Asymmetric synthesis of 4-substituted 2,6-dioxopiperidine-3-carbonitrile by using thioureacatalyzed asymmetric michael addition

Article abstract of DOI:10.3987/COM-08-S(D)18

An enantioselective Michael addition of several α,β-unsaturated carbonyl compounds with malononitrile catalyzed by a bifunctional thiourea is described. We also demonstrate the transformation of Michael adduct into an enantiomerically enriched functionali

Full text of DOI:10.3987/COM-08-S(D)18

HETEROCYCLES, Vol. 79, 2009
573
HETEROCYCLES, Vol. 79, 2009, pp. 573 - 582. © The Japan Institute of Heterocyclic Chemistry
Received, 6th September, 2008, Accepted, 22nd October, 2008, Published online, 30th October, 2008.
DOI: 10.3987/COM-08-S(D)18
ASYMMETRIC SYNTHESIS OF 4-SUBSTITUTED
2,6-DIOXOPIPERIDINE-3-CARBONITRILE BY USING THIOUREA-
CATALYZED ASYMMETRIC MICHAEL ADDITION†
Tsubasa Inokuma, Yuuki Nagamoto, Shota Sakamoto, Hideto Miyabe,
Kiyosei Takasu, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida,
Sakyo-ku, Kyoto 606-8501, Japan
E-mail: takemoto@pharm.kyoto-u.ac.jp
Abstract – An enantioselective Michael addition of several α,β-unsaturated
carbonyl compounds with malononitrile catalyzed by a bifunctional thiourea is
described. We also demonstrate the transformation of Michael adduct into an
enantiomerically enriched functionalized piperidine.
INTRODUCTION
Enantioselective formation of carbon-carbon bonds in a catalytic manner has been the subject of
significant interest in the field of synthetic chemistry. Among a lot of excellent efforts on the catalytic
enantioselective reactions, an asymmetric Michael reaction of α,β-unsaturated carbonyl compounds with
activated methylene compounds, such as nitroalkane, 1,3-diketones and malononitrile, has been
extensively studied.1 We have reported that bifunctinal thiourea catalyst (1)2 promoted the
enantioselective Michael reaction of α,β-unsaturated imides with several activated methylene compounds
(Scheme 1).3
The use of 2-methoxybenzimide 2, in which an intramolecular hydrogen bond between the methoxy
group and the imide proton would be formed, accelerated the reaction rate and achieved excellent
Scheme 1. Asymmetric Michael reaction catalyzed by bifunctional thioures 1
CF3
NC
CN
O
O
O
O
CH2(CN)2
thiourea 1
S
R
N
R
N
N
H
F3C
N
H
H
H
92-95% yield
90-93% ee
MeO
N
MeO
Me
Me
2
3
1
†This paper is dedicated to the memory of Dr. John Daly.

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HETEROCYCLES, Vol. 79, 2009
asymmetric induction in the thiourea-catalyzed reaction.3b We envisioned that the product 3 might be a
precursor of chiral piperidine derivatives such as 4 by the intramolecular cyclization (Scheme 2).4 A
piperidine ring is a ubiquitous molecular skeleton, which often appears in naturally occurring substances
such as antimalarial nakadomarin A 55 as well as synthetic pharmaceuticals such as anti-depressive
paroxetine 6.6 With an aim of the synthesis of 5, we further explored several substrates 7 bearing a 3-furyl
group as the β-substituent to reveal the effect of the substituent (X) of Michael acceptors 7 on the
reactivity with malononitrile. In addition, synthetic application of the Michael adducts 8 for the
preparation of chiral piperidine-2,6-dione derivative 10 was examined.
