Synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazoles via the oxidative cyclization of bisindolylmaleimides with Pd(TFA)2/Cu(OAc)2

Article abstract of DOI:10.1002/jhet.2134

A new synthetic approach for the synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazoles based on the Cu²⁺/Pd²⁺ catalytic system is described. The optimum condition is established via a systematic screening and utilized for the synthesis

Full text of DOI:10.1002/jhet.2134

Month 2014
Synthesis of Indolo[2,3-a]pyrrolo[3,4-c]carbazoles via the Oxidative
Cyclization of Bisindolylmaleimides with Pd(TFA)2/Cu(OAc)2
*
Xuan Pan, Ke Wang, Bao He Guan, and Zhan Zhu Liu
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking
Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, People’s Republic of China
*
E-mail: liuzhanzhu@imm.ac.cn
Received July 7, 2013
DOI 10.1002/jhet.2134
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A new synthetic approach for the synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazoles based on the Cu2+/Pd2+
catalytic system is described. The optimum condition is established via a systematic screening and utilized for
the synthesis of four indolocarbazole aglycones with a satisfied yield.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
oxidant. The Pd2+ mediated oxidative cyclization approach
either required more than 2.5 equivalents of the palladium
salt or did not work as well as reported. In this article, we
report our systematic studies on a Cu(OAc)2/Pd(TFA)2
catalytic system to efficiently realize the construction of the
indolocarbazole aglycone from the bisindolylmaleimides.
The indolocarbazole alkaloids represent an interesting
class of compounds that exhibit a wide range of biological
activities [1]. The well-known members of this family are
staurosporine [2], rebeccamycin [3] and K252a [4] with
potent protein kinase C inhibitory [2b] and antitumor activ-
ities [4,5] (Fig. 1). The novel structures and significant
biological activity have attracted intensive synthetic studies
on these natural products and their structural analogues [6].
Several synthetic strategies have been reported for the
synthesis of the indolocarbazole aglycone [7]. Among
these methods, the most attractive one is the oxidation of
the corresponding bisindolylmaleimides. The conversion
of the bisindolylmaleimides to the indolocarbazoles has been
explored by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ),7a-b iodine (with or without light),7c-d and
phenyliodine bis(trifluoroacetate) (PIFA) [7e]. Further-
more, it was reported that indolocarbazoles could be
synthesized from bisindolylmaleimides with the metallic
catalysis system of Pd(O2CCF3)2 [7f], PdCl2 [7b], Pd
(OAc)2 [7g], CuCl2 [7h], or Pd(OAc)2/CuCl2. [7i]
RESULTS AND DISCUSSION
Bisindolylmaleimides 1 were readily prepared by
reaction of two equivalents of indolyllithium salts with 2,3-
dibromomaleimide as reported [8]. Oxidative cyclization of
bisindolylmaleimide under various reaction conditions was
tested, and the results are summarized in Table 1.
All of the synthetic experiments were carried out under
the protection of argon. With Pd(TFA)2 (2.5 equiv.)
as the catalyst and DMF as the solvent at 90°C for 4 hours,
the reaction gave the desired product in 87% yield (entry 1).
When Pd(TFA)2 was replaced with PdCl2 (2.5 equiv.) or
Pd(OAc)2 (2.5 equiv. ), the yields decreased sharply
(entries 2 and 3). The results showed that, of the three
palladium catalysts, Pd(TFA)2 was the best catalyst. In
the case of Pd(TFA)2 (0.1 equiv.) as the catalyst, some
auxiliary oxidants were screened in order to reduce the
amount of the palladium salt. The results showed that Cu
(OAc)2 was more efficient than CuCl2 or FeCl3 (entries
4–6), which illustrated the importance of the matching of
both the cations and the anions of the oxidant agents. The
amount of the Pd(TFA)2 catalyst and the variety of
solvents were also screened in the presence of Cu(OAc)2
However, our synthetic efforts in constructing
indolocarbazole skeleton from bisindolylmaleimide
explored some disadvantages for the reported synthetic
methods. For example, with iodine as the oxidant, the
substrate concentration must be very dilute, and it was
difficult to carry out the operation in a large scale. With
DDQ as the oxidant, the product was difficult to isolate.
The yields were very low when CuCl2 was used as the
© 2014 HeteroCorporation

