Rhodium acetate-catalyzed aerobic Mukaiyama epoxidation of alkenes

Article abstract of DOI:10.1016/j.tet.2013.09.062

Mukaiyama epoxidation of alkenes under oxygen catalyzed by rhodium acetate with isobutyraldehyde as the reducing agent is as or more effective than previously reported procedures. A variety of alkenes, including terpenes and cholesterol derivatives, were oxidized. And high regioselectivity for monoepoxidation was observed with neryl, geranyl, and linalyl acetates.

Full text of DOI:10.1016/j.tet.2013.09.062

Tetrahedron 69 (2013) 10009e10013
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Rhodium acetate-catalyzed aerobic Mukaiyama epoxidation of
alkenes
*
Dmitry Shabashov, Michael P. Doyle
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 August 2013
Received in revised form 17 September 2013
Accepted 19 September 2013
Available online 25 September 2013
Mukaiyama epoxidation of alkenes under oxygen catalyzed by rhodium acetate with isobutyraldehyde as
the reducing agent is as or more effective than previously reported procedures. A variety of alkenes,
including terpenes and cholesterol derivatives, were oxidized. And high regioselectivity for mono-
epoxidation was observed with neryl, geranyl, and linalyl acetates.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Rhodium acetate
Oxygen
Mukaiyama epoxidation
Terpenes
1. Introduction
with aldehydes or alcohols as additives were used in epoxidation
reactions under conditions developed by Mukaiyama and co-
The development of selective alkene epoxidation reactions is an
area of intense investigations, and remarkable successes over the
past few decades.1 Well recognized peroxide-based asymmetric
methods, such as the titanium-catalyzed Sharpless epoxidations of
allylic alcohols, the Jacobsen epoxidations utilizing manganese-
salen complexes,2 and the organocatalytic Shi DMDO epoxida-
tions3 have wide applications. Although these methods are stan-
dards in the area, they are one-step removed from methodologies
that use the economical and environmentally benign molecular
oxygen.4 However, a major drawback of using dioxygen lies in the
identification of suitable reducing agents to accompany the trans-
formation. In early studies of aerobic epoxidations of alkenes using
manganese-porphyrin-based catalyst systems that mimic cyto-
chrome P-450, additives, such as ascorbate, NaBH4, or hydrogen gas
with colloidal platinum were required to effect catalyst turnover.5
Subsequently, aerobic oxidation of olefins using ruthenium por-
phyrin systems as stoichiometric oxidants or as catalysts with low
turnovers was developed.6 Others have investigated epoxidation of
alkenes using copper,7 cobalt,8 or ruthenium9 compounds as cata-
lysts with aldehydes as reducing agent.
workers. A variety of simple alkenes, as well as terpenes and ste-
roidal compounds, were converted into corresponding epoxides.
The cis-geometry of alkenes is not preserved during the reaction,
and mixtures of epoxides are formed with dominance of the trans-
isomer. Manganese-salen complexes were used by Mukaiyama
for asymmetric epoxidation of simple alkenes, such as 1,2-dihydro
naphthalene and chromene derivatives, but only moderate enan-
tioselectivity was achieved.11
We have investigated dirhodium(II)-catalyzed oxidations of or-
ganic compounds by tert-butyl hydroperoxide (TBHP),12 and have
reported evidence that molecular oxygen plays a role in the oxi-
dative transformation through entrapment of the radical formed
from hydrogen atom abstraction by the tert-butylperoxy radical.13
From these results we sought evidence that dirhodium(II) com-
pounds could entrap dioxygen to initiate oxidation and chose the
Mukaiyama epoxidation methodology to determine feasibility. We
report here the use of rhodium acetate as an effective and efficient
catalyst for Mukaiyama epoxidation of alkenes. Control of reaction
conditions to effect regioselective epoxidation and the effect
of aldehyde structure on epoxidation diastereoselectivity are
reported.
