An uncommon use of irradiated flavins: Br?nsted acid catalysis

Article abstract of DOI:10.1039/d0cc01960g

We present that thioacetalization of aldehydes can be induced by blue light irradiation in the presence of a catalytic amount of riboflavin tetraacetate (RFTA) under aerobic conditions. Several control experiments have suggested that the reaction is more

Full text of DOI:10.1039/d0cc01960g

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Conformational control of nonplanar free base porphyrins:
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DOI: 10.1039/D0CC01960G
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An Uncommon Use of Irradiated Flavins: Brønsted Acid Catalysis
Yukihiro Arakawa,*a Tomohiro Mihara,a Hiroki Fujii,a Keiji Minagawa,a,b and Yasushi Imada*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We present that thioacetalization of aldehydes can be induced by methoxybenzaldehyde (1a) reacted smoothly with 1,3-
blue light irradiation in the presence of a catalytic amount of propanedithiol (2a, 2 equiv) in the presence of riboflavin
riboflavin tetraacetate (RFTA) under aerobic conditions. Several tetraacetate (RFTA, 3 mol%)1d–1f,1h–1k,1m,1s–1u,2 in acetonitrile
control experiments have suggested that the reaction is more likely under consecutive blue LED irradiation (465 nm, 0.3 W) and air
to be catalyzed by acidic species generated in situ during the light
irradiation. We have proposed that single electron transfer from a Table 1 Catalytic thioacetalization of 1a with 2aa
thiol (RSH) to the excited state of RFTA can take place to give a one-
OAc
OAc
O
electron oxidized thiol (RSH+•) and the one-electron reduced RFTA
AcO
N
H
+
–
•
HS
SH
(RFTA ), which can be trapped by molecular oxygen to be stabilized
MeO
–
•
as Brønsted acids including the protonated RFTA (RFTAH•).
Finally, we have demonstrated that such acidic species can be
prepared in advance as a solution and used as Brønsted acid
catalysts for not only the thioacetalization but also Mannich-type
reactions.
OAc
1a
2a (2 equiv)
Me
Me
N
O
H
S
cat. (3 mol%)
N
N
S
h
(465 nm, 0.3 W)
CH3CN, r.t.

