Introduction of several trifluoromethyl groups onto the activated aromatic materials with CF3TMS-CuI-KF system

Article abstract of DOI:10.1016/j.jfluchem.2004.04.014

Trifluoromethylation onto the tetrafluorophthalonitrile and tetrafluoroisophthalonitrile has been carried out using CF₃TMS-CuI-KF system, and it was demonstrated that these trifluoromethylation enabled us to successfully construct di- and/or tr

Full text of DOI:10.1016/j.jfluchem.2004.04.014

Journal of Fluorine Chemistry 125 (2004) 1447–1449
Introduction of several trifluoromethyl groups onto the activated aromatic
materials with CF3TMS–CuI–KF system
Tomoya Kitazume*, Satoshi Nakajima
Graduate School of Biosceince & Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta,
Midori-ku Yokohama 226-8501, Japan
Received 25 March 2004; received in revised form 27 April 2004; accepted 28 April 2004
Available online 24 June 2004
Abstract
Trifluoromethylation onto the tetrafluorophthalonitrile and tetrafluoroisophthalonitrile has been carried out using CF3TMS–CuI–KF
system, and it was demonstrated that these trifluoromethylation enabled us to successfully construct di- and/or tri-trifluoromethylated
benzonitriles via the decyanotrifluoromethylation.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Trifluoromethylation; Decyanotrifluoromethylation; Multitrifluoromethylation
1. Introduction
trifluoromethyl group onto the specific position of the
molecule.
The challenge to develop new products, practical pro-
cesses, reaction media, conditions and/or utility of materials
is having one of the most important issues in fluorine
chemistry [1]. Especially, selective introduction of fluorine
into organic materials has been receiving attention in various
fields such as pharmacology or functionalized materials
because of their unique biological and physical properties
[2]. To date, the trifluoromethylation has been based on
several methods: (1) use of metal reagents [3] such as
(CF3)2Hg, (CF3)2Cd and CF3ZnI, (2) CF3Cu derived from
the reaction of CF3I with activated copper in DMF or HMPA
[4], (3) CF3SiMe3–fluoride ion system [5], or CF3SiMe3–
CuI–KF system [6], and (4) CF3SiMe3–base system [7].
In this paper, we would like to describe di- and/or tri-
trifluoromethylation onto tetrafluorophthalonitrile and tet-
rafluoroisophthalonitrile using CF3SiMe3–CuI–KF system
at 80 8C, and to explain the fluorescence intensity of
products.
In order for this trifluoromethylation to constitute a useful
synthetic strategy in fluorine chemistry, we examined the
trifluoromethylation onto the tetrafluorophthalonitrile and
tetrafluoroisophthalonitrile using CF3SiMe3–CuI–KF sys-
tem at 80 8C. In the case of tetrafluorophthalonitrile, com-
pounds 2 (54%), 3 (6%) and 4 (3%) obtained through the
substitution reaction of the activated substituents on the
benzene ring by a trifluoromethyl species generated from
CF3SiMe3–CuI–KF system. However, the main product is
the compound 2 (53%) generated from the substitution of
starting material by an amino group in a final quench. The
structures of compounds 2–4 were confirmed by 1H and 19
F
NMR spectrum and elementary analysis. On the basis of the
chemical shifts and coupling constants in the 19F NMR
spectra of compound 3, two signals occur in the region
d ¼ 104:8 and 106.8 ppm from internal C6F6 were the two
different types of trifluoromethyl groups (aCF3; d ¼ 106:8,
doublet of quartet (J ¼ 35:3, 16.4 Hz) and bCF3; 104.8,
quartet (J ¼ 16:4 Hz)), and the coupling pattern of a signal
of fluorine atom in the region d ¼ 46:6 ppm was quartet
(JFÀ CF ¼ 35.3 Hz). In the 1H NMR spectrum, the signal at
a
2. Results and discussion
3
d 5.40 was a NH2 group. Further, in the other product 4, three
The utility of CF3SiMe3–CuI–KF system [6] has been
generally recognized to be useful in the introduction of a
signals occur in the region d ¼ 103:0, 104.8 and 106.6 ppm
were the three different types of trifluoromethyl groups
(cCF3; d ¼ 106:6, doublet of quartet (J ¼ 35:3, 16.4 Hz)
and dCF3; d ¼ 104:8, quartet (J ¼ 16:4 Hz), eCF3;
d ¼ 103:0, doublet (J ¼ 21:5 Hz)), and the coupling pattern
* Corresponding author. Tel.: þ81-45-924-5754; fax: þ81-45-924-5780.
E-mail address: tkitazum@bio.titech.ac.jp (T. Kitazume).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.04.014

