Ruthenium(II)-catalyzed facile synthesis of 3-(phenylamino)-1H-indole-2-carboxylates from anilines and diazo pyruvates promoted by FeCl3

Article abstract of DOI:10.1016/j.tet.2020.131399

An unprecedented synthetic route towards a variety of 3-anilino-1H-indoles is accomplished from diazo pyruvates and anilines via a domino ruthenium-catalyzed annulation and subsequent iron promoted fragmentation and rearrangement. The current strategy was amenable to deliver diversely substituted indole esters, which were subjected to in vitro anti-cancer activity assessment using CCK-8 assay. Compound 4i displayed the best inhibition activity with IC₅₀ value of 0.05 μM, triggering the initiation towards discovering promising lead compounds in the future.

Full text of DOI:10.1016/j.tet.2020.131399

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Ruthenium(II)-catalyzed facile synthesis of 3-(phenylamino)-1H-indole-2-carboxylates
from anilines and diazo pyruvates promoted by FeCl
3
Farrukh Sajjad, Alavala Gopi Krishna Reddy, Dong Xing, Suzhen Dong, Wenhao Hu
PII:
S0040-4020(20)30561-5
https://doi.org/10.1016/j.tet.2020.131399
TET 131399
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 June 2020
Revised Date: 8 July 2020
Accepted Date: 10 July 2020
Please cite this article as: Sajjad F, Reddy AGK, Xing D, Dong S, Hu W, Ruthenium(II)-catalyzed facile
synthesis of 3-(phenylamino)-1H-indole-2-carboxylates from anilines and diazo pyruvates promoted by
FeCl , Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131399.
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Ruthenium(II)-Catalyzed Facile Synthesis of
3-(Phenylamino)-1H-indole-2-carboxylates
from Anilines and Diazo Pyruvates
Promoted by FeCl3
Leave this area blank for abstract info.
Farrukh Sajjad,a Alavala Gopi Krishna Reddy,b Dong Xing,a Suzhen Dong,a and Wenhao Hua,b*
aShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of
Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Rd., Shanghai,
200062, China.
bSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.

1
Tetrahedron
journal homepage: www.elsevier.com
Ruthenium(II)-Catalyzed Facile Synthesis of 3-(Phenylamino)-1H-
indole-2-carboxylates from Anilines and Diazo Pyruvates Promoted by
FeCl3
Farrukh Sajjad,a Alavala Gopi Krishna Reddy,b Dong Xing,a Suzhen Dong,a and Wenhao Hua,b*
aShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China
Normal University, 3663 North Zhongshan Rd., Shanghai, 200062, China.
bSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An unprecedented synthetic route towards a variety of 3-anilino-1H-indoles is accomplished
from diazo pyruvates and anilines via a domino ruthenium-catalyzed annulation and subsequent
iron promoted fragmentation and rearrangement. The current strategy was amenable to deliver
diversely substituted indole esters, which were subjected to in vitro anti-cancer activity
assessment using CCK-8 assay. Compound 4i displayed the best inhibition activity with IC50
value of 0.05 µM, triggering the initiation towards discovering promising lead compounds in the
future.
Available online
Keywords:
annulation
rearrangement
diazo pyruvates
indoles
2009 Elsevier Ltd. All rights reserved
.
anti-cancer activity
1. Introduction
Among the various serendipitous restructuring arrays, it was
found that the sensitivity of the substrate towards the employed
reaction conditions played a vital role. A few of such notable
examples include the formation of (E)-allylamines from aryl-N-
tosylazetidines through ring-opening and reorganization
mechanism by Cu(OTf)2 as Lewis acid (Scheme 1a) [3a], while
the treatment of diversely substituted tetrahydrofurans under mild
acidic conditions led to corresponding cyclopentenone analogs
(Scheme 1b) [3b]. In yet another example, trimethylsilyl bromide
Development of novel expedite routes, via multiple bonds
formation or reorganization, for the synthesis of molecular
frameworks of biological importance has been a long-standing
objective in organic chemistry. These routes prove their
efficiency in avoiding the isolation of intermediate products, thus
leading to time and cost-effectiveness [1]. Significance of such
protocols has been illustrated in unprecedented reaction patterns,
such as, molecular rearrangements/bond reorganizations [2].
facilitated
a
unique
skeletal
rearrangement
of
diketopyrrolopyrroles into isoindol-diones (Scheme 1c) [3c]. It is
notable that the reports highlight the role of Lewis acids in
contributing to rearrangements and heretofore transformations in
suitable precursors leading to various heterocycles.
Indole derivatives have attracted a considerable attention from
synthetic chemists over the decades for their existence as core-
part in molecules possessing anti-cancer, anti-hypertensive, anti-
histaminic,
anti-oxidant,
anti-HIV,
anti-diabetic,
photochemotherapeutic,
anti-depressant,
anti-convulsant,
tranquilizing, anti-inflammatory, anti-fungal, anti-microbial, anti-
viral and insecticidal properties [4]. For example, the indole-3-
acetic acid A possesses potent cytotoxic activity [5a], whereas,
the N-morpholine amide derivative of indole B showed excellent
inhibition property against all the tested tumor cell lines (GI50
11-17 M) [5b], melatonin C is used as medicine for sleep
improvement [5c], while the fused pyrimido[5,4-b]indole
tricyclic D was found to be anti-HIV in nature [5d] and the indole
imine E acted as analgesic & anti-inflammatory [5e] (Figure 1).
Scheme 1: Rearrangement of Compounds lead to form different class of
compounds.

