Reactivity of a hypervalent iodine trifluoromethylating reagent toward thf: ring opening and formation of trifluoromethyl ethers

Article abstract of DOI:10.1021/jo9025429

Chemical Equation Presentation 1-Trifluoromethyl-1,2- benziodoxol-3-(1H)-one (1) is able to transfer the electrophilic CF₃ group to the oxygen atom of THF in the presence of a Lewis or Bransted acid. This results in a new ring-opening reaction of THF yielding trifluoromethyl ethers. Details of this reaction and the insight gained into the mechanism of action of reagent 1 are reported.

Full text of DOI:10.1021/jo9025429

pubs.acs.org/joc
trifluoromethylation.4 The development of complementary
Reactivity of a Hypervalent Iodine
Trifluoromethylating Reagent toward THF: Ring
Opening and Formation of Trifluoromethyl Ethers
electrophilic approaches has, however, proven to be a non-
trivial task.5,6 Successful methods in this challenging area have
utilized sulfonium salt-based reagents active toward sulfur,
phosphorus, and carbon nucleophiles.7 Several years ago, our
group developed a new class of easily synthesized reagents for
electrophilic trifluoromethylation based on hypervalent iodine
derivatives.8 These compounds have shown high activities
toward a variety of nucleophiles.9 Remarkably, the CF3-bear-
ing 1,2-benziodoxole 1 (Figure 1) can be applied to directly tri-
fluoromethylate alcohols under mild conditions.10 Previously,
such transformations were only possible using Umemoto’s
O-(trifluoromethyl)dibenzofuranium salts.11
Serena Fantasia, Jan M. Welch, and Antonio Togni*
Department of Chemistry and Applied Bioscience, Swiss
Federal Institute of Technology, ETH Zurich, 8093 Zurich,
Switzerland
atogni@ethz.ch
Received December 9, 2009
Trifluoromethyl ethers are an interesting class of poten-
tially important pharmacophores. However, aside from the
aforementioned examples, hazardous reagents and harsh
conditions, incompatible with sensitive functional groups,
are required for their synthesis.12 Since the field of electro-
philic trifluoromethylation is still in its infancy, exploration
and understanding of the reactivity of appropriate reagents
toward oxygen nucleophiles is of extreme importance as it
may guide the design of future reagents and reaction condi-
tions.13 Herein we report the unprecedented transfer of a CF3
moiety to the oxygen atom of tetrahydrofuran and informa-
tion concerning the reactivity of reagent 1.
1-Trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1) is
able to transfer the electrophilic CF3 group to the oxygen
atom of THF in the presence of a Lewis or Bronsted acid.
This results in a new ring-opening reaction of THF yield-
ing trifluoromethyl ethers. Details of this reaction and the
insight gained into the mechanism of action of reagent 1
are reported.
During an effort to improve our current system for
trifluoromethylation of alcohols,10 we observed that reac-
tion of reagent 1 with 4-nitrobenzyl alcohol in THF in the
presence of a catalytic amount of Y(NTf2)3 gave rise to
several products other than, but not including, the desired
4-nitrobenzyl trifluoromethyl ether.
Although the 19F NMR spectrum of the reaction mixture
showed a resonance at δ=-60.1 ppm (JF-C=254 Hz), typi-
cal of an OCF3 group and corresponding to a 41% yield
Due to the special properties fluorine atoms impart to
organic molecules,1 organofluorine compounds have come into
wide application in fields such as crop treatment, medicinal
chemistry, and materials science.2 Notably, the introduction of
trifluoromethyl moieties has recently attracted considerable
attention.3 The main strategies are based on nucleophilic
1
(based on integration against an internal standard), the H
NMR spectrum of the isolated material clearly indicated the
(6) Umemoto, T. Chem. Rev. 1996, 96, 1757.
(7) (a) Yagupol’skii, L. M.; Kondratenko, N. V.; Timofeeva, G. N.
