One-pot synthesis of pyrrolo[3,4-a]indolizine-1,3-diones through [3+2] cycloaddition-oxidation reaction catalyzed by CuII salt and O 2 as the oxidant

Article abstract of DOI:10.1002/ejoc.201201488

An efficient one-pot synthesis of pyrrolo[3,4-a]indolizine-1,3-diones has been developed from maleimides, pyridines, and acyl bromides through a [3+2] cyclization-oxidation reaction catalyzed by Cu^II salt under O ₂ atmosphere. The advantage of this method is the use of molecular oxygen as the oxidant, in the presence of a catalytic amount of hydrated copper(II) chloride, to accomplish the reaction with broad substrate scope and excellent yields. An efficient approach for the synthesis of pyrrolo[3,4-a]indolizine-1,3-diones in excellent yields has been developed. In contrast to previous reports, this work uses molecular oxygen as the oxidant to replace traditional oxidants.

Full text of DOI:10.1002/ejoc.201201488

FULL PAPER
DOI: 10.1002/ejoc.201201488
One-Pot Synthesis of Pyrrolo[3,4-a]indolizine-1,3-diones through [3+2]
Cycloaddition-Oxidation Reaction Catalyzed by CuII Salt and O2 as the
Oxidant
Yun Liu,*[a] Hua-You Hu,[b] Xian-Bin Su,[c] Jin-Wei Sun,[a] Chang-Sheng Cao,*[a] and
Yan-Hui Shi[a]
Keywords: Synthetic methods / Homogeneous catalysis / Copper / Cycloaddition / Oxidation / Nitrogen heterocycles
An efficient one-pot synthesis of pyrrolo[3,4-a]indolizine-1,3-
diones has been developed from maleimides, pyridines, and
acyl bromides through a [3+2] cyclization–oxidation reaction
catalyzed by CuII salt under O2 atmosphere. The advantage
of this method is the use of molecular oxygen as the oxidant,
in the presence of a catalytic amount of hydrated copper(II)
chloride, to accomplish the reaction with broad substrate
scope and excellent yields.
Therefore, we tried to synthesize pyrrolo[3,4-a]indolizine-
1,3-diones to combine the maleimide and indolizine frame-
works, with the aim of exploring the potential biological
activity of this class of compounds.
Introduction
Indolizines, as an important class of N-heterocycles, have
received much attention in recent years.[1] These molecules
have found various pharmaceutical applications as anti-
tuberculosis agents,[2] PLA2 inhibitors,[3] histamine H3
receptor antagonists,[4] 5-HT3 receptor antagonists,[5]
MPtpA/MPtpB phosphatases inhibitors[6] and 15-lipoxy-
genase inhibitors.[7] They are playing an increasingly impor-
tant role in developing new pharmaceuticals for the treat-
ment of human diseases such as cancer,[8] cardiovascular
disease[9] and HIV infections.[10] It is also known that the
maleimide skeleton is an important core unit. Current stud-
ies have shown that maleimide is a potent inhibitor of topo-
isomerase II in vitro and in vivo, and that substituted male-
imides have strong antifungal activity.[11] In addition, poly-
cyclic N-heterocycles are ubiquitous in a variety of natural
products and biologically-active molecules,[12] and they
have been assigned as privileged structures in drug develop-
ment because N-heterocyclic moieties often exhibit im-
proved solubility and can facilitate salt formation, both of
which are important for oral absorption and bioavail-
ability.[13]
To the best of our knowledge, only isolated examples of
pyrrolo[3,4-a]indolizine-1,3-dione syntheses have been re-
ported by using the reaction of pyridinium salts with male-
imides followed by oxidation with a stoichiometric amount
of oxidant such as tetrakispyridinecobalt(II) dichromate[14]
or tBuOOH.[15] The shortcoming of these methods are the
limited substrate scope and a requirement for a stoichio-
metric amount of oxidant, which is not economical or envi-
ronmentally friendly, and complicates the work-up. Cop-
per(II) salt is a particularly attractive oxidant because, un-
der appropriate conditions and with suitable substrates, oxi-
dation reactions can be carried out with catalytic amounts
of Cu by using ambient air or O2 as the stoichiometric oxi-
dant.[16] In continuation of our ongoing research interest in
the synthesis of indolizine derivatives,[14b,17] and with the
aim of developing general and practical synthetic methods
for polycyclic N-heterocycles, we report the high-yielding
one-pot synthesis of pyrrolo[3,4-a]indolizine-1,3-diones
from maleimides, pyridines, and acyl bromides through a
[3+2] cyclization-oxidation reaction catalyzed by CuII salt
by using molecular oxygen as the oxidant.
[a] Department of Chemistry and Chemical Engineering, and
Jiangsu Key Laboratory of Green Synthetic Chemistry for
Functional Materials, Jiangsu Normal University,
Xuzhou 221116, Jiangsu, P. R. China
Results and Discussion
Homepage: http://www.jsnu.edu.cn/
E-mail: liu_yun3@sina.com.cn
Initially, N-phenylmaleimide (1a; 2.0 mmol) was sub-
jected to the copper(II)-promoted reaction with pyridine
(2a; 6.0 mmol) and acyl bromide 3a (2.0 mmol) in CH3CN
at reflux temperatures by using hydrated copper(II) chloride
(20 mol-%) as the catalyst under 1 atm O2 (Table 1). By
heating to reflux for 24 h, product 4a was obtained in 71%
yield. On the basis of this result, we began to optimize the
[b] Jiangsu Key Laboratory for Chemistry of Low-Dimensional
Materials, School of Chemistry and Chemical Engineering,
Huaiyin Normal University,
Huaian 223300, Jiangsu, P. R. China
[c] Department of Chemistry and Chemical Engineering, Nanjing
University of Technology,
Nanjing 211816, Jiangsu, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201488.
