Copper-mediated aerobic (phenylsulfonyl)difluoromethylation of arylboronic acids with difluoromethyl phenyl sulfone

Article abstract of DOI:10.1039/c5cc10550a

A new method for the generation of the "PhSO₂CF₂Cu" species from readily available difluoromethyl phenyl sulfone (PhSO₂CF₂H) has been developed. The "PhSO₂CF₂Cu" reagent can be applied in (phenylsulfonyl)difluoromethylation of arylboronic acids, which affords a convenient approach to introducing the PhSO₂CF₂ group into aromatics.

Full text of DOI:10.1039/c5cc10550a

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Graphic Abstract
The “PhSO2CF2Cu” reagent (from PhSO2CF2H) reacts with arylboronic acids, which represents a convenient
method to introduce CF2 moiety into aromatics.

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Journal Name
COMMUNICATION
Copper-Mediated Aerobic (Phenylsulfonyl)difluoromethylation of
Arylboronic Acids with Difluoromethyl Phenyl Sulfone
Received 00th January 20xx, xx,
Accepted 00th January 20xx
Xinjin Li,a,b Jingwei Zhao,b Mingyou Hu,b Dingben Chen,b Chuanfa Ni,b Limin Wang*a and
Jinbo Hu*b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new method for the generation of the “PhSO2CF2Cu” species
from readily available difluoromethyl phenyl sulfone (PhSO2CF2H)
has been developed. The “PhSO2CF2Cu” reagent can be applied in
(phenylsulfonyl)difluoromethylation of arylboronic acids, which
affords a convenient approach to introduce PhSO2CF2 group into
aromatics.
Fluorinated organic compounds have attracted extensive at-
tention in recent years due to their widespread applications in
pharmaceuticals, agrochemicals, and functional materials.1,2
Among them, aromatic compounds containing the difluoro-
methylene (CF2) group are of high importance, since the CF2
moiety is known to be an isostere to an oxygen atom.3 Hence,
it is of great interest to develop new methods for the selective
introduction of CF2 group(s) onto aromatic rings. In this con-
text, the transition-metal-assisted cross-coupling reaction rep-
resents one of the most straightforward strategies for incorpo-
rating CF2 into arenes,4-6 among which, copper-mediated
difluoroalkylation has significant advantages in its high effi-
ciency and the relatively low cost of copper.7
Scheme 1 Application of difluoromethyl phenyl sulfone.
Recently, a new method has been developed for the formation
of “CuCF3”14a and “CuC2F5”.14b We envisioned that the
“PhSO2CF2Cu” species could be generated from PhSO2CF2H.
Previously, we reported the “PhSO2CF2Cu” species generated
from
PhSO2CF2SiMe3,
and
its
(phenylsulfonyl)difluoromethylation of alkynyl halides.15 How-
ever, due to the lower stability of “PhSO2CF2Cu” than “CuCF3”,
the cross-coupling reaction of aryl iodides with “PhSO2CF2Cu”
is failed, because the oxidative addition process usually re-
quires high temperature and/or long reaction time. Thus, we
envisioned
that
the
synthesis
of
Selective (phenylsulfonyl)difluoromethylation reactions
have been systematically studied in recent years,8 since the
PhSO2CF2 group can be readily transformed into difluorome-
thyl (CF2H),9 difluoromethylene (−CF2−),10 and difluoromethyli-
dene (=CF2)11 functionalities. Difluoromethyl phenyl sulfone
(phenylsulfonyl)difluoromethylated arenes can be achieved via
a copper-mediated oxidative cross-coupling reaction of aryl-
boronic acids with PhSO2CF2H under mild conditions. Although
copper-mediated oxidative trifluoromethylation of arylboronic
acids via “CuCF3” intermediate has been well documented,16
while the oxidative gem-difluoromethylenation of arylboronic
acids has received less attention,17 probably because of the
low stability of the “RCF2Cu” intermediate. Herein, we wish to
disclose an efficient method for preparation of the
“PhSO2CF2Cu” species generated from PhSO2CF2H, and its ap-
plication in (phenylsulfonyl)difluoromethylation of arylboronic
acids.
