Novel cyclic ketones for catalytic oxidation reactions

Article abstract of DOI:10.1021/jo981659e

In our effort to search for C₂ symmetric and conformationally rigid chiral ketones as catalysts for asymmetric epoxidation, a series of cyclic ketones 4-10 were prepared from the corresponding diacids. Compared with acyclic ketones for epoxidation of trans-stilbene, those 9-, 10-, and 11- membered-ring cyclic ketones were found to have much higher catalytic activities, which were attributed to steric effects, electronic effects, and ring strains. By using the homogeneous acetonitrile-water solvent system, unfunctionalized olefins with various substitution patterns (with 5 mol % of ketone 9) and strongly electron-deficient olefins (with a 1:1 ketone 9:substrate ratio) were epoxidized with Oxone as terminal oxidant in 75-96% yield at room temperature and neutral pH. In addition, oxidation of alcohols (with 20 mol % of ketone 9) was carried out successfully with good isolated yields of aldehydes or ketones (75-88%).

Full text of DOI:10.1021/jo981659e

9888
J . Org. Chem. 1998, 63, 9888-9894
Novel Cyclic Keton es for Ca ta lytic Oxid a tion Rea ction s
Dan Yang,* Yiu-Chung Yip, Man-Wai Tang, Man-Kin Wong, and Kung-Kai Cheung
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong
Received August 17, 1998
In our effort to search for C2 symmetric and conformationally rigid chiral ketones as catalysts for
asymmetric epoxidation, a series of cyclic ketones 4-10 were prepared from the corresponding
diacids. Compared with acyclic ketones for epoxidation of trans-stilbene, those 9-, 10-, and 11-
membered-ring cyclic ketones were found to have much higher catalytic activities, which were
attributed to steric effects, electronic effects, and ring strains. By using the homogeneous
acetonitrile-water solvent system, unfunctionalized olefins with various substitution patterns (with
5 mol % of ketone 9) and strongly electron-deficient olefins (with a 1:1 ketone 9:substrate ratio)
were epoxidized with Oxone as terminal oxidant in 75-96% yield at room temperature and neutral
pH. In addition, oxidation of alcohols (with 20 mol % of ketone 9) was carried out successfully with
good isolated yields of aldehydes or ketones (75-88%).
I. In tr od u ction
olefins.6 In the past several years, substantial progress
has been made in developing chiral ketone catalysts7-12
for asymmetric epoxidation of a variety of olefins with
excellent enantioselectivity. As the first step in our
program to develop C2 symmetric chiral ketones for
catalytic asymmetric epoxidation,8a-c it is essential to
search for highly efficient ketone catalysts in which the
desired chiral element can be incorporated. In addition,
the design and synthesis of a cheap, robust, recyclable,
and environmentally friendly catalyst for epoxidation
with low catalyst loading10,13-15 is still a great challenge.
Using our in situ epoxidation protocol in which dioxiranes
are generated effectively from ketones and Oxone in a
homogeneous acetonitrile-water solvent system,16 we
have carried out a search for efficient ketone catalysts.
Dioxiranes1 are important oxidants for organic reac-
tions such as epoxidation,2 heteroatom oxidation,3 and
oxygenation of C-H bonds.4 In particular, epoxidation
mediated by dioxiranes is stereospecific and highly
efficient toward both electron-rich5 and electron-deficient
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387, 164. (b) Deshpande, P. P.; Kim, H. M.; Zatorski, A.; Park, T.-K.;
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R. W.; Rajadhyaksha, S. N.; Mohan, L. J . Org. Chem. 1989, 54, 5783.
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10.1021/jo981659e CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/21/1998

Cyclic Ketones for Catalytic Oxidation Reactions
J . Org. Chem., Vol. 63, No. 26, 1998 9889
Ch a r t 1
Sch em e 2. Th e Syn th etic P a th w a y of Keton e 9a
a
(a) Et3N, CH3CN, rt, 12 h.
Sch em e 3. Th e Syn th etic P a th w a y of Keton e 7a
Sch em e 1. Th e Syn th etic P a th w a y of Keton e 5a
a
(a) DMF, 95 °C, 10 h, (b) NaHCO3, CH3CN, H2O, rt, 40 min.
quent cleavage using RuCl3/Oxone20 (90% yield). The
synthetic pathway also applies to the preparation of
ketone 9.
a
(a) THF, reflux, 20 h; (b) Et3N, THF, -5 °C to rt; reflux, 15 h.
