Research Article
pubs.acs.org/acscombsci
An Efficient and Facile Method for the Synthesis of
Benzimidazoisoquinoline Derivatives via a Multicomponent Reaction
Wen-Li Liao,†,§ Shi-Qiang Li,†,§ Jun Wang,† Zhi-Yu Zhang,† Zhi-Wei Yang,† Di Xu,† Chuan Xu,‡,#
Hai-Tao Lan,∥ Zhong-Zhu Chen,*,† and Zhi-Gang Xu*,†
†
International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, 319 Honghe Avenue,
Yongchuan, Chongqing 402160, China
‡
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China
#
Department of Oncology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China
∥
Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Sichuan 610072, China
S Supporting Information
*
ABSTRACT: Two series of benzimidazoisoquinoline and fused
benzimidazoisoquinoline-benzimidazole derivatives have been synthesized using an efficient one-pot procedure. This process involves
an intramolecular nucleophilic substitution reaction and provides
facile access to two series of complexes and potentially interesting
biologically active scaffolds.
KEYWORDS: benzimidazoisoquinoline, multicomponent reactions (MCRs), benzimidazole, nucleophilic substitution reaction, one-pot
■
INTRODUCTION
soquinoline group to be readily modified and provide access to
a series of interesting structures.
Numerous biologically active natural product compounds
containing benzimidazoisoquinoline groups have been reported
in the literature, including an anti-Trypanosoma cruzi agent,4 an
antibiotic tryptanthrin,5 and a cytotoxic luotonin.6 Furthermore, compounds as Hsp90 inhibitors containing a benzimidazoisoquinoline core structure have been reported to exhibit
reasonable levels of bioactivity (20 μM).7
Considerable research efforts have been directed toward the
development of multicomponent reactions (MCRs) and their
use as general combinatorial chemistry strategies for the highspeed parallel synthesis of large libraries of compounds for drug
discovery applications.1 We previously reported the synthesis of
a series of benzimidazoles2 via a cyclization reaction using 2-(NBoc-amino)-phenyl-isocyanide in an Ugi reaction. This strategy
allows for the synthesis of an interesting 2,3-dihydro-1Hbenzo[d]imidazole compound 1{1} bearing an ester group, as
shown in Figure 1.3 For the unstable ethyl ester group at high
temperatures, it was envisaged, however, that the replacement
of this group with a phenyl ester group to give the
corresponding 2,3-dihydro-1H-benzo[d]imidazole 2{1} would
result in greater stability, which would allow the benzimidazoi-
■
RESULTS AND DISCUSSION
As part of our ongoing work toward the development of novel
MCRs for the synthesis of biologically interesting heterocyclic
scaffolds, we recently proposed a new method for the synthesis
of benzimidazoisoquinolines 3{1} according to the MCR
shown in Scheme 1. The benzimidazole group in compound
3{1} is an important moiety, and if the unstable ethyl ester
group was replaced with a phenyl ester group, it was envisaged
that this compound could be synthesized from compound 4{1}
using our previously published methodology.2,3 2,3-Dihydro1H-benzo[d]imidazole compound 4{1} was identified as a key
intermediate for this design strategy, and it was envisaged that
this compound could be synthesized by the intramolecular
Received: September 12, 2015
Revised: November 16, 2015
Published: December 4, 2015
Figure 1. Proposed replacement structures.
© 2015 American Chemical Society
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DOI: 10.1021/acscombsci.5b00145
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ACS Combinatorial Science
Scheme 1. Proposed Method for the Synthesis of
Benzimidazoisoquinolines
Table 1. Optimization of the Reaction Conditions
entry
solvent
1
2
3
4
5
6
7
10% TFA/DCE
10% TFA/DCE
10% TFA/DCE
10% TFA/DCE
5% HCl/AcOH
5% HCl/AcOH
5% HCl/AcOH
conditions
120
140
150
150
100
120
140
°C,
°C,
°C,
°C,
°C,
°C,
°C,
20
10
10
20
10
10
10
min
min
min
min
min
min
min
yield (%)
42a
63a
86a, 80b
78a
12a
43a
32a
a
Yield (%) based on the integral of the HPLC peaks detected at 254
nm. bIsolated yield (%) after column chromatography.
Compound 10{1} was prepared without purification in the
subsequent deprotection and cyclization reactions. Pleasingly,
heating the crude product under microwave irradiation
conditions at 150 °C for 10 min gave compound 11{1} in
62% yield over the two steps. The use of a one-pot synthetic
procedure did not lead to a significant decrease in the yield of
the reaction, and only one purification process was required to
deliver the desired product in high purity. A variety of different
amines 12{1−11} and carboxylic acids 13{1−10} were reacted
with isonitrile 6{1} and aldehyde 7{1} under the optimized
conditions to investigate the scope of this one-pot procedure,
and the results are shown in Scheme 3. Compound 15{1−11,
1−10} was formed via the Boc deprotection of product 14{1−
11, 1−10}. Compound 16{1−11, 1−10} was obtained from the
intramolecular cyclization of compound 15{1−11, 1−10},
which underwent a tautomerization reaction to give 17{1−11,
1−10} followed by an intramolecular cyclization to afford final
compound 18{1−11, 1−10}.
Desired benzimidazoisoquinoline compound 18{1−11, 1−
10} was isolated over two steps (Table 2). (2,4Dimethoxyphenyl)methanamine (12{6}) was the “convertible
amine” used for the synthesis of 18{6, 1} in 66% yield.8 This
use of this leaving group effectively generated more space for
the modification of this structure (see the Supporting
Information for details). This newly developed process provides
facile access to a wide range of benzimidazoisoquinoline
derivatives in good yields via a selective one-pot procedure and
could therefore be used to synthesize numerous compounds for
use in high through-put screening assays.9
A new strategy involving a second cyclization reaction to
form two rings from pendant amino and aldehyde functional
groups was designed to afford a series of fused benzimidazoisoquinoline-benzimidazoles 21{1−10}, as shown in Scheme 4
and Table 3. This one-pot procedure involving two steps was
evaluated using a variety of different substrates, and the desired
products were formed in good yields (58−75%). This data also
indicated that there could be additional opportunities to modify
the benzimidazoisoquinoline scaffolds.
The products of the Ugi reaction between 6{1}, 7{1}, 12{1−
11}, 13{1−10}, 13{3}, 12{5}, and 12{13} were subjected to an
intramolecular nucleophilic aromatic substitution reaction to
give the corresponding benzimidazoisoquinoline derivatives
23{1−10}, 25{5, 1−10}, and 25{13, 1} containing a new ring
system via the formation of a C−N bond, as shown in Scheme
5.2 Furthermore, several other ring-closing procedures can also
be used to promote the nucleophilic aromatic substitution
reaction.10 The details of the ring-closing routes are shown in
Table 4.
2-Bromobenzoic acid (13{3}) was used in the Ugi reaction
to give the corresponding target compounds 22{1−11} in 68−
cyclization of compound 5{1}. Compound 5{1} was a Boc
depotection intermediate coming from the Ugi product.
According to the above discussion in Figure 1, it is possible
to synthesize compound 4{1} if the Ugi product could be
obtained. Furthermore, compound 5{1} itself could be
synthesized via the Ugi reaction of 2-(N-Boc-amino)-phenylisocyanide (6{1}) with methyl 2-formylbenzoate (7{1}) and
two other starting materials bearing amine and acid functional
groups, which could be used to introduce further modifications
to the resulting benzimidazoisoquinoline derivative.
