Trifluoroacetylation of arylamines using poly-phosphoric acid trimethylsilylester (PPSE)

Article abstract of DOI:10.1016/j.jfluchem.2007.03.003

A new, simple and useful procedure is described for the trifluoroacetylation of arylamines using trifluoroacetic acid and poly-phosphoric acid trimethylsilylester (PPSE) as the condensation agent.

Full text of DOI:10.1016/j.jfluchem.2007.03.003

Journal of Fluorine Chemistry 128 (2007) 566–569
www.elsevier.com/locate/fluor
Short communication
Trifluoroacetylation of arylamines using poly-phosphoric acid
trimethylsilylester (PPSE)
a,
Sim o´ n E. L o´ pez , Yelsi P e´ rez , Jelem Restrepo , Jos e´ Salazar , Jaime Charris
a
a
a
b
*
a
Laboratorio de Qu ´ı mica Medicinal y Heterociclos, Departamento de Qu ´ı mica, Universidad Sim o´ n Bolivar,
Valle de Sartenejas, Baruta, Caracas 1080-A, Apartado 89000,Venezuela
Laboratorio de S ´ı ntesis Org a´ nica, Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela
b
Received 24 December 2006; received in revised form 1 March 2007; accepted 5 March 2007
Available online 12 March 2007
Abstract
A new, simple and useful procedure is described for the trifluoroacetylation of arylamines using trifluoroacetic acid and poly-phosphoric acid
trimethylsilylester (PPSE) as the condensation agent.
#
2007 Elsevier B.V. All rights reserved.
Keywords: Trifluoroacetylation; Trifluoroacetic acid; PPSE
1
. Introduction
leading to heterocycles [25], and Friedel–Crafts acylations with
carboxylic acids under strenuous [26] or mild reaction conditions
[27]. As seen above, most of those reactions implicate a key
dehydration step made possible by the action of PPSE. Inview of
our interest in the development of new methodologies for the
trifluoroacetylation of functional groups and the synthesis of
trifluoromethyl substituted heterocycles, we now decided to
explore the trifluoroacetylation of arylamines using trifluoroa-
cetic acid and PPSE as the condensation agent.
Trifluoroacetylation of amines, a common procedure for
this functional group protection [1], has been achieved by
different methodologies which include a variety of reagents
and conditions such as trifluoroacetic anhydride [2], S-ethyl
trifluorothioacetate [3], N-(trifluoroacetyl)imidazol [4], ethyl
trifluoroacetate [5–7], trifluoroacetyl-triflate [8,9], 2-[(trifluoro-
acetyl)-oxy]pyridine (TFAP) [10], trifluoroacetyl benzotriazole
[
11], N-(trifluoroacetyl)succinimide [12], TiO(CF COO) [13],
3 2
and sodium trifluoroacetate [14]. Other agents are the S-dodecyl
trifluorothioacetate [15] and N-methylbis (trifluoroacetamide)
named as MBTFA [16], useful for the GC–MS determination
of aminoacids and biological active amines, respectively.
Recently, we have described a direct microwave promoted
trifluoroacetylation of anilines with trifluoroacetic acid [17]. By
other hand, poly-phosphoric acid trimethylsilylester (PPSE,
Fig. 1), a stable, viscous and colorless liquid firstly prepared by
Imamoto in 1981 [18], has been used to promote several different
reactions such as dehydration of amides into nitriles [19],
conversion of alcohols into iodides [20], aldol condensations
2
. Results and discussion
The direct trifluoroacetylation of arylamines 1a–g using
trifluoroacetic acid and PPSE is depicted on Scheme 1. In order
to optimize the methodology, we decided to study how changes
on the preparation of the condensating agent, solvent and
temperature affect the trifluoroacetylation of p-toluidine 1a
(
Table 1). Temperature seems to be critical for this reaction;
expecting higher yields at a prolonged time we decided to
extend reaction times up to 19 h (entry 5), however, lower
yields were obtained, which means the condensating agent is
somehow affected at high temperatures and long reaction times.
The methodology was thus applied to other anilines
[
21], Beckmann rearrangements [22], Pummererrearrangements
23], Meyer–Schuster rearrangements [24], cyclodehydrations
[
(
Table 2) obtaining good yields but observing the reaction
seemed to be also affected by the esteric effect, cause orto-
substituted anilines gave lower yields. Encourage by those
results and that on the successful use of PPSE for the
*
Corresponding author. Tel.: +58 212 9063986; fax: +58 212 9063961.
E-mail address: slopez@usb.ve (S.E. L o´ pez).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.03.003

S.E. L o´ pez et al. / Journal of Fluorine Chemistry 128 (2007) 566–569
567
Table 2
Trifluoroacetylation of arylamines using PPSE and trifluoroacetic acid
Fig. 1. Preparation of poly-phosphoric acid trimethylsilylester (PPSE).
Compound
Melting point (8C)
R
Yield (%)
2
2
2
2
2
2
b
c
d
e
f
120–121 (Lit. 123–124) [28]
110–111 (Lit. 113–115) [28]
122–123 (Lit. 124–126) [29]
40–41 (Lit. 40–41) [17]
92–94
4-Cl
74
62
4-OMe
4-Br
a
83
2-Cl
20
21
73
2,4-(Me)
3-Me
2
g
61–62 (Lit. 62–64) [28]
a
5
equiv. of PPSE were needed, reaction time was prolonged up to 12 h.
Scheme 1.
construction of heterocycles [18(c)], we also made an
exploration for the preparation of a 3-trifuoromethylated
benzothiadiazine (Scheme 2). The 2-amino-5-bromo-benzene-
sulfonamide 1h, was reacted with trifluoroacetic acid and
reaction is not clear in detail, it has been postulated that an
amide or maybe a silylated amide derivative can be assumed as
the intermediate of this reaction, previous to the heterocycliza-
tion step for the preparation of some 3-alkyl and 3-aryl 2H-
1,2,4-benzothiadiazine 1,1-dioxides [30]. The developed
procedure represents a new, simple and useful alternative for
the trifluoroacetylation of arylamines and even for the direct
preparation of a 3-trifluoromethyl-benzothiadiazine, a metho-
dology which will be improved for the preparation of other
trifluorometyl-substituted heterocycles.
5
equiv. of PPSE giving a mixture of the expected trifluor-
omethyl heterocycle 3 and the uncyclic precursor trifluoroa-
cetylated benzenesulfonamide 2h in an almost 6:4 ratio,
respectively. This result was promising when compared with a
microwave attempted reaction using the same benzenesulfo-
namide and 1 equiv. of tryfluoroacetic acid. Because good
yields were obtained from our reported procedure for the
microwave promoted trifluoroacetylation on orto-substituted
anilines [17], it was reasonable to try the same methodology for
3. Experimental
1
h; however, only the starting material was detected using
Meltingpoints weredeterminedina Fischer–Johns microhot-
stage apparatus and are uncorrected. NMR spectra were obtained
on a JEOL Eclipse Plus spectrometer in deuterated chloroform or
similar reaction conditions. It means, despite the yields of
trifluoroacetylation are lower than those described for the
microwave reaction, the PPSE promoted trifluoroacetylation of
arylamines should also be applied for the synthesis of
trifluoromethyl heterocycles. Although the mechanism of this
1
hexadeuterated dimethylsulfoxide, operating at 400 MHz ( H,
1
internal standard TMS) and 376 MHz ( F, internal standard
9
CFCl );dvaluesinppmrelativetotheinternalstandardaregiven.
3
Table 1
Optimization conditions for the trifluoroacetylation of p-toluidine 1a
Entry
P
2
O
5
(equiv.)
(Me
3
Si)
2
O (equiv.)
Solvent
Temperature (8C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
10
10
5
10
10
5
Benzene
120
60
1
1
53
16
51
42
18
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
120
120
120
100
80
6
5
5
19
19
5
1
1
a
1
1
68
1
1
3
61
b
1
1
80
3
40
a
Pyridine (1 equiv.) was added to the reaction mixture.
b
mp 107–108 8C (Lit. 109.5–111) [28].

