Comparison of riboflavin-derived flavinium salts applied to catalytic H2O2 oxidations

Article abstract of DOI:10.1039/c8ob00856f

A series of flavinium salts, 5-ethylisoalloxazinium, 5-ethylalloxazinium, and 1,10-ethylene-bridged alloxazinium triflates, were prepared from commercially available riboflavin. This study presents a comparison between their optical and redox properties, and their catalytic activity in H₂O₂ oxidations of sulfide, tertiary amine, and cyclobutanone. Reflecting the difference between the π-conjugated ring structures, the flavinium salts displayed very different redox properties, with reduction potentials in the order of: 5-ethylisoalloxazinium > 5-ethylalloxazinium > 1,10-ethylene-bridged alloxazinium. A comparison of their catalytic activity revealed that 5-ethylisoalloxazinium triflate specifically oxidises sulfide and cyclobutanone, and 5-ethylalloxazinium triflate smoothly oxidises tertiary amine. 1,10-Bridged alloxazinium triflate, which can be readily obtained from riboflavin in large quantities, showed moderate catalytic activity for the H₂O₂ oxidation of sulfide and cyclobutanone.

Full text of DOI:10.1039/c8ob00856f

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ARTICLE
Comparison of Riboflavin-Derived Flavinium Salts Applied to
Catalytic H2O2 Oxidations
Received 00th January 20xx,
Accepted 00th January 20xx
Takuya Sakai,† Takuma Kumoi,† Tatsuro Ishikawa, Takahiro Nitta and Hiroki Iida*
DOI: 10.1039/x0xx00000x
A series of flavinium salts, 5-ethylisoalloxazinium, 5-ethylalloxazinium, and 1,10-ethylene-bridged alloxazinium triflates,
were prepared from commercially available riboflavin. This study presents a comparison between their optical and redox
properties, and their catalytic activity in H2O2 oxidations of sulfide, tertiary amine, and cyclobutanone. Reflecting the
difference between the π-conjugated ring structures, the flavinium salts displayed very different redox properties, with
reduction potentials in the order of: 5-ethylisoalloxazinium > 5-ethylalloxazinium > 1,10-ethylene-bridged alloxazinium. A
comparison of their catalytic activity revealed that 5-ethylisoalloxazinium triflate specifically oxidises sulfide and
cyclobutanone, and 5-ethylalloxazinium triflate smoothly oxidises tertiary amine. 1,10-Bridged alloxazinium triflate, which
can be readily obtained from riboflavin in large quantities, showed moderate catalytic activity for the H2O2 oxidation of
sulfide and cyclobutanone.
www.rsc.org/
types: 5-alkylisoalloxaziniums (
1,10-bridged alloxaziniums
between their conjugated systems (Fig. 1).2e,f Because
flavinium cations ( ) can be prepared by N-alkylation of
neutral flavins ( and ), a series of artificial flavins has been
1
), 5-alkylalloxaziniums (
2), and
Introduction
(3), based on the difference
Flavinium salts have previously been developed by mimicking
the functions of flavin-dependent monooxygenases.1 Recently,
flavinium salts have drawn much attention for their unique
biomimetic organocatalytic properties, which promote various
metal-free oxidative transformations.2 The flavinium catalysts
generally require O2 and H2O2 as easily available, inexpensive,
and minimally polluting terminal oxidants to carry out
chemoselective oxidative reactions under mild conditions,
such as the oxidation of sulfides,3,4 amines,5,6 ketones,7
aldehydes,8,9 boronic acids,10 thiols,4a metal complex,11 and
1–3
4
5
synthesized through a flavin ring formation reaction mainly by
using a condensation reaction between 1,2-diaminobenzenes
(
6
and
7) and alloxanes (
8
) (Fig. 1).3c,4b,8a,14b,f,h,18,19
R1
1
R10
10N 1 N
R8
R7
10 N
N
O
1
R8
R7
10 N
N
O
O
R8
O
N
other functional groups12,13
,
as well as asymmetric
N
5
R3
X–
N
N
R7
1•X
5 N
R3
X–
N
5
R5
R3
X–
oxidations.14 In addition, multiple catalytic systems based on
flavinium catalysis have been explored gradually by combining
metals,15 biocatalysts,16 and organocatalysts.17 Therefore, the
flavinium-catalysed system has emerged as a promising tool
for environmentally friendly transformations, and may fulfil
the increasing demand for green sustainable chemistry.
O
2•X
R5
3•X
O
N–alkylation
modification
R10
N
H
R8
R7
N
O
O
R8
N
N
N
O
OH
N
N
N
R3 R7
R3
OH
4
5
O
HO
condensation with 8
Flavinium catalysts are commonly classified into three
R10
HO
H
Me
Me
N
N
N
O
O
R8
R7
NH R8
NH2
NH2
O
O
N
O
NH
N
R3
NH2 R7
riboflavin
8
O
6
7
Fig.
1
Three types of flavinium salts; 5-alkylisoalloxaziniums (1
X), and 1,10-bridged alloxaziniums (3 X).
·
X), 5-
alkylalloxaziniums (2
·
·
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Naturally occurring riboflavin (vitamin B2), one of the most °C, alloxazine (12) was obtained in 70% yield (Scheme 2). In
important bioactive compounds, is synthesised by microbial contrast, the same oxidation gave 9 in 86% yield at 25 °C (Scheme
fermentation, and thus is obtained commercially with low- 1). After N1- and N3-dimethylation of 12, reductive N5-ethylation of
cost. Because of its abundance and because the use of 13 and subsequent oxidation with NaNO2 and TfOH successfully
riboflavin can avoid the multiple synthetic manipulations for afforded 5-ethylalloxazinium triflate (2Me·TfO) in 51% yield. It is
the synthesis of the flavin ring skeleton, some chemists have noteworthy that 1,10-ethylene-bridged alloxazinium triflates
attempted to synthesise semi-synthetic flavinium catalysts by (particularly 3H·TfO) could be synthesised through the most facile
the modification of riboflavin. However, very few examples of synthetic pathway through which upscaling can be readily
riboflavin-derived 7,8-dimethylflavinium catalysts have been carried out.
