Co-catalyzed autoxidation of alkene in the presence of silane. The effect of the structure of silanes on the efficiency of the reaction and on the product distribution

Article abstract of DOI:10.1016/j.tet.2005.08.025

A systematic investigation of the structural effect of silanes on the Co-catalyzed reductive oxygenation of alkene in the presence of silane (Mukaiyama-Isayama reaction) showed that the efficiency of the reaction decreases with the increase of the steric bulk of the silanes. A similar trend was observed for the metal-exchange reaction between Co(III)-alkylperoxo complex and silane, too. The peroxidation of (S)-limonene, followed by deprotection of the derived silyl peroxides, provides a mixture of the corresponding monocyclic hydroperoxide 24 and the bicyclic one 25, the ratio being a marked function of the steric bulk of silanes.

Full text of DOI:10.1016/j.tet.2005.08.025

Tetrahedron 61 (2005) 9961–9968
Co-catalyzed autoxidation of alkene in the presence of silane. The
effect of the structure of silanes on the efficiency of the reaction
and on the product distribution
Jin-Ming Wu,a Shigeki Kunikawa,a Takahiro Tokuyasu,a Araki Masuyama,a,
*
Masatomo Nojima,a Hye-Sook Kimb and Yusuke Watayab
aDepartment of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
bGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University,
Tsushima-naka 1-1-1, Okayama 700-8530, Japan
Received 15 July 2005; revised 5 August 2005; accepted 5 August 2005
Available online 24 August 2005
Abstract—A systematic investigation of the structural effect of silanes on the Co-catalyzed reductive oxygenation of alkene in the presence
of silane (Mukaiyama–Isayama reaction) showed that the efficiency of the reaction decreases with the increase of the steric bulk of the
silanes. A similar trend was observed for the metal-exchange reaction between Co(III)–alkylperoxo complex and silane, too. The
peroxidation of (S)-limonene, followed by deprotection of the derived silyl peroxides, provides a mixture of the corresponding monocyclic
hydroperoxide 24 and the bicyclic one 25, the ratio being a marked function of the steric bulk of silanes.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Much attention has been focused on selective oxygenations
of the C]C double bond moiety by molecular oxygen.1 Of
these, Mukaiyama–Isayama reaction would be the most
promising from the view of synthesis of the corresponding
sec- and tert-alkyl hydroperoxides. They have reported that
autoxidation of alkenes catalyzed by bis(1,3-diketonato)-
cobalt(II) in the presence of triethylsilane (Et3SiH) provides
the corresponding triethylsilyl peroxides in high yield.2,3 By
treatment with one drop of concd HCl in MeOH, the
triethylsilyl peroxides are easily desilylated to give the
Scheme 1. A proposed mechanism for Mukaiyama–Isayama reaction.
corresponding hydroperoxides. On the basis of a novel
catalytic role of Co(III)–alkylperoxo complex III and
complex and silane. In the synthesis of the antimalarial
Co(III)–alkyl complex II in the same peroxidation reaction
bicyclic peroxide from limonene, a similar substituent effect
of alkene with molecular oxygen and Et3SiH, we have
of silanes is observed.
proposed a mechanism involving the Co(III)–hydride
complex I, which would be produced by metal exchange
between Co(III)–alkylperoxo complex III and silane
2. Results and discussion
(Scheme 1).4 As a further insight, we report herein, that
the steric bulk of silanes plays an important role in
2.1. Co(II)-catalyzed autoxidation of 3-methyl-3-butenyl
benzoate in the presence of a series of silanes
efficiency of both the peroxidation of alkene and the metal
exchange between the isolated Co(III)–alkylperoxo
We conducted bis(1-morpholinocarbamoyl-4,4-dimethyl-1,
Keywords: Co-catalyzed autoxidation; Silyl peroxide; Yingzhaosu A
3-pentanedionato)cobalt(II) (Co(modp)2)-catalyzed autoxi-
analogue; Antimalarial activity.
dation of 3-methyl-3-butenyl benzoate 1 in the presence of a
series of silanes 2a–g in 1,2-dichloroethane (DCE) at room
*
Corresponding author. Tel./fax: C81 6 6879 7930;
e-mail: toratora@chem.eng.osaka-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.025

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J.-M. Wu et al. / Tetrahedron 61 (2005) 9961–9968
Table 1. Co(II)-catalyzed autoxidation of alkene 1 in the presence of silanea
Run
Silane 2 (BDE, kcal/mol)b
Reaction time (h)
Conv. (%)
Products (%)
3
4
5
1
2
3
4
5c
6
7
8
a: PhSiH3 (88.2)
b: PhMeSiH2
c: PhMe2SiH
d: Et3SiH (90.1)
d: Et3SiH
2
2
2
2
3.5
4
4
18
100
100
100
100
95
23
69
22
64
13
3
72
89
80
87
5
9
4
e: Ph2MeSiH
f: Ph3SiH (83.0)
g: Pr3SiH
75
4d
i
13d
a The reaction of alkene 1 was undertaken in the presence of Co(modp)2 (5 mol%) and a silane (2 equiv) at room temperature.
b BDE, bond dissociation energy, which was taken from the data in Ref. 10.
c Co(acac)2 was used as the catalyst instead of Co(modp)2.
d No oxidation product was identified.
