Copper-catalyzed domino synthesis of 2-imino-1H-imidazol-5(2H)-ones and Quinoxalines involving C-C bond cleavage with a 1,3-dicarbonyl unit as a leaving group

Article abstract of DOI:10.1002/chem.201403001

Although 2-imino-1H-imidazol-5(2H)-ones have important biological activities in metabolism, their synthesis has rarely been investigated. Quinoxalines as privileged scaffolds in medicinal chemistry have been extensively investigated, but the development of novel and efficient synthetic methods remains very attractive. Herein, we have developed two copper-catalyzed domino reactions for the synthesis of 2-imino-1H-imidazol-5(2H) -ones and quinoxalines involving C-C bond-cleavage with a 1,3-dicarbonyl unit as a leaving group. The domino sequence for the synthesis of 2-imino-1H-imidazol- 5(2H)-ones includes aza-Michael addition, intramolecular cyclization, C-C bond-cleavage, 1,2-rearrangement, and aerobic dehydrogenation reaction, whereas the domino sequence for the synthesis of quinoxalines includes aza-Michael addition, intramolecular cyclization, elimination reaction, and C-C bond-cleavage reaction. The two domino reactions have significant advantages including high efficiency, mild reaction conditions, and high tolerance of various functional groups.

Full text of DOI:10.1002/chem.201403001

DOI: 10.1002/chem.201403001
Full Paper
&
Synthetic Methods
Copper-Catalyzed Domino Synthesis of 2-Imino-1H-imidazol-
5(2H)-ones and Quinoxalines Involving CÀC Bond Cleavage with
a 1,3-Dicarbonyl Unit as a Leaving Group
Yan Yang,[a] Fan Ni,[a] Wen-Ming Shu,[a] and An-Xin Wu*[a, b]
Abstract: Although 2-imino-1H-imidazol-5(2H)-ones have im-
portant biological activities in metabolism, their synthesis
has rarely been investigated. Quinoxalines as “privileged
scaffolds” in medicinal chemistry have been extensively in-
vestigated, but the development of novel and efficient syn-
thetic methods remains very attractive. Herein, we have de-
veloped two copper-catalyzed domino reactions for the syn-
thesis of 2-imino-1H-imidazol-5(2H)-ones and quinoxalines
involving CÀC bond-cleavage with a 1,3-dicarbonyl unit as
a leaving group. The domino sequence for the synthesis of
2-imino-1H-imidazol-5(2H)-ones includes aza-Michael addi-
tion, intramolecular cyclization, CÀC bond-cleavage, 1,2-rear-
rangement, and aerobic dehydrogenation reaction, whereas
the domino sequence for the synthesis of quinoxalines in-
cludes aza-Michael addition, intramolecular cyclization, elimi-
nation reaction, and CÀC bond-cleavage reaction. The two
domino reactions have significant advantages including high
efficiency, mild reaction conditions, and high tolerance of
various functional groups.
Introduction
tions, which can afford complex products with high efficiency.
Inspired by previous studies on CÀC bond-cleavage reactions
and based on our interests in developing novel domino reac-
CarbonÀcarbon bond-cleavage reactions have attracted much
attention from chemists because of their broad applications in
synthetic chemistry.[1] To date, several efficient CÀC bond cleav-
age strategies have been developed, including release of strain
energy,[2] chelation assistance,[3] oxidative cleavage,[4] and cleav-
age of functional substrates with carbonyl,[5] cyano,[6] ester,[7] or
hydroxyl groups.[8] Very recently, 1,3-dicarbonyl units have
been shown to be excellent leaving groups for CÀC bond-
cleavage reactions (Scheme 1).[9] In 2004, Kotora et al. reported
a transition-metal-catalyzed CÀC bond-cleavage reaction be-
tween 1,3-dicarbonyl and allyl group.[9a] In 2009, Zhai et al. re-
ported a SmI2-promoted CÀC bond-fragmentation reaction of
a-aminomethyl malonates.[9b] Fillion et al. reported a Pd-cata-
lyzed hydrogenolysis reaction with Meldrum’s acid as leaving
group.[9c] In 2011 and 2013, Li et al. reported two iron-catalyzed
reactions for CÀC and CÀN bond-formation with 1,3-dicarbonyl
units as leaving groups.[9d,e] However, as far as we know, this
efficient CÀC bond-cleavage strategy with 1,3-dicarbonyl units
as leaving groups has not yet been applied in domino reac-
[a] Y. Yang, F. Ni, W.-M. Shu, Prof. A.-X. Wu
Key Laboratory of Pesticide & Chemical Biology
Ministry of Education, College of Chemistry
Central China Normal University
Hubei, Wuhan 430079 (P. R. China)
E-mail: chwuax@mail.ccnu.edu.cn
[b] Prof. A.-X. Wu
Department of Chemistry
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403001.