2
Tetrahedron
Scheme 2: Our approaches towards polysubstituted pyrrolidines 3 and amino
indole esters 4.
accessible anilines and diazo pyruvates [16]. Inspired by this
unusual finding, we have explored the reaction under different
conditions to investigate the versatile reactivity, which
delightfully led us to unveil a hitherto unknown [Ru(p-
cymene)Cl2]2/FeCl3 promoted synthesis of indoles from easily
accessible starting materials (Scheme 2).
Figure 1: Representative examples of biologically active indoles.
2. Results and discussion
As a result, numerous approaches were established towards
the preparation of indole, such as Fisher indole synthesis [6],
transition metal-catalyzed C-H activation of anilines with alkyne
[7], C-H activation carbene insertion [8], C-H amination of vinyl
or aryl azides [9], annulations of suitable ortho- alkyne [10a-c] or
olefin substituted anilines [10d-g], coupling reactions [11], and
diazo carbene transformations [12] are some of the powerful
strategies for the efficient construction of indoles. However,
these protocols required prefunctionalized substrates, expensive
metal catalysts, harsh reaction conditions and stoichiometric
amounts of reagents. Despite the handful indole derivatives
explored for biological assays, the demand has been high for the
development of new indole derivatives, using catalytic amount of
reagents commencing from easily accessible synthons leading to
high atom economy, to be identified as potential lead candidates
for various targets.
With the requisite starting materials, aniline 1a and the diazo
pyruvate 2a, a thorough examination was explored under
different reaction conditions by employing various catalysts in
combination with additives. Interestingly, 5 mol% [Ru(p-
cymeneCl2)]2 catalyst and copper(II)triflate as additive in DCM
at room temperature yielded a poly-functionalized indole 4a,
albeit in poor yield, (Table 1, entry 1). Intrigued by the novel
product 4a formation, we performed the reaction by using
different additives such as Cu(OAc)2, DDQ, TBHP, Na2CO3,
Al2O3 and p-TSA, which resulted in trace amounts of the product
4a (Table 1, entries 2 to 9). Interestingly, FeCl3 additive
displayed better efficiency, thus provided the desired product 4a
in fair yield (Table 1, entry 10). The reaction outcome was
similar in other solvents such as THF and toluene with slightly
lower yields (Table 1, entries 11 & 12), while attempts with other
catalysts RuCl3.xH2O, Rh2(OAc)4 and Cu(OTf)2, performed
poorly and gave the desired product in less yields (Table 1,
entries 13‒15). Other efforts on condition optimizations,
including increasing the amount of 1a, extending the reaction
time, or increasing the temperature, gave no improvement on the
yield of the desired product. No desired product 4a was observed
in the absence of [Ru(p-cymeneCl2)]2, indicating the inevitable
role of ruthenium catalyst in the transformation (Table 1, entry
16).
Inspired by the diversity in multi-component reactions
(MCRs) over the recent decade [13], metal-carbene induced
trapping strategies were developed efficiently towards the
stereoselective synthesis of elegant molecular scaffolds [14,15].
In continuation of our research interests in the construction of
heterocycle moieties of biological interest, very recently we have
disclosed an unprecedented and efficient ruthenium-catalyzed
highly diastereoselective synthesis of fully substituted
pyrrolidines bearing four contiguous stereocenters from easily-
Table 1: Optimization of indole 4a formation from aniline 1a and ethyl diazo pyruvate 2a.a,b
Entry
Catalyst (5 mol%)
Solvent
Additive (equiv) Time (h) Yield of 4a (%)
1
2
3
[Ru(p-cymene)Cl2]2 DCM
[Ru(p-cymene)Cl2]2 DCM
[Ru(p-cymene)Cl2]2 DCM
Cu(OTf)2 (0.1)
Cu(OAc)2 (0.1)
DDQ (0.5)
1
8
1
--
--
15

3
4
[Ru(p-cymene)Cl2]2 DCM
[Ru(p-cymene)Cl2]2 DCM
[Ru(p-cymene)Cl2]2 DCM
[Ru(p-cymene)Cl2]2 DCM
[Ru(p-cymene)Cl2]2 DCM
[Ru(p-cymene)Cl2]2 DCM
[Ru(p-cymene)Cl2]2 DCM
[Ru(p-cymene)Cl2]2 THF
[Ru(p-cymene)Cl2]2 Toluene
TBHP (1.0)
Na2CO3 (0.5)
Na2CO3 (1.0)
Al2O3 (0.5)
p-TSA (0.5)
p-TSA (1.0)
FeCl3 (1.0)
FeCl3 (1.0)
FeCl3 (1.0)
FeCl3 (1.0)
FeCl3 (1.0)
FeCl3 (1.0)
FeCl3 (1.0)
15
15
15
15
15
15
1
< 5
--
5
6
--
7
--
8
--
9
--
10
11
12
13
14
15
16
29
27
25
18
12
< 5
--
1
1
RuCl3.xH2O
Rh2(OAc)4
Cu(OTf)2
--
DCM
DCM
DCM
DCM
1
1
1
1
aReaction Conditions: Unless noted down, all the optimizations were performed by using 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol, 1
equiv) and 5 mol% of catalyst in 2 mL of solvent at 20 oC. bIsolated yields of chromatographically pure product 4a.
Of all the trials, the reaction parameters of entry 10 of Table 1
turned out be the best to furnish the desired indole product 4a.
