Additive-Free Copper(I)-Mediated Synthesis of 5- or 6-Brominated 2-Aryl-1 H-Indole-3-Carboxylates from α,α-Dibromo β-Iminoesters

Article abstract of DOI:10.1021/acs.joc.0c02497

Additive-free copper(I)-bromide-mediated radical cyclization reactions of α,α-dibromo β-iminoesters were investigated, enabling the synthesis of a series of 5- or 6-brominated 2-aryl-1H-indole-3-carboxylates in moderate to good yields. The mechanistic study showed that (i) the bromine atom originated from the substrates and (ii) the bromination might be related to a 3-bromo-3H indole intermediate via an electrophilic bromine atom transfer. Furthermore, the practicality of this method was demonstrated by gram-scale synthesis and the potential for product derivatization toward other valuable multisubstituted indoles.

Full text of DOI:10.1021/acs.joc.0c02497

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Additive-Free Copper(I)-Mediated Synthesis of 5- or 6‑Brominated
2‑Aryl‑1H‑Indole-3-Carboxylates from α,α-Dibromo β‑Iminoesters
Zhenfa Li,+ Lan Zhao,+ Liuyi Liang, Lixin Zhao, Fangyi Li,* Chunhua Wang,* and Zheng Li*
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ABSTRACT: Additive-free copper(I)-bromide-mediated radical cyclization reactions
of α,α-dibromo β-iminoesters were investigated, enabling the synthesis of a series of 5-
or 6-brominated 2-aryl-1H-indole-3-carboxylates in moderate to good yields. The
mechanistic study showed that (i) the bromine atom originated from the substrates and
(ii) the bromination might be related to a 3-bromo-3H indole intermediate via an
electrophilic bromine atom transfer. Furthermore, the practicality of this method was
demonstrated by gram-scale synthesis and the potential for product derivatization
toward other valuable multisubstituted indoles.
mines and their derivatives are versatile intermediates and
have been transformed to a variety of N-heterocycles with
by using a Ni (cod)2/DPEphos system in place of a palladium
N-heterocycle carbene (Scheme 1b).4b Exciting as these
achievements are, they are limited in that they all require
relatively expensive metal catalysts and additives. Thus, an
alternative method to the synthesis of indoles from imines
under a relatively simple reaction system would be desirable.
Recently, we reported an efficient method for the synthesis
of functionalized α,α-dihaloimines.5 During the course of our
research on the potential utility of these imines, we observed
that our dibromoimines could be transformed into an indole
skeleton by treatment of a stoichiometric amount of Cu(acac)2
in refluxing CH3CN.
I
significant biological activity.1 However, as synthetic precur-
sors for constructing an indole skeleton, they are rarely
reported, even though indoles are privileged motifs found
extensively in natural products, pharmaceuticals, and materi-
als.2 In 2012, Yoshikai et al. developed a palladium-catalyzed
aerobic oxidative cyclization of N-aryl imines derived from
common anilines and ketones to afford corresponding indoles
(Scheme 1a).3 This approach not only represents a break-
Scheme 1. Literature Report and Present Work
This interesting result spurred us to do further investigation
on the formation of the indole structure based on this biased
substrate by using copper metal. In the past few decades, it has
been extensively used as a promoter in cross-coupling reactions
of organic halides with diverse partners for the construction of
carbon−carbon and carbon−heteroatom bonds. Among them,
for the synthesis of complex halogenated cyclic systems,
copper-catalyzed/mediated halogen atom transfer radical
cyclization (ATRC) is regarded as a powerful strategy, wherein
activated mono-, di-, and trihalo derived compounds are
commonly used substrates and a Cu(I)−halogen derived
complex has proven to be more effective.6 To our knowledge,
this strategy for the synthesis of indole derivatives is rare, and
Steves et al. reported an elegant Cu(I)Cl-catalyzed chlorine
atom transfer radical cyclization of N-(indolylmethyl)-
trichloroacetamides to synthesize 3,3-spiro-3H-indoles.7 In-
Received: October 20, 2020
Published: January 4, 2021
through for indole synthesis from simple starting materials but
also opens a new reaction manifold for exploitation.
Subsequent to this work, Nolan et al. reported palladium N-
heterocycle carbene-catalyzed α-arylation of imines leading to
highly substituted indoles and azaindoles (Scheme 1b).4a Very
recently, Tian et al. developed the same elegant transformation
https://dx.doi.org/10.1021/acs.joc.0c02497
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 1964−1971
1964

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
spired by previous works, we envisioned that exposure of our
dibromoimines to the conditions in concert with known
ATRC reactions may provide a new access to brominated
indoles.
understanding of the reaction mechanism, some control
experiments were carried out (Scheme 2). In the radical
Scheme 2. Control Experiments
Herein, we report an additive-free copper(I)-mediated
cyclization of α,α-dibromo β-iminoesters for the synthesis of
multisubstituted bromoindoles. In particular, the C6−Br
indole scaffold is found in the core of Arbidol and several
drug candidates,8 while the direct synthetic methods to this
framework are rather limited.9 After extensive studies, our
dibromoimine substrates with an ester group, such as 1a, were
found to be particularly suitable for this process (Table 1).
a
Table 1. Selected Optimization Studies
b
entry
variation from standard conditions
none
w/o CuBr
CuBr·SMe2 instead of CuBr
CuCl instead of CuBr
CuI instead of CuBr
Cu2O instead of CuBr
CuCN instead of CuBr
CuBr (50%)
DMAP (1.0 equiv) was used
TMEDA (1.0 equiv) was used
2,2′-bipyridine (1.0 equiv) was used
1,10-phenanthroline (1.0 equiv) was used
1,4-dioxane instead of CH3CN
DCE instead of CH3CN
80 °C
2a (%) 3a (%)
1
2
3
4
5
6
7
8
78
<5
75
53
28
68
61
42
41
11
45
43
70
59
57
66
-
-
-
-
23
10
-
-
9
32
53
39
42
-
22
-
-
10
11
12
13
14
15
16
trapping experiments, the formation of either 2a or 3a was
completely suppressed when 2,2,6,6-tetramethylpiperidinooxy
(TEMPO) was added under the optimal conditions (Scheme
2, eq 1). The addition of 2,6-di-tert-butyl-4-methylphenol
(BHT) also inhibited the reaction, and meanwhile, an adduct
of the debromo-1a radical with BHT (4) was detected by
HRMS but was unable to be isolated. Compound 5 could be
separated from the reaction mixture, likely derived from the
decomposition of 4 (Scheme 2, eq 2). These results indicated
that this reaction may initiate via a radical intermediate
generated by clipping one of the C−Br bonds in the substrate.