2020
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2020–2026

Synthesis of Pyrrolo[3,4-a]indolizine-1,3-diones
reaction conditions. In screening the catalysts, hydrated
With the optimized reaction conditions in hand, we then
copper(II) chloride proved to be the most promising investigated the substrate scope for the copper-catalyzed re-
(Table 1, Entries 5–7). Relative to copper(II) chloride, cop- actions. First, a variety of acyl bromides 3 was treated with
per(II) bromide provided a similar yield but more by-prod- N-phenylmaleimide (1a) and pyridine (2a) under the opti-
ucts (Table 1, Entry 6). When copper(II) acetate was used mized reaction conditions. Both phenacyl bromides 3a–3c
as the catalyst, it led to a slightly lower yield (Table 1, En- and 2-bromoacetates 3d and 3e produced corresponding
try 7). The effect of the amount of the catalyst was also products 4a–4e smoothly in good to excellent yields
examined and it was found that 30 mol-% of hydrated cop- (Table 2, Entries 1–5). The results demonstrated that vari-
per(II) chloride gave the best result with 91% product yield ous acyl bromides showed similar reactivity and took part
(Table 1, Entries 1–5). Solvent screening showed that aceto- in the reaction efficiently to yield the final products. Mean-
nitrile offered optimal selectivity (Table 1, Entries 3 and 8– while, the reactivity of N-methylmaleimide (1b), and N-eth-
10). Finally, a significant decrease of the reaction yield was ylmaleimide (1c) were also studied. It was found that 1b and
observed when the reaction temperature was decreased 1c under the optimized conditions also reacted smoothly to
(Table 1, Entry 11 and 12). In this reaction, an excess of give 4f–4o in slightly higher yields than N-phenylmaleimide
pyridine was necessary for the deprotonation step and HBr (Table 2, Entries 6–15). All these pyrrolo[3,4-a]indolizine-
trapping. Decreasing the amount of pyridine led to a de- 1,3-diones were previously unknown and have been fully
creased yield. As the oxidant, oxygen is more efficient than characterized by analytical and spectroscopic (IR, NMR,
ambient air. When the reaction was carried out in air, an and HRMS) data. Moreover, the structure of 4j was further
increased amount of copper(II) salt was necessary to obtain established by X-ray crystallography (Figure 1). These re-
the product in high yield. In contrast, when the reaction sults showed that this reaction provides a general and con-
was carried out under an Ar atmosphere in the presence of venient high-yielding synthesis of pyrrolo[3,4-a]indolizine-
30% copper(II) salt, only trace amounts of product were 1,3-diones derivatives.
formed. However, by using a stoichiometric amount of CuII
salt, the reaction proceeds smoothly under an Ar atmo-
Table 2. Reaction scope with various maleimides and acyl brom-
ides.[a]
sphere to give the product in a yield similar to that when
using a catalytic amount of CuII salt under 1 atm oxygen.
Therefore, the optimal reaction condition are heating the
reactants in CH3CN to reflux with 30 mol-% of hydrated
copper(II) chloride as catalyst under 1 atm O2.
Table 1. Optimization of the reaction conditions.[a]
Entry
1, R
3, R1
Product
Yield [%][b]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Et
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
91
95
93
92
88
93
97
95
88
85
92
95
96
89
86
Entry Solvent
Catalyst
Temp. [°C] Yield [%][c]
C6H4Cl-p
C6H4Me-p
OCH2Ph
OEt
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
C6H6
CuCl2 (20 mol-%)
CuCl2 (25 mol-%)
CuCl2 (30 mol-%)
CuCl2 (35 mol-%)
none
CuBr2 (30 mol-%)
Cu(OAc)2 (30 mol-%)
CuCl2 (30 mol-%)
CuCl2 (30 mol-%)
CuCl2 (30 mol-%)
CuCl2 (30 mol-%)
CuCl2 (30 mol-%)
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
60
71
80
91
91
0[b]
87
80
72
67
85
62
0
Ph
C6H4Cl-p
OCH2Ph
OEt
OMe
Ph
C6H4Cl-p
OCH2Ph
OEt
9
10
11
12
13
14
15
9
C2H5OH
DMF
CH3CN
CH3CN
10
11
12
Et
Et
Et
Et
r.t.
OMe
[a] Reagents and conditions: pyridine (6.0 mmol), acyl bromide
(2.0 mmol), maleimide (2.0 mmol), and hydrated copper(II) chlor-
ide (0.6 mmol), heated to reflux in solvent for 24 h under 1 atm O2.
[b] Without copper salt, no product 4a was formed and the reaction
system was complicated with many byproducts. [c] Isolated yields.
[a] Reagents and conditions: pyridine (6.0 mmol), acyl bromide
(2.0 mmol), maleimide (2.0 mmol), and hydrated copper(II) chlor-
ide (0.6 mmol), reflux in acetonitrile for 24 h under 1 atm O2. [b]
Isolated yields.
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Y. Liu, H.-Y. Hu, X.-B. Su, J.-W. Sun, C.-S. Cao, Y.-H. Shi
FULL PAPER
For the synthesis of further annulated indolizine deriva-
tives, we also investigated the reactions of isoquinoline 5
with maleimides and acyl bromide. When N-phenylmale-
imide (1a; 2.0 mmol) was heated with isoquinoline (5;
6.0 mmol), phenacyl bromide (3a; 2.0 mmol), and hydrated
copper chloride (0.6 mmol) in acetonitrile at reflux tem-
peratures for 24 h, corresponding product 6a was obtained
in 92% yield. It was further found that the reaction of 5
with 2-bromoacetate 3b or 3c and N-phenylmaleimide (1a)
also led to corresponding annulated benzo[f]pyrrolo[3,4-a]-
indolizine-1,3-dione derivatives 6b and 6c in high yields.
Meanwhile, when N-methylmaleimide or N-ethylmaleimide
was used as the substrate to react with isoquinoline and
acyl bromides, desired products 6d–6g were generated in ex-
cellent yields (Table 4).
Figure 1. ORTEP drawing of 4j.
