Copper acetate monohydrate: A cheap but efficient oxidant for synthesizing multi-substituted indolizines from pyridinium ylides and electron deficient alkenes

Article abstract of DOI:10.1039/c2ra21213g

We report a highly practical one-pot method for synthesizing multi-substituted indolizines from ?±-halide carbonyl compounds, pyridines and electron deficient alkenes in the presence of copper acetate monohydrate and sodium acetate in DMF. A variety of function groups are tolerable in standard reaction conditions, including aldehyde. 36 examples were presented. The yield of indolizine was from moderate to high. Furthermore, multi-substituted indolizines can be prepared at gram scale by this method.

Full text of DOI:10.1039/c2ra21213g

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
RSC Advances
Cite this: RSC Advances, 2012, 2, 8637–8644
www.rsc.org/advances
PAPER
Copper acetate monohydrate: a cheap but efficient oxidant for synthesizing
multi-substituted indolizines from pyridinium ylides and electron deficient
alkenes{
Huayou Hu,*ab Junjun Feng,a Yulan Zhu,a Ning Gu*b and Yuhe Kan*a
Received 19th June 2012, Accepted 6th July 2012
DOI: 10.1039/c2ra21213g
We report a highly practical one-pot method for synthesizing multi-substituted indolizines from
a-halide carbonyl compounds, pyridines and electron deficient alkenes in the presence of copper
acetate monohydrate and sodium acetate in DMF. A variety of function groups are tolerable in
standard reaction conditions, including aldehyde. 36 examples were presented. The yield of indolizine
was from moderate to high. Furthermore, multi-substituted indolizines can be prepared at gram scale
by this method.
synthesis. However, when electron deficient alkenes are applied
Introduction
to synthesize indolizines through 1,3-dipolar cycloaddition, the
The indolizine skeleton is abundant in many natural products,1
corresponding indolizines can be obtained only by adding an
such as Erythrinan alkaloids,2a swainsonine,2b slaframine,2c
excess amount of oxidant, including freshly prepared MnO28 and
gephyrotoxine,2d cryptowoline,2e and Myrmicarin.2f These nat-
tetrakispyridinecobalt(II) dichromate (TPCD).9 These two kinds
ural products as well as their synthetic derivatives have been
of reagents are not commercially available and need to be
found to exhibit a variety of biological activities, including
prepared in the laboratory. Furthermore, indolizines were
antibacterial,3a phosphatase and aromatase inhibiting,3b–c anti-
synthesized from pyridine in two steps instead of through a
oxidant,3d antidepressant3e and antitumor activities.3f They are
more efficient one-pot reaction. Therefore,
a cheap and
also known as calcium entry blockers3g and 5-hydroxytrypta-
mine receptor antagonists.3h Furthermore, indolizine derivatives
were observed to have long wavelength absorption and
fluorescence with high quantum efficiency in the visible light
region.4a–c Therefore, the successful synthesis of these types of
compounds has facilitated the development of novel classes of
dyes and biological markers.4
commercially available oxidant which could be applied in a
one-pot reaction for synthesizing indolizines from electron
deficient alkenes is in great demand.
Copper acetate monohydrate [Cu(OAc)2?H2O] is the kind of
reagent that meets the above requirement. It’s priced at $350.0
per 5 Kg by Alfa Aesar in the US as chemical reagent10 and at
about $4000 per ton in China as an industrial product.11 Copper
acetate monohydrate has also been known as an oxidant for
many reactions for a long time, including dehydrogenated
aromatization reactions.12 As a follow-up to our reported
method,13 we herein report that copper acetate monohydrate is
an efficient oxidant for synthesizing multi-substituted indolizines
from electron deficient alkenes.
It is well recognized that 1,3-dipolar cycloaddition5 was one of
the most efficient methods to construct five member hetero-
cycles.6 This synthetic strategy has been applied to synthesizing
indolizines since the work of Boekelheide and co-workers in
1961.7 However, this kind of reaction has drawbacks relating to
the reaction scope due to the involvement of electron deficient
alkynes. Compared with electron deficient alkynes, electron
deficient alkenes are more readily available. Therefore, replacing
electron deficient alkynes with electron deficient alkenes can
dramatically extend the reaction scope and decrease the cost of
Results and discussion
In the preliminary study, in order to optimize the reaction
conditions, we chose 1-(2-oxo-2-phenylethyl)pyridinium bromide
4a (2.0 eq.) and ethyl acrylate 3a (1.0 eq.) as our model reaction
system. When potassium carbonate was used as the base and
N,N-dimethylformamide (DMF) as the solvent, the known
product 5a was isolated in good yield (Table 1, entry 1).14a
The result showed that copper acetate monohydrate was the
most efficient reagent among five kinds of copper salts (Table 1,
entries 1–5). Encouraged by this result, we then optimized the
reaction conditions by changing the solvent and base.
aDepartment: Jiangsu Key Laboratory for Chemistry of Low-Dimensional
Materials, School of Chemistry and Chemical Engineering, Huaiyin
Normal University, Huaian, 223300, P. R. China.
E-mail: njuhhy@hotmail.com; kyh@hytc.edu.cn;
Fax: (+)86(517)83525100-1; Tel: (+)86(517)83525100-4
bState Key Laboratory of Bioelectronics, School of Biological Science and
Medical Engineering, Southeast University, Nanjing, 210096, P. R. China.
E-mail: guning@seu.edu.cn
{ Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ra21213g
This journal is ß The Royal Society of Chemistry 2012
RSC Adv., 2012, 2, 8637–8644 | 8637

View Article Online
Table 1 The optimization of reaction conditions
Table 2 The scope and generality of pyridine derivatives
Yield(%)a
Entry Pyridine
Product
Yield (%)a Ref.
Entry Cu Salt (equiv.)
