Three-component domino reactions for regioselective formation of bis-indole derivatives

Article abstract of DOI:10.1021/co3001428

A microwave-assisted regioselective reaction dealing with arylglyoxal monohydrate, diverse N-aryl enaminones, and indoles to achieve 3,2′- and 3,3′-bis-indoles by varying a substituted indole substrate is reported. The 2-unsubstituted indoles resulted in the 3,2′-bis-indole skeleton, whereas indoles bearing a methyl or phenyl group at C2 led to the 3,3′-bis-indoles with simultaneous formation of three sigma-bonds. The procedures feature excellent regioselectivity, short reaction times, convenient one-pot manner, and operational simplicity.

Full text of DOI:10.1021/co3001428

Research Article
pubs.acs.org/acscombsci
Three-Component Domino Reactions for Regioselective Formation
of Bis-indole Derivatives
Li-Ping Fu,† Qing-Qing Shi,† Yu Shi,† Bo Jiang,* and Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu
Normal University, Xuzhou, 221116, P.R. China
S
* Supporting Information
ABSTRACT: A microwave-assisted regioselective reaction
dealing with arylglyoxal monohydrate, diverse N-aryl enami-
nones, and indoles to achieve 3,2′- and 3,3′-bis-indoles by
varying a substituted indole substrate is reported. The 2-
unsubstituted indoles resulted in the 3,2′-bis-indole skeleton,
whereas indoles bearing a methyl or phenyl group at C2 led to
the 3,3′-bis-indoles with simultaneous formation of three
sigma-bonds. The procedures feature excellent regioselectivity,
short reaction times, convenient one-pot manner, and operational simplicity.
KEYWORDS: multicomponent domino reaction, regioselective synthesis, indolation, enaminones, bis-indoles
intermediates, thereby minimized waste generation rendering
the transformations green.12 Recently, we have developed a
series of new, multicomponent domino reactions (MDRs) that
provide easy access to multiple functionalized ring structures of
chemical and pharmaceutical importance.13 We would like to
report another new synthetic strategy for the regioselective
preparation of polyfunctionalized bis-indoles through a three
component domino reaction. This reaction was achieved from
the readily available starting materials such as arylglyoxal
monohydrate (Figure 2), N-aryl enaminones (Figure 3), and
INTRODUCTION
■
The search for an efficient construction of indole skeletons of
chemical and biomedical importance has been an active theme
in organic synthesis.1,2 Structurally diverse bis-indole skeletons
commonly exist in nature and are represented by topsentins,3
isoborreverine,4 and indirubin (Figure 1)5 which exhibit a
Figure 1. Structures of some bis-indole alkaloids.
broad range of biological activities. For example, topsentins and
its dihydro analogues have shown antitumor, antiviral, and anti-
inflammatory activities,3 isoborreverine has exhibited antima-
larial activity,6 and indirubin and its analogues were found to
target glycogen synthase kinase-3 (GSK-3),7 and aurora
kinases,8 and acted as cyclin-dependent kinase (CDK)
inhibitors6 and dioxin receptor.9 Thus, these complex
architectures have inspired our interest in creating method-
ologies for their total synthesis.
Multicomponent domino reactions (MDRs) for use in total
syntheses of natural products10 or natural-like structures were
one of the key tools that allow the creation of several bonds in a
single operation and offer remarkable advantages like
convergence, operational simplicity, and facile automation.11
These reactions can avoid time-consuming and costly processes
for purification of various precursors and isolation of
Figure 2. Diversity of arylglyoxal monohydrate 1{1−6}.
indoles (Figure 4) in HOAc under microwave heating (Scheme
1). The great aspect of the present domino reaction is shown
by the fact that the synthesis of new polyfunctionalized bis-
indoles, which connected through C3−C2′ bond of the two
indole units, and its polyfunctionalities at C3 and C2′ positions
were readily achieved via HOAc-promoted three-component
Received: November 27, 2012
Revised: January 16, 2013
Published: January 22, 2013
© 2013 American Chemical Society
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ACS Combinatorial Science
Research Article
Figure 3. Diversity of enaminones 2{1−12}.
