Synthesis of new fused and substituted benzo and pyrido carbazoles via C-2 (het)arylindoles

Article abstract of DOI:10.1016/j.tet.2008.09.101

In the course of a program aimed at designing new antitumor agents, we were interested in the synthesis of new substituted benzo and pyrido carbazoles. The synthesis was performed through an efficient four-step sequence from a 2-trimethylstannylindole derivative and via C-2 (het)arylindoles. The synthetic sequence was developed using two palladium mediated reactions including, at the end of the synthesis, a direct (het)arylannulation, which led to the desired heterocycles.

Full text of DOI:10.1016/j.tet.2008.09.101

Tetrahedron 64 (2008) 11012–11019
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new fused and substituted benzo and pyrido carbazoles via C-2
(het)arylindoles
*
´
´
´
Aurelie Bourderioux, Pamela Kassis, Jean-Yves Merour, Sylvain Routier
Institut de Chimie Organique et Analytique, Universite´ d’Orle´ans, UMR-CNRS 6005, B.P. 6759, 45057 Orle´ans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2008
Received in revised form 10 September
2008
Accepted 30 September 2008
Available online 8 October 2008
In the course of a program aimed at designing new antitumor agents, we were interested in the synthesis
of new substituted benzo and pyrido carbazoles. The synthesis was performed through an efficient four-
step sequence from a 2-trimethylstannylindole derivative and via C-2 (het)arylindoles. The synthetic
sequence was developed using two palladium mediated reactions including, at the end of the synthesis,
a direct (het)arylannulation, which led to the desired heterocycles.
Ó 2008 Published by Elsevier Ltd.
1. Introduction
Alternatively, the Sanchez’s group and our team successfully
proposed an original route A. Starting from (het)Ar glyoxylate or
Indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids form a class of
compounds endowed with potent antitumor, antiviral and/or an-
timicrobial activities.1 During the past decade, two natural models
named rebeccamycin and staurosporin have been modified in order
to establish fine structure–activity relationships. Structural modi-
fications of rebeccamycin scaffold led to topoisomerase I inhibitors
such as NB-506 and J-107088, which were advanced to clinical
trials.2–4
acetamide, boron or stannyl derivatives, mono indolyl compounds
of type II were prepared and a C-2 indolic palladium-assisted
arylation achieved the synthesis of the non-substituted (het)aryl
derivatives I (R¼H).10,13 This global strategy (Fig. 2) appeared as
a major simplification for parented indolocarbazole synthesis
without any photochemical step. Nevertheless limitations
appeared to obtain trisubstituted (het)Ar derivatives II (RsH).
The generalization of route A would imply the preparation of
derivatives II bearing: (i) a leaving group X (halogen atom or tri-
flate), (ii) the appropriate substituent R in the ortho position to X,
and (iii) a useful function Fc for cross coupling (B(OH)2, SnR3,.).
Immediately this challenge appeared as difficult.
So, we elaborated an alternative retrosynthetic scheme, starting
from indole derivative 3, including two palladium catalyzed re-
actions (route B). Very recently, a related strategy was reported to
design pyridocarbazoles.14a The synthesis involved, in a first step,
a Suzuki cross coupling reaction between indoles and an halogen-
opyridine.14b Nevertheless, the final annulation was performed
exclusively under photochemical irradiation.
Concerning the staurosporin and its derivative UCN-01, strong
but unselective inhibition of protein kinases was found.5,6
In order to simplify the complex glycosylated models, some
groups focused their efforts on the arcyriaflavin skeleton (Fig. 1).7,8
Many synthetic challenges were next explored to modify the
indolocarbazolic structure. In this area, we replaced the indole
moeity by 5 or 7-azaindoles units and reported the synthesis and
the biological results of 5 or 7-aza-indolocarbazoles.9 We also re-
cently described the synthesis of naphtho and benzo carbazoles.10
From the beginning of the indolocarbazoles story, numerous
pathways were developed to build bis indolic derivatives. The most
representative consisted in the Grignard addition of indolyl lithium
or magnesium salts on the 2,3-dibromomaleimide 23.11 The second
classical way consisted in the preparation of indolyl-3 glyoxylate
and 3-indolyl acetamide, which led under basic conditions to
similar bis indolic maleimides.12 In both pathways the final annu-
lation step, leading to indolocarbazole skeleton, could be per-
formed either by photochemical irradiation or by [4þ2]
cycloaddition thus generating a C–C bond between the two C-2
indolic positions.
Our synthetic route B allowed the preparation of substituted
carbazoles of type I and involved the use of 2-phenyl (or 2-pyri-
dinyl) substituted indoles, which were obtained from the N-ben-
zenesulfonyl-2-trimethylstannyl indole
3 and the halogeno
derivatives IV through a Stille reaction. After protective group
removal and condensation of the dibromo maleimide 23, the in-
termediates V were obtained. The final step was devoted to the
bond formation between the C-sp2 of the maleimide moiety and
the (het)Ar fragment. This was performed by a second palladium
catalyzed Heck type arylation reaction. As in route A the central
ring formation is achieved by a C-2 cyclization on the indole ring,
this route B may be considered as an anti-clockwise building of
(het)arylcarbazoles. In order to complete our studies, each step was
* Corresponding author. Tel.: þ33 0 238494853; fax: þ33 0 238417281.
E-mail address: sylvain.routier@univ-orleans.fr (S. Routier).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.09.101

A. Bourderioux et al. / Tetrahedron 64 (2008) 11012–11019
11013
R1
N
CH3
N
R1
N
H
N
O
O
O
O
O
O
O
O
R2
R2
R2
R2
R
X
N
H
N
H
N
H
N
H
N
H
(Het)aryl carbazoles type I
X = CH, N
Arcyriaflavins
Naphthocarbazoles
Benzocarbazoles
R2 = H, OH
R2 = H, OH; R1 = H, CH3
R2 = H, OH; R1 = H, CH3
R = H, CH3, NO2, F, OH
Figure 1. Some representative indolocarbazole related compounds.
R1
N
R1
N
Sn(CH3)3
R1
N
N
SO2Ph
3
O
O
O
O
O
Fc
(Het)Ar
O
Route A
R = H
Route B
Br
X
(Het)Ar
R
(Het)Ar
R
(Het)Ar
X
X
(Het)Ar
R
R
N
H
N
P
N
H
II
(Het)Ar
R
III
V
I
phenyl, naphthyl, thienyl....
X = Br, OTf
X = OTf, Br
R1 = CH3
IV
R1 = H, CH3
P = Boc, SO2Ph, H
R1 = H, CH3
X = I, Br, OTf
Fc = SnR3, B(OH)2
acetamide,
glyoxal
Figure 2. Two routes toward indolocarbazoles and (het)arylcarbazoles.
optimized in the presence of various substituents either on the
phenyl or pyridine ring.
We next applied these last conditions [i.e., Pd(PPh3)4 (10%), CuI
(20%), DMA, 100 ꢁC] to the 2-bromo-6-methoxypyridine. After 14 h
the desired compound 5 was isolated without any difficulty in
a 70% yield (entry 2). Some limitations occurred starting from
2-bromopyridine N-oxide and 2-chloro-6-(O-MOM)-pyridine
(entries 3 and 4), only homocoupling of 3, leading to bis-(benze-
nesulfonyl[2,20]indole) 6, occurred.17
2. Results and discussion
2.1. Synthesis of bis 2-(het)aryl indolic derivatives
Nevertheless, compound 6 was not detected in the phenyl se-
ries. Compound 718 was quantitatively obtained after 12 h (entry
5a) from the volatile bromobenzene (10.0 equiv) and in 78% yield
after only 4 h (entry 5b) by using iodobenzene (3 equiv). Un-
fortunately, the electro-withdrawing groups (EWG) in position 2 of
the phenyl halide (entries 6–9) diminished the efficiency of the
cross coupling reaction. Indeed starting from 1-bromo-2-fluoro-
benzene, compound 8 was isolated in only 25% yield (entry 6a).
Since an increase of the reaction time was inefficient, we modified
the amount of halide (10.0 equiv) and thus the yield of 8 enhanced
to 75% (entry 6b). We next performed the reaction with 1-fluoro-2-
iodobenzene (3.0 equiv) and after 6 h, compound 8 was obtained in
82% yield (entry 6c).
Starting from 2-bromobenzaldehyde (3.0 equiv), the resulting
mixture led after purification to 919 in 45% yield. In this case,
a simple increase of the reaction time to 16 h enhanced the yield to
89% (entries 7a, b). The other assays performed with 2-bromo-
benzonitrile and 2-bromonitrobenzene were also realized in 16 h to
provide compounds 10 and 1120 in 84 and 88% yield, respectively
(entries 8 and 9). Despite the presence of EWG, the desired prod-
ucts were obtained in very good yields increasing the quantity of
halide and more specifically the reaction times. As a next assay, we
used the 1-bromo-3,5-dimethylbenzene, and after 12 h, the re-
action was completed to afford 12 in 78% yield (entry 10).
Lithiation of 1-benzenesulfonyl indole 2 (obtained from indole 1,
Scheme 1) was first carried out in presence of n-BuLi (1.2 equiv) at
ꢀ78 ꢁC during 1 h followed by addition of trimethylstannyl chloride
(1.5 equiv).15 After 1 h, compound 3 was isolated in only 37% yield.
Replacing n-BuLi by LDA (1.5 equiv) and warming up the mixture to
ꢀ30 ꢁC for 45 min led to quantitative anion formation. After cooling
again to ꢀ78 ꢁC the electrophile (1.7 equiv) was added and the
reaction mixture was allowed to reach room temperature. This
optimized conditions afforded, after 2 h, the desired trimethyl-
stannyl derivative 3 in a very good yield (83%).
b
c
SnMe3
SO2Ph
(Het)Ar
SO2Ph
4 - 12
N
N
N
R
3
1, R = H
2, R = SO2Ph
a
Scheme 1. Reagents and conditions: (a) PhSO2Cl (1.1 equiv), NaH (1.2 equiv), THF, 0 ꢁ
C
to rt, 6 h, 86%; (b) LDA (1.5 equiv), THF, ꢀ78 ꢁC to ꢀ30 ꢁC, 45 min then ClSn(CH3)3
(1.7 equiv), ꢀ78 ꢁC to rt, 2 h, 83%; (c) for conditions see Table 1.
Stille reactions involving 3 were, surprisingly, scarcely described
in the literature. In presence of 2-bromopyridine (2.5 equiv),
Pd(PPh3)4 (10%), and CuI (20%), the reaction led in refluxing THF to
compound 4 after 3 days in 65% yield (Table 1, entry 1a). Starting
material 3 was never fully consumed and a small amount of 3 was
isolated after the purification step (10%). Switching the solvent for
DMA had no effect on the yield but decreased the reaction time to
5 h (entry 1b). Postulating that the high temperature enhanced the
degradation of the reaction mixture, the reaction was next con-
duced at 100 ꢁC and after 6 h the compound 416 was quantitatively
isolated (entry 1c).
2.2. Deprotection and introduction of the maleimide moiety
on C-3 of indole
To perform the C-3 Michael addition, the indolic nitrogen must
be free of substituent. So the benzenesulfonyl group was removed,
using Bu4NF in refluxing THF (Scheme 2). The only reaction

11014
A. Bourderioux et al. / Tetrahedron 64 (2008) 11012–11019
Table 1
Experimental conditions for Stille reactions using 3
Entry
1
(Het)ArX
Equivalent
3.0
Conditions
Time
(Het)Ar
Yielda
a
b
c
Pd(PPh3)4 (10%), CuI (20%), THF, reflux
Pd(PPh3)4 (10%), CuI (20%), DMA, reflux
Pd(PPh3)4 (10%), CuI (20%), DMA, 100 ꢁ
3 days
5 h
6 h
4 (65%)
4 (65%)
4 (quant.)
O
N
2-Bromopyridine
C
O
N
OMe
2
2-Bromo-6-methoxy-pyridine
3.0
Pd(PPh3)4 (10%), CuI (20%), DMA, 100 ꢁ
C
14 h
5 (70%)
3
4
2-Bromo-pyridine-N-oxide
3.0
3.0
Idem
Idem
12 h
24 h
6 (46%)
6 (46%)
2-Choro-6-(O-MOM)pyridineb
O
N
SO2Ph
a
b
Bromobenzene
Iodobenzene
10.0
3.0
12 h
4 h
7 (quant.)
7 (78%)
O
5
6
7
8
9
Idem
Idem
Idem
Idem
Idem
a
b
c
1-Bromo-2-fluorobenzene
1-Bromo-2-fluorobenzene
1-Fluoro-2-iodobenzene
3.0
10.0
3.0
16 h
16 h
6 h
8 (25%)
8 (75%)
8 (82%)
O
F
a
b
8 h
16 h
9 (45%)
9 (89%)
O
2-Bromobenzaldehyde
2-Bromobenzonitrile
2-Bromonitrobenzene
3.0
3.0
3.0
OHC
O
16 h
16 h
10 (84%)
11 (88%)
NC
O
O2N
O
CH3
10
1-Bromo-3,5-dimethylbenzene
3.0
Idem
12 h
12 (78%)c
CH3
a
Yields are given for isolated products, which were fully characterized by IR, MS, 1H, and 13C NMR.
b
This compound was selectively obtained from 6-chloro-1H-pyridin-2-one and MOMCl (1.1 equiv) in THF at room temperature in presence of NaH (1.5 equiv) during 2 h in
72% yield.
c
A small amount of 12 was lost during the purification step.
providing degradation occurred with the formylated derivative 9.
Starting materials 4, 5, 7, 8, 10–12 led without any difficulties to
compounds 13–19, after a few hours and with a slight excess of
Bu4NF, in very good yields.16,20–24
In the previous Stille reaction, we were unable to obtain directly
the 2-(N-benzenesulfonylindolyl)-pyridin-N-oxide 20 from 3. As
an alternative, we prepared 20 from compound 4 in presence of
m-CPBA in CHCl3 at room temperature during 12 h in 74% yield
(Scheme 2). The benzenesulfonyl group of 20 was next removed
using 1.5 equiv of Bu4NF in refluxing THF without any difficulties
and compound 21 was isolated in 81% yield. In addition, the hy-
droxylated compound 22 was obtained from 14 in refluxing aque-
ous HBr solution in 89% yield (all assays with BBr3 from 5 and 14
failed). Compound 22 exists as a mixture of tautomers.
a
N
H
N
N
N
R2
R2
SO2Ph
13, R2 = H
The next step consisted in the regioselective Michael addition9
on the 3,5-dibromo-N-methylmaleimide 23 at C-3 indolic position.
In this new series, all reactions were performed with 2.2 equiv of
LiHMDS between ꢀ20 ꢁC and room temperature but it appeared
that results depended also on the nature of the C-2 indolic
substitution.10,11
4, R2 = H
14, R2 = OMe
5, R2 = OMe
c
22, R2 = OH
-
-
b
O
O
+
+
N
N
a
N
N
H
21
SO2Ph
20
R1
R
R
R1
2.2.1. Reactions with C-2 pyridinyl indoles
a
Compound 24 was the only product observed on TLC during the
Michael reaction of 13 and 23 (Scheme 3). But after hydrolysis and
heating to remove the volatiles, another strong polar yellow
product 25 appeared. Nevertheless after a fast silica gel pad filtra-
tion, the highly sensitive derivative 24 was only isolated in the
moderate yield of 43%. To identify the by-product, the crude ma-
terial was dissolved in DMA and the mixture was heated to reflux
for 30 min; after cooling, 25 was filtered and isolated in a 80% yield.
