Asymmetric Michael reactions of α,α-disubstituted aldehydes with maleimides using a primary amine thiourea organocatalyst

Article abstract of DOI:10.1016/j.tetasy.2011.09.006

Primary amine thiourea organocatalyst 8 was used to promote Michael additions of bulky α,α-disubstituted aldehydes, such as isobutyraldehyde with maleimides to afford the corresponding adducts in high to excellent yields and with up to 91% ee. Copyright

Full text of DOI:10.1016/j.tetasy.2011.09.006

Tetrahedron: Asymmetry 22 (2011) 1605–1609
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric Michael reactions of a,a-disubstituted aldehydes
with maleimides using a primary amine thiourea organocatalyst
⇑
Tsuyoshi Miura , Akira Masuda, Mariko Ina, Kosuke Nakashima, Shohei Nishida, 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:
Received 4 July 2011
Revised 1 September 2011
Accepted 2 September 2011
Available online 15 October 2011
Primary amine thiourea organocatalyst 8 was used to promote Michael additions of bulky a,a-disubsti-
tuted aldehydes, such as isobutyraldehyde with maleimides to afford the corresponding adducts in high
to excellent yields and with up to 91% ee.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
R2
R1
R2
Ph
Ph
S
Chiral a-substituted succinimides have attracted a great deal of
Ph
N
H
R1HN
attention because related compounds play an important role as
building blocks in synthetic and medicinal chemistry.1 The asym-
metric Michael reaction of maleimides using an organocatalyst is
one of the most practical synthetic procedures for effectively obtain-
N
H
N
H
OTMS
NHR2
5: R1 = H, R2 = SO2CF3
NH2
1
2: R1 = H, R2 = H
: R1 = H, R2 = CF3
4: R1 = C8F17, R2 = H
6
: R1 = SO2CF3, R2 = H
7: R1 = H, R2 = SO2C8F17
3
ing chiral
a-substituted succinimides. Many asymmetric Michael
additions of maleimides with a variety of nucleophiles promoted
by organocatalysts have been reported.2 However, reports with
aldehydes as nucleophiles are rare.3–5 Although Córdova et al. have
reported asymmetric Michael reactions of maleimides with
aldehydes using diphenylprolinol silyl ether 1 as a catalyst, only
moderate enantioselectivity and chemical yield were obtained
Figure 1. Structure of organocatalysts.
acid.6 Moreover, we had also developed recyclable organocatalyst
7 with a fluorous tag which promoted direct aldol reactions in
brine.7 We found that the simple skeleton of phenylalanine with
only one stereogenic center is suitable for organocatalyzed asym-
metric reactions. To further demonstrate the usefulness of the
phenylalanine structure as an organocatalyst, we attempted to
develop a novel organocatalyst, which introduced a 3,5-bis(trifluo-
romethyl)phenylthiourea group instead of a trifluoromethanesulf-
onamide group of 6, because it was reported that primary amine
thiourea organocatalysts are preferable to primary amine sulfon-
amide organocatalysts for Michael reactions of maleimides with
aldehydes.4a,b Herein, we describe the asymmetric Michael
when bulky a,a-disubstituted aldehydes such as isobutyraldehyde
were employed as nucleophiles (Fig. 1).3 In recent years, three re-
search groups have reported efficient asymmetric Michael additions
of a,a-disubstituted aldehydes to maleimides using thiourea organ-
ocatalysts 2 and 3 derived from 1,2-cyclohexanediamine as the
chiral source.4 We recently reported recyclable organocatalyst 4
which introduced a fluorous tag into a thiourea organocatalyst.5
Only thiourea organocatalysts 2–4 derived from 1,2-cyclohexanedi-
amine as the chiral source can successfully promote Michael
reactions of maleimides with a,a-disubstituted aldehydes using a
simple organocatalyst thiourea 8 prepared from L-phenylalanine.
reactions of maleimides with bulky
a,a-disubstituted aldehydes,
despite the utility of the resulting products as synthetic building
blocks.1 Therefore, the development of a novel organocatalyst for
2. Results and discussion
Michael reactions of maleimides with a,a-disubstituted aldehydes
remains a challenging research theme in organic chemistry.