Ca ta lytic Activities of Keton es 1-10 in th e Ep -
oxid a tion of tr a n s-Stilben e. The results of the epoxi-
dation of trans-stilbene catalyzed by ketones 1-10 (Chart
1) are summarized in Table 1. Several interesting
features were observed. (1) With a 1:1 ketone:substrate
ratio at rt, epoxidation of trans-stilbene catalyzed by
cyclic ketones 5-10 proceeded faster than those catalyzed
by 1,1,1-trifluoroacetone 1 and acyclic ketones 2-3. (2)
The activities of cyclic ketones were found to increase in
the order of 9-membered-ring ketones 4-6 < 10-mem-
bered-ring ketone 7 < 11-membered-ring ketones 8-10
and were dramatically affected by their remote substit-
uents as well (for example, entries 4-6). Among those
ketones screened, ketone 10 showed the highest catalytic
activity. (3) No considerable ketone-catalyzed Oxone
decomposition was observed for all ketones screened.
Only 3-4 equiv of Oxone was required for those epoxi-
dation reactions. (4) Cyclic ketones 6-10 were stable
under the reaction conditions but not very stable toward
silica gel. Therefore, triethylamine was added to buffer
the silica gel during flash column purification. Ketones
6-10 were recovered in high yield (over 80%) and reused
without loss of catalytic activities. (5) To demonstrate the
catalytic efficiency of cyclic ketones, epoxidation of trans-
stilbene was carried out using 1 mol % of ketone 9 at rt.
The reaction was complete in 12 h, and trans-stilbene
epoxide was isolated in 98% yield.
Here we report that a series of cyclic ketones of 2-fold
symmetry have unprecedented activities in oxidation
reactions. A portion of this work was published earlier.8a,c
II. Resu lts a n d Discu ssion
Ra tion a l Design of Keton es 4-10 for Ca ta lytic
Ep oxid a tion of tr a n s-Stilben e. We previously reported
that (1) ketones with electron-withdrawing groups, such
as F, Cl, and OAc, at R-positions would show higher
activities in catalyzing epoxidation reactions; and (2)
steric hindrance at R-positions would decrease the activ-
ity of a ketone.8a Therefore, a series of 2-fold symmetric
and conformationally rigid cyclic analogues of 1,3-di-
acetoxyacetone 3 (ketones 4-10; Chart 1) were examined
for their catalytic activities in oxidation reactions. This
series of ketones were found to be efficient catalysts for
not only epoxidation of various olefins but also oxidation
of alcohols.
P r ep a r a tion of Cyclic Keton es 4-10. Ketones 4 and
5 were prepared in 6-22% overall yield by refluxing the
corresponding acid anhydrides with 1,3-dihydroxyacetone
and subsequent intramolecular cyclization with isobut-
ylchloroformate and triethylamine.17 The synthetic scheme
of ketone 5 is illustrated as an example (Scheme 1).
Ketones 6 and 8-10 were prepared in one step (20-45%
yield) from the corresponding diacids and 1,3-dihydroxy-
acetone using 2-chloro-1-methylpyridinium iodide (Mu-
kaiyama reagent).18 The synthetic scheme of ketone 9 is
illustrated as an example (Scheme 2). As shown in
Scheme 3, ketone 7 was prepared by the coupling of the
corresponding diacid with 3-chloro-2-chloromethyl-1-pro-
Stu d ies of Hyd r a tion Equ ilibr iu m Con sta n ts. Two
steps are involved in the generation of dioxiranes in situ
(Figure 1): nucleophilic addition of Oxone (HSO5-) to
ketones and the cyclic peroxide formation.13a,21 For maxi-
mium dioxirane formation, the addition of Oxone to the
ketone carbonyl group should be favorable. Because the
common feature for addition of both Oxone and water to
the ketone is rehybridization of the carbonyl carbon from
19
pene in the presence of Cs2CO3 (67% yield) and subse-
(17) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J .
Tetrahedron Lett. 1991, 32, 923.
(18) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49.
(19) (a) Pfeffer, P. E.; Silbert, L. S. J . Org. Chem. 1976, 41, 1373.
(b) Wang, S.-S.; Gisin, B. F.; Winter, D. P.; Makofske, R.; Kulesha, I.
D. J . Org. Chem. 1977, 42, 1286.
(20) Yang, D.; Zhang, C. Unpublished results.
(21) Edwards, J . O.; Pater, R. H.; Curci, R.; DiFuria, F. Photochem.
Photobiol. 1979, 30, 63.

9890 J . Org. Chem., Vol. 63, No. 26, 1998
Yang et al.
Ta ble 1. Activities of Keton es 1-10 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 tioa a n d Hyd r a tion Equ ilibr iu m
Con sta n ts for Keton es 3 a n d 6-10b
F igu r e 2.
