Trifluoromethylation of various aromatic compounds by CF3I in the presence of Fe(II) compound, H2O2 and dimethylsulfoxide

Article abstract of DOI:10.1016/j.jfluchem.2009.09.007

Trifluoromethylation of aromatic and hetero-aromatic compounds by CF₃I in the presence of Fe(II) compound, H₂O₂ and dimethylsulfoxide was investigated. Various trifluoromethylated benzene derivatives, six-membered nitrogen-containing aromatic compounds and five-membered hetero-aromatic compounds were obtained under mild conditions. General orientation of electrophilic substitution of aromatic compounds was observed similarly as reported in other radical trifluoromethylation previously.

Full text of DOI:10.1016/j.jfluchem.2009.09.007

Journal of Fluorine Chemistry 131 (2010) 98–105
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Short communication
Trifluoromethylation of various aromatic compounds by CF3I in the presence
of Fe(II) compound, H2O2 and dimethylsulfoxide
Tatsuhito Kino a,b, Yu Nagase b, Yuhki Ohtsuka a, Kyoko Yamamoto a, Daisuke Uraguchi a,1
,
Kenji Tokuhisa c, Tetsu Yamakawa a,
*
a Sagami Chemical Research Center, Hayakawa 2743-1, Ayase, Kanagawa 252-1193, Japan
b Tokai University, Faculty of Engineering, Department of Applied Chemistry, Kitakaname 1117, Hiratsuka-shi, Kanagawa 259-1292, Japan
c Tosoh F-Tech Inc., Kaisei-cho 4988, Shunan, Yamaguchi 746-0006, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Trifluoromethylation of aromatic and hetero-aromatic compounds by CF3I in the presence of Fe(II)
compound, H2O2 and dimethylsulfoxide was investigated. Various trifluoromethylated benzene
derivatives, six-membered nitrogen-containing aromatic compounds and five-membered hetero-
aromatic compounds were obtained under mild conditions. General orientation of electrophilic
substitution of aromatic compounds was observed similarly as reported in other radical trifluor-
omethylation previously.
Received 22 July 2009
Received in revised form 8 September 2009
Accepted 14 September 2009
Available online 22 September 2009
Keywords:
ß 2009 Elsevier B.V. All rights reserved.
Trifluoromethylation
Trifluoromethyl iodide
Trifluoromethyl radical
1. Introduction
SO2 [13]; trifluoromethylation by a trifluoromethyl radical formed
from CF3I thermally is also known despite the low yield [14].
Trifluoromethylated aromatic, hetero-aromatic and pseudo-
aromatic compounds are important intermediates for synthesis of
pharmaceuticals and agricultural chemicals, and many synthetic
methods have been explored thus far [1]. Among them, direct
trifluoromethylation is simple and therefore promising as an
industrial process. A trifluoromethyl radical is widely used in direct
trifluoromethylation. It has electrophilic nature and can be readily
generated from various radical sources [1,2]. In the previous
methods of radical trifluoromethylation of aromatic, hetero-
Recently, we found that trifluoromethyl radicals can be generated
from CF3I with reagent composed of FeSO4, H2O2 and
a
dimethylsulfoxide (DMSO), which is the alkylation reagent of
aromatic and hetero-aromatic compounds with alkyl and per-
fluoroalkyl iodides [15], and that various nucleobases were able to
be trifluoromethylated by CF3I and this reagent [16]. Because this
reagent for trifluoromethylation is very versatile, it can provide an
industrial trifluoromethylation process. In fact, a single-step
process for the manufacture of 5-trifluoromethyluracil from uracil
and CF3I on an industrial scale has been realized by the use of this
reagent [16].
In this study, we examined trifluoromethylation using the
reagent of Fe(II), H2O2 and DMSO reagent in order to verify the
practical application to various aromatic and hetero-aromatic
compounds. Further, we investigated the orientation of the
products and the reactivity of the substrates on the basis of
electrophilic substitution of aromatic compounds [17].
aromatic and pseudo-aromatic compounds,
a trifluoromethyl
radical is formed from CF3Br photochemically [3] or in the
presence of Zn/SO2 or Na2S2O4 [4], CF3COOH electrochemically [5]
or in the presence of XeF2 [6], CF3COOAg photochemically [7],
CF3SO2M (M = Na or K) electrochemically [8], bis(trifluoroacetyl)-
peroxide [9] or Te(CF3)2 [10]. However, these methods seem
practically unsuitable because of the reagents and/or apparatus
required.
CF3I, which is one of the available radical sources of a
trifluoromethyl radical [11], was also utilized for radical trifluor-
omethylation under photoirradiation [12] or in the presence of Zn/
2. Results and discussion
2.1. Trifluoromethylation of benzene derivatives
In the previous study [16], we found that ferrocene (Cp2Fe) was
more effective than FeSO4 for the trifluoromethylation of certain
nucleobases and the addition of H2SO4 frequently improved the
yield. Thereafter, we carried out trifluoromethylation of each
* Corresponding author. Tel.: +81 467769268; fax: +81 467774113.
E-mail address: t_yamakawa@sagami.or.jp (T. Yamakawa).
1
Present address: Nagoya University, Graduate School of Engineering, Depart-
ment of Applied Chemistry, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8603, Japan.
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.09.007

T. Kino et al. / Journal of Fluorine Chemistry 131 (2010) 98–105
99
substrate by using the following four methods: (i) FeSO4 in the
presence of H2SO4 (method A), (ii) FeSO4 in the absence of H2SO4
(method B), (iii) Cp2Fe in the presence of H2SO4 (method C) and (iv)
Cp2Fe in the absence of H2SO4 (method D). Of them, the method
giving the highest yield is listed in the tables hereafter.
trifluoromethylation with pentamethylbenzene afforded a lower
yield than that with mesitylene (entry 3). This is presumably
because, as compared to mesitylene, pentamethylbenzene has
fewer positions that can be trifluoromethylated. A mixture of 2-
trifluoromethylaniline (4a), 4-trifluoromethylaniline (4b) and 2,4-
bis(trifluoromethyl)aniline (4c) was obtained in the reaction with
aniline (entry 4). Trifluoromethylated positions of these products
were ortho- and para-positions of the electron-donating amino
group. Other trifluoromethylation of aniline by a trifluoromethyl
radical [4a,4b,8a] also showed the same orientation, indicating
that the general trend of electrophilic substitution of aromatic
compounds can be applied to the radical trifluoromethylation.
In the trifluoromethylation of aniline, method B (in the absence
of H2SO4) was superior to method A (in the presence of H2SO4);
method A afforded 9% for 4a, 8% for 4b and 5% for 4c. This result
suggests that a part of the amino group of aniline is protonated by
H2SO4 into an aminium group. Therefore, the concentration of
aniline in the reaction mixture should be lower with method A
than with method B. In addition, the resulting anilinium ion is less
reactive to an electrophile than aniline due to the strong electron-
withdrawing nature of the aminium group. The higher reactivity of
Table 1 lists the results of trifluoromethylation of benzene
derivatives. The reaction with benzene was carried out using
method A. After the reaction, 19F NMR spectrum revealed the
formation of benzotrifluoride (1a) in 22% yield (entry 1). Because a
trifluoromethyl radical is known to be an electrophile [1], benzene
derivatives having an electron-donating group could exhibit the
higher reactivity than benzene. The reaction with mesitylene,
which possesses three electron-donating methyl groups, provided
trifluoromethylmesitylnene (2a) and bis(tirifluoromethyl)mesity-
lene (2b) in 26% and 68% yields, respectively (entry 2). Since 2b was
presumably formed through consecutive trifluoromethylation
from 2a, the reactivity of 2a can be considered to be higher than
that of benzene. Probably the effect of an electron-donating methyl
group was not cancelled by an electron-withdrawing trifluor-
omethyl group, for the decrease in electron density at meta-
position of an electron-withdrawing group is negligible. The
Table 1
Trifluoromethylation of benzene derivatives.
aSubstrate 1.0 mmol, CF3I 3.0 mmol, DMSO 5.0 mL. Method A: FeSO4 0.3 mmol, H2O2 2.0 mmol, H2SO4 1.0 mmol. Method B: FeSO4 0.3 mmol, H2O2 2.0 mmol. Method C: Cp2Fe
0.3 mmol, H2O2 2.0 mmol, H2SO4 1.0 mmol. Method D: Cp2Fe 0.3 mmol, H2O2 2.0 mmol.
bFeSO4 0.5 mmol, H2O2 6.0 mmol.

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T. Kino et al. / Journal of Fluorine Chemistry 131 (2010) 98–105
Table 2
Trifluoromethylation of nitrogen-containing six-membered aromatics compounds.
aSee footnote of Table 1.
bFeSO4 0.5 mmol, H2O2 6.0 mmol.
cCp2Fe 0.5 mmol, H2O2 10.0 mmol.
2-trifluoromethylaniline (entry 5), 2-chloroaniline (entry 6) and
2,6-dichloroaniline (entry 7) than aniline suggests that the
electron-withdrawing trifluoromethyl or chlorine group suppress
the protonation of the amino group. However, these substrates
provided the higher yields with method A (in the presence of
H2SO4) rather than method B (in the absence of H2SO4). Therefore,
it can be said that aniline is exceptionally low reactive among the
aniline derivatives tested in this trifluoromethylation and the
effect of H2SO4 seems rather complex.
Ortho- or para-position of amino group in chloroanilines were
trifluoromethylated moderately (entries 6 and 7). Chlorophenols
also gave the ortho- and para-oriented products 7a and 8a (entries
8 and 9). These substrates are also more reactive than aniline.
lated products were obtained from 2,6-diaminopyridine even in
the presence of H2SO4 (entry 2). The basicity of the nitrogen in the
ring should be enhanced by the two amino groups at the 2- and 6-
positions as expected generally, resulting in the protonation not at
the amino groups but at the nitrogen atom in the ring. Although
this protonation ought to cause the decrease in the reactivity to an
electrophile, electron-donating character of two amino groups can
cancel it and realized the high yields of 10a and 10b. At present, the
role of proton in these high yields is unknown as well as in the
reactions with aniline derivatives. Hydroxypyridines also gave the
ortho-oriented products (entries 3–5) moderately. An electro-
philically inactive 2-position of 3-hydroxypyridine was trifluor-
omethylated, though larger amounts of Cp2Fe and H2O2 than those
used typically in method C were necessary for the moderate yield
(entry 4). This suggests that an electron-donating character of
hydroxyl group is very effective in the trifluoromethylation.
Pyrimidine and pyradine derivatives also provided ortho- or
para-oriented products (entries 6–8). This orientation in the
products suggests that the nitrogen atoms in the rings of 2-
aminopyrimidine (entry 6) and aminopyradine (entry 8) were
protonated by H2SO4 like 2,6-diaminopyridine.
2.2. Trifluoromethylation of nitrogen-containing six-membered
aromatic compounds
We examined trifluoromethylation of nitrogen-containing six-
membered aromatic compounds (Table 2). Because these sub-
strates are electron-deficient, they are generally low reactive in
electrophilic substitution. Indeed, the reaction using pyridine
afforded a trace amount of certain trifluoromethylated products
[18]. In contrast, 3-aminopyridine (entry 1) gave a moderate yield
of ortho-oriented 3-amino-2-trifluoromethylpyridine (9a) in the
absence of H2SO4 (method D) [13], suggesting that the amino
group works effectively as an electron-donating group. Remark-
ably high total yield of ortho- and para-oriented trifluoromethy-
In the reaction with quinoline, 5-trifluoromethylquinoline
(17a) was exclusively obtained (Scheme 1), though electrophilic
substitution of quinoline occurs generally at 5- and 8-positions.
