Metal-free direct C-H perfluoroalkylation of arenes and heteroarenes using a photoredox organocatalyst

Article abstract of DOI:10.1002/adsc.201300199

We report the visible-light-induced trifluoromethylation of arenes and heteroarenes using sodium trifluoromethanesulfinate catalyzed by anthraquinone-2-carboxylic acid. This reaction is a metal-free trifluoromethylation of arenes and heteroarenes catalyzed by a photoredox organocatalyst. Perfluoroalkylated arenes were also produced using sodium perfluoroalkylsulfinates.

Full text of DOI:10.1002/adsc.201300199

COMMUNICATIONS
DOI: 10.1002/adsc.201300199
À
Metal-Free Direct C H Perfluoroalkylation of Arenes and
Heteroarenes Using a Photoredox Organocatalyst
Lei Cui,a Yoko Matusaki,a Norihiro Tada,a Tsuyoshi Miura,a Bunji Uno,a
and Akichika Itoha,*
a
Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
Fax : (+81)-58-230-8108; phone: (+81)-58-230-8108; e-mail: itoha@gifu-pu.ac.jp
Received: March 7, 2013; Revised: June 12, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300199.
Abstract: We report the visible-light-induced tri-
fluoromethylation of arenes and heteroarenes using
sodium trifluoromethanesulfinate catalyzed by an-
thraquinone-2-carboxylic acid. This reaction is
a metal-free trifluoromethylation of arenes and het-
eroarenes catalyzed by a photoredox organocata-
lyst. Perfluoroalkylated arenes were also produced
using sodium perfluoroalkylsulfinates.
however, these methods do require transition metal
catalysts, stoichiometric reagents, highly reactive re-
agents, potentially explosive reagents, or harsh reac-
tion conditions [Scheme 1, Eq. (1)].
On the other hand, light is an important factor in
many reactions; therefore, it can be considered as
a type of reagent. Because this clean reagent exudes
no residues and has neither shape nor weight, it is an
important component in developing environmentally
benign processes. Consequently, photoinduced radical
trifluoromethylations have also been reported.[17] In
2011, MacMillanꢀs group showed an impressive direct
À
Keywords: C H activation; electron transfer; orga-
nocatalysis; photochemistry; radical reactions
trifluoromethylation through
mechanism using polypyridyl organometallic com-
plexes such as Ru(phen)3Cl2 as a photoredoxcatalyst
a
radical-mediated
AHCTUNGTRENNUNG
The introduction of a CF3 group can change the phys- and CF3SO2Cl as a source of the trifluoromethyl
ical properties of a compound, such as solubility and
lipophilicity, and gives the compound better mem-
brane permeability and increased bioavailability than
its non-fluorinated analogues.[1] Therefore, the devel-
opment of new methods for the synthesis of com-
pounds with a CF3 group is one of the most important
areas of research in organic synthesis. Thus, many
studies have been published that investigate various
methods of trifluoromethylation. Although cross-cou-
pling reactions catalyzed by transition metals have
been reliable methods for the synthesis of trifluoro-
methylated arenes, they require prefunctionalized
arenes incorporating halides, boronic acids, or direct-
ing groups.[2] Thus, the direct radical trifluoromethyla-
À
tion of arene C H moieties has received much atten-
tion,[3] and useful methods include CF3I/D,[4] CF3I/
FeSO4/H2O2/DMSO,[5] CF3Br/Na2S2O4,[6] (CF3)2Te,[7]
(CF3CO2)2,[8] CF3CO2H/XeF2,[9] CF3SO2Na/Cu
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
[15]
A
R
and CF3SiMe3/
ACHTUNGTRENNUNG
for the synthesis of trifluoromethylated compounds
because prefunctionalized substrates are not required; Scheme 1. Trifluoromethylation of arenes and heteroarenes.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Lei Cui et al.
COMMUNICATIONS
Table 1. Study of the reaction conditions.[a]
Entry
Solvent
Catalyst
Additive
Yield [%][b] (2-CF3, 4-CF3)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOAc
acetone
hexane
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
MB
9,10-DCA
Acid Red 94
AQN
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
AcOH
H2SO4
AlCl3
–
TFA
TFA
TFA
TFA
TFA
TFA
TFA
25 (8, 17)
61 (21, 40)
36 (11, 25)
73 (21, 52)
79 (25, 54)
46 (14, 32)
45 (15, 30)
0
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
–
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
AQN-2-CO2H
9
9 (3, 6)
10
11
12
13
14
15[c]
16[d]
17[e]
18[f]
19[g]
20[h]
60 (20, 40)
70 (21, 49)
56 (17, 39)
49 (15, 34)
0
0
0
43 (14, 29)
84 (28, 56)
71 (22, 49)
0
[a]
Reaction conditions: 1a (0.15 mmol), CF3SO2Na (4.0 equiv.), catalyst (0.05 equiv.), and additive (0.06 equiv.) in solvent
(3 mL) under an argon atmosphere were stirred and irradiated with four fluorescent lamps at room temperature.
Yields determined by H NMR.
The reaction was carried out in the dark.
Galvinoxyl (1 equiv.) was added.
The reaction was carried out for 10 h.
The reaction was carried out for 30 h.
The reaction was carried out with one fluorescent lamp for 30 h.
CF3SO2Cl was used instead of CF3SO2Na.
[b]
[c]
[d]
[e]
[f]
1
[g]
[h]
group under visible light irradiation at room tempera- ported.[19] In the course of our study with organopho-
ture. Notably, this reaction uses no potentially explo- tocatalysts,[20] we examined metal-free photoredox re-
sive oxidant [Scheme 1, Eq. (2)].[18a] However, to the actions and successfully found that using CF3SO2Na
best of our knowledge, the metal-free photoredox tri- as a source of the trifluoromethyl group and a catalytic
fluoromethylation of arenes and heteroarenes via a tri- amount of anthraquinone-2-carboxylic acid (AQN-2-
fluoromethyl radical intermediate has not been re- CO2H) allowed us to perform the direct trifluorome-
2
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

À
Metal-Free Direct C H Perfluoroalkylation of Arenes and Heteroarenes
thylation of arenes and heteroarenes under visible
light irradiation from a general-purpose fluorescent
lamp.
On the other hand, fluorous tag techniques have
been extensively developed in the field of organic
chemistry; however, methods for the introduction of
fluorous chain groups, such as perfluoroalkyl groups,
are limited on account of the specific reactivity of flu-
orous compounds.[21] Therefore, the development of
synthetic methods that can effectively introduce fluo-
rous groups is highly desirable. We now report the de-
tails of a trifluoromethylation and perfluoroalkylation
process catalyzed by a photoredox organocatalyst
[Scheme 1, Eq. (3)].
Table 1 shows the results of an investigation of the
reaction conditions for trifluoromethylation of 1,3-di-
methoxybenzene (1a) under visible light irradiation
from four fluorescent lamps. Among the typical pho-
tosensitizers and solvents examined (entries 1–9), we
determined AQN-2-CO2H[22] and acetonitrile to be
the most effective for this reaction (entry 5). In addi-
tion, acids accelerate the reaction rate (entries 5 and
10–13), and TFA is the most effective. However, we
cannot explain yet why the addition of TFA acceler-
ates the reaction rate. It is noted that light irradiation
and AQN-2-CO2H were necessary for this reaction
(entries 14 and 15). Since no product could be ob-
tained in the presence of galvinoxyl, we believe that
this reaction could proceed through a radical mecha-
nism (entry 16). In addition, we extended the reaction
time to 30 h, which gave the best result (entry 18).
When the number of fluorescent lamps was reduced
to one, 2a was also obtained in good yield (entry 19).
It was also noted that CF3SO2Cl was an inactive re-
agent under our conditions (entry 20).
Using the optimized reaction conditions for tri-
ACHTUNGTRENNUNGfluoromethylation, the scope and limitations of the re-
action were explored (Scheme 2). Electron-rich
arenes gave the corresponding products in good
yields (2a, 2b, 2c, 2d, 2e, 2f, and 2g). In addition,
some substituted heteroarenes were also obtained in
good yields (2h, 2i, and 2j). In contrast, we got trace
amounts of product when benzene was used as sub-
strate, and nitrobenzene did not react at all. For fur-
ther studies, we used various sodium perfluoroalkyl-
Scheme 2. Scope and limitations
sulfinates and found that pentafluoroethyl (C2F5) and reacted with 1e to give the corresponding products in
heptafluoropropyl (C3F7) groups could be substituted good to high yields (2m and 2n).
on 1,3,5-trimethoxybenzene in good yields (2k and
The experimental (Figure 1) results suggest the fol-
2l). Furthermore, C6F13SO2Na and C8F17SO2Na also lowing catalytic cycle, as shown in Scheme 3: the
Figure 1. Oxidation-reduction potential determined by cyclic voltammetry.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Lei Cui et al.
COMMUNICATIONS
Scheme 3. Plausible reaction mechanism.
ground and excited redox states of AQN, an electron- Experimental Section
transfer mediator, are important for the formation of
the electron deficient trifluoromethyl radical (CCF3), General Procedure
which functioned as an oxidant of the substrate and
TFA (0.06 equiv., 0.15M MeCN solution) was added to a so-
lution of substrate (0.15 mmol), CF3SO2Na (4 equiv.), AQN-
2-CO2H (0.05 equiv.) in MeCN (3 mL) in a Pyrex test tube.
The reaction mixture under an argon balloon was stirred
and irradiated externally with four of 22 W fluorescent
lamps for the indicated time. Then the solution was basified
with saturated aqueous NaHCO3 and brine, the product was
extracted with EtOAc and washed with brine, followed by
MgSO4 drying. The product was purified by PTLC.
an active species for the formation of trifluoromethy-
larenes. The photoinduced downhill electron transfer
À
from CF3SO2 to the excited state of AQN (AQN*) is
expected to efficiently generate CF3SO2C and AQNCÀ
radicals on the basis of their redox potentials. Facile
oxidation of AQNCÀ by SO2 produced by cleavage of
CF3SO2C regenerates the ground state of AQN. The
À
expectation that an electron from CF3SO2 is turned
over during the photocatalytic electron-transfer cycle
based solely on the driving force predicted by the
redox potentials. At this stage, no detailed mechanis-
tic data on the two-fold reaction of an arene with CCF3
are available, but it is rationally considered that
a likely reaction pathway includes the radical addition
of CCF3 to an electron-rich position of the aromatic
ring, which is followed by oxidation of the generated
radical 3 to cation 4 by CCF3 followed by deprotona-
tion.[23] The later reaction may be considered as a hy-
drogen abstraction reaction of 3 by CCF3 rather than
an electron-transfer reaction facilitated by proton
transfer, as is shown in Scheme 3. At present we are
not able to differentiate between these two possibili-
ties.
In conclusion, we have developed a convenient
photoredox-based method for the direct trifluorome-
thylation of arenes and heteroarenes using an organo-
catalyst. This method is a metal-free, direct trifluoro-
methylation using a photoredox-based process under
visible light irradiation. Furthermore, perfluoroalky-
lated arenes can also be effectively obtained under
similar conditions. Therefore, this method is of great
value from both green chemistry and organic synthe-
sis perspectives because of its use of visible light irra-
diation and its application to the design and synthesis
of compounds with trifluoromethyl groups and fluo-
rous tags.
Acknowledgements
This work was supported by Grant-in-Aid for Young Scien-
tists (B)(No. 24790015) from the Japan Society for the Pro-
motion of Science (JSPS).
References
[1] K. Mꢂller, C. Faeh, F. Diederich, Science 2007, 317,
1881–1886.
[2] a) S. Roy, B. T. Gregg, G. W. Gribble, V.-D. Le, Tetrahe-
dron 2011, 67, 2161–2195; b) O. A. Tomashenko, V. V.
Grushin, Chem. Rev. 2011, 111, 4475–4521; c) T.
Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470–
477; d) T. Besset, C. Schneider, D. Cahard, Angew.
Chem. 2012, 124, 5134–5136; Angew. Chem. Int. Ed.
2012, 51, 5048–5050; e) T. Umemoto, A. Ando, Bull.
Chem. Soc. Jpn. 1986, 59, 447–452; f) X. Wang, L.
Truesdale, J. Yu, J. Am. Chem. Soc. 2010, 132, 3648–
3649; g) M. Oishi, H. Kondo, H. Amii, Chem.
Commun. 2009, 1909–1911; h) E. J. Cho, Science 2010,
328, 1679–1681; i) J. Xu, Chem. Commun. 2011, 47,
4300–4302.
[3] For reviews, see: a) A. Studer, Angew. Chem. 2012,
124, 9082–9090; Angew. Chem. Int. Ed. 2012, 51, 8950–
8958; b) H. Liu, Z. Gu, X. Jiang, Adv. Synth. Catal.
2013, 355, 617–626.
[4] a) G. V. D. Tiers, J. Am. Chem. Soc. 1960, 82, 5513–
5513; b) E. S. Huyser, E. Bedard, J. Org. Chem. 1964,
29, 1588–1890; c) A. B. Cowell, C. Tamborski, J. Fluo-
rine Chem. 1981, 17, 345–356.
4
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

À
Metal-Free Direct C H Perfluoroalkylation of Arenes and Heteroarenes
[5] T. Kino, Y. Nagase, Y. Ohtsuka, K. Yamamoto, D. Ura-
guchi, K. Tokuhisa, T. Yamakawa, J. Fluorine Chem.
2010, 131, 98–105.
[16] X. Wu, L. Chu, F.-L. Qing, Tetrahedron Lett. 2013, 54,
249–251.
[17] a) J. M. Birchall, G. P. Irvin, R. A. Boyson, J. Chem.
Soc. Perkin Trans. 2 1975, 435–439; b) C. Lai, T. E. Mal-
louk, J. Chem. Soc. Chem. Commun. 1993, 1359–1361.
[18] a) D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480,
224–228; b) N. Iqbal, S. Choi, E. Ko, E. J. Cho, Tetrahe-
dron Lett. 2012, 53, 2005–2008.
[19] Metal-free photoredox trifluoromethylation of tetrahy-
droisoquinoline using rose bengal have been reported,
see: W. Fu, W. Guo, G. Zou, C. Xu, J. Fluorine Chem.
2012, 140, 88–94.
[20] a) N. Tada, K. Hattori, T. Nobuta, T. Miura, A. Itoh,
Green Chem. 2011, 13, 1669–1671; b) L. Cui, N. Tada,
H. Okubo, T. Miura, A. Itoh, Green Chem. 2011, 13,
2347–2350; c) Y. Matsusaki, T. Yamaguchi, N. Tada, T.
Miura, A. Itoh, Synlett 2012, 2059–2062; d) N. Tada, Y.
Ikebata, T. Nobuta, S. Hirashima, T. Miura, A. Itoh,
Photochem. Photobiol. Sci. 2012, 11, 616–619.
[21] For a review on the fluorous tag technique, see: a) D. P.
Curran, Synlett 2001, 1488–1496; b) D. P. Curran, in:
The Handbook of Fluorous Chemistry, (Eds.: J. A. Gla-
dysz, I. T. Horvꢄth, D. P. Curran), Wiley-VCH, Wein-
heim, 2004; c) W. Thang, D. P. Curran, Tetrahedron
2006, 62, 11837–11865; d) W. Zhang, C. Cai, Chem.
Commun. 2008, 5686–5694.
[6] M. Tordeux, B. Langlois, C. Wakselman, J. Chem. Soc.
Perkin Trans. 1 1990, 2293–2299.
[7] a) D. Nalumann, B. Wilkes, J. Kischkewitz, J. Fluorine
Chem. 1985, 30, 73–87; b) D. Nalumann, J. Kischkewitz,
J. Fluorine Chem. 1990, 47, 283–299; c) D. Nalumann, J.
Kischkewitz, J. Fluorine Chem. 1990, 46, 265–281.
[8] a) H. Sawada, M. Nakayama, M. Yoshida, T. Yoshida,
N. Kamigata, J. Fluorine Chem. 1990, 46, 423–431;
b) M. Yoshida, T. Yoshida, M. Kobayashi, N. Kamigata,
J. Chem. Soc. Perkin Trans. 1 1989, 909–914.
[9] Y. Tanabe, N. Matsuo, N. Ohno, J. Org. Chem. 1988, 53,
4582–4585.
[10] B. R. Langlois, E. Laurent, N. Roidot, Tetrahedron Lett.
1991, 32, 7525–7528.
[11] Y. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple,
S. Su, D. G. Blackmond, P. S. Baran, Proc. Natl. Acad.
Sci. USA 2011, 108, 14411–14415.
[12] Y. Fujiwara, J. A. Dixon, F. OꢀHara, E. D. Funder,
D. D. Dixon, R. A. Rodoriguez, R. D. Baxter, B. Herlꢃ,
N. Sach, M. R. Collins, Y. Ishihara, P. S. Baran, Nature
2012, 492, 95–100.
[13] a) N. Kamigata, T. Fukushima, M. Yoshida, Chem. Lett.
1990, 649–650; b) N. Kamigata, T. Ohtsuka, T. Fukushi-
ma, M. Yoshida, T. Shimizu, J. Chem. Soc. Perkin
Trans. 1 1994, 1339–1346.
[22] Anthraquinone-2-carboxylic acid absorbs light with
wavelengths shorter than 450 nm.
[23] Unfortunately, CF3H was not detected by H NMR and
[14] Y. Ye, S. H. Lee, M. S. Sanford, Org. Lett. 2011, 13,
1
5464–5467.
GC-MS probably because of its low boiling point.
[15] E. Mejia, A. Togni, ACS Nano 2012, 2, 521–527.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
À
6 Metal-Free Direct C H Perfluoroalkylation of Arenes and
Heteroarenes Using a Photoredox Organocatalyst
Adv. Synth. Catal. 2013, 355, 1 – 6
Lei Cui, Yoko Matusaki, Norihiro Tada, Tsuyoshi Miura,
Bunji Uno, Akichika Itoh*
6
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!