Acid-mediated formation of trifluoromethyl sulfonates from sulfonic acids and a hypervalent iodine trifluoromethylating agent

Article abstract of DOI:10.1039/b913962a

A variety of sulfonic acids have been trifluoromethylated using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one under mild conditions in good to excellent yields. Initial mechanistic investigations of this reaction show a clean second-order kinetics and only

Full text of DOI:10.1039/b913962a

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Acid-mediated formation of trifluoromethyl sulfonates from sulfonic acids
and a hypervalent iodine trifluoromethylating agentwz
Raffael Koller, Quentin Huchet, Philip Battaglia, Jan M. Welch and Antonio Togni*
Received (in Cambridge, UK) 13th July 2009, Accepted 7th September 2009
First published as an Advance Article on the web 14th September 2009
DOI: 10.1039/b913962a
A variety of sulfonic acids have been trifluoromethylated
using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one under mild
conditions in good to excellent yields. Initial mechanistic
investigations of this reaction show a clean second-order kinetics
and only very weak substrate electronic effects.
only recently by direct trifluoromethylation of sulfonic acids
and sulfonates using a method which suffers from several
shortcomings, thus making it impractical for larger-scale
applications.10 In addition, there is one very recent report of
the synthesis of difluoromethyl sulfonates.11 Even so, the
chemical properties and potential utility of di- and trifluoro-
methyl sulfonic acid esters have yet to be investigated.
Following the above-mentioned observation that zinc salts
are necessary for successful trifluoromethylation, further
investigations were carried out which showed that 1 could
not only be activated by zinc salts (Lewis acids) but also by
Brønsted acids. When sulfonic acids were mixed with the
hypervalent iodine reagent 1 formation of trifluoromethyl
sulfonates took place under ambient conditions overnight in
good to excellent yields (see Scheme 2 and Table 1).
Since 1957, when the first fluorine-containing drug was
developed, the number of fluorinated drugs on the market
has risen steadily. Today, nearly 20% of new pharmaceutical
compounds contain one or more fluorine atoms and for
agrochemicals this percentage is even higher.1 This wide range
of applications is due to the drastic influence on metabolic
stability, lipophilicity, bioavailability, binding affinity and
selectivity conferred by fluorine and perfluoroalkyl substituents.2
Recently, the syntheses of recyclable electrophilic trifluoro-
methylating agents 1 and 2 based on hypervalent iodine have
been developed.3–7 Both reagents are easily accessible from
inexpensive starting materials in high overall yields. As out-
lined in Scheme 1, various substrates, including thiols, primary
and secondary phosphines, active-methylene compounds and
aromatic compounds, can be trifluoromethylated under mild
conditions in, partly, excellent yields.4–6 Recently, the scope of
the reagents has been extended to primary and secondary
alcohols, yielding the corresponding trifluoromethyl ethers.6
During a study directed towards the trifluoromethylation of
alkynes we made an interesting and unexpected observation.
When Zn(OTf)2 was used as an additive, trifluoromethylation of
the alkyne was unsuccessful, but the triflate anion was nearly
quantitatively converted to trifluoromethyl triflate (TFMT)
instead. Similar experiments using sodium, potassium or
copper(II) salts as triflate sources did not yield TFMT. However,
addition of zinc bromide to such reaction mixtures did afford
TFMT, along with considerable amounts of trifluoromethyl
bromide, thus suggesting that zinc salts are necessary for the
successful trifluoromethylation of the triflate anion. TFMT itself
is a well known material which may be prepared by several
methods and has found a variety of synthetic applications.8,9
However, other trifluoromethanesulfonates have been prepared
The presence of a strong Brønsted acid was crucial for the
reaction to take place, since trifluoromethylation of sodium,
potassium or ammonium toluenesulfonate failed. Addition of
a strong acid such as HBF4ꢀOEt2 to mixtures of 1 and
sulfonate salts did in fact trigger the formation of the trifluoro-
methyl esters, although in lower yields. Also, sulfonic acids
having an internal base such as 3j and 3k failed to afford the
desired product.
