Trifluoromethylation of carbonyl compounds with sodium trifluoroacetate

Article abstract of DOI:10.1016/j.jfluchem.2005.04.012

In the presence of copper(I) iodide as catalyst, a variety of carbonyl compounds, such as aldehydes, ketones and acid anhydrous, could be trifluoromethylated with sodium trifluoroacetate to give the corresponding alcohols in moderate to high yields, and a possible mechanism was proposed to explain the roles of catalyst and solvent in the reaction system.

Full text of DOI:10.1016/j.jfluchem.2005.04.012

Journal of Fluorine Chemistry 126 (2005) 937–940
www.elsevier.com/locate/fluor
Trifluoromethylation of carbonyl compounds
with sodium trifluoroacetate
*
Ying Chang , Chun Cai
a
School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiaoling Wei, Nanjing 210094, China
Received 24 February 2005; received in revised form 11 April 2005; accepted 12 April 2005
Abstract
In the presence of copper(I) iodide as catalyst, a variety of carbonyl compounds, such as aldehydes, ketones and acid anhydrous, could be
trifluoromethylated with sodium trifluoroacetate to give the corresponding alcohols in moderate to high yields, and a possible mechanism was
proposed to explain the roles of catalyst and solvent in the reaction system.
#
2005 Elsevier B.V. All rights reserved.
Keywords: Trifluoromethylation; Sodium trifluoroacetate; Carbonyl compounds; Mechanism
1
. Introduction
functions, despite of the great interest of carbonyl
compounds in trifluoromethylation.
Recently, an increasing interest has been focused on
In the pioneering paper [6], we have reported our
preliminary work on the trifluoromethylation of aldehydes
with sodium trifluoroacetate to afford the corresponding
trifluoromethylated alcohols in high yields. The ready
availability of this cheap and environmental benign reagent
led us to consider the further applications its use in the
trifluoromethylation of carbonyl compounds. In this paper,
we would like to describe the extension of our systematic
studies on the reaction of sodium trifluoroacteate with
carbonyl compounds, including aldehydes, ketones, acetyl
chloride and acid anhydrides. Various kinds of catalysts and
solvents were examined to determine the mechanism of the
trifluoromethylation reaction, and a possible mechanism
was proposed to explain the roles of catalyst and solvent in
the reaction system.
the trifluoroemthylation, because the introduction of the
trifluoromethyl group into an organic compound can cause
remarkable changes in the physical, chemical and biological
properties that results in new compounds/materials making
them suitable for diverse applications in the areas of material
science, agrochemistry and pharmaceuticals [1].
In the previous reports, trifluoromethylation of carbonyl
compounds was described on the basis of two methodol-
ogies: (1) addition of a trifluoromethyl group to the carbonyl
carbon through Ruppert–Prakash reagents [1–2], Barbier
procedure [3] and electrochemical methods [4] and (2)
substitution of a hydrogen atom or alkyloxy group [1,3].
These methods, however, generally suffer from the use of
toxic and expensive reagents or severe experimental
conditions requirements. Sodium trifluoroacetate constitutes
an ubiquitous and powerful tool for the introduction of a
trifluoromethyl moiety into organic substrates [5]. Never-
theless, though the reaction of sodium trifluoroacetate with
aromatic halides has been comparably extensively studied,
little work has been focused on its reaction with carbonyl
2. Results and discussion
To verify the applications of sodium trifluoroacetate
as a trifluoromethylating agent for carbonyl compounds
(
Scheme 1), aromatic and aliphatic aldehydes and ketones
were chosen as the substrates, and the results were
summarized in Table 1.
