Asymmetric michael addition of isobutyraldehyde to nitroolefins using an ?,?-Diphenyl-(S)-prolinol-derived chiral diamine catalyst

Article abstract of DOI:10.1246/bcsj.20200078

The enantioselective Michael addition of isobutyraldehyde to nitroolefin analogs was achieved by utilizing an ?,?-diphenyl(S)-prolinol-derived chiral diamine catalyst 1b. In this protocol, catalyst and additive loadings were reduced to 5 mol% respectively

Full text of DOI:10.1246/bcsj.20200078

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Asymmetric Michael addition of isobutyraldehyde to nitroolefins using an
,-diphenyl-(S)-prolinol-derived chiral diamine catalyst
Wei Han and Takeshi Oriyama*
Advance Publication on the web May 12, 2020
doi:10.1246/bcsj.20200078
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Asymmetric Michael addition of isobutyraldehyde to nitroolefins using an
,-diphenyl-(S)-prolinol-derived chiral diamine catalyst
Wei Han and Takeshi Oriyama*
Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 310-8512
E-mail: takeshi.oriyama.sci@vc.ibaraki.ac.jp
Abstract
shown to achieve high enantioselectivity for the Michael
addition of -branched aldehydes.5f,5h,6 Moreover, high catalyst
or additive loading of 20 mol% or more is often needed in
many circumstances.4,5b,5c,5g,5i,5k,6a,7 To date, procedures for this
transformation using the catalyst loading less than 5 mol% are
limited.5o,6b Thus, research on conducting more efficient
asymmetric Michael addition of ,-disubstituted aldehydes to
nitroolefins is still desired.
The
enantioselective
Michael
addition
of
isobutyraldehyde to nitroolefin analogs was achieved by
utilizing an ,-diphenyl-(S)-prolinol-derived chiral diamine
catalyst 1b. In this protocol, catalyst and additive loadings were
reduced to 5 mol% respectively, due to the presence of the
tertiary amine moiety in 1b.
Among the numerous chiral aminocatalysts currently in
use, diaryl-(S)-prolinol and the corresponding silyl ether
derivatives are known to be effective for various organic
reactions, including, asymmetric Michael additions, Mannich,
Keywords: asymmetric catalysis, Michael addition,
chiral diamine
1. Introduction
aldol,
Diels-Alder,
Friedel-Crafts,
-,
-
and
Enamine catalysis is one of the most powerful and
successful strategies for asymmetric synthesis.1 In particular,
chiral primary or secondary amine-based organocatalysts are
extremely useful for the enantioselective conjugate addition of
carbonyl compounds to nitroolefins via activation of the
enamine. The optically active -nitrocarbonyl products are
versatile precursors for constructing bioactive compounds.2
Although, the organocatalytic asymmetric Michael addition of
linear aldehydes/ketones to nitroolefins has been studied
extensively,3 Michael addition reactions using -branched
aldehydes as Michael donors have received little attention
owing to the difficulty in generating an all-carbon quaternary
center in the -nitroaldehyde Michael adducts.
-functionalization of carbonyl compounds, and cyclization
reactions.8 With these chiral aminocatalysts, high to excellent
enantioselectivity was achieved in these transformations.
By utilizing nitroolefins, the more catalytically activity
diphenyl-(S)-prolinol trimethylsilyl ether can be employed to
catalyze the asymmetric Michael addition of the -branched
aldehyde, isobutyraldehyde; this results in the Michael product
with moderate yield and enantioselectivity (68% ee).
Unfortunately, four days are needed to bring this result.8b
Recently, Juaristi et al. reported on the use of diamine
analogs derived from ,-diphenyl-(S)-prolinol and their
application as organocatalysts in asymmetric Michael and
Mannich reactions.5g In Juaristi’s report, diamine and diamine
analogs such as pyrrolidine-based azide, sulfonamide, amino
amide salts, and triazole were successfully synthesized and
examined via the asymmetric Michael addition of
isobutyraldehyde to nitroolefins. However, the catalytic activity
of these diamine analogs derived from diphenyl-(S)-prolinol
was unspectacular as better results could only be obtained after
high catalyst and additive loadings (20 mol% of amino azide
Generally, the construction of chiral compounds
containing a quaternary carbon center is a challenging task in
asymmetric synthesis. Despite the progress in research on the
organocatalytic
asymmetric
Michael
addition
of
,-disubstituted aldehydes to nitroolefins, as reported by
Barbas et al.,4 and the effort devoted to investigating this
transformation,5 only a few primary amine catalysts have been
Scheme 1. Effect of amino group on the right side of organocatalysts

