Efficient one-pot synthesis of substituted pyridines through multicomponent reaction

Article abstract of DOI:10.1039/c001117g

A facile and convenient synthesis of substituted pyridines has been developed via a one-pot multicomponent reaction of easily available 1,3-dicarbonyl compounds, aromatic aldehydes, malononitrile and alcohol in the presence of NaOH under mild conditions. A series of functionalized pyridines were thus obtained by this multicomponent reaction, in which four new bonds were formed in a highly chemo- and regioselective manner, and alcohol played dual roles as both reactant and reaction medium. Particularly valuable features of this protocol including mild conditions, simple execution, broad substrate scope, and good yields of products make it an efficient and promising synthetic strategy to build pyridine skeleton.

Full text of DOI:10.1039/c001117g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Efficient one-pot synthesis of substituted pyridines through multicomponent
reaction†
Xin Xin,a Yan Wang,a,b Santosh Kumar,a Xu Liu,a Yingjie Linb and Dewen Dong*a
Received 19th January 2010, Accepted 23rd April 2010
First published as an Advance Article on the web 18th May 2010
DOI: 10.1039/c001117g
A facile and convenient synthesis of substituted pyridines has been developed via a one-pot
multicomponent reaction of easily available 1,3-dicarbonyl compounds, aromatic aldehydes,
malononitrile and alcohol in the presence of NaOH under mild conditions. A series of functionalized
pyridines were thus obtained by this multicomponent reaction, in which four new bonds were formed in
a highly chemo- and regioselective manner, and alcohol played dual roles as both reactant and reaction
medium. Particularly valuable features of this protocol including mild conditions, simple execution,
broad substrate scope, and good yields of products make it an efficient and promising synthetic strategy
to build pyridine skeleton.
medium and hence improved the yields of the products.9 Chen et al.
Introduction
reported the synthesis of 3,5-dicarbonitrile-pyridines via a MCR
The pyridine substructure is one of the most prevalent hetero-
under basic conditions, also they applied the use of microwave
irradiation to the MCR preparation.10 Sridhar et al. investigated
cycles found in numerous natural and synthetic products along
with useful bio-, physio- and pharmacological activities.1 The
MCRs of aldehydes, malononitrile and thiophenol using a variety
synthesis of the pyridine derivatives can principally be realized
of Lewis acids such as ZnCl2, AlCl3 and FeCl3 as catalysts, and
achieved one-pot synthesis of 3,5-dicarbonitrile-pyridines.11 Simi-
larly, Thirmurugan et al. synthesized 3,5-dicarbonitrile-pyridines
via a MCR mediated by InCl3.12 Additionally, one-pot synthesis of
cyanopyridines through a four-component reaction using organic
acid, such as p-toluenesulfonic acid, as a catalyst was reported by
Shaabani et al.13
either by modification of the pre-constructed pyridine nucleus or
through the construction of the pyridine ring from appropriately
substituted open chain precursor, which have been extensively
reviewed.2 Nevertheless, simple and efficient synthetic protocols
for the construction of more elaborate and usefully functionalized
pyridines are still desirable.
Multicomponent reactions (MCRs) have emerged as powerful
and bond-forming efficient tools in organic, combinatorial, and
medicinal chemistry.3 The MCRs strategy offers significant ad-
vantages over conventional multistep synthesis due to its flexible,
convergent, and atom economic nature.4 In a true sense, MCRs
represent environmentally friendly processes by reducing the
number of steps, energy consumption, and waste production.5
These features make MCRs well-suited for the easy construction
of diversified arrays of, e.g., valuable heterocyclic scaffolds.
Actually, MCRs have been demonstrated as a straightforward
approach to the synthesis of pyridines, which often involves
classical carbonyl condensation chemistry.6 Besides aldehydes, 1,3-
dicarbonyl compounds and/or their analogous nitrile derivatives
constitute important synthetic intermediates, incorporating mul-
tiple functionalities that can be involved either as nucleophilic
or electrophilic species in a variety of synthetic transformations.7
Recently, Evdokimov et al. developed a one-pot synthesis of 3,5-
dicarbonitrile-pyridines by a MCR of an aldehyde, malononitrile,
and a thiol in the presence of a base catalyst such as piperidine,
DABCO or triethylamine.8 Ranu et al. modified this method
by employing a basic ionic liquid as both catalyst and reaction
During the course of our studies on the synthetic utility of
1,3-dicarbonyl compounds, we found that the easily available
and structurally flexible b-oxo amide derivatives showed fas-
cinating structural features as versatile organic intermediates,
and successfully developed a range of synthetic approaches to
construct aromatic and heterocyclic ring skeletons.14 In MCRs
of carbonyl compounds, we achieved efficient one-pot synthesis
of highly substituted thiophenes by using the sequential addition
of reactants,15 and one-pot synthesis of polysubstituted benzenes
via sequential Michael addition, Knoevenagel condensation and
nucleophilic cyclization reactions of readily available chalcones
with malononitrile and nitroethane in guanidinium ionic liquids.16
In connection with these studies and the aim to establish novel
synthetic approaches for heterocyles, we explored the reactions of
b-oxo amides, aromatic aldehydes, malononitrile in the presence of
a base. By this research, we developed efficient one-pot synthesis
of substituted pyridines via four-component reaction. Herein,
we wish to report our experimental results and the mechanism
involved.
