Reactivity of a 10-I-3 hypervalent iodine trifluoromethylation reagent with phenols

Article abstract of DOI:10.1021/jo8014825

(Chemical Equation Presented) The reaction of the 10-I-3 hypervalent iodine electrophilic trifluoromethylation reagent 1-trifluoromethyl-1,2-benziodoxol-3- (1H)-one (2) with 2,4,6-trimethylphenol, after deprotonation with NaH and in the presence of 18-crown-6 in a polar, nonprotic solvent, affords 1,3,5-trimethyl-2-(trifluoromethoxy)benzene (4) only as a byproduct. Trifluoromethylation occurs preferentially at the ortho- and para-positions of the aromatic core, giving the corresponding trifluoromethylcyclohexadienones 5 and 6. In case the ortho-and/or para-positions are not substituted, the corresponding products of an aromatic, electrophilic substitution are obtained in moderate yield, for example, 2-trifluoromethyl-4-tert-butylphenol (10a) from 4-tert-butylphenol (10).

Full text of DOI:10.1021/jo8014825

Reactivity of a 10-I-3 Hypervalent Iodine Trifluoromethylation
Reagent With Phenols
Kyrill Stanek, Raffael Koller, and Antonio Togni*
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology,
ETH Zurich, CH-8093 Zu¨rich, Switzerland
togni@inorg.chem.ethz.ch
ReceiVed July 18, 2008
The reaction of the 10-I-3 hypervalent iodine electrophilic trifluoromethylation reagent 1-trifluoromethyl-
1,2-benziodoxol-3-(1H)-one (2) with 2,4,6-trimethylphenol, after deprotonation with NaH and in the
presence of 18-crown-6 in a polar, nonprotic solvent, affords 1,3,5-trimethyl-2-(trifluoromethoxy)benzene
(4) only as a byproduct. Trifluoromethylation occurs preferentially at the ortho- and para-positions of
the aromatic core, giving the corresponding trifluoromethylcyclohexadienones 5 and 6. In case the ortho-
and/or para-positions are not substituted, the corresponding products of an aromatic, electrophilic
substitution are obtained in moderate yield, for example, 2-trifluoromethyl-4-tert-butylphenol (10a) from
4-tert-butylphenol (10).
Introduction
as amyotrophic lateral sclerosis, Celikalim,5 a potent potassium
channel opener in human airway smooth muscles, and CP-
122,721,6 a potent antagonist of neurokinin-1 receptor, with
potential indication for a variety of disorders, from depression
and pain to inflammatory diseases. Finally, the trifluoromethoxy
group is essential for the effect of pesticides such as Triflumu-
ron,7 a chitin synthesis inhibitor, or Indoxacarb,8 a sodium
channel blocking insecticide. For all these biologically active
compounds, the increased lipophilicity due to the trifluo-
Fluoroorganic molecules are eminently important for the
pharmaceutical industry such that about 15% of all newly
marketed pharmaceuticals contain one or more fluorine atoms.
Besides single fluorine atoms, very often at aromatic positions
the trifluoromethyl substituent also plays a very important role.1
The same is very much true for crop protection agents, in which
case the share of fluorinated molecules is much higher. However,
examples of trifluoromethoxy derivatives2 as medicines are still
quite rare.3 Examples among these are Riluzole,4 the first
approved drug for the treatment of neurological diseases such
(5) Celikalim is 2-((3S,4R)-3-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chro-
man-4-yl)isoindolin-1-one. See: Quagliato, D. A.; Humber, L. G.; Joslin, B. L.;
Soll, R. M.; Browne, E. N.; Shaw, C.; Van Engen, D. Bioorg. Med. Chem. Lett.
1991, 1, 39–42.
(6) CP-122,721 is (2S,3S)-2-phenyl-3-[(5-trifluoromethoxy-2-methoxy)ben-
zylamino]piperidine. See: (a) Obach, R. S.; Maroolis, J. M.; Logman, M. J. Drug
Metab. Pharmacokinet. 2007, 22, 336–349. (b) Yamazaki, N.; Atobe, M.;
Kibayashi, C. Tetrahedron Lett. 2002, 43, 7979–7982. (c) Rosen, T. J.; Coffman,
K. J.; McLean, S.; Crawford, R. T.; Bryce, D. K.; Gohda, Y.; Tsuchiya, M.;
Nagashisa, A.; Nakane, M.; Lowe, J. A. Bioorg. Med. Chem. Lett. 1998, 8, 281–
284.
(7) Triflumuron is 1-(2-chlorobenzoyl)-3-(4-trifluoromethoxyphenyl)urea. See:
(a) Sheets, J. J. In Modern Crop Protection Compounds; Kra¨mer, W., Schirmer,
U., Eds.; Wiley-VCH: Weinheim, Germany, 2007; Vol. 3, pp 813-824. See
also: (b) Tomlin, C. D. S., Ed. The e-Pesticide Manual. A world Compendium,
Version 3.2, 13th ed.; British Crop Production Council, 2005-2006.
* To whom correspondence should be addressed. Fax: (+41) 44-632-1310.
(1) For a recent overview, see: Thayer, A. M. Fabulous Fluorine. Chem. Eng.
News 2006, June 5, 15–32.
(2) For a recent review, see: Leroux, F.; Jeschke, P.; Schlosser, M. Chem.
ReV. 2005, 105, 827–856.
(3) Jeschke, P.; Baston, E.; Leroux, F. R. Mini-ReV. Med. Chem. 2007, 7,
1027–1034.
(4) Riluzole is 2-amino-6-(trifluoromethoxy)benzothiazole. See: Jimonet, P.;
Audiau, F.; Barreau, M.; Blanchard, J.-C.; Boireau, A.; Bour, Y.; Cole´no, M.-
A.; Doble, A.; Doerflinger, G.; Do Huu, C.; Donat, M.-H.; Duchesne, J. M.;
Ganil, P.; Gue´re´my, C.; Honore´, E.; Just, B.; Kerphirique, R.; Gontier, S.; Hubert,
P.; Laduron, P. M.; Le Blevec, J.; Meunier, M.; Miquet, J.-M.; Nemecek, C.;
Pasquet, M.; Piot, O.; Pratt, J.; Rataud, J.; Reibaud, M.; Stutzmann, J.-M.;
Mignani, S. J. Med. Chem. 1999, 42, 2828–2843.
7678 J. Org. Chem. 2008, 73, 7678–7685
10.1021/jo8014825 CCC: $40.75 2008 American Chemical Society
Published on Web 09/05/2008

10-I-3 HyperValent Iodine Trifluoromethylation Reagent
SCHEME 1. Improved Synthesis of Reagent 2
FIGURE 1. Electrophilic trifluoromethylation reagents.
pounds 2 and 3 (Figure 1) are derived from 2-iodobenzoic acid,
and they can be handled in air, are stable in a freezer over years,
and give good to excellent yields in the trifluoromethylation of
thiols and primary as well as secondary phosphines.15 Their easy
handling and synthesis and their possible recyclability make 2
and 3 attractive, possibly even for industrial applications.