K
reactn
epoxide
ketone
entry ketone (M-1
)
time (min)c yield (%)d recovery (%)
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
e
e
30
120
50
35
20
12
10
10
7
96
91
90
98
96
97
96
91
99
93
f
81g
85g
29h
30h
80g
82g
81g
93g
88g
0.90
e
e
0.68
7.85
1.60
0.70
3.98
10
10
6
a
Unless otherwise stated, reaction conditions were as follows:
rt, 0.1 mmol of ketone, 0.1 mmol of trans-stilbene, 0.4 mmol of
Oxone, 1.24 mmol of NaHCO3, 1.5 mL of CH3CN, 1.0 mL of
b
aqueous Na2‚EDTA solution (4 × 10-4 M). K ) Keq[H2O] )
55.5Keq (at 20 °C); Keq ) [hydrate]/{[ketone][H2O]/2.5}. For de-
termination of hydration equilibrium constants for ketones 3 and
6-10, see Supporting Information. c Time for epoxidation to
d
complete as shown by TLC. Isolated yield after flash column
chromatography. e Not determined. f Not attempted as the low
boiling point (22 °C) of ketone 1 assures complete removal during
h
the workup. g Flash column purification with Et3N. Flash column
purification without Et3N.
F igu r e 3. X-ray structure of ketone 5 (ORTEP view).
are also expected to be more reactive than the linear
one generated from ketone 3.
As revealed by the X-ray structures of ketones 5
(Figure 3) and 9 (Figure 4),22 both the 9- and 11-
membered-ring ketones have 2-fold symmetry with the
keto groups lying on the 2-fold axes and the two ester
groups of s-trans geometry. Selected bond angles and
dihedral angles of ketones 5 and 9 are shown in Table 2.
While the respective bond angles of C-CO-C, CO-
C-O, C-O-CO, and O-CO-C are found to be
similar for ketones 5 and 9, the dihedral angle of the ester
group ( C-O-CO-C) increased remarkably from 158°
in 9-membered-ring ketone 5 to about 176° in 11-
membered-ring ketone 9. Interestingly, the extent of ester
bending (deviation from its ideal 180° plane), indicating
ring strains of those cyclic ketones, seemed to correlate
with the activities of these two cyclic ketones in cata-
lyzing in situ epoxidation. Theoretical calculations re-
vealed that the bond angle C-C(O2)sC of dimethyl-
dioxirane is about 117.7°,23 very close to the bond angle
C-CO-C of acetone (117.2°). Therefore, dioxiranes
F igu r e 1.
sp2 to sp3, the hydration equilibrium constants may be
used as an indicator of the stability of the tetrahedral
adduct of the ketone and Oxone. As shown in Table 1,
ketones 3 and 6-10 all showed moderate hydration (K
> 0.6 M-1). However, we found that there was no direct
correlation between the activities of ketones in catalyzing
epoxidation and their hydration equilibrium constants.
Str u ctu r a l An a lysis of Cyclic Keton es. The fact
that medium-sized-ring cyclic ketones 4-10 have excel-
lent catalytic efficiencies compared with that of acyclic
ketone 3 may be understood by considering their struc-
tural properties. Given that ketones 3-10 are similarly
activated by the electron-withdrawing inductive effects
of the ester groups, cyclic ketones 4-10 with the two
ester groups at R-positions folded back in the ring are
sterically less hindered than ketone 3 and, thus, more
reactive. Moreover, the dipoles of the ester groups in
cyclic ketones 4-10 are opposite in direction to that of
the keto group (Figure 2), which provides further activa-
tion for those cyclic ketones by the field effect. Therefore,
cyclic ketones 4-10 should be more electrophilic than
acyclic ketone 3, which renders easier formation of cyclic
dioxiranes from ketones 4-10. On the other hand,
following the above steric and electronic arguments for
ketones, cyclic dioxiranes generated from ketones 4-10
(22) Crystal data of ketone 5: C7H8O5, monoclinic, Cc (No. 9) with
a ) 6.388(3) Å, b ) 15.594(2) Å, c ) 7.874(4) Å, â ) 109.15(4)°, V )
740.9(6) Å3, Z ) 4, Dc ) 1.543 g cm-1, with 451 reflections refined on
672 reflections having I > 3.0σ(I), R ) 0.046, and Rw ) 0.056. Crystal
data of ketone 9: C17H12O5, monoclinic, P21/n (No. 14) with a
)
14.503(3) Å, b ) 6.766(2) Å, c ) 15.709(5) Å, â ) 117.04(1)°, V )
1373.0(5) Å3, Z ) 4, Dc ) 1.433 g cm-1, with 2430 reflections refined
on 2470 reflections having I > 3.0σ(I), R ) 0.044, and Rw ) 0.049.
(The details of the X-ray analysis are provided as Supporting Informa-
tion.)
(23) Bach, R. D.; Andres, J . L.; Owensby, A. L.; Schlegel, H. B.;
McDouall, J . W. J . Am. Chem. Soc. 1992, 114, 7207.

Cyclic Ketones for Catalytic Oxidation Reactions
J . Org. Chem., Vol. 63, No. 26, 1998 9891
Ta ble 3. In Situ Ep oxid a tion a Ca ta lyzed by Keton e 9b
F igu r e 4. X-ray structure of ketone 9 (ORTEP view).