Results and discussion
aChangchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun, 130022, China. E-mail: dwdong@ciac.jl.cn; Fax: +86 431
85693057
In an initial attempt, the reaction of 3-oxo-N-phenylbutanamide
1a, benzaldehyde 2a (1.0 equiv.) and malononitrile 3 (1.0 equiv.)
was performed in ethanol in the presence of NaOH (2.0 equiv.)
at room temperature. As monitored by TLC, the reaction could
bDepartment of Chemistry, Jilin University, 130012, Changchun, China
† Electronic supplementary information (ESI) available: Copies of NMR
spectra for compounds 5. See DOI: 10.1039/c001117g
3078 | Org. Biomol. Chem., 2010, 8, 3078–3082
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Table 1 Optimization of reaction conditions of the multicomponent
reactions of 1a, 2a, 3 and 4a
optimization of the reaction conditions, including the nature of
base, amount of base and reaction medium was then investigated.
It was observed that when the amount of NaOH was increased to
3.0 equivalents, the reaction rate was speeded up for the shorter
reaction time and high conversion (Table 1, entry 2), but further
increase of the amount of NaOH had nearly no significant effect
on the reaction (Table 1, entry 3). When K2CO3 was used as a base,
the reaction proceeded sluggishly to afford 5a in very low yield even
after prolonged reaction time (Table 1, entry 4). Subjecting 1a, 2a
(1.0 equiv.), 3 (1.0 equiv.) and ethanol 4a (1.1 equiv.) in DMF or
CH2Cl2 at room temperature, however, no desired product 5a was
obtained (Table 1, entries 5, 6).
Next, we intended to determine the scope and limitations
of the multicomponent reaction with respect to the substrates
bearing varied substituted groups, e.g. R1, R2 and R3. Thus,
a series of reactions of malononitrile, aromatic aldehydes, 1,3-
dicarbonyl compounds and alcohol were carried out under the
reaction conditions as described in Table 1, entry 2. As shown
in Table 2, all the reactions of aromatic aldehydes 2a–e bearing
electron-donating groups (R2 = 4-CH3C6H4, 2-CH3OC6H4), and
electron-withdrawing groups (R2 = 4-ClC6H4, 4-NO2C6H4) with
3-oxo-N-phenylbutan-amide 1a and malononitrile 3 in ethanol
in the presence of NaOH proceeded smoothly to afford the
corresponding substituted pyridines 5a–e in good yields (entries 1–
5). The multicomponent reactions proved to be suitable for b-oxo
amides 1b–g bearing either an electron-donating or an electron-
withdrawing group in para or ortho position with benzaldehyde
Entrya Base
Amount (equiv.) Solvent
EtOH
Time/h
Yield b(%)
1
2
3
4
5
6
NaOH 2.0
NaOH 3.0
NaOH 4.0
K2CO3 3.0
NaOH 3.0
NaOH 3.0
8.0
3.0
3.0
8.0
8.0
8.0
56
82
83
24
0
EtOH
EtOH
EtOH
DMF
CH2Cl2
0
a In the cases of entries 5 and 6, EtOH was added as a reactant (1.1 equiv.).
b Isolated yields.
proceed, and a new product was formed though some of the
starting materials were still not consumed after 8.0 h. The reaction
was quenched by addition of diluted aqueous HCl. After work-
up and purification by column chromatography of the resulting
mixture, a white solid product was obtained, which was charac-
terized as 5-cyano-6-ethoxy-2-methyl-N, 4-diphenylnicotinamide
(56% yield), a substituted cyanopyridine 5a, on the basis of its
spectra and analytical data (Table 1, entry 1). Obviously, the result
indicated that ethanol took part in the reaction as a reactant. The
Table 2 Multicomponent reaction for the synthesis of substituted pyridines 5
Substrates
Products
Time
(h)
Yielda
(%)
Entry
1
R1
2
R2
4
R3
5
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1a
1b
1c
1d
1e
1f
C6H5NH
C6H5NH
C6H5NH
C6H5NH
2a
2b
2c
2d
2e
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
C6H5
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
4c
4d
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
n-C4H9
5a
5b
5c
5d
5e
5f
5g
5h
5i
3.0
4.0
3.5
3.5
5.5
3.5
3.5
4.0
3.0
3.5
4.0
2.5
4.0
4.0
4.5
4.5
5.0
4.0
4.5
4.5
2.0
4.0
5.0
82
85
85
79
71
79
73
81
85
77
86
89
0
87
83
76
84
73
87
79
88
73
0
4-CH3C6H4
2-CH3OC6H4
4-ClC6H4
4-NO2C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5NH
4-CH3C6H4NH
2-CH3C6H4NH
4-CH3OC6H4NH
2-CH3OC6H4NH
4-ClC6H4NH
2-ClC6H4NH
OC2H5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
5j
5k
5l
CH3
C6H5NH
5m
5n
5o
5p
5q
5r
5s
5t
4-CH3C6H4NH
2-CH3C6H4NH
4-CH3OC6H4NH
2-CH3OC6H4NH
4-ClC6H4NH
2-ClC6H4NH
OC2H5
1g
1h
1a
1a
C6H5
C6H5
C6H5
5u
5v
5w
C6H5NH
C6H5NH
CH(CH3)2
a Isolated yield.
