Tailoring flavins for visible light photocatalysis: organocatalytic [2+2] cycloadditions mediated by a flavin derivative and visible light

Article abstract of DOI:10.1039/c5cc01344e

A new application of flavin derivatives in visible light photocatalysis was found. 1-Butyl-7,8-dimethoxy-3-methylalloxazine, when irradiated by visible light, was shown to allow an efficient cyclobutane ring formation via an intramolecular [2+2] cycloaddition of both styrene dienes, considered as electron-rich substrates, and electron-poor bis(arylenones), presumably proceeding via an energy transfer mechanism.

Full text of DOI:10.1039/c5cc01344e

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New application of flavins in visible light photocatalysis: excited alloxazine allows fast cycloaddition
of both electron-poor and electron rich dienes.

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Tailoring Flavins for Visible Light Photocatalysis:
Organocatalytic [2+2] Cycloadditions Mediated by a
Flavin Derivative and Visible Light†
Cite this: DOI: 10.1039/x0xx00000x
Viktor Mojr,a Eva Svobodová,a Karolína Straková,a Tomáš Neveselý,a Josef
Chudoba,b Hana Dvořáková,b and Radek Cibulkaa,*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
across a broad substrate scope as they are not limited by the
electrochemical properties of the substrates. Nevertheless, such
processes utilising visible light are still very rare; an
iridium(III) polypyridyl complex (ET = 255 kJ mol-1) providing
an intramolecular [2+2] cycloaddition of substituted styrenes12
and very recent systems, based on a thioxanthone dye (ET = 264
kJ mol-1), designed by Bach13 and Sivaguru14 for stereoselective
[2+2] cycloadditions of a specific group of substrates are the
only examples.
New application of flavin derivatives in visible light
photocatalysis was found. 1-Butyl-7,8-dimethoxy-3-methyl-
alloxazine, when irradiated by visible light, was shown to
allow an efficient cyclobutane ring formation by an
intramolecular [2+2] cycloaddition of both styrene dienes,
considered as electron-rich substrates, and electron-poor
bis(arylenones), presumably proceeding by an energy
transfer mechanism.
Noble metal complexes still dominate as photoactive
species in visible light photocatalysis.1 Because of the price of
the dye, as well as environmental aspects representing
important issues, looking for a new, simple photoactive
organocatalyst and its application in photocatalysis represents
an important goal.2 One of the most prominent natural
chromophores is represented by flavin cofactors15 (Figure 1),
which are involved in several light-dependent processes, for
example, in light generation by bacterial luciferase,16 in plant
phototropism17 and in photolyases in the cleavage of
cyclobutane-pyrimidine dimers to repair DNA damage.18 Due
to interesting photochemical properties, flavins (e.g., riboflavin
Rapid development of visible light photocatalysis occurring
within the past decade has stimulated a renaissance of organic
photochemistry.1,2 Replacement of high-intensity UV light with
visible
light
in
combination
with
suitable
photocatalysts/sensitisers absorbing in the proper region made
photochemistry available for most laboratories3 as it can be
performed in common vessels made from borosilicate glass and
with conventional light sources, including the current light
emitting diodes (LEDs).4 Photoexcitation, in general, allows
several chemical transformations that are not accessible by
thermal reactions.5,6 Use of visible light even improves classical
photochemical methodologies by avoiding side reactions of
functionalities sensitive to UV light.
The [2+2] cycloaddition of alkenes, producing cyclobutane
derivatives, represents a typical challenge for photochemistry as
corresponding thermal procedures and four-membered ring
cyclisations are disfavoured.7 Conventional synthetic methods
for [2+2] photocycloadditions usually require high-intensity
UV light,8 but recently, new procedures based on visible light
tetraacetate
1
)
have been tested in photocatalysis;19,20
nevertheless, their applications, except of photolyase models,21
are still limited to photooxidations of benzylic derivatives,
amines and sulfides.
Our idea to apply flavins to sensitised visible light [2+2]
cycloadditions led us to consider their triplet energy, which is
too low in the case of blue light-absorbing isoalloxazines (max
= 450 nm; ET = 209 kJ mol-1 for riboflavin22) to excite
substituted styrenes usually used as substrates for this reaction
(ET = 249 and 259 kJ mol-1 for -methylstyrene23a and 1-
phenylbut-2-en-1-one23b, respectively). Indeed, our attempt to
photocatalysis have also appeared in this important area. Yoon
2+
reported radical [2+2] cycloadditions with
a Ru(bpy)3
photocatalyst, which occur after irradiation with visible light in
the presence of a sacrificial reducing or oxidising agent in the
case of either electron-poor (arylenones) or electron-rich
substrates (styrenes), respectively.9,10 Nicewicz described [2+2]
cycloadditions of electron-rich styrenes with tris-(4-
methoxyphenyl)pyrylium tetrafluoroborate working in the
excited state as a single electron oxidant;11a Zeitler showed
reductive cyclization of arylenones to take place with Eosin
Y.11b In contrast to electron transfer processes, [2+2]
photocycloadditions involving energy transfer are applicable
use
1 as photocatalyst of 3a cycloaddition did not lead to
cyclobutane product. Therefore, we turned our attention to
isomeric alloxazines (Figure 1) absorbing light on the border of
the visible region with triplet energies expected to be above
those of isoalloxazines (ET = 245 kJ mol-1 for 1,3,7,8-
tetramethyl-alloxazine).24 Moreover, alloxazines are known to
exhibit high intersystem crossing (ISC) yield (e.g. ISC = 0.71
for 7,8-dimethylalloxazine in acetonitrile).24b,25 For our
purpose, we tuned the alloxazine structure by introducing
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methoxy groups to the benzene ring to adjust the absorption (Entry 14). In acetonitrile, several blank experiments were
maximum to approximately 400 nm and added a butyl chain on performed to exclude spontaneous formation of the
the N(1) nitrogen to provide sufficient solubility for the catalyst cycloadduct, but cycloaddition or isomerisation of 3a did not
(for synthesis of
2
, see ESI).
occur without light or a photocatalyst. Our effort to study
substrate scope led us to blank experiments with dienes
3
,
5
,
7
2
,
.
9
and 11, which did not form a cycloadduct in the absence of
The only exception was the 4-nitroderivative 3e (R = NO2, in
Table 2), which formed a cyclobutane spontaneously after
irradiation as it has low but still sufficient absorption at 400 nm
(see ESI).
Table 1. [2+2] Photocycloaddition of 3a mediated by
2 and visible light
performed on analytical scale.a
acetonitrile
0.8
0.6
0.4
0.2
0.0
2
1
Conversionb [%]
Entry
Diene
Solvent
300
350
400
450
500
(Z)-3a
(E)-3a
4a
 (nm)
1
2
(E)-3a
(E)-3a
(E)-3a
(E)-3a
(E)-3a
(E)-3a
(E)-3a
(E)-3a
(E)-3a
(E)-3a
(Z)-3a
(E)-3a
(E)-3a
(E)-3a
CD2Cl2
CDCl3
THF-d8
19
24
23
28
28
23
23
12
7
57
Figure 1. Flavins involved in natural and artificial photochemical
processes, design of photocatalyst 2 and UV-VIS spectra of 1 and 2 (c =
5×10-5 mol L-1).
23
18
54
54
54
57
54
60
78
78
87
86
13
62
n.d.f
3
To our delight, irradiation of a solution of diene (E)-3a in
the presence of 2.5 mol% of with a 400 nm LED led to the
2
4
Toluene-d8 18
Acetone-d6 20
formation of the [2+2] cycloadduct 4a within a short time
(Table 1). The conversion to the [2+2] cycloadduct after 10
minutes of irradiation did not differ in most types of solvents
(Entries 1 – 7). Nevertheless, in alcohols (Entries 8 and 9) and
mainly in acetonitrile (Entry 10), it still increased. Additionally,
we detected the formation of (Z)-3a, providing evidence that a
triplet state E/Z photoisomerisation of the styrene double bond
occurs. The rate of isomerisation is faster than the rate of
cycloaddition, as demonstrated by the composition of the
reaction mixtures in acetonitrile after 1 and 10 minutes
irradiation (cf. Entries 10 and 12, see ESI for kinetic profile). It
is noteworthy that irradiation of (Z)-3a led to a mixture of the
same composition as that of (E)-3a (cf. Entries 10 and 11); the
cycloadduct of the same relative configuration was formed as
the major product, regardless of the configuration of the starting
styrene.
Flavins including alloxazines are known to sensitise the
formation of singlet oxygen.20a,25 Therefore, standard
experiments were performed in Schlenck tubes under an argon
atmosphere, not allowing singlet oxygen chemistry to proceed.
Nevertheless, no side products were observed after irradiation
under an air atmosphere, showing that the reaction could be
performed simply in a flask without the exclusion of oxygen.
Of course, it took place more slowly under air as the excited
catalyst was partially quenched by oxygen (cf. Entries 10 and
13). As expected, with RFTA, either isomerization or
cycloaddition did not proceed even under optimized conditions
5
6
DMF-d7
DMSO-d6
CD3OD
23
28
15
7
8
9
Ethanol-d6 15
7
10
11
12c
13d
14e
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
6
7
7
7
59
15
n.d.f
28
23
100
a
Reaction was performed in Schlenck tube in 1 mL of solvent under
argon atmosphere; c(2) = 5×10-4 mol L-1, c(3a) = 2×10-2 mol L-1;
Relative conversion determined by 1H NMR; total conversion was
b
c
proved not to drop under 95% using calibrated internal standard;
Reaction time: 1 min.; d Under air; e With 1 as catalyst; f Not detected.
2 | J. Name., 2012, 00, 1-3
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A
substrate scope investigation performed on
semipreparative scale under optimised conditions showed our presence of Lewis acid (lithium salt) only even with strong
photocatalytic system based on
to be a versatile tool for reductants such as excited Ru(bpy)3 or Eosin Y.9,10,11b In the
intramolecular [2+2] cycloadditions of various types of dienes [2+2] photocycloaddition mediated by , there is indirect
(Table 2), including styrenes with both electron-donating and evidence that it occurs presumably via an energy transfer
electron-withdrawing substituents, symmetrical and non- mechanism (Scheme 1) which could be allowed (despite it
symmetrical bis(styrenes) and , and, interestingly,
a
loadditions by a reductive radical pathway taking place in the
2
2
3
seems to be slightly endothermic26) by high ISC of
and/or by
nonvertical energy transfer27: (i) substrates 3c
3d, 9 and 11 are
2
5
,
7
9
bis(arylenones) 11, which belong among the electron-poor
,
substrates that are usually the subject of visible light photocyc-
too electron-poor to be oxidised with excited alloxazines (see
ESI), (ii) triplet state E/Z-photoisomerization occur after
irradiation of 1-phenylpropene, 1-(p-methoxyphenyl)propene as
well as of 1-(4-methoxyphenyl)but-2-en-1-one in the presence
Table 2. Substrate scope investigation for [2+2] photocycloadditions
mediated by
2
and visible light.a
of alloxazine
2 (see ESI), (iii) irradiation of (Z)-3a led to a
Yieldb
[%]
Time
[min]
d.r.c
mixture of the same composition as that of (E)-3a and (iv)
cyclization of (Z,Z)-11a gave almost the same mixture of
cyclobutane products preferentially with cis configuration of
arylcarbonyl groups as we observed with (E,E)-11a (cf. Entries
10 and 13). On the other hand, reductive mechanism cannot be
Entry Substrate
Cyclobutane
excluded for strongly electron-poor 11c
.
It is noteworthy that quantitative conversions were achieved
in all cases and that cycloadditions with electron-rich styrenes
were faster than with other substrates. Irradiation of 1-
phenylpropene and 1-(p-methoxyphenyl)propene led to only
photoisomerisation (see ESI), most likely because of the
extremely short lifetime23 of the triplet state of styrenes,
R = MeO (3a)
4a
4b
4c
4d
4a
1
2
3
4
5
10
10
45
30
10
82
87
76
81
65
>10:1
>10:1
>10:1
>10:1
>10:1
R = H (3b)
R = Br (3c)
R = CF3 (3d)
(Z)-3a
disfavouring
intermolecular
cyclisation.
Concerning
stereochemistry, our results correspond to those from
photocatalytic radical processes:9,10 i) exo diastereoisomers
were formed
diastereoselectivity for
as
major
products with excellent
and
3
, and ii) cycloadditions of 5, 7, 9
11 yielded predominantly products with cis configurations of
aryl and arylcarbonyl substituents.
6
7
R = H (5a)
6a
6b
10
10
61
97
7:3
5:1
R = CF3 (5b)
8
9
90
25
42
80
7:1
‒
Scheme 1. Proposed mechanism of [2+2] photocycloaddition mediated
by
2
and visible light.
In summary, we demonstrated the first application of a flavin
derivative for photocatalytic C-C bond formation thus opening a
completely new application area for flavin photocatalysts, which
have been used solely in photooxidations. The use of alloxazine
instead of isoalloxazine allowed us to perform an intramolecular
visible light [2+2] photocycloaddition, which is still considered
the domain of noble metal complex photocatalysts.
10
Ar = Ph (11a)
12a
12b
12c
12a
45
45
45
45
70
67
58
57
5:1
11 Ar = 4-MeOPh (11b)
12 Ar = 4-CF3Ph (11c)
4:1
Photocycloaddition with organocatalyst
2 was shown to take
1:1
place with a broad spectrum of dienes. Thanks to its versatility
and its utilisation of a combination of photoactive organocatalyst
13
(Z,Z)-11a
4.5:1
and visible light, the system with flavin
2 distinguishes itself
from those already published for visible light [2+2]
photocycloadditions. Some other flavin derivatives are expected
to be able to promote similar reactivity, which offers the
possibility for further enhancement of the photocatalytic system
presented.
a Reaction mixtures containing substrate (2×10-4 mol) and 2 (5×10-6 mol)
in acetonitrile (20 mL) under argon atmosphere were irradiated (LED,
b
400 nm) until complete conversion was achieved; Preparative yields;
c
1
Diastereoisomeric ratio determined by H NMR spectra of the reaction
mixture.
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This project was supported by the Czech Science Foundation
(Grant No. 14-09190S), and the German National Science
Foundation (GRK 1626 „Chemical Photocatalysis“).
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