Copper-catalyzed arylation of 1 H-perfluoroalkanes

Article abstract of DOI:10.1021/ja2041942

A general method has been developed for arylation of readily available 1H-perfluoroalkanes. The method employs aryl iodide and 1H-perfluoroalkane reagents, DMPU solvent, TMP₂Zn base, and a copper chloride/phenanthroline catalyst. Preliminary mechanistic studies are reported.

Full text of DOI:10.1021/ja2041942

COMMUNICATION
pubs.acs.org/JACS
Copper-Catalyzed Arylation of 1H-Perfluoroalkanes
Ilya Popov,† Sergey Lindeman,‡ and Olafs Daugulis*,†
†Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
‡Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881, United States
S Supporting Information
b
Scheme 1. Reaction Development Considerations
ABSTRACT: A general method has been developed for
arylation of readily available 1H-perfluoroalkanes. The method
employs aryl iodide and 1H-perfluoroalkane reagents, DMPU
solvent, TMP2Zn base, and a copper chloride/phenanthroline
catalyst. Preliminary mechanistic studies are reported.
any pharmaceuticals and agrochemicals contain aryl-triflu-
M
oromethyl or aryl-polyfluoroalkyl linkages.1 Consequently,
introduction of fluoroalkyl substituents into aromatic systems
has attracted intense interest. Trichloromethyl groups and other
functionalities can be converted to trifluoromethyl moieties by
treatment with a fluorinating reagent.2 A halide or, rarely, a
hydrogen on an aromatic ring can be replaced with a trifluoro-
methyl group under transition metal catalysis. Examples of such
reactions include palladium-catalyzed trifluoromethylation of
aryl chlorides3 and ortho-trifluoromethylation of 2-phenylpyri-
dines.4 More commonly, however, copper is employed for poly-
fluoroalkylation of aryl iodides. Typically, trifluoromethyltrialk-
ylsilane reagents are used in combination with a stoichiometric
copper source.5 A recent pioneering report describes reactions
catalytic in copper. However, only electron-deficient aryl iodides
react in high yields.6 Cross-coupling of aryl iodides and perfluoro-
alkyl iodides by employing 1À3 equiv copper metal has also been
reported.7 Arene reactions with RFI proceed by radical mechanisms
and often result in isomer mixtures.8
Scheme 2. Reaction Optimization
In most of the above cases, RFSiR3 reagents have been employ-
ed. However, only trifluoromethyl-, pentafluoroethyl-, and hep-
tafluoropropyltrialkylsilanes are commercially available. Thus, a
widely available perfluoroalkyl source should be sought to
develop a generally useful synthetic methodology. We report
here a method for copper-catalyzed 1H-perfluoroalkane arylation
by aryl iodides.
Based on previous work on copper-catalyzed arylation of
polyfluoroarenes,9 we considered the arylation of 1H-perfluor-
oalkanes (Scheme 1). The lowest homologues of 1H-perfluor-
oalkanes are among the cheapest sources of RF groups. Several
issues had to be addressed to develop a viable method (Scheme 1).
First, the stability of the perfluoroalkyl metal reagent generated
in the deprotonation step needs to be considered. In contrast
to pentafluoroaryl metals,10 most perfluoroalkyl metals are un-
stable.11 Only mercury, cadmium, bismuth, thallium, and zinc
perfluoroalkyls are relatively stable.11,12 A viable methodology will
not use highly toxic Cd, Hg, or Tl reagents; thus, Bi or Zn bases
must be employed. Second, the base type needs to be determined.
Trifluoromethane possesses a pKa of about 31 requiring an amide
base for deprotonation.13 Bismuth amides are photolytically and
thermally unstable.14 Consequently, a zinc amide base should be
employed. The amide moiety should be hindered to prevent
copper-catalyzed amination of aryl iodide.15 These considerations
led to the selection of the zinc bis-2,2,6,6-tetramethylpiperidide
(TMP2Zn) base.16
The reaction was optimized with respect to ligand and solvent
(Scheme 2). For perfluoroalkylation of electron-rich 2-meth-
oxyiodobenzene, a phenanthroline ligand additive afforded an
increased conversion. However, high conversion to the product
was observed for 2-iodopyridine perfluoroalkylation in both the
presence and absence of phenanthroline. Presumably, the phenan-
throline ligand stabilizes perfluoroalkyl copper species.6 Consequently,
Received: May 6, 2011
Published: May 31, 2011
r
2011 American Chemical Society
9286
dx.doi.org/10.1021/ja2041942 J. Am. Chem. Soc. 2011, 133, 9286–9289
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Perfluoroalkylation Scope with Respect to ArIa
a TMP2Zn (0.5 mmol), RFH (0.5 mmol), DMPU, then ArI (1.5 mmol), phenanthroline (0.1 mmol), and CuCl (0.05 mmol), 90 °C. b TMP2Zn (0.75
mmol), RFH (1.5 mmol), DMPU, then ArI (0.5 mmol), phenanthroline (0.1 mmol), and CuCl (0.05 mmol).
for functionalization of more reactive aryl iodides, phenanthroline
may be omitted. Solvent optimization showed that the best results
are obtained in DMPU which was used in all further reactions.
The perfluoroalkylation scope with respect to aryl iodides is
presented in Table 1. We were pleased to discover that benzylated
R,R,ω-trihydroperfluoroheptanol was arylated by a number of aryl
iodides under the optimized reaction conditions. Electron-rich
2-iodoanisole and 4-iodotoluene are reactive affording coupling
products in moderate yields (entries 1 and 2). Reactions with
electron-poor ArI are higher yielding (entries 3À5, 7, 11). Func-
tional groups such as trifluoromethoxy (entry 3), nitrile (entry 4),
bromide (entry 7), and ester (entry 11) are tolerated. Iodinated
heterocycles such as 2-iodopyridine, 2-iodo-4,5-dimethylthiazole,
and 8-iodocaffeine react to give products in good to excellent yields
(entries 8À10). 2,6-Disubstituted electron-rich aryl iodides do not
afford the coupling products. Instead, the iodide moiety is reduced.
Unactivated aryl bromides are unreactive. Thus, reaction of 4-bro-
mobiphenyl with benzylated R,R,ω-trihydroperfluoroheptanol
under standard reaction conditions afforded the coupling product
in <5% conversion.
The reaction scope with respect to 1H-perfluoroalkanes is pre-
sented in Table 2. The most difficult coupling partner is trifluoro-
methane (entry 1). Trifluoromethyl copper decomposes gener-
ating pentafluoroethylcopper unless it is stabilized by HMPA.17
About 10% of pentafluoroethylated substrate was observed in the
crude reaction mixture, and purification by HPLC was required to
obtain pure ethyl 2-(trifluoromethyl)benzoate. Reactions with other
1H-perfluoroalkanes, such as C2F5H, CF3CF2CF2H, and 1H-per-
fluorohexane, are high-yielding (entries 2À5). Substrates possessing
two ÀCF2H moieties can be either monoarylated (entries 6 and 7)
or diarylated (entry 8) depending on the reaction stoichiometry.
Some functionality such as chloro and amide (entries 9 and 10) is
tolerated. 2H-Heptafluoropropane is unreactive.18
Preliminary mechanistic studies have been performed. The
intermediate bis(perfluoroethyl)zinc species 1 was prepared by
the reaction of TMP2Zn with pentafluoroethane (Scheme 3).
9287
dx.doi.org/10.1021/ja2041942 |J. Am. Chem. Soc. 2011, 133, 9286–9289

Journal of the American Chemical Society
COMMUNICATION
Table 2. Perfluoroalkylation Scope with Respect to RFHa
a TMP2Zn (0.75 mmol), RFH (1.5À5 mmol), DMPU, ArI (0.5 mmol), phenanthroline (0.1 mmol), CuCl (0.05 mmol), 90 °C. b Phenanthroline
(1 mmol). c TMP2Zn (1 mmol), RFH (0.5 mmol), DMPU, ArI (4 mmol), phenanthroline (0.1 mmol), and CuCl (0.05 mmol). d TMP2Zn (0.5 mmol),
RFH (0.5 mmol), DMPU, ArI (1.5 mmol), phenanthroline (0.1 mmol), and CuCl (0.05 mmol).
1
The complex was characterized by H and 19F NMR, X-ray
crystallography, and elemental analysis. Additionally, anionic
copper complex 2 was prepared in low yield by reaction of CuCl,
KF, and TMSCF3 (Scheme 3). Complex 2 exists as a temperature
and moisture sensitive colorless solid that slowly decomposes at
RT under an argon atmosphere over the course of several hours,
but is stable for at least 4 weeks at À35 °C under an inert atmo-
sphere. It was characterized by 1H and 19F NMR as well as X-ray
crystallographic analysis.
were tentatively identified by comparison with NMR of authentic 2
and reported spectral data for 3 (Scheme 4).19 Furthermore, a
preformed mixture of 2 and 3 in the presence of excess 1 was
subjected to the reaction with ethyl-2-iodobenzoate at 25, 40, 60, and
90 °C. At 25 and 40 °C, consumption of 2 and 3 is observed and 5 is
formed; however, 1 does not undergo transmetalation with copper
halide. Further heating at 60 °C is required for transmetalation to
occur. Heating to 90 °C leads to the fast consumption of aryl iodide
and 1 followed by the reappearance of 2 and 3. These experiments
show that transmetalation appears to be the turnover-limiting step
for pentafluoroethylation of ethyl 2-iodobenzoate.
Several 19F NMR experiments were carried out to determine the
identity of the species present in the reaction mixture and their
reactivity. Mixing CuCl and excess 1 in DMPU solvent affords
negligible amounts of zinc to copper transmetalation products at
45 °C. However, the reaction at 90 °C affords several species that
The general reaction mechanism is presented in Scheme 5.
Deprotonation of 1H-perfluoroalkanes with TMP2Zn affords
bis(perfluoroalkyl)zinc species. Subsequent transmetalation with
9288
dx.doi.org/10.1021/ja2041942 |J. Am. Chem. Soc. 2011, 133, 9286–9289

Journal of the American Chemical Society
COMMUNICATION
Scheme 3. Reaction Intermediate Synthesis
Research Program for supporting this research. We thank Dr.
James Korp for collecting and solving the X-ray structures.
’ REFERENCES
(1) (a) Jeschke, P. ChemBioChem 2004, 5, 570. (b) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008,
37, 320. (c) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432.
(2) (a) Dmowski, W.; Wielgat, J. J. Fluorine Chem. 1987, 37, 429.
(b) Bloodworth, A. J.; Bowyer, K. J.; Mitchell, J. C. Tetrahedron Lett.
1987, 28, 5347. (c) Hudlicky, M. Org. React. 1988, 35, 513.
(3) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679.
Scheme 4. NMR Experiments
(4) (a) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 3648. (b) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc.
2010, 132, 2878.
(5) (a) Burton, D. J.; Lu, L. Top. Curr. Chem. 1997, 193, 45.
(b) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc.
2008, 130, 8600. (c) Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991,
32, 91. (d) Follꢀeas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L.
Tetrahedron 2000, 56, 275. Pd:(e) Grushin, V. V.; Marshall, W. J. J.
Am. Chem. Soc. 2006, 128, 4632. (f) Dubinina, G. G.; Ogikubo, J.; Vicic,
D. A. Organometallics 2008, 27, 6233.
(6) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.
(7) (a) Xiao, J.-C.; Ye, C.; Shreeve, J. M. Org. Lett. 2005, 7, 1963.
(b) Mcloughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921.
(c) Croxtall, B.; Fawcett, J.; Hope, E. G.; Stuart, A. M. J. Chem. Soc.,
Dalton Trans. 2002, 491.
(8) Review: Furin, G. G. Russ. Chem. Rev. 2000, 69, 491.
(9) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128.
(b) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008,
130, 15185.
(10) (a) Cairncross, A.; Sheppard, W. A. J. Am. Chem. Soc. 1968,
90, 2186. (b) Coe, P. L.; Stephens, R.; Tatlow, J. C. J. Chem. Soc.
1962, 3227. However, C6F5Li can be hazardous:(c) Kinsella, E.;
Massey, A. G. Chem. Ind. (London) 1971, 36, 1017B.
Scheme 5. Reaction Mechanism
(11) Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189.
(12) (a) Naumann, D.; Tyrra, W. J. Organomet. Chem. 1987,
334, 323. (b) Nair, H. K.; Morrison, J. A. Inorg. Chem. 1989, 28, 2816.
(13) (a) Andreades, S. J. Am. Chem. Soc. 1964, 86, 2003.
(b) Chabinyc, M. L.; Brauman, J. I. J. Am. Chem. Soc. 1998, 120, 10863.
(14) Vehkam€aki, M.; Hatanp€a€a, T.; Ritala, M.; Leskel€a, M. J. Mater.
Chem. 2004, 14, 3191.
(15) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(16) (a) Rees, W. S., Jr.; Just, O.; Schumann, H.; Weimann, R. Poly-
hedron 1998, 17, 1001. (b) Hlavinka, M. L.; Hagadorn, J. R. Organome-
tallics 2007, 26, 4105.
copper halide produces a mixture of anionic Cu species that re-
acts with aryl iodide, either directly or via a neutral perfluoroalkyl
compound,5f to give the coupling product.
In conclusion, we have developed a general method for arylation
of readily available 1H-perfluoroalkanes. The method employs aryl
iodide and 1H-perfluoroalkane reagents, a DMPU solvent, a
TMP2Zn base, and a copper chloride/phenanthroline catalyst.
(17) Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108, 832.
(18) Nair, H. K.; Burton, D. J. J. Fluorine Chem. 1992, 56, 341.
(19) (a) Naumann, D.; Schorn, C.; Tyrra, W. Z. Anorg. Allg. Chem.
1999, 625, 827. (b) Lange, H.; Naumann, D. J. Fluorine Chem. 1984,
26, 435. (c) Naumann, D.; Roy, T.; Caeners, B.; H€utten, D.; Tebbe,
K.-F.; Gilles, T. Z. Anorg. Allg. Chem. 2000, 626, 999.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization data for new compounds, and X-ray crystallography
data for 1 and 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
olafs@uh.edu
’ ACKNOWLEDGMENT
We thank the Welch Foundation (Grant No. E-1571), Na-
tional Institute of General Medical Sciences (Grant No.
R01GM077635), A. P. Sloan Foundation, Camille and Henry
Dreyfus Foundation, and Norman Hackerman Advanced
9289
dx.doi.org/10.1021/ja2041942 |J. Am. Chem. Soc. 2011, 133, 9286–9289