Enantioselective organocatalytic Michael addition of malonates to α,/β-unsaturated ketones

Article abstract of DOI:10.1021/ol802892h

(Chemical Equation Presented) A novel type of primary amine thiourea organocatalysts derived from 1,2-diaminocyclohexane and 9-amino (9-deoxy) cinchona alkaloid was developed into asymmetric Michael addition of malonates to enones. A series of cyclic and

Full text of DOI:10.1021/ol802892h

ORGANIC
LETTERS
2009
Vol. 11, No. 3
753-756
Enantioselective Organocatalytic Michael
Addition of Malonates to
r,ꢀ-Unsaturated Ketones
Pengfei Li,†,‡ Shigang Wen,‡ Feng Yu,‡ Qiaoxia Liu,‡ Wenjun Li,‡
Yongcan Wang,† Xinmiao Liang,*,†,‡ and Jinxing Ye*,‡
Dalian Institute of Chemical Physics, Chinese Academy of Science, 457 Zhongshan
Road, Dalian 116023, P. R. China, and Engineering Research Center of
Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East
China UniVersity of Science and Technology, 130 Meilong Road,
Shanghai 200237, P. R. China
liangxm@dicp.ac.cn; yejx@ecust.edu.cn
Received December 15, 2008
ABSTRACT
A novel type of primary amine thiourea organocatalysts derived from 1,2-diaminocyclohexane and 9-amino (9-deoxy) cinchona alkaloid was
developed into asymmetric Michael addition of malonates to enones. A series of cyclic and acyclic enones could react very well with different
malonates in the presence of 4 with 0.5-10 mol % catalyst loading affording chiral Michael adducts with excellent yields and ee values.
As one of the most powerful and typical carbon-carbon
bond-forming reactions, the asymmetric Michael reaction
enables access to a variety of optically active adducts
affording synthetically useful building blocks in organic
synthesis.1 Due to two electron-withdrawing esters leading
to enolate formation under mild conditions, malonates most
notably have been used as easily accessible nucleophilic
donors in the Michael addition.
and organocatalysts6 have been developed for the Michael
addition of malonates to enones. However, substrate depen-
dence still remains an important issue. Therefore, develop-
(2) (a) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem., Int.
Ed. 1993, 32, 1176. (b) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org.
Chem. 1996, 61, 3520.
(3) For some selected references in this area, see: (a) Sasai, H.; Arai,
T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117,
6194. (b) End, N.; Macko, L.; Zehnder, M.; Pfaltz, A. Chem.-Eur. J. 1998,
4, 818. (c) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506. (d) Christoffers, J.; Baro,
A. Angew. Chem., Int. Ed. 2003, 42, 1688. (e) Agostinho, M.; Kobayashi,
S. J. Am. Chem. Soc. 2008, 130, 2430.
Many types of catalysts such as proline salts,2 chiral metal
complexes,3 chiral ionic liquids,4 phase-transfer catalysts,5
† Chinese Academy of Science.
(4) (a) Toma, S.; Gotov, B.; Kmentova´, I.; Solc´a´niova´, E. Green Chem.
2000, 2, 149. (b) Wang, Z.; Wang, Q.; Zhang, Y.; Bao, W. Tetrahedron
Lett. 2005, 46, 4657. (c) Mec´iarova´, M.; Toma, Chem.-Eur. J. 2007, 13,
1268.
‡ East China University of Science and Technology.
(1) For several selected published books on asymmetric organocatalysis,
see: (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe
Asymmetric Catalysis; Springer: Berlin, 1999. (b) Berkessel, A.; Gro¨ger,
H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, Germany, 2004.
(c) Dalko, P. I. EnantioselectiVe Organo-catalysis; Wiley-VCH: Weinheim,
Germany, 2007.
(5) (a) Kim, D. Y.; Huh, S. C.; Kim, S. M. Tetrahedron Lett. 2001, 42,
6299. (b) Dere, R. T.; Pal, R. R.; Patil, P. S.; Salunkhe, M. M. Tetrahedron
Lett. 2003, 44, 5351. (c) Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka, K.
Org. Lett. 2005, 7, 3195.
10.1021/ol802892h CCC: $40.75
Published on Web 12/30/2008
2009 American Chemical Society

ment of an efficient catalyst with a broad range of enone
substrates is a goal of considerable importance.
