Diphenylprolinol silyl ether catalyzed asymmetric Michael reaction of nitroalkanes and β,β-disubstituted α,β-unsaturated aldehydes for the construction of all-carbon quaternary stereogenic centers

Article abstract of DOI:10.1002/chem.201403588

The asymmetric Michael reaction of nitroalkanes and β,β-disubstituted α,β-unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4-addition products with an all-carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for β-substituents such as β-aryl and β-alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)-ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,β-unsaturated aldehydes, the retro-Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.

Full text of DOI:10.1002/chem.201403588

DOI: 10.1002/chem.201403588
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&
Michael Reaction
Diphenylprolinol Silyl Ether Catalyzed Asymmetric Michael
Reaction of Nitroalkanes and b,b-Disubstituted a,b-Unsaturated
Aldehydes for the Construction of All-Carbon Quaternary
Stereogenic Centers
Yujiro Hayashi,* Yuya Kawamoto, Masaki Honda, Daichi Okamura, Shigenobu Umemiya,
Yuka Noguchi, Takasuke Mukaiyama, and Itaru Sato[a]
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Abstract: The asymmetric Michael reaction of nitroalkanes
and b,b-disubstituted a,b-unsaturated aldehydes was cata-
lyzed by diphenylprolinol silyl ether to afford 1,4-addition
products with an all-carbon quaternary stereogenic center
with excellent enantioselectivity. The reaction is general for
b-substituents such as b-aryl and b-alkyl groups, and both
nitromethane and nitroethane can be employed. The addi-
tion of nitroethane is considered a synthetic equivalent of
the asymmetric Michael reaction of ethyl and acetyl substitu-
ents by means of radical denitration and Nef reaction, re-
spectively. The short asymmetric synthesis of (S)-ethosuxi-
mide with a quaternary carbon center was accomplished by
using the present asymmetric Michael reaction as the key
step. The reaction mechanism that involves the E/Z isomeri-
zation of a,b-unsaturated aldehydes, the retro-Michael reac-
tion, and the different reactivity between nitromethane and
nitroethane is discussed.
Introduction
In 2007, we reported the asymmetric Michael reaction of ni-
troalkanes with b-monosubstituted a,b-unsaturated aldehydes
catalyzed by diphenylprolinol silyl ether [Eq. (1)],[11] an organo-
catalyst developed independently by our group[12] and Jørgen-
sen’s group.[13] The obtained g-nitro aldehyde can be trans-
formed into a g-amino carboxylic acid, and we synthesized pre-
gabalin and bachlofen by using this asymmetric Michael reac-
tion of nitromethane and b-monosubstituted a,b-unsaturated
aldehyde as the key step.[11a] In the present paper, we further
applied this reaction to b,b-disubstituted a,b-unsaturated alde-
hydes and describe in full the asymmetric Michael reaction of
nitroalkanes to construct all-carbon quaternary stereogenic
centers with high enantioselectivity [Eq. (2)].
The Michael reaction of carbon nucleophiles is one of the syn-
thetically useful carbon–carbon bond-forming reactions. Re-
cently, organocatalysts[1] have been employed in various asym-
metric catalytic Michael reactions with great success.[2] Con-
struction of an all-carbon quaternary stereogenic center is
a synthetically important topic in current synthetic organic
chemistry.[3] Even though there are several successful asymmet-
ric Michael reactions that use a,a-disubstituted aldehydes[4]
and 2-substituted-1,3-dicarbonyl compounds[5] as nucleophiles,
several challenges remain for the asymmetric Michael reaction
to construct an all-carbon quaternary stereogenic center using
an organocatalyst. The Michael reaction of carbon nucleophiles
onto b,b-disubstituted a,b-unsaturated carbonyl compounds is
another method for the construction of all-carbon quaternary
stereogenic centers. As a carbon nucleophile, nitroalkanes are
useful nucleophiles because they can be converted into several
functional groups.[6] Yet the asymmetric Michael reaction of
b,b-disubstituted a,b-unsaturated carbonyl compounds with
nitroalkanes using organocatalysts is still rare. Ley and co-
workers reported one example of the Michael reaction of 3-
methylcyclohexenone and nitromethane catalyzed by 5-pyrroli-
din-2-yltetrazole.[7] Kudo and Akagawa reported the peptide-
mediated asymmetric Michael reaction of nitromethane and
b,b-disubstituted a,b-unsaturated aldehydes with excellent
enantioselectivity.[8,9] Kwiatkowski and co-workers also reported
the asymmetric Michael reaction of b,b-disubstituted enones
with nitromethane catalyzed by a cinchonine-derived organo-
catalyst under high pressure.[10] In the peptide-mediated reac-
tion, the catalyst with a high molecular weight was employed
to obtain excellent enantioselectivity, and high pressure was
necessary for completion of the reaction. Only nitromethane
was employed in these reactions, and there is no successful
report of nitroethane.
