1,4-Cyclohexadienes as mechanistic probes for the Jacobsen epoxidation: Evidence for radical pathways

Article abstract of DOI:10.1039/b415723k

1,4-Cyclohexadienes allow a direct comparison of epoxidation and C-H oxidation within the same molecule and give evidence for radical pathways during the Jacobsen epoxidation. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b415723k

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1
,4-Cyclohexadienes as mechanistic probes for the Jacobsen
epoxidation: evidence for radical pathways{
Ulrike Engelhardt and Torsten Linker*
Received (in Cambridge, UK) 13th October 2004, Accepted 29th November 2004
First published as an Advance Article on the web 17th January 2005
DOI: 10.1039/b415723k
9
1
,4-Cyclohexadienes allow a direct comparison of epoxidation
in the literature, but no 1,4-cyclohexadienes were examined until
now.
and C–H oxidation within the same molecule and give evidence
for radical pathways during the Jacobsen epoxidation.
To establish the structure of the expected epoxides and to
compare the Jacobsen reaction with conventional epoxidations, we
first investigated the uncatalyzed epoxidation of various substi-
tuted 1,4-cyclohexadienes 2a–c with m-chloroperoxy-benzoic acid
(MCPBA) as oxidant (Scheme 1).
The enantioselective epoxidation of unfunctionalized olefins by
optically active Mn(III) salen complexes (Jacobsen–Katsuki
epoxidation) has become a very important and versatile tool for
1
organic synthesis. From the broad variety of salen ligands, the
The reactions proceed smoothly at room temperature, and the
epoxides 3 and 4 were isolated in almost quantitative yield.
Interestingly, only one double bond is oxidized in the unsubstituted
derivative 2a, whereas the methyl substituted cyclohexadienes 2b
and c afford mixtures of mono-3 and bis-epoxides 4. This is
contrary to known epoxidations of 1,4-cyclohexadienes in the
tert-butyl substituted catalyst 1 is most often used, since both
enantiomers are commercially available and provide epoxides with
excellent ee.
10
literature, but is immaterial to the planned mechanistic studies.
On the other hand, our observed diastereomeric ratios are in
accordance with these publications.
The crucial experiment was the oxidation of the 1,4-cyclohex-
adienes 2 in the presence of the Jacobsen catalyst 1. To directly
compare these reactions with the uncatalyzed epoxidations
(Scheme 1), MCPBA was chosen as the stoichiometric oxidant.
It was important that in a control experiment at 230 uC no
conversion was obtained with sole MCPBA. The best conditions
for the Jacobsen epoxidations were found with 0.1 equiv. of
catalyst (R,R)-1, 3 equiv. of oxidant, and N-methylmorpholine-
N-oxide (NMO) as co-ligand.{ Indeed, all 1,4-cyclohexadienes 2
gave complete conversion under such conditions (Scheme 2).
Besides the synthetic benefit of the Jacobsen epoxidation, the
mechanism of the oxygen transfer to the double bond is still a
matter of debate, and both radical and concerted pathways were
2
discussed in the literature. Recently, theoretical investigations
have demonstrated the importance of different spin states during
3
the reaction and Mn(V) and Mn(IV) species were detected by
4
spectroscopy. However, no information on the nature of the
organic intermediates was provided and radicals could not be
trapped. Furthermore, the epoxidation of vinylcyclopropanes as
‘‘radical clocks’’ did not give a clear-cut picture, since the amount
of ring-opening products strongly depends on the substitution
2,5
pattern at the double bond and on the stoichiometric oxidant.
Therefore, we became interested in the Jacobsen epoxidation of
substrates, which provide a double bond and a sensitive radical
probe within the same molecule. Thus, a direct comparison of
epoxidation and radical reaction would be possible.
Scheme 1
During the course of our studies on regio- and stereoselective
6
photooxygenations, we investigated the oxidation of 1,4-cyclo-
hexadienes 2, which are synthesized conveniently by Birch
7
reduction. Due to the bis-allylic hydrogen atoms, which can be
8
easily abstracted by a radical pathway, such compounds should
be ideal mechanistic probes for the Jacobsen epoxidation. Allylic
and benzylic C–H oxidations by metal oxo complexes are known
{
Electronic supplementary information (ESI) available: Experimental
procedures. See http://www.rsc.org/suppdata/cc/b4/b415723k/
linker@chem.uni-potsdam.de
*
Scheme 2
1
152 | Chem. Commun., 2005, 1152–1154
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Interestingly, no epoxides 3 or 4 could be detected, even in the
experiments under careful exclusion of air under an argon
atmosphere. Furthermore, control reactions with no manganese-
(salen) complex, no additive (NMO), or no MCPBA gave no
conversions. Therefore, the manganese(V)–oxo complex 6 is indeed
the oxidizing species, which affords the allylic alcohols 9 by a
radical pathway. In the last step of the reaction, the second allylic
hydrogen is abstracted even faster by the same mechanism, due to
the stabilizing effect of hydroxy groups to radicals. Thus, the
hydrate 10 is formed as an intermediate, and after dehydration the
ketones 5 were isolated as the final products, which is in
accordance with the oxidations of allylic alcohols by chromium-
crude reaction mixture, whereas 1,3-cyclohexadienes afford the
1
1
corresponding epoxides. This demonstrates the importance of
the bis-allylic position. The cyclohexadienones 5 were the sole
products, isolated after column chromatography. The moderate
yields are due to the formation of oligomeric and polymeric
material. This complete change in the product distribution of the
catalyzed and direct oxidation can only be rationalized by a
different reaction mechanism.
Obviously, a manganese(V)-oxo complex 6 is generated in the
first step, by reaction of the catalyst 1 with MCPBA. This
intermediate can transfer the oxygen to the double bonds to afford
epoxides 3 and 4. However, isolated alkyl-substituted alkenes are
13
(salen) complexes.
Finally, a direct concerted insertion of the manganese(V)–oxo
complex 6 into the allylic C–H-bond was excluded by the reaction
of unsubstituted 1,4-cyclohexadiene under our reaction conditions,
to afford benzene quantitatively by a second H-atom abstraction
in the 4-position.
1,2
epoxidized slower than conjugated systems. Furthermore, due to
the electron-withdrawing ester group, the 1,4-cyclohexadienes 2
8
should be less reactive. Thus, a hydrogen atom transfer from the
bis-allylic position can compete with the epoxidation (Scheme 3).
This result can only be rationalized by a radical character of the
manganese(V)–oxo complex 6, which is in accordance with the
To investigate the possibility of a kinetic resolution during the
14
oxidations, which is still a challenge for Jacobsen epoxidations,
3
recent theoretical postulation of a quintet state, and gives
we stopped the reaction of cyclohexadiene 2b at 50% conversion.
However, neither the reisolated starting material nor the product
5b exhibit any enantiomeric excess. Thus, the stereogenic center is
too far away from the reactive position, indicating again a
hydrogen atom transfer by a radical mechanism.
experimental evidence for a radical pathway during the attack of
the Jacobsen catalyst.
After the H-transfer the stabilized cyclohexadienyl radical 7 and
the manganese(IV)–hydroxy complex 8 are formed. Indeed, such
paramagnetic manganese(IV) intermediates were detected by EPR
In conclusion, we present experimental evidence for radical
pathways during the oxidation with the Jacobsen catalyst. 1,4-
Cyclohexadienes were used as mechanistic probes for the first time,
to distinguish between two reaction routes within the same
molecule. The Jacobsen catalyst attacked exclusively the homo-
lytically labile hydrogen atoms, whereas MCPBA oxidized the
double bond. This can be rationalized by a radical character of the
manganese(V)–oxo complex, which is the reactive intermediate for
both, epoxidations and allylic oxidations. Thus, double bonds with
no sensitive radical probes should be attacked by a radical
pathway as well, which is important for the mechanism of the
Jacobsen epoxidation.
4
spectroscopy very recently. The lifetime of the intermediary
bisallylic radical 7 must be very short, since no isomerization to
2
,4-allylic radicals and no formation of regioisomeric cyclohex-
adienones was observed. Furthermore, a homolytic cleavage of the
ester group, which was described in the literature for radicals like
8
, could not compete with the fast oxygen rebound from the
7
manganese(IV)–hydroxy complex 8. This is in accordance with the
well-known picosecond kinetics for the hydroxylation with
1
2
cytochrome P-450, Thus, the allylic alcohol 9 is formed and
the Jacobsen catalyst 1 is regenerated, closing the reaction cycle
after re-oxidation with MCPBA (Scheme 3). That molecular
oxygen is not involved in the allylic oxidation was proven by
This work was generously supported by the Fonds der
Chemischen Industrie and the Deutsche Forschungsgemeinschaft
(Li 556/6-1).
Ulrike Engelhardt and Torsten Linker*
Department of Chemistry, University of Potsdam, Karl-Liebknecht-Str.
2
4-25, D-14476, Potsdam, Germany.
E-mail: linker@chem.uni-potsdam.de; Fax: 49 331 9775056;
Tel: 49 331 9775212
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154 | Chem. Commun., 2005, 1152–1154
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