Efficient synthesis of pyrrolo[1,2-: A] quinoxalines catalyzed by a Br?nsted acid through cleavage of C-C bonds

Article abstract of DOI:10.1039/c6ob01401a

An efficient and convenient one-pot domino reaction for the direct synthesis of pyrrolo[1,2-a]quinoxalines has been developed. This approach utilizes an imine formation reaction, S_EAr reaction and cleavage of C-C bonds catalyzed by a Br?nsted acid. β-Diketones and β-keto esters are both well tolerated to give the corresponding products in moderate to excellent yields.

Full text of DOI:10.1039/c6ob01401a

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Received 00th January
Efficient Synthesis of Pyrrolo[1,2-a]quinoxalines Catalyzed by
Brønsted Acid through Cleavage of C-C Bond
20xx,
a
a
a
a
a
a
a,b
Caixia Xie , Lei Feng , Wanli Li , Xiaojun Ma , Xinkun Ma , Yihan Liu , and Chen Ma*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient and convenient one-pot domino reaction of the direct synthesis of pyrrolo[1,2-a]quinoxaline has been
developed. This approach utilizes imine formation reaction, S Ar reaction and cleavage of C-C bond catalyzed by Brønsted
E
acid. β-Diketones and β-keto esters are both well adaptive to give the corresponding products in moderate to excellent
yields.
Introduction
The quinoxaline skeleton is
a key structure unit in various
1
compounds with biological activities. Pyrrolo[1,2-a]quinoxaline as
an indispensable part of quinoxalines exhibits a wide range of
biological and medical properties. For example, ferrocenyl
pyrrolo[1,2-a]quinoxaline plays an effective role in fighting against
2
malaria, and 4-substituted pyrrolo[1,2-a]quinoxalines are anti-
3
leishmania agents. Furthermore, extensive uses have been proved,
4
5
such as the human protein kinase CK2 inhibitors, 5-HTR affinities,
6
7
anticancer and glucagon receptor antagonists.
Due to their wide applications, there emerged some synthetic
methods of pyrrolo[1,2-a]quinoxaline in recent years (Scheme 1).
Reaves and co-workers reported
a strategy of Cu-catalyzed
8
annulation of 2-formylazoles with o-aminoiodorarenes in 2010 (a).
Besides, based on 2-(1H-pyrrol-1-yl)aniline used by Cheeseman in
9
1
965 to synthesize this kind of coumpouds, many strategies have
1
0
been reported. It could react with benzaldenyde, aliphatic or
1
1
12
benzylic alcohols and benzylamines to obtain the desirable
compounds catalyzed by Lewis acids (b, c, e). In 2014, Jamison and
co-workers proposed
a
method using visible-light photoredox
1
3
catalysis (d). In addition, many other methods have also been
1
4
reported.
However, these methods suffered from several
disadvantages, like unsatisfactory yields, excessive reactants,
transition metal catalysts, unstable reactants and limitations of the
product structure. Our group has been dedicating to building this
skeletal structure, and quite remarkable progresses have been
Scheme 1 synthesis of pyrrolo[1,2-a]quinoxaline derivatives
1
5
made (Scheme 2) .
Recently, Bao and co-workers reported an efficient protocol to
synthesize a series of benzothiazoles and benzimidazoles through
16a-b
Brønsted acid catalyzed cylization reaction.
We envisioned that
a.
school of Chemistry and Chemical Engineering, Shandong University, Jinan,
50100, P R China.
a reaction strategy of C-C bond cleavage will become a feasible and
efficient synthetic option of pyrrolo[1,2-a]quinoxaline derivatives.
Different from their limitation of β-diketones, we discovered that
the reaction of β-keto esters could also be applied to this strategy,
so that the reaction scope and generality were greatly improved.
Based on these points and our previous works on synthesizing
2
b.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing, 100050, P. R. China.
†
Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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diphenylpropane-1,3-dione (2a) as the model substrates. In the
N
N
o
N
I2
presence of TsOH·H O (0.095 g, 0.5 mmol) in DMSO at 110 C, the
2
O
O
DMSO
desired product 4a was furnished in 78% (Table 1, entry 1). Next a
NH2
series of Brønsted acids, namely PivOH, AcOH, CF
3
COOH and
CH SO H, were investigated and none was better than TsOH·H O
3
3
2
(
Table 1, entries 2-5). Then several solvents were screened in the
N
R
N
Cu(AcO)2
K3PO4
reaction, and the reaction in DMSO produced the best yield of the
product (Table 1, entries 1, 6-8). Furthermore, when the
temperature was changed, to our delight, an enhancement in
HOOC
NH2
X
N
R
X = Br, I
o
product yield was observed in 120 C (Table 1, entries 1, 9 and 10).
Subsequently, the dosages of catalyst were examined and the
reaction with 50 mol% TsOH·H
2
O gave the highest yield of 89%
Scheme 2 our previous works on synthesis of the compound
(
Table 1, entries 11-13). And when the 1a / 2a ratio was changed,
the reaction of 0.5 mmol 1a with 0.75 mmol 2a gave the best yield
heterocyclic compounds, we report an efficient, convenient and
low-toxic one-pot reaction for the synthesis of pyrrolo[1,2-
a]quinoxaline derivatives (Scheme 1).