Wondering about the role of each bromine atom in 1a,
compound 6, in which one of the bromine atoms was replaced
with amethyl group, was prepared and thus subjected to the
optimal conditions (Scheme 2, eq 3). This reaction afforded
3H-indole 7 exclusively, without any brominated products 8.
When using α-bromo-α-chloro β-iminoester 1a′ instead of 1a
(Scheme 2, eq 4), a small amount of 2a was still obtained
probably due to the fact that this reaction was initiated with
partial cleavage of the C−Cl bond in 1a′. These results
revealed that the formation of 2a was not via a classical ATRC
reaction and the second bromine atom in 1a is key to final
product 2a formation and efficiency. In addition, treatment of
3a with 1 equiv of CuBr2 could afford 2a with recovery of more
than half of the unreacted 3a (Scheme 2, eq 5), suggesting that
this reaction pathway may be involved but unlikely dominant.
Furthermore, when subjecting 1,3,5-trimethoxybenzene into
this reaction, the brominated products 9 and 3a were obtained
with equal yields (Scheme 2, eq 6), implying that the
bromination step of 2a may proceed via a electrophilic
bromine transfer. Recently, Yeung’s group developed a series
120 °C
a
Reaction conditions: run on a 0.3 mmol scale for 3 h in a 15 mL
b
sealed tube. Yield of isolated products. DMAP = 4-dimethylamino-
pyridine. TMEDA = N,N,N′,N′-tetramethylethylenediamine. DCE =
1,2-dichloroethane.
Careful optimization of the reaction conditions eventually
afforded C6−Br indole 2a10 exclusively in 78% yield using
CH3CN as the solvent in a sealed tube at 100 °C (entry 1).
Interestingly, in the absence of CuBr, a trace amount of 2a was
still observed along with some unidentified products (entry 2).
Variation of the Cu(I) salts led to a decreased yield (entries 3−
7). A smaller amount of CuBr gave a lower yield (entry 8). A
collection of amines were employed as potential ligands in view
of their demonstrated versatility in radical cyclization.
However, they also led to a decreased yield of 2a and
increased amount of undesired 3a, indicating that basicity of
the ligand plays a negative role in this reaction (entries 9−12).
A survey of the solvent effect revealed CH3CN to be optimal
(entries 13 and 14). Finally, variation of reaction temperatures
gave unsatisfied results, as a lower temperature led to lower
conversion, while a higher temperature caused more
decomposition of 1a (entries 15 and 16).
With the optimal conditions in hand, we realized that this
reaction may not have proceeded via atom transfer radical
cyclization as we initially anticipated, with one bromine atom
present in the final product 2a. In order to gain a better
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Note
a b
,
of indole-catalyzed bromination reactions in lipophilic solvent,
in which the unstable methyl 3-bromo-3H-indole-3-carboxylate
is believed to be the key intermediate, providing a highly active
electrophilic bromine atom.11
Table 2. Substrate Scope
Based on the above experimental results and Yeung’s works,
a plausible mechanism involving intermediate A is proposed as
shown in Scheme 3. Homolytic cleavage of one of the C−Br
Scheme 3. Plausible Mechanism
bonds in 1a by CuBr form the alkyl radical A and CuBr2,
followed by intramolecular addition to the N-aryl ring in the
intermediate A affording the aryl radical intermediate B, which
sequentially undergoes single-electron oxidation by CuBr2.
Finally, deprotonation of the intermediate C offers unstable
intermediate D. There are two potential ways for intermediate
D to form C6−Br indole 2a: (i) directly delivering 2a by
intramolecular electrophilic bromine transfer to the electroni-
cally favored site and (ii) being decomposed into indole 3a
with the aid of Cu(I)Br, along with its oxidization to
Cu(II)Br2, which subsequently reacts with 3a, yielding 2a in
the end.
a
Reaction conditions: run on a 0.3 mmol scale for 3 h in a 15 mL
b
c
d
Following the optimal conditions, we next examined the
scope of this process (Table 2). First, the substituents (R1) on
the N-aryl group were varied to evaluate the effect on the
reaction efficiency. Compared with the electron-withdrawing
group in para-position of the N-aryl group (2d), the electron-
donating group enhanced the reaction efficiency significantly
(2a−2c). These results could be attributed to the fact that
electron-donating groups increase the electron density on the
phenyl ring and thus facilitate intramolecular electrophilic
bromine transfer. In the absence of a para-substituent or the
substituents on the ortho- or meta-positions of an N-aryl group,
the reaction efficiency vanished, and no desired products were
obtained. Furthermore, steric hindrance on the N-aryl group
influenced the reaction efficiency. The ethyl substituent
proceeded smoothly under optimal conditions, affording 2e
in comparable yield; nevertheless, the more bulky groups such
as isopropyl and tert-butyl substituents produced decreased
yields (2f, 2g), even with higher reaction temperatures and
longer reaction times. It should be pointed out that, in the
cases of 2d, 2f, and 2g, a considerable amount of
corresponding nonbrominated indoles were generated, pre-
sumably due to the decomposition of the 3-bromo-3H-indole
intermediates. As expected, isopropyl (2h) and benzyl (2i)
groups in the ester moiety (R2) had no adverse effect on the
reaction efficiency. Further scope examination showed that
substituents on the aryl ring (R3 = Ar) with electron-donating
and electron-withdrawing groups all worked well; albeit, the
presence of MeO (2j) or Me (2k) brought about slightly
sealed tube. Yield of isolated products. 120 °C, 6 h. 5 h.
higher yields than those of F, Cl, and Br (2l−2o). For starting
material 1p (R3 = Me), because of its temperature-sensitive
nature, the desired C6−Br indole 2p was obtained in relatively
low yield. Additionally, aiming to substantially expand the
generality of this reaction, the substrate scope with respect to
disubstituents on the N-aryl ring was also investigated. To our
delight, all the tested substrates (1q−1t) were competent in
this transformation, giving the brominated indoles in good
yield. Surprisingly, a small amount of dibrominated indole 2S
was observed in the case of 1s, probably arising from the
further bromination of 2s by CuBr2 in the reaction mixture.12
The location of bromine substituent in 2q−2t was determined
by 1H−1H NOESY experiments. Some α,α-dichloro β-
iminoesters were also employed to investigate this reaction.
