Prolinol tert-butyldiphenylsilyl ether as organocatalyst for the asymmetric michael addition of cyclohexanone to nitroolefins

Article abstract of DOI:10.1055/s-2007-985581

The direct Michael additions of cyclohexanone to nitroolefins catalyzed by prolinol tert-butyldiphenylsilyl ether were conducted successfully in good yields (up to 99%) and high stereo-selectivities (up to 98:2 diastereomeric ratio and 95% enantiomeric ex

Full text of DOI:10.1055/s-2007-985581

LETTER
2415
Prolinol tert-Butyldiphenylsilyl Ether as Organocatalyst for the Asymmetric
Michael Addition of Cyclohexanone to Nitroolefins
P
rolinol tert-B
e
utyldiphen
n
E
the
r
g
a
s
O
rganoca
y
i
Asymm
n
etric Micha
g
el
A
ddition Liu, Shiwen Wang, Ning Wang, Yungui Peng*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, P. R. of China
Fax +86(23)68254000; E-mail: pyg@swu.edu.cn
Received 4 June 2007
efficient formation of the enamine intermediate with
ketones, resulting in poor reactivities.
Abstract: The direct Michael additions of cyclohexanone to nitro-
olefins catalyzed by prolinol tert-butyldiphenylsilyl ether were
conducted successfully in good yields (up to 99%) and high stereo-
selectivities (up to 98:2 diastereomeric ratio and 95% enantiomeric
excess).
In our work directed toward devising highly enantioselec-
tive catalysts for the addition of ketones to nitroolefins,
we envisioned that by properly adjusting the size of the
shielding group or its distance from the second amine part
of the pyrrolidine-based catalyst, high reactivity and enan-
tioselectivity could be obtained. Therefore, we have de-
signed and synthesized several chiral pyrrolidine catalysts
by simply etherifying the prolinol or its analogue
(Figure 1), and found that 1b was an excellent catalyst for
the asymmetric Michael addition of cyclohexanone to
nitroolefins. Herein, we wish to report the preliminary
results on this subject.
Key words: asymmetric, organocatalyst, Michael addition, cyclo-
hexanone, nitroolefin
The Michael addition reaction is widely recognized as one
of the most important carbon–carbon bond-forming reac-
tions in organic synthesis.1 In particular, the asymmetric
Michael addition of carbonyl compounds to nitroalkenes
is a very useful synthetic method for the preparation of
nitroalkanes, which are valuable building blocks in organ-
ic synthesis and can be readily transformed into amines,
ketones, carboxylic acids, nitrile oxides, etc.2 As a result,
considerable efforts have been devoted to the develop-
ment of organocatalytic asymmetric Michael addition of
ketones and aldehydes to nitroolefins over recent years,3
and various effective catalytic systems have been devel-
oped,4 including chiral acyclic primary amines,4a
thiourea–amine bifunctional catalysts,4b–4e and small
dipeptides,4f,g as well as pyrrolidine-based catalytic
systems such as chiral pyrrolidinyl triazole,5 tetrazole,6
aminomethylpyrrolidine,7 2,2-bipyrrolidine,8 pyrrol-
idine–pyridine,9 pyrrolidine sulfonamide,10 pyrrolidine–
thiourea,11 diphenylprolinol ethers or their derivatives,12
and others.13 In general, the pyrrolidine-catalyzed
Michael addition occurs via an enamine intermediate, and
stereocontrol has been achieved by effectively shielding
one side of the enamine double bond and/or via hydrogen
bonding between the catalyst and the nitro group of b-ni-
trostyrene as suggested in the literature.9,14 (S)-Diphenyl-
prolinol trimethylsilyl ether has been employed as a
catalyst for this process and high levels of enantio- and
diastereoselectivity were obtained for aldehydes.12a The
bulky diphenyltrimethylsiloxymethyl group on the pyrrol-
idine ring efficiently blocks one side of the enamine
double bond, thus giving high levels of enantio- and dia-
stereoselectivity. However, poor reactivities were ob-
served with this catalyst when ketones were used as
substrates.10c It appears that the steric bulkiness of the
diphenyltrimethylsiloxymethyl group circumvents the
TBDPSO
OTBS
OTBDPS
N
H
N
H
N
H
1a
1b
1c
TBDPSO
TBSO
OMe
O
N
H
N
H
1e
1d
O
N
H
1f
Figure 1 Chiral catalysts tested
The experiments were conducted by taking cyclohex-
anone as a donor and b-nitrostyrene as an acceptor using
20 mol% of the catalyst 1 (Table 1). Catalyst 1b (Table 1,
entry 2) showed better catalytic activity (86% yield) and
higher enantioselectivity (87% ee) than the other screened
catalysts 1a, 1d–1f (Table 1, entries 1 and 4–6), probably
because 1b matches with our supposition and bears a
proper distance between the second amine part of the
pyrrolidine and the bulky group tert-butyldiphenylsilyl by
the C–O and O–Si bonds. The reduced steric repulsion
between the enamine and tert-butyldiphenylsilyl moieties
thus allowed the catalyst to exhibit higher reactivity.
Nonetheless, the bulky group could also effectively shield
one face of the enamine double bond for high enantiose-
lectivity. However, 1c gave no product enantioselectivity
in spite of showing good reactivity (Table 1, entry 3). This
indicated that the chiral center adjacent to the second
SYNLETT 2007, No. 15, pp 2415–2419
1
7
.0
9
.2
0
0
7
Advanced online publication: 13.08.2007
DOI: 10.1055/s-2007-985581; Art ID: W11007ST
© Georg Thieme Verlag Stuttgart · New York