Scheme 2. Conversion of the Michael adducts to piperidine derivatives
E
NC
R
CN
O
O
O
N
D
O
NH
NC
R
H
NR'
N
N
A
B
H
O
C
O
MeO
H
F
F
3
4
nakadomarin A (5) (−)-paroxetine (6)
RESULTS AND DISCUSSION
In an initial study, we selected 2-methoxybenzimide 7a as a substrate for the asymmetric Michael
reaction with malononitrile. In contrast to 2 (R = Ph),3b the reaction of 7a proceeded very slowly due to
the electron-rich furyl group (Scheme 3). In addition, simple benzimide 7b was much poorer substrate for
this reaction as expected. Then, in order to improve the reactivity of this reaction, we screened several
α,β-unsaturated carbonyl compounds 7c and 7d together with the imides 7e and 7f. The reaction of 7c-f
with malononitrile (2.0 equiv.) was carried out in toluene (0.1 M) at ambient temperature in the presence
of 10 mol% of 1 until the substrate was completely consumed or, otherwise, for 1 week (168 h). The
results are summarized in Scheme 3. The reaction of phenylketone 7c took place to give the desired
Michael adduct 8c in 63% yield.7 However, the reaction did not complete within 168 h and the ee was
modelate (70% ee). In a case of 7d bearing N-methyl imidazole as the acyl moiety, the reaction was
complete within 64 h to give 8d in 91% yield with 64% ee.8 As a result, all these substrates were inferior
to 7a in terms of both the reactivity and the enantioselectivity. Therefore, we reexamined other imides 7e
and 7f. We speculated that if the methoxy group of 7a was replaced by the fluoro group, its
electron-withdrawing property as well as its potential ability as a proton acceptor would make the
substrates 7e and 7f more reactive than 7a. When o-fluorobenzimide 7e was utilized as a substrate for this

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575
reaction, the reaction was complete within 24 h and desired product 8e was obtained in good yield with
95% ee. On the other hand, the reaction of 2,6-difluorobenzimide 7f led to significant decrease in both
reactivity and enantioselectivity.
Scheme 3. Thiourea catalyzed asymmetric Michael addition of α,β-unsaturated carbonyl compounds
with malononitrile
NC
CN
O
O
CH2(CN)2 (2.0 equiv.)
thiourea 1 (10 mol%)
X
X
O
O
toluene (0.1 M), rt
7
8
O
O
O
O
O
N
H
N
Ph
O
O
O
H
MeO
7a
7b
107 h
7c
168 h
31 h
91% yield
92% ee
88% yield
90% ee
63% yield
70% ee
O
O
O
O
O
F
N
N
N
O
O
O
H
H
N
Me
F
F
7d
7f
168 h
7e
24 h
64 h
91% yield
64% ee
88% yield
95% ee
43% yield
63% ee
1
We next elucidated the intramolecular hydrogen bond of the imide substrates by H NMR analysis
o
(Figure 1). As reported previously, the chemical shifts (CDCl3 at 25 C) of the imide proton of 7a was
observed at significant downfield area (10.24 ppm) compared with 7b, which undoubtedly indicate that
an intramolecular hydrogen bond between the alkoxy oxygen and the imide proton is formed in the
compound 7a. On the other hand, the imide proton of 2-fluorobenzimide 7e was observed at 8.89 ppm as
a doublet peak (J = 13.4 Hz). The observed spin-spin coupling indicated the formation of H-F hydrogen
bond.9 In sharp contrast, no H-F interaction, that is spin-spin coupling of the imide proton, was observed
in 1H NMR spectrum of difluorobenzimide 7f. 9 On the basis of these results, the conformation of 7a and
7e should be restricted by the formation of the intramolecular hydrogen bond, and therefore the
bifunctional thiourea 1 could appropriately activate them by the formation of intermolecular hydrogen
bond network.10 Consequently, the reaction of 7e proceeded much faster in a highly enantioselective
manner.

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HETEROCYCLES, Vol. 79, 2009
Figure 1. 1H-NMR spectrum of imide protons of the 7a, 7b, 7e and 7f
10.24
8.47
10.0
8.5
10.0
8.5
7b
7a
J
H - F = 13.4 Hz
8.89
8.35
10.0
8.5
10.0
8.5
7e
7f
Finally, to transform the obtained Michael adduct 8e into advanced derivative, we undertook the synthesis
of piperidine-2,6-dione 10, which might be a potential synthetic intermediate for nakadomarin A (5).
Treatment of benzimide 8e with benzylamine readily afforded benzylamide 9. Subsequently the reaction
of 9 with t-BuOK, followed by HCl hydrolysis, provided the desired piperidine-2,6-dione 10 in 60%
yield.
Scheme 4. Transformation of 8e into piperidine-2,6-dione 10.
O
1) t-BuOK (1.0 equiv.)
NC
CN
NC
THF, 50 oC, 3 h
O
BnNH2 (2.0 equiv.)
toluene, rt, 21 h
63%
NBn
O
Bn
8e
N
O
2) 1N HCl
H
O
reflux, 3 h
9
10
60% (2 steps)
In summary, we have screened several α,β-unsaturated carbonyl compounds for the organocatalytic
asymmetric Michael reaction with malononitrile and found that new Michael acceptor 7e possessed
potential property in terms of reactivity and stereoselectivity. Moreover, we have demonstrated the
transformation of 8e into piperidine-2,6-dione 10 bearing 3-furyl group at C(4) position, which
corresponds to a partial structure (A or C ring) of nakadomarin A. Further study is in progress towards
establishing synthetic routes for the natural product.

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EXPERIMENTAL
1
Melting Points were taken on a YANAGIMOTO micromelting point apparatus and are uncorrected. H
and 13C NMR spectra were recorded in CDCl3 at 500 and 126 MHz, respectively. Tetramethylsilane
(TMS) was used as an internal standard. IR spectra were recorded on a JASCO FT/IR-410 spectrometer.
Low and high resolution mass spectra were obtained by EI or FAB method. Optical rotations were
recorded on a JASCO DIP-360 polarimeter with a path length of 1 cm; concentrations are quoted in mg (1
mL). [α]D values are measured in 10−1 deg cm2 g−1. Enantiomeric excess was determined by high
performance liquid chromatography (HPLC) analysis.
Typical procedure for preparation of benzimide 7a.
n
A 1.58 M solution of BuLi in hexane (8.6 mL, 13.6 mmol) was added to a solution of diethyl
o
2-(2-methoxybenzamido)-2-oxoethylphosphonate3b,11 (2.23 g, 6.78 mmol) in THF (15 mL) at －78 C.
The resulting solution was stirred at the same temperature for 10 min. After addition of 3-furaldehyde
(0.59 mL, 6.78 mmol), the mixture was stirred at ambient temperature for 2 h. After dilution with H2O
and acidification with by 1 N HCl, the resulting mixture was extracted with EtOAc, dried over Na2SO4,
filtered, and concentrated in vacuo. The resulting residue was recrystallized from hexane-EtOAc to afford
7a (1.18 g, 64%) as colorless solids.
o
N-(E)-(3-(Furan-3-yl)acryloyl)-2-methoxybenzamide (7a): Colorless solids, mp 119-120 C (hexane-
EtOAc); 1H NMR δ 10.24 (s, 1H), 8.19 (dd, J = 7.3, 1.8 Hz, 1H), 7.81 (d, J = 15.5 Hz, 1H), 7.71 (s, 1H),
7.58 (d, J = 15.5 Hz, 1H), 7.55 (td, J = 7.3, 1.8 Hz, 1H), 7.45 (s, 1H), 7.13 (t, J = 7.3 Hz, 1H), 7.04 (d, J =
7.3 Hz, 1H), 6.74 (d, J = 1.2 Hz, 1H), 4.04 (s, 3H); 13C NMR δ 167.6, 164.0, 157.8, 145.2, 144.4, 135.9,
134.7, 132.8, 123.3, 121.7, 120.5, 120.2, 111.7, 107.8, 56.2; IR (KBr) ν 3343, 1697 cm−1; FABMS m/z
272 (M-H+, 100); Anal. Calcd for C15H13NO4: C, 66.41; H, 4.83; N, 5.16; Found: C, 66.13; H, 4.77; N,
5.16.
o
1
N-(E)-(3-(Furan-3-yl)acryloyl)benzamide (7b): Colorless solids, mp 142-143 C (hexane-EtOAc); H
NMR δ 9.10 (s, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.82 (d, J = 15.2 Hz, 1H), 7.72 (s, 1H), 7.61 (t, J = 7.3 Hz,
13
1H), 7.57 (d, J = 15.2 Hz, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.45 (s, 1H), 6.73 (s, 1H); C NMR δ 167.9,
166.1, 145.5, 144.5, 136.7, 133.2, 133.0, 128.9, 127.9, 123.2, 119.1, 107.8; IR (KBr) ν 3255, 1699 cm−1;
EIMS m/z 241 (M+, 5), 105 (100); Anal. Calcd for C14H11NO3: C, 69.70; H, 4.60; N, 5.81; Found: C,
69.78; H, 4.84; N, 5.88.

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HETEROCYCLES, Vol. 79, 2009
Typical procedure for preparation of α,β-unsaturated ketone 7c.
A mixture of 3-furaldehyde (45 µL, 0.667 mmol) and BzCH=PPh3 (300 mg, 0.789 mmol) in toluene (4.0
o
mL) was stirred at 70 C for 17 h. Then, the resulting mixture was concentrated in vacuo, purified with
silica gel column chromatography (hexane-EtOAc = 6 : 1) to afford 7c (78.7 mg, 76%).
o
1
(E)-3-(Furan-3-yl)-1-phenylprop-2-en-1-one (7c): Yellow solids, mp 77-78 C (hexane-EtOAc); H
NMR δ 7.99 (td, J = 6.9, 1.1 Hz, 2H), 7.74 (s, 1H), 7.72 (d, J = 15.0 Hz, 1H), 7.58 (tt, J = 6.9, 1.1 Hz,
1H), 7.51 (dd, J = 6.3, 1.1 Hz, 1H), 7.48 (dd, J = 3.5, 1.7 Hz, 2H), 7.25 (d, J = 15.0 Hz, 1H), 6.71 (d, J =
13
1.7 Hz, 1H); C NMR δ 190.4, 145.4, 144.5, 138.1, 134.8, 132.7, 128.6, 123.2, 122.0, 107.4; IR (KBr)
ν 3144, 1661 cm−1; FABMS m/z 199 (M-H+, 100); Anal. Calcd for C13H10O2: C, 78.77; H, 5.09; Found: C,
78.96; H, 5.18.
o
(E)-3-(Furan-3-yl)-1-(1-methyl-1H-imidazol-2-yl)prop-2-en-1-one (7d): White solids, mp 103-104 C
(hexane-EtOAc); 1H NMR δ 7.77 (d, J = 16.0 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 16.0 Hz, 1H),
7.45 (s, 1H), 7.21 (s, 1H), 7.07 (s, 1H), 6.77 (d, J = 1.6 Hz, 1H), 4.09 (s, 3H); 13C NMR δ 180.4, 145.5,
144.4, 143.9, 133.4, 129.2, 127.1, 123.4, 122.7, 107.8, 36.3; IR (KBr) ν 3128, 1660 cm−1; FABMS m/z
203 (M-H+, 100); Anal. Calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85; Found: C, 65.10; H, 4.92; N,
13.80.
o
N-(E)-(3-(Furan-3-yl)acryloyl)-2-fluorobenzamide (7e): Colorless solids, mp 113-114 C (hexane-
EtOAc); 1H NMR δ 8.89 (d, JC-F = 13.4 Hz, 1H), 8.09 (td, J = 8.0, 1.7 Hz, 1H), 7.83 (d, J = 15.4 Hz, 1H),
7.73 (s, 1H), 7.63-7.56 (m, 1H), 7.46 (d, J = 15.4 Hz, 1H), 7.46 (s, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.21 (dd,
13
J = 12.2, 8.9 Hz, 1H), 6.73 (d, J = 1.2 Hz, 1H); C NMR δ 166.8, 162.1, 161.5, 159.5, 144.2, 136.8,
135.0, 132.2, 125.2, 123.1, 120.4, 119.3, 116.5, 107.7; IR (KBr) ν 3123, 1678 cm−1; FABMS m/z 262
(M-H+, 100); Anal. Calcd for C14H10FNO3: C, 64.86; H, 3.89; N, 5.40; Found: C, 64.91; H, 3.90; N, 5.35.
o
N-(E)-(3-(Furan-3-yl)acryloyl)-2,6-difluorobenzamide (7f): Colorless solids, mp 152-153 C (hexane-
EtOAc); 1H NMR δ 8.35 (s, 1H), 7.80 (d, J = 15.5 Hz, 1H), 7.72 (s, 1H), 7.50-7.44 (m, 2H), 7.19 (d, J =
13
15.5 Hz, 1H), 7.01 (dd, J = 8.6, 8.1 Hz, 2H), 6.70 (d, J = 1.7 Hz, 1H); C NMR δ 165.6, 160.9, 159.9,
145.7, 144.6, 137.3, 133.1, 133.0, 122.9, 118.6, 112.2, 107.7; IR (KBr) ν 1682 cm−1; FABMS m/z 278
(M-H+, 100); Anal. Calcd for C14H9F2NO3: C, 60.66; H, 3.27; N, 5.05; Found: C, 60.50; H, 3.25; N, 4.95.
General procedure for the catalytic enantioselective Michael reaction.

HETEROCYCLES, Vol. 79, 2009
579
A mixture of 7, malononitrile (2 equiv.) and thiourea 1 (10 mol%) in toluene (0.1 M) was stirred at
ambient temperature. After concentration in vacuo, the reaction mixture was purified with silica gel
column chromatography (hexane-EtOAc = 4 : 1) to afford 8.
(R)-N-(4,4-Dicyano-3-(furan-3-yl)butanoyl)-2-methoxybenzamide (8a): colorless solids, mp 141-145
1
oC (hexane-EtOAc); [α]23 −8.5 (c 1.2, CHCl3, 92% ee); H NMR δ 10.42 (s, 1H), 8.15 (dd, J = 7.8, 1.8
D
Hz, 1H), 7.60 (s, 1H), 7.58 (td, J = 7.8, 1.8 Hz, 1H), 7.47 (t, J = 1.5 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.04
(d, J = 7.8 Hz, 1H), 6.60 (s, 1H), 4.63 (d, J = 4.9 Hz, 1H), 4.03 (s, 3H), 3.87 (ddd, J = 8.5, 5.5, 4.9 Hz,
13
1H), 3.62 (dd, J = 18.6, 5.5 Hz, 1H), 3.57 (dd, J = 18.6, 8.5 Hz, 1H); C NMR δ 172.9, 164.0, 157.8,
144.0, 140.8, 135.3, 132.9, 121.9, 121.1, 119.4, 112.2, 111.8, 111.6, 109.4, 56.2, 40.1, 33.4, 28.5; IR
(KBr) ν 3331, 1748, 1679 cm−1; FABMS m/z 338 (M-H+, 97), 135 (100); Anal. Calcd for C18H15N3O4: C,
64.09; H, 4.48; N, 12.46; Found: C, 64.10; H, 4.43; N, 12.48; HPLC analysis (DAICELL CIRALPAK
AS-H, Hexane:2-Propanol = 70:30, flow rate = 0.5 mL/min, 254 nm) retension time; major: 59.7 min and
minor: 73.9 min.
o
(R)-N-(4,4-Dicyano-3-(furan-3-yl)butanoyl)benzamide (8b): colorless solids, mp 138-139 C (hexane-
1
EtOAc); [α]23 －8.9 (c 2.4, CHCl3, 90% ee); H NMR δ 8.62 (s, 1H), 7.84 (dd, J = 8.3, 1.0 Hz, 2H),
D
7.66 (t, J = 8.3 Hz, 1H), 7.61 (s, 1H), 7.54 (t, J = 8.3 Hz, 2H), 7.49 (t, J = 1.5 Hz, 1H), 6.59 (s, 1H), 4.50
(d, J = 4.9 Hz, 1H), 3.88 (ddd, J = 8.9, 5.2, 4.9 Hz, 1H), 3.67 (dd, J = 18.9, 5.2 Hz, 1H), 3.61 (dd, J = 18.9,
4.9 Hz, 1H); 13C NMR δ 173.2, 165.7, 144.2, 140.9, 133.9, 131.9, 129.2, 127.8, 121.0, 112.0, 111.5,
109.3, 39.5, 33.4, 28.6; IR (KBr) ν 3244, 1724, 1673 cm−1; FABMS m/z 308 (M-H+, 100); Anal. Calcd
for C17H13N3O3: C, 66.44; H, 4.26; N, 13.67; Found: C, 66.36; H, 4.49; N, 13.54; HPLC analysis
(DAICELL CHIRALPAK AD-H, Hexane:2-Propanol = 50:50, flow rate = 0.5 mL/min, 254 nm)
retension time; major: 23.8 min and minor: 17.2 min.
(R)-2-(1-(Furan-3-yl)-3-oxo-3-phenylpropyl)malononitrile (8c): colorless oil; [α]32 －4.4 (c 1.0,
D
CHCl3, 70% ee); 1H NMR δ 7.90 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.52 (s, 1H), 7.43 (dd, J =
14.3, 7.5 Hz, 3H), 6.51 (s, 1H), 4.55 (d, J = 4.3 Hz, 1H), 3.88 (dt, J = 8.0, 5.2 Hz, 1H), 3.49 (dd, J = 7.7,
5.2 Hz, 2H); 13C NMR δ 196.6, 144.2, 140.7, 135.7, 134.3, 129.0, 128.1, 121.3, 112.0, 111.7, 109.2, 40.1,
33.3, 28.5; IR (KBr) ν 3749, 2360, 1683 cm−1; FABMS m/z 265 (M-H+, 22), 73 (100); HRMS (FAB+):
Calcd for C16H14N2O2 (M-H+) 265.0977, Found: 265.0930; HPLC analysis (DAICELL CHIRALCEL
OD-H, Hexane:2-Propanol = 90:10, flow rate = 1.0 mL/min, 254 nm) retension time; major: 42.3 min and
minor: 55.5 min.

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(R)-2-(1-(Furan-3-yl)-3-(1-methyl-1H-imidazol-2-yl)-3-oxopropyl)malononitrile (8d): colorless oil;
1
[α]30 －7.5 (c 1.0, CHCl3, 64% ee); H NMR δ 7.57 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H),
D
6.56 (s, 1H), 4.47 (d, J = 4.6 Hz, 1H), 3.99 (s, 3H), 3.91 (dt, J = 8.0, 6.3 Hz, 1H), 3.85 (dd, J = 17.8, 6.3
13
Hz, 1H), 3.64 (dd, J = 17.8, 8.0 Hz, 1H); C NMR δ 188.5, 144.0, 142.1, 140.8, 129.9, 127.9, 121.2,
112.0, 111.5, 109.3, 40.4, 36.1, 33.5, 28.9; IR (KBr) ν 3749, 2361, 1676 cm−1; FABMS m/z 269 (M-H+,
100); HRMS (FAB+): Calcd for C14H13N4O2 (M-H+) 269.1039, Found: 269.1039; HPLC analysis
(DAICELL CHIRALCEL OD-H, Hexane:2-Propanol = 70:30, flow rate = 0.5 mL/min, 254 nm) retension
time; major: 19.6 min and minor: 25.9 min.
o
(R)-N-(4,4-Dicyano-3-(furan-3-yl)butanoyl)-2-fluorobenzamide (8e): colorless solids, mp 105-106 C
1
(hexane-EtOAc); [α]23 −7.5 (c 1.0, CHCl3, 95% ee); H NMR δ 9,09 (d, J = 13.8 Hz, 1H), 8.06 (t, J =
D
7.5 Hz, 1H), 7.62 (t, J = 6.9 Hz, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.21 (dd, J = 8.6,
8.0 Hz, 1H), 6.58 (s, 1H), 4.58 (d, J = 5.2 Hz, 1H), 3.87 (ddd, J = 8.6, 5.2, 5.2 Hz, 1H), 3.63 (dd, J = 15.5,
5.2 Hz, 1H), 3.58 (dd, J = 15.5, 8.6 Hz, 1H); 13C NMR δ 172.3, 162.0, 161.6, 159.6, 144.1, 140.8, 135.8,
132.4, 125.5, 120.9, 119.2, 116.6, 112.0, 111.5, 109.3, 40.1, 33.4, 28.6; IR (KBr) ν 2361, 1697 cm−1;
FABMS m/z 326 (M-H+, 100); HRMS (FAB+): Calcd for C17H13FN3O3 (M-H+) 326.0941, Found:
326.1003; HPLC analysis (DAICELL CHIRALCEL OD-H, Hexane:2-Propanol = 80:20, flow rate = 0.5
mL/min, 254 nm) retension time; major: 71.8 min and minor: 88.7 min.
(R)-N-(4,4-Dicyano-3-(furan-3-yl)butanoyl)-2,6-difluorobenzamide (8f): colorless amorphous; [α]31
D
−4.4 (c 1.4, CHCl3,63% ee); 1H NMR δ 8.61 (s, 1H), 7.59 (s, 1H), 7.53 (td, J = 8.5, 2.3 Hz, 2H), 7.49 (t, J
= 1.8 Hz, 1H), 7.05 (t, J = 8.5 Hz, 2H), 4,54 (d, J = 4.6 z 1H), 3.84 (ddd, J = 8.6, 5.2, 5.2 Hz, 1H), 3.58
(dd, J = 18.9, 5.2 Hz, 1H), 3.53 (dd, J = 18.9, 8.6 Hz, 1H); 13C NMR δ 171.7, 161.1, 159.3, 159.1, 144.2,
140.9, 134.0, 120.7, 112.7, 112.5, 111.9, 111.4, 109.2, 39.8, 33.5, 30.9, 28.6; IR (KBr) ν 3289, 2258,
1624 cm−1; FABMS m/z 344 (M-H+, 2), 45 (100); HRMS (FAB+): Calcd for C17H12F2N3O3 (M-H+)
344.0847, Found: 344.0876; HPLC analysis (DAICELL CHIRALPAK AS-H, Hexane:2-Propanol =
90:10, flow rate = 0.5 mL/min, 254 nm) retension time; major: 62.6 min and minor: 85.2 min.
