Naphthyridine-Based Helical Foldamers and Macrocycles
3
3J ) 7.6 Hz, 2H), 7.73 (br s), 7.39 (d, J ) 8.2 Hz, 2H), 2.68 (t,
mixture was further cooled in ice and neutralized with concentrated
aqueous ammonia (pH 7-8). The light brown precipitate was
filtered, washed with water, and dried in vacuo. 1H NMR analysis
of the crude product indicated that the reaction was not complete,
probably due to the low solubility of the starting material in acidic
water. The precipitate was therefore solubilized in 70 mL of ethanol,
10 mL of concentrated hydrochloric acid were added, and the
solution was refluxed overnight. After being cooled in ice, the
yellow mixture was neutralized by addition of concentrated aqueous
ammonia (pH 8), filtered, dried in vacuo, and purified by flash
chromatography on silica gel (CH2Cl2/EtOAc 200:5) to yield a
yellow solid (70%). 1H NMR (CDCl3): 9.97 (s, 1H), 8.65 (s, 1H),
8.58 (d, 3J ) 8.8 Hz, 2H), 8.12 (d, 3J ) 7.7 Hz, 1H), 8.01 (d, 3J )
8.0 Hz, 1H), 7.04 (d, 3J ) 9.0 Hz, 2H), 6.8 (br s), 4.07 (t, 3J ) 6.6
Hz, 2H), 2.85 (s, 3H), 1.84 (quint, 3J ) 6.9 Hz, 2H), 1.2-1.5 (m,
20H), 0.88 (t, 3J ) 6.9 Hz, 3H). 13C NMR (CDCl3): 200.4, 192.7,
164.8, 164.4, 162.3, 160.9, 158.2, 145.5, 130.4, 129.7, 115.4, 114.9,-
111.3, 68.6, 32.3, 29.9, 29.8, 29.7, 29.6, 26.4, 26.2, 23.0, 14.5. Rf
(SiO2, CH2Cl2/EtOAc 200:5) ) 0.50. Mp ) 131 °C. EI: 502.4
(M-), 334.2 ((M - C12H25)-), 306.1 ((M - C12H25 - CO)-), 292
((M - C12H25 - COCH3)-). Anal. Calcd for C30H38N4O3‚0.04 CH2-
Cl2 (502.65): C, 71.30; H, 7.58; N, 11.07; O, 9.48. Found: C,
71.32; H, 7.64; N, 11.01.
3J ) 7.5 Hz, 2H), 1.62 (quint, J ) 7.9 Hz, 2H), 1.34 (sext, J )
3
3
7.0 Hz, 2H), 0.92 (t, J ) 7.2 Hz, 2H). 13C NMR (DMSO-d6):
3
193.3, 163.3, 163.0, 157.8, 157.2, 145.9, 145.8, 145.7, 145.5, 128.5,
128.0, 114.4, 110.0, 34.7, 32.7, 21.7, 13.7. Rf (SiO2, CH2Cl2/EtOAc
2.0:0.2) ) 0.34. Mp ) 209 °C. FAB+: 453.1 (MH+). Anal. Calcd
for C26H24N6O2‚0.045 CH2Cl2 (452.20): C, 68.55; H, 5.32; N,
18.42; O, 7.01. Found: C, 68.53; H, 5.33; N, 18.49.
1-[2-(4-n-Butylphenyl)-6-[1,8]naphthyridin-2-ylpyrimidin-4-
yl]ethyl Ketone (4nBu).31 General protocol: To a solution containing
1.89 g of 1-[2-(4-n-butylphenyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl]-
ethyl ketone (5.82 mmol) and 742 mg of 2-aminonicotinaldehyde21
(6.97 mmol, 1.04 equiv) in absolute ethanol (170 mL) at reflux
under argon were added 20 drops of 10% potassium hydroxide in
methanol, and the dark yellow solution was refluxed overnight.
After the solution was cooled to room temperature, the solvent was
evaporated and the residual solid taken up in acetone (100 mL).