Table 4. Reaction scope with isoquinoline.[a]
To further extend the utility of this tandem reaction, we
investigated the reactions of 4-substituted pyridines 2b, 2c,
and 2d in place of pyridine (Table 3). It was found that the
properties of the substituents on pyridine have little effect
on the reaction. Pyridines with either electron-donating
groups, such as 2b or 2c, or with electron-withdrawing
group, such as 2d, reacted equally well with maleimide 1
and acyl bromide 3 to give corresponding products 4p–4w
in high yields.
Table 3. Reaction scope with 4-substituted pyridines.[a]
Entry
1, R
3, R1
Product
Yield [%][b]
1
2
3
4
5
6
7
Ph
Ph
Ph
Me
Me
Et
Ph
OEt
OC(CH3)3
Ph
OC(CH3)3
Ph
6a
6b
6c
6d
6e
6f
92
87
89
95
91
93
90
Et
OC(CH3)3
6g
[a] Reagents and conditions: isoquinoline (6.0 mmol), acyl bromide
(2.0 mmol), maleimide (2.0 mmol), and hydrated copper(II) chlor-
ide (0.6 mmol), reflux in acetonitrile for 24 h under 1 atm O2.
[b] Isolated yields.
Entry
1
2
3
Product
Yield [%][b]
A possible mechanism for this reaction is suggested in
Scheme 1. First, deprotonation of the pyridinium salt
formed by the reaction of pyridine with acyl bromide yields
pyridinium ylide I. Subsequent [3+2] cycloaddition reaction
of I with N-phenylmaleimide affords II,[18] which on oxidat-
ive aromatization catalyzed by Cu2+ furnishes product 4a.
The copper(II) salt can be regenerated through oxidation
by oxygen. It is worth noting that copper(II) salt in this
reaction acts as an oxidation catalyst and also catalyzes the
cycloaddition reaction step owing to its Lewis acid charac-
ter.[15]
1
2
3
4
5
6
7
8
a
a
b
c
a
a
a
a
b
b
b
b
c
c
d
d
a
b
a
a
a
b
a
b
4p
4q
4r
4s
4t
4u
4v
4w
90
85
93
92
91
87
88
83
[a] Reagents and conditions: 4-substituted pyridine (6.0 mmol),
acyl bromide (2.0 mmol), maleimide (2.0 mmol), and hydrated cop-
per(II) chloride (0.6 mmol), at reflux temperatures in acetonitrile
for 24 h under 1 atm O2. [b] Isolated yields.
2022
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Synthesis of Pyrrolo[3,4-a]indolizine-1,3-diones
109.5 ppm. HRMS (ESI): calcd. for C23H13ClN2NaO3 [M + Na]+
423.0512; found 423.0510.
9-(4-Methylbenzoyl)-2-phenyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-
dione (4c): Yellow solid, m.p. 229–230 °C. IR (KBr): 1763, 1716,
1623, 1604, 1557, 1501, 1451, 1357, 1331, 1297, 1171, 1060, 875,
1
747 cm–1. H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 7.14 (t,
J = 7.2 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 7.6 Hz, 3
H), 7.43 (t, J = 8.0 Hz, 2 H), 7.50 (t, J = 8.0 Hz, 1 H), 7.82 (d, J
= 8.0 Hz, 2 H), 8.01 (d, J = 8.8 Hz, 1 H), 957 (d, J = 7.2 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.2, 162.7, 162.2,
144.1, 135.9, 132.4, 132.2, 130.0, 129.9, 129.6, 129.1, 128.9, 128.5,
127.7, 127.0, 118.8, 117.9, 116.4, 110.3, 21.9 ppm. HRMS (ESI):
calcd. for C24H16N2NaO3 [M + Na]+ 403.1059; found 403.1056.
Benzyl 1,3-Dioxo-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-a]indolizine-
9-carboxylate (4d): Yellow solid, m.p. 218–220 °C. IR (KBr): 1772,
1711, 1684, 1645, 1541, 1515, 1499, 1338, 1222, 1152, 1091, 1065,
811, 749, 735 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.51 (s, 2 H),
7.09 (td, J = 7.2, 1.2 Hz, 1 H), 7.29–7.33 (m, 1 H), 7.38–7.46 (m,
6 H), 7.50 (td, J = 7.6, 1.6 Hz, 2 H), 7.60 (d, J = 7.2 Hz, 2 H), 7.95
(d, J = 9.2 Hz, 1 H), 9.63 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 162.7, 162.0, 159.9, 135.7, 132.4, 132.1,
129.9, 129.4, 129.0, 128.6, 128.3, 128.2, 127.9, 127.6, 127.2, 118.9,
116.2, 110.5, 110.1, 66.8 ppm. HRMS (ESI): calcd. for
C24H16N2NaO4 [M + Na]+ 419.1008; found 419.1003.
Scheme 1. Proposed mechanism of the formation for 4a.
Conclusions
We have described a general and efficient method for the
synthesis of pyrrolo[3,4-a]indolizine-1,3-diones and their
further-annulated derivatives in one-pot, copper(II)-cata-
lyzed three-component reaction of maleimides, pyridines,
and acyl bromides. The most attractive features of this pro-
cedure are the broad reaction scope and the use of molecu-
lar oxygen as the oxidant in place of a stoichiometric
amount of oxidants through catalysis by hydrated cop-
per(II) chloride. The pyrrolo[3,4-a]indolizine-1,3-diones
prepared are currently being subjected to biological evalu-
ation.
Ethyl 1,3-Dioxo-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-a]indolizine-9-
carboxylate (4e): Yellow solid, m.p. 195–197 °C. IR (KBr): 1765,
1711, 1690, 1541, 1503, 1399, 1363, 1334, 1225, 1168, 1094, 1039,
1
930, 793, 754 cm–1. H NMR (400 MHz, CDCl3): δ = 1.50 (t, J =
7.2 Hz, 3 H), 4.48 (d, J = 7.2 Hz, 2 H), 7.10 (t, J = 6.8 Hz, 1 H),
7.39–7.46 (m, 4 H), 7.50 (t, J = 7.6 Hz, 2 H), 7.96 (d, J = 8.8 Hz,
1 H), 9.63 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 162.7, 162.1, 160.1, 132.5, 131.9, 129.7, 129.3, 129.0, 127.8,
127.4, 127.2, 118.9, 116.0, 110.5, 110.3, 61.5, 14.3 ppm. HRMS
(ESI): calcd. for C19H14N2NaO4 [M + Na]+ 357.0851; found
357.0840.
