Synthesis of 1-acyl-2-oxo-3-pyrrolidinecarbonitriles by the reaction of 2-acylamino-4,5-dihydro-3-furancarbonitriles with sodium iodide

Article abstract of DOI:10.1002/jhet.5570420411

The reaction of 2-acylamino-4,5-dihydro-3-furancarbonitriles 1 with sodium iodide in N,N-dimethyl-formamide gave the corresponding 1-acyl-2-oxo-3- pyrrolidinecarbonitriles 2 in good yields. Successive treatment of 1 with titanium(IV) chloride and potassiu

Full text of DOI:10.1002/jhet.5570420411

Synthesis of 1-Acyl-2-oxo-3-pyrrolidinecarbonitriles by the Reaction
May-Jun 2005
543
of 2-Acylamino-4,5-dihydro-3-furancarbonitriles with Sodium Iodide
Kenji Yamagata*, Fumi Okabe, Hiroshi Maruoka and Yoshinobu Tagawa
Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jounan-ku,
Fukuoka 814-0180, Japan
Received September 23, 2004
The reaction of 2-acylamino-4,5-dihydro-3-furancarbonitriles 1 with sodium iodide in N,N-dimethyl-
formamide gave the corresponding 1-acyl-2-oxo-3-pyrrolidinecarbonitriles 2 in good yields. Successive
treatment of 1 with titanium(IV) chloride and potassium carbonate resulted in the formation of N-acyl-1-
cyanocyclopropanecarboxamides 4. The same compounds 2 were also obtained by treatment of 4 with
sodium iodide. The starting compounds 1 were synthesized by the reaction of 2-amino-4,5-dihydro-3-furan-
carbonitrile with acyl chlorides in pyridine.
J. Heterocyclic Chem., 42, 543 (2005).
When a solution of 2-acetamido-4,5-dihydro-3-furancar-
bonitrile (1a) [13] and sodium iodide in N,N-dimethylfor-
mamide (DMF) was stirred at 150° for 1 hour, the ring
transforming product, 1-acetyl-2-oxo-3-pyrrolidinecar-
bonitrile (2a), was obtained in 84% yield. The ir spectrum
The 2-pyrrolidinone (γ-lactam) ring system is present
in a large number of molecules possessing medicinal val-
ues such as psychotropic agents [1,2], muscarinic acid
agonists [3], antihypertensive agents [4], peptide mimics
[5,6]. γ-Lactams are also versatile synthetic intermedi-
ates, particularly of pyrrolidine alkaloids and γ-aminobu-
tyric acid analogues [7-9]. Consequently, there has been
an ongoing interest in the synthesis of substituted
2-pyrrolidinones [10].
We have previously reported a synthesis of 1-benzoyl-2-
oxo-3-pyrrolidine carbonitrile or 3-ethyl-2-oxo-3-pyrro-
lidinecarbonitrile by the reaction of 2-benzamido-4,5-
dihydro-3-furancarbonitrile or ethyl N-2-(3-cyano-4,5-
dihydro-2-furyl)carbamate with sodium iodide [11]. Since
this procedure provides an attractive one-pot synthesis
from readily available dihydrofuran to pyrrolidine, we
have now extended to other furan substrates.
-1
of 2a reveals a band at 2255 cm due to a nonconjugated
-1
cyano group and two carbonyl bands at 1746 and 1698 cm
attributable to the acetyl and the 2-pyrrolidinone groups,
whereas that of 1a appears two N-H bands at 3220 and
-1
-1
3140 cm for an amide group, and a band at 2210 cm due
1
to a conjugated cyano group. Elemental analysis, H nmr
and C nmr spectra of 2a are consistent with the assigned
13
structure. Compounds 1b-j reacted with sodium iodide
under the same conditions to give the corresponding
1-acyl-2-oxo-3-pyrrolidinecarbonitriles 2b-j in good
The starting compounds, 2-acylamino-4,5-dihydro-3-
furancarbonitriles 1b-j, were prepared by reaction of
2-amino-4,5-dihydro-3-furancarbonitrile [12] with acyl
1
chlorides in pyridine. The H nmr spectra of 1d, f-i in
deuteriochloroform indicate that 1d, f-i consist of
approximately a 7:3 tautomeric mixture of the enamine
A and the imine B forms. Compounds 1b, c, e, j exist
predominantly in the enamine A forms in deuteriochlo-
roform (Scheme 1).

544
K. Yamagata, F. Okabe, H. Maruoka and Y. Tagawa
Vol. 42
yields.
In a previous communication [11], we suggested the fol-
lowing mechanism for the formation of 2 from 1. The reac-
tion proceeds by initial ring contraction to form the cyclo-
propane 4, which is converted into the carbanion C by
iodide ion, and then the carbanion rearranges into the
imide ion D, which undergoes intramolecular cyclization
to form 2 (Scheme 2).
Subsequently, we examine the reaction of the com-
pounds 4 with sodium iodide in DMF in order to prove
whether or not compounds 2 are formed. The required
cyclopropanes 4b-j were prepared from 4-chlorobu-
tanamides 3b-j and potassium carbonate according to the
1
method of ref. [13]. The H nmr spectra of 4b-j showed a
pair of two-proton multiplets at near δ 1.80 assignable to
the ring protons of the cyclopropane moiety. The cyclo-
propane ring proton signals in 4b-j appeared at higher
magnetic field than the proton signals at 3-H and 4-H in
3b-j. The ring-opening compounds 3b-j were synthesized
All melting points are uncorrected. Ir spectra were recorded on
a JASCO FT/IR-230 spectrometer. H nmr and C nmr spectra
were measured with a JEOL JNM-A500 instrument (500.00 MHz
1
13
1
13
for H, 125.65 MHz for C) in CDCl with TMS as internal
3
13
standard. C signal assignments were confirmed by the DEPT
13
1
and C- H COSY technique. FAB mass spectra were taken with
a JEOL JMS-HX100 instrument at 70 eV. Elemental analyses
were performed using a YANACO MT-6 elemental analyzer.
General Procedure for the Preparation of 2-Acylamino-4,5-dihy-
dro-3-furancarbonitriles 1.
A mixture of 2-amino-4,5-dihydro-3-furancarbonitrile [12]
(5.50 g, 50 mmoles) and acyl chloride (55 mmoles) in pyridine
(25 ml) was stirred at room temperature for 3 hours. After
removal of the solvent in vacuo, 5% sodium bicarbonate solution
(100 ml) was added to the residue. The resulting precipitate was
collected by filtration, washed with water and dried to give 1.
2-Cyclopropanecarboxamido-4,5-dihydro-3-furancarbonitrile
(1b).
This compound was obtained as pale yellow columns (5.16 g,
58%), mp 166-167° (acetone-petroleum ether); ir (potassium bro-
-1
1
mide): ν 3210, 3140 (NH), 2205 (CN), 1687 cm (C=O); H nmr
(deuteriochloroform): δ, ppm 0.90-0.92 (m, 2H, CH ), 1.11-1.13
2
(m, 2H, CH ), 1.66-1.70 (m, 1H, CH), 2.97 (t, J = 9.5 Hz, 2H, 4-
2
13
H), 4.54 (t, J = 9.5 Hz, 2H, 5-H); C nmr (deuteriochloro-
form):δ, ppm 9.4 (CH ), 14.9 (CH), 29.5 (C-4), 65.2 (C-3), 70.9
2
(C-5), 116.4 (CN), 159.1 (C-2), 171.2 (C=O); ms: m/z 179
+
[M+H] .
by reaction of 1b-j and titanium (IV) chloride (Scheme 3).
The reaction of 4a-j with sodium iodide resulted in the
formation of the expected compounds 2a-j in high yields
(Scheme 4).
Anal. Calcd. for C H N O (MW 178.2): C, 60.66; H, 5.66;
N, 15.72. Found: C, 60.61; H, 5.71; N, 15.63.
9
10 2 2
2-(2-Propanecarboxamido)-4,5-dihydro-3-furancarbonitrile (1c).
On the basis of the above observation, the reaction path-
way for the formation of 2a-j can be illustrated as shown in
Scheme 2.
This compound was obtained as colorless needles (6.84 g,
76%), mp 131-132° (acetone-petroleum ether); ir (potassium bro-
-1
1
mide): ν 3220, 3150 (NH), 2204 (CN), 1696 cm (C=O); H nmr
In conclusion, we have presented a useful method for the
synthesis of 1-acyl-2-oxo-3-pyrrolidinecarbonitriles in
good yields starting from easily accessible 2-acylamino-
4,5-dihydro-3-furancarbonitriles.
(deuteriochloroform): δ, ppm 1.21 (d, J = 7.0 Hz, 6H, 2CH ),
3
2.55-2.61 (m, 1H, CH), 2.98 (t, J = 9.2 Hz, 2H, 4-H), 4.53 (t, J =
13
9.2 Hz, 2H, 5-H), 7.76 (br.s, 1H, NH); C nmr (deuteriochloro-
form): δ, ppm 19.1, 19.4 (CH ) 29.8 (C-4), 35.8 (CH), 66.2 (C-3),
3
70.7 (C-5), 116.2 (CN), 158.6 (C-2), 173.8 (C=O); ms: m/z 181
+
[M+H] .
EXPERIMENTAL
Anal. Calcd. for C H N O (MW 180.2): C, 59.99; H, 6.71;
9
12 2 2

May-Jun 2005
Synthesis of 1-Acyl-2-oxo-3-pyrrolidinecarbonitriles
545
N, 15.55. Found: C, 59.96; H, 6.72; N, 15.50.
Anal. Calcd. for C H N O (MW 228.3): C, 68.41; H, 5.30;
13 12 2 2
N, 12.27. Found: C, 68.33; H, 5.38; N, 12.15.
2-Cyclobutanecarboxamido-4,5-dihydro-3-furancarbonitrile
(1d).
2-(4-Fluorobenzamido)-4,5-dihydro-3-furancarbonitrile (1h).
This compound was obtained as colorless needles (4.82 g,
This compound was obtained as pale yellow needles (9.45 g,
50%), mp 134-135° (acetone-petroleum ether); ir (potassium bro-
mide): ν 3218, 3139 (NH), 2203 (CN), 1694 cm (C=O); H nmr
81%), mp 156-157° (acetone-petroleum ether); ir (potassium bro-
-1
1
-1
1
mide): ν 3282 (NH), 2212 (CN), 1692 cm (C=O); H nmr (deu-
teriochloroform): δ, ppm 2.60-2.80 (m, 0.6H, 4-H), 3.04 (t, J =
9.2 Hz, 1.4H, 4-H), 3.72 (t, J = 9.4 Hz, 0.3H, 3-H), 4.35-4.50 (m,
0.6H, 5-H), 4.55 (t, J = 9.2 Hz, 1.4H, 5-H), 7.05-7.20 (m, 2H, aryl
(deuteriochloroform): δ, ppm 1.80-2.40 (m, 6H, 3CH ), 2.60-
3
2.80 (m, 1H, CH), 2.97 (t, J = 9.5 Hz, 1.4H, 4-H), 3.15-3.25 (m,
0.6H, 4-H), 3.70 (dd, J = 9.2, 10.1 Hz, 0.3H, 3-H), 4.53 (t, J = 9.5
13
13
Hz, 2H, 5-H), 7.49 (br. s, 0.7H, NH); C nmr (deuteriochloro-
H), 7.85-7.95 (m, 2H, aryl H), 8.22 (br. s, 0.7H, NH); C nmr
form): δ, ppm 17.9, 18.1, 24.9, 25.4, 26.5 (CH ), 27.8 (C-4), 29.7
(deuteriochloroform): δ, ppm 27.8 (C-4), 30.3 (C-4), 31.4 (C-3),
68.0 (C-3), 70.3 (C-5), 70.5 (C-5), 115.6 (CN), 116.0 (CN),
116.0, 128.4, 128.5, 129.8, 130.4, 132.4, (C aryl), 158.0 (C-2),
2
(C-4), 31.4 (C-3), 39.3 (CH), 39.9 (CH), 65.9 (C-3), 67.1 (C-5),
70.8 (C-5), 114.6 (CN), 116.1 (CN), 158.6 (C-2), 168.2 (C-2),
+
+
171.8, 175.2 (C=O); ms: m/z 193 [M+H] .
162.6 (C-2), 164.6, 166.7 (C=O); ms: m/z 233 [M+H] .
Anal. Calcd. for C
H
N O (MW 192.2): C, 62.49; H, 6.29;
Anal. Calcd. for C H FN O (MW 232.3): C, 62.07; H, 3.91;
10 12
2
2
12 9 2 2
N, 14.57. Found: C, 62.46; H, 6.32; N, 14.43.
N, 12.06. Found: C, 62.11; H, 3.97; N, 11.99.
2-Cyclopentanecarboxamido-4,5-dihydro-3-furancarbonitrile
2-(4-Chlorobenzamido)-4,5-dihydro-3-furancarbonitrile (1i).
(1e).
This compound was obtained as pale yellow prisms (10.41 g,
This compound was obtained as colorless columns (6.92 g,
84%), mp 172-173° (acetone); ir (potassium bromide): ν 3210,
-1
1
67%), mp 122-123° (acetone-petroleum ether); ir (potassium bro-
3155 (NH), 2206 (CN), 1707 cm (C=O); H nmr (deuteriochlo-
roform): δ, ppm 2.60-2.75 (m, 0.6H, 4-H), 3.05 (t, J = 9.2 Hz,
1.4H, 4-H), 3.68 (t, J = 9.5 Hz, 0.3H, 3-H), 4.30-4.50 (m, 0.6H, 5-
H), 4.56 (t, J = 9.2 Hz, 1.4H, 5-H), 7.35-7.50 (m, 2H, aryl H),
-1
1
mide): ν 3270, 3165 (NH), 2213 (CN), 1696 cm (C=O); H nmr
(deuteriochloroform): δ, ppm 1.55-2.00 (m, 8H, 4CH ), 2.60-
2
2.80 (m, 1H, CH), 2.97 (t, J = 9.5 Hz, 2H, 4-H), 4.52 (t, J = 9.5
13
13
Hz, 2H, 5-H), 7.69 (br. s, 1H, NH); C nmr (deuteriochloro-
7.70-7.80 (m, 2H, aryl H), 8.11 (br. s, 0.7H, NH); C nmr (deu-
form): δ, ppm 25.8, 25.9 (CH ), 29.8 (C-4), 30.1, 30.4 (CH ),
teriochloroform): δ, ppm 27.8 (C-4), 30.3 (C-4), 31.4 (C-3), 67.1
(C-5), 68.2 (C-3), 70.6 (C-5), 115.0 (CN), 115.9 (CN), 128.8,
128.9, 129.2, 129.3, 130.5, 131.2, 138.0, 139.7 (C aryl), 157.8
2
2
45.8 (CH), 65.9 (C-3), 116.2 (CN), 158.6 (C-2), 173.2 (C=O);
+
ms: m/z 207 [M+H] .
+
Anal. Calcd. for C H N O (MW 206.2): C, 64.06; H, 6.84;
(C-2), 162.6 (C-2), 168.0, 175.2 (C=O); ms: m/z 249 [M+H] .
11 14
2 2
N, 13.58. Found: C, 64.16; H 6.77; N, 13.58.
Anal. Calcd. for C H ClN O (MW 248.7): C, 57.96; H,
12
9
2 2
3.65; N, 11.27. Found: C, 57.95; H, 3.72; N, 11.26.
2-Cyclohexanecarboxamido-4,5-dihydro-3-furancarbonitrile
(1f).
2-(4-Methoxybenzamido)-4,5-dihydro-3-furancarbonitrile (1j).
This compound was obtained as colorless needles (9.43 g,
86%), mp 157-158°(acetone-petroleum ether); ir (potassium bro-
mide): ν 3278, 3163 (NH), 2212 (CN), 1697 cm (C=O); H nmr
This compound was obtained as pale yellow needles (9.48 g,
78%), mp 145-146° (acetone-petroleum ether); ir (potassium bro-
-1
1
-1
1
mide): ν 3296 (NH), 2205 (CN), 1685 cm (C=O); H nmr (deu-
teriochloroform): δ, ppm 3.03 (t, J = 9.2 Hz, 2H, 4-H), 3.86 (s,
(deuteriochloroform): δ, ppm 1.20-2.80 (m, 11.3H, 5CH , CH, 4-
2
H), 2.98 (t, J = 8.9 Hz, 1.4H, 4-H), 3.96 (dd, J = 9.5 Hz, 10.1H,
0.3H, 3-H), 4.34-4.39 (m, 0.6H, 5-H), 4.52 (t, J = 8.9 Hz, 1.4H, 5-
H), 7.50 (br. s, 0.7H, NH); C nmr (deuteriochloroform): δ, ppm
3H, OCH ), 4.53 (t, J = 9.2 Hz, 2H, 5-H), 6.90-7.00 (m, 2H, aryl
H), 7.80-7.85 (m, 2H, aryl H), 8.12 (br. s, 1H, NH); C nmr
3
13
13
(deuteriochloroform): δ, ppm 30.3 (C-4), 55.5 (OCH ), 67.2 (C-
3
25.1, 25.2, 25.4, 25.5, 25.67, 25.73 (CH ), 27.8 (C-4), 29.2 (C-4),
3), 70.5 (C-5), 113.8, 114.1 (C aryl), 116.3 (CN), 124.4, 129.8 (C
aryl) 158.2 (C-2), 163.5 (C=O); ms: m/z 245 [M+H] .
2
+
29.7, 29.8 (CH ), 31.4 (C-3), 44.8 (CH), 45.5 (CH), 66.3 (C-3),
2
67.1 (C-5), 70.7 (C-5), 114.6 (CN), 116.1 (CN), 158.4 (C-2),
168.2 (C-2), 172.6, 176.5 (C=O); ms: m/z 221 [M+H] .
Anal. Calcd. for C
N, 11.47. Found: C, 63.89; H, 5.12; N, 11.37.
H N O (MW 244.3): C, 63.93; H, 4.95;
13 12 2 3
+
Anal. Calcd. for C
N, 12.72. Found: C, 65.26; H, 7.35; N, 12.69.
H N O (MW 220.3): C, 65.43; H, 7.32;
12 16 2 2
General Procedure for the Preparation of 1-Acyl-2-oxo-3-pyrro-
lidinecarbonitriles 2.
2-Phenylacetamido-4,5-dihydro-3-furancarbonitrile (1g).
A solution of 1a-j (10 mmoles) and sodium iodide (3.00 g, 20
mmoles) in DMF (10 ml) was stirred at 150° for 1 hour. The sol-
vent was removed in vacuo and cold water was added to the
residue. The mixture was extracted with ethyl acetate. The
extract was washed with water, dried over anhydrous sodium sul-
fate and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel with dichloromethane as the
eluent to give 2.
This compound was obtained as colorless needles (5.89 g,
52%,) mp 193-194° (acetone); ir (potassium bromide): ν 3212,
-1
1
3152 (NH), 2203 (CN), 1697 cm (C=O); H nmr (deuteriochlo-
roform): δ, ppm 2.60-2.75 (m, 0.6H, 4-H), 2.95 (t, J = 9.2 Hz,
1.4H, 4-H), 3.59 (s, 0.6H, CH CO), 3.67 (dd, J = 9.2, 10.1 Hz,
2
0.3H, 3-H), 3.73 (s, 1.4H, CH CO), 4.47 (t, J = 9.2 Hz, 1.4H, 5-
2
H), 4.50-4.55 (m, 0.6H, 5-H), 7.27-7.40 (m, 5H, aryl H), 7.48 (br.
13
s, 0.7H, NH); C nmr (deuteriochloroform): δ, ppm 27.8 (C-4),
1-Acetyl-2-oxo-3-pyrrolidinecarbonitrile (2a).
29.9 (C-4), 31.4 (C-3), 43.3, 43.9 (CH ), 67.1 (C-5), 67.3 (C-3),
2
This compound was obtained as colorless prisms (1.27 g, 84%),
70.6 (C-5), 114.6 (CN), 115.7 (CN), 127.5, 128.0, 129.1, 129.3,
129.4, 129.5, 133.0, 134.8 (C aryl), 157.8 (C-2), 167.6 (C-2),
168.1, 173.2 (C=O); ms: m/z 229 [M+H] .
mp 68-69° (acetone-petroleum ether); ir (potassium bromide): ν
-1
1
+
2255 (CN), 1746, 1698 cm (C=O); H nmr (deuteriochloroform):

546
K. Yamagata, F. Okabe, H. Maruoka and Y. Tagawa
Vol. 42
δ, ppm 2.30-2.40 (m, 1H, 4-H), 2.50-2.60 (m, 1H, 4-H), 2.53 (s, 3H,
1-Cyclohexanecarbonyl-2-oxo-3-pyrrolidinecarbonitrile (2f).
CH ), 3.70 (ddd. J = 7.3, 9.2, 11.9 Hz, 1H, 5-H), 3.76 (dd, J = 8.9,
3
This compound was obtained as colorless scales (1.94 g, 88%),
13
10.1 Hz, 1H, 3-H), 4.03 (ddd, J = 3.4, 8.6, 11.9 Hz, 1H, 5-H);
C
mp 142-143° (acetone-petroleum ether); ir (potassium bromide):
-1
1
nmr (deuteriochloroform): δ, ppm 22.8 (C-4), 24.7 (CH ), 36.1 (C-
ν 2261 (CN), 1756, 1673 cm (C=O); H nmr (deuteriochloro-
3
3), 43.4 (C-5), 115.4 (CN), 166.5, 170.4 (C=O); ms: m/z 153
form): δ, ppm 1.20-1.90 (m, 10H, 5CH ), 2.30-2.40 (m, 1H, 4-
2
+
[M+H] .
H), 2.50-2.55 (m, 1H, 4-H), 3.30-3.40 (m, 1H, CH), 3.68 (ddd, J
= 7.4, 9.2, 11.9 Hz, 1H, 5-H), 3.73 (dd, J = 9.2, 10.4 Hz, 1H, 3-
Anal. Calcd. for C H N O (MW 152.2): C, 55.26; H, 5.30; N,
7
8 2 2
13
18.41. Found: C, 55.28; H, 5.30; N, 18.36.
H), 4.01 (ddd, J = 3.1, 8.9, 11.9 Hz, 1H, 5-H); C nmr (deuteri-
ochloroform): δ, ppm 22.9 (C-4), 25.4, 25.5, 25.7, 28.6, 29.1
1-Cyclopropanecarbonyl-2-oxo-3-pyrrolidinecarbonitrile (2b).
(CH ), 36.5 (C-3), 43.6 (CH), 43.9 (C-5), 115.4 (CN), 165.8,
2
This compound was obtained as colorless plates (1.35 g, 76%),
+
176.9 (C=O); ms: m/z 221 [M+H] .
mp 107-108° (acetone-petroleum ether); ir (potassium bromide):
Anal. Calcd. for C
H N O (MW 220.3): C, 65.43; H, 7.32;
12 16 2 2
-1
1
ν 2252 (CN), 1730, 1685 cm (C=O); H nmr (deuteriochloro-
N, 12.72. Found: C, 65.29; H, 7.32; N, 12.65.
form): δ, ppm 1.00-1.18 (m, 4H, 2CH ), 2.30-2.40 (m, 1H, 4-H),
2
1-Phenylacetyl-2-oxo-3-pyrrolidinecarbonitrile (2g).
2.50-2.60 (m, 1H, 4-H), 3.06-3.10 (m, 1H, CH), 3.71 (ddd. J =
7.1, 8.9, 11.9 Hz, 1H, 5-H), 3.78 (dd, J = 8.9, 10.4 Hz, 1H, 3-H),
4.02 (ddd, J = 3.1, 8.6, 11.9 Hz, 1H, 5-H); C nmr (deuteriochlo-
This compound was obtained as colorless needles (1.97 g,
13
86%), mp 124-125° (acetone-petroleum ether); ir (potassium bro-
roform): δ, ppm 11.23, 11.25 (CH ), 13.6 (CH), 22.8 (C-4), 36.5
-1
1
2
mide): ν 2250 (CN), 1736, 1714 cm (C=O); H nmr (deuteri-
ochloroform): δ, ppm 2.30-2.37 (m, 1H, 4-H), 2.45-2.55 (m, 1H,
4-H), 3.68 (ddd, J = 7.4, 9.2, 11.8 Hz, 1H, 5-H), 3.72 (dd, J = 8.9,
10.4 Hz, 1H, 3-H), 4.02 (ddd, J = 3.2, 9.8, 12.8 Hz, 1H, 5-H);
(C-3), 44.0 (C-5), 115.5 (CN), 166.7, 174.8 (C=O); ms: m/z 179
+
[M+H] .
Anal. Calcd. for C H N O (MW 178.2): C, 60.66; H, 5.66;
9
10 2 2
N, 15.72. Found: C, 60.58; H, 5.71; N, 15.60.
4.23 (AB quartet, J = 15.4 Hz, NCH CO), 7.25-7.35 (m, 5H, aryl
2
13
H); C nmr (deuteriochloroform): δ, ppm 22.8 (C-4), 36.3 (C-3),
1-(2-Propanecarbonyl)-2-oxo-3-pyrrolidinecarbonitrile (2c).
42.6 (CH ), 43.8 (C-5), 115.3 (CN), 127.3, 128.6, 129.7, 133.0
(C aryl), 166.3, 171.4 (C=O); ms: m/z 229 [M+H] .
2
This compound was obtained as colorless plates (1.47 g, 82%),
+
mp 92-93° (acetone-petroleum ether); ir (potassium bromide): ν
Anal. Calcd. for C
H N O (MW 228.3): C, 68.41; H, 5.30;
-1
1
13 12 2 2
2259 (CN), 1755, 1679 cm (C=O); H nmr (deuteriochloro-
N, 12.27. Found: C, 68.33; H, 5.36; N, 12.17.
form): δ, ppm 1.16 (d, J = 7.0 Hz, 3H, CH ), 1.19 (d, J = 7.0 Hz,
3
3H, CH ), 2.30-2.40 (m, 1H, 4-H), 2.50-2.56 (m, 1H, 4-H), 3.58-
1-(4-Fluorobenzoyl)-2-oxo-3-pyrrolidinecarbonitrile (2h).
3
3.67 (m, 1H, CH), 3.71 (ddd. J = 7.4, 9.2, 12.9 Hz, 1H, 5-H), 3.75
(dd, J = 8.9, 10.4 Hz, 1H, 3-H), 4.02 (ddd, J = 3.1, 8.8, 12.9 Hz,
This compound was obtained as colorless columns (1.80 g,
78%), mp 166-167° (acetone-petroleum ether); ir (potassium bro-
13
1H, 5-H); C nmr (deuteriochloroform): δ, ppm 18.4, 18.8
-1
1
mide): ν 2257 (CN), 1758, 1672 cm (C=O); H nmr (deuteri-
ochloroform): δ, ppm 2.42-2.52 (m, 1H, 4-H), 2.58-2.66 (m, 1H,
4-H), 3.73 (dd, J = 9.5, 10.2 Hz, 1H, 3-H), 3.93 (ddd, J = 7.5, 9.0,
11.5 Hz, 1H, 5-H), 4.10 (ddd, J = 3.0, 8.5, 11.5 Hz, 1H, 5-H),
(CH ), 22.9 (C-4), 34.1 (CH), 36.5 (C-3), 43.9 (C-5), 115.4 (CN),
3
+
165.8, 178.0 (C=O); ms: m/z 181[M+H] .
Anal. Calcd. for C H N O (MW 180.2): C, 59.99; H, 6.71;
9
12 2 2
N, 15.55. Found: C, 59.78; H, 6.73; N, 15.49.
13
7.01-7.10 (m, 2H, aryl H), 7.65-7.69 (m, 2H, aryl H); C nmr
1-Cyclobutanecarbonyl-2-oxo-3-pyrrolidinecarbonitrile (2d).
(deuteriochloroform): δ, ppm 23.2 (C-4), 35.9 (C-3), 44.7 (C-5),
115.2 (C aryl), 115.4 (CN), 128.9, 132.0 (C aryl), 164.5 (C=O),
166.0 (C aryl), 168.5 (C=O); ms: m/z 233 [M+H] .
This compound was obtained as colorless scales (1.56 g, 81%),
+
mp 68-69° (acetone-petroleum ether); ir (potassium bromide): ν
Anal. Calcd. for C H FN O (MW 232.2): C, 62.07; H, 3.91;
-1
1
12
9
2 2
2259 (CN), 1749, 1672 cm (C=O); H nmr (deuteriochloro-
N, 12.06. Found: C, 62.16; H, 3.95; N, 11.99.
form): δ, ppm 1.80-2.55 (m, 8H, 4-H, 3CH ), 3.67-3.73 (m, 2H,
2
5-H), 3.71 (dd, J = 9.2, 10.4 Hz, 1H, 3-H), 3.95-4.04 (m, 2H, 5-H,
1-(4-Chlorobenzoyl)-2-oxo-3-pyrrolidinecarbonitrile (2i).
13
CH); C nmr (deuteriochloroform): δ, ppm 17.9 (CH ), 23.1 (C-
2
This compound was obtained as colorless needles (1.93 g,
4), 24.2, 24.6 (CH ), 36.2 (C-3), 39.7 (CH), 43.6 (C-5), 115.4
2
+
78%), mp 138-139° (acetone-petroleum ether); ir (potassium bro-
(CN), 165.7, 175.0 (C=O); ms: m/z 193[M+H] .
Anal. Calcd. for C N O (MW 192.2): C, 62.49; H, 6.29;
-1
1
mide): ν 2256 (CN), 1763, 1678 cm (C=O); H nmr (deuteri-
ochloroform): δ, ppm 2.45-2.53 (m, 1H, 4-H), 2.60-2.67 (m, 1H,
4-H), 3.73 (dd, J = 8.9, 10.1 Hz, 1H, 3-H), 3.94 (ddd, J = 7.4, 8.9,
12.5 Hz, 1H, 5-H), 4.10 (ddd, J = 3.4, 8.6, 12.5 Hz, 1H, 5-H),
H
10 12
2 2
N, 14.57. Found: C, 62.36; H, 6.31; N, 14.48.
1-Cyclopentanecarbonyl-2-oxo-3-pyrrolidinecarbonitrile (2e).
13
7.25-7.42 (m, 2H, aryl H), 7.56-7.60 (m, 2H, aryl H); C nmr
This compound was obtained as colorless columns (1.67 g,
(deuteriochloroform): δ, ppm 23.2 (C-4), 35.9 (C-3), 44.6 (C-5),
81%), mp 63-64° (diethyl ether-petroleum ether); ir (potassium
bromide): ν 2256 (CN), 1751, 1679 cm (C=O); H nmr (deu-
-1
1
115.2 (CN), 128.4, 130.7, 131.2, 139.3 (C aryl), 165.6, 168.7
+
(C=O); ms: m/z 249 [M+H] .
teriochloroform): δ, ppm 1.60-2.00 (m, 8H, 4CH ), 2.30-2.40 (m,
2
Anal. Calcd. for C H ClN O (MW 248.7): C, 57.96; H,
3.65; N, 11.27. Found: C, 57.98; H, 3.74; N, 11.20.
1H, 4-H), 2.50-2.55 (m, 1H, 4-H), 3.68-3.78 (m, 3H, 3-H, 5-H,
CH), 4.02 (ddd, J = 3.1, 8.9, 11.9 Hz, 1H, 5-H); C nmr (deuteri-
12
9
2 2
13
ochloroform): δ, ppm 22.8 (C-4), 25.91, 25.94, 29.4, 29.9 (CH ),
2
1-(4-Methoxybenzoyl)-2-oxo-3-pyrrolidinecarbonitrile (2j).
36.5 (C-3), 43.9 (C-5), 44.4 (CH), 115.5 (CN), 165.9, 176.9
+
(C=O); ms: m/z 207[M+H] .
This compound was obtained as colorless needles (1.90 g, 78%),
Anal. Calcd. for C H N O (MW 206.2): C, 64.06; H, 6.84;
N, 13.58. Found: C, 63.84; H, 6.82; N, 13.53.
mp 106-107° (acetone-petroleum ether); ir (potassium bromide): ν
2253 (CN), 1758, 1673 cm (C=O); H nmr (deuteriochloroform):
11 14
2 2
-1
1
δ, ppm 2.40-2.50 (m, 1H, 4-H), 2.57-2.65 (m, 1H, 4-H), 3.71 (dd, J

May-Jun 2005
Synthesis of 1-Acyl-2-oxo-3-pyrrolidinecarbonitriles
547
= 8.9, 10.4 Hz, 1H, 3-H), 3.87 (s, 3H, OCH ), 3.93 (ddd, J = 6.7,
4-Chloro-2-cyano-N-cyclopentanecarbonylbutanamide (3e).
3
9.2, 11.5 Hz, 1H, 5-H), 4.06 (ddd, J = 3.4, 8.3, 11.5 Hz, 1H, 5-H),
6.90-6.94 (m, 2H, aryl H), 7.65-7.68 (m, 2H, aryl H); C nmr
(deuteriochloroform): δ, ppm 23.4 (C-4), 36.0 (C-3), 44.8 (C-5),
This compound was obtained as colorless needles (5.88 g,
13
61%), mp 124-125° (acetone-petroleum ether); ir (potassium
-1
bromide): ν 3269, 3184 (NH), 2260 (CN), 1739, 1712 cm
55.5 (OCH ), 113.4 (C aryl), 115.5 (CN), 124.7, 132.1, 163.7 (C
1
3
(C=O); H nmr (deuteriochloroform): δ, ppm 1.60-2.00 (m, 8H,
+
aryl), 165.6, 168.9 (C=O); ms: m/z 245[M+H] .
4CH ), 2.30-2.50 (m, 2H, 3-H), 2.85-2.95 (m, 1H, CH), 3.70-
2
Anal. Calcd. for C
H N O (MW 244.3): C, 63.93; H, 4.95;
13 12 2 3
3.80 (m, 2H, 4-H), 4.66 (dd, J = 6.1, 8.6 Hz, 1H, 2-H), 8.65 (br. s,
13
N, 11.47. Found: C, 63.86; H, 4.95; N, 11.38.
1H, NH); C nmr (deuteriochloroform): δ, ppm 25.9, 29.7, 29.8
(CH ), 31.8 (C-3), 36.9 (CH), 40.8 (C-4), 46.3 (C-2), 115.5 (CN),
166.0, 175.8 (C=O); ms: m/z 243 [M+H] .
2
General Procedure for the Preparation of N-Acyl-4-chloro-2-
cyanobutanamides 2.
+
Anal. Calcd. for C
H ClN O (MW 242.7): C, 54.44; H,
11 15 2 2
Titanium(IV) chloride (9.12 g, 48 mmoles) was added drop-
wise to an ice-cooled and stirred solution of 1b-j (40 mmoles) in
chloroform (80 ml). After the mixture was refluxed for 1 hour,
the precipitate was dissolved in 5% hydrochloric acid (50 ml)
with stirring and ice-cooling, and then the chloroform layer was
separated. The aqueous layer was extracted with chloroform. The
organic layer was washed with water, dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel with
dichloromethane as the eluent to yield 3b-j.
6.23; N, 11.54. Found: C, 54.44; H, 6.19; N, 11.47.
4-Chloro-2-cyano-N-cyclohexanecarbonylbutanamide (3f).
This compound was obtained as colorless needles (6.79 g,
66%), mp 128-129° (acetone-petroleum ether); ir (potassium bro-
-1
mide): ν 3266, 3181 (NH), 2253 (CN), 1739, 1712 cm (C=O);
1
H nmr (deuteriochloroform): δ, ppm 1.20-1.95 (m, 10H, 5CH ),
2
2.35-2.50 (m, 3H, 3-H, CH), 3.70-3.80 (m, 2H, 4-H), 4.67 (dd, J
13
= 5.8, 8.6 Hz, 1H, 2-H), 8.60 (br. s, 1H, NH); C nmr (deuteri-
ochloroform): δ, ppm 25.2, 25.4, 28.77, 28.8 (CH ), 31.8 (C-3),
2
37.0 (CH), 40.8 (C-4), 45.8 (C-2), 115.5 (CN), 166.2, 175.5
(C=O); ms: m/z 257 [M+H] .
4-Chloro-2-cyano-N-cyclopropanecarbonylbutanamide (3b).
+
This compound was obtained as colorless needles (4.58 g,
Anal. Calcd. for C
H ClN O (MW 256.7): C, 56.14; H,
12 17 2 2
54%), mp 134-135° (acetone-petroleum ether); ir (potassium bro-
6.67; N, 10.91. Found: C, 56.23; H, 6.65; N, 10.84.
-1
mide): ν 3258, 3169 (NH), 2253 (CN), 1735, 1694 cm (C=O);
1
4-Chloro-2-cyano-N-phenylacetylbutanamide (3g).
H nmr (deuteriochloroform): δ, ppm 1.00-1.10 (m, 2H, CH ),
2
1.15-1.25 (m, 2H, CH ), 1.95-2.05 (m, 1H, CH), 2.35-2.50 (m,
2
This compound was obtained as colorless needles (5.12 g,
2H, 3-H), 3.70-3.80 (m, 2H, 4-H), 4.59 (t, J = 8.0 Hz, 1H, 2-H),
48%), mp 113-114° (acetone-petroleum ether); ir (potassium bro-
13
9.22 (br. s, 1H, NH); C nmr (deuteriochloroform): δ, ppm 10.9,
-1
mide): ν 3267, 3183 (NH), 2252 (CN), 1745, 1707 cm (C=O);
11.0 (CH ), 15.4 (CH), 31.9 (C-3), 36.9 (C-2), 40.8 (C-4), 115.5
1
2
H nmr (deuteriochloroform): δ, ppm 2.30-2.50 (m, 2H, 3-H),
+
(CN), 165.7, 174.4 (C=O); ms: m/z 215 [M+H] .
3.70 (t, J = 5.5 Hz, 2H, 4-H), 3.85 (s, 2H, COCH ), 4.55 (dd, J =
2
Anal. Calcd. for C H ClN O (MW 214.7): C, 50.36; H,
9
11
2
2
6.1, 8.2 Hz, 1H, 2-H), 7.26-7.40 (m, 5H, aryl H), 8.51 (br. s, 1H,
13
5.17; N, 13.05. Found: C, 50.41; H, 5.07; N, 12.82.
NH); C nmr (deuteriochloroform): δ, ppm 31.8 (C-3), 36.9 (C-
2), 40.8 (C-4), 44.4 (CH ), 115.3 (CN), 128.2, 129.3, 129.5,
132.0 (C aryl), 165.5, 170.7 (C=O); ms: m/z 265 [M+H] .
2
4-Chloro-2-cyano-N-(2-propanecarbonyl)butanamide (3c).
+
This compound was obtained as colorless needles (3.12 g, 36%),
Anal. Calcd. for C
H ClN O (MW 264.7): C, 58.99; H,
13 13 2 2
mp 104-105° (acetone-petroleum ether); ir (potassium bromide): ν
4.95; N, 10.58. Found: C, 58.96; H, 4.83; N, 10.51.
-1
1
3273, 3189 (NH), 2255 (CN), 1740, 1700 cm (C=O); H nmr
(deuteriochloroform): δ, ppm 1.23 (d, J = 5.2 Hz, 3H, CH ), 1.24
4-Chloro-2-cyano-N-(4-fluorobenzoyl)butanamide (3h).
3
(d, J = 5.5 Hz, 3H, CH ), 2.35-2.50 (m, 2H, 3-H), 2.70-2.80 (m,
3
This compound was obtained as colorless prisms (4.69 g,
1H, CH), 3.70-3.80 (m, 2H, 4-H), 4.67 (dd, J = 5.8, 8.6 Hz, 1H, 2-
44%), mp 127-128° (acetone-petroleum ether); ir (potassium bro-
13
H), 8.78 (br. s, 1H, NH); C nmr (deuteriochloroform): δ, ppm
-1
mide): ν 3303, 3168 (NH), 2248 (CN), 1732, 1686 cm (C=O);
18.56, 18.6 (CH ), 31.8 (C-3), 36.3 (CH), 37.0 (C-2), 40.8 (C-4),
1
3
H nmr (deuteriochloroform): δ, ppm 2.40-2.60 (m, 2H, 3-H),
+
115.5 (CN), 166.3, 176.7 (C=O); ms: m/z 217 [M+H] .
3.70-3.82 (m, 2H, 4-H), 5.00 (dd, J = 5.5, 8.9 Hz, 1H, 2-H), 7.20-
7.25 (m, 2H, aryl H), 7.95-7.99 (m, 2H, aryl H), 9.21 (br. s, 1H,
Anal. Calcd. for C H ClN O (MW 216.7): C, 49.89; H,
9
13
2 2
13
6.05; N, 12.93. Found: C, 49.95; H, 6.12; N, 12.90.
NH); C nmr (deuteriochloroform): δ, ppm 31.9 (C-3), 37.3 (C-
2), 40.8 (C-4), 115.5 (CN), 116.5, 127.5, 130.8, 164.2 (C aryl),
165.3, 167.3 (C=O); ms: m/z 269 [M+H] .
4-Chloro-2-cyano-N-cyclobutanecarbonylbutanamide (3d).
+
This compound was obtained as colorless needles (4.51 g,
47%), mp 82-84° (diethyl ether-petroleum ether); ir (potassium
Anal. Calcd. for C
H ClFN O (MW 268.7): C, 53.65; H,
12 10 2 2
3.75; N, 10.43. Found: C, 53.61; H, 3.78; N, 10.38.
-1
bromide): ν 3267, 3181 (NH), 2251 (CN), 1738, 1702 cm
1
4-Chloro-N-(4-chlorobenzoyl)-2-cyanobutanamide (3i).
(C=O); H nmr (deuteriochloroform): δ, ppm 1.90-2.50 (m, 8H,
3-H, 3CH ), 3.35-3.45 (m, 1H, CH), 3.70-3.75 (m, 2H, 4-H), 4.57
(t, J = 7.9 Hz, 1H, 2-H), 8.79 (br. s, 1H, NH); C nmr (deuteri-
2
This compound was obtained as colorless prisms (6.01 g,
13
53%), mp 112-113° (acetone-petroleum ether); ir (potassium bro-
ochloroform): δ, ppm 17.8, 24.5, 24.6 (CH ), 31.9 (C-3), 36.9
-1
1
2
mide): ν 3327 (NH), 2251 (CN), 1715, 1688 cm (C=O); H nmr
(deuteriochloroform): δ, ppm 2.40-2.60 (m, 2H, 3-H), 3.70-3.80
(CH), 40.4 (C-2), 40.8 (C-4), 115.5 (CN), 165.6, 174.9 (C=O);
+
ms: m/z 229 [M+H] .
(m, 2H, 4-H), 4.98 (dd, J = 5.8, 8.5 Hz, 1H, 2-H), 7.50-7.54 (m,
13
Anal. Calcd. for C
H ClN O (MW 228.7): C, 52.52; H,
10 13 2 2
2H, aryl H), 7.86-7.90 (m, 2H, aryl H), 9.32 (br. s, 1H, NH);
C
5.73; N, 12.25. Found: C, 52.93; H, 5.82; N, 11.64.
nmr (deuteriochloroform): δ, ppm 31.9 (C-3), 37.4 (C-2), 40.8
(C-4), 115.5 (CN), 129.46, 129.56, 129.6, 140.9 (C aryl), 164.5,

548
K. Yamagata, F. Okabe, H. Maruoka and Y. Tagawa
Vol. 42
+
ppm 14.6 (C-1), 17.8, 19.6, 24.4 (CH ), 40.4 (CH), 118.7 (CN),
164.2, 175.0 (C=O); ms: m/z 193 [M+H] .
167.4 (C=O); ms: m/z 285 [M+H] .
Anal. Calcd. for C Cl N O (MW 285.1): C, 50.55; H,
2
+
H
12 10
2 2 2
Anal. Calcd. for C
H N O (MW 192.2): C, 62.49; H, 6.29;
3.54; N, 9.82. Found: C, 50.51; H, 3.55; N, 9.84.
10 12 2 2
N, 14.57. Found: C, 62.26; H, 6.36; N, 14.43.
4-Chloro-2-cyano-N-(4-methoxybenzoyl)butanamide (3j).
1-Cyano-N-cyclopentanecarbonylcyclopropanecarboxamide
(4e).
This compound was obtained as colorless columns (5.52 g,
49%), mp 113-114° (acetone-petroleum ether); ir (potassium bro-
mide): ν 3289, 3170 (NH), 2254 (CN), 1721, 1670 cm (C=O);
H nmr (deuteriochloroform): δ, ppm 2.40-2.60 (m, 2H, 3-H),
3.75-3.82 (m, 2H, 4-H), 3.89 (s, 3H, OCH ), 5.04 (dd, J = 5.5, 8.8
Hz, 1H, 2-H), 6.95-7.02 (m, 2H, aryl H), 7.80-7.92 (m, 2H, aryl
H), 9.18 (br. s, 1H, NH); C nmr (deuteriochloroform): δ, ppm
32.0 (C-3), 37.3 (C-2), 40.9 (C-4), 55.6 (OCH ), 114.5 (C aryl),
-1
This compound was obtained as colorless needles (2.58 g,
1
83%), mp 152-153° (acetone-petroleum ether); ir (potassium bro-
-1
mide): ν 3268, 3176 (NH), 2247 (CN), 1736, 1695 cm (C=O);
3
1
H nmr (deuteriochloroform): δ, ppm 1.56-1.96 (m, 12H, 6CH ),
2
13
13
3.35-3.42 (m, 1H, CH), 8.54 (br. s, 1H, NH); C nmr (deuteri-
ochloroform): δ, ppm 14.8 (C-1), 19.5, 25.9, 29.6 (CH ), 45.6
2
3
+
(CH), 118.8 (CN), 164.2, 176.2 (C=O); ms: m/z 207 [M+H] .
115.7 (CN), 123.2, 130.3, 164.4 (C aryl), 164.6, 167.4 (C=O);
+
Anal. Calcd. for C H N O (MW 206.2): C, 64.06; H, 6.84;
ms: m/z 281 [M+H] .
11 14
2 2
N, 13.58. Found: C, 63.85; H, 6.74; N, 13.54.
Anal. Calcd. for C
H ClN O (MW 280.7): C, 55.62; H,
13 13 2 3
4.67; N, 9.98. Found: C, 55.61; H, 4.63; N, 9.97.
1-Cyano-N-cyclohexanecarbonylcyclopropanecarboxamide (4f).
General Procedure for the Preparation of N-Acylcyclopropane-
carboxamides 4.
This compound was obtained as colorless needles (3.09 g,
94%), mp 152-153° (acetone-petroleum ether); ir (potassium bro-
-1
mide): ν 3263, 3177 (NH), 2242 (CN), 1740, 1702 cm (C=O);
A suspension of 3b-j (15 mmoles) and potassium carbonate
(2.07 g, 15 mmoles) in acetone (50 ml) was refluxed for l hour.
After the solvent had been removed under reduced pressure, cold
water was added to the residue. The mixture was acidified 5%
hydrochloric acid. The precipitate was collected by filtration,
washed with water and dried to give the corresponding 4b-j.
1
H nmr (deuteriochloroform): δ, ppm 1.20-1.93 (m, 14H, 7CH ),
2
13
2.90-2.97 (m, 1H, CH), 8.55 (br. s, 1H, NH); C nmr (deuteri-
ochloroform): δ, ppm 14.8 (C-1), 19.5, 25.4, 25.6, 28.7 (CH ),
2
44.9 (CH), 118.8 (CN), 164.2, 175.9 (C=O); ms: m/z 221
+
[M+H] .
Anal. Calcd. for C
H N O (MW 220.3): C, 65.43; H, 7.32;
12 16 2 2
1-Cyano-N-cyclopropanecarbonylcyclopropanecarboxamide
(4b).
N, 12.72. Found: C, 65.40; H, 7.24; N, 12.73.
1-Cyano-N-phenylacetylcyclopropanecarboxamide (4g).
This compound was obtained as colorless needles (2.01 g,
This compound was obtained as colorless needles (2.76 g,
75%), mp 162-163° (acetone-petroleum ether); ir (potassium bro-
-1
80%), mp 145-146° (acetone-petroleum ether); ir (potassium bro-
mide): ν 3266, 3175 (NH), 2246 (CN), 1728, 1693 cm (C=O);
-1
1
mide): ν 3245, 3173 (NH), 2241 (CN), 1742, 1685 cm (C=O);
H nmr (deuteriochloroform): δ, ppm 1.00-1.10 (m, 2H, CH ),
2
1
H nmr (deuteriochloroform): δ, ppm 1.62-1.66 (m, 2H, CH ),
1.18-1.24 (m, 2H, CH ), 1.65-1.70 (m, 2H, CH ), 1.79-1.84 (m,
2
2
2
13
1.75-1.78 (m, 2H, CH ), 4.06 (s, 2H, COCH ), 7.25-7.37 (m, 5H,
2H, CH ), 2.62-2.68 (m, 1H, CH), 8.65 (br. s, 1H, NH); C nmr
2
2
2
13
aryl H), 8.69 (br. s, 1H, NH); C nmr (deuteriochloroform): δ,
(deuteriochloroform): δ, ppm 11.1 (CH ), 14.6 (CH), 14.8 (C-1),
2
ppm 14.8 (C-1), 19.8, 43.9 (CH ), 118.5 (CN), 127.6, 128.8,
19.6 (CH ), 118.7 (CN), 164.8, 174.5 (C=O); ms: m/z 179
2
2
+
+
129.5, 132.7 (C aryl), 164.5, 171.0 (C=O); ms: m/z 229 [M+H] .
[M+H] .
Anal. Calcd. for C
H N O •0.1H 0 (MW 228.3): C, 67.87;
Anal. Calcd. for C H N O (MW 178.2): C, 60.66; H, 5.66;
13 12 2 2 2
9
10 2 2
H, 5.35; N, 12.18. Found: C, 67.93; H, 5.33; N, 12.16.
N, 15.72. Found: C, 60.54; H, 5.72; N, 15.66.
1-Cyano-N-(4-fluorobenzoyl)cyclopropanecarboxamide (4h).
1-Cyano-N-(2-propanecarbonyl)cyclopropanecarboxamide (4c).
This compound was obtained as colorless columns (3.07 g,
This compound was obtained as colorless needles (1.85 g,
88%), mp 118-119° (acetone-petroleum ether); ir (potassium bro-
69%), mp 121-122° (acetone-petroleum ether); ir (potassium bro-
-1
-1
mide): ν 3249, 3153 (NH), 2248 (CN), 1725, 1685 cm (C=O);
mide): ν 3258, 3175 (NH), 2247 (CN), 1737, 1694 cm (C=O);
1
1
H nmr (deuteriochloroform): δ, ppm 1.69-1.72 (m, 2H, CH ),
H nmr (deuteriochloroform): δ, ppm 1.99 (d, J = 6.7 Hz, 6H,
2
1.84-1.87 (m, 2H, CH ), 7.16-7.22 (m, 2H, aryl H), 7.88-7.92 (m,
2CH ), 1.65-1.70 (m, 2H, CH ), 1.75-1.80 (m, 2H, CH ), 3.18-
2
3
2
2
13
13
2H, aryl H), 9.33 (br. s, 1H, NH); C nmr (deuteriochloroform):
3.26 (m, 1H, CH), 8.55 (br. s, 1H, NH); C nmr (deuteriochloro-
δ, ppm 15.3 (C-1), 19.6 (CH ), 116.3 (C aryl), 119.2 (CN), 128.5,
form): δ, ppm 14.8 (C-1), 18.5 (CH ), 19.6 (CH ), 35.4 (CH),
2
3
2
+
130.6, 163.2, 164.6 (C aryl), 164.9, 166.9 (C=O); ms: m/z 233
118.8 (CN), 164.2, 177.1 (C=O); ms: m/z 181 [M+H] .