temperature (Table 1). By column chromatography of the
crude mixture of products on silica gel, silyl peroxide 3,
hydroperoxide 4 and alcohol 5 were isolated (the yields of
the products were calculated based on the consumed alkene
1). Consistent with the result found by Isayama and
Mukaiyama, Co(modp)2- or Co(acac)2-catalyzed peroxi-
dation of 1 in the presence of Et3SiH proceeded smoothly
and regioselectively, affording the corresponding triethyl-
silyl peroxide 3d in high yield (runs 4 and 5).4 A similar
trend was observed for PhMe2SiH 2c (run 3). In the case of
more bulky Ph2MeSiH 2e also the silyl peroxide 3e was the
major product (run 6), although the reaction rate was
significantly slower than that in the presence of 2c or 2d. In
the case of PhSiH3 2a or PhMeSiH2 2b the autoxidation
proceeded smoothly. However, the isolated products were
only hydroperoxide 4 and alcohol 5; the corresponding silyl
peroxide 3 was not isolated.5 When the autoxidation was
undertaken in the presence of the most bulky Ph3SiH 2f or
(isopropyl)3SiH 2g, no evidence was obtained for the
formation of oxidation product. These results demonstrate
that the structure of silane 2 plays an important role in
determining both the efficiency of autoxidation5a and the
product distribution.5b
(2-phenylpropan-2-ylperoxy)methyl(phenyl)silane 6b, pre-
pared by the reaction of cumyl hydroperoxide and
PhMeSi(H)Cl in the presence of Et3N,6 also decomposed
during the column chromatography on silica gel to give a
mixture of hydroperoxide 7 (49%) and alcohol 8 (38%)
(Scheme 2). In addition, the reaction of the hydroperoxide 7
with PhSiH3 2a in the presence of a catalytic amount of
Co(modp)2 resulted in the complete decomposition into
alcohol 8 (72%) (Scheme 2).
Scheme 2. Decomposition of silyl peroxide 6b and hydroperoxide 7.
The reaction in the presence of bulky Ph3SiH 2f or
(isopropyl)3SiH 2g did not give any oxidation product.
This leads us to deduce that the difference in steric crowding
rather than the difference in Si–H bond strength determines
the efficiency of Mukaiyama–Isayama reaction. To obtain
more clear-cut evidence for the effect of the steric bulk of
silane on the reaction rate, we undertook a competitive
reaction between PhSiH3 2a and bulkier Et3SiH 2d. Since
the products from the reaction with PhSiH3 2a are
hydroperoxide 4 and alcohol 5 and, in contrast, the reaction
with Et3SiH 2d gives exclusively the silyl peroxide 3d, it is
reasonable to consider that the product composition (4C5)/
3d indicates the relative reactivity between 2a and 2d.
When the reaction of alkene 1 was undertaken in the
Selective isolation of hydroperoxide 4 and alcohol 5 from
the reaction of alkene 1 in the presence of PhSiH3 2a or
PhMeSiH2 2b is discussed first. We thought that the
corresponding silyl peroxide 3a or 3b is certainly produced
by transmetallation between the corresponding Co(III)–
alkylperoxo complex and the silane 2 (Scheme 1). This was
confirmed by the measurement of the 1H NMR spectrum of
the crude product obtained from the reaction in the presence
of PhMeSiH2 2b; the silyl peroxide 3b was found to be the
major product. During column chromatography on silica gel
or alumina, however, the decomposition occurred easily,
thereby providing only hydroperoxide 4 and alcohol 5.
Exactly the same trend was observed for the reaction in
the presence of PhSiH3 2a. Consistent with this, treatment of

J.-M. Wu et al. / Tetrahedron 61 (2005) 9961–9968
9963
Scheme 3. The decomposition course of Co(III)–alkylperoxo complex 9 in the presence of silane.
presence of 2a and 2d (2 mol equiv in each silane), a
mixture of silyl peroxide 3d, hydroperoxide 4 and alcohol 5
were obtained in yields of 16, 25 and 43%, respectively. In
this respect, treatment of silyl peroxide 3d with PhSiH3
(2 mol equiv) in the presence of Co(modp)2 (5 mol%) under
an oxygen atmosphere for 2 h resulted in the complete
recovery of 3d, suggesting that silyl peroxide 3d is stable
under the reaction conditions. Thus, the (4C5)/3d ratio of
4:1 observed in the competitive reaction (Eq. 1) demon-
strates that the reactivity of the relatively smaller PhSiH3 2a
is much larger than that of Et3SiH 2d.
Thus, we found that the steric bulk of silane is an important
factor in determining the efficiency of the Mukaiyama–
Isayama reaction. The origin would be that the Co(III)–
alkylperoxo complex III is highly crowded and, therefore,
approach of the sterically congested silane is quite difficult.
