Synthesis of 11a- N -Arylsulfonyl-5-carbapterocarpans (Tetrahydro-5 H -benzo[ a ]carbazoles) by Azaarylation of Dihydronaphthalenes with o -Iodo- N -(Arylsulfonyl)anilines in Poly(ethylene glycol)

Article abstract of DOI:10.1055/s-0034-1380757

11a-N-Arylsulfonyl-5-carbapterocarpans (tetrahydro-5H-benzo[a]carbazoles) were synthesized by palladium-catalyzed azaarylation of dihydronaphthalenes with o-iodo-N-(arylsulfonyl)anilines in poly(ethylene glycol) (PEG-400). Better chemical yields (moderate

Full text of DOI:10.1055/s-0034-1380757

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 3013–3019
3013
paper
Synthesis
J. C. F. Barcellos et al.
Paper
Synthesis of 11a-N-Arylsulfonyl-5-carbapterocarpans (Tetrahy-
dro-5H-benzo[a]carbazoles) by Azaarylation of Dihydronaphtha-
lenes with o-Iodo-N-(Arylsulfonyl)anilines in Poly(ethylene glycol)
Julio C. F. Barcellosa
Beatriz H. F. Borgesa
Joseane A. Mendesb
Mauricio C. Ceronb
Camilla D. Buarque*b
Ayres G. Dias*c
Paulo R. R. Costa*a
a
Laboratório de Química Bioorgânica, Núcleo de Pesquisas de
Produtos Naturais, Universidade Federal do Rio de Janeiro,
Centro de Ciências da Saúde, Bloco H, Ilha da Cidade
Universitária, 21941-590, Rio de Janeiro, RJ, Brazil
b
Departamento de Química, Pontifícia Universidade Católica
do Rio de Janeiro, R. Marquês de S. Vicente 225, Gávea,
2
2435-900, Rio de Janeiro, RJ, Brazil
c
Instituto de Química, Universidade do Estado do Rio de
Janeiro, R. S. Francisco Xavier 524, 20550-900, Rio de
Janeiro, RJ, Brazil
prrcosta2011@gmail.com
Received: 06.02.2015
Accepted after revision: 16.04.2015
Published online: 24.06.2015
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H
H
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DOI: 10.1055/s-0034-1380757; Art ID: ss-2015-m0091-op
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Abstract 11a-N-Arylsulfonyl-5-carbapterocarpans
(tetrahydro-5H-
S
O
S
benzo[a]carbazoles) were synthesized by palladium-catalyzed azaaryla-
tion of dihydronaphthalenes with o-iodo-N-(arylsulfonyl)anilines in po-
ly(ethylene glycol) (PEG-400). Better chemical yields (moderate to
good) and shorter reaction times (a few minutes at 130–170 °C) were
observed in PEG-400 compared with the corresponding reactions in
acetone.
H
O
6
a)N)analogue of
+±)medicarpin
(
(± ±)LQB)226
(± ±)3a LQB)223
Figure 1 11a-N-Pterocarpans and a carba analogue
Key words arylations, sulfonamides, cyclizations, heterocyclic com-
pounds, polycyclic compounds, indolines, solvent effects, catalysis, pal-
ladium
LQB-223 (3a) displayed antineoplastic activities against
Crotonates undergo tandem Heck lactamizations with
a series of cancer cells lines3a (including leukemias with the
3b
arylpalladium species bearing an amine group or an N-pro-
tected derivative at the ortho-position to give six-mem-
multidrug-resistant phenotype), antileishmanial activity
in culture,3a and antimalarial activity in mice.3c Interesting-
ly, in 2013 the first example of a natural 11a-N-pterocar-
pan, an analogue of medicarpin isolated from the roots of
1a
bered heterocycles such as quinolones or naphthyridi-
1b
nones. In contrast, indolines are obtained by azaarylation
2
a
2a
2b
4
reactions when cyclohexadiene, acyclic dienes, indene,
Robinia pseudoacacia, was reported in the literature. The
2c
dihydronaphthalene,2b,c allenes,2d or
60]fullerene are used as olefins. A stereoselective aryl-
norbornadiene,
pharmacological properties of LQB-223 (3a) encouraged us
to study the scope of the azaarylation reactions of a group
of dihydronaphthalenes and N-(arylsulfonyl)-o-iodoani-
lines. We surmised that poly(ethylene glycol) with a molec-
ular weight of 400 (PEG-400) might be useful as a solvent
for these reactions, as it has been used as a green solvent for
palladium-catalyzed Heck reactions and Stille, Sonogashira,
2e
[
palladium-catalyzed cyclopentannulation of diazabicyclic
alkenes with ortho-functionalized aryl halides under mi-
2f
crowave irradiation has also been reported.
As part of a program to identify new compounds with
antineoplastic properties based on a modification of the
chemical structures of isoflavonoids, we previously synthe-
sized LQB-226, a 11a-N-tosylpterocarpan and its 5-carba
analogue LQB-223 (3a) by azaarylation of chromene or di-
hydronaphthalene, respectively, with N-(2-iodophenyl)-4-
5
and Suzuki–Miyaura cross-coupling reactions. Moreover,
Liu and co-workers5e and Razler et al. had shown that PEG-
400 and PEG-2000, respectively, promote the formation of
palladium nanoparticles, increasing the efficiency of the
catalyst in Suzuki coupling reactions. We report rapid, li-
5i
3a
toluenesulfonamide (Figure 1).
