Chloramphenicol base chemistry. Part 11: chloramphenicol base-derived thiourea-catalyzed enantioselective Michael addition of malononitrile to α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetasy.2017.05.015

The first chloramphenicol base-derived thiourea-catalyzed enantioselective Michael addition of malononitrile to α,β-unsaturated ketones is reported. The Michael adducts were obtained in good to excellent yields (up to 98% yield) and enantioselectivities (up to 94% ee). This reaction has a broad substrate scope to various α,β-unsaturated ketones. With this in mind, this methodology was successfully applied to the synthesis of a chiral piperidone, an advanced building block for dihydropyridinone P2X₇ receptor antagonists.

Full text of DOI:10.1016/j.tetasy.2017.05.015

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chloramphenicol base chemistry. Part 11:1 chloramphenicol
base-derived thiourea-catalyzed enantioselective Michael
addition of malononitrile to a,b-unsaturated ketones
⇑
Linjie Yan, Haifeng Wang, Fangjun Xiong, Yuan Tao, Yan Wu, Fener Chen
Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of China
Engineering Center of Catalysis and Synthesis for Chiral Molecules at Fudan University, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first chloramphenicol base-derived thiourea-catalyzed enantioselective Michael addition of
malononitrile to ,b-unsaturated ketones is reported. The Michael adducts were obtained in good to
excellent yields (up to 98% yield) and enantioselectivities (up to 94% ee). This reaction has a broad sub-
strate scope to various ,b-unsaturated ketones. With this in mind, this methodology was successfully
Received 15 March 2017
Revised 13 May 2017
Accepted 23 May 2017
Available online xxxx
a
a
applied to the synthesis of a chiral piperidone, an advanced building block for dihydropyridinone P2X7
receptor antagonists.
Ó 2017 Published by Elsevier Ltd.
1. Introduction
Motivated by the promising catalytic results and our continuing
interest in the chloramphenicol base organocatalysis, we decided
It is well known that there has been a growing interest in the
catalytic asymmetric Michael addition of malononitriles to ,b-
to investigate the possibility of enantioselective Michael additions
a
of malononitrile to
a,b-unsaturated ketones using our previously
unsaturated ketones,2 versatile building blocks for the preparation
of pharmaceuticals, agrochemicals and natural products.3 To date,
a variety of organocatalysts have been discovered and proven to be
highly effective and selective for this transformation.4 In particular,
chiral bifunctional amine-thiourea organocatalysts provide an
important subset (see Fig. 1),5 such as the cinchona alkaloids 1,
cyclohexane diamine 2, diphenyl ethylene diamine 3, natural
amino acid 4 and Brønsted acid/base BINOL 5, because of their
simultaneous activation of both nucleophile and electrophile
through efficient double-hydrogen-bonding interactions. However,
cinchona alkaloid-type organocatalysts are the most common,
while organocatalysts bearing unnatural scaffolds are rare. There-
fore, the search for alternative cost-effective and easily prepared
organocatalysts for the asymmetric Michael additions is warranted
in asymmetric catalysis.
N
H
N
H
N
S
Ar
Ar
MeO
S
N
H
N
H
N
N
1
2
S
Ph
N
S
Ar
N
Ph
Ar
N
H
N
N
Bn
H
H
H
NH2
4
3
Over the past few decades, we have developed an array of effi-
cient organocatalysts, which are readily available from the very
inexpensive chiral chloramphenicol base scaffold, including ureas,
thioureas 6, sulfonamides and squaramides, and reported their
application in various asymmetric transformations with high
stereocontrol.6
R1
R1
N
S
Ar
OR2
N
H
N
H
H
HN
N
O2N
N
Ar
S
6
5
⇑
Corresponding author.
E-mail address: rfchen@fudan.edu.cn (F. Chen).
Figure 1. Structures of bifunctional thiourea organocatalysts.
http://dx.doi.org/10.1016/j.tetasy.2017.05.015
0957-4166/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Yan, L.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.015

2
L. Yan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
developed bifunctional organocatalysts with a chloramphenicol
base motif.6d Herein, we report an account of the results on this
subject and their application in the asymmetric synthesis of a
key chiral piperidone intermediate for the preparation of
dihydropyridinone P2X7 receptor antagonists.6b,7
enantioselectivities (80–86% ee) (Table 1, entries 1–3). Catalyst
6a gave the most promising results in terms of the enantioselectiv-
ity (86% ee) and chemical yield (81%) of the product (Table 1, entry
1). Catalyst 6e bearing a p-methyl substituent on the aromatic ring
of its thiourea-moiety gave much lower enantioselectivity than
catalyst 6d bearing a p-trifluoromethyl group at the same position
(Table 1, entries 4 and 5). Furthermore, catalyst 6f without a tert-
butyldimethylsilyl (TBS) group showed lower enantioselectivity
(45% ee, Table 1, entry 6). Catalyst 7 gave lower enantioselectivity
than its regioisomeric counterpart 6a (56% ee, Table 1, entry 7). In
addition to thiourea organocatalysts, we also examined other types
of bifunctional organocatalysts derived from chloramphenicol
base. Moderate enantioselectivities were obtained with the urea
catalyst 8 (65% ee) and the squaramide catalyst 9 (68% ee) (Table 1,
entries 8–9). In contrast, the use of sulfonamide 10 featuring a sin-
gle N–H group led to a considerable decrease in the yield and enan-
tioselectivity (20% yield, 4% ee, Table 1, entry 10).
2. Results and discussion
We initially selected the asymmetric Michael addition of
malononitrile to a,b-unsaturated ketone 11a as a model reaction.
A variety of different bifunctional chloramphenicol base-derived
organocatalysts were screened against this reaction in toluene at
room temperature using a catalyst loading of 10 mol% (Table 1).
The results revealed that the outcome of the Michael addition reac-
tion varied greatly depending on the nature of the organocatalyst.
Thiourea catalysts 6a–c bearing modifications totheir tertiary
amine moiety were used in a similar manner to provide the desired
adduct 13a in moderate to good yields (67–81%) and with good
Having identified thiourea 6a as the optimal catalyst for this
transformation, we proceeded to investigate the effect of the sol-
vent on the reactivity and enantioselectivity of the asymmetric
Table 1
Michael addition of malononitrile to a,b-ketone 11a at room tem-
The screening of different bifunctional organocatalysts derived from chloramphenicol
perature. The results revealed that toluene gave the best enantios-
electivity (86% ee) (Table 2, entry 1), whereas MeCN and EtOH gave
low yields of the desired addition product with no enantioselectiv-
ity (Table 2, entries 9–10). A slight decrease in the enantioselectiv-
ity was observed in xylene (83% ee) (Table 2, entry 2). Hexane,
CH2Cl2 and CHCl3 gave moderate yields of the desired addition pro-
duct (55–74%) with reasonable enantioselectivities (67–76% ee),
while methyl tert-butyl ether gave a low yield (22%) (Table 2,
entries 3–6). The use of 1,4-dioxane or tetrahydrofuran (THF) led
to a decrease in the enantioselectivity (38–50% ee) and a poor yield
(12–18%) (Table 2, entries 7 and 8). Some of the other reaction
parameters were also investigated, including the catalyst loading,
concentration and temperature, but offered very little improve-
ment in the reaction rate with equivalent and lower levels of enan-
tioselectivities (55–86% ee) (Table 2, entries 11–13).
basea
S
R1
R1
N
Ar
HN
N
H
OR2
OTBS
H
O2N
HN
N
N
R3
O2N
S
Ar = 3,5-(CF3)2Ph
6
7
: R1 = Me, R2 = TBS, R3 = 3,5-(CF3)2;
O
6a
6b: R1 = (CH2)4, R2 = TBS, R3 = 3,5-(CF3)2;
6c: R1 = (CH2)5, R2 = TBS, R3 = 3,5-(CF3)2;
Ar
HN
N
: R1 = Me, R2 = TBS, R3 = 4-CF3;
: R1 = Me, R2 = TBS, R3 = 4-CH3;
H
6d
6e
OTr
6f: R1 = Me, R2 = OH, R3 = 3,5-(CF3)2.
With the optimal reaction conditions in hand, we proceeded to
investigate the scope of this asymmetric Michael addition by react-
N
O2N
ing malononitrile with a variety of a,b-unsaturated ketones 11, and
Ar = 3,5-(CF3)2Ph, Tr = Ph3C
the results are shown in Table 3. Substrates bearing a variety of dif-
ferent electronic and sterically demanding substituents on the aro-
matic ring (R1) were well tolerated, including naphthyl and
heteroaromatic groups, which reacted smoothly to afford the cor-
responding addition products in moderate to high yields (65–
98%) and with good enantioselectivities (78–86% ee) (Table 3,
entries 1–18). 2,4-Dien-1-one 11s afforded the 1,4-adduct with
84% ee (Table 3, entry 19). When R1 were alkyl groups, good enan-
tioselectivities (81–88% ee) were also obtained, albeit with low
yields (25–50%) (Table 3, entries 20–21). A variety of different sub-
stituents were also tolerated on the aromatic ring of the R2 group,
with the corresponding adducts being obtained in high yields (85–
95%) with good to high enantioselectivities (77–94% ee) after a long
reaction period (Table 3, entries 22–26).