To confirm this, we prepared the pyridine-coordinated
Co(III)–alkylperoxo complex 9 (the structure of the tert-
butylperoxo complex similar to 9 has been unambiguously
determined by the X-ray analysis; see Scheme 37) and tried
the reaction with a series of silanes (Table 2). It would be
reasonable to expect that the pyridine-coordinated complex
9 is more crowded than the relevant complex III generated
during the Mukaiyama–Isayama reaction and, therefore, a
larger steric effect would be observed in the metal exchange
reaction between 9 and a silane. In connection with this,
Talsi and his co-workers8 have found that Co(acac)2-
(OOCMe2Ph)Py 9 is stable in the solid state (one month
when kept at 0 8C) and in contrast, it decomposes very easily
(1)
in organic solvents (in benzene t1⁄
Z8 h; in CDCl3 t ⁄ Z3 h
1
2
2
at 20 8C). By MS and 1H NMR spectra, the volatile products
in decomposition have been found to be cumyl alcohol,
Table 2. The reaction of Co(III)–alkylperoxy complex 9 with a silanea
Run
Silane 2
Products (%)
6
7
8
1
2
3
4b
5
6
7
8
a: PhSiH3
c: PhMe2SiH
d: Et3SiH
54
19
26
33
38
37
27
42
37
23
60
15
5
24
d: Et3SiH
e: Ph2MeSiH
f: Ph3SiH
g: Pr3SiH
18
58
54
i
None
a Unless otherwise noted, the reaction was conducted in the presence of 2 mol equiv of a silane.
b The reaction in the presence of 20 mol equiv of the silane.4

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J.-M. Wu et al. / Tetrahedron 61 (2005) 9961–9968
acetophenone, acetylacetone, and pyridine (the yields have
not been determined). Also, they have found that Co(acac)3
is the main cobalt-containing product. We repeated the
decomposition of 9 in DCE under an Ar atmosphere and
found that only alcohol 8 was obtained in 42% yield
(Table 2, run 8). In the presence of a silane, however, silyl
peroxide 6 and hydroperoxide 7 were obtained together with
alcohol 8. Moreover, the product distribution is a marked
function of the structure of silanes. Thus, in the case of the
silane PhMe2SiH 2c (run 2), Et3SiH 2d (run 3) or Ph2MeSiH
2e (run 5) the corresponding silyl peroxide 6 was certainly
obtained, together with hydroperoxide 7 and alcohol 8.
When the reaction was performed in the presence of more
bulky silane such as Ph3SiH 2f (run 6) or (isopropyl)3SiH 2g
(run 7), however, only a mixture of hydroperoxide 7 and
alcohol 8 was obtained.
Scheme 4. Reaction of Co(II) with silane under an oxygen atmosphere.
superoxocobalt(III) 13 and m-peroxocobalt(III) 14.11 Sub-
sequent transmetallation of m-peroxocobalt(III) 14 complex
with a relatively small Et3SiH would give the corresponding
Co(III)–hydride complex I (Scheme 1). This has been
confirmed by the fact that treatment of Co(modp)2 with
Et3SiH (38 equiv) under an oxygen atmosphere for 18 h
gave Et3SiOOSiEt3 15 in 200% yield (based on the
Co(modp)2), together with Et3SiOH 16 (350%) (Scheme
4).4 The steric bulk of the m-peroxocobalt(III) 14 is similar
A reasonable mechanism for the formation of silyl peroxide
6, hydroperoxide 7, and alcohol 8 from the pyridine-
coordinated Co(III)–alkylperoxo complex 9 is shown in
Scheme 3. A probable mechanism for the formation of
alcohol 8 in the absence of silane is discussed first. In
solution the cleavage of the Co–O bond of the peroxo
complex 9 is known to occur very easily yielding the
cumylperoxyl radical 10 as determined by the measurement
of ESR spectrum.8 The reasonable mode of decay of the
peroxyl radical 10 is dimerization to give the tetroxide 11,
which in turn ejects oxygen molecule to give the alkoxyl
radical 12.9 Finally, the highly reactive oxy-radical 12
abstracts a hydrogen atom from solvent etc., thereby
providing the corresponding alcohol 8 (Scheme 3).
The formation of silyl peroxide 6 from the reaction with
2 mol equiv of silanes such as PhMe2SiH 2c, Et3SiH 2d and
Ph2MeSiH 2e may suggest that even in the case of the
pyridine-coordinated Co(III)–alkylperoxy complex 9 metal
exchange is possible to occur albeit inefficiently. When 9
was treated with 20 equiv of Et3SiH, however, the
corresponding triethylsilyl peroxide 6 was obtained in a
substantial yield of 60%, together the alcohol 8 (33%)
(Table 2, run 4).4 Since the metal exchange reaction
between 9 and silane is a slow process, cleavage of the
Co–O bond competitively occurs to yield the peroxyl radical
10, which in turn abstracts hydrogen from silanes 2 to give
the hydroperoxide 7. It should be noticed that the Si–H bond
dissociation energies (BDE) of silanes (Table 2) are similar
to that of the O–H bond of ROOH (ca. 89 kcal/mol).10 In the
case of the most bulky silanes 2f,g, metal exchange is a
disfavored process and, therefore, only the processes
involving the formation of the peroxyl radical 10 can
contribute, thereby yielding the hydroperoxide 7 and the
alcohol 8.
Thus, as an explanation for the inefficiency of the bulky
silanes such as Ph3SiH 2f and (isopropyl)3SiH 2g in the
Mukaiyama–Isayama reaction, we propose slow metal
exchange between the Co(III)–alkylperoxo complex III
and the bulky silane. However, a similar but alternative
explanation would be possible. That is, the initiation step
leading to the formation of Co(III)–hydride complex I may
be also difficult in the case of the bulky silanes, 2f and 2g. It
is well known that Co(II) complexes such as Co(acac)2 are
oxidized by molecular oxygen to afford the corresponding
Scheme 5. Peroxidation of (S)-limonene (17) in the presence of Et3SiH 2d.

