Improved one-pot synthesis of 1-aryl-3-trifluoroacetyl-1H-pyrroles under Swern oxidation

Article abstract of DOI:10.1055/s-0032-1317383

This study describes an improved one-pot, four-step synthesis of a new series of 1-aryl-3-trifluoroacetyl pyrroles from the reaction of 3-trifluoroacetyl-4,5-dihydrofuran with arylamines, giving 1,1,1-trifluoro-3-(2- hydroxyethyl)-4-arylamino-3-buten-2-ones, which were directly submitted to Swern oxidation to furnish 1,1,1-trifluoro-3-(2-ethanal)-4-arylamino-3-buten-2-ones. Subsequent intramolecular cyclization of the corresponding enaminoaldehydes followed by aromatization rendered the title compounds in a 30 to 56% overall yield.

Full text of DOI:10.1055/s-0032-1317383

PAPER
▌3477
paper
Improved One-Pot Synthesis of 1-Aryl-3-trifluoroacetyl-1H-pyrroles under
Swern Oxidation
1-Aryl-3-trifluoroacetyl-1H-pyrroles
Nilo Zanatta,* Estefania da C. Aquino, Fabio M. da Silva, Helio G. Bonacorso, Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900, Santa Maria,
Brazil
Fax +55(55)32208756; E-mail: zanatta@base.ufsm.br
Received: 10.07.2012; Accepted after revision: 18.09.2012
In view of their importance, several strategies have been
Abstract: This study describes an improved one-pot, four-step
developed for the synthesis of 1-aryl-substituted pyr-
synthesis of a new series of 1-aryl-3-trifluoroacetyl pyrroles from
roles.9 Classical procedures for their preparation include
the reaction of 3-trifluoroacetyl-4,5-dihydrofuran with arylamines,
giving 1,1,1-trifluoro-3-(2-hydroxyethyl)-4-arylamino-3-buten-2-
the cyclocondensation of primary amines with 1,4-dicar-
ones, which were directly submitted to Swern oxidation to furnish bonyl compounds (Paal–Knorr reaction)10 or 2,5-di-
1,1,1-trifluoro-3-(2-ethanal)-4-arylamino-3-buten-2-ones. Subse-
methoxy
tetrahydrofuran
(Clauson–Kass),11
and
quent intramolecular cyclization of the corresponding enaminoalde-
hydes followed by aromatization rendered the title compounds in a
30 to 56% overall yield.
cyclocondensation of β-enaminones and α-halocetonas
(Hantzsch reaction).12 There are also a variety of methods
available for obtaining these compounds such as the
cross-coupling reaction mediated by transition metals,13
oxidative-coupling reaction mediated by AgOAc,14 intra-
molecular Wittig reaction,15 and direct arylation of pyr-
roles.16
Key words: trifloroacetyl groups, pyrroles, Swern oxidation, aryl-
amines, trifluoromethyl
Pyrroles are an important class of organic compounds that
are found in many natural products and bioactive mole-
cules.1 They have also been widely used in materials sci-
ence and molecular recognition studies.2 In addition,
pyrrole derivatives are important intermediates in the syn-
thesis of not only drugs, pigments, and pharmaceuticals,
but also for the development of functional organic materi-
als.3
Organic fluorine compounds have attracted much atten-
tion in the materials and pharmaceutical sciences, because
the introduction of fluorine into an organic compound can
cause remarkable changes in the physical, chemical, and
biological properties.17 The introduction of fluorine or
fluoroalkyl substituents into biologically relevant com-
pounds has become an important tool in the drug discov-
ery process.18 Special attention is paid to trifluoromethyl-
containing compounds due to the unique properties of the
trifluoromethyl group, such as high electronegativity,
electron density, steric hindrance, and hydrophobic char-
acter, which can profoundly affect the pharmacokinetic
profiles of potential drugs.19
In turn, 1-aryl substituted pyrroles have received consid-
erable attention in areas such as: (i) chemistry, because of
the synthetic challenge of obtaining them4 as well as their
use as starting material for the synthesis of other, more
complex molecules; 5 (ii) pharmaceutical sciences, due to
their biological activities such as, for example, Cloripac,6
which is a nonsteroidal anti-inflammatory; and (iii) mate-
rial sciences, by their use as biosensors,7 such as poly[2,5-
di-(2-thienyl)-1H-pyrrole-1-(p-benzoic acid)] (PDPB)
and as semiconductors,8 such as hexa(N-pyrrolil)benzene
(Figure 1).
