Highly efficient asymmetric Michael addition reaction of malonates to α,β-unsaturated ketones promoted by a chiral thiourea/PPY dual-catalyst system

Article abstract of DOI:10.1055/s-0032-1317317

The enantioselective Michael addition reaction of malonates to α,β-unsaturated ketones is efficiently promoted by a combined dual-catalyst system composed of chiral thiourea and 4-pyrrolidinopyridine (PPY) in toluene. The expected Michael adducts with cyclic and acyclic enones are obtained in excellent yields and with excellent enantioselectivities. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317317

2554▌
LETTER
letter
Highly Efficient Asymmetric Michael Addition Reaction of Malonates to
α,β-Unsaturated Ketones Promoted by a Chiral Thiourea/PPY Dual-Catalyst
System
Michael Addition Reaction of Malonates to α,β-Unsaturated Ketones
Maya Moritaka, Naomu Miyamae, Keiji Nakano, Yoshiyasu Ichikawa, Hiyoshizo Kotsuki*
Laboratory of Natural Products Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Fax +81(88)8448359; E-mail: kotsuki@kochi-u.ac.jp
Received: 09.08.2012; Accepted after revision: 28.08.2012
room temperature as a model system.8 The results are
Abstract: The enantioselective Michael addition reaction of malo-
summarized in Table 1; catalysts A–F are shown in Figure
nates to α,β-unsaturated ketones is efficiently promoted by a com-
1.9
bined dual-catalyst system composed of chiral thiourea and
4-pyrrolidinopyridine (PPY) in toluene. The expected Michael ad-
ducts with cyclic and acyclic enones are obtained in excellent yields
and with excellent enantioselectivities.
Table 1 The Asymmetric Michael Addition Reaction of 2-Cyclo-
hexen-1-one (1a) with Diethyl Malonate (2a): Optimizationa
O
Key words: asymmetric Michael addition, malonates, α,β-unsatu-
O
rated ketones, chiral thiourea, 4-pyrrolidinopyridine (PPY)
catalyst
EtO2C
CO2Et
+
CO2Et
CO2Et
toluene, r.t.
1a
2a
3a
The Michael addition reaction is widely recognized as one
of the most important carbon–carbon bond-forming reac-
tions in organic synthesis.1 In the case of malonates, due
to the presence of two electron-withdrawing esters, the
corresponding conjugate bases are readily accessible un-
der relatively mild conditions and are frequently used as
nucleophilic donors in the Michael addition reaction. In
addition, the asymmetric Michael adducts of malonates to
α,β-unsaturated ketones can serve as convenient chiral
building blocks, particularly for the construction of bio-
logically interesting natural products.2 As a result, consid-
erable attention has been given to the development of
catalytic asymmetric transformations, and recent efforts
in this area have been directed toward the development of
asymmetric organocatalysis.3
Entry Catalyst (10 mol%)
Time (h)
Yield (%)b ee (%)c
1d
2d
3
A
24
24
10
16
24
24
24
24
24
24
24
51
60
54
13
16
96
98
–98
–
A + PPY
A + B
A + B + PPY
C
52
94
4d
5
99
80
6
C + PPY
D + PPY
E
95
7
94
8
trace
trace
0
9
E + PPY
F
–
In our laboratory, we have been working to develop a new
method for Michael addition reactions using 4-dimethyl-
aminopyridine (DMAP) and related organocatalysts.4 As
an extension of this work, we expected that the coopera-
tive use of chiral thiourea and aminopyridine catalysts
should be more effective for the asymmetric Michael ad-
dition reaction of malonates with α,β-unsaturated ketones.
Although there have been reports of related work using
cinchona alkaloid based bifunctional thiourea catalysts,5
we have been interested in the use of a much simpler
dual-catalyst system composed of chiral thioureas and
4-pyrrolidinopyridine (PPY) as a hydrogen-bonding
activator6 and a nucleophilic base.7 We describe here the
realization of this expectation.
10
11
–
F + PPY
trace
–
a Reaction conditions: 1a (1.0 mmol), 2a (1.5 equiv), toluene
(1.0 mL), r.t.
b Isolated yield.
c Determined by chiral HPLC using Chiralcel OD-H (hexane–
i-PrOH = 99:1).
d Conditions: 2 equiv of 1a were used.
As expected, cyclohexanediamine catalyst A itself gave
poor results even in the presence of PPY (Table 1, entries
1 and 2). Interestingly, the addition of thiourea B to these
systems dramatically improved the chemical yields, albeit
giving low enantioselectivities (Table 1, entries 3 and 4).
Subsequently, we found that the trans-1,2-cyclohexane-
diamine-thiourea conjugate catalyst C10 exhibited high
catalytic activity, and product 3a was formed with the best
yield and enantioselectivity when the reaction was con-
First, we examined the reaction of 2-cyclohexen-1-one
(1a) with diethyl malonate (2a) in the presence of several
thiourea organocatalysts with or without PPY in toluene at
SYNLETT 2012, 23, 2554–2558
Advanced online publication: 21.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317317; Art ID: ST-2012-U0675-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Michael Addition Reaction of Malonates to α,β-Unsaturated Ketones
2555
CF3
CF3
CF3
NH2
S
N
S
O
F3C
N
H
N
H
NH2
F3C
N
H
N
CF3
NH2
C
H
A
O
N
B
O
O
1a
PPY
CF3
CF3
EtO
OEt
CO2Et
CO2Et
H
2a
S
S
H2O
3a
N
N
F3C
N
N
H
F3C
N
N
H
H
H
NH2
NH2
D
C
H
Re-
face
H
N
CF3
HN
N
OEt
S
N
N
H
O
S
F3C
N
N
H
H
H
O
NH
Me2N
OEt
E
S
N
H
F3C
CO2Et
CO2Et
F
H
F3C
F3C
S
S
F3C
N
CF3
CF3
CF3
H
NH
HN
NH
G
HN
CF3
F
Scheme 1 A proposed catalytic cycle for the Michael addition reac-
tion of 1a with 2a in the presence of catalyst C and PPY
Figure 1
With the optimized reaction conditions in hand, we then
investigated the general scope of this chemistry by using
various α,β-unsaturated ketones as substrates. In all of
these examples, the reactions without using PPY as a co-
catalyst are shown for comparison (Table 2).9,16,17
ducted in the presence of PPY as a co-catalyst (Table 1,
entries 5 and 6). The replacement of the chiral core
(1R,2R)-cyclohexanediamine with its (1S,2S)-antipode
(catalyst D) caused a complete reversal of the configura-
tion of the product,11 which indicates that the chiral motif
of the 1,2-cyclohexanediamine skeleton plays a crucial
role in determining the stereochemical outcome (Table 1,
entry 7). In addition, we confirmed that the presence of a
free primary amine moiety in catalyst C (or D) was essen-
tial, since the dimethylamine homologue E12 and bisthio-
urea F13 showed no catalytic activity (Table 1, entries 8–
11).
First, we found that di-tert-butyl malonate (2b) reacted
quite slowly with 1a compared to the diethyl congener 2a
in the presence of catalyst C and PPY, and gave 3b in 86%
yield with 98% ee after 120 hours, while the same reaction
using catalyst C alone resulted in only 19% yield of 3b
even after one week (Table 2, entries 1 and 2). A very sim-
ilar behavior was observed for other Michael donors such
as alkyl- or aryl-substituted malonates 2c–e, and the de-
sired adducts bearing a quaternary carbon center at the do-
nor site were obtained in high yields with excellent
enantioselectivities (Table 2, entries 3–8). For the slug-
gish reactions, all attempts to suppress the formation of
the Rauhut–Currier-type adduct 4 (Figure 2)18 failed (Ta-
Based on the absolute configuration of the Michael adduct
3a11 and the important role of the free primary amine
functionality of catalyst C, we propose the following
mechanism to account for the present asymmetric Mi-
chael addition reaction (Scheme 1).
