Synthesis of polysubstituted pyridines under combined microwave and ultrasound irradiation: K2CO3-promoted tandem addition/cyclization/hydrogen shift process

Article abstract of DOI:10.1016/j.tetlet.2011.12.103

A convenient and efficient K₂CO₃-promoted tandem reaction of chalcone, malononitrile, and methanol for the synthesis of highly functionalized pyridines has been developed. This multi-component reaction employing the weak nucleophilic agent methanol proceeded smoothly under combined microwave and ultrasound irradiation (CMUI). The reaction mechanism was proposed to consist of a Michael addition, a methoxylation of CN bond, a cyclization to a 1,4-dihydropyridine and an intermolecular hydrogen shift between 1,4-dihydropyridine and initial chalcone.

Full text of DOI:10.1016/j.tetlet.2011.12.103

Tetrahedron Letters 53 (2012) 1160–1162
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of polysubstituted pyridines under combined microwave
and ultrasound irradiation: K2CO3-promoted tandem
addition/cyclization/hydrogen shift process
Huangdi Feng a,b, Yuan Li a, Erik V. Van der Eycken b, Yanqing Peng a, Gonghua Song a,
⇑
a Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China
b Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient K2CO3-promoted tandem reaction of chalcone, malononitrile, and methanol for
the synthesis of highly functionalized pyridines has been developed. This multi-component reaction
employing the weak nucleophilic agent methanol proceeded smoothly under combined microwave
and ultrasound irradiation (CMUI). The reaction mechanism was proposed to consist of a Michael addi-
tion, a methoxylation of C„N bond, a cyclization to a 1,4-dihydropyridine and an intermolecular hydro-
gen shift between 1,4-dihydropyridine and initial chalcone.
Received 19 November 2011
Revised 14 December 2011
Accepted 23 December 2011
Available online 30 December 2011
Keywords:
Pyridines
Ó 2011 Elsevier Ltd. All rights reserved.
Heterogeneous
Microwave
Ultrasound
Pyridines are frequently encountered as skeletal components
and valuable functional moieties of many biologically active
compounds and natural products.1 Therefore, the development of
efficient methods to facilitate the synthesis of pyridines has cur-
rently attracted much attention in both academia and industry.2
During recent years, one-pot multi-component reactions (MCRs)
as well as domino processes provide synthetic efficiency, intrinsic
atom economy, and procedural simplicity to construct highly com-
plex molecules.3 Meanwhile, microwave- and ultrasound-assisted
organic synthesis has been developed and well documented, owing
to the fact that these technologies can usually reduce the reaction
times, minimize energy consumption, and in certain cases, increase
the yield and selectivity of product formation.4
heterogeneous organic reactions,10 we found that CMUI could
strongly accelerate the synthesis of 4,6-diaryl-2-methoxynicoti-
nitriles, applying the weak nucleophilic methanol in the presence
of the weak base K2CO3 without the addition of any oxidant. To
the best of our knowledge, there are no example describing the
formation of 4,6-diaryl-2-methoxynicotinitriles employing a weak
base. However, the chalcone is else acting as an efficient reaction
promoter via the hydrogen shift between chalcone and 1,4-
dihydropyridine intermediate (Scheme 1, C).
In an initial investigation, we employed chalcone 1j, malononit-
rile, and methanol as nucleophilic agent in the presence of
different bases under CMUI. The reactions were performed at
In view of the multi-component synthesis of pyridines,5 we
focused our attention on the three-component condensation of a
chalcone, malononitrile, and a nucleophilic agent for the synthesis
of 4,6-diaryl-2-methoxynicotinitriles. Various nucleophilic agents
such as amines,6 benzenethiols,7 alkoxides8 have been used to
perform a nucleophilic attack at one of the nitrile groups of malon-
onitrile. However, the application of a weak nucleophilic agent
such as methanol often resulted in low yields of the target product
even in the presence of a strong base such as NaOH, KOH, or Na.9 As
part of our continuing efforts to explore the application of
combined microwave and ultrasound irradiation (CMUI) in
MeO
O
NC
Ar2
CN
NH
O
NC
Ar2
O
K2CO3
NC
CN
+
Ar1
Ar2
CH3OH
Ar1
Ar1
1
B
2
A
MeO
OMe
OMe
O
NH2
O
NC
Ar2
NC
Ar2
-H2O NC
Ar2
1
+
HN
+
N
Ar2
Ar1
-2H
Ar1
Ar1
Ar1
4
C
3
⇑
Corresponding author. Tel.: +86 021 6425 3540; fax: +86 021 6425 2603.
E-mail address: ghsong@ecust.edu.cn (G. Song).
Scheme 1. Proposed mechanism for the protocol.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.103

