Use of a modified Leimgruber-Batcho reaction to prepare 6-chloro-5-fluoroindole

Article abstract of DOI:10.1081/SCC-120038513

An efficient synthesis of the title indole, the heterocyclic core of the standard 5-HT_2C receptor agonist Ro 60-0175, via a modified Leimgruber-Batcho indole synthesis is presented. The process can be used to make > 100 g quantities of the targ

Full text of DOI:10.1081/SCC-120038513

This article was downloaded by: [University of Sydney]
On: 26 March 2013, At: 10:00
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Use of a Modified Leimgruber–Batcho Reaction to
Prepare 6‐Chloro‐5‐fluoroindole
a
a
a b
a
Jon M. Bentley , James E. Davidson , Matthew A. J. Duncton , Paul R. Giles
&
a
Robert M. Pratt
a
Department of Chemistry, Vernalis Research Ltd., Oakdene Court, Winnersh,
Wokingham, UK
b
ImClone Systems Inc., 710 Parkside Avenue, Suite 2, Brooklyn, NY, 11226, USA
Version of record first published: 17 Aug 2006.
To cite this article: Jon M. Bentley , James E. Davidson , Matthew A. J. Duncton , Paul R. Giles & Robert M. Pratt
(2004): Use of a Modified Leimgruber–Batcho Reaction to Prepare 6‐Chloro‐5‐fluoroindole, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:12, 2295-2301
To link to this article: http://dx.doi.org/10.1081/SCC-120038513
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss, actions,
claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 12, pp. 2295–2300, 2004
Use of a Modified Leimgruber–Batcho
Reaction to Prepare 6-Chloro-
5-fluoroindole
Jon M. Bentley, James E. Davidson, Matthew A. J. Duncton,*
Paul R. Giles, and Robert M. Pratt
Department of Chemistry, Vernalis Research Ltd., Oakdene Court,
Winnersh, Wokingham, UK
ABSTRACT
An efficient synthesis of the title indole, the heterocyclic core of the stan-
dard 5-HT2C receptor agonist Ro 60-0175, via a modified Leimgruber–
Batcho indole synthesis is presented. The process can be used to make
.
100 g quantities of the target indole.
Key Words: Indole; Ro 60-0175; Leimgruber–Batcho; 5-HT2C receptor.
*
Correspondence: Matthew A. J. Duncton, ImClone Systems Inc., 710 Parkside
Avenue, Suite 2, Brooklyn, NY 11226, USA; E-mail: matthew.duncton@imclone.com.
2
295
DOI: 10.1081/SCC-120038513
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
2
296
Bentley et al.
INTRODUCTION
Substituted indoles are found in many biological and non-naturally
[1]
occurring substances of significant pharmacological function. Many of
these molecules exert their biological effects by interacting with one of the
1
4 known receptor subtypes of the neurotransmitter serotonin [5-hydroxy-
[
2]
tryptamine (5-HT)]. Ro 60-0175 1 has been claimed to be a potent and
selective 5-HT2C receptor agonist and contains an a-methylethylamine
chain appended to a disubstituted indole nucleus. In this communication,
we disclose a large scale (.100 g) preparation of 6-chloro-5-fluoroindole 2,
the heterocyclic core of Ro 60-0175, via a modified Leimgruber–Batcho
[3]
[
4,5]
reaction.
The synthesis of the indole 2 began by a nitration reaction of 2-fluoro-4-
methylaniline 3 with HNO /H SO below 08C to afford the nitrotoluene
3
2
4
a
derivative 4 as a single regioisomer (Sch. 1). A Sandmeyer reaction con-
verted aniline 4 into 3-chloro-4-fluoro-6-methylnitrobenzene 5, which served
as the key precursor for investigation of the Leimgruber–Batcho indole
synthesis.
Our initial attempt to prepare 6-chloro-5-fluoroindole 2 involved, as a
first step, the reaction of the nitrobenzene 5 with N,N-dimethylformamide
dimethylacetal at 1408C (Sch. 2). However, this yielded varying amounts
of a methoxy-substituted side-product 7, in addition to the desired enamine
6
. Although the crude reaction mixture could be cyclised to the desired
indole 2 by exposure to Raney nickel and hydrazine in methanol, it was
found that the indole 2 could only be separated from the undesired methoxy
aniline 8 by careful column chromatography, and the overall yield for this
[6]
two-step procedure was very variable and never rose above 50%.
In an effort to improve the Leimgruber–Batcho reaction, we sought to
modify the enamine-generating first step of the process. It was reasoned that
an acetal of N,N-dimethylformamide possessing a hindered alkoxy group
a
If the mixture is allowed to rise above 08C then a mixture of regioisomeric products
forms.

ORDER
REPRINTS
Modified Leimgruber–Batcho Reaction to Prepare Indole
2297
Scheme 1.
Scheme 2.
would show a diminished propensity to undergo the unwanted nucleophilic
b
aromatic substitution reaction with the nitrotoluene starting material 5.
Thus, N,N-dimethylformamide di-iso-propylacetal and N,N-dimethylforma-
mide di-tert-butyacetal were selected for evaluation. Gratifyingly, both acetals
reacted smoothly with the nitrotoluene 5 to afford the desired enamine 6 as
the sole product, with no evidence of any material arising from nucleophilic
aromatic displacement, even when this reaction was performed on a multi-
gram scale (Sch. 3). Formation of the indole 2 from the enamine 6
proceeded as before by the use of Raney nickel and hydrazine with a simple
filtration through silica gel giving material of high purity (.98%) and in an
overall yield of 60%.
b
In an unrelated study, it was noted that fluoride could be displaced from 5-fluoro-2-
nitrotoluene by reaction with sodium methoxide. However, fluoride was not displaced
when 5-fluoro-2-nitrotoluene was reacted with sodium-iso-propoxide.

ORDER
REPRINTS
2
298
Bentley et al.
Scheme 3.
In conclusion, we have shown that 6-chloro-5-fluoroindole, the hetero-
cyclic core of the 5-HT2C receptor agonist Ro 60-0175, may be prepared in
an efficient manner by the use of a modified Leimgruber–Batcho reaction.
The key to this modified process is the use of an acetal of N,N-dimethylforma-
mide that possesses a hindered alkoxy group in order to avoid nucleophilic
aromatic displacement of an activated nitrotoluene starting material. It is
anticipated that this modification may be extended to the production of
other indole derivatives from nitrotoluene precursors which contain a group,
or atom, prone to displacement, or reaction, with unhindered alkoxides such
as methoxide or ethoxide.
EXPERIMENTAL
Melting points were determined on a Stuart Scientific melting point appar-
1
atus model SMP2 and are uncorrected. H NMR were obtained on a Bruker DPX
400 NMR spectrometer using tetramethylsilane as an internal standard. Micro-
analytical data were obtained on a CEC 240 XA or Caloebra 1106 microanalysis
machine. Reagents and solvents were purchased from The Aldrich Chemical
Company, Dorset, England or Fluorchem Limited, Derbyshire, England.
Preparation of 2-fluoro-4-methyl-5-nitroaniline 4. Concentrated nitric
acid (20 g) was added dropwise over 90 min to a stirred solution of 2-fluoro-4-
methylaniline 3 (25 g, 0.2 mol) in concentrated sulphuric acid (250 mL) at
2
108C. The mixture was then poured onto ice (1 L) and the solution adjusted
to pH 13 using solid sodium hydroxide (CARE: EXOTHERMIC REAC-
TION) keeping the internal temperature below 808C. After allowing to cool
to rt the mixture was extracted with ether (3 Â 250 mL) and the combined
organic extracts were washed with brine, dried (MgSO ), filtered, and concen-
4
trated in vacuo to leave the product (32 g, 94%) as an orange solid. A recrys-
tallised sample (heptane–ethyl acetate) gave mp 80–828C; dH (400 Hz;
CDCl ) 7.49 (1H, d, J ¼ 8.3 Hz), 6.91 (1H, d, J ¼ 11.1 Hz), 3.91 (2H, br.
3
s), 2.49 (3H, s); C H FN O requires: C, 49.42; H, 4.15; N, 16.46. Found
7
7
2 2
C, 49.60; H, 4.15; N, 16.57%.

ORDER
REPRINTS
Modified Leimgruber–Batcho Reaction to Prepare Indole
2299
The above reaction could be repeated using 498 g of the starting aniline 3
to give the crude product (705 g) in quantitative yield.
Preparation of 3-chloro-4-fluoro-6-methylnitrobenzene 5. A solution
of sodium nitrite (7.6 g, 0.11 mol) in water (20 mL) was added dropwise over
30 min at 08C to a stirred suspension of 2-fluoro-4-methyl-5-nitroaniline 4
(
17 g, 0.1 mol) in concentrated hydrochloric acid (200 mL). The mixture
was stirred at 08C for 20 min then transferred to a dropping funnel and
added dropwise over 30 min to a stirred suspension of copper(I) chloride
(16 g) in concentrated hydrochloric acid (150 mL) at 08C. The mixture was
allowed to warm to rt and stirred for 16 hr, then poured onto ice-water
(
extracts were washed with brine, dried (MgSO ), filtered, and concentrated in
1.5 L) and extracted with ethyl acetate (3 Â 250 mL). The combined organic
4
vacuo to leave a crude oil. The oil was purified by column chromatography
on silica gel using heptane as eluent to give the product (14.2 g, 75%) as a
yellow solid. A sample was recrystallised (heptane) to give a white solid mp
[
6]
5
7
7–588C (lit. 57–58 8C); d (400 MHz; CDCl ) 8.03 (1H, d, J ¼ 7.2 Hz),
H
3
.13 (1H, d, J ¼ 9.1 Hz), 2.6 (3H, s).
The above reaction could be repeated using 200 g of the starting aniline 4
to give the product (147 g) in 60% yield.
Preparation of [2-(4-Chloro-5-fluoro-2-nitro-phenyl)-vinyl]-dimethyl-
amine 6. A mixture of 3-chloro-4-fluoro-6-methylnitrobenzene 5 (230g, 1.2
mol), N,N-dimethylformamide di-iso-propylacetal (305mL, 1.5 mol), and
N,N-dimethylformamide (700mL) were heated to 1308C and stirred for 2 hr.
The mixture was cooled to 808C and the solvent was evaporated (the water
bath temperature was maintained at 808C) to leave a crude oil. Methanol
(
500mL) was added to the crude oil and the mixture was cooled in an ice
bath. The emerging precipitate was filtered to give a purple solid (290g)
containing solvent. A sample was dried further to provide the following data.
dH (400MHz; CDCl ) 8.02 (1H, d, J ¼ 8.1 Hz), 7.14 (1H, d, J ¼ 11.2Hz),
3
6
.96 (1H, d, J ¼ 13.3Hz), 5.92 (1H, dd, J ¼ 13.3, 1.7 Hz), 2.95 (6H, s).
Preparation of 6-chloro-5-fluoroindole 2. Raney nickel (5 spatula full)
was added to a stirred solution of [2-(4-chloro-5-fluoro-2-nitro-phenyl)-
vinyl]-dimethylamine 6 (290 g, wet with DMF–MeOH) in tetrahydrofuran
(
1.5 L) and methanol (1.5 L) at ?8C. Hydrazine hydrate (100 mL) was added
over 1 hr keeping the internal temperature below 40 8C by the use of ice
cooling. The mixture was then stirred at rt for 16 hr then filtered through a
c
c
Sometimes the presence of an intermediate (assumed to be the N-hydroxyindole) was
noted at this stage by thin layer chromatography. If such an intermediate was noted,
addition of further hydrazine hydrate and reaction for 30 min ensured complete for-
mation of the indole 2.

ORDER
REPRINTS
2
300
Bentley et al.
w
pad of celite and the filter cake washed with methanol (1 L). The filtrate was
concentrated in vacuo to leave a crude solid. The solid was purified by fil-
tration through a plug of silica gel (20 cm diameter  7 cm depth) eluting
with heptane–dichloromethane (4 : 1) to give an off-white solid (124 g, 60%
[
6]
over two steps). Mp 105–1078C (lit. 105–1078C); d (400 MHz; CDCl )
H
3
8
.01 (1H, br. s), 7.40 (1H, d, J ¼ 6 Hz), 7.35 (1H, d, J ¼ 9.4 Hz), 7.25 (1H,
t, J ¼ 2.8 Hz), 6.50–6.51 (1H, m).
ACKNOWLEDGMENTS
We thank Drs Ken Heatherington, Graeme Harden, Peter Clayton, and
Mr. Tim Haymes for performing the analysis on compounds 4–8.
REFERENCES
1
2
3
. Joshi, K.C.; Chand, P. Biologically active indole derivatives. Pharmazie
1982, 37, 1–12.
. Peroutka, S.J.; Howell, T.A. 5-Hydroxytryptamine receptors. Princ. Med.
Biol. 1997, 8A, 59–72.
. Bos, M.; Jenck, F.; Martin, J.R.; Moreau, J-L.; Sleight, A.J.; Wichmann, J.;
Widmer, U.J. Novel agonists of 5HT2C receptors. Synthesis and biological
evaluation of substituted 2-(indol-1-yl)-1-methylethylamines and
2-(indeno[1,2-b]pyrrol-1-yl)-1-methylethylamines. Improved therapeutics
for obsessive compulsive disorder. J. Med. Chem. 1997, 40, 2762–2769.
. Batcho, A.D.; Leimgruber, W. Intermediates for Indoles. US Patent
4
5
3,976,639, 31 March, 1976.
. Adams, D.R.; Duncton, M.A.J.; Roffey, J.R.A.; Spencer, J. Preparation
of 6-chloro-5-fluoroindole via the use of palladium and copper-mediated
heterocyclisations. Tet. Lett. 2002, 43, 7581–7583.
6
. Bentley, J.M.; Dawson, C.E.; George, A.R.; Hamlyn, R.J.; Pratt, R.M.;
Gaur, S.; Adams, D.R.; Bebbington, D.; Duncton, M.A.J. Preparation of
Indolinealkylamine Derivatives as 5-HT2B and/or 5-HT2C Receptor
Ligands. European Patent 1,109,784, 1 September 1999.
Received in the USA March 3, 2004

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(
AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120038513