Synthesis of 6-bromo-2-arylindoles using 2-iodobenzoic acid as precursor

Article abstract of DOI:10.1016/j.tetlet.2011.05.040

The synthesis of 6-bromo-2-arylindoles starting from readily available 2-iodobenzoic acid is presented. Regioselective bromination of the latter was followed by Curtius rearrangement and trapping of the isocyanate with benzyl alcohol led to the benzyl carbamate of 2-iodo-5-bromoaniline. Chemoselective Sonogashira coupling of this compound with arylacetylenes followed by TBAF induced 5-endo-dig cyclization gave the desired bromo indoles. The method allows selective introduction of a bromine atom at the indole C-6 position.

Full text of DOI:10.1016/j.tetlet.2011.05.040

Tetrahedron Letters 52 (2011) 3726–3728
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Tetrahedron Letters
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Synthesis of 6-bromo-2-arylindoles using 2-iodobenzoic acid as precursor
Ismael Valois-Escamilla a, Alejandro Alvarez-Hernandez a, , Luis Felipe Rangel-Ramos a,
⇑
Oscar Rodolfo Suárez-Castillo a, Francisco Ayala-Mata b, Gerardo Zepeda-Vallejo b
a Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Hidalgo, Carr. Pachuca Tulancingo km 4.5 Pachuca, Hidalgo 42184, Mexico
b Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala s/n, 11340 México, D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 6-bromo-2-arylindoles starting from readily available 2-iodobenzoic acid is presented.
Regioselective bromination of the latter was followed by Curtius rearrangement and trapping of the iso-
cyanate with benzyl alcohol led to the benzyl carbamate of 2-iodo-5-bromoaniline. Chemoselective Sono-
gashira coupling of this compound with arylacetylenes followed by TBAF induced 5-endo-dig cyclization
gave the desired bromo indoles. The method allows selective introduction of a bromine atom at the
indole C-6 position.
Received 14 April 2011
Revised 5 May 2011
Accepted 9 May 2011
Available online 19 May 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Curtius rearrangement
Sonogashira coupling
6-Bromoindole
Chemoselective coupling
2-Iodobenzoic acid
2-Arylindole derivatives have been shown to possess a wide
spectrum of pharmacological activities such as hepatitis C virus
polymerase- and farnesyl protein transferase inhibitors,1,2 antibac-
terial,3 liver X receptor-, NK1 receptor- and GnRH receptor-antag-
onists,4–6 and estrogen receptor ligands.7 Substituent groups in the
six member ring of indole derivatives are associated with an in-
crease of biological activity being the C-5 substitution the most fre-
quently found5,6 due to the availability of their para substituted
aniline precursors. Synthetic 6-bromo-2-arylindoles8 have been
much less studied than their C-5 isomers despite 6-bromoindole
natural products9 present in marine organisms exhibit a wide
spectrum of biological activity with a promising profile for phar-
maceutical development. At least in part, this is a consequence of
the issues to selectively introduce the bromine atom at the indole
C-6 position; direct bromination of indole at this position is only
possible in limited examples that require a blocking C-3 substitu-
ent.10 In consequence, C-6 bromoindoles have to be prepared from
suitable functionalized benzene precursors, already containing the
bromine atom, that form the azole ring,11 or alternatively, by bro-
mination of indolines12 followed by oxidation. Although a number
of methods to synthesize 2-arylindoles have been described13 we
became interested in developing a strategy to selectively obtain
6-bromo-2-arylindoles. Consequently, we focused our attention
to methods of indole synthesis that rely on transition metal cata-
lyzed transformations of alkynes14 such as the Sonogashira cou-
pling15 of an ortho-iodoaniline with arylacetylenes followed by
intramolecular 5-endo-dig cyclization of the corresponding ortho-
alkynylanilines to prepare 2-arylindoles. In this letter we show
that commercial 2-iodobenzoic acid can be regioselectively bromi-
nated at C-5 and then subjected to Curtius rearrangement to give a
carbamate derivative of 2-iodo-5-bromoaniline. This compound
can be submitted to a chemoselective Sonogashira coupling at
the C–I bond with arylacetylenes and the corresponding products
undergo TBAF induced cyclization to afford 6-bromo-2-arylindoles
(Scheme 1).
Starting from commercially available 2-iodobenzoic acid 1 reg-
16
ioselective bromination at C-5 was carried out with NBS in H2SO4
to give 5-bromo 2-iodobenzoic acid 2.17 Then, the C–N bond was
installed by means of a Curtius rearrangement.18 Accordingly, acid
2 was treated with thionyl chloride to give the corresponding
crude acyl chloride which was mixed with sodium azide in ace-
tone.19 Solvent evaporation (CAUTION, the acyl azide is potentially
explosive, the solution should not be evaporated to dryness) of the
crude reaction mixture gave the moisture sensitive acyl azide
which was dissolved in dry toluene and heated to afford the corre-
sponding isocyanate which was trapped as the corresponding car-
bamate 3 by addition of benzyl alcohol and catalytic DMAP. The
dihalogenated carbamate 3 was isolated and purified by crystalli-
zation. Notably, no chromatography for purification was needed
for this five-step sequence (Scheme 2).
⇑
Corresponding author. Tel.: +52 771 717 2000x2205; fax: +52 771 717
2000x6502.
With compound 3 in hand, a Sonogashira reaction with a series
of arylacetylenes 4a–o carrying functional groups at ortho, meta
and para positions was conducted to prepare the diarylacetylenes
E-mail addresses: alalvareher@yahoo.com, alvarez@uaeh.edu.mx (A. Alvarez-
Hernandez).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.040

I. Valois-Escamilla et al. / Tetrahedron Letters 52 (2011) 3726–3728
3727
Scheme 1. Strategy to prepare 6-bromo-2-arylindoles.
Scheme 2. Synthesis of the dihalogenated carbamate 3 from 2-iodobenzoic acid.
5a–o (Table 1). All arylalkynes used bearing either electron-donat-
ing or withdrawing groups worked well and coupled exclusively at
the C–I bond of 3. The strength of the C-I compared to that of the
C–Br bond (65 vs 85 kcal/mol)20 makes the oxidative addition of
Pd(0) chemoselectively to the weaker C–I bond21 during the cata-
lytic cycle.
ortho CHO group no indole product was observed. Likely, the base
sensitive aldehyde group induces substrate decomposition in the
basic conditions produced by use of TBAF before the slow cycliza-
tion to an indole can take place (Table 2, entry 6). In comparison,
under the same conditions the para CHO isomer 5e reacts faster
and the corresponding indole was obtained in acceptable yield (Ta-
ble 2, entry 5). Furthermore, in one case, the strong electron-donat-
ing group 4-NMe2 in the arylacetylene 5o makes the triple bond
unreactive and no cyclization occurred at all (Table 2, entry 15);
in this case only the corresponding free amine derived from 5o
could be isolated in low yield, this compound decomposed upon
standing.
In summary, we have developed a new approach to 6-bromo-2-
arylindoles starting from readily available ortho-iodobenzoic acid.
The regioselective bromination and Curtius rearrangement of the
latter compound enabled the synthesis of the benzyl carbamate
of 5-bromo-2-iodo aniline 3 that could be used in different variants
of indole synthesis. In the present work, we illustrate that chemo-
selective Sonogashira coupling of this compound with arylacetyl-
enes bearing functional groups followed by TBAF promoted
cyclization of the corresponding 2-alkynyl carbamates allowed
the preparation of a series of 2-arylindoles 6a–n bearing a bromine
atom at C-6. Ortho substituted acetylenes react slower than meta
Finally, the 5-endo-dig cyclization of ortho-alkynylaniline deriv-
atives 5a–o with concomitant removal of the carbamate group was
carried out by heating with 3 equiv of TBAF in THF22 leading to the
desired 6-bromo-2-arylindoles 6a–n (Table 2). It can be observed
that diarylalkynes with electron withdrawing groups cyclize faster
than those with electron-donating groups (entries 3 and 12, Ta-
ble 2) due to activation of the arylalkyne by electron-withdrawing
groups toward intramolecular nucleophilic attack. Furthermore,
the cyclization tolerates well arylacetylenes with substituent
groups at para and meta positions. However, an ortho substituent
makes the alkyne less reactive due to steric hindrance. Thus, short-
er reaction times are observed for cyclization of para and meta aryl-
acetylene isomers compared to those of their ortho substituted
counterparts in the CH3 and OCH3 series (entry 9 vs 11 and entry
12 vs 14, Table 2). In these cases, despite different reaction times
the yields of the corresponding indole are similar. On the contrary,
in the attempted cyclization of the arylacetylene 5f bearing an
Table 1
Chemoselective Sonogashira coupling of 5-bromo-2-iodophenylbenzyl carbamate 3 with arylacetylenes 4a–o to afford 5-bromo-2-(arylethynyl) phenylbenzyl carbamates 5a–o
Entry
Alkyne
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
H
4-CN
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
90
92
92
85
88
89
81
88
86
93
90
81
89
88
86
4-NO2
4-COCH3
4-CHO
2-CHO
4-CO2CH3
4-F
4-CH3
3-CH3
2-CH3
4-OCH3
3-OCH3
2-OCH3
4-N(CH3)2
9
10
11
12
13
14
15
a
Isolated yield after chromatography.

3728
I. Valois-Escamilla et al. / Tetrahedron Letters 52 (2011) 3726–3728
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Carbamate
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6k
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6o
76
89
80
85
75
0
78
67
68
70
63
69
67
73
0
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4-COCH3
4-CHO
2-CHO
4-CO2CH3
4-F
4-CH3
3-CH3
2-CH3
4-OCH3
3-OCH3
2-OCH3
4-N(CH3)2
9
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a
Decomposition of starting carbamate 5f to a complex mixture was observed.
Only deprotection of carbamate 5o was observed, the corresponding free ani-
line was isolated in low yield and decomposed upon standing.
b
c
Isolated yield after chromatography.
and para isomers. The mild conditions employed in the Sonogash-
ira coupling and the cyclization step, together with its tolerance to
a range of functional groups, make this method a useful comple-
ment to previous strategies to obtain 6-bromo-2-arylindoles that
could be extended to other C-6 functionalized congeners.
Acknowledgment
The authors are grateful for financial support of this work from
CONACYT (Grant CB-2006-61247) and predoctoral fellowships for
I.V. and L.F.R.
Supplementary data
Supplementary data (experimental procedures and copies of 1H
and 13C NMR spectra for all compounds) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2011.05.040.
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