Thiourea-catalyzed asymmetric michael addition of activated methylene compounds to α,β-unsaturated imides: Dual activation of imide by intra- and intermolecular hydrogen bonding

Article abstract of DOI:10.1021/ja061364f

A thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to α,β-unsaturated imides derived from 2-pyrrolidinone and 2-methoxybenzamide has been developed. In the case of 2-pyrrolidinone derivatives, the reaction with malononitrile

Full text of DOI:10.1021/ja061364f

Published on Web 06/28/2006
Thiourea-Catalyzed Asymmetric Michael Addition of Activated
Methylene Compounds to r,â-Unsaturated Imides: Dual
Activation of Imide by Intra- and Intermolecular Hydrogen
Bonding
Tsubasa Inokuma, Yasutaka Hoashi, and Yoshiji Takemoto*
Contribution from the Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida,
Sakyo-ku, Kyoto 606-8501, Japan
Received February 27, 2006; E-mail: takemoto@pharm.kyoto-u.ac.jp
Abstract: A thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to R,â-
unsaturated imides derived from 2-pyrrolidinone and 2-methoxybenzamide has been developed. In the
case of 2-pyrrolidinone derivatives, the reaction with malononitrile proceeded in toluene with high
enantioselectivity, providing the Michael adducts in good yields. However, the nucleophiles that could be
used for this reaction were limited to malononitrile due to poor reactivity of the substrate. Further examination
revealed that N-alkenoyl-2-methoxybenzamide was the best substrate among the corresponding benzamide
derivatives bearing different substituents on the aromatic ring. Indeed, several activated methylene
compounds such as malononitrile, methyl R-cyanoacetate, and nitromethane could be employed as a
nucleophile to give the Michael adducts in good to excellent yields with up to 93% ee. The results of
spectroscopic experiments clarified that this enhanced reactivity can be attributed to the intramolecular
hydrogen-bonding interaction between the N-H of the imide and the methoxy group of the benzamide
moiety. Thus, the key to the success of the catalytic enantioselective Michael addition is dual activation of
the substrate by both intramolecular hydrogen bonding in the imide and intermolecular hydrogen bonding
with thiourea 1a, as well as the activation of a nucleophile by the tertiary amine of the bifunctional thiourea.
Introduction
asymmetric Michael additions of aldehydes, ketones, and 1,3-
dicarbonyl compounds attract considerable attention due to their
The catalytic asymmetric formation of a carbon-carbon bond
is one of the most challenging fields in organic chemistry. From
the viewpoint of the availability of substrates and the versatility
of enantiomerically enriched addition products, asymmetric
Michael addition of enolate equivalents to R,â-unsaturated
carbonyl acceptors has been extensively studied.1 Considerable
effort has been directed to the development of Lewis acid-
promoted addition of enol silyl ethers to R,â-unsaturated
carbonyl compounds (Mukaiyama-Michael reaction) through
the use of various types of chiral ligands.2,3 Direct catalytic
simple manipulation and high atom economy, and successful
results have recently been reported by several groups.4-7
However, the acceptors used in these Michael additions of 1,3-
dicarbonyl compounds generally have been limited to enones4-6
and nitroalkenes.7 Similarly, although organocatalysts possessing
chiral secondary amines8 or thioureas9 have been shown to be
efficient catalysts for the Michael reaction with such acceptors,
there have been no reports on their application to R,â-
unsaturated acid derivatives. Therefore, the development of
general and highly enantioselective versions with R,â-unsatur-
ated acid derivatives still remains a challenging goal. Two
(1) For recent reviews, see: (a) Tomioka, K.; Nagaoka, Y. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 3, Charpter 31.1. (b) Kanai, M.; Shibasaki,
M. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New
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56, 8033. (d) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (e)
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Chem., Int. Ed. 2003, 42, 1688. (h) Fagnou, K.; Lautens, M. Chem. ReV.
2003, 103, 169.
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Tedrow, J. J. Am. Chem. Soc. 2000, 122, 9134. (d) Evans, D. A.; Scheidt,
K. A.; Johnston, N.; Willis, M. J. Am. Chem. Soc. 2001, 123, 4480.
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Corey, E. J. Org. Lett. 2001, 3, 639. (b) Brown, S. P.; Goodwin, N. C.;
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Shibasaki, M. Tetrahedron Lett. 2002, 43, 4661. (l) DiMauro, E. F.;
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9
10.1021/ja061364f CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 9413-9419
9413

A R T I C L E S
Inokuma et al.
groups independently achieved initial breakthroughs on these
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methylpyrazole with several nucleophiles such as nitromethane
and cyclohexadione derivative.10 Jacobsen also reported that the
Salen-Al complex-catalyzed Michael addition of malononitrile
and 2-substituted cyanoacetates to R,â-unsaturated imides
Figure 1. Hydrogen-bond interaction with thiourea 1a.