The reactivity of the trifluoromethyl sulfonic acid esters 5a
and 5f has been investigated. In contrast to their non-fluorinated
counterparts, trifluoromethyl sulfonates do not act as alkylating
agents. Kobayashi has shown that TFMT acts as a sulfonylating
agent with nucleophilic attack of the substrate at the sulfur
atom.12 Kolomeitsev also reported the use of TFMT for the
synthesis of trifluoromethanolates and their application as a
source of the trifluoromethoxy anion in nucleophilic substitution
reactions.8 It has been suggested that the reaction of nucleo-
philes with TFMT is directed to sulfur since it is relatively
electron-poor due to the high electronegativity of the
neighbouring CF3 group (Scheme 3).9
Department of Chemistry and Applied Biosciences, Swiss Federal
Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
E-mail: atogni@ethz.ch; Fax: +41(0) 44-632-1310;
Tel: +41(0) 44-632-2236
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, 1H, 13C and 19F NMR spectra of
new compounds and detailed kinetic data. See DOI: 10.1039/b913962a
Scheme 1 Applications of hypervalent iodine trifluoromethylation
reagents 1 and 2.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5993–5995 | 5993

Scheme 2 Trifluoromethylation of sulfonic acids using reagent 1.
Table 1 Trifluoromethylation of sulfonic acids by 1
Entry
Substrate
1
Yielda (%)
a
b
c
d
e
f
g
h
i
2-Naphthalenesulfonic acid
(ꢃ)-10-Camphorsulfonic acid
4-Nitrobenzenesulfonic acid
4-Chlorobenzenesulfonic acid
Benzenesulfonic acid
4-Methylbenzenesulfonic acid
4-Ethylbenzenesulfonic acid
4-Hydroxybenzenesulfonic acid
4-Methoxybenzenesulfonic acid
4-Aminobenzenesulfonic acid
2-Amino-3-sulfopropanoic acid
1.1 equiv.
87 (67)
99 (75)
76b
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
Fig. 1 Plot of kobs versus [3f] for the trifluoromethylation of 3f with 1
(0.005 M) in a 5 : 1 mixture of CDCl3 and tBuOH at 298 K. The curve
depicts the result of an unweighted least-squares fit to kobs = y0 + a[3f]b
where y0 = (ꢂ4 ꢃ 3) ꢄ 10ꢂ5, a = (2.8 ꢃ 0.2) ꢄ 10ꢂ3 and b = 1.04 ꢃ 0.08.
70b (60)
96b (42)
90b (51)
67 (32)
83b (45)
75b
second set of experiments the concentration of 3f was fixed to
be the limiting reagent and the concentration of 1 was varied.
The results of these experiments are plotted in Fig. 1 and 2,
respectively, and clearly show a first-order dependence of the
reaction rate on the concentration of both reaction partners.
In addition, the possibility of a competitive trifluoro-
methylation of 2-iodobenzoic acid formed as a by-product of
reagent 1 was also investigated. Using the solvent system
described above, the reaction rate appears to be independent
of 2-iodobenzoic acid concentration (see supporting information
for a plot of kobs versus [2-iodobenzoic acid] and further
detailsz).
j
k
0
0
a
Yields based on 19F-NMR with CF3Ph as internal standard. Isolated
yields in parentheses. All reactions run in CHCl3 unless specified
b
otherwise. Reaction run in 5 : 1 CDCl3 : BuOH.
t
We speculated that for trifluoromethyl sulfonates bearing
less electron-withdrawing substituents the attack by an
appropriate nucleophile might be directed to the oxygen, thus
resulting in a formal trifluoromethylation.
Therefore, esters 5a and 5f were treated with phenyl lithium.
After several hours reaction time at room temperature and
aqueous workup both esters were recovered intact. In pentanol
as both nucleophile and solvent the esters showed a similarly
inert behaviour at room temperature. At elevated temperatures
the reagents decomposed slowly. However, no fluorinated
products could be observed by 19F NMR spectroscopy, apart
Investigation of the effect of the solvents used (the addition
of tert-butanol is necessary to completely solvate toluene-
sulfonic acid monohydrate) and the water present in the
reaction mixture on the rate of reaction proved to be a complex
task. Although toluenesulfonic acid is easily dehydrated in
vacuum at elevated temperature yielding a strongly acidic
and hygroscopic material soluble in chloroform, the addition
of water or tert-butanol to solutions of anhydrous sulfonic
acid leads to immediate precipitation of the less soluble
monohydrate, rendering rate studies under these conditions
impractical. In order to circumvent solubility problems, the
test substrate was changed to 3b which is readily available as
anhydrous material. Pseudo-first order rates were measured
for the reaction of 0.005 M 1 with 0.15 M 3b in chloroform
and variable amounts of tert-butanol. The results of these
studies are shown as a plot in Fig. 3. The reaction rate is
ꢂ
from SiF6 (arising from Fꢂ and borosilicate glass). This
implies a cleavage of the S–OCF3 bond releasing trifluoro-
methanolate which decomposes to fluoride and fluorophosgene.
Lastly, given the substantial stability of the O–CF3 bond one
may view this trifluoromethylation reaction as a mild and
selective protection of sulfonic acids, provided an appropriate
deprotection reaction is found.
The reaction of 1 with sulfonic acids generates a minimum
of side products, it goes to completion on a reasonable time-
scale under ambient conditions and it is easily monitored by
19F-NMR spectroscopy. Therefore, it seemed an almost ideal
model system to begin investigations into the mechanism of
trifluoromethylation by 1 using rate studies. Initially, two
series of pseudo-first order rate experiments were carried out
in a 5 : 1 mixture of chloroform and tert-butanol. In the first
group of experiments, the concentration of the limiting reagent
1 was fixed and the concentration of 3f was varied and in the
Fig. 2 Plot of kobs versus [1] for the trifluoromethylation of 3f (0.003 M)
t
with 1 in a 5 : 1 mixture of CDCl3 and BuOH at 313 K. The curve
Scheme 3 Substitution at the sulfur leading to sulfonylation vs. the (as
depicts the result of an unweighted least-squares fit to kobs = y0 + a[1]b
where y0 = (ꢂ2 ꢃ 2) ꢄ 10ꢂ4, a = (1.0 ꢃ 0.2) ꢄ 10ꢂ2 and b = 0.9 ꢃ 0.2.
yet unknown) attack at carbon leading to a formal trifluoromethylation.
ꢁc
This journal is The Royal Society of Chemistry 2009
5994 | Chem. Commun., 2009, 5993–5995

Fig. 3 Plot of kobs versus [tert-butanol] for the trifluoromethylation of
3b (0.15 M) with 1 (0.005 M) in CDCl3–tert-butanol mixtures at 300 K.
Fig. 4 Plot of log kX/kH (where log kX/kH has been determined by a
competition experiment involving 1 equiv. of substituted sulfonic acid,
–OMe, –Me, –F, –CF3 or –NO2, 1 equiv. of benzenesulfonic acid and
1 equiv. of 1 at 298 K, solid line and 323 K, dashed line) versus sp for
various para-substituted benzenesulfonic acids. sp values taken from
reference 13, p. 144. r values were determined by linear least-squares
regression to log kX/kH = rs + b to be ꢂ0.02 ꢃ 0.01 with r = 0.60 at
298 K and ꢂ0.02 ꢃ 0.03 with r = 0.31 at 323 K.14
strongly decreased by the addition of tert-butanol. However, the
behaviour does not fit any simple, idealised inverse order
dependence. Such behaviour suggests that when tert-butanol is
used as a co-solvent, it participates in the rate determining
transition state and that the exact nature (stoichiometry) of this
species varies with tert-butanol concentration. Similar behaviour
for water or any other coordinating solvent might reasonably be
expected, but has yet to be exhaustively demonstrated.
programme for financial support to QH. Dr Heinz Ruegger
and Aitor Moreno are acknowledged for NMR support and
the assistance of Dr Mihai Viciu in analysis of the rate data is
gratefully acknowledged.