Base (equiv.) Solvent
1
2
3
2-methylpyridine 1b
90
—
—
—
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21e
a
Cu(OAc)2?H2O, 3.0 K2CO3, 4.0
Cu(NO3)2?3H2O, 3.0 K2CO3, 4.0
DMF
DMF
DMF
DMF
DMF
82
53
77
trace
trace
89
69
88
90
93
98
76
CuSO4, 3.0
CuBr2, 3.0
CuCl2, 3.0
K2CO3, 4.0
K2CO3, 4.0
K2CO3, 4.0
5b
5c
4-methylpyridine 1c
nicotinonitrile 1d
54
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 3.0
Cu(OAc)2?H2O, 2.0
Cu(OAc)2?H2O, 3.0
b
NaHCO3, 4.0 DMF
t-BuOK, 4.0
NaH, 4.0
DMF
DMF
DMF
DMF
DMF
DMF
Li2CO3, 4.0
Na2CO3, 4.0
NaOAc, 4.0
No
NaOAc, 4.0
NaOAc, 4.0
NaOAc, 4.0
NaOAc, 4.0
NaOAc, 4.0
NaOAc, 4.0
NaOAc, 4.0
NaOAc, 4.0
NaOAc, 4.0
39; 50
5d;
1,4-dioxane 56
benzene
DMSOb
DMAc
MeCN
NMPd
H2O
trace
60
86
75
92
6
5d9
4
5
DMAP 1eb
50
91
—
—
DMF
DMF
74
96
5e
c
Isolated yield.
DMSO
=
dimethyl sulfoxide.
DMA
=
d
e
N,N-dimethylacetamide. NMP = 1-methylpyrrolidin-2-one. Salt 4a
was synthesized in situ by mixing pyridine 1a with 2-bromo-1-
phenylethanone 2a at 60 uC for 2 h and without further purification.
methyl isonicotinate 1f
5f
6
7
quinoline 1g
63
61
14b
—
Entries 6–19 in Table 1 demonstrated that DMF was the
best solvent and sodium acetate was the best base, while entry
20 showed that when the amount of copper acetate decreased
from 3.0 equiv. to 2.0 equiv., the yield of 5a also decreased
from 98 to 74%. Notably, when the isolated salt 4a was
replaced by in situ formed salt 4a, the yield of 5a did not
change markedly (Table 1, entry 21). This result indicated that
more efficient one-pot reaction could be applied to this
transformation.
5g
4-methylquinoline 1h
5h
5i
5j
8
9
isoquinoline 1i
95
26
14c
With the optimal reaction conditions in hand (Table 1,
entry 21), the scope and generality of pyridine derivatives
in this transformation were examined (Table 2). A wide range
of substituents, either electron-donating or electron-with-
drawing groups in the pyridine ring, such as p-CO2Me,
o-Me, m-CN, p-Me, p-NMe2, etc., were tolerable in this
4-chloropyridine 1j
—
—
10
a
4-vinylpyridine 1k
b
Isolated yield. DMAP = N,N-dimethylpyridin-4-amine.
Complex mixture N. D.d
transformation. Interestingly, 2-methylpyridine 1b gave cor-
responding indolizine 5b in a high yield of 90%, although
2-phenylindolizine was also found in the reaction mixture.
This result should be attributed to the reaction speed of
pyridinium ylide with ethyl acrylate, which was much faster
than its intermolecular cyclization under standard conditions
(Table 2, entry 1). When the pyridine bore a cyano group at
the meta position, two isomers (5d and 5d9) were isolated in
the ratio of 4 : 5 (Table 2, entry 3). Fused pyridines also gave
the corresponding fused indolizine with good yield (Table 2,
entries 6–8). The reason that 4-vinylpyridine 1k did not give
Scheme 1 The formation of 5b, 5d and 5d9.
8638 | RSC Adv., 2012, 2, 8637–8644
This journal is ß The Royal Society of Chemistry 2012

View Article Online
multi-substituted indolizines from simple starting materials, such
as pyridines, a-halide ketones and electron-deficient alkenes. The
reaction runs under mild conditions and is easy to handle. This
reaction can be applied on the gram scale and without reducing
the yield. At last, further study of a catalytic version of this
transformation is now under thorough investigation.
Scheme 2 The formation of 6t, 6t9 and 6u9.
Experimental
General
Unless otherwise noted, all commercial reagents and solvents
were obtained from commercial providers and used without
further purification. 1H NMR and 13C NMR spectra were
recorded on Bruker 400 MHz spectrometers. Chemical shifts
were reported relative to internal tetramethylsilane (d 0.00 ppm)
or CDCl3 (d 7.26 ppm) for 1H NMR and CDCl3 (d 77.0 ppm) for
13C NMR. Flash column chromatography was performed on
300–400 mesh silica gels. Analytical thin layer chromatography
was performed with pre-coated glass baked plates (250 m) and
visualized by fluorescence. HRMS was recorded on a Bruker
micrOTOF-Q spectrometer. IR spectra were recorded on a
Nicolet Avatar 360 spectrometer.
Scheme 3 The formation of 6q9 and 7i9.
any designed product could be attributed to polymerization
of 1k.
Then, we turned to check the scope of alkenes. The results
were listed in Table 3. Many kinds of alkenes bearing a variety of
electron-withdrawing groups, including ester, aldehyde, amide,
cyano group, ketone and nitro group, were applied in this
reaction. Both terminal and non-terminal alkenes reacted with
pyridinium ylide smoothly. Some non-terminal alkenes such as 3l
and 3p, however, couldn’t give corresponding indolizines at high
yield even when the reaction time was extended to 72 h. The
fused conjugated alkenes 3l also gave indolizine at low yield.
Moreover, cyclic alkenes 3m and 3k gave complex mixtures from
which the corresponding indolizines could not be isolated.
Interestingly, aldehyde could survive under standard reaction
conditions and gave corresponding inlodizine at moderate yield
(Table 3, entries 17–18). Furthermore, alkenes bearing a nitro
group could also be applied in this transformation. When (E)-(2-
nitrovinyl) benzene 3t was used, two isomers were isolated. One
of the products 6t, which keeps the nitro group, was isolated in a
yield of 54%, while the other product 6t9, which loses the nitro
group, was isolated in a yield of 28%. When (E)-(2-nitroprop-1-
enyl) benzene 3u was used, the only product 6u9 was isolated in a
yield of 72%. This result should be attributed to the trend of
aromatizing the tetra-hydrogen indolizine intermediate.
At last, to demonstrate the scope of the reaction, we replaced
2-bromo-1-phenylethanone by several similar reagents. The
results were presented in Table 4. All of them gave indolizines
at moderate to high yield.
