Copper-catalyzed synthesis of indolyl diketones: Via C-H oxidation/diacylation of indoles with arylglyoxal hydrates

Article abstract of DOI:10.1039/c7ob01255a

An expedient protocol for Cu-catalyzed C-H oxidation/diacylation of indoles with arylglyoxal hydrates to construct indolyl diketones is developed. This methodology exhibits the synthetic utility of the synthesis of an indole-alkaloid 1,2-di(1H-indol-3-yl)ethane-1,2-dione and offers a straightforward means to produce different indolyl nitrogen-containing heterocycles such as indolyl quinoxaline, indolyl hydantoin and indolyl imidazole in high yields. Preliminary mechanistic studies indicate that two proposed pathways are involved in this process.

Full text of DOI:10.1039/c7ob01255a

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Copper-Catalyzed Synthesis of Indoly Diketones via C–H
Oxidation/Diacylation of Indoles with Arylglyoxal Hydrates
Received 00th January 20xx,
Accepted 00th January 20xx
Cuiping Wang,ab Zhiqiang Zhang,*a Kui Liu,a Jingbo Yan,c Tiexin Zhang,b Gonghao Lu,a Qingtao
Meng,a Haijun Chia and Chunying Duan*b
DOI: 10.1039/x0xx00000x
An expedient protocol for Cu-catalyzed C–H oxidation/diacylation of indoles with arylglyoxal hydrates to construct indolyl
diketones is developed. The methodology exhibits the synthetic utility by the synthesis of an indole-alkaloid 1,2-di(1H-
www.rsc.org/
indol-3-yl)ethane-1,2-dione and offers
a straightforward means to produce different indolyl nitrogen-containing
heterocycles such as indolyl quinoxaline, indolyl hydantoin and indolyl imidazole in high yields. Preliminary mechanistic
studies indicate that two proposed pathways are involved in this process.
Subsequently, Jiang and his co-workers reported a copper-
catalyzed aerobic oxidative C3-dicarbonylation of indoles and
α-hydroxyketones.8 In addition, arylglyoxals, aromatic α-keto
aldehydes containing both aldehyde and ketone functional
groups, have been also used as the diacylating agents for the
diacylation of indoles and N-substituted indoles using
pyrrolidine or morpholine as catalyst or CuBr-pyridine catalytic
system by Mupparapu et al.9 and Yang et al.10
Although significant advances have been achieved, there are
still some disadvantages, such as poor tolerance of functional
groups (OH, CN, NO2), the use of expensive palladium catalyst
and an excess of oxidant, a long reaction time, and particularly
for the introduction of a protecting group for N-position of
indole. Moreover, we found that all reactions proceeded
under oxidative conditions, or/and in the presence of an alkali
additive (pyridine) or an alkali catalyst (pyrrolidine,
morpholine). However, an acidic additive (HOAc) was used
only in Li’s work on the diacylation of indoles.3b These findings
inspired us to explore more explicit reaction mechanism and
develop an efficient approach to obtain indolyl diketones.
Recently, we developed a Cu-catalyzed decarboxylative C3-
acylation of free (N–H) indoles with α-oxocarboxylic acids.11 As
part of our ongoing interest in the development of new C–H
bond functionalization of indoles, we report herein an efficient
protocol for the Cu-catalyzed C–H oxidation/diacylation of
indoles with arylglyoxal hydrates under air atmosphere to
afford indolyl diketones in moderate to good yields.
Introduction
The indole moiety is ubiquitous in natural products,
pharmaceuticals and agrochemicals.1 Consequently, much
attention has been paid to the functionalization of indoles.
Among numerous efforts, transition-metal-catalyzed direct
C(3)–H bond functionalization of indoles has emerged as a
powerful tool in organic synthesis.2 For the past few years, C3-
acylation of indole has been widely reported because of the
versatile chemical transformations3 of 3-acylindoles and their
important applications in pharmaceutical compounds and
natural products.4
Usually, 3-acylindoles can be prepared by the mono- and di-
acylation of indoles. Many methods have been developed to
realize the mono-acylation of indoles to provide 3-acylindoles.5
Recently, a few examples have been reported to construct
indolyl diketones by utilizing the diacylation of indoles
approach. Two representative approaches have been first
established by Li’s group. One involves Cu-catalyzed C–H
oxidation/cross-coupling of indoles with secondary anilines
using TBHP as an oxidant under air atmosphere;6 Pd-catalyzed
oxidative cross-coupling of indoles with tertiary anilines using
Cu(OAc)2 as an oxidant provides a complementary method to
the synthesis of diacylation of indoles.3b Recently, Wu’s group
developed a direct oxidative cross-coupling of N-substituted
indoles with methyl ketones to construct indolyl diketones in
the presence of molecular iodine and pyrrolidine.7
Results and discussion
Our investigation commenced with the reaction of indole (1a
and 2-(4-bromophenyl)-2-oxoacetaldehyde hydrate (2a). In the
initial experiment, the treatment of indole 1a with substrate
2a in different solvents such as toluene, dioxane and DMSO
under air atmosphere afforded only a trace amount of the
desired product 1-(4-bromophenyl)-2-(1H-indol-3-yl)ethane-
a.Key Laboratory for Functional Material, Educational Department of Liaoning
Province, University of Science and Technology Liaoning, Anshan 114051, P. R.
China. E-mail: zhangzhiqiang@ustl.edu.cn; cyduan@dlut.edu.cn; Tel: (+86)-412-
5928009; (+86)-411-84986314
)
b.State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian
116024, P. R. China
c.
AmberMolTech LLC, Beijing 100081, P. R. China
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x

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1,2-dione 3a (Table 1, entries 1–3). Inspired by Li’s and Cao’s
works,3b,12 HOAc was added in the above reaction system.
Much to our satisfaction, the combination of toluene/HOAc or
dioxane/HOAc (4.0/0.5, v/v) increased the yield of 3a to 55%
and 60%, respectively (Table 1, entries 4 and 5). The results
indicated that the acid system could effectively promote the
diacylation of indole. To our delight, the yield of 3a was
enhanced significantly to 80% in dioxane/HOAc in the
presence of 20 mol% of Cu(OAc)2·H 2O (Table 1, entry 6).
Moreover, other Cu catalysts were also evaluated. The results
suggested that Cu(OAc)2·H 2O exhibited the highest catalytic
activity, and the appropriate amount of Cu(OAc)2·H 2O was 20
mol% (Table 1, entries 7–13). Subsequently, the stronger acids
such as TFA (CF3CO3H) and TfOH (CF3SO3H) were also tested.
The results showed that the reaction activity was suppressed
(Table 1, entries 14 and 15). In addition, the reaction
temperature was also examined. Unfortunately, elevating the
temperature did not improve the yield; lowering the reaction
temperature did result in low yield (Table 1, entries 16 and 17).
