One-pot copper-catalyzed three-component synthesis of quinoxalines by condensation and C-N bond formation

Article abstract of DOI:10.1055/s-0033-1339797

A novel way of synthesizing quinoxalines has been developed that involves condensation and C-N bond formation in a copper-catalyzed, one-pot, three-component reaction. The reaction was optimized when 2-iodoanilines (1.0 equiv), arylacetaldehydes (2.0 equiv), sodium azide (1.2 equiv), CuI (10 mol%), DMEDA (10 mol%), and K₂CO₃ (1.0 equiv) were reacted in DMSO at 80 °C for 20 hours. This approach was used to directly synthesize a variety of quinoxalines in moderate to good yields. Georg Thieme Verlag KG Stuttgart.

Full text of DOI:10.1055/s-0033-1339797

LETTER
▌2315
letter
One-Pot Copper-Catalyzed Three-Component Synthesis of Quinoxalines by
Condensation and C−N Bond Formation
Synthesis of Quinoxalines
Hua Yuan,a,b Kangning Li,a,b Yongxin Chen,a,b Yu Wang,a,b Jiaojiao Cui,a,b Baohua Chen*a,b
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu, Lanzhou 730000, P. R. of China
b
Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: chbh@lzu.edu.cn
Received: 06.07.2013; Accepted after revision: 20.08.2013
approach avoids the production of regioisomers in the
Abstract: A novel way of synthesizing quinoxalines has been de-
products when using 2-iodoanilines as starting materials
and provides a novel, convenient, economical, and practi-
cal synthetic route to quinoxalines.
veloped that involves condensation and C−N bond formation in a
copper-catalyzed, one-pot, three-component reaction. The reaction
was optimized when 2-iodoanilines (1.0 equiv), arylacetaldehydes
(2.0 equiv), sodium azide (1.2 equiv), CuI (10 mol%), DMEDA
(10 mol%), and K2CO3 (1.0 equiv) were reacted in DMSO at 80 °C
for 20 hours. This approach was used to directly synthesize a vari-
ety of quinoxalines in moderate to good yields.
(A) genaral strategies
R1
R2
O
O
R1
R2
R1
R2
N
N
N
N
NH2
NH2
NH2
NH2
+
Key words: quinoxalines, arylacetaldehydes, sodium azide, three-
component reaction
R1
R2
X
+
Nitrogen-containing heteroaromatic compounds are im-
portant structures that are found in many natural and syn-
thetic compounds. Among them, quinoxalines are crucial
core structures that are used to create pharmaceuticals and
agrochemicals.1 In addition, they are useful as electrolu-
minescent materials,2 organic semiconductors,3 dehy-
droannulenes,4 and dyes.5 During the last decades, a
number of synthetic strategies have been developed for
the preparation of substituted quinoxalines. Traditionally,
condensation of 1,2-diamines with 1,2-dicarbonyl com-
pounds,6 and oxidative cyclization of α-hydroxy ketones
or α-halide ketones with 1,2-diamines have been widely
used (Scheme 1, A).7
O
X = OH or halogen
(B) previous work in our group
NH2
N
Ph
+
NH2
N
N
Ph
NH2
CHO
+
N
N
N
Ph
Ph
R
NH2
NH2
NO2
+
Recently, we have reported a copper-catalyzed synthetic
approach to quinoxalines with o-phenylenediamine and
terminal alkyne in the presence of bases.8 Subsequent to
this discovery, the synthesis of quinoxalines with o-phen-
ylenediamine and phenylacetaldehyde under metal-free
conditions was reported.9 As part of our ongoing studies
on quinoxaline derivatives, we also reported a copper-cat-
alyzed synthesis of quinoxalines from o-phenylenedi-
amine and nitroolefin without additional base (Scheme 1,
B).10 Although these systems showed broad scope and
high efficiency under mild conditions, they all resulted in
the formation of regioisomers of the products when 1,2-
diamines were employed as starting materials. Neverthe-
less, encouraged by these transformations, we envisaged
that by using sodium azide as a nitrogen source, quinoxa-
lines could be synthesized through copper-catalyzed, one-
pot, there-component reaction from 2-iodoanilines, phen-
ylacetaldehydes and NaN3 in the presence of base. This
R
NH2
(C) this work
NH2
N
N
CHO
+
NaN
+
3
I
Ph
Scheme 1 Synthesis of quinoxaline derivatives
As a model reaction, 2-iodoaniline (1a), phenylacetalde-
hyde (2a), and sodium azide (3) were reacted under a va-
riety of reaction conditions (Table 1). The desired 2-
phenylquinoxaline (4aa) was not obtained in the absence
of metal catalyst when 1a (1.0 equiv), 2a (2.0 equiv), 3
(1.2 equiv), 10 mol% DMEDA, and K2CO3 (1.0 equiv)
were reacted in DMSO at 80 °C for 20 hours (Table 1, en-
try 1); therefore, we employed and tested several copper
catalysts. Gratifyingly, the desired product 4aa was ob-
tained in 61% yield with 10 mol% CuCl (Table 1, entry 2).
Furthermore, when the copper salts were changed to
CuBr, CuI, CuO, Cu(OAc)2, CuCl2 and CuBr2, it was
found that CuI showed the highest activity for this reaction,
SYNLETT 2013, 24, 2315–2319
Advanced online publication: 19.09.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339797; Art ID: ST-2013-W0618-L
© Georg Thieme Verlag Stuttgart · New York

