Asymmetric Conjugate Addition of α-Cyanoketones to Benzoyl Acrylonitrile Derivatives Using a Diaminomethylenemalononitrile Organocatalyst

Article abstract of DOI:10.1055/s-0040-1707285

A diaminomethylenemalononitrile (DMM) organocatalyst was used to efficiently promote asymmetric conjugate addition of various α-cyanoketones to benzoyl acrylonitrile derivatives. The corresponding 1,5-dicarbonyl compounds containing vicinal tertiary and quaternary stereogenic centers are versatile synthetic intermediates and were obtained in good yields and with excellent enantioselectivities (up to 96% ee). The present study describes the first successful examples of asymmetric conjugate addition reactions of α-cyanoketones with benzoyl acrylonitriles. In addition, the DMM organocatalyst can be recovered and reused up to five times without significant loss of either catalytic activity or enantioselectivity.

Full text of DOI:10.1055/s-0040-1707285

SYNTHESIS
0
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1
1
4
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7
-
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1
0
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–G
paper
A
en
H. Akutsu et al.
Paper
Synthesis
Asymmetric Conjugate Addition of -Cyanoketones to Benzoyl
Acrylonitrile Derivatives Using a Diaminomethylenemalononitrile
Organocatalyst
Hiroshi Akutsu
Kosuke Nakashima
NC
CN
Yuta Kanetsuna
N
Masahiro Kawada
Shin-ichi Hirashima
Tsuyoshi Miura*
n-Pr
N
H
N
H
N
O
CN
CN
O
(10 mol%)
O
O
MeO
Ar
Tokyo University of Pharmacy and Life Sciences,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
Japan
CN
( )n
NC
Ar
+
toluene (0.13 M)
rt, 24–48 h
( )n
up to 100%
up to 96% ee
tmiura@toyaku.ac.jp
Corresponding Author
Received: 28.07.2020
Accepted after revision: 20.08.2020
Published online: 22.09.2020
neering work using a chiral yttrium catalyst was reported
by Shibasaki et al.4 Furthermore, we have previously de-
scribed valuable asymmetric transformations, such as
Michael addition, aldol, and Pudovik reactions employing
organocatalysts bearing a diaminomethylenemalononitrile
(DMM) motif as the hydrogen-bond donor.5 In addition, we
have recently reported an asymmetric conjugate addition of
-cyanoketones to aromatic vinyl ketones using the afore-
mentioned DMM organocatalyst.6 Benzoyl acrylonitriles are
good Michael acceptors, allowing access to vicinal tertiary
and quaternary stereogenic centers. In addition, the nitrile
moiety is a versatile functional group because it can be
readily converted into a range of other functional groups.
Nevertheless, only one report on the asymmetric conjugate
addition using benzoyl acrylonitriles as Michael acceptors
currently exists, despite the value of chiral addition prod-
ucts as synthetic intermediates.7 Furthermore, to our
knowledge, asymmetric conjugate additions of -cyanoke-
tones to benzoyl acrylonitrile derivatives have not yet been
reported. In the present study, we describe a highly effi-
cient synthesis of chiral 1,5-dicarbonyl compounds con-
taining vicinal tertiary and quaternary stereogenic centers.
The conducted reactions involved asymmetric conjugate
addition of -cyanoketones to benzoyl acrylonitriles using
DMM organocatalysts.
Thiourea and squaramide scaffolds are popular motifs
that are often utilized as hydrogen-bond donors.8,9 Thus, in
the first instance, thiourea and squaramide organocatalysts
1 and 2, bearing a chiral cinchona moiety (Figure 1), were
examined as catalysts for the conjugate addition of 2-oxo-
cyclopentane-1-carbonitrile (7a) to (E)-4-oxo-4-phenylbut-
2-enenitrile (8a) at room temperature in toluene (Table 1).
Compounds 1 and 2 proved to be poor catalysts, affording
the products in low stereoselectivities (entries 1 and 2).
Pleasingly, when DMM organocatalyst 3 was used, higher
enantioselectivity was obtained (entry 3). Therefore, it was
DOI: 10.1055/s-0040-1707285; Art ID: ss-2020-f0400-op
Abstract A diaminomethylenemalononitrile (DMM) organocatalyst
was used to efficiently promote asymmetric conjugate addition of vari-
ous -cyanoketones to benzoyl acrylonitrile derivatives. The corre-
sponding 1,5-dicarbonyl compounds containing vicinal tertiary and
quaternary stereogenic centers are versatile synthetic intermediates
and were obtained in good yields and with excellent enantioselectivities
(up to 96% ee). The present study describes the first successful exam-
ples of asymmetric conjugate addition reactions of -cyanoketones
with benzoyl acrylonitriles. In addition, the DMM organocatalyst can be
recovered and reused up to five times without significant loss of either
catalytic activity or enantioselectivity.
Key words -cyanoketone, benzoyl acrylonitrile, organocatalyst,
asymmetric conjugate addition, vicinal tertiary and quaternary stereo-
genic centers
Stereoselective synthesis of highly functionalized qua-
ternary stereogenic centers is typically challenging due to
steric hindrance, and their construction involves highly re-
active reagents and harsh reaction conditions.1 Moreover,
although vicinal tertiary and quaternary stereogenic cen-
ters are ubiquitous in natural products and bioactive com-
pounds, the stereoselective construction of these motifs is
even more difficult.2 Asymmetric conjugate addition of a
Michael donor bearing an active methine moiety to an elec-
tron-deficient disubstituted alkene is one of the approaches
utilized for the synthesis of vicinal tertiary and quaternary
stereogenic centers. As -alkylated -cyanoketones are
good Michael donors and contain active methine groups,
several studies involving asymmetric conjugate additions to
electron-deficient alkenes, employing organocatalysts with
environmentally benign properties, have recently been re-
ported.3,4 However, although the reaction between -cya-
noketones and aromatic vinyl ketones is challenging, pio-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. Akutsu et al.