We recently reported direct aldol reactions in brine, catalyzed by
chiral b-aminosulfonamides 5 and 6 derived from L-phenylalanine,
Thiourea 8, an organocatalyst for the Michael reactions, was
prepared as shown in Scheme 1. Treatment of compound 9, which
is an intermediate for the preparation of organocatalyst 6,6b with
3,5-bis(trifluoromethyl)phenyl isothiocyanate in THF afforded
thiourea 10. The azide group of 10 was then reduced with triphen-
ylphosphine in THF–H2O to give the desired organocatalyst thio-
urea 8 in 75% yield (two steps).
which is a commercially available and inexpensive natural amino
⇑
Corresponding author.
E-mail address: miura@gifu-pu.ac.jp (T. Miura).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.09.006

1606
T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1605–1609
CF3
electron-withdrawing groups on the benzene ring of the maleimide.
CF3
The reactions of maleimides 11b–e with isobutyraldehyde smoothly
gave the corresponding adducts 12b–e in high to excellent yields
with 75%–83% ee (entries 2–5). N-Benzylmaleimide 11f successfully
coupled with isobutyraldehyde, to afford adduct 12f in 96% yield
with the highest enantioselectivity (91% ee) (entry 6). Next, we
examined the Michael reaction of N-phenylmaleimide 11a with var-
ious types of aldehydes. The reactions of cyclohexanecarboxalde-
hyde and cyclopentanecarboxaldehyde, which are aldehydes with
a cyclic structure, were performed in the presence of 0.1 equiv of 8
to afford the corresponding adducts 12g and 12h in high yields with
65% and 79% ee, respectively (entries 7 and 8). Organocatalyst 8 cat-
alyzedthe reactionsof thelinear aldehydedecanalwith 11a toafford
the corresponding adduct 12j in high yield with moderate enanti-
oselectivity and low diastereoselectivity (entry 10). The stereo-
chemistries of the Michael reaction products obtained using 8
were determined by comparison with the literature chiral-phase
HPLC retention times and the specific rotation data.4
We can infer that the Michael reactions of aldehydes with
maleimides using organocatalyst 8 proceed via a transition state
similar to that proposed by Xu et al.,4c which is based on the ste-
reochemistry of products 12. A plausible reaction mechanism for
Michael reaction is proposed in Scheme 2. From this hypothesis,
the primary amino group of 8 condenses with the aldehyde to gen-
erate the enamine intermediate. Then, the two acidic protons of
the thiourea group of 8 coordinate to the carbonyl oxygen of the
maleimide to control the direction of approach of the maleimides
to the enamine intermediate, affording the corresponding addition
products 12 with an (S)-configuration.
Ph
N3
Ph
N3
S
F3C
NCS
H2N
F3C
N
H
N
H
THF, rt, 24 h
CF3
9
10
Ph
S
Ph3P, H2O
F3C
N
N
H
THF, rt, 47 h
75% (2 steps)
H
NH2
8
Scheme 1. Preparation of organocatalyst.
The reaction conditions were optimized for the enantioselective
Michael reactions using 8 as shown in Table 1. Michael reactions
were performed using N-phenylmaleimide 11a and isobutyralde-
hyde (2 equiv) as test reactants in the presence of catalytic
amounts of 8. The representative solvents were examined at room
temperature (entries 1–3). Dichloromethane was found to be the
most suitable solvent and high enantioselectivity (90% ee) was ob-
tained (entry 3). Adding H2O (0.15 equiv) and conducting the reac-
tion at 0 °C under similar conditions resulted in a decrease of
stereoselectivities (entries 4–6). The addition of benzoic acid
(0.025 equiv) also resulted in a reduction of enantioselectivity (en-
try 7). Increasing the catalyst loading to 0.05 equiv shortened the
reaction time while retaining the high enantioselectivity (entry
8). Therefore, by considering the reaction time, the optimal condi-
tions were determined to be 0.05 equiv of 8 in dichloromethane at
room temperature. As expected, both sulfonamide catalysts 5 and
6 are poor catalysts for the Michael reaction of maleimides with
aldehydes under similar reaction conditions (entries 9 and 10).
CF3
Ph
O
S
O
Ph
N
F3C
N
H
N
H
(
)
S
Table 1
H
Optimization of reaction conditions
HN
O
O
CF3
12a
Ph
Ph
N
O
S
O
O
H
O
F3C
N
H
N
H
O
NH2
N
Ph
N
Ph
(2 equiv)
8
(0.025 equiv)
Scheme 2. Proposed transition state model of Michael reaction.
