Synthesis of aza-fused polycyclic quinolines through copper-catalyzed cascade reactions

Article abstract of DOI:10.1021/ol1002225

Figure Presented A new and efficient method for the synthesis of aza-fused polycyclic qulnollnes (e.g., benzimidazo[1,2-a]quinolines) is described. This protocol includes an intermolecular condensation followed by a copper-catalyzed intramolecular C-N coupling reaction. The method is applied to a wide range of 2-iodo, 2-bromo, and 2-chloro aryl aldehyde substrates to yield the aza-fused polycyclic qulnollnes In good yields.

Full text of DOI:10.1021/ol1002225

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1500-1503
Synthesis of Aza-Fused Polycyclic
Quinolines through Copper-Catalyzed
Cascade Reactions
Qian Cai,*,† Zhengqiu Li,‡ Jiajia Wei,† Liangbin Fu,† Chengyong Ha,‡
Duanqing Pei,† and Ke Ding*,†
Key Laboratory of RegeneratiVe Biology and Institute of Chemical Biology,
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No.
190, Kaiyuan AVenue, Science Park, Guangzhou, China, 510530 and Key Laboratory
of Cellulose and Lignocellulosics Chemistry, Guangzhou Institute of Chemistry,
Chinese Academy of Sciences
cai_qian@gibh.ac.cn; ding_ke@gibh.ac.cn
Received January 28, 2010
ABSTRACT
A new and efficient method for the synthesis of aza-fused polycyclic quinolines (e.g., benzimidazo[1,2-a]quinolines) is described. This
protocol includes an intermolecular condensation followed by a copper-catalyzed intramolecular C-N coupling reaction. The method
is applied to a wide range of 2-iodo, 2-bromo, and 2-chloro aryl aldehyde substrates to yield the aza-fused polycyclic quinolines in good
yields.
Subsituted quinolines represent a class of important
compounds that display a broad spectrum of biological
functions.1,2 They are also versatile as dyestuffs and
photographic sensitizers.3 However, the biological investiga-
tions on benzimidazo[1,2-a]quinolines, imidazo[1,2-a]quino-
lines, or other aza-fused polycyclic quinolines are rare, which
might be due to the lack of general methods for the synthesis
of these compounds.4 Traditional synthetic methods for aza-
fused quinolines included thermal or acid-catalyzed cycliza-
tion,5 photochemical dehydrocyclization,4,6 superelectrophilic
cylications,7 and other approaches.8,9 However, most of these
methods suffer from low yields and/or poor precursor scopes.
† Guangzhou Institutes of Biomedicine and Health.
‡ Guangzhou Institute of Chemistry.
(1) (a) Chauhan, P. M. S.; Srivastava, S. K. Curr. Med. Chem. 2001, 8,
1535. (b) Chen, Y.-L.; Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C.
J. Med. Chem. 2001, 44, 2374. (c) Roma, G.; Braccio, M. D.; Grossi, G.;
Mattioli, F.; Ghia, M. Eur. J. Med. Chem. 2000, 35, 1021. (d) Ferraini,
P. L.; Mori, C.; Badawneh, M.; Calderone, V.; Greco, R.; Manera, C.;
Martinelli, A.; Nieri, P.; Saccomanni, G. Eur. J. Med. Chem. 2000, 35,
815. (e) Maguire, M. P.; Sheets, K. R.; Mcvety, K.; Spada, A. P.; Zilberstein,
A. J. Med. Chem. 1994, 37, 2129. (f) Balasubramanian, M.; Keay, J. G. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon: New York, NY, 1996; Vol. 5, p 245.
ˇ
(4) Hranjec, M.; Kralj, M.; Piantanida, I.; Sedic´, M.; Suman, L.; Pavelic´,
K.; Karminski-Zamola, G. J. Med. Chem. 2007, 50, 5696.
(5) (a) Benincori, T.; Sannicolo`, F. J. Heterocycl. Chem. 1988, 25, 1029.
(b) Guenther, D. U.S. Patent 4,219, 651, 1980. (c) Roberts, E. M.; Gates,
M.; Boekelheide, V. J. Org. Chem. 1955, 20, 1443.
(6) (a) Hranjec, M.; Karminskin-Zamola, G. Molecules 2007, 12, 1817.
(b) Cooper, G.; Irwin, W. J. J. Chem. Soc., Perkin Trans. 1 1975, 75
.
(7) Li, A.; Gilbert, T. M.; Klumpp, D. A. J. Org. Chem. 2008, 73, 3654.
(8) van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron
(2) Antibiotics II, Biosynthesis; Gottlieb, D., Shaw, P. D., Eds; Springer:
Lett. 1980, 21, 3723.
New York, NY, 1967; Vol. 2, p 105
(3) Noverty, J.; Collins, C. H.; Starts, F. W. J. Pharm. Sci. 1974, 63,
1264.
.
(9) For reviews, see: (a) Abass, M. Heterocycles 2005, 65, 901. (b)
Kouznetsov, V. V.; Mendez, L. Y. V.; Gomez, C. M. M. Curr. Org. Chem.
2005, 9, 141
.
10.1021/ol1002225  2010 American Chemical Society
Published on Web 03/02/2010

Recently, coupling reactions catalyzed by transition metals,
such as Pd and Pt, have been successfully applied to the
preparation of this important class of heterocyclic com-
pounds.10
product 1 was obtained with 17% yield under the catalysis
of 10 mol % CuI at room temperature using K2CO3 as
the necessary base (Table 1, entry 1), indicating that
copper catalyst was essential for this cascade reaction.
Further investigation revealed that the well-known sup-
porting ligands such as quinolin-8-ol, picolinic acid, or
L-proline could significantly improve the reaction ef-
feciency (Table 1, entries 2-4). When 20 mol % of
L-proline was utilized, about 90% of the desired product
was isolated after the reaction was performed at room
temperature for 8 h. The following condition screening
suggested that most of the common inorganic bases such
as K2CO3, Cs2CO3, or K3PO4 were highly efficient for this
cascade reaction (Table 1, entries 4-7). Investigation on
the reaction medium revealed that DMSO was the optimal
solvent for this new reaction. When other solvents (DMF
or dioxane) were utilized, obviously lower yields were
obtained (Table 1, entries 8 and 9). It was also noteworthy
that nonpolar solvent such as toluene was highly detri-
mental to this reaction (Table 1, entry 10). The optimal
conditions of 10 mol % CuI, 20 mol % L-proline, and
200 mol % inexpensive K2CO3 in DMSO at room
temperature were used for further investigation.
Copper-catalyzed Ullmann-type coupling reactions11 have
been extensively explored and widely used in the synthesis
of diversified aromatic compounds, such as indole, ben-
zoimidazole, etc.12 In this paper, we would like to report a
simple and efficient synthesis of benzimidazol[1,2-a] or other
aza-fused polycyclic quinolines through a copper-catalyzed
cascade reaction under mild conditions.
The study was initiated by investigating the potential
reaction of 2-iodobenzene aldehyde with 2-(1H-ben-
zo[d]imidazole-2-yl)acetonitrile to form benzimidazolol[1,
2-a]quinoline 1 (Table 1). Although no desired product
Table 1. Synthesis of Benzimidazolol[1,2,a]quinoline through
Copper-Catalyzed Cascade Reactiona
Under the optimized conditions, the scope of this new
protocol was further explored by using the combinations
of 2-(1H-benzo[d]imidazole-2-yl) acetonitrile with a va-
riety of 2-iodo aryl aldehydes. As shown in Table 2,
almost all of the tested combinations successfully produced
the desired benzimidazolol[1,2-a]quinolines with good or
excellent isolated yields. The results also suggested that
the electronic density of the corresponding 2-iodo aryl
aldehydes might have some influences on the copper-
catalyzed cascade processess. Electron-deficient substrates
were more favorite than that with electron-rich groups to
deliver the corresponding products at room temperature
(Table 2, entries 1-7). However, significantly improved
results could be achieved for electron-rich 2-iodobenzal-
dehydes by slightly increasing the reaction temperature
to 50 °C (Table 2, entries 1-3). For instance, only a 52%
desired product was isolated wthen 5-hydroxy-2-iodoben-
zaldehyde reacted with 2-(1H-benzo[d]imidazol-2-yl)ac-
etonitrile at room temperature, but the yield was obviously
improved to 75% when the reaction was performed at 50
°C (Table 2, entry3). The reaction was also well tolerated
with a variety of functionized groups such as ester,
nitro, nitrile, alkyl, hydroxyl, halides, and trifluoromethyl
goups.
entry
ligandb
base
solvent
yield (%)c
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
NaOH
Cs2CO3
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
17
60
62
91
87
62
92
76
55
n.d.d
A
B
C
C
C
C
C
C
C
Dioxne
Toluene
10
a Reaction conditions: benzimidazole substrate (1.0 mmol), 2-iodoben-
zene aldehyde (1.0 mmol), CuI (0.1 mmol), ligand (0.2 mmol), base (2.0
mmol), solvent (1.0 mL), rt. b Ligand A, quinolin-8-ol; B, picolinic acid;
C: L-proline. c Isolated yields. d No desired product.
was detected in the absence of copper salts, we were
pleased to find that the benzimidazolol[1,2-a]quinoline
(10) (a) Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054. (b)
Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761. (c) Mamane, V.;
Hannen, P.; Fu¨rstner, A. Chem.sEur. J. 2004, 10, 4556. (d) Fu¨rstner, A.;
Mamane, V. J. Org. Chem. 2002, 67, 6264. (e) Venkatesh, C.; Sundaram,
G. S. M.; Ila, H.; Junjappa, H. J. Org. Chem. 2006, 71, 1280.
(11) For recent reviews about copper-catalysed Ullmann-type coupling
reactions, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004,
248, 2337. (c) Lindley, J. Tetrahedron 1984, 40, 1433. (d) Evano, G.;
Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108, 3054. (e) Monnier, F.;
Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954.
It was noteworthy that less reactive 2-bromobenzalde-
hydes could successfully react with the 2-(1H-ben-
zo[d]imidazole-2-yl) acetonitriles to produce the desired
benzimidazolol[1,2-a]quinolines with good yields when
the temperature was elevated to 80 °C for 4-6 h (Table
2, entries 8-13). In addition, the protocol also worked
well for the heteroaromatic bromide substrates (Table 2,
entries 13-15). Aryl chlorides are highly challenging
substrates for most Ullmann-type coupling reactions.11 We
also wished to investigate if our new protocol worked well
for o-chlorobenzaldehyde substrates. Although only a trace
(12) For some recent studies on the syntheses of N-heterocycles by
using copper-mediated couplings, see: (a) Ma, D.; Geng, Q.; Zhang, H.;
Jiang, Y. Angew.Chem. Int. Ed. 2010, 49, 1. (b) Cai, Q.; Li, Z.; Wei, J.;
Ha, C.; Pei, D.; Ding, K. Chem. Commun. 2009, 7581. (c) Liu, X.; Fu, H.;
Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 348. (d) Hirano, K.;
Biju, A. T.; Glorius, F. J. Org. Chem. 2009, 74, 9570. (e) Zou, B.; Yuan,
Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598. (f) Yuan, X.; Xu, X.;
Zhou, X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007, 72, 1510. (g) F.
Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2006, 8, 4351. (h)
Martin, R.; Rodriguez, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006,
45, 7079. (i) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802.
Org. Lett., Vol. 12, No. 7, 2010
1501

Table 2. Investigation on the Scope of o-Halogenated Aryl Aldehydes for the Formation of Benzimidazolol[1,2-a]quinolinesa
a Reaction conditions: for aryl iodides, rt, 6-8 h; for aryl bromides, 80 °C, 4-6 h; for aryl chlorides, 110 °C, 6-8 h. b Isolated yields. c Performed at
50 °C.
amount of the desired product was detected when 2-chlo-
robenzaldehyde reacted with 2-(1H-benzo[d]imidazole-2-
yl) acetonitrile at room temperature, the yield was
significantly improved to 62% when the reacting temper-
ature was elevated to 110 °C for 6 h (Table 2, entry 16).
The reactions were also performed well for two other 2-
chlorobenzene aldehyde substrates (Table 2, entries 17 and
18).
The scope of the heterocyclic substrates were also
explored, and the results are summarized in Table 3.
Almost all of the benzimidazoles or imidazoles bearing
electron-withdrawing groups were able to react with the
corresponding 2-halogenerated aryl aldehydes to offer the
desired products with good or moderate yields (Table 3,
entries 1-10). Other heterocyclic moieties such as sub-
stituted pyrroles were obviously less active and only about
1502
Org. Lett., Vol. 12, No. 7, 2010

25-30% yields were obtained under the similar conditions
(Table 3, entries 1-10). No obvious improvement was
obtained when the reaction was performed at 80 °C for
24 h. This might be due to the fact that the CH2 groups in
pyrrolic substrates were less nucleophilically active than
those in the benzimidazole or imidazole substrates. Our
results also revealed that many electron-withdrawing
groups such as -CO2Et, -SO2Ph, CN, or -COAr groups
were sufficiently activating groups for substituted benz-
imidazoles and imidazoles in the copper-catalyzed cascade
reaction.
Table 3. Investigation on the Scope of the Heterocyclic
Substratesa
In summary, a simple and efficient method for the
synthesis of benzimidazo[1,2-a]quinolines and other aza-
fused polycyclic quinolines through a copper-catalyzed
cascade reaction was described. The protocol worked well
for almost all of the 2-iodo, 2-bromo, and 2-chloro aryl
aldehydes and diplayed great functional group compatibility.
Our study provided a general way for the synthesis of
benzimidazo[1,2-a]quinolines or other aza-fused quinolines
from easily accessible starting materials and should find great
applications in the future.
Acknowledgment. We thank the Knowledge Innovation
Program of the Chinese Academy of Sciences, the 100-talent
program of CAS, National Natural Science Foundation
(Grant 90813033), and National Basic Research Program of
China (Grants 2010CB529706, 2009CB940904) for their
financial support.
Supporting Information Available: Experiment proce-
dures. This material is available free of charge via the Internet
at http://pubs.acs.org.
a Reaction conditions: K2CO3, DMSO, rt, 8 h. b Isolated yields. c 80
°C. d 110 °C. e 50 °C. f Cs2CO3 as base.
OL1002225
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