An efficient and enantioselective Michael addition of aromatic oximes to α,β-unsaturated aldehydes promoted by a chiral diamine catalyst derived from α,α-diphenyl prolinol

Article abstract of DOI:10.1002/chir.22699

Chiral diamine catalysts 11a–e derived from α,α-diphenyl prolinol were prepared and successfully applied to the Michael addition of aromatic oximes to α,β-unsaturated aldehydes in mediocre to good yields (up to 78%) and good to high enantioselectivities (up to 93% ee).

Full text of DOI:10.1002/chir.22699

Received: 15 September 2016
DOI: 10.1002/chir.22699
Revised: 13 December 2016
Accepted: 19 December 2016
R E G U L A R A R T I C L E
An efficient and enantioselective Michael addition of aromatic
oximes to α,β‐unsaturated aldehydes promoted by a chiral diamine
catalyst derived from α,α‐diphenyl prolinol
1
,2
1,2
1,2
1,2
1,2
Feng Chen
| Hong‐Xia Ren | Yu Yang | Shan‐Ping Ji | Zheng‐Bing Zhang
|
1
1
1
Fang Tian | Lin Peng | Li‐Xin Wang
1
Key Laboratory of Asymmetric Synthesis
Abstract
and Chirotechnology of Sichuan Province,
Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu,
China
Chiral diamine catalysts 11a–e derived from α,α‐diphenyl prolinol were prepared
and successfully applied to the Michael addition of aromatic oximes to α,β‐unsatu-
rated aldehydes in mediocre to good yields (up to 78%) and good to high
enantioselectivities (up to 93% ee).
2
University of Chinese Academy of
Sciences, Beijing, China
Correspondence
KEYWORDS
Lin Peng and Li‐Xin Wang, Key Laboratory of
Asymmetric Synthesis and Chirotechnology
of Sichuan Province, Chengdu Institute of
Organic Chemistry, Chinese Academy of
Sciences, Chengdu 61004, China.
aromatic oxime, diamine catalyst, Michael reaction, organocatalysis, α,β‐unsaturated aldehyde
Email: wlxioc@cioc.ac.cn; penglin@cioc.ac.cn
1
| INTRODUCTION
prolinol would be a better new type of catalyst for asymmet-
ric reactions and chiral ligands for organometallic catalysis
Over the past years, asymmetric organocatalysis has made
significant progress in the field of organic synthesis.
Discovery of new catalysts has drawn much attention from
(Figure 1). As far as we know, the synthesis and applications
1-10
of such diamine catalysts derived from α,α‐diphenyl prolinol
33
34
skeleton were still rare. In 2008, Juaristi reported the
reduction of prochiral ketones promoted by oxazaborolidine
derivatives prepared from α,α‐diphenyl‐(S)‐prolinol. In
chemists. Among those organic catalysts, proline‐derived
1
1
catalysts, such as α,α‐diaryl‐(S)‐prolinol and the corre-
1
2,13
35
sponding silyl ether derivatives,
as well as secondary
2013, a similar work was accomplished by Asami's group.
1
4
amine‐(thio)ureas or squaramides, have been extensively
applied in the field of aminocatalysis, especially the diaryl
prolinol silyl ethers, which were used as general catalysts in
activating aldehydes via the enamine or iminium transition
Compared to the single catalytic center and regioselective
controlling group of α,α‐diphenyl‐(S)‐prolinol silyl ether,
we recognized the diamine catalysts derived from α,α‐
diphenyl prolinol, bearing a secondary amine of pyrrolidine
moiety, diphenyl segment, and another amino group on the
chiral scaffold, in which the pyrrolidine amine might activate
the reaction substrate via an enamine or an iminium mecha-
nism, the diphenly segment having good enantioinducing
ability and the diamine would activate substrate with good
stereoselectivity (Figure 1).
15-18
state.
Generally, this privileged skeleton included second
amine as a single catalytic center and diaryl prolinol silyl
ether as a special steric and regioselective controlling group.
In recent years, diamine catalysts derived from (S)‐proline
19-25
have been widely used in asymmetric organocatalysis.
Based on the diaryl segment of α,α‐diaryl‐(S)‐prolinol with
2
6,27
good enantioinducing ability,
work
combined with our
with the secondary amine catalysis, we envisioned
that chiral diamine catalysts derived from α,α‐diphenyl
Enantioselective Michael addition is one of the most
important reactions in new bond (C‐C, C‐O, C‐S, C‐P, etc.)
formations, and many kinds of efficient chiral organocatalysts
28-32
Chirality. 2017;1–7.
wileyonlinelibrary.com/journal/chir
© 2017 Wiley Periodicals, Inc.
1

2
CHEN ET AL.
FIGURE 1 From α,α‐diphenylprolinol
silyl ether to diamine catalysts, general
activation mode of diamine catalyst
FIGURE 2 Efforts for the preparations of second amine thiourea bifunctional catalyst 5
FIGURE 3 Preparation of diamine catalysts 11
a
TABLE 1 Catalyst screenings
b
c
Entry
Cat.
Time (d)
Yield (%)
ee (%)
1
2
11a
11b
11b
11c
11d
11e
4
1
4
1
4
4
54
73
79
97
93
72
71
22
48
25
25
93
d
3
4
5
6
a
Unless otherwise specified, all the reactions were performed with crotonaldehyde 12a (0.25 mmol), (E)‐benzaldehyde oxime 13a (0.75 mmol), PhCO
2
H (0.05 mmol) and
4
cat. 11 (0.05 mmol) in toluene (1 ml) at –10 °C, after completion of the reaction, MeOH (0.5 mL) and NaBH (0.375 mmol) was added, after 20 min, the reduction was
quenched with NH Cl (aq.) and extracted with DCM (3 x 1 mL).
4
b
Isolated yield after silica gel column chromatography.
Determined by chiral HPLC analysis.
c
d
The reaction was conducted at –30 °C.

CHEN ET AL.
3
3
6-39
have been developed for such reactions,
and Oxa‐
group. Finally, the title catalysts 11b–e were successfully
obtained by deprotection with trifluoroacetic acid in
dichloromethane, as expected (Figure 3).
Michael reaction is a good way to build new chiral C‐O
4
0,41
bonds. Jørgensen's group
first reported the
enantioselective Michael reaction of aromatic oximes to
α,β‐unsaturated aldehydes catalyzed by α,α‐diaryl prolinol
silyl ether, and subsequent in situ reduction to give opti-
cally active β‐diols in excellent enantioselectivities. In
We initiated our work by evaluating the model reaction
between crotonaldehyde 12a and (E)‐benzaldehyde oxime
13a in the presence of diamine catalysts 11a–e and the results
are summarized in Table 1. Catalysts 11b–d gave good to
excellent yields while poor enantioselectivities (73–97%
yield, 22–25% enantiomeric excess, ee; Table 1, entries 2,
4–5) at –10 °C. Decreasing the temperature to –30 °C, cata-
lyst 11b gave only moderate enantioselectivity (48% ee;
Table 1, entry 3). Catalyst 11a gave moderate result (54%
yield, 71% ee; Table 1, entry 1). Secondary–secondary
diamine catalyst 11e gave good yield and excellent
enantioselectivity (72% yield, 93% ee; Table 1, entry 6) and
was chosen for further investigations.
42
2010, Pihko's group reported the enantioselective Michael
reaction of aromatic oximes to α,β‐unsaturated aldehydes
catalyzed by α,α‐diaryl prolinol silyl ether to obtain the
addition products, which rapidly cyclized into stable
isoxazoline under acidic conditions with good to excellent
enantioselectivities. In those reactions, aromatic oximes
4
3
are good nucleophiles and α,β‐unsaturated aldehydes are
4
4
good Michael receptors. We envisioned that the diamine
catalysts, bearing α,α‐diphenyl prolinol silyl ether and
diamine catalysts, would catalyze aromatic oximes and
α,β‐unsaturated aldehydes with good results. To our
knowledge, diamine catalysts derived from α,α‐diphenyl
prolinol have not drawn enough attention on asymmetric
organocatalysis yet. Herein, we report the enantioselective
Michael reaction of aromatic oximes to α,β‐unsaturated
aldehydes catalyzed by secondary–secondary diamine
catalyst.
To further optimize the reaction conditions, a series of
solvents were evaluated. Arene solvents afforded moderate
a
TABLE 2 Solvent screenings
b
c
Entry
Sol.
Toluene
Yield (%)
ee (%)
2
| RESULTS AND DISCUSSION
1
2
3
4
5
6
7
8
9
72
57
78
79
77
51
47
48
56
5
93
87
90
91
91
85
89
84
71
92
93
93
61
Before our study, we tried for years and failed to prepare
the “ideal” second amine thiourea bifunctional catalyst 5
which was derived from α,α‐diphenyl prolinol. At the
beginning of our work, we designed two routes to synthe-
size catalyst 5. We first used N‐Bn protected α,α‐diphenyl
Chlorobenzene
o‐xylene
m‐xylene
Mesitylene
DCM
45
prolinol
as a starting material and N‐Bn protected
thiourea was obtained. However, no desired thiourea
bifunctional catalyst 5 was obtained by hydrogenation
deprotection of 4 (Figure 2, route 1). When prepared
according to route 2, N‐Boc protected thiourea 9 was
smoothly obtained. Deprotection of thiourea 9 also failed
to give the title compound 5 (Figure 2, route 2). The result
CHCl3
DCE
Hexane
THF
1
0
11
12
Et
2
O
9
3
3
was consistent with that of Juaristi's group.
MTBE
9
Then we turned our attention to prepare chiral diamine
13
14
15
MeCN
14
Trace
40
catalysts. We first prepared the secondary–primary diamine
d
DMF
nd
4
6,47
catalyst 11a according to the literature.
N‐Boc
Diethyl carbonate
90
protected diamine 8 was prepared according to the litera-
4
8
49
a
ture. Treating 8 with halides, 10b–e were obtained.
When 8 was reacted with iodomethane, 1,4‐dibromobutane,
or 1,5‐dibromopentane, the disubstituted 10b–d were
obtained as expected. However, when 1‐bromobutane was
used as reactant, only monosubstituted catalyst 10e was
obtained even if a large quantity of 1‐bromobutane
Unless otherwise specified, all the reactions were performed with crotonaldehyde
2a (0.25 mmol), (E)‐benzaldehyde oxime 13a (0.75 mmol), PhCO
0.05 mmol) and 11e (0.05 mmol) in solvent (1 ml) at –10 °C for 4 days, after
completion of the reaction, MeOH (0.5 mL) and NaBH (0.375 mmol) was added,
Cl (aq.) and extracted with
1
(
2
H
4
after 20 min, the reduction was quenched with NH
4
DCM (3 x 1 mL).
b
Isolated yield after silica gel column chromatography.
Determined by chiral HPLC analysis.
c
(4 equiv.) was used. The possible reason might be the
d
steric hindrances of the diphenyl segment and n‐butyl
Not determined.

4
CHEN ET AL.
to good yields and good to excellent enantioselectivities (57–
(72% yield, 93% ee; Table 2, entry 1) and was chosen as
the most suitable solvent.
79% yield, 87–93% ee; Table 2, entries 1–5).
Halohydrocarbon solvents, such as DCM, CHCl , DCE, gave
moderate yields and good enantioselectivities (47–51% yield,
Amine activations are generally via an enamine or an
iminium transition state. So a series of acid additives
were also studied and the results were shown in
Table 3. The reaction gave 63% yield and 89% ee without
any additive (Table 3, entry 1). Strong Brønsted acid
additives such as TFA and CF SO H gave relatively lower
3
84–89% ee; Table 2, entries 6–8). Excellent
enantioselectivities were obtained when the reaction was per-
formed in ether solvents with poor yields (5–9% yield,
92–93% ee; Table 2, entries 10–12). No desired product
3
3
was detected when performed in DMF (Table 2, entry 14).
The possible reason might be the strong polarity of DMF.
Diethyl carbonate gave moderate yield and excellent
enantioselectivity (40% yield, 90% ee; Table 2, entry 15).
Toluene gave the highest enantioselectivity and good yield
yields and enantioselectivities (41–78% yield, 32–33% ee;
Table 3, entries 2, 3). A wide range of benzoic acids
were also investigated and the results indicated that
benzoic without substituent on the phenyl was the most
promising additive and the best result was afforded
(72% yield, 93% ee; Table 3, entry 5), benzoic acid with
electron‐withdrawing groups or electron‐donating groups
gave both lower yields and enantioselectivities (28–63%
yield, 65–90% ee; Table 3, entries 6–11). Chiral acids
such as (R/S)‐BINOL‐phosphoric acid and (D/L)‐
camphorsulfonic acid afforded relatively poor yields and
lower enantioselectivities (10–31% yield, 59–88% ee;
Table 3, entries 12–15). The loading of additive was also
studied and increasing or lowering the amount had little
effect on the enantioselectivities (63–80% yield, 86–93%
ee; Table 3, entries 1, 5, 16–18).
a
TABLE 3 Additive screenings
b
c
Entry
Additive
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
No
63
78
41
61
72
42
28
63
38
39
42
10
12
26
31
80
75
77
89
32
33
89
93
80
65
90
80
78
67
59
77
87
88
90
88
86
TFA
CF
AcOH
PhCO
2‐OH‐PhCO
2‐NO ‐PhCO
4‐MeO‐PhCO
2,3‐di‐OH‐PhCO
2,6‐di‐F‐PhCO
3,5‐di‐NO ‐PhCO
3 3
SO H
Based on those positive results, other reaction parame-
ters, such as the molar ratio of substrate 12a to 13a,
2
H
a
2
H
TABLE 4 Optimization of reaction conditions
2
2
H
2
H
2
H
10
11
12
13
14
15
16
17
18
2
H
b
c
Entry
12a:13a
T (°C)
Yield (%)
ee (%)
2
2
H
1
2
3
4
5
1:3
1:2
1:1
2:1
3:1
1:3
1:3
1:3
1:3
‐10
‐10
‐10
‐10
‐10
‐10
‐10
0
72
60
35
39
40
70
65
90
38
93
89
89
89
88
86
90
87
87
(R)‐BINOL‐phosphoric acid
(S)‐BINOL‐phosphoric acid
(D)‐Camphorsulfonic acid
(L)‐Camphorsulfonic acid
d
e
f
PhCO
PhCO
PhCO
2
2
2
H
H
H
d
6
e
7
8
9
a
Unless otherwise specified, all the reactions were performed with crotonaldehyde
2a (0.25 mmol), (E)‐benzaldehyde oxime 13a (0.75 mmol), additive (0.05 mmol)
and 11e (0.05 mmol) in toluene (1 ml) at –10 °C for 4 days, after completion of
the reaction, MeOH (0.5 mL) and NaBH
0 min, the reduction was quenched with NH
3 x 1 mL).
‐20
1
a
Unless otherwise specified, all the reactions were performed with crotonaldehyde
2a, (E)‐benzaldehyde oxime 13a, additive (0.05 mmol) and 11e (0.05 mmol) in
toluene (1 ml) at –10 °C for 4 days, after completion of the reaction, MeOH
0.5 mL) and NaBH was added, after 20 min, the reduction was quenched with
Cl (aq.) and extracted with DCM (3 x 1 mL).
4
(0.375 mmol) was added, after
Cl (aq.) and extracted with DCM
1
2
(
4
(
4
b
Isolated yield after silica gel column chromatography.
NH
4
c
b
Determined by chiral HPLC analysis.
Isolated yield after silica gel column chromatography.
d
c
0
.025 mmol PhCO
2
H was added.
Determined by chiral HPLC analysis.
e
d
e
0
.075 mmol PhCO
2
H was added.
0.5 ml toluene was added.
f
0
.1 mmol PhCO
2
H was added.
2 ml toluene was added.

CHEN ET AL.
5
a
TABLE 5 Scope of substrates
b
c
Entry
R
1
R
2
Ar
R
3
14
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
H
C
6
H
5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
14a
14b
14c
14d
14e
14f
14g
14h
14i
‐
72
61
93
84
83
89
83
84
86
89
89
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2‐FC
6
H
4
2‐ClC
6
H
4
6
4
77
2‐MeOC
3‐ClC
3‐BrC
3‐MeOC
4‐MeC
4‐MeOC
4‐NO
H
4
41
6
H
74
6
H
4
65
6
H
4
4
62
6
H
4
74
6
H
78
e
10
11
12
13
14
15
16
17
18
19
20
2
C
6
H
4
Trace
61
nd
4‐FC
6
H
4
14k
14l
14m
‐
85
85
92
4‐ClC
6
H
4
48
3,4,5‐(MeO)
3
C
6
H
2
29
e
4‐Py
Trace
19
nd
C
C
C
C
C
C
6
6
6
6
6
6
H
5
H
5
H
5
H
5
H
5
H
5
Me
H
14o
14p
14q
14r
‐
85
84
85
73
C
2
H
5
65
n‐C
CO
3
H
7
H
59
2
C
2
H
5
H
14
d
e
C
6
H
5
H
nr
nd
d
e
CH
3
CH
3
H
‐
nr
nd
a
Unless otherwise specified, all the reactions were performed with 12 (0.25 mmol), 13 (0.75 mmol), PhCO
2
H (0.05 mmol) and 11e (0.05 mmol) in toluene (1 ml) at –
Cl (aq.)
1
0 °C for 4 days, after completion of the reaction, MeOH (0.5 mL) and NaBH (0.375 mmol) was added, after 20 min, the reduction was quenched with NH
4
4
and extracted with DCM (3 x 1 mL).
b
Isolated yield after silica gel column chromatography.
c
Determined by chiral HPLC analysis.
d
No reaction.
e
Not determined.
concentrations of reactants and temperature were further
studied. As shown in Table 4, tuning the molar ratio of
substrate 12a to 13a significantly affected the yields, while
slightly affecting the ee values (35–72% yield, 88–93% ee;
Table 4, entries 1–5). Increasing or lowering concentrations
have less effect on the results (65–72% yield, 86–93% ee;
Table 4, entries 1, 6, 7). Raising the temperature to 0 °C,
the yield was increased to 90% with
a
lower
enantioselectivity (87% ee; Table 4, entry 8). Lowering the
temperature to –20 °C, the yield decreased (38% yield, 87%
ee; Table 4, entry 9). On the basis of those results, we
conducted the reaction under the optimal conditions as: 3
equiv. of 13, 20 mol% PhCO H as acid additive, with
2
20 mol% catalyst 11e in toluene at –10 °C for 4 days.
FIGURE 4 A probable bifunctional mechanism for the reaction

6
CHEN ET AL.
Under the optimized conditions, the substrate scope was
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donating substituents at para‐position oximes gave good
results (74–78% yield, 89% ee; Table 5, entries 8, 9); elec-
tron‐withdrawing substituents such as F‐ and Cl‐ at para‐
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lower yield and good enantioselectivity (19% yield, 85% ee;
Table 5, entry 15). Several α,β‐unsaturated aldehydes were
evaluated under the optimized conditions. Crotonaldehyde,
trans‐2‐pentenal and trans‐2‐hexenal gave moderate to good
yields and good to excellent enantioselectivities (59–72%
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9
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A.
Alpha,alpha‐diarylprolinols:
Bifunctional
poor yield (14% yield, 73% ee; Table 5, entry 18). It should
be noted that cinnamaldehyde and 3‐penten‐2‐one did not
react under the optimized conditions (Table 5, entries 19–20).
A probable bifunctional mechanism for the reaction was
proposed (Figure 4). We presumed that the secondary amine
of pyrrolidine moiety of catalyst 11e might activate the
α,β‐unsaturated aldehydes via the formation of an iminium
ion I while the another secondary amine might activate the
nucleophilic oxime via hydrogen bonding. Then I undergoes
the conjugate addition and thus renders an enamine interme-
diate II. A final hydrolysis step releases both the Michael
addition product and the amine catalyst. We determined the
specific rotation of the Michael products and compared it
1
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0
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| CONCLUSION
2
004;37:548‐557.
In conclusion, we synthesized a series of chiral diamine cat-
alysts derived from α,α‐diphenyl prolinol, and those catalysts
were well applied to the Michael reaction of aromatic oximes
to α,β‐unsaturated aldehydes. The products were obtained in
mediocre to good yields (up to 78%) and good to excellent
enantioselectivities (up to 93% ee).
1
1
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SUPPORTING INFORMATION
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How to cite this article: Chen F, Ren H‐X, Yang Y,
et al. An efficient and enantioselective Michael
addition of aromatic oximes to α,β‐unsaturated
aldehydes promoted by a chiral diamine catalyst
derived from α,α‐diphenyl prolinol. Chirality. 2017.
https://doi.org/10.1002/chir.22699
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