May-Jun 2005
Synthesis of Proton-Ionizable Acyclic, Macrocyclic and Macrobicyclic Compounds
627
and the organic layer was evaporated in vacuo. The tetrahydropy-
ranyl-protecting group was removed from the crude product by
stirring in 75 mL of 15% methanolic hydrochloric acid at room
temperature for several hours. The methanol was evaporated in
vacuo and the residue was neutralized with saturated aqueous
sodium bicarbonate. After addition of dichloromethane, the
organic layer was separated, dried over sodium sulfate and evapo-
rated in vacuo to give 3.57 g (80%) of 6 as a white solid with mp
62-64°. ir (deposit from dichloromethane solution on a sodium
of acetonitrile, 3.65 g (14.0 mmol) of pentafluorobenzyl bromide
was added dropwise over a 30-min period. The mixture was
stirred at room temperature for 24 h and filtered. The filtrate was
evaporated
in vacuo. The residue was chromatographed on silica
gel with dichloromethane and then dichloromethane-methanol
(19:1) as eluents to give 2.10 g (72%) of 9 as a white solid with
mp 38-40°. ir (deposit from dichloromethane solution on a
-1
1
sodium chloride plate): 3327 (NH) cm . H nmr (deuteriochlo-
19
roform): δ 1.59 (s, 2H), 2.66 (s, 4H), 3.87 (s, 4H). F nmr (deu-
-1
1
teriochloroform): δ -144.49 to –144.66 (m, 4F), -155.72 to
chloride plate): 3315 (NH), 1144 (C-O) cm . H nmr (deuteri-
-155.95 (t, 2F, J = 20.9Hz), -162.21 to -162.49 (m, 4F).
ochloroform): δ 4.02-4.16 (t, 4H, J = 13.8 Hz), 4.67 (s, 2H), 4.86
(s, 2H), (NH proton was not observed). MS: 894 (M ).
+
Anal. Calcd for C
H F N : C, 45.73; H, 2.40; N, 6.66.
16 10 10 2
Found: C, 45.88; H, 2.38; N, 6.66.
Anal. Calcd for C H F N O : C, 26.89; H, 1.02. Found: C,
20
9 30 3 2
27.10; H, 1.13.
'
'' '''
N,N ,N ,N -Tetra(pentafluorobenzyl) tetraazabistriazolo-18-
crown-6 (10).
3,5-Bis(aldimino-2-hydroxy-3-methoxyphenyl)-1,2,4-triazole
(7).
'
A mixture of N,N -di(pentafluorobenzyl) 1,2-ethylenediamine
(9) (2.10 g, 5.0 mmol) and 10.00 g of sodium carbonate in 150
mL of acetonitrile was refluxed for 30 min. Then, 1.25 g (5.0
mmole) of 1 dissolved in 30 ml of acetonitrile was added drop-
wise over a 3-h period. The mixture was stirred under reflux for
48 h, allowed to cool to room temperature, and filtered. The fil-
trate was evaporated in vacuo and the residue was chro-
matographed on silica gel with dichloromethane and then
dichloromethane-methanol (19:1) as eluents. The tetrahydropy-
ranyl-protecting groups were removed as described above. The
crude product was chromatographed on silica gel with
dichloromethane-methanol (19:1) as eluent followed by recrys-
tallization from dichloromethane to produce 0.27 g (5%) of 10 as
a white solid with mp 95-97°. ir (deposit from dichloromethane
A solution of 0.20 g (2.0 mmol) of 3,5-diamino-1,2,4-triazole
and 0.61 g (4.0 mmol) of 2-hydroxy-3-methoxybenzaldehyde in 50
mL of ethanol was stirred at 40-45 °C for 24 h. Upon cooling to
room temperature, a yellow solid formed. The solid was filtered
and recrystallized from ethanol to give 0.51 g (70%) of 7 as a yel-
low solid with mp 260-262°. ir (deposit from dichloromethane
solution on a sodium chloride plate): 3291 (NH, OH), 1611 (C=N),
1257, 1223, 1106 (C-O) cm . H nmr (deuteriodimethyl sulfox-
ide): δ 3.36 (s, 3H), 3.85 (s, 3H), 6.92-6.97 (t, 2H, J = 9 Hz), 7.19-
7.22 (d, 2H, J = 9 Hz), 7.44-7.47 (d, 2H, J = 9 Hz), 9.49 (s, 2H),
14.21 (s, 2H), (NH proton was not observed).
-1
1
Anal. Calcd for C
H N O : C, 58.85; H, 4.66; N, 19.06.