Table 1. Catalyst and Reaction Condition Screen for the
Reaction between 8a and 9aa
The potential of modified cinchona alkaloids7 and (thio)-
urea derivatives8 as efficient and enantioselective organo-
catalysts for asymmetric synthesis has been demonstrated.
As a result, a new type of organocatalyst derived from
modified cinchona alkaloids and (thio)urea was under
consideration, which is expected to exhibit synergistic
cooperation and effect organic reactions with excellent
efficiency and stereoselectivities. Recently, we have reported
a new type of primary amine thiourea consisting of 1,2-
diaminocyclohexane and 9-amino cinchona alkaloid deriva-
tives, which catalyzed Michael addition of nitroalkanes to
R,ꢀ-unsaturated ketones with high enantioselectivity and
efficiency.9 We wondered whether this approach could be
extended to Michael addition of malonate to enones. Fully
aware of the potential benefits but also of the many
difficulties we would likely encounter, we decided to pursue
this challenge.
At the outset of the investigation, we focused our attention
on the primary amine thiourea catalytic Michael addition of
diethyl malonate (9a) to cyclohex-2-enone (8a), and the
results are shown in Table 1. After the screening of catalysts,
it was confirmed by results that the reaction could be
entry
catalyst
solvent
toluene
convn (%)b
ee (%)b
1
2
3
4
5
6
1
2
3
4
5
6
7
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
59
73
78
88
9
82
82
84
92
10
-83
-79
84
50
48
76
94
94
80
88
91
88
92
95
97
94
96
96
93
toluene
toluene
toluene
toluene
toluene
toluene
neat
DMSO
MeOH
hexane
CH2Cl2
CHCl3
DMF
(6) (a) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 661. (b) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan,
W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (c) Knudsen, K. R.;
Mitchell, C. E. T.; Ley, S. V. Chem. Commun. 2006, 66. (d) Wascholowski,
V.; Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem.-Eur. J. 2008,
14, 6155. (e) Jiang, Z.; Ye, W.; Yang, Y.; Tan, C.-H. AdV. Synth. Catal.
2008, 350, 2345.
13
43
89
25
34
98
72
72
74
82
88
88
80
91
96
>99
95
>99
60
7
8c
(7) For several reviews on modified cinchona alkaloids, see: (a) Eames,
J. Angew. Chem., Int. Ed. 2000, 39, 885. (b) Chen, Y.; Mcdaid, P.; Deng,
L. Chem. ReV. 2003, 103, 2965. (c) Tian, S.-K.; Chen, Y.; Hang, J.; Tang,
L.; Mcdaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. (d) Marcelli, T.;
van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45,
7496For selected examples catalyzed by modified cinchona alkaloids, see:
(e) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542. (f)
Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195. (g) McDaid, P.;
Chen, Y.; Deng, L. Angew. Chem., Int. Ed. 2002, 41, 338. (h) Tiseni, P. S.;
Peters, R. Angew. Chem., Int. Ed. 2007, 46, 5325. (i) Poisson, T.; Dalla,
V.; Marsais, F.; Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int.
Ed. 2007, 46, 7090. (j) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda,
N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47,
4157. (k) Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura, S.; Toru, T.;
Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 8051. (l) Elsner, P.; Bernardi,
L.; Salla, G. D.; Overgaard, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2008,
130, 4897. (m) Bandini, M.; Sinisi, R.; Umani-Ronchi, A. Chem. Commun.
2008, 4360.
9
10
11
12
13
14
15
16
17
18
19
20d
21e
22f
23g
24h
Et2O
EtOAc
MeCN
1,4-dioxane
THF
THF
THF
THF
THF
THF
(8) For some reviews on (thio)urea derivatives, see: (a) Connon, S. J.
Chem.-Eur. J. 2006, 12, 5418. (b) Connon, S. J. Chem. Commun. 2008,
2499. (c) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81, 785.
(d) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
For selected examples catalysed by (thio)urea derivatives, see: (e) Curran,
D. P.; Kuo, H. L. J. Org. Chem. 1994, 59, 3259. (f) Sigman, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 1998, 120, 4901. (g) Wenzel, A. G.; Lalonde,
M. P.; Jacobsen, E. N. Synlett. 2003, 1919. (h) Okino, T.; Hoashi, Y.;
Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (i) Sohtome, Y.;
Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004, 45,
5589. (j) Okino, T.; Hoashi, Y.; Furukawa, T.; Takemoto, Y. J. Am. Chem.
