Angewandte
Chemie
DOI: 10.1002/anie.201402238
Phase-Transfer Catalysis
Mild Copper-Catalyzed Fluorination of Alkyl Triflates with Potassium
Fluoride**
Hester Dang, Melrose Mailig, and Gojko Lalic*
Abstract: A chemoselective catalytic fluorination of alkyl
triflates is described using potassium fluoride as a fluoride
source. Excellent yields of the desired alkyl fluorides are
obtained after one hour at 458C using 2 mol% of the copper
catalyst. With 10 mol% of the catalyst, full conversion can be
achieved in less than 10 minutes at 458C, and thus makes this
procedure potentially suited for the preparation of 18F-labeled
PET probes. As a result of the mild reaction conditions, only
the substitution products are observed with no evidence of
common side reactions, such as elimination. Reported is
a preliminary study of the reaction scope, which demonstrates
that the fluorination can be performed in the presence of a wide
range of functional groups. Evidence suggests an unusual role
of the [IPrCuOTf] catalyst as a phase-transfer catalyst and
points to [IPrCuF] as the active fluorinating reagent (IPr = 1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene).
In addition to the fundamental challenge of developing an
additive that can catalytically facilitate phase transfer of
fluoride ions, there is also a practical need for a catalyst which
would promote the reaction at lower temperature and with
a greater selectivity. The most commonly used phase-transfer
agent, crown ether Kryptofix-222,[10] allows fast fluorination
of alkyl electrophiles with KF as a fluoride source, and makes
it uniquely suited for the synthesis of PET probes.[10,13]
Unfortunately, the high reactivity is observed only at high
temperatures (often > 1108C). Furthermore, harsh reaction
conditions, together with the basicity of the fluoride anion[14]
lead to significant side reactions, such as elimination, even
with simple primary alkyl electrophiles.[15] Herein, we de-
scribe a new approach to a nucleophilic fluorination reaction
using transition-metal complexes as phase-transfer catalysts
and transition-metal fluorides as fluorinating reagents
[Eq. (1)].
T
he importance of organofluorine compounds in medicinal
chemistry[1] and as positron emission tomography (PET)
probes[2] has made the development of new fluorination
reactions a major focus of research in the field of transition-
metal catalysis.[3] As a result, a number of methods for the
synthesis of aryl[4] and allyl fluorides have been developed.[5]
In contrast, catalytic methods for the synthesis of aliphatic
fluorides are relatively underdeveloped.[6,7] In fact, the most
general method for the synthesis of this class of compounds
remains the nucleophilic substitution of alkyl electrophiles.
Because of the low solubility of fluorides in aprotic solvents
and poor nucleophilicity in protic ones, this reaction is usually
performed in aprotic solvents in the presence of additives
which increase the solubility of the fluoride source. Numerous
stoichiometric additives have been used to promote the phase
transfer, including tBuOH,[8] ionic liquids,[9] crown ethers,[10]
and tetrabutyl ammonium salts.[11] Early studies of tetrabutyl
ammonium salts indicated that catalyst poisoning with
common anions, such as bromides and iodides, is the major
obstacle for the development of catalytic phase-transfer
agents for nucleophilic fluorination.[11,12]
Nucleophilic properties of late-transition-metal fluorides,
and their stoichiometric reactions with various electrophiles
have been known since the early reports by the groups of
Bergman and Richmond.[16] However, two problems have
prevented the development of practical fluorination reactions
based on these early findings. One problem is that in most
cases fluorination of alkyl electrophiles with metal fluorides
occurs only at high temperature and usually leads to the
formation of a significant amount of elimination products. For
example, a significant amount of elimination products has
recently been observed in reactions of alkyl electrophiles with
a copper fluoride diamino complex, performed for over 15 h
at 1108C in MeCN.[17] The second problem is that the
formation of metal fluoride complexes is difficult to accom-
plish under catalytic conditions. Again, a good example is the
formation of copper fluoride diamino complex, which was
accomplished by protonation of a copper alkoxide precursor
using (HF)3·NEt3 as a fluoride source.
We chose to address both problems using [IPrCuF] (see
Table 1 for structure of IPr ligand) as a fluorinating reagent.
[IPrCuF] is soluble in organic solvents,[18] and we reasoned
that the sigma-donating ability of NHC ligands will contribute
to the nucleophilicity of the copper fluoride. Based on the
idea outlined in Equation (1) we explored the ability of
various [IPrCu] complexes to form [IPrCuF] in a reaction
with KF, and in such a way effectively function as a phase-
transfer catalyst. Not surprisingly, we found that with most
copper precursors an insignificant amount of [IPrCuF] was
formed in common organic solvents. However, [IPrCuOTf]
[*] H. Dang, M. Mailig, Prof. G. Lalic
Department of Chemistry, University of Washington
Seattle, WA 98195 (USA)
E-mail: lalic@chem.washington.edu
[**] We thank the Royalty Research Fund at University of Washington
and NSF (CAREER award no 1254636) for financial support. Prof.
Forrest Michael and Prof. Dustin Maly are gratefully acknowledged
for helpful discussions and suggestions.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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