Maki and Ishida
The corresponding carboxylic acid was obtained as a white solid.
The crude carboxylic acid was dissolved in CH2Cl2 (3 mL), and
N-hydroxysuccinimide (2mmol) and N-(3-dimethylaminopropyl)-
N′-ethylcarbodiimide hydrochloride (EDAC, 1.5 mmol) was added
successively. The solution was stirred for 3 h at room temperature.
Then the mixture was poured onto water and extracted with CH2-
Cl2 (3 × 5 mL). Then the organic portion was dried over magnesium
sulfate, filtered, and evaporated in vacuo. 5 was obtained as white
solid (95%). 5: White solid; mp 194-197 °C. IR (KBr, cm -1):
2.63(2H, t, J ) 6.6 Hz), 2.84(2H, t, J ) 6.3 Hz), 3.31-3.36(4H,
m), 4.96(2H, s), 6.19(1H, s), 7.66(2H, d, J ) 9.0 Hz), 7.71(2H, s),
8.29(2H, d, J ) 9.0 Hz). 13C NMR (400 MHz, CDCl3, TMS, rt) δ
(ppm); 16.5, 30.3, 33.9, 41.3, 42.0, 72.4, 123.8, 127.7, 129.3, 131.2,
132.8, 144.4, 147.6, 159.5, 172.4, 198.5. HRMS m/z calcd for
C21H25N3O5, 399.1794; found, 399.1774.
N-tert-Butyl-4-[3,5-dimethyl-4-(4-nitro-benzyloxy)-phenyl]-4-
oxo-butyramide (8). White solid; mp 124-125 °C. IR (KBr,
1
cm -1): 2969, 1678, 1642, 1530, 1344, 1152, 983, 853; H NMR
1
3450, 1737, 1679, 1525, 1347, 1206, 1155, 1063, 983, 854. H
(300 MHz, CDCl3, TMS, rt) δ (ppm); 1.35(9H, s), 2.32(6H, s),
2.54(2H, t, J ) 6.6 Hz), 3.30(2H, t, J ) 6.6 Hz), 4.95(2H, s), 5.61-
(1H, s), 7.66(2H, d, J ) 9.0 Hz), 7.69(2H, s), 8.28(2H, d, J ) 9.0
Hz); 13C NMR(400 MHz, CDCl3, TMS, rt) δ (ppm); 16.6, 28.9,
31.3, 34.1, 51.4, 72.7, 124.4, 128.3, 130.0, 131.8, 133.6, 145.2,
148.4, 160.3, 172.2, 199.5; HRMS m/z calcd for C23H28N2O5
412.1998 Found 412.1996.
NMR (400 MHz, CDCl3, TMS, rt) δ (ppm): 2.33(6H, s), 2.85(4H,
s), 3.07(2H, t, J ) 6.8 Hz), 3.39(2H, t, J ) 6.8 Hz), 4.96(2H, s),
7.66(2H, d, J ) 8.4 Hz), 7.70(2H, s), 8.27(2H, d, J ) 8.4 Hz). 13
C
NMR (400 MHz, CDCl3, TMS, rt) δ (ppm): 16.5, 25.44, 25.6,
32.9, 72.4, 123.8, 127.7, 129.3, 131.4, 132.3, 144.4, 147.7, 159.8,
168.4, 169, 196. HRMS m/z calcd for C23H22N2O8, 454.1376; found,
454.1367.
N-Cyclohexyl-4-[3,5-dimethyl-4-(4-nitro-benzyloxy)-phenyl]-
4-oxo-butyramide (9). White solid; mp 207-210 °C. IR (KBr,
N-[2-(2-Azido-ethoxy)-ethyl]-4-[3,5-dimethyl-4-(4-nitro-benzyl-
oxy)-phenyl]-4-oxo-butyramide (6). To a solution of 5 (1mmol)
in CH2Cl2 (3 mL) was added 2-(2-aminoethoxy)ethanol (2 mmol).
The solution was stirred for 3 h at room temperature. Then the
mixture was poured onto water and extracted with CH2Cl2 (3 × 5
mL). Then the organic portion was dried over magnesium sulfate,
filtered, and evaporated in vacuo. The residue was dissolved in
pyridine (5 mL) and added methanesulfonyl chloride (1.2 mmol).