Scheme 1. Previous studies on CÀC bond-cleavage reactions with 1,3-dicar-
bonyl units as leaving groups.
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tions, herein, we report two efficient copper-catalyzed domino
reactions for the synthesis of 2-imino-1H-imidazol-5(2H)-ones
and quinoxalines involving CÀC bond-cleavage with 1,3-dicar-
bonyl units as leaving groups.
Table 1. Optimization of the reaction conditions.[a]
The synthesis of novel heterocyclic skeletons is always a hot
topic in chemistry because it can provide enormous opportuni-
ties for the discovery of new pharmaceuticals and materials.[10]
2-Imino-1H-imidazol-5(2H)-one derivatives are important inter-
mediates in metabolism,[11] but methods for their synthesis
have rarely been investigated. Considering their potential ap-
plications in the pharmaceutical industry,[12] it is highly desira-
ble to develop an efficient method for their synthesis. Qui-
noxalines are “privileged scaffolds” in medicinal chemistry with
broad biological activities including antibiotic,[13] antiviral,[14]
anticancer,[15] and antidepressant[16] action. Although several
classical methods are available for their synthesis,[17] the devel-
opment of novel and efficient methods for the synthesis qui-
noxalines still attracts the attention of chemists.[18]
Entry
Catalyst [(equiv)]
Solvent
Temp. [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
22
23
24
25
Cu(OAc)2·H2O (0.20)
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
80
80
90
100
110
90
90
90
90
90
90
90
90
90
90
90
81
90
84
78
90
90
90
24
trace[c]
[d]
Cu(OAc)2·H2O (0.20)
Cu(OAc)2·H2O (0.20)
Cu(OAc)2·H2O (0.20)
Cu(OAc)2·H2O (0.20)
Cu(OAc)2·H2O (0.05)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.15)
CuO (0.15)
Cu2O (0.15)
CuBr (0.15)
CuCl (0.15)
CuI (0.15)
–
54
47
12
32
45
54
13
8
45
44
47
41
40
48
21
trace
9
trace
49
Previously, we reported an efficient method for the prepara-
tion of unsymmetrical 1,4-enediones from methyl ketones and
1,3-dicarbonyl compounds.[19] Herein, we reasoned that unsym-
metrical 1,4-enediones containing 1,3-dicarbonyl units can be
ideal substrates for the preparation of 2-imino-1H-imidazol-
5(2H)-ones and quinoxalines (Scheme 2).
CuCl2 (0.15)
CuBr2 (0.15)
CuSO4·5H2O (0.15)
Cu(OAc)2·H2O (0.15)
Cu(OAc)2·H2O (0.15)
Cu(OAc)2·H2O (0.15)
Cu(OAc)2·H2O (0.15)
Cu(OAc)2·H2O (0.15)
Cu(OAc)2·H2O (0.15)
Cu(OAc)2·H2O (0.15)
DMF
CH3CN
HOAc
ClCH2CH2Cl
EtOH
DMSO
toluene
1,4-dioxane
trace
trace
[a] Reaction conditions (unless otherwise specified): 1a (0.5 mmol,
1.0 equiv), 2a (0.55 mmol, 1.1 equiv), cat. (x equiv), solvent (2.5 mL),
under air, 36 h. [b] Isolated yield. [c] No copper catalyst. [d] Under Ar; no
desired product was obtained.
creased with higher temperature (100 and 1108C; entries 5–6).
The optimal catalyst amount was found to be 0.15 equiv Cu-
(OAc)2·H2O (entries 7–9). Other copper catalysts screened gave
lower yields (entries 10–17). We then screened other solvents
(CH3CN, HOAc, ClCH2CH2Cl, C2H5OH, dimethyl sulfoxide
(DMSO), toluene, 1,4-dioxane), but no better results were ob-
tained (entries 18–26). Based on these experiments, the opti-
mal reaction conditions were obtained with Cu(OAc)2·H2O
(0.15 equiv) in DMF at 908C under air.
