Asymmetric direct vinylogous carbon-carbon bond formation catalyzed by bifunctional organocatalysts

Article abstract of DOI:10.1016/j.tet.2007.04.011

The bifunctional chiral thiourea-tertiary amine organocatalysts have been applied to a direct asymmetric vinylogous Michael addition of α,α-dicyanoolefins to nitroolefins with 2-10 mol % catalyst loadings. The electronic properties of the thiourea-based c

Full text of DOI:10.1016/j.tet.2007.04.011

Tetrahedron 63 (2007) 5123–5128
Asymmetric direct vinylogous carbon–carbon bond formation
catalyzed by bifunctional organocatalysts
a
Lin Jiang, Hong-Ting Zheng, Tian-Yu Liu, Lei Yue and Ying-Chun Chen
b
a
a
a,*
a
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
b
Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
Received 5 February 2007; revised 2 April 2007; accepted 5 April 2007
Available online 11 April 2007
Abstract—The bifunctional chiral thiourea-tertiary amine organocatalysts have been applied to a direct asymmetric vinylogous Michael ad-
dition of a,a-dicyanoolefins to nitroolefins with 2–10 mol % catalyst loadings. The electronic properties of the thiourea-based catalysts have
significant influences on this reaction. Moderate to excellent enantioselectivities (57–95% ee) have been achieved with low to good isolated
yields through fine tuning the structures of the bifunctional organocatalysts. Much better ees were obtained for some a,a-dicyanoolefinic sub-
strates compared with that catalyzed by modified cinchona alkaloids.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
Recently bifunctional organocatalysts possessing thioureas
or ureas) and tertiary amine groups have received special at-
(
8
The Michael addition of nucleophiles to electron-deficient
olefins represents one of the best studied and versatile car-
bon–carbon bond construction strategies in synthetic organic
chemistry. New stereocenters are often generated, and ac-
cordingly the asymmetric conjugate reaction is the subject
of intensive research over the past decades. Considerable
efforts have been devoted to the Michael reactions by em-
ploying a-enolizable carbonyl compounds, nitroalkanes,
and organometallic reagents as the nucleophiles, however,
expanding the scope of nucleophilic substrates is highly
desirable. Recently we have established that the g-allylic
protons of a,a-dicyanoolefins are strongly acidic, and
subsequently direct vinylogous additions of a,a-dicyano-
tention, and a number of highly enantioselective 1,2- or 1,4-
addition reactions have been reported in the presence of such
catalysts. The double hydrogen-bonding interaction of N–H
9
of thioureas (or ureas) and reactants has been generally rec-
ognized to have a specific role in the efficient catalysis and
high enantiocontrol. As part of our continuing investigation
1
1
0
on thiourea-based organocatalysis, we realized that nitro-
olefin and a,a-dicyanoolefin should be concertedly activated
by the thiourea-tertiary amine catalyst (Scheme 1). Here we
would like to present the direct vinylogous Michael addition
of a,a-dicyanoolefins to nitroolefins promoted by bifunc-
tional thiourea-tertiary amine catalysts.
2
3
4
5
6
olefins to nitroolefins, a,b-unsaturated aldehydes, a,b-unsat-
urated ketones, and N-Boc imines have been successfully
developed, giving facile protocols to synthesize various
multifunctional products with two vicinal stereocenters. Al-
though excellent enantioselectivity has been achieved in the
S
N
chiral bone
Ar
N
H
O
N
H
O
N
H
7
R
CN
CN
2
O N
CN
CN
*
R1
R1
*
Michael reactions of a,a-dicyanoolefins and nitroolefins
catalyzed by modified cinchona alkaloids,
R2
R2
7
a,b
the substrate
scope of a,a-dicyanoolefins was generally limited to 1-tetra-
lone derivatives. We envisioned that the catalytic system
combining the synergistic activation of both the electro-
philes and nucleophiles might improve the stereoselectivity.
R
Scheme 1. Proposed reaction mode of a,a-dicyanoolefin to nitroolefin cat-
alyzed by bifunctional thiourea-tertiary amine.
2. Results and discussion
Motivated by this idea, we first studied the reaction between
a,a-dicyanoolefin 2a, derived from 1-tetralone, and b-
*
0
Corresponding author. Tel./fax: +86 28 85502609; e-mail: ycchenhuaxi@
yahoo.com.cn
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.011

5124
L. Jiang et al. / Tetrahedron 63 (2007) 5123–5128
CF3
S
CF3
S
N
CF3
N
H
N
H
N
H
N
H
CF3
NH
N
N
N
N
CF3
S
1b
H
1
c
1a
N
S
CF3
N
N
N
H
CF3
CF3
H
NH
N
NH
N
N
N
S
N
H
S
H
1
f
F
1d
1
e
F
S
CF3
S
F
S
N
H
F
F
N
H
N
H
N
H
N
N
H
N
N
H
N
1g
1h
1i
Figure 1. Structures of chiral thiourea-tertiary amine catalysts.
