One-pot multicomponent synthesis of polysubstituted indolizines

Article abstract of DOI:10.1016/j.tet.2011.10.083

Concise and efficient four-component tandem approaches to polysubstituted indolizines have been developed under metal-free and mild aerobic conditions in refluxing acetonitrile. The mechanism of the novel reactions was proposed involving the formation of

Full text of DOI:10.1016/j.tet.2011.10.083

Tetrahedron 68 (2012) 85e91
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot multicomponent synthesis of polysubstituted indolizines
*
Zhenjun Mao, Xuejian Li, Xufeng Lin , Ping Lu, Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2011
Received in revised form 20 October 2011
Accepted 25 October 2011
Available online 31 October 2011
Concise and efficient four-component tandem approaches to polysubstituted indolizines have been
developed under metal-free and mild aerobic conditions in refluxing acetonitrile. The mechanism of the
novel reactions was proposed involving the formation of pyridinium ylides and
with subsequent 1,3-dipolar cycloaddition and aromatization reaction.
a,b-unsaturated ketones
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indolizines
Multicomponent reaction
Heterocycles
Pyridinium ylide
1. Introduction
demonstrated as a straightforward approach to the synthesis of
indolizines.8
The chemistry of indolizines has assumed an interesting im-
portance as they widely occur as key structural subunits of many
bioactive natural products, organic fluorescent materials, and
As a part of our ongoing research into heterocyclic synthesis by
developing novel MCRs and tandem reaction strategy,9 we herein
report concise and efficient four-component tandem approaches to
polysubstituted indolizine derivatives involving the formation of
pharmaceutical substances.1 As
a successful calcium channel
blocker antihypertensive drug, Fantofarone is a prime example.2
Consequently, methods for the synthesis of various types of indo-
lizine derivatives bearing diverse substitution patterns have re-
ceived much attention.3 The reactions involved are classified as
condensation reactions, 1,3-dipolar cycloadditions, and 1,5-dipolar
cyclizations. Recent synthetic strategies also take advantage of
a variety of transition-metal catalysts.4 Whereas these methods
have proven very useful for the synthesis of pyrrole derivatives,
they generally involve multistep synthetic operations that limit the
scope of these reactions. Considering the continued importance of
the indolizine core in both biological and chemical fields, new di-
rect approaches remain highly valuable to the contemporary col-
lection of synthetic methods.
Multicomponent reactions (MCRs) have emerged as powerful
and bond-forming efficient tools in organic, combinatorial, and
medicinal chemistry.5 Various MCRs have been developed not only
for their facileness and efficiency, but also for their economy and
ecology in organic synthesis.6 These features make MCRs well-
suited for the easy construction of diversified heterocyclic scaf-
folds and perfectly amenable to automation for combinatorial
synthesis.7 Actually, three-component reactions have been
pyridinium ylides and a,b-unsaturated ketones with subsequent
1,3-dipolar cycloaddition and aromatization reaction.
2. Results and discussion
We began our investigations by treating pyridine (1) and phe-
nacyl bromide (2a) with ethyl glyoxalate (3) in the presence of
Na2CO3 under aerobic conditions in refluxing acetonitrile for 16 h.
The resulting polysubstituted indolizine derivative 4a (ethyl 1,3-
dibenzoylindolizine-2-carboxylate) was isolated in 61% yield after
workup. Similarly, various 2-bromoacetophenones reacted well
under the same conditions to give the corresponding poly-
substituted indolizine derivatives 4be4e in moderate yields, and
the results are shown in Table
1
(entries 1e5). 2-
Bromoacetophenones with electron-withdrawing groups such as
bromo and chloro gave the polysubstituted indolizines in slightly
higher yield than those with electrondonating groups such as
methoxy and methyl. As expected, aliphatic bromo ketone such as
1-bromobutan-2-one (2f) afforded the desired product (4f) in low
yield (Table 1, entry 6). On the other hand, the replacement of
pyridine with quinoline was smoothly transformed into the ex-
pected product in good yields (Table 1, entries 7 and 8). The
structures of products 4 (4aeh) were characterized by 1H NMR, 13
NMR, IR, MS, and HRMS spectra. The typical structure of compound
C
* Corresponding author. Tel.: þ86 571 87952759; fax: þ86 571 87953816; e-mail
address: lxfok@zju.edu.cn (X. Lin).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.083

86
Z. Mao et al. / Tetrahedron 68 (2012) 85e91
Table 1
Synthesis of indolizines 4a
Entry
Product
Yieldb (%)
Entry
Product
Yieldb (%)
O
O
Br
O
CO2Et
1
CO2Et
61
5
62
N
O
N
Br 4e
4a
O
O
Cl
O
O
Et
CO2Et
CO2Et
2
63
6
32
N
N
Et
Cl 4b
4f
CH3
O
O
3
CO2Et
55
7
CO2Et
89
N
N
O
O
CH
34c
4g
OMe
O
Br
O
O
CO2Et
CO2Et
4
58
8
70
N
N
Br 4h
O
4d
OMe
a
Reaction conditions: 3 (1.0 mmol), 2 (2.2 mmol), and 1 (2.5 mmol) and Na2CO3 (2.5 mmol) in CH3CN (5 mL).
Isolated yield based on 3.
b
4a (Table 1, entry 1) was unambiguously confirmed by single-
Surprisingly, the unexpected product of 1,2,3-triaroylindolizine
5a was generated in 44% isolated yield after addition of piperi-
dine into this reaction under the similar conditions. The type of
compound has previously been accessed only by more cumber-
some multistep procedures.11 We are pleased to find a conve-
nient method for the synthesis of 1,2,3-triaroylindolizines 5 via
a four-component reaction with a molecular of pyridine and
three phenacyl bromide in the presence of Na2CO3 and piperi-
dine under metal-free and mild aerobic conditions in refluxing
acetonitrile.
crystal X-ray analysis (Fig. 1).10
To explain the mechanism of this one-pot multicomponent
tandem reaction, we propose a possible mechanism as shown in
Scheme 1. The first step is the formation of phenacylpyridinium
bromide A from the addition of phenacyl bromide to pyridine. The
second step is the nucleophilic attack of a pyridinium ylide B, which
is generated in situ via deprotonation of A on ethyl glyoxalate 3 to
afford C. Then, the reactive alkene E is generated via a 1,2-H shift of
C followed by elimination of pyridine. Intermediate E subsequently
reacts with another pyridinium ylide B via 1,3-dipolar cycloaddition
followed by elimination of H2O to give the regioselective in-
termediate G. Finally, G is oxidized by O2 in air to give the desired
product 4.
We then tested the reaction between phenacyl bromide and
pyridine in the absence of ethyl glyoxalate (3) under the similar
conditions, and no indolizine was obtained other than pyr-
idinium ylide (B). An exploration of several parameters (in-
cluding base catalyst, solvent, temperature, the sequence of
addition of substrates) provided dramatic improvements.
Subsequently, we investigated the reaction scope, as shown in
Table 2.
A variety of electron-poor and electron-rich 2-
bromoacetophenones were found to react to provide the analo-
gous 1,2,3-triaroylindolizines 5 with 35e46% yields (Table 2, entries
1e8). The replacement of pyridine with isoquinoline or quinoline
was transformed into the expected products (Table 2, entries 9 and
10). The structures of products 5 (5aej) were characterized by 1H
NMR, 13C NMR, IR, MS, and HRMS spectra. The typical structure of
compound 5a (Table 2, entry 1) was unambiguously confirmed by
single-crystal X-ray analysis (Fig. 2).12

Z. Mao et al. / Tetrahedron 68 (2012) 85e91
87
dipolar cycloaddition followed by mild aerobic aromatization
strategy. This strategy takes advantage of the successful use of
pyridinium ylides generated in situ as the dipoles, the electron-
deficient alkenes generated in situ as dipolarophiles, and oxygen
in air as the oxidizer of aromatization in the reactions.
4. Experimental section
4.1. General
All reagents were purchased from a commercial supplier and
used as received. IR spectra were recorded on an ATR spectrometer
(neat) and reported in reciprocal centimeters (cmꢀ1). NMR spectra
were recorded for 1H NMR at 400 MHz and for 13C NMR at
100 MHz. For 1H NMR, tetramethylsilane (TMS) served as internal
standard (
d
¼0) and data are reported as follows: chemical shift,
integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad), and coupling constant in
hertz. For 13C NMR, CDCl3 (
d
¼77.00) was used as internal standard
and spectra were obtained with complete proton decoupling. Low-
resolution MS data were obtained using ESI ionization. HRMS data
were obtained using EI ionization. Mp data were measured with
micro melting point apparatus.
