Nonconventional difluoroalkylation of C(sp2)-H bonds through hydroarylation

Article abstract of DOI:10.1039/c7cc04842d

An unprecedented Rh-catalyzed C2-difluoroalkylation of indole derivatives with 2,2-difluorovinyl arenesulfonates has been reported. This reaction provides a rare instance of catalytic difluoroalkylation through hydroarylation of gem-difluoroalkenes. The sulfonate group works as a chelating ligand, thus stabilizing the rhodacycle intermediate, leading to the uncommon transformation.

Full text of DOI:10.1039/c7cc04842d

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: C. Zhu, S. Song, L.
Zhou, D. Wang, C. Feng and T. P. Loh, Chem. Commun., 2017, DOI: 10.1039/C7CC04842D.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 5
View Article Online
DOI: 10.1039/C7CC04842D
Journal Name
COMMUNICATION
Nonconventional Difluoroalkylation of C(sp2)−H Bonds Through
Hydroarylation
Chuan Zhu,a,† Shengjin Song,a,b,† Lu Zhou,a Ding-Xing Wang,a Chao Fenga,* and Teck-Peng Lohb,c,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Me
H
N
An unprecedented Rh-catalyzed C2-difluoroalkylation of indole
derivatives with 2,2-difluorovinyl arenesulfonates has been
reported. This reaction provides a rare instance of catalytic
difluoroalkylation through hydroarylation of gem-difluoroalkenes.
The sulfonate group works as a chelating ligand thus stabilizing
the rhodacycle intermediate leading to the uncommon
transformation.
CN
F
F
NH
O
H
N
F
O
H2
N
N
O
N
N
N
N
H
NH2
H
H
F
F
F
thrombininhibitor
nitricoxide synthase (NOS) inhibitors
SF5
O
N
N
S
HN
N
OH
OH
N
O
F
O
O
N
N
Me
C12H25
F
N
Me
Me
F
F
Me
NH2
N
Me
F
F
antimalarial agent
antitumer agent
GPR119 agonist
Figure 1. Bioactive compounds containing difluoromethylene moiety.
Because of their wide application in pharmaceutical, ag-
rochemical and material sciences, fluorine-containing
compounds have been attracting increasing interest from
synthetic community.1 Therefore, many synthetic tactics as
well as novel fluoronating reagents were developed, which
profoundly revolutionized the assembly of fluorine-containing
molecular skeletons.2 In this particular context, significant
progresses have been obtained for the introduction of magic
“CF3” group into organic frameworks with potential
bioactivities.3 In contrast, research advancement with respect
to the incorporation of difluoroalkyl congeners, which are also
of considerable importance, however, lagged far behind
despite of their ubiquity in biologically relevant molecular
architectures (Figure 1).4 As for the introduction of
difluoroalkyl groups, several conventional strategies (i.e., the
cross-coupling with difluoroaklyl reagents; deoxyfluorination
of carbonyl functionalities; visible light-induced radical
difluoroalkylation) have been extensively investigated.5-7 While
effective and synthetically important, there still lies significant
drawbacks because of their heavy reliance on the use of
elaborated starting materials or the employment of harsh
fluorinating reagents. As such, the development of a mild and
environmentally benign protocol for the incorporation of
difluoroalkyl moieties, which use readily available chemical
reagents, is still highly desirable and synthetically appealing.
From the atom-economical point of view, the scission of
targeting C-H bond and adding across to gem-difluoroalkenes
constitutes to be the ideal objective.8 Recently, our group has
reported some efficient sp2 C-H bond functionalizations with
gem-difluoroalkenes,9 wherein the fluorine substituents were
revealed to play diplex roles in guaranteeing a regiospecific
redox neutral process: i) enabling regioselective C-C double
bond insertion on one hand,10 ii) acting as a leaving group in β-
fluoride elimination on the other (Scheme 1a).11,12
Prompted by these advancement, we are intrigued in de-
veloping difluoroalkyation by transition-metal catalyzed
hydroarylation of gem-difluoroalkenes through C-H bond
activation. However, to render the priority of protonative
demetalation over the β-defluorination pathway, some
prominent obstacles are to be delicately overcome. To obviate
such overwhelmingly competitive pathway, a novel strategy
needs to be formulated. Specifically, we are about to make use
of gem-difluoroalkene that holds a tethered Lewis basic
pendent as the difluoroalkyl donor.
We envisioned that the role of Lewis basic pendent would be
dichotomous, on one hand acting as potential chelation ligand
for the stabilization of macro-rhodacycle intermediate thus
preventing the otherwise preferred β-fluoride elimination,13
and taking part in the catalyst regeneration step as a latent
proton shuttle, thereby facilitating the protodemetalation of
the proximate metal-carbon bond (Scheme 1b). If successful,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
View Article Online
DOI: 10.1039/C7CC04842D
COMMUNICATION
Journal Name
8 and 9).8 In addition, basic additives inhibited the reaction to
some extent (entries 10 and 11). Particularly, copper salt which
are proved to be an effective promoter for the protonation
step resulted in much lower yield of 3aa (entry 12).15
Table 2. Substrates scope of indole derivatives.[a]
H
OSO2Ar
R
H
R
OSO2Ar
5 mol% Cp*Rh(MeCN)3(SbF6
DCE, 50 °C
)
2
N
F
N
+
F
F
N
F
N
N
N
1
2a
3
Me
Scheme 1. Divergent transformation of α-gem-difluoro metallacycles:
protodemetalation vs defluorination.
H
H
H
Me
OSO2Ar
OSO2Ar
OSO2Ar
F
F
F
F
N
N
F
N
F
Me
N
N
N
N
N
N
this strategy would not only set the stage for the
straightforward difluoroalkylation of sp2 C-H bonds but more
3ba, 82%
3ca, 68%
3da, 73%
OMe
H
H
H
OSO2Ar
OSO2Ar
MeO
OSO2Ar
F
F
importantly exert
a
far-reaching influence on further
F
N
N
F
F
N
F
Me
N
N
exploration of novel C-H functionalizations. To meet the
criterion of our hypothesis, 2,2-difluorovinyl arenesulfonate,
which is easily prepared from readily available
trifluoroethanol, is selected as the model coupling partner.14
Initially, the model reaction of N-pyrimidylindole 1a and 2,2-
difluorovinyl 2,4,6-triisopropylbenzenesulfonate 2a was
investigated (Table 1). We were happy to find that the reaction
proceed smoothly in the presence of a catalytic amount of
cationic rhodium complex Cp*Rh(MeCN)3(SbF6)2 and afforded
hydroarylation product 3aa in 70% yield in DCE (entry 1).
Switching the atmosphere from air to N2 made no change to
the reaction which imply the robustness of the protocol (entry
2). In the absence of the rhodium catalyst, both 1a and 2a
were re-covered, and no desired product 3aa was observed
(entry 3). Palladium, copper, cobalt, iridium salts were found
to be ineffective to promote the desired transformation (entry
4).
N
N
N
N
3ea, 60%
3fa, 81%
3ga, 64%
AcO
OBn
H
H
H
OSO2Ar
OSO2Ar
OSO2Ar
OSO2Ar
OSO2Ar
F
F
F
F
F
N
N
N
N
F
F
F
F
F
MeO
N
N
N
N
N
3ia, 78%
3ja, 49%
3ha, 72%
Ph
H
H
H
PinB
Ph
OSO2Ar
OSO2Ar
F
F
N
N
N
F
F
N
N
N
N
N
N
3ka, 37%
3la, 70%
3ma, 66%
COOMe
H
H
H
MeOOC
F
OSO2Ar
OSO2Ar
F
F
N
N
N
N
F
F
N
N
N
N
N
3na, 34%
3oa, 49%
3pa, 56%
Cl
H
H
H
Cl
OSO2Ar
OSO2Ar
OSO2Ar
F
F
F
N
N
N
N
F
F
F
F
N
N
N
N
N
3qa, 66%
3ra, 62%
3sa, 43%
Br
H
H
H
Br
OSO2Ar
OSO2Ar
Table 1. Optimization of reaction conditions.
OSO2Ar
F
F
F
N
N
F
F
N
F
Br
N
N
N
N
N
N
3ta, 53%
3ua, 48%
3va, 52%
OMe
H
H
H
MeO
OSO2Ar
OSO2Ar
OSO2Ar
F
F
F
N
N
N
F
F
F
N
N
N
3wa, 44%
3xa, 51%
3ya, 45%
H
H
H
H
OSO2Ar
ArO2SO
OSO2Ar
OSO2Ar
Me
F
N
N
F
F
F
N
F
F
F
F
MeO
N
N
N
N
N
3za, 38%
3aaa, 40%
3aba, 47%
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.3 mmol) and Cp*Rh(MeCN)3(SbF6)2
(0.005 mmol, 5 mol%) in 3 mL of DCE at 50 °C, unless otherwise noted. Ar: 2,4,6-
triisopropylphenyl. Yields of products isolated after chromatography.
[a] Standard conditions: 1a (0.10 mmol), 2a (0.30 mmol), Cp*Rh(MeCN)3(SbF6)2
(5.0 mol%), DCE (3.0 mL), stirring under air at 50 °C for 16 h. [b] Yields were
determined by 1H NMR with CH2Br2 as internal standard. [c] Isolated yield
indicated in the parentheses. [d] 2.5 mol% [RuCl2(p-cymeme)]2/10 mol% AgSbF6,
2.5 mol% [Cp*IrCl2]2/10 mol% AgSbF6, 2.5 mol% [Cp*CoI2]2/10 mol% AgSbF6 or 5
mol% Pd(OAc)2 was examined.
With the set of optimized reaction conditions in hand, we first
investigated the scope of various indole motifs in this direct
C2-difluoroalkylation process (Table 2). Hydroarylation
reactions
of
2,2-difluorovinyl
2,4,6-
triisopropylbenzenesulfonate (2a) with a variety of N-pyrimidyl
indoles were examined. Substrates with methyl substitution on
Screening with other solvents, such as 1,4-dioxane, toluene
and tert-amyl alcohol, confirmed DCE to be the optimal solvent
for this reaction (entries 5 to 7). Acid additives, such as H2O
and HOAc which are commonly used to promote the
protonation step did not affect the reaction efficiency (entries
C4−C7 posiꢀon
hydroarylation
(
1b
−
e)
all underwent the site-selective
readily afforded the desired
and
difluoroalkylated products in moderate to good yields
3ba ea). The efficient formation of 3fa ia illustrated that
(
−
−
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 5
View Article Online
DOI: 10.1039/C7CC04842D
Journal Name
COMMUNICATION
D content
40%
D content
11%
electron-rich substituents were preferred in this reaction.
Remarkably, easily removable -OBn and -OAc group was well
tolerated which allowed simple further derivatization. It was
very interesting that boryl indole derivative provided
difluoroalkylatd product 3ka, albeit in low yield. N-pyrimidyl
indoles bearing electron-neutral phenyl group at the C4 and C5
positions were good substrates for the reaction, thus providing
the corresponding products 3la and 3ma in 70% and 66%
yields, respectively. However, C3 substitution on indole that
exerts steric effect to C2 position failed to afford the
difluoroalkylation product (see supporting information).
Indoles substituted with electron-withdrawing ester group
were also competent substrates giving rise to the desired
products in moderate yields (3na and 3oa). The halogen motifs
(F, Cl, Br) were well tolerated under the optimized conditions
D/H
D/H
OSO2Ar
D
OSO2Ar
N
F
F
standard condition
3.5 h
N
(1)
+
F
N
N
F
N
N
D1-1a
2a
D2-3aa
33%
D content
57%
D content
73%
D/H D/H
OSO2Ar
standard condition
H
OSO2Ar
N
N
10.0 eq CD3CO2
D
F
F
N
+
(2)
F
N
3.5 h
N
F
D/H
N
D content
61%
1a
2a
D3-3aa
11%
Scheme 2. Isotopic experiments.
To probe the reaction mechanism, a set of isotopic ex-
periments were carried out (Scheme 2). First, the reaction was
conducted with D-labeled substrate D1-1a and 2a under the
optimized conditions and the product D2-3aa was obtained in
33% yield with 11% deuterium incorporation at methylene
group of D2-3a (Scheme 2, eqn 1). It should be noted that
exchange of H/D was observed in D2-3aa on C3 and recovered
D1-1a on C2 and C3 (see supporting information) which
demonstrates the initial C-H bond cleavage is a reversible
process.15 The low deuterium content in D2-3aa suggests the
incorporation of proton is largely preferred to that of
deuterium in the protodemetalation step. Subsequently the
kinetic isotope effect (KH/KD = 1.06) for the C2-H bond-
breaking was clearly obtained from the parallel competing
experiments (see supporting information). These results
indicate the protodemetalation rather than C-H/D bond
cleavage should be the rate-determining step in this reaction.
To further confirm the origin of proton introduced into the
methylene group, we ran the reaction with 10 equiv of D4-
acetic acid and 57% deuterium content was identified in the
product (Scheme 2, eqn 2). This result strongly suggests that
protons engaged in the demetalation step originate from the
reaction medium and therefore ruling out the possibility for
product formation through direct proton migration from
indole substrate.
(
3pa−va), indicating the potential for the further synthetic
elaboration. N-pyridyl indoles were proved to be viable
substrates, as well, delivering the hydroarylation products
3wa−za in moderate yields. It’s worth mentioning that apart
from indole derivatives N-pyrimidyl pyrrole was amenable to
the reaction and afforded the disubstituted product 3aaa in
40% yield uneventfully. Expectedly, pyrrole bearing 2-methyl
substitution also underwent this facile transformation to
afford the desired product 3aba in 47% yield. The moderate
yields of some products was attributed to the formation of
untraceable dark purple solid, nevertheless, the attempts to
identify the structures of these side products has been
fruitless.
Table 3. Evaluation of α,α-difluorovinyl sulfonates.[a]
[a] Reaction conditions: 1a (0.1 mmol), 2 (0.3 mmol) and Cp*Rh(MeCN)3(SbF6)2
(0.005 mmol, 5 mol%) in 3 mL of DCE at 50 °C. Yields of products isolated after
chromatography.
Next the influence of the substitution on the phenyl ring of
2,2-difluorovinyl arenesulfonate was evaluated (Table 3).
Electron-rich substituents on the aromatic ring were all
accommodated in this transformation, producing the
corresponding products 3aa−ad in 43−70% yields. When a
plain phenyl group was employed, the yield of desired product
3ae decreased to 29%. Furthermore, electron-deficient
substituents proved to be deleterious to the reaction. For
example, in the case of the substrate bearing para-CF3 group
only trace amount of the desired product 3af was detected
which could be rationalized by the attenuated chelation
potential of its sulfonate group. It is noticeable that the
sterically more hindered aryl group led to higher yield of the
product suggesting the cyclometalated rhodium complex may
be further stabilized with a bulky substituent.
Scheme 3. Plausible reaction mechanism.
Based on these isotopic experimental results, a plausible
mechanism was proposed (Scheme 3). At first, pyrimidine
directed C2-rhodation of indole substrate
Rh(III) complex Subsequently, 2,2-difluorovinyl
arenesulfonate coordinates to the rhodium centre which
1 occurs to generate
a
I.
2
further undergoes a migratory insertion to form intermediate
III. In contrast to the previous reports, the sulfonate group
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
View Article Online
DOI: 10.1039/C7CC04842D
COMMUNICATION
Journal Name
B. Hawes, T. Kowalski, Bioorg. Med. Chem. Lett. 2011, 21,
3290-3296.
could coordinate with rhodium simultaneously and
consequently impede the common defluoronation.12 With the
assistance of the sulfonate group proton would approach the
Rh-C bond and then protonation occurs to afford the
hydroarylation product along with the regeneration of Rh(III)
catalyst.
5
Selected examples of difluoroalkylation via cross-coupling:
(a) G. Li, T. Wang, F. Fei, Y. Su, Y. Li, Q. Lan, X. Wang, Angew.
Chem. Int. Ed. 2016, 55, 3491-3495. (b) M. V. Ivanova, A.
Bayle, T. Besset, T. Poisson, X. Pannecoucke, Angew. Chem.
Int. Ed. 2015, 54, 13406-13410. (c) W.-H. Guo, Z.-J. Luo, W.
Zeng, X. Zhang, ACS Catal. 2017, 7, 896-901. (d) X. Nie, C.
Cheng, G. Zhu, Angew. Chem. Int. Ed. 2017, 56, 1898-1902.
Selected examples for deoxofluoronation of ketone: (a) L. N.
Markovsi, V. E. Pahinnik, A. V. Kirsanov, Synthesis 1973, 787-
789. (b) G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M. Prozonic, H.
Cheng, J. Org. Chem. 1999, 64, 7048-7054. (c) Y. Chang, A.
Tewari, A.-I. Adi, C. Bae, Tetrahedron 2008, 64, 9837-9842.
Selected examples for visible-light induced radical difluoro-
alkylation: (a) Q. Lin, L. Chu, F.-L. Qing, Chin. J. Chem. 2013
31, 885-891. (b) Y.-M. Su, Y. Hou, F. Yin, Y.-M. Xu, Y. Li, X.
Zheng, X.-S. Wang, Org. Lett. 2014, 16, 2958-2961. (c) J. Jung,
E. Kim, Y. You, E. J. Cho, Adv. Synth. Catal. 2014, 356, 2741-
2748.
For the hydroarylation of alkenes via C-H activation: (a) L.
Yang, H. Huang, Chem. Rev. 2015, 115, 3468-3517. (b) Z.
Zhang, M. Tang, S. Han, L. Ackermann, J. Li, J. Org. Chem.
2017, 82, 664-672. (c) P. Keshri, K. R. Bettadapur, V. Lanke, K.
R. Prabhu, J. Org. Chem. 2016, 81, 6056-6065.
(a) P. Tian, C. Feng, T.-P. Loh, Nature Commun. 2015, 6,
7472-7478. (b) H. Liu, S. S, C.-Q. Wang, C. Feng, T.-P. Loh,
ChemSusChem 2017, 10, 58-61. (c) J.-Q. Wu, S.-S. Zhang, H.
Gao, Z. Qi, C.-J. Zhou, W.-W. Ji, Y. Liu, Y. Chen, Q. Li, X. Li, H.
Wang, J. Am. Chem. Soc. 2017, 139, 3537-3545.
6
7
Conclusions
In summary, we documented a new protocol that represents
an ideal mode for difluoroalkylation through a C-H bond
activation and addition to 2,2-difluorovinyl arenesulfonate.
This unprecedented hydroarylation event features operational
simplicity, mild reaction conditions and remarkable atom
economy. By virtue of the chelation of sulfonate the otherwise
favoured β-defluoronation is diverted completely to
protonative demetalation. The further application of this
method to construct complex molecules is ongoing in our
laboratory.
,
8
9
We thank the “1000-Youth Talents Plan”, a Start-up Grant
(39837110) from Nanjing Tech University and financial support
by SICAM Fellowship by Jiangsu National Synergetic Innovation
Center for Advanced Materials.
10 (a) J. Ichikawa, M. Yokota, T. Kudo, S. Umezaki, Angew.
Chem. Int. Ed. 2008, 47, 4870-4873. (b) B. Gao, Y. Zhao, J. Hu,
Angew. Chem. Int. Ed. 2015, 54, 638-642. (c) P. Tian, C.-Q.
Wang, S.-H. Cai, S. Song, L. Ye, C. Feng, T.-P. Loh, J. Am.
Chem. Soc. 2016, 138, 15869-15872.
11 (a) Ye, B.; Cramer, N. Science, 2012, 338, 504-506. (b) H.
Wang, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 7318-7322.
(c) D. Zhao, Z. Shi, F. Glorius, Angew. Chem. Int. Ed. 2013, 52,
12426-12429. (d) H. Zhang, K. Wang, B. Wang, H. Yi, F. Hu, C.
Li, Y. Zhang, J. Wang, Angew. Chem. Int. Ed. 2014, 53, 13234-
13238. (e) S. Yu, S. Liu, Y. Lan, B. Wan, X. Li, J. Am. Chem. Soc.
2015, 137, 1623-1631.
Notes and references
1
Selected reviews: (a) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320-330. (b) E. P.
Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell,
J. Med. Chem. 2015, 58, 8315-8359. (c) F. Babudri, G. M.
Farinola, F. Naso, R. Ragni, Chem. Commun. 2007, 43, 1003-
1022. (d) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L.
Aceña, V. A. Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016
116, 422-518.
,
2
3
Selected reviews: (a) C. Hollingworth, V. Gouverneur, Chem.
Commun. 2012, 48, 2929-2942. (b) J.-W. Lee, M. T. Oliveira,
H. B. Jang, S. Lee, D. Y. Chi, D. W. Kim, C. E. Song, Chem. Soc.
Rev. 2016, 45, 4638-4650.
Selected reviews: (a) O. A. Tomashenko, V. V. Grushin, Chem.
Rev. 2011, 111, 4475-4521. (b) C. Alonso, E. M. de Marigorta,
G. Rubiales, F. Palacios, Chem. Rev. 2015, 115, 1847-1935. (c)
A. Studer, Angew. Chem. Int. Ed. 2012, 51, 8950-8958. (d) X.
Yang, T. Wu, R. J. Phipps, F. D. Toste, Chem. Rev. 2015, 115,
826-870. (e) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem.
Int. Ed. 2013, 52, 8214-8264.
12 (a) J. Ichikawa, R. Nadano, N. Ito, Chem. Commun. 2006, 42,
4425-4427. (b) M. Hu, Z. He, B. Gao, L. Li, C. Ni, J. Hu, J. Am.
Chem. Soc. 2013, 135, 17302-17305. (c) T. Ichitsuka, T. Fujita,
J. Ichikawa, ACS Catal. 2015, 5, 5947-5950. (d) Z. Zhang, Q.
Zhou, W. Yu, T. Li, G Wu, Y. Zhang, J. Wang, Org. Lett. 2015
17, 2474-2477. (e) Y. Huang, T. Hayashi, J. Am. Chem. Soc.
2016, 138, 12340-12343. (f) Y. Liu, Y. Zhou, Y. Zhao, J. Qu,
Org. Lett. 2017, 19, 946-949.
,
13 (a) X. Li, S. Yu, F. Wang, B. Wan, X. Yu, Angew. Chem. Int. Ed.
2013, 52, 2577-2580. (b) K. Nobushige, K. Hirano, T. Satoh,
M. Miura, Tetrahedron 2015, 71, 6506-6512.
14 (a) T. M. Gøgsig, L. S. Søbjerg, A. T. Lindhardt, K. L. Jensen, T.
Skrydstrup, J. Org. Chem. 2008, 73, 3404-3410. (b) B. Zhang,
X. Zhang, Chem. Commun. 2016, 52, 1238-1241. (c) I.
McAlpine, M Tran-Dubé, F. Wang, S. Scales, J. Matthews, M.
R. Collins, S. K. Nair, M. Nguyen, J. Bian, L. M. Alsina, J. Sun, J.
Zhong, J. S. Warmus, B. T. O’Neill, J. Org. Chem. 2015, 80,
7266-7274.
15 P. Lu, C. Feng, T.-P. Loh, Org. Lett. 2015, 17, 3210-3213.
16 (a) L. Liang, S. Fu, D. Lin, X.-Q. Zhang, Y. Deng, H. Jiang, W.
Zeng, J. Org. Chem. 2014, 79, 9472-9480. (b) X. Qin, H. Liu, D.
Qin, Q. Wu, J. You, D. Zhao, Q. Guo, X. Huang, J. Lan, Chem.
Sci. 2013, 4, 1964-1969. (c) J.-Q. Wu, Z. Yang, S.-S. Zhang, C.-
Y. Jiang, Q. Li, Z.-S. Huang, H. Wang, ACS Catal. 2015, 5,
6453-6457.
4
(a) J. M. Coteron, M. Marco, J. Esquivias, X. Deng, K. L. White,
J. White, M. Koltun, F. E. Mazouni, S. Kokkonda, K. Katneni,
R. Bhamidipati, D. M. Shackleford, I. Angulo-Barturen, S. B.
Ferrer, M. B. Jiménez-Díaz, F.-J. Gamo, E. J. Goldsmith, W. N.
Charman, N. Bathurst, D. Floyd, D. Matthews, J. N. Burrows,
P. K. Rathod, S. A. Charman, M. A. Phillips, J. Med. Chem.
2012, 54, 5540-5561. (b) E. J. Miller, S. G. Mays, M. T. Baillie,
R. B. Howard, D. G. Culver, M. Saindane, S. T. Pruett, J. J.
Holt, D. S. Menaldino, T. J. Evers, G. P. Reddy, R. F. Arrendale,
M. G. Natchus, J. A. Petros, D. C. Liotta, ACS Med. Chem. Lett.
2016, 7, 537-542. (c) S. Gnaim, A. Scomparin, X. Li, P. S.
Baran, C. Rader, R. Satchi-Fainaro, D. Shabat, Bioconjugate
Chem. 2016, 27, 1965-1971. (d) F. Xue, H. Li, S. L. Delker, J.
Fang, P. Martásek, L. J. Roman, T. L. Poulos, R. B. Silverman,
J. Am. Chem. Soc. 2010, 132, 14229-14238. (e) Y. Xia, S.
Chackalamannil, W. J. Greenlee, C. Jayne, B. Neustadt, A.
Stamford, H. Vaccaro, X. Xu, H. Baker, K. O’Neill, M. Woods,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/C7CC04842D
A nonconventional difluoroalkylation of C(sp2)-H bond is achieved by Rh(III)-catalyazed hydroarylation of
2,2-difluorovinyl arenesulfonate.