Zinc-mediated formation of trifluoromethyl ethers from alcohols and hypervalent iodine trifluoromethylation reagents

Full text of DOI:10.1002/anie.200900974

Communications
DOI: 10.1002/anie.200900974
Synthetic Methods
Zinc-Mediated Formation of Trifluoromethyl Ethers from Alcohols
and Hypervalent Iodine Trifluoromethylation Reagents**
Raffael Koller, Kyrill Stanek, Daniel Stolz, Raphael Aardoom, Katrin Niedermann, and
Antonio Togni*
The incorporation of fluorine atoms into biologically active
organic molecules has become an increasingly important tool
in the life science industry.[1] Properties such as the metabolic
stability, lipophilicity, and bioavailability of drug candidates
and crop protection agents[2] may be drastically improved by
the presence of just one fluorine atom, or by a trifluoromethyl
group. The trifluoromethoxy substituent is less often encoun-
tered. However, the drug Riluzole[3] and the pesticide
Triflumuron[4] are prominent examples of compounds con-
taining the OCF3 group at an aromatic position, and aliphatic
trifluoromethyl ethers have been incorporated, for example,
into liquid crystalline materials.[5]
Generally speaking, this is very true for any trifluoromethyl
group.
Recently, our group developed a new class of electrophilic
trifluoromethylation reagents based on hypervalent iodine-
(III) derivatives (1 and 2; Scheme 1). Both reagents are easily
None of the trifluorohalomethane compounds react with
alcohols or their deprotonated form to afford the correspond-
ing trifluoromethyl ethers. The syntheses of these compounds
require special reagents and equipment. Thus, anisoles are
converted into the corresponding trifluoromethoxy deriva-
tives by a chlorination/fluorination sequence using PCl5/Cl2
and anhydrous HF.[6] Similar considerations apply for the
in situ sequence starting from the aryl alcohol, HF, and CCl4.[7]
Moreover, concentrated HF solutions are needed in the
Scheme 1. Applications of hypervalent iodine trifluoromethylation
reagents 1 and 2.
oxidative
desulfurization/fluorination
of
xanthates.[8]
Recently, Umemoto et al. reported a conceptually important
approach for the direct, electrophilic trifluoromethylation of
both alcohols and amines using O-(trifluoromethyl)dibenzo-
furanium salts.[9] However, these highly reactive species need
to be generated in situ from diazonium salts already contain-
ing a trifluoromethoxy group.
accessible from commercially available 2-iodobenzoic acid.[10]
As outlined in Scheme 1, various substrates, such as thiols,
phosphines, active methylene compounds, or aromatic com-
pounds can be trifluoromethylated under mild reaction
conditions in good to excellent yields.[11]
From the above considerations it is safe to say that a mild,
reliable, and broadly applicable method for the formation of
trifluoromethyl ethers starting from alcohols is still lacking.
The synthesis of relatively complex target molecules contain-
ing a trifluoromethoxy fragment has to rely heavily upon the
use of small building blocks already containing this entity.
However, the direct O-trifluoromethylation of phenols
remains an unsolved problem. For the model substrate, 2,4,6-
trimethylphenol, the desired product was obtained in only
15% yield after tedious variation of the reaction parameters
(Scheme 2). The major products are a mixture of C-trifluoro-
methylated derivatives,[12] the formation of which may be
explained by an oxidation/trifluoromethylation sequence of
the starting phenol.[13]
[*] R. Koller, K. Stanek, Dr. D. Stolz, R. Aardoom,[+] K. Niedermann,[+]
Prof. Dr. A. Togni
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology, ETH Zꢀrich
8093 Zꢀrich (Switzerland)
Fax: (+41)44-632-1310
E-mail: togni@inorg.chem.ethz.ch
[+] R. Aardoom and K. Niedermann carried out the X-ray crystal
structural study of compound 5.
Scheme 2. Trifluoromethylation of 2,4,6-trimethylphenol using 1.
[**] This work was supported by SSCI (Stipendienfonds der Schweizer-
ischen Chemischen Industrie), ETH Zꢀrich, and DAAD. Dr. H.
Rꢀegger and A. Moreno are acknowledged for their help with NMR
spectroscopy.
While considering the fundamental question as to whether
the direct and synthetically efficient transfer of an intact CF3
group from an electrophilic source to an alcohol oxygen atom
would be possible, we focused on aliphatic alcohols, thereby
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900974.
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most likely circumventing potential problems associated with
oxidations.
used, the reaction did not afford the desired product. At
last, zinc(II) bis(trifluoromethylsulfonyl)imide, Zn(NTf2)2,
was chosen because of its satisfactory solubility in polar and
chlorinated solvents, and the non-nucleophilic and nonbasic
character of the anion. These characteristics are partly
illustrated by (CF3SO2)2NH being one of the strongest acids
known in the gas phase.[16] Moreover, DesMarteau and co-
workers recently reported the synthesis of hypervalent
While investigating the activation of alkynes with zinc
triflate towards possible trifluoromethylation with reagent 1
we observed the unexpected formation of trifluoromethyl
triflate (TFMT).[14] Similar experiments with sodium, potas-
sium, or copper(II) triflate did not afford any conversion into
TFMT, as indicated by 19F NMR spectroscopy. However, the
addition of one equivalent of zinc bromide to such reaction
mixtures triggered the formation of TFMT, indicating the
crucial role of zinc(II). The trifluoromethylation of triflate per
se does not seem to be a particularly relevant reaction.
However, it clearly indicates that our reagent is capable of
trifluoromethylating an oxygen-centered nucleophile, despite
the fact that it had been identified as being too soft of a
reagent for this purpose.[15] At this point we focused on the
direct trifluoromethylation of alcohols. Preliminary studies
were carried out in 1-pentanol as both the solvent and the
substrate, using Zn(OTf)2 as zinc source and 1 as electrophilic
CF3-transfer reagent (Scheme 3).
À
iodonium salts bearing NTf2 as a counter ion, which
displayed remarkable arylating and alkylating powers.[17a–c]
We found that Zn(NTf2)2 gave better yields and generated
fewer side products than all other zinc(II) salts. By using a
stoichiometric amount of Zn(NTf2)2 (with respect to reagent
1) 1-trifluoromethoxypentane was obtained in a yield of 93%
instead of 83% (Table 2, entry 1). Again, catalytic amounts of
zinc(II) did not significantly lower the yield of the ether.
When the amount of the alcohol was reduced to 10 equiv-
alents, using chloroform as the solvent, the yield fell to 67%
(Table 2, entry 3), representing a significant improvement
compared to the 25% yield obtained with Zn(OTf)2. Further
reduction of the amount of alcohol used to 5 equivalents
slowed down the reaction and resulted in only 17–19% yield
of the desired trifluoromethyl ether (Table 2, entry 4). By
using Zn(NTf2)2 in catalytic amounts (34 mol%) the trifluoro-
methyl ether was afforded in significantly improved yields of
À
up to 61% (Table 2, entry 5). Notably, the NTf2 anion can
undergo trifluoromethylation at the oxygen atom to give
TfN = SO(OCF3)CF3 (3), despite its extremely low nucleo-
philicity. However, the formation of this side product can be
minimized by reducing the amount of Zn(NTf2)2. Further-
more, 2-iodobenzoic acid is O-trifluoromethylated giving
Scheme 3. Zn(OTf)2-assisted direct trifluoromethylation of 1-pentanol.
By using one equivalent of Zn-
(OTf)2, the trifluoromethylation
Table 1: Trifluoromethylation of 1-pentanol using 1 and Zn(OTf)2.
took place under very mild reaction
conditions, giving the desired tri- Entry[a]
fluoromethyl ether in 83% yield,
1-Pentanol[b]
(equiv)
Zn(OTf)2
(equiv)
Solvent[c]
Yield [%]
(conv)[d]
Side products[e]
based on 1 (Table 1, entry 1). Better
results were obtained with substoi-
chiometric amounts of Zn(OTf)2
(Table 1, entries 2 and 3). There-
fore, by using 20 mol% of Zn(OTf)2
the formation of the undesired side
product TFMT was suppressed
completely. When the amount of
alcohol used was reduced to
10 equivalents, in either chloroform
or toluene as the solvent, the reac-
tion became slow and larger
amounts of TFMT were formed
(Table 1, entries 4 and 5).
To exclude the formation of
TFMT we screened various zinc
sources. Zinc(II) halides (ClÀ, BrÀ,
IÀ) also assisted the alcohol tri-
fluoromethylation, but the major
product was always the correspond-
1
2
3
4
5
75
75
75
10
10
1.00
0.50
0.20
0.50
0.50
1-pentanol
1-pentanol
1-pentanol
toluene
83 (quant.)
89 (quant.)
84 (quant.)
25 (63%)
26 (59%)
2% TFMT
2% TFMT
–
8% TFMT
22% TFMT
CHCl3
[a] Reaction conditions: 1 was stirred with 1-pentanol in the solvent at RT for 48 h. [b] Distilled prior to
use. [c] The concentration of 1 was approximately 0.15m in all experiments. [d] The conversion of 1 and
the product yield were calculated based on 19F NMR methods using C6H5CF3 as an internal standard.
[e] Observed by 19F NMR methods.
Table 2: Trifluoromethylation of 1-pentanol using 1 and Zn(NTf2)2.
Entry[a]
1-Pentanol[b]
(equiv)
Zn(NTf2)2
(equiv)
Solvent[c]
Yield [%]
(conv.)[d]
Side products[e]
1
2
3
4
5
6
75
75
10
5
5
1.5
1.00
0.20
1.00
1.00
0.34
0.34
1-pentanol
1-pentanol
CHCl3
CHCl3
CHCl3
93 (quant.)
89 (quant.)
67 (quant.)
19 (45%)
61 (quant.)
21 (86%)
–
–
3% 4
18% 3
3% 4
CHCl3
[a] Reaction conditions: 1 was stirred with 1-pentanol in the solvent at RT for 48 h. [b] Distilled prior to
use. [c] The concentration of 1 was approximately 0.15m in all experiments. [d] The conversion of 1 and
the product yield were calculated based on 19F NMR methods using C6H5CF3 as an internal standard.
ing trifluoromethyl halide. If basic
2À
anions such as CO3
or acacÀ
(acac = acetylacetonate)
were [e] Observed by 19F NMR methods.
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trifluoromethyl 2-iodobenzoate (4) as the second side
product.
After optimization of the reaction conditions for 1-
pentanol, we focused our attention on more challenging
substrates. As shown in Table 3, excellent results were
obtained using less volatile alcohols, which can be used as
both the solvent and the substrate (Table 3, entries 1–3). The
of 1-adamantyl methanol, the corresponding CF3 ether could
be isolated in 39% yield (Table 3, entry 4). However, some
substrates were less tolerant to the acidic reaction conditions,
giving the desired products in less than 20% yield. Therefore,
the trifluoromethylation of a tetra-acetylated glucose deriv-
ative was rather sluggish, affording the desired product in low
yield along with four minor, uncharacterized side products,
possibly arising from deacylation reactions or epimerization
(Table 3, entry 9). Finally, we were pleased to find that
secondary alcohols also undergo trifluoromethylation quite
cleanly; the CF3 ether of ethyl lactate forms in 62% yield,
whereas trifluoromethoxycyclohexane is obtained from cyclo-
hexanol in 74% yield (Table 3, entries 11–12). Alcohols such
as t-BuOH, as well as phenols, still cannot be O-trifluorome-
thylated.
Table 3: Trifluoromethylations of alcohols using 1 and Zn(NTf2)2.
Entry
Substrate
Zn(NTf2)2
(equiv)
Yield[c] [%]
1[a]
2[a]
1.0
1.0
99 (81)
92 (75)
19F NMR and ESI-MS measurements of the reaction
mixture of reagent 1, p-nitrobenzyl alcohol, and Zn(NTf2)2
provided the first important mechanistic insights. The corre-
sponding 19F NMR spectra showed a shift of the CF3 signal of
our hypervalent iodine species from d = À33.0 ppm to d =
À26.9 ppm after a few minutes at room temperature, indicat-
ing the formation of a relatively stable intermediate which
subsequently decayed under reaction conditions. The major
peak in the ESI-MS spectrum depicted in Figure 1 corre-
sponds to a cationic species of stoichiometry [Zn(1)2(NTf2)]+.
We tentatively assign the structure of a zinc(II) dicarboxylato
complex to this cation. This assignment reveals the very
nature of the activation process of reagent 1 by Zn2+,
3[a]
4[b]
5[b]
1.0
62[d]
0.50
55 (39)
0.50
0.33
0.25
49 (37)
48
44
6[b]
7[b]
0.50
0.50
43[d]
28 (12)
0.50
0.30
27 (19)
26
8[b]
À
consisting of the cleavage of the I O bond, thus generating
a more reactive (harder) trifluoromethyl iodonium derivative
(Figure 1).
9[b]
0.50
0.30
18 (2)
12
Although several attempts to prepare an aryl trifluoro-
methyl iodonium salt have been already reported in the
literature, so far none have succeeded.[18] The reported
approach starting from bis(trifluoroacetoxy)-iodoperfluoroal-
kanes was restricted to perfluoroalkyl groups larger than CF3.
Our experiments indicate a possible new avenue which relies
on the sequestration of the carboxyl group from iodine by
coordination to an appropriate metal center, in this case Zn2+.
Pulsed-field gradient spin echo (PGSE) diffusion measure-
ments[19] of the same solution supported the formulation of a
1:2 adduct of Zn2+ with the reagent. This intermediate showed
10[b]
11[a]
12[a]
1.0
1.0
62[d]
74[d]
[a] Reaction conditions: reagent 1 was stirred with 1 equiv of Zn(NTf2)2 in
the alcohol as the solvent (75 equiv) for 24 h. [b] Reaction conditions: 1
was stirred with Zn(NTf2)2 and 5 equiv of alcohol in CDCl3 at RT for 2–
3 days. [c] Yields were calculated based on reagent 1 as determined from
19F NMR integrals using C6H5CF3 as an internal standard. Yields of
isolated products are given in brackets. [d] Not isolated in pure form.
À
a strong interaction with the NTf2 anion, displaying a very
similar diffusion constant. This was not the case for the
alcohol (see the Supporting Information).
A systematic variation of the crystallization conditions
allowed the isolation and analysis by X-ray diffraction of a
crystalline material in the form of very thin platelets,
corresponding to the bis(triflimide) salt of the dicationic
octahedral complex [Zn(1)2(4-NO2C6H4CH2OH)2(H2O)2]2+
(5). An ORTEP view of the asymmetric unit is shown in
Figure 2.
The salient features of the structure of compound 5 are,
firstly, the coordination of water (from an adventitious
source), 4-nitrobenzyl alcohol, and reagent 1 as monodentate
ligands, thus forming a slightly distorted octahedral ZnO6
coordination environment. Secondly, and more importantly in
view of understanding the activation mechanism of 1 by Zn2+,
is the effect of the coordination to the metal center on the
excess alcohol allowed preparation of the corresponding
trifluoromethyl ethers in yields up to 99% with only traces of
the side product 3. Notably, from a practical point of view, the
trifluoromethylated products can be easily separated from the
much more polar alcohols by simple flash column chroma-
tography. Since an excess of alcohol is necessary to obtain
good yields, a molar ratio of 5:1 between the alcohol and
reagent 1 is a tenable compromise, even in the case of using
solid and expensive substrates; higher ratios are likely to give
better yields (Table 3, entries 4–10). We tried a series of
primary alcohols in chloroform and found that all could be
trifluoromethylated in fair yields (up to 55%). Although both
side products 3 and 4 were formed in the trifluoromethylation
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illustrated in Scheme 4. We
assume that reagent 1 reacts
with the zinc salt under forma-
tion of the zinc dicarboxylato
complex A, corresponding to
the species detected by ESI-
MS methods. This species then
reacts with alcohols to form the
intermediate B, resulting from
the addition of an alcoholate to
an iodonium moiety. A subse-
quent reductive elimination
step[22] is responsible for the
formation of the trifluoromethyl
ether product and species C. At
the present stage we cannot
exclude that, alternatively, the
iodonium species
A
might
undergo an intermolecular
attack by the nucleophile lead-
ing to product formation via an
SN2-type process, enhanced by
the exceedingly large nucleofu-
gality of phenyliodonium deriv-
Figure 1. ESI-MS spectrum of a mixture of Zn(NTf2)2 with reagent 1 indicating the formation of a 1:2
adduct, tentatively formulated as a carboxylato complex/iodonium ion.
Figure 2. ORTEP-view (50% probability ellipsoids) of the asymmetric
unit of [Zn(1)2(4-NO2C6H4CH2OH)2(H2O)2](NTf2)2 (5) in which the Zn
atom lies on a crystallographic inversion center. Selected bond lengths
[ꢁ] and angles [8]: I–O2 2.403(12), I–C8 2.195(16), I–C1 2.103(19), I–
O6 3.078(14), Zn–O1 2.029(13), Zn–O3 2.145(13), Zn–O10 2.090(15),
C7–O1 1.27(2), C7–O1 1.26(2); C1-I-O2 75.0(6), C1-I-C8 95.4(7), O1-I-
C8 169.9(5), O1-Zn-O5 92.1(5), O1-Zn-O10 87.7(5), O3-Zn-O10
92.2(5).
Scheme 4. Mechanistic hypothesis for the zinc-mediated electrophilic
trifluoromethylation of alcohols using 1, based on the postulated
formation of trifluoromethyl iodonium salts.
structural parameters of the reagent. Thus, a significant
[10]
À
elongation of the I O bond from 2.283(2) ꢀ in free 1 to
2.403(12) ꢀ and a larger C(1)-I-(CF3) angle of 95.4(7)8
(versus 93.78) may be interpreted as distortions towards the
formation of an iodonium species.[20] Furthermore, a weak
atives.[23] Intermediate A could also react with 2-iodoben-
zoate (accumulating in the course of the reaction) or with
NTf2À forming complexes analogous to B, which could explain
the formation of the observed by-products 3 and 4. Species C
can undergo ligand exchange with reagent 1, thus liberating 2-
iodobenzoate and ending the catalytic cycle. It is reasonable
to assume that this step is facilitated by the protonation of the
carboxylate to 2-iodobenzoic acid. The latter can easily be
À
interaction between the proximal oxygen atom of an NTf2
ion and the iodine atom is indicated by a relatively short O(6)-
I distance of 3.078(14) ꢀ.[21]
With these results in hand it is possible to formulate a
plausible working hypothesis for the reaction mechanism, as
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Communications
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detected in the reaction mixture by NMR spectroscopy. In
this context, the activation of 1 is not restricted to zinc salts. It
is also possible to use other Lewis acids or even Brønsted
acids such as HNTf2 to trigger the formation of trifluoro-
methyl ethers, even though Zn(NTf2)2 is far superior; for
example the maximum yield of 1-trifluoromethoxypentane is
35% (NMR) when using HNTf2 instead of Zn(NTf2)2 (93%
yield), under otherwise identical conditions.
In conclusion, we have shown that it is possible to
trifluoromethylate aliphatic alcohols using the hypervalent
iodine reagent 1. In reactions with primary alcohols the
trifluoromethyl ethers are obtained in yields up to 99% under
very mild and easy to manipulate reaction conditions. Only a
zinc(II) salt with an appropriate counter ion is the key to
promoting the reaction. We are currently exploring other
Lewis acidic metal complexes to additionally improve the
generality of this unique reaction and to discover more
effective catalytic conditions.
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[14] R. Koller, P. Battaglia, Q. Huchet, J. M. Welch, A. Togni, to be
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Experimental Section
[15] L. M. Yagupolskii, A. V. Matsnev, R. K. Orlava, B. G. Deryab-
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Supporting Information available: Experimental procedures and
characterization for selected new compounds, PGSE diffusion data,
and ESI-MS spectra. CCDC 720606 (5) contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[17] a) C. Lu, D. VanDerveer, D. D. DesMarteau, Org. Lett. 2008, 10,
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[18] a) L. M. Yagupolskii, I. I. Maletina, N. V. Kondratenko, V. V.
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[20] It is known that solvents may also play an important role in
facilitating the formation of iodonium salts. See: T. Dohi, M. Ito,
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Received: February 19, 2009
Revised: April 17, 2009
Published online: May 11, 2009
Keywords: etherification · synthetic methods ·
.
hypervalent compounds · iodine · trifluoromethylation
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À
[21] The corresponding I O distances in [IPh2]NTf2 and
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