Further experiments showed that the reaction atmosphere
plays a crucial role in this transformation, in the presence of
sole N2 or O2, only moderate yields were obtained (Table 1,
Table 1 Optimization of Reaction Conditionsa
View Article Online
DOI: 10.1039/C7OB01255A
Entry Catalyst
Solvent (v/v mL)
Temp. Yieldb (%)
(oC)
1
2
3
4
—
—
—
—
—
toluene (4.5)
dioxane (4.5)
DMSO (4.5)
toluene/HOAc (4.0/0.5) 100
dioxane/HOAc (4.0/0.5) 100
100
100
100
trace
trace
trace
55
60
80
76
56
46
39
—
—
69
20
trace
78
40
55
62
5
6
Cu(OAc)2·H 2O dioxane/HOAc (4.0/0.5) 100
7
8
9
CuO
Cu2(OH)2CO3
CuI
Cu2O
CuCl2·2H2O
CuSO4·5H2O
Cu(OAc)2·H 2O dioxane/HOAc (4.0/0.5) 100
Cu(OAc)2·H 2O dioxane/TFA (4.0/0.5)
Cu(OAc)2·H 2O dioxane/TfOH (4.0/0.5)
Cu(OAc)2·H 2O dioxane/HOAc (4.0/0.5) 120
Cu(OAc)2·H 2O dioxane/HOAc (4.0/0.5) 80
Cu(OAc)2·H 2O dioxane/HOAc (4.0/0.5) 100
Cu(OAc)2·H 2O dioxane/HOAc (4.0/0.5) 100
dioxane/HOAc (4.0/0.5) 100
dioxane/HOAc (4.0/0.5) 100
dioxane/HOAc (4.0/0.5) 100
dioxane/HOAc (4.0/0.5) 100
dioxane/HOAc (4.0/0.5) 100
dioxane/HOAc (4.0/0.5) 100
10
11
12
13c
14
15
16
17
18d
19e
100
100
entries 18 and 19). Therefore, all reactions were performed in
the presence of Cu(OAc)2·H 2O (20 mol%) in dioxane/HOAc
(4.0/0.5, v/v) at 100 °C under air atmosphere.
Using the optimized reaction conditions, the diacylation of a
series of indoles was performed, and the results were
summarized in Table 2. The reaction afforded the
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (20 mol%), solvent
(4.5 mL), 100 oC, 6 h, under air atmosphere. b Isolated yields. c Cu(OAc)2·H 2O (10
d
e
mol%) was used. The reaction was performed under N2 atmosphere. The
reaction was performed under O2 atmosphere.
corresponding products 3aa-3ka in moderate to good yields. It
was observed that free (N–H) indoles with electron-rich groups
groups (CH3 and OCH3) reacted with indoles. It is worth noting
that ortho- or meta-substituted 2-(2,4-dimethylphenyl)-2-oxo-
acetaldehyde hydrate, 2-(3-chlorophenyl)-2-oxoacetaldehyde
hydrate and 2-(3-methylphenyl)-2-oxoacetaldehyde hydrate
such as 5-OCH3, 5-CH3, 4-CH3, 7-CH3 and 2-CH3 exhibited high
reactivity and furnished the desired products 3ba–3fa in good
yields. Moreover, the diacylation of an N-substituted indole
such as N-methylindole could also proceed smoothly to
provide the target product 3ga in good yield. However,
electron-rich 6-methoxyindole showed low efficiency and gave
the corresponding product 3ha only in moderate yield.
Particularly, the diacylation process was compatible with the
sensitive OH, CN group and electron-deficient NO2 group,
although only moderate yields of products 3ia, 3ja and 3ka
were obtained, which were hard to be obtained by other
reported methods. The above experiment results
demonstrated that although the electronic properties of the
indole rings had a strong influence on the yield, the reaction
exhibited high tolerance towards various functional groups.
Subsequently, the scope with respect to arylglyoxal hydrates
was investigated under the optimized conditions. Arylglyoxal
hydrates with both electron-donating groups and electron-
withdrawing groups smoothly underwent diacylation to
also provided the target product 3ak, 3ac and 3aj in 60%, 70%
and 60% yields, respectively. Furthermore, electron-rich
indoles bearing 5-OCH3, 4-OH, 2-CH3 and N-CH3 groups also
successfully reacted with arylglyoxal hydrates bearing p-NO2,
p-Cl, p-CH3 and p-OCH3 groups under the optimized reaction
conditions, thus providing the corresponding products 3bb–3gi
in moderate to good yields.
To demonstrate the synthetic utility of the method, the
diacylation was applied for the synthesis of 1,2-di(1H-indol-3-
yl)ethane-1,2-dione
6
, an indole alkaloid from the marine
is also an important
sponge Smenospongia sp.13 Moreover,
6
intermediate for the construction of anion sensors including
indolylquinoxalines14a and indolocarbazolequinoxalines.14b The
treatment of indole 1a with 2-(1H-indol-3-yl)-2-oxoacetalde-
hyde afforded the product
6 in 71% yield under the standard
conditions
(
Scheme 1).15 Gratifyingly, the obtained indolyl
generate the desired products 3ab–3al in moderate to good
diketone products were further used to construct indolyl
nitrogen-containing heterocycles including indolyl quinoxaline
yields. It was noticed that arylglyoxal hydrates with electron-
deficient groups (Cl, F, I, NO2 and COOCH3) were well-tolerated
to deliver the desired products 3ab–3ag in relatively high
(7 8) and indolyl imidazole (9)
),8 indolyl hydantoin ( 16 in 90%, 85%
and 88% yields, respectively, by the reaction of indolyl
diketones with o-phenylenediamine, urea, benzaldehyde and
ammonium acetate under conventional heating or microwave
irradiation conditions (Scheme 2).
yields. Importantly, halogen substituents on the arylglyoxal
hydrates remained intact, which could potentially be used for
further functionalization. Moderate yields of products 3ag–3ai
were obtained when arylglyoxal hydrates with electron-rich
2 | J. Name., 2012, 00, 1-3
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Table 2 Cu-catalyzed C–H oxidation/diacylation of Indoles with arylglyoxal hydratesa
To gain further insight into the reaction mechanism,
representative LC-MS analyses were shown in Figure 1A.
Interestingly, two isomeric intermediates 4a (major) and 5a
(minor) were detected under all reaction conditions (Figure
View Article Online
DOI: 10.1039/C7OB01255A
S2–S3 in supporting information). It is noteworthy that Ivonin
et al. first reported the two isomers and indolyl diketone by
the reaction of indole with phenylglyoxal hydrate and
subsequent isomerization or oxidation under basic condition
such as NEt3 and KOH (Figure 1B).17 Recently, Mupparapu et al.
reported another similar result that the aminocatalytic
reaction of indole and phenylglyoxal hydrate with pyrrolidine
as catalyst in toluene or morpholine as catalyst in DMSO
afforded indolyl diketone via three-component intermediate
10 and 11 (detected by LC-MS result) transformed by iminium
ion.9 However, our detailed experiment results demonstrated
that the different intermediates were obtained in different
solvents in this reaction system (Figure 1C, detailed LC-MS
results in Figure S4-S7). The three-component intermediates
10 and 11 were detected by LC-MS results with pyrrolidine or
morpholine as catalyst in DMSO, while two isomeric
intermediates 4a and 5a were detected by LC-MS results with
pyrrolidine or morpholine as catalyst in toluene. Furthermore,
the two intermediates 4a and 5a were also detected under
acidic conditions in our reaction systems. The result indicated
that both acid and base could promote the formation of the
two intermediates 4a and 5a. Another control experiment was
also performed to prove the crucial role of HOAc. The product
3a was obtained in 65% yield in dioxane without HOAc and the
two isomeric intermediates 4a and 5a were also detected by
LC-MS result (Figure 1D, LC-MS result in Figure S8). These
results demonstrated that both Cu(OAc)2·H 2O and HOAc
played a role of promotor for the formation of the two
isomeric intermediates 4a and 5a; moreover, Cu(OAc)2·H 2O/air
or only air played a role of the oxidant for the subsequent
formation of the product 3a (the result vs Table 1, entries 2
and 5).