Soc. 2005, 127, 119. (k) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 4032. (l) McCooey, S. H.; Connon, S. J. Angew. Chem.,
Int. Ed. 2005, 44, 6367. (m) Vakulya, B.; Varga, S.; Csa´mpai, A.; Soo´s, T.
Org. Lett. 2005, 7, 1967. (n) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem.
Commun. 2005, 4481. (o) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org.
Lett. 2005, 7, 4293. (p) Wang, Y.; Song, J.; Hong, R.; Li, H.; Deng, L.
J. Am. Chem. Soc. 2006, 128, 8156. (q) Song, J.; Wang, Y.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 6048. (r) Gao, P.; Wang, C.; Wu, Y.; Zhou, Z.;
Tang, C. Eur. J. Org. Chem. 2008, 4563. (s) Peng, F.; Shao, Z.; Fan, B.;
Song, H.; Li, G.; Zhang, H. J. Org. Chem. 2008, 73, 5202.
a Reaction conditions: A mixture of 5a (1.0 mmol), 6a (3.0 mmol), and
the catalyst (10 mol %) in the solvent (2.0 mL) was stirred at ambient
temperature for the time given. b Conversion and enantiomeric excess were
determined by chiral GC. c For 12 h. d At 40 °C for 12 h. e At 70 °C for
8 h. f With 2 mol % catalyst loading at 40 °C for 36 h. g With 1 mol %
catalyst loading at 40 °C for 72 h. h 8a (4.0 mmol) reacted with 9a (12.0
mmol) at 40 °C for 48 h with 0.5 mol % catalyst loading.
catalyzed by the primary amine thiourea (Table 1, entries
1-4). Especially, up to 88% of conversion and 92% ee were
obtained in toluene after 48 h with 4 prepared from (1R,2R)-
1,2-diaminocyclohexane and 9-amino (9-deoxy) epiquinine
(Table 1, entry 4). However, poor results were obtained when
catalyst 5 was employed, in which the primary amine was
substituted with two methyl groups (Table 1, entry 5).
(9) Li, P.; Wang, Y.; Liang, X.; Ye, J. Chem. Commun. 2008, 3302.
754
Org. Lett., Vol. 11, No. 3, 2009

Table 2. 4-Catalyzed Michael Addition Reactions between 8 and 9a
entry
n
R
time (h)
adduct
yield (%)b
ee (%)c
1
2
3
2 (8a)
2 (8a)
2 (8a)
2 (8a)
2 (8a)
2 (8a)
3 (8b)
1 (8c)
2e (8d)
Et (9a)
Me (9b)
i-Pr (9c)
Et (9a)
Me (9b)
i-Pr (9c)
Et (9a)
Et (9a)
Et (9a)
60
60
72
12
18
18
72
72
72
10aa
10ab
10ac
10aa
10ab
10ac
10ba
10ca
10da
88
83
80
95
91
95
83
64
77
96
96
95
96
93
96
93
63
91
4d
5d
6d
7d
8d
9d
a Reaction conditions: A mixture of 8 (1.0 mmol), 9 (3.0 mmol), and the catalyst 4 (10 mol %) in THF (2.0 mL) was stirred at ambient temperature for
the time given. b Isolated yield. c Enantiomeric excess was determined by chiral HPLC or GC. d Reaction temperature was 40 °C. e The enone used was
4,4-dimethylcyclohex-2-enone.
Recently, 9-amino (9-deoxy) epicinchona alkaloids have been
successfully used as chiral catalysts in the asymmetric
reactions, which exhibited high efficiency and enantioselec-
tivity.10 However, the conjugate addition of malonate to
enone catalyzed by 9-amino (9-deoxy) epiquinine afforded
poor conversion (Table 1, entry 6). Therefore, it could be
concluded that both the primary amine and thiourea played
an important role in the process. If (1R,2R)-1,2-diaminocy-
clohexane was replaced with (1S,2S)-1,2-diaminocyclohex-
ane, instead of catalyst 4 with catalyst 7, the configuration
of adduct was reversed, which indicated that the stereochem-
istry was controlled by the 1,2-diaminocyclohexane motif
(Table 1, entry 7). This could explain the fact that low
enantioselectivity was obtained when the primary amine was
blocked.
