Electrophilic trifluoromethylation of arenes and N-heteroarenes using hypervalent iodine reagents

Article abstract of DOI:10.1016/j.jfluchem.2010.06.020

The reaction of hypervalent iodine trifluoromethylating reagents with a variety of arenes and N-heteroarenes gives access to the corresponding trifluoromethylated compounds. In comparative studies, 1-trifluoromethyl-1,3- dihydro-3,3-dimethyl-1,2-benziodoxole (2) proved to be the superior to 1-trifluoromethyl-1,2-benziodoxol-3-(¹H)-one (1) for the direct aromatic trifluoromethylation. Depending on the individual substrates, additives such as zinc bis(trifluoromethylsulfonyl)imide or tris(trimethylsilyl)silyl chloride proved helpful in promoting the reactions. In the case of nitrogen heterocycles a pronounced tendency for the incorporation of the trifluoromethyl group at the position adjacent to nitrogen was observed.

Full text of DOI:10.1016/j.jfluchem.2010.06.020

Journal of Fluorine Chemistry 131 (2010) 951–957
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Electrophilic trifluoromethylation of arenes and N-heteroarenes using
hypervalent iodine reagents
*
Matthias S. Wiehn, Ekaterina V. Vinogradova, Antonio Togni
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Wolfgang-Pauli-Strasse 10, ETH Zurich, 8093 Zurich, Switzerland
A R T I C L E I N F O
A B S T R A C T
Article history:
The reaction of hypervalent iodine trifluoromethylating reagents with a variety of arenes and N-
heteroarenes gives access to the corresponding trifluoromethylated compounds. In comparative studies,
1-trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (2) proved to be the superior to 1-
trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1) for the direct aromatic trifluoromethylation. Depending
on the individual substrates, additives such as zinc bis(trifluoromethylsulfonyl)imide or tris(trimethyl-
silyl)silyl chloride proved helpful in promoting the reactions. In the case of nitrogen heterocycles a
pronounced tendency for the incorporation of the trifluoromethyl group at the position adjacent to
nitrogen was observed.
Received 18 May 2010
Received in revised form 25 June 2010
Accepted 29 June 2010
Available online 6 July 2010
Keywords:
Electrophilic trifluoromethylation
Hypervalent iodine
ß 2010 Elsevier B.V. All rights reserved.
Aromatic trifluoromethylation
Hypersilyl chloride
1. Introduction
reagents can be easily prepared from 2-iodobenzoic acid and can
be used for the trifluoromethylation of a variety of nucleophiles
Organofluorine compounds are of great interest in material
sciences and play an important role as active pharmaceutical
ingredients and crop protecting agents. Fluorinated drugs nowa-
days make up ca. 20% of all newly marketed pharmaceuticals and
at least 30% of all agrochemicals [1]. Apart from single fluorine
atoms, trifluoromethyl groups especially at aromatic positions are
the most important fluorine-containing units used in the design of
new potential drugs and crop protection agents. Popular examples
of bioactive aromatics and heteroaromatics bearing CF3 substi-
tuents are the antidepressant Fluoxetine (Prozac1), the malaria
agent Mefloquine (Lariam1) and the insecticide Chlorfenapyr
(Fig. 1). Therefore, development of new methods for trifluoro-
methylation of aromatic and heteroaromatic compounds is an
important task.
Main strategies for the direct introduction of CF3 groups are
based on the use of nucleophilic transfer reagents such as
(trifluoromethyl)trimethylsilane (TMSCF3, Ruppert-Prakash re-
agent) [2]. In contrast, trifluoromethylation requiring an electro-
philic approach [3] has proven to be very challenging, though
advances have been achieved recently. So far two principal classes
of reagents showed their potential for electrophilic CF3 transfer:
trifluoromethyl chalcogenium salts [4] initially introduced by
Yagupolskii and extensively explored by Umemoto and hyperva-
lent iodine derivatives developed by our group [5]. The latter
(Scheme 1). The results of our previous studies on the trifluor-
omethylation of various substrates reveal a general trend in the
activity of both reagents suggesting that benziodoxolone 1 is
usually more suitable in reactions with harder reactants such as
alcohols and sulfonic acids, while dimethyl benziodoxole 2 shows
higher activitity with softer sulfur, phosphorous and carbon
nucleophiles [6].
In general, the introduction of CF3 units into aromatic systems is
not trivial. The trifluoromethylation of electron-rich aromatic
compounds such as phenol or aniline has been achieved upon
reaction with trifluoromethanesulfinate salts [7], or under radical
reaction conditions using CF3Br [8]. Most aromatic CF3 building
blocks are synthesized by treatment of corresponding benzoic acid
derivatives with sulfur tetrafluoride [9], or with the newly
developed phenylsulfur trifluoride [10] or by halogen exchange
reactions of trichloromethyl arenes using Lewis acids and HF as
fluoride source [11]. However, such reaction conditions are not
compatible with a large number of functional groups, thus amply
justifying the search for mild and reliable methods for a direct
trifluoromethylation, i.e. involving the transfer of an intact CF3
group from a suited source. Benziodoxole 2 has been used very
recently by MacMillan and co-worker in the organocatalytic
trifluoromethylation of aldehydes [12] and by Yu and co-workers
in the Pd-catalyzed ortho-trifluoromethylation of arenes [13].
In the course of a systematic study of the reactivity of our new
reagents 1 and 2 toward a variety of potential nucleophilic CF3
acceptors we investigated a series of representative arenes and
heterocyclic compounds as substrates. While we have found that
* Corresponding author. Tel.: +41 44 632 2236; fax: +41 44 632 1310.
E-mail address: togni@inorg.chem.ethz.ch (A. Togni).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.06.020

[
M.S. Wiehn et al. / Journal of Fluorine Chemistry 131 (2010) 951–957
Scheme 1. Application of hypervalent iodine trifluoromethylation reagents 1 and 2.
