Highly enantioselective Michael addition of α,α-disubstituted aldehydes to nitroolefins

Article abstract of DOI:10.1007/s11164-016-2468-0

A highly enantioselective Michael addition reaction of α,α-disubstituted aldehydes to β-nitrostyrenes has been developed. In the presence of rosin-based chiral primary amine-thiourea, γ-nitroaldehydes were afforded in excellent enantioselectivities (up to

Full text of DOI:10.1007/s11164-016-2468-0

Res Chem Intermed
DOI 10.1007/s11164-016-2468-0
Highly enantioselective Michael addition
of a,a-disubstituted aldehydes to nitroolefins
Xing-Tao Guo1 Feng Sha1 Xin-Yan Wu1
•
•
Received: 10 December 2015 / Accepted: 30 January 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A highly enantioselective Michael addition reaction of a,a-disubstituted
aldehydes to b-nitrostyrenes has been developed. In the presence of rosin-based
chiral primary amine-thiourea, c-nitroaldehydes were afforded in excellent enan-
tioselectivities (up to 99 % ee) with up to 99 % yield.
Keywords Chiral primary amine-thiourea Á a,a-Disubstituted aldehydes Á
Enantioselective organocatalysis Á Michael addition Á Nitroolefins
Introduction
The Michael addition reaction of aldehydes with nitroalkenes is an important
approach to form C–C bonds in organic synthesis [1, 2]. The corresponding
c-nitroaldehydes are used as versatile synthetic precursors for bioactive compounds
[3, 4]. So far, the utilization of a,a-disubstituted aldehydes as Michael donors has
been a topical area, and much effort has been devoted to the organocatalytic
asymmetric conjugate addition of a,a-disubstituted aldehydes with nitroalkenes [5–
25]. Primary amine reacts more easily with aldehydes to produce enamine
intermediates than secondary amine did. These reactions typically involve
hydrogen-bond donors to improve drastically the enantioselectivity [2]. For
asymmetric conjugate additions of isobutyraldehyde to b-nitrostyrenes, high
stereoselectivities (C90 % ee) could be obtained by bifunctional primary amine
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2468-0)
contains supplementary material, which is available to authorized users.
&
Xin-Yan Wu
xinyanwu@ecust.edu.cn
1
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University
of Science and Technology, Shanghai 200237, People’s Republic of China
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X.-T. Guo et al.
organocatalysts such as primary amine-sulfamides [12] and primary amine-
thioureas [13, 14, 16, 20]. However, for the formation of all-carbon quaternary
stereogenic centers through the asymmetric Michael reaction of a,a-disubstituted
aldehydes with nitroalkenes, only primary amine catalysts involving Jacobsen’s
catalyst (92–99 % ee) [5] and OtBu-L-threonine (90–99 % ee) [19] have been
proven highly efficient in controlling enantioelectivity. As a consequence, it remains
challenging to explore highly effective catalytic systems for the asymmetric
Michael reaction of a,a-disubstituted aldehydes.
Chiral bifunctional organocatalysts using dehydroabietic amine as a thiourea
scaffold, as first developed by Wang and co-workers [26], have shown high
efficiency for a variety of reactions including aldol condensation [27], Henry
reaction [28], Michael addition [26, 29–34], Mannich reaction [35, 36], etc. [37–54].
However, the corresponding primary amine-thioureas have been only used in a few
reactions, such as the Michael reaction of methyl ketones with nitrostyrenes [26],
conjugate addition of nitroalkanes with a,b-unsaturated ketones [34], and a Diels–
Alder reaction [45]. In addition, rosin-based primary amine-thiourea has never been
reported as a chiral catalyst in a Michael reaction with aldehyde as the donor. With
continuing interest in the development of new enantioselective Michael reactions
[16, 34, 55–58], we sought to use primary amine-thioureas to promote the Michael
addition of aldehydes with nitroalkenes. Herein, a new asymmetric Michael reaction
between a,a-disubstituted aldehydes and nitroolefins is reported.
Results and discussion
To begin with, the Michael addition reaction of isobutyraldehyde to b-nitro-4-
nitrostyrene was performed as a model reaction to survey the chiral organocatalysts
(Fig. 1). The reactions with dehydroabietic amine-based catalysts 1a–c were found
to complete with a short reaction time (Table 1, entries 1–3). Both enantiomers of
the desired product were obtained in 99 % yield with 99 % ee by using chiral
catalysts 1a and 1b. However, catalyst 1c containing racemic diaminocyclohexane
backbone gave a racemic Michael adduct. These results revealed that dehydroa-
bietic amine had no effect on the enantioselectivity but remarkable influence on the
reactivity. This observation was in agreement with Wang’s previous report on the
enantioselective Michael reaction of methyl ketones with b-nitrostyrenes [26],
providing a new protocol for the selective synthesis of both enantiomers [16]. For
comparison, thioureas 1d–g without a rosin scaffold were examined. We determined
that while these catalysts also promoted the Michael reaction to produce the desired
product with excellent enantioselectivity (98 % ee for each, entries 4–7), their
catalytic activities were lower than amine-thioureas 1a–c. Due to a slow conversion,
catalysts 1d and 1e bearing different chiral a-phenylethyl groups provided the
product with moderate yield after stirring for 24 h (65 and 55 % yields with 1d and
1e, respectively). This result accorded with Yan’s previous research that the chiral
a-phenylethyl moiety adjacent to the thiourea group had an impact on the reactivity,
but the stereoselectivity depends on the chiral diaminocyclohexane backbone
(entries 4 and 5) [13]. When catalyst 1f was used, the Michael adduct was provided
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Highly enantioselective Michael addition of…
Fig. 1 Structure of chiral bifunctional organocatalysts 1a–g
Table 1 Catalyst screening for the Michael reaction of isobutyraldehyde
Entry
Catalyst
Time (h)
Yielda (%)
Eeb (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
10
10
10
24
24
24
20
99
99
99
65
55
73
93
99
-99
0
98
98
98
1g
98
Reaction conditions: isobutyraldehyde (1.25 mmol), b-nitro-4-nitrostyrene (0.25 mmol), catalyst
(0.0375 mmol), CH2Cl2 (2 mL), 25 °C
a
Isolated yield
b
Determined by chiral HPLC analysis
with only 73 % yield even after reacting 24 h, and a certain amount of b-nitro-4-
nitrostyrene still was observed. A previous report [13] suggested that the catalytic
activity of 1f was improved when DMAP was used as co-catalyst for the same
reaction. For amine-thiourea 1g, a longer reaction time was required for higher
conversion (entry 7 vs. 1).
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X.-T. Guo et al.
Table 2 Optimization of the reaction conditions for the Michael reaction
Entry
2a/3a
1a (mol%)
Solvent
Time (h)
Yielda (%)
Eeb (%)
1
5
5
5
5
5
5
5
5
5
4
3
15
15
15
15
15
15
15
10
5
Toluene
CH2Cl2
CHCl3
THF
10
10
12
48
48
48
48
24
48
24
48
99
99
99
88
87
90
16
99
70
99
75
98
99
99
96
94
89
4
2
3
4
5
EtOAc
MeCN
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
6
7
8
99
99
99
99
9
10
11
10
10
Reaction conditions: isobutyraldehyde, b-nitro-4-nitrostyrene (0.25 mmol), catalyst 1a, CH2Cl2 (2 mL),
25 °C
a
Isolated yield
b
Determined by chiral HPLC analysis
We then optimized the reaction conditions of the conjugate addition in the
presence of 15 mol% of catalyst 1a (Table 2). The solvent effect was probed
(entries 1–7). The desired product was obtained in excellent yields and ee values in
toluene, CH2Cl2 and CHCl3 (entries 1–3). Polar solvents such as THF, EtOAc, and
MeCN led to slower reaction rates and good yields with high enantioselectivities
(87–90 % yield, 89–96 % ee, entries 4–6). Because of a low conversion, the yield
dropped largely when DMSO was used as solvent, and the desired product was
given with only 16 % yield and 4 % ee even after stirring for 2 days (entry 7). It
was found that the catalyst loading had an influence on the reaction rate but not the
enantioselectivity. c-Nitroaldehyde was obtained with 99 % yield in 24 h when the
catalyst loading was cut down from 15 to 10 mol% (entry 8). Subsequently,
decrease of the catalyst loading to 5 mol% resulted in an apparently slower reaction
rate, and only 70 % yield was obtained after 2-day stirring (entry 9). Moreover,
while use of 4 equivalents of isobutyraldehyde (relative to b-nitro-4-nitrostyrene)
did not change the resulting yield and enantioselectivity, further decrease of
aldehyde resulted in a much lower conversion with 75 % yield obtained in 48 h
(entries 10 and 11). On the basis of the above results, the optimal reaction condition
was determined as 0.125 mol/L of b-nitro-4-nitrostyrene in CH2Cl2, 4 equivalents
of aldehyde at 25 °C with addition 10 mol% of 1a.
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Highly enantioselective Michael addition of…
Table 3 Asymmetric Michael addition of isobutyraldehyde to various b-nitroolefins
Entry
Ar
Time (h)
Yielda (%)
Eeb (%)
1
4-NO2C6H4
2-NO2C6H4
3-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-FC6H4
24
72
36
48
48
72
72
72
72
96
96
96
99
86
95
92
80
80
85
82
78
75
64
86
99
94
99
99
97
98
98
98
98
98
98
98
2
3
4
5
6
7
4-ClC6H4
4-BrC6H4
C6H5
8
9c
10c
11c
12
4-MeC6H4
4-MeOC6H4
2-Furyl
Unless stated otherwise, the reactions were carried out with isobutyraldehyde (1.0 mmol), nitroolefin
(0.25 mmol), and catalyst 1a (0.025 mmol) in CH2Cl2 (2 mL) at 25 °C
a
Isolated yield
b
Determined by chiral HPLC analysis
c
The catalyst loading of 1a was 20 mol%
Under the optimal reaction condition, the scope of nitroolefins was tested by
using isobutyraldehyde as donor (Table 3). The reaction had a wide substrate scope
with respect to nitroalkenes. The Michael products were produced in excellent
enantioselectivities (94–99 % ee) in all assays. The reactivities of the b-nitrostyre-
nes were sensitive to the electronic effect of the substituents on the phenyl group. b-
Nitrostyrenes containing electron-withdrawing substituents were more reactive than
those without substituent or with electron-donating substituents (entries 1–8 vs.
9–11). However, the less reactive b-nitrostyrenes could result in good yields when
the catalyst loading was increased to 20 mol% (entries 9–11). Compared with para-
substituent, b-nitrostyrene bearing ortho-substituted phenyl groups also could afford
high yield and excellent enantioselectivity, despite a longer reaction time, probably
due to a steric effect (entry 2). Moreover, (E)-2-(2-nitrovinyl)furan was well
tolerated and gave 86 % yield with 98 % ee (entry 12). Nevertheless, aliphatic
substituted nitroolefins, such as (E)-4-methyl-1-nitropent-1-ene [59] and (E)-(4-
nitrobut-3-en-1-yl)benzene [60], were not reactive under the typical reaction
conditions. Referring to the optical rotation values described in the literature [14,
16], the absolute configuration of these desired products was assigned as the (R)-
configuration.
Next, the scope of a,a-disubstituted aldehydes was explored using b-nitro-4-
nitrostyrene as the Michael acceptor (Table 4). Whereas only 48 % yield was
obtained even after 96-hour stirring when using 2-methylbutanal as the nucleophile
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X.-T. Guo et al.
Table 4 Asymmetric Michael addition of different a,a-disubstituted aldehydes to b-nitro-4-nitrostyrene
Entry
R1
R2
Time (h)
Yielda (%)
Drb
Eec (%)
1
2
3
4
5
6
7
Me
Et
nPr
48
48
60
72
48
84
72
85
85
83
81
80
75
78
66:34
70:30
82:18
83:17
80:20
–
94 (93)
99 (98)
99 (99)
99 (97)
34 (50)
94
Me
Me
Me2C=CH(CH2)2
4-tBuC6H4CH2
C6H5
Me
Me
Et
Et
–(CH2)5–
–
95
Reaction conditions: aldehyde (1.0 mmol), b-nitro-4-nitrostyrene (0.25 mmol), catalyst 1a (0.05 mmol),
CH2Cl2 (2 mL), 25 °C
a
Isolated yield of both diastereomers
b
The dr values were determined by chiral HPLC analysis
c
The ee values were determined by chiral HPLC analysis, and the data in the parenthesis related to the
minor diastereomer
under the optimal reaction conditions, good yield could be provided when the catalyst
loading was increased to 20 mol% (entry 1). Therefore, the reaction was further
carried out in the presence of 20 mol% of catalyst 1a. The steric hindrance of
aldehydes had a significant effect on the Michael reaction. Although the diastere-
oselectivities were unsatisfactory when changing the nucleophilic reagents to a-
methyl-a-alkyl aldehydes including 2-methylbutanal, 2-methylpentanal, melonal and
lylialdehyde, two diastereomers were both provided in excellent enantioselectivities
(entries 1–4). Donors with larger steric hindrance such as 2-ethylbutanal and
cyclohexanecarbaldehyde were found tolerant to give the product in excellent
enantioselectivities (entries 6 and 7). However, 2-phenylpropanal provided the two
diastereomers with poor enantioselectivities, probably due to the electronic effect of
the phenyl group (entry 5). In general, the Michael adducts were afforded with high
yields (75–85 %) for all assays. According to the identical transition-state of the
Michael addition catalyzed by amine-thiourea 1a, the carbon stereocenters on the b-
position of c-nitroaldehydes were determined as (R)-configuration.
Conclusions
In summary, a highly enantioselective Michael addition reaction of a,a-disubstituted
aldehydes with b-nitrostyrenes was developed using dehydroabietic amine-based
chiral primary amine-thiourea as catalyst. In all assays investigated, except
123

Highly enantioselective Michael addition of…
2-phenylpropanal, chiral c-nitroaldehydes were achieved in excellent enantioselec-
tivities (94–99 % ee) along with high yield (up to 99 %). The methodology
developed here provides an efficient protocol for the formation of all-carbon
quaternary stereogenic centers.
Experimental
General procedure for the enantioselective Michael addition reaction: Catalyst 1a
(0.025 mmol), CH2Cl2 (2 mL), aldehyde (1.0 mmol) and nitroolefin (0.25 mmol)
were added sequentially to the tube, and the resulting mixture was stirred at 25 °C.
After the reaction was completed (monitored by TLC), the solvent was removed
under reduced pressure, and the residue was purified by flash chromatography to
obtain the desired product.
Acknowledgments We are grateful for the financial support from National Natural Science Foundation
of China (21242007, 21102043), and the Fundamental Research Funds for the Central Universities.
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