An aerobic, organocatalytic, and chemoselective method for Baeyer-Villiger oxidation

Article abstract of DOI:10.1002/anie.200462429

(Chemical Equation Presented) Highly chemoselective Baeyer-Villiger oxidations can be performed in the presence of other reactive functionalities such as alcohols, olefins, and sulfides, which would undergo electrophilic oxidation under conventional conditions (see scheme). [DMRFlEt] ⁺[ClO₄]^- (depicted blue) is a new class of flavin compound that catalyzes aerobic Baeyer-Villiger oxidations in the presence of Zn dust as the electron source.

Full text of DOI:10.1002/anie.200462429

Communications
Organocatalysis
An Aerobic, Organocatalytic, and
Chemoselective Method for Baeyer–Villiger
Oxidation**
catalytic reactions.[9a,b,11,12] The aerobic method for Baeyer–
Villiger oxidations is limited to reactions that involve the
in situ generation of peracids from aldehydes by a transition-
metal-mediated radical-chain process with molecular
oxygen.[12] Thus, there has been no exploitation of organo-
catalytic methods and no molecular design of the catalysts.
Furthermore, one of the unsolved problems of catalytic
Baeyer–Villiger oxidations is the lack of chemoselectivity for
nucleophilic oxidations over electrophilic oxidations. There is
no report of a chemoselective catalytic method in the
presence of heteroatomic moieties. This omission is due to
the strong electrophilic character of their peroxo intermedi-
ates. Although catalytic methods that resist epoxidation have
been reported,[13] the strength of the oxidant usually results in
electrophilic oxidation of heteroatomic compounds.[14] The
application of our new strategy has meant that we can
overcome these long-unsolved problems to produce a selec-
tive, sustainable, and highly practical method.
The catalytic activity of a series of flavin compounds was
examined for the aerobic oxidation of 3-(2-naphthyl)cyclo-
butanone (1) with zinc dust (1.5 equiv) in CH3CN/EtOAc/
H2O (8:1:1, v/v) under oxygen (1 atm). Unlike electrophilic
oxidations that need specific flavins,[6] the present nucleo-
philic oxidation exhibits high catalytic activities for a variety
of 5-ethylisoalloxazinium perchlorates that bear 3,10-
dimethyl, 3,7,8,10-tetramethyl, or 3-methyl-10-phenyl func-
tionalities. A new type of flavin catalyst—5-ethyl-3-methyl-
Yasushi Imada,* Hiroki Iida, Shun-Ichi Murahashi,*
and Takeshi Naota*
Direct incorporation of molecular oxygen into organic sub-
strates has recently attained widespread interest as a forward-
looking technology for mild and green molecular trans-
formations.[1] One subject of great urgency is the development
of organocatalytic methods.[2] These methods should facilitate
new strategies that provide an alternative to the conventional
unsustainable processes, which use oxygenated transition-
metal complexes.[3] A limited number of organocatalytic
aerobic oxidations has been reported. These reactions involve
a multistep radical-transfer process from O2 by using semi-
stable organic radicals[4] and photoinduced electron-transfer
systems.[5]
A new method for organocatalytic aerobic oxidation of
heteroatomic organic compounds[6] was recently developed
by simulating the enzymatic function of microsomal FAD-
containing monooxygenase.[7] As this new system includes the
direct conversion of molecular oxygen into synthetic flavin
hydroperoxides, which are highly reactive towards various
organic substrates,[8,9] the principle of the reaction should
enable sustainable aerobic oxidation chemistry with high
selectivity and controllability. As a variation on this system,
we describe herein the first organocatalytic aerobic method of
the Baeyer–Villiger oxidation, which exhibits rare and high
chemoselectivity for this nucleophilic oxidation [Eq. (1)].
The Baeyer–Villiger oxidation is a special class of
nucleophilic oxidative transformation that proceeds specifi-
cally with peroxides and peracids through noncatalytic[10] and
2’,4’:3’,5’-di-O-methyleneriboflavinium
perchlorate
([DMRFlEt]+[ClO4]À), which can be readily derived from
commercially available vitamin B2 (Scheme 1)—also shows
[*] Prof. Dr. Y. Imada, H. Iida, Prof. Dr. S.-I. Murahashi,[+]
Prof. Dr. T. Naota
Department of Chemistry
Graduate School of Engineering Science
Osaka University
Machikaneyama, Toyonaka, Osaka 560-8531 (Japan)
Fax: (+81)6-6850-6222
E-mail: imada@chem.es.osaka-u.ac.jp
murahashi@high.ous.ac.jp
Scheme 1. Synthesis of [DMRFlEt]+[ClO4]À: a) HCHO, HCl, 608C,
3 days; b) CH3I, K2CO3, DMF, RT, overnight; c) CH3CHO, NaBH3CN,
Na2S2O4, DMF, 608C, 2 h; d) NaNO2, HClO4, NaClO4, 08C.
naota@chem.es.osaka-u.ac.jp
Prof. Dr. T. Naota
PRESTO, Japan Science and Technology Agency (JST)
Machikaneyama, Toyonaka, Osaka 560-8531 (Japan)
Fax: (+81)6-6850-6224
high catalytic activity, comparable with that of 3,7,8,10-
tetramethyl flavins. The preparation is quite easy compared
with the multistep methods that are required for conventional
flavin catalysts.[15] Zinc dust acts as an efficient reductant for
the activation of the flavin catalysts. Water is an essential
proton source for this system, and the use of water-containing
solvent mixtures, such as CH3CN/EtOAc/H2O, results in the
production of the corresponding lactones.
[+] Present address:
Department of Applied Chemistry
Okayama University of Science
1–1, Ridaicho, Okayama 700-0005 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research,
the Ministry of Education, Science, Sports, and Culture of Japan,
and JSPS Research Fellowship for Young Scientists.
Representative results for the aerobic Baeyer–Villiger
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
oxidation catalyzed with [DMRFlEt]+[ClO4]À are summar-
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DOI: 10.1002/anie.200462429
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Angewandte
Chemie
Table 1: Aerobic Baeyer–Villiger oxidation of ketones with
[DMRFlEt]+[ClO4]À.
Entry
Substrate
Product
t [h] Yield [%]
1
2
3
7
7
12
94
91[a]
88[b]
4 (X=H)
5 (X=F)
6 (X=Cl)
4
4
6
78
80
84
7
8
4
8
95[c]
86
(72:28)[d]
83[e]
9
4
(57:43)[e]
Scheme 2. Performance of [DMRFlEt]+[ClO4]À in Baeyer–Villiger
reactions of 1. mCPBA=meta-chloroperbenzoic acid.
[a] 5-Ethyl-3,7,8,10-tetramethylisoalloxazinium perchlorate (2 mol%)
was used instead of [DMRFlEt]+[ClO4]À. [b] The reaction was performed
in air. [c] Zinc dust (2.0 equiv) was used. [d] [DMRFlEt]+[ClO4]À (4 mol%)
was used. [e] Regioselectivities of the expected and unexpected lactones
were determined by 1H NMR spectroscopy.
chemoselective catalytic method for nucleophilic oxidation in
preference to oxidation at the heteroatom. Even the use of
mCPBA, a specific oxidant for the Baeyer–Villiger oxidation,
shows unsatisfactory results, as exemplified in Equations (3)
ized in Table 1. Various substituted cyclobutanones can be
converted into the corresponding lactones efficiently when a
1.0m solution of the substrate is stirred in a mixture of
CH3CN/EtOAc/H2O (8:1:1 v/v) at 608C in the presence of the
catalyst (2 mol%), zinc dust (1.5 equiv), and oxygen (1 atm).
The products can be isolated simply by filtration and
extraction because the reactions are generally clean and are
accompanied only by the formation of insoluble Zn(OH)2.
The reaction can be also conveniently performed in air
(Table 1, entry 3). Similar treatment of bicyclic ketones gave a
mixture of expected and unexpected lactones (Table 1,
entries 8 and 9), both of which are important synthetic
intermediates for various biologically active compounds such
as prostaglandins and pheromones.[16b] Baeyer–Villiger mono-
oxygenase, which is also an important class of flavoenzyme,
also exhibits similar selectivity,[16] whereas conventional
synthetic methods generally give an expected lactone by the
ordinary electronic limitations of the Criegee rearrange-
ment.[10,11]
One important feature of the new method is the chemo-
selective oxidation of ketones in the presence of other
reactive functionalities. Indeed, the flavin-catalyzed reaction
of an equimolar mixture of 1 and cyclooctene gave exclusively
the Baeyer–Villiger product 2, without the formation of
cyclooctene oxide [Eq. (2); Scheme 2]. Similar treatment with
methyl p-tolyl sulfide also afforded 2 with extraordinarily
high selectivity [Eq. (4)]. The intramolecular version of such a
preference is also exhibited in entries 8 and 9 of Table 1, in
which highly reactive cyclopentanol and cyclopentene moi-
eties are completely tolerated under the stated conditions, as
they are with an enzymatic oxidation.[16b] This selectivity is
rare under artificial oxidative conditions,[14] and this is the first
and (5) (Scheme 2). Furthermore, the flavin-catalyzed
[9a,b]
Baeyer–Villiger oxidation with H2O2
does not exhibit
chemoselectivity for nucleophilic oxidations, as shown in the
preferential formation of the sulfoxide [Eq. (6)].
The reaction can be rationalized by the formation and
subsequent oxidative transformation of the reactive 4a-
peroxyflavin intermediate, as already described for the
aerobic oxidation of heteroatomic compounds.[6] The flavin
cation, FlEt+, undergoes a two-electron reduction with zinc to
afford the reduced flavin, FlEtÀ.[17] The FlEtÀ intermediate
and its semiquinone radical precursor, FlEtC, have been
confirmed by the UV/Vis analysis of the control experiments
of [DMRFlEt]+[ClO4]À with zinc dust.[18] Incorporation of
molecular oxygen into FlEtÀ affords the flavin 4a-peroxy
anion FlEtOOÀ,[19] which effects nucleophilic oxidation of
ketones to afford the corresponding lactones. Dehydrogen-
ation of the resulting FlEtOH regenerates FlEt+ to complete
the catalytic cycle. Chemoselective Baeyer–Villiger oxida-
tions in this process can be ascribed to the neutrality of the
reaction media and the highly nucleophilic character of the
anionic peroxy intermediate,[20] which forms under the
influence of the zinc counterion. Indeed, dramatic loss of
the chemoselectivity has been observed when acidic
CF3CH2OH was employed as one component of the solvent
mixture. Research is currently underway to elucidate the
mechanism and to apply the reaction to other systems.
Received: October 26, 2004
Published online: February 3, 2005
Keywords: chemoselectivity · green chemistry · lactones ·
.
organocatalysis · oxidation
Angew. Chem. Int. Ed. 2005, 44, 1704 –1706
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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