A novel sodium iodide-promoted ring transformation of 2-amino-4,5-dihydro-3-furancarbonitriles to 2-pyrrolidinones and dihydropyrans

Article abstract of DOI:10.3987/com-07-s(w)16

A novel and efficient approach to 2-pyrrolidinones and dihydropyrans via the ring transformation of 3-phenacylated tetrahydro-2-imino-3-furancarbonitriles in the presence of sodium iodide is described. The key feature in the ring transformation is that C-

Full text of DOI:10.3987/com-07-s(w)16

HETEROCYCLES, Vol. 74, 2007
383
HETEROCYCLES, Vol. 74, 2007, pp. 383 -396. © The Japan Institute of Heterocyclic Chemistry
Received, 24th July, 2007, Accepted, 18th September, 2007, Published online, 20th September, 2007. COM-07-S(W)16
A NOVEL SODIUM IODIDE-PROMOTED RING TRANSFORMATION
OF
2-AMINO-4,5-DIHYDRO-3-FURANCARBONITRILES
TO
2-PYRROLIDINONES AND DIHYDROPYRANS
Hiroshi Maruoka, Fumi Okabe, and Kenji Yamagata*
Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma,
Jonan-ku, Fukuoka 814-0180, Japan
e-mail:yamagata@fukuoka-u.ac.jp
Abstract – A novel and efficient approach to 2-pyrrolidinones and dihydropyrans
via the ring transformation of 3-phenacylated
tetrahydro-2-imino-3-furancarbonitriles in the presence of sodium iodide is
described. The key feature in the ring transformation is that C-phenacylation of
2-amino-4,5-dihydro-3-furancarbonitriles using phenacyl bromides, e.g. phenacyl
bromide, 4-chlorophenacyl bromide and 4-methoxyphenacyl bromide, proceeds
smoothly and the ring-opening intermediate having leaving group such as iodide
ion is produced.
INTRODUCTION
γ-Lactams1-5 and dihydropyrans6-8 are important synthetic targets due to their occurrence in numerous
natural products and biologically active compounds. The γ-lactam system occurs in pyrrolidine alkaloids
and in γ-aminobutyric acid analogues.9-11 Dihydropyrans have been proven to be particularly useful in the
synthesis of cyclic components of macrocyclic antibiotics12,13 and also as precursors in the preparation of
C-glycosides.14 In the past several years, a number of methods for construction of γ-lactams15-21 and
dihydropyrans22-25 have been developed. Although these methods are efficient and selective pathways for
the formation of γ-lactams (2-pyrrolidinones) and dihydropyrans, these are still interest to develop a new
methodology for the efficient synthesis of these compounds. Continuing with our interest in this area, we
focused our attention on the development of a new method for the synthesis of 2-pyrrolidinones and
dihydropyrans, and now report the results of our investigation, a ring transformation of 3-phenacylated
tetrahydro-2-imino-3-furancarbonitriles in the presence of sodium iodide.
This paper is dedicated to Professor Dr. Ekkehard Winterfeldt on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 74, 2007
RESULTS AND DISCUSSION
In the course of our studies on heterocyclic β-enaminonitriles, we have already investigated the synthesis
of 3-pyrrolidinecarbonitriles by the reaction of 2-amino-4,5-dihydro-3-furancarbonitriles with sodium
iodide26-28 (Scheme 1). However, when we tried the similar sodium iodide-mediated ring transformation
using
4,5-dihydro-2-(phenylamino)-3-furancarbonitrile
as
the
substrate,
the
desired
2-oxo-1-phenyl-3-pyrrolidinecarbonitrile was not detected at all but instead cyclopropane derivative was
obtained.
CN
CN
NaI
O
N
ref. 26, 27
O
O
O
NHCOC6H5
COC6H5
CN
CN
NaI
Et
ref. 28
O
NHCO2Et
N
H
CN
CN
NaI
CN
O
N
CONHC6H5
NHC6H5
C6H5
not obtained
Scheme 1
In our previous paper, we have reported the C-phenacylation29 and C-acetylation30 of
2-amino-4,5-dihydro-3-furancarbonitriles with phenacyl bromide or acetyl chloride (Scheme 2).
Encouraged by these results, we envisioned that the ring opening of 3-phenacylated
tetrahydro-2-imino-3-furancarbonitriles 4a-c with iodide ion would afford attractive ring-opening
CN
CN
CH2COC6H5
+
+
C6H5COCH2Br
ref.29
O
O
NH2
O
O
NH
CN
CN
N
COMe
MeCOCl
ref.30
Cl
N
Scheme 2

HETEROCYCLES, Vol. 74, 2007
385
CN
CN
CN
CH2COR
RCOCH2Br, NaH
O
NC6H5
O
O
4a-c
NHC6H5
NC6H5
1
NaI
CN
CN
CH2COR
CH2COR
O
N
I
O
N
C6H5
C6H5
A
5a-c
a: R = C6H5, b: R = 4-Cl-C6H4, c: R = 4-MeO-C6H4
Scheme 3
intermediate A, and that a subsequent intramolecular cyclization of A would give 2-pyrrolidinones 5a-c
(Scheme 3).
When a mixture of 4,5-dihydro-2-(phenylamino)-3-furancarbonitrile (1) and phenacyl bromides, e.g.
phenacyl
bromide,
4-cholorophenacyl
bromide
and
4-methoxyphenacyl
bromide,
in
DMF in the presence of sodium hydride was stirred at room temperature for 1 hour according to our
previous procedure,29 3-phenacylated tetrahydro-2-imino-3-furancarbonitriles 4a-c were obtained in
moderate yields (Scheme 3 and entries 1-3 in Table 1). The IR spectra of 4a-c display bands near 2240
cm-1 due to a non-conjugated cyano group and near 1720 cm-1 due to a carbonyl group. Elemental
1
13
analyses, mass spectra, H and C NMR spectra of 4a-c are consistent with the assigned structures (see
experimental section).
In the next step, we examined the ring transformation of the imino derivatives 4a-c into the
2-pyrrolidinones 5a-c. As a consequence, when 4a-c were treated with sodium iodide in DMF at 150 °C
for 2 hours, the expected 2-pyrrolidinones 5a-c were produced in good yields (Scheme 3 and entries 1-3
in Table 1). The IR spectra of 5a-c display bands near 2240 cm-1 due to a non-conjugated cyano group,
near 1710 cm-1 due to a carbonyl group and near 1680 cm-1 due to an amido group. The 1H NMR spectra
of 5a-c exhibit two one-proton doublets near δ 4 attributable to the phenacyl methylene protons. The 13C
NMR spectra of 5a-c show a signal near δ 118 due to the cyano carbon, a signal near δ 167 due to the
amido carbonyl carbon and a signal near δ 193 due to the phenacyl carbonyl carbon. Elemental analyses
and spectral data of 5a-c are consistent with the proposed structures (see experimental section). This
indicates that sodium iodide plays a key role in the ring transformation mechanism.

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HETEROCYCLES, Vol. 74, 2007
Table 1. Synthesis and reaction of 4a-c according to Scheme 3.
Entry
R
Product 4 Yield (%) of 4 Product 5 Yield (%) of 5
C6H5
47
72
76
4a
4b
4c
1
2
3
5a
5b
5c
95
92
91
4-Cl-C6H4
4-MeO-C6H4
On the basis of these results, we have tried to directly convert 1 into 2-pyrrolidinones 5 in a one-pot
process. The results are summarized in Table 2. Indeed, when a mixture of 1 and phenacyl bromides in
DMF in the presence of sodium hydride was stirred at room temperature for 1 hour and then the reaction
mixture was treated with sodium iodide at 150 °C for 2 hours, the 2-pyrrolidinones 5a-c were obtained in
moderate yields (entries 1-3 in Table 2). Similarly, the reactions of 4,5-dihydro-2-(4-substituted
phenylamino)-3-furancarbonitriles 2 and/or 3 with phenacyl bromides gave the corresponding ring
transformation products 6a-c and 7a-c (entries 4-9 in Table 2). By comparison of the IR spectra, NMR
spectra, mass spectra and elemental analyses of 6 and 7, it seems that the structural assignments given to
these compounds are correct.
Table 2. Synthesis of 2-pyrrolidinones 5-7 starting from 1-3.
CN
CN
CH2COR
1) RCOCH2Br, NaH
2) NaI
O
N
O
NHR'
R'
5a-c, 6a-c, 7a-c
1-3
Product
5a
Yield (%)
Entry
Substrate R'
R
67
71
72
55
70
75
79
68
67
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
3
3
3
C6H5
C6H5
C6H5
5b
4-Cl-C6H4
5c
C6H5
4-MeO-C6H4
C6H5
6a
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-MeO-C6H4
4-Cl-C6H4
6b
6c
4-MeO-C6H4
C6H5
7a
4-Cl-C6H4
7b
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
7c

HETEROCYCLES, Vol. 74, 2007
387
We have examined the hydrolysis of 4a in order to confirm its structure (Scheme 4). Treatment of
compound 4a with 5% hydrochloric acid produced the γ-lactone 8 (85%), which was identical with an
authentic sample prepared from γ-lactone 9 and phenacyl bromide.29 Furthermore, the reactions of
2-pyrrolidinone 1031 with phenacyl bromides in the presence of sodium hydride gave the corresponding
2-pyrrolidinones 5a-c (5a: 78%, 5b: 82%, 5c: 76%), which were identical with authentic samples
prepared according to Scheme 3.
CN
CN
CH2COC6H5
C6H5COCH2Br
ref.29
5% HCl
4a
O
O
O
O
9
8
R
5
a
CN
RCOCH2Br
C6H5
5a-c
O
N
b
c
4-Cl-C6H4
C6H5
4-MeO-C6H4
10
Scheme 4
During
the
aforementioned
sodium
iodide-promoted
ring
transformation
of
2-amino-4,5-dihydro-3-furancarbonitriles, we found that 3-phenacylated imines B, which were readily
produced from 1132 and phenacyl bromides, reacted with sodium iodide to yield dihydropyrans 12a-c
(12a: 32%, 12b: 27%, 12c: 8%) (Scheme 5). The IR spectra of 12a-c display bands near 2240 cm-1 due to
a non-conjugated cyano group, near 1700 cm-1 due to an amido carbonyl group. The 1H NMR spectra of
12a-c exhibit a one-proton singlet near δ 5.7 attributable to the olefin proton and two one-proton singlets
near δ 7.7 assignable to the amido protons. The 13C NMR spectra of 12a-c show a signal near δ 120 due
to the cyano carbon and a signal near δ 168 due to the amido carbonyl carbon. Elemental analyses and
spectral data of 12a-c are consistent with the proposed structures (see experimental section). In this case,
the expected 2-pyrrolidinones were not detected at all. The reason for this change of behavior is not clear
at present. The formation of dihydropyrans 12 can be rationalized by the mechanism shown in Scheme 5.
One explanation could reply on the fact that a transformation of the carboxamide anion C to the enolate
anion D easily occurs because the intramolecular cyclization of D is more reactive than that of C.
Therefore, it is proposed that in the reaction of B with sodium iodide, the intermediate D could undergo
intramolecular cyclization with elimination of iodide ion to form dihydropyrans 12a-c.

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HETEROCYCLES, Vol. 74, 2007
CN
CN
CN
CH2COR
CH2COR
RCOCH2Br
NaI
I
O
HN
O
NH
O
NH2
C
B
11
CN
CONH2
R
CN
NC
CONH2
CONH2
I
I
O
O
O
R
12a-c
R
D
a: R = C6H5, b: R = 4-Cl-C6H4, c: R = 4-MeO-C6H4
Scheme 5
In conclusion, we have developed a novel and efficient methodology to prepare 2-pyrrolidinones and
dihydropyrans via the ring transformation of 2-amino-4,5-dihydro-3-furancarbonitriles. A key step is the
generation of an intermediate carboxamide anion having leaving group such as iodide ion through the ring
opening of 3-phenacylated tetrahydro-2-imino-3-furancarbonitriles, which are produced by the reaction of
2-amino-4,5-dihydro-3-furancarbonitriles with phenacyl bromides, in the presence of sodium iodide. This
method is useful because of the easy of operation.
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded on a JASCO FT/IR-230 spectrometer or
1
FT/IR-4100 spectrometer. The H and 13C NMR spectra were measured with a JEOL JNM-A500
1
13
spectrometer at 500.0 and 125.65 MHz, respectively. The H and C chemical sifts (δ) are reported in
parts per million (ppm) relative to tetramethylsilane as internal standard. Positive FAB mass spectra were
obtained on a JEOL JMS-700T spectrometer. Elemental analyses were performed on YANACO MT-6
CHN analyzer.
General procedure for the preparation of starting compounds 1-3.
A mixture of 1132 (2.20 g, 20 mmol) and aniline hydrochloride (2.85 g, 22 mmol), 4-chloroaniline
hydrochloride (3.61 g, 22 mmol) or 4-methoxyaniline hydrochloride (3.51 g, 22 mmol) in 1,4-dioxane (10
mL) was stirred at rt for 2 h. After removal of the solvent in vacuo, cold water was added to the residue.
The precipitate was collected by filtration, washed with water, dried and recrystallized from an
appropriate solvent to yield 1-3.

HETEROCYCLES, Vol. 74, 2007
389
4,5-Dihydro-2-(phenylamino)-3-furancarbonitrile (1)
Colorless columns (2.06 g, 55%), mp 112-115 °C (acetone/petroleum ether); IR (KBr): 3208 (NH), 2192
1
(C≡N) cm-1; H NMR (CDCl3): δ 2.50−2.65 (m, 1.6H, 4-H), 2.93 (t, J = 8.9 Hz, 0.4H, 4-H), 3.92 (t, J =
8.7 Hz, 0.8H, 3-H), 4.30-4.38 (m, 0.8H, 5-H), 4.43-4.52 (m, 0.8H, 5-H), 4.55 (t, J = 8.9 Hz, 0.4 H, 5-H),
4.79 (br. s, 0.2H, NH), 7.04-7.16 (m, 3H, aryl H), 7.21-7.38 (m, 2H, aryl H); 13C NMR (CDCl3):
δ 28.4, 28.5 (C-4), 33.0, 53.5 (C-3), 69.8, 71.8 (C-5), 116.5, 119.0 (C≡N), 120.1, 122.8, 123.9, 124.8,
128.7, 129.1, 137.6, 145.2 (C aryl), 155.1, 165.2 (C-2); MS: m/z 187 [M+H]+. Anal. Calcd for C11H10N2O:
C, 70.95; H, 5.41; N, 15.04. Found: C, 70.97; H, 5.50; N, 14.99.
2-[(4-Chlorophenyl)amino]-4,5-dihydro-3-furancarbonitrile (2)
Colorless columns (3.34 g, 76%), mp 141-143 °C (acetone/petroleum ether); IR (KBr): 3211 (NH), 2185
1
(C≡N) cm-1; H NMR (CDCl3): δ 2.52−2.67 (m, 1.2H, 4-H), 2.94 (t, J = 8.7 Hz, 0.8H, 4-H), 3.91 (t, J =
8.7 Hz, 0.6H, 3-H), 4.34-4.39 (m, 0.6H, 5-H), 4.48-4.54 (m, 1.0H, 5-H), 4.51 (br. s, 0.4H, NH), 4.56 (t, J
= 8.7 Hz, 0.4 H, 5-H), 7.07-7.12 (m, 2H, aryl H), 7.22-7.28 (m, 2H, aryl H); 13C NMR (CDCl3):
δ 28.39, 28.44 (C-4), 33.1, 54.0 (C-3), 70.0, 71.9 (C-5), 116.3, 118.8 (C≡N), 121.1, 124.4, 128.7, 129.0,
129.1, 130.1, 136.3, 143.7 (C aryl), 155.5, 164.8 (C-2); MS: m/z 221 [M+H]+. Anal. Calcd for
C11H9ClN2O: C, 59.88; H, 4.11; N, 12.70. Found: C, 59.92; H, 4.14; N, 12.78.
4,5-Dihydro-2-[(4-methoxyphenyl)amino]-3-furancarbonitrile (3)
Colorless prisms (3.06 g, 71%), mp 99-101 °C (acetone/petroleum ether); IR (KBr): 3212 (NH), 2188
(C≡N) cm-1; 1H NMR (CDCl3): δ 2.49−2.64 (m, 1.4H, 4-H), 2.92 (t, J = 8.7 Hz, 0.6H, 4-H), 3.78 (s, 0.9H,
OCH3), 3.79 (s, 2.1H, OCH3), 3.89 (t, J = 8.5 Hz, 0.7H, 3-H), 4.33-4.38 (m, 0.6H, 5-H), 4.48-4.53 (m,
1.4H, 5-H), 6.60 (br. s, 0.3H, NH), 6.82-6.86 (m, 2H, aryl H), 7.06-7.10 (m, 0.6H, aryl H), 7.16-7.22 (m,
13
1.4H, aryl H); C NMR (CDCl3): δ 28.5, 28.7 (C-4), 33.1, 52.1 (C-3), 55.4, 55.5 (OCH3), 69.7, 71.5
(C-5), 113.8, 114.3 (C aryl), 116.7, 119.2 (C≡N), 123.1, 124.8, 130.3, 138.0, 153.9, 156.9 (C aryl), 157.0,
165.6 (C-2); MS: m/z 217 [M+H]+. Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.95. Found: C,
66.64; H, 5.69; N, 12.88.
General procedure for the preparation of imino derivatives 4a-c from 1 and phenacyl bromides.
To an ice-cooled and stirred mixture of 1 (2.79 g, 15 mmol) in DMF (15 mL) was added 60% NaH (0.60
g, 15 mmol). The stirring was continued at rt until evolution of gas ceased. To the obtained solution was
added phenacyl bromide (2.99 g, 15 mmol), 4-chlorophenacyl bromide (3.50 g, 15 mmol) or
4-methoxyphenacyl bromide (3.44 g, 15 mmol) with stirring and ice-cooling and the mixture was stirred
at rt for 1 h. After removal of the solvent in vacuo, cold water added to the residue. The resulting mixture

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HETEROCYCLES, Vol. 74, 2007
was extracted with AcOEt. The extract was washed with water, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on alumina with CH2Cl2 as the eluent to give
4a-c.
Tetrahydro-3-(2-oxo-2-phenylethyl)-2-(phenylimino)-3-furancarbonitrile (4a)
Colorless prisms (2.14 g, 47%), mp 126-127 °C (acetone/petroleum ether); IR (KBr): 2235 (C≡N), 1700
(C=O) cm-1; 1H NMR (CDCl3): δ 2.46−2.52 (m, 1H, 4-H), 3.04 (ddd, J = 3.1, 6.0, 13.3 Hz, 1H, 4-H), 3.63
(d, J = 18.3 Hz, 1H, CHCOC6H5), 4.10 (d, J = 18.3 Hz, 1H, CHCOC6H5), 4.49-4.56 (m, 2H, 5-H),
7.08-7.14 (m, 3H, aryl H), 7.28-7.32 (m, 2H, aryl H), 7.48-7.52 (m, 2H, aryl H), 7.60-7.64 (m, 1H, aryl
13
H), 7.99-8.01 (m, 2H, aryl H); C NMR (CDCl3): δ 34.4 (C-4), 41.2 (C-3), 44.1 (CH2COC6H5), 68.7
(C-5), 118.9 (C≡N), 122.7, 124.7, 128.1, 128.7, 128.9, 134.0, 135.8, 145.3 (C aryl), 157.8 (C-2), 194.5
(C=O); MS: m/z 305 [M+H]+. Anal. Calcd for C19H16N2O2: C, 74.98; H, 5.30; N, 9.20. Found: C, 75.03; H,
5.32; N, 9.10.
3-[2-(4-Chlorophenyl)-2-oxoethyl]tetrahydro-2-(phenylimino)-3-furancarbonitrile (4b)
Colorless prisms (3.66 g, 72%), mp 205-206 °C (acetone/petroleum ether); IR (KBr): 2251 (C≡N), 1690
1
(C=O) cm-1; H NMR (DMSO-d6): δ 2.53−2.60 (m, 1H, 4-H), 2.87 (ddd, J = 4.9, 7.2, 13.3 Hz, 1H, 4-H),
3.97 [d, J = 18.6 Hz, 1H, CHCOC6H4-Cl(4)], 4.05 [d, J = 18.6 Hz, 1H, CHCOC6H4-Cl(4)], 4.43-4.48 (m,
1H, 5-H), 4.50-4.55 (m, 1H, 5-H), 7.04-7.10 (m, 3H, aryl H), 7.30-7.33 (m, 2H, aryl H), 7.62-7.65 (m, 2H,
aryl H), 8.04-8.07 (m, 2H, aryl H); 13C NMR (DMSO-d6): δ 33.2 (C-4), 41.0 (C-3), 43.4
[CH2COC6H4-Cl(4)], 69.2 (C-5), 119.6 (C≡N), 122.5, 124.2, 128.6, 128.9, 130.0, 134.5, 138.7, 145.5 (C
aryl), 159.2 (C-2), 194.5 (C=O); MS: m/z 339 [M+H]+. Anal. Calcd for C19H15ClN2O2• 0.1 H2O: C, 67.00;
H, 4.50; N, 8.22. Found: C, 67.04; H, 4.57; N, 8.09.
Tetrahydro-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2-(phenylimino)-3-furancarbonitrile (4c)
Colorless prisms (3.82 g, 76%), mp 142-143 °C (acetone/petroleum ether); IR (KBr): 2245 (C≡N), 1693
(C=O) cm-1; 1H NMR (CDCl3): δ 2.46−2.53 (m, 1H, 4-H), 3.02 (ddd, J = 3.1, 6.0, 13.2 Hz, 1H, 4-H), 3.56
[d, J = 18 Hz, 1H, CHCOC6H4-OCH3(4)], 3.88 (s, 3H, OCH3), 4.04 [d, J = 18 Hz, 1H,
CHCOC6H4-OCH3(4)], 4.48-4.53 (m 2H, 5-H), 6.94-6.97 (m, 2H, aryl H), 7.08-7.25 (m, 3H, aryl H),
13
7.29-7.32 (m, 2H, aryl H), 7.95-7.99 (m, 2H, aryl H); C NMR (CDCl3): δ 34.4 (C-4), 41.3 (C-3), 43.8
[CH2COC6H4-OCH3(4)], 55.5 (OCH3), 68.7 (C-5), 114.0 (C aryl), 119.0 (C≡N), 122.7, 124.6, 128.6,
128.9, 130.5, 145.4, 158.0 (C aryl), 164.2 (C-2), 192.8 (C=O); MS: m/z 335 [M+H]+. Anal. Calcd for
C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C, 71.86; H, 5.50; N, 8.38.

