Design of efficient ketone catalysts for epoxidation by using the field effect

Article abstract of DOI:10.1021/jo981270r

By using the field effect (through-space charge-dipole or dipole-dipole interactions), efficient ketone catalysts 7 and 10 were developed for in situ epoxidation of olefins with Oxone. With either ketone 7 (10-20 mol %) or 10 (5-10 mol %) as catalyst, epoxidation of various olefins (2 mmol scale) at room temperature with 1.5 equiv of Oxone was complete in a short period of time with excellent isolated yields of epoxides (80-97%) and good ketone recovery (~80%) Furthermore, the in situ epoxidation of olefins can be performed on a large scale (20-100 mmol) directly with 5 mol % of commercially available tetrahydrothiopyran-4-one, which is oxidized by Oxone to ketone 10 during the epoxidation reactions.

Full text of DOI:10.1021/jo981270r

8952
J . Org. Chem. 1998, 63, 8952-8956
Design of Efficien t Keton e Ca ta lysts for Ep oxid a tion by Usin g th e
F ield Effect
Dan Yang,* Yiu-Chung Yip, Guan-Sheng J iao, and Man-Kin Wong
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong
Received J une 29, 1998
By using the field effect (through-space charge-dipole or dipole-dipole interactions), efficient ketone
catalysts 7 and 10 were developed for in situ epoxidation of olefins with Oxone. With either ketone
7 (10-20 mol %) or 10 (5-10 mol %) as catalyst, epoxidation of various olefins (2 mmol scale) at
room temperature with 1.5 equiv of Oxone was complete in a short period of time with excellent
isolated yields of epoxides (80-97%) and good ketone recovery (∼80%). Furthermore, the in situ
epoxidation of olefins can be performed on a large scale (20-100 mmol) directly with 5 mol % of
commercially available tetrahydrothiopyran-4-one, which is oxidized by Oxone to ketone 10 during
the epoxidation reactions.
In tr od u ction
there is a need to search for highly efficient ketone
catalysts that are readily available, especially for asym-
metric epoxidation.8-12 Recently, three classes of ketones,
4-oxopiperidinium salts,7 R-fluoro ketones,12 and R,R′-bis-
(ammonium) ketone,13 have been reported by Denmark
and co-workers for epoxidation with 10 mol % catalyst
loading. However, those ketone catalysts require 10
equiv of Oxone to complete the epoxidation reactions.
Here, we report that by using the field effect14 (through-
space charge-dipole or dipole-dipole interactions) ef-
ficient ketone catalysts are developed for in situ epoxi-
dation with 5-20 mol % catalyst loading and 1.5 equiv
of Oxone.
Dioxiranes1 are powerful oxidants for epoxidation of
olefins under mild and neutral reaction conditions.2 The
most commonly used dioxiranes, i.e., dimethyldioxirane
and methyl(trifluoromethyl)dioxirane, can be obtained by
distillation.3 For preparative epoxidation, an operation-
ally simple method is to generate dioxiranes in situ from
ketones and Oxone.4-7 Compared with acetone, 1,1,1-
trifluoroacetone is much more reactive for in situ epoxi-
dation though 10-fold excess is usually used.6 Thus,
(1) For excellent reviews on dioxirane chemistry, see: (a) Adam, W.;
Curci, R.; Edwards, J . O. Acc. Chem. Res. 1989, 22, 205. (b) Murray,
R. W. Chem. Rev. 1989, 89, 1187. (c) Curci, R. In Advances in
Oxygenated Processes; Baumstark, A. L., Ed.; J AI Press: Greenwich,
CT, 1990; Vol. 2, p 1. (d) Adam, W.; Hadjiarapoglou, L. P. Topics in
Current Chemistry; Springer-Verlag: Berlin, 1993; Vol. 164, p 45. (e)
Curci, R.; Dinoi, A.; Rubino, M. F. Pure Appl. Chem. 1995, 67, 811. (f)
Adam, W.; Curci, R.; D’Accolti, L.; Dinoi, A.; Fusco, C.; Gasparrini, F.;
Kluge, R.; Paredes, R.; Schulz, M.; Smerz, A. K.; Veloza, L. A.;
Weinkotz, S.; Winde, R. Chem. Eur. J . 1997, 3, 105.
(2) For recent examples of synthetic applications of dioxirane
epoxidation, see: (a) Deshpande, P. P.; Danishefsky, S. J . Nature 1997,
387, 164. (b) Deshpande, P. P.; Kim, H. M.; Zatorski, A.; Park, T.-K.;
Ragupathi, G.; Livingston, P. O.; Live, D.; Danishefsky, S. J . J . Am.
