Synthesis of trifluoromethylpyrroles and related heterocycles from 4-Ethyloxy-1,1,1-trifluorobut-3-ene-2-one

Article abstract of DOI:10.1016/S0040-4020(00)00598-6

Syntheses of intermediate 4-dialkylamino-1,1,1-trifluorobut-3-ene-2-ones are described from 4-ethyloxy-1,1,1-trifluorobut-3-ene-2-one and α-aminoacids. In subsequent cyclisations pyrroles and other bicyclic heteroaromatics having trifluoromethyl substitut

Full text of DOI:10.1016/S0040-4020(00)00598-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7267–7272
Synthesis of Trifluoromethylpyrroles and Related Heterocycles
from 4-Ethyloxy-1,1,1-trifluorobut-3-ene-2-one
*
Rebecca J. Andrew and John M. Mellor
Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Received 22 March 2000; revised 8 June 2000; accepted 22 June 2000
Abstract—Syntheses of intermediate 4-dialkylamino-1,1,1-trifluorobut-3-ene-2-ones are described from 4-ethyloxy-1,1,1-trifluorobut-3-
ene-2-one and a-aminoacids. In subsequent cyclisations pyrroles and other bicyclic heteroaromatics having trifluoromethyl substitution are
obtained either by simple dehydration or with concomitant decarboxylation. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
the procedure of Hojo et al.26 we find that the ketone (2)
is easily prepared from trifluoroacetic anhydride and ethyl-
vinyl ether. We have used the ketone (2) in preparation of
4-dimethylamino-1,1,1-trifluorobut-3-ene-2-one (1) in other
studies24 and find preparation of diverse 4-dialkylamino-
1,1,1-trifluoro-3-buten-2-ones can readily be extended by
using a-aminoacids directly. We now report that their
subsequent cyclisation provides an efficient route both to
trifluoromethylpyrroles and related trifluoromethylated
heterocyclic skeletons.
The synthesis of trifluoromethyl substituted heterocycles
has become an important objective. The use of trifluoro-
methyl substituted heterocycles as herbicides and as
compounds of pharmaceutical interest illustrates the need
for efficient syntheses of these heterocycles. The synthesis
of the following skeletons having trifluoromethyl substi-
tution has recently been reported: pyridines1 including
dihydropyridines,2 furans,3 pyrroles,4–6 pyrazoles,7,8 isoxa-
zolidines,9 imidazoles,10 thiazoles,11 oxazoles,11 oxadia-
zoles,12 purines,13 pyrimidines,14 pyrazolines,15 pyrid-
azines,16 triazines,17 indoles,18 quinolines,19 thiazines,20
benzodiazepines,21 piperidines,22 and indolizidinone deriva-
tives.23 Most of these syntheses depend upon a cyclisation of
an acyclic building block incorporating a trifluoromethyl
group. In the accompanying papers24,25 we describe the
use of 4-dimethylamino-1,1,1-trifluorobut-3-ene-2-one (1)
and of 4-ethyloxy-1,1,1-trifluoro-3-buten-2-one (2) in the
synthesis of alicyclic compounds having trifluoromethyl
substitution and in the synthesis of unsaturated trifluoro-
methyl ketones. In this paper we report the use of 4-ethyl-
oxy-1,1,1-trifluoro-3-buten-2-one (2) in the synthesis of
trifluoromethylpyrroles.
