TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4849–4851
A facile bromination of hydroxyheteroarenes
Yoshiaki Kato,* Shigemitsu Okada, Koji Tomimoto and Toshiaki Mase
Process Research, Process R&D, Laboratories for Technology Development, Banyu Pharmaceutical Co. Ltd.,
Kamimutsuna 3-9-1, Okazaki, Aichi 444-0858, Japan
Received 12 April 2001; revised 14 May 2001; accepted 18 May 2001
Abstract—Bromination of hydroxyheteroarenes using P2O5/Bu4NBr proceeds under mild conditions to afford high yields of
various bromoheteroarenes. This procedure is successfully applied to large-scale syntheses of bromoheteroarenes. © 2001 Elsevier
Science Ltd. All rights reserved.
Halogenoheteroarenes are useful intermediates for the
syntheses of bioactive natural products and pharmaceu-
tical drugs. Thus, these halides undergo carbonꢀcarbon
bond formation via cross-coupling reactions, such as
the Stille/Suzuki,1 Heck,2 Sonogashira3 or car-
bonꢀheteroatom bond formation, via recent aromatic
functionalization protocols.4 Although a variety of syn-
theses starting from chloroheteroarenes has been
reported in recent years,5 bromo- and iodoheteroarenes
are still widely used as common substrates. In particu-
lar, the former heteroarenes are preferably utilized due
to their availability compared to the iodo compounds.
In general, the bromoheteroarenes have been prepared
bromide ion, respectively. For example, compound 1
was converted by treatment with P2O5 and Bu4NBr in
toluene at 100°C for 1 h into the corresponding bro-
mide 2 in 75% yield (Scheme 1).
Several variations of this reaction are summarized in
Table 1. Heteroarenes carrying an electron-withdrawing
substituent such as a cyano or a carboxylic group were
smoothly brominated, in which the reaction was com-
pleted within 1.5 h. In contrast, the bromination of
2-pyridone, which has no activating substituent, needed
more severe conditions (entry 6). The use of Bu4NCl
instead of the bromo analogue similarly led to chlorina-
tion of pyridone (entry 7). This procedure was success-
fully applied to the bromination of pyrone and
coumarin (entries 11 and 12) as well as various types of
heteroarenes such as pyrimidine, quinoxaline and ben-
zothiazole (entries 8–10).
6
by treatment of hydroxyheteroarenes with PBr3 or
POBr3,7 but those bromination procedures suffer from
some drawbacks such as the handling of hazardous
reagents, exact reaction-temperature control and evolu-
tion of toxic hydrogen bromide by quenching with
water. Therefore, a convenient method is highly desir-
able for laboratory-scale as well as large-scale prepara-
tions. Herein, we wish to report a facile bromination of
hydroxyheteroarenes using P2O5 and a quaternary
ammonium bromide as a bromide-ion source.
2-Bromo-6-butyl-3-cyanopyridine is the key intermedi-
ate for the synthesis of an endothelin receptor antago-
nist;8 therefore, this bromination method was applied
to large-scale preparation (entry 2). The procedure is as
follows: A mixture of 6-butyl-3-cyanopyrid-2-one (15.6
kg, 88.5 mol), P2O5 (30.0 kg, 211 mol) and Bu4NBr
The halogenation of hydroxyheteroarenes with POX3
involves initial formation of dihalogenophosphate ester
followed by nucleophilic displacement by halide ion
along with removal of the phosphate ion. We found
that P2O5 and Bu4NBr play roles in the bromination for
formation of the leaving moiety and the supply of
P2O5, TBAB
CN
OH
CN
Br
N
N
Toluene
100 oC, 1 h
75%
2
1
Keywords: bromination; hydroxyheteroarene; bromoheteroarene;
phosphorus pentoxide; tetrabutylammonium bromide.
* Corresponding author.
Scheme 1.
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