Novel strategy for synthesis of substituted benzimidazo[1,2-a]quinolines

Article abstract of DOI:10.1021/ol4017723

An efficient method for the synthesis of benzimidazo[1,2-a]quinolines under transition-metal-free conditions has been developed through a cascade reaction involving sequential aromatic nucleophilic substitution and intramolecular Knoevenagel condensation reactions. This method is applicable for the synthesis of a wide range of benzimidazo[1,2-a]quinoline derivatives from readily available 2-fluoroarylaldehyde and benzimidazole substrates.

Full text of DOI:10.1021/ol4017723

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Novel Strategy for Synthesis of
Substituted Benzimidazo[1,2‑a]quinolines
Jun-ya Kato, Yutaro Ito, Ryosuke Ijuin, Hiroshi Aoyama, and Tsutomu Yokomatsu*
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1
Horinouchi, Hachioji, Tokyo 192-0392, Japan
yokomatu@toyaku.ac.jp
Received June 23, 2013
ABSTRACT
An efficient method for the synthesis of benzimidazo[1,2-a]quinolines under transition-metal-free conditions has been developed through a cascade
reaction involving sequential aromatic nucleophilic substitution and intramolecular Knoevenagel condensation reactions. This method is applicable
for the synthesis of a wide range of benzimidazo[1,2-a]quinoline derivatives from readily available 2-fluoroarylaldehyde and benzimidazole
substrates.
Fused benzimidazoles represent a class of important
compounds that display a broad spectrum of bio-
logical functions.1 Among fused benzimidazoles, some
benzimidazo[1,2-a]quinolines have been recently reported
to show powerful activity of DNA-intercalation as well as the
inhibition of topoisomerase II activity.2 To discover biologi-
cally more active compounds, the structureÀactivity rela-
tionships of substituted benzimidazo[1,2-a]quinolines having
a variety of substituents at a varied position of the hetero-
cycle are required. However, such a study has not been
intensively examined, which might be due to the lack of
facile and general methods for the synthesis of substituted
benzimidazo[1,2-a]quinoline derivatives.
Substituted benzimidazo[1,2-a]quinolinesaremostcom-
monly synthesized by inconvenient multistep methods,2À8
and these literature methods do not meet the demands in
the study of structureÀactivity relationships.
In recent efforts to develop more facile methods for
the synthesis of substituted benzimidazo[1,2-a]quinolines,
a cascade reaction involving sequential intermolecular
Knoevenagel condensation and Cu-catalyzed intramole-
cular CÀN coupling has been developed (Scheme 1).9
However, a direct-activating group such as NCÀ should
be incorporated into the R-position to the reacting methy-
lene to induce the intermolecular Knoevenagel condensa-
tion effectively.
In our study directed on the development for novel
synthetic methods of fused aza-heterocycles, we have
reported a conceptually new cascade reaction for the syn-
thesisof pyrazolo[1,5-a]quinolines.10 Thiscascade reaction
involves sequential intermolecular aromatic nucleophilic
substitution (SNAr) and intramolecular Knoevenagel con-
densation. Remarkable features of the SNAr/Knoevenagel
(1) Bansal, Y.; Silakari, O. Bioorg. Med. Chem. 2012, 20, 6208 and
references cited therein.
(2) (a) Sedic, M.; Poznic, M.; Gehring, P.; Scott, M.; Schlapbach, R.;
Hranjec, M.; Karminski-Zamola, G.; Pavelic, K.; Pavelic, S. K. Mol.
Cancer Ther. 2008, 7, 2121. (b) Hranjec, M.; Kralj, M.; Piantanida, I.;
Sedic, M.; Suman, L.; Pavelic, K.; Karminski-Zamola, G. J. Med. Chem.
2007, 50, 5696. (c) Hranjec, M.; Lucic, B.; Ratkaj, I.; Pavelic, S. K.;
Piantanida, I.; Pavelic, K.; Karminski-Zamola, G. Eur. J. Med. Chem.
2011, 46, 2748. (d) Perin, N.; Uzelac, L.; Piantanida, I.; Karminski-
Zamola, G.; Kralj, M.; Hranjec, M. Bioorg. Med. Chem. 2011, 19, 6329.
(3) Morgan, G.; Stewart, J. J. Chem. Soc. 1938, 1292.
(4) Benincori, T.; Sannicolo, F. J. Heterocycl. Chem. 1988, 25, 1029.
(5) (a) Shenoy, V. U.; Seshadri, S. Dyes Pigm. 1989, 11, 137. (b)
Khilya, O. V.; Volovenko, Y. M. Chem. Heterocycl. Compd. 2004, 40,
1063.
(8) (a) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am.