Results and Discussion
The viability of a reaction sequence based on reaction of an
a-aminoacid with the alkoxy unsaturated ketone (2)
followed by a cyclisation was established with three
aminoacids with isolation of the intermediate b-dialkyl-
amino unsaturated ketones. Reaction of proline with freshly
prepared 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (2) gave
aminoacid (3) in 73% yield. Similarly racemic N-methyl-
alanine and N-benzylglycine gave the amino acids (4) and
(5) in 35 and 41% yields, respectively. The NMR spectra of
the product (3) were somewhat complex. At room tempera-
ture in CDCl3 the two conformers (3a) and (3b) were
observed in a ratio of 85:15. In DMSO at 403 K the rota-
tional equilibrium was established and signal coalescence
occurred. In a similar manner the aminoacid (4) was
observed at room temperature in CDCl3 to give two sets
of signals, again corresponding to the conformers (4a) and
(4b). At 358 K complete coalescence of the signals of the
two conformers was observed. Observation of a trans
There is a recent report5 of the use of 4-substituted-1,1,1-
trifluoro-3-buten-2-ones in the synthesis of pyrroles. In this
French study the key substrates for cyclisations were
prepared by reaction of 4-chloro-1,1,1-trifluoro-3-buten-2-
ones with esters of a-aminoacids. Five examples of subse-
quent cyclisations afforded trifluoromethylated pyrroles. In
our study we have chosen 4-ethyloxy-1,1,1-trifluoro-3-
buten-2-one (2) as our readily available substrate. Using
Keywords: amino acids; pyrroles; thiaproline; trifluoromethyl.
* Corresponding author. Tel.: ϩ44-(0)23-8059-2392; fax: ϩ44-(0)23-
8059-6805; e-mail: jmm4@soton.ac.uk
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00598-6

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R. J. Andrew, J. M. Mellor / Tetrahedron 56 (2000) 7267–7272
Scheme 1.
coupling constant (Jˆ12 Hz) in both the major conformer at
8.05 ppm and in the minor conformer at 7.99 ppm indicated
that the origin of the conformational equilibria were rota-
tions about the carbon–nitrogen bonds rather than rotations
about the carbon–carbon double bonds. The major confor-
mer (4a) gave rise to a resonance at 4.71 ppm and the minor
conformer (4b) to an equivalent resonance at 4.66 ppm.
Wojcik et al.27 have associated lower field signals with the
Z configuration about the carbon–nitrogen bonds and our
tentative assignment is based on their findings. The product
(5) from N-benzylglcine again showed two conformers in an
approximate ratio of 55:45. However no variable tempera-
ture studies were made in this case.
involving trifluoroacetylation of the enamines (3) and (4).
Cyclisation in the proline series of the resulting dione (8) is
followed by loss of water and carbon dioxide to give the
aromatic product (6) (see Scheme 1). In contrast in the case
of N-benzylglycine loss of water alone from the dione inter-
mediate (9) leads to the aromatic carboxylic acid (7).
Support for this reaction scheme can be found in the work
of Levy et al.,28 who reported the reaction of the dione (10)
with an ester of N-benzylglycine to give a pyrrole (11). The
formation of the bicyclic (6) through a final decarboxylation
provides a contrasting and novel extension of the chemistry
of enamines derived from the vinyl ether (2).
Reaction of the aminoacid (3) with trifluoroacetic anhydride
gave the fluorinated pyrrole (6) in 70% yield. In contrast
under similar conditions the aminoacid (5) gave the fluori-
nated pyrrole carboxylic acid (7) in 43% yield. The forma-
tion of the pyrroles can be rationalised by a sequence
An obvious simplification of this pyrrole synthesis might be
a one-pot procedure involving the sequence of Friedel–
Crafts trifluoroacetylation of ethyl vinyl ether, enamine

R. J. Andrew, J. M. Mellor / Tetrahedron 56 (2000) 7267–7272
7269
formation and final cyclisation of the intermediate enamine.
This three step sequence was applied to pipecolic acid,
N-methylglycine and thiaproline. Pipecolic acid and
N-methylglycine gave the pyrroles (12) and (13) in 24
and 33% overall yields, respectively. Hence pipecolic acid
and proline behave in analogous manner and again the
outcome with N-methylglycine is analogous to that with
N-benzylglycine. In the case of thiaproline two products
(14) and (15) are obtained. The former product (14) is
clearly analogous to the product (6) isolated from proline.
The origin of the second product (15) could be through one
of two routes. Either the pyrrole (15) could be a product
formed by detrifluoroacetylation of the trifluoroacetylated
pyrrole (14), or it might arise via cyclisation of the inter-
mediate monoketone (16). A cyclisation of a related ketone
has been reported29 earlier and we consider reaction via the
latter pathway is the more probable. In contrast to these
successful cyclisations, no product was obtained from
the attempted cyclisation of the intermediate (4) from
N-methylalanine, or the intermediate (17) from N-benzyl-
alanine.
results extend to a different range of compounds, but more
importantly they illustrate a different reaction pathway with
proline, thiaproline and pipecolic acid involving decarb-
oxylation. These decarboxylations afford fluorinated
derivatives of heterocyclic skeletons known to exhibit
interesting biological activity. Overall our results provide
a rapid entry to an interesting range of fluorinated pyrroles.
Experimental
General experimental methods are described in the previous
paper.25
(2S)-1-[(E)-4,4,4-Trifluoro-3-oxo-1-butenyl]tetrahydro-
1H-2-pyrrolecarboxylic acid (3). To a stirred solution of
4-dimethylaminopyridine (4 mg) and trifluoroacetic
anhydride (1.16 g) in dichloromethane (6 ml), ethyl vinyl
ether (0.36 g) was added dropwise at Ϫ10ЊC. After stirring
for 19 h at 0ЊC the mixture was allowed to warm to room
temperature and the solvent was removed in vacuo. To the
stirred resulting oil acetonitrile (10 ml) and l-(Ϫ)-proline
(0.75 g) were added at room temperature. After stirring for
4 h, the solvent was removed in vacuo and the resulting
yellow semi-solid was purified by flash chromatography
(silica gel; light petroleum 50%, ethyl acetate 50%) and
recrystallised (ethyl acetate/light petroleum) to give the
title compound (3) as pale yellow crystals (0.86 g, 73%)
mp 109–110ЊC (lit.30 mp 103ЊC); dH (room temperature)
8.22 (0.85H, d, Jˆ12 Hz, H-10), 8.08 (0.15H, d, Jˆ10 Hz,
H-10), 7.33 (1H, br s, OH), 5.42 (0.85H, d, Jˆ12.5 Hz,
H-20), 5.22 (0.15H, d, Jˆ13 Hz, H-20), 4.45 (0.85H, t,
Jˆ5.7 Hz, H-2), 4.23 (0.15H, dd, Jˆ8.8, 3.7 Hz, H-2),
3.76 (0.30H, m, H-5), 3.48 (1.70H, m, H-5) and 2.23 (4H,
m, H-3 Hz, H-4); dC 177.40 (q, JCFˆ33 Hz, C-30), 173.05
(COOH), 155.54 and 154.10 (C-10), 117.94 (q, JCFˆ197 Hz,
C-40), 90.25 and 89.66 (C-20), 65.01 and 60.53 (C-2), 54.02
and 48.67 (C-5), 30.69 and 29.60 (C-4) and 23.71 and 23.53
(C-3); dF Ϫ84.98 (CF3); nmax 3448 (OH), 2956, 2884, 1727
(CO), 1649 (CO), 1555 (CvC), 1257, 1187, 1137 and
1098 cmϪ1
;
m/z 236 (MϪϪH, 100%) and 192
(MϪϪCOOH, 17).
2-{(Methyl)[(E)-4,4,4-trifluoro-3-oxo-1-butenyl]amino}-
propanoic acid (4). In a similar manner ethyl vinyl ether
(0.23 g) was reacted with trifluoroacetic anhydride (0.73 g)
in the presence of DMAP (2 mg) and the product was heated
under reflux for 12 h in acetonitrile (6 ml) with d,l-N-
methylalanine (0.66 g). The mixture was allowed to cool
to room temperature and the solvent was removed in
vacuo. Diethyl ether (6 ml) and water (6 ml) were added
and the two phases separated. The aqueous phase was
further extracted with diethyl ether (5×6 ml), the combined
ether extracts dried (MgSO4) and the solvent was removed
in vacuo. The resulting orange solid was purified by flash
chromatography (silica gel; light petroleum 50%, ethyl
acetate 50%) and recrystallised (diethyl ether/n-pentane)
to give the title compound (4) as white crystals (0.25 g,
35%) mp 129–130ЊC; dH (room temperature) 8.05 (0.83H,
d, Jˆ12 Hz, H-10), 7.99 (0.17H, d, Jˆ12.5 Hz, H-10), 5.50
(0.17H, d, Jˆ12.5 Hz, H-20), 5.41 (0.83H, d, Jˆ12 Hz,
H-20), 4.71 (0.83H, q, Jˆ7 Hz, H-2), 4.66 (0.17H, q,
Jˆ7 Hz, H-2), 2.90 (3H, s, NCH3), 1.45 (2.49H, d,
These cyclisations based on enamines derived from amino-
acids provide a one-pot direct synthesis of a variety of
pyrroles. Although no such routes have been reported
from aminoacids, there are two related studies based on
esters of aminoacids. In the work of Levy et al.28 the esters
of the aminoacids are reacted with the unstable diketone
(10), which itself is only obtained in 25% yield by reaction
of trifluoroacetic anhydride with triethylamine. Clearly in
this instance the pyrrole synthesis based on the aminoacids
is preferable. The formation of pyrrole carboxylic acids is
closely related to the study of Laurent et al.5 leading to the
esters of pyrrole carboxylic acids. However, not only do our

7270
R. J. Andrew, J. M. Mellor / Tetrahedron 56 (2000) 7267–7272
Jˆ7.4 Hz, H-3) and 1.40 (0.51H, d, Jˆ7 Hz, H-3); dH
(358 K) 8.08 (1H, d, Jˆ12 Hz, H-10), 5.48 (1H, d,
Jˆ12 Hz, H-20), 4.66 (1H, q, Jˆ7 Hz, H-2), 3.01 (3H, s,
NCH3) and 1.56 (3H, d, Jˆ7 Hz, H-3); dC (room tempera-
ture) 175.02 (q, JCFˆ31 Hz, C-30), 171.83 and 170.94 (C-1),
157.93 and 157.02 (C-10), 117.61 (q, JCFˆ292 Hz, C-40),
86.76 (C-20), 63.36 and 55.87 (C-2), 33.62 (NCH3) and
15.26 and13.70 (C-3); dC (366 K) 174.72 (q, JCFˆ31 Hz,
C-30), 170.95 (C-1), 155.91 (C-10), 117.19 (q,
JCFˆ292 Hz, C-40), 86.85 (C-20), 62.99 (C-2), 33.49
(NCH3), 14.91 (C-3); nmax 1736 (CO), 1658 (CO), 1572
(CvC), 1186, 1139 and 1103 cmϪ1 Found Mϩ 225.0614
C8H10F3NO3 requires Mϩ 225.0613; m/z 224 (MϪϪH,
62%) and 180 (MϪϪCOOH, 100); Found: C, 42.6; H, 4.6;
N, 6.0 C8H10F3NO3 requires C, 42.7; H, 4.5; N, 6.2%.
C10H7F6NO requires 271.0432, m/z 272 (MϩϩH, 100%),
202 (76).
1-(Phenylmethyl)-4-(2,2,2-trifluoroacetyl)-3-(trifluoro-
methyl)-1H-2-pyrrolecarboxylic acid (7). To a stirred
solution of 2-{(phenylmethyl)[(E)-4,4,4-trifluoro-3-oxo-1-
butenyl]amino}ethanoic acid (5) (0.11 g) in anhydrous
dichloromethane (4 ml) under nitrogen was added dropwise
at room temperature trifluoroacetic anhydride (0.17 g).
After stirring for 6 h at room temperature, the solvent was
removed in vacuo and the resulting brown oil was purified
by flash column chromatography (silica gel, petroleum
ether/ethyl acetate 9:1) to give the title compound (7) as
impure orange crystals (0.06 g, 43%) mp 37–41ЊC dH
9.78 (1H, s, OH), 7.54 (1H, br d, Jˆ1.5 Hz, H-5), 7.29
(5H, m, Ar–H) 5.54 (2H, s, NCH2); dC 178.98 (COOH),
169.44 (q, JC–Fˆ39 Hz, COCF3), 159.46 (C-2), 134.52 (q,
JC–Fˆ4 Hz, C-5), 134.29 (C-10), 129.39, 129.03 and 127.66
(C-20, C-30, C-40, C-50, C-60), 116.26 and 116.02 (q,
JC–Fˆ288 Hz, C-3–CF3 and COCF3), 112.46 and 104.96
(C-3 and C-4), 55.59 (NCH2); dF Ϫ87.32 (C-3–CF3),
85.40 (COCF3); nmax (cmϪ1) 3546 (OH), 1659 (CO), 1585
(CvC), 1514 (CvC), 1210 and 1153; Found Mϩ 365.0487
C15H9F6NO3 requires 365.0485 m/z 364 (MϪϪH, 100)
(APCI mode).