J.-M. Wu et al. / Tetrahedron 61 (2005) 9961–9968
9965
to that of Co(III)–alkylperoxo complex III and, therefore, in
the case of bulky silanes the formation of Co(III)–hydride
complex I in the initiation step would be also quite difficult.
peroxo complex 20, derived from the regioselective
oxidation of the less hindered double bond of (S)-limonene
17, occurs very rapidly and as a result, the monocyclic silyl
peroxide 22b is produced exclusively (reference Scheme 5).
In the case of bulky Ph2MeSiH 2e, however, the similar
metal exchange must be very slow from steric reasons and,
therefore, the reversible formation of the peroxyl radical 18
from the alkylperoxo complex 20, followed by intra-
molecular cyclization leading to the formation of the
bicyclic one 19, becomes a favorable process. Thus, the
bicyclic silyl peroxide 23e is produced as the major product.
From the view of an efficient synthesis of a bicyclic
hydroperoxide 25, however, the reaction in the presence of
Ph2MeSiH 2e is similar to that in the presence of Et3SiH 2d.
The former reaction using 2e is very slow and, therefore,
some competitive processes leading to the formation of
undesired products seem to contribute in a larger extent (see
Section 4).
2.2. Preparation of yingzhaosu A analogue from
(S)-limonene
Finally, the effect of the structure of silanes on the ratio of
the monocyclic hydroperoxide 24 and the bicyclic one 25 in
the peroxidation of (S)-limonene (17) is described. We have
already reported that the Co(modp)2-catalyzed autoxidation
of 17 in the presence of Et3SiH, followed by deprotection of
the derived triethylsilyl peroxides, 22d and 23d, provides a
mixture of monocyclic hydroperoxide 24 and the bicyclic
one 25 in yields of 36 and 22%, respectively.12 Reduction of
25 with PPh3 gives the corresponding alcohol 26, which is in
turn acetylated to yield the yingzhaosu A analogue 27
having a remarkable antimalarial activity; the EC50 value of
27 (3.0!10K9 M) is superior to that of artemisinin, a
natural antimalarial (1.0!10K8 M). The problem of this
procedure is the low yield of the desired bicyclic
hydroperoxide 25, because of the concomitant formation
of a larger amount of the monocyclic one 24 (Scheme 5).
In Table 4 are shown the in vivo antimalarial activities of
the bicyclic acetate 270,12 obtained by peroxidation of
(R)-limonene (170) and the subsequent transformations
shown in Scheme 5, together with the data for artemisinin13
and yingzhaosu A.14 It is interesting to note that the
activity of 270 in po administration is very similar to that
of artemisinin.
As an approach to develop a more improved method in
synthesis of the antimalarial acetate 27, therefore, we
investigated the effect of the structure of silanes 2b,d,e on
the composition of two hydroperoxides, 24 and 25 (Table 3).
The Co(modp)2-catalyzed autoxidation of (S)-limonene 17
in the presence of PhMeSiH2 2b for 2 h gave only the
monocyclic hydroperoxide 24 in 48% yield; no formation of
the bicyclic one 25 was observed. When the same reaction
was repeated in the presence of more bulky Ph2MeSiH 2e
for 24 h, a mixture of the corresponding silyl peroxides, 22e
and 23e, were obtained together with a substantial amount
of the highly polar unidentified products. Subsequent
deprotection gave the desired bicyclic hydroperoxide 25 in
a yield of 21%, together with the monocyclic one 24 (14%).
This clearly demonstrates that the ratio of 24/25 decreases
with the increase in steric bulk of the silanes; PhMeSiH2
2bOEt3SiH 2dOPh2MeSiH 2e. This notable structural
effect of silane on the product distribution would be
explained in terms of the decrease in rate of the metal
exchange between Co–alkylperoxo complex and silane with
the increase in steric bulk of silane. In the case of small
PhMeSiH2 2b, the transmetallation with the Co–alkyl-
Table 4. In vivo antimalarial activity of the yingzhaosu A analogue 270
derived from (R)-limonenea
Compound
Method of
administration
ED50 (mg/kg)
ED90 (mg/kg)
270
ip
po
ip
po
sc
12
38
5
32
250b
48
O50
13
89
Artemisinin
Yingzhaosu A
a ip, intraperitoneal; po, per oral; sc, subcutaneous injection.
b Taken from the data in Ref. 14.
Table 3. Effect of the structure of silanes on the composition of the
peroxidation products 24 and 25
3. Conclusion
Systematic study of the structural effect of silanes on the
Co-catalyzed reductive oxygenation of alkene in the
presence of silane (Mukaiyama–Isayama reaction) and on
the metal-exchange reaction between Co(III)–alkylperoxo
complex and silane demonstrates that the efficiency of both
reactions decreases with the increase of the steric bulk of the
silanes. Also, the product distributions are significantly
influenced by the steric bulk of silanes. The in vivo
antimalarial activity of (1R),(5R),(8R)-4,4,8-trimethyl-2,3-
dioxabicyclo[3.3.1]nonan-8-yl acetate 270 derived from
(R)-limonene is very similar to that of artemisinin, a natural
peroxidic antimalarial.
