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S. Foister et al. / Bioorg. Med. Chem. 11 (2003) 4333–4340
purchased from NOVA Biochem. Trifluoroacetic acid
(TFA) was purchased from Halocarbon. N-Butyl-
lithium was obtained as a solution in hexanes from
Strem. All other solvents were reagent grade from EM.
The resulting aqueous solution was extracted with di-
chloromethane (3ꢂ150 mL) and the combined organic
solutions were washed with water (3ꢂ150 mL), dried
over MgSO4, filtered, and concentrated to give a dark
oil. The oil was subjected to column chromatography
on silica gel (20:1 hexanes/ethyl acetate) to give (12)
(18.4 g) as a crystalline solid in 64% yield. TLC (20:1
hexanes/ethyl acetate) Rf 0.47; 1H NMR (CDCl3) d 9.58
(s, 1H), 7.59 (d, J=5.7 Hz, 1H), 6.75 (d, J=4.8 Hz,
1H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) d 166.8,
164.7, 131.7, 119.4, 52.2; EI-MS m/e 158.0039 (M+
calculated 158.0038 for C6H6O3S).
NMR spectra were recorded on a Varian spectrometer
at 300 MHz in DMSO-d6 or CDCl3 with chemical shifts
reported in parts per million relative to residual solvent.
Fluorotrichloromethane was used as an internal stan-
dard for 19F NMR. UV spectra were measured on a
Hewlett-Packard Model 8452A diode array spectro-
photometer. High-resolution EI mass spectra were
recorded at the Mass Spectrometry Laboratory at the
California Institute of Technology. Matrix-assisted,
laser desorption/ionization time of flight mass spectro-
metry (MALDI-TOF-MS) was conducted at the Protein
and Peptide Micronanalytical Facility at the California
Institute of Technology.
3-Methoxy-2-thiophenecarboxylic acid (13). A mixture
of (12) (2.3 g, 14.5 mmol), K2CO3 (5.02g, 36.3 mmol),
and iodomethane (10.4 g, 73 mmol) was suspended in
acetone (25 mL) and acetonitrile (5 mL). The resulting
mixture was stirred vigorously at reflux for 3 h. The
reaction was filtered and the resulting solid was washed
with acetone and dichloromethane. The reaction and
washes were combined and concentrated in vacuo to
yield a yellow solid (1.9 g) that was used without further
purification. The yellow solid was dissolved in methanol
(17 mL) and 50% NaOH (3 mL) and was stirred for 3 h.
The reaction was diluted to 40 mL with water and con-
centrated briefly in vacuo to yield a suspension. The
aqueous suspension was washed with diethyl ether
(2ꢂ25 mL), cooled to 0 ꢁC, and acidified to pH 2with
10% sulfuric acid. The aqueous mixture was then
washed with dichloromethane (3ꢂ50 mL) and the com-
bined organic washes were dried over sodium sulfate,
filtered, and concentrated in vacuo to give a yellow oil.
The oil was suspended in 3:1 petroleum ether/dichloro-
methane at ꢀ20 ꢁC overnight. Filtration gave (13) as a
finely divided white solid (0.736 g) in 33% yield over
Monomer synthesis
3 - [(tert - Butoxy)carbonylamino] - 2 - thiophenecarboxylic
acid (11). A mixture of methyl 3-amino-2-thiophene-
carboxylate (2.53 g, 15.9 mmol), Boc2O (7.64 g, 35
mmol), and DMAP (2.04 g, 16.7 mmol) was dissolved in
acetone (15 mL) and TEA (5 mL). The reaction mixture
was stirred vigorously for 4 h and diluted to a volume of
75 mL with dichloromethane. The resulting solution
was washed with cold 1 N HCl (3ꢂ50 mL), 1 N NaOH
(3ꢂ50 mL), and brine (50 mL). The dichloromethane
solution was then dried over MgSO4, filtered, and con-
centrated in vacuo to yield a yellow oil. The crude pro-
duct was loaded onto a short plug of silica and eluted
with 9:1 hexanes/ethyl acetate to yield a pale yellow
solid (1.2g) that was used without further purification.
The solid was dissolved in methanol (76 mL) and 50%
NaOH (4 mL) and the mixture was stirred for 4 h. The
reaction was diluted to a volume of 160 mL with water
and concentrated briefly in vacuo. The remaining aqu-
eous solution was washed with diethyl ether (2ꢂ80 mL),
cooled in an ice bath, and cautiously acidified to pH 2
with sulfuric acid. The suspension was washed with
ethyl acetate (3ꢂ50 mL) and the combined organic
washes were dried over MgSO4, filtered, and con-
centrated in vacuo to yield (11) as a white solid (0.79 g)
1
two steps. TLC (4:1 ethyl acetate/hexanes) Rf 0.5; H
NMR (DMSO-d6) d 12.4 (s, 1H), 7.74 (d, J=5.7 Hz,
1H), 7.06 (d, J=5.4 Hz, 1H), 3.85 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) d 163.0, 161.9, 131.9, 118.0, 109.9,
59.4; EI-MS m/e 158.0034 (M+ calcd 158.0038 for
C6H6O3S).
3-Fluoro-2-thiophenecarboxylic acid (14). 2-Thiophene-
carboxylic acid (1.7 g, 13.3 mmol) was dissolved in
anhydrous THF (30 mL) and the solution was cooled to
ꢀ78 ꢁC under Ar, with stirring. n-Butyllithium (18.3
mL, 29.3 mmol) in hexanes was added to the above
solution and the mixture was stirred for 30 min. A
solution of N-fluorobenzenesulfonimide (5 g, 15.9
mmol) in THF (30 mL) was then added and the result-
ing solution was stirred at ꢀ78 ꢁC for 4 h and allowed to
warm to ambient temperature over a period of 6 h. The
reaction was diluted with diethyl ether (100 mL), cooled
to 0 ꢁC, and 1 N HCl (15 mL) was added to give a
biphasic mixture. The aqueous layer was isolated and
washed with diethyl ether (3ꢂ50 mL). The combined
ethereal layers were dried over MgSO4, filtered, and
concentrated in vacuo to yield an orange oil. The oil
was subjected to column chromatography on silica gel
using 1:1 hexanes/ethyl acetate as the eluent. (14) was
obtained as a slightly brown solid (0.777 g) in 40%
yield. TLC (1:1 ethyl acetate/hexanes) Rf 0.17; 1H NMR
(CDCl3) d 10.7 (s, 1H), 7.53 (dd, J=5.4, 3.6 Hz, 1H),
1
in 69% yield over two steps. H NMR (DMSO-d6) d
9.43 (s, 1H), 7.80 (d, J=5.4 Hz, 1H), 7.72(d, J=5.4 Hz,
1H), 1.46 (s, 9H); 13C NMR (75 MHz, DMSO-d6) d
165.8, 151.8, 144.9, 133.1, 121.2, 109.9, 81.5, 28.6; EI-
MS m/e 243.0563 (M+ calculated 243.0565 for
C10H13NO4S).
Methyl 3-hydroxy-2-thiophenecarboxylate (12). To dry
methanol (81 mL), under nitrogen, was added sodium
metal (3.68 g, 304 mmol). After H2 evolution has
ceased, the solution was cooled to 0 ꢁC and methyl
thioglycolate (10 g, 179 mmol) was added dropwise. A
solution of methyl-2-chloroacrylate (10.88 g, 179 mmol)
in methanol (21 mL) was then added slowly, resulting in
the formation of yellow precipitate. The solution was
allowed to warm to ambient temperature and stirred for
2h. The solvent was removed in vacuo to give a dark
yellow solid that was acidified to pH 2with 4 N HCl.