Chiral primary amine thiourea promoted highly enantioselective Michael reactions of isobutylaldehyde with maleimides

Article abstract of DOI:10.1016/j.tet.2010.09.044

Chiral primary amine thiourea catalysts were first successfully applied to promote Michael addition of isobutyraldehyde to maleimides. A variety of N-aryl and N-aliphatic maleimides provided Michael adducts in excellent yields (up to 98%) and enantioselectivities (up to 99% ee) with 5 mol % catalyst.

Full text of DOI:10.1016/j.tet.2010.09.044

Tetrahedron 66 (2010) 8928e8932
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Chiral primary amine thiourea promoted highly enantioselective Michael
reactions of isobutylaldehyde with maleimides
,
,
,
,
a,
Jian-Fei Bai a b, Lin Peng a b, Liang-liang Wang a b, Li-Xin Wang a , Xiao-Ying Xu
*
*
a Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, PR China
b Graduate School of Chinese Academy of Sciences, Beijing 100039, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2010
Received in revised form 10 September 2010
Accepted 14 September 2010
Available online 18 September 2010
Chiral primary amine thiourea catalysts were first successfully applied to promote Michael addition of
isobutyraldehyde to maleimides. A variety of N-aryl and N-aliphatic maleimides provided Michael ad-
ducts in excellent yields (up to 98%) and enantioselectivities (up to 99% ee) with 5 mol % catalyst.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Primary amine thiourea
Michael reactions
Isobutylaldehyde
Maleimides
Enantioselective
1. Introduction
amines-thioureas are proved to be effective in Michael addition10
because primary amine was suitable for the generation of nucleo-
Michael reaction is one of the most efficient carbonecarbon
bond formation reactions in organic chemistry and much attention
have focused on this organocatalytic reaction.1 To the best of our
knowledge, the acceptors in this powerful type of strategy involved
enones,2 nitroalkenes,3 and unsaturated imides.4,5 Asymmetric
conjugate addition of nucleophile to maleimides5 has been studied
extensively for it is a straightforward method to access syntheti-
cally and biologically interesting building blocks and nature prod-
ucts, such as substituted succinimides and functionalized
pyrrolidines.6 The donors of Michael reaction with maleimides in-
cluded 1,3-dicarbonyl compounds,5fei 2-mercaptobenzaldehydes,5j
dicyanoolefins,5k azlactones,5l ketones,7 and aldehydes.8 In 2007,
Córdova reported the first highly enantioselective addition of un-
modified aldehydes to maleimides employing chiral diphenylpro-
philic enamines, which could lead to an efficient addition to elec-
tron-deficient alkenes. Inspired by this concept, we envision that
chiral primary amine-thioureas should be suitable catalysts for the
addition of isobutylaldehyde to maleimides, affording the corre-
sponding optically active desired products via a postulated transi-
tion state (TS) as shown in Scheme 1. As a part of our continuing
interests in asymmetric synthesis,11 herein we wish to report the
enantioselective conjugate addition of isobutylaldehyde to mal-
eimides promoted by chiral primary amine thiourea in excellent
yields (up to 98%) and enantioselectivities (up to 99% ee).12
chiral bifunctional
CF3
CF3
scaffold
O
S
N
HN
N
O
N
Ph
linol silyl ether.8 However, the addition of
a,a-disubstituted
R1
H
*
H
H
O
*
aldehydes to maleimides, such as isobutylaldehyde, was rarely
reported. Therefore, catalytic asymmetric Michael addition of iso-
butylaldehyde to maleimides remains a challenge, and both ster-
eoselectivity and substrate scope are highly desirable to explore.
Bifunctional thiourea catalysts, which were powerful tools to
simultaneously activate both donors and acceptors, have been in-
vestigated extensively in asymmetric Michael addition.9 Primary
O
R2
R2
R1
N
Ph
O
Scheme 1. Proposed transition state.