[(ig._1)TD$FIG]
out an additional screening involving selected zinc Lewis acids as
additives promoting the reaction of N-phenylpyrrole (4) as the
model substrate (Table 2).
In line with the results obtained for the trifluoromethylation of
alcohols, good to excellent yields were achieved when excess of the
pyrrole derivative was used with either one of the zinc additives
(entries 1–3). However, in terms of adjusting the procedure for
potential applications it is preferable to avoid using excess of the
starting material. Thus, when the substrate was used in equimolar
or substoichiomeric amounts, the yields dropped significantly in
the case of the additive Zn(NTf2)2. At the same time, formation of a
stable intermediate was observed by 19F NMR spectroscopy in
form of a broad signal, probably originating from a complex formed
by Zn(NTf2)2 and the reagent [6d]. The intermediate slowly
decomposed to give mainly volatile HCF3, which was detected by
19F NMR spectroscopy, and the fluorinated target compound in
moderate yields (entries 4 + 5). A similar intermediate complex
was observed with ZnBr2 after 24 h, however, this complex further
reacted to give 1-phenyl-2-(trifluoromethyl)pyrrole (6) in almost
quantitative yield after 48 h.
Fig. 1. Examples of aromatic and heteroaromatic trifluoromethylated drugs.
the reactivity is quite broad and trifluoromethylation indeed
occurs, the use of this reaction as a method for the efficient and
high-yield synthesis of specific target compounds is less general.
2. Results and discussion
In a first screening, we compared the reactivity of both reagents
in the reaction with the electron-rich substrates pyrrole and N-
phenylpyrrole [14] (Table 1). Chloroform was chosen as the solvent
ensuring good solubility of both reagent and substrates. While the
transformation of pyrrole (3) gave trifluoromethylated compound
5 in very good yield within 5 h in both cases (with a slightly better
result using 2, entries 1, 2), the reaction with N-phenyl pyrrole (4)
revealed a clear difference between the reactivities of the two
reagents. Using benziodoxolone 1, no CF3 transfer was observed.
Longer reaction times or higher temperature led mainly to
decomposition of the reagent (entries 3–5). In contrast, trifluor-
omethylation was successful when dimethyl benziodoxole 2 was
used. The best result was achieved using a slight excess of the
reagent (1.5 equiv.) at 60 8C giving 1-phenyl-2-(trifluoromethyl)-
pyrrole (6) in 76% yield (entry 9). These results indicate that the
softer reagent 2 is more prone to react with soft nucleophiles, such
as aromatic systems, than the harder benziodoxolone 1, this going
along with our previous observations on the comparative
reactivity of both reagents. Moreover, after the initial screening
it became clear that only electron-rich aromatic compounds such
as pyrrole may be trifluoromethylated at room temperature,
whereas less reactive systems require additional activation for the
reaction to take place. Elevated temperature is a possible solution,
however, it also favors decomposition of the reagent, at least to
some extent. It has previously been shown in our group that zinc
salts can significantly improve the yields in trifluoromethylation
reactions of aliphatic alcohols [6d]. Therefore, we decided to carry
Table 1
Comparison of reagents 1 and 2 in the trifluoromethylation of pyrrole (3) and N-
phenylpyrrole (4).
[
.
Entry
Substrate
Reagent (equiv.)
T [8C]
t [h]
Yield [%]a
1
2
3
4
5
6
7
8
9
3
3
4
4
4
4
4
4
4
1 (1.0)
2 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
2 (1.0)
2 (1.0)
2 (1.0)
2 (1.5)
20
20
20
20
60
20
20
60
60
5
5
89
92 (87)
0b
24
120
24
0c
7c
24
5b
120
24
25
58
24
76 (38)
a
Yields were determined by 19F NMR using C6H5CF3 as internal standard.
Numbers in brackets are isolated yields.
b
Reaction not complete, >90% of the reagent not consumed.
c
Decomposition of the reagent.

M.S. Wiehn et al. / Journal of Fluorine Chemistry 131 (2010) 951–957
953
Table 2
Zinc-mediated trifluoromethylation of N-phenylpyrrole (4).
Entry
Ratio s/ra
Additive (equiv.)
T [8C]
t [h]
Yield [%]b
1
2
3
4
5
6
10:1
3:1
3:1
1:1
1:2
1:2
Zn(NTf2)2 (1.0)
Zn(NTf2)2 (1.0)
ZnBr2 (1.0)
20
20
20
20
20
20
24
24
24
24
48
48
>99
>99
79
Zn(NTf2)2 (1.0)
Zn(NTf2)2 (0.5)
ZnBr2 (0.5)
23c
25c
96 (89)
a
Molar ratio substrate 4/reagent 2.
b
c
Yields – based on the limiting component – were determined by 19F NMR using C6H5CF3 as internal standard. Numbers in brackets are isolated yields.
Formation of a stable intermediate, see text.
Table 3
Trifluoromethylation of different indoles 7–9.
Entry
Substrate
Reagent [equiv.]
Additive [equiv.]
T [8C]
t [h]
Product
Yield [%]a
1
2
3
4
1.5
2.0
2.0
2.0
–
80
20
60
60
24
48
24
24
30 (30)
25
Zn(NTf2)2 (0.5)
Zn(NTf2)2 (0.5)
ZnBr2 (0.5)
]
7
8
]
10
11
12
27
22
5
6
7
8
9
1.5
2.0
2.0
2.0
2.0
–
80
20
80
20
80
48
24
24
48
24
71 (53)
64
ZnBr2 (0.5)
ZnBr2 (0.5)
Zn(NTf2)2 (0.5)
Zn(NTf2)2 (0.5)
94
]
92
98
10
11
12
1.5
2.0
2.0
–
80
60
80
24
48
24
17
–
65 (52)
27
Zn(NTf2)2 (0.5)
N
9
a
Yields – based on substrate – were determined by 19F NMR using C6H5CF3 as internal standard. Numbers in brackets are isolated yields.