The Ugi reaction of isonitrile 6{1} with aldehyde 7{1},
benzyl amine 8{1}, and benzoic acid 9{1} was conducted in
methanol at room temperature to afford desired Ugi product
10{1} in 87% yield (Scheme 2). With compound 10{1} in
Scheme 2. Synthetic Route and X-ray Structure of
Compound 11{1}
hand, we proceeded to optimize the conditions for the
subsequent deprotection and cyclization reactions, and the
results are shown in Table 1. Two different solvent systems,
including 10% TFA in DCE and 5% HCl in AcOH were
evaluated under a variety of different microwave irradiation
conditions. The results of these screening experiments revealed
that the use of 10% TFA in DCE at a temperature of 150 °C
over 10 min gave the highest yield of desired product 11{1}
(Table 1, entry 3), which was reduced to 80% yield following
the purification of the product by column chromatography over
silica gel. The structure of this compound was confirmed by Xray crystallographic analysis (see the Supporting Information
for further details). With the optimized conditions in hand, we
proceeded to investigate the possibility of conducting this
reaction as a one-pot procedure.
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Scheme 3. Synthetic Route and Building Blocks for Benzimidazoisoquinoline Compounds 18{1−11, 1−10}
Table 2. Detailed Structures and Yields of the
Benzimidazoisoquinoline Compounds 18{1−11, 1−10}
a
entry
building blocks R1
R2
1
2
3
4
5
6b
12{1}
12{2}
12{3}
12{4}
12{5}
12{6}
13{1}
13{1}
13{2}
13{1}
13{3}
13{1}
Scheme 4. Synthetic Route of Compounds 21{1−10}
yield (%)a
11{1}:
18{2, 1}:
18{3, 2}:
18{4, 1}:
18{5, 3}:
18{6, 1}:
Isolated yield (%) after column chromatography.
amine” in this reaction (see Supporting Information).
b
62
71
67
52
63
66
“Convertible
78% yields over two steps using a one-pot process (Table 4,
entries 1−6). The subsequent nucleophilic substitution reaction
was tested under microwave irradiation conditions in the
presence of CuI to give compounds 23{1−11} in 86−95%
yields. When the reaction was conducted in the absence of CuI
under a variety of different microwave irradiation conditions,
the desired product was formed in poor yield. With this in
mind, it was envisaged that other halogen atoms would be well
tolerated in the amine compounds for similar nucleophilic
substitution reactions. Two different halogen-containing
amines, 2-bromoaniline and 2-fluoroaniline, were tested under
the optimized conditions, and the results of these experiments
are shown in Table 4, entries 7−10.
The one-pot Ugi procedure was conducted to give
compounds 24{5, 1−10} and 24{13, 1} in 58−67% yields.
These compounds were then subjected to the intramolecular
nucleophilic aromatic substitution conditions described above.
Both of the halogen atoms in these substrates could react to
close the quinoxaline ring under microwave irradiation
conditions to form the corresponding fused benzimidazoiso67
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ACS Combinatorial Science
Table 3. Detailed Structures and Yields of Fused
Benzimidazoisoquinoline-Benzimidazole Compounds
21{1−10}
a
entry
building block R2
1
2
3
4
5
6
7
13{1}
13{4}
13{5}
13{6}
13{7}
13{8}
13{9}
Table 4. Detailed Structures and Yields of
Benzimidazoisoquinoline Derivatives
yield (%)a
21{1}:
21{4}:
21{5}:
21{6}:
21{7}:
21{8}:
21{9}:
entry
building
blocks R1 and
R2
1
2
3
4
5
6
7
8
9
10
12{2}
12{7}
12{8}
12{9}
12{10}
12{11}
13{5}
13{7}
13{10}
13{1}
75
58
63
67
61
66
69
Isolated yield (%) after column chromatography.
quinoline-quinoxaline compounds 25{5, 1−10} and 25{13, 1}
in yields of 80−87%. The fluoro and bromo substituents both
underwent the nucleophilic aromatic substitution reaction
under the microwave irradiation conditions in the presence of
CuI to give the desired products in good yields. This process
proceeded in a facile and selective manner and could be used
for the preparation of large libraries of compounds.
a
R3 and
R4
12{5}
12{5}
12{5}
12{13}
yield (%)a
22{2}:
22{7}:
22{8}:
22{9}:
22{10}:
22{11}:
24{5, 5}:
24{5, 7}:
24{5, 10}:
24{13, 1}:
72
78
68
73
77
70
58
63
59
67
23{2}:
23{7}:
23{8}:
23{9}:
23{10}:
23{11}:
25{5, 5}:
25{5, 7}:
25{5, 10}:
25{13, 1}:
86
94
92
87
95
89
83
80
87
85
Isolated yield (%) after column chromatography.
General Procedures for Compounds 11{1} and 18{1−
11, 1−10}. A solution of aldehyde (0.50 mmol) and amine
(0.50 mmol) in MeOH (1 mL) was stirred at room
temperature for 10 min in a 5 mL microwave vial. Then, acid
(0.50 mmol) and isonitrile (0.50 mmol) were added separately.
The mixture was stirred at room temperature overnight and
monitored by TLC. When no isonitrile was present, the solvent
was removed under a nitrogen stream. The residue was
dissolved in 10% TFA/DCE (3 mL), sealed, and heated in a
microwave at 150 °C for 10 min. After the microwave vial was
cooled to room temperature, the solvent was removed under
reduced pressure, diluted with EtOAc (15 mL), and washed
with sat. Na2CO3 and brine. The organic layer was dried over
MgSO4 and concentrated. The residue was purified by silica gel
column chromatography using a gradient of ethyl acetate/
hexane (1−100%) to afford the relative benzimidazoisoquinoline products 11{1} and 18{1−11, 1−10}.
■
CONCLUSIONS
In summary, we have developed a MCR for the synthesis of
benzimidazoisoquinoline derivatives according to a facile, onepot procedure. A subsequent nucleophilic substitution reaction
provided access to two fused scaffolds with excellent yields.
These products could be subjected to a range of different
modifications and therefore represent interesting structures for
the design of novel libraries for use in medicinal chemistry.
■
EXPERIMENTAL PROCEDURES
All reagents, unless otherwise stated, were used as received
from commercial suppliers. 1H NMR (400 MHz) and 13C
NMR (100 MHz) spectra were recorded on a Bruker Avance
400 spectrometer using CDCl3 or DMSO-d6 as solvent and
TMS as internal standard (δ in ppm). Abbreviations used for
NMR signals are s = singlet, d = doublet, t = triplet, and m =
multiplet. LC/MS were recorded on a Shimadzu LCMS-2020.
All microwave irradiation reactions were carried out in a
Biotage Initiator Classic.
■
ASSOCIATED CONTENT
S Supporting Information
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombsci.5b00145.
Scheme 5. Synthetic Route and Building Blocks for Benzimidazoisoquinoline Derivatives
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General methods, synthetic procedures, and characterization data for intermediates and final products (PDF)
Crystallographic information for compound 11{1} (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: [email protected].
*E-mail: [email protected].
Author Contributions
§
W.-L.L. and S.-Q.L. contributed equally to this work.
Funding
This work was supported by the Scientific Research Foundation
of Chongqing University of Arts and Sciences (Grant No.
R2013XY01, R2013XY02), the Chongqing Science and
Technology Commission (Grant No. CSTC2013JCYJA50028),
the National Natural Science Foundations of China (Grant No.
81272598), SRF for ROCS, SEM and Key Laboratory of
Tumor Immunopathology, Ministry of Education of China
(Grant No. 2013jsz102 and 2015SZ0187).
Notes
The authors declare no competing financial interest.
■
■
ACKNOWLEDGMENTS
We thank Ms. H.Z. Liu for obtaining LC/MS and NMR data.
ABBREVIATIONS
MCR, multicomponent reaction; TFA, trifluoroacetic acid;
BOC, tertiary butoxy carbonyl; DCE, dichloromethane; MW,
microwave
■
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