nitrostyrene 3a in DCM catalyzed by 2 mol % of 1a bearing
a bis(trifluoromethyl)phenyl substituent (Fig. 1) at room
temperature. The starting materials were smoothly con-
sumed after 24 h, unfortunately, the desired addition product
from cinchonidine (entry 2). We ascribed the formation of
1
1
the byproducts to the polymerization because of the strong
electron-withdrawing effects of the thiourea group on nitro-
styrene, so better results might be expected in the reactions
catalyzed by the thiourea catalysts with lower electron-with-
4
a with complete anti-selectivity was isolated only in 18%
1
2
yield due to the formation of large amount of unidentified in-
soluble byproducts, with 58% ee (Table 1, entry 1). Similar
phenomena were observed in the case of catalyst 1b derived
drawing ability. We were pleased to find that the isolated
yield was indeed improved, though still low, catalyzed by
1c with a 4-trifluoromethylphenyl group. More gratifyingly,
much higher enantioselectivity (82% ee) was obtained (entry
3
). Therefore, other similar bifunctional catalysts 1d–1f with
various chiral scaffolds were tested (entries 4–6), and the
results were found to be inferior to that of 1c. In addition,
slightly lower ee (78%) was received catalyzed by 1g with
a 4-fluorophenyl substitution compared with that of 1c (entry
Table 1. Screening studies of vinylogous Michael addition of a,a-dicyano-
olefin 2a to nitrostyrene 3a
a
NC
CN
NC
CN NO2
H
1
(2 mol%)
+
Ph
7
). The more bulky catalysts 1h and 1i also gave lower enan-
NO2 solvent, rt, 24 h
H
tioselectivity in the model reaction (entries 8 and 9). Subse-
quently, some solvents were screened (entries 10–13), and
the ees were dramatically decreased in THF and acetone (en-
tries 12 and 13). Finally we conducted the Michael addition
2a
3a
4a
b
Yield (%)
c
ee (%)
Entry
Catalyst
Solvent
t (h)
ꢀ
in DCM at 0 C with 5 mol % of 1c. The side reactions could
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
1c
1c
1c
1c
1c
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
DCE
24
24
24
24
24
24
24
24
24
24
24
24
24
48
18
20
44
37
64
38
52
26
43
33
53
63
76
64
58
55
82
ꢁ68
be further inhibited, and good isolated yield (64%) was ob-
tained with slightly elevated ee (86%) after 48 h, while some
starting material still remained unchanged.
d
72
d
ꢁ25
With the optimal reaction conditions in hand, the scope
and limitation of the bifunctional thiourea-tertiary amine 1c
catalyzed vinylogous Michael addition were probed using
a range of a,a-dicyanoolefins (Fig. 2) and nitroolefins with
5 mol % of 1c. The results are summarized in Table 2. In
general, only one diastereomer was detected in the reactions.
78
d
ꢁ68
65
83
75
36
48
86
0
1
2
3
4
THF
Acetone
DCM
e
a
Otherwise noted, the reaction was conducted with 0.12 mmol of 2a and
.1 mmol of 3a in the presence of 2 mol % of 1 in 1 mL solvent at
room temperature for 24 h.
CN
NC
COOEt
NC
CN
NC
CN NC
CN NC
0
2
a X = CH
b X = S
b
c
2
Isolated yield.
Determined by chiral HPLC analysis. The absolute configuration was
2
2c X = O
7a
X
determined by comparison with the authentic sample.
Product with the opposite configuration was obtained.
At 0 C with 5 mol % of 1c for 48 h.
2d
2e
2f
2g
d
e
ꢀ
Figure 2. Structures of various a,a-dicyanoolefins.

L. Jiang et al. / Tetrahedron 63 (2007) 5123–5128
5125
Table 2. Asymmetric vinylogous Michael addition of a,a-dicyanoolefins 2
to nitroolefins 3
while the ee was also poor (entry 17). Notably the aliphatic
aldehyde derivative 2f showed better conversion, and high
ee (81%) was achieved while the yield was low (entry 18).
The nitroolefin 3h with alkyl substitution also exhibited
low reactivity in the reaction with 2b in the presence of
10 mol % of 1c, and a modest ee was obtained (entry 19).
In addition, we found that the activated olefin 2g showed
good reactivity with nitrostyrene 3a catalyzed by 1c, unfor-
a
NC
CN
NC
CN NO2
H
1
c (5 mol%)
DCM
+
R
NO2
R
H
X
X
2
3
4
ꢀ
c
d
14
Entry
2
R
T ( C) t (h) Conversion Yield
of 3 (%) (%)
ee
(%)
tunately, the racemic product was obtained.
b
1
2
3
2a Ph (3a)
0
0
0
0
0
0
0
0
0
48
48
48
48
24
48
48
48
24
72
72
72
72
48
72
72
72
72
72
77
60
80
61
87
57
72
44
—
63
75
60
74
—
45
58
56
77
85
64 (4a) 86
Based on the absolute configuration of 4a, a plausible cata-
lytic reaction model was proposed. As outlined in Scheme
, nitroolefin 3a and a,a-dicyanoolefin 2a would be concert-
edly activated by thiourea and tertiary amine groups. Then
vinylogous Michael addition could take place from the si-
face of 2a, giving the adduct 4a with (S)-configuration in
the benzylic carbon. In addition, trans-structures were gener-
ally generated in the exclusive diastereoselectivity owing to
the steric reason.
9
d
2a p-MeO–Ph (3b)
2a p-Me–Ph (3c)
2a p-Cl–Ph (3d)
2a p-Cl–Ph (3d)
2a p-Br–Ph (3e)
2a p-Me N–Ph (3f)
2
2a 2-Furanyl (3g)
2b p-MeO–Ph (3b)
49 (4b) 89
70 (4c) 88
47 (4d) 88
43 (4d) 86
45 (4e) 89
65 (4f) 91
35 (4g) 88
65 (4h) 86
54 (4h) 95
66 (4i) 94
52 (4j) 94
64 (4k) 90
89 (4l) 85
36 (4l) 92
31 (4m) 63
24 (4n) 57
22 (4o) 81
21 (4p) 69
b
2
4
5
e
6
7
8
9
10
11
12
13
14
15
16
17
18
19
2b p-MeO–Ph (3b) ꢁ40
2b Ph (3a)
ꢁ40
2b p-Me
N–Ph (3f) ꢁ40
2
2b 2-Furanyl (3g) ꢁ40
f
2c Ph (3a)
2c Ph (3a)
2d Ph (3a)
2e Ph (3a)
2f Ph (3a)
2b i-Propyl (3h)
ꢁ10
ꢁ40
0
f
S
NC
CN NO2
f
F3C
N
H
O
N
H
O
H
S
N
H
g
g
e
0
0
0
Ph
CN
CN
H
N
4a
a
Otherwise noted, the reaction was conducted with 0.12 mmol of 2 and
.1 mmol of 3 catalyzed by 5 mol % of 1c in 1 mL DCM.