reported.3k,m,7b,13b,d,e In particular, 1,10-bridged 7,8-
dimethylalloxazinium catalysts have not previously been
developed except for in our recent reports,17a although
OH
OH
analogous 1,10-bridged alloxaziniums have recently been
applied to various reactions.3g,h,n,o,6,8b,13c,14h,16,17a,18a,20
OH
HO
HO
HO
In this study, three types of 7,8-dimethylflavinium catalysts
were synthesised from naturally occurring riboflavin: 5-ethyl-
Me
N
N
N
O
O
Me
Me
N
N
O
O
NaIO4, 25 ˚C
NH
NH
H2O, 17 h
86%
Me
N
7,8-dimethylisoalloxazinium
(
1
·
TfO),
5-ethylalloxazinium
TfO). Their
riboflavin
9
(
2·
TfO), and 1,10-ethylenealloxazinium triflates (3·
NaBH4, EtOH
25 ˚C, overnight
70%
optical and redox properties were investigated, and their
catalytic activity was analysed in several oxidations using H2O2
as a terminal oxidant to compare the three types of flavinium
salts. The results are expected to provide insight into the
possibility and application of riboflavin-derived flavinium
catalysts. Despite the obvious synthetic advantage of the 7,8-
dimethylflavinium skeleton, little attention has been given to
the systematic study on the property differences and catalytic
1. SOCl2
Me
Me
N
N
O
50 ˚C, 20 h
2. TfOH
72%
OH
NH
N
Me
Me
N
N
O
O
X–
3H•TfO
NH
N
OH
N
10
O
Me
Me
N
O
1. CH3CHO, H2
Pd-C, 21 h
2. TfOH, NaNO2
NH
N
activity between 3 and 1/2, although the difference between 1
has been well examined previously.2e,3j
TfO–
MeI, K2CO3
DMF, 60 ˚C
5 h
Et
O
N
1H•TfO
75%
and
2
83%
Me
Me
N
N
O
1. SOCl2
50 ˚C, 6 h
N
Results and discussion
Me
TfO–
OH
N
2. TfOH
81%
3Me•TfO
O
Me
Me
N
O
Synthesis of riboflavin-derived flavinium salts
N
OH
N
As shown in Schemes 1 and 2, a series of flavinium triflates (1–
3·TfOs) was synthesized from riboflavin. Through oxidation with
NaIO4 at 25 °C followed by the reduction of 9 with NaBH4, 10-(2-
hydroxyethyl)-7,8-dimethylisoalloxazine (10) can be readily in large
quantities (>10 g) obtained from riboflavin.4d,21 Due to the ease of
synthesis and the possibility to obtain 10 in large quantities, it is
N
Me
Me
Me
N
O
11
O
1. CH3CHO, H2
Pd-C, 22 h
2. TfOH, NaNO2
N
N
Me
Et
O
1Me•TfO
TfO–
85%
Scheme
1
Synthesis of 1,10-ethylene-bridged alloxazinium triflates (3H·TfO and
3Me·TfO) and 5-ethylisoalloxazinium triflates (1H·TfO and 1Me·TfO) from riboflavin.
employed as
a key synthetic intermediate of flavinium salts
riboflavin
(Scheme 1). Intramolecular cyclisation of 10 with SOCl2 and
subsequent treatment with TfOH afforded 1,10-ethylene-bridged
alloxazinium triflate (3H·TfO)17a in 72% yield. Because of facile
intramolecular cyclisation, 3H·TfO was readily synthesised and
obtained on the gram scale. Reductive N5-ethylation of 10 with
CH3CHO, followed by oxidation with NaNO2 and TfOH, gave 5-
ethylisoalloxazinium triflate (1H·TfO) in 75 yield. To investigate the
substitution effect of the N3-position, 3-methylated 1,10-ethylene-
bridged alloxazinium triflate (3Me·TfO) and 5-ethylisoalloxazinium
triflate (1Me·TfO)4d were synthesised in 81 and 85% yields,
respectively, from 10-(2-hydroxyethyl)-3,7,8-trimethylisoalloxazine
(10), prepared by the methylation of 9 with MeI. Interestingly,
when the oxidation of riboflavin with NaIO4 was carried out at 50
NaIO4, 50 ˚C, H2O, 24 h, 70%
H
Me
Me
N
N
O
O
NH
N
12
MeI, K2CO3, r.t., 3 h, 78%
Me
Me
N
1. CH3CHO, H2
Pd-C, 2 d
Me
Me
N
O
Me
Me
N
N
O
N
N
2. TfOH, NaNO2
51%
N
Me
TfO–
N
Me
Et
O
O
2Me•TfO
13
Scheme 2 Synthesis of 5-ethylalloxazinium triflate (2Me·TfO) from riboflavin.
2 | J. Name., 2012, 00, 1-3
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Optical properties of flavinium salts
To explore the optical properties of the flavinium salts,
their absorption and fluorescence spectra were measured
Table 1. Chemical shifts and absorption peaks of flavinium cationsa
Entry
1
Flavinium
Absorption
Fluorescence
λF,max a,b, nm
648
from
a
CH3CN-salt solution (Fig.
2
and Table 1). The
λmax (log ε)a, nm
isoalloxazinium triflates (1H
·
TfO and 1Me
·
TfO) gave rise to the
1H·TfO
559 (3.91), 417 (3.96),
286 (4.59), 224 (4.49)
typical absorption signals centred at around 420 and 560 nm,
assigned to the transitions of the π-conjugated
isoalloxazinium ring (Fig. 2A).22 In comparison with 1H
TfO and
1Me TfO 2Me TfO presented blue-shifted absorption signals at
π–π*
2
3
4
5
1Me·TfO
2Me·TfO
3H·TfO
645
545
486
485
560 (3.87), 416 (3.96),
285 (4.58), 224 (4.47)
·
·
,
·
460 (3.78), 395 (4.10),
268 (4.65), 220 (4.44)
395 and 460 nm. The π-conjugated system of the
isoalloxazinium ring includes its imide moiety, whereas the π-
conjugation of the alloxazinium ring does not extend to the
imide moiety. Therefore, the
380 (4.11), 261 (4.46),
218 (4.42)
3Me·TfO
376 (4.09), 263 (4.46),
218 (4.38)
a In CH3CN. b Excitation wavelength (λΕx) was 560 nm for 1H·TfO and 1Me·TfO, and 380
nm for 2Me·TfO 3H·TfO, and 3Me·TfO.
