An efficient one-pot synthesis of benzo[4,5]imidazo[1,2-A]quinoxalines via copper-catalyzed process

Article abstract of DOI:10.1021/ol4026292

A copper-catalyzed one-pot process for the construction of benzo[4,5]imidazo[1,2-a]quinoxalines under air is described. Aryl chlorides, aryl bromides, and aryl iodides can be applied to the synthesis of these compounds.

Full text of DOI:10.1021/ol4026292

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
An Efficient One-Pot Synthesis of
Benzo[4,5]imidazo[1,2‑a]quinoxalines via
Copper-Catalyzed Process
Aiping Huang,† Yimu Chen,† Yige Zhou,† Wei Guo,† Xiaodong Wu,† and Chen Ma*,†,‡
School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100,
P. R. China, and State Key Laboratory of Natural and Biomimetic Drugs,
Peking University, Beijing, 100191, P. R. China
chenma@sdu.edu.cn
Received September 11, 2013
ABSTRACT
A copper-catalyzed one-pot process for the construction of benzo[4,5]imidazo[1,2-a]quinoxalines under air is described. Aryl chlorides,
aryl bromides, and aryl iodides can be applied to the synthesis of these compounds.
Imidazo[1,2-a]quinoxaline derivatives have attracted con-
siderable interest due to their outstanding biological and
medicinal activities.1 For example, EAPB0203 and its
† Shandong University.
‡ Peking University.
(1) (a) Hazeldine, S. T.; Polin, L.; Kushner, J.; White, K.; Corbett,
T. H.; Biehl, J.; Horwitz, J. P. Bioorg. Med. Chem. 2005, 13, 1069. (b)
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2009, 44, 3406. (c) Khier, S.; Deleuze-Masquefa, C.; Moarbess, G.;
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Figure 1. Some biologically active imidazo[1,2-a]quinoxalines.
ꢀ
Parra, S.; Laurent, F.; Subra, G.; Deleuze-Masquefa, C.; Benezech, V.;
Fabreguettes, J.-R.; Vidal, J. P.; Pocock, T.; Elliott, K.; Small, R.;
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1998, 33, 943. (i) Ager, I. R.; Barnes, A. C.; Danswan, G. W.; Hairsine,
P. W.; Kay, D. P.; Kennewell, P. D.; Matharu, S. S.; Miller, P.; Robson,
P.; Rowlands, D. A.; Tully, W. R.; Westwood, R. J. Med. Chem. 1988,
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Gemma, S.; Colombo, L.; Forloni, G.; Savini, L.; Fracasso, C.; Caccia,
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Taglialatela-Scafati, O.; Novellino, E.; Fiorini, I.; Campiani, G.; Butini,
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analogues exhibit high antitumor activities.1aꢀd Now,
EAPB0203 is a promising candidate in the treatment of
melanoma and T lymphomas.1c BMS-345541 is a highly
selective inhibitor of IκB kinase.1e 3 And 4 act as an
adenosine A1 receptor antagonist.1g,h Many imidazo[1,2-a]-
quinoxalines have been found to possess other biological
activities, including antiallergic (6),1i antimicrobial,1j and
cyclic nucleotide phosphordiesterase inhibitory (5)1f activ-
ities. In addition, some of them are also used as flurescent
probes for Aβ1ꢀ42 fibrils (Figure 1).1k Benzimidazoles also
r
10.1021/ol4026292
XXXX American Chemical Society

show various biological properties and are often used as
enzyme inhibitors2aꢀc and drugs.2d We envision that the
combined molecules of imidazo[1,2-a]quinoxaline and
benzimidazole frameworks, benzo[4,5] imidazo[1,2-a]-
quinoxaline derivatives, would be biologically active mo-
lecules and intermediates. However, the methods for pre-
paration of benzo[4,5]imidazo[1,2-a]quinoxalines remain
rare. The Maes group presented a Pd-catalyzed synthetic
method to construct imidazo[1,2-a]quinoxalines from
2-chloro-3-iodopyridine or 2,3-dibromopyridine, but this
method needs a multistep synthesis.3a Reeves et al. devel-
oped a Cu-catalyzed strategy from 2-formylpyrroles and
o-aminoiodoarenes to assemble these compounds, but this
approach needs a high temperature and very long reaction
time.3b Shen et al. synthesized benzo[4,5]imidazo[1,2-a]-
quinoxaline derivatives from 1-fluoro-2-nitrobenzene and
2-bromoanilines, but this method needs a multistep synth-
esis and high temperature.4 Therefore, it is highly desirable
to develop a convenient, efficient approach for the synth-
esis of these heterocycles.