H
O
O
11a
12a
Yielda
3. Conclusion
Entry
Solvent
H2O (equiv)
Temp
Time (h)
% eeb
In conclusion, novel organocatalyst thiourea 8 bearing a pri-
mary amino group can be easily prepared from -phenylalanine,
1
2
3
4
5
THF
—
—
—
0.15
—
0.15
—
—
—
—
rt
rt
rt
rt
0 °C
0 °C
rt
rt
rt
48
48
48
48
67
67
48
24
48
48
45
42
71
96
36
68
83
96
15
40
69
76
90
83
84
84
70
88
65
30
L
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
a commercially available, inexpensive natural amino acid. The sim-
ple primary amine thiourea 8, which has only one stereogenic cen-
ter, functions as an efficient catalyst for the Michael reactions of
various aldehydes with maleimides in dichloromethane to give
the corresponding adducts 12 in high to excellent yields and with
high enantioselectivities. Further applications of this process to the
synthesis of bioactive compounds and to novel reactions are cur-
rently in progress in our laboratory.
6
7c
8d
9e
10f
rt
a
b
c
d
e
f
Isolated yields.
Determined by HPLC analysis.
Benzoic acid (0.025 equiv) was added.
0.05 equiv of 8 was used.
Organocatalyst 5 (0.025 equiv) was used instead of 8.
Organocatalyst 6 (0.025 equiv) was used instead of 8.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were measured with a JEOL AL
400 spectrometer (400 MHz for 1H NMR and 100 MHz for 13C
NMR), or JEOL ECA-500 spectrometer (500 MHz for 1H NMR and
125 MHz for 13C NMR). The chemical shifts are expressed in ppm
downfield from tetramethylsilane (d = 0.00) as an internal stan-
dard. The high-resolution mass spectra (HRMS) of the compounds
To examine the scope and limitations of the reaction substrates,
we next investigated the Michael reaction of various maleimides
and aldehydes under the optimal conditions (Table 2). We selected
methoxy and methyl substituents as the representative electron-
donating group, and nitro and halogen substituents as the

T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1605–1609
1607
Table 2
Michael reactions of various maleimides with aldehyde in the presence of 8
CF3
Ph
O
S
R2
O
H
O
F3C
N
H
N
H
O
R3
N
R1
NH2
N
R1
8
(0.05 equiv)
(2 equiv)
H
O
R2 R3
CH2Cl2, rt
O
11
12
Entry
1
Maleimide
Aldehyde
Product
Time (h)
24
Yielda (%)
% eeb
O
O
O
O
H
N
Ph
N
Ph
96
88
83
75
77
82
91
65
H
O
O
12a
12b
12c
12d
12e
O
11a
O
H
O
O
N
OMe
Me
N
OMe
Me
2
3
48
48
96
85
87
81
96
90
H
H
H
H
H
H
O
O
O
O
11b
O
H
O
O
O
O
O
N
N
O
O
O
O
11c
11d
11e
O
H
N
NO2
N
NO2
4
48
O
O
O
O
O
H
N
Cl
N
Cl
5
46
O
O
O
O
O
H
N
Bn
N
Bn
6
48
O
O
12f
O
O
11f
O
H
N
Ph
7c
168
N
Ph
O
O
O
O
12g
11a
O
H
O
O
N
Ph
8c
25
98
79
79
60
N
Ph
H
H
O
O
O
O
12h
11a
O
H
N
Ph
9c
144
N
Ph
O
O
12i
11a
(continued on next page)

1608
T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1605–1609
Table 2 (continued)
Entry
Maleimide
Aldehyde
Product
Time (h)
168
Yielda (%)
% eeb
O
O
O
n-C8H17
O
H
H
N
Ph
N Ph
10c
87d
42 (28)e
O
O
11a
n-C8H17
12j
a
b
c
Isolated yields.
Determined by HPLC analysis.
0.1 equiv of 8 was used.
The ratio of syn and anti isomers was 56:44.
Enantio excess of syn isomer. Enantio excess of anti isomer in parentheses.
d
e
were recorded using a LEOL JMS-T100TD (ESI-TOF-MS) spectrome-
ter. For thin layer chromatographic (TLC) analyses, Merck pre-
coated TLC plates (Silica Gel 60 F254, Art 5715) were used. The
products were isolated by flash column chromatography on silica
was purified by flash column chromatography on silica gel with a
2:1 mixture of hexane and AcOEt to afford the pure 12a (188 mg,
96%) as a colorless powder.
All the Michael addition products in the paper are known com-
pounds that exhibited spectroscopic data identical to those re-
ported in the literature.
gel (Kanto Chemical, silica gel 60N, spherical, neutral, 40–50 lm).
4.2. Preparation of the organocatalyst
4.3.1. (S)-2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-
4.2.1. (S)-1-(1-Azido-3-phenylpropan-2-yl)-3-(3,5-bis(trifluoro-
methylpropanal 12a4
a 2D7
ꢀ
¼ ꢁ4:8 (c 1.02, CHCl3). 88% ee; Enantiomeric excess was
methyl)phenyl)thiourea 10
½
To
(570 mg, 3.23 mmol) in dry THF (9 mL) was added 3,5-bis
(trifluoromethyl)phenyl isothiocyanate (590 L, 3.23 mmol) at rt
a
solution of (S)-1-azido-3-phenylpropan-2-amine 96b
determined by HPLC with Chiralcel OD-H column (hexane/
2-propanol = 75:25), flow rate = 0.9 mL/min; k = 240 nm; tmajor
25.4 min, tminor = 34.7 min.
=
l
under an argon atmosphere. After stirring for 24 h, the reaction
mixture was evaporated under reduced pressure. The residue
was purified by flash column chromatography on silica gel with a
4:1 mixture of hexane and AcOEt to afford pure 10 (1.44 g, 100%)
4.3.2. (S)-2-(1-(4-Methoxyphenyl)-2,5-dioxopyrrolidin-3-yl)-2-
methylpropanal 12b4
a 2D5
ꢀ
¼ ꢁ11:0 (c 0.63, CHCl3); 83% ee; Enantiomeric excess was
as a colorless powder. Mp = 97–99 °C; ½a D22
ꢀ
¼ þ4:8 (c 1.00, CHCl3);
½
1H NMR (500 MHz, CDCl3): d = 2.85 (dd, J = 8.0, 13.7 Hz, 1H), 3.03
(dd, J = 6.3, 13.7 Hz, 1H), 3.44 (d, J = 12.0 Hz, 1H), 3.68 (dd, J = 4.0,
12.0 Hz, 1H), 4.87 (br s, 1H), 6.39 (br s, 1H), 7.20–7.32 (m, 5H),
7.69 (s, 2H), 7.72 (s, 1H); 13C NMR (125 MHz, CDCl3): d = 37.3,
determined by HPLC with Chiralpak AS-H column (hexane/
ethanol = 80:20), flow rate = 0.6 mL/min; k = 240 nm; tminor = 43.6 -
min, tmajor = 46.7 min.
1
52.3, 55.3, 119.7, 122.6 (q, JC-F = 274 Hz), 124.0, 127.1, 128.9,
4.3.3. (S)-2-(2,5-Dioxo-1-p-tolylpyrrolidin-3-yl)-2-methylprop-
2
anal 12c4
129.0, 133.1 (q, JC-F = 33.6 Hz), 136.2, 138.3, 179.8; HRMS (ESI-
a 2D4
ꢀ
¼ ꢁ4:4 (c 0.74, CHCl3); 75% ee; Enantiomeric excess was
TOF): calcd for C18H16F6N5S (M+H)+: 448.1025, found: 448.1007.
½
determined by HPLC with Chiralcel OD-H column (hexane/
4.2.2. (S)-1-(1-Amino-3-phenylpropan-2-yl)-3-(3,5-
bis(trifluoromethyl)phenyl)thiourea 8
2-propanol = 75:25), flow rate = 0.9 mL/min; k = 240 nm; tmajor
18.6 min, tminor = 23.0 min.
=
To a solution of 10 (1.44 g, 3.23 mmol) in dry THF (36 mL) were
added PPh3 (1.05 g, 4.01 mmol) and H2O (197 lL, 10.9 mmol) at rt.
4.3.4. (S)-2-Methyl-2-(1-(4-nitrophenyl)-2,5-dioxopyrrolidin-3-
After stirring for 47 h at rt, the reaction mixture was evaporated.
The residue was purified by flash column chromatography on silica
gel with a 9:1:0.08 mixture of CHCl3, MeOH and H2O to give pure 8
yl)propanal 12d4a
½
a 2D5
ꢀ
¼ ꢁ6:8 (c 0.63, CHCl3); 77% ee; Enantiomeric excess was
determined by HPLC with Chiralcel OD-H column (hexane/
(1.02 g, 75%) as a colorless powder. Mp = 41–43 °C; ½a D20
¼ ꢁ57:6 (c
ꢀ
2-propanol = 80:20), flow rate = 1.0 mL/min; k = 240 nm; tmajor
47.1 min, tminor = 64.8 min.
=
1.00, CHCl3); 1H NMR (500 MHz, CD3OD): d = 2.75 (dd, J = 13.2,
7.5 Hz, 1H), 2.85–2.91 (m, 3H), 2.95 (br s, 1H), 7.20 (m, 1H), 7.30
(m, 6H), 7.26 (s, 1H); 13C NMR (125 MHz, CD3OD): d = 39.0, 45.2,
1
4.3.5. (S)-2-(1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
58.5, 117.9, 123.8, 124.7 (q, JC-F = 272 Hz), 127.5, 129.5, 130.3,
methylpropanal 12e4b,c
2
132.6 (q, JC-F = 33.6 Hz), 139.3, 143.1, 183.1; HRMS (ESI-TOF):
½
a 2D7
ꢀ
¼ ꢁ5:0 (c 0.35, CHCl3); 82% ee; Enantiomeric excess was
calcd for C18H18F6N3S (M+H)+: 422.1120, found: 422.1097.
determined by HPLC with Chiralcel OD-H column (hexane/
2-propanol = 75:25), flow rate = 0.9 mL/min; k = 240 nm; tmajor
19.0 min, tminor = 36.3 min.
=
4.3. Typical procedure for a Michael reaction using
organocatalyst 8 (Table 2)
A typical procedure for a Michael reaction using 8 and 11a is as
follows: to a solution of thiourea organocatalyst 8 (16.8 mg,
4.3.6. (S)-2-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)-2-
methylpropanal 12f4
½
a 2D6
ꢀ
¼ ꢁ8:6 (c 0.88, CHCl3); 91% ee; Enantiomeric excess was
40.0
(147
l
l
mol) in 1 mL of CH2Cl2 were added isobutyraldehyde
L, 1.60 mmol) and 11a (139 mg, 0.80 mmol) at room tem-
determined by HPLC with Chiralpak AD-H column (hexane/
perature. After stirring at room temperature for 24 h, the reaction
mixture was evaporated under reduced pressure. The residue
2-propanol = 80:20), flow rate = 1.0 mL/min; k = 240 nm; tmajor
9.8 min, tminor = 22.7 min.
=

T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1605–1609
1609
4.3.7. (S)-1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclohexane-
carbaldehyde 12g4
¼ ꢁ2:2 (c 0.71, CHCl3); 65% ee; Enantiomeric excess was
determined by HPLC with Chiralcel OD-H column (hexane/
References
½ ꢀ
a 2D7
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2-propanol = 75:25), flow rate = 0.9 mL/min; k = 240 nm; tmajor
21.5 min, tminor = 28.2 min.
=
4.3.8. (S)-1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclopentane-
carbaldehyde 12h4a
½
a 2D6
ꢀ
¼ þ13:0 (c 1.00, CHCl3); 79% ee; Enantiomeric excess was
determined by HPLC with Chiralcel OD-H column (hexane/
2-propanol = 75:25), flow rate = 0.5 mL/min; k = 240 nm; tmajor
36.1 min, tminor = 51.1 min.
=
4.3.9. (S)-2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-ethylbutanal
12i4b
½
a 2D6
ꢀ
¼ ꢁ5:0 (c 0.53, CH2Cl2); 60% ee; Enantiomeric excess
was determined by HPLC with Chiralpak AS-H column (hexane/
ethanol = 70:30), flow rate = 0.8 mL/min; k = 240 nm; tminor
11.3 min, tmajor = 14.1 min.
=
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4.3.10. (S)-2-((S)-2,5-Dioxo-1-phenylpyrrolidin-3-yl)decanal
12j4a
Enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (hexane/2-propanol = 90:10), flow rate = 0.5
mL/min; k = 240 nm; major diastereomer: tminor = 36.8 min, tmajor
=
38.8 min; minor diastereomer: tmajor = 32.8 min, tminor = 61.4 min.
Acknowledgment
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.