Sodium trifluoroacetate: An efficient precursor for the trifluoromethylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2005.03.072

In a convenient and efficient procedure, the nucleophilic trifluoromethylation of aldehydes with sodium trifluoroacetate was achieved, using copper(I) halides as the catalyst.

Full text of DOI:10.1016/j.tetlet.2005.03.072

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3161–3164
Sodium trifluoroacetate: an efficient precursor for the
trifluoromethylation of aldehydes
*
Ying Chang and Chun Cai
School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiaoling Wei, Nanjing 210094, China
Received 16 December 2004; revised 10 March 2005; accepted 13 March 2005
Available online 26 March 2005
Abstract—In a convenient and efficient procedure, the nucleophilic trifluoromethylation of aldehydes with sodium trifluoroacetate
was achieved, using copper(I) halides as the catalyst.
Ó 2005 Elsevier Ltd. All rights reserved.
Due to the peculiar chemical and biological properties
of organic compounds containing trifluoromethyl
group, considerable efforts have been devoted to develop
effective methods for introducing CF3 group into
organic molecules. To date, trifluoromethylation has
been mainly based on the five methods: (1) generation
agent for aromatic halides and has been reported in
8
numerous papers.
In the recent years, aldehydes are of great interest in the
research of trifluoromethylation, and in most cases,
CF TMS was employed as the trifluoromethylating re-
3
1
9
of the trifluoromethyl radicals from precursors; (2) use
2
of trifluoromethyl-copper (or -cadmium, -zinc, etc.);
agent. Consideration of the comparable performance
of sodium trifluoroacetate with the Ruppert reagents
in the reaction with aromatic halides and the high
reactivity of Ruppert reagents towards aldehydes,
we envisaged that it could be also employed as a
trifluoromethylating agent in the reaction with aromatic
carbonyl compounds, especially with aldehydes.
(
etc.) systems; (4) electrochemical methods; (5) indirect
3) Ruppert reagent CF SiMe /KF (Me NF, t-BuOK,
3 3 4
3
4
routes, such as halogen exchange of CCl with HF/
3
5
SbF . These methods, however, generally suffer from
5
the use of toxic or expensive reagents, some of which
are inconvenient to handle. Therefore, it is still a chal-
lenge to develop new efficient precursors of trifluoro-
methyl group and selectively introduce them into the
desired position of organic molecules.
In this letter, we would like to describe a novel trifluo-
romethylation route for aldehydes with sodium trifluo-
roacetate, using copper(I) halides as the catalyst
(
Scheme 1). To the best of our knowledge, there is no
Sodium trifluoroacetate was first reported by Kiyohide
et al. as a trifluoromethylating agent for aromatic
halides, and latter Hitomi et al. studied the reaction
7
of sodium trifluoroacetate with nonactivated iodoarenes.
Based on these pioneering work, we further researched
the copper(I) iodide catalyzed trifluoromethylation of
aromatic halides, and it was shown that the electron-
withdrawing substituents, such as nitro group, favored
the trifluoromethylation. Besides sodium trifluoroace-
related report on the trifluoromethylation of aldehydes
with sodium trifluoroacetate.
6
Sodium trifluoroacetate was prepared by treatment of
sodium hydroxide with an equivalent of trifluoroacetic
O
tate, CF TMS is also an effective trifluoromethylating
3
i. CuX/DMF HO
CF
R
3
CF
3
COONa
CO2
ii. H
3
O+
Ar
R
Ar
R=H, CH
X=I, Br, Cl
3
;
Keywords: Trifluoromethylation; Nucleophilic addition; Sodium tri-
fluoroacetate; Aldehyde.
*
Corresponding author. Tel.: +86 25 84315514; fax: +86 25
4315030; e-mail: chyingxia@163.com
Scheme 1. Trifluoromethylation of aldehydes and ketones with sodium
trifluoroacetate.
8
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.072

3162
Y. Chang, C. Cai / Tetrahedron Letters 46 (2005) 3161–3164
acid and dried in vacuo before storage under nitrogen.
All other reagents and solvents were further dried prior
to use.
intrigued by the effects of KF and t-BuOK. In an at-
tempt to enhance the reactivity of ketone, both of them
were examined in this trifluoromethylation system,
respectively. The results, however, were not significantly
improved.
