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toluene/ethanol gave 3b of mp 141—144 °C (lit., 120—121 °C).6a) IR (KBr)
C18H19ClN2O5: C, 57.07; H, 5.06; N, 7.39. Found: C, 56.88; H, 4.89; N,
7.35.
1
cmϪ1: 3324 (N–H), 1730 (ester CO), 1609 (amido CO). H-NMR (DMSO-
N-(2-Furylmethyl)-2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)-
propanamide (8d) 8d was prepared as above through the reaction of
the half acid (3b) (2.1 g, 8 mmol) with 2-furylmethylamine (13d) (0.9 g,
d6) d: 1.17 (3H, t, Jϭ7 Hz, –CH2CH3), 1.92 (3H, s, –COCH3), 3.52 (2H, q,
Jϭ15 Hz, furan-CH2), 4.14 (2H, q, Jϭ7 Hz, –CH2CH3), 6.0—6.1 (1H, m,
furan-4H), 6.2—6.3 (1H, m, furan-3H), 4.7—7.5 (1H, m, furan-5H), 7.98
(1H, s, NH). Anal. Calcd for C12H15NO6: C, 53.53; H, 5.57; N, 5.20. Found:
C, 53.67; H, 5.64; N, 5.37.
8.8 mmol) in 71% yield. mp 75—78 °C (toluene/AcOEt). IR (KBr) cmϪ1
:
3388 (N–H), 1738 (ester CO), 1690 (amido CO), 1652 (amido CO).
1H-NMR (DMSO-d6) d: 1.20 (3H, t, Jϭ7 Hz, –CH2CH3), 2.00 (3H, s,
–COCH3), 3.6—3.7 (two H, each d, Jϭ15 Hz, furan-CH2), 4.15—4.26 (2H,
m, –CH2CH3), 5.18 (2H, d, Jϭ5 Hz, furan-CH2), 6.0—7.2 (three m, each
1H, furan-3H, 4H and 5H), 6.2—6.6 (three m, each 1H, furan-3H, 4H
and 5H), 6.64 (1H, t, Jϭ5 Hz, NH), 8.01 (1H, s, NH). Anal. Calcd for
C17H20N2O6: C, 58.61; H, 5.79; N, 8.04. Found: C, 58.54; H, 5.79; N, 8.00.
N-(2-Thiazolyl)-2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)propan-
amide (8e) 8e was prepared as above through the reaction of the half acid
(3b) (2.1 g, 8 mmol) with 2-aminothiazole (13e) (0.9 g, 8.8 mmol) in 68%
yield, mp 228—231 °C (EtOH/toluene). IR (KBr) cmϪ1: 3256 (N–H), 1746
Decarboxylation of the Half Acid (3b) Leading to 2-Acetylamino-3-(2-
furyl)propanoic Acid Ethyl Ester (12) A solution of oxalyl chloride (1.1
g, 8.6 mmol) in acetonitrile (5 ml) was added dropwise to an ice-cold, stirred
solution of imidazole (2.4 g, 35 mmol) in acetonitrile (50 ml). The mixture
was stirred at room temperature for 15 min, then 2-acetylamino-2-ethoxycar-
bonyl-3-(2-furyl)propanoic acid (3b) (2.1 g, 8 mmol) was added rapidly in a
single portion. The mixture was stirred at 60 °C for 1.5 h. The solvent was
removed in vacuo, and the residue was poured onto ice-water and extracted
with ethyl acetate. Washing of the ethyl acetate extract with 5% hydrochloric
acid and water, followed by drying over Na2SO4 and evaporation of the sol-
vent left 1.2 g (66%) of crude product (12). Distillation using the Kugelrohr
apparatus gave 1.0 g of pure product (12) of bp 210—215° at 1 mmHg. IR
(KBr) cmϪ1: 3296 (N–H), 1740 (ester CO), 1660 (amido CO). 1H-NMR
(DMSO-d6) d: 1.16 (3H, t, Jϭ7.1 Hz, –CH2CH3), 2.01 (3H, s, –COCH3),
3.46—3.57 (two 1H, each d, Jϭ15 Hz, furan-CH2), 4.11—4.17 (2H, q, Jϭ7
Hz, –CH2CH3), 4.79—4.86 (1H, m, –CH2–CHϭ), 6.04 (1H, m, furan-4H),
6.27 (1H, m, furan-3H), 7.31 (1H, m, furan-5H), 7.98 (1H, s, NH). Anal.
