Tunable synthesis of indolo[3,2- c]quinolines or 3-(2-Aminophenyl)Quinolines via aerobic/anaerobic dimerization of 2-alkynylanilines

Article abstract of DOI:10.1021/acs.orglett.9b01534

In this paper, an unprecedented selective synthesis of indolo[3,2-c]quinoline or 3-(2-aminophenyl)quinoline derivatives through Rh(III)-catalyzed stepwise dimerization of 2-alkynylanilines under aerobic or anaerobic conditions is presented. Notably, hexafluoroisopropanol is found to be a crucial solvent and promoter for the success of these reactions. In addition, the utility of the products thus obtained was showcased by their facile transformations into the pharmaceutically and photophysically significant naphthyridine derivatives.

Full text of DOI:10.1021/acs.orglett.9b01534

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tunable Synthesis of Indolo[3,2‑c]quinolines or 3‑(2-
Aminophenyl)quinolines via Aerobic/Anaerobic Dimerization of
2‑Alkynylanilines
Ruixue Jia, Bin Li, Rong Liang, Xinying Zhang,* and 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 University, Xinxiang, Henan 453007,
China
S
* Supporting Information
ABSTRACT: In this paper, an unprecedented selective syn-
thesis of indolo[3,2-c]quinoline or 3-(2-aminophenyl)quinoline
derivatives through Rh(III)-catalyzed stepwise dimerization of
2-alkynylanilines under aerobic or anaerobic conditions is
presented. Notably, hexafluoroisopropanol is found to be a
crucial solvent and promoter for the success of these reactions.
In addition, the utility of the products thus obtained was
showcased by their facile transformations into the pharmaceuti-
cally and photophysically significant naphthyridine derivatives.
catalyst with good compatibility of diverse functional groups.15
he indolo[3,2-c]quinoline scaffold, also known as γ-
During a recent study in this regard, we serendipitously found
Tcarboline, is an important structural unit embedded in a
a novel dimerization of 2-(phenylethynyl)aniline (1a)16,17 with
plethora of natural products and synthetic compounds
the promotion of Rh(III)/HFIP under aerobic or anaerobic
conditions giving 6-phenyl-11H-indolo[3,2-c]quinoline (2a) or
2-(4-benzyl-2-phenylquinolin-3-yl)aniline (3a) in an efficient
and tunable manner (Scheme 1, eq 1). Because the
possessing a broad spectrum of pharmaceutical activities such
as anticancer activity,1a antimalarial activity,1b antiproliferative
activity,1c etc.1d (Figure 1).
Scheme 1. Different Reaction Patterns Shown by 2-
(Phenylethynyl)aniline
Figure 1. Pharmaceutically interesting indolo[3,2-c]quinolines.
controllable synthesis of different products from the same
substrates is a highly rewarding but still challenging issue for
modern synthesis, this switchable synthesis of 2a or 3a from
the reaction of 1a is not only mechanistically intriguing but
also synthetically promising. Herein, we report the detailed
results.
Our study was initiated by treating 1a with [RhCp*Cl2]2 in
toluene at 100 °C for 20 h. Under these conditions, 1a
remained intact as indicated by TLC analysis (Table 1, entry
1). A similar result was observed when the reaction was carried
Due to its importance, a number of methods based on
different synthetic strategies for the construction of the
indolo[3,2-c]quinoline scaffold have been developed.2−14
While these elegant literature protocols are generally reliable,
some of them still suffer from difficult-to-obtain starting
materials, multistep synthetic procedures, and the inherently
inevitable production of halide byproducts. Therefore, a more
convenient and sustainable synthesis of indolo[3,2-c]quinoline
derivatives is urgently needed.
In the past several years, we have engaged in the
development of novel methods for the synthesis of fused
heterocycles with biological and material significance by using
a Rh(III) complex as an easy-to-handle and highly effective
Received: May 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01534
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Formation of 2a and 3a
Scheme 2. Substrate Scope for the Synthesis of 2
b
yield (%)
entry
catalyst
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
solvent t (°C)
2a 3a
1
2
3
4
5
6
7
8
toluene
DCE
MeOH
TFE
100
100
100
100
100
100
100
100
100
100
100
100
80
−
−
−
−
21
42
65
trace
trace
53
10
−
trace
trace
trace
trace
trace
trace
trace
−
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
MeOH
TFE
[Rh(cod)Cl]2
[RhCp*(MeCN)3][SbF6]2
RhCl3·3H2O
Pd(OAc)2
RuCl3
InBr3
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
9
10
11
12
13
14
trace
26
60
82
trace
trace
trace
trace
trace
78
120
120
120
120
120
c
15
83
d
d
d
,
,
,
e
e
e
16
17
18
trace
trace
trace
19
35
a
Reaction conditions: 1a (0.3 mmol), catalyst (0.015 mmol), solvent
b
c
d
(2 mL), air, sealed tube, 20 h. Isolated yield. Under O2. Under N2.
e
For 15 h.
out in DCE (entry 2). When MeOH or trifluoroethanol (TFE)
was used as the solvent, 2a was obtained in 21% or 42% yield
(entry 3 or 4, respectively). When it was run in HFIP,18 the
yield of 2a increased to 65% (entry 5). It should be noted that
Sakai et al. have reported that under the catalysis of InBr3, 1a
predominantly underwent an intramolecular triple bond
hydroamination to afford 2-phenylindole (Scheme 1, eq
2).19a A similar result was also observed by Messerle et al.
using a combination of an Ir(III) complex with AgBF4 as the
catalyst (Scheme 1, eq 2).19b Thus, the facile formation of 2a
from 1a under the catalysis of [RhCp*Cl2]2 in HFIP
demonstrates a novel reaction pattern of 2-alkynylanilines
and provides alternative access to indolo[3,2-c]quinolines.
Further study showed that in the absence of a Rh(III) catalyst,
the yield of 2a was negligible (entry 6). Then, [Rh(cod)Cl]2,
[RhCp*(MeCN)3][SbF6]2, RhCl3·3H2O, Pd(OAc)2, and
RuCl3 were used as catalysts, but they were either much less
effective than [RhCp*Cl2]2 or totally ineffective (entries 7−11,
respectively). In the presence of InBr3, the reaction gave 2a in
a 26% yield (entry 12). Meanwhile, 2-phenylindole was
obtained in a 44% yield. A study of the effect of different
temperatures showed that the yield of 2a could be improved to
82% at 120 °C (entry 14 vs entries 5 and 13). When 1a was
treated with [RhCp*Cl2]2 in HFIP under an oxygen
atmosphere, there was no obvious change in the yield of 2a
(entry 15). To our surprise, when the reaction was run under
nitrogen, a totally different product (3a) was obtained in a 78%
yield. Under this condition, 2a was isolated in only a trace
amount (entry 16). With methanol or TFE as the solvent, the
yield of 3a decreased significantly (entry 17 or 18,
respectively).
a
Reaction conditions: 1 (0.3 mmol), [RhCp*Cl2]2 (0.015 mmol),
HFIP (2 mL), 120 °C, air, 20 h. Isolated yields.
unit of 1 can be a methyl, ethyl, methoxy, chloro, or bromo
attached at different positions of the connecting benzene ring
to afford the corresponding products 2b−2g in moderate to
good yields. Meanwhile, an electronic effect was observed in
that electron-rich substrates generally gave yields higher than
those of electron-poor ones. Next, the scope of R2 was studied,
and the results thus obtained showed that the R2 unit could be
an electron-rich or electron-deficient phenyl, naphthyl, or
thienyl moiety; the corresponding reactions took place
smoothly to give 2h−2u in yields ranging from 46% to 75%.
Moreover, it was also demonstrated that with a methyl group
as R1, the R2 unit could be a 4-methoxyphenyl, 4-chlorophenyl,
or 2-chlorophenyl unit to afford 2v, 2w, or 2x, respectively,
with a good efficiency. It should be noted herein that the
structure of 2b was confirmed by single-crystal X-ray
diffraction analysis (see the Supporting Information).