Therefore, as part of a general assessment of the reactivity of
our reagents, it was an obvious step to examine their trifluo-
romethylation ability toward hard oxygen nucleophiles, espe-
cially phenols. Herein we present our findings and describe
experiments carried out with a series of model systems.
romethoxy group seems to play a crucial role influencing
bioavailability and activity.9
In the synthesis of complex trifluoromethoxy compounds, the
chemical industry is still strongly dependent on the availability
of corresponding building blocks. Simple trifluoromethoxy aryls
are indeed commercial compounds, and in these cases, the
fluorine atoms have been introduced by hazardous and harsh
reaction conditions using, for example, CCl4/HF, COF2, SF4,
or SbF5.10 Obviously, simple, late stage and functional group
tolerant methods for the trifluoromethylation of phenols is
needed, has been eagerly sought for decades, and continues to
be so at present.11
Results and Discussion
Electrophilic trifluoromethylation reagents have been intro-
duced by the Yagupol’skii research group12 and further devel-
oped by Umemoto and co-workers.13 They are based on S-,
Se-, and Te-(trifluoromethyl)dibenzothio-, seleno-, and tel-
lurophenium salts and are suitable for the trifluoromethylation
of metal enolates, silyl enolates, thiolates, enamines, and
electron-rich aromatics in moderate to good yields. However,
no direct O-trifluoromethylation is observed with these reagents.
Very recently, again Umemoto and co-workers reported a
first solution to the problem of the direct, electrophilic O- or
N-trifluoromethylation of both aliphatic and aromatic alcohols
and amines, respectively.14 They introduced a new series of
O-(trifluoromethyl)dibenzofuranium salts of type 1 (Figure 1),
which are more reactive toward hard nucleophiles, giving the
corresponding trifluoromethylated products in good yields. The
drawbacks one could mention are the in situ preparation at -90
°C, the lack of recyclability, and the fact that they need in the
starting material an OCF3 group, which needs to be constructed
in the first place.
With respect to the originally reported synthesis of reagent
2, we were able to simplify and improve its preparation such
that it is now available on a multigram scale in 76% overall
yield starting from 2-iodobenzoic acid (Scheme 1). This
reagent may be purified by column chromatography or
sublimation and is air as well as moisture stable over months
at room temperature.
Trifluoromethylation of 2,4,6-Trimethylphenol. First ex-
periments with the most simple substrate, such as phenol, gave
products of aromatic electrophilic substitution only, in a 9:4
ratio by 19F NMR spectroscopy of the para and ortho regioi-
somers, accompanied by traces of the meta isomer. We therefore
decided to carry out reactions of compound 2 with 2,4,6-
trimethylphenol, thus speculating that the “occupied” ortho and
para positions could favor reaction at the oxygen atom. Since
reagent 2 has no incorporated alcoholate functionality acting
as a sufficiently strong base as in the case of 3, the phenol has
been deprotonated with NaH in a polar nonprotic solvent such
as DMF prior to the addition of reagent 2. Furthermore, in order
to ensure solubility of the corresponding sodium phenolate and
avoid the possible formation of oligomeric aggregates,16 reac-
tions have been carried out in the presence of 1 equiv of the
crown ether 18-crown-6. It is known that crown ethers are able
to stabilize iodonium salts by weak iodine-oxygen interactions
and that such complexes may be isolated in crystalline form.17
However, it is not clear whether or not this type of interaction
plays any significant role in the reactions reported here.
Thus, the desired 1,3,5-trimethyl-2-(trifluoromethoxy)benzene
(4) could indeed be detected but only as a minor product. The
cyclohexadienones 5, 6, and 7 arising from the oxidation/
trifluoromethylation of the starting phenol constituted the major
products (Scheme 2). Oxidation/methoxylation reactions of
Our research group contributed to the growing family of
electrophilic trifluoromethylation reagents with a new type of
10-I-3 hypervalent trifluoromethyliodine derivatives. Com-
(8) Indoxacarb is (S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-
(trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-
4a(3H)carboxylate. See: McCann, S. F. ; Cordova, D. ; Andaloro, J. T. ; Lahm,
G. P. In Modern Crop Protection Compounds; Kra¨mer, W., Schirmer, U., Eds.;
Wiley-VCH: Weinheim, Germany, 2007; Vol. 3, pp 1031-1048.
(9) For substituent effects on lipophilicity as expressed by log P, see: Fujita,
T.; Iwasa, J.; Hansch, C. J. Am. Chem. Soc. 1964, 86, 5175–5180.
(10) For a review, see: (a) Langlois, B.; Desbois, M. Ann. Chim. Fr. 1984,
9, 729–741. For specific examples, see: (b) Feiring, A. E. J. Org. Chem. 1979,
44, 2907–2910. (c) Salome´, J.; Mauger, C.; Brunet, S.; Schanen, V. J. Fluorine
Chem. 2004, 125, 1947–1950. (d) Yagupol’skii, L. M. Dokl. Akad. Nauk SSSR
1955, 105, 100–102. (e) Yarovenko, N. N.; Vasil’eva, A. S. Zh. Obshch. Khim.
1958, 28, 2502–2504. (f) Yagupol’skii, L. M.; Orda, V. V. Zh. Obshch. Khim.
1961, 31, 915–924.
(11) For leading references, see: (a) Leroux, F. R. ; Manteau, B.; Vors, J.-P. ;
Pazenok, S. Beilstein J. Org. Chem. 2008, 10.3762/bjoc.4.13. (b) Kirsch, P. Modern
Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany, 2004.
(12) Yagupol’skii, L. M.; Kondratenko, N. V.; Timofeeva, G. N. Zh. Org.
Khim. 1984, 20, 115–118.
(13) (a) Umemoto, T.; Ishihara, S. Tetrahedron Lett. 1990, 31, 3579–3582.
(b) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156–2164. (c)
Umemoto, T.; Adachi, K. J. Org. Chem. 1994, 59, 5692–5699.
(14) Umemoto, T.; Adachi, K.; Ishihara, S. J. Org. Chem. 2007, 72, 6905–
6917.
(15) (a) Eisenberger, P.; Gischig, S.; Togni, A. Chem.sEur. J. 2006, 12,
2579–2586. (b) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed.
2007, 46, 754–757. (c) Eisenberger, P.; Kieltsch, I.; Armanino, N.; Togni, A.
Chem. Commun. 2008, 1575–1577.