One of the best methods to introduce a trifluoromethyl
group into a molecule is based in the trifluoromethylated
building block approach. These building blocks are easily
obtained from the trifluoroacetylation of enol ethers or
acetals, to give, in one-step and good yield, 4-alkoxy-
1,1,1-trifluoroalk-3-en-2-ones,20 which proved to be use-
ful precursors for the synthesis of series of heterocycles21
as well as other aliphatic compounds.22
CO2H
S
N
N
In a previous study, a new, one-pot, four-step synthesis of
a large series of 1-substituted 3-trifluoroacetyl pyrroles,
was reported.23 These compounds were obtained from the
reaction of 3-trifluoroacetyl-4,5-dihydrofuran and prima-
ry amines, followed by in situ oxidation with PCC and in-
tramolecular cyclization and subsequent aromatization.
However, under the reaction conditions reported in the
previous study (Scheme 1),23 aniline and arylamines
failed to react with 3-trifluoroacetyl-4,5-dihydrofuran (1).
In this study, we present a modified procedure that allows
the title compounds to be obtained in the same range of
yields as those reported in the previous study.23
N
N
N
N
N
S
N
COOH
PDPB
Cl
Cloripac
hexa(N-pyrrolyl)benzene
Figure 1 Examples of 1-aryl-substituted pyrroles
SYNTHESIS 2012, 44, 3477–3482
Advanced online publication: 02.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317383; Art ID: SS-2012-M0580-OP
© Georg Thieme Verlag Stuttgart · New York

3478
N. Zanatta et al.
PAPER
The synthetic strategy used to synthesize the 1-aryl-sub-
stituted 3-trifluoroacetylpyrroles is outlined in Scheme 1.
3-Trifluoroacetyl-4,5-dihydrofuran (1) was prepared ac-
cording to the literature.20 The reaction of compound 1
with primary arylamines 2a–o (1 equiv) in either dichlo-
romethane or tetrahydrofuran (THF) in the presence of tri-
ethylamine, furnished the enamino alcohols 3, which were
not isolated because these compounds were not sufficient-
ly stable.23 However, the formation of intermediates 3a–o
could be followed by TLC, and when the spots of enone 1
and arylamine 2 completely disappeared, the reaction
mixture was submitted to Swern oxidation,24 thereby lead-
ing to the aldehydes 4, which underwent intramolecular
cyclization followed by elimination of water to give 1-
aryl-substituted-3-trifluoroacetylpyrroles 5a–o with over-
all yields of 30–56% (Table 1).
Table 1 Optimized Synthesis of Pyrroles 5a–o
Entry
Compd
Amine (2a–o)a
Product
Yield (%)b
1
2a
2b
2c
2d
2e
2f
Ph
5a
5b
5c
5d
5e
5f
41
38
50
40
30
35
45
32
40
45
43
56
39
49
34
2
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
3-FC6H4
3
4
5
6
7
2g
2h
2i
5g
5h
5i
8
9
4-FC6H4
10
11
12
13c
14c
15c
2j
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-HOC6H4
5j
O
O
2k
2l
5k
5l
CF3
ii
F3C
NHAr
i
O
OH
3a–o
1
2m
2n
2o
5m
2-HO-5-MeC6H3 5n
3-HO-4-MeC6H3 5o
O
O
O
O
H
H
CF3
F3C
H
NHAr
– H2O
CF3
a Reaction conditions: (i) 3-trifluoroacetyl-4,5-dihydrofuran
(2 mmol), aryl amine (2.0 mmol), Et3N (2.0 mmol), CH2Cl2, 4–5 h,
r.t.; (ii) (COCl)2 (2.4 mmol), DMSO (4.47 mmol), CH2Cl2, Et3N
(9.94 mmol).