Having identified the best catalyst (catalyst 4) for the
conjugate addition, optimizing reaction conditions were under
investigation. It was found that the reaction media had an
impact on the process (Table 1, entries 8-19). Without
solvent, the adduct was formed quickly with an 84% ee value
(Table 1, entry 8). Except in DMSO (Table 1, entry 9, 25%
conversion and 50% ee) and MeOH (Table 1, entry 10, 34%
conversion and 48% ee), the reactions were carried out
smoothly and afforded the 1,4-adduct with good enantiose-
lectivities and conversions in the rest of the media probed
in Table 1, and the best results were obtained with THF
(Table 1, entry 19, 95% ee and 91% conversion). For most
catalytic systems, higher conversion could be achieved at
elevated reaction temperature within a shorter time but
generally accompanied by decreased enantioselectivity. It
should be noted that up to 97% ee and 96% of conversion
were obtained at 40 °C (Table 1, entry 20). When the reaction
temperature was elevated to 70 °C, 8a was almost completely
converted to adduct just after 8 h (Table 1, entry 21). A lower
catalyst loading also afforded excellent conversions and
enantioselectivities. When a catalyst loading of 2.0 mol %
was employed, up to 96% ee and 95% of conversion were
obtained after 36 h (Table 1, entry 22). Even with a catalyst
loading of 1.0 mol %, more than 99% of conversion and
96% ee could still be obtained after three days (Table 1,
entry 23). When catalyst loading was decreased to 0.5 mol
%, the 1,4-adduct was formed in 60% of conversion with
93% ee in 48 h (Table 1, entry 24). These encouraging results
indicated that this methodology might be a very efficient tool
for construction of chiral building blocks from asymmetric
Michael addition in total syntheses of bioactive natural
products.11
Under the optimized conditions, the primary amino
thiourea 4-catalyzed Michael additions with a variety of
cyclic enones 8a-d and malonates 9a-c were tested, and
the results are presented in Table 2. It is known that the ester
group has a large effect on the asymmetric induction of the
reaction. To our great delight, all malonates reacted smoothly
with 8a to generate adducts with high yields and excellent
enantioselectivities (Table 2, entries 1-3). Moreover, excel-
lent yields were obtained accompanied by similar ee values
within shorter time when the reactions were carried out at
40 °C (Table 2, entries 4-6). The reaction of 8b was
relatively slow, but 83% yield and 95% ee were still obtained
after a longer time (Table 2, entry 7). The only exception
(10) For selected recent publications on 9-amino (9-deoxy) epicinchona
alkloid, see: (a) Xie, J.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.;
Chen, Y. Org. Lett. 2007, 9, 413. (b) Xie, J.; Chen, W.; Li, R.; Zeng, M.;
Du, W.; Yue, L.; Chen, Y.; Wu, Y.; Zhu, J.; Deng, J. Angew. Chem., Int.
Ed. 2007, 46, 389. (c) Zheng, B.; Liu, Q.; Guo, C.; Wang, X.; He, L. Org.
Biomol. Chem. 2007, 5, 2913. (d) Chen, W.; Du, W.; Duan, Y.; Wu, Y.;
Yang, S.; Chen, Y. Angew. Chem., Int. Ed. 2007, 46, 7667. (e) McCooey,
S. H.; Connon, S. J. Org. Lett. 2007, 9, 599. (f) Bartoli, G.; Bosco, M.;
Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9,
1403. (g) Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng, L.
J. Am. Chem. Soc. 2008, 130, 2422. (h) Lu, X.; Liu, Y.; Sun, B.; Cindric,
B.; Deng, L. J. Am. Chem. Soc. 2008, 130, 8134. (i) Wang, X.; Reisinger,
C. M.; List, B. J. Am. Chem. Soc. 2008, 130, 6070.
(11) Ohshima, T. Chem. Pharm. Bull. 2004, 52, 1031.
Org. Lett., Vol. 11, No. 3, 2009
755

enantioselectivity. All of the substituted aromatic enones
afforded the Michael adducts with more than 90% ee values
in good to excellent yields, and the effect of ester group on
yield and enantioselectivity was also insignificant. The 1,4-
adduct was formed from dimethyl malonate with 93% of
asymmetric induction and 93% yield (Table 3, entry 13).