(16) See, for example: (a) Kunert, M.; Dinjus, E.; Nauck, M.; Sieler, J. Chem.
Ber./Recueil 1997, 130, 1461–1465. (b) Czado, W.; Mu¨ller, U. Z. Kristallogr.
NCS 1999, 214, 63–64.
(17) For recent reviews, see: (a) Ochiai, M. Coord. Chem. ReV. 2006, 250,
2771–2781. (b) Ochiai, M. Chem. Rec. 2007, 7, 12–23, and references cited
therein.
J. Org. Chem. Vol. 73, No. 19, 2008 7679

Stanek et al.
TABLE 1. Trifluoromethylation of 2,4,6-Trimethylphenolate
SCHEME 2. Products Observed in the Reaction of 2 with
2,4,6-Trimethylphenol
yielda (%)
ratio
run substrate/2 solvent
T (°C)
additive
4
5
6
7
8
1b
2
3
4
5
6
7
8
9
10
11
12
13
1/1.2
1/1.2
1/1.6
1/2.5
1/1.2
1/1.2
1/1.6
1/1.6
2.5/1
2.5/1
2.5/1
2.5/1
2.5/1
DMF
DMF
DMF
DMF
DMA
DMSO rt to 75
sulfolane rt to 60
DMF-d7 rt to 60
-20 to rt
rt to 75
rt to 60
rt to 75
rt to 75
18-crown-6
18-crown-6
18-crown-6
18-crown-6
-
18-crown-6
18-crown-6
CsCl
4
8
3
2
2
2
4
2
3
5
6
-
-
-
-
-
1
12 17
11 16
9
11 17
14 16
15 10
7
2
3
8
7
2
1
-
-
-
-
-
2
3
3
4
3
13
8
11
DMF
DMF
DMF
rt
55
18-crown-6
18-crown-6
12 24 20
10 20 20
7
7
- 40 to rt 18-crown-6
33 25
29 22
DMF-d7 -60 to -40
DMF -40 to rt
-
3
-
18-crown-6 and 13 32 26
Phenyl N-tert-
phenols have already been described by Kita as well as Pelter
using PhI(OCOCF3)2 and/or PhI(OAc)2 in MeOH acting as an
external nucleophile giving corresponding ketones.18 Also, in
Friedel-Crafts-type reactions on substituted phenols, similar
cyclohexadienones had been observed as early as in 1906.19
On the other hand, rare examples of compounds containing the
structural elements of a geminal alkyl/trifluoromethyl disubsti-
tution pattern adjacent or in vinylogous position to the carbonyl
group in a cyclohexanone system are known in the literature,
and they have been prepared by a variety of methods from
already trifluoromethylated starting materials.20 The access to
such structures by a direct trifluoromethylation process, as it is
here the case, is new.
In an attempt to influence the selectivity of the reaction, either
toward the trifluoromethoxy derivative 4 or to the not less
interesting cyclohexadienones 5 and 6, we carried out a series
of experiments, thereby varying several reaction parameters,
such as temperature, solvent, substrate/reagent ratio, and addi-
tives. The results are collected in Table 1.
butylnitrone
a Yields were determined by 19F NMR with C6H5CF3 as internal
standard and calculated based on the compound in deficit. b Run 1 did
not go to completion within 6 days.
especially at lower temperatures and shortened the reaction time
from about 24 h (runs 2-8) to 50 min at -50 °C. Although the
total yield of trifluoromethylated products increased to ca. 70%,
the drawback was the lowered yield of 4.
Since it proved very difficult to obtain the desired product
(4) with high selectivity and useful yields, we also investi-
gated the possible catalytic effect of various metal salts and
complexes. However, FeCl3, FeCl2, MnCl2, CoCl2, Pb(OAc)4,
AlCl3, or RuCl2(PPh3)3 just favored the formation of side
products 7 and 8 along with other unidentified products.
Furthermore, addition of a base is crucial for the reaction to
occur, but when Hu¨nig’s base was used instead of NaH,
compound 8 was formed predominatly as part of a complex
mixture of unidentified products.
Other Substituted Phenols. The possibility to oxidize and
trifluoromethylate 2,4,6-trimethylphenol encouraged us to extend
this type of reacivity to various other substituted phenols.
The results collected in Table 2 clearly demonstrate that the
oxidized products are only accessible when both the ortho and
para positions of the phenol are already substituted (blocked).
If not, trifluoromethylation exclusively takes place at these
positions in moderate yields. Furthermore, bistrifluoromethy-
lation is possible despite the decreased nucleophilicity of the
monotrifluoromethylated intermediate. This is apparent in the
cases of 4-tert-butyl phenol 10 and 5-indanol 12. The 2,6-
bis(trifluoromethyl) substitution pattern of product 12b has been
verified by a 1H/19F HOESY NMR experiment (see Supporting
Information). In the case of estradiol 13, the 19F NMR spectrum
of the reaction mixture showed, besides the main product 13a,
another monosubstituted derivative (at -60.5 ppm) along with
a disubstituted product (at -52.1 and -61.7 ppm), accounting
for 12 and 8% yield, respectively. Unfortunately, we were not
able to isolate these two derivatives in pure form, but we assume
that the observed product mixture reflects an analogous ortho
substitution pattern as for indanol 12. A substrate such as
ꢀ-estradiol (13) could have given access, in case of a quater-
nization of the para position, to a hitherto unknown derivative
of testosterone in which the methyl group at the A/B ring
junction of the steroid system has been replaced by a CF3 group.
Finally, a remarkable result was obtained when 2,4,6-
trimethylphenol was reacted with reagent 3. Trifluoromethylation
took place at the benzylic position and products 4, 5, and 6
were only detected in traces (<5%). This benzylic trifluorom-
These reactivity studies put forward several interesting
aspects. When reagent 2 was used in excess, 97% of trimeth-
ylphenol was consumed within 2 days (run 8, conversion
1
monitored by H NMR; see Supporting Information), but only
a total of 29% of trifluoromethylated products could be detected.
HCF3 and DCF3 were also observed (the reaction was carried
out in deuterated DMF), approximately accounting for the
missing 71% of the CF3 unit by 19F NMR spectroscopy. Thus,
a major decomposition pathway of reagent 2 seems to involve
hydrogen abstraction from the solvent. Moreover, the reaction
did also work in other aprotic, polar solvents such as DMSO,
DMA, sulfolane, and NMP but not in CH2Cl2, CCl4, or H2O.
For the case of excess reagent 2, elevated temperatures were
needed to complete the reaction. Higher temperatures favor the
formation of the desired product 4 but concomitantly also trigger
the decomposition of 2 to HCF3. Higher excess of 2 unexpect-
edly lowered the total yield of fluorinated products (run 4). This
prompted us to use trimethylphenol in excess instead (runs
9-13). This change of reaction conditions drastically increased
the yields of cyclohexadienones 5 and 6, based on reagent 2,
(18) (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987,
52, 3927–3930. (b) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T.
