Silver-mediated methoxycarbonyltetrafluoroethylation of arenes

Article abstract of DOI:10.1021/ol401558z

In the presence of silver(I) fluoride, highly fluorinated olefins react readily under solvent-free conditions with arenes via CH-substitution. This transformation could be used to synthesize various methoxycarbonyltetrafluoroethylated aromatic triazenes and anisoles under high functional group tolerance. The method could be applied to the synthesis of a formal fluorinated bioisostere of the NSAID flurbiprofen. To the best of our knowledge, this is the first example which uses highly fluorinated olefins for the perfluoroalkylation of aromatic substrates.

Full text of DOI:10.1021/ol401558z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Silver-Mediated Methoxycarbonyl-
tetrafluoroethylation of Arenes
†
Andreas Hafner, Thomas J. Feuerstein, and Stefan Brase*
†
,†,‡
€
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT),
Fritz-Haber Weg 6, 76131 Karlsruhe, Germany, and Institute of Toxicology and
Genetics, Karlsruhe Institute of Technology (KIT), Herrmann-von-Helmholtz Platz 1,
76344 Eggenstein-Leopoldshafen, Germany
braese@kit.edu
Received June 3, 2013
ABSTRACT
In the presence of silver(I) fluoride, highly fluorinated olefins react readily under solvent-free conditions with arenes via CH-substitution. This
transformation could be used to synthesize various methoxycarbonyltetrafluoroethylated aromatic triazenes and anisoles under high functional
group tolerance. The method could be applied to the synthesis of a formal fluorinated bioisostere of the NSAID flurbiprofen. To the best of our
knowledge, this is the first example which uses highly fluorinated olefins for the perfluoroalkylation of aromatic substrates.
Despite the nearly complete absence of fluorine in
natural products, a vast number of pharmaceuticals and
agrochemicals are fluorinated compounds. Fluorine as
well as fluorinated moieties offer unique chemical and
physical properties, which can dramatically enhance the
biological effectiveness of organic compounds and make
them interesting in terms of bioisosteric replacement.
Thus, numerous examples show that the introduction of
fluorinated groups improve the metabolic activity, bio-
availability, or lipophilicity of an active agent.1 This ex-
plains why the interest in direct fluorination as well as
direct perfluoroalkylation reactions has substantially
grown over recent years. Especially the trifluoromethyl
group plays an important role in modern synthetic organic
† Institute of Organic Chemistry.
‡ Institute of Toxicology and Genetics.
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, Germany, 2004. (b) Filler, R.; Kobayashi, Y.; Yagupolskii, Y. L.
Organofluorine Compounds in Medicinal Chemistry and Biological Ap-
plications; Elsevier: Amsterdam, 1993. (c) Purser, S.; Moore, P. R.; Swallow,
S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(2) Recent examples of aromatic trifluoromethylation: (a) Zhang,
L.-S.; Chen, K.; Chen, G.; Li, B.-J.; Luo, S.; Guo, Q.-Y.; Wei, J.-B.; Shi,
Z.-J. Org. Lett. 2013, 15, 10. (b) Chu, L.; Qing, F.-L. J. Am. Chem. Soc.
2012, 134, 1298. (c) Zhang, X.-G.; Dai, H.-X.; Wasa, M.; Yu, J.-Q.
J. Am. Chem. Soc. 2012, 134, 11948. (d) Hafner, A.; Brase, S. Adv. Synth.
Catal. 2013, 355, 996. (e) Review: Tomashenko, O. A.; Grushin, V. V.
Chem. Rev. 2011, 111, 4475.
(4) Examples of metal-mediated trifluoromethylation of halides: (a)
ꢀ
Tomashenko, O. A.; Escudero-Adan, E. C.; Martınez Belmonte, M.;
´
Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50, 7655. (b) Weng, Z.; Lee,
R.; Jia, W.; Yuan, Y.; Wang, W.; Feng, X.; Huang, K.-W. Organome-
tallics 2011, 30, 3229. (c) Kondo, H.; Oishi, M.; Fujikawa, K.; Amii, H.
Adv. Synth. Catal. 2011, 353, 1247. (d) Morimoto, H.; Tsubogo, T.;
Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2011, 50, 3793.
(e) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679. (f) Oishi, M.; Kondo, H.; Amii,
H. Chem. Commun. 2009, 1909.
€
(3) Recent examples of nonaromatic trifluoromethylation: (a) Xu, J.;
Xiao, B.; Xie, C.-Q.; Luo, D.-F.; Liu, L.; Fu, Y. Angew. Chem., Int. Ed.
2012, 51, 12551. (b) Hu, M.; Ni, C.; Hu, J. J. Am. Chem. Soc. 2012, 134,
15257. (c) Li, Y.; Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8221.
(d) Chu, L.; Qing, F.-L. Org. Lett. 2012, 14, 2106. (e) Parsons, A. T.;
Senecal, T. D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51, 2947. (f)
Cho, E. J.; Buchwald, S. L. Org. Lett. 2011, 13, 6552. (g) Hafner, A.;
(5) Examples of metal-mediated trifluoromethylation of boronic
ꢀ
acids: (a) Novak, P.; Lishchynskyi, A.; Grushin, V. V. Angew. Chem.,
Int. Ed. 2012, 51, 7767. (b) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc.
2012, 134, 9034. (c) Khan, B. A.; Buba, A. E.; Goossen, L. J. Chem.;
Eur. J. 2012, 18, 1577. (d) Li, Y.; Wu, L.; Neumann, H.; Beller, M. Chem.
Commun. 2013, 49, 2628. (e) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2011, 51, 536. (f) Knauber, T.; Arikan, F.;
€
Brase, S. Adv. Synth. Catal. 2011, 353, 3044. (h) Zhao, T. S. N.; Szabo,
K. J. Org. Lett. 2012, 14, 3966. (i) Janson, P. G.; Ghoneim, I.; Ilchenko,
N. O.; Szabo, K. J. Org. Lett. 2012, 14, 2882. (j) Kawai, H.; Furukawa,
T.; Nomura, Y.; Tokunaga, E.; Shibata, N. Org. Lett. 2011, 13, 3596.
(k) Wu, X.; Chu, L.; Qing, F. L. Angew. Chem., Int. Ed. 2013, 52, 2198.
€
Roschenthaler, G.-V.; Goossen, L. J. Chem.;Eur. J. 2011, 17, 2689.
r
10.1021/ol401558z
XXXX American Chemical Society

chemistry. Today, there are several protocols known that
allow the introduction of this group into aromatic2 and
nonaromatic3 systems. While most metal-mediated trifluo-
romethylation reactions require functionalized reactants
(e.g. halides4 or boronic acids5), radical trifluoromethyla-
tion reactions can be realized under a simple and straight-
forward CH-substitution.6 However, when radical inter-
mediates are involved, there is often a lack of selectivity.
Recently, we could demonstrate that aromatic triazenes
are suitable substrates for silver-mediated trifluoromethy-
lation reactions.7 These transformations were based on an
“AgCF3” species, which could be easily generated in situ
and decompose to CF3-radicals. In literature, the synthesis
of silver perfluoroorganyls is well-documented but their
applications as precursors for perfluoroalkyl radicals are
limited.8 Besides our work, only the Sanford group reported
the use of AgCF3 for the trifluoromethylation of aromatic
compounds.9 Both examples were based on a trimethylsilyl
substituted CF3-source.
In donor solvents like acetonitrile, this occurrence can be
used to generate silver perfluoroorganyls by adding AgF re-
gioselectively to the fluorinated double bond (Scheme 1).8aÀc
This regioselective addition is interesting, as it allows
rapid access to secondary metal perfluoroalkyl species.
However, fluoride abstraction of fluorinated olefins also
enables the possibility of dimerization/oligomerization.
This competing reaction limits the synthetic potential of
these fluorinated compounds.11 We assume that there-
fore metal-mediated perfluoroalkylation of organic com-
pounds using highly fluorinated olefins has not yet been
reported.12
We believed that a method allowing the usage of highly
fluorinated olefins in simple aromatic substitution reac-
tions would be interesting, as they would give access to
complete new perfluoroalkylated arenes. Therefore, we
started investigating this reaction using the commercially
available methyl 2,3,3-trifluoroacrylate as a fluorinated
olefin in the presence of silver(I) fluoride and the aromatic
triazene 1a (Table 1). While standard protocols for the
synthesis of silver perfluoroorganyls use donor solvents
like acetonitrile, in which dimerization/oligomerization of
highly fluorinated olefins is the preferred reaction, our own
observations with AgCF3 showed that the trifluoromethyl-
ation of aromatic triazenes worked best in perfluorohexane
as solvent. Although the conversion was not comparable
to the one obtained for the trifluoromethylation reaction,
the desired methoxycarbonyltetrafluoroethylated product
could be obtained in 12% yield (entry 1).
