Mild manganese(III) acetate catalyzed allylic oxidation: Application to simple and complex alkenes

Article abstract of DOI:10.1021/ol0612298

Manganese(III) acetate catalyzed allylic oxidation of alkenes to the corresponding enones was investigated, showing excellent regioselectivity and chemoselectivity (functional group compatibility). Δ⁵-Steroids were transformed into bioactive Δ⁵-en-7-ones under a nitrogen atmosphere, whereas simple alkenes were converted into the corresponding enones under an oxygen atmosphere in good yields.

Full text of DOI:10.1021/ol0612298

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3149-3151
Mild Manganese(III) Acetate Catalyzed
Allylic Oxidation: Application to Simple
and Complex Alkenes
Tony K. M. Shing,* Ying-Yeung Yeung, and Pak L. Su
Department of Chemistry, The Chinese UniVersity of Hong Kong,
Shatin, NT, Hong Kong, China
tonyshing@cuhk.edu.hk
Received May 19, 2006
ABSTRACT
Manganese(III) acetate catalyzed allylic oxidation of alkenes to the corresponding enones was investigated, showing excellent regioselectivity
and chemoselectivity (functional group compatibility).
5-Steroids were transformed into bioactive 5-en-7-ones under a nitrogen atmosphere,
whereas simple alkenes were converted into the corresponding enones under an oxygen atmosphere in good yields.
∆
∆
Allylic oxidation is an important and useful reaction in many
areas of organic synthesis.1 Allylic oxidation of ∆5-steroids
to ∆5-en-7-ones is of interest because ∆5-en-7-ones show
excellent results in the prevention and treatment of cancer
and can inhibit the biosynthesis of sterol.2 Allylic oxidation
with metal complexes frequently encounters problems such
as low functional group tolerance, low regioselectivity, high
cost, and difficult catalyst preparation.3 Herein, we report
the use of inexpensive and commercially available manga-
nese(III) acetate as the catalyst and of tert-butylhydroper-
oxide (TBHP) as the cooxidant for mild, efficient, regiose-
lective, chemoselective (functional group compatible), allylic
oxidation of simple and complex alkenes.
Manganese(III) acetate is commonly used as a radical
cyclization4 or R-keto-acetoxylation5 reagent. Few reports6
used Mn(III) in allylic oxidation, with epoxide and allyl
acetate as the major products, and an enone was isolated in
an exceptional case.6a Mn(III) is an unstable state which
readily disproportionates to Mn(II) and Mn(IV) in aqueous
media.7 Fortunately, manganese(III) acetate has a trinuclear
structure;4,8 hence, the Mn(III) state can be stabilized, and
the reactive acetate radical is a well-known source for
acetoxylation.4
Initially, cholesteryl acetate (1a) was subjected to inves-
tigation using commercially available manganese(III) acetate
dihydrate as the catalyst and TBHP as the cooxidant in
various solvents at room temperature. 3 Å Molecular sieves
were added to remove the trace amount of water to alleviate
the disproportionation of manganese(III) acetate.7 After 48
h, the best yield of ∆5-en-7-one 2a (87%) (Table 1) was
recorded using 10 mol % of catalyst, 5 equiv of TBHP, and
(3) Examples for metal-based allylic oxidation. Cr-based: (a) Muzart,
J. Chem. ReV. 1992, 92, 113. Cu-based: (b) Salvador, J. A. R.; Sa´ e Melo,
M. L.; Campos Neves, A. S. Tetrahedron Lett. 1997, 38, 119. Co-based:
(c) Salvador, J. A. R.; Clark, J. H. Chem. Commun. 2001, 6, 33. (d) Jurado-
Gonzalez, M.; Sullivan, A. C.; Wilson, J. R. H. Tetrahedron Lett. 2003,
44, 4283. Fe-based: (e) Barton, D. R. H.; Le Gloahec, V. N. Tetrahedron
1998, 54, 15457. Pd-based: (f) Yu, J. Q.; Corey, E. J. J. Am. Chem. Soc.
2003, 125, 3232. (g) Yu, J. Q.; Wu, H. C.; Corey, E. J. Org. Lett. 2005, 7,
1415. Rh-based: (h) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am.
Chem. Soc. 2004, 126, 13622.
(4) Snider, B. B. Chem. ReV. 1996, 96, 339.
(5) Snider, B. B.; Han, L.; Xie, C. J. Org. Chem. 1997, 62, 6978.
(6) (a) Tabushi, I.; Koga, N. J. Am. Chem. Soc. 1979, 101, 6456. (b)
Appleton, A. J.; Evans, S.; Smith, J. R. L. J. Chem. Soc., Perkin Trans. 2
1996, 281.
(1) Page, P. C. B.; McCarthy, T. ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon: Oxford, U.K., 1991; Vol. 7, p 83.
(2) (a) Cheng, K. P.; Nagana, H.; Bang, L.; Ourisson, G. J. Chem. Res.
(S) 1977, 217. (b) Nagana, H.; Poyser, J. P.; Cheng, K. P.; Bang, L.;
Ourisson, G. J. Chem. Res. (S) 1977, 218.
(7) McAuliffe, C. A.; Godfrey, S. M.; Watkinson, M. In Encyclopedia
of Inorganic Chemistry; King, R. B., Ed.; John-Wiley and Sons: New York,
1994; Vol. 4, pp 2075.
(8) (a) Lis, T. Acta Crystallogr. 1980, B36, 2042. (b) Hessel, L. W.;
Romers, C. Recueil 1969, 545.
10.1021/ol0612298 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/10/2006

