Copper-Catalyzed C-H Difluoroalkylations and Perfluoroalkylations of Alkenes and (Hetero)arenes

Article abstract of DOI:10.1021/acs.orglett.7b01712

A general and facile synthetic method for C(sp²)-H difluoroalkylations and perfluoroalkylations of alkenes and (hetero)arenes with commercially available fluoroalkyl halides has been developed with a copper-amine catalyst system. This method is characterized by high yields, mild reaction conditions, low-cost catalyst, broad substrate scope, and excellent functional group compatibility, therefore providing a convenient synthetic strategy toward various difluoroalkyl- and perfluoroalkyl-substituted alkenes and (hetero)arenes.

Full text of DOI:10.1021/acs.orglett.7b01712

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed C−H Difluoroalkylations and Perfluoroalkylations
of Alkenes and (Hetero)arenes
Xiaoyang Wang,† Shuang Zhao,† Jing Liu,† Dingsheng Zhu,† Minjie Guo,*,‡ Xiangyang Tang,*,†
and Guangwei Wang*,†
†Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin University,
Tianjin 300072, P. R. China
‡Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072,
P. R. China
S
* Supporting Information
ABSTRACT: A general and facile synthetic method for C(sp2)−H difluoroalkylations and
perfluoroalkylations of alkenes and (hetero)arenes with commercially available fluoroalkyl
halides has been developed with a copper-amine catalyst system. This method is
characterized by high yields, mild reaction conditions, low-cost catalyst, broad substrate
scope, and excellent functional group compatibility, therefore providing a convenient
synthetic strategy toward various difluoroalkyl- and perfluoroalkyl-substituted alkenes and
(hetero)arenes.
ncorporation of fluorine atoms into organic motifs has a
Isignificant influence on the lipophilicity, metabolic stability,
and bioavailability of organic molecules.1 During the past several
years, transition metal catalysis has emerged as a powerful tool
for fluoroalkylation reactions. The direct C−H fluoroalkylation
of alkenes and (hetero)arenes has been developed as an attractive
approach to generate C−Rf bonds for the synthesis of
corresponding fluoroalkylated compounds.2,3 However, highly
active trifluoromethyl reagents such as Togni’s reagent and
Umemoto’s reagent are generally required as the fluorine
sources. Recently, fluoroalkylation using relatively mild
fluoroalkyl halides as a fluorine source has also been exploited
by several research groups. For example, Zhang et al.4 reported a
Heck-type reaction for the synthesis of difluoromethylated
alkenes using Pd as a catalyst and xantphos as a ligand (Scheme 1,
eq 1). In addition, the Ru- or Ir-catalyzed fluoroalkylation of
alkenes through a visible-light-induced reaction5 was also
developed (Scheme 1, eq 2). Despite all these achievements,
the wide application of these strategies is limited by the high cost
of the Pd or Ru catalyst systems, especially for application in
large-scale synthesis of fluorinated molecules. More mild and
practical catalytic systems need to be developed to provide a
convenient strategy for the construction of fluorinated
compounds.
Ethyl bromodifluoroacetate (BrCF2CO2Et, 2a) is an inex-
pensive and commercially available reagent, which can serve not
only as a gem-difluoromethylene (CF2) group precursor but also
as useful CF2CO2Et-containing synthons for the preparation of
various difluoroalkylated compounds.6 Cuprous iodide (CuI),
which is a very cheap, bench stable, and easily handled catalyst,
has been proven to be versatile for various types of reactions such
as Goldberg reaction, Ullman coupling, Sonogashira coupling,
and click reaction. Recently, CuI has also been proven effective in
the direct transfer of the CF2CO2Et group from ethyl
bromodifluoroacetate onto various alkenes.7 However, these
alkenes are limited to electron-rich alkenes such as enol ethers,
enamides, dihydropyrans, and so on (Scheme 1, eq 3). Among
these reports, phenanthroline is required as a ligand of copper
and at least 1 equiv of inorganic base should be added. To study
the difluoroalkylation of general alkenes, various reaction
parameters especially ligands have been screened in our group.
Herein we report an efficient and cost-effective strategy for the
difluoroalkylation of a wide range of alkenes and (hetero)arenes
using a cheap and easily accessible copper−amine catalyst system
(Scheme 1, eq 4).
Scheme 1. C−H Fluoroalkylation of Alkenes and
(Hetero)arenes Using Fluoroalkyl Halides
Received: June 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01712
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Organic Letters
Letter
Our initial studies were focused on the difluoroalkylation of
styrene (1a) with ethyl bromodifluoroacetate (2a) in the
presence of CuI (10 mol %) and ligand in CH3CN under an
Ar atmosphere at 80 °C. In order to simplify the reaction system,
1.5 equiv of basic ligands were added, serving dual roles as ligand
and base. As shown in Table 1, the choice of ligand is crucial in
Scheme 2. Copper-Catalyzed C−H Difluoromethylation of
a
Alkenes
a
Table 1. Optimization of Reaction Conditions
b
entry
[Cu]
CuI
base
none
solvent
yield (%)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DMSO
DMF
n.d.
n.d.
<5
CuI
K2CO3
CuI
DBU
CuI
Et3N
<5
CuI
phen
<5
CuI
TMEDA
TMPDA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
73
CuI
51
CuI
97(92)
94(91)
75
c
9
CuI
10
11
12
13
14
15
16
CuCl
CuBr
CuBr2
Cu(OTf)2
CuI
80
65
67
26
CuI
77
CuI
86
a
Reaction conditions: Unless otherwise noted, all reactions were
performed with 1a (1.0 mmol), 2a (1.5 mmol), base (1.5 mmol), and
[Cu] (10 mol %), in CH3CN (2 mL) at 80 °C under Ar for 12 h.
b
Determined by GC with dodecane as an internal standard. The values
a
Reaction conditions: 1 (1.0 mmol, 1.0 equiv), 2a (1.5 mmol, 1.5
in parentheses are the isolated yields. n.d. = not detected. phen =
phenanthroline. 1.0 mol % of CuI was used.
c
equiv), PMDETA (1.5 mmol, 1.5 equiv), CuI (1.0 mol %), CH3CN
b
(2.0 mL), under Ar at 80 °C for 12 h. 5.0 mol % of CuI was used.
c
The reaction temperature was set at 100 °C.
obtaining the desired product 3a. No reaction occurred in the
absence of ligand (entry 1). General bases such as K2CO3, Et3N,
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and 1,10-phenan-
throline led to no desired compounds (entries 2−5). However,
when a multidentate amine such as TMEDA (N,N,N′,N′-
tetramethyl-ethylenediamine), TMPDA (N,N,N′,N′-tetrameth-
yl-1,3-propane-diamine), and PMDETA (pentamethyl-
diethylenetriamine) were applied, the desired product 3a can
be afforded in good to excellent yields (entries 6−9). The key
role of the multidentate amine might be its ability to stabilize the
alkyl copper intermediates generated from corresponding alkyl
halides and a copper catalyst.8 Other copper salts, including
CuBr, CuCl, CuBr2, and Cu(OTf)2, have also been screened
(entries 10−13). Although good yields can be obtained, they are
not higher than the yield of CuI as a catalyst. Therefore, CuI was
chosen as the optimized catalyst for further reaction screening.
Furthermore, when the catalyst loading was reduced to 1 mol %,
the corresponding product 3a can be achieved with a similar yield
(entry 8). Various solvents, such as toluene, DMSO, and DMF
(entries 14−16), were also examined, and DMF led to a similar
yield as CH3CN. Due to its easier workup procedure than in the
case of DMF, CH3CN was chosen as the most suitable solvent.
Eventually, the reaction conditions in entry 8 were chosen as the
optimized conditions.
substituents on the aromatic ring were initially examined (3a−
3p). Various functional groups, such as halogen, ester, nitro,
nitrile, ketone, and hydroxyl, were well tolerated to give desired
products in moderate to excellent yields. It is noteworthy that the
B(OH)2 group can also be tolerated, and the product (3h) can be
utilized for the synthesis of complex organofluoro compounds
via Suzuki cross-coupling. Internal alkenes can also provide the
corresponding products in high yield (3o) with high
regioselectivity, which is difficult to realize through known
methods. 1,1-Disubstituted alkenes also gave the corresponding
products in high yields (3p and 3u). Besides electron-rich
alkenes, electron-poor alkenes can also be used as substrates to
give the fluorinated alkenes (3r, 3u, and 3v) which could undergo
Diels−Alder reaction to afford more complicated fluorine-
containing organic molecules. Moreover, nonactivated aliphatic
alkenes provided the corresponding products in high yields with
high regio- and stereoselectivities under the standard conditions
(3w−3z).
Encouraged by the above results, other functionalized
difluoroalkylated bromides and perfluoroalkyl iodides were
studied (Scheme 3). Gratifyingly, good yields (4a−4c) were
obtained when bromodifluoroacetamides were used as fluorinat-
ing reagents. The α-bromo-α,α-difluoro-acetophenone was also
a suitable substrate, providing its corresponding difluoroalky-
lated styrene (4d). It is noteworthy that bromodifluoromethyl-
With the optimized reaction conditions in hand, the substrate
scope of the alkenes was investigated, and the results are
summarized in Scheme 2. A variety of styrenes bearing different
B
DOI: 10.1021/acs.orglett.7b01712
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Organic Letters
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Scheme 3. Copper-Catalyzed C−H Fluoroalkylation of
Scheme 4. Copper-Catalyzed C−H Difluoromethylation of
a
a
Alkenes
(Hetero)arenes
a
Reaction conditions: 1a (1.0 mmol, 1.0 equiv), 2′ (1.5 mmol, 1.5
equiv), PMDETA (1.5 mmol, 1.5 equiv), CuI (10 mol %), CH3CN
(2.0 mL), under Ar at 80 °C for 12 h. The reaction temperature was
set at 50 °C. CF3I (4.0 equiv), 90 °C.
b
c
a
Reaction conditions: 5 (1.0 mmol, 1.0 equiv), 2a (3.0 mmol, 3.0
equiv), PMDETA (1.5 mmol, 1.5 equiv), CuI (10 mol %), CH3CN
b
benzoxazole and its derivatives can also be subjected to the above
conditions, affording more diverse difluoromethyl benzoxazole
compounds (4e and 4f) which are potential pharmaceuticals and
agrochemicals.9 The reaction can also be applied to trifluor-
omethyl iodides, and a series of trifluoromethylated alkenes (4g−
4i) were obtained through this method. Similarly, perfluoroalkyl
iodides also underwent a similar transformation in good yields
(4j−4l), thus providing a facile and general access to a wide range
of perfluoroalkylated alkenes.
(2.0 mL), under Ar at 80 °C for 12 h. 2a (1.5 mmol, 1.5 equiv) was
c
used. Bisdifluoroalkylation product (6cc) was also obtained in 21%
yield.
Scheme 5. Synthesis of Perfluorinated 3-Methyl-indole
We next turned our attention to heterocycles since
difluoroalkylated heterocycles are known as valuable pharmaco-
phores. As shown in Scheme 4, a wide range of heterocycles is
compatible with this new difluoroalkylation approach. The
difluoroalkylation of indoles, pyrroles, furans, and thiophenes
generally occurred with moderate yields and excellent
regioselectivities, except that 6c was accompanied by a
bisdifluoroalkylated product (6cc). The major benefit of this
facile difluoroalkylation method is that the late-stage incorpo-
ration of difluoroalkyl group into biologically active molecules
could be realized in a regioselective manner. For instance, a uracil
analog (6h), coumarin (6j), and flavones (6k) were selectively
difluoroalkylated at specific positions, respectively. Furthermore,
it was found that a 3,3-difluoro-oxindole derivative can be
obtained with high efficiency when the heterocycle was replaced
by β-naphthylamine (6l). The difluoroalkylation of corannulene
(6o) can also occur in moderate yield. The trifluoromethylation
and perfluoroalkylation of 3-methylindole can also be realized
with good yields by improving the temperature in the standard
conditions (Scheme 5).
Scheme 6. Multigram-Scale Experiment
To gain some mechanistic insight into the reaction, the radical
scavenger 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO, 1.5
equiv) was added to the standard reaction mixture of 2a and
1a. Instead of forming 3a, the TEMPO−CF2CO2Et was obtained
as the only product (49% yield as estimated by 19F NMR
spectroscopy). β-Pinene, a known radical clock, was also used
and gave the desired ring-opened diene in 81% yield (see the
Supporting Information). In light of this result, a plausible radical
pathway was proposed (Scheme 7).
In conclusion, direct C−H fluoroalkylation of alkenes and
(hetero)arenes has been achieved with the bench stable cuprous
iodide as a catalyst and commercially available fluoroalkyl halides
(RfX) as fluorinated reagents. Through this strategy, various
types of alkenes, arenes, and heteroarenes can be regioselectively
fluoroalkylated, demonstrating its broad applicability and general
compatibility. The resulting fluoroalkylated alkenes and
(hetero)arenes can serve as potential intermediates for further
synthesis of biologically active compounds. Therefore, this
Importantly, a multigram-scale experiment has been demon-
strated using styrene (1a) as a model substrate. Remarkably,
gram-scale synthesis of 3a in the presence of 0.5 mol % copper
catalyst proceeded smoothly with high yield and stereoselectivity
(Scheme 6). Thus, this general, facile, mild, and cost-effective
method may offer a practical access to highly functionalized
fluoroalkylated molecules.