Encouraged by our first results, we imagined that it
should be possible to expand our protocol to other fluori-
nated silverspecies, whichwouldallow thesynthesisof new
fluorinated arenes via a radical pathway.
Scheme 1. Selective Addition of AgF to the Fluorinated Double
Bond
Table 1. Optimization of the Methoxycarbonyltetrafluoro-
ethylation of Aromatic Triazenesa
In contrast to common perfluoroalkyl sources such
as perfluoroiodides, TMS agents, or hypervalent iodine
agents, the use of highly fluorinated olefins as a perfluo-
roalkyl source has not been well-investigated. Due to the
repulsive interactions between the lone electron pairs of the
fluorine substituent and the π-orbital of the sp2-carbon,
fluorinated olefins regioselectively add fluoride ions.1a,10
(6) (a) Wu, X.; Chu, L.; Qing, F.-L. Tetrahedron Lett. 2013, 54, 249.
(b) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224. (c) 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.
(d) Review: Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950.
entry
MTA (equiv)
solvent
yield [%]b
1
2
3
4
5
6
7
2
3
4
2
4
4
4
C6F14
C6F14
C6F14
À
12
20
43
38
49
13
À
€
(7) Hafner, A.; Brase, S. Angew. Chem., Int. Ed. 2012, 51, 3713.
(8) Silverperfluoroorganyls: (a) Miller, W. T., Jr.; Burnard, R. J.
J. Am. Chem. Soc. 1968, 90, 7367. (b) Burch, R. R.; Calabrese, J. C.
J. Am. Chem. Soc. 1986, 108, 5359. (c) Dyatkin, B.; Martynov, B.;
Martynova, L.; Kizim, N.; Sterlin, S.; Stumbrevichute, Z.; Fedorov, L.
J. Organomet. Chem. 1973, 57, 423. (d) Naumann, D.; Wessel, W.; Hahn,
J.; Tyrra, W. J. Organomet. Chem. 1997, 547, 79. (e) Review: Tyrra, W.;
Naumann, D. J. Fluorine Chem. 2004, 125, 823. (f) Tyrra, W. E.
J. Fluorine Chem. 2001, 112, 149. (g) King, R. B.; Zipperer, W. C. Inorg.
Chem. 1972, 11, 2119. (h) Zeng, Y.; Zhang, L.; Zhao, Y.; Ni, C.; Zhao, J.;
Hu, J. J. Am. Chem. Soc. 2013, 135, 2955. (i) Kremlev, M. M.; Mushta,
A. I.; Tyrra, W.; Naumann, D.; Fischer, H. T. M.; Yagupolskii, Y. L.
J. Fluorine Chem. 2007, 128, 1385. In fact, silver perfluoroorganyls are
mostly used as transmetallation agents. Furthermore, only oxygenation,
halogenation, elimination, and dimerization reactions are known. Re-
ferences 8h and 8i reported the use of AgCF3 as the source of nucleo-
philic CF3. However, these protocols do not use AgCF3 as the precursor
of CF3 radicals.
À
DCE
MeCN
a Reaction conditions: 1a (0.40 mmol), AgF (1.60 mmol), methyl
2,3,3-trifluoroacrylate (MTA), solvent (1 mL), 100 °C, 16 h. b Yields were
determined by 19F NMR using 2-fluoronitrobenzene or 2-fluoroaniline
as the internal standard.
However, the yields could be increased by doubling the
methyl 2,3,3-trifluoroacylate (MTA) equivalents (entry 3).
(9) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464.
(10) Bartlett, P. D.; Wheland, R. C. J. Am. Chem. Soc. 1972, 94, 2145.
(11) Paleta, O.; Svoboda, J.; Dedek, V. J. Fluorine Chem. 1983, 23,
171.
B
Org. Lett., Vol. XX, No. XX, XXXX

Lastly, we tried the reaction under neat (solvent-free)
conditions, which further increased the yields to 49%
(entry 5). When the reaction was carried out in dichlo-
roethane, the yield dropped to 13% (entry 6), while in
acetonitrile no conversion to the desired product occurred.
Herein, dimerization/oligomerization of the fluoroolefin
was observed as a major reaction (entry 7). Noteworthy,
dimerization of MTA still occurred under solvent-free
conditions, which did not allow the recovery of excess
MTA, but could be significantly reduced.