In the early 1990s, Mukaiyama and co-workers published a se-
ries of papers on epoxidation of olefins with molecular oxygen.10
Transition metals, such as nickel, iron, and vanadium together
2. Results and discussion
Optimization of epoxidation conditions using trans-stilbene as
a substrate revealed that the combination of 1.0 mol % rhodium
acetate and isobutyraldehyde (3.0 equiv) in acetone affords trans-
* Corresponding author. Tel.: þ1 301 405 1788; fax: þ1 301 314 9121; e-mail
address: mdoyle3@umd.edu (M.P. Doyle).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.062

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D. Shabashov, M.P. Doyle / Tetrahedron 69 (2013) 10009e10013
Table 1
Epoxidation of alkenes
stilbene oxide in 88% isolated yield. Dichloroethane was also suit-
able as the solvent for epoxidation, but reaction times required to
reach full conversion were nearly two times longer than those in
acetone. Rhodium caprolactamate, known to be the optimum dir-
hodium catalyst for oxidations using TBHP,12 did not provide con-
sistent results. We have investigated the epoxidation reaction
kinetics using commercially available metal salts and compared
them to the bis-[1,3-bis(p-methoxyphenyl)-1,3-propanedionato]-
nickel(II) [Ni(dmp)2]done of the most active catalysts used by
Mukaiyama.10a All reactions were run with trans-stilbene as sub-
strate, 1.0 mol % of metal salt catalyst, and 3.0 equiv of iso-
butyraldehyde in acetone under oxygen balloon pressure. Results
revealed the following trends that are reported in Fig. 1: (1) Rho-
dium acetate and tris(triphenylphosphino)ruthenium dichloride
provided excellent conversion of trans-stilbene to trans-stilbene
oxide in 1.5 h without an evident induction period, but use of
Rh2(OAc)4 exhibited a faster initial rate. (2) Induction periods were
evident in reactions catalyzed by Mn(OAc)2$4H2O, RuCl3, and
Ni(dmp)2. However, despite the initiation period detected in the
reaction with Mn(OAc)2$4H2O, full conversion was reached in ap-
proximately the same amount of time as in reactions catalyzed by
rhodium acetate and tris-(triphenylphosphino)-ruthenium dichlo
ride. Slower turnover rates were observed for RuCl3 and bis-[1,3-
bis(p-methoxyphenyl)-1,3-propanedionato]nickel(II) [Ni(dmp)2].
The obtained results suggest that rhodium acetate and the ruthe-
nium dichloride phosphine complex have advantages as epoxida-
tion catalysts over the reported nickel(II) catalyst.
Entry
Alkene
Epoxide
Time
Isolated
yield, %
1
1 h
88
2a
30 h
77c
3
30 min
95
4
4 h
3 h
91
81
5b
6
2.5 h
76
7
8
40 min
7 h
60
78
100
90
80
70
Rh2(OAc)4
RuCl2(PPh3)3
60
50
40
30
20
10
0
Mn(OAc)2*4H2O
RuCl3
Ni(dmp)2
9a
24 h
27 h
55
71
0
1
2
3
4
10a
time, h
a
Conditions: iBuCHO (4 equiv), DCE solvent.
DCE was used as solvent.
3:1 mixture of trans:cis isomers; 1.4:1 ratio when RuCl2(Ph3P)3 is the catalyst
Fig. 1. Evaluation of catalysts kinetic performance using trans-stilbene as the substrate.
Conditions: alkene (1.0 mmol), 1.0 mol % catalyst, iPrCHO (3 equiv), acetone (3 mL),
room temperature, oxygen balloon at 1 atm.
b
c
(1 mol %).
A variety of alkenes were epoxidized using 1.0 mol % of rhodium
acetate catalyst, isobutyraldehyde (3 equiv) in acetone (Table 1).
trans-Stilbene, triphenylethylene, and trans-b-methylstyrene gave
their corresponding epoxide products in high yields (Table 1, en-
tries 1, 3, and 4). The strained norbornene reacted efficiently to
produce the exo-epoxide in 76% yield. 1-Phenylcyclohexene was
also reactive, and its epoxide product was obtained in good yield
(Table 1, entry 7). Interestingly, the geometry of the alkene double
bond had a noticeable influence on reactivity. However, oxidation
methylstyrene was not retained under these oxidation conditions,
and only the trans epoxide was formed; with cis-stilbene a 3:1
mixture of trans-/cis-isomers was obtained. In a competition ex-
periment between cis- and trans-
trans-isomer was approximately six times more reactive than the
cis isomer, and cis- -methylstyrene did not rearrange to trans-b-
b-methylstyrene in acetone, the
b
methylstyrene under these conditions. 1,5-Cyclooctadiene un-
derwent epoxidation to give the cis-mono epoxide without evi-
dence for either trans epoxide or transannular product(s).
Oxidation of 1-dodecene in acetone gave poor conversion with
isobutyraldehyde in acetone, but the combination of 3-methyl
butyraldehyde and dichloroethane allowed epoxidation of 1-
dodecene to occur over an extended time, and the corresponding
epoxide was isolated in 71% yield (Table 1, entry 10).
of cis-
tions gave low conversions to epoxide products (43% for cis-
methylstyrene after 5 h and 23% for cis-stilbene after 7 h). Since
previous report by Mukaiyama reported that use of 3-
b-methylstyrene and cis-stilbene under these same condi-
b
-
a
methylbutyraldehyde in combination with 1,2-dichloroethane
was beneficial for alkenes that were difficult to oxidize,10a use of
the same approach for epoxidation of cis-stilbene and cis-
b-meth-
Modest diastereocontrol for the 5,6b-isomer 3 in the epoxida-
ylstyrene was attempted. Under these conditions the epoxide
products were obtained in high yield (Table 1, entries 2 and 5) at
shorter reaction times. The geometry of double bond of cis-b-
tion of cholesteryl benzoate 1 has been reported under Mukaiya-
ma’s epoxidation conditions compared to that with m-
chloroperbenzoic acid, but the specific metal employed has little

D. Shabashov, M.P. Doyle / Tetrahedron 69 (2013) 10009e10013
10011
impact on diastereoselectivity (Scheme 1).14 The same is true with
the use of rhodium acetate, but the structure of the aldehyde
employed as reductant, which has not been previously explored,
does have a significant influence on diastereoselectivity. Results
were subjected to the same conditions used for oxidation
of simple alkenes in Table 1 [1.0 mol % Rh2(OAc)4, iPrCHO
(3.0 equiv) in acetone under oxygen]. Oxidation of neryl acetate 7
provided the mono-epoxide 10 as major product in 69% isolated
yield (Table 2, entry 1) and in a 2.7-molar excess over its di-
epoxide, which was obtained in 26% isolated yield. The cis-ge-
ometry of the reactant neryl acetate double bond was not pre-
served in the di-epoxide product. Epoxidation of geranyl acetate
8 produced a separable mixture of mono- and di-epoxide prod-
ucts. The mono-epoxide 11 was obtained in 59% isolated yield,
and the di-epoxide was isolated in 22% yield (Table 2, entry 3).
Interestingly, decreasing the amount of aldehyde from 3.0 to
1.5 equiv provided only mono-epoxidation products for neryl
and geranyl acetate 10 and 11, which were obtained in 65 and
74% yield, respectively (Table 2, entries 2 and 4). Excellent se-
lectivity was also attained in differentiating terminal and in-
ternal double bonds in linalyl acetate 7dthe internal epoxide 12
was isolated as the sole epoxidation product in 82% yield (Table
2, entry 5).
Oxidation of farnesyl acetate 13 using 4.0 equiv of iso-
butyraldehyde and 1.0 mol % of rhodium acetate catalyst gave far-
nesyl acetate di-epoxide 16 as the major product in 42% yield and
a mixture of mono-epoxides 15 and 14 in 9% combined yield
(Scheme 3). Selective formation of the di-epoxide of farnesyl ace-
tate has been reported using mCPBA,17c peracetic acid,17d or
DMDO,17a,b but the Mukaiyama epoxidation of trienes has not been
previously reported.