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proceeded with high enantioselectivity.11 Quite recently, Evans
developed the Ni(II)-catalyzed conjugate reaction of â-keto
esters with unsaturated N-acyl-1,3-thiazolidine-2-thiones.12 How-
ever, because there have been no reports concerning the
asymmetric reaction without a metallic catalyst, we investigated
the thiourea-catalyzed asymmetric Michael reaction of 1,3-
dicarbonyl compounds to R,â-unsaturated carboxylic acid
derivatives based on our previous results with nitroolefins.9a,b
We expected that an imide moiety could be activated by
bifunctional thiourea 1a13,14 through a hydrogen-bonding inter-
action15,16 in a manner similar to that of the nitro group (Figure
1). A similar concept was successfully applied by Schreiner to
the thiourea-catalyzed Diels-Alder reaction of chiral N-alk-
enoly-1,3-oxazolidinone with cyclopentadiene.15c In practice, we
developed the first organocatalyst-mediated enantioselective
Michael reactions of malononitrile to N-alkenoyl-2-pyrrol-
idinone.13b Further examination of this reaction revealed that
N-alkenoyl-2-methoxybenzamide was a more reactive substrate
than N-alkenoylpyrrolidinone and the corresponding benzamide
derivatives, and several activated methylene compounds such
as malononitrile, methyl R-cyanoacetate, and nitromethane could
(12) Evans, D. A.; Thomson, R. J.; Franco, F. J. Am. Chem. Soc. 2005, 127,
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P.; Takemoto, Y. Synlett 2006, 137.
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4901. (b) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int.
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9414 J. AM. CHEM. SOC. VOL. 128, NO. 29, 2006

Addition of Methylene Compounds to
R
,
â
-Unsaturated Imides
A R T I C L E S
Table 1. Enantioselective Michael Addition of Malonotrile 2a with
R,â-Unsaturated Acid Derivatives 3A-Ga
Table 2. Reaction of R,â-Unsaturated Imide 3D in Various
Solventa
concentration
(M)
1a
time
(h)
yield
(%)b
ee
(%)c
entry
solvent
(mol %)
1
2
3
4
5
6
7
8
MeOH
THF
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
10
10
10
10
10
5
72
120
120
72
22
57
58
77
93
94
50
92
7
62
44
81
87
88
86
93
CH3CN
CH2Cl2
toluene
toluene
toluene
toluene
60
120
168
168
1
10
a The reaction was conducted with 1a, 2a (2 equiv), and 3D. b Isolated
yield. c Enantiomeric excess was determined by HPLC analysis of 4D using
a chiral column.
zolidinone 3C, which possesses a cyclic urea moiety, as a
Michael acceptor, but both the chemical yield and the enanti-
oselectivity decreased to afford the adduct 4C in 59% yield with
81% ee (entry 3). In contrast, with 3C, N-acylpyrrolidinone 3D
exhibited good reactivity to 2a, providing the corresponding
product 4D in 93% yield with the best enantioselectivity (87%
ee) (entry 4).
The use of N-acylpiperidinone 3E and acyclic imide 3G for
the Michael addition reaction resulted in a significant decrease
in both chemical yield and enantioselectivity (entries 5 and 7).
In contrast to the results with 3D, the reaction of 2a with
N-acylpyrrolidine-2,5-dione 3F under the same conditions did
not occur at all, leading to recovery of the starting material (entry
6). With a good Michael acceptor, N-acylpyrrolidinone 3D, we
examined the optimal reaction conditions for the Michael
addition (Table 2). The use of a polar solvent such as methanol
and acetonitrile significantly lowered the stereoselectivity.
Among the solvents examined, toluene was the best solvent in
terms of chemical yield and enantioselectivity (entries 1-5).
The amount of the catalyst 1a could be reduced to 1 mol %
without affecting the enantioselectivity, but the chemical yield
of the product was reduced (entries 6 and 7). Although the best
enantioselectivity (93% ee) was obtained in a 0.1 M solution
of the substrate, the reaction required a prolonged reaction time
(7 d) (entry 8).
To overcome this problem, we reexamined the N-acylben-
zamide derivatives 5A-D and 7A, which are considered to be
potential Michael acceptors for Lewis acid-catalyzed Michael
reactions17 (Table 3). All reactions were carried out in a 0.1 M
solution of the substrate with 2 equiv of 2a and 10 mol % of
1a. As expected, the reaction of 2a with 5A proceeded smoothly
and was complete within 26 h, giving the corresponding adduct
6A in 84% yield with 88% ee (entry 1). When the more electron-
deficient substrate 5B, bearing a 3,5-bis(trifluoromethyl)phenyl
group, was subjected to the same reaction conditions, a miserable
result was obtained in terms of chemical yield due to the poor
solubility of 5B in the reaction solvent (entry 2). Surprisingly,
the electron-rich substrate 7A exhibited high reactivity in the
a The reaction was conducted with 1a (10 mol %), 2a (2 equiv), and
3A-G in toluene (0.5 M solution). b Isolated yield. c Enantiomeric excess
was determined by HPLC analysis of 4A-G using a chiral column.
be used as a nucleophile to give the Michael adducts with up
to 93% ee. We report here the details of the organocatalytic
enantioselective Michael reactions of different nucleophiles with
various R,â-unsaturated imides as well as a mechanistic
investigation of Michael addition.
Results and Discussion
Investigation of the Reaction Conditions for the Thiourea-
Catalyzed Asymmetric Michael Reaction of Malononitrile.
Although we reported that the bifunctional thiourea-catalyzed
Michael reaction of 1,3-dicarbonyl compounds such as methyl
malonate and â-keto esters with nitroalkenes proceeded with
high enantioselectivity of up to 93% ee,9a,b the same reaction
with R,â-unsaturated acid derivatives gave no addition products.
To extend the synthetic utility of bifunctional thiourea 1a in
the asymmetric reaction, we then undertook screening of proper
Michael acceptors other than nitroalkenes by using malononitrile
as a reactive nucleophile. For this purpose, R,â-unsaturated
imides seem to have an ideal structure to form hydrogen bonds
with the thiourea catalyst 1a as shown in Figure 1.15
We first investigated the Michael addition of malononitrile
2a to several types of R,â-unsaturated acid derivatives 3A-G
(Table 1). The reaction of 2a (2 equiv) with 3A-G (a 0.5 M
toluene solution) was carried out at room temperature in the
presence of 10 mol % of 1a. Although the conjugate addition
of 2a with amide 3A gave no desired product, the same reaction
with N-acyl-1,3-oxazolidinone 3B15c was complete after 96 h,
giving the Michael adduct 4B in 89% yield (entries 1 and 2).
The enantioselectivity of 4B was revealed to be 83% ee by
HPLC analysis. We expected to enhance the hydrogen-bonding
interaction with thiourea 1a, and thus used N-acyl-1,3-imida-
(17) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959. (b)
Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442. (c)
Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem.
Soc. 2003, 125, 11796. (d) Vanderwal, C. D.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 14724.
9
J. AM. CHEM. SOC. VOL. 128, NO. 29, 2006 9415

A R T I C L E S
Inokuma et al.
Table 3. Thiourea-Catalyzed Michael Addition of 2a with
N-Cinnamoylbenzamide Derivatives 5A-D and 7Aa
Table 4. Thiourea-Catalyzed Michael Addition of 2a-c with
Various R,â-Unsaturated Imides 7A-Ea
temp
C)
time
(h)
yield
(%)b
ee
(%)c
entry
7
2
(
°
product
1
2
3
4
5
6
7
8
9
7B
7C
7D
7E
7A
7B
7D
7E
7A
7B
7D
7E
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
rt
rt
rt
rt
80
80
rt
7
24
3
5
52
8B
8C
8D
8E
9A
9B
9D
9E
10A
10B
10D
10E
99
92
96
95
92
90
90
93
94d
91d
90d
96d
56
82e
85e
92e
92e
87
48
87
rt
137
168
168
135
256
60
60
rt
10
11
12
60
91
82
86
83
80
rt
a The reaction was conducted with 1a, 2a-c (2-40 equiv), and 7A-E.
b Isolated yield. c Enantiomeric excess (ee) was determined by HPLC
analysis of 8-10 using a chiral column. d Product was obtained as a mixture
of two diastereoisomers. e The ee values were estimated from ee of the
decarboxylated nitrile.
a The reaction was conducted with 1a (10 mol %), 2a (2 equiv), and
5A-D, 7A in toluene (0.1 M solution). b Isolated yield. c Enantiomeric
excess was determined by HPLC analysis of 6A-D and 8A using a chiral
column.