Having demonstrated that zinc salts successfully promote
aromatic trifluoromethylation of N-phenylpyrrole, we subse-
quently applied these additives for the corresponding transforma-
tion of different indole derivatives (Table 3). However, the results
of our extensive studies led us to the conclusion that the use of zinc
additives is not the universal solution for trifluoromethylation of
heteroaromatic compounds. Thus, while both zinc salts promoted
the reaction with 3-methylindole (8) to give the corresponding
trifluoromethylated derivative 11 in excellent yields (entries 5–9),
they did not significantly affect the CF3 transfer to 1-H-indole (7)
(entries 2–4). In the contrary, the use of Zn(NTf2)2 led to a
decreased yield of the trifluoromethylation of N-methylindole (9)
(entry 12). The reactions were complete after 24 h at 80 8C, lower
temperatures required longer reaction times of 48 h in order to
obtain almost quantitative transformations.
These results point out the delicate balance between necessary
activation and facilitated decomposition of the reagent. The
outcome of the reaction seems to be strongly dependent on the
electronic structure of the respective substrates. Nevertheless,
compared to the only two radical processes reported in the
literature [15] our yields represent the best results in terms of
direct trifluoromethylation of indoles. Interestingly, and in
Table 4
Trifluoromethylation of various N-heteroarenesa.
Entry
Substrate
Additive [equiv.]
t [h]
Product(s)
Yield [%]b
1
2
–
96
24
5-CF3: 37c 2-CF3: 25
5-CF3: 29 2-CF3: 20
TTMSSCl (0.3)
]
20
]
13
3
4
–
48
48
18d
42
TTMSSCl (0.3)
]
14
]
21
5
–
96
2-CF3: 17e 3-CF3: 16 4-CF3: 3
[
15
16
[
22
6
7
–
96
24
32f
16
TTMSSCl (0.3)
N
N
23

954
M.S. Wiehn et al. / Journal of Fluorine Chemistry 131 (2010) 951–957
Table 4 (Continued )
Entry
8
Substrate
Additive [equiv.]
–
t [h]
Product(s)
Yield [%]b
48
2-CF3: 20f 3-CF3: 9
[
24
[
17
9
10
11
–
24
24
24
10
TTMSSCl (0.3)
TTMSSCl (1.0)
49
]
18
[
25
52 (47)
12
13
14
–
48
24
24
5
TTMSSCl (0.3)
TTMSSCl (1.0)
41
]
19
[
26
58 (6)
a
2.0 equiv. of 2, 80 8C, CH3CN as solvent.
b
Yields – based on substrate – were determined by 19F NMR using C6H5CF3 as internal standard. Numbers in brackets are isolated yields. Not isolated compounds were
identified by comparing the characteristic shifts of the respective 19F NMR signal with the literature data.
c
d 19F = 59.7 ppm (5-CF3) and 62.0 ppm (2-CF3) [18].
d
d 19F = 61.2 ppm [19].
e
d 19F =68.0 ppm (2-CF3), -62.5 ppm (3-CF3) and -64.9 ppm (4-CF3) [20].
f
Chemical shift compared to that of trifluoromethylated pyridine 22.
contrast to usual electrophilic substitutions on indoles, the transfer
of the CF3 unit occurs exclusively to the 2-position for all substrates
7–9, likely indicating a directing effect by the N-atom of the indole
ring.
In general, trifluoromethylation of more electron deficient N-
heteroarenes required higher reaction temperatures of 80 8C, while
longer reaction times at lower temperatures mainly resulted in
slow decomposition of the reagent (Table 4). Surprisingly, the use
of zinc additives led exclusively to decomposition of the reagent.
Thermal activation gave corresponding trifluoromethylated N-
heteroarenes in moderate yields. In the case of N-methylimidazole
(13), pyridine (15) and 4-methoxypyridine (17) (entries 1 + 2,
5 + 8) the reaction afforded regioisomeric mixtures that could not
be isolated. However, they were identified by comparing the
Table 5
Trifluoromethylation of activated arenes.
Entry
Substrate
Reagent [equiv.]
Additive [equiv.]
t [h]
Product
Yield [%]a
1
2
2.0
2.0
–
24
24
22b
43
TTMSSCl (1.0)
[
27
[
32
3
4
2.0
2.0
–
72
24
0
TTMSSCl (1.5)
58 (58)
[
28
[
33
5
2.0
TTMSSCl (1.0)
24
27
[
29
[
34
6
7
8
2.0
2.0
2.0
–
24
24
24
29
TTMSSCl (0.3)
TTMSSCl (1.0)
57c
]
30
66 (61)
]
35
9
1.5
1.5
–
24
24
85
10
TTMSSCl (0.3)
94 (87)
]
31
]
36
a
Yields – based on substrate – were determined by 19F NMR using C6H5CF3 as internal standard. Numbers in brackets are isolated yields. Not isolated compounds were
identified by comparing the characteristic shifts of the respective 19F NMR signal with the literature data.
b
d
= 62.0 ppm [21].
c
The use of 4 equiv. of CF3 reagent 2 under the same conditions gave 43% of 2,6-CF3-4-tBu-aniline.

M.S. Wiehn et al. / Journal of Fluorine Chemistry 131 (2010) 951–957
955
characteristic shifts of the respective 19F NMR signals with the
literature data. In the case of pyridines, electrophilic substitution
also occurred mainly at the 2-position indicating again the
directing effect of the heteroatom via a possible interaction with
the iodine atom of the reagent.