Paper
Synthesis
Table 1 Catalyst Screening
O
O
O
CN
CN
O
O
catalyst
(10 mol%)
N
N
O
S
CN
+
F3C
F3C
N
Ph
NC
Ph
N
H
N
N
N
toluene
rt, 24 h
H
H
H
8a
N
7a
(1 equiv)
9a
CF3
CF3
MeO
MeO
Entry
Catalyst
Yield (%)a
syn/antib
ee (%)c
1
2
1
2
3
4
5
6
1
2
3
4
5
6
99
76
96
90
87
95
44:56
49:51
44:56
44:56
59:41
56:44
21
40
63
56
86
83
NC
CN
N
NC
CN
N
Me
N
F3C
N
H
N
H
N
H
H
N
N
CF3
MeO
MeO
a Yield of both diastereomers.
4
b Determined by 1H NMR analysis.
c Determined by chiral HPLC analysis.
3
NC
CN
N
NC
CN
longer (entries 11–13). Based on the obtained results, tak-
ing into account both yield and enantioselectivity, we de-
termined that the reaction conditions summarized in entry
9 were optimal.
N
n-Pr
Et
N
N
H
N
H
N
H
H
N
N
With the optimized reaction conditions in hand, we ex-
amined the scope and limitations of the asymmetric conju-
gate additions of -cyanoketones to benzoyl acrylonitrile
derivatives 8 (Scheme 1). The reactions of 2-oxocyclopen-
MeO
MeO
6
5
Figure 1 Structure of organocatalysts
Table 2 Optimization of Reaction Conditions Using Organocatalyst 6
found that in comparison to the thiourea and squaramide
motifs, the DMM skeleton was preferable for the asymmet-
ric conjugate addition of 7a to 8a. Moreover, organocatalyst
4, which bears a methyl functionality instead of the 3,5-
bis(trifluoromethyl)benzylamine group, provided lower
stereoselectivity (entry 4). Organocatalysts 5 and 6, con-
taining alkyl groups of varying lengths, including ethyl and
n-propyl chains, afforded the corresponding adduct 9a with
high enantioselectivities (entries 5 and 6). Overall, consid-
ering both the yield and stereoselectivity, organocatalyst 6,
bearing the n-propyl group, was the most effective.
Subsequently, the optimal reaction medium for the
asymmetric conjugate addition of 7a to 8a using organocat-
alyst 6 was investigated (Table 2). We examined a variety of
organic solvents for the transformation, including toluene,
xylene, hexane, CH2Cl2, EtOAc, and MeOH (entries 1–6). It
was determined that toluene was the most suitable reac-
tion medium (entry 1). To further improve the stereoselec-
tivity, we then examined the reaction concentration (0.50–
0.06 M) (entries 7–10). It is noteworthy that when the reac-
tion was carried out at a concentration of 0.13 M, higher
enantioselectivity and diastereoselectivity were obtained
(entry 9). In addition, the reactions performed at lower
temperatures (0, –20, and –40 °C) resulted in improve-
ments in the stereoselectivity; however, in this case, the
achieved yields were lower and the reaction times were
O
CN
O
O
O
catalyst 6
(10 mol%)
CN
Ph
+
NC
Ph
solvent (M)
CN
8a
(1 equiv)
7a
9a
Entry Solvent (M)
Temp (°C) Time (h) Yield (%)a syn/antib ee (%)c
1
2
toluene (1.0)
rt
rt
24
24
24
24
24
24
24
24
24
48
72
96
84
95
87
83
98
88
97
91
92
83
72
71
74
41
56:44
60:40
45:55
60:40
50:50
43:57
64:36
69:31
71:29
69:31
75:25
79:21
79:21
83
83
34
81
65
–4
87
90
93d
90
96
97
96
xylene (1.0)
3
hexane (1.0)
CH2Cl2 (1.0)
rt
4
rt
5
EtOAc (1.0)
rt
6
MeOH (1.0)
rt
7
toluene (0.50)
toluene (0.25)
toluene (0.13)
toluene (0.06)
toluene (0.13)
toluene (0.13)
toluene (0.13)
rt
8
rt
9
rt
10
11
11
12
rt
0
–20
–40
a Yield of both diastereomers.
b Determined by 1H NMR analysis.
c Determined by chiral HPLC analysis.
d 46% ee for the anti isomer.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

C
H. Akutsu et al.
Paper
Synthesis
tane-1-carbonitrile (7a) with benzoyl acrylonitrile deriva-
tives 8b and 8c, containing a methyl moiety at the para-
and meta-positions on the benzene ring, afforded the corre-
sponding addition products 9b and 9c with high enantiose-
lectivities. Moreover, the benzoyl acrylonitrile derivative
8d, bearing a methyl functionality at the ortho-position, re-
acted with 7a to provide adduct 9d in low enantioselectivi-
ty due to steric hindrance. On the other hand, the addition
of 7a to substrate 8e, containing two methyl groups, pro-
ceeded with high enantioselectivity and afforded product
9e. Benzoyl acrylonitrile derivatives 8f, possessing methoxy
groups as representative electron-donating moieties, pro-
vided the expected products also with high stereoselectivi-
ty. Pleasingly, substrates 8g–j, which contain electron-with-
drawing groups, such as chloro, bromo, trifluoromethyl,
and cyano functionalities at the para-position, reacted with
7a to obtain addition products 9g–j in good to high yields
with high enantioselectivities. Furthermore, conjugate ad-
dition to 8k–l, bearing thiophene and furan rings, smoothly
provided adducts 9k–l with excellent enantioselectivities.
We subsequently examined other types of -cyanoketones
for the transformation. The reaction between 2-oxocyclo-
hexane-1-carbonitrile (7b) and 8a resulted in the formation
of adduct 9m in high yield and excellent enantioselectivity.
In addition, 1-oxo-2,3-dihydro-1H-indene-2-carbonitrile
(7c) reacted with 8a, providing adduct 9n in high yield;
however, in this case, the stereoselectivity decreased. 2-
Oxocycloheptane-1-carbonitrile (7d) also smoothly cou-
pled with 8a to afford adduct 9o in moderate stereoselec-
tivity. The absolute configuration of the addition product
9h was determined by X-ray crystallographic analysis. The
stereochemistry of the remaining products with the gener-
al structure 9 were tentatively assigned by analogy.
O
O
CN
O
catalyst 6
(10 mol%)
O
CN
Ar
+
NC
O
Ar
toluene
(0.13 M)
rt
CN
( )n
( )n
8
9
7
(1 equiv)
O
CN
CN
O
O
CN
CN
9b, 83% (48 h)
syn/anti = 69:31
92% ee
9c, 75% (48 h)
syn/anti = 78:22
93% ee
O
O
CN
O
CN
CN
O
CN
9e, 72% (24 h)
syn/anti = 65:35
92% ee
9d, 75% (48 h)
syn/anti = 68:32
24% ee
O
CN
O
O
CN
O
CN
CN
Br
OMe
9g, 84% (24 h)
syn/anti = 65:35
90% ee
9f, 70% (48 h)
syn/anti = 70:30
89% ee
O
CN
O
CN
9h, 81% (24 h)
Cl
syn/anti = 61:39
85% ee
O
CN
CN
O
O
CN
CN
O
CN
CF3
9j, 79% (24 h)
syn/anti = 58:42
9i, 71% (24 h)
syn/anti = 61:39
88% ee
78% ee
O
CN
O
O
CN
O
To demonstrate the usefulness of the asymmetric conju-
gate addition reactions utilizing organocatalyst 6, we car-
ried out the synthesis of adduct 9a on gram scale and ob-
tained the desired product in a high yield and excellent en-
antioselectivity (Scheme 2). According to the previous
report,4 the treatment of 9a with SmI2 in tetrahydrofuran
(THF) resulted in the formation of the cyclized product 10
in 73% yield (Scheme 3). Furthermore, we aimed to deter-
mine whether organocatalyst 6 could be recycled and re-
used. Based on the conducted evaluation, we established
that the catalyst is stable and can be easily recovered (89–
100%) from the reaction mixture using flash silica gel chro-
O
S
CN
CN
9l, 77% (24 h)
syn/anti = 81:19
96% ee
9k, 76% (24 h)
syn/anti = 78:22
96% ee
O
CN
O
O
CN
CN
O
Ph
Ph
CN
9m, 76% (24 h)
syn/anti = 63:37
9n, 99% (24 h)
syn/anti = 52:48
78% ee
93% ee
O
CN
CN
O
Ph
O
CN
O
O
catalyst 6
(10 mol%)
O
9o, 100% (96 h)
syn/anti = 64:36
72% ee
CN
+
Ph
NC
Ph
toluene
(0.13 M)
rt
CN
8a
(1 equiv)
9a
94% ee
syn/anti = 73:27
7a
Scheme 1 Asymmetric conjugate additions using organocatalyst 6.
Yields are given for both diastereomers. Diastereomeric ratio was deter-
mined by 1H NMR analysis; enantiomeric excess was determined by chi-
ral HPLC analysis.
80%
(1.07 g)
Scheme 2 Gram-scale synthesis of 9a using organocatalyst 6
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

D
H. Akutsu et al.
Paper
Synthesis
matography. Notably, the recovered catalyst 6 can be re-
peatedly reused without any loss in the catalytic activity
and with the same level of enantioselectivity for five cycles
(Table 3). Therefore, we demonstrated that the degradation
of catalyst 6 does not occur in the reaction system.
In conclusion, in the current study, we successfully
demonstrated that the DMM organocatalyst 6 efficiently
promoted the asymmetric conjugate addition of -cyanoke-
tones to benzoyl acrylonitrile derivatives 8 to afford the en-
antiomerically enriched 1,5-dicarbonyl compounds 9. The
products 9 possess vicinal tertiary and quaternary stereo-
genic centers and were obtained in high yields with high to
excellent enantioselectivities. The present work is the first
example of efficient asymmetric conjugate additions of -
cyanoketones to benzoyl acrylonitrile derivatives. The syn-
thesized chiral addition products are highly desirable as
versatile synthetic intermediates. Further applications of
the DMM catalysts to other types of asymmetric reactions
as well as the development of novel DMM organocatalysts
are being investigated in our laboratory.
Ph
HO
HO
O
CN
O
SmI2 (1.2 equiv)
Ph
CN
THF, rt, 5 h
73%
CN
CN
9a
10
Scheme 3 Transformation of the conjugate addition products
Table 3 Recycling and Reuse of Organocatalyst 6
O
O
CN
O
catalyst 6
(10 mol%)
O
CN
Ph
+
NC
Ph
toluene
(0.13 M)
rt
CN
8a
(1 equiv)
NMR spectra were recorded with a Bruker Avance III Nanobay 400
9a
7a
1
MHz spectrometer (400 MHz for H, 100 MHz for 13C). The chemical
shifts are expressed in ppm downfield from tetramethylsilane ( =
0.00 ppm) as an internal standard and CDCl3 ( = 77.16 ppm). Mass
spectra were recorded with an electrospray ionization-time of flight
(ESI-TOF) mass spectrometer (Xevo G2-XS QTof). Specific rotations
were measured with a Jasco P-2200. Melting points were obtained
with a Yanaco MP-J3. For thin-layer chromatographic (TLC) analyses,
Merck precoated TLC plates (silica gel 60 F254) were used. Flash col-
umn chromatography was performed on neutral silica gel (Kanto Sili-
ca gel 60N, 40–50 m).
Entry
initial
Time (h) Yield (%)a syn/antib
ee (%)c Cat. recovery (%)
24
24
24
48
48
48
80
76
79
81
77
82
73:27
78:22
76:24
78:22
78:22
77:23
94
92
93
92
92
91
100
99
93
89
97
97
first reuse
second reuse
third reuse
fourth reuse
fifth reuse
Preparation of Organocatalysts
a Yield of both diastereomers.
b Determined by 1H NMR analysis.
c Determined by chiral HPLC analysis.
Organocatalysts 1–6 were prepared according to a reported proce-
dure.6
Preparation of -Cyanoenones
We did not attempt to elucidate the reaction mecha-
nism experimentally; however, it was inferred that the con-
jugate addition of -cyanoketones to benzoyl acrylonitrile
using organocatalyst 6 would proceed via a plausible transi-
tion state, as shown in Figure 2, based on the stereochemis-
try of the adduct 9. The tertiary amine functionality of the
quinuclidine group in organocatalyst 6 removes a proton
from -cyanoketones to afford a reactive enol intermediate.
Subsequently, the hydrogen atoms of the DMM motif inter-
act with the carbonyl oxygen atom in benzoyl acrylonitrile
8, directing the approach of the enol to enone (Re-face at-
tack). Finally, it is suspected that these interactions result in
the formation of addition products 9 with excellent enanti-
oselectivities.
(E)-4-Oxo-4-phenylbut-2-enenitrile (8a) was prepared according to a
reported procedure.10
Preparation of -Cyanoenones 8b–m; General Procedure10,11
To a 100 mL two-neck round-bottom flask, SeO2 (2.00 g, 18.0 mmol),
H2O (0.31 g, 17.0 mmol) and 1,4-dioxane (10.0 mL) were added and
the flask was fitted with a condenser. The mixture was heated to re-
flux with stirring until the solid dissolved. Then, substituted aryl ke-
tone (10.0 mmol) was added into the solution and the reaction mix-
ture was allowed to reflux. After the reaction was completed, the re-
action mixture was cooled to r.t. and filtered through a Celite pad,
which was then washed several times with diethyl ether. The com-
bined filtrate was evaporated on a rotary evaporator to afford the
crude product, which was used in the next step without further puri-
fication. A solution of aryllglyoxal monohydrate (10.0 mmol) in ben-
zene (40 mL) was heated under reflux with azeotropic removal of wa-
ter (Dean–Stark). Thereafter, cyanomethylidenetriphenylphos-
phorane (3.80 g, 12.6 mmol) and benzoic acid (211 mg, 1.73 mmol)
were added and the mixture was stirred for 10 h under an argon at-
mosphere at 80 °C. The cooled mixture was concentrated in vacuo
and the residue was subjected to column chromatography on silica gel
(hexane/EtOAc, 2:1) and recrystallization to give 8 as yellow crystals.
NC
CN
Ar
N
H
N
H
N
H
O
Re-face
O
CN
CN
Figure 2 Plausible transition-state models
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

E
H. Akutsu et al.
Paper
Synthesis
Asymmetric Conjugate Addition; Typical Procedure
(S)-1-((S)-1-Cyano-3-oxo-3-(o-tolyl)propyl)-2-oxocyclopentane-1-
carbonitrile (9d)
To a solution of -cyanoenone (8a, 31.4 mg, 0.200 mmol) and organo-
catalyst 6 (9.1 mg, 0.020 mmol) in toluene (1.6 mL) was added -cya-
noketone (7a, 20.0 L, 0.200 mmol) at r.t. After stirring at r.t. for the
indicated time, the reaction mixture was purified by flash column
chromatography on silica gel with a 10:1 to 6:1 mixture of hexane
and acetone to afford 9a.
Yield: 42.3 mg (75%); white solid; mp 138–139 °C; syn/anti = 68:32;
24
[]D = −1.5 (c 0.45, CH2Cl2); HPLC (ChiralPak IG; hexane/i-PrOH,
80:20; 1.0 mL/min;  =254 nm): tR = 21.9 (minor), 30.4 (major) min;
24% ee.
1H NMR (400 MHz, CDCl3):  = 2.13–2.24 (m, 1 H), 2.25–2.31 (m, 1 H),
2.33–2.42 (m, 1 H), 2.46–2.53 (m, 1 H), 2.56 (s, 3 H), 2.65–2.73 (m, 2
H), 3.58 (dd, J = 18.1, 3.5 Hz, 1 H), 3.80 (dd, J = 9.9, 3.4 Hz, 1 H), 4.02
(dd, J = 18.1, 9.9 Hz, 1 H), 7.29–7.35 (m, 2 H), 7.43–7.47 (m, 1 H), 7.73–
7.76 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 19.5, 21.8, 31.4, 34.7, 37.4, 40.2, 49.2,
116.0, 117.7, 126.2, 129.2, 132.6, 132.8, 135.5, 139.7, 197.1, 206.0.
(S)-1-((S)-1-Cyano-3-oxo-3-phenylpropyl)-2-oxocyclopentane-1-
carbonitrile (9a)
Yield: 44.4 mg (83%); white solid; mp 116–117 °C; syn/anti = 71:29;
26
[]D = −2.6 (c 1.00, CH2Cl2); HPLC (ChiralPak IB; hexane/i-PrOH,
90:10; 1.0 mL/min;  =254 nm): tR = 31.7 (minor), 35.9 (major) min;
93% ee.
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C17H16N2O2Na: 303.1104;
found: 303.1110.
1H NMR (400 MHz, CDCl3):  = 2.13–2.24 (m, 1 H), 2.26–2.30 (m, 1 H),
2.34–2.43 (m, 1 H), 2.47–2.56 (m, 1 H), 2.67–2.73 (m, 2 H), 3.58 (dd,
J = 18.1, 3.5 Hz, 1 H), 3.80 (dd, J = 9.9, 3.4 Hz, 1 H), 4.02 (dd, J = 18.1,
9.9 Hz, 1 H), 7.52 (dd, J = 7.6, 7.6 Hz, 2 H), 7.64 (t, J = 7.3 Hz, 1 H), 8.00
(d, J = 7.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 19.5, 31.2, 34.6, 37.4, 38.0, 49.2, 115.9,
117.6, 128.4, 129.1, 134.4, 135.3, 194.3, 206.1.
(S)-1-((S)-1-Cyano-3-(3,4-dimethylphenyl)-3-oxopropyl)-2-oxocy-
clopentane-1-carbonitrile (9e)
Yield: 42.4 mg (72%); yellow solid; mp 132–133 °C; syn/anti = 65:35;
24
[]D = +3.1 (c 0.90, CH2Cl2); HPLC (ChiralPak IG; hexane/i-PrOH,
80:20; 1.0 mL/min;  =254 nm): tR = 36.7 (minor), 39.6 (major) min;
92% ee.
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C16H14N2O2Na: 289.0947;
found: 289.0956.
1H NMR (400 MHz, CDCl3):  = 2.13–2.24 (m, 1 H), 2.26–2.32 (m, 1 H),
2.34 (s, 6 H), 2.36–2.42 (m, 1 H), 2.47–2.57 (m, 1 H), 2.67–2.74 (m, 2
H), 3.54 (dd, J = 18.0, 3.7 Hz, 1 H), 3.80 (dd, J = 9.7, 3.7 Hz, 1 H), 3.97
(dd, J = 18.0, 9.7 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 1 H), 7.73 (dd, J = 7.8, 2.0
Hz, 1 H), 7.76 (d, J = 2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 19.5, 19.9, 20.3, 31.2, 34.6, 37.4, 38.0,
49.3, 116.0, 117.7, 126.1, 129.5, 130.3, 133.4, 137.5, 144.2, 194.0,
206.1.