Calcd for C11H15NO4: C, 58.66; H, 6.66; N, 6.22. Found: C, 58.53; H, 6.78;
N, 6.20.
1
(ester CO), 1698 (amido CO), 1652 (amido CO). H-NMR (DMSO-d6) d:
1.16 (3H, t, Jϭ7 Hz, –CH2CH3), 1.96 (3H, s, –COCH3), 3.59—3.81 (two
1H, each d, Jϭ15 Hz, furan-CH2), 4.13—4.25 (2H, m, –CH2CH3), 6.08 (1H,
m, furan-4H), 6.34 (1H, m, furan-3H), 7.50 (1H, m, furan-5H), 7.10 (1H, d,
Jϭ3 Hz, thiazole-5H), 7.32 (1H, d, Jϭ3 Hz, thiazole-4H), 7.54 (1H, s, NH),
7.96 (1H, s, NH). Anal. Calcd for C15H17N3O5S: C, 51.28; H, 4.84; N, 11.96.
Found: C, 51.20; H, 5.05; N, 11.83.
N-(5-Methyl-2-thiazolyl)-2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)-
propanamide (8f) 8f was prepared as above through the reaction of the
half acid (3b) (2.1 g, 8 mmol) with 2-amino-5-methylthiazole (13f) (1.3 g,
Preparation of N-Substituted 2-Acetylamino-2-ethoxycarbonyl-3-(2-
furyl)propanamides (8) General Procedure A solution of oxalyl chlo-
ride (1.1 g, 8.6 mmol) in acetonitrile (5 ml) was added dropwise to an ice-
cold, stirred solution of imidazole (2.4 g, 35 mmol) in acetonitrile (50 ml).
The mixture was stirred at room temperature for 15 min, then 2-acety-
lamino-2-ethoxycarbonyl-3-(2-furyl)propanoic acid (3b) (2.1 g, 8 mmol) was
added rapidly in a single portion. The mixture was stirred at 45 °C for
40 min, and then a solution of an appropriate amine (13a—i) (8.8 mmol) in
acetonitrile (2 ml) was added dropwise at room temperature. The resultant
mixture was stirred for 1.5 h at 55 °C. The solvent was removed in vacuo,
and the residue was poured onto ice-water and extracted with ethyl acetate.
Washing of the ethyl acetate extract with 5% hydrochloric acid and water,
followed by drying over Na2SO4 and evaporation of the solvent, left the
crude product (8), which was chromatographed on a silica gel column (50 g,
70—230 mesh) with ethyl acetate/tolueneϭ3/7 to give the product (8).
N-Butyl-2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)propanamide
(8a) 8a was prepared as above through the reaction of the half acid (3b)
(2.1 g, 8 mmol) with n-butylamine (13a) (0.6 g, 8.8 mmol) in 51% yield. mp
74—77 °C (cyclohexane/ethyl acetate). IR (KBr) cmϪ1: 3350 (N–H), 1742
8.8 mmol) in 66% yield. mp 176—179 °C (EtOH/toluene). IR (KBr) cmϪ1
:
3304 (N–H), 1746 (ester CO), 1700 (amido CO), 1664 (amido CO). 1H-
NMR (DMSO-d6) d: 1.12 (3H, t, Jϭ7 Hz, –CH2CH3), 1.93 (3H, s, thiazole-
CH3), 2.31 (3H, s, –COCH3), 3.59—3.72 (two 1H, each d, Jϭ15 Hz, furan-
CH2), 4.12—4.09 (2H, q, Jϭ7 Hz, –CH2CH3), 6.02 (1H, m, furan-4H), 6.32
(1H, m, furan-3H), 7.10 (1H, m, furan-5H), 7.45 (1H, s, thiazole-4H), 8.05
(1H, s, NH), 12.3 (1H, s, NH). Anal. Calcd for C16H19N3O5S: C, 52.50; H,
5.20; N, 11.50. Found: C, 52.48; H, 5.12; N, 11.52.
