Synthesis of functionalized 2-aminohydropyridines and 2-pyridinones via domino reactions of arylamines, methyl propiolate, aromatic aldehydes, and substituted acetonitriles

Article abstract of DOI:10.1021/co200071v

An efficient and practical synthetic method for the functionalized 2-amino hydropyridines and 2-pyridinones was successfully developed via the domino reactions of arylamines, methyl propiolate, aromatic aldehydes and the substituted acetonitriles with tri

Full text of DOI:10.1021/co200071v

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Synthesis of Functionalized 2-Aminohydropyridines and
2-Pyridinones via Domino Reactions of Arylamines, Methyl Propiolate,
Aromatic Aldehydes, and Substituted Acetonitriles
Jing Sun, Yan Sun, Er-Yan Xia, and Chao-Guo Yan*
College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China
S Supporting Information
b
ABSTRACT:
An efficient and practical synthetic method for the functionalized 2-amino hydropyridines and 2-pyridinones was successfully
developed via the domino reactions of arylamines, methyl propiolate, aromatic aldehydes and the substituted acetonitriles with
triethylamine as base catalyst. Reactions involving malononitrile and cyanoacetamide gave exclusively the 2-aminohydropyridines.
On the other hand ethyl cyanoacetate resulted in the 2-pyridinones as main products.
KEYWORDS: dihydropyridine, 2-pyridinone, electron-deficient alkyne, β-enamino ester, domino reaction
’ INTRODUCTION
propiolate, and malononitrile with triethylamine as base catalyst
in ethanol at room temperature resulted in a complicate mixture
of products, which is not worthy for separation. The reason is
that the addition reaction of aniline to methyl propiolate to give
the adduct 3-arylaminoacrylates need more than twelve hours for
completion,15 while the addition of aniline to dimethyl acetyle-
nedicarboxylate could be finished in 5ꢀ10 min.16 Thus we
decided first to let p-toluidine and methyl propiolate reacted in
ethanol at room temperature for overnight. TLC analysis in-
dicated that the addition reaction has finished and nearly merely
the desired β-enamino ester existed in solution. Then benzalde-
hyde and malononitrile, as well as triethylamine, were added to
the system, and the mixture was stirred at room temperature for
additional ten hours. After workup, we are pleased to find that the
expected 2-aminohydropyridine 1a was obtained in 70% yields.
Thus methyl propiolate has been successfully utilized in a one-
pot domino four-component reaction. Subsequently, various
aromatic aldehydes and amines were used in the reactions under
the similar reaction conditions. The results are summarized in
Table 1. From these results, we could see that all reactions
proceeded smoothly to afford the corresponding N-aryl-2-ami-
nohydropyridines 1bꢀ1m in high yields (70ꢀ88%) (Table 1).
The substituents with different electronic effects on aromatic ring
showed marginal effect to the reactivity and all aromatic aldehydes
and arylamines reacted efficiently to give the desired products.
To extend the scope of the domino reactions further, benzyl-
amine and β-phenylethylamine were also utilized in the reaction
1,4-Dihydropyridines present ubiquitous structural motifs,
which are frequently found in natural products and in com-
pounds for the pharmaceutical, agrochemical, and other chemical
industries.1,2 Traditional methods for synthesis of 1,4-dihydro-
pyridines involve Hantzsch reaction,3,4 cycloaddition reactions,5,6
Michael condensation,7 and others.8,9 In the past few years, the
Lewis acid-induced cyclization of enamines has become an
attractive alternative method for 1,4-dihydropyridine synthesis.
Vohra et al used the Lewis acid-catalyzed condensation of enamines
and R,β-unsaturated aldehydes to prepare dihydropyridines.10,11
Kikuchi et al. found the formation of 1,4-dihydropyridine deriva-
tives from the reaction of aniline with ethyl propiolate in the
presence of Sc(OTf)3.12 Under the catalysis of TiCl4 β-enamino
esters also cyclized to give 1,4-dihydropridines.13 Recently, we
found that the four-component reactions of aromatic aldehydes,
arylamines, acetylenedicarboxylate, and acetonitrile derivatives
provided an efficient method for the polysubstituted 1,4-
dihydropyridines.14 However the substrate scope and limitation
of this novel domino reaction have not fully developed yet. In this
text we wish to report the efficient synthesis of structurally
diverse 1,4-dihydropyridine and 2-pyridinone derivatives via
the domino reactions of arylamines, methyl propiolate, aromatic
aldehydes, and the substituted acetonitriles.
