Organocatalytic asymmetric direct Michael addition of aromatic ketones to alkylidenemalononitriles

Article abstract of DOI:10.1016/j.tetlet.2008.04.069

The asymmetric direct Michael addition of aromatic ketones to highly active alkylidenemalononitriles was investigated by employing a chiral primary amine 9-amino-9-deoxyepicinchonine. In general modest to good enantioselectivities (71-84% ee) could be obtained in acceptable isolated yields (48-85%) for an array of substrates.

Full text of DOI:10.1016/j.tetlet.2008.04.069

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3881–3884
Organocatalytic asymmetric direct Michael addition
of aromatic ketones to alkylidenemalononitriles
Lei Yue a, Wei Du a, Yan-Kai Liu a, Ying-Chun Chen a,b,
*
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 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
Received 22 December 2007; revised 7 April 2008; accepted 11 April 2008
Available online 14 April 2008
Abstract
The asymmetric direct Michael addition of aromatic ketones to highly active alkylidenemalononitriles was investigated by employing
a chiral primary amine 9-amino-9-deoxyepicinchonine. In general modest to good enantioselectivities (71–84% ee) could be obtained in
acceptable isolated yields (48–85%) for an array of substrates.
Ó 2008 Elsevier Ltd. All rights reserved.
The catalytic asymmetric Michael reaction is generally
regarded as one of the most powerful and efficient transfor-
mations in carbon–carbon bond forming reactions, because
a diversity of nucleophiles and activated olefins could be
expected to give versatile arrangements.1 In particular,
the recently developed small organic molecule catalyzed
asymmetric Michael additions triggered special interest.2
Among them, a number of successful examples in the
asymmetric direct Michael reactions of aldehydes and
ketones through enamine activation have been reported;
however, further expansion of the substrate scopes is still
desirable.3 Most studies in this area are focused on the
reactions of simple aliphatic ketones and aldehydes, while
much less attention has been paid on the application of
aromatic ketones as enamine precursors due to their more
crowded structures.4 On the other hand, the development
of asymmetric Michael addition of rarely applied olefinic
electrophiles is also attractive because new chiral skeletons
could be constructed. Very recently we and Melchiorre
have established that primary amines derived from natural
cinchona alkaloids could serve as excellent iminium cata-
lysts for the asymmetric Michael reactions of a,b-unsatu-
rated ketones.5 Subsequently, we found that these
primary amines also could activate aromatic ketones for
the highly enantioselective direct a-amination reaction with
diethyl azodicarboxylate (DEAD).6 Encouraged by these
results, here we would like to present the asymmetric direct
Michael addition of aryl ketones to alkylidenemalononitr-
iles7 promoted by primary aminocatalysts,8 giving a facile
route to multifunctional enantiomerically enriched com-
pounds (Eq. 1 ). To the best of our knowledge, this
reaction has not been well explored in the literature.9
O
CN
O
CN
CN
ð1Þ
*
+
NH2
Ar
R
CN
Ar
enamine activation
R
In the initial study, primary aminocatalysts 1a–c5 (Fig. 1)
were tested for the asymmetric Michael addition of
acetophenone 2a and benzylidenemalononitrile 3a in the
OH
OMe
Ph
N
H
N
Ph
OR
H
N
H
Ph
NH2
NH2
NH2
NH2
N
N
1d R = H
1e R = TMS
N
1c
1b
1a
*
Corresponding author. Tel./fax: +86 28 85502609.
Fig. 1. Structures of primary aminocatalysts.
E-mail address: ycchenhuaxi@yahoo.com.cn (Y.-C. Chen).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.069

