Practical synthesis of the rebeccamycin aglycone and related analogs by oxidative cyclization of bisindolylmaleimides with a Wacker-type catalytic system

Article abstract of DOI:10.1016/S0040-4039(01)02021-4

Using atmospheric O₂ as the stoichiometric oxidant, Pd²⁺/Cu²⁺-catalyzed oxidative cyclization of the corresponding bisindolylmaleimides provides the rebeccamycin aglycone and related indolo[2,3-a]pyrrolo[3,4-c]carbazoles in 58-88% yield. The method is operationally simple and utilizes readily prepared substrates, making the process amenable to scaleup.

Full text of DOI:10.1016/S0040-4039(01)02021-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8935–8937
Practical synthesis of the rebeccamycin aglycone and related
analogs by oxidative cyclization of bisindolylmaleimides with a
Wacker-type catalytic system
Jianji Wang,* Miguel Rosingana, Daniel J. Watson, Eric D. Dowdy, Robert P. Discordia,
Nachimuthu Soundarajan and Wen-Sen Li
Bristol-Myers Squibb Pharmaceutical Research Institute, Process Research & Development, One Squibb Drive, New Brunswick,
NJ 08903, USA
Received 1 October 2001; revised 18 October 2001; accepted 22 October 2001
Abstract—Using atmospheric O2 as the stoichiometric oxidant, Pd2+/Cu2+-catalyzed oxidative cyclization of the corresponding
bisindolylmaleimides provides the rebeccamycin aglycone and related indolo[2,3-a]pyrrolo[3,4-c]carbazoles in 58–88% yield. The
method is operationally simple and utilizes readily prepared substrates, making the process amenable to scaleup. © 2001 Elsevier
Science Ltd. All rights reserved.
Rebeccamycin 11 and its family members2 are potent
antitumor agents. As part of a program for optimization
of their biological activity by modification of the aglycone
portion, we required an efficient route to the indolo[2,3-
a]pyrrolo[3,4-c]carbazole ring system 2. In particular, we
were interested in a practical synthesis of carbazole 2b,
which we needed in large quantities.
by-products were formed during the reaction, resulting
in poor quality and low yields. It has also been reported
in the literature that Pd(O2CCF3)2,11,12 PdCl2 and
6
Pd(OAc)213 may act as alternative oxidants. However, 1–5
equiv. of the palladium reagents were required to achieve
the desired oxidation. We also found that Pd(OAc)2 could
oxidize bisindolylmaleimides 3 to carbazoles 2 in good
yields, but the reactions required 2.5 equiv. of Pd(OAc)2,
which would not be amenable to large scale production
due to the cost of the palladium reagent. In this commu-
nication we describe our efforts toward the construction
of the central six-membered ring of the indolo[2,3-
a]pyrrolo[3,4-c]carbazole ring systems (2a–i) using oxida-
tive cyclization of the corresponding bisindolyl-
maleimides (3a–i) with a Wacker-type catalytic system,14
resulting in the need for only 5 mol% of the Pd(II) catalyst
(Scheme 1).
Several routes to the indolo[2,3-a]pyrrolo[3,4-c]carbazole
ring system 2 have been reported.3–5 Among them, the
approach via bisindolylmaleimides 3 is the most attractive
because it is short and the starting materials are readily
available. Conversion of the bisindolylmaleimides 3 to the
corresponding carbazoles 2 has been achieved with
DDQ,5,6 I2,7–9 and CuCl2.10 However, in our case, with
DDQ as the oxidant, the product was difficult to isolate
due to poor solubility. With iodine and CuCl2 as oxidants,
H
N
O
O
R2
N
N
O
O
O
O
N
H
N
F
F
Cl
OH
Cl
R1
R1
O
N
H
N
H
N
H
N
H
HO
OH
MeO
2
2b
1
* Corresponding author. Fax (732)-519-3240; e-mail: jianji.wang@bms.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02021-4

