Palladium-Catalyzed Tandem Regioselective Oxidative Coupling from Indoles and Maleimides: One-Pot Synthesis of Indolopyrrolocarbazoles and Related Indolylmaleimides

Article abstract of DOI:10.1021/acs.orglett.5b02944

An efficient Pd(II)-catalyzed approach for the direct synthesis of indolo[3,2-a]pyrrolo[3,4-c]carbazole-6,8-diones has been developed from both free and protected (NH) indoles and maleimides via a regioselective tandem oxidative coupling reaction. The yie

Full text of DOI:10.1021/acs.orglett.5b02944

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Tandem Regioselective Oxidative Coupling
from Indoles and Maleimides: One-Pot Synthesis of
Indolopyrrolocarbazoles and Related Indolylmaleimides
Yu-Long An,† Zhen-Hua Yang,† He-Hui Zhang,† and Sheng-Yin Zhao*,†,‡
†Department of Chemistry, Donghua University, Shanghai 201620, China
‡State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: An efficient Pd(II)-catalyzed approach for the
direct synthesis of indolo[3,2-a]pyrrolo[3,4-c]carbazole-6,8-dio-
nes has been developed from both free and protected (NH)
indoles and maleimides via a regioselective tandem oxidative
coupling reaction. The yields are moderate to excellent. In
addition, 2-substituted indoles are suitable substrates in this
protocol, leading to the formation of indolylmaleimides. The
present methodology provides a concise route to highly functionalized indolopyrrolocarbazole derivatives.
he indolocarbazole nucleus is incorporated in a wide range
of natural products,1 pharmaceuticals,2 photorefractive
been reported continuously.15,16 Itami et al. demonstrated the
formation of carbazoles from N-protected indoles via a Diels−
Alder reaction using trimetallic and bimetallic systems of Pd−
Cu−Ag.16a Most carbazole syntheses are successful with N-
protected indoles and remain challenging with a free (NH)
indole. Notably, during the preparation of this paper, a Pd-
catalyzed alkenylation of indoles and subsequent conversion to
the 1,3-disubstituted carbazoles appeared.16b A tandem approach
to functionlized carbazoles from indoles with alkenes via two
successive regioselctive oxidative Heck reactions followed by
thermal electrocyclization was also developed (Scheme 1).16c
T
materials, and organic dyes.3 Staurosporine was the first
discovered indolocarbazole from Actinomyces. A variety of
indolocarbazole analogues have since been isolated and
confirmed.1 Most of them have shown to be effective protein
kinase inhibitors, offering tremendous promise in anticancer
activity. However, staurosporine has significant specificity to
kinases in the human body.4 Previous researchers modified the
structure of staurosporine to obtain novel skeletons, such as
indolylmaleimides and indolopyrrolocarbazoles.5 However, al-
most all of the indolopyrrolocarbazoles isolated from nature are
indolo[2,3-a]pyrrolo[3,4-c]carbazoles; little attention has been
paid to its isomers, such as indolo[3,2-a]pyrrolo[3,4-c]carbazole-
6,8-dione.6 Fonseca et al. reported the indolo[3,2-a]pyrrolo[3,4-
c]carbazole-6,8-dione in the synthesis of arcyriaflavin-A with low
yield.6a Subsequently, Bergman and Janosik finished the
synthesis from indole6b and 2,3′-biindolyl,6c respectively. The
yields were still unsatisfactory (<26%). Derivatives were
obtained as byproducts in the synthesis of indolylsuccinimides
with 1−2% yield.6d,e Thus, an efficient synthetic methodology is
highly desirable for this process.
