Preparation of 6-chloro-5-fluoroindole via the use of palladium and copper-mediated heterocyclisations

Article abstract of DOI:10.1016/S0040-4039(02)01758-6

The title indole, the heterocyclic core of the 5-HT_2C receptor agonist Ro 60-0175, was prepared by a modification to the Stille indole synthesis, or by the method of Gonzalez and co-workers.

Full text of DOI:10.1016/S0040-4039(02)01758-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7581–7583
Preparation of 6-chloro-5-fluoroindole via the use of palladium
and copper-mediated heterocyclisations
†
David R. Adams, Matthew A. J. Duncton,* Jonathan R. A. Roffey and John Spencer
Department of Chemistry, Vernalis Research Ltd, Oakdene Court, 613 Reading Road, Winnersh, Wokingham RG41 5UA, UK
Received 12 June 2002; revised 12 August 2002; accepted 22 August 2002
Abstract—The title indole, the heterocyclic core of the 5-HT2C receptor agonist Ro 60-0175, was prepared by a modification to
the Stille indole synthesis, or by the method of Gonzalez and co-workers. © 2002 Elsevier Science Ltd. All rights reserved.
The palladium-mediated synthesis of heterocycles is an
active area of research and is being increasingly
employed for the formation of molecules of biological
1
importance. Of special note has been the use of these
palladium-mediated methods to prepare substituted
2
indole derivatives in a regioselective manner. One such
approach, described by Stille and co-workers, combines
the use of a palladium(0)-catalysed coupling reaction
between (vinyl)tributyltin and an N-protected 2-bro-
Scheme 2.
two steps from 5a and in an overall yield of ca. 30%. A
previous preparation of 6-chloro-5-fluoroindole
required a sequence of four steps from the bromoani-
line 5a and required the use of methyllithium and
moaniline, followed by
a
palladium(II)-mediated
intramolecular aminopalladation/dehydropalladation
protocol, to afford N-protected indole derivatives
3
4
(
Scheme 1). In this letter, we disclose a modification to
tert-butyllithium.
the Stille method for preparing substituted indole
derivatives, which alleviates the need for N-protection,
or the use of (vinyl)tributyltin, a highly toxic organotin
reagent. The usefulness of this modification was illus-
trated by preparing 6-chloro-5-fluoroindole 4a, the het-
erocyclic core of the 5-HT2C receptor agonist, Ro
The synthesis of the indole 4a commenced with a
palladium(0)-catalysed coupling reaction between the
bromoaniline 5a and 3 equiv. of vinylmagnesium bro-
mide in refluxing THF to give the vinylaniline 6a in
good yield after column chromatography (Scheme 2).
This palladium(0)-catalysed coupling of vinylmagne-
sium bromide was also extended to other bromoanilines
(Table 1) and constitutes a useful synthesis of 2-
4
5
6
0-0175, from the known bromoaniline 5a. A comple-
mentary approach to the indole 4a from the bromoani-
line 5a using palladium and copper chemistry is also
disclosed. Both methods afford the desired indole 4a in
6,7
alkenylanilines.
Scheme 1.
Keywords: indoles; palladium and compounds; catalysis; coupling reactions.
*
Corresponding author. Present address: OSI Pharmaceuticals, Windrush Court, Watlington Road, Cowley, Oxford OX4 6LT, UK. Tel.: 44
0)1865 871227; e-mail: mduncton@osip.com
Present address: James Black Foundation, 68 Half Moon Lane, Dulwich SE24 9JE, UK.
(
†
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01758-6

7
582
D. R. Adams et al. / Tetrahedron Letters 43 (2002) 7581–7583
Table 1. Palladium catalysed alkenylaniline and indole
formation
standard conditions of palladium(II) chloride/p-benzo-
quinone, whereas the reaction of 6c, using an identical
method, gave no indole product at all.
The capricious nature of the palladium(II)-catalysed
aromatisation step prompted us to explore a more
robust synthesis of indoles and in particular 6-chloro-5-
fluoroindole. Towards this end we decided to employ
8
the method of Gonzalez et al. Thus, the bromoaniline
5
a was coupled with (trimethylsilyl)acetylene under pal-
ladium(0)-catalysis to afford the 2-alkynylaniline 7,
which was cyclised to the target indole 4a, by the use of
copper(I) iodide in DMF at 100°C (Scheme 4). The
overall yield for this two step process (ca. 30%) was
comparable to the overall yield obtained using our
modified Stille indole synthesis (30–35%). However,
unlike our previous synthesis, we found that the forma-
tion of 4a from 7 could be performed on a reasonably
large scale (up to 25 mmol of 7).
In conclusion, we have developed a modification to the
Stille synthesis of indoles and used this modified proce-
dure to prepare 6-chloro-5-fluoroindole. In addition, we
have shown that 6-chloro-5-fluoroindole may be syn-
thesised on a larger scale using the protocol described
9
by Gonzalez and co-workers.
Experimental section
Preparation of 2-bromo-5-chloro-4-fluoroaniline 5a:
Bromine (27.4 g, 170 mmol) in dichloromethane (100
mL) was added dropwise over 4 h to a stirred solution
of 3-chloro-4-fluoroaniline (25 g, 170 mmol) and pyri-
dine (20.1 g, 250 mmol) in dichloromethane (300 mL)
at 0°C. After complete addition of the bromine, the
mixture was stirred for 1 h at 0°C then washed with
Scheme 3.
H O (3×100 mL) and brine (1×100 mL), dried
2
(
MgSO ), filtered and concentrated in vacuo to leave a
4
The conversion of the vinylaniline 6a into the requisite
indole 4a was accomplished by using a catalytic amount
of palladium(II) chloride (10 mol%) in the presence of
crude oil. The oil was purified by column chromatogra-
phy on silica gel using heptane/ethyl acetate (24:1) as
eluent to give the title compound (15.3 g, 41%) as a
white solid. l (400 MHz; CDCl ) 3.98 (2H, br. s), 6.76
p-benzoquinone as a stoichiometric co-oxidant (Scheme
3
H
3
3
). This method gave a good yield (50–60%) of the
(
1H, d, J=6.6 Hz), 7.21 (1H, d, J=8.2 Hz).
desired heterocycle 4a when the reaction was carried
out on a small scale (up to 5 mmol of 6a). However,
when greater quantities of the precursor 6a were
employed, it was found that the yield of the desired
indole 4a decreased substantially. The conversion of
other 2-vinylanilines into indoles by the use of this
Preparation of 3-chloro-4-fluoro-6-vinylaniline 6a:
Triphenylphosphine (1.1 g, 4.0 mmol) was added in one
portion to a stirred solution of palladium(II) acetate
(
0.23 g, 1.0 mmol) in THF (50 mL) under argon at
room temperature. The mixture was stirred for 15 min
then 2-bromo-5-chloro-4-fluoroaniline 5a (11 g, 50
mmol) was added in one portion. The mixture was
stirred for 5 min, cooled to 0°C and a solution of
aminopalladation/dehydropalladation
procedure
proved to be substrate dependent (Table 1). For exam-
ple, 6b gave the desired indole 4b in low yield under the
Scheme 4.

D. R. Adams et al. / Tetrahedron Letters 43 (2002) 7581–7583
7583
vinylmagnesium bromide in THF (1 M; 150 mL, 150
mmol) was added dropwise over 40 min. The mixture
was then stirred at reflux for 1 h. After allowing to cool
to room temperature, the mixture was quenched by
pouring into saturated aqueous ammonium chloride
Preparation of 6-chloro-5-fluoroindole 4a from 7: Cop-
per(I) iodide (7.1 g, 38 mmol) was added in one portion
to a stirred solution of 5-chloro-4-fluoro-2-(trimethylsil-
ylethynyl)aniline 7 (4.5 g, 19 mmol) in DMF (80 mL)
under an argon atmosphere. The suspension was stirred
at room temperature for 10 min then at 100°C for 2 h.
After allowing to cool to room temperature, ether (100
mL) was added and the mixture was filtered through a
(
500 mL) and ether (100 mL). The aqueous and organic
layers were partitioned and the aqueous layer was
extracted with ether (2×100 mL). The combined organic
phases were washed with brine (1×100 mL), dried
®
bed of Celite . The filter cake was washed with ether
(
2×100 mL) and the filtrate was dried (MgSO ), filtered
(
MgSO ), filtered and the solvent removed in vacuo to
4
4
and concentrated in vacuo to leave a crude oil. The oil
was purified by column chromatography on silica gel
using heptane/ethyl acetate (5:1) as eluent to give the
title compound (1.5 g, 48%) as a pale brown solid. The
data was identical to previously synthesised material.
leave a crude oil. The oil was purified by column
chromatography on silica gel using heptane/ethyl ace-
tate (20:1) as eluent to give the title compound (5.3 g,
6
2%) as a colourless solid. lH (400 MHz; CDCl ) 3.70
3
(
2H, br. s), 5.38 (1H, d, J=9.5 Hz), 5.62 (1H, d,
J=17.5 Hz), 6.65 (1H, m), 6.70 (1H, d, J=6.5 Hz and
.06 (1H, d, J=10 Hz).
7
Acknowledgements
Preparation of 6-chloro-5-fluoroindole 4a from 6a: A
mixture of 3-chloro-4-fluoro-6-vinylaniline 6a (0.34 g, 2
mmol) and THF (20 mL) was stirred at room tempera-
ture under an argon atmosphere. Lithium chloride (0.42
g, 10 mmol), palladium(II) chloride (0.035 g, 0.2 mmol)
and p-benzoquinone (0.34 g, 3.2 mmol) were added and
the mixture was stirred at reflux for 16 h. After allow-
ing to cool to room temperature, the mixture was
concentrated in vacuo to leave a crude solid. The solid
was purified by column chromatography on silica gel
using heptane/dichloromethane (3:1) as eluent to give
the title compound (0.18 g, 53%) as a pale brown solid.
We thank Ken Heatherington, Graeme Harden, Peter
Clayton and Tim Haymes for performing the analysis
of all compounds synthesised in this paper.
References
1
. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chem-
istry. A Guide for the Synthetic Chemist; Tetrahedron
Organic Series, Pergamon Press, 2000; Vol. 20.
Mp 105–107°C; lH (400 MHz; CDCl ) 6.50–6.51 (1H,
3
2. (a) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27,
m), 7.25 (1H, t, J=2.8 Hz), 7.35 (1H, d, J=9.4 Hz),
1
113; (b) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc.
7.40 (1H, d, J=9.4 Hz) and 8.01 (1H, br. s).
1991, 113, 6689.
3
4
. Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J.
K. J. Org. Chem. 1988, 53, 1170.
. B o¨ s, M.; Jenck, F.; Martin, J. R.; Moreau, J.-L.; Sleight,
A. J.; Wichmann, J.; Widmer, U. J. Med. Chem. 1997, 40,
Preparation of 5-chloro-4-fluoro-2-(trimethylsilylethynyl)
aniline 7: A mixture of 2-bromo-5-chloro-4-fluoroani-
line 5a (6.6 g, 30 mmol) and triethylamine (60 mL) was
stirred at room temperature under an argon atmo-
sphere. Bis(triphenylphosphine) palladium(II) chloride
2762.
5. Ishikura, T.; Gunji, T. Japanese Patent 01,311, 056, 1989;
(
0.4 g, 0.6 mmol) and trimethylacetylene (7.8 mL, 54
Chem. Abstr. 1990, 112, 216418w.
mmol) were added and the mixture was stirred at 60°C
for 16 h. After allowing to cool to room temperature,
ether (100 mL) was added and the mixture was filtered
through a bed of Celite . The filter cake was washed
with ether (2×100 mL) and the filtrate was dried
6. Harmata, M.; Mehmet, K. Synthesis 1995, 713 and refer-
ences cited therein.
7. The palladium(0)-catalysed cross-coupling of a Grignard
reagent with halobenzoic acids, halophenols and haloanili-
nes has been disclosed previously. See Bumagin, N. A.;
Luzikova, E. V. J. Organomet. Chem. 1997, 532, 271.
8. Ezquerra, C.; Pedregal, C.; Lamas, J.; Barluenga, J.; Perez,
M.; Garcia-Martin, M. A.; Gonzalez, J. M. J. Org. Chem.
1996, 61, 5804.
®
(
MgSO ), filtered and concentrated in vacuo to leave a
4
crude oil. The oil was purified by column chromatogra-
phy on silica gel using heptane/ethyl acetate (30:1) as
eluent to give the title compound (4.5 g, 63%) as a pale
brown oil. lH (400 MHz; CDCl ) 0.26 (9H, s), 4.13
9. A large scale preparation of 6-chloro-5-fluoroindole using
a modified Leimgruber–Batcho route will be detailed else-
where.
3
(
2H, br. s), 6.70 (1H, d, J=6.5 Hz) and 7.05 (1H, d,
J=9 Hz).