Chem. Soc. 2010, 132, 13217. (b) Masters, K.-S.; Rauws, T. R. M.;
Yadav, A. K.; Herrebout, W. A.; Van der Veken, B. Chem.;Eur. J.
2011, 17, 6315.
(9) (a) Cai, Q.; Li, Z.; Wei, J.; Fu, L.; Ha, C.; Pei, D.; Ding, K. Org.
Lett. 2010, 12, 1500. (b) Zhou, B.-W.; Gao, J.-R.; Jiang, D.; Jia, J.-H.;
Yang, Z.-P.; Jin, H.-W. Synthesis 2010, 2794.
(6) Hranjec, M.; Karminski-Zamola, G. Molecules 2007, 12, 1817.
(7) Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Junjappa, H. J. Org.
Chem. 2006, 71, 1280.
(10) Kato, J.; Aoyama, H.; Yokomatsu, T. Org. Biomol. Chem. 2013,
11, 1171.
r
10.1021/ol4017723
XXXX American Chemical Society

cyclization cascade reaction are that a direct-activating
group such as NCÀ is not necessary for the Knoevenagel
condensation and transition-metal-free conditions are
available for the SNAr reaction. In continuous research
to develop facile and general methods for the synthesis of
fused aza-heterocycles, we applied the SNAr/Knoevenagel
cyclization cascade reaction to the synthesis of benzimidazo-
[1,2-a]quinolines and the related heterocycles. In this paper
we describe the simple and efficient synthesis of benzimidazo-
[1,2-a]quinolines using our cascade reaction.
cascade reaction were determined to be as conducted with
300 mol % of Cs2CO3 in DMF at 120 °C.
When the reaction was carried out at 0.5 h for the
conditions of entry 2, 3aa was isolated in a 19% yield
along with trace amounts of 4aa (entry 14 and Scheme 1).
The obtained 3aa was resubmitted to the same conditions
of entry 4 to give 4aa in a 68% yield. These experiments
show that the proposed cascade reaction works well. To the
best of our knowledge, the present cascade reaction is the
first example in which the methyl group of the 2-methyl-1H-
benzimidazoles participates in the Knoevenagel cyclization
upon arylation at the nitrogen of the 2-methyl-1H-benzi-
midazoles through the SNAr substitution.
Scheme 1. Strategies for Synthesis of Benzimidazo-
[1,2-a]quinolines through Cascade Reactions
Table 1. Optimization of the SNAr/Knoevenagel Cyclization
Cascade Reactiona
temp
time
(h)
yieldb
(%)
entry
base
solvent
(°C)
1
K2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
dioxane
toluene
DMF
DMF
DMF
DMF
120
120
120
120
120
120
120
120
reflux
reflux
140
100
80
16
1
56
First, we examined the SNAr/Knoevenagel cyclization
cascade reaction utilizing 1a and 2a as model substrates
to optimize the reaction conditions (Table 1). When the
reaction was conducted in DMF in the presence of K2CO3
for 16 h at 120 °C, the optimized conditions for synthesis of
the pyrazolo[1,5-a]quinolines as reported in a previous
paper,10 the desired benzimidazo[1,2-a]quinoline 4aa was
obtained as expected in a 56% yield (entry 1). This reaction
seemed to proceed rather slowly as only a small amount of
product was obtained upon terminating the reaction with-
in 1 h (entry 2). The reaction rate slightly accelerated upon
using K3PO4 instead of K2CO3 (entry 2 vs 3). We were
pleased to find that the reaction rate significantly acceler-
2
12
3
1
38
4
16
1
83
5
86
6
1
nrc
trace
70
7
DBU
1
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
1
9
1
trace
trace
78
10
11
12
13
14
1
1
2
73
4
41
traced
120
0.5
a All reactions were carried out in the presence of 1a (1.0 mmol),
2-fluorobenzaldehyde 2a (1.2 mmol), and base (3.0 mmol) in the indicated
solvent (5 mL). b Isolated yield. c No reaction. d The intermediate 3aa was
isolated in a 19% yield.