(3, 34.0 mg, 0.500 mmol) was added and the mixture was stirred in
the dark for 5 h at room temperature. After removal of the solvent
under reduced pressure, the brownish crude product was purified
by bulb to bulb destillation (60 mbar, 60 8C) to give 59.0 mg
(0.437 mmol, 87%) of a colorless oil. 1H NMR (250 MHz, acetone-
4
During previous attempts to investigate the mechanism of
aromatic trifluoromethylations, we had successfully used tris(tri-
methylsilyl)silane (TTMSS) as an additive, often otherwise used in
radical transformations as substitute fortoxic tinreagents due to the
similar Si–H and Sn–H bond dissociation energies [16,17]. However,
tris(trimethylsilyl)silyl chloride (TMSSCl) showed exactly the same
positive effect as the silane in a comparative study in promoting the
reaction. Thus, we clearly established the obvious potential of these
hypersilyl additives in supporting the trifluoromethylation reaction.
While TTMSSCl did not improve the transformations of N-
methylimidazole (13) and tert-butylpyridine (16) (entries 1 + 2,
6 + 7), it had a remarkable effect in the trifluoromethylations of
benzimidazole (14), 3-amino-6-chloropyridine (18) and 3-amino-
pyrazine (19) leading to moderate yields of 42–58% (entries 3 + 4, 9–
14). Notably, only the hypersilyl derivative was a suitable promotor
of the reaction. Other silyl additives such as trimethylsilyl triflate or
the corresponding chloride exclusively led to a rapid decomposition
of the reagent. The exact role of this additive remains obscure. An
activation through coordination by the oxygen atom of the reagent
similar to the activation by zinc additives can be postulated. The fact
that especially the yields of the substrates bearing free amino
functionalitiesissignificantlyincreased usingTTMSSCl may indicate
a template effect of the additive in combination with these
substituents.
D6):
d
= 6.29 (m, 1H, HAr), 6.64 (m, 1H, HAr), 6.92 (q, JHF = 1.8 Hz,
1H, HAr), 8.72 (br s, 1H, NH) ppm. 13C NMR (125 MHz, CDCl3):
d
= 109.7 (CAr), 110.4 (q, 3JCF = 2.9 Hz, CArCArCF3), 120.9 (CAr), 121.7
(q, JCF = 265.8 Hz, CF3), 128.6 (CArCF3) ppm. 19F NMR (188 MHz,
1
acetone-D6)
d
= ꢀ59.2 ppm.
4.3. 1-Phenyl-2-(trifluoromethyl)pyrrole (6)
Reagent 2 (200 mg, 0.600 mmol) and zinc dibromide (34.0 mg,
0.150 mmol) were suspended in dry CHCl3 (2 mL). N-phenylpyr-
role (4, 42.0 mg, 0.300 mmol) was added and the mixture was
stirred for 2 d at room temperature. The solvent was removed
under reduced pressure. Purification by column chromatography
(hexane/dichloromethane
(0.265 mmol, 89%) of a colorless oil. 1H NMR (500 MHz, CDCl3):
= 6.30 (m, 1H, HAr), 6.76 (m, 1H, HAr), 6.91 (m, 1H, HAr), 7.40–7.43
30:1,
Rf = 0.60)
gave
56.0 mg
d
(m, 2 H, HAr), 7.46–7.49 (m, 3 H, HAr) ppm. 13C NMR (125 MHz,
CDCl3):
d
= 108.6 (CAr), 113.1 (q, 3JCF = 3.4 Hz, CArCArCF3), 121.6 (q,
2
1JCF = 268.7 Hz, CF3), 122.7 (q, JCF = 38.6 Hz, CArCF3), 126.9 (q,
4JCF = 1.0 Hz, CArNCArCF3), 127.6 (q, JCF = 1.9 Hz, CArCArCArCF3),
128.9 (CAr), 129.4 (CAr), 139.6 (CAr) ppm. 19F NMR (188 MHz, CDCl3)
4
˜
d
= ꢀ55.9 ppm. IR (KBr): V ¼ 2922 (w), 2852 (vw), 1463 (w), 1259
(w, n
(CF)), 1120 (w) cmꢀ1. MS (EI): m/z (%): 211 (25) [M+], 191 (28)
[M+–HF], 164 (29), 77 (82) [C6H5+]. HRMS (C11H8F3N): calcd.
211.0604; found 211.0604.
The successful conditions using hypersilyl chloride as the
additive were also applied to the trifluoromethylation of different
homoaromatic compounds (27–31) bearing activating substitu-
ents such as hydroxy, methoxy or amino groups (Table 5).
Compared to the reactions carried out using only thermal
activation, the transformations using hypersilyl agent TMSSCl
gave significantly higher yields with all substrates.
4.4. 2-(Trifluoromethyl)indole (10)
Reagent 2 (247 mg, 0.750 mmol) was dissolved in dry CH3CN
(2 mL). Indole (7, 59.0 mg, 0.500 mmol) was added and the
mixture was stirred for 24 h at 80 8C. The solvent was removed
under reduced pressure. Purification by column chromatography
3. Conclusion
(hexane/dichloromethane
(0.151 mmol, 30%) of a colorless solid. 1H NMR (500 MHz, CDCl3):
= 6.97 (s, 1H, HAr), 7.24 (t, 3J = 7.4 Hz, 1H, HAr), 7.37 (t, 3J = 7.5 Hz,
1H, HAr), 7.46 (d, 3J = 8.1 Hz, 1H, HAr), 7.73 (d, 3J = 8.2 Hz, 1H, HAr),
3:2,
Rf = 0.40)
gave
28.0 mg
In summary, we have shown the high potential of benziodoxole
2 as a reagent for the direct trifluoromethylation of aromatic
systems. To our knowledge, this is the most detailed study in direct
electrophilic aromatic trifluoromethylation with the broadest
substrate scope so far. Due to the straightforward synthesis of
the reagent and the simple reaction procedures, this method
represents a viable access to various trifluoromethylated arenes
and N-heteroarenes of otherwise difficult synthesis.