Fig. 1. X-ray crystal structure of 4a.
4.2. General procedure for the synthesis of indolizines 4
Py
O
O
O
Na2CO3
Py Br
R
Py
Br
R
To a solution of ethyl glyoxylate (1.0 mmol), phenacyl bromide
(2.2 mmol), and pyridine (2.5 mmol) in CH3CN (5 mL) was added
Na2CO3 (2.5 mmol). The resulting mixture was refluxed for 16 h and
then filtered through a Celite plug. The filtrate was concentrated in
vacuum and the residue was subjected to a flash chromatography
on silica gel with petroleum ether/ethyl acetate (4:1) as eluent to
afford the corresponding product 4.
R
2
A
B
EtO2C
OH
Py
O
EtO2C
H
O
O
R
CO2Et
O
3
Py
R
D
C
Py
4.3. General procedure for the synthesis of indolizines 5
R
O
R
N
N
To a solution of phenacyl bromide (1.5 mmol), Na2CO3 (2 mmol),
and pyridine (1.0 mmol) in CH3CN (5 mL) was added piperidine
(0.5 mmol). The resulting mixture was refluxed for 16 h, and then
filtered through a Celite plug. The filtrate was concentrated in
vacuum, and the residue was subjected to a flash chromatography
on silica gel with petroleum ether/ethyl acetate (3:1) as eluent to
afford the corresponding product 5.
EtO2C
OH
B
O
OH
CO2Et
R
R
[3+2]
CO2Et
O
H2O
O
O
G
F
E
R
[O]
R
N
O
R
CO2Et
4.4. Characterization data
O
4
4.4.1. Ethyl-1,3-dibenzoylindolizine-2-carboxylate (4a). Light yel-
Scheme 1.
low solid, mp 130e131 ꢁC; IR (neat)
n
2977, 1709, 1603, 1487, 1420,
1383, 1223, 1052, 1020, 891, 862, 793, 761, 697, 654 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d
9.53 (d, J¼7.2 Hz, 1H), 8.15 (d, J¼9.2 Hz, 1H),
Scheme 2 shows a plausible reaction mechanism for the mul-
ticomponent transformations, starting with the formation of pyr-
idinium ylide B and the reactive H from the addition of phenacyl
bromide to piperidine. A nucleophilic substitution reaction be-
tween B and H affords the pyridinium salt I. Subsequently, I re-
leases piperidine to generate J, which undergoes an elimination of
pyridine to give the intermediate K. The 1,2,3-triaroylindolizine 5 is
finally obtained via 1,3-dipolar cycloaddition between the electron-
deficient alkene K and another pyridinium ylide B followed by
aromatization.
7.69e7.67 (m, 4H), 7.51e7.46 (m, 2H), 7.42e7.35 (m, 5H),
7.11e7.08 (m, 1H), 3.10 (q, J¼7.2 Hz, 2H), 0.73 (t, J¼7.2 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3)
d 191.1, 187.1, 164.1, 140.2, 140.0,
138.0, 132.2, 132.1, 130.2, 128.6, 128.6, 128.2, 128.2, 127.6, 127.5,
121.0, 119.8, 116.2, 113.3, 61.5, 13.2 ppm; MS (ESI): m/z ([MþH]þ):
398; HRMS (EI): m/z calcd for (C25H19NO4): 397.1314; found:
397.1317.