X. Pan, K. Wang, B. H. Guan, and Z. Z. Liu
Vol 000
Scheme 1. Synthesis of indolocarbazole from bisindolylmaleimides.
Figure 1. Structures of three indolocarbazole alkaloids.
Scheme 2. Synthesis of indolocarbazole derivatives using the optimized
Cu2+/Pd2+ catalytic system.
(3.0 equiv.) at 90°C (entries 7–9). The experimental results
showed that with DMF as the solvent, the catalytic system
of Pd(TFA)2 (0.1 equiv.) and Cu(OAc)2 (3.0 equiv.) gave
the optimum results (entry 5).
To further investigate the efficiency of the new catalytic
system for the preparation of indolocarbazoles through the
oxidative cyclization of bisindolylmaleimides, 1a-d were
tested under the optimum reaction conditions. The desired
indolo[2,3-a]pyrrolo[3,4-c]carbazoles 2a-d were obtained
in 83–94% yields (Schemes 1 and 2).
A plausible Pd(0)/Pd(II) mechanism for the oxidative
cyclization is outlined in Scheme 3. Most likely, the
cyclization is initiated by an electrophilic Pd(II) species
that is capable of inducing a cationic-driven ring closure,
and the formed Pd(0) is oxidized back to Pd(II) by Cu
(II) salts in the system to furnish the cycle.
Scheme 3. The possible mechanism of the Palladium-catalyzed cycliza-
tion of bisindolylmaleimides.
CONCLUSION
In conclusion, an efficient procedure was developed for the
synthesis of pharmacologically important indolocarbazole
aglycones and related analogues by the oxidative cyclization
of bisindolylmaleimides with the Cu(OAc)2/Pd(TFA)2
catalytic system. Synthesis of indolocarbazole alkaloids and
analogues with this method is ongoing in our laboratory.
Table 1
Conditions and yields for the oxidative cyclization of bisindolylmaleimides.
Entry
Catalyst (equiv.)
Oxidant (equiv.)
Solvent
Time
Yield [%]a
1
2
3
4
5
6
7
8
9
10
Pd(TFA)2 (2.5)
PdCl2 (2.5)
—
—
—
DMF
DMF
DMF
DMF
DMF
DMF
toluene
THF
4 h
4 h
4 h
4 h
2 h
4 h
4 h
4 h
3 h
2 h
87%
25%
34%
20%
85%
minor
37%
12%
72%
86%
Pd(OAc)2 (2.5)
Pd(TFA)2 (10%)
Pd(TFA)2 (0.1)
Pd(TFA)2 (0.1)
Pd(TFA)2 (0.1)
Pd(TFA)2 (0.1)
Pd(TFA)2 (0.05)
Pd(TFA)2 (0.2)
CuCl2 (3.0)
Cu(OAc)2 (3.0)
FeCl3 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
DMF
DMF
ayields of isolated products.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Indolo[2,3-a]pyrrolo[3,4-c]carbazoles via the Oxidative Cyclization of
Bisindolylmaleimides with Pd(TFA)2/Cu(OAc)2
113.07, 106.04, 23.64. HRMS (EI): calcd 375.0819 for
EXPERIMENTAL
C21H11N3O2F2 [M]+; found 375.0812.
General.
1H-NMR spectra were recorded at 600 or
12,13-Dihydro-3,9-dibenzyloxy-6-methyl-5H-indolo[2,3-a]
300 MHz spectrometer at 24°C in the same solvent (DMSO-d6)
and are reported in parts per million relative to tetramethylsilane
and referenced internally to the residually protonated solvent.
13C-NMR spectra were recorded at 150 or 75 MHz spectrometer
at 24°C in the same solvent (DMSO-d6) and are reported in
parts per million relative to tetramethylsilane and referenced
