An efficient synthesis of 3-(indol-3-yl)quinoxalin-2-ones with TfOH-catalyzed Friedel-Crafts type coupling reaction in air

Article abstract of DOI:10.1016/j.tetlet.2010.02.031

An efficient one-pot synthetic approach to access a variety of 3-(indol-3-yl)quinoxalin-2-ones from various quinoxalin-2-ones and very wide scope of indoles through TfOH-catalyzed Friedel-Crafts type coupling reaction in DMF has been developed. Only 10 mol % Br?nsted acid as a catalyst, air as an oxidizer, and very wide range of substrates are the prominent advantages of this method.

Full text of DOI:10.1016/j.tetlet.2010.02.031

Tetrahedron Letters 51 (2010) 2023–2028
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An efficient synthesis of 3-(indol-3-yl)quinoxalin-2-ones with TfOH-catalyzed
Friedel–Crafts type coupling reaction in air
Yan-Yan Han a,c, Zhi-Jun Wu b,c, Xiao-Mei Zhang a, Wei-Cheng Yuan a,
*
a Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, PR China
b Chengdu Institute of Biological, Chinese Academy of Sciences, Chengdu 610041, PR China
c Graduate School of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthetic approach to access a variety of 3-(indol-3-yl)quinoxalin-2-ones from var-
ious quinoxalin-2-ones and very wide scope of indoles through TfOH-catalyzed Friedel–Crafts type cou-
pling reaction in DMF has been developed. Only 10 mol % Brønsted acid as a catalyst, air as an oxidizer,
and very wide range of substrates are the prominent advantages of this method.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 November 2009
Revised 2 February 2010
Accepted 8 February 2010
Available online 11 February 2010
Keywords:
Quinoxalin-2-ones
Indoles
Trifluoromethanesulfonic acid
Friedel–Crafts reaction
3-(Indol-3-yl)quinoxalin-2-ones
The prevalence and diversity of aromatic nitrogen-containing
heterocycles found in natural products and used in medicinal
chemistry continue to fuel the development of new methods and
strategies for their syntheses.1 As one of an important class of
nitrogen-containing heterocycle compounds, quinoxalin-2-ones,
and their derivatives have been extensively studied during the
past three decades and used as synthetic precursors for antihyper-
tensives and analgesics.2,3 Among them, 3-(indol-3-yl)quinoxalin-
2-ones have proven to be a class of efficient small-molecule
inhibitors for blocking abnormal PDGF-induced cell proliferation
to treat proliferative disorders.4,5 Despite this, the full potential
of 3-(indol-3-yl)quinoxalin-2-ones has not been profoundly evalu-
ated in part due to the scarcity of them. In addition, few efficient
synthetic protocols have been reported for generating such 3-(in-
dol-3-yl)quinoxalin-2-ones up to now.5a,6 Moreover, some major
drawbacks are obvious in the developed methods, such as using
large amount acid as a promoter, harsh reaction conditions, high-
cost oxidizer, and limited range of substrates. Accordingly, it is
not only meaningful but also strongly required to develop more
efficient approaches to access these compounds.
increasing attention.8 It has been well reported that the C-3 posi-
tion of quinoxalin-2-ones is susceptible to nucleophilic attack
and Friedel–Crafts type reaction is readily performed.5 Based on
these chem-information, we speculated that the reaction between
quinoxalin-2-ones and highly nucleophilic reagents indoles9 may
be able to proceed smoothly under certain mild reaction conditions
leading to 3-(indol-3-yl)quinoxalin-2-ones. However, through
carefully researching literature, we found Aoki et al. reported the
direct condensation of indole or 7-azaindole with various substi-
tuted quinoxalin-2-ones,5a but the reaction must be carried out
in DMF with 10% (v/v to solvent DMF) TFA, and a large amount
of MnO2 was inevitable as an oxidizer for the oxidation to generate
the desired products. In addition, there had been no reports on cat-
alytic processes. Fortunately, we recently found a series of 3-(in-
dol-3-yl)quinoxalin-2-ones could even be efficiently formed in
one-pot through Friedel–Crafts type reaction between quinoxa-
lin-2-ones10 and indoles in air with 10 mol % trifluoromethanesul-
fonic acid (TfOH) as a catalyst. In this Letter, we hope to present the
results of our studies.
At the outset of our study, we first examined the reaction of qui-
noxalin-2-one 1a and indole (2a) with 10 mol % diphenyl phospho-
ric acid as a catalyst leading to 3-(indol-3-yl)quinoxalin-2-one (3a)
for a screening solvent. With examination to a series of solvents, it
revealed that dimethyl formamide (DMF) was superior to other
solvents, such as DMSO, toluene, EtOAc, CH2Cl2, THF, and CH3OH,11
providing the desired product 3a in 74% yield (Table 1, entry 1). In
addition, this reaction worked well in dimethylacetamide (DMAC)
The Friedel–Crafts reaction promoted by Lewis acid or Brønsted
acid is one of the most efficient methods for the construction of
carbon–carbon bonds to aromatics and hetroaromatics.7 Notably,
the Friedel–Crafts type reaction of imines with indole has arisen
* Corresponding author. Fax: +86 28 85229250.
E-mail address: yuanwc@cioc.ac.cn (W.-C. Yuan).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.031