Moreover, the yield of 17a (10%) was lower than 1a (22%, entry 1 in
Table 1), indicating that reactivity of benzene ring of quinoline is
lower than that of benzene. The protonation possibly occurred

T. Kino et al. / Journal of Fluorine Chemistry 131 (2010) 98–105
101
Scheme 1. Trifluoromethylation of quinoline and 8-aminoquinoline by the use of method A.
both at
N
atom in the ring and at the amino group. 8-
2.3. Trifluoromethylation of five-membered hetero-aromatic
compounds
Aminoquinoline exhibited much higher reactivity than quinoline
and all the trifluoromethylated positions of the products were
ortho- and para-positions of the amino group on benzene ring [13].
Therefore, the protonation possibly occurred at the nitrogen atom
in the ring; this protonation should little affect the reactivity of the
benzene ring. Such a high reactivity of 8-aminoquinoline also
supports the exceptionally low reactivity of aniline in this
trifluoromethylation.
Trifluoromethylation of various five-membered hetero-aro-
matic compounds were also investigated using this reagent.
Table 3 shows the results of the trifluoromethylation with pyrrole,
thiophene and furan derivatives. Pyrrole was readily trifluoro-
methylated at the 2-position as expected by the general trend of
electrophilic substitution [9b,12c,12h,17]. The yield was slightly
Table 3
Trifluoromethylation of five-membered hetero-aromatic compounds (I).
aSee footnote of Table 1.

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T. Kino et al. / Journal of Fluorine Chemistry 131 (2010) 98–105
diminished by an electron-withdrawing acyl group (entry 2).
Khanna and co-workers reported that trifluoromethylation of 1-(4-
fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrrole by CF3I in the
presence of FeSO4, H2O2 and DMSO gave the product trifluor-
omethylated at the 2-position in a yield of 43% [19]. We now
assume that difference in yield occurs due to the addition of H2SO4.
We performed the reactions in entries 1 and 2 in the presence of
H2SO4 (method A for entry 1 and method C for entry 2). Although
the effect of H2SO4 is unknown at present as described above, the
addition of H2SO4 is one of the factors that improve a yield.
2-Trifluoromethylindole (21a) was exclusively obtained from
indole despite the low yield (entry 3); the photochemical
trifluoromethylation of indole by CF3I afforded a mixture of 2-
and 3-trifluoromethylindole [12e]. In this reaction, other products,
which may have been trifluoromethylated on the phenyl ring, were
also observed in 19F NMR spectrum in ca. 10% total yield; however,
those compounds have not been identified yet. Thiophene and 2-
bromothiophene were trifluoromethylated at the 2-position,
giving 22a and 23a in moderate yields. Interestingly, when 2-
and 5-positions of thiophene were blocked with bromine, the
product 24a that was trifluoromethylated at the 3-position was
obtained despite the lower yield (entry 6). 2-Trifluoromethylben-
zo[b]thiophene (25a) was obtained selectively with this reagent,
while the trifluoromethylation by CF3Br photochemically [3] or
using bis(trifluoromethyl)peroxide [9a] of benzo[b]thiophene
afforded mixtures of 2-, 3-, 4- and 7-trifluoromathylated products.
The present method seems superior to these trifluoromethylation
in the selectivity for certain substrates.
Contrastingly, the selective trifluoromethylation at the 2-
position of furan derivatives was observed similarly as other
radical trifluoromethylation [9a,12e]. However, the reactivity was
slightly unusual. The yield of 2-trifluoromethylfuran (26a) was
Table 4
Trifluoromethylation of five-membered hetero-aromatic compounds (II).
aSee footnote of Table 1.
bFeSO4 1.0 mmol, H2O2 10.0 mmol.
cCp2Fe 0.5 mmol, H2O2 10.0 mmol.

T. Kino et al. / Journal of Fluorine Chemistry 131 (2010) 98–105
103
lower than that of 2-trifluoromethylthiophene (22a). This differs
3. Conclusion
from the general order of nucleophilicity, where furan > thio-
thiophene. On the other hand, the order of reactivity of
benzo[b]furan > benzo[b]thiophene is reasonable (30% for 27a in
entry 9 > 17% for 25a in entry 7).
Trifluoromethylation of pyrazole is unusual with respect to
orientation and reactivity (entry 1 in Table 4). The main product was
Here, we presented the trifluoromethylation of various
aromatic compounds by using the reagent comprising Fe(II),
H2O2 and DMSO. The orientation of trifluoromethylated position
was able to be predicted by the general trend of electrophilic
substitution of aromatic compounds, though some substrates were
exceptional. This method can provide economical process for
industrial purposes, because (i) the reaction is simple and
conventional single-step reaction, (ii) the reaction proceeds under
mild conditions and (iii) the components of the reagent are
inexpensive.
3-trifluoromethyl (28a) with
a concomitant formation of 4-
trifluoromethylpyrazole (28b), though electrophilic substitution
generallyoccursatthe4-position.Moreover,ratherlow yieldsof28a
and 28b are unexpected, because pyrazole is highly electron-
excessive. 4-Methylpyrazole having an electron-donating methyl
group gave 29a in 49% yield (entry 2), which implies that an
electron-donating methyl group worked effectively toward a higher
yield. On the other hand, 3-methylpyrazole afforded lower yields of
the5-and4-trifluoromethylatedproducts(entry3)thanentry1.The
substrate in entry 4, 3-methyl-3-pyrazolin-5-one which is the keto
4. Experimental
4.1. General techniques
1H, 13C and 19F NMR spectra were recorded in CDCl3, DMSO-d6
or acetone-d6 on Bruker DRX-500 (13C 125 MHz) and DRX-250 (1H
250 MHz, 19F 235 MHz) spectrometers using tetramethylsilane as
an internal reference for 1H and 13C NMR and fluorotrichlor-
omethane as an external reference for 19F NMR. Chemical shifts are
form of aromatic 5-hydroxy-3-methylpyrazole, is one of the
unsaturated amides similar to uracil derivatives. Although larger
amounts of FeSO4 and H2O2 were required, the trifluoromethylated
a,b-
product at the a-position was obtained in a similar manner as were
uracil derivatives [15]. Of the other electron-excessive compounds
tested, only 2,4-diphenyloxazole provided a satisfactory yield (entry
11). Interestingly, no by-products trifluoromethylated on phenyl
rings were found. Despite the low yields, electron-deficient
compounds such as 1,2,4-triazole (entry 6) and 1,3,4-thiadiazole
(entry 10) was able to be trifluoromethylated. In the reaction with 2-
amino-5-methyl-1,3-triazole (entry 9), the position that can be
trifluoromethylated is only the 4-position. Therefore, the protona-
tioncannotbepredicted bythereactivityororientation, but possibly
occurs at the nitrogen atom.
expressed in ppm (d). Multiplicities are indicated by s (singlet), brs
(broad singlet), d (doublet), t (triplet), q (quartet), quint (quintet),
hept (heptet), sept (septet), dd (doublet of doublet), ddd (doublet
of doublet of doublet), ddq (doublet of doublet of quintet) and m
(multiplet). 19F NMR yields were calculated with 2,2,2-trifluor-
oethanol as an internal standard. The measurement of IR, high-
resolution mass spectroscopy (HR-MS) and melting point (Mp)
¨
were carried out using HORIBA FT-720, JEOL JMS600 and BUCHI
530, respectively. IR-spectra were obtained in the reflective mode.
CF3I was supplied by Tosoh F-Tech Co., Ltd. All the commercially
available reagents were used without further purification.
Therefore, when trifluoromethylation of five-membered het-
ero-aromatic compounds is performed with this reagent, the
reactivity and orientation should be thoroughly noted.
Although some of the substrates that were tested afforded low
yields, a simple trifluoromethylation process was achieved by
using this reagent. We believe that this reagent can be applied to
the synthesis of useful synthetic intermediates. For example, 6a,
29a and 37a have been included in the structures of acetoprole
(insecticide) [20], penthiopyrad (fungicide) [21] and thiazfluron
(insecticide) [22], respectively (Fig. 1). Moreover, 13 new
trifluoromethylated compounds were synthesized here by this
reagent.
With regard to the reaction mechanism, we now consider as
follows on the basis of the reported alkylation mechanism: (i) a
hydroxyl radical is formed through the reduction of H2O2 by Fe(II)
(Fe(III) is formed simultaneously); (ii) the hydroxyl radical is
rapidly trapped by DMSO to form a methyl radical and (iii) the
reaction of CF3I and the methyl radical releases a trifluoromethyl
radical [15a]. Supposing this mechanism, the reason why certain
substrates favour Cp2Fe and H2SO4 is unclear. The details of the
mechanism are now under investigation.
4.2. Reaction procedures of trifluoromethylation
4.2.1. General procedure
In all the reactions, the amount of substrate was 1.0 mmol.
DMSO solutions of CF3I (3.0 mol/L) and H2SO4 (1.0 mol/L) were
prepared just before use. FeSO4 was dissolved in H2O to a
concentration of 1.0 mol/L. Cp2Fe was used as a solid. Commer-
cially available 30% H2O2 aqueous solution was used as received.
During typical reactions, the molar ratio of [Fe]/[substrate], [CF3I]/
[substrate], [H2O2]/[substrate] and [H2SO4]/[substrate] were 0.3,
3.0, 2.0 and 1.0, respectively. An aqueous solution of FeSO4 or
Cp2Fe, a DMSO solution of CF3I and a DMSO solution of H2SO4 in
some cases were charged in a two-neck flask in an argon
atmosphere. The total amount of DMSO was adjusted to 5.0 mL
by adding additional DMSO. Subsequently, a 30% aqueous solution
of H2O2 was added drop-wise at the rate of 0.04 mL/min using a
syringe pump. The temperature of the mixture thus obtained rose
up to 40–50 8C; the mixture was stirred at this temperature for
Fig. 1. Molecular structure of acetoprole, penthiopyrad and thiazfluron.

104
T. Kino et al. / Journal of Fluorine Chemistry 131 (2010) 98–105
20 min. After cooling to room temperature, an aliquot of the
solution was taken for measuring the 19F NMR yield. Purification
and isolation were carried out by means of thin layer silica
chromatography, silica gel column chromatography or extraction.
The choice of method (A–D) has been listed in Tables 1–4 and
Scheme 1. With respect to 2-chloroaniline (entry 5 in Table 1), 4-
hydroxypyridine (entry 3 in Table 2), 3-hydroxypyridine (entry 4
in Table 2), 3-methyl-3-pyrazolin-5-one (entry 4 in Table 4) and 5-
4.3. Characterization of products
The compounds 2b, 10a, 10b, 11a, 12a, 15a, 18a, 18b, 20a,
31a,34a,35a and 38a are new compounds. These compounds
except 2b and 10a have been fully characterized by NMR (1H, 13
and 19F), IR and HR-MS herein. HR-MS and/or elementary analyses
of 2b and 10a showed little reliability probably due to high
volatility and/or low thermal and chemical stability. Therefore, EI–
MS data were listed. The other compounds are not new and each
compound is given a CAS number. Their characterization data are
included in our patents previously reported [23].
C
(2-hydroxyethyl)-4-methylthiazole (entry
7 in Table 4), the
charged amount of Fe(II) compound and 30% aqueous solution
of H2O2 was modified in order to obtain higher yields, as given in
the footnotes of each table.
Typical procedures for 19a (method A), 15a (method B), 2a and
2b (method C) and 35a (method D) are listed.
4.3.1. 2,4-Bis(trifluoromethyl)-1,3,5-trimethylbenzene (2b)
Colorless oil. 1H NMR (CDCl3)
d
2.43–2.54 (m, 9H), 6.97 (s, 1H).
17.2 (hept, JCF = 4.4 Hz), 21.9 (q, JCF = 4.9 Hz),
125.6 (q, JCF = 276.4 Hz), 127.8 (q, JCF = 28.4 Hz), 134.5, 138.7 (hept,
13C NMR (CDCl3)
d
4.2.2. Method A: synthesis of 2-trifluoromethylpyrrole (19a)
Pyrrole (0.07 mL, 1.0 mmol), DMSO (2.0 mL), a DMSO solution
of H2SO4 (0.5 mol/L, 2.0 mL), a DMSO solution of CF3I (3.0 mol/L,
1.0 mL) and an aqueous solution of FeSO4 (1.0 mol/L, 0.3 mL) were
charged in a two-neck flask. A 30% aqueous solution of H2O2
(0.2 mL) was added subsequently. The reaction mixture was
neutralized by adding an aqueous solution of Na2CO3, and the
desired product was extracted into ethyl acetate. Purification and
isolation of the product by thin layer silica chromatography (eluent
hexane:ethyl acetate = 1:1) gave 2-trifluoromethylpyrrole (19a) as
a colorless oil in an isolated yield of 72%.
JCF = 1.9 Hz), 140.1. 19F NMR (CDCl3)
1456, 1429, 1387, 1367, 1308, 1149 (C–F) cmÀ1. EI–MS Calcd for
C11H10F6 (M) 256 Found 256.
d
À53.2. IR 2927, 1743, 1601,
4.3.2. 2,6-Diamino-3-trifluoromethylpyridine (10a)
White solid. 1H NMR (CDCl3)
d
5.45 (brs, 2H), 5.71 (brs, 2H), 7.70
(d, JHH = 5.9 Hz, 1H), 8.39 (d, JHH = 5.9 Hz, 1H). 13C NMR (CDCl3)
105.6, 120.4 (q, JCF = 31.4 H), 122.7 (q, JCF = 271.3 Hz), 139.2, 140.7
d
(q, JCF = 4.9 Hz), 161.4. 19F NMR (DMSO-d6)
2933, 1628, 1577, 1417, 1176 (C–F) cmÀ1. EI–MS Calcd for
d
À61.4. IR 3421, 3016,
C6H6N3F3 177. Found 177. Mp 98–100 8C.
4.2.3. Method B: synthesis of 2-amino-5-trifluoromethyl-4-hydroxy-
6-mehylpyrimidine (15a)
4.3.3. 2,6-Diamino-3,5-bis(trifluoromethyl)pyridine (10b)
2-Amino-4-hydroxy-6-methylpyrimidine (125 mg, 1.0 mmol),
DMSO (4.0 mL) and a DMSO solution of CF3I (3.0 mol/L, 1.0 mL)
were charged in a two-neck flask. Then a 30% aqueous solution of
H2O2 (0.2 mL) and an aqueous solution of FeSO4 (1.0 mol/L, 0.3 mL)
were added subsequently. The desired product was extracted into
ethyl acetate. Removing the solvent under vacuo gave 2-amino-5-
trifluoromethyl-4-hydroxy-6-mehylpyrimidine (15a) as a white
solid in an isolated yield of 70%.
White solid. 1H NMR (CDCl3) 5.12 (brs. 4H), 7.70 (s, 1H). 13C
d
NMR (CDCl3)
(quint, JCF = 4.7 Hz), 156.6. 19F NMR (CDCl3)
3336, 3205, 1628, 1577, 1473, 1381, 1323, 1290, 1184 (C–F) cmÀ1
d
98.0 (q, JCF = 33.2 Hz), 124.5 (q, JCF = 269.6 Hz), 135.6
d
À62.0. IR 3502, 3448,
.
HR-MS Calcd for C7H5N3F6 245.0388. Found 245.0382. Mp 95–98 8C.
4.3.4. 4-Hydroxy-3,5-bis(trifluoromethyl)pyridine (11a)
White solid. 1H NMR (acetone-d6)
13C NMR (acetone-d6)
JCF = 271.0 Hz), 139.9 (q, JCF = 6.4 Hz), 170.6. 19F NMR (acetone-
d
8.18 (s, 2H), 11.35 (brs, 1H).
d
120.6 (q, JCF = 29.8 Hz), 124.0 (q,
4.2.4. Method C: synthesis of 1,3,5-trimethyl-2-
trifluoromethylbenzene (2a) and 1,3,5-trimethyl-2,4-
bis(trifluoromethyl)benzene (2b)
d6)
d
À65.9. IR 3032, 2912, 2866, 1658, 1549, 1331, 1280, 1167 (C–
F) cmÀ1. HR-MS Calcd for C7H4NOF6 (M+H) 232.0197. Found
1,3,5-Trimethylbenzene (140
m
L, 1.0 mmol), Cp2Fe (56 mg,
232.0187. Mp 300 8C < .
0.3 mmol), DMSO (2.0 mL), a DMSO solution of H2SO4 (0.5 mol/L,
2.0 mL) and a DMSO solution of CF3I (3.0 mol/L, 1.0 mL) were
charged in a two-neck flask. A 30% aqueous solution of H2O2
(0.2 mL) was added subsequently. The reaction mixture was
neutralized by adding an aqueous solution of Na2CO3, and the
desired product was extracted into ethyl acetate. Purification and
isolation by passing through silica gel column (eluent hexane)
gave 1,3,5-trimethyl-2-trifluoromethylbenzene (2a) as a pale
yellow oil in an isolated yield of 48% and 1,3,5-trimethyl-2,4-
bis(trifluoromethyl)benzene (2b) as a colorless oil in an isolated
yield of 25%.