Conversion was determined based on recovered nitroolefin.
Isolated yield.
Determined by chiral HPLC analysis.
With 10 mol % of (R,R)-1c.
With 5 mol % of (R,R)-1c.
si-face attack
0
b
c
d
e
f
Ph
Scheme 2. Transition-state model of vinylogous Michael addition.
g
With 10 mol % of 1e.
3. Conclusion
In conclusion, we have demonstrated that the bifunctional
chiral thiourea-tertiary amine compounds were effective or-
ganocatalysts in the direct asymmetric vinylogous Michael
addition of a,a-dicyanoolefins to nitroolefins. The reactions
displayed high regio- and diastereoselectivities, and moder-
ate to excellent enantioselectivities (57–95% ee) have been
achieved with low to good isolated yields. Moreover,
much better ees were obtained for some a,a-dicyanoolefinic
substrates compared with that catalyzed by modified cin-
chona alkaloids. Moderate enantioselectivities with low
yields were obtained using aliphatic a,a-dicyanoolefin or
alkyl-substituted nitroolefin as the substrate, and studies
are underway to improve these reactions.
Various nitrostyrenes 3a–3f with electron-donating or
withdrawing substituents could smoothly react with a,a-
dicyanoolefin 2a at 0 C (Table 2, entries 1–7). High enantio-
selectivities were generally observed, and the isolated yields
were moderate due to the incomplete conversion of the
substrates after 48 h. Increasing the catalytic loading
-
ꢀ
(
10 mol %) did not give better results probably due to the po-
lymerization side reaction (entry 4 vs 5). A good ee was also
obtained for furanyl derivative 3g (entry 8). Sulfur-contain-
ing substrate 2b displayed better reactivity, and good yield
ꢀ
with 86% ee was received in the reaction of 3b at 0 C after
2
be conducted at much lower temperature, and excellent ees
4 h (entry 9). The reactions of 2b with nitrostyrenes could
ꢀ
for 72 h (entries 9–12). While a modest ee (74%) was ob-
(
90–95%) were obtained with moderate yields at ꢁ40 C
4. Experimental
4.1. General
1
3
tained in the reaction of 2c and nitrostyrene 3a catalyzed by
modified cinchona alkaloid, current catalytic conditions
gave better results, and 85% ee with 89% yield was obtained
7
a
Melting points were determined in open capillaries and are
uncorrected. TLC was performed on glass-backed silica
plates. Column chromatography was performed using silica
gel (200–300 mesh) eluting with ethyl acetate and petroleum
ether. NMR was recorded on Bruker 200, 300 or 400 MHz
spectrometers. Chemical shifts are reported in parts per
million downfield from tetramethylsilane with the solvent
resonance as the internal standard. Enantiomeric excess
was determined by HPLC analysis on Chiralpak OD or AS
ꢀ
at ꢁ10 C in 48 h (entry 14). Moreover, the enantioselectiv-
ꢀ
ity could be further improved to 92% at ꢁ40 C, while the
yield was not satisfying (entry 15). On the other hand, a,a-
dicyanoolefins 2d–2f derived from aliphatic ketones and
ꢀ
aldehydes were tested at 0 C with 10 mol % of 1e. Sluggish
reactivity was generally observed, and low isolated yields
were obtained. The ee (63%) was moderate in the reaction
of acyclic substrate 2d and 3a (entry 16). The desymmetriza-
tion of cyclic substrate 2e was attempted, and only one dia-
stereomer with three chiral carbon centers was isolated,
column. DCM was distilled from CaH . All other reagents
2
were used as commercially available without purification.

5126
L. Jiang et al. / Tetrahedron 63 (2007) 5123–5128
4
.1.1. General procedures for the synthesis of bifunc-
0
(br s, 1H), 3.82 (s, 1H), 2.58 (br s, 1H), 2.30 (t,
J¼10.8 Hz, 1H), 2.15 (s, 6H), 1.77 (t, J¼9.2 Hz, 2H), 1.62
(d, J¼13.6 Hz, 1H), 1.31–1.07 (m, 4H), 1.05–0.93 (m,
0
tional catalysts 1a–li. To the N ,N -disubstituted diamine
2 mmol) in dry DCM (10 mL) was added a solution of
(
1
3
aryl isothiocyanate (2.5 mmol) in dry DCM (5 mL). After
stirred at room temperature for 2 h, the reaction mixture
was concentrated under vacuum. The residue was purified
by column chromatography on silica gel (DCM/MeOH) to
give the desired thiourea-tertiary amine compound. Cata-
1H); C NMR (CDCl , 50 MHz) d (ppm) 180.2, 163.0,
3
158.1, 126.9, 126.8, 116.2, 115.8, 66.7, 55.9, 39.8, 32.8,
25.0, 24.5, 21.4; IR (KBr) n 3222, 2934, 2860, 1508, 1222,
ꢁ
1
833, 796 cm ; HRMS (EI) calcd for C H FN S
22
15
3
2
0
295.1518, found 295.1512; [a]D +42.5 (c 0.2, EtOAc).
1
0
lysts 1a and 1b have been reported.
ꢀ
1
Catalyst 1h. Mp: 72–74 C; H NMR (CDCl , 400 MHz)
3
ꢀ
1
Catalyst 1c. Mp: 64–66 C; H NMR (400 MHz, CDCl )
3
d (ppm) 7.50–7.41 (m, 4H), 4.12 (br s, 1H), 2.76 (br s,
d (ppm) 7.61 (d, J¼8.4 Hz, 2H), 7.49 (d, J¼8.0 Hz, 2H),
4.02 (br s, 1H), 2.82–2.72 (m, 4H), 2.46 (m, 3H), 1.89 (t,
J¼14.4 Hz, 2H), 1.76 (d, J¼14.4 Hz, 1H), 1.40–1.10 (m,
1
1
1
1
2
1
3
H), 2.43 (s, 6H), 2.26 (s, 1H), 1.90 (d, J¼13.2 Hz, 1H),
1
3
.83 (d, J¼12.8 Hz, 1H), 1.71 (d, J¼12.8 Hz, 1H), 1.31–
5H), 1.04 (t, J¼7.2 Hz, 6H); C NMR (CDCl , 50 MHz)
3
1
3
.13 (m, 4H); C NMR (CDCl , 50 MHz) d (ppm) 180.6,
3
d (ppm) 180.2, 140.9, 126.6, 126.5, 126.4, 123.4, 121.2,
63.7, 55.7, 43.8, 32.5, 29.6, 25.3, 24.4, 23.6, 13.4; IR
(KBr) n 3221, 2934, 2859, 1616, 1523, 1324, 1166, 1122,
1067, 1015, 841, 716, 594 cm ; HRMS (ESI) calcd for
C H F N S (M+H) 374.1872, found 374.1878; [a]
D
41.8, 125.9, 123.0, 121.3, 116.8, 67.2, 55.0, 39.8, 32.5,
4.4, 24.3, 22.2; IR (KBr) n 3275, 2937, 1540, 1325, 1117,
ꢁ
1
ꢁ1
067, 841, 715 cm ; HRMS (EI) calcd for C H F N S
1
6 22 3 3
2
0
20
45.1487, found 345.1476; [a]D +96.0 (c 0.1, EtOAc).
18
27
3
3
ꢁ
91.0 (c 0.1, EtOAc).
ꢀ
1
Catalyst 1d. Mp: 100–102 C; H NMR (400 MHz, CDCl )
3
ꢀ
1
d (ppm) 8.85 (d, J¼4.4 Hz, 1H), 8.27 (br s, 1H), 8.12 (d,
Catalyst 1i. Mp: 122–124 C; H NMR (400 MHz, CDCl )
3
J¼8.0 Hz, 1H), 7.69 (t, J¼7.2 Hz, 1H), 7.60–7.53 (m, 4H),
d (ppm) 7.62 (s, 2H), 7.42 (s, 1H), 7.24 (s, 1H), 7.11–7.06
(m, 3H), 6.81–6.73 (m, 2H), 4.28 (br s, 1H), 2.82–2.60 (m,
3H), 2.45 (s, 6H), 2.07–1.87 (m, 2H), 1.76–1.73 (d,
J¼13.2 Hz, 1H), 1.39–1.31 (m, 2H), 1.27–1.14 (m, 3H);
7
5
2
1
.41 (d, J¼14.8 Hz, 2H), 7.30 (d, J¼4.4 Hz, 1H), 5.83–
.70 (br s, 2H), 5.26–5.03 (m, 2H), 3.26–3.05 (m, 1H), 2.97–
.83 (m, 4H), 2.33–2.27 (m, 1H), 1.55–1.44 (m, 2H),
.34–1.12 (m, 1H), 0.93–0.86 (m, 1H), 0.84–0.72 (m, 2H);
1
3
C NMR (CDCl , 50 MHz) d (ppm) 165.8, 160.6, 143.2,
3
1
3
C NMR (CDCl , 50 MHz) d (ppm) 181.0, 150.0, 148.6,
3
140.5, 139.5, 122.3, 110.3, 109.7, 103.6, 103.1, 102.6,
66.9, 55.6, 39.8, 32.7, 24.7, 24.4, 21.7; IR (KBr) n 3445,
2933, 1624, 1591, 1542, 1120, 990, 849 cm ; HRMS (EI)
calcd for C H F N S 501.1862, found 501.1853; [a]
27 27 4 3 D
1
1
3
1
41.6, 132.2, 132.0, 130.4, 129.5, 128.7, 128.5, 127.0,
26.3, 123.6, 123.3, 120.7, 119.4, 115.6, 61.6, 48.7, 47.1,
8.8, 37.7, 28.1, 27.2, 25.9, 24.9; IR (KBr) n 3446, 2928,
ꢁ
1
2
0
ꢁ
1
540, 1324, 1118, 1067, 843, 757 cm ; HRMS (ESI) calcd
+28.0 (c 0.2, EtOAc).
2
0
for C H F N S (M+H) 497.1981, found 497.1974; [a]
D
2
7
28
3
4
+
203.0 (c 0.1, EtOAc).