General procedure for the preparation of indolizines 4
Pyridine (1a) 0.40 mmol and 2-bromo-1-phenylethanone (2a)
0.42 mmol were mixed in a test tube and the mixture was heated
to 60 uC for 4 h. Then copper acetate monohydrate 0.60 mmol,
NaOAc 1.20 mmol, DMF 2.0 mL and ethyl acrylate (3a)
0.20 mmol were added to the mixture. The mixture was then
heated at 80 uC for another 4 h (the reaction course was
monitored by TLC). Then the mixture was cooled to r.t., poured
into water and extracted with CHCl3 (10 mL 6 3). The
extractions were combined and washed with saturated brine,
dried with Na2SO4, and filtered. The solvent was removed by
reduce pressure. The residue was purified by flash chromato-
graphy on silica gel using petroleum ether/ethyl acetate (the ratio
depends on product’s polarity) as eluate.
Preparation of indolizine 6f at gram scale
Pyridine (1a) 20.0 mmol and 2-bromo-1-phenylethanone (2a)
21.0 mmol and 10.0 mL DMF were mixed in a round bottom
flask at r.t.. The mixture was stirred for 2 h (the temperature of
mixture rose to 80 uC automatically and then cooled down to
r.t.), and white solid was precipitated. Then copper acetate
monohydrate 30.0 mmol, NaOAc 60.0 mmol, DMF 70.0 mL and
N,N-dimethylacrylamide (3f) 10.0 mmol were added to the
mixture. The mixture was then heated at 80 uC for another 4 h
(the reaction course was monitored by TLC). Then the mixture
was cooled to r.t., poured into 160 mL water and filtered. The
mother liquid was extracted with CHCl3 (30 mL 6 3) and the
filter cake was washed with CHCl3 (10 mL 6 3). The organic
layers were combined and washed with saturated brine, dried
with Na2SO4, and filtered. Then the solvent was removed by
reduce pressure. The residue was purified by flash chromato-
graphy on silica gel using petroleum ether/ethyl acetate (1 : 1,
v : v) as eluate to give the corresponding indolizine 6f as a yellow
solid.
Moreover, (E)-(2-nitroprop-1-enyl)benzene 3q gave (1,19-car-
bonylbis(2-phenylindolizine-3,1-diyl))bis(phenylmethanone) 6q9
in a yield of 35% (Table 3, entry 16), and 1,3-dichloropropan-
2-one 2i also gave diethyl 3,39-carbonyldiindolizine-1-carbox-
ylate 7i9 in a yield of 33% (Table 4, entry 8).
Furthermore, the reaction scale was easily enlarged to gram
scale and the yield did not decrease (Scheme 4).
Conclusions
In conclusion, we have demonstrated that copper acetate
monohydrate is a cheap and efficient reagent for synthesizing
This journal is ß The Royal Society of Chemistry 2012
RSC Adv., 2012, 2, 8637–8644 | 8639

View Article Online
Table 3 The scope and generality of alkene derivatives
Entry
1
Alkene
Product
Yield (%)a
95
Ref.
methyl acrylate 3b
14a
6b
2
tert-butyl acrylate 3c
80
—
6c
6d
3
4
n-butyl acrylate 3d
acrylonitrile 3e
85
78
14a
14a
6e
6f
5
6
N,N-dimethylacrylamide 3f
(E)-methyl but-2-enoate 3g
82
90
14d
—
6g
6h
6i
7
8
9
diethyl fumarate 3h
dimethyl maleate 3i
dibutyl maleate 3j
92
80
80
14a
14a
—
6j
10
11
1-phenyl-1H-pyrrole-2,5-dione 3k
2H-chromen-2-one 3l
Complex mixture
C. M.b
—
13c
43 (59)c
6l
12
13
naphthalene-1,4-dione 3m
(E)-1-phenyl-3-p-tolylprop-2-en-1-one 3n
Complex mixture
C. M.b
66
—
—
6n
6o
14
(E)-3-(4-fluorophenyl)-1-phenylprop-2-en-1-one 3o
50
8640 | RSC Adv., 2012, 2, 8637–8644
This journal is ß The Royal Society of Chemistry 2012

View Article Online
Table 3 (Continued)
15
ethyl cinnamate 3p
25 (32)c
14e
6p
16
17
(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one 3q
(E)-but-2-enal 3r
6q9 (see Scheme 3)
35
54
—
—
6r
6s
6t;
18
19
cinnamaldehyde 3s
39
—
(E)-(2-nitrovinyl)benzene 3t
45; 28d
—; 14f
6t9
20
(E)-(2-nitroprop-1-enyl)benzene 3u
72
—
6u9
a
b
Isolated yield. Complex mixture. 72 h, the yield in parentheses was based on recovered starting material. Two isomers were isolated.
c
d
Ethyl 3-benzoyl-7-methylindolizine-1-carboxylate (5b)
101.3, 60.7, 14.5; IR (NaCl): 3102, 2963, 2918, 2849, 2235, 1704,
1630, 1598, 1576, 1541, 1481, 1431, 1366, 1326; HRMS
Calculated for [C19H14N2O3+Na]+: 341.0897, Found: 341.0879.
Yellow solid; mp 154–155 uC; 1H NMR (CDCl3, 400 MHz): 9.87
(d, J = 7.1 Hz, 1H), 8.20 (s, 1H), 7.82 (dd, J = 6.9, 1.4 Hz, 2H),
7.78 (s, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.3 Hz, 2H),
6.94 (dd, J = 7.1, 1.6 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.51 (s,
3H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
185.2, 164.2, 140.5, 140.1, 139.4, 131.3, 129.3, 128.9, 128.7, 128.3,
122.2, 118.3, 117.7, 105.2, 60.0, 21.6, 14.6; IR (NaCl): 2978,
2919, 1697, 1643, 1611, 1575, 1524, 1481, 1464, 1428, 1344;
HRMS Calculated for [C19H17NO3+Na]+: 330.1101, Found:
330.1089.
