Synthesis of fused benzimidazole-quinoxalinones via UDC strategy and following the intermolecular nucleophilic substitution reaction

Article abstract of DOI:10.1016/j.tetlet.2014.03.063

A series of fused benzimidazole-quinoxalinones were synthesized utilizing a one-pot UDC (Ugi/de-protection/cyclization) strategy to form a benzimidazole group with subsequent intermolecular nucleophilic substitution reaction to form quinoxalinone functionality. Using combinations of either a tethered ketone acid or aldehyde acid input the Ugi reaction was shown to afford (1) a ring system through lactamization, (2) a benzimidazole through de-protection and cyclization, and (3) a quinoxalinone through the nucleophilic substitution reaction. Scaffolds were produced in good yields and facile operation.

Full text of DOI:10.1016/j.tetlet.2014.03.063

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of fused benzimidazole–quinoxalinones via UDC strategy
and following the intermolecular nucleophilic substitution reaction
⇑
Zhong-Zhu Chen, Jin Zhang, Dian-Yong Tang, Zhi-Gang Xu
Chongqing Key Laboratory of Environmental Materials and Remediation Technologies, Drug Discovery Center of Innovation, Chongqing University of Arts and Sciences, 319
Honghe Avenue, Yongchuan, Chongqing 402160, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A
series of fused benzimidazole–quinoxalinones were synthesized utilizing a one-pot UDC
Received 2 January 2014
Revised 7 March 2014
Accepted 13 March 2014
Available online xxxx
(Ugi/de-protection/cyclization) strategy to form a benzimidazole group with subsequent intermolecular
nucleophilic substitution reaction to form quinoxalinone functionality. Using combinations of either a
tethered ketone acid or aldehyde acid input the Ugi reaction was shown to afford (1) a ring system
through lactamization, (2)
a benzimidazole through de-protection and cyclization, and (3) a
quinoxalinone through the nucleophilic substitution reaction. Scaffolds were produced in good yields
and facile operation.
Keywords:
Benzimidazole
Quinoxalinones
Ó 2014 Elsevier Ltd. All rights reserved.
UDC strategy
Nucleophilic substitution reaction
One-pot operation
Substituted benzimidazoles and quinoxalinones are important
pharmacophores and privileged structures in medicinal chemistry1
for use as anticancer,2 anxiolytic,3 anti-inflammatory,4 and
antimicrobial agents.5 Benzimidazoles fused with aza-aromatic
ring systems have been used as antiviral,6 antitumor,7,8 and antihy-
pertensive agents.9 The scaffolds such as I,3,6 II,8 III,6 and IV10 have
been reported bioactive against GABA-A receptor and RSV
(Scheme 1). Recently, the synthesis of new benzimidazole scaffolds
has been reported in our group.11 In the synthesis of pyridoquinox-
alinedione, an additional nucleophilic substitution reaction,
combined with the Aldol reaction, was introduced to form the
new CAN bond.12 This indicates that the nucleophilic substitution
reaction could be used on benzimidazole groups which could be
obtained from UDC (Ugi/de-protection/cyclization) strategy to
afford a new ring system through CAN bond formation.
Shen’s group introduced an intramolecular Goldberg reaction to
afford a series of compounds IV (Scheme 1) after a 3-step starting
material preparation.10 The UDC strategy, with its advantage of
one-pot operation, could be used to synthesize similar starting
material with a 2-step reaction. The difference between these
two methods is that the first can form a new quinoxalinone ring
from benzimidazole cyclizing the other group. However, in the
UDC strategy, the quinoxalinone ring could be formed by closing
the benzimidazole group. Herein, we report our result of a facile
R1
N
O
S
O
N
R2
O
N
R1
N
N
N
R3
R3
R2
I
II
R2
N
R1
N
N
N
N
R2
R1
O
N
O
III
IV
Scheme 1. Bioactive scaffolds of fused benzimidazoles.
synthesis of fused benzimidazole–quinoxalinone compounds with
only two purification processes.
One typical reaction route is shown in Scheme 2. 2-(N-Boc-ami-
no)-phenyl-isocyanide 1, 4-pyridinecarboxylic acid 2, and valeral-
dehyde 3 with 2-fluoroaniline 4 could afford the Ugi product 5
after overnight stirring in methanol at room temperature. After
de-protection and cyclization in 10% TFA/DCE, benzimidazole com-
pound 6 was obtained with yield as high as 67% in one-pot. With
compound 6 in hand, the next nucleophilic substitution reaction
was optimized and the results are shown in Table 1.