Aqueous 2 N hydrochloric acid (35 mL) was added, and the mixture
was stirred at room temperature overnight. After evaporation of
the acetone, the residue was taken up in dichloromethane (300 mL)
and neutralized with K2CO3 (s) (up to pH 8) and the aqueous layer
extracted twice with dichloromethane. The combined organic layers
were dried over sodium sulfate, filtered, concentrated, and purified
by flash chromatography (silica gel, CH2Cl2/EtOAc 40:8 to 40:12)
to yield 1.5 g of a white solid (69%) which was recrystallized from
6-[6-Acetyl-2-(4-n-butylphenyl)pyrimidin-4-yl]-2-aminopyri-
dine-3-carboxaldehyde (6nBu). To (6′nBu) (114 mg, 277 µmol)
solubilized in 25 mL of warm ethanol were added 10 mL of water
and 7 mL of concentrated aqueous hydrochloric acid. The brown
solution was refluxed for 1 h. Another 15 mL of water and 5 mL
of concentrated hydrochloric acid were added, and the yellow
solution was refluxed for an additional 2 h. After being cooled in
ice, the mixture was neutralized with concentrated aquous ammonia
and the mixture extracted with dichloromethane. The combined
organic layers were dried (Na2SO4), filtered, concentrated, and
purified by flash chromatography on silica gel (CH2Cl2) to yield
1
3
dichloromethane/hexane. H NMR (CDCl3): 9.22 (dd, J ) 4.2
Hz, 4J) 1.9 Hz, 1H), 9.15 (s, 1H), 8.92 (d, 3J ) 8.9 Hz, 1H), 8.57
(d, 3J ) 8.2 Hz, 2H), 8.41 (d, 3J ) 8.5 Hz, 1H), 8.28 (dd, 3J ) 8.1
4
3
3
Hz, J ) 2.0 Hz, 1H), 7.56 (dd, J ) 8.2 Hz, J ) 4.3 Hz, 1H),
7.37 (d, 3J ) 8.5 Hz, 2H), 2.85 (s, 3H), 2.73 (t, 3J ) 7.6 Hz, 2H),
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3
1.69 (quint, J ) 7.6 Hz, 2H), 1.41 (sext, J ) 7.3 Hz, 2H), 0.96
(t, 3J ) 7.3 Hz, 2H). 13C NMR (CDCl3): 199.5, 164.8, 164.7, 160.9,
157.3, 155.8, 154.5, 146.7, 138.4, 137.1, 134.6, 128.9, 128.5, 124.0,
123.1, 120.2, 112.2, 35.7, 33.5, 26.0, 22.4, 14.0. Rf (SiO2, CH2-
Cl2/EtOAc 2.0:0.5) ) 0.31. mp ) 229 °C. FAB+: 383.1 (MH+).
Anal. Calcd for C24H22N4O‚0.105 CH2Cl2 (382.46): C, 73.98; H,
5.72; N, 14.31; O, 4.09. Found: C, 73.95; H, 5.57; N, 14.30.
7-[2-(4-Dodecyloxyphenyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl]-
pyrido[2,3-d]pyrimidine (6′OC12H25). To a solution containing 254
mg of 1-[2-(4-dodecyloxyphenyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl]-
ethyl ketone (5.61 mmol) and 76 mg of 4-aminopyrimidine-5-
carboxaldehyde20 (6.17 mmol, 1.1 equiv) in warm absolute ethanol
(10 mL) under argon were added 10 drops of 10% potassium
hydroxide. After 1 h of reflux, the solvent was evaporated and the
mixture taken up in minimal amount of ethanol, filtered, and dried.
1
54 mg of a yellow solid (52% for two steps). H NMR (CDCl3):
9.94 (s, 1H), 8.66 (s, 1H), 8.51 (d, 3J ) 7.0 Hz, 2H), 8.10 (d, 3J )
7.9 Hz, 1H), 7.99 (d, 3J ) 7.9 Hz, 1H), 7.35 (d, 3J ) 7.0 Hz, 2H),
3
3
6.8 (br s), 2.84 (s, 3H), 2.72 (t, J ) 7.5 Hz, 2H), 1.67 (quint, J
) 7.5 Hz, 2H), 1.38 (sext, 3J ) 7.3 Hz, 2H), 0.96 (t, 3J ) 6.7 Hz,
3H). 13C NMR (CDCl3): 200.0, 192.4, 164.7, 164.2, 160.6, 157.8,
157.7, 146.7,145.2, 134.5, 128.8, 128.4, 115.0, 111.5, 111.0, 35.7,
33.5, 26.5, 22.4, 14.0. Rf (SiO2, CH2Cl2) ) 0.39. Mp ) 167 °C.
FAB+: 375.2 (MH+). Anal. Calcd for C22H22N4O2‚0.025 CH2Cl2
(374.44): C, 70.25; H, 5.90; N, 14.88; O, 8.50. Found: C, 70.24;
H, 6.05; N, 14.72.
1H NMR (CDCl3): 9.62 (s, 1H), 9.56 (s, 1H), 9.08 (d, J ) 8.5
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1
OBz. Diaminodialdehyde 3OBz (50.3 mg, 1.00 × 10-4 mol) and
Hz, 1H), 8.83 (s, 1H), 8.60 (d, 3J ) 8.9 Hz, 2H), 8.51 (d, 3J ) 8.5
ketone (4OBz) (88 mg, 2.03 × 10-4 mol, 2.03 equiv) were solubilized
in DMF (10 mL) and heated at 50 °C. Two drops of 10% KOH in
methanol were added, and the red solution was stirred at 50 °C for
5 h. The reaction mixture was diluted with 30 mL of water,
centrifuged, and washed with water and the precipitate recrystallized
from dichloromethane and acetone to yield 113 mg of an off-white
3
2
Hz, 1H), 7.04 (d, J ) 8.9 Hz, 2H), 5.91 (d, J ) 1.8 Hz, 1H),
4.59 (d, 2J ) 1.7 Hz, 1H), 4.0-4.2 (m, 4H), 1.84 (quint, 3J ) 7.7
3
3
Hz, 2H), 1.53 (t, J ) 7.0 Hz, 3H), 1.2-1.5 (m, 20H), 0.88 (t, J
) 6.2 Hz, 3H). 13C NMR (CDCl3): 163.5, 163.0, 162.6, 162.2,
161.7, 159.0, 157.8, 157.4, 137.3, 130.0, 122.1, 120.3, 114.4, 110.6,
87.9, 68.2, 64.0, 31.9, 29.7, 29.4, 29.3, 22.7, 26.1, 14.6, 14.1. Mp
) 140 °C. EI: 539.5 (M-), 524.5 ((M - CH3)-), 340.1 ((M -
C2H5 - C12H25)-). Anal. Calcd for C33H41N5O2‚0.15CH2Cl2
(539.71): C, 72.07; H, 7.54; N, 12.68; O, 5.79. Found: C, 72.05;
H, 7.48; N, 12.74.
1
solid (87%). H NMR (CDCl3): 9.87 (s, 1H), 9.23 (s, 2H), 8.7-
8.9 (m, 6H), 8.2-8.6 (m, 12H), 8.10 (d, 3J ) 8.5 Hz, 2H), 7.73 (d,
3J ) 8.5 Hz, J ) 1.8 Hz, 2H), 7.4-7.6 (m, 15H), 7.18 (d, J )
8.8 Hz, 2H), 6.8-6.9 (m, 6H), 5.20 (s, 2H), 5.05 (s, 4H). 13C NMR
(CDCl3): not soluble enough. Mp ) 255 °C dec. FAB+: 1296.5
(MH+), 1205.5 [(M - CH2Ph)H+], 1113.4 [(M - 2CH2Ph) H+],
1023.4 [(M - 3CH2Ph)H+], 1317.5 (MNa+), 1333.5 (MK+). Anal.
Calcd for C83H54N14O3‚0.49 CH2Cl2: C, 75.00; H, 4.14; N, 14.67;
O, 3.59. Found: C, 75.08; H, 4.37; N, 14.94.
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7-[2-(4-n-Butylphenyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl]pyrido-
[2,3-d]pyrimidine (6′nBu). Same protocol as for the C12 chain (mp
) 173 °C); the crude product is hydrolyzed (see below) without
further purification.
6-[6-Acetyl-2-(4-dodecyloxyphenyl)pyrimidin-4-yl]-2-ami-
2-Amino-6-(2-(4-n-butylphenyl)-6-{7-[2-(4-n-butylphenyl)-6-
[1,8]naphthyridin-2-ylpyrimidin-4-yl][1,8]naphthyridin-2-yl}-
pyrimidin-4-yl)pyridine-3-carboxaldehyde 5(nBu)2. To bisami-
noaldehyde 3(nBu) (99 mg, 2.2 × 10-4 mol) and ketone 4(nBu) (85.3
mg, 2.2 × 10-4 mol, 1.0 equiv) solubilized in warm absolute ethanol
(55 mL) were added three drops of 10% potassium hydroxide in
methanol, and the solution was refluxed for 6 h. After being cooled
to room temperature, the yellow precipitate was centrifuged, washed
nopyridine-3-carboxaldehyde (6OC12H25). Vinyl ether (6′OC12H25
)
(200 mg, 3.71 mmol) suspended in 3 N aqueous hydrochloric acid
(100 mL) was refluxed with vigorous stirring for 24 h under a
nitrogen atmosphere. After being cooled to room temperature, the
(31) (a) Caluwe, P.; Majewicz, T. G. J. Org. Chem. 1975, 40, 2566-
2567. (b) Caluwe, P. Tetrahedron 1980, 36, 2359-2407.
J. Org. Chem, Vol. 73, No. 7, 2008 2493