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2a and malononitrile 3 in ethanol in the presence of NaOH
(Table 2, entries 6–11). The validity of this pyridine synthesis was
further evaluated by subjecting b-oxo ester 1h to the identical
conditions (Table 2, entry 12). However, the synthesis of pyridine
of type 5 from acetyl acetone 1i was unsuccessful (Table 2, entry
13). To expand the scope of the above cyclization, a series of
reactions was performed on substrates 1–3 in other alcohols. Thus,
the corresponding substituted pyridines 5n–u were synthesized
in moderate to good yields when b-oxo amides 1a–g or b-oxo
ester 1h were reacted with benzaldehyde 2a and malononitrile 3 in
methanol in the presence of NaOH (Table 2, entries 14–21). It was
also observed that the reaction of 3-oxo-N-phenyl butanamide 1a,
benzaldehyde 2a and malononitrile 3 in n-butanol could proceed
to afford substituted pyridine 5v in 73% yield (Table 2 entry
22). Unfortunately, in the case of sterically hindered isopropanol,
the desired pyridine 5w was not obtained (Table 2 entry 23).
Nevertheless, all the obtained results demonstrated the efficiency
and synthetic value of the one-pot multicomponent reaction for
the synthesis of substituted pyridines of type 5, in which four new
bonds were formed in highly chemo- and regioselective manner. It
should be noted that the richness of the functionality of substituted
pyridines 5, for example acyl and cyano groups, may render them
versatile as synthons in further synthetic transformations.17
To gain much more clear insight into the mechanism for the
pyridine synthesis, some supporting experiments were conducted.
No reaction was observed when 1a was treated with 2a or
malononitrile 3 in ethanol in the presence of NaOH at room
temperature. The results indicated the synthesis of pyridine of
type 5 should be initiated from the Knoevenagel reaction of 2a
and malononitrile 3, which prompted us to perform a stepwise
reaction. Thus, the reaction of 2a and malononitrile 3 was carried
out in N,N-dimethylformamide, to circumvent the influence of
ethanol, in the presence of weak base triethylamine at room
temperature, which furnished the Knoevenagel adduct 6a in 91%
yield. By treatment of adduct 6a with 1a in ethanol in presence
of NaOH at room temperature for 2.0 h, a product was obtained,
which was characterized as pyridine 5a (84% yield).
Scheme
pyridines 5.
1
Plausible mechanism for the synthesis of substituted
potential applications. The scope and synthetic applications of the
methodology are currently under investigation in our laboratory.
Experimental
General remarks
All chemicals used were reagent grade and were used as received
without further purification. The products were purified by
column chromatography over silica gel. 1H NMR and 13C NMR
spectra were recorded at 25 ◦C at 300 MHz and 75 MHz,
respectively, using TMS as internal standard. IR spectra (KBr)
were recorded on a FTIR spectrophotometer in the range of 400–
4000 cm-1.
General experimental procedure
On the basis of the above results together with reported
literatures,8,10,18 a plausible mechanism for the formation of substi-
tuted pyridines 5 is depicted in Scheme 1. In the presence of NaOH,
Knoevenagel condensation between aldehyde 2 and malononitrile
3 occurs to generate an adduct 6. Subsequent Michael addition
of 1,3-dicarbonyl compounds 1 to 6 leads to the fomation of
intermediate 7. The attack of alcohol 4 to intermediate 8, tautomer
of 7, forms intermediate 9, which undergoes intramolecular
cyclization to afford Hantzsch dihydropyridine derivative 10 with
an elimination of water.19 Finally, aromatization of 10 via an
oxidation process gives rise to substituted pyridine of type 5.10–12,20
Typical procedure for the synthesis of substituted pyridines 5 (5a
as an example). To a solution of 3-oxo-N-phenylbutanamide 1a
(354 mg, 2.0 mmol), benzaldehyde 2a (0.20 mL, 2.0 mmol), and
malononitrile 3 (132 mg, 2.0 mmol) in ethanol (20 mL) was added
NaOH (240 mg, 6.0 mmol) in one portion at room temperature.
The reaction mixture was stirred at room temperature for 3.0 h.
After the starting material was consumed (monitored by TLC),
and then the reaction mixture was poured into saturated aqueous
NaCl (20 mL). The mixture was extracted with dichloromethane
(3 ¥ 20 mL). The combined organic phase was washed with
water (3 ¥ 20 mL), dried over anhydrous MgSO4, filtered and
concentrated by evaporation. The crude product was purified by
flash chromatography (silica gel, petroleum ether: diethyl ether =
10: 1) to give product 5a (585 mg, 82%) as a white solid.
Conclusion
In summary, we have developed a novel, convenient, and efficient
one-pot four-component synthesis of substituted pyridines of
potential synthetic and pharmacological interest, and a plausible
mechanism for the reaction was proposed. The use of easily
available starting materials, mild reaction conditions, high chemo-
and regioselectivity, and good yields of products are the main
advantages of this method. High efficiency and simple execution
make this new strategy attractive for academic research and
Physical data of compounds isolated. 5a: White solid: mp 228–
◦
1
230 C; H NMR (300 MHz, CDCl3) d = 1.48 (t, J = 6.6 Hz,
3H), 2.67 (s, 3H), 4.58 (q, J = 7.2 Hz, 2H), 6.79 (s, 1H), 7.08–
7.10 (m, 3H), 7.21–7.27 (m, 2H), 7.46–7.48 (m, 5H). 13C NMR
(75 MHz, CDCl3) d = 14.4, 23.4, 63.7, 90.4, 114.7, 120.4, 125.2,
125.7, 128.2, 128.9, 129.0, 130.0, 134.2, 136.7, 153.6, 159.7, 164.9.
IR (KBr, cm-1) 747, 1161, 1327, 1442, 1550, 1645, 2228, 2986. anal.