Experimental Section
General Procedure for the Preparation of Benzo[f]pyrrolo[3,4-a]-
indolizine-1,3-diones 4: Pyridine 1 (6.0 mmol), acyl bromide 2
(2.0 mmol), maleimide 3 (2.0 mmol), and hydrated copper(II)
chloride (0.6 mmol) were mixed in CH3CN (15 mL) and heated to
reflux for 24 h under an oxygen atmosphere. The reaction mixture
was then allowed to cool to room temperature. After evaporation
of the solvent under vacuum, the mixture was purified by column
chromatography on silica gel to afford pure product 4.
9-Benzoyl-2-methyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-dione (4f):
Yellow solid, m.p. 254–256 °C. IR (KBr): 1756, 1715, 1651, 1621,
1500, 1377, 1353, 1333, 1170, 1144, 898, 842, 789, 732, 665 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.03 (s, 3 H), 7.11 (t, J = 6.8 Hz,
1 H), 7.46–7.55 (m, 3 H), 7.68 (td, J = 7.2, 0.8 Hz, 1 H), 7.83 (d,
J = 6.8 Hz, 2 H), 7.94 (d, J = 8.8 Hz, 1 H), 9.61 (d, J = 7.2 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.6, 163.8, 163.2,
139.0, 132.9, 132.1, 131.0, 130.0, 129.5, 128.5, 128.3, 118.6, 116.2,
111.1, 24.2 ppm. HRMS (ESI): calcd. for C18H12N2NaO3
[M + Na]+ 327.0746; found 327.0740.
9-Benzoyl-2-phenyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-dione (4a):
Yellow solid, m.p. 223–224 °C. IR (KBr): 1765, 1718, 1622, 1578,
1512, 1501, 1334, 1299, 1219, 1169, 1087, 872, 751, 685 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.16 (td, J = 7.2, 1.2 Hz, 1 H), 7.30–
7.34 (m, 3 H), 7.42 (t, J = 9.0 Hz, 2 H), 7.48–7.55 (m, 3 H), 7.62
(t, J = 7.6 Hz, 1 H), 7.87 (d, J = 7.2 Hz, 2 H), 8.02 (d, J = 9.2 Hz,
1 H), 9.65 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 185.6, 162.4, 162.0, 138.8, 133.1, 132.6, 132.2, 130.1, 130.0,
129.5, 128.9, 128.7, 128.4, 127.8, 127.0, 118.9, 117.7, 116.6 ppm.
HRMS (ESI): calcd. for C23H14N2NaO3 [M + Na]+ 389.0902;
found 389.0903.
9-(4-Chlorobenzoyl)-2-methyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-
dione (4g): Yellow solid, m.p. 277–279 °C. IR (KBr): 1754, 1716,
1652, 1615, 1590, 1500, 1456, 1356, 1331, 1172, 1091, 838, 743,
1
685 cm–1. H NMR (400 MHz, CDCl3): δ = 3.06 (s, 3 H), 7.14 (t,
J = 7.2 Hz, 1 H), 7.46–7.53 (m, 3 H), 7.80 (d, J = 8.4 Hz, 2 H),
7.96 (d, J = 8.8 Hz, 1 H), 9.60 (d, J = 6.8 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 184.1, 163.7, 163.3, 139.4, 137.1, 132.3,
131.6, 131.0, 130.9, 130.0, 128.9, 128.7, 118.7, 117.0, 116.4,
24.3 ppm. HRMS (ESI): calcd. for C18H11ClN2NaO3 [M + Na]+
361.0356; found 361.0359.
9-(4-Chlorobenzoyl)-2-phenyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-di-
one (4b): Yellow solid, m.p. 287–289 °C. IR (KBr): 1715, 1682,
1645, 1621, 1592, 1556, 1425, 1323, 1296, 1219, 1176, 1092, 853,
762, 747 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.20 (t, J = Benzyl 2-Methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-a]indolizine-
.
6.8 Hz, 1 H), 7.38 (t, J = 7.2 Hz, 3 H), 7.48 (t, J = 7.6 Hz, 4 H),
7.57 (t, J = 8.0 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 2 H), 8.06 (d, J =
8.4 Hz, 1 H), 9.66 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 184.0, 162.6, 162.2, 141.0, 139.3, 137.1, 133.2, 132.1,
9-carboxylate (4h): Yellow solid, m.p. 157–159 °C. IR (KBr): 1756,
1704, 1682, 1647, 1533, 1517, 1434, 1355, 1240, 1218, 1116, 1068,
1
989, 885, 752, 710 cm–1. H NMR (400 MHz, CDCl3): δ = 3.15 (s,
3 H), 5.50 (s, 2 H), 7.03 (td, J = 7.2, 1.2 Hz, 1 H), 7.34–7.43 (m, 4
130.9, 129.4, 129.0, 128.7, 127.8, 126.9, 119.3, 117.5, 116.9, H), 7.62 (d, J = 7.2 Hz, 2 H), 7.86 (d, J = 7.2 Hz, 1 H), 956 (d, J
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y. Liu, H.-Y. Hu, X.-B. Su, J.-W. Sun, C.-S. Cao, Y.-H. Shi
FULL PAPER
= 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.9,
163.2, 160.0, 135.7, 131.6, 130.6, 129.3, 128.6, 128.3, 128.2, 128.1,
127.3, 118.7, 115.7, 66.8, 24.3 ppm. HRMS (ESI): calcd. for
C19H14N2NaO4 [M + Na]+ 357.0851; found 357.0853.