(S)-1-((S)-1-Cyano-3-oxo-3-(p-tolyl)propyl)-2-oxocyclopentane-1-
carbonitrile (9b)
Yield: 46.5 mg (83%); brown solid; mp 117–118 °C; syn/anti = 69:31;
23
[]D = +3.7 (c 0.35, CH2Cl2); HPLC (ChiralPak IB; hexane/i-PrOH,
90:10; 1.0 mL/min;  =254 nm): tR = 32.9 (minor), 35.5 (major) min;
92% ee.
1H NMR (400 MHz, CDCl3):  = 2.14–2.25 (m, 1 H), 2.26–2.35 (m, 1 H),
2.36–2.42 (m, 1 H), 2.44 (s, 3 H), 2.47–2.57 (m, 1 H), 2.66–2.74 (m, 2
H), 3.56 (dd, J = 18.0, 3.7 Hz, 1 H), 3.80 (dd, J = 9.8, 3.7 Hz, 1 H), 3.99
(dd, J = 18.0, 9.8 Hz, 1 H), 7.30–7.32 (m, 2 H), 7.88–7.91 (m, 2 H).
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C18H18N2O2Na: 317.1260;
found: 317.1259.
(S)-1-((S)-1-Cyano-3-(4-methoxyphenyl)-3-oxopropyl)-2-oxocy-
clopentane-1-carbonitrile (9f)
13C NMR (100 MHz, CDCl3):  = 19.5, 21.8, 31.2, 34.7, 37.4, 37.9, 49.3,
116.0, 117.6, 128.5, 129.7, 133.0, 145.5, 193.8, 206.1.
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C17H16N2O2Na: 303.1104;
Yield: 41.5 mg (70%); white solid; mp 128–129 °C; syn/anti = 70:30;
[]D = +9.6 (c 1.00, CH2Cl2); HPLC (ChiralPak IC; hexane/i-PrOH,
23
found: 303.1102.
70:30; 1.0 mL/min;  =270 nm): tR = 47.0 (major), 71.2 (minor) min;
89% ee.
1H NMR (400 MHz, CDCl3):  = 2.13–2.24 (m, 1 H), 2.26–2.34 (m, 1 H),
2.35–2.43 (m, 1 H), 2.46–2.56 (m, 1 H), 2.65–2.73 (m, 2 H), 3.52 (dd,
J = 17.8, 3.7 Hz, 1 H), 3.80 (dd, J = 9.7, 3.7 Hz, 1 H), 3.89 (s, 3 H), 3.95
(dd, J = 17.8, 9.7 Hz, 1 H), 6.96–6.99 (m, 2 H), 7.96–7.99 (m, 2 H).
(S)-1-((S)-1-Cyano-3-oxo-3-(m-tolyl)propyl)-2-oxocyclopentane-
1-carbonitrile (9c)
Yield: 41.9 mg (75%); white solid; mp 92–93 °C; syn/anti = 78:22;
24
[]D = +0.5 (c 1.00, CH2Cl2); HPLC (ChiralPak IG; hexane/i-PrOH,
13C NMR (100 MHz, CDCl3):  = 19.5, 31.2, 34.6, 37.3, 37.7, 49.3, 55.7,
114.2, 116.0, 117.7, 128.5, 130.8, 164.5, 192.6, 206.1.
80:20; 1.0 mL/min;  =254 nm): tR = 26.7 (minor), 35.3 (major) min;
93% ee.
1H NMR (400 MHz, CDCl3):  = 2.14–2.25 (m, 1 H), 2.27–2.33 (m, 1 H),
2.34–2.42 (m, 1 H), 2.44 (s, 3 H), 2.47–2.57 (m, 1 H), 2.67–2.75 (m, 2
H), 3.57 (dd, J = 18.1, 3.6 Hz, 1 H), 3.80 (dd, J = 9.8, 3.6 Hz, 1 H), 4.01
(dd, J = 18.1, 9.8 Hz, 1 H), 7.38–7.42 (m, 1 H), 7.44–7.46 (m, 1 H), 7.79–
7.80 (m, 2 H).
13C NMR (100 MHz, CDCl3):  = 19.5, 21.4, 31.2, 34.6, 37.3, 38.1, 49.3,
116.0, 117.6, 125.6, 128.9, 128.9, 135.1, 135.4, 139.0, 194.4, 206.1.
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C17H16N2O3Na: 319.1053;
found: 319.1062.
(S)-1-((S)-3-(4-Bromophenyl)-1-cyano-3-oxopropyl)-2-oxocyclo-
pentane-1-carbonitrile (9g)
Yield: 57.8 mg (84%); brown solid; mp 177–179 °C; syn/anti = 65:35;
25
[]D = +4.8 (c 1.0, CH2Cl2); HPLC (ChiralPak IB; hexane/i-PrOH,
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C17H16N2O2Na: 303.1104;
90:10; 1.0 mL/min;  =254 nm): tR = 48.5 (minor), 58.0 (major) min;
found: 303.1112.
90% ee.
1H NMR (400 MHz, CDCl3):  = 2.14–2.25 (m, 1 H), 2.27–2.33 (m, 1 H),
2.33–2.45 (m, 1 H), 2.47–2.57 (m, 1 H), 2.68–2.74 (m, 2 H), 3.56 (dd,
J = 18.1, 3.6 Hz, 1 H), 3.78 (dd, J = 9.8, 3.5 Hz, 1 H), 4.00 (dd, J = 18.1,
9.9 Hz, 1 H), 7.67 (d, J = 8.4, 7.6 Hz, 2 H), 7.87 (d, J = 8.4 Hz, 2 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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H. Akutsu et al.
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Synthesis
13C NMR (100 MHz, CDCl3):  = 19.5, 31.2, 34.7, 37.4, 38.0, 49.1, 115.9,
117.4, 129.8, 129.9, 132.5, 134.1, 193.4, 206.1.
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C16H13N2O2BrNa: 367.0053;
found: 367.0051.
1H NMR (400 MHz, CDCl3):  = 2.14–2.25 (m, 1 H), 2.26–2.32 (m, 1 H),
2.34–2.42 (m, 1 H), 2.47–2.56 (m, 1 H), 2.66–2.74 (m, 2 H), 3.53 (dd,
J = 17.7, 3.8 Hz, 1 H), 3.79 (dd, J = 9.7, 3.8 Hz, 1 H), 3.96 (dd, J = 17.6,
9.7 Hz, 1 H), 7.20 (dd, J = 4.8, 3.9 Hz, 1 H), 7.75 (dd, J = 4.9, 0.9 Hz, 1 H),
7.84 (dd, J = 3.8, 0.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 19.5, 31.0, 34.6, 37.3, 38.4, 49.2, 115.8,
117.3, 128.6, 133.3, 135.4, 142.2, 186.9, 206.0.
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C14H12N2O2SNa: 295.0512;
found: 295.0519.
(S)-1-((S)-3-(4-Chlorophenyl)-1-cyano-3-oxopropyl)-2-oxocyclo-
pentane-1-carbonitrile (9h)
Yield: 48.8 mg (81%); brown solid; mp 167–169 °C; syn/anti = 61:39;
25
[]D = +3.5 (c 0.75, CH2Cl2); HPLC (ChiralPak IB; hexane/i-PrOH,
90:10; 1.0 mL/min;  =254 nm): tR = 39.7 (minor), 50.1 (major) min;
85% ee.
(S)-1-((S)-1-Cyano-3-(furan-2-yl)-3-oxopropyl)-2-oxocyclopen-
1H NMR (400 MHz, CDCl3):  = 2.14–2.25 (m, 1 H), 2.27–2.31 (m, 1 H),
2.34–2.44 (m, 1 H), 2.47–2.57 (m, 1 H), 2.68–2.74 (m, 2 H), 3.56 (dd,
J = 18.1, 3.6 Hz, 1 H), 3.79 (dd, J = 9.8, 3.5 Hz, 1 H), 4.01 (dd, J = 18.1,
9.9 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 2 H), 7.95 (d, J = 8.4 Hz, 2 H).
tane-1-carbonitrile (9l)
Yield: 39.7 mg (77%); white solid; mp 121–123 °C; syn/anti = 81:19;
25
[]D = +20.0 (c 1.00, CH2Cl2); HPLC (ChiralPak IC; hexane/i-PrOH,
70:30; 1.0 mL/min;  = 254 nm): tR = 41.2 (major), 95.6 (minor) min;
96% ee.
13C NMR (100 MHz, CDCl3):  = 19.6, 31.2, 34.7, 37.4, 38.0, 49.1, 115.9,
117.4, 129.4, 129.8, 133.6, 141.0, 193.2, 206.2.
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C16H13N2O2ClNa: 323.0558;
found: 323.0563.
1H NMR (400 MHz, CDCl3):  = 2.14–2.24 (m, 1 H), 2.24–2.31 (m, 1 H),
2.31–2.39 (m, 1 H), 2.45–2.55 (m, 1 H), 2.64–2.74 (m, 2 H), 3.42 (dd,
J = 17.7, 3.5 Hz, 1 H), 3.77 (dd, J = 9.9, 3.5 Hz, 1 H), 3.87 (dd, J = 17.7,
9.9 Hz, 1 H), 6.61 (dd, J = 3.6, 1.7 Hz, 1 H), 7.34 (dd, J = 3.6, 0.7 Hz, 1 H),
7.66 (dd, J = 1.7, 0.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 19.4, 30.4, 34.3, 37.2, 37.6, 49.3, 113.0,
115.8, 117.3, 118.7, 147.5, 151.5, 183.0, 205.9.
(S)-1-((S)-1-Cyano-3-oxo-3-(4-(trifluoromethyl)phenyl)propyl)-2-
oxocyclopentane-1-carbonitrile (9i)
Yield: 47.4 mg (71%); white solid; mp 167–169 °C; syn/anti = 61:39;
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C14H12N2O3Na: 279.0740;
24
[]D = −2.0 (c 0.75, CH2Cl2); HPLC (ChiralPak IB; hexane/i-PrOH,
found: 279.0742.
90:10; 1.0 mL/min;  =230 nm): tR = 38.7 (minor), 50.0 (major) min;
88% ee.
1H NMR (400 MHz, CDCl3):  = 2.15–2.26 (m, 1 H), 2.28–2.37 (m, 1 H),
2.38–2.48 (m, 1 H), 2.50–2.58 (m, 1 H), 2.68–2.76 (m, 2 H), 3.64 (dd,
J = 18.3, 3.7 Hz, 1 H), 3.80 (dd, J = 9.8, 3.6 Hz, 1 H), 4.08 (dd, J = 18.3,
9.8 Hz, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 8.12 (d, J = 8.3 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 19.6, 31.2, 34.7, 37.4, 38.3, 49.1, 115.8,
117.3, 123.5 (q, 1JC–F = 273.4 Hz), 126.2 (q, 3JC–F = 3.7 Hz), 135.7 (q, 2JC–F
= 32.0 Hz), 138.0, 193.6, 206.1.
(S)-1-((S)-1-Cyano-3-oxo-3-phenylpropyl)-2-oxocyclohexane-1-
carbonitrile (9m)
24
Yield: 42.4 mg (76%); yellow oil; syn/anti = 63:37; []D = +88.2 (c
0.50, CH2Cl2); HPLC (ChiralPak IG; hexane/i-PrOH, 70:30; 1.0 mL/min;
 = 254 nm): tR = 20.7 (minor), 47.7 (major) min; 93% ee.
1H NMR (400 MHz, CDCl3):  = 1.74–1.86 (m, 1 H), 2.02–2.10 (m, 1 H),
2.11–2.19 (m, 2 H), 2.22–2.28 (m, 1 H), 2.38–2.50 (m, 1 H), 2.59–2.64
(m, 1 H), 2.86–2.95 (m, 1 H), 3.37 (dd, J = 18.0, 3.6 Hz, 1 H), 3.75 (dd,
J = 9.2, 3.5 Hz, 1 H), 3.94 (dd, J = 18.0, 9.2 Hz, 1 H), 7.48–7.52 (m, 2 H),
7.61–7.65 (m, 1 H), 7.96–7.99 (m, 2 H).
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C17H13N2O2F3Na: 357.0821;
found: 357.0821.
13C NMR (100 MHz, CDCl3):  = 22.5, 27.6, 31.1, 37.8, 38.2, 39.5, 53.1,
117.0, 117.8, 128.3, 129.0, 134.3, 135.5, 194.2, 199.7.
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C17H16N2O2Na: 303.1104;
found: 303.1106.
4-((S)-3-Cyano-3-((S)-1-cyano-2-oxocyclopentyl)propanoyl)ben-
zonitrile (9j)
Yield: 46.2 mg (79%); white solid; mp 138–140 °C; syn/anti = 58:42;
25
[]D = +3.2 (c 0.75, CH2Cl2); HPLC (ChiralPak IG; hexane/i-PrOH,
70:30; 1.0 mL/min;  = 254 nm): tR = 23.8 (minor), 32.6 (major) min;
78% ee.
(S)-2-((S)-1-Cyano-3-oxo-3-phenylpropyl)-1-oxo-2,3-dihydro-1H-
1H NMR (400 MHz, CDCl3):  = 2.15–2.26 (m, 1 H), 2.26–2.37 (m, 1 H),
2.39–2.46 (m, 1 H), 2.48–2.58 (m, 1 H), 2.68–2.76 (m, 2 H), 3.63 (dd,
J = 18.4, 3.6 Hz, 1 H), 3.79 (dd, J = 9.9, 3.6 Hz, 1 H), 4.08 (dd, J = 18.4,
9.9 Hz, 1 H), 7.82–7.85 (m, 2 H), 8.09–8.12 (m, 2 H).
indene-2-carbonitrile (9n)
Yield: 62.2 mg (99%); white solid; mp 151–153 °C; syn/anti = 52:48;
[]D24 = −1.2 (c 1.00, CH2Cl2).
HPLC (ChiralPak IG; hexane/i-PrOH, 80:20; 1.0 mL/min;  = 254 nm):
tR = 48.5 (minor), 65.8 (major) min; 78% ee.
13C NMR (100 MHz, CDCl3):  = 19.4, 31.1, 34.6, 37.3, 38.2, 48.9, 115.7,
117.0, 117.6, 128.7, 132.8, 138.1, 193.2, 206.0.
HRMS (ESI−-TOF): m/z [M – H]– calcd for C17H12N3O2: 290.0935;
found: 290.0930.
1H NMR (400 MHz, CDCl3):  = 3.63 (d, J = 17.8 Hz, 1 H), 3.67 (dd, J =
17.8, 3.0 Hz, 1 H), 3.92 (d, J = 17.7 Hz, 1 H), 3.97 (dd, J = 17.8, 10.3 Hz,
1 H), 4.07 (dd, J = 10.3, 3.0 Hz, 1 H), 7.50–7.54 (m, 2 H), 7.54–7.59 (m,
2 H), 7.62–7.66 (m, 1 H), 7.77–7.91 (m, 1 H), 7.89–7.91 (m, 1 H), 7.99–
8.01 (m, 2 H).
(S)-1-((S)-1-Cyano-3-oxo-3-(thiophen-2-yl)propyl)-2-oxocyclo-
13C NMR (100 MHz, CDCl3):  = 33.0, 37.6, 38.4, 47.6, 116.8, 117.1,
126.1, 126.7, 128.4, 129.0, 129.5, 133.3, 134.3, 135.4, 137.6, 150.4,
194.2, 194.5.
pentane-1-carbonitrile (9k)
Yield: 41.3 mg (76%); white solid; mp 166–168 °C; syn/anti = 78:22;
25
[]D = +7.6 (c 1.00, CH2Cl2); HPLC (ChiralPak IB; hexane/i-PrOH,
HRMS (ESI+-TOF): m/z [M + Na]+ calcd for C20H14N2O2Na: 337.0947;
found: 337.0948.
90:10; 1.0 mL/min;  = 254 nm): tR = 55.6 (minor), 60.7 (major) min;
96% ee.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

G
H. Akutsu et al.
Paper
Synthesis
(S)-1-((S)-1-Cyano-3-oxo-3-phenylpropyl)-2-oxocycloheptane-1-
carbonitrile (9o)
References
(1) For reviews, see: (a) Hawner, C.; Alexakis, A. Chem. Commun.
2010, 46, 7295. (b) Shimizu, M. Angew. Chem. Int. Ed. 2011, 50,
5998. (c) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593; and
references cited therein.
(2) For reviews, see: Pierrot, D.; Marek, I. Angew. Chem. Int. Ed.
2020, 59, 36.
(3) (a) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928.
(b) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc.
2007, 129, 768. (c) Luo, J.; Xu, L. W.; Hay, R. A. S.; Lu, Y. Org. Lett.
2009, 11, 437. (d) Li, H.; Song, J.; Deng, L. Tetrahedron 2009, 65,
3139. (e) Chen, P.; Bao, X.; Zhang, L.-F.; Ding, M.; Han, X.-J.; Li,
J.; Zhang, G.-B.; Tu, Y.-Q.; Fan, C.-A. Angew. Chem. Int. Ed. 2011,
50, 8161. (f) Lee, H. J.; Woo, S. B.; Kim, D. Y. Tetrahedron Lett.
2012, 53, 3374. (g) Wei, M.-X.; Wang, C.-T.; Du, J.-Y.; Qu, H.; Yin,
P.-R.; Bao, X.; Ma, X.-Y.; Zhao, X.-H.; Zhang, G.-B.; Fun, C.-A.
Chem. Asian J. 2013, 8, 1966. (h) Chen, P.; Bao, X.; Zhang, L.-F.;
Liu, G.-J.; Jiang, Y.-J. Eur. J. Org. Chem. 2016, 704.
Yield: 61.4 mg (quant.); white solid; mp 154–156 °C; syn/anti =
64:36; []D = –10.6 (c 0.50, CH2Cl2); HPLC (ChiralPak IB; hexane/i-
PrOH, 90:10; 1.0 mL/min;  = 254 nm): tR = 29.4 (minor), 32.8 (major)
min; 72% ee.