Scheme 2. Our hypothesis.
Results and Discussion
Synthesis of 2-imino-1H-imidazol-5(2H)-ones
With this optimized result in hand, the generality of this re-
action was then explored. Based on our previously reported
method, a series of various 1,4-enediones 1 with b-keto ester
units as leaving groups were first prepared.[19] As shown in
Table 2, the scope of R1 substituents was first examined. To our
delight, the reaction proceeded efficiently with R1 substituents
bearing either electron-neutral (-H, -Me) or electron-donating
(-OMe) groups (3a–d; 47–54%). However, a lower yield was
obtained with R1 substituent bearing an electron-withdrawing
(-NO2) group (3e; 16%). For sterically hindered (1-naphthyl, 2-
naphthyl) and halogenated (-Cl, -Br, -F) R1 substituents, the cor-
responding products were obtained in good yields (3 f–j; 44–
53%). Fortunately, the structure of 3 f was further confirmed
by X-ray diffraction (Figure 1).[20] To our delight, heteroaryl R1
Initially, we investigated the proposed strategy by using 1,4-
enedione 1a and 1,3-diphenylguanidine (2a) as model sub-
strates. When the reaction was conducted in N,N-dimethylfor-
mamide (DMF) with Cu(OAc)2·H2O (0.2 equiv) as catalyst under
air at 808C, product 3a was isolated in 24% yield (Table 1,
entry 1). In the absence of copper catalyst, only trace amounts
of 3a and a major by-product of imidazole derivative 11 (60%
yield) was obtained (entry 2).[20] When the reaction was con-
ducted under argon, only an inseparable mixture was obtained
and no desired product 3a was observed (entry 3). These re-
sults suggested that both copper catalyst and air are necessary
for this reaction. When the temperature was increased to
908C, the yield was improved to 54%. However, the yields de-
Chem. Eur. J. 2014, 20, 11776 – 11782
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Table 2. Scope of the reaction with unsymmetrical 1,4-enediones 1.[a]
Entry
1
R1
R2
R3
3
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3a
3a
3a
3a
3a
54
52
53
47
16
53
51
46
44
45
48
47
53
4-MeC6H4
4-OMeC6H4
3-OMeC6H4
4-NO2C6H4
1-naphthyl
2-naphthyl
4-ClC6H4
4-BrC6H4
4-FC6H4
2-benzofuryl
3-thienyl
2-thienyl
CH3
Figure 1. X-ray structure of 3 f.
ones (Scheme 3) with 1,4-enedione 1a and 1,3-diphenylguani-
dine (2a) as an example. 1,4-Enedione 1a first reacts with 2a
through copper-catalyzed aza-Michael addition to generate in-
termediate A, which then undergoes intramolecular cyclization
to afford intermediate B.[22] Because the copper catalyst could
also promote CÀC bond-cleavage reaction by forming stable
coordination complex with the 1,3-dicarbonyl leaving
groups,[23] and the aryl R1 groups can facilitate the 1,2-rear-
rangement reaction by forming phenonium ion intermedi-
ates,[24] intermediate B undergoes further CÀC bond-cleavage
and 1,2-rearrangement reaction to generate intermediate D.
The product 3aa was finally obtained by copper-catalyzed
aerobic dehydrogenation reaction.[22]
[c]
–
Ph
Ph
Ph
Ph
4-MeOeC6H4
4-NO2C6H4
4-ClC6H4
4-FC6H4
Ph
52
50
49
51
7
6a
Ph
[a] Reaction conditions: 1 (1.0 mmol, 1.0 equiv), 2a (1.1 mmol, 1.1 equiv),
Cu(OAc)2·H2O (0.15 mmol, 0.15 equiv), DMF (5 mL), 908C, under air. [b] Iso-
lated yield. [c] No desired product was obtained.