Contrary to expectation, the corresponding chlorinated indoles
were not observed in our experiments. Instead, nonchlorinated
indoles were obtained as major products accompanied by some
unidentified side-products. The unsuccessful cases may be
attributed to the lesser electrophilic property of chlorine than
that of bromine, and thus, the unstable 3-chloro-3H-indole
intermediate is prone to be decomposed into the correspond-
ing nonchlorinated indole in this process.13
To test the practicality of this method, a gram-scale reaction
was performed, and a similar yield of 2a was obtained (Scheme
4). Some representative transformations were employed to
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Note
Q-TOF mass spectrometer, Waters. Melting points were measured on
an MP90, Mettler Toledo.
Scheme 4. Multigram Synthesis and Further
Transformations
General Procedure for the Synthesis of Brominated
Indoles. To a 15 mL sealed tube was added 1 (0.30 mmol, 1.0
equiv), CuBr (0.30 mmol, 1.0 equiv), and dry CH3CN (3 mL, 0.1 M).
The resulting mixture was heated at 100 °C in an oil bath until the
complete consumption of starting material as monitored by TLC or
GC−MS analysis (During the reaction, the sealed tube was let to cool
down before the samples could be taken out for TLC or GC−MS
analysis.). After cooling, the reaction mixture was filtered through a
pad of Celite and washed with ethyl acetate. The filtrate was
concentrated in vacuo, and the obtained residue was purified by silica
gel column chromatography (ethyl acetate (EA)/hexane) to afford
the desired product. Structural assignments (2q−2s) were made with
1
additional information from H−1H NOESY experiments.
Ethyl 6-Bromo-5-methoxy-2-phenyl-1H-indole-3-carboxylate
(2a). 87 mg, 78% yield; white solid; Rf = 0.24 (EA/hexane = 1:5,
V:V); mp 212−214 °C; 1H NMR (500 MHz, DMSO-d6) δ 12.09 (s,
1H), 7.70−7.68 (m, 3H), 7.65 (s, 1H), 7.65 (s, 1H), 7.51−7.46 (m,
3H), 4.19 (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 164.3, 150.8, 145.1, 131.6,
130.7, 129.9, 129.0, 127.8, 127.7, 115.8, 106.8, 103.3, 102.8, 59.1,
56.1, 14.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C18H16BrNNaO3 396.0206, found 396.0205.
a
Reagents and conditions: (a) phenylboric acid, Pd(PPh3)4 (5 mol
%), K2CO3 (2.0 equiv), N2, toluene, 100 °C, 2 h; (b) phenylacetylene,
CuI (5 mol %), Pd(PPh3)2Cl2 (10 mol %), Et3N/THF, N2, 80 °C, 5
h; (c) BBr3 (1.3 equiv), DCM, 0 °C, 6 h; (d) 1N NaOH (4 equiv),
THF, 90 °C, 20 h.
Ethyl 6-Bromo-5-(methylthio)-2-phenyl-1H-indole-3-carboxylate
(2b). 85 mg, 73% yield; white solid; Rf = 0.33 (EA/hexane = 1:5,
V:V); mp 179−181 °C; 1H NMR (500 MHz, chloroform-d) δ 8.58 (s,
1H), 8.08 (s, 1H), 7.62 (brs, 2H), 7.58 (s, 1H), 7.43 (brs, 3H), 4.28
(q, J = 7.0 Hz, 2H), 2.56 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 165.1, 145.3, 133.8, 132.4, 131.6,
129.7, 129.6, 128.3, 128.1, 120.0, 117.6, 115.3, 104.3, 60.0, 17.1, 14.4;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H17BrNO2S
390.0158, found 390.0149.
Ethyl 6-Bromo-5-methyl-2-phenyl-1H-indole-3-carboxylate (2c).
86 mg, 80% yield; white solid; Rf = 0.42 (EA/hexane = 1:5, V:V); mp
187−189 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.00
(s, 1H), 7.68 (brs, 2H), 7.63 (s, 1H), 7.49 (brs, 3H), 4.19 (q, J = 7.2
Hz, 2H), 2.46 (s, 3H), 1.21 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 164.1, 145.2, 134.9, 131.5, 129.9, 129.3, 129.0,
127.8, 127.1, 122.5, 118.1, 114.8, 102.5, 59.1, 23.0, 14.1; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C18H17BrNO2 358.0437, found
358.0431.
Ethyl 6-Bromo-5-fluoro-2-phenyl-1H-indole-3-carboxylate (2d).
42 mg, 39% yield; white solid; Rf = 0.38 (EA/hexane = 1:5, V:V); mp
163−165 °C; 1H NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H), 7.86
(d, J = 10 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.69−7.67 (m, 2H),
7.52−7.48 (m, 3H), 4.20 (q, J = 7.0 Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.9, 154.0 (d, J = 233.9
Hz), 146.7, 132.6, 131.1, 129.9, 129.4, 127.9, 127.3 (d, J = 9.9 Hz),
115.8, 107.3 (d, J = 26 Hz), 103.3 (d, J = 4.4 Hz), 102.7 (d, J = 24.5
Hz), 59.4, 14.1; 19F NMR (376 MHz, DMSO-d6) δ −117.09; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C17H13BrFNNaO2 [M + Na]+
384.0006, found 384.0007.
Ethyl 6-Bromo-5-ethyl-2-phenyl-1H-indole-3-carboxylate (2e).
85 mg, 76% yield; white solid; Rf = 0.48 (EA/hexane = 1:5, V:V);
mp 148−150 °C; 1H NMR (400 MHz, chloroform-d) δ 8.56 (s, 1H),
8.09 (s, 1H), 7.59 (brs, 2H), 7.54 (s, 1H), 7.41 (brs, 3H), 4.27 (q, J =
7.2 Hz, 2H), 2.89 (q, J = 7.2 Hz, 2H), 1.30 (m, 6H); 13C{1H} NMR
(100 MHz, chloroform-d) δ 165.3, 145.1, 136.9, 134.5, 131.9, 129.7,
129.4, 128.3, 127.6, 122.1, 119.3, 114.9, 104.5, 59.9, 29.8, 15.1, 14.4;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19BrNO2 372.0594,
found 372.0590.
Ethyl 6-Bromo-5-isopropyl-2-phenyl-1H-indole-3-carboxylate
(2f). 73 mg, 63% yield; white solid; Rf = 0.57 (EA/hexane = 1:5,
V:V); mp 156−158 °C; 1H NMR (500 MHz, chloroform-d) δ 8.42 (s,
1H), 8.18 (s, 1H), 7.65−7.61 (m, 2H), 7.59 (s, 1H), 7.46−7.43 (m,
3H), 4.30 (q, J = 7.0 Hz, 2H), 3.50−3.45 (m, 1H), 1.34 (d, J = 6.5
Hz, 6H), 1.31 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126 MHz,
chloroform-d) δ 165.2, 145.2, 141.1, 134.3, 131.9, 129.7, 129.5, 128.3,
127.7, 119.6, 119.5, 114.9, 104.7, 59.9, 33.0, 23.6, 14.4; HRMS (ESI-
extend the utility of the product 2a. Palladium-catalyzed cross-
coupling reactions of 2a with phenylboronic acid and
phenylacetylene proceed smoothly to afford 10 and 11,
respectively. The methyl group in 2a could be easily removed
in the presence of BBr3/DCM to give 12. Hydrolysis of 2a in
refluxing a 1N NaOH solution delivered the decarboxylated 13
as the only product.
In conclusion, we have introduced a new synthetic route to
5- or 6-brominated 2-aryl-1H-indole-3-carboxylates from α,α-
dibromo β-iminoesters via copper(I)-mediated radical cycliza-
tion/electrophilic bromination cascade in one pot. The
protocol enables the facile synthesis of various C6−Br and
other brominated indoles from readily available starting
materials. Further derivatization of the product highlights the
utility of this method. Hopefully, our approach has augmented
the numerous methods that have been reported for the indole
synthesis.
EXPERIMENTAL SECTION
■
General Information. All the substrates and solvents for the
synthesis of compounds were purchased from a commercial source
and used as received without any further purification. All the α,α-
dibromo β-iminoesters were synthesized using earlier reported
methods.5b Thin layer chromatography was performed on plates
(GF254) supplied by Yantai Chemicals (China), and visualization was
accomplished using UV light, iodine stains, or potassium permanga-
nate solution. Silica gel (200−300 mesh) supplied by Tsingdao
Haiyang Chemicals (China) was used for column chromatography
1
purification with a hexane/ethyl acetate mixture as the eluent. H
NMR spectra were measured on a Bruker (400 or 500 MHz)
spectrometer. 13C NMR spectra were measured on a Bruker (100 or
126 MHz) spectrometer with complete proton decoupling. 19F NMR
spectra were measured on a Bruker (376 MHz) spectrometer.
Chemical shifts were reported in parts per million (ppm), and the
residual solvent peak was used as an internal reference: proton
(chloroform: δ 7.26, acetone: δ 2.05, dimethyl sulfoxide: δ 2.50),
carbon (chloroform δ 77.16, acetone: δ 206.26, 29.84, dimethyl
sulfoxide: δ 39.52), or tetramethylsilane (TMS δ 0.00) was used as a
reference. Multiplicity was indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of
doublet), bs (broad singlet). Coupling constants were reported in
Hertz (Hz). High-resolution mass spectra (HRMS) were recorded on
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Note
TOF) m/z: [M + Na]+ calcd for C20H20BrNNaO2 408.0570, found
408.0560.
7.46 (m, 2H), 4.28 (q, J = 7.0 Hz, 2H), 3.96 (s, 3H), 1.30 (t, J = 7.0
Hz, 3H); 13C{1H} NMR (126 MHz, chloroform-d) δ 165.2, 152.1,
143.6, 131.5, 131.2, 130.8, 130.4, 128.0, 123.9, 115.7, 108.8, 105.0,
104.0, 60.1, 56.7, 14.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H16Br2NO3 451.9491, found 451.9472.
Ethyl 6-Bromo-5-(tert-butyl)-2-phenyl-1H-indole-3-carboxylate
(2g). 36 mg, 30% yield; white solid; Rf = 0.42 (EA/hexane = 1:5,
V:V); mp 156−158 °C; 1H NMR (500 MHz, chloroform-d) δ 8.50 (s,
1H), 8.23 (d, J = 1.0 Hz, 1H), 7.68−7.66 (m, 2H), 7.49 (d, J = 1.5
Hz, 1H), 7.48−7.47 (m, 3H), 4.31 (q, J = 7.0 Hz, 2H), 1.42 (s, 9H),
1.31 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126 MHz, chloroform-d) δ
165.2, 147.2, 145.0, 132.3, 131.9, 129.8, 129.6, 128.7, 128.3, 124.0,
117.7, 106.0, 104.1, 59.9, 35.2, 31.9, 14.3; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C21H23BrNO2 400.0907, found 400.0908.
Isopropyl 6-Bromo-5-methoxy-2-phenyl-1H-indole-3-carboxy-
late (2h). 92 mg, 79% yield; white solid; Rf = 0.27 (EA/hexane =
Ethyl 6-Bromo-2-(2-bromophenyl)-5-methoxy-1H-indole-3-car-
boxylate (2o). 82 mg, 60% yield; white solid; Rf = 0.26 (EA/hexane
1
= 1:5, V:V); mp 183−186 °C; H NMR (500 MHz, acetone-d6) δ
11.04 (s, 1H), 7.83 (s, 1H), 7.74−7.72 (m, 2H), 7.55−7.52 (m, 1H),
7.51−7.47 (m, 1H), 7.44−7.40 (m, 1H), 4.11 (q, J = 7.0 Hz, 2H),
3.96 (s, 3H), 1.08 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126 MHz,
acetone-d6) δ 164.8, 152.5, 144.2, 135.3, 133.2, 132.8, 131.7, 131.4,
128.2, 127.9, 124.6, 116.9, 108.6, 106.7, 104.3, 59.8, 56.8, 14.3;
HRMS (ESI) m/z: [M + H]+ calcd for C18H16Br2NO3 451.9491,
found 451.9476.