Ta ble 2. Selected Bon d An gles a n d Dih ed r a l An gles of
Keton es 5 a n d 9
ketone 5
ketone 9
bond angle (deg)
CsCOsC
122.8
108.1
118.3
111.1
119.8
111.6
116.9
109.8
COsCsO
CsOsCO
OsCOsC
dihedral angle (deg)
COsCsOsCO
CsOsCOsC
111.1
158.1
119.3
175.9
generated from less strained ketones are expected to be
more stable and more readily formed. This possibly
accounts for the higher activity of ketone 9 than that of
ketone 5. The strong field effect of the nitro groups can
further enhance the electrophilicity of ketone 10, which
shows the highest activity among ketones 4-10.
In Situ Ep oxid a tion of Olefin s Ca ta lyzed by
Keton e 9. As one of the most efficient catalysts, ketone
9 was chosen for further screening with a variety of
substrates. The results are summarized in Table 3. With
5 mol % of ketone 9 as the catalyst, epoxidation of simple
olefins (entries 1-9) with 2 equiv of Oxone at rt can be
finished at appreciable rates with excellent isolated yields
of epoxides (75-96%). As the pH of the reaction mixture
is maintained at 7-7.5 by sodium bicarbonate, those acid-
or base-labile epoxides (entries 4, 6, and 8) can be easily
isolated without decomposition. In addition, epoxidation
of electron-deficient olefins (such as R,â-unsaturated
ketones, esters, and acids; entries 10-14) with a 1:1
ketone 9:substrate ratio at rt can be finished in 1-6 h,
which is comparable in rate to those reactions catalyzed
by trifluoroacetone 1 with a 10:1 ketone:substrate ratio
at 0 °C. Besides, in all epoxidation reactions, ketone 9
can be recovered by flash column chromatography in over
90% yield.
a
Unless otherwise stated, reaction conditions were as follows:
rt, 0.01 mmol (5 mol %) of ketone 9, 0.2 mmol of substrate, 0.4
mmol of Oxone, 1.24 mmol of NaHCO3, 1.5 mL of CH3CN, 1.0 mL
of aqueous Na2‚EDTA solution (4 × 10-4 M). Ketone 8 was
b
recovered in over 90% yield by flash column chromatography with
Et3N buffered silica gel. c Time for epoxidation to complete as
d
shown by TLC. Isolated yield after flash column chromatography.
e 0.1 mmol of ketone 9, 0.1 mmol of substrate, 0.5 mmol of Oxone,
1.55 mmol of NaHCO3. f The value in parentheses was the reaction
time for epoxidation carried out under the following conditions: 0
°C, 0.1 mmol of substrate, 1.0 mmol of trifluoroacetone, 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). 82% conversion as
g
determined by 1H NMR.
aldehyde in 77% isolated yield (entry 1). Secondary
benzylic alcohols25 were efficiently oxidized to the corre-
(24) For recent examples of catalytic oxidation of alcohols, see: (a)
Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639. (b) Marko, I. E.; Giles, P. R.; Tsukazaki, M.; Brown, S. M.; Urch,
C. J . Science 1996, 274, 2044. (c) Marko, I. E.; Giles, P. R.; Tsukazaki,
M.; Chelle-Regnaut, I.; Urch, C. J ., Brown, S. M. J . Am. Chem. Soc.
1997, 119, 12661. (d) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi,
A.; Piancatelli, G. J . Org. Chem. 1997, 62, 6974. (e) Fung, W.-H.; Yu,
W.-Y.; Che, C.-M. J . Org. Chem. 1998, 63, 2873.
Ca ta lytic Oxid a tion of Alcoh ols.24 Apart from ep-
oxidation reactions, oxidation of various alcohols with 2
equiv of Oxone in the presence of 20 mol % of ketone 9
at rt can be finished in a reasonable period of time (3.2-
12 h). The results are summarized in Table 4. 4-tert-
Butylbenzyl alcohol was oxidized to 4-tert-butylbenz-
(25) For oxidation of R-methylbenzyl alcohols by excess amounts of
dimethyldioxirane, see: Kovac, F.; Baumstark, A. L. Tetrahedron Lett.
1994, 35, 8751.

9892 J . Org. Chem., Vol. 63, No. 26, 1998
Yang et al.
Ta ble 4. In Situ Oxid a tion of Alcoh olsa Ca ta lyzed by
P r ep a r a tion of Keton e 4. (+)-Di-O-acetyltartaric anhy-
dride26 (0.67 g, 3.08 mmol) and 1,3-dihydroxyacetone (0.28 g,
3.08 mmol) were dissolved in THF (8 mL). The resulting
solution was refluxed under N2 atmosphere for 20 h. After
dilution with CH2Cl2, the organic phase was washed with
saturated NaHCO3 solution and brine. The combined organic
layers were dried over anhydrous Na2SO4, filtered, and
concentrated to a white solid (0.58 g), which was used in the
next step without further purification. The crude solid (0.52
g, 1.69 mmol) was dissolved in THF (10 mL) and treated with
Et3N (0.28 mL, 2.04 mmol). The reaction mixture was stirred
at -5 °C for 10 min. Isobutyl chloroformate (0.24 mL, 1.87
mmol) was added dropwise to the reaction mixture. The
mixture was stirred at -5 °C for 10 min and at rt for 20 min.