catalyst and 0.5 equiv. of benzoic acid) and long reaction times
(12 days).
is not unclear, we propose that alcohol solvents effect the nitro
group of nitroolefin differently by H-bonding interactions
leading to these results.6c The use of THF and DMSO showed
that polar aprotic solvents were also ineffective for this
transformation (Table 2, Entries 9 and 10).
According to literatures9 and Juaristi’s research on the
mechanism of cyclization for amino amide and amino
thiourea catalysts,5g it was proposed that these catalysts’ loss of
activity was due to the generation of an aminal A, via an
intramolecular attack initiated by the catalysts’ amide or the
secondary amine moiety (Scheme 1a). It was theorized that
introducing a tertiary amino group on the right side of the
organocatalyst would circumvent the formation of the
catalyst-derived aminal and assist the proton transfer process,
thereby accelerating the Michael reaction (Scheme
1b).5c,5d,7a,7b,7d,10 Furthermore, the utilization of the diamine
catalysts 1a and 1b (Figure 1), and their analogs for
asymmetric synthesis is still rare and challenging task for
researchers.5g,11
Table 1. Screening of catalysts and acid additivesa
Entry Catalyst
Additive
PhCOOH
Yieldb (%)
eec (%)
1d
2
1a
1b
1b
1b
1b
trace
45
-
PhCOOH
89
89
90
-
3
salicylic acid
chloroacetic acid
(-)-CSA
43
4
21
Figure 1. Diamine catalysts derived from diphenyl-(S)-prolinol
5
NR
aReactions were carried out with isobutyraldehyde 2 (0.2
mmol), nitroolefin 3a (0.1 mmol), catalysts 1a or 1b, and the
additives in i-PrOH (0.2 ml) at room temperature. NR = No
reaction. bIsolated yield. cDetermined by chiral HPLC.
dReaction time was 2 days.
In this context, we report an efficient asymmetric Michael
addition of isobutyraldehyde to nitroolefins using a chiral
diamine catalyst 1b derived from ,-diphenyl-(S)-prolinol.
Herein, the Michael reaction was achieved with low catalyst
and additive loadings of 5 mol%, respectively, due to the
presence of the tertiary amine moiety in 1b.
2. Results and Discussion
The chiral diamine catalysts 1a12 and 1b were initially
synthesized according to the reported protocol (Figure 1).11c To
prove our hypothesis, we explored the catalytic activity of these
chiral diamines in the Michael addition of isobutyraldehyde to
the nitroalkene 3a using benzoic acid as an additive (both the
catalyst and additive loadings were 10 mol%, respectively) in
isopropanol.5g When 1a was used, only trace amounts of the
Michael adduct 4a were observed even though the reaction was
conducted over two days; in contrast, catalyst 1b provided 4a
with moderate yields of 45% and a high enantioselectivity
value of 89% ee (Table 1, Entries 1 and 2). Encouraged by
these results, we then investigated the use of carboxylic acids
Table 2. Screening of solvents for asymmetric Michael
addition
Entry
Solvent
Yieldb (%)
eec (%)
1d
2
3
4
5
6
7
8
9
neat
CH2Cl2
CHCl3
toluene
H2O
i-PrOH
MeOH
t-BuOH
THF
26
18
21
trace
NR
91
95
95
94
-
such
as
salicylic
acid,
chloroacetic
acid,
and
(-)-camphorsulfonic acid (Table 1, Entries 3-5) as possible
additives. However, since the best result of these series were
obtained with benzoic acid (Table 1, Entry 2), we decided to
use 1b as the catalyst and benzoic acid as the additive to screen
other reaction conditions.
-
93
87
-
-
77
40
NR
NR
30
Next, the effects of solvents were investigated (Table 2).
Here, 4 equiv. of isobutyraldehyde was used instead of the
usual 5 or 10 equiv. employed in previously reported studies.
Under neat reaction conditions, as well as with CH2Cl2 and
CHCl3, the Michael product 4a was obtained with high
enantioselectivity 94-95% ee but low yields (Table 2, Entries
1-3). Toluene and water were also examined and found to be
unsuitable for the Michael addition (Table 2, Entries 4 and 5).
The use of i-PrOH as a solvent afforded product 4a with 91%
yield and a high enantioselectivity value of, 93% ee (Table 2,
Entry 6). It is worth noting that polar protic solvents such as
MeOH and t-BuOH exerted significant effects on the overall
reactivity. The use of MeOH only slightly reduced
enantioselectivity and caused a notable decline in the yield
(Table 2, Entries 6 and 7), whereas, the reaction was
unsuccessful in t-BuOH (Table 2, Entry 8). Although the reason
10
DMSO
aReactions were carried out with isobutyraldehyde 2
(0.4 mmol), nitroolefin 3a (0.1 mmol), catalyst 1b, and
PhCOOH in the relevant solvent (0.2 ml) at room
temperature. NR = No reaction. bIsolated yield.
cDetermined by chiral HPLC.
isobutyraldehyde were used.
8
equiv. of
d
Next, the impact of various catalyst and additive loadings
on the Michael addition reaction was investigated (Table 3).
The ratio of catalyst 1b and PhCOOH only slightly affected the
Michael addition of isobutyraldehyde to nitroolefin 3a, as both
the yield and the enantiomeric purity were obtained with almost
the same degree (Table 3, Entries 1-3). Fortunately, reducing

the amount of catalyst and PhCOOH to 5 mol% respectively,
also resulted in successful catalyzation of the Michael reaction
(Table 3, Entries 1 and 4). Using 5 mol% 1b and reducing
PhCOOH to 3 mol% afforded the Michael adduct 4a with
excellent enantioselectivity (95% ee), but decreased the yield to
70% (Table 3, Entries 4 and 5). Given this, we stopped
reducing the amount of 1b and PhCOOH altogether and
concluded that increasing the amount of isobutyraldehyde from
4 to 5 equiv. provided product 4a with better yield and higher
enantiomeric purity (Table 3, Entries 4 and 6). Therefore, we
chose to conduct the Michael addition reactions with 5 equiv.
of aldehyde 2. This was consistent with previous reports in
which the influence13 exerted by the acid additive affected the
reaction rate but not the enantioselectivity (Table 3, Entries 6
and 7). From the above results, the optimal reaction conditions
were as follows: nitroolefins (0.1 mmol), 5 mol% each of
catalyst 1b and PhCOOH, as well as 5 equiv. of aldehyde 2, in
0.2 ml i-PrOH at room temperature (Table 3, Entry 6).
contained halogen atoms, such as 4-chloro, 4-bromo, 3-bromo,
on the phenyl ring also afforded the Michael adducts 4d-f in
good to excellent yields 66-99% with high enantioselectivity
values of 94-96% ee (Table 4, Entries 4-6). It should be noted
that the groups substituted at the ortho position on the phenyl
ring significantly lowered both the reactivity and the
enantioselectivity of the nitroolefins, as evidenced by the
relatively poor yields and moderate enantiomeric purity of the
adduct products 4g-h (Table 4, Entries 7 and 8 vs. 5 and 6).
Fortunately, nitroolefins with
a 2-naphthyl group or a
heteroaryl ring, such as 2-furyl and 2-thiophenyl groups,
afforded the Michael products 4i-k in 33-97% yields with high
enantioselectivity values of 90-91% ee (Table 4, Entries 9-11).
In addition to the electronic effect and ortho-substituted
influence exerted on nitroolefins, it was theorized that their
reduced solubility in i-PrOH might have led to diminished
chemical yields in some cases (Table 4, Entries 5, 7 and 9).
In
addition,
cyclopentanecarboxaldehyde
(cyclic
With the optimized reaction conditions in hand, we next
examined various nitroolefins using isobutyraldehyde as a
Michael donor (Table 4) and found that nitroolefins bearing
an electron-withdrawing 4-cyano group were more reactive
than those that had an electron-donating 4-methyl group in the
aromatic ring (Table 4, Entries 2 and 3). Although the
electronic effect of 4-methyl substitution resulted in long
reaction time, the corresponding products 4b and 4c were
obtained in moderate to good yields of 39% and 78% with high
to excellent enantioselectivity values of 90% and 97% ee,
respectively (Table 4, Entries 2 and 3). Nitroolefins that
-branched aldehyde) and 3-methylbutanal (an aliphatic
-branched aldehyde) were also examined as the Michael
donors. Cyclopentanecarboxaldehyde reacted with nitroolefin
3a under the optimized reaction conditions to give the
corresponding Michael adduct 4l in 34% yield with 57% ee
after 12 h. The Michael product of 3-methylbutanal (4m) was
obtained in 80% yield, syn/anti = 87/13 dr, and 98% ee for the
syn diastereomer (see supporting information).
Table 3. Optimization of reaction conditionsa
Entry
Aldehyde 2 (equiv.)
1b (mol%)
10
PhCOOH (mol%)
10
Yieldb (%)
eec (%)
93
1
2
3
4
5
6
7
4
4
4
4
4
5
5
91
97
94
94
70
96
39
10
5
5
10
5
92
92
5
92
5
3
95
5
5
93
5
-
92
aReactions were carried out with isobutyraldehyde 2, nitroolefin 3a (0.1 mmol), catalyst 1b, and PhCOOH
in i-PrOH (0.2 ml) at room temperature. bIsolated yield. cDetermined by chiral HPLC.

Table 4. Asymmetric Michael addition of isobutyraldehyde to various nitroolefinsa
Entry
1
Ar
Product 4
Yieldb (%)
eec (%)
93
Ph
4a
4b
4c
4d
4e
4f
96
78
39
95
66
99
26
60
33
97
78
2
4-CNC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
2-MeOC6H4
2-naphthyl
2-furyl
97
3d
4
90
94
5e
6
96
96
7f
4g
4h
4i
74
8f
81
9d
10
11
91
4j
91
2-thiophenyl
4k
90
aReactions were carried out with isobutyraldehyde 2 (0.5 mmol), nitroolefin 3a (0.1 mmol), catalyst 1b, and
b
c
d
PhCOOH in i-PrOH (0.2 ml) at room temperature. Isolated yield. Determined by chiral HPLC. Reaction
time was 3 days. eReaction time was 2 days. fReaction time was 4 days.
3. Conclusion
In conclusion, an efficient method for the asymmetric
Michael addition of isobutyraldehyde to nitroolefins was
achieved via the use of a chiral diamine catalyst derived from
,-diphenyl-(S)-prolinol. In our protocol, the Michael
addition was successfully conducted with low catalyst and
additive loadings of 5 mol%, respectively, due to the
presence of the tertiary amine group in the catalyst 1b.
Moreover, various quaternary carbon containing optically
active -nitroaldehydes were obtained in good yields (up to
99%) and good to excellent enantioselectivity (up to 97% ee).
Supporting Information: (Experimental data is in the
material).
This
material
is
available
on
http://dx.doi.org/10.1246/bcsj.***.

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