To explain the stereoselectivity observed in this reaction, we
have proposed a plausible reaction pathway for the Michael addi-
tion of malononitrile 12 to a,b-unsaturated ketone 11a in the pres-
ence of the bifunctional chloramphenicol base-derived thiourea
organocatalyst 6a, which is shown in Scheme 1. The chlorampheni-
col base-derived thiourea organocatalyst 6a plays a bifunctional
role in the catalytic process. Malononitrile 12 would be deproto-
nated by the tertiary amine moiety of 6a, and the resulting pronu-
cleophile would be activated by hydrogen bonding with the
protonated tertiary amine nitrogen, whereas the thiourea moiety
8
O
O
O
O
S
Ar
HN
Ar
HN
N
H
OTr
OTr
N
N
O2N
O2N
Ar = 3,5-(CF3)2Ph, Tr = Ph3C
Ar = 3,5-(CF3)2Ph, Tr = Ph3C
10
9
Entry
Catalyst
Yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
9
10
6a
6b
6c
6d
6e
6f
7
8
9
10
81
67
71
63
68
88
69
80
66
20
86
82
80
76
34
45
56
65
68
4
a
Unless otherwise noted, all reactions were carried out with
a
, b-unsaturated
ketone 11a (0.2 mmol), malononitrile 12 (0.3 mmol) and catalyst (10 mol%) in 0.4
mL toluene at r.t. for 7 days.
b
Yield of isolated product.
Determined by HPLC.
of 6a would activate the carbonyl group of the
a,b-unsaturated
c
d
ketone 11a through double hydrogen bonding, to give a ternary
Absolute configuration was determined by comparing the sign of the specific
rotation of the major enantiomer with known data.
complex. The pronucleophile would subsequently attack the acti-
Please cite this article in press as: Yan, L.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.015

L. Yan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 2
Optimization of the reaction conditions with catalyst 6aa
O
NC
Ph
CN
NC
CN
O
, 6a (10 mol%)
12
Ph
Ph
Ph
solvent, r.t.
11a
13a
Entry
Solvent
t (d)
Yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
Toluene
Xylene
Hexane
CHCl3
CH2Cl2
MTBE
1,4-Dioxane
THF
EtOH
7
7
7
7
7
7
7
7
7
7
6.5
4
5
81
89
71
74
55
22
18
12
21
15
82
93
73
86
83
67
76
68
74
50
38
6
rac
86
63
55
9
10
11e
12f
13g
MeCN
Toluene
Toluene
Toluene
a
Unless otherwise noted, all reactions were carried out with
solvent at r.t.
a, b-unsaturated ketone 11a (0.2 mmol), malononitrile 12 (0.3 mmol) and catalyst 6a (10 mol%) in 0.4 mL
b
Yield of isolated product.
Determined by HPLC.
c
d
e
f
Absolute configuration was determined by comparing the sign of the specific rotation of the major enantiomer with known data.
20 mol% catalyst was used.
0.2 mL toluene was used.
g
Reaction was performed at 50 °C.
Table 3
Asymmetric Michael addition of malononitrile 12 to a series of
a
,b-unsaturated ketones 11 in the presence of catalyst 6aa
CN
NC
O
NC
CN
O
6a
,
(10 mol%)
12
R1
R2
R1
R2
toluene, r.t.
11
13
Entry
R1
R2
t (d)
Yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7
7
7
7
7
7
7
7
7
7
7
7
7
8
8
7
8
81 13a
81 13b
78 13c
83 13d
98 13e
89 13f
96 13g
91 13h
95 13i
88 13j
85 13k
96 13l
93 13m
65 13n
88 13o
85 13p
88 13q
83 13r
30 13s
50 13t
25 13u
90 13v
95 13w
93 13x
85 13y
95 13z
86
82
80
80
79
78
82
80
84
80
82
82
80
80
84
82
75
79
84
86
88
94
85
77
87
91
4-MePh
4-MeOPh
3-MeOPh
4-FPh
2-FPh
4-ClPh
3-ClPh
4-BrPh
3-BrPh
2-BrPh
4-CF3Ph
3-CF3Ph
4-tBuPh
3,4-Cl2Ph
2-Naphthyl
2-Thienyl
5-Cl-2-Thienyl
Ph(CH)2
Cyclohexyl
t-Bu
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
8
10
10
10
8
3.5
8
Ph
Ph
Ph
Ph
4-MeOPh
4-NO2Ph
4-ClPh
2-Naphthyl
2-Thienyl
8
8
Ph
a
Unless otherwise noted, all reactions were carried out with
toluene at r.t.
a, b-unsaturated ketones 11 (0.2 mmol), malononitrile 12 (0.3 mmol) and catalyst 6a (10 mol%) in 0.4 mL
b
Yield of isolated product.
Determined by HPLC.
c
d
Absolute configuration was determined by comparing the sign of the specific rotation of the major enantiomer with known data.
Please cite this article in press as: Yan, L.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.015

4
L. Yan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
vated 11a from the Si face leading to the formation of the (S)-con-
figured product as the major stereoisomer, which is consistent
with the observed results.
To illustrate the synthetic utility of this methodology, we con-
ducted a novel enantioselective synthesis of the chiral piperidone
(S)-19, which is a key intermediate in the synthesis of dihydropy-
ridinone P2X7 receptor antagonists (Scheme 2).6b,7 Our synthetic
N
NC
Ph
CN
O
OTBS
Ar
CN
H
Ph
HN
N
CF3
13a
NC
12
S
6a
CF3
strategy started from the known
which was obtained via the aldol condensation of 4-
fluorobenzaldehyde and acetophenone under standard
a,b-unsaturated ketone 11e,
CF3
CF3
Ar = p-NO2-Phenyl
conditions.8 The asymmetric Michael addition of malononitrile to
11e in the presence of 10 mol% catalyst 6a was carried out in toluene
at room temperature to give the addition product (S)-13e in 92%
yield and with 89% ee. The enantiomeric purity of 13e was upgraded
to >99% ee following a single recrystallization from n-hexane/EtOAc
(8:1, v/v). The hydrolysis and decarboxylation of (S)-13e with acetic
acid and concentrated HCl were conducted as a one-pot procedure
to give acid 14 in 90% yield. Acid 14 was treated with thionyl chlo-
ride in toluene at reflux, and the resulting acid chloride was reacted
with benzyl alcohol and triethylamine to give ester 15 in 92% yield.
Ester 15 was converted into diester 16 in 66% yield via a Baeyer–Vil-
liger oxidation using m-chloroperoxy benzoic acid (mCPBA) as an
oxidant in the presence of KH2PO4 in boiling CH2Cl2.9 Diester 16
was then debenzylated by hydrogenation with Pd/C in THF at
60 °C to provide acid 17, which was transesterified in MeOH with
Na2CO3 to furnish 18 in 83% yield. The chiral acid methyl ester 18
F3C
F3C
NC
S
S
N
N
OTBS
Ar
H
H
N
N
CN
N
OTBS
O
H
H
H
N
C
Ph
Ph
CF3
Ar
N
H
HC
C
N
F3C
S
N
H
N
N
N
C
OTBS
Ph
O
H
H
H
N
C
C
Ph
O
11a
Ar
Ph
Ph
Scheme 1. Plausible mechanism for the Michael addition of malononitrile 12 to
b-unsaturated ketone 11a in the presence of the bifunctional chloramphenicol
base-derived thiourea organocatalyst 6a.
a
,
was converted into chiral piperidone (S)-19 through sequential a-
formylation and cyclization reactions using Huang’s procedure.7
3. Conclusion
NC
CN
O
CN
NC
6a (10 mol%),
toluene, r.t., 7 days
O
In conclusion, bifunctional chloramphenicol base-derived
thiourea organocatalysts were successfully applied for the first
12
Ph
Ph
time to the asymmetric Michael addition of malononitrile to
unsaturated ketones. The optimal catalyst 6a allowed for the addi-
tion of malononitrile to a broad range of ,b-unsaturated ketones
a,b-
F
F
13e
11e
5.7 g scale
a
92% yield, 89% ee
after recrystallization: 71% yield, >99% ee
to afford the corresponding adducts with good yields and enantios-
electivities. Moreover, the utility of this methodology was demon-
strated by the synthesis of the chiral piperidone, an advanced
building block in the construction of P2X7 receptor antagonists.
Further investigation into the application of these catalysts in other
asymmetric transformations is currently underway in our
laboratory.
COOH
O
SOCl2, BnOH, Et3N
con. HCl, AcOH
reflux
Ph
toluene, reflux
F
14
90% yield
COOBn
O
COOBn
4. Experimental
4.1. General
m-CPBA, KH2PO4
COOPh
Ph
CH2Cl2, reflux
F
F
15
92% yield
16
66% yield
Unless otherwise specified, all reagents and solvent were pur-
chased from commercial sources and used as received. 1H
(400 MHz) and 13C (100 MHz) NMR were recorded on a Bruker
Avance 400 spectrometer in CDCl3 or d6-DMSO using tetramethyl
silane (TMS) as internal standards. Coupling constant (J) values
are given in Hz. Melting points were measured on WRS-1B digital
melting-point apparatus. Products were purified by flash column
chromatography on silica gel purchased from Qingdao Haiyang
Chemical Co., Ltd. Optical rotations were measured by a Rudolph
AUTOPOL I Automatic Polarimeter. HRMS were recorded on a Bru-
ker micrOTOF spectrometer. HPLC analysis were performed with
COOH
MeOH
Pd/C, H2
THF, 60 oC
COOPh
Na2CO3
F
F
17
80% yield
COOH
COOMe
ref. 6
COOMe
Daicel Chiralpak AD-H column (25 cm  4.6 mm  5
pak OD-H column (25 cm  4.6 mm  5 m) and Chiralpak AS-H
column (25 cm  4.6 mm  5 m). All catalysts were prepared
according to reported procedure.6d
,b-Unsaturated ketones were
prepared via aldol condensation using standard conditions.8
lm), Chiral-
O
N
H
F
l
18
83% yield
l
19
a
Scheme 2. Application of 6a in the asymmetric synthesis of (S)-piperidone 19.
Please cite this article in press as: Yan, L.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.015

L. Yan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
4.2. Typical procedure for asymmetric Michael addition of
malononitrile 12 to ,b-unsaturated ketones 11
4.2.5. (S)-2-(1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl)malono-
a
nitrile 13e
White solid, yield 98%, 79% ee; m.p. 103.8–106.2 °C; [
a]
20 = À0.4
D
To
a
stirred solution of the
a
,b-unsaturated ketones 11
(c 1.0, CH2Cl2) (lit.2h
[a
]
D
20 = À5.6 (c 0.288 in CH2Cl2)); chiral HPLC
(0.2 mmol) and catalyst 6a (12.5 mg, 0.02 mmol) in toluene
(0.4 mL) was added the malononitrile 12 (0.3 mmol) at room tem-
perature. The reaction was monitored by TLC; after complete con-
(Chiralcel AD-H column), hexane/i-PrOH = 80/20, flow rate:
1.0 mL/min, UV detection at 254 nm, t(minor) = 9.023 min,
t
(major) = 12.8 min; 1H NMR (400 MHz, CDCl3) d = 8.00–7.93 (m,
2H), 7.67–7.60 (m, 1H), 7.55–7.41 (m, 4H), 7.18–7.09 (m, 2H),
4.62 (d, J = 5.1 Hz, 1H), 3.97 (dt, J = 8.4, 5.3 Hz, 1H), 3.65 ppm (qd,
J = 18.4, 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) d = 196.47,
164.27, 161.80, 135.74, 134.29, 132.40, 129.93, 129.84, 129.00,
128.14, 116.50, 116.28, 111.85, 111.63, 40.58, 40.18, 28.93 ppm.
sumption of the
a,b-unsaturated ketones 11, the solvent was
evaporated under reduced pressure and the crude product was
purified by flash chromatography with petroleum ether (PE)/
EtOAc = 8/1.
4.2.1. (S)-2-(3-Oxo-1,3-diphenylpropyl)malononitrile 13a
White solid, yield 81%, 86% ee; m.p. 123.2–128.1 °C; [
a
]
20 = À4.0
4.2.6. (S)-2-(1-(2-Fluorophenyl)-3-oxo-3-phenylpropyl)malono-
D
(c 1.0, CH2Cl2) (lit.2h
[
a]
D
20 = À12.6 (c 0.27, CH2Cl2)); chiral HPLC
nitrile 13f
(Chiralcel AD-H column), hexane/i-PrOH = 80/20, flow rate:
Yellow solid, yield 89%, 78% ee; m.p. 82.8–84.2 °C; [a]
20 = +20 (c
D
1.0 mL/min, UV detection at 254 nm, t(minor) = 8.965 min,
t
0.24, CH2Cl2); chiral HPLC (Chiralcel AD-H column), hexane/i-
PrOH = 80/20, flow rate: 1.0 mL/min, UV detection at 254 nm, t
(minor) = 9.745 min, t(major) = 11.047 min; 1H NMR (400 MHz,
CDCl3) d = 8.01–7.92 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.49 (t,
J = 7.7 Hz, 3H), 7.38 (td, J = 7.4, 1.5 Hz, 1H), 7.28–7.10 (m, 2H),
4.63 (d, J = 6.3 Hz, 1H), 4.39 (q, J = 6.8 Hz, 1H), 3.71 ppm (d,
J = 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) d = 196.07, 161.78,
159.32, 135.76, 134.17, 130.88, 130.79, 129.11, 129.08, 128.95,
128.13, 125.09, 125.05, 123.80, 123.67, 116.49, 116.27, 111.63,
111.59, 39.52, 35.11, 27.66 ppm. HRMS (ESI+) calcd for C18H13FN2-
O [M+H]+ = 293.1085, found: 293.1092.
(major) = 11.695 min; 1H NMR (400 MHz, CDCl3) d = 7.97 (d,
J = 7.6 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.54–7.37 (m, 7H), 4.64 (d,
J = 5.1 Hz, 1H), 3.97 (dt, J = 7.9, 5.4 Hz, 1H), 3.78–3.59 ppm (m,
2H). 13C NMR (100 MHz, CDCl3) d = 196.69, 136.60, 135.85,
134.19, 129.37, 129.20, 128.96, 128.15, 128.05, 111.94, 111.78,
41.24, 40.15, 28.84 ppm.
4.2.2. (S)-2-(1-(4-Methylphenyl)-3-oxo-3-phenylpropyl)malono-
nitrile 13b
Yellow oil, yield 81%, 82% ee; [
a
]
D
20 = À1.3 (c 1.0, CH2Cl2) (lit.2h
[
a]
D
20 = À2.4 (c 0.166, CH2Cl2)); chiral HPLC (Chiralcel AD-H
column), hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV
detection at 254 nm, t(minor) = 8.767 min, t(major) = 12.262 min;
1H NMR (400 MHz, CDCl3) d = 8.01–7.93 (m, 2H), 7.68–7.58 (m,
1H), 7.50 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.24 (d,
J = 8.0 Hz, 2H), 4.62 (d, J = 5.1 Hz, 1H), 3.93 (dt, J = 8.3, 5.3 Hz,
2H), 3.66 ppm (qd, J = 18.4, 6.9 Hz, 2H). 13C NMR (100 MHz,
CDCl3) d = 196.78, 139.08, 135.91, 134.14, 133.61, 130.01, 128.95,
128.15, 127.90, 112.08, 111.89, 40.93, 40.20, 29.00, 21.19 ppm.
4.2.7. (S)-2-(1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl)malono-
nitrile 13g
Yellow solid, yield 96%, 82% ee, m.p. 124.4–126.8 °C; [
a]
20 = À3.4
D
(c 0.5, CH2Cl2) (lit.2h
[
a]
20 = À5.15 (c 0.194, CH2Cl2)); chiral HPLC
D
(Chiralcel AD-H column), hexane/i-PrOH = 80/20, flow rate:
1.0 mL/min, UV detection at 254 nm, t(minor) = 9.459 min,
t
(major) = 14.071 min; 1H NMR (400 MHz, CDCl3) d = 7.99–7.93 (m,
2H), 7.64 (ddd, J = 8.7, 2.5, 1.2 Hz, 1H), 7.54–7.47 (m, 2H), 7.45–
7.38 (m, 4H), 4.62 (d, J = 5.1 Hz, 1H), 3.95 (dt, J = 8.3, 5.3 Hz, 1H),
3.65 ppm (qd, J = 18.4, 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d = 196.35, 135.69, 135.27, 134.99, 134.33, 129.59, 129.45, 129.01,
128.14, 111.75, 111.55, 40.71, 40.01, 28.74 ppm.
4.2.3. (S)-2-(1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl)malono-
nitrile 13c
Yellow solid, yield 78%, 80% ee, m.p. 110.8–114.3 °C;
[
a]
D
20 = À2.0 (c 0.48, CH2Cl2) (lit.2h
[
a]
D
20 = À0.5 (c 0.208, CH2Cl2));
chiral HPLC (Chiralcel AD-H column), hexane/i-PrOH = 80/20,
flow rate: 1.0 mL/min, UV detection at 254 nm, t(minor)
= 11.481 min, t(major) = 17.773 min; 1H NMR (400 MHz, CDCl3)
d = 8.05–7.88 (m, 1H), 7.73–7.57 (m, 2H), 7.49 (dd, J = 10.6,
4.8 Hz, 1H), 7.44–7.30 (m, 2H), 7.01–6.88 (m, 2H), 4.60 (d,
J = 5.1 Hz, 1H), 3.92 (dt, J = 8.3, 5.3 Hz, 1H), 3.82 (s, 3H), 3.64 ppm
(qd, J = 18.3, 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) d = 196.82,
160.09, 135.89, 134.15, 129.22, 128.95, 128.52, 128.14, 114.68,
112.12, 111.89, 55.36, 40.62, 40.28, 29.16 ppm.
4.2.8. (S)-2-(1-(3-Chlorophenyl)-3-oxo-3-phenylpropyl)malono-
nitrile 13h
Yellow oil, yield 91%, 80% ee, [
a]
20 = À0.5 (c 0.3, CH2Cl2) (lit.2h
D
[a
]
D
20 = À13.48 (c = 0.178 in CH2Cl2)); chiral HPLC (Chiralcel AD-H
column), hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV
detection at 254 nm, t(minor) = 8.205 min, t(major) = 10.137 min;
1H NMR (400 MHz, CDCl3) d = 8.03–7.93 (m, 2H), 7.64 (t,
J = 7.4 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 7.45 (d, J = 1.2 Hz, 1H),
7.44–7.33 (m, 3H), 4.64 (d, J = 5.2 Hz, 1H), 3.95 (dt, J = 8.3, 5.3 Hz,
1H), 3.66 ppm (qd, J = 18.4, 6.9 Hz, 2H). 13C NMR (100 MHz,
CDCl3) d = 196.26, 138.54, 135.68, 135.23, 134.32, 130.65, 129.49,
129.00, 128.24, 128.16, 126.34, 111.66, 111.49, 40.90, 40.03,
28.60 ppm.