The results reported in Table 1 deserved several com-
ments: benzaldehyde exhibited fairly good reactivity in
the trifluoromethylation, and the yield amounted to
The possible reaction mechanism might involve the
nucleophilic addition of trifluoromethyl anion or some
kinds of its complexes generated in situ. Evolution of
9
9.2%. Reasonably high yields were obtained when tolu-
aldehyde (o-, m-, and p-) and chlorobenzaldehyde (o-,
m-, and p-) were employed as substrates, and as could
be seen from the results summarized in Table 1 that,
the yields of chlorobenzaldehydes were a little higher
than that of tolualdehydes. Cyclohexanecarboxaldehyde
also showed high reactivity under the experimental con-
ditions and the yield amounted to 95.7%. Although
cyclohexanone could be trifluoromethylated to give the
corresponding alcohol in 56.7% yield, rather low yield
was obtained when acetophenone was used as substrate.
CO began at around 140 °C, which was in accordance
2
6
with the result reported by Kiyohide et al.
Various kinds of copper compounds, such as CuI, CuCl,
CuBr, CuBr , and Cu, were examined as the copper
2
source in this system (Table 2). The results showed that,
the product was obtained in 85.1% when 0.5 equiv CuI
was used, and increasing the amount of catalyst led to
a higher yield. While copper(I) iodide was found to be
the most effective for this purpose, considerable amount
of the trifluoromethylated products could be obtained
when the other copper compounds were employed as
the catalysts. As the results indicated that, there was
Initiators, such as potassium fluoride and potassium
tert-butoxide (t-BuOK), are generally used with silane
trifluoromethylating reagents. In this regards, we were
Table 1. Trifluoromethylation of aldehydes and ketones with sodium trifluoroacetate
b
Mass spectra data (m/z)
Carbonyl compounds Product
Conditions (time/h)
Overall
a
yield (%)
Trifluoromethylation Hydrolysis
+
1
07 (MÀ69, 100) 176 (M , 7.5)
CHO
CH CF
3
2
4
99.2
92.4
1
2
79 (MÀ96, 60)
OH
CH3
CH3
+
2
4
190 (M , 8), 121 (MÀ69, 90),
CH CF3
OH
CHO
9
1 (MÀ99, 100), 93 (MÀ97, 85)
CH3
CH3
CH3
+
3
2
2
2
4
4
4
82.7
96.0
96.7
190 (M , 38), 121 (MÀ69, 100),
CH CF3
OH
CHO
9
1 (MÀ99, 77), 93 (MÀ97, 85)
CH3
CH CF
3
+
CHO
4
190 (M , 20), 121 (MÀ69, 100),
OH
91 (MÀ99, 60), 93 (MÀ97, 60)
Cl
Cl
+
210, 212 (M , 13, 5,) 141, 143
5
CH CF3
OH
CHO
(
(
MÀ69, 100, 40), 113, 115
MÀ97, 35, 10), 77 (85), 58 (100)
Cl
Cl
Cl
Cl
+
210, 212 (M , 18, 5,) 141, 143
6
CF3
2
2
4
4
86.8
98.6
CH
OH
CHO
(
(
MÀ69, 38, 15), 113, 115
MÀ97, 25, 8), 77 (35)
CH
OH
CF3
+
210, 212 (M , 32.5, 10), 141, 143
CHO
7
(MÀ69, 100, 42.5), 113, 115
(
MÀ97, 32.5,12), 77 (80)
CH CF3
OH
+
CHO
O
8
2
2
4
4
95.7
56.2
182 (M , 1), 113 (MÀ69, 2), 83 (100)
OH
9
+
168 (M , 0.1), 99 (MÀ69, 100)
CF3
OH
O
C
+
C
CH3 10
2
6
2.3
190 (M , 0.9), 121 (MÀ69, 100)
CH3
CF3
a
The yields were calculated from GLC of the mixture by incorporating an internal standard.
Mass data was obtained on Saturn 2000 GC/MS instrument, only selected data are shown.
b

Y. Chang, C. Cai / Tetrahedron Letters 46 (2005) 3161–3164
3163
Table 2. Trifluoromethylation of benzaldehyde with different catalysts
thoroughly dried CF COONa (4.90 g, 36 mmol), N,N-
3
a
1 (%)
dimethylformamide (DMF) 30 mL, benzaldehyde
Entry
Catalyst
x (equiv)
(
0.9 mL, 9 mmol), copper(I) iodide (1.71 g, 9 mmol).