Therefore, various anilines 1 and diazo pyruvates 2 with diverse
substitutions were applied to the above sequence to evaluate the
substrate scope. A series of anilines bearing electron-donating
groups such as methyl, methoxy, phenyl, and thiomethyl
substituents, halogens such as chloro and bromo as substituents
were tolerated well regardless of their electronic features and
afforded corresponding indole products in fair to good yields
(Table 2, 4b-4l). An interesting pattern was noticed with the
meta-substituted anilines that resulted in regioselective products,
which might be accounted for the competitive reactivity of both
the ortho-carbons of aniline towards the annulation, a common
phenomenon encountered with meta-substituted
partners (Table 2, 4f‒4l). Weak activating groups like halo and
methyl groups were less selective, thus produced the desired
products with poor regioselective ratio, whereas, the strong
activating methoxy group resulted in single isomeric product.
Moreover, methyl, allyl and isopropyl diazo pyruvates were also
compatible to the current transformation (Table 2, 4j‒4l). ortho-
substituted anilines were not appropriate to afford the desired
product probably owing to steric crowding from the ortho-
substituent. Notably the amount of FeCl3 and the reaction time
varied with respect to the substrates highlighting the sensitivity
of protocol. In addition to spectroscopic analysis, the structure of
indole was confirmed by single-crystal X-ray diffraction report of
both 4a and 4l (Table 2).
Table 2: Substrate-scope of the reaction for the formation of indoles 4.a

4
Tetrahedron
aReaction conditions: Unless noted down, all the reactions were performed by using 0.3 mmol of 1a, 0.2 mmol of 2a, 5 mol% of [Ru(p-
o
cymene)Cl2]2 and FeCl3 (0.1‒2.0 equiv) in DCM (2 mL) at 20‒48 C for 0.8‒3 h. For detailed amount of FeCl3 being used for each
substrate, see the Supporting Information. Isolated yields were reported. Regioisomeric ratios (rr) were determined by 1H NMR of the
crude reaction mixture. b Reaction was performed at 48 oC.
In order to unlock the reaction pathway by determining the
reaction intermediate, the pyrrolidine 3a obtained from our
previous report [16] was treated with FeCl3. Delightfully, FeCl3
was able to transform pyrrolidine 3a to the desired indole
evidencing pyrrolidine as the key reaction intermediate. On the
other hand, after thorough assessment of different pyrrolidine
intermediates with FeCl3, we were able to isolate the enol of
methoxy system 5i, upon controlling the reaction time, which
illustrated possibility of reaction through the formation of enol
via the cleavage of pyrrolidine 3 [17]. It’s noteworthy that the
enol substrate is sensitive to the ruthenium catalyst being
employed [16] and hence no enol side product was observed in
this one-pot strategy (Scheme 3).
Scheme 3: Control experiments.
A plausible reaction pathway was proposed for the surprising
formation of indoles 4. We suppose that after the formation of
pyrrolidine 3a from aniline 1a and ethyl diazo pyruvate 2a under
ruthenium catalysis [16], the addition of FeCl3 leads to the
activation of tertiary amine of pyrrolidine 3a, triggering the

5
3. Conclusions
fragmentation leading to imine 6a and enol 5a [18].
On the other
hand, the possibility that 6a was directly formed from 1a and 2a
under [Ru]/[Fe] catalysis could not be ruled out under current
stage. The imine intermediate 6a might undergo an
intramolecular Friedel-Crafts annulation which was facilitated by
FeCl3, to give indanol 7a. Further dehydration of 7a would
deliver the desired indole product 4a.
In conclusion, we have developed a unique access to
substituted indoles via unprecedented Lewis acid-promoted
fragmentation and rearrangement processes from simple starting
materials. The transformation tolerates a variety of substrates and
yielded variedly substituted indoles. One of the indole 4i, has
demonstrated excellent anti-cancer potency. Further work is
under way to fully study the biological effect of these newly
synthesized indole molecules.
4. Experimental section:
4.1. General Information:
All the reactions were carried in a flame-dried or oven-dried flask
1
containing a magnetic stir. All H-NMR (400 MHz), and 13C-
NMR (101 MHz) spectra were recorded on
a Bruker
spectrometer in CDCl3 and DMSO-d6. Tetramethylsilane (TMS)
1
served as an internal standard (δ = 0) for H-NMR, CDCl3 (δ =
77.0) and DMSO (δ = 39.5) were used as internal standards for
13C-NMR respectively. Chemical shifts (δ) are reported in parts
per million (ppm) as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br s =
broad singlet). HRMS spectra were recorded on an Ion Spec FT-
ICR mass spectrometer in ESI mode. Dichloromethane (DCM)
was distilled over calcium hydride prior to use. Diazo pyruvates
were prepared based on the reported methods [19].
4.2. General procedure (GP-1) for the synthesis of Indoles (4):
To an oven dried 10 mL test tube containing a well stirred
mixture of [Ru(p-cymene)Cl2]2 (5 mol%), FeCl3 (0.1-2.0 equiv.),
aniline 1 (0.30 mmol) in 1.0 mL of dichlormethane at 20 to 48
oC, was added diazo compound 2 (0.20 mmol) in 1.0 mL of
dichloromethane over 15 minutes via syringe. The tube was
sealed with a rubber stopper and the mixture was allowed to stir
for 0.8-3 h, monitored the progress of the reaction by TLC until
complete consumption of starting materials. Filtered the reaction
mixture through celite and concentrated under reduced pressure
to obtain the crude residue. The crude mass was purified by flash
column chromatography on silica gel (eluent: petroleum ether/
EtOAc = 20:1 to 15:1) to give the pure product 4.
Scheme 4: Mechanism for the formation of indole ester 4a.