(R)-N-Benzyl-4,4-dicyano-3-(furan-3-yl)butanamide (9): A mixture of 8e (252 mg, 0.775 mmol) and
benzylamine (110 µL, 1.01 mmol) in toluene (4.0 mL) was stirred at rt for 21 h. After concentrated in
vacuo, the reaction mixture was purified by silica gel column chromatography (hexane-EtOAc = 3 : 1) to
afford 9 (107 mg, 63%) as a brownish oil: [α]32D +14.6 (c 1.1, CHCl3); 1H NMR δ 7.51 (s, 1H), 7.46 (t, J
= 1.3 Hz, 1H), 7.38-7.29 (m, 3H), 7.21 (d, J = 7.0 Hz, 2H), 6.49 (s, 1H), 5.90 (brs, 1H), 4,75 (d, J = 4.9
Hz, 1H), 4.46 (dd, J = 14.7, 5.8 Hz, 1H), 4.39 (dd, J = 14.7, 5.5 Hz, 1H), 3.77 (ddd, J = 8.9, 5.2, 4.9 Hz,

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13
1H), 2.78 (dd, J = 16.2, 8.9 Hz, 1H), 2.71 (dd, J = 16.2, 5.2 Hz, 1H); C NMR δ 168.8, 144.2, 140.7,
137.3, 128.9, 127.8, 121.0, 112.1, 111.7, 109.1, 43.8, 37.7, 34.4, 28.4; IR (neat) ν 3301, 1640 cm−1;
FABMS m/z 294 (M-H+, 100); HRMS (FAB+): Calcd for C17H16N3O2 (M-H+) 294.1243, Found:
294.1243.
(R)-1-Benzyl-4-(furan-3-yl)-2,6-dioxopiperidine-3-carbonitrile (10): To a stirred solution of 9 (105
mg, 0.359 mmol) in THF (3.6 mL) at rt, t-BuOK (40.2 mg, 0.359 mmol) was added and stirred at 50 ℃
for 3 h. After the reaction mixture was diluted with H2O and acidified with 1N HCl, the resulting mixture
was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Resulting crude
enamine product was directly used for the next reaction. A suspension of the crude enamine in 1N HCl
(1.71 mL, 1.71 mmol) was stirred at reflux for 3 h. After the reaction mixture was diluted with H2O, the
resulting mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexane-EtOAc = 7 : 2) to afford 10 (46.1 mg,
1
60% from 9) as brownish oil: [α]32D +2.6 (c 2.5, CHCl3); H NMR (3 : 1 mixture of diastereomers, with
signals corresponding to the major indicated by) δ 7.44-7.26 (m, 7H), 6.33-6.30 (m, 1H), 5.02 (dd, J =
13.9, 2.7 Hz, 1H), 4.96 (dd, J = 13.9, 5.1 Hz, 1H), 4.71 (dd, J = 17.6, 8.8 Hz, 1H), 4.05 (dd, J = 4.4, 1.0
Hz, 1H), 3.17 (dd, J = 17.6, 4.4 Hz, 1H), 3.05 (dd, J = 5.1, 1.0 Hz, 1H), 2.84 (dd, J = 10.5, 7.6 Hz, 1H);
13C NMR δ 169.1, 168.8, 163.9, 163.8, 144.5, 144.3, 143.9, 139.8, 139.7, 135.8, 135.7, 135.6, 129.1,
129.0, 128.8, 128.7, 128.58, 128.57, 128.02, 128.00, 122.0, 120.8, 114.4, 114.0, 109.1, 108.8, 44.0, 43.9,
43.0, 42.7, 42.1, 37.6, 36.9, 36.8, 35.8, 30.3, 29.3; IR (neat) ν 3136, 2259, 1705, 1677 cm−1; FABMS m/z
295 (M-H+, 51), 73 (100); HRMS (FAB+): Calcd for C17H15N2O3 (M-H+) 295.1083, Found: 295.1039.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research (B) (Y.T.) and Scientific
Research on Priority Areas: Advanced Molecular Transformations of Carbon Resources (Y.T. and K.T.),
“Targeted Proteins Research Program” from Ministry of Education, Culture, Sports, Science and
Technology of Japan, and JSPS KAKENHI (3316). T. I thanks the JSPS for a Fellowship.
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