4). In contrast to the Michael addition with N-acylpyrrolidinone
3D mentioned above,13b the present reaction with 2-methoxy-
benzimides 7A-E occurred smoothly to afford the desired
products 8A-E within 3-24 h. Encouraged by this result, we
next investigated the Michael addition of other nucleophiles,
such as methyl R-cyanoacetate 2b, but the reaction was sluggish
even with 7A. After many experiments, the desired Michael
adducts 9A and 9B were obtained in good yield by simply
heating the reaction mixture at 80 °C (entries 5, 6). It is
noteworthy that the enantioselectivity of the products 9A,B
remained fairly high (82-85% ee) even at high temperature.
In contrast to the aromatic imides 7A,B, the reaction of aliphatic
imides 7D and 7E with 2b occurred even at room temperature,
providing 9D and 9E with somewhat higher enantioselectivity
(92% ee) (entries 7, 8). Furthermore, it was revealed that
nitromethane 2c could be used as a nucleophile for the Michael
addition with imides 7, whereas the reaction took place slowly
even at 60 °C. The corresponding Michael adducts 10A,B and
10D,E were produced in moderate to good yields with up to
87% ee (entries 9-12). Consequently, we succeeded in the first
organocatalyzed enantioselective Michael addition of methyl
R-cyanoacetate 2b and nitromethane 2c with 2-methoxybenz-
imides 7A,B and 7D,E by using bifunctional thiourea 1a.
The absolute configurations of the Michael adducts 8B, 9B,
and 10A were determined by their transformation to known
compounds 11,11a 12,11a and 1318 (Scheme 1). Treatment of 8B
with a catalytic amount of Er(OTf)3 in methanol provided the
corresponding methyl ester 11 ([R]24D ) +17: c 1.2, CH3CN)
in 96% yield. In the case of 9B, the obtained product 9B was
converted into nitrile 12 in two steps according to the reported
Michael addition; the reaction was complete after only 14 h,
and the desired product 8A was obtained in 95% yield with
91% ee (entry 3). In contrast to this result, the reaction of 2,6-
dimethoxybenzimide 5C led to significant decreases in both the
reaction rate and the enantioselectivity (entry 4). By comparing
the result of 2-methylbenzimide 5D with that of 7A, the
2-methoxy group was proved to play an important role for the
acceleration of the conjugate reaction. We assumed that the
intramolecular hydrogen bonding between NH and OMe groups
of 7A enhanced the electrophilicity of the N-alkenoyl moiety
of the imide 7A due to the decrease of electron density of the
nitrogen atom as well as coplanar orientation of the 2-meth-
oxybenzamide moiety (entries 3 and 5). These results demon-
strated that the 2-methoxybenzimide 7A was the best choice
for a substrate in all respects.
Scope and Limitation of the Thiourea-Catalyzed Asym-
metric Michael Reaction with 2-Methoxybenzimides. Having
established the optimal reaction conditions for the enantiose-
lective Michael reaction of malononitrile 2a, we next screened
a series of substrates 7A-E bearing various â-substituents and
nucleophiles 2a-c. As illustrated in Table 4, 2-methoxybenz-
imides 7B-E underwent conjugate addition of malononitrile
2a in the presence of catalyst 1a in high yield and ee, and these
results were almost independent of steric hindrance and the
electronic properties of the â-substituents. The reactions with
aryl-substituted imides 7B and 7C proceeded with high enan-
tioselectivity to furnish the addition adducts 8B and 8C, while
the rate of the reaction was somewhat decreased for 7C (R )
p-methoxyphenyl) due to the electron-rich substrate (entries 1,
2). Similarly, imides 7D and 7E bearing alkyl groups as the
â-substituent underwent a clean reaction as well, giving the
corresponding adducts 8D and 8E with 90-93% ee (entries 3,
procedure11a ([R]25 ) +7: c 1.1, CH3CN). Based on a
D
comparison of their specific rotations with those of authentic
(18) Felluga, F.; Gombac, V.; Pitaco, G.; Valentin, E. Tetrahedron: Asymmetry
2005, 16, 383.
