A new, convenient and selective 4-dimethylaminopyridine-catalyzed trifluoroacetylation of anilines with ethyl trifluoroacetate

Article abstract of DOI:10.1016/S0040-4039(00)01812-8

A new, convenient, and selective 4-dimethylaminopyridine-catalyzed trifluoroacetylation of anilines with ethyl trifluoroacetate is described. Anilines, containing other functional groups, e.g. alcohols, phenols, hindered secondary amines, and secondary anilines, are also selectively trifluoroacetylated in high yields under these newly developed conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01812-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9957–9961
A new, convenient and selective
4
-dimethylaminopyridine-catalyzed trifluoroacetylation of
anilines with ethyl trifluoroacetate
Mahavir Prashad,* Bin Hu, Denis Har, Oljan Repi cˇ and Thomas J. Blacklock
Process Research and Development, Chemical and Analytical Development,
Novartis Institute for Biomedical Research, 59 Route 10, East Hanover, NJ 07936, USA
Received 1 September 2000; accepted 14 September 2000
Abstract
A new, convenient, and selective 4-dimethylaminopyridine-catalyzed trifluoroacetylation of anilines
with ethyl trifluoroacetate is described. Anilines, containing other functional groups, e.g. alcohols,
phenols, hindered secondary amines, and secondary anilines, are also selectively trifluoroacetylated in high
yields under these newly developed conditions. © 2000 Elsevier Science Ltd. All rights reserved.
Trifluoroacetylation is an important transformation for the protection of several functional
1
groups, e.g. alcohols, phenols, amines, and anilines. In one of our projects we needed to
2–9
selectively trifluoroacetylate an aniline. There are a number of reagents and methods reported
for the trifluoroacetylation of anilines and other functional groups, with trifluoroacetic
1
0
anhydride being the most popular reagent of choice. Most of these reagents, however, have
drawbacks and limitations due to either undesired by-products and handling issues on a plant
scale, or they are not readily available and have to be synthesized. Additionally, selective
trifluoroacetylation of anilines in the presence of other functional groups with these reagents,
including commercially readily available trifluoroacetic anhydride, has not been reported.
Because it is important in organic synthesis to distinguish between various functional groups in
a polyfunctional molecule to avoid a cumbersome and time-consuming protection and deprotec-
tion sequence, we became interested in studying the selective trifluoroacetylation of anilines with
1
1
ethyl trifluoroacetate. Ethyl trifluoroacetate is a commercially available reagent, which is also
easy to handle on a large scale. Herein, we report a new, convenient, and selective 4-dimethy-
laminopyridine-catalyzed trifluoroacetylation of anilines with ethyl trifluoroacetate (Scheme 1).
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01812-8

9958
Scheme 1.
Trifluoroacetylation of aniline itself was first chosen as the representative example to develop
appropriate conditions. Treatment of a solution of aniline (10 mmol) in THF (7.0 mL) with
ethyl trifluoroacetate (1.13 equiv.) at 85°C for 24 h gave only 5% of N-phenyltrifluoroacetamide
(
1). Use of catalytic amounts of pyridine (0.1 equiv.) and triethylamine (0.1 equiv.) under these
conditions led to only a slight increase in the yield of 1 to 10 and 26%, respectively. An increase
in the amount of ETFA to 2.0 equiv. also led to a slight increase in the yield of 1 to 10%.
12,13
However, use of 0.1 equiv. of 4-dimethylaminopyridine (DMAP)
yielded 1 in 79% yield. An
increase in the amount of ETFA to 2.0 equiv. in the presence of 0.1 equiv. of DMAP further
increased the yield of 1 to 85%. Such a 4-dimethylaminopyridine-catalyzed trifluoroacetylation
of anilines with ethyl trifluoroacetate is not known to the best of our knowledge. To test the
1
4
general synthetic utility of these newly developed conditions (Scheme 1) we studied the
trifluoroacetylation of several anilines. The results are listed in Table 1. All the anilines gave
excellent yields of the corresponding N-aryltrifluoroacetamides (2–7). ortho-Toluidine yielded
only 30% of 4 (entry 4, Table 1) under these conditions, perhaps due to steric hindrance. An
increase in the amount of ETFA led to an increase in the yield of 4 to 49% (entry 5). However,
an increase in the amount of DMAP to 1.0 equiv. led to a substantial increase in the yield of
4
4
to 93% (entry 6). Use of 1.0 equiv. of DMAP also led to a satisfactory trifluoroacetylation of
-cyanoaniline, an aniline containing a strong electron-withdrawing group, affording 7 in 79%
yield (entry 9). No trifluoroacetylation was observed with N-methylaniline even with 1.0 equiv.
of DMAP and 2.0 equiv. of ETFA (entry 10).
Selective trifluoroacetylation of anilines in the presence of other functional groups, e.g.
alcohols, phenols, secondary amines, and secondary anilines, will be of great importance. We
next demonstrated the synthetic utility of our newly developed conditions in selective tri-
fluoroacetylation of various anilines containing these functional groups. The results are summa-
rized in Table 2. Results in entries 1–5 clearly demonstrated that anilines containing an alcohol
or phenol functionality were selectively trifluoroacetylated in high yields. Towards studying the
selective trifluoroacetylation of anilines in the presence of hindered secondary amines, first an
equimolar mixture of aniline and N-benzylisopropylamine was treated with ETFA in THF in
the presence of DMAP at 85°C. Only aniline underwent trifluoroacetylation to afford 1. No
trifluoroacetylation of N-benzylisopropylamine was observed. These results suggested that
anilines could be selectively trifluoroacetylated in the presence of hindered secondary amines.
This supposition was confirmed by trifluoroacetylation of anilines reported in entries 6 and 7
(
Table 2), containing a hindered secondary amine functionality. These results clearly demon-
strated that anilines are selectively trifluoroacetylated in excellent yields in the presence of
hindered secondary amines under our new conditions. This method, however, is not suitable for
selective trifluoroacetylation of anilines in the presence of unhindered secondary amines as
treatment of an equimolar mixture of aniline and N-benzylmethylamine led to trifluoroacetyla-
tion of N-benzylmethylamine.

9959
Table 1
Trifluoroacetylation of anilines with ETFA in the presence of DMAP
Selective trifluoroacetylation of primary anilines in the presence of secondary anilines was
studied next. Trifluoroacetylation of an equimolar mixture of aniline and N-methylaniline was
carried out in the presence of 1.0 equiv. of DMAP and 2.0 equiv. of ETFA in THF at 85°C.
Only aniline underwent trifluoroacetylation to afford 1. These results suggested that primary
anilines could be selectively trifluoroacetylated in the presence of secondary anilines. To this
end, trifluoroacetylation of N-methyl-1,2-phenylenediamine, a molecule containing both primary
and secondary aniline, was studied. Only primary aniline group underwent trifluoroacetylation
affording 16 in excellent yield (entry 8, Table 2). These results confirmed that primary anilines
are selectively trifluoroacetylated in the presence of secondary anilines under our new condi-
tions. Selective protection of primary amines in the presence of secondary amines is known in
1
5–17
the literature.
A plausible mechanism for the DMAP-catalyzed trifluoroacetylation of anilines with ethyl
18,19
trifluoroacetate is depicted in Scheme 2. The N-acylpyridinium salt (A)
undergoes a
nucleophilic attack with aniline to afford a tetrahedral intermediate, which liberates N-arytri-
fluoroacetamide product, ethanol by-product and DMAP.

9960
Table 2
Selective trifluoroacetylation of anilines with ETFA in the presence of DMAP
In summary, a new, convenient, and selective 4-dimethylaminopyridine-catalyzed tri-
fluoroacetylation of anilines with ethyl trifluoroacetate is described. Anilines, containing other
functional groups, e.g. alcohols, phenols, hindered secondary amines, and secondary ani-
lines, are also selectively trifluoroacetylated in high yields under these newly developed condi-
tions.

9961
Scheme 2.
References
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4. General Procedure: A round-bottomed flask, equipped with a magnetic stirrer bar and a reflux condenser, was
charged with an appropriate aniline (10.0 mmol), THF (7.0 mL), ethyl trifluoroacetate (11.35 mmol or specified
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1
gel. All the compounds gave satisfactory spectroscopic data. 9: H NMR (300 MHz, CDCl ) l 2.02 (s, 1H), 2.89
3
(
t, 2H, J=5.2 Hz), 4.02 (t, 2H, J=5.2 Hz), 7.2 (m, 2H), 7.31 (m, 1H), 7.86 (d, 1H, J=7.9 Hz), 10.31 (bs, 1H).
1
1
7
2
1: H NMR (300 MHz, DMSO-d ) l 4.51 (s, 2H), 7.16 (d, 1H, J=7.53 Hz), 7.35 (dd, 1H, J=7.53 and 8.28 Hz),
6
1
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3
1
3
l 2.26 (bs, 1H), 2.66 (m, 2H), 3.02 (m, 2H), 3.57 (m, 1H), 3.85 (s, 2H), 7.02–7.16 (m, 3H), 7.23 (d, 1H, J=7.9
1
Hz), 7.32 (s, 1H), 7.56 (m, 1H), 8.45 (d, 1H, J=4.71 Hz), 9.12 (bs, 1H). 16: H NMR (300 MHz, CDCl ) l 3.93
3
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