N
HO
N
Ar
Ar
b Yield of products after purification by column chromatography.
c Reaction performed in THF as solvent.
5a–o
4a–o
Scheme 1 Synthesis of 1-aryl-3-trifluoroacetyl pyrroles. Reagents
and conditions: (i) ArNH2, CH2Cl2 or THF, Et3N; (ii) (COCl)2,
DMSO, CH2Cl2, Et3N.
Table 2 Oxidation of Intermediate 3ga
Entry
Reagent
Conversion Yield Yield
The aryl amines used in this study were less reactive than
the aliphatic amines used in the previous study,23 requir-
ing the use of triethylamine and longer reaction times (4–
5 h) to obtain the enaminone intermediates 3a–o. In addi-
tion, it was difficult to carry out the reaction due to the low
solubility of some aryl amines, such as 4-aminophenol, 2-
amino-4-methylphenol, and 5-amino-2-methylphenol in
dichloromethane. For these arylamines, the solvent of
choice was THF because it is inert under Swern oxidation
conditions and it dissolved all the reactants (Table 1).
(%)b
(%)c
(%)d
1
2
3
4
5
PCC
98
90
89
36
12
25
75
69
–
10
45
–
oxalyl chloride
cyanuric chloride
thionyl chloride
trifluoroacetic anhydride
–
–
–
a Reaction conditions: 3-trifluoroacetyl-4,5-dihydrofuran (2 mmol),
4-methylaniline (2.0 mmol), Et3N (2.0 mmol), CH2Cl2, r.t., 4 h.
b Conversion measured by GC-MS total ion chromatography.
c Yield of the crude mixture.
One of the crucial steps of this study involved the oxida-
tion of a primary alcohol to an aldehyde. In this study we
tested different oxidation procedures (see Table 2) such as
PCC (entry 1), and dimethyl sulfoxide activated by differ-
ent electrophilic reagents, such as oxalyl chloride (entry
2),25 cyanuric chloride (entry 3),26 thionyl chloride (entry
4),27 and trifluoroacetic anhydride (entry 5).28
d Yield of products after purification by column chromatography.
nished good conversion and yields, but this reaction gave
rise to a small amount of the corresponding dihydropyr-
role as a side product. Thus, the use of dimethyl sulfoxide
activated by oxalyl chloride constituted the best reaction
conditions for the oxidation step.
In Table 2, the method involving the use of PCC for the
oxidation step (entry 1), resulted in low yields and a te-
dious workup process.29 For the reactions given in entries
4 and 5, the conversion into product was very low. The re-
action carried out using cyanuric chloride (entry 3) fur-
Synthesis 2012, 44, 3477–3482
© Georg Thieme Verlag Stuttgart · New York

PAPER
1-Aryl-3-trifluoroacetyl-1H-pyrroles
3479
In order to confirm the superior performance of the Swern tion of readily available 3-trifluoroacetyl-4,5-dihydro-
oxidation over PCC, we tested three reactions using pri- furan with arylamines to give 1,1,1-trifluoro-3-(2-
mary alkyl amines instead of arylamines; the results of hydroxyethyl)-4-arylamino-3-buten-2-ones, which were
these reactions are reported in Table 3. It can be seen that directly submitted to Swern oxidation to furnish 1,1,1-tri-
the method used in this study rendered overall yields that fluoro-3-(2-ethanal)-4-arylamino-3-buten-2-ones. Subse-
were approximately 15% higher than the previous report- quent intramolecular cyclization of the corresponding
ed method.23
enaminoaldehydes followed by aromatization rendered
the title compounds in 30 to 56% overall yield.