Results
We chose the reaction of ethyl 2-methyl-4-oxobut-2-enoate (E/
Z=95:5) and nitromethane as a model and examined the reac-
tion conditions [Table 1, Eq. (3)]. In the previous reaction of b-
monosubstituted a,b-unsaturated aldehydes, the reaction pro-
ceeded in MeOH catalyzed by diphenylprolinol trimethylsilyl
ether 1 (Figure 1) to afford the Michael product in good yield
with excellent enantioselectivity [Eq. (1)].[11a] When we em-
ployed the same catalyst 1 and MeOH as a solvent, the Henry
reaction proceeded to afford b-hydroxynitro compound 5 in
72% yield with no desired Michael product (Table 1, entry 1).
In toluene, the reaction barely proceeded (Table 1, entry 2),
and both Michael and Henry reaction products were obtained
in CH3CN (Table 1, entry 3). The Michael product was obtained
in good yield with good enantioselectivity in hexane, in which
two-phases formed owing to the low solubility of nitrome-
[a] Prof. Dr. Y. Hayashi, Y. Kawamoto, M. Honda, D. Okamura, S. Umemiya,
Y. Noguchi, T. Mukaiyama, Prof. Dr. I. Sato
Department of Chemistry, Graduate School of Science
Tohoku University, 6–3 Aramaki-Aza Aoba
Aoba-ku, Sendai 980-8578 (Japan)
E-mail: yhayashi@m.tohoku.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403588.
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Having optimized the Michael reaction conditions for ethyl
2-methyl-4-oxobut-2-enoate, the generality of the reaction
with the other b,b-disubstituted a,b-unsaturated aldehydes
was investigated [Table 2, Eq. (4)]. As the reaction was slow
with tert-butyl 2-methyl-4-oxobut-2-enoate on account of the
bulkiness of the tert-butyl ester, 10 equivalents of nitrome-
thane were employed to afford the product in good yield with
89%ee (Table 2, entry 2). Although an E/Z mixture of Michael
acceptors with low isomeric ratios was employed in the reac-
tion with dimethoxy and diethoxy butenal derivatives, excel-
lent enantioselectivities resulted (see below; Table 2, entries 3
and 4). 3-Methyl-4-oxopent-2-enal can be employed as a Mi-
chael acceptor, and the desired product was generated in
good yield and enantioselectivity (Table 2, entry 5). The enan-
tioselectivity of the reaction of 3-methyl-5-phenylpent-2-enal,
which bears two different alkyl b-substituents, was 72%. Al-
though lower than other substrates, similar steric effects
appear to exist between the two substituents at the b-posi-
tion, such as the methyl and 2-phenylethyl substituents
(Table 2, entry 6). For the reaction of 3,4-dimethylpent-2-enal,
which bears the sterically distinct b-substituents isopropyl and
methyl, good enantioselectivity resulted (Table 2, entry 7).
When the methyl b-substituent was extended to ethyl, such as
in ethyl 2-ethyl-4-oxobut-2-enoate, the enantioselectivity drop-
ped to 80%ee (Table 2, entry 8).
Table 1. Effect of solvent, acid additive, and stoichiometry of CH3NO2 on
the organocatalytic Michael reaction of ethyl 2-methyl-4-oxobut-2-
enoate.[a]
Entry Catalyst
X
Solvent Additive
t
Yield ee
[equiv][b]
[h] [%][c] [%][d]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
2
3
10
10
10
10
10
10
10
10
5
MeOH
toluene
MeCN
hexane
neat
neat
neat
neat
neat
–
–
–
–
–
16 <5[e]
24 <5
–
–
–
120
32[f]
77
77
27
22
7
24
22
24
83
86
84
91
82
91
88
90
90
PhCO2H
p-NO2C6H4OH 24
ClCH2CO2H
24
24
19
24
19
9
–
–
–
–
87
90
82
91
10
11
12
28
5
5
neat
neat
neat
[a] Unless noted otherwise, reactions were performed by employing ethyl
2-methyl-4-oxobut-2-enoate (0.5 mmol), nitromethane (2.5, 5, 14 mmol),
organocatalyst (0.05 mmol, 10 mol%) and additive (0.1 mmol) in solvent
(1.0 mL) or neat at room temperature for the indicated time. [b] Equiva-
lents of nitromethane. [c] Yield of purified Michael product. [d] Enantio-
meric excess of the Michael product, which was determined by HPLC
analysis on a chiral phase. [e] Henry product 5 was obtained in 72%
yield. [f] Henry product 5 was obtained in 12% yield.
Next, the Michael reaction of b-aryl-substituted substrate
was examined. Akagawa and Kudo reported the resin-support-
ed peptide catalyst Pro-d-Pro-Aib-(Trp)2-(Leu)6-resin as an effi-
cient catalyst for the Michael addition of nitromethane to 3-
phenylbut-2-enal.[8] In their investigation, they used diphenyl-
prolinol silyl ether 1 as a control catalyst under nonoptimized
conditions and found that the product was obtained in 12%
yield with 88%ee. They used 20 mol% of catalyst with five
equivalents of nitromethane in water in the presence of
20 mol% of benzoic acid at room temperature. Using our best
reaction conditions for catalyst 1 (see above) under neat condi-
tions using five equivalents of nitromethane, several byprod-
ucts were obtained with the desired product in low yield. After
some optimization, the reaction of 3-phenyl-2-butenal and ni-
tromethane (28 equiv) proceeded well when catalyzed by TBS-
ether 2 (TBS=tert-butyldimethylsilyl). This provided the Mi-
chael product in 49% yield with 88%ee (Table 2, entry 9). The
generality of the reaction of b-aryl, b-alkyl a,b-unsaturated al-
dehydes was investigated under these reaction conditions. Not
only phenyl but also p-bromophenyl, p-nitrophenyl, p-toluene-
sulfonyloxylphenyl, and trifluoromethanesulfonyloxyphenyl
were found to be suitable aryl substituents, and the reaction
proceeded efficiently to afford the Michael products with ex-
cellent enantioselectivity (Table 2, entries 10–13).
Figure 1. Catalysts examined in this study.
thane in hexane (Table 1, entry 4). When the reaction was per-
formed neat (10 equiv of CH3NO2), the product was obtained
in 77% yield with 86%ee (Table 1, entry 5). Next, we investigat-
ed the potential effects of acid as described previously.[11a]
Acids such as benzoic acid, p-nitrobenzoic acid, chloroacetic
acid, and trifluoroacetic acid were found to be unsuitable, as
they provided several side products, and the desired product
was obtained in low yield (Table 1, entries 6–8). The amount of
nitromethane could be reduced to five equivalents (Table 1,
entry 9). The effect of the bulky silyl ether substituents on
enantioselectivity of the catalyst was also investigated. Not
only trimethylsilyl ether 1, but also tert-butyldimethylsilyl ether
2 and diphenylmethylsilyl ether 3[14] were found to be efficient
catalysts; they afforded the Michael product in similarly high
enantioselectivities (Table 1, entries 11, 12). Thus, trimethylsilyl
ether 1 and tert-butyldimethylsilyl ether 2 were selected for
further study.
Next, we examined the reaction using nitroethane instead of
nitromethane. Under reaction conditions with five equivalents
of nitroalkane, the Michael product was obtained in low yield
with moderate enantioselectivity owing to side products such
as 7 [Eq. (5); Table 3, entry 1]. Cyclohexadiene derivative 7
would be generated by the Michael reaction of dienamine[15]
and a,b-enal followed by intramolecular aldol reaction and de-
hydration (Scheme 1). When the amount of nitroethane was in-
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Table 2. Michael reaction of nitromethane and b,b-disubstituted a,b-unsaturated aldehydes.[a]
Entry
Starting
material
Catalyst
t
[h]
Yield
[%][b]
ee
[%][c]
Entry
Starting
material
Catalyst
t
[h]
Yield
[%][b]
ee
[%][c]
1
1
24
24
28
87
76
78
91
89
91
8[g]
1
18
69
82
67
49
81
80
88
88
2[d]
1
1
9[h]
2
2
3
10[h]
4
5
1
1
16
76
88
91
90
11[h]
12[h]
13[h]
2
2
2
49
52
54
69
89
38
89
90
87
7
6[e]
1
1
2
74
62
72
86
7[f]
10
[a] Unless noted otherwise, reactions were performed by employing Michael acceptor (0.5 mmol), nitromethane (2.5 mmol), and organocatalyst
1 (0.05 mmol, 10 mol%) or 2 (0.10 mmol, 20 mol%) at room temperature for the indicated time. [b] Isolated yield of Michael product. [c] Enantiomeric
excess of the Michael product, which was determined by HPLC analysis on a chiral phase. [d] Nitromethane (5 mmol) was employed. [e] Catalyst
(0.1 mmol) was employed. [f] Nitromethane (14 mmol) and H2O (1 mmol) were employed. [g] Catalyst (0.1 mmol) and nitromethane (7.5 mmol) were em-
ployed and the reaction was performed at 08C. [h] Nitromethane (14 mmol) was employed and the reaction was performed at 08C to RT.