Scheme 1. Diastereoselectivity in Mukaiyama epoxidation of cholesteryl benzoate
compared with peracid epoxidation.14
from the epoxidation of cholesteryl acetate 4 using a variety of al-
dehydes show that increasing the steric size of the alkyl substituent
increases selectivity for formation of the 5,6
up to a dr of approximately 5:1. The low product yield obtained
from the use of -methylcyclohexylcarboxaldehyde is the result of
b-isomer 6 (Scheme 2)
Mechanistic studies are uniform in suggesting a radical mech-
anism for the Mukaiyama epoxidation reaction.18 Mizuno18b and
Valentine18c have proposed acyl peroxy radicals while Kaneda19 is
favoring peracids as oxygen transfer species. In 2000, Beak has
reported the free radical internal epoxidation of 2,2-dimethyl-5-
phenylpent-4-enal using oxygen and catalytic amount of TBHP as
initiator.20 His studies clearly suggested acyl peroxy radicals as
oxygen transfer species. Later, Feiters reported mechanistic studies
evaluating the role of metal catalyst and ratio of aldehyde to alkene
in the epoxidation of alkenes18a and concluded that by increasing
the aldehyde to alkene ratio oxidation proceeds through an in-
ternally formed peroxyacid. This conclusion is, however, in dis-
agreement with Mukaiyama’s original discoveries and our present
studies. Epoxidation of cholesterol derivatives clearly shows dif-
ferences in the epoxide isomer ratio when peracid or Mukaiyama
epoxidation is used (Scheme 2). To resolve this mechanistic dis-
agreement we applied the conditions of Table 1 to the oxidation of
2,2-dimethyl-5-phenylpent-4-enal. If the outcome of the reaction
is not dependent on the initiation step, as we suspected, we should
obtain same products as in Beak’s report. Indeed, the products
obtained are the same (Scheme 4), and this result points to acyl
peroxy radical rather than peracid participation in the epoxidation
of alkenes.
When the epoxidation of cholesteryl acetate (Scheme 2) was
performed using 2-methyl-2-phenylpropanal as the aldehyde re-
ductant, no epoxidation products (5 and/or 6) were observed over
the same reaction time. Instead, reactant cholesteryl acetate 4 was
isolated, and both cumyl alcohol (major) and cumyl hydroperoxide
(minor) were isolated and identified. This outcome is consistent
with the steric influence of the aldehyde in the delivery of the
epoxide oxygen and with the rapid loss of carbon monoxide from
the acyl radical formed by hydrogen abstraction from 2-methyl-2-
phenylpropanal.
a
a slow turnover, and unreacted starting material remained after the
reaction time of 3 h.
Scheme 2. Effect of aldehyde on diastereoselectivity in the Mukaiyama epoxidation of
cholesteryl acetate.
Epoxidation selectivity for reactions with terpenes has been
investigated by several groups.15e17 Moderate selectivity for mono-
and di-epoxide products (20 and 58%, respectively) of neryl acetate
has been reported using a catalytic system containing perox-
otungstophosphate and hydrogen peroxide as the terminal oxi-
dant.15 In another study selectivity in epoxidation of geranyl acetate
utilizing in situ prepared dioxirane from OxoneÒ and tri-
fluoroacetophenone was greatly affected by temperature, where at
Based on these observations the mechanism for epoxidation is
proposed to occur in the manner described in Scheme 5. Reaction is
propagated by acyl radical formation that then reacts with molec-
ular oxygen to form the acyl peroxy radical. Oxygen atom transfer
from the acyl peroxy radical to the alkene occurs in a two-step
process that includes addition of the acyl peroxy radical and
0
ꢀC the mono epoxide was obtained in 76% yield, while at room
temperature oxidation resulted in a 1:1 mixture of mono and
diepoxides.16
To assess selectivity for epoxidation under Mukaiyama con-
ditions with rhodium acetate as the catalyst selected terpenes

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D. Shabashov, M.P. Doyle / Tetrahedron 69 (2013) 10009e10013
Table 2
Regioselective Mukaiyama epoxidation of terpenes
Entry
Terpene
iPrCHO (equiv)
Mono-epoxide
Isolated yield, % of
mono-epoxide
Ratio of mono- to di-epoxide
1
3
69a
2.7
2
1.5
65
>20:1
3
4
3
59b
74
2.7
1.5
>20:1
5
2
82
>20:1
a
Di-epoxide was isolated in 26% yield.
Di-epoxide was isolated in 22% yield.
b
Scheme 5. Mechanism for the Mukaiyama epoxidation of alkenes.
of epoxide explains the isomerization, that is, observed in epoxide
formation. Less certain is the initiation step, which we propose to
occur via coordination of molecular oxygen with rhodium acetate
followed by hydrogen atom abstraction from the aldehyde; al-
though rhodium acetate has not been reported to bind dioxygen,
other dirhodium compounds have been demonstrated to do so as
superoxide complexes.21
Scheme 3. Regioselective Mukaiyama epoxidation of farnesyl acetate.
3. Conclusions
The epoxidation of alkenes was evaluated using rhodium ace-
tate in the Mukaiyama protocol. Simple alkenes are transformed in
epoxides in good yields, and conditions have been established
for mono-epoxidation of terpenes. Increasing the steric bulk
around the aldehyde functional group increases epoxidation dia-
stereoselectivity. The rhodium acetate catalyst was found to per-
form at a faster rate then previously developed catalysts for this
transformation.
Scheme 4. Intramolecular epoxidation.
subsequent elimination of the acyloxy radical to form the epoxide.
Abstraction of the acyl hydrogen from the aldehyde by an acyloxy
radical form the carboxylic acid product and reforms the acyl rad-
ical to continue the catalytic chain reaction. The stepwise formation

D. Shabashov, M.P. Doyle / Tetrahedron 69 (2013) 10009e10013
10013
2005, 105, 1603e1662; (d) McGarrigle, E. M.; Gilheany, D. G. Chem. Rev. 2005,
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4. Experimental section
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H.; Nishikawa, H.; Uchida, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132,
12034e12041 For reviews of biological epoxidation, see: (d) Guengerich, F. P. J.
Biochem. Mol. Toxicol. 2007, 21, 163e168; (e) Mahammed, A.; Gross, Z. J. Am.
Chem. Soc. 2005, 127, 2883e2887; (f) Groves, J. T. Proc. Natl. Acad. Sci. U.S.A.
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2000, 11, 554e564; (h) Sono, M.; Roach, M. P.; Coulter, E. D.; Dawson, J. H. Chem.
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4.1. General considerations
Reactions were performed in oven-dried (140 ꢀC) glassware.
Solvents were used as received. Thin layer chromatography (TLC)
was carried out using EM Science silica gel 60 F254 plates. The de-
veloped chromatogram was analyzed by a UV lamp (254 nm) and/
or phosphormolibdic acid as stain reagent. Liquid chromatography
was performed using flash chromatography on silica gel
(230e400 mesh). 1H NMR spectra were recorded in CDCl3 on
a Bruker Avance 400 MHz spectrometer; chemical shifts are re-
ported in parts per million using TMS signals as reference. Dirho-
dium tetraacetate was purchased from Pressure Chemical
Company. Alkenes were used as received. Farnesyl acetate was
prepared according to literature procedure.22
ꢀ
6. (a) Lai, T.-S.; Zhang, R.; Cheung, K.-K.; Kwong, H.-L.; Che, C.-M. Chem. Commun.
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1995, 493, 143e147; (c) Marchon, J.-C.; Ramasseul, R. J. Chem. Soc., Chem. Com-
mun. 1988, 298e299; (d) Tavares, M.; Ramasseul, R.; Marchon, J.-C.; Bachet, B.;
Brassy, C.; Mornon, J.-P. J. Chem. Soc., Perkin Trans. 2 1992, 1321e1329; (e)
Marchon, J.-C.; Ramasseul, R. Synthesis 1989, 389e391.
