Selective synthesis of fused 1,4-and 1,2-dihydropyridines by domino reactions of arylamines, acetylenedicarboxylate, aldehydes, and cyclic 1,3-diketones

Article abstract of DOI:10.1002/ejoc.201101198

A practical procedure for the preparation of fused 1,4-dihydropyridines was developed through the domino four-component reactions of arylamines, acetylenedicarboxylate, aromatic aldehydes, and cyclic 1,3-diketones in acetic acid. Unusual fused 1,2-dihydropyridines can also be efficiently prepared by controlling the reaction conditions.

Full text of DOI:10.1002/ejoc.201101198

FULL PAPER
DOI: 10.1002/ejoc.201101198
Selective Synthesis of Fused 1,4- and 1,2-Dihydropyridines by Domino
Reactions of Arylamines, Acetylenedicarboxylate, Aldehydes, and Cyclic 1,3-
Diketones
Jing Sun,[a] Yan Sun,[a] Hong Gao,[a] and Chao-Guo Yan*[a]
Keywords: Nitrogen heterocycles / Domino reactions / Alkynes / Multicomponent reactions
A practical procedure for the preparation of fused 1,4-dihy-
matic aldehydes, and cyclic 1,3-diketones in acetic acid. Un-
dropyridines was developed through the domino four-com- usual fused 1,2-dihydropyridines can also be efficiently pre-
ponent reactions of arylamines, acetylenedicarboxylate, aro- pared by controlling the reaction conditions.
tical procedure for the preparation of fused 1,4-dihydropyr-
Introduction
idines in good yields and also found an efficient synthetic
In recent years, versatile Huisgen 1,4-dipoles, which are
method for structurally diverse 1,2-dihydropyridines.
easily formed from the addition reaction of nitrogen hetero-
cycles or amines to electron-deficient alkynes,[1] have been
widely recognized as practical synthons that can be used in
the preparation of diverse carbon–carbon bonds and het-
erocycles.[2–5] In particular, domino reactions containing a
primary amine, acetylenedicarboxylate, and a third compo-
nent have provided many elegant procedures for the synthe-
sis of various N and N,O heterocycles.[6–11] Last year, we
reported that the domino four-component reactions of
aromatic aldehydes, arylamines, acetylenedicarboxylate,
and acetonitrile derivatives provided an efficient method
for the synthesis of polysubstituted dihydropyridines[12a] Scheme 1. Formation of 1,4-dihydropyridine (Equation 1) and 3,4-
dihydro-2H-pyran (Equation 2) through a four-component reac-
tion.
(Scheme 1, Equation 1). Very recently, we found that a sim-
ilar four-component reaction of aromatic aldehydes, aryl-
amines, acetylenedicarboxylate, and cyclic 1,3-diketones
yielded 3,4-dihydro-2H-pyran derivatives[12b] (Scheme 1,
Equation 2) as the main products. The formation 3,4-dihy-
dro-2H-pyrans indicated that one carbonyl group of di-
medone took part in the sequential substitution step to
form the pyranyl ring, whereas the amino group did not
Results and Discussions
As we reported previously, the four-component reaction
of p-methoxyaniline, p-methylbenzaldehyde, dimedone, and
dimethyl acetylenedicarboxylate in ethanol resulted in 3,4-
dihydro-2H-pyrans in high yield without the use of any base
take part in a further reaction with the carbonyl group to
form the pyridyl ring. By surveying several reported results
or acid catalyst. If a base catalyst such as triethylamine was
in the multicomponent reactions of amines with electron-
deficient alkynes and other components[13–17] and by com-
paring the substrates and reactivities of the two above-men-
tioned four-component reactions, we envisioned that fused
1,4-dihydropyridines would be the most probable products
in the second four-component reaction. Thus, we concen-
trated our investigation on the reaction conditions of this
four-component reaction and successfully developed a prac-
added to the reaction system, a very complicated mixture
was formed. When an acid catalyst such as trifluoroacetic
acid was added, the reaction gave a mixture of products, in
which 3,4-dihydro-2H-pyrans were the main products. After
heating this mixture for several days we were pleased to
find that the initially formed 3,4-dihydro-2H-pyrans slowly
converted into new products with some decomposition
products. Thus, the acid-catalyzed reaction conditions were
examined thoroughly, including the choice of acid, solvent,
temperature, and the sequence of addition of the substrates.
