Enantioselectively organocatalytic Michael addition of ketones to alkylidene malonates

Article abstract of DOI:10.1021/jo070070p

(Chemical Equation Presented) An organocatalytic asymmetric Michael addition of ketones to alkylidene malonates has been developed. In the presence of 20 mol % of urea 1a or N′-(pyrrolidin-2-ylmethyl) trifluoromethanesulfonamide 1j, the reactions of keton

Full text of DOI:10.1021/jo070070p

Enantioselectively Organocatalytic Michael Addition of Ketones to
Alkylidene Malonates
Chun-Li Cao, Xiu-Li Sun, Jiao-Long Zhou, and Yong Tang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
tangy@mail.sioc.ac.cn
ReceiVed January 12, 2007
An organocatalytic asymmetric Michael addition of ketones to alkylidene malonates has been developed.
In the presence of 20 mol % of urea 1a or N-(pyrrolidin-2-ylmethyl)trifluoromethanesulfonamide 1j, the
reactions of ketones with alkylidene malonates afford the desired Michael adducts in moderate to good
yields with good to high enantioselectivities under mild conditions.
Introduction
bifunctional products in an atom-economical manner. Recent
studies on this subject show that R,â-unsaturated aldehyde,4
ketone,5 sulfone,6 and nitrostyrene7 are suitable substrates to
give the desired adducts with high enantioselectivities. For
Asymmetric carbon-carbon bond formation reactions are
among the most challenging endeavors in organic synthesis. The
Michael reaction is one of the most efficient transformations,
and thus, considerable attention has been given to its catalytic
asymmetric version in the past decades.1,2 Of the asymmetric
reaction developed,1-8 directly organocatalytic Michael addition3-8
of ketones or aldehydes to R,â-unsaturated compounds provides
a particular attractive method for the synthesis of versatile
(5) (a) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151.
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127, 11598. (d) Chi, Y.-G.; Gellman, S. H. Org. Lett. 2005, 7, 4253. (e)
Wang, J.; Li, H.; Zu, L.-S.; Wang, W. AdV. Synth. Catal. 2006, 348, 425.
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Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737. (c) Ishii, T.;
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J. Org. Chem. 2004, 1577. (f) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S.
V. Synlett 2005, 4, 611. (g) Wang, W.; Wang, J.; Hao, H. Angew. Chem.,
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Commun. 2006, 460. (j) Xu, Y.-M.; Zou, W.-B.; Sunde´n, H.; Ibrahem, I.;
Co´rdova, A. AdV. Synth. Catal. 2006, 348, 418. (k) Cao, C.-L.; Ye, M.-C.;
Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901. (l) Luo, S.-Z.; Mi, X.-L.;
Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed. 2006, 45, 3039. (m)
Zu, L.-S.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077. (n) Wang,
J.; Hao, H.; Lou, B.; Zu, L.-S.; Guo, H.; Wang, W. Chem.sEur. J. 2006,
12, 4321. (o) Huang, H.-B.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128,
7170. (p) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624.
(q) Tsogoeva, S. B.; Wei, S.-W. Chem. Commun. 2006, 1451. (r) Cao, Y.-
J.; Lai, Y.-Y.; Wang, X.; Li, Y.-J.; Xiao, W.-J. Tetrahedron Lett. 2007, 48,
21.
(1) Perlmutter, P. Conjugated Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992.
(2) For recent reviews of asymmetric conjugate addition reactions, see:
(a) Tomioka, K.; Nagaoka, Y.; Yamaguchi, M. In ComprehensiVe Asym-
metric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999; Vol. III, pp 1105-1139. (b) Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171. (c) Berner, O. M.; Tedeschi, L.;
Enders, D. Eur. J. Org. Chem. 2002, 1877. (d) Christoffers, J.; Baro, A.
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Chem. ReV. 2005, 105, 933.
(3) For selected examples for organocatalytically asymmetric addition,
see: (a) Brandau, S.; Landa, A.; Franze´n, J.; Marigo, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 4305. (b) Chen, Y. K.; Yoshida, M.;
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Chem. Soc. 2006, 128, 5475.
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10.1021/jo070070p CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/03/2007
J. Org. Chem. 2007, 72, 4073-4076
4073