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Synthesis
J. C. F. Barcellos et al.
Paper
R1
I
R2
R3
H
O
;
N
S
O
2 a, X = Y = H, Z = Me
b, X = NO2, Y = Z = H
c, X = H, Y = NO2, Z = H
d, X = Y = H, Z = NO2
1
1e
X
Y
1
2
3
a, R = R = R = H
1
2
3
b, R = OMe, R = R = H
1
2
3
c, R = H, R = OMe, R = H
1
2
3
Z
d, R = R = H, R = OMe
H
R1
R2
H
O
N
5
1
2
3
H
3a, R = R = R = H, X = Y = H, Z = Me
S
1
2
3
O
R3
3b, R = OMe, R = R = H, X = Y = H, Z = Me
3c, R2 = OMe, R1 = R3 = H, X = Y = H, Z = Me
H
N
3
1
2
O
3d, R = OMe, R = R = H, X = Y = H, Z = Me
S
1
2
3
3
f, R = R = R = H, Y = Z = H, X = NO2
O
1
2
3
X
3g, R = R = R = H, X = Z = H, Y = NO2
3
e
1
2
3
3
3
h, R = R = R = H, X = Y = H, Z = NO2
2
1
3
i, R = OMe, R = R = H, X = Y = H, Z = NO2
Y
Z
Figure 2 Olefins 1a–e, N-(phenylsulfonyl)-o-iodoanilines 2a–d, and tetrahydro(benzo)carbazoles 3a–i
gand-free, azaarylations of 1,2-dihydronaphthalene (1a), its
oxygenated derivatives 1b–d, and cyclohexa-1,3-diene (1e)
with N-(2-iodophenyl)-4-toluenesulfonamide (2a) or its ni-
tro derivatives 2b–d in the presence of palladium(II) acetate
as a precatalyst, silver(I) carbonate as a base, and PEG-400
as the solvent to give the tetrahydro(benzo)carbazoles 3a–i
in PEG-400 was clean, and the crude products could be
readily purified by flash chromatography and subsequent
crystallization.
To examine further the scope of this reaction, we select-
ed the methoxylated dihydronaphthalenes 1b–d as olefins.
These compounds were prepared from the corresponding
commercially available α-tetralones by carbonyl-group re-
(Figure 2).
3
As previously described, tetrahydrobenzocarbazole 3a
was obtained in good yield by palladium-catalyzed [10
mol% Pd(OAc) ] azaarylation of 1,2-dihydronaphthalene
H
H
2
(
1a) with sulfonamide 2a in refluxing acetone containing
H
i, ii
H
H
N
N
three equivalents of silver carbonate (Table 1, entry 1). The
same yield was obtained when 1.2 equivalents of silver car-
bonate were used, although the reaction time increased
from 12 hours to 20 hours (entry 2). With microwave irra-
diation (200 W, 120 °C) in acetone, the reaction was faster,
but the yield fell from 85% to 70% (entry 3). We then exam-
ined the use of PEG-400 as solvent and, after some experi-
mentation, we decided to use 10 mol% of palladium(II) ace-
tate and 1.2 equivalents of silver carbonate at 170 °C (entry
O
H
40%
S
O
3
f
CF3CO2
iv
4
NO2
iv
iv
iii
H
H
H
H
H
H
O
N
N
N
O
O
O
S
O
S
O
S
4
); under these conditions, compound 3a was obtained in
80% yield after only three minutes. Similar yields were ob-
tained when 5 or 2.5 mol% of palladium(II) acetate was used
as the precatalyst (entries 6 and 7, respectively), although
longer reaction times of 25 and 40 minutes, respectively,
were required. A moderate yield was obtained in the pres-
ence of 1 mol% of palladium(II) acetate after two hours of
reaction (entry 7). In contrast with acetone, the reaction in
3
l
3k
51%
3j
5
2%
3
5
2% from 4
0% from 3f
O
N
Scheme 1 Synthetic approaches to sulfonamides 3j, 3k, and 3l. Reac-
tion conditions: (i) PhSH (5% in DMF), K CO , r.t., 5 min; (ii) TFA, Et O,
r.t., 5 min; (iii) RSO Cl, py, CHCl , 40 °C, 20 h; (iv) (i) then (iii) (N–H in-
2
3
2
2
3
termediate used without purification).
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Synthesis
J. C. F. Barcellos et al.
Paper
duction followed by elimination of water from the resulting
alcohols. Cyclohexa-1,3-diene (1e) is commercially avail-
able.
The substituted dihydronaphthalene 1b was as reactive
as 1a, but the reactions were less clean and gave lower
yields of tetrahydrobenzocarbazole 3a (Table 1; entries 8–
mol% of palladium(II) diacetate in PEG-400 than for the cor-
responding reactions in acetone (entries 11–16). As in the
case of 1b, the reactions of 1c and 1d were also performed
at 130 °C to minimize the formation of byproducts.
When cyclohexadiene reacted with sulfonamide 2a in
acetone, extensive degradation was observed and, after 4
hours, all the starting materials were consumed and adduct
3e obtained in only 20% yield (entry 17). Interestingly, ad-
duct 3e was obtained in 41% yield in PEG-400, but 25 hours
at 100 °C was necessary to ensure complete consumption of
1e, demonstrating the low reactivity of this conjugate diene
(entry 18).
As the antineoplastic action of compounds this type is
dependent on the type of substituent on the nitrogen atom,
we examined the azaarylation of 1a and 1c with sulfon-
amides 2b–d to give tetrahydrobenzocarbazoles 3f–i (Table
2).
6
10). In acetone, 3b was obtained in 45% yield, after 20 hours
of reaction (entry 8). Extensive degradation was observed
when olefin 1b was allowed to react with sulfonamide 2a in
PEG-400 at 170 °C; however, when the temperature was de-
creased to 130 °C, product 3b was obtained in the same
yield after 10 minutes of reaction (entry 9). The yield in
PEG-400 decreased when 5 mol% of palladium(II) acetate
was used as the precatalyst (entry 10). The same trend was
observed for the other azaarylations reactions studied, and
adducts 3c and 3d were obtained in shorter reaction times
and in better chemical yields in the presence of 5 or 10
Table 1 Azaarylation of 1,2-Dihydronaphthalenes 1a–d with N-(2-Iodophenyl)-4-toluenesulfonamide (2a)
H
N
R1
I
O
S
R2
H
O
R1
H
R2
Pd(OAc±2
Ag2CO3
Pd(OAc±2
Ag CO
H
+
R3
1e 2a
+
H
N
2
3
R3
N
O
S
S
O
O
O
1a–d
2a
3
3e
Entry
1
R1
R2
R3
Conditionsa Pd(OAc)
2
(mol%) Temp (°C)
Time
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
H
H
H
A
B
10
10
10
10
5
60
60
12 h
20 h
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3c
3c
3c
3d
3d
3d
3e
3e
85
85
70
80
80
73
45
45
45
35
35
55
50
24
42
30
20
41
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C
D
D
D
D
B
120
170
170
170
170
60
20 min
3 min
25 min
40 min
2 h
H
H
H
2.5
H
1
10
10
5
OMe
OMe
OMe
H
H
20 h
H
D
D
B
130
130
60
10 min
10 min
20 h
10
11
12
13
14
15
16
17
8
H
OMe
OMe
OMe
H
H
10
10
5
H
H
D
D
B
130
130
60
10 min
40 min
20
H
H
H
OMe
OMe
OMe
10
10
5
H
H
D
D
B
130
130
60
30 min
50 min
4 h
H
H
cyclohexa-1,3-diene
cyclohexa-1,3-diene
10
10
1
E
100
25 h
a
Conditions A: Pd(OAc)
2
, Ag
2
CO
3
(3 equiv), acetone, reflux. Conditions B: Pd(OAc)
2
, Ag
2
CO
3
2 2 3
(1.2 equiv), acetone, reflux. Conditions C: Pd(OAc) , Ag CO (1.1
equiv), acetone, MW (200 W), 120 °C, 20 min. Conditions D: Pd(OAc)
2
, Ag
2
CO
3
(1.2 equiv), PEG-400; E: Pd(OAc)
2
, Ag CO (2 equiv), PEG-400.
2
3
b
Yield after crystallization of the crude product (MeOH–hexane).
c
2 3
Ag CO (2 equiv).
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Table 2 Azaarylation of Dihydronaphthalenes 1a and 1c with Sulfonamides 2b–d
R1
R2
R3
H
H
I
R1
O
conditions
B or D
H
R2
R3
N
O
N
S
O
O
+
X
S
X
Y
Y
1a,c
2
3
Z
Z
Entry
1
R1
R2
R3
2
X
Y
Z
Conditionsa Time (h)
Product Yield (%)
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1c
1c
H
H
H
2b
2b
2c
2c
2d
2d
2d
2d
NO
2
H
H
H
H
H
B
20
1
3f
46
60
30
43
35
60
40
41
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
D
B
3f
NO
NO
H
2
20
3g
3g
3h
3h
3i
2
D
B
1.5
NO
NO
NO
NO
2
2
2
2
20
1
H
D
B
OMe
OMe
H
20
2
8
H
D
3i
a
2 2 3 2 2 3
Conditions B: Pd(OAc) (10 mol%), Ag CO (1.2 equiv), acetone, reflux. Conditions D: Pd(OAc) (10 mol%), Ag CO (1.2 equiv), PEG-400, 100 °C.
As observed for 2a, shorter reaction times were re-
quired in PEG-400 at 100 °C than in refluxing acetone (Table
chloride [5-(dimethylamino)naphthalene-1-sulfonyl chlo-
ride] in pyridine gave the dansyl derivative 3j in 32% yield.
5
2
). Azaarylation of 1a with 2b–d gave the corresponding
tetrahydrobenzocarbazoles 3f–h in moderate yields in PEG-
00 (Conditions D; Table 2, entries 2, 4, and 6), but in low
To increase the efficiency of this process, we decided to in-
vestigate the use of the unpurified free amino derivative in-
termediate obtained from 3f. Under these conditions, sul-
fonamides 3j, 3k, and 3l were obtained in yields of about
50%. The dansyl group is fluorescent, and its chloride reacts
with basic amino acids of proteins, permitting studies of
4
yields in acetone (Conditions B; entries 1, 3, and 5).
Azaarylation of olefin 1c with 2d under Conditions B and D
gave adduct 3i in similar moderate yields (entries 7 and 8).
The relative configuration of H6a and H11a in com-
8
the cellular localization of the resulting marked proteins.
1
pounds 3a–i and 4 was determined by H NMR spectrosco-
py. The presence of doublets for H11a (δ = 5.2–5.5 ppm)
with JH11a,6a = 8.0–8.9 Hz in each of their spectra is in agree-
ment with the proposed cis-stereochemistry; this configu-
3
Table 3 Chemical Shifts in CDCl
3
and NOESY Interactions for Adduct
3
b
ration was confirmed by a NOESY experiment; Table 3
shows the NOESY interactions for adduct 3b as an example.
An additional possibility for the introduction of chemi-
cal diversity at the nitrogen atom is the removal of the N-
arylsulfonyl group (Scheme 1). The use of thiophenol to
cleave an o-nitroarylsulfonyl group in the corresponding
O
H5'
H6
H5
H6'
H
6
a
H1
H
7
N
sulfonamide had been reported, and we therefore tried us-
11a
ing these conditions. The reaction of tetrahydrobenzocar-
bazole 3f was very rapid, and the resulting amine was ob-
tained in pure form by dissolving the crude product in di-
ethyl ether and adding trifluoroacetic acid to precipitate the
corresponding trifluoroacetate salt 4. As expected, neither
Ts
3b
H atom
δ (ppm)
NOESY
H1
7.61
2.15
3.01
5.41
H-11a
3
g nor 3h gave 4 when treated under similar conditions.7c
Compound 4 was used in an alternative approach to
H6
H-6a, H-5
H-11a, H-6, H-5
H-6a, H-1
H6a
H11a
prepare
other
N-(arylsulfonyl)-5-carbapterocarpans
(Scheme 1). Treatment of the isolated salt 4 with dansyl
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3013–3019

3
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Synthesis
J. C. F. Barcellos et al.
Paper
1
In conclusion, the use of PEG-400 as solvent permitted
the desired transformations to be carried out in the absence
of ligands within 10–60 minutes at 130–170 °C. Protection
of the nitrogen atom with a (2-nitrobenzenesulfonyl) group
provides an alternative approach to the preparation of the
target compounds. The pharmacological properties of these
new compounds and their derivatives are under investiga-
tion.
H NMR (400 MHz, CDCl ): δ = 7.97 (d, J = 7.8 Hz, 1 H), 7.59 (d, J = 8.0
3
Hz, 1 H), 7.48 (d, J = 8.3 Hz, 2 H), 7.28–7.06 (m, 6 H), 7.02 (d, J = 7.4 Hz,
H), 6.91 (d, J = 7.6 Hz, 1 H), 5.38 (d, J = 8.5 Hz, 1 H), 3.10–3.04 (m, 1
H), 2.50–2.44 (m, 2 H), 2.35 (s, 3 H), 2.16–1.90 (m, 2 H).
1
13
C NMR (APT; 101 MHz, CDCl ): δ = 152.15, 137.57, 136.24, 135.60,
3
1
1
34.37, 130.49, 129.56, 127.97, 127.86, 127.34, 127.07, 126.82,
25.71, 123.39, 119.96, 64.01, 39.45, 24.85, 23.64, 21.553.
+
HRMS (ESI): m/z [M + Na] calcd for C23H21NNaO S: 398.1185; found:
3
2
98.1187.
4
-Methoxy-11-tosyl-6,6a,11,11a-tetrahydro-5H-benzo[a]carba-
Starting materials (dihydronaphthalene, 1,3-cyclohexadiene, methox-
ylated tetralones and 2-iodoaniline) and PEG-400 were purchased
from Sigma-Aldrich .
zole (3b)
White solid; yield: 182.3 mg (45%); mp 205–208 °C.
®
1
H NMR (COSY; 400 MHz, CDCl ): δ = 7.62–7.56 (m, 2 H), 7.49 (d, J =
3
Microwave irradiation experiments described herein were performed
using a single-mode Discover Labmate System from CEM Corp. using
standard Pyrex vessels (capacity 10 mL).
7.8 Hz, 2 H), 7.27–6.96 (m, 6 H), 6.66 (d, J = 8.0 Hz, 1 H), 5.41 (d, J = 8.1
Hz, 1 H), 3.70 (s, 3 H), 3.03–2.97 (m, 1 H), 2.69 (d, J = 17.6 Hz, 1 H),
2
.34 (s, 3 H), 2.19–2.13 (m, 2 H), 1.90–1.84 (m, 1 H).
Melting points measurements were determinated in
a Thomas
13
C NMR (HSQC; 100 MHz, CDCl ): δ = 155.77, 143.81, 142.03, 136.12,
3
Hoover capillary melting point apparatus.
1
1
1
35.63, 135.31, 129.56, 127.78, 127.00, 126.82, 126.63, 125.68,
23.30, 122.58, 120.11, 108.39, 64.06, 55.27, 38.95, 22.28, 21.57,
7.28.
The H NMR and 13C NMR spectra were recorded on a Varian Gemini-
1
200 (400 MHz and 500 MHz). The coupling constants (J) are in hertz
(
0
7
Hz). The chemical shifts are reported in ppm downfield to TMS (δ =
+
HRMS (ESI): m/z [M + Na] calcd for C24H NNaO S: 428.1291; found:
1
23
3
.00) for H NMR and relative to the central CDCl resonance (δ =
3
428.1280.
13
6.90) for C NMR, and the relative areas of peaks obtained by elec-
tronic integration. Spectra apodization (exponential filter with LB =
3
-Methoxy-11-tosyl-6,6a,11,11a-tetrahydro-5H-benzo[α]carba-
–0.1–0.5 Hz, Gaussian with LB = 0.1–0.4 GB [Hz], Sine Bell with LB =
–10 Deg, Sine Square with LB = 90–50 Deg) was realized through
zole (3c)
4
MestReNova program version 6.0.2-5475, copyright 2009 Mestrelab
Research S. L.
White solid; yield: 222.7 mg (55%); mp 168–169 °C.
1
H NMR (COSY; 400 MHz, CDCl ): δ = 7.89 (d, J = 8.7 Hz, 1 H), 7.59 (d,
3
ESI-HRMS analyses were realized in a Bruker MicrOTOF II instrument.
Solvents were evaporated under reduced pressure and controlled
temperature in an IKA RV 10 control rotary evaporator and IKA HB 10
control water bath. The flash chromatographic separations were per-
formed on silica gel columns using Merck granulation 0.040 to 0.063
mm. The monitoring of chromatographic separations and reaction
processes were performed in SiliCycle Twin Layer Chromatography
aluminum silica gel 60 F254 leaves, visualized by irradiation with UV at
J = 7.9 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 2 H), 7.23–6.97 (m, 5 H), 6.82 (dd,
J = 8.6, 2.0 Hz, 1 H), 6.43 (s, 1 H), 5.38 (d, J = 8.5 Hz, 1 H), 3.72 (s, 3 H),
3.21–2.96 (m, 1 H), 2.60–2.28 (m, 5 H), 2.15–2.07 (m, 1 H), 2.00–1.91
(m, 1 H).
13
C NMR (HSQC; 101 MHz, CDCl ): δ = 158.61, 143.79, 138.94, 136.10,
3
131.95, 129.55, 127.86, 127.00, 126.46, 125.64, 123.36, 119.95,
113.08, 112.45, 63.80, 55.15, 39.36, 25.01, 23.53, 21.57.
+
HRMS (ESI): m/z [M + Na] calcd for C24H23NNaO S: 428.1291; found:
3
2
54 nm, I or 7% phosphomolybdic acid in ethanol, followed by heat-
2
428.1283.
ing.
4
-Methoxy-11-tosyl-6,6a,11,11a-tetrahydro-5H-benzo[α]carba-
Tetrahydro(benzo)carbazoles 3; General Procedure
zole (3d)
A mixture of the appropriate dihydronaphthalene 1a–e (1.0 mmol),
White solid; yield: 169.5 mg (42%); mp 177°C.
9
sulfonamide 2a–d (1.2 mmol), Pd(OAc)2 (1–10 mol%), and Ag CO
2
3
1
H NMR (COSY; 500 MHz, CDCl ): δ = 7.61 (d, J = 8.0 Hz, 1 H), 7.55 (d,
(1.2 mmol) in PEG-400 (1 mL) was immersed in a preheated graphite
3
J = 1.7 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 2 H), 7.20 (t, J = 7.7 Hz, 1 H), 7.15 (d,
J = 8.0 Hz, 2 H), 7.10 (t, J = 7.4 Hz, 1 H), 7.03 (d, J = 7.4 Hz, 1 H), 6.82 (d,
J = 8.4 Hz, 1 H), 6.71 (dd, J = 8.3, 2.2 Hz, 1 H), 5.36 (d, J = 8.5 Hz, 1 H),
bath and stirred for the times and temperatures shown in Tables 1
and 2. EtOAc (10 mL) and brine (50 mL) were then added, and the
mixture was extracted with CH Cl2 (3 × 50 mL). The organic layers
2
3.85 (s, 3 H), 3.13–2.99 (m, 1 H), 2.50–2.30 (m, 5 H), 2.16–2.05 (m, 1
were combined, dried (Na SO ), and concentrated. The crude mixture
2
4
H), 2.02–1.91 (m, 1 H).
was pre-purified by flash chromatography [silica gel, 20% EtOAc–hex-
ane] to give brute 3a–i as oils. For 3a–d, the oil was dissolved in a
minimal volume of a warm MeOH (~5 mL) and cold hexane (~5 mL)
was added. The mixture was allowed to stand overnight in a freezer,
and then the pure products were collected as solids by filtration. For
adducts 3f–i, the oils were dissolved in a minimal volume of warm 5%
CH Cl –EtOH solution (~5 mL), cold EtOH (~5 mL) was added, and the
13
C NMR (HSQC; 101 MHz, CDCl ): δ = 158.41, 143.83, 142.10, 136.13,
3
135.59, 135.28, 129.61, 129.56, 128.97, 127.85, 127.03, 125.66,
123.33, 119.96, 114.93, 113.75, 64.18, 55.34, 39.31, 23.91, 23.73,
21.55.
+
HRMS (ESI): m/z [M + Na] calcd for C24H23NNaO S: 428.1291; found:
3
2
2
428.1284.
products were collected by filtration. The product 3e was obtained
pure directly from the flash chromatography.
9-Tosyl-4,4a,9,9a-tetrahydro-3H-carbazole (3e)
Yellow solid; 133.3 mg (41%); mp 134°C.
11-Tosyl-6,6a,11,11a-tetrahydro-5H-benzo[a]carbazole (3a)
White solid; yield: 318.7 mg (85%); mp 165 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3013–3019

3
018
Synthesis
J. C. F. Barcellos et al.
Paper
1
1
H NMR (500 MHz, CDCl ): δ = 7.65 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.1
H NMR (COSY; 400 MHz, CDCl ): δ = 8.18 (d, J = 8.6 Hz, 2 H), 7.82–
3
3
Hz, 2 H), 7.21 (t, J = 7.7 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.06 (t, J = 7.4
Hz, 1 H), 7.01 (d, J = 7.3 Hz, 1 H), 5.88–5.84 (m, 2 H), 4.71 (d, J = 8.0 Hz,
7.80 (m, 3 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.26–7.18 (m, 1 H), 7.13 (t, J =
7.4 Hz, 1 H), 7.06 (d, J = 7.4 Hz, 1 H), 6.82 (dd, J = 8.6, 2.4 Hz, 1 H), 6.43
(d, J = 2.02 Hz, 1 H), 5.44 (d, J = 8.5 Hz, 1 H), 3.73 (s, 3 H), 3.14–3.04 (m,
1 H), 2.52–2.32 (m, 2 H), 2.16–2.07 (m, 1 H), 2.01–1.88 (m, 1 H).
1
H), 3.08–3.04 (m, 1 H), 2.35 (s, 3 H), 1.97–1.82 (m, 4 H).
13
C NMR (HSQC; 101 MHz, CDCl ): δ = 143.70, 141.66, 135.69, 135.05,
3
13
131.26, 129.55, 127.84, 126.92, 126.11, 124.69, 123.38, 118.06, 61.45,
C NMR (101 MHz, CDCl ): δ = 158.85, 150.16, 144.26, 141.03,
3
3
8.62, 22.66, 21.51, 20.08.
139.14, 135.74, 131.87, 128.25, 128.16, 126.32, 125.48, 124.11,
123.84, 119.54, 113.18, 112.58, 64.33, 55.17, 39.47, 24.86, 23.62.
+
HRMS (ESI): m/z [M + Na] calcd for C19H19NNaO S: 348.1029; found:
2
+
348.1022.
HRMS (ESI): m/z [M + Na] calcd for C23H20N NaO S: 459.0985; found:
2
5
459.0986.
11-[(2-Nitrophenyl)sulfonyl]-6,6a,11,11a-tetrahydro-5H-ben-
zo[a]carbazole (3f)
6,6a,11,11a-Tetrahydro-5H-benzo[a]carbazolium Trifluoroace-
tate (4)
Yellow solid; yield: 244.0 mg (60%); mp 124–126 °C.
1
A solution of PhSH (28 mg, 0.25 mmol) in DMF (0.5 mL) was added to
H NMR (COSY; 400 MHz, CDCl ): δ = 7.85 (d, J = 7.8 Hz, 1 H), 7.64–
.48 (m, 4 H), 7.44 –7.36 (m, 1 H), 7.28–7.08 (m, 5 H), 6.93 (d, J = 7.5
3
a mixture of sulfonamide 3f (100 mg, 0.25 mmol) and K CO (52 mg,
7
2
3
0.38 mmol), and the mixture was stirred for 5 min. EtOAc (2 mL) was
Hz, 1 H), 5.81 (d, J = 8.3 Hz, 1 H), 3.76–3.54 (m, 1 H), 2.63–2.42 (m, 2
H), 2.27–2.06 (m, 2 H).
added and the mixture was washed with brine (3 × 3 mL). The organic
layer was dried (Na SO ) and concentrated under vacuum. The crude
2
4
13
C NMR (HSQC; 101 MHz, CDCl ): δ = 148.12, 140.88, 137.80, 135.89,
3
product was filtered through silica gel with hexane as eluent to give a
1
1
33.97, 131.25, 131.05, 130.77, 130.39, 128.16, 127.99, 127.53,
26.84, 125.97, 123.94, 123.81, 118.69, 64.67, 39.71, 24.80, 23.63.
yellow oil (58 mg) that was dissolved Et O (1 mL) and treated with
2
TFA (23 μL, 0.3 mmol). The precipitate was collected by filtration to
give a white crystal; yield: 22.1 mg (40%); mp 157 °C.
+
HRMS (ESI): m/z [M + Na] calcd for C22H18N NaO S: 429.0879; found:
2
4
429.0871.
1
H NMR (COSY; 400 MHz, CDCl ): δ = 8.82 (s, 2 H), 7.62–7.50 (m, 1 H),
3
7.46–7.17 (m, 7 H), 5.21 (d, J = 7.6 Hz, 1 H), 3.76–3.56 (m, 1 H), 3.00–
2.69 (m, 2 H), 2.14 (dq, J = 14.0, 4.7 Hz, 1 H), 1.96 (dtd, J = 15.2, 10.5,
4.7 Hz, 1 H).
1
1-[(3-Nitrophenyl)sulfonyl]-6,6a,11,11a-tetrahydro-5H-ben-
zo[a]carbazole (3g)
Yellow solid; yield: 174.6 mg (43%); mp 154–156 °C.
13
C NMR (101 MHz, CDCl ): δ = 138.79, 138.20, 137.37, 129.72,
3
1
H NMR (COSY; 400 MHz, CDCl ): δ = 8.47 (t, J = 1.8 Hz, 1 H), 8.35 (dd,
129.26, 128.64, 129.02, 128.69, 127.05, 124.95, 118.64, 60.55, 41.48,
28.19, 26.68.
HRMS (ESI): m/z [M + H]+ calcd for C18H16N: 222.1277; found:
3
J = 8.2, 2.2 Hz, 1 H), 7.95–7.86 (m, 2 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.56 (t,
J = 8.0 Hz, 1 H), 7.30–7.22 (m, 2 H), 7.17–7.10 (m, 2 H), 7.05 (d, J = 7.5
Hz, 1 H), 6.92 (d, J = 7.5 Hz, 1 H), 5.49 (d, J = 8.6 Hz, 1 H), 3.15–3.09 (m,
222.1271.
1
H), 2.50–2.44 (m, 2 H), 2.12–2.08 (m, 1 H), 2.07–1.95 (m, 1 H).
1
3
C NMR (HSQC; 101 MHz, CDCl ): δ = 148.06, 141.18, 140.62, 137.78,
3
N,N-Dimethyl-5-(5,6,6a,11a-tetrahydro-11H-benzo[a]carbazol-11-
ylsulfonyl)naphthalen-1-amine (3j)
1
1
2
35.75, 133.43, 132.34, 130.49, 130.46, 130.29, 130.24, 128.33,
28.14, 127.72, 127.37, 126.93, 126.38, 123.85, 119.42, 64.55, 39.63,
4.72, 23.96.
Anhydrous pyridine (28 μL) was added to a mixture of TFA salt 4 (62.5
mg, 0.28 mmol) and dansyl chloride (91.5 mg, 0.34 mmol) in anhy-
drous chloroform (0.28 mL) under argon, and the mixture was kept
for 20 h at 40 °C. The crude product was purified by chromatography
+
HRMS (ESI): m/z [M + Na] calcd for C22H18N NaO S: 429.0879; found:
4
2
4
29.0878.
(silica gel, 10% EtOAc–hexane) to give 3j as a yellow oil; yield: 40.5 mg
11-[(4-Nitrophenyl)sulfonyl]-6,6a,11,11a-tetrahydro-5H-ben-
(32%).
zo[a]carbazole (3h)
1
H NMR (COSY; 400 MHz, CDCl ): δ = 8.49 (d, J = 8.5 Hz, 1 H), 8.24 (d,
3
Yellow solid; yield: 243.7 mg (60%); mp 97–100 °C.
J = 8.7 Hz, 1 H), 8.16 (d, J = 7.4 Hz, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 7.55 (d,
J = 8.0 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H), 7.30–7.01 (m, 6 H), 6.90 (t, J =
1
H NMR (COSY; 400 MHz, CDCl ): δ = 8.21 (d, J = 8.8 Hz, 2 H), 7.94 (d,
3
7.1 Hz, 2 H), 5.56 (d, J = 8.3 Hz, 1 H), 3.04–2.94 (m, 1 H), 2.84 (s, 6 H),
J = 7.8 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.29–
2.56–2.44 (m, 1 H), 2.41 (m, 1 H), 2.06–1.96 (m, 1 H), 1.92–1.84 (m, 1
7.25 (m, 2 H), 7.18–7.14 (m, 2 H), 7.08 (d, J = 7.5 Hz, 1 H), 6.94 (d, J =
7.6 Hz, 1 H), 5.47 (d, J = 8.5 Hz, 1 H), 3.18–3.07 (m, 1 H), 2.55–2.44 (m,
2 H), 2.19–1.94 (m, 2 H).
H).
13
C NMR (HSQC; 101 MHz, CDCl ): δ = 151.31, 142.20, 137.75, 135.95,
3
1
3
134.80, 134.35, 130.53, 130.47, 130.37, 130.25, 129.80, 128.04,
C NMR (HSQC; 101 MHz, CDCl ): δ = 150.20, 144.14, 141.07, 137.68,
3
127.72, 127.59, 127.39, 126.70, 125.47, 123.42, 123.12, 119.79,
1
1
35.83, 133.41, 130.40, 128.26, 128.21, 128.18, 127.71, 126.93,
26.41, 124.13, 123.86, 119.62, 64.47, 39.52, 29.70, 24.64, 23.64.
119.46, 115.16, 64.19, 45.37, 39.58, 24.86, 23.57.
+
+
HRMS (ESI): m/z [M + Na] calcd for C28
H
26
N
2
NaO
2
S: 477.1607; found:
HRMS (ESI): m/z [M + Na] calcd for C22H18N NaO S: 429.0879; found:
4
2
4
477.1611.
29.0882.
1
1-(Arylsulfonyl)-6,6a,11,11a-tetrahydro-5H-benzo[a]carbazoles
3
5
-Methoxy-11-[(4-nitrophenyl)sulfonyl]-6,6a,11,11a-tetrahydro-
H-benzo[a]carbazole (3i)
(3j–l); General Procedure
A solution of PhSH (56 mg, 0.5 mmol) in DMF (1.0 mL) was added to a
Yellow solid; yield: 178.8 mg (41%); mp 167–168 °C.
mixture of sulfonamide 3f (200 mg, 0.5 mmol) and K CO (152 mg,
2
3
1.2 mmol), and the mixture was stirred for 5 min. EtOAc (3 mL) was
added, and the mixture was washed with brine (3 × 3 mL). The organ-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3013–3019

3
019
Synthesis
J. C. F. Barcellos et al.
Paper
ic layer was dried (Na SO ) and concentrated under vacuum, and the
Supporting Information
2
4
crude product was filtered through silica gel (5% EtOAc–hexane elu-
ent). The resulting yellow oil (189.5 mg) was dissolved in anhydrous
CH Cl (0.4 mL) and the appropriate sulfonyl chloride (0.5 mmol) and
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380757.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
2
2
anhydrous pyridine (40 μL, 0.5 mmol) were added under argon. The
mixture was kept for 20 h at 40 °C and then purified by chromatogra-
phy (silica gel; 10% EtOAc–hexane).
References
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2) (a) Larock, R. C.; Berrios-Pena, N.; Narayanan, K. J. Org. Chem.
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zole (3k)
White solid; yield: 94.0 mg (52%); mp 167–169 °C.
1
H NMR (COSY; 400 MHz, CDCl ): δ = 8.29 (d, J = 7.8 Hz, 1 H), 7.93–
3
7.87 (m, 3 H), 7.81–7.75 (m, 1 H), 7.66–7.59 (m, 2 H), 7.57–7.51 (m, 1
H), 7.50–7.44 (m, 1 H), 7.41–7.37 (m, 2 H), 7.31 (d, J = 7.5 Hz, 1 H),
(
3) (a) Buarque, C. D.; Militão, G. C. G.; Lima, D. J. B.; Costa-Lotufo, L.
V.; Pessoa, C.; de Moraes, M. O.; Cunha-Junior, E. F.; Torres-
Santos, E. C.; Netto, C. D.; Costa, P. R. R. Bioorg. Med. Chem. 2011,
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7.19 (d, J = 7.6 Hz, 1 H), 5.72 (d, J = 8.6 Hz, 1 H), 3.40–3.32 (m, 1 H),
2.85–2.67 (m, 2 H), 2.42–2.21 (m, 2 H).
13
C NMR (HSQC; 101 MHz, CDCl ): δ = 141.96, 138.35, 137.64, 136.23,
3
1
1
34.26, 133.11, 130.49, 129.00, 128.08, 127.91, 127.41, 127.01,
26.81, 125.90, 123.51, 119.90, 64.11, 39.42, 24.80, 23.57.
(c) Cortopassi, W. A.; Penna-Coutinho, J.; Aguiar, A. C. C.;
+
Pimentel, A. S.; Buarque, C. D.; Costa, P. R. R.; Alves, B. R. M.;
França, T. C. C.; Krettli, A. U. PLoS One 2014, 9, e91191.
4) Dejon, L.; Mohammed, H.; Du, P.; Jacob, C.; Speicher, A. Med-
ChemComm 2013, 4, 1580.
HRMS (ESI): m/z [M + Na] calcd for C22H19NNaO S: 384.1029; found:
2
384.1037.
(
(
11-[(4-Methoxyphenyl)sulfonyl]-6,6a,11,11a-tetrahydro-5H-ben-
5) (a) Li, J.-H.; Hu, X.-C.; Liang, Y.; Xie, Y.-X. Tetrahedron. 2006, 62,
zo[a]carbazole (3l)
31. (b) Wang, W.; Yang, Q.; Zhou, R.; Fu, H.-Y.; Li, R.-X.; Chen, H.;
White solid; yield: 99.5 mg (51%); mp 154–155 °C.
Li, X.-J. J. Organomet. Chem. 2012, 697, 1. (c) Audebert, P.; Sadki,
S.; Miomandre, F.; Clavier, G.; Vernières, M. C.; Saoud, M.;
Hapiot, P. New J. Chem. 2004, 28, 387. (d) Firouzabadi, H.;
Iranpoor, N.; Ghaderi, A. Org. Biomol. Chem. 2011, 9, 865.
1
H NMR (COSY; 400 MHz, CDCl ): δ = 8.55 (d, J = 7.8 Hz, 1 H), 8.16 (d,
3
J = 7.9 Hz, 1 H), 8.11 (d, J = 8.8 Hz, 2 H), 7.82 (t, J = 7.5 Hz, 1 H), 7.75 (t,
J = 7.5 Hz, 1 H), 7.71–7.65 (m, 2 H), 7.60 (d, J = 7.4 Hz, 1 H), 7.48 (d, J =
7.5 Hz, 1 H), 7.38 (d, J = 8.7 Hz, 2 H), 5.96 (d, J = 8.5 Hz, 1 H), 4.36 (s, 3
(e) Han, W.; Liu, N.; Liu, C.; Jin, Z. L. Chin. Chem. Lett. 2010, 21,
H), 3.74–3.62 (m, 1 H), 3.16–2.95 (m, 2 H), 2.72–2.51 (m, 2 H).
1411. (f) Xue, J.; Zhou, Z.; Peng, J.; Du, X.; Huang, G.; Xie, Y.
13
Transition Met. Chem. 2014, 39, 221. (g) Tundo, P.; Perosa, A.
Chem. Soc. Rev. 2007, 36, 532. (h) Han, W.; Liu, C.; Jin, Z.-L. Org.
Lett. 2007, 9, 4005. (i) Razler, T. M.; Hsiao, Y.; Qian, F.; Fu, R.;
Khan, R. K.; Doubleday, W. J. Org. Chem. 2009, 74, 1381.
6) Silva, L. F. Jr.; Sousa, R. M. F.; Ferraz, H. C. F.; Aguilar, A. M. J. Braz.
Chem. Soc. 2005, 16, 1160.
C NMR (HSQC; 101 MHz, CDCl ): δ = 163.14, 142.19, 137.54, 136.29,
3
1
1
3
34.38, 130.48, 130.12, 129.09, 127.97, 127.83, 127.31, 126.79,
25.72, 123.39, 120.05, 114.08, 77.36, 77.04, 76.72, 63.95, 55.52,
9.46, 24.81, 23.62.
(
(
+
HRMS (ESI): m/z [M + Na] calcd for C23H21NNaO S: 414.1134; found:
3
414.1137.
7) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373. (b) Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1998,
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Acknowledgment
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Financial support from the Brazilian agencies CAPES, CNPq, FAPERJ,
and UFRJ is acknowledged. J.C.F.B. is grateful to FAPERJ for Bolsa Dou-
torado Nota 10. P.R.R.C. is grateful to CNPq for Bolsa de Produtividade.
(
(
b) Kato, T.; Sasaki, M.; Kimura, S. Anal. Biochem. 1975, 66, 515.
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3013–3019