4.2.4. (S)-2-(1-(3-Methoxyphenyl)-3-oxo-3-phenylpropyl)malono-
nitrile 13d
Yellow oil, yield 83%, 80% ee, [
a]
20 = À3.13 (c = 0.37 in CH2Cl2)
D
(lit.2h
[a
]
D
20 = À8.33 (c = 0.144 in CH2Cl2)); chiral HPLC (Chiralcel
AD-H column), hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV
4.2.9. (S)-2-(1-(4-Bromophenyl)-3-oxo-3-phenylpropyl)malono-
detection
at
254 nm,
t(minor) = 10.298 min,
t(major)
nitrile 13i
= 11.945 min; 1H NMR (400 MHz, CDCl3) d = 1H NMR (400 MHz,
CDCl3) d 7.98–7.92 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t,
J = 7.7 Hz, 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.97
(t, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.3, 2.4 Hz, 1H), 4.61 (d, J = 5.2 Hz,
1H), 3.96–3.87 (m, 1H), 3.81 (s, 3H), 3.72–3.58 (m, 2H). 13C NMR
(100 MHz, CDCl3) d = 196.67, 160.12, 138.15, 135.87, 134.16,
130.43, 128.95, 128.16, 120.14, 114.36, 114.06, 112.03, 111.90,
55.38, 41.21, 40.19, 28.79 ppm.
Yellow oil, yield 95%, 84% ee, [
a
]
D
20 = À4.28 (c = 1.15 in CH2Cl2)
(lit.2t
[
a]
20 = À2.3 (c 0.35, CH2Cl2)); chiral HPLC (Chiralcel AD-H
D
column), hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV
detection at 254 nm, t(minor) = 9.858 min, t(major) = 14.919 min;
1H NMR (400 MHz, CDCl3) d = 8.00–7.93 (m, 1H), 7.64 (t,
J = 7.4 Hz, 1H), 7.60–7.54 (m, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.34 (d,
J = 8.5 Hz, 1H), 4.62 (d, J = 5.1 Hz, 1H), 3.94 (dt, J = 8.4, 5.3 Hz,
1H), 3.65 ppm (qd, J = 18.4, 6.9 Hz, 1H). 13C NMR (100 MHz,
Please cite this article in press as: Yan, L.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.015

6
L. Yan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
CDCl3) d = 196.32, 135.68, 135.50, 134.33, 132.56, 129.73, 129.01,
128.14, 123.44, 111.72, 111.53, 40.78, 39.95, 28.65 ppm.
40.80, 40.20, 34.68, 31.26, 28.86 ppm. HRMS (ESI+) calcd for
22H22N2O [M+H]+ = 331.1805, found: 331.1801.
C
4.2.10. (S)-2-(1-(3-Bromophenyl)-3-oxo-3-phenylpropyl)malono-
4.2.15. (S)-2-(1-(3,4-Dichlorophenyl)-3-oxo-3-phenylpropyl)
nitrile 13j
malononitrile 13o
Yellow oil, yield 88%, 80% ee, [
a]
D
20 = À0.25 (c 1.2, CH2Cl2) (lit.2t
Yellow oil, yield 88%, 84% ee; [a]
20 = +6.6 (c 0.44, CH2Cl2); chiral
D
[a
]
D
20 = À6.0 (c 1.47, CH2Cl2)); chiral HPLC (Chiralcel AD-H column),
HPLC (Chiralcel AD-H column), hexane/i-PrOH = 80/20, flow rate:
1.0 mL/min, UV detection at 254 nm, t(minor) = 8.534 min, t(ma-
jor) = 11.674 min; 1H NMR (400 MHz, d6-DMSO) d = 8.00 (d,
J = 7.4 Hz, 2H), 7.84 (d, J = 2.0 Hz, 1H), 7.71–7.62 (m, 2H), 7.53 (t,
J = 7.6 Hz, 3H), 5.29 (d, J = 6.5 Hz, 1H), 4.18 (dt, J = 8.1, 6.0 Hz,
1H), 3.93 (dd, J = 18.3, 8.5 Hz, 1H), 3.70 ppm (dd, J = 18.3, 5.5 Hz,
1H). 13C NMR (100 MHz, d6-DMSO) d = 196.66, 139.53, 136.39,
134.16, 131.75, 131.50, 131.22, 131.01, 129.23, 128.61, 113.65,
113.41, 29.39 ppm. HRMS (ESI+) calcd for C18H12Cl2N2O [M
+Na]+ = 365.0226, found: 365.0226.
hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV detection at
254 nm, t(minor) = 8.464 min, t(major) = 10.569 min; 1H NMR
(400 MHz, CDCl3) d = 8.05–7.95 (m, 2H), 7.70–7.61 (m, 2H), 7.54
(dt, J = 15.5, 7.9 Hz, 3H), 7.43 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.9 Hz,
1H), 4.66 (d, J = 5.2 Hz, 1H), 3.96 (dt, J = 8.2, 5.4 Hz, 1H), 3.68 ppm
(qd, J = 18.4, 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) d = 196.24,
138.75, 135.64, 134.34, 132.46, 131.12, 130.90, 129.00, 128.16,
126.79, 123.36, 111.61, 111.44, 40.84, 40.02, 28.59 ppm.
4.2.11. (S)-2-(1-(2-Bromophenyl)-3-oxo-3-phenylpropyl)malono-
nitrile 13k
4.2.16. (S)-2-(1-(Naphthalen-2-yl)-3-oxo-3-phenylpropyl)malono-
nitrile 13p
Yellow oil, yield 85%, 82% ee, [a]
20 = +16 (c 1.0, CH2Cl2); chiral
D
HPLC (Chiralcel AS-H column), hexane/i-PrOH = 90/10, flow rate:
1.0 mL/min, UV detection at 254 nm, t(minor) = 23.756 min, t(ma-
jor) = 27.856 min; 1H NMR (400 MHz, CDCl3) d = 7.97 (d, J = 7.4 Hz,
2H), 7.72–7.58 (m, 2H), 7.50 (t, J = 7.8 Hz, 3H), 7.38 (t, J = 7.4 Hz,
1H), 7.29–7.20 (m, 1H), 4.64 (dt, J = 12.6, 3.8 Hz, 1H), 3.85–3.74
(m, 1H), 3.74–3.62 ppm (m, 1H). 13C NMR (100 MHz, CDCl3)
d = 195.84, 135.76, 134.17, 134.01, 130.42, 128.96, 128.48,
128.17, 127.91, 124.95, 111.86, 111.31, 77.42, 77.10, 76.79, 39.74,
39.48, 27.34 ppm. HRMS (ESI+) calcd for C18H13BrN2O [M
+H]+ = 353.0284, found: 353.0293.
Yellow solid, yield 85%, 82% ee; m.p. 122.2–125.5 °C;
[a]
20 = À9.0 (c 0.8, CH2Cl2) (lit.2h
[a]
20 = À4.55 (c 0.198, CH2Cl2));
D
D
chiral HPLC (Chiralcel AD-H column), hexane/i-PrOH = 80/20,
flow rate: 1.0 mL/min, UV detection at 254 nm, t(minor)
= 12.185 min, t (major) = 16.772 min; 1H NMR (400 MHz, CDCl3)
d = 8.03–7.96 (m, 2H), 7.96–7.91 (m, 2H), 7.88 (td, J = 7.2, 3.4 Hz,
2H), 7.63 (t, J = 7.4 Hz, 1H), 7.59–7.47 (m, 5H), 4.73 (d, J = 5.2 Hz,
1H), 4.15 (dt, J = 8.4, 5.3 Hz, 1H), 3.79 ppm (qd, J = 18.4, 6.9 Hz,
2H). 13C NMR (100 MHz, CDCl3) d = 196.62, 135.85, 134.20,
134.00, 133.43, 133.31, 129.37, 128.97, 128.22, 128.17, 127.81,
127.52, 126.88, 126.84, 125.23, 111.93, 111.83, 41.41, 40.34,
28.85 ppm.
4.2.12. (S)-2-(1-(4-Trifluoromethylphenyl)-3-oxo-3-phenylpro-
pyl) malononitrile 13l
Yellow solid, yield 96%, 82% ee; m.p. 88.7–91.1 °C; [
a]
20 = À2.5
4.2.17. (S)-2-(1-(Thiophen-2-yl)-3-oxo-3-phenylpropyl)malono-
D
(c 0.8, CHCl3) (lit.2i
[a]
20 = À7.0 (c 0.3, CHCl3)); chiral HPLC (Chiral-
nitrile 13q
D
cel AD-H column), hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min,
UV detection at 254 nm, t(minor) = 7.251 min, t(major)
= 10.627 min; 1H NMR (400 MHz, CDCl3) d = 8.01–7.94 (m, 2H),
7.75–7.68 (m, 2H), 7.63 (dt, J = 11.7, 7.8 Hz, 3H), 7.51 (t,
J = 7.8 Hz, 2H), 4.67 (d, J = 5.1 Hz, 1H), 4.05 (dt, J = 8.2, 5.3 Hz,
1H), 3.70 ppm (qd, J = 18.4, 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d = 196.13, 140.41, 135.59, 134.41, 129.03, 128.63, 128.14, 126.39,
126.36, 111.56, 111.40, 41.03, 39.89, 28.49 ppm.