*
Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: chyingxia@163.com (Y. Chang).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.04.012

938
Y. Chang, C. Cai / Journal of Fluorine Chemistry 126 (2005) 937–940
Table 2
Trifluoromethylation of benzaldehyde with different catalysts and solvents
a
Yield (%)
Entry
Solvent
Catalyst
x (equivalent)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
–
–
59.8
85.1
99.2
98.1
96.9
96.8
82.5
82.2
Trace
Trace
41.9
Trace
42.7
CuI
CuI
CuBr
CuCl
0.5
1
1
Scheme 1. Trifluoromethylation of aldehydes and ketones with sodium
trifluoroacetate.
1
CuBr
Cu
2
1
1
Zn
1
We can obviously see from Table 1 that a wide range of
carbonyl compounds, including aromatic aldehydes and
aliphatic ketones, can undergo smooth condensation with
sodium trifluoroacetate to give trifluoromethylated alcohols
in reasonably high yields. Under these conditions, however,
acetophenone was trifluoromethylated to afford the corre-
sponding carbinol in 2.3% yield, and only trace amount of
desired product was obtained in the reaction of methyl
benzoate with sodium trifluoroacetate. Moreover, improve-
ment of the reaction conditions, such as initiators to the
system, the amount of catalyst and the reaction time, did not
significantly enhance the yields. The results show that steric
hindrance, especially the strongly electron-donating groups
adjacent to the carbonyl (alkoxy for example), is a limiting
factor in the reactions of sodium trifluoroacetate under these
CuI
CuI
CuI
CuI
CuI
1
1
1
1
0
1
2
Pyridine
NMP
1
1
CH
THF/DMF
Isolated yields.
3
CN
1
b
13
a
1
b
THF/DMF = 1:1 (v/v).
As shown in Table 2, various kinds of copper compounds,
including CuI, CuBr, CuBr and copper and zinc powder
2
could effectively catalyze the reaction of benzaldehyde and
sodium trifluoroacetate to give desired product in good
yields. In our experiments, moreover, it was observed that
bezaldehyde could smoothly react with sodium trifluor-
oacetate in the absence of any catalysts to afford reasonably
high yield 59.8% (entry 1, Table 2). This result shows that
benzaldhyde is sufficient to react with the trifluoro-methyl
anion generated from the decarboxylation of sodium
trifluoroacetate. The presence of catalyst might promote
the reaction through the formation of trifluoromethyl–metal
complex as an intermediate, which favors the further
decarboxylation of sodium trifluoroacetate and the follow-
ing addition of trifluoromethyl or its equivalent to substrates.
In our experiments, N,N-dimethylformamide (DMF) was
found to be the most suitable solvent for this reaction.
Only trace amounts of trifluoromethyl products, however,
were obtained when tetrahydrofuran (THF), pyridine and
acetonitrile were employed as solvent instead of DMF.
This low yield maybe partly due to the low boiled points
of the solvent, but the still poor yield in the case of N-
methylpyrrolidone (NMP) denied this opinion. Meanwhile,
conditions. The reason may lie in the fact that the CF group
3
has an electronegativity similar to that of oxygen [7]. Thus, it
appears that the present trifluoromethylation method is not
suitable for such compounds possessing strongly electron-
donating groups.
According to the literature, there are mainly two different
views on the intermediate formed in the trifluoromethyla-
tion: one is, the formation of an intermediate trifluoromethyl
ꢀ
metal, CF Cu or CF CuI [5,8]; the other is that, the
3
3
trifluoromethyl anion generated in the reaction was soon
trapped in situ by the carbonyl moiety of DMF to form the
gem-aminoalcoholate [9].
To determine the mechanism of the reaction of sodium
trifluoroacetate with carbonyl compounds, different cata-
lysts and solvents were explored and the results were
summarized in Table 2.