substituents (2-benzofuryl, 3-thienyl and 2-thienyl) were also
compatible with this reaction, and good yields were obtained
(3k–m; 47–53%). However, for alkyl R1 substituent (-CH3), no
desired product was obtained (entry 14). With R2 or R3 substitu-
ents, the reaction proceeded efficiently with good yields for al-
koxyl groups (MeO, EtO), electron-donating (-OMe), electron-
withdrawing (-NO2), or halogenated (-F, -Cl) aryl groups (49–
52%, entries 15–18). When 1,4-enedione 6a was used as sub-
strate (R2 =R3 =Ph), only a low
To provide insight into the 1,2-rearrangement mechanism in
this reaction,
a
13C-labeling experiment was performed
(Scheme 4). First, 1,4-enedione 4 was prepared from 13C-la-
beled acetophenone and ethyl 3-oxo-3-phenylpropanoate.[19]
Then, 1,4-enedione 4 and 2a were treated under the standard
reaction conditions; the product 5 was obtained in 52% yield
with 13C-labeled carbon directly connected with to phenyl ring,
which was confirmed by 13C NMR spectroscopic analysis. This
yield of the desired product was
obtained (7%; entry 19), possibly
because the two bulky phenyl
substituents on the 1,3-dicarbon-
yl units were not beneficial for
this reaction. Unfortunately, only
an inseparable mixture was ob-
tained for other alkyl substituted
guanidine derivatives, such as
guanidine hydrochloride (2b),
1,1-dimethylguanidine (2c), and
l-Arginine (2d), possibly because
the corresponding products
could easily undergo hydrolysis
reactions.[11]
Based on the above results,
a possible reaction mechanism
was proposed for the synthesis
of
2-imino-1H-imidazol-5(2H)- Scheme 3. Proposed reaction mechanism for the synthesis of 2-imino-1H-imidazol-5(2H)-ones 3.
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Table 4. Scope of the reaction with unsymmetrical 1,4-enediones 6 and
o-phenylenediamine 7.[a]
Entry
R1
R2
R3
R4
8
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OEt
OEt
OEt
OMe
OMe
CH3
CH3
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
Cl
8a
8b
8c
8d
8e
8 f
8g
8h
8i
94
95
89
91
85
92
91
93
94
89
94
92
93
85
93
92
91
92
94
96
93
86
4-MeC6H4
4-OMeC6H4
4-NO2C6H4
1-naphthyl
2-naphthyl
4-ClC6H4
4-BrC6H4
4-FC6H4
2-furyl
2-benzofuryl
3-thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Scheme 4. The 13C-labeling experiment for the preparation of 2-imino-1H-
imidazol-5(2H)-ones 5.
result unambiguously verified the 1,2-rearrangement reaction
in the proposed domino sequence.
8j
8k
8l
Synthesis of quinoxalines
Ph
8a
8a
8a
8a
8a
8a
8a
8m
8n
8o
Initially, we investigated the feasibility of synthesis of quinoxa-
lines by using 1,4-enedione 6a, with a 1,3-diketone unit as the
leaving group, and o-phenylenediamine 7a as model sub-
strates. Fortunately, when the reaction was conducted in DMF
with Cu(OAc)2·H2O (0.05 equiv) as catalyst under air at 808C
(Table 3, entry 1), the desired product 8a was obtained in 82%
yield and 1,3-diphenylpropane-1,3-dione was recovered in
83% yield. The yield increased to 93% by increasing the
amount of catalyst to 0.1 equiv (entry 2). Much to our satisfac-
tion, when the reaction was conducted at room temperature,
the reaction efficiency was not affected (94%; entry 3). When
the reaction was conducted under argon, the product was also
obtained in high yield (93%; entry 4). However, in the absence
of copper catalyst, product 8a was obtained in only 12% yield
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
4-FC6H4
Ph
CH3
Ph
Ph
Ph
Ph
Ph
CH3
[a] Reaction conditions: 6 (1.0 mmol, 1.0 equiv), 7 (1.1 mmol, 1.1 equiv),
Cu(OAc)2·H2O (0.1 mmol, 0.1 equiv), DMF (5 mL) at RT. [b] Isolated yield.
(entry 5). These results suggested that copper catalyst is neces-
sary for this reaction. Other copper catalysts were then
screened, but most of them were unfavorable for this reac-
tion and low yields were obtained (entries 6–13). We also
screened other solvents, but no better results were ob-
tained (entries 14–21).