As indoles are well-documented to possess varied biological
properties, we headed to explore the new compounds for possible
anticancer activity. CCK-8 assay was used to validate the
cytotoxicity of these compounds in HCT116 cells. The results are
summarized in Table 3. Among all the screened derivatives, five
compounds showed good growth inhibitory activity when used at
30 µM. Three of these compounds were further measured for
their IC50 values of cytotoxic effects and provided values ranging
from 0.05 to 2.4 µM. Overall it was noticed that compound 4i
showed the most potent inhibitory effect with IC50 value of 0.05
µM (Table 3).
4.3. Cytotoxicity Data (CCK-8 Assay):
Cancer cell line HCT116 (colon cancer) were used in the study
was purchased from Cell bank of China Science Academy
(Shanghai, China), and cultured aseptically in 5% CO2 at 37
with the corresponding medium supplemented with 10% (V/V)
fetal bovine serum and 100 units per ML each of penicillin G and
streptomycin. In vitro cytotoxicity of the compounds was
evaluated by CCK-8 assay. HCT116 cells were respectively
seeded in 96-well plates at a concentration 3000-3500 cells/well
and incubated for 24 h before compound administration. Each
tested compound was dissolved in DMSO (30 mM) and diluted
in media. Then the compound was added to the cells at 30 ꢀM.
The control cells were treated with the vehicle DMSO. After 72 h
of incubation, the old medium was removed and 100 ꢀL new
medium containing 10 ꢀL CCK-8 solution (5 gL-1) was added to
each well, incubated for additional 4 h. Finally, the optical
density (OD) was measured at 450 nm and 620 nm (reference
wavelength) using a microplate reader (spectraMax M5/M5e,
Sunnyvale, CA, USA). IC50 value was determined by testing the
inhibitory effects of the compound with 10 gradient-dilution
concentrations with at least three replicates per concentration.
Table 3: Cytotoxicity Data of Indoles 4a‒4l.a
Entry
Compound
Inhibition (%)a
12.65
IC50(µM)
b
1
2
3
4
5
6
7
4a
4b
4c
4h
4i
-
95.24
-
27.99
-
86.68
-
97.07
0.05
0.7
2.4
4j
84.45
4k
88.24
aInhibition of HCT116 cell proliferation produced by the tested
compounds at 30 µM. bThe IC50 of compounds were not determined
since the inhibition rate at 10 µM was lower than 50%.

6
Tetrahedron
4.4. Characterization Data of Products:
This desired compound 4e (7.4 mg, 11% yield) as white solid
was obtained by following representative procedure using FeCl3
4.4.1. Ethyl 3-(phenylamino)-1H-indole-2-
carboxylate (4a):
(2 equiv), 4-bromoaniline 1e (0.30 mmol, 53.1 mg) and ethyl
o
1
diazopyruvate 2a (0.20 mmol, 28.2 mg) at 48 C. H NMR (400
MHz, DMSO-d6) δ 11.74 (s, 1H), 7.94 (s, 1H), 7.50 (s, 1H), 7.40
(s, 2H), 7.28 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 4.25
(q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, DMSO-d6) δ 166.00, 150.42, 139.29, 136.54, 133.21,
128.98, 128.80, 127.78, 123.94, 121.75, 120.29, 116.75, 114.23,
65.51, 19.28.
This desired compound 4a (12 mg, 29% yield) as white solid was
obtained by following representative procedure using FeCl3 (1.0
equiv), aniline 1a (0.3 mmol, 29.2 mg) and ethyl diazopyruvate
2a (0.2 mmol, 28.4 mg) at 20 oC. 1H NMR (400 MHz, CDCl3) δ
8.23 (s, 1H), 7.42 – 7.38 (m, 1H), 7.36 – 7.28 (m, 3H), 7.28 –
7.22 (m, 2H), 7.05 (d, J = 7.7 Hz, 2H), 7.00 – 6.92 (m, 2H), 4.40
(q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 162.43, 143.64, 135.87, 128.99, 126.29, 122.96,
121.13, 120.49, 119.05, 118.27, 113.01, 112.02, 60.55, 14.53.
HRMS: Calcd. for C17H16N2NaO2 [M+Na] =303.1109, found
303.1104.
HRMS: Calcd. for C17H15Br2N2O2 [M+H] = 436.9495, found
436.9462.
4.4.6. Ethyl 6-chloro-3-((3-chlorophenyl)amino)-
1H-indole-2-carboxylate (4f):
This desired compound 4f (13.8 mg, 26% yield) as white solid
was obtained by following representative procedure using FeCl3
(1.5 equiv), 3-chloroaniline 1f (0.3 mmol, 39 mg) and ethyl
4.4.2. Ethyl 5-methyl-3-(p-tolylamino)-1H-indole-2-
carboxylate (4b):
o
1
This desired compound 4b (12.5 mg, 27% yield) as white solid
was obtained by following representative procedure using FeCl3
(0.2 equiv), 4-toluidine 1b (0.30 mmol, 32 mg) and ethyl
diazopyruvate 2a (0.2 mmol, 28.0 mg) at 20 C. H NMR (400
MHz, CDCl3) δ 8.32 (s, 1H), 7.35 (s, 1H), 7.32 (d, J = 8.7 Hz,
1H), 7.25 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.98 (br
s, 1H), 6.89 (dd, J = 20.3, 8.0 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H),
1.41 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 161.97,
144.76, 135.77, 134.79, 132.47, 130.06, 128.59, 123.49, 121.11,
120.54, 119.01, 117.68, 115.92, 114.23, 111.86, 60.90, 14.50.