Table 3 Comparison of Oxidation Methods for the Synthesis of 3-
Trifluoroacetyl Pyrroles
The 3-trifluoroacetyl-4,5-dihydrofuran (1) was prepared according
to the literature.20 All melting points were determined with a Kofler
Reichert Thermovar or a MQAPF-301 apparatus and are uncorrect-
ed. High-resolution mass spectra were recorded in ESI-mode. GC-
MS spectra were registered with a HP 5973 MSD instrument con-
nected to a HP 6890 GC. The GC was equipped with a split-splitless
injector, auto-sampler, cross-linked HP-5 capillary column (30 m,
0.32 mm of internal diameter), and helium was used as the carrier
gas. 1H and 13C NMR spectra were acquired with a Bruker DPX200
or DPX400 spectrometer in CDCl3 or DMSO-d6 with TMS as inter-
nal reference.
Oxidation method [yield (%)]a
Amine
PCCb
Swernc
PhCH2CH2NH2
i-PrNH2
50
52
46
65
67
59
n-PrNH2
a Yield after purification by column chromatography.
b Yields reported by Zanatta et al.23
c Yields obtained in this study.
Synthesis of 1-Aryl-3-trifluoroacetyl-1H-pyrroles; General
Procedure
To a solution of 3-trifluoroacetyl-4,5-dihydrofuran (1; 0.332 g, 2.0
mmol) in either CH2Cl2 or THF (6 mL), arylamine (2.0 mmol) and
Et3N (0.27 mL, 2.0 mmol) were added and the reaction was main-
tained at r.t. for 4–5 h under magnetic stirring. In another flask that
was previously flame-dried, a solution of oxalyl chloride (0.2 mL,
2.4 mmol) in CH2Cl2 (10 mL) was added and the solution was
stirred at –78 °C until the temperature was stabilized, then a solu-
tion of DMSO (0.33 mL, 4.47 mmol) in CH2Cl2 (1 mL) was added
dropwise. After 30 min, the solution of the previously prepared en-
aminones was added to the oxalyl chloride solution and the mixture
was stirred for 30 min. After this time, Et3N (1.36 mL, 9.94 mmol)
was added dropwise and the temperature of the resulting suspension
1-Arylpyrroles 5a–o, were identified by 1H and 13C NMR
techniques, mass spectrometry (GC-MS), and high-reso-
lution mass spectrometry analysis.
It is interesting to mention that an enone analogous to 1,
but with a trichloromethyl group in the place of the triflu-
oromethyl, when reacted with primary amines, furnished
3-aminomethylenedihydrofuran-2-ones instead of 1-sub-
stituted 3-trichloroacetyl pyrroles, as shown in Scheme
2.30 This probably happens because the trichloromethyl
group is easily eliminated (structure IV) to form a stable was raised to 0 °C and kept at this temperature under stirring for 30
min. The ice bath was removed and the reaction mixture was stirred
until the reaction mixture reached r.t. The solvent was evaporated
and the resulting solid was dissolved in EtOAc (30 mL) and washed
with 3% HCl (10 mL) and subsequently with 1 M brine (10 mL).
The organic phase was dried with anhydrous sodium sulfate and
concentrated in a rotary evaporator. Products were purified by col-
lactone, but structure IV, with a trifluoromethyl group in
the place of CCl3, is not likely to be eliminated and the re-
action returns to the structure analogous to III (intermedi-
ates 3, Scheme 1), which could be isolated but was not
stable enough to be adequately characterized.23
umn chromatography on silica gel (EtOAc–hexane, 1:9).
In summary, we have described the synthesis of a series of
new 1-aryl-3-trifluoroacetyl-1H-pyrroles by an improved
one-pot, four-step reaction protocol starting from the reac-
1-Phenyl-3-trifluoroacetyl-1H-pyrrole (5a)
Yield: 195 mg (41%); yellow solid; mp 60–64 °C.
O
NHR
CCl3
RNH2, solvent, 1–4 h
71–91%
O
O
O
H2NR
– CHCl3
H
O
O
O
NHR
CCl3
CCl3
Cl3C
NHR
O
H
CCl3
NHR
O
IV
NH2R
O
O
OH
I
II
III
Scheme 2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3477–3482

3480
N. Zanatta et al.
PAPER
1H NMR (200 MHz, CDCl3): δ = 7.84 (br s, 1 H), 7.54–7.36 (m,
5 H), 7.10 (dd, J = 3.1, 2.4 Hz, 1 H), 6.92 (br s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.1 Hz), 139.1,
129.9, 127.9, 127.5 (q, 4JC–F = 3.5 Hz), 122.5, 121.4, 119.8, 116.9
(q, 1JC–F = 290.7 Hz, CF3), 111.9.
13C NMR (100 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.5 Hz), 140.2,
139.1, 129.7, 128.7, 127.5 (q, 4JC–F = 3.4 Hz), 122.2, 122.6, 119.5,
118.6, 116.9 (q, 3JC–F = 290.7 Hz), 111.8, 21.4.
GC-MS (EI, 70 eV): m/z (%) = 253 (100) [M+], 184 (100), 154 (16).
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO: 254.0792;
GC-MS (EI, 70 eV): m/z (%) = 239 (53) [M+], 170 (100).
found: 254.0789.
HRMS (ESI): m/z [M + H]+ calcd for C12H9F3NO: 240.0636; found:
240.0627.
1-(4-Methylphenyl)-3-trifluoroacetyl-1H-pyrrole (5g)
Yield: 227 mg (45%); yellow hygroscopic solid.
1H NMR (200 MHz, CDCl3): δ = 7.81 (br s, 1 H), 7.30 (s, 4 H), 7.07
(dd, J = 3.1, 2.1 Hz, 1 H), 6.90 (br s, 1 H), 2.41 (s, 3 H).
1-(2-Methoxyphenyl)-3-trifluoroacetyl-1H-pyrrole (5b)
Yield: 204 mg (38%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.74 (br s, 1 H), 7.36 (m, 1 H),
7.26 (dd, J = 7.7, 1.6 Hz, 1 H), 7.11–7.06 (m, 2 H), 6.99 (dd, J = 3.1,
2.0 Hz, 1 H), 6.83 (br s, 1 H), 3.83 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.5 Hz), 138.1,
4
136.9, 130.5, 127.5 (q, JC–F = 3.7 Hz), 122.6, 121.5, 119.6, 116.9
(q, 1JC–F = 290.7 Hz), 111.8, 20.9.
13C NMR (100 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.2 Hz), 152.7,
130.7 (q, 4JC–F = 3.6 Hz), 129.5, 128.3, 125.7, 124.9, 121.1, 118.5,
117.0 (q, 1JC–F = 290.8 Hz), 112.5, 110.4, 55.8.
GC-MS (EI, 70 eV): m/z (%) = 269 (100) [M+], 200 (100), 185 (90),
157 (24).
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO2: 270.0742;
found: 270.0735.
GC-MS (EI, 70 eV): m/z (%) = 253 (95) [M+], 184 (100), 169 (10).
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO: 254.0792;
found: 254.0794.
1-(3-Fluorophenyl)-3-trifluoroacetyl-1H-pyrrole (5h)
Yield: 164 mg (32%); yellow hygroscopic solid.
1H NMR (400 MHz, CDCl3): δ = 7.82 (br s, 1 H), 7.50–7.44 (m,
1 H), 7.25–7.23 (m, 1 H), 7.18–7.08 (m, 3 H), 6.92 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.7 Hz), 163.3
1-(3-Methoxyphenyl)-3-trifluoroacetyl-1H-pyrrole (5c)
Yield: 269 mg (50%); yellow oil.
1
3
3
(d, JC–F = 249.1 Hz), 140.5 (d, JC–F = 9.8 Hz), 131.4 (d, JC–F
=
=
4
4
1H NMR (200 MHz, CDCl3): δ = 7.83 (br s, 1 H), 7.40 (m, 1 H),
7.09 (m, 1 H), 7.00 (m, 1 H), 6.91 (m, 3 H), 3.86 (s, 3 H).
9.3 Hz), 127.2 (q, JC–F = 3.5 Hz), 122.4, 120.1, 117.0 (d, JC–F
1
2
3.1 Hz), 116.9 (q, JC–F = 290.7 Hz), 114.9 (d, JC–F = 21.2 Hz),
112.3, 109.2 (d, 2JC–F = 25.4 Hz).
13C NMR (50 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.4 Hz), 160.7,
4
140.2, 130.8, 127.5 (q, JC–F = 3.4 Hz), 122.6, 119.5, 117.0 (q,
GC-MS (EI, 70 eV): m/z (%) = 257 (56) [M+], 188 (100), 133 (22).
HRMS (ESI): m/z [M + H]+ calcd for C12H8F4NO: 258.0542; found:
1JC–F = 290.7 Hz), 113.6, 113.0, 111.8, 107.7, 55.5.
GC-MS (EI, 70 eV): m/z (%) = 269 (55) [M+], 200 (100), 185 (15).
258.0539.
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO2: 270.0742;
found: 270.0740.
1-(4-Fluorophenyl)-3-trifluoroacetyl-1H-pyrrole (5i)
Yield: 205 mg (40%); white solid; mp 79–82 °C.
1H NMR (400 MHz, CDCl3): δ = 7.76 (br s, 1 H), 7.42–7.39 (m,
2 H), 7.21–7.17 (m, 2 H), 7.02 (dd, J = 2.9, 2.0 Hz, 1 H), 6.91 (br s,
1 H).
1-(4-Methoxyphenyl)-3-trifluoroacetyl-1H-pyrrole (5d)
Yield: 152 mg (38%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.75 (br s, 1 H), 7.34 (d, J =
9.0 Hz, 2 H), 7.05 (br s, 1 H), 6.99 (d, J = 9.0 Hz, 2 H), 6.89 (br s,
1 H), 3.85 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.4 Hz), 161.9
1
4
4
(d, JC–F = 248.7 Hz), 135.4 (d, JC–F = 2.9 Hz), 127.6 (q, JC–F
=
=
3
1
3.5 Hz), 123.5 (d, JC–F = 8.4 Hz), 122.8, 119.6, 116.9 (q, JC–F
13C NMR (100 MHz, CDCl3): δ = 175.5 (q, 2JC–F = 35.3 Hz), 159.3,
290.9 Hz), 116.9 (d, 2JC–F = 23.1 Hz), 112.0.
4
132.5, 127.7 (q, JC–F = 3.4 Hz), 123.0, 122.9, 119.2, 116.9 (q,
1JC–F = 290.9 Hz), 114.9, 111.6, 55.6.
GC-MS (EI, 70 eV): m/z (%) = 257 (55) [M+], 188 (100), 133 (25).
GC-MS (EI, 70 eV): m/z (%) = 269 (100) [M+], 200 (100), 185 (37).
HRMS (ESI): m/z [M + H]+ calcd for C12H8F4NO: 258.0542; found:
258.0535.
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO2: 270.0742;
found: 270.0741.
1-(3-Chlorophenyl)-3-trifluoroacetyl-1H-pyrrole (5j)
Yield: 245 mg (45%); yellow oil.
1-(2-Methylphenyl)-3-trifluoroacetyl-1H-pyrrole (5e)
Yield: 152 mg (38%); yellow oil.