4.4.2. Ethyl-1,3-bis(4-chlorobenzoyl)indolizine-2-carboxylate
(4b). Light yellow solid, mp 171e172 ꢁC; IR (neat)
n
2987,1727, 1617,
1586, 1491, 1423, 1382, 1219, 1080, 1052, 1013, 868, 830, 776, 750,
683 cmꢀ1 1H NMR (400 MHz, CDCl3)
3. Conclusion
;
d
9.48 (d, J¼7.2 Hz, 1H), 8.11
(d, J¼9.6 Hz, 1H), 7.64 (dd, J¼8.4, 2.0 Hz, 4H), 7.44e7.35 (m, 5H),
7.14e7.10 (m, 1H), 3.26 (q, J¼7.2 Hz, 2H), 0.80 (t, J¼7.2 Hz, 3H) ppm;
In summary, we have demonstrated the concise and efficient
four-component tandem approaches to polysubstituted indolizines
from easily available starting materials by the more general 1,3-
13C NMR (100 MHz, CDCl3)
d 189.6, 185.7, 164.0, 138.7, 138.6, 138.4,
138.2, 138.0, 130.1, 130.0, 129.8, 128.6, 128.6, 127.8, 127.6, 120.8,

88
Z. Mao et al. / Tetrahedron 68 (2012) 85e91
Table 2
Synthesis of indolizines 5a
Entry
Product
Yieldb (%)
Entry
Product
Yieldb (%)
O
O
H
C
1
44
6
42
N
N
O
O
O
O
5f
5a
Br
Me
Br
Me
O
O
H
C
N
2
47
7
N
40
O
O
O
O
Me
5b
Br
5g
Cl
Cl
MeO
OMe
O
O
H
C
N
N
3
36
8
46
O
O
O
O
MeO
5h
Cl
5c
OMe
O
O
OMe
4
45
9
35
N
N
O
O
O
O
MeO
5d
5i
MeO
OMe
O
O
N
5
43
10
33
O
N
O
O
O
5j
MeO
5e
a
Reaction conditions: 2 (1.5 mmol) and 1 (1.0 mmol), piperidine (0.5 mmol) and Na2CO3 (2.0 mmol) in CH3CN (5 mL).
Isolated yield based on 2.
b
119.7, 116.5, 113.0, 61.8, 13.3 ppm; MS (ESI): m/z ([MþH]þ): 466;
J¼7.2 Hz, 2H), 2.37 (s, 6H), 0.76 (t, J¼7.2 Hz, 3H) ppm; 13C NMR
HRMS (EI): m/z calcd for (C25H17Cl2NO4): 465.0535; found:
(100 MHz, CDCl3) d 190.8, 186.9, 164.2, 142.9, 142.8, 137.6, 137.6,
465.0534.
137.4, 129.6, 128.9, 128.8, 127.4, 126.9, 121.2, 119.7, 115.9, 113.5, 61.3,
21.5, 13.2 ppm; MS (ESI): m/z ([MþH]þ): 426; HRMS (EI): m/z calcd
for (C27H23NO4): 425.1627; found: 425.1631.
4.4.3. Ethyl-1,3-bis(4-methylbenzoyl)indolizine-2-carboxylate
(4c). Light yellow solid, mp 153e154 ꢁC; IR (neat)
n
2922, 1719,
1603, 1492, 1427, 1381, 1222, 1176, 1050, 1015, 897, 866, 825, 775,
750, 699 cmꢀ1; 1H NMR (400 MHz, CDCl3)
4.4.4. Ethyl-1,3-bis(3-methoxybenzoyl)indolizine-2-carboxylate
d
9.45 (d, J¼6.8 Hz, 1H),
(4d). Light yellow solid, mp 145e146 ꢁC; IR (neat)
n
2938,1711,1623,
1580, 1490, 1427, 1385, 1242, 1201, 1176, 1045, 921, 851, 771, 702,
655 cmꢀ1; 1H NMR (400 MHz, CDCl3)
9.53 (d, J¼7.2 Hz,1H), 8.19 (d,
8.07 (d, J¼8.8 Hz, 1H), 7.62e7.60 (m, 4H), 7.51e7.46 (m, 2H),
7.36e7.32 (m, 1H), 7.20e7.17 (m, 4H), 7.05 (t, J¼6.8 Hz, 1H), 3.22 (q,
d

Z. Mao et al. / Tetrahedron 68 (2012) 85e91
89
J¼7.2 Hz, 1H), 3.25 (q, J¼7.2 Hz, 2H), 0.80 (t, J¼7.2 Hz, 3H) ppm; 13
C
O
O
O
Na2CO3
NMR (100 MHz, CDCl3)
d
189.7, 185.8, 164.0, 138.8, 138.6, 138.0,
Py
Py Br
Br
Br
R
R
R
131.5, 131.5, 130.1, 130.1, 129.9, 127.9, 127.6, 127.2, 127.1, 120.7, 119.7,
116.5, 112.3, 61.8, 13.2 ppm; MS (ESI): m/z ([MþH]þ): 554; HRMS
(EI): m/z calcd for (C25H17Br2NO4): 552.9524; found: 552.9518.
2
A
B
OH
Py
O
Br
R
N
4.4.6. Ethyl-1,3-dipropionylindolizine-2-carboxylate
liquid; IR (neat) 2979, 2938, 1728, 1643, 1492, 1427, 1383, 1232,
1180, 1160,1113,1056,1020, 900, 816, 761 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
(4f). Yellow
R
n
2
Na2CO3
H
d
10.05 (d, J¼7.6 Hz, 1H), 8.39 (d, J¼9.2 Hz, 1H), 7.47 (t,
HN
Py•HBr
J¼7.6 Hz,1H), 7.47 (t, J¼6.8 Hz,1H), 4.55 (q, J¼7.2 Hz, 2H), 2.91e2.85
O
(m, 4H), 1.46 (t, J¼7.2 Hz, 3H), 1.27e1.21 (m, 6H) ppm; 13C NMR
Br
OH Py
Br
R
O
Py
(100 MHz, CDCl3)
d 194.6, 191.5, 167.9, 137.2, 129.8, 129.3, 128.5,
R
R
R
R
120.1, 119.8, 116.0, 113.0, 62.7, 34.5, 33.0, 13.9, 8.2, 8.0 ppm; MS
(ESI): m/z ([MþNa]þ): 330; HRMS (EI): m/z calcd for
(C17H19NO4):301.1314; found: 301.1409.
R
N
O
K
O
H
O
J
I
B
4.4.7. Ethyl-1,3-dibenzoylpyrrolo[1,2-a]quinoline-2-carboxylate
[3+2]
(4g). Light yellow solid, mp 181e182 ꢁC; IR (neat)
n
2990, 1705,
1639, 1427, 1228, 1204, 1228, 1204, 1178, 1061, 977, 931, 861, 796,
726, 681, 642 cmꢀ1 1H NMR (400 MHz, CDCl3)
R
R
;
d
7.99 (d, J¼7.2 Hz,
air
N
N
2H), 7.85 (d, J¼6.8 Hz, 2H), 7.75e7.68 (m, 3H), 7.61e7.60 (m, 1H),
7.52e7.46 (m, 3H), 7.44e7.35 (m, 5H), 3.57 (q, J¼7.2 Hz, 2H), 0.67 (t,
O
O
O
R
R
J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
191.7, 190.7, 163.2,
O
O
5
O
R
R
139.9, 137.7, 134.8, 134.2, 132.4, 129.7, 129.3, 129.1, 129.0, 128.9,
128.3, 127.9, 125.8, 125.7, 122.3, 117.8, 117.8, 115.1, 61.0, 13.1 ppm; MS
(ESI): m/z ([MþH]þ): 448; HRMS (EI): m/z calcd for (C29H21NO4):
447.1471; found: 447.1465.
L
Scheme 2.
4.4.8. Ethyl-1,3-bis(4-bromobenzoyl)pyrrolo[1,2-a]quinoline-2-
carboxylate (4h). Light yellow solid, mp 190e191 ꢁC; IR (neat)
n
2982, 1715, 1649, 1581, 1429, 1394, 1207, 1170, 1112, 1065, 975, 924,
844, 799, 738, 689, 636 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.85 (d,
J¼8.8 Hz, 2H), 7.75e7.68 (m, 4H), 7.65e7.61 (m, 3H), 7.58e7.43 (m,
2H), 7.40e7.37 (m, 3H), 3.68 (q, J¼7.2 Hz, 2H), 0.75 (t, J¼7.2 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3)
d 190.5, 189.7, 163.0, 138.6, 136.4,
134.9,132.4,132.3,131.6,131.0,130.6,129.8,129.5,129.1,127.6,127.5,
126.1, 125.9, 125.4, 121.8, 117.5, 117.5, 114.7, 61.2, 13.2 ppm; MS (ESI):
m/z ([MþH]þ): 604; HRMS (EI): m/z calcd for (C29H19Br2NO4):
602.9681; found: 602.9683.