Scheme 2. Methoxycarbonyltetrafluoroethylation of Different
Aromatic Triazenesa
With the optimized reaction conditions in hand, we
further explored the scope of the methoxycarbonyltetra-
fluoroethylation reaction. As summarized in Scheme 2
several functionalized aromatic triazenes can be used for
this kind of transformation. Most interestingly, this meth-
od tolerates various functional groups, e.g. iodides, bro-
mides, chlorides, fluorides, nitriles and ethoxycarbonyl
moieties. When para-substituted aromatic triazenes were
used, the ortho-methoxycarbonyltetrafluoroethylated tri-
azenes were always the major products. This is consistent
with our observations during the trifluoromethylation reac-
tion.7 Surprisingly, ortho-substituted triazenes (e.g. 2gÀ2k)
yielded the para-methoxycarbonyltetrafluoroethylated
triazenes as major products. In contrast to these results,
the trifluoromethylation reaction showed a high ortho-
selectivity with these substrates.7
a Reaction conditions: triazene 1 (0.40 mmol), AgF (1.60 mmol),
methyl 2,3,3-trifluoroacrylate (MTA) (1.60 mmol), 100 °C, 16 h. Yields
were determined by 19F NMR using 2-fluoroaniline as the internal
b
standard. Yields in parentheses are isolated yields. Ortho/para =
c
d
e
1:10. Ortho/para = 1:7.6. Ortho/para = 1:6.8. Ortho/para =
1:6.2. f Ortho/para = 1:14.5. g Mixture of ortho/para-isomer.
We believe that this “loss” of ortho-selectivity can be
explained by the steric hindrance of the silver organyl,
which prevents any type of coordination to the triazene
moiety. The reactionsworked best when substitution at the
para- and ortho-position was possible (up to 65%, 2j).
When the para-position was blocked (e.g. 2aÀ2f), the
yields dropped slightly toaround 54%(2c) for halogenated
triazenes. Aromatic triazenes bearing a strong electron-
withdrawing group could be only methoxycarbonyltetra-
fluoroethylated in low yields (2e, 2f). This circumstance
could also explain why no disubstitution was observed.
Thus, the electron-withdrawing effect of the methoxycar-
bonyltetrafluoroethyl group deactivates the aromatic core
for a second substitution. Altogether, most yields were
reasonable considering the electronic and steric properties
of the silver perfluoroorganyl.
functional groups, e.g. halides,14 azides,15 nitriles,16 or
amines.17 On the other hand, the triazene moiety allows
further functionalization on the aromatic core like cross-
coupling reactions.14a,18
Scheme 3. Conversion of the Triazene Moiety in Different
Groups
Aromatic triazenes offer various functionalization
possibilities.13 On one hand, they can be seen as protected
diazonium salts; thus they can be converted into different
(12) In fact, only few examples are known in which highly fluorinated
olefins are used for the perfluoroalkylation of arenes. These examples
are either nucleophilic aromatic substitution reactions (e.g., Chambers,
R. D.; Jackson, J. A.; Musgrave, W. K. R.; Storey, R. A. J. Chem. Soc.
(C) 1968, 2221. ) or (mostly transition metal mediated) substitution
reactions of the CF bond (e.g., Ohashi, M.; Kambara, T.; Hatanaka, T.;
Saijo, H.; Doi, R.; Ogoshi, S. J. Am. Chem. Soc. 2011, 133, 3256.).
(13) Review: (a) Kimball, D. B.; Haley, M. M. Angew. Chem., Int. Ed.
Exemplarily, triazene 2k was converted into the corre-
sponding azide 3 and cross-coupled with cyclopentene (4),
while triazene 2c was converted into iodide 6 and defunc-
tionalized to 5 (Scheme 3). This versatility combined with
the methoxycarbonyltetrafluoroethylation reaction can be
used for the synthesis of various compounds. Interestingly,
€
2002, 41, 3338. (b) Brase, S. Acc. Chem. Res. 2004, 37, 805.
(14) Representative transformations: (a) Liu, C.-Y.; Knochel, P. Org.
Lett. 2005, 7, 2543. (b) Barbero, M.; Degani, I.; Diulgheroff, N.; Dughera,
€
S.; Fochi, R. Synthesis 2001, 2180. (c) Dobele, M.; Vanderheiden, S.; Jung,
€
N.; Brase, S. Angew. Chem., Int. Ed. 2010, 49, 5986.