J. Org. Chem. 1991, 56, 435–438. (c) Pelter, A.; Ward, R. S. Tetrahedron 2001,
57, 273–282.
(19) Zincke, T.; Suhl, R. Ber. 1906, 39, 4148.
(20) (a) Blazejewski, J.-C.; Le Guyader, F.; Wakselman, C. J. Chem. Soc.,
Perkin Trans. 2 1991, 1121–1125. (b) Kim, B. T.; Min, Y. K.; Asami, T.; Park,
N. K.; Jeong, I. H.; Cho, K. Y.; Yoshida, S. Bioorg. Med. Chem. Lett. 1995, 5,
275–278. (c) Allen, D. M.; Batsanov, A. S.; Brooke, G. M.; Lockett, S. J. J.
Fluorine Chem. 2001, 108, 57–67. (d) England, D. C.; Krespan, C. G. J. Org.
Chem. 1970, 35, 3308–3312. (e) England, D. C.; Donald, E. A.; Weigert, F. J.
J. Org. Chem. 1981, 46, 144–147.
7680 J. Org. Chem. Vol. 73, No. 19, 2008

10-I-3 HyperValent Iodine Trifluoromethylation Reagent
TABLE 2. Trifluoromethylation of Various Phenols
a The phenol was reacted with 1.2 equiv of reagent 3 in CH2Cl2 at rt. b Sodium phenolate (2.5 equiv) was reacted with reagent 2 (1 equiv) in DMF
with 18-crown-6 as additive at -60 °C to rt. Yields were calculated on the basis of 2 by 19F NMR spectroscopy of the reaction mixture using C6H5CF3
as standard; isolated yields are given in brackets.
SCHEME 3. Possible Mechanistic Descriptions for the
Reaction of 2 with 2,4,6-Trimethylphenol
catalyzed electrophilic fluorination of ꢀ-keto esters, as indicated
by computational chemistry studies.21 Product formation would
then occur by the transfer of a CF3 radical, that is, by a radical
recombination. A comparable SET pathway has been suggested
by Kita and co-workers for the oxidative coupling of arenes
using hypervalent iodine oxidants.22 Path B initially invokes a
nucleophilic ligand exchange at iodine(III), with the phenolate
replacing the carboxylate (1B). Such an exchange seems realistic
due to the stronger trans influence of the CF3 group and the
resulting weakening of the I-O bond in the 4e-3c hypervalent
interaction in reagent 2.23 Intermediate 1B may be viewed as
an adduct between an iodonium cation and the phenolate anion.
Liberation of the CF3 anion leads to a system having, attached
to the phenol oxygen, a phenyliodonium leaving group which
is generally known for its extreme nucleofugality.24 This means
that the phenol fragment is an equivalent of a phenoxonium
cation and is therefore susceptible to nucleophilic attack by
CF3-. Kita18a,b and, independently, Pelter18c discussed similar
ionic pathways in their work about phenol oxidation/methoxy-
lation. Moreover, Ozanne-Beaudenon and Quideau reported a
phenylation reaction of phenols by chlorodiphenyl-λ3-iodane for
ethylation could not be observed under the same conditions for
electron-poor substrates such as 4-nitrotoluene. This is indicative
of different mechanistic characteristics for the two reagents.
Mechanistic Aspects. Two limiting mechanistic descriptions,
as shown in Scheme 3, are conceivable. Path A involves the
formation of a charge-transfer complex between reagent 2 and
the phenolate anion (1A), followed by a single electron transfer
(SET). This leads to a cyclohexadienone radical still associated
with and antiferromagnetically coupled with the one-electron-
reduced form of the reagent (i.e., 2A is a singlet diradical). This
description is reminiscent of the situation occurring in the Ti-
(21) Piana, S.; Devillers, I.; Togni, A.; Rothlisberger, U. Angew. Chem., Int.
Ed. 2002, 41, 979–982.
(22) Dohi, T.; Ito, M.; Morimoto, K.; Iwata, M.; Kita, Y. Angew. Chem.,
Int. Ed. 2008, 47, 1301–1304.
(23) Ochiai, M.; Sueda, T.; Miyamoto, K.; Kiprof, P.; Zhdankin, V. V. Angew.
Chem., Int. Ed. 2006, 45, 8203–8206.
(24) Okuyama, T.; Takino, T.; Sueda, T.; Ochiai, M. J. Am. Chem. Soc. 1995,
117, 3360–3367.
J. Org. Chem. Vol. 73, No. 19, 2008 7681

Stanek et al.
FIGURE 2. 19F NMR series of the trifluoromethylation of trimethylphenol. Time (t) is given in minutes, temperature (T) in °C.
which they envisaged a ligand exchange followed by a ligand
coupling at iodine.25 Most recent investigations by Kita using
chiral iodine(III) reagents in enantioselective dearomatization
reactions of phenols strongly support the formation of stable
phenoxy-λ3-iodane intermediates.26
at that temperature for a specified time, cooled again to -93
°C, at which temperature spectra were recorded (see Supporting
Information). These spectra show two singlet radical species
accumulating with time, the concentration of the major one
reaching ca. 2.9 × 10-9 mol/mL after 10 min at rt. This is very
low, as compared to the initial concentration of 1.8 × 10-4 mol/
mL for the reagent. We interpret this as being indicative of minor
iodo-radical byproducts, not directly involved with the main
transformation. That the reaction does not generate free radicals
was also corroborated by the fact that the addition of the radical
scavanger phenyl N-tert-butylnitrone (run 13, Table 1) did not
affect the reaction to any significant extent, both in terms of
rate and product yield.
For the reaction corresponding to run 12 in Table 1, a sample
of trimethylphenolate and reagent 2 in DMF-d7 was prepared
at -100 °C (MeOH/N2(l)). After carefully warming the frozen
sample to -55 °C, a series of 19F NMR spectra were recorded
as a function of time and are illustrated in Figure 2. This
monitoring shows the rapid consumption of reagent 2 and the
formation of products 4-7, accompanied by traces of trifluo-
romethane. Interestingly, there are two broad signals, at ca. -34
and -42 ppm, respectively, initially increasing in intensity and
then disappearing from the spectrum at later stages of the
reaction. We tentatively assign these two signals to possible
reaction intermediates. Although no structural information is
available, these two species could coincide with intermediates
of type 1A and/or 1B (Scheme 3). Since pathway B would imply
the involvement of the trifluoromethyl anion, one could imagine
this ion to be temporarily trapped by DMF as the corresponding
aminoalcoholate, which is known to be stable for hours at
temperatures below -20 °C.27 However, the corresponding
signal (-78 ppm, J ) 7.6 Hz) could not be detected.