3882
L. Yue et al. / Tetrahedron Letters 49 (2008) 3881–3884
presence of PTSA in THF. The reaction was sluggish at
ambient temperature and high concentration was required
to ensure better conversion. Addition product 4a was com-
monly isolated in low yield after 72 h. ADC 1a emerged as
a superior catalyst in terms of both isolated yield and
enantioselectivity (Table 1, entry 1). ADQ 1b gave slightly
lower ee value while the product has the opposite configu-
ration (entry 2). Nevertheless, the ee was greatly reduced
when the reaction was catalyzed by 1c5d with a free OH
group (entry 3). In addition, primary amines 1d and 1e
derived from L-phenylalanine were almost inert in the
tested Michael reaction (entries 4 and 5). Then other acidic
additives were screened in combination with catalyst 1a,
and only sulfonic acids gave reasonable results (entries 6–
10). Various solvents were also investigated, and inferior
results were generally obtained (entries 11–17). Interest-
ingly, the stereoselectivity was inversed when the reaction
was conducted in DMF (entry 14). Notably the reaction
could proceed smoothly in H2O,10 but much lower ee was
obtained (entry 17). We found that the enantioselectivity
was not affected with slightly higher yield at 45 °C in a
diluted solution (entry 18), and good isolated yield could
be attained after the time was extended to 6 d (entry 19).
Unfortunately, decreased ee was attained by utilizing a
more bulky additive MSA (mesitylsulfonic acid, entry
20). Further increasing the temperature to 60 °C also
resulted in a reduced yield due to some side reactions (entry
21).
With the optimized conditions in hand, we then exam-
ined a variety of aromatic ketones and alkylidenemalono-
nitriles to establish the general utility of this asymmetric
transformation (Table 2). The reactions were performed
in THF at 45 °C in the presence of 20 mol % of 1a and
40 mol % of TsOH for 4–6 days.11 As outlined in Table
2, good enantioselectivities were generally obtained for a
broad spectrum of acetophenones bearing electron-with-
drawing or donating substitutions (entries 2–8). 2-Acetyl-
naphthalene exhibited relatively lower reactivity (entry 9),
but heteroaryl ketones, such as 2-acetylthiophene and 3-
acetylpyridine, failed to give the desired Michael adduct.
On the other hand, a few substituted benzylidenemalono-
nitriles were also tested, and higher ee values were gained
for substrates with electron-withdrawing groups (entries
10–12). Most of the adducts are solid and enantiopure
products could be attained after recrystallization. It should
be noted that the reaction of p-bromoacetophenone and
alkylidenemalononitriles with c-CH was not successful,
and complex mixtures were commonly observed, probably
because of the side reactions resulting from the active c-CH
of alkylidenemalononitriles.12
Table 1
Screening studies of asymmetric direct Michael addition of acetophenone
2a to benzylidenemalononitrile 3aa
Furthermore, we investigated the reaction of benzylid-
enemalononitrile 3a and aryl ketones with a-substitution.
Very sluggish reaction was detected when propiophenone
was applied. However, cyclic 1-indanone exhibited better
O
1 (20 mol %)
CN
CN
O
CN
CN
acid (40 mol %)
+
Ph
Ph
Ph
solvent, rt
Ph
2a
4a
3a
Entry
1
Acid
Solvent
t (d) Yieldb (%) eec (%)
Table 2
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
PTSA
PTSA
PTSA
PTSA
PTSA
PNBA
AcOH
TFA
THF
THF
THF
THF
THF
THF
THF
THF
3
3
3
3
3
3
3
3
3
3
2
4
4
2
5
5
4
3
6
3
6
30
23
43
—
—
14
29
—
32
10
35
38
18
20
17
10
53
39
73
10
30
72
ꢀ65
ꢀ23
—
—
2
Asymmetric direct Michael addition of aromatic ketones 2 to alkylidene-
malononitriles 3a
O
1a (20 mol %)
CN
CN
O
CN
CN
PTSA (40 mol %)
+
Ar
Ar1
THF, 45 oC
Ar
Ar1
2
4
0
3
—
45
74
14
60
72
ꢀ41
33
61
34
71
71
43
70
Entry
Ar
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
2-Np
4-BrC6H4
4-BrC6H4
4-BrC6H4
Ar1
t (d)
Yieldb (%)
eec (%)
MeSO3H THF
10
11
12
13
14
15
16
17
18d
19d
20d
21e
a
L-CSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
MSA
THF
2-PrOH
Diox
DME
DMF
Toluene
CH3CN
H2O
THF
THF
THF
THF
1
2
3
4
5
6
7
8
9
10
11
12
a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6
6
6
6
4
6
4
6
6
6
6
6
4a–73
4b–72
4c–72
4d–69
4e–79
4f–77
4g–76
4h–85
4i–48
4j–65
4k–75
4l–69
71
75
78
81d
78
74
71
72
72
80
84
71
4-NO2C6H4
4-F C6H4
4-NO2C6H4
4-MeOC6H4
PTSA
Reactions were performed with 0.2 mmol of 2, 0.1 mmol of 3a,
0.02 mmol of 1a, and 0.04 mmol of PTSA in 0.3 mL THF at 45 °C.
Unless otherwise noted, reactions were performed with 0.2 mmol of 2a,
0.1 mmol of 3a, 0.02 mmol of 1 and 0.04 mmol of acid in 0.05 mL solvent
at rt.
b
Isolated yield.
Determined by chiral HPLC analysis.
The absolute configuration of enantiopure 4d (after recrystallization)
b
c
Isolated yield.
Determined by chiral HPLC analysis.
At 45 °C in 0.3 mL of THF.
c
d
d
was determined by X-ray analysis, and other products were assigned by
analogy.
e At 60 °C in 0.5 mL THF.