4.1.2. General procedure for asymmetric direct vinylo-
gous Michael reaction. Catalyst 1c (0.005 mmol,
˚
5 mol %), nitroolefin 3 (0.1 mmol), and 4 A MS (30 mg)
ꢀ
1
Catalyst 1e. Mp: 100–102 C; H NMR (400 MHz, CDCl )
3
d (ppm) 8.89 (d, J¼15.2 Hz, 1H), 8.40 (br s, 1H), 8.16 (d,
were stirred in dry DCM (0.5 mL) and cooled to the desired
2
J¼7.6 Hz, 1H), 7.76 (t, J¼7.2 Hz, 1H), 7.71–7.69 (m, 4H),
temperature under argon. Then a,a-dicyanoolefin
7
1
3
1
.43 (d, J¼8.4 Hz, 2H), 7.37 (d, J¼4.4 Hz, 1H), 5.81 (br s,
H), 5.71–5.63 (m, 1H), 5.03–4.95 (m, 2H), 3.25–3.15 (m,
H), 2.80 (br s, 2H), 2.33 (m, 1H), 1.72–1.65 (m, 2H),
(0.12 mmol) in dry DCM (0.5 mL) was added. After the
stated reaction time, the product was purified by flash chro-
matography on silica gel (ethyl acetate/petroleum) to give
the addition product. The enantiomeric excess was deter-
mined by HPLC analysis on chiral column. The absolute
configuration of 4a was determined by comparison with
1
3
.38–1.31 (m, 1H), 0.98 (br s, 1H), 0.90–0.83 (m, 2H);
C
NMR (CDCl , 100 MHz) 180.7, 150.1, 149.9, 148.6,
3
1
1
2
1
4
40.4, 130.5, 129.4, 129.3, 127.0, 126.8, 126.5, 123.8,
23.6, 123.4, 122.5, 61.5, 56.6, 55.1, 41.2, 39.1, 27.3,
7.1, 25.5; IR (KBr) n 3280, 2940, 1540, 1324, 1119,
1
the authentic sample reported early (through H NMR and
7
a
HPLC analysis), and other products were assigned accord-
ingly. The characterization of the new addition products has
been shown below.
ꢁ1
067, 842, 760 cm ; HRMS (EI) calcd for C H F N S
2
7 27 3 4
2
0
96.1909, found 496.1900; [a]D ꢁ75.0 (c 0.1, EtOAc).
ꢀ
1
Catalyst 1f. Mp: 88–90 C; H NMR (CDCl , 300 MHz)
3
4.1.2.1. 2-[3-(1-p-Methoxy-phenyl-2-nitroethyl)-thio-
chroman-4-ylidene]-malononitrile (4h). Mp: 176–
178 C; yield: 54%; H NMR (CDCl , 400 MHz) d (ppm)
3
d (ppm) 8.07 (s, 1H), 7.61 (d, J¼8.4 Hz, 2H), 7.39 (d,
ꢀ
1
J¼8.2 Hz, 2H), 7.30–7.24 (m, 3H), 7.15 (br s, 5H), 7.08–
7
2
1
1
.05 (m, 2H), 5.36 (br s, 1H), 3.76 (d, J¼10.8 Hz, 1H),
7.94 (d, J¼8.0 Hz, 1H), 7.50 (t, J¼8.0 Hz, 1H), 7.32–7.24
(m, 4H), 6.93 (d, J¼9.6 Hz, 2H), 4.68 (dd, J¼12.8,
10.4 Hz, 1H), 4.33 (dd, J¼12.4, 4.8 Hz, 1H), 3.81 (s, 3H),
3.77 (m, 1H), 3.68 (td, J¼11.6, 3.2 Hz, 1H), 3.33 (dd,
1
3
.20 (s, 6H); C NMR (CDCl , 75 MHz) d (ppm) 180.4,
3
41.1, 139.6, 131.8, 129.9, 125.5, 128.1, 128.0, 127.9,
27.6, 127.4, 126.6, 125.8, 123.6, 122.2, 74.1, 59.3, 40.7;
IR (CH Cl ) n 3264, 2940, 2871, 2835, 2790, 1521, 1456,
2
325, 1162, 1125 cm
C H F N S (M+H) 444.1716, found 444.1740; [a]
D
J¼14.0, 3.2 Hz, 1H), 2.67 (dd, J¼13.6, 3.2 Hz, 1H);
2
ꢁ
1
13
1
;
HRMS (ESI) calcd for
C NMR (CDCl , 50 MHz) d (ppm) 170.8, 143.2,
3
2
0
134.5, 131.6, 130.4, 130.3, 129.5, 129.1, 129.0, 127.4,
126.3, 125.3, 116.7, 114.9, 114.5, 78.1, 55.3, 42.9, 41.8,
2
4
25
3
3
+170.5 (c 0.4, CHCl3).
2
1250, 1180, 841, 755 cm ; HRMS (ESI) calcd for
C H N O SNa (M+Na) 414.0833, found 414.0891; [a]
21 17 3 3 D
9.1, 29.0; IR (KBr) n 3363, 2208, 1641, 1514, 1286,
ꢀ
1
ꢁ1
Catalyst 1g. Mp: 52–54 C; H NMR (CDCl , 400 MHz)
3
2
0
d (ppm) 7.20–7.09 (m, 2H), 7.00–6.95 (m, 2H), 6.87–6.77

L. Jiang et al. / Tetrahedron 63 (2007) 5123–5128
5127
+
511.0 (c 0.10, EtOAc), 95% ee was determined by HPLC
on OD column, 40% 2-propanol/hexane, 1.0 mL/min, UV
54 nm, tmajor¼12.3 min, tminor¼36.9 min.
187.6, 135.8, 129.5, 128.8, 128.0, 111.4, 111.1, 88.1, 78.6,
47.7, 44.9, 25.7, 16.7, 14.0; IR (KBr) n 3446, 2986, 2234,
ꢁ
1
2
1557, 1435, 1378, 760, 702 cm ; HRMS (ESI) calcd for
C H N O Na (M+Na) 306.1213, found 306.1217; [a]
D
2
0
1
6
17
3
2
4
.1.2.2. 2-{3-[1-(4-Dimethylamino-phenyl)-2-nitro-
+71.4 (c 0.14, EtOAc), 63% ee was determined by HPLC
on OD column, 40% 2-propanol/hexane, 1.0 mL/min, UV
254 nm, tminor¼9.2 min, tmajor¼10.8 min.
ethyl]-thiochroman-4-ylidene}-malononitrile (4j). Mp:
ꢀ
85–187 C; yield: 52%; H NMR (CDCl , 400 MHz)
3
1
1
d (ppm) 7.93 (d, J¼8.0 Hz, 1H), 7.48 (t, J¼7.6 Hz, 1H),
7
.30 (d, J¼8.4 Hz, 1H), 7.23–7.27 (m, 1H), 7.18 (d,
4.1.2.6. 2-[2-(1-Phenyl-2-nitroethyl)-4-tolyl-cyclo-
hexan-1-ylidene]-malononitrile (4n). Mp: 128–130 C;
ꢀ
yield: 24%; H NMR (CDCl , 400 MHz) d (ppm) 7.43–
J¼8.4 Hz, 2H), 6.69 (d, J¼8.4 Hz, 2H), 4.66 (dd, J¼12.0,
1
9
2
.2 Hz, 1H), 4.32 (dd, J¼12.4, 4.4 Hz, 1H), 3.65–3.75 (m,
H), 3.31 (dd, J¼14.0, 3.2 Hz, 1H), 2.96 (s, 6H), 2.73 (dd,
3
7.33 (m, 3H), 7.25 (m, 2H), 4.64 (dd, J¼12.4, 10.8 Hz,
1H), 4.34 (dd, J¼12.8, 4.8 Hz, 1H), 3.87 (td, J¼10.8,
4.8 Hz, 1H), 3.34 (d, J¼11.6 Hz, 1H), 3.09 (d, J¼12.8 Hz,
1H), 2.66 (td, J¼14.0, 5.6 Hz, 1H), 2.16 (m, 1H), 2.00 (m,
1
3
J¼14.0, 3.2 Hz, 1H); C NMR (CDCl , 50 MHz) d (ppm)
3
1
1
2
1
71.0, 150.6, 136.2, 134.4, 130.4, 128.6, 127.3, 125.1,
24.5, 121.8, 112.7, 112.6, 82.7, 78.2, 42.9, 42.0, 40.3,
9.1; IR (KBr) n 3429, 2919, 2235, 1615, 1562, 1528,
1H), 1.53 (d, J¼14.0 Hz, 1H), 1.29–1.21 (m, 1H), 1.19–
ꢁ1
13
435, 1367, 814, 773, 742 cm ; HRMS (ESI) calcd for
1.09 (m, 1H), 0.81 (d, J¼6.4 Hz, 3H); C NMR (CDCl ,
3
2
0
C H N O SNa (M+Na) 427.1199, found 427.1213; [a]
D
50 MHz) d (ppm) 184.6, 135.9, 129.5, 128.7, 127.7, 111.3,
110.9, 85.2, 78.4, 46.3, 45.2, 38.0, 36.3, 31.3, 25.8, 20.7;
IR (KBr) n 3382, 2961, 2929, 2235, 1595, 1455, 1379,
2
2
20
4
2
+
435.0 (c 0.10, EtOAc), 94% ee was determined by HPLC
on OD column, 30% 2-propanol/hexane, 1.0 mL/min, UV
54 nm, tmajor¼12.7 min, tminor¼39.1 min.
ꢁ
763, 701, 599 cm ; HRMS (ESI) calcd for C H N O Na
18 19 3 2
1
2
2
0
(
M+Na) 332.1369, found 332.1372; [a]D ꢁ30.8 (c 0.13,
4
.1.2.3.
man-4-ylidene]-malononitrile (4k). Mp: 158–160 C;
2-[3-(1-Furan-2-yl-2-nitroethyl)-thiochro-
ꢀ
EtOAc), 57% ee was determined by HPLC on AS column,
20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm, tmajor
12.6 min, tminor¼15.3 min.
¼
1
yield: 64%; H NMR (CDCl , 400 MHz) d (ppm) 7.89 (d,
3
J¼8.0 Hz, 1H), 7.50–7.45 (m, 2H), 7.30–7.23 (m, 2H),
6
9
3
1
5
1
3
1
.42 (d, J¼3.2 Hz, 1H), 6.36 (m, 1H), 4.77 (dd, J¼12.4,
.6 Hz, 1H), 4.30 (dd, J¼12.8, 4.8 Hz, 1H), 3.94 (m, 1H),
.87 (td, J¼11.2, 3.6 Hz, 1H), 3.41 (dd, J¼14.0, 3.6 Hz,
4.1.2.7. 2-[2-(1-Phenyl-2-nitroethyl)-2-ethyl-1-yl-
idene]-malononitrile (4o). Mp: 94–96 C; yield: 22%; H
ꢀ
NMR (CDCl , 400 MHz) d (ppm) 7.42–7.33 (m, 3H), 7.19
1
3
1
3
H), 2.73 (dd, J¼14.0, 3.6 Hz, 1H); C NMR (CDCl ,
(m, 2H), 7.14 (d, J¼11.2 Hz, 1H), 4.64 (dd, J¼12.8,
9.2 Hz, 1H), 4.54 (dd, J¼12.8, 6.0 Hz, 1H), 3.57 (m, 1H),
3.01 (m, 1H), 1.57–1.50 (m, 1H), 1.38–1.28 (m, 1H), 0.84
3
0 MHz) d (ppm) 169.7, 144.3, 143.6, 134.4, 130.3, 129.1,
27.3, 126.4, 125.3, 112.7, 111.7, 111.0, 110.7, 75.8, 39.5,
7.9, 29.7, 29.2, 28.7; IR (KBr) n 3467, 3346, 2923, 2230,
1
3
(t, J¼7.6 Hz, 3H); C NMR (CDCl , 50 MHz) d (ppm)
3
ꢁ1
561, 1429, 1379, 1016, 777, 756, 735 cm ; HRMS (ESI)
calcd for C H N O SNa (M+Na) 374.0570, found
1
74.0564; [a] +633.0 (c 0.20, EtOAc), 90% ee was deter-
mined by HPLC on AS column, 30% 2-propanol/hexane,
.0 mL/min, UV 254 nm, tmajor¼15.1 min, tminor¼29.0 min.
169.0, 135.6, 129.5, 128.8, 128.0, 111.3, 110.3, 92.1, 78.4,
48.5, 47.3, 29.7, 25.0, 11.2; IR (KBr) n 3447, 2964, 2927,
8 13 3 3
2
0
ꢁ1
3
2240, 1557, 1383, 1201, 763, 697, 643, 580 cm ; HRMS
(ESI) calcd for C H N O Na (M+Na) 292.1056, found
D
1
5 15 3 2
2
0
1
292.1046; [a]D ꢁ83.3 (c 0.03, EtOAc), 81% ee was deter-
mined by HPLC on OD column, 20% 2-propanol/hexane,
1.0 mL/min, UV 254 nm, tminor¼20.9 min, tmajor¼29.1 min.
4
idene]-malononitrile (4l). Mp: 108–110 C; yield: 36%;
.1.2.4.
2-[3-(1-Phenyl-2-nitroethyl)-chroman-4-yl-
ꢀ
1
H NMR (CDCl , 400 MHz) d (ppm) 8.25 (d, J¼8.4 Hz,
4.1.2.8. 2-[3-(1-Isopropyl-2-nitroethyl)-thiochroman-
4-ylidene]-malononitrile (4p). Mp: 156–158 C; yield:
3
ꢀ
21%; H NMR (CDCl , 300 MHz) d (ppm) 7.80 (d,
1
2
(
H), 7.61 (t, J¼7.6 Hz, 1H), 7.45–7.36 (m, 3H), 7.32 (m,
H), 7.15 (t, J¼7.6 Hz, 1H), 7.06 (d, J¼8.4 Hz, 1H), 4.85
1
3
dd, J¼13.2, 10.4 Hz, 1H), 4.51 (dd, J¼12.8, 5.2 Hz, 1H),
J¼8.7 Hz, 1H), 7.42 (t, J¼8.4 Hz, 1H), 7.19 (m, 2H), 4.38
(dd, J¼13.5, 3.9 Hz, 1H), 4.16 (dd, J¼13.5, 6.6 Hz, 1H),
3.56–3.47 (m, 2H), 3.20 (dd, J¼14.7, 4.2 Hz, 1H), 2.70
(m, 1H), 2.22 (m, 1H), 1.06 (d, J¼6.9 Hz, 3H), 0.94 (d,
4
.09 (m, 2H), 3.73 (td, J¼10.8, 5.6 Hz, 1H), 3.31 (d,
3
1
3
J¼11.2 Hz, 1H); C NMR (CDCl , 100 MHz) d (ppm)
1
1
65.2, 156.0, 137.6, 129.6, 129.0, 128.1, 127.9, 122.4,
18.5, 114.9, 113.1, 112.8, 77.5, 66.5, 43.5, 43.0; IR (KBr)
1
3
J¼7.2 Hz, 3H); C NMR (CDCl , 100 MHz) d (ppm)
3
n 3421, 2917, 2223, 1608, 1553, 1480, 1454, 1327, 1259,
1
171.1, 137.2, 134.0, 130.9, 126.9, 125.3, 125.1, 112.8,
112.6, 74.3, 41.3, 39.9, 29.7, 28.8, 27.3, 20.7, 15.7; IR
(KBr) n 3445, 2965, 2229, 1555, 1434, 768, 737 cm
ꢁ1
219, 767, 751, 702 cm ; HRMS (ESI) calcd for
C H N O Na (M+Na) 368.1006, found 368.1009; [a]
D
2
0
ꢁ1
;
2
0
15
3
3
ꢁ
160.0 (c 0.10, EtOAc), 92% ee was determined by
HPLC on OD column, 40% 2-propanol/hexane, 1.0 mL/
HRMS (ESI) calcd for C H N O SNa (M+Na)
17 17 3 2
2
0
350.0934, found 350.0931; [a]D ꢁ241.2 (c 0.04, EtOAc),
69% ee was determined by HPLC on OD column, 40% 2-
propanol/hexane, 1.0 mL/min, UV 254 nm, tminor¼7.9 min,
tmajor¼30.1 min.
min, UV 254 nm, tminor¼12.3 min, tmajor¼14.0 min.
4.1.2.5. 2-[2-(1-Phenyl-2-nitroethyl)-2-tolyl-1-ethyl-1-
ylidene]-malononitrile (4m). Mp: 92–94 C; yield: 31%;
ꢀ
H NMR (CDCl , 400 MHz) d (ppm) 7.42–7.33 (m, 3H),
1
3
7
.23 (m, 2H), 4.64 (dd, J¼12.8, 10.4 Hz, 1H), 4.39 (dd,
Acknowledgements
J¼12.4, 4.8 Hz, 1H), 3.55 (td, J¼10.8, 4.8 Hz, 1H), 3.38
(
(
m, 1H), 2.73–2.55 (m, 2H), 1.38 (t, J¼8.0 Hz, 3H), 1.00
The project sponsored by SRF for ROCS, SEM, China. We
are grateful for the financial support from the National
1
3
d, J¼6.8 Hz, 3H); C NMR (CDCl , 50 MHz) d (ppm)
3

5128
L. Jiang et al. / Tetrahedron 63 (2007) 5123–5128
Natural Science Foundation of China (20502018), Educa-
tion of Ministry (NCET-05-0781), and Fok Ying Tung
Education Foundation (101037).
8. For reviews on hydrogen-bonding of organocatalysts, see: (a)
Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289; (b) Pihko,
P. M. Angew. Chem., Int. Ed. 2004, 43, 2062; (c) Takemoto,
Y. Org. Biomol. Chem. 2005, 3, 4299; (d) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520;
Supplementary data
(
e) Connon, S. T. Chem.—Eur. J. 2006, 12, 5418.
. (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
25, 12672; (b) Okino, T.; Nakamura, S.; Furukawa, T.;
9
HPLC chromatograms of the Michael addition products.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.04.011.
1
Takemoto, Y. Org. Lett. 2004, 6, 625; (c) Xu, X.; Furukawa,
T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem.—Eur. J.
2
006, 12, 466; (d) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu,
References and notes
X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119; (e)
Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed.
1
. For reviews, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033; (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001,
2
005, 44, 4032; (f) Inokuma, T.; Hoashi, Y.; Takemoto, Y.
J. Am. Chem. Soc. 2006, 128, 9413; (g) Vakulya, B.; Varga,
S.; Csampai, A.; S ꢀo os, T. Org. Lett. 2005, 7, 1967; (h)
Berkessel, A.; Cleemann, F.; Mukherjee, S.; M €u ller, T. N.;
Lex, J. Angew. Chem., Int. Ed. 2005, 44, 807; (i) Berkessel,
A.; Mukherjee, S.; Cleemann, F.; M €u ller, T. N.; Lex, J.
Chem. Commun. 2005, 1898; (j) Berkessel, A.; Cleemann, F.;
Mukherjee, S. Angew. Chem., Int. Ed. 2005, 44, 7466; (k) Ye,
J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481; (l)
McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005,
171; (c) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719;
(
4
d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
3, 5138.
2
. For some leading references, see: (a) Peelen, T. J.; Chi, Y.;
Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598; (b)
Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212; (c) Taylor, M. S.; Zalatan, D. N.;
Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005,
127, 1313; (d) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am.
4
4, 6367; (m) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W.
Chem. Soc. 2005, 127, 8948; (e) Xu, Y.; C ꢀo rdava, A. Chem.
Commun. 2006, 460; (f) Luo, S.; Mi, X.; Zhang, L.; Liu, S.;
Xu, H.; Cheng, J. Angew. Chem., Int. Ed. 2006, 45, 3093;
Org. Lett. 2005, 7, 4293; (n) Wang, J.; Li, H.; Duan, W.; Zu,
L.; Wang, W. Org. Lett. 2005, 7, 4713; (o) Tillman, A. L.;
Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191; (p) Song, J.;
Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048; (q)
Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang,
W. J. Am. Chem. Soc. 2006, 128, 12652; (r) Wang, B.;
Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007,
(
1
g) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006,
28, 1454; (h) Carlone, A.; Cabrera, S.; Marigo, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1101.
. (a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975; (b) Itoh,
K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394; (c)
Ooi, T.; Fujioka, S.; Maruoka, K. J. Am. Chem. Soc. 2004,
3
1
29, 768.
1
0. (a) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y.
Synlett 2005, 603; (b) Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang, L.;
Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem.
126, 11790; (d) Prieto, A.; Halland, N.; Jørgensen, K. A.
Org. Lett. 2005, 7, 3897; (e) Tsogoeva, S. B.; Jagtap, S. B.
Synlett 2004, 2624; (f) Mitchell, C. E. T.; Brenner, S. E.; Ley,
S. V. Chem. Commun. 2005, 5346; (g) Lu, S.-F.; Du, D.-M.;
Xu, J.; Zhang, S.-W. J. Am. Chem. Soc. 2006, 128, 7418.
. (a) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am.
Chem. Soc. 2004, 126, 6240; (b) Paquin, J.-F.; Defieber, C.;
Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005,
2
006, 4, 2097; (c) Liu, T.-Y.; Li, R.; Chai, Q.; Long, J.; Li,
B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Chem.—Eur. J. 2007,
3, 319; (d) See Ref. 7e.
1
4
5
1
1. The formation of insoluble solid side products has also
been observed in the Michale addition of ketones to b-nitro-
styrenes, see: Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006,
127, 10850; (c) Wu, J.; Mampreian, D. M.; Hoveyda, A. H.
J. Am. Chem. Soc. 2005, 127, 4584; (d) Hird, A. W.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 14988; (e)
Fillion, E.; Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774.
. (a) Chen, Y.-C.; Xue, D.; Deng, J.-G.; Cui, X.; Zhu, J.; Jiang,
Y.-Z. Tetrahedron Lett. 2004, 45, 1555; (b) For a similar
strategy, see: Poulsen, T. B.; Alemparte, C.; Jørgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 11614.
1
27, 4966.
1
2. Usually better results could be obtained in the presence of ter-
tiary amine-thiourea catalyst with strong electron-withdrawing
group.
3. In the reaction of 2b and 3a catalyzed by modified cinchona
alkaloid 86% ee was obtained, see Ref. 7a.
4. Although the formation of racemic product from 2g and 3a
catalyzed by 1c is not clear yet, the following plausible cata-
lytic model might account for the observed results.
1
1
6
7
. For a recent review on vinylogous reaction, see: Denmark,
S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int.
Ed. 2005, 44, 4682.
. (a) Xue, D.; Chen, Y.-C.; Cun, L.-F.; Wang, Q.-W.; Zhu, J.;
Deng, J.-G. Org. Lett. 2005, 7, 5293; (b) Poulsen, T. B.; Bell,
M.; Jørgensen, K. A. Org. Biomol. Chem. 2006, 4, 63; (c)
Xie, J.-W.; Yue, L.; Xue, D.; Ma, X.-L.; Chen, Y.-C.; Wu, Y.;
Zhu, J.; Deng, J.-G. Chem. Commun. 2006, 1563; (d) Xie, J.-
W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-
C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007,
S
F3C
N
H
O
N
H
O
flexible
N
COOEt
NO2
NC
interaction
H
O
*
OEt
CN
Ph
*
N
racemic adduct
Ph
47, 389; (e) Liu, T.-Y.; Cui, H.-L.; Long, J.; Li, B.-J.; Wu, Y.;
Ding, L.-S.; Chen, Y.-C. J. Am. Chem. Soc. 2007, 129, 1878.
nucleophilic carbon remote
from the chiral center