1448
T. Kitazume, S. Nakajima / Journal of Fluorine Chemistry 125 (2004) 1447–1449
F
F
F
F
aCF3
bCF3
CN
CN
F
F
CN
CN
H2N
F
CN
CN
cCF3
dCF3
eCF3
CN
CF3SiMe3
CuI / KF
aq. NH4OH
+
+
NH2
F
F
NH2
1
(53%)
2
3 (6%)
4 (3%)
Scheme 1. Multitrifluoromethylation onto the tetrafluorophatalonitrile.
of a signal of fluorine atom in the region d ¼ 38:3 ppm was
In the 19F NMR spectra of compound 7, two signals
occur in the region d ¼ 103:0 and 36.6 ppm from internal
C6F6 were the two different types of fluorines (such as fCF3;
c
e
quartet of quartet (JFÀ CF ¼ 35.3 Hz, JFÀ CF ¼ 21.5 Hz),
3
3
1
and the signal at d 5.40 was a NH2 group in the H NMR
spectrum. In the 19F NMR spectrum of compound 2, three
signals appear at d 16.0 (dd, J ¼ 19:8, 8.6 Hz), 30.7 (dd,
J ¼ 19:8, 8.6 Hz) and 35.1 (dd, J ¼ 19:8, 19.8 Hz) ppm
with equal intensity, and the signal at d 4.70 was a NH2
group in the 1H NMR spectrum. From the these NMR data
and elemental analysis (see Section 3), the structure of
products 2–4 was identified as the following one shown
in Scheme 1.
103.0, doublet (J ¼ 21:5 Hz), 36.6, quartet (JFÀCF
¼
3
1
21.5 Hz)). In the H NMR spectrum, the signal at d 5.60
was a NH2 group.
In the above reactions (Schemes 2 and 3), we examined
the various types of reaction conditions (temperature, time,
substrate ratio, etc.), however the yields of target multi
functionalized trifluoromethyl materials did not increase.
The reaction mechanism to give di- and/or tri-trifluoro-
methylated compounds is the following way. The step is the
substitution at p-position of electron withdrawing cyano
group by a trifluoromethyl group, and the second step is
also the substitution at p-position at another cyano group,
giving the compound 9. The next step is the decyanotri-
fluoromethylation which is the substitution of activated
cyano group by the trifluoromethyl cuprate reagent. After
quenching the reaction mixture with aq. NH4OH, final
Further, in the case of tetrafluoroisophthalonitrile 5, three
kinds of products were also obtained. Spectral data of one of
them supported the structure of compound 4. Other products
have the same substitution pattern in the above case. One of
products (compound 6) has three signals at d 1.70 (dd,
J ¼ 19:0, 11.2 Hz), 40.4 (doublet, J ¼ 19:0 Hz) and 60.1
(doublet, J ¼ 11:2 Hz) in the 19F NMR spectrum, and the
signal at d 5.40 was a NH2 group in the 1H NMR spectrum.
F
F
F
F
fCF3
NC
fCF3
CN
cCF3
dCF3
eCF3
CN
F
F
H2N
NC
F
CF3SiMe3
CuI / KF
aq. NH4OH
+
+
NC
CN
CN
NH2
NH2
F
F
5
6 (28%)
7 (16%)
4 (3%)
Scheme 2. Multitrifluoromethylation onto the tetrafluoroisophatalonitrile.
F
F
F
F
F
F
F
CN
CN
CF3
F
CN
CN
CF3
CF3
CN
CN
CF3
CF3
CF3
CN
CF3SiMe3
CuI / KF / DMF
F
F
F
8
9
10
F
F
CF3
CF3
CN
CN
CF3
CF3
CF3
CN
NH2
NH2
3
4
Scheme 3. Reaction mechanism to di- and tri-trifluoromethylated compounds.

T. Kitazume, S. Nakajima / Journal of Fluorine Chemistry 125 (2004) 1447–1449
1449
product 4 was produced. In the present reactions, the decya-
3.3. Trifluoromethylation of tetrafluoroisophthalonitrile
mixture of tetrafluoroisophthalonitrile (1.00 g,
notrifluoromethylation is an example for the substitution of
cyano group by a trifluoromethyl group [8], however it is not
able to explain the mechanism of the decyanotrifluoro-
methylation in present time.
In conclusion, we have found the first example of decya-
notrifluoromethylation to produce the multi functionalized
trifluoromethyl materials.
A
5 mmol), trifluoromethyltrimethylsilane (0.85 g, 6 mmol),
potassium fluoride (0.35 g, 6 mmol) and copper iodide
(1.43 g, 7.5 mmol) in DMF (5 ml) and NMP (5 ml) was
heated at 80 8C, and worked-up similarly. The yield was
determined by the 19F NMR integral intensities using ben-
zotrifluoride as an internal standard. Products were purified
by column chromatography on silica gel using a mixture of
hexane-ethyl acetate (4:1), giving compounds 4, 6 and 7.
3. Experimental
3.1. General
3.3.1. Compound 7
1H NMR (CDCl3): d 5.60. 19F NMR (CDCl3): d 36.6 (1 F,
All commercially available reagents were used without
1
quartet, JFÀ CF ¼ 21.5 Hz), 103.0 (fCF3 ꢀ 2, doublet,
f
3
further purification. Chemical shifts of H (300 MHz) and
J ¼ 21:5 Hz) ppm from internal C6F6. 13C NMR
(CD3COCD3): d 99.766, 113.044, 122.282 (q, J ¼ 274:8
Hz), 126.319 (d, J ¼ 15:2 Hz), 126.871 (d, J ¼ 15:5 Hz),
148.853 (d, J ¼ 254:5 Hz), 152.815. Anal. Calcd. for
C10H2F7N3, C, 40.42, H, 0.68, N, 14.14. Found C, 40.29, H,
0.80, N, 13.92.
13C NMR (75 MHz) spectra were recorded in ppm (d)
downfield from the following internal standard (Me4Si, d
0.00) in CDCl3. The 19F (282 MHz) NMR spectra were
recorded in ppm downfield from internal standard C6F6 in
CDCl3 using a VXR 300 instrument.
3.2. Trifluoromethylation of tetrafluorophthalonitrile
References
A mixture of tetrafluorophthalonitrile (1.00 g, 5 mmol),
trifluoromethyltrimethylsilane (0.85 g, 6 mmol), potassium
fluoride (0.35 g, 6 mmol) and copper iodide (1.43 g,
7.5 mmol) in DMF (5 ml) and NMP (5 ml) was heated at
80 8C. After heating for 8 h, the mixture was quenched with
aq. NH4OH, and then the products were extracted with
diethyl ether. The organic layer was dried over anhydrous
MgSO4, and then the solvent was removed. The yield was
determined by the 19F NMR integral intensities using ben-
zotrifluoride as an internal standard. Products were purified
by column chromatography on silica gel using a mixture of
hexane–ethyl acetate (4:1), giving compounds 2–4.
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3
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