L. Yue et al. / Tetrahedron Letters 49 (2008) 3881–3884
3883
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.04.069.
References and notes
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CN
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O
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4d
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reactivity, and moderate yield was obtained with good ste-
reoselectivity (dr 17:1, 81% ee) under the optimal condi-
tions after 3 d (Eq. 2). It is also found that diethyl
benzylidenemalonate13 and cinnamonitrile are almost inert
in the catalytic reaction with acetophenone, indicating that
the more electrophilic alkylidenemalononitriles are of the
essence to the success of primary amine catalyzed direct
Michael addition of aryl ketones.
Chem., Int. Ed. 2006, 45, 3093; (i) Enders, D.; Huttl, M. R. M.;
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Grondal, C.; Raabe, G. Nature 2006, 441, 861; a,b-Unsaturated
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O
O
Ph
1a (20 mol %)
CN
CN
PTSA (40 mol %)
CN
CN
4m dr 17:1, 81% ee
+
ð2Þ
THF, 45 oC, 3 d
60% yield
Ph
3a
´
Mosse, S.; Alexakis, A. Org. Lett. 2005, 7, 4361; Vinyl phosphates (o)
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In order to determine the absolute configuration of the Mi-
chael addition products, single crystals suitable for X-ray
crystallographic analysis were obtained from compound
4d bearing a bromine atom. Over 99% ee could be gained
after recrystallization from 4d (81% ee) in a mixture of
ethyl acetate and hexane. The absolute configuration of
4d was determined to be (S) in the benzylic carbon (Fig. 2).
In conclusion, we have developed the new asymmetric
direct Michael addition of aromatic ketones to alkylidene-
malononitriles catalyzed by a primary amine derived from
cinchonine. The reaction proceeds well at higher tempera-
ture (45 °C), and good enantioselectivities are generally
obtained (71–84% ee) for an array of substrates. Further
developments of the asymmetric direct reactions of aryl
ketones catalyzed by chiral primary amines are in progress
in our laboratory.
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2839; (d) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto,
H. Angew. Chem., Int. Ed. 2004, 43, 1983.
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Acknowledgements
7. Alkylidenemalononitriles are rarely applied in the catalytic asymmet-
ric synthesis despite their highly electrophilic features, probably
because of the relatively lower affinity of manolonitrile group to Lewis
acids or Brønsted acids. For limited applications in asymmetric
Michael addition, see: (a) Kojima, S.; Suzuki, M.; Watanabe, A.;
Ohkata, K. Tetrahedron Lett. 2006, 47, 9061; (b) Kojima, S.;
Fujitomo, K.; Itoh, Y.; Hiroike, K.; Murakami, M.; Ohkata, K.
We are grateful for the financial support from the Na-
tional Natural Science Foundation of China (20772084),
Ministry of Education (NCET-05-0781), and Sichuan
Province Government (07ZQ026-027).
´
´
Heterocycles 2006, 67, 679; (c) Fernandez, I.; Araujo, C. S.; Romero,
M. J.; Alcudia, F.; Khiar, N. Tetrahedron 2000, 56, 3749; (d) Marco,
J. L. J. Org. Chem. 1997, 62, 6575.
Supplementary data
8. For selected examples on enamine catalysis with primary amines, see:
(a) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. J.
Am. Chem. Soc. 2007, 129, 288; (b) Wu, X.; Jiang, Z.; Shen, H.-M.;
Supplementary data (experimental procedures, charac-
terization, and HPLC spectra of the products) associated