Table 1
Trifluoromethylation of aldehydes and ketones with sodium trifluoroacetate
a
b
Yield (%)
Entry
R
1
R
2
Product
Reaction temperature (8C)
Reaction/hydrolysis time (h)
1
2
3
4
5
6
7
8
C
6
H
5
H
2a
2b
2c
2d
2e
2f
2g
2h
2a
170
170
170
170
180
160
160
170
170
2/4
2/4
2/4
2/4
2/4
2/4
2/4
2/4
99.2
98.6
96.0
85.8
2.3
4-Cl–C
6
H
4
H
4-Me–C
n-Pr
6
H
4
H
H
C
6
H
5
CH
CH
CH
CH
3
3
3
3
c
CH
3
73.5
c
C
C
C
2
3
6
H
5
H
7
H
5
53.7
c
43.9
d
c
9
OCH
3
6/–
Trace
a
All the reaction was catalyzed by CuI.
Isolated yields.
b
c
d
DMF 20 ml.
Without hydrolysis.

Y. Chang, C. Cai / Journal of Fluorine Chemistry 126 (2005) 937–940
939
Scheme 2. Mechansim for the trifluoromethylation of carbonyl compounds
with sodium trifluoroacetate.
Scheme 3. Trifluoromethylation of benzoyl chloride and benzene sulphonyl
chloride.
when THF/DMF was employed as the solvent, bezaldehyde
could react with sodium trifluoroacetate to afford the
corresponding trifluoromethyl carbinol in 42.7% yield (entry
Acid anhydrous also showed good reactivity via the
hydrolysis of reaction mixture, and surprisingly that, only
the mono-adducts were obtained in 67.4% yield (Eq. (3)).
1
3, Table 2). Such results underlined the crucial role of DMF
during the trifluoromethylation with sodium trifluoroacetate,
and from the mechanistic point of view, it can be reasonably
to assume that DMF takes a positive role in the generation of
trifluoromethyl anion or transferring it to the carbonyl group,
in a way which is similar to Foll e´ as et al. [9] (Scheme 2). This
mechanism was supported by the observation that a little
amount of N,N-dimethyltrifluoroacetamide obtained as side
product when DMF was used as solvent.
(
3)
In summary, a concise and convenient method for the
trifluoromethylation of carbonyl compounds with easily
prepared and commercially available sodium trifluoroace-
tate has been developed. We believe that this methodology
would be widely used in organofluorine chemistry as a novel
and efficient trifluoromethylation reaction.
Having established that sodium trifluoroacetate is a
versatile reagent to prepare trifluoromethyl-substituted
carbinols from aldehydes and ketones, we set out to explore
a number of reactions of sodium trifluoroacetate with other
substrates containing other carbonyl functional groups. We
first examined the acetyl chloride for its reactivity toward
sodium trifluoroacetate with copper(I) iodide catalysis in
DMF. Indeed, acetyl chloride reacts smoothly with sodium
trifluoroacetate under above conditions (Eq. (1)), and the
yield (4) amounted to 62.9%.
3. Experimental
Sodium trifluoroacetate was prepared by treatment of
sodium hydroxide and equivalent trifluoroacetic acid and
dried in vacuo before storage under nitrogen. All the other
reagents and solvents were further dried prior to use.
CuX=DMF
CH3COCl þCF3COONa ꢀ! CH3COCF3 þCO2
(1)
1
3
4
IR was recorded on Bumen MB154S infrared analyzer. H
NMR spectra were measured on Bruke Advance DMX500.
Mass spectra were obtained on Saturn 2000 GC/MS
instrument.
Analogous result was obtained when benzene sulphonyl
chloride was employed as substrate, and the yield of the
trifluoromethyl sulfone (6) was 83.5% (Eq. (2)).
CuX=DMF
C6H5SO2Cl þCF3COONa ꢀ! C6H5SO2CF3 þCO2
3.1. General experimental procedure
5
6
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
(
2)
Moreover, it was demonstrated that our novel trifluoro-
methylation of carbonyl compounds by reaction with sodium
trifluoroacetate in the presence of copper(I) halides is also
applicable for benzoyl chloride, but the products were highly
dependent on the treatment of the reaction mixture. The
results showed that hydrolysis of the reaction mixture with
aqueous HCl leads to the formation of the mixture of
trifluoromethyl carbinol (2a, 43.5%) and bis-trifluro-methyl
carbinol (9, 56.5%), while trifluoromethyl ketone was formed
exclusively (8, 80.3%) without hydrolysis (Scheme 3).