In addition to absolute rate studies, competition experiments
were utilized to compare the rate of trifluoromethylation of
various para-substituted benzenesulfonic acids. A plot of the
data acquired at 298 and 323 K against the Hammett parameter
sp shows an apparent linear relationship with only slightly
negative slopes (r), as shown in Fig. 4. The linear relationship
to sp suggests that the mechanism of reaction remains constant
across the range of substituents tested. This seems to
substantiate (though not rigorously prove) the assumption
that under the conditions used the reaction mechanisms for
3f and 3b with 1 are very similar if not identical. The very small
value of r indicates that substituent effects on the reaction rate
are minimal. This may indicate that single electron transfer
(SET) plays a role in the trifluoromethylation of sulfonic acids
by 1 and/or that protons from the sulfonic acid are involved in
the rate determining transition structure and the sulfonate
portion is not.
Notes and references
1 A. M. Thayer, Chem. Eng. News, 2006, 84, 15–24.
2 K. Muller, C. Faeh and F. Diederich, Science, 2007, 317,
1881–1886 and references therein.
3 P. Eisenberger, S. Gischig and A. Togni, Chem.–Eur. J., 2006, 12,
2579–2586.
4 I. Kieltsch, P. Eisenberger and A. Togni, Angew. Chem., Int. Ed.,
2007, 46, 754–757.
5 K. Stanek, R. Koller and A. Togni, J. Org. Chem., 2008, 73,
7678–7685.
6 R. Koller, K. Stanek, D. Stolz, R. Aardoom, K. Niedermann and
A. Togni, Angew. Chem., Int. Ed., 2009, 48, 4332–4336.
7 For recent reviews see: (a) T. Dohi and Y. Kita, Chem. Commun.,
2009, 2073–2085; (b) M. Uyanik and K. Ishihara, Chem. Commun.,
2009, 2086–2099; (c) Hypervalent Iodine Chemistry, ed. T. Wirth,
Springer, Berlin/Heidelberg, 2003 (Top. Curr. Chem. Vol. 224);
(d) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2008, 108,
5299–5358.
8 A. A. Kolomeitsev, M. Vorobyev and H. Gillandt, Tetrahedron
Lett., 2008, 49, 449–454.
9 S. L. Taylor and J. C. Martin, J. Org. Chem., 1987, 52, 4147–4156
and references therein.
10 T. Umemoto, K. Adachi and S. Ishihara, J. Org. Chem., 2007, 72,
6905–6917.
11 V. V. Levin, A. D. Dilman, P. A. Belyakov, M. I. Struchkova and
V. A. Tartakovsky, J. Fluorine Chem., 2009, 130, 667–670.
12 Y. Kobayashi, T. Yoshida and I. Kumadaki, Tetrahedron Lett.,
1979, 20, 3865–3866.
13 T. H. Lowry and K. Schueller Richardson, Mechanism and Theory
in Organic Chemistry, Harper & Row Publishers, New York, 1987.
14 The reason for intrinsically poor values of the correlation factors
for substituent effect data in the case of an almost vanishing slope
is given in the ESIz.
In conclusion, sulfonic acids are easily trifluoromethylated
in good to excellent yields under mild conditions by 1 to form
trifluoromethyl sulfonates. Initial investigations suggest that
these materials are largely unreactive toward nucleophiles.
Rate studies show the involvement of both sulfonic acid and
1 in the rate-determining step, as well as coordinating
co-solvent, when present. We are currently continuing our
investigations of the mechanism of trifluoromethylation by 1
and 2 as well as of the properties and potential synthetic utility
of trifluoromethyl sulfonates.
This work was supported by ETH Zurich and the
Stipendienfonds der Schweizerischen Chemischen Industrie.
We thank the bilateral French–Swiss Germaine de Stael
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5993–5995 | 5995