Silane 2
Reaction time (h)
Yield (%)
24
25
b: PhMeSiH2
d: Et3SiH
e: Ph2MeSiH
2
2
24
48
36
14
22
21

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J.-M. Wu et al. / Tetrahedron 61 (2005) 9961–9968
4. Experimental
(2C), 129.39 (2C), 129.90, 132.92, 166.86. Anal. Calcd for
C12H16O4: C, 64.27; H, 7.19. Found: C, 64.17; H, 7.25.
4.1. General procedures
1
4.3.3. 3-Hydroxy-3-methylbutyl benzoate (5). An oil; H
NMR d 1.33 (s, 6H), 1.89 (br s, 1H), 1.99 (t, JZ6.8 Hz, 2H),
4.51 (t, JZ6.8 Hz, 2H), 7.4–7.5 (m, 2H), 7.5–7.6 (m, 1H),
8.0–8.1 (m, 2H); 13C NMR d 29.78 (2C), 41.73, 61.96,
70.04, 128.27 (2C), 129.37 (2C), 130.05, 132.83, 166.45.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C,
69.29; H, 7.75.
1H (270 MHz) and 13C (67.5 MHz) NMR spectra were
obtained in CDCl3 solution with SiMe4 as the internal
standard. Preparation of the cobalt(III) cumyldioxy complex
9 was already reported by Talsi et al.8 The alkene 1 was
prepared by the reported method.4 Spectral data and
elemental analysis of bicyclic acetate 270 derived from
(R)-limonene12 and the method of determination of the
in vivo antimalarial activity13 have been already reported.
4.3.4. Co(modp)2-catalyzed autoxidation of alkene 1 in
the presence of PhMeSiH2 2b. A mixture of alkene 1
(198 mg, 1.04 mmol), Co(modp)2 (27 mg, 0.05 mmol),
PhMeSiH2 2b (272 mg, 2.0 mmol) in DCE (2.5 mL) were
stirred at room temperature under an oxygen atmosphere
for 2 h. After conventional work-up as described before,
4.2. Caution
Since organic peroxides are potentially hazardous com-
pounds, they must be handled with due care; avoid exposure
to strong heat or light, or mechanical shock, or oxidizable
organic materials, or transition metal ions. No particular
difficulties were experienced in handling any of the new
peroxides synthesized in this work using the reaction scales
and procedures described below together with the safeguard
mentioned above.
1
the H NMR spectrum of the crude mixture of products
was measured, which showed the presence of mainly
3-(methylphenylsilyl)dioxy-3-methylbutyl benzoate (3b);
1H NMR d 0.45 (t, JZ4.05 Hz, 3H), 2.07 (t, JZ7 Hz,
2H), 1.25 (s, 6H), 4.36 (q, JZ4.05 Hz, 2H), 7.4 (m, 3H), 7.6
(m, 2H); 13C NMR dK7.5, 127.9, 129.4, 133.3, 134.7.
However, the silyl peroxide 3b was labile to the column
chromatography on silica gel. Thus, elution with ether/
hexane 10:90 gave the hydroperoxide 4 (155 mg, 70%).
Subsequent elution with ether/hexane 30:70 gave the
alcohol 5 (26 mg, 13%).
4.3. Co(modp)2-catalyzed autoxidation of 3-methyl-3-
buten-1-yl benzoate (1) in the presence of PhMe2SiH 2c
Into a two-neck 50 mL flask, charged with dioxygen, alkene
1 (198 mg, 1.04 mmol), Co(modp)2 (27 mg, 0.05 mmol)
and DCE (2.5 mL) were added, and then the flask was again
charged with dioxygen. PhMe2SiH 2c (272 mg, 2.0 mmol)
was added via 1.0 mL gas-tight syringe, and the reaction
mixture was stirred vigorously under an oxygen atmosphere
at room temperature. After stirring for 2 h, the solvent was
evaporated under reduced pressure. Hexane (10 mL) was
added to the residue, and then the precipitated solid
materials were removed by filtration over Celite. After
concentration of the filtrate, the components of the residue
were separated by column chromatography on silica gel.
Elution with diethyl ether/hexane 2:98 gave the silyl
peroxides 3c (270 mg, 72%); the deprotection of the silyl
group was easily undertaken by treatment with one portion
of concd HCl in methanol for 2 min providing quantitatively
the corresponding hydroperoxide 4. From the second
fraction (elution with ether/hexane 10:90) was obtained
3-hydroperoxy-3-methylbutyl benzoate 44 (156 mg, 87%).
Subsequent elution with diethyl ether/hexane 30:70 gave
3-hydroxy-3-methylbutyl benzoate 54 (7 mg, 4%).
4.4. Co(modp)2-catalyzed autoxidation of alkene 1 in the
presence of two silanes 2a and 2d
A mixture of alkene 1 (160 mg, 1.1 mmol), Co(modp)2
(27 mg, 0.05 mmol), PhSiH3 2a (217 mg, 2.0 mmol),
Et3SiH 2d (231 mg, 2.0 mmol), and 3,5-dimethylanisole
(internal standard, 85 mg, 0.5 mmol) in DCE (2.5 mL) was
stirred at room temperature for 2 h under an oxygen
atmosphere. After the conventional workup as described
above, the products were separated by column chromato-
graphy on silica gel. The first fraction (elution with ether/
hexane 3:97) gave a mixture of alkene 1, triethylsilyl
peroxide 3d4 and 3.5-dimethylanisole (227 mg). By the
comparison of the peak areas of the characteristic signals
1
of these compounds in the H NMR spectrum, the mixture
was determined to contain 1 (145 mg, conv. 61%) and 3d
(34 mg, 16%). Subsequent elution with ether/hexane 10:90
gave hydroperoxide 4 (49 mg, 25%). From the final fraction
(elution with ether/hexane 40:60) was obtained alcohol 5
(106 mg, 43%).
4.3.1. 3-(Dimethylphenylsilyl)dioxy-3-methylbutyl ben-
zoate (3c). An oil; 1H NMR d 0.48 (s, 6H), 1.25 (s, 6H), 2.07
(t, JZ7 Hz, 2H), 4.37 (t, JZ7 Hz, 2H), 7.38–7.46 (m, 5H),
7.55 (t, JZ7 Hz, 1H), 7.63 (d, JZ7 Hz, 2H), 8.02 (d, JZ
7 Hz, 2H); 13C NMR dK2.6, 24.8, 37.3, 61.6, 81.7, 127.6,
128.2, 129.4, 129.8, 130.3, 132.7, 133.7, 136.2, 166.4. Anal.
Calcd for C20H26O4Si: C, 67.00; H, 7.31. Found: C, 67.02;
H, 7.43.
4.4.1. Decomposition of silyl peroxide 6b during the
column chromatography on silica gel. (2-Phenylpropan-2-
ylperoxy)methyl(phenyl)silane (6b) was prepared by the
reported method.6 To a solution of triethylamine (2.6 g,
26 mmol), cumyl hydroperoxide (3.6 g, 24 mmol) in hexane
(50 mL), was added chloro(methyl)phenylsilane (3.9 g,
25 mmol) in hexane at 0 8C and the mixture was stirred at
0 C for 10 h. After filtration of the solid material over Celite,
the residue was concentrated under reduced pressure to
leave almost pure 6b as an oil (1.7 g, 23%); 1H NMR d 0.55
(d, JZ3 Hz, 3H), 1.58 (s, 6H), 5.11 (q, JZ3 Hz, 1H), 7.3–
7.7 (m, 10H); 13C NMR dK4.1, 26.4, 84.5, 124.2, 125.2,
125.5, 127.9, 128.5, 130.3, 134.4, 144.7. Then the column
4.3.2. 3-Hydroperoxy-3-methylbutyl benzoate (4). An oil;
1H NMR d 1.30 (s, 6H), 2.10 (t, JZ7.1 Hz, 2H), 4.48 (t, JZ
7.1 Hz, 2H), 7.4–7.6 (m, 3H), 8.0–8.1 (m, 2H), 8.79 (br s,
1H); 13C NMR d 24.44 (2C), 36.57, 61.53, 81.16, 128.24

J.-M. Wu et al. / Tetrahedron 61 (2005) 9961–9968
9967
chromatography of 6b (194 mg, 0.66 mmol) on silica gel
was undertaken. Elution with ether/hexane 20:80 gave
cumyl hydroperoxide 7 (49 mg, 49%). From the second
fraction (elution with ether/hexane 40:60) was obtained
alcohol 8 (34 mg, 38%).
(S)-limonene 17 (272 mg, 2.0 mmol), Co(modp)2 (54 mg,
0.10 mmol), Ph2MeSiH (775 mg, 4 mmol) in DCE (5 mL)
was stirred at room temperature for 24 h under an oxygen
atmosphere. After a conventional work-up, components of
the residue were separated by column chromatography on
silica gel. Elution with diethyl ether/hexane 2:98 gave a
mixture of compounds (250 mg) containing mainly 1-methyl-
1-(4-methyl-3-cyclohexenyl)ethyl methyldiphenylsilyl per-
oxide (22e); [1H NMR d 0.76 (s, 3H), 1.16 (s, 6H), 1.19–
1.24 (m, 1H), 1.65 (s, 3H), 1.71–1.98 (m, 6H), 5.37 (m, 1H),
7.56 (m, 6H), 7.65 (m, 4H); 13C NMR dK3.5, 21.7, 21.9,
23.5, 24.1, 26.7, 31.0, 40.9, 88.5, 120.7, 127.6, 129.8, 134.7]
and (1S),(5S),(8S)-4,4,8-trimethyl-2,3-dioxabicyclo[3.3.1]-
nonan-8-yl methyldiphenylsilyl peroxide (23e); [1H NMR d
0.75 (s, 3H), 1.13 (s, 3H), 1.42 (s, 3H), 1.52 (s, 3H), 1.53–
2.23 (m, 6H), 4.30 (m, 1H), 7.42 (m, 6H), 7.99 (m, 4H); 13C
NMR d K3.7, 22.0, 23.8, 24.4, 24.6, 24.8, 31.9, 32.5, 40.9,
81.3, 83.8, 127.7, 130.0, 134.6], which could be separated
by repeated column chromatography. Subsequent elution
with ether gave a complex mixture of highly polar products
(85 mg). After treatment of the mixture of the silyl
peroxides, 22e and 23e, with a drop of concd HCl in
methanol (2 mL) for 5 min, solid sodium bicarbonate and
anhydrous MgSO4 were added. The reaction mixture was
stirred for an additional 10 min, and solid materials were
removed by filtration over Celite. After evaporation of the
solvent under reduced pressure, components of the residue
were separated by column chromatography on silica gel.