Due to the high efficiency observed in this dual-catalyst ble 2, entries 1, 3, 7, and 8).19
system composed of chiral thiourea C and PPY, we be-
lieve that 2a would be activated by a thiourea moiety
through double hydrogen bonding, thus enhancing the
acidity of 2a (pKa = 14.2 in DMSO)14 and facilitating pro-
ton abstraction by PPY (pKa = ca. 9.6 for the conjugate
acid in H2O, from the resemblance to DMAP).15 Catalyst
C would then interact with 1a to form the activated ket-
O
O
4
iminium cation intermediate F, which could enable the Figure 2
nucleophilic attack of the malonate ion from the Re face
with respect to the double bond as in an intramolecular
The reaction of 4,4-disubstituted cyclohexenone 1b with
2a proceeded without any difficulty under the catalysis of
catalyst C and PPY to afford sterically congested 3f (Ta-
ble 2, entries 9 and 10). Cyclopentenone (1c) and cyclo-
heptenone (1d) smoothly underwent the desired Michael
approach. Next, the generated enamine intermediate G
undergoes hydrolysis to release the product 3a and cata-
lyst C.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2554–2558

2556
M. Moritaka et al.
LETTER
addition reaction to give the corresponding adducts 3g and adducts 3i and 3j were obtained in high yields and with
3h in high efficiency (Table 2, entries 11–14). Finally, we high enantioselectivities, whereas the sole use of catalyst
found that the reaction was also successful for acyclic C gave somewhat better results (Table 2, entries 15–18).
enone substrates such as 1e and 1f, and the corresponding
Table 2 The Asymmetric Michael Addition Reaction of α,β-Unsaturated Enones 1 with Malonates 2a
O
O
C (10 mol%)
PPY (10 mol%)
R3O2C
R1
CO2R3
O
O
CO2R3
R4
or
or
+
R4
R1
R2
CO2R3
CO2R3
CO2R3
toluene, r.t.
R2
n
n
(1.5 equiv)
Entry
Acceptor 1
Donor 2
Product 3b
Catalyst
Time (h)
Yield (%)c ee (%)d
O
CO2t-Bu
CO2t-Bu
2b
1
2
C
168
19e,f
86
93
98
CO2t-Bu
CO2t-Bu
1a
C + PPY 120
3b
3c
3d
3e
3f
O
CO2Et
CO2Et
3
4
C
168
52
16f,g
84
99
99
CO2Et
CO2Et
1a
1a
C + PPY
2c
O
CO2Et
CO2Et
5
6
C
69
52
47f
99
99
99
CO2Et
CO2Et
C + PPY
2d
O
CO2Et
CO2Et
Ph
Ph
7h
8h
C
168
53
15f,i
47j
99
98
CO2Et
1a
C + PPY
CO2Et
2e
O
O
9
10
C
93
48
64f
91
90
96
CO2Et
CO2Et
2a
2a
C + PPY
1b
O
O
11h
12h
C
96
51f
64f
74
76
CO2Et
CO2Et
C + PPY 120
1c
3g
Synlett 2012, 23, 2554–2558
© Georg Thieme Verlag Stuttgart · New York

LETTER
Michael Addition Reaction of Malonates to α,β-Unsaturated Ketones
2557
Table 2 The Asymmetric Michael Addition Reaction of α,β-Unsaturated Enones 1 with Malonates 2a (continued)
O
O
C (10 mol%)
PPY (10 mol%)
R3O2C
R1
CO2R3
O
O
CO2R3
R4
or
or
+
R4
R1
R2
CO2R3
CO2R3
CO2R3
toluene, r.t.
R2
n
n
(1.5 equiv)
Entry
Acceptor 1
Donor 2
Product 3b
Catalyst
Time (h)
Yield (%)c ee (%)d
O
O
13
14
C
84
72
68f
95
99
98
CO2Et
CO2Et
2a
C + PPY
1d
1e
3h
EtO2C
CO2Et
O
O
15
16
C
96
72
97
99
93
91
2a
2a
C + PPY
3i
EtO2C
CO2Et
O
O
17
18
C
138
94
90
93
88
C + PPY 120
O2N
O2N
1f
3j
a Reaction conditions: 1 (1.0 mmol), 2 (1.5 equiv), catalyst C (10 mol%), PPY (10 mol%), toluene (1.0 mL), r.t.
b The absolute configuration of the products 3c–e was surmised by analogy. See ref. 16 and 17.
c Isolated yield.
d Determined by chiral HPLC analysis: Chiralpak AD for 3b,e–g,i; Chiralpak AS-H for 3c,h; Chiralcel OD-H for 3d; Chiralpak AD-H for 3j.
e Byproduct 4 was isolated in 39% yield (20% ee).
f Additional unidentified byproducts were formed.
g Byproduct 4 was isolated in 27% yield (21% ee).
h Conditions: 3 equiv of 2 were used.
i Byproduct 4 was isolated in 16% yield (29% ee).
j Byproduct 4 was isolated in 36% yield (38% ee).
