Organocatalyst-mediated dehydrogenation of aldehydes to α,β-unsaturated aldehydes, and oxidative and enantioselective reaction of aldehydes and nitromethane catalyzed by diphenylprolinol silyl ether

Article abstract of DOI:10.1002/adsc.201300919

A one-pot transformation of aldehydes into α,β-unsaturated aldehydes was developed using both N-benzyl-N-methylamine and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as catalysts and MnO₂ as a terminal oxidant. An oxidative and enantioselective reaction of aldehydes and nitromethane was established using both diphenylprolinol silyl ether and DDQ as a catalyst with MnO₂ as a terminal oxidant, in which synthetically important β-substituted γ-nitro aldehydes were obtained with excellent enantioselectivity. Copyright

Full text of DOI:10.1002/adsc.201300919

FULL PAPERS
DOI: 10.1002/adsc.201300919
Organocatalyst-Mediated Dehydrogenation of Aldehydes to
a,b-Unsaturated Aldehydes, and Oxidative and Enantioselective
Reaction of Aldehydes and Nitromethane Catalyzed by
Diphenylprolinol Silyl Ether
Yujiro Hayashi,a,b,* Takahiko Itoh,b and Hayato Ishikawab,c
a
Department of Chemistry, Graduate School of Science, Tohoku University, 6–3 Aramaki-Aza Aoba, Aoba-ku, Sendai
980-8578, Japan
Fax : (+81)-22-795-6566; phone: (+81)-22-795-3554; e-mail: yhayashi@m.tohoku.ac.jp (home page:
http://www.ykbsc.chem.tohoku.ac.jp)
Before June 20, 2012: Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science,
b
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Present address: Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, 2-39-1,
c
Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
Received: October 16, 2013; Published online: December 6, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300919.
Abstract: A one-pot transformation of aldehydes ether and DDQ as a catalyst with MnO2 as a terminal
into a,b-unsaturated aldehydes was developed using oxidant, in which synthetically important b-substitut-
both N-benzyl-N-methylamine and 2,3-dichloro-5,6- ed g-nitro aldehydes were obtained with excellent
dicyano-1,4-benzoquinone (DDQ) as catalysts and enantioselectivity.
MnO2 as a terminal oxidant. An oxidative and enan-
tioselective reaction of aldehydes and nitromethane Keywords: asymmetric reaction; one-pot reaction;
was established using both diphenylprolinol silyl organocatalysis; oxidative reaction
Introduction
direct method, aldehydes are converted into a-seleno
aldehydes, which afford a,b-unsaturated aldehydes via
a,b-Unsaturated aldehydes are synthetically impor- oxidation and elimination.[2] Ito–Saegusa oxidation
tant functional compounds, and there exist many using Pd(II) is also known for the direct conversion.[3]
methods for their synthesis. Dehydrogenation of alde- The direct dehydrogenation of aldehydes is catalyzed
hydes into the corresponding a,b-unsaturated alde- by PdACTHNUTRGNEUNG(OAc)2 in the presence of allyl diethyl phos-
hydes is one of the methods for their preparation, but phate.[4] IBX[5] and IBS[6] oxidations are further meth-
other useful synthetic methods are limited. For in- ods for the direct conversion of aldehydes into a,b-
stance, silyl enol ethers, generated from aldehydes, unsaturated aldehydes.
are converted into a,b-unsaturated aldehydes by reac-
We have previously reported the oxidative and
tion with allyl carbonates via palladium catalysis as enantioselective carbon-carbon bond forming reaction
reported by Tsuji,[1] in which aldehydes have to be at the b-position of aldehydes by the use of diphenyl-
converted into silyl enol ethers in advance. As for the prolinol silyl ether[7] as a catalyst and DDQ as an oxi-
Scheme 1. Transformation of aldehydes into a,b-unsaturated aldehydes and b-substituted aldehydes.
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Yujiro Hayashi et al.
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dant (Scheme 1).[8] In this reaction, the chiral amine
catalyst reacts with an aldehyde to afford an enamine.