Table 1. Optimization of the Reaction Conditionsa
entry
cat.
ligand
base
solvent yield (%)b
1
Cu(OAc)2 H2O
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
-
Cs2CO3 NMP
96
90
53
67
21
19
74
67
92
64
59
trace
82
73
47
72
84
trace
65
84
93
83
95
3
2
Cu(OAc)2 H2O
K2CO3
K3PO4
KOH
NMP
NMP
NMP
3
3
Cu(OAc)2 H2O
3
4
Cu(OAc)2 H2O
3
5
Cu(OAc)2 H2O
NaOt-Bu NMP
3
6
Cu(OAc)2 H2O
KOt-Bu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
THF
3
7
CuI
8
CuBr
CuCl
CuBr2
Copper-catalyzed Ullmann coupling reactions have
made significant progress,5ꢀ9 and the N-arylation strategy
has been extensively explored to construct nitrogen hetero-
cycles.10ꢀ13 Many pharmaceutical molecules have been
9
10
11
12
13
14
15
16
17
18c
19
20
21
22
CuCl2 2H2O
3
ꢀ
Cu(OAc)2 H2O
3
3
3
3
3
3
3
3
Cu(OAc)2 H2O
(2) (a) Zarrinmayeh, H.; Nunes, A. M.; Ornstein, P. L.; Zimmerman,
D. M.; Arnold, M. B.; Schober, D. A.; Gackenheimer, S. L.; Bruns,
R. F.; Hipskind, P. A.; Britton, T. C.; Cantrell, B. E.; Gehlert, D. R.
J. Med. Chem. 1998, 41, 2709. (b) White, A. W.; Almassy, R.; Calvert,
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2010, 12, 222.
Cu(OAc)2 H2O
Cu(OAc)2 H2O
Cu(OAc)2 H2O
Cu(OAc)2 H2O
L1
L1
L1
L1
L1
L1
Cu(OAc)2 H2O
DMSO
DMF
dioxane
toluene
NMP
Cu(OAc)2 H2O
Cu(OAc)2 H2O
3
3
Cu(OAc)2 H2O
23d Cu(OAc)2 H2O
3
a Reaction conditions: N-(2-iodophenyl)-4-methylbenzenesulfon-
amide 7a (0.5 mmol), 2-(chloromethyl)-1H-benzo[d]imidazole 8a
(0.5 mmol), Cu (10 mol %), ligand (20 mol %), base (3.5 equiv), solvent
(3 mL), 80 °C, in air. b Isolated yield. c Reaction was refluxed. d Reaction
was carried out under N2.
(5) For recent reviews on copper-catalyzed cross-couplings, see: (a)
Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
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Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954. (h) Corbet, J.-P.;
synthesized by the use of Cu-catalyzed coupling strategy.14
However, most of these reactions were performed under a
nitrogen or argon atmosphere, which could prevent oxida-
tion of the catalysts. In particular, the use of inexpensive
but less reactive aryl chlorides in Cu-catalyzed coupling is
still a challenge compared to the commonly used aryl
bromides and aryl iodides. In addition, the application of
Cu-catalyzed transformation for benzo[4,5]imidazo[1,2-a]-
quinoxalines is rarely reported. On the basis of base-
catalyzed elimination of the sulfinate group from N-tosyl
derivatives to afford imines,15 we used N-tosyl-2-haloanilines
ꢀ
Mignani, G. Chem. Rev. 2006, 106, 2651. (i) Hassan, J.; Sevignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
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Chaitanya, G. K.; Bhanuprakash, K. Tetrahedron 2008, 64, 2471.
(10) (a) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed.
