Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF2H-Containing Alcohols

Article abstract of DOI:10.1002/chem.201504838

We have developed a novel and simple protocol for the direct incorporation of a difluoromethyl (CF₂H) group into alkenes by visible-light-driven photoredox catalysis. The use of fac-[Ir(ppy)₃] (ppy=2-pyridylphenyl) photocatalyst and shelf-stable Hu's reagent, N-tosyl-S-difluoromethyl-S-phenylsulfoximine, as a CF₂H source is the key to success. The well-designed photoredox system achieves synthesis of not only β-CF₂H-substituted alcohols but also ethers and an ester from alkenes through solvolytic processes. The present method allows a single-step and regioselective formation of C(sp³)-CF₂H and C(sp³)-O bonds from C=C moiety in alkenes, such as hydroxydifluoromethylation, regardless of terminal or internal alkenes. Moreover, this methodology tolerates a variety of functional groups. Light up the bulb! A novel and simple protocol for the direct incorporation of a difluoromethyl (CF₂H) group into alkenes by visible-light-driven photoredox catalysis has been developed (see scheme). An Ir photocatalyst is useful for the generation of a CF₂H radical through one-electron reduction of Hu's reagent. The present reaction system produces not only various β-CF₂H-substituted alcohols, but also ethers and esters in regiospecific manners under mild conditions.

Full text of DOI:10.1002/chem.201504838

DOI: 10.1002/chem.201504838
Communication
&
Photocatalysis
Oxydifluoromethylation of Alkenes by Photoredox Catalysis:
Simple Synthesis of CF2H-Containing Alcohols
Yusuke Arai, Ren Tomita, Gaku Ando, Takashi Koike,* and Munetaka Akita*[a]
Abstract: We have developed a novel and simple protocol
for the direct incorporation of a difluoromethyl (CF2H)
group into alkenes by visible-light-driven photoredox cat-
alysis. The use of fac-[Ir(ppy)3] (ppy=2-pyridylphenyl) pho-
tocatalyst and shelf-stable Hu’s reagent, N-tosyl-S-difluoro-
methyl-S-phenylsulfoximine, as a CF2H source is the key to
success. The well-designed photoredox system achieves
synthesis of not only b-CF2H-substituted alcohols but also
ethers and an ester from alkenes through solvolytic pro-
cesses. The present method allows a single-step and re-
gioselective formation of C(sp3)–CF2H and C(sp3)ÀO bonds
from C=C moiety in alkenes, such as hydroxydifluorome-
thylation, regardless of terminal or internal alkenes. More-
over, this methodology tolerates a variety of functional
groups.
Scheme 1. Direct difluoromethylation of alkenes for the construction of
C(sp3)–CF2H bond.
Organofluorine compounds continue to increase in importance
in the fields of pharmaceuticals, agrochemicals and functional
materials, because installation of fluorine atoms frequently in-
fluences the medicinal action as well as the chemical and phys-
ical properties.[1] Thus, considerable research efforts have been
made so far towards the development of new methodologies
for the selective incorporation of fluorine atoms or fluoroalkyl
groups. There have been great advances in catalytic methods
for the fluorination and trifluoromethylation in the past few
years.[2,3] In contrast, simple and widely applicable introduction
of a difluoromethyl (CF2H) group to various carbon skeletons is
still underdeveloped,[4] even though the CF2H group is an intri-
guing structural motif, especially in medicinal chemistry.[5,6] In
the past decade, multistep strategies for the preparation of
CF2H-containing compounds, that is, incorporation of a di-
fluoroalkyl unit (CF2-PG: PG=a protective group) into the
carbon skeletons followed by deprotection, have been well-de-
veloped. However, a direct difluoromethylation is still highly
desir-
able.[5,7]
Alkenes are fundamental carbon feedstock and functionality,
but the direct difluoromethylation of alkenes has been limit-
ed.[8] In 1994, Chen and co-workers reported a radical iododi-
fluoromethylation using CF2HI, which is a gaseous and hard to
prepare reagent (Scheme 1a).[8a] More recently, Dolbier and co-
workers exploited CF2HSO2Cl as a difluoromethyl radical source
and developed alkene difluoromethylation, for example,
chloro-, carbo- and aminodifluoromethylation (Scheme 1b).[8b–e]
Furthermore, the groups of Tan and Hu developed a silver-cat-
alyzed intramolecular carbodifluoromethylation with difluoro-
methylsulfinate salts, (CF2HSO2)nM, such as (CF2HSO2)2Zn and
CF2HSO2Na (Scheme 1c).[8f,g]
For the past several years, our group has been extensively
developing a photoredox-catalyzed trifluoromethylative difunc-
tionalization[9,10] of alkenes and alkynes using electrophilic tri-
fluoromethylating reagents, such as Umemoto’s[11] and Togni’s
reagent.[12] We envisaged that the appropriate choice of a di-
fluoromethylating reagent could open an unprecedented pho-
toredox-catalyzed difluoromethylation of alkenes. Herein, we
describe the first example of a photocatalytic oxydifluorome-
thylation of alkenes with shelf-stable and easy-to-handle N-
tosyl-S-difluoromethyl-S-phenylsulfoximine (1a), so-called Hu’s
reagent, which has been previously reported to be a useful di-
fluorocarbene source by Hu and co-workers (Scheme 1d).[13,14]
[a] Y. Arai, R. Tomita, G. Ando, Dr. T. Koike, Prof. Dr. M. Akita
Chemical Resources Laboratory
Tokyo Institute of Technology
R1-27, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503 (Japan)
E-mail: koike.t.ad@m.titech.ac.jp
makita@res.titech.ac.jp
Supporting information and ORCIDs from the authors for this article are
available on the WWW under http://dx.doi.org/10.1002/chem.201504838.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of Creative Commons Attri-
bution NonCommercial License, which permits use, distribution and repro-
duction in any medium, provided the original work is properly cited and is
not used for commercial purposes.
Chem. Eur. J. 2016, 22, 1262 – 1265
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Communication
Table 1. Optimization of the photocatalytic hydroxydifluoromethylation
of 4-methylstyrene (2a).[a]
Table 2. Scope of the photocatalytic hydroxydifluoromethylation.[a]
3a: 67%[b,c]
3b: 65%
3e: 50%
3c: 72%[b,d]
Entry
Photocatalyst
CF2H reagent 1
Yield of 3a [%][b]
3d: 83%[b,d]
3 f: 73%[e]
1
2
3
4
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
[Ru(bpy)3][PF6]2
[Ir(ppy)2(dtbbpy)][PF6]
fac-[Ir(ppy)3]
none
1b
1c
1a
1a
1a
1a
1a
0
29
88
0
0
0
5
6[c]
7
3g: 84%
3j: 88%[f]
3h: 56%
3i: 64%
0
[a] For detailed reaction conditions, see the Supporting Information.
[b] Yields were determined by H NMR spectroscopy using Si(Et)4 as an in-
ternal standard. [c] In the dark. LED=light-emitting diode.
1
3k: 87%[e,g]
3l: 32%[g]
This protocol allows us simple and versatile access to a wide
range of CF2H alcohols through regioselective installation of
the CF2H group and an oxygen nucleophile onto alkenes.
We initially explored CF2H reagent 1 for the photocatalytic
hydroxydifluoromethylation of 4-methylstyrene (2a) at room
temperature under visible-light irradiation with blue LEDs
(lmax =425 nm; Table 1). Taking account of the reaction condi-
tions of the photocatalytic hydroxytrifluoromethylation report-
ed by us,[10a] we conducted the reaction in a mixed solvent
system of [D6]acetone and D2O (9:1) in the presence of fac-
[Ir(ppy)3] (ppy=2-pyridylphenyl) (5 mol%), which serves as
a strong reducing agent when photoexcited (E1/2 =À2.14 V
versus. [Cp2Fe]).[15] Under these reaction conditions, sulfone-
based commercially available CF2H reagents, CF2HSO2Ph (1b)
and CF2HSO2Py (1c; Py=2-pyridyl), were tested (entries 1 and
2). Reagent 1b was scarcely converted. In contrast, 1c gave
the corresponding CF2H alcohol 3a in 29% NMR yield together
with a mixture of unidentified products. Encouraged by these
results, we continued to examine the analogous CF2H reagent
(sulfoximine-based CF2H reagent 1a).[16] To our delight,
3m: 43%, 1:1.2 d.r.[d,g]
3p: 67%, 1:1.3 d.r.
3n: 53%, 1:3.3 d.r.[g]
3o: 64%, 1:1.6 d.r.
3q: 63%, 1:3.3 d.r.[d,e,g] 3r: 43%, 1:1.1 d.r.[d,e,g]
[a] For detailed reaction conditions, see the Supporting Information; dia-
stereomer ratios (d.r.) were determined by 1H NMR spectra of crude reac-
tion mixtures; yields were obtained after purification. [b] Ir photocatalyst
(0.5 mol%) was used. [c] Reaction time=2 h. [d] The ratio of 2 and 1a
was 1.5:1; yields were calculated on the basis of starting 1a. [e] Ir photo-
catalyst (5 mol%) was used. [f] Reaction time=72 h. [g] Reaction time=
36 h.
duced the corresponding CF2H-containing alcohols (3a–i) in
good yields (50–84%, 2–24 h). In contrast, the reaction of sty-
rene with an electron-donating group on the benzene ring, 4-
methoxystyrene (2j), required longer time, but the correspond-
ing product 3j was obtained in good yield (88%, 72 h). In ad-
dition, a-methylstyrene (2k) and the aliphatic alkene, 1,1-dicy-
clohexylethene (2l), were also successfully applied to the pres-
ent photocatalytic reaction, leading to the corresponding CF2H
alcohols (3k, l) in 87 and 32% yields, respectively.
Furthermore, the present photocatalytic system enables the
difluoromethylation of internal alkenes, including a trisubstitut-
ed alkene. Reactions of b-methylstyrene (2m), trans-stilbene
(2n), indene (2o), trans-cinnamyl alcohol (2p), trans-cinnamic
acid methyl ester (2q), and a,b-dimethylstyrene (2r; E/Z=
1:5.6) afforded the corresponding difluoromethylated products
(3m–r) in 43–67% yields as sole regioisomers but mixtures of
diastereomers. It should be noted that the present photocata-
lytic system with Hu’s reagent 1a is compatible for a wide vari-
hydroxydifluoromethylation proceeded in
a regioselective
manner to afford 3,3-difluoro-1-tolylpropanol (3a) as a sole re-
gioisomer in 88% NMR yield (entry 3). Next, the examination
of typical photocatalysts revealed that fac-[Ir(ppy)3] was the
best catalyst (entries 3–5).[15] Finally, the present photocatalytic
reaction did not proceed at all either in the dark or in the ab-
sence of photocatalyst (entries 6 and 7), indicating that photo-
activated species is involved in the present transformation.
The scope of the present photocatalytic hydroxydifluorome-
thylation of alkenes is summarized in Table 2. Styrenes with
various functional groups on the benzene ring, such as alkyls
(2a, b), halogens (2d–f), Boc-protected amino (2g), boronic
acid ester (2h), and cyanomethyl (2i) groups, smoothly pro-
Chem. Eur. J. 2016, 22, 1262 – 1265
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Communication
ety of functionalities, such as hydroxyl, N-protected amino, hal-
ogens, nitrile, ester, and boronic acid ester groups. Moreover
a regiospecific addition of the CF2H and OH groups, regardless
of terminal or internal alkenes, is particularly significant. These
results prompted us to investigate reactions of more structural-
ly complex substrates. It was found that the present reaction
system was amenable to the hydroxydifluoromethylation of vi-
nylestrone (2s) and vinyl-N-benzoyl-l-tyrosine ethyl ester (2t),
leading to the corresponding difluoromethylated alcohols (3s:
61%; 3t: 73%; Scheme 2). These results suggest that the pres-
ent protocol would be valuable for the late-stage difluorome-
tively. Carboxylic acid substrate 4c produced CF2H-containing
ester 5c in 54% yield.
To gain insight into the reaction mechanism, the reaction of
1-phenyl-2-(1-phenylethenyl)cyclopropane (2u) was examined
(Scheme 4). As a result, the difluoromethylated alcohol 3u was
obtained in 83% yield (E/Z=1:2.3) through a ring-opening pro-
cess of the cyclopropane unit. In addition, when photocatalytic
hydroxydifluoromethylation of 2a was conducted in the pres-
ence of 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO), which
is a radical scavenger, the hydroxydifluoromethylation was
completely inhibited (See the Supporting Information for de-
tails). These results suggest that radical intermediates are in-
volved in the present photocatalytic reaction.
Scheme 2. Direct difluoromethylation of alkenes with estrone and amino
acid skeleton.
Scheme 5. A plausible reaction mechanism.
On the basis of these observations and our previous re-
ports,[10] a plausible reaction mechanism is shown in Scheme 5.
First, the photocatalyst IrIII is excited by visible light to give the
excited species *IrIII. The formed excited species *IrIII serves as
a strong one-electron reductant to undergo single-electron
transfer (SET) to Hu’s reagent 1a, leading to generation of the
highly oxidized species IrIV. Reduced 1a fragmentizes into the
CF2H radical and sulfinamide 6. The generated CF2H radical
reacts with alkene 2 in a regioselective manner to afford the
stabilized radical intermediate 7, which is then oxidized by the
strongly oxidizing species IrIV to generate a-CF2H carbocationic
intermediate 8 together with regeneration of the photocatalyst
IrIII of the ground state. Finally, the carbocationic intermediate
8 undergoes solvolysis by ROH to produce oxydifluoromethy-
lated products 3 or 5.
In conclusion, we have developed a novel photoredox-cata-
lyzed oxydifluoromethylation of alkenes. The present work is
the first report to use Hu’s reagent, N-tosyl-S-difluoromethyl-S-
phenylsulfoximine (1a), as a CF2H radical precursor. Visible-
light-driven photoredox catalysis by the Ir photocatalyst, fac-
[Ir(ppy)3], has opened a new possibility of radical difluorome-
thylation by the difluorocarbene source 1a. The designed
redox-neutral reaction system enables step-economical synthe-
sis of b-CF2H-substituted alcohols, ethers, and esters under
mild reaction conditions. Remarkably, the present photocatalyt-
ic difluoromethylation system exhibits excellent functional
group compatibility. A development of new synthetic methods
for organofluorine compounds through a photoredox-cata-
lyzed fluoroalkylation is currently underway in our laboratory.
Scheme 3. Oxydifluoromethylation of 4-methylstyrene (2a): simple synthesis
of CF2H ester and CF2H ethers.
thylation in a synthetic process.
Next, we examined other oxygen nucleophiles, ROH (4),
such as alcohols and carboxylic acids, for the reaction of 4-
methylstyrene (2a; Scheme 3). All reactions were conducted in
dry CH2Cl2/ROH (9:1). It turned out that the alkoxydifluorome-
thylation and carboxydifluoromethylation smoothly proceeded
regioselectively not only to introduce a CF2H group but also to
construct ether and ester functionalities onto the C=C bond.
Reactions with MeOH (4a) and tBuOH (4b) gave the corre-
sponding CF2H ethers 5a and 5b in 69 and 54% yields, respec-
Scheme 4. Photocatalytic hydroxydifluoromethylation of 1-phenyl-2-(1-phe-
nylethenyl)cyclopropane (2u).
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Communication
Int. Ed. 2005, 44, 5882–5886; Angew. Chem. 2005, 117, 6032–6036; c) C.
Ni, J. Liu, L. Zhang, J. Hu, Angew. Chem. Int. Ed. 2007, 46, 786–789;
Angew. Chem. 2007, 119, 800–803; d) J. Liu, C. Ni, F. Wang, J. Hu, Tetra-
hedron Lett. 2008, 49, 1605–1608; e) K. Fujikawa, Y. Fujioka, A. Kobaya-
shi, H. Amii, Org. Lett. 2011, 13, 5560–5563; f) Z. He, M. Hu, T. Luo, L. Li,
J. Hu, Angew. Chem. Int. Ed. 2012, 51, 11545–11547; Angew. Chem.
2012, 124, 11713–11715; g) K. Fujikawa, A. Kobayashi, H. Amii, Synthesis
2012, 44, 3015–3018; h) X. Wang, G. Liu, X.-H. Xu, N. Shibata, E. Tokuna-
ga, N. Shibata, Angew. Chem. Int. Ed. 2014, 53, 1827–1831; Angew.
Chem. 2014, 126, 1858–1862; i) C. Yu, N. Iqbal, S. Park, E. J. Cho, Chem.
Commun. 2014, 50, 12884–12887; j) J. Jung, E. Kim, Y. You, E. J. Cho,
Adv. Synth. Catal. 2014, 356, 2741–2748; k) X. Sun, S. Yu, Org. Lett.
2014, 16, 2938–2941; l) R. Hashimoto, T. Iida, K. Aikawa, S. Ito, K.
Mikami, Chem. Eur. J. 2014, 20, 2750–2754; m) X. Shen, Q. Liu, T. Luo, J.
Hu, Chem. Eur. J. 2014, 20, 6795–6800; n) J.-Y. Wang, Y.-M. Su, F. Yin, Y.
Bao, X. Zhang, Y.-M. Xu, X.-S. Wang, Chem. Commun. 2014, 50, 4108–
4111; o) M.-C. Belhomme, T. Poisson, X. Pannecoucke, J. Org. Chem.
2014, 79, 7205–7211; p) P. Salomon, S. Z. Zard, Org. Lett. 2014, 16,
2926–2929; q) W. Fu, M. Zhu, G. Zou, C. Xu, Z. Wang, B. Ji, J. Org. Chem.
2015, 80, 4766–4770; r) C. Qu, P. Xu, W. Ma, Y. Cheng, C. Zhu, Chem.
Commun. 2015, 51, 13508–13510; s) C. Won, S. Dae, Y. Kim, Tetrahedron
Lett. 2015, 56, 5661–5664.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
(26288045, 15K13689, and 15J12072) and the Naito Founda-
tion.
Keywords: alcohols
· fluorine · homogeneous catalysis ·
iridium · photochemistry
[1] a) T. Hiyama, Organofluorine Compounds: Chemistry and Applications,
Springer, Berlin (Germany), 2000; b) K. Müller, C. Faeh, F. Diederich, Sci-
ence 2007, 317, 1881–1886; c) W. K. Hagmann, J. Med. Chem. 2008, 51,
4359–4369; d) Fluorine in Medicinal Chemistry and Chemical Biology
(Eds.: I. Ojima), Wiley-Blackwell, Chichester (UK), 2009; e) P. Kirsch,
Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim (Germany), 2013.
[2] For recent reviews on synthesis of organofluorine compounds, see:
a) C. Hollingworth, V. Gouverneur, Chem. Commun. 2012, 48, 2929–
2942; b) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 2013,
52, 8214–8264; Angew. Chem. 2013, 125, 8372–8423; c) T. Besset, T.
Poisson, X. Pannecoucke, Chem. Eur. J. 2014, 20, 16830–16845; d) C. Ni,
M. Hu, J. Hu, Chem. Rev. 2015, 115, 765–825.
[3] For recent reviews on trifluoromethylation, see: a) J. Nie, H.-C. Guo, D.
Cahard, J.-A. Ma, Chem. Rev. 2011, 111, 455–529; b) O. A. Tomashenko,
V. V. Grushin, Chem. Rev. 2011, 111, 4475–4521; c) A. Studer, Angew.
Chem. Int. Ed. 2012, 51, 8950–8958; Angew. Chem. 2012, 124, 9082–
9090; d) H. Liu, Z. Gu, X. Jiang, Adv. Synth. Catal. 2013, 355, 617–626;
e) T. Koike, M. Akita, J. Fluorine Chem. 2014, 167, 30–36; f) J. Xu, X. Liu,
Y. Fu, Tetrahedron Lett. 2014, 55, 585–594; g) H. Egami, M. Sodeoka,
Angew. Chem. Int. Ed. 2014, 53, 8294–8308; Angew. Chem. 2014, 126,
8434–8449; h) S. Barata-Vallejo, B. LantaÇo, A. Postigo, Chem. Eur. J.
2014, 20, 16806–16829; i) T. Koike, M. Akita, Top. Catal. 2014, 57, 967–
974; j) E. Merino, C. Nevado, Chem. Rev. Soc. 2014, 43, 6598–6608; k) X.
Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev. 2015, 115, 683–730; l) C. Alonso,
E. M. de Marigorta, G. Rubiales, F. Palacios, Chem. Rev. 2015, 115, 1847–
1935; m) P. Gao, X.-R. Song, X.-Y. Liu, Y.-M. Liang, Chem. Eur. J. 2015, 21,
7648–7661.
[4] For direct difluoromethylation with TMSCF2H, (CF2HSO2)2Zn and others,
see: a) Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D. Dixon,
M. R. Collins, D. G. Blackmond, P. S. Baran, J. Am. Chem. Soc. 2012, 134,
1494–1497; b) Y. Fujiwara, J. A. Dixon, F. O’Hara, E. D. Funder, D. D.
Dixon, R. A. Rodriguez, R. D. Baxter, B. HerlØ, N. Sach, M. R. Collins, Y. Ish-
ihara, P. S. Baran, Nature 2012, 492, 95–99; c) P. S. Fier, J. F. Hartwig, J.
Am. Chem. Soc. 2012, 134, 5524–5527; d) G. K. S. Prakash, S. K. Ganesh,
J.-P. Jones, A. Kulkarni, K. Masood, J. K. Swabeck, G. A. Olah, Angew.
Chem. Int. Ed. 2012, 51, 12090–12094; Angew. Chem. 2012, 124, 12256–
12260; e) T. Iida, R. Hashimoto, K. Aikawa, S. Ito, K. Mikami, Angew.
Chem. Int. Ed. 2012, 51, 9535–9538; Angew. Chem. 2012, 124, 9673–
9676; f) Z. Li, Z. Cui, Z.-Q. Liu, Org. Lett. 2013, 15, 406–409; g) C. Math-
eis, K. Jouvin, L. J. Goossen, Org. Lett. 2014, 16, 5984–5987; h) X.-L.
Jiang, Z.-H. Chen, X.-H. Xu, F.-L. Qing, Org. Chem. Front. 2014, 1, 774–
776; i) V. V. Levin, A. L. Trifonov, A. A. Zemtsov, M. I. Struchkova, D. E. Ar-
khipov, A. D. Dilman, Org. Lett. 2014, 16, 6256–6259.
[8] a) P. Cao, J.-X. Duan, Q.-Y. Chen, J. Chem. Soc. Chem. Commun. 1994,
737–738; b) X.-J. Tang, C. S. Thomoson, W. R. Dolbier Jr., Org. Lett. 2014,
16, 4594–4597; c) C. S. Thomoson, X.-J. Tang, W. R. Dolbier, Jr. , J. Org.
Chem. 2015, 80, 1264–1268; d) X.-J. Tang, W. R. Dolbier, Jr. , Angew.
Chem. Int. Ed. 2015, 54, 4246–4249; Angew. Chem. 2015, 127, 4320–
4323; e) Z. Zhang, X. Tang, C. S. Thomoson, W. R. Dolbier Jr. , Org. Lett.
2015, 17, 3528–3531; f) J. Liu, S. Zhuang, Q. Gui, X. Chen, Z. Yang, Z.
Tan, Eur. J. Org. Chem. 2014, 3196–3202; g) Z. He, P. Tan, C. Ni, J. Hu,
Org. Lett. 2015, 17, 1838–1841.
[9] For selected reviews on photoredox catalysis, see: a) T. P. Yoon, M. A.
Ischay, J. Du, Nat. Chem. 2010, 2, 527–532; b) J. M. R. Narayanam,
C. R. J. Stephenson, Chem. Soc. Rev. 2011, 40, 102–113; c) J. Xuan, W.-J.
Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828–6838; Angew. Chem. 2012,
124, 6934–6944; d) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem.
Rev. 2013, 113, 5322–5363; e) D. P. Hari, B. Kçnig, Angew. Chem. Int. Ed.
2013, 52, 4734–4743; Angew. Chem. 2013, 125, 4832–4842; f) T. Koike,
M. Akita, Inorg. Chem. Front. 2014, 1, 562–576; g) M.-Y. Cao, X. Ren, Z.
Lu, Tetrahedron Lett. 2015, 56, 3732–3742.
[10] a) Y. Yasu, T. Koike, M. Akita, Angew. Chem. Int. Ed. 2012, 51, 9567–9571;
Angew. Chem. 2012, 124, 9705–9709; b) T. Koike, M. Akita, Synlett 2013,
24, 2492–2505; c) Y. Yasu, T. Koike, M. Akita, Org. Lett. 2013, 15, 2136–
2139; d) Y. Yasu, Y. Arai, R. Tomita, T. Koike, M. Akita, Org. Lett. 2014, 16,
780–783; e) R. Tomita, Y. Yasu, T. Koike, M. Akita, Angew. Chem. Int. Ed.
2014, 53, 7144–7148; Angew. Chem. 2014, 126, 7272–7276; f) N. Noto,
K. Miyazawa, T. Koike, M. Akita, Org. Lett. 2015, 17, 3710–3713; g) R.
Tomita, T. Koike, M. Akita, Angew. Chem. Int. Ed. 2015, 54, 12923–12927;
Angew. Chem. 2015, 127, 13115–13119.
[11] T. Umemoto, Chem. Rev. 1996, 96, 1757–1777.
[12] J. Charpentier, N. Früh, A. Togni, Chem. Rev. 2015, 115, 650–682.
[13] a) W. Zhang, F. Wang, J. Hu, Org. Lett. 2009, 11, 2109–2112; b) V. Bizet,
R. Kowalczyk, C. Bolm, Chem. Soc. Rev. 2014, 43, 2426–2438.
[14] The group of Hu reported that the corresponding CFH2 reagent, N-
tosyl-S-fluoromethyl-S-phenylsulfoximine, serves as a monofluoromethyl
radical precursor, for details see: X. Shen, M. Zhou, C. Ni, W. Zhang, J.
Hu, Chem. Sci. 2014, 5, 117–122.
[5] a) G. K. S. Prakash, J. Hu, Acc. Chem. Res. 2007, 40, 921–930; b) J. Hu, W.
Zhang, F. Wang, Chem. Commun. 2009, 7465–7478; c) C. Ni, J. Hu, Syn-
thesis 2014, 46, 842–863; d) M.-C. Belhomme, T. Besset, T. Poisson, X.
Pannecoucke, Chem. Eur. J. 2015, 21, 12836–12865; e) T. Besset, T. Pois-
son, X. Pannecoucke, Eur. J. Org. Chem. 2015, 2765–2789.
[6] a) J. T. Welch, Tetrahedron 1987, 43, 3123–3197; b) T. Yamazaki, J. Haga,
T. Kitazume, Bioorg. Med. Chem. Lett. 1991, 1, 271–276; c) J. S. Houlton,
W. B. Motherwell, B. C. Ross, M. J. Tozer, D. J. Williams, A. M. Z. Slawin,
Tetrahedron 1993, 49, 8087–8106; d) B. Manteau, S. Pazenok, J.-P. Vors,
F. R. Leroux, J. Fluorine Chem. 2010, 131, 140–158; e) N. A. Meanwell, J.
Med. Chem. 2011, 54, 2529–2591.
[15] The photoexcited state of fac-[Ir(ppy)3] is a reductant (E1/2 =À2.14 V
versus [Cp2Fe]), stronger than those of [Ir(ppy)2(dtbbpy)]+ (E1/2
=
À1.37 V versus [Cp2Fe]) and [Ru(bpy)3]2+ (E1/2 =À1.22 V versus [Cp2Fe]),
for details see references [9d,f].
[16] We modified the reported synthetic method for 1a to avoid use of gas-
eous reagent (see the Supporting Information). For the reference, see:
V. P. Mehta, M. F. Greaney, Org. Lett. 2013, 15, 5036–5039.
[7] For selected examples of multistep difluoromethylation, see: a) C. Ni, J.
Hu, Tetrahedron Lett. 2005, 46, 8273–8277; b) Y. Li, J. Hu, Angew. Chem.
Received: December 2, 2015
Published online on December 16, 2015
Chem. Eur. J. 2016, 22, 1262 – 1265
www.chemeurj.org
1265 ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim