A new protocol for in situ dioxirane reactions: Stoichiometric in oxone and catalytic in fluorinated acetophenones

Article abstract of DOI:10.1021/ol0348957

(Matrix presented) Dioxiranes made in situ from the commercially available tetrafluoroacetophenones (7, 8) and pentafluoroacetophenone (9) are reported for highly efficient epoxidation of olefins for the first time. Studies showed that ketone 7, 8, or 9 c

Full text of DOI:10.1021/ol0348957

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2853-2856
A New Protocol for in Situ Dioxirane
Reactions: Stoichiometric in Oxone and
Catalytic in Fluorinated Acetophenones
Wei Li and Philip L. Fuchs*
Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
pfuchs@purdue.edu
Received May 21, 2003
ABSTRACT
Dioxiranes made in situ from the commercially available tetrafluoroacetophenones (7, 8) and pentafluoroacetophenone (9) are reported for
highly efficient epoxidation of olefins for the first time. Studies showed that ketone 7, 8, or 9 can be used in catalytic amount (0.2 equiv) with
only 0.6 equiv of Oxone (equal to 1.2 equiv of peroxymonosulfate) to selectively oxidize diene 1 to epoxide 2. The epoxidation reactions of
dioxiranes of fluoroacetophenones are compared with the recently described complementary aliphatic acyclic fluorinated ketones.
In the preceding Letter we reported a particularly demanding
epoxidation of steroidal D-ring cyclopentadiene (1) needed
Scheme 2
to complete the synthesis of 23-deoxy,17R-hydroxy South
1 (3, Scheme 1). The relative rate of epoxidation of this
Scheme 1
To improve the synthesis of monoepoxide 2 from diene
1, we initially considered using enantiopure dioxiranes
developed by Shi2 and Denmark.3 Such species would both
be more sterically demanding than the parent DMDO while
material with mCPBA and dimethyldioxirane (DMDO) to
give 2 was only about twice as fast as the oxidation to the
unwanted epoxide 4 (Scheme 2). To further complicate the
problem, both 2 and 4 suffered competitive subsequent
epoxidation to give the same bis-epoxide 5.1
(2) For the epoxidation of diene 1 using mCPBA and DMDO, see the
preceding Letter.
(3) (a) Tu, Y.; Wang, Z.; Shi. Y. J. Am. Chem. Soc. 1996, 118, 9806-
9807. (b) Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293-296.
(1) Cephalostatin support studies 27. Oxidations 5.2
10.1021/ol0348957 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/08/2003

simultaneously providing the advantage of double stero-
selection. Unfortunately, diene 1 was inert to the bulky
dioxirane reagents. The smaller dioxirane from trifluoro-
acetophenone (6, Figure 1) previously applied several times
Before examining other fluorinated acetophenones, we
optimized the reaction conditions using ketone 7. The results
are summarized in Table 2. Increasing the concentration to
Table 2. Optimization of Epoxidation of Diene 1 Using
Ketone 7
7/Oxone concnb
temp/time
(°C)/(h)
ratiod
runa
(equiv)
(M)
conversionc 2:(4 + 5)
1
2
3
4
5
0.5/2
0.5/2
1.5/2
1.5/2
0.1/0.6
0.024 0/34.5
0.1 0/34.5
0.024 0/44
0.024 0/1.5, 25/9
0.024 0/1.5, 25/1.5
86%
45%
100%
100%
92%
6.8:1
5.3:1
6.3:1
1:1.3e
7.4:1
a All reactions employed diene 1 (1 equiv), ketone 7, Oxone, NaHCO3
(4 times of Oxone), and n-Bu4NHSO4 (5% equiv) in (1.5:1) CH3CN-0.05
M Na2B4O7 in 4 × 10-4 M aqueous Na2EDTA. b The concentration of diene
1
1 in CH3CN. c,d Based on H NMR integration. e Large amount of bisep-
oxide 5 formed.
Figure 1. Fluorinated acetophenones and 19F NMR data (CDCl3).
0.1 M greatly decreased the conversion (runs 1 and 2).
Reaction temperature has a major effect on the reaction rates,
as shown in runs 3 and 4. Using excess of ketone 7 gave
100% conversion. However, run 4 produced a large amount
of bis epoxide 5 as a result of the high reactivity of the
dioxirane at room temperature. Ketone 7 and its dioxirane
peaks were seen in the 19F NMR after workup; however,
only the peaks from ketone 7 appeared after 12 h at room
temperature. No Baeyer-Villiger product from ketone 7 was
formed, in comparison with methyl(trifluoromethyl) diox-
irane, which decomposes to methyl trifluoroacetate,6 the
Baeyer-Villiger product.
for epoxidation4 gave increased selectivity for conversion
of diene 1 to epoxide 2 (Table 1).
Table 1. Epoxidation of Diene 1 with Dioxiranes Derived
from Ketone 6, 7, and 10
runa
ketone
time (h)
conversionb
ratioc 2:(4 + 5)
1
2
3
6
7
10
24
<10
24
88%
100%
97%
4.7:1
6.3:1
5.0:1
19F NMR of an initial 1:1 mixture of ketone 7 and its
dioxirane revealed only ketone 7 remaining after 12 h. These
observations indicated that (1) the reaction rate is fast at room
temperature; (2) decomposition of the dioxirane only gave
the ketone; and (3) ketone 7 could serve as a catalyst with
near stoichiometric amounts of Oxone. Indeed, epoxidation
of 1 using 0.1 equiv of ketone 7 and 0.6 equiv of Oxone
(equal to 1.2 equiv of oxidant) within 3 h gave 92%
conversion with 7.4:1 ratio between the desired monoepoxide
2 and the other two unwanted epoxides (run 5).
The Denmark research group demonstrated that strict
control of pH was critical for the in situ generated biphasic
dioxirane epoxidations.7 They reported that the best pH range
was 7.8-8.0. Reactions conducted outside of this region
resulted in either Oxone decomposition to give oxygen at
high pH (>8) or dioxirane destruction by the peroxymono-
sulfate at lower pH (<7.5). However, Shi reported that
highest conversion of trans-â-methylstyrene was achieved
at pH 10-12 (0 °C, homogeneous) using the fructose
a All reactions were carried out at 0 °C with diene 1 (1 equiv), ketone
(2 equiv), Oxone (2 equiv), NaHCO3 (8 equiv), and n-Bu4NHSO4 (5%
equiv) in (1.5:1) CH3CN-0.05 M Na2B4O7 in 4 × 10-4 M aqueous
1
Na2EDTA. b,c Based on H NMR integration.
Encouraged by this result, we envisioned that reactivity
and selectivity could be further increased by introducing
fluorine atoms on the phenyl ring of trifluoroacetophenone.
A 1999 review by Denmark reported that inductive activation
of the carbonyl carbon of acyclic ketones by proximal
fluorine atoms was sensitive to both the location and number
of fluorines.4a Surprisingly, dioxiranes deriVed from more
highly fluorinated trifluoroacetophenone analogs haVe neVer
appeared in the literature. Commercially available (Aldrich)
fluorinated ketones used in this study are shown in Figure
1.
We first investigated epoxidation of diene 1 following
Shi’s procedure5 using ketones 7 and 10 instead of the
fructose-derived ketone. The results are shown in Table 1.
Ketone 7 gave the best reaction rate and good selectivity
with 100% conversion within 10 h at 0 °C (run 2).
(5) (a) Grocock, E. L.; Marples, B. A.; Toon, R. C. Tetrahedron 2000,
56, 989-992. (b) Harburn, J. J.; Loftus, G. C.; Marples. B. A. Tetrahedron
1998, 54, 11907-11924.
(6) (a) Wu, X. Y.; She, X.; Shi. Y. J. Am. Chem. Soc. 2002, 124, 8792-
8793. (b) Wang, Z. X.; Tu, Y.; Frohn, M.; Shi, Y. J. Org. Chem. 1997, 62,
2328-2329.
(4) For recent reviews on enantioselective epoxidation of alkenes using
chiral, nonracemic dioxiranes, see: (a) Denmark, S. E.; Wu, Z. Synlett 1999,
847-859. (b) Frohn, M.; Shi, Y. Synthesis 2000, 1979-2000.
(7) Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J. Org. Chem.
1988, 53, 3891-3893.
2854
Org. Lett., Vol. 5, No. 16, 2003

next conducted. Tetrafluoroacetophenones (7, 8) and penta-
fluoroacetophenone 9 gave best combination of reaction rate
and selectivity (Table 3).
Table 3. Comparison of Epoxidations of 1 with Fluorinated
Acetophenonesa
A recent seminal study by a CNRS group has provided
the definitive architecture of dioxirane precursors from
synthetic fluorinated acyclic aliphatic ketones (Table 4).8
Table 5 compares a series of epoxidations using the dioxirane
from tetrafluoroacetophenone 7 with the olefin testing set
employed by the CNRS group. As previously observed,
smaller amounts of Oxone were required when the reaction
pH decreased from 10 (Method A) to 8-9 (Method B). The
reaction rate was faster when the addition period of the
Oxone/NaHCO3 extended (runs 8 and 9). In all cases ketone
7 was unchanged on the basis of GC analysis, so the
epoxidations could be completed simply by adding more
Oxone/NaHCO3 if the reaction was incomplete (runs 6, 9,
and 10). As low as 5 mol % of ketone 7 and 1.0 equiv of
Oxone (equals 2.0 equiv of oxidant) can be used for reactive
cyclooctene (run 3). Although 1-dodecene is far less reactive,
10 mol % of ketone 7 and 1.5 equiv of Oxone still gave
97% conversion (run 10). However, the rate of epoxidation
of diene 1 was slow using method B. Only 92% conversion
was observed after 3 h at room temperature when 0.2 equiv
of ketone 7 and 0.6 equiv of Oxone were used. The rate of
Oxone decomposition was increased by using hexafluoro-
2-propanol (HFIP) as cosolvent (run 12, Method C), requiring
additional oxidant when using the CNRS protocol.
ketone
conversion
ratio 2:4:5
ratio 2:(4 + 5)
6
7
8
9
10
11
12
13
85%
96%
96%
94%
88%
40%
20%
33%
40:5.5:1
39:5.1:1
59:7.5:1
308:37:1
23:3.4:1
no 5
4.9:1
6.4:1
6.9:1
8.1:1
5.2:1
2.6:1
2.0:1
1.9:1
no 5
no 5
a All reactions were carried out at 0 °C (60 min) and rt (80 min) with
diene 1 (1 equiv), ketone (0.2 equiv), Oxone (0.6 equiv, equal to 1.2 equiv
oxidant), NaHCO3 (2.4 equiv), and n-Bu4NHSO4 (0.1 equiv) in (1.5:1)
CH3CN-0.05 M Na2B4O7 in 4 × 10-4 M aqueous Na2EDTA. Data were
1
based on H NMR integration.
ketone.4b Oxone decomposition was significant at room
temperature but very slow at 0 °C under our reaction
conditions (homogeneous, pH ∼10). Slow epoxidation reac-
tions therefore require additional amounts of Oxone because
the reaction must be run at room temperature. This was the
case using 2 mol % of ketone 7. The reaction was very slow
and diene 1 reacted with oxygen derived from Oxone
decomposition to give significant amount of singlet oxygen
product 14 (Scheme 3).2
It has been reported that hydrogen peroxide can be used
as the terminal oxidant in dioxirane epoxidations of olefins.9
The conversion and pH relationship has been studied by Shi’s
group who determined the best condition is pH 11.10(b) With
our protocol, hydrogen peroxide was found to smoothly
epoxidize cyclooctene. The reaction gave 100% conversion
within 1 h by using H2O2 (30%, 6 equiv, added in 1 h) and
ketone 7 (0.1 equiv) in 1:1 acetonitrile (0.5 M) and 1.5 M
K2CO3 in 4 × 10-4 M EDTA solution. For the less reactive
1-dodecene, the same conditions only gave 10% conversion
because the H2O2 was more rapidly undergoing decomposi-
tion than epoxidation at the high reaction pH.
Scheme 3
A systematic study of the general class of commercially
available fluorinated acetophenones (Aldrich, Figure 1) was
In summary, dioxiranes derived from commercially avail-
able tetrafluoroacetophenones (7, 8) and pentafluoro-
Table 4. Key Experiments from CNRS Group Using 1 Equiv of Synthetic Aliphatic Fluoroketones
R1/R2
CH3/C7F15
CH3/C7F15
CF3/C8F17
olefin
Oxone (equiv); solvent; add’n time + rx time
olefin:epoxide (GC yield)
cyclooctene
cyclooctene
1-dodecene
1-dodecene
1-dodecene
1-dodecene
1-dodecene
5; MeCN/H2O; 2 h + 3 h
0:100 (96%)
0:100 (78%)
30:70
2.5; HFIP/H2O 3:1; 1 h + 1 h
2.5; HFIP/H2O 3:1; 2 h + 1 h
4; HFIP/H2O 3:1; 2 h + 0 h
2.5; HFIP/H2O 3:1; 2 h + 1 h
2.5; HFIP/H2O 3:1; 2 h + 1 h
2.5; HFIP/H2O 3:1; 2 h + 1 h
CF3/C8F17
0:100 (90%)
0:100a (95%)
45:55a
CF3/CH2CH2C6F13
C3F7/CH2CH2C6F13
C7F15/CH2CH2C6F13
100:0a
a R1COR2 was found unchanged (>98% by GC analysis). HFIP ) hexafuoro-2-propanol.
Org. Lett., Vol. 5, No. 16, 2003
2855

Table 5. Oxidation of Common Olefins with Ketone 7
runa
olefin
7 (equiv);b method
Oxone (equiv);c addn time + rx time
conversiond (yield)e
1
2
3
4
5
6
cyclooctene
cyclooctene
cyclooctene
styrene
styrene
styrene
0.2; A
0.1; B
0.05; B
0.2; A
0.2; B
0.1; B
1.5; 7h + 2h
100% (92%)
>99% (90%)
98%
100%
100% (83%)
86%
100%
97%
>99%
91%
100%
70%
97% (86%)
62%
74%
1.0; 2h + 10h
1.0; 2 h + 22 h
1.5; 10 h + 1.5 h
1.0; 2h + 13h
1.0; 2h + 21h
0.5; 0 h + 7 h
3.0; 30 h + 6 h
1.5; 12 h + 2 h
1.5; 2 h + 27 h
0.5; 0 h + 1 h
1.0; 2 h + 22 h
0.5; 0 h + 12h
1.5; 2 h + 9 h
1.5;f 2 h + 9 h
7
8
9
1-dodecene
1-dodecene
1-dodecene
0.2; A
0.2; B
0.2; B
10
1-dodecene
0.1; B
11
12
1-dodecene
1-dodecene
0.2; B
0.2; C
a All reactions were carried at room temperature with olefin, ketone 7, Oxone, and NaHCO3 (4 × Oxone) in (1.5:1) acetonitrile-0.05 M Na2B4O7 in 4
× 10-4 M aqueous Na2EDTA (Method A, reaction pH is about 10), or in (1.5:1) acetonitrile-4 × 10-4 M aqueous Na2EDTA (Method B, reaction pH is
8-9), or in (1.5:1) HFIP-4 × 10-4 M aqueous Na2EDTA (Method C). b Ketone 7 was shown to be unchanged by GC analysis. c Oxone remaining when
method B was used as assayed by potassium iodide-starch paper. d Based on GC. e Isolated yield. f No Oxone remained.
acetophenone 9 are demonstrated for the first time to have
very good reactivity for epoxidation of olefins. The fluori-
nated acetophenones do not suffer from Baeyer-Villiger
oxidations. Thus catalytic amounts of ketones can be used,
and less reactive olefins can be driven to completion by
adding excess of Oxone and extending the reaction time.
Although many epoxidation reagents have been developed,
the dioxiranes reported here proVide excellent alternatiVes
for the catalytic epoxidation of olefins using a minimum of
terminal oxidant.
Acknowledgment. We thank the National Institute of
Health (CA 60548) for support of this project.
(8) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; DePue, J. S.; Wilde, R.
G. J. Org. Chem. 1995, 60, 1391-1407.
Supporting Information Available: Experimental pro-
cedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) Legros, J.; Crousse, B.; Bonnet-Delpon, D.; Be´gue´, J. Tetrahedron
2002, 58, 3993-3998.
(10) (a) Shu, L.; Shi, Y. Tetrahedron Lett. 1999, 40, 8721-8724. (b)
Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807-8810.
OL0348957
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Org. Lett., Vol. 5, No. 16, 2003