Asymmetric Michael additions of aldehydes to maleimides using a recyclable fluorous thiourea organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2011.05.145

Fluorous thiourea organocatalyst 3 promotes the Michael reaction of aldehydes with maleimides to afford the corresponding adducts in high yields with up to 99% ee. Fluorous organocatalyst 3 can be easily recovered as an insoluble precipitate from the reac

Full text of DOI:10.1016/j.tetlet.2011.05.145

Tetrahedron Letters 52 (2011) 4158–4160
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Tetrahedron Letters
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Asymmetric Michael additions of aldehydes to maleimides using a recyclable
fluorous thiourea organocatalyst
⇑
Tsuyoshi Miura , Shohei Nishida, Akira Masuda, Norihiro Tada, Akichika Itoh
Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Fluorous thiourea organocatalyst 3 promotes the Michael reaction of aldehydes with maleimides to
afford the corresponding adducts in high yields with up to 99% ee. Fluorous organocatalyst 3 can be easily
recovered as an insoluble precipitate from the reaction mixture by simple filtration and can be reused
without significant loss of catalytic activity.
Received 10 May 2011
Revised 24 May 2011
Accepted 30 May 2011
Available online 12 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Fluorous
Organocatalyst
Michael
Maleimide
Thiourea
Takemoto catalyst 1 is one of the most versatile organocatalysts
and promotes various important asymmetric carbon–carbon bond-
forming reactions.1 Likewise, related primary amine organocata-
lyst 2 has also attracted much attention because it is an efficient
alyst 2, we have attempted to develop a novel organocatalyst 3
with a fluorous tag that can promote asymmetric Michael reac-
tions. Herein, we describe the asymmetric Michael reactions of
maleimides with aldehydes using the recyclable fluorous organo-
catalyst 3 (Fig. 1).
To recover and reuse 2 for Michael reactions with maleimides,
we prepared 3, which contains a perfluorooctyl group as a fluorous
tag to 2 instead of two trifluoromethyl groups (Scheme 1). Fluorous
aniline 4 was condensed with chiral diamine 6 in the presence of 5
according to the Berkessel’s method8 to afford the desired 39 in
excellent yield.
The reaction conditions were optimized for the enantioselective
Michael reactions using fluorous organocatalyst 3 as shown in Ta-
ble 1. Michael reactions were performed using N-phenylmaleimide
(7a) and isobutyl aldehyde (2 equiv) as test reactants in the pres-
ence of catalytic amounts of 3. The representative solvents were
examined at room temperature (entries 1–4). Dichloromethane
was found to be the most suitable solvent and excellent enantiose-
lectivity (>99% ee) was obtained (entry 4). Lowering catalyst load-
ing to 0.05 and 0.01 equiv prolonged the reaction and led to
organocatalyst for Michael additions,
a-alkylations of aldehydes,
and tandem reactions.2 In recent years, there have been a few re-
ports of efficient asymmetric Michael additions of aldehydes to
maleimides using 2.3 Organocatalyst 2 is the only organic catalyst
that can successfully promote Michael reactions of maleimides
with bulky a,a-disubstituted aldehydes such as isobutyl aldehyde,
despite the utility of the resulting products as synthetic building
blocks.3,4 However, most valuable and expensive organocatalysts
such as 1 and 2 are discarded after use because of difficulties re-
lated to their recovery and reuse. Recovery of organocatalysts from
reaction mixtures and their recycling are highly desired because
most organocatalysts are expensive and have lengthy synthesis
procedures. The fluorous tag technique using fluorous solid-phase
extraction or fluorous-organic solvent extraction can be used for
recycling catalysts.5 There are many reports of catalyst-recyclable
asymmetric reactions using fluorous organocatalysts.6 We have re-
cently reported a direct aldol reaction in water using a fluorous sul-
fonamide organocatalyst and an oxidation reaction using fluorous
IBX.7
CF3
F17C8
S
Organocatalyst 2 cannot be recovered by fluorous solid-phase
extraction or fluorous-organic solvent extraction because fluorine
content of 2 is very low. Therefore, to recover and reuse organocat-
S
N
H
N
H
F3C
N
H
N
H
NH2
NR2
3
1
2
: R = Me
: R = H
⇑
Corresponding author.
E-mail address: miura@gifu-pu.ac.jp (T. Miura).
