Asymmetric Michael Reaction of Aldehydes and Dicyanoalkenes Catalyzed by Diphenylprolinol Silyl Ether

Article abstract of DOI:10.1002/ejoc.201800831

Asymmetric Michael reactions of aldehydes and dicyanoalkenes catalyzed by diphenylprolinol silyl ether give the corresponding Michael adducts in good yields with excellent enantioselectivities. The diastereoselectivity is dependent on the bulkiness of the Michael donor. The Michael adducts can be easily transformed into useful chiral compounds such as lactones, esters, and monocyanated derivatives.

Full text of DOI:10.1002/ejoc.201800831

DOI: 10.1002/ejoc.201800831
Communication
Asymmetric Organocatalysis
Asymmetric Michael Reaction of Aldehydes and Dicyanoalkenes
Catalyzed by Diphenylprolinol Silyl Ether
Yujiro Hayashi,*[a] Nektarios Kranidiotis-Hisatomi,[a] Daisuke Sakamoto,[a] Kyohei Oritani,[b]
Takuji Kawamoto,[b] and Akio Kamimura[b]
Abstract: Asymmetric Michael reactions of aldehydes and di- the bulkiness of the Michael donor. The Michael adducts can
cyanoalkenes catalyzed by diphenylprolinol silyl ether give the
corresponding Michael adducts in good yields with excellent
enantioselectivities. The diastereoselectivity is dependent on
be easily transformed into useful chiral compounds such as lact-
ones, esters, and monocyanated derivatives.
Introduction
such as THF, MeOH, MeCN or DMF, no reaction was observed.
Further solvent investigation led us to toluene, in which the
reaction proceeded in moderate yield (36 %) with excellent
diastereo- and enantioselectivities (anti/syn = 10:1, 95 % ee,
Table 1, entry 1).
Organocatalysts[1] constitute one of the main categories of cata-
lysts, along with organometallic and biocatalysts. Organocata-
lysts have been successfully applied to the Michael reaction,
which represents one of the most powerful methods for form-
ing carbon–carbon bonds in organic synthesis.[2]
Table 1. Effect of acids in the Michael reaction of 2 and 3 catalyzed by 1.[a]
Our group[3] and Jørgensen's group[4] independently devel-
oped diphenylprolinol silyl ether 1[5] as an effective organocata-
lyst involving an enamine and an iminium ion as reactive inter-
mediates. This catalyst has been applied to many Michael
reactions of aldehydes as the Michael donors, and a variety of
Michael acceptors, such as nitroalkenes,[3] vinyl sulfones,[6]
methyl vinyl ketones,[3,7] ꢀ-substituted α-nitroacrylates,[8] etc.
Dicyanoalkenes are useful Michael acceptors,[9] and are also
used in asymmetric Michael reactions catalyzed by organo-
catalysts. Zhao and co-workers used enals and tritylisatylidene-
malononitriles via a tandem Michael–Michael reaction catalyzed
by 1 to synthesize highly functionalized spirooxindole deriva-
tives,[10] whereas Wennemers reported the Michael reaction of
acetophenones and dicyanoalkenes catalyzed by tripeptide.[11]
However, as far as we are aware, there are no reports on the
asymmetric catalytic Michael reaction of aldehydes and di-
cyanoalkenes, which we will describe here.
[b]
Entry Additive [equiv.]
pKa
Yield [%][c]
syn/anti[d] ee [%][e]
1
2
3
4
5
6
7
8
9
–
–
36
< 5
68
1:10
–
95
–
p-Nitrophenol (1.0)
7.15
2,4,6-Trichlorophenol (1.0) 6.21
1:8
1:2
–
99
97
–
Acetic acid (1.0)
Formic acid (1.0)
Chloroacetic acid (1.0)
4.76
3.75
2.85
81
< 5
< 5
60
45
35
–
–
2,4,6-Trichlorophenol (0.5) 6.21
2,4,6-Trichlorophenol (1.5) 6.21
2,4,6-Trichlorophenol (2.0) 6.21
1:8
1:5
1:5
97
99
99
[a] Unless otherwise shown, the reaction was performed by employing 3-
phenylpropanal (2) (0.9 mmol), benzylidenemalononitrile (3) (0.3 mmol), cata-
lyst 1 (0.03 mmol), additive (0.3 mmol) and toluene (0.6 mL) at 0 °C for
3 h. Next, trimethyl orthoformate (1.35 mmol) and p-toluenesulfonic acid
monohydrate (0.09 mmol) were added. See supporting information for de-
tails. [b] pKa values (in H2O) were exported from www.zirchrom.com/
organic.htm and the references therein. [c] Isolated yield after column chro-
matography. [d] Determined by 1H-NMR of the crude product. [e] Determined
by HPLC analysis on a chiral column.
Results and Discussion
3-Phenylpropanal (2) and benzylidenemalononitrile (3) were se-
lected as a model Michael donor and acceptor, respectively.
When 2 and 3 were treated with catalyst 1 in polar solvents
[a] Department of Chemistry, Graduate School of Science, Tohoku University,
6-3 Aramaki-Aza Aoba-ku, Sendai, Miyagi 980-8578 Japan
E-mail: yhayashi@m.tohoku.ac.jp
http://www.ykbsc.chem.tohoku.ac.jp
[b] Department of Applied Chemistry, Yamaguchi University,
2-16-1 Tokiwadai, Ube, Yamaguchi 755-8611 Japan
To improve the yield, the reaction conditions were thor-
oughly investigated. Our previous works on similar Michael re-
actions indicated the important role of acid.[3,8,12] Our investiga-
tions into the effect of acid began with a selection of acids
covering a wide range of pKa values (Table 1). The results indi-
cate a mutual relationship between the pKa value of acid and
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800831.
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reaction efficiency. The addition of acetic acid decreased the case of propanal, syn-isomer was obtained as the major product
diastereoselectivity but increased slightly the enantioselectivity (entry 4). This would be explained as follows. According to See-
and doubled the yield compared with the absence of the acid bach's topological rule,[13] enamine approaches via two transi-
(entry 4; pKa 4.76). The reaction proceeded in 68 % yield in tion states (Figure 1). When R is bulky, the syn-transition state
the presence of less acidic 2,4,6-trichlorophenol, giving the best is unfavorable because of the steric repulsion, and therefore the
combination of yield, diastereo- and enantioselectivity (entry 3; anti-isomer predominates.
pKa 6.21). Weaker acids with pKa > 7 or stronger acids with
pKa < 4 inhibited the reaction, resulting in a dramatically de-
creased reactivity (entries 2, 5, 6). In addition, the amount of
Table 3. Generality of aldehydes in the Michael reaction with benzylidene-
malononitrile (3) catalyzed by 1.[a]
acid was investigated. Fewer or more equivalents of additive
than the optimal one equivalent decreased the reactivity and
diastereoselectivity (entries 7–9).
Next, the ratio of the starting materials was investigated
(Table 2). In our initial investigations, we used an excess amount
of aldehyde (3 equiv.). After optimizing the solvent, tempera-
ture, catalyst-loading and additive, we examined the possibility
of reducing the amount of aldehyde. However, when the
amount of aldehyde was reduced to 1.5 equiv. and 1.0 equiv.
(entries 2 and 3), the reaction proceeded in lower yields and
with lower diastereo- and enantioselectivities. When instead of
aldehyde, an excess amount of Michael acceptor (3 equiv.) was
used, the reaction was completed more quickly but in slightly
lower yield and with lower diastereoselectivity (entry 4).
Table 2. Ratio of starting materials in the Michael reaction of 2 and 3 cata-
lyzed by 1.[a]
[a] Unless otherwise shown, the reaction was performed by employing alde-
hyde (0.9 mmol), benzylidenemalononitrile (3) (0.3 mmol), catalyst
1
(0.03 mmol), 2,4,6-trichlorophenol (0.3 mmol) and toluene (0.6 mL) at 0 °C
for the indicated time. After the reaction, trimethyl orthoformate (1.35 mmol)
and p-toluenesulfonic acid monohydrate (0.09 mmol) were added. See sup-
porting information for details. [b] Isolated yield after column chromatogra-
phy. [c] Determined by 1H-NMR of the crude product. [d] Enantiomeric excess
of the major isomer determined by HPLC analysis on a chiral column.
Entry
X [equiv.]
Y [equiv.]
Yield [%][b]
syn/anti[c]
ee [%][d]
1
2
3
1.5
1
1
1
1
3
68
48
35
51
1:8
1:3
1:3
1:7
99
97
97
99
3
4[e]
1
[a] Unless otherwise shown, the reaction was performed by employing 3-
phenylpropanal (2), benzylidenemalononitrile (3), catalyst 1, 2,4,6-trichloro-
phenol and toluene at 0 °C for 3 h. Next, trimethyl orthoformate and p-
toluenesulfonic acid monohydrate were added. See supporting information
for details. [b] Isolated yield after column chromatography. [c] Determined
by 1H-NMR of the crude product. [d] Determined by HPLC analysis on a chiral
column. [e] Reaction time = 30 min.
Figure 1. The transition state models in the reaction of enamine and benzyl-
idenemalononitrile (3).
Next, the generality of dicyanoalkenes was investigated with
a variety of ꢀ-aromatic and ꢀ-aliphatic substituted dicyanoalk-
enes, using propanal as the Michael donor (Table 4). Not only
a unsubstituted phenyl group (entry 1), but also phenyl groups
with electron-deficient substituents such as p-bromo and p-
nitro groups (entries 2, 3) or electron-rich substituents such as
the p-methoxy group (entry 4) are suitable to afford the corre-
sponding Michael adducts in good yields with moderate
syn-selectivities and excellent enantioselectivities. Aliphatic di-
cyanoalkenes such as 3-phenylpropylidenepropane-dinitrile
(entry 5) are also suitable Michael acceptors to provide prod-
ucts with high diastereo- and excellent enantioselectivities.
Then, the generality of dicyanoalkenes was investigated in
As the best conditions were determined (3 equiv. of alde-
hyde, 1 equiv. of 2,4,6-trichlorophenol, 10 mol-% of catalyst 1
in toluene at 0 °C), the generality of the reaction was investi-
gated. The results of the aldehyde scoping are summarized in
Table 3. Not only 3-phenylpropanal (entry 1), but also pent-4-
enal, butanal and propanal (entries 2, 3, 4) are effective Michael
donors that afford Michael products with excellent enantio-
selectivities. When 2-(benzyloxy)ethanal or 3-(4-methoxybenz-
yloxy)propanal were used, the desired compounds could not
be obtained. As for the diastereoselectivity, it depends on the
aldehyde bulkiness. In the reaction of 3-phenylpropanal, anti-
isomer was obtained in high selectivity, whereas the anti/syn case of 3-phenylpropanal as the Michael donor for generation
ratio decreased as the bulkiness of aldehyde decreased. In the of anti-isomers (Table 5). Not only a unsubstituted phenyl group
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Table 4. Generality of dicyanoalkenes in the Michael reaction with propanal
(entry 1) but also phenyl groups with electron-deficient substit-
uents such as p-nitro and p-chloro groups (entries 2, 3) or elec-
tron-rich substituents such as the p-methyl group (entry 4) af-
ford the corresponding Michael adducts in moderate yields
with good anti-selectivities and excellent enantioselectivities.
Having completed the generality investigation, we turned
our attention to the results of Table 2, which indicate that an
excess amount of aldehyde 2 is necessary to obtain high yield.
To this end, we performed some NMR studies. The reaction pro-
files in the cases of three equivalents and one equivalent of
aldehyde 2 showed that both reactions finished within 30 min-
utes.[14]
catalyzed by 1.[a]
We suspected that this could be because of the retro-
Michael reaction. To confirm the presence of the retro-Michael
reaction, the product 6 was subjected to the reaction condi-
tions. When the Michael adduct 6 was treated with the catalyst
1, 2,4,6-trichlorophenol in toluene at 0 °C, 3-phenylpropanal (2)
and benzylidenemalononitrile (3) were obtained in 39 % and
37 % yields after 30 minutes (Figure 2). According to the profile
of the reaction, the retro-Michael reaction is rather rapid. Al-
though a retro-Michael reaction occurs, an excess of aldehyde
2 gave a good yield (Table 2, entry 1), whereas an excess of
dicyanoalkene 3 was not effective (Table 2, entry 4). Next, we
treated a mixture of the product 6 and two equivalents of 3-
tolylpropanal (7) with catalyst 1 and 2,4,6-trichlorophenol in tol-
uene at 0 °C for 30 minutes. As shown in Equation (7), the
generation of 3-phenylpropanal (2) and benzylidenemalono-
nitrile (3) was suppressed, and the cross Michael product 8 was
not observed. The reason that excess aldehyde is effective is
not because the excess aldehyde shifted the equilibrium to the
products, but because catalyst 1 reacted preferentially with less
[a] Unless otherwise shown, the reaction was performed by employing
propanal (5) (0.9 mmol), dicyanoalkene (0.3 mmol), catalyst 1 (0.03 mmol),
2,4,6-trichlorophenol (0.3 mmol) and toluene (0.6 mL) at 0 °C for the indicated
time. After the reaction, trimethyl orthoformate (1.35 mmol) and p-toluene-
sulfonic acid monohydrate (0.09 mmol) were added. See supporting informa-
tion for details. [b] Isolated yield after column chromatography. [c] Deter-
mined by 1H-NMR of the crude product. [d] Determined by HPLC analysis on
a chiral column.
Table 5. Generality of dicyanoalkenes in the Michael reaction with 3-phenyl-
propanal catalyzed by 1.[a]
[a] Unless otherwise shown, the reaction was performed by employing 3-
phenylpropanal (2) (0.9 mmol), dicyanoalkene (0.3 mmol), catalyst
1
Figure 2. The retro-Michael reaction of 6 under the optimal reaction condi-
tions[a] [a] Michael adduct 6 (0.14 mmol), catalyst 1 (0.014 mmol), 2,4,6-tri-
chlorophenol (0.14 mmol) and 1,3,5-trimethoxybenzene (0.047 mmol) as an
internal standard, were dissolved in toluene at 0 °C. The reaction was moni-
tored by 1H spectroscopy. The concentration of each compound was calcu-
lated by integration of selected peaks in the 1H NMR spectra and plotted on
the graph. See supporting information for details.
(0.03 mmol), 2,4,6-trichlorophenol (0.3 mmol) and toluene (0.6 mL) at 0 °C
for the indicated time. After the reaction, trimethyl orthoformate (1.35 mmol)
and p-toluenesulfonic acid monohydrate (0.09 mmol) were added. See sup-
porting information for details. [b] Isolated yield after column chromatogra-
phy. [c] Determined by 1H-NMR of the crude product. [d] Determined by
HPLC analysis on a chiral column. [e] Catalyst amount = 20 mol %.
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sterically hindered 3-tolylpropanal (7) and the reaction of cata- tionally simple protocol for accessing a variety of useful struc-
lyst 1 with the product 6 became slow, suppressing the retro- tural motifs from readily available nonmodified aldehydes and
Michael reaction.
dicyanoalkenes as starting materials.
Experimental Section
Asymmetric Michael Reaction of Aldehydes and Dicyanoalk-
enes Followed by Acetalization: To a mixture of dicyanoalkene
(0.3 mmol), 2,4,6-trichlorophenol (0.3 mmol) and catalyst
1
(0.03 mmol) in toluene (0.6 mL) was added aldehyde (0.9 mmol) at
0 °C. After stirring for specified time, shown in the above tables
trimethyl orthoformate (1.35 mmol) and p-toluenesulfonic acid
monohydrate (0.09 mmol) were added to the reaction mixture at
the same temperature. After 30 min, aq. saturated NaHCO3 (1 mL)
was added to the reaction mixture. The separated aqueous layer
was extracted with EtOAc (3 × 3 mL). The combined organic layers
were dried with Na2SO4, filtered, concentrated in vacuo and the
crude material was purified by flash column chromatography on
silica gel to afford the desired product.
Since the obtained Michael products contained several func-
tional groups such as formyl and dicyano moieties, they would
make versatile synthetic intermediates. The potential of this cat-
alytic methodology is shown below by some transformations of
the Michael products into useful chiral building blocks. Namely,
lactonization of reduced Michael adduct 9 under acidic condi-
tions, results in the respective lactone 10 with excellent enan-
tioselectivity [Equation (8)]. Treatment of silyl-ether-protected
Michael adduct 11 with magnesium monoperoxyphthalate
(MMPP) provides the corresponding methyl ester 12 in excel-
lent enantioselectivity [Equation (9)].[15] Moreover, treatment of
the acetalized Michael adduct 4 with 1,3-dimethylimidazol-2-
ylidene borane resulted in the mono-cyanated Michael product
13 in high yield without decreasing the excellent enantioselec-
tivity [Equation (10)].[16]
Acknowledgments
N. K.-H. thanks Alexander S. Onassis Public Benefit Foundation
for a postgraduate scholarship (F ZM 045-1/2016-2017). This
work was supported by JSPS KAKENHI Grant Number
JP18H04380 in Middle Molecular Strategy.
Keywords: Organocatalysis · Asymmetric catalysis · Michael
addition · Dicyanoalkenes
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Conclusions
We have achieved the asymmetric Michael reaction of alde-
hydes and dicyanoalkenes catalyzed by diphenylprolinol silyl
ether 1, which was applied successfully to a variety of Michael
donors and acceptors. The reaction delivered moderate to high
yields with good diastereoselectivities and excellent enantio-
selectivities. The present catalytic system introduces an opera-
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[14] See the Supporting Information.
Received: May 30, 2018
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Asymmetric Organocatalysis
Y. Hayashi,* N. Kranidiotis-Hisatomi,
D. Sakamoto, K. Oritani,
T. Kawamoto, A. Kamimura ............ 1–6
Asymmetric Michael Reaction of Al-
dehydes and Dicyanoalkenes Cata-
lyzed by Diphenylprolinol Silyl Ether
Asymmetric Michael reaction of alde- selectivities. The Michael adducts can
hydes and dicyanoalkenes catalyzed be easily transformed into useful chiral
by diphenylprolinol silyl ether gives compounds such as lactones, esters
the corresponding Michael adducts in and monocyanated derivatives.
good yields with excellent enantio-
DOI: 10.1002/ejoc.201800831
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