A new preparative route to substituted carbazoles by benzannulation

Article abstract of DOI:10.1055/s-2005-863741

A new regioselective pathway to substituted carbazole derivatives is described here. According to this procedure substituted 2-alkoxycarbonyl-4- acetoxy-9-(p-toluenesulfonyl) carbazoles are obtained by treatment of substituted 6-[2-(p-toluenesulfonyl-amin

Full text of DOI:10.1055/s-2005-863741

LETTER
809
A New Preparative Route to Substituted Carbazoles by Benzannulation
A
New Route
t
to Subs
e
titute
d
Ca
r
f
C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘Adolfo Quilico’ presso Dipatimento di Chimica, Materiali ed
Ingegneria Chimica ‘Giulio Natta’ del Politecnico, Via Mancinelli 7, 20133 Milano, Italy
Fax +39(2)23993080; E-mail: stefano.serra@polimi.it
Received 17 January 2005
nolic derivatives 3 and 4, respectively (Scheme 1). The
latter processes probably involves the ynenylketene 2,
formed from mixed anhydride of acid 1, which may be
cyclized through electrophilic attack and nucleophilic ad-
Abstract: A new regioselective pathway to substituted carbazole
derivatives is described here. According to this procedure substitut-
ed 2-alkoxycarbonyl-4-acetoxy-9-(p-toluenesulfonyl) carbazoles
are obtained by treatment of substituted 6-[2-(p-toluenesulfonyl-
amino)-aryl]-3-alkoxycarbonylhex-3-en-5-ynoic acids with acetic dition to the triple bond. If the substituent in position 6 of
anhydride in the presence of sodium acetate. The latter acids are
prepared from the easily available substituted o-iodo-anilines by
the ynoic acid shows the o-heteroaryl framework, the het-
eroatom could act as nucleophile to give addition to the
Sonogashira coupling with propargylic alcohol and Wittig reaction
triple bond. Both the heterocyclic ring and the phenolic
as the key steps. The described benzannulation reaction proceeds in
ring are building up in the cyclization step to afford diben-
regiospecific fashion and a range of substituents are tolerated.
zofurans 4 and carbazoles 5 depending of the heteroatom
used. We herein report the new synthetic route to carba-
Key words: annulations, enynes, carbazoles, phenols, heterocycles
zole compounds 5 by benzannulation reaction of acids 1.
Carbazoles are relevant heteroaromatic compounds,
AcO
G
CO2R'
CO2R'
COOH
which have attracted considerable attention because of
their remarkable properties. Many natural alkaloids be-
long to this class and some of these display a wide range
of biological activities.1 Moreover, the photorefractive,2
electrical,3 light-emitting4 and termal5 properties of differ-
ent carbazole derivatives have found several applications
in the field of the sciences of the materials.
G
1
3
OAc
Ac2O
NaOAc
HOAc
AcO–
R = hydrogen,
alkyl, vinyl, aryl,
heteroaryl
CO2R'
CO2R'
G
G
A large number of synthetic approaches to this kind of
compounds have been established.6 The conventional
methodologies are based mainly on electrophilic substitu-
tion that takes place at the 3-, 6- and 9-position of the car-
bazole framework. For this reason the regioselective
functionalization of the other positions still remains the
major problem in carbazole synthesis.
2
C
C
O
O
O
CO2R'
G = ortho
heterosubstituted
aryl
OAc
R''
4
X = O
ROAc
ROAc
R
X
Therefore, considerable effort has been devoted to the de-
velopment of versatile and regioselective synthetic routes
to carbazoles with functional groups at specific positions.
The most recent applications are based on annulation
reactions,7 which allow the construction of carbazole
nucleus by ring-formation approach.
CO2R'
CO2R'
C
R''
1
O
X = NH
2
R
9a
9
N
3
2
8a
4
4a
8
7
4b
OAc
R''
5
We have previously developed the benzannulation reac-
tion of the substituted 3,5-hexadienoic acids8 to give the
4-substituted 3-hydroxy-benzoic acid derivatives. Recent-
ly, we described the annulation reaction of 3-alkoxycarbo-
nylhex-3-en-5-ynoic acids9 and of 6-(2-methoxyaryl)-3-
alkoxycarbonylhex-3-en-5-ynoic acids10 to give the 4-
substituted 3,5-dihydroxybenzoic acid derivatives and the
1-acetoxy-3-alkoxycarbonyl dibenzofurans, respectively.
We found that the treatment of the above-mentioned acids
with acetic anhydride and sodium acetate affords the phe-
5
6
Scheme 1 Proposed pathways to 4-substituted 3,5-diacetoxy-
benzoates, 1-acetoxy-3-alkoxycarbonyl dibenzofurans and 2-alkoxy-
carbonyl-4-acetoxy carbazoles.
An essential aspect of our approach is the specific prepa-
ration of the acids 1. Preliminary studies focused on the
selection of the protecting group on nitrogen atom. As
mentioned above the heteroatom gives nucleophile addi-
tion to the triple bond providing that it will be unaffected
by the activating agent (Ac2O) used in the cyclization
step. Moreover, the protecting group should be easily re-
moved once the carbazole as be obtained. Therefore, few
SYNLETT 2005, No. 5, pp 0809–0812
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863741; Art ID: G02605ST
© Georg Thieme Verlag Stuttgart · New York

810
S. Serra, C. Fuganti
LETTER
functional groups are suitable to this end. We choose the N-Tosylation of the aniline functionality was carried out
amidic linkage and then we tested the annulation reaction with tosyl chloride and pyridine to give the substituted
on acids 6a–c (Scheme 2).
sulfonylamides 9a–f. Sonogashira coupling13 between
9a–f and propargylic alcohol afforded alcohols 10a–f,
which were smoothly oxidized with MnO2 to the corre-
sponding aldehydes 11a–f in quantitative yields. The
subsequent Wittig reaction14 with triphenyl-(a-ethoxy-
carbonyl-b-carboxyethyl)phosphonium ylide 1215 gave
regioselectively16 the suitable 6-[2-(p-toluenesulfonyl-
CO2Et
R
N
NHR
CO2Et
CO2H
Ac2O
OAc
NaOAc
6a–c
amino)-aryl]-3-ethoxycarbonylhex-3-en-5-ynoic
13a–f in yields ranging from 73% to 89% (Table 1).
acids
a) R = Ac,
b) R = Ts,
c) R = Ms
35% yield
91% yield
65% yield
The conversion of 13a–f into benzannulated carbazoles
was established by treatment17 of the latter acids with an
excess of acetic anhydride (10 equiv) in presence of
sodium acetate (2 equiv) and hydroquinone (0.05 equiv)
heating at reflux for one hour. The 2-ethoxycarbonyl-4-
acetoxy-9-(p-toluenesulfonyl) carbazoles 14a–f were
obtained regioselectively in good yields (77–91%).
Scheme 2 Reagents and conditions: a) Ac2O (30 equiv) and NaOAc
(3 equiv), hydroquinone (0.05 equiv), then heating 3 h at reflux.
The results show that nitrogen on acetamide 6a is not
adequately nucleophile to obtain the cyclization product
in good yields. Otherwise, the sulfonylamides 6b and 6c
afforded the carbazoles 7b and 7c in good and moderate
yields, respectively.
Speculation on the substitution pattern of the aromatic
ring of the acids 13a–f suggests some relevant consider-
ations. Both position and quality of the substituents does
not alter the reaction course. Moreover, this synthetic
method proves to be very flexible since alkyl-, alkoxy-,
carboxyalkyl-, halo-, and nitro groups were unaffected
under the reaction conditions.
In all the described experiments the annulation do not
proceeded further if the reaction time was prolonged. In
forcing condition, only additional tar material was ob-
tained.
In agreement with the latter optimization study and in
consideration that N-sulfonycarbazoles are easily de-
sulfonylated,7p,11 we settled on the tosylamide derivatives
to be employed in our synthetic route. The suitable substi-
In conclusion, we have developed a new preparative
method to substituted 2-alkoxycarbonyl-4-acetoxy carba-
zoles starting from substituted o-iodoanilines. Both the
heterocyclic ring and one aromatic ring are formed in a
single annulation step. Our approach is regiospecific, effi-
cient and experimentally simple. Moreover, the starting
materials are easily available or can be easily made. This
route show some advantages over the classical processes
as demonstrated by the synthesis of several new substitut-
ed carbazoles. Further application of this methodology for
the preparation of the natural highly functionalized carba-
zoles and drug-related targets are underway.
tuted
6-[2-(p-toluenesulfonylamino)-aryl]-3-ethoxy-
carbonylhex-3-en-5-ynoic acids were prepared in four
steps from the easily available substituted o-iodoanilines12
8a–f (Scheme 3).
NH2
NHTs
NHTs
OH
R
I
R
I
R
a
b
R'
R'''
R'
R'''
R'
R'''
10a–f
8a–f
9a–f
R''
R''
R''
Acknowledgment
NHTs
P3P
CO2Et
We thank MIUR for partial financial support.
O
R
12
c
COOH
d
References
R'
R'''
11a–f
R''
(1) (a) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
4303. (b) Chakraborty, D. P. In The Alkaloids, Vol. 44;
Brossi, A., Ed.; Academic Press: New York, 1993, 257.
(2) Zhang, Y.; Wada, T.; Sasabe, H. J. Mater. Chem. 1998, 8,
809.
(3) Sonntag, M.; Strohriegl, P. Chem. Mater. 2004, 16, 4736.
(4) (a) Van Dijken, A.; Bastiaansen, J. J. A. M.; Kiggen, N. M.
M.; Langeveld, B. M. W.; Rothe, C.; Monkman, A.; Bach,
I.; Stössel, P.; Brunner, K. J. Am. Chem. Soc. 2004, 126,
7718. (b) Thomas, K. R. J.; Lin, J. T.; Tao, Y.-T.; Ko, C.-W.
J. Am. Chem. Soc. 2001, 123, 9404.
Ts
N
NHTs
CO2Et
CO2Et
R
e
R
COOH
R'
R'
R'''
R'' 13a–f
OAc
R'''
R''
14a–f
Scheme 3 Reagents and conditions: a) TsCl (1.2 equiv), pyridine;
b) propargyl alcohol (2 equiv), Et3N (3 equiv), CuI (0.01 equiv),
(Ph3P)2PdCl2 (0.01 equiv); c) MnO2, CH2Cl2, 8 h at r.t.; d) 11a–f and
12, toluene–CHCl3, r.t., 2 d; e) Ac2O (10 equiv) and NaOAc (2 equiv),
hydroquinone (0.05 equiv), then heating 1 h at reflux.
(5) Biswas, M.; Mishra, G. C. Makromol. Chem. 1981, 182, 261.
(6) Sunderg, R. J. In Comprehensive Heterocyclic Chemistry II,
Vol. 2; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Oxford, 1996, 119.
Synlett 2005, No. 5, 809–812 © Thieme Stuttgart · New York

LETTER
A New Route to Substituted Carbazoles
811
Table 1 Synthesis of Aldehydes 11, Acids 13 and Carbazoles 14 from o-Iodoamides 9 (Scheme 3)
En- o-Iodoamides 9 Aldehydes 11
try
Cou- Acids 13
pling/
Oxida-
tion
Wittig Carbazoles 14
Annu-
(yields,
lation
(yields,
%)a
%)a
(yields,
%)
a
NHTs
NHTs
NHTs
NHTs
93
87
89
89
90
Ts
NHTs
CO2Et
COOH
O
CO2Et
N
I
OAc
OAc
b
94
Ts
NHTs
CO2Et
COOH
O
CO2Et
N
I
c
90
84
82
82
87
NHTs
NHTs
CO2Et
COOH
NHTs
Ts
O
CO2Et
N
I
MeO
MeO
MeO
MeO
OAc
d
92
NHTs
Ts
NHTs
NHTs
CO2Et
COOH
O
CO2Et
N
I
OAc
CO2Et
NHTs
CO2Et
NHTs
CO2Et
EtO2C
e
f
93
86
89
73
91
77
NHTs
CO2Et
COOH
Ts
O
CO2Et
N
I
OAc
F
F
F
F
NHTs
Ts
NHTs
NHTs
CO2Et
COOH
O
CO2Et
N
I
OAc
NO2
NO2
NO2
O2N
a After chromatography and/or crystallization.
(7) (a) Kuwahara, A.; Nakano, K.; Nozaki, K. J. Org. Chem.
2005, 70, 413. (b) Lee, C.-Y.; Lin, C.-F.; Lee, J.-L.; Chiu,
Commun. 2002, 2310. (r) Venkatesh, C.; Ila, H.; Junjappa,
H.; Mathur, S.; Huch, V. J. Org. Chem. 2002, 67, 9477.
(8) Serra, S.; Fuganti, C.; Moro, A. J. Org. Chem. 2001, 66,
7883; and references cited therein.
C.-C.; Lu, W.-D.; Wu, M.-J. J. Org. Chem. 2004, 69, 2106.
(c) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 3739.
(d) Knölker, H.-J.; Krahl, M. P. Synlett 2004, 528.
(9) Serra, S.; Fuganti, C. Synlett 2002, 1661.
(e) Haider, N.; Käferböck, J. Tetrahedron 2004, 60, 6495.
(f) Crich, D.; Rumthao, S. Tetrahedron 2004, 60, 1513.
(g) Cai, X.; Snieckus, V. Org. Lett. 2004, 6, 2293.
(h) Smitrovich, J. H.; Davies, I. W. Org. Lett. 2004, 6, 533.
(i) Duval, E.; Cuny, G. D. Tetrahedron Lett. 2004, 45, 5411.
(j) Knölker, H.-J. Curr. Org. Synth. 2004, 1, 309.
(k) Huang, Q.; Larock, R. C. J. Org. Chem. 2003, 68, 7342.
(l) Back, T. G.; Pandyra, A.; Wulff, J. E. J. Org. Chem. 2003,
68, 3299. (m) Rawat, M.; Wulff, W. D. Org. Lett. 2003, 6,
329. (n) Knölker, H.-J. Chem. Commun. 2003, 1170.
(o) Scott, T. L.; Söderberg, B. C. G. Tetrahedron 2003, 59,
6323. (p) Witulski, B.; Alayrac, C. Angew. Chem. Int. Ed.
2002, 41, 3281. (q) Bedford, R. B.; Cazin, C. S. J. Chem.
(10) Serra, S.; Fuganti, C. Synlett 2003, 2005.
(11) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595.
(12) (a) 2-Iodoaniline 8a is commercially available. The
substituted 2-iodoanilines 8b, 8c and 8e were prepared from
the commercially available 4-methylaniline, 2-nitro-4-
methoxyaniline and 4-fluoroaniline, respectively, according
to the procedure described by Ma et al.12b Ethyl 4-amino-3-
iodobenzoate 8d and 4-nitro-2-iodoaniline 8f were prepared
from commercially available ethyl 4-aminobenzoate and 4-
nitroaniline, respectively by iodination according to the
procedure described by Spivey et al. and Adimurthy et al.,
respectively.12c,d (b) Ma, C.; Liu, X.; Li, X.; Flippen-
Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001, 66,
Synlett 2005, No. 5, 809–812 © Thieme Stuttgart · New York

812
S. Serra, C. Fuganti
LETTER
4525. (c) Spivey, A. C.; McKendrick, J.; Srikaran, R. J. Org.
Chem. 2003, 68, 1843. (d) Adimurthy, S.; Ramachandraiah,
G.; Ghosh, P. K.; Bedekar, A. V. Tetrahedron Lett. 2003, 44,
5099.
at reflux for 1 h under a nitrogen atmosphere. After cooling
to r.t., the acetic anhydride was removed in vacuo and the
residue was treated with EtOAc (300 mL) and H2O (100
mL). The organic phase was separated, dried (Na2SO4) and
concentrated under reduced pressure. The residue was
purified by chromatography and crystallization to give
carbazoles derivatives 14a–f.
(13) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) The coupling reaction was performed
in THF solution using 2 equiv of propargyl alcohol, Et3N as
base and an equimolar amount of copper and palladium
catalysts (0.01 equiv). Iododerivatives 9d and 9f show low
solubility in THF and a mixture of THF–DMF was used as
solvent.
(14) The Wittig reaction between aldehydes 11a–f and ylide 12
was performed in toluene–CHCl3 solution. The amount of
CHCl3 was adjusted depending on the solubility of the
starting aldehydes. The above-mentioned reaction proceeds
slowly at r.t. (typically 2 d). Notably, worse results have
been obtained by heating the reaction mixture.
All new compounds were fully characterized. Selected
analytical data:
Compound 13e: Anal. Calcd for C22H20FNO6S: C, 59.32; H,
4.53. Found: C, 59.45; H, 4.55. Mp 154 °C. FT-IR (nujol):
670, 954, 1030, 1100, 1189, 1280, 1363, 1448, 1466, 1539,
1594, 1633, 1697 cm–1. 1H NMR (250 MHz, CDCl3): d =
1.40 (3 H, t, J = 7.2 Hz), 2.31 (3 H, s), 3.54 (2 H, s), 4.36 (2
H, q, J = 7.2 Hz), 6.75 (1 H, s), 7.06–7.20 (2 H, m), 7.16 (2
H, d, J = 8.3 Hz), 7.58 (2 H, d, J = 8.3 Hz), 8.18 (1 H, q,
J = 4.4 Hz), 8.27 (1 H, s), 11.25 (1 H, br s). MS (EI): m/z =
446 [M+ + 1], 445 [M+], 290, 262, 246, 216, 200, 172, 155,
91, 65.
(15) For the preparation of this ylide see: Hudson, R. F.; Chopard,
P. A. Helv. Chim. Acta 1963, 46, 2178.
(16) (a) Only E-isomers of acids 13 were obtained (NMR
analysis). The Wittig reaction of ylide 12 with the aldehydes
affords the 3-(E)-alkylidene-succinic acid monoalkyl esters
in a highly stereoselective way; for previous studies on this
reaction see: Paquette, L. A.; Schulze, M. M.; Bolin, D. J.
Org. Chem. 1994, 59, 2043. (b) Röder, E.; Krauss, H.
Liebigs Ann. Chem. 1992, 177.
(17) Acids 13a–f (50 mmol) were dissolved in acetic anhydride
(48 mL, 0.5 mol). To this solution, anhyd NaOAc (8.2 g, 0.1
mol) and hydroquinone (275 mg, 2.5 mmol) were added in
one portion. The obtained heterogeneous mixture was heated
Compound 14e: Anal. Calcd for C24H20FNO6S: C, 61.40; H,
4.29. Found: C, 61.50; H, 4.30. Mp 197–198 °C (hexane–
CHCl3). FT-IR (nujol): 666, 861, 1027, 1087, 1175, 1207,
1299, 1369, 1417, 1472, 1591, 1722, 1763 cm–1. 1H NMR
(250 MHz, CDCl3): d = 1.46 (3 H, t, J = 7.2 Hz), 2.27 (3 H,
s), 2.49 (3 H, s), 4.47 (2 H, q, J = 7.2 Hz), 7.13 (2 H, d,
J = 8.3 Hz), 7.27 (1 H, dt, J = 9.0, 2.5 Hz), 7.54 (1 H, dd,
J = 8.2, 2.5 Hz), 7.69 (2 H, d, J = 8.3 Hz), 7.85 (1 H, s), 8.31
(1 H, dd, J = 9.0, 4.3 Hz), 8.86 (1 H, s). MS (EI): m/z = 470
[M+ + 1], 469 [M+], 427, 382, 354, 334, 315, 290, 272, 244,
227, 200, 171, 155, 139, 120, 91, 65.
Synlett 2005, No. 5, 809–812 © Thieme Stuttgart · New York