Bromination of indomethacin

Article abstract of DOI:10.1016/j.mencom.2010.03.016

Treatment of indomethacin with N-bromosuccinimide in AcOH results in bromination in aromatic positions 4 and 6, while the use of tetrachloromethane allows ultimate bromination at the C(2) Me group of the indole moiety to proceed.

Full text of DOI:10.1016/j.mencom.2010.03.016

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 111–112
Bromination of indomethacin
Alexandre V. Ivachtchenko,a,b Pavel M. Yamanushkin,*a Oleg D. Mitkina and Oleg I. Kiselevc
a Department of Organic Chemistry, Chemical Diversity Research Institute, 114401 Khimki, Moscow Region,
Russian Federation. Fax: +7 495 626 9780; e-mail: ypm@iihr.ru
b ChemDiv Inc., San Diego, CA 92121, USA. Fax: +1 858 794 4931; e-mail: ChemDiv@chemdiv.com
c Influenza Research Institute of the Russian Academy of Medical Sciences, 196376 St. Petersburg,
Russian Federation. Fax: +7 812 234 5973; e-mail: office@influenza.spb.ru
DOI: 10.1016/j.mencom.2010.03.016
Treatment of indomethacin with N-bromosuccinimide in AcOH results in bromination in aromatic positions 4 and 6, while the use
of tetrachloromethane allows ultimate bromination at the C(2) Me group of the indole moiety to proceed.
Indomethacin (2-methyl-5-methoxy-[1-(4-chlorobenzoyl)-1H-
AcOH, room temperature
indol-3-yl]acetic acid) 1, which relates to 3-indolylacetic acid
O
O
type, is one of the most active nonsteroidal anti-inflammatory
drugs. Discovered in 1963,1,2 it is used for treatment of rheu-
matoid arthritis, periarthritises, ankylosing spondylitis, osteo-
arthrosis, gout, inflammatory diseases of connective tissue and
musculoskeletal system, thrombophlebitis and other diseases
accompanied by inflammation. It is also used in curing of
neurotic syndrome. Indomethacin is a non-selective inhibitor
of cyclooxygenases 1 and 2, strong blocker of enzymes parti-
cipating in prostaglandin synthesis and possesses analgesic
activity.3–6 Surprisingly, despite its broad application, its chemistry
is not studied sufficiently.
Br
OBr
OH
Me
MeO
MeO
Me
N
N
O
O
Cl
Cl
4
2
NBS, CCl4
O
NBS
CCl4,
reflux
1
AcOH,
room
temperature
O
O
OH
OH
Me
MeO
MeO
Br
OH
MeO
CH2Br
Me
N
N
N
O
O
Cl
Scheme 1
Cl
O
Cl
5
3
1
Here, we have investigated bromination of indomethacin,
since introduction of bromine atom into a molecule allows one
to succeed in further diversity of derivatization.
Acyl hypohalites are usually unstable (synthesis and extrac-
tion of acetyl hypobromite from solution was first described in
19747). Such compounds are used as brominating agents and
donors of bromine cation.8 Hypobromite 4 obtained is surpris-
ingly relatively stable and could be recrystallized from carbon
tetrachloride.
In principle, bromination of compound 1 may occur either
at the benzene ring or at the methyl group at position 2. Pre-
liminary experiments using tetrabutylammonium or pyridinium
tribromide and molecular bromine gave dibromo or polybromo-
substituted products. The use of N-bromosuccinimide (NBS)
provided selective monobromination depending on reaction
conditions. Reaction in AcOH at room temperature occurred as
aromatic electrophilic substitution and gave 4- and 6-bromo
derivatives 2 and 3 (Scheme 1), with their ratio being dependent
on the concentration of indomethacin. Unfortunately, this method
did not provide good selectivity. Use of carbon tetrachloride as
the solvent resulted in the formation of 2-[1-(4-chlorobenzoyl)-
5-methoxy-2-methyl-1H-indol-3-yl]acetyl hypobromite 4. In
the 1H NMR spectrum of compound 4, the signals of all aromatic
and aliphatic protons are clearly observed, while the carboxylic
proton is absent. In the LC-MS spectra, there are two molecular
ions of similar intensity with a m/z difference of two units
typical of isotopic cluster for monobromo compounds. Elemental
analysis data also agree with the proposed molecular formula.
We have discovered that keeping hypobromite 4 in acetic
acid at room temperature results in migration of bromine into
1
position 4 of the indole ring. H NMR spectrum of the pro-
duct 2 thus obtained contains signal of the carboxylic proton
at 12.37 ppm, while only two aromatic doublets at 7.09 and
6.87 ppm with J 8.9 Hz are present. This two-step protocol
allows selective preparation of 4-bromo indole derivative 2 to
be carried out. On the other hand, refluxing hypobromite 4 in
CCl4 gave 2-bromomethyl-1H-indole 5, the product of bromine
migration to the methyl group. We failed in isolating compound
5 in the pure form and made assignment of its structure based
on the structures of its further transformation products 6–8
(Scheme 2). These products contain substituted benzylic methylene
group.
Similar phenomena were described by Gopalakrishnan and
Hogg.9 In polar solvent, a heterolysis of O–Br bond and electro-
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© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 111–112
products under LC-MS conditions conform to their molecular
masses, and values of proton chemical shifts in 1H NMR spectra
are identical to literature data.
O
OH
CH2OH
In summary, we have developed convenient selective and
efficient procedures for the bromination of indomethacin at
position 4 or at C(2) Me group of the indole moiety. The inter-
mediate, the corresponding acyl hypobromite, turned out to be a
relatively stable compound. The results obtained may be of
interest for both medicinal combinatorial and fundamental
organic chemistry.
MeO
H3O+
N
5
O
Cl
HN(Me)R
O
6
reflux TsOH, toluene
O
OH
MeO
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2010.03.016.
CH2N(Me)R
MeO
Cl
N
O
O
References
N
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8a R = H
8b R = Me
O
Cl
7
Scheme 2
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ring occurred. In non-polar solvent, its homolysis induced intra-
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The bromine in derivatives 2, 3 and 5 can be easily replaced
by various functional groups to give promising indomethacin
derivatives.
Hydrolysis of compound 5 in dilute trifluoroacetic acid resulted
in hydroxymethyl derivative 6. Alcohol 6 thus obtained easily
cyclizes into pyranoindolone 7 during reflux in toluene in the
presence of catalytic amount of TsOH. Benzylic bromine atom
in compound 5 can be readily replaced with various nucleo-
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The structure of the obtained compounds 2–8 were confirmed
1
by LC-MS and H NMR spectroscopy;† molecular ions of the
†
For the full NMR data, see Online Supplementary Materials.
Received: 29th April 2009; Com. 09/3332
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