DOI: 10.1002/chem.201406292
Communication
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Perfluoroalkylation |Hot Paper|
Dialkylzinc-Mediated Cross-Coupling Reactions of Perfluoroalkyl
and Perfluoroaryl Halides with Aryl Halides
Hisano Kato,[a] Keiichi Hirano,*[a, b] Daisuke Kurauchi,[a] Naoyuki Toriumi,[a] and
Masanobu Uchiyama*[a, b]
strated deprotonative metalation of a 1H-perfluoroalkane by
Abstract: A highly chemoselective perfluoroalkylation re-
TMP2Zn (TMP=2,2,6,6-tetramethylpiperidido) to form RF2Zn
action of aromatic halides is reported. Thermally stable
and utilized it in copper-catalyzed cross-coupling reactions
perfluoroalkylzinc reagents, generated by a rapid halo-
with aryl iodides.[10] However, this metalation process required
gen–zinc exchange reaction between diorganozinc and
laborious preparation of TMP2Zn. We became interested in RF
perfluoroalkyl halide species, couple with a wide range of
halides as metalation precursors to obtain RF-zinc reagents for
aryl halides in the presence of a copper catalyst, in moder-
cross-coupling, because RF halides have a number of synthetic
ate to high yields. Good stability of the perfluoroalkylzinc
advantages as RF sources, including ready availability of a great
species was indicated by DFT calculation and the reagents
variety of RF halides, low cost,[11] and ease in handling in both
were storable for at least three months under argon with-
laboratory research and in industry as compared to RFÀH[10,11]
out loss of activity. This method is applicable to gram-
or RFÀSiR3 species.[12,13] Herein, we report operationally benign,
scale synthesis, and its functional group tolerance com-
chemo-/regioselective, copper(I)-catalyzed cross-coupling reac-
pares favorably with reported protocols.
tions between RF halides and aryl halides, via the formation of
thermally and chemically stable RF–zinc species.[14]
Our investigation commenced with exploration of an appro-
Fluorine-containing organic compounds, especially aromatic
and p-conjugated molecules, have attracted much attention in
medicinal chemical and materials sciences and tremendous ef-
forts have been devoted to development of efficient methods
for introduction of fluorine atoms or the trifluoromethyl
groups into organic molecules.[1] Perfluoroalkyl (RF) groups
have been less well utilized as functional building blocks,[2,3]
mainly due to the lack of an efficient synthetic methodology
for regiocontrolled installation of RF groups on aromatic
rings.[4,5] The Swarts-type transformation[6] is not applicable to
the synthesis of perfluoroalkylated aromatics from their alkyl
counterparts. The main hurdle is that RF–metal species are very
unstable, even at very low temperatures, and readily decom-
pose via a- or b-elimination of fluoride.[7] This largely accounts
for the immaturity of perfluoroalkylation reactions to date. Our
approach capitalizes on the soft reactivity of organozinc re-
agents. We have been working on development of methods
for chemoselective zincation of organic molecules based on
halogen–zinc exchange, utilizing monoanion- and dianion-type
ate complexes,[8] as well as deprotonative zincation by zinc ate
bases.[9] In 2011, Daugulis and co-workers elegantly demon-
priate metalation method to form RF–zinc species using nona-
fluorobutyl iodide as the RF source. As a model reaction, we se-
lected the coupling reaction between the intermediate RF–zinc
species and ortho-iodobenzoate 1a in the presence of
10 mol% of CuCl (Table 1). When mono-anionic [Me3Zn]Li was
Table 1. Zincation of perfluoroalkyl iodide.
Entry
C4F9I [equiv]
Zinc reagent
Yield [%][a]
1[b]
2[b]
3
4
5[c]
1.2
1.2
1.5
1.5
1.5
[Me3Zn]Li [1.0 equiv]
[Me4Zn]Li2 [1.0 equiv]
Me2Zn [1.5 equiv]
Et2Zn [1.5 equiv]
trace
0
17
20
64
Et2Zn [1.5 equiv]
[a] Determined by GC using mesitylene as an internal standard. [b] Halo-
gen–zinc exchange for 1 h at 08C. [c] T=908C.
[a] H. Kato, Dr. K. Hirano, D. Kurauchi, N. Toriumi, Prof. Dr. M. Uchiyama
Graduate School of Pharmaceutical Sciences, The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
used, a trace amount of the desired coupling product 2aa was
detected by GC/MS (Table 1, entry 1). The dianion-type zincate
[Me4Zn]Li2 developed by our group[8b] was found to be unpro-
ductive (Table 1, entry 2). In both cases, unreacted 1a was not
recovered, which might be attributed to the instability of the
generated RF–zincate species at the reaction temperature. The
use of less reactive Me2Zn led to the formation of 2aa in 17%
[b] Dr. K. Hirano, Prof. Dr. M. Uchiyama
Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable
Resource Science, and Elements Chemistry Laboratory RIKEN
2-1 Hirosawa, Wako-shi, Saitama 351-0198 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406292.
Chem. Eur. J. 2015, 21, 1 – 7
1
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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