To date, althogh tremendous effort has been devoted to
searching for new methods for the preparation of quinolines,20
reports of the synthesis of 3-(2-aminophenyl)quinoline
derivatives like 3a are surprisingly rare.21 To develop a general
method for this purpose, a range of 1 bearing various R1 units
on the connecting phenyl moiety were treated with
[RhCp*Cl2]2 in HFIP under nitrogen. The results included
in Scheme 3 revealed that this reaction could tolerate methyl,
ethyl, methoxy, chloro, and bromo groups very well to give
3b−3g in good to excellent yields. When 1-(phenylethynyl)-
naphthalen-2-amine was used as the substrate, a functionalized
benzo[f]quinoline derivative 3h was obtained in a 55% yield.
Next, the suitability of 1 bearing a diversely substituted alkynyl
Next, the substrate generality for the synthesis of 2 was
explored. The results listed in Scheme 2 showed that the R1
B
DOI: 10.1021/acs.orglett.9b01534
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
On the basis of the experimental results described above, a
plausible mechanism accounting for the formation of 3a is
proposed in Scheme 5. First, coordination of Rh(III) with the
Scheme 3. Substrate Scope for the Synthesis of 3
Scheme 5. Plausible Mechanism Accounting for the
Formation of 3a
triple bond and the amino unit of 1a gives intermediate I.18
Then, 1a undergoes an intramolecular nucleophilic addition to
the activated triple bond of I to afford intermediate II, which is
then protonated by HFIP18 to give an enamine intermediate
III and release the Rh(III) catalyst. The in situ-formed
enamine moiety of III undertakes an intramolecular
nucleophilic addition to the Rh(III)-activated triple bond to
give intermediate V, most likely through the formation of
intermediate IV. Protonation of V by HFIP affords VI and
releases the Rh(III) catalyst for the next catalytic cycle. Finally,
a tautomerization occurs with VI to give 3a.
As for the formation of 5, it should follow a concerted
pathway as shown in Scheme 6.19a Initially, direct approaching
a
Reaction conditions: 1 (0.3 mmol), [RhCp*Cl2]2 (0.015 mmol),
HFIP (2 mL), 120 °C, N2, 15 h. Isolated yields.
Scheme 6. Plausible Mechanism Accounting for the
Formation of 5
moiety was probed. It turned out that with R2 as a substituted
phenyl, naphthyl, or thienyl unit, the corresponding reactions
took place successfully to give 3i−3t with yields ranging from
50% to 82%. It should be noted that substrates bearing an
alkyl-substituted alkynyl moiety could also take part in this
reaction to give 3u and 3v, but the yields were lower. Finally,
with a methyl unit as R1 and a 4-methoxyphenyl or 4-
chlorophenyl moiety as R2, 3w and 3x were obtained
efficiently. Notably, the structure of 3b was unambiguously
confirmed by single-crystal X-ray diffraction analysis (see the
Supporting Information).
and dimerization of two molecules of 4 under the activation of
Rh(III) leads to the formation of a cyclic enamine
intermediate, which then undergoes a tautomerization and
aromatization to afford 5. With 1a as the substrate, however,
the presence of a phenyl group on the terminal position of the
triple bond would prevent the two molecules from approaching
each other due to steric repulsion. As a result, the formation of
the envisioned 5′ was not observed. Instead, 1a chooses to
follow a stepwise process as shown in Scheme 3 to give 3a, a
quinoline product with a different substitution pattern
compared with 5.
To gain some insight into the reaction mechanism
accounting for the formation of 2a, the following control
experiments were carried out. First, 3a was subjected to the
standard reaction conditions for the formation of 2a. From this
reaction, 2a was formed in a 78% yield, indicating that 3a
should be a key intermediate in the formation of 2a (Scheme 7,
eq 1). A similar result was observed in the absence of
To further expand the substrate scope, 2-ethynylaniline (4)
featuring a terminal alkyne moiety was subjected to the
standard reaction conditions used for the preparation of 2 or 3.
To our surprise, both reactions afforded 2-(4-methylquinolin-
2-yl)aniline (5) rather than the initially expected 11H-
indolo[3,2-c]quinoline (6) or 2-(4-methylquinolin-3-yl)aniline
(7) (Scheme 4), indicating that under these conditions
terminal alkyne substrate 4 chooses to follow a different
reaction pathway compared with internal alkyne 1.