’ RESULTS AND DISCUSSION
At first we carried out the reaction of methyl propiolate in
four-component manner according to the previously reported
procedure for the reactions of dimethyl acetylenedicarboxylate.14
The four-componentmixtureof benzaldehyde, p-toluidine, methyl
Received: April 17, 2011
Revised:
May 23, 2011
Published: June 06, 2011
r
2011 American Chemical Society
436
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RESEARCH ARTICLE
Table 1. Synthesis of Polysubstituted
2-Aminohydropyridines
entry
compd
Ar
Ar0
yield (%)
1
1a
1b
1c
1d
1e
1f
C6H5
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
C6H5
70
85
80
82
87
80
86
88
85
85
70
70
82
83
88
65
87
81
75
78
82
88
2
p-CH3C6H4
p-CH3OC6H4
p-(CH3)2CHC6H4
p-ClC6H4
3
4
5
6
m-NO2C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-(CH3)2CHC6H4
p-CH3OC6H4
p-ClC6H4
7
1g
1h
1i
8
p-ClC6H4
9
o-CH3C6H4
p-CH3OC6H4
m-ClC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
1j
1k
1l
m-CH3C6H4
R-Naph
1m
1n
1o
1p
1q
1r
1s
1t
C6H5CH2
C6H5CH2
Figure 1. Molecular structure of 2-aminohydropyridine 1k.
C6H5CH2
C6H5CH2
p-CH3C6H4
p-CH3OC6H4
C6H5
C6H5CH2CH2
C6H5CH2CH2
C6H5CH2CH2
C6H5CH2CH2
C6H5CH2CH2
1u
1v
p-ClC6H4
p-BrC6H4
and the corresponding N-benzyl-2-aminohydropyridines 1nꢀ1q and
N-phenyl-2-aminoethylhydropyridines 1rꢀ1v were also prepared
in satisfactory yields (65ꢀ88%). These results demonstrated that
this domino reaction has a wide variety of substrates. The
structures of twenty-two prepared 2-aminohydropyridines were
fully characterized by elemental analysis, 1H and 13C NMR, MS,
IR spectra, and were further confirmed by single-crystal studies
performed for three representative compounds 1f, 1k (Figure 1),
and 1t. As observed in the molecular structure of 1k the five
carbon atoms and one nitrogen atom in hydropyridine ring exist
nearly in one plane with the small degree of ring distortion from
planarity. The 4-p-methylphenyl group is perpendicular to the
hydropyridine ring and N-m-chlorophenyl exists nearly coplane to
hydropyridine ring.
To explore the generality and scope of this domino reaction
other substituted acetonitriles, such as ethyl cyanoacetate was
also utilized in the reaction. The reaction of p-chlorobenzalde-
hyde, ethyl cyanoacetate and β-enamino ester derived from
p-toluidine and methyl propiolate in ethanol with triethylamine
as base catalyst resulted in the two products. After separation
with thin-layer chromatography the expected 2-aminohydropyr-
idine 2a was obtained only in 30% yield. Another product was
successfully separated in 53% yield, and its structure was assigned
as 2-pyridinone 3a after analysis. At the similar reaction condi-
tions, various aromatic aldehydes and arylamines were used in
Figure 2. Molecular structure of 2-pyridinone 3a.