noteworthy because various functional and protecting groups
(acetate, acetal, lactam, ketone, cyclic ether, and silyl ether)
survived the mild oxidation conditions. The chemoselective
allylic oxidation proceeded smoothly without oxidizing a free
secondary hydroxyl group which is unprecedented (entry 12).
Furthermore, the present protocol was successfully applied
to complex alkene 9, without isomerizing the trisubstituted
alkene to the tetrasubstituted alkene, to give enone 10, a key
step in the first total synthesis of (-)-samaderine Y (entry
18).10
Table 1. Allylic Oxidation of Complex Alkenes
Allylic oxidation of simple alkenes was also investigated.
They were oxidized to the corresponding enones smoothly
under an oxygen atmosphere7 (Table 2, entries 19-27).9
Table 2. Allylic Oxidation of Simple Alkenes
a For experimental details, see Supporting Information. b 1.0 g scale.
c Reaction performed at 40 °C. d Starting material was recovered. See
Supporting Information. e Dichloromethane was added due to solubility;
EtOAc/CH2Cl2 ) 1:1.
ethyl acetate as the solvent.9 The workup procedure is simple,
involving filtration and removal of solvent from the filtrate.
In addition to cholesteryl acetate (1a), good yields were
obtained for other steroids with different carbon skeletons
and functionalities (1b-j, 3, 5, and 7)9 (Table 1, entries
1-17). Excellent regioselectivities were achieved in entries
1-16, in which the less-hindered C-7’s were selectively
oxidized to the corresponding ∆5-en-7-ones.
Scaling up to a gram-scale reaction did not affect the
chemical yield (entry 2). Increasing the temperature enhanced
the reaction rate dramatically but with a reduction in yield
(entry 3). The excellent chemoselectivity of the reaction is
a For experimental details, see Supporting Information. b Starting material
was recovered; see Supporting Information. c High volatility of the substrate
and/or product resulted in material loss and, hence, low reaction yield.
Similar to allylic oxidation of complex alkenes, excellent
regioselectivities in the abstraction of the hydrogen atom on
secondary over primary carbon were observed. Interestingly,
(+)-2-carene (25) (after isomerization) and (+)-3-carene (27)
(10) Shing, T. K. M.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2005, 44,
7981.
(9) For details, please refer to the Supporting Information.
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Org. Lett., Vol. 8, No. 14, 2006

were transformed into the same enedione 26. Moreover,
functional group (phenyl, ketone, acetal) compatibility was
further demonstrated here. Rigid cyclopropane and cyclobu-
tane rings survived the conditions without ring opening.
For mechanistic studies, the pH value dropped gradually
during the reaction. After 6 h, a reddish-brown suspension
was observed and the pH was about 5. The acidity increased
to pH 4 after 36 h. A plausible explanation is that an acetate
unit in Mn3O(OAc)9 was displaced by a TBHP molecule to
give in situ acetic acid which is responsible for the mild
acidity of the reaction (Scheme 1). Fortunately, acid-sensitive
phenomenon. On the basis of the above findings, a proposed
catalytic cycle of the allylic oxidation is illustrated in Scheme
1, which involves selective allylic hydrogen abstraction to
generate the allyl radical, transfer of the tert-butyl peroxy
ligand from the metal center to the allyl radical, and acid-
promoted degradation of the tert-butyl peroxy ether to the
corresponding enone. The oxidation preference of the allylic
methylene group to the methyl group (entries 18, 19, 22,
and 24-27) should attribute to the greater radical stability
of the secondary carbon than that of the primary carbon.12
For allylic oxidation of simple alkenes in an oxygen
atmosphere (entries 19-27), oxygen would react with a
cyclohexene radical to give a peroxy radical which should
be useful in the hydrogen abstraction of cyclohexene or
t-BuOOH to give more radical species (Scheme 2).3f,9 The
resulting peroxide could be oxidized to enone.
Scheme 1. Proposed Catalytic Cycle of Manganese(III)
Acetate Catalyzed Allylic Oxidation
Scheme 2. Proposed Reaction between Cyclohexene and
Oxygen
acetal moieties survived the conditions (entries 7, 15, 16,
18, and 23).
In summary, a mild, efficient, regioselective, and highly
functional group compatible allylic oxidation protocol using
manganese(III) acetate dihydrate as the catalyst has been
developed.
1H NMR studies supported our proposal that a new t-Bu
signal was observed at 1.18 ppm after the addition of
manganese(III) acetate to a solution of TBHP.9 We believe
that t-BuOOMn3O(OAc)8 is the active species. For the
reaction of 1-phenylcyclohexene (13), the corresponding tert-
butyl peroxy ether was isolated.9 Resubmitting the tert-butyl
peroxy ether to allylic oxidation gave the corresponding
enone 14, a mechanism in accordance with that reported in
the literature.3f,g The formation of acetone and molecular
oxygen during the reaction indicated the existence of tert-
butoxy and tert-butyl peroxy radicals, respectively, which
is consistent with the radical nature of the reaction.9 Facile
oxidation of benzylic carbons to the corresponding ketones
also demonstrated the case.9 The tert-butyl peroxy radical
was successfully traced9 using electron paramagnetic reso-
nance (EPR) spectroscopy, and the results matched those
reported in the literature.11 Termination of the reaction upon
addition of 2,6-di-tert-butyl-4-methylphenol corroborated this
Acknowledgment. This work was supported by a CUHK
direct grant. Special thanks go to Prof. H. K. Lee, Department
of Chemistry, The Chinese University of Hong Kong, for
valuable advice on mechanistic studies.
Supporting Information Available: Experimental pro-
cedures and additional information. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0612298
(11) (a) Janzen, E. G.; Haire, D. L. In AdVances in Free Radical
Chemistry; Tanner, D. D., Ed.; Jai Press Inc.: 1990; p 253. (b) Chamulitrat,
W.; Takahashi, N.; Mason, R. P. J. Biol. Chem. 1989, 264, 7889.
(12) Cainelli, G.; Cardillo, G. In Chromium Oxidations in Organic
Chemistry; Cainelli, G., Cardillo, G., Eds.; Springer-Verlag: New York,
1984; p 41.
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