1H NMR (400 MHz, CDCl3):  = 1.35–1.44 (m, 1 H), 1.79–1.88 (m, 2 H),
1.98–2.10 (m, 4 H), 2.22–2.28 (m, 1 H), 2.79–2.96 (m, 2 H), 3.45 (dd,
J = 18.1, 3.4 Hz, 1 H), 3.66 (dd, J = 18.1, 9.5 Hz, 1 H), 3.83 (dd, J = 9.5,
3.4 Hz, 1 H), 7.50 (t, J = 7.7 Hz, 2 H), 7.63 (t, J = 7.3 Hz, 1 H), 7.96 (d, J =
7.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 24.0, 26.2, 28.2, 35.0, 38.3, 42.2, 55.6,
117.6, 117.7, 128.4, 129.1, 134.4, 135.4, 194.0, 202.6.
29
HRMS (ESI+-TOF): m/z [M + H]+ calcd for C18H19N2O2: 295.1447;
found: 295.1439.
Procedure for the Gram-Scale Experiment
To a solution of -cyanoenone 8a (785.9 mg, 5.0 mmol) and organo-
catalyst 6 (228.3 mg, 0.5 mmol) in toluene (40 mL) was added -cya-
noketone 7a (501. L, 5.0 mmol) at r.t. After stirring at r.t. the for indi-
cated time, the reaction mixture was purified by flash column chro-
matography on silica gel with a 10:1 to 6:1 mixture of hexane and
acetone to afford 9a (1.07 g, 80% yield, syn/anti = 73:27, 94% ee).
(4) Kawato, Y.; Takahashi, N.; Kumagai, N.; Shibasaki, M. Org. Lett.
2010, 12, 1484.
(5) (a) Kanada, Y.; Yuasa, H.; Nakashima, K.; Murahashi, M.; Tada,
N.; Itoh, A.; Koseki, Y.; Miura, T. Tetrahedron Lett. 2013, 54, 4896.
(b) Nakashima, K.; Hirashima, S.; Kawada, M.; Koseki, Y.; Tada,
N.; Itoh, A.; Miura, T. Tetrahedron Lett. 2014, 55, 2703.
(c) Hirashima, S.; Sakai, T.; Nakashima, K.; Watanabe, N.; Koseki,
Y.; Mukai, K.; Kanada, Y.; Tada, N.; Itoh, A.; Miura, T. Tetrahedron
Lett. 2014, 55, 4334. (d) Hirashima, S.; Nakashima, K.; Fujino, Y.;
Arai, R.; Sakai, T.; Kawada, M.; Koseki, Y.; Murahashi, M.; Tada,
N.; Itoh, A.; Miura, T. Tetrahedron Lett. 2014, 55, 4619.
(e) Nakashima, K.; Hirashima, S.; Akutsu, H.; Koseki, Y.; Tada, N.;
Itoh, A.; Miura, T. Tetrahedron Lett. 2015, 56, 558. (f) Hirashima,
S.; Arai, R.; Nakashima, K.; Kawai, N.; Kondo, J.; Koseki, Y.;
Miura, T. Adv. Synth. Catal. 2015, 357, 3863. (g) Akutsu, H.;
Nakashima, K.; Hirashima, S.; Kitahara, M.; Koseki, Y.; Miura, T.
Tetrahedron Lett. 2017, 58, 4759. (h) Arai, R.; Hirashima, S.;
Kondo, J.; Nakashima, K.; Koseki, Y.; Miura, T. Org. Lett. 2018, 20,
5569. (i) Arai, R.; Hirashima, S.; Nakano, T.; Kawada, M.; Akutsu,
H.; Nakashima, K.; Miura, T. J. Org. Chem. 2020, 85, 3872.
(6) Nakashima, K.; Noda, Y.; Hirashima, S.; Koseki, Y.; Miura, T.
J. Org. Chem. 2018, 83, 2402.
Transformation of the Conjugate Addition Products
To a solution of (S)-1-((S)-1-cyano-3-oxo-3-phenylpropyl)-2-oxocy-
clopentane-1-carbonitrile (9a; 93% ee, 79.9 mg, 0.3 mmol) in THF (4
mL) was added SmI2 (12 mL, 1.2 mmol; 0.1 M in THF) at r.t. After stir-
ring at r.t. for 5 h, the mixture was diluted with Et2O and the reaction
was quenched with sat. NaHCO3 aq., then the resulting biphasic mix-
ture was extracted with Et2O. The combined organic layers were
washed with brine and dried over Na2SO4. The mixture was concen-
trated in vacuo and the residue was purified by flash column chromatog-
raphy on silica gel with a 3:1 mixture of hexane and EtOAc to afford 10.
(1S,3R,3aR,6aS)-3,3a-Dihydroxy-3-phenylhexahydropentalene-
1,6a(1H)-dicarbonitrile (10)
24
Yield: 58.8 mg (73%); white solid; mp 120–122 °C; []D = +44.7 (c
1.00, CHCl3).
(7) Liu, Y.; Nappi, M.; Escudero-Adán, E. C.; Melchiorre, P. Org. Lett.
2012, 14, 1310.
1H NMR (400 MHz, CDCl3):  = 1.25–1.35 (m, 1 H), 1.57–1.63 (m, 1 H),
1.71–1.79 (m, 1 H), 1.91–2.02 (m, 1 H), 2.10–2.17 (m, 1 H), 2.50–2.54
(m, 1 H), 2.55–2.57 (m, 1 H), 2.58–2.60 (m, 1 H), 2.69 (d, J = 9.9 Hz, 1
H), 3.84–3.87 (m, 1 H), 3.89 (s, 1 H), 7.39–7.42 (m, 3 H), 7.48–7.51 (m, 2 H).
13C NMR (100 MHz, CDCl3):  = 25.7, 34.3, 38.0, 38.1, 38.4, 53.1, 81.1,
94.3, 118.1, 120.6, 126.1, 128.8, 129.1, 139.2.
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HRMS (ESI−-TOF): m/z [M − H]− calcd for C16H15N2O2: 267.1139;
found: 267.1129.
Acknowledgment
The authors would like to thank Enago (www.enago.jp) for the En-
glish language review.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707285. Su
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