The flask was submerged in an oil bath preheated to
70 °C, and the reaction solution was stirred for 2 h un-
1
2
3
4
5
6
7
—
—
0.5
1
59.8
85.1
99.2
98.1
96.9
96.8
82.5
CuI
CuI
CuBr
CuCl
1
der the protection of nitrogen atmosphere. The flask was
then cooled to a lower temperature, aqueous HCl (12 M,
1 mL) was quickly added, and the mixture was vigor-
ously stirred for a further 4 h at 170 °C. After comple-
tion of the reaction, distillation was performed to
afford the crude products. The solvent was removed
under reduced pressure and the residue was purified by
silica gel column chromatography. The prepared com-
pounds were characterized on the basis of analytical
1
1
CuBr
Cu
2
1
1
a
The yields were calculated from GLC of the mixture by incorporating
an internal standard.
not much difference between the effects of copper(I)
halides and copper(II) bromide, nevertheless, consider-
able lower yield was obtained when copper powder was
used as the catalyst. It should be pointed out that, when
benzaldehyde was employed as the substrate, the
reaction could go on smoothly in the absence of any
catalysts mentioned above, and the yield was 59.8%,
though lower than that of the typical procedure.
1
2
and spectroscopic data.
Further studies on examining the reaction mechanism
and improving the experimental conditions as well as
the scope and applicabilities of this method to esters
and sulfur containing compounds, are currently in pro-
gress in our group and will be published in due course.
With these results in hand, we then performed the trifluo-
romethylation reaction with a more extensive range of
carbonyl compounds, and benzoyl chloride was first
examined as the substrate (Scheme 2).
References and notes
1
2
. (a) Birchall, J. M.; Geoffrey, P. I.; Robert, A. B. J. Chem.
Soc., Perkin Trans. 2 1975, 435–439; (b) Lai, C.; Thomas,
E. M. J. Chem. Soc., Chem. Commun. 1993, 1359–1361; (c)
Tordeux, M.; Langlois, B.; Wakselman, C. J. Chem. Soc.,
Perkin Trans. 1 1990, 2293–2299.
. (a) Qing, F. L.; Zhang, X. G.; Peng, Y. Y. J. Fluorine
Chem. 2001, 111, 185–187; (b) Kobayashi, Y.; Yamamoto,
K.; Toyohira, A.; Masanori, N.; Itsumaro, K. J. Chem.
Soc., Perkin Trans. 1 1980, 2755–2761; (c) James, H. C.;
McClinton, M. A.; Jones, C. W.; Landon, P.; Bishop, D.;
Blade, R. J. Tetrahedron Lett. 1989, 30(6), 2133–2136.
. (a) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56,
When benzoyl chloride was employed as the substrate
under the experimental conditions, 2,2,2-trifluorophenyl-
ethanol (1, 43.5%) was obtained together with a,a-
bis(trifluoromethyl)-benzyl alcohol (11, 56.5%) MS:
+
+
+
2
7
44 (M , 24), 175 (M À69, 95), 105 (M À138, 100),
+
7 (M À166, 26).
In summary, the present reaction of sodium trifluoroace-
tate with aldehydes catalyzed by copper(I) halides was
found to be an excellent method for trifluoromethyl-
ation. This method has the following attractive character-
istic features: (a) the reaction can be carried out without
use of special apparatus, such as electrochemical equip-
ments, (b) the reaction gives good to excellent yields, (c)
sodium trifluoroacetate is a solid (mp 206 °C) and can
be easily handled at ambient temperature, whereas
3
4
7
613–7618; (b) Prakash, G. K. S.; Mandal, M. J. Fluorine
Chem. 2001, 112, 123; (c) Prakash, G. K. S.; Yudin, A. K.
Chem. Rev. 1997, 97, 757–786.
. (a) Sibille, S.; Mcharek, S.; Perichon, J. Tetrahedron 1989,
4
5(5), 1423–1428; (b) Rarhdadi, R.; Troupel, M.; P e´ ri-
chon, J. Chem. Commun. 1998, 1251–1252; (c) Dmowski,
W.; Biernacki, A. J. Fluorine Chem. 1996, 78, 193–194.
CF TMS, a well known trifluoromethylating reagent,
3
is expensive and troublesome to use in laboratories, nev-
ertheless, the technology suffers from the fact that,
5. Debarge, S.; Violeau, B.; Bendaoud, N.; Jouannetaud,
M. P.; Jacquesy, J. C. Tetrahedron Lett. 2003, 44, 1747–
1750.
1
0
CF TMS is presently prepared from ecotoxic CF Br,
3
3
6
7
8
. Kiyohide, M.; Etsuko, T.; Midori, A.; Kiyosi, K. Chem.
Lett. 1981, 1719–1720.
. Hitomi, S.; Yoshiki, Y.; Atsuhiro, O. Chem. Lett. 1982,
(
d) copper(I) halides and copper powder, in contrast
to other catalysts, such as palladium compounds
1
1
Pd(OAc) , Pd(PPh ) , are easily accessible.
2 3 4
1
35–136.
. (a) Hisao, U.; Takamasa, F. Tetrahedron Lett. 1991, 32(1),
1–94; (b) Kitazume, T.; Nakajima, S. J. Fluorine Chem.
2004, 125, 1447–1449.
General experimental procedure: To a 100 mL four-
necked round bottomed flask equipped with a mechanic
stirrer, thermometer, reflux condenser attached to an
inlet for maintaining inert nitrogen was quickly added
9
9. (a) Prakash, G. K. S.; Krishnamuri, R.; Olah, G. A. J.
Am. Chem. Soc. 1989, 111, 393–395; (b) Sevenard, D. V.;
Sosnovskikh, V. Y.; Kolomeitsev, A. A.; K o¨ nigsmann, M.
H.; R o¨ schenthaler, G. V. Tetrahedron Lett. 2003, 44,
7
623–7627; (c) Kotum, S. P.; Anderson, J. D. O.;
O
OH
HO
Ar
CF
CF
3
3
DesMarteau, D. D. J. Org. Chem. 1992, 57, 1124–1131;
(d) Singh, R. P.; Cao, G. F.; Kirchmeier, R. L.; Shreeve, J.
M. J. Org. Chem. 1999, 64, 2873–2876.
i. CuX/DMF
ii. H
3
O+
CF
3
COONa
Ar CH CF3
CO2
Ar
R
1
0. Large, S.; Roques, N.; Bernard, R. L. J. Org. Chem. 2000,
6
Ar= Ph, R= Cl
1
11
5, 8848–8856.
11. Kitazume, T.; Ishikawa, N. J. Am. Chem. Soc. 1985,
107(18), 5186–5191.
Scheme 2. Trifluoromethylation of benzoyl chloride with sodium
trifluoroacetate.

3164
Y. Chang, C. Cai / Tetrahedron Letters 46 (2005) 3161–3164
1
2. Selected data: compound 1: H NMR (300 MHz, CDCl
1
3
):
3
NMR (300 MHz, CDCl ): d 3.64 (m, 1H), 2.74 (m, 1H),
d 7.45 (m, 5H), 4.9 (q, 1H), 3.1 (OH); IR (KBr): m 3405,
1.82 (m, 1H), 1.77–1.58 (m, 5H), 1.28–1.03 (m, 5H); IR
(KBr): m 3410, 1445, 1280, 1165, 1130 cm . Compound 9:
À1
1
À1
1
500, 1460, 1268, 1175, 1130 cm . Compound 4:
): d 7.0–7.31 (m, 4H), 2.39 (s,
H), 2.84 (q, 1H), 3.2 (OH); IR (KBr): m 3375, 2870, 1540,
H
1
NMR (300 MHz, CDCl
3
1
3
H NMR (300 MHz, CDCl
3
): d 1.00–1.19 (m, 10H), 1.93
À1
(br s, 1H); IR (KBr): m 3365 (s), 1280 (s), 1140 (s) cm
.
À1
1
1
280, 1185 cm . Compound 7: H NMR (300 MHz,
3
Compound 10: H NMR (300 MHz, CDCl ): d 7.7–7.2
CDCl ): d 7.5 (m, 4H), 5.0 (q, 1H), 3.1 (OH); IR (KBr): m
3
(m, 5H), 3.2 (OH), 1.7 (3H); IR (KBr): m 3445, 1290, 1275,
3
À1
1
400, 1605, 1500, 1270, 1170, 1135 cm . Compound 8: H
À1
1170 cm
.