Synthesis of 3,4-dihydropyridin-2(1H)-ones and 3,4-dihydro-2H-pyrans via four-component reactions of aromatic aldehydes, cyclic 1,3-carbonyls, arylamines, and dimethyl acetylenedicarboxylate

Article abstract of DOI:10.1021/co200045t

A protocol has been developed for the efficient synthesis of structurally diverse 3,4-dihydropyridin-2(1H)-ones and 3,4-dihydro-2H-pyrans via four-component reactions of arylamines, acetylenedicarboxylate, aromatic aldehydes and cyclic 1,3-diketones. The

Full text of DOI:10.1021/co200045t

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Synthesis of 3,4-Dihydropyridin-2(1H)-ones and 3,4-Dihydro-2H-
pyrans via Four-Component Reactions of Aromatic Aldehydes, Cyclic
1,3-Carbonyls, Arylamines, and Dimethyl Acetylenedicarboxylate
Jing Sun, Er-Yan Xia, Qun Wu, and Chao-Guo Yan*
College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China
S Supporting Information
b
ABSTRACT: A protocol has been developed for the efficient
synthesis of structurally diverse 3,4-dihydropyridin-2(1H)-ones
and 3,4-dihydro-2H-pyrans via four-component reactions of
arylamines, acetylenedicarboxylate, aromatic aldehydes and
cyclic 1,3-diketones. The selective formation of the very different
pyridinone or pyran derivatives depends on the structure of cyclic 1,3-diketone. The key steps are proposed to involve Michael
addition of the enamino ester formed in situ from the reaction of arylamine with dimethyl acetylenedicarboxylate to arylidine cyclic
1,3-diketones.
KEYWORDS: multicomponent reaction, 1, 3-dipolar addition, pyridinone, pyran, β-enamino ester
Table 1. Synthesis of Polysubstituted 3,4-Dihydropyridin-
’ INTRODUCTION
2(1H)-ones
Multicomponent reactions have received considerable atten-
tion because of their wide range of applications in organic and
medical chemistry. Such reactions are able to create combinatorial
libraries of complex and diverse structures in efficient fashion by
virtue of their convergent nature.1,2 Several new designed multi-
component reactions have been reported recently,3,4 including
processes that take advantage of Huisgen 1,4-dipoles formed from
the addition of nitrogen heterocycles or amines to electron-
deficient alkynes.5ꢀ10 Thus, domino reactions involving primary
amines, acetylenedicarboxylates, and a third component have been
provided elegant procedures for the synthesis of various N- and N,
O-heterocycles.11ꢀ13 We have reported related four-component
reactions of aromatic aldehydes, arylamines, acetylenedicarboxy-
late and acetonitrile derivatives, providing quick access to poly-
substituted dihydropyridines.14 To obtain moreinformation about
this novel multicomponent reaction and to examine its substrate
scope and limitations, we replaced nitrile-activated components
with cyclic 1,3-dicarbonyl compounds. We report here efficient
four-component assemblies with these building blocks, producing
structurally diverse 3,4-dihydropyridin-2(1H)-one and 3,4-dihy-
dro-2H-pyran derivatives.
entry
compd
Ar
Ar0
yield (%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
C6H5
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
C6H5
41
46
58
53
60
45
47
52
p-(CH3)2CHC6H4
p-ClC6H4
m-ClC6H4
m-NO2C6H4
C6H5
1g
C6H5
p-ClC6H4
p-ClC6H4
1h
p-ClC6H4
a Isolated yields. All compounds were characterized by H, 13C NMR.
Reaction conditions: Et3N(0.5 equiv.), EtOH, 50ꢀ60 °C, 6 h.
1
the products might be due to a competitive ring-opening and
subsequent decarboxylation of the Meldrum’s acid moiety in
hot basic solution. The four-component reaction proceeded
smoothly with normal and electron-deficient aromatic amines
and aldehydes. The structures of the two representative com-
pounds (1c and 1h) were determined by X-ray diffraction; the
structure of 1c is shown in Figure 1. The reaction mechanism
(Scheme 1) is believed to involve Michael addition of the 1,3-dipole
’ RESULTS AND DISCUSSION
At first we investigated the reactivity of Meldrum acid in the
four-component reaction. Meldrum’s acid proved to be an active
component in reactions performed in ethanol solution in the
presence of triethylamine as base catalyst at elevated temperature
(50ꢀ60 °C) for six hours. 3,4-Dihydropyridin-2(1H)-ones
1aꢀ1h were produced in moderate yields (41ꢀ60%) as shown
in Table 1. To increase the yields of 3,4-dihydropyridin-2(1H)-
ones, the reaction conditions were also examined. But these
trying did not provided much better results. The lower yields of
Received: March 3, 2011
Revised:
April 26, 2011
Published: May 15, 2011
r
2011 American Chemical Society
421
dx.doi.org/10.1021/co200045t ACS Comb. Sci. 2011, 13, 421–426
|

ACS Combinatorial Science
RESEARCH ARTICLE
Figure 1. Molecular structure of 3,4-dihydropyridin-2(1H)-one 1c and 3,4-dihydro-2H-pyrans 2f, 4b.
Scheme 1. Proposed Mechanism of the Formation of 3,4-
Dihydropyridin-2(1H)-ones
The structures of 3,4-dihydro-2H-pyrans 2aꢀ2m were fully
suppported by elemental analysis, 1H and 13C NMR, MS, and IR
spectra, and were further confirmed by single-crystal X-ray
diffraction studies performed on compounds 2f (Figure 1) and
2j. The most surprising feature of the structure of 2aꢀ2m is the
fact that one carbonyl group of dimedone took part in cyclization,
rather than the amino group, giving the oxygen-containing six-
membered ring. Two diastereomers in each product were clearly
identified in 1H NMR spectra in ratios of 5:1 to 7:1, reflecting the
cis/trans relationship of the two ester groups. For example, 2a
showed a doublet at 4.20 ppm for the proton at C-4 of the major
(trans) isomer and a corresponding doublet at 4.33 ppm for the
minor (cis) isomer; other resonances showed similar differences.
The X-ray single-crystal molecular structure of 2f and 2j showed
the aryl group at C-4, ester group at C-3 and ester group at C-2 to
be in the all trans-configuration, corresponding to the major
isomer of the product.
A similar reactivity pattern was observed with 1,3-cyclohex-
anedione and 4-hydroxycoumarin as dicarbonyl components,
giving the corresponding polysubstituted 3,4-dihydro-2H-pyrans
(3aꢀ3e) in 66ꢀ78% yields (Table 3) and tricyclic compounds
(4aꢀ4e) in 62ꢀ75% yields (Table 3). Benzylamine was also
incorporated in place of anilines in reactions with dimedone,
giving 3,4-dihydro-2H-pyrans 5aꢀ5j in 63ꢀ81% yields. Taken
together, these reactions provided 20 new 3,4-dihydro-2H-pyran
derivatives, of which three were characterized by X-ray crystal-
lography (3b, 4b (Figure 1) and 5b. 1H NMR spectra indicated a
strong preference for only one isomer, presumably that observed
by crystallography having trans relationships between the two
ester groups and between the aryl group at C-4 and ester at C-3.
Scheme 2 shows a plausible reaction mechanism for these
multicomponent transformations, starting with the same type of
Knoevenagel and Michael condensation intermediates (A and B)
employed in the Meldrums acid reactions above.17 Michael
addition of 1,3-dipolar intermediate B to A should give C, which
is isomerized to D by ketone-enol tautomerization. Intramolec-
ular addition of the enolate to the electron-deficient alkene unit
(or its imine/iminium tautomer, not shown) provides inter-
mediate E, which in turn is converted to the final 3,4-dihydro-2H-
pyran 2 by protononation. The stereochemistry of the 3,4-
dihydro-2H-pyran is controlled by the cis/trans configuration
of the in situ formed intermediate (B) and the three sequential
reaction steps in the reaction mechanism. The addition of
arylamines to but-2-enedioates has been reported to give both
intermediate (B) to the arylidene Meldrum’s acid condensate
(A), followed by intramolecular nucleophilic substitution in inter-
mediate (C) to form the cyclic amide with elimination of acetone
and carbon dioxide. Dihydropyridinone ring system constitutes a
group of natural biologically active compounds such as alkaloids
which have attracted much attention owing to their wide range of
biological activities. The most synthetic approaches have been
concentrated on the 1,4-dihydropyridinone and its derivatives.
But the synthesis of 3,4-dihydropyridin-2-one has not been explored
widely and there were only limited literature precedents for their
synthesis.15,16 Here we are successfully provided an efficient route to
polysubstituted 3,4-dihydropyridin-2-ones starting from readily
available starting materials.
The replacement of Meldrum’s acid with dimedone produced
complex mixtures of products when triethylamine was used to
catalyze the four-component reaction. An exploration of several
parameters (including base catalyst, solvent, temperature, the
sequence of addition of substrates) provided dramatic improve-
ments. Optimal results were obtained by carrying out the four
component reaction at room temperature for about one day without
using any catalyst. The resulting precipitates were collected by
filtration and were found to be novel polysubstituted 3,4-dihydro-
2H-pyrans such as 2a (Table 2). 3,4-Dihydro-2H-pyran moiety is a
fundamental structural unit of biologically active compounds. These
types of compounds have previously been accessed only by more
cumbersome multistep procedures.17ꢀ20 We are pleased to find a
convenient method for the synthsis of polysusbtituted 3,4-dihydro-
2H-pyrans via a four-component reaction. A variety of electron-poor
and electron-rich aromatic aldehydes and amines were found to
react very smoothly to provide the analogous dihydro-2H-pyrans in
satisfactory yields (64ꢀ85%) as shown in Table 2.
