A one-pot procedure for trifluoroacetylation of arylamines using trifluoroacetic acid as a trifluoroacetylating reagent

Article abstract of DOI:10.1016/j.tetlet.2009.01.088

A convenient procedure for the preparation of aryl trifluoroacetamides from aryl amines is described that employs 2-4 M equiv of trifluoroacetic acid in refluxing xylene as a trifluoroacetylating agent. Addition of an amount of pyridine that is equimolar to the amount of trifluoroacetic acid present in the reaction mixture facilitates the trifluoroacetylation of rather basic arylamines.

Full text of DOI:10.1016/j.tetlet.2009.01.088

Tetrahedron Letters 50 (2009) 1681–1683
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A one-pot procedure for trifluoroacetylation of arylamines using
trifluoroacetic acid as a trifluoroacetylating reagent
*
Junpei Ohtaka, Takeshi Sakamoto, Yasuo Kikugawa
Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient procedure for the preparation of aryl trifluoroacetamides from aryl amines is described that
employs 2–4 M equiv of trifluoroacetic acid in refluxing xylene as a trifluoroacetylating agent. Addition of
an amount of pyridine that is equimolar to the amount of trifluoroacetic acid present in the reaction mix-
ture facilitates the trifluoroacetylation of rather basic arylamines.
Received 2 December 2008
Revised 27 December 2008
Accepted 9 January 2009
Available online 20 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoroacetylation
Trifluoroacetic acid
Arylamine
Xylene
Pyridine
N-Trifluoroacetylation has become a common and useful procedure
for the protection of a wide variety of amines.1 Ease of removal is one
important factor that has contributed to the many applications of the
N-trifluoroacetyl protecting group in organic chemistry. Because of this
widespread use, several reagents and methods for the trifluoroacetyla-
tion of amines have been developed. Reagents for trifluoroacetamida-
tion that have been reported include, for example, trifluoroacetic
anhydride,1 S-ethyl trifluorothioacetate,2 N-(trifluoroacetyl)imidaz-
ole,3 2-[(trifluoroacetyl)oxy]pyridine,4 trifluoroacetyl triflate,5 N-(tri-
fluoroacetoxy)succinimide,6 (trifluoroacetyl)benzotriazole,7 and N-
(trifluoroacetyl)succinimide.8 Most of these reagents, however, have
drawbacks and limitations due to either formation of undesirable
by-products and/or handling issues on a plant scale. A convenient
method has been developed for the selective 4-dimethylaminopyri-
dine-catalyzed trifluoroacetylation of anilines with ethyl trifluoroace-
tate, but the reaction times are prolonged and the presence of
4-dimethylaminopyridine is essential.9 Recently, a direct microwave-
promoted trifluoroacetylation of anilines with trifluoroacetic acid
(TFA) was reported.10 The reaction was carried out without solvent
and was simple and clean. However, further experiments might be
necessary for the large scale production. Very recently, trifluoroacetyla-
tion of arylamines using trifluoroacetic acid (TFA) and poly-phosphoric
acid trimethylsilylester as the condensation agent was reported.11
For several reasons, it is evident that the use of TFA alone would
be both economically and environmentally advantageous. How-
ever, we found only one published report of this process. This
described the trifluoroacetylation of anilines using TFA alone in
dry ether at 0 °C for 1 h.12
However, following this experimental procedure, we could not
obtain the trifluoroacetylated product (Table 1, entry 5).
Herein, we report a new, convenient, and environmentally
friendly trifluoroacetylation method using TFA as the trifuoroacety-
lating reagent.
Initially, we examined the trifluoroacetylation of aniline (1a)
with TFA in various solvents, and the results are presented in Table 1.
The use of excess TFA provided the TFA salt of aniline and a trace
amount of the desired product (Table 1, entry 3). When the amount of
TFAwas reduced, the yieldwasdramaticallyincreased(Table1,entry1).
NH2
NHCOCF3
R
R
1
2
a: R=H
e
i: R=4-OH
j: R=2-Cl
m
: R=2-OMe
: R=4-COOEt
b
: R=2-Me
f: R=3-OMe
g: R=4-OMe
n: R=2-NO2
c: R=4-Me
k: R=4-Cl
o
: R=3-NO2
d: R=2,6-diMe
h
: R=4-OEt
l: R=2,4,6-triCl
p: R=4-NO2
NHR
3: R=H 4: R=COCF3
NHR
N
* Corresponding author. Tel.: +81 49 271 7680.
E-mail address: kikugawa@josai.ac.jp (Y. Kikugawa).
5
6
: R=H : R=COCF3
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.088

1682
J. Ohtaka et al. / Tetrahedron Letters 50 (2009) 1681–1683
Table 1
solution, the concentration of free amine is reduced because of
formation of the TFA salt and this results in less efficient amide
formation.
Trifluoroacetylation of aniline in various solvents
Entry Aniline
(mmol)
TFA
Solvent
Reaction
time (h)
Reaction
temp (°C)
Product
yield (%)
(mmol) (mL)
A proposed mechanism is illustrated in Scheme 1.
In the case of weak bases such as aniline, in particular anilines
which have an electron-withdrawing substituent, the concentra-
tion of free aniline remains significant and trifluoroacetylation
can proceed with ease.
1
2
3.0
3.0
6.0
6.0
Xylene
(5)
Toluene 3.5
(5)
TFA (5)
THF (5)
Et2O (3) 2.0
3.5
150
94
44
130
3
4
5
2.2
1.1
1.0
—
3.0
1.0
1.5
2.0
100
80
0
—
13
—
On the other hand, in the case of anilines which have an elec-
tron-releasing substituent such as a methoxy or a hydroxyl group,
the equilibrium favors salt formation and unreacted TFA salt re-
mains in the reaction mixture. However, addition of an equimolar
amount of pyridine to TFA is effective in the trifluoroacetylation of
rather strongly basic anilines which have pKa values similar to
those of pyridine (Table 2, entries 6–11). The exact role of pyridine
is not clear. However, it is assumed that the population of free
amines in the reaction mixture increases by the addition of pyri-
dine. Addition of stronger base such as triethylamine is not effec-
tive probably because the TFA salt of triethylamine does not
liberate free TFA during the reaction. In this case, 2a was obtained
in 5% yield and 1a was recovered in 92% yield (Table 2, entry 2).
Aliphatic amines which are more basic than anilines form the tight
TFA salts with TFA and yields of trifluoroacetylation are low even
with addition of pyridine.
On the basis of these preliminary results, the application of this
procedure to various amines was investigated. The results are pre-
sented in Table 2.
Normally, it is assumed that electron-releasing groups in ani-
line facilitate trifluoroacetylation and electron-withdrawing
groups do not. In this case, it is worth noting that the presence
of electron-withdrawing groups such as nitro, ester, and chloro
groups in anilines facilitates the trifluoroacetylation, whereas
the electron-releasing group has less effect and can even retard
trifluoroacetylation. However, use of pyridinium trifluoroacetate
instead of TFA improved the yields substantially in these cases
(Table 2, entries 6–11).
In conclusion, we have developed an economic and environ-
mentally friendly procedure for trifluoroacetylation of anilines
using trifluoroacetic acid as the acetylating reagent. Low cost
and availability of the reagent, and the ease of operation and
workup make this method a useful addition to the available
methodologies.
At high temperature (150 °C), the reaction between TFA and an
amine has two routes, one is to form a salt by nucleophilic attack
of the amine on the hydrogen and the other is to form an amide
by the nucleophilic attack of the amine on the carbonyl carbon.
The presence of a free amine and TFA in the reaction mixture
is required for trifluoroacetamide formation. In excess TFA
Table 2
Trifluoroacetylation of aromatic amines in refluxing xylene13
Entry
Starting compd.
Methoda
Reaction time (h)
Product
Yield (%)
Melting point (°C)
Found
Lit.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1a
1b
1c
1d
1e
1f
1g
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
3
A
A
A
A
B
B
A
B
B
A
B
B
A
A
A
B
A
B
B
A
5.5
6.5
7.0
5.5
5.5
5.0
5.5
6.5
1.5
2.0
6.5
3.5
3.0
5.5
2.5
6.5
2.0
5.5
5.0
3.0
2a
2a
2b
2c
2d
2e
2f
2g
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
4
94 (92)b
5c
86
85
90.5–91
—
89–9014
—
79–79.5
113–113.5
94.5–95
50.5–51
75.5–76
117–117.5
—
144.5–145
172–173
41.5–42
128–128.5
103–103.5
129.5–130
89.5–90
92–92.5
151.5–152
105.5–106
130–130.5
78–7914
11114
65
89–9014
47–4810
7514
72 (95)b
76 (94)b
78 (98)b
53 (88)b
68 (98)b
62 (95)b
89
113–11515
—
141–14315
167–16914
40–4110
123–12416
92
20
88
50
94
89
73
78
17
—
—
17
90.418
94.218
151–15215
102–10314
127–12814
5
6
a
A: TFA (2 equiv) was used. B: TFA (4 equiv) was used.
Figures in parentheses indicate the yields using pyridinium trifluoroacetate instead of TFA.
Triethylaminium trifluoroacetate was used instead of TFA.
b
c
+
NH3
NH2
+
NHCOCF3
CF3COOH
+
H2O
CF3COO-
Scheme 1.

