Oxidative Coupling of 3-Oxindoles with Indoles and Arenes

Article abstract of DOI:10.1002/cssc.201900438

A highly efficient method for the oxidative coupling of 2-substituted 3-oxindoles with aromatic compounds to form 2,2-disubstituted indolin-3-ones with broad scope is described. This work utilized oxygen as the terminal oxidant and a base-metal catalyst under mild conditions instead of toxic/precious-metal reagents and higher-molecular-weight oxidants. Quaternary structures were produced in modest-to-excellent yields (up to 96 %) without prefunctionalization.

Full text of DOI:10.1002/cssc.201900438

Accepted Article
Title: Oxidative Coupling of 3-Oxindoles with Indoles and Arenes
Authors: Houng Kang, Adriana Jemison, Erin Nigro, and Marisa C
Kozlowski
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To be cited as: ChemSusChem 10.1002/cssc.201900438
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10.1002/cssc.201900438
ChemSusChem
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Oxidative Coupling of 3-Oxindoles with Indoles and Arenes
Houng Kang, Adriana L. Jemison, Erin Nigro, and Marisa C. Kozlowski[a]
Abstract: A highly efficient method for the oxidative coupling of 2-
substituted-3-oxindoles with aromatic compounds to form 2,2-
disubstituted indolin-3-ones with broad scope is described. This work
utilizes oxygen as the terminal oxidant and a base metal catalyst
under mild conditions instead of toxic/precious metal reagents and
higher molecular weight oxidants. Quaternary structures are
produced in modest to excellent yields (up to 96%) without pre-
functionalization.
nucleophile (Scheme 1B).[5] While functional group compatibility
of this method is good, it requires an expensive palladium catalyst
and multiple equivalents of oxidant. A similar reaction was
reported by Zhou and coworkers using ruthenium for the oxidative
coupling of indoles where one molecule of indole is oxidized to
form the oxindole and a molecule of the indole acts as the
nucleophile to form the C-C bond (Scheme 1C).[6] A similar
mechanism has been employed to construct spirocycles via an
intramolecular cyclization of a substituted indole.[7]
Scheme 1. Reported Methods for the Formation of 2,2-Disubstituted 3-
Oxindoles by Oxidative Methods
Introduction
Quaternary structures featuring the 2,2-disubstituted indolin-3-
one moiety are common in nature, especially among the indole
alkaloid natural products.[1] Many efforts to synthesize these types
of molecular frameworks have relied upon rearrangements and
cyclization reactions that require designed substrates or strongly
acidic/basic conditions, limiting functional group compatibility.[2]
Recent advents in oxidative dearomatization[3] chemistry have
allowed a more convergent approach to synthesis of 2,2,-
disubstituted indolin-3-one scaffolds.
A. Baran et al. (2011)
H
OH
N
O
NaHCO3 (3 equiv)
CAN (2 equiv)
HN
CO2Me
N
H
N
H
CO2Me
B. Guchhait et al. (2016)
H
N
5 mol% PdCl2
TBHP (2.2 equiv)
MnO2 (2 equiv)
O
R2
R1
N
H
N
H
R1
N
H
R2
H
O
N
R2
N
C. Zhou et al. (2018)
O
OMe
R1
O
CO2Me
O
5 mol% RuCl3•3H2O
NaIO4 (1 equiv)
H
N
N
N
R1
O
N
H
N
N
R2
O
R1
N
OH
R2
OH
OH
O
OH
Cephalinone
O
Fluorocurine
(-)-Isatisine A
D. Reddy et al. (2018)
SiPh3
O
O
O
O
N
H
O
OH
HN
O
O
O
O
P
5 mol%
N
OH
H
N
N
H
N
O
O
OH
H
H
N
O
N
N
H
SiPh3
H
CO2Me
N
H
N
H
DDQ (1.1 equiv), o-xylene
Notoamide O
(+)-Austamide
Halichrome A
N
H
CO2Me
5 Å MS
1.5 equiv
Figure 1. Examples of 2,2-Disubstituted 3-Oxindole Natural Products.
An earlier report by Liu and Qin described similar reactivity with
TEMPO and silver nitrate to give 3,3’-biindolin-2-ones from the
homocoupling of unsubstituted indoles.[8] Indoles lacking
substitution at the 2-position have also been shown to form
trimers in good yield under oxidative conditions.[9] Notably, these
oxidation methods proceed well regardless of the electronic
character of the indole substrate. Recently, dearomative coupling
reactions have also been affected in an asymmetric manner
utilizing a chiral phosphoric acid catalyst and DDQ in an oxidative
aza-Friedel-Crafts alkylation of indoles with 3-oxindoles as the
nucleophile (Scheme 1D).[10]
In 2011, the Baran group reported the oxidative coupling of
oxindoles with indoles and pyrroles using an excess of CAN under
basic conditions (Scheme 1A).[4] However, this method was
limited to electron-poor coupling partners and yields with pyrrole
were also quite low. Another oxidative transformation was
reported by Guchhait and coworkers, utilizing the dearomatization
and oxidation of one indole partner to affect the coupling with the
[a]
Dr. H. Kang, A. L. Jemison, Dr. E Nigro, and Prof. M. C. Kozlowski
Department of Chemistry, Roy and Diana Vagelos Laboratories
University of Pennsylvania
Coupling strategies for indoles with other aromatic compounds
have also been reported (Scheme 2). Vincent and coworkers
described the coupling of a substituted indole with an electron rich
phenol, giving a benzofuroindoline scaffold.[11] The reported
method, while diastereoselective, has limited scope and
Philadelphia, Pennsylvania 19104, United States
E-mail: marisa@sas.upenn.edu
Supporting information for this article is given via a link at the end of
the document
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10.1002/cssc.201900438
ChemSusChem
FULL PAPER
moderate yields. Other 3-aryl indolines are readily accessible
through a variety of oxidation methods.[12]
byproducts formed. Thus, this catalyst was used to probe the
scope of coupling partners.
Scheme 2. Oxidative coupling of indole and phenol moieties
H
OH
N
10 mol % catalyst, 0.1 M,
O2, DCE, 50 ℃, 16 h
O
+
CO2Me
N
N
H
N
CO2Me
H
1:1 ratio
OMe
H
1
2
3
1)NIS (1.1 equiv)
2) 4-MeO phenol (2.5 equiv)
3) AgBF4 (2 equiv)
Co-salen-Cy
Cr-salan-Cy
Cu-salan-Ph
Co-salen-H Cr-salen-Cy
Cr-salen-H
Cr-salen-Ph
O
N
R
N
R
Cu-salen-Cy
Fe-salen-H
Fe-salen-Cy Fe-salan-Cy
Cu-salen-H
Cu-salen-Ph
Mn-salen-H
maximum yield, 55%
Mn-salan-Cy
Ru-salan-Cy
V-salen-H
Ru-salen-H
V-salan-Ph
Ru-salen-Cy
V-salan-Cy
Results and Discussion
Ru-salen-Ph Ru-salan-Ph V-salen-Cy
Recent work in our laboratory has shown that salen/salan
transition metal catalysts are effective in oxidative coupling
transformations using dioxygen as the terminal oxidant.[13]
Inspired by this and the literature cited above, we aimed to
develop a general and mild method for the oxidative coupling of
oxindoles with a broad range of aromatic molecules. A high-
throughput experimentation (HTE) screen utilizing twenty-four
unique catalysts spanning seven metals and five ligands was
performed to find candidates for the oxidative coupling of
oxindoles with indole substrates (Figure 2).