N-(5-Nitro-2-thiazolyl)-2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)-
propanamide (8g) 8g was prepared as above through the reaction of the
half acid (3b) (2.1 g, 8 mmol) with 2-amino-5-nitrothiazole (13g) (1.3 g, 8.8
mmol) in 62% yield. mp 182—185 °C (ether/AcOEt). IR (KBr) cmϪ1: 3408
(N–H), 1738 (ester CO), 1706 (amido CO), 1640 (amido CO). 1H-NMR
(DMSO-d6) d: 1.15 (3H, t, Jϭ7 Hz, –CH2CH3), 1.97 (3H, s, –COCH3),
3.58—3.73 (two 1H, each d, Jϭ15 Hz, furan-CH2), 4.14—4.23 (2H, m,
–CH2CH3), 6.15 (1H, m, furan-4H), 6.35 (1H, m, furan-3H), 7.53 (1H, m,
furan-5H), 8.17 (1H, s, thiazole-4H), 8.65 (1H, s, NH), 13.33 (1H, s, NH).
Anal. Calcd for C15H16N4O7S: C, 45.45; H, 4.04; N, 14.14. Found: C, 45.65;
H, 4.24; N, 13.88.
1
(ester CO), 1690 (amido CO), 1642 (amido CO). H-NMR (DMSO-d6) d:
N-(5-Bromo-2-thiazolyl)-2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)-
propanamide (8h) 8h was prepared as above through the reaction of the
half acid (3b) (2.1 g, 8 mmol) with 2-amino-5-bromothiazole (13h) [2-
amino-5-bromothiazole monohydrobromide (2.3 g, 8.8 mmol) was neutral-
ized with triethylamine (0.9 g, 8.8 mmol) in acetonitrile (5 ml)] in 63% yield.
mp 198—200 °C (ether/toluene). IR (KBr) cmϪ1: 3402 (N–H), 1750 (ester
0.83 (3H, t, Jϭ7 Hz, –(CH2)3CH3), 1.14 (3H, t, Jϭ7 Hz, –CH2CH3), 1.13—
3.10 (6H, m, –(CH2)3CH3), 1.90 (3H, s, –COCH3), 3.54—3.64 (two 1H,
each d, Jϭ15 Hz, furan-CH2), 4.04—4.16 (2H, m, –CH2CH3), 6.05—6.10
(1H, m, furan-4H), 6.2—6.3 (1H, m, furan-3H) 7.4—7.5 (1H,m, furan-5H),
7.75 (1H, s, NH), 8.05 (1H, t, Jϭ5.7 Hz, NH). Anal. Calcd for C16H24N2O5:
C, 59.25; H, 7.46; N, 8.64. Found: C, 59.01; H, 7.25; N, 8.57.
N-Phenyl-2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)propanamide
(8b) 8b was prepared as above through the reaction of the half acid (3b)
(2.1 g, 8 mmol) with aniline (13b) (0.8 g, 8.8 mmol) in 69% yield. mp 163—
165 °C (toluene). IR (KBr) cmϪ1: 3412 (N–H), 1740 (ester CO), 1714
(amido CO), 1652 (amido CO). 1H-NMR (DMSO-d6) d: 1.16 (3H, t,
Jϭ7 Hz, –CH2CH3), 1.96 (3H, s, –COCH3), 3.60—3.82 (two 1H, each d,
Jϭ15 Hz, furan-CH2), 4.11—4.24 (2H, m, –CH2CH3), 6.0—6.1 (1H, m,
furan-4H), 6.3—6.4 (1H, m, furan-3H), 7.5 (1H, m, furan-5H), 7.10 (1H, bt,
Jϭ7.4 Hz, phenyl-4H), 7.34 (2H, d, Jϭ7.4 Hz, phenyl-3, 5H), 7.54 (2H, d,
Jϭ7.4 Hz, phenyl-2, 6H), 7.96 (1H, s, NH), 9.79 (1H, s, NH). Anal. Calcd
for C18H20N2O5: C, 62.79; H, 5.81; N, 8.14. Found: C, 63.06; H, 5.88; N,
8.11.