the reactions. In some cases 2-aminohydropyridines 2bꢀ2e were
obtained in lower yields and in most cases very lower yields
of 2-aminohydropyridines were formed, which are not worthy to
separate. But in each case the polysubstituted 2-pyridinones
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RESEARCH ARTICLE
Table 2. Synthesis of Polysubstituted 2-Aminohydropyridines and 2-Pyridinones
entry
Ar
p-ClC6H4
Ar0
compd 2
yield (%)
compd 3
yield (%)
1
p-CH3C6H4
p-ClC6H4
2a
2b
2c
2d
2e
2f
28
30
19
23
15
3a
3b
3c
3d
3e
3f
53
51
55
43
53
55
56
58
50
61
63
66
60
2
p-CH3C6H4
p-ClC6H4
3
p-CH3OC6H4
p-CH3C6H4
C6H5
4
m-NO2C6H4
p-(CH3)2CHC6H4
C6H5
5
6
p-CH3OC6H4
p-CH3OC6H4
C6H5CH2
7
p-(CH3)2CHC6H4
p-ClC6H4
2g
2h
2i
3g
3h
3i
8
9
m-NO2C6H4
p-CH3OC6H4
p-(CH3)3CC6H4
p-ClC6H4
C6H5CH2
10
11
12
13
C6H5CH2CH2
C6H5CH2CH2
C6H5CH2CH2
C6H5CH2CH2
2j
3j
2k
2l
3k
3l
m-NO2C6H4
2m
3m
Table 3. Synthesis of 2-Aminohydropyridines from Reac-
tions of Cyanoacetamide
entry
compd
Ar
Ar0
yield (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
p-ClC6H4
C6H5
C6H5
80
78
76
86
76
82
82
80
84
m-NO2C6H4
p-CH3C6H4
m-NO2C6H4
p-ClC6H4
p-CH3C6H4
p-CH3C6H4
m-CH3C6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-ClC6H4
4g
4h
4i
m-ClC6H4
p-CH3C6H4
p-(CH3)3CC6H4
compounds 2t, 3a (Figure 2), and 3h. These results indicated
that ethyl cyanoacetate showed different reactivity to that of
malononitrile. Formation of 2-aminohydropyridine in this reac-
tion clearly indicated the cyano group took part in the reaction,
while the formation of 2-pyridinone showed the esteric group
transferred to cyclic amido group. Thus the selective synthesis of
2-aminohydropyridine and 2-pyridinone could be finished in this
domino reaction.
Figure 3. Molecular structure of 2-aminohydropyridine 4a.
Encouraged by the above interesting results and to shine more
light on the formation mechanism of two kinds of products,
cyanoacetamide was also introduced in this domino reaction. At
the same conditions the reaction of aromatic aldehydes, cyanoa-
cetamide and the in situ formed β-enamino ester proceeded
smoothly to give the polysubstituted 2-aminohydropyridines
3bꢀ3m were formed as the main products, which were separated
in moderate to good yields (43ꢀ78%) (Table 2). The structures
of the prepared 2-aminohydropyridines 2aꢀ2e and 2-pyridinones
3aꢀ3m were also fully characterized by spectroscopic methods
and confirmed by X-ray diffraction determination of three
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RESEARCH ARTICLE
Scheme 1. Proposed Formation Mechanism of 2-Aminohy-
dropyridine and 2-Pyridinone
’ CONCLUSION
In summary, we have developed a domino reaction of
arylamine, methyl propiolate, aromatic aldehydes, and substi-
tuted acetonitrile based on easily formation and novel reactivity
of β-enamino ester. Furthermore, we established the scope and
limitation of this domino reaction and found two types of
reaction modes in the reactions of ethyl cyanoacetate, which
enabled further modification of the reaction to give more
molecular diversity. This reaction provides a convenient and
selective procedure for the preparation of functionalized 2-ami-
nohydropyridines and 2-pyridinones. The potential uses of the
reaction in synthetic and medicinal chemistry might be quite
significant.
’ EXPERIMENTAL PROCEDURES
1. Typical Procedure for the Domino Reactions of Aro-
matic Aldehydes, Malononitrile, Arylamines, and Methyl
Propiolate. In a round-bottom flask a mixture of arylamine
(2.0 mmol) and methyl propiolate (2.0 mmol, 0.168 g) in 5.0 mL
of ethanol was stirred at room temperature for 8ꢀ12 h. Then
aromatic aldehyde (2.0 mmol), malononitrile (2.0 mmol, 0.144 g),
and triethylamine (2.0 mmol, 0.202 g) in 5.0 mL of ethanol
were added to it. The solution was stirred at room temperature
for additional ten hours. The solvent was removed by rotary
evaporator. The resulting oil was titrated by ethanol to give the
solid product, which was collected by filtration and washed with
cold alcohol to give the pure product 1a: white solid, 70%,
m.p.198ꢀ199 °C; 1H NMR (600 MHz, CDCl3) δ 7.34ꢀ7.31 (m,
7H, ArH, CH), 7.22 (d, J = 6.0 Hz, 3H, ArH), 4.64 (s, 1H, CH),
4.15 (s, 2H, NH2), 3.60 (s, 3H, OCH3), 2.42 (s, 3H, CH3); 13
C
(4aꢀ4i) in 76ꢀ86% yields (Table 3). It should be pointed that
the four-component reaction of aldehyde, arylamine, cyanoace-
tamide and dimethyl acetylenedicarboxylate is very sluggish even
in refluxing ethanol and the expected 2-aminohydropyridines
were only prepared in lower yields.14 Here the reaction of methyl
propiolate gave much better results. The structures of the
prepared 2-aminohydropyridines (4aꢀ4i) were fully established
by spectroscopic method and confirmed by the X-ray diffraction
of the single crystal 4a (Figure 3).
