Photoinduced Copper-Catalyzed Regioselective Synthesis of Indoles: Three-Component Coupling of Arylamines, Terminal Alkynes, and Quinones

Article abstract of DOI:10.1002/anie.201506579

The first successful example of a visible-light-induced copper-catalyzed process for C-H annulation of arylamines with terminal alkynes and benzoquinone is described. This three-component reaction allows use of a variety of commercial terminal alkynes as coupling partners for the one-step regioselective synthesis of functionalized indoles. Moreover, the current process represents a sustainable and atom-economical approach for the preparation of complex indoles from easily accessible starting materials under visible-light irradiation, without the need for expensive metals and harsh reaction conditions.

Full text of DOI:10.1002/anie.201506579

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International Edition: DOI: 10.1002/anie.201506579
German Edition: DOI: 10.1002/ange.201506579
Heterocycles
Hot Paper
Photoinduced Copper-Catalyzed Regioselective
Synthesis of Indoles: Three-Component Coupling of
Arylamines, Terminal Alkynes, and Quinones
Arunachalam Sagadevan, Ayyakkannu Ragupathi, and Kuo Chu Hwang*
Angewandte
Chemie
13896
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Abstract: The first successful example of a visible-light-
À
induced copper-catalyzed process for C H annulation of
arylamines with terminal alkynes and benzoquinone is
described. This three-component reaction allows use of
a variety of commercial terminal alkynes as coupling partners
for the one-step regioselective synthesis of functionalized
indoles. Moreover, the current process represents a sustainable
and atom-economical approach for the preparation of complex
indoles from easily accessible starting materials under visible-
light irradiation, without the need for expensive metals and
harsh reaction conditions.
T
he indole scaffold is an important structural component of
numerous natural products, pharmaceutical drugs, and
organic materials.[1] Over the last 100 years, an array of
powerful approaches have been developed for the synthesis of
the indole moiety, including the classical Fischer indole
synthesis.[2] Among them, palladium/copper-catalyzed ani-
line–alkyne cyclizations are the predominent methods for
constructing indoles.[3] However, these methods mostly
require prefunctionalized anilines (Scheme 1a). To address
this challenge, researchers have recently focused on exploit-
Scheme 1. Transition-metal-catalyzed indole synthesis.
[11]
À
À
À
and various C N, C S, and C O cross-coupling reactions.
À
ing the C H annulation of easily accessible arylamines
We have recently reported a visible-light-induced CuCl-
[4]
À
À
À
without a C X bond. Thus far, expensive metal catalysts
catalyzed process for efficient C C and C N cross-coupling
reactions.[12] We envisioned that these visible-light-mediated
couplings may proceed through the initial photoexcitation of
copper(I) acetylides.[12a,d] Herein we report the discovery of
the first visible-light-induced three-component coupling
(TCC) of aniline, alkynes, and benzoquinone to assemble
such as palladium, ruthenium, and rhodium complexes play
a central role in the preparation of indoles by C H annulation
À
of internal alkynes with aryl amines (Scheme 1b).[5] Despite
the increased attention, common disadvantages of all these
methods include: a) the requirement of stoichiometric
amounts of oxidants, such as, Cu(OAc)2, AgOAc, PhI(OAc)2,
and tBuOOH, thus leading to the generation of undesired
waste, b) the need for high-reaction temperatures, c) the fact
that the reaction works only with internal alkynes, and
d) generation of unsymmetrical aryl indoles as a mixture of
regioisomers. Recently, copper complexes have been success-
À
indoles through a C H annulation under mild reaction
conditions (room temperature) by using a simple and inex-
pensive process (5% CuCl, without the use of external
oxidants; Scheme 1c). The current process is unprecedented,
and is complementary to well-known copper-catalyzed A3-
coupling reactions (amine, alkyne, and aldehyde).[13] Further-
more, installation of a phenol functional group on the indole
ring is attractive because the phenol motif not only allows
fully employed as an inexpensive catalyst/mediator for
[6]
À
oxidative C H alkynylation of arenes/heretoarenes, as
À
well as for intra- and intermolecular coupling reactions
a broad range of transformations, including Ullmann C O
[7]
through C H functionalization. Despite the many advan-
couplings,[14] electrophilic aromatic substitutions (alkylation
and acylation), and other processes/transformations,[15] but
also facilitates stronger b-binding affinity toward estrogen
receptors (ER) than does an unfunctionlized phenyl ring.[16]
The current work represents the very first literature method
for single-step regioselective synthesis of 3-p-hydroxyphenyl-
substituted indoles (Scheme 1c).
À
À
tages, a copper-catalysis strategy for C H annulation of
arylamines with terminal or internal alkynes remains unex-
plored for either photochemical or thermal (dark) conditions.
Thus, further the discovery of new types of copper-catalyzed
C H annulations using unactivated terminal alkynes as
a coupling partner, especially under low-energy visible-light
irradiation, remains unexplored.
Visible-light-activated photoredox catalysis has recently
emerged as a novel activation mode and an alternative to
thermal metal-catalyzed reactions.[8] Moreover, photoiniti-
ated copper redox catalysis has been shown to be an
À
In an initial study (Table 1), we were delighted to find that
visible-light irradiation of aniline (1a), phenylacetylene (2a),
and benzoquinone (3a) in CH3CN/CH3OH (1:1 v/v) in the
presence of CuCl (5 mol%) at 258C for 6 hours furnished the
corresponding indole 4a in 55% yield[17] (Table 1, entry 1).
After optimization, we found that in CH3OH, the product
yield is improved to 85% (entry 2), and the presence of water
(0.5 mL) does not affect the reaction (entry 8). However,
other solvents were examined and poor yields were obtained
(entries 5–7). Different copper catalysts were screened, and
CuX (X = Cl or Br) turns out to be the most effective catalyst
(entries 2 and 3). Control experiments show that, in the
absence of either light, CuCl ,or benzoquinone, no reaction
occurs (entries 10–12). Meanwhile, the reaction can be
inexpensive and potentially useful method for alkyne–azide
cycloaddition (CuAAC) reactions,[9] C C cross-couplings,
[10]
À
[*] Dr. A. Sagadevan, A. Ragupathi, Prof. K. C. Hwang
Department of Chemistry, National Tsing Hua University
Hsinchu (Taiwan, R. O. C.)
E-mail: kchwang@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506579.
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Table 1: Optimization of reaction conditions.[a]
Table 2: Scope of arylamines (1).[a]
Entry
[Cu] Catalyst
Solvent
Yield [%][b]
1
2
3
4
5
6
7
CuCl
CuCl
CuBr
CuCl2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
none
CuCl
CH3CN/MeOH (1:1)
MeOH
MeOH
CH3CN/MeOH (1:1)
CH3CN
EtOH
DMF
MeOH/H2O
MeOH
MeOH
MeOH
55
85
85
0
10
76
trace
74
60
0
8[c]
9[d]
10[e]
11[f]
12[g]
n.r
n.r
MeOH
[a] Unless otherwise noted, reaction conditions are as follows; 1a
(0.5 mmol), 2a (0.55 mmol), 3a (0.6 mmol), [Cu] catalyst (5 mol%), and
solvent (7 mL). The mixture was irradiated with blue LEDs (power
density: 40 mWcmÀ2 at 460 nm) for 6 h in a N2 atmosphere. [b] Yield of
the isolated product. [c] 0.5 mL water was added. [d] Reaction irradiated
with an ambient white light bulb for 15 h (power density: 8 mWcmÀ2 at
460 nm). [e] Reaction conducted in the dark at 608C. [f] In the absence of
[Cu] catalyst. [g] In the absence of benzoquinone (3a). n.r.=no reaction,
DMF=N,N-dimethylformamide.
[a] Standard reaction conditions. Yield of product isolated after purifi-
cation by column chromatography on silica gel. [b] The reaction was
performed on a 5 mmol (0.96 g) scale (a preparative scale).
Table 3: Scope of terminal alkynes (2).[a]
conducted using other light sources (ambient white light;
entry 9), however blue LEDs provided better yields.
By using the optimal reaction conditions (Table 1,
entry 2), we explored the scope of the reaction with various
substituted anilines (Table 2). In most of cases, both electron-
rich and electron-neutral anilines proceed smoothly to afford
the corresponding indole products (4a–e; 85 to 88% yield).
However, the reaction of a meta-substituted aniline (1d)
resulted in the formation of a mixture of regioisomers
(inseparable). It was found that the current protocol was
well tolerated by a wide range of substrates, such as, 1-
naphthyl amine, 2-naphthyl amine, and 2-amino-anthracene,
and facilitates the expedient synthesis of complex indoles (4i–
k). Notably, a halo-substituted aniline selectively underwent
À
the C H annulation (4 f), and the competitive Sonogashira
reaction[12a,18] does not occur. Moreover, anilines containing
ester and benzylnitrile moieties could also be employed to
generate indole scaffolds in good to moderate yields (4g,h). In
addition, the current process can be readily scaled up to
a gram scale (0.96 g); 1.56 grams of 4k (81% yield) can be
obtained after 12 hours of irradiation with blue LEDs at room
temperature (see Scheme S1 in the Supporting Information).
Next, the scope with respect to the terminal alkynes was
examined under the optimized reaction conditions. As shown
in Table 3, a wide range of phenylacetylenes, including both
elecrton-rich and electron-deficient groups, are amenable to
the current protocol (5b–h, 82 to 88%; 5k–p, 54-88% yield).
Notably, the indole 5d has good binding affinities to the
estrogen receptor (ER).[19] In addition, aryl alkynes bearing
halo-substituents (2i,j) can readily react with 1a and 3a to
[a] Standard reaction conditions. Yield of the product isolated after
purification by column chromatography on silica gel.
yield the desired indoles (5i,j). In general, copper-catalyzed
À
oxidative C H annulation reactions involving terminal
alkynes often suffer from homocoupling by-product forma-
tion.[6] In the current three-component C H annulation
À
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reactions, no alkyne homocoupling product was observed.
Besides aryl alkynes, other terminal alkynes, including bulky
naphthalenyl, heteroaryl, cyclohexyl, and octyl alkynes, also
underwent the reaction to furnish the desired indoles in good
yields (5q–u). Notably, terminal alkynes, which are challeng-
ing coupling partners for rhodium-, palladium-, nickel-, and
ruthenium-catalyzed indole synthesis,[5] proved to be amena-
ble to the current system.
As shown in Table 4, substituted benzoquinones (6b–h)
also successfully underwent the reaction to provide indole
products in good yields (56–84% yields). It is notable that
unsymmetrical benzoquinones, such as 2-methyl benzoqui-
none (3b) and 2-chloro benzoquinone (3e), selectively
To study the reaction mechanism, a set of control experi-
ments were carried out [Eq. (2)–(4)]. First, we synthesized the
copper(I) phenylacetylide 2a’[21] and investigated its reaction
with 1a and 3a under standard reaction conditions. The
copper(I) phenylacetylide 2a’ (1.2 equiv) reacted with 1a to
afford the indole product 4a in 54% upon isolation [Eq. (2)].
Notably, copper-catalyzed 1,3 nucleophilic addition of aryl
amines to benzoquinone is already known in the literature.[7b]
However, in the absence of 2a under the standard reaction
conditions, the reaction of 1a with 3a does not occur
[Eq. (3)]. This result indicates that in situ generated copper(I)
phenylacetylide might be the key light-absorbing catalyst.
Furthermore, the reaction of 1a, 2a, and 3a in the presence of
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) was examined
under the standard reaction condition. The formation of 4a
was completely inhibited [Eq. (4)], thus suggesting that
a radical process might be involved in the reaction. Finally,
we found that benzoquinone quenches the excited state of the
copper(I) phenylacetylide (7), as indicated by luminescence
quenching experiments (see Figure S7 in the Supporting
Information).
À
underwent the C H annulation reaction to deliver a single
regioisomer (6b, 6d, and 6e–h).
Table 4: Scope of benzoquinones (3).[a]
Moreover, the presence of 1 mm benzoquinone reduces
the lifetime of 7 from 15.95 ms to 11.05 ms (see Figure S8 in the
Supporting Information). Since copper is not a heavy metal
and does not have strong spin-orbital coupling character,
most organocopper metal complexes stay at the singlet
excited state upon photoexcitation, and thus have short
excited-state lifetimes, typically shorter than 1 ms. However,
some photoexcited copper metal complexes do undergo
intersystem crossing to become triplet excited states. As
a result of spin-forbidden transition, the triplet excited-state
metal complexes have long excited-state lifetimes, ranging
from 1 microsecond to milliseconds.[22] These results suggest
that the photoexcited triplet 7 would undergo single-electron
transfer (SET) to benzoquinone, and thus would have formed
the benzoquinone radical anion 9 (see Scheme 2), and the
copper(II) phenylacetylide 8. The presence of 9 and a copper-
(II) species were further confirmed by EPR measurements
under standard reaction conditions at 77 K. However, no
EPR signal was observed in either the dark or in the absence
of CuCl or benzoquinone (see Figures S1–S6 in the Support-
ing Information). Moreover, we have compared the redox
potentials of copper(I) acetylide and quinones. Based on
cyclic voltammetry (CV), the redox potential of 2a’ was
determined to be À2.048 VSCE in CH3CN (see Figure S11 in
the Supporting Information). The excitation and emission
profiles of in situ generated 2a’ are shown in Figure 1. A
bandgap energy of E00 = 2.52 eV was obtained from the
[a] Standard reaction conditions. Yield of the product isolated after
purification by column chromatography on silica gel.
The structures of 4a, 4k, 6b, and 6g were confirmed by
single-crystal X-ray diffraction.[20] A selected example of N-
methyl aniline (1l) coupled with 2a and 3a to afford the
target indole (4l) in a lower yield of 22% [Eq. (1)], but N-
phenyl aniline (1m) does not work in the current system.
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furnish the copper(I)-coordinated alkyne complex 10. It is
known that free CuCl could coordinate to the disubstitued
alkyne moiety through a p-alkyne complex,[27] thereby
enhancing its electrophilicity. The resulting electron-deficient
triple bond then undergoes nucleophilic attack by aniline (at
the b-carbon atom) to provide the complex 11, thus leading to
formation of the complex 12. Friedel–Crafts-type cyclization
of 12 generates the intermediate 13,[28] and finally affords the
desired indole product (4a) by the liberation of the catalyst
CuCl through re-aromatization process.
In conclusion, we have developed a novel visible-light
mediated CuCl-catalyzed three-component coupling of ani-
lines, terminal alkynes, and benzoquinones, thus leading to
facile one-step regioselective synthesis of functionalized
indoles at room temperature. Overall, 39 examples are
described with substrates having a wide range of functional
groups, including, halides, methoxy, alkyl, ester, nitro, cyano,
acetanilide, etc. The current method can be readily scaled up
to a preparative (1–2 g) scale. This transformation represents
Figure 1. Excitation and emission spectra of in situ generated 2a’ in
CH3OH.
intersection of 2a’ emission and excitation profiles. This redox
potential is sufficiently higher than that (À0.92 VSCE) for 1,4-
benzoquinone.[23] Therefore, SET from a photoexcited triplet
copper(I) phenylacetylide to benzoquinone is exothermic and
can occur spontaneously.
Based on the above mechanistic data, a plausible mech-
anism is proposed in Scheme 2. Initially, photoirradiation of
in situ generated 2a’[24] by blue LEDs (see UV-visible
À
the first example of a copper-catalyzed C H annulation of
arylamines with terminal alkynes and provides substituted
indoles as a single regioisomer. From a synthetic point of view,
the current method represents a sustainable and atom-
economical approach to construct indoles from easily acces-
sible starting materials under visible-light irradiation, without
the need for expensive metals and external oxidants or
additives.
Experimental Section
General procedure: A dry test tube (20 mL) containing 5 mol% CuCl
was evacuated and purged with dry N2 gas. And then 7 mL of dry
CH3OH was added by syringe, followed by aniline (0.5 mmol) and the
terminal acetylene (0.55 mmol). A yellow suspension was formed and
then benzoquinone (0.60 mmol) added was added. The reaction
mixture was irradiated with blue LEDs (40 mWcmÀ2 at 460 nm) at
room temperature (25–288C) until completion of the reaction
(monitored by TLC). The reaction mixture was diluted with 40%
ethyl acetate in n-hexane and stirred for 10 min. The mixture was
filtered through Celite and silica gel pads, and washed with ethyl
acetate. The filtrate was concentrated and the residue was purified by
column chromatography on silica gel to collect the indole product.
Acknowledgements
Scheme 2. A proposed reaction mechanism.
This work was supported by the Ministry of Science and
Technology, Taiwan.
absorption spectra in Figure S10 in the Supporting Informa-
tion) produces the long-lived triplet photoexcited 7 (t =
15.95 ms) by ligand to metal charge transfer (LMCT).[12d,25]
Then, the singlet excited state of copper(I) phenylacetylide
undergoes facile intersystem crossing to the triplet excited
state,[12b, 26] and then undergoes a SET process with benzoqui-
none (BQ; 3a) to afford the benzoquinone radical anion 9
and the copper(II) phenylacetylide 8, as evidenced by EPR
measurements (see Figures S1 and S3 in the Supporting
Information). The radical anion 9 (benzoquinone radical
anion) has the propensity to attack onto the CuII-phenyl-
acetylide 8 to regenerate the copper(I) catalyst[11a,12b] and
Keywords: annulations · copper · heterocycles ·
photochemistry · radicals
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13896–13901
Angew. Chem. 2015, 127, 14102–14107
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Received: July 16, 2015
Published online: September 4, 2015
Angew. Chem. Int. Ed. 2015, 54, 13896 –13901
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13901