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Y.-Y. Han et al. / Tetrahedron Letters 51 (2010) 2023–2028
Table 1
and N-methyl-2-pyrrolidinone (NMP), respectively, but the yields
Optimization of the reaction conditionsa
were slightly inferior to that in DMF (Table 1, entry 1 vs entries
2 and 3). We then turned our attention to the optimization of the
same reaction in DMF aimed at improving the reaction efficiency.
Among the various Brønsted acids surveyed (Table 1, entries 1
and 4–8), the best result was achieved by 10 mol % TfOH (Table
1, entry 6). However, attempting to perform this reaction with
some base12 as a catalyst, no any corresponding product was ob-
served (Table 1, entries 9–11). This suggested that protonic acid-
initiated Friedel–Crafts type reaction was crucial in this process.
Unfortunately, when the reaction was carried out at room temper-
ature, only trace amount product was obtained (Table 1, entry 12).
Further examining to the catalyst loading, it revealed that 10 mol %
catalyst loading was favorable and acceptable (Table 1, entry 6 vs
entries 13 and 14). As a result, above-mentioned studies led us
to conclude the optimal reaction conditions: quinoxalin-2-one 1a
and two-equivalent indole (2a) using 10 mol % TfOH as a catalyst
in DMF (c = 0.4 M for 1a) at 80 °C with opening to air.
Having established the optimal reaction conditions, the sub-
strates’ scope for the formation of 3-(indol-3-yl)quinoxalin-2-ones
was investigated. As shown in Table 2, we firstly subjected 1-meth-
ly-quinoxalin-2-one (1a) to the reaction using various indole deriv-
atives 2b–j as partner, in general, these reactions proceeded
smoothly and afforded the corresponding products with good
yields (Table 2, entries 1–9). Particularly, the reaction was fast be-
tween 1a and 2j and completed even in 4 h while provided product
3j with up to 92% yield (Table 2, entry 9). With further using free
quinoxalin-2-one (2b) as a substrate to validate the generality
and efficiency of our synthetic methodology, it was gratified that
Cat.(10 mol %)
Solvent, 80 oC
in air, 5 h
N
N +
N
N
N
H
Me
Me
O
O
N
H
2a
Cat
1a
3a
Entry
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
(PhO)2PO2H
(PhO)2PO2H
(PhO)2PO2H
F3CCO2H
TsOH
DMF
DMAC
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
74
62
71
60
74
95
42
38
N.R.
N.R.
N.R.
Trace
60
TfOH
PhCO2H
H2NSO3H
DABCO
DBU
Cs2CO3
TfOH
9
10
11
12c
13d
14e
TfOH
TfOH
93
a
Unless otherwise noted, reactions were carried out with 1a (0.4 mmol) and 2a
(0.8 mmol) in 1.0 mL solvent at 80 °C for 5 h in air.
b
Yield of isolated product.
c
The reaction was carried out with 10 mol % catalyst at room temperature for
5 h.
d
The reaction was carried out with 5 mol % catalyst at 80 °C for 5 h.
The reaction was carried out with 20 mol % catalyst at 80 °C for 5 h. TsOH = p-
toluenesulfonic acid, TfOH = trifluoromethanesulfonic acid, N.R. = no reaction.
e
Table 2
Extension of substrates for 3-(indol-3-yl)quinoxalin-2-ones synthesisa
R4
R5
R4
R5
N
N
TfOH (10 mol %)
DMF, 80 oC
in air
N
+
R3
R1
N
N
R2
R1
O
N
R3
O
1a-d
R2
2a-k
3b-t
2a, R2=H, R3=H, R4=H, R5=H
2b, R2=H, R3=Me, R4=H, R5=H
2c, R2=H, R3=OH, R4=H, R5=H
2d, R2=H, R3=H, R4=Br, R5=H
2e, R2=H, R3=H, R4=OMe, R5=H
2f, R2=H, R3=H, R4=H, R5=OMe
2g, R2=H, R3=H, R4=H, R5=OBn
2h, R2=H, R3=H, R4=H, R5=Br
2i, R2=H, R3=H, R4=H, R5=NO2
2j, R2=Bn, R3=H, R4=H, R5=H
1a, R1=Me
1b, R1=H
1c, R1=Bn
1d, R1=Allyl
Entry
1
2
3
Time (h)
Yieldb (%)
N
1
1a
2b
6
69
N
Me
O
N
H
Me
3b
3c
3d
N
2
3
1a
1a
2c
5
69
64
N
Me
O
N
H
HO
Br
N
2d
20
N
Me
O
N
H