(15) Liu, C.-Y.; Knochel, P. J. Org. Chem. 2007, 72, 7106–7115.
(16) Patrick, T. B.; Juehne, T.; Reeb, E.; Hennessy, D. Tetrahedron
Lett. 2001, 42, 3553.
(17) Gross, M. L.; Blank, D. H.; Welch, W. M. J. Org. Chem. 1993,
58, 2104.
(18) Reingruber, R.; Vanderheiden, S.; Wagner, A.; Nieger, M.;
€
Muller, T.; Es-Sayed, M.; Brase, S. Eur. J. Org. Chem. 2008, 3314.
(19) Rieu, J.-P.; Boucherle, A.; Cousse, H.; Mouzin, G. Tetrahedron
1986, 42, 4095.
Org. Lett., Vol. XX, No. XX, XXXX
C

most successful NSAIDs (nonsteroidal anti-inflammatory
drugs), e.g. ibuprofen or flurbiprofen, possess an arylpro-
panoic acid group as the central structural motif.19
Scheme 5. Methoxycarbonyltetrafluoroethylation of Different
Anisolesa
Scheme 4. Four-Step Synthesis of Flurbiperfluoroprofen (9)
Due to the unique properties of fluorine substituents,
much effort has been made to synthesize fluorinated
profene analogues in terms of bioisosteric replacement.20
To demonstrate the synthetic usefulness of our new meth-
od, we planned the synthesis of the corresponding flurbi-
perfluoroprofen (9), a tetrafluorinated analogue of the
NSAID flurbiprofen. Starting from commercially avail-
able 2-fluoroaniline (7), this synthesis could be accom-
plished in 24% overall yield over four steps (Scheme 4).
Noteworthy, the methoxycarbonyltetrafluoroethylation
(step 2) could be upscaled to 500 mg with comparable
isolated yields (50% vs 49%).
Furthermore, it was possible to expand this reaction to
anisole derivatives. While electron-poor arenes such as
nitrobenzene derivatives or aromatic nitriles showed no
conversion at all under our conditions, electron-rich ani-
soles could be methoxycarbonyltetrafluoroethylated with
similar yields compared to aromatic triazenes without
further optimization of the reaction conditions (Scheme 5).
In conclusion, we herein report the silver-mediated meth-
oxycarbonyltetrafluoroethylation of functionalized arenes
by simple CH-substitution. This functionalization is based
on the in situ generation of methoxycarbonyltetrafluoroethyl
silver from commercially available silver(I) fluoride and
a Reaction conditions: anisole 10 (0.40 mmol), AgF (1.60 mmol),
MTA (1.60 mmol), 100 °C, 16 h. Yields determined by 19F NMR using
2-fluoroaniline as the internal standard. Yields in parentheses are
isolated yields. b Ortho/para = 1:1.8.
methyl 2,3,3-trifluoroacrylate (MTA). This perfluoroalkyla-
tion protocol tolerates a broad range of functional groups
(e.g. iodides, bromides, nitriles), which combined with the
versatility of the triazene group makes it interesting for the
synthesis of various methoxycarbonyltetrafluoroethylated
building blocks. Furthermore, we demonstrated the syn-
thetic potential of this transformation through the synthesis
of flurbiperfluoroprofen (a tetrafluorinated analogue of the
NSAID flurbiprofen). In addition, we showed that this
protocol is also suitable for the methoxycarbonyltetrafluoro-
ethylation of anisole derivatives. To the best of our
knowledge, this is the first example of the usage of highly
fluorinated olefins for the perfluoroalkylation of aromatic
substrates.
€
Acknowledgment. We thank the Landesgraduiertenfor-
€
derung Baden Wurttemberg for financial support.
Supporting Information Available. Experimental pro-
cedures and characterization and spectra data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) For example: (a) Goj, O.; Kotila, S.; Haufe, G. Tetrahedron
1996, 52, 12761. (b) Schlosser, M.; Michel, D.; Guo, Z.-W.; Sih, C. J.
Tetrahedron 1996, 52, 8257. (c) Rozen, S.; Hagooly, A.; Harduf, R.
J. Org. Chem. 2001, 66, 7464. (d) Ricci, G.; Ruzziconi, R. J. Org. Chem.
2005, 70, 611.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX