Copper-catalyzed tandem reaction of 2-alkynylanilines with benzoquinones: Efficient access to 3-indolylquinones

Article abstract of DOI:10.1039/c8ra03712d

A simple, mild, catalytic and efficient method for the straightforward synthesis of an interesting class of 2-aryl/alkyl-substituted-3-indolyl quinones in good to high yields is reported for the first time. This atom-efficient method proceeds via copper-catalyzed one-pot sequential intramolecular hydroamination (C-N bond formation) of 2-alkynylanilines followed by oxidative C-C coupling with benzoquinones.

Full text of DOI:10.1039/c8ra03712d

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Copper-catalyzed tandem reaction of 2-
alkynylanilines with benzoquinones: efficient
access to 3-indolylquinones†
Cite this: RSC Adv., 2018, 8, 22122
Raveendra Jillella and Chang Ho Oh
*
Received 30th April 2018
Accepted 4th June 2018
A simple, mild, catalytic and efficient method for the straightforward synthesis of an interesting class of 2-
aryl/alkyl-substituted-3-indolyl quinones in good to high yields is reported for the first time. This atom-
efficient method proceeds via copper-catalyzed one-pot sequential intramolecular hydroamination (C–
N bond formation) of 2-alkynylanilines followed by oxidative C–C coupling with benzoquinones.
DOI: 10.1039/c8ra03712d
rsc.li/rsc-advances
For the synthesis of 3-indolylquinones, in the past, several
approaches have been reported from indolic starting materials
Introduction
Indole scaffolds represent one of the privileged structural as efficient methodologies. For instance, in 1911, Mohlau et al.
motifs in biologically active natural products and drug mole- described this for the rst time using the reaction of benzo-
1
6
cules which have vital medicinal value. Among the family of quinone and indole, however the product was not isolated.
indole derivatives, 3-indolylquinones, mainly bis(indolyl) Later, Bu’Lock reinvestigated and isolated 3-indolylquinones
7
quinone, are a signicant structural unit in many natural with a very low yield. Subsequently, various catalytic routes
2
8
products because of their numerous biological activities.
Among these indolylquinones, asterriquinones show the most products from indoles and benzoquinones using various Lewis
potential as pharmacophores, and could be used in a wide acids such as InBr and Bi(OTf) under mild reaction condi-
were developed in this scenario. Yadav et al. reported these
3
3
range of biological activities, including the inhibition of human tions. Likewise, Park and co-workers synthesized 3-indolylqui-
3
immunodeciency virus reverse transcriptase (Fig. 1). These nones with indoles and benzoquinones using mineral acids like
9
asterriquinones mostly possess a symmetrical benzoquinone Zn(OTf)
2
and mercury reagents along with Pd(II)/Cu(OAc)
2
. In
unit containing two oppositely N1-prenylated tryptophanyl addition, 3-indolylquinones were also prepared using ultra-
moieties which are isolated from Aspergillus terreus, Chaeto- sound activation between the indole and quinone using
4
10
11
mium sp., and Pseudomassaria sp. It is worth mentioning molecular iodine as a catalyst. Very recently, Kamble et al.
demethylasterriquinone B1, described as
non-peptidyl developed 3-indolylquinones using the in situ oxidation of
a
mimetic of insulin with excellent antidiabetic activity in hydroquinone followed by C–C bonding with indole using
5
recent studies.
a combination of Ag O in H O and an Fe O /PVP–PWA catalytic
2 2 2 3 4
system. These are all reported in the literature, mainly from
indolic starting materials. Therefore, it is highly necessary to
develop an efficient catalytic and high yielding tandem protocol
that allows the quick preparation of 3-indolylquinones from
simple 2-alkynylanilines and benzoquinone as raw materials in
the presence of copper cyanide as a catalyst (Scheme 1).
Interestingly, the transition metal-catalyzed tandem one-pot
annulation of o-alkynylanilines followed by in situ trapping with
suitable electrophiles has become an extremely useful protocol
12
for the construction of 2,3-difunctionalized indoles. Previ-
13
ously, we reported an efficient silver catalyzed domino process
for the synthesis of 2,3-disubstituted indoles from alkyne imino
ethers. Furthermore, the copper catalysed three-component
synthesis of 2-[(2-alkyl-1H-indol-3-yl)methylene]malonates
from o-alkynylanilines, triethyl orthoformate and diethyl
malonoate followed by Sc-catalyzed intramolecular Friedel–
Cras reactions to the corresponding heterocyclic compounds
Fig. 1 Biologically active asterriquinone derivatives.
Department of Chemistry and Research Institute of Natural Science, Hanyang
University, Seoul 04763, South Korea. E-mail: changho@hanyang.ac.kr
†
Electronic supplementary information (ESI) available. CCDC 1844842. For ESI
and crystallographic data in CIF or other electronic format see DOI:
0.1039/c8ra03712d
14
was also reported. Based on these studies, we believe that it is
1
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a
Table 1 Optimization of the reaction conditions
0
b
3aa +3aa
Entry
Catalyst
Solvent
Time [h]
Yield %
c
1
2
3
4
5
6
7
8
9
CuCN
CuCN
CuCN
CuI
CuCl
Cu(OTf)
Cu(NO
Cu(OAc)
Cu(OAc)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCE
DMSO
Toluene
2
H O
MeOH
ACN
DMF
DMF
DCM
DCM
12
12
12
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
12
(20 + 55)
(52 + 30)
80 + <5
d
64 + trace
68 + trace
<5 g
Scheme 1 Methods of synthesis of 3-indolylquinones.
2
2
)
3
ND
58
2
$H
2
O
2
60 g
possible to access 3-indolylquinones using the same protocol
with benzoquinone as a good electrophile. Despite considerable
progress observed in the synthesis of 3-indolylquinones,
10
11
12
InCl
3
ND
e
NaAuCl
Pd(OAc)
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
Iodine
PTSA
4
$3H
2
O
57f
2
60
ND
g
nobody has reported on the transition-metal-catalyzed hetero- 13
1
1
1
1
1
4
5
6
7
8
<5 g
NDg
ND
cyclization reaction between 2-alkyanilines and quinones.
Nevertheless, this combination constitutes an interesting class
of 3-quinone-substituted indole scaffolds.
<5 g
However, the cyclization of 2-alkynylanilines followed by
ND
functionalization at the C
3
-position of free (N–H) indoles is 19
25 g
ND
20
a highly complex step because it oen suffers from competing
e
15
21
NaAuCl
Pd(OAc)
4
$3H
2
O
78f
reactions of amines and alkynes with benzoquinones which
are predominantly expected to form the addition products of
benzoquinone and amines under acidic conditions. However,
the present study primarily exploits indole formation instead of
22
2
65
a
All the reactions were performed with 1a (38.6 mg, 0.2 mmol), 2a (2
equiv.) at 100 C under air. All the yields are isolated yields.
ꢀ
b
c
d
e
Reaction with 1 eq. of 2a. f Reaction with 1.5 equiv. of 2a. Reaction
side reactions with benzoquinone and this concept is reported with 2 mol% gold catalyst. Reaction with 5 mol% palladium catalyst.
g
ND denotes not determined.
for the rst time in the presence of benzoquinone.
Results and discussion
salts such as CuI, CuCl, Cu(OTf)
2
, Cu(NO
2
)
3
, Cu(OAc)
2
,
Cu(OAc) $H O, InCl , NaAuCl $3H O and Pd(OAc)
2
2
3
4
2
2
, as well-
We commenced optimization studies using readily available o-
alkynylaniline 1a and benzoquinone 2a (1 eq.) as coupling
partners. The tandem heterocyclization reaction was performed
in the presence of 20 mol% CuCN as a Lewis acid catalyst at
known alkyne bond activators, were tested for this tandem
cyclization process as shown in Table 1 (entries 4–12) using
DMF as a solvent. Among them, CuCN is observed as the best
catalyst to form the desired product with 80%, yield (entry 3).
The obtained results from screening reactions of 2-alkynylani-
line (1a) and benzoquinone (2a) with common organic solvents
such as toluene, DCE, MeCN, THF, DMSO and MeOH revealed
that none of the solvents (except DMF) could promote the
tandem process signicantly (entries 13–18, Table 1). However,
ꢀ
a temperature of 100 C in DMF under an air atmosphere.
Pleasingly, a new class of 3-indolyl quinone (3aa, 20%) and 3-
0
indolyl hydroquinone (3aa , 55%) were obtained as a mixture of
products with moderate yield, aer 12 h (entry 1, Table 1).
Pleasantly, when the same reaction was conducted with 1.5
equivalents of 2a, surprisingly, the yield of 3aa was 52% and
0
0
4 2 2
NaAuCl $3H O (2 mol%) and Pd(OAc) (5 mol%) afford 72%
that of 3aa was 30%. These products (3aa & 3aa ) can be
distinguished by proton & carbon NMR spectroscopy: 3aa shows
and 60% yields, respectively, at room temperature in 12 h, with
DCM as the solvent (entry 21, 22, Table 1). Aer optimization of
the reaction conditions, we established an efficient route to the
formation of 3-indolylquinones. The optimal reaction condi-
tions are 1a (0.2 mmol) and 2a (0.4 mmol) as the reactants with
0
two C]O signals in the carbon NMR spectrum but for 3aa , the
corresponding C]O peaks disappear.
From this study, we observed that formed 3-indolylhy-
droquinone undergoes oxidation in the presence of excess
benzoquinone. Hence, in the same reaction repeated with 2eq.
of 2a, the yield of 3aa signicantly improved to 80% with a trace
ꢀ
CuCN (0.04 mmol) and DMF (2 mL) at 100 C for 12 h.
With the optimized reaction conditions in hand, we next
explored the efficiency and generality of this tandem hetero-
cyclization process using the reactions of several 2-(aryl/
alkylethynyl) aniline derivatives with various quinones using
0
amount of 3aa (entry 3). These results prompted us to examine
various Lewis-acid promoted tandem heterocyclization reac-
tions in more detail. In this context, a variety of transition-metal
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CuCN as an efficient Lewis acid catalyst. These results are such as methyl, phenyl and methoxy benzoquinone (2b–2e) and
summarized in Table 2. First, various 2-alkyl-substituted (phenyl, symmetrical benzoquinones such as 2,6-ditertiary butyl and 2,5-
ethyl benzene, cyclohexyl, hydroxyl alkane, biphenyl, benzyl) dibromo benzoquinone (2g and 2h). The tandem coupling of 2-
ethynylanilines (1a–f) were reacted efficiently with benzoquinone alkynyl aniline with aliphatic substituted unsymmetrical ben-
to give the desired products 3aa–3fa in good to excellent yields zoquinones (methyl, methoxy) affords a mixture of isomers with
(52–90%). Contrarily, N-acylated 2-alkynyl aniline (2j) does not a 1 : 1 ratio of 3ac and 3ad in 80% and 82% yields, respectively.
undergo the domino cyclization due to the low efficiency of N-acyl However, phenyl substituted unsymmetrical benzoquinone (2b)
amine donation of a loan pair of electrons to the pi activated under the present reaction conditions exclusively gives the regio
electron decient alkyne. Halogen substitute alkynyl anilines like selective and more substituted side coupling product as shown
chlorine and uorine have little inuence under optimized in Table 2. Thus, these unprecedented results motivated us to
reaction conditions on the formation of the corresponding work on different 2-alkynyl anilines with 2-phenyl benzoqui-
products 3ga and 3ha in moderate yields (59% & 63%). Both alkyl nones under the present conditions and good to excellent yields
and aryl substituted ethynylaniline (1i) produce 3ia in 82% yield. were attained (3ab–3cb) and the results are shown in Table 2.
In the case of lower yields of the nal compounds, the annulated Additionally, reactions with 1,4-naphthoquinone show
indole is the main by-product along with trace amounts of the 3- moderate yields (3ae, 60%). Furthermore, the structure of
indolyl hydroquinone.
To further investigate the substrate scope, we turned our (CCDC 1844842†).
attention to examine various unsymmetrical benzoquinones However, due to the highly bulky nature of 2,6-ditertiary
compound 3fa was unambiguously conrmed by X-ray analysis
butyl substituted symmetrical benzoquinones (2ag), they
produce only the indole derivative without undergoing C–C
bond formation. On the other hand, 2,5-dibromo benzoquinone
achieves a 55% yield of 3af as shown in Table 2, along with the
intermediate indole.
Table
benzoquinones
2 Tandem cyclization of 2-alkynyl anilines with
a
At this stage, to gain an understanding of the detailed
mechanism of this reaction, several control experiments were
carried out, as demonstrated in Scheme 2. Initially, we believed
that the reaction proceeds via a 2-substituted indole derivative
(through an aminocuprate step), which then adds to benzo-
quinone in a 1,4-fashion to generate the 3-indolyl hydroqui-
nones followed by oxidation. To get a better understanding,
a couple of control experiments were performed in which 2-
phenylindole (1 equiv.) was treated with benzoquinone (2
ꢀ
equiv.) in the presence or absence of the Cu catalyst at 100 C in
DMF. In the presence of the Cu catalyst, the product 3aa is
obtained in 82% quantitative yield aer 12 h whereas in the
absence of the Cu catalyst, the present reaction does not
proceed and no products are observed even aer 24 h in DMF at
ꢀ
1
00 C.
In addition, we also investigated the standard reaction
conditions in the absence of benzoquinone and surprisingly,
a quantitative amount of anticipated products formed aer 24 h.
Based on these control experiments, a plausible mechanism
for the formation of 3-indolyl quinones was proposed as shown
a
The reaction was carried out with 1 (0.2 mmol), 2 (0.4 mmol) and
ꢀ
CuCN (20 mol%) in DMF (2 mL) at 100 C, 12 h.
Scheme 2 Control experiments.
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Acknowledgements
This work was supported by a grant from the National Research
Foundation of Korea (NRF), funded by the Korean Government,
through the Center for New Directions in Organic Synthesis
(NRF-2014R1A5A1011165).
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