3080 | Org. Biomol. Chem., 2010, 8, 3078–3082
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calcd for C22H19N3O2: C, 73.93; H, 5.36; N, 11.76; found: C, 73.79;
H, 5.41; N, 11.66.
6.6 Hz, 2H), 6.75 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H),
7.03–7.06 (m, 1H), 7.39–7.46 (m, 6H), 8.17 (d, J = 8.7 Hz, 1H). 13
C
5b: White solid: mp 219–220 ◦C; 1H NMR (400 MHz, CDCl3)
d = 1.47 (t, J = 6.8 Hz, 3H), 2.35 (s, 3H), 2.65 (s, 3H), 4.55–4.60
(q, J = 6.8 Hz, 2H), 6.76 (s, 1H), 7.08–7.13 (m, 3H), 7.23–7.25 (m,
4H), 7.38 (s, 1H). 13C NMR (100 MHz, CDCl3) d = 14.4, 23.1, 23.4,
63.7, 93.6, 114.8, 120.4, 125.1, 125.7, 128.2, 128.9, 129.8, 131.3,
136.9, 140.2, 153.8, 159.7, 163.8, 165.1. anal. calcd for C23H21N3O2:
C, 74.37; H, 5.70; N, 11.31; found: C, 74.45; H, 5.61; N, 11.25.
5c: White solid: mp 226–228 ◦C; 1H NMR (400 MHz, CDCl3)
d = 1.47 (t, J = 6.8 Hz, 3H), 2.35 (s, 3H), 2.65 (s, 3H), 4.55–4.60
(q, J = 6.8 Hz, 2H), 6.76 (s, 1H), 7.08–7.13 (m, 3H), 7.23–7.25 (m,
4H), 7.38 (s, 1H). 13C NMR (100 MHz, CDCl3) d = 14.4, 23.4,
56.0, 63.6, 95.0, 111.6, 114.4, 120.0, 121.6, 123.7, 124.8, 126.3,
128.9, 129.7, 131.5, 137.1, 151.3, 155.4, 159.7, 163.3, 164.7. anal.
calcd for C23H21N3O3: C, 71.30; H, 5.46; N, 10.85; found: C, 71.48;
H, 5.40; N, 10.79.
NMR (75 MHz, DMSO) d = 14.3, 22.9, 55.7, 63.2, 92.8, 111.5,
114.7, 120.0, 123.7, 125.8, 126.0, 127.3, 128.2, 128.5, 129.4, 134.5,
151.2, 153.8, 157.8, 162.5, 164.5. IR (KBr, cm-1) 751, 1028, 1160,
1325, 1462, 1542, 1649, 2226, 2980. anal. calcd for C23H21N3O3: C,
71.30; H, 5.46; N, 10.85; found:◦C, 71.75; H, 5.37; N, 10.81.
1
5j: White solid: mp 256–257 C; H NMR (300 MHz, CDCl3)
d = 1.46 (t, J = 6.9 Hz, 3H), 2.62 (s, 3H), 4.56 (q, J = 8.2 Hz, 2H),
7.01–7.04 (d, J = 7.5 Hz, 3H), 7.17 (d, J = 8.1 Hz, 2H), 7.42 (m,
5H). 13C NMR (75 MHz, CDCl3) d = 14.3, 23.3, 63.8, 93.4, 114.5,
121.5, 125.4, 128.1, 128.9, 129.0, 130.2, 134.1, 135.3, 153.6, 159.8,
163.7, 164.9. anal. calcd for C23H19ClN2O2: C, 70.68; H, 4.90; N,
7.17; found: C, 70.88; H, 4.87; N, 7.21.
5k: White solid: mp 179–180 ◦C; 1H NMR (300 MHz, CDCl3)
d = 1.48 (t, J = 7.2 Hz, 3H), 2.67 (s, 3H), 4.59 (q, J = 6.6 Hz, 2H),
7.00–7.05 (m, 1H), 7.20–7.29 (m, 3H), 7.42–7.47 (m, 5H), 8.10 (t,
J = 8.1 Hz, 1H). 13C NMR (75 MHz, DMSO) d = 14.3, 23.0, 63.3,
92.9, 114.6, 126.7, 126.9, 127.4, 127.9, 128.4, 128.5, 129.6, 133.8,
134.4, 154.0, 157.8, 162.7, 164.8. anal. calcd for C22H18ClN3O2: C,
67.43; H, 4.63; N, 10.72; fou◦nd: C, 67.67; H, 4.61; N, 10.81.
5l: White solid: mp 62–64 C; 1H NMR (300 MHz, CDCl3) d =
0.88 (t, J = 6.6 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H), 2.57 (s, 3H), 3.67
(q, J = 7.2 Hz, 2H), 4.56 (q, J = 6.6 Hz, 2H), 7.35 (m, 2H), 7.45
(m, 3H). 13C NMR (75 MHz, CDCl3) d = 13.4, 14.3, 23.3, 61.4,
63.6, 94.0, 114.4, 128.0, 128.5, 129.4, 135.1, 155.0, 159.1, 163.5,
167.1. IR (KBr, cm-1) 704, 1019, 1152, 1274, 1561, 1721, 2226,
2979, 3020. anal. calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03;
found: C, 69.73; H, 5.82; N, 9.00.