C
DOI: 10.1021/acs.orglett.7b01712
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Organic Letters
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Org. Lett. 2011, 13, 2548. (c) He, L.; Natte, K.; Rabeah, J.; Taeschler, C.;
Scheme 7. Proposed Mechanism
Neumann, H.; Bruckner, A.; Beller, M. Angew. Chem., Int. Ed. 2015, 54,
̈
4320. (d) Nishida, T.; Ida, H.; Kuninobu, Y.; Kanai, M. Nat. Commun.
2014, 5, 3387. (e) Sladojevich, F.; McNeill, E.; Borgel, J.; Zheng, S.-L.;
̈
Ritter, T. Angew. Chem., Int. Ed. 2015, 54, 3712. (f) Sahoo, B.; Li, J.-L.;
Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 11577. (g) Natte, K.;
Jagadeesh, R. V.; He, L.; Rabeah, J.; Chen, J.; Taeschler, C.; Ellinger, S.;
Zaragoza, F.; Neumann, H.; Brîckner, A.; Beller, M. Angew. Chem., Int.
Ed. 2016, 55, 2782. (h) Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K.
Chem. Rev. 2017, 117, 9302.
(3) (a) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
3648. (b) Zhang, X.-G.; Dai, H.-X.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc.
2012, 134, 11948. (c) Shang, M.; Sun, S.-Z.; Wang, H.-L.; Laforteza, B.
N.; Dai, H.-X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2014, 53, 10439.
method will not only provide a cost-effective and facile synthesis
toward novel fluoroalkyl containing pharmaceutical molecules
but also prompt research in low-cost transition-metal-catalyzed
C(sp2)−H fluoroalkylation reactions. Further study to elucidate
the mechanism and apply this method to the synthesis of
complicated bioactive molecules is underway in our laboratory.
(d) Hafner, A.; Brase, S. Angew. Chem., Int. Ed. 2012, 51, 3713. (e) Feng,
̈
C.; Loh, T.-P. Angew. Chem., Int. Ed. 2013, 52, 12414. (f) Ruan, Z.;
Zhang, S.-K.; Zhu, C.; Ruth, P. N.; Stalke, D.; Ackermann, L. Angew.
Chem., Int. Ed. 2017, 56, 2045. (g) Zhou, Q.; Ruffoni, A.; Gianatassio, R.;
Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Angew. Chem., Int. Ed.
2013, 52, 3949. (h) Caillot, G.; Dufour, J.; Belhomme, M.-C.; Poisson,
T.; Grimaud, L.; Pannecoucke, X.; Gillaizeau, I. Chem. Commun. 2014,
50, 5887.
ASSOCIATED CONTENT
* Supporting Information
■
(4) (a) Feng, Z.; Min, Q.-Q.; Zhao, H.-Y.; Gu, J.-W.; Zhang, X. Angew.
Chem., Int. Ed. 2015, 54, 1270. (b) Zhang, F.; Min, Q.-Q.; Zhang, X.
Synthesis 2015, 47, 2912. (c) Feng, Z.; Xiao, Y.-L.; Zhang, X. Org. Chem.
Front. 2016, 3, 466.
(5) (a) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224.
(b) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;
Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U. S. A. 2011, 108,
14411. (c) Chatterjee, T.; Iqbal, N.; You, Y.; Cho, E. J. Acc. Chem. Res.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01712.
Experimental procedures, spectral and analytical data,
1
copies of H and 13C NMR spectra for new compounds
(PDF)
2016, 49, 2284. (d) Straathof, N. J. W.; Cramer, S. E.; Hessel, V.; Noel,
̈
T. Angew. Chem., Int. Ed. 2016, 55, 15549. (e) He, C.-Y.; Kong, J.; Li, X.;
Li, X.; Yao, Q.; Yuan, F.-M. J. Org. Chem. 2017, 82, 910.
AUTHOR INFORMATION
Corresponding Authors
■
(6) For recent examples, see: (a) Yang, M.-H.; Orsi, D. L.; Altman, R.
A. Angew. Chem., Int. Ed. 2015, 54, 2361. (b) Yu, J.-S.; Liao, F.-M.; Gao,
W.-M.; Liao, K.; Zuo, R.-L.; Zhou, J. Angew. Chem., Int. Ed. 2015, 54,
7381. (c) Ye, Z.; Gettys, K. E.; Shen, X.; Dai, M. Org. Lett. 2015, 17,
6074. (d) Wan, W.; Ma, G.; Li, J.; Chen, Y.; Hu, Q.; Li, M.; Jiang, H.;
Deng, H.; Hao, J. Chem. Commun. 2016, 52, 1598.
*E-mail: guomj2016@tju.edu.cn.
*E-mail: txy@tju.edu.cn.
*E-mail: wanggw@tju.edu.cn.
ORCID
Guangwei Wang: 0000-0003-4466-9809
Notes
(7) (a) Belhomme, M.-C.; Dru, D.; Xiong, H.-Y.; Cahard, D.; Besset,
T.; Poisson, T.; Pannecoucke, X. Synthesis 2014, 46, 1859. (b) Caillot,
G.; Dufour, J.; Belhomme, M.-C.; Poisson, T.; Grimaud, L.;
Pannecoucke, X.; Gillaizeau, I. Chem. Commun. 2014, 50, 5887.
(c) Mishra, S.; Mondal, P.; Ghosh, M.; Mondal, S.; Hajra, A. Org.
Biomol. Chem. 2016, 14, 1432. (d) Belhomme, M.-C.; Poisson, T.;
Pannecoucke, X. J. Org. Chem. 2014, 79, 7205. (e) Belhomme, M.-C.;
Poisson, T.; Pannecoucke, X. Org. Lett. 2013, 15, 3428. (f) Xu, H.;
Wang, D.; Chen, Y.; Wan, W.; Deng, H.; Ma, K.; Wu, S.; Hao, J.; Jiang,
H. Org. Chem. Front. 2017, 4, 1239.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (No.
2015CB856500) and the Natural Science Foundation of Tianjin
(No. 16JCYBJC20100) for support of this research.
(8) (a) Taylor, M. J. W.; Eckenhoff, W. T.; Pintauer, T. Dalton Trans.
2010, 39, 11475. (b) Eckenhoff, W. T.; Pintauer, T. Dalton Trans. 2011,
40, 4909. (c) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am.
Chem. Soc. 2013, 135, 16372. (d) Theunissen, C.; Wang, J.; Evano, G.
Chem. Sci. 2017, 8, 3465.
(9) (a) Feng, Z.; Min, Q.-Q.; Xiao, Y.-L.; Zhang, B.; Zhang, X. Angew.
Chem., Int. Ed. 2014, 53, 1669. (b) Min, Q.-Q.; Yin, Z.; Feng, Z.; Guo,
W.-H.; Zhang, X. J. Am. Chem. Soc. 2014, 136, 1230. (c) Xiao, Y.-L.; Guo,
W.-H.; He, G.-Z.; Pan, Q.; Zhang, X. Angew. Chem., Int. Ed. 2014, 53,
9909.
REFERENCES
■
(1) (a) Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R., Kobayashi, Y., Yagupolskii, L. M.,
Eds.; Elsevier: Amsterdam, 1993. (b) Purser, S.; Moore, R. P.; Swallow,
S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Furuya, T.;
Kuttruff, C.; Ritter, T. Curr. Opin. Drug Discovery Dev. 2008, 11, 803.
(d) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. Angew. Chem., Int. Ed.
2014, 53, 1881. (e) Gouverneur, V.; Seppelt, K. Chem. Rev. 2015, 115,
563. (f) Honeker, R.; Ernst, J. B.; Glorius, F. Chem. - Eur. J. 2015, 21,
8047. (g) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.;
̃
Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422. (h) Ni,
C.; Hu, J. Chem. Soc. Rev. 2016, 45, 5441. (i) Ni, C.; Hu, M.; Hu, J. Chem.
Rev. 2015, 115, 765. (j) Arlow, S. I.; Hartwig, J. F. Angew. Chem., Int. Ed.
2016, 55, 4567. (k) Li, X.; Zhao, J.; Hu, M.; Chen, D.; Ni, C.; Wang, L.;
Hu, J. Chem. Commun. 2016, 52, 3657. (l) Zhu, J.; Liu, Y.; Shen, Q.
Angew. Chem., Int. Ed. 2016, 55, 9050. (m) Lu, C.; Gu, Y.; Wu, J.; Gu, Y.;
Shen, Q. Chem. Sci. 2017, 8, 4848. (n) Lai, Y.-L.; Lin, D.-Z.; Huang, J.-M.
J. Org. Chem. 2017, 82, 597.
(2) Recent examples on C−H fluoroalkylation: (a) Ye, Y.; Lee, S. H.;
Sanford, M. S. Org. Lett. 2011, 13, 5464. (b) Loy, R. N.; Sanford, M. S.
D
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