G. Nesi et al. / European Journal of Medicinal Chemistry 76 (2014) 558e566
563
were purchased from SigmaeAldrich. The UVevis spectra of com-
pounds and the corresponding calibration curves were recorded
with a PerkinElmer LAMBDA BIO-20 spectrophotometer.
5.1.1. 6. 1-[(3, 4, 5-Triimethoxybenzyl)oxy]-2-[2-(3, 4, 5-
trimethoxyphenyl)ethyl]-benzene (10). The crude oil did not neces-
sitate further purification (71% yield). 1H NMR (CDCl3):
d 2.86e2.97
(m, 4H, CH2); 3,74 (s, 3H, OCH3); 3.81 (s, 3H, OCH3); 3.83 (s, 3H,
OCH3); 3.84 (s, 3H, OCH3); 3.85 (s, 3H, OCH3); 3.87 (s, 3H, OCH3);
4.99 (s, 2H, CH2); 6.31 (s, 2H, Ar); 6.69 (s, 2H, Ar); 6.88e6.95 (m, 2H,
5.1.1. General procedure for the synthesis of compounds 5e15
A solution of appropriate phenol 4aed (1.0 mmol) in a small
amount of DMSO (2 mL) was added to a solution of KOH (174 mg,
3.11 mmol) in DMSO (2.5 mL). The mixture was stirred at rt for
15 min, and then a solution of the appropriate arylmethylchloride
(1.0 mmol) in DMSO (2 mL) was added dropwise to the solution of
4. The suspension was stirred at room temperature for 12 h, and
then it was diluted with AcOEt and washed with water and brine.
The organic layer was dried and concentrated.
Ar); 7.13e7.24 (m, 2H, Ar). 13C NMR (CDCl3):
d 156.73, 153.49, 153.11,
137.99, 136.54, 133.08, 130.58, 130.25, 127.34, 120.97, 111.97, 105.82,
104.71, 70.35, 60.88, 56.27, 56.15, 36.90, 33.00, 29.80. Anal.
(C26H30O6) C, H.
5.1.1.7. 1-[(3,5-Dimethoxybenzyl)oxy]-2-[2-(3,4,5-trimethoxyphenyl)
ethyl]-benzene (11). Purified with hexane/AcOEt (70:30) (27%
yield) as an oil. 1H NMR (CDCl3):
d 2.82e3.03 (m, 4H, CH2); 3.79 (s,
9H, OCH3); 3.83 (s, 6H, OCH3); 5.04 (s, 2H, CH2); 6.37 (s, 2H, Ar);
5.1.1.1. 1-[(3,4,5-Trimethoxybenzyl)oxy]-2-[2-(3-methoxyphenyl)
6.40e6.44 (m, 1H, Ar); 6.64 (d, 2H, J ¼ 2.2 Hz, Ar); 6.94 (d, 2H,
ethyl]-benzene (5). The crude oil did not necessitate further puri-
J ¼ 7.7 Hz, Ar); 7.09e7.25 (m, 2H, Ar). 13C NMR (CDCl3):
d 161.15,
fication (75% yield). 1H NMR (CDCl3):
d 2.87e3.07 (m, 4H, CH2CH2),
156.73, 153.12, 139.96, 138.14, 136.54, 130.64, 130.27, 127.34, 120.93,
111.94, 105.89, 105.29, 99.74, 70.13, 60.88, 56.15, 55.40, 37.01, 33.17.
Anal. (C26H30O6) C, H.
3.76 (s, 3H, OCH3), 3.85 (s, 6H, OCH3), 3.89 (s, 3H, OCH3), 5.04 (s, 2H,
OCH2), 6.72e6.81 (m, 5H, Ar), 6.95 (d, 2H, J ¼ 7.9 Hz, Ar), 7.16e7.26
(m, 3H, Ar). 13C NMR (CDCl3):
d 159.79, 156.73, 153.56, 144.04,
138.03, 133.15, 130.80, 130.16, 129.25, 127.32, 121.02, 120.91, 114.36,
112.08, 111.32, 104.67, 70.40, 60.94, 56.33, 55.22, 36.57, 32.79. Anal.
5.1.1.8. 2-({2-[2-(3-Methoxyphenyl)ethyl]phenoxy}methyl)pyrimi-
dine (12). Purified with hexane/AcOEt (50:50) (50% yield) as an oil.
(C25H28O5) C, H. UVevis (solvent: PBS)
l
¼ 230 nm, ε ¼ 16,350.
1H NMR (CDCl3):
d 2.89e3.07 (m, 4H, CH2CH2); 3.76 (s, 3H, OCH3);
5.31 (s, 2H, OCH2); 6.70e6.92 (m, 5H, Ar); 7.10e7.28 (m, 4H, Ar);
5.1.1.2. 1-[(3,4-Dimethoxybenzyl)oxy]-2-[2-(3,4-dimethoxyphenyl)
ethyl]-benzene (6). The crude product was purified by crystalliza-
tion from AcOEt, affording 5 as a white solid (40% yield). Mp: 127e
d 2.79e2.98 (m, 4H, CH2); 3.75 (s, 3H,
OCH3); 3.85 (s, 6H, OCH3); 3.90 (s, 3H, OCH3); 5.02 (s, 2H, CH2); 6.60
8.78e8.80 (d, 2H, J ¼ 4.8 Hz, Pyrimidine). 13C NMR (CDCl3):
d 219.06,
166.54, 159.57, 157.37, 156.67, 144.33, 130.95, 120.15, 129.11, 127.14,
121.11, 119.93, 114.47, 112.23, 111.14, 71.37, 55.22, 36.39, 32.86. Anal.
129 ꢁC. 1H NMR (CDCl3):
(C20H20N2O2) C, H, N. UVevis (solvent: PBS)
l
¼ 225 nm, ε ¼ 22,560.
(d, 1H, J ¼ 1.5, Ar); 6.66e6.78 (m, 2H, Ar); 6.85e7.01 (m, 5H, Ar);
5.1.1.9. 1-[(2,4-Dichlorobenzyl)oxy]-2-(2-phenylethyl)benzene (13).
The crude product was purified by crystallization from MeOH
affording 13 (30% yield) as a white solid. mp: 68e70 ꢁC. 1H NMR
7.11e7.25 (m, 2H, Ar). 13C NMR (CDCl3):
d 157.44, 150.01, 149.65,
148.06, 135.90, 131.40, 130.82, 127.81, 121.44, 121.02, 120.62, 113.05,
112.65, 112.37, 112.21, 111.83, 70.84, 56.77, 56.66, 56.51, 36.72, 33.81.
Anal. (C25H28O5) C, H.
(CDCl3):
2H, Ar); 7.15e7.30 (m, 7H, Ar); 7.43e7.52 (m, 2H, Ar). 13C NMR
(CDCl3): 156.33, 142.38, 134.21, 134.04, 133.26, 130.86, 130.38,
d 2.86e3.05 (m, 4H, CH2); 5.12 (s, 2H, OCH2); 6.87e6.96 (m,
d
5.1.1.3. 1-[(3,4,5-Trimethoxybenzyl)oxy]-2-[2-(2,3-dimethoxyphenyl)
129.60, 129.34, 128.58, 128.38, 127.41, 125.94, 121.39, 111.99, 66.98,
36.70, 32.79. Anal. (C21H18Cl2O) C, H. UVevis (solvent: PBS)
ethyl]-benzene (7). Purified with hexane/AcOEt affording 7 (50%
yield) as an oil. 1H NMR (CDCl3):
d 2.93e2.99 (m, 4H, CH2); 3.72 (s,
l
¼ 230 nm, ε ¼ 16,350.
3H, OCH3); 3.84 (s, 6H, OCH3); 3.85 (s, 3H, OCH3); 3.86 (s, 3H,
OCH3); 5.03 (s, 2H, CH2); 6.70e6.78 (m, 4H, Ar); 6.87e6.99 (m, 3H,
5.1.1.10. 5-({2-[2-(3-Methoxyphenyl)ethyl]phenoxy}methyl)1,3ben-
Ar); 7.14e7.23 (m, 2H, Ar). 13C NMR (CDCl3):
d 156.77, 153.54, 152.87,
zodioxole (14). Purified with CHCl3 (80% yield) as an oil. 1H NMR
147.50, 137.99, 136.21, 133.20, 131.18, 130.20, 127.21, 123.68, 122.04,
120.99, 112.06, 110.63, 104.73, 70.40, 60.94, 60.59, 56.33, 55.93,
32.02, 30.55. Anal. (C26H30O6) C, H.
(CDCl3):
5.97 (s, 2H, OCH2O); 6.70e6.94 (m, 8H, Ar); 7.12e7.22 (m, 3H, Ar).
13C NMR (CDCl3):
166.73, 159.75, 157.40, 156.84, 144.42, 131.15,
d 2.81e3.00 (m, 4H, CH2); (s, 3H, OCH3); 4.98 (s, 2H, OCH2);
d
130.24, 129.14, 127.18, 121.21, 119.93, 114.61, 112.45, 111.28, 71.57,
55.31, 36.48, 32.89, 29.87. Anal. (C23H22O4) C, H. UVevis (solvent:
5.1.1.4. 1-[(2,3-Dimethoxybenzyl)oxy]-2-[2-(3,4,5-trimethoxyphenyl)
ethyl]-benzene (8). The crude solid did not necessitate further pu-
PBS)
l
¼ 225 nm, ε ¼ 22,560.
rification (59% yield). Mp: 68e70 ꢁC. 1H NMR (CDCl3):
d 2.78e2.99
(m, 4H, CH2); 3,77 (s, 6H, OCH3); 3.81 (s, 3H, OCH3); 3.89 (s, 6H,
5.1.1.11. 2-({2-[2-(3-Methoxyphenyl)ethyl]phenoxy}methyl)thio-
OCH3); 5.15 (s, 2H, CH2); 6.35 (s, 2H, Ar); 6.87e6.94 (m, 2H, Ar);
phene (15). Purified with hexane/AcOEt (80:20) (50% yield) as an
6.99e7.24 (m, 5H, Ar). 13C NMR (CDCl3):
d 156.27, 152.47, 152.05,
oil. 1H NMR (CDCl3):
d
2.80e2.99 (m, 4H, CH2CH2); 3.75 (s, 3H,
OCH3); 5.25 (s, 2H, OCH2); 6.71e6.80 (m, 3H, Ar); 6.87e7.04 (m, 3H,
Ar); 7.12e7.34 (m, 5H, Ar). 13C NMR (CDCl3):
159.77,156.46,144.18,
146.44, 137.59, 135.88, 130.78, 129.93, 129.53, 126.70, 123.43,
120.22, 120.13, 111.77, 111.37, 105.29, 64.71, 60.44, 60.26, 55.56,
55.36, 36.39, 32.55. Anal. (C26H30O6) C, H.
d
140.12, 131.11, 130.36, 129.23, 127.25, 126.80, 126.18, 125.88, 121.26,
121.11, 114.30, 112.17, 111.57, 65.58, 55.27, 36.68, 32.95. Anal.
5.1.1.5. 1-[(3,4-Dimethoxybenzyl)oxy]-2-[2-(3,4,5-trimethoxyphenyl)
(C20H20SO2) C, H. UVevis (solvent: PBS)
l
¼ 225 nm, ε ¼ 22,560.
ethyl]-benzene (9). Purified with hexane/AcOEt (70:30) affording 9
(41% yield) as an oil. 1H NMR (CDCl3):
d
2.78e2.98 (m, 4H, CH2);
5.1.2. 2-[2-(3-Methoxyphenyl)ethyl]-N-(pyridin-4-ylmethyl)aniline
(16)
3.73 (s, 6H, OCH3); 3.81 (s, 3H, OCH3); 3.85 (s, 3H, OCH3); 3.89 (s,
3H, OCH3); 5.01 (s, 2H, CH2); 6.30 (s, 2H, Ar); 6.85e7.02 (m, 5H, Ar);
To a solution of 19 [8] (0.88 mmol) in ethanol (10 mL) was added
the pyridine-4-carbaldehyde (0.88 mmol), and the resulting solu-
tion was stirred and refluxed for 12 h until the disappearance of
aniline. The reaction mixture was then cooled at 0 ꢁC and treated
with a solution of NaBH4 (33.3 mg, 0.88 mmol) in H2O (2 mL). The
7.12e7.24 (m, 2H, Ar). 13C NMR (CDCl3):
d 156.89, 153.14, 149.39,
149.08, 138.14, 136.61, 130.67, 130.25, 127.34, 120.89, 120.13, 112.03,
111.59, 111.35, 105.93, 70.30, 60.92, 56.20, 56.09, 36.97, 33.17. Anal.
(C26H30O6) C, H.