2. Results and discussion
The direct Michael reaction of isobutyraldehyde (1a) with N-
phenylmaleimide (2a) at room temperature was used as a model
* Corresponding authors. Tel./fax: þ86 28 85255208; e-mail addresses: wlxioc@
cioc.ac.cn (L.-X. Wang), xuxy@cioc.ac.cn (X.-Y. Xu).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.044

J.-F. Bai et al. / Tetrahedron 66 (2010) 8928e8932
8929
case to determine the asymmetric reaction conditions and the re-
sults were summarized in Table 1. To our delight, the model re-
action was performed smoothly in CH2Cl2 catalyzed by 20 mol %
chiral primary amine thiourea catalyst. When the reaction was
promoted by catalyst I with (1R,2R)-1,2-diphenyldiamine, moder-
ate yield (84%) and enantioselectivity (87% ee) were obtained
(Table 1, entry 1). In contrast, catalyst II with (R,R)-1,2-cyclo-
hexanediamine as chiral scaffold afforded excellent ee value (99%
ee) and yield (98%, Table 1, entry 2), and it was selected for further
optimization.
with a variety of maleimides and the results were listed in Table 3.
The maleimides included those bearing electron-withdrawing and
electron-donating substituents on the aryl ring, as well as N-ali-
phatic maleimides. The Michael addition reactions were performed
smoothly under the optimal reaction conditions and all the sub-
strates gave excellent yields (up to 98%) and enantioselctivities (up
to 99% ee). Various substituted N-phenyl maleimides 2ae2i (Table 3,
entries 1e9) gave the desired adducts 3ae3i in excellent yields
(82e99%) and enantioselectivities (95e99% ee). Notably, the re-
action with N-aliphatic substituted maleimides as substrate also
worked well (Table 3, entries 10 and 11) and afforded excellent
results (up to 98% yield, 99% ee). Encouraged by the above results,
the scope of aldehyde was investigated by using 2a as acceptor. The
conversion was also underwent well and provided the corre-
sponding product in moderate yield (55%) and excellent
Table 1
Organocatalytic enantioselective Michael reaction between isobutylaldehyde (1a)
and maleimide (2a)a
O
O
O
20 mol% cat
solvent, rt
O
N
Ph
+
N Ph
H
Table 2
H
Effect of catalyst loading for the Michael reactions of isobutylaldehyde (1a) with
O
O
maleimides (1b)a
3a
1a
2a
O
O
O
CF3
CF3
cat II
O
N
Ph
+
N Ph
H
Ph
S
S
CH2Cl2, rt
H
Ph
O
N
H
N
H
CF3
N
N
H
CF3
O
2a
H
3a
1a
NH2
NH2
I
II
Entry
Catalyst loading (mol %)
Time (h)
Yieldb (%)
Eec (%)
Entry
Catalyst
Solvent
Yieldb (%)
Eec,d (%)
1a
2a
3a
4a
5d
6d
20
15
10
5
2
1
5
6
7
8
15
24
98
98
98
98
91
85
99
99
99
99
99
99
1
2
3
4
5
6
7
I
CH2Cl2
CH2Cl2
CHCl3
Toluene
CH3CN
THF
84
98
95
96
90
96
98
87
99
99
99
74
92
5
II
II
II
II
II
II
a
Unless otherwise specified, all reactions were carried out with aldehyde (1a,
0.40 mmol), N-phenylmaleimide (2a, 0.20 mmol), and the catalyst in CH2Cl2
(0.5 mL) at rt.
CH3OH
a
Unless otherwise specified, all reactions were carried out with aldehyde (1a,
0.40 mmol), N-phenylmaleimide (2a, 0.20 mmol), and the catalyst (0.04 mmol) in
solvent (0.5 mL) at rt for 5 h.
b
Isolated yields.
Determined by chiral HPLC analysis (Chiralcel OD-H).
Reactions were carried out with N-phenylmaleimide in 1 mmol.
c
d
b
Isolated yields.
Determined by chiral HPLC analysis (Chiralcel OD-H).
The absolute configuration of the product was determined as R by comparing
c
d
Table 3
with reported data.8
Scope of organocatalytic conjugates addition of isobutyraldehyde to maleimidesa
O
O
O
Next, the effect of the solvent was investigated with 20 mol %
catalyst II at room temperature and the results were listed in
Table 1. This transformation was carried out well in all solvents and
gave excellent yields (90e98%). It was found that solvents have
remarkable effects on the enantioselectivities.
O
5 mol% cat II
R2
N
R3
H
+
N
R3
CH2Cl2, rt
H
R1
1a-d
O
R1 R2
3a-n
O
2a-k
Aprotic solvents such as CH2Cl2, CHCl3, toluene, CH3CN, and THF
gave good to excellent enantioselectivities (74e99% ee, Table 1,
entries 2e6), whereas protic solvent such as CH3OH gave a low
enantioselectivity (5%, Table 1, entry 7). A survey of solvents
revealed that CH2Cl2 was the best suitable solvent, which gave the
highest ee (99%) with good yield (98%) (Table 1, entry 2). The effect
of the catalyst loading was also evaluated and the results were
summarized in Table 2. Lowering the catalyst loading did not affect
the enantioselectivities, whereas slightly sacrificed the yield despite
prolonging the reaction time. In the presence of 5 mol % catalyst, the
reaction finished nearly in 8 h and gave the corresponding adduct
3a with nearly the same yield (98%) and enantioselectivity (99% ee)
as in the presence of 20 mol % catalyst II (Table 2, entry 4 vs entry 1).
Notably, the presence of 1 mol % of catalyst II is sufficient to afford
the reaction in a good yield (85%) and excellent enantioselectivity
(99% ee, Table 2, entry 6). Based on all of the above results, a set of
acceptable reaction conditions, 2.0 equiv 1a and 1.0 equiv 2a in
0.5 mL CH2Cl2 with 5 mol % catalyst II at room temperature were
established. After having established the optimal reaction condi-
tions, we expanded the optimal protocol to this catalytic system
Entry R1
R2
R3
Product Yieldb (%) drc
Eed (%)
1e
2
CH3
CH3
CH3 1a
CH3 1a
CH3 1a
CH3 1a
CH3 1a
CH3 1a
CH3 1a
CH3 1a
CH3 1a
CH3 1a
CH3 1a
C6H5 2a
4-CH3C6H4 2b 3b
4-CH3OC6H4 2c 3c
4-FC6H4 2d
4-ClC6H4 2e
3-FC6H4 2f
3-NO2C6H4 2g 3g
3-OHC6H4 2h 3h
3a
98
94
82
94
93
97
92
98
97
94
98
55
98
85
d
d
d
d
d
d
d
d
d
d
d
d
99
99
99
99
99
99
99
95
99
99
99
98
3
4
5
6
7
8
9
10
11
12
13
14
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
3d
3e
3f
2-FC6H4 2i
CH3 2j
Bn 2k
3i
3j
3k
3l
eCH2(CH2)3CH2e 1b C6H5 2a
H
Bn
CH3 1c
CH3 1d
C6H5 2a
C6H5 2a
3m
3n
1:1.3 96/97
1:1 93/94
a
Unless otherwise specified, all reactions were carried out with aldehyde
(0.60 mmol), maleimide (0.30 mmol), and the catalyst II (5 mol %) in CH2Cl2 (0.5 mL)
at rt for 6 h.
b
Isolated yields.
Determined by HPLC.
Determined by chiral HPLC analysis.
Reaction was carried out with N-phenylmaleimide in 0.2 mmol.
c
d
e

8930
J.-F. Bai et al. / Tetrahedron 66 (2010) 8928e8932
enantioselectivity (98% ee, Table 3, entry 12). Additionally, propanal
and 2-methyl-3-phenylpropanal were also investigated, and affor-
ded excellent enantioselectivities and low diastereoselectivities
(Table 3, entries 13 and 14).
Enantiomeric excess: 99%, determined by chiral HPLC analysis
(Chiralpak OD-H column, hexane/2-propanol¼75/25, 0.9 mL/min,
210 nm), tR (minor)¼17.4 min, tR (major)¼21.3 min.
Based on the configuration of 3a, a plausible transition state
model was proposed. As outlined in Scheme 2, isobutyraldehyde
(1a) and N-phenylmaleimide (2a) would be activated by primary
amine and thiourea simultaneously. Then Michael addition could
take place from re-face of 1a, give the adduct 3a with (R)-
configuration.
4.2.2. 2-(2,5-Dioxo-1-p-tolylpyrrolidin-3-yl)-2-methylpropanal
(3b). The product was obtained in 94% yield, white bright solid.