9
9416 J. AM. CHEM. SOC. VOL. 128, NO. 29, 2006

Addition of Methylene Compounds to
R
,
â
-Unsaturated Imides
A R T I C L E S
Scheme 1. Transformation of Michael Adducts to Methyl Esters
11-13
Figure 2. 1H NMR of a 1:1 mixture of 1a and 7A in toluene-d8 (0.02 M)
(the values in parentheses are chemical shifts of 7A without 1a).
was supported by 1H NMR spectroscopic experiments, as shown
in Figure 2.19 The chemical shift of the imide N-H of 7A was
gradually shifted downfield with an increase in the ratio of 1a
to 7A. When 1a was mixed with 7A (1a/7A ) 1/1), the chemical
shift of N-H was shifted from 10.22 to 10.24 ppm. In contrast,
the chemical shifts of HR and Hâ of 7A were gradually shifted
upfield with an increase in the amount of 1a. This implies that
the acidic protons (NH) of 1a interacted with two carbonyl
oxygens of the imide 7A, as shown in Figure 2.20
To obtain further information about the reaction mechanism,
we carried out kinetic studies on the Michael reaction. When
the reaction was carried out with a large excess of 2a, plotting
ln([7A]/[7A0]) versus time gave a straight line (R2 ) 0.9988,
A in Figure 3), which indicates that the reaction is first-order
with respect to 7A. Although the order with regard to nucleo-
phile 2a could not be determined due to the poor solubility of
the substrate 7A, when the order with regard to the catalyst
Table 5. 1H NMR and IR Experiments of Imides 5A, 7A, 5c, and
5D
imide
1H NMR (CDCl3, 0.015 M)
IR (CHCl3, 0.01 M)
5A
8.59 (NH)
7.86 (HR)
7.95 (Hâ)
10.30 (NH)
7.86 (HR)
7.91 (Hâ)
8.19 (NH)
7.75 (HR)
7.89 (Hâ)
8.21 (NH)
7.76 (HR)
7.94 (Hâ)
3405 (N-H)
1680 (CdO)
1619 (CdC)
3330 (N-H)
1671 (CdO)
1619 (CdC)
3393 (N-H)
1679 (CdO)
1620 (CdC)
3391 (N-H)
1680 (CdO)
1618 (CdC)
7A
5C
5D
was also examined by plotting the kinetic rate constant (kobs
)
against the loading of 1a (B in Figure 3), the reaction was shown
to be first-order with respect to 1a. In addition, Figure 3 shows
the relationship (Michaelis-Menten plot) between the substrate
concentration [S0] of 7A and reaction rate (VM/min) (C in
Figure 4). This result unambiguously indicates that equilibrium
between catalyst 1a (or a binary complex of 1a and malono-
nitrile 2a) and substrate 7A exists in the thiourea-catalyzed
samples (11, [R]25D ) +19, c 1.0, CH3CN; 12, [R]25D ) +11,
c 1.1, CH3CN),11a the absolute configurations of 8B and 9B
were determined to be R and S, respectively. The same treatment
of 10A as 8B afforded the corresponding methyl esters 13
([R]29 ) -13.3: c 0.20, CHCl3), whose configuration was
D
confirmed to be S by comparison of its specific rotation with
that of the authentic sample,18 and those of the other adducts
8A, 8C-E, 9A, and 10B were presumed on the basis of the
above results. Consequently, these results indicated that all
nucleophiles tend to attack the Michael acceptors from the same
side in the presence of 1a, regardless of the functional groups
of the nucleophiles.
Michael addition. Therefore, the reaction constants of KM, Vmax
,
and kcat were calculated from the Lineweaver-Burk plot (R2 )
0.9936, D in Figure 4): KM ) 0.300 M, Vmax ) 4.42 × 10-3
M/min, kcat ) 0.442 min-1, kcat/KM ) 1.47 (1/M‚min).
On the basis of these results, we propose a ternary complex
of catalyst 1a, malononitrile 2a, and imide 7 as a plausible
transition state (Figure 5). Successive interaction of malononitrile
2a and 2-methoxybenzimide 7 with catalyst 1a took place
through the deprotonation of 2a by the tertiary amine of 1a
and the coordination of 7 to the thiourea moiety of 1a, producing
ternary complex A, which is composed of 1a, 7, and the anion
of malononitrile 2a. Consequently, the activated nucleophile
attacks the imide 7 from the front of ternary complex A, giving
the (R)-adduct 8 predominantly. This proposed mechanism is
consistent with the experimental results described above.