Organic bases (DIPA, DIPEA, and TEA) and inorganic bases
(NaOH, NaH, K3PO4, Na2CO3, K2CO3, and Cs2CO3) were all tested.
However, organic catalysts did not produce satisfactory results as
⇑
Corresponding author. Tel.: +86 023 6116 2838; fax: +86 023 6116 2836.
E-mail address: xuzhigangyours@yahoo.com (Z.-G. Xu).
http://dx.doi.org/10.1016/j.tetlet.2014.03.063
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Chen, Z.-Z.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.03.063

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Z.-Z. Chen et al. / Tetrahedron Letters xxx (2014) xxx–xxx
N
gave good yield (48–68%) in two steps and the next following
nucleophilic substitution gave similar good yields (75–96%). Inter-
estingly, we found the yields of alkyl aldehyde compounds 7a–7f
are higher than those of compounds 7g–7k with aromatic aldehyde
groups.13 The possible reason is the aromatic ring would reduce
the electron cloud density of the benzimidazole group, so that
the attraction affinity of NH was weakened and led to low yield.
However, yields are still good enough for compound preparation
in high through-put screening in drug discovery.
NHBoc
N
N
COOH
NH2
2
MeOH, r.t
O
1
N
O
F
BocHN
NH
O
F
3
4a
5
N
N
Similar to this Letter, another series of benzimidazole com-
pounds had also been obtained by using combinations of tethered
Ugi inputs typically via tethered ketone acid or aldehyde acid in-
puts with excellent yields in an operationally friendly manner.
The nucleophilic substitution reaction was employed after benz-
imidazole compounds formed from UDC strategy. The synthetic
route is shown in Scheme 4.
10% TFA/DCE
MW 120 °C, 10 min
Cs2CO3, DMF
O
N
N
N
O
N
F
N
NH
6
7a
Scheme 2. Synthetic route of benzimidazole–quinoxalinone compound 7a.
The difference from our previous report11b is the replace of nor-
mal amines or anilines with substituted 2-fluoroanilines 4. Follow-
ing the normal UDC strategy conditions as shown in Scheme 4, one
new ring in compound 9 could be formed in the Ugi reaction using
tethered ketone acids or aldehyde acids and another benzimid-
azole ring coming from the isonitrile in the de-protection and
cyclization reactions to compound 11. The nucleophilic substitu-
tion reaction was treated in the microwave at 150 °C for 10 min
to form the new quinoxalinone ring to compound 12. So, the nucle-
ophilic substitution reaction connected the other two ring systems
and formed a new scaffold of fused benzimidazole–quinoxalinone
with high skeletal diversity.
Six different tethered ketone acids or aldehyde acids were intro-
duced in the reaction and the UDC strategy gave good yields rang-
ing from 46% to 62%. However, the next nucleophilic substitution
reaction gave different yields for different ketone acids or aldehyde
acids as shown in Scheme 4, such as compounds 12a–12c with 90–
95% yield and compounds 12d–12f with 62–65% yield.13 The rea-
son should be the same as aromatic rings reduce electron cloud
density in the benzimidazole ring and increase the cyclization dif-
ficulty. However, the substituted 2-fluoroanilines and ketone acids
or aldehyde acids would provide more opportunities for structure
modification and enhanced drug discovery (see Scheme 5).
In summary, besides the normal acids and aldehydes, a range of
tethered ketone acids or aldehyde acids were all successfully em-
ployed in the Ugi reaction, followed by an amino-cyclodehydration
to afford benzimidazole with good yields in a general one pot,
two-step protocol. The following intermolecular nucleophilic
Table 1
Optimization of the reaction conditions to obtain fused benzimidazole–quinoxalinone
compound 7a
Entry
Catalyst
Solvent
Temp. (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
7
8
DIPA
DIPEA
TEA
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
THF
MW 140
MW 160
MW 140
MW 120
MW 140
rt
MW 140
MW 120
MW 140
MW 140
MW 150
10
20
10
10
10
Overnight
10
10
10
10
10
Trace
6a
Trace
NaOH
NaOH
NaH
K3PO4
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
15a
22a
—
11a
17a
DMF
DMF
DMF
31a
9
10
55a
94a, 90b
a
Yield (%) was based on the integration area of HPLC peaks detected at 214 nm.
Isolated yield (%) after column chromatography.
b
shown in entry 1–3. Strong inorganic base, such as sodium hydride,
was also used at room temperature overnight. However, the reac-
tion did not proceed, leaving only starting material. Sodium
hydroxide at high temperature brought more side products. This
is shown in entry 5 in terms of LC/MS results. Among all bases,
Cs2CO3 gave excellent yield with 90% after purification under
microwave irradiation at 150 °C for 10 min. Using these conditions,
a series of benzimidazole–quinoxalinone compounds were designed
and synthesized as shown in Scheme 3. The one-pot UDC strategy
S
N
N
N
O
O
O
N
N
O
N
N
N
N
N
N
O
N
N
N
N
N
SO2Me
O
Br
Cl
Cl
7f 51%a, 86%b
7b 56%a, 92%b
7c 62%a, 88%b
7d 48%a, 90%b
7e 65%a, 96%b
N
O
O
S
N
N
N
N
O
O
O
O
N
N
N
N
N
N
N
N
N
O
N
N
Cl
N
Cl
NO2
Cl
Br
Cl
7i 68%a, 77%b
7g 66%a, 76%b
7h 62%a, 80%b
7j 61%a, 75%b
7k 67%a, 78%b
Scheme 3. The detailed structures and yields of benzimidazole–quinoxalinone compounds 7. aIsolated yield (%) of UDC strategy for two steps. bIsolated yield (%) of
nucleophilic substitution reaction.
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Z.-Z. Chen et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
R3
N
R3
COOH
O
R1
F
F
O
O
MeOH,r.t
10% TFA/DCE
R2
N
R
H
H
2
R2
NH2
N
8
N
R3
MW 120 °C, 10 min
NC
F
R1
R1
O
O
4
NH2
NHBoc
NHBoc
9
10
1
R3
R3
O
F
Cs2CO3, DMF
MW 150 °C, 10 min
O
N
N
H
N
N
N
N
R1
R1
R2
12
R2
11
Scheme 4. Synthetic route of benzimidazole–quinoxalinone compounds 12.
4. Chen, G.; Liu, Z.; Zhang, Y.; Shan, X.; Jiang, L.; Zhao, Y.; He, W.; Feng, Z.; Yang, S.;
Liang, G. ACS Med. Chem. Lett. 2013, 4, 69–74.
5. Badawey, E. A. M.; Gohar, Y. M. Farmaco 1992, 47, 489–496.
Cl
O
6. Chiba, T.; Shigeta, S.; Numazaki, Y. Biol. Pharm. Bull. 1995, 18, 1081–1083.
7. Zhang, Z.; Meng, T.; He, J.; Li, M.; Tong, L.; Xiong, B.; Lin, L.; Shen, J.; Miao, Z.;
Ding, J. Invest. New Drug 2010, 28, 715–728.
8. Askew, B. C.; Bednar, R. A.; Bednar, B.; Claremon, D. A.; Cook, J. J.; McIntyre, C. J.;
Hunt, C. A.; Gould, R. J.; Lynch, R. J.; Lynch, J. J., Jr.; Gaul, S. L.; Stranieri, M. T.;
Sitko, G. R.; Holahan, M. A.; Glass, J. D.; Hamill, T.; Gorham, L. M.;
Prueksaritanont, T.; Baldwin, J. J.; Hartman, G. D. J. Med. Chem. 1997, 40,
1779–1788.
N
N
N
O
N
N
O
N
N
O
N
N
55%a, 93%b
61%a, 95%b
58%a, 90%b
12c
12a
12b
Cl
Br
9. Adhikary, P. F.; Das, S. K.; Hess, B. A., Jr. J. Med. Chem. 1976, 19, 1352–1354.
10. Meng, T.; Zhang, Y.; Li, M.; Wang, X.; Shen, J. J. Comb. Chem. 2010, 12, 222–224.
11. (a) Xu, Z.; Shaw, A. Y.; Dietrich, J.; Cappelli, A. P.; Nichol, G.; Hulme, C. Mol.
Divers. 2012, 16, 73–79; (b) Xu, Z.; Ayaz, M.; Cappelli, A. P.; Hulme, C. ACS Comb.
Chem. 2012, 14, 460–464; (c) Xu, Z.; Shaw, A. Y.; Nichol, G.; Cappelli, A. P.;
Hulme, C. Mol. Divers. 2012, 16, 607–612.
12. (a) Xu, Z.; Moliner, F. D.; Cappelli, A. P.; Hulme, C. Org. Lett. 2013, 15, 2738–
2741; (b) Xu, Z.; Moliner, F. D.; Cappelli, A. P.; Hulme, C. Angew. Chem., Int. Ed.
2012, 51, 8037–8040.
O
N
O
O
N
N
N
N
N
N
N
N
12d
57%a, 65%b
46%a, 62%b
12f
62%a, 63%b
12e
13. General procedures for compounds 7 and 12: A solution of aldehyde (0.50 mmol)
and substituted 2-fluoroamine (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 2-(N-Boc-amino)-phenyl-isocyanide (0.50 mmol) were added separately
(for compound 12, three starting materials (per 0.5 mmol) were added
together in MeOH). The mixture was stirred at room temperature overnight.
The reaction was monitored by TLC and when there was no 2-(N-Boc-amino)-
phenyl-isocyanide, the solvent was removed under nitrogen blowing. The
residue was dissolved in 10% TFA/DCE (3 mL) and treated in a microwave at
120 °C for 10 min. After the microwave vial was cooled to room temperature,
the solvent was diluted with EtOAc (15 mL) and washed with satd Na2CO3
(15 mL). 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 (10–80%) to afford the relative benzimidazole products.
In a solution of benzimidazole compound (0.5 mmol) in 5 mL DMF, Cs2CO3
(1.0 mmol) was added and the reaction mixture was treated in a microwave at
150 °C for 10 min. After the microwave vial was cooled to room temperature,
the solvent was diluted with EtOAc (15 mL) and washed with brine
(2 Â 10 mL). 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 (0–60%) to afford the relative fused benzimidazole–
quinoxalinones. Compound 7a: (yield 90%) 1H NMR (400 MHz, CDCl3) d 8.74–
8.50 (m, 2H), 7.99–7.89 (m, 2H), 7.92–7.84 (m, 1H), 7.49–7.35 (m, 3H),
7.27–7.15 (m, 2H), 7.00 (s, 1H), 6.73 (s, 1H), 6.24 (s, 1H), 1.81–1.61 (m, 2H),
1.58–1.41 (m, 2H), 1.39–1.22 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d 166.7, 151.6, 150.2, 143.6, 142.0, 131.1, 128.9, 127.3, 127.2,
125.1, 124.0, 123.7, 122.7, 120.7, 116.9, 111.4, 52.7, 31.5, 27.7, 22.2, 13.8.
HRMS calculated for C24H23N4O [M+H]+, 383.1866; found 383.1868. Compound
12a: (yield 93%) 1H NMR (400 MHz, CDCl3) d 8.22 (dd, J = 7.9, 1.7 Hz, 1H),
8.01–7.93 (m, 2H), 7.86–7.80 (m, 1H), 7.45–7.32 (m, 4H), 3.11–3.00 (m, 1H),
2.88 (dt, J = 18.0, 9.7 Hz, 1H), 2.71–2.58 (m, 2H), 1.53 (s, 3H). 13C NMR
(100 MHz, CDCl3) d 172.9, 154.6, 143.5, 131.6, 127.9, 126.0, 125.8, 124.1, 123.7,
123.5, 120.6, 116.4, 111.7, 60.5, 30.4, 25.0. HRMS calculated for C18H16N3O
[M+H]+, 290.1288; found 290.1287.
Scheme 5. The detailed structures and yields of compounds 12. aIsolated yield (%)
of UDC strategy for two steps. bIsolated yield (%) of nucleophilic substitution
reaction.
substitution reaction provided the polycyclic heterocycles, benz-
imidazole–quinoxalinones with high skeletal diversity in good to
excellent yields. This novel protocol will facilitate the preparation
at a large amount of compounds in high through-put screening
in medicinal chemistry.
Acknowledgements
The authors thank the Scientific Research Foundation of Chon-
gqing University of Arts and Sciences (R2013XY01, R2013XY02,
R2013CJ03), the Chongqing Science & Technology Commission,
(Grant No. CSTC2013JCYJA50028) for funding this research.
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