Cerium(iii)-catalyzed cascade cyclization: An efficient approach to functionalized pyrrolo[1,2-a]quinolines

Article abstract of DOI:10.1039/c4ob00708e

A general and practical route to the synthesis of multisubstituted pyrrolo[1,2-a]quinolines has been described from 2-alkylazaarenes and nitroolefins using cerium chloride as a catalyst via a tandem Michael addition, cyclization and aromatization. This protocol features readily available starting materials, operational simplicity and high regioselectivity to access multifunctionalized pyrrolo[1,2-a]quinolines with the formation of multiple C-C and C-N bonds in one pot. In addition, various substitution patterns and functional groups were found to be compatible under the optimized conditions, which was lacking in the existing procedures. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00708e

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Cerium(III)-catalyzed cascade cyclization:
an efficient approach to functionalized
pyrrolo[1,2-a]quinolines†
Cite this: DOI: 10.1039/c4ob00708e
Received 3rd April 2014,
Accepted 19th May 2014
Chengtao Feng, Yizhe Yan, Zhenglei Zhang, Kun Xu and Zhiyong Wang*
DOI: 10.1039/c4ob00708e
www.rsc.org/obc
A general and practical route to the synthesis of multisubstituted copper-catalyzed [3 + 2] cyclization of quinolines with alkenyl-
pyrrolo[1,2-a]quinolines has been described from 2-alkylazaarenes diazoacetates (C),7 or copper-catalyzed annulation of 2-alkyl-
and nitroolefins using cerium chloride as a catalyst via a tandem azaarenes with α,β-unsaturated carboxylic acids (D).8 Besides,
Michael addition, cyclization and aromatization. This protocol fea- a multicomponent approach for the synthesis of pyrrolo[1,2-a]-
tures readily available starting materials, operational simplicity and quinoline derivatives was also reported.9 Despite the great suc-
high regioselectivity to access multifunctionalized pyrrolo[1,2-a]- cesses achieved in this field, these methods still suffer from
quinolines with the formation of multiple C–C and C–N bonds in some limitations, such as harsh reaction conditions, limited
one pot. In addition, various substitution patterns and functional substrate scope and substitution pattern, and involvement of
groups were found to be compatible under the optimized con- multistage synthesis. Recently, a comprehensive structure–
ditions, which was lacking in the existing procedures.
activity relationship (SAR) study in drug design has raised a
growing demand for a variation in the substitution patterns of
this type of target molecule. Therefore, developing more practi-
cal synthetic approaches to pyrrolo[1,2-a]quinolines with a
variety of substitution patterns is highly desirable.
A domino reaction is a consecutive series of intramolecular
or intermolecular organic reactions. It allows the organic syn-
thesis of complex multinuclear molecules from acyclic precur-
sors.10 The benzylic C–H bond of 2-alkylazaarenes has been
functionalized with a variety of unsaturated bonds by various
groups including our own.11,12d Among these reports, only
acyclic compounds were formed. If a suitable substrate com-
bined with a suitable catalyst were chosen, subsequent amin-
ation process could provide a fused heterocycle. The domino
reaction is a more attractive strategy to construct polycyclic
nitrogen heterocycles. Until recently, very few reports have
appeared on this method (D).8,12a
The chemistry of fused nitrogen heterocycles is of great impor-
tance due to their wide applications.1 Among these com-
pounds, the pyrrolo[1,2-a]quinoline derivatives raised special
interest because of their potential biological activity2 and
physical properties.3 Moreover, the skeleton of pyrrolo[1,2-a]-
quinoline exists in gephyrotoxin, a natural alkaloid which was
subjected to numerous studies to investigate its biological
activity.4 However, only a few relevant synthetic methodologies
have been reported (Scheme 1), which mainly rely on 1,3-
dipolar cycloaddition of quinolinium N-ylides with electron-
deficient alkynes or alkenes (A),5 or transition metal-catalyzed
intramolecular cycloisomerizations of pyrroles with specific
C-2 functionalization (B).6 Recently published reports involve
Our group have reported a series of domino processes for
the synthesis of heterocyclic compounds with the formation of
multiple C–C and C–hetero bonds in one pot.12 As a continu-
ation of our effort on these domino processes, herein we
report a general and practical domino reaction to access multi-
functionalized pyrrolo[1,2-a]quinolines from readily available
2-alkylazaarenes with active methylene and nitroolefins using
cerium(III) chloride as the catalyst under mild conditions.
Initially, trans-(Z)nitrostyrene (2a) and ethyl 2-(quinolin-
2-yl)acetate (1a) were employed as model substrates to optimize
the reaction conditions. Stirring a mixture of ethyl 2-(quinolin-
2-yl)acetate 1a (1.5 equiv.), trans-(Z)nitrostyrene 2a (1.0 equiv.),
and TsOH·H2O (10 mol%) in EtOH at room temperature
Scheme 1 Disconnection approaches to the pyrrolo[1,2-a]quinoline
core.
Hefei National Laboratory for Physical Science at Microscale, CAS Key Laboratory of
Soft Matter Chemistry & Collaborative Innovation Center of Suzhou Nano Science
and Technology, University of Science and Technology of China, Hefei, Anhui
230026, P. R. China. E-mail: zwang3@ustc.edu.cn
†Electronic supplementary information (ESI) available: Experimental procedures
and NMR data. See DOI: 10.1039/c4ob00708e
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Table 1 Optimization of the reaction conditionsa