Chem. Soc. 1998, 120, 1600. (c) Roberge, J . Y.; Beebe, X.; Danishefsky,
S. J . J . Am. Chem. Soc. 1998, 120, 3915. (d) Balog, A.; Meng, D.;
Kamenecka, T.; Bertinato, P.; Su, D.-S.; Sorensen, E. J .; Danishefsky,
S. J . Angew. Chem., Int. Ed. Engl. 1996, 35, 2801. (e) Nicolaou, K. C.;
Winssinger, N.; Pastor, J . A.; Ninkovic, S.; Sarabia, F.; He, Y.;
Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature
1997, 387, 268. (f) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg,
H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J . I.
J . Am. Chem. Soc. 1997, 119, 7960. (g) Nicolaou, K. C.; Ninkovic, S.;
Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.; Finlay, M. R. V.;
Yang, Z. J . Am. Chem. Soc. 1997, 119, 7974. (h) Yang, D.; Wong, M.-
K.; Cheung, K.-K.; Chan, E. W. C.; Xie, Y. Tetrahedron Lett. 1997, 38,
6865.
Resu lts a n d Discu ssion
Efficient ketone catalysts for in situ epoxidation should
have the following features given the possible reaction
pathways shown in Scheme 1.4,7 (1) Ketones are acti-
vated toward nucleophilic addition of Oxone to form
dioxiranes; (2) the nonproductive decomposition of Oxone
mediated by dioxiranes is minimized; and (3) ketones are
stable under the neutral oxidation conditions.
A recent report of using the electrostatic field effect to
design a new class of enzyme inhibitors containing
(8) (a) Curci, R.; Fiorentino, M.; Serio, M. R. J . Chem. Soc., Chem.
Commun. 1984, 155. (b) Curci, R.; D’Accolti, L.; Fiorentino, M.; Rosa,
A. Tetrahedron Lett. 1995, 36, 5831.
(9) (a) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J .-
H.; Cheung, K.-K. J . Am. Chem. Soc. 1996, 118, 491. (b) Yang, D.;
Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J . Am. Chem. Soc.
1996, 118, 11311. (c) Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.;
Tang, M.-W.; Zheng, J .-H.; Cheung, K.-K. J . Am. Chem. Soc. 1998,
120, 5943. (d) Yang, D.; Yip, Y.-C.; Chen, J .; Cheung, K.-K. J . Am.
Chem. Soc. 1998, 120, 7659.
(10) (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J . Am. Chem. Soc. 1996, 118,
9806. (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Shi, Y. J . Org. Chem. 1997,
62, 2328. (c) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J .-R.; Shi, Y. J .
Am. Chem. Soc. 1997, 119, 11224. (d) Wang, Z.-X.; Shi, Y. J . Org. Chem.
1997, 62, 8622. (e) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi,
Y. J . Org. Chem. 1998, 63, 2948. (f) Wang, Z.-X.; Shi, Y. J . Org. Chem.
1998, 63, 3099.
(3) For example of the isolation of dimethyldioxirane by a distillation
method, see: (a) Murray, R. W.; J eyaraman, R. J . Org. Chem. 1985,
50, 2847. For examples of the isolation of methy(trifluoromethyl)-
ldioxirane by a distillation method, see: (b) Mello, R.; Fiorentino, M.;
Fusco, C.; Curci, R. J . Am. Chem. Soc. 1989, 111, 6749. (c) Adam, W.;
Gonzalez-Nunez, M. E.; Mello, R.; Curci, R. J . Am. Chem. Soc. 1991,
113, 7654.
(4) Edwards, J . O.; Pater, R. H.; Curci, R.; DiFuria, F. Photochem.
Photobiol. 1979, 30, 63.
(5) (a) Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J . O.; Pater,
R. H. J . Org. Chem. 1980, 45, 4758. (b) Corey, P. F.; Ward, F. E. J .
Org. Chem. 1986, 51, 1925. (c) Kurihara, M.; Ito, S.; Tsutsumi, N.;
Miyata, N. Tetrahedron Lett. 1994, 35, 1577.
(6) Yang, D.; Wong, M.-K.; Yip, Y.-C. J . Org. Chem. 1995, 60, 3887.
(7) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; DePue, J . S.; Wilde,
R. G. J . Org. Chem. 1995, 60, 1391.
(11) Adam, W.; Zhao, C.-G. Tetrahedron: Asymmetry 1997, 8, 3995.
(12) Denmark, S. E.; Wu, Z.; Crudden, C. M.; Matsuhashi, H. J . Org.
Chem. 1997, 62, 8288.
(13) Denmark, S. E.; Wu, Z. J . Org. Chem. 1998, 63, 2810.
(14) For a recent review of field effects on chemical reactivity in
organic reactions, see: Bowden, K.; Grubbs, E. J . Chem. Soc. Rev. 1996,
171.
10.1021/jo981270r CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/29/1998

Design of Efficient Ketone Catalysts for Epoxidation
J . Org. Chem., Vol. 63, No. 24, 1998 8953
Sch em e 1
Sch em e 3a
Ch a r t 1
a
Reagents and conditions: (a) benzaldehyde, NH4OAc, 95%
EtOH, reflux; (b) MeI, K2CO3, acetone, reflux; (c) methyl triflate,
CH2Cl2, 0 °C to rt.
1, under our previously reported in situ conditions,6
ketones 1-3 (entries 1-3) were highly active in cata-
lyzing decomposition of Oxone (20 equiv of Oxone were
consumed within 5 min), and only ketone 3 gave some
trans-stilbene epoxide product.7,18 This could be under-
stood as that, at neutral pH, the in situ generated
dioxiranes bearing the positively charged ammonium
groups19 would attract HSO5- anion and thereby decom-
pose Oxone rapidly. We expect the nonproductive de-
composition of Oxone to be slowed if the positive charges
are shielded by bulky groups such as phenyl rings.
Indeed, ketones 4-7 were found to give slower Oxone
decomposition and higher epoxide yield (entries 4-7,
Table 1). Ketones 5 and 6 were unstable under the
reaction conditions and self-decomposed to unsaturated
ketones 1120 and 12,21 respectively. In contrast, the two
equatorial methyl groups of ketone 722 apparently in-
creased its stability by preventing the anti elimination
of the ammonium group. Among this series of am-
monium ketones, ketone 7 has the best catalytic activity.
As revealed in Table 1, ketones 3-7 showed moderate
to high hydration (K ) 0.1-13.5 M-1), yet no general
correlation between the activities of ketones in catalyzing
epoxidation and their hydration equilibrium constants
was found.
Sch em e 2. Syn th esis of Keton e 4a
a
Reagents and conditions: (a) benzyl bromide, CH3CN, rt; (b)
silver triflate, CH3CN/H2O, rt.
4-heterocyclohexanone rings15 has brought our attention
to the possibility of applying the concept in designing new
ketone catalysts for epoxidation. Thus, a series of
4-heterocyclohexanones 1-10 (Chart 1) was chosen to
probe the importance of the field effect of the heterosub-
stituents to the catalytic activities of those ketones.
Ketone 4 was synthesized in two steps: reaction of
N-methylpiperidone 1 with benzyl bromide and exchange
of bromide ion of ketone 4a by triflate ion (Scheme 2).
Ketones 5-7 were prepared by using the Mannich
reaction16 followed by the two methylation steps (Scheme
3). Ketone 10 was prepared from the commercially
available tetrahydrothiopyran-4-one by oxidation with
Oxone in 75% yield.17
Ketones with positively charged ammonium groups as
the heterosubstituents are highly electrophilic because
the unfavorable through-space charge-dipole repulsion
(the field effect) between the ammonium groups and the
carbonyl group can be dissipated by rapid addition of
nucleophiles such as HSO5- or water. As shown in Table
Another way to enhance the electrophilicity of 4-het-
erocyclohexanones is to introduce the unfavorable dipole-
dipole repulsion (the field effect) between the neutral
heterosubstituents and the carbonyl group. Indeed, the
hydration equilibrium constants15,23 and rates of epoxi-
dation increased dramatically as the field effect of the
heterosubstituents increased (from cyclohexanone 8 to
tetrahydropyran-4-one 9 to sulfone ketone 10; entries
(18) Montgomery, R. E. J . Am. Chem. Soc. 1974, 96, 7820.
(19) The pKa value of ketone 1 is 7.9. (Geneste, P.; Hugon, I.;
Reminiac, C.; Lamaty, G.; Roque, J . P. Bull. Soc. Chim. Fr. 1976, 845.)
As we previously reported, the pH of the reaction was maintained at
7.0-7.5 by Oxone and sodium bicarbonate (see ref 6); the amino group
of ketone 1 would be mostly protonated. The ratio of protonated form
to ketone 1 would be 2.5:1 to 7.9:1 at pH 7.5-7.0. Similar to ketone 1,
ketone 2 would also be protonated during the reaction.
(20) The characterization data of 11 were consistent with those
reported in the literature. Rampal, J . B.; Satyamurthy, N.; Bowen, J .
M.; Purdie, N.; Berlin, K. D. J . Am. Chem. Soc. 1981, 103, 7602.
(21) The characterization data of 12 were consistent with those
reported in the literature. Ramalingam, K.; Berlin, K. D. J . Org. Chem.
1979, 44, 477.
(15) Conroy, J . L.; Sanders, T. C.; Seto, C. T. J . Am. Chem. Soc.
1997, 119, 4285. The experimental results suggested that the apparent
equilibrium constants for addition of thiol to 4-heterocyclohexanones
gave a linear correlation with the field substituent constants F of the
heterosubstituents at the 1-position of the ring.
(16) Preparations of 5b-7b were carried out according to the
literature procedure: Ravindran, T.; J eyaraman, R. J . Org. Chem.
1991, 56, 4833. Preparations of 5c-7c were carried out according to
the literature procedure: Balasubramanian, M.; Padma, N. Tetrahe-
dron 1963, 19, 2135.
(17) Casy, G.; Sutherland, A. G.; Taylor, R. J . K.; Urben, P. G.
Synthesis 1989, 767.

8954 J . Org. Chem., Vol. 63, No. 24, 1998
Yang et al.
Ta ble 1. Hyd r a tion Equ ilibr iu m Con sta n tsa for Keton es
1-10 a n d Th eir Activities in Ca ta lyzin g in Situ
Ep oxid a tion of tr a n s-Stilben e w ith a 1:1 Keton e/
Su bstr a te Ra tiob
Ta ble 2. Ep oxid a tion of Olefin s w ith Keton es 7 (10-20
m ol %) a n d 10 (5-10 m ol %) a s Ca ta lystsa
K
reaction
epoxide
ketone
entry ketone (M-1
)
time (min)c yieldd (%) recovery (%)
1e
2e
3e
4
1
2
3
4
5
6
7
8
9
0.28
h
13.5
12.1
13.5
1.8
f
f
i
f
f
i
95
92
87
94
p
g
g
g
g
k
l
45
120
120
15
p
30
2-3
5j
6j
7
0.1
82m,n
q
8
9
10
0.04o
0.23
11.1
93
97
q
10
96m,r
cat. loading reaction
(mol %)
epoxide
a
K ) Keq[H2O] ) 55.5Keq (at 20 °C); Keq ) [hydrate]/[[ketone]-
entry substrate ketoneb
timec (h) yieldd (%)
[H2O](1/2.5)]. For determination of hydration equilibrium con-
stants for ketones 1, 3-7, 9, and 10, see the Supporting Informa-
tion. Unless otherwise stated, reaction conditions were as fol-
1
2
13
13
14
14
15
15
16
16
17
17
18
18
19
19
20
20
21
21
22
22
23
23
24
24
25
25
26
26
27
27
7
10
7
20
5
1.5
5
9710c
95
b
3
10
5
20
5
10
5
20
5
3
8510c
87
lows: room temperature, 0.1 mmol of ketone, 0.1 mmol of trans-
stilbene, 0.5 mmol of Oxone, 1.55 mmol of NaHCO3, 1.5 mL of
CH3CN, 1.0 mL of aqueous Na2‚EDTA solution (4 × 10-4 M).
4
5
10
7
4.5
0.5
1.5
8
1.5
2.5
4
9626
95
c Time for epoxidation to complete as shown by TLC. Isolated
d
6
7
10
7
8727
81
yield after flash column chromatography. e 2.0 mmol of Oxone and
6.2 mmol of NaHCO3 were used. f No epoxidation occurred, but
Oxone was consumed within 5 min. g Not attempted as the ketone
8
9
10
7
9510c
97
h
i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
10
7
10
7
10
7
10
7
10
7
10
7
10
7
10
7
was soluble in water. Not determined. After Oxone was con-
sumed within 5 min, the reaction was worked up as usual. From
the 1H NMR, the ratio of trans-stilbene to its epoxide was found
to be 1:6.6. 1.0 mmol of Oxone and 3.1 mmol of NaHCO3 were
used. The decomposed product was found to be the unsaturated
20
10
20
5
10
5
4.5
6
2
2.5
0.75
0.5
3
9610c
97
9210c
94
j
k
8510c
83
ketone 11
20
5
9128
95
4
l
8310c
85
(85% yield). The decomposed product was found to be the
unsaturated ketone 12
20
5
20
5
1.5
2.5
2
9429
96
3
9529
96
m
10
5
10
5
20
5
10
5
1.5
0.5
7
4.5
2.5
3.5
8
(69% yield). The reaction mixture was diluted with CH2Cl2, dried
over MgSO4, filtered, and evaporated to dryness. After the
n
8230
80
workup, ketone 7 was precipitated with hexane as a white solid.
o Data taken from ref 15. After 12 h, the reaction was worked
p
10
7
10
7
9431
95
up as usual. From the 1H NMR spectrum, the ratio of trans-
q
stilbene to its epoxide was found to be 1:0.5. After the usual
9027
92
workup, the 1H NMR spectrum of the reaction mixture showed
r
10
2.5
that the ketone was stable. Ketone was recovered by flash column
chromatography.
a
Unless otherwise stated, reaction conditions were as follows:
room temperature, ketone (5-20 mol % as indicated), 2 mmol of
substrate, 3 mmol of Oxone, 9.3 mmol of NaHCO3, 9 mL of CH3CN,
8-10, Table 1). In addition, unlike those ammonium
ketones, much slower decomposition of Oxone was ob-
served with neutral ketones 8-10. Using a 1:1 ratio of
ketone/substrate, epoxidation of trans-stilbene catalyzed
by ketone 10 was complete in 2-3 min. This experimen-
tal result indicates that ketone 10 has the highest
catalytic activity among those ketones screened.
To further probe the catalytic efficiency of ketones,
epoxidation of 15 olefins 13-27 was examined on a 2
mmol scale with either ketone 7 (10-20 mol %) or 10
6 mL of aqueous Na2‚EDTA solution (4 × 10-4 M). Ketone 7 was
b
precipitated with hexane as a white solid (∼80% recovery). Ketone
10 was purified by flash column chromatography (∼80% recovery).
c Time for epoxidation to complete as shown by TLC or GC
d
analysis. Isolated yield.
(5-10 mol %) as catalyst. As shown in Table 2, all of
the epoxidation reactions were complete with only 1.5
equiv of Oxone in a short period of time (0.5-8 h). The
epoxides can be isolated in excellent yields (80-97%), and
ketones 7 and 10 can be recovered in good yields (∼80%)
by precipitation with hexane and by flash column chro-
matography, respectively. Compared with the previous
reports of employing either 4-oxopiperidinium salts or
R,R′-bis(ammonium) ketone as catalysts (10 mol %),24
epoxidation reactions of substrates 14, 15, and 27 cata-
lyzed by ketone 10 (5 mol %) were complete in a much
(22) As revealed by the X-ray structure of ketone 7, both methyl
groups and phenyl rings are in equatorial positions. Crystal data:
ketone 7, C21H26NO+CF3SO3-, monoclinic, P21/n (No. 14) with a )
11.214(2) Å, b ) 18.374(3) Å, c ) 11.511(2) Å, â ) 105.82(2)°, V )
2282.0(7) Å3, Z ) 4, Dc ) 1.332 g cm-1, with 1822 reflections refined
on 3248 reflections having I > 3.0σ(I), R ) 0.066 and Rw ) 0.092 (the
details of the X-ray analysis are provided as Supporting Information).
(23) Burkey, T. J .; Fahey, R. C. J . Org. Chem. 1985, 50, 1304.

Design of Efficient Ketone Catalysts for Epoxidation
J . Org. Chem., Vol. 63, No. 24, 1998 8955
204.1380, found 204.1383; MS (FAB +ve) m/z 222 (M+ + H2O,
100), 204 (M+, 19), 154 (13), 91 (23); MS (FAB -ve) m/z, 149
(-OTf, 100).
shorter period of time (1.5-5 h). More importantly, we
found that the in situ epoxidation of olefins can be
performed directly with 5 mol % of tetrahydrothiopyran-
4-one, which is oxidized immediately by Oxone to ketone
10 during the epoxidation reactions. For example, with
5 mol % of tetrahydrothiopyran-4-one, substrates 15, 17
(20 mmol each), and 24 (100 mmol) were epoxidized in
excellent isolated yields of epoxides (91-96%).25 We
believe that the method for in situ epoxidation of olefins
catalyzed by ketone 10 with inexpensive Oxone as
terminal oxidant should make the dioxirane a benchtop
reagent for other organic oxidation reactions.