1709, 1644, 1541, 1513, 1347, 1335, 1229, 1159, 1038, 1019,
760,744 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.27 (t, J = 7.2 Hz,
3 H), 1.52 (t, J = 7.2 Hz, 3 H), 3.70 (q, J = 7.2 Hz, 2 H), 4.48 (q,
J = 7.2 Hz, 2 H), 7.03 (t, J = 6.8 Hz, 1 H), 7.38 (t, J = 6.8 Hz, 1
H), 7.87 (d, J = 8.8 Hz, 1 H), 9.56 (d, J = 7.6 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 163.7, 163.1, 160.1, 131.5, 130.4,
129.2, 127.1, 118.7, 115.6, 110.7, 110.0, 61.4, 33.0, 14.3, 14.2 ppm.
HRMS (ESI): calcd. for C15H14N2NaO4 [M + Na]+ 309.0851;
found 309.0853.
Ethyl 2-Methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-a]indolizine-9-
carboxylate (4i): Yellow solid, m.p. 200–202 °C. IR (KBr): 1765,
1717, 1650, 1541, 1502, 1424, 1379, 1348, 1235, 1166, 1091, 1021,
1
804, 755, 734 cm–1. H NMR (400 MHz, CDCl3): δ = 1.51 (t, J =
7.2 Hz, 3 H), 3.14 (s, 3 H), 4.49 (qd, J = 7.2, 2.0 Hz, 2 H), 7.03 (t,
J = 6.4 Hz, 1 H), 7.37 (t, J = 7.2 Hz, 1 H), 7.86 (d, J = 9.2 Hz, 1
H), 9.55 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 163.9, 163.3, 160.1, 131.5, 130.3, 129.2, 127.1, 118.6, 115.6,
110.6, 110.1, 61.4, 24.2, 14.3 ppm. HRMS (ESI): calcd. for
C14H12N2NaO4 [M + Na]+ 295.0695; found 295.0697.
Methyl 2-Ethyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-a]indolizine-9-
carboxylate (4o): Yellow solid, m.p. 210–212 °C. IR (KBr): 1756,
1707, 1646, 1542, 1514, 1438, 1347, 1232, 1156, 1028, 808, 758,
1
744 cm–1. H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.2 Hz, 3
H), 3.71 (d, J = 7.2 Hz, 2 H), 4.06 (s, 3 H), 7.06 (t, J = 7.2 Hz, 1
H), 7.40 (t, J = 76 Hz, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 9.58 (d, J
= 6.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.6,
163.2, 160.5, 131.6, 130.5, 129.2, 127.2, 118.7, 115.7, 110.8, 109.5,
52.3. 33.1, 14.2 ppm. HRMS (ESI): calcd. for C14H12N2NaO4 [M
+ Na]+ 295.0695; found 295.0698.
Methyl 2-Methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-a]indolizine-
9-carboxylate (4j): Yellow solid, m.p. 231–233 °C. IR (KBr): 1762,
1693, 1641, 1545, 1512, 1428, 1339, 1242, 1221, 1166, 1064, 998,
762, 735 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.14 (s, 3 H), 4.04
(s, 3 H), 7.06 (d, J = 6.4 Hz, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 7.88
(d, J = 8.8 Hz, 1 H), 9.56 (d, J = 6.8 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 163.8, 163.3, 160.5, 131.5, 130.1, 129.1,
127.2, 118.7, 115.7, 110.7, 109.6, 52.2, 24.2 ppm. HRMS (ESI):
calcd. for C13H10N2NaO4 [M + Na]+ 281.0528; found 281.0522.
4-Benzoyl-8-methyl-2-phenyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-di-
one (4p): Yellow solid, m.p. 243–245 °C. IR (KBr): 1757, 1716,
1651, 1620, 1599, 1501, 1420, 1354, 1334, 1299, 1222, 1170, 1089,
843, 791, 733 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.54 (s, 3 H),
7.01 (d, J = 7.2 Hz, 1 H), 7.33 (t, J = 8.0 Hz, 3 H), 7.44 (t, J =
8.0 Hz, 2 H), 7.50 (t, J = 7.6 Hz, 2 H), 7.63 (t, J = 7.2 Hz, 1 H),
7.82 (s, 1 H), 7.88 (d, J = 7.2 Hz, 2 H), 9.55 (d, J = 7.6 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.5, 162.7, 162.1,
140.8, 138.9, 133.1, 132.9, 132.3, 130.3, 129.5, 128.9, 128.3, 127.7,
127.0, 119.2, 117.5, 117.4, 109.4, 21.5 ppm. HRMS (ESI): calcd.
for C24H16N2NaO3 [M + Na]+ 403.1059; found 403.1061.
CCDC-909367 (for 4j) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
9-Benzoyl-2-ethyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-dione (4k):
Yellow solid, m.p. 205–207 °C. IR (KBr): 1756, 1713, 1625, 1510,
1341, 1225, 1183, 1014, 878, 753 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 1.19 (t, J = 7.2 Hz, 3 H), 3.60 (q, J = 7.2 Hz, 2 H),
7.12 (t, J = 6.4 Hz, 1 H), 7.48–7.57 (m, 3 H), 7.70 (t, J = 7.2 Hz,
1 H), 7.86 (d, J = 6.8 Hz, 2 H), 7.96 (d, J = 8.4 Hz, 1 H), 9.64 (d,
J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.6,
163.7, 162.9, 138.9, 132.9, 132.1, 131.0, 130.2, 130.0, 129.5, 128.5,
128.4, 128.3, 118.6, 117.3, 116.2, 111.2, 33.0, 14.1 ppm. HRMS
(ESI): calcd. for C19H14N2NaO3 [M + Na]+ 341.0902; found
341.0907.
