Internal Oxidant-Triggered Aerobic Oxygenation and Cyclization of Indoles under Copper Catalysis

Article abstract of DOI:10.1002/anie.201508076

A concise synthesis of pyrazolo[1,5-a]indole derivatives by copper-catalyzed aerobic oxygenation and cyclization of indoles with oxime acetates is described. This protocol represents an elegant example of N-1, C-2, and C-3 tri-functionalization of indoles

Full text of DOI:10.1002/anie.201508076

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International Edition: DOI: 10.1002/anie.201508076
German Edition: DOI: 10.1002/ange.201508076
Indole Oxygenation
Internal Oxidant-Triggered Aerobic Oxygenation and Cyclization of
Indoles under Copper Catalysis
Huawen Huang,* Jinhui Cai, Xiaochen Ji, Fuhong Xiao, Ya Chen, and Guo-Jun Deng*
Abstract: A concise synthesis of pyrazolo[1,5-a]indole deriv-
atives by copper-catalyzed aerobic oxygenation and cycliza-
tion of indoles with oxime acetates is described. This protocol
represents an elegant example of N-1, C-2, and C-3 tri-
functionalization of indoles in one-pot. Mechanistic studies
indicate the reaction proceeds through a radical procedure.
Oximes as an internal oxidant have been demonstrated to be
a driver to initiate aerobic oxidation, which provides a new
oxidative pattern for C-H functionalization even with high
atom- and step-economy.
I
ndole is a privileged structure among pharmacological
compounds and natural products.[1] Consequently, the func-
tionalization of indoles to introduce chemical functional
groups around the indole ring is still an active field of research
in synthetic chemistry.[2] Numerous catalytic systems dedi-
cated to N-1, C-2, or C-3 mono-functionalization of indoles
have been developed to prepare a broad range of function-
alized indoles.[3] Di-functionalization of indoles, including
indole-involved cycloaddition, was frequently performed at
the C-2 and C-3 positions, which gave convenient access to
significant indole-fused heterocycles or other di-functional-
ized indoles.[4] N-1 and C-3 di-functionalization of indoles
were also discovered.[5] To our knowledge, however, examples
of N-1, C-2, and C-3 tri-functionalization of indoles in one pot
are rather rare.[6] The key challenge may be attributed to the
fact that chemoselectivity can be difficult to control in a one
pot reaction. You and co-workers described a Ru/TsOH co-
catalyzed allylic dearomatization/cyclization/allylic amination
cascade reaction of indoles, enabling N-1, C-2, and C-3 tri-
functionalization of indoles in one pot.[6a] The asymmetric
synthesis was realized later under an iridium-based catalytic
system.[6b] This multi-functionalization strategy is of great
significance for providing facile access to highly functional-
ized indoles with step-economy, and thereby improved overall
efficiency.
À
Scheme 1. C H functionalization by internal or/and aerobic oxidation.
TM=transition metal catalyst.