d
8.40 (br s, 1H, NH) ppm. 13C NMR (125 MHz, CDCl3):
d = 104.7 (q,
3JCF = 3.5 Hz, CArCArCF3), 112.1 (CAr), 121.6 (CAr), 121.7 (q,
1JCF = 268.4 Hz, CF3), 122.5 (CAr), 125.2 (CAr), 126.2 (q,
2JCF = 38.0 Hz, CArCF3), 127.0 (CAr), 136.6 (CAr) ppm. 19F NMR
˜
(188 MHz, CDCl3)
d
= ꢀ60.5 ppm. IR (KBr): V ¼ 3384 (w), 2924
(w), 2359 (w), 1705 (w), 1590 (w), 1557 (vw), 1455 (w), 1371 (w),
1305 (w), 1250 (w, (CF)), 1231 (w), 1162 (m), 1113 (s), 1083 (m),
n
4. Experimental
1031 (w), 1006 (w), 942 (w), 808 (w), 741 (m), 725 (w), 641 (vw)
cmꢀ1. MS (EI): m/z (%): 185 (100) [M+], 165 (72) [M+–HF]. HRMS
(C9H6F3N): calcd. 185.0447; found 185.0447.
4.1. General considerations
All reactions were carried out in Schlenk flasks under an Ar
atmosphere. The reactions were monitored by TLC or 19F NMR
spectroscopy. After no more reagent 2 was detectable, a defined
amount of benzotrifluoride (BTF) as internal standard and C6D6 or
CD3CN, respectively, were added. The yields were calculated from
the 19F NMR integrals.
4.5. 1-Methyl-2-(trifluoromethyl)indole (11)
Reagent 2 (330 mg (1.00 mmol) was dissolved in dry CH3CN
(2 mL). N-methylindole (8, 65.0 mg, 0.500 mmol) was added and
the mixture was stirred for 24 h at 80 8C. The solvent was removed
under reduced pressure. Purification by column chromatography
The products were isolated after removal of the solvent under
reduced pressure and purification by distillation, flash column
chromatography or preparative HPLC.
(hexane/dichloromethane
10:1,
Rf = 0.70)
gave
52.0 mg
(0.261 mmol, 52%) of a colorless oil. 1H NMR (200 MHz, CDCl3):
d
= 3.89 (s, 3 H, NCH3), 6.98 (m, 1H, HAr), 7.22–7.26 (m, 1H, HAr),
7.40–7.42 (m, 2 H, HAr), 7.72 (d, 3J = 8.2 Hz, 1H, HAr) ppm. 13C NMR
3
4.2. 2-(Trifluoromethyl)pyrrole (5)
(125 MHz, CDCl3):
d
= 31.1 (NCH3), 104.7 (q, JCF = 3.9 Hz, CAr-
CArCF3), 110.2 (CAr), 121.1 (CAr), 121.9 (q, 1JCF = 269.0 Hz, CF3), 122.6
(CAr), 124.8 (CAr), 126.1 (CAr), 127.6 (q, 2JCF = 36.8 Hz, CArCF3), 138.9
1-Trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole
(2, 165 mg, 0.500 mmol) was dissolved in dry CHCl3 (2 mL). Pyrrole
(CAr) ppm. 19F NMR (188 MHz, CDCl3)
d
= ꢀ59.5 ppm. IR (KBr):

956
M.S. Wiehn et al. / Journal of Fluorine Chemistry 131 (2010) 951–957
˜
V ¼ 2918 (m), 2641 (m), 1669 (s), 1579 (m), 1560 (m), 1464 (m),
CH3CN (2 mL). After addition of 4-tert-butylanisole (28, 49.0 mg,
0.300 mmol,), the mixture was stirred for 24 h at 80 8C. The solvent
was removed under reduced pressure. Purification by column
chromatography (hexane/dichloromethane 4:1, Rf = 0.40) gave
40.0 mg (0.173 mmol, 58%) of a colorless oil. 1H NMR (500 MHz,
1428 (m), 1402 (m), 1293 (m), 1264 (m, n(CF)), 1164 (m), 1147 (m),
1109 (m), 1044 (w), 1013 (m), 989 (m), 955 (w), 890 (m), 806 (m),
794 (m), 733 (m), 677 (m), 633 (m) cmꢀ1. MS (EI): m/z (%): 199
(100) [M+], 130 (61) [M+–CF3]. HRMS (C10H8F3N): calcd. 199.0604;
found 199.0605.
CDCl3):
3J = 8.4 Hz, 1H, HAr), 7.54 (dd, 3J = 8.4 Hz, 4J = 2.0 Hz, 1H, HAr), 7.61
(d, 4J = 2.0 Hz, 1H, HAr) ppm. 13C NMR (500 MHz, CDCl3):
= 31.7
d = 1.35 (s, 9 H, C(CH3)3), 3.92 (s, 3 H, OCH3), 6.98 (d,
4.6. 3-Methyl-2-(trifluoromethyl)indole (12)
d
(C(CH3)3), 34.6 (C(CH3)3), 56.4 (OCH3), 112.1 (CAr), 118.4 (q,
3
Reagent 2 (247 mg, 0.750 mmol) was dissolved in dry CH3CN
(2 mL). 3-Methylindole (9, 65.0 mg, 0.500 mmol) was added and
the mixture was stirred for 48 h at 80 8C. The solvent was removed
under reduced pressure. Purification by column chromatography
2JCF = 30.7 Hz, CArCF3), 124.3 (q, JCF = 5.3 Hz, CArCArCF3), 124.4 (q,
1JCF = 272.5 Hz, CF3), 130.3 (CAr), 143.4 (CArC(CH3)3), 155.7 (q,
3JCF = 5.3 Hz, CArO) ppm. 19F NMR (188 MHz, CDCl3)
d = –62.1 ppm.