H. Feng et al. / Tetrahedron Letters 53 (2012) 1160–1162
1161
Table 1
appearance of 3-(4-fluorophenyl)-1-(4-methoxyphenyl) propan-
1-one 4j. It provided us the clue that compound 4j may be formed
via intermolecular hydrogen shift between chalcone 1j and 1,
4-dihydropyridine the intermediate for the formation of product
3j.15 To examine the feasibility of this hydrogen shift reaction,
more than the stoichiometric ratio of chalcone 1j was used (Table 1,
entries 14–16). To our delight, when the amount of chalcone 1a
was increased to 1.8 equiv, product 3j was obtained in an 84% yield
together with the corresponding reduction product 4j (Table 1,
entry 15). Increasing the amount of chalcone to 2 equiv resulted
in only a slight increase of the yield of 3j (Table 1, entry 16). This
investigation indicated that apart from the participation in the
main reaction, chalcone 1j was also acting as an efficient hydrogen
acceptor which played a key role to increase the yield of desired
product. Interestingly, under conventional heating the desired
product 3j was obtained in a moderate yield of 64% after refluxing
for 6 h (Table 1, entry 17). The dramatic increase in reaction rate
under combined microwave and ultrasound irradiation could be
ascribed to the simultaneous intensive enhancements of both heat
and mass transfer.
Optimization of the conditionsa
OCH3
CN
O
N
CN
base CH3OH
+
MW+US, 4.5 min
CN
2
H3CO
F
H3CO
F
1j
3j
Entry
1a/2 (mmol)
Base (equiv)
Oxidant (equiv)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
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
1.5:1
1.8:1
2:1
2:1
Na2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (2.5)
K2CO3 (3)
NaOH (3)
KOH (3)
—
—
—
—
—
—
—
—
38
43
45
45
48
50
10
8
16
36
22
40
7
NEt3 (3)
Pyridine (3)
Piperidine (3)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
—
DDQ (1.5)
H2O2 (2)
MnO2 (2.5)
FeCl3 (2)
—
—
—
—
Having the optimized conditions at hand (Table 1, entry 16), we
next evaluated the tandem addition/cyclization/hydrogen shift
process of various chalcones with malononitrile and methanol.
As listed in Table 2, all reactions went on smoothly and quickly
under CMUI. Both electron-rich and electron-deficient chalcones
1 provided the desired product 3 in good yields. In addition, the
1,3-diphenylpropan-1-ones 4, could be obtained in moderate
yields of 40–61% (Table 2).
78
84
85
64c
a
Reactions were performed under reflux using malononitriles (1.0 mmol) and
methanol (6 mL) for 4.5 min. CMUI (microwave: 100 W; ultrasound: 50 W).
b
Conversion based on malononitriles.
Conventional heating under reflux conditions for 6 h.
c
Based on the previous work6a and our present results, a mech-
anism for the formation of products 3 and 4 is proposed (Scheme 1).
Upon Michael addition of chalcones 1 with malononitrile 2
compounds A are formed. Nucleophilic addition of methanol to
the C„N bond of the adduct gives intermediate B. Dehydrative
cyclization of B affords dihydropyridine C. Subsequently the
important step is that intermolecular hydrogen shift from C to
chalcone 1 produces the desired products 3 and 4.7a,15
reflux for 4.5 min. The desired product 3j was easily isolated by
filtration. Among the bases tested, all of the inorganic and organic
bases led to unsatisfactory results (Table 1, entries 1–9), as the
yields did not exceeded 50%. Interestingly, only a slightly lower
yield was obtained when the relatively weak base K2CO3 was used
(Table 1, entries 1–6). In an attempt to improve the yield, we
executed the reactions in the presence of a known 1,4-dihydropyr-
idine oxidizing agent such as DDQ,11 H2O2,12 MnO213, or FeCl3.14
However, it was found that none of them had positive effect
(Table 1, entries 10–13). Analysis of the filtrate showed the
In conclusion, we have successfully developed an efficient
methodology for the preparation of poly-substituted pyridines
via
a
K2CO3-promoted multi-component tandem reaction of
Table 2
Scope and limitations of the protocola
OCH3
O
O
CN
CN
CH3OH, K2CO3
MW-US
N
+
+
R2
R2
R2
R1
R1
CN
R1
2
1
3
4
Entry
R1
R2
Time (min)
Product 3
Yieldb (%)
Product 4
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
4-Cl
3,4-O-CH2-O–
4-F
4-CH3O
3,4,5-(CH3O)3
4-CH3O
4-F
4
5
2
5
6
4
4.5
5.5
4
4.5
5
4.5
5
4.5
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
81
82
82
90
71
82
74
75
83
85
79
73
86
82
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
56
58
57
41
52
54
50
49
45
53
40
61
43
52
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3
4-CH(CH3)2
3,4,5-(CH3O)3
4-F
3-Br
4-CH3
H
4-CH3O
a
A mixture of chalcones (2.0 mmol), malononitrile (1.0 mmol), K2CO3 (1.5 mmol), and methanol (6 mL) was subjected to CMUI (microwave: 100 W; ultrasound: 50 W) for
the indicated time (monitored by TLC) under reflux.
b
Isolated yields.

1162
H. Feng et al. / Tetrahedron Letters 53 (2012) 1160–1162
chalcone, malononitrile, and methanol under CMUI.16 The forma-
tion of the final pyridine via intermolecular hydrogen shift from
1,4-dihydropyridine to chalcone is more effective than applying a
standard oxidant. Moreover, our results prove that the strong base
can be successfully replaced by K2CO3 without a additional oxi-
dant, and good yield of the desired product is obtained.
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Acknowledgments
Financial support for this work from the National Basic Re-
search Program of China (973 Program) (Grant 2010CB126101)
and the Shanghai Leading Academic Discipline Project (Project
Number: B507) are gratefully acknowledged.
Supplementary data
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the online version, at doi:10.1016/j.tetlet.2011.12.103.
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