challenge of elusive oxygen activation remains an issue. In
this field, copper catalysts are powerful reagents to engage
molecular oxygen in organic synthesis owing to their abun-
dant valence states and the affinity with oxygen.[7] As a result,
a large number of facile copper-based catalytic systems have
been developed for aerobic synthesis.[8] In recent years,
oximes as an internal oxidant were found to be versatile
building blocks (Scheme 1b),[9] especially in copper-catalyzed
systems.[10] While in most cases, single-electron transfer (SET)
is a basic process in copper-based aerobic oxidation,[7d] we set
out to design oxime-based aerobic transformations under
copper catalysis, in which the radical intermediate derived
from the internal oxidant oximes would trigger external
aerobic oxidation of the desired reactant. The strategy of
internal/external co-oxidation with oxygen would provide
À
a specific paradigm for oxidative C H functionalization even
with high activity and high atom-economy, and moreover this
synergistic effect may achieve high levels of chemo- and
regio-selectivity. Based on this conception, a range of simple
organic chemicals have been treated with oxime acetates in
copper/oxygen-based system in our initial attempts. Herein,
we describe an internal oxidant-triggered aerobic oxygen-
ation and cyclization of indoles with oximes (Scheme 1c),
which enables N1, C2, and C3 tri-functionalization of indoles
in a one-pot manner and, more importantly, provides a concise
route to pharmacologically significant pyrazolo[1,5-a]indole
derivatives.[11]
With our continuing interest in the functionalization of
indoles,[12] 2-phenyl-1H-indole 1a and acetophenone oxime
acetate 2a were chosen as the model system to explore the
reaction conditions (Supporting Information, Table S1–S4).[13]
The final optimized reaction conditions include indole and
oxime (1.2 equiv) with 15 mol% of CuCl2 in 1,4-dioxane
Molecular oxygen is well feted as an ideal oxidant and
À
oxygenating reagent in organic synthesis. Direct C H func-
tionalization by aerobic oxidation with molecular oxygen is
a fascinating topic of research (Scheme 1a), however the
[*] Dr. H. Huang, J. Cai, Dr. X. Ji, Dr. F. Xiao, Y. Chen, Prof. Dr. G.-J. Deng
Key Laboratory of Environmentally Friendly Chemistry and
Application of Ministry of Education
College of Chemistry, Xiangtan University
Xiangtan 411105 (China)
E-mail: hwhuang@xtu.edu.cn
gjdeng@xtu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508076.
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(0.2m) under 1 atm O2 at 808C for 4 h, affording 3aa in 77%
isolated yield. With these optimized conditions in hand, the
scope and generality of the aerobic oxygenation and cycliza-
tion were next probed. Firstly, various substituted acetophe-
none oxime acetates were subjected to the copper-catalyzed
aerobic system (Table 1). Generally, the aromatic methylox-
oximes 2u and 2v produced furyl and thienyl pyrazolo[1,5-
a]indoles (3au–3av) in good yields (62% and 85%, respec-
tively; entries 21–22). Vinyl oxime 2w also worked, albeit in
a moderate yield (entry 23). Finally, we found either aliphatic
oxime 2x or non-methyl oximes 2y–z could transfer into the
desired products on the basis of GC-MS analysis with very
low yield (entries 24–26), however, no purified products could
be obtained after column chromatography.
Table 1: Oxime scope for the cyclization.[a]
Subsequently, a range of indoles were subjected to this
copper/O2-based system (Scheme 2). 2-Phenyl-substituted
Entry
Oximes (2)
Product (3)
Yield [%][b]
1
2
3
4
5
6
7
8
2a (R=H)
2b (R=4-Me)
2c (R=4-tBu)
2d (R=4-iBu)
2e (R=4-OMe)
2 f (R=4-F)
2g (R=4-Cl)
2h (R=4-Br)
2i (R=4-I)
2j (R=4-NO2)
2k (R=4-Ph)
2l (R=3-OMe)
2m (R=3-Cl)
2n (R=3-Br)
2o (R=3-NO2)
2p (R=3-CF3)
2q (R=2-Cl)
2r (R=2-NO2)
2s (R=3,4-Cl2)
2t
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
77
74
83
71
86
67
73
80
54
43
73
72
81
67
58
74
66
76
84
37
62
85
41
15[c]
6[c]
18[c]
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
3at
3au
3av
3aw
3ax
3ay
3az
2u
2v
2w
2x
2y
2z
[a] Reactions were conducted on a 0.2 mmol scale relative to 1.
[b] Isolated yields are given. [c] GC analysis using dodecane as the
internal standard.
imes screened reacted smoothly to give the corresponding
pyrazolo[1,5-a]indoles (3aa–3as) in moderate to good yields
(Table 1, entries 1–19), regardless of the functional groups at
the para-, meta-, or ortho-positions. A large range of func-
tional groups on the benzene ring, such as alkyl (2b–d),
methoxyl (2e and 2l), fluoro (2 f), and trifluoromethyl (2p)
were all tolerated well. Both the steric and electronic effects
of the substituents are not apparent, however, the oximes with
iodo- and nitro-groups afforded relatively low yield
(entries 9–10). While naphthyl oxime 2t furnished the corre-
sponding product 3at in 37% yield (entry 20), heteroaromatic
Scheme 2. Indole scope for the cyclization. PMP=para-MeO-C6H4.
