A two-step synthesis of unsymmetrical 1,4-disubstituted carbazoles from sulfonylindoles under heterogeneous catalysis

Article abstract of DOI:10.1002/adsc.201000394

Reaction of sulfonylindoles with protected β-nitro ketones affords the corresponding 3-(2-nitroalkyl)indoles that, under acidic conditions, undergo a sequence of cascade processes finally leading to unsymmetrical 1,4-disubstituted carbazoles.

Full text of DOI:10.1002/adsc.201000394

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DOI: 10.1002/adsc.201000394
A Two-Step Synthesis of Unsymmetrical 1,4-Disubstituted
Carbazoles from Sulfonylindoles Under Heterogeneous Catalysis
Roberto Ballini,a Serena Gabrielli,a Alessandro Palmieri,a,* and Marino Petrinia,*
a
School of Science and Technology, Chemistry Division, Universitꢀ di Camerino, via S. Agostino 1, 62032 Camerino, Italy
Fax : (+39)-0737-402-297; e-mail: alessandro.palmieri@unicam.it or marino.petrini@unicam.it
Received: May 18, 2010; Published online: September 14, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000394.
Abstract: Reaction of sulfonylindoles with protect-
ed b-nitro ketones affords the corresponding 3-(2-
nitroalkyl)indoles that, under acidic conditions, un-
dergo a sequence of cascade processes finally lead-
ing to unsymmetrical 1,4-disubstituted carbazoles.
the preparation of 1,4-dialkylcarbazoles.[7] Unfortu-
nately, this approach is only useful for the synthesis of
symmetrical carbazole derivatives because of the un-
avoidable lack in regioselectivity in the double elec-
trophilic substitution.[8] In order to circumvent this
drawback, the carbon-carbon bond connection at the
indole ring would be done in two distinct steps, with
final aromatization of the resulting partially unsatu-
rated carbacycle. Thus a suitable indole system with a
reactive electrophilic ꢁbenzylicꢂ position, e.g., 1, could
react with a stabilized carbanion 2 leading to the first
carbon-carbon bond connection (Scheme 1).
Keywords: carbazoles; electrophilic substitution;
heterogeneous catalysis; nitro compounds
Carbazoles are tricyclic heteroaromatic compounds
featured by a central pyrrole ring, which are endowed
of a considerable practical interest. Many natural
products embedding the carbazole moiety as the main
core structure, present an enhanced pharmacological
profile as effective antibiotic and antiviral agents.[1]
Furthermore, the carbazole unit is easily recognizable
in many polymeric materials that evidence particular
physical properties.[2] From a synthetic standpoint, the
formation of the carbazole system can be carried out
exploiting two main general procedures.The first one
is based on the direct formation of the tricyclic
system starting from functionalized benzene precur-
sors. The second approach employs indole derivatives
as substrates on which the third benzene ring is built Scheme 1. General strategy for the synthesis of carbazoles.
up. Metal-catalyzed coupling reactions of anilines
with functionalized arenes, followed by an oxidative
ring closure, belong to the former approach.[3] Similar-
The resulting intermediate 3 undergoes a Friedel–
ly, reductive ring closures of nitrogenated biphenyl Crafts (F-C) reaction by which the tricyclic skeleton 4
derivatives[4] and cycloaddition reactions of diyne is formed. Aromatization of the latter cycle occurs
compounds,[5] allow the preparation of carbazoles upon elimination of the activating electron-withdraw-
from functionalized benzene systems. Conversion of ing group (EWG) leading to the carbazole compound
indoles to carbazole derivatives can be achieved ex- 5.[9] The depicted synthetic strategy requires a three-
ploiting Diels–Alder processes or related pericyclic step process that, however, could be shortened if the
reactions such as electrocyclizations.[6] The Friedel– ring closure and the aromatization steps are joined in
Crafts reaction is widely used for the synthesis of 3- a tandem operation. Among carbanion stabilizing
substituted indoles and this process carried out using groups, the nitro group occupies a prominent position
1,4-dicarbonyl derivatives on indoles is effective for since its formidable electron-withdrawing power
Adv. Synth. Catal. 2010, 352, 2459 – 2462
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Roberto Ballini et al.
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allows the generation of the corresponding nitronate
Particularly, these sulfonyl derivatives may react
anions under mild conditions.[10] Furthermore, nitroal- with nitroalkanes, in the presence of a basic promoter,
kanes are deeply involved in several synthetic ap- leading to the corresponding 3-(2-nitroalkyl)in-
proaches aimed at the synthesis of benzene deriva- doles.[14] Although a large variety of functionalized ni-
tives, with the easy elimination of nitrous acid being troalkanes successfully react with sulfonylindoles 6, b-
one of the key steps in the aromatization process.[11] nitro ketones 2 (EWG=NO2, R2 =Me, Et) gave dis-
Reactive indolyl intermediates of type 1 are readily appointing results in the same reaction under differ-
available starting from stable precursors having a ent solvent/base combinations. The failure is probably
good leaving group at the ꢁbenzylicꢂ position.[12] Re- ascribable to a preliminary retro-Michael reaction suf-
cently, we have introduced a new class of indole de- fered by b-nitro ketones under basic conditions which
rivatives, namely 3-(1-arylsulfonylalkyl)indoles 6, that leads to a decomposition of the nitro derivative.[15]
have been demonstrated to be efficient precursors of This unwanted side process could be avoided by a
alkylideneindolenines 7, or their parent iminium ions, suitable protection of the carbonyl group that pre-
for the synthesis of 3-substituted indoles 8 by reaction vents the retro-Michael process. As a matter of fact,
with suitable nucleophiles (Scheme 2).[13]
conversion of b-nitro ketones into the corresponding
nitro acetals 9[16] and their reaction with sulfonylin-
doles 6 in the presence of KF-basic alumina generate
adducts 10 in good yield (Table 1, entries 3, 5, 8, 10,
13).
The subsequent transformation of 3-(2-nitroal-
AHCTUNGTREGkNNUN yl)indoles 10 into carbazoles 11 would entail three
different transformations, namely acetal cleavage,
Friedel–Crafts cyclization and final aromatization by
elimination of nitrous acid. In principle, all these syn-
thetic operations could be performed under acidic
Scheme 2. Synthetic approach to 3-substituted indoles using
sulfonylindoles.
Table 1. Synthesis of carbazoles 11 by reaction of sulfonylindoles 6 with nitro acetals 9, followed by tandem cleavage-cycliza-
tion and aromatization of the intermediate adducts 10.
Entry Indole 6 R1
Nitro Acetal 9 R2
10 Time [h] Yield[a] [%] 11 Time [h] Yield[b] [%]
1
2
3
4
5
6
7
8
6a
6a
6b
6b
6b
6b
6b
6c
6c
6d
6d
6d
6d
6d
6e
6f
Me
Me
Et
Et
Et
Et
Et
c-C6H11
c-C6H11
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
9b
9d
9b
9b
9a
9a
9d
9c
9c
9c
9c
9e
9f
9f
Me
Ph(CH2)2
Me
Me
H
10a 3.0
10b 7.0
10c 3.5
10c 3.5
10d 3.5
10d 3.5
10e 9.0
10f 16
10f 16
10g 5.0
10g 5.0
–
–
89
–
83
–
–
78
–
90
–
–
11a 1.5
11b 2.0
11c 1.5
11c 1.5
11d 1.5
11d 1.5
11e 2.0
11f 1.5
11f 1.5
11g 2.5
11g 2.5
11h 4.5
11i 2.0
11i 2.0
11j 6.0
11k 1.5
55
U
54
64[c]
61
68[c]
62
H
Ph
Et
Et
Et
Et
N
56
65[c]
62
9
10
11
12
13
14
15
16
56[c]
53
4-MeO-C6H4 10h 5.0
44
Me
Me
Et
10i 7.0
10i 7.0
10j 9.0
10k 9.0
84
–
–
58[c]
55
CH2=CH
4-MeO-C6H4
G
47
68
Me
–
[a]
[b]
[c]
Yield of pure, isolated products.
Yield of pure, isolated products from substrates 6.
Yield of pure, isolated products from intermediates 10.
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Adv. Synth. Catal. 2010, 352, 2459 – 2462

A Two-Step Synthesis of Unsymmetrical 1,4-Disubstituted Carbazoles
tained after removal of the solvent at reduced pressure was
conditions so that different promoters have been
tested to efficiently obtain conversion of compounds
10 into carbazoles 11. Solid acid systems are known to
be efficient promoters in many synthetic processes in-
cluding cleavage of various carbonyl protecting
groups.[17] Furthermore, working under heterogeneous
conditions allows an easy recovery of the solid acid
and a considerable speeding up in the subsequent
work-up operations. The best conditions for this pro-
cess have been found in the utilization of Amberlyst
15 as proton source in isopropyl alcohol at reflux as
evidenced by the satisfactory results displayed in
Table 1. Although the intermediate adducts 10 can be
isolated, we have observed that crude products 10,
obtained by simple filtration of the solid basic pro-
moter and solvent evaporation, are suitable for the
next cyclization step. This simplified procedure has a
beneficial effect on the overall waste reduction and
allows us to record a better chemical yield over the
two-step process involving purification of intermedi-
ate compounds 10 (Table 1, compare entries 3/4, 5/6,
8/9, 10/11, 13/14). In a couple of examples we changed
the nature of the acetal protection from 1,3-dioxolan-
yl to 5,5-dimethyl-1,3-dioxanyl without evidencing
any substantial advantage (Table 1, entries 13, 14, 16).
In summary, unsymmetrical 1,4-disubstituted carba-
zoles can be easily prepared by a two-step procedure
starting from sulfonylindoles. The first reaction con-
sists in the nucleophilic addition of acetal protected
b-nitro ketones to alkylideneindolenine intermediates
generated from sulfonylindoles under basic condi-
tions. The following transformation includes three
consecutive synthetic operations involving acetal
cleavage, Friedel–Crafts cyclization and final aromati-
zation by elimination of nitrous acid. Every single
step is carried out under heterogeneous conditions so
that work-up operations are minimized and isolation
is required only to obtain the target carbazole.
purified by flash chromatography (hexanes/toluene 90:10).
4-Methyl-1-phenethyl-9H-carbazole (11b): Yield: 54%;
yellow solid, mp 116–1198C. IR (nujol): n=1250, 1588,
3030, 3420 cmÀ1 1H NMR (CDCl3, 400 MHz): d=2.88 (s,
;
3H), 3.08 (t, 2H, J=6.8 Hz), 3.21 (t, 2H, J=6.8 Hz), 6.98
(d, 1H, J=7.3 Hz), 7.16 (d, 1H, J=7.3 Hz), 7.20–7.34 (m,
6H), 7.38–7.41 (m, 2H), 7.83 (bs, 1H), 8.18 (d, 1H, J=
7.7 Hz); 13C NMR (CDCl3, 100 MHz): d=20.7, 33.6, 36.4,
110.6, 119.3, 121.0, 121.3, 122.6, 124.4, 125.1, 125.4, 126.3,
126.6, 127.7, 128.7, 131.3, 138.6, 139.7, 142.1; GC-MS
(70 eV): m/z=285 ([M+], 40), 195 (26), 194 (100), 167 (6),
91 (8), 65 (3); anal. calcd. for C21H19N (285.38): C 88.38, H
6.71, N 4.91; found: C 88.50, H 6.78 N, 4.98.
4-Cyclohexyl-1-ethyl-9H-carbazole (11f): Yield: 65%
(from pure 10f), 62% (from crude 10f); white solid, mp 71–
738C. IR (nujol): n=1228, 1580, 1619, 3055, 3409 cmÀ1
;
1H NMR (CDCl3, 400 MHz): d=1.34–1.47 (m, 1H), 1.42 (t,
3H, J=7.7 Hz), 1.54–1.72 (m, 4H), 1.84–1.93 (m, 1H), 1.95–
2.03 (m, 2H), 2.16–2.26 (m, 2H), 2.92 (q, 2H, J=7.7 Hz),
3.46–3.56 (m, 1H), 7.10 (d, 1H, J=7.7 Hz), 7.23–7.30 (m,
2H), 7.39–7.45 (m, 1H), 7.49 (dt, 1H, J=0.9, 8.1 Hz), 8.06
(bs, 1H), 8.13 (d, 1H, J=7.7 Hz); 13C NMR (CDCl3,
100 MHz): d=13.9, 24.1, 26.8, 27.5, 33.4, 41.0, 110.7, 116.0,
119.6, 120.6, 123.0, 123.3, 123.8, 124.6, 125.1, 138.4, 139.6,
141.5; GC-MS (70 eV): m/z=277 ([M+], 100), 262 (11), 248
(10), 234 (14), 208 (30), 206 (24), 205 (28), 204 (31), 191
(23), 180 (36); anal. calcd. for C20H23N (277.40): C 86.59, H
8.36, N 5.05; found: C 86.21, H 8.45, N 5.02.
Acknowledgements
Financial support from the University of Camerino and Ital-
ian MIUR (National Project “Sintesi organiche ecosostenibili
mediate da nuovi sistemi catalitici) is gratefully acknowl-
edged.
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11
To a stirred solution of sulfonylindole 6 (1.0 mmol) and ni-
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Adv. Synth. Catal. 2010, 352, 2459 – 2462