The unsaturated hydroperoxide 2412 (46 mg, 14%) was
isolated by elution with diethyl ether/hexane 10:90.
Subsequent elution with diethyl ether/hexane 15:85 gave
the bicyclic hydroperoxide 2512 (85 mg, 21%).
4.5. Co(modp)2-catalyzed decomposition of cumyl
hydroperoxide 7 in the presence of PhSiH3 2a
A mixture of hydroperoxide 7 (160 mg, 1.1 mmol),
Co(modp)2 (27 mg, 0.05 mmol) and PhSiH3 2a (222 mg,
2.1 mmol) in DCE (2.5 mL) was stirred at room temperature
for 4 h under an oxygen atmosphere. After the conventional
workup, the products were separated by column chroma-
tography on silica gel. Elution with ether/hexane 40:60 gave
alcohol 8 (103 mg, 72%).
4.6. Decomposition of the Co(III)–alkylperoxo complex 9
in the presence of PhMe2SiH 2c
To a solution of the complex 9 (245 mg, 0.50 mmol) in DCE
(2.0 mL), was added PhMe2SiH 2c (136 mg, 1.0 mmol).
After stirring for 2 h at room temperature under an argon
atmosphere, solvent was evaporated under reduced press-
ure. Hexane (10 mL) was added to the residue, and the
precipitated solid materials were removed by filtration over
Celite. After concentration of the filtrate, products were
separated by column chromatography on silica gel. Elution
with ether/hexane 10:90 gave the silyl peroxide 6c (52 mg,
37%). Subsequent elution with ether/hexane 18:82 gave the
hydroperoxide 7 (4 mg, 5%). From the final fraction (elution
with ether/hexane 40:60) was obtained the alcohol 8 (13 mg,
19%).
4.6.1. (2-Phenylpropan-2-ylperoxy)dimethyl(phenyl)
Acknowledgements
1
silane (6c). An oil; H NMR d 0.45 (s, 6H), 1.52 (s, 6H),
7.15–7.42 (m, 8H), 7.62 (m, 2H); 13C NMR dK2.5, 26.5,
83.9, 125.5, 126.8, 127.8, 129.7, 133.8, 136.5, 145.2. Anal.
Calcd for C17H22O2Si: C, 71.28; H, 7.74. Found: C, 71.05;
H, 7.74.
This work was supported by the Grant-in-Aid for Scientific
Research on Priority Areas from the Ministry of Education,
Science, Sports and Culture of Japan (15019060 and
14021072) and by the Program for Promotion of Funda-
mental Studies in Health Sciences of the Pharmaceuticals
and Medical Devices Agency (PMDA).
4.6.2. Co(modp)2-catalyzed autoxidation of (S)-limonene
(17) in the presence of PhMeSiH2 2b. Into a two-necked
50 mL flask, charged with dioxygen, were added (S)-
limonene (17: 272 mg, 2.0 mmol), Co(modp)2 (54 mg,
0.10 mmol), and DCE (5 mL), and then the flask was
again charged with dioxygen. PhMeSiH2 2b (513 mg,
4.2 mmol) was added via a 1.0 mL gastight syringe, and
the reaction mixture was stirred vigorously under an oxygen
atmosphere at room temperature for 2 h. After the
References and notes
1. (a) Mukaiyama, T.; Yamada, T. Bull. Chem. Soc. Jpn. 1995,
68, 17. (b) Hayashi, T.; Okazaki, K.; Urakawa, N.;
Shimakoshi, H.; Sessler, J. L.; Vogel, E.; Hisaeda, Y.
Organometallics 2001, 20, 3074. (c) Hirano, K.; Sakaguchi,
S.; Ishii, Y. Tetrahedron Lett. 2002, 43, 3617. (d) Kato, K.;
Yamada, T.; Takai, T.; Inoki, S.; Isayama, S. Bull. Chem. Soc.
Jpn. 1990, 63, 179. (e) Nishimura, T.; Kakiuchi, N.; Onoue, T.;
Ohe, K.; Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000,
1915. (f) Meunier, B. Biomimetic Oxidations Catalyzed by
Transition Metal Complexes; Imperial College: London, 2000.
(g) Barf, G. A.; Sheldon, R. A. J. Mol. Catal. 1995, 102, 23.
(h) Katsuki, T. J. Mol. Catal. 1996, 113, 87. (i) Yu, H.-B.;
Zheng, X.-F.; Lin, Z.-M.; Hu, Q.-S.; Huang, W.-S.; Pu, L.
J. Org. Chem. 1999, 64, 8149.
1
conventional work-up, the H NMR spectrum of the crude
mixture of products was measured, which showed the
presence of mainly 1-methyl-1-(4-methyl-3-cyclohexenyl)-
ethyl methylphenylsilyl peroxide (22b); H NMR d 1.19
1
(s, 6H), 1.20–1.27 (m, 1H), 1.65 (s, 3H), 1.78–2.03 (m, 6H),
5.15 (d, JZ2.7 Hz, 3H), 5.24 (q, JZ2.7 Hz, 1H), 5.36 (m,
1H), 7.35–7.39 (m, 3H), 7.55–7.65 (m, 2H). The crude
products were separated by column chromatography on
silica gel. Elution with diethyl ether/hexane 10:90 gave the
unsaturated hydroperoxide 2412 (164 mg, 48%).