Gen er a l P r oced u r e for P r ep a r a tion of Keton es 5-7.
P r ep a r a t ion of Ket on e 5. To a solution of 5c (2.5 g, 9.4
mmol) in CH2Cl2 (45 mL) at 0 °C under N2 atmosphere was
added methyl trifluoromethanesulfonate (1.5 mL, 13.3 mmol).
After 10 min, the reaction mixture was warmed to room
temperature and stirred for another 6 h. The mixture was
concentrated in vacuo to give a solid, which was recrystallized
from EtOAc/hexane (v/v ) 1:4, 10 mL) to afford 5 (3.8 g, 94%
yield) as a white solid: mp 205.0-205.5 °C; 1H NMR (300
MHz, CD3CN) δ 7.61-7.53 (m, 10H), 5.18 (d, J ) 13.9 Hz, 2H),
3.67 (t, J ) 17.1 Hz, 2H), 3.00 (s, 3H), 2.82 (d, J ) 17.1 Hz,
2H), 2.61 (s, 3H); 13C NMR (67.94 MHz, CD3CN) δ 199.31,
131.30, 130.09, 129.34, 121.04 (q, J ) 320.7 Hz), 74.96, 50.59,
41.32, 37.13; IR (KBr) 1739 cm-1; MS (FAB +ve) m/z 280 (M+,
68), 134 (100); MS (FAB -ve) m/z 149 (-OTf, 100). Anal.
Calcd for C20H22F3O4NS: C, 55.94; H, 5.16; N, 3.26. Found:
C, 56.08; H, 5.12; N, 3.43.
Con clu sion
We have demonstrated that efficient ketone catalysts
can be developed by using the field effect. Future efforts
will be devoted to explore other important factors for the
catalytic efficiency of ketones in epoxidation reactions.
Keton e 6 (82% yield as a white solid): mp 199-200 °C; 1H
NMR (300 MHz, CD3CN) δ 7.63-7.53 (m, 10H), 5.17 (dd, J )
14.4 Hz, 3.2 Hz, 1H), 4.88 (d, J ) 12.8 Hz, 1H), 3.74 (dd, J )
17.0 Hz, 14.4 Hz, 1H), 3.64-3.53 (m, 1H), 3.04 (s, 3H), 2.84
(dd, J ) 17.0 Hz, 3.2 Hz, 1H), 2.58 (s, 3H), 0.85 (d, J ) 6.6 Hz,
3H); 13C NMR (67.94 MHz, CD3CN) δ 202.20, 135.36, 132.39,
132.20, 131.25, 130.69, 130.41, 129.59, 122.15 (q, J ) 320.7
Hz), 81.72, 75.93, 52.41, 44.69, 42.11, 38.83, 12.33; IR (KBr)
1737 cm-1; MS (FAB +ve) m/z 294 (M+, 100), 154 (22), 134
(28); MS (FAB -ve) m/z 149 (-OTf, 100). Anal. Calcd for
Exp er im en ta l Section
Gen er a l Meth od s. The ketones 1, 2, 8 and 9, tetrahy-
drothiopyran-4-one, olefins, and Oxone were purchased from
Aldrich Chemical Co. and used without further purification.
Ketone 3 was prepared according to the literature procedure.7
P r ep a r a tion of Keton e 4. To a CH3CN solution (5 mL)
of N-methylpiperidone (1) (2 g, 17.7 mmol) was added benzyl
bromide (2.1 mL, 17.7 mmol) dropwise at room temperature
under N2 atmosphere. Precipitation occurred gradually. After
being stirred for 5 min, the reaction mixture was evaporated
in vacuo to afford 4a as a pale yellow solid, which was used in
the next step without further purification. To a solution of
4a (2 g, 7.04 mmol) in CH3CN (10 mL) and H2O (10 mL) was
added silver trifluoromethanesulfonate (1.8 g, 7.04 mmol)
portionwise over 2 min at room temperature. The precipita-
tion of yellow silver bromide was observed immediately. After
being stirred for 2 h, the reaction mixture was filtered through
a plug of Celite, and the filtrate was concentrated at low
temperature under reduced pressure until the product began
to crystallize. The precipitate was collected by filtration and
washed with a small portion of cold water (8 mL). The
resulting solid was dried in vacuo overnight to give 4 (1 g, 40%
C
21H24F3O4NS: C, 56.88; H, 5.45; N, 3.16. Found: C, 57.04;
H, 5.43; N, 3.29.
Keton e 7 (93% yield as a white solid): mp 270.0-270.5 °C;
1H NMR (300 MHz, CD3CN) δ 7.67-7.48 (m, 10H), 4.87 (d, J
) 13.0 Hz, 2H), 3.72-3.61 (m, 2H), 3.11 (s, 3H), 2.54 (s, 3H),
0.85 (d, J ) 6.5 Hz, 6H); 13C NMR (67.94 MHz, CD3CN) δ
204.19, 135.40, 132.19, 130.70, 130.61, 130.43, 129.94, 122.14
(q, J ) 320.7 Hz), 81.66, 53.11, 44.10, 39.48, 12.65; IR (KBr)
1727 cm-1; MS (FAB +ve) m/z 308 (M+, 100), 134 (26); MS
(FAB -ve) m/z 149 (-OTf, 100). Anal. Calcd for C22H26F3O4-
NS: C, 57.76; H, 5.73; N, 3.06. Found: C, 57.85; H, 5.71; N,
3.18.
P r ep a r a tion of Keton e 10. To a CH3CN solution (4.5 mL)
of tetrahydrothiopyran-4-one (0.4 g, 3.4 mmol) at room tem-
perature was added an aqueous Na2‚EDTA solution (3 mL, 4
× 10-4 M). To this mixture was added in portions a mixture
of Oxone (6.3 g, 10.3 mmol) and sodium bicarbonate (2.7 g,
32.0 mmol) within 30 min. The reaction was complete after
40 min. The reaction mixture was diluted with CH2Cl2 (80
mL), dried over anhydrous MgSO4, and filtered. The filtrate
was concentrated to dryness under reduced pressure to afford
ketone 10 as a white solid (0.38 g, 75% yield): mp 168-170
°C (lit.17 163-170 °C); 1H NMR (300 MHz, CDCl3) δ 3.39 (t, J
) 6.8 Hz, 4H), 2.99 (t, J ) 6.8 Hz, 4H); 13C NMR (67.94 MHz,
1
yield) as a white solid: mp 167-168 °C; H NMR (300 MHz,
CD3CN) δ 7.62-7.51 (m, 5H), 4.63 (s, 2H), 3.80-3.60 (m, 4H),
3.13 (s, 3H), 2.92-2.64 (m, 4H); 13C NMR (125.76 MHz, CD3-
CN) δ 200.95, 134.11, 131.87, 130.20, 127.77, 122.1 (q, J )
321.6 Hz), 69.28, 59.43, 47.11, 35.78; IR (KBr) 3400 (br,
hydrate) cm-1; HRMS (FAB +ve) for C13H18NO (M+) calcd
(24) Epoxidation of substrates 14, 15, and 27 on a 1-2 mmol scale
catalyzed by either 4-oxopiperidinium salts (10 mol %) in a biphasic
CH2Cl2-H2O system (pH 7.8) or R,R′-bis(ammonium) ketone (10 mol
%) in a homogeneous CH3CN-H2O system (pH 6.0) at 0 °C was
complete in 8-24 h with 10 equiv of Oxone (see refs 7 and 13).
(25) Epoxidation reactions of substrates 15 and 17 were complete
in 1.7 and 3.5 h with 96% and 91% isolated yields of epoxides,
respectively. Reaction conditions were as follows: room temperature,
1 mmol of tetrahydrothiopyran-4-one, 20 mmol of substrate, 30 mmol
of Oxone, 93 mmol of NaHCO3, 90 mL of CH3CN, 60 mL of aqueous
Na2‚EDTA solution (4 × 10-4 M). Epoxidation of substrate 24 was
complete in 2 h with 92% isolated yield of the epoxide. Reaction
conditions were as follows: room temperature, 5 mmol of tetrahy-
drothiopyran-4-one, 100 mmol of substrate 24, 150 mmol of Oxone,
465 mmol of NaHCO3, 450 mL of CH3CN, 300 mL of aqueous Na2‚
EDTA solution (4 × 10-4 M).
CDCl3) δ 202.09, 49.60, 38.22; IR (CH2Cl2) 1725 cm-1
.
Gen er a l in Situ Ep oxid a tion P r oced u r e. To a CH3CN
solution (9 mL) of olefin (2 mmol) and ketone 7 (10-20 mol %
as stated in Table 2) or 10 (5-10 mol % as stated in Table 2)
at room temperature was added an aqueous Na2‚EDTA solu-
tion (6 mL, 4 × 10-4 M). To this mixture was added in portions
a mixture of Oxone (1.84 g, 3 mmol) and sodium bicarbonate
(0.78 g, 9.3 mmol) over the reaction period. The reaction
progress was followed by TLC or GC analysis, and the reaction
was worked up according to the following procedures.
Wor k u p P r oced u r e A (F or Keton e 7, Su bstr a tes 13, 15,
17-19, 21-24, a n d 26). The reaction mixture was diluted
with CH2Cl2 (50 mL). The organic phase was separated, dried
over anhydrous MgSO4, filtered, and concentrated. The
residue was extracted with hexane/CH2Cl2 (v/v ) 99.5:0.5, 2
× 50 mL) and then filtered to give ketone 7 as a white solid
(∼80% recovery). The filtrate was concentrated under reduced
pressure, and the residue was purified by flash column
chromatography to give epoxide.
(26) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
K.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(27) Ueno, S.; Yamaguchi, K.; Yoshida, K.; Ebitani, K.; Kaneda, K.
J . Chem. Soc., Chem. Commun. 1998, 295.
(28) Murray, R. W.; Singh, M.; J eyaraman, R. J . Am. Chem. Soc.
1992, 114, 1346.
(29) Kende, A. S.; Delair, P.; Blass, B. E. Tetrahedron Lett. 1994,
35, 8123.
(30) Murray, R. W.; Iyanar, K. J . Org. Chem. 1998, 63, 1730.
(31) Berk, S. C.; Buchwald, S. L. J . Org. Chem. 1992, 57, 3751.
Wor k u p P r oced u r e B (F or Keton e 7, Su bstr a tes 14, 16,
20, 25, a n d 27). The reaction mixture was extracted with

8956 J . Org. Chem., Vol. 63, No. 24, 1998
Yang et al.
n-pentane (2 × 50 mL). The combined pentane layers were
dried over anhydrous MgSO4, filtered through a plug of silica
gel, and concentrated under reduced pressure at low temper-
ature to afford epoxide. The mixed CH3CN/H2O layers were
then extracted with CH2Cl2 (2 × 50 mL). The combined
organic layers were dried over anhydrous MgSO4, filtered, and
concentrated to give ketone 7 as a white solid (∼80% recovery).
Wor k u p P r oced u r e C (F or Keton e 10, Su bstr a tes 13,
15, 17-19, 21-24, a n d 26). The reaction mixture was
extracted with EtOAc (2 × 50 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered, and con-
centrated. The residue was purified by flash column chroma-
tography to afford epoxide and ketone 10 (∼80% recovery).
Wor k u p P r oced u r e D (F or Keton e 10, Su bstr a tes 14,
16, 20, 25, a n d 27). The reaction mixture was extracted with
n-pentane (2 × 50 mL). The combined pentane layers were
dried over anhydrous MgSO4, filtered through a plug of silica
gel, and concentrated under reduced pressure at low temper-
ature to afford epoxide. The mixed CH3CN/H2O layers were
then extracted with EtOAc (2 × 50 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered, and con-
centrated. The residue was purified by flash column chroma-
tography to afford ketone 10 (∼80% recovery).
equilibrated for 10 min, the 1H and 13C NMR spectra were
taken at 20 °C. In addition, two more measurements were
taken after the sample was equilibrated for 1 and 24 h. For
the detail assignments of the chemical shift values of the
ketone and its hydrate see the Supporting Information.
Ack n ow led gm en t. This work was supported by The
University of Hong Kong and Hong Kong Research
Grants Council. Y.-C.Y. and M.-K.W. are the recipients
of the University Postdoctoral Fellowships. We thank
Dr. K. K. Cheung for determination of the X-ray
structure of ketone 7 and Prof. D. T. W. Chan for
determination of the HRMS of ketone 4.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for the product epoxides shown in Table 2; determination
of hydration equilibrium constants for ketones 1, 3-7, 9, and
10; 1H and 13C NMR spectra for ketone 4; X-ray structural
analysis of ketone 7 containing tables of atomic coordinates,
thermal parameters, bond lengths, and angles (20 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Gen er a l P r oced u r e for Deter m in a tion of th e Hyd r a -
tion Equ ilibr iu m Con sta n ts for Keton es 1, 3-7, 9, a n d
10. A solution of ketone (0.1 mmol) in CD3CN (1.5 mL) and
D2O (1 mL) was prepared. A portion of this solution (0.5 mL)
was transferred to an NMR tube. After the sample was
J O981270R