added thoroughly dried CF COONa (4.9 g and 36 mmol),
3
N,N-dimethylformamide(DMF)30 ml,benzaldehyde(0.9 ml
and 9 mmol) and copper(I) iodide (1.71 g and 9 mmol). The
flaskwassubmergedinanoilbathpreheatedto170 8C,andthe
reaction mixture was stirred for 2 h under the protection of
nitrogen atmosphere. The flask was then cooled to a lower
temperature, aqueous HCl (12 M and 1 ml) was quickly
added, and the mixture was vigorously stirred for a further 4 h
at 170 8C. After completion of the reaction, distillation was

940
Y. Chang, C. Cai / Journal of Fluorine Chemistry 126 (2005) 937–940
[
2] (a) R. Krishnamurti, D.R. Bellew, G.K.S. Prakash, J. Org. Chem. 56
performed to afford the crude product. The solvent was
removed under reduced pressure and the residue was purified
by silica gel column chromatograph. Isolated yields are given
inTables1and2.Thepreparedcompoundswerecharacterized
on the basis of analytical and spectroscopic data [10], and
some analytic data were compared with the published
observations [1,11]. Selected data are given below.
(
(
(
1991) 984;
b) S.P. Kotun, J.O. Anderson, D.D. DesMarteau, J. Org. Chem. 57
1992) 1124.
[
3] (a) M. Tordeux, C. Francese, C. Wakselman, J. Chem. Soc., Perkin
Trans. 1 (1990) 1951;
(
(
(
b) C. Franc e` se, M. Tordeux, C. Wakselman, Tetrahedron Lett. 29
1988) 1029;
c) C. Franc e` se, M. Tordeux, C. Wakselman, J. Chem. Soc., Chem.
Commun. 9 (1987) 642.
1
Phenyl-2,2,2-trifluoroethanol (2a): H NMR (300 MHz,
TMS, CDCl ): d 7.45 (m, 5H), 4.9 (q, 1H), 3.1 (OH); IR
[
[
4] (a) T. Shono, M. Ishifune, T. Okada, S. Kashimura, J. Org. Chem. 56
(1991) 2;
3
ꢀ
1
KBr) y 3405, 1500, 1460, 1268, 1175, 1130 cm ; MS (EI)
(
b) T. Kitazume, T. Ikeya, J. Org. Chem. 53 (1988) 2349;
(c) R. Barhdadi, M. Troupel, J. P e´ richon, Chem. Commun. 5 (1998)
251.
(
m/z: 107 (M-69, 100), 176 (M , 7.5), 79 (M-17-69, 60).
+
1
1
2
,2,2-Trifluoro-1-(4-chlorophenyl)ethanol (2b): H NMR
300 MHz, TMS, CDCl ): d 7.5 (m, 4H), 5.0 (q, 1H), 3.1
5] (a) M. Kiyohide, T. Etsuko, A. Midori, K. Kiyosi, Chem. Lett. 10
(1981) 1719;
(
3
(
OH); IR (KBr): y 3400, 1605, 1500, 1270, 1170,
(b) G.E. Carr, R.D. Chambers, T.F. Holmes, J. Chem. Soc., Perkin
Trans. 1 (1988) 921.
ꢀ
1
+
135 cm ; MS (EI) m/z: 210, 212 (M , 32.5, 10), 141,
1
1
2
[
[
[
6] Y. Chang, C. Cai, Tetrahedron Lett. 46 (2005) 3161.
7] J.A. Ma, D. Cahard, Chem. Rev. 104 (2004) 6119.
8] (a) K. Yoshiro, K. Itsumaro, J. Chem. Soc., Perkin Trans. 1 (1980)
661;
43(M-69, 100, 42.5), 113,115(M-17-69, 32.5,12), 77 (80).
1
,2,2-Trifluoro-1-(4-methylphenyl)ethanol (2c): H NMR
300 MHz, TMS, CDCl ): d 7.0–7.31 (m, 4H), 2.39 (s, 3H),
3
(
2
1
1
1
.84 (q, 1H), 3.2 (OH); IR (KBr): y 3375, 2870, 1540, 1280,
ꢀ
(b) D.M. Wiemers, D.J. Burton, J. Am. Chem. Soc. 108 (1986)
1
+
+
8
32;
c) J.X. Duan, Q.Y. Chen, J. Chem. Soc., Perkin Trans. 1 (1994)
25;
d) Q.Y. Chen, J.X. Duan, Tetrahedron Lett. 34 (1993) 4241;
185 cm ; MS (EI) m/z: 190 (M , 20), 121 (M ꢀ CF ,
3
(
00), 91 (60).
7
1
-Methyl-1-phenyl-2,2,2-trifluoroethanol (2e): H NMR
(
(
300 MHz, TMS, CDCl ): d 7.7–7.2 (m, 5H), 3.2 (OH),
3
(e) Q.Y. Chen, J.X. Duan, J. Chem. Soc., Chem. Commun. 18 (1993)
ꢀ
1
.7 (3H); IR (KBr): y 3440, 1290, 1275, 1170 cm ; MS
1
1389.
9] (a) B. Foll e´ as, I. Marek, J.F. Normant, S.J. Laurent, Tetrahedron 56
+
[
(
EI) m/z: 190 (M , 0.9), 121 (M-69, 100).
-Hydroxy-3-(trifluoromethyl)phthalide (11):
300 MHz, TMS, CDCl ): d 8.0–7.5 (m, 4H), 4.4 (OH);
1
(2000) 275;
b) B. Foll e´ as, I. Marek, J.F. Normant, S.J. Laurent, Tetrahedron Lett.
3
H NMR
(
(
3
3
9 (1998) 2973.
ꢀ
1
+
+
IR (KBr): y 3350, 1765, 1605 cm ; MS (EI) m/z: 219
+
[
10] MS (EI) m/z: (2d): 141 (M ꢀ H, 30), 110 (M ꢀ CH
2
OH, 12), 72
+
+
+
+
+
(
M + H, 57), 201 (M ꢀ OH, 13), 149 (M ꢀ CF , 100),
(M ꢀ CF
3
ꢀH, 21), 44 (100); (2f): 127 (M ꢀ H, 15), 58 (M ꢀ CF
3
–
3
+
+
+
H, 100), 44 (77); (2g): 141 (M ꢀ H, 52), 110 (M ꢀ CH
2
OH, 3), 72
1
21 (M ꢀ CF –CO, 22), 93 (15).
3
+
+
+
(
M ꢀ CF
3
–H, 100); (2h): 156 (M , 3), 87 (10), 70 (M ꢀ CF
3
–OH,
+
+
+
1
1
1
7), 44 (100); (4): 112 (M , 35), 43 (M ꢀ CF
3
, 100); (6): 210 (M , 8),
+
+
+
References
41 (M ꢀ CF
3
, 75), 93 (100); (8): 175 (M + H, 95), 105 (M ꢀ CF
3
,
+
+
+
00), 77 (C
+
6
H
5
, 35); (9): 244 (M , 18), 175 (M ꢀ CF
3
, 100), 105
+
[
1] (a) S. Large, N. Roques, B.R. Langlois, J. Org. Chem. 65 (2000) 8848;
b) R.P. Singh, G.F. Cao, R.L. Kirchmeier, J.M. Shreeve, J. Org.
Chem. 64 (1999) 2873.
(M ꢀ CF
3
–CF
3
, 97), 77 (C
6
H
5
, 30).
(
[11] G.K.S. Prakash, R. Krishnamurti, G.A. Olah, J. Am. Chem. Soc. 111
(1989) 393.