1
1:5, V:V); mp 146−148 °C; H NMR (500 MHz, chloroform-d) δ
8.47 (s, 1H), 7.79 (s, 1H), 7.62−7.60 (m, 2H), 7.56 (s, 1H), 7.44−
7.42 (m, 3H), 5.20−5.14 (m, 1H), 3.97 (s, 3H), 1.25 (d, J = 6.0 Hz,
6H); 13C{1H} NMR (126 MHz, chloroform-d) δ 164.8, 151.9, 145.0,
132.1, 130.4, 129.7, 129.4, 128.2, 128.2, 115.5, 108.4, 105.1, 104.1,
67.3, 56.7, 22.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C19H18BrNNaO3 4100362, found 410.0358.
Ethyl 6-Bromo-5-methoxy-2-methyl-1H-indole-3-carboxylate
(2p). 37 mg, 40% yield; white solid; Rf = 0.16 (EA/hexane = 1:5,
V:V); mp 158−160 °C; 1H NMR (500 MHz, chloroform-d) δ 8.22 (s,
1H), 7.67 (s, 1H), 7.49 (s, 1H), 4.39 (q, J = 7.0 Hz, 2H), 3.95 (s,
3H), 2.71 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126
MHz, chloroform-d) δ 165.9, 151.7, 144.4, 129.6, 127.7, 115.0, 107.2,
104.9, 103.7, 59.7, 56.7, 14.7, 14.6; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C13H14BrNNaO3 334.0049, found 334.0044.
Ethyl 6-Bromo-5,7-dimethyl-2-phenyl-1H-indole-3-carboxylate
(2q). 87 mg, 78% yield; white solid; Rf = 0.48 (EA/hexane = 1:5,
V:V); mp 145−147 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.91 (s,
1H), 7.87 (s, 1H), 7.65−7.63 (m, 2H), 7.50−7.48 (m, 3H), 4.16 (q, J
= 7.0 Hz, 2H), 2.60 (s, 3H), 2.47 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 164.2, 145.4, 134.1, 131.7,
Benzyl 6-Bromo-5-methoxy-2-phenyl-1H-indole-3-carboxylate
(2i). 94 mg, 72% yield; white solid; Rf = 0.27 (EA/hexane = 1:5,
V:V); mp 168−171 °C; 1H NMR (500 MHz, chloroform-d) δ 8.46 (s,
1H), 7.69 (s, 1H), 7.59 (brs, 2H), 7.56 (s, 1H), 7.41 (brs, 3H), 7.31
(brs, 5H), 5.27 (s, 2H), 3.83 (s, 3H); 13C{1H} NMR (126 MHz,
chloroform-d) δ 164.9, 152.0, 145.4, 136.3, 131.8, 130.3, 129.7, 129.5,
128.6, 128.4, 128.4, 128.2, 128.1, 115.6, 108.4, 104.5, 104.1, 66.0,
56.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H19BrNO3
436.0543, found 436.0539.
Ethyl 6-Bromo-5-methoxy-2-(4-methoxyphenyl)-1H-indole-3-
carboxylate (2j). 91 mg, 75% yield; white solid; Rf = 0.22 (EA/
hexane = 1:5, V:V); mp 172−174 °C; 1H NMR (500 MHz,
chloroform-d) δ 8.54 (s, 1H), 7.73 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H),
7.51 (s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 4.28 (q, J = 7.0 Hz, 2H), 3.96
(s, 3H), 3.81 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126
MHz, chloroform-d) δ 165.5, 160.6, 151.8, 145.3, 131.0, 130.3, 128.2,
124.1, 115.5, 113.7, 108.0, 104.1, 104.0, 59.9, 56.7, 55.5, 14.4; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H18BrNO4 404.0492, found
404.0475.
130.3, 130.0, 128.9, 127.6, 126.1, 121.3, 121.2, 119.8, 103.1, 59.0,
24.3, 17.7, 14.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C19H19BrNO2 372.0594, found 372.0586.
Ethyl 5-Bromo-4,6-dimethoxy-2-phenyl-1H-indole-3-carboxylate
(2r). 92 mg, 76% yield; white solid; Rf = 0.46 (EA/hexane = 1:5, V:V);
mp 151−153 °C; 1H NMR (500 MHz, chloroform-d) δ 8.74 (s, 1H),
7.56−7.54 (m, 2H), 7.43−7.38 (m, 3H), 6.80 (s, 1H), 4.28 (q, J = 7.0
Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 166.0, 144.4, 142.7, 140.6, 131.6,
129.1, 128.7, 128.6, 126.6, 121.9, 108.4, 107.6, 106.6, 61.6, 60.9, 56.1,
14.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H18BrNNaO4
426.0311, found 426.0309.
Ethyl 5-Bromo-4,6-dimethyl-2-phenyl-1H-indole-3-carboxylate
(2s). 59 mg, 53% yield; white solid; Rf = 0.36 (EA/hexane = 1:5,
V:V); mp 147−149 °C; 1H NMR (500 MHz, chloroform-d) δ 8.40 (s,
1H), 7.51−7.49 (m, 2H), 7.41−7.38 (m, 3H), 7.07 (s, 1H), 4.23 (q, J
= 7.0 Hz, 2H), 2.71 (s, 3H), 2.50 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (126 MHz, chloroform-d) δ 167.3, 140.5, 134.5,
Ethyl 6-Bromo-5-methoxy-2-(p-tolyl)-1H-indole-3-carboxylate
(2k). 86 mg, 74% yield; white solid; Rf = 0.24 (EA/hexane = 1:5,
V:V); mp 170−172 °C; 1H NMR (400 MHz, chloroform-d) δ 8.60 (s,
1H), 7.73 (s, 1H), 7.49 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.16 (d, J =
8.0 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 2.35 (s, 3H), 1.29
(t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) δ 165.5,
151.8, 145.5, 139.5, 130.4, 129.4, 128.9, 128.8, 128.1, 115.6, 108.1,
104.2, 104.0, 59.9, 56.7, 21.5, 14.4; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C19H18BrNNaO3 410.0362, found 410.0355.
Ethyl 6-Bromo-2-(4-fluorophenyl)-5-methoxy-1H-indole-3-car-
boxylate (2l). 64 mg, 54% yield; white solid; Rf = 0.26 (EA/hexane
133.4, 132.0, 130.7, 129.0, 128.6, 125.2, 122.0, 110.2, 107.7, 61.0,
25.1, 21.2, 14.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C19H18BrNNaO2 394.0413, found 394.0416.