Table 3. Optimization of the reaction conditions.[a]
With this optimized result in hand, we next explored the
scope of this reaction (Table 4). The scope of 1,4-enedione
1 or 6 with various 1,3-dicarbonyl units as leaving groups
were all examined. As shown in Table 4, substrates with
electron-neutral (-H, -Me), electron-donating (-OMe), elec-
tron-withdrawing (-NO2), or sterically hindered (1-naphthyl,
2-naphthyl) R1 substituents were smoothly transformed
into their respective products in high yields (85–95%;
Table 2, entries 1–6). Substrates with halogenated and het-
eroaryl R1 substituents were also compatible with the reac-
tion, and excellent yields were obtained (89–94%, en-
tries 7–12). The substrate scope was then expanded with
different units, with R2 and R3 substituents including
alkoxy (-OEt, -OMe), alkyl (-CH3), electron-neutral (-H), elec-
tron-donating (-OMe), electron-withdrawing (-NO2), or
halogenated (-F, -Cl) aryl substituents, and high to excel-
lent yields were obtained (85–94%; entries 13–19). To our
delight, excellent yields were also obtained for substituted
o-phenylenediamines such as 4,5-dimethylbenzene-1,2-dia-
mine and 4,5-dichlorobenzene-1,2-diamine (93–96%; en-
tries 20–21). When R1 was an alkyl substituent (-CH3), the
corresponding product 8o was also obtained in high yield
(86%; entry 22).
Entry
Catalyst [(equiv)]
Solvent
Temp. [8C]
Yield [%][b]
1
2
3
4[c]
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)2·H2O (0.05)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.1)
–
CuO (0.1)
Cu2O (0.1)
CuBr2 (0.1)
CuCl2 (0.1)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
80
RT
RT
80
80
80
80
80
80
80
80
80
80
80
80
80
80
78
80
80
82
93
94
93
12
14
16
12
10
13
11
12
13
91
90
76
71
63
56
72
27
CuSO4·5H2O (0.1)
CuBr (0.1)
CuCl (0.1)
CuI (0.1)
DMF
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.1)
CH3CN
HOAc
CH2ClCH2Cl
C2H5OH
DMSO
C2H5OH
toluene
1,4-dioxane
[a] Reaction conditions (unless otherwise specified): 6a (0.5 mmol, 1.0 equiv),
7a (0.55 mmol, 1.1 equiv), catalyst (x equiv), solvent (2.5 mL), under air, 1 h.
[b] Isolated yield. [c] Under Ar.
Based on the previous results, a possible reaction mech-
anism for the synthesis of quinoxazlines 8 was proposed
Chem. Eur. J. 2014, 20, 11776 – 11782
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through domino integration of
aza-Michael addition, intramolec-
ular cyclization, elimination reac-
tion, and carbonÀcarbon bond-
cleavage reaction. It is worth
noting that a range of 1,3-dicar-
bonyl units could act as leaving
groups for the CÀC bond-cleav-
age reaction to afford the de-
sired products. These reactions
also have significant advantages
in high efficiency, mild reaction
conditions, and high tolerance
of various functional groups.
Scheme 5. Proposed reaction mechanism for the synthesis of quinoxazlines 8.
Experimental Section
General methods
Dimethyl formamide was freshly distilled from anhydrous magnesi-
um sulfate, and dimethyl sulfoxide was freshly distilled from calci-
um hydride. Other reagents were purchased from commercial sup-
pliers and used without further purification. 1,4-Enediones 1 and 6
were prepared according to our previous reports.[19] IR spectra
were recorded with a Perkin-Elmer PE-983 infrared spectrometer as
with 1,4-enedione 6a and o-phenylenediamine (7a) as an ex-
ample (Scheme 5). Initially, 7a reacts with 1,4-enedione 6a
through copper-catalyzed aza-Michael addition to form inter-
mediate A’,[21] which could then undergoes intramolecular cyc-
lization reaction and elimination of one equivalent of water to
afford intermediate C’. The latter intermediate could finally
afford the thermally stable quinoxazline product 8a through
CÀC bond-cleavage reaction catalyzed by copper catalyst,
which can form a stable coordination complex with the 1,3-di-
carbonyl leaving groups.[23]
1
KBr pellets with absorption reported in cmÀ1. H spectra were re-
corded in CDCl3 or [D6]DMSO with a Varian Mercury 400/600 MHz
NMR spectrometer and resonances (d) are given in ppm relative to
tetramethylsilane. Data are reported as follows: chemical shift, mul-
tiplicity (s=singlet, d=doublet, t=triplet, m=multiplet, br s=
broad singlet), coupling constants (Hz) and integration. 13C NMR
spectra were recorded in CDCl3 or [D6]DMSO with a Varian Mercury
100/150 MHz spectrometer and resonances (d) are given in ppm
relative to the center line of a triplet at d=77.0 ppm of CDCl3 or
a heptet at d=39.5 ppm of [D6]DMSO. HRMS were obtained with
a Fourier transform ion cyclotron resonance (FTICR) mass spec-
trometer (Bruker Daltonik Company, USA). Melting points were de-
termined without correction. The structure of 3 f was confirmed by
X-ray diffraction. Column chromatography was performed on silica
gel (200–300 mesh).
We also conducted 13C labeling experiments by reacting 13C-
labeled 1,4-enedione 9 with 7a under the standard reaction
conditions (Scheme 6) and found that 13C-labeled product 10
Scheme 6. The 13C-labeling experiment for the preparation of quinoxaline
10.
Experimental procedures
General experimental procedure for the preparation of 2-imino-
1H-imidazol-5(2H)-ones 3 from 1,4-enediones 1 and 1,3-diphe-
nylguanidines 2 (3aa as an example): A mixture of ethyl 2-benzo-
yl-4-oxo-4-phenylbut-2-enoate (1a; 308 mg, 1.0 mmol), 1,3-diphe-
nylguanidine (2a; 232 mg, 1.1 mmol), and Cu(OAc)2·H2O (30 mg,
0.15 mmol) in DMF (5 mL) was stirred at 908C for 36 h under air.
Upon completion of the reaction, the mixture was diluted with
water and extracted with CH2Cl2 (3ꢁ30 mL), the combined organic
extracts were washed with water (four times) and brine successive-
ly. After drying over Na2SO4 and concentration under reduced pres-
sure, the crude product was purified by column chromatography
on silica gel (petroleum ether/CH2Cl2 =3:1) to afford 3a (176 mg,
54%) as a yellow solid.
1
was obtained in 92% yield; the H NMR spectrum of the latter
shows that the proton connected with the 13C atom is split
into doublet peaks (J=181.2 Hz), which suggests the 1,2-
phenyl rearrangement reaction did not occur in the prepara-
tion of quinoxalines.
Conclusion
We have developed two facile and efficient copper-catalyzed
domino reactions for the synthesis of 2-imino-1H-imidazol-
5(2H)-ones and quinoxalines. 2-Imino-1H-imidazol-5(2H)-one
derivatives were synthesized through domino integration of
aza-Michael addition, intramolecular cyclization, carbonÀ
carbon bond-cleavage reaction, 1,2-rearrangement, and aero-
bic dehydrogenation; whereas quinoxalines were obtained
General experimental procedures for the preparation of qui-
noxalines 8 from 1,4-enediones 6 and o-phenylenediamine 7
(8a as an example): A mixture of 2-benzoyl-1,4-diphenylbut-2-ene-
1,4-dione (6a; 340 mg, 1.0 mmol), o-phenylenediamine (7a;
119 mg, 1.1 mmol), and Cu(OAc)2·H2O (20.0 mg, 0.1 mmol) in DMF
(5 mL) was stirred at RT for 1 h under air. Upon completion of the
Chem. Eur. J. 2014, 20, 11776 – 11782
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9
A mixture of 13C-labeled 2-benzoyl-1,4-diphenylbut-2-ene-1,4-dione
(9; 341 mg, 1.0 mmol), o-phenylenediamine (7a; 119 mg,
1.1 mmol), and Cu(OAc)2·H2O (20.0 mg, 0.1 mmol) in DMF (5 mL)
was stirred at RT for 1 h under air. Upon completion of the reac-
tion, the mixture was diluted with water and extracted with CH2Cl2
(3ꢁ30 mL), and the combined organic extracts were washed with
water (four times) and brine successively. After drying over Na2SO4
and concentration under reduced pressure, the crude product was
purified by column chromatography on silica gel (petroleum ether/
EtOAc=20:1) to afford 10 (190 mg, 92%) as a white solid.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant 21032001 and 21272085). We also thank Dr. Chuanqi
Zhou for his help in performing HRMS analysis and Dr. Xiang-
gao Meng for performing X-ray diffraction analysis.
Keywords: CÀC bond cleavage · 1,3-dicarbonyl units · domino
reactions · nitrogen heterocycles · quinoxalines
[20] For details, please see the Supporting Information.
Chem. Eur. J. 2014, 20, 11776 – 11782
www.chemeurj.org
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Full Paper
[21] CCDC-965187 (3 f) contains the supplementary crystallographic data for
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Published online on July 30, 2014
Chem. Eur. J. 2014, 20, 11776 – 11782
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