20
[a
]
þ6.2 (c 0.9, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.50 (s, 1H),
D
7.25 (d, J¼7.95 Hz, 2H), 7.13 (d, J¼8.13 Hz, 2H), 3.12 (dd, J¼5.4,
9.4 Hz, 1H), 2.93 (dd, J¼9.51, 18.22 Hz, 1H), 2.57 (dd, J¼5.37, 18.2 Hz,
1H), 2.36 (s, 3H), 1.28 (s, 3H), 1.25 (s, 3H). 13C NMR (CDCl3, 75 MHz)
d
202.7, 176.9, 174.8, 138.7, 129.7, 129.1, 126.2, 48.3, 44.9, 31.6, 21.1,
F3C
20.15, 19.3; HRMS (ESI) calcd for C15H17NNaO3(MþNa) 282.1101,
found 282.1103. Enantiomeric excess: 99%, determined by chiral
HPLC analysis (Chiralpak OD-H column, hexane/2-propanol¼75/25,
0.9 mL/min, 210 nm), tR (minor)¼18.2 min, tR (major)¼21.1 min.
O
S
O
N
H
N
H
N
Ph
R
F3C
NH
H
O
O
3a
4.2.3. 2-(1-(4-Methoxyphenyl)-2,5-dioxopyrrolidin-3-yl)-2-methyl-
N
Ph
propanal (3c). The product was obtained in 82% yield, white bright
re-face attack
20
þ6.0 (c 0.8, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.50 (s,
O
solid. [
a
]
D
1H), 7.17 (d, J¼8.82 Hz, 2H), 6.95 (d, J¼8.82 Hz, 2H), 3.80 (s, 3H), 3.11
(dd, J¼5.4, 9.4 Hz, 1H), 2.93 (dd, J¼9.48, 18.24 Hz, 1H), 2.57 (dd,
J¼5.37,18.2 Hz,1H),1.30 (s, 3H),1.25 (s, 3H).13C NMR (CDCl3, 75 MHz)
Scheme 2. Transition state model of Michael addition.
3. Conclusion
d
202.7, 176.1, 174.99, 159.5, 127.7, 124.3, 114.4, 55.4, 48.4, 44.9, 31.7,
In conclusion, chiral primary amine thiourea catalysts were suc-
cessfully applied to promote Michael addition of isobutyraldehyde
to maleimides. It provided Michael adducts in excellent yields (up to
98%) and enantioselectivities (up to 99% ee) with 5 mol % catalyst
loading merely.
20.2, 19.4; HRMS (ESI) calcd for C15H17NNaO4 (MþNa) 298.1050,
found 298.1059. Enantiomeric excess: 99%, determined by chiral
HPLC analysis (Chiralpak AS-H column, hexane/2-propanol¼80/20,
1 mL/min, 210 nm), tR (minor)¼53.4 min, tR (major)¼58.7 min.
4.2.4. 2-(1-(4-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methyl-
4. Experimental
4.1. General
propanal (3d). The product was obtained in 94% yield, white bright
solid. [
a
]
20 þ2.1 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.48(s, 1H),
D
7.25 (m, 2H), 7.15(m, 2H), 3.09 (dd, J¼5.49, 9.49 Hz,1H), 2.93 (dd, J¼9.51,
18.2 Hz, 1H), 2.58 (dd, J¼5.46, 18.2 Hz, 1H), 1.32 (s, 3H), 1.25 (s, 3H). 13C
All reagents were obtained from commercial supplier without
further purification. Commercial grade solvent was dried and puri-
fied by standard procedures as specified in Purification of Laboratory
Chemicals, 4th ed.13 NMR spectra were recorded with tetrame-
thylsilane as the internal standard. 1H NMR spectra were recorded at
300 MHz, and 13C NMR spectra were recorded at 75 MHz (Bruker
NMR (CDCl3, 75 MHz)d 202.7,176.8,174.6,162.1,128.3,127.6,116.1, 48.5,
44.8, 31.6, 20.4, 19.6; HRMS (ESI) calcd for C14H14FNNaO3 (MþNa)
286.0850, found 286.0853. Enantiomeric excess: 99%, determined by
chiral HPLC analysis (Chiralpak OD-H column, hexane/2-propanol¼75/
25, 0.9 mL/min, 210 nm), tR (minor)¼17.0 min, tR (major)¼29.8 min.
Avance). Chemical shifts (d) are reported in parts per million down-
4.2.5. 2-(1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methyl-
field from CDCl3 (
d
¼7.26 ppm) for 1H NMR and relative to the central
propanal (3e). The product was obtained in 93% yield, white bright
¼77.0 ppm) for 13C NMR spectroscopy. Flash col-
solid. [
a
]
20 þ3.0 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.46 (s,
CDCl3 resonance (
d
D
umn chromatography was carried out using silica gel eluting with
ethyl acetate and petroleum ether. Reactions were monitored by TLC
and visualized with ultraviolet light. Enantiomeric excess was de-
termined by HPLC analysis on Chiralpak OD-H, AD-H, AS-H.
1H), 7.42 (d, J¼8.67 Hz, 2H), 7.23 (d, J¼8.7 Hz, 2H), 3.08 (dd, J¼5.52,
9.48 Hz, 1H), 2.92 (dd, J¼9.51, 18.18 Hz, 1H), 2.57 (dd, J¼5.49,
18.18 Hz, 1H), 1.31 (s, 3H), 1.24 (s, 3H). 13C NMR (CDCl3, 75 MHz)
d
202.7, 176.6, 174.4, 134.3, 130.3, 129.2, 127.7, 48.5, 44.8, 31.8, 20.4,
19.6; HRMS (ESI) calcd for C14H14ClNNaO3 (MþNa) 302.0554, found
302.0560. Enantiomeric excess: 99%, determined by chiral HPLC
analysis (Chiralpak OD-H column, hexane/2-propanol¼75/25,
0.9 mL/min, 210 nm), tR (minor)¼17.2 min, tR (major)¼29.7 min.
4.2. Representative experimental procedure for Michael
addition
In a typical experiment, isobutyraldehyde (0.60 mmol, 2 equiv),
maleimides (0.30 mmol, 1 equiv), and the catalyst (0.015 mmol,
0.05 equiv) in CH2Cl2 (0.5 mL) were magnetically stirred at room
temperature for 6 h (monitored by TLC). The corresponding prod-
uct was obtained after column chromatography (silica gel, eluent
PE/EtOAc¼4/1). All products were identified by spectroscopic data
(1H, 13C NMR and HRMS).
4.2.6. 2-(1-(3-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methyl-
propanal (3f). The product was obtained in 97% yield, white bright
solid. [
a
]
20 þ5.2 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.46 (s,
D
1H), 7.41 (m, 1H), 7.06 (m, 3H), 3.08 (dd, J¼5.52, 9.49 Hz, 1H), 2.93
(dd, J¼9.54, 18.2 Hz, 1H), 2.57 (dd, J¼5.52, 18.22 Hz, 1H), 1.31 (s, 3H),
1.24 (s, 3H). 13C NMR (CDCl3, 75 MHz)
d 202.7, 176.5, 174.3, 162.5,
133.0, 130.2, 122.1, 115.6, 114.0, 48.5, 44.8, 31.7, 20.3, 19.6; HRMS
(ESI) calcd for C14H14FNNaO3 (MþNa) 286.0850, found 286.0858.
Enantiomeric excess: 99%, determined by chiral HPLC analysis
(Chiralpak OD-H column, hexane/2-propanol¼75/25, 0.9 mL/min,
210 nm), tR (minor)¼14.1 min, tR (major)¼17.3 min.
4.2.1. 2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methyl-propionalde-
hyde (3a). The product was obtained in 98% yield, white bright
solid. [
a
]
20 þ4.1 (c 0.7, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.50 (s,
D
1H), 7.40 (m, 3H), 7.27 (d, J¼7.2 Hz, 2H), 3.14(dd, J¼5.5, 9.4 Hz, 1H),
2.95 (dd, J¼9.5, 18.2 Hz, 1H), 2.60 (dd, J¼5.4, 18.2 Hz, 1H), 1.31
(s, 3H), 1.26 (s, 3H). 13C NMR (CDCl3, 75 MHz)
d
202.6, 176.8, 174.7,
4.2.7. 2-Methyl-2-(1-(3-nitrophenyl)-2,5-dioxopyrrolidin-3-yl)
131.8, 129.1, 128.6, 126.5, 48.4, 44.9, 31.7, 20.2, 19.5; HRMS (ESI)
calcd for C14H15NNaO3 (MþNa) 268.0944, found 268.0948.
propanal (3g). The product was obtained in 92% yield, white bright
solid. [
a
]
20 ꢀ2.7 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.45 (s,
D

J.-F. Bai et al. / Tetrahedron 66 (2010) 8928e8932
8931
1H), 8.2 (m, 2H), 7.63 (m, 2H), 3.12 (dd, J¼5.58, 9.45 Hz, 1H), 2.99
(dd, J¼9.54, 18.14 Hz, 1H), 2.57 (dd, J¼5.46, 16.8 Hz, 1H), 1.36 (s, 3H),
propanol¼75/25, 0.9 mL/min, 210 nm), tR (minor)¼19.4 min, tR
(major)¼24.5 min.
1.27 (s, 3H). 13C NMR (CDCl3, 75 MHz)
d 202.6, 176.3, 173.9, 148.5,
132.9, 132.4, 129.8, 123.2, 121.8, 48.9, 44.9, 32.0, 20.7, 20.2; HRMS
(ESI) calcd for C14H14N2NaO5 313.0913, found 313.0915. Enantio-
meric excess: 99%, determined by chiral HPLC analysis (Chiralpak
OD-H column, hexane/2-propanol¼75/25, 0.9 mL/min, 210 nm), tR
(minor)¼26.7 min, tR (major)¼32.1 min.
4.2.13. 2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-propionaldehyde
(3m)8. The product was obtained in 98% yield, white bright solid.1H
NMR (CDCl3, 300 MHz) d 9.72 (s, 1H), 7.50e7.24 (m, 5H), 3.44e3.36
(m,1H), 3.18 (dd, J¼7.6, 3.6 Hz,1H), 3.03 (dd, J¼18.4, 9.6 Hz,1H), 2.52
(dd, J¼18.4, 5.2 Hz, 1H), 1.33 (d, J¼7.6 Hz, 3H); The ee of the product
was determined by chiral HPLC analysis (Chiralpak AD-H
column, hexane/2-propanol¼80/20, 0.8 mL/min, 210 nm), major
diastereomer: tR (minor)¼14.91 min, tR (major)¼23.5 min; minor
diastereomer: tR (minor)¼16.45 min, tR (major)¼18.64 min.
4.2.8. 2-(1-(3-Hydroxyphenyl)-2,5-dioxopyrrolidin-3-yl)-2-methyl-
propanal (3h). The product was obtained in 98% yield, white bright
solid. [
a
]
20 þ2.6 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.49 (s,
D
1H), 7.29 (m, 1H), 6.81 (m, 3H), 3.12 (m, 1H), 2.95 (m, 1H), 2.60 (dd,
J¼5.4, 18.23 Hz, 1H), 1.33 (s, 3H), 1.27 (s, 3H). 13C NMR (CDCl3,
4.2.14. 2-(2, 5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methyl-3-phenyl-
75 MHz)
d
202.7, 176.6, 174.6, 157.6, 132.4, 129.5, 117.2, 115.9, 113.8,
propanal (3n). The product was obtained in 85% yield, white bright
48.1, 44.7, 31.3, 20.1, 18.8; HRMS (ESI) calcd for C14H15NNaO4
(MþNa) 284.0893, found 284.0899. Enantiomeric excess: 95%, de-
termined by chiral HPLC analysis (Chiralpak AS-H column, hexane/
2-propanol¼80/20, 1 mL/min, 210 nm), tR (minor)¼47.5 min, tR
(major)¼82.5 min.
solid. 1H NMR (30 MHz, CHCl3):
d
9.61(s, 1H), 7.50e7.21 (m, 10H),
3.34 (t, 1H), 3.14 (m, 1H,), 3.07(m, 2H), 2.66 (dd, J¼4.8 Hz, 17.6 Hz,
1H), 1.23 (s, 3H). 13C NMR (CDCl3, 75 MHz)
201.2, 178.0, 175.0,
d
136.7, 132.1e126.5 (ArC), 53.5, 38.5, 32.7, 31.2, 29.6; HRMS (ESI)
calcd for C20H19NNaO3 (MþNa) 344.1367, found 344.1360. The ee of
the product was determined by chiral HPLC analysis (Chiralpak
AD-H column, hexane/2-propanol¼80/20, 0.8 mL/min, 210 nm),
major diastereomer: tR (minor)¼13.9 min, tR (major)¼19.82 min;
minor diastereomer: tR (minor)¼18.85 min, tR (major)¼24.4 min.
4.2.9. 2-(1-(2-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methyl-
propanal (3i). The product was obtained in 97% yield, white bright
solid. [
a
]
20 þ4.2 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.49 (s,
D
1H), 7.40 (m, 1H), 7.24 (m, 3H), 3.18 (m, 1H), 2.98 (dd, J¼9.51,
18.36 Hz, 1H), 2.62 (dd, J¼4.44, 18.26 Hz, 1H), 1.33 (s, 3H), 1.26 (s,
Acknowledgements
3H). 13C NMR (CDCl3, 75 MHz)
d 202.6, 173.9, 158.9, 155.6, 130.9,
129.2, 124.6, 116.5, 45.1, 31.7, 20.4, 19.8, 19.3, 18.8; HRMS (ESI) calcd
for C14H14FNNaO3 (MþNa) 286.0850, found 286.0863. Enantio-
meric excess: 99%, determined by chiral HPLC analysis (Chiralpak
OD-H column, hexane/2-propanol¼75/25, 0.9 mL/min, 210 nm), tR
(minor)¼17.5 min, tR (major)¼23.1 min.
We are grateful for the financial support from National Natural
Science Foundation of China (20802075) and the Chinese Academy
of Sciences.
Supplementary data
4.2.10. 2-Methyl-2-(1-methyl-2,5-dioxopyrrolidin-3-yl)
propanal
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.09.044. These data
include MOL files and InChIKeys of the most important compounds
described in this article.
20
(3j). The product was obtained in 94% yield, colorless oil. [a]
D
ꢀ11.7 (c 0.8, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 9.46 (s, 1H), 3.00
(dd, J¼5.43, 9.24 Hz, 1H), 2.93 (s, 3H), 2.77 (dd, J¼9.3, 18.2 Hz, 1H),
2.40 (dd, J¼5.34, 18.2 Hz, 1H), 1.17 (s, 3H), 1.15 (s, 3H). 13C NMR
(CDCl3, 75 MHz) d 202.9, 177.7,175.8, 49.8, 44.9, 31.3, 24.7,19.9,18.9;
References and notes
HRMS (ESI) calcd for C9H13NNaO3 (MþNa) 206.0788, found
206.0789. Enantiomeric excess: 99%, determined by chiral HPLC
analysis (Chiralpak AS-H column, hexane/2-propanol¼80/20, 1 mL/
min, 210 nm), tR (major)¼16.5 min, tR (minor)¼19.8 min.
1. For recent reviews of asymmetric Michael addition reactions, see: (a) Krause,
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4.2.11. 2-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
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(3k). The product was obtained in 98% yield, white bright solid.
20
[
a]
ꢀ9.8 (c 1.2, CHCl3), 1H NMR (CDCl3, 300 MHz)
d 9.46 (s, 1H),
D
7.28 (m, 5H), 4.61 (dd, J¼14.1, 17.9 Hz, 2H), 3.00 (dd, J¼5.41, 9.30 Hz,
1H), 2.78 (dd, J¼9.35, 18.2 Hz, 1H), 2.42 (dd, J¼5.37, 18.25 Hz, 1H),
1.14 (s, 3H), 1.13 (s, 3H). 13C NMR (CDCl3, 75 MHz)
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tiomeric excess: 99%, determined by chiral HPLC analysis (Chiralpak
AD-H column, hexane/2-propanol¼80/20, 1 mL/min, 220 nm), tR
(minor)¼8.2 min, tR (major)¼17.5 min.
4 . 2 .12 . 1 - ( 2 , 5 - D i o x o - 1 - p h e nyl p y r r o l i d i n - 3 - yl ) c yc l o -
hexanecarbaldehyde (3l). The product was obtained in 55% yield,
20
white bright solid. [
300 MHz)
a]
þ4.5 (c 0.5, CHCl3). 1H NMR (CDCl3,
D
d
9.53 (s, 1H), 7.45 (m, 3H), 7.27 (m, 2H), 3.20 (dd,
J¼5.97, 9.26 Hz, 1H), 2.83 (m, 1H), 2.66 (dd, J¼5.94, 18.15 Hz, 1H),
1.94 (m, 3H), 1.60 (m, 7H). 13C NMR (CDCl3, 75 MHz)
d
204.5,
177.0, 174.7, 131.9, 129.1, 128.6, 126.6, 52.2, 42.7, 31.5, 28.6, 28.0,
25.1, 21.3, 21.2; HRMS (ESI) calcd for C17H19NNaO3 (MþNa)
308.1257, found 308.1260. Enantiomeric excess: 98%, determined
by chiral HPLC analysis (Chiralpak OD-H column, hexane/2-

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