Selective synthesis of 2-indolyl-3-oxoindolines or 2-(2-aminophenyl)quinolines through Cu(II)- or Bi(III)-catalyzed tunable dimerizations of 2-alkynylanilines

Article abstract of DOI:10.1021/acs.orglett.0c02323

A novel and selective synthesis of 2-indolyl-3-oxoindolines or 2-(2-aminophenyl)quinolines through tunable dimerizations of 2-alkynylanilines is presented. Mechanistically, the formation of 2-indolyl-3-oxoindolines involves a Cu(OAc)2/O2-promoted intramolecular cyclization of 2-alkynylaniline to give the required indole and 3H-indol-3-one intermediates followed by the indolylation of 3H-indol-3-one. On the other hand, the formation of 2-(2-aminophenyl)quinolines is believed to go through a Bi(OTf)3/MesCO2H-catalyzed intermolecular N-nucleophilic addition between two 2-alkynylaniline molecules to give an enamine intermediate followed by its intramolecular C-nucleophilic addition/annulation. Notable features of these new methods include easily obtainable substrates, economical catalysts and oxidant, controllable selectivity, and high versatility toward diverse products.

Full text of DOI:10.1021/acs.orglett.0c02323

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Letter
Selective Synthesis of 2‑Indolyl-3-oxoindolines or 2‑(2-
Aminophenyl)quinolines through Cu(II)- or Bi(III)-Catalyzed Tunable
Dimerizations of 2‑Alkynylanilines
Ruixue Jia, Bin Li,* Xinying Zhang, and Xuesen Fan*
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ABSTRACT: A novel and selective synthesis of 2-indolyl-3-
oxoindolines or 2-(2-aminophenyl)quinolines through tunable
dimerizations of 2-alkynylanilines is presented. Mechanistically,
the formation of 2-indolyl-3-oxoindolines involves a Cu(OAc)2/
O2-promoted intramolecular cyclization of 2-alkynylaniline to give
the required indole and 3H-indol-3-one intermediates followed by
the indolylation of 3H-indol-3-one. On the other hand, the
formation of 2-(2-aminophenyl)quinolines is believed to go
through a Bi(OTf)3/MesCO2H-catalyzed intermolecular N-nucle-
ophilic addition between two 2-alkynylaniline molecules to give an
enamine intermediate followed by its intramolecular C-nucleophilic addition/annulation. Notable features of these new methods
include easily obtainable substrates, economical catalysts and oxidant, controllable selectivity, and high versatility toward diverse
products.
2,2-Disubstituted indolin-3-one constitutes the scaffold of
numerous natural products such as Austamdine, Cephalinone,
LipidGreen, Aristotelon, Isatisine A, and Halichrome A,1
fluorescence probes, and solar-cell materials.2 Among different
kinds of 2,2-disubstituted indolin-3-one derivatives, 2-indolyl-
3-oxoindolines are particularly attractive. This is because they
not only have unique structural features but also demonstrate
potent antiviral activities.3 To date, several reliable methods for
the preparation of 2-indolyl-3-oxoindolines have been reported
by Ramana, Guchhait, Jiang, Liu, and many others.4−6
In the past several years, we have developed some methods
for the synthesis of biologically interesting heterocyclic
compounds.7 In this regard, we recently disclosed the synthesis
of indolo[3,2-c]quinolines and 3-(2-aminophenyl)quinolines
via [RhCp*Cl2]2-catalyzed dimerization of 2-alkynylanilines
under aerobic/anaerobic conditions (Schemes 1a and 1b).7d In
continuation of our study, we have studied the reaction of 2-
alkynylanilines under the catalysis of some non-noble metal
catalysts. Through this study, we serendipitously developed an
unrevealed selective synthesis of 2-indolyl-3-oxo-indolines or
2-(2-aminophenyl)quinolines from 2-alkynylanilines upon
finely tuning the reaction conditions (Scheme 1c, 1d, and
1e). Herein, we report the results obtained in this regard.
Initially, 1a was treated with Cu(OAc)2 in HFIP at 80 °C
under air for 20 h. From this reaction, 2a was obtained in 42%
yield (Table 1, entry 1). To increase the yield, several solvents
were tried, but they were inferior to HFIP in mediating this
reaction (entries 2−6). Next, several other Cu(II) salts were
used as catalyst (entries 7−11). Among them, Cu(OAc)2·H2O
gave the best yield of 2a (entry 7). Under the catalysis of
Cu(OTf)2 or CuSO4, to our surprise, 2a was formed only in a
trace amount, while 3a was obtained in 39% and 21% yield
(entries 10 and 11). To facilitate the formation of 2a, m-CPBA
or TBHP was used as oxidant. In these cases, however, the
yield of 2a decreased (entries 12 and 13). When this reaction
was run under O2, gratifyingly, the yield of 2a was improved to
61% (entry 14).
Scheme 1. Diverse Reactions of 2-(Phenylethynyl)aniline
Received: July 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02323
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Table 1. Optimization Study for the Formation of 2a/3a/4a
b
yield (%)
entry
catalyst
additive
solvent
2a
42
32
trace
15
trace
trace
53
3a
4a
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2·H2O
CuCl2·2H2O
CuBr2
HFIP
TFE
MeOH
DCE
ND
ND
ND
ND
ND
ND
ND
ND
ND
39
ND
ND
ND
ND
ND
ND
ND
ND
ND
trace
trace
ND
ND
ND
trace
trace
trace
trace
trace
trace
14
THF
dioxane
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
22
9
trace
trace
trace
28
24
61
ND
ND
ND
ND
ND
ND
ND
ND
10
11
12
13
14
15
16
17
Cu(OTf)2
CuSO4
21
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Bi(OTf)3
m-CPBA
TBHP
O2
ND
ND
ND
36
55
41
60
72
40
45
TFA
MesCO2H
1-AdCO2H
MesCO2H
MesCO2H
MesCO2H
MesCO2H
MesCO2H
c
18
c
19
c
20
c
LiOTf
Bi(OAc)3
Bi(OTf)3
21
c d
,
22
trace
64
a
b
Reaction conditions: 1a (0.3 mmol), catalyst (0.015 mmol), additive (0.3 mmol), solvent (2 mL), 80 °C, air, sealed tube, 20 h. Isolated yield.
c
d
0.03 mmol of catalyst. Under N2.
After the optimal conditions for the formation of 2a had
been established, we moved our attention to 3a. We realized
that the formation of 3a is synthetically and mechanistically
attractive due to the following reasons: (1) This is the first
example in which 2-indolyl-3-oxo-indoline and 2-(2-amino
phenyl)quinoline derivatives were selectively formed from the
same acyclic substrate under slightly varied reaction con-
ditions. (2) Functionalized quinolines like 3a are among the
most useful pharmacophores of clinical drugs and most
ubiquitous building blocks of natural products.8 (3) Literature
searching revealed that the synthesis of 2-(2-aminophenyl)-
quinolines has only been sporadically reported, which are
mostly associated with the dimerization of 2-ethynylanilines. In
addition, these limited literature methods are only viable to
terminal alkynes. In those cases, the more sterically handed and
less reactive internal alkynes chose to undergo intramolecular
cyclization to give indoles rather than dimerization.9 To
develop this intriguing reaction into a general and efficient
synthesis of 2-(2-aminophenyl)quinolines from internal
alkynes, several parameters possibly affecting its efficiency
were screened. First, different Brønsted acids such as
trifluoroacetic acid (TFA), 2,4,6-trimethylbenzoic acid (Mes-
CO2H), and 1-adamantane carboxylic acid (1-AdCO2H) were
used as additives (entries 15−17). It was thus found that the
yield of 3a could be improved to 55% in the presence of
MesCO2H. Next, the loading of catalyst was increased from 5
mol % to 10 mol %. Under this circumstance, the yield of 3a
increased to 60% (entry 18). Then, Bi(OTf)3, LiOTf, or
Bi(OAc)3 was tried as catalyst (entries 19−21). To our
pleasure, 3a was formed in 72% yield under the catalysis of
Bi(OTf)3 (entry 19). When this reaction was run under an
inert atmosphere (N2) instead of air, 4a, the 4-alkyl
counterpart of 3a, was selectively obtained in 64% yield
(entry 22). Interestingly, 4a has a different substitution pattern
compared with the quinoline product obtained from
[RhCp*Cl2]2-catalyzed dimerization of the same substrate
(Scheme 1e vs 1b),7 indicating that two different dimerization
pathways must have been involved.
With the optimal reaction conditions in hands, the substrate
generality for the synthesis of 2 was first explored. The results
included in Table 2 showed that 1 bearing a methyl, methoxy,
chloro, or bromo group as the R1 unit attached on different
sites of the connecting benzene ring readily underwent this
oxidative dimerization reaction to afford 2b−2f in moderate
yields. In addition, 1 bearing a phenyl unit attached with either
an electron-donating group (EDG) such as methyl, ethyl, tert-
butyl, and methoxy or an electron-withdrawing group (EWG)
including fluoro, chloro, or bromo on its para-, meta-, or ortho-
position as the R2 moiety took part in this reaction to give 2g−
2o. 1 bearing a cyclopropyl or 2-naphthyl group as the R2 unit
could afford 2p and 2q. With R1 as a 4-methyl group and R2 as
a 4-chlorophenyl or 3-chlorophenyl unit, the reactions could
also take place smoothly to give 2r and 2s. Attractively, the
tolerance of various functional groups enables structural
elaboration of the products. It is also worth noting that the
structure of 2o was established based on its single-crystal X-ray
diffraction analysis (see the Supporting Information).
Next, the substrate scope for the preparation of 3 was
studied. Thus, a range of 1 bearing various R1 units were
subjected to the optimal reaction conditions to give the desired
B
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a b
,
the structure of 3d was confirmed based on its single-crystal X-
ray diffraction analysis (see the Supporting Information).
Third, the substrate scope for the formation of 4 was
explored. The results listed in Table 4 showed that under the
Table 2. Substrate Scope for the Synthesis of 2
a b
,
Table 4. Substrate Scope for the Synthesis of 4
a
Reaction conditions: 1 (0.3 mmol), Cu(OAc)2·H2O (0.015 mmol),
b
a
HFIP (2 mL), 80 °C, O2, sealed tube, 20 h. Isolated yield.
Reaction conditions: 1 (0.3 mmol), Bi(OTf)3 (0.03 mmol),
MesCO2H (0.3 mmol), HFIP (2 mL), 80 °C, N2, sealed tube, 20
b
h. Isolated yield.
products 3b−3e in moderate to good yields (Table 3). Then,
the suitability of 1 bearing diversely substituted alkynyl
optimized conditions for the formation of 4a all the selected 2-
alkynylaniline substrates underwent the dimerization to give
4a−4n in reasonably good yields, thus setting up a general
synthesis of diversely substituted 2-(2-aminophenyl)quinoline
derivatives from the inactive internal alkynes.
a b
,
Table 3. Substrate Scope for the Synthesis of 3
Based on experimental outcomes and literature reports,5,6
a
reaction pathway leading to the formation of 2a is proposed in
Scheme 2. As a first step, complexation of Cu(II) with 1a
Scheme 2. Plausible Mechanism for the Formation of 2a
affords intermediate I, from which intermediate II is formed
through an intramolecular N-cyclization. Protonation of II
with HFIP as a proton source affords 2-phenylindole (III).
Meanwhile, II could also be trapped by O2 to give a peroxic
species IV. Next, protonation and decomposition of IV give 2-
phenylindolin-3-one (V). Under the reaction conditions, V
takes part in an oxidative dehydrogenation to give 2-phenyl-
3H-indol-3-one (VI). In the final stage of this cascade process,
III undergoes a C-nucleophilic addition onto VI to give 2a.
The mechanism as proposed in Scheme 2 is supported by
the following control experiments. First, 1a was treated with
Cu(OAc)2·H2O in HFIP at 80 °C under nitrogen for 20 h. As
a result, the proposed intermediate III was obtained in a yield
of 82%. Then, III was subjected to I2/KOH and then silica gel
under air to give VI (Scheme 3a).1f Next, III was treated with
VI under the promotion of Cu(OAc)2·H2O in HFIP at 80 °C
under N2 to give 2a in 83% yield (Scheme 3b).
a
Reaction conditions: 1 (0.3 mmol), Bi(OTf)3 (0.03 mmol),
MesCO2H (0.3 mmol), HFIP (2 mL), 80 °C, air, sealed tube, 20
b
h. Isolated yield.
moieties was also probed. It was thus found that the R2 unit
could be a phenyl unit bearing either an EDG or an EWG to
give 3f−3o. In general, substrates bearing an electron-deficient
R2 unit showed higher efficiency than those bearing an
electron-rich R2 moiety (3f−3i vs 3j−3o). Our further study
found that substrates bearing a thienyl moiety at the alkyne
terminus took part in this reaction readily to produce 3p. Apart
from aryl groups, this reaction was also suitable for substrate 1
bearing a cyclopropyl group as the R2 unit to give product 3q.
Furthermore, the desired products 3r and 3s were obtained
from substrates with different substituents attached on the
connecting benzene and the alkyne moiety. Last but not least,
In another aspect, reaction pathways leading to the
formation of 3a and 4a are proposed in Scheme 4. Initially,
the triple bond of 1a is activated by Bi(III) to form a π-
complex VII, which allows for the nucleophilic attack of the
C
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out that under these conditions 4a could be successfully
Scheme 3. Control Experiments
furnished in 54% yield (Scheme 6).
Scheme 6. Gram-Scale Synthesis of 4a
Scheme 4. Plausible Mechanism for the Formation of 3a/4a
To conclude, we have developed a selective and versatile
synthesis of 2-indolyl-3-oxo-indoline and 2-(2-aminophenyl)-
quinoline derivatives through controllable dimerization of 2-
alkynylanilines. To our knowledge, this should be the first
example in which 2-indolyl-3-oxo-indolines and 2-(2-
aminophenyl)quinolines were formed selectively from the
same acyclic substrates by finely turning the reaction
conditions. This is also the first report that 2-(2-aminophenyl)-
quinolines were formed via the dimerization of sterically
hindered and less reactive internal alkynes. In addition, the
usefulness of one of the 2-(2-aminophenyl)quinoline products
was showcased by its ready transformation into important
fused heterocycles such as dibenzo[a,c]acridine and indazolo-
[2,3-a]quinoline derivatives. With advantages including acces-
sible substrates, benign oxidant, inexpensive catalysts, control-
lable selectivity, and high versatility toward different kinds of
valuable products, these novel synthetic protocols might be
used in the preparation of related functional molecules.
NH2 group of another molecule of 1a to form intermediate
VIII. Next, intermediate IX is formed through protonation of
VIII with HFIP. IX undergoes an intramolecular C-
nucleophilic addition of the enamine unit onto the activated
triple bond to give X. Under N2, X undergoes a demetalation/
protonation/tautomerization cascade process to deliver 4a and
regenerate the Bi(III) catalyst. When the reaction is carried out
under air, on the other hand, intermediate X is believed to
undergo an oxidation and protonation/tautomerization to give
intermediate XI. Finally, XI is oxidized in situ by air to give 3a.
To demonstrate the usefulness of 3a as an intermediate in
organic synthesis, we performed the following transformations.
First, 3a was treated with NaNO2/HCl at 0 °C for 1 h and
then at 60 °C for 3 h to afford dibenzo[a,c]acridine 5 in a yield
of 64%. Upon treatment with LiAlH4, 5 could be transformed
into its debenzoylation counterpart 6 in 72% yield (Scheme
5a). These transformations are valuable since dibenzo[a,c]-
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02323.
Experimental procedures, mechanism studies, data, and
1
copies of H and 13C NMR spectra of all products
(PDF)
Accession Codes
CCDC 2008500 and 2008507 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 5. Structural Elaborations of 3a
AUTHOR INFORMATION
Corresponding Authors
■
Bin Li − Henan Key Laboratory of Organic Functional Molecules
and Drug Innovation, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Collaborative
Innovation Center of Henan Province for Green Manufacturing
of Fine Chemicals, School of Chemistry and Chemical
Engineering, School of Environment, Henan Normal University,
Xinxiang, Henan 453007, China; Email: libin@htu.edu.cn
Xuesen Fan − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, School of Environment, Henan Normal
acridine derivatives possess remarkable biological activities and
electronic properties.10 Notwithstanding of their importance,
reliable methods for their synthesis are rare.11 As another
aspect, 3a was treated with diluted H2SO4, NaNO2/NaN3, and
1,2,4-trichlorobenzene sequentially to furnish a synthetically
and pharmaceutically important indazolo[2,3-a]quinoline
derivative 7 (Scheme 5b).12,13
Finally, a gram-scale reaction of 1a (6 mmol) was also tried
under the optimal conditions for the formation of 4a. It turned
D
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Organic Letters
University, Xinxiang, Henan 453007, China; orcid.org/
pubs.acs.org/OrgLett
Letter
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0000-0002-2040-6919; Email: xuesen.fan@htu.cn
Authors
Ruixue Jia − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, School of Environment, Henan Normal
University, Xinxiang, Henan 453007, China
Xinying Zhang − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, School of Environment, Henan Normal
University, Xinxiang, Henan 453007, China; orcid.org/
0000-0002-3416-4623
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02323
(4) (a) Kumar, C. V. S.; Puranik, V. G.; Ramana, C. V. InCl3-
Mediated Addition of Indole to Isatogens: An Expeditious Synthesis
of 13-deoxy-Isatisine A. Chem. - Eur. J. 2012, 18, 9601. (b) Guchhait,
S. K.; Chaudhary, V.; Rana, V. A.; Priyadarshani, G.; Kandekar, S.;
Kashyap, M. Oxidative Dearomatization of Indoles via Pd-Catalyzed
C−H Oxygenation: An Entry to C2-Quaternary Indolin-3-ones. Org.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
̌
Lett. 2016, 18, 1534. (c) Zhang, C.; Li, S.; Bures, F.; Lee, R.; Ye, X.;
■
Jiang, Z. Visible Light Photocatalytic Aerobic Oxygenation of Indoles
and pH as a Chemoselective Switch. ACS Catal. 2016, 6, 6853.
(d) Deng, Z.; Peng, X.; Huang, P.; Jiang, L.; Ye, D.; Liu, L. A
Multifunctionalized Strategy of Indoles to C2-Quaternary Indolin-3-
ones via a TEMPO/Pd-Catalyzed Cascade Process. Org. Biomol.
Chem. 2017, 15, 442. (e) Yarlagadda, S.; Sridhar, B.; Subba Reddy, B.
V. BINOL-Phosphoric Acid Catalyzed Oxidative Asymmetric Aza-
Friedel-Crafts Alkylation of Indoles with 3-Indolinone-2-carboxylates
Promoted by DDQ. Chem. - Asian J. 2018, 13, 1327. (f) Zhou, X.-Y.;
Chen, X.; Wang, L.-G.; Yang, D.; Li, J.-H. Ruthenium-Catalyzed
Oxidative Dearomatization of Indoles for the Construction of C2-
Quaternary Indolin-3-ones. Synlett 2018, 29, 835. (g) Jiang, X.; Zhu,
B.; Lin, K.; Wang, G.; Su, W.-K.; Yu, C. Metal-Free Synthesis of 2,2-
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(5) (a) Liu, R.-R.; Ye, S.-C.; Lu, C.-J.; Zhuang, G.-L.; Gao, J.-R.; Jia,
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We are grateful to the National Natural Science Foundation of
China (NSFC) (21572047), Program for Innovative Research
Team in Science and Technology in Universities of Henan
Province (20IRTSTHN005), Key Project of Science and
Technology of Henan Province (192102310412), and 111
Project (D17007) for financial support.
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