Rose bengal as photocatalyst: Visible light-mediated Friedel-Crafts alkylation of indoles with nitroalkenes in water

Article abstract of DOI:10.1039/c9ra09227g

A novel and facile visible-light-mediated alkylation of indoles and nitroalkenes has been developed. In this protocol, rose bengal acts as a photosensitizer, and environmentally benign water was used as the green and efficient reaction medium. Indoles rea

Full text of DOI:10.1039/c9ra09227g

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Rose bengal as photocatalyst: visible light-
mediated Friedel–Crafts alkylation of indoles with
nitroalkenes in water†
Cite this: RSC Adv., 2020, 10, 4825
Zong-Yi Yu,ab Jing-Nan Zhao,ab Fan Yang,ab Xiao-Fei Tang,ab Yu-Feng Wu,ab
ab
Cun-Fei Ma,ab Bo Song,ab Lei Yunab and Qing-Wei Meng
*
Received 7th November 2019
Accepted 21st January 2020
A novel and facile visible-light-mediated alkylation of indoles and nitroalkenes has been developed. In this
protocol, rose bengal acts as a photosensitizer, and environmentally benign water was used as the green
and efficient reaction medium. Indoles reacted smoothly with nitroalkenes under the irradiation of
visible-light and generated corresponding 3-(2-nitroalkyl)indoles in moderate to good yields (up to 87%).
DOI: 10.1039/c9ra09227g
rsc.li/rsc-advances
time (24 h). Besides, although impressive works have been
accomplished in various Lewis acid catalytic systems in water,
such as InBr3, CeCl3 and Sc(OTf)3,8 little is still known in the
Introduction
Indole is a versatile building block that is widely used to
synthesize bioactive natural products and drugs. The addition
of indoles to electron-decient-olens, which can be considered
as a Friedel–Cras type alkylation, is a signicant reaction in
the formation of key C–C bonds.1
aqueous organic catalytic system.
In 2016, Jagdamba and coworkers developed an novel
visible-light mediated method on the synthesis of 3-substituted
indoles, employing green LED as light source in ethanol. The
reaction has mild conditions and good to excellent yields, but
only eight substrates were expanded.9 Wu and co-workers
further investigated into the direct alkylation of unfunctional-
ized C–H bonds via photoredox induced radical cation depro-
tonation.9 Organic photoredox catalyst eosin-Y and 9-mesityl-
10-methylacridinium ion (Mes–Acr+) have been employed in
C–H bond activation for electron-decient olens. Compared
with metal-containing photocatalyst, organic dyes such as eosin
Y, rose bengal and uorescein10 are mild in reaction conditions
and easier to modify. In recent years, numerous works were
reported using organic dyes11 as photoredox catalysts under
visible light irradiation from low power source.
According to R. Lambert's research12 in 1997, which reported
the triplet state rose bengal's reduction potential was 1.77 eV.
That is, the reduction quenching will be thermodynamically
favorable for indoles with relatively lower reduction potentials.13
To the best of our knowledge, rose bengal involved, visible light-
mediated Friedel–Cras alkylation of indoles with nitroalkenes
in water has not been reported yet. In this process, the reaction
was performed under a more gentle conditions in totally green
solvent, combining the advantage of the high efficiency of
photoinduced electron transfer (PET) process (Scheme 1).14
Many useful methods for preparing 3-(2-nitroalkyl)indoles
have been reported by predecessors. For the past few years,
several groups have been devoted to realizing asymmetric
Friedel–Cras alkylation of indoles with nitroalkenes by
designing various kinds of new chiral catalysts, such as thio-
urea, azaindole, sulfonamide2 and organic metal complexes
catalysts.3,4 In spite of the efficiency and generality of these
reactions, it remains not enough for green and sustainable
chemistry because these methods still involve the use of organic
solvents, such as toluene and chloroform. Therefore, the
development of a facile, efficient, economic and eco-friendly
method to construct 3-(2-nitroalkyl)indoles is still highly
desirable. Taking into account the ecological and sustainable
point of view, water-soluble organic catalytic systems5 have
attracted continuously increasing attention for applications in
organic synthesis. Nevertheless, as a green alternative to organic
solvents, the catalysis of reaction in water is still a major chal-
lenge in synthetic chemistry.6 In 2008, water has previously
been found to drive the Michael reaction of indoles with
nitroalkenes without the assistance of any catalyst, as reported
7
´ ˆ
by Jerome and co-workers, but this method has the disadvan-
tages of high reaction temperature (90 ꢀC) and long reaction
Results and discussion
aState Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and
Technology, Dalian University of Technology, Dalian 116024, P. R. China
bDalian University of Technology, Dalian 116024, P. R. China. E-mail: mengqw@dlut.
edu.cn
Initially, the visible light mediated alkylation of indoles with
nitroalkenes was probed with N-methyl indole (1a) and (E)-2-
nitroethenylbenzene (2a) as model substrates. Various kinds of
photosensitizers were rstly investigated for the process. The
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra09227g
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effect, 3a was obtained in 31% yield. In spite of different kinds
of organic solvents were examined for this catalytic system, poor
yields were obtained (Table 1, entries 6–12). In contrast, reac-
tions in THF and diethyl ether which have lower solubility to the
system achieved relatively high yields (Table 1, entries 1, 9).
Therefore, it is reducing the solubility of reaction system that
may promote the reaction. To our delight, when water was used
as the solvent, 3a was obtained in 54% yield (Table 1, entry 13).
Control experiments were carried out in darkness or in the
absence rose bengal, the yield decreased dramatically, thus
verifying light and rose bengal are pivotal in the reaction (Table
1, entries 14–17).
To further optimize the reaction conditions, the effect of
reaction temperature was investigated. To our delight, when
reaction temperature raised from 20 ꢀC to 60 ꢀC, yield increased
from 54% to 61% (Table 2, entries 1–3). What's more, reaction
time reduced from 18 hours to 7 hours. On the contrary, when
the reaction temperature continued to rise, side reaction
increased, and the yield decreased to 53% (Table 2, entry 4).
Taking the effect of the catalyst loading into account, the
loading of catalyst was rstly reduced from 5 mol% to 0.5 mol%.
However, as the catalyst loading reduced, reaction yield
decreased from 61% to 52% (Table 2, entries 4–7), and the
reaction time increased from 7 h to 12 h. Increasing catalyst
loading to 10 mol%, yield of 3a raised to 64% (Table 2, entry 8).
However, yield of 3a did not increase obviously when the cata-
lyst loading raised to 20 mol% (Table 2, entry 9). Therefore,
10 mol% of rose bengal was chosen as the best photosensitizer
loading. Subsequently, the molar ratio of substrates was
Scheme 1 Comparative approaches for direct synthesis of 3-(2-
nitroalkyl)indoles between the reported and this work.
reaction was carried out in tetrahydrofuran under the irradia-
tion of 21 W white LED light (Table 1, entries 1–5). Among the
photosensitizers tested, rose bengal showed the best catalytic
Table
ethenylbenzene (2a)a
1
Alkylation of N-methyl indole (1a)a and (E)-2-nitro-
Table 2 Optimization of reaction conditionsa
Entry
Catalyst
Solvent
Yieldb (%)
1
Eosin Y
THF
26
2
3
4
Eosin B
THF
THF
THF
21
Trace
31
Mes–Acr+ (ClO4
Rose bengal
)
ꢁ
Entry
1a : 2a
Cat (%)
Temp (ꢀC)
Time (h)
Yieldb (%)
5
6
7
8
Methylene blue
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
None
THF
Trace
Trace
21
Trace
35
20
24
Trace
54
61
Toluene
Paraxylene
Cyclohexane
Diethyl ether
Ethyl acetate
Acetone
Methanol
Water
Water
Water
Water
Water
1
2
3
4
5
6
7
8
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
5
5
5
5
3
20
40
60
80
60
60
60
60
60
60
60
60
60
60
18
10
7
2
9
10
12
5
5
5
54
58
61
53
58
56
52
64
66
69
63
58
43
42
9
10
11
12
13
14c
15c,d
16c
17c,d
1
0.5
10
20
10
10
10
10
10
9
1 : 1
18
32
17
10
11
12
13
14
1 : 1.5
1 : 1.25
1 : 1
1.25 : 1
1.5 : 1
5
5
5
5
None
a
Unless otherwise specied, N-methyl indole 1a (39.4 mg, 0.3 mmol),
(E)-2-nitroethenylbenzene 2a (44.7 mg, 0.3 mmol), and catalyst
(0.015 mmol, 5 mol%), were added to a test tube equipped with
a stirring bar and dissolved in 3 mL solvent. The mixture was stirred
a
N-Methyl indole 1a (39.4 mg, 0.3 mmol), (E)-2-nitroethenylbenzene 2a
in air with exposure to 21 W white LED lamps at 20 ꢀC for 24 h. and catalyst were added to a test tube equipped with a stirring bar and
b
c
d
Isolated yields. Reaction was performed at 60 ꢀC for 6 h. Reaction dissolved in water (3 mL) under the exposure of 21 W white LED lamps.
b
was performed in darkness.
Isolated yields.
4826 | RSC Adv., 2020, 10, 4825–4831
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screened, when the ratio of N-methyl indole and (E)-2-nitro- substrates with substituents on the benzene ring of (E)-2-
ethenylbenzene was 1 : 1.5, 3a was generated in the highest nitroethenylbenzenes were performed under this protocol. To
yield of 69% (Table 2, entries 10–14).
our delight, (E)-2-nitroethenylbenzenes with electron with-
Under the optimum reaction conditions, indoles and (E)-2- drawing groups generated desired products (3p–3t) in 82–87%
nitroethenylbenzenes with different kinds of substituents were yields. What's more, 2-nitrovinylthiophene also reacted with 2-
investigated and the results were summarized in Table 3. (E)-2- methylindole smoothly, and the corresponding product (3o)
Nitroethenylbenzene with divers functional groups at para was obtained in 81% yield.
position can smoothly carry out the Friedel–Cras alkylation
The reaction was scaled up to gram scale. Under the opti-
reaction with N-methyl indoles and afforded the desired prod- mized reaction conditions, 2-methylindole 1i (1.318 g, 10 mmol)
ucts (3b–3d) in 75–81% yields, the para-uoro-substituted (E)-2- was treated with 4-uoro-b-(E)-2-nitroethenylbenzene 2e (2.51 g,
nitroethenylbenzene substrate is capable of achieving a yield of 15 mmol). Corresponding alkylated product 3i was obtained in
up to 82%. Substrates with different functional groups attached 82% yield (Scheme 2).
to the indole ring were further investigated. It was gratifying to
In order to expound the mechanism of the process, a series
nd that the substrates with both electron donating and elec- of control experiments were carried out (Scheme 3). A trace
tron withdrawing groups reacted smoothly and generated cor- amount of expected product 3a was observed in the presence of
responding products (3f–3n) in 57–81% yields. In order to 2 equiv. of radical scavenger (TEMPO). And the raw material 1a
further demonstrate the tolerance of functional group, several was nearly quantitatively recovered (Scheme 3a). To further
investigate whether oxygen is involved in this process, control
experiments under oxygen and nitrogen atmosphere were per-
formed (Scheme 3b). The results turned that oxygen is unnec-
essary in the reaction.
Table 3 Visible-light induced Friedel–Craft alkylation of indoles with
nitroalkenes in the presence of rose bengala
Cyclic voltammetry experiments were performed in a CH
Instruments Electrochemical Analyzer. From the result, E1/2ox
(4) ¼ ꢁ1.211 V vs. SCE (Fig. 1) is higher than E1/2red (1a) ¼
ꢁ1.977 V vs. SCE (Fig. 2) so the photoredox reaction between
rose bengal 4 and N-methyl indole (1a) could occur spontane-
ously. (Fig. S1 and S2†).
Based on the experiment results and relevant references,
plausible mechanism of this transformation was established.
Due to the high oxidizing power of excited state rose bengal,14,15
olens could be conveniently oxidized to radical cations by 4*.
We proposed that the radical cation I tends to deprotonate to
give the radical II.3 Addition of II to a Michael acceptor such as
(E)-2-nitroethenylbenzene 2a will give alkyl III. Electron-
Scheme 2 Gram scale Friedel–Crafts alkylation reaction.
a
Indole 1a–1m (1 equiv. 0.3 mmol), trans-b-nitrostyrenes 2a–2j (1.5
equiv. 0.45 mmol), water (3 mL) and 10 mol% of the rose bengal
b
under a 21 W white LED lamps at 60 ꢀC for 12 h. Isolated yield by
column chromatography.
Scheme 3 Control experiment.
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Conclusions
In summary, we have developed a visible-light-mediated alkyl-
ation of indoles with nitroalkenes employing rose bengal as the
photocatalyst. Various types of nitroalkylated indoles were ob-
tained in 45–87% yields. Compared with the previous methods,
this process is environmental friendly, using water as the
solvent without any bases and metals being involved. As
a result, the method is simple in operation, mild in condition
and high in atomic economy.
Experimental
General
Unless otherwise stated, all commercial reagents and solvents
were used without further additional purication. Purication
of reaction products was carried out with chromatography on
Fig. 1 Cyclic voltammetry experiment of 4.