(2) For example, see: Jiricek, J.; Blechert, S. J. Am. Chem. Soc.
2004, 126, 3534.
(3) Vicario, J. L.; Badía, D.; Carrillo, L.; Reyes, E.
Organocatalytic Enantioselective Conjugate Addition
Reactions; RSC Publishing: Cambridge, 2010.
(4) (a) Kotsuki, H.; Sakai, H.; Shinohara, T. Synlett 2000, 116.
(b) Kotsuki, H.; Sakai, H.; Jun, J.-G.; Shiro, M. Heterocycles
2000, 52, 661. (c) Ishii, T.; Fujioka, S.; Sekiguchi, Y.;
Kotsuki, H. J. Am. Chem. Soc. 2004, 124, 9558. (d) Ko, K.;
Nakano, K.; Watanabe, S.; Ichikawa, Y.; Kotsuki, H.
Tetrahedron Lett. 2009, 50, 4025.
In summary, we have developed a new combined dual-
catalyst system composed of chiral thiourea catalyst C
and PPY in toluene for the asymmetric Michael addition
reaction of malonates with α,β-unsaturated ketones to ob-
tain the desired products in high chemical yields with high
enantioselectivities. This method is particularly useful for
constructing complex molecules bearing sterically con-
gested stereogenic centers. Further studies on the applica-
tion of this method to natural product synthesis are now in
progress in our laboratory.20
(5) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang, Y.; Liang, X.;
Ye, J. Org. Lett. 2009, 11, 753.
(6) (a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289.
(b) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299.
(c) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal.
2006, 348, 999. (d) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2006, 45, 1520. (e) Connon, S. J. Chem.–Eur.
J. 2006, 12, 5418. (f) Doyle, A. G.; Jacobsen, E. N. Chem.
Rev. 2007, 107, 5713. (g) Miyabe, H.; Takemoto, Y. Bull.
Chem. Soc. Jpn. 2008, 81, 785. (h) Connon, S. J. Chem.
Commun. 2008, 2499. (i) Connon, S. J. Synlett 2009, 354.
(j) Etzenbach-Effers, K.; Berkessel, A. Top. Curr. Chem.
2010, 291, 1.
Acknowledgment
This work was supported in part by the Yamada Science Foundation
and by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT) in Ja-
pan.
References and Notes
(1) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: New York, 1992.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2554–2558

2558
M. Moritaka et al.
LETTER
(16) (a) The absolute configuration of the products was
(7) (a) Höfle, G.; Steglich, W.; Vorbrüggen, H. Angew. Chem.,
Int. Ed. Engl. 1978, 17, 569. (b) Scriven, E. F. V. Chem.
Soc. Rev. 1983, 129. (c) Ragnarsson, U.; Grehn, L. Acc.
Chem. Res. 1998, 31, 494. (d) Berry, D. J.; Digiovanna, C.
V.; Metrick, S. S.; Murugan, R. ARKIVOC 2001, 201.
(e) Murugan, R.; Scriven, E. F. V. Aldrichimica Acta 2003,
36, 21. (f) Spivey, A. C.; Arseniyadis, S. Angew. Chem. Int.
Ed. 2004, 43, 5436.
(8) Based on our previous observations of thiourea-based
organocatalysis, we chose toluene as the best solvent. See:
(a) Mori, K.; Maddaluno, J.; Nakano, K.; Ichikawa, Y.;
Kotsuki, H. Synlett 2009, 2346. (b) Mori, K.; Yamauchi, T.;
Maddaluno, J.; Nakano, K.; Ichikawa, Y.; Kotsuki, H.
Synlett 2011, 2080.
determined by comparison with data in the literature. (R)-3b:
[α]D24 +5.32 (c 1.00, CHCl3; 98% ee); lit.16b [α]D20 +3.7 (c
1.00, CHCl3; 86% ee).