1
= 1:5, V:V); mp 161−163 °C; H NMR (500 MHz, DMSO-d6) δ
Ethyl 5,7-Dibromo-4,6-dimethyl-2-phenyl-1H-indole-3-carboxy-
late (2S). 26 mg, 19% yield; white solid; Rf = 0.26 (EA/hexane = 1:5,
V:V); mp 149−151 °C; 1H NMR (500 MHz, chloroform-d) δ 8.35 (s,
1H), 7.56−7.54 (m, 2H), 7.44−7.40 (m, 3H), 4.23 (q, J = 7.0 Hz,
2H), 2.65 (s, 3H), 2.43 (s, 3H), 1.17 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 167.1, 140.6, 134.1, 132.0, 129.1,
128.7, 128.6, 127.9, 127.9, 126.5, 119.4, 118.3, 108.6, 61.0, 20.1, 16.1,
14.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H17Br2NNaO2
471.9518, found 471.9514.
Ethyl 5-Bromo-6,7-dimethyl-2-phenyl-1H-indole-3-carboxylate
(2t). 83 mg, 75% yield; white solid; Rf = 0.52 (EA/hexane = 1:5,
V:V); mp 146−148 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.86 (s,
1H), 8.11 (s, 1H), 7.66−7.63 (m, 2H), 7.50−7.48 (m, 3H), 4.16 (q, J
= 7.0 Hz, 2H), 2.52 (s, 3H), 2.41 (s, 3H), 1.17 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 164.1, 145.6, 135.0, 131.6,
12.13 (s, 1H), 7.74−7.70 (m, 2H), 7.67 (s, 1H), 7.62 (s, 1H), 7.36−
7.32 (m, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.23 (t, J = 7.0
Hz, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 164.2, 161.5,
150.8, 144.1, 132.2 (d, J = 8.5 Hz), 130.6, 127.9 (d, J = 3.3 Hz),
127.5, 115.8, 114.8 (d, J = 21.6), 106.8, 103.2, 102.9, 59.1, 56.2, 14.0;
19F NMR (376 MHz, DMSO-d6) δ −112.29; HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C18H15BrFNNaO3 414.0112, found 414.0099.
Ethyl 6-Bromo-2-(4-chlorophenyl)-5-methoxy-1H-indole-3-car-
boxylate (2m). 82 mg, 67% yield; white solid; Rf = 0.52 (EA/hexane
= 1:5, V:V); mp 152−154 °C; 1H NMR (500 MHz, chloroform-d) δ
8.73 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.53−7.51 (m, 2H), 7.38−
7.35 (m, 2H), 4.27 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 1.30 (t, J = 7.0
Hz, 3H); 13C{1H} NMR (126 MHz, chloroform-d) δ 165.2, 152.1,
143.7, 135.6, 131.0, 130.4, 130.3, 128.5, 128.0, 115.6, 108.8, 105.0,
104.1, 60.1, 56.7, 14.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H16BrClNO3 407.9997, found 407.9978.
130.3, 128.9, 128.4, 127.6, 126.4, 121.6, 121.4, 118.5, 102.7, 59.0,
19.1, 14.7, 14.1; HRMS (ESI) m/z: [M + H]+ calcd for C19H19BrNO2
372.0594, found 372.0590.
Procedure for the Synthesis of 5. To a 15 mL sealed tube was
added 1a (137 mg, 0.30 mmol, 1.0 equiv), CuBr (43 mg, 0.30 mmol,
Ethyl 6-Bromo-2-(4-bromophenyl)-5-methoxy-1H-indole-3-car-
boxylate (2n). 90 mg, 66% yield; white solid; Rf = 0.41 (EA/hexane
= 1:5, V:V); mp 163−165 °C; 1H NMR (500 MHz, chloroform-d) δ
8.57 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.55−7.52 (m, 2H), 7.49−
1968
https://dx.doi.org/10.1021/acs.joc.0c02497
J. Org. Chem. 2021, 86, 1964−1971

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
1
1.0 equiv), BHT (132 mg, 0.6 mmol, 2.0 equiv), and dry CH3CN (3
mL, 0.1 M). The resulting mixture was heated at 100 °C in an oil bath
for 3 h. After cooling, the reaction mixture was filtered through a pad
of Celite and washed with ethyl acetate. The filtrate was concentrated
in vacuo, and the obtained residue was purified by silica gel column
chromatography (EA/hexane = 1:15) to afford compound 5.
238−240 °C; H NMR (500 MHz, chloroform-d) δ 8.75 (s, 1H),
7.81 (s, 1H), 7.62−7.60 (m, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.43−7.41
(m, 2H), 7.39 (brs, 3H), 7.34−7.31 (m, 1H), 7.23 (brs, 1H), 4.29 (q,
J = 7.0 Hz, 2H), 3.86 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H); 13C{1H} NMR
(126 MHz, chloroform-d) δ 165.7, 153.1, 145.0, 139.2, 132.2, 130.3,
129.9, 129.6, 129.2, 128.2, 128.1, 128.1, 128.0, 126.9, 113.1, 104.3,
103.2, 59.8, 56.0, 14.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C24H22NO3 372.1594, found 372.1592.
Ethyl 2-Bromo-2-(3,5-di-tert-butyl-4-hydroxybenzyl)-3-((4-
methoxyphenyl)amino)-3-phenylpro panoate (5). 47 mg, 31%
yield; yellow solid; Rf = 0.55 (EA/hexane = 1:5, V:V); mp 171−
Procedure for the Synthesis of 11. Compound 2a (373 mg, 1
mmol, 1.0 equiv), Pd(PPh3)Cl2 (21 mg, 0.05 mmol, 5 mol %), and
CuI (19 mg, 0.1 mmol, 10 mol %) were added into a 50 mL two-neck
round-bottom flask equipped with a reflux condenser, which was
evacuated and backfilled with N2 three times. Then, phenylacetylene
(153 mg, 1.5 mmol, 1.5 equiv), Et3N (5 mL, 0.2 M), and THF (5 mL,
0.2 M) were added, and the resulting mixture was stirred at 80 °C in
an oil bath for 5 h (monitored by TLC). After cooling, the reaction
mixture was filtered through a pad of Celite and washed with EA. The
filtrate was concentrated in vacuo, and the obtained residue was then
purified by silica gel column chromatography (EA/hexane = 1:25−
1:10) to afford 11.
1
173 °C; H NMR (500 MHz, chloroform-d) δ 7.30−7.28 (m, 2H),
7.22−7.20 (m, 3H), 6.75 (s, 2H), 6.63 (d, J = 9.0 Hz, 2H), 6.50 (d, J
= 9.0 Hz, 2H), 4.04 (q, J = 7.0 Hz, 2H), 3.63 (s, 3H), 3.18 (s, 2H),
1.14 (s, 18H), 1.10 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126 MHz,
chloroform-d) δ 185.9, 166.0, 158.9, 157.7, 146.7, 140.6, 132.5, 131.7,
129.9, 129.4, 128.9, 127.6, 113.3, 99.7, 66.5, 59.2, 55.4, 41.0, 34.8,
29.4, 14.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H42NO4
516.3108, found 516.3104.
Procedure for the Synthesis of 7. To a 15 mL sealed tube was
added 6 (117 mg, 0.30 mmol, 1.0 equiv), CuBr (43 mg, 0.30 mmol,
1.0 equiv), and dry CH3CN (3 mL, 0.1 M). The resulting mixture was
heated at 100 °C in an oil bath for 3 h. After cooling, the reaction
mixture was filtered through a pad of Celite and washed with ethyl
acetate. The filtrate was concentrated in vacuo, and the obtained
residue was purified by silica gel column chromatography (EA/hexane
= 1:10) to afford compound 7.
Ethyl 5-Methoxy-2-phenyl-6-(phenylethynyl)-1H-indole-3-car-
boxylate (11). 320 mg, 81% yield; yellow solid; Rf = 0.21 (EA/
hexane = 1:5, V:V); mp 173−175 °C; H NMR (500 MHz, DMSO-
1
d6) δ 12.16 (s, 1H), 7.70−7.69 (m, 2H), 7.64 (s, 1H), 7.56 (s, 1H),
7.55 (brs, 2H), 7.51−7.49 (m, 3H), 7.44−7.40 (m, 3H), 4.20 (q, J =
7.0 Hz, 2H), 3.91 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H); 13C{1H} NMR
(126 MHz, DMSO-d6) δ 164.3, 155.2, 146.1, 131.6, 131.2, 129.9,
129.1, 128.9, 128.7, 128.3, 127.8, 123.1, 116.2, 107.4, 103.1, 101.9,
92.0, 87.4, 59.8, 59.1, 55.7, 14.1; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C26H22NO3 396.1594, found 396.1597.
Procedure for the Synthesis of 12. To a solution of 2a (373
mg, 1 mmol, 1.0 equiv) in dry DCM (10 mL, 0.1 M) was added BBr3
(0.125 mL, 25.6 mg, 1.3 mmol, 1.3 equiv) at −20 °C, and the
resulting mixture was stirred at 0 °C. TLC indicated completion of
the reaction (6 h), and water was added to quench the reaction. The
organic layer was separated, and the aqueous layer was extracted with
DCM (10 mL × 3). The combined organic layer was washed with
brine, dried with Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography (EA/
hexane = 1:10) to afford compound 12.
Ethyl 6-Bromo-5-hydroxy-2-phenyl-1H-indole-3-carboxylate
(12). 263 mg, 73%; yellow solid; Rf = 0.41 (EA/hexane = 1:3,
V:V); mp 205−207 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s,
1H), 9.80 (s, 1H), 7.70 (s, 1H), 7.67−7.64 (m, 2H), 7.52 (s, 1H),
7.48−7.46 (m, 3H), 4.17 (q, J = 7.0 Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 164.3, 149.0, 145.2, 131.7,
Ethyl 5-Methoxy-3-methyl-2-phenyl-3H-indole-3-carboxylate
(7). 58 mg, 62% yield; yellow oil; Rf = 0.28 (EA/hexane = 1:10,
1
V:V); mp 148−150 °C; H NMR (400 MHz, CDCl3) δ 7.96−7.88
(m, 2H), 7.64−7.59 (m, 1H), 7.48−7.40 (m, 3 H), 6.98−6.90 (m,
2H), 4.19−4.10 (m, 1H), 4.03−3.94 (m, 1H), 3.84 (s, 3H), 1.70 (s,
3H), 0.99 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
176.1, 171.8, 158.9, 148.7, 143.6, 132.3, 130.7, 128.8, 128.1, 121.8,
114.2, 107.7, 62.3, 61.9, 55.9, 21.3, 13.9; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C19H20NO3 310.1438, found 310.1434.
Procedure for the Synthesis of 3a and 9 from 1a. To a 15 mL
sealed tube was added 1a (137 mg, 0.3 mmol, 1.0 equiv), CuBr (43
mg, 0.30 mmol, 1.0 equiv), 1,3,5-trimethoxybenzene (101 mg, 0.6
mmol, 2.0 equiv), and dry CH3CN (3 mL, 0.1 M). The resulting
mixture was heated at 100 °C in an oil bath for 3 h. After cooling, the
reaction mixture was filtered through a pad of Celite and washed with
ethyl acetate. The filtrate was concentrated in vacuo, and the obtained
residue was purified by silica gel column chromatography (EA/hexane
= 1:20−1:10) to afford 3a and 9 with equal yields.
Ethyl 5-Methoxy-2-phenyl-1H-indole-3-carboxylate (3a). 70 mg,
79% yield; white solid; Rf = 0.24 (EA/hexane = 1:5, V:V); mp 188−
190 °C; 1H NMR (500 MHz, chloroform-d) δ 9.06 (s, 1H), 7.74 (d, J
= 2.0 Hz, 1H), 7.58−7.56 (m, 2H), 7.36−7.33 (m, 3H), 7.18 (d, J = 9
Hz, 1H), 6.88 (dd, J = 2.5, 9.0 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 3.87
(s, 3H), 1.26 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126 MHz,
chloroform-d) δ 165.9, 155.7, 145.1, 132.2, 130.4, 129.6, 129.0, 128.6,
128.0, 113.3, 112.2, 104.1, 103.6, 59.7, 55.7, 14.3; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C18H17NNaO3 318.1101, found 318.1088.
2-Bromo-1,3,5-trimethoxybenzene (9). 59 mg, 79% yield; white
130.3, 129.8, 128.9, 127.9, 127.8, 115.2, 106.5, 106.1, 102.1, 59.0,
14.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H15BrNO3
360.0230, found 360.0226.
Procedure for the Synthesis of 13. To a solution of 2a (93 mg,
0.25 mmol, 1.0 equiv) in THF (5 mL, 0.05 M) was added 1N NaOH
(1 mL, 4.0 equiv), and the resulting mixture was stirred at 90 °C in an
oil bath for 20 h. After cooling, 1 N HCl was introduced into the
reaction mixture to adjust the pH value (2−3). The reaction mixture
was extracted with ethyl acetate (20 mL × 3), washed with saturated
brine, and dried over Na2SO4. Then, the solvent was evaporated
under reduced pressure, and the residue was purified by column
chromatography (EA/hexane = 1:10) to afford compound 13.
6-Bromo-5-methoxy-2-phenyl-1H-indole (13). 51 mg, 68% yield;
white solid; Rf = 0.53 (EA/hexane = 1:5, V:V); mp 160−162 °C; 1H
NMR (500 MHz, DMSO-d6) δ 11.49 (s, 1H), 7.82 (d, J = 7.5 Hz,
2H), 7.55 (s, 1H), 7.49−7.44 (m, 2H), 7.35−7.31 (m 1H), 7.19 (s,
1H), 6.85 (d, J = 1 Hz, 1H), 3.84 (s, 3H); 13C{1H} NMR (126 MHz,
DMSO-d6) δ 149.4, 138.9, 132.5, 131.9, 128.9, 128.6, 127.6, 125.0,
115.1, 105.9, 102.3, 98.7, 56.3; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C15H12BrNNaO 323.9994, found 323.9980.
1
solid; Rf = 0.55 (EA/hexane = 1:5, V:V); mp 98−100 °C; H NMR
(500 MHz, chloroform-d) δ 6.16 (s, 2H), 3.86 (s, 6H), 3.80 (s, 3H);
13C{1H} NMR (126 MHz, chloroform-d) δ 160.6, 157.6, 92.1, 91.7,
56.5, 55.6; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C9H11BrNaO3 268.9784, found 268.9783.
Procedure for the Synthesis of 10. Under N2 atmosphere, to a
solution of 2a (93 mg, 0.25 mmol, 1.0 equiv) and Pd(PPh3)4 (15 mg,
0.0125 mmol, 5 mol %) in dry toluene (5 mL, 0.05 M) was added
K2CO3 (70 mg, 0.5 mmol, 2 equiv) and PhB(OH)2 (61 mg, 0.5
mmol, 2 equiv). The vigorously stirred mixture was heated to 100 °C
in an oil bath for 2 h (monitored by TLC). After cooling, the mixture
was filtered through a pad of Celite, and the filter cake was washed
with EA. The organic mixture was concentrated in vacuo, and the
residue was purified by column chromatography (EA/hexane = 1:10)
to afford 10.
Ethyl 5-Methoxy-2,6-diphenyl-1H-indole-3-carboxylate (10). 81
mg, 87% yield; white solid; Rf = 0.24 (EA/hexane = 1:5, V:V); mp
1969
https://dx.doi.org/10.1021/acs.joc.0c02497
J. Org. Chem. 2021, 86, 1964−1971

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Notes
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02497.
■
The authors declare no competing financial interest.
sı
ACKNOWLEDGMENTS
■
This work is financially supported by the National S&T Major
Project of China (No. 2018ZX09201011) and the Science &
Technology Development Fund of Tianjin Education
Commission for Higher Education (2017KJ138).
NMR spectra of synthesized compounds (2a−2t, 3a, 5,
7, 9−13), 1H−1H NOESY experiments of 2q−2t, X-ray
crystallography data (2a) (PDF)
FAIR data, including the primary NMR FID files, for
compounds 2a−2o (ZIP)
FAIR data, including the primary NMR FID files, for
compounds 2q−2t, 3a, 5, 7, and 9−13 (ZIP)
FAIR data, including the primary NMR FID files, for
compounds 2q−2t (ZIP)
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Accession Codes
CCDC 2035288 contains the supplementary crystallographic
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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AUTHOR INFORMATION
Corresponding Authors
■
Fangyi Li − College of Pharmaceutical Engineering of
Traditional Chinese Medicine and State Key Laboratory of
Component-Based Chinese Medicine, Tianjin University of
Traditional Chinese Medicine, Tianjin 301617, P. R. China;
orcid.org/0000-0001-7820-9507; Email: lifangyi@
tjutcm.edu.cn
Chunhua Wang − College of Pharmaceutical Engineering of
Traditional Chinese Medicine and State Key Laboratory of
Component-Based Chinese Medicine, Tianjin University of
Traditional Chinese Medicine, Tianjin 301617, P. R. China;
Email: pharmwch@126.com
Zheng Li − College of Pharmaceutical Engineering of
Traditional Chinese Medicine and State Key Laboratory of
Component-Based Chinese Medicine, Tianjin University of
Traditional Chinese Medicine, Tianjin 301617, P. R. China;
Email: lizheng@tjutcm.edu.cn
Authors
Zhenfa Li − College of Pharmaceutical Engineering of
Traditional Chinese Medicine and State Key Laboratory of
Component-Based Chinese Medicine, Tianjin University of
Traditional Chinese Medicine, Tianjin 301617, P. R. China
Lan Zhao − College of Pharmaceutical Engineering of
Traditional Chinese Medicine and State Key Laboratory of
Component-Based Chinese Medicine, Tianjin University of
Traditional Chinese Medicine, Tianjin 301617, P. R. China;
orcid.org/0000-0003-0316-7001
Liuyi Liang − College of Pharmaceutical Engineering of
Traditional Chinese Medicine and State Key Laboratory of
Component-Based Chinese Medicine, Tianjin University of
Traditional Chinese Medicine, Tianjin 301617, P. R. China
Lixin Zhao − College of Pharmaceutical Engineering of
Traditional Chinese Medicine, Tianjin University of
Traditional Chinese Medicine, Tianjin 301617, P. R. China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02497
Author Contributions
+Zhenfa Li and Lan Zhao contributed equally to this work.
1970
https://dx.doi.org/10.1021/acs.joc.0c02497
J. Org. Chem. 2021, 86, 1964−1971

The Journal of Organic Chemistry
pubs.acs.org/joc
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https://dx.doi.org/10.1021/acs.joc.0c02497
J. Org. Chem. 2021, 86, 1964−1971