,
relatively narrow conjugated system of 2Me
results in the blue-shift. The absorption spectra of 3H
3Me TfO were not equivalent to that of 2Me TfO, although they
·
TfO presumably
·
TfO and
·
·
possess the similar alloxazinium ring structure, and the
absorption signals were further blue-shifted to around 260 and
380 nm maybe due to the difference of the cation
delocalisation within the conjugated ring system. As a result,
1H
·
TfO and 1Me
·
TfO were purple, while 2Me
TfO appeared yellow. The CH3CN solution of 1H
TfO exhibited very weak fluorescence (λFmax = 648 and 645
·
TfO
,
3H
·
TfO, and
3Me
1Me
·
·
·TfO and
nm, respectively) upon excitation at 560 nm (Fig. 2B). In
contrast to the isoalloxazinium salts, the alloxazinium salts
provided strong fluorescence signals upon excitation at 380
nm; 2Me·TfO showed blue-shifted, yellow fluorescence (λFmax
545 nm) and 3H
=
·
TfO and 3Me·TfO displayed strong yellowish-
green fluorescence (λFmax = 486 and 485 nm, respectively) (Fig.
2C).
Redox property of flavinium salts
To investigate the redox activity, the reduction potentials
OH
N
OH
N
e–
e–
e–
e–
Me
Me
N
O
Me
Me
N
N
O
1Me
N
N
N
Me
Me
–
1Me rad Et
O
1Me red Et
O
Me
N
Me
N
e–
e–
e–
e–
Me
Me
N
N
O
Me
Me
N
O
2Me
N
N
Me
N
Me
–
Et
O
N
Et
O
N
2Me rad
2Me red
Fig. 2 (A) Absorption spectra of 0.1 mM 1H·TfO, 1Me·TfO, 2Me·TfO, 3H·TfO, and 3Me·TfO
in CH3CN measured at 25 °C. (B) Fluorescence spectra of 0.20 μM 1H·TfO, 1Me·TfO,
e–
e–
e–
e–
Me
Me
N
N
O
Me
Me
N
N
O
2Me·TfO, 3H·TfO, and 3Me·TfO in CH3CN measured at 25 °C (1H·TfO and 1Me·TfO: λΕx
=
3Me
N
N
Me
Me
560 nm; 2Me·TfO, 3H·TfO, and 3 Me·TfO: λΕx = 380 nm). (C) Photographs of 0.1 mM
2Me·TfO, 2H·TfO, and 3·TfO in CH3CN under UV light (λΕx = 365 nm)
–
3Me rad
3Me red
O
O
Scheme 3 Redox reactions of flavinium cations.
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3Me
3H TfO, showed comparatively positive reduction potentials to
the corresponding N3-substituted 1Me
TfO and 3Me TfO
· ·TfO and
TfO. The N3-unsubstituted flavinium salts, 1H
·
of the synthesized flavinium salts were determined by cyclic
voltammetry (CV) in a solution of CH3CN containing Bu4NClO4
(0.1 M); the results are summarised in Table 2. The obtained
voltammograms exhibit two reversible reduction peaks, which
correspond to the two-electron reduction of flavinium salts
(Scheme 3).4b,22 Among the three N3-substituted flavinium salts,
·
·
because of the lack of an electronegative methyl substituent
(entries 1 and 4). Although the two reversible reduction peaks
were observed for N3-substituted flavinium salts,4b,22 the
second reduction peaks of the N3-unsubstituted 1H
3H TfO (E2 = –0.256 and –0.725 V, respectively) were likely
·TfO and
·
1Me
potentials (E1 and E2) of 0.263 and –0.365 V vs SCE, followed in
order by 2Me TfO and 3Me TfO (Table 2, entries 2, 3, and 5,
respectively). The first and second reductions of 3Me TfO (–
0.255 and –1.25 V vs SCE) were largely unfavourable in
comparison with those of 1Me TfO. Therefore, the LUMO
orbital of 1Me seems to be stabilized rather than those of 2Me
and 3Me, and 1Me TfO is more electrophilic than 2Me TfO and
·TfO showed the most positive potentials, with reduction
irreversible (Fig. S1). The irreversible peaks would result from
the complex formation of the flavin radical or reduced forms.23
These results indicated that the redox activity of the flavinium
salts can be significantly regulated by the initial modification of
riboflavin.
·
·
·
·
·
·
Table 2. Reduction potentials of flavinium triflatesa
Entry
Flavinium
1H·TfO
1Me·TfO
2Me·TfO
3H·TfO
Epc (V vs SCE) b
0.246, -0.372
0.231, -0.397
-0.058, -0.818
-0.236, -0.748
-0.291, -1.28
Epa (V vs SCE) b
E1 (V vs SCE) b
0.281
0.263
-0.026
-0.203
-0.255
E2 (V vs SCE) b
-0.256
-0.365
-0.787
-0.725
-1.25
1
2
3
4
5
0.315, -0.140
0.295, -0.332
0.007, -0.755
-0.170, -0.702
-0.219, -1.23
3Me·TfO
a The redox potentials of the flavins were measured by cyclic voltammetry at a scan rate of 100 mV/s in tetrabutylammonium perchlorate (0.1 M) containing CH3CN. [b] The
electrochemical potentials (E1 and E2) of each flavinium were determined by the relationship E = (Ecp+Eap)/2 relative to SCE.
Table 3. Catalytic activities of flavinium salts for H2O2 oxidation of various substratesa
oxidation of sulfide
Baeyer-Villiger oxidation of cyclobutanone
O
S
O
S
O
flavinium salt (5 mol%)
Me
Me
O
flavinium salt (5 mol%)
19a major
30% H2O2 aq. (1.1 equiv.)
MeOH, 25 ˚C
O
Me
Me
30% H2O2 aq. (1.1 equiv.)
MeOH, 25 ˚C
15
14
18
O
19b minor
oxidation of amine
Me
flavinium salt (2.5 mol%)
O
N
Me
N
30% H2O2 aq. (1.0 equiv.)
MeOH, 25 ˚C
O
17
16
Sulfide a
Tertiary amine b
vobs (μmol/h)
6.2 (= v0)
Cyclobutanone c
vobs (μmol/h)
0.80 a (= v0)
Entry
1
Catalyst
None
vobs (μmol/h)
vobs/v0
–
vobs/v0
–
vobs/v0
–
2.3 d (= v0)
2
3
4
5
6
1H·TfO
1Me·TfO
2Me·TfO
3H·TfO
3Me·TfO
>1.9 x 102 d
>2.2 x 102 d
4.7 d
>83
>98
2.1
5.6
2.2
56 d
9.1
94
>1.2 x 102
5.3
>1.5 x 102
8.6
16
5.8 x 102
10
13 d
1.7
13
4.8 d
(>93) e
(>15) e
a Conditions: 14 (0.1 M), flavinium salt (5 mol%), diethylene glycol diethyl ether (0.5 equiv, internal standard), 30% H2O2 aq. (1.1 equiv), and MeOH at 25 °C. b Conditions: 16 (0.5 M),
flavinium salt (2.5 mol%), mesitylene (0.5 equiv, internal standard), 30% H2O2 aq. (1.0 equiv), and CD3OD at 25 °C. c Conditions: 18 (0.1 M), flavinium salt (5 mol%), 1,1,2,2-
tetrachloroethane (0.5 equiv, internal standard), 30% H2O2 aq. (1.1 equiv), and MeOH at 25 °C. d Average of two runs. e Decomposition of the catalyst presumably occurred.
4 | J. Name., 2012, 00, 1-3
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R10
R10
H2O2
HX
R8
R7
N
N
O
O
R8
R7
N
N
O
Catalytic activity
N
N
N
R5
R3
X–
N
R5
R3
step I
To gain insight into the influence of structural difference of the
riboflavin-derived flavinium salts on their catalytic activity, the
flavinium triflates were compared on the basis of flavinium-
catalysed oxidations of sulfide, amine, and cyclobutanone in
the presence of H2O2 (Table 3). The initial rates of these
reactions were determined both with and without the catalyst
(νobs and ν0, respectively). The enhancement in the reaction
rate in the presence of a flavinium catalyst, relative to that of
the non-catalysed process (νobs/ν0), was calculated for each of
the flavinium triflates. In the oxidation of sulfide (14), the
O
OOH
1•X
1OOH
R10
N
S
R8
R7
N
O
O
H2O
step III
HX
S=O step II
N
N
R3
X–
R5
1OH
S: substrate
OH
Scheme 4. Catalytic cycle of the flavinium-catalysed H2O2 oxidation, illustrated using
simple 1·X.
isoalloxazinium salts (1H
higher activities than that of the alloxazinium salts (2Me
3H TfO, and 3Me TfO). The reaction mechanism of flavinium-
catalysed H2O2 oxidation is shown in Scheme 4.2,3a The
flavinium salt (Fl+
) undergoes a reaction with H2O2 to form
·
TfO and 1Me
·
TfO) showed significantly
·
TfO
,
(A)
O
S
S
3H•TfO (5 mol%)
·
·
Me
Me
30% H2O2 aq. (1.1 equiv.)
CH3CN, 25 ˚C, 6 h
84%
Me
Me
15
14
·
X
HX and oxidatively active hydroperoxyflavin (FlOOH) (step I),
which is responsible for the oxygenation of various substrates.
Through the transfer of oxygen to the substrates, FlOOH is
converted to a hydroxy adduct (FlOH) (step II), and then H2O
H
(B)
O
H
O
HO
O
3H•TfO (5 mol%)
HO
21a
H
H
30% H2O2 aq. (2.0 equiv.)
+
O
elimination of FlOH with HX affords Fl+
rate-limiting step of the 5-alkylated isoalloxazinium catalysts
1H TfO and 1Me
TfO).3a As revealed by the electrochemical
measurements, 1H TfO and 1Me TfO were more electrophilic
than 2Me TfO 3H TfO and 3Me TfO. The relatively higher
activity of 1H TfO and 1Me TfO can be explained by their
·X (step III), which is the
H
20
t-BuOH, 25 ˚C, 18 h
94% (21a:21b = 7:1)
HO
O
21b
(
·
·
H
·
·
Scheme 5 (A) Sulfoxidation of 14 and (B) Bayer-Villiger oxidation of 20, catalysed by
3H·TfO in the presence of H2O2.
·
,
·
·
·
·
and
oxidations tested in this study. However, 3H
readily synthesised on a large scale from riboflavin. Therefore,
we confirmed the availability of 3H TfO in the catalytic
sulfoxidation and Bayer-Villiger reactions with H2O2 (Scheme 5).
Although 3H TfO showed a lower catalytic activity than TfO
the chemoselective sulfoxidation of 14 was efficiently
performed by 5 mol% of 3H TfO, yielding the corresponding
2
·
TfO
,
3
·
TfO showed moderate catalytic activity for H2O2
electrophilic character which enhances the smooth generation
of the oxidatively active FlOOH from Fl+ in the presence of H2O2.
As Cibulka and coworkers reported,2e,3j the alloxazinium salts
are less electrophilic than the isoalloxazinium salts, and much
more difficult to react with H2O2. Therefore, H2O2 addition
·
TfO is more
·
·
1·
,
seems to be the rate-limiting step of 2Me
3Me TfO (step I). This is supported by the revelation of a
slightly lower activity of the more electronegative N3-
·TfO, 3H·TfO, and
·
·
methylated 3Me
·
·
TfO than that of the corresponding N3-
TfO
sulfoxide without overoxidation to sulfone (Scheme 5A). The
Baeyer-Villiger oxidation of 20 was also promoted to give the
corresponding lactones (21a and 21b) in good yield (Scheme
5B).
unsubstituted 3H
.
In the N-oxidation of tertiary amine (16), the most efficient
catalyst was 2Me TfO, followed in order by 3Me TfO 1Me TfO
and 3H TfO, because the basic condition can accelerate the
rate-limiting H2O2 addition step of 2Me (step I).2e,3j N-Oxidation
with 3Me TfO rapidly decelerated before reaching the 10%
·
·
,
·
,
·
Conclusions
·
yield, presumably owing to the decomposition of the catalyst
under basic conditions.3h The Baeyer-Villiger oxidation of
We
synthesized
5-ethylisoalloxazinium
TfO), and 1,10-ethylene alloxazinium
3·TfO) from commercially available riboflavin in three
(
1
·
TfO),
5-
ethylalloxazinium
(2·
cyclobutanone (18) was also conducted using 1Me
and 3H TfO. Because the reaction conditions were neutral like
that of sulfoxidation, the order of the most efficient catalyst
1Me TfO 3H TfO 2Me TfO) was identical to that of the
sulfoxidation of 14. In conclusion, TfO displayed outstanding
activity for oxidation under neutral conditions, while TfO
TfO
·TfO, 2Me·TfO,
triflates (
·
or four steps. Their redox properties and catalytic activity were
largely different from each other depending on the π-
conjugated ring structures, although these flavinium salts
possess the same 7,8-dimethyl substituents originating from
riboflavin. These results indicated that simple modification of
riboflavin can provide unique flavin compounds with diverse
(
·
>
·
>
·
1·
2·
favoured oxidation under basic conditions. Contrary to 1·
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functionalities, which are useful in
a wide variety of MeOH (500 mL), and the resulting mixture was dried by
applications. This information would be useful for designing evaporation. The residue was then washed with diethyl ether
further efficient redox organocatalysts with high accessibility, (250 mL) and dried in vacuo to obtain 3H•TfO (1.92 g, 72%) as
as well as for developing novel riboflavin-containing functional a yellow powder. IR (KBr): νmax/cm-1 1744br (NCO), 1629s
materials.24
(NCO), 1602s (NCO). δH (500 MHz; DMSO-d6; r.t.) 12.75 (s, 1H,
NH), 8.38 (s, 1H, ArH), 8.12 (s, 1H, ArH), 5.31 (t, J = 9.5 Hz, 2H,
CH2), 4.64 (t, J = 9.3 Hz, 2H, CH2), 2.66 (s, 3H, CH3), 2.56 (s, 3H,
CH3). The spectral properties of 3H•TfO were in good
agreement with the reported data.17a
Experimental
Large scale synthesis of 9. Sodium periodate (159 g, 0.74 mol)
was added to a suspension of riboflavin (100 g, 0.27 mol) in
water (4.0 L) in five portions, and the mixture was stirred at ca.
25 ˚C for 17 h. The yellow precipitate was collected by
filtration, washed with water (700 mL), MeOH (700 mL), and
diethyl ether (400 mL), and dried under reduced pressure to
Synthesis of 1H•TfO. Acetaldehyde (3.00 mL, 54 mmol) was
added to a mixture of 10 (552 mg, 1.9 mmol), 10% Pd-C (41.2
mg, 0.039 mmol), conc. HCl (3.0 mL), EtOH (32 mL), and water
(32 mL), and the mixture was stirred at room temperature for
21 h under molecular hydrogen. The reaction mixture was
filtered through a pad of Celite under nitrogen, and the filtrate
solvents were evaporated under reduced pressure. After
successive addition of 2 M aqueous TfOH (4.00 mL, 8.0 mmol),
NaNO2 (612 mg, 8.9 mmol), and NaOTf (3.10 g, 19 mmol), the
mixture was stirred at room temperature for 30 min. The
resulting purple precipitate was collected by filtration, washed
with cold water (40 mL) and diethyl ether (40 mL x 2) to give
1H•TfO (672 mg, 75%) as a purple powder. mp 195.9-196.7 °C.
Elemental analysis: Found: C, 43.7; H, 4.2; N, 11.9. Calc. for
C17H19F3N4O6S: C, 44.0; H, 4.1; N, 12.1%. IR (KBr): νmax/cm-1
1702s (NCO), 1675s (NCO), 1597s (NCO), 1545vs (NCO). δH
(400 MHz; CD3CN; r.t.) 9.96 (br s, 1H, NH), 8.17 (s, 1H, ArH),
8.12 (s, 1H, ArH), 6.08 (br s, 2H, CH2), 4.94 (t, J = 5.4 Hz, 2H,
CH2), 4.04 (t, J = 5.5 Hz, 2H, CH2), 2.62 (s, 3H, CH3), 2.56 (s, 3H,
CH3), 1.75 (t, J = 7.1 Hz, 3H, CH3). δC (126 MHz; CD3CN; r.t.)
156.90, 153.94, 153.28, 152.12, 143.52, 138.01, 132.19, 127.27,
124.84 (q, J = 353 Hz, CF3), 121.31, 120.20, 58.88, 53.34, 51.10,
21.54, 20.26, 15.35. The corresponding molecular ion peak was
give
9
(69.0 g, 86%) as a yellow powder. IR (KBr): νmax/cm-1
3180br (OH), 1723s (NCO), 1656s (NCO), 1578s (NCO), 1546s
(NCO). δH (500 MHz; TFA-d; r.t.) 8.49 (s,1H, ArH), 8.04 (s, 1H,
ArH), 7.16 (dd, 1H, J =3.0, 7.0 Hz, CH), 5.68 (dd, J =7.0, 15 Hz,
1H, CHH), 5.44 (dd, J = 2.5, 15 Hz, 1H, CHH), 2.90 (s, 3H, CH3),
2.79 (s, 3H, CH3). The spectral properties of
agreement with the reported data.4d
9 were in good
Large scale synthesis of 10. To a suspension of
9 (25.0 g, 83
mmol) in Solmix AP-7 (8.7 L, 85:5:10 EtOH/2-propanol/1-
propanol), NaBH4 (5.15 g, 0.14 mol) was added in five portions,
and the mixture was stirred at 25 °C overnight. After adding
water (1.7 L), the resulting precipitate was collected by
filtration, washed with methanol (1.7 L) and diethyl ether (0.8
L), and then suspended in MeOH (280 mL). After evaporation
of the solvents, the residue was washed with water (0.3 L) and
dried in vacuo to afford 10 (16.7 g, 70%) as a yellow powder. IR
(KBr): νmax/cm-1 3225br (OH), 1712s (NCO), 1672s (NCO), 1578s
(NCO), 1547s (NCO). δH (400 MHz; DMSO-d6; r.t.) 11.33 (s, 1H,
-CONHCO-), 7.89 (s, 2H, ArH), 4.95 (t, J=5.8 Hz, 1H, OH), 4.69 (t,
J=5.8 Hz, 2H, CH2), 3.80 (m, 2H, CH2), 2.53-2.45 (3H, CH3,
overlapped with DMSO-d5), 2.40 (s, 3H, CH3). The spectral
properties of 10 were in good agreement with the reported
data.4d
not detected in the HRMS spectrum for 1H•TfO
.
Synthesis of 11. To a mixture of 10 (2.99 g, 11 mmol), K2CO3
(7.41 g, 58 mmol), and DMF (300 mL) was added MeI (3.40 mL,
55 mmol), and the mixture was stirred at 60 ˚C for 5 h under
molecular nitrogen. After most of the solvents was removed
under reduced pressure, 0.3 M aqueous HCl (0.30 L) was
added to the residue and the mixture was stirred for 30 min.
The resulting powder was collected by filtration and washed
with hexane (100 mL). A part of the crude product (558
mg/2.78 g) was washed with water (50 mL) and dried in vacuo
to give 11 (527 mg, 83%) as a yellow powder. IR (KBr): νmax/cm-
Large scale synthesis of 3H•TfO. A mixture of 10 (7.08 g, 25
mmol) and SOCl2 (43.0 mL, 0.59 mol) was stirred at 50 ˚C for 20
h under molecular nitrogen. The resulting yellow precipitate
was collected by filtration, washed with CH2Cl2 (350 mL), and
purified by reprecipitation from formic acid (42 mL) by diethyl
ether (800 mL). After a collection by filtration, the crude
product was washed with 6% aqueous HCl (14 mL x 2) and
dissolved into 1.5% aqueous HCl (640 mL). After solvent
evaporation under reduced pressure, the resulting residue was
redissolved into 1.5% aqueous HCl (640 mL) and lyophilized to
1
3422br (OH), 1698s (NCO), 1644s (NCO), 1582s (NCO), 1550s
(NCO). δH (500 MHz; DMSO-d6; r.t.) 7.94 (s, 1H, ArH), 7.92 (s,
1H, ArH), 4.97 (t, J = 6.0 Hz, 1H, OH), 4.71 (t, J = 6.0 Hz, 2H,
CH2), 3.81 (m, 2H, CH2), 3.27 (s, 3H, CH3), 2.54-2.45 (3H, CH3,
overlapped with DMSO-d5), 2.40 (s, 3H, CH3). The spectral
properties of 11 were in good agreement with the reported
data.4d
obtain the chloride salt of 3H (3H•Cl, 5.80 g) as a yellow
powder. To exchange the counter anion, TfOH (479 μL, 5.4
mmol) was added to a solution of 3H•Cl (1.50 g, 4.9 mmol) in
6 | J. Name., 2012, 00, 1-3
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Synthesis of 1Me•TfO. Acetaldehyde (2.80 mL, 50 mmol) was δH (500 MHz; DMSO-d6; r.t.) 11.82 (s, 1H, -CONHCO-), 11.66
added to a mixture of 11 (507 mg, 1.7 mmol), 10% Pd/C (73.5 (s, 1H, -CONHC-), 7.91 (s, 1H, ArH), 7.70 (s, 1H, ArH), 2.49 (s,
mg, 0.069 mmol), conc. HCl (2.7 mL), EtOH (32 mL), and H2O 3H, ArCH3), 2.46 (s, 3H, ArCH3). The spectral properties of 12
(32 mL), and the mixture was stirred at room temperature for were in good agreement with the reported data.3i
22 h under molecular hydrogen. The reaction mixture was
filtered through a pad of Celite under nitrogen, and the filtrate Synthesis of 13.17b A mixture of 12 (4.00 g, 17 mmol), K2CO3
solvents were evaporated under reduced pressure. After (11.8 g, 86 mmol), and methyl iodide (2.40 mL, 39 mmol) in dry
successive addition of 2 M aqueous TfOH (2.50 mL, 5.0 mmol), DMF (150 mL) was stirred for 3 h at room temperature. After
TfONa (2.70 g, 16 mmol), and NaNO2 (574 mg, 8.3 mmol) at 0 most of the solvent was evaporated under reduced pressure at
˚C, the mixture was stirred for 15 min. An additional 2 M 50 ˚C, water (200 mL) was added to the residue, and the crude
aqueous TfOH (2.50 mL, 5.0 mmol) was added to this, and the mixture was extracted with CHCl3 (700 mL). The organic layer
resulting purple precipitate was collected by filtration, washed was washed with brine (200 mL) and dried over MgSO4,
with cold water (10 mL x 2) and diethyl ether (20 mL x 3), and filtrated, and evaporated to dryness. No further purification
dried under reduced pressure to give 1Me•TfO (687 mg, 85%) was required in order to obtain 13 (3.48 g, 78%) as a yellow
as a purple powder. IR (KBr): νmax/cm-1 1712s (NCO), 1650vs solid. IR (KBr): νmax/cm-1 1720s (NCO), 1677s (NCO), 1556s
(NCO), 1600s (NCO), 1559vs (NCO). δH (400 MHz; CD3CN; r.t.) (NCO). δH (400 MHz; CDCl3; r.t.) 8.07 (s, 1H, ArH), 7.79 (s, 1H,
8.19 (s, 1H, ArH), 8.12 (s, 1H, ArH), 6.08 (br, 2H, CH2), 4.96 (br, ArH), 3.81 (s, 3H, NCH3), 3.60 (s, 3H, NCH3), 2.54 (s, 3H, ArCH3),
2H, CH2), 4.04 (t, J = 5.6 Hz, 2H, CH2), 3.42 (s, 3H, CH3), 2.62 (s, 2.51 (s, 3H, ArCH3). The spectral properties of 12 were in good
3H, CH3), 2.57 (s, 3H, CH3), 1.79 (t, J = 7.2 Hz, 3H, CH3). The agreement with the reported data.8a
spectral properties of 1Me•TfO were in good agreement with
the reported data.4d
Synthesis of 2Me•TfO.17b Acetaldehyde (8.50 mL, 0.15 mol) was
added to a mixture of 13 (1.02 g, 3.7 mmol), 10% Pd-C (400
Synthesis of 3Me•TfO. A mixture of 11 (700 mg, 2.3 mmol) and mg), H2O (12.5 mL), and acetic acid (125 mL), and the mixture
SOCl2 (4.20 mL, 58 mmol) was stirred at 50 ˚C for 6 h. The was stirred for 2 days under molecular hydrogen. The reaction
solvent was removed under reduced pressure, and the residue mixture was filtered through a pad of Celite under molecular
was washed with diethyl ether (50 mL x 4) and dried in vacuo nitrogen, and the filtrate solvents were evaporated under
to afford orange powder (796 mg). After some of the crude reduced pressure. After successive addition of 2 M aqueous
product (529 mg) was dissolved in water (300 mL), the TfOH solution (10 mL, 20 mmol), TfONa (5.07 g, 30 mmol), and
aqueous layer was washed with CHCl3 (150 mL x 3) and NaNO2 (1.07 g, 16 mmol), the mixture was stirred under air at
lyophilized to obtain the chloride salt of 3Me (3Me•Cl, 457 mg) 0 ˚C for 30 min. The resulting purple precipitate was collected
as an orange powder. To exchange the counter anion, TfOH by filtration, washed with cold water (10 mL) and diethyl ether
(22.9 µL, 0.26 mmol) was added to a solution of 3Me•Cl (74.5 (200 mL) to give the crude product (1.11 g). The product (680
mg, 0.23 mmol) in MeOH (47 mL), and the resulting mixture mg) was then purified by the reprecipitation from CH3Cl to
was dried by evaporation. The resulting residue was washed diethyl ether to give 2•TfO (533 mg, 51%) as a yellow powder.
with diethyl ether (47 mL), dried in vacuo, and dissolved in mp 171 ˚C (dec). IR (KBr): νmax/cm-1 1728s (NCO), 1685s (NCO),
water (10 mL), and lyophilized to obtain 3Me•TfO (88.1 mg, 1666s (NCO). δH (500 MHz; CDCl3; r.t.) 8.10 (s, 1H, ArH), 8.05
81%) as a yellow powder. mp 164˚C (dec). IR (KBr): νmax/cm-1 (s, 1H, ArH), 6.12 (br, 1H, N+CHHCH3), 5.34 (br, 1H, N+CHHCH3),
1747s (NCO), 1703s (NCO), 1636s (NCO), 1610s (NCO). δH (500 3.85 (s, 3H, 1-NCH3), 3.57 (s, 3H, 3-NCH3), 2.68 (s, 3H, ArCH3),
MHz; DMSO-d6; r.t.) 8.43 (s, 1H, ArH), 8.15 (s, 1H, ArH), 5.34 (t, 2.61(s, 3H, ArCH3), 1.85 (t, J = 7.2 Hz, 3H, NCH2CH3). δC (126
J = 9.3 Hz, 2H, CH2), 4.71 (t, J = 9.3 Hz, 2H, CH2), 3.41 (s, 3H, MHz; CDCl3; r.t.) 155.27, 149.25, 148.70, 148.62, 147.25,
CH3), 2.67 (s, 3H, CH3), 2.57 (s, 3H, CH3). δC (126 MHz; DMSO- 146.10, 129.13, 128.95, 120.01 (q, J = 320 Hz, CF3), 119.63,
d6; r.t.) 157.91, 152.49, 147.15, 142.56, 142.49, 139.13, 117.40, 51.57, 30.88, 30.01, 21.76, 20.65, 15.23. HRMS (ESI-
131.74, 131.19, 127.81, 121.06 (q, J = 317 Hz, CF3) 117.26, TOF) m/z: [M – TfO–]+ calcd for C17H19F3N4O5S, 299.1503,
50.62, 45.81, 28.95, 21.27, 19.76. HRMS (ESI+): m/z calcd for found, 299.1503.
C15H15N4O2 (M - TfO-), 283.1190; found, 283.1192.
Cyclic voltammetry. Cyclic voltammograms were collected
Synthesis of 12.17b Sodium periodate (4.77 g, 22 mmol) was using an electrochemical analyzer model 1210B (BAS, Tokyo,
added to a suspension of riboflavin (3.00 g, 8.0 mmol) in water Japan) with a conventional three-electrode cell employing a Pt
(120 mL), and the mixture was stirred at 50 ˚C for 24 h. The working electrode, a Pt counter electrode, and a Ag/Ag+
brown precipitate was collected by filtration, washed with reference electrode (BAS, Tokyo, Japan). The electrochemical
water (180 mL), MeOH (130 mL), and diethyl ether (20 mL), analysis of flavinium salts were carried out in acetonitrile (1.0
and dried in vacuo to give 12 (1.34 g, 70%) as a yellow powder. mM) containing Bu4NClO4 (0.1 M) at a sweep rate of 100 mV/s
IR (KBr): νmax/cm-1 1699br (NCO), 1577s (NCO), 1485s (NCO). at 25 ˚C under nitrogen atmosphere. The electrochemical
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1
potentials were converted into values relative to SCE using determined to be 82 and 12%, respectively, by H NMR using
standard redox couple Fc/Fc+ according to the previously 1,1,2,2-tetrachloroethane as an internal standard. The spectral
reported method,12c and were calculated as the mean of properties of 21a25a and 21b25b were in good agreement with
cathodic and anodic peak potentials [E
=
(Ec +Ea )/2].
the reported data.
p
p
Comparison of flavinium catalysts in sulfoxidation of 14.
A
Conflicts of interest
30% aqueous H2O2 solution (24.9 mg, 0.22 mmol) was added
to a mixture of 14 (27.6 mg, 0.20 mmol), flavinium salt (0.01
mmol), and diethylene glycol diethyl ether (16.2 mg, 0.10
mmol, internal standard) in MeOH (2.0 mL), and the reaction
mixture was stirred at 25 ˚C. The reaction was monitored by
GC, and the yield of 15 was calculated based on the calibration
curves using diethylene glycol diethyl ether as an internal
standard. These results are summarised in Fig. S2 and Table 3.
There are no conflicts to declare.
Acknowledgements
This work was supported in part by JSPS KAKENHI (Grant-in-Aid
for Scientific Research (C), no. 16K05797), the Electric
Technology Research Foundation of Chugoku, and the Shorai
Foundation for Science and Technology. This work was also
performed under the Cooperative Research Program of the
Institute for Protein Research, Osaka University, CR-17-05. The
authors thank Prof. Takahisa Ikeue of Shimane University for
his help with the electrochemical analysis.
Comparison of flavinium catalysts in N-oxidation of 16. A 30%
aqueous H2O2 solution (45.3 mg, 0.40 mmol) was added to a
mixture of 16 (40.5 mg, 0.40 mmol), flavinium salt (0.01
mmol), and mesitylene (24.0 mg, 0.20 mmol, internal
standard) in CD3OD (0.8 mL), and the reaction mixture was
1
stirred at 25 ˚C. The reaction was monitored by H NMR, and
the yield of 17 was calculated using an internal standard.
Notes and references
These results are summarised in Fig. S3 and Table 3.
1
(a) F. Müller, Chemistry and Biochemistry of Flavoenzymes,
CRC Press, Boston, 1991; (b) W. J. H. van Berkel, N. M.
Kamerbeek and M. W. Fraaije, J. Biotechnol. 2006, 124, 670-
689.
Comparison of flavinium catalysts in Baeyer-Villiger oxidation
of 18. A 30% aqueous H2O2 solution (45.3 mg, 0.40 mmol) was
added to a mixture of 18 (21.6 mg, 0.20 mmol), flavinium salt
(0.01 mmol), and 1,1,2,2-tetrachloroethane (16.8 mg, 0.10
mmol, internal standard) in MeOH (2.0 mL), and the reaction
mixture was stirred at 25 ˚C. The reaction was monitored by
GC, and the total yield of 19a and 19b was calculated based on
the calibration curves using 1,1,2,2-tetrachloroethane as an
internal standard. These results are summarised in Fig. S4 and
Table 3.
2
(a) Y. Imada and T. Naota, Chem. Rec., 2007, 7, 354-361; (b) F.
G. Gelalcha, Chem. Rev., 2007, 107, 3338-3361; (c) J. Piera and
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G. de Gonzalo and M. W. Fraaije, ChemCatChem, 2013, 5, 403-
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H. Iida, Y. Imada and S.-I. Murahashi, Org. Biomol. Chem.,
2015, 13, 7599–7613.
3
For examples of H2O2 oxidation of sulfides, see: (a) S.-I.
Murahashi, T. Oda and Y. Masui, J. Am. Chem. Soc. 1989, 111,
5002-5003; (b) A. A. Lindén, L. Krüger and J.-E. Bäckvall, J. Org.
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Ott, L. Krüger and J. E. Bäckvall, Chem. Eur. J., 2005, 11, 112-
119; (d) A. A. Lindén, M. Johansson, N. Hermanns and J.-E.
Bäckvall, J. Org. Chem., 2006, 71, 3849-3853; (e) Y. Imada, T.
Ohno and T. Naota, Tetrahedron Lett., 2007, 48, 937-939; (f)
R. Cibulka, L. Baxová, H. Dvořáková, F. Hampl, P. Ménová, V.
Mojr, B. Plancq and S. Sayin, Collect. Czech. Chem. Commun.
2009, 74, 973-993; (g) B. J. Marsh and D. R. Carbery,
Tetrahedron Lett., 2010, 51, 2362-2365; (h) J. Žurek, R.
Cibulka, H. Dvořáková and J. Svoboda, Tetrahedron Lett.,
2010, 51, 1083-1086; (i) G. de Gonzalo, C. Smit, J. Jin, A. J.
Minnaard and M. W. Fraaije, Chem. Commun. 2011, 47,
11050-11052; (j) P. Ménová and R. Cibulka, J. Mol. Catal. A:
Chemical 2012, 363–364, 362-370; (k) H. Iida, S. Iwahana, T.
Mizoguchi and E. Yashima, J. Am. Chem. Soc., 2012, 134,
15103-15113; (l) P. Ménová, H. Dvořáková, V. Eigner, J. Ludvík
and R. Cibulka, Adv. Synth. Cat., 2013, 355, 3451-3462; (m) Y.
Imada, M. Takagishi, N. Komiya and T. Naota, Synth.
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Sulfoxidation of 14 catalyzed by 3H•TfO. A 30% aqueous H2O2
solution (112 µL, 1.1 mmol) was added to a mixture of 14 (138
mg, 1.0 mmol), 3H•TfO (21.0 mg, 0.050 mmol) in MeCN (1.0
mL), and the reaction mixture was stirred at 25 ˚C for 6 h. After
an addition of sat. aqueous NaSO3 (1.0 mL) and CHCl3 (20 mL),
the organic layer was washed with water (10 mL x 2) and brine
(10 mL), dried over MgSO4, and filtered. After the solvent was
removed by evaporation, the residue was purified by column
chromatography (SiO2, hexane/ethyl acetate = 4/1 to 1/3, v/v)
to give to give 15 (130 mg, 84%) as a white solid. The spectral
properties of 15 were in good agreement with the reported
data.4d
Baeyer-Villiger oxidation of 20 catalyzed by 3H•TfO. A 30%
aqueous H2O2 solution (102 µL, 1.0 mmol) was added to a
mixture of 20 (63.1 mg, 0.50 mmol), 3H•TfO (10.5 mg, 0.026
mmol) in t-BuOH (0.5 mL), and the reaction mixture was
stirred at 25 ˚C for 18 h. The yields of 21a and 21b were
8 | J. Name., 2012, 00, 1-3
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A series of flavinium salts were prepared from commercially
available riboflavin, and their optical and redox properties and their
catalytic activity were compared.
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