creased from five to ten equivalents, a good yield of the de-
sired Michael product 6 resulted. Even though the diastereose-
lectivity was not high, and the relative stereochemistry was
not determined, the two diastereomers possessed similarly
good enantioselectivity (Table 3, entry 4).
tained (Table 4, entries 1–3). When both b-substituents are
alkyl groups, such as in 3-methyl-5-phenylpent-2-enal, moder-
ate enantioselectivity was obtained (Table 4, entry 4). When the
trans-b-substituent was an aryl group, phenyl, p-bromophenyl,
p-nitrophenyl, p-toluenesulfonyloxyphenyl, and trifluorometh-
anesulfonyloxyphenyl were all found to be suitable aryl sub-
stituents, and the reaction proceeded efficiently to afford the
Michael products with excellent enantioselectivity (Table 4, en-
tries 5–10). However, diastereoselectivity of the reaction of ni-
troethane is low. It should be noted that the reaction of nitro-
The generality of the reaction of nitroethane with b,b-disub-
stituted a,b-unsaturated aldehydes is summarized in Table 4
[Eq. (6)]. When one of the b-substituents is an electron-with-
drawing group—for example, ethoxycarbonyl, methoxycarbon-
yl, or diethoxymethyl—excellent enantioselectivity was ob-
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Table 3. Effect of nitroethane stoichiometry on the organocatalytic Mi-
chael reaction of ethyl 2-methyl-4-oxobut-2-enoate.[a]
Entry
X
t
[h]
Yield 6
[%][c]
Yield 7
[%][c]
d.r.[d]
ee
[%][e]
[equiv][b]
1
2
3
4[f]
5
10
28
28
50
17
7
45
85
78
77
34
<5
<5
<5
1.3:1
54, 59
1.6:1
1.4:1
1.5:1
85, 88
85, 88
91, 91
Scheme 1. Michael–aldol–dehydrative sequence to generate 7.
22
ethane is much faster than that of nitromethane in most of
the cases (see below).
[a] Unless noted otherwise, reactions were performed with ethyl 2-
methyl-4-oxobut-2-enoate (0.5 mmol), nitroethane (2.5, 5 or 14 mmol),
and organocatalyst 1 (0.05 mmol, 10 mol%) at room temperature for the
indicated time. [b] Equivalents of nitroethane. [c] Isolated yield. [d] Diaste-
reomer ratio, as determined by 1H NMR spectroscopy. [e] Enantiomeric
excess of the Michael product, as determined by HPLC analysis on
a chiral phase. [f] Reaction was performed at 08C.
Synthetic utility and determination of the absolute configu-
ration
As the Michael product possesses a g-nitro aldehyde moiety, it
can be converted into a g-amino carboxylic acid with b,b-di-
Table 4. Michael reaction of nitroethane and b,b-disubstituted a,b-unsaturated aldehyde.[a]
Entry
Starting
material
Catalyst
t
[h]
Yield
[%][b]
d.r.[c]
1.5:1
ee
Entry
Starting
material
Catalyst
t
[h]
Yield
[%][b]
d.r.[c]
ee
[%][d]
[%][d]
1
1
22
24
23
77
75
72
91, 91
94, 92
96, 93
6
2
27
27
25
77
72
77
1:1
85, 89
83, 88
92, 93
2
3
4
5
1
1
1
2
1.2:1
7
1
2
2
2
1:1
1:1
1:1
1:1
2:1
8
17
94
60
1:1
75, 68
88, 93
9
25
24
94
62
88, 90
86, 91
8
1:1
10
[a] Unless noted otherwise, reactions were performed by employing Michael acceptor (0.5 mmol), nitroethane (14 mmol), and organocatalyst 1 or 2
(0.1 mmol, 20 mol%) at 08C for the indicated time. [b] Yield of purified compound. [c] Diastereomer ratio, as determined by 1H NMR spectroscopy.
[d] Enantiomeric excess of the Michael product, as determined by HPLC analysis on a chiral phase.
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be the synthetic equivalent (um-
polung) for a nucleophilic acetyl
group.
Even though the diastereose-
lectivity of the Michael reaction
of nitroethane is relatively low,
the conversion of nitroethyl
group into ethyl group or acetyl
group can be achieved readily, in
which both diastereomers can
be converted into the same syn-
thetically useful compound.
Scheme 2. Asymmetric synthesis of (S)-ethosuximide.
substituents. Akagawa and Kudo already demonstrated this
transformation and also described the importance of these Discussion
compounds.[8] The reaction of nitroethane afforded the Michael
Isomerization between E and Z isomers of a,b-unsaturated
aldehyde
product with low diastereoselectivity. Both diastereomers can
be transformed into the same synthetically useful compounds.
As the nitro moiety can be converted into hydrogen by means
of radical denitration,[6,16] the asymmetric Michael reaction of
nitroethane is a synthetic equivalent of an asymmetric Michael
reaction of an ethyl group.
A mixture of E and Z isomers of the a,b-unsaturated aldehyde
was employed in the previous reactions. Even though the E/Z
ratio of the starting a,b-unsaturated aldehyde was rather low
in some cases, excellent enantioselectivity was obtained. As
opposite enantiomers would be generated between the E and
Z isomers, we began to investigate the effect of the E/Z ratio
of the a,b-unsaturated aldehyde toward the enantioselectivity
of the Michael product. MacMillan et al.[22] and List et al.[23] in-
dependently reported similar phenomena in the organo-cata-
lyzed Hantzsch ester reduction of b,b-disubstituted a,b-unsatu-
rated aldehydes, in which a facile E/Z isomerization of the a,b-
unsaturated aldehyde was demonstrated. Kudo et al. also ob-
served the same phenomena in the peptide-catalyzed Michael
reaction of b,b-disubstituted a,b-unsaturated aldehyde and ni-
tromethane.[8] We prepared 3-(4-toluenesulfonyloxyphenyl)but-
2-enal with different E/Z ratios: Z/E= >95:<5 or Z/E=56:44.
These a,b-unsaturated aldehydes were treated with diphenyl-
prolinol silyl ether 2 in iPrNO2 as a solvent because it does not
react with a,b-unsaturated aldehydes owing to steric reasons,
and the reaction was monitored for changes in the E/Z ratio
over time. The results are shown in Figure 2 [Eq. (8)]. Starting
from pure E isomer, the Z isomer was generated gradually.
After 8 h, the reaction reached equilibrium, in which the E/Z
ratio was 72:28. The same ratio was reached after 8 h when
starting from an E and Z mixture of E/Z=56:44. These results
indicate that there is equilibration between the E and Z iso-
mers, and a steady-state E/Z equilibration was reached within
8 h.
To illustrate this utility, we synthesized (S)-ethosuximide,
which is used to treat petit mal epilepsy,[17] by means of our di-
phenylprolinol silyl ether mediated Michael reaction of nitro-
ethane as the key step (Scheme 2). The Michael product of
methyl 2-methyl-4-oxobut-2-enoate and nitroethane catalyzed
by TMS ether 1 (1.2:1 diastereomer mixture, 94 and 92%ee;
Table 4, entry 2) was oxidized to its carboxylic acid by means
of Kraus oxidation[18] in 71% yield. Amide coupling with p-
methoxybenzylamine (PMB-NH2) using 1-[bis(dimethylamino)-
methylene]-1H-1,2,3-triazolo-[4,5-b]pyridinium-3-oxide
hexa-
fluorophosphate (HATU) and iPr2EtN afforded its amide, which
was directly treated with NaHCO3 to provide its imide in 60%
yield in two steps. Radical denitration with Bu3SnH in the pres-
ence of catalytic azobisisobutyronitrile (AIBN) provided the de-
nitrated compound in 64% yield. Subsequent treatment of the
imide with ammonium hexanitratocerate(IV) (CAN)[19] afforded
(S)-(+)-ethosuximide in 55% yield. All spectroscopic and opti-
cal properties were found to be in good agreement with the
literature.[17c]
The absolute configuration of the Michael adduct between
methyl 2-methyl-4-oxobut-2-enoate and nitroethane was also
confirmed after conversion to a known dimethyl 2-ethyl-2-
methylsuccinate (Scheme 3). The Michael adduct (Table 4,
entry 2) was converted into its carboxylic acid by Kraus oxida-
tion, which was treated with TMSCHN2 to afford the bis-methyl
ester. Radical denitration afforded dimethyl 2-ethyl-2-methyl-
succinate. Comparison of the optical rotation of the literature
data[20] indicated that the Michael product had an S configura-
tion.
We also investigated the progress of the reaction of nitro-
methane and 3-(4-toluenesulfonyloxyphenyl)but-2-enal starting
from the a,b-unsaturated aldehyde with different E/Z ratios.
The results are summarized in Figure 3 [Eq. (9)]. The profile of
the E/Z ratio of the a,b-unsaturated aldehyde according to
time was found to be different between the reactions with ni-
tromethane with a,b-unsaturated aldehyde using a pure E
isomer relative to a starting mixture of E and Z isomers (E/Z=
56:44). In the reaction starting with pure E isomer, the E/Z ratio
gradually decreased to 80:20 after 55 h. In comparison, the E/Z
ratio initially decreases and then increases to reach 40:60 after
The nitro group can be converted into the carbonyl group
using the Nef reaction.[6] After the Michael product was re-
duced to alcohol, it was protected as its benzyl ether. When
the nitro compound was treated with KMnO4 supported on
SiO2,[21] the ketone was obtained in 52% yield [Eq. (7)]. Thus,
the asymmetric Michael reaction of nitroethane was shown to
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Scheme 3. Determination of the absolute configuration.
Figure 3. Reaction profiles of Michael reaction starting from a,b-unsaturated
aldehydes with different E/Z ratios. Top: Starting from only the E isomer.
Bottom: Starting from the E/Z mixture (E/Z=56:44).
time, and profile of enantioselectivity according to time, are
identical between the two reactions, whether by using a,b-un-
saturated aldehyde as a pure E isomer or as a mixture of E and
Z isomers (E/Z=56:44). Notably, the resultant yield and enan-
tioselectivity are identical for both reactions, despite the start-
Figure 2. Relationship between the E/Z ratio of the Michael acceptor and
the reaction time in the presence of catalyst 2 and iPrNO2.
55 h when starting from a mix-
ture of E and Z isomers (E/Z=
56:44). These results indicate
that the E isomer reacts prefer-
entially with nitromethane over
the
Z isomer and there is
a slower process of isomerization
between the E and Z isomers.
Isomerization between Z and E
isomers would proceed through
a
dienamine intermediate or
through the addition–elimina-
tion of water to the iminium ion
(Figure 4). The reaction profile of
Figure 4. Relative reaction rates between the interconversion of E- and Z-a,b-unsaturated aldehydes and proline-
yields according to reaction catalyst derivatives, and eventual addition of nitromethane.
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ing E/Z ratio of the a,b-unsaturated aldehyde and the appa-
rently slow isomerization rate between the E and Z isomers.
This can be reasonably explained by considering the following
three conditions (Figure 4): 1) the condensation reactions of
the a,b-unsaturated aldehydes 8E and 8Z with the catalyst 2
to afford iminium salts 9E and 9Z are the slowest processes;
2) the isomerization processes between 9E and 9Z are relative-
ly fast; and 3) the nitronate anion reacts with the iminium salts
9E and 9Z by means of an acyclic synclinical transition state
as proposed by Seebach et al.[24] Figure 4 shows the transition-
state model for the reaction of E and Z isomers of 3-phenyl-
but-2-enal. In this model, electrostatic interactions between
the nitro group and iminium ion are proposed to operate.
There are larger steric repulsions between the phenyl and nitro
groups at the synclinical position in the Z isomer relative to
the repulsions between the methyl and nitro groups in the E
isomer. Thus, the reaction of the E isomer (9E) is rationalized
to be much faster. Under these considerations, the reaction
profiles of Figures 2 and 3 would thus be observed.
8 h, the reaction proceeded slowly but the enantioselectivity
was excellent and constant. When the reaction temperature
was increased to room temperature, the enantioselectivity
began to decrease. These results suggest a retro-Michael reac-
tion that occurs at room temperature for the present sub-
strate.
To confirm the retro-Michael reaction, we monitored the fol-
lowing reaction [Figure 6, Eq. (11)]. We thus treated the Mi-
chael product of nitroethane and 3-(4-bromophenyl)but-2-enal
with nitromethane in the presence of diphenylprolinol silyl
Importantly, these reactivity profiles mean that it is not nec-
essary to prepare pure E or Z a,b-unsaturated aldehydes,
which is a practical advantage. It is also noteworthy that the
enantioselectivity remained constant during the course of
these reactions with nitromethane (see below).
Michael reaction and retro-Michael reaction
Figure 6. Generation of the Michael adduct of nitromethane from the Mi-
chael product of nitroethane.
When we investigated the reaction of nitroethane and b-aryl-
substituted a,b-unsaturated aldehydes, we observed a decrease
in enantioselectivity during the reaction. Although the enantio-
selectivity of the Michael product of the reaction of nitrome-
thane is constant during the reaction, as shown in Figure 3
(see above), the reaction of nitroethane and b-aryl-substituted
a,b-unsaturated aldehyde was found to change [Figure 5,
Eq. (10)]. When the reaction was conducted at 08C for the first
ether 2. The starting Michael product with nitroethane was
gradually converted into a new Michael adduct with nitro-
methane, which at all time points gave excellent enantioselec-
tivity throughout the reaction time.
However, when the Michael product of 3-(4-bromophenyl)-
but-2-enal and nitromethane was treated with nitroethane in
the presence of catalyst 2, the reaction did not proceed. These
results indicate that a retro-Michael reaction proceeded from
the Michael product of nitroethane at room temperature, and
that this retro reaction was slower at 08C. For nitromethane,
the retro-Michael reaction did not proceed during the reaction
of the Michael product at room temperature. We also investi-
gated other b,b-disubstituted a,b-unsaturated aldehydes and
found that no retro-Michael reaction occurred in the b,b-di-
alkyl-substituted a,b-unsaturated aldehyde, even at room tem-
perature. Thus, the retro-Michael reaction was found to be de-
pendent on the substrate and temperature. The steric hin-
drance in the Michael product of nitroethane and b-aryl-substi-
tuted a,b-unsaturated aldehyde would facilitate the retro-Mi-
chael reaction. Thus, it was found essential to carry out the
Michael reaction of these substrates at 08C to obtain high
enantioselectivity.
The reactivity of nitromethane and nitroethane
When we were investigating the generality of the reaction
using nitromethane and nitroethane, we noticed that in most
Figure 5. Relationship between enantioselectivity and reaction time in the
Michael reaction of nitroethane and 3-(4-bromophenyl)but-2-enal.
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cases the reaction of nitroethane was faster than the reaction
of nitromethane. These results are counterintuitive to the idea
that nitromethane should be more nucleophilic and react
faster than nitroethane under pure steric grounds. We there-
fore decided to investigate the reactivity between nitrometh-
ane and nitroethane systematically.
We chose four representative Michael acceptors such as 3-
methyl-5-pent-2-enal, 3,4-dimethylpent-2-enal, ethyl 2-methyl-
4-oxobut-2-enoate, and 3-(4-bromophenyl)but-2-enal. The re-
actions were performed as follows: A mixture of Michael ac-
ceptor, nitromethane (14 equiv), and nitroethane (14 equiv)
was treated with diphenylprolinol silyl ether (10 or 20 mol%)
and the progress of the reaction was monitored over time by
1H NMR spectroscopy (Figures 7–10).
In the reaction of 3-(4-bromophenyl)but-2-enal, the reaction
was first carried out at 08C for 116 h. After this time, the reac-
tion temperature was increased to room temperature
[Figure 7, Eq. (12)]. The reactivity of nitroethane was found to
be higher than that of nitromethane at 08C. The reaction pro-
file dramatically changed at 116 h. The yield of Michael adduct
of nitroethane decreased, whereas that of nitromethane in-
creased rapidly. At 212 h, the yield of nitromethane adducts
overtook that of nitroethane. This is because a retro-Michael
reaction of the Michael adduct of nitroethane occurs at room
temperature, whereas retro-Michael reactions for nitromethane
do not proceed, as illustrated in the previous section. Even
though the reaction profile is complicated after 116 h, the re-
sultant reactivity of nitroethane was clearly found to be higher
than that of nitromethane in these cases.
Figure 8. Competitive reaction of ethyl 2-methyl-4-oxobut-2-enoate with ni-
tromethane and nitroethane.
In other reactions of 3-methyl-5-phenylpent-2-enal and ethyl
2-methyl-4-oxobut-2-enoate, nitroethane was also more reac-
Figure 9. Competitive reaction of 3-methyl-5-phenylpent-2-enal with nitro-
methane and nitroethane.
tive than nitromethane [Figures 8 and 9; Eqs. (13) and (14)].
Only in the reaction of 3,4-dimethylpent-2-enal was nitrome-
thane found to be more reactive than nitroethane [Figure 10,
Eq. (15)]. This can be explained by the reaction mechanism
given in Scheme 4. The reaction begins by formation of an imi-
nium ion and hydroxy ion from the a,b-unsaturated aldehyde
and catalyst. The hydroxide anion acts as a base to transform
Figure 7. Competitive reaction of 3-(4-bromophenyl)but-2-enal with nitro-
methane and nitroethane.
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reaction of 3,4-dimethylpent-2-enal, which is much more steri-
cally hindered than other Michael acceptors. In the reaction of
3,4-dimethylpent-2-enal, which possesses a bulky isopropyl
group and a methyl group at the b-position of the a,b-unsatu-
rated aldehyde, the anion of nitroethane can not react on ac-
count of steric repulsions, whereas the anion of nitromethane,
the smaller nucleophile, reacts more readily.
Conclusion
We have developed the asymmetric Michael reaction of nitroal-
kanes and b,b-disubstituted a,b-unsaturated aldehydes cata-
lyzed by diphenylprolinol silyl ether to afford Michael adducts
with all-carbon quaternary stereogenic centers in excellent
enantioselectivity. There are several noteworthy features in this
reaction: 1) As there is a facile E/Z isomerization between the E
and Z isomers of the b,b-disubstituted a,b-unsaturated alde-
hyde under the reaction conditions, it is not necessary to sepa-
rate the E and Z isomers, which is a practical advantage. 2) Not
only nitromethane but also nitroethane can be employed as
the nucleophile. 3) Although the diastereoselectivity of the re-
action using nitroethane is low, the addition of nitroethane is
regarded as a Michael reaction of an ethyl group or an acetyl
group by successive radical denitration or Nef reactions, re-
spectively. 4) The Michael products are known to be readily
converted into medicinally useful b,b-disubstituted g-amino
acids. 5) Temperature-dependent retro-Michael reactions can
decrease the enantioselectivity during the course of the reac-
tion, as observed during the reaction of nitroethane and b-
aryl-b-alkyl-substituted a,b-unsaturated aldehydes, and a careful
selection of reaction conditions needs to be considered for
some substrates. 6) Generally the reactivity of nitroethane is
higher than that of nitromethane owing largely to the acidity
of the a-proton of the nitro group, but the order of reactivity
may be reversed in some cases on account of overriding steric
effects.
Figure 10. Competitive reaction of 3,4-dimethylpent-2-enal with nitrometh-
ane and nitroethane.
the nitroalkane to its aci-nitronate ion, which then reacts with
the iminium ion in a 1,4-addition manner to generate an en-
amine. During this addition reaction, the nucleophile attacks
from the Si face of the iminium salt preferentially because the
opposite Re face is covered by the bulky diphenyltrimethylsi-
loxymethyl moiety of the catalyst. This is one reason why ex-
cellent enantioselectivity was obtained. The enamine reacts
with water to afford the Michael product with recovery of the
catalyst. The pKa of nitromethane is 17.2 in DMSO, whereas
that of nitroethane is 16.7.[25] As nitroethane is more acidic
than nitromethane, the anion of nitroethane would generate
more readily, thereby reacting with the iminium ion faster than
the anion of nitromethane. Thus, the reaction of nitroethane is
faster than that of nitromethane in general. This said, the reac-
tivity of nitromethane is higher than that of nitroethane in the
Acknowledgements
This work was supported by the Mitsubishi Foundation and
a Grant-in-Aid for Scientific Research on Innovative Areas “Ad-
vanced Molecular Transformations by Organocatalysts” from
The Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan.
Keywords: asymmetric synthesis
·
enantioselectivity
·
isomerization · Michael addition · organocatalysis
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Received: May 19, 2014
Published online on August 27, 2014
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