Yellow oil, yield 88%, 75% ee; [a]
20 = +10 (c 0.5, CH2Cl2) (lit.2h
D
[
a
]
20 = À1.5 (c 0.068, CH2Cl2)); chiral HPLC (Chiralcel AD-H
D
column), hexane/i-PrOH = 97/3, flow rate: 1.0 mL/min, UV
detection
at
254 nm,
t(minor) = 44.382 min,
t(major)
= 60.619 min; 1H NMR (400 MHz, CDCl3) d = 8.01–7.94 (m, 2H),
7.63 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.33 (dd, J = 5.1,
0.7 Hz, 1H), 7.23 (d, J = 3.5 Hz, 1H), 7.05 (dd, J = 5.1, 3.6 Hz, 1H),
4.67 (d, J = 5.0 Hz, 1H), 4.30 (dt, J = 11.2, 5.6 Hz, 1H), 3.77–
3.63 ppm (m, 2H). 13C NMR (100 MHz, CDCl3) d = 196.24, 138.63,
135.66, 134.31, 129.00, 128.20, 127.51, 127.21, 126.11, 111.81,
111.53, 41.49, 37.26, 29.59 ppm.
4.2.13. (S)-2-(1-(3-Trifluoromethylphenyl)-3-oxo-3-phenylpro-
pyl) malononitrile 13m
Yellow oil, yield 93%, 80% ee; [
a]
20 = À0.4 (c = 0.32, CH2Cl2); chi-
D
ral HPLC (Chiralcel AD-H column), hexane/i-PrOH = 80/20, flow
rate: 1.0 mL/min, UV detection at 254 nm, t(minor) = 6.196 min, t(-
major) = 8.099 min; 1H NMR (400 MHz, CDCl3) d = 8.02–7.94 (m,
2H), 7.75–7.46 (m, 7H), 4.66 (d, J = 5.2 Hz, 1H), 4.06 (dt, J = 8.5,
5.2 Hz, 1H), 3.70 ppm (qd, J = 18.4, 6.9 Hz, 2H). 13C NMR
(100 MHz, CDCl3) d = 196.18, 137.57, 135.61, 134.39, 131.56,
129.98, 129.02, 128.16, 126.17, 125.01, 124.97, 111.58, 111.40,
77.41, 77.09, 76.77, 41.09, 39.93, 28.60 ppm. HRMS (ESI+) calcd
for C19H13F3N2O [M+Na]+ = 365.0872, found: 365.0872.
4.2.18. (S)-2-(1-(5-Chlorothiophen-2-yl)-3-oxo-3-phenylpro-
pyl)malono nitrile 13r
Yellow solid, yield 83%, 79% ee; m.p. 75.3–78.9 °C; [a]
20 = +17.6
D
(c 0.37, CH2Cl2); chiral HPLC (Chiralcel AD-H column), hexane/i-
PrOH = 80/20, flow rate: 1.0 mL/min, UV detection at 254 nm, t
(minor) = 8.87 min, t(major) = 12.169 min;1H NMR (400 MHz,
CDCl3) d = 7.97 (d, J = 7.5 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.51 (t,
J = 7.7 Hz, 2H), 7.00 (d, J = 3.8 Hz, 1H), 6.86 (d, J = 3.8 Hz, 1H),
4.65 (d, J = 5.1 Hz, 1H), 4.16 (dt, J = 7.7, 5.4 Hz, 1H), 3.75–
3.55 ppm (m, 2H). 13C NMR (100 MHz, CDCl3) d = 195.92, 137.09,
135.48, 134.46, 130.93, 129.04, 128.19, 126.93, 126.44, 111.56,
111.28, 41.07, 37.78, 29.26 ppm. HRMS (ESI+) calcd for C16H11ClN2-
OS [M+Na]+ = 337.0184, found: 337.0184.
4.2.14. (S)-2-(1-(4-tert-Butylphenyl)-3-oxo-3-phenylpropyl)-
malononitrile 13n
Yellow oil, yield 65%, 80% ee; [a]
20 = +37.5 (c 0.8, CH2Cl2); chiral
D
HPLC (Chiralcel AD-H column), hexane/i-PrOH = 80/20, flow rate:
1.0 mL/min, UV detection at 254 nm, t(minor) = 6.66 min, t(ma-
jor) = 9.393 min; 1H NMR (400 MHz, CDCl3) d = 7.97 (d, J = 7.5 Hz,
2H), 7.62 (t, J = 7.4 Hz, 1H), 7.55–7.35 (m, 6H), 4.64 (d, J = 5.0 Hz,
1H), 3.95 (dt, J = 8.2, 5.3 Hz, 1H), 3.76–3.59 (m, 2H), 1.33 ppm (s,
9H). 13C NMR (100 MHz, CDCl3) d = 196.84, 152.17, 135.89,
134.14, 133.49, 128.94, 128.14, 127.70, 126.26, 112.03, 111.86,
4.2.19. (R,E)-2-(5-Oxo-1,5-diphenylpent-1-en-3-yl)malono-
nitrile 13s
Yellow oil, yield 30%, 82% ee; [
a]
D
20 = À5.65 (c 0.23, CH2Cl2) (lit.2h
[
a
]
20 = À0.65 (c 0.154, CH2Cl2)); chiral HPLC (Chiralcel AD-H
D
column), hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV
detection at 254 nm, t(minor) = 9.58 min, t(major) = 12.647 min;
Please cite this article in press as: Yan, L.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.015

L. Yan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
1H NMR (400 MHz, CDCl3) d = 8.02–7.93 (m, 2H), 7.64 (t, J = 7.4 Hz,
1H), 7.55–7.47 (m, 2H), 7.46–7.39 (m, 2H), 7.39–7.28 (m, 3H), 6.80
(d, J = 15.7 Hz, 1H), 6.24 (dd, J = 15.7, 8.9 Hz, 1H), 4.56 (d, J = 4.8 Hz,
1H), 3.61–3.52 (m, 1H), 3.52–3.38 ppm (m, 2H). 13C NMR
(100 MHz, CDCl3) d = 196.76, 136.35, 135.90, 135.45, 134.21,
128.99, 128.79, 128.71, 128.15, 126.88, 123.41, 112.10, 111.66,
40.02, 39.73, 27.63 ppm.
HPLC (Chiralcel AD-H column), hexane/i-PrOH = 80/20, flow rate:
1.0 mL/min, UV detection at 254 nm, t(minor) = 10.994 min, t
(major) = 13.159 min; 1H NMR (400 MHz, CDCl3) d = 7.90 (d,
J = 8.6 Hz, 2H), 7.51–7.37 (m, 7H), 4.60 (d, J = 5.2 Hz, 1H), 3.96
(dt, J = 7.8, 5.6 Hz, 1H), 3.74–3.54 ppm (m, 2H). 13C NMR
(100 MHz, CDCl3) d = 195.46, 140.77, 136.44, 134.14, 129.54,
129.41, 129.30, 129.28, 127.98, 111.84, 111.73, 41.19, 40.15,
28.84 ppm.
4.2.20. (S)-2-(1-Cyclohexyl-3-oxo-3-phenylpropyl)malononitrile
13t
4.2.25. (S)-2-(3-(2-Naphthyl)-3-oxo-1-phenylpropyl)malononitrile
Yellow oil, yield 50%, 86% ee; [
(lit.2h 20 = +37.2 (c 0.086, CH2Cl2)); chiral HPLC (Chiralcel AD-H
column), hexane/i-PrOH = 95/5, flow rate: 1.0 mL/min, UV
detection at 254 nm, t(minor) = 12.674 min, t(major)
a]
20 = +40.65 (c 0.46, CH2Cl2)
13y
D
20
[a
]
D
Yellow solid, yield 85%, 87% ee; m.p. 49.5–53.2 °C; [
+41.67 (c = 0.22 in CH2Cl2) (lit.2h 20 = +26.7 (c = 0.206 in
[a]
D
a
]
=
D
CH2Cl2)); chiral HPLC (Chiralcel AD-H column), hexane/i-
PrOH = 80/20, flow rate: 1.0 mL/min, UV detection at 254 nm, t
(minor) = 12.848 min, t(major) = 27.705 min; 1H NMR (400 MHz,
CDCl3) d = 8.48 (s, 1H), 8.05–7.94 (m, 2H), 7.94–7.84 (m, 2H),
7.68–7.55 (m, 2H), 7.55–7.36 (m, 5H), 4.69 (d, J = 5.1 Hz, 1H),
4.03 (dt, J = 7.9, 5.5 Hz, 1H), 3.90–3.73 ppm (m, 2H). 13C NMR
(100 MHz, CDCl3) d = 196.57, 136.68, 136.01, 133.18, 132.41,
130.22, 129.73, 129.39, 129.22, 129.15, 128.91, 128.10, 127.91,
127.23, 123.39, 112.02, 111.88, 41.37, 40.19, 28.93 ppm.
= 14.18 min;1H NMR (400 MHz, CDCl3) d = 8.02–7.93 (m, 2H),
7.62 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 4.36 (d, J = 4.8 Hz,
1H), 3.36 (dd, J = 18.5, 4.6 Hz, 1H), 3.16 (dd, J = 18.5, 7.9 Hz, 1H),
2.74 (dq, J = 9.9, 4.9 Hz, 1H), 1.93–1.67 (m, 6H), 1.42–1.03 ppm
(m, 5H). 13C NMR (100 MHz, CDCl3) d = 197.26, 136.06, 133.98,
128.90, 128.12, 112.57, 112.49, 40.21, 40.06, 37.01, 31.20, 29.31,
26.22, 26.10, 25.95, 25.34 ppm.
4.2.21. (S)-3-(2, 2-Methyl-5-oxo-5-phenylpentyl)malononitrile
13u
4.2.26. (S)-2-(3-(2-Thienyl)-3-oxo-1-phenylpropyl)malononitrile
Yellow oil, yield 25%, 88% ee; [
a
]
D
20 = +26.3 (c 0.19, CH2Cl2) (lit.2h
13z
[
a]
D
20 = +38.1 (c 0.042, CH2Cl2)); chiral HPLC (Chiralcel AD-H
Yellow solid, yield 95%, 91% ee; m.p. 83.8–87.2 °C; [a]
20 = +5.8 (c
D
column), hexane/i-PrOH = 95/5, flow rate: 1.0 mL/min, UV
detection at 254 nm, t(major) = 13.667 min, t(minor)
0.38, CH2Cl2) (lit.2h
[a]
20 = À1.8 (c 0.278, CH2Cl2)); chiral HPLC
D
(Chiralcel AD-H column), hexane/i-PrOH = 80/20, flow rate:
1.0 mL/min, UV detection at 254 nm, t(minor) = 10.688 min, t
(major) = 13.131 min; 1H NMR (400 MHz, d6-DMSO) d = 8.04 (dd,
J = 32.5, 3.6 Hz, 2H), 7.55–7.19 (m, 6H), 5.27 (d, J = 6.2 Hz, 1H),
4.17–3.97 (m, 1H), 3.81 (dd, J = 17.2, 8.5 Hz, 1H), 3.56 ppm (dd,
J = 17.2, 5.4 Hz, 1H). 13C NMR (100 MHz, d6-DMSO) d = 189.84,
143.61, 137.95, 136.01, 134.52, 129.34, 129.16, 128.81, 128.67,
113.87, 113.61, 40.95, 29.67 ppm.
= 15.556 min; 1H NMR (400 MHz, CDCl3) d = 8.06–7.97 (m, 2H),
7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 4.10 (d, J = 2.9 Hz,
1H), 3.40 (dd, J = 18.5, 4.4 Hz, 1H), 3.19 (dd, J = 18.5, 7.1 Hz, 1H),
2.93 (ddd, J = 7.2, 4.4, 2.9 Hz, 1H), 1.09 ppm (s, 9H). 13C NMR
(100 MHz, CDCl3) d = 196.76, 136.11, 133.87, 128.89, 128.19,
113.16, 113.09, 44.46, 37.22, 34.28, 27.72, 24.00 ppm.
4.2.22. (S)-2-(3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl)malono-
nitrile 13v
4.3. Catalytic asymmetric synthesis of (S)-piperidone 19
Yellow oil, yield 90%, 94% ee; [
a]
20 = +13.8 (c 0.3, CH2Cl2) (lit.2t
D
[
a]
D
20 = +12.2 (c 1.21, CH2Cl2)); chiral HPLC (Chiralcel AD-H
4.3.1. (S)-2-(1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl)malono-
column), hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV
nitrile 13e
detection at 254 nm, t(minor) = 15.705 min, t(major)
To the stirred solution of the
a,b-unsaturated ketones 11e
= 23.465 min; 1H NMR (400 MHz, CDCl3) d = 7.95 (d, J = 8.8 Hz,
2H), 7.51–7.35 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 4.68 (d, J = 5.1 Hz,
1H), 4.00–3.90 (m, 1H), 3.88 (s, 3H), 3.61 ppm (qd, J = 18.2,
6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) d = 195.07, 164.34,
136.75, 130.52, 129.32, 129.13, 128.92, 128.07, 114.11, 112.03,
111.85, 55.63, 41.32, 39.68, 28.80 ppm.
(5.7 g, 25.3 mmol) and catalyst 6a (1.58 g, 2.53 mmol) in toluene
(50.6 mL) was added malononitrile 12 (2.5 g, 38 mmol) at room
temperature. The reaction was monitored by TLC; after complete
consumption of the a,b-unsaturated ketones 11e, the solvent was
evaporated under reduced pressure and the crude product was
purified by flash chromatography with PE/EtOAc = 8/1 to give the
product as a white solid, yield 92%, 89% ee; [
a
]
D
20 = À0.4 (c 1.0, CH2-
4.2.23. (S)-2-(3-(4-Nitrophenyl)-3-oxo-1-phenylpropyl)malono-
nitrile 13w
Cl2) (lit.2h
[a]
20 = À5.6 (c 0.288, CH2Cl2)); chiral HPLC (Chiralcel AD-
D
H column), hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV
detection at 254 nm, t(minor) = 8.909 min, t(major) = 12.617 min.
After a single recrystallization from hexane/AcOEt 8:1, white thin
Yellow oil, yield 95%, 85% ee; [a]
D
20 = +16.8 (c 0.31, CH2Cl2) (lit.2w
D
[
a]
20 = À6.67 (c = 0.854 in CH2Cl2) for (R)-isomer); chiral HPLC
(Chiralcel AD-H column), hexane/i-PrOH = 80/20, flow rate:
1.0 mL/min, UV detection at 254 nm, t(major) = 22.313 min, t
(minor) = 25.990 min; 1H NMR (400 MHz, d6-DMSO) d = 7.46 (d,
J = 8.8 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 6.64 (d, J = 7.2 Hz, 2H), 6.49
(ddd, J = 10.9, 9.6, 5.8 Hz, 3H), 4.37 (d, J = 6.1 Hz, 1H), 3.22 (dd,
J = 13.9, 6.0 Hz, 1H), 3.09 (dd, J = 18.2, 8.1 Hz, 1H), 2.90 ppm (dd,
J = 18.2, 5.8 Hz, 1H). 13C NMR (100 MHz, d6-DMSO) d = 201.01,
155.35, 145.81, 142.80, 134.78, 133.89, 133.54, 133.48, 129.05,
118.62, 118.33, 117.29, 46.03, 45.45, 34.50, 13.65 ppm.
piece crystals were obtained in 71% yield, 99% ee, [
1.0, CH2Cl2).
a
]
20 = À6.9 (c
D
4.3.2. (S)-3-(4-Fluorophenyl)-5-oxo-5-phenylpentanoic acid 14
To the solution of 13e (5.2 g, 18 mmol) in AcOH (45 mL) was
added con. HCl (36 ml), the mixture was refluxed overnight. The
reaction mixture was cooled room temperature, the solid were fil-
tered, washed with water and dried at 80 °C to give 14 as white
solid, yield 90%, m.p. 136.6–139.8 °C; [a]
20 = 16 (c 1.0, CH2Cl2);
D
1H NMR (400 MHz, d6-DMSO) d = 12.11 (s, 1H), 7.92 (d, J = 7.5 Hz,
2H), 7.60 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.34 (dd,
J = 8.2, 5.7 Hz, 2H), 7.06 (t, J = 8.8 Hz, 2H), 3.68 (dt, J = 14.2,
7.0 Hz, 1H), 3.47 (d, J = 7.8 Hz, 1H), 2.72 (dd, J = 15.8, 6.1 Hz, 1H),
2.56 ppm (dd, J = 15.8, 8.7 Hz, 1H). 13C NMR (100 MHz, d6-DMSO)
4.2.24. (S)-2-(3-(4-Chlorophenyl)-3-oxo-1-phenylpropyl)malono-
nitrile 13x
20
White solid, yield 93%, 77% ee; m.p. 148.9–151.3 °C; [
+21.8 (c 0.22, CH2Cl2) (lit.2h 20 = +7.9 (c 0.254, CH2Cl2)); chiral
[a]
D
a]
=
D
Please cite this article in press as: Yan, L.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.015

8
L. Yan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
d = 198.89, 173.35, 162.44, 160.04, 140.47, 140.44, 137.15, 133.65,
129.93, 129.85, 129.15, 128.37, 115.37, 115.16, 44.49, 40.92,
37.06 ppm. HRMS (ESI+) calcd for C17H15FO4 [M+H]+ = 287.1078,
found: 287.1088.
white solid yield 80%, 99% ee, m.p. 109.1–111.9 °C; [
a
]
20 = À11.3
D
(c 1.0, CHCl3); chiral HPLC (Chiralcel AS-H) column, hexane/i-
PrOH = 90/10, flow rate: 0.5 mL/min, UV detection at 225 nm, t(-
major) = 27.048 min, t(minor) = 31.807 min. 1H NMR (400 MHz,
CDCl3) d = 7.38–7.24 (m, 4H), 7.20 (t, J = 7.4 Hz, 1H), 7.04 (t,
J = 8.6 Hz, 2H), 6.87 (d, J = 7.9 Hz, 2H), 3.82–3.69 (m, 1H), 3.01
(dd, J = 15.5, 6.4 Hz, 1H), 2.93–2.79 (m, 2H), 2.74 ppm (dd,
J = 16.1, 7.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) d = 177.52,
169.99, 163.18, 160.74, 150.40, 137.57, 137.54, 129.44, 129.05,
128.97, 125.97, 121.40, 115.77, 115.56, 40.70, 40.40, 37.50 ppm.
HRMS (ESI+) calcd for C17H15FO4 [M+Na]+ = 325.0847, found:
325.0848.
4.3.3. Benzyl (S)-3-(4-fluorophenyl)-5-oxo-5-phenylpentanoate
15
Thionyl chloride (24.3 mmol, 1.76 mL) was added to a suspen-
sion of 14 (4.6 g, 16.2 mmol) in dry toluene (32 mL) at 0 °C. After
the addition, the mixture was heated at reflux for 12 h, and then
the reaction mixture was cooled to room temperature and concen-
trated under reduced pressure to give a yellow oil. The obtained oil
was added to the solution of triethylamine (1.0 mmol, 0.14 mL)
and benzyl alcohol (0.32 mmol, 42
l
L) at 0 °C. The mixture was
4.3.6. (R)-3-(4-Fluorophenyl)-5-methoxy-5-oxopentanoic acid
18
refluxed for 12 h after the addition, then cooled to room tempera-
ture and quenched with saturated aq. NaHCO3 (30 mL). The mix-
ture was diluted with ethyl acetate (30 mL), the organic solution
was washed with saturated aq. NaHCO3 (30 mL), water (30 mL)
and brine (10 mL). The organic layer was then dried over Na2SO4
and concentrated in vacuo to give a brown oil. The crude product
was purified by flash chromatography with PE/EtOAc = 12/1 to give
the product as a white solid, yield 92%, 99% ee, m.p. 60.1–63.3 °C;
To a solution of 17 (0.604 g, 2.0 mmol) in MeOH (10 mL) was
added Na2CO3 (0.636 g, 6.0 mmol). The mixture was stirred at
room temperature for 24 and then concentrated under reduced
pressure. The residue was dissolved in H2O (30 mL), the solution
was washed with CH2Cl2 (2 Â 20 mL) and the aqueous layers were
acidified with excess 2 M HCl, followed by extraction with EtOAc
(3 Â 30 mL). The combined organic layers were dried over Na2SO4
and concentrated to afford 18 as a white solid without further
purification by flash chromatography. Yield 83%, 92% ee, m.p.
[a]
20 = +8.5 (c 1.0, CH2Cl2); chiral HPLC (Chiralcel AD-H column),
D
hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, UV detection at
254 nm, t(minor) = 10.486 min, t(major) = 13.747 min. 1H NMR
(400 MHz, CDCl3) d = 7.89 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.0 Hz,
1H), 7.43 (t, J = 7.1 Hz, 2H), 7.37–7.14 (m, 7H), 6.94 (t, J = 8.0 Hz,
2H), 5.03 (s, 2H), 3.99–3.83 (m, 1H), 3.45–3.24 (m, 2H), 2.86 (dd,
J = 15.4, 6.6 Hz, 1H), 2.72 ppm (dd, J = 15.2, 8.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d = 197.91, 171.50, 162.87, 160.44, 138.82,
136.83, 135.75, 133.23, 128.99, 128.91, 128.65, 128.53, 128.27,
128.06, 115.53, 115.32, 66.34, 44.60, 40.89, 36.94 ppm. HRMS
(ESI+) calcd for C24H21FO3 [M+H]+ = 377.1547, found: 377.1538.
95.7–99.1 °C; [a] [a]
20 = +8.0 (c 1.0, CHCl3) (lit.6d 20 = +5.7 (c 1.0,
D
D
CHCl3)); chiral HPLC (Chiralcel AD-H) column, hexane/i-
PrOH = 90/10, flow rate: 0.5 mL/min, UV detection at 254 nm, t(-
major) = 21.708 min, t(minor) = 19.202 min. After a single recrys-
tallization from toluene/hexane 3:2, white solids were obtained
from mother liquid in 66% yield, 97% ee, [a]
20 = +8.5 (c = 1.0 in
D
CHCl3). 1H NMR (400 MHz, CDCl3) d 9.39 (s, 1H), 7.23–7.13 (m,
2H), 6.97 (t, J = 8.5 Hz, 2H), 3.74–3.51 (m, 4H), 2.92–2.47 (m, 4H)
ppm. 13C NMR (100 MHz, CDCl3)
d 177.68, 172.28, 163.28,
160.84, 138.27, 138.24, 129.09, 129.01, 115.89, 115.68, 51.99,
40.78, 40.64, 37.58 ppm.
4.3.4. 1-Benzyl 5-phenyl (R)-3-(4-fluorophenyl)pentanedioate
16
To a stirred solution of 15 (5.6 mg, 15 mmol) in dichloroethane
(150 mL) at room temperature were added KH2PO4 (20 g,
150 mmol) and m-chloroperbenzoic acid (25.8 g, 150 mmol). After
being stirred for 4 days at 60 °C, the reaction mixture was
quenched with saturated aqueous Na2S2O3. The resulting mixture
was extracted with diethyl ether. The combined organic extracts
were washed with ice-cooled saturated aqueous NaHCO3 and
brine, dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was purified by flash silica gel
column chromatography with PE/EtOAc = 8/1 to give 16 as a white
4.3.7. (S)-4-(4-Fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-
3-carboxylic acid methyl ester 19
To a solution of diisopropylamine (0.352 mL, 2.5 mmol) in THF
(1 mL) was added n-BuLi (1 mL, 2.5 mmol, 2.5 M in hexane) at
À10 °C. After the addition, the mixture was stirred at 0 °C for
15 min. The mixture was then cooled to À55 °C, after which the
solution of 18 (0.24 g, 1.0 mmol) in THF (1 mL) was added to the
reaction mixture. After the addition, the reaction mixture was stir-
red at À55 °C for 40 min. Then methyl formate (0.16 mL,
2.79 mmol) was added to the reaction mixture, after which the
reaction mixture was slowly warmed to À20 °C, and then stirred
at À20 °C for 1 h. Next, 3 M HCl (2.1 mL) was slowly added to the
reaction mixture and extracted with EtOAc (15 mL). The organic
phase was washed with brine and concentrated to give a yellow
oil. To this oil, AcOH (0.86 mL, 15 mmol) and NH4OAc (0.23 g,
3 mmol) were added and the mixture was warmed to 80 °C and
stirred overnight. The reaction mixture was cooled to room tem-
perature and H2O (2.1 mL) was added slowly to the reaction mix-
ture. After the addition, the mixture was stirred at room
temperature for 2 h. Next, EtOAc (20 mL) was added to the reaction
mixture, and the mixture was washed with H2O (3 Â 15 mL) and
brine, dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was purified by flash silica gel
column chromatography with PE/EtOAc = 4/1 to give 19 as a white
solid yield 66%, 99% ee, m.p. 89.7–92.5 °C; [a]
20 = +20.5 (c 1.0, CH2-
D
Cl2); chiral HPLC (Chiralcel AD-H column), hexane/i-PrOH = 80/20,
flow rate: 1.0 mL/min, UV detection at 254 nm, t(major)
= 9.44 min, t(minor) = 10.491 min. 1H NMR (400 MHz, CDCl3)
d = 7.33 (t, J = 7.4 Hz, 5H), 7.29–7.17 (m, 5H), 7.01 (t, J = 8.6 Hz,
2H), 6.88 (d, J = 8.1 Hz, 2H), 5.07 (s, 2H), 3.87–3.74 (m, 1H), 3.00
(dd, J = 15.5, 6.4 Hz, 1H), 2.92–2.81 (m, 2H), 2.77 ppm (dd,
J = 15.5, 8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) d = 171.17,
169.94, 163.14, 160.70, 150.46, 137.66, 135.68, 129.43, 129.09,
129.01, 128.58, 128.33, 128.28, 125.92, 121.43, 115.69, 115.48,
66.48, 40.78, 37.96 ppm. HRMS (ESI+) calcd for C24H21FO4 [M
+H]+ = 393.1497, found: 393.1490.
4.3.5. (R)-3-(4-Fluorophenyl)-5-oxo-5-phenoxypentanoic acid
17
solid yield 41%, 97% ee, m.p. 191.8–194.2 °C; [a]
20 = +52.4 (c 1.2,
D
Compound 16 (3.85 g, 9.8 mmol) and 5% Pd/C (1.0 g) were sus-
pended in THF (50 mL) and stirred under an H2 atmosphere at
30 °C for 12 h. The reaction mixture was filtered and evaporated
to give a light yellow oil. The residue was purified by flash silica
gel column chromatography with PE/EtOAc = 5/1 to give 17 as a
CHCl3); chiral HPLC (Chiralcel AD-H column), hexane/i-
PrOH = 90/10, flow rate: 0.5 mL/min, UV detection at 254 nm, t(-
major) = 31.373 min, t(minor) = 23.192 min. 1H NMR (400 MHz,
d6-DMSO) d 9.97 (d, J = 4.7 Hz, 1H), 7.44 (d, J = 5.5 Hz, 1H), 7.25–
7.16 (m, 2H), 7.11 (t, J = 8.8 Hz, 2H), 4.07 (d, J = 7.9 Hz, 1H), 3.60
Please cite this article in press as: Yan, L.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.015

L. Yan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
(s, 3H), 3.02 (dd, J = 16.4, 8.3 Hz, 1H), 2.42 (d, J = 16.4 Hz, 1H). 13C
NMR (100 MHz, d6-DMSO) d 169.75, 166.49, 162.77, 160.36,
138.79, 138.76, 137.75, 128.85, 128.77, 116.00, 115.79, 108.84,
51.74, 38.78, 35.79.
Paul, T.; Drew, M. G. B.; Mukherjee, D. Tetrahedron Lett. 2003, 44, 4835; (e) Chen,
Y. C.; Xue, D.; Deng, J. G.; Cui, X.; Zhu, J.; Jiang, Y. Z. Tetrahedron Lett. 2004, 7,
1555; (f) Mueller, J.; Wuertele, C.; Walter, O.; Schindler, S. Angew. Chem. Int. Ed.
2007, 46, 7775; (g) Zhu, D. M.; Ankati, H.; Mukherjee, C.; Yang, Y.; Biehl, E. R.;
Hua, L. Org. Lett. 2007, 9, 2561; (h) Föster, S.; Tverskoy, O.; Helmchen, G. Synlett
2008, 2803; (i) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am. Chem.
Soc. 2013, 135, 16050; (j) Khan, A.; Yang, L.; Xu, J.; Jin, L. Y.; Zhang, Y. J. Angew.
Chem. Int. Ed. 2014, 53, 11257.
A. Supplementary data
4. For selected reviews of asymmetric Michael addition, see: (a) Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033; (b) Krause, N.; Hoffmann-Roder, A.
Synthesis 2001, 171; (c) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem.
1877, 2002; (d) Kanemasa, S.; Ito, K. Eur. J. Org. Chem. 2004, 4741; (e) Sarah, M.;
Olivier, A.; Alexandre, A. Chimia 2006, 60, 216; (f) Tsogoeva, S. B. Eur. J. Org.
Chem. 2007, 1701; (g) Sulzer-Mossé, S.; Alexakis, A. Chem. Commun. 2007, 3123;
(h) Vicario, J. L.; Badía, D.; Carrillo, L. Synthesis 2007, 2065; (i) Almasi, D.; Alonso,
D. A. Tetrahedron: Asymmetry 2007, 18, 299; (j) Christoffers, J.; Koripelly, G.;
Rosiak, A.; Rösle, M. Synthesis 2007, 1279; (k) Alexakis, A.; Bäkvall, J. E.; Krause,
N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108, 2796; (l) Jautze, S.; Peters, R.
Synthesis 2010, 365; Somanathan, R.; Chavez, D.; Servin, F. A.; Romero, J. A.;
Navarrete, A.; Parra-Hake, M.; Aguirre, G.; Anaya de Parrodi, C.; Gonzalez, J. Curr.
Org. Chem. 2012, 16, 2440.
5. For selected reviews of bifunctional amine-thiourea organocatalysts, see: (a)
Groger, H. Chem. Eur. J. 2001, 7, 5246; (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev.
2002, 102, 2187; (c) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138;
(d) Ma, J. A.; Cahard, D. Angew. Chem. Int. Ed. 2004, 43, 4566; (e) Pihko, P. M.
Angew. Chem. Int. Ed. 2004, 43, 2062; (f) Takemoto, Y. Org. Biomol. Chem. 2005, 3,
4299; (g) Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491; (h)
Connon, S. J. Chem. Eur. J. 2006, 12, 5418; (i) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2006, 45, 1520; (j) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal.
2006, 348, 999; (k) Connon, S. J. Chem. Commun. 2008, 2499; (l) Fang, X.; Wang,
C. J.; Fang, X. Chem. Commun. 2015, 51, 1185.
6. (a) Wang, S. X.; Chen, F. E. Adv. Synth. Catal. 2009, 351, 547; (b) Yang, H. J.; Xiong,
F. J.; Li, J.; Chen, F. E. Chin. Chem. Lett. 2013, 24, 553; (c) Yang, H. J.; Xiong, F. J.;
Chen, X. F.; Chen, F. E. Eur. J. Org. Chem. 2013, 4495; (d) Yan, L. J.; Wang, H. F.;
Chen, W. X.; Tao, Y.; Jin, K. J.; Chen, F. E. ChemCatChem 2016, 8, 2249; (e) Wang,
H.; Yan, L.; Xiong, F.; Wu, Y.; Chen, F. RSC Adv. 2016, 6, 75470; (f) Wang, X. L.; Xu,
L. J.; Yan, L. J.; Wang, H. F.; Han, S.; Wu, Y.; Chen, F. E. Tetrahedron 2016, 72, 1787;
(g) Wang, X. L.; Xu, L. J.; Xiong, F. J.; Wu, Y.; Chen, F. E. RSC Adv. 2016, 6, 37701.
7. (a) Huang, X.; Zhu, J.; Broadbent, S. Tetrahedron Lett. 2010, 51, 1554; (b) Huang,
X.; Broadbent, S.; Dvorak, C.; Zhao, S. H. Org. Process Res. Dev. 2010, 14, 612.
8. (a) Kohler, E. P.; Chadwell, H. M. Org. Synth. Col. 1932, I, 78; (b) Riahi, A.; Thorey,
C.; Hénin, F.; Muzart, J. Synth. Commun. 1998, 28, 4339.
Supplementary data (NMR spectra for all of the new com-
pounds) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetasy.2017.05.015.
References
1. For Part 10 see: Wang, H.; Yan, L.; Wu, Y.; Chen, F. Tetrahedron 2017, 19, 2793.
2. For selected examples of asymmetric conjugate additions of malononitriles, see:
(a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204; (b) Itoh, K.;
Oderaotoshi, Y. Tetrahedron: Asymmetry 2003, 14, 635; (c) Taylor, M. S.; Zalatan,
D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313; (d)
Hoash, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44, 4032; (e)
Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413; (f) Wang,
J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128,
12652; (g) Li, X. F.; Cun, L. F.; Lian, C. X.; Zhong, L.; Chen, Y. C.; Liao, J.; Zhu, J.;
Deng, J. G. Org. Biomol. Chem. 2008, 6, 349; (h) Shi, J.; Wang, M.; He, L.; Zheng, K.;
Liu, X. H.; Lin, L. L.; Feng, X. M. Chem. Commun. 2009, 4711; (i) Russo, A.; Perfetto,
A.; Lattanzi, A. Adv. Synth. Catal. 2009, 351, 3067; (j) Xie, J. W.; Huang, X.; Fan, L.
P.; Xu, D. C.; Li, X. S.; Su, H.; Wen, Y. H. Adv. Synth. Catal. 2009, 351, 3077; (k)
Zhao, S. L.; Zheng, C. W. Tetrahedron: Asymmetry 2009, 1046, 20; (l) Huang, X.; Li,
P.; Li, X. S.; Xu, D. C.; Xie, J. W. Org. Biomol. Chem. 2010, 8, 4527; (m) Ren, Q.; Gao,
Y. J.; Wang, J. Chem. Eur. J 2010, 16, 13594; (n) Jing, L. H.; Wei, J. T.; Zhou, L.;
Huang, Z. Y.; Li, Z. K.; Wu, D.; Xiang, H. F.; Zhou, X. G. Chem. Eur. J. 2010, 16,
10955; (o) Oliva, C. G.; Silva, A. M. S.; Resende, D. I. S. P.; Paz, F. A. A.; Cavaleiro, J.
A. S. Eur. J. Org. Chem. 2010, 3449; (p) Hu, Z. P.; Lou, C. L.; Wang, J. J.; Chen, C. X.;
Yan, M. J. Org. Chem. 2011, 76, 3797; (q) Li, X. M.; Wang, B.; Zhang, J. M.; Yan, M.
Org. Lett. 2011, 13, 374; (r) Russo, A.; Capobianco, A.; Perfetto, A.; Lattanzi, A.;
Peluso, A. Eur. J. Org. Chem. 1922, 2011; (s) Molleti, N.; Rana, N. K.; Singh, V. C.
Org. Lett. 2012, 14, 4322; (t) Yang, W.; Jia, Y.; Du, D. M. Org. Biomol. Chem. 2012,
10, 332; (u) Gao, Y.; Yang, W.; Du, D. Tetrahedron: Asymmetry 2012, 23, 339; (v)
Arai, T.; Oka, I.; Morihata, T.; Awata, A.; Masu, H. Chem. Eur. J. 2013, 19, 1554; (w)
Li, X.; Ma, Y.; Xing, Z.; Tang, N.; Zhu, J.; Deng, J. Tetrahedron Lett. 2014, 55, 3868.
3. (a) Freeman, F. Chem. Rev. 1969, 69, 591; (b) van Es, T.; Staskun, B. Org. Synth.
1971, 51, 20; (c) Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1987, 52, 3901; (d) Roy, A.;
9. Yang, D.; Wang, L.; Zhao, D.; Han, F.; Zhang, B.; Wang, R. Chem. Eur. J. 2013, 19,
4691.
Please cite this article in press as: Yan, L.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.015