To explain the mechanism of this one-pot multicomponent
reaction, a plausible reaction course was proposed to account for
the different products based on the reaction containing ethyl
cyanoacetate, which is illustrated in Scheme 1. At first, addition
of arylamine to methyl propiolate gave the key intermediate
β-enamino ester A. Second, under the catalysis of triethylamine
Knoevenagel condensation of aromatic aldehyde with ethyl cyanoa-
cetate resulted in arylidene cyanoacetate B. Third, Michael addition
of β-enamino ester intermediate A to arylidene cyanoacetate B
yielded the addition intermediate C. Then, in intermediate C, the
intramolecular nucleophilic addition of amino group to CꢀN triple
band formed the cyclic intermediate D. At last the tautomerization
of imino group to amino group resulted in the final product
2-aminohydropyridine 2. On the other hand, in intermediate C,
the amino group could also attack the ester group to give cyclic
amide E with the elimination of ethanol, which in turn was
dehydrogenated in air to give the 2-pyridinone 3 as the product.
In the cases of reactions of malononitrile and cyanoacatoamide, the
polysubstituted hydropyridine 1 and 4 were formed as products due
to only cyano group could be attacked by amino group in the similar
intermediate C. In this reaction course, the easily formation and high
reactivity of β-enamino ester played a key factor.
NMR (150 MHz, CDCl3) δ 166.7, 149.8, 145.5, 139.8, 138.6,
136.2, 131.0, 128.6, 127.3, 127.2, 126.9, 121.2, 107.4, 62.6, 51.5,
39.1, 21.2; IR (KBr) υ 3427, 3235, 3225, 3028, 2948, 2884, 2178,
1709, 1661, 1614, 1561, 1510, 1428, 1331, 1271, 1214, 1145,
1089, 1025, 828, 763 cmꢀ1; MS (m/z) 346.30 ([M þ 1]þ)
100%. Anal. Calcd for C21H19N3O2: C 73.03, H 5.54, N 12.17;
Found C 72.64, H 5.49, N 11.88.
2. Typical Procedure for the Domino Reaction of Aromatic
Aldehydes, Ethyl Cyanoacetate, Arylamines, and Methyl
Propiolate. A mixture of arylamine (2.0 mmol) and methyl
propiolate (2.0 mmol, 0.168 g) in 5.0 mL of ethanol was stirred
at room temperature for 8ꢀ12 h. Then aromatic aldehyde
(2.0 mmol), ethyl cyanoacetate (2.0 mmol, 0.226 g), and
triethylamine (2.0 mmol, 0.202 g) in 5.0 mL ethanol were added
to it. The whole solution was stirred at room temperature for
about ten additional hours. The solvent was removed by rotary
evaporator. The resulting oil was subjected to thin-layer column
chromatography with ethyl acetate and light petroleum (V/V =
1:4) as developing solvent to give the products 2 and 3 for
1
analysis. 2a: white solid, 28%, m.p.167ꢀ170 °C; H NMR
(600 MHz, CDCl3) δ 7.32 (brs, 4H, ArH), 7.29 (s, 1H, CH),
7.25 (brs, 2H, ArH), 7.22 (d, J = 7.2 Hz, 2H, ArH), 6.32 (brs, 2H,
NH2), 4.94 (s, 1H, CH), 4.05 (brs, 2H, CH2), 3.62 (s, 3H,
OCH3), 2.43 (s, 3H, CH3), 1.19 (t, J = 7.2 Hz, 3H, CH3); 13
C
NMR (150 MHz, CDCl3) δ 169.8, 167.0, 151.4, 146.4, 139.5,
138.4, 136.3, 131.5, 130.9, 129.4, 127.9, 127.5, 109.6, 80.0, 59.3,
51.3, 37.2, 21.2, 14.4; IR (KBr) υ 3729, 3458, 3233, 2980, 2353,
1704, 1672, 1595, 1505, 1438, 1370, 1340, 1303, 1238, 1197,
1084, 1034, 907, 831, 804, 760 cmꢀ1;MS(m/z) 427.23([Mþ 1]þ)
100%. Anal. Calcd for C23H23ClN2O4: C 64.71, H 5.43,
N 6.56; Found C 64.57, H 5.68, N 6.27. 3a: white solid, 53%,
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(s, 1H, CH), 7.59 (d, J = 7.8 Hz, 2H, ArH), 7.45ꢀ7 0.42 (m,
4H, ArH), 7.39 (d, J = 7.8 Hz, 2H, ArH), 3.56 (s, 3H, OCH3),
2.40 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6) δ 133.6,
129.2, 128.8, 127.8, 125.8, 114.4, 108.9, 104.5, 51.5, 20.2; IR
(KBr) υ 3066, 2952, 2221, 1730, 1671, 1596, 1493, 1436, 1346,
1297, 1218, 1181, 1133, 1089, 990, 931, 815, 788 cmꢀ1; MS (m/
z) 379.21 ([M þ 1]þ) 100%. Anal. Calcd for C21H15ClN2O3: C
66.58, H 3.99, N 7.40; Found C 66.45, H 4.37, N 7.21.