Figure 1. Structure of organocatalysts.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.145

T. Miura et al. / Tetrahedron Letters 52 (2011) 4158–4160
4159
Table 2
DIPEA F17C8
Pyridine
F17C8
S
S
Michael reactions of various maleimides with aldehydes in the presence of 3
+
+
H2N
CH2Cl2, rt
95 %
N
H
N
H
F17C8
Cl
OPh
O
NH2
S
NH2
NH2
R2
O
5
4
6
3
H
O
N
H
N
H
R3
O
R1
NH2
N
N
R1
(2 equiv)
Scheme 1. Preparation of fluorous thiourea organocatalyst 3.
3
(0.1 equiv)
H
O
R2 R3
CH2Cl2, rt
O
8
7a: R1 = Ph
7b: R1 = Bn
Table 1
1
7c
7d
7e
: R = 4-CH3OC6H4
Optimization of reaction conditions
: R1 = 4-CH3C6H4
F17C8
O
1
: R = 4-NO2C6H4
S
7f: R1 = 4-ClC6H4
O
O
H
N
H
3
N
H
Entry
Product
Time (h)
24
Yielda (%)
85
% eeb
>99
NH2
O
N
Ph
(2 equiv)
N
Ph
O
H
rt
O
O
7a
O
H
N
Bn
8b
1
2
3
8a
Yielda (%)
% eeb
O
O
Entry
Solvent
Catalyst 3 (equiv)
Time (h)
1
2
3
4
5
6
THF
0.1
0.1
0.1
0.1
0.05
0.01
80
48
44
24
84
168
84
93
82
86
90
2
94
95
97
>99
>99
98
AcOEt
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
O
H
N
OMe
Me
68
34
93
78
99
O
O
8c
O
H
a
N
Isolated yield.
Determined by HPLC analysis.
>99
b
O
O
8d
8e
O
H
N
NO2
4
5
48
48
86
89
>99
99
decrease in yield; however, high enantioselectivities were retained
(entries 5–6). Therefore, by considering the reaction time, the opti-
mal conditions were determined to be 0.1 equiv of 3 in dichloro-
methane at room temperature.
O
O
O
H
N
Cl
To explain the scope and limitations of the reaction substrates,
we next investigated Michael reactions of various maleimides and
aldehydes under the optimal conditions (Table 2). We chose nitro
and halogen substituents as the representative electron-withdraw-
ing groups and methoxy and methyl substituents as the electron-
donating groups on the benzene ring of the maleimide. The reactions
of maleimides (7c–f) with isobutylaldehyde smoothly resulted in
the corresponding adducts (8c–f) in high yields with excellent
enantioselectivities (entries 2–5). Next, we examined Michael reac-
tions of N-phenyl maleimide (7a) with various types of aldehydes.
The reactions of cyclohexanecarboxaldehyde and cyclopentanecar-
boxaldehyde, which are aldehydes with cyclic structures, were
performed in the presence of the additive benzoic acid3b to afford
the desired adducts 8g and 8h in high yields with 99% and 91% ee,
respectively (entries 6 and 7). Fluorous organocatalyst 3 catalyzed
the reactions of linear aldehydes propanal and decanal with 7a to af-
ford the corresponding adducts 8j and 8k in moderate to good yields
with high enantioselectivities; however, low diastereoselectivities
were observed (entries 9 and 10). The stereochemistry of all the
Michael reaction products obtained using 3 was determined by
chiral-phase HPLC analysis and NMR spectroscopy.
The main objective of our study is to recover and reuse fluorous
organocatalyst 3. Recovery of 3 required only simple filtration (60–
100%) because of its insolubility in a 1:1 mixture of hexane and
chloroform. Fluorous solid-phase extraction or fluorous-organic
solvent extraction was not necessary for recycling. Recovered 3 re-
tained its catalytic activity without any further purification for all
three reuse cycles, although a longer reaction time was needed
for the second and third cycle (Table 3).10
In conclusion, fluorous organocatalyst 3 can be easily prepared
in a single step from commercially available reagents. Compound
3, which has a simple structure, functions as an efficient catalyst
for Michael reactions of various aldehydes with maleimides in
dichloromethane to give the corresponding adducts 8 in high
O
O
8f
O
H
N
Ph
6c
72
76
74
92
99
91
99
O
O
8g
O
H
N
Ph
7c
O
O
8h
O
H
N
Ph
8c
168
96
99
O
O
8i
O
H
9c
43d
99 (99)e
99 (98)e
N
Ph
O
O
8j
O
H
N
Ph
10c
24
63f
O
n-C8H17
8k
a
b
c
d
e
f
Isolated yields.