1,2-Nucleophilic Addition of Hard Nucleophiles to the
Michael Adducts. To transform the obtained Michael adducts
into advanced compounds, a wide range of reactions have been
developed.10-12,17 However, these reactions have required a
catalytic amount of additional Lewis acids or a stoichiometric
Mechanistic Studies. To gain insight into the different
reactivity of the imides 7A and 5A-D, we performed experi-
1
ments using IR and H NMR spectroscopy. The results are
1
summarized in Table 5. Although almost all of the H NMR
signals such as the vinylic protons (HR and Hâ) of 5A, 5C,D,
and 7A possessed similar chemical shifts; the signal of the N-H
proton of 7A was observed downfield as compared to those of
5A and 5C,D. In addition, the stretching absorption of the N-H
bond in the IR spectrum of 7A (0.01 M) appeared at a slightly
lower wavenumber (3330 cm-1) than those of 5A and 5C,D
(3391-3405 cm-1). On the basis of these facts, we speculated
that intramolecular hydrogen bonding between the imide N-H
moiety and the methoxy group was formed in the case of 7A,
by which the R,â-unsaturated carbonyl moiety of 2-methoxy-
benzimide 7A would be more reactive as a Michael acceptor
than the other imides. To identify additional hydrogen bonding
between 2-methoxybenzimides 7 and thiourea 1a, we took the
1H NMR spectra of 7A in the presence of different amounts of
1a. In contrast to nitroolefins9a,b and N-Boc imines,13a,c the
formation of a substrate-catalyst complex 7A‚1a in toluene-d8
(19) A similar phenomenon was observed on the 1H NMR titration studies of
malononitrile 2a with thiourea 1a. The chemical shift of the methylene
protons of malononitrile 2a was shifted from 0.92 to 0.95 ppm by the
addition of 1.0 equiv of thiourea 1a in toluene-d8 (0.02 M).
(20) At this stage, it is not clear why the chemical shifts of HR and Hâ of 7A
shifted upfield with an increase of additional amounts of 1a. The same
upfield-shifts were observed in the 1H NMR spectra of 5A and 5C.
9
J. AM. CHEM. SOC. VOL. 128, NO. 29, 2006 9417

A R T I C L E S
Inokuma et al.
Figure 3. Kinetic studies on the Michael reaction of malonotrile 2a to imide 7A in the presence of 1a.
Figure 4. Michaelis-Menten and Lineweaver-Burk plots of the Michael reaction of 2a with 7A.
Table 6. Thiourea-Catalyzed Transformation of Imides 4D, 6A,
6C, and 8A into Various Carboxylic Acid Derivatives 14A-D
entry
substrate
reaction conditions
product
yielda
1
2
3
4
5b
6
7
8
4D
6A
6C
8A
8A
8A
8A
8A
MeOH (neat), 60 °C, 24 h
MeOH (neat), rt, 24 h
MeOH (neat), rt, 24 h
MeOH (neat), rt, 24 h
MeOH (neat), rt, 24 h
BnOH (neat), rt, 88 h
BnNH2 (2 equiv), rt, 3 h
MeNHOMe (3 equiv), 60 °C, 20 h
14A
14A
14A
14A
14A
14B
14C
14D
82
94
88
87
9
89
77
75
Figure 5. Plausible reaction mechanism of the Michael addition of imide
7 with malonotrile 2a in the presence of 1a.
amount of bases. From an atom-economical point of view, it
would be desirable to develop a new method for the subsequent
reaction, which does not demand additional catalyst. The
bifunctional thiourea catalyst 1a was designed on the basis of
a mechanism of hydrolytic enzymes such as serine protease.21
This means that the thiourea 1a might catalyze the transforma-
tion of the imides to other carboxylic acid derivatives.14j,m
Therefore, we next explored the one-pot transformation of 7
into carboxylic acid derivatives such as ester, amide, and
Weinreb amide by tandem Michael addition of soft nucleophile
and 1,2-nucleophilic addition of a hard nucleophile. Because
we have already developed the asymmetric Michael addition
of malononitrile 2a to imides 7, a key to the success of one-pot
transformation would be the second reaction of the Michael
adducts 8 with hard nucleophiles (Table 6). Therefore, we first
examined the reaction of several Michael adducts 4D, 6A, 6C,
and 8A with methanol as a hard nucleophile. The reaction was
a Isolated yield. b Without thiourea catalyst 1a.
carried out in methanol in the presence of 10 mol % 1a. In the
case of 4D, the reaction required heating at 60 °C to go to
completion and provided the methyl ester 14A in 82% yield
(entry 1). In contrast to this result, the same reaction of
benzimides 6A, 6C, and 8A proceeded at room temperature to
give the desired product 14A in good yields, respectively (entries
2-4). Distinct from the Michael addition of soft nucleophiles,
these benzimides exhibited almost the same reactivities to
methanol. However, the yield of 14A was low without thiourea
catalyst 1a, while the reaction occurred slowly (entry 5).
Similarly, benzyl alcohol could be employed as a nucleophile
for this transformation, affording the corresponding ester 14B
in 89% yield (entry 6). Although the amide 14C could be
obtained by treatment of 8A with benzylamine (2 equiv) in
toluene at room temperature, the reaction with N,O-dimethyl-
hydroxyamine required heating at 60 °C to furnish the desired
(21) Wharton, C. W. In ComprehensiVe Biological Catalysis; Sinnott, M., Ed.;
Academic Press: London, 1998; Vol. 1, pp 345-379.
9
9418 J. AM. CHEM. SOC. VOL. 128, NO. 29, 2006

Addition of Methylene Compounds to
R
,
â
-Unsaturated Imides
A R T I C L E S
Scheme 2. One-Pot Transformation of 7A into 14A, 14C, and
14D
acceptors in terms of reaction rate and stereoselectivity. Among
them, N-alkenoyl-2-methoxybenzamides 7 is the best Michael
acceptor. The high reactivity of 7 can be attributed to intramo-
lecular hydrogen bonding between the imide N-H moiety and
the methoxy group of the benzamide. The reaction can be
applied to a variety of R,â-unsaturated imides 7A-E bearing
aryl and alkyl groups as a â-substituent, with high enantiose-
lectivity. Furthermore, the Michael addition of other carbon-
nucleophiles such as methyl R-cyanoacetate 2b and nitromethane
2c with 7A-E also proceeds at elevated temperature, giving
the corresponding Michael adducts with good enantioselectivity.
Subsequent treatment of the obtained Michael adducts with hard
nucleophiles such as alcohol, amine, and N,O-dimethylhy-
droxyamine in the presence of thiourea 1a promotes the 1,2-
nucleophilic addition into imides to afford the corresponding
ester, amide, and Weinreb amide in good yield. Thus, different
soft and hard nucleophiles can be introduced to N-alkenoyl-2-
methoxybenzamides 7 in a highly regio- and enantioselective
manner by using a single chiral catalyst.
Weinreb amide 14D. Having established the optimal reaction
conditions for the 1,2-nucleophilic addition of hard nucleophiles,
we finally undertook the one-pot reaction of R,â-unsaturated
imide 7A with malononitrile 2a and methanol (Scheme 2). After
the Michael addition of 2a to 7A under the standard conditions,
methanol was added to the reaction mixture and the resulting
mixture was stirred at room temperature to provide the desired
methyl ester 14A in 85% yield. Similarly, the one-pot reactions
of 7A with BnNH2 and MeNHOMe proceeded efficiently, giving
the corresponding adducts 14C and 14D in good yields. In this
way, we succeeded in the tandem reaction of enantioselective
Michael addition of soft nucleophile and the 1,2-nucleophilic
addition of a hard nucleophile with a single chiral organocatalyst.
Acknowledgment. This work was supported by grants from
the 21st Century COE Program “Knowledge Information
Infrastructure for Genome Science”, Grant-in-Aid for Scientific
Research on Priority Areas (17035043) from MEXT, and JSPS
KAKENHI (16390006).
Conclusion
We successfully developed the first highly enantioselective
organocatalytic Michael addition of several soft nucleophiles
2a-c with R,â-unsaturated imides 4D and 7A-E using a
bifunctional thiourea 1a. Although the pyrrolidinone moiety of
R,â-unsaturated imides 4D is demonstrated to play a key role
in the Michael reaction of malononitrile 2a, the N-alkenoyl-
benzamide derivatives 5 and 7 are more promising Michael
Supporting Information Available: Experimental procedures
and characterization of the products and other detailed results.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA061364F
9
J. AM. CHEM. SOC. VOL. 128, NO. 29, 2006 9419