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Buranaprasertsuk, P.; Tangsakol, Y.; Chavasiri, W. Catal. Commun. 2007,
310e314; (c) Liu, C.; Shen, D.-M.; Chen, Q.-Y. Eur. J. Org. Chem. 2006,
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M.; Muratsugu, S.; Kinoshita, M.; Sasaki, T.; Iwasawa, Y. J. Am. Chem. Soc. 2010,
132, 713e724.
4.2. General procedure
A two-neck round bottom flask was charged with Rh2(OAc)4
(4.4 mg, 0.01 mmol), and alkene (1.0 mmol) followed by addition of
acetone (3.0 mL). A dry-ice condenser was attached to the flask,
then, isobutyraldehyde (274 mL, 3.0 mmol) was added; and a con-
stant flow of oxygen was introduced to the system via an oxygen-
filled balloon. Reaction completion was monitored by GCeMS.
When the reaction was complete, solvent was removed under re-
duced pressure and the oily residue was separated by flash chro-
matography using etherehexanes solvent mixtures. All epoxide
product spectroscopic data were in accord with literature data.
10. (a) Yamada, T.; Takai, T.; Rhode, O.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1991, 64,
2109e2117; (b) Takai, T.; Hata, E.; Yamada, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1991, 64, 2513e2518; (c) Takai, T.; Yamada, T.; Mukaiyama, T. Chem. Lett. 1990,
1657e1660; (d) Mukaiyama, T.; Takai, T.; Yamada, T.; Rhode, O. Chem. Lett. 1990,
1661e1664; (e) Mukaiyama, T.; Yamada, T.; Nagata, T.; Imagawa, K. Chem. Lett.
1993, 327e328; (f) Nagata, T.; Imagawa, K.; Yamada, T.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1995, 68, 3241e3246 For other asymmetric oxidation using
Mukaiyama condition, see: (g) Bolm, C.; Schlingloff, G.; Weickhardt, K. Angew.
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11. (a) Nagata, T.; Imagawa, K.; Yamada, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1995,
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12. (a) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004, 126,
13622e13623; (b) Catino, A. J.; Nichols, J. M.; Choi, H.; Gottipamula, S.; Doyle,
M. P. Org. Lett. 2005, 7, 5167e5170; (c) Catino, A. J.; Nichols, J. M.; Nettles, B. J.;
Doyle, M. P. J. Am. Chem. Soc. 2006, 128, 5648e5649; (d) Choi, H.; Doyle, M. P.
Chem. Commun. 2007, 745e747; (e) McLaughlin, E. C.; Doyle, M. P. J. Org. Chem.
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4.3. General procedure for epoxidation of alkenes in Table 1,
entries 2, 9, and 10
The round bottom flask was charged with Rh2(OAc)4 (4.4 mg,
0.01 mmol), and alkene (1.0 mmol) followed by addition of di-
chloroethane (3.0 mL). Then, isovaleraldehyde (433 mL, 4.0 mmol)
was added in one portion. Flask was capped with septa and balloon
with oxygen was attached. Completion of reaction was monitored
by GCeMS. When done, solvent was removed on rotary evaporator
and oily residue was purified by flash chromatography using
etherehexanes solvent mixtures. All epoxide product spectroscopic
data were in agreement with literature data.
13. (a) Choi, H.; Doyle, M. P. Org. Lett. 2007, 9, 5349e5352; (b) Ratnikov, M. O.;
Farkas, L. E.; McLaughlin, E. C.; Chiou, G.; Choi, H.; El-Khalafy, S. H.; Doyle, M. P.
J. Org. Chem. 2011, 73, 2585e2593.
Acknowledgements
We are grateful to the National Science Foundation (CHE-
0748121) for their support of this research.
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.09.062.
References and notes
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