Based on the above experimental results, a plausible
mechanism was proposed as shown in Scheme 3. Initially, the
reaction of indole 1a and 2-(4-bromophenyl)-2-oxoacetalde-
hyde hydrate 2a in the presence of Cu(OAc)2·H 2O (path a) or
HOAc (path b) resulted in the formation of two isomeric
intermediates 4a and 5a (4a could be converted to 5a in the
presence of Cu(OAc)2·H 2O or HOAc), followed by further rapid
oxidation by Cu(OAc)2·H 2O/air (path a) or only air (path b) to
afford the desired product 3a. Finally, Cu(OAc)2·H 2O was
reduced to Cu2O after the reaction in path a. Notably, a
precipitate was collected after the reaction at a 4 mmol scale
and was analyzed by XRD (X-ray powder diffraction)
significant diffraction peak was assigned to Cu2O (see Figure S1
in supporting information) The result suggested that
. The
.
a Conditions: 1 (0.5 mmol), 2 (0.6 mmol), Cu(OAc)2·H 2O (20 mol%), dioxane/HOAc
(4.0/0.5, v/v, 4.5 mL), 100 oC, under air atmosphere; the isolated yields are given.
Cu(OAc)2·H 2O can be considered as both the catalyst and the
oxidant in the reaction.
Scheme 1 Synthesis of the indole alkaloid 6 by Cu-catalyzed C–H oxidation/diacylation
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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(A) Reprecentative LC-MS result
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DOI: 10.1039/C7OB01255A
Scheme 2 Synthetic application of indolyl diketones
indolyl diketones in moderate to good yields with a broad
substrate scope and good tolerance of functional groups.
Furthermore, the synthetic utility of the reaction is also
achieved by the synthesis of the natural alkaloid 1,2-di(1H-
indol-3-yl)ethane-1,2-dione. Gratifyingly, the obtained indolyl
diketone products could be further used to construct indolyl
nitrogen-containing heterocycles such as indolyl quinoxaline,
indolyl hydantoin and indolyl imidazole in high yields.
Preliminary mechanistic studies indicate that two proposed
pathways are involved in this process. Further investigations
on the detailed reaction mechanism and studies on transition-
metal-catalyzed C–H functionalization of indoles are currently
underway in our laboratory.
(B) Ivonin’s work on two isomeric intermediates
(C) Detailed experiment results on the different intermediates by LC-MS results
Scheme 3 Plausible reaction mechanism
Experimental
General procedure for the synthesis of product 3
(D) Control experiment
A dried 25mL two-neck round bottom flask was charged with
indole
1 (0.5 mmol), arylglyoxal hydrates 2 (0.6 mmol),
Cu(OAc)2·H 2O (20.0 mg, 20 mol%) and dioxane/HOAc (4.0/0.5,
v/v, 4.5 mL) under air atmosphere. The reaction mixture was
stirred at 100 °C. After completion of the reaction, the reaction
Figure
1 (A) Reprecentative LC-MS result. (B) Ivonin’s work on two isomeric
intermediates. (C) Detailed experiment results on the different intermediates by LC-MS mixture was cooled to room temperature and diluted with
results. (D) Control experiment.
ethyl acetate and water. The aqueous phase was extracted
with ethyl acetate. The combined organic extracts were
washed with saturated brine, dried with anhydrous Na2SO4
and evaporated under reduced pressure. The crude products
were purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate, 10/1, v/v) to afford the
Conclusions
In conclusion, we have successfully established an efficient Cu-
catalyzed C–H oxidation/diacylation of indoles with
arylglyoxals hydrates under air atmosphere. The reaction
provides a new and expedient alternative synthetic method for
corresponding products 3.
1-(4-bromophenyl)-2-(1H-indol-3-yl)ethane-1,2-dione (3aa)9
4 | J. Name., 2012, 00, 1-3
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o
1
Yellow solid, m.p.: 205.1-206.5 C. H NMR (500 MHz, DMSO- ([M+Na]+): calcd 363.9949, 365.9929, foundView3A6rti3cl.e9O9n4lin0e,
DOI: 10.1039/C7OB01255A
d6): δ 12.44 (s, 1H), 8.20 (s, 2H), 7.89 (d, J=8.5 Hz, 2H), 7.79 (d, 365.9925.
J=8.0 Hz, 2H), 7.55 (dd, J=2.0, 5.5 Hz, 1H), 7.30 (dd, J=3.5, 3.5 1-(4-bromophenyl)-2-(1-methyl-1H-indol-3-yl)ethane-1,2-
Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 193.30, 188.21, dione (3ga)
o
138.64, 137.48, 132.74, 132.52, 132.08, 129.40, 125.54, 124.37, Yellow solid, m.p.: 160.4-161.4 C. 1H NMR (500 MHz, DMSO-
123.37, 121.67, 113.25, 112.95. HRMS (ESI) for C16H10NO2NaBr d6): δ 8.24 (s, 1H), 8.22 (d, J=7.0 Hz, 1H), 7.88 (d, J=8.5 Hz, 2H),
([M+Na]+): calcd 349.9793, 351.9772, found 349.9803, 7.80 (d, J=8.5 Hz, 2H), 7.61 (d, J=7.5 Hz, 1H), 7.39-7.33 (m, 2H),
349.9780.
3.86 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 194.23, 188.53,
142.76, 139.13, 133.70, 133.38, 132.98, 130.39, 126.88, 125.34,
124.68, 122.71, 112.68, 34.85. HRMS (ESI) for C17H12NO2NaBr
1-(4-bromophenyl)-2-(5-methoxy-1H-indol-3-yl)ethane-1,2-
dione (3ba)
Yellow solid, m.p.: 201.6-202.3 oC. 1H NMR (500 MHz, acetone- ([M+Na]+): calcd 363.9949, 365.9929, found 363.9940,
d6): δ 8.02 (s, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.82 (s, 1H), 7.76 (d, 365.9925.
J=8.0 Hz, 2H), 7.46 (d, J=8.5 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 3.84 1-(4-bromophenyl)-2-(6-methoxy-1H-indol-3-yl)ethane-1,2-
(s, 3H); 13C NMR (125 MHz, acetone-d6) δ 192.77, 187.70, dione (3ha)
o
1
156.87, 137.04, 132.69, 131.85, 131.63, 128.90, 126.51, 113.91, Yellow solid, m.p.: 220.3-220.5 C. H NMR (500 MHz, DMSO-
113.22, 113.11, 103.45, 55.06. HRMS (ESI) for C17H12NO3NaBr d6): δ 12.24 (s, 1H), 8.05 (d, J=8.0 Hz, 2H), 7.87 (d, J=8.5 Hz, 2H),
([M+Na]+): calcd 379.9898, 381.9878, found 379.9900, 7.79 (d, J=8.5 Hz, 2H), 7.02 (s, 1H), 6.93 (d, J=8.5 Hz, 1H), 3.80
381.9884.
(s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 193.28, 188.00, 157.58,
138.51, 137.84, 132.72, 132.57, 132.05, 129.34, 122.30, 119.34,
113.06, 112.99, 96.40, 55.84. HRMS (ESI) for C17H12NO3NaBr
1-(4-bromophenyl)-2-(5-methyl-1H-indol-3-yl)ethane-1,2-
dione (3ca)
Grey solid, m.p.: 226.4-227.8 oC. 1H NMR (500 MHz, DMSO-d6): ([M+Na]+): calcd 379.9898, 381.9878, found 379.9900,
δ 12.33 (s, 1H), 8.12 (d, J=3.0 Hz, 1H), 8.03 (s, 1H), 7.87 (d, 381.9884.
J=8.5 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.13 1-(4-bromophenyl)-2-(4-hydroxy-1H-indol-3-yl)ethane-1,2-
(d, J=7.5 Hz, 1H), 2.43 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ dione (3ia)
193.34, 188.12, 138.49, 135.77, 132.72, 132.58, 132.44, 132.05, Brown solid, m.p.: 203.5-204.6 C. H NMR (500 MHz, DMSO-
129.34, 125.82, 125.80, 121.45, 112.86, 112.58, 21.74. HRMS d6): δ 11.98 (s, 1H), 8.52 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.51 (s,
(ESI) for C17H12NO2NaBr ([M+Na]+): calcd 363.9949, 365.9929, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.24-7.19 (m, 2H), 6.75 (s, 1H); 13C
o
1
found 363.9940, 365.9925.
1-(4-bromophenyl)-2-(4-methyl-1H-indol-3-yl)ethane-1,2-
dione (3da)
NMR (125 MHz, DMSO-d6) δ 195.92, 167.22, 143.52, 137.31,
131.80, 128.42, 126.97, 122.78, 116.88, 113.21, 108.85, 108.55,
105.26, 100.28. HRMS (ESI) for C16H10NO3NaBr ([M+Na]+):
Yellow solid, m.p.: 152.8-154.8 oC. 1H NMR (500 MHz, acetone- calcd 365.9742, 367.9721, found 365.9728, 367.9705.
d6): δ 8.01 (s, 1H), 7.91 (d, J=7.0 Hz, 2H), 7.75 (d, J=7.0 Hz, 2H), 3-(2-(4-bromophenyl)-2-oxoacetyl)-1H-indole-4-carbonitrile
7.36 (d, J=8.0 Hz, 1H), 7.17 (dd, J=7.0, 7.0 Hz, 1H), 7.04 (d, (3ja)
J=6.5 Hz, 1H), 2.90 (s, 3H); 13C NMR (125 MHz, acetone-d6) δ Yellow solid, m.p.: 256.9-257.8 C. H NMR (500 MHz, DMSO-
193.86, 188.08, 139.09, 138.26, 132.83, 132.60, 132.22, 131.52, d6): δ 12.95 (s, 1H), 8.41 (s, 1H), 7.90 (d, J=7.5 Hz, 3H), 7.82 (d,
128.81, 124.62, 124.39, 124.24, 114.57, 109.95, 22.50. HRMS J=8.5 Hz, 2H), 7.79 (d, J=7.5 Hz, 1H), 7.79 (dd, J=7.0, 7.5 Hz, 1H);
(ESI) for C17H12NO2NaBr ([M+Na]+): calcd 363.9949, 365.9929, 13C NMR (125 MHz, DMSO-d6) δ 193.10, 187.47, 141.11,
o
1
found 363.9940, 365.9925.
138.43, 132.77, 132.16, 130.97, 129.55, 124.57, 124.12, 119.22,
118.70, 112.66, 104.41. HRMS (ESI) for C17H9N2O2NaBr
([M+Na]+): calcd 374.9745, 376.9725, found 374.9741,
1-(4-bromophenyl)-2-(7-methyl-1H-indol-3-yl)ethane-1,2-
dione (3ea)
Yellow solid, m.p.: 229.9-230.5 oC. 1H NMR (500 MHz, acetone- 376.9723.
d6): δ 8.13 (d, J=8.0 Hz, 1H), 8.05 (s, 1H), 7.93 (d, J=7.0 Hz, 2H), 1-(4-bromophenyl)-2-(5-nitro-1H-indol-3-yl)ethane-1,2-dione
7.75 (d, J=7.5 Hz, 2H), 7.19 (dd, J=6.5, 7.5 Hz, 1H), 7.10 (d, (3ka)
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1
J=7.0 Hz, 1H), 2.51 (s, 3H); 13C NMR (125 MHz, acetone-d6) δ Brown solid, m.p.: 266.5-268.4 C. H NMR (500 MHz, DMSO-
192.79, 187.91, 136.67, 136.57, 132.67, 132.18, 131.61, 128.92, d6): δ 12.98 (s, 1H), 9.05 (s, 1H), 8.50 (s, 1H), 8.19 (dd, J=9.0,
125.34, 124.66, 123.15, 122.02, 119.29, 113.59, 15.93. HRMS 2.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.5 Hz, 2H), 7.73
(ESI) for C17H12NO2NaBr ([M+Na]+): calcd 363.9949, 365.9929, (d, J=9.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 192.41,
found 363.9940, 365.9925.
1-(4-bromophenyl)-2-(2-methyl-1H-indol-3-yl)ethane-1,2-
dione (3fa)
188.04, 143.91, 141.89, 140.61, 132.75, 132.25, 132.17, 129.68,
125.17, 119.68, 117.90, 114.08, 114.05. HRMS (ESI) for
C16H9N2O4NaBr ([M+Na]+): calcd 394.9643, 394.9623 found
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Yellow solid, m.p.: 235.9-236.4 C. H NMR (500 MHz, DMSO- 394.9637, 396.9614.
d6): δ 12.42 (s, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.5 Hz, 3H), 1-(4-chlorophenyl)-2-(1H-indol-3-yl)ethane-1,2-dione (3ab)6,9
1
7.44 (d, J=7.5 Hz, 1H), 7.19 (dd, J=7.5, 2.0 Hz, 1H), 7.19 (dd, Yellow solid. H NMR (500 MHz, DMSO-d6): δ 12.48 (s, 1H),
J=7.5, 2.0 Hz, 1H), 7.15 (dd, J=7.5, 2.0 Hz, 1H), 2.48 (s, 3H); 13C 8.24-8.23 (m, 2H), 8.01-7.98 (m, 2H), 7.71-7.68 (m, 2H), 7.60-
NMR (125 MHz, DMSO-d6) δ 195.76, 190.17, 149.37, 136.77, 7.59 (m, 1H), 7.36-7.31 (m, 2H); 13C NMR (125 MHz, DMSO-d6)
134.01, 133.16, 132.68, 130.64, 127.77, 124.36, 123.86, 121.29, δ 193.09, 188.23, 140.08, 138.62, 137.47, 132.20, 132.05,
113.25, 110.93, 15.67. HRMS (ESI) for C17H12NO2NaBr 129.79, 125.52, 124.37, 123.36, 121.64, 113.24, 112.93. HRMS
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Organic & Biomolecular Chemistry
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Journal Name
(ESI) for C16H10NO2NaCl ([M+Na]+): calcd 306.0298, 308.0268, 145.91, 138.15, 137.44, 131.03, 130.30, 130.15, 125.49, 124.26,
View Article Online
found 306.0290, 308.0258.
1-(3-chlorophenyl)-2-(1H-indol-3-yl)ethane-1,2-dione (3ac)
Yellow solid, m.p.: 216.7-218.5 C. H NMR (500 MHz, DMSO- 1-(1H-indol-3-yl)-2-(m-tolyl)ethane-1,2-dione (3aj)
123.24, 121.62, 113.20, 113.12, 21.8D3O.I: 1H0.R10M39S/C7(OESBI0)125f5oAr
C17H13NO2Na ([M+Na]+): calcd 286.0844, found 286.0840.
o
1
o
1
d6): δ 12.49 (s, 1H), 8.25 (m, 2H), 7.96 (s, 1H), 7.92 (d, J=6.5 Hz, Yellow solid, m.p.: 317.1-318.8 C. H NMR (500 MHz, DMSO-
1H), 7.82 (d, J=8.0 Hz, 1H), 7.63 (dd, J=7.5, 8.0 Hz, 1H), 7.58 (d, d6): δ 12.43 (s, 1H), 8.22 (d, J=3.0 Hz, 1H), 8.17 (s, 1H), 7.78-
J=6.5 Hz, 1H), 7.34-7.33 (m, 2H); 13C NMR (125 MHz, DMSO-d6) 7.76 (m, 2H), 7.56-7.53 (m, 3H), 7.33-7.31 (m, 2H), 2.39 (s, 3H);
δ 192.06, 187.10, 170.13, 138.20, 136.83, 134.68, 134.11, 13C NMR (125 MHz, DMSO-d6) δ 195.49, 190.15, 145.65,
133.75, 131.00, 128.63, 128.48, 124.89, 123.76, 122.76, 121.04, 138.36, 136.95, 134.48, 134.34, 131.23, 131.07, 128.12, 126.48,
112.61, 112.22. HRMS (APCI) for C16H11NO2Cl ([M+H]+): calcd 125.37, 124.12, 122.14, 113.44, 113.36, 22.20. HRMS (APCI)
284.0478, 286.0449, found 284.0476, 286.0450.
for C17H14NO2 ([M+H]+): calcd 264.1025, found 264.1022.
1-(2,4-dimethylphenyl)-2-(1H-indol-3-yl)ethane-1,2-dione
1-(4-fluorophenyl)-2-(1H-indol-3-yl)ethane-1,2-dione (3ad)6
1
Yellow solid. H NMR (500 MHz, DMSO-d6): δ 12.44 (s, 1H), (3ak)
o
1
8.23-8.20 (m, 2H), 8.07-8.05 (m, 2H), 7.57-7.55 (m, 1H), 7.46- Yellow solid, m.p.: 192.5-194.1 C. H NMR (500 MHz, DMSO-
7.42 (m, 2H), 7.34-7.30 (m, 2H); 13C NMR (125 MHz, DMSO-d6) d6): δ 12.39 (s, 1H), 8.20-8.16 (m, 2H), 7.59 (d, J=8.0 Hz, 1H),
δ 193.73, 189.44, 167.17 (d, J=252.5 Hz), 139.40, 138.38, 7.56 (dd, J=7.0, 2.0 Hz, 1H), 7.33-7.28 (m, 2H), 7.24 (s, 1H),
134.26 (d, J=10.0 Hz), 131.20 (d, J=2.5 Hz), 126.46, 125.25, 7.15 (d, J=8.0 Hz, 1H), 2.59 (s, 3H), 2.35 (s, 3H); 13C NMR (125
124.24, 122.56, 117.75 (d, J=21.3 Hz), 114.14, 113.91. HRMS MHz, DMSO-d6) δ 197.50, 190.74, 145.35, 141.60, 138.78,
(ESI) for C16H10NO2NaF ([M+Na]+): calcd 290.0593, found 138.31, 134.31, 134.20, 131.06, 128.08, 126.54, 125.09, 124.06,
290.0589.
122.49, 114.08, 114.03, 22.55, 22.49. HRMS (ESI) for
1-(1H-indol-3-yl)-2-(4-iodophenyl)ethane-1,2-dione (3ae)
C18H15NO2Na ([M+Na]+): calcd 300.1000, found 299.9994.
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Yellow solid, m.p.: 219.9-220.5 C. H NMR (500 MHz, DMSO- 1-(1H-indol-3-yl)-2-(4-methoxyphenyl)ethane-1,2-dione
d6): δ 12.45 (s, 1H), 8.22-8.20 (m, 2H), 8.02-8.00 (m, 2H), 7.73- (3al)6,9
7.70 (m, 2H), 7.57-7.54 (m, 1H), 7.34-7.29 (m, 2H); 13C NMR Yellow solid. H NMR (500 MHz, DMSO-d6): δ 12.40 (s, 1H),
1
(125 MHz, DMSO-d6) δ 194.67, 189.25, 139.54, 138.38, 133.70, 8.23 (dd, J=6.0, 2.5 Hz, 1H), 8.15 (d, J=3.0 Hz, 1H), 7.97-7.94 (m,
132.59, 126.42, 125.29, 124.27, 122.56, 114.16, 113.86, 106.73, 2H), 7.59-7.55 (m, 1H), 7.35-7.30 (m, 2H), 7.15-7.12 (m, 2H),
105.22. HRMS (ESI) for C16H10NO2NaI ([M+Na]+): calcd 3.88 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 193.15, 189.55,
397.9654, found 397.9652.
1-(1H-indol-3-yl)-2-(4-nitrophenyl)ethane-1,2-dione (3af)
164.79, 138.01, 137.42, 132.66, 126.34, 125.53, 124.20, 123.19,
121.61, 114.98, 113.22, 113.18, 56.21. HRMS (ESI) for
Brown solid, m.p.: 238.6-239.5 C. H NMR (500 MHz, DMSO- C17H13NO3Na ([M+Na]+): calcd 302.0793, found 302.0795.
d6): δ 12.52 (s, 1H), 8.40 (d, J=8.5 Hz, 2H), 8.29 (s, 1H), 8.22 (d, 1-(4-chlorophenyl)-2-(5-methoxy-1H-indol-3-yl)ethane-1,2-
J=8.5 Hz, 3H), 7.57 (d, J=5.5 Hz, 1H), 7.33 (dd, J=3.5, 3.5 Hz, 2H); dione (3bb)
o
1
13C NMR (125 MHz, DMSO-d6) δ 192.50, 187.15, 151.06, Yellow solid, m.p.: 194.1-195.0 C. H NMR (500 MHz, DMSO-
139.09, 138.19, 137.50, 131.68, 125.60, 124.59, 124.49, 123.48, d6): δ 12.36 (s, 1H), 8.12 (d, J=3.0 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H),
121.70, 113.30, 112.77. HRMS (ESI) for C16H10N2O4Na 7.73 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.45 (d, J=9.0 Hz, 1H), 6.94
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([M+Na]+): calcd 317.0538, found 317.0537.