Y.-Y. Han et al. / Tetrahedron Letters 51 (2010) 2023–2028
2025
Table 2 (continued)
Entry
1
2
3
Time (h)
Yieldb (%)
MeO
N
4
5
6
7
8
1a
2e
24
93
70
86
91
71
N
Me
O
N
H
3e
OMe
N
1a
1a
1a
1a
2f
24
24
28
28
N
Me
O
N
H
3f
OBn
N
2g
2h
2i
N
Me
O
N
H
3g
Br
N
N
Me
O
N
H
3h
NO2
N
N
Me
O
N
H
3i
N
N
9
1a
2j
4
92
Me
O
N
Bn
3j
N
10
11
12
1b
1b
1b
2b
2c
2d
6
1
86
69
HN
O
N
H
Me
N
3k
3l
HN
HN
O
N
H
HO
N
Br
11
66
O
N
H
3m
(continued on next page)

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Y.-Y. Han et al. / Tetrahedron Letters 51 (2010) 2023–2028
Table 2 (continued)
Entry
1
2
3
Time (h)
Yieldb (%)
MeO
N
13
14
15
16
17
18
19
1b
2e
11
72
HN
O
N
H
3n
OMe
N
1b
1b
1b
1b
1c
1d
1b
2f
6
6
92
91
86
75
94
91
85c
HN
O
N
H
3o
OBn
N
2g
2h
2i
HN
O
N
H
3p
Br
N
6
HN
O
N
H
3q
NO2
N
5
HN
O
N
H
3r
N
2a
2a
2a
3
N
Bn
O
N
H
3s
N
N
3
O
N
H
3t
N
20
15
N
Bn
O
N
H
3u
a
Reactions were conducted using 1 (0.4 mmol), 2 (0.8 mmol), and TfOH (10 mol %) in 1.0 mL DMF at 80 °C in air.
Yield of isolated product.
The reaction was carried out in 5.0 g scale.
b
c
free quinoxalin-2-one (2b) also smoothly provided the desired
(Table 2, entries 18 and 19). Additionally, it is pertinent to note
that we also demonstrated that the synthetic method described
here could be carried out in large scale to 5.0 g, giving the desired
product in 85% yield (Table 2. entry 20). Remarkably, very
wide range of substrate was tolerated to this method as shown
in Table 2.
products (3k–r) with 69–92% yields at the same optimal reaction
conditions (Table 2, entries 10–18). It was worth mentioning this
method could successfully yield 3m with 69% yield only in 1 h (Ta-
ble 2, entry 12). For other 1-substituted-quinoxalin-2-ones tested,
such as 2c and 2d as substrates, it was found that both of them
showed higher reactivity (3 h) in reaction with indole and afforded
the corresponding products with 94% and 91% yield, respectively
To probe the reaction mechanism, the following three verifica-
tion experiments were performed with 10 mol % TfOH in DMF,