4.3.5. 3-Hydroxy-2-trifluoromethylpyridine (12a)
White solid. 1H NMR (acetone-d6)
d
7.51 (dd, JHH = 8.3, 3.8 Hz,
1H), 7.56 (dd, JHH = 8.3, 2.0 Hz, 1H), 8.16 (dd, JHH = 3.8, 2.0 Hz, 1H),
9.86 (brs, 1H). 13C NMR (acetone-d6)
122.6 (q, JCF = 273.4 Hz),
d
122.5, 128.4, 134.6 (q, JCF = 33.2 Hz), 140.1, 152.6. 19F NMR (acetone-
d6)
d
À66.8. IR 2900, 1592, 1340, 1298, 1174 (C–F) cmÀ1. HR-MS
Calcd for C6H4NOF3 163.0245. Found 163.0243. Mp 135–137 8C.
4.3.6. 2-Amino-4-hydroxy-6-methyl-5-trifluoromethylpyrimidine
(15a)
White solid. 1H NMR (DMSO-d6)
d
2.23 (q, JHF =2.8 Hz, 3H), 7.09
(brs, 2H), 11.23 (brs, 1H). 13C NMR (DMSO-d6)
22.8, 101.1 (q,
JCF = 29.2 Hz), 125.4 (q, JCF = 271.0 Hz), 155.9, 160.9, 166.0. 19F
4.2.5. Method D: synthesis of N-(5-trifluoromethyl-1,3-thiazole-2-
yl)acetoamide (35a)
d
N-(1,3-Thiazole-2-yl)acetoamide (142 mg, 1.0 mmol), Cp2Fe
(56 mg, 0.3 mmol), DMSO (4.0 mL) and a DMSO solution of CF3I
(3.0 mol/L, 1.0 mL) were charged in a two-neck flask. Then a 30%
aqueous solution of H2O2 (0.2 mL) was added subsequently. The
reaction mixture was neutralized by adding an aqueous solution of
Na2CO3, and the desired product was extracted into ethyl acetate.
Purification and isolation of the product by passing through silica
gel column (eluent hexane:ethyl acetate = 1:1) gave N-(5-trifluor-
omethyl-1,3-thiazole-2-yl)acetoamide (35a) as a white solid in an
isolated yield of 48%.
NMR (DMSO-d6)
d
À53.8. IR 3386, 3016, 2933, 1676, 1647, 1593,
1560, 1506, 1408, 1360, 1288, 1130 (C–F) cmÀ1. HR-MS Calcd for
C6H7N3OF3 (M+H) 194.0541. Found 194.0535. Mp < 300 8C.
4.3.7. 8-Amino-5-trifluoromethylquinoline (18a)
White solid. 1H NMR (CDCl3)
d 6.34 (brs, 2H), 6.95 (dd,
JHH = 8.2 Hz, JHF = 0.2 Hz, 1H), 7.64 (dd, JHH = 8.7, 4.1 Hz, 1H), 7.72
(dd, JHH = 8.2 Hz, JHF = 0.5 Hz, 1H), 8.39 (ddq, JHH = 8.7,
1.5 Hz, JHF = 1.8 Hz, 1H), 8.84 (dd, JHH = 4.1, 1.5 Hz, 1H). 13C NMR
(CDCl3)
d 106.7, 111.6 (q, JCF = 30.5 Hz), 123.8, 126.0, 126.4 (q,

T. Kino et al. / Journal of Fluorine Chemistry 131 (2010) 98–105
105
References
JCF = 268.9 Hz), 128.0 (q, JCF = 5.8 Hz), 132.8 (q, JCF = 2.3 Hz), 138.3,
148.5, 150.2. 19F NMR (CDCl3)
À58.5. IR 3408, 3290, 1620, 1597,
1508, 1379, 1317, 1263, 1138 (C–F) cmÀ1. HR-MS Calcd for
10H7N2F3 212.0561. Found 212.0569. Mp 78–79 8C.
d
[1] (a) W.R. Dolbier Jr., Chem. Rev. 96 (1996) 1557–1584;
(b) J.-P. Begue, in: D. Bonnet-Delpon (Ed.), Bioorganic and Medicinal Chemistry of
Fluorine, Wiley, Hoboken, 2008.
C
[2] M.A. McClinton, D.A. McClington, Tetrahedron 48 (1992) 6555–6666.
[3] T. Akiyama, K. Kato, M. Kajitani, Y. Sakaguchi, J. Nakamura, H. Hayashi, A.
Sugimori, Bull. Chem. Soc. Jpn. 61 (1988) 3531–3537.
[4] (a) C. Wakselman, M. Tordeux, J. Chem. Soc., Chem. Commun. (1987) 1701–1703;
(b) M. Tordeux, B. Langlois, C. Wakselman, J. Chem. Soc., Perkin Trans. 1 (1990)
2293–2299.