1
silica gel 60 (200–400 meshꢀ). H NMR (400 MHz) or (500 MHz)
spectra was obtained at 25 C; 13C NMR (101 MHz) were recor-
ded on a Varian INOVA-400M and AVANCE II 400 spectrometer
at 25 ꢀC. Chemical shis are reported as d (ppm) values relative
to TMS as internal standard and coupling constants (J) in Hz.
HPLC analysis were performed on a waters liquid chromato-
graph equipped with a Yilite SinoChrom ODS-BP 5 mm column
(4.6 mm ꢂ 250 mm), using mixtures of methanol/H2O as
mobile phase, at 25 ꢀC. HRMS analysis were performed on LTQ
Orbitrap XL of Thermo Scientic. Cyclic voltammetry (CV)
experiments were performed on CHI600E of Chenhua.
General procedure for the catalytic Friedel–Cras reaction
In a dry vial bottle equipped with magnetic stirrer was added
rose bengal (33.9 mg, 0.03 mmol), N-methylindole (41.0 mg, 0.3
mmol) and nitroalkenes (69.2 mg, 0.45 mmol) under an air
atmosphere followed by the addition of water (3 mL). The
solution was stirred under the irradiation of 21 W white LED
lamps for 5 hours at 60 ꢀC. The resulting suspension was cooled
to room temperature. The aqueous layer was extracted with
ethyl acetate (5 ꢂ 3 mL). The combined organic layer was dried
over anhydrous Na2SO4 and ltered. The solvent was evaporated
under reduced pressure. The residue was puried through silica
gel column chromatography using hexane/ethyl acetate (5 : 1)
as the eluent to afford 1-methyl-3-(2-nitro-1-phenylethyl)-1H-
indole. There is about 5.0 cm distance between the lamps and
reactors. The light intensity of the reaction system is 50 000 lux.
Fig. 2 Cyclic voltammetry experiment of 1a.
concentrating group III was reduced by the rose bengal catalyst
4c, and deliver the alkylated product 3a aer protonation while
regenerating the photocatalyst 4 (Scheme 4).16
1-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole
(3a).
Compound 3a was puried through silica gel column chroma-
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
1
obtained as a yellow liquid, yield: 0.061 g, 71%; H NMR (500
MHz, CDCl3): d 7.44 (d, J ¼ 8.0 Hz, 1H), 7.37–7.17 (m, 7H), 7.07
(t, J ¼ 7.5 Hz, 1H), 6.85 (s, 1H), 5.17 (t, J ¼ 8.0 Hz, 1H), 5.04 (dd, J
¼ 12.5, 7.5 Hz, 1H), 4.92 (dd, J ¼ 12.6, 8.5 Hz, 1H), 3.73 (s, 3H).
1-Methyl-3-(2-nitro-1-(p-tolyl)ethyl)-1H-indole
(3b).
Compound 3b was puried through silica gel column chroma-
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
1
obtained as a yellow liquid, yield: 0.066 g, 75%; H NMR (500
Scheme 4 Plausible mechanism.
MHz, CDCl3): d 7.43 (d, J ¼ 8.0 Hz, 1H), 7.25 (d, J ¼ 8.2 Hz, 1H),
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7.20 (dd, J ¼ 7.6, 4.6 Hz, 3H), 7.09 (d, J ¼ 7.8 Hz, 2H), 7.04 (t, J ¼ 8.0 Hz, 1H), 4.99 (dd, J ¼ 12.4, 8.0 Hz, 1H), 4.88 (dd, J ¼ 12.4,
7.5 Hz, 1H), 6.80 (s, 1H), 5.11 (t, J ¼ 8.1 Hz, 1H), 4.98 (dd, J ¼ 7.9 Hz, 1H), 2.29 (s, 3H).
12.5, 7.5 Hz, 1H), 4.86 (dd, J ¼ 12.5, 8.6 Hz, 1H), 3.66 (s, 3H),
3-(1-(4-Fluorophenyl)-2-nitroethyl)-4-methyl-1H-indole (3j).
Compound 3j was puried through silica gel column chroma-
2.28 (s, 3H).
3-(1-(4-Methoxyphenyl)-2-nitroethyl)-1-methyl-1H-indole
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
1
(3c). Compound 3c was puried through silica gel column obtained as a yellow liquid, yield: 0.062 g, 70%; H NMR (500
chromatography using hexane/ethyl acetate (5 : 1) as the eluent MHz, CDCl3): 1H NMR (500 MHz, chloroform-d) d 8.15–7.95 (m,
and was obtained as a yellow liquid, yield: 0.071 g, 77%; 1H 1H), 7.32–7.27 (m, 2H), 7.26 (d, J ¼ 4.7 Hz, 1H), 7.09–6.81 (m,
NMR (500 MHz, CDCl3): d 7.43 (dd, J ¼ 8.2, 1.2 Hz, 1H), 7.36– 5H), 5.16 (t, J ¼ 8.0 Hz, 1H), 5.05 (dd, J ¼ 12.5, 7.4 Hz, 1H), 4.90
7.14 (m, 4H), 7.05 (ddd, J ¼ 8.0, 7.0, 1.1 Hz, 1H), 6.83 (d, J ¼ (dd, J ¼ 12.5, 8.6 Hz, 1H), 2.47 (s, 3H). 13C NMR (101 MHz,
8.6 Hz, 3H), 5.11 (t, J ¼ 8.0 Hz, 1H), 5.00 (dd, J ¼ 12.4, 7.4 Hz, CDCl3) d 163.29, 160.85, 136.13, 129.40, 129.32, 125.51, 123.34,
1H), 4.86 (dd, J ¼ 12.4, 8.6 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H).
121.15, 120.69, 120.30, 116.57, 115.91, 115.70, 114.77, 79.54,
3-(1-(4-Fluorophenyl)-2-nitroethyl)-1-methyl-1H-indole (3d). 40.99, 16.51. HRMS (m/z): (ESI) calcd for C17H15FN2O2 [M + H]+:
Compound 3d was puried through silica gel column chroma- 219.1190, found: 219.1196.
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
3-(1-(4-Fluorophenyl)-2-nitroethyl)-6-methyl-1H-indole (3k).
1
obtained as a yellow liquid, yield: 0.073 g, 81%; H NMR (500 Compound 3k was puried through silica gel column chroma-
MHz, CDCl3): d 7.39 (d, J ¼ 8.0 Hz, 1H), 7.28 (dt, J ¼ 8.9, 2.5 Hz, tography using hexane/ethyl acetate (5 : 1) as the eluent and was
1
3H), 7.21 (dd, J ¼ 9.5, 5.8 Hz, 1H), 7.06 (t, J ¼ 7.5 Hz, 1H), 6.98 (t, obtained as a yellow liquid, yield: 0.041 g, 45%; H NMR (500
J ¼ 8.5 Hz, 2H), 6.82 (s, 1H), 5.14 (t, J ¼ 8.0 Hz, 1H), 5.00 (dd, J ¼ MHz, CDCl3): d 7.98 (s, 1H), 7.35–7.21 (m, 3H), 7.15 (s, 1H),
12.5, 7.4 Hz, 1H), 4.86 (dd, J ¼ 12.6, 8.7 Hz, 1H), 3.71 (s, 3H).
7.06–6.96 (m, 2H), 6.96–6.83 (m, 2H), 5.14 (t, J ¼ 8.0 Hz, 1H),
3-(2-Nitro-1-phenylethyl)-1H-indole (3e). Compound 3e was 5.04 (dd, J ¼ 12.5, 7.4 Hz, 1H), 4.88 (dd, J ¼ 12.4, 8.6 Hz, 1H),
puried through silica gel column chromatography using 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3) d 163.31, 160.87,
hexane/ethyl acetate (5 : 1) as the eluent and was obtained as 137.03, 135.09, 132.80, 129.43, 123.83, 121.85, 120.83, 118.52,
a yellow liquid, yield: 0.045 g, 56%; 1H NMR (500 MHz, CDCl3): 115.92, 115.71, 114.13, 111.40, 79.60, 40.97, 21.66. HRMS (m/z):
d 8.02 (s, 1H), 7.42 (d, J ¼ 8.0 Hz, 1H), 7.29 (d, J ¼ 6.9 Hz, 5H), (ESI) calcd for C17H15FN2O2 [M + H]+: 219.1190, found:
7.25–7.20 (m, 1H), 7.17 (t, J ¼ 7.6 Hz, 1H), 7.05 (t, J ¼ 7.5 Hz, 1H), 219.1197.
6.93 (d, J ¼ 2.5 Hz, 1H), 5.15 (t, J ¼ 8.0 Hz, 1H), 5.01 (dd, J ¼ 12.5,
7.7 Hz, 1H), 4.90 (dd, J ¼ 12.6, 8.4 Hz, 1H).
3-(1-(4-Fluorophenyl)-2-nitroethyl)-5-methoxy-1H-indole (3l).
Compound 3l was puried through silica gel column chroma-
5-Fluoro-3-(2-nitro-1-phenylethyl)-1H-indole (3f). Compound tography using hexane/ethyl acetate (5 : 1) as the eluent and was
1
3f was puried through silica gel column chromatography using obtained as a yellow liquid, yield: 0.072 g, 76%; H NMR (500
hexane/ethyl acetate (5 : 1) as the eluent and was obtained as MHz, CDCl3): d 8.04 (s, 1H), 7.25 (dd, J ¼ 8.3, 5.3 Hz, 2H), 7.18
a yellow liquid, yield: 0.051 g, 57%; 1H NMR (500 MHz, CDCl3): (d, J ¼ 8.8 Hz, 1H), 6.96 (t, J ¼ 8.5 Hz, 2H), 6.93–6.89 (m, 1H),
d 8.11 (s, 1H), 7.33–7.16 (m, 6H), 7.05–7.00 (m, 2H), 6.90 (td, J ¼ 6.84 (dd, J ¼ 8.8, 2.3 Hz, 1H), 6.79 (d, J ¼ 2.5 Hz, 1H), 5.08 (t, J ¼
9.0, 2.5 Hz, 1H), 5.08 (t, J ¼ 7.9 Hz, 1H), 5.00 (dd, J ¼ 12.4, 8.0 Hz, 8.0 Hz, 1H), 4.98 (dd, J ¼ 12.4, 7.5 Hz, 1H), 4.84 (dd, J ¼ 12.5,
1H), 4.89 (dd, J ¼ 12.3, 7.9 Hz, 1H).
8.5 Hz, 1H), 3.75 (s, 3H).
5-Chloro-3-(2-nitro-1-phenylethyl)-1H-indole
(3g).
3-(1-(4-Fluorophenyl)-2-nitroethyl)-6-methoxy-1H-indole
Compound 3g was puried through silica gel column chroma- (3m). Compound 3m was puried through silica gel column
tography using hexane/ethyl acetate (5 : 1) as the eluent and was chromatography using hexane/ethyl acetate (5 : 1) as the eluent
1
obtained as a yellow liquid, yield: 0.067 g, 74%; H NMR (500 and was obtained as a yellow liquid, yield: 0.067 g, 71%; 1H
MHz, CDCl3): d 8.15 (s, 1H), 7.39–7.21 (m, 7H), 7.12 (dd, J ¼ 8.6, NMR (500 MHz, CDCl3): d 8.00 (s, 1H), 7.35–7.17 (m, 3H), 7.04–
2.0 Hz, 1H), 7.04 (dd, J ¼ 10.8, 2.5 Hz, 1H), 5.11 (t, J ¼ 8.0 Hz, 6.93 (m, 2H), 6.88 (dd, J ¼ 2.5, 0.9 Hz, 1H), 6.82 (d, J ¼ 2.2 Hz,
1H), 5.06–4.94 (m, 1H), 4.90 (dd, J ¼ 12.5, 7.9 Hz, 1H).
5-Bromo-3-(2-nitro-1-phenylethyl)-1H-indole
1H), 6.73 (dd, J ¼ 8.7, 2.3 Hz, 1H), 5.10 (t, J ¼ 7.9 Hz, 1H), 5.01
(3h). (dd, J ¼ 12.4, 7.4 Hz, 1H), 4.86 (dd, J ¼ 12.4, 8.5 Hz, 1H), 3.80 (s,
Compound 3h was puried through silica gel column chro- 3H). HRMS (m/z): (ESI) calcd for C17H15FN2O3 [M + H]+:
matography using hexane/ethyl acetate (5 : 1) as the eluent and 315.1140, found: 315.1140.
1
was obtained as a yellow liquid, yield: 0.076 g, 74%; H NMR
3-(1-(4-Fluorophenyl)-2-nitroethyl)-7-methyl-1H-indole (3n).
(500 MHz, CDCl3): d 8.14 (s, 1H), 7.54 (d, J ¼ 1.7 Hz, 1H), 7.32 (t, Compound 3n was puried through silica gel column chro-
J ¼ 1.3 Hz, 1H), 7.31–7.28 (m, 2H), 7.29–7.25 (m, 2H), 7.24 (d, J ¼ matography using hexane/ethyl acetate (5 : 1) as the eluent and
1
1.7 Hz, 1H), 7.18 (d, J ¼ 8.6 Hz, 1H), 7.03 (d, J ¼ 2.6 Hz, 1H), 5.11 was obtained as a yellow liquid, yield: 0.058 g, 65%; H NMR
(t, J ¼ 8.0 Hz, 1H), 5.03–4.97 (m, 1H), 4.90 (dd, J ¼ 12.6, 8.0 Hz, (500 MHz, CDCl3): d 8.15 (s, 1H), 7.28–7.14 (m, 3H), 7.14–7.04
1H).
(m, 2H), 7.03–6.94 (m, 2H), 6.81 (d, J ¼ 7.2 Hz, 1H), 5.52 (t, J ¼
3-(1-(4-Fluorophenyl)-2-nitroethyl)-2-methyl-1H-indole (3i). 8.1 Hz, 1H), 4.95 (dd, J ¼ 12.6, 8.3 Hz, 1H), 4.81 (dd, J ¼ 12.6,
Compound 3i was puried through silica gel column chroma- 7.9 Hz, 1H), 2.53 (s, 3H). HRMS (m/z): (ESI) calcd for
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
C
17H15FN2O2 [M + H]+: 219.1190, found: 219.1194.
1
obtained as a yellow liquid, yield: 0.105 g, 83%; H NMR (500
1-Methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-1H-indole
(3o).
MHz, CDCl3): d 8.09 (s, 1H), 7.45 (d, J ¼ 1.6 Hz, 1H), 7.27–7.21 Compound 3o was puried through silica gel column chroma-
(m, 1H), 7.20–7.07 (m, 5H), 6.98 (d, J ¼ 2.5 Hz, 1H), 5.08 (t, J ¼ tography using hexane/ethyl acetate (5 : 1) as the eluent and was
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1
obtained as a yellow liquid, yield: 0.070 g, 81%; H NMR (500 7.6, 7.1, 1.1 Hz, 1H), 5.20 (dd, J ¼ 11.1, 6.5 Hz, 1H), 5.17–5.12 (m,
MHz, CDCl3): d 7.49 (d, J ¼ 8.0 Hz, 1H), 7.28 (d, J ¼ 8.2 Hz, 1H), 1H), 5.08 (dd, J ¼ 11.1, 8.2 Hz, 1H), 2.37 (s, 3H), 2.29 (s, 3H).
7.22 (t, J ¼ 7.6 Hz, 1H), 7.16 (d, J ¼ 5.1 Hz, 1H), 7.08 (t, J ¼ 7.5 Hz,
3-(1-(4-Methoxyphenyl)-2-nitroethyl)-2-methyl-1H-indole
1H), 7.00–6.87 (m, 3H), 5.42 (t, J ¼ 7.9 Hz, 1H), 4.96 (qd, J ¼ 12.6, (3v). Compound 3v was puried through silica gel column
8.0 Hz, 2H), 3.69 (s, 3H).
chromatography using hexane/ethyl acetate (5 : 1) as the eluent
2-Methyl-3-(2-nitro-1-(3-nitrophenyl)ethyl)-1H-indole (3p). and was obtained as a yellow liquid, yield: 0.068 g, 73%; 1H
Compound 3p was puried through silica gel column chroma- NMR (500 MHz, CDCl3): d 7.84 (s, 1H), 7.35 (d, J ¼ 7.9 Hz, 1H),
tography using hexane/ethyl acetate (5 : 1) as the eluent and was 7.23–7.15 (m, 3H), 7.10–7.04 (m, 1H), 7.00 (ddd, J ¼ 8.2, 7.1,
1
obtained as a yellow liquid, yield: 0.079 g, 82%; H NMR (500 1.1 Hz, 1H), 6.82–6.76 (m, 2H), 5.18–5.07 (m, 2H), 5.03 (dd, J ¼
MHz, CDCl3): d 7.81 (s, 1H), 7.46 (d, J ¼ 7.8 Hz, 1H), 7.36 (td, J ¼ 10.6, 7.8 Hz, 1H), 3.71 (s, 3H), 2.28 (s, 3H).
7.8, 1.8 Hz, 1H), 7.21–7.13 (m, 2H), 7.11–6.95 (m, 4H), 5.38 (dd, J
¼ 9.3, 6.8 Hz, 1H), 5.18 (dd, J ¼ 12.7, 6.8 Hz, 1H), 5.11 (dd, J ¼
Conflicts of interest
12.7, 9.3 Hz, 1H), 2.32 (s, 3H).