O
RFTA
MeO
3a
entry
1
2
3
4
5
6
cat.
RFTA
–
RFTA
RFTA
RFTA
MFl
DMA
Eosin Y
MB
h
atmos.
air
air
air
N2
O2
air
air
air
time (h)
6
6
6
6
3
1 [6]
1
1
yield (%)b
99
0
0
0
100
30 [88]
15
0
Flavin molecules, such as riboflavin and its derivatives, have
attracted increasing attentions as versatile photoredox
/photosensitizing catalysts over a decade,1 which are generally
utilized under consecutive irradiation with visible light. Our
research group has recently joined this seminal field by
introducing the first photoredox/enamine dual catalysis with a
peptide-bridged flavin–amine hybrid,2 in addition to
continuously contributing to the development of flavin-
catalyzed thermal reactions under non-irradiation conditions.3
In this article, we introduce a new aspect of such flavin
molecules for organic synthesis, which uncommonly allows for
the use of a flavin molecule like a Brønsted acid catalyst after
short time irradiation in the presence of a thiol and molecular
oxygen (O2).
on
on
off
on
on
on
on
on
on
on
7
8c
9
air
air
1
1
0
0
10d
Ir(ppy)3
aReactions were performed with 0.735 mmol of 1a and 1.47
mmol of 2a in 3.5 mL of acetonitrile under defined conditions.
bDetermined by H NMR spectroscopy using 1,4-dioxane as an
1
internal standard. cPerformed in acetonitrile/DMF (6/1) with
green LED light (525 nm). dPerformed in DMF.
During our research on the development of flavin
catalysis,2,3
we
serendipitously
found
that
4-
at room temperature to afford the corresponding dithiane
derivative 3a in quantitative yield within 6 hours (Table 1, entry
1). No desired reaction occurred in the absence of either RFTA,
light, or O2, indicating that all of them could be essential for the
reaction (entries 2–4). Although increasing the partial pressure
of O2 made the reaction more efficient (entry 5), reaction
conditions under air were used for further studies because they
are efficient enough. To understand the effectiveness of RFTA,
a. Department of Applied Chemistry, Tokushima University, Minamijosanjima,
Tokushima 770-8506, Japan. E-mail: imada@tokushima-u.ac.jp
b. Institute of Liberal Arts and Sciences, Tokushima University, Minamijosanjima,
Tokushima 770-8502, Japan.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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other organic dyes including 3-methyllumiflavin (MFl), 1,3- substrate, 2a as a reactant, and RFTA as a catalyst unless
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dimethylalloxazine (DMA), Eosin Y, and methylene blue (MB) as otherwise noted (Fig. 1). First of all, an iDnOteI:r1m0.i1t0te39n/tDi0rCraCd0i1a9t6io0Gn
well as a transition metal complex, Ir(ppy)3, which could be experiment was performed, in which irradiation (ON) /non-
excited by absorbing visible lights, were also tested as a irradiation (OFF) of the blue light was switched every one hour,
photocatalyst for the present reaction. Interestingly, the flavin started from the ON state. There was no difference in overall
type molecules RFTA, MFl, and DMA were specifically effective, reaction profiles between the reaction irradiated continuously
while the non-flavin type dyes Eosin Y, MB, and Ir(ppy)3 showed and that irradiated intermittently, showing that the irradiation
no catalytic activity (entries 6–10). Particularly effective was could be required only for initiating the reaction (Fig. 1a). The
RFTA, probably because of its higher reduction potential quantum yield of reaction () was determined to be 8.1 by
퐸red
compared to that of MFl in their ground state (RFTA:
=
–
chemical actinometry with potassium ferrioxalate,4 which also
= –809 mV, vs Ag/AgCl)3e and its higher implied that chain propagation pathways could be involved (Fig.
1/2
red
퐸
1/2
725 mV, MFl:
absorption efficiency compared to that of DMA at 465 nm 1a). However, the reaction was not prevented at all by the
abs
abs
휆
휆
(RFTA:
≈ 450 nm, DMA:
≈ 400 nm).1f Further addition of galvinoxyl free radical after 0.5 h reaction, which led
max
max
optimization of the reaction parameters showed that us to exclude radical chain mechanisms (Fig. 1b, upper). On the
acetonitrile as a solvent, 465 nm as a LED wavelength, and 0.3 other hand, the addition of a catalytic amount of triethylamine
W as an electric power of the blue LED could be the best choice completely suppressed the reaction with a change of color of
(see supporting information).
the reaction mixture from yellowish brown to fluorescence
yellow that is characteristic of RFTA (Fig. 1b, lower), which
suggested that the present reaction could be catalyzed by less-
fluorescence RFTA-related acidic species, recoverable with a
base, generated in situ under the visible light irradiation.
Indeed, an obvious induction period within 10 minutes was
observed by closely pursuing the reaction under optimized
(a)
RFTA (3 mol%)
(465 nm, 0.3 W)
3a
1a
+
2a
(2 equiv)
h

= 8.1

CH3CN, air, r.t.
ON
40
30
20
conditions (Fig. 1a). In addition,
a Hammett plot was
constructed with different p-substituted benzaldehydes to
determine the  value of –1.13 (Fig. 1c), indicating substituent
effects for stabilization of ionic intermediates. The involvement
of singlet oxygen was ruled out since the reaction was not
affected by the addition of anthracene (Fig. 1d). A deuterium
labeling experiment revealed that acyl radical formation was
not involved (Fig. 1e). A similar cyclization took place using 3-
mercapto-1-propanol instead of 2a as a reactant to afford the
corresponding S,O-acetal, while 1,3-propanediol and dibenzyl
disulfide were totally unreactive (Fig. 1f), showing that
catalytically active species could be formed only in the presence
of mercapto functionality (RSH). Quenching experiments by
fluorescence spectroscopy suggested that there was a high
possibility of photochemical electron transfer (PET) between
the excited state of RFTA and RSH to give the one-electron
induction period
10
0
0
10
20
30
40
50
time (min)
OFF
galvinoxyl
(5 mol%)
(b)
1a
3a, 33%
3a, 28%
3a, 57%
3a, 28%
RFTA (3 mol%)
(465 nm, 0.3 W)
+
no light, 0.5 h
h

2a
CH3CN, air, r.t., 0.5 h
(2 equiv)
Et3N
(5 mol%)
(c)
–
•
reduced RFTA, RFTA , and a one-electron oxidized RSH, RSH+•
(see supporting information). Although the aerobic atmosphere
was essential for the reaction (Table 1, entry 4), no consumption
of O2 was apparently observed by a gas burette and no
formation of 2a-derived stable oxoacids such as sulfinic acid and
1
sulfonic acid was observed by H NMR analysis of the reaction
(d)
(e)
2a (2 equiv)
RFTA (3 mol%)
anthracene (1 equiv)
RFTA (3 mol%)
mixture. To ensure that such sulfur oxoacids should not be
involved, we exposed thiols including 1-dodecanethiol and
benzyl mercaptan under the reaction conditions in the absence
of any aldehydes, which afforded only the corresponding
disulfides in very low yields (see supporting information).5
1a
O
+
3a
S
S
D
h
(465 nm, 0.3 W)
h (465 nm, 0.3 W)

CH3CN, air, r.t., 6 h

Ph
D
quant.
Ph
2a
CH3CN, air, r.t., 6 h
quant.
(2 equiv)
(f)
conditions: reactant (2 equiv), RFTA (3 mol%), CH CN, h (465 nm, 0.3 W), air, r.t.

3
1a
S
HO
OH
–
•
1a
1a
no reaction
no reaction
Although RFTA has a reducing ability that can readily react
with even O2 in air,2 it must be much less reducing and more
stable under acidic conditions due to undergoing protonation.3f
It should also be noted that only a trace amount of hydrogen
peroxide was recognized from the mixture of 2a and RFTA after
2 h
92% conv.
+
O
BnS SBn
HS
OH
MeO
Fig 1. Control experiments.
To gain insights into the mechanism of this unexpected
catalysis, additional experiments were carried out using 1a as a
30 min irradiation (see supporting information). As
a
consequence, we are currently proposing that, after the PET
2 | J. Name., 2012, 00, 1-3
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process, a proton transfer (PT) takes place from RSH+• to
RFTA to give RS• and RFTAH•, and the RFTAH• (pKa~8)6 can reacted a range of different aldehydes 1a–1h and dithiols 2a–
cause the present Brønsted acid catalysis (Fig 2). On one hand, 2b in the presence of 3 mol% of RFTA, which were irradiated for
the RS• may be stabilized through its O2 adduct RSOO• in initial 30 minutes prior to leaving them under non-irradiation
equilibrium7 or stored as the corresponding disulfide, although conditions for 9–15 hours (Table 2). Various aromatic aldehydes
COMMUNICATION
We next evaluated the scope of the thioacetVaieliwzaArttiioclenOanlninde
–
•
DOI: 10.1039/D0CC01960G
it is not clear at the moment.
1a–1f with both electron-donating and electron-withdrawing
substituents (entries 1–6) as well as aliphatic aldehydes 1g–1h
(entries 7 and 8) reacted smoothly with 2a to give the
corresponding 1,3-dithianes 3a–3h in good yields. It should be
noted that piperonal 1f bearing an acetal functional group that
are typically acid-labile was tolerated to afford 3f (entry 6). The
use of 2b instead of 2a allowed for the formation of 1,3-
dithiolane such as 4 (entry 9).
1/2 RSSR
R
S
OO
O2
O2
R
SH
+
R
SH
R
S
h

+
+
PET
PT
RFTA
RFTA
RFTAH
Finally, we preliminarily explored whether such photo-
induced Brønsted acid catalysts could be prepared in advance
and used for other reactions. To a solution of 1-dodecanethiol
(4.7 mM, 3 mol%) and RFTA (4.7 mM, 3 mol%) in acetonitrile
pre-irradiated by blue LED light (465 nm, 0.3 W) for 1 h under
O2 (1 atm) (Fig. 3a) was added trans-benzylideneaniline (1
equiv) and the trimethylsilyl (TMS) enol ether derived from
acetophenone (5, 3 equiv), which was stirred for 1 h under dark
and nitrogen atmosphere and evaluated by 1H NMR
spectroscopy. The desired Mannich-type reaction8 proceeded
smoothly to give the corresponding -amino ketone 6a in 99%
yield (Fig. 3b), while the same reaction performed without the
pre-irradiation afforded 6a only in 19% yield. These results
indicated that catalytically active species was prepared by
irradiating the initial RFTA–thiol–O2 mixture as expected. The
feasibility of this catalytic system was also demonstrated with
other imines and silyl enol ethers as substrates under the same
procedure and conditions, providing various -amino ketones
6b–6e in high NMR yields (Fig. 3b). Moreover, the prepared
catalyst was found to be effective for promoting three-
component Mannich-type reactions using different p-
substituted benzaldehydes, aniline, and 5, which efficiently
afforded the adducts 6a and 6f–6i without aldol by-products
(Fig. 3c).
In conclusion, we have found that visible light irradiation to
a RFTA-thiol-O2 mixture can generate Brønsted acidic species
that can be used as efficient catalysts for thioacetalization of
aldehydes as well as Mannich-type reactions under non-
irradiation and mild conditions. To our knowledge, this is the
first example of Brønsted acid catalysis with flavin molecules,
which have so far been typically used for redox catalysis and
energy transfer catalysis, and distinct from previous
photochemical strategies.9,10 Since RFTA and its analogues are
inexpensive, metal-free, and versatile as catalysts,1 we believe
that the present method should open wide application in
organic synthesis—as a catalyst that plays multiple roles in one-
pot synthesis, for example.
Fig 2. Plausible mechanism for the in situ generation of
Brønsted acidic species.
Table 2 Scope of catalytic thioacetalizationa
SH
S
n
O
HS
RFTA (3 mol%)
(465 nm, 0.3 W)
n
+
S
R
H
(2 equiv)
no light, r.t.
h
R

1a-1h
2a: n = 2
2b: n = 1
3a-3h, 4
CH3CN, air, r.t., 0.5 h
entry
substrate
time
(h)
10
product
yield
(%)b
85
1
2
1a
3a
O
S
8
82
H
S
Me
1b
3b
Me
S
3
4
5
6
7
8
9
O
9
84
S
H
1c
3c
O
S
15
15
12
12
6
86
H
S
Cl
1d
3d
Cl
O
S
73
H
S
Br
1e
3e
Br
O
S
74
O
O
H
S
O
O
1f
3f
59
S
O
S
H
1g
3g
100c
85
O
S
S
H
1h
3h
S
10
S
1a
MeO
4
aReactions were performed with 0.735 mmol of 1 and 1.47
mmol of 2 in 3.5 mL of acetonitrile in the presence of 3 mol%
of RFTA under air at room temperature, which was irradiated
Conflicts of interest
There are no conflicts to declare.
b
by blue LED light only for the initial 30 minutes. Isolated
yields. CConversion of
spectroscopy.
1
determined by 1H NMR
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Acknowledgement
This work was supported by Grant-in-Aid for Scientific Research
on Innovative Areas ‘Advanced Molecular Transformation by
Organocatalysts’ for MEXT and the Research Clusters program
of Tokushima University (no. 1802001).
2
3
(a)
h (465 nm, 0.3 W)
SH
11
cat. solution
+
RFTA
O2 (1 atm)
CH3CN, r.t., 1 h
(1 equiv)
R1
(b)
R1
cat. solution
(4.7 mM in CH3CN)
NH
O
N
TMS enol ethers
(3 equiv)
+
Ph
R3
r.t.
Ph
R2
MeO
OH
NH
Ph
Ph
NH
O
NH
O
O
Ph
6a 99%/1 h
Ph
Ph
Ph
Ph
6b 96%/20 h
6c 80%/26 h
Ph
Ph
Ph
NH
O
NH
O
from
OTBS
Ph
Ph
6d 100%/20 h
6e 70%/25 h
4
5
A. Saritha, B. Raju, M. Ramachary, P. Raghavaiah, K. A. Hussain,
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(c)
O
OTMS
+
+
H
PhNH2
Ph
(1.5 equiv)
(1 equiv)
5
R
Ph
6a (R = H)
6f (R = NO )
:
:
:
:
:
93%/5 h
80%/6 h
83%/5 h
63%/5 h
85%/44 h
NH
O
6
7
2
cat. solution
r.t., CH3CN
6g (R = Cl)
6h (R = Me)
6i (R = OMe)
Ph
R
Fig. 3 Catalytic Mannich-type reactions.
8
9
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DOI: 10.1039/D0CC01960G
Graphical Abstract:
Visible light irradiation to flavin in the presence of thiol and O2 provides Bronsted acidic species that
can be used as efficient catalysts for thioacetalization of aldehydes as well as Mannich-type reactions
under non-irradiation and mild conditions.