4.3.8. 8-Amino-7-trifluoromethylquinoline (18b)
White solid. 1H NMR (acetone-d6)
6.17 (brs, 2H), 7.06 (d,
d
JHH = 8.8 Hz, 1H), 7.37 (d, JHH = 8.8 Hz, 1H), 7.49 (dd, JHH = 8.4,
4.3 Hz, 1H), 8.14 (dd, JHH = 8.4, 1.5 Hz, 1H), 8.71 (dd, JHH = 4.3,
[5] C. Depecker, H. Marzouk, S. Trevin, J. Devynck, New J. Chem. 23 (1999) 739–742.
1.5 Hz, 1H). 13C NMR (acetone-d6)
d
106.0 (q, JCF = 30.0 Hz), 113.9,
ˇ ˇ
[6] (a) A. Gregorcic, M. Zupan, J. Org. Chem. 44 (1979) 4120–4122;
(b) Y. Tanabe, N. Matsuo, N. Ohno, J. Org. Chem. 53 (1988) 4582–4585.
[7] C. Lai, T.E. Mallouk, J. Chem. Soc., Chem. Commun. (1993) 1359–1361.
[8] (a) B.R. Langlois, E. Laurent, N. Roidot, Tetrahedron Lett. 32 (1991) 7525–7528;
(b) J.-B. Tommasino, A. Brondex, M. Me´debielle, M. Thomalla, B.R. Langlois, T.
Billard, Synlett (2002) 1697–1699.
[9] (a) H. Sawada, M. Nakayama, J. Fluorine Chem. 46 (1990) 423–431;
(b) M. Yoshida, T. Yoshida, M. Kobayashi, N. Kamigata, J. Chem. Soc., Perkin Trans.
1 (1989) 909–914.
[10] D. Naumann, J. Kischkewitz, J. Fluorine Chem. 47 (1990) 283–299.
[11] (a) N.B. Shustova, A.A. Popov, M.A. Mackey, C.E. Coumbe, J.P. Phillips, S. Steven-
son, S.H. Strauss, O.V. Boltalina, J. Am. Chem. Soc. 129 (2007) 11676–11677;
(b) Y. Itoh, K.N. Houk, K. Mikami, J. Org. Chem. 71 (2006) 8918–8925;
(c) K. Mikami, Y. Tomita, Y. Ichikawa, K. Amikura, Y. Itoh, Org. Lett. 8 (2006)
4671–4673;
123.1 (q, JCF = 4.7 Hz), 123.6, 125.9 (q, JCF = 271.1 Hz), 130.2, 136.1,
138.1, 143.6, 148.3. 19F NMR (acetone-d6)
d
À62.3. IR 3521, 3363,
1724, 1614, 1593, 1508, 1390, 1308, 1186 (C–F) cmÀ1. HR-MS
Calcd for C10H7N2F3 212.0561. Found 212.0552. Mp 52–54 8C.
4.3.9. 2-Acetyl-1-methyl-5-trifluoromethylpyrrole (20a)
pale yellow oil. 1H NMR (CDCl3)
d
2.48 (s, 3H), 4.02 (s, 3H), 6.54
(d, JHH = 4.2 Hz, 1H), 6.89 (d, JHH = 4.2 Hz, 1H). 13C NMR (CDCl3)
27.8, 34.2 (q, JCF = 1.9 Hz), 110.2 (q, JCF = 3.6 Hz), 113.6, 117.4, 120.6
d
(q, JCF = 268.3 Hz), 128.0 (q, JCF = 37.6 Hz), 189.7. 19F NMR (CDCl3)
d
À60.1. IR 2670, 1670, 1541, 1389, 1346, 1147 (C–F) cmÀ1. HR-MS
(d) W. Xu, W.R. Dolbier Jr., J. Org. Chem. 70 (2005) 4741–4745;
(e) Y. Itoh, K. Mikami, Org. Lett. 7 (2005) 649–651;
Calcd for C8H9NOF3 (M+H) 192.0636. Found 192.0645.
(f) K. Sato, M. Omote, A. Ando, I. Kumadaki, Org. Lett. 6 (2004) 4359–4361;
(g) K. Iseki, T. Nagai, Y. Kobayashi, Tetrahedron: Asymmetry 5 (1994) 961–974;
(h) Y. Hanzawa, J. Uda, Y. Kobayashi, Y. Ishida, T. Taguchi, M. Shiro, Chem. Pharm.
Bull. 39 (1991) 2459–2461.
4.3.10. 3-Methyl-4-trifluoromethyl-3-pyrazolin-5-one (31a)
Pale yellow solid. 1H NMR (DMSO-d6)
d
2.23 (q, JHF = 1.2 Hz, 3H),
10.43 (brs, 1H), 12.05 (brs, 1H). 13C NMR (DMSO-d6)
10.8, 92.8 (q,
JCF = 36.0 Hz), 124.2 (q, JCF = 265.0 Hz), 140.0, 158.7. 19F NMR
d
[12] (a) E.S. Huyser, E. Bedard, J. Org. Chem. 29 (1964) 1588–1590;
(b) J.M. Birchall, G.P. Irvin, R.A. Boyson, J. Chem. Soc., Perkin Trans. 2 (1975) 435–
439;
(DMSO-d6)
d
À54.1. IR 2933, 1734, 1558, 1456, 1439, 1363, 1290,
(c) Y. Kobayashi, I. Kumadaki, A. Ohsawa, S.-I. Murakami, T. Nakano, Chem.
Pharm. Bull. 26 (1978) 1247–1249;
1151 (C–F) cmÀ1. HR-MS Calcd for C5H6N2OF3 167.0432 (M+H).
(d) H. Kimoto, S. Fujii, L.A. Cohen, J. Org. Chem. 47 (1982) 2867–2872;
Found 167.0428. Mp ca. 91 8C (decomp.).
´
(e) 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;
(f) H. Kimoto, S. Fujii, L.A. Cohen, J. Org. Chem. 49 (1984) 1060–1064;
(g) V.M. Labroo, R.B. Labroo, L.A. Cohen, Tetrahedron Lett. 31 (1990) 5705–5708;
(h) M. Nishida, H. Kimoto, S. Fujii, Y. Hayakawa, L.A. Cohen, Bull. Chem. Soc. Jpn.
64 (1991) 2255–2259;
4.3.11. 2-Trifluoromethyl-5-(2-hydroxyethyl)-4-methylthiazole
(34a)
pale yellow oil. 1H NMR (CDCl3)
d
2.42 (s, 3H), 2.54 (brs, 1H),
3.04 (t, JHH = 6.0 Hz, 2H), 3.86 (t, JHH = 6.0 Hz, 2H). 13C NMR (CDCl3)
14.9, 29.5, 62.0, 119.8 (q, JCF = 271.6 Hz), 133.0, 150.5, 152.0 (q,
(i) K.L. Kirk, M. Nishida, S. Fujii, H. Kimoto, J. Fluorine Chem. 59 (1992) 197–
202.
d
JCF = 40.4 Hz). 19F NMR (CDCl3)
d
À61.4. IR 3300, 2931, 2881, 1734,
[13] L. Strekowski, M. Hojjat, S.E. Patterson, A.S. Kiselyov, J. Heterocyclic Chem. 31
(1994) 1413–1416.
[14] A.B. Cowell, C. Tamborski, J. Fluorine Chem. 17 (1981) 345–356.
[15] (a) F. Minisci, E. Vismara, F. Fontana, J. Org. Chem. 54 (1989) 5224–5227;
(b) A. Bravo, H.-R. Bjørsvik, F. Fontana, L. Liguori, A. Mele, F. Minisci, J. Org. Chem.
62 (1997) 7128–7136;
(c) E. Baciocchi, E. Muraglia, Tetrahedron Lett. 34 (1993) 3799–3800;
(d) E. Baciocchi, E. Muraglia, Tetrahedron Lett. 34 (1993) 5015–5018.
[16] D. Uraguchi, K. Yamamoto, Y. Otsuka, K. Tokuhisa, T. Yamakawa, Appl. Catal. A:
Gen. 342 (2008) 137–143.
[17] (a) T. Eicher, S. Hauptmann (Eds.), Chemistry of Heterocycles, Wiley, Weinheim,
2003;
(b) A.R. Katrizsky, W.-Q. Fan, Heterocycles 34 (1992) 2179–2229.
[18] Kobayashi and co-workers obtained 2-, 3- and 4-trifluoromethylpyridine in 38%,
27% and 16% yield by the photochemical radical trifluoromethylation by CF3I in
ref. 12c. However, 3 days of the reaction time is required under their conditions.
[19] I.K. Khanna, R.M. Weider, Y. Yu, P.W. Collins, J.M. Miyashita, C.M. Koboldt, A.W.
Veenhuizen, J.L. Currie, K. Seibert, P.C. Isakson, J. Med. Chem. 40 (1997) 1619–
1633.
1716, 1541, 1466, 1302, 1184 (C–F) cmÀ1. HR-MS Calcd for
C7H9NOSF3 (M+H) 212.0357. Found 212.0366.
4.3.12. N-(5-Trifluoromethyl-1,3-thiazole-2-yl)acetoamide (35a)
White solid. 1H NMR (CDCl3)
d
2.38 (s, 3H), 7.75 (s, 1H), 11.76
23.1, 120.9 (q, JCF = 38.2 Hz), 122.3 (q,
JCF = 268.5 Hz), 137.7 (q, JCF = 4.5 Hz), 162.2, 168.3. 19F NMR
(brs, 1H). 13C NMR (CDCl3)
d
(CDCl3)
d
À54.8. IR 3167, 2929, 1703, 1564, 1529, 1371, 1335,
1290, 1273, 1176 (C–F) cmÀ1. HR-MS Calcd for C6H6N2OSF3 (M+H)
211.0153. Found 211.0159. Mp 152–153 8C.
4.3.13. 2,4-Diphenyl-5-trifluoromethyloxazole (38a)
Pale yellow solid. 1H NMR (CDCl3)
d
7.43–7.57 (m, 6H), 7.75–
7.80 (m, 2H), 8.13–8.18 (m, 2H). 13C NMR (CDCl3)
d
119.8 (q,
[20] P. Jeschke, ChemBioChem 5 (2004) 570–589.
JCF = 267.8 Hz), 126.1, 127.1, 128.5 (q, JCF = 1.6 Hz), 128.6, 129.0,
129.4, 129.6, 131.6, 133.5 (q, JCF = 42.7 Hz), 142.5 (q, JCF = 2.5 Hz),
[21] C. Neumann, C.E. Mils, U.U. Haas, WO-2007/128428.
[22] R.K. Achqill, L.W. Call, US Patent 4,987,233 (1991).
[23] (a) T. Yamakawa, D. Uraguchi, K. Yamamoto, K. Tokuhisa, JP 2008-239572.;
(b) T. Yamakawa, D. Uraguchi, K. Yamamoto, K. Tokuhisa, JP 2008-231039.;
(c) T. Yamakawa, D. Uraguchi, K. Yamamoto, K. Tokuhisa, JP 2008-137992.;
(d) T. Yamakawa, D. Uraguchi, K. Yamamoto, K. Tokuhisa, JP 2008-115105.
161.7. 19F NMR (CDCl3)
d
À60.4. IR 3062, 1610, 1558, 1489, 1387,
1367, 1325, 1163 (C–F) cmÀ1. HR-MS Calcd for C16H11NOF3 (M+H)
290.0793. Found 290.0783. Mp 46–48 8C.