4.6.3. Co(modp)2-catalyzed autoxidation of (S)-limonene
(17) in the presence of Ph2MeSiH 2e. A mixture of
2. (a) Isayama, S. Bull. Chem. Soc. Jpn. 1990, 63, 1305.

9968
J.-M. Wu et al. / Tetrahedron 61 (2005) 9961–9968
(b) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 573.
9. (a) Porter, N. A. In Organic Peroxides; Ando, W., Ed.; Wiley:
New York, 1992. (b) Tokuyasu, T.; Kunikawa, S.; McCul-
lough, K. J.; Masuyama, A.; Nojima, M. J. Org. Chem. 2005,
70, 251.
A similar Co(II) porphyrin complex-catalyzed peroxy-
genation in isopropanol leading to the corresponding
hydroperoxide has been also reported by Sugamoto and
his co-workers: Sugamoto, K.; Matsushita, Y.; Matsui, T.
J. Chem. Soc., Perkin Trans. 1 1998, 3989. Furthermore,
Magnus and co-workers reported the Mn(III) complex-
catalyzed hydroperoxidation of alkenes in the presence
of phenylsilane under an oxygen atmosphere: Magnus,
P.; Scott, D. A.; Fielding, M. R. Tetrahedron Lett. 2001,
42, 4127.
10. Bond dissociation energy of silanes: PhSi(H2)–H, Walsh, R.
Acc. Chem. Res. 1981, 14, 246. Et3Si–H, Kanabus-Kaminska,
J. M.; Hawari, J. A.; Griller, D.; Chatgilialogu, C. J. Am.
Chem. Soc. 1987, 109, 5267. Ph3Si–H, Lesage, M.; Simoes,
J. A. M.; Griller, D. J. Org. Chem. 1990, 55, 5413. Bond
dissociation energy of ROO–H,Minici, F.; Punta, C.;
Recupero, F.; Fontana, F.; Pedulli, G. F. J. Org. Chem.
2002, 67, 2671.
3. Synthetic application of Mukaiyama–Isayama peroxidation:
(a) O’Neill, P. M.; Hindley, S.; Pugh, M. D.; Davies, J.; Bray,
P. G.; Park, B. K.; Kapu, D. S.; Ward, S. A.; Stocks, P. A.
Tetrahedron Lett. 2003, 44, 8135. (b) Ahmed, A.; Dussault,
P. H. Org. Lett. 2004, 6, 3609. (c) Tokuyasu, T.; Masuyama,
A.; Nojima, M.; McCullough, K. J.; Kim, H.-S.; Wataya, Y.
Tetrahedron 2001, 57, 5979. (d) Oh, C. H.; Kim, H. J.; Wu,
S. H.; Won, H. S. Tetrahedron Lett. 1999, 40, 8391. (e) Xu,
X.-X.; Dong, H.-Q. J. Org. Chem. 1995, 60, 3039.
11. (a) Talsi, E. P.; Zimin, Y. S.; Nekipelov, V. M. React. Kinet.
Catal. Lett. 1985, 27, 361. (b) Yoshino, Y.; Hayashi, Y.;
Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1997, 62,
6810 and references cited therein. (c) Bianchini, C.; Zoellner,
R. W. Adv. Inorg. Chem. 1997, 44, 263.
12. Tokuyasu, T.; Kunikawa, S.; Masuyama, A.; Abe, M.; Nojima,
M.; Kim, H.; Begum, K.; Wataya, U. J. Org. Chem. 2003, 68,
7361.
4. Tokuyasu, T.; Kunikawa, S.; Masuyama, A.; Nojima, M. Org.
Lett. 2002, 4, 3595.
13. Kim, H.-S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.;
Hamada, Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M.;
McCullough, K. J. J. Med. Chem. 2001, 44, 2357.
14. Szpilman, A. M.; Korshin, E. E.; Rozenberg, H.; Bachi, M. D.
J. Org. Chem. 2005, 70, 3618. However, some yingzhaosu
A analogues having a phenylsulfonyl functionality show
remarkable anti-malarial activities in vitro and in vivo;
Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.;
Ploypradith, P.; Xie, S.; Shapiro, P. A.; Posner, G. H. J. Med.
Chem. 2003, 46, 2516.
5. Similar steric effects of silanes on the efficiency of the
reaction5a and on the product distributon5b have been already
found by Isayama and Mukaiyama. (a) Isayama, S.;
Mukaiyama, T. Chem. Lett. 1989, 569. (b) Isayama, S.;
Mukaiyama, T. Chem. Lett. 1989, 1071.
6. Razuvaev, V. A. J. Organomet. Chem. 1981, 212, 43.
7. Chavez, F. A.; Mascharak, P. K. Acc. Chem. Res. 2000, 33, 539
and references cited therein.
8. Talsi, E. P.; Chinakoc, V. D.; Babenko, V. P.; Sidelnikov,
V. N.; Zamaraev, K. I. J. Mol. Catal. 1993, 81, 215.