Journal of Medicinal Chemistry
Article
1-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4′-
methoxy-[1,1′-biphenyl]-4-yl)ethanone (5b). Yellow solid. Eluted
The organic phase was separated, the aqueous phase was extracted with
CHCl3 (3 × 50 mL), and the combined solution was dried over Na2SO4
and evaporated. The residue was purified by silica gel column
chromatography. Brown oil. Eluted with CHCl3/MeOH (9:1). Yield
1
with CHCl3. Yield 36%. H NMR (CDCl3) δ 2.63 (m, 1H), 2.83 (m,
1H), 3.64 (m, 2H), 3.91−4.22 (m, 11 H), 4.53 (s, 1H), 4.73 (s, 1H),
6.55 (s, 1 H), 6.62 (s, 1H), 6.95 (d, 2H, J = 8 Hz), 7.25−7.30 (m, 2H),
7.48−7.53 (m, 4H). ESI+/MS m/z: 418 [M + H]+; ESI+/MS/MS m/z:
194 (100), 165 (54). Anal. C, H, N [C26H27NO4]. mp 144−146 °C.
1-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4′-flu-
oro-[1,1′-biphenyl]-4-yl)ethanone (5c). Yellow oil. Eluted with
CHCl3/AcOEt 1:1. Yield 40%. 1H NMR (CDCl3) δ 3.11−3.13 (m, 2H)
3.82−3.86 (m, 12H), 6.54 (s, 1H), 6.61 (s, 1H), 7.29−7.33 (m, 8H).
GC-MS m/z: 405 (M+, 100), 220 (62), 185 (54).
1-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-((4′-
methoxy-[1,1′-biphenyl]-4-yl)oxy)ethanone (14). Yellow solid.
Eluted with CHCl3/AcOEt 1:1. Yield 31%. 1H NMR (CDCl3) δ 2.66−
2.88 (m, 2H), 3.77−3.86 (m, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 4.68 (s,
2H), 4.79 (s, 2H), 6.83 (s, 1H), 6.85 (s, 1H), 7.02−7.14 (m, 4H) 7.37−
7.58 (m, 4H). ESI+/MS m/z: 456 [M + H]+; ESI+/MS/MS m/z: 335
(100), 216 (29).
1
20%. H NMR (CDCl3) δ 2.14−2−16 (m, 2H), 3.35−3.37 (m, 2H),
3.68−3.71 (m, 2H), 6.71 (d, 2H, J = 8 Hz), 7.10 (d, 2H, J = 8 Hz), 7.57
(d, 2H, J = 8 Hz), 7.68 (d, 2H, J = 8 Hz). GC-MS m/z: 275 (M+, 52), 212
(100).
General Procedure for Synthesis of 7f,g and 12. A solution of
biphenyl 4f or 4g (commercially available) or 11 (1 mmol) in dry
toluene (10 mL) was added to a suspension of NaH (0.5 mmol) in dry
toluene (15 mL) and was stirred for 1 h. Chloroalkylderivative (2 mmol)
in dry toluene (5 mL) was added, and the reaction mixture was refluxed
overnight. H2O was added until effervescence ceased. The aqueous
phase was extracted with CHCl3 (3 × 50 mL), and the combined
solution was dried over Na2SO4 and evaporated. The residue was
purified by silica gel column chromatography.
4′-(4-Chlorobutoxy)biphenyl-4-ol (7f). White solid. Eluted with
CHCl3/ MeOH (95:5). Yield 22%. 1H NMR (CDCl3) δ 1.76−1.78 (m,
4H), 3.66−3.68 (m, 2H), 4.06 (m, 2H), 5.01 (br s, 1H, exchangeable
with D2O), 6.85 (d, 2H, J = 8 Hz), 7.06 (d, 2H, J = 8 Hz), 7.62 (d, 2H, J =
8 Hz), 7.69 (d, 2H, J = 8 Hz). GC-MS m/z: 276 (M+, 39), 186 (100).
4-(4-Chlorobutoxy)-4′-methoxy-1,1′-biphenyl (7g). White
1-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-(3′-hy-
droxy-[1,1′-biphenyl]-2-yl)ethanone (19a). White oil. Eluted with
CHCl3/AcOEt 1:1. Yield 40%. 1H NMR (CDCl3) δ 2.45 (m, 1H) 2.70
(m, 1H), 3.10−3−12 (m, 2H), 3.60−3.87 (m, 8H), 4.20 (s, 1H), 4.63 (s,
1H), 5.69 (br s, 1H, exchangeable with D2O), 6.37 (s, 1H), 6.39 (s, 1H),
6.92 (m, 1H), 7.29−7.39 (m, 6H), 7.60−7.62 (m, 1H). ESI−/MS m/z:
403 [M − H]−; ESI−/MS/MS m/z: 387 (100), 209 (23).
1
solid. Eluted with CHCl3. Yield 63%. H NMR (CDCl3) δ 1.77−1.80
(m, 4H), 3.66−3.68 (m, 2H), 3.86 (s, 3H), 4.03 (m, 2H), 6.83 (d, 2H, J
= 8 Hz), 6.85 (d, 2H, J = 8 Hz), 7.62 (d, 2H, J = 8 Hz), 7.67 (d, 2H, J = 8
Hz). GC-MS m/z: 290 (M+, 100), 200 (91), 185 (65).
1-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-(3′-
methoxy-[1,1′-biphenyl]-2-yl)ethanone (19b). Yellow oil. Eluted
1
2-((4′-Methoxy-[1,1′-biphenyl]-4-yl)oxy)acetonitrile (12).
White solid. Eluted with CHCl3. Yield 96%. 1H NMR (CDCl3) δ 3.85
(s, 3H), 4.79 (s, 2H), 6.94−7.03 (m, 4H), 7.37−7.55 (m, 4H). ESI+/MS
m/z: 262 [M + Na]+; ESI+/MS/MS m/z: 179 (100).
General Procedure for Synthesis of Amines 6a−c, 15, 20a,b,
25a,b, and 31. A solution of appropriate amide 5a−c (1 mmol) was
added to a suspension of LiAlH4 (2 mmol) in dry THF and refluxed for 2
h. Water was added to the cooled reaction until effervescence ceased.
The aqueous phase was extracted with Et2O (3 × 50 mL), and the
combined solution was dried over Na2SO4 and evaporated. The residue
was purified by silica gel column chromatography.
with CH2Cl2/AcOEt (95:5). Quantitative yield. H NMR (CDCl3) δ
2.40−2.44 (m, 1H), 2.68−2.72 (m, 1H), 3.30−3.34 (m, 1H), 3.47−3.59
(m, 1H), 3.74−3.91 (m, 11H), 4.12 (s, 1H), 4.12 (s, 1H), 6.52 (s, 1H),
6.59 (s, 1H), 6.82−6.92 (m, 2H), 7.24−7.34 (m, 5H), 7.40−7.42 (m,
1H). ESI +/MS m/z: 418 [M + H]+; ESI+/MS/MS m/z: 213 (18), 194
(100).
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-[5-(4-me-
thoxyphenyl)-2-furyl]methanone (24a). White solid. Eluted with
1
CHCl3. Yield 93%. H NMR (CDCl3) δ 2.92−2.99 (m, 2H), 3.84 (s,
3H), 3.86 (s, 3H), 3.87 (s, 3H), 3.91−4.11 (m, 2H), 4.78−4.92 (m, 2H),
6.65 (s, 1H), 6.66 (s, 1H), 7.07−7.12 (m, 3H), 7.41 (d, 1H, J = 3.3 Hz),
7.67 (d, 2H, J = 8 Hz). ESI+/MS m/z: 416 [M + Na]+; ESI+/MS/MS m/
z: 302 (100), 171 (34). Anal. [C23H23NO5] C, H, N. mp 175 °C.
Recrystallized from CHCl3/hexane.
2-((4′-Fluoro-[1,1′-biphenyl]-4-yl)methyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (6a). White solid. Eluted with
1
CHCl3/MeOH (9:1). Yield 40%. H NMR (CDCl3) δ 2.77−2.98 (m,
4H) 3.57 (s, 2H), 3.73 (s, 2H), 3.77 (s, 3H), 3.84 (s, 3H), 6.49 (s, 1H),
6.60 (s, 1H), 7.09−7.12 (m, 2H) 7.40−7.58 (m, 6H). Anal. C, H, N
[C24H24NO2F·2H2O·HCl]. mp 198−201 °C.
(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(5-(4-
hydroxyphenyl)furan-2-yl)methanone (24b). White solid. Eluted
with CHCl3. Yield 33%. 1H NMR (DMSO) δ 2.82−2.88 (m, 2H), 3.71
(s, 3H), 3.72 (s, 3H), 3.85−3.92 (m, 2H), 4.63−4.81 (m, 2H), 6.75 (s,
1H), 6.76 (s, 1H), 6.86 (d, 2H, J= 8 Hz), 7.13 (d, 1H, J = 3.3 Hz), 7.35
(d, 1H, J = 3.3 Hz), 7.81 (d, 2H), 9.77 (br s, 1H, OH exchangeable with
D2O). ESI−/MS m/z: 378 [M − H]−; ESI−/MS/MS m/z: 363 (100),
187 (38). ESI+/MS m/z: 402 [M + Na]+; ESI+/MS/MS m/z: 355 (35),
301 (100), 168 (58). Anal. [C22H21O5] C, H, N. mp 110−112 °C.
Recrystallized from CHCl3/hexane.