The heteroaromatic enone was also found to react with
malonate successfully, which generated adduct with 83%
yield and 90% ee (Table 3, entry 14). The alkyl-substituted
enones were found to react also very well, and the Michael
adducts were formed in excellent yields and ee values (Table
3, entries 15 and 16). Besides the methyl ketone, ethyl
ketones were also investigated. The use of 1-phenylpent-1-
en-3-one afforded 80% yield and 83% ee value (Table 3,
entry 17). Even at refluxing temprature, the reaction was slow
when sterically more hindered 4-methyl-1-phenylpent-1-en-
3-one was used (40% yield after 48 h, not given in Table
3).
Table 3. 4-Catalyzed Michael Addition Reactions between 11
and 9a
entry
R1
R2
R
adduct yield (%)b ee (%)c
1
2
3
4
5
6
7
8
Ph (11a)
Ph (11a)
Ph (11a)
Me 9a 12aa
Me 9b 12ab
Me 9c 12ac
Me 9a 12ba
Me 9a 12ca
Me 9a 12da
92
92
90
95
94
94
97
90
92
86
91
71
93
83
91
90
80
96
94
96
93
94
94
94
93
93
94
94
97
93
90
96
97
83
4-ClPh (11b)
2-BrPh (11c)
4-BrPh (11d)
2-NO2Ph (11e) Me 9a 12ea
4-NO2Ph (11f) Me 9a 12fa
2-MePh (11g)
3-MePh (11h)
4-MePh (11i)
2-MeOPh (11j) Me 9a 12ja
2-NO2Ph (11e) Me 9b 12eb
2-thienyl (11k) Me 9a 12ka
9
Me 9a 12ga
Me 9a 12ha
Me 9a 12ia
10d
11d
12d
13
14d
15
16
17e
The absolute configuration of 4-catalytic Michael adducts
diethyl 2-(3-oxocyclohexyl)malonate was R, which was
determined by comparison of optical rotations according to
the literature.6d
n-Pr (11l)
n-Bu (11m)
Ph (11n)
Me 9a 12la
Me 9a 12ma
Et 9a 12na
In summary, we have developed a new organocatalytic
method for asymmetric Michael addition of malonate to R,ꢀ-
unsaturated ketone with high efficiency and excellent enan-
tioselectivity employing a type of primary amine thiourea
derived from the cinchona alkaloid and 1,2-diaminocyclo-
hexane. It is noteworthy that, in contrast to previous reports,
this reaction system exhibits excellent catalysis in asymmetric
Michael addition of malonates to acyclic enone and has a
broad substrate scope. Further investigations to clarify the
exact catalytic mechanism, as well as the capacity of this
methodology, are currently under investigation in our labora-
tory, and results from these studies will be presented in the
future.
a Reaction conditions: A mixture of 11 (1.0 mmol), 9 (3.0 mmol), and
the catalyst 4 (10 mol %) in THF (2.0 mL) was stirred at ambient
temperature for the time given. b Isolated yield. c Determined by chiral
HPLC. d Reaction time was 72 h. e Reaction temperature was 40 °C.
was 8c, which gave 64% yield and 63% ee (Table 2, entry
8). It is noteworthy that the sterically more hindered enone
8d was also successfully used in this Michael reaction, and
91% ee value and 77% yield were obtained (Table 2, entry
9).
On the basis of these satisfying results, the acyclic R,ꢀ-
unsaturated ketone substrates were surveyed, and the results
are displayed in Table 3.
Catalyzed by primary amino thiourea 4, the Michael
additions of malonates to the acyclic enones were quite
successful. The Michael adducts, 12aa and 12ab, were
formed in excellent yields and enantioselectivities (Table 3,
entries 1 and 2). Even though from sterically more hindered
9c, excellent yield and asymmetric induction were also
obtained (Table 3, entry 3). It should be noted that electron-
withdrawing (Table 3, entries 4-8) and electron-donating
substituents (Table 3, entries 9-12) can be introduced into
the aromatic ring, with a little effect on the yield or
Acknowledgment. This work was sponsored by the start-
up fund from East China University of Science and Technol-
ogy and Shanghai Pujiang Program (08PJ1403300).
Supporting Information Available: Experimental pro-
cedures and characterizations, copies of CSP-GC or CSP-
1
HPLC analysis, and H NMR and 13C NMR spectra of
adducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802892H
756
Org. Lett., Vol. 11, No. 3, 2009