11
ated upon using Cs2CO3 as a base instead of K2CO3
and comparable high yields (83À86%) were obtained
when reactions were conducted for 16 and 1 h, respectively
(entries 4 and 5). Further condition screening suggested
that most of the common organic bases were highly
detrimental to this reaction (entries 6 and 7). The choice
ofsolvent isalsocriticalfor thiscascade reaction. Whenthe
reaction was carried out in the presence of Cs2CO3 at
reflux, upon switching the solvents from DMF to dioxane
or toluene, trace amounts of desired product 4aa were
detected (entries 9 and 10). On the other hand, DMSO
was found to also be an efficient solvent to give 4aa in
a comparative yield (entry 8). The cascade reaction was
highly affected by the reaction temperature; the yield
significantly decreased when the reaction was conducted
above or below 120 °C (entry 5 vs entries 11À13). Based on
these results, at this stage, the optimal conditions for the
Next, we explored the scope with respect to 2-fluoro-
benzaldehydes (Table 2). This survey revealed that a range
of 2-fluorobenzaldehydes bearing an electron-donating
group such as CH3À and CH3OÀ are good substrates
for the cascade reaction under the optimized conditions
(Cs2CO3, DMF, 120 °C) to give benzimidazo[1,2-
a]quinolines 4ahÀ4am in good to excellent yields (entries
8À13). However, 2-fluorobenzaldehydes bearing an elec-
tron-withdrawing group such as FÀ, BrÀ, CF3À, and
NCÀ are found to be surprisingly poor substrates, and
desired products 4abÀ4ae and 4ag were obtained with low
yields under the conditions (entries 2À5, 7). These low yields
resulted from the formation of significant amounts of
unidentified byproducts. Upon switching the solvent and
base to DMSO and K2CO3, respectively, these low yields
significantly improved to moderate yields (entries 2À5).
(11) Recently, Cs2CO3 was reported to be a better base than K2CO3
in an SNAr reaction of unactivated 2-fluorobenzenes with 1H-benzimi-
dazoles: Diness, F.; Fairlie, P. D. Angew. Chem., Int. Ed. 2012, 51, 8012.
B
Org. Lett., Vol. XX, No. XX, XXXX

in Table 3, almost all of the tested combinations success-
fully produced the desired benzimidazo[1,2-a]quinolines
4aaÀ4ka with moderate to good isolated yields. Although
2,5-dimethyl-1H-benzimidazole (1b) reacted with 2a to
give an inseparable regioisomeric mixture of 4ba in a
modest yield (entry 2), the reaction with unsymmetrical
2-methyl-1H-benzimidazoles having a substituent at the
4-position, such as 1e, 1f, and 1g, selectively produced 4ea,
4fa, and 4ga in good yields (entries 5À7). The structure of
4ga was confirmed by X-ray crystallographic analysis (see
Supporting Information). Selective formation of 4da, 4ea,
and 4fa may have arisen when the SNAr reaction regiose-
lectively occurred at the nitrogen opposite to the substituent
to avoid the steric hindrance. It is noteworthy that 2-methyl-
1H-benzimidazole derivatives 1h, 1i, 1j, and 1k having an
electron-donating group, such as CH3À, CH3OÀ, CH3SÀ,
and the 4-molpholinyl moiety, at the 2-methyl group,
reacted with 2a to give 4ha, 4ia, 4ja, and 4ka in good yields
(entries 8À11). Since these compounds have not been
synthesized by methods in the literature,9 our method is
complementary to the classical methods to synthesize a
variety of substituted benzimidazo[1,2-a]quinolines.
In an effort to apply the present cascade reaction to the
synthesis of heterocycles related to benzimidazo[1,2-
a]quinolines, the feasibility of the cascade reactions with
heteroaromatic aldehydes 5a, 5b and 7a, 7b was examined
(Scheme 2). Although the reaction of 1a with 3-fluoroiso-
nicotinealdehyde (5b) gave the corresponding adduct 6ab,
3-fluoronicotinaldehyde (5a) was found to be a better
substrate, giving 6aa in a modest yield. Pyrazolo-fused
analogues 8aa and 8ab were also synthesized from chlor-
opyrazoles 7a and 7b in low yields (Scheme 2).12
Table 2. Scope of 2-Fluorobenzaldehydesa
aldehyde
R
product
time
(h)
yield
(%)b
entry
2
4
R
1
2a
2b
2c
H
4aa
H
1
24
2
1
3
1
3
3
2
4
1
2
3
86
2
3-F
5-F
4ab 1-F
4ac 3-F
4ad 3-CF3
38 (61)c
41 (61)c
29 (65)d
40 (59)d
82
3
4
2d 5-CF3
5
2e
2f
5-Br
4-Br
5-CN
4ae
4af
4ag
3-Br
2-Br
3-CN
6
7
2g
41c
8
2h 5-CH3
4ah 3-CH3
85
9
2i
2j
6-CH3O
5-CH3O
4ai
4aj
4-CH3O
3-CH3O
88
10
11
12
13
74
2k 4-CH3O
2l 3-CH3O
2m 4,5-(CH3O)2 4am 2,3-(CH3O)2
4ak 2-CH3O
87
4al 1-CH3O
98
72
a All reactions were carried out in the presence of 1a (1.0 mmol),
aromatic aldehydes 2 (1.2 mmol), and Cs2CO3 (3.0 mmol) in DMF
(5 mL) at 120 °C for the indicated time unless otherwise stated. b Isolated
yield. c DMSO was used instead of DMF. d K2CO3 and DMSO were
used instead of Cs2CO3 and DMF.