The mixture was stirred for 12 h at room temperature. To the
mixture was added EtOAc (20 mL), and this was washed with 1
M HCl (20 mL × 3) and brine (20 mL × 1). Then the organic
portion was dried over magnesium sulfate, filtered, and evaporated
in vacuo. The resulting residue was dissolved in DMF (5 mL) and
added sodium azide (3mmol). The suspension was stirred for 12 h
at room temperature. To the mixture was added EtOAc (20 mL),
and this was washed with 1 M HCl (20 mL × 3) and brine (20 mL
× 1). Then the organic portion was dried over magnesium sulfate,
filtered, and evaporated in vacuo. The residue was purified by silica
gel column chromatography (n-hexane/EtOAc ) 1:1 to 1:2), and
6 was obtained as a yellowish solid (70%). 6: yellow solid; mp
112-115 °C. IR (KBr, cm -1): 2103, 1755, 1641, 1343, 1233,
1052. 1H NMR (400 MHz, CDCl3, TMS, rt) δ (ppm): 2.33(6H, s),
2.63(2H, t, J ) 6.8 Hz), 3.32(2H, t, J ) 6.8 Hz), 3.40(2H, t, J )
4.8 Hz), 3.50(2H, t, J ) 4.8 Hz), 3.58(2H, t, J ) 4.8 Hz), 3.69(2H,
t, J ) 4.8 Hz), 4.96(2H, s), 7.66(2H, d, J ) 8.4 Hz), 7.71(2H, s),
8.28(2H, d, J ) 8.8 Hz). 13C NMR (500 MHz, CDCl3, TMS, rt) δ
(ppm); 16.6, 30.2, 33.8, 39.2, 50.6, 69.9, 70.14, 72.4, 123.8, 127.7,
129.3, 131.2, 132.9, 144.5, 147.6, 159.5, 172.2, 198.2. HRMS m/z
calcd for C23H27N5O6, 469.1961; found, 469.1959.
1
cm -1): 2933, 2854, 1640, 1527, 1343, 1302, 1152, 987, 855. H
NMR (300 MHz, CDCl3, TMS, rt) δ (ppm): 1.11-1.23(3H, m),
1.29-1.38(3H, m), 1.68-1.73(2H, m), 1.88-1.92(2H, m), 2.32-
(6H, s), 2.58(2H, t, J ) 6.6 Hz), 3.31(2H, t, J ) 6.6 Hz), 3.74-
3.76(1H, m), 4.95(2H, s), 5.61(1H, s), 7.65(2H, d, J ) 8.4 Hz),
7.74(2H, s), 8.28(2H, d, J ) 8.4 Hz). 13C NMR(500 MHz, CDCl3,
TMS, rt) δ (ppm): 16.5, 24.8, 25.5, 30.7, 33.1, 34.1, 48.3, 72.4,
123.8, 127.7, 129.3, 131.2, 133.0, 144.4, 147.7, 159.6, 171.1, 198.5.
HRMS m/z calcd for C25H30N2O5, 438.2155; found, 438.2148.
4-[3,5-Dimethyl-4-(4-nitro-benzyloxy)-phenyl]-4-oxo-N-
phenethyl-butyramide (10). White solid; mp 176-178 °C. IR
(KBr, cm -1): 2942, 1678, 1632, 1527, 1342, 1233, 1211, 1149,
1
981, 855. H NMR (400 MHz, CDCl3, TMS, rt) δ (ppm): 2.33-
(6H, s), 2.57(2H, t, J ) 6.8 Hz), 2.82(2H, t, J ) 6.8 Hz), 3.30(2H,
t, J ) 6.8 Hz), 3.53(2H, q, J ) 6.4 Hz), 4.96(2H, s), 5.74(1H, s),
7.20-7.32(5H, m), 7.66(2H, d, J ) 8.8 Hz), 7.70(2H, s), 8.28(2H,
d, J ) 8.8 Hz). 13C NMR(400 MHz, CDCl3, TMS, rt) δ (ppm):
16.5, 30.3, 33.9, 35.7, 40.68, 72.4, 123.8, 126.4, 127.6, 128.7, 129.3,
131.2, 132.8, 138.9, 144.4, 147.6, 159.5, 172.0, 198.3. HRMS m/z
calcd for C27H28N2O5, 460.1998; found, 460.1996.
4-[3,5-Dimethyl-4-(4-nitro-benzyloxy)-phenyl]-N-dodecyl-4-
oxo-butyramide (11). White solid; mp 147-149 °C. IR (KBr, cm
-1): 3088, 2918, 2850, 1642, 1528, 1343, 1234, 1150, 983, 855.
1H NMR (300 MHz, CDCl3, TMS, rt) δ (ppm): 0.88(3H, t, J )
6.6 Hz), 1.25(15H, s), 1.50(3H, t, J ) 7.2 Hz), 2.48(6H, s), 2.60-
(2H, t, J ) 6.6 Hz), 3.24(2H, q, J ) 6.6 Hz), 3.33(2H, t, J ) 6.6
Hz), 4.95(2H, s), 5.77(1H, t, J ) 9.0 Hz), 7.65(2H, d, J ) 8.7 Hz),
7.74(2H, s), 8.82(2H, d, J ) 8.7 Hz). 13C NMR(500 MHz, CDCl3,
TMS, rt) δ (ppm): 16.5, 24.8, 25.5, 30.7, 33.1, 34.1, 48.3, 72.4,
123.8, 127.7, 129.3, 131.2, 133.0, 144.4, 147.7, 159.6, 171.1, 198.5.
HRMS m/z calcd for C31H44N2O5, 524.3250; found, 524.3234.
4-[3,5-Dimethyl-4-(4-nitro-benzyloxy)-phenyl]-N-octadecyl-4-
oxo-butyramide (12). White solid; mp 147-149 °C. IR (KBr, cm
-1): 3088, 2918, 2850, 1642, 1528, 1343, 1212, 1150, 983, 855.
1H NMR (400 MHz, CDCl3, TMS, rt) δ (ppm): 0.88(6H, t, J )
6.6 Hz), 1.25(22H, s), 1.44-1.49(4H, m), 2.32(6H, s), 2.60(2H, t,
J ) 6.6 Hz), 3.24(2H, q, J ) 6.6 Hz), 3.32(2H, t, J ) 6.6 Hz),
4.95(2H, s), 5.74(1H, s), 7.65(2H, d, J ) 9.0 Hz), 7.71(2H, s),
8.28(2H, d, J ) 9.0 Hz). 13C NMR(500 MHz, CDCl3, TMS, rt) δ
(ppm): 14.1, 16.5, 22.7, 26.9, 29.3, 29.6, 29.7, 30.5, 31.9, 34.1,
39.7, 72.4, 123.8, 127.7, 129.4, 131.2, 132.9, 144.4, 147.7, 159.6,
172.0, 198.5. HRMS m/z calcd for C37H56N2O5, 608.4189; found,
608.4177.
General Synthetic Procedure of Amides (4 and 7 to 12). To
a solution of 5 (1 mmol) in CH2Cl2(3 mL) was added amine (1.2
mmol). The solution was stirred for 3 h at room temperature. Then
the mixture was poured onto water and extracted with CH2Cl2 (3
× 5 mL). Then the organic portion was dried over magnesium
sulfate, filtered, and evaporated in vacuo. The residue was purified
by silica gel column chromatography (n-hexane/EtOAc ) 5:1 to
1:1) and 4 and 7-12 were obtained as white solids.
4-[3,5-Dimethyl-4-(4-nitro-benzyloxy)-phenyl]-4-oxo-N-pro-
pyl-butyramide (4). White solid; mp 170-172 °C. IR (KBr,
1
cm -1): 2961, 1678, 1641, 1527, 1343, 1322, 1150, 982, 854. H
NMR (300 MHz, CDCl3, TMS, rt) δ (ppm): 0.93(3H, t, J ) 7.2
Hz), 1.50-1.58(2H, m), 2.32(6H, s), 2.63(2H, t, J ) 6.6 Hz), 3.23-
(2H, t, J ) 6.6 Hz), 3.34(2H, t, J ) 6.6 Hz), 4.96(2H, s), 5.99(1H,
s), 7.66(2H, d, J ) 8.4 Hz), 7.71(2H, s), 8.28(2H, d, J ) 8.4 Hz).
13C NMR (400 MHz, CDCl3, TMS, rt) δ (ppm): 11.3, 16.5, 22.8,
30.4, 34.0, 41.3, 72.4, 123.8, 127.7, 129.3, 1321.2, 132.9, 144.4,
147.7, 159.6, 172.0, 198.5. HRMS m/z calcd for C22H26N2O5,
398.1842; found, 398.1837.
General Synthetic Procedure of Azide Coupling (“Click
Chemistry”) (16 to 18). To a solution of 13, 14, or 15 (1mmol)
and 6 (1mmol) was added copper sulfate solution and sodium
ascorbate (2.8 mL). The mixture was stirred for 12 h at room
temperature. Then the mixture was poured onto water and extracted
EtOAc (10 mL × 3). Then the organic portion was dried over
magnesium sulfate, filtered, and evaporated in vacuo. The residue
N-(2-Amino-ethyl)-4-[3,5-dimethyl-4-(4-nitro-benzyloxy)-
phenyl]-4-oxo-butyramide (7). White solid; mp 123-125 °C. IR
(KBr, cm -1): 3363, 2898, 1665, 1514, 1346, 1296, 1151, 1007.65,
1
850. H NMR (300 MHz, CDCl3, TMS, rt) δ (ppm): 2.32(6H, s),
6432 J. Org. Chem., Vol. 72, No. 17, 2007