Novel synthesis of gem-dichloroaziridines from imines via the KF/Al 2O3-promoted generation of dichlorocarbene from chloroform

Article abstract of DOI:10.1021/jo050321z

KF/Al₂O₃ was found to be an efficient base for the reaction of imines with chloroform in acetonitrile to give gem- dichloroaziridines 2 in moderate to high yields. The KF/ Al₂O ₃-promoted dichloroaziridination c

Full text of DOI:10.1021/jo050321z

reaction conditions are mild, and the presence of water
is not a critical factor.6e However, it presents problems
with regard to the use of a large excess of the carbene
source and the complexity of the procedures. Conse-
quently, a general, efficient, and simple method for
dichloroaziridination of imines is strongly desired.
On the other hand, the use of solid-supported reagents
has become popular due to their characteristic properties
such as enhanced reactivity and selectivity, a straight-
forward workup procedure, and milder reaction condi-
tions.7 For example, KF/Al2O3 is known to be a useful
and interesting solid-supported reagent for base-induced
organic reactions.8 We recently reported on the
convenient N-formylation of secondary amines using KF/
Al2O3 and chloroform in acetonitrile.9 As a result, the
KF/Al2O3-promoted generation method of dichlorocarbene
has proved to be a powerful tool for the synthesis of
N-formamide derivatives from imines. However, since the
KF/Al2O3-promoted methods, one of which requires both
phase-transfer catalysts and KF/Al2O3,10b were regarded
as being less effective than the phase-transfer-catalyzed
method in addition reactions of dichlorocarbene to cyclo-
hexene,10 it has not been widely applied to other trans-
formations, except in our previous report. Herein, we
report on a general and convenient KF/Al2O3-promoted
synthesis of gem-dichloroaziridines 2 from imines 1 and
chloroform under mild reaction conditions.
Detailed studies of the reaction of N-benzylideneaniline
(1a) with chloroform leading to 2,2-dichloro-1,3-diphenyl-
aziridine (2a) showed that this addition reaction is
influenced to a considerable extent, by bases and sol-
vents, as shown in Scheme 1 and Table 1 (method A).
The reaction of 1a with chloroform in the presence of KF
or Al2O3 (neutral) did not proceed at all (entries 1 and
2), while the use of commercially available KF/Al2O3 led
to the production of the desired gem-dichloroaziridine 2a
in high yield. For example, when 1a (0.5 mmol) was
treated with chloroform (1.5 mmol) in the presence of
KF/Al2O3 (2 g) in acetonitrile, 2a was obtained in 95%
yield (entry 3). As a result of an investigation of a suitable
solvent for the aziridination, acetonitrile was found to
Novel Synthesis of gem-Dichloroaziridines
from Imines via the KF/Al2O3-Promoted
Generation of Dichlorocarbene from
Chloroform
Masatoshi Mihara,† Yoshio Ishino,*,†
Satoshi Minakata,‡ and Mitsuo Komatsu*,‡
Osaka Municipal Technical Research Institute, Morinomiya
1-6-50, Joto-ku, Osaka 536-8553, Japan, and Department of
Applied Chemistry, Graduate School of Engineering, Osaka
University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
ishino@omtri.city.osaka.jp; komatsu@chem.eng.osaka-u.ac.jp
Received February 21, 2005
KF/Al2O3 was found to be an efficient base for the reaction
of imines with chloroform in acetonitrile to give gem-
dichloroaziridines 2 in moderate to high yields. The KF/
Al2O3-promoted dichloroaziridination can be carried out with
simple workup, tolerates a variety of functional groups
present in the imines, and proceeds smoothly with a smaller
amount of carbene source.
gem-Dichloroaziridines are valuable precursors for the
preparation of pharmacologically active compounds such
as indolinones,1 analogues of natural alkaloids such as
isoquinolinones2 and isoquinolines,3 and nitrogen-con-
taining building blocks such as amidines4 and aziridino-
nes.5 As a result, several methods for synthesis of gem-
dichloroaziridines have been reported.6 The preparation
has been accomplished by the addition of dichlorocarbene,
generated from chloroform,6a,c,e,f hexachloroacetone,6b or
ethyl trichloroacetate6d with the appropriate bases, to
imines. Among these, dichlorocarbene, which is generated
from chloroform under phase-transfer-catalyzed condi-
tions, is most frequently used for the synthesis of gem-
dichloroaziridines because the yields are acceptable, the
(7) (a) Posner, G. H. Angew. Chem., Int. Ed. Engl. 1978, 17, 487.
(b) McKillop, A.; Young, D. W. Synthesis 1979, 401. (c) McKillop, A.;
Young, D. W. Synthesis 1979, 481. (d) Kabalka, G. W.; Pagni, R. M.
Tetrahedron 1997, 53, 7999. (e) Minakata, S.; Mihara, M.; Sugoh, N.;
Komatsu, M. Heterocycles 1998, 47, 133. (f) Mihara, M.; Ishino, Y.;
Minakata, S.; Komatsu, M. Synthesis 2001, 2397. (g) Mihara, M.;
Ishino, Y.; Minakata, S.; Komatsu, M. Synlett 2002, 1526. (h) Varma,
R. S. Tetrahedron 2002, 58, 1235. (i) Kawabata, T.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2003, 125, 10486.
(j) Agarwal, A.; Rani, S.; Vankar, Y. D. J. Org. Chem. 2004, 69, 6137.
(k) Kamata, K.; Kasai, J.; Yamaguchi, K.; Mizuno, N. Org. Lett. 2004,
6, 3577.
† Osaka Municipal Technical Research Institute.
‡ Osaka University.
(1) Seno, M.; Shiraishi, S.; Suzuki, Y.; Asahara, T. Bull. Chem. Soc.
Jpn. 1978, 51, 1413.
(2) Petrov, O. S.; Ognyanov, V. I.; Mollov, N. M. Synthesis 1987,
637.
(3) Khlebnikov, A. F.; Nikiforova, T. Yu.; Novikov, M. S.; Kostikov,
R. R. Synthesis 1997, 677.
(8) (a) Yamawaki, J.; Ando, T. Chem. Lett. 1979, 755. (b) Foucaud,
A.; Bram, G.; Loupy, A. In Preparative Chemistry Using Supported
Reagents; Laszlo, P., Ed.; Academic: San Diego, 1987; p 317. (c) Blass,
B. E. Tetrahedron 2002, 58, 9301. (d) Kabalka, G. W.; Wang, L.; Pagni,
R. M.; Hair, C. M.; Namboodiri, V. Synthesis 2003, 217. (e) Hamelin,
J.; Saoudi, A.; Benhaoua, H. Synthesis 2003, 2185. (f) Hosseinzadeh,
R.; Tajbakhsh, M.; Mohadjerani, M.; Mehdinejad, H. Synlett 2004,
1517. (g) Basu, B.; Das, P.; Hossain, I. Synlett 2004, 2224.
(9) Mihara, M.; Ishino, Y.; Minakata, S.; Komatsu, M. Synthesis
2003, 2317.
(4) Meilahn, M. K.; Augenstein, L. L.; McManaman, J. L. J. Org.
Chem. 1971, 36, 3627.
(5) Ohshiro, Y.; Ohnishi, H.; Komatsu, M. J. Jpn. Oil Chem. Soc.
1987, 36, 884.
(6) (a) Fields, E. K.; Sandri, J. M. Chem. Ind. (London) 1959, 1216.
(b) Kadaba, P. K.; Edwards, J. O. J. Org. Chem. 1960, 25, 1431.
(c) Cook, A. G.; Fields, E. K. J. Org. Chem. 1962, 27, 3686. (d) Brooks,
R. E.; Edwards, J. O.; Levey, G.; Smyth, F. Tetrahedron 1966, 22, 1279.
(e) Makosza, M.; Kacprowicz, A. Rocz. Chem. 1974, 48, 2129.
(f) Khlebnikov, A. F.; Novikov, M. S.; Nikiforova, T. Yu.; Kostikov, R.
R. Russ. J. Org. Chem. 1999.
(10) (a) Yamawaki, J.; Kawate, T.; Ando, T.; Hanafusa T. Bull.
Chem. Soc. Jpn. 1983, 56, 1885. (b) Ting, X.; Liu, C. Youji Huaxue
1988, 8, 511; Chem. Abstr. 1989, 111, 133319t.
10.1021/jo050321z CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/19/2005
5320
J. Org. Chem. 2005, 70, 5320-5322

SCHEME 1. KF/Al2O3-Promoted Synthesis of 2a
from 1aa
SCHEME 2. KF/Al2O3-Promoted
Dichloroaziridination of Various Imines
a Method A: without addition of H2O. Method B: with addition
of H2O.
TABLE 1. Synthesis of 2a from 1a under the Conditions
of Method Aa
TABLE 3. KF/Al2O3-Promoted Synthesis of 2 (or 3) from
1a
CHCl3
yield of recovery
entry (mmol)
base (g)
KF (0.8)
Al2O3 (neutral) (1.2) MeCN
solvent 2ab (%) of 1ab (%)
yield (%)
1
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
MeCN
0
0
100
74
0
16
62
74
80
66
11
13
entry
1
R1
R2
R3
2
3
3
KF/Al2O3 (2)
KF/Al2O3 (2)
KF/Al2O3 (2)
KF/Al2O3 (2)
KF/Al2O3 (2)
KF/Al2O3 (2)
MeCN 95 (77)c
1
2
3
4
5
6
7
8
1a
1b
H
H
Ph
Ph
Ph
2a, 85
4
DMF
81
1-naphthyl 2b, 79
5
CHCl3 32
hexane 17
1c Ph Ph
benzyl
2c, 69
2d, 42
2e, 49
2f, 66
1d
1e
1f
1g
1h
H
H
H
H
H
4-CO2MeC6H4 Ph
4-CNC6H4 Ph
6
7
DME
none
14
22
4-styrylphenyl Ph
8
Ph
Ph
benzyl
n-octyl
(2g, 56b) 3g, 47
(2h, 29b) 3h, 29
9
0.75 KF/Al2O3 (2)
1.5 KF/Al2O3 (1)
MeCN 84
MeCN 76
10
a Reaction conditions are described in the Supporting Informa-
tion. b NMR yields.
a Method A: the imine is treated with chloroform in the
indicated solvent (3 mL) in the presence of KF/Al2O3 without added
water. All reactions were performed at room temperature for
1.5 h on a 0.5 mmol scale. b NMR yields. c An isolated yield.
1.5 to 0.75 mmol (entries 4 and 5). Thus, the addition of
water permitted the amount of KF/Al2O3 and chloroform
used to be decreased. In particular, it should be noted
that, although conventional methods for generation of
dichlorocarbene require excessive amounts of the carbene
source (more than 4 equiv), the amount of chloroform
needed could be reduced considerably when the present
KF/Al2O3-promoted method was used. In addition, the
solid-promoted reaction is very useful in terms of simple
and nonaqueous workup, i.e., filtration of the inorganic
reagent and evaporation of the solvent.
Several imines 1 were examined for the KF/Al2O3-
promoted synthesis of dichloroaziridines 2 under the
conditions of method B (Scheme 2). As shown in Table
3, a variety of imines reacted smoothly with chloroform
in acetonitrile in the presence of KF/Al2O3 and water to
afford the corresponding dichloroaziridines 2 in moderate
to high yields (entries 1-8). The reaction of N-benzyl-
ideneaniline and N-benzylidenenaphthylamine with chlo-
roform under the conditions of method B gave dichloro-
aziridines (2a and 2b) in high yields (entries 1 and 2).
Treatment of a ketimine such as 1c with chloroform
under the same conditions provided 2c in good yield
(entry 3). The reaction was shown to tolerate ester, cyano,
and styryl functional groups (entries 4-6). The dichloro-
aziridination of 1g and 1h, derived from unsubstituted
benzaldehyde and primary aliphatic amines, was also
accomplished (entries 7 and 8). In these cases, N-alkyl-
R-chlorophenylacetamides (3g and 3h) were isolated as
the ring-opening products of their dichloroaziridines (2g
and 2h). Accordingly, this method offers an efficient route
for converting various aldimines and ketimines to the
corresponding dichloroaziridines.
TABLE 2. Synthesis of 2a from 1a under the Conditions
of Method Ba
b
CHCl3
(mmol)
H2O
(mmol)
time
(h)
yield of
recovery
entry
2ac (%)
of 1ac (%)
1
2
3
4
5
1.5
none
1.5
1.5
1.5
61
28
1
40
8
1
1.5
88
1.5
0.75
0.75
5.0
1.5
55
1.5
1.5
1.5
15.0
90
98 (85)d
a Method B: the imine is treated with chloroform (dried and
distilled) in acetonitrile (dried and distilled) in the presence of
KF/Al2O3 and water. All reactions were performed in acetonitrile
(3 mL) in the presence of KF/Al2O3 (1 g) at room temperature on
a 0.5 mmol scale. b Dried and distilled. c NMR yields. d An isolated
yield.
be acceptable (entries 3-8). A decrease in the amount of
chloroform or KF/Al2O3 to 0.75 mmol or 1 g, respectively,
reduced the efficiency of the reaction (entries 9 and 10).
It is well-known that the efficiency of KF/Al2O3 as a
base is strongly affected by the amount of water present
in the KF/Al2O3.11 The reaction conditions were optimized
by the addition of water to an acetonitrile solution of 1a
in the presence of KF/Al2O3 (1 g) (Scheme 1, Table 2
method B). As a consequence, the addition of water
(1.5 mmol) to KF/Al2O3 (1 g) brought about the almost
complete consumption of 1a (entry 1 vs 2). However, the
addition of a larger amount of water (5.0 mmol) decreased
the rate of conversion (entry 3). Unlike the case of method
A, the use of KF/Al2O3 (1 g) under the conditions of
method B led the near completion of the reaction (Table
1 entry 10 vs Table 2 entry 2). Moreover, the yield of 2a
could be further improved by prolonging the reaction time
even when the amount of chloroform was reduced from
Although the mechanistic details still remain ambigu-
ous, the KF/Al2O3-promoted reaction might proceed
through addition of in situ generated dichlorocarbene to
imines on KF/Al2O3.
In summary, KF/Al2O3 was found to be a useful solid-
supported base for the generation of dichlorocarbene from
(11) Ando, T.; Brown, S. J.; Clark, J. H.; Cork, D. G.; Hanafusa, T.;
Ichihara, J.; Miller, J. M.; Robertson, M. S. J. Chem. Soc., Perkin Trans.
2 1986, 1133.
J. Org. Chem, Vol. 70, No. 13, 2005 5321

0.75 mmol) was then added slowly under an Ar atmosphere. The
reaction mixture was stirred for 15 h at room temperature. The
KF/Al2O3 was removed by filtration and washed with ether. The
combined filtrate was evaporated and purified by recrystal-
lization from hexane to give 2a (112.2 mg, 85%).
chloroform in the synthesis of gem-dichloroaziridines. The
present KF/Al2O3-promoted dichloroaziridination, which
uses reasonable amounts of chloroform, may be charac-
terized by wide generality, simple procedures, good
yields, and mild reaction conditions.
Supporting Information Available: Experimental pro-
cedures, reaction conditions for dichloroaziridination of 1 in
Table 3, and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
Typical Procedure of Method B: 2,2-Dichloro-1,3-diphe-
nylaziridine (2a). To a suspension of KF/Al2O3 (1 g) and 1a
(90.6 mg, 0.5 mmol) in distilled acetonitrile (3.0 mL) was added
water (27.0 µL, 1.5 mmol), and distilled chloroform (60.0 µL,
JO050321Z
5322 J. Org. Chem., Vol. 70, No. 13, 2005