Anion effect of 5-ethylisoalloxazinium salts on flavin-catalyzed oxidations with H2O2

Article abstract of DOI:10.1016/j.tetlet.2016.08.076

The anion effect of the 5-ethylisoalloxazinium salts on their catalytic activity was investigated for the oxidation of sulfide with aq H₂O₂in order to design more practical and safer flavinium salt catalysts that can replace the conventional perchlorate salt. The anions forming stronger conjugated acids were found to accelerate the catalytic sulfoxidation. The riboflavin-derived isoalloxazinium triflate salt was chosen as a readily accessible flavin with an efficient catalytic activity. In fact, the isoalloxazinium triflate 1b is an excellent organocatalyst for the chemoselective oxidations of a sulfide to a sulfoxide, Bayer–Villiger reaction of a cyclobutanone to a γ-butyrolactone, Dakin reaction of an arylaldehyde to a phenol, and oxidation of an aldehyde to a carboxylic acid using aq H₂O₂as a terminal oxidant under mild conditions.

Full text of DOI:10.1016/j.tetlet.2016.08.076

Tetrahedron Letters 57 (2016) 4488–4491
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Tetrahedron Letters
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Anion effect of 5-ethylisoalloxazinium salts on flavin-catalyzed
oxidations with H2O2
a
a
b,
Hiroki Iida a, , Tatsuro Ishikawa , Keisuke Nomura , Shun-Ichi Murahashi
⇑
⇑
a Department of Chemistry, Interdisciplinary Graduate School of Science and Engineering, Shimane University, 1060 Nishikawatsu, Matsue 690-8504, Japan
b Department of Chemistry, Okayama University of Science, Ridai-cho, Kita-ku, Okayama 700-0005, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The anion effect of the 5-ethylisoalloxazinium salts on their catalytic activity was investigated for the oxi-
dation of sulfide with aq H2O2 in order to design more practical and safer flavinium salt catalysts that can
replace the conventional perchlorate salt. The anions forming stronger conjugated acids were found to
accelerate the catalytic sulfoxidation. The riboflavin-derived isoalloxazinium triflate salt was chosen as
a readily accessible flavin with an efficient catalytic activity. In fact, the isoalloxazinium triflate 1b is
an excellent organocatalyst for the chemoselective oxidations of a sulfide to a sulfoxide, Bayer–Villiger
Received 28 June 2016
Revised 13 August 2016
Accepted 23 August 2016
Available online 24 August 2016
Keywords:
Flavin
Oxidation
Organocatalyst
Isoalloxazinium salt
Anion effect
reaction of a cyclobutanone to a c-butyrolactone, Dakin reaction of an arylaldehyde to a phenol, and oxi-
dation of an aldehyde to a carboxylic acid using aq H2O2 as a terminal oxidant under mild conditions.
Ó 2016 Elsevier Ltd. All rights reserved.
Introduction
the H2O2 oxidations has not been investigated, and the
conventional ClOÀ4 remains being used as the counter anion of
Flavin compounds have attracted widespread interest in the