J. Org. Chem. USSR (Engl. Transl.) 1984, 20, 103. (b) Umemoto, T.;
Ishihara, S. Tetrahedron Lett. 1990, 31, 3579. (c) Umemoto, T.; Ishihara,
S. J. Am. Chem. Soc. 1993, 115, 2156. (d) Umemoto, T.; Ishihara, S.; Adachi,
K. J. Fluorine Chem. 1995, 74, 77. (e) Yang, J.-J.; Kirchmeier, R. L.; Shreeve,
J. M. J. Org. Chem. 1998, 63, 2656. (f) Umemoto, T.; Ishihara, S. J. Fluorine
Chem. 1999, 98, 75. (g) Magnier, E.; Blazejewski, J.-C.; Tordeux, M.;
Wakselman, C. Ang. Chem. Int. Ed. 2006, 45, 1279. (h) Yagupolskii, L. M.;
Matsnev, A. V.; Orlova, R. K.; Deryabkin, B. G.; Yagupolskii, Y. L.
*To whom correspondence should be addressed. Tel: þ41(0)44-632-2236.
Fax: þ41(0)44-632-1310.
(1) (a) Chambers, R. D. Fluorine in Organic Chemistry; Wiley: New York,
1973. (b) Uneyama, K. Organofluorine Chemistry; Blackwell Publishing:
Oxford, 2006. (c) M€uller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(2) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications; Wiley-VCH: Weinheim, 2004. (b) Thayer, A. M. Chem. Eng. News
2006, 84, 15. (c) Kirk, K. L.; et al. Proc. Res. Dev. 2008, 12, 305. (d) Jeschke, P.
ChemBioChem 2004, 5, 570.
ꢀ
J. Fluorine Chem. 2008, 129, 131. (i) Mace, Y.; Raymondeau, B.; Pradet, C.;
Blazejewski, J.-C.; Magnier, E. Eur. J. Org. Chem. 2009, 1390. (j) Umemoto, T.;
Adachi, K. J. Org. Chem. 1994, 59, 5692. (k) Ma, J.-A.; Cahard, D. J. Org.
Chem. 2003, 68, 8726.
(8) Eisenberger, P.; Gischig, S.; Togni, A. Chem.;Eur. J. 2006, 12, 2579.
(9) (a) Kieltsch, I.; Eisenberg, P.; Togni, A. Angew. Chem., Int. Ed. 2007,
46, 754. (b) Kieltsch, I.; Eisenberg, P.; Stanek, K.; Togni, A. Chimia 2008, 62,
(3) (a) McClinton, M. A. M.; McClinton, D. A. M. Tetrahedron 1992, 48,
6555. (b) Dixon, D. A.; Fukunaga, T.; Smart, B. E. J. Am. Chem. Soc. 1986,
108, 4027. (c) Arnone, A.; Bernardi, R.; Blasco, F.; Cardillo, R.; Rasnati, G.;
Gerus, I. I.; Kukhar, V. P. Tetrahedron 1998, 54, 2809. (d) Smart, B. E.
J. Fluorine Chem. 2001, 109, 3.
€
260. (c) Capone, S.; Kieltsch, I.; Flogel, O.; Lelais, G.; Togni, A.; Seebach, D.
(4) (a) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635. (b) Shimizu, M.;
Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214. (c) Ma, J.-A.; Cahard, D.
J. Fluorine Chem. 2007, 128, 975.
Helv. Chim. Acta 2008, 91, 2035. (d) Eisenberg, P.; Kieltsch, I.; Armanino,
N.; Togni, A. Chem. Commun. 2008, 1575.
(10) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.;
Togni, A. Angew. Chem., Int. Ed. 2009, 48, 4332.
(11) Umemoto, T.; Adachi, K.; Ishihara, S. J. Org. Chem. 2007, 72, 6905.
(12) (a) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827.
(b) Leroux, F. R.; Manteau, B.; Vors, J.-P.; Pazenok, S. Beilstein J. Org. Chem.
2008, 4, 10.3762/bjoc.4.13.
(5) The existence of CF3þ cation, due to the high electronegativity of CF3
group, was thought for a long time to violate common sense: (a) Huheey,
J. E. J. Phys. Chem. 1965, 69, 3284. (b) Olah, G. A.; Heiliger, L.; Prakash,
G. K. S. J. Am. Chem. Soc. 1989, 111, 8020. (c) Reynolds, C. H. J. Chem. Soc.,
Chem. Commun. 1991, 975. For reports on formation of CF3þ species, see:
(d) Olah, G. A.; Ohyama, T. Synthesis 1976, 319. (e) Mayer, P. S.; Leblanc,
D.; Morton, T. H. J. Am. Chem. Soc. 2002, 124, 14185.
(13) For studies on reactivity of 1 toward phenols, see: Stanek, K.; Koller,
R.; Togni, A. J. Org. Chem. 2008, 73, 7678.
DOI: 10.1021/jo9025429
r
Published on Web 02/02/2010
J. Org. Chem. 2010, 75, 1779–1782 1779
2010 American Chemical Society

Fantasia et al.
JOCNote
SCHEME 2. Proposed Mechanism for Ring-Opening Trifluoro-
methylation of THF
FIGURE 1. Reagents for direct trifluoromethylation of alcohols.
SCHEME 1. Formation of Trifluoromethyl Ethers from 1
and THF
SCHEME 3. Rearrangement of 1 Assisted by a Strong Bronsted
Acid
absence of 4-nitrobenzyl trifluoromethyl ether. Structural
assignment was then carried out using 2D NMR techniques
(19F-13C HMQC, 1H-13C HMBC; see the Supporting
Information), thus revealing that the major products of this
reaction are the two trifluoromethyl ethers 2 (27% yield) and
3 (19% yield, 19F NMR δ=-60.2 ppm) derived from a THF
ring-opening process (see Scheme 1). In addition to these two
compounds, the trifluoromethyl ester 4 was also isolated in
24% yield (19F NMR δ=-57.1 ppm for 4). Furthermore, a
FAB-mass analysis of the crude reaction mixture showed
qualitatively that higher oligomers of 2 were also formed
(mainly analogues incorporating 3, 4, and 5 molecules of
THF), which may explain the large discrepancy between
NMR and isolated yields of 2.
Further investigations showed that the presence of alcohol
in the reaction mixture was unnecessary. However, traces of
water were essential to avoid decomposition of reagent 1.14
Moreover, screening different NTf2 lanthanide salts as Lewis
acids (M = Y, La, Sm, Eu, Gd) showed that the product
distribution was independent of the catalyst used. Finally,
HNTf2 was also found to promote the reaction, suggesting
that the reaction is acid catalyzed.
From the nature of the products, it was clear that two
different reactions were occurring: the ring opening of THF
and the formation of an O-CF3 bond. Determination of the
sequence of these reactions is paramount to understanding
the reactivity of 1 toward oxygen nucleophiles. It is well-
known that ring-opening polymerization of THF can be
promoted by strong Lewis or Bronsted acids.15 However,
solutions of Y(NTf2)3 in THF appeared to be stable and no
polymerization was observed, suggesting that the lanthanide
is not primarily responsible for the ring opening of THF.
This observation seems to exclude a mechanism in which an
initial ring opening is followed by transfer of CF3 to the
resulting alkoxide. It is well-known that the first step in
polymerization of THF is formation of a tetrahydrofura-
nium (oxonium) cation through protonation (or coordina-
tion) by the acid. This oxonium species then undergoes
attack by a second molecule of THF at the R-carbon,
initiating the polymerization.15 Therefore, the mechanism
depicted in Scheme 2 seems to most plausibly explain the
formation of 2 and 3 and their higher oligomers.
Carbonyl coordination of reagent 1 to Y(NTf2)3 (or
protonation by HNTf2) would lead to the reactive inter-
mediate 5 in which the CF3-I bond is activated. Transfer of
the CF3 group to THF would form 6, an “Umemoto-like”11
CF3-bearing oxonium salt. Compound 6 could then undergo
ring opening by another molecule of THF to form 2 or 2-
iodobenzoate to form 3. Higher oligomers could be formed
by further additions of THF before termination of the
oligomerization process by 2-iodobenzoate.
We have previously suggested that 1 may be activated
either by Lewis10 or Bronsted acid.16 This has also found
further confirmation in the behavior of the present system,
since reagent 1 is stable in THF in the absence of acid.
Solutions of 1 in CHCl3 or benzene are also stable by
themselves, but 1 is converted to 4 when Y(NTf2)3 or HX
(X = NTf2, BArF (3,5-(CF3)2C6H3)4B (OEt2)2)) was added,
3
providing further evidence of acid-mediated activation of 1.
In addition, the formation of trifluoromethyl ethers from
alcohols and 1 is also accompanied by the formation of 4
when the alcohol is not present in excess.10 Therefore, an
understanding of the formation of 4 from 1 under acidic
conditions might also be useful.
To this end, rate studies were utilized to provide informa-
tion concerning the mechanism of conversion of 1 to 4. 19F
NMR spectroscopy was used to monitor the reaction of 1 to
4 in wet CDCl3 in the presence of various quantities of the
strong Bronsted acid HBArF (Scheme 3).17
Additionally, a series of experiments were also run in
which the concentration of acid was constant and the con-
centration of 1 was varied. The time vs concentration reac-
tion profiles collected (see Figure 2 for a representative
example) do not show the simple linear or exponential
behavior expected under the pseudo first-order conditions
(14) Su, J. T.; Goddard, W. A. J. Am. Chem. Soc. 2005, 127, 14146.
(15) Penczek, S.; Kubisa, P. In Comprehensive Polymer Science, The
Synthesis, Characterization, Reactions & Applications of Polymers; East-
mond, G. C., Ledwith, A., Russo, S., Sigwalt, P., Eds.; Pergamon Press:
New York, 1989; Vol. 3, pp 751-786.
(16) Koller, R.; Huchet, Q.; Battaglia, P.; Welch, J. M.; Togni, A. Chem.
Commun. 2009, 5993.
(17) Brookhart, M.; Grant, B.; Volpe, A. F. Organometallics 1992, 11,
3920.
1780 J. Org. Chem. Vol. 75, No. 5, 2010

Fantasia et al.
JOCNote
the rate experiments do not exclude any particular possible
reaction pathway or set of pathways leading to the formation
of 4, they do conclusively demonstrate that reagent 1 is
activated (rate of reaction increases) under acidic conditions.
Lastly, attempts were made to determine if the reactivity of
1 toward THF can be extended to other ethers. Preliminary
experiments with HBArF as acid showed that 4 is produced
predominantly when dioxane or diethyl ether are used as
solvent. More interestingly, in both cases 19F NMR spectro-
scopy showed the presence of a peak in the OCF3 region,
accounting for 10% (δ = -60.5 ppm) and 6% yield respec-
tively (δ = -60.7 ppm). Although deeper studies are needed
to fully characterize the products of these reactions, the data
obtained strongly suggest that reactivity of 1 toward ethers is
general.
In conclusion, both Lewis and Bronsted acids activate
reagent 1 toward transfer of the CF3 group. Once activated, 1
is a highly potent source of the electrophilic trifluoromethyl
group which can react with THF or other ethers at oxygen or
undergo rearrangement/decomposition to the trifluoro-
methyl ester 4. These results demonstrate the higher than
previously supposed reactivity and potentially broader ap-
plicability of reagent 1. Further efforts to expand the scope of
trifluoromethylation with 1 and to gain insight into the
mechanistic aspects thereof continue in our laboratories.
FIGURE 2. Plot of 19F NMR integrals versus time (reaction
profile) showing decay of 1 (filled circles) and formation of 4
(unfilled circles) for the reaction of 0.1 M 1 with 0.020 M
[(3,5-(CF3)2C6H3)4B]-[H(OEt2)2]þ in CDCl3 at 300 K.
Experimental Section
Formation of 2-4. A 5 mL vial was charged with 1 (50 mg,
0.158 mmol) and Y(NTf2)3 (1.5 mg, 1.58 μmol). THF (1 mL) was
added, and the mixture was stirred for 18 h at room temperature.
The solvent was removed under reduced pressure, and the
different products were separated and isolated through column
chromatography on silica gel (eluent: hexane/ethyl acetate 92:8).
When the reaction was performed in deuterated THF, 2-d16 and
3-d8 were obtained.
FIGURE 3. Plot of [4] against time for the reaction of 0.1 M 1 with
0.005 M (circles), 0.01 M (triangles), 0.015 M (squares), and 0.02 M
(diamonds) HBArF in wet CDCl3 at 300 K.
2: colorless oil; Rf = 0.26, 27% yield; 1H NMR (C6D6, 400
MHz) 7.67 (d, 3J = 8 Hz, 1H, CH), 7.63 (d, 3J = 8 Hz, 1H, CH),
6.81 (t, 3J = 8 Hz, 1H, CH), 6.48 (t, 3J = 8 Hz, 1H, CH), 4.19 (t,
3J = 6 Hz, 2H, OCH2), 3.55 (t, 3J = 6 Hz, 2H, OCH2), 3.10 (t,
3J = 6 Hz, 2H, OCH2), 3.03 (t, 3J = 6 Hz, 2H, OCH2), 1.63 (m,
2H, CH2), 1.50 (m, 2H, CH2), 1.39 (m, 2H, CH2), 1.33 (m, 2H,
CH2); 1H NMR (C6D6, 200 MHz) 7.65 (t, 3J = 8 Hz, 2H, CH),
6.81 (t, 3J = 8 Hz, 1H, CH), 6.48 (t, 3J = 8 Hz, 1H, CH), 4.19 (t,
3J = 6 Hz, 2H, OCH2), 3.55 (t, 3J = 6 Hz, 2H, OCH2), 3.10 (t,
3J = 6 Hz, 2H, OCH2), 3.03 (t, 3J = 6 Hz, 2H, OCH2), 1.4-1.8
(m, 8H, CH2); 13C NMR (C6D6, 100.6 MHz) 166.6 (CO2), 141.6
(CH arom), 136.7 (CCO2), 132.5 (CH arom), 131.1 (CH arom),
1
127.9 (CH arom), 122.6 (quartet, JC-F = 254 Hz, CF3), 94.5
(CI), 70.5 (OCH2), 70.1 (OCH2), 67.8 (quartet, JC-F=3 Hz,
3
CH2OCF3), 65.6 (OCH2) 26.8 (CH2), 26.1 (CH2), 26.1 (CH2),
26.1 (CH2); 19F NMR (C6D6, 188.3 MHz) -60.1 (s, CF3); exact
mass (ESIþ) calcd for C16H20F3INaO4 ([M] þ Naþ) 483.0251,
found 483.0272.
FIGURE 4. Plot of [4] against time for the reaction of 0.003 M
HBArF with 0.03 M (circles), 0.09 M (triangles), and 0.15 M
(squares) 1 in wet CDCl3 at 320 K.
2-d16: 1H NMR (C6D6, 200 MHz) 7.65 (t, 3J = 8 Hz, 2H, CH),
6.81 (t, 3J = 8 Hz, 1H, CH), 6.47 (t, 3J = 8 Hz, 1H, CH); 19
F
NMR (C6D6, 188.3 MHz) -60.1 (s, CF3); exact mass (ESIþ)
calcd for C16H4D16F3INaO4 ([M] þ Naþ) 499.1255, found
499.1264.
used. Indeed, the profile shapes are a strong indicator of a
more complex mechanism.
3: obtained as colorless oil; Rf = 0.42, 19% yield; 1H NMR
(C6D6, 300 MHz) 7.67 (d, 3J = 8 Hz, 1H, CH), 7.58 (d, 3J = 8
Hz, 1H, CH), 6.82 (t, 3J = 8 Hz, 1H, CH), 6.48 (t, 3J = 8 Hz, 1H,
Although the extraction of numerical rate information
from the profiles obtained would be a difficult task, simple
inspection shows that the reaction is strongly accelerated by
increasing acid concentration (see Figure 3) and is largely
unaffected by the concentration of 1 (see Figure 4). Although
3
3
CH), 3.95 (t, J = 6 Hz, 2H, OCH2), 3.39 (t, J = 6 Hz, 2H,
OCH2), 1.25 (m, 4H, CH2); 13C NMR (C6D6, 75.5 MHz) 166.0
(CO2), 141.3 (CH arom), 136.0 (C arom), 132.2 (CH arom),
J. Org. Chem. Vol. 75, No. 5, 2010 1781

Fantasia et al.
JOCNote
130.7 (CH arom), 127.6 (CH arom), 122.1 (quartet, 1JC-F = 254
(quartet, JC-F = 267 Hz, CF3), 95.6 (C, CI); 19F NMR
(CDCl3, 188.3 MHz) -57.1 (s, CF3); exact mass (ESIþ) calcd
for C8H4F3IO2 315.9203, found 315.9201
1
3
Hz, CF3) 94.0 (CI), 66.8 (quartet, JC-F = 3 Hz, CH2OCF3),
64.4 (OCH2), 25.2 (CH2), 24.5 (CH2); 19F NMR (C6D6, 188.3
MHz) -60.2 (s, CF3); GC-MS retention time = 21.73 min,
mass = 388.10 (calcd = 387.98); exact mass (ESIþ) calcd for
C12H12F3INaO3 ([M] þ Naþ) 410.9675, found 410.9666.
3-d8: 1H NMR (C6D6, 200 MHz) 7.67 (d, 3J = 8 Hz, 1H, CH),
7.58 (d, 3J = 8 Hz, 1H, CH), 6.81 (t, 3J = 8 Hz, 1H, CH), 6.47
Acknowledgment. This work was supported by ETH
€
€
Zurich. Dr. Heinz Ruegger and Aitor Moreno are acknow-
ledged for NMR support, the assistance of Dr. Mihai Viciu
in analysis of the rate data is gratefully acknowledged, and
we are also grateful to Raffael Koller for supplying
3
(t, J = 8 Hz, 1H, CH); 19F NMR (C6D6, 188.3 MHz) -60.2
(s, CF3); GC-MS retention time = 21.62, mass = 396.14
(calcd =396.03).
HBArF 2Et2O.
3
1
4: obtained as white solid; Rf = 0.67, 24% yield; H NMR
(CDCl3, 300 MHz) 8.13 (d, 3J = 8 Hz, 1H, CH), 7.98 (d, 3J = 8
Hz, 1H, CH), 7.51 (t, 3J = 8 Hz, 1H, CH), 7.29 (t, 3J = 8 Hz, 1H,
CH); 13C NMR (CDCl3, 75.5 MHz) 157.9 (C, CO2), 142.6 (CH),
134.7 (CH), 132.5 (CH), 130.3 (CCO2), 128.7 (CH), 119.7
Supporting Information Available: General experimental
methods, experimental procedures, and full characterization
data and copies of NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
1782 J. Org. Chem. Vol. 75, No. 5, 2010