5d: White solid: mp 198–199 ◦C; 1H NMR (300 MHz, CDCl3)
d = 1.47 (t, J = 7.2 Hz, 3H), 2.66 (s, 3H), 4.58 (q, J = 7.2 Hz,
2H), 7.16 (t, J = 8.1 Hz, 2H), 7.28–7.31 (m, 4H), 7.45 (m, 3H). 13
C
NMR (75 MHz, DMSO) d = 14.3, 22.8, 63.4, 93.0, 114.4, 119.6,
124.1, 128.4, 128.5, 128.8, 130.2, 131.0, 132.2, 134.6, 138.2, 152.6,
158.0, 162.6, 164.0. IR (KBr, cm-1) 748, 1093, 1183, 1325, 1445,
1549, 1639, 2227, 2989. anal. calcd for C22H18ClN3O2: C, 67.43; H,
4.63; N, 10.72; found: C, 67.47; H, 4.66; N, 10.75.
5e: Yellow solid: mp 236–237 ◦C; 1H NMR (400 MHz, CDCl3)
d = 1.48 (t, J = 7.2 Hz, 3H), 2.67 (s, 3H), 4.58–4.63 (m, 2H), 6.96
(s, 1H), 7.13–7.16 (m, 1H), 7.19–7.21 (m, 2H), 7.27–7.29 (m, 2H),
7.69 (d, J = 8.8 Hz, 2H), 8.32 (d, J = 8.4 Hz, 2H). 13C NMR
(100 MHz, CDCl3) d = 14.3, 23.3, 64.1, 93.4, 114.0, 120.0,124.0,
125.5, 129.1, 129.6, 129.8, 136.6, 140.4, 148.5, 151.4, 159.7, 163.6,
164.2. anal. calcd for C23H20N4O4: C, 66.34; H, 4.84; N, 13.45;
found: C, 66.63; H, 4.81; N, 13.62.
5n: White solid: mp 238–239 ◦C; 1H NMR (300 MHz, CDCl3)
d = 2.68 (s, 3H), 4.13 (s, 3H), 6.84–6.87 (d, J = 10.5 Hz, 1H), 7.09–
7.11 (m, 3H), 7.22–7.24 (m, 2H), 7.46–7.47 (m, 5H). 13C NMR
(75 MHz, CDCl3) d = 23.3, 54.8, 114.6, 120.4, 125.1, 128.2, 128.8,
129.0, 130.0, 134.0, 136.7, 153.6, 159.7, 163.8, 164.8, 173.2. IR
(KBr, cm-1) 744, 1154, 1320, 1377, 1442, 1560, 1647, 2223, 2950,
3441. anal. calcd for C21H17N3O2: C, 73.45; H, 4.99; N, 12.24;
found: C, 73.57; H, 5.00; N, 12.31.
5f: White solid: mp 256–258 ◦C; 1H NMR (300 MHz, CDCl3)
d = 1.46 (t, J = 8.5 Hz, 3H), 1.75 (s, 3H), 2.62 (s, 3H), 4.55 (q,
J = 7.2 Hz, 2H), 7.04–7.15 (m, 5H), 7.44 (m, 4H). 13C NMR
(75 MHz, CDCl3) d = 14.4, 17.2, 23.2, 63.7, 93.5, 114.6, 123.8,
126.1, 126.5, 128.5, 128.9, 130.0, 130.5, 134.3, 134.4, 153.4, 159.3,
163.6, 165.3. IR (KBr, cm-1) 700, 1023, 1165, 1319, 1584, 1625,
1654, 2230, 2985, 3463. anal. calcd for C23H21N3O2: C, 74.37; H,
5.70; N, 11.31; found: C, 74.33; ◦H, 5.74; N, 11.25.
5o: White solid: mp 270–271 ◦C; 1H NMR (300 MHz, CDCl3)
d = 2.27 (s, 3H), 2.66 (s, 3H), 4.11 (s, 3H), 6.86 (s, 1H), 6.95 (d,
J = 8.1 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 7.45–7.46 (m, 5H). 13
C
NMR (75 MHz, CDCl3) d = 20.8, 23.3, 54.8, 114.6, 120.6, 126.0,
128.2, 128.9, 129.3, 130.0, 134.0, 134.9, 153.6, 159.7, 163.8, 164.7.
IR (KBr, cm-1) 699, 820, 1326, 1513, 1560, 1659, 2227, 3040. anal.
calcd for C22H19N3O2: C, 73.93; H, 5.36; N, 11.76; found: C, 73.87;
H, 5.43; N, 11.79.
5g: White solid: mp 182–183 C; 1H NMR (300 MHz, CDCl3)
d = 1.47 (t, J = 7.2 Hz, 3H), 1.79 (s, 3H), 2.67 (s, 3H), 4.58
(q, J = 5.7 Hz, 2H), 6.75–6.78 (d, J = 8.7 Hz, 1H), 7.07–7.12
(m, 3H), 7.23 (s, 1H), 7.48 (m, 5H). 13C NMR (75 MHz, CDCl3)
d = 14.3, 17.1, 23.1, 63.6, 114.5, 123.6, 126.0, 126.4, 128.4, 128.8,
129.9, 130.4, 134.2, 134.3, 153.3, 159.3, 163.5, 165.1. anal. calcd
for C23H21N3O2: C, 74.37; H, 5.70; N, 11.31; found: C, 74.45; H,
5.63; N, 11.25.