Stavber and co-workers28 showed that the fluorination of
4-tert-butyl anisole with F-TEDA proceeds via SET, whereby
the resulting radical cation eliminates the stable tert-butyl cation
and radical recombination leads to para-fluoroanisole. A similar
mechanism is conceivable in the case of electrophilic trifluo-
romethylation, and para-trifluoromethyl anisole would be the
expected product. Surprisingly, the corresponding experiment
produced a completely different result. When reagent 2 was
exposed to either 1 equiv or a catalytic amount (10 mol %) of
4-tert-butyl anisole (14), we observed its decomposition to
2-iodobenzoic acid fluoride (15, Scheme 4) as the main isolable
product. The missing “OCF2” unit could not be identified in
form of any byproduct by 19F NMR spectroscopy.
The same reacting mixture was also examined by EPR
spectroscopy. The frozen sample was warmed to -55 °C, held
(25) Ozanne-Beaudenon, A.; Quideau, S. Angew. Chem., Int. Ed. 2005, 44,
7065–7069.
(26) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.;
Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787–
3790.
(28) Iskra, J.; Zupan, M.; Stavber, S.; Evidence for Cation-Radical Intermedi-
ates in the Electrophilic Fluorination of Aromatic Molecules with N-F Reagents
In 15th European Symposium on Fluorine Chemistry; Prague, 2007.
(27) Folle´as, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L. Tetrahedron 2000,
56, 275–283.
7682 J. Org. Chem. Vol. 73, No. 19, 2008

10-I-3 HyperValent Iodine Trifluoromethylation Reagent
SCHEME 4. Decomposition of 2 with 4-tert-Butyl Anisole
fractions: Fraction one contained the OCF3 products; a second
highly UV-active fraction contained a mixture of the oxidized
products, and a third fraction contained starting phenol. The
individual products could be further separated and purified by
additional steps as described below.
1 -(Trifluoromethoxy)- 2,4,6 -trimethylbenzene (4). This com-
pound was purified by flash column chromatography (SiO2, pentane/
Et2O ) 20/1 to 15/1) where the product and disubstituted impurities
were in the very first fractions, showing very poor UV activity and
could not be stained. A second chromatography (SiO2, pentane)
afforded reasonably clean volatile oil. It is also possible to extract
the product with pentane directly from the DMF reaction mixture,
Conclusions
Our reactivity studies of reagent 2 with phenols have shown
that it is possible to generate the corresponding trifluorometh-
ylether, however, only in the case of 2,4,6-trimethylphenol and
up to an extent of only ca. 15%. The main products observed
are generated by carbon functionalization. As noted recently
by Umemoto,14 the trifluoromethylation ability of a reagent
toward hard nucleophiles, such as the oxygen atom of a
phenolate, strongly depends on the hardness of the atom initially
bearing the CF3 unit. Reagent 2 is therefore to be described as
a soft reagent with a particular affinity for soft nucleophiles
such as, for example, thiols15b and primary or secondary
phosphines.15c From a mechanistic point of view, our observa-
tions are still inconclusive as to the exact course of the
trifluoromethyl transfer from reagent 2 to phenols. The inter-
mediate formation of phenoxy-λ3-iodane species that would
undergo nucleophilic attack by a transient trifluoromethyl anion
is probable and would reflect the general reactivity pattern of a
number of known hypervalent iodine compounds. Equally, an
SET pathway not involving free radicals cannot be excluded.
However, for both scenarios, solid experimental evidence is still
lacking.
1
although in lower yields: H NMR (CDCl3, 400.13 MHz) δ 6.87
(s, 2H), 2.27 (s, 9H); 13C NMR (CDCl3, 100.6 MHz) δ 136.8, 132.1,
130.1, 121.7 (q, J ) 256 Hz, CF3), 21.1, 17.0; 19F NMR (CDCl3,
188.3 MHz) δ -56.7; GC-MS (EI, m/z) calcd for C10H11F3O
204.08 (M+, 100%), 205.08 (11.1%), found 204.07 (100%), 205.09
(11%).
4 -(Trifluoromethyl)- 2,4,6- trimethylcyclohexa- 2,5-dienone (5).
This compound could be separated by an additional flash column
chromatography with pure toluene: Rf (toluene, KMnO4 stain) )
1
0.4; H NMR (CDCl3, 300.1 MHz) δ 6.60 (s, 2H), 1.95 (s, 6H),
1.41 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 186.1, 139.9 (q, J )
16 Hz), 138.4, 126.3 (q, J ) 283 Hz, CF3), 45.6 (q, J ) 27 Hz),
20.8 (q, J ) 2 Hz), 16.7; 19F NMR (CDCl3, 188.3 MHz) δ -74.6;
MS (HR-EI, m/z) calcd for C10H11F3O 204.0762 (M+, 100%), found
204.0746 (100%).
2,4,6 - Trimethyl- 6-(trifluoromethyl)cyclohexa -2,4-dienone (6).
This compound was part of the UV-active fraction of the first
column chromatography (SiO2, pentane/Et2O ) 20/1 to 15/1) and
could be fully characterized by 1D and 2D NMR techniques and
GC-MS: 1H NMR (CDCl3, 300.1 MHz) δ 6.70 (m, 1H), 5.85 (br
s, 1H), 1.96 (s, 6H), 1.41 (s, 3H); 13C NMR (CDCl3, 62.9 MHz) δ
196.6 (q, J ) 0.8 Hz), 141.9, 139.5, 125.0 (q, J ) 284 Hz), 52.9
(q, J ) 24.3 Hz), 21.5, 19.7 (q, J ) 2 Hz), 15.3; 19F NMR (CDCl3,
188.3 MHz) δ -72.6; GC-MS (EI, m/z) calcd for C10H11F3O
204.08 (M+, 100%), 205.08 (11.1%), found 204.05 (100%), 205.13.
2,4,6-Trimethyl-3,6-bis(trifluoromethyl)cyclohexa-2,4-dienone (7).
This compound was part of the UV-active fraction of the first
column chromatography (SiO2, pentane/Et2O ) 20/1 to 15/1) and
could be fully characterized by 1D and 2D NMR techniques and
Experimental Section
1-Trifluoromethyl-1,2-benziodoxol-3-(1H)-one (2). 1-Hydroxy-
1,2-benziodoxol-3-(1H)-one (6.00 g, 21.1 mmol) was refluxed in
Ac2O for a few minutes until a clear solution was obtained. Upon
cooling, white crystals began to separate and cooling was continued
to -20 °C for 4 h. The solution was decanted, and the crystals
were dried under vacuum for 24 h under stirring. The resulting
white powder was identified as 1-acetoxy-1,2-benziodoxol-3-(1H)-
one. This was dissolved in dry MeCN (50 mL) under Ar. TMSCF3
(4.5 mL, 30.4 mmol) followed by dry CsF (0.05 g, 0.33 mmol)
was added, and the suspension was vigorously stirred at rt for 22 h.
The solvent was evaporated under reduced pressure, and the brown
residue was purified by column chromatography (SiO2, CH2Cl2/
MeOH ) 15/1) giving the title compound in 5.65 g (79% yield
over 2 steps, 76% from 2-iodobenzoic acid). Purification is also
possible by sublimation (HV, 40 °C). NMR data are in agreement
with the reported data.15a Anal. Calcd for C8H4O2F3I: C, 30.41; H,
1.28. Found: C, 30.56; H, 1.11.
Standard Method for the Trifluoromethylation of 2,4,6-Trim-
ethylphenol. In a representative experiment, 2,4,6-trimethylphenol
(100 mg, 0.734 mmol) was dissolved in dry DMF (2 mL) and
deprotonated with NaH (18.5 mg, 0.771 mmol, previously washed
with hexane). After ca. 15 min, the reaction temperature was set
and reagent 2 (0.4-2.5 equiv) was added in one portion. The
reaction was monitored by TLC or 19F NMR. After no more reagent
2 was detectable, BTF (10 µL) as internal standard and C6D6 were
added. The yields were calculated from the 19F NMR integrals.
To isolate the products, the mixture was poured into water (ca.
10 mL) and extracted with Et2O (3 × 10 mL). The combined
organic layers were washed with brine, dried with MgSO4, and
concentrated under reduced pressure (>200 mbar due to the
volatility of some products). Purification by flash column chroma-
tography (SiO2, pentane/Et2O ) 20/1 to 15/1) gave three different
1
GC-MS: H NMR (CDCl3, 400.13 MHz) δ 6.0 (br s, 1 H), 2.16
(q, J ) 4.3 Hz, 3H), 2.12 (m, 3H), 1.49 (s, 3H); 13C NMR (CDCl3,
100.6 MHz) δ 197.4, 137.2, 135.4, 131.0, 130.0, 124.9 (q, J )
281 Hz, o-CF3), 53.1 (q, J ) 65 Hz), 21.4, 19.5, 12.6; 19F NMR
(CDCl3, 376.5 MHz) δ -57.3 (qqd, J ) 4.3, 2.9, 1.2 Hz,), -72.6;
GC-MS (EI, m/z) calcd for C11H10F6O 272.06 (M+, 100%), 273.07
(12.2%), found 272.03 (100%), 273.06 (12%).
1-(Trifluoromethoxy)-3-(trifluoromethyl)-2,4,6-trimethylbenzene.
This compound was an impurity of the first fraction of the first
column chromatography (SiO2, pentane/Et2O ) 20/1 to 15/1) and
1
could be fully characterized by 1D and 2D NMR techniques: H
NMR (CDCl3, 400.13 MHz) δ 7.01 (br s, 1H), 2.47 (q, J ) 3.7
Hz, 3H), 2.43 (m, 3H), 2.34 (s, 3H); 13C NMR (CDCl3, 100.6 MHz)
δ 145.8, 136.0, 135.7, 133.4, 132.8, 127.5, 21.8, 17.1, 14.0; 19F
NMR (CDCl3, 376.5 MHz) δ -53.9 (m, Ar-CF3), -56.4 (s, OCF3).
2-Iodobenzoic Acid 3-(Trifluoromethyl)-2,4,6-trimethylphenyl
ester (8). This compound was part of the UV-active fraction of the
first column chromatography (SiO2, pentane/Et2O ) 20/1 to 15/1)
and could be further purified by a second chromatography (SiO2,
pentane/Et2O ) 20/1 to 15/1) and a third chromatography (SiO2,
1
hexane/toluene ) 3/1 to 1/1): H NMR (CDCl3, 400.13 MHz) δ
8.16 (d, J ) 7.8 Hz, 1H), 8.12 (d, J ) 8.0 Hz, 1H), 7.52 (dd, J )
7.8, 7.4 Hz, 1H), 7.26 (dd, J ) 8.0, 7.4 Hz, 1H), 7.02 (br s, 1H),
2.47 (q, J ) 3.8 Hz, 3H), 2.33 (q, J ) 2.9 Hz, 3H), 2.24 (s, 3H);
13C NMR (CDCl3, 62.9 MHz) δ 163.8, 146.8, 142.1 135.0 (q, J )
2 Hz), 133.6, 133.2, 132.6, 131.5, 130.3 (q, J ) 2 Hz), 128.2, 125.5
(q, J ) 277 Hz, CF3), 95.1, 21.5 (q, J ) 4.5 Hz), 16.9, 13.6 (q, J
) 4.2 Hz); 19F NMR (CDCl3, 376.5 MHz) δ -53.9 (qqd, J ) 3.8,
J. Org. Chem. Vol. 73, No. 19, 2008 7683

Stanek et al.
2.9, 0.9 Hz); MS (HR-EI, m/z) calcd for C17H14F3IO2 433.9991
(M+, 100%), 435.0024 (18.9%), found 433.9987 (100%), 435.0025
(18.7%).
NMR (CDCl3, 300.1 MHz) δ 6.53 (s, 2H), 1.27 (s, 18H); 13C NMR
(CDCl3, 75.5 MHz) δ 184.1, 155.5, 124.9 (hept, J ) 1.6 Hz), 52.7
(hept, J ) 27 Hz), 35.8, 29.1; 19F NMR (CDCl3, 282.4 MHz) δ
-69.7 (s, 6F); MS (HR-EI, m/z) calcd for C16H20F6O 342.1418
(M+, 100%), found 342.1398 (100%).
2,6-Dimethyl-4-(2,2,2-trifluoroethyl)phenol (9). 2,4,6-Trimeth-
ylphenol (50 mg, 0.367 mmol) was dissolved in 1 mL of CH2Cl2
and cooled to -20 °C. Reagent 3 (145 mg, 0.441 mmol) was added
portionwise, and the mixture was slowly warmed to rt. After 4 days,
the reagent could no longer be detected in the reaction mixture by
19F NMR spectroscopy. Twenty microliters of BTF as internal
standard was added, and the yield was calculated to be 49%. The
mixture was concentrated and purified by flash column chroma-
tography (SiO2, pentane/Et2O ) 9:1 to 5:1) to give the title
compound as colorless needles in 35% yield (27 mg). Further
purification was possible by sublimation (16 mbar, 40 °C): Rf
(hexane/EtOAc ) 9/1) ) 0.27; mp ) 81-82 °C; 1H NMR (CDCl3,
300.13 MHz) δ 6.91 (s, 2H), 4.66 (s, 1H), 3.23 (q, J ) 10.8 Hz,
2H), 2.25 (s, 6H); 13C NMR (CDCl3, 100.6 MHz) δ 152.5, 130.7,
126.4 (q, J ) 276.6 Hz, CF3), 123.7, 122.0 (q, J ) 3.4 Hz), 39.8
(q, J ) 29.5 Hz), 16.2; 19F NMR (CDCl3, 376.5 MHz) δ -66.3 (t,
J ) 10.8 Hz); MS (HR-EI, m/z) calcd 204.0762 (M+, 100%),
205.0796 (11.1%), found 204.0755 (100%), 205.0789 (11.6%).