3-(1-(2-Fluorophenyl)-2-nitroethyl)-2-methyl-1H-indole (3q). There are no conicts to declare.
Compound 3q was puried through silica gel column chroma-
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
obtained as a yellow liquid, yield: 0.077 g, 86%; H NMR (500
Acknowledgements
1
MHz, CDCl3): d 8.18 (t, J ¼ 2.0 Hz, 1H), 8.08 (ddd, J ¼ 8.2, 2.3, We would like to thank the National Natural Science Founda-
1.0 Hz, 1H), 8.01 (s, 1H), 7.69–7.61 (m, 1H), 7.46 (t, J ¼ 8.0 Hz, tion of China (No. 21476041, U1608224, 61633006) and the State
1H), 7.33–7.20 (m, 2H), 7.17–7.09 (m, 1H), 7.03 (td, J ¼ 7.5, 7.1, Key Laboratory of Fine Chemicals for their support.
1.0 Hz, 1H), 5.33–5.23 (m, 2H), 5.16–5.06 (m, 1H), 2.43 (s, 3H).
13C NMR (101 MHz, CDCl3) d 148.53, 141.88, 135.50, 133.49,
133.19, 129.84, 126.33, 122.29, 121.77, 120.16, 118.02, 111.03,
Notes and references
107.68, 77.90, 40.14, 29.73, 12.07. HRMS (m/z): (ESI) calcd for
C
3-(1-(3-Fluorophenyl)-2-nitroethyl)-2-methyl-1H-indole (3r).
Compound 3r was puried through silica gel column chroma-
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17H15FN2O2 [M + H]+: 219.1190, found: 219.1197.
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
1
obtained as a yellow liquid, yield: 0.078 g, 87%; H NMR (500
MHz, CDCl3): d 7.86 (s, 1H), 7.31 (d, J ¼ 7.9 Hz, 1H), 7.26–7.17
(m, 2H), 7.13–7.05 (m, 2H), 7.04–6.94 (m, 2H), 6.89 (td, J ¼ 8.4,
2.6 Hz, 1H), 5.20–5.11 (m, 2H), 5.09–4.99 (m, 1H), 2.31 (s, 3H).
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found: 219.1195.
3-(1-(2-Chlorophenyl)-2-nitroethyl)-2-methyl-1H-indole (3s).
Compound 3s was puried through silica gel column chroma-
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
1
obtained as a yellow liquid, yield: 0.079 g, 84%; H NMR (500
MHz, CDCl3): d 7.81 (s, 1H), 7.54–7.44 (m, 2H), 7.34 (dd, J ¼ 7.6,
1.8 Hz, 1H), 7.22–7.12 (m, 3H), 7.11–6.98 (m, 2H), 5.47 (dd, J ¼
8.8, 7.3 Hz, 1H), 5.16–5.06 (m, 2H), 2.31 (s, 3H).
3-(1-(3-Chlorophenyl)-2-nitroethyl)-2-methyl-1H-indole (3t).
Compound 3t was puried through silica gel column chroma-
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
1
obtained as a yellow liquid, yield: 0.079 g, 84%; H NMR (500
MHz, CDCl3): d 7.91 (s, 1H), 7.36–7.30 (m, 1H), 7.29–7.22 (m,
2H), 7.22–7.15 (m, 3H), 7.11 (ddd, J ¼ 8.0, 7.1, 1.1 Hz, 1H), 7.03
(td, J ¼ 7.5, 7.0, 1.1 Hz, 1H), 5.22–5.11 (m, 2H), 5.06 (dd, J ¼ 11.2,
7.7 Hz, 1H), 2.37 (s, 3H). HRMS (m/z): (ESI) calcd for
C
17H15ClN2O2 [M + H]+: 315.0895, found: 315.0881.
2-Methyl-3-(2-nitro-1-(p-tolyl)ethyl)-1H-indole
(3u).
Compound 3u was puried through silica gel column chroma-
tography using hexane/ethyl acetate (5 : 1) as the eluent and was
1
obtained as a yellow liquid, yield: 0.061 g, 69%; H NMR (500
MHz, CDCl3): d 7.83 (s, 1H), 7.36 (d, J ¼ 8.0 Hz, 1H), 7.27–7.22
(m, 1H), 7.19 (d, J ¼ 8.0 Hz, 2H), 7.13–7.06 (m, 3H), 7.02 (td, J ¼
4830 | RSC Adv., 2020, 10, 4825–4831
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