Scheme 1. Synthesis of Carbazoles from Indoles
Palladium-catalyzed oxidative cross-coupling reactions have
drawn much interest due to their C−C bond formations via
direct C−H functionalization.7−16 Indeed, they have been widely
utilized in the synthesis of heterocycles through oxidative cross-
coupling of alkenes with arenes8 or heteroarenes,9 acrylates with
vinyl carboxylates,10 2-oxazolones with olefins,11 heteroarenes
with alkynes,12 and arenes with arenes.13
Gaunt et al. reported indole alkenylation in a formal C−H/C−
H coupling fashion in 2005, elegantly achieving C-2- or C-3-
selective introduction of various alkenyl groups to indoles.14a In
recent years, research topics on Pd-catalyzed intermolecular
alkenylation of indoles or pyrrole via C−H functionalization have
Nevertheless, a literature survey revealed that the synthesis of
both indolopyrrolocarbazoles and indolylmaleimides via oxida-
tive Heck reactions has not been reported. In our continued
research program directed toward the synthesis of indolylsucci-
mides and related indolylmaleimides in this area,17 and intrigued
Received: October 12, 2015
© XXXX American Chemical Society
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a
Table 1. Optimization of Reaction Conditions
b
d
entry
catalyst (mol %)
oxidant (equiv)
solvent
DMSO
temp (°C)/time (h)
yield (%)
1
2
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
PdCl2/15
Cu(OAc)2/1.5
Ag2CO3/1.5
AgNO3/1.5
80/18
80/24
80/24
80/24
80/24
80/36
80/18
80/24
80/18
rt/120
120/18
80/18
80/18
80/18
56
17
15
0
DMSO
3
DMSO
4
DDQ/1.5
DMSO
5
O2
DMSO
0
6
Cu(OAc)2/0.5
Cu(OAc)2/1.5
Cu(OAc)2/1.5
Cu(OAc)2/1.5
Cu(OAc)2/1.5
Cu(OAc)2/1.5
Cu(OAc)2/1.5
Cu(OAc)2/1.5
Cu(OAc)2/1.5
DMSO
13
34
trace
75
27
58
16
25
62
7
DMF
8
dioxane
c
c
c
c
9
DMF/DMSO
DMF/DMSO
DMF/DMSO
DMF/DMSO
10
11
b
12
c
13
14
AcOH/DMSO
c
DMF/DMSO
a
b
Reactions were performed using indole 1a (1.5 mmol), maleimide 2a (0.75 mmol), catalyst, and oxidant in 3 mL of solvent. Indole 1a (0.75
c
d
mmol) and maleimide 2a (1.5 mmol) were used. v/v = 1:5. Isolated yield based on maleimide.
by the advantages of using direct Pd-catalyzed C−H function-
alization for C−C bond formation, we envisioned that free or
protected (NH) indoles could be linked with the CC bond of
maleimides via oxidative Heck reactions. Herein, we report the
direct synthesis of indolo[3,2-a]pyrrolo[3,4-c]carbazole-6,8-
diones and 3-(2-substituted indol-3-yl)maleimides via Pd-
catalyzed regioselective tandem cross-coupling reactions.
without any catalyst, the reaction did not generate the desired
product at all.
With the optimal reaction conditions in hand, the scope of
various indoles 1 and maleimides 2 was explored to probe the
general protocol (Table 2). Maleimide 1a reacted with indoles to
Table 2. Substrate Scope for the Synthesis of
a
Initially, we began our study with indole 1a and maleimide 2a
to screen the reaction conditions in the presence of 10 mol % of
Pd(OAc)2 as the catalyst and 150 mol % of Cu(OAc)2 as the
oxidant (Table 1). Compound indolo[3,2-a]-pyrrolo-[3,4-c]-
carbazole-6,8-dione 3a was obtained in 56% yield in DMSO at 80
°C (Table 1, entry 1). Product 3a was fully characterized by
spectrum analysis, which was identical to the data reported in the
literature.6a,b Next, to improve the yield, our research plan was
returned to screen various oxidants and solvents to get the
optimal reaction conditions (Table 1). Unfortunately, poor
results were obtained when oxidants such as Ag2CO3 and AgNO3
were used (Table 1, entries 2 and 3). DDQ and O2 barely worked
as oxidant (Table 1, entries 4 and 5). Decreasing the dosage of
Cu(OAc)2 gave a poor yield of product 3a around 13% (Table 1,
entry 6). The reaction did not work well using DMF and dioxane
as solvent (Table 1, entries 7 and 8). The process afforded 3a in
75% yield using a mixture of DMF/DMSO (v/v, 1/5) as solvent
(Table 1, entry 9). The reaction could work at room temperature
for a long time and gave a low yield (27%, Table 1, entry 10).
However, increasing the temperature to 120 °C, the reaction
became complex, and the yield decreased to 58% due to the
partial polymerization of maleimides (Table 1, entry 11). When
the ratio of indole to maleimide was decreased to 1:2, only 3a was
collected in 16% yield (Table 1, entry 12). Our results indicated 2
equiv of indoles and 1 equiv of maleimide took part in the
formation of the indolo[3,2-a]pyrrolo[3,4-c]carbazole-6,8-dione
annulations even if a large excess maleimide was used. Protonic
acid did not work well as cosolvent (Table 1, entry 13). PdCl2 as
catalyst did not improve the results (Table 1, entry 14). The
above result demonstrated that Pd(OAc)2/Cu(OAc)2 is a more
effective catalyst/oxidant in this reaction. It should be noted that
Indolopyrrolocarbazoles (3)
b
entry
1 R1, R2
H, H
2 R3
3, yield (%)
1
2
H
3a, 75
3b, 81
3c, 60
3d, 55
3e, 82
3f, 73
3g, 80
3h, 85
3i, 78
3j, 83
3k, 63
H, 5-OCH3
CH3, H
H
3
H
4
H, 5-Cl
H
5
H, 5-OCH3
H, H
CH3
CH3
Ph
Ph
Ph
Ph
Bn
6
7
H, H
8
H, 5-OCH3
H, 5-OBn
H, 7-CH3
H, H
9
10
11
a
Reactions were performed using indoles 1 (1.5 mmol) and
b
maleimides 2 (0.75 mmol). Isolated yield.
form the target products 3a−3d in 55−85% yields. Both free and
protected (NH) indoles could work well in this protocol (Table
2, entry 3). The substituent group in the indole moiety played an
important role in reaction yield. That is, an electron-rich indole
(e.g., 5-methoxylindole) had an excellent yield (Table 2, entries
2, 5, and 8), and an electron-deficient indole (e.g., 5-
chloroindole) gave a moderate yield (Table 2, entry 4). The
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substituent from (NH) maleimides showed no obvious impact
on yields (Table 2, entries 1, 6, 7, and 11). As we know, this is the
first two reported indole molecules that can react with one
maleimide molecule to produce the indolo[3,2-a]pyrrolo[3,4-
c]carbazole-6,8-diones involving in C-3/C-2 alkenylation for
indoles.
(Scheme 3). Besides product 4f with a poor yield, both
indolopyrrolocarbazoles (3a, 3l) and bisindolylmaleimides (5b,
Scheme 3. Indolylsuccinimide and Indolylmaleimide
Experiments
Subsequently, we turned our attention to investigating the
reaction of 2-substituent indoles with maleimides. First, the
maleimides were reacted with 2-substituted indoles to form 3-
indolylmaleimide products 4a−4e in 77−88% yields using the
protocol (Table 3). When 2-methylindole and maleimide were
a
Table 3. Synthesis of Indolylmaleimides
b
entry
1
1 R1
CH3
2 R2
4, 5 yield (%)
c
H
4a, 85; 5a, 5
cd
,
4a, 43; 5a, 31
4b, 77
2
3
4
5
COOC2H5
CH3
H
CH3
Ph
4c, 83
CH3
4d, 88
5c) could be obtained. Similarly, indolopyrrolocarbazoles (3g,
3m) were prepared from indolylmaleimides and indoles via the
Pd-catalyzed protocol in 22 and 32% yields, accompanied by
bisindolylmaleimides (5d, 5e) with 37 and 42% yields. In
addition, 2,3′-biindolylsuccinimides 9 were synthesized and
subjected to oxidative dehydrogenation by SeO2. Products 3
were obtained around 50% yield instead of compounds 10.19 We
suppose that compounds 10 could be formed and quickly
undergo thermal electrocyclization to provide indolopyrrolo-
carbazoles 3. Compounds 9 were also performed in Pd-catalyzed
protocol to give products 3 in about 75% yield (Scheme 3).
Finally, we conducted the reactions of indolylmaleimides with
maleimides in the protocol (Scheme 4). The dipyrrolocarbazo-
CH3
Bn
4e, 80
a
Reactions were performed using indoles 1 (0.75 mmol) and
b
c
maleimides 2 (0.75 mmol). Isolated yield. 1.5 mmol of indole 1
was used. In DMSO.
d
treated in ratio of 2:1 in this protocol, 4a was obtained in 85%
yield and 5a was formed around 5% yield (Table 3, entry 1).
Interestingly, when DMSO was used as the solvent, 4a was
obtained in 43% yield, and bisindolylmaleimide 5a was isolated in
31% yield (Table 3, entry 1). It seemed that DMF could prevent
the formation of bisindolylmaleimide in a cosolvent. Thus, when
the ratio of indole to maleimide was decreased to 1:1,
indolylmaleimides 4 were obtained in moderate to excellent
yields in cosolvent conditions (Table 3, entries 2−5).
To understand the sequence of the reaction and identify the
possible reaction intermediates, additional experiments were
carried out. First, 2,3′-biindolyl 8 could not be obtained when
indole 1a solely reacted under the optimized conditions (Scheme
2). It was not subjected to Diels−Alder reaction with maleimides
Scheme 4. Diels−Alder Reactions
Scheme 2. Indole and Indolylsuccinimide Experiments
letetraones 7a and 7b were obtained in 68 and 84% yields,
respectively. It explains the fact that Pd-catalyzed alkenylation
occurs initially at the C-3-positon of indole. However, we had
used 1 equiv of indole to react with 2 equiv of maleimide via the
Pd-catalyzed protocol, leading to 3a in a yield of 16%. 7a was not
observed (Table 1, entry 12), which may be because C−H
functionalization occurs rather than the Diels−Alder reaction.
These results indicate (i) the second C−H activation starts as
soon as the β-hydride elimination of the first oxidative Heck
reaction; (ii) the second C−H activation occurs exclusively on
the indole fraction; (iii) thermal electrocyclization occurs after
the second oxidative Heck reaction.
Based on above evidence, the plausible pathway is proposed in
Scheme 5. DMSO could prevent the precipitation of Pd0 with its
Pd coordination ability in the reaction.14a,20 The desired
products 3 were synthesized directly from indoles and
maleimides via regioselective double successive oxidative Heck
to provide indolopyrrolocarbazoles.18 3-Indolylsuccinimide 6a
and 6b, obtained from indole and maleimides catalyzed by
ZnCl2,17b could be well oxidized in the Pd-catalyzed protocol,
leading to the formation of 3-indolylmaleimides 4f and 4g in 81
and 86%, respectively (Scheme 2). Indeed, the reactions of
indoles 1a and 1b with 3-indolylsuccinimide 6a were conducted
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Scheme 5. Plausible Mechanism for the Synthesis of
Indolopyrrolocarbazoles and Indolylmaleimides
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reactions and thermal electrocyclization. The first oxidative
coupling reaction took place via regioselective C-3 palladation
(I), maleimide insertion (II), and β-hydride elimination to form
compouds 4 (R4 ≠ H). Simultaneously, the following fast
intramolecular regioselective C-2 palladation of II (R4 = H) was
performed, and the reduced Pd(0) complex was oxidized by
Cu(OAc)2 to generate Pd(II). The intermediates 10 were
formed via the second oxidative coupling reaction (III−IV).
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molecular ring closure to provide products 3. When 2-
substituent indoles were used in this protocol, compounds 4
were produced and subjected to the second oxidative coupling
reaction to provide compounds 5.
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direct synthesis of indolopyrrolocarbazoles from both free and
protected (NH) indoles and maleimides via a regioselective
oxidative cross-coupling reaction has been successfully devel-
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regioselective C-2,C-3 alkenylation of indole and will lead to
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02944.
Experimental details, characterization data of all com-
pounds, and copies of 1H and 13C NMR spectra (PDF)
(15) Guo, T.; Jiang, Q.; Yu, Z. Org. Chem. Front. 2015, 2, 1361.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: syzhao8@dhu.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We acknowledge financial support from Shanghai Manucipical
Natural Science Foundation (No. 15ZR1401400), the Open
Funds from the State Key Laboratory of Bioorganic & Natural
Products Chemistry (2013) and Donghua University (CUSF-
DH-D-2015048).
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DOI: 10.1021/acs.orglett.5b02944
Org. Lett. XXXX, XXX, XXX−XXX