Anal. Calcd for C10H11OF3: C, 58.82; H, 5.43. Found: C, 58.86;
H, 5.61.
4-tert-Butyl-2-trifluoromethylphenol (10a). 4-tert-Butylphenol
(119 mg, 0.791 mmol) was dissolved in DMF (2 mL) and
deprotonated with NaH (19 mg, 0.791 mmol), and 18-crown-6 (209
mg, 0.791 mmol) was added. The mixture was cooled to -60 °C,
and reagent 2 (100 mg, 0.316 mmol) was added in one portion.
The reaction was heated slowly to rt overnight. DMF was
evaporated, and the residue was extracted with hexane, which gave
mainly 18-crown-6. The residue was therefore purified by flash
column chromatography (SiO2, hexane/Et2O ) 3:1) to give a
mixture of starting phenol and compound 10a. The two products
could be separated by preparative HPLC (OD-H, hexane/isopro-
panol ) 98:2): 1H NMR (CDCl3, 400.1 MHz) δ 7.48 (m, 1H), 7.44
(m, 1H), 6.89 (d, J ) 8.6 Hz, 1H), 5.28 (br s, 1H), 1.31 (s, 9H);
13C NMR (CDCl3, 100.6 MHz) δ 144.0, 131.0, 123.5, 34.5, 31.7;
19F NMR (CDCl3, 376.5 MHz) δ -60.5; MS (HR-EI, m/z) calcd
for C11H13F3O 218.0918 (M+, 100%), 219.0952 (12.2%), found
218.0915 (100%), 219.0946 (12.3%). NMR data are in agreement
with the literature.29
4-Trifluoromethylindan-5-ol (12a). Indan-5-ol (106 mg, 0.791
mmol) was deprotonated using NaH (19 mg, 0.791 mmol) in 2
mL of DMF. 18-Crown-6 (209 mg, 0.791 mmol) was added, and
the mixture was cooled to -60 °C. Reagent 2 (100 mg, 0.316 mmol)
was added in one portion, and the mixture was slowly warmed to
rt overnight. The yields were calculated from 19F NMR using 10
µL of C6H5CF3 as internal standard. The mixture was poured into
water and extracted with EtOAc, and the combined organic layers
were washed with brine, dried with MgSO4, and concentrated.
Purification by column chromatography (SiO2, hexane/EtOAc )
9:1) gave a mixture of starting phenol and the two monosubstituted
products in one fraction. The two products could be separated by
preparative HPLC (OD-H, hexane/isopropanol ) 98.5:1.5) giving
1
the title compound as colorless needles in 3.5 mg (5%) yield: H
NMR (CDCl3, 400.1 MHz) δ 7.25 (d, J ) 8.3 Hz, 1H), 6.77 (d, J
) 8.3 Hz, 1H), 5.53 (s, 1H), 3.08 (m, 2H), 2.86 (t, J ) 7.5 Hz,
2H), 2.11 (quint, J ) 7.5 Hz, 2H); 13C NMR (CDCl3, 100.6 MHz)
δ 152.8 (m), 144.0, 138.0, 129.0, 116.5, 33.3 (q, J ) 2.6 Hz), 32.0,
25.7; 19F NMR (CDCl3, 282.4 MHz) δ -55.9; MS (HR-EI, m/z)
calcd for C10H9F3O 202.0605 (M+, 100%), 203.0639 (11.1%), found
202.0596 (100%), 203.0631 (14.1%).
6-Trifluoromethylindan-5-ol (12b). This compound was obtained
in the same way as 12a in 5% yield (3 mg) as colorless needles:
1H NMR (CDCl3, 400.1 MHz) δ 7.35 (s, 1H), 6.83 (s, 1H), 5.29
(s, 1H), 2.91 (t, J ) 7.5 Hz, 2H), 2.88 (t, J ) 7.5 Hz, 2H), 2.12
(quint, J ) 7.5 Hz, 2H); 13C NMR (CDCl3, 100.6 MHz) δ 151.7
(q, J ) 165 Hz), 151.2, 136.8, 122.3 (q, J ) 5 Hz), 114.1, 33.5,
32.2, 26.0; 19F NMR (CDCl3, 282.4 MHz) δ -60.2; MS (HR-EI,
m/z) calcd for C10H9F3O 202.0605 (M+, 100%), 203.0639 (11.1%),
found 202.0599 (100%), 203.0638 (10.6%).
4,6-Bis(trifluoromethyl)indan-5-ol (12c). Indan-5-ol (76 mg,
0.566 mmol) was dissolved in DMF (1 mL); NaH (14.9 mg, 0.623
mmol) and CsCl (105 mg, 0.623 mmol) were added, and the mixture
was stirred for 15 min. Reagent 2 (215 mg, 0.68 mmol) was added
in one portion at rt, and the reaction mixture was warmed to 50 °C
and kept at this temperature for 24 h. The mixture was poured into
water and extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine, dried with MgSO4, and
concentrated under reduced pressure. Compound 12c could be
isolated by column chromatography (SiO2, pentane/Et2O ) 20:1
to 4:1), the first fraction containing pure ditrifluoromethylated
2,6-Bis(trifluoromethyl)-4-tert-butylphenol (10b). This compound
was obtained in the same reaction as 10a but could not be isolated
in pure form. It was idientified in the crude mixture by GC-MS
(EI, m/z), calcd for C12H12F6O 286.08, found 286.09. NMR data
are in agreement with the literature.29
1
2,6-Di-tert-butyl-4-trifluoromethylphenol (11a). 2,6-Di-tert-bu-
tylphenol (75 mg, 0.364 mmol) was dissolved in DMA and
deprotonated with NaH (9.6 mg, 0.40 mmol), and 18-crown-6 (106
mg, 0.40 mmol) followed by reagent 2 (138 mg, 0.436 mmol) was
added at rt. The mixture was heated to 60 °C for 24 h and then
poured into diluted brine. The aqueous layer was extracted with
Et2O (3 × 10 mL), and the combined organic layers were washed
with brine, dried with MgSO4, and concentrated under reduced
pressure. Purification by flash column chromatography (SiO2,
pentane/Et2O ) 1:0 to 10:1) gave a 1:1 mixture of mono- and
product in 5% yield (7.5 mg): H NMR (CDCl3, 400.1 MHz) δ
7.54 (s, 1H), 6.09 (q, J ) 4 Hz, 1H), 3.11 (t, J ) 7.5 Hz, 2H), 2.89
(t, J ) 7.5 Hz, 2H), 2.13 (quint, J ) 7.5 Hz, 2H); 13C NMR (CDCl3,
100.6 MHz) δ 151.3 (m), 148.8, 138.0, 126.2 (m), 125.1 (q, J )
275 Hz), 124.0 (q, J ) 273 Hz), 117.4, 114.7, 33.7 (q, J ) 3 Hz),
31.1, 25.5; 19F NMR (CDCl3, 282.4 MHz) δ -56.1 (m), -61.4
(s); MS (HR-EI, m/z) calcd for C11H8F6O 270.0479 (M+, 100%),
found 270.0474.
4-Trifluoromethyl-estra-1,3,5(10)-triene-3,17ꢀ-diol (13a). ꢀ-Es-
tradiol (70 mg, 0.257 mmol) was suspended in DMF (1 mL) and
deprotonated with NaH (6.8 mg, 0.283 mmol) giving a yellowish
solution. 18-Crown-6 (75 mg, 0.283 mmol) followed by reagent 2
(98 mg, 0.308 mmol) was added at rt. The mixture was kept at rt
for 4 h, then heated to 50 °C for 1 day and kept for additional 3
days at 60 °C, after which it was poured into water and extracted
with EtOAc (3 × 10 mL). The combined organic layers were
washed with brine, dried with MgSO4, and concentrated under
reduced pressure. Purification by column chromatography (SiO2,
hexane/EtOAc ) 4/1 to 1/1 and a second hexane/Et2O ) 1/2) gave
pure product in 13% yield (11 mg): 1H NMR (CDCl3, 300.1 MHz)
δ 7.36 (d, J ) 8.8 Hz, 1H), 6.79 (d, J ) 8.8 Hz, 1H), 6.06 (q, J )
7.4 Hz, 1H), 3.74 (t, J ) 8.4 Hz, 1H), 2.96 (m, 2H), 2.32-1.13
(m, 20H), 0.79 (s, 3H); 13C NMR (CDCl3, 62.9 MHz) δ 152.5 (q,
1
ditrifluoromethylated products in 15% yield (17 mg): H NMR
(CDCl3, 300.1 MHz) δ 7.41 (s, 2H), 5.55 (s, 1H), 1.46 (s, 9H); 13
C
NMR (CDCl3, 75.5 MHz) δ 156.5 (q, J ) 1.4 Hz, C-OH), 136.2,
125.0 (q, J ) 271 Hz, CF3), 122.2 (q, J ) 3.8 Hz), 121.5 (q, J )
32 Hz), 34.4, 30.1; 19F NMR (CDCl3, 282.4 MHz) δ -61.1; MS
(HR-EI, m/z) calcd for C15H21F3O 274.1544 (M+, 100%), 275.1578
(16.7%), found 274.1539 (100%), 275.1585 (18.8%).
4,4-Bis(trifluoromethyl)-2,6-di-tert-butylcyclohexa-2,5-dienone
(11b). This compound was obtained in the same way as the
monotrifluoromethylated di-tert-butylphenol, but the two products
could not be separated by standard chromatography techniques: 1H
(29) Umemoto, T.; Ando, A. Bull. Chem. Soc. Jpn. 1986, 59, 447–452.
7684 J. Org. Chem. Vol. 73, No. 19, 2008

10-I-3 HyperValent Iodine Trifluoromethylation Reagent
J ) 2.2 Hz), 137.3 (q, J ) 1.4 Hz), 134.0, 130.5, 126.3 (q, J )
275.6 Hz, CF3), 116.1, 113.1 (q, J ) 26.4 Hz), 81.8, 50.0, 44.3,
43.2, 37.7, 36.7, 30.7, 26.8, 26.7, 23.0, 11.1; 19F NMR (CDCl3,
188.3 MHz) δ -52.6 (br s); MS (HR-EI, m/z) calcd 340.1650 (M+,
100%), 341.1684 (21.1%), found 340.1645 (100%), 341.1688
(20.6%). Anal. Calcd for C19H23O2F3: C, 67.04; H, 6.81. Found:
C, 66.77; H, 6.97.
COF), 142.9 (d, J ) 3.8 Hz), 136.0, 133.7 (d, J ) 1.9 Hz), 129.1,
128.6 (d, J ) 60.9 Hz), 97.3 (d, J ) 5.7 Hz); 19F NMR (DMF-d7,
282.4 MHz) δ 29.0; MS (HR-EI, m/z) calcd for C7H4FOI 249.9291
(M+, 100%), 250.9324 (7.8%), found 249.9291 (100%), 250.9316
(7.4%).
Acknowledgment. We thank Dr. Heinz Ru¨egger for NMR
support, Dr. Reinhard Kissner for the ESR studies, and Dr.
Daniel Stolz and Dr. Mihai Viciu for fruitful discussions.
Financial support from ETH Zurich (Ph.D. grants to K.S. and
R.K.) is gratefully acknowledged.
2-Iodobenzoyl Fluoride (15). Reagent 2 (67 mg, 0.212 mmol)
was dissolved in DMF-d7, and 4-tert-butyl anisole (31.6 mg, 0.192
mmol) was added in one portion. After 1 h at rt, the mixture was
heated to 60 °C for 1.5 h. The 19F NMR spectrum of the crude
reaction mixture showed quantitative decomposition of reagent 2
to 2-iodobenzoyl fluoride. This decomposition takes place also with
catalytic (0.1 equiv) amounts of anisole. After aqueous workup and
column chromatography (SiO2, pentane/Et2O ) 1/0 to 20/1),
Supporting Information Available: 1H and 13C NMR
spectra of compounds described in the Experimental Section.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
compound 15 could be isolated in 13% yield: H NMR (DMF-d7,
300.1 MHz) δ 8.44 (td, J ) 7.9, 1.3 Hz, 1H), 8.30 (dd, J ) 7.9,
1.7 Hz, 1H), 7.87 (dt, J ) 7.9, 1.2 Hz, 1H), 7.69 (dt, J ) 7.9, 1.7
Hz, 1H); 13C NMR (DMF-d7, 75 MHz) δ 155.7 (d, J ) 345 Hz,
JO8014825
J. Org. Chem. Vol. 73, No. 19, 2008 7685