Aerobic oxidation of sulfides with a vitamin B2-derived organocatalyst

Article abstract of DOI:10.1055/s-0033-1339276

5-Ethyl-3-methyl-2′,4′:3′,5′-di-O-methylenedioxy- riboflavinium perchlorate (DMRFlEt⁺ClO₄^-) is readily derived from commercially available vitamin B₂ (riboflavin) and exhibits high catalytic activity for the oxidation of organic sulfides under an oxygen atmosphere (1 atm) with the assistance of hydrazine hydrate as a reductant. This is an inexpensive, convenient, and environmentally benign method for the selective oxidative transformation of sulfides into sulfoxides. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339276

LETTER
▌1679
lAetteerrobic Oxidation of Sulfides with a Vitamin B2-Derived Organocatalyst
Aerobic Oxidation of Sulfides
Yasushi Imada,*a,b Itoko Tonomura,a Naruyoshi Komiya,a Takeshi Naota*a
a
Department of Chemistry, Graduate School of Engineering Science, Osaka University, Machikaneyama 1-3, Toyonaka, Osaka 560-8531,
Japan
Fax +81(6)68506222; E-mail: naota@chem.es.osaka-u.ac.jp
b
Department of Chemical Science and Technology, Institute of Technology and Science, The University of Tokushima, Minamijosanjima 2-1,
Tokushima 770-8506, Japan
Fax +81(88)6567407; E-mail: imada@chem.tokushima-u.ac.jp
Received: 29.03.2013; Accepted after revision: 21.05.2013
product (SO) (path b), and dehydration to complete the
catalytic cycle. Various heteroatom compounds, includ-
ing amines,16a,c sulfides,16a,c and ketones16b undergo aero-
bic oxygenation reactions by this catalytic process.
Abstract: 5-Ethyl-3-methyl-2′,4′:3′,5′-di-O-methylenedioxy-ribo-
–
flavinium perchlorate (DMRFlEt+ClO4 ) is readily derived from
commercially available vitamin B2 (riboflavin) and exhibits high
catalytic activity for the oxidation of organic sulfides under an oxy-
gen atmosphere (1 atm) with the assistance of hydrazine hydrate as
a reductant. This is an inexpensive, convenient, and environmental-
ly benign method for the selective oxidative transformation of sul-
fides into sulfoxides.
AH2
SO, H2O
Flox
Key words: organocatalysis, aerobic oxidation, sulfides, sulf-
(b)
oxides, flavin catalyst
H2O2
(a)
S
A
The development of organocatalytic methods for oxida-
tive transformation is an important subject with great ur-
gency in view of recent requirements to deliver
environmentally benign processes.1,2 Although much ef-
fort has been devoted to the exploitation of organocatalyt-
ic methods2 for C–C bond formation,3 reduction,4 and
oxidation,5–7 reports on organocatalytic aerobic oxidation,
which is an enhanced, sustainable process, have been lim-
ited.6,7,11 Organophoto6 and organoradical7 catalysts have
been employed for the aerobic oxidation of hydrocar-
bons,6a,b,7a,d,e,g sulfides,6d,7b and alcohols6c,7c,f under mild
conditions.
Flred
FlOOH
O2
Scheme 1 Catalytic cycle for dehydrogenative (path a) and oxygen-
ative (path b) transformations with synthetic flavins and molecular
oxygen
Simulation of the enzymatic functions8 of flavin-contain-
ing oxidases9 and oxygenase10 with synthetic flavin cata-
lysts provides a new synthetic methodology for
organocatalytic oxidative transformation.11 A typical cat-
alytic cycle for flavin-catalyzed oxidative transformation
is shown in Scheme 1. Model reactions of flavin-contain-
ing oxidases include anaerobic dehydrogenation of the
substrate (AH2) with oxidized flavins (Flox), the formation
of hydroperoxyflavin (FlOOH)12 by the incorporation of
O2, and the elimination of H2O2 (path a). This process pro-
vides for various dehydrogenative transformations of al-
cohols,13 amines,14 and thiols15 under an O2 atmosphere.
An alternative strategy is the simulation of oxygenases,
which provides another type of organocatalytic oxidative
transformation whereby the reaction proceeds through a
similar redox process that includes the reduction of Flox
with AH2, the incorporation of O2, oxygen atom transfer
from FlOOH to the substrate (S) to form the oxygenated
From our systematic studies on the simulation of enzy-
matic functions with synthetic flavin catalysts,11a,16,17c,f we
have found that 5-ethyl-3-methyl-2′,4′:3′,5′-di-O-methyl-
–
enedioxyriboflavinium perchlorate (1; DMRFlEt+ClO4 ),
which is readily derived from vitamin B2 (riboflavin), acts
O
1 (cat.)
S
S
(1)
R1
R2
R1
R2
O2 (1 atm), NH2NH2•H2O
CF3CH2OH, 35 ºC
O
O
O
O
Me
N
Me
Me
N
N
O
O
Me
Me
N
O
–
–
•ClO4
Me
•ClO4
Me
+
N
+
N
N
N
SYNLETT 2013, 24, 1679–1682
Et
Et
O
Advanced online publication: 28.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
1
2
DOI: 10.1055/s-0033-1339276; Art ID: ST-2013-U0282-L
© Georg Thieme Verlag Stuttgart · New York
Equation 1

1680
Y. Imada et al.
LETTER
as a highly efficient and robust organocatalyst for the aer-
obic oxidation of organic sulfides to afford the corre-
sponding sulfoxides selectively under mild conditions
(Equation 1).
OH
O
OH
O
HO
HO
O
O
The oxidative transformation of sulfides has been per-
formed with metallo-18 and organocatalysts11,16a,c,17,19 us-
ing peroxides11,17–19 or molecular oxygen6d,7b,11,16a,c as an
oxidant. The present reaction provides a facile, inexpen-
sive, and sustainable method for the oxidative transforma-
tion of sulfides into sulfoxides.
Me
Me
N
N
N
O
O
Me
Me
N
N
N
O
O
a,b
c,d
1
NH
N
Me
vitamin B2
Scheme 2 Preparation of DMRFlEt+ClO4 1. Reagents and condi-
tions: (a) HCHO, HCl; (b) MeI, K2CO3, DMF; (c) MeCHO,
NaBH3CN, Na2S2O4, DMF; (d) NaNO2, HClO4.
–
The catalytic activities of representative flavin com-
pounds were examined for the aerobic oxidation of dibu-
tyl sulfide (0.25 mmol) with NH2NH2·H2O (0.25 mmol) in
CF3CH2OH (0.25 mL) at 35 °C. The use of CF3CH2OH as
a solvent is essential to prevent over-consumption of hy-
drazine. Figure 1 shows the time dependence for the yield
sulfides were converted into the corresponding sulfoxides
with high efficiency when the reaction was performed in
CF3CH2OH with flavin catalyst 1 (1–5 mol%) and
NH2NH2·H2O (1 equiv) under an O2 atmosphere (1 atm)
at 35 °C. In all cases, the reaction affords the sulfoxides
exclusively without the formation of sulfones as the cor-
responding over-oxidation products. The product sulfox-
ides can be obtained conveniently with a simple
evaporation/extraction process because catalyst 1 is high-
ly soluble in water, and the reaction proceeds quantitative-
ly and selectively. The reaction can be completed with
high selectivity after prolonged reaction time, even when
the amount of catalyst was reduced to 1 mol% (entries 2
and 7). Oxidation of 1,3-dithiane gives the corresponding
monosulfoxide exclusively (entries 6 and 7). In addition,
ester moieties are tolerated by the reaction (entry 5). Aro-
matic sulfides bearing various substituents are quantita-
tively converted into the corresponding sulfoxides,
although electron-donating groups accelerate the reaction
(entries 8 and 9). Carbon–carbon double bonds are simul-
taneously reduced during oxidation (entry 11).21 Bulky
and less electrophilic sulfides such as diphenyl sulfide
(entry 12) can be converted into the product quantitatively
after a prolonged reaction time of 30 h with no degrada-
tion of the catalytic activity (entry 12), which is in contrast
to frequent degradation of catalyst 2 under similar condi-
tions.22
–
of dibutyl sulfoxide in reactions with DMRFlEt+ClO4 (1)
and 5-ethyl-3-methyllumiflavinium perchlorate (2) cata-
lysts. Yields of the product sulfoxide were determined
periodically by using gas-liquid chromatography analysis
with an internal standard. Oxidation with lumiflavin 2
(1 mol%) gave the product in quantitative yield after stir-
ring for 2 hours. Similar treatment with catalyst 1 (1
mol%) also afforded the product in over 99% yield, al-
though a longer time of 20 hours was required for comple-
tion of the reaction. The reaction could be completed
within 9 and 4 hours upon treatment with 3 and 5 mol% of
catalyst 1, respectively.
In summary, we have presented an inexpensive, conve-
nient, and environmentally benign method for the aerobic
Figure 1 Reaction profiles for the oxidative transformation of dibu-
tyl sulfide into dibutyl sulfoxide upon treatment with NH2NH2·H2O
(1.0 equiv) in the presence of flavin catalysts under O2 atmosphere at oxidation of sulfides using an organocatalyst that can be
35 °C
readily derived from vitamin B2. This approach provides
a safe, facile, and economic means for the catalytic oxy-
genation of various heteroatom compounds. Efforts are
under way to investigate the full scope of the reaction.
Flavin 1 can be readily obtained from vitamin B2, an in-
expensive mass-produced material, by a conventional
process shown in Scheme 2, which is in contrast to the
long synthetic route required to obtain compound 2.16,17
These results indicate that compound 1 is a more conve-
nient, robust, and practical organocatalyst for the aerobic
oxidation of sulfides.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan.
Representative results for the aerobic oxidation of organic
sulfides with catalyst 1 are summarized in Table 1.20 A va-
riety of aliphatic (entries 1–7) and aromatic (entries 8–12)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Synlett 2013, 24, 1679–1682
© Georg Thieme Verlag Stuttgart · New York

LETTER
Aerobic Oxidation of Sulfides
1681
Table 1 Aerobic Oxidation of Sulfides with Catalyst 1a
Entry
Sulfide
Product
Time (h)
4
Yield (%)b
O
1
Me(CH2)3S(CH2)3Me
97
Me(CH2)3S(CH2)3Me
O
Me(CH2)3S(CH2)3Me
Me(CH2)7SMe
2
3
4
20
3
95c
95
87
Me(CH2)3S(CH2)3Me
O
Me(CH2)7SMe
O
Me(CH2)7S(CH2)7Me
5
Me(CH2)7S(CH2)7Me
O
EtO
S
Me
EtO
S
5
6
3
2
93
97
Me
O
S
O
S
O
S
S
O
S
S
7
8
10
4
96c
98
S
S
O
S
Me
S
Me
Me
Me
O
S
Me
S
9
4
92
Me
MeO
MeO
O
S
S
Me
10
11
12
7
7
92d
90e
95f
Me
O
S
S
S
O
S
30
a Reaction conditions: sulfide (0.25 mmol), 1 (5 mol%), NH2NH2·H2O (0.25 mmol), CF3CH2OH (0.25 mL), O2 atm, 35 °C.
b Isolated yield.
c Reaction conducted with 1 mol% catalyst 1.
d CF3CH2OH (0.50 mL) was used.
e NH2NH2·H2O (0.75 mmol) was used.
f NH2NH2·H2O (0.50 mmol) was used.
Catalysis; Wiley-VCH: Weinheim, 2007. (c) Sheldon, R. A.
Chem. Commun. 2008, 3352.
(2) (a) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005. (b) Dalko, P. I.; Moisan, L.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1679–1682

1682
Y. Imada et al.
LETTER
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