biological and chemical fields, and recently recognized as unique
organocatalysts for biomimetic and selective oxidation reactions.1
The first flavin-catalyzed oxidation mimicking the function of fla-
vin monooxygenase was reported in 1989 in which an artificial
5-ethylisoalloxazinium perchlorate salt (1aÁClO4) and H2O2 were
employed as an organocatalyst and terminal oxidant, respectively.2
Because aq H2O2 is relatively safe, inexpensive, and environmen-
tally friendly oxidant, a number of flavin-catalyzed H2O2 oxida-
tions have been developed for diverse substrates such as
sulfides,2,3 secondary amines,2 tertiary amines,3a,i,j,4 ketones,3i,5
aldehydes,6,7 and methylrhenium trioxide.8
the isoalloxaziniums in spite of its unstable feature. In this study,
we investigated the anion effect of 1ÁX to develop a more
practical and safer flavin catalyst, and examined the applicability
of 1ÁX for a variety of catalytic H2O2 oxidations.
Results and discussion
To elucidate the influence of the counter anion, a variety of
1aÁXs (X = CF3SO3 (TfO), ClO4, p-tolSO3 (TsO), CH3SO3, CF3CO2,
and CH3CO2) was in situ prepared by dehydration of the corre-
sponding 4a-hydroxy adduct 1aOH with acids (HXs) through the
equilibrium between 1aÁX and 1aOH (step a in Scheme 1).9 We
determined the catalytic activity for the oxidation of methyl p-tolyl
sulfide (2a) to the corresponding sulfoxide 3a in the presence of
1aOH (1 mol %) and the conjugate acid HX (1 mol %) in CD3OD
(0.1 M) in which the corresponding 1aÁX salt is generated in situ.
The results of the catalytic sulfoxidation with H2O2 are summa-
rized in Table 1 and Figure 1. The reaction rate using 1aOH in the
absence of an acid was almost comparable to that of the blank test
without the flavin catalyst under this condition (entries 1 and 2,
Table 1). However, the addition of strong acids (pKa 6 À10), such
as TfOH and HClO4, significantly accelerated the sulfoxidation
(entries 3 and 4). The acceleration moderated in the presence of
the relatively weaker acids (pKa = À2.8–0.5), such as TsOH,
CH3SO3H, and CF3CO2H (entries 5–7), whereas no enhancement
Among the various flavin catalysts, the 5-ethylisoalloxazinium
salts 1ÁXs have been widely used for the oxidative transformations
due to their excellent catalytic activity, broad versatility, and ease
in handling and storage.1 During the course of developing effective
catalysts, the substituent effect of the flavin ring system has been
proven to be useful in regulating the catalytic activity.3a,c,d,3g–j,
m,6,7
One may expect that the catalytic efficiency of 1ÁX would
also be controlled by the choice of the counter anion (X).
However, to the best of our knowledge, the anion effect of 1ÁX on
⇑
Corresponding authors.
E-mail addresses: iida@riko.shimane-u.ac.jp (H. Iida), murasyt@pearl.ocn.ne.jp
(S.-I. Murahashi).
http://dx.doi.org/10.1016/j.tetlet.2016.08.076
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

H. Iida et al. / Tetrahedron Letters 57 (2016) 4488–4491
4489
without overoxidation to the sulfone (entries 1–4 and 7).11 We
then used the readily available isoalloxazinium salts 1bÁXs
(X = ClO4 and TfO) as a catalyst. The 1bÁXs could be readily pre-
pared from the naturally-occurring, inexpensive riboflavin (vita-
min B2), thus these have many advantages regarding the
synthetic, economic, and environmental aspects.12 Although 1b
possesses a 2-hydroxyethyl group at the N10-position instead of
the methyl group of 1a, the substituent effect was negligible under
the present conditions (entries 1 and 4–6). Therefore, we chose
1bÁTfO as a practical catalyst for the H2O2 oxidation discussed
below.
The chemoselective oxidation of sulfides is among the key
transformations because of the importance of the sulfoxides in
organic synthesis, which can be used as useful intermediates for
the preparation of physiologically-active substances.13 To demon-
strate the substrate scope and chemoselectivity of 1bÁTfO as well
as 1aÁClO4, a variety of sulfides was oxidized (Table 3). The elec-
tron-rich 2b was oxidized to the corresponding sulfoxide 3b with-
out overoxidation (entries 1 and 2). The mono-oxidation of 1,3-
dithiane (2c) selectively occurred to give the mono-sulfoxide 3c
in good yields (entries 3 and 4). The intriguing chemoselectivity
of the flavin-catalyzed system is exhibited by the oxidation of sul-
fides bearing other reactive functionalities such as allylic and
vinylic groups.3b,e Indeed, the sulfide with an allylic substituent
2d was successfully converted to the corresponding sulfoxide 3d
in 85% yield by 1bÁTfO, whereas other oxidation products were
not observed (entry 5). Phenyl propargyl sulfide (2e) also
afforded the corresponding sulfoxide 3e in 83% yield (entry 6).
Due to the significantly lowered-HOMO of the vinylic sulfides,
the flavin-catalyzed oxidations of the vinylic sulfides were
Scheme 1. Mechanism of flavin-catalyzed oxidation with H2O2.
was observed in the presence of CH3CO2H with a very weak acidity
(pKa = 4.8) (entry 8). Therefore, the acceleration effect increased
with the decreasing pKa of HX. In other words, 1aÁX with an anion
providing a stronger conjugate acid showed a higher catalytic
activity. The mechanism of the 1ÁX-catalyzed oxidation with
H2O2 is shown in Scheme 1. The catalyst 1ÁX reacts with H2O2 to
generate the 4a-hydroperoxy adduct 1OOH and HX (step b), and
1OOH can transfer an oxygen atom to the substrate, thus forming
the 4a-hydroxy adduct 1OH (step c). To complete the cycle, H2O
is eliminated from 1OH in the presence of HX giving 1ÁX (step a).
The kinetic study revealed that the H2O elimination (step a) was
the rate-determining step in the catalytic sulfoxidation.2 HX with a
stronger acidity presumably bias the rate-determining dehydration
equilibrium in the catalytic cycle.10
Next, we investigated the catalytic activity and chemoselectiv-
ity of the isolated salts 1aÁXs (X = BF4, PF6, and TfO) with the antic-
ipation that all of these anions producing HXs with a strong acidity
enable the sufficient acceleration of the reaction without lacking
the unique chemoselective feature of the conventional 1aÁClO4.
Table 2 shows the results of the sulfoxidation with 1aÁX (1 mol
%) in CH3OH (1 M) in the presence of 30% H2O2 aq (1.1 equiv). As
expected, 1aÁBF4, 1aÁPF6, and 1aÁTfO as well as 1aÁClO4 showed
an excellent catalytic activity and chemoselectivity without excep-
tion; the chemoselective oxidation of 2a was smoothly completed
within 15 min, giving 3a almost quantitatively (92–98% yields)
relatively difficult and generally required
a higher catalyst
loading and an excess amount of H2O2.3b However, 1bÁTfO
promoted the oxidation of a phenyl vinyl sulfide (2f) with a
1 mol % catalyst loading and a small excess of H2O2 (1.5 equiv),
giving the phenyl vinyl sulfoxide (3f) in 75% yield (entry 7).
Finally, we applied the riboflavin-derived catalyst 1bÁTfO to
diverse oxidative transformations that have been achieved using
other artificial isoalloxazine- and alloxizane-based catalysts. For
the aerobic oxidation of sulfide 2b using hydrazine hydrate as a
reductant,14 1bÁTfO showed a comparable catalytic activity with
1aÁClO4 (Scheme 2A). Both 1bÁTfO and 1aÁClO4 could be employed
as an efficient catalyst for the catalytic Baeyer–Villiger reaction of
cyclobutanone 4 with H2O2,5 in which the oxidation of the ketone
occurred with toleration of the alkene functionality (Scheme 2B).
Recently, the Dakin reaction of aryl aldehydes to phenols6 and
Table 1
Catalytic H2O2 oxidation of 2a with/without 1aOH and HXa
O
1aOH (1 mol%), HX (1 mol%)
S
S
p-tol
Me
p-tol
Me
30% H2O2 aq. (1.0 equiv.)
CD3OD, 25 oC, 1 h
2a
3a
Entry
HX
pKa
Yieldb (%)
1
2
3
4
5
6
7
8
None
None
TfOH
HClO4
TsOH
CH3SO3H
CF3CO2H
CH3CO2H
—
—
2
1
c
À12
À10
À2.8
À1.9
0.5
31
27
17
19
12
2
4.8
a
The reactions were carried out using 2a in CD3OD (0.1 M) in the presence or
absence of 1aOH (1 mol %), HX (1 mol %), Cl2CHCHCl2 (0.5 equiv, internal standard),
and 30% H2O2 aq (1.0 equiv) at 25 °C.
b
Yield of 3a after 1 h was determined by 1H NMR.
c
In the absence of 1aOH
.
Figure 1. Rate of reaction for H2O2 oxidation of 2a with/without 1aOH and HX.

4490
H. Iida et al. / Tetrahedron Letters 57 (2016) 4488–4491
Table 2
Catalytic H2O2 oxidation of 2a with 1ÁXa
O
S
flavin (1 mol%)
S
p-tol
Me
p-tol
Me
30% H2O2 aq. (1.1 equiv.)
CH3OH, 25 oC, 15 min
2a
3a
Entry
1aÁX
Yieldb (%)
1
2
3
4
5
6
7
1aÁClO4
1aÁBF4
1aÁPF6
1aÁTfO
1bÁClO4
1bÁTfO
None
98
93
92
93
95
99
11
a
The reactions were carried out using 2a in CH3OH (1 M) in the presence of 1aÁX
(1 mol %) and 30% H2O2 aq (1.1 equiv) at 25 °C for 15 min.
b
Yield of 3a was determined by 1H NMR.
oxidation of aryl and alkyl aldehydes to the corresponding car-
boxylic acids7 were reported using alloxazine-based organocata-
lysts. The present isoalloxazinium catalysts could catalyze the
Dakin reaction of 6 to 7 and the oxidation of 8 to 9 in 78–98%
yields, although it took over one day (Scheme 2C and D).
In conclusion, the anion of the isoalloxazinium catalysts 1ÁXs
was found to play an important role in the catalytic efficiency of
the H2O2 oxidation of the sulfide, and the rate followed the order
TfOÀ ꢀ ClO4À > CH3SO3À ꢀ TsOÀ > CF3CO2À >> CH3COÀ2 , indicating that
the counter anions forming stronger conjugated acids accelerated
the reaction rate. The TfO salts, in particular, the riboflavin-derived
1bÁTfO could be used as a safe and readily accessible flavin catalyst,
smoothly promoting the chemoselective oxidations of sulfides,
ketones, and aldehydes. These findings would provide useful infor-
mation for designing novel and effective flavin catalysts with a
controlled catalytic activity and selectivity, that can be applied
for natural product and pharmaceutical syntheses.
Scheme 2. Flavin-catalyzed (A) aerobic oxidation of a sulfide and (B) Baeyer–
Villiger reaction of a cyclobutanone, (C) Dakin reaction of an aldehyde, and (D)
oxidation of an aldehyde using H2O2.
Acknowledgments
This work was supported in part by JSPS KAKENHI Grant Num-
ber JP16K05797 and JP26105724 and a Sumitomo Foundation.
Supplementary data
Supplementary data (experimental details and characterization
data, and 1H and 13C NMR spectra of novel compounds) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2016.08.076.
Table 3
Substrate scope of chemoselective sulfoxidationa
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Entry
Substrate
Flavin
Time (h)
Yieldb (%)
1
2
1aÁClO4
1bÁTfO
0.5
0.5
93
93
3
4
1aÁClO4
0.5
0.5
85c
1bÁTfO
85c
5
6
7
1bÁTfO
1bÁTfO
1bÁTfO
1
85
83
75
15
16
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a
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1aÁClO4 or 1bÁTfO (1 mol %) and 30% H2O2 aq (1.5 equiv) at 25 °C.
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7. Murray, A. T.; Matton, P.; Fairhurst, N. W. G.; John, M. P.; Carbery, D. R. Org. Lett.
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b
Isolated yield.
Yield was determined by 1H NMR.
c

H. Iida et al. / Tetrahedron Letters 57 (2016) 4488–4491
4491
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10295–10298.
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ˇ
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12. These catalysts were recently reported for the aerobic oxidation of sulfides
using formic acid as a reductant. See, Murahashi, S.-I.; Zhang, D.; Iida, H.;
14. (a) Imada, Y.; Iida, H.; Ono, S.; Murahashi, S. I. J. Am. Chem. Soc. 2003, 125,
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