Flavin catalyzed oxidations of sulfides and amines with molecular oxygen

Article abstract of DOI:10.1021/ja028276p

Novel biomimetic, aerobic oxidation with an organocatalyst was performed. The oxidations of organic substrates such as sulfides, secondary amines, N-hydroxylamines, and tertiary amines with molecular oxygen (1 atm) or even in air in the presence of 5-ethyl-3-methyllumiflavinium perchlorate catalyst and hydrazine monohydrate in 2,2,2-trifluoroethanol occur highly efficiently to give the corresponding oxidized compounds in excellent yields along with water and molecular nitrogen, which are environmentally benign. The TON of the oxidation of sulfides amounts to 19000. Copyright

Full text of DOI:10.1021/ja028276p

Published on Web 02/12/2003
Flavin Catalyzed Oxidations of Sulfides and Amines with Molecular Oxygen
Yasushi Imada,* Hiroki Iida, Satoshi Ono, and Shun-Ichi Murahashi*
Department of Chemistry, Graduate School of Engineering Science, Osaka UniVersity, 1-3, Machikaneyama,
Toyonaka, Osaka 560-8531, Japan, and Department of Applied Chemistry, Okayama UniVersity of Science, 1-1,
Ridaicho, Okayama 700-0005, Japan
Received August 26, 2002 ; E-mail: mura@chem.es.osaka-u.ac.jp
The metabolism of enzymes occurs under mild reaction condi-
tions with high selectivity. The simulation of the function of
Scheme 1. Catalytic Cycle for the Oxidation of Flavoenzyme
Using Simplified 5-Ethyl-3-methyllumiflavin
1
enzymes with simple organic catalysts may lead to the discovery
of biomimetic, catalytic oxidations with molecular oxygen, which
are environmentally benign.2 There is a strong need to have greener
technology for clean catalytic aerobic oxidation; however, reports
on aerobic oxidation incorporating the oxygen atom to organic
substrates are still scarce.4
,3
Microsomal FAD-containing monooxygenase (FADMO) acti-
vates molecular oxygen and oxidatively metabolizes xenobiotic
5
substances in the hepatic tissue. The active site responsible for
the oxidation has been established as the enzyme-bound 4a-
6
hydroperoxyflavin. 4a-Hydroperoxylumiflavin has been prepared
and subjected to the model study on stoichiometric oxidations.7,8
The catalytic cycle of FADMO is shown in Scheme 1 using
6
simplified 5-ethyl-3-methyllumiflavin. 4a-Hydroperoxyflavin (FlE-
tOOH, 1) undergoes monooxygenation of substrate (S) to give
8
oxidized product (SO) and 4a-hydroxyflavin (FlEtOH, 2), which
+
+
undergoes dehydration to give oxidized flavin (FlEt , 3). FlEt (3)
is reduced upon treatment with ZH (hydrogen donor, NADPH) to
give the reduced flavin (FlEtH, 4), which reacts with molecular
oxygen to generate FlEtOOH (1) to complete the catalytic cycle.
Detailed stopped-flow studies on the kinetics of FlEtOH (2)
revealed that pseudo S
occurs readily to give FlEtOOH (1), and in 1989 we discovered
that the oxidation of amines and sulfides with H
N
1 type substitution of FlEtOH (2) with H
2
O
2
correspond to NADPH. We turned our attention on the fact that
hydrazine derivatives are suicide inhibitors for flavoenzymes such
as mammalian monoamine oxidase16 and found that hydrazine
monohydrate serves as an excellent reductant. Oxidation of methyl
p-tolyl sulfide (5) with molecular oxygen (1 atm, balloon) in the
presence of 1 mol % 3 and hydrazine monohydrate in TFE at room
temperature gave the corresponding sulfoxide in >99% yield along
with the generation of water and molecular nitrogen.
9
2 2
O occurs in the
presence of organocatalysts of flavins such as FlEtOOH (1), FlEtOH
+
-
(
2), FlEt ‚ClO
4
(3), and FlEtH (4) highly efficiently (the shunt
9
process in Scheme 1). Flavin catalyzed reactions are highly
attractive, and related flavin catalyzed oxidations of tertiary
amines,1 sulfides, and ketones with H
0,11
12
13
O
2 2
have been reported
continuously. Another important aspect is asymmetric flavin
catalyzed oxidation with H
knowledge, there is no report on the aerobic flavin catalyzed
oxidation reactions, which may correspond to FADMO.
We wish to report that the aerobic oxidations of sulfides,
secondary amines, N-hydroxylamines, and tertiary amines occur
The oxidized flavinium salt 3 is the most effective catalyst among
14
2 2
O .
However, to the best of our
9
those examined. The solvent effect for the aerobic oxidation is
dramatic. Fluorinated alcohols such as TFE and 1,1,1,3,3,3-
hexafluoro-2-propanol are essential for the aerobic oxidation. TFE
17
is a common industrial solvent, and its solubility of molecular
18
oxygen is very high. To clarify the stoichiometry of molecular
+
-
in the presence of FlEt ‚ClO
4
catalyst (3) and hydrazine mono-
oxygen and hydrazine monohydrate, the gas composition, the water
content before and after the reaction, and the uptake and release of
each gas and water were measured. When 1 equiv of sulfide 5 was
oxidized, consumption of 1 equiv of molecular oxygen and
production of 1 equiv of water and 0.5 equiv of molecular nitrogen
were observed. The aerobic oxidation of 5 in the presence of 0.5
equiv of hydrazine monohydrate gave the corresponding sulfoxide
in 96% yield. These results clearly indicate that hydrazine mono-
hydrate in 2,2,2-trifluoroethanol (TFE) to give the corresponding
oxidized compounds in excellent yields along with water and
molecular nitrogen as the environmentally benign byproduct (eq
1). This is the first demonstration of environmentally benign
oxidation using molecular oxygen and organic catalysts. It is
noteworthy that, although molecular oxygen has been used for the
oxidation of reduced flavins,9 its purpose is for the preparation
-12
+
of the catalyst for oxidation with H
2
O .
2
hydrate reduces FlEt twice to give water and molecular nitrogen.
The oxidation of the reduced flavin (FlEtH) with molecular
oxygen occurs readily to give hydroperoxyflavins;15 therefore, the
crucial step of the catalytic cycle of Scheme 1 is the transformation
On the basis of these results, flavoenzyme-mimic aerobic
oxidation has been accomplished using simple and stable lumiflavin
catalyst 3. The representative results are summarized in Table 1.
Although 0.5 equiv of hydrazine is enough to oxidize sulfides to
+
of FlEt to FlEtH with an appropriate reductant which may
2868
9
J. AM. CHEM. SOC. 2003, 125, 2868-2869
10.1021/ja028276p CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Table 1. Flavin Catalyzed Aerobic Oxidationsa
FlEtOOH (F ) -1.47)20 and also is similar to the F value (F )
2 2
-1.90) obtained by catalytic oxidation of sulfides with a H O
solution in the presence of the catalyst 3, indicating that oxidation
of sulfides with 4a-FlEtOOH occurs electrophilically to give
N
sulfoxides and FlEtOH. The FlEtOH undergoes a pseudo S 1
+
9
2
reaction to give H O and FlEt , which is reduced with hydrazine
monohydrate to give FlEtH. Thus, hydrazine would attack at the
+
4
a(C) position of the isoalloxazine ring of FlEt to form the 4a-
adduct (FlEtNHNH
2
), which undergoes â-elimination of diazene
(
NHdNH) to afford FlEtH.16 Diazene thus formed again reacts with
+
FlEt similarly to give FlEtNdNH, which undergoes â-elimination
to afford FlEtH and molecular nitrogen. The FlEtH thus formed
would undergo reaction with molecular oxygen to form FlEtOOH
to complete the catalytic cycle.
In conclusion, we found that lumiflavin catalyzes oxidation of
substrates such as sulfides and amines with molecular oxygen or
even air in the presence of hydrazine monohydrate in TFE to give
the corresponding oxides along with water and molecular nitrogen.
This catalytic aerobic oxidation is extremely efficient and clean.
Further extension of this unique catalytic reaction is under
investigation.
Acknowledgment. This work was supported by the Research
for the Future program, the Japan Society for the Promotion of
Science, and a Grant-in-Aid for Scientific Research, the Ministry
of Education, Science, Sports and Culture of Japan.
Supporting Information Available: Experimental procedures
(
PDF). This material is available free of charge via the Internet at http://
a
The aerobic oxidation was carried out in the presence of 3 (1 mol %)
pubs.acs.org.
and NH2NH2‚H2O (1 equiv) in TFE (1 mL) at 35 °C under O2 (1 atm).
Isolated yield. Under air. At 60 °C. 3 (5 mol %) and NH2NH2‚H2O
1.1 equiv) were used. f 3 (5 mol %) was used.
b
c
d
e
(
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(
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-
X
H
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