Synthesis of n,n-disubstituted 1-cyanocyclopropanecarboxamides

Article abstract of DOI:10.1002/ejoc.200200516

2-(Disubstituted amino)-4,5-dihydro-3-furancarbonitriles 1a-i reacted with acetyl chloride to yield the corresponding ring-opening products 2a-i. The cyclization of compounds 2a-i with bases gave the corresponding N,N-disubstituted 1-cyanocyclopropanecarb

Full text of DOI:10.1002/ejoc.200200516

FULL PAPER
Synthesis of N,N-Disubstituted 1-Cyanocyclopropanecarboxamides
Kenji Yamagata,*[a] Fumi Okabe,[a] and Yoshinobu Tagawa[a]
Keywords: Acetyl chloride / Cyclization / Cyclopropanes / Furans / Ring opening
2-(Disubstituted
1a−i reacted with acetyl chloride to yield the corresponding
ring-opening products 2a−i. The cyclization of compounds
amino)-4,5-dihydro-3-furancarbonitriles
phenylcyclopropanecarboxamides 3d−f. The same com-
pounds 3d−f were also obtained by treatment of compounds
2g−i with sodium methoxide.
2a−f with bases gave the corresponding N,N-disubstituted 1- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
cyanocyclopropanecarboxamides 3a−c and (E)-1-cyano-2-
Germany, 2003)
Introduction
Results and Discussion
Cyclopropane derivatives have been recognized as an im-
When a mixture of 2-pyrrolidin-1-yl-4,5-dihydrofuran-3-
portant class of compounds found in natural and synthetic carbonitrile (1a) and acetyl chloride in acetonitrile was
substances, with particularly significant applications in stirred at room temperature, the ring-opening product, 1-
medicinal and agricultural chemistry.[1,2] Hence, the syn- (2-acetyl-4-chloro-2-cyanobutanoyl)pyrrolidine (2a), was
thetic organic chemistry of cyclopropane-containing com- obtained in 96% yield, and no formation of 4-chloro-2-cy-
pounds has been extensively explored.[3] Ring cleavage by ano-1-pyrrolidinyl-1-butenyl acetate (2aЈ) was observed
nucleophiles of cyclopropanes substituted at the same ring (Scheme 1). The IR spectrum of 2a reveals a band at 2240
carbon by two electron-withdrawing groups has been cmϪ1 due to a nonconjugated cyano group and two bands
known and studied in
a
variety of systems.[4,5] at 1730 and 1660 cmϪ1 attributable to the acetyl and the
Photolysis[6Ϫ10] or thermolysis[11Ϫ13] of dihydrofurans is pyrrolidinylcarbonyl groups. The 13C NMR spectrum exhi-
known to produce cyclopropanes having one or two elec- bits a quaternary carbon atom signal at δ ϭ 60.0 ppm and
tron-withdrawing substituents. However, these methods the signals due to olefinic carbon atoms are not observed.
have unsatisfactory yields, and this disadvantage has
prompted us to develop a more efficient method. In the
course of our studies on heterocyclic enamino nitriles, we
showed that 2-amino-4,5-dihydro-3-furancarbonitrile reacts
with sodium iodide to give 1-cyanocyclopropanecarbox-
amide.[14] Under the same conditions, in the case of 2-(di-
substituted amino)-4,5-dihydro-3-furancarbonitriles 1, a
ring-contraction reaction did not take place. Acetyl halides
have been used as reagents for the cleavage of cyclic
ethers.[16Ϫ18] For example, acetyl chloride converts tetra-
hydrofuran to 4-chlorobutyl acetate. In a previous paper we
reported that N-benzoyl-4-chloro-2-cyanobutanamides,
when refluxed with potassium carbonate in acetone, cyclize
to cyclopropanes.[19] These findings suggest the possibility
that when compounds 1 are treated with acetyl chloride and
base successively, the ring-opening products initially formed
may undergo cyclization to furnish cyclopropane derivatives.
Hence, we examined the reaction of compounds 1 with
acetyl chloride and then with base.
[a]
Faculty of Pharmaceutical Sciences, Fukuoka University,
814-0180 Fukuoka, Japan
Fax: (internat.) ϩ 81-92/863-0389
E-mail: yamagata@fukuoka-u.ac.jp
Scheme 1. Reaction of 2-(disubstituted amino)-4,5-dihydro-3-
furancarbonitriles 1aϪi with acetyl chloride
Eur. J. Org. Chem. 2003, 2383Ϫ2387
DOI: 10.1002/ejoc.200200516
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K. Yamagata, F. Okabe, Y. Tagawa
FULL PAPER
The carbon signal at δ ϭ 60.0 ppm has been assigned to the amides 3aϪc or (E)-1-cyano-2-phenylcyclopropanecarbox-
C-2 carbon atom bearing acetyl and pyrrolidinylcarbonyl amides 3dϪf in 34Ϫ72% yields. Thus, compounds 3dϪf
groups. These spectroscopic data are consistent with 1-but- have the (E) configuration.
anoylpyrrolidine 2a rather than 1-butenyl acetate 2aЈ. Com-
pounds 1bϪi react with acetyl chloride under the same con-
ditions to afford the corresponding 2-acetyl-4-chlorobut-
anenitriles 2bϪi in good to excellent yields. All nine ring-
opening products 2aϪi are relatively unstable, so crystalline
compounds 2cϪi are partially decomposed during recrys-
tallization.
Subsequently, in order to obtain the cyclopropane deriva-
tives, we examined the cyclization of compounds 2aϪi with
Scheme 3. Synthesis of 3aϪf from 1-cyanocyclopropanecarboxylic
acid and (E)-1-cyano-2-phenylcyclopropanecarboxylic acid
bases. The reactions of 2aϪc with aqueous potassium car-
bonate resulted in the formation of the expected cyclopro-
panes 3aϪc in good yields (Scheme 2). Compounds 2dϪf
were easily cyclized to the cyclopropane derivatives 3dϪf
when treated with sodium methoxide. The same compounds
3dϪf were also obtained by treatment of 2gϪi with sodium
methoxide. The structures of 3aϪf were confirmed by direct
comparison with authentic samples, which were synthesized
The formation of 3 can be rationalized by the mechanism
shown in Schemes 1 and Scheme 2. Acetyl chloride attacks
at the 3-position of 1 to form the intermediate iminium salts
A, which undergo ring opening between the oxygen atom
and the C-5 position of A by a chloride ion to produce 2.
The hydroxide or the methoxide ion attacks the carbonyl
carbon atom of the acetyl group of 2 to form the alkoxide
B/C, which then is cyclized to 3.
Finally, we investigated a one-pot synthesis of 3 by a ring-
cleavage/cyclization process. The typical procedure was as
follows: Acetyl chloride was added to a suspension of 1dϪf
in acetonitrile at room temperature. After the starting mate-
rials 1dϪf had disappeared, the solvent was removed, and
sodium methoxide in methanol was added to the residue.
The mixture was stirred at room temperature for 1 h to give
3d,e,f in 94, 94, and 93% yields, respectively. Similar reac-
tions of 1gϪi gave 3gϪi in good yields. Successive treatment
of 1a,b,c with acetyl chloride and aqueous potassium car-
bonate resulted in the formation of 3a,b,c in 77, 80, and
77% yields, respectively.
by the following methods (Scheme 3): Conversion of 1-cy-
[20]
anocyclopropanecarboxylic acid
nylcyclopropanecarboxylic acid
or (E)-1-cyano-2-phe-
with thionyl chloride
[21]
provided cyclopropanecarbonyl chlorides, and subsequent
treatment with amines gave 1-cyanocyclopropanecarbox-
In conclusion, from a viewpoint of simple operation,
mild conditions, and good yields in the preparation of 2-
acetyl-4-chlorobutanenitriles as well as in the cyclization
step, the present reactions provide a useful method for the
synthesis of N,N-disubstituted 1-cyanocyclopropanecarbox-
amides.
Experimental Section
General: All melting points are uncorrected. IR spectra were taken
1
with a Jasco A-302 spectrometer. H and 13C NMR spectra were
1
measured with a Jeol JNM-A500 instrument (500.00 MHz for H,
125.65 MHz for 13C) in CDCl3 with TMS as internal standard. 13
C
signal assignments were confirmed by the DEPT technique. Mass
spectra were recorded with a Jeol JMS-HX110 instrument at 70 eV.
Elemental analyses were performed using an MT-6 elemental ana-
lyzer (Yanaco). The starting compounds 1aϪi were prepared as
previously described.[15,22]
General Procedures for the Synthesis of 2-Acetyl-4-chloro-2-cyano-
butanamides 2. Procedure A: Acetyl chloride (1.73 g, 22 mmol) was
added to an ice-cooled and stirred solution of 1aϪc (20 mmol) in
acetonitrile (20 mL). The mixture was stirred at room temperature
Scheme 2. Synthesis of N, N-disubstituted 1-cyanocyclopropane-
carboxamides 3aϪf
2384
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Eur. J. Org. Chem. 2003, 2383Ϫ2387

N,N-Disubstituted 1-Cyanocyclopropanecarboxamides
FULL PAPER
for 4 h. After removal of the solvent in vacuo, the residue was chro-
matographed on silica gel with CH2Cl2 as the eluent to give 2aϪc.
Procedure B: A suspension of 1dϪi (20 mmol) and acetyl chloride
(1.73 g, 22 mmol) in acetonitrile (20 mL) was stirred at room tem-
1 H, 3-H), 4.13Ϫ4.19 (m, 2 H, 4-H), 7.30Ϫ7.40 (m, 5 H, aryl) ppm.
13C NMR: δ ϭ 24.1 (CH3), 25.2 (CH2), 26.6 (CH2), 45.6 (C-4),
47.5 (NCH2), 51.3 (C-3), 63.8 (C-2), 115.8 (CϵN), 128.9, 129.1,
129.4, 134.3 (C aryl), 159.6 (CϭO), 195.2 (CϭO) ppm. MS (FAB):
perature for 4 h (in the case of the preparation of 2d,e,gϪi) or 20 h m/z (%) ϭ 333 (63) [Mϩ ϩ H]. C18H21ClN2O2 (332.8): calcd. C
(2f). The solvent was removed and diisopropyl ether (30 mL) was 64.96, H 6.36, N 8.42; found C 64.97, H 6.42, N 8.48.
added to the residue. The precipitate was collected and washed with
1-(2-Acetyl-4-chloro-2-cyano-3-phenylbutanoyl)morpholine
(2f):
diisopropyl ether.
Yield 5.43 g (81%). M.p. 174 °C (dec.). Colorless prisms (acetone/
petroleum ether). IR (KBr): ν˜ ϭ 2240 [ν(CϵN)], 1730 [ν(CϭO)],
1660 [ν(CϭO)] cmϪ1. 1H NMR: δ ϭ 1.85 (s, 3 H, CH3), 3.50Ϫ3.80
1-(2-Acetyl-4-chloro-2-cyanobutanoyl)pyrrolidine (2a): Yield 4.64 g
(96%). Colorless oil. IR (neat): ν˜ ϭ 2240 [ν(CϵN)], 1730 [ν(Cϭ
O)], 1660 [ν(CϭO)] cmϪ1 1H NMR: δ ϭ 1.86Ϫ2.08 (m, 4 H, (m, 8 H, NCH2CH2O) 3.95 (t, J ϭ 10.7 Hz, 1 H, 3-H), 4.12 (dd,
.
NCH2CH2), 2.35 (s, 3 H, CH3), 2.53 (ddd, J ϭ 6.4, 9.2, 14.2 Hz, 1 J ϭ 3.6, 10.7 Hz, 1 H, 4-H), 4.18 (dd, J ϭ 3.6, 10.7 Hz, 1 H, 4-H),
H, 3-H), 2.74 (ddd, J ϭ 5.5, 9.2, 14.2 Hz, 1 H, 3-H), 3.32Ϫ3.58
7.37Ϫ7.40 (m, 5 H, aryl) ppm. 13C NMR: δ ϭ 26.6 (CH3), 44.6
(m, 4 H, NCH2), 3.63 (ddd, J ϭ 6.4, 9.2, 11.0 Hz, 1 H, 4-H), 3.77 (NCH2), 45.4 (C-4), 47.0 (NCH2) 51.1 (C-3), 63.9 (C-2), 65.7
(ddd, J ϭ 5.5, 9.2, 11.0 Hz, 1 H, 4-H) ppm. 13C NMR: δ ϭ 23.5
(OCH2), 66.3 (OCH2), 115.5 (CϵN), 129.1, 129.2, 129.3, 134.0 (C
(CH2), 25.8 (CH3), 26.6 (CH2), 36.3 (C-3), 39.4 (C-4), 47.5 (NCH2), aryl) 160.1 (CϭO), 195.0 (CϭO) ppm. MS (FAB): m/z (%) ϭ 335
48.4 (NCH2), 60.0 (C-2), 115.2 (CϵN), 159.2 (CϭO), 195.0 (Cϭ
(64) [Mϩ ϩ H]. C17H19ClN2O3 (334.8): calcd. C 60.99, H 5.72, N
8.37; found C 61.04, H 5.67, N 8.53.
O) ppm. MS (FAB): m/z (%) H].
ϭ
243 (100) [Mϩ
ϩ
C11H15ClN2O2 (242.7): calcd. C 54.44, H 6.23, N 11.54; found C
54.60, H 6.26, N 11.70.
1-(2-Acetyl-4-chloro-2-cyano-4-phenylbutanoyl)pyrrolidine
(2g):
Yield 5.31 g (83%). M.p. 108Ϫ110 °C. Colorless prisms (acetone/
petroleum ether). IR (KBr): ν˜ ϭ 2260 [ν(CϵN)], 1730 [ν(CϭO)],
1-(2-Acetyl-4-chloro-2-cyanobutanoyl)piperidine (2b): Yield 4.70 g
(92%). Pale yellow oil. IR (neat): ν˜ ϭ 2250 [ν(CϵN)], 1730 [ν(Cϭ
1670 [ν(CϭO)] cmϪ1 1H NMR: δ ϭ 1.80Ϫ2.00 (m, 4 H,
.
O)], 1660 [ν(CϭO)] cmϪ1 1H NMR: δ ϭ 1.50Ϫ1.75 (m, 6 H, NCH2CH2), 2.18 (s, 3 H, CH3), 2.94 (dd, J ϭ 6.8, 15.0 Hz, 1 H, 3-
.
NCH2CH2CH2CH2), 2.36 (s, 3 H, CH3), 2.52 (ddd, J ϭ 6.1, 9.5,
H), 3.13 (dd, J ϭ 6.8, 15.0 Hz, 1 H, 3-H), 3.40Ϫ3.75 (m, 4 H,
14.1 Hz, 1 H, 3-H), 2.73 (ddd, J ϭ 5.2, 9.5, 14.1 Hz, 1 H, 3-H), NCH2), 5.18 (t, J ϭ 6.8 Hz, 1 H, 4-H), 7.30Ϫ7.45 (m, 5 H, aryl)
3.35Ϫ3.58 (m, 4 H, NCH2), 3.62 (ddd, J ϭ 6.1, 9.5, 11.3 Hz, 1 H, ppm. 13C NMR: δ ϭ 23.3 (CH3), 26.1 (CH2), 26.6 (CH2), 43.1 (C-
4-H), 3.77 (ddd, J ϭ 5.2, 9.5, 11.3 Hz, 1 H, 4-H) ppm. 13C NMR: 3), 47.6 (NCH2), 48.5 (NCH2), 58.8(C-4), 59.5 (C-2), 115.5 (CϵN),
δ ϭ 24.1 (CH2), 25.3 (CH2), 25.7 (CH3), 36.7 (C-3), 39.4 (C-4), 127.4, 128.8, 129.0, 140.0 (C aryl), 159.7 (CϭO), 194.7 (CϭO)
45.2 (NCH2), 47.6 (NCH2), 59.1 (C-2), 115.5 (CϵN), 159.8 (Cϭ
ppm. MS (FAB): m/z (%) ϭ 319 (45) [Mϩ ϩ H]. C17H19ClN2O2
O), 195.5 (CϭO) ppm. MS (FAB): m/z (%) ϭ 257 (100) [Mϩ ϩ H]. (318.8): calcd. C 64.05, H 6.01, N 8.79; found C 63.95, H 6.09,
C12H17ClN2O2 (256.7): calcd. C 56.14, H 6.67, N 10.91; found C N 8.82.
56.32, H 6.73, N 11.03.
1-(2-Acetyl-4-chloro-2-cyano-4-phenylbutanoyl)piperidine
(2h):
1-(2-Acetyl-4-chloro-2-cyanobutanoyl)morpholine (2c): Yield 4.50 g
(87%). M.p. 66Ϫ67 °C. Colorless prisms (diethyl ether/petroleum
Yield 5.04 g (76%). M.p. 86Ϫ87 °C. Colorless prisms (diethyl ether/
petroleum ether). IR (KBr): ν˜ ϭ 2250 [ν(CϵN)], 1725 [ν(CϭO)],
ether). IR (KBr): ν˜ ϭ 2260 [ν(CϵN)], 1725 [ν(CϭO)], 1660 [ν(Cϭ
1660 [ν(CϭO)] cmϪ1 1H NMR: δ ϭ 1.50Ϫ1.70 (m, 6 H,
.
1
O)] cmϪ1. H NMR: δ ϭ 2.38 (s, 3 H, CH3), 2.55 (ddd, J ϭ 6.4, NCH2CH2CH2CH2), 2.17 (s, 3 H, CH3), 3.00 (dd, J ϭ 6.7, 15.0 Hz,
9.2, 14.4 Hz, 1 H, 3-H), 2.75 (ddd, J ϭ 5.5, 9.2, 14.4 Hz, 1 H, 3-
1 H, 3-H), 3.06 (dd, J ϭ 6.7, 15.0 Hz, 1 H, 3-H), 3.40Ϫ3.60 (m, 4
H), 3.40Ϫ3.80 (m, 10 H, 4-H, NCH2CH2O) ppm. 13C NMR: δ ϭ H, NCH2), 5.17 (t, J ϭ 6.7 Hz, 1 H, 4-H), 7.30Ϫ7.45 (m, 5 H, aryl)
25.7 (CH3), 36.6 (C-3), 39.2 (C-4), 44.2 (NCH2), 47.2 (NCH2), 59.1 ppm. 13C NMR: δ ϭ 24.1 (CH3), 25.2 (CH2), 25.5 (CH2), 26.1
(C-2), 66.0 (OCH2), 66.3 (OCH2), 115.2 (CϵN), 160.2 (CϭO), (CH2), 43.8 (C-3), 45.2 (NCH2), 47.7 (NCH2), 58.6 (C-2), 58.7 (C-
195.3 (CϭO) ppm. MS (FAB): m/z (%) ϭ 259 (89) [Mϩ ϩ H]. 4), 115.8 (CϵN), 127.5, 128.8, 129.0, 140.1 (C aryl), 160.3 (CϭO),
C11H15ClN2O3 (258.7): calcd. C 51.07, H 5.84, N 10.83; found C 195.3 (CϭO) ppm. MS (FAB): m/z (%) ϭ 333 (20) [Mϩ ϩ H].
51.02, H 5.83, N 10.81.
C18H21ClN2O2 (332.8): calcd. C 64.96, H 6.36, N 8.42; found C
65.05, H 6.31, N 8.44.
1-(2-Acetyl-4-chloro-2-cyano-3-phenylbutanoyl)pyrrolidine
(2d):
Yield 4.63 g (73%). M.p. 141 °C (dec.). Colorless prisms (acetone/ 1-(2-Acetyl-4-chloro-2-cyano-4-phenylbutanoyl)morpholine
petroleum ether). IR (KBr): ν˜ ϭ 2260 [ν(CϵN)], 1725 [ν(CϭO)], Yield 5.22 g (78%). M.p. 121Ϫ122 °C. Colorless prisms (acetone/
1660 [ν(CϭO)] cmϪ1 1H NMR: δ ϭ 1.80Ϫ2.10 (m, 4 H,
petroleum ether). IR (KBr): ν˜ ϭ 2240 [ν(CϵN)], 1730 [ν(CϭO)],
(2i):
.
1
NCH2CH2), 1.88 (s, 3 H, CH3), 3.10Ϫ3.20 (m, 1 H, NCH2), 1670 [ν(CϭO)] cmϪ1. H NMR: δ ϭ 2.19 (s, 3 H, CH3), 2.99 (dd,
3.55Ϫ3.80 (m, 3 H, NCH2), 3.94 (t, J ϭ 10.4 Hz, 3-H), 4.15 (dd, J ϭ 6.7, 15.0 Hz, 1 H, 3-H), 3.08 (dd, J ϭ 6.7, 15.0 Hz, 1 H, 3-H),
J ϭ 3.7, 10.4 Hz, 4-H), 4.20 (dd, J ϭ 3.7, 10.4 Hz, 4-H), 7.30Ϫ7.40 3.40Ϫ3.75 (m, 8 H, NCH2CH2O), 5.16 (t, J ϭ 6.7 Hz, 1 H, 4-H),
(m, 5 H, aryl) ppm. 13C NMR: δ ϭ 23.4 (CH3), 26.6 (CH2), 27.0
7.30Ϫ7.45 (m, 5 H, aryl) ppm. 13C NMR: δ ϭ 26.1 (CH3), 43.7
(CH2), 45.3 (C-4), 47.4 (NCH2), 48.7 (NCH2), 50.9 (C-3), 65.0 (C- (C-3), 44.6 (NCH2), 47.0 (NCH2), 58.5 (C-4), 58.7 (C-2), 63.8
2), 115.4 (CϵN), 129.0, 129.1, 129.3, 134.4 (C aryl), 158.8 (CϭO), (OCH2), 66.1 (OCH2), 115.6 (CϵN), 127.4, 128.9, 129.2, 139.9 (C
194.9 (CϭO) ppm. MS (FAB): m/z (%) ϭ 319 (75) [Mϩ ϩ H]. aryl), 160.7 (CϭO), 195.1 (CϭO) ppm. MS (FAB): m/z (%) ϭ 335
C17H19ClN2O2 (318.8): calcd. C 64.05, H 6.01, N 8.79; found C (44) [Mϩ ϩ H]. C17H19ClN2O3 (334.8): calcd. C 60.99, H 5.72, N
64.00, H 6.02, N8.76.
8.37; found C 60.91, H 5.72, N 8.37.
1-(2-Acetyl-4-chloro-2-cyano-3-phenylbutanoyl)piperidine (2e): Yield
4.94 g (74%). M.p. 136 °C (dec.). Colorless prisms (diethyl ether).
General Procedures for the Synthesis of 1-Cyanocyclopropanecar-
boxamides 3. Procedure A: A mixture of 2aϪc (5 mmol), 20%
IR (KBr): ν˜ ϭ 2240 [ν(CϵN)], 1730 [ν(CϭO)], 1640 [ν(CϭO)] K2CO3 (10 mL), and EtOH (10 mL) was stirred at room tempera-
cmϪ1
.
1H NMR: δ ϭ 1.30Ϫ1.75 (m, 6 H, NCH2CH2CH2CH2),
ture for 2 h. The solvent was removed and H2O (20 mL) was added
1.83 (s, 3 H, CH3), 3.20Ϫ3.70 (m, 4 H, NCH2), 3.95 (t, J ϭ 11.6 Hz,
to the residue. The mixture was extracted with EtOAc. The extract
Eur. J. Org. Chem. 2003, 2383Ϫ2387
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K. Yamagata, F. Okabe, Y. Tagawa
FULL PAPER
was washed with H2O, dried with Na2SO4, and concentrated in
vacuo. The residue was purified by column chromatography on sil-
(m,
4 H, CH2), 1.50Ϫ1.75 (m, 6 H, NCH2CH2CH2CH2),
3.40Ϫ3.80 (m, 4 H, NCH2) ppm. 13C NMR: δ ϭ 13.1 (C-1), 15.4
ica gel with CH2Cl2/acetone (4:1) as the eluent to yield 3a (0.68 g, (CH2), 24.4 (CH2), 25.5 (CH2), 44.6 (NCH2), 47.5 (NCH2), 120.2
83%), 3b (0.76 g, 85%), and 3c (0.71 g, 79%). Procedure B: A mix-
(CϵN), 162.9 (CϭO) ppm. MS (FAB): m/z (%) ϭ 179 (100) [Mϩ
ture of 2dϪi (5 mmol) and MeONa (0.30 g, 5.5 mmol) in MeOH ϩ H]. C10H14N2O (178.2): calcd. C 67.39, H 7.92, N 15.72; found
(15 mL) was stirred at room temperature for 1 h. After removal of C 67.22, H 7.87, N 15.62.
the MeOH in vacuo, H2O (20 mL) was added to the residue and
1-[(1-Cyanocyclopropyl)carbonyl]morpholine (3c): M.p. 84Ϫ85 °C.
the mixture was extracted with EtOAc. The extract was washed
with H2O, dried with Na2SO4, and concentrated in vacuo. The resi-
due was chromatographed on silica gel with CH2Cl2/acetone (4:1)
as the eluent to give 3d [from 2d: 1.14 g (95%); from 2g: 1.15 g
(96%)], 3e [from 2e: 1.12 g (96%); from 2h: 1.20 g (94%)], 3f [from
2f: 1.16 g (91%); from 2i: 1.01 g (79%)]. Procedure C: A mixture of
1aϪc (20 mmol) and acetyl chloride (1.73 g, 22 mmol) in aceto-
nitrile (20 mL) was stirred at room temperature for 4 h. After re-
moval of the solvent in vacuo, 20% K2CO3 (25 mL) and EtOH
(25 mL) were added to the residue. The resulting mixture was
stirred at room temperature for 2 h. The solvent was removed and
H2O (40 mL) was added to the residue. The mixture was extracted
with EtOAc. The extract was washed with H2O, dried with
Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel with CH2Cl2/acetone (4:1) as
the eluent to afford 3a (2.51 g, 77%), 3b (2.83 g, 80%), and 3c
(2.76 g, 77%). Procedure D: A mixture of 1dϪi (20 mmol) and ace-
tyl chloride (1.73 g, 22 mmol) in acetonitrile (20 mL) was stirred at
room temperature for 4 h (in the case of the reaction of 1d,e,gϪi)
or 20 h (1f). After removal of the solvent in vacuo, MeONa (1.19 g,
22 mmol) in MeOH (30 mL) was added to the residue. The re-
sulting mixture was stirred at room temperature for 1 h. The sol-
vent was removed and H2O (40 mL) was added to the residue. The
mixture was extracted with EtOAc. The extract was washed with
H2O, dried with Na2SO4, and concentrated in vacuo. The residue
was chromatographed on silica gel with CH2Cl2/acetone (4:1) as
the eluent to give 3d [from 1d: 4.60 g (94%); from 1g: 4.61 g (94%)],
3e [from 1e: 4.76 g (94%); from 1h 4.82 g (95%)], and 3f [from 1f:
4.78 g (93%); from 1i: 3.23 g (63%)]. Procedure E: A mixture of 1-
cyanocyclopropanecarboxylic acid (0.56 g, 5 mmol) or (E)-1-cyano-
2-phenylcyclopropanecarboxylic acid (0.94 g, 5 mmol) and SOCl2
(3 mL) was refluxed for 1 h. After removal of the SOCl2 under
reduced pressure, a solution of pyrrolidine (0.71 g, 10 mmol) [pip-
eridine (0.85 g, 10 mmol) or morpholine (0.87 g, 10 mmol)] and tri-
ethylamine (1.01 g, 10 mmol) in THF (10 mL) was added to the
residue. The mixture was stirred at room temperature for 30 min.
The solvent was removed and H2O (20 mL) was added to the resi-
due. The mixture was extracted with EtOAc. The extract was
washed with H2O, dried with Na2SO4, and concentrated in vacuo.
The residue was chromatographed on silica gel with CH2Cl2 as the
eluent to give 3a (0.39 g, 48%), 3b (0.64 g, 72%), 3c (0.57 g, 63%),
3d (0.65 g, 54%), 3e (0.75 g, 59%), and 3f (0.43 g, 34%).
Colorless columns (diethyl ether). IR (KBr): ν˜ ϭ 2240 [ν(CϵN)],
1645 [ν(CϭO)] cmϪ1 1H NMR: δ ϭ 1.51Ϫ1.54 (m, 2 H, CH2),
.
1.59Ϫ1.62 (m, 2 H, CH2), 3.50Ϫ3.90 (m, 8 H, NCH2CH2O) ppm.
13C NMR: δ ϭ 12.8 (C-1), 15.6 (CH2), 43.7 (NCH2), 46.8 (NCH2),
66.4 (OCH2), 119.9 (CϵN), 163.4 (CϭO) ppm. MS (FAB): m/z
(%) ϭ 181 (100) [Mϩ ϩ H]. C9H12N2O2 (180.2): calcd. C 59.98, H
6.71, N 15.55; found C 59.79, H 6.68, N 15.52.
(E)-1-[(1-Cyano-2-phenylcyclopropyl)carbonyl]pyrrolidine (3d): Col-
1
orless oil. IR (neat): ν˜ ϭ 2240 [ν(CϵN)], 1650 [ν(CϭO)] cmϪ1. H
NMR: δ ϭ 1.90Ϫ2.03 (m, 5 H, 3-H, NCH2CH2), 2.24 (dd, J ϭ
5.5, 8.6 Hz, 1 H, 3-H), 3.02 (t, J ϭ 8.6 Hz, 1 H, 2-H), 3.50Ϫ3.55
(m, 2 H, NCH2CH2), 3.70Ϫ3.85 (m, 2 H, NCH2CH2), 7.28Ϫ7.40
(m, 5 H, aryl) ppm. 13C NMR: δ ϭ 20.4 (C-3), 23.6 (C-1), 24.0
(CH2), 26.5 (CH2), 33.0 (C-2), 47.6 (NCH2), 47.8 (NCH2), 117.8
(CϵN), 128.1, 128.7, 133.9 (C aryl), 162.5 (CϭO) ppm. MS (FAB):
m/z (%) ϭ 241 (100) [Mϩ ϩ H]. C15H16N2·0.2H2O (243.9): calcd.
C 73.87, H 6.78, N 11.49; found C 73.89, H 6.76, N 11.51.
(E)-1-[(1-Cyano-2-phenylcyclopropyl)carbonyl]piperidine (3e): Col-
1
orless oil. IR (neat): ν˜ ϭ 2250 [ν(CϵN)], 1660 [ν(CϭO)] cmϪ1. H
NMR: δ ϭ 1.60Ϫ1.70 (m, 6 H, NCH2CH2CH2CH2), 1.96 (dd, J ϭ
5.8, 8.5 Hz, 1 H, 3-H), 2.21 (t, J ϭ 5.8, 8.5 Hz, 1 H, 3-H), 2.84 (t,
J ϭ 8.5 Hz, 1 H, 2-H) 3.50Ϫ3.70 (m, 4 H, NCH2), 7.25Ϫ7.40 (m,
5 H, aryl) ppm. 13C NMR: δ ϭ 19.0 (C-3), 23.2 (C-1), 24.4 (CH2),
25.8 (CH2), 31.9 (C-2), 44.6 (NCH2), 47.6 (NCH2), 117.7 (CϵN),
127.8, 128.2, 128.8, 133.6 (C aryl), 162.8 (CϭO) ppm. MS (FAB):
m/z (%) ϭ 255 (100) [Mϩ ϩ H]. C16H18N2O (254.3): calcd. C 75.56,
H 7.13, N 11.01; found C 75.45, H 7.25, N 10.92.
(E)-1-[(1-Cyano-2-phenylcyclopropyl)carbonyl]morpholine (3f): M.p.
91Ϫ92 °C. Colorless needles (diethyl ether/petroleum ether). IR
1
(KBr): ν˜ ϭ 2240 [ν(CϵN)], 1670 [ν(CϭO)] cmϪ1. H NMR: δ ϭ
2.01 (dd, J ϭ 5.8, 9.2 Hz, 1 H, 3-H), 2.23 (dd, J ϭ 5.8, 9.2 Hz, 1
H, 3-H), 2.89 (t, J ϭ 9.2 Hz, 1 H, 2-H), 3.60Ϫ3.80 (m, 8 H,
NCH2CH2O), 7.25Ϫ7.42 (m, 5 H, aryl) ppm.13C NMR: δ ϭ 19.2
(C-3), 22.9 (C-1), 32.3 (C-2), 44.0 (NCH2), 47.0 (NCH2), 66.4
(OCH2), 117.5 (CϵN), 127.7, 128.4, 128.9, 133.2 (C aryl), 163.3
(CϭO) ppm. MS (FAB): m/z (%) ϭ 257 (100) [Mϩ ϩ H].
C15H16N2O2 (256.3): calcd. C 70.29, H 6.29, N 10.93; found C
70.26, H 6.39, N 10.81.
1-[(1-Cyanocyclopropyl)carbonyl]pyrrolidine (3a): M.p. 51Ϫ52 °C.
Colorless columns (diethyl ether/petroleum ether). IR (KBr): ν˜ ϭ
[1] [1a]
H. W. Lin, C. T. Walsh, The Chemistry of the Cyclopropyl
2260 [ν(CϵN)], 1640 [ν(CϭO)] cmϪ1 1H NMR: δ ϭ 1.47Ϫ1.50
.
Group (Eds: S. Patai, Z. Rappoport); John Wiley & Sons, New
[1b]
(m, 2 H, CH2), 1.64Ϫ1.70 (m, 2 H, CH2), 1.88Ϫ1.93 (m, 2 H,
NCH2CH2), 1.99Ϫ2.03 (m, 2 H, NCH2CH2), 3.47Ϫ3.50 (m, 2 H,
NCH2CH2), 3.84Ϫ3.90 (m, 2 H, NCH2CH2) ppm. 13C NMR: δ ϭ
13.5 (C-1), 16.6 (CH2), 24.0 (CH2), 26.4 (CH2), 47.5 (NCH2), 47.6
(NCH2), 120.2 (CϵN), 162.6 (CϭO) ppm. MS (FAB): m/z (%) ϭ
165 (100) [Mϩ ϩ H]. C9H12N2O (164.2): calcd. C 65.83, H 7.37, N
17.06; found C 65.80, H 7.46, N 17.06.
York, 1987, pp. 959Ϫ1025.
C. J. Suckling, Angew. Chem.
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J. Salaün, Top. Curr. Chem. 2000, 207, 1Ϫ67.
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[2c]
Stammer, Tetrahedron 1990, 46, 2231Ϫ2254.
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For recent books, see: ‘‘Carbocyclic Three- and Four-mem-
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(Ed.: A. de Meijere), Thieme, Stuttgart, New York, 1997, vol.
E17a/b.
1-[(1-Cyanocyclopropyl)carbonyl]piperidine (3b): M.p. 91Ϫ92 °C.
Colorless columns (diethyl ether/petroleum ether). IR (KBr): ν˜ ϭ
H. N. C. Wong, M. Y. Hon, C. W. Tse, Y. C. Yip, Chem. Rev.
1989, 89, 165Ϫ198.
2240 [ν(CϵN)], 1640 [ν(CϭO)] cmϪ1 1H NMR: δ ϭ 1.46Ϫ1.58
.
2386
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2383Ϫ2387

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Received September 17, 2002
Eur. J. Org. Chem. 2003, 2383Ϫ2387
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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