Methyl 4-(2-(1H-indol-3-yl)-2-oxoacetly)benzoate (3ag)
(dd, J=9.0, 2.5 Hz, 1H), 3.83 (s, 3H); 13C NMR (125 MHz, DMSO-
d6) δ 193.10, 188.04, 156.71, 140.05, 138.49, 132.20, 132.05,
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Yellow solid, m.p.: 352.3-353.9 C. H NMR (500 MHz, C3D6O): 131.60, 129.78, 126.48, 114.10, 114.04, 112.81, 103.58, 55.86.
δ 11.45 (s, 1H), 8.40-8.39 (m, 1H), 8.22-8.16 (m, 5H), 7.63 (dd, HRMS (ESI) for C17H12NO3NaCl ([M+Na]+): calcd 336.0403,
J=3.0, 3.5 Hz, 1H), 7.37 (dd, J=3.0, 3.0 Hz, 2H), 3.95 (s, 3H); 13C 338.0374, found 336.0416, 338.0381.
NMR (125 MHz, C3D6O) δ 192.29, 186.98, 164.88, 136.60, 1-(5-methoxy-1H-indol-3-yl)-2-(4-nitrophenyl)ethane-1,2-
136.57, 136.36, 134.17, 129.32, 129.00, 125.00, 123.41, 122.27, dione (3be)
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121.11, 112.74, 111.78, 51.26. HRMS (APCI) for C18H14NO4 Yellow solid, m.p.: 236.1-236.9 C. H NMR (500 MHz, DMSO-
([M+H]+): calcd 308.0923, found 308.0923.
d6): δ 12.43 (s, 1H), 8.42 (dd, J=9.0, 4.0 Hz, 2H), 8.23 (dd, J=9.0,
4.0 Hz, 3H), 7.75 (s, 1H), 7.48 (dd, J=9.0, 3.5 Hz, 1H), 6.97 (dd,
1-(1H-indol-3-yl)-2-phenylethane-1,2-dione (3ah)6,9
1
Brown solid. H NMR (500 MHz, DMSO-d6): δ 12.37 (s, 1H), J=9.0, 2.5 Hz, 1H), 3.85 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ
8.21 (d, J=5.5 Hz, 1H), 8.15 (d, J=3.0 Hz, 1H), 7.96 (d, J=7.0 Hz, 192.53, 186.96, 156.81, 151.06, 138.92, 138.23, 132.21, 131.67,
2H), 7.74-7.71 (m, 1H), 7.60-7.54 (m, 3H), 7.32-7.29 (m, 2H); 126.56, 124.59, 114.18, 114.10, 112.64, 103.66, 55.89. HRMS
13C NMR (125 MHz, DMSO-d6) δ 194.45, 189.01, 138.31, (ESI) for C17H12N2O5Na ([M+Na]+): calcd 347.0644, found
137.47, 135.10, 133.51, 130.18, 129.59, 125.51, 124.30, 123.28, 347.0656.
121.63, 113.22, 113.09. HRMS (ESI) for C16H11NO2Na ([M+Na]+): 1-(5-methoxy-1H-indol-3-yl)-2-p-tolylethane-1,2-dione (3bg)
o
calcd 272.0687, found 272.0689.
Brown solid, m.p.: 165.4-167.3 C. 1H NMR (500 MHz, DMSO-
1-(1H-indol-3-yl)-2-(p-tolyl)ethane-1,2-dione (3ai)6
d6): δ 12.27 (s, 1H), 8.03 (d, J=3.5 Hz, 1H), 7.85 (d, J=8.0 Hz, 2H),
1
Yellow solid. H NMR (500 MHz, DMSO-d6): δ 12.42 (s, 1H), 7.71 (s, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 2H), 6.92
8.23 (d, J=6.0 Hz, 1H), 8.16 (d, J=3.0 Hz, 1H), 7.88 (d, J=8.0 Hz, (dd, J=9.0, 2.5 Hz, 1H), 3.81 (s, 3H), 2.39 (s, 3H); 13C NMR (125
2H), 7.58-7.56 (m, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.35-7.30 (m, 2H), MHz, DMSO-d6) δ 194.17, 189.10, 156.63, 145.86, 138.02,
2.42 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 194.16, 189.30, 132.19, 131.08, 130.28, 130.13, 126.43, 114.00, 113.97, 113.00,
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
103.57, 55.87, 21.82. HRMS (ESI) for C18H15NO3Na ([M+Na]+): 1-(1-methyl-1H-indol-3-yl)-2-p-tolylethane-1,2-dione (3gg)7
View Article Online
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1
DOI: 10.1039/C7OB01255A
Yellow solid, m.p.: 114.2-115.3 C. H NMR (500 MHz, DMSO-
calcd 316.0950, found 316.0963.
1-(5-methoxy-1H-indol-3-yl)-2-(4-methoxyphenyl)ethane-1,2- d6): δ 8.24 (d, J=7.5 Hz, 1H), 8.21 (s, 1H), 7.95 (d, J=8.5 Hz, 2H),
dione (3bi)
7.64 (d, J=7.5 Hz, 1H), 7.41-7.35 (m, 2H), 7.14 (d, J=8.5 Hz, 2H),
o
Brown solid, m.p.: 212.8-213.6 C. 1H NMR (500 MHz, DMSO- 3.89 (s, 3H), 3.88 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ
d6): δ 12.28 (s, 1H), 8.04 (d, J=3.0 Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 193.12, 188.99, 164.83, 141.30, 138.14, 132.65, 126.26, 125.94,
7.73 (s, 1H), 7.45 (d, J=9.0 Hz, 1H), 7.13 (d, J=9.0 Hz, 2H), 6.95 124.26, 123.59, 121.74, 115.01, 112.04, 111.68, 56.24, 33.83.
(dd, J=8.5, 2.5 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H); 13C NMR (125 HRMS (ESI) for C18H15NO2Na ([M+Na]+): calcd 300.1000, found
MHz, DMSO-d6) δ 193.16, 189.37, 164.76, 156.59, 137.94, 300.1009.
132.64, 132.15, 126.38, 126.27, 114.97, 113.95, 113.06, 103.53, 1-(4-methoxyphenyl)-2-(1-methyl-1H-indol-3-yl)ethane-1,2-
56.23, 55.86. HRMS (ESI) for C18H15NO4Na ([M+Na]+): calcd dione (3gi)7
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332.0899, found 332.0898.
1-(4-chlorophenyl)-2-(4-hydroxy-1H-indol-3-yl)ethane-1,2-
dione (3ib)
Yellow solid, m.p.: 123.7-125.0 C. H NMR (500 MHz, DMSO-
d6): δ 8.25 (d, J=7.5 Hz, 1H), 8.23 (s, 1H), 7.88 (d, J=8.0 Hz, 2H),
7.64 (d, J=8.0 Hz, 1H), 7.43-7.36 (m, 4H), 3.89 (s, 3H), 2.42 (s,
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Yellow solid, m.p.: 196.3-197.4 C. H NMR (500 MHz, DMSO- 3H); 13C NMR (125 MHz, DMSO-d6) δ 194.13, 188.73, 145.98,
d6): δ 11.98 (s, 1H), 8.52 (s, 1H), 7.51-7.44 (m, 5H), 7.25-7.20 141.41, 138.17, 130.96, 130.29, 130.18, 125.92, 124.31, 123.64,
(m, 2H), 6.76 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 195.97, 121.75, 111.96, 111.70, 33.85, 21.83. HRMS (ESI) for
167.22, 143.53, 136.88, 134.15, 128.87, 128.12, 126.97, 116.90, C18H15NO3Na ([M+Na]+): calcd 316.0950, found 316.0963.
113.22, 108.86, 108.56, 105.22, 100.29. HRMS (ESI) for 1-(4-bromophenyl)-2-hydroxy-2-(1H-indol-3-yl)ethanone
C16H10NO3NaCl ([M+Na]+): calcd 322.0247, 324.0217, found (4a)17a
322.0258, 324.0220.
1-(4-hydroxy-1H-indol-3-yl)-2-p-tolylethane-1,2-dione (3ig)
Recrystallization from benzene, white solid, m.p.: 158.5-160.1
oC. 1H NMR (500 MHz, DMSO-d6): δ 11.10 (s, 1H), 7.94 (d, J=8.5
o
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Yellow solid, m.p.: 192.2-193.6 C. H NMR (500 MHz, DMSO- Hz, 2H), 7.61 (d, J=8.5 Hz, 3H), 7.37-7.32 (m, 2H), 7.06 (dd,
d6): δ 11.95 (s, 1H), 8.33 (s, 1H), 7.51 (s, 1H), 7.37 (d, J=8.0 Hz, J=7.0, 7.5 Hz, 1H), 6.98 (dd, J=7.5, 7.5 Hz, 1H), 6.33 (d, J=5.5 Hz,
2H), 7.24-7.18 (m, 4H), 6.75 (s, 1H), 2.30 (s, 3H); 13C NMR (125 1H), 5.64 (d, J=5.5 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ
MHz, DMSO-d6) δ 196.50, 167.26, 143.40, 138.68, 134.99, 198.69, 136.80, 134.50, 131.99, 130.98, 128.78, 127.40, 126.03,
129.25, 126.79, 126.09, 116.87, 113.23, 109.09, 108.25, 105.89, 125.32, 121.80, 119.61, 119.44, 113.46, 112.08, 70.30. HRMS
100.25, 21.20. HRMS (ESI) for C16H10NO3NaCl ([M+Na]+): calcd (ESI) for C16H12NO2NaBr ([M+Na]+): calcd 351.9949, found
302.0793, found 302.0805.
1-(4-chlorophenyl)-2-(2-methyl-1H-indol-3-yl)ethane-1,2-
dione (3fb)
351.9945.
1,2-di(1H-indol-3-yl)ethane-1,2-dione (6)13,15b
o
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Yellow solid, m.p.: 279.1-280.5 C. H NMR (500 MHz, DMSO-
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Yellow solid, m.p.: 243.9-244.5 C. H NMR (500 MHz, DMSO- d6): δ 12.23 (s, 2H), 8.26 (m, 2H), 8.20 (s, 2H), 7.53 (m, 2H),
d6): δ 12.44 (s, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.79 (s, 1H), 7.68 (d, 7.28 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ 189.24, 137.78,
J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 1H), 7.21 (dd, J=7.0, 2.5 Hz, 1H), 137.70, 126.15, 123.86, 122.84, 121.78, 113.05, 113.01. HRMS
7.16 (dd, J=7.0, 2.5 Hz, 1H), 2.49 (s, 3H); 13C NMR (125 MHz, (ESI) for C24H17N2O2Na ([M+Na]+): calcd 311.0796, found
DMSO-d6) δ 194.63, 189.27, 148.44, 140.39, 135.83, 131.91, 311.0792.
131.73, 130.15, 126.82, 123.44, 122.94, 120.34, 112.32, 109.97, General procedure for the synthesis of product 7
14.73. HRMS (ESI) for C17H12NO2NaCl ([M+Na]+): calcd
320.0454, 322.0425, found 320.0447, 322.0414.
A
mixture of 1-(4-bromophenyl)-2-(1-methyl-1H-indol-3-
yl)ethane-1,2-dione (0.15 mmol, 51.33 mg) and o-
1-(2-methyl-1H-indol-3-yl)-2-p-tolylethane-1,2-dione (3fg)
phenylenediamine (0.225 mmol, 24.33 mg) was dissolved in
o
1
Yellow solid, m.p.: 188.9-189.6 C. H NMR (500 MHz, DMSO- HOAc (1 mL) and EtOH (5 mL). The reaction mixture was stirred
d6): δ 12.38 (s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.80 (s, 1H), 7.44 (d, at 80 oC for 10 min under microwave irradiation (a Biotage
J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.20 (dd, J=7.5, 2.5 Hz, 1H), Initiator 8 reactor from Sweden). After the completion of the
7.15 (dd, J=7.5, 2.5 Hz, 1H), 2.49 (s, 3H), 2.39 (s, 3H); 13C NMR reaction, water (6 mL) was added. The solid was filtered under
(125 MHz, DMSO-d6) δ 195.59, 190.19, 148.01, 146.16, 135.78, reduced pressure and washed with small portions of a mixture
130.84, 130.46, 130.00, 126.86, 123.31, 122.79, 120.38, 112.24, of cooled EtOH/H2O (1:1, v:v). The crude product was purified
110.11, 21.84, 14.65. HRMS (ESI) for C18H15NO2Na ([M+Na]+): by flash column chromatography on silica gel (petroleum
calcd 300.1000, found 300.1009.
ether/ethyl acetate, 5/1, v/v) to afford the target product 2-(4-
1-(1-methyl-1H-indol-3-yl)-2-(4-nitrophenyl)ethane-1,2-dione bromophenyl)-3-(1-methyl-1H-indol-3-yl)quinoxaline in 90%
o
1
(3ge)7
yield. Yellow solid, m.p.: 196.1-196.8 C. H NMR (500 MHz,
o
1
Yellow solid, m.p.: 198.9-200.0 C H NMR (500 MHz, DMSO- DMSO-d6): δ 8.19 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 8.02
d6): δ 8.42 (d, J=9.0 Hz, 2H), 8.37 (s, 1H), 8.27 (d, J=7.5 Hz, 1H), (d, J=8.0 Hz, 1H), 7.81 (dd, J=7.0, 7.5 Hz, 1H), 7.74 (dd, J=7.0,
8.23 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.0 Hz, 1H), 7.44-7.39 (m, 2H), 7.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.46
3.91 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 192.53, 186.54, (d, J=8.5 Hz, 1H), 7.21 (dd, J=7.5, 7.5 Hz, 1H), 7.11 (dd, J=8.0,
151.10, 142.26, 138.26, 138.09, 131.67, 126.01, 124.64, 124.55, 7.5 Hz, 1H), 7.00 (s, 1H), 3.69 (s, 3H); 13C NMR (125 MHz,
123.90, 121.83, 111.85, 111.58, 34.00. HRMS (ESI) for DMSO-d6) δ 153.43, 150.14, 142.25, 140.41, 140.35, 138.18,
C17H12N2O4Na ([M+Na]+): calcd 331.0695, found 331.0706.
133.99, 132.76, 132.59, 131.64, 130.37, 130.03, 129.60, 127.83,
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123.81, 123.69, 123.06, 121.99, 113.74, 111.56, 34.25. HRMS Talents in University (LR2014009), Department ofVeiedwuAcrtaictleioOnnlionef
(APCI) for C23H17N3Br ([M+H]+): calcd 414.0606, 416.0585, Liaoning Province (2016TSPY01), ExcellenDtOTIa: l1e0n.1t0s39in/CU7OniBv0e1r2s5i5tAy
found 414.0616, 416.0588.
of Science and Technology Liaoning (2015RC08).
General procedure for the synthesis of product 8
A
mixture of 1-(4-bromophenyl)-2-(1-methyl-1H-indol-3-
Notes and references
yl)ethane-1,2-dione (0.15 mmol, 51.33 mg), urea (0.30 mmol,
18.02 mg) and KOH (0.60 mmol, 33.70 mg) was dissolved in
DMSO (3 mL). The reaction mixture was stirred at 120 C for 30
1
(a) R. J. Sundberg, Comprehensive Heterocyclic Chemistry II
(Eds. A. R. Katritzky, C. W. Rees, E. F .V. Scriven and C. W.
Bird), Pergamon Press, Oxford, UK, 1996, pp. 119–206; (b) J.
A. Joule, Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations (Ed. E. J. Thomas), George
Thieme Verlag, Stuttgart, Germany, 2000, p 361; (c) K.
Higuchi and T. Kawasaki, Nat. Prod. Rep., 2007, 24, 843–868.
(a) J. -Q. Yu and Z. Shi, C–H Activation, Topics in Current
Chemistry, Springer: Heidelberg, 2010, Vol. 292, pp. 85–121;
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o
min. After the completion of the reaction, the reaction mixture
was poured into cold water. The solution was acidified with
glacial acetic acid. The solid was filtered under reduced
pressure and washed with cold water. The product was
recrystallized from ethanol. The product 5-(4-bromophenyl)-5-
(1-methyl-1H-indol-3-yl)imidazolidine-2,4-dione was obtained
in 85% yield. Off-white solid, m.p.: 269.8-270.5 oC. IR (KBr, cm-1)
ν 3264 (NH), 1763 (C=O), 1711 (C=O); 1H NMR (500 MHz,
DMSO-d6): δ 11.10 (s, 1H), 9.14 (s, 1H), 7.62 (d, J=8.5 Hz, 2H),
7.44 (dd, J=7.5, 6.0 Hz, 3H), 7.21-7.15 (m, 2H), 7.05 (s, 1H),
6.98 (dd, J=8.0, 7.5 Hz, 1H), 3.75 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 175.37, 156.55, 139.11, 137.72, 131.70, 129.40,
129.15, 125.38, 122.16, 121.89, 120.00, 119.69, 113.43, 110.60,
66.91, 32.89. HRMS (APCI) for C18H15N3O2Br ([M+H]+): calcd
384.0348, 386.0327, found 384.0343, 386.0325.
2
(c) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36
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2920; (f) A. H. Sandtorva, Adv. Synth. Catal., 2015, 357
,
2403–2435; (g) M. Ishikura, T. Abe, T. Choshi and S. Hibino,
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3
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(a) J. L. Sessler, D. Cho and V. Lynch, J. Am. Chem. Soc., 2006,
128, 16518–16519; (b) R.-Y. Tang, X.-K. Guo, J.-N. Xiang and
J.-H. Li, J. Org. Chem., 2013, 78, 11163–11171; (c) Z. Che, S.
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General procedure for the synthesis of product 9
A
yl)ethane-1,2-dione (0.15 mmol, 51.33 mg), 4-
mixture of 1-(4-bromophenyl)-2-(1-methyl-1H-indol-3-
bromobenzaldehyde (0.15 mmol, 27.27 mg), NH4OAc (10 equiv,
1.50 mmol, 115.62 mg) and SnCl2·2H2O (10 mol%, 3.4 mg) was
dissolved in EtOH (6 mL). The reaction mixture was stirred at
80 oC for 10 min under microwave irradiation (a Biotage
Initiator 8 reactor from Sweden). After the completion of the
reaction, water (6 mL) was added. The solid was filtered under
reduced pressure and washed with small portions of a mixture
of cooled EtOH/H2O (1:1, v:v). The crude product was purified
by flash column chromatography on silica gel (petroleum
ether/ethyl acetate, 5/1, v/v) to afford the target product 3-
(2,5-bis(4-bromophenyl)-1H-imidazol-4-yl)-1-methyl-1H-indole
in 88% yield. NMR spectrum show that the imidazole ring
exists in prototropic tautomers. Light yellow solid, m.p.: 308.5-
308.9 C. H NMR (500 MHz, DMSO-d6): δ 12.73, 12.70 (s, 1H),
8.07, 8.03 (d, J=8.5 Hz, 2H), 7.71, 7.68 (d, J=7.5 Hz, 3H), 7.56
(dd, J=8.0, 6.5 Hz, 3H), 7.50 (dd, J=7.5, 7.0 Hz, 0.58H), 7.44 (dd,
J=4.5, 3.5 Hz, 0.34H), 7.39 (d, J=8.0 Hz, 1.74H), 7.22 (dd, J=6.5,
8.0 Hz, 0.89H), 7.15 (dd, J=7.5, 7.5 Hz, 0.20H), 7.11 (d, J= 8.0 Hz,
0.85H), 7.01 (dd, J= 7.0, 8.0 Hz, 0.87H), 6.97 (dd, J= 7.5, 7.5 Hz,
0.87H), 3.91 (s, 2.65H), 3.81 (s, 0.45H); 13C NMR (125 MHz,
DMSO-d6) δ 144.62, 137.13, 136.41, 135.04, 132.14, 131.86,
131.36, 130.11, 130.05, 129.67, 128.36, 127.56, 127.39, 126.48,
123.51, 122.26, 121.73, 121.66, 120.21, 120.09, 119.47, 119.27,
110.74, 104.65, 33.16. HRMS (APCI) for C24H18N3Br2 ([M+H]+):
calcd 505.9867, 507.9847, 509.9827, found 505.9923,
507.9959, 509.9891.
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Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (21542017), Liaoning Excellent
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