28
(S)-3f: [α]D24 +13.0 (c 1.00, CHCl3; 96% ee); lit.5 [α]D
+11.8 (c 1.03, CHCl3; 91% ee).
(R)-3g: [α]D25 +63.9 (c 1.00, CHCl3; 76% ee); lit.5 [α]D
27.5
+50.8 (c 1.07, CHCl3; 63% ee).
(R)-3h: [α]D24 +40.5 (c 1.00, CHCl3; 99% ee); lit.5 [α]D
27
+41.7 (c 1.02, CHCl3; 93% ee).
28
(S)-3i: [α]D25 +16.4 (c 1.00, CHCl3; 91% ee); lit.5 [α]D
+17.8 (c 1.02, CHCl3; 96% ee).
29
(S)-3j: [α]D25 +17.2 (c 1.00, CHCl3; 88% ee); lit.5 [α]D
+18.5 (c 1.02, CHCl3; 93% ee). (b) Yoshida, M.; Narita, M.;
Hara, S. J. Org. Chem. 2011, 76, 8513.
(9) General Procedure
To a solution of PPY (14.8 mg, 0.1 mmol), α,β-unsaturated
ketone (1, 1.0 mmol), and dialkyl malonate (2, 1.5 mmol) in
toluene (1.0 mL) thiourea catalyst C (38.5 mg, 0.1 mmol)
was added and the mixture was stirred until the reaction was
complete. After concentration, the mixture was purified by
silica gel column chromatography (elution with hexane–
EtOAc = 4:1) to afford pure product 3.
(17) The absolute configuration of the products 3c–e was
assigned by analogy.
Compound 3c: [α]D25 +17.9 (c 1.00, CHCl3; 99% ee).
Compound 3d: [α]D24 +9.27 (c 1.00, CHCl3; 99% ee).
Compound 3e: [α]D25 –3.04 (c 1.00, CHCl3; 98% ee).
(18) (a) For a review on the Rauhut–Currier reaction, see:
Aroyan, C. E.; Dermenci, A.; Miller, S. J. Tetrahedron 2009,
65, 4069. (b) The absolute configuration of 4 was
determined by comparison with data in the literature. (S)-4:
[α]D25 +3.52 (c 0.09, CHCl3, 38% ee); lit.18c (R)-4: [α]Dr.t. –3
(c 1.00, CH2Cl2; 47% ee) (c) Ceccarelli, R.; Insogna, S.;
Bella, M. Org. Biomol. Chem. 2006, 4, 4281. (d) The ee was
determined by chiral HPLC analysis [Chiralpak AD column,
0.46 × 25 cm, hexane–2-PrOH (95:5), 1.0 cm3/min): tR
(R) = 25.1 min; tR (S) = 35.7 min.
(10) Mei, K.; Zhang, S.; He, S.; Li, P.; Jin, M.; Xue, F.; Luo, G.;
Zhang, H.; Song, L.; Duan, W.; Wang, W. Tetrahedron Lett.
2008, 49, 2681.
(11) The absolute configuration of 3a was determined to be R by
comparison of its optical rotation with that in the literature 5.
22
(R)-3a: [α]D22 +3.14 (c 1.00, CHCl3; 98% ee); lit. 5 [α]D
+3.3 (c 1.00, CHCl3; 93% ee). The ee was determined by
chiral HPLC analysis [Chiralpak AS-H column, 0.46 × 25
cm, hexane–2-PrOH (70:30), 0.2 cm3/min]: tR (R) = 44.4
min; tR (S) = 49.9 min.
(19) Although we did not examine the role of PPY in detail, it can
be supposed that PPY could suppress the formation of
byproduct 4 by promoting the nucleophilic attack of 2 via
deprotonation (Scheme 1).
(12) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672.
(13) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett. 2004, 45, 5589.
(20) During the final preparation of a revised version of this
paper, Kwiatkowski and co-workers reported a closely
related work using catalyst C with benzoic acid in warmed
toluene. See: Dudzinski, K.; Pakulska, A. M.; Kwiatkowski,
P. Org. Lett. 2012, 14, 4222.
(14) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 4568.
(15) (a) Chrystiuk, E.; Williams, A. J. Am. Chem. Soc. 1987, 109,
3040. (b) Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.;
Mäemets, V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70,
1019.
Synlett 2012, 23, 2554–2558
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