Determined by HPLC analysis.
PhCO2H (0.1 equiv) was added.
The ratio of syn and anti isomers was 58:42.
Enantio excess of syn isomer. Enantio excess of anti isomer in parentheses.
The ratio of syn and anti isomers was 73:27.
yields with excellent enantioselectivities, which are nearly equal
to those of original catalyst 2.3 Recovery of organocatalyst 3 can

4160
T. Miura et al. / Tetrahedron Letters 52 (2011) 4158–4160
5246; (m) Li, X.; Hu, S.; Xi, Z.; Zhang, L.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2010,
Table 3
75, 8697; (n) Alba, A. R.; Valero, G.; Calbert, T.; Font-Bardia, M.; Moyano, A.;
Rios, R. Chem. Eur. J. 2010, 16, 9884; (o) Yu, C.; Zhang, Y.; Song, A.; Ji, Y.; Wang,
W. Chem. Eur. J. 2011, 17, 770.
Recycling and reuse of the fluorous organocatalyst 3 by filtration
F17C8
O
S
O
O
2. (a) Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue, F.; Duan, W.; Wang,
W. Org. Lett. 2009, 11, 2864; (b) Uehara, H.; Barbas, C. F., III Angew. Chem., Int.
Ed. 2009, 48, 9848; (c) Imashiro, R.; Uehara, H.; Barbas, C. F., III Org. Lett. 2010,
12, 5250; (d) Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am. Chem. Soc. 2010,
132, 9286.
3. For Michael reaction with maleimide using catalyst 2, see: (a) Xue, F.; Liu, L.;
Zhang, S.; Duan, W.; Wang, W. Chem. Eur. J. 2010, 16, 7979; (b) Yu, F.; Jin, Z.;
Huang, H.; Ye, T.; Liang, X.; Ye, J. Org. Biomol. Chem. 2010, 8, 4767; (c) Bai, J.-F.;
Peng, L.; Wang, L.-L.; Wang, L.-X.; Xu, X.-Y. Tetrahedron 2010, 66, 8928.
4. Zhao, G.-L.; Xu, Y.; Sundén, H.; Eriksson, L.; Sayah, M.; Córdova, A. Chem.
Commun. 2007, 734.
H
N
H
N
H
O
NH2
N
Ph
N Ph
(2 equiv)
3
(0.1 equiv)
CH2Cl2, rt
Yielda (%)
H
O
7a
O
8a
Entry
Initial
1st reuse
2nd reuse
3rd reuse
Time (h)
% ee
Cat. recovery (%)
24
24
43
46
86
91
95
91
>99
99
>99
95
100
72
61
5. For a review on fluorous tag technique, see (a) Curran, D. P. Synlett 2001, 1488;
(b) Curran, D. P. In The Handbook of Fluorous Chemistry; Gladysz, J. A., Horváth, I.
T., Curran, D. P., Eds.; Wiley-VCH: Weinheim, 2004; (c) Thang, W.; Curran, D. P.
Tetrahedron 2006, 62, 11837.
60
a
Isolated yields.
6. For review on fluorous organocatalysts, see: Zhang, W.; Cai, C. Chem. Commun.
2008, 5686; For examples of fluorous organocatalysts, see: (a) Fache, F.; Piva, O.
Tetrahedron Lett. 2001, 42, 5655; (b) Fache, F.; Piva, O. Tetrahedron: Asymmetry
2003, 14, 139; (c) Dalicsek, Z.; Pollreisz, F.; Gomory, A.; Soóa, T. Org. Lett. 2005,
7, 3243; (d) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077; (e) Zu, L.;
Wang, J.; Li, H.; Yu, X.-H.; Wang, W. Tetrahedron Lett. 2006, 47, 5131; (f) Chu, Q.;
Zhang, W.; Curran, D. P. Tetrahedron Lett. 2006, 47, 9287; (g) Malkov, A. V.;
be readily performed by simple filtration without the need for
expensive fluorous solvents and fluorous silica gels. The catalytic
activity and enantioselectivity of 3 do not change significantly up
to three repetitive reaction cycles. Further applications of com-
pound 3 to the synthesis of bioactive compounds and to novel
reactions are currently underway in our laboratory.
ˇ
ˇ
´
Figlus, M.; Stoncius, S.; Kocovsky, P. J. Org. Chem. 2007, 72, 1315; (h) Goushi, S.;
Funabiki, K.; Ohta, M.; Hatano, K.; Matsui, M. Tetrahedron 2007, 63, 4061; (i)
Cui, H.; Li, Y.; Zheng, C.; Zhao, G.; Zhu, S. J. Fluorine Chem. 2008, 129, 45; (j) Chu,
Q.; Yu, M. S.; Curran, D. P. Org. Lett. 2008, 10, 749; (k) Wang, L.; Cai, C.; Curran,
D. P.; Zhang, W. Synlett 2010, 433.
Acknowledgment
7. (a) Miura, T.; Imai, K.; Ina, M.; Tada, N.; Imai, N.; Itoh, A. Org. Lett. 2010, 12,
1620; (b) Miura, T.; Nakashima, K.; Tada, N.; Itoh, A. Chem. Commun. 2011, 47,
1875.
This work was supported in part by Grants-in-Aid for Scientific
Research (C) (No. 22590007) from the Japan Society for the Promo-
tion of Science.
8. Berkessel, A.; Seelig, B. Synthesis 2009, 2113.
9. Fluorous organocatalyst 3: pale yellow powder; mp = 162–164 °C; ½a D24
ꢀ = + 56.6°
(c 0.42 in CH2Cl2); 1H NMR (500 MHz, CD3OD): d = 1.24–1.41 (m, 4H), 1.77–
1.78 (m, 2H), 2.00 (m, 1H), 2.09–2.11 (m, 1H), 2.64–2.69 (m, 1H), 4.30 (br s, 1H),
7.57 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H); Anal. Calcd for C21H18F17N3S: C,
37.79; H, 2.72; N, 6.30. Found: C, 37.60; H, 2.68; N, 6.30.
References and notes
10. A typical procedure of Michael reaction using 3 and 7a is as follows: To a solution
1. For Takemoto catalyst 1, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672; (b) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y.
Org. Lett. 2004, 6, 625; (c) Okino, T.; Hoashi, Y.; Furukawa, T.; Yu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119; (d) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.;
Ding, L.-S.; Wu, Y. Synlett 2005, 603; (e) Okino, T.; Hoashi, Y.; Takemoto, Y.
Angew. Chem., Int. Ed. 2005, 44, 4032; (f) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J.
Am. Chem. Soc. 2006, 128, 9413; (g) Takemoto, Y.; Miyabe, H. Chimia 2007, 61,
269; (h) Liao, Y.-H.; Zhang, H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
Tetrahedron: Asymmetry 2009, 20, 2397; (i) Wang, X.; Chen, Y.-F.; Niu, L.-F.; Xu,
P.-F. Org. Lett. 2009, 11, 3310; (j) Liao, Y.-H.; Chen, W.-B.; Wu, Z.-J.; Du, X.-L.;
Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Adv. Synth. Cat. 2010, 352, 827; (k) Zhang,
Y.; Yu, C.; Ji, Y.; Wang, W. Chem. Asian J. 2010, 5, 1303; (l) Baslé, O.; Raimondi,
W.; Duque, M.; Bonne, D.; Constantieux, T.; Rodriguez, J. Org. Lett. 2010, 12,
of 7a (277 mg, 1.60 mmol) and fluorous organocatalyst
0.160 mmol) in 20 mL of CH2Cl2 was added isobutyl aldehyde (293
3
(107 mg,
L,
l
3.20 mmol) at room temperature. After stirring at room temperature for
22 h, the reaction mixture was evaporated under reduced pressure. Then, a 1:1
mixture of hexane and chloroform was added to the residue. The precipitated
fluorous organocatalyst 3 was filtered, and washed with a 1:1 mixture of
hexane and chloroform. The collected 3 was dried under reduced pressure, and
was used in the next step without further purification. The filtrate was
evaporated, and the residue was purified by flash column chromatography on
silica gel with a 2:1 mixture of hexane and AcOEt to afford the pure 8a
(343 mg, 87%) as a colorless powder.