2142 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 9
Vazquez et al.
removed under reduced pressure until dry. The residue was
dissolved in MeOH (10 mL), and NaBH3CN (0.050 g, 0.8 mmol)
was added to the solution at 0 °C. After this, another 3 mL of 0.4
M HCl in MeOH was added, and the reaction was allowed to stir
for 30 min at 0 °C. The reaction was warmed up to rt for 30 min,
and the solvent was removed under reduced pressure until almost
dry. The residue was diluted with water (20 mL), and 3 M NaOH
was added until pH 7. The product was extracted with chloroform
(3 × 30 mL). The organic phase was dried over Na2SO4 and filtered,
and the solvent was removed under reduced pressure. The residue
was purified by silica gel column chromatography, eluting with a
gradient from hexanes/EtOAc (4:1) to hexanes/EtOAc (1:4) to give
0.244 g of an orange oil (87%). HRMS (ESI-TOF) m/z calcd for
and brine. The organic phase was dried over Na2SO4 and filtered.
The solvent was then removed under reduced pressure to afford
0.049 g of a yellow solid (46%). HRMS (ESI-TOF) m/z calcd for
[M
+
H]+, 428.1942; found, 428.1938. Anal. Calcd for
C23H27N2O6: C, 64.62; H, 6.37. Found: C, 64.23; H, 6.56.
(E)-Methyl 3-(5-(4-Nitrophenyl)furan-2-yl)acrylate 11a. A
suspension of aldehyde 10a (0.5 g, 2.3 mmol), methyl diethyl
phosphonoacetate (0.485 mL, 2.5 mmol), and LiOH (0.062 g, 2.5
mmol) in THF (10 mL) was stirred at rt under Ar for 4 h. After the
usual workup, purification by silica gel column chromatography
with hexanes/EtOAc (4:1) as eluent was done to give 0.56 g of a
1
yellow solid (89%). H NMR (300 MHz, DMSO-d6) δ 3.75 (s,
3H, 3H, CHdCHCO2Me), 6.55 (d, J ) 15.8 Hz, 1H, CH)CHCO2-
Me), 7.16 (d, J ) 3.6 Hz, 1H, CH furanyl), 7.47 (d, J ) 6.3 Hz,
1H, CH furanyl), 7.53 (d, J ) 15.8 Hz, 1H, CHdCHCO2Me), 8.11
(d, J ) 8.9 Hz, 1H, aromatic), 8.30 (d, J ) 8.8 Hz, 1H, aromatic);
13C NMR (75 MHz, DMSO-d6) δ 52.2, 52.5, 113.5, 116.7, 117.0,
119.2, 119.5, 124.8, 125.3, 125.4, 126.0, 131.2, 131.4, 135.6, 152.3,
167.1; MS (ESI) m/z 274.1 [M + H]+; Rf (hexanes/EtOAc (4:1))
) 0.83.
[M
+
H]+, 402.2149; found, 402.2141. Anal. Calcd for
C22H29N2O5: C, 65.82; H, 7.28. Found: C, 66.04; H, 7.21. Rf
(EtOAc/MeOH (4:1)) ) 0.48.
Compound 2b. Compound 2a (0.1 g, 0.25 mmol) was dissolved
in MeOH (3 mL) and cooled to 0 °C. NaOH (2 N, 3 mL) was
added dropwise over a period of 10 min, and the reaction was placed
at rt for 16 h. After this time, MeOH was removed under reduced
pressure and water (15 mL) was added. Extractions with EtOAc
(2 × 15 mL) were done, and the pH of the water solution was
acidified to 6. Then the product was extracted with EtOAc (3 ×
15 mL). The organic solution was dried over Na2SO4 and filtered.
The solvent was removed under reduced pressure to give a yellow
solid (0.051 g) in 52% yield. HRMS (ESI-TOF) m/z calcd for [M
+ H]+, 388.1993; found, 388.2002. Anal. Calcd for C21H27N2O5:
C, 65.10; H, 7.02. Found: H, 7.35; C, 63.85. Rf (EtOAc/MeOH
(4:1)) ) 0.07.
(E)-Methyl 3-(5-(3-Nitrophenyl)furan-2-yl)acrylate 11b. The
same procedure as before was employed with the aldehyde 10b
obtaining a yellow solid (83%). 1H NMR (300 MHz, DMSO-d6) δ
3.74 (s, 3H, CHdCHCO2Me), 6.54 (d, J ) 15.8 Hz, 1H,
CH)CHCO2Me), 7.14 (d, J ) 3.5 Hz, 1H, CH furanyl), 7.45 (d,
J ) 3.6 Hz, 1H, CHdCHCO2Me), 7.52 (d, J ) 15.8 Hz, 1H, CH
furanyl), 7.76 (t, J ) 8.0 Hz, 1H, aromatic), 8.19 (dd, J1 ) 8.1 Hz,
J2 ) 1.5 Hz, 1H, aromatic), 8.30 (dd, J1 ) 8.1 Hz, J2 ) 1.6 Hz,
1H, aromatic), 8.60 (t, J ) 1.6 Hz, 1H, aromatic); 13C NMR (75
MHz, DMSO-d6) δ 52.1, 52.4, 111.8, 116.2, 119.0, 119.3, 123.2,
123.8, 130.6, 131.1, 131.2, 131.4, 131.6, 149.2, 151.5, 164.6, 167.2;
MS (ESI) m/z 274.2 [M + H]+; Rf (hexanes/EtOAc (4:1)) ) 0.83.
(E)-3-(5-(4-Nitrophenyl)furan-2-yl)acrylic Acid 12a. To solu-
tion of compound 11a (0.4 g, 1.5 mmol) in MeOH (10 mL) at 0
°C was added dropwise 2 N NaOH (10 mL). After the addition,
the solution was warmed up to rt and then it was heated to 80 °C
for 2 h. After the reaction was cooled down, it was acidified to pH
6 after dilution with water (20 mL). The methanol was removed
under reduced pressure, and the product was extracted with EtOAc
(3 × 20 mL). The organic phase was dried over Na2SO4 and filtered,
and the solvent was removed under reduced pressure. Purification
by silica gel column chromatography, with hexanes/EtOAc (4:1)
as eluent, afforded 0.345 g of a pale orange solid (91%). 1H NMR
(300 MHz, DMSO-d6) δ 6.46 (d, J ) 15.7 Hz, 1H, CHdCHCO2H),
7.13 (d, J ) 3.6 Hz, 1H, CH furanyl), 7.44 (d, J ) 15.6 Hz, 1H,
CHdCHCO2H), 7.46 (d, J ) 3.6 Hz, 1H, CH furanyl), 8.10 (d, J
) 8.9 Hz, 1H, aromatic), 8.30 (d, J ) 9.0 Hz, 1H, aromatic); 13C
NMR (75 MHz, DMSO-d6) δ 113.5, 118.3, 118.5, 118.8, 124.8,
125.2, 125.4, 125.5, 130.8, 131.7, 152.5, 168.0; MS (ESI) m/z 260.1
[M + H]+; Rf (hexanes/EtOAc (1:1)) ) 0.46.
(E)-3-(5-(3-Nitrophenyl)furan-2-yl)acrylic Acid 12b. The same
procedure as before was employed with the compound 11b
obtaining a yellow solid (93%). 1H NMR (300 MHz, DMSO-d6) δ
6.45 (d, J ) 15.8 Hz, 1H, CHdCHCO2H), 7.10 (d, J ) 3.6 Hz,
1H, CH furanyl), 7.43 (d, J ) 3.7 Hz, 1H, CH furanyl), 7.45 (d, J
) 15.7 Hz, 1H, CHdCHCO2H), 7.76 (t, J ) 8.0 Hz, 1H, arom),
8.19 (dd, J1 ) 1.3 Hz, J2 ) 8.4 Hz, 1H, arom), 8.30 (dd, J1 ) 1.3
Hz, J2 ) 8.3 Hz, 1H, arom), 8.58 (t, J ) 1.4 Hz, 1H, arom); 13C
NMR (75 MHz, DMSO-d6) δ 111.8, 117.8, 118.1, 118.3, 118.8,
119.3, 123.1, 123.7, 130.5, 131.0, 131.2, 131.5, 151.7, 153.3, 168.0;
MS (ESI) m/z: 260.1 [M + H] +; Rf (hexanes/EtOAc (1:1)) )
0.45.
Compound 4a. To a solution of the carboxylic acid 12a (0.133
g, 0.51 mmol) in a mixture of anhydrous DCM/DMF (4:1; 5 mL)
in an ice bath WSC (0.108 g, 0.56 mmol) was added already
dissolved in the same previous solution (5 mL). After 30 min of
agitation, the 4-amino TEMPO (0.205 g, 1.02 mmol) was added,
and the reaction was allowed to reach room temperature and
continue for 16 h. After this time, the solution was diluted with
DCM (20 mL) and washed with 0.1 N HCl (3 × 20 mL), H2O (3
× 20 mL), and brine. The organic phase was dried over Na2SO4
(E)-Methyl 2-hydroxy-5-(5-(3-methoxy-3-oxoprop-1-enyl)fu-
ran-2-yl)benzoate 8. A suspension of aldehyde 7 (0.125 g, 0.51
mmol), methyl diethyl phosphonoacetate (0.105 mL, 0.56 mmol),
and LiOH (0.014 g, 0.56 mmol) in THF (10 mL) was stirred at rt
under Ar for 4 h. After the usual workup, purification by silica gel
column chromatography with hexanes/EtOAc (6:1) as eluent was
1
done to give 0.128 g of a pale yellow solid (84%). H NMR (300
MHz, DMSO-d6) δ 3.72 (s, 3H, CO2Me), 3.93(s, 3H, CO2Me), 6.34
(d, J ) 15.7 Hz, 1H, CHdCHCO2Me), 7.05-7.06 (m, 2H, furanyl),
7.08 (d, J ) 8.7 Hz, 1H, aromatic), 7.47 (d, J ) 15.7 Hz, 1H,
CHdCHCO2Me), 7.97 (dd, J1 ) 8.7 Hz J2 ) 2.3 Hz, 1H, aromatic),
8.13 (d, J ) 2.3 Hz, 1H, aromatic), 10.69 (br s, 1H, PhOH); 13C
NMR (75 MHz, DMSO-d6) δ 52.0, 52.3, 53.1, 53.5, 108.3, 108.7,
114.3, 114.6, 114.8, 118.9, 119.3, 119.7, 121.8, 125.9, 126.6, 131.6,
132.4, 150.2, 155.3, 160.5, 167.3, 169.2; MS (ESI) m/z 303.1 [M
+ H] +; Rf (Hexanes/EtOAc (4:1)) ) 0.49.
(E)-5-(5-(2-Carboxyvinyl)furan-2-yl)-2-hydroxybenzoic Acid
9. To suspension of compound 8 (0.1 g, 0.33 mmol) in MeOH (5
mL) at 0 °C was added dropwise 2 N NaOH (5 mL). After the
addition, the solution was warmed up to rt and then it was heated
to 80 °C for 2 h. After this time, the reaction was cooled down and
the methanol was removed under reduced pressure. The solution
was diluted with water (20 mL), and extractions with EtOAc (2 ×
15 mL) were done. The water solution was then acidified to pH 5,
and the product was extracted with EtOAc (3 × 15 mL). The
organic phase was dried over Na2SO4 and filtered, and the solvent
was removed under reduced pressure, affording 0.080 g of a yellow
1
solid (88%). H NMR (300 MHz, DMSO-d6) δ 6.27 (d, J ) 15.7
Hz, 1H, CHdCHCO2H), 6.95-7.10 (m, 3H), 7.40 (d, J ) 15.7
Hz, 1H, CHdCHCO2H), 7.97 (dd, J1 ) 8.7 Hz, J2 ) 2.3 Hz, 1H,
aromatic), 8.16 (d, J ) 2.3 Hz, 1H, aromatic); 13C NMR (75 MHz,
DMSO-d6) δ 108.1, 108.5, 114.3, 115.9, 116.2, 118.6, 119.0, 121.7,
126.0, 126.7, 131.1, 150.3, 155.1, 161.8, 168.1, 172.1; MS (ESI)
m/z 275.0 [M + H] +; Rf (EtOAc) ) 0.1.
Compound 3. To a solution of the dicarboxylic acid 9 (0.070 g,
0.25 mmol) in a mixture of anhydrous DCM/DMF (4:1; 3 mL) in
an ice bath WSC (0.054 g, 0.28 mmol) was added already dissolved
in the same previous solution (2 mL). After 30 min of agitation,
the 4-amino TEMPO (0.087 g, 0.51 mmol) was added, and the
reaction was allowed to reach room temperature and to continue
for 16 h. After this time, the solution was diluted with DCM (20
mL) and washed with 0.1 N HCl (3 × 20 mL), H2O (3 × 20 mL),