3884
L. Yue et al. / Tetrahedron Letters 49 (2008) 3881–3884
20
´
Lu, Y., Adv. Synth. Catal. 2007, 349, 812; (c) Xu, Y.; Cordova, A.
(petroleum ether/EtOAc = 15:1); ½aꢂD þ5:6 (c 0.19, in EtOAc), 81%
Chem. Commun. 2006, 460; (d) Bassan, A.; Zou, W.; Reyes, E.; Himo,
ee, determined by HPLC analysis [Daicel chiralpak AD, n-hexane/i-
´
F.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44, 7028; (e) Pizzarello,
PrOH = 80/20, 1.0 mL/min, k = 254 nm, t (minor) = 12.58 min, t
S.; Weber, A. L. Science 2004, 303, 1151; (f) Tanaka, F.; Thayuman-
avan, R.; Mase, N.; Barbas, C. F., III. Tetrahedron Lett. 2004, 45,
325; (g) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451; (h)
Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 6366; (i) McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9,
599; (j) Luo, S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J.-P. J. Am. Chem.
Soc. 2007, 129, 3074.
(major) = 15.23 min]; 1H NMR (300 MHz, CDCl3): d = 7.83 (d,
J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.45–7.37 (m, 5H), 4.62 (d,
J = 5.1 Hz, 1H), 3.98–3.92 (m, 1H), 3.72–3.58 (m, 2H) ppm; 13C NMR
(75 MHz, CDCl3): d = 195.6, 136.3, 134.4, 132.3, 129.5, 129.4, 129.2,
127.9, 111.7, 111.6, 41.1, 40.1, 28.7 ppm; ESI-HRMS: calcd for
C18H13BrN2O+Na 375.0109; found 375.0105.
12. For direct vinylogous reactions of alkylidenemalononitriles with
active c-CH, see: (a) Xue, D.; Chen, Y.-C.; Cun, L.-F.; Wang, Q.-W.;
Zhu, J.; Deng, J.-G. Org. Lett. 2005, 7, 5293; (b) Xie, J.-W.; Yue, L.;
Xue, D.; Ma, X.-L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Chem.
Commun. 2006, 1563; (c) 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, 1879;
(d) Jiang, L.; Zheng, H.-T.; Liu, T.-Y.; Yue, L.; Chen, Y.-C.
Tetrahedron 2007, 63, 5123. For independent work by Jørgensen, see:
(e) Poulsen, T. B.; Alemparte, C.; Jørgensen, K. A. J. Am. Chem. Soc.
2005, 127, 11614.
13. For asymmetric Michael addition of simple ketones to alkylidene-
malonates, see: (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan,
R.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 4441; (b) Betancort,
J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F.,
III. Synthesis 2004, 1509; (c) Blarer, S. J.; Seebach, D. Chem. Ber.
1983, 116, 2250.
9. Only datum has been reported for asymmetric Michael addition of
acetophenone to benzylidenemalononitrile in 10% ee, see: Yasuda,
K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1996, 37, 6343.
10. For selected examples of organocatalytic Michael addition in water,
see: (a) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka,
F., ; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 4966; (b)
Vishnumaya, ; Singh, V. K. Org. Lett. 2007, 9, 1117; (c) Zhu, S.; Yu,
S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545.
11. General procedure for asymmetric Michael addition of aryl ketones to
alkylidenemalononitriles: Benzylidenemalononitrile (15.4 mg, 0.1 mmol),
p-bromoacetophenone (40 mg, 0.2 mmol), ADC 1a (5.9 mg,
20 mol %) and TsOHꢁ H2O (7.6 mg, 40 mol %) were stirred in THF
(0.3 mL) at 45 °C. The reaction was monitored by TLC analysis.
After 6 d, the product was purified by flash chromatography on
silica gel to give product 4d. 69% yield, white soild; Rf = 0.1