HRMS: Calcd. for C17H13N2O2Cl2 [M‒H] =347.0354, found
347.0356.
o
1
diazopyruvate 2a (0.20 mmol, 27.9 mg) at 20 C. H NMR (400
MHz, DMSO-d6) δ 11.02 (s, 1H), 7.33 (s, 1H), 7.14 (d, J = 8.4
Hz, 1H), 6.93 (dd, J = 8.5, 1.4 Hz, 1H), 6.89 (s, 1H), 6.81 (d, J =
8.2 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H),
2.12 (s, 3H), 2.05 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H).13C NMR (101
MHz, DMSO-d6) δ 161.28, 145.72, 138.33, 136.26, 135.41,
129.20, 125.77, 121.48, 119.07, 118.43, 116.14, 115.61, 112.40,
112.02, 108.99, 59.96, 15.10, 14.54, 14.21.
4.4.7. Ethyl 4-chloro-3-((3-chlorophenyl)amino)-
HRMS: Calcd. for C19H21N2O2 [M+H] =309.1603, found
309.1613.
1H-indole-2-carboxylate (4f′):
This desired compound 4f′ (14.7 mg, 28% yield) as white solid
was obtained by following representative procedure using FeCl3
(1.5 equiv), 3-chloroaniline 1f (0.3 mmol, 39 mg) and ethyl
diazopyruvate 2a (0.2 mmol, 28.0 mg) at 20 C. H NMR (400
MHz, CDCl3) δ 8.76 (s, 1H), 7.35 – 7.20 (m, 2H), 7.10 – 7.06
(m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 6.68 (d, J = 7.9
Hz, 1H), 6.50 (s, 1H), 4.34 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 161.34, 148.36, 136.36,
134.61, 129.81, 127.41, 126.72, 125.17, 121.82, 121.12, 119.80,
119.23, 115.53, 113.91, 110.80, 61.23, 14.19.
4.4.3. Ethyl 5-methoxy-3-((4-
methoxyphenyl)amino)-1H-indole-2-carboxylate
(4c):
o
1
This desired compound 4c (16 mg, 31% yield) as yellow solid
was obtained by following representative procedure using FeCl3
(0.1 equiv), 4-methoxyaniline 1c (0.30 mmol, 38 mg) and ethyl
o
diazopyruvate 2a (0.20 mmol, 27.6 mg) at 20 C. 4c contains ca.
1
7% unidentified impurities. H NMR (400 MHz, DMSO-d6) δ
8.45 (s, 1H), 7.46 – 7.40 (m, 2H), 7.11 – 6.95 (m, 6H), 4.24 (q, J
= 7.1 Hz, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, DMSO-d6) δ 164.72, 160.28, 159.27,
158.79, 155.69, 141.86, 141.42, 124.18, 122.74, 115.11, 114.97,
61.75, 55.86, 14.34.
HRMS: Calcd. for C17H13N2O2Cl2 [M‒H] =347.0354, found
347.0356.
4.4.8. Ethyl 6-methyl-3-(m-tolylamino)-1H-indole-
2-carboxylate (4g):
HRMS: Calcd. for C19H21N2O4 [M+H] = 341.1501, found
341.1482.
The desired compound 4g (11.2 mg, 24% yield) as white solid
was obtained by following representative procedure using FeCl3
(1.0 equiv), 3-toluidine 1g (0.30 mmol, 33.4 mg) and ethyl
diazopyruvate 2a (0.20 mmol, 28.6 mg) at 20 C. 1H NMR (400
4.4.4. Ethyl 3-([1,1'-biphenyl]-4-ylamino)-5-
phenyl-1H-indole-2-carboxylate (4d):
o
MHz, CDCl3) δ 8.06 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.20 –
7.07 (m, 2H), 6.92 – 6.73 (m, 4H), 4.39 (q, J = 7.1 Hz, 2H), 2.45
(s, 3H), 2.29 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 162.51, 143.53, 138.87, 136.65, 136.46, 128.82,
122.70, 121.98, 121.14, 119.08, 118.38, 116.54, 115.40, 112.24,
111.61, 60.42, 21.98, 21.56, 14.60.
This desired compound 4d (13.4 mg, 21% yield) as yellow solid
was obtained by following representative procedure using FeCl3
(1.0 equiv), 4-aminobiphenyl 1d (0.30 mmol, 51.1 mg) and ethyl
o
1
diazopyruvate 2a (0.20 mmol, 28.1 mg) at 20 C. H NMR (400
MHz, CDCl3) δ 8.29 (s, 1H), 7.69 (s, 1H), 7.60 (t, J = 9.2 Hz,
3H), 7.52 (d, J = 6.8 Hz, 4H), 7.47 – 7.34 (m, 6H), 7.30 (t, J =
8.5 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 4.43 (q, J = 7.1 Hz, 2H),
1.44 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ
161.78, 145.68, 141.53, 140.69, 135.71, 132.04, 130.71, 129.37,
129.25, 127.47, 127.12, 126.63, 126.32, 126.16, 125.49, 122.79,
119.21, 117.63, 115.90, 113.93, 60.59, 14.67.
HRMS: Calcd. for C19H19N2O2 [M-H] =307.1447, found
307.1436.
4.4.9. thyl 4-methyl-3-(m-tolylamino)-1H-indole-2-
carboxylate (4g′):
HRMS: Calcd. for C29H24N2NaO2 [M+Na] =455.1735, found
455.1732.
The desired compound 4g′ (9.8 mg, 21% yield) as white solid
was obtained by following representative procedure using FeCl3
(1.0 equiv), 3-toluidine 1g (0.30 mmol, 33.4 mg) and ethyl
diazopyruvate 2a (0.20 mmol, 28.6 mg) at 20 oC. 4g′ contains ca.
4.4.5. Ethyl 5-bromo-3-((4-bromophenyl)amino)-
1H-indole-2-carboxylate (4e):

7
1
12% of major isomer 4g. H NMR (400 MHz, CDCl3) δ 8.46 (s,
This desired compound 4k (28.7 mg, 54% yield) as white solid
1H), 7.25 – 7.17 (m, 2H), 7.04 (t, J = 7.7 Hz, 1H), 6.84 (d, J =
6.5 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.62 (s, 1H), 6.56 (d, J =
8.0 Hz, 1H), 6.50 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H),
2.24 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 162.05, 148.02, 138.87, 135.80, 133.55, 128.89,
128.64, 126.33, 123.83, 121.78, 120.82, 117.62, 116.55, 112.83,
109.45, 60.73, 21.55, 18.88, 14.38.
was obtained by following representative procedure using FeCl3
(0.8 equiv), 3-methoxyaniline 1i (0.30 mmol, 37.4 mg) and allyl
o
1
diazopyruvate 2c (0.20 mmol, 30.2 mg) at 20 C. H NMR (400
MHz, DMSO-d6) δ 11.23 (s, 1H), 7.76 (s, 1H), 7.21 (d, J = 8.9
Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.85 (s, 1H), 6.65 (d, J = 8.9
Hz, 1H), 6.48 (d, J = 8.5 Hz, 2H), 6.36 (d, J = 8.8 Hz, 1H), 6.08 –
5.93 (m, 1H), 5.40 (d, J = 17.3 Hz, 1H), 5.24 (d, J = 10.5 Hz,
1H), 4.79 (d, J = 4.9 Hz, 2H), 3.79 (s, 3H), 3.65 (s, 3H). 13C
NMR (101 MHz, DMSO-d6) δ 160.95, 159.99, 158.47, 146.15,
137.17, 132.87, 129.49, 127.33, 122.34, 117.50, 115.28, 113.73,
110.50, 108.41, 104.55, 101.35, 93.98, 64.08, 55.08, 54.69.
HRMS: Calcd. for C20H21N2O4 [M+H] =353.1501, found
353.1482.
HRMS: Calcd. for C19H20N2O2Na [M+Na] =331.1422, found
331.1416.
4.4.10. Ethyl 6-(methylthio)-3-((3-
(methylthio)phenyl)amino)-1H-indole-2-carboxylate
(4h):
This desired compound 4h (19.8 mg, 35% yield) as light yellow
solid was obtained by following representative procedure using
FeCl3 (1.5 equiv), 3-(methylthio)aniline 1h (0.30 mmol, 42.6 mg)
4.4.14. Isopropyl 6-methoxy-3-((3-
methoxyphenyl)amino)-1H-indole-2-carboxylate
(4l):
o
1
and ethyl diazopyruvate 2a (0.20 mmol, 28.4 mg) at 20 C. H
NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.31 (d, J = 9.1 Hz,
2H), 7.19 – 7.13 (m, 2H), 6.94 – 6.88 (m, 2H), 6.86 – 6.84 (m,
1H), 6.82 (dd, J = 20.7, 7.9 Hz, 1H), 4.40 (q, J = 7.1, 2H), 2.53
(s, 3H), 2.41 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, DMSO-d6) δ 161.28, 145.71, 138.34, 136.26, 135.41,
129.19, 125.78, 121.46, 119.07, 118.43, 116.16, 115.61, 112.42,
112.03, 109.00, 59.96, 15.11, 14.55, 14.20.
This desired compound 4l (29.1 mg, 55% yield) as white solid
was obtained by following representative procedure using FeCl3
(0.8 equiv), 3-methoxyaniline 1i (0.30 mmol, 37 mg) and allyl
o
1
diazopyruvate 2c (0.20 mmol, 30.2 mg) at 20 C. H NMR (400
MHz, CDCl3) δ 8.12 (s, 1H), 7.41 (s, 1H), 7.35 (d, J = 9.0 Hz,
1H), 7.15 (t, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.65 (d, J = 8.8 Hz,
2H), 6.62 (s, 1H), 6.51 (d, J = 8.1 Hz, 1H), 5.25 (h, J = 6.4 Hz,
1H), 3.84 (s, 3H), 3.73 (s, 3H), 1.38 (d, J = 6.2 Hz, 7H). 13C
NMR (101 MHz, CDCl3) δ 161.94, 160.46, 159.45, 144.95,
137.08, 129.75, 123.93, 114.83, 110.81, 110.47, 106.83, 103.67,
93.62, 67.94, 55.45, 55.18, 22.26.
HRMS: Calcd. for C19H21N2O2S2 [M+H] = 373.1044, found
373.1056.
4.4.11. Ethyl 6-methoxy-3-((3-
methoxyphenyl)amino)-1H-indole-2-carboxylate
(4i):
HRMS: Calcd. for C20H23N2O4 [M+H] =355.1658, found
355.1649.
This desired compound 4i (29.9 mg, 58% yield) as white solid
was obtained by following representative procedure using FeCl3
(0.8 equiv), 3-methoxyaniline 1i (0.30 mmol, 37.6 mg) and ethyl
4.4.15. Ethyl (Z)-2-hydroxy-3-((3-
methoxyphenyl)amino)acrylate (5i):
o
1
diazopyruvate 2a (0.20 mmol, 27 mg) at 20 C. H NMR (400
MHz, CDCl3) δ 8.15 (s, 1H), 7.41 – 7.30 (m, 2H), 7.15 (t, J = 8.1
Hz, 1H), 6.72 (d, J = 2.2 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 6.64
(d, J = 2.1 Hz, 1H), 6.62 (t, J = 2.3 Hz, 1H), 6.52 (dd, J = 8.0, 2.2
Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 1.40
(t, J = 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 162.33,
160.47, 159.52, 144.87, 137.22, 129.76, 123.96, 114.78, 111.86,
110.93, 110.53, 106.93, 103.81, 93.62, 60.35, 55.45, 55.19,
14.61.