Table 2 Synthesis of pyrrolo[1,2-a]quinolinesa
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
TsOH·H2O
I2
MgCl2·6H2O
NiCl2·6H2O
AlCl3·6H2O
ZrCl4
FeCl3·6H2O
CoCl2·6H2O
CuCl2·2H2O
CeCl3·7H2O
Ce(NO3)3·6H2O
Ce(SO4)2·4H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
EtOAc
Toluene
DMSO
DMF
CH3CN
EtOH
65
57
61
75
69
82
73
81
62
88
76
52
38
43
20
55
46
50
70
9
10
11
12
13
14
15
16
17
18
19c
a Reaction conditions: 1a (0.25 mmol), 2a (0.20 mmol), catalyst
(0.02 mmol), solvent (2 mL), room temperature, 24 h. b Isolated yield.
c The reaction was at 80 °C.
afforded pyrrolo[1,2-a]quinoline (3a) in 65% isolated yield
(Table 1, entry 1). The use of iodine as a catalyst did not
improve the yield (Table 1, entry 2). Then various metal Lewis
acids were employed as potential catalysts for this transform-
ation. The results showed that when CeCl3·7H2O was used as
the catalyst, the reaction gave the corresponding product with
the highest yield (88%, Table 1, entry 10). In view of its excel-
lent catalytic performance, outstanding stability and low toxi-
city, CeCl3·7H2O was chosen as the most effective catalyst for
the domino reaction. On the other hand, the solvent also
played a crucial role in the reaction. Among various solvents
examined, ethanol was found to be optimal. Other solvents
reduced the yield of this reaction (Table 1, entries 13–18).
Subsequently, we raised the temperature to 80 °C. However,
the yield decreased to 70% because of unknown side reactions
(Table 1, entry 19).
With the optimal conditions in hand, the substrate scope of
the reaction was extended. First of all, the substrate scope of
nitroolefin 2 was screened. As illustrated in Table 2, aromatic
nitroalkenes with both electron-rich (4-Me, 4-OMe, 4-NMe2)
and electron-deficient (CF3) substituents on the aromatic ring
participated in this reaction smoothly to afford the expected
products in good to excellent yields. Generally, an electron-
donating substituent on the aromatic ring has a positive effect
on the yield. When R1 was replaced by a 2-chlorophenyl group,
the reaction gave a lower yield in comparison with the corres-
ponding compound where R1 was a 4-chlorophenyl group
a Standard reaction conditions:
CeCl3·7H2O (0.02 mmol), 2 mL EtOH, room temperature, 24 h,
isolated yield. b The reaction was performed at 40 °C under ultrasound
for 3 h.
1 (0.25 mmol), 2 (0.20 mmol),
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(Table 2, entries 3i, 3k). This implied that steric effects had an
influence on the reaction. An unprotected phenol moiety was
also well tolerated under the reaction conditions, and 3d was
obtained in 90% yield. Pleasingly, the reaction of ring-fused
(2m), heterocyclic (2n and 2o), styryl (2p) and phenylethynyl
(2q) nitroalkenes also afforded the corresponding products in
good yields (Table 2, entries 3m–3q). When R1 was replaced by
an aliphatic group, the use of ultrasound was necessary to
obtain good yields in the reaction (3r and 3s). Notably, when a
disubstituted nitroalkene was employed as the substrate, the
reaction also proceeded smoothly to provide the trisubstituted
product 3t in 56% yield.
Scheme 3 Plausible reaction mechanism.
Subsequently, different quinoline derivatives 1 were investi-
gated. Both electron-withdrawing and electron-donating sub-
stituents on the aromatic ring were tolerated in this reaction.
An electron-rich group on the aromatic ring was unfavorable
for the formation of pyrrolo[1,2-a]quinolines, while electron-
deficient substituents increased the reaction yields (Table 2,
3u–3x). Additionally, when R4 was a phenyl group, the product
3y was obtained in 82% yield.
considering the above features, we believe that this one-pot
catalytic transformation is an attractive approach for the syn-
thesis of pyrrolo[1,2-a]quinoline derivatives.
We are grateful to the National Nature Science Foundation
of China (2127222, 91213303, 21172205, J1030412).
Presumably, this process involves Michael addition of
2-alkyl-quinolines to α,β-unsaturated nitroalkenes followed by
cyclization, thereby leading to the final product. We were able
to isolate the intermediate 4a from the reaction of ethyl 2-(qui-
nolin-2-yl)acetate 1a and trans-(Z)nitrostyrene 2a. It is note-
worthy that the Michael adduct 4a gave the final product 3a in
excellent yield in the presence of CeCl3·7H2O in EtOH, as
shown in Scheme 2. However, only traces of the product 3a
were observed in the absence of catalyst under similar reaction
conditions. Therefore, CeCl3·7H2O plays an essential role to
enhance the rate of this transformation.
A plausible reaction mechanism is suggested on the basis
of these preliminary data and literature precedents
(Scheme 3).13 The first step of the reaction is the Michael
addition of 2-alkyl-quinoline I with nitroolefin II to form the
intermediate III. Ce(III) chloride may accelerate the reaction by
increasing the electrophilicity of the nitroolefin through
coordination. Subsequently, the intermediate III is converted
into intermediate IV by a Ce(III)-catalyzed intramolecular cycli-
zation. Finally, the intermediate IV eliminates a water mole-
cule and a nitroxyl (HNO) group to form the final product V.14
In summary, we have developed a facile domino cyclization
to construct pyrrolo[1,2-a]quinoline derivatives from α,β-un-
saturated nitroalkenes with 2-alkyl-quinolines catalyzed
by cerium chloride. Compared to previous reports, the
present method has the advantages of general applicability,
simple operation, mild conditions and good yields. Therefore,
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