1H NMR (200 MHz, CDCl3): δ = 7.82 (br s, 1 H), 7.45–7.30 (m,
4 H), 7.01 (dd, J = 3.1, 2.1 Hz, 1 H), 6.93 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.3 Hz), 140.2,
135.8, 131.0, 128.1, 127.2 (q, 4JC–F = 3.5 Hz), 122.4, 121.9, 120.1,
119.6, 116.9 (q, 1JC–F = 290.7 Hz), 111.2.
1H NMR (400 MHz, CDCl3): δ = 7.57 (br s, 1 H), 7.37–7.26 (m,
4 H), 6.89 (br s, 1 H), 6.81 (dd, J = 3.2, 2.2 Hz, 1 H), 2.20 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.4 Hz), 138.7,
133.6, 131.4, 129.1, 126.9, 126.3, 130.1 (q, 4JC–F = 3.3 Hz), 124.9,
118.7, 116.9 (q, 1JC–F = 290.9 Hz), 110.8, 17.5.
GC-MS (EI, 70 eV): m/z (%) = 273 (21) [M+], 204 (100), 169 (16).
GC-MS (EI, 70 eV): m/z (%) = 253 (70) [M+], 184 (100), 154 (10).
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO: 254.0792;
HRMS (ESI): m/z [M + H]+ calcd for C12H8ClF3NO: 274.0246;
found: 274.0239.
found: 254.0786.
1-(4-Chlorophenyl)-3-trifluoroacetyl-1H-pyrrole (5k)
Yield: 234 mg (43%); yellow solid; mp 102–106 °C.
1-(3-Methylphenyl)-3-trifluoroacetyl-1H-pyrrole (5f)
Yield: 177 mg (35%); yellow oil.
1H NMR (200 MHz, CDCl3): δ = 7.82 (br s, 1 H), 7.41–7.19 (m,
4 H), 7.08 (dd, J = 3.1, 2.2 Hz, 1 H), 6.91 (br s, 1 H), 2.44 (s, 3 H).
1H NMR (200 MHz, CDCl3): δ = 7.80 (br s, 1 H), 7.48 (d, J =
8.9 Hz, 2 H), 7.38 (d, J = 8.9 Hz, 2 H), 7.06 (dd, J = 3.2, 2.2 Hz,
1 H), 6.93 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.6 Hz), 137.8,
4
133.9, 130.2, 127.3 (q, JC–F = 3.5 Hz), 122.8, 122.5, 120.1, 116.9
(q, 1JC–F = 290.7 Hz), 112.3.
Synthesis 2012, 44, 3477–3482
© Georg Thieme Verlag Stuttgart · New York

PAPER
1-Aryl-3-trifluoroacetyl-1H-pyrroles
3481
GC-MS (EI, 70 eV): m/z (%) = 273 (69) [M+], 204 (100), 169 (26).
HRMS (ESI): m/z [M + H]+ calcd for C12H8ClF3NO: 274.0246;
References
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1-(4-Bromophenyl)-3-trifluoroacetyl-1H-pyrrole (5l)
Yield: 353 mg (56%); brown hygroscopic solid.
1H NMR (200 MHz, CDCl3): δ = 7.80 (br s, 1 H), 7.63 (d, J =
8.9 Hz, 2 H), 7.32 (d, J = 8.9 Hz, 2 H), 7.06 (dd, J = 3.1, 2.2 Hz,
1 H), 6.93 (br s, 1 H).
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13C NMR (100 MHz, CDCl3): δ = 175.6 (q, 2JC–F = 35.5 Hz), 138.2,
4
133.1, 127.2 (q, JC–F = 3.5 Hz), 123.0, 122.4, 121.5, 119.9, 116.9
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(q, 1JC–F = 290.9 Hz), 112.3.
GC-MS (EI, 70 eV): m/z (%) = 317 (26) [M+], 248 (100), 169 (57),
141 (26).
HRMS (ESI): m/z [M + Na]+ calcd for C12H8BrF3NO: 339.9561;
found: 339.9559.
1-(4-Hydroxyphenyl)-3-trifluoroacetyl-1H-pyrrole (5m)
Yield: 198 mg (39%); brown solid; mp 125–129 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.82 (br s, 1 H), 8.17 (br s,
1 H), 7.52 (d, J = 8.7 Hz, 2 H), 7.47 (t, J = 2.6 Hz, 1 H), 7.90 (d, J =
8.7 Hz, 2 H), 6.83 (br s, 1 H).
2
13C NMR (100 MHz, DMSO-d6): δ = 174.2 (q, JC–F = 34.4 Hz),
156.9, 130.3, 127.8 (q, 4JC–F = 3.4 Hz), 123.6, 122.5, 117.8, 116.6
(q, 1JC–F = 291.4 Hz), 115.9, 110.7.
GC-MS (EI, 70 eV): m/z (%) = 255 (70) [M+], 186 (100).
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HRMS (ESI): m/z [M + H]+ calcd for C12H9F3NO2: 256.0585;
found: 256.0580.
1-(2-Hydroxy-5-methylphenyl)-3-trifluoroacetyl-1H-
pyrrole (5n)
Yield: 263 mg (49%); brown hygroscopic solid.
1H NMR (400 MHz, DMSO-d6): δ = 9.98 (br s, 1 H), 8.02 (br s,
1 H), 7.28 (dd, J = 3.0, 2.2 Hz, 1 H), 7.21 (br s, 1 H), 7.06 (d, J =
8.3 Hz, 1 H), 6.96 (d, J = 8.3 Hz, 1 H), 6.78 (br s, 1 H), 2.26 (s, 3 H).
2
13C NMR (100 MHz, DMSO-d6): δ = 174.2 (q, JC–F = 34.3 Hz),
147.8, 130.8 (q, 3JC–F = 3.6 Hz), 129.6, 128.6, 125.7, 125.6, 125.8,
117.0, 116.8, 116.7 (q, 1JC–F = 291.4 Hz), 109.5, 19.7.
GC-MS (EI, 70 eV): m/z (%) = 269 (68) [M+], 200 (100).
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO2: 270.0742;
found: 270.0738.
1-(3-Hydroxy-4-methylphenyl)-3-trifluoroacetyl-1H-
pyrrole (5o)
Yield: 182 mg (34%); brown hygroscopic solid.
1H NMR (400 MHz, DMSO-d6): δ = 9.66 (br s, 1 H), 8.09 (br s,
1 H), 7.43 (dd, J = 3.2, 2.2 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.02
(m, 2 H), 6.83 (s, 1 H), 2.17 (s, 3 H).
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2
13C NMR (100 MHz, DMSO-d6): δ = 174.2 (q, JC–F = 34.6 Hz),
156.0, 136.9, 131.2, 127.5 (q, 4JC–F = 3.4 Hz), 123.9, 123.3, 117.9,
116.5 (q, 1JC–F = 291.5 Hz), 111.4, 110.8, 107.5, 15.2.
GC-MS (EI, 70 eV): m/z (%) = 269 (59) [M+], 200 (100).
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO2: 270.0742;
found: 270.0743.
Acknowledgment
The authors thank the Fundação de Apoio à Tecnologia e Ciência
do Estado do Rio Grande do Sul (FAPERGS, PRONEX No.
10/0037-8) and Conselho Nacional de Desenvolvimento Científico
e Tecnológico (CNPq – Universal grant No. 473512/2009-2) for fi-
nancial support, and fellowships from CAPES (F.M.S.) and CNPq
(E.C.A).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3477–3482

3482
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Synthesis 2012, 44, 3477–3482
© Georg Thieme Verlag Stuttgart · New York