indoles bearing alkyl, halogen, methoxyl, and trifluoromethyl
at the benzene rings are all readily accommodated, affording
the corresponding products in moderate to good yields
(Scheme 2, 3be–3me). Analogously, there seems to be no
steric effect among the benzene substituents (Scheme 2, 3he–
3me), which, in connection to the previous observation,
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indicates the copper complex may not be involved in the
other oxidants such as pyridine-N-oxide, 1,4-benzoquinone
formation of the quaternary carbon at the indole C-2 position.
2-Heteroaryl-substituted indoles, such as 2,2’-biindole and 2-
thienyl-indole, reacted smoothly, albeit in moderate yields
(Scheme 2, 3ne–3oe). An unexpected result was observed
when using 2,2’-biindole as the reactant, which has two
reaction sites, but only coupled with one molecule of reaction
partner even with excessive oxime acetate. When treated with
2-alkyl indoles, including 2-tBu-indole, the reactions afforded
the target products in good yields (Scheme 2, 3pe–3re and
3sa). While the indole with TBS-protected hydroxy group
gave a moderate yield of product 3te, free hydroxy group
decreased the yield to 34% (3ua). Notably, indoles with alkyl
chloro and alkyne functional groups were well tolerated in the
present system, delivering the corresponding pyrazolo[1,5-
a]indoles in 76% (3va) and 38% (3we) yield, respectively.
Unforunately, all of the 2-non-substituted or 2,3-disubstituted
indoles tested did not work in this system.
(BQ), and tert-butylhydroperoxide (TBHP) did not enable
this transformation. Finally, the addition of a radical scav-
enger, such as tert-butylhydroxytoluene (BHT) and BQ,
under the standard conditions prevented the desired trans-
formation completely (Scheme 3d). These observations indi-
cate the oxygenation of indole probably proceeds via a radical
intermediate.
To gain more information about the mechanism of this
reaction, electroparamagnetic resonance (EPR) experiments
were performed with the addition of the free radical spin-
trapping agent 5,5-dimethyl-1-pyrroline N-oxide (DMPO;
Supporting Information, Figures S1–S5).[13] Despite reports of
copper(I)-triggered nitrogen radical formation from oxi-
mes,[10j] we detected no signals of nitrogen radicals, but we
did observe signals corresponding to acetoxyl radical under
the present copper(II) system without 1a under Ar atmos-
phere (Supporting Information, Figure S1). Moreover, in an
O2 system, other signals appeared, albeit at low intensity,
which potentially correspond to superoxide radical (Support-
ing Information, Figure S2). Some signals of organic radicals
were readily observed in the reaction system, which are
classical 6 peaks corresponding to an alkoxyl radical (Sup-
porting Information, Figure S3), and these signals did not
disappear with the addition of superoxide dismutase (SOD;
Supporting Information, Figure S4). These results imply that
some unknown radicals, such as an alkoxyl radical, probably
exist during the reaction, and that superoxide radical may not
be involved.
For the mechanistic studies of this transformation, a series
of control experiments were conducted (Supporting Informa-
tion, Schemes S1,S2 and Table S5).[13] The reactions with 18O-
labeling molecular oxygen and water reveal that oxygen
would be involved in the indole dehydrogenation and oxy-
genation (Scheme 3a,b). Furthermore, indole derivatives 4
On the basis of the results from the mechanistic studies,[13]
a plausible reaction mechanism was proposed (Scheme 4). An
imine-[CuIII] species A forms in situ by [CuII]-mediated
reduction of ketonoximes 2, simultaneously releasing an
acetoxyl radical. Then, under an oxygen system, A would be
oxidized and converted to vinyl nitrene or an azirine
intermediate B[14] while generating peroxyl radical. On the
other hand, acetoxyl radical would seize an electron from the
electron-rich indole 1 to form intermediate C. Subsequently,
intermediate C affords indolyl radical D by isomerization and
Scheme 3. Mechanistic experiments. ND=not detected.
and 5 were often detected in the system. The two products,
however, could not produce the desired products under the
standard reaction conditions (Scheme 3c). We also performed
the reactions under a range of external oxidants in the
absence of O2. While TEMPO, which can generally serve as
an oxygenating reagent through a radical process, was found
to be effective for the reaction and H2O2 gave a low yield,
Scheme 4. Possible reaction mechanism.
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proton elimination. Also, indolyl radical D could be directly
formed by the copper/O2 treatment, which are suspected to
convert to 3-Cl-indole 4 in the absence of oxime, as well as
one of observed byproducts in the conditions optimization.
Then D traps peroxyl radical to form peroxyl intermediate E,
which could be delivered to the byproduct 5. For the fact that
5 could not transfer into our desired product under the
optimal conditions, intermediate E is supposed to participate
in the cycloaddition with azirine B.[15] The intermediate
product F would afford the final product, probably, through
an alkoxyl radical G and with the assistance of the copper
catalyst. Notably, azirine B could directly react with indole to
form 4H-pyrazolo[1,5-a]indole H, which subsequently trans-
fers into pyrazolo[1,5-a]indolone by a radical oxidation.
However, such a pathway was found to be unfavorable
because only a trace amount of the desired product was
detected when directly using azirine instead of oxime
(Supporting Information, Scheme S2d).[13] This also indicates
that the radical formed in situ from the oxime had activated
the indole.
In summary, a concise copper-catalyzed oxygenation and
cyclization of 2-substituted indoles with oximes has been
developed, providing a rapid access to complex and pharma-
cologically significant pyrazolo[1,5-a]indole derivatives. The
advantages of the present protocol include low-cost catalyst,
green oxidant, facile conditions, easy handling, and high
atom-economy. This is an elegant example of indole tri-
functionalization in which the obvious feature resides in the
internal oxidant-triggered aerobic oxygenation and annula-
tions through a radical-mediated pathway. The present co-
oxidative transformation represents a new pattern for dehy-
drogenative coupling with high efficiency, excellent chemo-
and regio-selectivities, and robust synthetic flexibility.
Detailed mechanistic studies and further applications of this
methodology are currently under way in our laboratory.
Ministry of Education of China (1337304). Particular thanks
also go to Chen Yayun for her guidance in EPR experiments.
Keywords: aerobic oxygenation · copper catalysis · cyclization ·
indoles · internal oxidants
How to cite: Angew. Chem. Int. Ed. 2016, 55, 307–311
Angew. Chem. 2016, 128, 315–319
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Experimental Section
Indole 1a (0.2 mmol, 1.0 equiv), oxime acetate 2a (0.24 mmol,
1.2 equiv), and CuCl2 (0.03 mmol, 15 mol%) were charged in
a septum capped vial (10 mL). The vial was placed under vacuum
for 10 min and then oxygen was pumped into it (approximately
10 mL, 0.4 mmol). The solvent 1,4-dioxane (1 mL, 0.2m) was added
into the vial by syringe. The reaction mixture was stirred at 808C for
4 h. The mixture was then allowed to cool down to room temperature
and flushed through a short column of silica gel with ethyl acetate,
and, after rotary evaporation, the residue was separated by column
chromatography (petroleum ether/EtOAc 15:1) to give the pure
product 3aa as a yellow solid in 77% yield. 1H NMR (400 MHz,
CDCl3, ppm) d = 7.77–7.55 (m, 7H), 7.39–7.23 (m, 6H), 7.14 (t, J =
7.2 Hz, 1H), 3.94 (d, J = 17.6 Hz, 1H), 3.51 (d, J = 17.6 Hz, 1H).
13C NMR: (100 MHz, CDCl3, ppm) d = 202.7, 162.0, 158.3, 139.9,
137.2, 131.2, 130.3, 128.8, 128.6, 128.1, 126.7, 125.6, 125.2, 124.6, 124.5,
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Received: August 28, 2015
Revised: September 25, 2015
Published online: October 20, 2015
Angew. Chem. Int. Ed. 2016, 55, 307 –311
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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