Highly convenient and large scale synthesis of 5-chloroindole and its 3-substituted analogues

Article abstract of DOI:10.5012/jkcs.2011.55.2.240

A large scale and commercially feasible synthesis of 5-chloroindole and its 3-substituted analogues has been described via a halogen - halogen exchange reaction from 5-bromoindole and its derivatives using cuprous chloride and dipolar aprotic solvent N-methyl-2-pyrrolidone in one pot with good yields.

Full text of DOI:10.5012/jkcs.2011.55.2.240

Journal of the Korean Chemical Society
011, Vol. 55, No. 2
Printed in the Republic of Korea
DOI 10.5012/jkcs.2011.55.2.240
2
5-Chloroindole계 화합물의 Large Scale 합성
†
Laxminarayana Keetha , Sadanandam Palle , Vinodkumar Ramanatham *,
,‡
†
†,
‡
Mukkanti Khagga, and Rajendiran Chinnapillai
†
Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 072, India.
‡
R&D Center, Suven Life Sciences Ltd., Unit-2, Plot No-18, Phase-III, IDA Jeedimetla, Hyderabad-500055, India.
(접수 2010. 6. 1; 수정 2010. 6. 25; 게재확정 2010. 9. 7)
Highly Convenient and Large Scale Synthesis of 5-chloroindole and its
-substituted Analogues
3
†
,‡
†
†,
Laxminarayana Keetha , Sadanandam Palle , Vinodkumar Ramanatham *,
‡
Mukkanti Khagga, and Rajendiran Chinnapillai
†
Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 072, India.
*
E-mail: rvinodk@gmail.com
‡
R&D Center, Suven Life Sciences Ltd., Unit-2, Plot No-18, Phase-III, IDA Jeedimetla, Hyderabad-500055, India.
(Received June 1, 2010; Revised June 25, 2010; Accepted September 7, 2010)
요
약. CuCl과 N-methyl-2-pyrrolidone을 이용하여 5-bromoindole을 halogen - halogen 교환반응을 통하여 5-chloroindole계
화합물을 합성하는 one-pot대량합성방법을 개발하였다.
주제어: 5-haloindoles, 염화 구리 (I) , N-methyl-2-pyrrolidone, halogen-halogen 교환반응
ABSTRACT. A large scale and commercially feasible synthesis of 5-chloroindole and its 3-substituted analogues has been
described via a halogen - halogen exchange reaction from 5-bromoindole and its derivatives using cuprous chloride and dipo-
lar aprotic solvent N-methyl-2-pyrrolidone in one pot with good yields.
Keywords: 5-haloindoles, copper (I) chloride, N-methyl-2-pyrrolidone, halogen-halogen exchange.
6
tion, from the direct oxidation of 5-chloroindoline with
INTRODUCTION
7
chloranil etc. Other recent methods include palladium
8
The synthesis of nitrogen-containing heterocycles con-
tinues to attract both synthetic and medicinal chemists,
especially indole derivatives due to their excellent bio-
assisted cyclization from 2-bromoanilines with enamines,
9
vinylstannanes etc. Ruthenium catalysed reactions have
also been reported for the synthesis of 5-chloroindoles,
which include, a sequence of acylation, chlorination,
1
logical activities. Indole and its derivatives are important
10
deacylating, and oxidation of indoline, via indole-ruthe-
intermediates in organic synthesis and exhibit various
2
properties and pharmacological activites. In connection
11
nium complexes, from anilines and ethylene glycol
12
through a combination of ruthenium and tin catalysis.
Similarly, ruthenium-catalyzed heteroannulation of anilines
with our on-going project for the large-scale industrial
production of 5-chloroindole, we were interested in a method
that can have high commercial viability and which can utilize
very cheap and commercially available starting materials.
Literature survey revealed that there are several meth-
ods available for the synthesis of 5-chloroindole such as
13
with alkanolammonium chlorides or thermal cycliza-
14
tion of 4-chloroaniline with 1,2-dibromoethane have
also been reported. Recently, rhodium catalysed cycloi-
somerisation of 4-chloroanilines with trimethylsilyl acet-
3
the general one being the classical decarboxylation of 5-
15
ylenes to obtain 5-chloroindoles was reported. Although
chloroindole-2-carboxylic acid, ortho chloroacetylation
the above methods are good to some extent for the small
scale synthesis of 5-chloroindole, but they suffer from one
or other disadvantages such as either low yields or use of
expensive starting materials and reagents which limits the
4
of anilines following by cyclization and oxidation, or
5
from substituted N-aryl-1-alkenylsulfinamides, by direct
chlorination of 1-acetylindoline followed by saponifica-
-240-

5-Chloroindole계 화합물의 Large Scale 합성
241
applicability of the above methods for the scale up and
production at an industrial scale.
RESULTS AND DISCUSSION
Looking at the above literature cited method’s, we
envisaged that a direct one step method that can utilize
cheap raw materials could address the problem and which
in turn would be of high commercial feasibility. However,
direct synthesis of 5-chloroindole by the single step pro-
cess from 5-bromoindole is not known in the literature so far.
In this regard, we thought of using a halogen - halogen
Scheme 2.
Table 2. Synthesis of 5-chloroindole and its analogues
Sr. No. Starting Material
Product
M.P. ( C) Yield (%)
1
.
70-72
85
83
76
79
16-17
exchange reaction
as this could be the best method to
obtain 5-chloroindole in a single step starting from com-
18
mercially available and cheap raw material 5-bromoindole
2.
212-215
190-194
240-246
and the present paper deals with our efforts in this direc-
tion.
3.
Initially, we have carried out the reaction of 5-bromoin-
dole with cuprous chloride in presence of N, N-dimeth-
o
ylformamide at 100 C and obtained the halogen exchanged
4.
product as expected in only 57% yield after 6 h. Increas-
ing the heating time of the reaction to 12-24 h did not
improve the reaction yield (Scheme 1).
Therefore, we decided to screen a set of solvents as well
as refluxing times for the reactions to see if we can obtain
better yields and the results are summarised in Table 1 and
best condition for the reaction is depicted in Scheme 2.
The screening results indicate that among all the solvents
tested for the reaction NMP was found to be the superior
choice for the reaction with good to excellent yields.
Having succeeded the synthesis of required 5-chloroin-
dole starting from 5-bromoindole in good yields, we have
then extended the applicability of the present method to
see if we can do this transformation on some other sub-
stituted indoles and the results are summarized in Table 2.
EXPERIMENTAL
Melting points were obtained on a MP apparatus SP 62
and are un-corrected. Infrared spectra were recorded on a
FT-IR, Perkin-Elmer Spectrum-I spectrometer and the
NMR spectra on a Bruker at 400 M Hz instrument-using
TMS as internal standard.
Synthesis of 5-chloroindole (2a)
Scheme 1.
A mixture of 5-bromoindole (1a, 100 g, 0.51 mmole, 1.0
eq), cuprous chloride (115 g, 1.28 mmole, 1.15 eq) were
dissolved in N-methyl-2-pyrrolidone (400 mL). The reac-
Table 1. Formation of 2a under a range of solvents and temper-
atures
o
tion mixture was slowly heated to 205-210 C in an oil
S. No.
Solvent
DMF
Time (h)*
Isolated yield (%)
bath and maintained at the same temperature for 15 h (GC
analysis). The reaction mixture was then cooled to room
temperature and was added aq. ammonia (2 L, 20-25%),
stirred for 30 min and extracted with chloroform (4 × 500 mL).
The layers were separated and the organic layer was washed
1
2
3
4
5
6
7
6
57
63
76
85
43
47
59
DMF
12
12
15
15
15
15
NMP
NMP
DMA
DMSO
HMPA
H
with water (2 × 400 mL) until basic to p . Evaporation of
the solvent under reduced pressure resulted the crude
compound as a brown viscous liquid, which upon high
*Temperatures are the best average with respect to yields obtained
2011, Vol. 55, No. 2

242
Laxminarayana Keetha, Sadanandam Palle, Vinodkumar Ramanatham, Mukkanti Khagga, and Rajendiran Chinnapillai
vacuum distillation using an oil bath at vapor temperature
CONCLUSION
o
1
10-130 C/1 mm/Hg yielded the pure product. The pure
fraction was further crystallized in n-hexane yielding the
pure product as white plates, 65.7 grams with GC purity of
9.8%.
I.R (KBr): 3386, 1446, 761 cm ; NMR (400 MHz,
DMSO-d ): δ 6.40 (s, 1H), 7.05 (dd, J=8.6, 2.0 Hz, 1H),
.39 (d, J=9.4 Hz, 1H) 7.40 (d, J=3.12 Hz, 1H), 7.56 (d,
In conclusion, we have developed the best industrially
scalable and commercially feasible method for the pro-
duction of 5-chloroindole starting from commercially
available and cheap 5-bromoindole. The protocol has been
extended towards the synthesis of other substituted indole
analogues in good yields. The advantage of the present
method lies in its operational simplicity and yet very pro-
ductive for producing 5-chloroindole and analogues, which
are very useful and important intermediates in drug industry.
9
-1 1H
6
7
1
3
J=2.0 Hz, 1H, 11.26 (s, 1H); C NMR (100 MHz, DMSO-
):134.74, 129.21, 127.38, 123.87, 121.25, 119.57, 113.23,
01.26; MS (ESI): m/z (%)=150.1 (M-H).
-chloroindole-3-carboxyaldehyde (2b)
Following the general procedure for 2a from 5-bro-
d
6
1
5
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9
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2
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7
-1 1
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6
): 166.7,
1
(
Journal of the Korean Chemical Society