2009, 48, 348. (b) Wang, F.; Liu, H.; Fu, H.; Jiang, Y.; Zhao, Y. Org.
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4067. (b) Chen, D.; Bao, W. Adv. Synth. Catal. 2010, 352, 955.
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B
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Table 2. Synthesis of Benzo[4,5]imidazo[1,2-a]quinoxalinesa
a Reaction conditions: N-(2-iodophenyl)-4-methylbenzenesulfonamide 7 (0.5 mmol), 2-(chloromethyl)-1H-benzo[d]imidazole 8 (0.5 mmol),
Cu(OAc)2 H2O (10 mol %), L-proline (20 mol %), Cs2CO3 (3.5 equiv), NMP (3 mL), 80 °C, in air. b Isolated yield. c Reaction performed at 120 °C.
3
as starting material. Herein, we report a convenient, effi-
cient Cu-catalyzed one-pot reaction of N-tosyl-2-haloa-
nilines and 2-(chloromethyl)-1H-benzo[d]imidazoles for the
construction of benzo[4,5]imidazo[1,2-a]quinoxalines in air.
Aryl chlorides, aryl bromides, and aryl iodides can be
applied to the synthesis of these compounds.
ligand, Cs2CO3 as the base, and NMP as the solvent at
80 °C under air. We collected the product of benzo-
[4,5]imidazo[1,2-a]quinoxaline 9a in 96% yield (Table 1,
entry 1). As shown in Table 1, we investigated the effect of
bases, and Cs2CO3 showed the best activity (entry 1).
K2CO3, K3PO4, and KOH gave moderate to good yields
(entries 2ꢀ4). Only 21% and 19% isolated yields were
obtained by the use of NaOt-Bu and KOt-Bu (entries 5 and 6).
The efficiency of six Cu catalysts were tested (entries 1 and
7ꢀ11). It was found that CuI, CuBr, CuCl, CuBr2, and
CuCl2 2H2O were active, but Cu(OAc)2 H2O afforded
the highest yield. A Cu catalyst was absolutely required in
this reaction; only a trace amount of target product was
observed in the absence of copper salt (entry 12). Differ-
ent ligands were screened (L1ꢀL5); 4-hydro-L-proline,
First, we examined the reaction of N-tosyl-2-iodoaniline
7a16 and 2-(chloromethyl)-1H-benzo[d]imidazole 8a
with Cu(OAc)2 H2O as the catalyst, L-proline (L1) as the
3
(16) (a) Mailyan, A. K.; Geraskin, I. M.; Nemykin, V. N.; Zhdankin,
V. V. J. Org. Chem. 2009, 74, 8444. (b) Witulski, B.; Alayrac, C.;
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Org. Biomol. Chem. 2010, 8, 3338.
3
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Org. Lett., Vol. XX, No. XX, XXXX
C

1,10-phenanthronine, N,N0-dimethylethylenediamine
(DMEDA), and picolinic acid were not suitable for this
reaction (entries 13ꢀ16). Ligands play an important role
same reaction conditions (entries 20ꢀ26). Notably, reac-
tions of 2-(chloromethyl)-1H-benzo[d]imidazole 8c and 8e
provided two regioisomers. In addition, several interesting
functional groups, such as fluoro, chloro, and trifluoro-
methoxy, were well tolerated in this process (entries 4, 5,
9ꢀ11, 18, 21, 24, and 25). These functionalities in
the products might be useful for further synthetic
modifications.
A possible pathway for the formation of imidazo[1,2-a]-
quinoxaline derivatives is proposed in Scheme 1. First, the
intermolecular nucleophilic substitution of N-(2-halo-
phenyl)-4-methylbenzenesulfonamide 7 with 2-(chloro-
methyl)-1H-benzo[d]imidazole 8 provided 10 in the
presence of Cs2CO3. The next step was the formation of
11 via the Cu-catalyzed intramolecular Ullmann-type
coupling reaction of 10. Finally, elimination of cesium
p-toluenesulfinate provided the target product 9.
in the reaction. Cu(OAc)2 H2O alone gave the product in
3
a lower yield (entry 17). Finally, the effect of solvents
on the reaction was examined under the same reaction
conditions (entries 18ꢀ22). NMP proved to be the most
effective solvent (entry 1). DMSO, DMF, dioxane, and
toluene also gave the product in good yields (entries
19ꢀ22). Only a trace amount of product were observed
in THF (entry 18). We attempted the reaction under a
nitrogen atmosphere, and a 95% yield was obtained
(entry 23). The result indicated that oxygen in air did
not affect the reaction.
With the optimal reaction conditions in hand, the scope
of Cu-catalyzed domino reactions of various substituted
N-tosyl-2-haloanilines 7 with 2-(chloromethyl)-1H-benzo-
[d]imidazoles 817 was examined as shown in Table 2. We
initially investigated reactions of N-tosyl-2-iodoanilines
with 2-(chlorome-thyl)-1H-benzo[d]imidazole 8a. All the
tested substrates worked well giving the corresponding
products in good to excellent yields. It is noteworthy that
the substrates N-tosyl-2-iodoanilines with no substituted
group (entry 1) and electron-donating groups (entry 3)
afforded higher yields than the others with electron-
withdrawing groups (entries 4ꢀ6), but the substrates with
electron-withdrawing groups reacted faster. Moreover, the
optimized conditions could also be applied to N-(2-
iodophenyl)benzenesulfonamide 7b to obtain the corre-
sponding product 9a (entry 2). We next studied reactions
of N-tosyl-2-bromoanilines. To our delight, the desired
products were also obtained in good to excellent yields
(entries 7ꢀ12). In general, no significant difference of
reactivity was observed between N-tosyl-2-iodoanilines
and N-tosyl-2-bromoanilines. We investigated the reaction
of N-tosyl-2-chloroaniline, and only a trace amount of the
product was observed. However, when the reaction was
examined at 120 °C, the desired product was obtained
in moderate yield (entry 15). The conditions were also
applied to N-tosyl-2-chloro-5-methylaniline 7p to ob-
tain the corresponding product 9f (entry 16). N-Tosyl-
2-chloroanilines with electron-withdrawing groups could
proceed easily to give the products in good yields (entries
13 and 14).
Scheme 1. Proposed Reaction Pathway for Synthesis of
Benzo[4,5]imidazo[1,2-a]quinoxalines
In summary, we have developed a convenient, efficient
Cu-catalyzed domino process for the construction of
benzo[4,5]imidazo[1,2-a]quinoxalines from N-tosyl-2-halo-
anilines and 2-(chloromethyl)-1H-benzo[d]imidazoles un-
der mild conditions. A variety of benzo[4,5]imidazo-
[1,2-a]quinoxaline derivatives were obtained in good to
excellent yields. Notably, N-tosyl-2-chloroanilines were
compatible with this process, giving the corresponding
productsingoodyields. ThisCu-catalyzedone-potprocess
has potential applications in the synthesis of biologically
and medicinally relevant compounds.
We next examined substituted 2-(chloromethyl)-1H-
benzo[d]imidazoles. All substrates provided the products
in moderate to good yields. Reactions of 2-(1-chloroethyl)-
1H-benzo[d]imidazole 8b with N-tosyl-2-iodoaniline 7a,
N-tosyl-4-chloro-2-iodoamide 7e, and N-tosyl-2-bromo-
aniline 7g proceeded smoothly to afford the products in
good yields (entries 17ꢀ19). 2-(Chloromethyl)-1H-benzo-
[d]imidazoles 8c, 8d, 8e, and 8f also worked well under the
Acknowledgment. We are grateful to the National
Science Foundation of China (No. 21172131) and the
State Key Laboratory of Natural and Biomimetic Drugs
of Peking University (No. K20130212) for financial sup-
port of this research.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra of all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) (a) Sheng, C.; Che, X.; Wang, W.; Wang, S.; Cao, Y.; Yao, J.;
Miao, Z.; Zhang, W. Eur. J. Med. Chem. 2011, 46, 1706. (b) Cowart, M.;
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M. A.; Chang, R.; Donnelly-Roberts, D. L.; Namovic, M. T.; Hollingsworth,
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The authors declare no competing financial interest.
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