Figure 3. Catalyst Screening Results, Size of the Sphere Indicates Yield of 3
Relative to An Internal Standard (see Supporting Information for
Product/Internal Standard Ratios).
Using the best of the screening conditions, we were able to couple
the oxindole substrate with twelve electronically and sterically
diverse indoles in good to excellent yield. Notably, the screening
conditions could be used directly and the only modification
necessary was increased temperature to 80 °C for a longer
reaction period for those substrates that were less reactive
(Scheme 2). Indoles react selectively at the more nucleophilic 3-
position, unless this site is blocked, as with substrate 2j, which
reacts at the 2-position. The method tolerates both electron
withdrawing and donating groups for indole substrates, making it
more general than the current state of the art. Compatibility with
an array of functional groups, such as halogens, ethers, esters,
and nitriles, provides opportunity for later modification of the
resultant quaternary structures.
Ph
N
Ph
N
H
N
H
N
O
M
M
t-Bu
O
O
t-Bu
t-Bu
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
M = Co, Cr, Cu, Fe, Mn, Ru, C
M = Cr, Cu, Ru
M-salen-H
M-salen-Ph
Ph
Ph
N
H
N
H
N
O
N
O
M
M
t-Bu
O
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
M = Co, Cr, Cu, Fe, Ru, V
M = Cu, Ru, V
M-salen-Cy
M-salan-Ph
Scheme 3. Scope of the Coupling of 3-Oxindoles with Indoles
N
H
N
H
M
t-Bu
O
O
t-Bu
t-Bu
t-Bu
M = Cr, Fe, Mn, Ru, V
M-salan-Cy
Figure 2. Catalysts Screened for Activity in the Cross-Coupling of 3-Oxindoles
and Indoles.
Cobalt, copper, and vanadium catalysts gave the best results,
while chromium, iron, manganese, and ruthenium catalysts gave
more moderate yields. In general, the imine type salen ligands
outperformed the amine-type salan ligands though no strong
preference for any one ligand was observed (Figure 3). The
screen revealed Cu-salan-Ph (catalyst D, M = Cu) to be the most
efficient among the working catalysts for the test reaction as
judged by both amount of product formed and amount of
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10.1002/cssc.201900438
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H
N
OH
After exploring the efficacy in the oxidative coupling of oxindoles
with indoles, we turned our attention to other arene coupling
partners. Pyrroles, substituted furans, anilines, and trimethoxy
benzene were all shown to be competent coupling partners
across nine examples (Scheme 3). For these aromatic
compounds, the electron-withdrawing substituents have a much
more pronounced effect on reactivity and the yield is significantly
reduced as in the case of substrate 4b relative to 4a and 4c.
Modest to good yields are possible for electron-rich coupling
partners. No reaction or low yield is observed for less electron-
rich furans and dimethoxybenzene. This trend is further supported
by the low product yield with phenol 4f, which has a much higher
oxidation potential than the coupling partners shown in Figure 4.
O
10 mol % Cu-Salan-Ph
R
+
CO2Me
N
O2, DCE, 50 °C
N
H
R
H
N
H
CO2Me
1
2
3
Cl
F
N
H
N
N
H
H
2b
73%
2c
96%
2a
94% (96% at 1mmol scale)
CO2Me
N
N
N
H
H
I
N
MeO
H
H
N
H
Br
2d
80%
2e
95%
2f
94%
2g
84%
2h
77%a
Me
NC
Me
N
N
H
N
N
H
Me
Scheme 5. Scope of the Cross-Coupling of 3-Oxindoles with Simple Arenes
H
2i
88%
2j
62%
2k
88%
2l
77%
areaction at 80 ℃
OH
Several of the resulting molecules are known in the literature as
products of similar transformations. However, these reactions are
milder, give better yield, and allow access to more substrates than
previously reported methods. For example, Baran and coworkers
report a poor 17% yield for substrate 2g and modest yields of 48%
and 66% for substrates 2j and 2f, respectively. The method is
readily scalable and no decrease in yield was observed when
moving from 0.1 mmol to 1 mmol for 2a.
X
O
R
10 mol % Cu-Salan-Ph
R
CO2Me
O2, DCE, 50 °C
X
N
CO2Me
N
H
H
4
1
5
X = NH, NR, O
H
Me
H
H
N
O
N
N
N
Me
OMe
CN
Me
4a
4b
<19% (58% brsm)
4d
37%
4e
68%
4c
65%
49%
Scheme 4. Scope of 3-oxindoles with indole 2c.
Me
Me
OMe
OH
N
N
NC
t-Bu
t-Bu
N
F
MeO
OMe
H
N
4g
4h
4i
4j
4f
10%
60%a
52%a
66%a
62%a
OH
O
10 mol % Cu-Salan-Ph
R1
CO2R3
R1
+
F
CO2R3
N
R2
N
R2
areaction at 80 ℃
N
H
O2, DCE, 50 °C
1
2c
3
Pyrroles (4a-d, 4i) and 2-methoxy furan (4e) couple selectively at
the 2-position. Similarly, adducts arising from N,N-dialkyl anilines
(4g, 4h) undergo coupling at the less hindered para-position. The
majority of these structures have not been reported to date,
highlighting the broader scope of this method.
OH
OH
OH
MeO
CO2Me
CO2Me
CO2Me
N
N
N
H
H
1n
1m
85%
1
96%
25% (45%)a
OH
OH
OH
In order to shed light on the mechanism, cyclic voltammetry
measurements were undertaken for the 3-oxindole substrate (1)
as well as for 2-phenyl indole (2a) and N,N-dimethyl aniline (4g)
(Figure 4). Typically, the second coupling partner is more
oxidizable than or comparable to 1. Partners with higher oxidation
potentials, such as 4b and 4f give much lower yield indicating that
oxidation of this component is key. However, oxidation of the 3-
oxindole leads quickly to formation of homo-dimers. This species
is observed under the reaction conditions after only a few minutes.
Notably, this homo-dimer of 3-oxindole has a high oxidation
potential and may induce oxidation of the second coupling partner.
CO2Bn
CO2Ad
CO2Me
N
H
N
N
H
Cl
H
1p
90% (51%)b
1o
77%
1q
57% (22%)b
areaction at 80 ℃
brecovered after precipitation with hexanes from chloroform to remove grease from solvent
The scope of the 3-oxindole coupling partner was also explored
(Scheme 3). Substituents of both electron donating (1m) and
withdrawing (1o) character had only a moderate effect on yield.
N-Substitution had a much more dramatic effect, decreasing the
yield from 96% in the case of 3c, to 25%. The outcome was
somewhat improved by heating the reaction to 80 °C. The steric
bulk of the ester also significantly affects the outcome of the
reaction with the hindered adamantyl group giving only 57% yield,
relative to 98% for the methyl ester 1 and 90% for the benzyl ester
1p. Both of these observations might be attributed to less efficient
binding of the oxidized species to the active catalyst.
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10.1002/cssc.201900438
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Me
Me
OH
N
Experimental Section
CO2Me
N
H
N
H
Unless otherwise noted, all non-aqueous reactions were carried out under
an atmosphere of dry N2 in dried glassware. When necessary, solvents
and reagents were dried prior to use. THF was distilled from sodium
benzophenone ketyl. CH2Cl2, ClCH2CH2Cl, and toluene were distilled from
CaH2. High throughput experiments were performed at the Penn/Merck
High Throughput Experimentation Laboratory at the University of
Pennsylvania. The screens were analyzed by HPLC by addition of an
internal standard. Analytical thin layer chromatography (TLC) was
performed on EM Reagents 0.25 mm silica-gel 254-F plates. Visualization
was accomplished with UV light. Chromatography was performed using a
forced flow of the indicated solvent system on EM Reagents Silica Gel 60
(230-400 mesh). When necessary, the column was pre-washed with 1%
Et3N in the eluent system. Compounds chromatographed via autocolumn
were separated using pre-packed silica columns on a Biotage CombiFlash
system. 1H NMR spectra were recorded on a 500 MHz spectrometer.
Chemical shifts are reported in ppm from tetramethylsilane (0 ppm) or from
the solvent resonance (CDCl3 7.26 ppm, DMSO-d6 3.58 ppm, acetone-d6
2.05 ppm, DMF-d7 2.50 ppm, CD3CN 1.94 ppm, CD2Cl2 5.32 ppm). Data
are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, br = broad, m = multiplet), coupling constants, and
number of protons. Decoupled 13C NMR spectra were recorded at 125
MHz. IR spectra were taken on an FT-IR spectrometer. Accurate mass
measurement analyses were conducted via time-of-flight mass analyzer
GCMS with electron ionization (EI) or via time-of-flight mass analyzer
LCMS with electrospray ionization (ESI). The signals were measured
against an internal reference of perfluorotributylamine for EI-GCMS and
leucine enkephalin for ESI-LCMS. The instrument was calibrated, and
measurements were made using neutral atomic masses; the mass of the
electron removed or added to create the charged species is not taken into
account. Low resolution LCMS data were obtained by use of a UPLC
system with a SQD mass analyzer equipped with electrospray ionization.
Cyclic voltammograms were recorded using a CH Instruments CHI600E
Electrochemical Analyzer. Measurements were taken using 0.02 M
tetrabutylammonium hexafluorophosphate as electrolyte in distilled
acetonitrile. Substrate was dissolved at a concentration of approximately
1
2a
0.66 V
4g
0.64 V, 1.16 V
0.45 V
Figure 4. Measured Oxidation Potentials for Select Substrates.
A mechanism consistent with these observations is outlined in
Figure 5. Coordination of the hydroxyl group of substrate 1 with
the Cu(II) salen gives rise to enolate that 6 can undergo rapid,
reversible inner sphere oxidation and dimerization to form 7,
which can be observed during the reaction. Outer sphere
oxidation of the other reaction partner by either Cu(II) or the dimer
7 generates a radical cation 8 which then reacts with the
copper(II) enolate 6 to yield 9. A second oxidation of 9 with the
copper from the enolate leads to stabilized cation 10, which
undergoes proton elimination to regenerate the aromatic ring of
3d. The rearomatization to 3d is irreversible such that 3d cannot
reenter the reaction cycle in the same manner as 6. The cross
selectivity is controlled by the nucleophilic nature of copper
enolate 6 and the electrophilic character of 8.
CuI
2 CuIICl
CuII
2 HCl
OH
H
O
O
E
E
N
2
2
CO2Me
CO2Me
N
N
N
H
H
O
H
CuI
E = CO2Me
1
6
2CuI
2 HCl
2 CuIICl
7
H
N
N
H
N
H
H
2d
8
CuII
NH
CuI
H
O
O
O
NH
NH
6 + 8
H
N
- H+
N
N
H CO2Me
H CO2Me
H CO2Me
0.001
M and voltammograms were internally referenced using an
3d
9
10
equimolar concentration of ferrocene. Measurements employed glassy
carbon and platinum working electrodes, and an Ag/AgCl wire
reference electrode. Voltammograms were recorded at a scan rate of 100
mV/s in the positive direction to observe irreversible oxidation.
4CuI + 4 HCl
+
O2
4CuIICl + 2 H2O
Figure 5. Possible Mechanism for the Oxidative Cross-Coupling of Oxindoles
and Simple Aromatics.
General procedure: oxidative 3-oxindole coupling. To a microwave vial
was added 3-oxindole (0.13 mmol), indole (0.13 mmol) and Cu-salan-Ph
catalyst (9.3 mg, 0.01 mmol). The vial was sealed with a septum and the
1,2-dichloroethane (1.3 mL) was added. After purging and refilling with O2
three times, the vial was sealed with a microwave vial cap and was stirred
at 50 oC for 20 h. Upon completion, the reaction mixture was then directly
chromatographed using silica gel.
Conclusions
In summary, HTE screening allowed rapid identification of a
general method for the cross-coupling of 3-oxindoles with an
electronically and structurally diverse set of aromatic compounds.
Using dioxygen as the terminal oxidant significantly reduces the
amount of chemical waste generated. Copper is also an abundant
base metal, and the copper (II) catalyst is bench stable. This
convergent method accesses novel structures as well as
improving the yields for similar transformations. Overall, this
method is broader in scope, more general, and more efficient than
similar reports[4-6, 10] in the literature, providing easy access to new
quaternary structures.
Methyl-3-hydroxy-1H-indole-2-carboxylate (1). Following the literature
protocol, the product was obtained as a yellow solid (1.74 g). Spectral data
were in agreement with those reported.[4]
Methyl-3-hydroxy-5-methoxy-1H-indole-2-carboxylate
(1m).
Commercially available methyl-5-methoxy-2-amino benzoate (0.45 g, 2.5
mmol) was dissolved in DMF (2.5 mL) with methyl-a-bromo-acetate (0.33
mL, 3.5 mmol) and sodium carbonate (0.27 g, 2.6 mmol) before heating to
80 °C under argon. The suspension was stirred for 10 h before cooling and
pouring into water. The aqueous layer was extracted with Et2O. The
combined organic layers were washed with brine before drying over
Na2SO4 and evaporating. The residue was chromatographed via
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10.1002/cssc.201900438
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FULL PAPER
autocolumn using 0-25% EtOAc/hexanes to give an off-white solid (0.40
g) in 63% yield.
mmol) was added dropwise as a suspension in THF (2.3 mL) causing the
mixture to turn yellow. After the reaction was complete as judged by TLC,
the THF was evaporated and the residue dissolved in 20% aq AcOH and
CH2Cl2. The layers were separated and the aqueous layer was extracted
again with CH2Cl2. The combined organic layers were washed with brine
before drying over Na2SO4 and loading onto silica. The material was
chromatographed via autocolumn using 1:4 CH2Cl2:hexanes to give a pale
yellow solid (0.28 g) in 64% yield. Rf = 0.6 (1:9 EtOAc:hexanes); 1H NMR
(500 MHz, CDCl3) d 8.59 (br s, 1H), 7.75 (dt J = 8.1, 0.9 Hz , 1H), 7.38
(ddd, J = 7.8, 1.4, 1.2 Hz, 1H), 7.26 (m, 1H), 7.07 (ddd, J = 7.5, 1.0, 0.8
Hz, 1H), 4.00 (s, 3H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) d 164.7,
148.8, 137.8, 127.4, 120.4, 119.1, 116.5, 110.0, 109.5, 51.7, 31.8; IR
(neat) 3300, 2951, 1651, 1615, 1542, 1458, 1433, 1390, 1371, 1299, 1233,
1194, 1166, 1150, 1121, 1044, 982, 967, 734, 636, 604, 544 HRMS (ES-
TOF) calcd for C11H11NO3 [M-H] m/z = 204.0661; found 204.0649.
The diester synthesized above was dissolved in anhydrous THF (5 mL)
and cooled to 0 °C under argon. Potassium tert-butoxide (0.19 g, 1.7
mmol) was added as a suspension in THF (1.7 mL) dropwise, which
caused the mixture to turn brown. After 25 min the reaction was complete
as judged by TLC. The THF was evaporated and the residue dissolved in
20% aq AcOH and CH2Cl2. The aqueous was extracted a second time with
CH2Cl2. The combined organic layers were washed with brine before
drying over Na2SO4 and concentrating. The residue was chromatographed
via autocolumn using 20% CH2Cl2/hexanes to give an off-white solid (0.11
g) in 31% yield. Rf = 0.3 (EtOAc:hexanes 1:9) 1H NMR (500 MHz, CDCl3)
d 7.64 (br s, 1H), 7.17 (d, J = 9.0 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.02
(dd, J = 9.0, 2.5 Hz, 1H), 3.96 (s, 3H), 3.85 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 154.0, 131.1, 123.1, 119.5, 117.7, 114.9, 113.3, 108.8, 99.7, 55.8,
51.7; IR (neat) 3352, 3004, 2961, 2845 1662, 1555, 1439, 1389, 1280,
1254, 1205, 1167, 1135, 1019, 995, 933, 851, 823, 810, 770, 595, 574,
512; HRMS (ES-TOF) calcd for C11H11NO4 [M-H] m/z = 220.0610; found
220.0618.
Benzyl-3-hydroxy-1H-indole-2-carboxylate
(1p).
Commercially
available methyl anthranilate (5.0 mL, 28 mmol) was dissolved in DMF (29
mL) with benzyl-bromoacetate (8.0 mL, 24 mmol) and sodium carbonate
(4.50 g, 43 mmol) before heating to 80 °C under argon. The suspension
was stirred for 31 h before the mixture was cooled and poured into water.
The aqueous layer was extracted with Et2O. The organic layer was washed
with brine before drying over Na2SO4 and concentrating.The residue was
chromatographed to give pure diester as needle-like crystals (7.20 g) in
62% yield.
Methyl-3-hydroxy-4-chloro-1H-indole-2-carboxylate
(1o).
Commercially available methyl-4-chloro-2-amino benzoate (1.85 g, 10
mmol) was dissolved in DMF (10 mL) with methyl-a-bromo-acetate (1.34
mL, 14 mmol) and sodium carbonate (1.09 g, 10.3 mmol) before heating
to 80 °C under argon. The suspension was stirred for 20 h before adding
an additional aliquot of methyl-a-bromo-acetate (0.20 mL, 2 mmol). After
a further 8 h, the mixture was cooled and poured into water. The aqueous
portion was then extracted with Et2O. The organic layer was washed with
brine before drying over Na2SO4 and evaporating. The residue was loaded
onto silica and chromatographed via autocolumn using 5%
EtOAc/hexanes to give a white solid (0.70 g) in 27% yield.
The diester synthesized above was dissolved in anhydrous THF (10 mL)
and was cooled to 0 °C under argon. Potassium tert-butoxide (0.37 g, 3.3
mmol) was added dropwise as a suspension in THF (3.3 mL). After the
addition was complete, i-PrOH was added to quench the remaining base
at 0 °C. The THF and alcohol mixture was evaporated and the crude
residue dissolved in 20% aq AcOH and CH2Cl2. The layers were separated
and the organic layer was washed with brine before drying over Na2SO4
and concentrating. The material was chromatographed via autocolumn
using 0-50% CH2Cl2/hexanes to give a white solid after trituration with
hexanes (0.06 g) in 24% yield. Rf = 0.6 (EtOAc:hexanes 1:9) 1H NMR (500
MHz, CDCl3) d 7.76 (br s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.40 (m, 5H), 7.24
(m, 1H), 7.10 (t, J = 7.5 Hz, 1H), 5.4 (br s, 2H); 13C NMR (125 MHz, d6-
acetone) d 163.8, 137.5, 136.8, 129.5,129.5, 129.2, 129.1, 127.6, 120.4,
120.0, 118.7, 113.4, 66.5; IR (neat) 3328, 3205, 2964, 2491, 1678, 1619,
1479, 1457, 1447, 1390, 1356, 1326, 1249, 1198, 1151, 1130, 1100, 948,
759, 736, 697, 597.37, 494; HRMS (ES-TOF) calcd for C16H13NO3 [M-H]
m/z = 266.0817; found 266.0819.
The diester synthesized above was dissolved in anhydrous THF (4 mL)
and added dropwise to a stirring suspension of potassium tert-butoxide
(0.45 g, 4 mmol in 7 mL) at 0 °C under argon. The flask was warmed to
room temperature. After the starting material was consumed as judged by
TLC, the mixture was diluted with water and acidified with glacial HOAc.
The mixture was extracted twice with CH2Cl2. The combined organic layer
were dried over Na2SO4 and concentrated. The residue was
chromatographed via autocolumn using 10%:9 EtOAc/:hexanes to give a
pale yellow solid. This material was triturated with hexanes to remove
hydrocarbon impurities and gave the pure solid (0.06 g) in 14% yield. Rf =
0.3 (1:9 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) d 7.77 (br s, 1H),
7.66 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.07 (dd, J = 8.6, 1.7 Hz,
1H), 3.97 (s, 3H); 13C NMR (125 MHz, d6-acetone) d 163.8, 146.0, 136.6,
132.8, 121.9, 120.7, 117.6, 112.9, 110.2, 51.8; IR (neat) 3447, 3289, 2956,
2450, 1695, 1619, 1578, 1547, 1505, 1497, 1320, 1266, 1223, 1204, 1135,
1104, 1055, 976, 921, 849, 797, 763, 587; HRMS (ES-TOF) calcd for
C10H8ClNO3 [M-H] m/z = 224.0114; found 224.0138.
Adamantyl-3-hydroxy-1H-indole-2-carboxylate (1p). Commercially
available methyl anthranilate (10 mL, 56 mmol) was dissolved in dry THF
(175 mL) and cooled to 0 °C. Sodium bicarbonate (7.14 g, 85 mmol) was
added, followed by benzyl chloroformate (12 mL, 59 mmol). The mixture
was stirred for 15 min before warming to room temperature. After stirring
a further 20 h, the reaction was then quenched with water and extracted
with EtOAc. The organic layer was dried over Mg2SO4
before
concentrating. The residue was eluted from a pad of silica gel using 5%
EtOAc/ hexanes to give the protected aniline as a colorless solid (18.0 g)
in 82% yield.
Methyl-3-hydroxy-1-methyl-indole-2-carboxylate (1n). Commercially
available N-methyl methyl anthranilate (1.5 mL, 10 mmol) was dissolved
in DMF (10 mL) with methyl-a-bromo-acetate (1.3 mL, 14 mmol) and
sodium carbonate (1.09 g, 10.3 mmol) before heating to 80 °C under argon.
The suspension was stirred for 20 h before it was cooled and poured into
water. The aqueous portion was extracted with Et2O and the layers
separated. The organic layer was washed with brine before drying over
Na2SO4 and evaporating. The residue was loaded onto silica and
chromatographed via autocolumn using 10% EtOAc/hexanes to give a
yellow oil (0.92 g) in 39% yield.
