4
64
Chemistry Letters Vol.33, No.4 (2004)
Synthesis of cis-2-Fluorocyclopropylamine by Stereoselective Cyclopropanation
Under Phase-transfer Conditions
ꢀ
y
y
Jun-ichi Matsuo, Yu-ichirou Tani, and Yu-ichirou Hayakawa
Center for Basic Research, The Kitasato Institute, 6-15-5, Toshima, Kita-ku, Tokyo 114-0003
y
Chemical Technology Research Laboratories, Daiichi Pharmaceutical Co., Ltd.,
1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630
(Received February 2, 2004; CL-040125)
cis-2-Fluorocyclopropylamine is stereoselectively synthe-
of the vinyl group. 2-Vinyl-3-(methoxy)isoindol-1-one (4) was
afforded in 95% yield by the following procedure; N-vinylphtha-
limide was reduced by using NaBH4 in EtOH to afford 2-vinyl-
3-hydroxyisoindol-1-one (3), followed by methylation with
NaH and MeI (Scheme 1).
sized by cyclopropanation of 3-aryl-2-vinyl-3-(methoxy)isoin-
dol-1-one by treating dibromofluoromethane with saturated
aqueous KOH solution in the presence of 18-crown-6 in di-
chloromethane, followed by removal of a bromine atom of the
formed bromofluorocyclopropane derivative with Raney Ni,
and successive three steps-deprotection procedures for generat-
ing an amino group on the cyclopropane ring.
5
Quinolonecarboxylic acids are widely used for therapy of
1
various infections, and sitafloxacin (1) was recently found as
a new generation of quinolone antibacterial agent having excel-
lent antibacterial activity. In order to synthesize 1 efficiently,
stereoselective synthesis of (1R,2S)-2-fluorocyclopropylamine
2
Scheme 1. a) NaH, MeI, DMF (95%); b) CHFBr2, sat. KOH,
n
BnN Bu3Cl, CHCl2 (92%); c) Raney Ni, H2, EtOH (90%).
(
2) is an important key step. Therefore, several synthetic trials
Cyclopropanation of thus-obtained 4 under the above-men-
tioned phase-transfer conditions proceeded smoothly to give the
desired compound 5 in 92% yield as a mixture of four diaster-
eomers (60:27:8:5). Since it was difficult to determine cis/trans
selectivity of 5 directly, it was determined after a bromine atom
of 5 was reductively removed by using Raney Ni in EtOH under
a hydrogen atmosphere: a fluorocyclopropane derivative 6 was
then obtained as a mixture of diastereomers (60:25:9:6), and
its cis/trans selectivity was found to be cis/trans = 31:69 by
3,4
have been reported: e.g., Terashima et al. reported that cyclo-
propanation of an N-vinylcarbamate with zinc-monofluorocarbe-
noid generated from fluorodiiodomethane and diethylzinc gave
N-(2-fluorocyclopropyl)carbamates stereoselectively (cis/trans
a,c,e
=
93:7).3
However, pyrophoric nature of diethylzinc is a ma-
jor drawback of the above method, especially in large-scale syn-
thesis. Then, stereoselective cyclopropanation under phase-
transfer conditions was planned to establish a useful and safe
method. Only one non-stereoselective cyclopropanation of en-
amide under phase-transfer conditions affording an equal
amount of cis- and trans-fluorocyclopropylamines was reported
1
H NMR analysis (Scheme 1). In order to improve the cis/trans
selectivity, the reaction conditions concerning phase-transfer
catalysts (Aliquatoo1 336, 18-crown-6), solvents (1,2-dichloro-
4
to date. We would like to describe here cis-selective cyclopro-
ethane, benzene, toluene, benzotrifluoride, petroleum ether,
ether, CCl4), and bases (NaOH, CsOH) were further investigat-
ed. However, not only the cis/trans selectivity but the diaster-
eomer ratio did not change drastically. On the other hand, pro-
tecting groups of the hydroxy group of 3 gave slight influence
on the diastereomer ratio: that is, only two diastereomers were
formed when the 3-hydroxy group was protected with trityl
panation of cyclic enamides with bromofluorocarbene under
phase-transfer conditions and transformation of thus-obtained
bromofluorocyclopropane derivative to cis-2-fluorocyclopropyl-
amine salt.
6
group (dr = 70:30:0:0, cis/trans = 30:70). It was then suggest-
ed that when the 3-hydroxy group was protected with the bulky
group, bromofluorocarbene would approach to the N-vinyl group
from the ꢀ-face opposite to the triyl group, while the direction of
a fluorine group was still not controlled on that ꢀ-face. Then, a
bulky substituent was introduced at the 3-carbon of 5 in order to
control the orientation of the fluorine group cis to the 2-nitrogen
group.
Cyclopropanation of commercially available N-vinylphtha-
limide was tried first under phase-transfer conditions by using
Br2CHF, saturated aq KOH, and a catalytic amount of
þ
ꢁ
BnBu3N Cl : however, only a trace amount of the desired bro-
4
3-Aryl(alkyl)-2-vinyl-3-methoxyisoindol-1-ones
7
were
mofluorocyclopropane derivative was obtained probably be-
prepared by 1,2-addition of Grignard reagent to vinylphthali-
mide, followed by protection of a hydroxy group by using
NaH and MeI in DMF. Cyclopropanation of thus-prepared en-
amides 7 with bromofluorocarbene under phase-transfer condi-
tions was shown in Table 1. By introducing phenyl group at
cause electron density of the vinyl group of N-vinylphthalimide
was insufficient for the reaction with the electrophilic bromo-
fluorocarbene. Then, one of the two carbonyl groups of N-vinyl-
phthalimide was reduced in order to increase the electron density
Copyright Ó 2004 The Chemical Society of Japan
Matsuo, Jun-Ichi