a
Table 2 Substrate scope of β-diketones
Results and discussion
b
Entry
1
1(R
1
/ R
2
)
2 (R
3
/ R
4
)
Product
Yield(%)
We initiated our proposal with exploring the optimized reaction
conditions using 2-(1H-pyrrol-1-yl)aniline (1a) and 1,3-
d
H / H
Ph / Ph
4a
89
d
2
3
4
5
6
7
8
H / Me
H / OMe
H/ Cl
Ph / Ph
Ph / Ph
Ph / Ph
Ph / Ph
Ph / Ph
Ph / Ph
Ph / Ph
4b
4c
4d
4e
4f
78
Table 1 Optimization of reaction conditions for the one-pot
d
a
83
synthesis of 4a
d
94
d
Cl / H
91
d
H / F
96
o
b
Entry
Catalyst / mol %
TsOH / 100
T / C
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
Yield (%)
78
d
F / H
4g
4h
87
1
2
3
4
5
6
7
8
9
110
110
110
110
110
110
110
110
120
130
120
120
120
120
120
120
120
120
d
2-(1H-imidazol-1-
0
PivOH / 100
AcOH / 100
27
yl)aniline
N. R.
71
d
9
2-(1H-indol-1-
Ph / Ph
Ph / Ph
4i
4j
46
CF
3
COOH / 100
yl)aniline
CH SO H / 100
75
3
3
d
1
0
2-(3-methyl-1H-
75
TsOH·H O/ 100
CH CN
3
56
2
indol-1-yl)aniline
TsOH·H O / 100
DMF
66
2
c
1
1
1
2
H / H
H / H
Me / Ph
Me / Me
Et / Et
4k
4k
4l
87
TsOH·H
TsOH·H
TsOH·H
TsOH·H
TsOH·H
TsOH·H
none
2
2
2
2
2
2
O / 100
O / 100
O / 100
O / 200
O / 50
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
49
c
90
87
c
89
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
67
13
H / H
60
c,d
1
1
1
1
4
5
6
7
H / H
t-Bu / t-Bu
Me / Ph
Me / Ph
Me / Ph
4m
4n
4o
4p
4k
0
89
c
79
H / Me
H / Cl
O / 20
67
c
89
13
c
78
c
H / OMe
H / H
TsOH·H
2
O / 50
74
d
c
76
TsOH·H O / 50
88
18
3
CF / Me
2
e
TsOH·H O /100 /O
81
a
2
2
Reaction conditions: 1 (0.5 mmol.), 2 (0.75 mmol), solvent (2 mL),
e
b
c
8
TsOH·H
2
O / 100 / N
2
71
TsOH·H O (0.048 g, 0.25 mmol) 12 h. Isolated yields. Reaction
2
a
d
o
Reaction conditions: 1a (0.079 g, 0.5 mmol.), 2a (0.168 g, 0.75
occurred at room temperature. Reaction occurred at 120 C.
Table 1, entries 1, 15-16). For further investigation, the reaction
was protected by O or N with a balloon, but did not significantly
affect this reaction (Table 1, entries 17-18).
b
c
mmol), solvent (2 mL). Isolated yields. 1a (0.079 g, 0.5 mmol.),
(
d
2
a (0.112 g, 0.5 mmol). 1a (0.079 g, 0.5 mmol.), 2a (0.224 g, 1
2
2
e
mmol). The gas was in the balloon.
2
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With the optimized reaction conditions, the substrate scope
ARTICLE
entry 14). Besides, reactions of unsymmetrical β -diketones showed
of this method was investigated. In general, compound 1 bearing that the main products carry alkyl group (Table 2, entries 11, 15-17).
electron-withdrawing groups provided better yields than electron- Then, 1,1,1-trifluoropentane-2,4-dione was used and the obtained
donating groups (Table 2, entries 1-7). It was worth mentioning that product suggested the part with electron-withdrawing group was
2-(1H-indol-1-yl)aniline proceeded well and the reaction of 2-(3- the leaving group (Table 2, entry 18).
methyl-1H-indol-1-yl)aniline with an electron-donating methyl
group at 3-position afforded a better yield (Table 2, entries 9-10).
However, reaction of electron-deficient 2-(1H-imidazol-1-yl)aniline
failed to give any desired product (Table 2, entry 8). This
Similar results were obtained when β-keto esters substituted for
β-diketones as reaction substrates. Compound 1 with a variety of
3 3
substituents (H, CH , OCH , Cl and F) reacting with ethyl 3-oxo-3-
10
phenylpropanoate furnished the products in moderate to good
yields (Table 3, entries 1-5). Ethyl 3-oxobutanoate and ethyl 3-
oxopentanoate also preceeded well (Table 3, entries 6-7). In
addition, ethyl 3-oxo-3-phenylpropanoate with a fluorine group
gave a better yield than that with a methoxy group (Table 3, entries
phenomenon was similar to a previous study reported by Chardra.
Then the reactions of 2-(1H-pyrrol-1-yl)aniline with β-diketones
were examined, and the desired products were obtained in good to
excellent yields. To our delight, β-diketones bearing aliphatic groups
3 4
(any of R and R or both of them) reacted at room temperature to
8
and 10). And the yields had no significant differences between
fluorine in ortho-position and meta-position (Table 3, entries 9 and
0). But 2-(1H-indol-1-yl)aniline and 2-(3-methyl-1H-indol-1-
give satisfactory yields (Table 2, entries 11-13, 15-17). But 2,2,6,6-
tetramethylheptane-3,5-dione failed to give any product at any
temperature possibly because of stereo-hindrance effect (Table 2,
1
yl)aniline reacted with ethyl 3-oxo-3-phenyl-propanoate (1a) to
afford product in low yield of 34% and 57%, respectively. Finally
benzhydryl 3-oxobutanoate with a sterically hindered ester group
also gave a satisfying yield of 84% (Table 3, entry 23).
a
Table 3 Substrate scope of β-keto esters
b
Entry
1 (R
H / H
H / Me
1
/ R
2
)
3 (R
5
)
Product
4a
4b
4c
Yield(%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Me
Et
84
79
H / OMe
H / Cl
81
4d
4f
91
H / F
64
H / H
4k
4l
87
H / H
54
H / H
p-Methoxyphenyl
m-fluorophenyl
p-fluorophenyl
Me
4q
4r
71
H / H
87
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
8
9
0
1
H / H
4s
84
Scheme 3 Control experiments.
H / Cl
4o
4n
4p
4t
87
H / Me
H / OMe
H / Me
H / Me
H / Cl
Me
82
Me
85
p-fluorophenyl
p-Methoxyphenyl
m-fluorophenyl
p-fluorophenyl
p-Methoxyphenyl
m-fluorophenyl
Ph
86
4u
4v
4w
4x
69
90
H / Cl
84
H / OMe
H / OMe
2-(1H-indol-1-
74
4y
4i
82
34
yl)aniline
2
2
2-(3-methyl-
Ph
4j
57
Scheme 4 Plausible mechanism for formation of pyrrolo[1,2-
a]quinoxalines.
1
Hindol-1-
yl)aniline
H
c
5a
2
3
4k
84
a
Subsequently, to further extend this proposal, several control
Reaction conditions: 1 (0.5 mmol.), 2 (0.75 mmol), TsOH·H
2
O (0.048
b
c
experiments were carried out (Scheme 3). Cyclohexane-1,3-dione
g, 0.25 mmol), 12 h. Isolated yields. 5a = benzhydryl 3-oxobutanoate.
o
and 2-(1H-pyrrol-1-yl)aniline were treated with TsOH·H O at 120 C
2
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in DMSO, and the product 5-(pyrrolo[1,2-a]quinoxalin-4-yl)pentan-
-one 4z was obtained in 70% (a), which showed that circular
diketone compounds were also appropriate for this proposal and
113.99, 113.63, 108.74, 77.4; HRMS calcd for C17
+
[(M+H) ]: 245.1073; found, 245.1073.
H
12
N
2
2
7-methyl-4-phenylpyrrolo[1,2-a]quinoxaline (4b)
1
the by-products were the corroding ketones. Then we observed the Light yellow solid. Mp: 93-95 ºC. H NMR (300 MHz, CDCl
3
): δ =7.94-
o
imine intermediate 6 by HRMS analysis successfully at 80 C (b). 7.70 (m, 2H), 7.85-7.83 (m, J = 1.2 Hz, 1H), 7.76 (d, J = 0.6 Hz, 1H),
Besides, the imine 5c was easily obtained under standard conditions 7.66 (d, J = 8.4 Hz, 1H), 7.48-7.39 (m, 3H), 7.23 (dd, J = 8.4 Hz, 1.5 Hz,
1
3
C
(
c), which confirmed our conjecture of the mechanism.
1H), 6.88 (dd, J = 3.9 Hz, 1.2 Hz 1H), 6.77 (m, 1H), 2.40 (s, 3H);
NMR (75 MHz ,CDCl ): δ = 153.25, 137.57, 135.17, 133.98, 129.01,
possible 128.65, 127.58, 127.54, 127.49, 127.14, 124.65, 124.27, 123.98,
14 2
mechanism for the generation of pyrrolo[1,2-a]quinoxaline was 113.31, 112.64, 112.28, 107.35, 20.06; HRMS calcd for C18H N
3
1
6, 17
On the basis of the previous literatures
, a
+
2
proposed (Scheme 4). The TsOH·H O catalyzed the condensation of [(M+H) ]: 259.1230; found, 259.1230.
compounds 1 and 2 to generate the imine intermediate 6. Then 6
would convert into 7 in the presence of acid. And an intramolecular
nucleophilic addition occurred to the intermediate 8. At last, C-C
bond parted and the desired product 9 was generated.
7
-methoxy-4-phenylpyrrolo[1,2-a]quinoxaline (4c)
1
Light yellow solid. Mp: 117-118 ºC. H NMR (300 MHz, CDCl
3
): δ =
.03-7.97 (m, 2H), 7.95-7.93(m, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.58-
.49 (m, 4H), 7.16 (dd, J = 9.0 Hz, 3 Hz, 1H), 6.99 (dd, J = 3.9 Hz, 0.9
8
7
13
Hz, 1H), 6.88 ( dd, J = 3.9 Hz, 2.7 Hz), 3.93 (s, 3H); C NMR (75 MHz,
CDCl ): δ = 157.25, 154.70, 129.84, 128.64, 128.60, 125.11, 121.47,
16.79, 114.60, 114.37, 113.77, 111.29, 108.50, 55.76; HRMS calcd
Conclusions
3
1
In summary, we have developed an efficient and straightforward
one-pot domino reaction for the formation of pyrrolo[1,2-
a]quinoxalines without metal catalyst. A variety of pyrrolo[1,2-
a]quinoxaline derivatives were synthesized in moderate to excellent
yields. This one-pot metal-free process for the construction of
pyrrolo[1,2-a]quinoxalines has potential applications in the
synthesis of biologically and medicinally relevant compounds.
+
for C18
H
14
N
2
O [(M+H) ]: 275.1179; found, 275.1179.
7
-chloro-4-phenylpyrrolo[1,2-a]quinoxaline (4d)
1
Light yellow solid. Mp: 154-155 ºC. H NMR (300 MHz, CDCl
3
): δ =
.05 (s, 1H), 8.01-7.97 (m, 3H), 7.81 (d, J = 8.7 Hz, 1H), 7.59-7.53 (m,
H), 7.48 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.92-
8
3
6
1
1
13
.90 (m, 1H), C NMR (75 MHz, CDCl
3
): δ = 155.38, 137.05, 130.45,
30.17, 129.47, 128.65, 127.49, 125.78, 125.24, 115.07, 114.79,
+
Experimental
11 2
14.47, 109.52; HRMS calcd for C17H N Cl [(M+H) ]: 279.0684;
found, 279.0695.
General procedure
8
-chloro-4-phenylpyrrolo[1,2-a]quinoxaline (4e)
1
13
H and C NMR spectra were recorded with a 300 MHz Bruker
instrument or a 400 MHz Bruker instrument in CDCl or DMSO-
6,and and tetramethylsilane (TMS) was used as the internal
1
Light yellow solid. Mp: 189-191 ºC. H NMR (300 MHz, CDCl
3
): δ =
.01-7.93 (m, 3H), 7.91 (dd, J = 2.7Hz, 1.2Hz, 1H), 7.84 (d, J = 2.1 Hz,
H), 7.58-7.50 (m, 3H), 7.41 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 7.01 (dd, J =
3
8
1
4
d
standard. HRMS spectra were determined on a Q-TOF spectrograph.
Compounds 1 and Benzhydryl 3-oxobutanoate were prepared
1
3
.2 Hz, 1.2 Hz, 1H), 6.91 (dd, J = 3.9 Hz, 2.7 Hz, 1H); C NMR (75
according to the literature (see supporting information). Other MHz, CDCl
3
): δ = 154.48, 138.12, 134.82, 132.81, 131.36, 130.01,
reagents were commercially available and were used without 128.64, 128.59, 127.71, 125.68, 125.25, 114.85, 114.54, 113.78,
+
further purification. All reactions were monitored by thin-layer 109.25; HRMS calcd for C17H11N Cl [(M+H) ]: 279.0684; found,
2
chromatography (TLC).
2
79.0689.
General experimental procedure for 4-phenylpyrrolo[1,2-
a]quinoxaline (4a)
7-fluoro-4-phenylpyrrolo[1,2-a]quinoxaline (4f)
1
To a solution of DMSO (2 ml), 2-(1H-pyrrol-1-yl)aniline (0.079 g, White solid. Mp: 135-136 ºC. H NMR (400 MHz, CDCl
3
): δ =8.00-
0
.5 mmol) , 1,3-diphenylpropane-1,3-dione (0.168 g, 0.75 7.94 (m, 3H), 7.84-7.80 (m, 1H), 7.56 -7.52 (m, 3H), 7,73 (dd, J = 9.5
mmol) and TsOH·H
2
O (0.048 g, 0.25 mmol) were added and Hz, 2.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.01 (dd, J = 4.0 Hz, 1.1 Hz, 1H),
o
13
stirred for 12 h at 120 C, Then cooled to room temperature. 6.89 (dd, J = 4.0 Hz, 2.8 Hz, 1H); C NMR (100 MHz, CDCl
3
) : δ =
1
3
Brine (30 ml) was poured into the solution and the mixture 161.16 ( JC, F = 243 Hz), 155.48, 138.15, 137.55 ( JC, F = 11 Hz),
4
2
was extracted with EtOAc (3 × 30 mL). The organic layers were 130.05, 128.64 ( JC, F =2 Hz), 125.21, 123.87, 123.85, 115.55 ( JC, F
combined and dried by anhydrous MgSO
. The product was 23 Hz), 115.27, 115.03, 114.85, 114.79, 114.69, 114.14, 109.19;
purified by flash chromatography on silica gel HRMS calcd for C17
petroleum ether / EtOAc = 20: 1). Compound 4a was obtained
as light yellow solid in 89% yield (0.109 g). Light yellw solid. Mp:
=
4
+
H
2
11FN [(M+H) ]: 263.0979 ; found, 263.0977.
(
8
-fluoro-4-phenylpyrrolo[1,2-a]quinoxaline (4g)
o
1
1
Yellow solid. Mp: 144-145 C. H NMR (300 MHz, CDCl
3
): δ = 8.04-
.95 (m, 3H ), 7.86 (dd, J = 2.7 Hz, 1.2 Hz, 1H), 7.58-7.51 (m, 4H),
.20 (td, J = 8.7 Hz, 2.7 Hz, 1H ), 7.00 (dd, J = 3.9 Hz, 1.2 Hz, 1H),
9
7
7
9-100
3
ºC. H NMR (300 MHz, CDCl ): δ = 8.07-7.97 (m, 4H),
.89 (dd, J = 8.1 Hz, 1.5 Hz, 1H), 7.58-7.43 (m,5H), 7.25 (s, 1H),
7
7
6
1
(
1
3
.00 (dd, J = 12 Hz, 1.2 Hz, 1H), 6.90-6.88 (m, 1H); C NMR (75
): = 154.1, 138.46, 136.26, 130.26, 129.80,
28.64, 128.59, 127.48, 127.18, 125.42, 125.28, 114.62,
1
3
.91 (dd, J = 3.6 Hz, 2.7 Hz, 1H); C NMR (75 MHz, CDCl ): δ =
3
MHz, CDCl
3
δ
1
4
63.45 ( JC, F = 247 Hz), 153.99 ( JC, F =2 Hz), 138.59, 133.23, 132.49
1
3
3
J
C, F = 10 Hz), 130.29, 129.04, 128.97, 128.27 ( JC, F = 11 Hz), 125.46,
4
| J. Name., 2012, 00, 1-3
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ARTICLE
2
2
1
15.20 ( JC, F = 23 Hz), 113.76 ( JC, F = 22 Hz), 109.37, 101.05, 100.69. 7-chloro-4-methylpyrrolo[1,2-a]quinoxaline (4o)
+
o
1
HRMS calcd for C17
H
11FN
2
[(M+H) ]: 263.0979 ; found, 263.0991.
Light yellow solid. Mp: 173-175 C. H NMR (400 MHz, CDCl
3
): δ =
7
.85-7.80 (m, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.7 Hz, 2.2
13
6
-phenylindolo[1,2-a]quinoxaline (4i)
Hz, 1H), 6.89-6.82 (m, 2H), 2.69 (s, 3H); C NMR (100 MHz, CDCl
3
): δ
o
1
Yellow solid. Mp: 170-171 C. H NMR (300 MHz, DMSO-d
6
): δ = 8.78
=
1
2
154.81, 136.64, 130.17, 128.55, 126.89, 126.04, 125.82, 114.70,
+
(
d, J = 8.7 Hz, 2H), 8.06-8.01 (m, 4H), 7.76- 7.70 (m, 1H), 7.65-7.56
14.62, 113.94, 107.24, 21.92; HRMS calcd for C12
17.0527; found, 217.0528.
9 2
H ClN [(M+H) ]:
1
3
(
m, 4H), 7.53-7.47 (m, 2H), 7.36 (s, 1H); C NMR (75 MHz, DMSO-d
6
): δ = 155.16, 137.55, 135.51, 132.34, 130.17, 130.03, 129.25,
1
1
2
29.07, 128.69, 128.59, 128.47, 128.11, 124.72, 122.81, 115.15, 7-methoxy-4-methylpyrrolo[1,2-a]quinoxaline (4p)
+
o
1
14.93, 102.29; HRMS calcd for C21
H
14
N
2
[(M+H) ]: 295.1230; found, Light yellow solid. Mp: 81-82 C. H NMR (400 MHz, CDCl
3
): δ = 7.83-
95.1230.
7.82 (m, 1H), 7.73 (d, J = 9.0 Hz,1H), 7.41-7.26 (m, 1H), 7.09 (dd, J =
9
3
1
2
.0 Hz, 2.8 Hz, 1H), 6.89 (m, 1H), 6.82 (m, 1H), 3.91 (s, 3H), 2.73 (s,
1
3
7
-methyl-6-phenylindolo[1,2-a]quinoxaline (4j)
H); C NMR (100 MHz, CDCl
3
): δ =157.16, 153.89, 136.59, 125.89,
o
1
Yellow solid. Mp: 159-161 C. H NMR (300 MHz, CDCl
3
): δ = 8.50-
21.53, 116.10, 114.58, 114.17, 113.33, 110.42, 106.57, 55.69,
+
8
7
.46 (m, 2H), 8.03 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.1 Hz 1H), 7.65-
1.79; HRMS calcd for
13
C H
12
N
2
O
[(M+H) ]: 213.1022;
1
3
.51 (m, 7H), 7.48-7.37 (m, 2H), 2.06 (s, 3H); C NMR (75 MHz,
): δ = 157.64, 132.10, 130.58, 130.31, 129.28, 128.60, 128.47,
28.31, 125.74, 124.81, 123.81, 122.06, 120.79, 114.40, 11.12; 4-(4-methoxyphenyl)pyrrolo[1,2-a]quinoxaline (4q)
found,213.1026.
CDCl
3
1
+
o
1
HRMS calcd forC22
H
16
N
2
[(M+H) ]: 309.1386 ; found, 309.1385.
Light yellow solid. Mp: 112-113 C. H NMR (300 MHz, CDCl
8.03-7.97 (m, 4H), 7.87 (d, J = 7.5 Hz, 1H), 7.51-7.41 (m, 2H), 7.07
d, J = 8.7 Hz, 2H), 7.01 (d, J = 3.3 Hz, 1H), 6.89-6.87 (m, 1H), 3.89 (s,
3
): δ
=
General experimental procedure for 4-methylpyrrolo[1,2-
(
1
3
a]quinoxaline (4k)
3
1
1
3
H); C NMR (100 MHz, CDCl ): δ = 161.19, 123.73, 135.95, 130.22,
29.80, 127.27, 125.33, 125.27, 114.83, 114.08, 114.03, 113.60,
To a solution of DMSO (2 ml), 2-(1H-pyrrol-1-yl)aniline (0.079 g, 0.5
+
09.11, 55.44; HRMS calcd for [(M+H) ]: 275.1179; found, 275.1179.
mmol), pentane-2,4-dione (0.075 g, 0.75 mmol) and TsOH·H
2
O
(
0.048 g, 0.25 mmol) were added and stirred at room temperature,
4
-(3-fluorophenyl)pyrrolo[1,2-a]quinoxaline (4r)
o
1
until no 2-(1H-pyrrol-1-yl)aniline left, and was monitored by thin-
layer chromatography (TLC). Then it was cooled to room
temperature. Brine (30 ml) was poured into the solution and the
mixture was extracted with EtOAc (3 × 30 mL). The organic layers
Light yellow solid. Mp: 125-127 C. H NMR (400 MHz, CDCl
3
): δ =
.05-8.01 (m, 2H), 7.90 (dd, J = 8.2 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H),
.74-7.71 (m, 1H), 7.56-7.45 (m, 3H), 7.25-7.20 (m, 1H), 7.00 (dd, J =
8
7
4
=
1
1
1
2
1
3
.0 Hz, 1.0 Hz, 1H), 6.92-6.90 (m, 1H)； C NMR (100 MHz, CDCl ): δ
3
1
4
3
4
were combined and dried by anhydrous MgSO . The product was
164.12 ( JC, F = 245 Hz), 152.96 ( JC,F = 3 Hz), 140.60 ( JC,F = 8 Hz),
3
purified by flash chromatography on silica gel (petroleum ether /
36.05, 130.34, 130.21 ( JC,F = 8 Hz), 127.82, 127.20, 125.41, 125.09,
4
2
2
EtOAc = 10: 1). Compound 4k was obtained as light yellow solids in
24.37 ( JC,F = 3 Hz), 116.85 ( JC,F = 21 Hz), 115.84 ( JC,F = 23 Hz),
o
1
+
8
d
1
7%. Light yellow solid. Mp: 137-138 C. H NMR (300 MHz, DMSO-
): δ = 8.43 (dd, J = 2.7 Hz, 1.2 Hz, 1H), 8.26 (dd, J = 8.1 Hz, 0.9Hz,
H), 7.83 (dd, J = 8.1 Hz, 1.5 Hz, 1H), 7.57-7.52 (m, 1H), 7.48-7.43
14.85, 114.16, 113.67, 108.56; HRMS calcd for C17
63.0979; found, 263.0951.
2
H11FN [(M+H) ]:
6
(
m, 1H), 7.03 (dd, J = 3.9 Hz, 0.9 Hz, 1H), 6.92-6.89 (m, 1H), 2.65 (s, 4-(4-fluorophenyl)pyrrolo[1,2-a]quinoxaline (4s)
13
o
1
3
1
2
1
H); C NMR (100 MHz, DMSO-d
6
): δ = 153.59, 135.80, 129.13, Light yellow solid. Mp: 158-160 C. H NMR (400 MHz, CDCl ): δ =
3
27.52, 127.33, 125.88, 125.59, 116.32, 115.06, 114.03, 107.21, 8.06-8.02 (m, 4H), 7.92 (d, J = 8.0 Hz), 7.57-7.53 (m, 1H), 7.51-7.47
+
13
1.99; HRMS calcd for
83.0916.
C
12
H
10
N
2
[(M+H) ]: 183.0917
;
found, (m, 1H), 7.28-7.24 (m, 2H), 6.99 (d, J = 4.8 Hz), 6.94-6.92 (m, 1H); C
1
NMR (100 MHz, CDCl ): δ = 165.07 ( JC, F = 243 Hz), 153.24, 136.19,
3
3
1
34.61, 130.60 ( JC,F = 8 Hz), 130.23, 127.57, 127.13, 125.36, 125.24,
2
4
-ethylpyrrolo[1,2-a]quinoxaline (4l)
1
15.71 ( JC,F = 22 Hz), 114.74, 114.06, 113.65, 108.52; HRMS calcd
o
1
+
Light yellow solid. Mp: 73-74 C. H NMR (300 MHz, CDCl
3
): δ = 7.93-
for C17
H11FN
2
[(M+H) ]: 263.0979; found, 263.0977.
7.90 (m, 1H), 7.88-7.85 (m, 1H), 7.78 (d, J = 6.6 Hz, 1H), 7.45-7.37
(
m, 2H), 6.88-6.80 (m, 2H), 3.08 (q, J = 7.5 Hz), 1.48 (t, J = 7.5 Hz, 4-(4-fluorophenyl)-7-methylpyrrolo[1,2-a]quinoxaline (4t)
1
3
o
1
3
H); C NMR (100 MHz, CDCl
3
): δ = 158.29, 136.07, 129.48, 126.80,
3
White solid. Mp: 158-160 C. H NMR (300 MHz, CDCl ): δ = 8.03-
1
25.71, 124.99, 114.05, 113.55, 113.38, 106.04, 28.90, 12.50; HRMS
7.97 (m, 2H), 7.96-7.94 (m, 1H), 7.83 (d, J = 0.9Hz, 1H), 7.77 (d, J =
+
calcd for C13
12 2
H N [(M+H) ]: 197.1073; found, 197.1073.
8.4 Hz, 1H), 7.34 (dd, J = 8.0 Hz, 1.8 Hz, 1H), 7.25-7.18 (m, 2H),
1
3
6
.94-6.92 (m, 1H), 6.88-6.86 (m, 1H), 2.50 (s, 3H); C NMR (100
1
4,7-dimethylpyrrolo[1,2-a]quinoxaline (4n)
MHz, CDCl ): δ = 165.03 ( JC, F = 248 Hz)，153.13, 136.12, 135.16,
34.75 ( JC,F = 4 Hz), 130.59 ( JC,F = 9 Hz), 130.00, 128.71, 125.14,
3
o
1
4
3
Light yellow solid. Mp: 141-142 C. H NMR (400 MHz, CDCl
3
): δ =
1
1
2
2
2
7
4
.83-7.82 (m, 1H), 7.69-7.66 (m, 2H), 7.27-7.24 (m, 1H), 6.85 (dd, J =
24.98, 115.66 ( JC,F = 22 Hz), 114.52, 113.78, 113.36, 108.23,
13
+
.0 Hz, 1.2 Hz), 6.81-6.79 (m, 1H), 2.70 (s, 3H), 2.47 (s, 3H); C NMR
): δ = 153.51, 135.83, 134.85, 129.11, 127.98,
26.19, 125.14, 114.00, 113.33, 106.22, 21.99, 21.12; HRMS calcd
1.10; HRMS calcd for C18
77.1137.
2
H13FN [(M+H) ]: 277.1136; found,
(100 MHz, CDCl
3
1
+
for C13
H N
12 2
[(M+H) ]: 197.1073; found,197.1072.
4-(4-methoxyphenyl)-7-methylpyrrolo[1,2-a]quinoxaline (4u)
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J. Name., 2013, 00, 1-3 | 5
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DOI: 10.1039/C6OB01401A
ARTICLE
Light brown solid. Mp: 102-104 C. H NMR (400 MHz, CDCl
Journal Name
o
1
3
): δ = (Z)-1,3-diphenyl-3-(phenylamino)prop-2-en-1-one (5c)
o 1
7
7
6
.98 (d, J = 8.6 Hz, 2H), 7.89-7.81 (m, 2H), 7.70 (d, J = 8.3 Hz, 1H), Yellow solid. Mp: 144-145 C. H NMR (300 MHz, CDCl
3
): δ = 7.99-
.27-7.24 (m, 1H), 7.05 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 3.4 Hz, 1H), 7.95 (m, 2H), 7.55-7.30 (M, 8H), 7.14-7.09 (m, 2H), 7.01-7.96 (t, J =
13
13
.81-6.83 (m, 1H), 3.87 (s, 3H), 2.47 (s, 3H); C NMR (100 MHz, 7.5 Hz, 1H), 6.86-6.78 (m, 2H); C NMR (75 MHz, CDCl ): δ = 189.69,
3
CDCl
3
): δ = 160.99, 153.74, 136.27, 134.95, 131.22, 130.09, 129.86,
1
61.49, 139.92, 139.50, 135.88, 131.28, 129.67, 128.71, 128.56,
1
5
2
28.28, 125.28, 124.92, 114.29, 113.95, 113.60, 113.29, 108.32,
1
28.38, 128.36, 127.27, 127.18, 124.12, 123.21, 97.05; HRMS calcd
+
5.41, 21.11; HRMS calcd for C19
H
16
N
2
O [(M+H) ]: 289.1335; found,
+
for C21H17NO[(M+H) ]: 300.1383 ; found,300.1376.
89.1341.
Acetophenone (5f)
7
-chloro-4-(3-fluorophenyl)pyrrolo[1,2-a]quinoxaline (4v)
1
o
1
Light yellow liquid, H NMR (300 MHz, CDCl ): δ = 7.95-7.91 (m,
3
Off white solid. Mp: 163-165 C. H NMR (400 MHz, CDCl
3
): δ = 8.03-
.97 (m, 2H), 7.81-7.78 (m, 2H), 7.72 (dt, J = 9.7 Hz, 2.3 Hz, 1H),
.54-7.46 (m, 1H), 7.03 (dd, J = 4.0 Hz, 0.9 Hz, 1H), 6.93-6.92 (m,
2
H), 7.55-7.49 (m, 1H), 7.44-7.39 (m, 2H), 2.55 (s, 3H).
7
7
1
1
1
1
13
1
H); C NMR (100 MHz, CDCl
40.04, 136.93, 130.56, 130.29 ( JC,F = 8 Hz), 129.61, 127.81, 125.81,
3
): δ = 164.09 ( JC, F = 245 Hz)，153.94, Acknowledgements
3
2
2
24.94, 124.38 ( JC,F = 22 Hz), 115.85 ( JC,F = 23 Hz), 115.24, 114.83,
We are grateful to the National Science Foundation of China
No. 21572117) and State Key Laboratory of Bioactive Substance
+
2
14.60, 109.25; HRMS calcd for C17H10ClFN [(M+H) ]: 297.0589;
(
found, 297.0587.
and Function of Natural Medicines, Institute of Materia Medica,
Chinese Academy of Medical Sciences and Peking Union Medical
College (No. GTZK201405) for financial support of this research.
7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-a]quinoxaline (4w)
o
1
Light yellow solid. Mp: 219-221 C. H NMR (400 MHz, CDCl
3
): δ =
8.01-7.94 (m, 4H), 7.78 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.8 Hz, 2,2
Hz, 1H), 7.24-7.19 (m, 2H), 6.98 (d, J = 4.0 Hz, 1H), 6.89-6.91 (m,
Notes and references
13
1
1
1
1
H); C NMR (100 MHz, CDCl
3
): δ =165.28 ( JC, F = 248 Hz), 154.15,
3
1. (a) E. Torres, E. Moreno, S. Ancizu, C. Barea, S. Galiano, I.
Aldana, A. Monge, S. Perez-Silanes, Bioorg. Med. Chem., 2011, 21,
3699. (b) H.-Q. Xia, C.-P. Kong, J. Wang, F.-Q. Bai, H.-X. Zhang, RSC
Adv., 2014, 4, 50338. (c) T. Le, H. Yu, X. Niu, Food chemistry, 2015,
37.14, 134.21, 130.65 ( JC, F = 9 Hz), 129.55, 127.49, 125.76,
2
25.14, 115.68 ( JC, F = 22 Hz)，115.04, 114.70, 114.42, 109.14;
+
HRMS calcd for C17
H
10ClFN
2
[(M+H) ]: 297.0589; found, 297.0586.
1
75, 85. (d) L. Wang, X. Yang, X. Wang, L. Sun, Dyes Pigments, 2015,
7
-methoxy-4-(4-methoxyphenyl)pyrrolo[1,2-a]quinoxaline (4x)
o
1
113, 581. (e) N. Primas, P. Suzanne, P. Verhaeghe, S. Hutter, C.
Kieffer, M. Laget, A. Cohen, J. Broggi, J. C. Lancelot, A. Lesnard, P.
Dallemagne, P. Rathelot, S. Rault, P. Vanelle, N. Azas, Eur. J. Med.
Chem., 2014, 83, 26. (f) A. Carta, M. Loriga, G. Paglietti, A. Mattana,
P. L. Fiori, P. Mollicotti, L. Sechi, S. Zanetti, Eur. J. Med. Chem., 2004,
Light yellow solid. Mp: 106-107 C. H NMR (300 MHz, CDCl
3
): δ =
8.00-7.95 (m, 2H), 7.92-7.90 (m, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.50 (d,
J = 2.7 Hz, 1H), 7.13-7.07 (m, 1H), 7.07-7.03 (m, 2H), 6.99 (dd, J = 4.2
Hz, 1.2 Hz, 1H), 6.87 (dd, J = 4.2 Hz, 2.7 Hz, 1H), 3.92 (s, 3H), 3.90 (s,
1
3
3H); C NMR (75 MHz, CDCl
131.05, 130.08, 125.08, 121.38, 116.39, 114.53, 114.21, 113.97,
16 2 2
113.60, 111.18, 108.34, 55.74, 55.43; HRMS calcd for C19H O N
3
): δ = 161.01, 157.19, 154.21, 137.35,
3
9, 195. (g) J. Cogo, V. Kaplum, D. P. Sangi, T. Ueda-Nakamura, A. G.
Correa, C. V. Nakamura, Eur. J. Med. Chem., 2015, 90, 107. (h) H.
Behzadi, P. Roonasi, K. Assle taghipour, D. van der Spoel, S.
Manzetti, J. Mol. Struct., 2015, 1091, 196. (i) W. Su, M. Xiao, Q. Fan,
J. Zhong, J. Chen, D. Dang, J. Shi, W. Xiong, X. Duan, H. Tan, Y. Liu,
+
[(M+H) ]: 305.1285; found, 305.1284.
4-(3-fluorophenyl)-7-methoxypyrrolo[1,2-a]quinoxaline (4y)
o
1
Light yellow solid. Mp: 147-149 C. H NMR (400 MHz, CDCl
.90-7.89 (m, 1H), 7.79-7.69 (m, 3H), 7.52-7.46 (m, 2H), 7.25-7.19 2. (a) J. Guillon, S. Moreau, E. Mouray, V. Sinou, I. Forfar, S. B.
m, 1H), 7.13 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 6.96 (dd, J = 4.0 Hz, 1.1 Hz, Fabre, V. Desplat, P. Millet, D. Parzy, C. Jarry, P. Grellier, Bioorg.
3
): δ = W. Zhu, Org. Electron., 2015, 17, 129.
7
(
1
3
1H), 6.86-6.84 (m, 1H), 3.91 (s, 3H); C NMR (100 MHz, CDCl
1
3
): δ = Med. Chem., 2008, 16, 9133. (b) J. Guillon, E. Mouray, S. Moreau, C.
64.10 ( JC, F = 244 Hz), 157.28, 153.23 ( JC, F = 2 Hz), 140.67 ( JC, F = 7 Mullie, I. Forfar, V. Desplat, S. Belisle-Fabre, N. Pinaud, F. Ravanello,
Hz), 137.13, 130.20 ( JC, F = 8 Hz), 124.79, 124.35 ( JC, F = 3 Hz), A. Le-Naour, J. M. Leger, G. Gosmann, C. Jarry, G. Deleris, P. Sonnet,
21.48, 117.05, 116.81 ( JC, F = 21 Hz), 115.82 ( JC, F = 23 Hz), 114.59, P. Grellier, Eur. J. Med. Chem., 2011, 46, 2310.
1
4
3
3
4
2
2
1
1
14.47, 113.84, 111.38, 108.16, 55.73; HRMS calcd for C18
H
13ON
2
F
3. J. Guillon, I. Forfar, M. Mamani-Matsuda, V. Desplat, M. Saliege,
D. Thiolat, S. Massip, A. Tabourier, J. M. Leger, B. Dufaure, G.
Haumont, C. Jarry, D. Mossalayi, Bioorg. Med. Chem., 2007, 15, 194.
4. J. Guillon, M. Le Borgne, C. Rimbault, S. Moreau, S. Savrimoutou,
+
[(M+H) ]: 293.1085; found, 293.1084.
5-(pyrrolo[1,2-a]quinoxalin-4-yl)pentan-2-one (4z)
o
1
Light yellow solid. Mp: 71-72 C. H NMR (300 MHz, CDCl
3
): δ = 7.91 N. Pinaud, S. Baratin, M. Marchivie, S. Roche, A. Bollacke, A. Pecci,
(dd, J = 5.7 Hz, 1.8 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.49-7.38 (m, L. Alvarez, V. Desplat, J. Jose, Eur. J. Med. Chem., 2013, 65, 205.
2
H), 6.95 (d, J = 3.9 Hz, 1H), 6.85-6.83 (m, 1H), 3.05 (t, J = 7.2 Hz, 5. S. Butini, R. Budriesi, M. Hamon, E. Morelli, S. Gemma, M.
1
3
2
H), 2.62 (t, J = 7.2 Hz, 2H), 2.23-2.13 (m, 5H); C NMR (75 MHz, Brindisi, G. Borrelli, E. Novellino, I. Fiorini, P. Ioan, A. Chiarini, A.
): δ = 208.50, 156.41, 135.84, 129.45, 127.28, 127.00, 125.92, Cagnotto, T. Mennini, C. Fracasso, S. Caccia, G. Campiani, J. Med.
25.06, 114.24, 113.62, 113.58, 106.42, 42.95, 34.59, 29.99, 22.13; Chem., 2009, 52, 6946.
CDCl
3
1
+
HRMS calcd for C16
H
16ON
2
[(M+H) ]: 253.1335; found, 253.1331.
6. G. Moarbess, C. Deleuze-Masquefa, V. Bonnard, S. Gayraud-
Paniagua, J. R. Vidal, F. Bressolle, F. Pinguet, P. A. Bonnet, Bioorg.
6
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB01401A
Journal Name
ARTICLE
Med. Chem., 2008, 16, 6601.
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. P. D. J. Guillom, B. Pfeifferb, P. Renard, A. K. D. Manechez, S.
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. J. T. Reeves, D. R. Fandrick, Z. Tan, J. J. Song, H. Lee, N. K. Yee, J.
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W. H. Cheeseman, B. Tuck, J. Chem. Soc. C, 1966, 852.
0. A. K. Verma, R. R. Jha, V. K. Sankar, T. Aggarwal, R. P. Singh, R.
Chandra, Eur. J. Med. Chem., 2011, 34, 6998.
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9
1
11. M. F. Pereira, T. Valerie, Org. Lett., 2012, 14, 4754.
12. S. Jayaprakash, M. Ramamohan, R. Sridhar, K. Raghavendrarao,
N. Paradesi, K. Chandrasekhar, Synlett, 2015, 26, 1096.
1
5
1
2
1
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