Y.-Y. Han et al. / Tetrahedron Letters 51 (2010) 2023–2028
2027
DMF, 80 oC
in air, 3 h
TfOH (10 mol %)
NH
N +
N
DMF, 80 oC
N2, 5 h
N
H
N
N
N
Me
Me
Me
(1)
O
O
1a
O
N
H
N
H
2a
3a
A
65% yield
DMF, 80 oC
in air, 3 h
TfOH (10 mol %)
NH
N
N +
DMF, 80 oC
N2, 5 h
(2)
N
N
N
N
H
Bn
Bn
Bn
O
O
O
1c
N
N
H
2a
H
3s
B
O
OH
TfOH (10 mol %)
DMF, 80 oC
N
+
N +
+
(3)
N
H
N
N
Me
N2, 5 h
Me
O
OH
O
O
N
H
2a
1a
3a
5
6
72% yield
Scheme 1. Verification experiments.
N
2a
NH
H
N
H+
[O]
in air
N
N
N
N
Me
Me
N
N
Me
Me
O
N
O
N
O
H
3a
O
1a
A
H
-H+
Scheme 2. Proposed mechanism for the transformation.
respectively (Scheme 1). In experiment (1), the reaction was car-
ried out under argon atmosphere for 5 h leading to the only forma-
tion of A, as confirmed by crude 1H NMR analysis. This suggested
that acid-catalyzed Friedel–Crafts type reaction was the initial
reaction. The same reaction mixture was opened to air and stirred
at 80 °C for 3 h, after working up, the desired product 3a was ob-
tained with 65% yield. This revealed that the intermediate A was
subjected to oxidation by air in the second period. To the experi-
ment (2), we successfully obtained the intermediate B.13 Addition-
ally, in experiment (3), the mixture of 1a, 2a, 1,4-quinone (5),14 and
10 mol % TfOH in DMF was vigorously stirred at 80 °C for 5 h under
argon atmosphere, the reaction occurred well and the same desired
product 3a was formed with 72% isolated yield. Concurrently,
hydroquinone (6), reduced product of 1,4-quinone (5), was ob-
served as confirmed by TLC analysis. This also led us to ascertain
that the reaction experienced tandem Friedel–Crafts and oxidation
reactions.
In summary, we have presented an efficient approach for the
synthesis of various 3-(indol-3-yl)quinoxalin-2-ones through Fri-
edel–Crafts type coupling reaction between quinoxalin-2-ones
and indoles with catalytic amount TfOH (10 mol %) as a catalyst
and using air as an oxidizer. This procedure tolerates to a wide
range of substrates not only for quinoxalin-2-ones but also for in-
doles. Two verification experiments for the possible reaction
mechanism have been successfully conducted. Further applications
of quinoxalin-2-ones to synthesize a range of other aromatic nitro-
gen-containing heterocycles are currently in progress and will be
reported in due course.
Acknowledgement
We are grateful for financial support from the National Natural
Science Foundation of China (No. 20802074).
Based on the above-mentioned results and on Aoki’s study,5 we
postulate a mechanism for this transformation between quinoxa-
lin-2-ones 1 and indoles 2 to yield various 3-(indol-3-yl)quinoxa-
lin-2-ones 3 in Scheme 1. Firstly, quinoxalin-2-one (1a) was
activated by Brønsted acid forming cationic intermediate, then
the cationic intermediate and 2a took Friedel–Crafts type reaction
generating intermediate A while releasing catalyst acid. Finally, A
underwent oxidation by air yielding the desired product 3a
(Scheme 2).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.031.
References and notes
1. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, fourth ed.; Blackwell: Oxford,
2000; (b) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-VCH:

