Nitrofuranylamides
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5281
1-(S)-phenylethylamine (245 µL, 1.9 mmol) in DMF (5 mL)
were treated with EDCI (730 mg, 3.8 mmol) followed by DMAP
(582 mg, 4.7 mmol). The reaction mixture was stirred for 14 h
at room temperature and worked up as explained in the
general procedure to afford 422 mg of product (85% yield).
dd, J ) 8 Hz, 2.5 Hz), 6.81 (1H, d, J ) 3.5 Hz), 7.15 (1H, dd,
J ) 8 Hz, 1.5 Hz), 7.29 (1H, d, J ) 3.5 Hz), 7.32 (1H, d, J ) 8
Hz), 7.42 (1H, t, J ) 2 Hz), 7.64 (3H, t, J ) 3 Hz), 7.82 (2H,
dd, J ) 6 Hz, 3.5 Hz, 2.5 Hz), 8.2 (1H, s). 13C NMR (75 MHz,
CDCl3): δ 54.8, 105.3, 110.4, 111.7, 115.1, 116.5, 124.4, 129.0,
129.2, 131.5, 137.4, 140.3, 150.7, 154.3, 159.6. ESI-MS, m/z:
340.6 (M - 1).
Com p ou n d 39. TLC: Rf ) 0.70 (1:1 petroleum ether/ethyl
acetate). 1H NMR (500 MHz, CDCl3): δ 4.85 (3H, s), 6.79 (1H,
dd, J ) 8 Hz, 2.2 Hz, 1.7 Hz), 7.18 (1H, dd, J ) 7.4 Hz, 1.5
Hz), 7.28-7.34 (3H, m), 7.4 (1H, t, J ) 2.5 Hz), 7.62 (2H, t, J
) 8 Hz), 7.72 (1H, t, J ) 7 Hz), 8.09 (2H, d, J ) 7 Hz), 8.22
(1H, s). 13C NMR (75 MHz, CDCl3): δ 54.8, 105.5, 110.6, 112.0,
115.2, 118.4, 127.4, 129.0, 129.3, 133.8, 137.2, 138.6, 150.3,
1
TLC: Rf ) 0.75 (1:1 petroleum ether/ethyl acetate). H NMR
(300 MHz, CDCl3): δ 1.65 (3H, d, J ) 7.2 Hz), 5.32 (1H, quin,
J ) 7.2 Hz), 6.8-6.92 (1H, bd, J ) 7.2 Hz), 7.24-7.45 (7H,
m). 13C NMR (75 MHz, CDCl3): δ 20.9, 48.6, 111.9, 115.5,
125.7, 127.3, 128.3, 141.4, 147.5, 154.8. ESI-MS, m/z: 258.8
(M - 1). Anal. Calcd. for C13H12N2O4: C, 60.0; H, 4.65; N,
10.76. Found: C, 59.54; H, 4.68; N, 10.66.
5-Nit r ofu r a n -2-ca r b oxylic Acid [2-(3,4-Dim et h oxy-
p h en yl)eth yl]a m id e (31). 5-Nitro-2-furancarboxylic acid (300
mg, 1.9 mmol) and 2,4-dimethoxyphenethylamine (319 µL, 1.9
mmol) in DMF (5 mL) were treated with EDCI (730 mg, 3.8
mmol) followed by DMAP (582 mg, 4.7 mmol). The reaction
mixture was stirred for 14 h at room temperature and worked
up as explained in the general procedure to afford 550 mg of
product (90% yield). TLC: Rf ) 0.75 (1:1 petroleum ether/ethyl
acetate). 1H NMR (300 MHz, CDCl3): δ 2.89 (2H, t, J ) 7.3
Hz), 3.69 (2H, q, J ) 7.3 Hz), 3.86 (3H, s), 3.88 (3H, s), 6.7-
6.87 (4H, m), 7.24 (1H, d, J ) 4 Hz), 7.35 (1H, d, J ) 4 Hz).
13C NMR (75 MHz, CDCl3): δ 34.5, 40.3, 55.3, 55.4, 111.0,
111.3, 111.8, 115.2, 120.1, 130.1, 147.4, 147.5, 148.7, 155.6.
ESI-MS, m/z: 318.9 (M - 1). Anal. (C15H16N2O6) C, H, N.
150.6, 154.0, 159.6. ESI-MS, m/z: 356.5 (M - 1). Anal. (C18H15
NO5S) C, H, N.
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P r ep a r a tion of 5-Nitr ofu r a n -2-ca r bon yl Ch lor id e (6).
5-Nitro-furan-2-carboxylic acid (942 mg, 6 mmol) in DCM (10
mL) was treated with oxalyl chloride (1.05 mL, 12 mmol)
followed by 2 drops of DMF and stirred at room temperature
for 4 h. The reaction mixture was concentrated in a vacuum
to obtain acid chloride, and the crude was used in further
reactions without purification.
Gen er a l P r oced u r e for P r ep a r a t ion of Am id es 6.
Meth od 1. 5-Nitrofuran-2-carbonyl chloride (526 mg, 3 mmol)
in DMF (5 mL) was added to amine (3 mmol) in pyridine (5
mL), and the reaction was carried out at 60 °C. The reaction
mixture was diluted with ethyl acetate (100 mL) and washed
with 10% aqueous NaHCO3 (2 × 50 mL), water (2 × 50 mL),
and brine (2 × 50 mL). The organic phase was dried over
Na2SO4, filtered, and concentrated followed by flash column
purification to provide the corresponding amides.
5-Nit r ofu r a n -2-ca r b oxylic Acid (3-Hyd r oxyp h en yl)-
a m id e (35). 5-Nitro-2-furancarboxylic acid (300 mg, 1.9 mmol)
and 3-aminophenol (208 mg, 1.9 mmol) in DMF (5 mL) were
treated with EDCI (730 mg, 3.8 mmol) followed by DMAP (582
mg, 4.7 mmol). The reaction mixture was stirred for 14 h at
room temperature and worked up as explained in the general
procedure to afford 331 mg of product (70% yield). TLC: Rf )
Meth od 2. 5-Nitrofuran-2-carbonyl chloride (930 mg, 5.3
mmol) in CH2Cl2 (10 mL) was added to the amine (5.3 mmol,
1 equiv) in Et3N (3 mL), and the mixture was stirred for 14 h
at 47 °C. Reaction was followed by TLC. After completion of
reaction, 100 mL of ethyl acetate was added and the mixture
was washed with 10% aqueous NaHCO3 (2 × 50 mL), water
(2 × 50 mL), and brine (2 × 50 mL). The organic phase was
dried over Na2SO4, filtered, and concentrated followed by flash
column purification to provide the corresponding amides.
(2,3-D ih y d r o in d o l-1-y l)-(5-n it r o fu r a n -2-y l)m e t h a -
n on e (43). 5-Nitrofuran-2-carbonyl chloride (526 mg, 3 mmol)
in CH2Cl2 (5 mL) was added to a mixture of indoline (336 µL,
3 mmol), N,N-diisopropylethylamine (1.04 mL, 6 mmol) in CH2-
Cl2 (20 mL), followed by DMAP (2 mg), and the reaction
mixture was stirred for 14 h at room temperature. The reaction
mixture was worked up as explained in method 2 to yield 600
mg (77%) of compound 43. TLC: Rf ) 0.42 (1:1 petroleum
ether/ethyl acetate). 1H NMR (500 MHz, DMSO-d6): δ 3.23
(2H, t, J ) 8.30 Hz), 4.46 (2H, t, J ) 8.30 Hz), 7.11 (1H, dt, J
) 0.7 Hz, 7.5 Hz), 7.23 (1H, t, J ) 7.8 Hz), 7.32 (1H, d, J ) 7.5
Hz), 7.51 (1H, d, J ) 4.1 Hz), 7.82 (1H, d, J ) 3.9 Hz), 8.0-8.2
(1H, bs). 13C NMR (75 MHz, DMSO): δ 27.9, 48.9, 112.9, 117.0,
118.2, 124.7, 124.9, 127.0, 132.5, 142.2, 147.9, 151.3, 154.8.
ESI-MS, m/z: 281.9 (M + 23). Anal. (C13H10N2O4) C, H, N.
5-Nitr ofu r a n -2-ca r boxylic Acid (P yr id in -2-ylm eth yl)-
a m id e (49). 5-Nitrofuran-2-carbonyl chloride (930 mg, 5.3
mmol) in CH2Cl2 (10 mL) was added to 2-aminomethylpyridine
(0.54 mL, 5.3 mmol) in Et3N (3 mL) and stirred for 14 h at 47
°C. The reaction was followed as explained in method 2 to yield
1.12 g (85%) of product 49. TLC: Rf ) 0.11 (1:1 petroleum
1
0.50 (1:1 petroleum ether/ethyl acetate). H NMR (500 MHz,
CD3OD): δ 5.09 (1H, ddd, J ) 8.0 Hz, 2.5 Hz, 1.0 Hz), 5.59
(1H, ddd, J ) 8.0 Hz, 2.0 Hz, 1.0 Hz), 5.64 (1H, t, J ) 8.0 Hz),
5.78 (1H, t, J ) 2.0 Hz), 5.9 (1H, d, J , ) 4.0 Hz), 6.45 (1H, d,
J ) 4.0 Hz), 6.45 (1H, s). 13C NMR (75 MHz, CDCl3): δ 110.2,
114.2, 114.3, 118.3, 131.5, 140.1, 150.1, 157.2, 159.4. ESI-MS,
m/z: 247.2 (M - 1). Anal. (C11H8N2O5) C, H, N.
5-Nitr ofu r a n -2-ca r boxylic Acid (3-Ben zyloxyp h en yl)-
a m id e (37). Compound 35 (150 mg, 0.6 mmol) was dissolved
in dry THF (5 mL) and K2CO3 (167 mg, 1.2 mmol) followed by
benzyl bromide (146 µL, 1.2 mmol). The reaction mixture was
stirred for 12 h at room temperature. The reaction mixture
was diluted with 30 mL of ethyl acetate and washed with H2O
(25 mL) brine (25 mL). The ethyl acetate was dried and
concentrated. The crude product was purified with flash
column chromatography using 15% ethyl acetate in petroleum
ether to afford 147 mg of product (72% yields). TLC: Rf ) 0.82
(1:1 petroleum ether/ethyl acetate). 1H NMR (500 MHz,
CDCl3): δ 5.16 (2H, s), 6.9 (1H, dd, J ) 8.3, 2.4, 1.0 Hz), 7.23
(1H, dd, J ) 8.1, 2.0, 0.8 Hz), 7.35 (1H, t, J ) 8 Hz), 7.39 (1H,
dt, J ) 7.0, 2.5 Hz), 7.42-7.44 (4H, m), 7.5-7.52 (2H, m), 7.56
(1H, t, J ) 2.2 Hz), 8.26-8.3 (1H, bs). 13C NMR (75 MHz,
CDCl3): δ 69.5, 106.5, 111.8, 112.1, 112.2, 116.2, 126.9, 127.5,
128.0, 129.4, 136.1, 136.9, 147.2, 153.3, 158.9. ESI-MS, m/z:
337.6 (M - 1).
5-Ben zen esu lfin ylfu r a n -2-ca r boxylic Acid (3-Meth oxy-
p h en yl)a m id e (38) a n d 5-Ben zen esu lfon ylfu r a n -2-ca r -
boxylic Acid (3-Meth oxyp h en yl)a m id e (39). A mixture of
compound 36 (0.1 g, 0.3 mmol) and NaHCO3 (0.116 g, 1.3
mmol) in CH2Cl2 (5 mL) at 0° C was treated with m-
chloroperbenzoic acid (0.116 g, 0.67 mmol) and stirred at for
3 h. The reaction mixture was quenched with diluted aqueous
NH4OH solution (5 mL) and diluted with CH2Cl2 (30 mL). The
organic layer was washed with diluted aqueous NH4OH
solution (30 mL), water (30 mL), and brine (30 mL) and dried
over Na2SO4. The organic solution was concentrated in a
vacuum followed by flash column purification with petroleum
ether and ethyl acetate in 5:1 ratio, which afforded 31 mg of
38 and 38 mg of 39 in 30% and 35% yields, respectively.
1
ether/ethyl acetate). H NMR (500 MHz, CDCl3): δ 4.83 (2H,
d, J ) 5.3 Hz), 7.32 (1H, d, J ) 3.9 Hz), 7.38 (1H, d, J ) 3.6
Hz), 7.39-7.42 (1H, m), 7.48 (1H, d, J ) 7.8 Hz), 7.86 (1H, dt,
J ) 1.7 Hz, 7.8 Hz), 8.10-8.22 (1H, bs), 8.65 (1H, d, J ) 4.8
Hz). 13C NMR (75 MHz, CDCl3): δ 43.7, 111.7, 115.3, 121.5,
122.1, 136.4, 147.6, 148.7, 154.7, 155.7. ESI-MS, m/z: 248.1
(M + 1). IR: 1670, 3305 cm-1. Anal. (C11H9N3O4) C, H, N.
5-Nitr ofu r a n -2-ca r boxylic Acid (4-Meth oxyben zoth ia -
zol-2-yl)a m id e (50). 5-Nitrofuran-2-carbonyl chloride (667
mg, 3.8 mmol) in CH2Cl2 (5 mL) was added to 2-amino-4-
methoxybenzothiazole (684 mg, 3.8 mmol) followed by pyridine
(5 mL), and the reaction mixture was stirred for 14 h at room
Com p ou n d 38. TLC: Rf ) 0.30 (1:1 petroleum ether/ethyl
acetate). 1H NMR (500 MHz, CDCl3): δ 4.87 (3H, s), 6.78 (1H,