internally to the residually protonated solvent. HRMS was
carried out by Agilent LC/MSD TOF. All reagents were
obtained from commercial suppliers unless otherwise stated.
pyrrolo[3,4-c]carbazole-5,7(6H)-dione (2d).
Yellow solid;
1
yield 87%. mp: 130–133°C. H-NMR (DMSO-d6, 300 MHz, δ
ppm): 11.54(s, 2H), 8.59(d, 2H, J = 2.1 Hz), 7.65(d, 2H,
J = 8.7 Hz), 7.55(d, 4H, J = 7.2 Hz), 7.42(t, 4H, J = 6.9 Hz),
7.34(t, 2H, J = 7.2 Hz), 7.22(dd, 2H, J = 8.7, 2.4 Hz), 5.20
(s, 4H), 3.13(s, 3H). 13C-NMR (DMSO-d6, 125 MHz, δ ppm):
169.93, 152.78, 137.33, 135.22, 129.45, 128.36, 127.81,
127.74, 121.96, 118.52, 116.63, 115.31, 112.66, 107.69,
69.86, 23.51. HRMS (EI): calcd 551.1845 for C35H25N3O4
[M]+; found 551.1840.
General procedure.
Under the protection of argon, a
solution of bisindolylmaleimide 1a-d (12.0 mmol), Cu(OAc)2
(36.0 mmol), Pd(TFA)2 (1.2 mmol) in DMF (100 mL) was
heated at 120°C in a three-necked flask until TLC showed
complete consumption of the bisindolylmaleimide. Thereafter,
the reaction mixture was poured into aqueous HCl (0.2 M,
500 mL) and was extracted with EtOAc (3 × 100 mL). The
organic phase was washed with aqueous NaHCO3 (50 mL), H2O
(50 mL), and brine (50 mL). Then, it was dried (MgSO4), filtered
through Celite, and concentrated. The residue was purified by
column chromatography (silica gel; petroleum ether-EtOAc) to
give indolocarbazole compounds 2a-d in yields of 83–94%.
12,13-Dihydro-1,11-dimethyl-6-methyl-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazole-5,7(6H)-dione (2a). Yellow solid; yield
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1
83%. mp: 105–107°C. H-NMR (DMSO-d6, 300 MHz, δ ppm):
11.46(s, 2H), 8.77(d, 2H, J = 7.5 Hz), 7.36(d, 2H, J = 6.6 Hz), 7.26
(t, 2H, J = 7.2 Hz), 3.13(s, 3H), 2.67(s, 6H). 13C-NMR (DMSO-
d6, 125 MHz, δ ppm): 169.84, 139.52, 128.72, 127.16, 121.80,
121.04, 120.49, 120.29, 118.88, 115.67, 23.49, 16.71. HRMS
(EI): calcd 367.1321 for C23H17N3O2 [M]+; found 367.1321.
12,13-Dihydro-3,9-dimethoxy-6-methyl-5H-indolo[2,3-a]pyrrolo
[3,4-c]carbazole-5,7(6H)-dione (2b). Yellow solid; yield 94%.
1
mp: 112–114°C. H-NMR (DMSO-d6, 300 MHz, δ ppm): 11.54
(s, 2H), 8.54(d, 2H, J = 2.1 Hz), 7.68(d, 2H, J = 8.7 Hz), 7.16(dd,
2H, J = 8.7, 2.4 Hz), 3.90(s, 6H), 3.16(s, 3H). 13C-NMR (DMSO-
d6, 125 MHz, δ ppm): 170.07, 153.86, 135.11, 129.47, 122.01,
118.56, 116.18, 115.40, 112.77, 106.14, 55.44, 23.54. HRMS
(EI): calcd 399.1219 for C23H17N3O4 [M]+; found 399.1216.
12,13-Dihydro-2,10-difluoro-6-methyl-5H-indolo[2,3-a]pyrrolo
[3,4-c]carbazole-5,7(6H)-dione (2c). Yellow solid; yield 84%.
1
mp: 123–125°C. H-NMR (DMSO-d6, 300 MHz, δ ppm): 11.64
(s, 2H), 8.82(q, 2H, J = 5.7 Hz), 7.54(d, 2H), 7.13(t, 2H,
J = 9.0 Hz), 3.02(s, 3H). 13C-NMR (DMSO-d6, 125 MHz, δ ppm):
171.08, 154.77, 136.01, 120.53, 123.11, 119.23, 117.11, 115.40,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet