Journal of Medicinal Chemistry
Article
Methyl 2-[((4-tert-Butylphenyl)carbonyl)amino]-4-ethyl-5-
2.33 (s, 3 H), 1.10 (t, J = 7.4 Hz, 3 H). MALDI-TOF: 349.865 [M +
H]+.
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methylthiophene-3-carboxylate (7). Mp 102−104 °C. H NMR
(400 MHz, CDCl3): δ 7.93 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz,
2H), 3.91 (s, 3H), 2.74 (q, J = 7.4 Hz, 2H), 2.28 (s, 3H), 1.33 (s, 9H),
1.07 (t, J = 7.4 Hz, 3H). MS (ESI): 382 [M + Na]+.
Methyl 2-[(Cyclohexylcarbonyl)amino]-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (20). Eluent C.
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Colorless oil. H NMR (400 MHz, CDCl3): δ 11.34 (s, 1 H), 3.85
Methyl 4-Ethyl-2-[((4-methoxyphenyl)carbonyl)amino]-5-
methyl-thiophene-3-carboxylate (8). Eluent A. Mp 150−153 °C.
1H NMR (200 MHz, CDCl3): δ 12.22 (s, 1H), 7.93 (d, J = 8.7 Hz,
2H), 6.95 (d, J = 8.7 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 2.71 (q, J =
7.4 Hz, 2H), 2.26 (s, 3H), 1.05 (t, J = 7.4 Hz, 3H). MS (ESI): 338 [M
+ H]+, 360 [M + Na]+.
Methyl 4-Ethyl-5-methyl-2-[((4-trifluoromethylphenyl)-
carbonyl)amino]thiophene-3-carboxylate (10). Eluent D. Mp
122−123 °C. 1H NMR (400 MHz, CDCl3): δ 12.48 (s, 1 H), 8.12 (d,
J = 8.2 Hz, 2 H), 7.79 (d, J = 8.2 Hz, 2 H), 3.95 (s, 3 H), 2.77 (q, J =
7.4 Hz, 2 H), 2.32 (s, 3 H), 1.10 (t, J = 7.4 Hz, 3 H). MALDI-TOF:
370.913 [M]+, 371.914 [M + H]+.
Methyl 2-[((4-Chlorophenyl)carbonyl)amino]-4-ethyl-5-
methylthiophene-3-carboxylate (11). Mp 113 °C. 1H NMR
(400 MHz, CDCl3): δ 12.38 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.51 (d,
J = 8.5 Hz, 2H), 3.96 (s, 3H), 2.79 (q, J = 7.4 Hz, 2H), 2.34 (s, 3H),
1.11 (t, J = 7.4 Hz, 3H). MS (ESI): 360 [M + Na]+.
Methyl 2-[((3-Chlorophenyl)carbonyl)amino]-4-ethyl-5-
methylthiophene-3-carboxylate (12). Eluent B. Mp 99−102 °C.
1H NMR (200 MHz, CDCl3): δ 12.31 (s, 1H), 7.97 (s, 1H), 7.83−
7.79 (m, 1H), 7.49−7.41 (m, 2H), 3.91 (s, 3H), 2.71 (q, J = 7.2 Hz,
2H), 2.27 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H). MS (ESI): 338 [M + H]+,
360 [M + Na]+.
Methyl 2-[((2-Chlorophenyl)carbonyl)amino]-4-ethyl-5-
methylthiophene-3-carboxylate (13). Eluent B. Mp 95−97 °C.
1H NMR (200 MHz, CDCl3): δ 11.90 (s, 1H), 7.77−7.72 (m, 1H),
7.47−7.31 (m, 3H), 3.85 (s, 3H), 2.73 (q, J = 7.4 Hz, 2H), 2.28 (s,
3H), 1.05 (t, J = 7.4 Hz, 3H). MS (ESI): 338 [M + H]+, 360 [M +
Na]+.
(s, 3 H), 2.73 (m, 2 H), 2.62 (m, 2 H), 2.37 (tt, J1 = 11.6, J2 = 3.5 Hz,
1 H), 2.01 (m, 2 H), 1.85−1.68 (m, 6 H), 1.54 (dd, J1 = 12.1, J2 = 2.9
Hz, 1 H), 1.48 (dd, J1 = 12.1, J2 = 2.9 Hz, 1 H), 1.38−1.22 (m, 4 H).
MALDI-TOF: 321.816 [M + H]+.
Methyl 2-[((3,4-Dimethoxyphenyl)carbonyl)amino]-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (22). Eluent G.
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Mp 164−165 °C. H NMR (400 MHz, CDCl3): δ 12.25 (s, 1 H),
7.63 (d, J = 2.1 Hz, 1 H), 7.57 (dd, J = 8.2, 2.1 Hz, 1 H), 6.95 (d, J =
8.2 Hz, 1 H), 3.97 (s, 3 H), 3.95 (s, 3 H), 3.90 (s, 3 H), 2.78 (m, 2 H),
2.68 (m, 2 H), 1.81 (m, 4 H). MALDI-TOF: 375.863 [M + H]+.
2-[(Cyclohexylcarbonyl)amino]-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carbonitrile (23). Eluent C. Mp 186−188 °C. 1H
NMR (400 MHz, CDCl3): δ 8.33 (s, 1 H), 2.65−2.58 (m, 4 H), 2.37
(tt, J = 11.7, 3.5 Hz, 1 H), 1.99−1.95 (m, 2 H), 1.88−1.79 (m, 6 H),
1.74−1.71 (m, 1 H), 1.59−1.50 (m, 2 H), 1.39−1.24 (m, 3 H).
MALDI-TOF: 288.951 [M]+.
2-[((3,4-Dimethoxyphenyl)carbonyl)amino]-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carbonitrile (24). Eluent G. Mp
230−232 °C. 1H NMR (400 MHz, CDCl3): δ 8.80 (s, 1 H), 7.53 (d, J
= 2.1 Hz, 1 H), 7.44 (dd, J = 8.3, 2.1 Hz, 1 H), 6.94 (d, J = 8.3 Hz, 1
H), 3.97 (s, 3 H), 3.96 (s, 3 H), 2.68−2.61 (m, 4 H), 1.87−1.83 (m, 2
H). MALDI-TOF: 342.936 [M]+.
General Procedure for the Synthesis of Methyl 2-
(Sulfonylamino)thiophene-3-carboxylates 26 and 27. Method
D. The appropriate sulfonyl chloride (1.0 mmol equiv) was slowly
added to a 0 °C solution of 37 (199 mg, 1 mmol) in pyridine (10 mL).
The reaction mixture was stirred at room temperature under inert
atmosphere for 6 h. After addition of EtOAc the solution was washed
with 1 N HCl and brine. The organic phase was dried over MgSO4 and
evaporated under high vacuum. The residue was purified by flash
chromatography using the reported eluent system.
Methyl 4-Ethyl-5-methyl-2-[((4-methylphenyl)sulfonyl)-
amino]thiophene-3-carboxylate (26). Eluent F. Mp 92−94 °C.
1H NMR (400 MHz, CDCl3): δ 10.32 (s, 1 H), 7.78 (d, J = 8.2 Hz, 2
H), 7.26 (d, J = 8.2 Hz, 2 H), 3.79 (s, 3 H), 2.62 (q, J = 7.4 Hz, 2 H),
2.40 (s, 3 H), 2.23 (s, 3 H) 0.99 (t, J = 7.4 Hz, 3 H). MALDI-TOF:
353.791 [M]+.
Methyl 2-[(Cyclohexylsulfonyl)amino]-4-ethyl-5-methylthio-
phene-3-carboxylate (27). Eluent C. Mp 81−83 °C. 1H NMR (400
MHz, CDCl3): δ 10.18 (s, 1 H), 3.88 (s, 3 H), 3.08 (tt, J = 12.1, 3.5
Hz, 1 H), 2.69 (q, J = 7.4 Hz, 2 H), 2.24 (s, 3 H), 2.13 (bs, 2 H), 1.87
(bs, 2 H), 1.69−1.51 (bs, 4 H), 1.26−1.18 (bs, 2 H), 1.06 (t, J = 7.4
Hz, 3 H). MALDI-TOF: 344.982 [M]+, 345.981 [M + H]+.
Synthesis of Methyl 4-Ethyl-5-methyl-2-[(phenylsulfonyl)-
amino]thiophene-3-carboxylate (25). Method E. To a solution of
37 (199 mg, 1 mmol) and TEA (210 μL, 1.5 mmol) in DCM (20 mL)
cooled at 0 °C, a solution of benzensulfonyl chloride (264 mg, 1.5
mmol) in 10 mL of DCM was added dropwise. The reaction mixture
was stirred at room temperature under N2 atmosphere for 36 h. The
organic layer was washed with 1 N HCl and saturated solution of
NaHCO3, dried over anhydrous Na2SO4, and evaporated to dryness.
The crude product was purified by flash chromatography using eluent
D to obtained the intermediate 40 (68%).
Methyl 2-[((4-Bromophenyl)carbonyl)amino]-4-ethyl-5-
methylthiophene-3-carboxylate (14). Eluent B. Mp 128−130
°C. 1H NMR (400 MHz, CDCl3): δ 12.30 (s, 1H), 7.82 (d, J = 8.1 Hz,
2H), 7.61 (d, J = 8.1 Hz, 2H), 3.91 (s, 3H), 2.72 (q, J = 7.5 Hz, 2H),
2.27 (s, 3H), 1.06 (t, J = 7.5 Hz, 3H). MS (ESI): 383 [M + H]+.
Methyl 4-Ethyl-2-[((4-iodophenyl)carbonyl)amino]-5-meth-
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ylthiophene-3-carboxylate (15). Eluent B. Mp 164−165 °C. H
NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4
Hz, 2H), 3.91 (s, 3H), 2.74 (q, J = 7.4 Hz, 2H), 2.29 (s, 3H), 1.06 (t, J
= 7.4 Hz, 3H). MS (ESI): 452 [M + Na]+.
Methyl 2-[(Phenylacetyl)amino]-4-ethyl-5-methylthio-
phene-3-carboxylate (17). Mp 80 °C. 1H NMR (200 MHz,
CDCl3): δ 10.96 (s, 1H), 7.33 (m, 5H), 3.76 (s, 2H), 3.67 (s, 3H),
2.66 (q, J = 7.5 Hz, 2H), 2.21 (s, 3H), 0.99 (t, J = 7.5 Hz, 3H). MS
(ESI): 340 [M + Na]+.
Methyl 2-[((4-Chlorophenyl)carbonyl)amino]thiophene-3-
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carboxylate (19). Mp 189−191 °C. H NMR (400 MHz, CDCl3):
δ 12.00 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.25
(d, J = 5.8 Hz, 1H), 6.80 (d, J = 5.8 Hz, 1H), 3.94 (s, 3H). MS (ESI):
318 [M + Na]+, 296 [M + H]+.
General Procedure for the Synthesis of Methyl 2-
(Acylamino)thiophene-3-carboxylates 9, 20, 22 and 2-
(Acylamino)thiophene-3-carbonitriles 23, 24. Method C.
N,N′-Diisopropylcarbodiimide (DIC, 190 mg, 1.5 mmol) was added
under inert atmosphere to a 0 °C solution of the appropriate
carboxylic acid (1.5 mmol) in dry DCM (15 mL). After 0.5 h at 0 °C a
DCM solution (15 mL) of the appropriate aminothiophene 37−39
(1.0 mmol) and 4-dimethylaminopyridine (DMAP, 122 mg, 1.0
mmol) were added and the reaction mixture was stirred at room
temperature overnight. The organic solution was extracted with 1 N
HCl, dried over Na2SO4, filtered and the solvent removed under
vacuum. The crude product was purified by flash column
chromatography using the reported eluent system.
This compound (290 mg, 0.6 mmol) was dissolved in THF/H2O
(4:1, 3 mL). Sodium hydroxide (400 mg, 10 mmol) was added, and
the solution was warmed at 50 °C under stirring for 7 h. The solution
was concentrated in vacuo, and the residue was dissolved in water,
cooled to 0 °C, and acidified to pH 3−4 with 12 N HCl. The solid was
filtered and purified by flash chromatography using eluent D to give 25
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in 85% (58% overall) yield. Mp 74−76 °C. H NMR (200 MHz,
CDCl3): δ 10.32 (s, 1H), 7.88−7.84 (m, 2H), 7.54−7.40 (m, 3H),
3.75 (s, 3H), 2.58 (q, J = 7.5 Hz, 2H), 2.19 (s, 3H), 0.95 (t, J = 7.5 Hz,
3H). MS (ESI): 340 [M + H]+, 362 [M + Na]+.
Methyl 4-Ethyl-5-methyl-2-[((4-nitrophenyl)carbonyl)-
amino]thiophene-3-carboxylate (9). Eluent C. Mp 152−154 °C.
1H NMR (400 MHz, CDCl3): δ 12.58 (s, 1 H), 8.38 (d, J = 8,6 Hz, 2
Synthesis of Methyl N-Methyl-2-[((4-chlorophenyl)-
carbonyl)amino]-4-ethyl-5-methylthiophene-3-carboxylate
(28). Method F. Solid 95% potassium tert-butoxide (140 mg, 1.2
H), 8.18 (d, J = 8,6 Hz, 2 H), 3.96 (s, 3 H), 2.78 (q, J = 7.4 Hz, 2 H),
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dx.doi.org/10.1021/jm400144w | J. Med. Chem. 2013, 56, 3620−3635