Ethyl 3-benzoyl-8-cyanoindolizine-1-carboxylate (5d9)
1
Yellow solid; mp 147–148; H NMR (CDCl3, 400 MHz): 10.19
(d, J = 6.7 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.82 (d,
J = 7.2 Hz, 2H), 7.62 (d, J = 7.4 Hz, 1H), 7.55 (t, J = 7.2 Hz, 2H),
7.15 (t, J = 7.2 Hz,1H), 4.47 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1
Hz, 3H); 13C NMR (CDCl3, 100 MHz):185.8, 162.7, 139.0,
136.8, 134.4, 133.0, 132.2, 130.4, 129.1, 128.6, 123.2, 116.3, 113.7,
108.6, 104.7, 60.8, 14.4; IR (NaCl): 3114, 2979, 2925, 2233, 1715,
1627, 1599, 1527, 1476, 1436, 1355; HRMS Calculated for
[C19H14N2O3+Na]+: 341.0897, Found: 341.0919.
Ethyl 3-benzoyl-5-methylindolizine-1-carboxylate (5c)
1
Yellow oil; H NMR (CDCl3, 400 MHz): 8.39 (d, J = 8.8 Hz,
1H), 8.06 (d, J = 7.2 Hz, 2H), 7.76 (s, 1H), 7.65 (t, J = 7.4 Hz,
1H), 7.55 (t, J = 7.5 Hz, 2H), 7.44 (dd, J = 8.6, 7.1 Hz, 1H), 6.94
(d, J = 6.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.62 (s, 3H), 1.39 (t,
J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): 182.9, 164.1,
141.9, 139.8 138.6, 132.6, 130.3, 129.6, 128.4, 127.4, 125.4, 117.2,
116.7, 105.5, 60.0, 23.2, 14.6; IR (NaCl): 3059, 2977, 2926, 1698,
1632, 1596, 1577, 1524, 1480, 1422, 1335; HRMS Calculated for
[C19H17NO3+Na]+: 330.1101, Found: 330.1105.
Ethyl 3-benzoyl-7-(dimethylamino)indolizine-1-carboxylate (5e)
Yellow solid; mp 162–164 uC; 1H NMR (CDCl3, 400 MHz): 9.77
(d, J = 7.8 Hz, 1H), 7.80 (d, J = 6.7 Hz, 2H), 7.67 (s, 1H), 7.56–
7.46 (m, 3H), 7.37 (d, J = 2.7 Hz, 1H), 6.63 (dd, J = 7.8, 2.8 Hz,
1H), 4.33 (q, J = 7.1 Hz, 2H), 3.14 (s, 6H), 1.38 (t, J = 7.1 Hz,
3H); 13C NMR (CDCl3, 100 MHz): 183.8, 164.6, 149.5, 143.3,
140.6, 130.8, 130.7, 130.3, 128.8, 128.2, 120.8, 104.2, 102.8, 95.6,
59.6, 39.9, 14.6; IR (NaCl): 3058, 2978, 2930, 1690, 1646,
1597, 1532, 1490, 1440, 1340; HRMS Calculated for
[C20H20N2O3+H]+: 337.1547, Found: 337.1533.
Ethyl 3-benzoyl-6-cyanoindolizine-1-carboxylate (5d)
1
Yellow solid; mp 163–164; H NMR (CDCl3, 400 MHz): 10.39
(s, 1H), 8.49 (d, J = 9.2 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J = 7.2 Hz,
2H), 7.65 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.5 Hz, 2H), 7.50 (dd, J
= 9.3, 1.2 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz,
3H); 13C NMR (CDCl3, 100 MHz): 185.9, 163.3, 138.9, 138.7,
134.8, 132.3, 129.8, 128.0, 128.6, 126.5, 123.4, 120.5, 116.3, 108.3,
1-Ethyl 7-methyl 3-benzoylindolizine-1,7-dicarboxylate (5f)
Yellow solid; mp 149–151 uC; 1H NMR (CDCl3, 400 MHz): 9.88
(d, J = 7.3 Hz, 1H), 9.00 (s, 1H), 7.87–7.79 (m, 3H), 7.63–7.55
(m, 2H), 7.52 (t, J = 7.4 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.98 (s,
This journal is ß The Royal Society of Chemistry 2012
RSC Adv., 2012, 2, 8637–8644 | 8641

View Article Online
Table 4 The scope and generality of a-halide carbonyl derivatives
Entry
1
R, X
Product
Yield (%)a
80
Ref.
—
4-nitrobenzoyl, Br 2b
7b
7c
7d
2
3
4
4-methoxybenzoyl, Br 2c
2-bromo-1-(4-bromophenyl)ethanone 2d
CO2Et, Cl 2e
88
96
75
14g
—
14h
7e
7e
5
6
CO2Et, Br 2f
CN, Br 2g
38
55
14h
—
7g
7
1-(bromomethyl)-4-nitrobenzene 2h
1,3-dichloropropan-2-one 2i
58
33
14i
7h
8
7i9 (see Scheme 3)
—
a
Isolated yield.
Ethyl 3-benzoyl-7-chloroindolizine-1-carboxylate (5j)
Yellow solid; mp 134–136 uC; 1H NMR (CDCl3, 400 MHz): 9.91 (d,
J = 7.5 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 7.0 Hz, 2H),
7.82 (s, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.4 Hz, 2H), 7.07
(dd, J = 7.4, 2.2 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz,
3H); 13C NMR (CDCl3, 100 MHz): 185.6, 163.7, 139.9, 139.5, 134.5,
131.7, 129.7, 129.3, 129.0, 128.5, 122.7, 118.6, 116.5, 106.1, 60.3, 14.5;
IR (NaCl): 3123, 2980, 1700, 1619, 1523, 1473, 1442, 1343; HRMS
Calculated for [C18H14ClNO3+H]+: 328.0735, Found: 328.0737.
Scheme 4 The synthesis of indolizine 6f on the gram scale.
3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
185.8, 165.1, 163.5, 139.4, 138.2, 131.9, 129.0, 128.9, 128.49,
128.46, 128.0, 123.6, 121.7, 114.1, 109.1, 60.5, 52.7, 14.5; IR
(NaCl): 2983, 1724, 1627, 1573, 1527, 1473, 1432, 1347; HRMS
Calculated for [C20H17NO5+Na]+: 374.0999, Found: 374.0988.
tert-Butyl 3-benzoylindolizine-1-carboxylate (6c)
Yellow solid; mp 125–126 uC; 1H NMR (CDCl3, 400 MHz): 9.99 (d,
J = 7.0 Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 7.1 Hz, 2H),
7.80 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 7.44
(dd, J = 7.7, 7.0 Hz, 1H), 7.08 (t, J = 6.8 Hz, 1H), 1.63 (s, 9H); 13C
NMR (CDCl3, 100 MHz): 185.5, 163.5, 140.0, 139.6, 131.4, 129.24,
129.18, 129.0, 128.4, 127.4, 122.3, 119.6, 115.1, 108.0, 80.6, 28.5; IR
(NaCl): 2976, 2931, 1696, 1616, 1521, 1479, 1449, 1367, 1343; HRMS
Calculated for [C20H19NO3+Na]+: 344.1257, Found: 344.1264.
Ethyl 1-benzoyl-5-methylpyrrolo[1,2-a]quinoline-3-carboxylate (5h)
Yellow solid; mp 164–166 uC; 1H NMR (CDCl3, 400 MHz): 8.21
(s, 1H), 8.14–8.09 (m, 3H), 7.95 (dd, J = 8.0, 0.9 Hz, 1H), 7.67 (t,
J = 7.4 Hz, 1H), 7.62 (s, 1H), 7.61–7.50 (m, 4H), 4.38 (q, J = 7.1
Hz, 2H), 2.71 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): 184.7, 164.2, 140.5, 138.6, 136.5, 133.0,
132.7, 130.1, 129.9, 128.5, 128.4, 127.9, 125.4, 125.3, 125.2, 120.6,
117.3, 106.7, 60.1, 19.6, 14.6; IR (NaCl): 3060, 2978, 2926, 2855,
1699, 1633, 1597, 1556, 1538, 1499, 1465, 1447, 1416; HRMS
Calculated for [C23H19NO3+Na]+: 380.1257, Found: 380.1256.
3-Benzoyl-N,N-dimethylindolizine-1-carboxamide (6f)
1
Yellow solid; mp 91–93 uC; H NMR (CDCl3, 400 MHz): 9.94
(d, J = 7.0 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 7.2 Hz,
8642 | RSC Adv., 2012, 2, 8637–8644
This journal is ß The Royal Society of Chemistry 2012

View Article Online
2H), 7.55 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.44 (s,
1H), 7.35 (dd, J = 8.1, 7.6 Hz, 1H), 7.04 (t, J = 6.9 Hz, 1H), 3.14
(s, 6H); 13C NMR (CDCl3, 100 MHz): 185.1, 166.5, 140.2, 139.3,
131.3, 128.9, 128.7, 128.3, 126.44, 126.37, 121.5, 119.4, 115.0,
109.7; IR (NaCl): 3057, 2928, 1713, 1609, 1573, 1526, 1474, 1415,
1346; HRMS Calculated for [C18H16N2O2+Na]+: 315.1104,
Found: 315.1106.
3-Benzoyl-2-methylindolizine-1-carbaldehyde (6r)
Yellow solid; mp 171–173 uC; 1H NMR (CDCl3, 400 MHz):
10.17 (s, 1H), 9.55 (d, J = 7.0 Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H),
7.70 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.56–7.46 (m,
3H), 7.08 (t, J = 6.7 Hz, 1H), 2.21 (s, 3H); 13C NMR (CDCl3,
100 MHz): 187.7, 184.2, 140.8, 139.3, 137.8, 132.1, 129.1, 128.7,
128.7, 128.6, 122.8, 118.6, 115.8, 113.6, 12.4; IR (NaCl): 3058,
2724, 2854, 1714, 1655, 1609, 1503, 1441, 1391, 1335; HRMS
Calculated for [C17H13NO2+Na]+: 286.0838, Found: 286.0834.
Dibutyl 3-benzoylindolizine-1,2-dicarboxylate (6j)
1
Yellow oil. H NMR (CDCl3, 400 MHz): 9.63 (d, J = 7.1 Hz,
3-Benzoyl-2-phenylindolizine-1-carbaldehyde (6s)
1H), 8.42 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 7.1 Hz, 2H), 7.55 (t,
J = 7.4 Hz, 1H), 7.42–7.48 (m, 3H), 7.10 (dd, J = 6.9, 1.0 Hz,
1H), 4.29 (t, J = 6.6 Hz, 2H), 3.55 (t, J = 6.8 Hz, 2H), 1.70 (qu,
J = 7.1 Hz, 2H), 1.49–1.35 (m, 4H), 1.31–1.20 (m, 2H), 0.94 (t,
J = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100
MHz): 186.8, 165.0, 163.1, 139.6, 138.5, 131.9, 131.7, 128.8,
128.5, 128.1, 127.9, 120.7, 120.0, 115.9, 104.3, 65.7, 64.4, 30.8,
30.1, 19.2, 19.1, 13.7; IR (NaCl): 3059, 2959, 2872, 1738, 1702,
1624, 1577, 1506, 1447, 1376, 1344; HRMS Calculated for
[C25H27NO5+Na]+: 444.1781, Found: 444.1780.
Yellow solid; mp 183–185 uC; 1H NMR (CDCl3, 400 MHz): 9.79
(s, 1H), 9.76 (d, J = 7.0 Hz, 1H), 8.69 (d, J = 8.8 Hz, 1H), 7.59 (t,
J = 7.8 Hz, 1H), 7.41 (d, J = 7.3 Hz, 2H), 7.23–7.17 (m, 2H),
7.17–7.08 (m, 5H), 7.04 (t, J = 7.7 Hz, 2H); 13C NMR (CDCl3,
100 MHz): 188.0, 186.7, 142.6, 139.0, 138.3, 131.5, 131.5, 131.3,
129.4, 129.2, 128.6, 127.9, 127.7, 127.6, 121.5, 119.9, 116.5, 113.2;
IR (NaCl): 3058, 2921, 2793, 1657, 1612, 1575, 1497, 1467, 1435,
1390, 1334; HRMS Calculated for [C22H15NO2+Na]+: 348.0995,
Found: 348.0983.
(2-p-Tolylindolizine-1,3-diyl)bis(phenylmethanone) (6n)
(1-Nitro-2-phenylindolizin-3-yl)(phenyl)methanone (6t)
Yellow solid; 181–182 uC; 1H NMR (CDCl3, 400 MHz): 9.68
(d, J = 7.1 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 7.3
Hz, 2H), 7.41–7.32 (m, 3H), 7.20 (t, J = 7.4 Hz, 1H), 7.13 (t,
J = 7.4 Hz, 1H), 7.08–7.02 (m, 3H), 6.97 (t, J = 7.7 Hz, 2H),
6.73 (d, J = 7.9 Hz, 2H), 6.49 (t, J = 7.8 Hz, 2H), 2.00 (s, 3H);
13C NMR (CDCl3, 100 MHz): 192.9, 188.5, 139.4, 139.2, 139.0,
136.5, 131.5, 131.3, 130.9, 130.3, 129.5, 129.4, 129.4, 127.8,
127.7, 127.5, 127.4, 127.0, 121.1, 119.1, 115.1, 114.1, 20.9; IR
(NaCl): 3060, 2923, 1633, 1612, 1597, 1576, 1499, 1386, 1343;
HRMS Calculated for [C29H21NO2+Na]+: 438.1465, Found:
438.1469.
Yellow solid; mp 139–140 uC; 1H NMR (CDCl3, 400 MHz): 9.50
(d, J = 7.0 Hz, 1H), 8.69 (d, J = 9.0 Hz, 1H), 7.68 (dd, J = 8.2, 7.5
Hz, 1H), 7.42 (d, J = 7.4 Hz, 2H), 7.27–7.17 (m, 4H), 7.11–7.05
(m, 5H); 13C NMR (CDCl3, 100 MHz): 188.4, 138.6, 134.6,
133.9, 132.0, 131.1, 130.9, 130.3, 129.3, 128.2, 128.1, 127.7, 127.7,
127.5, 121.5, 119.4, 116.4; IR (NaCl): 3152, 3056, 2963, 2922,
1624, 1598, 1576, 1500, 1469, 1409, 1370, 1327; HRMS
Calculated for [C21H14N2O3+Na]+: 365.0897, Found: 365.0905.
(1-Methyl-2-phenylindolizin-3-yl)(phenyl)methanone (6u9)
1
Yellow solid. H NMR (CDCl3, 400 MHz): 9.90 (d, J = 7.1 Hz,
1H), 7.55 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 7.4 Hz, 2H), 7.20 (dd, J
= 8.0, 7.4 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 7.05–6.95 (m, 7H),
6.91 (t, J = 6.8 Hz, 1H), 2.26 (s, 3H); 13C NMR (CDCl3,
100 MHz): 186.3, 140.5, 137.8, 136.5, 135.0, 131.0, 130.0, 129.2,
128.3, 127.4, 127.2, 126.4, 123.5, 120.3, 116.8, 113.6, 110.7, 9.2;
IR (NaCl): 3058, 2920, 2851, 1593, 1571, 1520, 1452, 1432, 1388,
1371; HRMS Calculated for [C22H17NO+Na]+: 334.1202,
Found: 334.1208.
(2-(4-Fluorophenyl)indolizine-1,3-diyl)bis(phenylmethanone) (6o)
1
Yellow solid. H NMR (CDCl3, 400 MHz): 9.69 (d, J = 7.1 Hz,
1H), 8.18 (d, J = 8.9 Hz, 1H), 7.47–7.38 (m, 3H), 7.35 (d, J = 7.3
Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.11–
7.05 (m, 3H), 7.01 (t, J = 7.6 Hz, 2H), 6.82 (dd, J = 8.4, 5.6 Hz,
2H), 6.41 (t, J = 8.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
192.6, 188.2, 162.9, 160.5, 139.2, 139.1, 139.1, 137.9, 133.2, 133.1,
131.6, 131.3, 129.4, 129.3, 127.8, 127.7, 127.6, 127.4, 121.3, 119.2,
115.4, 114.2, 114.2, 114.0; IR (NaCl): 3062, 1606, 1576, 1525,
1496, 1426, 1386; HRMS Calculated for [C28H18FNO2+Na]+:
442.1214, Found: 442.1162.
Ethyl 3-(4-nitrobenzoyl)indolizine-1-carboxylate (7b)
Yellow solid; mp 144–145 uC; 1H NMR (CDCl3, 400 MHz):
10.01 (d, J = 7.0 Hz, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.40 (d, J =
8.6 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H), 7.76 (s, 1H), 7.56 (dd, J =
8.1, 7.1 Hz, 1H), 7.20 (t, J = 6.9 Hz, 1H), 4.41 (q, J = 7.1 Hz,
2H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
182.9, 163.7, 149.4, 145.4, 140.4, 129.7, 129.3, 129.2, 128.6, 123.7,
121.9, 119.7, 116.0, 107.3, 60.3, 14.5; IR (NaCl): 3110, 2924,
2852, 1706, 1619, 1596, 1521, 1482, 1341; HRMS Calculated for
[C18H14N2O5+Na]+: 361.0795, Found: 368.0801.
(1,19-Carbonylbis(2-phenylindolizine-3,1-diyl))bis(phenylmethanone) (6q9)
1
Yellow solid. H NMR (CDCl3, 400 MHz): 9.41 (d, J = 7.0 Hz,
2H), 7.86 (d, J = 8.8 Hz, 2H), 7.30–7.22 (m, 6H), 7.09 (t, J = 7.3
Hz, 2H), 6.96–6.88 (m, 6H), 6.85–6.78 (m, 6H), 6.71 (t, J = 7.4
Hz, 4H); 13C NMR (CDCl3, 100 MHz): 187.9, 187.0, 139.2,
138.5, 138.1, 132. 7, 131.2, 131.0, 129.3, 127.5, 127.3, 126.8,
126.6, 126.3, 121.0, 118.7, 116.9, 114.7; IR (NaCl): 3058, 2923,
2851, 1659, 1603, 1575, 1492, 1465, 1449, 1429, 1387, 1340, 1316;
HRMS Calculated for [C43H28N2O3+H]+: 621.2173, Found:
621.2185.
Ethyl 3-(4-bromobenzoyl)indolizine-1-carboxylate (7d)
Yellow solid; mp 109–110 uC; 1H NMR (CDCl3, 400 MHz): 9.95
(d, J = 7.0 Hz, 1H), 8.42 (d, J = 8.9 Hz, 1H), 7.79 (s, 1H), 7.71
This journal is ß The Royal Society of Chemistry 2012
RSC Adv., 2012, 2, 8637–8644 | 8643

View Article Online
Joiner, F. D. King, W. D. Miner and G. J. Sanger, J. Med. Chem.,
1990, 33, 1924.
(d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.48 (dd, J = 8.0, 7.5
Hz, 1H), 7.12 (t, J = 7.0 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.42 (t,
J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): 184.1, 163.9,
140.0, 138.7, 131.7, 130.5, 129.2, 128.8, 127.9, 126.2, 122.2, 119.6,
115.5, 106.6, 60.2, 14.6; IR (NaCl): 3123, 2979, 1700, 1615,
1585, 1521, 1480, 1430, 1342; HRMS Calculated for
[C18H14BrNO3+H]+: 372.0230, Found: 372.0239.
4 (a) A. Vlahovici, M. Andrei and I. Druta, J. Lumin., 2002, 96, 279; (b)
A. Vlahovici, I. Druta, M. Andrei, M. Cotlet and R. Dinica,
J. Lumin., 1999, 82, 155; (c) T. Mitsumori, M. Bendikov, O. Dautel,
F. Wudl, T. Shioya, H. Sato and Y. Sato, J. Am. Chem. Soc., 2004,
126, 16793; (d) F. D. Saeva and H. R. Luss, J. Org. Chem., 1988, 53,
1804; (e) G. L. Fletetcher, S. L. Bender and D. H. Wadsworth. US
Patent 4577024, 1986; Chem. Abstr., 1984, 100, 122772; (f) H.
Sonnenschein, G. Henrich, U. Resch-Genger and B. Schulz, Dyes
Pigm., 2000, 46, 23; (g) A. V. Retaru, L. D. Druta, T. Deser and T. J.
Mueller, Helv. Chim. Acta, 2005, 88, 1798; (h) F. Delattre, P. Woisel,
G. Surpateanu, F. Cazier and P. Blach, Tetrahedron, 2005, 61, 3939.
5 (a) F. Amblard, J. H. Cho and R. F. Schinazi, Chem. Rev., 2009, 109,
4207; (b) V. Nair and T. D. Suja, Tetrahedron, 2007, 63, 12247; (c)
N. A. Bokach and V. Y. Kukushkin, Russ. Chem. Bull., 2006, 55,
1869; (d) C. Najera and J. M. Sansano, Angew. Chem., Int. Ed., 2005,
44, 6272; (e) K. Rueck-Braun, T. H. E. Freysoldt and F. Wierschem,
Chem. Soc. Rev., 2005, 34, 507; (f) K. Harju and J. Yli-Kauhaluoma,
Rec. Dev. Org. Chem., 2004, 8, 111.
6 (a) K. Matsumoto, Synthesis, 1976, 209; (b) Y. Shang, M. Zhang, S.
Yu, K. Ju, C. Wang and X. He, Tetrahedron Lett., 2009, 50, 6981; (c)
M. K. Bayazit and K. S. Coleman, J. Am. Chem. Soc., 2009, 131,
10670; (d) B.-X. Wang, Z.-X. Xu and J. Wu, Youji Huaxue, 2006, 26,
1587; (e) B.-X. Wang, W.-W. Liu, T. He and H.-W. Hu, Chin. J.
Chem., 2006, 24, 279; (f) A. V. Retaru, I. D. Druta, T. Oeser and T.
Mueller, Helv. Chim. Acta, 2005, 88, 1798; (g) E. M. Mmutlane, J. M.
Harris and A. Padwa, J. Org. Chem., 2005, 70, 8055; (h) K. Wu and
Q.-Y. Chen, Synthesis, 2003, 35; (i) R. M. Dinica, I. I. Druta and C.
Pettinari, Synlett, 2000, 1013.
Ethyl 3-cyanoindolizine-1-carboxylate (7g)
White solid; mp 102–103 uC; 1H NMR (CDCl3, 400 MHz): 8.38–
8.33 (m, 2H), 7.81 (s, 1H), 7.36 (dd, J = 8.8, 6.9 Hz, 1H), 7.06 (td,
J = 7.3, 1.0 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz,
3H); 13C NMR (CDCl3, 100 MHz): 163.3, 137.8, 126.0, 125.7,
125.2, 120.5, 115.0, 112.6, 106.1, 96.7, 60.3, 14.5; IR (NaCl):
3119, 2987, 2210, 1691, 1515, 1486, 1445, 1390; HRMS
Calculated for [C12H10N2O2+Na]+: 237.0634, Found: 237.0631.
3,39-Carbonyldiindolizine-1-carboxylate (7i9)
Yellow solid; mp 223–225 uC; 1H NMR (CDCl3, 400 MHz): 9.67
(d, J = 7.0 Hz, 1H), 8.38 (d, J = 9.0 Hz, 1H), 8.00 (s, 1H), 7.38
(dd, J = 8.2, 7.4 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 4.43 (q, J = 7.1
Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
174.5, 164.3, 139.6, 128.6, 126.7, 126.1, 122.9, 119.7, 114.6, 106.0,
60.1, 14.6; IR (NaCl): 2981, 2961, 2923, 2852, 1699, 1626, 1520,
1480, 1441, 1369; HRMS Calculated for [C23H20N2O5+Na]+:
427.1264, Found: 427.1263.
7 V. Boekelheide and k. Fahrenholtz, J. Am. Chem. Soc., 1961, 83, 458.
8 (a) K. M. Dawood, E. A. Ragab and N. A. Khedr, J. Chin. Chem.
Soc. (Taipei, Taiwan), 2009, 56, 1180; (b) E. S. Darwish, Molecules,
2008, 13, 1066; (c) N. A. Kheder, E. S. Darwish and K. M. Dawood,
Heterocycles, 2009, 78, 177.
9 (a) Y.-M. Shen, B.-X. Wang, Y.-Y. Feng, Z.-Y. Shen, J. Shen, C. Li
and H.-W. Hu, Gaodeng Xuexiao Huaxue Xuebao, 2006, 27, 651; (b)
N. S. Prostakov, A. V. Varlamov, N. Islam, N. Saksena and D.
Nende, Khim. Geterotsikl. Soedin., 1987, 707; (c) A. Tanaka and T.
Usui, Chem. Pharm. Bull., 1979, 27, 3078; (d) B.-X. Wang and H.-W.
Hu, Gaodeng Xuexiao Huaxue Xuebao, 2004, 25, 273; (e) Y.
Tominaga, S. Hidaki, Y. Matsuda, G. Kobayashi and K. Sakemi,
Yakugaku Zasshi, 1979, 99, 540.
10 http://www.alfa.com/en/gp100w.pgm?dsstk=A16203; Data was pre-
sent on 2012-3-20, which may be changed by website holder..
11 Data from http://china.chemnet.com on 2012-3-20, which may be
changed by website holder..
Acknowledgements
We are grateful to Jiangsu Province NSF (No.: BK2011408),
Jiangsu
Province
Department
of
Education
(No.:
10KJB150002), China Postdoctoral Science Foundation funded
project (No.: 2012M511645), JSKLCLDM (No.: JSKC11093),
HYNU and NBRPC (No.: 2011CB933503) for their financial
support.
12 (a) C. Han, M. Yu, W. Sun and X. Yao, Synlett, 2011, 2363; (b) X.
Jia, K. Yin, C. Li, J. Li and H. Bian, Green Chem., 2011, 13, 2175; (c)
C. P. Frazier, J. R. Engelking and J. R. Alaniz, J. Am. Chem. Soc.,
2011, 133, 10430; (d) R. D. Patil and S. Adimurthy, Adv. Synth.
Catal., 2011, 353, 1695; (e) C. Zhang and N. Jiao, Angew. Chem., Int.
Ed., 2010, 49, 6174; (f) D. Yang, H. Yang and H. Fu, Chem.
Commun., 2011, 47, 2348; (g) L. Chu and F. Qing, J. Am. Chem. Soc.,
2010, 132, 7262.
13 (a) H. Hu, K. Shi, R. Hou, Z. Zhang, Y. Zhu and J. Zhou, Synthesis,
2010, 4007; (b) Y. Liu, H. Hu, Y. Zhang, H. Hu and J. Xu, Org.
Biomol. Chem., 2010, 8, 4921; (c) Y. Liu, H. Hu, Q. Liu, H. Hu and J.
Xu, Tetrahedron, 2007, 63, 2024; (d) H. Hu, Y. Liu, H. Zhong, Y.
Zhu, C. Wang and M. Ji, Chem.–Asian J., 2012, 7, 884.
14 (a) Y. Yang, L. Chen, Z. Zhang and Y. Zhang, Org. Lett., 2011, 13,
342; (b) E. Georgescu, M. R. Caira, F. Georgescu, B. Draghici,
M. M. Popa and F. Dumitrascu, Synlett, 2009, 1795; (c) A. Hazra, S.
Mondal, A. Maity, S. Naskar, P. Saha, R. Paira, K. B. Sahu, P.
Paira, S. Ghosh, C. Sinha, A. Samanta, S. Banerjee and N. B.
Mondal, Eur. J. Med. Chem., 2011, 46, 2132; (d) S. Som and A. K.
Das, Orient. J. Chem., 2006, 22, 415; (e) R. A. Nugent and M.
Murphy, J. Org. Chem., 1987, 52, 2206; (f) Y. Shang, M. Zhang, S.
Yu, K. Ju, C. Wang and X. He, Tetrahedron Lett., 2009, 50, 6981; (g)
I. Kim, S. G. Kim, J. Y. Kim and G. H. Lee, Tetrahedron Lett., 2007,
48, 8976; (h) S. Recnik, J. Svete and B. Stanovnik, Eur. J. Org. Chem.,
2001, 3705; (i) C. Zhu, X. Wei, J. Hu, D. Wang and H. Hu, Chem.
Res. Chin. Univ., 1994, 10, 93.
References
1 (a) W. Flisch, in Comprehensive Heterocyclic Chemistry, ed. A. R.
Katritzky and C. W. Rees, Pergamon, Oxford, vol. 4, 1984, pp. 476;
(b) J. Ewing, G. K. Hughes, E. Ritchie and W. C. Taylor, Nature,
1952, 169, 618.
2 (a) E. Reimann, Prog. Chem. Org. Nat. Prod., 2007, 88, 1; (b) J. P.
Michael, Nat. Prod. Rep., 2008, 25, 139; (c) J. P. Michael, Nat. Prod.
Rep., 2003, 20, 458; (d) J. W. Daly, T. F. Spande and H. M. Garraffo,
J. Nat. Prod., 2005, 68, 1556; (e) M. Lebceuf, A. Cave, A. Ranaivo
and H. Moskowitz, Can. J. Chem., 1989, 67, 947; (f) S. A. Snyder,
A. M. ElSohly and F. Kontes, Angew. Chem., Int. Ed., 2010, 49, 9693.
3 (a) A. K.Ghosh, G. Bilcer and G. Schiltz, Synthesis, 2001, 2203; (b) B.
List and C. Castello, Synlett, 2001, 1687; (c) P. Sonnet, P.
Dallemagne, J. Guillon, C. Enguehard, S. Stiebing, J. Tanguy, R.
Bureau, S. Rault, P. Auvray, S. Moslemi, P. Sourdaine and G. E.
Seralini, Bioorg. Med. Chem., 2000, 8, 945; (d) O. B. Ostby, B.
Dalhus, L.-L. Gundersen, F. Rise, A. Bast and G. R. M. M. Haenen,
Eur. J. Org. Chem., 2000, 3763; (e) B. E. Maryanoff, J. L. Vaught,
R. P. Shank, D. F. McComsey, M. J. Costanzo and S. O. Nortey,
J. Med. Chem., 1990, 33, 2793; (f) V. H. Lillelund, H. H. Jensen, X.
Liang and M. Bols, Chem. Rev., 2002, 102, 515; (g) J. Gubin, H. D.
Vogelaer, H. Inion, C. Houben, J. Lucchetti, J. Mahaux, G. Rosseels,
M. Peiren, M. Clinet, P. Polster and P. Chatelain, J. Med. Chem.,
1993, 36, 1425; (h) J. Bermudez, C. S. Fake, G. F. Joiner, K. A.
8644 | RSC Adv., 2012, 2, 8637–8644
This journal is ß The Royal Society of Chemistry 2012