2-{(Phenylmethyl)[(E)-4,4,4-trifluoro-3-oxo-1-butenyl]-
amino}ethanoic acid (5). In a similar manner ethyl vinyl
ether (0.22 g) was reacted with trifluoroacetic anhydride
(0.69 g) and the product was stirred for 3 h at room tempera-
ture with N-benzylglycine hydrochloride (0.6 g) in 2.5 M
sodium hydroxide solution (3.0 ml). The solution was acidi-
fied to pH 3 and extracted with diethyl ether (4×3 ml). The
combined organic phase was dried (MgSO4) and the solvent
removed in vacuo. The resulting yellow oil was purified by
flash chromatography (silica gel, ethyl acetate) and recrys-
tallised (diethyl ether/n-pentane) to give the title compound
(5) as orange crystals (0.36 g, 41%) mp 113–114ЊC; dH 8.74
(1H, br s, OH), 8.19 (0.55H, d, Jˆ13 Hz, H-10), 8.15
(0.45H, d, Jˆ13 Hz, H-10), 7.39 (3H, m, Ar–H), 7.22 (2H,
m, Ar–H), 5.69 (0.45H, d, Jˆ12 Hz, H-20), 5.37 (0.55H, d,
Jˆ12.5 Hz, H-20), 4.62 (1.10H, s, NCH2Ph), 4.54 (0.90H, s,
NCH2Ph), 4.07 (0.90H, s, H-2) and 3.91 (1.1H, s, H-2); dC
178.68 (q, JCFˆ33 Hz, C-30), 171.28 and 170.49 (C-1),
159.33 and 157.54 (C-10), 133.64 and 132.97 (Ar),
129.46, 129.27, 128.96, 128.47 and 127.94 (Ar), 117.61
(q, JCFˆ290 Hz, C-40), 89.92 and 89.05 (C-20), 61.46 and
55.49 (NCH2Ph) and 53.64 and 48.59 (C-2); dF Ϫ84.73
(CF3); nmax 3029, 2937, 1718 (CO), 1673 (CO), 1568
(CvC), 1258, 1089, 925, 778 and 705 cmϪ1; Found Mϩ
287.0769 C13H12F3NO3 requires Mϩ 287.0769; m/z 286
(MϪϪH, 67%) and 242 (MϪϪCOOH, 100).
2,2,2-Trifluoro-1-[1-(trifluoromethyl)-5,6,7,8-tetrahydro-
2-indolizinyl]-1-ethanone (12). To a stirred solution of
4-dimethylaminopyridine (2 mg) and trifluoroacetic
anhydride (0.73 g) in anhydrous dichloromethane (4 ml)
was added dropwise at Ϫ10ЊC ethyl vinyl ether (0.23 g).
After stirring for 19 h at 0ЊC the mixture was allowed to
warm to room temperature and the solvent removed in
vacuo. To the stirred resulting oil was added dropwise at
room temperature d,l-pipecolic acid (0.83 g) in acetonitrile
(6 ml). After heating under reflux for 6 h, the mixture was
allowed to cool to room temperature and the solvents were
removed in vacuo. Diethyl ether (10 ml) and water (10 ml)
were added and the two phases separated. The aqueous
phase was further extracted with diethyl ether (9×10 ml)
and the combined organic phases were dried (MgSO4) and
the solvent removed in vacuo. To the resulting orange solid
at room temperature under nitrogen was added trifluoro-
acetic anhydride (1.34 g) in anhydrous dichloromethane
(30 ml). After stirring at room temperature for 24 h, the
solvent was removed in vacuo. The resulting brown oil
was purified by flash column chromatography (silica gel,
petroleum ether/ethyl acetate 4:1) and then by recrystallisa-
tion (ethanol/water) to give the title compound (12) as
colourless needles (0.22 g, 24%) mp 61–62ЊC; Found: C,
46.1; H, 3.2; N, 4.9. C11H9F6NO requires C, 46.3; H, 3.2; N,
4.9%; dH 7.36 (1H, s, H-30), 4.40 (2H, t, Jˆ6.1 Hz, H-50),
2.98 (2H, t, Jˆ6.3 Hz, H-80), 2.03 (2H, dquin, Jˆ3.3,
5.9 Hz, H-60 or H-70), 1.91 (2H, dquin, Jˆ3.3, 6.0 Hz,
H-60 or H-70); dC 169.91 (q, JC–Fˆ35 Hz, C-1), 141.46
(C-8a0), 123.22 (C-20), 123.14 (q, JC–Fˆ267 Hz, C-10 –
CF3), 121.21 (quin, JC–Fˆ3 Hz, C-30), 117.00 (q, JC–
2,2,2-Trifluoro-1-[7-(trifluoromethyl)-2,3-dihydro-1H-6-
pyrrolizinyl]-1-ethanone (6). To a stirred solution of (2S)-
1-[(E)-4,4,4-trifluoro-3-oxo-1-butenyl]
tetrahydro-1H-2-
pyrrolecarboxylic acid (3) (0.10 g) in anhydrous dichloro-
methane (4 ml) was added dropwise at room temperature
under nitrogen trifluoroacetic anhydride (0.12 g). After stir-
ring for 4 h at room temperature, the solvent was removed in
vacuo and the resulting brown solid was purified by flash
column chromatography (silica gel; petroleum ether/diethyl
ether 7:3). Recrystallisation (ethanol/water) gave the title
compound (6) as white crystals (0.08 g, 70%) mp 38–
39ЊC; dH 7.33 (1H, s, H-50), 4.40 (2H, t, Jˆ7.4 Hz, H-30),
3.04 (2H, t, Jˆ7.5 Hz, H-10), 2.65 (2H, quin, Jˆ7.5 Hz, H-
20); dC 170.17 (q, JC–Fˆ36 Hz, C-1), 147.93 (C-7a0), 122.96
(q, JC–Fˆ267 Hz, C-70 –CF3), 122.94 (quin, JC–Fˆ3 Hz, C-
50), 121.41 (C-60), 116.85 (q, JC–Fˆ290 Hz, C-2), 109.87 (q,
JC–Fˆ39 Hz, C-70), 49.34 (C-30), 26.64 and 24.44 (C-10 and
ˆ291 Hz, C-2), 113.47 (quin, JC–Fˆ37 Hz, C-10), 47.13
F
(C-50), 22.87 (C-80), 22.62 and 18.60 (C-60 and C-70); dF
Ϫ92.46 (C-10 –CF3), 90.17 (C-2–F3); nmax (cmϪ1) 2940,
1679 (CO), 1556 (CvC), 1507, 1171, 1134, 1099; Found
Mϩ 285.0584 C11H9F6NO requires Mϩ 285.0588, m/z 285
(Mϩ, 60%), 266 (10), 216 (100), 188 (9).
C-20); dF Ϫ92.40 (C-70 –CF3), 89.22 (C-2–F3); nmax (cmϪ1
)
3151, 2976, 2932, 2866, 1680 (CO), 1568 (CvC), 1499,
1245, 1165, 1116, 1052, 945; found Mϩ 271.0452

R. J. Andrew, J. M. Mellor / Tetrahedron 56 (2000) 7267–7272
7271
1-Methyl-4-(2,2,2-trifluoroacetyl)-3-(trifluoromethyl)-1H-
2-pyrrolecarboxylic acid (13). To a stirred solution of
4-dimethylaminopyridine (2 mg) and trifluoroacetic
anhydride (0.73 g) in dichloromethane (4 ml) was added
dropwise at Ϫ10ЊC ethyl vinyl ether (0.23 g). After stirring
for 19 h at 0ЊC the mixture was allowed to warm to room
temperature and the solvent removed in vacuo. To the
stirred resulting oil was added dropwise at room tempera-
ture N-methylgylcine (0.57 g) in acetonitrile (6 ml). After
stirring at room temperature for 23 h, the solvents were
removed in vacuo. Diethyl ether (6 ml) and water (6 ml)
were added and the two phases separated. The aqueous
phase was further extracted with diethyl ether (7×6 ml)
and the combined organic phases were dried (MgSO4) and
the solvent removed in vacuo. To the resulting yellow solid
was added at room temperature with stirring under nitrogen
trifluoroacetic anhydride (1.34 g) in anhydrous dichloro-
methane (30 ml) and after stirring at room temperature for
24 h, the solvents were removed in vacuo. The resulting
brown solid was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate 4:1). Recrystallisa-
tion (ethanol/water) afforded the title compound (13) as off
white crystals (0.30 g, 33%) mp 79–80ЊC; Found: C, 37.2;
H, 1.6; N, 4.8 C9H5F6NO3 requires C, 37.4; H, 1.7; N, 4.8%;
dH 9.75 (1H, s, OH), 7.48 (1H, br q, Jˆ0.7 Hz, H-5), 4.00
(3H, s, NCH3); dC 178.78 and 178.27 (COOH), 169.79 (q,
JC–Fˆ39 Hz, COCF3), 159.12 (C-2), 134.98 (d, JC–Fˆ4 Hz,
C-5), 116.32 and 116.07 (both q, JC–Fˆ288 Hz, C-3–CF3,
COCF3), 113.02 and 104.56 (C-3 and C-4), 40.65 (NCH3);
dF Ϫ87.21 (C-3–CF3), 85.23 (COCF3); nmax (cmϪ1) 3435
(OH), 1649 (CO), 1582 (CvC), 1462, 1206, 1161, 1122;
found Mϩ 289.0171 C9H5F6NO3 requires 289.0174 m/z 288
(MϪϪH, 100) (APCI mode).
(q, JC–Fˆ289 Hz, C-2), 110.30 (q, JC–Fˆ39 Hz, C-70), 51.13
(C-30), 27.98 (C-10); dF Ϫ92.58 (C-70 –CF3), Ϫ89.25 (C-2–
F3); nmax (cmϪ1) 3152, 2924, 1676 (CO), 1564 (CvC),
1501, 1213, 1166, 1147, 1117 and 955; Found Mϩ
289.0001 C9H5F6NOS requires 288.9996, m/z 289
(Mϩ100%), 270 (13), 256 (42), 244 (13), 220 (37).
Recrystallisation (ethanol–water) of the second fraction
afforded the title compound, 7-(trifluoromethyl)-1H-
pyrrolo[1.2-c][1.3]thiazole (15) as yellow crystals (0.32 g,
52%) mp 38–39ЊC Found: C, 43.3; H, 2.9; N, 7.0.
C7H6F3NS requires C, 43.5; H, 3.1; N, 7.3%; dH 6.64 (1H,
d, Jˆ3.0 Hz, H-5), 6.45 (1H, d, Jˆ3.0 Hz, H-6), 5.03 (2H, s,
H-3), 4.15 (2H, q, Jˆ1.3 Hz, H-1); dC 134.48 (d,
JC–Fˆ4 Hz, C-7a), 124.01 (q, JC–Fˆ266 Hz, CF3), 115.92
(C-5), 111.55 (d, JC–Fˆ3 Hz, C-6), 106.69 (q,
JC–Fˆ38 Hz, C-7), 48.83 (C-3), 28.36 (C-1); dF Ϫ91.21
(CF3); nmax (cmϪ1) 3109, 2942, 2900, 2863, 1584 (CvC),
1500, 1436, 1374, 1268, 1177, 1125, 975; found Mϩ
193.0170 C7H6F3NS requires 193.0173, m/z 193
(Mϩ100%), 148 (75), 124 (19).
Acknowledgements
We thank EPSRC for a Quota Award (R. J. A.) and Melloney
Tyte for experimental support.
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