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D. Rennison et al. / Bioorg. Med. Chem. 21 (2013) 5886–5899
octanoic acid (4.43 g, 30.74 mmol) and thionyl chloride (20 mL)
was heated under reflux for 3 h. The excess thionyl chloride was
removed in vacuo and the crude octanoyl chloride taken through
to the next step without further purification. A solution of 2
(12.0 g, 21.55 mmol), triethylamine (4.6 mL, 33.3 mmol), dimeth-
ylaminopyridine (0.26 g, 2.16 mmol) and crude octanoyl chloride
in dimethylformamide (150 mL) was then stirred at room temper-
ature for 3 h. The mixture was then diluted with ethyl acetate
(200 mL) and washed with water (200 mL). The separated aqueous
phase was further extracted with ethyl acetate (2 ꢀ 100 mL) and
the combined organic phases washed with brine (4 ꢀ 100 mL),
dried over anhydrous magnesium sulfate, filtered and the solvent
removed in vacuo. Purification by flash chromatography (hexane/
ethyl acetate 2:1) afforded 10 as an off-white solid (9.92 g,
14.66 mmol, 68%). mp 60–65 °C; 1H NMR (300 MHz, CDCl3) d
0.84–0.88 (3H, m, (CH2)6CH3), 1.24–1.29 (8H, m, (CH2)4CH3),
1.55–1.60 (2H, m, CH2CH2(CH2)4CH3), 2.12–2.26 (2H, m,
CH2(CH2)5CH3), 3.33–3.85 (4.15H, NCH2CH2O, H-2, H-3, W/H-4),
3.86–3.89 (0.47H, m, U/H-1, V/H-1), 3.94 (0.38H, m, Y/H-4), 4.14
(0.13H, m, U/H-4), 4.21–4.32 (2.34H, m, NCH2CH2O, V/H-4), 4.43–
4.53 (0.53H, m, W/H-1, Y/H-1), 5.50 (0.34H, m, V/H-6), 5.53
(0.38H, m, Y/H-6), 5.55 (0.13H, s, U/OH), 5.56 (0.15H, s, W/OH),
5.57 (0.38H, s, Y/OH), 5.63 (0.34H, s, V/OH), 6.01 (0.13H, m, U/H-
6), 6.05 (0.15H, m, W/H-6), 6.75–7.56 (16H, m, Ar), 8.42–8.62
(0.13H, m, U/OH), 5.61 (0.18H, m, W/OH), 5.63 (0.38H, m, Y/OH),
5.68 (0.31H, m, V/OH), 6.03 (0.13H, m, U/H-6), 6.06 (0.18H, m,
W/H-6), 6.72–7.63 (22H, m, COC(Me)@CH, Ar), 8.41–8.65 (2H, m,
a
Pyr); m
max(NaCl) cm–1 1113 and 1247 (C–O ester), 1585 (C@O
imide), 1701 (C@O ester); m/z (ESI, 70 eV) (Found: MH+
700.2812, C45H37N3O5 requires 700.2820).
4.1.8. 5-(
phenylpropioyloxyethyl-7-(
a
-Hydroxy-
a
-2-pyridylbenzyl)-N-20-
-2-pyridylbenzylidene)-5-
a
norbornene-2,3-dicarboximide (22)
A similar procedure31,32 to that previously described for the
preparation of 17 was followed using phenylpropiolic acid
(105 mg, 0.72 mmol) and oxalyl chloride (1 mL), under reflux for
2 h. A solution of 2 (200 mg, 0.36 mmol) and crude phenylpropio-
loyl chloride in pyridine (1.5 mL) was then stirred at 70 °C for 16 h,
with purification by flash chromatography (hexane/ethyl acetate
1:2) affording 22 as a colourless solid (18 mg, 0.03 mmol, 7%).
mp 97–103 °C; 1H NMR (400 MHz, CDCl3) d 3.38–3.96 (5H, m,
NCH2CH2O, H-2, H-3, V/H-1, Y/H-4, W/H-4), 4.22 (0.4H, m,
V/H-4), 4.30–4.42 (2.6H, m, NCH2CH2O, W/H-1, Y/H-1), 5.54–5.61
(1.4H, m, V/H-6, Y/H-6, OH), 6.10 (0.2H, m, W/H-6), 6.24 (0.1H, s,
OH), 6.49 (0.3H, s, OH), 6.77–7.71 (21H, m, Ar), 8.43–8.70 (2H, m,
a
Pyr); mmax cm–1 1080 and 1241 (C–O ester), 1585 (C@O imide),
1711 (C@O ester); m/z (FAB+) 684 (MH+, 54%), 120 (100); (Found:
(2H, m,
aPyr);
m
max(NaCl) cm–1 1185 and 1251 (C–O ester), 1583
MH+ 684.2503, C44H34N3O5 requires 684.2498).
(C@O imide), 1706 (C@O ester); m/z (ESI, 70 eV) (Found: MH+
682.3267, C43H44N3O5 requires 682.3275).
4.1.9. 5-(
methoxycinnamoyloxy)ethyl]-7-(
norbornene-2,3-dicarboximide (25)
a
-Hydroxy-
a
-2-pyridylbenzyl)-N-[20-(4’’-
-2-pyridyl benzylidene)-5-
a
4.1.6. N-20-Diphenylacetyloxyethyl-5-(
pyridylbenzyl)-7-( -2-pyridylbenzylidene)-5-norbornene-2,3-
dicarboximide (17)
a-hydroxy-a-2-
a
A similar procedure31,32 to that previously described for the
preparation of 10 was followed using 4-methoxycinnamic acid
(9.63 g, 54.06 mmol) and thionyl chloride (40 mL), under reflux
for 3 h. A solution of 2 (15.05 g, 27.03 mmol), triethylamine
(8.6 mL, 62.11 mmol), dimethylaminopyridine (330 mg, 2.7 mmol)
and crude 4-methoxycinnamoyl chloride in dimethylformamide
(150 mL) was then stirred at room temperature for 5 h, with puri-
fication by flash chromatography (hexane/ethyl acetate 2:1)
affording 25 as a white solid (18.03 g, 25.24 mmol, 93%). mp
125–130 °C; 1H NMR (300 MHz, CDCl3) d 3.35–3.91 (4.63H, m,
NCH2CH2O, H-2, H-3, U/H-1, V/H-1, W/H-4), 3.83–3.85 (3H, m,
OMe), 3.95 (0.37H, m, Y/H-4), 4.15 (0.15H, m, U/H-4), 4.28–4.44
(2.3H, m, NCH2CH2O, V/H-4), 4.47–4.50 (0.55H, m, W/H-1, Y/H-
1), 5.53 (0.30H, dd, J = 3.4 and 1.2 Hz, V/H-6), 5.56 (0.37H, dd,
J = 3.4 and 1.2 Hz, Y/H-6), 5.57 (0.33H, s, W/OH, U/OH), 5.61
(0.37H, s, Y/OH), 5.67 (0.30H, s, V/OH), 6.03 (0.15H, dd, J = 3.4
and 1.2 Hz, U/H-6), 6.06 (0.18H, dd, J = 3.4 and 1.2 Hz, W/H-6),
6.14 (0.33H, d, J = 15.8 Hz, COCH@CH), 6.22 (0.67H, d, J = 15.8 Hz,
COCH@CH), 6.70–7.65 (21H, m, Ar and COCH@CH), 8.40–8.62
A similar procedure31,32 to that previously described for the
preparation of 10 was followed using diphenylacetic acid (98 mg,
0.46 mmol) and oxalyl chloride (1 mL), under reflux for 3 h. A solu-
tion of 2 (128 mg, 0.23 mmol) and crude diphenylacetyl chloride in
pyridine (2 mL) was then stirred at room temperature for 16 h,
with purification by flash chromatography (hexane/ethyl acetate
1:2) affording 17 as an off-white residue (122 mg, 0.16 mmol,
71%); 1H NMR (400 MHz, CDCl3) d 3.19–3.92 (4.5H, m, NCH2CH2O,
H-2, H-3, U/H-1, V/H-1, W/H-4,), 3.96 (0.5H, dt, J = 4.6 and 1.5 Hz,
Y/H-4), 4.11 (0.1H, m, U/H-4), 4.24 (0.2H, dt, J = 4.5 and 1.4 Hz, V/
H-4), 4.28–4.44 (2.7H, m, NCH2CH2O, W/H-1, Y/H-1), 5.04 (1H, s,
CHPh2), 5.49 (0.2H, dd, J = 3.2 and 1.2 Hz, V/H-6), 5.54 (0.5H, dd,
J = 3.3 and 1.3 Hz, Y/H-6), 5.60–5.63 (1H, br s, OH), 5.96 (0.1H,
dd, J = 3.3 and 1.2 Hz, U/H-6), 6.00 (0.2H, dd, J = 3.3 and 1.2 Hz,
W/H-6), 6.78–7.65 (26H, m, Ar), 8.43–8.70 (2H, m,
aPyr);
m
max(NaCl) cm–1 1149 and 1187 (C–O ester), 1585 (C@O imide),
1704 (C@O ester); m/z (FAB+) 750 (MH+, 25%), 120 (100); (Found:
MH+ 750.2962, C49H40N3O5 requires 750.2968).
(2H, m, a
Pyr); mmax cm–1 1163 and 1251 (C–O ester), 1633 (C@O
imide), 1705 (C@O ester); m/z (FAB+) 716 (MH+, 60%), 116 (100);
4.1.7. 5-(
methylcinnamoyloxyethyl-7-(
a
-Hydroxy-
a
-2-pyridylbenzyl)-N-20-
-2-pyridylbenzylidene)-5-
a-
(Found: MH+ 716.2765, C45H38N3O6 requires 716.2761).
a
norbornene-2,3-dicarboximide (20)
4.1.10. N-[20-(400-Ethylcinnamoyloxy)ethyl]-5-(
pyridylbenzyl)-7-( -2-pyridyl benzylidene)-5-norbornene-2,3-
dicarboximide (28)
a-hydroxy-a-2-
A similar procedure31,32 to that previously described for the
a
preparation of 10 was followed using
a-methylcinnamic acid
(1.23 g, 7.61 mmol) and thionyl chloride (5 mL), under reflux for
3 h. A solution of 2 (2.11 g, 3.79 mmol), triethylamine (1.2 mL,
8.75 mmol), dimethylaminopyridine (46 mg, 0.38 mmol) and
A similar procedure31,32 to that previously described for the
preparation of 10 was followed using 4-ethylcinnamic acid
(1.36 g, 7.71 mmol) and thionyl chloride (15 mL), under reflux for
3 h. A solution of 2 (2.14 g, 3.85 mmol), triethylamine (1.23 mL,
8.86 mmol), dimethylaminopyridine (47 mg, 0.39 mmol) and
crude 4-methoxycinnamoyl chloride in dimethylformamide
(20 mL) was then stirred at room temperature for 5 h, with purifi-
cation by flash chromatography (hexane/ethyl acetate 1:1) afford-
ing 28 as a white solid (1.15 g, 1.62 mmol, 42%). mp 90–95 °C; 1H
NMR (300 MHz, CDCl3) d 1.22–1.28 (3H, m, CH2CH3), 2.62–2.70
(2H, m, CH2CH3), 3.35–3.90 (4.61H, m, NCH2CH2O, H-2, H-3,
crude
a-methylcinnamoyl chloride in dimethylformamide
(20 mL) was then stirred at 70 °C for 16 h, with purification by flash
chromatography (hexane/ethyl acetate 2:1) affording 20 as a white
solid (2.24 g, 3.2 mmol, 84%). mp 75–80 °C; 1H NMR (300 MHz,
CDCl3) d 2.03–2.08 (3H, m, Me), 3.40–3.96 (5H, m, NCH2CH2O, H-
2, H-3, U/H-1, V/H-1, Y/H-4, W/H-4), 4.15 (0.13H, m, U/H-4),
4.27–4.42 (2.31H, m, NCH2CH2O, V/H-4), 4.47–4.51 (0.56H, m, Y/
H-1, W/H-1), 5.53 (0.31H, m, V/H-6), 5.57 (0.38H, m, Y/H-6), 5.59