Co(thd)2: A superior catalyst for aerobic epoxidation and hydroperoxysilylation of unactivated alkenes: Application to the synthesis of spiro-1,2,4-trioxanes

Article abstract of DOI:10.1016/j.tetlet.2003.09.033

Bis(2,2,6,6-tetramethyl-3,5-heptanedionato)cobalt(II) (Co(thd) ₂), a β-diketonate prepared in a simple one-step procedure, is an excellent catalyst for aerobic epoxidation and Mukaiyama-Isayama hydroperoxysilylation of unactivated alkenes. For hydroperoxysilylation, Co(thd)₂ is superior to Co(acac)₂ and can catalyse oxidation of cyclic alkenes in excellent yield. Chiral β-diketonate or keto iminato catalysts failed to catalyse this reaction in an enantioselective manner and a free radical mechanism consistent with this observation is proposed. Hydroperoxysilylation of cyclohex-1-enylmethanol by Co(thd) ₂ followed by addition of a ketone/TsOH provides a simple one-pot procedure for the synthesis of spiro-1,2,4-trioxane antimalarials.

Full text of DOI:10.1016/j.tetlet.2003.09.033

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8135–8138
Co(thd)2: a superior catalyst for aerobic epoxidation and
hydroperoxysilylation of unactivated alkenes: application to the
synthesis of spiro-1,2,4-trioxanes
Paul M. O’Neill,a,b,* Stephen Hindley,a Matthew D. Pugh,a Jill Davies,c Patrick G. Bray,c
B. Kevin Park,b Dauda S. Kapu,c Stephen A. Wardc and Paul A. Stocksa
aDepartment of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK
bDepartment of Pharmacology, University of Liverpool, Liverpool L69 3GE, UK
cSchool of Tropical Medicine, Pembroke Place, University of Liverpool, Liverpool L3 5QA, UK
Received 21 July 2003; revised 12 August 2003; accepted 3 September 2003
Abstract—Bis(2,2,6,6-tetramethyl-3,5-heptanedionato)cobalt(II) (Co(thd)2), a b-diketonate prepared in a simple one-step proce-
dure, is an excellent catalyst for aerobic epoxidation and Mukaiyama–Isayama hydroperoxysilylation of unactivated alkenes. For
hydroperoxysilylation, Co(thd)2 is superior to Co(acac)2 and can catalyse oxidation of cyclic alkenes in excellent yield. Chiral
b-diketonate or keto iminato catalysts failed to catalyse this reaction in an enantioselective manner and a free radical mechanism
consistent with this observation is proposed. Hydroperoxysilylation of cyclohex-1-enylmethanol by Co(thd)2 followed by addition
of a ketone/TsOH provides a simple one-pot procedure for the synthesis of spiro-1,2,4-trioxane antimalarials.
© 2003 Published by Elsevier Ltd.
The selective monooxygenation of various organic com-
pounds utilising molecular oxygen is one of the most
challenging topics in synthetic organic chemistry.1
Recently, a great deal of effort has been directed
towards monooxygenation of olefins via single oxygen
atom transfer by combined use of molecular oxygen
and an appropriate reducing agent.2 In 1992
Mukaiyama described conditions for the aerobic epoxi-
dation of a range of alkenes by employing Co(II) Schiff
base catalysts, e.g. 1 in the presence of ketones as
reducing agents (Scheme 1).3
The yields for epoxidation were excellent (up to 98%).
Equally impressive, was the discovery that several bis-
(diketonato)Co(II) derivatives, e.g. Co(acac)2 could
effect aerobic epoxidation of alkenes in the presence of
propionaldehyde diethyl acetal as the reducing agent.4
Further advances in this field have led to the develop-
ment of aerobic asymmetric epoxidation, using either
Co(II) salen derived Jacobsen type ligands5 or chiral
Mn(III) b-diketonate derivatives.6 Both systems give
reasonable yields of epoxide with excellent enantiomeric
excesses.
In parallel with this research, Isayama reported that
modification of the above reaction conditions by
replacement of the ketone with triethylsilane, as the
reducing agent, enabled the smooth and regioselective
conversion of alkenes into the corresponding triethyl-
silylperoxide derivatives 2 in good yield (Scheme 2).7
Replacement of triethylsilane with phenylsilane in this
reaction, gave the corresponding alcohol 3 as the
product under neutral conditions. Further work
demonstrated that silyl peroxides 2 could be smoothly
reduced to alcohols 3 by reduction with catalytic quan-
tities of Co(acac)2 under an atmosphere of argon
(Scheme 2, B).8
Scheme 1. Aerobic epoxidation of alkenes.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.033