Cao et al.
TABLE 1. Effects of Reaction Conditions on the Asymmetric Michael Additiona
additive
(10 mol %)
time
(days)
convb
(%)
eec
(%)
entry
solvent
syn/antib
1
2
3
4
5
6
7
8
9
benzene
i-BuOH
t-BuOH
ethyl acetate
THF
CH2Cl2
neat
neat
neat
neat
neat
neat
n-butyric acid
n-butyric acid
n-butyric acid
n-butyric acid
n-butyric acid
n-butyric acid
n-butyric acid
n-butyric acid
i-butyric acid
heptanoic acid
D-campher-10-sulfonic acid
4-methylbenzenesulfonic acid
2
2
2
2
2
2
4
2
2
2
2
2
51
50
33
33
26
25
100
72
76
68
15
10
87/13
90/10
90/10
88/12
82/18
88/12
90/10
90/10
90/10
91/9
86
87
88
87
88
86
90
90
89
87
-
10
11
12
-
-
-
a Unless otherwise noted, all reactions were carried out using 2a (474 mg, 5 mmol) and 3a (0.25 mmol) in the presence of 20 mol % of catalyst in neat
1
conditions, with n-butyric acid as an additive. b Determined by H NMR. c Determined by chiral HPLC analysis.
alkylidene malonates as Michael acceptors, however, organo-
catalyst-promoted asymmetric Michael addition of ketones is
less successful. So far, only pyrrolidine-based diamine catalysts
were reported by Barbas and co-workers,8 and they described
that both ketones and aldehyde could react with alkylidene
malonates9 to afford the Michael adducts with moderate to good
enantioselectivities (up to 73% ee). Very recently, we designed
and synthesized two pyrrolidine-urea (thiourea)-based bifunc-
tional organocatalysts 1a and 1b.7k These catalysts were
successfully applied to the asymmetric Michael reaction of
cyclohexanone with both aryl- and alkylnitroolefins to give the
adducts in high yields with high diastereoselectivities and high
enantioselectivities under operationally simple conditions. Fur-
ther studies showed that the urea10 could also catalyze the
Michael addition of cyclohexanone with dimethyl 2-(4-nitroben-
zylidene) malonate to afford the desired product in good yield
with high enantiomeric excess as shown in eq 1. In this paper,
we wish to report this reaction in detail.
Results and Discussion
Initially, it was found that a mixture of cyclohexanone and
dimethyl 2-(4-nitrobenzylidene) malonate was stirred for 4 days
to afford the Michael adduct in 72% yield with 90% ee in the
presence of 10 mol % of n-butyric acid under solvent-free
conditions. This result encouraged us to optimize the reaction
conditions to further improve the diastereoselectivity and
enantioselectivity. As shown in Table 1, although benzene,
i-butanol, tert-butanol, ethyl acetate, THF, and CH2Cl2 could
be employed as the solvents of the reaction to give good
diastereoselectivity and high enantioselectivity (entries 1-6,
Table 1), the optimal one is to perform the reaction in neat
conditions (entries 7-12, Table 1). In addition to n-butyric acid,
i-butyric acid, heptanoic acid, D-campher-10-sulfonic acid, and
4-methylbenzenesulfonic acid were tested as additives. Under
the screened conditions, n-butyric acid gave the best results
(entry 7, Table 1).
We also screened several readily accessible L-proline deriva-
tives (1a-1j, Figure 1) as the catalysts using dimethyl 2-(4-
nitrobenzylidene) malonate as a model substrate in solvent-free
conditions at room temperature. As shown in Table 1, both
pyrrolidine-urea 1a and pyrrolidine-thiourea 1b could promote
the Michael reaction in moderate to good yield with high ee
values (entries 1 and 2, Table 2). Although compounds 1c-1e
could catalyze the reaction to furnish the desired product, the
reactions were sluggish (entries 3-5, Table 2). When 1f-1h
were employed (entries 6-8, Table 2), no Michael adduct was
(9) For alkylidene malonates as Michael acceptors in asymmetric
catalysis, see: (a) Zhuang, W.; Hansen, T.; Jørgensen, K. A. Chem.
Commun. 2001, 347. (b) Yamazaki, S.; Iwata, Y. J. Org. Chem. 2006, 71,
739. (c) Zhou, J.; Tang, Y. Chem. Commun. 2004, 432. (d) Zhou, J.; Tang,
Y. J. Am. Chem. Soc. 2002, 124, 9030. (e) Zhou, J.; Ye, M.-C.; Huang,
Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309. (f) Zhou, J.; Ye, M.-C.;
Tang, Y. J. Comb. Chem. 2004, 6, 301. (g) Ye, M.-C.; Li, B.; Zhou, J.;
Sun, X.-L.; Tang, Y. J. Org. Chem. 2005, 70, 6108. (h) Rasappan, R.; Hager,
M.; Gissibl, A.; Reiser, O. Org. Lett. 2006, 8, 6099.
(10) For chiral urea- and thiourea-catalyzed reactions, please see: (a)
Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (b)
Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int.
Ed. 2005, 44, 6576. (c) McCooey, S. H.; Connon, S. J. Angew. Chem., Int.
Ed. 2005, 44, 6367. (d) Wang, J.; Li, H.; Yu, X.-H.; Zu, L.-S.; Wang, W.
Org. Lett. 2005, 7, 4293. (e) Okinoi, T.; Hoashi, Y.; Furukawa, T.; Xu,
X.-N.; Takemoto. Y. J. Am. Chem. Soc. 2005, 127, 119. (f) Berkessel, A.;
Cleemann, F.; Mukherjee, S.; Mu¨ller, T. N.; Lex, J. Angew. Chem., Int.
Ed. 2005, 44, 807. (g) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 466. (h) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004,
126, 10558. (i) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
4102. (j) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Chem.
Pharm. Bull. 2004, 52, 477. (k) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.;
Nagasawa, K. Tetrahedron Lett. 2004, 45, 5589. (l) Wenzel, A. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 12964. (m) Vachal, P.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 10012. (n) Su, J. T.; Vachal, P.; Jacobsen, E.
N. AdV. Synth. Catal. 2001, 343, 197. (o) Sigman, M. S.; Vachal, P.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279. (p) Vachal, P.;
Jacobsen, E. N. Org. Lett. 2000, 2, 867. (q) Sigman, M. S.; Jacobsen, E. N.
J. Am. Chem. Soc. 1998, 120, 4901.
4074 J. Org. Chem., Vol. 72, No. 11, 2007

Michael Addition of Ketones to Alkylidene Malonates
TABLE 3. Michael Addition Reactions of Ketones to Alkylidene
Malonatesa
yieldb
(%)
eec
(%)
entry
2
R3
R4
4
syn/antib
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2d
p-NO2-C6H4
C6H5
Me
Et
Et
Et
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
98
36
71
48
95
20
27
60
74
36
trace
93/7
90/10
93/7
95/5
91/9
95/5
nd
89/11
-
-
-
90
88
90
88
90
87
nd
94
54
62
-
p-Br-C6H4
o-Cl-C6H4
m-NO2-C6H4
R-C10H7
Et
i-Bu
Me
Me
Me
Me
Me
FIGURE 1. Structures of chiral catalysts.
p-NO2-C6H4
p-NO2-C6H4
p-NO2-C6H4
p-NO2-C6H4
10d,e
11
4i
4j
TABLE 2. The Effects of Proline-Derived Catalysts on the
Asymmetric Michael Addition of Cyclohexanone 2a to Alkylidene
Malonate 3aa
a Unless otherwise noted, all reactions were carried out in neat conditions
using 2 (0.5 mL, 5 mmol, 20 equiv) and 3 (0.25 mmol) in the presence of
20 mol % of 1j and 10 mol % of n-butyric acid. b Determined by 1H NMR.
c Determined by chiral HPLC analysis. d 1a as a catalyst. e At 0 °C.
convb
(%)
eec
(%)
entry
catalyst
syn/antib
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
72
43
17
17
90/10
80/20
-
90
88
-
FIGURE 2. A proposed transition state.
-
-
13
-
-
diastereoselectivities and enantioselectivities (entries 1-6, Table
3) but affected strongly the yields. Generally, malonates with
electron-withdrawing groups were more reactive than phen-
ylidene malonate and gave higher yields (entries 1, 3, and 5 vs
entry 2). Dimethyl 2-(3-methylbutylidene) malonate worked well
to give the corresponding product in 27% yield, but the ee value
was not determined since the racemic product could not be
separated on a chiral column. The reaction of 2b proceeded
well to give good diastereoselectivity and enantioselectivity
(entry 8, Table 3). Acetone also was a suitable Michael donor
to produce the desired adducts in moderate yields with moderate
ee values (entries 9 and 10, Table 3). For pentan-3-one, its
reaction was very sluggish (entry 11, Table 3).
NR
NR
NR
85
99
91
-
-
-
-
-
-
85/15
93/7
93/7
33
90
90
10
1j
1j
11d
a Unless otherwise noted, all reactions were carried out for 2 days in the
presence of 20 mol % of catalyst in neat conditions and 10 mol % of
n-butyric acid using 2a (474 mg, 5 mmol) and 3a (0.25 mmol). b Determined
by 1H NMR. c Determined by chiral HPLC analysis. d Without n-butyric
acid.
observed. L-Proline 1i worked well to give good yield but with
only 33% ee. To our delight, when pyrrolidine trifluoromethane-
sulfonamide 1j was used, the product was isolated in nearly
quantitative yield with high diastereoselectivity (93/7) and high
enantioselectivity (90%) in the presence of 10 mol % of
n-butyric acid (entry 10, Table 2). Without the acid, catalyst 1j
also gave the same diastereoselectivity and enantioselectivity
with a slight reduction of the reaction rate (entry 11, Table 2).
The relative and absolute configurations of the Michael
adducts are shown in Table 2. The relative configurations were
1
assigned by comparison of H and 13C NMR of the products
with the known compounds. The absolute configurations were
determined by comparing the optical rotations with those in
literature.
Under the optimized conditions, a variety of ketones and
alkylidene malonates with different structure were tested to
investigate the generality of the present reaction, and the results
are summarized in Table 3. All reactions were performed under
solvent-free conditions at room temperature in the presence of
20 mol % of 1a or 1j3c with 10 mol % of butyric acid as an
additive. Various alkylidene malonates reacted smoothly with
cyclohexanone in moderate to good yields with high enantio-
selectivities. Substituents on aryl groups influenced slightly the
In the reaction of cyclohexanone with chalcones catalyzed
by 1j, Wang et al. developed a transition state model to explain
the stereochemistry. In the model, they proposed that the
hydrogen bonding interactions of both NH in 1j and i-PrOH
with the chalcone carbonyl group brought out higher stereo-
selectivities.5e In the present reaction, a similar transition state
model, as shown in Figure 2, could rationalize its high enantio-
and diastereoselectivity. In this model, the hydrogen bonding
of both NH in 1j and n-butyric acid with the carbonyl group of
J. Org. Chem, Vol. 72, No. 11, 2007 4075

Cao et al.
yield 98%, 90% ee, determined by HPLC analysis (Chiralcel AD-
H, i-PrOH/hexane ) 10/90, 0.7 mL/min, 238 nm; tr (minor) ) 35.21
min, tr (major) ) 42.21 min); [R]D20 ) -46.7 (c ) 1.045, CHCl3);
alkylidene malonates activated the substrate, explaining well
that a catalytic amount of n-butyric acid can speed up the
reaction.
In conclusion, we have developed a directly organocatalytic,
asymmetric Michael addition reaction of ketones with alkylidene
malonates. This reaction can be carried out under mild condi-
tions to afford potentially useful 1,3-diester compounds in
moderate to good yields with good to high enantio- and
diastereoselectivities. Further investigations of the mechanism
and synthetic applications of the current reaction are in progress.
1
syn/anti ) 93/7; H NMR (300 MHz, CDCl3) δ 8.14 (d, J ) 8.4
Hz, 2H), 7.48 (d, J ) 8.4 Hz, 2H), 4.19-4.06 (m, 2H), 3.70 (s,
3H), 3.53 (s, 3H), 3.03-2.95 (m, 1H), 2.48-2.40 (m, 2H), 2.04
(m, 1H), 1.80-1.77 (m, 2H), 1.64-1.58 (m, 2H), 1.37-1.06 (m,
1H).
Acknowledgment. We are grateful for the financial sup-
ported from the National Natural Science Foundation of China,
the Major State Basic Research Development Program (Grant
No. 2006CB806105), The Chinese Academy of Sciences, and
the Science and Technology Commission of Shanghai Munici-
pality.
Experimental Section
Representative Procedure for the Michael Addition of Cy-
clohexanone to Dimethyl 2-(4-nitrobenzylidene) Malonate. 1j
(11.6 mg, 0.05 mmol) in cyclohexanone (474 mg, 5 mmol) was
stirred for 10 min at room temperature, and then 3a (66.25 mg,
0.25 mmol) was added. The reaction was allowed to be stirred at
room temperature for 2 days. After the reaction was complete
(monitored by TLC), the resulting mixture was concentrated under
reduced pressure and the residue was then purified by flash
chromatography (petroleum/EtOAc ) 1/5) to give the product 4a:
Supporting Information Available: Characterization data for
all new compounds noted in Table 3, and experimental procedures
(PDF) are available. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO070070P
4076 J. Org. Chem., Vol. 72, No. 11, 2007