2028
Y.-Y. Han et al. / Tetrahedron Letters 51 (2010) 2023–2028
Weinheim; (c) Katrizky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic
Chemistry, second ed.; Pergamon: Amsterdam, 2000.
7. (a) Olah, G. A.. In Friedel–Crafts and Related Reactions; Interscience: New York,
1964; Vol. III. Part 1; (b) Heaney, H. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: New York, 1991.
2. (a) Vega, A. M.; Gil, M. J.; Basilio, A.; Giraldez, A.; Fernandez-Alvarez, E. Eur. J.
Med. Chem. 1986, 21, 251–254; (b) Manca, P.; Peana, A.; Savelli, F.; Mulé, A.;
Pirisino, G. Farmaco 1992, 47, 519–522.
3. (a) Loriga, M.; Fiore, M.; Sannaand, P.; Paglietti, G. Farmaco 1995, 50, 289–301;
(b) Epperson, J. R.; Hewawasam, P.; Meanwell, N. A.; Boissard, C. G.; Gribkoff, V.
K.; Post-Munson, D. Bioorg. Med. Chem. Lett. 1993, 3, 2801–2804; (c) McQuaid,
L. A.; Smith, E. C. R.; South, K. K.; Mitch, C. H.; Schoepp, D. D.; True, R. A.;
Calligaro, D. O.; O’Malley, P. J.; Lodge, D.; Ornstein, P. L. J. Med. Chem. 1992, 35,
3319–3324.
4. (a) Heldin, C. H.; Westermark, B.; Wasteson, A. Proc. Natl. Acad. Sci. U.S.A. 1979,
76, 3722–3726; (b) Heldin, C. H.; Westermark, B. Cell Regul. 1990, 1, 555–566;
(c) Heldin, C. H. EMBO J. 1992, 11, 4251–4259; (d) Myers, M. R.; He, W.; Hanney,
B.; Setzer, N.; Maguire, M. P.; Zulli, A.; Bilder, G.; Galzcinski, H.; Amin, D.;
Needle, S.; Spada, A. P. Bioorg. Med. Chem. Lett. 2003, 13, 3091–3095; (e) He, W.;
Myers, M. R.; Hanney, B.; Spada, A. P.; Bilder, G.; Galzcinski, H.; Amin, D.;
Needle, S.; Page, K.; Jayyosi, Z.; Perrone, M. H. Bioorg. Med. Chem. Lett. 2003, 13,
3097–3100; (f) Gazit, A.; Yee, K.; Uecker, A.; Bohmer, F. D.; Sjoblom, T.; Ostman,
A.; Waltenberger, J.; Golomb, G.; Banai, S.; Heinrich, M. C.; Levitzki, A. Bioorg.
Med. Chem. 2003, 11, 2007–2018.
5. (a) Aoki, K.; Obata, T.; Yamazaki, Y.; Mori, Y.; Hirokawa, H.; Koseki, J.; Hattori,
T.; Niitsu, K.; Takeda, S.; Aburada, M.; Miyamoto, K. Chem. Pharm. Bull. 2007, 55,
255–267; (b) Aoki, K.; Koseki, J.; Takeda, S.; Aburada, M.; Miyamoto, K. Chem.
Pharm. Bull. 2007, 55, 922–925.
6. (a) Bergstrand, H.; Karabelas, K.; Sjo, P. PCT Int. WO9813368 A1 19980402
(1998).; (b) Karabelas, K.; Lonn, H., Sjo, P. PCT Int. Appl. WO9946260 A1
19990916 (1999).; (c) Karabelas, K.; Sjo, P. PCT Int. WO9946264 A1 19990916
(1999).; (d) Nixey, T.; Temperst, P.; Hulme, C. Tetrahedron Lett. 2002, 43, 1637–
1639; (e) Chupakhin, O. N.; Sidorov, E. O.; Postovskii, I. Y. Khimiya
Geterotsiklicheskikh Soedinenii 1975, 10, 1433–1434.
8. For selected examples, see: (a) Johannsen, M. Chem. Commun. 1999, 2233–
2234; (b) Janczuk, A.; Zhang, W.; Xie, W. H.; Lou, S. Z.; Cheng, J. P.; Wang, P. G.
Tetrahedron Lett. 2002, 43, 4271–4274; (c) Endo, A.; Yanagisawa, A.; Abe, M.;
Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552–6554; (d) Lei,
F.; Chen, Y.-J.; Sui, Y.; Liu, L.; Wang, D. Synlett 2003, 1160–1164.
9. (a) Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495–2497; (b) Lakhdar,
S.; Westermaier, M.; Terrier, F.; Goumont, R.; Boubaker, T.; Ofial, A. R.; Mayr, H.
J. Org. Chem. 2006, 71, 9088–9095; (c) Tsuchimoto, T.; Matsubayashi, H.;
Kaneko, M.; Nagase, Y.; Miyamura, T.; Shirakawa, E. J. Am. Chem. Soc. 2008, 130,
15823–15835.
10. Various quinoxalin-2-ones were prepared according to the reported procedure,
see: McAtee, J. J.; Dodson, J. W.; Dowdell, S. E.; Girard, G. R.; Goodman, K. B.;
Hilfiker, M. A.; Sehon, C. A.; Sha, D.; Wang, G. Z.; Wang, N.; Viet, A. Q.; Zhang,
D.; Aiyar, N. V.; Behm, D. J.; Carballo, L. H.; Evans, C. A.; Fries, H. E.; Nagilla, R.;
Roethke, T. J.; Xu, X.; Yuan, C. C. K.; Douglas, S. A.; Neeb, M. J. Bioorg. Med. Chem.
Lett. 2008, 18, 3500–3503.
11. Using DMSO, toluene, EtOAc, CH2Cl2, THF, and CH3OH as solvents, respectively,
only trace amount of the corresponding product was monitored by thin layer
chromatography (TLC).
12. DABCO = 1,4-diazabicyclo[2.2.2]octane, DBU = 1,8-diazabicyclo[5.4.0]undec-7-
ene.
13. The corresponding N-benzyl intermediate
B was successfully isolated
and was ascertained by 1H NMR and 13C NMR spectra (See Supplementary
data).
14. In this verification experiment, the reaction was run with the amount 1a/2a/
5 = 0.4 mmol/0.8 mmol/0.5 mmol in 1.0 mL DMF.