4.4.9. Indolizine-1,2,3-triyltris(phenylmethanone)11c (5a). Light yel-
low solid, mp 203e204 ꢁC; IR (neat)
n
2926, 1661, 1636, 1610, 1495,
1476, 1448, 1421, 1370, 1340, 1222, 1174, 1072, 1048, 922, 744, 701,
646, 631 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
9.64 (d, J¼6.8 Hz, 1H),
8.04 (d, J¼8.8 Hz, 1H), 7.46e7.42 (m, 3H), 7.40e7.32 (m, 4H),
7.28e7.24 (m, 3H), 7.16e7.12(m, 5H), 7.03 (t, J¼7.2 Hz, 2H) ppm; 13C
NMR (100 MHz, CDCl3) d 191.8,191.3,187.6,139.9,139.8,138.4,138.1,
136.9, 132.7, 131.9, 131.8, 128.8, 128.7, 128.7, 127.9, 127.9, 127.6, 122.2,
119.7, 116.1, 115.1 ppm; MS (ESI): m/z ([MþH]þ): 430; HRMS (EI): m/
z calcd for (C29H19NO3): 429.1365; found: 429.1353.
Fig. 2. X-ray crystal structure of 5a.
4.4.10. Indolizine-1,2,3-triyltris(p-tolylmethanone)11c
yellow solid, mp 208e209 ꢁC; IR (neat)
2917, 1656, 1602, 1472,
1418, 1376, 1228, 1172, 1049, 1025, 847, 802, 769, 748, 687 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
(5b). Light
J¼8.4 Hz,1H), 7.42 (t, J¼8.0 Hz,1H), 7.29e7.21 (m, 4H), 7.12e7.09 (m,
2H), 7.05e7.04 (m, 1H), 7.03e7.02 (m, 2H), 3.79 (s, 6H), 3.18 (q,
J¼7.2 Hz, 2H), 0.77 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
n
d
9.55 (d, J¼7.2 Hz, 1H), 7.95 (d, J¼9.2 Hz,
d
190.8, 186.8, 164.2, 159.4, 159.3, 141.4, 141.3, 138.1, 130.3, 129.3,
1H), 7.40e7.33 (m, 3H), 7.27 (d, J¼8.4 Hz, 2H), 7.07 (t, J¼6.8 Hz, 1H),
6.95 (dd, J¼12.4, 8.0 Hz, 4H), 6.84 (d, J¼7.6 Hz, 2H), 2.32 (s, 3H), 2.28
129.2, 127.6, 121.3, 121.2, 120.9, 119.1, 118.9, 116.3, 113.2, 112.6, 112.5,
61.5, 55.3, 13.1 ppm; MS (ESI): m/z ([MþH]þ): 458; HRMS (EI): m/z
calcd for (C27H23NO6): 457.1525; found: 457.1507.
(s, 3H), 2.23 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d 191.6, 191.0,
187.4, 143.4, 142.6, 142.5, 137.7, 137.3, 137.2, 136.8, 136.3, 129.1, 128.9,
128.8, 128.7, 128.5, 128.4, 127.9, 127.0, 122.3, 119.6, 115.7, 115.3, 21.6,
21.5, 21.4 ppm; MS (ESI): m/z ([MþH]þ): 472; HRMS (EI): m/z calcd
for (C32H25NO3): 471.1834; found: 471.1841.
4.4.5. Ethyl-1,3-bis(4-bromobenzoyl)indolizine-2-carboxylate
(4e). Light yellow solid, mp 178e179 ꢁC; IR (neat)
n
3093, 1726,
1617, 1492, 1423, 1383, 1217, 1108, 1056, 1007, 955, 898, 845, 774,
728, 676 cmꢀ1 1H NMR (400 MHz, CDCl3)
9.49 (d, J¼7.2 Hz, 1H),
8.11 (d, J¼8.8 Hz, 1H), 7.56e7.51 (m, 8H), 7.44e7.40 (m, 1H), 7.11 (t,
4.4.11. Indolizine-1,2,3-triyltris((4-chlorophenyl)methanone)11c
;
d
(5c). Light yellow solid, mp 203e204 ꢁC; IR (neat)
n 1668, 1612,

90
Z. Mao et al. / Tetrahedron 68 (2012) 85e91
1488, 1464, 1416, 1221, 1168, 1085, 1050, 996, 896, 877, 775, 735,
679 cmꢀ1 1H NMR (400 MHz, CDCl3)
9.61 (d, J¼7.2 Hz, 1H), 7.96
([MþH]þ): 534; HRMS (EI): m/z calcd for (C33H27NO6): 533.1838;
;
d
found: 533.1844.
(d, J¼8.8 Hz, 1H), 7.27 (t, J¼8.0 Hz, 4H), 7.20e7.15 (m, 5H), 7.06 (d,
J¼8.0 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d
190.7, 189.5, 185.9,
4.4.17. Pyrrolo[2,1-a]isoquinoline-1,2,3-triyltris(phenylmethanone)11c
139.7, 138.6, 138.5, 138.1, 138.1, 137.9, 136.6, 136.5, 130.2, 130.1, 129.9,
128.5, 128.5, 128.3, 128.2, 121.8, 119.6,116.5,114.9 ppm; MS (ESI): m/
z ([MþH]þ): 532; HRMS (EI): m/z calcd for (C29H16Cl3NO3):
531.0196; found: 531.0204.
(5i). Light yellow solid, mp 223e224 ꢁC; IR (neat)
n
1654,1627,1596,
1490,1472,1451,1391,1269,1227,1175,1029, 997, 956, 910, 796, 730,
691 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
9.10 (d, J¼7.2 Hz,1H), 8.08 (d,
J¼8.0 Hz, 1H), 7.79 (d, J¼7.2 Hz, 2H), 7.73 (d, J¼7.2 Hz, 1H), 7.54(t,
J¼7.2 Hz, 1H), 7.51e7.21 (m, 11H), 7.12e7.06 (m, 4H) ppm; 13C NMR
4.4.12. Indolizine-1,2,3-triyltris((3-methoxyphenyl)methanone)
(100 MHz, CDCl3) d 194.5, 191.6, 187.4, 140.3, 139.0, 138.4, 133.6,
(5d). Light yellow liquid; IR (neat)
1487, 1427, 1376, 1317, 1263, 1202, 1176, 1033, 911, 849, 763, 729,
687, 650 cmꢀ1 1H NMR (400 MHz, CDCl3)
n
2938, 2836, 1662, 1621, 1583,
133.4,132.4,132.2,131.9,129.6,129.0,128.7, 128.4,127.9, 127.3, 125.2,
124.2, 123.9, 118.7, 115.9 ppm; MS (ESI): m/z ([MþH]þ): 480; HRMS
(EI): m/z calcd for (C33H21NO3): 479.1521; found: 479.1535.
;
d
9.61 (d, J¼6.8 Hz, 1H),
8.10 (d, J¼9.2 Hz, 1H), 7.43(t, J¼7.6 Hz, 1H), 7.15e7.00 (m, 5H),
6.96e6.81 (m, 7H), 6.67 (s, 1H), 3.66 (s, 3H), 3.65 (s, 3H), 3.59 (s,
4.4.18. Pyrrolo[1,2-a]quinoline-1,2,3-triyltris(phenylmethanone)
3H) ppm; 13C NMR (100 MHz, CDCl3)
d
191.4, 191.1, 187.3, 159.3,
(5j). Light yellow solid, mp 213e214 ꢁC; IR (neat)
n
1676, 1641, 1597,
1500, 1448, 1420, 1315, 1262, 1231, 1177, 999, 956, 808, 738, 717,
692 cmꢀ1 1H NMR (400 MHz, CDCl3)
159.1,141.3,140.0,138.1,137.0,129.0,128.8,128.0,127.6,122.5,122.3,
121.7, 119.9, 119.8, 119.0, 116.2, 115.2, 112.5, 112.5, 111.5, 55.2, 55.2,
55.1 ppm; MS (ESI): m/z ([MþH]þ): 520; HRMS (EI): m/z calcd for
(C32H25NO6): 519.1682; found: 519.1671.
;
d
7.88 (d, J¼9.6 Hz, 1H),
7.85e7.83 (m, 2H), 7.80e7.78 (m, 1H), 7.71 (d, J¼8.0 Hz, 1H), 7.54 (d,
J¼10.0 Hz, 1H), 7.49e7.41 (m, 5H), 7.39e7.28 (m, 6H), 7.19e7.10 (m,
4H) ppm; 13C NMR (100 MHz, CDCl3)
d 191.9, 191.4, 189.5, 140.2,
4.4.13. Indolizine-1,2,3-triyltris((4-methoxyphenyl)methanone)11c
138.7, 137.7,136.1, 133.9,132.4, 132.4, 132.0, 129.7,129.3, 129.1, 128.8,
128.7, 128.6, 128.1, 128.0, 128.0, 127.3, 125.5, 118.7, 117.9, 116.0 ppm;
MS (ESI): m/z ([MþH]þ): 480; HRMS (EI): m/z calcd for
(C33H21NO3): 479.1521; found: 479.1525.
(5e). Light yellow solid, mp 209e210 ꢁC; IR (neat)
n
2936, 2839,
1595, 1573, 1492, 1423, 1377, 1311, 1252, 1232, 1165, 1052, 1024, 905,
847, 773, 728, 695, 645 cmꢀ1; 1H NMR (400 MHz, CDCl3)
9.46 (d,
d
J¼7.2 Hz, 1H), 7.96 (d, J¼8.8 Hz, 1H), 7.50 (d, J¼8.8 Hz, 2H), 7.39 (d,
J¼8.4 Hz, 2H), 7.35e7.31 (m, 3H), 7.04 (t, J¼7.2 Hz, 2H), 3.80 (s, 3H),
Acknowledgements
3.76 (s, 3H), 3.72 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d 190.6,
190.1, 186.5, 163.1, 162.8, 162.8, 137.5, 136.2, 132.8, 132.7, 132.2, 131.2,
131.0, 130.9, 127.7, 126.6, 122.2, 119.6, 115.5, 115.1, 113.2, 113.2, 113.2,
55.4, 55.3 ppm; MS (ESI): m/z ([MþH]þ): 520; HRMS (EI): m/z calcd
for (C32H25NO6): 519.1682; found: 519.1700.
The authors thank the National Natural Science Foundation of
China (Nos. 20702047 and 21032005) and Zhejiang Provincial
Natural Science Foundation of China (Y4090028) for financial
support of this research.
4.4.14. (7-Methylindolizine-1,2,3-triyl)tris(phenylmethanone)
(5f). Light yellow solid, mp 205e206 ꢁC; IR (neat)
n
2923, 1617,
1489, 1416, 1374, 1338, 1227, 1175, 1050, 1009, 926, 796, 739, 698,
661 cmꢀ1 1H NMR (400 MHz, CDCl3)
Supplementary data
Copies of the 1H, 13C NMR spectra. Supplementary data associ-
ated with this article can be found in online version, at doi:10.1016/
j.tet.2011.10.083.
;
d
9.56 (d, J¼7.2 Hz, 1H), 7.91
(s, 1H), 9.40 (d, J¼8.0 Hz, 2H), 7.33e7.28 (m, 4H), 7.26e7.22 (m, 3H),
7.14e7.08 (m, 4H), 7.02e6.98 (m, 3H), 2.47 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3)
d 191.9, 191.6, 187.5, 140.1, 140.1, 139.6, 138.7,
138.4, 137.2, 132.6, 131.8, 131.7, 129.0, 128.7, 128.7, 128.1, 127.9, 127.8,
127.5, 121.8, 118.8, 118.4, 114.1, 21.6 ppm; MS (ESI): m/z ([MþH]þ):
444; HRMS (EI): m/z calcd for (C30H21NO3): 443.1521; found:
443.1510.
References and notes
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n
3084,
1610, 1583, 1480, 1419, 1253, 1225, 1171, 1068, 1005, 908, 844, 784,
729, 676, 648 cmꢀ1; 1H NMR (400 MHz, CDCl3)
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d
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Windgassen, R. J., Jr. J. Am. Chem. Soc. 1959, 81, 1456e1459; (c) Bora, U.; Saikia,
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n
2837,
1658, 1593, 1484, 1416, 1312, 1253, 1229, 1161, 1020, 956, 841, 804,
774, 734, 694 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
9.38 (d, J¼6.8 Hz,
1H), 7.82 (s, 1H), 7.46 (d, J¼8.8 Hz, 2H), 7.37 (d, J¼9.2 Hz, 2H), 7.31
(d, J¼8.8 Hz, 2H), 6.90 (d, J¼7.2 Hz, 1H), 6.64 (d, J¼8.8 Hz, 4H), 6.55
(d, J¼8.4 Hz, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H), 2.43 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3)
d 190.6, 190.3, 186.3, 163.1, 162.6,
162.6, 138.4, 138.2, 136.4, 132.9, 132.9, 132.2, 131.1, 130.9, 127.1, 121.8,
118.2, 118.1, 114.0, 113.1, 113.1, 55.4, 55.3, 21.4 ppm; MS (ESI): m/z

Z. Mao et al. / Tetrahedron 68 (2012) 85e91
91
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