The best results were obtained by carrying out the four-
component reaction in a domino-type fashion by using
[a] College of Chemistry & Chemical Engineering,
Yangzhou University,
Yangzhou 225002, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101198.
6952
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6952–6956

Selective Synthesis of the Fused 1,4- and 1,2-Dihydropyridines
acetic acid as both the catalyst and the solvent. Thus, p-
methoxyaniline was first treated with dimethyl acetylenedi-
carboxylate in acetic acid at room temperature overnight to
result in the formation of the active intermediate β-enamino
ester. Then, equal amounts of p-methylbenzaldehyde and
dimedone were added, and the reaction proceeded
smoothly at 80–90 °C for 12 h to give desired 1,4-dihy-
dropyridine 1a in good yield after thick-layer chromatog-
raphy (57%; Table 1, Entry 1). Then, various aromatic alde-
hydes and amines with different substituents were utilized
under the same reaction conditions. From these results
(Table 1) we could see that all of the reactions proceeded
smoothly to afford the corresponding 1,4-dihydropyridines
in satisfactory yields. Aromatic aldehydes carrying either
electron-donating or electron-withdrawing substituents
showed similar reactivities and reacted efficiently to yield
the desired products. Arylamines with substituents such as
methyl, methoxy, and chloride groups also gave 1,4-dihy-
dropyridines in good yields. The structures of the 1,4-dihy-
dropyridines were fully characterized by elemental analysis;
1H NMR, 13C NMR, and IR spectroscopy; and mass spec-
trometry and were further confirmed by single-crystal X-
ray diffraction studies (see Figure 1 for 1b). In the 1H NMR
spectra of 1,4-dihydropyridines 1a–k, two methylene groups
usually show four doublets, which indicates that the two
protons in each CH2 group are diastereotopic protons. For
an example, the 1H NMR spectrum of 1c displays four dou-
blets at δ = 2.23, 2.15, 2.09, 1.82 ppm with geminal coupling
constants J = 16–17 Hz. The proton at the C-4 position of
the 1,4-dihydropyridyl ring displays a singlet at δ =
5.17 ppm.
Figure 1. Molecular structure of 1,4-dihydropyridine 1b.
domino four-component reactions containing these two cy-
clic 1,3-diketones resulted in the corresponding polysubsti-
tuted 1,4-dihydropyridines 2a–o in 58–71% yield (Table 2).
Unfortunately, the use of 4-hydroxycoumarin or 4-hydroxy-
quinoline-2-one as one component in the reaction was not
successful. Even when the four-component reaction con-
taining the 4-hydroxycoumarin in ethanol was run first to
yield the 3,4-dihydro-2H-pyran, subsequent heating of this
product in acetic acid did not produce the desired 1,4-hy-
dropyridine derivative. In total, 15 new polysubstituted 1,4-
Table 1. Synthesis of polysubstituted 1,4-dihydropyridines by a
domino reaction.
Table 2. Synthesis of polysubstituted 1,4-dihydropyridines by a
domino reaction.
Entry
1
Ar
ArЈ
Yield [%]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
p-CH3C6H4
p-ClC6H4
p-BrC6H4
m-NO2C6H4
C6H5
p-ClC6H4
p-CH3OC6H4
p-ClC6H4
p-ClC6H4
p-CH3C6H4
p-(CH3)3CC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
m-CH3C6H4
C6H5
57[a]
60[a]
68
67
58
Entry
2
Ar
ArЈ
n
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
p-CH3OC6H4
p-ClC6H4
C6H5
p-ClC6H4
p-BrC6H4
p-ClC6H4
p-CH3C6H4
p-(CH3)2CHC6H4
p-ClC6H4
p-(CH3)3CC6H4
p-ClC6H4
p-BrC6H4
m-NO2C6H4
p-ClC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
m-CH3C6H4
p-BrC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
C6H5
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
65
63[a]
58
60
59
63
62
66
71
70
64
63
65
61
60
65
56[a]
65
60
62
67
10
11
1j
1k
p-ClC6H4
p-ClC6H4
[a] A few polysubstituted 1,2-dihydropyridines were separated in
the reactions.