This desired compound 5i (5.4 mg, 16% yield) as Pale yellow
semi-solid was obtained by using pyrrolidine 3i (0.14 mmol, 83
mg) with FeCl3 (0.8 equiv) in dichloromethane at 25 oC. H
1
NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 7.07 (t, J = 8.0 Hz, 1H),
6.66 (s, 1H), 6.43 (d, J = 8.5 Hz, 1H), 6.30 (d, J = 8.2 Hz, 1H),
6.25 (s, 1H), 5.81 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H),
1.21 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.60,
160.27, 142.81, 132.33, 129.53, 114.15, 110.53, 107.00, 103.95,
62.01, 55.20, 14.08.
HRMS: Calcd. for C19H21N2O4 [M+H] = 341.1501, found
341.1482.
HRMS: Calcd. for C12H16NO4 [M+H] =238.1079, found
238.1074.
4.4.12. Methyl 6-methoxy-3-((3-
methoxyphenyl)amino)-1H-indole-2-carboxylate
(4j):
Declaration of competing interest
The authors have declared that they have no conflict of interest.
Acknowledgements:
This desired compound 4j (29.3 mg, 60% yield) as white solid
was obtained by following representative procedure using FeCl3
(0.8 equiv), 3-methoxyaniline 1i (0.30 mmol, 37.2 mg) and
methyl diazopyruvate 2b (0.20 mmol, 25 mg) at 20 oC. 1H NMR
(400 MHz, DMSO-d6) δ 11.22 (s, 1H), 7.74 (s, 1H), 7.17 (d, J =
8.9 Hz, 1H), 7.05 (t, J = 8.2 Hz, 1H), 6.81 (s, 1H), 6.63 (d, J =
8.9 Hz, 1H), 6.47 (d, J = 6.6 Hz, 2H), 6.36 (d, J = 8.9 Hz, 1H),
3.82 (s, 3H), 3.78 (s, 3H), 3.64 (s, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 161.80, 159.97, 158.39, 146.18, 137.10, 129.47,
126.98, 122.37, 115.23, 113.86, 110.43, 108.48, 104.56, 101.45,
93.96, 55.10, 54.70, 51.13.
We thank the National Natural Science Foundation of China
(21772043) and the Fundamental Research Funds for the Central
Universities for financial support. We also thank the financial
support from Guangdong Innovative and Entrepreneurial
Research Team Program (No. 2016ZT06Y337).
References and notes
1. (a) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195.
(b) Bruggink, A.; Schoevaart, R.; Kieboom, T. Org. Process Res. Dev.
2003, 7, 622. (c) Ulaczyk-Lesanko, A.; Hall, D. G. Curr. Opin. Chem.
Biol. 2005, 9, 266. (d) Domling, A. Chem. Rev. 2006, 106, 17. (e)
Touré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439.
HRMS: Calcd. for C18H19N2O4 [M+H] =327.1345, found
327.1349.
2. Tietze, L. F. Chem. Rev. 1996, 96, 115.
4.4.13. Allyl 6-methoxy-3-((3-
methoxyphenyl)amino)-1H-indole-2-carboxylate
(4k):

8
Tetrahedron
3. (a) Ghorai, M. K.; Kumar, A.; Das, K. Org. Lett. 2007, 9, 5441. (b)
Lu, B. Z.; Wei, H.-X.; Zhang, Y.; Zhao, W.; Dufour, M.; Li, G.; Farina,
Jung, M. E.; Yoo, D. J. Org. Chem. 2007, 72, 8565. (c) Vakuliuk, O.;
Ooi, S.; Deperasińska, I.; Staszewska-Krajewska, O.; Banasiewicz, M.;
Kozankiewicz, B.; Danylyukc, O.; Gryko, D. T. Chem. Commun. 2017,
53, 11877.
V.; Senanayake, C. H. J. Org. Chem. 2013, 78, 4558.
12. (a) Zhou, L.; Doyle, M. P. J. Org. Chem. 2009, 74, 9222. (b) Levesque,
P.; Forunier, P.-A. J. Org. Chem. 2010, 75, 7033. (c) Reddy, B. V. S.;
Reddy, M. R.; Rao, Y. G.; Yadav, J. S.; Srighar, B. Org. Lett. 2013, 15,
464.
4. (a) Akue-Gedu, R.; Debiton, E.; Ferandin, Y.; Meijer, L.; Prudhomme,
M.; Anizon, F.; Moreau, P. Bioorg. Med. Chem. 2009, 17, 4420. (b)
Sharma, V.; Kumar, P.; Pathak, D. J. Heterocyclic. Chem. 2010, 47,
491. (c) Nosovaa, E. V.; Lipunovaa, G. N.; Charushina, V. N.;
Chupakhina, O. N. J. Fluorine Chem. 2018, 212, 51.
13. (a) Guo, X.; Hu, W. Acc. Chem. Res. 2013, 46, 2427. (b) Xing, D.; Hu,
W. Tetrahedron Lett. 2014, 55, 777; (c) Thumar, N. J.; Wei, Q.; Hu, W.
Adv. Organomet. Chem. 2016, 66, 33. (d) Zhang, D.; Hu, W. Chem.
Rec. 2017, 17, 739.
5. (a) Rossiter, S.; Folkes, L. K.; Wardman, P. Bioorg. Med. Chem. Lett.
2002, 12, 2523. (b) Zheng, M.; Zheng, M.; Ye, D.; Deng, Y.; Qiu, S.;
Luo, X.; Chen, K.; Liu, H.; Jiang, H. Bioorg. Med. Chem. Lett. 2007,
17, 2414. (c) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem.
2014, 57, 10257. (d) Merino, I.; Monge, A.; Font, M.; Irujo, J. J. M.;
Alberdi, E.; Santiago, E.; Prieto, I.; Lasarte, J. J.; Sarobe, P. ; Borrás, F.;
Il Farmaco 1999, 54, 255. (e) Abele, E.; Abele, R.; Dzenitis, O.;
Lukevics, E. Chem. Heterocycl. Compd. 2003, 39, 3.
14. (a) Zhou, C.-Y.; Wang, J.-C.; Wei, J.; Xu, Z.-J.; Guo, Z.; Low, K.-H.;
Che, C.-M. Angew. Chem. Int. Ed. 2012, 51, 11376. (b) Jing, C.-C.;
Xing, D.; Qian, Y.; Shi, T.-D.; Zhao, Y.; Hu, W. Angew. Chem. Int. Ed.
2013, 52, 9289. (c) Liu, K.; Zhu, C.; Min, J.; Peng, S.; Xu, G.; Sun, J.
Angew. Chem. Int. Ed. 2015, 54, 12962. (d) Yang, J.; Ke, C.; Zhang, D.;
Liu, X.; Feng, X. Org. Lett. 2018, 20, 4536.
15. (a) Reddy, A. G. K.; Sajjad, F.; Shi, T.; Kang, Z.; Ma, M.; Xing, D.; Hu,
W. Chem. Commun. 2018, 54, 12650. (b) Xiao, G.; Ma, C.; Xing, D.;
Hu, W. Org. Lett. 2016, 18, 6086. (c) Zhang, M.; Tang, W. Org. Lett.
2012, 14, 3756; (d) Reddy, A. G. K.; Niharika, P.; Zhou, S.; Jia, S.-K.;
Shi, T.; Xu, X.; Qian, Y.; Hu, W. Org. Lett. 2020, 22, 2925.
6. (a) Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241. (b)
Fischer, E.; Hess, O. Ber. Dtsch. Chem. Ges. 1884, 17, 559. (c) Reddy
A. G. K.; Satyanarayana, G. Synthesis 2015, 47, 1269.
7. Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew
Chem. Int. Ed. 2009, 48, 4572.
16. Sajjad, F.; Reddy, A. G. K.; Che, J.; Hu, W.; Xing, D. Org. Lett. 2020,
22, 3094.
8. (a) Yang, Y.; Wang, X.; Li, Y.; Zhou, B. Angew. Chem. Int. Ed. 2015,
54, 15400. (b) Li,Y.; Qi, Z.; Wang, H.; Yang, X.; Li, X.; Angew. Chem.
Int. Ed. 2016, 55, 11877. (c) Yu, K.; Liang, Y.; Li, B.; Wang, B. Adv.
Synth. Catal. 2016, 358, 661.
17. As 3a was proposed as the key intermediate, a one-pot sequence in
which [Ru] was added to allow the complete formation of 3a, followed
by the addition of FeCl3 has been conducted, but no further
improvement on the yield of 4a was observed.
9. (a) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G.
J. Am. Chem. Soc. 2007, 129, 7500. (b) Liu, Y.; Wei, J.; Che, C. M.
Chem. Commun. 2010, 46, 6926. (c) Lu, B.; Luo, Y.; Liu, L.; Ye, L.;
Wang, Y.; Zhang, L. Angew. Chem. Int. Ed. 2011, 50, 8358.
18. Lee, J. M.; Bae, D. Y.; Park, J. Y.; Jo, H. Y.; Lee, E.; Rhee, Y. H.; Park,
J. Org. Lett. 2020, 22, 4608.
19. Muller, P.; Chappellet, S. Helv. Chim. Acta 2005, 88, 1010.
10. (a) Zhao, F.; Zhang, D.; Nian, Y.; Zhang, L.; Yang, W.; Liu, H. Org.
Lett. 2014, 16, 5124. (b) Mizukami, A.; Ise, Y.; Kimachi, T.; Inamoto,
K. Org. Lett. 2016, 18, 748. (c) Rode, N. D.; Abdalghani, I.; Arcadi,
A.; Aschi, M.; Chiarini, M.; Marinelli, F. J. Org. Chem. 2018, 83, 6354.
(d) Kondo, T.; Okada, T.; Mitsudo, T.-A. J. Am. Chem. Soc. 2002, 124,
186. (e) Coleman, C. M.; O'Shea, D. F. J. Am. Chem. Soc. 2003, 125,
4054. (f) Ni, J.; Jiang, Y.; An, Z.; Yan, R. Org. Lett. 2018, 20, 1534. (g)
Xia, H.-D.; Zhang, Y.-D.; Wang, Y.-H.; Zhang, C. Org. Lett. 2018, 20,
4052.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
11. (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 6621. (b) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem.
Int. Ed. 2005, 44, 403. (c) Newman, S. G.; Lautens, M. J. Am. Chem.
Soc. 2010, 132, 11416. (d) Selander, N.; Worrell, B. T.; Chuprakov, S.;
Velaparthi, S.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134, 14670. (e)
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Highlights
ꢀ Domino [Ru]-catalyzed annulation followed by iron promoted fragmentation
ꢀ One-pot synthesis of indole esters
ꢀ Usage of easily accessible starting materials
ꢀ Application to anti-cancer activity