˜
IR (KBr): V ¼ 2962 (w), 1619 (w), 1587 (vw), 1508 (m), 1463 (w),
(hexane/dichloromethane
(0.266 mmol, 53%) of a colorless solid. 1H NMR (500 MHz, CDCl3):
= 2.49 (q, 5JHF = 1.8 Hz, 3 H, CH3), 7.23 (m, 1H, HAr), 7.34–7.37 (m,
2 H, HAr), 7.69 (d, 3J = 8.2 Hz, 1H, HAr), 8.17 (br s, 1H, NH) ppm. 13
3:1,
Rf = 0.35)
gave
53.0 mg
1419 (vw), 1365 (w), 1324 (m), 1279 (m), 1252 (s, n(CF)), 1182 (w),
1118 (s), 1056 (s), 1026 (m), 901 (w), 879 (w), 819 (m), 760 (w),
685 (m), 651 (w), 612 (w) cmꢀ1. MS (EI): m/z (%): 232 (13) [M+], 217
(100) [M+–CH3], 189 (17). HRMS (C12H15F3O): calcd. 232.1070;
found 232.1069.
d
C
NMR (125 MHz, CDCl3):
d = 8.7 (CH3), 112.0 (CAr), 114.5 (q,
3JCF = 3.1 Hz, CArCArCF3), 120.5 (CAr), 120.8 (CAr), 121.8 (q,
2JCF = 36.4 Hz, CArCF3), 122.6 (q, JCF = 268.3 Hz, CF3), 125.2 (CAr),
4.10. 4-tert-Butyl-2-(trifluoromethyl)aniline (35)
1
128.5 (CAr), 135.6 (CAr
)
ppm. 19F NMR (188 MHz, CDCl3)
˜
d
= ꢀ58.6 ppm. IR (KBr): V ¼ 3383 (m), 2927 (w), 1693 (vw),
Reagent 2 (200 mg, 0.600 mmol) and tris(trimethylsilyl)silyl
chloride (24.0 mg, 90.0 mmol) were dissolved in dry CH3CN (2 mL).
1592 (w), 1569 (w), 1452 (m), 1373 (m), 1316 (m), 1256 (m, (CF)),
n
1196 (m), 1150 (s), 1106 (s), 1077 (m), 1030 (m), 1002 (m), 888 (w),
798 (w), 755 (m), 734 (w), 716 (w), 692 (w) cmꢀ1. MS (EI): m/z (%):
199 (100) [M+], 130 (61) [M+–CF3]. HRMS (C10H8F3N): calcd.
199.0604; found 199.0601.
After addition of 4-tert-butylaniline (30, 45.0 mg, 0.300 mmol), the
mixture was stirred for 24 h at 80 8C. The solvent was removed
under reduced pressure. Purification by column chromatography
(hexane/dichloromethane
(0.183 mmol, 61%) of a colorless oil. 1H NMR (500 MHz, CDCl3):
= 1.32 (s, 9 H, C(CH3)3), 4.08 (br s, 2 H, NH2), 6.73 (d, 3J = 8.4 Hz,
3:2,
Rf = 0.40)
gave
40.0 mg
4.7. 3-Amino-6-chloro-2-(trifluoromethyl)pyridine (25)
d
1H, HAr), 7.37 (dd, 3J = 8.4 Hz, 4J = 1.9 Hz, 1H, HAr), 7.45 (d,
Reagent 2 (200 mg, 0.600 mmol), tris(trimethylsilyl)silyl chlo-
ride (80.0 mg, 0.300 mmol) and 3-amino-6-chloropyridine (18,
39.0 mg, 0.300 mmol) were dissolved in dry CH3CN (2 mL) and the
mixture was stirred for 24 h at 80 8C. The solvent was removed
under reduced pressure. Purification by column chromatography
4J = 1.9 Hz, 1H, HAr) ppm. 13C NMR (500 MHz, CDCl3):
(C(CH3)3), 34.4 (C(CH3)3), 113.8 (q, JCF = 29.4 Hz, CArCF3), 117.6
d
= 31.7
2
3
1
(CAr), 123.3 (q, JCF = 5.3 Hz, CArCArCF3), 125.6 (q, JCF = 272.8 Hz,
4
CF3), 130.4 (q, JCF = 1.2 Hz, CAr), 141.1 (CArC(CH3)3), 142.4 (q,
3JCF = 1.7 Hz, CArN) ppm. 19F NMR (188 MHz, CDCl3)
d
= ꢀ62.3 ppm.
˜
(hexane/dichloromethane
(0.141 mmol, 47%) of a beige solid. 1H NMR (500 MHz, CDCl3):
= 4.31 (br s, 2 H, NH2), 7.12 (d, 3J = 8.6 Hz, 1H, HAr), 7.27 (d,
3:2,
Rf = 0.40)
gave
28.0 mg
IR (KBr): V ¼ 2961 (w), 1632 (m), 1582 (vw), 1508 (m), 1465 (vw),
1428 (w), 1365 (w), 1330 (w), 1314 (w), 1296 (m), 1254 (s, n(CF)),
d
1140 (m), 1100 (s), 1050 (m), 897 (w), 886 (w), 824 (m), 760 (w),
694 (w), 662 (w), 648 (w) cmꢀ1. MS (EI): m/z (%): 217 (19) [M+], 202
(100) [M+–CH3]. HRMS (C11H14F3N): calcd. 217.1073; found.
217.1073.
3J = 8.6 Hz, 1H, HAr) ppm. 13C NMR (500 MHz, CDCl3):
d = 122.5 (q,
1JCF = 274.2 Hz, CF3), 128.5 (q, 3J = 1.0 Hz, CArNH2), 128.8 (CAr),
130.1 (q, 2J = 34.4 Hz, CArCF3), 139.1 (CAr), 140.4 (CAr) ppm. 19F NMR
˜
(188 MHz, CDCl3)
d
= ꢀ66.0 ppm. IR (KBr): V ¼ 3523 (m), 3360 (m),
3252 (w), 3236 (w), 2922 (vw), 1640 (m), 1596 (m), 1462 (s), 1418
(s), 1344 (m), 1307 (m), 1252 (m, (CF)), 1174 (m), 1157 (m), 1120
4.11. 2-(Trifluoromethyl)naphthtyl-1-amine (36)
n
(s), 1090 (s), 1052 (s), 871 (s), 826 (s), 755 (m), 682 (s), 644 (s), 539
(w) cmꢀ1. MS (EI): m/z (%): 198/196 (34/100) [M+], 176 (48) [M+–
HF], 149 (48), 141 (38). HRMS (C6H4ClF3N2): calcd. 196.0010;
found 196.0009.
Reagent 2 (150 mg, 0.450 mmol) and tris(trimethylsilyl)silyl
chloride (25.0 mg, 90.0
mmol) were dissolved in dry CH3CN
(2 mL). After the addition of 2-naphthylamine (31, 43.0 mg,
0.300 mmol), the mixture was stirred for 24 h at 80 8C. The
solvent was removed under reduced pressure. Purification by
4.8. 2-Amino-3-(trifluoromethyl)pyrazine (26)
column
chromatography
(hexane/dichloromethane
3:2,
Rf = 0.35) gave 55.0 mg (0.261 mmol, 87%) of a reddish solid.
Reagent 2 (200 mg, 0.600 mmol), tris(trimethylsilyl)silyl chlo-
ride (80.0 mg, 0.300 mmol) and 2-amino-pyrazine (19, 29.0 mg,
0.300 mmol) were dissolved in dry CH3CN (2 mL) and the mixture
was stirred for 24 h at 80 8C. The solvent was removed under
reduced pressure. The crude product was purified by preparative
HPLC (hexane/isopropanol 95:5, OD-H column) to give 3.0 mg
(0.018 mmol, 6%) of a colorless solid. 1H NMR (400 MHz, CDCl3):
1H NMR (500 MHz, CDCl3):
d = 4.65 (br s, 2 H, NH), 6.82 (d,
3J = 8.8 Hz, 1H, HAr), 7.33 (t, 3J = 7.3 Hz, 1H, HAr), 7.54 (m, 1H, HAr),
7.70–7.74 (m, 2 H, HAr), 8.02–8.06 (m, 1H, HAr) ppm. 13C NMR
(125 MHz, CDCl3):
d
= 103.0 (q, 2JCF = 32.4 Hz, CArCF3), 120.3 (CAr),
3
123.4 (CAr), 123.5 (q, JCF = 4.3 Hz, CArCArCF3), 127.5 (q,
1JCF = 268.7 Hz, CF3), 128.3 (CAr), 128.4 (CAr), 128.9 (CAr), 131.9
4
3
(q, JCF = 1.9 Hz, CArCArCArCF3), 133.8 (CAr), 144.2 (q, JCF = 2.3 Hz,
d
= 5.06 (br s, 2 H, NH2), 8.01 (d, 3J = 2.4 Hz, 1H, HAr), 8.21 (d,
CArNH2) ppm. 19F NMR (188 MHz, CDCl3)
d
= ꢀ51.9 ppm. IR (KBr):
3J = 2.0 Hz, 1H, HAr
)
ppm. 19F NMR (188 MHz, CDCl3)
d
= –
V ¼ 3424 (w), 3057 (vw), 1630 (m), 1577 (w), 1512 (w), 1479 (m),
˜
67.5 ppm.
1434 (m), 1415 (w), 1378 (m), 1353 (w), 1309 (m), 1263 (m),
1243 (m, n(CF)), 1178 (w), 1142 (m), 1129 (m), 1077 (s), 986 (m),
4.9. 4-tert-Butyl-1-methoxy-2-(trifluoromethyl)benzene (33)
941 (m), 860 (vw), 834 (vw), 813 (m), 780 (vw), 745 (m), 724 (w),
696 (vw), 678 (w), 642 (w) cmꢀ1. MS (EI): m/z (%): 211 (100) [M+],
191 (52) [M+–HF], 164 (69). HRMS (C11H8F3N): calcd. 211.0604;
found 211.0605.
Reagent 2 (200 mg, 0.600 mmol) and tris(trimethylsilyl)silyl
chloride (125 mg, 0.450 mmol, 1.50 equiv.) were dissolved in dry

M.S. Wiehn et al. / Journal of Fluorine Chemistry 131 (2010) 951–957
957
(c) P. Eisenberger, I. Kieltsch, N. Armanino, A. Togni, Chem. Commun. (2008)
1575–1577;
Acknowledgements
(d) R. Koller, K. Stanek, D. Stolz, R. Aardoom, K. Niedermann, A. Togni, Angew.
Chem. Int. Ed. 48 (2009) 4332–4336;
(e) K. Stanek, R. Koller, A. Togni, J. Org. Chem. 73 (2008) 7678–7685;
(f) R. Koller, Q. Huchet, P. Battaglia, J.M. Welch, A. Togni, Chem. Commun. (2009)
5993–5995;
This work was supported by ETH Zu¨rich. We thank Aitor
Moreno for NMR support and Dr. Jan Cvengros for helpful
discussions. The Karlsruhe House of Young Scientists (KHYS) is
gratefully acknowledged for financial support (fellowship to
Matthias S. Wiehn).
