The effect of phenolates in the (salen)Mn-catalyzed epoxidation reactions

Article abstract of DOI:10.1016/j.tetlet.2005.06.008

By addition of 2,4,6-tri-tert-butylphenolate in the Mn(salen) catalyzed epoxidation of cis-alkenes with iodosobenzene, essentially pure trans-epoxides can be obtained.

Full text of DOI:10.1016/j.tetlet.2005.06.008

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5597–5600
The effect of phenolates in the (salen)Mn-catalyzed
epoxidation reactions
a
Christian Linde, Magnus F. Anderlund and Bjo¨rn Akermark
b
b,
*
˚
aAstraZeneca, R&D, SE-151 85 So¨derta¨lje, Sweden
bDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 14 March 2005; revised 26 May 2005; accepted 2 June 2005
Available online 1July 2005
Abstract—By addition of 2,4,6-tri-tert-butylphenolate in the Mn(salen) catalyzed epoxidation of cis-alkenes with iodosobenzene,
essentially pure trans-epoxides can be obtained.
Ó 2005 Elsevier Ltd. All rights reserved.
The development of the (salen)Mn-catalyzed epoxida-
tion reaction,1 especially as a procedure for asymmetric
epoxidation of alkenes, has provided a useful tool for
the formation of chiral centers with carbon–oxygen
bonds.2–5 The highest enantiomeric selectivities have
been obtained for cis-1,2-disubstituted alkenes but the
epoxidation of tri- and tetrasubstituted alkenes is also
highly enantioselective.6,7 Recently, it was found that
optically active (salen)Cr complexes catalyze the epoxi-
dation of trans-alkenes with high enantioselectivity.8
The enantioselectivity in (salen)Mn catalyzed systems is
generally low for this substrate class.5,9 However, some
time ago, Jacobsen and co-workers found an alternative
enantioselective route to trans-epoxides. They reported
that the addition of chiral quaternary ammonium salts,
derived from naturally occurring cinchona alkaloids,
promoted a dramatic increase in the preference for
trans-epoxide formation starting from conjugated cis-
alkenes.10 Somewhat later, we found that the addition
of 2,4,6-tri-tert-butylphenol and base to the catalytic sys-
tem could induce highly enantio- and diastereoselective
formation of trans-stilbene oxide from cis-stilbene.11
species are possible intermediates both in Mn(salen)-cat-
alyzed epoxidation and in the water oxidizing system in
photosystem II (PS II),17–19 an understanding of the
mechanism of epoxidation could also have bearing on
the mechanism for water oxidation in PS II.
There are several potential reasons for the influence of
counterions and oxidants in epoxidation. One is that
the manganese(V) oxo species, which is formed from
the reaction of the oxidant, for example, iodosobenzene,
with the MnIII-salen precatalyst, is not the sole epoxida-
tion catalyst, but that another competing mechanism
also operates. This is suggested by the fact that the prod-
uct pattern can vary with factors such as temperature
and solvent. One such differing pathway could be direct
epoxidation by the oxidant coordinated to the MnIII–V
,
which simply acts as a Lewis acid. General catalysis of
epoxidation by Lewis acids has in fact been observed
earlier by Valentine and co-workers.20,21 More recently,
evidence for salen catalyzed epoxidation and related
reactions going both via MnV oxo species and an Mn-
activated oxidant has been reported.12–16 In a related
study of sulfimidation of sulfides, Ohta and Katsuki
were able to show that both a MnV imido complex
and the precursor MnIII complex with coordinated
phenyliodosylimide are responsible for imidation at
sulfur.22
A number of research groups have since shown that
both the counterion and oxidant have a considerable
influence on the diastereoselectivity of the manga-
nese(salen)-catalyzed epoxidation.12–16 Since, MnV oxo
It has also been noted that with non-coordinating coun-
terions, such as triflate, in Mn(salen)(triflate) complexes,
fairly specific cis-epoxidation occurred, while with coor-
dinating counterions such as chloride, mixed cis- and
trans-epoxidation was observed. This could be explained
Keywords: Asymmetric catalysis; Manganese; Schiff bases; Oxygen-
ations; Reaction mechanisms.
*
Corresponding author. Tel.: +46 (0)8 163223; fax: +46 (0)8
154908; e-mail: bjorn.akermark@organ.su.se
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.008

5598
C. Linde et al. / Tetrahedron Letters 46 (2005) 5597–5600
by reactions of a MnV oxo species via different spin
states since coordinating and non-coordinating counte-
rions could affect the relative energies of these different
states.12–16,23–27 However, it could also be explained in
terms of formation of Mn(salen) oxo complexes with
both MnV and MnIV. The latter species would be ex-
pected to react unselectively via radicals. In fact, quite
some time ago, Groves and Stern showed that epoxida-
tion catalyzed by a manganese–porphyrin complex
probably proceeded via a manganese(V) species at low
temperature and a manganese(IV) species at room tem-
perature, based on observations of both different Mn
species and different product patterns at high and low
temperatures.28 Mass spectrometric evidence for the
presence of both MnV oxo and MnIV species, produced
from MnIII salen complexes and iodosobenzene has
been presented by Feichtinger and Plattner and Adam
et al.29,30 This supports the idea that the primary MnV
oxo complexes can give rise to MnIV species during
the epoxidation reactions.31 A recent Hammett study
also supports this conclusion.32
Table 1. Epoxidation results with 2,4,6-tri-tert-butylphenol and base
in benzene using PhIO as the oxidant
Entrya
Baseb
Conv. [%]
cis:trans [%]c
ee [%]d
1e
2
—
—
100
100
100
100
75
25:75
26:76
4:96
10:90
7:93
—
75
80
86
89
87
—
3f
t-BuOK
n-BuLi
2 M KOH
Et3N
4
5
6
0
a 1mmol of cis-stilbene, 2 equiv PhIO, benzene, 0.5 equiv of 2,4,6-tri-
tert-butylphenol, 4 mol% of (R,R)-1.
b 0.5 equiv.
c cis/trans epoxide ratio.
d ee of trans-stilbene oxide.
e No 2,4,6-tri-tert-butylphenol added.
f 8 mol% of (R,R)-1.
with both n-BuLi and t-BuOK as base, the phenolate
had to be generated prior to the addition of alkene
and catalyst. As the trans-product selectivity was in-
creased, also the enantioselectivity of the formed trans-
epoxide was improved. The best result was obtained
with n-BuLi as base (Table 1, entry 4), while the use
of triethylamine as base effectively inhibited the catalytic
activity (Table 1, entry 6). The effect of the weaker base
pyridine was also similar.
Since phenolate ions are readily oxidized by high valent
manganese species and we have seen a number of exam-
ples, where we have been unable to oxidize phenolate
manganese complexes beyond the MnIV state,33 we
decided to study in some detail the effects of phenolates
added as ligands to the presumed (salen)MnV oxo inter-
mediates in epoxidation with (salen)Mn-catalysts.
The catalytic activity was generally low and the repro-
ducibility of the experiments was not always satisfactory
when t-BuOK was used as base, perhaps because depro-
tonation is slow due to poor solubility in benzene. It was
found that excess t-BuOK deactivated the catalyst but
under optimized conditions, including a doubling of
the catalyst concentration, the reaction proceeded with
full conversion and excellent trans-selectivity with this
base also. The relatively poor yield with hydroxide as
base can probably also be explained by solubility prob-
lems. In contrast, no such problems should be associated
with n-BuLi, with which the deprotonation was efficient
and instantaneous. This base was therefore preferred.
H
H
N
N
O
Mn
Cl
O
(R,R)-1
Our initial studies focused on the epoxidation of cis-stil-
bene, using (R,R)-1 as the catalyst. Whereas very high
cis-selectivity and high enantioselectivity have been ob-
served under optimal conditions, see for example, Ref.
34 the use of iodosobenzene as oxidant and either benz-
ene11 or dichloromethane12–14 as solvent has been shown
to give cis/trans ratios below 0.5. When a two phase sys-
tem with hypochlorite as oxidant was used, and phenol
was added, it had a substantial influence on the cis/trans
ratio, 2,4,6-tri-tert-butylphenol giving the highest yield
of trans-product.11 This phenol was therefore also used
in the present study.35 It was found that the phenol itself
had no effect (Table 1, entries 1and 2). Since, the aque-
ous hypochlorite solution is strongly basic, it seemed
reasonable that the formation of the deprotonated form
of 2,4,6-tri-tert-butylphenol, which is an excellent single
electron donor, is required. The effect of added bases
was therefore studied. As anticipated, the trans-selectiv-
ity of the reaction was significantly increased when the
phenolate was generated by the addition of base, for
example, t-BuOK, n-BuLi or aqueous potassium
hydroxide (Table 1, entries 3–5). It should be noted that
The influence of the structure of the added phenols was
also studied. In the reaction in the presence of the elec-
tron poor p-nitrophenol, the trans-selectivity was de-
creased, while the enantioselectivity was increased
(Table 2, entries 1and 2). A possible reason is that p-
nitrophenolate could act as a fairly loosely coordinated
Table 2. Epoxidation results with added phenols and n-BuLi in
benzene using PhIO as the oxidant
Entrya Phenolb
Conv. [%] cis:trans [%]c ee [%]d
1
2
3
4
5
6
7
p-NO2–
—
p-Me–
100
100
39:61
25:75
23:77
82
75
89
89
4:86 611
47
p-MeO–
2,6-Di-t-Bu–
90
8:92
10:90
86
89
2,4,6-Tri-t-Bu– 100
p-Octyl– 718:92
88
a 1mmol of cis-stilbene, 4 mol% of (R,R)-1, benzene, 2 equiv of PhIO.
b 0.6 equiv phenol to cis-stilbene + 0.5 equiv of n-BuLi.
c cis/trans epoxide ratio.
d ee of trans-stilbene oxide.