5p: White solid: mp 186–188 ◦C; 1H NMR (300 MHz, CDCl3)
d = 1.79 (s, 3H), 2.71 (s, 3H), 4.13 (s, 3H), 6.67 (s, 1H), 7.08–7.13
(m, 3H), 7.29 (m, 1H), 7.49 (m, 5H). 13C NMR (75 MHz, CDCl3)
d = 17.2, 23.2, 54.8, 93.3, 114.6, 124.0, 126.2, 126.4, 128.5, 128.9,
130.0, 130.5, 130.9, 134.2, 134.4, 153.5, 159.3, 163.7, 165.2. anal.
calcd for C22H19N3O2: C, 73.93; H, 5.36; N, 11.76; found: C, 73.82;
H, 5.43; N, 11.87.
5h: White solid: mp 192–193 ◦C; 1H NMR (300 MHz, CDCl3)
d = 1.47 (t, J = 7.5 Hz, 3H), 2.66 (s, 3H), 3.75 (s, 3H), 4.58 (q,
J = 7.5 Hz, 2H), 6.66 (s, 1H), 6.76 (d, J = 8.1 Hz, 2H), 6.94
(d, J = 8.1 Hz, 2H), 7.47 (m, 4H). 13C NMR (75 MHz, DMSO)
d = 14.3, 22.9, 55.1, 63.3, 93.0, 113.9, 114.6, 121.3, 127.1, 128.3,
129.5, 131.2, 134.4, 153.8, 155.8, 157.9, 162.6, 163.7. anal. calcd
for C24H22N2O3: C, 74.59; H, 5.74; N, 7.25; found: C, 74.67; H,
5.77; N, 7.31.
5q: White solid: mp 235–236 ◦C; 1H NMR (300 MHz, CDCl3)
d = 2.68 (s, 3H), 3.76 (s, 3H), 4.12 (s, 3H), 6.68 (s, 1H), 6.76 (d,
J = 9.6 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 7.48 (m, 5H). 13C NMR
(75 MHz, DMSO) d = 22.8, 54.8, 55.1, 92.9, 113.8, 114.6, 121.3,
127.3, 128.3, 128.6, 129.5, 130.3, 131.2, 134.3, 153.8, 155.8, 157.9,
162.9, 163.7. anal. calcd for C22H19N3O3: C, 70.76; H, 5.13; N,
11.25; found: C, 70.71; H, 5.11; N, 11.23.
◦
1
5i: White solid: mp 180–182 C; H NMR (300 MHz, CDCl3)
d = 1.48 (t, J = 6.3 Hz, 3H), 2.66 (s, 3H), 3.67 (s, 3H), 4.58 (q, J =
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5r: White solid: mp 158–160 ◦C; 1H NMR (300 MHz, CDCl3)
d = 2.68 (s, 3H), 3.67 (s, 3H), 4.12 (s, 3H), 6.76 (d, J = 7.2 Hz, 1H),
6.91–6.94 (m, 1H), 7.00–7.02 (m, 1H), 7.39–7.47 (m, 6H), 8.17 (d,
J = 8.1 Hz, 1H). 13C NMR (75 MHz, DMSO) d = 22.8, 54.7, 55.6,
92.8, 111.5, 114.7, 120.0, 123.6, 125.8, 126.0, 127.5, 128.2, 128.5,
129.4, 134.5, 151.2, 153.8, 157.8, 162.8, 164.4. IR (KBr, cm-1) 768,
1255, 1460, 1530, 1560, 1664, 2227, 2975, 3334. anal. calcd for
C22H19N3O3: C, 70.76; H, 5.13; N, 11.25; found: C, 70.89; H, 5.17;
N, 11.21.
3 (a) S. Tu, B. Jiang, Y. Zhang, R. Jia, J. Zhang, C. Yao and S. Feng, Org.
Biomol. Chem., 2007, 5, 355–359; (b) D. Tejedor and F. Garcia-Tellado,
Chem. Soc. Rev., 2007, 36, 484–491; (c) D. J. Ramon and Y. Miguel,
Angew. Chem., Int. Ed., 2005, 44, 1602–1634; (d) Multicomponent
Reactions: J. Zhu, H. Bienayme, Wiley-VCH: Weinheim, Germany
2005; (e) A. Do¨mling, Chem. Rev., 2006, 106, 17–89.
4 J. P. Wan, S. F. Gan, G. L. Sun and Y. J. Pan, J. Org. Chem., 2009, 74,
2862–2865.
5 (a) P. A. Wender, S. T. Handy and D. L. Wright, Chem. Ind., 1997, 765–
769; (b) B. M. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259–281.
6 (a) M. Movassaghi, M. D. Hill and O. K. Ahmad, J. Am. Chem. Soc.,
2007, 129, 10096–10097; (b) S. Cui, X. Lin and Y. Wang, J. Org. Chem.,
2005, 70, 2866–2869; (c) C. Allais, T. Constantieux and J. Rodriguez,
Chem.–Eur. J., 2009, 15, 12945–12948.
7 (a) C. Simon, T. Constantieux and J. Rodriguez, Eur. J. Org. Chem.,
2004, 4957–4980; (b) S. Benetti, R. Romagnoli, C. De Risi, G. Spalluto
and V. Zanirato, Chem. Rev., 1995, 95, 1065–1114; (c) P. Langer, Chem.–
Eur. J., 2001, 7, 3858–3866; (d) P. Langer, Synthesis, 2002, 441–459;
(e) V. Nair, N. Vidya, A. T. Biju, A. Deepthi, K. G. Abhilash and E.
Suresh, Tetrahedron, 2006, 62, 10136–10140.
8 (a) N. M. Evdokimov, I. V. Magedov, A. S. Kireev and A. Kornienko,
Org. Lett., 2006, 8, 899–902; (b) N. M. Evdokimov, A. S. Kireev, A. A.