18 17 5 4
Found: C, 58.92; H, 4.83; N, 18.84.
-1
1
solution on a sodium chloride plate): 3320 (NH) cm . H nmr
Macrocycle 8.
(deuteriochloroform): δ 2.66 (s, 8H), 3.61 (s, 8H), 3.83 (s, 8H),
19
Bisphenol 2 (1.23 g, 3.5 mmol) in 40 ml of tetrahydrofuran
was added dropwise to a stirred suspension of 0.72 g (30.0 mol)
of sodium hydride in 50 mL of tetrahydrofuran at room tempera-
ture under nitrogen. The mixture was stirred at room temperature
for 30 min and then at reflux for 10-15 min. Then 0.87 g (3.5
mmol) of 2,6-bis(bromomethyl)pyridine in 40 mL of tetrahydro-
furan was added dropwise over a 3-h period. Reflux with stirring
was continued for 24 h, after which the mixture was allowed to
cool to room temperature. The unconsumed sodium hydride was
carefully destroyed by addition of cold water. The tetrahydrofu-
ran was evaporated in vacuo and the aqueous layer was extracted
with dichloromethane. The organic layer was evaporated in
vacuo and the residue was chromatographed on silica gel with
dichloromethane-ethyl acetate (9:1) as eluent. The tetrahydropy-
ranyl-protecting group was removed as described previously.
The crude product was chromatographed on silica gel with
dichloromethane-ethyl acetate (9:1) as eluent to give 0.80 g
(55%) of 8 as a white solid with mp 88-90°. ir (deposit from
dichloromethane solution on a sodium chloride plate): 3328
(NH protons were not observed). F nmr (deuteriochloroform):
δ -143.36 to -143.53 (m, 8F), -154.27 to -154.49 (t, 4F, J = 20.9
+
Hz), -161.94 to -162.61 (m, 8F); MS: 1027 (M ).
Anal. Calcd for C
H F N : C, 46.79; H, 2.55; N, 13.64.
40 26 20 10
Found: C, 46.57; H, 2.58; N, 13.65.
3,5-Bis(methyl-aza-15-crown-5)-1,2,4-triazole (12).
A mixture of aza-15-crown-5 (0.87 g, 4.0 mmol), 0.50 g (2.0
mmol) of 1 and 0.55 g (4.0 mmol) of potassium carbonate in 20
mL of acetonitrile was stirred under reflux for 12 h, allowed to
cool to room temperature and filtered. The filtrate was evapo-
rated in vacuo and the residue was dissolved in dichloromethane
.
The organic solution was washed with water and evaporated in
vacuo. The tetrahydropyranyl-protecting group was removed as
described above. The crude product was chromatographed on
silica gel with dichloromethane and then dichloromethane-
methanol (9:1) as eluents to give 0.74 g (70%) of 12 as an oil. ir
(deposit from dichloromethane solution on a sodium chloride
-1
1
plate): 3280 (NH), 1249, 1124 (C-O) cm . H nmr (deuteri-
ochloroform): δ 2.82-2.89 (m, 8H), 3.52-3.90 (m, 32H), 4.01 (s,
4H), (NH proton was not observed).
-1
1
(NH), 1253, 1123 (C-O) cm . H nmr (deuteriochlrorform): δ
5.15-5.21 (d, 8H, J = 11.8 Hz), 6.95-7.08 (m, 8H), 7.34-7.38 (d,
2H, J = 7.8 Hz), 7.69-7.77 (q, 1H, J = 7.6 Hz), (NH proton was
Anal. Calcd for C
H N O : C, 54.22; H, 8.53; N, 13.17.
24 45 5 8
+
not observed). MS: 417 (M ).
Found: C, 53.96; H, 8.57; N, 12.98.
Anal. Calcd for C
Found: C, 66.48; H, 5.08; N, 13.12.
H N O : C, 66.34; H, 4.84; N, 13.45.
23 20 4 4
3,5-Bis[oxymethyl-sym-(decyl)dibenzo-16-crown-5]-1,2,4-tria-
zole (14).
'
N,N-Dipentafluorobenzyl 1,2-ethylenediamine (9).
To a mixture of sodium hydride (0.43 g, 18 mmol) in 20 mL of
tetrahydrofuran under nitrogen, a solution of 1.46 g (3.0 mmol)
of sym-(decyl)(hydroxy)dibenzo-16-crown-5 (13) in 20 mL of
To a cooled mixture (ice bath) of 1,2-ethylenediamine (0.42 g,
7.0 mmol), 0.96 g (7.0 mmol) of potassium carbonate and 40 mL