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J. Kertesz et al. / Tetrahedron 67 (2011) 5206e5212
5210
EtOHeEtOAcehexane (1:1:8) mixture as eluent to give 7 (2.84 g,
67%) as a colorless oil.
Rf: 0.73 (silica gel TLC, EtOHeEtOAcehexane 0.5:3:2); IR (neat)
nmax 3080, 3060, 2952, 2870, 1740, 1720, 1704, 1600, 1464, 1416,
1360, 1236, 1176, 1168, 1132, 1056, 924, 816, 768, 700, 664 cmꢁ1; 1H
hydrogenated in the presence of Pd/C catalyst (33 mg, palladium on
charcoal; activated, 10% Pd). After the reaction was completed, the
catalyst was filtered off and the solvent evaporated at 25 ꢃC (bath
temperature) to give acridono-crown ether 9 (119 mg, 98%) as an
off-white solid. This product was used without further purification.
Mp: 196e197 ꢃC; Rf: 0.71 (alumina TLC, EtOHetoluene 1:2); IR
(KBr) nmax 3460, 3416, 2928, 1624, 1616, 1592, 1536, 1488, 1448,
NMR (500 MHz, CDCl3)
d
(ppm) 2.36 (s, 6H), 3.35 (t, J¼6 Hz, 4H),
3.41e3.55 (m, 8H), 4.01e4.06 (m, 4H), 5.03 (s, 2H), 7.23e7.29 (m,
9H), 7.71 (d, J¼8 Hz, 4H); 13C NMR (125 MHz, CDCl3)
d
(ppm) 21.84,
1276, 1224, 1124, 1084, 752, 608 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
47.92, 48.40, 67.35, 68.56, 68.65, 69.37, 69.89, 70.20, 128.07, 128.13,
128.23, 128.72, 130.07, 133.19, 136.87, 145.06, 156.23; MS calcd for
C30H37NO10S2: 635.2. Found (Mþ1)þ: 636.1. Anal. Calcd for
C30H37NO10S2: C, 56.68; H, 5.87; N, 2.20; S, 10.09. Found: C, 56.46;
H, 5.86; N, 2.09; S, 9.80.
d (ppm) 1.94 (s, br, NH, disappears shaken with D2O, 1H), 2.88 (t,
J¼5 Hz, 4H), 3.75 (t, J¼5 Hz, 4H), 3.94 (t, J¼4 Hz, 4H), 4.39 (t, J¼4 Hz,
4H), 7.08 (d, J¼7 Hz, 2H), 7.17 (d, J¼8 Hz, 2H), 8.07 (d, J¼8 Hz, 2H),
9.21 (s, NH, disappears shaken with D2O, 1H); 13C NMR (125 MHz,
CDCl3)
d (ppm) 49.24, 68.38, 69.08, 71.07, 112.20, 118.81, 120.86,
122.36, 131.53, 146.64, 178.16; MS calcd for C21H24N2O5: 384.2.
Found (Mþ1)þ: 385.2. Anal. Calcd for C21H24N2O5: C, 65.61; H, 6.29;
N, 7.29. Found: C, 65.50; H, 6.27; N, 7.29.
4.5.2. Applying a mixture of CH2Cl2 and 40% aqueous KOH sol-
ution. To a vigorously stirred mixture of N-benzyloxycarbonyl-
protected diol 11 (0.49 g, 1.53 mmol), CH2Cl2 (16 mL) and 40%
aqueous KOH solution (20 mL), was added tosyl chloride (0.70 g,
3.67 mmol) in CH2Cl2 (4 mL) at 0 ꢃC. The mixture was stirred at 0 ꢃC
for 10 min and then at rt for 4 h. After the reaction was completed,
CH2Cl2 (40 mL) and water (20 mL) were added. The phases were
shaken well and separated. The aqueous phase was extracted with
CH2Cl2 (3ꢂ20 mL). The combined organic phase was dried over
MgSO4, filtered and the solvent removed. The crude product was
purified by column chromatography on silica gel using
EtOHeEtOAcehexane (1:1:8) mixture as eluent to give 7 (0.53 g,
54%) as a colorless oil.
4.8. 2,20-{[(Benzyloxycarbonyl)azanediyl]bis(ethane-2,1-
diyloxy)}diethanol (11) (see Scheme 2)
N-Benzyloxycarbonyl-protected diol 11 was prepared with mi-
nor modification as described for N-benzyloxycarbonyl-protected
L
-serine.33
To a solution of monoaza-tetraethylene glycol 1032 (7.0 g,
36.2 mmol) and NaHCO3 (21.6 g, 257.1 mmol) in water (255 mL) was
added dropwise benzyl chloroformate (11.5 g, 67.41 mmol) at room
temperature (rt). The reaction mixture was stirred at rt for 6 h. After
the reaction was completed the reaction mixture was extracted
with EtOAc (4ꢂ200 mL). The combined organic phase was shaken
with saturated brine (2ꢂ200 mL), dried over MgSO4, filtered and
the solvent evaporated. The crude product was purified by column
chromatography on silica gel using EtOHeEtOAcehexane (1:6:4)
mixture as eluent to give 11 (8.23 g, 69%) as a colorless oil.
Compound 7 had the same IR and NMR spectra as the one
prepared above using triethylamine as solvent.
4.6. Benzyl 27-oxo-6,9,15,18-tetraoxa-12,25-diazatetracyclo
[21.3.1.05,26.019,24]heptacosa-1(26),2,4,19,21,23-hexaene-12-
carboxylate (8) (see Scheme 1)
Rf: 0.16 (silica gel TLC, EtOHeEtOAcehexane 1:6:4); IR (neat)
nmax 3416, 3080, 3040, 2960, 2872, 1688, 1615, 1596, 1540, 1476,
A mixture of 4,5-dihydroxyacridine-9(10H)-one31 (6) (1.97 g,
8.68 mmol), N-benzyloxycarbonyl-protected ditosylate 7 (6.07 g,
9.55 mmol), finely powdered anhydrous K2CO3 (12.00 g, 86.8 mmol),
and dry DMF (200 mL) was stirred vigorously under Ar at 50 ꢃC for 3
days. The solvent was removed at 25 ꢃC (bath temperature) and the
residue was taken up in a mixture of water (600 mL) and EtOAc
(400 mL). The aqueous phase was extracted with EtOAc (3ꢂ200 mL).
The combined organic phase was dried over MgSO4, filtered and the
solvent removed. The crude product was purified by column chro-
matography on silica gel using acetoneehexane (1:2) mixture as el-
uent. The yellow solid (2.11g, 47%) was recrystallized from 1,2-
dichloroethane to give the protected acridono-crown ether 8
(1.62g, 36%) as pale yellow crystals.
1448, 1420, 1368, 1232, 1128, 1096, 1064, 888, 768, 740, 700 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
(m, 16H), 5.06 (s, 2H), 7.22e7.30 (m, 5H); 13C NMR (75 MHz, CDCl3)
(ppm) 48.09, 48.68, 61.75, 67.39, 69.51, 69.86, 72.55, 128.05,
d (ppm) 3.02 (s, br, OH, 2H), 3.46e3.61
d
128.21, 128.65, 136.73, 156.54; MS calcd for C16H25NO6: 327.2.
Found (Mþ1)þ: 328.3. Anal. Calcd for C16H25NO6: C, 58.70; H, 7.70;
N, 4.28. Found: C, 58.43; H, 7.64; N, 4.02.
4.9. 6,9,15,18-Tetraoxa-12,25-diazatetracyclo[21.3.1.05,26.019,24
heptacosa-1(26),2,4,19,21,23-hexaene (12) (see Scheme 3)
]
Acridano-crown ether 12 was prepared by the usual method as
described for the reduction of acridones.34 To a suspension of
acridono-crown ether 9 (200 mg, 0.52 mmol) in ethanol (20 mL)
and water (1 mL) was added finely powdered sodium amalgam
(10 g of 2%, 8.70 mmol Na) under Ar at rt. After addition of the
sodium amalgam, the mixture was stirred for 2 h at 70 ꢃC. The
reaction mixture was removed from the mercury by decantation.
The suspension was filtered and the solvent was removed. The
crude product was purified by triturating it thoroughly with water.
The precipitate was filtered and dried over KOH in a vacuum des-
iccator to give off-white crystals of acridano-crown ether 12
(175 mg, 91%). It should be noted here that every step of the
preparation was carried out under inert atmosphere. The product
was used without further purification.
Mp: 165.5e166.5 ꢃC (1,2-dichloroethane); Rf: 0.54 (silica gel TLC,
MeOHeCH2Cl2 1:15); IR (KBr) nmax 3424, 3080, 3060, 2928, 2880,
1708, 1628, 1616, 1596, 1536, 1488, 1424, 1272, 1224, 1152, 1136,
1080, 996, 752, 688, 592 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d (ppm)
3.52e3.57 (m, 4H), 3.64e3.71 (m, 4H), 3.79e3.84 (m, 4H), 3.96 (s, br
half mol of complexed H2O, 1H), 4.19e4.24 (m, 4H), 5.01 (s, 2H),
6.99e7.03 (m, 2H), 7.09 (t, J¼7 Hz, 2H), 7.16e7.21 (m, 5H), 8.00 (d,
J¼8 Hz, 2H), 9.19 (s, NH, 1H); 13C NMR (125 MHz, CDCl3)
d (ppm)
48.52, 49.01, 67.38, 69.04, 69.21, 69.45, 70.05, 70.57, 113.32, 113.52,
119.16, 120.90, 120.98, 122.25, 128.00, 128.17, 128.61, 131.85, 136.79,
146.68, 156.36, 178.06; MS calcd for C29H30N2O7: 518.2. Found
(Mþ1)þ: 519.2. Anal. Calcd for C29H30N2O7$0.5H2O: C, 66.02; H,
5.92; N, 5.31. Found: C, 66.01; H, 5.71; N, 5.23.
Mp: 149e151 ꢃC; Rf: 0.88 (alumina TLC, EtOHetoluene 1:2); IR
(KBr) nmax 3408, 3319, 3080, 2936, 2920, 2902, 2860, 1612, 1592,
1580, 1552, 1496, 1488, 1448, 1360, 1336, 1260, 1136, 1100, 1048,
4.7. 6,9,15,18-Tetraoxa-12,25-diazatetracyclo[21.3.1.05,26.019,24
]
heptacosa-1(26),2,4,19,21,23-hexaene-27-one (9) (see Scheme 1)
960, 920, 888, 824, 764, 720, 684, 616 cmꢁ1 1H NMR (500 MHz,
;
N-Benzyloxycarbonyl-protected acridono-crown ether
(163 mg, 0.314 mmol) was dissolved in DMF (25 mL) and
8
CDCl3)
d
(ppm) 2.13 (s, br, NHþH2O, disappears shaken with D2O,
3H), 2.87 (t, J¼5 Hz, 4H), 3.72 (t, J¼5 Hz, 4H), 3.85e3.87 (m, 4H),