Table 1. Optimization for the Synthesis of 4{1,1,1} under
MW
Figure 4. Diversity of substituted indoles 3{1−5}.
Scheme 1. Regioselective Synthesis of Bis-Indoles 4
a
c
entry
solvent
DMF
T (°C)
time (min)
yield (%)
1
2
3
4
5
6
7
80
80
80
80
80
100
20
20
20
20
20
20
20
CH2Cl2
EtCOOH
HCOOH
HOAc
trace
42
58
84
HOAc
63
b
HOAc
80
60
67
reaction in a single step, and regioselectivity was controlled well
in an intermolecular manner.
a
b
Microwave (MW) Irradiation. Classical Heating (CH) conditions.
c
Isolated yields.
RESULT AND DISCUSSION
■
Indole, possessing three nucleophilic centers, is an important
type of nucleophile. Indeed, C-nucleophilicity at the C3
position is stronger than that of the C2 position, which has
been described widely in the literature.2 The utilization of its
C2 position as a nucleophilic center to the preparation of 2-
substituted indoles has been neglected. Arylglyoxal monohy-
drate, as readily available 1,2-biacceptors,14 can provide two
active sites (C−O and CO bonds), which can be attacked by
the electron-rich β-C atom and NH group in β-enaminones15
for C−C and C−N bonds formation via [3 + 2] cyclization
mechanism. Meanwhile, nucleophilic substitution between
indole and arylglyoxal monohydrate occurs, in which
functionalities at C3 and C2′ positions of two indole units
can be realized through the control of an intermolecular
hydrogen bond. Based on the above analysis, we started this
study by subjecting a preformed N-p-ClPh substituted
enaminones 2{1} to the reaction with phenylglyoxal mono-
hydrate 1{1} and indole 3{1} in HOAc at 80 °C under
microwave irradiation. The reaction smoothly gave the desired
product 4{1,1,1} in 84% chemical yield. Indole 3 has two C-
electrophilic centers, which may lead to two different products
4{1,1,1} or 5{1,1,1} (Table 1). In this reaction, only product
4{1,1,1} was isolated; it is obvious that the reaction has high
regioselectivity. An overview of the synthetic details is
summarized in Table 1. This result prompted us to further
optimize reaction conditions. The same reactions were
performed in dimethylformamide (DMF) and CH2Cl2, and
both cases scarcely proceeded. We reasoned that the acidic
solvent can be used as a Brønsted acid promotor and improve
the yield of the desired product 4{1,1,1}. Next, this chemistry
was carried out in EtCOOH and HCOOH. An incomplete
reaction was observed using EtCOOH as an acidic solvent
while HCOOH gave the 58% yield of 4{1,1,1}. Therefore,
HOAc proved to be a best case (Table 1, entry 5).
Subsequently, the reaction was performed in HOAc and
repeated many times at different temperatures in a sealed vessel
under microwave (MW) irradiation for 20 min. The lower yield
of product 4{1,1,1} (63%) was obtained as the reaction
temperature was increased to 100 °C. Subsequently, the
identical reaction was investigated under classical heating (CH)
conditions at 80 °C for 60 min, providing the desired product
4{1,1,1} in 67% chemical yield (Table 1, entry 7).
With these optimized conditions in hand, we examined the
scope of this MDR process by using various easily available
starting materials. As revealed in Table 2, the reaction resulted
in corresponding desired products in good to excellent yields.
The regioselective transformation is easy to perform simply by
subjecting a mixture of arylglyoxal monohydrate, various
enaminones 2, and indoles 3 in acetic acid to microwave
heating. As shown in Table 2 (entries 1−6), we explored the
enaminone substrate scope, phenylglyoxal monohydrate 1{1}
and indole 3{1} were used as model substrates, with the results
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Table 2. Domino Synthesis of 3,2′-Bis-indoles 4 under MW
Table 3. Domino Synthesis of 3,3′-Bis-indoles 4 under MW
a
entry
4
time/min
yield/%
entry
4 and 4′
time/min
yield /%
1
4{1,1,1}
4{1,2,1}
4{1,3,1}
4{1,4,1}
4{1,5,1}
4{1,6,1}
4{1,1,2}
4{1,2,2}
4{1,3,2}
4{1,4,2}
4{7,4,2}
4{1,5,2}
4{1,6,2}
4{1,5,3}
4{1,6,3}
4{1,7,1}
4{1,8,1}
4{1,9,1}
4{1,10,1}
4{1,11,1}
4{1,12,1}
4{1,7,2}
4{1,8,2}
4{1,9,2}
4{1,10,2}
4{1,12,2}
20
30
20
30
24
22
30
25
28
30
28
26
28
32
28
36
38
30
36
30
30
36
34
40
36
32
84
71
81
82
77
85
83
86
81
76
88
89
83
70
65
76
75
80
63
78
82
79
73
79
68
72
1
4{1,1,4}
4{1,2,4}
4{1,4,4}
4{1,5,4}
4{1,6,4}
4{1,2,5}
4{2,1,5}
4{2,2,5}
4{3,1,5}
4{3,5,5}
4{4,2,5}
4{4,5,5}
4{5,5,5}
4{1,7,5}
4{1,9,5}
4{1,12,5}
30
32
30
30
32
38
35
38
34
30
28
30
38
40
38
36
73
60
79
80
78
70
78
75
79
83
78
88
71
73
75
70
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
10
11
12
13
14
15
16
a
Isolated yield of two isomers.
Scheme 2. Domino Synthesis of 3,3′-Bis-indoles 4
indicating the tolerance of some functional groups in the
substrates 2 including ether and C−Cl (or F, Br) bonds. 4-
Nitrophenylglyoxal monohydrate amine 1{7} was also suitable
for this three-component domino reaction (entry 11). The 5,5-
unsubstituted enaminones 2{7−12} were subjected to this
reaction providing corresponding bis-indoles 4{1,7,1}-4{1,12,1}
in 63−82% yields. Next, we further examined the generality of
this system. Various indole substrates 3 bearing either electron-
donating or electron-withdrawing functional groups such as
bromo or methoxyl were used to give the corresponding
polysubstituted bis-indoles through metal-free intermolecular
indolation. It is worth noting that functional groups like
bromide and chloride were well tolerated. These functional
groups provide ample opportunity for further functional group
manipulations, for example, by modern cross-coupling
reactions. This result is significant since there is no literature
precedent for the synthesis of such highly functionalized 3,2′-
bis-indoles.
Since bis-3-indoles show important bioactivities as selective
inhibitors of cyclin-dependent-kinases (CDK4)16 and anti-
cancer agents,17 we turned our attention to investigate several
differently 2-substituted indoles to synthesize a series of
polyfunctionalized bis-3-indoles. Next, the reactions of
arylglyoxal monohydrate 1, N-aryl enaminones 2 with 2-
substituted indoles 3{4,5} in acetic acid were performed under
the conditions described above for a short period (28−40 min)
(Table 3). In all these cases, the reactions proceeded smoothly
to give the corresponding bis-3-indoles in good yields of 60−
88% (Scheme 2). The bulkiness of 2-phenyl indoles 3{5} did
not hamper the reaction process. Several different N-
substituents were compared and substituents bearing elec-
tron-withdrawing (4-ClPh 2{1} and 4-FPh 2{2}) or electron-
donating (4-MeOPh, 2{6}) groups were found to be suitable
for this domino reaction. Impressively, the 1H NMR analysis of
the products 4{1,1,4}−4{1,12,5} indicates the presence of a
mixture of two isomers resulting from generation of axial chiral
molecules due to large steric hindrance of 2-substituted indoles
(Scheme 2). The ratio of the isomers was in 1:1 as
1
demonstrated by H NMR integration and HPLC analysis of
the crude mixture (See Supporting Information). Indeed, the
protocol provides a straightforward pathway to construct highly
functionalized 3,2′- and 3,3′-bis-indoles. The resulting
functionalities of these 3,2′- and 3,3′-bis-indoles offer a great
flexibility for further structural modifications. These special
3,2′- and 3,3′-bis-indoles may be directly useful for drug design,
discovery, and development.
In all cases, the functional complexity of the resulting
products from this new reaction illustrates the remarkable
regioselectivity of the sequence starting from very common and
easily accessible starting materials. The structural elucidation
and the attribution of regioselectivity were unequivocally
determined by NMR spectroscopic analysis. To further
ascertain structures of the newly synthesized bis-indole
derivatives (4), single crystals of 4{1,5,3} and 4{4,2,5} were
successfully obtained with their structures (Figures 5 and 6)
unambiguously confirmed by X-ray diffraction analysis (see
Supporting Information).
Similar to our previous multicomponent domino process,12
the present reaction also showed the following attractive
characteristics: (1) the environmentally friendly process in
which water is the major byproduct; (2) the convenient workup
which only needs simple filtration; (3) readily available starting
materials of arylglyoxal monohydrate, preformed enaminones
and indoles. Moreover, during these domino processes, the
formation of indole skeleton and its indolation were readily
achieved via regioselective three-component domino reaction
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Research Article
Scheme 3. The reaction involves the ring closure cascade
process that consist of initial protonation (1 to A), nucleophilic
substitution (A to B), and subsequent second protonation (B
to C), second nucleophilic substitution (C to D and E),
intramolecular cyclization and final dehydration (E to 4). This
regioselectivity is attributed to intramolecular hydrogen bond of
intermediate B.
In conclusion, we have developed a three-component
domino reaction (arylglyoxal monohydrates, enaminones, and
indoles) as a novel method for regioselective synthesis of 3,2′-
and 3,3′-bis-indoles by varying the substituted indole substrate.
The reaction under acidic condition proceeds by selective [3 +
2] heterocyclization obtaining bis-indoles 4 in good yields,
showing that the synthetic route allows us to build blocks of
bis-indole derivatives with a wide diversity of substituents. This
methodology is simple, practical, and is a regioselective
alternative synthetic route to obtain good yields of bis-indole
derivatives by microwave irradiation. Features of this strategy
include the mild condition, convenient one-pot operation, and
excellent regioselectivity. Further investigations are in progress
in our laboratory to evaluate the process with a broader range
of substrates, and to synthesize more complex products and test
their biological activity.
Figure 5. X-ray structure of product 4{1,5,3}.
EXPERIMENTAL PROCEDURES
■
Microwave irradiation was carried out with Initiator 2.5
Microwave Synthesizers from Biotage, Uppsala, Sweden.
Melting points were determined in open capillaries and were
uncorrected. IR spectra were taken on a FT-IR-Tensor 27
spectrometer in KBr pellets and reported in cm−1. H NMR
1
spectra were measured on a Bruker DPX 400 MHz
spectrometer in DMSO-d6 with chemical shift (δ) given in
ppm relative to TMS as internal standard. HRMS (ESI) was
determined by using microTOF-QII HRMS/MS instrument
(BRUKER). X-ray crystallographic analysis was performed with
a Siemens SMART CCD and a Siemens P4 diffractometer.
Typical Procedure for the Preparation of Bis-indoles
4{1,1,1}. In a 10-mL reaction vial, phenylglyoxal monohydrate
1{1} (0.153 g, 1 mmol), 3-((4-chlorophenyl)amino)-5,5-
dimethylcyclohex-2-enone 2{1} (0.25g, 1 mmol), indole 3{1}
(0.12 g, 1 mmol), and HOAc (1.5 mL) were mixed and then
capped (the automatic mode stirring helped the mixing and
uniform heating of the reactants). The mixture was heated for
20 min at 80 °C under microwave irradiation. Upon
Figure 6. X-ray structure of product 4{4,2,5}.
in a one-pot operation. Up to three sigma-bonds were formed
accompanied by the cleavage of CO and C−O bonds of the aryl
glyoxal via intermolecular indolation (Scheme 3).
On the basis of all the above results, a possible mechanism
has been proposed for the formation of bis-indoles as shown in
Scheme 3. Reasonable Mechanism for the Product 4
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Research Article
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Buchner filtration, subsequently washed with two different
̈
solvents of ethanol and ethylether in sequence to give the pure
white solid (0.39 g, yield 84%). m.p.: 270−272 °C.
IR (KBr, ν, cm−1): 3287, 1650, 1494, 1424, 1362, 1132,
1
1093, 1015, 834, 739, 700, 638, 519; H NMR (400 MHz,
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DMSO-d6) δ: 10.91 (s, 1H, NH), 7.48 (d, J = 8.8 Hz, 2H,
ArH), 7.31−7.27 (m, 3H, ArH), 7.14 (s, 1H, ArH), 7.04 (t, J =
3.2 Hz, 3H, ArH), 6.98−6.95 (m, 4H, ArH), 6.75 (t, J = 7.2 Hz,
1H, ArH), 2.59 (s, 2H, CH2), 2.31 (s, 2H, CH2), 1.08 (s, 6H,
CH3); 13C NMR (100 MHz, DMSO-d6) δ: 192.2, 143.4, 136.1,
135.6, 132.7, 132.7, 131.4, 130.5, 129.9, 129.2, 127.6, 127.3,
126.9, 125.2, 120.3, 119.9, 118.1, 117.6, 113.9, 111.0, 1.7.6,
52.8, 36.5, 34.5, 28.1; HRMS (ESI): m/z calcd for:
C30H25ClN2NaO, 487.1548 [M+Na]+, found: 487.1544.
ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic data in CIF format. Further details on the
experimental procedures and results. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Caledonia. LV. Isoborreverine and borreverine, bis(indole) alkaloids
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AUTHOR INFORMATION
Corresponding Author
*Phone: 0086-516-83500065. Fax: 0086-516-83500065. E-mail:
jiangchem@jsnu.edu.cn (B.J.), laotu@jsnu.edu.cn (S.-J.T.).
■
(5) (a) Hoessel, R.; Leclerc, S.; Endicott, J.; Noble, M.; Lawrie, A.;
Tunnah, P.; Leost, M.; Damiens, E.; Marie, D.; Marko, D.;
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active constituent of a Chinese antileukemia medicine, inhibits cyclin-
dependent kinases. Nat. Cell Biol. 1999, 1, 60−67. (b) Kritsanida, M.;
Magiatis, P.; Skaltsounis, A.-L.; Peng, Y.; Li, P.; Wennogle, L. P.
Synthesis and antiproliferative activity of 7-azaindirubin-3′-oxime, a 7-
aza Isostere of the natural indirubin pharmacophore. J. Nat. Prod.
2009, 72, 2199−2202.
(6) (a) Fernandez, L. S.; Jobling, M. F.; Andrews, K. T.; Avery, V. M.
Antimalarial activity of natural product extracts from papua new
guinean and australian plants against plasmodium falciparum.
Phytother. Res. 2008, 22, 1409−1412. (b) Fernandez, L. S.;
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Author Contributions
†These authors have equal contributions to this work.
Funding
We are grateful to financial support from the National Science
Foundation of China (Nos. 21232004, 21072163, and
21102124), PAPD of Jiangsu Higher Education Institutions,
the NSF of Jiangsu Education Committee (11KJB150016), and
Qing Lan Project of Jiangsu Education Committee (No.
12QLG006).
Notes
The authors declare no competing financial interest.
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