2416
F. Liu et al.
LETTER
Table 1 Catalytic Asymmetric Michael Addition Reaction of Cyclohexanone 2 to Nitroolefin 3 under Various Conditionsa
O
O
Ph
NO2
20 mol% cat.
10 °C, solvent
NO2
+
Ph
2
Entry
1
3a
4
Cat.
Solvent
hexane
hexane
hexane
hexane
hexane
hexane
Time (h)
30
Yield (%)b
Temp.
r.t
syn/antic
89:11
98:2
n.d.
eed (%)
71
87
0
1a15
1b15
1c
79
86
87
23
24
10
80
42
78
46
15
10
43
0
2
35
r.t
3
14
–10 °C
r.t.
4
1d
1e
35
n.d.
43
65
84
85
87
86
88
n.d.
85
83
–
5
35
r.t.
n.d.
6
1f
35
r.t.
n.d.
7
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
cyclohexane
35
r.t
99:1
96:4
98:2
96:4
n.d.
8
CHCl3
PE
35
r.t
9
35
r.t
10
11
12
13
14
15
16
Et2O
35
r.t
DMF
CH2Cl2
THF
35
r.t
35
r.t
97:3
97:3
–
32
r.t
MeOH
hexane
hexane
40
r.t
35
65
34
10 °C
0 °C
97:3
99:1
89
93
35
a All reactions were carried out using 2 (0.5 mL, 10 equiv) and 3 (0.5 mmol, 1 equiv) in the presence of catalyst (20 mol%) in solvent (2 mL).
b Isolated yields.
c Determined by 1H NMR of the crude products.
d Determined by chiral HPLC analysis.
amine of the pyrrolidine was very crucial for high enantio- tries 2, 15 and 16) and found that reactions ran at 10 °C
selectivity. A naphthyl group could provide good enantio- afforded the product in high yield and with better enantio-
selectivity, but the catalytic activity was low (Table 1, selectivity.
entry 6). The existence of trans-3-(tert-butyldimethyl-
silyloxy) group also proved to be detrimental to enantio-
selectivity (Table 1, entries 5 and 6).
With the optimal conditions in hand, we investigated a
variety of nitroolefins and the results are summarized in
Table 2. All reactions were conducted in hexane (2 mL) at
Various conditions were examined using 1b as the cata- 10 °C in the presence of catalyst 1b. In general, b-nitro-
lyst (Table 1, entries 2 and 7–16). Polar aprotic solvents, styrenes with both electron-withdrawing and electron-do-
such as CHCl3, Et2O, DMF, CH2Cl2, THF, gave low nating aryl group reacted efficiently (50–99% yield) with
yields (10–46%) but good enantioselectivities (83–88% high diastereoselectivity (>92%) and enantioselectivity
ee) (Table 1, entries 8 and 10–13). No conversion was ob- (73–95% ee) for syn adduct. Finally, the substitution posi-
served with protic solvent such as anhydrous methanol tion of b-nitrostyrenes also had an influence not only on
(Table 1, entry 14), whereas in nonpolar solvents, such as reactivity but also on the enantioselectivities. For exam-
hexane, cyclohexane, petroleum ether, the Michael reac- ple, when the nitro group position of b-nitrostyrene was
tion proceeded smoothly with good enantioselectivities changed from para to meta, the yield decreased from 95%
(Table 1, entries 2, 7 and 9). The best solvent was hexane. to 50% and the enantioselectivity increased from 84% ee
We also optimized the reaction temperature (Table 1, en- to 92% ee (Table 2, entries 4 and 7).
Synlett 2007, No. 15, 2415–2419 © Thieme Stuttgart · New York

LETTER
Prolinol tert-Butyldiphenylsilyl Ether as Organocatalyst for the Asymmetric Michael Addition
2417
Table 2 Catalytic Asymmetric Michael Addition Reactions of
Cyclohexanone with trans-Nitroolefins16
Table 2 Catalytic Asymmetric Michael Addition Reactions of
Cyclohexanone with trans-Nitroolefins16 (continued)
O
R
O
R
O
O
NO2
NO2
1b (20 mol%)
1b (20 mol%)
NO2
NO2
+
R
+
R
hexane, 10 °C
hexane, 10 °C
2
3
4
2
3
4
Entrya Product
Time
(h)
syn/antib Yieldc
eed
(%)
Entrya Product
Time
(h)
syn/antib Yieldc
eed
(%)
(%)
(%)
O
O
1
69
71
94:6
96:4
92
63
87
89
O
Br
9
48
96:4
99
90
NO2
NO2
a All reactions were carried out using 2 (0.5 mL, 10 equiv) and
S
O
nitroolefins (0.5 mmol, l 1 equiv) in the presence of cat. 1b (20 mol%)
in hexane (2 mL) at 10 °C.
2
NO2
b Determined by comparison with the known 1H NMR spectral data
and optical rotation values.
c Isolated yields.
d Determined by chiral HPLC analysis.
O
Cl
3
72.5
72.5
97:3
96:4
99
95
94
84
NO2
O
Ph
O
O
1b (20 mol%)
NO2
NO2
+
Ph
NO2
hexane, 10 °C
73 h
3a
43%, ee = 54%
Ph
4
O
O
1b (20 mol%)
NO2
NO2
NO2
H
+
Ph
hexane, 10 °C
71 h
H
Me
3a
94%, syn/anti = 83:17
syn: ee = 27%
Br
O
O
C7H15
5e
71
98:2
95:5
89
96
95
73
O
NO2
1b (20 mol%)
NO2
NO2
C7H15
+
hexane, 20 °C
48 h
41%, syn/anti = 78:22
syn: ee = 83%; anti: ee = 83%
OMe
Scheme 1 Michael addition reactions of other substrates catalyzed
by 1b
6
131
O
NO2
NO2
The asymmetric additions of acetone and propanal to ni-
trostyrene 3a using 1b as a catalyst were also investigated.
As shown in Scheme 1, acetone gave the desired product
in 43% yield with 54% ee. Propanal also worked well to
give the desired products in excellent yield with moderate
regioselectivity (83:17) but poor enantioselectivity
(27%). (E)-1-Nitronon-1-ene gave the corresponding
product with moderate diastereoselectivity (78:22) and
enantioselectivity (83% ee) in 41% yield. Cyclopentanone
was inactive and failed to afford the desired adduct.
O
7
74.5
92:8
98:2
50
96
92
89
NO2
O
8
71
In summary, we have successfully developed a new
pyrrolidine-based organocatalyst for the asymmetric
direct Michael addition of cyclohexanone to various
NO2
Synlett 2007, No. 15, 2415–2419 © Thieme Stuttgart · New York

2418
F. Liu et al.
LETTER
(5) (a) Luo, S. Z.; Xu, H.; Mi, X. L.; Li, J. Y.; Zheng, X. X.;
nitroolefins by simply etherifying the prolinol with tert-
butyldiphenylsilyl chloride in one step. Good yields (up to
99%) and high stereoselectivities (up to 98:2 dr and 95%
ee) were obtained when this catalyst was used in the
Michael reaction. Further studies to apply this catalyst to
other reactions are currently in progress in our laboratory.
Cheng, J. P. J. Org. Chem. 2006, 71, 9244. (b) Yan, Z. Y.;
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Acknowledgment
This work was supported by the Natural Science Foundation of
China (NSFC 20572087), the Ministry of Education, P. R. of China
(No. 106141) and the Program for New Century Excellent Talents
in University.
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Synlett 2007, No. 15, 2415–2419 © Thieme Stuttgart · New York

LETTER
Prolinol tert-Butyldiphenylsilyl Ether as Organocatalyst for the Asymmetric Michael Addition
2419
(15) Procedure for the Preparation of Catalyst 1a: To a DMF
(10 mL) solution of prolinol (3.36 mmol) and imidazole
(10.1 mmol) was added TBSCl (6.73 mmol) at 0 °C. The
reaction mixture was stirred for 17 h at r.t. and quenched
with aq NH4Cl and the organic materials were extracted with
EtOAc and the combined organic phase was washed with
brine. Then the organic extracts were dried over anhyd
Na2SO4 and concentrated in vacuo after filtration.
(16) General Procedure for the Asymmetric Michael
Addition of Cyclohexanone 2 to Nitroolefin 3 Catalyzed
by 1b: The catalyst 1b (0.1 mmol) and cyclohexanone 2 (0.5
mL) were mixed in hexane (2 mL) at r.t. After stirring for 20
min and then cooling to 10 °C, the nitroolefin 3 was added.
The mixture was stirred at 10 °C for the specified time
(Table 2) and then directly purified by silica gel column
chromatography (PE and EtOAc as the eluent) to obtain the
product 4,17 which was confirmed by the comparison of IR,
1H NMR and 13C NMR data with that reported in the
literature. The enantiomeric ratios were identified by HPLC
analysis.
Purification by silica gel column chromatography gave (S)-
2-[(tert-butyldimethylsilyloxy)methyl]pyrrolidine (1a) in
77% yield; [a]Dr.t. –6.63 (c = 0.8, CHCl3). IR (neat): 3406,
2929, 2857, 2738, 1680, 1460, 1394, 1255, 1100, 840, 775
cm–1. 1H NMR (300 MHz, CDCl3): d = 0.10–0.12 (d, J = 4.6
Hz, 6 H), 0.90 (s, 9 H), 1.84–1.89 (m, 1 H), 1.93–2.11 (m, 3
H), 3.29–3.38 (m, 2 H), 3.76–3.81 (m, 2 H), 3.94–3.98 (m, 1
H). 13C NMR (75 MHz, CDCl3): d = –5.5, –5.3, 24.0, 25.8,
26.8, 45.7, 60.0, 62.1. Preparation of catalyst (S)-2-[(tert-
butyldiphenylsilyloxy)methyl]pyrrolidine (1b) was similar
to that of catalyst 1a. 1b: 85% yield; [a]Dr.t. –5.8 (c = 0.94,
CHCl3). IR (neat): 3419, 2935, 2866, 2734, 1112, 708, 504
cm–1. 1H NMR (300 MHz, CDCl3): d = 1.09 (s, 9 H), 1.80–
1.99 (m, 1 H), 2.02–2.04 (m, 3 H), 3.30–3.35 (t, J = 6.5 Hz,
2 H), 3.71–3.79 (m, 1 H), 3.83–3.84 (m, 1 H), 3.91–3.96 (m,
1 H), 7.39–7.73 (m, 10 H). 13C NMR (75 MHz, CDCl3): d =
19.1, 23.8, 26.8, 45.6, 59.9, 63.0, 127.8, 129.9, 132.5, 135.6,
135.7.
(17) (S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone (4): mp
125–126 °C; [a]Dr.t. –26.1 (c = 1.42, CHCl3). IR (neat): 2958,
2929, 1699, 1551, 1495, 1448, 1384, 1129, 697 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.21–1.58 (m, 1 H), 1.62–1.75
(m, 4 H), 2.04–2.10 (m, 1 H), 2.38–2.47 (m, 2 H), 2.68 (m,
1 H), 3.72–3.80 (dt, J = 4.5, 9.9 Hz, 1 H), 4.53–4.66 (dd, J =
10.0, 12.3 Hz, 1 H), 4.91–4.97 (dd, J = 4.5, 12.4 Hz, 1 H),
7.15–7.17 (d, J = 6.9 Hz, 2 H), 7.23–7.34 (m, 3 H). 13C NMR
(75 MHz, CDCl3): d = 25.0, 28.5, 33.1, 42.7, 43.9, 52.5,
78.8, 127.7, 128.1, 128.9, 137.7, 211.9. HPLC condition:
Chiralpak AD-H, l = 254 nm, flow rate: 0.5 mL/min, eluent:
hexane–i-PrOH (90:10), t and the paragraph.
Synlett 2007, No. 15, 2415–2419 © Thieme Stuttgart · New York

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