Its formation is certainly due to the nucleophilic addition of the
pyridine nitrogen atom on the maleimide Michael acceptor by
a spontaneous intramolecular 1,4-addition followed by bromide
N
N
H
R2
SO2Ph
R1 = R2 = H,
R2
7, R = H
R1 = R2 = H,
15, R = H
16, R = F
17, R = CN
18, R = NO2
19, R = H
8, R = F
10, R = CN
11, R = NO2
R1 = R2 = CH3, 12, R = H
R1 = R2 = CH3,
Scheme 2. Reagent and conditions: (a) Bu4NF (1.5 equiv), THF, reflux, 13 (4 h, quant.), 14
(1 h 30 min, 94%), 15 (3 h, quant.), 16 (2 h, 91%), 17 (2 h, 88%), 18 (1 h 30 min, 94%), 21
(3 h, 81%), 19 (Bu4NF 2.5 equiv, 1 h 30 min, 87%); (b) m-CPBA (1.2 equiv), CHCl3, rt, 12 h,
79%; (c) H2O/HBr 30% in acetic acid 1:1, reflux, 6 h, 89%.

A. Bourderioux et al. / Tetrahedron 64 (2008) 11012–11019
11015
elimination. It must be pointed out that Bregman14 indicated the
formation of a pyridinium salt as traces (no data reported) during
the photocyclisation of analogous derivative; here 25 was obtained
according to a quasi spontaneous nucleophilic displacement. The
structure of 25 is supported by NMR data and HRMS.
amount of 23 (2.0 equiv), and the reaction time (5 h), 30 was finally
obtained in a yield of 65%.
The effect of the EWG was reinforced with the nitro derivative
18, limiting the formation of compound 31, which was obtained in
a poor 38% yield. One hypothesis to explain this result consisted in
the stabilization of the nitrogen indolic anion by an intramolecular
6-center ring including the electronegative group. The reactivity of
the C-3 center decreased considerably.
O
N
N
O
O
O
+ , Br -
Br
N
N
a
b
2.3. Intramolecular Heck reaction
13
N
N
N
H
O
O
H
In the absence of pyridinyl derivatives, which require further
studies, we focused our effort on the intramolecular Heck arylation
reaction of compounds 28–32, between the bromoalkene and the
C-2 indolyl phenyl ring (Scheme 5). This reaction was first tried
using compound 28 in presence of KOAc as a base, Pd(PPh3)4 (10%)
as catalyst, in refluxing DMA.13 After 12 h, only 10% of the desired
products 33 were isolated. Based on our experimental knowledge,
we performed the reaction using a catalytic amount of Pd(OAc)2
(0.1 equiv), PPh3 (0.2 equiv), and NaOAc (2.0 equiv) in presence of
Bu4NCl (1.0 equiv).10 Nevertheless, after 12 h, in dioxane at 110 ꢁC,
the desired product 33 was obtained in a disappointing 15% yield.
25
24
Br
Br
23
O
N
N
O
O
O
Br
d
c
22
23
N
H
N
H
N
N
O
H
OH
27
26
Scheme 3. Reagent and conditions: (a) LiHMDS (2.2 equiv), THF, ꢀ20 ꢁC, 45 min then
23 (1.3 equiv), ꢀ20 ꢁC to rt, 1 h, 43%; (b) DMA, 120 ꢁC, 30 min, 80%; (c) LiHMDS
(3.2 equiv), THF, ꢀ20 ꢁC, 45 min then 23 (1.3 equiv), ꢀ20 ꢁC to rt, 1 h, 58%; (d) DMSO,
50 ꢁC, 48 h, quant.
O
N
N
O
Starting from the N-oxide derivative 21, degradation occurred
whereas the reaction of the pyridine 22 led to the expected com-
pound 26 in 58% yield. This last reaction required 3.2 equiv of base.
The two first equivalents formed the dianion of 22 whereas the
third one achieved the aromatization step after the nucleophilic
addition on 23. Under basic media or after hydrolysis, the intra-
molecular reaction due to the pyridinic nitrogen atom was not
observed. The tautomeric equilibrium pyridinone/hydroxypyridine
decreased also the nucleophilicity of the nitrogen atom. In order to
promote the cyclization, compound 26 was stirred in at room
temperature for 48 h but surprisingly 27 was the sole isolated
compound in a quantitative manner. The corresponding pyridinium
salt was not observed.
O
O
R2
R2
R1
Br
N
H
N
R2
H
R
R
R1 = R2 = H,
R1 = R2 = H,
28, R = H
29, R = F
33, R = H
34, R = F
35, R = NO2
36, R = H
31, R = NO2
R1 = R2 = CH ,
32, R = H
3
R1 = R2 = CH ,
3
Scheme 5. Reagent and conditions: AcONa (2.0 equiv), Bu4NCl (1.0 equiv), PPh3
(2.0 equiv), Pd(OAc)2 (1.0 equiv), dioxane, 110 ꢁC, 33 (7 h, 70%), 34 (5 h, 78%), 35 (6 h,
36%), 36 (7 h, 80%).
As described in our previous reports, we observed a linearity
between the amount of the catalytic system and the yield of the
reaction. So, after several assays, we used a stoichiometric amount
of palladium acetate and after only 7 h the compound 33 was iso-
lated in the best yield of 73%. Direct application of these conditions
to 29 led without any surprise after 6 h to 34 in 78% yield. It should
be noted that during the purification step of 29 or when the com-
pound 29 was maintained in solution on air and light for 24 h, the
compound 34 appeared on the TLC. So we deliberately maintained
29 in acetone in presence of silica gel and, after 12 h, 22% of 34 were
isolated. Compound 29 was the sole compound able to spontane-
ously promote the [4þ2] oxidative cycloaddition.
2.2.2. Reactions with C-2 phenyl indoles
Michael condensations were next regioselectively carried out in
C-3 position of indole, starting from the 2-phenylated indoles 15–19,
under the previously reported conditions (Scheme 4). Starting from
15 and 16, the reaction led without any difficulty to compounds 281b
and 29, respectively, both in verygood yields. From 19 the attempted
product 32 was isolated in 75% yield after the increase of the
amounts of base (3.0 equiv) and compound 23 (2.0 equiv).
O
N
O
Benzannulation of 32 occurred after 7 h, the targeted product 36
was isolated in 80% yield. Direct application to the cyano compound
30 led only to degradation. Immediately during the heating phase,
the solution turned off to red and degradation occurred. Starting
from the nitro derivative 31, compound 35 was obtained with the
poor yield of 36%; the presence of strong EWG led also to modest
results. So the electrophilic step involved in the Heck arylation
mechanism is fully compromised in the presence of a strong elec-
tron-withdrawing group.
R1
R2
R
R2
R1
Br
N
H
N
H
R
R1 = R2 = H,
15, R = H
R1 = R2 = H,
28, R = H
29, R = F
16, R = F
17, R = CN
18, R = NO2
30, R = CN
31, R = NO2
32, R = H
R1 = R2 = CH3,19, R = H
R1 = R2 = CH ,
3
Scheme 4. Reagent and conditions: LiHMDS, THF, ꢀ20 ꢁC then 23, ꢀ20 ꢁC to rt, 28
(75%), 29 (92%), 32 (75%), 30 (65%), 31 (38%).
3. Conclusion
We here reported an efficient synthesis of new fused and
substituted benzo and pyrido carbazoles. The reported strategy
involved four efficient steps from the N-benzenesulfonyl-2-trime-
thylstannyl indole 3. As an additional novelty, in the pyridine series,
a new spontaneous cyclization occurring in C-3 was highlighted.
The presence of the cyano and nitro groups decreased dramat-
ically the reactivity of the lithiated indole. From 17, using 2.2 equiv
of base and 1.3 equiv of maleimide 23, the product 30 was isolated
in only 56% yield. By modifying the amount of base (3.0 equiv), the

11016
A. Bourderioux et al. / Tetrahedron 64 (2008) 11012–11019
This reaction will be further studied and fully utilized for new
substituted-pyridinyl series. As far as the phenyl series was con-
cerned, the final reaction was completed following an intra-
molecular Heck reaction. Several efforts are in progress to apply
this work and design potent bioactive molecules. Results will be
reported in due course.
(CH), 121.6 (CH), 124.5 (CH), 125.4 (CH), 126.4 (2CH), 129.3 (2CH),
129.6 (C), 134.3 (CH), 136.9 (C), 137.0 (C), 139.1 (C), 140.4 (C), 148.4
(C), 162.6 (C); HRMS (EI) calcd for C20H16N2O3S 364.08816, found
ꢃ
364.0896 (M)þ
.
4.2.2. 1-Benzenesulfonyl-2-(2-fluoro-phenyl)-1H-indole (8)
The reaction was performed with 2-iodofluorobenzene
(3.0 equiv) during 6 h. Compound 8 was isolated after column
chromatography purification (PE/EtOAc 9:1 then 8:2) as a white
glassy solid in 82% yield. Rf (PE/EtOAc 9:1) 0.32. Mp 96 ꢁC; IR (KBr,
4. Experimental section
4.1. General
cmꢀ1
)
n
1501, 1380, 1220, 1190, 605; 1H NMR (DMSO-d6, 250 MHz):
0
d
6.90 (s, 1H, H3 ), 7.25–7.61 (m, 12H), 8.11 (d, 1H, J¼8.5 Hz); 13C
1H and 13C NMR spectra were recorded on a Bruker Advance
DPX 250 or 500 instruments using CDCl3 or DMSO-d6. The chemical
shifts are reported in parts per million (d scale) and all J values are in
hertz. Melting points are uncorrected. IR absorption spectra were
recorded on a Perkin–Elmer FT PARAGON 1000 PC and values were
reported in cmꢀ1. MS spectra (Ion Spray) were performed on
a Perkin–Elmer SCIEX API 300. HRMS were realized by the Centre
NMR (DMSO-d6, 62.5 MHz): d 114.4 (CH), 115.2 (CH), 115.3 (C), 118.4
(C), 121.3 (CH), 123.9 (CH), 125.3 (CH), 126.2 (2CH), 124.3 (CH), 125.3
(CH), 126.2 (CH), 129.4 (2CH), 131.3 (CH), 131.7 (CH), 134.4 (CH),
136.8 (C), 158.2 (C), 162.1 (C); HRMS (EI) calcd for C20H15FNO2S
352.0819, found 352.0808 (Mþ1)þ.
4.2.3. 2-(1-Benzenesulfonyl-1H-indol-2-yl)-benzonitrile (10)
The reaction was performed with 2-bromobenzonitrile
(3.0 equiv) for 16 h. Compound 10 was isolated after column
chromatography purification (PE/EtOAc 8:2) as tan soꢀli1d in 84%
) n 2224,
´
Regional de Mesures Physiques de l’Ouest (CRMPO, Rennes) or by
the Centre Re´gional de Mesure Physique (CRMP, Clermont-
Ferrand). Monitoring of the reactions was performed using silica gel
TLC plates silica Merck 60 F254. Spots were visualized by UV light at
254 and 365 nm. Column chromatographies were performed using
silica gel 60 (40–63 mm, Merck). Only the new products are de-
scribed (not found on CAS-online) (Scheme 6).
yield. Rf (PE/EtOAc 9:1) 0.24. Mp 148–150 ꢁC; IR (KBr, cm
1477, 1442, 1062, 748; 1H NMR (DMSO-d6, 500 MHz):
d
7.05 (s, 1H,
0
0
0
H3 ), 7.34 (t, 1H, J¼7.6 Hz, H5 ), 7.46 (dt, 1H, J¼7.9, 1.1 Hz, H6 ), 7.48–
0
7.49 (m, 4H, Ha, Hb), 7.62–7.64 (m, 2H, H4 , Hc), 7.68–7.71 (m, 2H, H3,
H5), 7.83 (dt, 1H, J¼7.7, 1.3 Hz, H4), 7.98 (d, 1H, J¼7.5 Hz, H6), 8.15 (d,
1H, J¼8.3 Hz, H7 ); 13C NMR (DMSO-d6, 62.5 MHz):
d 113.1 (C), 115.4
0
O
N
(CH), 115.6 (CH), 117.7 (C)CN, 121.7 (CH), 124.7 (CH), 125.8 (CH), 126.3
O
(2CH), 129.6 (3CHþC), 131.6 (CH), 132.5 (CH), 132.7 (CH), 134.7 (CH),
b
a
Br
4'
4
3'
3
135.2 (C),136.2 (C), 136.5 (C), 136.9 (C); HRMS (EI) calcd for
5'
6'
ꢃ
C21H14N2O2S 358.07760, found 358.0770 (M)þ
.
5
2
N
6
1
7'
R
SO2
4.2.4. 1-Benzenesulfonyl-2-(3,5-dimethyl-phenyl)-1H-indole (12)
The reaction was performed with 3,5-dimethylbromobenzene
(3.0 equiv) for 12 h. Compound 12 was isolated after column
chromatography purification (PE/EtOAc 5:5 then MeOH) as a white
solid in a 78% yield. Rf (PE/EtOAc 9:1) 0.37. Mp 168 ꢁC; IR (KBr,
Φ a
Φ b
Φ c
Scheme 6. Atom labeling for NMR spectra assignation.
cmꢀ1 3063, 1528, 1444, 1375, 744; 1H NMR (DMSO-d6, 250 MHz):
) n
d
2.36 (s, 6H), 7.04 (s, 1H), 7.32 (d, 1H, J¼7.5 Hz), 7.45–7.52 (m, 5H),
4.2. General procedure for Stille reaction
7.58–7.64 (m, 2H), 7.68 (d, 2H, J¼8.7 Hz), 7.85 (d, 1H, J¼7.0 Hz), 7.99
(d, 1H, J¼7.5 Hz), 8.18 (d, 1H, J¼8.2 Hz); 13C NMR (DMSO-d6,
The reaction was performed in a 1–5 mmol scale. A solution
containing the trimethylstannyl derivative 3 (1 mmol), the desired
halide (3 equiv), CuI (0.2 equiv), and DMA (15 mL) was degassed by
argon bubbling during 30 min. Pd(PPh3)4 (0.1 mmol) was then
added in one portion and the reaction mixture immersed into
a preheated oil bath at 100 ꢁC for the desired time. After cooling,
water (15 mL) and EtOAc (15 mL) were added, and the solution was
filtered. The precipitate was washed with EtOAc (2ꢂ10 mL) and the
aqueous layers were discarded. The combined organic layers were
dried over MgSO4, evaporated under reduced pressure, and the
crude material was purified by flash chromatography on silica gel.
62.5 MHz): d 20.1 (2CH3), 115.3 (Cq), 117.5 (CH), 117.8 (CH), 119.9
(CH),123.9 (CH),126.8 (CH),128.0 (CH),128.4 (CH),130.8 (2CHþCq),
131.7 (Cq), 133.8 (CH), 134.6 (CH), 134.8 (CH), 136.8 (CH), 137.4 (Cq),
138.4 (Cq), 138.7 (Cq), 139.1 (Cq); HRMS (EI) calcd for C22H20NO2S
362.1215, found 362.1210 (Mþ1)þ.
4.3. General procedure for the deprotection step
The reaction was performed in a 1–5 mmol scale under argon.
To a solution of the N-benzenesulfonylindoles 4, 5, 7–12, 20
(1 mmol) in THF (12 mL) was added the desired amount of Bu4NF
(1 M in THF) at room temperature. The solution was heated to
reflux for the desired time and after cooling water (10 mL) and
EtOAc (10 mL) were added. The aqueous layers were extracted with
EtOAc (3ꢂ10 mL) and the combined organic layers were washed
with brine (2ꢂ10 mL) then dried over MgSO4. The solvents were
removed under reduced pressure and the crude material was
purified by flash chromatography.
4.2.1. 1-Benzenesulfonyl-2-(6-methoxypyridine-2-yl)-1H-indole (5)
The reaction was performed with 2-bromo-6-methoxypyridine
(3.0 equiv) for 14 h. Compound 5 was isolated after column chro-
matography purification (PE/EtOAc 2:8 then MeOH) as a white solid
in 70% yield. Rf (petroleum ether/EtOAc 9:1) 0.25. Mp 106 ꢁC; IR
(KBr, cmꢀ1
)
n
1598, 1423, 1361, 1094; 1H NMR (DMSO-d6, 500 MHz):
d
3.80 (s, 3H, CH3), 6.89 (dd, 1H, J¼8.3, 0.6 Hz, H5), 7.00 (d, 1H,
0
0
J¼0.5 Hz, H3 ), 7.27–7.31 (m, 2H, H3, H5 ), 7.39 (ddd, 1H, J¼8.5, 7.2,
4.3.1. 2-(6-Methoxypyridin-2-yl)-1H-indole (14)
0
0
1.2 Hz, H6 ), 7.51 (t, 2H, J¼7.9 Hz, Hb), 7.58 (d, 1H, J¼7.9 Hz, H4 ), 7.62
(tt,1H, J¼7.5,1.3 Hz, Hc), 7.73 (dd, 2H, J¼8.5, 0.2 Hz, Ha), 7.82 (dd,1H,
The reaction was performed with 5 for 1 h 30 min to afford
after column chromatography purification (PE then PE/EtOAc 8:2)
compound 14 as a white solid in 94% yield. Rf (PE/EtOAc 8:2) 0.85.
J¼8.3, 7.2 Hz, H4), 8.02 (dd, 1H, J¼8.5, 0.8 Hz, H7 ); 13C NMR (DMSO-
0
d6, 62.9 MHz):
d
53.1 (CH3), 110.5 (CH), 114.2 (CH), 115.4 (CH), 118.4
Mp 139 ꢁC; IR (KBr, cmꢀ1 3435, 1593, 1465, 1416; 1H NMR
) n

A. Bourderioux et al. / Tetrahedron 64 (2008) 11012–11019
11017
(DMSO-d6, 500 MHz):
d
4.03 (s, 3H, CH3), 6.71 (d, 1H, J¼8.1 Hz,
J¼8.2 Hz), 7.64 (t, 1H, J¼8.3 Hz), 8.01 (d, 1H, J¼8.2 Hz), 8.34 (t, 1H,
J¼7.5 Hz), 8.66 (t, 1H, J¼8.8 Hz), 8.92 (d, 1H, J¼8.3 Hz), 9.26 (d, 1H,
J¼8.8 Hz), 10.56 (d, 1H, J¼7.0 Hz), 14.26 (s, 1H); 13C NMR (DMSO-d6,
0
0
H3), 7.01 (dt, 1H, J¼7.9, 0.8 Hz, H5 ), 7.12 (d, 1H, J¼1.5 Hz, H3 ), 7.14
0
0
(dt, 1H, J¼7.5, 1.0 Hz, H6 ), 7.50 (d, 1H, J¼8.1 Hz, H7 ), 7.55–7.58 (m,
2H, H4 , H5), 7.75 (t, 1H, J¼7.8 Hz, H4), 11.68 (s, 1H, NH); 13C NMR
125.8 MHz, 80 ꢁC):
d 24.5 (CH3), 111.7 (C), 113.7 (CH), 113.9 (CH),
0
(DMSO-d6, 62.5 MHz):
d
53.2 (CH3), 100.2 (CH), 108.6 (CH), 111.9
116.2 (CH), 119.3 (C), 122.7 (CH), 123.7 (CH), 124.8 (CH), 124.9 (CH),
131.1 (C), 132.7 (C), 133.3 (C), 134.9 (C), 138.0 (CH), 142.4 (C), 163.9
(CH), 112.5 (CH), 119.5 (CH), 120.6 (CH), 122.3 (CH), 128.4 (C), 136.9
(C), 137.0 (C), 139.8 (CH), 148.1 (C), 163.2 (C); HRMS (EI) calcd for
(CO), 165.1 (CO); HRMS (EI) calcd for C18H12N3O2 302.0930, found
ꢃ
ꢃ
C14H12N2O 224.09496, found 224.0947 (M)þ
.
302.0915 (M)þ
.
4.3.2. 2-(1H-Indol-2-yl)benzonitrile (17)
4.4.2. 6-[3-(4-Bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-
3-yl)-1H-indol-2-yl]-1H-pyridin-2-one (26)
The reaction was performed with 10 for 2 h to afford after col-
umn chromatography purification (PE/EtOAc 9:1 to 7:3) compound
17 as a pale yellow solid in a 88% yield. Rf (PE/EtOAc 8:2) 0.43. Mp
The reaction was performed starting from 22 and 23 (1.1 equiv)
with LiHMDS (3.2 equiv) at ꢀ20 ꢁC to rt for 1 h. After column
chromatography purification (PE/EtOAc 8:2 then 7:3) compound 26
was isolated as an orange solid in 58% yield. Rf (PE/EtOAc 2:8) 0.16.
150 ꢁC; IR (KBr, cmꢀ1
(DMSO-d6, 500 MHz):
)
d
n
3323, 2232, 1559, 1482, 748; 1H NMR
0
(ppm): 7.06 (dt, 1H, J¼7.5, 0.9 Hz, H5 ), 7.13
(dd, 1H, J¼2.1, 0.9 Hz, H3 ), 7.19 (ddd, 1H, J¼8.1, 7.0, 1.0 Hz, H6 ), 7.47
Mp 201–204 ꢁC (dec); IR (KBr, cmꢀ1
1441, 1379, 738; 1H NMR (DMSO-d6, 250 MHz, 80 ꢁC):
) n
3262, 2932, 1775, 1714, 1657,
2.99 (s, 3H,
0
0
0
(dd, 1H, J¼8.1, 0.9 Hz, H7 ), 7.53 (dt, 1H, J¼7.6, 1.2 Hz, H5), 7.64 (d, 1H,
d
0
J¼7.9 Hz, H4 ), 7.83 (dt, 1H, J¼7.7, 1.3 Hz, H4), 7.90 (d, 1H, J¼7.3 Hz,
CH3), 6.49 (d,1H, J¼8.5 Hz, H5), 7.00 (br s,1H, H3), 7.12 (dt, 1H, J¼7.5,
H3), 7.96 (dd, 1H, J¼7.8, 1.1 Hz, H6), 11.68 (s, 1H, NH); 13C NMR
1.0 Hz, H5 ), 7.25 (dt, 1H, J¼7.4, 1.0 Hz, H6 ), 7.49–7.52 (m, 2H, H4 ,
0
0
0
H7 ), 7.63 (t, 1H, J¼7.9 Hz, H4), 12.25 (s, 1H, NH); 13C NMR (DMSO-d6,
0
(DMSO-d6, 62.5 MHz):
d
102.7 (CH), 108.5 (C), 111.6 (CH), 119.0
(C)CN, 119.8 (CH), 120.8 (CH), 122.7 (CH), 128.0 (CH), 128.1 (C), 128.3
(CH), 133.6 (CH), 133.7 (C), 134.6 (CH), 135.1 (C), 137.1 (C); HRMS (EI)
calcd for C15H11N2 219.0922, found 219.0916 (Mþ1)þ.
62.5 MHz, HMBC): d 24.4 (CH3), 102.1 (C), 112.4 (CH), 120.5 (CH),
120.7 (CH), 123.4 (CH), 126.0 (C), 136.8 (CH), 140.2 (CH), 162.7 (CO),
167.1 (CO); HRMS (EI) calcd for C18H12N3O3 318.08787, found
ꢃ
318.0872 (MꢀBr)þ
.
4.3.3. 2-(Pyridin-N-oxide-2-yl)-1H-indole (21)
The reaction was performed with 20 during 3 h to afford after
purification (CH2Cl2/MeOH 9:1) compound 21 in 81% yield as
a yellow solid. Rf (CH2Cl2/MeOH 98:2) 0.19. Mp 120–124 ꢁC (dec); IR
4.4.3. 3-Bromo-4-[2-(2-fluoro-phenyl)-1H-indol-3-yl]-1-methyl-
pyrrole-2,5-dione (29)
The reaction was performed starting from 16 and 23 (1.3 equiv)
with LiHMDS (2.2 equiv) at ꢀ20 ꢁC to rt for 45 min. After purifica-
tion (PE/EtOAc 8:2) compound 29 was isolated as an orange solid
(KBr, cmꢀ1
250 MHz):
) n
3297, 3054, 1593, 1441, 1151, 747; 1H NMR (DMSO-d6,
d
7.02 (t, 1H, J¼6.0, 8.1 Hz), 7.16 (t, 1H, J¼8.1 Hz), 7.33 (td,
1H, J¼7.5, 2.1 Hz), 7.46 (t, 1H, J¼8.1 Hz), 7.53 (s, 1H), 7.61 (d, 2H,
in a 92% yield. Rf (PE/EtOAc 8:2) 0.20. Mp 183–185 ꢁC; IR (KBr, cmꢀ1
)
J¼8.1 Hz), 8.18 (dd, 1H, J¼8.1, 2.1 Hz), 8.37 (d, 1H, J¼7.5 Hz) 12.33 (s,
n
3528, 3282, 1752, 1697, 1466, 1419, 1222, 747; 1H NMR (DMSO-d6,
1H, NH); 13C NMR (DMSO-d6, 62.5 MHz):
d
105.7 (CH), 113.3 (CH),
250 MHz):
d
2.97 (s, 3H), 7.10 (t, 1H, J¼7.5 Hz), 7.22–7.46 (m, 3H),
120.6 (CH),121.3 (CH), 123.8 (CH),124.5 (CH),125.1 (CH), 126.7 (CH),
127.8 (C), 132.1 (C), 136.8 (C), 140.8 (C), 141.4 (CH); HRMS (EI) calcd
for C13H11N2O 211.0871, found 211.0867 (Mþ1)þ.
7.47–7.48 (m, 4H), 12.22 (s, 1H, NH); 13C NMR (DMSO-d6,
62.5 MHz):
d 24.7 (CH3), 106.4 (Cq), 113.1 (CH), 120.7 (CH), 120.9
(Cq), 123.0 (CH), 124.7 (C), 125.6 (C), 128.2 (CH), 130.5 (CH), 131.3
(CH), 133.0 (CH), 135.2 (C), 135.6 (C), 135.7 (C), 137.4 (CH), 148.0 (C),
163.7 (CO), 166.1 (CO); HRMS (EI) calcd for C19H12BrFN2O2
399.0144, found 399.0148 (Mþ1)þ.
4.4. General procedure for Michael addition
The reaction was performed in a 0.3–2.0 mmol scale under ar-
gon. To a cooled solution (ꢀ20 ꢁC) of deprotected indolyl com-
pounds 13, 15–19, 22 (1 mmol) in THF (10 mL) was added the
desired amount of LiHMDS (1 M in hexane). After 45 min the
electrophile 23 in THF (10 mL for 1 mmol) was added and the re-
action temperature adapted. After a few hours, the reaction was
hydrolyzed with an aqueous hydrochloric solution (1 N, pH¼2 or
pH¼7 with derivative 13) and the resulting mixture was extracted
with EtOAc (3ꢂ20 mL). The combined organic layers were washed
with brine (25 mL), dried over MgSO4, and the volatiles were re-
moved under reduced pressure. The crude residue was purified by
flash chromatography on silica gel.
4.4.4. 2-[3-(4-Bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-
3-yl)-1H-indol-2-yl]-benzonitrile (30)
The reaction was performed starting from 17 and 23 (2.0 equiv)
with LiHMDS (3.2 equiv) at ꢀ20 ꢁC to rt for 45 min. After purifica-
tion (PE/EtOAc 8:2 then 7:3) compound 30 was isolated as an or-
ange solid in a 65% yield. Rf (PE/EtOAc 8:2) 0.13. Mp 125–127 ꢁC
(dec); IR (KBr, cmꢀ1
(DMSO-d6, 500 MHz):
)
n
3320, 2223, 1774, 1710, 1382, 737; 1H NMR
0
d
2.96 (s, 3H, CH3), 7.18 (t, 1H, J¼7.4 Hz, H5 ),
0
0
7.29 (t, 1H, J¼7.2 Hz, H6 ), 7.54 (d, 1H, J¼8.3 Hz, H7 ), 7.61–7.65 (m,
0
2H, H4 , H5), 7.68 (d, 1H, J¼7.7 Hz, H3), 7.82 (d, 1H, J¼6.6 Hz, H4), 7.97
(d, 1H, J¼7.2 Hz, H6), 12.45 (s, 1H, NH); 13C NMR (DMSO-d6,
62.5 MHz):
d 25.1 (CH3), 103.4 (C), 111.5 (C), 112.6 (CH), 118.6 (C),
4.4.1. 2-Methyl-1H-indolo[2,3-a]pyrrolo[3,4-c]quinolizinium-1,3-
(2H)-dione bromide (25)
121.1 (CH), 121.8 (CH), 121.9 (C), 123.8 (CH), 126.7 (C), 129.8 (CH),
131.5 (CH),134.1 (CH),134.6 (CH),136.2 (C),136.4 (C),137.0 (C),139.1
The reaction was performed starting from 13 and 23 (2.3 equiv)
with LiHMDS (2.2 equiv) at ꢀ20 ꢁC to rt for 1 h. After hydrolysis and
a rapid flash chromatography (PE/EtOAc 7:3) the very instable
compound 24 could be isolated in a 43% yield as an orange solid.
After hydrolysis and removing of the volatiles, the crude material
containing in majority 24 was dissolved in DMA (30 mL) and the
solution was heated at 120 ꢁC for 30 min. After cooling, the reaction
mixture was filtered and the solid was washed successively with
THF (10 mL) and Et2O (10 mL), and dried under reduced pressure to
afford compound 25 as a yellow solid in 80% yield. Rf (MeOH) 0.01.
(C), 166.5 (CO), 168.6 (CO); HRMS (EI) calcd for C20H12N3O2Br
ꢃ
405.01129, found 405.0116 (M)þ
.
4.4.5. 3-Bromo-1-methyl-4-[2-(2-nitro-phenyl)-1H-indol-3-yl]-
pyrrole-2,5-dione (31)
The reaction was performed starting from 18 and 23 (2.0 equiv)
with LiHMDS (3.2 equiv) at ꢀ20 ꢁC to rt for 5 h. After column
chromatography purification (PE/EtOAc 8:2) compound 31 was
isolated as an orange solid in a 38% yield. Rf (PE/EtOAc 8:2) 0.15. Mp
190–192 ꢁC; IR (KBr, cmꢀ1
735; 1H NMR (DMSO-d6, 250 MHz):
J¼7.5 Hz), 7.28 (t, 1H, J¼7.8 Hz), 7.46 (d, 1H, J¼8.1 Hz), 7.54–7.63 (m,
)
n
3310, 3046, 1774,1707, 1529, 1382, 983,
2.99 (s, 3H), 7.14 (t, 1H,
Mp >250 ꢁC; IR (KBr, cmꢀ1
766; 1H NMR (DMSO-d6, 500 MHz, 80 ꢁC):
)
n
3033, 1750, 1725, 1528, 1426, 1350,
3.31 (s, 3H), 7.47 (t, 1H,
d
d

11018
A. Bourderioux et al. / Tetrahedron 64 (2008) 11012–11019
2H), 7.67 (t, 1H, J¼7.2 Hz), 7.78 (s, 1H, J¼7.2 Hz), 8.11 (d, 1H,
orange solid in a 80% yield. Rf (PE/EtOAc 85:15) 0.45. Mp 188–
190 ꢁC; IR (KBr, cmꢀ1
3292, 1751, 1682, 1446, 1378, 1052, 743;
1H NMR (DMSO-d6, 250 MHz):
2.48 (s, 3H), 2.93 (s, 3H, CH3),
J¼7.8 Hz), 12.30 (s, 1H, NH); 13C NMR (DMSO-d6, 62.5 MHz):
d
25.7
) n
(CH3), 103.4 (C), 113.0 (CH), 121.5 (CH), 122.4 (C), 122.8 (C), 124.1 (C),
126.2 (CH), 127.2 (CH), 128.0 (CH), 121.4 (CH), 131.4 (CH), 134.0 (CH),
134.8 (C), 136.6 (C), 137.6 (C), 138.8 (C), 149.3 (C), 167.1 (CO), 169.2
(CO); MS (IS): 426.5 ((Mþ1)þ, 79Br), 428.5 ((Mþ1)þ, 81Br).
d
3.05 (s, 3H, CH3), 7.29–7.34 (m, 2H), 7.48 (t, 1H, J¼7.8 Hz), 7.67 (d,
1H, J¼7.8 Hz), 8.22 (s, 1H), 7.87 (d, 1H, J¼7.8 Hz), 12.63 (s, 1H,
NH); 13C NMR (DMSO-d6, 62.5 MHz):
d 22.8 (CH3), 25.3 (CH3),
27.3 (CH3), 113.1 (CH), 113.2 (C), 120.6 (C), 121.5 (CH), 122.0 (CH),
122.9 (C), 125.6 (C), 125.9 (C), 126.2 (CH), 127.9 (CH), 130.3 (C),
134.6 (CH), 137.1 (C), 138.4 (C), 141.8 (Cq), 142.6 (Cq), 170.3 (CO),
4.4.6. 3-Bromo-4-[2-(3,5-dimethyl-phenyl)-1H-indol-3-yl]-1-
methyl-pyrrole-2,5-dione (32)
The reaction was performed starting from 19 and 23 (2.0 equiv)
with LiHMDS (3.0 equiv) at ꢀ20 ꢁC to rt for 45 min. After purifica-
tion on a silica gel column (PE/EtOAc 8:2) compound 32 was
isolated as a red solid in 75% yield. Rf (PE/EtOAc 8/2) 0.65. Mp
170.4 (CO); HRMS (EI) calcd for C21H16N2O2 328.12118, found
ꢃ
328.1213 (M)þ
.
4.5.4. 1-Benzenesulfonyl-2-(pyridin-N-oxide-2-yl)-1H-indole (20)
To a solution of compound 4 (473 mg, 1.41 mmol) in CHCl3
(20 mL) was portionwise added at 0 ꢁC m-CPBA (400 mg, 70% in
water, 1.62 mmol). The reaction mixture was stirred at room tem-
perature for 12 h then a saturated aqueous solution of NaHCO3
(20 mL) was added. The aqueous layers were extracted with EtOAc
(3ꢂ20 mL) and the combined organic layers were washed with
brine (20 mL) and dried over MgSO4. After filtration the solvents
were removed under reduced pressure and a flash chromatography
(CH2Cl2/MeOH 98:2) afforded the compound 20 as a pale yellow
solid (393 mg, 79%). Rf (CH2Cl2/MeOH 98:2) 0.15. Mp 204–206 ꢁC
194–196 ꢁC; IR (KBr, cmꢀ1
1384, 746; 1H NMR (DMSO-d6, 250 MHz):
)
n
3380, 2934, 2854, 1710, 1618, 1450,
2.30 (s, 6H, CH3), 2.97 (s,
d
3H), 7.01 (s, 1H), 7.09 (t, 1H, J¼7.9 Hz), 7.18–7.23 (m, 3H), 7.45–7.48
(d, 2H, J¼7.1 Hz), 12.11 (s, 1H, NH); 13C NMR (DMSO-d6, 62.5 MHz):
d
19.7 (2CH3), 23.4 (CH3), 98.5 (C), 110.6 (CH), 118.9 (CH), 119.3 (CH),
120.9 (CH), 121.2 (C), 124.2 (C), 125.5 (2CH), 128.7 (C), 130.7 (CH),
135.0 (C), 136.6 (2C), 138.2 (2C), 164.8 (CO), 167.0 (CO); HRMS (EI)
calcd for C21H18BrN2O2 409.0552, found 409.0569 (Mþ1)þ.
4.5. General procedure for palladium assisted
benzannulation
(dec); IR (KBr, cmꢀ1
(DMSO-d6, 250 MHz):
)
n
1433, 1466, 1376, 1172, 1069, 756; 1H NMR
7.04 (s,1H), 7.24 (t,1H, J¼7.5 Hz), 7.32 (t,1H,
d
The reaction was performed in a 0.3–0.8 mmol scale. A solution
containing the bromo derivative 28, 29, 31, and 32(0.5 mmol), Bu4NCl
(1.0 equiv), AcONa (2.0 equiv), PPh3 (2.0 equiv) in dioxane (5 mL) was
degassed by argon bubbling during 30 min. Pd(OAc)2 (1.0 equiv) was
then added in one portion and the reaction mixture was immersed
into a preheated oil bath at 110 ꢁC for the desired time. After cooling,
water (15 mL) and EtOAc (15 mL) were added, and the solution was
filtered. The precipitate was washed with EtOAc (3ꢂ10 mL) and the
aqueous layers were discarded. The combined organic layers were
dried over MgSO4, evaporated under reduced pressure, and the crude
material was purified by flash chromatography.
J¼8.3 Hz), 7.49–7.63 (m, H), 7.72 (dd, 1H, J¼2.2, 7.9 Hz), 7.81 (d, 1H,
J¼8.1 Hz), 7.92 (d, 2H, J¼7.6 Hz), 8.39 (d, 1H, J¼6.0 Hz); 13C NMR
(DMSO-d6, 62.5 MHz):
d 116.9 (CH), 117.1 (CH), 124.9 (CH), 126.9
(CH), 128.0 (CH), 128.6 (CH), 128.8 (2CH), 132.0 (Cq), 132.3 (CH),
132.6 (3CH), 135.3 (C), 137.6 (CH), 138.9 (C), 140.5 (CH), 142.5 (C),
144.9 (C); HRMS (EI) calcd for C19H15N2O3S 351.0807, found
351.0807 (Mþ1)þ.
4.5.5. 6-(1H-Indol-2-yl)-1H-pyridin-2-one (22)
A solution of compound 14 (300 mg, 1.34 mmol) water (15 mL),
and an acetic HBr solution (15 mL, 30% in acetic acid) was refluxed
for 6 h. After cooling at room temperature, a saturated aqueous
NaHCO3 solution was next slowly added till pH¼7. After extraction
with EtOAc (3ꢂ100 mL), the combined organic layers were
washed with water (2ꢂ100 mL), dried over MgSO4, filtered, and
evaporated under reduced pressure. The compound 22 was iso-
lated as a pale yellow solid (249 mg, 89% yield). Rf (petroleum
4.5.1. 2-(Methyl)-9-(fluoro)benzo[a]pyrrolo[3,4-c]carbazole-1,3-
(2H,8H)dione (34)
The reaction was performed starting from 29 for 5 h. After puri-
fication (PE/EtOAc 8:2) compound 34 was isolated as a yellow solid
in 75% yield. Rf (PE/EtOAc 8:2) 0.55. Mp 235–237 ꢁC; IR (KBr, cmꢀ1
) n
3290, 3053, 1750, 1700, 1220, 765; 1H NMR (DMSO-d6, 250 MHz):
ether/EtOAc 8:2) 0.53. Mp >250 ꢁC; IR (KBr, cmꢀ1
)
n
3261, 1662,
1
d
3.11 (s, 3H, CH3), 7.29–7.37 (d, 1H, J¼7.5 Hz), 7.49–7.60 (m, 2H),
1615, 1464, 798; H NMR (DMSO-d6, 500 MHz, 50 ꢁC): 6.35 (d, 1H,
J¼8.7 Hz, H5), 6.89 (br d, 1H, J¼6.5 Hz, H3), 7.03 (dt, 1H, J¼7.5,
7.72–7.82 (m, 1H), 7.85 (d, 1H, J¼8.2 Hz), 8.75 (d, 1H, J¼8.2 Hz), 8.93
(d, 1H, J¼7.8 Hz), 12.31 (s, 1H, NH). Compound was not soluble
0
0
0.8 Hz, H5 ), 7.17 (dt, 1H, J¼7.7, 1.1 Hz, H6 ), 7.21 (d, 1H, J¼1.5 Hz,
13
enough to perform a C NMR experiment at 80 ꢁC (125.8 MHz);
H3 ), 7.43 (d, 1H, J¼8.3 Hz, H7 ), 7.54 (dd, 1H, J¼8.8, 7.1 Hz, H4), 7.57
0
0
ꢃ
HRMS (EI) calcd for C19H11N2O2F 318.08046, found 318.0810 (M)þ
.
(d, 1H, J¼7.9 Hz, H4 ), 11.33 (br s, 2H, NH); 13C NMR (DMSO-d6,
0
62.5 MHz):
d 101.6 (CH), 103.8 (CH), 111.3 (CH), 115.1 (CH), 119.4
4.5.2. 2-(Methyl)-9-(nitro)benzo[a]pyrrolo[3,4-c]carbazole-1,3-
(CH), 120.4 (CH), 122.5 (CH), 127.7 (C), 132.1 (C), 137.0 (Cq), 140.0
(2H,8H)dione (35)
(CH), 141.5 (C), 162.5 (C]O); HRMS (EI) calcd for C13H10N2O
ꢃ
The reaction was performed starting from 31 for 6 h. After pu-
rification (petroleum ether/EtOAc 8:2) compound 35 was isolated
as an orange solid in 36% yield. Rf (PE/EtOAc 85:15) 0.38. Mp 196–
210.07931, found 210.0803 (M)þ
.
4.5.6. 5-Methyl-4,6-dioxopyrrolo[3,4-c]carbazole-
[a-4,5] pyridinone (27)
198 ꢁC; IR (KBr, cmꢀ1
(DMSO-d6, 250 MHz):
)
n
3420, 1752, 1702, 1516, 1340, 737; 1H NMR
3.13 (s, 3H, CH3), 7.41–7.51 (t, 1H, J¼7.8 Hz),
d
A solution of compound 26 (100 mg, 0.251 mmol) in DMSO
(2 mL) was stirred at room temperature for 48 h. The precipitate
was filtered, washed with MeOH (3ꢂ1 mL) to afford compound 27
as an orange solid in a quantitative manner (79 mg). Rf (PE/EtOAc
7.85–7.94 (m, 3H), 7.94 (d, 1H, J¼7.8 Hz), 9.01 (d, 1H, J¼7.8 Hz), 9.37
(d, 1H, J¼8.1 Hz), 12.76 (s, 1H, NH); 13C DEPT NMR (DMSO-d6,
125.8 MHz, 80 ꢁC):
d 24.1 (CH3), 112.8 (CH), 123.4 (CH), 124.4 (CH),
127.0 (CH), 127.6 (CH), 129.1 (CH), 131.8 (CH); HRMS (EI) calcd for
2:8) 0.68. Mp 173–175 ꢁC (dec); IR (KBr, cmꢀ1
1438, 1384; 1H NMR (DMSO-d6, 500 MHz):
)
n
3384, 1756, 1675,
ꢃ
C19H11N3O4 345.07496, found 345.0748 (M)þ
.
d 3.04 (s, 3H), 6.74 (d,
0
1H, J¼10.0 Hz, H3), 7.33 (t, 1H, J¼7.5 Hz, H5 ), 7.57 (t, 1H, J¼7.7 Hz,
0
0
4.5.3. 2-(Methyl)-10,12-(dimethyl)benzo[a]pyrrolo[3,4-c]-
carbazole-1,3-(2H,8H)dione (36)
The reaction was performed starting from 32 for 7 h. After
purification (PE/EtOAc 8:2) compound 36 was isolated as an
H6 ), 7.68 (d, 1H, J¼8.1 Hz, H7 ), 8.68 (d,1H, J¼9.7 Hz, H4), 8.74 (d, 1H,
J¼8.1 Hz, H4 ), 11.85 (s, 2H, NH); 13C NMR (DMSO-d6, 62.5 MHz):
0
d 23.5 (CH3), 93.5 (C), 111.4 (C), 112.0 (CH), 117.7 (C), 118.7 (C),
120.2 (C), 120.9 (CH), 123.3 (CH), 124.3 (CH), 128.1 (CH), 128.5 (C),

A. Bourderioux et al. / Tetrahedron 64 (2008) 11012–11019
11019
9. (a) Routier, S.; Ayerbe, N.; Me´rour, J.-Y.; Coudert, G.; Bailly, C.; Pierre, A.; Pfeiffer,
B.; Caignard, D.-H.; Renard, P. Tetrahedron 2002, 58, 6621–6630; (b) Lefoix, M.;
Coudert, M.; Routier, S.; Pfeiffer, B.; Caignard, D. H.; Alain Pierre´, A.; Golsteyn,
135.7 (CH), 140.3 (C), 161.2 (CO), 169.1 (CO); HRMS (EI) calcd for
ꢃ
C18H11N3O3 317.08004, found 317.0785 (M)þ
.
´
´
R.; Leonce, S.; Bossard, C.; Merour, J. Y. Bioorg. Med. Chem. 2008, 16, 5303–5321.
10. (a) Routier, S.; Peixoto, P.; Me´rour, J.-Y.; Coudert, G.; Bailly, C.; Pierre, A.; Le´once,
Acknowledgements
´rour, J.-Y.;
S.; Caignard, D.-H. J. Med. Chem. 2005, 48,1401–1413; (b) Routier, S.; Me
Dias, N.; Lansiaux, A.; Bailly, C.; Lozach, O.; Meijer, L. J. Med. Chem. 2006, 49,
789–799.
´
ˆ
We thank the Canceropole Grand Ouest and the Association
pour la Recherche contre le Cancer (ARC) for the financial support
of this work.
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