(PhSO2CF2H),9,12
a
useful
nucleophilic
(phenylsulfonyl)difluoromethylation agent, has been investi-
gated extensively, partially owing to its simple preparative
procedure (Scheme 1). However, the introduction of
(phenylsulfonyl)difluoromethyl group into sp2 carbons via a
transition-metal-assisted protocol is rare.13 To the best of our
knowledge, there has no report on the transition-metal-
mediated (phenylsulfonyl)difluoromethylation with PhSO2CF2H.
It is known that the hydrogen atom of the CF2H group in
PhSO2CF2H (1) is rather acidic, and a common base such as
sodium methoxide or even aqueous sodium hydroxide can
deprotonate it in an equilibrium mode to generate
9b,10,12

PhSO2CF2 .
At the onset of our investigation, sodium
methoxide was employed as the base. Into the mixture of CuCl
(0.2 mmol) and MeONa (2 equiv) in DMF at room temperature,
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J. Name., 2013, 00, 1-3 | 1
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reagent
1
was added dropwise at the same temperature for 30 to 65% after 24 h at -12 oC and to 58% after 60VhiewuAnrtdicleerOntlhinee
min under an argon atmosphere. To our delight, exception of same conditions (see ESI†, section 4 forDdOeIt: a10il.s1)0.3A9/cCc5oCrCd1i0n5g50toA
the starting reagent 1, “PhSO2CF2Cu” (δ = -92.0 ppm) was previous reports19 and our experiment, we reasoned that the
formed in 34% yield by 19F NMR spectroscopy (Table 1, entry addition of 18-crown-6, with a strong affinity for metal cation
1). The low yield of “PhSO2CF2Cu” generated from
1
probably (Na+ in this case), would diminish the electrophilicity of Na+,
due to two reasons: First of all, the using of 2MeONa−CuCl did thereby decreasing the decomposition of “PhSO2CF2Cu”.
give small quantities of “PhSO2CF2Cu” under the conditions.
Table 1 Screening of formation of “PhSO2CF2Cu”a
Second, the “PhSO2CF2Cu” species possesses low thermal sta-
bility at this temperature.15 As expected, when the reaction
was carried out at 0 oC (Table 1, entry 2), the yield of
“PhSO2CF2Cu” was increased to 45%. Therefore, it seems that
entry
CuX
base (equiv)
temp. (oC)
yieldb (%)
a proper base is critical for the generation of “PhSO2CF2Cu”.
The results obtained under various reaction conditions are
listed in Table 1. With the consideration in mind, we attempt-
1
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
MeONa (2.0)
MeONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuOK (2.0)
tBuONa (1.2)
tBuONa (2.4)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
tBuONa (2.0)
rt
34
45
56
64
62
56
36
63
57
62
74
88
96
94
2
0
t
ed the reaction using other bases such as BuONa at a lower
3
0
temperature (-20 oC), as a result, the yield of “PhSO2CF2Cu”
was increased to 64% (Table 1, entry 4). However, when tBuOK
was used, it was found that some side reactions occurred,
even though this copper species was formed in a moderate
yield (Table 1, entry 5). In addition, the reaction should be car-
4
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
5
6
7
8
t
ried out by using 2 equiv of BuONa, which was necessary to
9
CuSCN
CuCl
CuCl
CuCl
CuCl
CuCl
obtain “PhSO2CF2Cu” in good yields. As our previous report,18
the “CuCF3” species can be generated from PhSO2CF3 or
10 c
11d
12e
13f
14g
t
PhSOCF3 via treatment of CuCl and 2 equiv of BuOK. It is
noteworthy that no formation of “CuCF2H” was detected when
PhSO2CF2H or PhSOCF2H was employed under the same condi-
tions. These results also proved that cleavage of CF2−H bond is
much easier than S−CF2H bond in PhSO2CF2H. Furthermore, the
use of CuI or CuSCN failed to improve the yield of “PhSO2CF2Cu”
(Table 1, entries 8−9). For solvent screening, it was found that
NMP was inferior to DMF (Table 1, entry 10).
aReaction conditions: 1 (0.2 mmol), CuX (0.2 mmol), DMF (1 mL). bYields
were determined by 19F NMR spectroscopy using PhCF3 as an internal stand-
ard. cNMP was used as the solvent. d1 (0.24 mmol) was used. e1 (0.28 mmol)
was used. “*(PhSO2CF2)2Cu]” (11%, 19F NMR) was produced. 1 (0.32 mmol)
f
was used. “*(PhSO2CF2)2Cu]” (29%, 19F NMR) was produced. gReaction con-
ditions: 1 (0.8 mmol), CuCl (0.5 mmol), DMF (2 mL).
To improve the yield of “PhSO2CF2Cu”, we increased the
With the efficient method for the generating of the
“PhSO2CF2Cu” species from PhSO2CF2H in hand (Table 1, entry
13), we further employed this copper species for the
(phenylsulfonyl)difluoromethylation of various arylboronic
acids (Table 2). Initially, we attempted the reaction of aryl-
boronic acid (2a) with the “PhSO2CF2Cu” species generated
loading of
amount of
1
under the optimized conditions. When the
1
was increased to 1.2 equiv, the yield was corre-
spondingly enhanced to 74% (Table 1, entry 11). It is notewor-
thy that a little excess of
1 results in a new species (96.3 ppm
in 19F NMR spectroscopy), which is assigned as
“*(PhSO2CF2)2Cu]” on the basis of our experiment results and
o
the literature data.15 Consequently, when 1.6 equiv of
1 was
from PhSO2CF2H at 0 C under an air atmosphere. However,
only 16% yield of the (phenylsulfonyl)difluoromethylated
used, the total yield of the “PhSO2CF2Cu” species was in-
product was detected, and the aryl chloride (B) as a main by-
creased to 97% (Table 1, entry 13), with 66% contribution from
“PhSO2CF2Cu” (
from “*(PhSO2CF2)2Cu]” (
(see ESI†, section

92.1 ppm in 19F NMR spectroscopy) and 29%
product was formed in the case of CuCl (Table 2, entry 1).
When the reaction was carried out at rt, to our delight, the
product was obtained in 67% yield after 4 h, but the byproduct

96.3 ppm in 19F NMR spectroscopy)
2
for details). It is noted that
“*(PhSO2CF2)2Cu]” possesses lower thermal stability than
“PhSO2CF2Cu”, and the former species can be transformed into
the latter species at room temperature (see ESI†, section 3 for
details).
B
was still generated (Table 2, entry 2). Using a copper source
without a halide counterion, such as CuOTf, did not generate
the analogous byproduct, while the formation of “PhSO2CF2Cu”
was inhibited. To overcome this hurdle, various additives were
further screened, which enable improvement of the desired
Next, we examined the stability of “PhSO2CF2Cu” under
various conditions. Unlike previously reported the “CuCF3”
species generated from phenyl trifluoromethyl sulfoxide,18 the
“PhSO2CF2Cu” species generated from PhSO2CF2H was
gradually decomposed at rt and decomposed completely after
4 h. Furthermore, the yield of “PhSO2CF2Cu” decreased from
80% to 46% at -12 oC after 24 h under an argon atmosphere.
Interestingly, it was found that the addition of 18-crown-6
could stabilize the “PhSO2CF2Cu” species which was decreased
product yield and/or reduce the generation of byproduct B.
The addition of 1,10-phenanthroline, as a ligand for coordina-
tion of Cu to stabilize “PhSO2CF2Cu”, failed to give the product
(Table 2, entry 3). As previously reported,16a,c K3PO4 can im-
prove the desired product yield, but not fit our reaction system.
Fortunately, when a portion of AgNO3 was added to the reac-
tion mixture, the product yield was increased to 72% (Table 2,
entry 5).
2 | J. Name., 2012, 00, 1-3
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Table 2 Optimization of reaction conditionsa
lation with an arylboronic acid. The formed “PhSO2CF2Cu(III)Ar”
View Article Online
DOI: 10.1039/C5CC10550A
species undergoes reductive elimination to give the coupling
product 3 16f
Based on our experimental data, it can be con-
.
cluded that oxygen (O2) is a crucial oxidant in our coupling re-
action (Table 2, entries 2 and 9). The presence of AgNO3 and
Cu(OAc)2·H2O is also beneficial to the O2-involved oxidative
coupling process.
entry
additive (equiv)
temp.
yieldb of A (B)
(%)
−
1
0 oC
rt
16 (28)
67 (18)
0 (0)
−
2
3
1,10-phen (1.0)
rt
4
K3PO4 (1.0)
rt
68 (18)
72 (15)
73 (10)
75 (7)
80 (7)
0 (−)
5
AgNO3 (0.5 )
rt
6
AgNO3 (1.0 )
rt
7
AgNO3 (0.5) + Cu(OAc)2·H 2O (0.2)
AgNO3 (0.6) + Cu(OAc)2·H 2O (0.3)
AgNO3 (0.6) + Cu(OAc)2·H 2O (0.3)
rt
8 c
9d
rt
rt
aReaction conditions: 2a (0.2 mmol), “PhSO2CF2Cu” (2.0-2.5 equiv), DMF (2
mL). Yields were determined by 19F NMR using PhCF3 as an internal stand-
b
ard. cThe reaction was conducted with 0.4 mmol of 2a for 6 h. cThe reaction
was conducted under argon atmosphere.
Silver nitrate (AgNO3) was used to trap the chloride ions, thus
diminishing the generation of aryl chloride
5 and 6). Furthermore, a spot of Cu(OAc)2·H2O was found to be
favorable to the generation of the
(phenylsulfonyl)difluoromethylated product (Table 2, entry 7).
Consequently, mixture of AgNO3 (0.6 equiv) and
B (Table 2, entries 2,
a
Cu(OAc)2·H2O (0.3 equiv) was selected as the optimum addi-
tives for the (phenylsulfonyl)difluoromethylation of aryl-
boronic acid 2a with “PhSO2CF2Cu” generated from PhSO2CF2H.
Having identified the optimum reaction conditions, we fur-
ther explored the scope and the limitations of the
(phenylsulfonyl)difluoromethylation of arylboronic acids with
“PhSO2CF2Cu” generated from PhSO2CF2H (Scheme 2). The
(phenylsulfonyl)difluoromethylation can tolerate various sub-
stituents at the ortho-position such as trifluoromethoxy, tri-
fluoromethyl, formyl, nitrile, sulfonyl, halides (−F, −Cl, −Br),
nitro, and methoxyl, affording the desired products in moder-
Scheme 2 The substrate scope of arylboronic acids. Reaction conditions:
ArB(OH)2 (0.2 mmol), “PhSO2CF2Cu” (2.0-2.5 equiv), AgNO3 (0.6 equiv),
Cu(OAc)2·H2O (0.3 equiv), DMF (2 mL). Yields were of isolated products. aThe
reaction were conducted in 0.4 mmol of arylboronic acides in DMF (4 mL)
c
for 6 h. bNo addition of AgNO3 and Cu(OAc)2·H2O. Yields were determined
by 19F NMR using PhCF3 as an internal standard.
To demonstrate the synthetic applications of the
(phenylsulfonyl)difluoromethylated heteroarenes (3), reduc-
tive desulfonylation20 of
3
with Mg0/HOAc/NaOAc could give
ate to good yields (Scheme 2, 3a
a little low yields with meta- and para-substituted arylboronic
acids (Scheme 2, 3j 3k). Generally, the electron-deficient sub-
−3i, 3u). The reaction afforded
difluoromethyl arenes (4) in good yields. Some representative
results are summarized in Scheme 3.
−
strates provide superior yields to electron-rich substrates. In
addition, this transformation was also applicable to various N-,
O-, and S-containing heterocyclic arylboronic acids, and the
(phenylsulfonyl)difluoromethylated heteroarenes were ob-
tained in good yields (Scheme 2, 3l
some products can be obtained in good yields without the aid
of additives (Scheme 2, 3e, 3i, 3q 3t).
−3t). It is worth noting that
−
Regarding the reaction mechanism, we envisioned that the
present copper-mediated (phenylsulfonyl)difluoromethylation
reaction proceeds through a similar reaction mechanism to the
previously reported CuCF3-mediated coupling reaction with
arylboronic acids.16a,b,f The pregenerated “PhSO2CF2Cu(I)” spe-
cies is firstly oxidized to Cu(III) species, followed by transmetal-
Scheme 3 Synthesis of difluoromethylated aromatics by reductive desul-
fonylation. Reaction conditions: 3 (0.2 mmol), Mg (3 mmol), HOAc/NaOAc
b
(1:1) (1.5 mL), and DMF (2 mL). Yields were determined by 19F NMR spec-
troscopy using PhCF3 as an internal standard. cThe yield was of isolated
product.
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Chem., Int. Ed., 2014, 53, 9909; (b) Y.-L. Xiao, Q. Pan and X.
View Article Online
Zhang, Acta Chim. Sinica, 2015, 73, 383. DOI: 10.1039/C5CC10550A
For selected examples, see: (a) T. Taguchi, O. Kitagawa, T. Mori-
kawa, T. Nisiwaki, H. Uehara, H. Endo and Y. Kobayashi, Tetra-
hedron Lett., 1986, 27, 6103; (b) W. Qiu and D. J. Burton, Tetra-
hedron Lett., 1996, 37, 2745; (c) T. Yokomatsu, T. Murano, K.
Suemune and S. Shibuya, Tetrahedron, 1997, 53, 815; (d) K. Sato,
R. Kawata, F. Ama, M. Omote, A. Ando and I. Kumadaki, Chem.
Pharm. Bull., 1999, 47, 1013; (e) M. S. Ashwood, I. F. Cottrell, C.
J. Cowden, D. J. Wallace, A. J. Davies, D. J. Kennedy and U. H.
Dolling, Tetrahedron Lett., 2002, 43, 9271; (f) J. Zhu, W. Zhang, L.
Zhang, J. Liu, J. Zheng and J. Hu, J. Org. Chem., 2010, 75, 5505;
(g) K. Fujikawa, Y. Fujioka, A. Kobayashi and H. Amii, Org. Lett.,
2011, 13, 5560; (h) P. S. Fier, and J. F. Hartwig, J. Am. Chem. Soc.,
2012, 134, 5524; (i) G. K. S. Prakash, S. K. Ganesh, J.-P. Jones, A.
Kulkarni, K. Masood, J. K. Swabeck and G. A. Olah, Angew.
Chem.; Int. Ed., 2012, 51, 12090; (j) Z. Feng, F. Chen and X.
Zhang, Org. Lett., 2012, 14, 1938; (k) Z. Feng, Y.-L. Xiao and X.
Zhang, Org. Chem. Front., 2014, 1, 113; (l) H. Jiang, W. Lu, K.
Yang, G. Ma, M. Xu, J. Li, J. Yao, W. Wan, H. Deng, S. Wu, S. Zhu
and J. Hao, Chem.— Eur. J., 2014, 20, 10084; (m) X.-L. Jiang, Z.-H.
Chen, X.-H. Xu and F.-L. Qing, Org. Chem. Front., 2014, 1, 774; (n)
M.-C. Belhomme, T. Poisson and X. Pannecoucke, J. Org. Chem.,
2014, 79, 7205; (o) C. Matheis, K. Jouvin and L. J. Goossen, Org.
Lett., 2014, 16, 5984.
In summary, we have developed an efficient method for
generation of “PhSO2CF2Cu” with readily available difluorome-
thyl phenyl sulfone. The “PhSO2CF2Cu” species was applied in
the reaction of (phenylsulfonyl)difluoromethylation of aryl-
boronic acids under mild conditions. The reaction can tolerate
formyl, nitrile, sulfonyl, halides, nitro, and various N-, O-, and
7
S-containing
heterocycle,
affording
(phenylsulfonyl)difluoromethylated products in moderate to
good yields. Furthermore, the reductive desulfonylation of
some (phenylsulfonyl)difluoromethylated products with
Mg0/HOAc/NaOAc gave difluoromethyl arenes in good yields.
It is also worth noting that the active copper species is con-
firmed for the first time involving the oxidative gem-
difluoromethylenation of arylboronic acids.
This work was supported by the National Basic Research Pro-
gram of China (grant No. 2015CB931900, 2012CB215500), Na-
tional Natural Science Foundation of China (No. 21421002,
21372246, 21272069, 21102163). We thank Professor
Shizheng Zhu (SIOC) for helpful discussions.
8
(a) G. K. S. Prakash and J. Hu, Acc. Chem. Res., 2007, 40, 921; (b)
J. Hu, J. Fluorine Chem., 2009, 130, 1130; (c) C. Ni, M. Hu and J.
Hu, Chem. Rev., 2015, 115, 765. (d) X. Wang, G. Liu, X.-H. X., N.
Shibata, E. Tokunaga and N. Shibata. Angew. Chem., Int. Ed.,
2014, 53, 1827.
(a) G. K. S. Prakash, J. Hu and G. A. Olah, J. Org. Chem., 2003, 68,
4457; (b) G. K. S. Prakash, J. Hu, Y. Wang and G. A. Olah, Org.
Lett., 2004, 6, 4315; (c) G. K. S. Prakash, J. Hu, Y. Wang and G. A.
Olah, Eur. J. Org. Chem., 2005, 11, 2218.
Notes and references
1
(a) J.-P. Bégué and D. Bonnet-Delpon, Bioorganic and Medicinal
Chemistry of Fluorine, Wiley: Hoboken, NJ, 2008; (b) K. Une-
yama, Organofluorine Chemistry, Blackwell: Oxford, U.K., 2006;
(c) D. A. Nagib and D. W. C. MacMillan, Nature, 2011, 480, 224;
(d) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470;
(e) Y. Fujiwara, J. A. Dixon, F. O’Hara, E. D. Funder, D. D. Dixon, R.
A. Rodriguez, R. D. Baxter, B. Herlé, N. Sach, M. R. Collins, Y.
Ishihara and P. S. Baran, Nature, 2012, 492, 95.
For reviews, see: (a) M. Schlosser, Angew. Chem., Int. Ed., 2006,
45, 5432; (b) D. O’Hagan, Chem. Soc. Rev., 2008, 37, 308; (c) T.
Furuya, J. E. M. N. Klein and T. Ritter, Synthesis, 2010, 11, 1804;
(d) O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111,
4475; (e) X.-F. Wu, H. Neumann and M. Beller, Chem. — Asian J.,
2012, 7, 1744; (f) F.-L. Qing, Chin. J. Org. Chem., 2012, 32, 815.
(a) P. Kirsch, Modern fluoroorganic chemistry: Synthesis, reactiv-
ity, applications, Wiley-VCH: Weinheim, 2013; (b) G. M. Black-
burn, D. E. Kent, and F. J. Kolkmann, J. Chem. Soc., Perkin Trans.
1, 1984, 1119; (c) D. B. Berkowitz and M. Bose, J. Fluorine Chem.,
2001, 112, 13; (d) D. O’Hagan, Y. Wang, M. Skibinski and A. M. Z.
Slawin, Pure Appl. Chem., 2012, 84, 1587.
For reviews, see: (a) B. Chen and D. A. Vicic, Top Organomet.
Chem., 2015, 52, 113; (b) B. Gao, C. Ni and J. Hu, Chimia, 2014,
68, 414; (c) C. Ni, L. Zhu and J. Hu, Acta Chim. Sinica, 2015, 73,
90; (d) P. Xu, S. Guo, L. Wang and P. Tang, Synlett, 2015, 26, 36;
(e) M.-C. Belhomme, T. Besset, T. Poisson and X. Pannecoucke,
Chem. — Eur. J., 2015, 21, 12836.
For selected examples of palladium-catalyzed difluoroalkylation:
(a) Y. Guo and J. M. Shreeve, Chem. Commun., 2007, 3583; (b) C.
Guo, R.-W. Wang and F.-L. Qing, J. Fluorine Chem., 2012, 143,
135; (c) S. Ge, W. Chaladaj and J. F. Hartwig, J. Am. Chem. Soc.,
2014, 136, 4149; (d) Q.-Q. Min, Z. Yin, Z. Feng, W.-H. Guo and X.
Zhang, J. Am. Chem. Soc., 2014, 136, 1230; (e) Z. Feng, Q.-Q.
Min, Y.-L. Xiao, B. Zhang and X. Zhang, Angew. Chem., Int. Ed.,
2014, 53, 1669; (f) Y.-B. Yu, G.-Z. He and X. Zhang, Angew.
Chem., Int. Ed., 2014, 53, 10457; (g) Y. Gu, X. Leng and Q. Shen,
Nat. Commum., 2014, 5, 5405.
9
10 G. K. S. Prakash, J. Hu, T. Mathew and G. A. Olah, Angew. Chem.,
Int. Ed., 2003, 42, 5216.
11 G. K. S. Prakash, J. Hu, Y. Wang and G. A. Olah, Angew. Chem.,
Int. Ed., 2004, 43, 5203.
12 (a) J. Hine and J. J. Porter, J. Am. Chem. Soc., 1960, 82, 6178; (b)
G. P. Stahly, J. Fluorine Chem., 1989, 43, 53.
13 (a) J.-Y. Wang, Y.-M. Su, F. Yin, Y. Bao, X. Zhang, Y.-M. Xu and X.-
S. Wang, Chem. Commun., 2014, 50, 4108; (b) Y.-M. Su, Y. Hou,
F. Yin, Y.-M. Xu, Y. Li, X. Zheng and X.-S. Wang, Org. Lett., 2014,
16, 2958.
14 (a) A. Zanardi, M. A. Novikov, E. Martin, J. Benet-Buchholz and V.
V. Grushin, J. Am. Chem. Soc., 2011, 133, 20901; (b) A. Lishchyn-
skyi and V. V. Grushin, J. Am. Chem. Soc., 2013, 135, 12584.
15 J. Zhu, F. Wang, W. Huang, Y. Zhao, W. Ye and J. Hu, Synlett,
2011, 7, 899.
16 For selected examples, see: (a) L. Chu and F.-L. Qing, Org. Lett.,
2010, 12, 5060; (b) T. D. Senecal, A. T. Parsons and S. L. Buch-
wald, J. Org. Chem., 2011, 76, 1174; (c) X. L. Jiang, L. L. Chu and
F.-L. Qing, J. Org. Chem., 2012, 77, 1251; (d) P. Novák, A.
Lishchynskyi and V. V. Grushin, Angew. Chem., Int. Ed., 2012, 51,
7767; (e) H. Serizawa, K. Aikawa and K. Mikami, Chem.— Eur. J.,
2013, 19, 17692; (f) N. Nebra and V. V. Grushin, J. Am. Chem.
Soc., 2014, 136, 16998.
17 (a) Q. Qi, Q. Shen and L. Lu, J. Am. Chem. Soc., 2012, 134, 6548;
(b) X. Jiang, L. Chu and F.-L. Qing, New J. Chem., 2013, 37, 1736;
(c) G. Ma, W. Wan, Q. Hu, H. Jiang, J. Wang, S. Zhu and J. Hao,
Chem. Commun., 2014, 50, 7527.
18 X. Li, J. Zhao, L. Zhang, M. Hu, L. Wang and J. Hu, Org. Lett.,
2015, 17, 298.
2
3
4
5
19 (a) T. Kawashima, J. Organomet. Chem., 2000, 611, 256; (b) A. I.
Konovalov, J. Benet-Buchholz, E. Martin and V. V. Grushin, An-
gew. Chem., Int. Ed., 2013, 52, 11637.
6
For selected examples of nickel-catalyzed difluoroalkylation: (a)
Y.-L. Xiao, W.-H. Guo, G.-Z. He, Q. Pan and X. Zhang, Angew.
20 C. Ni and J. Hu, Tetrahedron Lett., 2005, 46, 8273.
4 | J. Name., 2012, 00, 1-3
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