After dilution with THF (160 mL), the mixture was refluxed
for 15 h. The solvent was evaporated off under reduced
pressure. The residue was diluted with CH2Cl2 and washed
with saturated NaHCO3 solution and brine. The organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated.
The residue was purified by flash column chromatography
(10% to 35% EtOAc in hexane) to give ketone 4 (86 mg, 22%
yield) as a white solid: analytical TLC (silica gel 60), 50%
Keton e 9b
1
EtOAc in hexane, Rf ) 0.48; mp 152-154 °C; H NMR (270
MHz, CDCl3) δ 5.67 (d, J ) 16.9 Hz, 2H), 5.24 (s, 2H), 4.38 (d,
J ) 16.4 Hz, 2H), 2.23 (s, 6H); 13C NMR (67.94 MHz, CDCl3)
δ 199.56, 169.74, 165.91, 71.86, 69.11, 20.35; IR (CCl4) 1788,
1765, 1735 cm-1; HRMS for C11H12O9 (M+) calcd 288.0481,
found 288.0476; CIMS m/z 288 (M+, 14), 198 (100).
a
Unless otherwise stated, reaction conditions were as follows:
rt, 0.06 mmol (20 mol %) of ketone 9, 0.3 mmol of substrate, 0.6
mmol of Oxone, 1.86 mmol of NaHCO3, 1.5 mL of CH3CN, 1.0 mL
b
of aqueous Na2‚EDTA solution (4 × 10-4 M). Ketone 9 was
recovered in over 90% yield by flash column chromatography with
Et3N buffered silica gel. c Isolated yield after flash column chro-
P r ep a r a tion of Keton e 5. Succinic anhydride (2.5 g, 25
mmol) and 1,3-dihydroxyacetone (2.25 g, 25 mmol) were
dissolved in THF (80 mL). The resulting solution was refluxed
under N2 atmosphere for 20 h. Solvent removal by evaporation
provided a white solid (4.7 g), which was used in the next step
without further purification. The crude soild (2 g, 10.5 mmol)
was dissolved in THF (50 mL) and treated with Et3N (1.8 mL,
12.6 mmol). The reaction mixture was stirred at -5 °C for 10
min. Isobutyl chloroformate (1.5 mL, 11.6 mmol) was added
dropwise to the reaction mixture. The mixture was stirred at
-5 °C for 10 min and at rt for 20 min. After dilution with THF
(150 mL), the mixture was refluxed for 15 h. The solvent was
evaporated off under reduced pressure. The residue was
d
matography. Time for oxidation to complete as shown by TLC.
e The conversion was quantitative as determined by GLC.
sponding ketones in 80-94% yield (entries 2-4). Cyclic
secondary alcohols were oxidized to ketones in 75-95%
yield without the formation of the Baeyer-Villiger
products (entries 5-7). Again, the ketone catalyst can
be recovered in over 90% yield by column chromatogra-
phy. To the best of our knowledge, this is the first report
of ketone-catalyzed oxidation of alcohols with Oxone.
However, we should point out that oxidation of unac-
tivated primary alcohols such as 2-phenylethanol with
ketone 9 as catalyst was found to be ineffective. For
substrates such as 10-undecen-1-ol (Table 3, entry 8) and
cinnamyl alcohol (Table 3, entry 9), the olefinic double
bonds were oxidized instead of the primary hydroxyl
groups.
diluted with CH
2Cl2 and washed with saturated NaHCO3
solution and brine. The organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified
by flash column chromatography (40% EtOAc in hexane) to
give ketone 5 (109 mg, 6% yield) as a white solid: analytical
1
TLC (silica gel 60), 50% EtOAc in hexane, Rf ) 0.5; H NMR
(270 MHz, CDCl3) δ 4.94 (s, 4H), 2.72 (s, 4H); 13C NMR (67.94
MHz, CDCl3) δ 202.14, 171.17, 68.93, 32.54; IR (CCl4) 1769,
1738 cm-1; HRMS for C7H8O5 (M+) calcd 172.0372, found
172.0367; EIMS (20 eV) m/z 173 (M+ + 1, 55), 159 (100).
III. Con clu sion
In this paper, we have demonstrated that the readily
available cyclic ketones 5-10 have exceptional activities
in catalyzing the oxidation of olefins. The steric and
electronic effects as well as ring strains contribute
significantly to the catalytic activities of those cyclic
ketones. Epoxidation of various olefins and oxidation of
alcohols catalyzed by ketone 9 can be finished at ap-
preciable rates with excellent isolated yields of products
and ketone recovery (>90%). These oxidation reactions
are green processes as the terminal oxidant Oxone only
produces nontoxic potassium hydrogen sulfate and oxy-
gen as the byproducts. We believe a robust, recyclable,
and environmentally friendly catalyst like ketone 9
should have great potential to be used as a benchtop
catalyst for many other oxidation reactions.
P r ep a r a tion of Keton e 6. trans-1,2-Cyclohexanedicar-
boxylic acid (344 mg, 2 mmol) and 1,3-dihydroxyacetone (270
mg, 3 mmol) were dissolved in anhydrous CH3CN (200 mL).
Triethylamine (1.8 mL, 12 mmol) was added to the reaction
mixture. The resulting solution was stirred at rt for 15 min,
followed by addition of 2-chloro-1-methylpyridinium iodide
(1.22 g, 4.8 mmol). The reaction mixture was refluxed under
N2 atmosphere for 15 h. The solvent was evaporated off under
reduced pressure. The dark-brown residue was diluted with
CH2Cl2. The organic phase was washed twice with H2O, dried
over anhydrous Na2SO4, filtered, and concentrated. The resi-
due was purified by flash column chromatography: 40 g of
silica gel (Merck, 230-400 mesh) in hexane (300 mL) and Et3N
(3 mL) was poured into a column of 30 mm diameter. The
column was eluted with hexane followed by 30% EtOAc in
hexane to give ketone 6 (122 mg, 24% yield) as a white solid:
analytical TLC (silica gel 60), 30% EtOAc in hexane, Rf ) 0.52;
1
mp 84-85 °C; H NMR (300 MHz, CDCl3) δ 5.68 (d, J ) 16.6
IV. Exp er im en ta l Section
Hz, 2H), 4.19 (d, J ) 16.6 Hz, 2H), 2.49-2.45 (m, 2H), 2.00-
1.71 (m, 6H), 1.36-1.26 (m, 2H); 13C NMR (125.76 MHz,
CDCl3) δ 202.66, 173.40, 68.58, 47.81, 27.05, 24.03; IR (CCl4)
The olefins, alcohols, and Oxone were purchased from
Aldrich Chemical Co. and used without further purification.
The known epoxides were identified by comparison of the
spectral and physical data with those reported.
(26) Dobashi, Y.; Hara, S. J . Org. Chem. 1987, 52, 2490.

Cyclic Ketones for Catalytic Oxidation Reactions
J . Org. Chem., Vol. 63, No. 26, 1998 9893
1761, 1732 cm-1; HRMS for C11H14O5 (M+) calcd 226.0841,
found 226.0842; CIMS m/z 227 (M+ + 1, 100).
g, 3.3 mmol) was added to this solution. The resulting mixture
was stirred at 95 °C under N2 atmosphere for 10 h. The
reaction mixture was diluted with EtOAc and washed four
times with water. The organic layer was dried over MgSO4
and concentrated. The residue was purified by flash column
chromatography (20% EtOAc in hexane) to give compound 7b
(253 mg, 67% yield) as a white solid: analytical TLC (silica
gel 60), 30% EtOAc in hexane, Rf ) 0.6; mp 54-55 °C; 1H NMR
(300 MHz, CDCl3) δ 5.29 (s, 2H), 4.77 (s, 4H), 2.38 (s, 4H),
1.61-1.44 (m, 10H); 13C NMR (75.47 MHz, CDCl3) δ 171.67,
137.98, 120.44, 66.69, 44.07, 37.48, 37.19, 25.81, 21.60; IR
(CH2Cl2) 1737 cm-1; HRMS for C14H20O4 (M+) calcd 252.1362,
found 252.1359.
A stock solution of ruthenium trichloride hydrate (843 mg,
4 mmol) in water (100 mL) was prepared. Compound 7b (50.4
mg, 0.2 mmol) was dissolved in CH3CN (3 mL) and water (2
mL). The stock solution (0.2 mL) was transferred to the
reaction mixture. To this mixture was added, in portions, a
mixture of Oxone (307 mg, 0.5 mol) and sodium bicarbonate
(130 mg, 1.55 mol) over a period of 30 min at rt. The reaction
was complete in 40 min as shown by TLC. The reaction
mixture was diluted with EtOAc and washed twice with brine.
The organic layer was dried over anhydrous MgSO4, filtered,
and concentrated. The residue was purified by flash column
chromatography: 30 g of silica gel (Merck, 230-400 mesh) in
hexane (200 mL) and Et3N (2 mL) was poured into a column
of 30 mm diameter. The column was eluted with hexane,
followed by 35% EtOAc in hexane to give ketone 7 (46.1 mg,
90%) as a colorless oil: analytical TLC (silica gel 60), 30%
EtOAc in hexane, Rf ) 0.3; 1H NMR (300 MHz, CDCl3) δ 4.76
(s, 4H), 2.49 (s, 4H), 1.70-1.40 (m, 10H); 13C NMR (67.94 MHz,
CDCl3) 201.80, 171.01, 68.03, 42.97, 37.68, 36.53, 25.66, 21.56;
IR (CCl4) 1755 cm-1; HRMS for C13H18O5 (M+) calcd for
254.1154, found 254.1152; EIMS (20 eV) m/z 254 (M+, 9), 94
(100).
P r ep a r a t ion of Ket on e 9. Following the procedure for
compound 7b: from diphenic acid (606 mg, 2.5 mmol), 3-chloro-
2-chloromethyl-1-propene (313 mg, 2.5 mmol), anhydrous DMF
(200 mL), and cesium carbonate (1.8 g, 5.5 mmol), at 95 °C
for 24 h, was obtained compound 9b (409 mg, 56% yield) as a
white solid: analytical TLC (silica gel 60), 20% EtOAc in
hexane, Rf ) 0.5; mp 240-241 °C; 1H NMR (300 MHz, CDCl3)
δ 7.59-7.38 (m, 8H), 5.66 (d, J ) 14.2 Hz, 2H), 5.20 (s, 2H),
4.41 (d, J ) 14.2 Hz, 2H); 13C NMR (75.47 MHz, CDCl3) δ
168.37, 140.22, 138.97, 133.15, 130.94, 130.52, 127.62, 126.93,
114.19, 64.60; IR (CCl4) 1752 cm-1; HRMS for C18H14O4 (M+)
calcd 294.0892, found 294.0893; EIMS (20 eV) m/z 294 (M+,
100). Following the cleavage procedure for ketone 7: from
compound 9b (58.8 mg, 0.2 mmol) was obtained ketone 9 (49.7
mg, 84% yield) as a white solid.
Gen er a l in Situ Ep oxid a tion P r oced u r e. P r ep a r a tion
of tr a n s-Stilben e Ep oxid e (En tr y 9, Ta ble 1). To an CH3-
CN solution (1.5 mL) of trans-stilbene (18 mg, 0.1 mmol) and
cyclic ketone 9 (29.6 mg, 0.1 mmol) at rt was added an aqueous
Na2‚EDTA solution (1 mL, 4 × 10-4 M). To this mixture was
added, in portions, a mixture of Oxone (246 mg, 0.4 mmol) and
sodium bicarbonate (104 mg, 1.24 mmol). The reaction was
complete in 7 min at rt as shown by TLC. The reaction mixture
was poured into water and extracted three times with CH2-
Cl2. The organic layer was dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, the residue
was purified by flash column chromatography: 20 g of silica
gel (Merck, 230-400 mesh) in hexane (100 mL) and Et3N (1
mL) was poured into a column of 20 mm diameter. The column
was eluted with hexane, followed by 5% EtOAc in hexane to
give trans-stilbene epoxide (19.6 mg, 99% yield), and with 35%
EtOAc in hexane to recover ketone 9 (28.4 mg, 93% recovery).
P r ep a r a tion of Keton e 8. Following the procedure for
ketone 6: from (()-6,6′-dimethyl-2,2′-diphenic acid27 (135 mg,
0.5 mmol), 1,3-dihydroxyacetone (67.6 mg, 0.75 mmol), anhy-
drous CH3CN (50 mL), triethylamine (0.42 mL, 3.0 mmol), and
2-chloro-1-methylpyridinium iodide (306.6 mg, 1.2 mmol) was
obtained ketone 8 (20 mg, 12% yield) as a white solid:
analytical TLC (silica gel 60), 30% EtOAc in hexane, Rf ) 0.30;
1
mp 135-137 °C; H NMR (270 MHz, CDCl3) δ 7.48-7.32 (m,
6H), 5.45 (d, J ) 15 Hz, 2H), 4.14 (d, J ) 15 Hz, 2H), 2.12 (s,
6 H); 13C NMR (67.94 MHz, CDCl3) δ 202.31, 167.13, 137.90,
136.31, 132.61, 132.09, 127.72, 124.79, 66.91, 19.80; IR (CCl4)
1759, 1739 cm-1; HRMS for C19H16O5 (M+) calcd 324.0998,
found 324.0990; CIMS m/z 325 (M+ + 1, 100).
P r ep a r a tion of Keton e 10. Following the procedure for
ketone 6: from (()-6,6′-dinitro-2,2′-diphenic acid28 (44.5 mg,
0.13 mmol), 1,3-dihydroxyacetone (18 mg, 0.20 mmol), anhy-
drous CH3CN (14 mL), triethylamine (0.2 mL, 1.07 mmol), and
2-chloro-1-methylpyridinium iodide (137 mg, 0.54 mmol) was
obtained ketone 9 (20 mg, 12% yield) as a pale yellow solid:
analytical TLC (silica gel 60), 80% EtOAc in hexane, Rf ) 0.6;
1H NMR (300 MHz, CDCl3) δ 8.39 (dd, J ) 8.2 Hz, 1.2 Hz,
2H), 7.88 (dd, J ) 7.7 Hz, 1.2 Hz, 2H), 7.73 (t, J ) 8.0 Hz,
2H), 5.5 (d, J ) 15.2 Hz, 2H), 4.21 (d, J ) 15.2 Hz, 2H); 13C
NMR (67.94 MHz, CDCl3) δ 200.20, 164.52, 148.34, 133.70,
132.69, 129.97, 129.68, 127.54, 67.22; IR (CCl4) 1769, 1744,
1543, 1350 cm-1; EIMS (20 eV) m/z 340 (M+ - NO2, 100); CIMS
m/z 387 (M+ + 1, 100).
P r ep a r a tion of Keton e 9. Diphenic acid (121 mg, 0.5
mmol) and 1,3-dihydroxyacetone (67.6 mg, 0.75 mmol) were
dissolved in anhydrous CH3CN (50 mL). Triethylamine (1.1
mL, 8 mmol) was added to the reaction mixture. The resulting
solution was stirred at rt for 15 min followed by addition of
2-chloro-1-methylpyridinium iodide (1.02 g, 4 mmol). The
reaction mixture was stirred under N2 atmosphere at rt for
12 h and then refluxed for 1 h. The solvent was evaporated
off under reduced pressure. The dark-brown residue was
diluted with CH2Cl2. The organic phase was washed twice with
H2O, dried over Na2SO4, filtered, and concentrated. The
residue was purified by flash column chromatography: 30 g
of silica gel (Merck, 230-400 mesh) in hexane (200 mL) and
Et3N (2 mL) was poured into a column of 30 mm diameter.
The column was eluted with hexane followed by 35% EtOAc
in hexane to give ketone 98a (67 mg, 45% yield) as a white
solid: analytical TLC (silica gel 60), 30% EtOAc in hexane, Rf
1
) 0.33; mp 166-167 °C; H NMR (300 MHz, CDCl3) δ 7.43-
7.65 (m, 8H), 5.73 (d, J ) 15.6 Hz, 2H), 4.23 (d, J ) 15.6 Hz,
2H); 13C NMR (75.47 MHz, CDCl3) δ 202.085, 167.21, 138.76,
132.23, 131.57, 130.56, 127.86, 127.24, 66.81; IR (CCl4) 1758,
1737 cm-1; HRMS for C17H12O5 (M+) calcd 296.0685, found
296.0683; EIMS (20 eV) m/z 296 (M+, 52), 180 (100); CIMS
m/z 297 (M+ + 1, 7), 296 (M+, 48), 180 (100).
P r ep a r a tion of Keton e 7. 1,1-Cyclohexanediacetic acid
(300 mg, 1.5 mmol; azeotroped three times with toluene) and
3-chloro-2-chloromethyl-1-propene (187.5 mg, 1.5 mmol) were
dissolved in anhydrous DMF (150 mL). Cesium carbonate (1.08
(27) Synthesis of (()-6,6′-dimethyl-2,2′-diphenic acid was carried out
according to the literature procedure, see: Fourniss, B. S.; Vogel, A. I.
Textbook of Practical Organic Chemistry, 5th ed.; Wiley: New York,
1989; p 837.
(28) Synthesis of (()-6,6′-dinitro-2,2′-diphenic acid was carried out
according to the literature procedures, see: (a) Whitmore, F. C.;
Culhane, P. J .; Neher, H. T. Organic Syntheses; Wiley & Sons: New
York, 1976; Collect Vol. I, 56. (b) Culhane, P. J . Organic Syntheses,
Wiley & Sons: New York, 1976; Collect Vol. I, 125.
(29) Gunstone, F. D.; Harwood, J . L.; Padley, F. B. The Lipid
Handbook; Chapman and Hall: Cambridge, 1986; p 461.
(30) Berk, S. C.; Buchwald, S. L. J . Org. Chem. 1992, 57, 3751.
(31) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
K.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(32) Murray, R. W.; Singh, M.; J eyaraman, R. J . Am. Chem. Soc.
1992, 114, 1346.
Ack n ow led gm en t. This work was supported by The
University of Hong Kong and the Hong Kong Research
Grants Council. Y.-C.Y. and M.-K.W are the recipients
of university postdoctoral fellowships.
(33) Conan, A.; Sibille, S.; Perichon, J . J . Org. Chem. 1991, 56, 2018.
(34) J ames, R. A.; Kohn, C. A.; Rees, A. H.; Verschuren, R. E. J .
Heterocyclic Chem. 1989, 26, 793.
Su p p or tin g In for m a tion Ava ila ble: Determination of
the hydration equilibrium constants for ketones 3 and 6-10,

9894 J . Org. Chem., Vol. 63, No. 26, 1998
Yang et al.
1H and 13C NMR spectra for ketones 4-10, 7b, and 9b, and
X-ray structural analyses of ketones 5 and 9 containing tables
of atomic coordinates, thermal parameters, bond lengths, and
angles (33 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.
J O981659E