2316
H. Yuan et al.
LETTER
resulting in 75% yield (Table 1, entries 3–8). Performing Having established the optimal reaction conditions, the
the reaction for a shorter time (12 h) resulted in a lower scope of the reaction was then examined; the results are il-
yield, and no improvement was achieved when the reac- lustrated in Table 2. Various 2-iodoanilines were exam-
tion time was prolonged to 24 hours (Table 1, entry 9).
ined. Generally, the reaction of a series of 2-iodoanilines
1 with phenylacetaldehyde (2a) and sodium azide (3) pro-
ceeded smoothly and led to the desired product 4 in mod-
erate to good yields. Upon examining the electronic
effects of these reactions, we found that 2-iodoanilines
with electron-donating groups, such as methoxy and
methyl groups (Table 2, entries 1–3) showed better activ-
ities and gave higher yields than those with electron-with-
drawing groups such as chloro and bromo (Table 2,
entries 4–7). To our delight, strongly electron-withdraw-
ing substituents (CF3, NO2) were also compatible with the
reaction conditions. However, when 3-iodopyridin-2-
When the temperature of the reaction was reduced to
room temperature, none of the desired product was
formed, and a lower yield was obtained when the temper-
ature was increased to 100 °C (Table 1, entry 10). Other
ligands such as TMEDA, 1,10-phenanthroline and 2,2′-bi-
pyridine were evaluated, but no better result was obtained
(Table 1, entries 11–13). Several bases (Na2CO3, KHCO3,
DMAP, Cs2CO3, KOH, Li2CO3) were also tested, howev-
er, these bases were less efficient than K2CO3 (Table 1,
entries 14–19). We then attempted several different sol-
vents, including DMF, toluene and 1,4-dioxane, however
no products were formed.
Table 1 Optimization of Reaction Conditionsa
NH2
N
catalyst, base
solvent
CHO
NaN3
3
+
+
I
N
4aa
Ph
1a
2a
Entry
Catalyst
Ligand
Base
Yield (%)b
1
2
–
DMEDA
DMEDA
DMEDA
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KHCO3
DMAP
Cs2CO3
KOH
0
CuCl
CuBr
CuI
CuO
Cu(OAc)2
CuCl2
CuBr2
CuI
61
3
54
4
DMEDA
DMEDA
75
5
0
6
DMEDA
23
7
DMEDA
34
8
DMEDA
28
9
DMEDA
56,c 74d
0,e 71f
48
10
11
12
13
14
15
16
17
18
19
CuI
DMEDA
CuI
TMEDA
CuI
1,10-phenanthroline
2,2′-bipyridine
DMEDA
0
CuI
0
CuI
64
CuI
DMEDA
68
CuI
DMEDA
0
CuI
DMEDA
60
CuI
DMEDA
0
CuI
DMEDA
Li2CO3
trace
a Reaction conditions: 1a (0.25 mmol), 2a (0.50 mmol), 3 (0.30 mmol), catalyst (0.025 mmol), ligand (0.025 mmol), base (1.0 equiv), solvent
(1.0 mL), 80 °C, 20 h.
b Isolated yield.
c Reacted for 12 h.
d Reacted for 24 h.
e Reacted at r.t.
f Reacted at 100 °C.
Synlett 2013, 24, 2315–2319
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Quinoxalines
2317
Table 2 Reactions of Substituted 2-Iodoanilines with Phenylacetaldehyde and Sodium Azidea
NH2
N
CuI, DMEDA, K2CO3
DMSO, 80 °C, 20 h
CHO
R
+
+
NaN3
I
3
R
N
Ph
1
2a
4
Entry
1
2-Iodoaniline 1
Product 4
Yield (%)b
81
NH2
I
N
N
1b
4ba
MeO
MeO
Ph
N
N
NH2
2
3
1c
4ca
4da
84
74
Ph
I
Cl
NH2
I
Cl
N
N
1d
Ph
Ph
N
NH2
4
5
6
7
8
1e
1f
4ea
4fa
4ga
4ha
4ia
52
54
64
37
0
F3C
Cl
F3C
Cl
N
I
NH2
N
I
N
N
Ph
NH2
1g
1h
1i
Br
Br
I
N
Ph
Ph
NH2
N
O2N
O2N
I
N
NH2
I
N
a All reactions were carried out in sealed tubes by using 1 (0.25 mmol), 2a (0.5 mmol), 3 (0.3 mmol), K2CO3 (1 equiv), DMSO, 80 °C, 20 h.
b Isolated yield.
amine was tested, no reaction was observed (Table 2, sis of this result, a possible mechanism of quinoxaline
entry 8).
formation was proposed (Scheme 2, B). The reaction of 2-
iodoaniline (1a) and arylacetaldehyde (2a) first affords I,
which equilibrates to enamine II. Coordination of II with
The substrate scope of the reaction with phenylacetalde-
hydes 2 was further investigated under the optimized con-
ditions (Table 3). These results indicated that electron-
donating phenylacetaldehydes could be successfully em-
ployed (Table 3, entries 2 and 3), and gave higher yields
than electron-withdrawing substrates (Table 3, entries 4
and 5). Furthermore, substrates with a methoxy moiety on
the phenylacetaldehyde and 2-iodoanilines with several
–
CuI forms III, and exchange of I– in III with N3 of NaN3
gives IV. Reductive elimination of IV leads to V and thus
to VI by cyclization with leaving N2. Finally, VI could be
easily oxidized to the target compound 4aa in the pres-
ence of base. We will focus on the reaction mechanism in
further studies.
substituents also proceeded smoothly with sodium azide In summary, an efficient method with which to synthesize
and gave good yields (Table 3, entries 6–10). To our dis- quinoxalines was developed involving copper-catalyzed,
appointment, when an alkylaldehyde and a heteroaryl ac- one-pot, three-component reactions of 2-iodoanilines,
etaldehyde were tested, none of the desired product was phenylacetaldehydes and NaN3 in the presence of
formed (Table 3, entries 11 and 12).
K2CO3.11 The approach avoids production of regioisomers
in the products through the use of sodium azide as the ni-
trogen source. The reaction requires commercially avail-
able substrates as starting materials and is suitable for the
construction of a variety of quinoxalines in moderate to
good yields.
To understand the reaction mechanism, reaction of 2-io-
doaniline (1a) with NaN3 (3) was performed under our
standard conditions as shown in Scheme 2 (A), but no
products were obtained. This indicates that no o-phenyl-
enediamine 5 is created in this transformation. On the ba-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2315–2319