422
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ACS Combinatorial Science
RESEARCH ARTICLE
Table 2. Synthesis of Polysubstituted 3,4-Dihydro-2H-pyrans
Table 3. Synthesis of 3,4-Dihydro-2H-pyran Derivatives
entry compd
Ar
Ar0
yield (%, trans/cis)a
entry
compd
Ar
p-ClC6H4
Ar0
C6H5
yielda (%)
1
2a
2b
2c
2d
2e
2f
C6H5
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
71 (6:1)
67 (6:1)
72 (5:1)
64 (6:1)
69 (7:1)
78 (7:1)
75 (7:1)
85 (7:1)
62 (7:1)
74 (6:1)
75 (6:1)
76 (6:1)
2
1
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5f
66
71
78
75
69
66
62
70
72
75
65
68
68
73
68
70
63
73
70
81
3
p-(CH3)2CHC6H4 p-CH3C6H4
2
p-ClC6H4
p-CH3C6H4
p-CH3C6H4
p-ClC6H4
4
p-CH3OC6H4
p-FC6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
C6H5
3
m-NO2C6H4
p-ClC6H4
5
4
6
p-ClC6H4
5
p-CH3C6H4
p-ClC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
p-ClC6H4
7
2g
2h
2i
p-BrC6H4
6
8
m-NO2C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-(CH3)2NC6H4
7
m-ClC6H4
9
8
p-CH3C6H4
m-NO2C6H4
m-NO2C6H4
C6H5
10
11
12
13
2j
m-ClC6H4
p-ClC6H4
9
p-CH3C6H4
p-ClC6H4
2k
2l
10
11
12
13
14
15
16
17
18
19
20
p-CH3OC6H4
p-CH3OC6H4
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
2m
71 (6:1)
1
p-CH3C6H4
p-(CH3)2CHC6H4
m-(CH3)3CC6H4
p-CH3OC6H4
p-FC6H4
a Isolated yields. All compounds were characterized by H, 13C NMR.
The ratios of trans/cis were estimated by 1H NMR. Reaction conditions:
EtOH, r.t., 24 h.
cis- and trans-isomers, depending on the nature of the solvent,
substituent, and concentration of the reactants.21 Recently Jiang
reported 2-arylamino fumarates (trans-isomers) to be favored in
protic solvents such as methanol and ethanol and the corre-
sponding maleates (cis-isomers) to be favored in nonprotic
media such as DMF.22 In our case, the two Michael addition
steps and the protonation step in Scheme 2 are all reversible and
in thermodynamic equilibrium, giving rise to the more stable 2,3-
trans/3,4-trans isomer as the major product. A direct hetero-
DielsꢀAlder addition of the 1,3-dipolar intermediate (B) to
arylidene dimedone (A),23,24 could be ruled out as an alter-
native mechanism, since the stereochemical outcome should be
different.
5g
5h
5i
m-ClC6H4
p-ClC6H4
p-BrC6H4
5j
m-NO2C6H4
a Isolated yields. All compounds were characterized by H, 13C NMR.
Reaction conditions: EtOH, r.t. 24 h.
1
(2.0 mmol), meldrum acid (2.0 mmol, 0.288 g), and triethylamine
(1.0 mmol, 0.101 g) in 5.0 mL ethanol was stirred at room for ten
minutes. Then a solution of arylamine (2.0 mmol) and dimethyl
acetylenedicarboxylate (2.0 mmol, 0.284 g) in 5.0 mL ethanol was
added to it. The whole solution was stirred the elevated temperature
(50ꢀ60 °C) for six hours. In most cases the resulting precipitates were
collected by filtration and washed with cold alcohol to give the pure
product for analysis. In fewer cases the products were further purified
with SiO2 thin-layer chromatograph with ethyl acetate and light
petroleum (V/V = 1/3) as elute to give the product 1a: yellow solid,
’ CONCLUSION
In summary, we have developed an interesting four-
component reaction of aromatic aldehydes, cyclic 1,3-diketones,
aryl amines, and dimethyl acetylenedicarboxylate providing two
different classes of products depending on the nature of the
dicarbonyl component. Mechanisms for the formation of the
resulting 3,4-dihydropyridin-2(1H)-ones and 3,4-dihydro-2H-
pyrans derivatives are proposed in which stereochemistry is
controlled by thermodynamic factors. The potential uses of the
reaction in synthetic and medicinal chemistry may be significant,
since the products share structural and functional group proper-
ties with a variety of biologically active molecules. Further
expansion of the reaction scope and synthetic applications of
this methodology are in progress in our laboratory.
1
41%, mp 147ꢀ149 °C; H NMR (600 MHz, CDCl3) δ 7.38ꢀ7.34
(m, 4H, ArH), 7.27 (t, J = 6.6 Hz, 1H, ArH), 7.19 (d, J = 7.8 Hz, 2H,
ArH), 7.05 (d, J = 6.6 Hz, 2H, ArH), 4.31 (d, J = 7.2 Hz, 1H, CH), 3.68
(s, 3H, OCH3), 3.50 (s, 3H, OCH3), 3.21 (dd, J1 = 7.8 Hz, J2 = 16.2 Hz,
1H, CH2), 2.96 (d, J = 16.2 Hz, 1H, CH2), 2.35 (s, 3H, CH3); 13C NMR
(150 MHz, CDCl3) δ 168.5, 165.6, 163.3, 144.7, 139.9, 139.2, 133.3,
129.8, 129.1, 128.8, 127.5, 126.7, 109.4, 52.6, 52.3, 38.6, 36.7, 21.3;
IR(KBr) υ 3021, 2953, 1739, 1707, 1633, 1506, 1433, 1347, 1300, 1257,
1204, 1146, 1112, 1069, 987, 849, 803, 754 cmꢀ1; MS (m/z) 378.26
([M ꢀ 1]þ) 100%. Anal. Calcd for C22H21NO5: C 69.64, H 5.58, N
3.69; Found C 69.78, H 5.81, N 3.54.
2. Typical Procedure for the Four-Component Reaction of
Arylamines, Dimethyl Acetylenedicarboxylate, Aromatic
Aldehydes, and Dimedone. A mixture of arylamine (2.0 mmol)
and dimethyl acetylenedicarboxylate (2.0 mmol, 0.284 g) in 5.0 mL
ethanol was stirred at room for ten minutes. Then aromatic aldehyde
(2.0 mmol), dimedone (2.0 mmol, 0.284 g) was added. The whole
’ EXPERIMENTAL SECTION
1. Typical Procedure for the Four-Component Reaction of
Arylamines, Dimethyl Acetylenedicarboxylate, Aromatic
Aldehydes and Meldrum Acid. A mixture of aromatic aldehyde
423
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ACS Combinatorial Science
RESEARCH ARTICLE
Scheme 2. Formation Mechanism of Polysubstituted 3,4-Di-
hydro-2H-pyrans
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solution was stirred at room temperature for additional about 24 h. The
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pure product for analysis. 2a: white solid, 71%, mp 171ꢀ172 °C; H
1
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NMR (600 MHz, CDCl3) δ 7.26ꢀ7.24 (m, 3H, ArH), 7.13 (d, J = 7.8
Hz, 2H, ArH), 6.98 (d, J = 8.4 Hz, 2H, ArH), 6.74 (d, J = 8.4 Hz, 2H,
ArH), 5.44 (brs, 1H, NH), 4.20 (d, J = 10.2 Hz, 1H, CH), 3.56 (s, 3H,
OCH3), 3.51 (s, 3H, OCH3), 3.18 (d, J = 10.2 Hz, 1H, CH), 2.60 (d, J =
17.4 Hz, 1H, CH2), 2.34 (d, J = 17.4 Hz, 1H, CH2), 2.24 (s, 3H, CH3),
2.17 (s, 2H, CH2), 1.15 (s, 3H, CH3), 1.01 (s, 3H, CH3); 13C NMR (150
MHz, CDCl3) δ 195.9, 171.5, 168.7, 166.5, 141.2, 140.8, 129.7, 128.6,
128.2, 127.2, 126.9, 126.8, 125.9, 115.6, 113.3, 87.8, 54.1, 53.1, 52.6, 50.7,
42.0, 38.8, 31.7, 31.4, 29.2, 27.6, 20.5; IR(KBr) υ 3391, 3022, 2960,
2876, 1759, 1729, 1643, 1592, 1519, 1434, 1370, 1348, 1317, 1265, 1232,
1168, 1047, 1006, 940, 820, 756 cmꢀ1; MS (m/z) 478.55 ([M þ 1]þ)
100%. Anal. Calcd for C28H31NO6: C 70.42, H 6.54, N 2.93; Found C
70.35, H 6.82, N 2.71. The same reaction procedure was carried out by
using other cyclic 1,3-dicarbonyl compounds and other amines in the
reactions to give 3,4-dihydro-2H-pyran derivatives 2bꢀ2m, 3aꢀ3e,
4aꢀ4e, and 5aꢀ5j.
’ ASSOCIATED CONTENT
S
Supporting Information. The experimental details and
b
the spectroscopic data, including crystallographic data (CIF) of
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ 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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