3. Typical Procedure for the Domino Reactions of Aro-
matic Aldehydes, Cyanoacetamide, Arylamines, and Methyl
Propiolate. A mixture of arylamine (2.0 mmol) and methyl
propiolate (2.0 mmol, 0.168 g) in 5.0 mL of ethanol was stirred
at room temperature for 8ꢀ12 h. Then aromatic aldehyde (2.0
mmol), cyanoacetamide (2.0 mmol, 0.208 g), and trietylamine
(2.0 mmol, 0.202 g) in 5.0 mL of ethanol were added to it. The
whole solution was stirred at room temperature for additional
about ten hours. The solvent was removed by rotary evapora-
tor. The resulting oil was titrated by ethanol to give the solid
product, which was recystallized in ethanol to give the pure
product 4a: white solid, 80%, mp 202ꢀ204 °C; 1H NMR (600
MHz, CDCl3) δ 7.54 (d, J = 6.6 Hz, 2H, ArH), 7.48 (t, J = 6.6
Hz, 1H, ArH), 7.41 (d, J = 6.6 Hz, 2H, ArH), 7.38 (d, J = 7.2 Hz,
2H, ArH), 7.29 (d, J = 7.2 Hz, 2H, ArH), 7.23 (s, 1H, CH), 6.79
(brs, 2H, NH2), 4.95 (s, 2H, NH2), 4.73 (s, 1H, CH), 3.65 (s,
3H, OCH3), 2.42 (s, 3H, CH3), 2.31 (s, 3H, CH3); 13C NMR
(150 MHz, CDCl3) δ 172.4, 166.9, 151.1, 144.7, 138.9, 132.5,
130.4, 129.3, 129.1, 128.8, 128.7, 127.8, 108.6, 79.7, 51.4, 38.4;
IR (KBr) υ 3454, 3351, 3219, 2952, 1669, 1573, 1483, 1405,
1253, 1182, 1094, 1024, 900, 844, 812, 773 cmꢀ1; MS (m/z)
384.16 ([M þ 1]þ) 100%, 386.19 ([M þ 3]þ) 50%. Anal. Calcd
for C20H18ClN3O3: C 62.58, H 4.73, N 10.95; Found C 62.24,
H 5.11, N 10.67.
’ ASSOCIATED CONTENT
S
Supporting Information. Additional figures, tables, and
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
b
Accession Codes
Crystallographic data (1f, CCDC 802248; 1k, CCDC 802249;
1t, CCDC 802318; 2d, CCDC 802250; 3a, CCDC 802251; 3h,
CCDC 802252; 4a, CCDC 802319) have been deposited at the
Cambridge Crystallographic Database Centreand is available on
request from the Director, CCDC, 12 Union Road, Cambridge,
CB2 1EZ, U.K. (Fax þ44-1223-336033; e-mail deposit@
ccdc.cam.ac.uk or http//www.ccdc.cam.ac.uk).
’ AUTHOR INFORMATION
Corresponding Author
* E-mail: cgyan@yzu.edu.cn.
Funding Sources
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 20972132).
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