2-(6-Bromo-2H-chromen-3-yl)-1-(6,7-dimethoxy-3,4-dihy-
droisoquinolin-2(1H)-yl)ethanone (29). Brown oil. Eluted with
CH2Cl2/MeOH 98:2. Yield 48%. 1H NMR (CDCl3) δ 2.76−2.86 (m,
6H), 3.84 (s, 3H), 3.86 (s, 3H), (s, 2H), 4.46 (s, 2H), 6.84 (s, 1H),
6.86−6.88 (m, 2H), 7.32−7.35 (m, 2H), 8.07 (d, 1H, J = 2 Hz). ESI+/
MS m/z: 466 [M + Na]+; ESI+/MS/MS m/z: 275 (62), 214 (100).
4′-Methoxybiphenyl-4-amine (4e). A solution of biphenyl 3d (1
mmol) in EOH (40 mL) and Pd/C 10% (1 mol) was purged with H2.
The reaction mixture was stirred under 1 atm H2(g) at room
temperature for 8 h. The resulting mixture was filtered, and the filtrate
was concentrated to provide an oil that was purified on a silica gel
column. Pink solid. Eluted with CHCl3. Yield 52%. 1H NMR (CDCl3) δ
3.52 (s, 2H), 3.75 (s, 3H, OCH3), 6.94 (d, 2H, J = 8 Hz), 7.03 (d, 2H, J =
8 Hz), 7.38 (d, 2H, J = 8 Hz), 7.52 (d, 2H, J = 8 Hz). GC-MS m/z: 199
(M+, 100), 184 (86), 156 (28). mp 238−240 °C.
6,7-Dimethoxy-2-(2-(4′-methoxy-[1,1′-biphenyl]-4-yl)ethyl)-
1,2,3,4-tetrahydroisoquinoline (6b). White solid. Eluted with
1
CHCl3. Yield 26%. H NMR (CDCl3) δ 2.67−3.10 (m, 8H), 3.67 (s,
2H), 3.85 (s, 9H), 6.56 (s, 1 H), 6.68 (s, 1H), 7.01 (d, 2H, J = 8 Hz)
7.26−7.30 (m, 2H), 7.47−7.55 (m, 4H). ESI+/MS m/z: 404 [M + H]+;
ESI+/MS/MS m/z: 240 (36), 211 (100), 179 (78). Anal. C, H, N
[C26H29NO3·2H2O2·HCl]. mp 214−216 °C.
2-(2-(4′-Fluoro-[1,1′-biphenyl]-4-yl)ethyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (6c). White solid. Eluted with
1
CHCl3. Yield 58%. H NMR (CDCl3) δ 2.77−2.98 (m, 8H) 3.64 (s,
2H), 3.85 (s, 6H), 6.54 (s, 1H), 6.60 (s, 1H), 7.09−7.12 (m, 2H) 7.29−
7.32 (d, 2H, J = 8 Hz), 7.46−7.59 (m, 4H). ESI+/MS m/z: 414 [M +
Na]+; ESI+/MS/MS m/z: 240 (36), 211 (100), 179 (78). Anal. C, H, N
[C26H29NO2F·HCl]. mp 202−203 °C.
6,7-Dimethoxy-2-(2-((4′-methoxy-[1,1′-biphenyl]-4-yl)oxy)-
ethyl)-1,2,3,4-tetrahydroisoquinoline (15). Yellow solid. Eluted
with CHCl3/AcOEt 1:1. Yield 76%. 1H NMR (CDCl3) δ 2.86 (m, 4H),
2.95−3.00 (m, 2H), 3.76 (s, 2H), 3.83 (s, 6H), 3.86 (s, 3H), 4.25 (m,
2H), 6.52 (s, 1H), 6.59 (s, 1H), 6.94−6.99 (m, 4H), 7.35 (d, 2H, J = 8
Hz), 7.55 (d, 2H, J = 8 Hz). ESI+/MS m/z: 420 [M + H]+; ESI+/MS/MS
m/z: 218 (100), 179 (61).
2′-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-
ethyl)-[1,1′-biphenyl]-3-ol (20a). White solid. Eluted with CHCl3.
N-(3-Chloropropyl)-4′-methoxybiphenyl-4-amine (7e). A sol-
ution of biphenyl 4e (1 mmol), 1-bromo-3-chloropropane (0.6 mmol),
and K2CO3 (0.7 mmol) in ACN (50 mL) was stirred for 4 h. The solvent
was evaporated, and H2O (40 mL) and CHCl3 (40 mL) were added.
1
Yield 26%. H NMR (CDCl3) δ 2.66−2.69 (m, 4H), 2.79−2.95 (m,
4H), 3.49 (s, 2H), 3.75 (s, 3H), 3.79 (s, 3H), 5.40 (br s, 1H,
exchangeable with D2O), 6.38 (s, 1H), 6.51 (s, 1H), 6.53−6.60 (m, 1H),
I
dx.doi.org/10.1021/jm501640e | J. Med. Chem. XXXX, XXX, XXX−XXX