568
S.E. L o´ pez et al. / Journal of Fluorine Chemistry 128 (2007) 566–569
1
Scheme 2. (*)Determined by H NMR, the mixture couldn’t be separated by column chromatography, although it was effectively separated by fractional
crystallisation from EtOH–H O.
2
The IR spectra were recorded as potassium bromide discs using a
Shimadzu CW/IR 470 spectrometer. Mass spectra (GC–MS)
were recorded using a gas chromathograph Hewlet Packard 5890
Serie I coupled to a mass detector (EI, 60 eV) Hewlet Packard
reached. The corresponding aniline (2 mmol) was added as a
dicloromethane solution (1 mL) dropped with a syringe at room
temperature. After addition was completed the reaction mixture
was heated at 100 8C for 5 h. The resulting solution was
allowed to stand at room temperature, ice cold water was added,
the organic layer extracted three times with dichloromethane
(3 Â 3 mL), dried over anhydrous sodium sulphate and
evaporated to give the indicated trifluoroacetamides, which
were recrystallised from ethanol-water.
5917 A. Microanalyses of new synthesized compounds were
performed by Atlantic Microlab Inc. (Norcross, GA, USA);
results fell in the range of Æ0.4% of the required theoretical
1
values. Silica gel plates ALUGRAM
(
SIL G/UV254
Macherey-Nagel GmbH & Co., Germany) were used for
TLC testing. Reagents were obtained from Aldrich (Milwaukee,
MI, USA) or Merck (Darmstadt, Germany) and used without
further purification. The 5-bromo-2-amino-benzenesulfonamide
3.1.2.1. N-(2,4-dimethylphenyl)-2,2,2-trifluoroacetamide
1
(2f). 0.09 g (21% yield), beige solid, H NMR (400 MHz,
1
h was prepared according to the literature procedure [31].
CDCl ): d 7.71(bs, 1H, NH), 7.55 (d, 1H, J = 7.0 Hz, H-arom),
3
Microwave irradiation was made with a Goldstar Microwave
conventional oven, model MA-690M (600W, 2450 MHz).
7.05 (m, 2H, H-arom), 2.31 (s, 3H, CH ), 2.23 (s, 3H, CH ). IR
3
3
À1
+
(KBr, cm ): 3400, 1762, 1549. MS (EI): m/z 217 (M ). Anal
Calcd for C H F NO; C, 55.30; H, 4.64; N, 6.45. Found: C,
1
0 10 3
3
3
.1. Experimental procedures
55.23; H, 4.69; N, 6.40.
.1.1. General procedure for the preparation of poly-
3.1.2.2. N-(3-methylphenyl)-2,2,2-trifluoroacetamide
1
(2g). 0.3 g (73% yield), white crystals, H NMR (400 MHz,
phosphoric acid trimethylsilylester (PPSE) in solution
A mixture of phosphorus pentoxide (2.83 g; 20 mmol),
hexamethyldisiloxane (4 mL; 20 mmol) and dichloromethane
CDCl ): d 7.95 (bs, 1H, NH), 7.30 (m, 3H, H-arom), 7.04 (d, 1H,
3
À1
J = 7.4 Hz, H-arom), 2.35 (s, 3H, CH ). IR (KBr, cm ): 3312,
3
+
1769, 1654. MS (EI): m/z 203 (M ). Anal Calcd for C H F NO;
C, 53.21; H, 3.97; N, 6.89. Found: C, 53.32; H, 3.94; N, 6.91.
(
20 mL) or benzene (20 mL) is refluxed at 80 8C under an argon
9
8 3
atmosphere for 2 h, until the solution is clear. Solvent was
removed under vacuo and the resulting yellowish liquid was
diluted with dicholoromethane (20 mL) or benzene (20 mL).
The volatile solution was used for the condensation step with
trifluoroacetic acid, and could be stored in a refrigerator for at
least 2 weeks without a considerable decrease in its
condensation properties.
3.1.3. Preliminary procedure for the preparation of 7-
bromo-3-trifluoromethyl-2H-1,2,4-benzothiadiazine-1,1-
dioxide 3 using PPSE
To a solution of PPSE (10 mL, prepared as above) was added
trifluoroacetic acid (2 mmol) and the solution heated at 120 8C
for 2 h, then allowed to stand until room temperature was
reached. 5-bromo-2-aminobenzenesulfonamide 1h (0.5 g;
2 mmol) crystals were added at room temperature. After
addition was completed, the reaction mixture was heated at
100 8C for 6 h. The resulting mixture was allowed to stand at
room temperature, ice cold water was added, the organic layer
extracted three times with dichloromethane (3 Â 5 mL), dried
over anhydrous sodium sulphate and evaporated to give a
3
.1.2. General procedure for the preparation of N-(phenyl-
substituted)-2,2,2-trifluoro-acetamides 2a–g using
trifluoroacetic acid and PPSE as the condensating agent.
optimized methodology
To a solution of PPSE (2 mL, prepared as above) was added
trifluoroacetic acid (2 mmol) and the solution heated at 120 8C
for 2 h, then allowed to stand until room temperature was

S.E. L o´ pez et al. / Journal of Fluorine Chemistry 128 (2007) 566–569
569
violet-like coloured solid (0.42 g). A 57:43 ratio mixture of
both 7-bromo-3-trifluoromethyl-2H-1,2,4-benzothiadiazine-
,1-dioxide 3 and 2-trifluoroacetamido-5-bromo-benzenesulfo-
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1
2
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1
[
9
6
1
-
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(
(
(
(
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1
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19
F
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Authors would like to thank Decanato de Investigaci o´ n y
Desarrollo (Universidad Sim o´ n Bol ´ı var, Caracas) for its
financial support. J.R. thanks Fonacit (Caracas, Venezuela)
for a Doctoral Fellowship. Y.P. thanks Decanato de Estudios
Profesionales (Universidad Sim o´ n Bol ´ı var, Caracas) for an
undergraduate research financial support.
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