2318
H. Yuan et al.
LETTER
Table 3 Reactions of Substituted Phenylacetaldehydes with 2-Iodoanilines and Sodium Azidea
N
N
NH2
I
CuI, DMEDA, K2CO3
DMSO, 80 °C, 20 h
CHO
R2
R1
NaN3
+
+
R1
R2
3
1
2
4
Entry
1
R1
2
R2
Ph
Product 4
Yield (%)b
1
2
1a
1a
1a
1a
1a
1c
1d
1e
1f
H
2a
2b
2c
2d
2e
2b
2b
2b
2b
2b
2f
4aa
4ab
4ac
4ad
4ae
4cb
4db
4eb
4fb
4gb
4af
75
64
60
52
0
H
4-MeOC6H4
4-MeC6H4
4-ClC6H4
3
H
4
H
5
H
4-O2NC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
n-Pr
6
4,5-Me2
4-Cl-5-Me
4-CF3
4-Cl
68
65
67
62
58
0
7
8
9
10
11
12
1g
1a
1a
4-Br
H
H
2g
heteroarylc
4ag
0
a All reactions were carried out in sealed tubes by using 1 (0.25 mmol), 2a (0.5 mmol), 3 (0.3 mmol), K2CO3 (1 equiv), DMSO, 80 °C, 20 h.
b Isolated yield.
c 2-(Pyridin-4-yl)acetaldehyde.
CuI,DMEDA
K2CO3
NH2
I
NH2
NH2
A
B
NaN3
+
DMSO
3
5
1a
1a
O
H
N
H
N
NH2 Ph
N
I
CuI/L
2a
I
Cu
Ph
Ph
I
Ph
H2O
L
I
II
III
I
NaN3
3
NaI
H
N
H
N
H
N
base
DMSO
N
N
Cu
Ph
N3
Ph
N
H
Ph
Ph
N2
CuL
L
N3
IV
2 H
4aa
VI
V
Scheme 2 Proposed mechanism of the reaction
Acknowledgment
References and Notes
We are grateful for support of this project by the National Natural
Science Foundation of China (No. 21372102) and the project of Sci-
ence Foundation of Gansu Province (No. 1208RJZA266).
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http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
Synlett 2013, 24, 2315–2319
© Georg Thieme Verlag Stuttgart · New York

LETTER
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(11) Synthesis of 2-Phenylquinoxaline (4aa); Typical
Procedure: 2-Iodoaniline (1a; 54.8 mg, 0.25 mmol),
sodium azide (3; 19.5 mg, 0.3 mmol), CuI (4.8 mg, 0.025
mmol), K2CO3 (34.5 mg, 0.25 mmol), phenylacetaldehyde
(2a; 58 μL, 0.5 mmol), DMEDA (3 μL, 0.025 mmol), and
DMSO (1.0 mL) were added to a round-bottom flask
equipped with stirrer, and the reaction mixture was heated to
80 °C for 20 h. After cooling to room temperature, the
reaction mixture was added to water (2 mL), and extracted
with EtOAc (3 × 10 mL). The combined organic phases
were washed with brine (2 × 5 mL), dried over anhydrous
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© Georg Thieme Verlag Stuttgart · New York
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