1984
LETTER
Practical and Efficient Chlorination of Deactivated Anilines and Anilides with
NCS in 2-Propanol
Atsuhiko Zanka,* Ariyoshi Kubota
Technological Development Laboratories, Fujisawa Pharmaceutical Co. Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka, 532-8514, Japan
Fax +81 6 6390 1183; E-mail: atsuhiko_zanka@po.fujisawa.co.jp
Received 24 September 1999
crucial for avoiding dichlorination products or other by-
Abstract: Deactivated anilines and anilides were efficiently mono-
products. Whilst efficient enough to afford the material in
chlorinated with NCS in 2-propanol. The described method was ap-
gram quantities, several complications were identified in
this method from the standpoint of large scale manufac-
tureability. For example, acetonitrile is toxic and rather
plicable to a large scale synthesis.
Key words: aniline, anilide, chlorination, 2-propyl hypochlorite, N-
chlorosuccinimide
expensive. Furthermore, careful attention must be paid to
the safe disposal of mother liquors containing a high con-
tent of acetonitrile so as to avoid evolution of hydrogen
Ring-chlorinated anilines and anilides are very useful in-
cyanide. Additionally, tedious work-up using methylene
termediates in organic synthesis and medicinal chemis-
chloride is problematic on a large scale. Herein, we wish
try,1 and the most conceptually simple way to prepare
to report an efficient procedure for chlorination of anilines
these materials is the chlorination of anilines and anilides.
and anilides with 2-propyl hypochlorite prepared in situ
Whilst several methods for activated anilines have been
from NCS and 2-propanol suitable for a large scale syn-
investigated to date,2 there appears to be few practical
thesis.
methods for aromatic ring chlorination of deactivated
We initiated our studies by evaluating solvents which
could give the product in excellent yield and quality with
a view to developing an improved chlorination system. It
was uncovered during these investigations that the reac-
tion using 2-propanol was dramatically accelerated and
did not afford dichlorination products or other by-prod-
ucts. This result suggested that hypochlorite produced in
situ from NCS and 2-propanol acted as a potent and selec-
tive chlorinating agent, leading to efficient monochlorina-
tion of 1a to 1b (Scheme 2).
anilines suitable for a large scale synthesis. Recently, we
required a large quantity of 4-amino-3-chlorobenzonitrile
(1b), a common intermediate to FK867 and FR115068,
potent COX-II (cyclooxygenase-2) selective inhibitors
discovered in Fujisawa (Scheme 1).3
Na+
F
-NSO2Me
O
F
NH2
CN
Cl
FK867
NH2
O
NCl
Cl
F
NHSO2Me
OH
CN
S
O
1b
CN
F
CONH2
O
NH2
FR115068
NH
OCl
Scheme 1
O
CN
Lengyel et al. reported ring chlorination of N-methyl-
aniline and acetoanilide using tert-butyl hypochlorite as a
powerful chlorinating agent.4 However, this method can
not be directly applied on a large scale since a lack of
proper temperature control during the preparation of tert-
butyl hypochlorite readily leads to explosion.5 In addition,
chlorination of benzanilide could not be achieved by this
methodology.4 More conveniently, 1b was prepared by
chlorination of 4-aminobenzonitrile (1a) with N-chloro-
succinimide (NCS) in acetonitrile as solvent as originally
reported by Nickson et al.6 These authors emphasized that
the use of a dipolar aprotic solvent such as acetonitrile was
Scheme 2
2-Propyl hypochlorite as a chlorinating reagent has been
scarcely employed in organic synthesis presumably due to
lack of stability,7 and thus the features of this agent have
not been reported to date. During our studies it became ap-
parent that 2-propyl hypochlorite is not only a potent chlo-
rinating agent, but also applicable to a large scale
preparation without serious safety concerns. In effect, this
agent easily decomposed in 2-propanol without causing a
harsh exotherm at reflux, cleanly leading to acetone and
Synlett 1999, No. 12, 1984–1986 ISSN 0936-5214 © Thieme Stuttgart · New York