Yakovenko, M. Y. Antipin, I. V. Magedov and A. Kornienko, J. Org.
Chem., 2007, 72, 3443–3453.
9 B. C. Ranu, R. Jana and S. Sowmiah, J. Org. Chem., 2007, 72, 3152–
3154.
10 (a) T. R. K. Reddy, R. Mutter, W. Heal, K. Guo, V. Gillet, S. Pratt
and B. Chen, J. Med. Chem., 2006, 49, 607–615; (b) K. Guo, M. J.
Thompson, T. R. K. Reddy, R. Mutter and B. Chen, Tetrahedron,
2007, 63, 5300–5311; (c) V. Mathew, J. Keshavayya, V. P. Vaidya and D.
Giles, Eur. J. Med. Chem., 2007, 42, 823–824.
11 M. Sridhar, B. C. Ramanaiah, C. Narsaiha, B. Mahesh, M.
Kumarswamy, K. K. R. Mallu, V. M. Ankathi and P. S. Rao,
Tetrahedron Lett., 2009, 50, 3897–3900.
5s: White solid: mp 243–245 ◦C; 1H NMR (300 MHz, CDCl3)
d = 2.68 (s, 3H), 4.13 (s, 3H), 6.73 (s, 1H), 7.03 (d, J = 8.1 Hz,
2H), 7.19 (d, J = 8.1 Hz, 2H), 7.47 (m, 5H). 13C NMR (75 MHz,
CDCl3) d = 22.8, 54.9, 93.1, 114.5, 121.1, 127.0, 127.8, 128.3,
128.4, 128.7, 129.6, 134.2, 137.1, 153.9, 157.9, 163.0, 164.3. anal.
calcd for C21H16ClN3O2: C, 66.76; H, 4.27; N, 11.12; found: C,
66.87; H, 4.21; N, 11.17.
5t: White solid: mp 189–190 ◦C; 1H NMR (300 MHz, CDCl3)
d = 2.69 (s, 3H), 4.14 (s, 3H), 7.03–7.06 (m, 1H), 7.25 (m, 3H),
7.42–7.48 (m, 5H), 8.11 (d, J = 8.1 Hz, 1H). 13C NMR (75 MHz,
DMSO) d = 22.9, 54.8, 93.0, 114.6, 126.88, 126.9, 127.3, 127.9,
128.4, 128.6, 129.6, 133.8, 134.3, 153.9, 157.8, 163.0, 164.8. anal.
calcd for C21H16ClN3O2: C, 66.76; H, 4.27; N, 11.12; found: C,
66.87; H, 4.22; N, 11.17.
5u: White solid: mp 104–106 ◦C; 1H NMR (300 MHz, CDCl3)
d = 0.88 (t, J = 7.2 Hz, 3H), 2.59 (s, 3H), 3.98 (q, J = 7.2 Hz,
2H), 4.10 (s, 3H), 7.36 (m, 2H), 7.45 (m, 3H). 13C NMR (75 MHz,
CDCl3) d = 13.3, 23.2, 54.7, 61.4, 93.9, 114.2, 123.1, 127.9, 128.4,
128.5, 129.4, 134.9, 154.9, 159.1, 163.7, 166.9. IR (KBr, cm-1) 757,
1001, 1153, 1274, 1558, 1732, 2228, 2954, 2990. anal. calcd for
C17H16N2O3: C, 68.91; H, 5.44; N, 9.45; found: C, 68.84; H, 5.47;
N, 9.41.
12 P. Thirmurugan and P. T. Perumal, Tetrahedron, 2009, 65, 7620–7629.
13 A. Shaabani, M. Seyyedhamzeh, A. Maleki, M. Behnam and F.
Rezazadeh, Tetrahedron Lett., 2009, 50, 2911–2913.
14 For formal [5+1] annulations, see: (a) X. Bi, D. Dong, Q. Liu, W. Pan, L.
Zhao and B. Li, J. Am. Chem. Soc., 2005, 127, 4578–4579; (b) D. Dong,
X. Bi, Q. Liu and F. Cong, Chem. Commun., 2005, 3580–3582. For
Vilsmeier reactions, see: (c) W. Pan, D. Dong, K. Wang, J. Zhang, R.
Wu, D. Xiang and Q. Liu, Org. Lett., 2007, 9, 2421–2423; (d) D. Xiang,
Y. Yang, R. Zhang, Y. Liang, W. Pan, J. Huang and D. Dong, J. Org.
Chem., 2007, 72, 8593–8596; (e) D. Xiang, K. Wang, Y. Liang, G. Zhou
and D. Dong, Org. Lett., 2008, 10, 345–348; (f) R. Zhang, Y. Liang,
G. Zhou, K. Wang and D. Dong, J. Org. Chem., 2008, 73, 8089–8092;
(g) K. Wang, D. Xiang, J. Liu, W. Pan and D. Dong, Org. Lett., 2008,
10, 1691–1694; (h) Y. Yang, D. Xiang, X. Zhao, Y. Liang, J. Huang
and D. Dong, Tetrahedron, 2008, 64, 4959–4966. For PIFA-mediated
oxidative cyclization, see: (i) J. Huang, Y. Lu, B. Qiu, Y. Liang, N. Li
and D. Dong, Synthesis, 2007, 2791–2796; (j) J. Huang, Y. Liang, W.
Pan, Y. Yang and D. Dong, Org. Lett., 2007, 9, 5345–5348; (k) K. Wang,
X. Fu, J. Liu, Y. Liang and D. Dong, Org. Lett., 2009, 11, 1015–1018.
15 (a) Y. Wang, D. Dong, Y. Yang, J. Huang, Y. Ouyang and Q. Liu,
Tetrahedron, 2007, 63, 2724–2728; (b) Y. Wang, J. Huang, Y. Chai, Q.
Liu, Y. Liang and D. Dong, J. Comb. Chem., 2008, 10, 511–516.
16 X. Xin, Y. Wang, W. Xu, Y. Lin, H. Duan and D. Dong, Green Chem.,
2010, 12, 893–898.
5v: White solid: mp 174–175 ◦C; 1H NMR (400 MHz, CDCl3)
d = 1.00 (t, J = 7.6 Hz, 3H), 1.50–1.54 (m, 2H), 1.80–1.85 (m, 2H),
2.66 (s, 3H), 4.52 (t, J = 6.4 Hz, 2H), 6.78 (s, 1H), 7.07–7.10 (m,
3H), 7.21–7.25 (m, 2H), 7.44–7.47 (m, 1H). 13C NMR (100 MHz,
CDCl3) d = 13.8, 19.1, 23.4, 30.8, 67.6, 93.6, 114.5, 120.5, 125.2,
125.7, 128.2, 128.2, 128.9, 129.3, 130.0, 134.3, 136.7, 153.6, 159.8,
163.9, 164.9. anal. calcd for C24H23N3O2: C, 74.78; H, 6.01; N,
10.90; found: C, 74.86; H, 5.97; N, 10.79.
References
1 (a) G. Jones, In Comprehensive Heterocyclic Chemistry II, A. R.
Katritzky, C. W. Rees, E. F. V. Scriven, A. McKillop, ed. Pergamon:
Oxford, 1996; Vol. 5, p 167; (b) X. Ma and D. R. Gang, Nat. Prod.
Rep., 2004, 21, 752–772; (c) G. D. Henry, Tetrahedron, 2004, 60, 6043–
6061; (d) J. P. Michael, Nat. Prod. Rep., 2005, 22, 627–646; (e) F. F.
Wagner and D. L. Comins, Tetrahedron, 2007, 63, 8065–8082; (f) S.
Sun, Y. Liu, Q. Liu, Y. Zhao and D. Dong, Synlett, 2004, 1731–1734;
(g) S. J. Teague, J. Org. Chem., 2008, 73, 9765–9766; (h) A. R. Katritzky,
A. A. A. Abdel-Fattah, D. O. Tymoshenko and S. A. Essawy, Synthesis,
1999, 2114–2118; (i) M. Movassaghi and M. D. Hill, J. Am. Chem. Soc.,
2006, 128, 4592–4593; (j) J. Hu, Q. Zhang, H. Yuan and Q. Liu, J. Org.
Chem., 2008, 73, 2442–2445; (k) R. Leo´n, J. Marco-Contelles, A. G.
Garc´ıa and M. Villarroya, Bioorg. Med. Chem., 2005, 13, 1167–1175.
2 (a) Comprehensive Heterocyclic Chemistry II, A. R. Katritzky,
C. W. Rees, E. F. V. Scriven, Eds, Pergamon Press: Oxford, 1996;
Vol. 5; (b) J. A. Varela and C. Saa´, Chem. Rev., 2003, 103, 3787–3802;
(c) A. R. Katritzky, Chem. Rev., 2004, 104, 2125–2126; (d) G. D. Henry,
Tetrahedron, 2004, 60, 6043–6061; (e) F. Mongin and G. Queguiner,
Tetrahedron, 2001, 57, 4059–4090; (f) M. C. Bagley, C. Glover and
E. A. Merritt, Synlett, 2007, 2459–2482.
17 (a) J. A. Varela, L. Castedo and C. Saa´, J. Org. Chem., 2003, 68, 8595–
8598; (b) A. H. H. Elghandour, M. K. A. Ibrahim and S. M. M. Elshikh,
Tetrahedron, 1992, 48, 9295–9304; (c) W. Liu, H. Jiang, S. Zhu and
W. Wa n g , Tetrahedron, 2009, 65, 7985–7988; (d) C. V. Asokan, E. R.
Anabha, A. D. Thomas, A. M. Jose, K. C. Lethesh, M. Prasanth and
K. U. Krishanraj, Tetrahedron Lett., 2007, 48, 5641–5643.
18 X. Xin, X. Guo, H. Duan, Y. Lin and H. Sun, Catal. Commun., 2007,
8, 115–117.
19 (a) E. M. Bottorff, R. G. Jones, E. C. Kornfeld and M. J. Mann, J. Am.
Chem. Soc., 1951, 73, 4380–4383; (b) G. E. H. Elgemeie, H. A. Elfahham
and H. A. Nabey, Bull. Chem. Soc. Jpn., 1988, 61, 4431–4433; (c) S.
Kobayashi, R. Akiyama and M. Moriwaki, Tetrahedron Lett., 1997, 38,
4819–4822; (d) M. Hagimori, N. Mizuyama, Y. Hisadome, J. Nagaoka,
K. Uedab and Y. Tominagab, Tetrahedron, 2007, 63, 2511–2518.
20 K. Guo, M. J. Thompson and B. Chen, J. Org. Chem., 2009, 74, 6999–
7006.
3082 | Org. Biomol. Chem., 2010, 8, 3078–3082
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The Royal Society of Chemistry 2010
©