Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin-Amine Hybrid

Article abstract of DOI:10.1021/acs.orglett.9b02567

An isoalloxazine (flavin) ring system and a secondary amine have been integrated through a short peptide linker with the aim of using photons as efficiently as possible in photoredox/enamine dual catalysis. We herein report a peptide-bridged flavin-amine

Full text of DOI:10.1021/acs.orglett.9b02567

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with
a Peptide-Bridged Flavin−Amine Hybrid
Takuma Tagami,† Yukihiro Arakawa,*,† Keiji Minagawa,†,‡ and Yasushi Imada*,†
†Department of Applied Chemistry, Tokushima University, Minamijosanjima, Tokushima 770-8506, Japan
‡Institute of Liberal Arts and Sciences, Tokushima University, Minamijosanjima, Tokushima 770-8502, Japan
S
* Supporting Information
ABSTRACT: An isoalloxazine (flavin) ring system and a
secondary amine have been integrated through a short peptide
linker with the aim of using photons as efficiently as possible
in photoredox/enamine dual catalysis. We herein report a
peptide-bridged flavin−amine hybrid that can catalyze α-
oxyamination of aldehydes with TEMPO under weak blue
light irradiation to achieve an extremely high quantum yield of
reaction (Φ = 0.80).
he concept of combining visible-light driven photoredox
catalysis with enamine catalysis, pioneered by MacMillan
T
et al. in 2008,1 has given rise to many unique reactivities that
are not accessible with each of them independently. For
example, the catalytic C−C bond formation at the α-position
of aldehydes with an alkyl halide, which is not trivial to achieve
with a solo enamine catalysis, has become feasible in an
enantioselective manner.2 A similar concept was also
introduced by Akita et al. in 2009 for the catalytic C−O
bond formation at the α-position of aldehydes with 2,2,6,6-
tetramethylpiperidin-1-oxyl (TEMPO) in a nonenantioselec-
tive manner.3 Such a dual catalysis involves a single electron
transfer (SET) between an excited photocatalyst and an
enamine formed in situ or an α-amino radical derived from the
enamine at a point of contact between merged catalytic cycles
(Figure 1a, left). Since both are catalytic species and the
excited form of photocatalyst is particularly labile, their
concentration in solution tends to be too low to make their
SET efficient, which can be reflected in a very low quantum
yield (Φ) of reaction when any chain process is absent. Indeed,
Zeitler et al. reported Φ values of 0.06−0.09 for the
enantioselective α-alkylation of aldehydes catalyzed by Eosin
Y as a photocatalyst combined with a chiral imidazolidinone
cocatalyst.4 Another recent example was reported by
MacMillan et al. for the direct enantioselective α-benzylation
of aldehydes with alcohols using an iridium-based photo-
catalyst and a chiral secondary amine cocatalyst, in which the
Φ value was determined to be 0.071.5 Unfortunately, the α-
oxyamination of aldehydes with TEMPO introduced by Akita
et al.3 has been followed by only a limited number of reports so
far and their quantum yield has not been determined.6 Such a
Φ value, which represents how many molecules react as
desired with a photon absorbed (Φ ≤ 1), is typically evaluated
only for gaining mechanistic insight, but it would be ideal to be
closer to the maximum for economical use of photons
concerning the actual reaction efficiency.
Figure 1. Concept of flavin−amine hybrid catalyst.
With the aim of using photons as efficiently as possible in
the photoredox/enamine dual catalysis, we focused attention
toward covalently linked donor−acceptor molecules found in
the chemistry of artificial photosynthesis.7 It is known that the
rate of photoinduced intramolecular electron transfers from an
excited donor moiety to an acceptor moiety highly depends on
their distance and orientation. We envisioned that this
knowledge could be applied for developing a new type of
photoredox catalysts that integrated an amine functionality and
a photoactive functionality within a molecule, which might
Received: July 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
render SET from/to an enamine-related species to/from an
excited photocatalyst more efficiently to provide not only high
quantum efficiency but also unusual reactivity (Figure 1a,
lysts. We chose the α-oxyamination of aldehydes with TEMPO
as a benchmark reaction, which previously require tris-
(bipyridyl)ruthenium(II) complex [Ru(bpy)3(PF6)2] as a
photoredox catalyst along with morpholine as an amine
cocatalyst,3 and explored whether RFTA could commute
Ru(bpy)3(PF6)2 for this reaction (Scheme 1). Using blue LED
light (465 nm, 1.1 W) that was shed to a tubular reactor with a
diameter of 5 mm at a distance of 1 cm, 3-phenylpropanal (1)
was fully consumed within 6 h in the presence of 2 mol % of
RFTA and 5 mol % of morpholine and 2 equiv of TEMPO in
acetonitrile under a nitrogen (N2) atmosphere and the desired
α-oxyaminated product 2 was obtained in 80% yield along with
20% of unclear byproducts. Ru(bpy)3(PF6)2 instead of RFTA
was less active under the same conditions, and a similar level of
selectivity was observed. Other organic dyes including 1,3-
dimethylalloxazine and Eosin Y were also considerably less
effective (see Supporting Information). The Φ values obtained
with RFTA and Ru(bpy)3(PF6)2 have been determined to be
0.40 and 0.19, respectively, by chemical actinometry with
potassium ferrioxalate,11 indicating that no radical chain
pathway is involved. The superior photoredox activity of
RFTA may be explained by its excited-state reduction potential
(E*red = 1.67 V vs SCE)12 higher than that of Ru(bpy)3(PF6)2
(E*red = 0.77 V vs SCE).2a In fact, 3-methyllumiflavin (MLF),
which is known to be slightly less oxidizing than RFTA in their
ground state (RFTA: Ered = −0.73 V, MFl: Ered = −0.81 V),
showed comparable photocatalytic activity under identical
conditions. The RFTA catalytic system was demonstrated to
be applicable for other aldehydes such as n-butanal,
isovaleraldehyde, n-octanal, and phenylacetaldehyde as a
substrate with a similar level of efficiency (Table 1, entries
́
right). Only recently, Aleman et al. reported such a
bifunctional photoaminocatalyst consisting of imidazolidinone
and thioxanthone for the α-alkylation of aldehydes, which
involved a chain propagation pathway (Φ > 1).8
To externalize our own idea that targets a chain process-free
photoredox/enamine dual catalysis (Φ < 1), we focused on
riboflavin, namely vitamin B2, which is a naturally occurring
photoactive organic molecule easily functionalizable at its N3
and N10 positions without affecting its optical properties such
as absorbance and fluorescence. For example, riboflavin
tetraacetate (RFTA, Scheme 1) is one of the readily accessible
Scheme 1. Comparison of Photoredox Activity between
RFTA, Ru(bpy)3(PF6)2, and MLF in the Visible-Light
Induced α-Oxyamination of 1 with TEMPO Cocatalyzed by
Morpholine
Table 1. Scope of α-Oxyamination with TEMPO in RFTA/
a
Morpholine Catalyst System
riboflavin derivatives well soluble in organic solvents, which
absorbs purple and blue light to emit green/yellow light (for
the UV−vis absorbance, emission, and excitation spectra of
RFTA, see Supporting Information). Although there have been
a number of reports on such flavin molecules as a photoredox
catalyst for visible-light induced reactions,9 their catalytic
activity in any dual photoredox/enamine catalysis has never
been reported so far. In addition, our research group has much
experience in using flavin molecules through the developments
of their thermal catalysis,10 which are the reason for choosing
them as a chromophore in this study. On the other hand, we
selected light emitting diodes (LED) as a visible-light source
possessing a rather narrow emission band to realize the
efficient use of photons. Herein, we first present that flavin
molecules including RFTA can efficiently promote the α-
oxyamination of aldehydes with TEMPO by cooperating with
a secondary amine cocatalyst under visible-light irradiation
through a chain process-free photoredox/enamine dual
catalysis. Then, we introduce a new type of photoredox hybrid
catalysts consisting of a flavin ring system and a secondary
amino group bridged by a peptide linker, in which extremely
high Φ values up to 0.80 are achieved (Figure 1b).
b
entry
R
time (h)
yield (%)
1
2
3
4
5
Bn
Et
6
4
8
8
4
80
71
79
78
52
i-Pr
n-C6H13
Ph
a
Reactions were performed with 50 μmol of aldehyde and 100 μmol
of TEMPO in 0.5 mL of acetonitrile in the presence of 17 μmol of
1,3,5-trimethoxybenzene as an NMR internal standard, 2 mol % of
RFTA, and 5 mol % of morpholine and under a nitrogen atmosphere
b
and blue LED light irradiation. NMR yields.
2−5). It should be noted that the lack of any one of flavin,
morpholine, and LED light did not allow for the present
reaction with 1, which led us to propose the photoredox/
enamine dual catalysis (Scheme 2) involving SET from the
enamine D to the excited flavin Fl* for generating the enamine
radical cation D+• that reacts with TEMPO and then
undergoes hydrolysis to regenerate the amine cocatalyst by
releasing the adduct. Although a nitrogen atmosphere was
required for the efficient catalysis (see Supporting Informa-
tion), a trace amount of unremoved oxygen might act as a
terminal oxidant2a that could receive an electron from the
flavin radical anion Fl−• to regenerate Fl.
As mentioned above, flavin molecules have never been found
to be a photoredox catalyst in the dual catalytic system merged
with enamine catalysis despite their potential especially as an
alternative to conventional transition-metal-based photocata-
B
DOI: 10.1021/acs.orglett.9b02567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
could force the amino group and the flavin ring to get close to
each other, as prolyl-containing flavopeptides we previously
introduced.10g,i,j As expected, a remarkable quantum yield of
reaction (48% yield, Φ = 0.24) was attained when the TFA salt
of 3c was used as a catalyst, while it was almost halved by
replacing either Bn with a methyl group (Me-Ahx-Pro-NH-10-
FlEt, 3d, 20% yield, Φ = 0.09) or Bn-Ahx with a hydrogen
atom (3f, 23% yield, Φ = 0.10). These results indicated that
the Bn-Ahx-Pro moiety in 3c is responsible for its catalytic
activity.15 On the contrary, a comparable performance to 3c
was observed with its analogue Bn-Ahx-Pro-NMe-10-FlEt (3e,
57% yield, Φ = 0.25), showing that the amide hydrogen of N-
terminus in 3c could be less important. Unfortunately, the
moderate yield (48%) obtained with 3c was not improved with
prolonged reaction times due to its own decomposition during
the reaction as clearly shown in reaction profiles with the yield
of 2 (Figure 2, blue solid line, plateaued) and the absorbance
Scheme 2. Proposed Dual Catalysis with Separate Flavin
and Amine
Encouraged by the results of the separate catalyst system, we
turned our attention to flavin−amine hybrids initially
envisioned (Figure 1b). First of all, flavin derivatives 3a and
3b containing an N-alkylbenzylamino moiety tethered to a
N10 position via different kinds of spacers were prepared and
their catalytic activity was compared in the visible-light
induced α-oxyamination of 1. Reactions were carried out
with 2 equiv of TEMPO and 2 mol % of a trifluoroacetic acid
(TFA) salt13 of the flavin-amine hybrid catalysts in DMF14
under a N2 atmosphere and blue LED irradiation (465 nm, 1.1
W) for 6 h (Scheme 3). Although bifunctional catalytic
Scheme 3. Catalytic Performance of Flavin−Amine Hybrids
3a−3f
Figure 2. Profiles of the α-oxyamination of 1 and the decomposition
of 3c under blue light irradiation with different electric powers: the
left vertical axis shows the yield of 2 obtained with an electric power
of 1.1 W (blue solid line) or 0.09 W (red solid line), while the right
vertical axis shows the absorbance at 447 nm obtained with that of 1.1
W (blue dotted line) or 0.09 W (red dotted line).
of 3c at 447 nm (Figure 2, blue dotted line, disappeared). In
fact, 7,8-dimethylalloxazine (4) possibly derived from 3c via its
photoactivation was observed from the reaction mixture, which
had almost no catalytic activity under identical conditions.
Thus we sought to optimize reaction conditions to suppress
such catalyst decomposition, and as a result, reducing the
electric power of LED light was found to be effective. For
example, when an electric power of 0.09 W was used, the
decomposition of 3c was considerably suppressed (Figure 2,
red dotted line) to afford 2 more slowly but in a higher yield of
64% in 24 h (Figure 2, red solid line).16 Particularly notable is
its Φ value which was determined to be 0.80, which is to the
best of our knowledge the highest value ever reported for
photoredox/enamine dual catalysis. It should also be noted
that any separate catalyst system with EtNHBn·TFA and
typical photocatalysts including MLF, Ru(bpy)3(PF6)2, tris(2-
phenylpyridinato)iridium(III) [Ir(ppy)3], and Eosin Y resulted
in no reaction under identical conditions (see Supporting
Information), showing that the present activity and quantum
efficiency are unique to the hybrid catalyst.
behaviors of 3a and 3b were observed, the corresponding Φ
values (0.02 and 0.03, respectively) were unremarkable and
even less than that of a separate catalyst system (0.05)
catalyzed by the combination of MLF and N-benzylethylamine
TFA salt (EtNHBn·TFA). However, these initial results were
still within our anticipation because the distance between a
flavin ring and an assuming enamine moiety in 3a and 3b could
be too far from each other in their stable conformation. We
then relied on our intuition to determine the subsequent
candidate, Bn-Ahx-Pro-NH-10-FlEt (3c, Bn = benzyl, Ahx = 6-
aminohexanoic acid, Pro = proline, 10-FlEt = 2′-(3,7,8-
trimethyl-10-isoalloxazyl)ethyl) featuring a prolyl linker that
The dual catalytic behavior of 3c for the α-oxyamination of
aldehydes with TEMPO may be explained by considering an
C
DOI: 10.1021/acs.orglett.9b02567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
efficient intramolecular SET process enabled by its balanced
conformational rigidity and flexibility with the key peptide
linker. A certain rigidity of the Pro residue could bring the
enamine moiety and the excited flavin ring system close to
make their SET efficient (Scheme 4, left),15 while a certain
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI (Grant-in-Aid
for Scientific Research (C), No. 19K05457) and the Research
Clusters program of Tokushima University (No. 1802001).
Scheme 4. A Plausible Explanation for the Catalytic
Performance of 3c
REFERENCES
■
(1) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77−80.
(2) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322−5363. (b) Nicewicz, D. A.; Nguyen, T. M. ACS
Catal. 2014, 4, 355−360. (c) Romero, N. A.; Nicewicz, D. A. Chem.
Rev. 2016, 116, 10075−10166.
(3) Koike, T.; Akita, M. Chem. Lett. 2009, 38, 166−167.
(4) Neumann, M.; Fuldner, S.; Konig, B.; Zeitler, K. Angew. Chem.,
̈
̈
Int. Ed. 2011, 50, 951−954.
(5) Nacsa, E. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2018, 140,
3322−3330.
(6) (a) Yoon, H.-S.; Ho, X.-H.; Jang, J.; Lee, H.-J.; Kim, S.-J.; Jang,
flexibility of the Ahx residue could entropically favor an open
conformation within which the resulting free radical cation and
anion are liberated to rapidly react with TEMPO and probably
the remaining oxygen, respectively, accordingly suppressing
back electron transfer (BET) (Scheme 4, right). The undesired
decomposition of 3c into 4 (Figure 2), probably triggered by
the β-hydrogen abstraction with N1 nitrogen of the flavin ring
system in 3c through a six-membered transition state (see
Supporting Information), could be minimized by making the
concentration of enamine sufficiently higher than that of the
excited flavin ring under the slow photon irradiation, which
brought about the unprecedented quantum yield of reaction.
In summary, we have demonstrated that simple flavin
molecules such as RFTA and MLF can be used as a
photoredox catalyst for α-oxyamination of aldehydes with
TEMPO under blue LED light irradiation, which are chain-
process-free (Φ < 1) and much more efficient compared to
Ru(bpy)3(PF6)2 previously reported under identical condi-
tions. Furthermore, we have introduced the peptide-bridged
flavin−amine hybrid 3c, Bn-Ahx-Pro-NH-10-FlEt, which can
promote the same reaction as a dual functional catalyst with an
extremely high quantum yield of reaction (Φ = 0.80) under
suitable conditions. This study will provide a guide for the
design of new photoredox/enamine dual catalysis that allows
for efficient use of photons in a useful molecular trans-
formation.
́
H.-Y. Org. Lett. 2012, 14, 3272−3275. (b) Ciszewski, Ł. W.; Smolen,
S.; Gryko, D. ARKIVOC 2017, ii, 251−259.
(7) Wasielewski, M. R. Chem. Rev. 1992, 92, 435−461.
́
́
(8) Rigotti, T.; Casado-Sanchez, A.; Cabrera, S.; Perez-Ruiz, R.;
́
̃
a O’Shea, V. A.; Aleman, J. ACS Catal. 2018, 8,
Liras, M.; de la Pen
5928−5940.
(9) For selected examples, see: (a) Svoboda, J.; Schmaderer, H.;
̈
̈
Konig, B. Chem. - Eur. J. 2008, 14, 1854−1865. (b) Lechner, R.;
Konig, B. Synthesis 2010, 2010, 1712−1718. (c) Muhldorf, B.; Wolf,
̈
R. Angew. Chem., Int. Ed. 2016, 55, 427−430. (d) Hering, T.;
Muhldorf, B.; Wolf, R.; Konig, B. Angew. Chem., Int. Ed. 2016, 55,
̈
̈
5342−5345. (e) Metternich, J. B.; Gilmour, R. J. Am. Chem. Soc.
2016, 138, 1040−1045. (f) Hartman, T.; Cibulka, R. Org. Lett. 2016,
18, 3710−3713. (g) Muhldorf, B.; Wolf, R. ChemCatChem 2017, 9,
̈
̈
́
920−923. (h) Marz, M.; Kohout, M.; Nevesely, T.; Chudoba, J.;
́
́
Prukata, D.; Nizinski, S.; Sikorski, M.; Burdzinski, G.; Cibulka, R. Org.
Biomol. Chem. 2018, 16, 6809−6817. (i) Morack, T.; Metternich, J.
B.; Gilmour, R. Org. Lett. 2018, 20, 1316−1319. (j) Zelenka, J.;
́
́
́
́
Svobodova, E.; Tarabek, J.; Hoskovcova, I.; Boguschova, V.; Bailly, S.;
́
Sikorski, M.; Roithova, J.; Cibulka, R. Org. Lett. 2019, 21, 114−119.
(k) Ramirez, N. P.; Konig, B.; Gonzalez-Gomez, J. C. Org. Lett. 2019,
̈
21, 1368−1373.
(10) For selected examples, see: (a) Imada, Y.; Iida, H.; Ono, S.;
Murahashi, S.-I. J. Am. Chem. Soc. 2003, 125, 2868−2869. (b) Imada,
Y.; Iida, H.; Murahashi, S.-I.; Naota, T. Angew. Chem., Int. Ed. 2005,
44, 1704−1706. (c) Imada, Y.; Iida, H.; Naota, T. J. Am. Chem. Soc.
2005, 127, 14544−14545. (d) Imada, Y.; Kitagawa, T.; Ohno, T.;
Iida, H.; Naota, T. Org. Lett. 2010, 12, 32−35. (e) Imada, Y.; Iida, H.;
Kitagawa, T.; Naota, T. Chem. - Eur. J. 2011, 17, 5908−5920.
(f) Arakawa, Y.; Oonishi, T.; Kohda, T.; Minagawa, K.; Imada, Y.
ChemSusChem 2016, 9, 2769−2773. (g) Arakawa, Y.; Yamanomoto,
K.; Kita, H.; Minagawa, K.; Tanaka, M.; Haraguchi, N.; Itsuno, S.;
Imada, Y. Chem. Sci. 2017, 8, 5468−5475. (h) Arakawa, Y.; Kawachi,
R.; Tezuka, Y.; Minagawa, K.; Imada, Y. J. Polym. Sci., Part A: Polym.
Chem. 2017, 55, 1706−1713. (i) Yamanomoto, K.; Kita, H.; Arakawa,
Y.; Minagawa, K.; Imada, Y. Chimia 2018, 72, 866−869. (j) Arakawa,
Y.; Minagawa, K.; Imada, Y. Polym. J. 2018, 50, 941−949. (k) Oonishi,
T.; Kawahara, T.; Arakawa, Y.; Minagawa, K.; Imada, Y. Eur. J. Org.
Chem. 2019, 2019, 1791−1795.
(11) Saritha, A.; Raju, B.; Ramachary, M.; Raghavaiah, P.; Hussain,
K. A. Phys. B 2012, 407, 4208−4213.
(12) Fukuzumi, S.; Yasui, K.; Suenobu, T.; Ohkubo, K.; Fujitsuka,
M.; Ito, O. J. Phys. Chem. A 2001, 105, 10501−10510.
(13) TFA salts of 3 were used not only to promote enamine
formation but also to minimize possible intramolecular photoinduced
electron transfer between the flavin and secondary amine moiety in
the catalyst: Porcal, G.; Bertolotti, S. G.; Previtali, C. M.; Encinas, M.
V. Phys. Chem. Chem. Phys. 2003, 5, 4123−4128.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02567.
Experimantal protocols and selected NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: arakawa.yukihiro@tokushima-u.ac.jp.
*E-mail: imada@tokushima-u.ac.jp.
ORCID
Yukihiro Arakawa: 0000-0003-1000-5799
Yasushi Imada: 0000-0002-4844-5418
D
DOI: 10.1021/acs.orglett.9b02567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(14) DMF was used as a solvent to fully solubilize the hybrid
catalysts, since no significant difference in reaction efficiency between
DMF and acetonitrile was found in the separate catalyst system using
RFTA and morpholine as catalysts. For details, see Supporting
Information.
(15) The role of the Bn group remains unclear. We estimated lowest
energy conformations of flavin−enamine hybrid species derived from
3c and 3d, respectively, by DFT calculation at the B3LYP/6-31G*
level in the ground state and found that the distance between the N5
of flavin ring and the nitrogen atom of enamine in the 3c-derived
model was relatively shorter (4.55 Å) than that in the 3d-derived
model (5.92 Å), which may explain the higher quantum efficiency of
3c. Such a strained conformation may be explained by the observed
intramolecular hydrogen bond between the CO neighboring the
nitrogen atom of Pro and NH of 10-FlEt as well as the observed
gauche conformation of ethylene moiety of 10-FlEt residue. For
details, see Supporting Information.
(16) The reaction was not enantioselective despite the chirality of
3c.
E
DOI: 10.1021/acs.orglett.9b02567
Org. Lett. XXXX, XXX, XXX−XXX