HETEROCYCLES, Vol. 74, 2007
391
General procedure for the preparation of 2-pyrrolidinones 5a-c from 4a-c and sodium iodide.
A mixture of 4a-c (5 mmol) and NaI (1.50 g, 10 mmol) in DMF (5 mL) were stirred at 150 °C for 2 h.
After removal of the solvent in vacuo, cold water was added to the residue. The resulting mixture was
extracted with AcOEt. The extract was washed with water, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel with CH2Cl2 as the eluent to afford
5a-c.
2-Oxo-3-(2-oxo-2-phenylethyl)-1-phenyl-3-pyrrolidinecarbonitrile (5a)
Colorless prisms (1.45 g, 95%), mp 139-140 °C (acetone/petroleum ether); IR (KBr): 2241 (C≡N), 1712,
1687 (C=O) cm-1; 1H NMR (CDCl3): δ 2.42−2.49 (m, 1H, 4-H), 2.93 (ddd, J = 2.7, 7.6, 13.4 Hz, 1H, 4-H),
3.61 (d, J = 18 Hz, 1H, CHCOC6H5), 3.94-3.98 (m, 1H, 5-H), 3.95 (d, J = 18 Hz, 1H, CHCOC6H5),
4.08-4.15 (m, 1H, 5-H), 7.21-7.26 (m, 1H, aryl H), 7.40-7.43 (m, 2H, aryl H), 7.47-7.51 (m, 2H, aryl H),
7.60-7.64 (m, 3H, aryl H), 7.96-7.98 (m, 2H, aryl H); 13C NMR (CDCl3): δ 29.6 (C-4), 42.87
(CH2COC6H5), 42.91 (C-3), 46.0 (C-5), 118.8 (C≡N), 120.5, 125.8, 128.1, 128.9, 129.1, 134.0, 135.7,
138.5 (C aryl), 166.8 (C-2), 194.5 (C=O); MS: m/z 305 [M+H]+. Anal. Calcd for C19H16N2O2: C, 74.98; H,
5.30; N, 9.20. Found: C, 75.07; H, 5.44; N, 9.06.
3-[2-(4-Chlorophenyl)-2-oxoethyl]-2-oxo-1-phenyl-3-pyrrolidinecarbonitrile (5b)
Colorless prisms (1.56 g, 92%), mp 158-159 °C (acetone/petroleum ether); IR (KBr): 2231 (C≡N), 1713,
1685 (C=O) cm-1; 1H NMR (CDCl3): δ 2.41−2.48 (m, 1H, 4-H), 2.93 (ddd, J = 2.8, 7.4, 13.4 Hz, 1H, 4-H),
3.56 [d, J = 18 Hz, 1H, CHCOC6H4-Cl(4)], 3.91 [d, J = 18 Hz, 1H, CHCOC6H4-Cl(4)], 3.92-3.97 (m, 1H,
5-H), 4.08-4.15 (m, 1H, 5-H), 7.21-7.26 (m, 1H, aryl H), 7.39-7.43 (m, 2H, aryl H), 7.46-7.48 (m, 2H,
13
aryl H), 7.60-7.63 (m, 2H, aryl H), 7.89-7.92 (m, 2H, aryl H); C NMR (CDCl3): δ 29.6 (C-4), 42.8
[CH2COC6H4-Cl(4)], 42.9 (C-3), 46.0 (C-5), 118.6 (C≡N), 120.5, 125.9, 129.1, 129.2, 129.5, 134.1, 138.4,
140.7 (C aryl), 166.7 (C-2), 193.3 (C=O); MS: m/z 339 [M+H]+. Anal. Calcd for C19H15ClN2O2: C, 67.36;
H, 4.46; N, 8.27. Found: C, 67.35; H, 4.54; N, 8.17.
3-[2-(4-Methoxyphenyl)-2-oxoethyl]-2-oxo-1-phenyl-3-pyrrolidinecarbonitrile (5c)
Colorless columns (1.53 g 91%), mp 91-92 °C (acetone/petroleum ether); IR (KBr): 2246 (C≡N), 1708,
1668 (C=O) cm-1; 1H NMR (CDCl3): δ 2.43−2.50 (m, 1H, 4-H), 2.91 (ddd, J = 2.8, 7.6, 13.4 Hz, 1H, 4-H),
3.55 [d, J = 18 Hz, 1H, CHCOC6H4-OCH3(4)], 3.88 (s, 3H, OCH3), 3.89 [d, J = 18 Hz, 1H,
CHCOC6H4-OCH3(4)], 3.92-3.96 (m 1H, 5-H), 4.06-4.12 (m, 1H, 5-H), 6.94-6.96 (m, 2H, aryl H),
7.20-7.24 (m, 1H, aryl H), 7.39-7.42 (m, 2H, aryl H), 7.62-7.63 (m, 2H, aryl H), 7.93-7.95 (m, 2H, aryl
13
H); C NMR (CDCl3): δ 29.6 (C-4), 42.5 [CH2COC6H4-OCH3(4)], 43.0 (C-3), 46.0 (C-5), 55.5 (OCH3),

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114.0 (C aryl), 119.0 (C≡N), 120.5, 125.8, 128.9, 129.1, 130.5, 138.5, 164.2 (C aryl), 167.0 (C-2), 192.8
(C=O); MS: m/z 335 [M+H]+. Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C, 71.80; H,
5.49; N, 8.31.
General procedure for the preparation of 2-pyrrolidinones 5a-c, 6a-c and 7a-c from 1-3.
To an ice-cooled and stirred mixture of 1 (1.86 g, 10 mmol) in DMF (10 mL) was added 60% NaH (0.40
g, 10 mmol). The stirring was continued at rt until evolution of gas ceased. To the obtained mixture was
added phenacyl bromide (1.99 g, 10 mmol), 4-chlorophenacyl bromide (2.33 g, 10 mmol) and
4-methoxyphenacyl bromide (2.29 g, 10 mmol) with stirring and ice-cooling, and the mixture was stirred
at rt for 1 h. To the resulting mixture was added NaI (3.00 g, 20 mmol) with stirring, and then the mixture
was stirred at 150 °C for 2 h. After work-up as described for the preparation of 5a-c, 2-pyrrolidinones
5a-c (5a: 67 %, 5b: 71 %, 5c: 72 %), 6a-c and 7a-c were obtained.
1-(4-Chlorophenyl)-2-oxo-3-(2-oxo-2-phenylethyl)-3-pyrrolidinecarbonitrile (6a)
Colorless plates (1.88 g, 55%), mp 113-114 °C (acetone/petroleum ether); IR (KBr): 2252 (C≡N), 1705,
1687 (C=O) cm-1; 1H NMR (CDCl3): δ 2.44−2.51 (m, 1H, 4-H), 2.91 (ddd, J = 2.8, 7.6, 13.4 Hz, 1H, 4-H),
3.64 (d, J = 18.3 Hz, 1H, CHCOC6H5), 3.91-3.96 (m, 1H, 5-H), 3.93 (d, J = 18.3 Hz, 1H, CHCOC6H5),
4.05-4.11 (m, 1H, 5-H), 7.35-7.39 (m, 2H, aryl H), 7.47-7.51 (m, 2H, aryl H), 7.57-7.63 (m, 3H, aryl H),
13
7.94-7.97 (m, 2H, aryl H); C NMR (CDCl3): δ 29.4 (C-4), 42.8 (CH2COC6H5), 42.9 (C-3), 45.9 (C-5),
118.6 (C≡N), 121.6, 128.1, 128.9, 129.2, 131.1, 134.1, 135.7, 137.0 (C aryl), 166.9 (C-2), 194.4 (C=O);
MS: m/z 339 [M+H]+. Anal. Calcd for C19H15ClN2O2: C, 67.36; H, 4.46; N, 8.27. Found: C, 67.41; H,
4.51; N, 8.21.
1-(4-Chlorophenyl)-3-[2-(4-chlorophenyl)-2-oxoethyl]-2-oxo-3-pyrrolidinecarbonitrile (6b)
Colorless prisms (2.63 g, 70%), mp 146-148 °C (acetone/petroleum ether); IR (KBr): 2232 (C≡N), 1701,
1682 (C=O) cm-1; 1H NMR (CDCl3): δ 2.43−2.50 (m, 1H, 4-H), 2.91 (ddd, J = 2.8, 7.5, 13.4 Hz, 1H, 4-H),
3.59 [d, J = 18.3 Hz, 1H, CHCOC6H4-Cl(4)], 3.89 [d, J = 18.3 Hz, 1H, CHCOC6H4-Cl(4)], 3.91-3.96 (m,
1H, 5-H), 4.06-4.11 (m, 1H, 5-H), 7.35-7.39 (m, 2H, aryl H), 7.45-7.48 (m, 2H, aryl H), 7.56-7.60 (m, 2H,
aryl H), 7.88-7.91 (m, 2H, aryl H); 13C NMR (CDCl3): δ 29.4 (C-4), 42.7 [CH2COC6H4-Cl(4)], 42.8 (C-3),
45.9 (C-5), 118.5 (C≡N), 121.6, 129.2, 129.3, 129.5, 131.2, 134.0, 137.0, 140.8 (C aryl), 166.7 (C-2),
193.3 (C=O); MS: m/z 374 [M+H]+. Anal. Calcd for C19H14Cl2N2O2: C, 61.14; H, 3.78; N, 7.51. Found: C,
61.17; H, 3.84; N, 7.36.
1-(4-Chlorophenyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2-oxo-3-pyrrolidinecarbonitrile (6c)

