Visible-Light-Triggered Monofluoromethylation of Alkenes by Strongly Reducing 1,4-Bis(diphenylamino)naphthalene Photoredox Catalysis

Article abstract of DOI:10.1021/acscatal.9b00473

Monofluoromethyl (CH₂F) radical can be easily generated from a sulfoximine-based precursor (CH₂F-S(=O)(=NTs)-Ph) by the action of visible-light metal-free photoredox catalysis with readily accessible 1,4-bis(diphenylamino)naphthalene

Full text of DOI:10.1021/acscatal.9b00473

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Letter
Visible Light-Triggered Monofluoromethylation of Alkenes by Strongly
Reducing 1,4-Bis(diphenylamino)naphthalene Photoredox Catalysis
Naoki Noto, Takashi Koike, and Munetaka Akita
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00473 • Publication Date (Web): 12 Apr 2019
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Visible Light-Triggered Monofluoromethylation of Alkenes by
Strongly Reducing 1,4-Bis(diphenylamino)naphthalene Photoredox
Catalysis
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Naoki Noto,‡ Takashi Koike,*†,‡ Munetaka Akita*†,‡
†Laboratory for Chemistry and Life Science, Institute of Innovative Research, ‡School of Materials and Chemical
Technology, Tokyo Institute of Technology, R1-27, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan.
ABSTRACT: Monofluoromethyl (CH2F) radical can be easily generated from a sulfoximine-based precursor (CH2F-
S(=O)(=NTs)-Ph) by the action of visible light metal-free photoredox catalysis with readily accessible 1,4-
bis(diphenylamino)naphthalene. The catalyst design based on the high excitation energy (E0,0) and interchromophoric
conjugation features a strong reducing power and a high quantum yield of emission of the photocatalyst. In addition, their
photophysical properties are preserved in various polar solvents. The present system is amenable to oxy-
monofluoromethylation of alkenes with high functional-group tolerance, i.e., single-step synthesis of -fluoroalcohol
scaffolds from various alkenes. Applications to late-stage functionalization of potentially bioactive molecules are also
shown.
photoredox catalysis, organic photocatalyst, monofluoromethylation, radical reaction, alkene difunctionalization.
Development of methodologies for synthesis of
organofluorine compounds attracts increasing attention of
synthetic chemists because of their unique properties as
pharmaceuticals, agrochemicals, and functional materials.1
Recently, various methods for fluorination and
introduction of fluorinated organic units have been
developed.2 However, compared to a large number of
successful examples for tri- and di-fluoromethylation
monofluoromethylation, single-step synthesis of various -
fluoro substiuted products from alkenes is enabled, which
are not always easy to be accessed by simple fluorination.
Herein
we
disclose
photocatalytic
monofluoromethylative difunctionalization of alkenes
under mild and metal-free conditions (Scheme 1b). A major
obstacle of reductive monofluoromethylation is due to the
reduction potentials of the sulfonium-
reactions, strategies for direct incorporation of
a
Scheme
1.
Strategy
for
Radical
monofluoromethyl (CH2F) group into carbon skeletons,
i.e., fluorinative homologation, are still underdeveloped.3,4
In particular, monofluoromethylation of alkenes is limited
to the two types of radical reactions with CH2FSO2Cl
reported by the group of Dolbier, and they require harsh
conditions or a stoichiometric amount of a peroxide,
Monofluoromethylation of Alkenes by Organic
Photoredox Catalysis.
leading
to
halo-
and
intramolecular
carbo-
monofluoromethylation (Scheme 1a).4
For the past several years, our group has revealed that a
combination of photoredox catalysis and shelf-stable
electrophilic fluoroalkylating reagents such as sulfonium-
and sulfoximine-based tri- and di-fluoromethylating
reagents (4, 6, 7) is a reliable way for fluoroalkylation of
unsaturated carbon–carbon bonds.5 This catalytic system
is triggered by 1e-reduction of the electrophilic reagents by
the excited photocatalyst (PC*). Finally, unsaturated bonds
are functionalized with fluoroalkyl and nucleophilic
groups to furnish various difunctionalized products
bearing a fluoroalkyl group under mild conditions without
sacrificial
redox
agents.
In
the
case
of
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interchromophoric conjugation,9 but it is not strong
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enough to reduce the CH2F precursors (3, 5) (Scheme 1c
and 1d). The reducing power of a catalyst in the photo-
excited state (E*ox) can be estimated according to the
equation, E*ox = Eox – E0,0 (Eox: oxidation potential in the
ground state, E0,0: excitation energy).10 In addition,
emission energy (em) is strongly connected to excitation
energy (E0,0 ≈ hc/em, h: Planck constant, c: speed of light).
In brief, naphthalene derivatives with higher emission
energy are expected to show stronger reducing power than
anthracene derivatives (emission (em): em(naphthalene) =
338 nm, em(anthracene) = 403 nm).11 Therefore, we
designed 1,4-bis(diphenylamino)naphthalene 1 (Scheme
1d), which was easily prepared in a good yield and in a gram
scale by the palladium-catalyzed Buchwald-Hartwig
amination reaction (Scheme 2: 85%, 1.57 g).12
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We commenced hydroxy-monofluoromethylation of
alkenes with sulfoximine-based CH2F-reagent 313 (Ered = –
2.43 V) in the presence of photocatalyst 1. To our delight,
visible light irradiation ( = 425 nm) of a mixture of p-
vinylbiphenyl 13a and 1.5 equivalents of 3 dissolved in
acetone-d6/D2O in the presence of 5 mol % of 1 afforded the
expected monofluoromethylated alcohol 14a-d1 in an 83%
NMR yield (Table 1, entry 1). Then, we scrutinized the
reaction system. For the CH2F reagent, the sulfonium-type
reagent 53b (Ered = –2.10 V) afforded 14a-d1 in a lower yield
because a considerable amount of ArS–CH2F was formed
from 5 through cleavage of the S–Ar bonds rather than the
desired S–CH2F bond (entry 2, see the Supporting
Information). The sulfone-type reagent 814 turned out to be
sluggish presumably due to its very low reduction potential
(Ered = –2.64 V) (entry 3). For the photocatalyst, several
strongly reducing ones such as fac-[Ir(ppy)3] (9),
phenothiazine (10)15 and 5,10-dihydrophenazine (11)
derivatives,16 perylene (12),5e,17 and 28 were examined, but
they turned out to be much less effective than 1 (entries 4–
9). The higher catalytic performance of 1 may be ascribed
to compatibility of the stronger reducing power (E*ox), the
visible light absorption ability, and its robustness.
aThe potentials are those reported in the literatures.5b,c,e,6
bThe reducing power is that reported in the literature.8
Scheme 2. Gram-Scale Synthesis of Photocatalyst 1
and sulfoximine-based CH2F precursors (3, 5), which are
significantly lower than those of the corresponding di- and
tri-fluoromethylating reagents (4, 6, 7) to make the 1e-
reduction of them difficult (Scheme 1c).6 Therefore,
development of a strongly reducing catalyst is essential to
achieve the reaction.
Table 1. Optimization of Photocatalytic Hydroxy-
Monofluoromethylation of p-Vinylbiphenyl (13a)
Most of the previous photoredox catalysts have relied on
use of their triplet excited species with longer lifetimes
because they may have more chances to interact with
reactants.7 But the triplet species in general show the
significant downward trend in energy compared to the
singlet species, resulting in disadvantage as reductants. To
explore a strongly reducing photocatalyst, we turned our
attention to energetically favorable design of molecules.
Entry
Photocat.
CH2F-reagent Yield of 14a-d1,%
Recently,
we
reported
that
9,10-
bis(diphenylamino)anthracene 2 serves as an efficient
1
1
1
3
5
8
3
83
36
<5
0
organophotocatalyst
for
radical
fluoroalkylative
2
3
4
difunctionalization under visible light irradiation.8
1
Catalyst 2 exhibits a visible light absorption band and
2
excellent
emission
properties
derived
from
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eReaction was performed under air. f1,3,5,7-Cyclooctatetraene
(1 equiv.) was added.
5
6
7b
9 (E*ox = –1.98 V)
10 (E*ox = –2.52 V)a
3
3
3
3
3
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3
3
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3
29
12
19
6
1
2
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4
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6
7
8
Notably, the catalytic activity of 1 is drastically changed
compared to 2 by the alternation of the anthracene core to
naphthalene. Visible light irradiation and the photoredox
catalyst are essential to the reaction (entries 10 and 11). In
the presence of TEMPO, TEMPO-CH2F was formed instead
of 14a-d1 (entry 12). In the presence of triplet quenchers
such as O2 and 1,3,5,7-cyclooctatetraene, the reaction was
retarded but afforded 14a-d1 in 53% and 77% NMR yields,
respectively (entries 13 and14).
10
8
11 (E*ox = –2.10 V)a
12 (E*ox = –2.23 V)a
9
9
10
11c
12d
13e
14f
0
–
1
1
1
1
0
9
0
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77
With the optimized reaction conditions in hand, we next
examined the reactions of various alkenes (Chart 1A).
Styrene derivatives with a variety of functional groups such
as Ph, Me, F, Cl, Br, OMe, OAc and TMS groups (13a–13i,
13k, 13l) and indene 13j afforded the corresponding 3-
fluoropropanols 14a–14l in 27–70% yields. Unfortunately,
aliphatic alkenes such as 1-octene and 1,1-
dicyclohexylethene did not provide the corresponding
products under the present conditions. gem-Diarylalkenes
(15a–15m) also afforded the corresponding alcohols 16a–
16m in moderate to good yields (42–84%).
1
Yields were determined by H NMR spectroscopy using
tetraethylsilane as an internal standard. Typically, the
reaction was performed with p-vinylbiphenyl 13a (0.0250
mmol), 3 (0.0375 mmol), and photoredox catalyst (1.25 mol)
in a mixture of acetone-d6 (0.45 mL) and D2O (0.05 mL) under
irradiation with blue LEDs ( = 425 nm) at room temperature.
The reducing powers (E*ox V vs. Cp2Fe) are values reported in
a
the literatures except 9. [E*ox vs. Cp2Fe] = [E*ox vs. SCE] –
0.41.15b,16b,5e bLED ( = 380 nm) was used. cReaction was
performed in the dark. dTEMPO (3 equiv.) was added.
Chart 1. Scope of the Present Photocatalytic Monofluoromethylation of Alkenes
For the details of the conditions, see the Supporting Information. DCE = 1,2-dichloroethane. aReaction time = 24 h. b8 mol% of
1 was used. cGram-scale synthesis. dReaction time = 18 h.
It is noteworthy that functionalities such as NO2 (16g:
50%), pyridyl (16k: 42%), and thienyl (16l: 52%) groups
were also tolerated with the reaction. In addition, the
gram-scale synthesis of 16h was performed in an 80% yield
(1.30 g), demonstrating the scalability of the present
organic photocatalytic system. The reactions of -
alkylstyrene derivatives (17a–17d) and methylidene
substrates (19a–19c) were relatively slow but afforded the
products 18a–18d and 20a–20c in moderate yields (55–
76%) after prolonged irradiation. Furthermore,
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functionalization of potentially bioactive alkenes such as
steroid and flavonoid was also possible (22: 30%, 24: 74%).
Notably, a CH2F group was successfully incorporated into
an anti-cancer drug, bexarotene (26: 45%). In addition to
the hydroxy-monofluoromethylation mentioned above,
methoxy- (27a: 75%) and dehydro-monofluoromethylation
(28a: 52%), and intramolecular monofluoromethylative
lactonization (30: 63%) were also achieved (Chart 1B) in
various solvents such as DCE, MeCN and DMSO.
Page 4 of 7
localized on the donor and acceptor moieties, respectively,
and thus their distributions are separated. The separated
orbital distributions of them might be connected to the
long-lived excited states (11: 4.3 s in DMA,16b 31: 250 ns in
THF18) but weaker absorption bands derived from
intramolecular CT and lower quantum yields of emission.
Furthermore, it is noteworthy that the photophysical
properties of 1 is not significantly affected by solvents
(Figure 1a). The difference between the emission maxima
(∆em) of 1 observed in toluene and DMSO is only 18 nm.
Additionally, 1 also maintains the excited state lifetime (
= 8–10 ns) and the quantum yield ( = 0.94–0.99) (see the
Supporting Information). In contrast, for organic
photocatalysts with the separated frontier orbital
distributions such as 11 and 31, large bathochromic shifts of
emission (∆em = 100–200 nm)16c,18 induced by solvents were
reported, which are associated with decrease of the
reducing power (E*ox).10
1
2
3
4
5
6
7
8
9
To obtain insights into the efficient catalytic ability of 1,
its photophysical and electrochemical properties were
examined (Figure 1a). Catalyst 1 (in acetone) shows an
absorption band extended to the visible region (abs = 375
nm) and a blue emission (em = 449 nm) with a very high
quantum yield of fluorescence ( = 0.99), whereas an
excited state lifetime of 1 is very short ( = 9 ns), indicating
that the photo-excited species with a nanosecond span of
lifetime causes efficient photoredox reaction. According to
DFT and TD-DFT calculations, the visible absorption band
is assigned to the HOMO–LUMO transition (Figure 1b).
The distributions of the HOMO and LUMO partially
overlap with each other. Delocalization of the HOMO over
the whole molecule are caused by interchromophoric
conjugation derived from the distorted (neither coplanar
nor orthogonal) arrangements around the amino group
with respect to the naphthalene core and phenyl groups.
These features of the orbitals arouse the efficient
intramolecular charge transfer (CT), leading to the
characteristic extension of the absorption band to the
visible region and the high quantum yield.9
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A cyclic voltammogram of 1 contains two reversible
redox waves. The first oxidation potential determined by
DPV analysis (Eox
= +0.36 V, see the Supporting
Information) is comparable to those of the previously
reported strongly reducing catalysts (9,10,19 1015b). The
reducing powers (E*ox vs. Cp2Fe) of 1 in the excited state in
various solvent are estimated as follows: –2.40 V (in
acetone), –2.41 V (in 1,2-dichloroethane), –2.35 V (in
acetonitrile), and –2.30 V (in DMSO).10 These preserved
strong reducing powers due to the insensitivity of the
emission to solvents mentioned above make
monofluoromethylation in various polar solvents
successful.
(a) UV-vis and fluorescence spectra.
Fluorescence quenching experiments revealed that 1*
was not quenched by alkene 13a but by 3 (see the
Supporting Information). Together with the result of the
radical trapping experiment by TEMPO (Table 1, entry 12),
the reductive ·CH2F radical generation from 3 should
trigger the reaction. In addition, from a result of the
quantum yield measurement of the reaction ( = 8%),
contribution of the radical chain mechanism in this
reaction turned out to be minor component (see the
Supporting Information). The high quantum yield of
fluorescence implies that a considerable amount of the
active excited species of 1 is allowed to take part in the
reaction. The combination of (i) the strong reducing power
caused by the high emission energy level and (ii) the high
fluorescent quantum yield of 1 may compensate its short
excited state lifetime.
Absorption
1
1
acetone
Emission
DMSO
MeCN
DCE
acetone
toluene
0.5
0.5
0
300
0
700
400
500
600
Wavelength (nm)
(b) Frontier orbitals & electronic transition around visible region
 = 339 nm
f = 0.3792
HOMO
LUMO
In conclusion, we have developed a strongly reducing
(95%)
photoredox
system
with
1,4-
HOMO
LUMO
bis(diphenylamino)naphthalene catalyst 1, which is easily
accessible and shelf-stable. The present system promotes
metal-free hydroxy-monofluoromethylation of alkenes
with the easy-to-handle sulfoximine-based CH2F reagent
under mild conditions, leading to facile synthesis of -
fluoroalcohols from alkenes. Moreover, extension to other
monofluoromethylation of alkenes is feasible due to the
retention of the high reducing power in various solvents.
The present work offers a new strategy for development of
Figure 1. Photophysical Data for 1. (a) UV-vis (in acetone) and
fluorescence spectra (in various solvents). (b) Frontier orbitals
& electronic transition calculated by DFT and TD-DFT
calculations.
In contrast, the HOMOs and LUMOs of the previously
reported strongly reducing organic photoredox catalysts
such as 11 and the carbazole derivative (31)18 are rather
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409–437. (i) Barata-Vallejo, S.; Cooke, M. V.; Postigo, A. Radical
visible light organic photocatalysts with high reducing
power but short excited state lifetime, which are useful for
reactions elusive by the conventional Ir photocatalyst.
Further development of reactions which require the higher
reducing power is currently under way in our laboratory.
Fluoroalkylation Reactions. ACS Catal. 2018, 8, 7287–7307. (j)
Song, H.-X. Han; Q.-Y.; Zhao C.-L.; Zhang, C.-P. Fluoroalkylation
Reactions in Aqueous Media: A Review. Green Chem. 2018, 20,
1662–1731.
1
2
3
4
5
6
7
8
9
(3) For selected reports on monofluoromethylation of
heteroatoms and carbon skeletons, see: (a) Zhang, W.; Zhu, L.;
Hu, J. Electrophilic monofluoromethylation of O-, S-, and N-
nucleophiles with chlorofluoromethane. Tetrahedron 2007, 63,
10569–10575. (b) Prakash, G. K. S.; Ledneczki, I.; Chacko, S.; Olah,
G. A. Direct Electrophilic Monofluoromethylation. Org. Lett.
2008, 10, 557–560. (c) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder,
E. D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herlé, B.; Sach,
N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Practical and Innate
Carbon–Hydrogen Functionalization of Heterocycles. Nature
2012, 492, 95–99. (d) Shen, X.; Zhou, M.; Ni, C.; Zhang, W.; Hu, J.
Direct Monofluoromethylation of O-, S-, N-, and P- Nucleophiles
with PhSO(NTs)CH2F: The Accelerating Effect of -Fluorine
Substitution. Chem. Sci. 2014, 5, 117–122. (e) Hu, J.; Gao, B.; Li, L.;
Ni, C.; Hu, J. Palladium-Catalyzed Monofluoromethylation of
Arylboronic Esters with Fluoromethyl Iodide. Org. Lett. 2015, 17,
3086–3089. (f) An, L.; Xiao, Y.-L.; Min, Q.-Q.; Zhang, X. Facile
Access to Fluoromethylated Arenes by Nickel-Catalyzed Cross-
Coupling between Arylboronic Acids and Fluoromethyl Bromide.
Angew. Chem. Int. Ed. 2015, 54, 9079–9083. (g) Rong, J.; Deng, L.;
Tan, P.; Ni, C.; Gu, Y.; Hu J. Radical Fluoroalkylation of
Isocyanides with Fluorinated Sulfones by Visible-Light
Photoredox Catalysis. Angew. Chem. Int. Ed. 2016, 55, 2743–2747.
(h) Fang, J.; Shen, W.-G.; Ao, G.-Z.; Liu, F. Transition-Metal-Free
Radical Fluoroalkylation of Isocyanides for the Synthesis of Tri-
/Di-/Monofluoromethylated Phenanthridines. Org. Chem. Front.
2017, 4, 2049–2053. (i) Liu, Y.; Lu, L.; Shen, Q. Monofluoromethyl-
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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Experimental procedures, characterization, crystallographic
data of 1, photo- and electro-chemical experiments, control
experiments, DFT calculations and H, 13C, and 19F NMR
1
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: koike.t.ad@m.titech.ac.jp.
*E-mail: makita@res.titech.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank the JSPS (KAKENHI Grants 22350026,
17J07953, JP16H06038, and JP18H04241 in Precisely Designed
Catalysts with Customized Scaffolding), JST CREST (Grant
Number JPMJCR18R4) and the Naito Foundation. This work
was performed under the Cooperative Research Program of
the “Network Joint Research Center for Materials and
Devices”. The authors credit Suzukakedai Materials Analysis
Division, Technical Department, Tokyo Institute of
Technology, and Prof. Masahisa Osawa, Nippon Institute of
Technology, for measurements and discussion of
photochemical phenomena.
Substituted
Sulfonium
Ylides:
Electrophilic
Monofluoromethylating Reagents with Broad Substrate Scopes.
Angew. Chem. Int. Ed. 2017, 56, 9930–9934. (j) Sheng, J. Ni, H.-Q.;
Zhang, H.-R.; Zhang, K.-F.; Wang, Y.-N.; Wang, X.-S. Nickel-
Catalyzed Reductive Cross-Coupling of Aryl Halides with
Monofluoroalkyl Halides for Late-Stage Monofluoroalkylation.
Angew. Chem. Int. Ed. 2018, 57, 7634–7639.
(4) For examples of monofluoromethylation of alkenes, see: (a)
Tang, X.-J.; Thomoson, C. S.; Dolbier Jr., W. R. Photoredox-
Catalyzed Tandem Radical Cyclization of N-Arylacrylamides:
General Methods to Construct Fluorinated 3,3-Disubstituted 2-
Oxindoles Using Fluoroalkylsulfonyl Chlorides. Org. Lett. 2014,
16, 4594–4597. (b) Tang, X.-J.; Dolbier Jr., W. R. Efficient Cu-
catalyzed Atom Transfer Radical Addition Reactions of
Fluoroalkylsulfonyl Chlorides with Electron-deficient Alkenes
Induced by Visible Light. Angew. Chem. Int. Ed. 2015, 54, 4246–
4249.
(5) (a) Yasu, Y.; Koike, T.; Akita, M. Three-component
Oxytrifluoromethylation of Alkenes: Highly Efficient and
Regioselective Difunctionalization of C=C Bonds Mediated by
Photoredox Catalysts. Angew. Chem., Int. Ed., 2012, 51, 9567–9571.
(b) Tomita, R.; Koike, T.; Akita, M. Photoredox-Catalyzed
Stereoselective Conversion of Alkynes into Tetrasubstituted
Trifluoromethylated Alkenes. Angew. Chem. Int. Ed. 2015, 54,
12923–12927. (c) Arai, Y.; Tomita, R.; Ando, G.; Koike, T.; Akita, M.
Oxydifluoromethylation of Alkenes by Photoredox Catalysis:
Simple Synthesis of CF2H-Containing Alcohols. Chem. Eur. J. 2016,
22, 1262–1265. (d) Koike, T.; Akita, M. Fine Design of Photoredox
Systems for Catalytic Fluoromethylation of Carbon − Carbon
Multiple Bonds. Acc. Chem. Res. 2016, 49, 1937–1945. (e) Noto, N.;
Koike, T.; Akita, M. Metal-free Di- and Tri-fluoromethylation of
Alkenes Realized by Visible-light-Induced Perylene Photoredox
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9
10
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(12) (a) Synthesis of 1 in different manners was recently
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Kawakami, H.; Yashita, A.; Kawai, K. (Gifu University, Japan;
Miyoshi Oil and Fat Co., Ltd.). Jpn. Kokai Tokkyo Koho
JP 2018127451 A 20180816, 2018. (b) CCDC 1880269 contains the
supplementary crystallographic data for 1. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(13) Shen, X.; Zhang, W.; Zhang, L.; Luo, T.; Wan, X.; Gu, Y.; Hu,
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Fluorinated Tertiary Stereogenic Carbon Centers: A Chiral -
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(19) The E*ox value of 9 (vs. Cp2Fe in acetone) was determined
to be –1.98 V on the basis of Eox = 0.40 V and em = 522 nm.
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