Ethyl 8-Methyl-1,3-dioxo-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-a]-
indolizine-4-carboxylate (4q): Yellow solid, m.p. 228–229 °C. IR
(KBr): 1766, 1710, 1690, 1545, 1450, 1399, 1361, 1332, 1220, 1088,
1042, 804, 755 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.49 (t, J =
7.2 Hz, 3 H), 2.49 (s, 3 H), 4.47 (q, J = 7.2 Hz, 2 H), 6.93 (dd, J =
7.2, 1.5 Hz, 1 H), 7.38–7.43 (m, 3 H), 7.49 (t, J = 7.6 Hz, 2 H),
7.74 (s, 1 H), 9.50 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 162.9, 162.3, 160.2, 139.3, 132.6, 132.4, 129.8, 129.0,
128.6, 127.7, 127.2, 127.1, 118.6, 117.5, 61.4, 21.4, 14.3 ppm.
HRMS (ESI): calcd. for C20H16N2NaO4 [M + Na]+ 371.1008;
found 371.1009.
9-(4-Chlorobenzoyl)-2-ethyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-
dione (4l): Yellow solid, m.p. 230–232 °C. IR (KBr): 1752, 1712,
1622, 1592, 1534, 1509, 1401, 1342, 1299, 1224, 1149, 1088, 1063,
880, 757 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.18 (t, J =
7.2 Hz, 3 H), 3.60 (q, J = 7.2 Hz, 2 H), 7.11 (td, J = 7.2, 0.8 Hz, 1
H), 7.47–7.50 (m, 3 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.95 (d, J =
8.8 Hz, 1 H), 9.59 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 184.1, 163.5, 163.0, 139.4, 137.1, 132.3. 131.0, 130.9,
130.0, 128.6, 128.5, 118.6, 116.9, 116.3, 111.4, 33.1, 14.1 ppm.
HRMS (ESI): calcd. for C19H13ClN2NaO3 [M + Na]+ 375.0512;
found 375.0508.
4-Benzoyl-2,8-dimethyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-dione
(4r): Yellow solid, m.p. 214–216 °C. IR (KBr): 1751, 1714, 1650,
1626, 1527, 1515, 1427, 1373, 1359, 1300, 1220, 1159, 1059, 973,
842, 746 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3 H), 3.01
(s, 3 H), 6.94 (dd, J = 7.2, 1.2 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 2 H),
7.66 (t, J = 7.6 Hz, 1 H), 7.71 (s, 1 H), 7.81 (dd, J = 8.4, 1.2 Hz, 2
H), 9.51 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 185.5, 164.0, 163.3, 140.5, 139.1, 132.7, 132.6, 131.2, 129.4,
129.3, 128.3, 118.8, 117.2, 117.0, 110.0, 24.2, 21.5 ppm. HRMS
(ESI): calcd. for C19H14N2NaO3 [M + Na]+ 341.0902; found
341.0905.
Benzyl 2-Ethyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-a]indolizine-9-
carboxylate (4m): Yellow solid, m.p. 178–180 °C. IR (KBr): 1759,
1702, 1688, 1640, 1542, 1513, 1348, 1256, 1217, 1142, 1019, 951,
1
756 cm–1. H NMR (400 MHz, CDCl3): δ = 1.27 (t, J = 7.2 Hz, 3
H), 3.70 (q, J = 7.2 Hz, 2 H), 5.50 (s, 2 H), 7.00 (td, J = 7.2, 1.2 Hz,
1 H), 7.33–7.42 (m, 4 H), 7.62 (d, J = 7.2 Hz, 2 H), 7.85 (d, J =
8.8 Hz, 1 H), 9.55 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 163.7, 162.9, 159.9, 135.7, 131.6, 130.6, 129.3, 128.6,
128.5, 128.3, 128.2, 128.1, 127.2, 127.0, 118.6, 115.7, 66.7, 33.1,
14.2 ppm. HRMS (ESI): calcd. for C20H16N2NaO4 [M + Na]+
371.1008; found 371.1006.
4-Benzoyl-2-ethyl-8-methyl-1H-pyrrolo[3,4-a]in-dolizine-1,3(2H)-
dione (4s): Yellow solid, m.p. 232–234 °C. IR (KBr): 1752, 1709,
1649, 1624, 1559, 1509, 1418, 1341, 1262, 1226, 1097, 1022, 801,
695, 663 cm–1 1H NMR (400 MHz, CDCl3): δ = 1.16 (t, J =
.
7.2 Hz, 3 H), 2.50 (s, 3 H), 3.56 (q, J = 7.2 Hz, 2 H), 6.93 (dd, J =
7.2, 1.6 Hz, 1 H), 7.51 (t, J = 7.6 Hz, 2 H), 7.65 (d, J = 7.2 Hz, 1
H), 7.72 (s, 1 H), 7.82 (d, J = 8.0 Hz, 2 H), 9.52 (d, J = 7.6 Hz, 1
Ethyl 2-Ethyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-a]indolizine-9- H) ppm. 13C NMR (100 MHz, CDCl3): δ = 198.4, 163.8, 163.0,
carboxylate (4n): Yellow solid, m.p. 195–197 °C. IR (KBr): 1756,
140.4, 139.1, 132.8, 132.6, 129.4, 129.3, 128.2, 118.8, 117.2, 33.0,
2024
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Eur. J. Org. Chem. 2013, 2020–2026

Synthesis of Pyrrolo[3,4-a]indolizine-1,3-diones
21.5, 14.1 ppm. HRMS (ESI): calcd. for C20H16N2NaO3 355.1059; 7.6 Hz, 2 H), 7.54 (t, J = 7.6 Hz, 2 H), 7.67 (t, J = 7.6 Hz, 1 H),
found 355.1063.
7.78–7.86 (m, 3 H), 7.97 (d, J = 7.2 Hz, 2 H), 9.19 (d, J = 7.6 Hz,
1 H), 9.40 (dd, J = 7.6, 0.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 185.8, 180.4, 178.2, 142.8, 141.4, 138.5, 138.4, 130.7,
129.8, 129.2, 128.9, 128.5, 127.8, 127.0, 126.8, 125.4, 125.0, 124.5,
116.7, 112.3 ppm. HRMS (ESI): calcd. for C27H16N2NaO3 [M +
Na]+ 439.1059; found 439.1051.
4-Benzoyl-8-ethyl-2-phenyl-1H-pyrrolo[3,4-a]indolizine-1,3(2H)-
dione (4t): Yellow solid, m.p. 199–200 °C. IR (KBr): 1762, 1715,
1652, 1611, 1531, 1499, 1423, 1351, 1261, 1225, 1170, 1087, 1053,
879, 808, 730 cm–1. H NMR (400 MHz, CDCl3): δ = 1.29 (t, J =
1
7.6 Hz, 3 H), 2.75 (d, J = 7.6 Hz, 2 H), 6.95 (dd, J = 7.6, 1.5 Hz,
1 H), 7.25 (d, J = 8.4 Hz, 3 H), 7.34 (t, J = 7.6 Hz, 2 H), 7.40 (t,
J = 7.6 Hz, 2 H), 7.53 (t, J = 7.6 Hz, 1 H), 7.73 (s, 1 H), 7.79 (dd,
J = 8.0, 1.2 Hz, 2 H), 9.49 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 185.5, 162.8, 162.1, 146.7, 138.9, 133.2,
132.9, 132.3, 130.3, 129.6, 129.5, 129.4, 128.9, 128.8, 128.4, 128.3,
127.7, 127.0, 126.9, 118.2, 117.4, 116.1, 109.6, 28.6, 14.2 ppm.
HRMS (ESI): calcd. for C25H18N2NaO3 [M + Na]+ 417.1215;
found 417.1210.
Ethyl 9,11-Dioxo-10-phenyl-10,11-dihydro-9H-pyrrolo[3Ј,4Ј:3,4]-
pyrrolo[2,1-a]isoquinoline-8-carboxylate (6b): White solid, m.p. 247–
249 °C. IR (KBr): 1763, 1709, 1603, 1541, 1500, 1361, 1247, 1050,
1
809, 747, 674 cm–1. H NMR (400 MHz, CDCl3): δ = 1.52 (t, J =
7.2 Hz, 3 H), 4.51 (q, J = 7.2 Hz, 2 H), 7.29 (d, J = 7.6 Hz, 1 H),
7.41 (t, J = 7.2 Hz, 1 H), 7.46–7.52 (m, 4 H), 7.70–7.79 (m, 3 H),
9.29 (dd, J = 7.2, 1.6 Hz, 1 H), 9.37 (d, J = 7.6 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 163.0, 161.8, 160.0, 132.6, 131.6,
131.0, 130.4, 129.3, 129.1, 129.0, 127.9, 127.8, 127.4, 127.2, 126.7,
124.9, 123.9, 116.4, 112.6, 112.5, 61.7, 14.3 ppm. HRMS (ESI):
calcd. for C23H16N2NaO4 407.1008; found 407.1011.
Ethyl 8-Ethyl-1,3-dioxo-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-a]-
indolizine-4-carboxylate (4u): Yellow solid, m.p. 205–207 °C. IR
(KBr): 1762, 1709, 1541, 1500, 1359, 1248, 1215, 1167, 1116, 1049,
962, 810, 747, 682, 619 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.36 (t, J = 7.2 Hz, 3 H), 1.53 (t, J = 7.2 Hz, 3 H), 2.80 (q, J =
7.2, Hz, 2 H), 4.50 (q, J = 7.2 Hz, 2 H), 6.98 (d, J = 7.2 Hz, 1 H),
7.40–7.45 (m, 3 H), 7.50–7.54 (m, 2 H), 7.76 (s, 1 H), 9.54 (d, J =
7.2 Hz,1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1, 162.9,
160.2, 132.6, 129.0, 128.9, 128.8, 127.7, 127.2, 127.1, 126.2, 124.5,
121.1, 117.7, 116.1, 113.2, 61.4, 28.5, 14.3, 14.1 ppm. HRMS (ESI):
calcd. for C21H18N2NaO4 [M + Na]+ 385.1164; found 385.1168.
tert-Butyl 9,11-Dioxo-10-phenyl-10,11-dihydro-9H-pyrrolo[3Ј,4Ј:3,4-
]pyrrolo[2,1-a]isoquinoline-8-carboxylate (6c): White solid, m.p.
235–237 °C. IR (KBr): 1765, 1710, 1542, 1499, 1456, 1420, 1394,
1366, 1247, 1217, 1161, 1115, 1093, 1047, 963, 891, 841, 803, 733,
692, 652, 622 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.64 (s, 9 H),
7.34–7.47 (m, 6 H), 7.62–7.71 (m, 3 H), 9.23 (d, J = 7.6 Hz, 1 H),
9.30 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
163.2, 161.8, 159.4, 132.7, 131.3, 130.2, 129.2, 129.0, 128.9, 127.9,
127.5, 127.4, 127.3, 126.6, 125.0, 124.0, 116.1, 114.0, 112.4, 83.6,
28.4 ppm. HRMS (ESI): calcd. for C25H20N2NaO4 435.1321; found
435.1319.
Methyl 4-Benzoyl-1,3-dioxo-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-
a]indolizine-8-carboxylate (4v): Yellow solid, m.p. 229–230 °C. IR
(KBr): 1761, 1720, 1630, 1597, 1518, 1503, 1459, 1403, 1371, 1288,
1249, 1150, 1086, 976, 895, 749 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 4.03 (s, 3 H), 7.34 (t, J = 7.6 Hz, 3 H), 7.44 (t, J = 7.6 Hz, 2
H), 7.51 (t, J = 7.6 Hz, 2 H), 7.63–7.68 (m, 2 H), 7.89 (d, J =
8.0 Hz, 2 H), 8.71 (s, 1 H), 9.59 (d, J = 8.0 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 185.6, 164.5, 162.1, 161.6, 138.2,
133.5, 132.0, 130.9, 130.5, 129.6, 129.4, 129.2, 129.0, 128.9, 128.5,
127.9, 126.9, 121.0, 118.8, 115.3, 113.6, 53.1 ppm. HRMS (ESI):
calcd. for C25H16N2NaO5 [M + Na]+ 447.0957; found 447.0960.