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393
Colorless prisms (2.77 g, 75%), mp 164-165 °C (acetone/petroleum ether); IR (KBr): 2322 (C≡N), 1713,
1671 (C=O) cm-1; 1H NMR (CDCl3): δ 2.45−2.52 (m, 1H, 4-H), 2.89 (ddd, J = 2.9, 7.5, 13.3 Hz, 1H, 4-H),
3.59 [d, J = 18 Hz, 1H, CHCOC6H4-OCH3(4)], 3.87 [d, J = 18 Hz, 1H, CHCOC6H4-OCH3(4)], 3.88 (s, 3H,
OCH3), 3.90-3.95 (m 1H, 5-H), 4.04-4.10 (m, 1H, 5-H), 6.93-6.96 (m, 2H, aryl H), 7.35-7.38 (m, 2H, aryl
H), 7.58-7.61 (m, 2H, aryl H), 7.92-7.95 (m, 2H, aryl H); 13C NMR (CDCl3): δ 29.4 (C-4), 42.4
[CH2COC6H4-OCH3(4)], 42.9 (C-3), 45.9 (C-5), 55.6 (OCH3), 114.1 (C aryl), 118.8 (C≡N), 121.6, 128.8,
129.1, 130.5, 131.0, 137.1, 164.3 (C aryl), 167.1 (C-2), 192.8 (C=O); MS: m/z 369 [M+H]+. Anal. Calcd
for C20H17ClN2O3: C, 65.13; H, 4.65; N, 7.60. Found: C, 65.14; H, 4.67; N, 7.50.
1-(4-Methoxyphenyl)-2-oxo-3-(2-oxo-2-phenylethyl)-3-pyrrolidinecarbonitrile (7a)
Colorless needles (2.21 g, 79%), mp 119-120 °C (acetone/petroleum ether); IR (KBr): 2238 (C≡N), 1730,
1679 (C=O) cm-1; 1H NMR (CDCl3): δ 2.40−2.47 (m, 1H, 4-H), 2.91 (ddd, J = 2.9, 7.5, 13.4 Hz, 1H, 4-H),
3.59 (d, J = 18 Hz, 1H, CHCOC6H5), 3.81 (s, 3H, OCH3), 3.87-3.92 (m, 1H, 5-H), 3.94 (d, J = 18 Hz, 1H,
CHCOC6H5), 4.03-4.09 (m, 1H, 5-H), 6.91-6.95 (m, 2H, aryl H), 7.47-7.53 (m, 4H, aryl H), 7.59-7.63 (m,
1H, aryl H), 7.95-7.98 (m, 2H, aryl H); 13C NMR (CDCl3): δ 29.7 (C-4), 42.7 (C-3), 42.9 (CH2COC6H5),
46.4 (C-5), 55.5 (OCH3), 114.3 (C aryl), 118.9 (C≡N), 122.4, 128.1, 128.8, 131.6, 134.0, 135.8, 157.6 (C
aryl), 166.6 (C-2), 194.5 (C=O); MS: m/z 335 [M+H]+. Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N,
8.38. Found: C, 71.82; H, 5.46; N, 8.29.
3-[2-(4-Chlorophenyl)-2-oxoethyl]-1-(4-methoxyphenyl)-2-oxo-3-pyrrolidinecarbonitrile (7b)
Colorless prisms (2.49 g, 68%), mp 179-180 °C (acetone/petroleum ether); IR (KBr): 2232 (C≡N), 1694,
1681 (C=O) cm-1; 1H NMR (CDCl3): δ 2.39−2.46 (m, 1H, 4-H), 2.91 (ddd, J = 2.8, 7.4, 13.4 Hz, 1H, 4-H),
3.54 [d, J = 18 Hz, 1H, CHCOC6H4-Cl(4)], 3.81 (s, 3H, OCH3), 3.86-3.91 (m, 1H, 5-H), 3.90 [d, J = 18
Hz, 1H, CHCOC6H4-Cl(4)], 4.03-4.09 (m, 1H, 5-H), 6.91-6.94 (m, 2H, aryl H), 7.44-7.51 (m, 4H, aryl H),
13
7.88-7.91 (m, 2H, aryl H); C NMR (CDCl3): δ 29.7 (C-4), 42.6 (C-3), 42.9 [CH2COC6H4-Cl(4)], 46.4
(C-5), 55.5 (OCH3), 114.3 (C aryl), 118.9 (C≡N), 122.4, 129.2, 129.5, 131.4, 134.1, 140.6, 157.6 (C aryl),
166.4 (C-2), 193.4 (C=O); MS: m/z 369 [M+H]+. Anal. Calcd for C20H17ClN2O3: C, 65.13; H, 4.56; N,
7.60. Found: C, 65.21; H, 4.65; N, 7.50.
1-(4-Methoxyphenyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2-oxo-3-pyrrolidinecarbonitrile (7c)
Colorless prisms (2.43 g, 67%), mp 162-164 °C (acetone); IR (KBr): 2242 (C≡N), 1701, 1683 (C=O)
cm-1; 1H NMR (CDCl3): δ 2.41−2.48 (m, 1H, 4-H), 2.90 (ddd, J = 2.9, 7.5, 13.4 Hz, 1H, 4-H), 3.53 [d, J =
18 Hz, 1H, CHCOC6H4-OCH3(4)], 3.81 (s, 3H, OCH3), 3.86-3.90 (m, 1H, 5-H), 3.87 (s, 3H, OCH3), 3.88
[d, J = 18 Hz, 1H, CHCOC6H4-OCH3(4)], 4.01-4.07 (m, 1H, 5-H), 6.91-6.96 (m, 4H, aryl H), 7.26-7.53

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(m, 2H, aryl H), 7.92-7.95 (m, 2H, aryl H); 13C NMR (CDCl3): δ 29.7 (C-4), 42.5
[CH2COC6H4-OCH3(4)], 42.7 (C-3), 46.4 (C-5), 55.48, 55.53 (OCH3), 114.0, 114.3 (C aryl), 119.0 (C≡N),
122.3, 128.9, 130.4, 131.6, 157.5, 164.2 (C aryl), 166.7 (C-2), 192.9 (C=O); MS: m/z 365 [M+H]+. Anal.
Calcd for C21H20N2O4: C, 69.22; H, 5.53; N, 7.69. Found: C, 69.20; H, 5.57; N, 7.61.
The preparation of 8 from 4a.
After a mixture of 4a (1.54 g, 5 mmol) and 5% HCl (40 mL) was stirred at rt for 20 h, cold water was
added to the reaction mixture. The precipitate was collected by filtration, washed with water, dried and
recrystallized from acetone/petroleum ether to yield 8 (85%), which was identical with an authentic
sample29 prepared from 9 and phenacyl bromide on the basis of a mixed melting point determination and
comparison of the IR spectra.
The preparation of 5a-c from 10 and phenacyl bromides.
To an ice-cooled and stirred mixture of 1031 (0.56 g, 3 mmol) in DMF (3 mL) was added 60% NaH (0.12
g, 3 mmol). The stirring was continued at rt until evolution of gas ceased. To the obtained mixture was
added phenacyl bromide (0.60 g, 3 mmol), 4-chlorophenacyl bromide (0.70 g, 3 mmol) or
4-methoxyphenacyl bromide (0.69 g, 3 mmol) with stirring and ice-cooling, and then the mixture was
stirred at rt for 2 h. After removal of the solvent in vacuo, cold water was added to the residue. The
resulting mixture was extracted with AcOEt. After work-up as described for the preparation of 4a-c, 5a-c
were obtained in 78%, 82% and 76% yields, respectively. The melting points and IR spectra of 5a-c
coincided with those of authentic samples prepared from 4a-c and phenacyl bromides.
General procedure for the preparation of dihydropyrans 12a-c from 11.
To an ice-cooled and stirred mixture of 11 (1.10 g, 10 mmol) in DMF (10 mL) was added 60% NaH (0.40
g, 10 mmol). The stirring was continued at rt until evolution of gas ceased. To the obtained mixture was
added phenacyl bromide (1.99 g, 10 mmol), 4-chlorophenacyl bromide (2.33g, 10 mmol) or
4-methoxyphenacyl bromide (2.29 g, 10 mmol) with stirring and ice-cooling, and then the mixture was
stirred at rt for 1 h. To the resulting mixture was added NaI (1.50 g, 10 mmol) with stirring, and then the
mixture was stirred at 100 °C for 4 h. After removal of the solvent in vacuo, cold water was added to the
residue. The resulting mixture was extracted with AcOEt. The extract was washed with water, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel
with CH2Cl2 as the eluent to give 12a-c.
4-Cyano-3,4-dihydro-6-phenyl-2H-pyran-4-carboxamide (12a)

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395
Colorless needles (0.73 g, 32%), mp 167-169 °C (acetone/petroleum ether); IR (KBr): 3410, 3169 (NH),
1
2234 (C≡N), 1690 (C=O) cm-1; H NMR (DMSO-d6): δ 2.30 (ddd, J = 3.4, 7.0, 14.0 Hz, 1H, 3-H), 2.45
(ddd, J = 3.4, 7.7, 13.8 Hz, 1H, 3-H), 4.19-4.30 (m, 2H, 2-H), 5.69 (s, 1H, 5-H), 7.39-7.43 (m, 3H, aryl H),
7.60-7.64 (m, 2H, aryl H), 7.72 (s, 1H, NH), 7.79 (s, 1H, NH); 13C NMR (DMSO- d6): δ 29.4 (C-3), 40.5
(C-4), 63.3 (C-2), 92.5 (C-5), 120.5 (C≡N), 124.9, 128.3, 129.2, 133.8 (C aryl), 153.5 (C-6), 168.0
(C=O); MS: m/z 229 [M+H]+. Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.51;
H, 5.37; N, 12.29.
6-(4-Chlorophenyl)-4-cyano-3,4-dihydro-2H-pyran-4-carboxamide (12b)
Colorless columns (0.72 g, 27%), mp 164-165 °C (acetone/petroleum ether); IR (KBr): 3377, 3163 (NH),
1
2245 (C≡N), 1700 (C=O) cm-1; H NMR (DMSO- d6): δ 2.31 (ddd, J = 3.7, 6.6, 14.0 Hz, 1H, 3-H), 2.43
(ddd, J = 3.7, 7.7, 13.9 Hz, 1H, 3-H), 4.20-4.30 (m, 2H, 2-H), 5.74 (s, 1H, 5-H), 7.45-7.48 (m, 2H, aryl H),
7.63-7.66 (m, 2H, aryl H), 7.73 (s, 1H, NH), 7.79 (s, 1H, NH); 13C NMR (DMSO- d6): δ 29.3 (C-3), 40.5
(C-4), 63.4 (C-2), 93.1 (C-5), 120.4 (C≡N), 126.7, 128.3, 132.7, 133.8 (C aryl), 153.5 (C-6), 167.9
(C=O); MS: m/z 263 [M+H]+. Anal. Calcd for C13H11ClN2O2: C, 59.44; H, 4.22; N, 10.66. Found: C,
59.56; H, 4.31; N, 10.62.
4-Cyano-3,4-dihydro-6-(4-methoxyphenyl)-2H-pyran-4-carboxamide (12c)
Colorless prisms (0.21 g, 8%), mp 163-164 °C (acetone/petroleum ether); IR (KBr): 3429, 3156 (NH),
1
2239 (C≡N), 1715 (C=O) cm-1; H NMR (DMSO- d6): δ 2.28 (ddd, J = 2.7, 6.6, 14.9 Hz, 1H, 3-H), 2.43
(ddd, J = 3.7, 6.9, 15.0 Hz, 1H, 3-H), 3.78 (s, 3H, OCH3), 4.18-4.27 (m, 2H, 2-H), 5.55 (s, 1H, 5-H),
13
6.93-6.97 (m, 2H, aryl H), 7.54-7.57 (m, 2H, aryl H), 7.68 (s, 1H, NH), 7.75 (s, 1H, NH); C NMR
(DMSO- d6): δ 29.4 (C-3), 40.6 (C-4), 55.1 (OCH3), 63.2 (C-2), 90.7 (C-5), 113.6 (C aryl), 120.7 (C≡N),
126.3, 126.4 (C aryl), 153.4 (C-6), 160.0 (C aryl), 168.2 (C=O); MS: m/z 259 [M+H]+. Anal. Calcd for
C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C, 65.12; H, 5.54; N, 10.86.
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