+
[M+H] .
Anal. Calcd. for C H N O (MW 180.2): C, 59.99; H, 6.71;
9
12 2 2
Anal. Calcd. for C H FN O (MW 232.2): C, 62.07; H, 3.91;
N, 15.55. Found: C, 59.94; H, 6.71; N, 15.55.
12
9
2 2
N, 12.06. Found: C, 62.15; H, 3.85; N, 12.06.
1-Cyano-N-cyclobutanecarbonylcyclopropanecarboxamide (4d).
N-(4-Chlorobenzoyl)-1-cyanocyclopropanecarboxamide (4i).
This compound was obtained as colorless needles (1.99 g,
This compound was obtained as colorless scales (3.55 g, 95%),
69%), mp 131-132° (acetone-petroleum ether); ir (potassium bro-
-1
mp 127-128° (acetone-petroleum ether); ir (potassium bromide):
mide): ν 3257, 3178 (NH), 2246 (CN), 1737, 1705 cm (C=O);
-1
1
1
ν 3243, 3150 (NH), 2249 (CN), 1725, 1683 cm (C=O); H nmr
H nmr (deuteriochloroform): δ, ppm 1.64-1.67 (m, 2H, CH ),
2
(deuteriochloroform): δ, ppm 1.69-1.72 (m, 2H, CH ), 1.84-1.87
1.74-1.78 (m, 2H, CH ), 1.86-2.37 (m, 6H, 3CH ), 3.72-3.76 (m,
2
2
2
13
(m, 2H, CH ), 7.47-7.51 (m, 2H, aryl H), 7.80-7.82 (m, 2H, aryl
1H, CH), 8.52 (br. s, 1H, NH); C nmr (deuteriochloroform): δ,
2

May-Jun 2005
Synthesis of 1-Acyl-2-oxo-3-pyrrolidinecarbonitriles
549
REFERENCES AND NOTES
13
H), 9.32 (br. s, 1H, NH); C nmr (deuteriochloroform): δ, ppm
15.3 (C-1), 19.6 (CH ), 119.1 (CN), 129.3, 129.4, 130.6, 140.2
(C aryl), 163.4, 164.2 (C=O); ms: m/z 249 [M+H] .
2
+
[1] A. I. Meyers and L. J. Snyder, J. Org. Chem., 58, 36 (1993).
[2] B. Rigo, D. Fasseur, N. Cherepy and D. Couturier,
Tetrahedron Lett., 30, 7057 (1989).
[3] B. M. Nilsson, B. Ringdahl and U. Hacksell, J. Med.
Chem., 33, 580 (1990).
Anal. Calcd. for C H ClN O (MW 248.7): C, 57.96; H,
12
9
2 2
3.65; N, 11.27. Found: C, 57.94; H, 3.64; N, 11.23.
1-Cyano-N-(4-methoxybenzoyl)cyclopropanecarboxamide (4j).
[4] R. Bergmann and R. Gericke, J. Med. Chem., 33, 492
(1990).
[5] D. S. Garvey, P. D. May and A. M. Nadzan, J. Org. Chem.,
55, 936 (1990).
[6] N. J. Ede, I. D. Rae and M. T. W. Hearn, Aust. J. Chem.,
44, 891 (1991).
[7a] B. B. Snider, Y. Ahn and B. M. Foxman, Tetrahedron, 40,
3339 (1999); [b] B. B. Snider, H. Lin and B. M. Foxman, J. Org.
Chem., 63, 6442 (1998); [c] A. Kanazawa, S. Gillet, P. Delair and A.
E. Greene, J. Org. Chem., 63, 4660 (1998); [d] P. Nebois and A. E.
Greene, J. Org. Chem., 61, 5210 (1996).
[8a] L. E. Burgess and A. I. Meyers, J. Org. Chem., 57, 1656
(1992); [b] M. Ikeda, T. Sato and H. Ishibashi, Heterocycles, 27,
1465 (1988).
This compound was obtained as colorless needles (3.35 g,
92%), mp 114-115° (acetone-petroleum ether); ir (potassium bro-
-1
mide): ν 3307, 3170 (NH), 2240 (CN), 1740, 1685 cm (C=O);
1
H nmr (deuteriochloroform): δ, ppm 1.67-1.70 (m, 2H, CH ),
2
1.84-1.87 (m, 2H, CH ), 3.88 (s, 3H, OCH ), 6.97-7.01 (m, 2H,
2
3
13
aryl H), 7.83-7.87 (m, 2H, aryl H), 9.28 (br. s, 1H, NH); C nmr
(deuteriochloroform): δ, ppm 15.2 (C-1), 19.4 (CH ), 55.6
2
(OCH ), 114.4 (C aryl), 119.4 (CN), 124.4, 130.1, 163.3 (C aryl),
3
+
163.96, 164.0 (C=O); ms: m/z 245 [M+H] .
Anal. Calcd. for C
H N O (MW 244.3): C, 63.93; H, 4.95;
13 12 2 3
N, 11.47. Found: C, 63.96; H, 5.00; N, 11.39.
General Procedure for the Reaction of 4 with Sodium Iodide.
A solution of 4a-j (5 mmoles) and sodium iodide (1.50 g, 10
mmoles) in DMF (5 ml) was stirred at 150° for 1 hour. After
removal of the solvent in vacuo, cold water was added to the
residue. The mixture was extracted with ethyl acetate. The
extract was washed with water, dried over anhydrous sodium sul-
fate and concentrated in vacuo. The residue was chro-
matographed on silica gel with dichloromethane as the eluent to
yield 2a (0.66 g, 87%), 2b (0.75 g, 84%), 2c (0.78 g, 87%), 2d
(0.80 g, 83%), 2e (0.90 g, 87%), 2f (0.98 g, 89%), 2g (1.01 g,
89%), 2h (1.00 g, 86%), 2i (1.05 g, 84%) and 2j (1.07 g, 88%).
[9a] Z. Y. Wei and E. E. Knaus, Synlett, 295 (1991); [b] L. E.
Burgess and A. I. Meyers, J. Am. Chem. Soc., 113, 9858 (1991).
[10a] X. Lin, G. D. Artman, D. Stien and S. M. Weinreb,
Tetrahedron, 57, 8779 (2000); [b] K. Iwamoto, M. Kojima, N.
Chatani and S. Murai, J. Org. Chem., 66, 169 (2001); [c] A. R.
Katritzky, S. Meha, H. Y. He and X. Cui, J. Org. Chem., 65, 4364
(2000); [d] H. Stamm and L. Schneider, Chem. Ber., 108, 500
(1975); [e] H. Stamm, Chem. Ber., 99, 2556 (1966); [f] J. Lehmann
and H. Wamhoff, Synthesis, 546 (1973).
[11a] K. Yamagata, H. Maruoka, Y. Hashimoto and M.
Yamazaki, Heterocycles, 29, 5 (1989); [b] H. Maruoka, K. Yamagata
and M. Yamazaki, Liebigs Ann. Chem., 625 (1993).
[12] T. Matsuda, K. Yamagata, Y. Tomioka and M. Yamazaki, Chem. Pharm. Bull., 33, 937 (1985).
[13] H. Maruoka, K. Yamagata and M. Yamazaki, Heterocycles, 31, 2011 (1990).