J. Ohtaka et al. / Tetrahedron Letters 50 (2009) 1681–1683
1683
AcOEt (20 mL Â 2). The organic layer was washed with brine (10 mL), dried
over Na2SO4, and concentrated. The residue was chromatographed on a column
of silica gel with AcOEt/n-hexane (1:1) to afford 2,2,2-trifluoro-N-(4-
hydroxyphenyl)acetamide (2i) (195 mg, 95%). (3) Large scale preparation of
2k: to a solution of 4-chloroaniline (1k) (50 g, 0.392 mol) in xylene (580 mL)
was added trifluoroacetic acid (58 mL, 0.784 mol) at 0 °C. The mixture was
refluxed (bath temp. 150 °C) for 3.0 h. After the reaction, the solvent was
evaporated in vacuo. Five percentage HCl (150 mL) was added to the residue
and the aqueous layer was extracted with AcOEt (250 mL Â 2). The organic
layer was washed with brine (200 mL Â 2), dried over Na2SO4, and
concentrated. The crude product was recrystallized from AcOEt-n-hexane to
afford 2,2,2-trifluoro-N-(4-chlorophenyl)acetamide (2k) (74 g, 84%); mp 123–
124 °C (lit. 123–124 °C16).
References and notes
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Interscience: New York, 2007.
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2252–2256.
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9957–9961.
10. Salazar, J.; López, S. E.; Rebollo, O. J. Fluorine Chem. 2003, 124, 111–113.
11. López, S. E.; Pérez, Y.; Restrepo, J.; Salazar, J.; Charris, J. J. Fluorine Chem. 2007,
128, 566–569.
14. Pailer, M.; Hüebsch, W. J. Monatsh. Chem. 1966, 97, 1541–1553.
15. Bourne, E. J.; Henry, S. H.; Tatlow, C. E. M.; Tatlow, J. C. J. Chem. Soc. 1952, 4014–
4017.
16. Stauffer, C. E. J. Am. Chem. Soc. 1972, 94, 7887–7891.
17. 2,2,2-Trifluoro-N-(2,4,6-trichlorophenyl)acetamide (2l): colorless crystal: mp
12. Joshi, K. C.; Misra, R. A.; Jain, R.; Sharma, K. J. Heterocycl. Chem. 1989, 26, 409–
412.
103–103.5 °C (AcOEt/n-hexane); IR (KBr) 3320, 3150, 1770 cmÀ1 1H NMR
;
(270 MHz, CDCl3) d 7.45 (2 H, s), 7.67 (1 H, br s); EI-MS m/z; 293, 291 (M+), 258,
256 (100%), 196, 194, 169, 167. Anal. Calcd for C8H3Cl3F3NO: C; 32.85, H; 1.03,
N; 4.79. Found: C; 33.13, H; 1.13, N; 4.91.Ethyl 4-(2,2,2-trifluoroacetyl-
amino)benzoate (2m): colorless needle: mp 129.5–130 °C (AcOEt/n-hexane);
13. Typical procedure for one-pot procedure for trifluoroacetylation of arylamines: (1)
A mixture of aniline (1a) (279 mg, 3 mmol), TFA (684 mg, 6 mmol), and xylene
(5 mL) was refluxed (bath temp. 150 °C) for 5.5 h. After the reaction, the
solvent was evaporated in vacuo. The residue was chromatographed on a
column of silica gel with AcOEt/n-hexane (1:4) to afford 2,2,2-trifluoro-N-
phenylacetamide (2a) (534 mg, 94%). (2) To pyridinium trifluoroacetate
(386 mg, 2 mmol) in xylene (3 mL) was added 4-aminophenol (1i) (109 mg,
1 mmol), and the reaction mixture was refluxed for 6.5 h. After the reaction,
10% NaHCO3 (10 mL) was added and the aqueous layer was extracted with
IR (KBr) 3350, 1710 cmÀ1 1H NMR (270 MHz, CDCl3) d 1.40 (3 H, t, J = 7.09 Hz),
;
4.38 (2 H, q, J = 7.09 Hz), 7.68 (2 H, d, J = 8.57 Hz), 8.09 (2 H, d, J = 8.74 Hz)) 8.17
(1 H, br s); EI-MS m/z; 261 (M+), 233, 216 (100%). Anal. Calcd for C11H10F3NO3:
C; 50.58, H; 3.86, N; 5.36. Found: C; 50.73, H; 3.90, N; 5.33.
18. Bissell, E. R.; Swansiger, R. W. J. Fluorine Chem. 1978, 12, 293–305.