To extend the scope of this domino four-component re-
action, the reactivities of additional cyclic 1,3-diketones
such as 1,3-cyclohexanedione and 1,3-cyclopentanedione
p-CH3C6H4
p-ClC6H4
[a] A few polysubstituted 1,2-dihydropyridines were separated in
were also explored. Under similar reaction conditions, the this reaction.
Eur. J. Org. Chem. 2011, 6952–6956
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6953

J. Sun, Y. Sun, H. Gao, C.-G. Yan
FULL PAPER
dihydropyridines were successfully prepared, and their
structures were fully confirmed by characterization; in ad-
dition, three representative single-crystal structures of 2d
(Figure 2), 2i (Figure 3), and 2m (Figure 4) were determined
by X-ray diffraction. This result indicated that we were able
to establish successfully a practical procedure for the prepa-
ration of fused 1,4-dihydropyridines. To explain the mecha-
nism of this domino four-component reaction, we propose
a plausible reaction mechanism (Scheme 2). At first, the
arylamine was added to dimethyl acetylenedicarboxylate to
give β-enamino ester A. Secondly, Knoevenagel condensa-
tion of the aromatic aldehyde with dimedone yielded 2-aryl-
idenedimedone B. Thirdly, Michael addition of A to B pro-
duced intermediate C. Then, intramolecular condensation
of the carbonyl group with the amino group converted in-
termediate C into final 1,4-dihydropyridine 1.
Figure 4. Molecular structure of 1,2-dihydropyridine 3a.
Figure 2. Molecular structure of 1,4-dihydropyridine 2d.
Scheme 2. Formation mechanism of 1,4-dihydropyridine.
aryl-2,3-dimethoxycarbonyl-1,4-dihydropyridines 1a, 1b,
1g, and 2b were observed (Tables 1 and 2). The formation
of 1,2-dihydropyrdines clearly indicated that other reaction
routes existed in this four-component reaction. Thus, we
turned our attention to the selective preparation of 1,2-di-
hydropyridines by optimizing the reaction conditions. After
examining several factors including catalyst, solvent, tem-
perature, and the sequences of addition of the reactants,
we found that 1,2-dihydropyridines could be obtained in
satisfactory yields by using the following procedure; that is,
firstly, independent preparation of imine in the reaction of
the aromatic aldehydes and arylamines in acetic acid, and
Figure 3. Molecular structure of 1,4-dihydropyridine 2m.
In the preparation of 1,4-dihydropyridines through dom- the adduct from the reaction of dimedone with dimethyl
ino four-component reactions containing dimedone and acetylenedicarboxylate in ethanol in the presence of trieth-
1,3-cyclohexanedione in acetic acid, we noticed that a few ylamine as the base catalyst. Then, the two solutions were
unusual 2-aryl-3,4-dimethoxycarbonyl-1,2-dihydropyridines mixed and the whole solution was heated at 80–90 °C for
could be separated in about 10% yield by thick-layer 12 h. By using this reaction procedure, 1,2-dihydropyridines
chromatography in cases where the formation of normal 4- 3a–e could be obtained in good yields (Table 3, Entries 1–
6954
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Eur. J. Org. Chem. 2011, 6952–6956

Selective Synthesis of the Fused 1,4- and 1,2-Dihydropyridines
5) and the formation of the normal 1,4-dihydropyridines possible, in which intermediate D may be converted into its
was greatly decreased, which could be easily separated out enol form, and then the Diels–Alder reaction takes place
by thick-layer chromatography. Similarly, the reaction of between the enol and imine E, followed finally by dehy-
1,3-cyclohexanedione also gave satisfactory yields of 1,2- dration to give 3. The formation of 1,2-dihydropyridines
dihydropyridines 3f–i (Table 3, Entries 6–9). 1,2-Dihydropy- and 1,4-dihydropyridines comes from the same four reac-
ridines were not produced in the reactions of 1,3-cyclopen- tants and the main difference is the reaction sequence of
tanedione. At present, the reaction mechanism for the for- the four components in the process.
mation of 1,2-dihydropyridines is not very clear, and we
tentatively present a plausible reaction route based on the
analysis of similar reactions of electron-deficient alkynes
Conclusions
In summary, we have developed a practical procedure for
the selective preparation of 1,2-dihydropyridines and 1,4-
dihydropyridines by a domino four-component reaction of
arylamines, acetylenedicarboxylate, aromatic aldehydes,
and cyclic 1,3-diketones. Furthermore, we established the
scope and limitations of this domino reaction and found
two types of reaction modes, which enabled further modifi-
cation of the reaction to give more molecular diversity. The
potential uses of the reaction in synthetic and medicinal
chemistry might be quite significant.
(Scheme 3). The first step is reaction of dimedone with di-
methyl acetylenedicarboxylate in ethanol in the presence of
triethylamine as the base catalyst to form adduct D, which
has been described in several reports.[18] Secondly, reaction
of the aromatic aldehyde with arylamine in acetic acid
forms imine E. The third step is the Michael addition of
intermediate D to the imine to give adduct F. The last cycli-
zation step through the intramolecular condensation of the
amino group with the carbonyl group gives the expected
1,2-dihydropyridine 3. At present, another reaction mecha-
nism involving an imino-Diels–Alder reaction might also be
Experimental Section
Table 3. Synthesis of polysubstituted 1,2-dihydropyridines by a
domino reaction.
Typical Procedure for the Synthesis of Functionalized 1,4-Dihy-
dropyridines 1a–k and 2a–o: In a round-bottomed flask, a solution
of arylamine (2.0 mmol) and dimethyl acetylenedicarboxylate
(2.0 mmol, 0.284 g) in acetic acid (5.0 mL) was stirred at room tem-
perature overnight. Then, the aromatic aldehyde (2.0 mmol) and
dimedone (2.0 mmol, 0.288 g) were added, and the whole mixture
was heated to 80–90 °C for 12 h. After cooling to room tempera-
ture, water (50 mL) was added. The resulting precipitates were col-
lected and subjected to thick-layer chromatography (SiO2; ethyl
acetate/light petroleum ether, 1:2) to give the pure product for
analysis.
1a: Yellow solid, 57% yield. M.p.164–166 °C. 1H NMR (600 MHz,
CDCl3): δ = 7.33 (d, J = 7.8 Hz, 2 H, ArH), 7.19 (d, J = 9.0 Hz, 2
H, ArH), 7.10 (d, J = 7.2 Hz, 2 H, ArH), 6.94 (d, J = 8.4 Hz, 2 H,
ArH), 5.16 (s, 1 H, CH), 3.86 (s, 3 H, OCH3), 3.63 (s, 3 H, OCH3),
3.48 (s, 3 H, OCH3), 2.30 (s, 3 H, CH3), 2.22 (d, J = 16.3 Hz, 1 H,
CH), 2.15 (d, J = 16.3 Hz, 1 H, CH), 2.09 (d, J = 17.5 Hz, 1 H,
CH), 1.83 (d, J = 17.5 Hz, 1 H, CH), 0.96 (s, 3 H, CH3), 0.77 (s, 3
H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 195.9, 166.2,
164.4, 160.0, 150.0, 143.0, 142.4, 135.8, 131.2, 130.2, 129.0, 127.6,
114.4, 113.6, 106.6, 55.5, 52.4, 51.8, 50.2, 40.8, 34.1, 32.3, 29.6,
R
Yield
[%]
Entry
3
Ar
ArЈ
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
p-CH3C6H4
p-ClC6H4
p-CH3OC6H4
p-ClC6H4
m-NO2C6H4 p-CH3OC6H4
p-ClC6H4
C6H5
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
p-CH3C6H4
CH3
CH3
CH3
CH3
CH3
H
H
H
H
56
50
52
42
55
46
45
52
47
p-CH3OC6H4
p-CH3C6H4
p-CH3C6H4
m-CH3C6H4
p-ClC6H4
p-ClC6H4
26.6, 21.1 ppm. IR (KBr): ν = 2952, 1749, 1707, 1643, 1593, 1510,
˜
1433, 1369, 1301, 1254, 1202, 1102, 1066, 1033, 850, 774 cm–1. MS:
m/z (%) = 490.36 (100) [M + 1]+. C29H31NO6 (489.57): calcd. C
71.15, H 6.38, N 2.86; found C 70.85, H 6.50, N 2.77.
Typical Procedure for the Synthesis of Functionalized 1,2-Dihy-
dropyridines 3a–i: In a round-bottomed flask, a solution of di-
methyl acetylenedicarboxylate (2.0 mmol, 0.284 g), dimedone
(2.0 mmol, 0.288 g), and triethylamine (1.0 mmol, 0.100 g) in etha-
nol (5.0 mL) was stirred at room temperature for 1 h. In another
round-bottomed flask, the aromatic aldehyde (2.0 mmol) and aryl-
amine (2.0 mmol) in acetic acid (10.0 mL) were stirred at room
temperature for 4 h. Then, the two solutions were combined to-
gether in one flask, and the whole mixture was heated to 80–90 °C
for 12 h. After cooling to room temperature, water (50 mL) was
added. The resulting precipitates were collected and subjected to
thick-layer chromatography (SiO2; ethyl acetate/light petroleum
ether, 1:2) to give the pure product for analysis.
Scheme 3. Mechanism for the formation of 1,2-dihydropyridine 3.
Eur. J. Org. Chem. 2011, 6952–6956
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6955

J. Sun, Y. Sun, H. Gao, C.-G. Yan
FULL PAPER
3a: Yellow solid, 56% yield. M.p. 200–202 °C. 1H NMR (600 MHz,
CDCl3): δ = 7.19 (d, J = 7.8 Hz, 2 H, ArH), 7.10 (d, J = 7.8 Hz, 2
H, ArH), 6.86 (br. s, 4 H, ArH), 5.55 (s, 1 H, CH), 3.95 (s, 3 H,
OCH3), 3.83 (s, 3 H, OCH3), 3.63 (s, 3 H, OCH3), 2.33 (s, 3 H,
CH3), 2.29 (br. s, 2 H, CH2), 2.17 (d, J = 16.8 Hz, 1 H, CH), 2.06–
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NMR (150 MHz, CDCl3): δ = 190.7, 164.6, 162.3, 159.6, 138.7,
137.7, 137.5, 134.9, 129.4, 127.5, 114.8, 110.6, 105.5, 65.3, 55.5,
52.4, 51.9, 50.1, 42.8, 32.1, 28.5, 28.1, 21.2 ppm. IR (KBr): ν =
˜
2953, 1737, 1703, 1637, 1608, 1499, 1447, 1376, 1333, 1295, 1273,
1239, 1200, 1148, 1107, 1021, 970, 845, 798, 752 cm–1. MS: m/z (%)
= 490.57 (100) [M + 1]+. C29H31NO6 (489.57): calcd. C 71.15, H
6.38, N 2.86; found C 70.76, H 6.72, N 2.54.
CCDC-8836357 (for 1b), -836355 (for 2d), -836358 (for 2m),
-836360 (for 2i), -836359 (for 3a), -836361 (for 3b), and -836356
(for 3g) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data and copies of the 1H and 13C NMR
spectra.
Acknowledgments
This work was financially supported by the National Natural Sci-
ence Foundation of China (Grant No. 20972132 and 21172189).
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Received: August 18, 2011
Published Online: October 10, 2011
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Eur. J. Org. Chem. 2011, 6952–6956