Scheme 4. A Different Reaction Pattern Shown by 2-
Ethynylaniline (4)
C
DOI: 10.1021/acs.orglett.9b01534
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derivatives possess remarkable pharmaceutical and fluorescent
properties,22 this synthetic protocol holds promising potential
in medicinal and material chemistry.
Scheme 7. Some Control Experiments
Finally, to further demonstrate the power of this newly
developed synthetic protocol, the preparation of 3a was carried
out on an enlarged scale of 5 mmol. It turned out that the
corresponding reaction proceeded smoothly to afford 3a in
75% yield (Scheme 10).
[RhCp*Cl2]2, indicating that the presence of [RhCp*Cl2]2 is
not crucial for the formation of 2a from 3a (Scheme 7, eq 2).
On the other hand, when this reaction was carried out under
nitrogen, 2a was formed in only a trace amount (Scheme 7, eq
3), revealing that air as an oxidant is indispensable for the
efficient transformation of 3a toward 2a.
Scheme 10. Gram Scale Synthesis of 3a
On the basis of these control experiments, a mechanism
accounting for the formation of 2a is proposed in Scheme 8.
In summary, we have developed a tunable stepwise
dimerization of 2-alkynylanilines leading to the selective
formation of indolo[3,2-c]quinoline or 3-(2-aminophenyl)-
quinoline derivatives under aerobic or anaerobic conditions by
using HFIP as the reaction medium and promoter. To the best
of our knowledge, this is the first example in which the title
compounds were synthesized from 2-alkynylanilines, and the
selectivity toward different products could be easily tuned by
switching the reaction atmosphere between air and nitrogen.
Compared with literature protocols, these novel methods have
notable features such as easily obtainable substrates, a
sustainable and cost-free oxidant, mild reaction conditions,
good chemoselectivity, and excellent atom economy. Further
studies to elucidate the reaction mechanism and to expand the
synthetic applications are ongoing in our lab.
Scheme 8. Plausible Mechanism Accounting for the
Formation of 2a from 3a
Initially, 1a undergoes a stepwise dimerization to give 3a as
shown in Scheme 3. Then, oxidation of 3a by air affords
benzoyl-substituted quinoline VII. Next, an intramolecular N-
nucleophilic addition occurs with VII to give intermediate
VIII. The following aromatization-driven elimination of
benzaldehyde occurs with VIII, most likely assisted by
HFIP,18 to give 2a. Alternatively, 3a might also directly
undergo an intramolecular N-nucleophilic addition to give
intermediate IX. Next, oxidation of IX by air affords a tertiary
alcohol intermediate X. Finally, HFIP-assisted and aromatiza-
tion-driven elimination of benzyl alcohol from X under the
assistance of HFIP affords 2a. The reaction pathways described
above were supported by a GC-MS study of the mixture that
resulted from the reaction of 3a in HFIP at 120 °C under air
for 3 h, from which the formation of benzaldehyde and benzyl
alcohol was confirmed (see the Supporting Information).
To showcase the usability of the products obtained above,
the following transformations were carried out. First, 3a was
treated with N-bromosuccinimide (NBS) in refluxing chloro-
form, from which 1,3-dibromo-5,11-diphenyldibenzo[c,h]-
[2,6]naphthyridine (8) was obtained. Next, 8 was treated
with phenylboronic acid in the presence of Pd(PPh3)4 and
K2CO3 to give 1,3,5,11-tetraphenyldibenzo[c,h][2,6]-
naphthyridine (9) (Scheme 9). As many naphthyridine
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01534.
1
Copies of H and 13C NMR spectra of all products and
the X-ray crystal structures and data of 2b and 3b (PDF)
Accession Codes
CCDC 1912734 and 1912739 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.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xuesen.fan@htu.cn.
*E-mail: xinyingzhang@htu.cn.
ORCID
Xinying Zhang: 0000-0002-3416-4623
Xuesen Fan: 0000-0002-2040-6919
Notes
Scheme 9. Structural Elaboration of 3a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are grateful to the National Natural Science
Foundation of China (NSFC) (21572047), the Plan for
■
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DOI: 10.1021/acs.orglett.9b01534
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