1
CO), 1696 (amido CO), 1686 (amido CO). H-NMR (DMSO-d6) d: 1.14
(3H, t, Jϭ7 Hz, –CH2CH3), 1.95 (3H, s, –COCH3), 3.57—3.75 (two 1H,
each d, Jϭ15 Hz, furan-CH2), 4.18—4.14 (2H, m, –CH2CH3), 6.10 (1H, m,
furan-4H), 6.33 (1H, m, furan-3H), 7.50 (1H, m, furan-5H), 7.60 (1H, s, thi-
azole-4H), 8.05 (1H, s, NH), 12.52 (1H, s, NH). Anal. Calcd for
C15H16BrN3O5S: C, 41.87; H, 3.75; N, 9.77. Found: C, 42.09; H, 3.71; N,
9.76.
N-(4-Chloro-2-benzothiazolyl)-2-acetylamino-2-ethoxycarbonyl-3-(2-
furyl)propanamide (8i) 8i was prepared as above through the reaction of
the half acid (3b) (2.1 g, 8 mmol) with 2-amino-4-chlorobenzothiazole (13i)
(1.63 g, 8.8 mmol) in 63% yield. mp 154—157 °C (ether/AcOEt). IR (KBr)
cmϪ1: 3420 (N–H), 1780 (ester CO), 1720 (amido CO), 1660 (amido CO).
1H-NMR (DMSO-d6) d: 1.16 (3H, t, Jϭ7 Hz, –CH2CH3), 1.99 (3H, s,
–COCH3), 3.60—3.82 (two 1H, each d, Jϭ15 Hz, furan-CH2), 4.15—4.24
(2H, m, –CH2CH3), 6.15 (1H, m, furan-4H), 6.36 (1H, m, furan-3H), 7.53
(1H, m, furan-5H), 7.55 and 8.00 (each 1H, each d, Jϭ8 Hz, benzothiazole-
5H, 7H) 7.33 (1H, t, Jϭ8 Hz, benzothiazole-6H), 8.05 (1H, s, NH), 12.85
(1H, s, NH). Anal. Calcd for C19H18ClN3O5S: C, 52.35; H, 4.13; N, 9.64.
Found: C, 52.32; H, 4.12; N, 9.52.
N-(4-Chlorophenyl)-2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)-
propanamide (8c) 8c was prepared as above through the reaction of the
half acid (3b) (2.1 g, 8 mmol) with 4-chloroaniline (13c) (1.1 g, 8.8 mmol) in
50% yield. mp 225—229 °C (toluene/AcOEt). IR (KBr) cmϪ1: 3443 (N–H),
1
1738 (ester CO), 174 (amido CO), 1652 (amido CO). H-NMR (DMSO-d6)
d: 1.15 (3H, t, Jϭ7 Hz, –CH2CH3), 1.96 (3H, s, –COCH3), 3.58—3.78 (two
1H, each d, Jϭ15 Hz, furan-CH2), 4.11—4.23 (2H, m, –CH2CH3), 6.07—
6.10 (1H, m, furan-4H), 6.33—6.36 (1H, m, furan-3H), 7.50—7.52 (1H, m,
furan-5H), 7.37—7.61 (two 2H, each d, Jϭ7.4 Hz, phenyl-2H, -6H and
phenyl-3H, 5H), 7.99 (1H, s, NH), 9.95 (1H, s, NH). Anal. Calcd for
Plant Growth-modulating Activity Test This test was carried out ac-
cording to the method reported by Inamori et al.15) A DMSO solution
(1.0 ml) containing an amide derivative (8a—i) or DMSO alone (1.0 ml) as a