6-Iodo-3-methoxy-4-(4¢-methoxyacetophenone-2-oxy)-N-
nonanoylbenzylamine (5)
dichloromethane–diethyl ether); nmax (CHCl3)/cm-1 3268 (m),
2925 (s), 2855 (s), 1635 (s), 1583 (w), 1543 (m), 1524 (s), 1509
(m), 1466 (s), 1387 (m), 1320 (s), 1280 (s), 1233 (s), 1198 (w), 1168
(w), 1140 (m), 1076 (m), 1035 (m), 992 (w), 872 (m), 851 (w), 820
(w), 797 (m), 756 (w), 722 (w); dH (CDCl3, 400 MHz) 7.76 (1H, s,
CH–CNO2), 7.49 (1H, s, CH–COCH3–COCH3), 6.89 (1H, br s,
CH–COCH3) 6.87 (1H, d, J 8.2, CH–C–O–CH2Ar), 6.78 (1H, dd,
J 8.2, 1.9, CH–CCH2–NH), 5.70 (1H, br s, NH), 5.54 (2H, s, CH2–
O), 4.39 (2H, d, J 5.7, CH2–NH), 3.97 (6H, s, COCH3–COCH3),
3.90 (3H, s, OCH3), 2.21 (2H, t, J 7.6, C(O)–CH2–CH2), 1.71–1.61
(2H, m, C(O)–CH2–CH2), 1.36–1.22 (10H, m, CH2(CH2)5CH3)
and 0.88 (3H, t, J 6.8, CH2CH3); dC (100 MHz; CDCl3) 173.0,
154.0, 150.0, 147.8, 147.0, 138.9, 132.6, 129.9, 120.2, 114.5, 111.8,
107.9, 68.5, 56.3, 56.0, 43.3, 36.9, 31.8, 29.3, 29.2, 25.8, 22.6, 14.1;
HRMS m/z (ES+) [found (M + Na)+ 511.2402, C26H36N2O7Na
requires M+ 511.2420]; m/z (ES+) 511 ([M + Na]+, 100).
To a stirred mixture of sodium hydride (9.6 mg, 0.286 mmol, 60%
dispersion in mineral oil) in DMF (5 ml) was added slowly a so-
lution of 4-hydroxy-6-iodo-3-methoxy-N-nonanoylbenzylamine
(18, 100 mg, 0.238 mmol) in DMF (5 ml) at 0 ◦C. The mixture
was allowed to warm to rt and stirred for 3 h. After this
time the mixture was re-cooled to 0 ◦C and a solution 2-
bromo-4¢-methoxyacetophenone (109 mg, 0.477 mmol) in DMF
(5 ml) was added and stirred at 0 ◦C for 2 h and allowed to
warm to rt and stirred overnight. TLC analysis indicated that
the reaction was complete, therefore the reaction mixture was
partitioned between diethyl ether (20 ml) and water (20 ml).
The aqueous layer was extracted with further diethyl ether
(2 ¥ 20 ml), the ethereal layers were combined and washed
with brine (20 ml), dried (MgSO4) and filtered. The resulting
solid was purified using silica gel column chromatography,
eluting with ethyl acetate and petroleum ether (20 : 80), to
furnish 6-iodo-3-methoxy-4-(4¢-methoxyacetophenone-2-oxy)-N-
nonanoylbenzylamine (5, 44 mg, 33%) as an off white solid (found:
C, 54.99; H, 6.31; N, 2.40. C26H34INO5 requires C, 55.03; H, 6.04;
N, 2.47%); Rf 0.30 (ethyl acetate–petroleum ether, 50 : 50); mp 127–
128 ◦C (from ethyl acetate–hexane); nmax (KBr disc)/cm-1 3302 (s),
6-Bromo-3-methoxy-4-(4,5-dimethoxy-2-nitrobenzyl)-N-
(nonanoyl)benzylamine (7)
To a solution of 6-bromo-4-hydroxy-3-methoxy-N-(nonanoyl)-
benzylamine (17, 0.40 g, 1.07 mmol) in THF (20 ml) was added
potassium tert-butoxide in THF (1 M, 1.07 ml, 1.07 mmol)
and the resulting solution stirred at rt for 20 min. After this
time, 4,5-dimethoxy-2-nitrobenzyl bromide (0.30 g, 1.07 mmol)
was added and the resulting mixture stirred for 16 h. TLC
analysis showed full consumption of the starting material and
therefore the solvent was removed in vacuo. The resulting solid
was purified by silica gel column chromatography, eluting with
ethyl acetate and petroleum ether (50 : 50) then ethyl acetate
to afford 6-bromo-3-methoxy-4-(4,5-dimethoxy-2-nitrobenzyl)-
N-(nonanoyl)benzylamine (7, 0.32 g, 53%) as a light yellow solid
(found: C, 55.30; H, 6.55; N, 4.82. C26H35BrN2O7 requires C, 55.03;
H, 6.22; N, 4.94); Rf 0.58 (methanol–dichloromethane, 5 : 95); mp
185–186 ◦C (from ethyl acetate); nmax (nujol mull)/cm-1 3274 (m),
2925 (s), 2854 (s), 1645 (s), 1547 (w), 1524 (s), 1510 (m), 1460
(s), 1411 (w), 1171 (w), 1074 (m), 1043 (w), 990 (w), 956 (w), 873
(m), 853 (w), 797 (w), 765 (w), 723 (w); dH (CDCl3, 300 MHz)
7.78 (1H, s, CH–CNO2), 7.46 (1H, s, CH–COCH3–COCH3), 7.09
(1H, s, CH–CBr), 7.02 (1H, br s, CH–COCH3), 5.93 (1H, t, J 5.7,
NH), 5.51 (2H, O–CH2), 4.45 (2H, d, J 5.7, CH2–NH), 3.98 (3H, s,
OCH3), 3.97 (3H, s, OCH3), 3.89 (3H, s, OCH3), 2.20 (2H, t, J 7.6,
C(O)–CH2–CH2), 1.69–1.59 (2H, m, C(O)–CH2–CH2), 1.35–1.20
(10H, m, CH2(CH2)5CH3) and 0.87 (3H, t, J 6.7, CH2CH3); dC
(75 MHz; CDCl3) 173.1, 154.1, 149.3, 147.9, 147.6, 138.9, 131.2,
129.1, 118.4, 114.2, 113.8, 109.4, 108.0, 68.6, 56.4, 56.2, 43.6, 36.8,
31.8, 29.3, 29.1, 25.7, 22.6, 14.1; HRMS m/z (ES+) [found (81M +
Na)+ 591.1512, C26H3581BrN2NaO7 requires M+ 591.1505], [found
(79M + Na)+ 589.1529, C26H3579BrN2NaO7 requires M+ 589.1525];
m/z (ES+) 591 ([81M + Na]+, 80), 589 ([79M + Na]+, 100).
=
2918 (m), 1691 (NHC O, s), 1648 (s), 1602 (s), 1550 (m), 1502 (m),
1380 (m), 1201 (s), 1167 (s), 1027 (w), 975 (m), 851 (w), 835 (w),
795 (w) and 576 (w); dH (CDCl3, 300 MHz) 7.97 (2H, m, 2 ¥ CH–
C–C(O)), 7.16 (1H, s, CH–CI), 6.96 (2H, m, 2 ¥ CH–COCH3),
6.95 (1H, s, CH–COCH3), 5.98 (1H, t, J 5.8, NH), 5.27 (2H, s, O–
CH2–C(O)), 4.38 (2H, d, J 5.8, CH2NH), 3.88 (3H, s, OCH3), 3.84
(3H, s, OCH3), 2.20 (2H, t, J 7.6, C(O)–CH2–CH2), 1.69–1.58 (2H,
m, C(O)–CH2–CH2), 1.35–1.21 (10H, m, CH2–(CH2)5–CH3) and
0.87 (3H, t, J 6.8, (CH2)7–CH3); dC (75 MHz; CDCl3) 192.5, 173.4,
164.5, 150.5, 147.8, 135.1, 130.8, 127.8, 124.9, 114.5, 114.1, 87.1,
72.1, 56.4, 56.0, 48.2, 37.1, 32.2, 29.7, 29.6, 26.1, 23.0 and 14.5;
HRMS m/z (ES+) [found (M + Na)+ 590.1376, C26H34INaNO5
requires M+ 590.1379]; m/z (ES+) 585 ([M + NH4]+, 40), 568 ([M +
H]+, 90), 60 (100).
3-Methoxy-4-(4,5-dimethoxy-2-nitrobenzyl)-N-
(nonanoyl)benzylamine (6)
To a solution of 4-hydroxy-3-methoxy-N-(nonanoyl)benzylamine
(2, 0.40 g, 1.36 mmol) in dry THF (25 ml) was added potassion
tert-butoxide (0.15 g, 1.36 ml, 1 M solution in tetrahydrofuran,
1.36 mmol) and the mixture was stirred for 25 min at rt. After this
time, 4,5-dimethoxy-2-nitrobenzyl bromide (0.38 g, 1.36 mmol)
was added and the resulting mixture stirred for 16 h. TLC analysis
indicated full consumption of the starting material, therefore
the solvent was removed in vacuo. The residue was partitioned
between water (100 ml) and ethyl acetate (100 ml) and the
aqueous layer extracted with further ethyl acetate (2 ¥ 150 ml).
The combined organic fractions were dried (MgSO4), filtered and
concentrated in vacuo. The resulting solid was crystallised from
dichloromethane and diethyl ether affording 3-methoxy-4-(4,5-
dimethoxy-2-nitrobenzyl)-N-(nonanoyl)benzylamine (6, 0.44 g,
66%) as a yellow solid (found: C, 63.98; H, 7.30; N, 5.60.
C26H36N2O7 requires C, 63.92; H, 7.43; N, 5.73); Rf 0.20
(ethyl acetate–petroleum ether, 50 : 50); mp 137–138 ◦C (from
6-Bromo-3-methoxy-4-(2-nitrobenzyl)-N-(nonanoyl)benzylamine
(8)
To a solution of 6-bromo-4-hydroxy-3-methoxy-N-(nonanoyl)-
benzylamine (17, 0.3 g, 0.81 mmol) in THF (15 ml) was added
potassium tert-butoxide in THF (1 M, 806 ml, 0.81 mmol) and
the resulting solution stirred at rt for 20 min. After this time,
2-nitrobenzyl bromide (0.17 g, 0.81 mmol) was added and the
4704 | Org. Biomol. Chem., 2009, 7, 4695–4707
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