and 4-positions of pyrrolidine significantly influenced the
reaction rates. As illustrated in entry 4, epoxidation with
amine 4 bearing an acetoxy group at the 4-position and an
amide group at the 2-position proceeded faster than that with
pyrrolidine (1) (entries 1 vs 4) and afforded trans-stilbene
epoxide with 30% ee in 25 min. When the epoxidation was
performed in the presence of C2 symmetric amine 5 and
hexanal (7), trans-stilbene epoxide was obtained with 40%
ee in 3 h (entry 5). Interestingly, unlike amines 1 and 2,
epoxidation reactions with amines 3-5 only gave a small
amount of trans-stilbene epoxide in the absence of hexanal
(7) (entries 1 and 2 vs 3-5).
increase in ee was observed (50%; entry 6). The same trend
was observed in the epoxidation reactions when C2 sym-
metric amine 5 was used (entries 7-9). When the reaction
temperature was lowered to 0 °C, the ee value increased from
54% to 65% (entries 9 vs 10).
As iminium salts are known to be highly reactive catalysts,
we anticipated that less than stoichiometric amounts of
amines and aldehydes could be used for epoxidation. Indeed,
we were pleased to find that epoxidation could proceed
smoothly with 20-50 mol % of amine 4 and aldehyde 11,
and the results are summarized in Table 3.10 It was noted
With amines 4 and 5 in hand, we investigated the effect
of aldehydes in epoxidation (Figure 2), and the results are
illustrated in Table 2. It was noticed that the reaction rates
Table 3. Catalytic Asymmetric Epoxidation of Olefins Using
Amine 4 and Aldehyde 11a
cat.
loading time conversionb yieldc eed epoxide
Table 2. Asymmetric Epoxidation of trans-Stilbene 12a
entry olefin (mol %) (h)
(%)
(%) (%) confige
conversionb yieldc eed
1
2
3f
4g
5
6f
7
8
9
12
13
13
13
14
14
15
16
17
18
50
50
20
50
50
20
50
50
50
50
5
81
100
96
100
98
81
85
97
81
86 46
100 51
95 51
99 59
91 54
93 52
94 46h
73 25h
51 26
75 17
(S,S)
(S,S)
(S,S)
(S,S)
(S)
(S)
(S,S)
(S)
0.5
1.5
1.3
2
2.5
1.5
8
entry amine aldehyde
time
(%)
(%)
(%)
1
2
4
4
4
4
4
4
5
5
5
5
6
7
25 min
25 min
25 min
25 min
25 min
2 h
3 h
3 h
3 h
3 h
100
95
<2
0
100
99
16
30
3
8
4
9
5
6
7e
8e
9e
10e,f
10
11
6
7
11
11
0
96
79
63
66
80
100
91
92
97
93
50
16
40
54
65
8
8
n.d.
(S,S)
10
94
a Unless otherwise indicated, all epoxidation reactions were carried out
at room temperature with 0.1 mmol of olefins, 0.05 mmol of amine, 0.05
mmol of aldehyde, 0.4 mmol of Oxone, and 1.0 mmol of NaHCO3 in 1.0
mL of CH3CN and 0.1 mL of H2O. b Conversion was calculated from the
recovery of olefins by flash column chromatography. c Yield based on
conversion after flash column chromatography. d Determined by chiral
HPLC (OD column). e The configuration of the major enantiomer of the
epoxides was determined by correlation to the known chiral epoxides.
f Using 0.02 mmol of amine and 0.02 mmol of aldehyde. g At 0 °C.
a Unless otherwise indicated, all epoxidation reactions were carried out
at room temperature with 0.1 mmol of trans-stilbene, 0.1 mmol of amine,
0.1 mmol of aldehyde, 0.4 mmol of Oxone, and 1.0 mmol of NaHCO3 in
2.0 mL of CH3CN and 0.2 mL of H2O. b Conversion was calculated from
the recovery of trans-stilbene by flash column chromatography. c Yield
based on conversion after flash column chromatography. d Determined by
chiral HPLC (OD column); the configuration of the major enantiomer of
the epoxide was found to be (S,S). e Using 0.05 mmol of trans-stilbene,
0.05 mmol of amine, 0.05 mmol of aldehyde, 0.2 mmol of Oxone, and 0.5
mmol of NaHCO3 in 1.0 mL of CH3CN and 0.1 mL of H2O. f At 0 °C.
h Determined by H NMR using chiral shift reagent Eu(hfc)3 (Aldrich no.
16,474-7).
1
that amine 4 and aldehyde 11 gave higher catalytic efficiency
and enantioselectivities for epoxidation of trans-stilbene (12)
(entry 1) and trisubstituted olefins 13-15 (entries 2-7) than
trans-â-methyl styrene (16) (entry 8), cis-olefin 17 (entry
9), and allylic alcohol 18 (entry 10). For trisubstituted olefins
13 and 14, only 20 mol % of amine and aldehyde were
required to effect epoxidation without compromise on
reactivity and enantioselectivity (entries 2 vs 3; entries 5 vs
6). For trans-â-methyl stilbene (13), a further increase in
enantioselectivity from 51% to 59% was observed when the
reaction was conducted at 0 °C. Epoxidation of 1-phenyl-
cyclohexene (15) proceeded smoothly to afford the chiral
epoxide with 46% ee. However, for less reactive olefins 16-
18, longer reaction time was required, and the enantio-
selectivities of epoxides were low.
decreased as the steric bulkiness of aldehydes at the
R-position increased (entries 1-5). Epoxidation reactions
with sterically less hindered formaldehyde (6) and hexanal
(7) gave almost complete conversion in 25 min, whereas
reactions with more bulky cyclohexanecarboxaldehyde (8),
benzaldehyde (9), and trimethylacetaldehyde (10) gave less
than 2% conversion in the same reaction time (entries 1 and
2 vs 3-5). This may be due to the steric effect, which
disfavors the formation of iminium salts. More interestingly,
the structure of aldehydes plays an important role on
enantioselectivity. In the epoxidation reactions with amine
4, the enantioselectivities increased from 16% to 30% when
formaldehyde (6) was replaced by hexanal (7) (entries 1 vs
2). When a â-branching aldehyde 11 was employed, a further
(10) Control experiments were performed in the absence of aldehyde
for epoxidation reactions in Table 3, and it was found that less than 5%
conversion of olefins were observed for olefins 12-15 within the indicated
reaction time. However, for olefins 16-18, up to 48% conversion of styrene
16 and 25% conversion of olefins 17 and 18 were observed in 8 h. The
origin of these amine promoted epoxidation reactions is under investigation.
(9) While our work was ongoing, Aggarwal and co-workers reported
that amines could be used as catalysts for epoxidation with Oxone as the
primary oxidant, and the reaction conditions were quite similar to ours;
see: Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. J. Am. Chem. Soc.
2000, 122, 8317.
Org. Lett., Vol. 3, No. 16, 2001
2589