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A. E. Shinkwin et al. / Bioorg. Med. Chem. 7 (1999) 297±308
970 mmol) in CF3CO2H (10 mL) at 15 ꢀC and the mix-
ture was stirred at 15 ꢀC for 5 min. The evaporation
residue, in EtOAc, was washed (water, brine). Drying,
evaporation and chromatography (CH2Cl2/MeOH 100/
1) gꢀave 25b (110 mg, 36%) as yellow crystals: mp 294±
d, J=16 Hz, 5-H, major), 3.81 (0.8H, t, J=7 Hz, 3-H,
major), 4.06 (0.2H, ddd, J=7.9, 7.1, 1.5 Hz, 3-H,
minor), 4.21 (0.4 H, q, J=7.1 Hz, OCH2, minor), 4.23
(1.6 H, q, J=7.2 Hz, OCH2, major), 8.45 (0.2 H, br,
OH, minor), 8.65 (0.8 H, br, OH, major); MS (EI) m/z
190.0506 (M) (13C12C6H11NO3S requires 190.0493),
189.0474 (M) (12C7H11NO3S requires 189.0460), 116.
1
295 C; H NMR (Table 1); MS (FAB) m/z 318.0207
(M+H) (12C13H8N3O5S requires 318.0185).
4-Bromo-5-nitrothiophene-3-carboxylic acid (26). Fum-
ing HNO3 (90%, 1.0 mL, 24 mmol) was added slowly to
Ac2O (2.3 mL, 24 mmol) at 10 ꢀC, followed by 11
(1.00 g, 4.8 mmol) in AcOH (5 mL). The mixture was
stirred for 20 min at 10 ꢀC. Water (30 mL) was added.
The mixture was extracted with EtOAc. Washing (aq
NaHCO3 (3Â), water), drying, evaporation and chro-
matography (hexane/EtOAc/AcOH 100/100/1) yielded
26 (66 mg, 54%) as a pale-yellow solid: mp 228±231 ꢀC
Ethyl 4-aminothiophene-3-carboxylate hydrochloride (32).
Compound 31 (1.30 g, 6.9 mmol) was stirred with
hydrogen chloride (7.9 mmol) in dry Et2O (24 mL) for
24 h. Evaporation gave crude 32 (1.36 g, 95%) as a dark
1
hygroscopic solid: H NMR d 1.32 (3 H, t, J=7.3 Hz,
Me), 4.30 (2H, q, J=7.3 Hz, CH2), 7.73 (1H, d, J=
3.7 Hz, 5-H), 8.45 (1H, d, J=3.7 Hz, 2-H); MS (FAB)
m/z 172.0437 (M+H) (12C7H10NO2S requires 172.0432).
This material was used directly without further
puri®cation.
(lit.35 mp 236±238 ꢀC); H NMR d 8.69 (1H, s, 2-H),
1
13.62 (1H, br, CO2H); MS (CI) m/z 253 (M+H).
Ethyl 4-acetamidothiophene-3-carboxylate (33a). Com-
pound 32 (110 mg, 530 mmol) was stirred with AcCl
(50 mg, 640 mmol), Et3N (133 mg, 1.3 mmol) and 4-
(dimethylamino)pyridine (20 mg, 160 mmol) in CHCl3
(1.5 mL) for 16 h. CHCl3 (20 mL) was added and the
solution was washed (dilute HCl, aq Na2CO3, water).
Drying, evaporation and chromatography (hexane/
EtOAc 10/1) gave 33a (90 mg, 80%) as white crystals:
mp 57±59 ꢀC; Found: C, 50.70; H, 5.19; N, 6.36.
Ethyl 4-oxotetrahydrothiophene-3-carboxylate (30). Na
(140 mg, 6.2 mmol) was dissolved in dry EtOH (20 mL).
Methyl 3-(methoxycarbonylmethylthio)propanoate (28)45
(1.0 g, 5.2 mmol) was added and the mixture was boiled
under re¯ux for 16 h. The evaporation residue was
brought to pH 5 with dilute HCl and was extracted with
EtOAc. Drying, evaporation and chromatography
(hexane/EtOAc 40/1) yielded 30 (130 mg, 14%) as a pale-
yellow oil: (lit.44 oil); IR (®lm) 3500±3100, 1724, 1665,
1
C9H11NO3S requires C, 50.68; H, 5.21; N, 6.57%; H
1
1618 cm 1; H NMR (CDCl3) d 1.30 (1H, t, J=6.8 Hz,
NMR (CDCl3) d 1.40 (3H, t, J=7.1 Hz, CH2Me), 2.21 (3
H, s, COMe), 4.36 (2H, q, J=7.1 Hz, CH2), 8.01 (1H, d,
J=3.6 Hz) and 8.04 (1H, d, J=3.5 Hz) (thiophene 2,5-
H), 11.05 (1H, br, NH); MS (EI) m/z 213 (M), 125.
Me, keto), 1.31 (2H, t, J=6.8 Hz, Me, enol), 3.21 (0.3
H, dd, J=1.7, 7.8 Hz, 2-H, keto), 3.32 (0.3 H, d,
J=17.6 Hz, 5-H, keto), 3.39 (0.3H, d, J=18 Hz, 5-H,
keto), 3.54 (0.3H, dd, J=9.3, 7.8 Hz, 2-H, keto), 3.77
(1.4H, t, J=2.9 Hz, 5-H, enol), 3.82 (1.4H, t, J=2.9 Hz,
2-H2, enol), 4.26 (0.7 H, q, J=6.8 Hz, OCH2, keto),
4.26 (1.4H, q, J=6.8 Hz, OCH2, enol), 4.37 (0.3H, m, 3-
H, keto), 11.03 (0.7 H, br, OH, enol); MS (EI) m/z
174.0351 (M) (12C7H10O3S requires 174.0351). Further
elution gave 29 (88 mg, 10%) as a pale-yellow oil: (lit.44
oil); IR (®lm) 3500±3100, 1750 cm 1; 1H NMR (CDCl3)
d 1.27 (2H, t, J=7.0 Hz, Me, keto), 1.27 (1H, t,
J=7.0 Hz, Me, enol), 2.02±2.54 (8H, m, 4,5-H2,
(enol+keto), 3.69 (0.3 H, m, 2-H, keto), 4.13 (1.4 H, q,
J=7.0 Hz, OCH2, keto), 4.26 (0.7H, q, J=7.0 Hz,
OCH2, enol), 11.05 (0.7H, br, OH, enol).
Ethyl 4-benzamidothiophene-3-carboxylate (33b). Com-
pound 32 (150 mg, 720 mmol) was stirred with PhCOCl
(120 mg, 870 mmol), Et3N (180 mg, 1.8 mmol) and 4-
(dimethylamino)pyridine (20 mg, 160 mmol) in CHCl3
(2.0 mL) for 16 h. CHCl3 (20 mL) was added and the
solution was washed (dilute HCl, aq Na2CO3, water).
Drying, evaporation and chromatography (hexane/
EtOAc 20/1) gave 33b (150 mg, 75%) as white crystals:
mp 106±108 ꢀC; Found: C, 61.30; H, 4.77; N, 5.01.
1
C14H13NO3S requires C, 61.07; H, 4.77; N, 5.09%; H
NMR (CDCl3) d 1.43 (3H, t, J=7.0 Hz, Me), 4.41 (2H,
q, J=7.0 Hz, CH2), 7.52 (3H, m, Ph 3,4,5-H3), 8.0 (2H,
dd, J=7.7, 1.5 Hz, Ph 2,6-H2), 8.11 (1H, d, J=3.7 Hz,
thiophene 5-H), 8.21 (1H, d, J=3.7 Hz, thiophene 2-H),
11.05 (1H, br, NH); MS (EI) m/z 275 (M), 105.
Ethyl EZ-4-oximinotetrahydrothiophene-3-carboxylate (31).
Compound 30 (1.32 g, 7.6 mmol) was boiled under
re¯ux with BaCO3 (3.43 g, 17.4 mmol) and NH2OH.HCl
(1.21 g, 17.4 mmol) in MeOH (20 mL) for 16 h. The
mixture was ®ltered and the solvent was evaporated
from the ®ltrate. The residue, in EtOAc, was washed
(water) and dried. Evaporation gave 31 (1.36 g, 95%) as
4-Acetamidothiophene-3-carboxylic acid (34a). The ester
33a was treated with NaOH in aq EtOH, as for the
synthesis of 34b, to give 34a (40.3 mg, 86%) as a white
solid: mp 203±205 ꢀC (lit.54 mp 207±208 ꢀC); H NMR
1
1
a pale-yellow oil: IR (®lm) 3332, 1732 cm 1; H NMR
(CDCl3) d 2.24 (3H, s, Me), 8.07 (1H, d, J=3.6 Hz, 5-
H), 8.19 (1H, d, J=3.6 Hz, thiophene 2-H), 9.85 (1 H,
br, NH); MS (FAB) m/z 186.0257 (M) (12C7H8NO3S
requires 186.0202).
(CDCl3) d 1.28 (0.6H, t, J=7.1 Hz, Me, minor geome-
trical isomer), 1.29 (2.4H, t, J=7.1 Hz, Me, major geo-
metrical isomer), 3.10 (0.8H, dd, J=11.5, 7.0 Hz, 2-H,
major), 3.15 (0.2H, dd, J=14, 7.1 Hz, 2-H, minor), 3.26
(0.2H, dd, J=14, 7.9 Hz, 2-H, minor), 3.27 (0.8H, dd,
J=11.5, 6.6 Hz, 2-H, major), 3.55 (0.2H, d, J=16 Hz, 5-
H, minor), 3.65 (0.8H, dd, J=16, 1.5 Hz, 5-H, major),
3.67 (0.2H, dd, J=16, 1.5 Hz, 5-H, minor), 3.75 (0.8 H,
4-Benzamidothiophene-3-carboxylic acid (34b). The ester
33b (63 mg, 229 mmol) was boiled under re¯ux with
NaOH (20 mg, 500 mmol) in EtOH (0.5 mL) and water
(0.5 mL) for 1 h. The evaporation residue, in water, was