J. Lu et al. / Tetrahedron Letters 49 (2008) 5389–5392
5391
obtained in 71% ee, while the diastereomer was formed in 8% yield
and 32% ee. When the unsaturated ketone, trans-4-phenyl-3-
buten-2-one was tested under the same reaction conditions, no
product was observed even after a long reaction time.
CO H
CO H
2
CO H
CO H
2
2
2
O N
2
NO
2
NO
2
In summary, this Letter has described an efficient method for
the organocatalytic and asymmetric direct vinylogous Michael
addition that employs electron deficient vinyl malononitriles as
the nucleophilic species in the presence of a catalytic amount of
chiral 2-azanorbornyl derivatives. The organocatalyst 3 exhibited
high stereoselectivity and catalytic activity in the vinylogous
Michael addition. The reaction features a metal-free approach, high
efficiency of the catalyst, mild reaction conditions, high yields, and
good enantioselectivities, providing a practical method to syn-
thesize highly enantiopure multi-functional compounds. Many of
these products can be obtained in almost optically pure form after
a single crystallization from isopropanol. These results open a new
avenue for the design of chiral azabicyclo[2.2.1] heptane analogues
as organocatalysts. Further work on redesigning high affinity chiral
2-azanorbornyl derivatives applicable to the asymmetric synthesis
of estrone methyl ether is in progress.
I
II
III
IV
Figure 3. Structures of the additives.
(Table 2, entries 5–8). When the polar solvent methyl alcohol was
tested, no product was obtained (Table 2, entry 9). In general, low-
ering the temperature resulted in a decrease of the reaction rate
but an increase of the enantioselectivity. In the presence of
20 mol % of catalyst, an 88% ee of 8aa was obtained at 0 °C, but
the yield was only 42% after a long reaction time. Further decreas-
ing the temperature to ꢀ30 °C resulted in no product even after
24 h (Table 2, entry 11). When a small amount of water was intro-
duced to the reaction system, the desired product was formed in a
slightly lower yield and enantioselectivity (Table 2, entry 12). From
the results obtained, it can be seen that the combination of catalyst
3 (20 mol %) and PNBA II (20 mol %) exhibited the best catalytic
activity in THF at room temperature.
Typical procedure: (Table 3, entry 1): A mixture of 6a (19.4 mg,
0.1 mmol), 7a (32 lL, 0.4 mmol), catalyst 3 (5.6 mg, 0.02 mmol)
and PNBA (3.4 mg, 0.02 mmol) in THF (1 mL) was stirred for 20 h
at rt. Then the reaction mixture was quenched by adding 0.5 mL
of 1 M HCl. The mixture was extracted with EtOAc and dried with
anhydrous sodium sulfate. The crude product was purified by col-
umn chromatography on silica gel to give the desired product 8aa
Having established the optimal reaction conditions, we next
examined a range of
2) and ,b-unsaturated aldehydes in order to explore the generality
of this catalytic system. The results are summarized in Table 3.
Several -disubstituted vinyl malononitriles were tested in
a,a-disubstituted vinyl malononitriles (Fig.
a
a,a
in 78% yield and 87% ee; ½a D22
ꢀ324 (c 0.81, DCM), Rf = 0.32 (hex-
ꢁ
the reaction with crotonaldehyde. In all cases, high enantioselec-
tivities were obtained (Table 3, entries 1–5). However, by introduc-
ing an electron-donating group into the vinyl malononitrile, we
observed a decrease in the yields (Table 3, entries 4 and 5). Good
ee values could also be obtained in the reaction of other alkyl
ane/EtOAc = 4:1); 1H NMR (400 MHz, CDCl3): d 9.64 (s, 1H), 7.93
(d, J = 7.9 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H),
7.28–7.26 (m, 1H), 3.04–3.02 (m, 1H), 3.00–2.96 (m, 1H), 2.91–
2.84 (m, 1H), 2.45–2.41 (m, 2H), 2.38–2.19 (m, 2H), 2.12–2.04
(m, 1H), 1.05 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
200.4, 177.4, 140.2, 133.8, 129.5, 129.2, 128.3, 127.0, 113.5,
a
,b-unsaturated aldehydes (Table 3, entries 7–11). Unfortunately,
when an aryl ,b-unsaturated aldehyde was tested, only moderate
a
113.3, 81.1, 48.7, 47.1, 28.8, 24.9, 24.5, 17.3; IR (KBr):
1762 cmꢀ1; MS: C17H16N2O 264.12 [M]+. The enantiomeric ratio
was determined by HPLC on Chiralpak AS column (20%
m 2226,
enantioselectivity was obtained (Table 3, entry 12). In all the reac-
tions of cyclic substrates, only the anti-products were formed.
When the acyclic substrate 6f was tested, a major product was
a
2-propanol/hexane, 1 mL/min), t minor = 18.756 min, t major =
26.674 min.
Table 3
Asymmetric vinylogous Michael addition of dicyanoolefins
6 to a,b-unsaturated
Acknowledgments
aldehydes 7a
NC
CN
+
NC
CN CHO
H
We gratefully acknowledge the Nanyang Technological
University, Ministry of Education and Biomedical Research Council
(A*STAR Grant M47110003) for funding of this research.
3
CHO
R
R'
R
H
PNBA
R'
X
6a-f
X
Supplementary data
7a-d
8
Entry
6
R
Product
Yieldb (%)
eec (%)
Supplementary data associated with this article can be found, in
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6b
6c
6d
6a
6c
6b
Me (7a)
Me (7a)
Me (7a)
Me (7a)
Me (7a)
Me (7a)
Et (7b)
Et (7b)
Et (7b)
n-Pr (7c)
n-Pr (7c)
Ph (7d)
8aa
8ba
8ca
8da
8ea
8fa
8bb
8cb
8db
8ac
8cc
8bd
78
81
86
56
41
42/8
75
83
40
60
74
80
87 (97)d
91
90 (>99)d
86 (97)d
87 (96)d
71/32
88
References and notes
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1952, 74, 4223.
2. Ananchenko, S. N.; Torgov, I. V. Tetrahedron Lett. 1963, 4, 1553.
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Tetrahedron 1962, 18, 1355.
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Payen, A. J. J. Am. Chem. Soc. 1999, 121, 8237; (c) Tanaka, K.; Nakashima, H.;
Taniguchi, T.; Ogasawara, K. Org. Lett. 2000, 2, 1915; (d) Tsogoeva, S. B.; Durner,
G.; Bolte, M.; Gobel, M. W. Eur. J. Org. Chem. 2003, 1661; (e) Soorukram, D.;
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Chem. Soc. 2007, 129, 10346.
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Chem. Commun. 2006, 1563; (b) Chen, Y. C.; Xue, D.; Deng, J. G.; Cui, X.; Zhu, J.;
Jiang, Y.-Z. Tetrahedron Lett. 2004, 45, 1555; (c) Xue, D.; Chen, Y. C.; Cui, X.;
Wang, Q. W.; Zhu, J.; Deng, J. G. J. Org. Chem. 2005, 70, 3584; (d) Xue, D.; Chen, Y.
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88 (>99)d
81
80
81
57
10
11
12
a
Reactions performed with 0.1 mmol of 6, 0.4 mmol of 7, 20 mol % of catalyst and
20 mol % of PNBA in 1 mL of THF at rt for 20 h.
b
Isolated yield.
c
Determined by HPLC analysis on a Chiral phase, the absolute configuration of
the products was assigned by comparison with optical rotation and/or retention
time on chiral HPLC in Ref. 5a.
d
After recrystallization from i-PrOH.