8936
J. Wang et al. / Tetrahedron Letters 42 (2001) 8935–8937
R2
N
R2
N
O
O
O
O
Pd(OAc)2, 5 mol%; CuCl2, 100 mol%
R1
R1
R1
R1
air sparge, DMF, 90-120oC, 4-16 h
N
H
N
H
N
H
N
H
3
2
Scheme 1.
A series of bisindolylmaleimides 3a–i were readily pre-
pared by reaction of the appropriate substituted indolyl-
magnesium bromide with N-substituted 3,4-dihalo-
maleimides.15 Oxidative cyclization of these bisindolyl-
maleimides under the reaction conditions described in
Scheme 1 gave the desired indolo[2,3-a]pyrrolo[3,4-
c]carbazoles 2a–i in 58–88% yields (Table 1). It is
noteworthy that even without protection of the imide
N–H, the reaction still gives a satisfactory yield (2d, 78%).
With an electron-rich system (3f,h and i), the reaction
proceeds under milder conditions (90°C, 4–8 h). This
observation could be attributable to the differences in the
electron densities of the ring systems. As illustrated in
Scheme 2, an electron-donating group (such as MeO)
makes the ring system more electron rich and facilitates
formation of complex 4, presumably the turnover-limit-
ing step, by stabilizing cation intermediate 5. The reac-
tion conditions and results are listed in Table 1.
intermediate for our program, with an overall yield of
52% (Scheme 3). N-4-t-Butylbenzyl-protected dibromo-
maleimide 7 was prepared in 78% yield by the amidation
of the readily available dibromomaleic acid 6 with
4-t-butylbenzyl amine mediated by EDCI (1.05 equiv.),
followed by reflux in acetic acid for 3 h. Subsequently,
reaction of 5-fluoroindolylmagnesium bromide, derived
by treatment of 5-fluoroindole (2.2 equiv.) with EtMgBr
(2.3 equiv.), gave bisindolylmaleimide 3b in 82% yield.
Finally, using our developed method, oxidative cycliza-
tion of 3b afforded the desired indolo[2,3-a]pyrrolo[3,4-
c]carbazole 2b in 81% yield. This operation was carried
out on greater than 3 kg scale, and proved to be
operationally very practical.
In conclusion, oxidative cyclization of bisindolyl-
maleimides facilitated by a Wacker-type catalytic system
has been developed as a general and practical approach
for the preparation of rebeccamycin aglycones and
related analogs.
Using this practical oxidation as a key step, we developed
a scalable, three-step synthesis of carbazole 2b, a key
Table 1. Wacker-type oxidation of bisindolylmaleimides 3a–i to carbazoles 2a–i
Entry
Product
R1; R1
R2
Temperature (°C)
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
1-Cl; 11-Cl
3-F; 9-F
3-Br; 9-Br
3-F; 9-F
2-F, 3-F; 9-F, 10-F
3-OMe; 9-OMe
H; H
p-t-Bu-Bn
p-t-Bu-Bn
p-t-Bu-Bn
H
p-t-Bu-Bn
p-t-Bu-Bn
p-t-Bu-Bn
t-Bu
120
120
120
120
120
90
90
90
90
12
16
10
8
16
4
8
6
5
8816
81
74
78
82
86
79
62
58
3-F; 9-F
3-F; 9-F
DMB
Wacker-type catalytic system
R2
N
R2
N
O
O
O
O
Pd
+
- Pdo
- 2H+
+ Pd2+
+
Pd2+
3
2
R1
R1
R1
R1
N
H
N
H
N
H
N
H
H
H
4
5
Scheme 2. Proposed mechanism of oxidative cyclisation of bisindolylmaleimides 3a–i.

J. Wang et al. / Tetrahedron Letters 42 (2001) 8935–8937
8937
P
N
P
N
F
O
O
1) 4-tert-butylbenzyl amine
EDCI, r.t. 1.5 h
N
MgBr
OH HO
, 2.2 eq
O
O
O
O
F
F
PhMe, 105oC, 12 h
82%
2) HOAc, reflux, 7 h
78%
Br
Br
Br
Br
N
H
N
H
6
7
3b
P
N
O
O
Pd(OAc)2, 5 mol%; CuCl2, 100 mol%
F
F
P =
air, DMF,120oC, 16 h
81%
N
H
N
H
2b
Scheme 3. Three-step synthesis of 2b.
Acknowledgements
charged 3b (100 g, 0.196 mol), Pd(OAc)2 (2.2 g, 0.0098
mol) and DMF (700 ml). The resulting brown-reddish
solution was stirred at ambient temperature for 10 min.
CuCl2 (26.4 g, 0.196 mol) was added portionwise over 5
min. Air was sparged into the resulting suspension. The
suspension was heated with stirring for 16 h. The oil bath
temperature was controlled at 125°C and the internal
temperature was 120°C. The reaction progress was moni-
tored by HPLC. During this period, a greenish-yellow
solid precipitated. The suspension was cooled to 5°C with
an ice–water bath, and water (1 L) was added slowly (20
min). The resulting brownish suspension was kept at 5°C
for 4 h, filtered through a sintered glass funnel (type C)
and washed with water (2×50 ml) to give a crude product
(170 g) as a brown solid. Recrystallization from N-
methyl-2-pyrrolidinone (2 L) and water (100 ml) gave 2b
(81 g, 81%) as a greenish-yellow solid. (HPLC, AP 98).
MS: (M+H)+ 541; 1H NMR (400 MHz, DMSO-d6): l
11.75 (s, 2H, N–H), 8.84 (d, J=7.8, 2H), 7.95 (s, 2H),
7.65 (d, J=7.8, 2H), 7.40–7.33 (m, 4H), 4.81 (s, 2H), 1.23
(s, 9H) ppm; 13C NMR (100 MHz, DMSO-d6): l 168.7,
162.9, 149.6, 137.4, 134.5, 128.8, 127.9, 125.9, 124.9,
123.4, 120.9, 119.9, 116.4, 116.2, 41.0, 31.3169.1, 154.4,
149.3, 135.3, 134.9, 129.6, 127.5(2C), 124.9(2C), 122.8,
119.1, 116.4, 111.5, 106.4, 55.3, 40.9, 31.3 ppm.
The authors would like to thank Dr. E. Mattas, Mr. A.
Fritz and Mr. C. Nilsen for the scaleup preparation of
2b. We also thank Dr. R. Polniaszek and Dr. B. Kaller
for helpful discussions.
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Compound 2c: MS: (M+H)+ 630; 1H NMR (400 MHz,
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