C-C double bonds with unsaturated esters or amides having
(Z)-stereochemistry6a remains clear.
Table 1. Study of the Reaction Conditions Based on
N,N-Diethylcinnamamide 1e
In the established case of cyclopropyl ketones, various
methods for their preparation have been developed since the
cyclopropyl ketone moiety exhibits important properties in
mechanistic studies and it is also found in marine organisms
conferring important physiological properties.7 Generally, the
cyclopropyl ketone moiety is mostly synthesized by using
the cyclopropanation methodology of Michael acceptors;8
nevertheless some other methods for their preparation are
also reported in the literature.9
CrCl2
(equiv)
CH2ICl
(equiv)
t
(h)
yield
(%)a
entry
T
1
2
3
4
5
6
2.5
3.0
4.0
4.0
4.0
4.0
2.5
3.0
3.75
3.75
3.75
3.75
rt
rt
rt
rt
rt
96
96
96
96
96
18
61
75
89
85b
76c
98
reflux
a Yield of the isolated product after column chromatography based on
compound 1e. b TMEDA was added (see ref 10). c CH2I2 was employed
instead of CH2ICl.
For all of these reasons, an efficient synthesis of cyclo-
propanecarboxamides and cyclopropyl ketones is desirable.
Very recently, CrCl2-promoted cyclopropanation processes
of terminal alkenes, in moderate or good stereoselectivity,
were reported.10 Consequently, no information about the
conservation of the olefin geometry during the cyclopropa-
nation reaction can be established. In addition, alkenes in
which the olefinic carbons were di-, tri-, or tetrasubstituted
could not be cyclopropanated by using these CrCl2-mediated
methods. Previously, we have reported the stereospecific
cyclopropanation of (E)- and (Z)-R,â-unsaturated amides by
using a mixture of samarium and diiodomethane.11
Thus, our own results11 and Takai’s fore-mentioned work10
prompted us to test the possible cyclopropanation reaction
of R,â-unsaturated amides promoted by CrCl2. Thus, in this
Letter we describe the cyclopropanation of R,â-unsaturated
amides by reaction with chloroiodomethane in the presence
of CrCl2. It is noteworthy that this reaction can be carried
out from (E)- or (Z)-enamides in which the C-C double
bond is di-, tri-, or tetrasubstituted and takes place with
complete stereospecificity and in higher yield than with Sm/
CH2I2. In addition, cyclopropyl ketones were readily prepared
by reaction of the obtained cyclopropanecarboxamides
(derived from morpholine) with a range of organolithium
compounds. A mechanism has been proposed to explain the
cyclopropanation reaction.
reaction time, and temperature being varied. The obtained
results are shown in Table 1.
After testing the reaction conditions shown in Table 1,
the best results were obtained by treatment of the N,N-
diethylcinnamamide 1e (0.4 mmol, 1 equiv)13 with a mixture
of CrCl2 (4.0 equiv) and CH2ICl (3.75 equiv) at reflux. These
reaction conditions afforded, after hydrolysis, the corre-
sponding cyclopropylamide 2e with total stereoselectivity and
in high yields (Table 2).
After this study, the cyclopropanation reaction was then
performed on various R,â-unsaturated amides. As is shown
in Table 2, the reaction seems to be general and cyclopro-
panation can be carried out on a variety of aliphatic (linear,
cyclic, branched, and unsaturated) and aromatic R,â-unsatur-
ated amides 1. Taking into account the absence of alternative
methods to cyclopropanate the highly substituted C-C
double bond, the results obtained in the cyclopropanation
of enamides in which the C-C double bond is tri- or
tetrasubstituted were especially interesting. It is noteworthy
that the process took place with total chemoselectivity since
only the cyclopropanation reaction of the 2,3-double bond
took place in the case of the polyunsaturated amide 1b (Table
2).
Other significant aspects of the described cyclopropanation
were the following: (1) No important differences were
observed when the reaction was performed on amides derived
from different amines, so no lower stereoselectivity was
observed from amides with bulky groups (R4) i-Pr) on the
carbonyl amide (Table 2). (2) No additives were necessary
to perform the cyclopropanation reaction, in opposition to
other previously described methods.10 (3) Cyclopropylamides
were prepared in higher yields (approximately a 20%
Initially the cyclopropanation reaction of R,â-unsaturated
amides 112 was carried out on N,N-diethylcinnamamide 1e
at room temperature, with the amount of ICH2Cl, CrCl2,
(7) (a) Rodr´ıguez, A. D.; Shi, J.-G. Org. Lett. 1999, 1, 337-340. (b)
Tanko, J. M.; Phillips, J. P. J. Am. Chem. Soc. 1999, 121, 6078-6079. (c)
Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 5248-5249. (d) Mash, E.
A.; Gregg, T. M.; Kaczynski, M. A. J. Org. Chem. 1996, 61, 2743-2752.
(e) White, J. D.; Jensen, M. S. J. Am. Soc. Chem. 1993, 115, 2970-2971.
(8) (a) Yadav, A. K.; Peruncheralathan, S.; Ila, H.; Junjappa, H. J. Org.
Chem. 2007, 72, 1388-1394. (b) Tang, Y.; Huang, Y.-Z.; Dai, L.-X.; Sun,
J.; Xia, W. J. Org. Chem. 1997, 62, 954-959. (c) Rodriques, K. E.
Tetrahedron Lett. 1991, 32, 1275-1278. (d) Artaud, I.; Seyden-Penne, J.;
Viout, P. Synthesis 1980, 34-36; and ref 6d.
(9) (a) Bhat, N. G.; Garc´ıa, L.; Tamez, V., Jr. Tetrahedron Lett. 2003,
44, 7175-7177. (b) Che, H.; Deng, M.-Z. Org. Lett. 2000, 2, 1649-1651.
(c) Pohmakotr, M.; Thisayukta, J. Tetrahedron Lett. 1997, 38, 6759-6762.
(d) Nelson, A.; Warren, S. Tetrahedron Lett. 1996, 37, 1501-1504. (e)
Shimazaki, M.; Hara, H.; Suzuki, K. Tetrahedron Lett. 1989, 30, 5443-
5446. (f) Grignon-Dubois, M.; Dunogues, J.; Calas, R. Synthesis 1976, 737-
738.
(10) (a) Takai, K.; Hirano, M.; Toshikawa, S. Synlett 2004, 1347-1350.
(b) Takai, K.; Toshikawa, S.; Inoue, A.; Kokumai, R. J. Am. Chem. Soc.
2003, 125, 12990-12991.
(11) (a) Concello´n, J. M.; Rodr´ıguez-Solla, H.; Go´mez, C. Angew. Chem.,
Int. Ed. 2002, 41, 1917-1919. (b) Concello´n, J. M.; Rodr´ıguez-Solla, H.;
Llavona, R. J. Org. Chem. 2003, 68, 1132-1133.
(12) (a) R,â-Unsaturated amides 1 were prepared following the method
described in: Concello´n, J. M.; Pe´rez-Andre´s, J. A.; Rodr´ıguez-Solla, H.
Chem. Eur. J. 2001, 7, 3062-3068. (b) Compounds 1e-g were easily
obtained through the amination of cinnamoyl chloride in THF. (c) (Z)-
Cinnamamide 1h was obtained from the catalytic Lindlar’s hydrogenation
of N,N-diethyl-3-phenylpropiolamide. (d) (Z)-Amide 1o was prepared by
using the method described in: Concello´n, J. M.; Bardales, E. J. Org. Chem.
2003, 68, 9492-9495.
(13) Although the reactions were all carried out on a 0.4 mmol scale,
when this process was carried out on a 3 mmol scale no differences were
observed. However, 4 equiv of CrCl2 were necessary; when a lower amount
of CrCl2 was employed (3 equiv) lower yields were obtained (see also Table
1).
2982
Org. Lett., Vol. 9, No. 16, 2007