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the Mukaiyama aerobic epoxidation ranging from the
generation of oxo-metal intermediates9 to the metal
catalysed formation of a per-acid.10 More recent studies
by Nolte and co-workers, suggest that for nickel-b-
diketonates, the mechanism of the observed epoxida-
tion is radical in nature with the formation of a
nickel-bound acylperoxy radical which stays bound to
the metal complex for stabilisation.11 Evidence for dis-
tinct radical intermediates was provided by EPR stud-
ies. Whether this mechanism is involved in
Co(thd)2-mediated oxidations reported here remains to
be established by appropriate additional experiments.
Scheme 2. Aerobic hydroperoxysilylation and hydration.
In addition to being a superior catalyst for epoxidation,
Co(thd)2 is also an excellent catalyst for effecting
hydroperoxysilylation of alkenes. Substituting pivalde-
hyde for triethylsilane, we carried out hydroperoxysilyl-
ation on a number of different alkenes. Table 2 lists five
examples which clearly show that this catalyst is supe-
rior to Co(acac)2. Indeed, the final two entries show
that Co(acac)2 is a very poor catalyst for effecting
oxidation of cyclic alkenes and allylic alcohols. In
contrast, Co(thd)2 can effect peroxysilylation in excel-
lent yield. In all cases, the reactions proceed with high
Markovnikov regioselectivity The solvent of choice in
these reactions was found to be 1,2-dichloroethane
(DCE).
Scheme 3. Synthesis of Co(thd)2 and structures of Co(II)
b-diketonates.
Table 1. Co(II)-mediated aerobic epoxidation of alkenes
One of the best catalysts that has been employed in
aerobic oxidation reactions of the type described in this
report is bis(1-morpholinocarbamoyl-4,4-dimethyl-1,3-
pentanedio-nato)cobalt(II) Co(modp)2 (Scheme 3).8
This catalyst is superior to Co(acac)2 but requires a
three-step synthesis. The overall yield for the synthesis
of this catalyst is low. We reasoned that the corre-
sponding catalyst derived from the ligand 2,2,6,6-tetra-
methylheptane-3,5-dione would have similar structural
and electronic properties to Co(modp)2. In this letter,
we describe the synthesis and use of this catalyst in
aerobic epoxidation and hydroperoxysilylation reac-
tions on a variety of different alkene substrates. Results
are compared with Co(acac)2. We also describe the
application of this catalyst to the synthesis of some
simplified spiro 1,2,4-trioxane analogues of artemisinin
by a simple one-pot operation.
Bis(2,2,6,6 - tetramethyl - 3,5 - heptanedionato)cobalt(II)
was prepared in 70% yield from the 1,3-diketone as
shown in Scheme 3.
Several epoxidation reactions were carried out under a
positive oxygen atmosphere using pivaldehyde as co-
reducing agent. In all cases, Co(thd)2 gave good to
excellent yields of epoxide, with significant improve-
ments over Co(acac)2. The yields recorded in Table 1
correspond to isolated yields after column chromato-
graphy on silica gel. All reactions were complete after 4
h. A number of mechanisms have been proposed for

P. M. O’Neill et al. / Tetrahedron Letters 44 (2003) 8135–8138
8137
Table 2. Co(II)-mediated aerobic hydroperoxysilylation of
Table 3. Chiral Co(II) complex mediated aerobic
alkenesa
hydroperoxysilylation of alkenesa
Until recently, the mechanism for this useful transfor-
mation was poorly understood. Based on this fact and
several recent reports on the asymmetric aerobic epoxi-
dation using cobalt Schiff base complexes, we examined
the possibility of carrying out hydroperoxysilylation in
an enantioselective manner.
Table 3 summarises our attempts at carrying out asym-
metric hydroperoxysilylation chemistry using different
chiral Co(II) complexes. From Table 3, it is clear that
the best catalysts for effecting this transformation are
analogues of Co(acac)2. Thus the camphor derived
chiral complex 4a provided target peroxysilyl alkanes in
good yield.
Scheme 4. Mechanism of the Isayama–Mukaiyama peroxy-
genation of alkenes.
Addition of the Co(III)-H across the double bond of
the alkene provides the chiral cobalt species 5a. Homoly-
sis of the Coꢀcarbon bond then ensues to produce a
carbon centred radical 5b that can capture triplet oxy-
gen from either face of the radical centre. It is this
process that is responsible for the complete lack of
asymmetric induction using chiral complexes 4a and 4b.
The final stage of the proposed mechanism involves a
metal exchange between 5d and triethylsilane to give
the observed product 2.
The ketoiminato catalyst 4b was also capable of
catalysing these reactions, albeit in lower yields than 4a.
Disappointingly, there was no asymmetric induction in
any of these oxidation reactions.
Mechanism of the hydroperoxysilylation reaction—In
contrast to the reported use of chiral cobalt complexes
for aerobic asymmetric epoxidation it is clear that the
Mukaiyama hydroperoxysilylation reaction proceeds
through a mechanism that leads to optically inactive
products (Scheme 4). Based on a mechanism proposed
by Magnus for tandem Mn(dpm)3 mediated aerobic
enone reduction/alpha hydroxylation,12 we reasoned
that a similar Co(III) hydride species may be involved
in the key step. A proposed mechanism that would
account for the lack of asymmetric induction was
recently proposed by Nojima and co-workers and pro-
vides a rationale for the results in Table 3.13
We recently reported on a simple synthesis of 1,2,4-tri-
oxanes using Co(acac)2.14 In contrast to Co(acac)2, the
key finding that Co(thd)2 can catalyse the regioselective
hydroperoxysilylation of cyclic allylic alcohols has
enabled us to broaden this methodology to the synthe-
sis of some potent spiro 1,2,4-trioxane antimalarials
(Table 4). The allylic alcohol prepared in 72% yield
from cyclohex-1-enyl-methanol was allowed to react
under the standard conditions and the resulting silica
gel purified peroxysilyl species was then cyclised with

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P. M. O’Neill et al. / Tetrahedron Letters 44 (2003) 8135–8138
Table 4. Synthesis of spiro 1,2,4-trioxanes
active spiro 1,2,4-trioxanes. This procedure provides a
simple and cost-effective route to potential new anti-
malarial drugs.
Acknowledgements
We thank the EPSRC (SH, PON) (GR/N65875/01) and
BBSRC (PAS, PON, SAW) (26/B13581) for financial
support of this work. The authors also thank Pfizer,
Sandwich, Kent, UK for a CASE award to MDP.
References
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7. Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 573.
8. Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 1071.
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Tetrahedron Lett. 1992, 45, 6827.
11. Wentzel, B. B.; Gosling, P. A.; Feiters, M. C.; Nolte, R.
J. M. J. Chem. Soc., Dalton Trans. 1998, 2241.
12. Magnus, P.; Fielding, M. R. Tetrahedron Lett. 2001, 42,
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13. Tokuyasu, T.; Kunikawa, S.; Masuyama, A.; Nojima, M.
Org. Lett. 2002, 3595.
14. O’Neill, P. M.; Pugh, M. D.; Davies, J. D.; Ward, S. A.;
Park, B. K. Tetrahedron Lett. 2001, 42, 4569.
15. Compound 6c: mp 70–72°C; IR wmax (Nujol mull)/cm−1
2928.0 (C-H), 1086.0 (C-O), 874.0 (O-O), 851.0 (O-O); 1H
the appropriate aldehyde or ketone in the presence of
tosic acid (catalytic amounts). As in our previous com-
munication, the procedure can also be adopted to a
one-pot procedure, whereby the silyl alcohol is not
isolated but used crude for the cyclisation step.
Table 4 summarises the results for the synthesis of some
simple 1,2,4-trioxanes. Significantly, some of these com-
pounds that can be synthesised in a one-pot procedure
are active in the low nanomolar region. It is also clear
that the structure of the 1,2,4-trioxane has a huge
bearing on the pharmacological activity of these
endoperoxides. In a full paper, we will subsequently
describe SAR and mechanistic ferrous mediated degra-
dation studies for this class of antimalarial.
NMR (400 MHz, CDCl3) l 3.71 (2H, brm, C(22)H6 2),
2.37–1.25 (32H, brm); 13C NMR (100 MHz, CDCl3) l
106.21, 77.23, 66.22, 26.10, 26.03, 25.95, 22.35; MS m/z
(CI) [M+H]+ 311 (56), 295 (26), 200 (21), 183 (27), 129
(100), 95 (22). HRMS. Found 311.25935. C19H3503 [M+
H]+ requires 311.25861; found: C, 74.12; H, 11.17;
requires C, 73.50; H, 11.04%.
Summary
Bis(2,2,6,6 - tetramethyl - 3,5 - heptanedionato)cobalt(II)
(Co(II)(thd)2) was found to be an excellent catalyst for
both aerobic epoxidation and hydroperoxysilylation of
unactivated alkenes. In all cases, the yields for oxida-
tion reactions were superior to Co(acac)2. A mechanism
for hydroperoxysilylation is provided that is consistent
with the fact that chiral Co(II) complex catalysed reac-
tions proceed without asymmetric induction. An impor-
tant application of Co(thd)2 is outlined which involves
a one-pot procedure for the synthesis of antimalarially
16. Compound 6h: IR wmax (neat)/cm−1 2923.9 (C-H), 1452.5
1
(Ar), 1094.3 (C-O), 868.4 (O-O), 820.2 (O-O); H NMR
(400 MHz, CDCl3) l 7.36 (5H, m, Ar), 4.21 (2H, brm,
C(4)H6
2), 1.86–0.92 (13H, brm); MS m/z (CI) [M+NH4]+
266 (27), [M+H]+ 249 (7), 233 (35), 151 (100), 138 (52),
116 (61), 105 (37). HRMS. Found 249.14971. C15H2103
[M+H]+requires 249.14907; found: C, 72.70; H, 8.18;
requires C, 72.55; H, 8.12%.