C. Linde et al. / Tetrahedron Letters 46 (2005) 5597–5600
5599
ligand, which is not readily oxidized but yields a small
amount of the cationic complex. In contrast, all pheno-
lates with electron donating substituents increased both
the enantio and the trans-selectivity (Table 2, entries 3–
7). Electronic properties, as well as solubility are proba-
bly important factors. Thus p-octylphenolate gave
substantially higher trans-selectivity than p-methylpheno-
late although these two phenols should be very similar
electronically. The bulky and electron rich 2,4-di-tert-
butyl- and 2,4,6-tri-tert-butylphenolates gave trans-
epoxides with fairly high yields and ee (Table 2, entries
5 and 6). However, the conversion was much lower with
2,4-di-tert-butylphenolate, perhaps because it has a free
ortho-position and is more readily degraded by oxida-
tion. Reaction in the presence of 2,4,6-tri-tert-butyl-
phenolate is thus superior in that both high trans-
selectivity, high ee and high conversion were obtained.
It is easy to explain this as the result of a facile one-elec-
tron reduction of an intermediate oxomanganese(V) to
an oxomanganese(IV) complex, which will react via
diradicals (Scheme 1) and thus be more trans-selective
than the oxomanganese(V) species. This is in analogy
with observations from manganese porphyrin systems.28
cis ratio is obtained with a lower concentration of the
catalyst. The ee was fairly high, especially for the trans-
epoxides (Table 3). Finally, styrene itself was epoxidized.
Even in the absence of phenolate the ee was very low
(20%) and it was decreased to 10% when phenolate was
added (Table 3). In principle, the result could be largely
due to low face-selectivity in the epoxidation. However,
styrene does not appear to be much inferior to cis-alk-
enes in (salen)Mn-catalyzed epoxidation.34 An alterna-
tive explanation is therefore that the Mn-catalyst
attacks at the unsubstituted terminus of styrene, to give
a benzylic radical intermediate in which rotation of the
phenyl group is efficient, leading to extensive racemiza-
tion. Using deuterium labeled styrene, Jacobsen and
co-workers have in fact shown that about 10% trans-
epoxidation takes place using hypochlorite as oxidant,
presumably due to a radical pathway.36 Provided that
the primary attack, Scheme 1, is enantioselective, cis-stil-
bene and cis-b-methylstyrene will give both cis and trans
products with ee corresponding to those of the primary
attack. For styrene, however, rotation will cause racemi-
zation. The results are thus compatible with the mecha-
nism in Scheme 1, with an attack that is highly
enantioselective but where ca. 90% of the reaction goes
via radical intermediates when a good one-electron
donor such as 2,4,6-tri-tert-butylphenolate is present.
The epoxidations of cis-b-methylstyrene 2 and styrene 3
are recorded in Table 3. The results show that 2 also gives
a higher relative yield of the trans isomer in the presence
of phenolate. It also suggests that a slightly higher trans/
The results clearly show the potential of phenolates as
tools for increasing the usefulness of the Jacobsen–
Katsuki epoxidation reaction. Carried over to the
models that we have so far prepared for the water oxida-
tion center in PS II, they also suggest that MnV oxo
complexes can be readily converted to MnIV complexes
by electron transfer from phenolate ligands.
O
O
Ph
Ph
O
O
Ph
Ph
MnV
Cl
MnIV
reduction
Ph
Ph
Acknowledgements
oxygen
donor
O
Ph
Ph
Ph
Ph
MnIII
This work was supported by the Swedish Foundation for
Strategic Research (Selchem program) and the Swedish
Energy Agency. C.L. thanks KTH for a research
scholarship.
O
O
MnIII
Cl
MnII
oxidation
Ph
Ph
cis + trans
O
trans
References and notes
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e
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(2 equiv) and the mixture was stirred for another 12 h. The
catalyst residues were separated on a short silica column.
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