(g) N. Armanino, R. Koller, A. Togni, Organometallics 29 (2010) 1771–1777.
[7] (a) B.R. Langlois, E. Laurent, N. Roidot, Tetrahedron Lett. 32 (1991) 7525–7528;
(b) For recent uses of trifluoromethanesulfinates for the preparation of trifluor-
omethylsulfonium salts as electrophilic reagents, see: Y. Mace´, B. Raymondeau, C.
Pradet, J.-C. Blazejewski, E. Magnier, Eur. J. Org. Chem. (2009) 1390–1397.
[8] C. Wakselman, M. Tordeux, J. Chem. Soc., Chem. Commun. (1987) 1701–1703.
[9] G.A. Boswell Jr., W.C. Ripka, R.M. Scribner, C.W. Tullock, Org. React. 21 (1974) 1–
124.
[10] T. Umemoto, R.P. Singh, U.S. Pat. Appl. Publ. 2008039660 (2008).
[11] H.S. Booth, H.M. Elsey, P.E. Burchfield, J. Am. Chem. Soc. 57 (1935) 2066–2069.
[12] A.E. Allen, D.W.C. MacMillan, J. Am. Chem. Soc. 132 (2010) 4986–4987.
[13] X. Wang, L. Truesdale, J.-Q. Yu, J. Am. Chem. Soc. 132 (2010) 3648–3649.
[14] For a review on trifluoromethyl pyrroles, see: V.M. Muzalevskiy, A.V. Shastin, E.S.
Balenkova, G. Haufe, V.G. Nenajdenko, Synthesis, (2009) 3905–3929.
[15] (a) Y. Girard, J.G. Atkinson, P.C. Belanger, J.J. Fuentes, J. Rokach, C.S. Rooney, D.C.
Remy, C.A. Hunt, J. Org. Chem. 48 (1983) 3220–3234;
References
[1] (a) See, e.g.: (a) K. Mu¨ ller, C. Faeh, F. Diederich, Science 317 (2007) 1881–1887.
(b) P. Kirsch, Modern Fluororganic Chemistry, Wiley VCH, Weinheim, 2004;
(c) T. Hiyama, Organofluorine Compounds: Chemistry and Applications, Spring-
er, Berlin, 2000.
[2] G.K.S. Prakash, A.K. Yudin, Chem. Rev. 97 (1997) 757–786.
[3] The existence of CF3+ cations has been reported only in the gas phase so far: P.S.
Mayer, D. Leblanc, T.H. Morton, J. Am. Chem. Soc. 124 (2002) 14185–14194.
[4] (a) For reagents based on trifluoromethylchalcogenium salts, see: L.M. Yagupols-
kii, N.V. Kondratenko, G.N. Timofeeva, Zh. Org. Khim. 20 (1984) 115–118;
(b) J.J. Yang, R.L. Kirchmeier, J.M. Shreeve, J. Org. Chem. 63 (1998) 2656–2660;
(c) L.M. Yagupolskii, A.V. Matsnev, R.K. Orlova, B.G. Deryabkin, Y.L. Yagupolskii, J.
Fluorine Chem. 129 (2008) 131–136;
(b) M. Yoshida, T. Yoshida, M. Kobayashi, N. Kamigata, J. Chem. Soc., Perkin Trans.
1 (1989) 909–914.
(d) E. Magnier, J.C. Blazejewski, M. Tordeux, C. Wakselman, Angew. Chem. Int. Ed.
45 (2006) 1279–1282;
[16] (a) For a review of the use of TTMSS see: J.-F. Brazeau, Synlett, (2007) 1972–1973;
(b) For the application of TTMSSCl see e.g.: M.B. Boxer, H. Yamamoto, J. Am.
Chem. Soc. 128 (2006) 48–49.
[17] (a) For the effects of silicon-containing groups such as the hypersilyl group
(TTMSS) see: H. Bock, Angew. Int. Ed. Engl. 28 (1989) 1627–1650;
(b) H. Bock, J. Meuret, R. Baur, K. Ruppert, J. Organomet. Chem. 446 (1993) 113–
122.
[18] D. Owen, R.G. Plevey, J.C. Tatlow, J. Fluorine Chem. 17 (1981) 179–186.
[19] L.V. Saloutina, A.Y. Zapevalov, V.I. Saloutin, M.I. Kodess, V.E. Kirichenko, M.G.
Pervova, O.N. Chupakhin, J. Fluorine Chem. 126 (2005) 976–983.
[20] D. Naumann, B. Wilkes, J. Kirschkewitz, J. Fluorine Chem. 30 (1985) 73–87.
[21] A.E. Feiring, W.A. Sheppard, J. Org. Chem. 40 (1975) 2543–2545.
(e) T. Umemoto, S. Ishihara, Tetrahedron Lett. 31 (1990) 3579–3582;
(f) T. Umemoto, S. Ishihara, J. Am. Chem. Soc. 115 (1993) 2156–2164;
(g) T. Umemoto, K. Adachi, J. Org. Chem. 59 (1994) 5692–5699;
(h) T. Umemoto, K. Adachi, S. Ishihara, J. Org. Chem. 72 (2007) 6905–6917;
(i) S. Noritake, N. Shibata, S. Nakamura, T. Toru, M. Shiro, Eur. J. Org. Chem. (2008)
3465–3468;
(j) A. Matsnev, S. Noritake, Y. Nomura, E. Tokunaga, S. Nakamura, N. Shibata,
Angew. Chem. Int. Ed. 49 (2010) 572–576.
[5] P. Eisenberger, S. Gischig, A. Togni, Chem. Eur. J. 12 (2006) 2579–2586.
[6] (a) I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. Int. Ed. 46 (2007) 754–757;
(b) I. Kieltsch, P. Eisenberger, K. Stanek, A. Togni, Chimia 62 (2008) 260–263;