bkca
71
83
3c
24
25
1b
1b
2k
2k
3a
3a
MeCHO
4b
5bkab
84
67
4cd
5bkac
a Reaction conditions: alkynoate/alkynone (1.0 mmol), amine (1.0 mmol), b-dicarbonyl compound (1.5 mmol), aldehyde (1.2 mmol), ethanol (3 mL),
L-proline (10 mol%), RT, 12 h. b Isolated yield. c 2.0 mmol. d 50 ◦C, 24 h.
aldehyde 4 (1.2 mmol) and L-proline (12 mg, 10 mol%) were
added successively, and stirring continued for another 12 h. The
progress of the reaction was followed by TLC. After completion
of the reaction, the solvent was removed under reduced pressure,
then the mixture was diluted with water and extracted with
diethyl ether (15 mL ¥ 3). The organic phase was washed with
saturated brine, and dried with anhydrous MgSO4. The solvent was
removed in vacuo and the crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate = 2:1) to afford
the products 5aaaa–5ajaa, 5baaa–5gkaa, 5bkca and 5bkab in 62–
86% yields.
General procedure for the synthesis of 1,4-dihydropyridine 5
(B). Amine 2 (1.0 mmol) was added to a stirring solution of
alkyne 1 (1.0 mmol) in ethanol (3 mL). After the mixture was
stirred at room temperature for 30 min, ethyl acetoacetate 3b
(260mg, 2.0 mmol), 35% formaldehyde 4a (103 mg, 1.2 mmol) and
L-proline (12 mg, 10 mol%) were added successively, and stirring
continued for another 12 h. The progress of the reaction was
followed by TLC. After completion of the reaction, the solvent was
removed under reduced pressure, then the mixture was diluted with
water and extracted with diethyl ether (15 mL ¥ 3). The organic
phase was washed with saturated brine, and dried with anhydrous
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Scheme 3 A plausible mechanism for this MCR.
MgSO4. The solvent was removed in vacuo and the crude product
was purified by silica gel chromatography (petroleum ether/ethyl
acetate = 4:1) to afford the products 5aaba, 5acba, 5alba and 5bkba
in 64–71% yields.
163.7, 161.3, 145.4, 143.6, 134.6, 132.8,132.7, 116.1, 115.9, 110.4,
101.9, 61.7, 60.7, 29.9, 24.9, 17.9, 14.2,13.4; EI-MS: m/z =
375(M+, 18), 332(62), 286(73), 258(100), 186(56); Anal. Calcd for
C20H22FNO5: C, 63.99; H, 5.91; N, 3.73; Found: C, 63.82; H, 6.03;
N, 3.68.
General procedure for the synthesis of 1,4-dihydropyridine 5
(C). 30% methanamine 2k (103mg, 1.0 mmol) was added to a
stirring solution of alkynone 1b (206mg, 1.0 mmol) in ethanol
(3 mL). After the mixture was stirred at room temperature for
30 min, acetylacetone 3a (150mg, 1.5 mmol), 4-nitrobenzaldehyde
4c (181 mg, 1.2 mmol) and L-proline (12 mg, 10 mol%) were
added successively, and stirring continued for another 24 h at
Diethyl 5-acetyl-1-(4-chlorophenyl)-1,4-dihydro-6-methylpyri-
dine-2,3-dicarboxylate (5acaa). Yellow oil; IR (KBr): Vmax
=
1
2984, 1766, 1698, 1489, 1373, 1244, 1112, 1053 cm-1; H NMR
(400 MHz, CDCl3): d = 7.31–7.28(m, 2H), 7.13–7.11(m, 2H),
4.11(q, J = 7.2 Hz, 2H), 3.81(q, J = 7.2 Hz, 2H), 3.41(s, 2H),
2.19(s, 3H), 1.77(s, 3H), 1.19 (t, J = 7.2 Hz, 3H), 0.93 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 199.5, 165.7,
163.7, 145.2, 143.3, 137.1, 135.2, 132.2, 129.3, 110.4, 101.9,
61.7, 60.7, 30.0, 24.8, 18.0, 14.2, 13.4; EI-MS: m/z = 391(M+,
14), 348(28), 302(23), 274(24), 202(17), 28(100); Anal. Calcd for
C20H22ClNO5: C, 61.30; H, 5.66; N, 3.57; Found: C, 61.08; H,
5.81; N, 3.49.
◦
50 C. The progress of the reaction was followed by TLC. After
completion of the reaction, the solvent was removed under reduced
pressure, then the mixture was diluted with water and extracted
with diethyl ether (15 mL ¥ 3). The organic phase was washed with
saturated brine, and dried with anhydrous MgSO4. The solvent was
removed in vacuo and the crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate = 2:1) to afford
the product 5bkac in 67% yield.
Diethyl 5-acetyl-1-(4-bromophenyl)-1,4-dihydro-6-methylpyri-
dine-2,3-dicarboxylate (5adaa). Yellow oil; IR (KBr): Vmax
=
1
Diethyl
5-acetyl-1,4-dihydro-6-methyl-1-phenylpyridine-2,3-
2991, 1765, 1699, 1458, 1375, 1244, 1108, 1054 cm-1; H NMR
(400 MHz, CDCl3): d = 7.46–7.44(m, 2H), 7.06–7.04(m, 2H),
4.11(q, J = 7.2 Hz, 2H), 3.81(q, J = 7.2 Hz, 2H), 3.41(s, 2H),
2.19(s, 3H), 1.77(s, 3H), 1.18 (t, J = 7.2 Hz, 3H), 0.93 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 199.4, 165.7,
163.7, 145.1, 143.3, 137.7, 132.5, 132.3, 123.3, 110.5, 102.0, 61.7,
60.7, 29.9, 24.9, 18.0, 14.2, 13.4; EI-MS: m/z = 435(M+, 17),
392(41), 318(62), 246(21), 28(100); Anal. Calcd for C20H22BrNO5:
C, 55.06; H, 5.08; N, 3.21; Found: C, 55.24; H, 5.16; N, 3.07.
dicarboxylate (5aaaa). Yellow oil; IR (KBr): Vmax = 2992, 1765,
1
1699, 1458, 1376, 1243, 1107, 1055 cm-1; H NMR (400 MHz,
CDCl3): d = 7.32–7.30(m, 3H), 7.18–7.16(m, 2H), 4.11(q, J =
7.2 Hz, 2H), 3.75(q, J = 7.2 Hz, 2H), 3.43(s, 2H), 2.19(s, 3H),
1.78(s, 3H), 1.18 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3): d = 199.5, 165.9, 163.8, 145.9, 143.7,
138.6, 130.9, 129.1, 129.0, 110.0, 101.5, 61.5, 60.6, 30.0, 24.9,18.0,
14.2,13.4; EI-MS: m/z = 357(M+, 8), 314(37), 268(45), 240(61),
168(34), 28(100); Anal. Calcd for C20H23NO5: C, 67.21; H, 6.49;
N, 3.92; Found: C, 67.43; H, 6.58; N, 4.01.
Diethyl 5-acetyl-1,4-dihydro-6-methyl-1-(3,4-dimethylphenyl)-
pyridine-2,3-dicarboxylate (5aeaa). Yellow oil; IR (KBr): Vmax
=
1
Diethyl 5-acetyl-1-(4-fluorophenyl)-1,4-dihydro-6-methylpyri-
2992, 1766, 1699, 1457, 1376, 1244, 1108, 1057 cm-1; H NMR
(400 MHz, CDCl3): d = 7.05–7.03(d, J = 8 Hz, 1H), 6.92–6.86(m,
2H), 4.10(q, J = 7.2 Hz, 2H), 3.79(q, J = 7.2 Hz, 2H), 3.41(s, 2H),
2.18(s, 6H), 2.17(s, 3H), 1.79(s, 3H), 1.18 (t, J = 7.2 Hz, 3H), 0.90
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 199.5, 165.9,
163.8, 146.4, 143.9, 137.8, 137.5, 136.0, 131.5, 130.0, 127.9, 109.7,
101.2, 61.4, 60.6, 30.0, 24.9, 19.6, 19.4, 18.0, 14.2,13.4; EI-MS:
dine-2,3-dicarboxylate (5abaa). Yellow oil; IR (KBr): Vmax
=
2991, 1740, 1699, 1456, 1372, 1245, 1114, 1053 cm-1; H NMR
(400 MHz, CDCl3): d = 7.18–7.14(m, 2H), 6.98–7.02(m, 2H),
4.11(q, J = 7.2 Hz, 2H), 3.80(q, J = 7.2 Hz, 2H), 3.41(s, 2H),
2.19(s, 3H), 1.77(s, 3H), 1.18 (t, J = 7.2 Hz, 3H), 0.93 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 199.5, 165.7,
1
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m/z = 385(M+, 25), 342(17), 296(12), 268(34), 196(9), 28(100);
Anal. Calcd for C22H27NO5: C, 68.55; H, 7.06; N, 3.63; Found: C,
68.42; H, 7.12; N, 3.56.
165.0, 145.6, 144.0, 111.5, 102.3, 62.2, 60.6, 42.0, 30.0, 24.5, 16.0,
15.5, 14.2, 13.8; EI-MS: m/z = 309(M+, 19), 266(44), 220(41),
192(61), 120(22), 28(100); Anal. Calcd for C16H23NO5: C, 62.12;
H, 7.49; N, 4.53; Found: C, 62.29; H, 7.62; N, 4.45.
Diethyl 5-acetyl-1,4-dihydro-1-(4-methoxyphenyl)-6-methylpyri-
dine-2,3-dicarboxylate (5afaa). Yellow oil; IR (KBr): Vmax
=
5-Acetyl-3-benzoyl-1,4-dihydro-1,2-diphenyl-6-methylpyridine
2992, 1767, 1698, 1472, 1376, 1243, 1107, 1054 cm-1; H NMR
(400 MHz, CDCl3): d = 7.13–7.11(m, 2H), 6.86–6.84(m, 2H),
4.15(q, J = 7.2 Hz, 2H), 3.85(q, J = 7.2 Hz, 2H), 3.79(s, 3H),
3.47(s, 2H), 2.24(s, 3H), 1.83(s, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.98
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 199.5, 165.9,
163.8, 159.8, 146.5, 144.1, 131.9, 131.1, 114.1, 110.0, 101.4, 61.5,
60.6, 55.5, 29.5, 24.9, 17.9, 14.2,13.5; EI-MS: m/z = 387(M+, 22),
344(46), 298(73), 270(100), 198(33); Anal. Calcd for C21H25NO6:
C, 65.10; H, 6.50; N, 3.62; Found: C, 65.36; H, 6.64; N, 3.51.
1
(5baaa). Reddish brown oil; IR (KBr): Vmax = 2923, 2852, 1740,
1
1640, 1457, 1108, 939, 533 cm-1; H NMR (400 MHz, CDCl3):
d = 7.52-7.50(m, 2H), 7.27-7.01 (m, 8H), 6.86-6.77(m, 5H), 3.70(s,
2H), 2.30(s, 3H), 2.07(s, 3H); 13C NMR (100 MHz, CDCl3): d =
199.6, 198.0, 148.6, 147.3, 140.7, 138.9, 134.3, 131.3, 131.1, 131.0,
128.7, 128.6, 128.1, 127.6, 127.2, 114.2, 110.1, 30.1, 28.0, 18.7; EI-
MS: m/z = 393(M+, 21), 350(9), 316(14), 288(12), 245(11) 28(100);
Anal. Calcd for C27H23NO2: C, 82.42; H, 5.89; N, 3.56; Found: C,
82.23; H, 5.99; N, 3.48.
Diethyl
5-acetyl-1,4-dihydro-6-methyl-1-o-tolylpyridine-2,3-
5-Acetyl-3-benzoyl-1-benzyl-1,4-dihydro-6-methyl-2-phenylpyri-
dine (5biaa). Reddish brown oil; IR (KBr): Vmax = 2921, 2853,
1739, 1649, 1459, 1103, 941, 530 cm-1; 1H NMR (400 MHz,
CDCl3): d = 7.43–7.41(m, 2H), 7.29–7.03(m, 13H), 4.54(s, 2H),
3.45(s, 2H), 2.42(s, 3H), 2.27(s, 3H); 13C NMR (100 MHz, CDCl3):
d = 199.1, 197.0, 151.2, 149.3, 139.2, 138.2, 133.8, 131.0, 130.6,
129.4, 128.9, 128.8, 128.2, 127.5, 126.2, 113.3, 50.8, 30.2, 27.3,16.2;
EI-MS: m/z = 407(M+, 6), 364(12), 316(42), 269(33), 91(100);
Anal. Calcd for C28H25NO2: C, 82.53; H, 6.18; N, 3.44; Found: C,
82.74; H, 6.33; N, 3.37.
dicarboxylate (5agaa). Yellow oil; IR (KBr): Vmax = 2991, 1766,
1698, 1458, 1375, 1244, 1108, 1056 cm-1; H NMR (400 MHz,
1
CDCl3): d = 7.30–7.15 (m, 4H), 4.18(q, J = 7.2 Hz, 2H),
3.85–3.75(m, 2H), 3.53(q, J = 17.6 Hz, 2H), 2.31(s, 3H), 1.81(s,
3H), 2.27(s, 3H), 1.26 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d = 199.5, 166.0, 163.6, 145.9,
143.4, 138.9, 137.3, 131.3, 130.8, 129.5, 126.5, 109.7, 101.6, 61.5,
60.7, 30.1, 25.0, 17.7, 17.3, 14.2,13.4; EI-MS: m/z = 371(M+, 32),
328(37), 282(87), 254(100), 182(31); Anal. Calcd for C21H25NO5:
C, 67.91; H, 6.78; N, 3.77; Found: C, 68.06; H, 6.64; N, 3.85.
5-Acetyl-3-benzoyl-1,4-dihydro-1,6-dimethyl-2-phenylpyridine
Diethyl 5-acetyl-1,4-dihydro-6-methyl-1-(naphthalen-1-yl)pyri-
(5bkaa). Reddish brown oil; IR (KBr): Vmax = 2923, 2853, 1740,
dine-2,3-dicarboxylate (5ahaa). Yellow oil; IR (KBr): Vmax
=
1
1645, 1456, 1110, 938, 530 cm-1; H NMR (400 MHz, CDCl3):
2991, 1764, 1698, 1457, 1375, 1244, 1111, 1053 cm-1; H NMR
(400 MHz, CDCl3): d = 8.02–8.00(d, J = 8 Hz, 1H), 7.90–7.87(m,
2H), 7.62–7.42(m, 4H), 4.18(q, J = 7.2 Hz, 2H), 3.64(q, J =
17.6 Hz, 2H), 3.62–3.51(m, 2H), 2.31(s, 3H), 1.79(s, 3H), 1.24 (t,
J = 7.2 Hz, 3H), 0.48 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d = 199.6, 165.9, 163.6, 146.5, 144.1, 134.9, 134.0,
132.3, 129.9, 129.5, 128.2, 127.6, 126.8, 124.9, 123.0, 109.9, 101.8,
61.2, 60.7, 30.2, 25.1, 17.3, 14.2,12.9; EI-MS: m/z = 407(M+,
14), 364(29), 318(32), 290(25), 218(53), 28(100); Anal. Calcd for
C24H25NO5: C, 70.74; H, 6.18; N, 3.44; Found: C, 70.98; H, 6.27;
N, 3.35.
1
d = 7.34–7.32(m, 2H), 7.11–6.96(m, 8H), 3.34(s, 2H), 2.86(s, 3H),
2.43(s, 3H), 2.22(s, 3H); 13C NMR (100 MHz, CDCl3): d = 198.5,
196.5, 151.2, 150.1, 139.3, 133.6, 130.7, 130.3, 129.1, 128.7, 127.9,
127.3, 111.8, 110.5, 36.3, 29.9, 27.0, 15.9; EI-MS: m/z = 331(M+,
26), 288(21), 254(37), 226(25), 183(17), 28(100); Anal. Calcd for
C22H21NO2: C, 79.73; H, 6.39; N, 4.23; Found: C, 79.87; H, 6.46;
N, 4.19.
5-Acetyl-1,4-dihydro-1,6-dimethyl-3-(2-chlorobenzoyl)-◦2-phe-
nylpyridine (5ckaa). Reddish brown solid; m.p.:145–147 C; IR
(KBr): Vmax = 2921, 2851, 1738, 1652, 1466, 1088, 941, 528 cm-1;
1H NMR (400 MHz, CDCl3): d = 7.06–6.84(m, 9H), 3.47(s, 2H),
2.82(s, 3H), 2.43(s, 3H), 2.35(s, 3H); 13C NMR (100 MHz, CDCl3):
d = 199.2, 193.4, 155.5, 147.9, 141.0, 133.5, 130.8, 129.8, 129.4,
129.2, 128.1, 125.5, 112.4, 111.5, 36.3, 30.0, 25.3, 15.8; EI-MS:
m/z = 365(M+, 10), 322(8), 288(16), 139(15), 28(100); Anal. Calcd
for C22H20ClNO2: C, 72.22; H, 5.51; N, 3.83; Found: C, 72.31; H,
5.56; N, 3.76.
Diethyl
5-acetyl-1-benzyl-1,4-dihydro-6-methylpyridine-2,3-
dicarboxylate (5aiaa). Yellow oil; IR (KBr): Vmax = 2992, 1765,
1
1698, 1459, 1376, 1243, 1112, 1056 cm-1; H NMR (400 MHz,
CDCl3): d = 7.35–7.22(m, 5H), 4.62(s, 2H), 4.13–4.20(m, 4H),
3.36(s, 2H), 2.23(s, 3H), 2.19(s, 3H), 1.26 (t, J = 7.2 Hz, 3H),
1.13 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d =
199.4, 165.7, 164.8, 146.4, 144.5, 137.2, 128.8, 127.6, 126.0, 111.7,
102.7, 62.1, 60.7, 50.4, 30.0, 24.6, 15.9, 14.2, 13.5; EI-MS: m/z =
371(M+, 12), 328(39), 282(32), 254(46), 192(45), 28(100); Anal.
Calcd for C21H25NO5: C, 67.91; H, 6.78; N, 3.77; Found: C, 67.82;
H, 6.85; N, 3.84.
5-Acetyl-1,4-dihydro-1,6-dimethyl-3-(4-methylbenzoyl)-2-phe-
nylpyridine (5dkaa). Reddish brown oil; IR (KBr): Vmax = 2928,
2851, 1742, 1650, 1460, 1106, 940, 529 cm-1; 1H NMR (400 MHz,
CDCl3): d = 7.36–7.34(d, J = 8 Hz, 2H), 7.10–7.06(m, 5H),
6.88–6.86(d, J = 8 Hz, 2H), 3.37(s, 2H), 2.92(s, 3H), 2.49(s, 3H),
2.26(s, 3H), 2.20(s, 3H); 13C NMR (100 MHz, CDCl3): d = 198.5,
196.2, 150.6, 150.0, 141.4, 136.2, 133.6, 130.2, 129.0, 128.9, 128.1,
127.9, 112.2, 110.0, 36.2, 30.0, 27.3, 21.2, 16.0; EI-MS: m/z =
345(M+, 40), 302(46), 268(39), 226(42), 28(100); Anal. Calcd for
C23H23NO2: C, 79.97; H, 6.71; N, 4.05; Found: C, 79.80; H, 6.82;
N, 3.99.
Diethyl
5-acetyl-1-ethyl-1,4-dihydro-6-methylpyridine-2,3-di-
carboxylate (5ajaa). Yellow oil; IR (KBr): Vmax = 2992, 1766,
1
1700, 1457, 1376, 1243, 1099, 1056 cm-1; H NMR (400 MHz,
CDCl3): d = 4.34(q, J = 7.2 Hz, 2H), 4.16(q, J = 7.2 Hz, 2H),
3.42(q, J = 17.6 Hz, 2H), 3.29(s, 2H), 2.24(s, 3H), 2.22(s, 3H),
1.36 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.20 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 199.6, 165.8,
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5-Acetyl-1,4-dihydro-1,6-dimethyl-2-phenyl-3-(thiophene-2-
3.42(s, 2H), 2.36(s, 3H), 1.93(s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.25
(t, J = 7.2 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d = 167.9, 166.1, 164.0, 147.6, 143.7, 139.1, 136.1, 130.6,
129.5, 101.9, 101.4, 61.4, 60.5, 60.0, 23.8, 21.1, 17.6, 14.3, 14.2,
13.4; EI-MS: m/z = 401(M+, 7), 356(5), 328(24), 282(12), 254(17),
210(20), 28(100); Anal. Calcd for C22H27NO6: C, 65.82; H, 6.78;
N, 3.49; Found: C, 65.62; H, 6.93; N, 3.38.
carbonyl)pyridine (5ekaa). Reddish brown oil; IR (KBr):
1
Vmax = 2924, 2851, 1739, 1647, 1465, 1109, 939, 530 cm-1; H
NMR (400 MHz, CDCl3): d = 7.32–7.31(m, 1H), 7.18–7.14(m,
6H), 6.72–6.70(m, 1H), 3.40(s, 2H), 2.96(s, 3H), 2.48(s, 3H), 2.26(s,
3H); 13C NMR (100 MHz, CDCl3): d = 198.4, 187.9, 150.7, 149.1,
144.6, 133.7, 132.7, 132.2, 130.1, 129.2, 128.2, 126.8, 112.6, 110.2,
36.3, 30.0, 27.5,16.1; EI-MS: m/z = 337(M+, 62), 294(55), 260(52),
226(56), 111(100); Anal. Calcd for C20H19NO2S: C, 71.19; H, 5.68;
N, 4.15; Found: C, 71.43; H, 5.78; N, 4.04.
Ethyl 3-benzoyl-1,4-dihydro-1,6-dimethyl-2-phenylpyridine-5-
carboxylate (5bkba). Reddish brown oil; IR (KBr): Vmax = 2995,
2852, 1764, 1650, 1458, 1370, 1242, 1105, 939, 529 cm-1; 1H NMR
(400 MHz, CDCl3): d = 7.43–7.03(m, 10H), 4.19(q, J = 7.2 Hz,
2H), 3.38(s, 2H), 2.90 (s, 3H), 2.53(s, 3H), 1.28 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d = 196.8, 167.7, 151.4, 150.7,
139.4, 134.0, 130.8, 130.4, 129.0, 128.9, 128.0, 127.3, 112.1, 102.3,
59.8, 36.4, 26.0, 15.9, 14.3; EI-MS: m/z = 361(M+, 48), 332(43),
284(64), 256(100), 212(47); Anal. Calcd for C23H23NO3: C, 76.43;
H, 6.41; N, 3.88; Found: C, 76.60; H, 6.54; N, 3.78.
5-Acetyl-1,4-dihydro-1,6-dimethyl-3-cyclohexanecarbonyl-2-
phenylpyridine (5fkaa). Reddish brown oil; IR (KBr): Vmax
=
2927, 2853, 1742, 1655, 1448, 1112, 940, 530 cm-1; 1H NMR
(400 MHz, CDCl3): d = 7.49–7.43(m, 3H), 7.26–7.24(m, 2H),
3.23(s, 2H), 2.89(s, 3H), 2.42(s, 3H), 2.28(s, 3H), 1.62–0.94(m, 8H),
0.67–0.57(m, 2H); 13C NMR (100 MHz, CDCl3): d = 205.5, 198.9,
150.6, 149.3, 135.0, 129.7, 128.7, 112.2, 110.9, 48.3, 36.1, 30.0,
29.5, 26.0, 25.7, 25.6,15.9; EI-MS: m/z = 337(M+,65), 294(63),
260(100), 226(79), 212(87); Anal. Calcd for C22H27NO2: C, 78.30;
H, 8.06; N, 4.15; Found: C, 78.21; H, 8.13; N, 4.10.
3,5-Dibenzoyl-1,4-dihydro-1,6-dimethyl-2-phenylpyridine (5bkca).
Reddish brown solid; m.p.:120–122 ◦C; IR (KBr): Vmax = 2992,
2854, 1743, 1652, 1458, 1108, 940, 529 cm-1; 1H NMR (400 MHz,
CDCl3): d = 7.74(d, J = 8 Hz, 2H), 7.45–7.33(m, 5H), 7.13–7.01(m,
8H), 3.32(s, 2H), 2.95(s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz,
CDCl3): d = 196.9, 196.2, 152.0, 148.1, 139.5, 139.2, 133.8, 131.8,
130.7, 130.5, 129.2, 128.7, 128.6, 128.4, 128.3, 128.1, 127.4, 111.0,
110.6, 36.2, 28.3, 16.7; EI-MS: m/z = 393(M+, 6), 377(32), 348(55),
300(18), 105(100); Anal. Calcd for C27H23NO2: C, 82.42; H, 5.89;
N, 3.56; Found: C, 82.60; H, 5.95; N, 3.50.
5-Acetyl-3-benzoyl-1,4-dihydro-2-hexyl-1,6-dimethylpyridine
(5gkaa). Reddish brown oil; IR (KBr): Vmax = 2925, 2852, 1744,
1
1649, 1461, 1101, 938, 529 cm-1; H NMR (400 MHz, CDCl3):
d = 7.75–7.40(m, 5H), 3.25(s, 3H), 3.05(s, 2H), 2.44(s, 3H), 2.13(s,
3H), 1.41–0.80(m, 13H); 13C NMR (100 MHz, CDCl3): d = 198.2,
197.6, 151.5, 150.8, 139.4, 131.9, 128.7, 128.4, 111.3, 108.9, 33.4,
31.3, 30.0, 29.1, 29.0, 28.9, 27.6, 22.5, 16.1, 13.9; EI-MS: m/z =
339(M+, 14), 296(23), 254(21), 234(16), 28(100); Anal. Calcd for
C22H29NO2: C, 77.84; H, 8.61; N, 4.13; Found: C, 78.06; H, 8.78;
N, 4.01.
5-Acetyl-3-benzoyl-1,4-dihydro-2-phenyl-1,4,6-trimethylpyri-
dine (5bkab). Yellowish green solid; m.p.: 109–110 ◦C; IR
(KBr): Vmax = 2991, 2836, 1765, 1606, 1445, 1367, 1243, 1057,
Triethyl
1,4-dihydro-6-methyl-1-phenylpyridine-2,3,5-tricar-
1
868, cm-1; H NMR (400 MHz, CDCl3): d = 7.32–7.30(m, 2H),
boxylate (5aaba). Yellow oil; IR (KBr): Vmax = 2994, 1765, 1699,
1459, 1375, 1243, 1108, 1056 cm-1; 1H NMR (400 MHz, CDCl3):
d = 7.36–7.21(m, 5H), 4.20–4.11(m, 4H), 3.80(q, J = 7.2 Hz,
2H), 3.41(s, 2H), 1.91(s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.23 (t,
J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d = 167.9, 166.1, 164.0, 147.3, 143.6, 138.9, 131.0, 129.0,
102.1, 101.7, 61.5, 60.5, 60.0, 23.9, 17.7, 14.3, 14.2, 13.4; EI-MS:
m/z = 387(M+, 23), 342(25), 314(100), 268(45), 240(97), 196(77);
Anal. Calcd for C21H25NO6: C, 65.10; H, 6.50; N, 3.62; Found: C,
65.38; H, 6.66; N, 3.50.
7.11–6.96(m, 8H), 3.68 (t, J = 6.8 Hz, 1H), 2.94(s, 3H), 2.52(s,
3H), 2.32(s, 3H), 1.18 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d = 199.0, 196.7, 150.1, 148.6, 139.8, 133.8, 130.8, 130.5,
129.3, 128.8, 128.0, 127.2, 117.5, 116.9, 36.5, 31.3, 29.5, 21.8, 16.5;
EI-MS: m/z = 345(M+, 5), 330(100), 302(13), 268(4), 240(12);
Anal. Calcd for C23H23NO2: C, 79.97; H, 6.71; N, 4.05; Found: C,
80.08; H, 6.78; N, 4.01.