Subsequent reaction with DDQ, acting as a hydride
abstracting reagent,[9] provides the iminium ion. The
iminium ion further reacts with nitromethane as a nu-
cleophile to afford the addition product with excellent
enantioselectivity. If the intermediate iminium ion
were trapped with water, an a,b-unsaturated aldehyde
would be generated. In this way, aldehydes could be
converted into a,b-unsaturated aldehydes in a “one-
pot” operation. It would be desirable that an inexpen-
sive achiral amine could be employed in this transfor-
mation instead of the chiral diphenylprolinol silyl
ether as catalyst. Moreover, if DDQ can be used in
a catalytic amount with an inexpensive terminal oxi-
dant, this would be a practical synthetic transforma-
tion. In this paper, we describe the successful realiza-
tion of this scenario: a practical oxidation of alde-
hydes into a,b-unsaturated aldehydes using a catalytic
amount of achiral amine and DDQ in a one-pot oper-
ation. We also reveal the full details of the oxidative
and enantioselective carbon-carbon bond forming re-
action using diphenylprolinol silyl ether and DDQ,
which is used both in an equimolar and a catalytic
amount. When we reported our oxidative and enan-
tioselective carbon-carbon bond forming reaction
using an equimolar amount of DDQ in 2011,[8] Wang
and co-workers reported the similar oxidative and
enantioselective reaction using diphenylprolinol silyl
ether as a catalyst and IBX as an oxidant.[10] They
also reported the transformation of aldehydes into
Table 1. Effect of amine and solvent in the conversion of 3-
phenylpropanal into cinnamaldehyde.[a]
Entry Amine
Solvent Time Yield
[h]
[%][b]
1
2
3
4
diisopropylamine
THF
THF
THF
THF
THF
THF
3
2
3
2
3
2
2
2
2
2
2
0.5
5
<5
<5
55
47
25
59
71
74
96
76
26
94
75
diphenylamine
diisobutylamine
dibutylamine
pyrrolidine
dibenzylamine
N-cyclohexyl-N-methylamine THF
5[c]
6[c]
7
8
9
10
11
12[d]
13[e]
N-methylaniline
THF
THF
CH2Cl2
toluene
THF
N-benzyl-N-methylamine
N-benzyl-N-methylamine
N-benzyl-N-methylamine
N-benzyl-N-methylamine
N-benzyl-N-methylamine
THF
[a]
Unless otherwise shown, the reaction was performed
using 3-phenylpropanal (0.4 mmol), DDQ (0.4 mmol),
amine (0.08 mmol) and solvent (1.6 mL) at room temper-
ature.
Yield of the isolated cinnamaldehyde.
A substantial amount of the self-aldol product of 3-phe-
nylpropanal was obtained.
[b]
[c]
[d]
[e]
THF (0.4 mL) was employed.
N-Benzyl-N-methylamine (0.04 mmol) was employed.
a,b-unsaturated aldehydes, using chiral diphenylproli- though diisopropylamine and diphenylamine did not
nol siyl ether or MacMillanꢁs catalyst with IBX, ceric promote the reaction (entries 1 and 2), diisobutyl-
ammonium nitrate (CAN), or a combination of
ACHTUNGTRENaNGNU mine and dibutylamine afforded the product in mod-
Pd
ACHTUNGTRENNUNG
the achiral nature of the reaction, the use of a chiral amine afforded the product in moderate yield, due in
catalyst is superfluous. Recently MacMillan and co- part to a self-aldol reaction of 3-phenylpropanal (en-
workers reported the direct b-arylation of carbonyl tries 5 and 6). These results indicate that a bulky
compounds via photoredox catalyst in combination of amine is not suitable because of the slow generation
organocatalyst.[12]
of the enamine, while the self-aldol reaction becomes
problematic in the case of a sterically less hindered
amine. After further screening of the amine catalysts,
N-cyclohexyl-N-methylamine, N-methylaniline, and
N-benzyl-N-methylamine were found to promote the
desired oxidative reaction with good yield (entries 7–
9). As N-benzyl-N-methylamine gave the best yield
(entry 9), we selected this amine for the further opti-
Results and Discussion
Transformation of Aldehydes into a,b-Unsaturated
Aldehydes
Upon investigating the transformation of aldehydes mization.
into the corresponding a,b-unsaturated aldehydes, 3-
Next the solvent and concentration were examined.
phenylpropanal was selected as a model aldehyde. As Although the reaction was slow in toluene (entry 11),
we already reported that diphenylprolinol silyl ether the reaction proceeded in CH2Cl2 and THF. An excel-
is an effective chiral organocatalyst for the transfor- lent yield was obtained in THF (entry 9) using a con-
mation of aldehydes into enamines,[13] achiral secon- centration between 0.5M and 1.0M. When the reac-
dary amine catalysts were examined. The reaction tion was performed under concentrated conditions
was carried out in the presence of 20 mol% of several (1.0M), the reaction was completed within 30 min
amine catalysts with an equimolar amount of DDQ in (entry 12). When catalyst loading was reduced to
THF, and the results are summarized in Table 1. Al- 10 mol%, the product was obtained in 75% yield with
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Organocatalyst-Mediated Dehydrogenation of Aldehydes to a,b-Unsaturated Aldehydes
Table 2. Effect of amounts of amine catalyst, DDQ, and
MnO2 in the conversion of 3-phenylpropanal into cinnamal-
dehyde.[a]
amine and DDQ (entries 1–5), which indicated that
5 equivalents of MnO2 were necessary to afford
cinnamaldehyde in good yield. When the amount of
MnO2 was decreased, a by-product 4 was generated in
a substantial amount, which would be formed via
a Michael reaction of amine to 3 and DDQ oxidation,
subsequently derived from the aldol condensation of
3-phenylpropanal (1) and cinnamaldehyde (2) [Eq.
(3)]. Next, the amount of DDQ was investigated with
5 equivalents of MnO2 (entries 6 and 7), which indi-
cated that 10 mol% of DDQ was efficient and the
amount of N-benzyl-N-methylamine could also be re-
duced to 10 mol% (entry 8). Thus, the optimized reac-
tion conditions are the use of 10 mol% of both amine
catalyst and DDQ.
Entry X [mol%][b] Y [mol%][c] Z [mol%][d] Yield [%][e]
1
2
3
4
5
6
7
8
30
30
30
30
30
30
30
10
20
20
20
20
20
10
5
600
500
300
150
100
500
500
500
87
87
64[f]
51[f]
41[f]
82
<30
78
10
[a]
Unless otherwise shown, the reaction was performed
using 3-phenylpropanal (0.4 mmol), THF (0.4 mL) at
room temperature for 6 h. Amounts of DDQ, MnO2 and
MeBnNH are listed in the Table.
Amount of BnMeNH.
Amount of DDQ.
Generality of the Catalytic DDQ Oxidation
Once the best reaction conditions for the conversion
of 3-phenylpropanal into cinnamaldehyde via the cat-
alytic use of N-benzyl-N-methylamine and DDQ had
been established, the generality of the reaction was
investigated (Table 3). As for the b-substituent of the
a,b-unsaturated aldehydes, not only phenyl (entry 1),
but also electron-rich p-methoxyphenyl (entry 2) and
electron-deficient p-bromophenyl, p-nitrophenyl, p-
[b]
[c]
[d]
[e]
[f]
Amount of MnO2.
Yield of the isolated cinnamaldehyde.
Substantial amounts (17–27%) of a by-product 4 were
obtained.
recovery of the starting material (entry 13). Thus, the trifluoromethylphenyl groups were suitable (en-
best reaction conditions comprise the use of N- tries 3–5). In addition to the aromatic substituents,
benzyl-N-methylamine as a catalyst in THF with heteroaromatic groups such as furyl and indole were
1.0M concentration (entry 12).
successfully employed as b-substituent (entries 6 and
In this oxidation reaction, DDQ is reduced to its 7). Pent-4-enal derivatives were also suitable sub-
hydroquinone derivative. If hydroquinone is oxidized strates (entries 8–12). As for the substituents at the 5-
in situ back to DDQ by an inexpensive oxidant, DDQ position of pent-4-enal, aromatic groups with both
could be used in catalytic quantities. As Floreancig re- electron-rich and electron-deficient substituents were
ported that several oxidative reactions can be promot- used to afford the products with good yield. Unfortu-
ed by a catalytic use of DDQ with MnO2 as a terminal nately, aldehydes such as 7-phenylhept-4-enal and 3-
oxidant,[14] we investigated this transformation of al- benzyloxypropanal were not suitable substrates and
dehyde into a,b-unsaturated aldehyde via a catalytic did not afford the oxidized product. A linear unsubsti-
use of DDQ with MnO2 as a terminal oxidant tuted aliphatic aldehyde such as nonanal was also not
(Table 2). First, the amount of MnO2 was screened in a suitable substrate with the recovery of the starting
the presence of 20 mol% of both N-benzyl-N-methyl- material. In the case of 3,7-dimethyloctanal, 3,7-dime-
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Table 3. The generality of the conversion of aldehyde into
a,b-unsaturated aldehyde.[a]
Conversion of Aldehydes into a,b-Unsaturated
Aldehydes Catalyzed by Diphenylprolinol Silyl Ether
We have described the oxidation of aldehydes into
a,b-unsaturated aldehydes via an achiral amine as
a catalyst. When a chiral amine catalyst can be em-
ployed in this reaction instead of N-benzyl-N-methyl-
amine, a chiral iminium ion would be formed in situ.
When the nucleophile reacts with this chiral iminium
ion, a chiral stereogenetic center at the b-position of
the formyl moiety could be constructed (Scheme 1).
As we have already reported this type of oxidative
and enantioselective reaction, utilizing stoichiometric
quantities of DDQ, it was envisioned that DDQ
could be employed in catalytic quantities by use of
MnO2 as a terminal oxidant. Before investigation of
the oxidative and enantioselective carbon-carbon
bond forming reaction in the catalytic use of both di-
phenylprolinol silyl ether and DDQ, we investigated
the first oxidation reaction using a chiral amine cata-
lyst instead of achiral N-benzyl-N-methylamine
(Table 4). When 3-phenylpropanal was treated with
10 mol% of both diphenylprolinol silyl ether and
DDQ and 500 mol% of MnO2, which are the best re-
action conditions for the reaction using N-benzyl-N-
methylamine, a good yield was obtained (80%,
entry 1). The concentration of the reaction was found
to be important, and dilute reaction condition
(0.25M) gave an excellent result (entry 4). Further-
Table 4. Effects of the amount of MnO2 and concentration
in the transformation of 3-phenylpropanal to cinnamalde-
hyde catalyzed by diphenylprolinol silyl ether.[a]
Entry Conc. [M][b] X [mol%][c] Time [h] Yield [%][d]
1
2
3
4
5
6
7
8
9
1.00
0.75
0.50
0.25
0.25
0.25
0.25
0.25
0.25
500
500
500
500
400
300
200
150
100
6
6
6
6
6
6
6
9
9
80
87
86
97
94
87
91
57
37
[a]
Unless otherwise shown, the reaction was performed
using aldehyde (0.4 mmol), DDQ (0.04 mmol), MeBnNH
(0.04 mmol), MnO2 (2.0 mmol), and THF (0.4 mL) at
room temperature for 6 h.
[b]
Yield of the isolated a,b-unsaturated aldehyde.
thyloct-2-enal was obtained in 34% yield catalyzed by
40 mol% of diisopropylamine in dichloroethane at
808C for 4 h [Eq. (5)].
[a]
Unless otherwise shown, the reaction was performed
using 3-phenylpropanal (0.4 mmol), diphenylprolinol silyl
ether (0.04 mmol) and DDQ (0.04 mmol) at room tem-
perature for 6 h.
Concentration of the reaction mixture.
Amount of MnO2.
[b]
[c]
[d]
Yield of the isolated cinnamaldehyde.
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Organocatalyst-Mediated Dehydrogenation of Aldehydes to a,b-Unsaturated Aldehydes
Table 5. The effects of additive on the one-pot reaction of 3-
more, we found the amount of MnO2 can be reduced
to 2 equivalents (entry 7), which is in contrast to the
reaction of N-benzyl-N-methylamine, requiring
5 equivalents of MnO2. As the side reaction is the
self-aldol reaction of the aldehyde, it is necessary to
oxidize the hydroquinone derivative to DDQ before
the self-aldol reaction proceeds. In the case of N-
benzyl-N-methylamine, the self-aldol reaction is
rather fast and we have to oxidize the hydroquinone
rapidly. In this case we have to use 5 equivalents of
MnO2. On the other hand, as the self-aldol reaction is
slow in the case of the bulky diphenylprolinol silyl
ether, we do not have to oxidize the hydroquinone
derivative readily, and two equivalents of MnO2 are
enough to promote efficient reaction.
phenylpropanal and nitromethane catalyzed by diphenylpro-
linol silyl ether using equimolar amounts of DDQ.[a]
Entry Additive
Time [h][b] Yield [%][c] ee [%][d]
1
2
3
4
5
6
7
8
9
C6H5CO2H
p-NO2C6H4OH 48
48
<5
<5
<5
36
38
50
36
53
76
nd
nd
nd
93
90
85
92
94
92
KH2PO4
Na2HPO4
NaHCO3
Et3N
AcONH4
AcOLi
48
48
48
48
48
24
24
One-Pot Oxidation and 1,4-Addition using an
Equimolar Amount of DDQ
With reaction conditions for the transformation of al-
dehydes into a,b-unsaturated aldehydes by the cata-
lytic use of both diphenylprolinol silyl ether and
DDQ in hand, the one-pot sequential oxidation and
asymmetric Michael reaction were investigated. As
we have already reported the asymmetric Michael re-
action of nitromethane with a,b-unsaturated alde-
hydes catalyzed by diphenylprolinol silyl ether [Eq.
(7)],[15] we chose nitromethane as a nucleophile for
the one-pot reaction. Our previous study of the asym-
metric Michael reaction indicates that MeOH and
benzoic acid are effective as solvent and additive.
Therefore we utilized these previously defined condi-
AcONa
[a]
Unless otherwise shown, the reaction was performed
using 3-phenylpropanal (0.4 mmol), diphenylprolinol silyl
ether
(0.08 mmol),
DDQ
(0.4 mmol),
MeNO2
(4.0 mmol), additive (0.96 mmol), THF (1.6 mL) and
MeOH (0.8 mL) at room temperature. The first oxidation
is for 6 h.
The reaction time for the second Michael reaction.
Yield of the isolated Michael product.
[b]
[c]
[d]
Enantiomeric excess of the Michael product, which was
determined by HPLC analysis of chiral column.
tions as a starting point, employing DDQ as a stoi- Et3N, NH4OAc, AcOLi and AcONa is effective (en-
chiometric oxidant. 3-Phenylpropanal was treated tries 4–9). AcONa was found to be a suitable additive,
with 20 mol% of diphenylprolinol silyl ether and an affording the product in good yield with excellent
equimolar amount of DDQ in THF. After the oxida- enantioselectivity (entry 9). After the first oxidation
tion was complete, we added MeOH, MeNO2 and was complete, AcONa was added. The sodium salt of
benzoic acid, but the reaction scarcely proceeded. Al- hydroquinone was precipitated within 5 min. The ef-
though the second reaction proceeds by the use of fective removal of the acidic hydroquinone from the
isolated cinnamaldehyde, it did not proceed in se- solution could be the key to the success of this addi-
quential reactions. The difference would be the pres- tive. After the generation of the precipitate, addition
ence of the hydroquinone derivative, which is gener- of MeNO2 and MeOH promoted the second Michael
ated in the first oxidation. Hydroquinone would sup- reaction to afford the product. Evaporation and sol-
press the second Michael reaction. To promote the vent swap are not necessary. What we do is to add re-
second Michael reaction, we investigated the effect of agents and solvent. The absolute configuration of the
additives (Table 5). Although acids such as benzoic reaction product was determined by comparison with
acid and p-nitrophenol were not suitable (entries 1 the product synthesized by our previous procedure.[15]
and 2), a weak base such as Na2HPO4, NaHCO3,
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Table 6. Amount of AcONa in the one-pot oxidation and
MnO2 as a terminal oxidant (conditions B). In condi-
tions A, where an equimolar amount of DDQ was
employed, diphenylprolinol silyl ether was employed
in 20 mol% as we could not reduce the amount of
this catalyst to 10 mol% because of the gradual reac-
tion of this catalyst with DDQ. The results are sum-
marized in Table 7. In both sets of reaction conditions,
the results are similar. As for the b-substituent of the
a,b-unsaturated aldehyde, not only a phenyl group
(entry 1) but also electron-rich p-methoxyphenyl
(entry 2) and electron-deficient p-bromophenyl and
p-nitrophenyl groups (entries 3 and 4) were suitable,
where hydride abstraction and subsequent asymmetric
Michael reaction proceeded efficiently to afford the
product with excellent enantioselectivity. In addition
to the aromatic group, heteroaromatic groups such as
furyl and indole were successfully employed as b-sub-
stituent of the a,b-unsaturated aldehydes (entries 5
and 6). Pent-4-enal derivatives were also suitable sub-
strates. As for the substituents at the 5-position of
pent-4-enal, aromatic groups with both electron-rich
and electron-deficient substituents and heteroaromat-
ic substituents were employed as suitable substrates
to afford the products with excellent enantioselectivi-
ty (entries 7–10).
Michael reaction.[a]
Entry
X [mol%][b]
Yield [%][c]
ee [%][d]
1
2
3
24
10
5
73
72
56
95
96
95
[a]
Unless otherwise shown, the reaction was performed
using 3-phenylpropanal (0.4 mmol), diphenylprolinol silyl
ether (0.04 mmol), DDQ (0.04 mmol), MnO2 (0.8 mmol),
MeNO2 (4.0 mmol), THF (1.6 mL) and MeOH (0.8 mL)
at room temperature. Amount of AcONa is listed in
Table. The first oxidation is for 6 h, and the second Mi-
chael reaction is for 24 h.
Amount of AcONa.
Yield of the isolated Michael product.
Enantiomeric excess of the Michael product, which was
determined by HPLC analysis of chiral column.
[b]
[c]
[d]
Mechanism of the One-Pot DDQ Oxidation/Michael
Reaction
One-Pot Oxidation and 1,4-Addition using Catalytic
Amounts of both Diphenylprolinol Silyl Ether and
DDQ
The reaction is thought to proceed via two reaction
pathways (Scheme 2). The first path is oxidation,
which is rather fast, while the second reaction is the
Once we had established the one-pot sequential oxi- addition to nitromethane, which is slow. Diphenylpro-
dation and Michael reaction using an equimolar linol silyl ether reacts with the aldehyde to afford an
amount of DDQ, the reaction using DDQ in catalytic enamine along with the generation of water. The en-
amounts was investigated (Table 6). We have already amine reacts with DDQ, which abstracts a hydride, to
described the reaction using DDQ in a catalytic provide an iminium ion, and further with water to
amount with MnO2 as a terminal oxidant. These cata- afford an a,b-unsaturated aldehyde with regeneration
lytic conditions were applied to the one-pot sequen- of the catalyst. The a,b-unsaturated aldehyde then
tial reaction, which was found to proceed in good reacts with diphenylprolinol silyl ether to generate
yield with excellent enantioselectivity (entry 1). More- the iminium ion, which reacts with nitromethane to
over, the amount of AcONa could be reduced to afford the enamine. The enamine reacts with water to
10 mol% (entry 2). When it was reduced to 5 mol%, give the product with regeneration of the catalyst.
the reaction did not proceed to completion (entry 3). The iminium ion is also generated directly from an
Thus, as reagents such as diphenylprolinol silyl ether, iminium ion by reaction with AcONa. 4,5-Dichloro-
DDQ and AcONa can be employed in 10 mol%, the 3,6-dihydroxy-1,2-benzenecarbonitrile is too acidic
reaction can be regarded to be efficient and green.
and suppresses the second addition reaction of nitro-
methane. Addition of AcONa is essential for the suc-
cess for the sequential reaction, which reacts with the
hydroquinone derivative to generate its sodium salt.
This sodium salt is efficiently removed from the reac-
Generality of the One-Pot Reaction
After the best reaction conditions for the one-pot re- tion mixture by the precipitation.
action had been determined, the generality of the re-
action was investigated using two different stes of
conditions: the use of an equimolar amount of DDQ
(conditions A) and the catalytic use of DDQ with
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Organocatalyst-Mediated Dehydrogenation of Aldehydes to a,b-Unsaturated Aldehydes
Table 7. The generality of the one-pot, oxidative asymmetric Michael reaction.[a]
Entry
Product
Time [h][b]
Conditions A
Conditions B
Yield [%][c]
ee [%][d]
Yield [%][c]
ee [%][d]
1
2
3
12
12
12
75
77
66
92
72
76
63
96
95
95
94
96
95
95
4
12
65
62
5
6
20
12
62
70
94
92
60
62
81
94
7
8
9
4
3
78
80
91
92
71
74
90
91
4
8
71
64
90
85
73
62
90
87
10
[a]
Conditions A: aldehyde (0.4 mmol), DDQ (0.4 mmol), diphenylprolinol silyl ether (0.08 mmol), THF (1.6 mL), MeNO2
(4.0 mmol), AcONa (0.96 mmol), MeOH (0.8 mL). Conditions B: aldehyde (0.4 mmol), DDQ (0.04 mmol), diphenylproli-
nol silyl ether (0.04 mmol), MnO2 (0.8 mmol), THF (1.6 mL), MeNO2 (4.0 mmol), AcONa (0.04 mmol), MeOH (0.8 mL).
The reaction time of the addition reaction of nitromethane.
Yield of the isolated product.
For the determination of enantiomeric excess, see the Supporting Information.
[b]
[c]
[d]
Adv. Synth. Catal. 2013, 355, 3661 – 3669
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asc.wiley-vch.de
3667

Yujiro Hayashi et al.
FULL PAPERS
Scheme 2. Proposed reaction mechanism for the asymmetric oxidative reaction.
Conclusions
Experimental Section
We have developed a one-pot transformation of alde- Representative Procedure for the One-Pot, Oxidative
hydes into a,b-unsaturated aldehydes using both N- Asymmetric Michael Reaction using
benzyl-N-methylamine and DDQ as catalysts and Diphenylprolinol Silyl Ether and DDQ in Catalytic
MnO2 as a terminal oxidant. We also disclosed the ox- Amounts (Table 7, Entry 1, Conditions B)
idative and enantioselective reaction of aldehydes and
To a solution of 3-phenylpropanal (53.6 mg, 0.4 mmol), di-
nitromethane catalyzed by both diphenylprolinol silyl
phenylprolinol silyl ether (13.0 mg, 0.04 mmol) and MnO2
ether and DDQ as a catalyst using MnO2 as a terminal
(69.5 mg, 0.8 mmol) in THF (1.6 mL) was added 2,3-di-
oxidant. There are several noteworthy features in the
present reactions. As for the oxidation of aldehyde
into a,b-unsaturated aldehyde: (i) an achiral amine
can be used as a catalyst; and (ii) DDQ can be used
in catalytic amount. As for the oxidative enantioselec-
tive addition reaction: (i) the proton at the b-carbon
atom of an aldehyde was substituted with nitromethyl
(CH2NO2) enantioselectively, (ii) this reaction is a syn-
chloro-5,6-dicyano-1,4-benzoquinone (9.0 mg, 0.04 mmol) at
room temperature. After stirring the reaction mixture at
room temperature for 6 h, sodium acetate (3.3 mg,
0.04 mmol) was added to the resulting mixture. The reaction
mixture was stirred for additional 5 min. Then, MeOH
(800 mL) and nitromethane (214 mL, 4.0 mmol) were added
to the reaction mixture. The resulting solution was stirred
for 24 h at room temperature. The reaction was quenched
with saturated aqueous NaHCO3, and then filtered to
remove MnO2. The organic materials were extracted with
ethyl acetate three times, and then washed with brine. The
combined organic extracts were dried over anhydrous
Na2SO4, and concentrated under vacuum after filtration. Pu-
rification by column chromatography (ethyl acetate:hex-
ane=1:6) gave (S)-4-nitro-3-phenylbutanal; yield: 55.6 mg
(0.28 mmol, 72%).
À
thetic equivalent of C H activation at the b-carbon
atom of an aldehyde; (iii) b-substituted g-nitro alde-
hydes, an class of important synthetic intermediate,
can be synthesized with excellent enantioselectivity;
(iv) the secondary amine catalyst plays two different
roles: one is the generation of an enamine and the
other is the generation of an a,b-unsaturated iminium
ion; and finally (v) DDQ can act as a catalyst.
3668
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3661 – 3669

Organocatalyst-Mediated Dehydrogenation of Aldehydes to a,b-Unsaturated Aldehydes
Liang, C. Erikkson, Org. Lett. 1999, 1, 1599; c) B. P.
Acknowledgements
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This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Advanced Molecular Transfor-
mations by Organocatalysts” from The Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
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3669