8-Benzoyl-10-methylpyrrolo[3Ј,4Ј:3,4]pyrrolo[2,1-a]isoquinoline-
9,11-dione (6d): Yellow solid, m.p. 258–260 °C. IR (KBr): 1749,
1
1704, 1630, 1531, 1449, 1341, 1283, 1014, 941, 805 cm–1. H NMR
(400 MHz, CDCl3): δ = 3.01 (s, 3 H), 7.19 (s, 1 H), 7.46 (t, J =
7.6 Hz, 2 H), 7.60–7.70 (m, 4 H), 7.82 (dd, J = 8.0, 1.2 Hz, 2 H),
9.03 (d, J = 7.6 Hz, 1 H), 9.16 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 185.7, 164.0, 162.9, 138.7, 133.3, 131.8,
130.8, 130.5, 129.7, 129.0, 128.9, 128.4, 127.6, 126.6, 126.5, 125.3,
123.7, 119.2, 116.2, 113.1, 24.5 ppm. HRMS (ESI): calcd. for
C22H14N2NaO3 377.0902; found 377.0905.
4-Ethyl 8-Methyl 1,3-Dioxo-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-
a]indolizine-4,8-dicarboxylate (4w): Yellow solid, m.p. 212–214 °C.
IR (KBr): 1770, 1724, 1693, 1597, 1519, 1499, 1458, 1377, 1345,
1291, 1159, 1085, 1026, 895, 830, 753, 692, 617 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 1.50 (t, J = 7.2 Hz, 3 H), 4.00 (s, 3 H),
4.51 (q, J = 7.2 Hz, 2 H), 7.40–7.43 (m, 3 H), 7.51 (t, J = 8.0 Hz,
2 H), 7.62 (dd, J = 7.6, 2.0 Hz, 1 H), 8.64 (s, 1 H), 9.64 (d, J =
7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.5, 162.2,
161.6, 159.8, 132.2, 130.4, 130.2, 129.1, 128.8, 128.7, 128.1, 128.0,
127.1, 121.0, 114.9, 113.5, 111.9, 61.9, 53.0, 14.2 ppm. HRMS
(ESI): calcd. for C21H16N2NaO6 [M + Na]+ 415.0906; found
415.0912.
tert-Butyl 10-Methyl-9,11-dioxo-10,11-dihydro-9H-pyrrolo[3Ј,4Ј:
3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate (6e): White solid, m.p.
217–219 °C. IR (KBr): 1763, 1703, 1543, 1461, 1428, 1363, 1350,
1253, 1150, 1131, 979, 801 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.65 (s, 9 H), 3.12 (s, 3 H), 7.10 (d, J = 7.6 Hz, 1 H), 7.61–7.64 (m,
3 H), 9.11 (d, J = 8.0 Hz, 1 H), 9.19 (d, J = 7.6 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 164.1, 163.1, 159.3, 130.7, 130.0,
129.0, 128.8, 127.9, 127.2, 126.5, 124.9, 123.8, 115.6, 113.5, 112.7,
83.3, 28.4, 24.4 ppm. HRMS (ESI): calcd. for C20H18N2NaO4
373.1164; found 373.1169.
8-Benzoyl-10-ethylpyrrolo[3Ј,4Ј:3,4]pyrrolo[2,1-a]isoquinoline-
9,11-dione (6f): Yellow solid, m.p. 229–230 °C. IR (KBr): 1748,
1707, 1629, 1532, 1452, 1341, 1237, 1014, 941, 805, 748 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.14 (t, J = 7.2 Hz, 3 H), 3.58 (q, J
= 7.2 Hz, 2 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 2 H),
7.62–7.70 (m, 4 H), 7.84 (dd, J = 7.2, 1.2 Hz, 2 H), 9.06 (d, J =
7.6 Hz, 1 H), 9.20 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 185.8, 163.8, 162.7, 138.7, 133.3, 131.9, 130.5, 129.8,
129.0, 128.9, 128.4, 128.3, 127.6, 126.7, 125.4, 123.8, 119.2, 116.2,
113.3, 33.3, 14.1 ppm. HRMS (ESI): calcd. for C23H16N2NaO3
391.1059; found 391.1053.
General Procedure for the Preparation of Benzo[f]pyrrolo[3,4-a]-
indolizine-1,3-diones 6: Isoquinoline 5 (6.0 mmol), acyl bromide 2
(2.0 mmol), maleimide 3 (2.0 mmol), and hydrated copper(II)
chloride (0.6 mmol) were mixed in CH3CN (15 mL) and heated to
reflux for 24 h under an oxygen atmosphere. The reaction mixture
was then allowed to cool to room temperature. After evaporation
of the solvent under vacuum, the mixture was purified by column
chromatography on silica gel to afford pure product 6.
8-Benzoyl-10-phenylpyrrolo[3Ј,4Ј:3,4]pyrrolo[2,1-a]isoquinoline-
9,11-dione (6a): Yellow solid, m.p. 293–295 °C. IR (KBr): 1760,
1713, 1611, 1532, 1498, 1403, 1339, 1154, 1094, 803, 755, 695 cm–1. tert-Butyl 10-Ethyl-9,11-dioxo-10,11-dihydro-9H-pyrrolo[3Ј,4Ј:3,4]-
1H NMR (400 MHz, CDCl3): δ = 7.36–7.42 (m, 4 H), 7.47 (t, J =
pyrrolo[2,1-a]isoquinoline-8-carboxylate (6g): White solid, m.p. 183–
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Y. Liu, H.-Y. Hu, X.-B. Su, J.-W. Sun, C.-S. Cao, Y.-H. Shi
FULL PAPER
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Acknowledgments
The authors gratefully acknowledge the Research Funds of
Xuzhou City (XZZD1213), the Jiangsu Education Committee
(Qing Lan Project, grant numbers 08QLT001 and 08QLD006), the
Scientific Research Foundation (SRF) for the Returned Overseas
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the Priority Academic Program Development of Jiangsu Higher
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Foundation of China (NSFC) (grant numbers 21071121 and
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Received: November 7, 2012
Published Online: February 18, 2013
2026
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2020–2026