5-Acetyl-3-benzoyl-1,4-dihydro-1,6-dimethyl-4-p-nitrophenyl-2-
phenylpyridine (5bkac). Yellowish green oil; IR (KBr): Vmax
=
2835, 1707, 1616, 1453, 1345, 1236, 1164, 781, 589cm-1; 1H NMR
(400 MHz, CDCl3): d = 8.14(d, J = 8.8 Hz, 2H), 7.61(d, J = 8.8 Hz,
2H), 7.25(d, J = 8.8 Hz, 2H), 7.09–6.95(m, 8H), 5.08(s, 1H), 2.87(s,
3H), 2.65(s, 3H), 2.28(s, 3H); 13C NMR (100 MHz, CDCl3): d =
198.1, 196.5, 152.7, 152.3, 149.6, 146.4, 139.8, 132.8, 130.5, 129.8,
128.6, 128.1, 127.8, 127.2, 123.5, 114.4, 114.3, 40.1,16.5, 36.6, 29.8;
EI-MS: m/z = 452(M+, 4), 409(9), 375(13), 347(8), 28(100); Anal.
Calcd for C28H24N2O4: C, 74.32; H, 5.35; N, 6.19; Found: C, 74.41;
H, 5.39; N, 6.11.
Triethyl 1-(4-chlorophenyl)-1,4-dihydro-6-methylpyridine-2,3,5-
tricarboxylate (5acba). Yellow oil; IR (KBr): Vmax = 2992, 1766,
1
1698, 1486, 1375, 1244, 1110, 1053 cm-1; H NMR (400 MHz,
CDCl3): d = 7.35–7.35(m, 2H), 7.21–7.18(m, 2H), 4.23–4.15(m,
4H), 3.88(q, J = 7.2 Hz, 2H), 3.41(s, 2H), 1.93(s, 3H), 1.30 (t, J =
7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3): d = 167.7, 165.9, 163.9, 146.7, 143.1,
137.3, 135.1, 132.3, 129.2, 102.6, 102.1, 61.7, 60.6, 60.2, 23.8, 17.7,
14.3, 14.2, 13.4; EI-MS: m/z = 421(M+, 11), 376(10), 348(32),
302(13), 274(26), 230(17), 28(100); Anal. Calcd for C21H24ClNO6:
C, 59.79; H, 5.73; N, 3.32; Found: C, 59.56; H, 5.89; N, 3.23.
Acknowledgements
Triethyl
1,4-dihydro-6-methyl-1-p-tolylpyridine-2,3,5-tricar-
The authors thank the National Natural Science Foundation of
China (Nos. 20772034 and 20625205) and Guangdong Natural
Science Foundation (No. 07118070) for financial support of this
work.
boxylate (5alba). Yellow oil; IR (KBr): Vmax = 2991, 1766, 1699,
1460, 1375, 1243, 1108, 1056 cm-1; 1H NMR (400 MHz, CDCl3):
d = 7.18–7.10(m, 4H), 4.22–4.14(m, 4H), 3.85(q, J = 7.2 Hz, 2H),
4952 | Org. Biomol. Chem., 2009, 7, 4943–4953
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13 J. H. Lee, Tetrahedron Lett., 2005, 46, 7329–7330.
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26 Crystal data for X-ray structure of 5ckaa: C22H20ClNO2, Mr = 365.84,
˚
orthorhombic system, space group Pbca, T = 293(◦2)K, a = 17.530(3)A,
3
˚
˚
˚
b = 14.759(3)A, c = 14.559(3)A, a = b = g = 90.00 , V = 3766.8(13) A ,
Z = 8, Goodness-of-fit on F2 = 1.147, Independent reflections = 3357,
Rint = 0.0524, Final R indices [I > 2s(I)]: R = 0.0663, wR = 0.2385.
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