The protected aniline (1.4 g, 5 mmol) was dissolved in DMF (10 mL) with
1-adamantyl 2-bromoacetate (2.0 g, 7.5 mmol) prepared according to a
literature procedure[14] and cesium carbonate (3.3 g, 10 mmol) under argon.
The suspension was stirred for 18 h before it was cooled and acidified with
saturated aqueous NH4Cl. The aqueous layer was extracted with Et2O
(3X). The combined organic layers were washed with water and brine
before drying over Na2SO4 and concentrating. The residue
chromatographed via autocolumn using 0-25% EtOAc/hexanes to give a
clear viscous oil (1.8 g) in 76% yield.
The diester synthesized above was dissolved in anhydrous THF (7 mL)
and cooled to 0 °C under argon. Potassium tert-butoxide (0.26 g, 2.3
This article is protected by copyright. All rights reserved.

10.1002/cssc.201900438
ChemSusChem
FULL PAPER
The diester synthesized above was dissolved in anhydrous THF (38 mL)
and cooled to - 78 °C under argon. Potassium tert-butoxide (0.63 g, 5.6
mmol) was added in one portion. The mixture was allowed to warm slowly
to room temperature. After 3 h, saturated aqueous NH4Cl was added to
quench the remaining base. The aqueous layer was extracted with CH2Cl2
(2X ). The combined organic layers were washed with brine before drying
over Na2SO4 and loading onto silica. The resultant material was used
without further purification.
1498, 1457, 1434, 1325, 1294, 1225, 1197, 1157, 1094, 1015, 974, 894
cm-1; HRMS (ESI-TOF) calcd for C24H18FN2O3 [M+H]+ 401.1301, found
401.1306.
Methyl-2-(1H-indol-3-yl)-3-oxoindoline-2-carboxylate (3d). Following
the General Procedure for 22 h, the product was obtained as a yellow
solid in 90% NMR yield (50 mg, 82% isolated yield). Spectral data were in
agreement with those reported.[4]
The protected 3-oxindole was dissolved in EtOAc (38 mL) under argon.
Pd/C (0.40 g, 10 wt% Pd) was added to the flask before purging and
backfilling with H2 3X. The suspension was stirred for 3 h at room
temperature. The H2 was removed before filtering the mixture through
Celite®. The Celite® pad was washed with MeOH and the filtrate was
concentrated to give analytically pure oxindole as a pale yellow solid (0.93
g, 79% over two steps) Rf = 0.8 (1:9 EtOAc:hexanes); 1H NMR (500 MHz,
CDCl3) d 8.35 (br s, 1H), 7.72 (m, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.26 (d, J
= 8.3 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 2.29 (br s, 6H), 2.25 (br s, 3H), 1.73
(m, 6H); 13C NMR (125 MHz, d6-acetone) 163.8, 146.9, 136.2, 127.3, 120.2,
119.9, 118.5, 113.3, 110.3, 82.5, 42.5, 36.8, 31.9; IR (neat) 3483, 3320,
2907, 1682, 1622, 1581, 1548, 1509, 1492, 1337, 1231, 1203, 1184, 1127,
1097 1048, 963, 923, 736, 621, 532; HRMS (ES-TOF) calcd for C19H21NO3
[M-H] m/z = 310.1443; found 310.1458.
Methyl-2-(7-iodo-1H-indol-3-yl)-3-oxoindoline-2-carboxylate
(3e).
Following the General Procedure for 16 h, the product was obtained as a
yellow solid (58 mg) in 95% yield. Rf = 0.27 (EtOAc:Hexanes = 1:2): 1H
NMR (500 MHz, CDCl3) d 8.35 (br s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.62 (d,
J = 8.0 Hz, 1H), 7.55–7.50 (m, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.00 (d, J =
8.5 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 5.76 (br s,
1H), 3.80 (s, 3H); 13C NMR (125 MHz, CDCl3) d 194.4, 168.8, 161.1, 138.3,
138.0, 131.4, 125.6, 124.0, 122.0, 120.6, 120.0, 119.8, 113.6, 113.2, 77.0,
72.6, 53.9, 29.8; IR (neat) 3348, 2920, 2850, 1731, 1693, 1611, 1485,
1466, 1428, 1323, 1291, 1230, 1150, 1101, 1083, 1050, 971 cm–1; HRMS
(ESI-TOF) calcd for C18H14IN2O3 [M+H]+ 433.0049, found 433.0045.
Methyl-2-(7-bromo-1H-indol-3-yl)-3-oxoindoline-2-carboxylate
(3f).
Following the General Procedure for 22 h, the product was obtained as a
brown solid (47 mg) in 94% yield. Spectral data were in agreement with
those reported.[4]
Methyl-3-oxo-2-(2-phenyl-1H-indol-3-yl)indoline-2-carboxylate (3a).
Following the General Procedure for 19 h, the product was obtained as a
yellow solid (47 mg) in 94% yield. Rf = 0.27 (EtOAc:Hexanes = 1:2): 1H
NMR (500 MHz, CDCl3) d 8.31 (br s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.54 (t,
J = 7.5 Hz, 1H), 7.42 (d, J = 7.5 Hz, 2H), 7.37–7.34 (m, 3H), 7.30 (d, J =
8.0 Hz, 1H), 7.19–7.14 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.5
Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 5.61 (br s, 1H), 3.18 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 195.2, 168.8, 160.9, 138.1, 138.0, 135.5, 132.5, 129.6,
128.8, 128.4, 126.8, 125.3, 122.7, 120.6, 120.4, 120.2, 119.7, 113.4, 111.2,
108.2, 73.3, 53.2; IR (neat) 3345, 3052, 2950, 2920, 1697, 1613, 1485,
1457, 1431, 1323, 1292, 1233, 1196, 1150, 1099, 1072, 1013, 972, 896
cm–1; HRMS (ESI-TOF) calcd for C24H19N2O3 [M+H]+ m/z = 383.1396;
found 383.1414.
Methyl-2-(6-methoxy-1H-indol-3-yl)-3-oxoindoline-2-carboxylate (3g).
Following the General Procedure for 21 h, the product was obtained as a
yellow solid (37 mg) in 84% yield. Spectral data were in agreement with
those reported.[4]
Methyl-3-(2-(methoxycarbonyl)-3-oxoindolin-2-yl)-1H-indole-4-
carboxylate (3h). Following the General Procedure for 22 h at 80 °C, the
product was obtained as a yellow solid (37 mg) in 77% yield. Spectral data
were in agreement with those reported.[4]
Methyl-2-(5-cyano-1H-indol-3-yl)-3-oxoindoline-2-carboxylate
(3i).
Following the General Procedure for 16 h, the product was obtained as a
yellow solid (39 mg) in 88% yield. Spectral data were in agreement with
those reported.[4]
Methyl-2-(2-(4-chlorophenyl)-1H-indol-3-yl)-3-oxoindoline-2-
carboxylate (3b). Following the General Procedure for 22 h, the product
was obtained as a yellow solid (40 mg) in 73% yield. Rf = 0.40
(EtOAc:Hexanes = 1:2): 1H NMR (500 MHz, CDCl3) d 8.27 (br s, 1H), 7.59
(d, J = 8.0 Hz, 1H), 7.55 (td, J = 8.5, 1.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H),
7.32 (d, J = 8.0 Hz, 1H), 7.28 (d, J =8.0 Hz, 2H), 7.22 (d, J = 8.5 Hz, 1H),
7.18 (td, J = 8.0, 1.0 Hz, 1H), 7.03 (td, J = 8.0, 1.0 Hz, 1H), 6.98 (d, J = 8.0
Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 5.59 (br s, 1H), 3.32 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 195.0, 168.9, 160.6, 138.1, 136.6, 135.6, 135.0, 131.1,
130.9, 128.6, 126.9, 125.3, 123.0, 120.8, 120.6, 120.3, 119.6, 113.4, 111.3,
108.8, 73.1, 53.4; IR (neat) 3341, 3052, 2950, 1698, 1610, 1483, 1467,
1456, 1432, 1324, 1293, 1234, 1196, 1150, 1089, 1014, 973, 893, cm-1;
HRMS (ESI-TOF) calcd for C24H18ClN2O3 [M+H]+ 417.1006, Found
417.1012.
Methyl-2-(3-methyl-1H-indol-2-yl)-3-oxoindoline-2-carboxylate
(3j).
Following the General Procedure for 19 h, the product was obtained as a
yellow solid (26 mg) in 62% yield. Spectral data were in agreement with
those reported.[4]
Methyl-2-(1-methyl-1H-indol-3-yl)-3-oxoindoline-2-carboxylate (3k).
Following the General Procedure for 19 h, the product was obtained as a
yellow solid (45 mg) in 88% yield. Spectral data were in agreement with
those reported.[4]
Methyl-2-(2-methyl-1H-indol-3-yl)-3-oxoindoline-2-carboxylate
(3l).
Methyl-2-(2-(4-fluorophenyl)-1H-indol-3-yl)-3-oxoindoline-2-
Following the General Procedure for 19 h, the product was obtained as a
yellow solid (58 mg) in 77% yield. Spectral data were in agreement with
those reported.[4]
carboxylate (3c). Following the General Procedure for 21 h, the product
was obtained as a yellow solid (50 mg) in 96% yield. Rf = 0.4
(EtOAc:Hexanes = 1:2): 1H NMR (500 MHz, CDCl3) d 8.35 (br s, 1H), 7.57
(d, J = 8.0 Hz, 1H), 7.54 (td, J = 8.0, 1.0 Hz, 1H), 7.38-7.35 (m, 2H), 7.29
(d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16 (td, J = 8.0, 1.0 Hz, 1H),
7.03 (td, J = 8.0, 1.0 Hz, 1H), 6.99–6.95 (m, 3H), 6.93 (t, J = 7.5 Hz, 1H),
5.62 (br s, 1H), 3.30 (s, 3H); 13C NMR (125 MHz, CDCl3) d 195.2, 168.9,
163.0 (d, J = 249 Hz), 160.7, 138.1, 136.8, 135.5, 131.6 (d, J = 8.3 Hz),
128.7, 126.9, 125.3, 122.8, 120.7, 120.5, 120.3, 119.5, 115.4 (d, J = 21.5
Hz), 113.4, 111.4, 108.5, 73.1, 53.4; IR (neat) 3354, 2951, 1704, 1613,
Methyl-2-(2-(4-fluorophenyl)-1H-indol-3-yl)-3-oxo-5-methoxy-
indoline-2-carboxylate (3m). Following the General Procedure for 18 h,
the product was obtained as a yellow solid (48 mg) in 85% yield. Rf = 0.2
(1:9 EtOAc:hexanes) 1H NMR (500 MHz, CDCl3) d 8.18 (br s, 1H), 7.41
(dd, J = 6.7, 6.5 Hz, 2H), 7.34 (d J = 8.1 Hz, 1H), 7.24 (dd, J = 8.8, 2.7 Hz,
1H), 7.18 (d, J = 6.6 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 7.04 (m, 4H), 6.98
(d, J = 8.9, 1.0 Hz, 1H), 3.79 (s, 3H), 3.32 (s, 3H); 13C NMR (125 MHz,
This article is protected by copyright. All rights reserved.

10.1002/cssc.201900438
ChemSusChem
FULL PAPER
CDCl3) d 195.4, 169.1, 163.1 (d, J = 249.2 Hz), 162.1, 156.6, 154.7, 136.8,
135.6, 131.6 (d, J = 8.3 Hz), 128.7, 126.9, 123.0, 120.9, 120.8, 119.6,
115.5 (d, J = 11.7 Hz), 115.3, 111.4, 108.9, 104.9, 74.3, 56.0, 53.5; IR
(neat); 3341, 3061, 2951, 1731, 1693, 1491, 1456, 1435, 1265, 1220, 1193,
1156, 1094, 1070, 1026, 840, 805, 793, 745, 696, 568, 538; HRMS (ES-
TOF) calcd for C25H19FN2O4 [M-H] m/z = 429.1251; found 429.1246.
83.8, 74.0, 40.6, 36.0, 30.9; IR (neat) 3340, 3058, 2912, 2853, 1704, 1614,
1498, 1485, 1468, 1458, 1439, 1321, 1224, 1197, 1155, 1102, 1093, 1046,
963, 839, 740, 700, 667; HRMS (ES-TOF) calcd for C33H29FN2O3 [M+H]+
m/z = 521.2240; found 521.2253.
Methyl-3-oxo-2-(1H-pyrrol-2-yl)indoline-2-carboxylate (5a). Following
the General Procedure for 15 h, the product was obtained as a brown oil
(16 mg) in 49% yield. The C2-substituion on this and related pyrroles was
assigned on the basis of a vicinal coupling >3 Hz, which is absent in the
Methyl-2-(2-(4-fluorophenyl)-1-methyl-indol-3-yl)-3-oxo-indoline-2-
carboxylate (3n). Following the General Procedure for 20 h, the product
was obtained as a yellow solid (14 mg) in 25% yield. Rf = 0.3 (1:9
EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) d 8.35 (br s, 1H), 7.55 (ddd
J = 8.4, 8.4,1.3 Hz, 1H), 7.49 (m, 3H), 7.36 (d, J = 8.1 Hz, 1H), 7.18 (m,
2H), 7.04 (t, J = 7.4 Hz, 1H), 6.98 (m, 2H), 6.81 (d, J = 8.3 Hz, 1H), 6.77
(t, J = 7.4 Hz, 1H), 3.40 (br s, 3H), 3.00 (s, 3H); 13C NMR (125 MHz, d6-
acetone) d 167.9, 164.7, 160.9, 139.1, 139.0, 136.9, 132.4 (d, J = 8.3 Hz),
130.8, 128.2, 125.5, 122.9, 120.9, 120.1, 119.9, 118.6, 115.7 (d, J = 21.5
Hz), 112.4, 109.6, 105.9, 77.1, 52.7; IR (neat); 3324, 3063, 2925, 1736,
1696, 1613, 1497, 1457, 1432, 1366, 1321, 1221, 1198, 1159, 1114, 1094,
1016, 993, 840, 803,745, 706, 565; HRMS (ES-TOF) calcd for
C25H19FN2O3 [M-H] m/z = 413.1301; found 413.1298.
1
C3-substituted version. Rf = 0.50 (EtOAc:Hexanes = 1:2): H NMR (500
MHz, CDCl3) d 9.38 (br s, 1H), 7.59 (ddd, J = 7.7, 1.3, 0.7 Hz, 1H), 7.52
(ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.05 (dt, J = 8.2, 0.8 Hz, 1H), 6.91 (ddd, J
= 7.9, 7.1, 0.8 Hz, 1H), 6.83 (td, J = 2.6, 1.6 Hz, 1H), 6.29 (ddd, J = 3.5,
2.5, 1.6 Hz, 1H), 6.14 (dt, J = 3.5, 2.7 Hz, 1H), 5.61 (br s, 1H), 3.81 (s, 3H);
13C NMR (125 MHz, CDCl3) d 193.2, 167.7, 161.7, 138.1, 125.8, 124.9,
120.8, 119.3, 118.9, 113.6, 108.3, 106.3, 71.9, 54.0; IR (neat) 3364, 2951,
1733, 1693, 1613, 1486, 1467, 1433, 1324, 1233, 1197, 1153, 1139, 1101,
1028, 1008, 950 cm-1; HRMS (ESI-TOF) calcd for C14H12N2O3Na [M+Na]+
m/z = 279.0746; found 279.0756.
Methyl-2-(3,5-dimethyl-1H-pyrrol-2-yl)-3-oxoindoline-2-carboxylate
(5c). Following the General Procedure for 16 h, the product was obtained
as a yellow solid (25 mg) in 65% yield. Spectral data were in agreement
with those reported.[4]
Methyl-2-(2-(4-fluorophenyl)-1H-indol-3-yl)-3-oxo-4-chloro-indoline-
2-carboxylate (3o). Following the General Procedure for 16 h, the
product was obtained as a yellow solid (48 mg) in 77% yield. Rf = 0.3 (1:9
EtOAc:hexanes) 1H NMR (500 MHz, CDCl3) d 8.36 (br s, 1H), 7.47 (d, J =
8.3 Hz, 1H), 7.33 (m, 2H), 7.28 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H),
7.16 (d, J = 7.4 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.94 (m, 3H), 6.88 (dd, J
= 8.2, 1.4 Hz, 1H), 5.70 (br s, 1H) 3.30 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 193.8, 168.6, 163.1 (d, J = 247.8 Hz), 160.8, 144.6, 137.0, 135.5, 131.6
(d, J = 8.14 Hz), 128.6, 126.8, 126.3, 123.0, 121.3, 120.9, 119.4, 118.6,
115.5 (d, J = 21.7 Hz), 113.2, 111.5, 108.1, 73.6, 53.5; IR (neat); 3351,
3059, 2952, 1705, 1606, 1578, 1498, 1456, 1433, 1319, 1287, 1222, 1193,
1158, 1105, 1094, 1062, 1015, 919, 840, 812, 744, 538; HRMS (ES-TOF)
calcd for C24H16ClFN2O3 [M-H] m/z = 433.0753; found 433.0769.
Methyl-2-(1-methyl-1H-pyrrol-2-yl)-3-oxoindoline-2-carboxylate (5d).
Following the General Procedure for 18 h, the product was obtained as a
yellow solid (13 mg) in 37% yield. Rf = 0.5 (EtOAc:Hexanes = 1:2): 1H
NMR (500 MHz, CDCl3) d 7.67 (d, J = 7.5 Hz, 1H), 7.53 (td, J = 7.5, 1.2
Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.61 (dd, J = 2.7,
1.9 Hz, 1H), 6.13 (dd, J = 3.7, 1.8 Hz, 1H), 6.06 (dd, J = 3.8, 2.7 Hz, 1H),
5.50 (br s, 1H), 3.87 (s, 3H), 3.42 (s, 3H); 13C NMR (125 MHz, CDCl3) d
193.8, 168.4, 160.6, 138.1, 126.2, 125.5, 125.4, 120.9, 119.9, 113.8, 110.8,
107.2, 73.1, 54.2, 35.0; IR (neat) 3352, 2950, 1737, 1703, 1613, 1484,
1467, 1434, 1322, 1306, 1291, 1246, 1230, 1196, 1150, 1092, 1027 cm–1
HRMS (ESI-TOF) calcd for C15H15N2O3 [M+H]+ 271.1083, found 271.1095.
;
Benzyl-2-(2-(4-fluorophenyl)-1H-indol-3-yl)-3-oxo-indoline-2-
carboxylate (3o). Following the General Procedure for 16 h, the product
was obtained as a yellow solid (48 mg) in 90% yield (31 mg remained after
precipitation from chloroform with hexanes to remove hydrocarbon
impurities). Rf = 0.3 (1:9 EtOAc:hexanes) 1H NMR (500 MHz, CDCl3) d
8.22 (br s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.53 (td J = 7.7, 1.2 Hz, 1H), 7.33
(dd, J = 8.6, 5.3 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.23 (m, 4H), 7.14 (t, J
= 5.1 Hz, 1H), 7.10 (m, 2H), 6.98 (t, J = 7.6 Hz, 1H), 6.91 (m, 4H), 5.54 (br
s, 1H), 4.81 (d, J = 12.6 Hz, 1H), 4.58 (d, J = 12.6 Hz, 1H); 13C NMR (125
MHz, CDCl3) d195.0, 168.4, 163.1 (d, J = 249.0 Hz), 138.0, 136.7, 135.5,
134.9, 131.6 (d, J = 8.3 Hz), 128.7, 128.7, 128.5, 128.3, 127.9, 126.9,
125.3, 122.8, 120.7, 120.5, 120.3, 119.8, 115.5 (d, J = 21.6 Hz), 113.3,
111.3,108.4, 73.2, 68.06; IR (neat); 3356, 3064, 1704, 1609, 1498, 1486,
1467, 1457, 1435, 1324, 1220, 1197, 1152, 1093, 1071, 1015, 891, 840,
743, 696, 666; HRMS (ES-TOF) calcd for C30H21FN2O3 [M-H] m/z =
475.1458; found 475.1443.
Methyl-2-(5-methoxyfuran-2-yl)-3-oxoindoline-2-carboxylate
(5e).
Following the General Procedure for 21 h, the product was obtained as a
brown oil (26 mg) in 68% yield. Rf = 0.33 (EtOAc:Hexanes = 1:2): 1H NMR
(500 MHz, CDCl3) d 7.64 (d, J = 8.0 Hz, 1H), 7.51 (td, J = 8.0, 1.0 Hz, 1H),
6.97 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.37 (d, J = 3.5 Hz, 1H),
5.56 (br s, 1H), 5.12 (d, J = 3.5 Hz, 1H), 3.81 (s, 6H); 13C NMR (125 MHz,
CDCl3) d 191.8, 167.1, 162.0, 161.2, 138.4, 138.2, 125.7, 120.7, 119.4,
113.7, 110.7, 80.5, 71.6, 58.0, 54.2; IR (neat) 3358, 2920, 1744, 1705,
1613, 1576, 1486, 1467, 1435, 1367, 1324, 1295, 1258, 1199, 1152, 1099,
1027, 962 cm–1; HRMS (ESI-TOF) calcd for C15H14NO5 [M+H]+ 288.0872,
found 288.0860.
Methyl-2-(4-(dimethylamino)phenyl)-3-oxoindoline-2-carboxylate
(5g). Following the General Procedure for 19 h at 80 °C, the product was
obtained as a yellow solid (21 mg) in 52% yield. Rf = 0.4 (EtOAc:Hexanes
1
Adamantyl-2-(2-(4-fluorophenyl)-1H-indol-3-yl)-3-oxo-indoline-2-
carboxylate (3o). Following the General Procedure for 16 h, the product
was obtained as a yellow solid (48 mg) in 57% yield (15 mg remained after
precipitation from chloroform with hexanes to remove hydrocarbon
impurities). Rf = 0.4 (1:9 EtOAc:hexanes) 1H NMR (500 MHz, CDCl3) d
8.15 (br s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.44 (d, J
= 8.2 Hz, 1H), 7.40 (dd, J = 8.3, 5.5 Hz, 2H), 7.23 (d, J = 8.1 Hz, 1H), 7.17
(t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 7.00 (dd, J = 9.5, 8.5 Hz, 2H),
6.90 (m, 2H), 5.41 (br s, 1H), 2.02 (br s, 3H), 1.77 (m, 6H), 1.51 (m, 6H);
13C NMR (125 MHz, CDCl3) d 195.5, 166.9, 163.2 (d, J = 248.8 Hz), 160.4,
137.6, 136.4, 135.7, 131.4 (d, J = 8.2 Hz), 129.5, 127.2, 125.2, 122.7,
120.6, 120.5, 120.4, 120.2, 115.6 (d, J = 21.6 Hz), 113.1, 111.1, 108.5,
= 1:2): H NMR (500 MHz, CDCl3) d 7.60 (d, J = 8.0 Hz, 1H), 7.57 (d, J =
9.0 Hz, 2H), 7.49 (td, J = 7.0, 1.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.88 (t,
J = 7.5 Hz, 1H), 6.70 (d, J = 9.0 Hz, 2H), 5.61 (br s, 1H), 3.80 (s, 3H), 2.93
(s, 6H); 13C NMR (125 MHz, CDCl3) d 194.5, 169.0, 160.8, 150.8, 137.6,
127.2, 125.6, 123.4, 120.3, 120.0, 113.3, 112.5, 74.8, 53.8, 40.6; IR (neat)
3352, 2950, 2922, 1740, 1698, 1608, 1519, 1485, 1468, 1434, 1355, 1322,
1291, 1233, 1195, 1166, 1152, 1096, 1061, 984 cm-1; HRMS (ESI-TOF)
calcd for C18H19N2O3 [M+H]+ 311.1396, Found 311.1408.
Methyl-2-(4-(diethylamino)phenyl)-3-oxoindoline-2-carboxylate (5h).
Following the General Procedure for 18 h at 80 °C, the product was
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obtained as a yellow solid (29 mg) in 66% yield. Rf = 0.50 (EtOAc:Hexanes
= 1:2): H NMR (500 MHz, CDCl3) d 7.60 (d, J = 7.5 Hz, 1H), 7.51 (d, J =
Keywords: catalysis • oxidative coupling • sustainable • coinage
1
metal • oxygen
9.0 Hz, 2H), 7.48 (td, J = 7.5, 1.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.87 (t,
J = 7.5 Hz, 1H), 6.63 (d, J = 9.0 Hz, 2H), 5.60 (br s, 1H), 3.80 (s, 3H), 3.33
(q, J = 7.0 Hz, 4H), 1.13 (t, J = 7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) d
194.7, 169.1, 160.8, 148.0, 137.6, 127.4, 125.6, 124.3, 120.2, 120.0, 113.3,
111.6, 74.9, 53.7, 44.5, 12.7; IR (neat) 3355, 2970, 1738, 1697, 1607,
1589, 1517, 1486, 1468, 1452, 1434, 1355, 1321, 1291, 1264, 1231, 1194,
1153, 1089 cm-1; HRMS (ESI-TOF) calcd for C20H23N2O3 [M+H]+ 339.1709,
Found 339.1719.
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Methyl-2-(1-(2-cyanoethyl)-1H-pyrrol-2-yl)-3-oxoindoline-2-
carboxylate (5i). Following the General Procedure for 24 h at 80 °C , the
product was obtained as a brown oil (24 mg) in 60% yield. Rf = 0.25
(EtOAc:Hexanes = 1:2): 1H NMR (500 MHz, CDCl3) d 7.67 (dd, J = 8.0, 1.0
Hz, 1H), 7.57 (td, J = 8.0, 1.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.00 (t, J =
7.5 Hz, 1H), 6.80 (t, J = 2.4 Hz, 1H), 6.16 (d, J = 2.3 Hz, 2H), 5.55 (s, 1H),
3.98–3.89 (m, 2H), 3.88 (s, 3H), 2.73 (t, J = 7.0 Hz, 2H); 13C NMR (125
MHz, CDCl3) d 193.8, 168.1, 160.4, 138.4, 125.7, 125.6, 124.0, 121.5,
119.6, 117.4, 113.8, 111.7, 109.0, 73.1, 54.3, 43.3, 20.0; IR (neat) 3347,
2952, 2250, 1737, 1704, 1613, 1483, 1468, 1434, 1323, 1292, 1234, 1198,
1151, 1085, 1045, 979, 894 cm–1; HRMS (ESI-TOF) calcd for C17H16N3O3
[M+H]+ m/z = 310.1192; found 310.1180.
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M. Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 2015, 115, 12138-
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Methyl 3-oxo-2-(2,4,6-trimethoxyphenyl)indoline-2-carboxylate (5j).
Following the General Procedure for 24 h at 80 °C, the product was
obtained as a yellow solid (29 mg) in 62% yield. Rf = 0.13 (EtOAc:Hexanes
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X.-Y. Zhou, X. Chen, L.-G. Wang, D. Yang, J.-H. Li, Synlett 2018, 29,
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1
= 1:2): H NMR (500 MHz, CDCl3) d 7.66 (d, J = 8.0 Hz, 1H), 7.45 (t, J =
8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.13 (s, 2H),
5.47 (br s, 1H), 3.77 (s, 6H), 3.65 (s, 6H); 13C NMR (125 MHz, CDCl3) d
195.1, 169.8, 161.7, 160.2, 159.4, 136.7, 124.7, 120.9, 120.0, 113.5, 108.5,
92.5, 72.3, 56.0, 55.6, 53.6; IR (neat) 3353, 2948, 1716, 1605, 1587, 1484,
1468, 1435, 1417, 1322, 1226, 1204, 1152, 1126, 1093, 1057, 1029, 993
cm-1; HRMS (ESI-TOF) calcd for C19H20NO6 [M+H]+ 358.1291 Found:
358.1281.
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Acknowledgements
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We are grateful to the NIH (GM-112684) and the NSF
(CHE1764298) for financial support of this research. Partial
instrumentation support was provided by the NIH and NSF
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(1S10RR023444, 1S10RR022442,
CHE-0840438,
CHE-
0848460, 1S10OD011980). Drs. Rakesh Kohli and Charles W.
Ross III (UPenn) are acknowledged for obtaining HRMS data.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Ph
Ph
Houng Kang, Adriana L. Jemison, Erin
Nigro, and Marisa C. Kozlowski*
10 mol %
N
H
O
N
H
O
Cu
H
N
t-Bu
t-Bu
O
OH
t-Bu
t-Bu
Page No. – Page No.
R
CO2Me
+
R
N
N
H
CO2Me
O2, DCE, 50 °C
N
H
H
Oxidative Coupling of 3-Oxindoles
with Indoles and Arenes
21 examples, up to 96% yield
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