To extend the scope of the 2-methyl-1H-benzimidazole
substrates for our cascade reaction, we next examined the
reaction of 2-fluorobenzaldehyde 2a with a variety of
2-methyl-1H-benzimidazole derivatives 1aÀ1k under the
optimized conditions (Cs2CO3, DMF, 120 °C). As shown
Finally, the cascade reactions of 2a with 2-methyl-1H-
imidazopyridine (9a) and 8-methyl-7H-purine (9b) were
Table 3. Scope of 1H-Benzimidazolesa
1H-benzimidazole
R1
product
entry
1
R2
4
R1
R2
yield (%)b
1
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
4aa
4ba
4ca
4da
4ea
4fa
H
H
H
H
H
H
H
H
83
49c
69
62
67
71
65
58
80
66
39
2
5-CH3
5,6-(CH3)2
5,6-(Cl)2
4-CH3
4-CH3O
4-Br
9- and 10-CH3
3
9,10-(CH3)2
4
9,10-(Cl)2
5
8-CH3
8-CH3O
8-Br
H
6
7
1g
1h
1i
4ga
4ha
4ia
8
H
CH3O
CH3O
9
H
CH3S
H
CH3S
10
11
1j
H
CH3
4ja
H
CH3
1k
H
4-molpholinyl
4ka
H
4-molpholinyl
a All reactions were carried out in the presence of 1H-benzimidazole 1aÀ1k (1.0 mmol), 2-fluorobenzaldehyde (2a) (1.2 mmol), and Cs2CO3
(3.0 mmol) in DMF (5 mL) at 120 °C for 16 h. b Isolated yield. c For a 1:1 mixture of regioisomers.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Cascade Reaction of 1a with Heteroaromatic
Aldehydes 5 and 7 in the Presence of Cs2CO3
Scheme 3. Cascade Reaction of 2a with 2-Methyl-1H-
imidazopyridine (9a) and 8-Methyl-7H-purine (9b)
a
a Conditions: (a) Cs2CO3, DMF, 120 °C, 20 h for 6aa; (b) Cs2CO3,
DMSO, 120 °C, 6 h for 6ab; (c) Cs2CO3, DMA, 150 °C, 8 h for 8aa; (d)
Cs2CO3, DMF, 120 °C, 20 h for 8ab.
examined to verify the effects of their heteroaromatic
moiety fused to the imidazole on the yield and their
regioselective outcome (Scheme 3). This survey re-
vealed that, among the possible regioisomeric adducts,
regioisomers 10aa and 10ba are predominantly pro-
duced from 9a and 9b in 54% and 22% yields, respec-
tively. The structure of 10aa was determined by direct
comparison with the authentic sample prepared by the
method previously reported.13 The structure of the new
heterocycle 10ba was unambiguously confirmed by
X-ray crystallographic analysis (Figure 1). The reaction
between 2-methyl-1H-imidazole and 2a under the opti-
mized conditions produced a complex mixture of uniden-
tified compounds.14 The results suggest to us that phenyl
moieties of 1aÀ1k make a contribution to the successful
process of our cascade reaction.
Figure 1. ORTEP drawing of 10ba.
with 2-fluorobenzaldehydes, followed by the Knoevenagel
cyclization of the resulting adducts. Our method potentially
provides a variety of substituted benzimidazo[1,2-a]quinolines
without using any transition metal catalysts upon fine-tuning
a combination of two readily available substrates.
Acknowledgment. The authors wish to thank Mr.
Haruhiko Fukaya (the Analytical Center, Tokyo University
of Pharmacy and Life Sciences) for the X-ray crystallo-
graphic analysis. We also wish to thank Mr. Hisashi Naruse
(Tokyo University of Pharmacy and Life Sciences) for his
technical assistance.
In summary, a concise and general method for the
synthesis of benzimidazo[1,2-a]quinolines and related
heterocycles has been developed. The method is based
upon a novel cascade reaction through an aromatic
nucleophilic substitution of 2-methyl-1H-benzimidazoles
(12) When the reaction with the chloro-analogue of 5a was carried
out under the same conditions, the yield of 6aa significantly decreased.
The details are described in the Supporting Information.
(13) Loones, K. T. J.; Maes, B. U. W.; Meyers, C.; Deruytter, J. J.
Org. Chem. 2006, 71, 260.
(14) The reaction of substituted methyl-1H-imidazoles with 2a was
examined. The details of the results are described in the Supporting
Information.
Supporting Information Available. Experimental pro-
1
cedures, full spectroscopic data, H/13C NMR spectra,
and X-ray crystallographic data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX