C. Kelley et al. / Bioorg. Med. Chem. xxx (2012) xxx–xxx
11
sealed vial at 70 °C overnight. After cooling to RT, acetone (5 mL)
was added and solids were collected by filtration to yield product
as an off-white solid (40 mg, 50% yield); mp 222–224 °C; 1H NMR
(400 MHz) (CDCl3) d 8.21(s, 1H), 7.97 (m, 1H), 7.86–7.82 (m, 3H),
7.76–7.68 (m, 2H), 7.70–7.60 (m, 4H), 7.56 (t, J = 7.7 Hz, 1H),
7.51–7.47 (m, 2H), 7.41–7.30 (m, 2H), 4.29 (s, 3H), 4.11 (s, 3H),
4.01 (s, 3H), 3.38 (s, 3H); 13C NMR (100 MHz) (CDCl3) d 157.4,
155.4, 152.6, 145.3, 140.9, 140.3, 137.7, 135.4, 134.0, 129.5,
128.9, 128.7, 128.0, 127.6, 127.6, 127.0, 123.5, 123.3, 106.6,
104.8, 58.1, 56.6, 44.6, 19.9; HRMS (ESI) Calcd for C31H29INO2
(MꢀI)+ 446.2120. Found 446.2104.
1H NMR (400 MHz) (CDCl3) d 7.69 (s, 1H), 7.39 (d, J = 1.9 Hz, 1H),
7.31 (d, J = 2.0 Hz, 1H), 6.94 (s, 1H), 5.83 (s, 1H), 4.05 (s, 3H), 4.04
(s, 3H), 4.03 (s, 3H), 3.99 (s, 3H), 3.97 (s, 3H), 3.15 (s, 3H); 13C
NMR (100 MHz) (CDCl3) d 156.6, 156.1, 152.6, 150.9, 149.4,
149.0, 142.4, 136.0, 135.9, 135.8, 118.0, 113.9, 106.5, 103.2,
102.2, 61.2, 61.0, 56.0, 55.9, 27.2; HRMS (ESI) Calcd for
C
21H24NO6 (M+H)+ 386.1604. Found 386.1606.
7.7.4. 2,3-Dimethoxy-5-(6,7,8-trimethoxy-1-methylisoquinolin-
3-yl)phenyl trifluoromethanesulfonate
2,3-Dimethoxy-5-(6,7,8-trimethoxy-1-methylisoquinolin-3-
yl)phenol (1.66 g, 4.31 mmol) in DCM (100 mL) and triethylamine
(1.20 mL, 8.62 mmol) was cooled to ꢀ70 °C and triflic anhydride
(0.80 mL, 4.74 mmol) was added slowly. The resulting reaction
mixture was stirred at ꢀ70 -to ꢀ30 °C for 30 min. Reaction was
then diluted with DCM and washed with saturated NaHCO3 fol-
lowed by brine. Organic layer was collected, dried over sodium sul-
fate, and concentrated. Chromatography achieved using ISCO max
gradient 20% EtOAc/hexane yielding product as a clear golden oil
7.7. General procedure for synthesis of compound (6)
7.7.1. 6,7,8-Trimethoxy-1-methylisoquinolin-3-yl
trifluoromethanesulfonate
6,7,8-Trimethoxy-1-methylisoquinolin-3-ol
(200 mg,
0.80 mmol) and Et3N (0.22 mL, 1.60 mmol) in anhydrous DCM
(15 mL) were cooled to ꢀ70 °C and Tf2O (0.15 mL, 0.88 mmol)
was slowly added. The reaction mixture was stirred at ꢀ70 to
ꢀ40 °C for 30 min then diluted with DCM and washed with satu-
rated NaHCO3 followed by brine. Organic layer was collected, dried
over MgSO4, and concentrated. Chromatography achieved using
ISCO max gradient 100% DCM yielding product as a white solid
(210 mg, 69% yield); mp 46–47 °C; 1H NMR (400 MHz) (CDCl3) d
7.13 (s, 1H), 6.83 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.88 (s, 3H),
2.96 (s, 3H); 13C NMR (100 MHz) (CDCl3) d 158.4, 157.3, 151.1,
150.9, 143.1, 137.7, 120.4, 119.3–117.2 (m), 107.2, 102.0, 61.3,
61.1, 56.1, 26.5; HRMS (ESI) Calcd for C14H15F3NO6S (M+H)+
382.0567. Found 382.0560.
(2.21 g, 99% yield); 1H NMR (400 MHz) (CDCl3)
d 7.72 (d,
J = 1.9 Hz, 1H), 7.59 (s, 1H), 7.45 (d, J = 1.8 Hz, 1H), 6.89 (s, 1H),
3.96 (s, 6H), 3.95 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.06 (s, 3H);
13C NMR (100 MHz) (CDCl3) d 157.1, 156.3, 153.9, 151.0, 147.2,
142.9, 142.8, 141.5, 135.8, 135.7, 118.3, 114.0, 112.3, 110.8,
102.3, 61.4, 61.2, 61.1, 56.4, 56.0, 27.2; HRMS (ESI) Calcd for
C
22H23F3NO8S (M+H)+ 518.1096. Found 518.1091.
7.7.5. 3-(5,6-Dimethoxy-[1,10:40,100-terphenyl]-3-yl)-6,7,8-
trimethoxy-1-methylisoquinoline (6a)
2,3-Dimethoxy-5-(6,7,8-trimethoxy-1-methylisoquinolin-3-
yl)phenyl trifluoromethanesulfonate (100 mg, 0.19 mmol), [1,10-
biphenyl]-4-ylboronic acid (58 mg, 0.29 mmol), K2CO3 (66 mg,
0.48 mmol), and XPhos (10 mg, 0.02 mmol) in ACN (4 mL) and
H2O (2 mL) were degassed then Pd(OAc)2 (3.0 mg, 0.065 mmol)
was added and solution was carefully degassed again. The reaction
mixture was warmed to 100 °C and stirred for 1 h. After cooling to
RT, the reaction mixture was diluted with EtOAc and washed with
saturated NaHCO3 followed by brine. Organic layer was collected,
dried over sodium sulfate, and concentrated. Chromatography
achieved with ISCO max gradient 30% EtOAc/hexane yielding prod-
uct as a clear oil (56 mg, 57% yield); 1H NMR (400 MHz) (CDCl3) d
7.82 (d, J = 2.0 Hz, 1H), 7.78–7.69 (m, 8H), 7.52–7.47 (m, 2H), 7.41–
7.37 (m, 1H), 6.96 (s, 1H), 4.09 (s, 3H), 4.06 (s, 3H), 4.03 (s, 3H), 3.99
(s, 3H), 3.71 (s, 3H), 3.17 (s, 3H); 13C NMR (100 MHz) (CDCl3) d
156.7, 156.1, 153.4, 151.0, 149.1, 147.1, 142.4, 141.0, 139.9,
137.6, 136.0, 135.8, 135.4, 129.8, 128.8, 127.3, 127.1, 126.8,
121.1, 118.0, 113.9, 110.5, 102.2, 61.2, 61.1, 60.8, 56.1, 55.9, 27.3;
7.7.2. 3-(3-(Benzyloxy)-4,5-dimethoxyphenyl)-6,7,8-
trimethoxy-1-methylisoquinoline
A flask containing 6,7,8-trimethoxy-1-methylisoquinolin-3-yl
trifluoromethanesulfonate (1.7 g, 4.46 mmol), (3-(benzyloxy)-4,5-
dimethoxyphenyl)boronic acid (1.54 g, 5.35 mmol), K2CO3
(1.54 mg, 11.2 mmol), and XPhos (212 mg, 0.45 mmol) in ACN
(20 mL) and H2O (10 mL) was degassed and then Pd(OAc)2
(50 mg, 0.22 mmol) was added. The resulting solution was care-
fully degassed again. Reaction was then heated at 90 °C for 4 h.
After cooling to RT, the reaction mixture was diluted with EtOAc
and washed with saturated NaHCO3 followed by brine. Organic
layer was collected, dried over sodium sulfate, and concentrated.
Chromatography achieved using ISCO max gradient 20% EtOAc/
hexane yielding product as a light yellow oil (2.03 g, 96% yield);
1H NMR (400 MHz) (CDCl3) d 7.66 (s, 1H), 7.73–7.55 (m, 2H),
7.44–7.39 (m, 4H), 7.37–7.33 (m, 1H), 6.95 (s, 1H), 5.28 (s, 2H),
4.05 (s, 3H), 4.04 (s, 3H), 4.02 (s, 3H), 3.99 (s, 3H), 3.94 (s, 3H),
3.15 (s, 3H); 13C NMR (CDCl3) d 156.6, 156.1, 153.7, 152.7, 150.9,
149.1, 142.4, 139.5, 137.4, 135.9, 135.3, 128.5, 127.9, 127.5,
117.9, 113.8, 106.6, 104.6, 102.2, 71.4, 61.2, 61.0, 60.9, 56.3, 55.9,
27.3; HRMS (ESI) Calcd for C28H30NO6 (M+H)+ 476.2073. Found
476.2078.
HRMS (ESI) Calcd for
522.2288.
C
33H32NO5 (M+H)+ 522.2280. Found
7.7.6. 3-(5,6-Dimethoxy-[1,10:40,100-terphenyl]-3-yl)-6,7,8-
trimethoxy-1,2-dimethylisoquinolin-2-ium iodide (6b)
A
solution of 3-(5,6-dimethoxy-[1,10:40,100-terphenyl]-3-yl)-
6,7,8-trimethoxy-1-methylisoquinoline (50 mg, 0.096 mmol) in
MeI (1.5 mL) was stirred in a sealed vial at 70 °C overnight. After
cooling to RT, acetone (5 mL) was added and solids were collected
by filtration to yield product as a white solid (32 mg, 50% yield);
mp 222–224 °C; 1H NMR (400 MHz) (CDCl3) d 7.88 (s, 1H), 7.84
(d, J = 2.0 Hz, 1H), 7.78–7.64 (m, 6H), 7.51–7.46 (m, 2H), 7.41–
7.38 (m, 1H), 7.12 (s, 1H), 7.09 (d, J = 2.0 Hz, 1H), 4.35 (s, 3H),
4.14 (s, 3H), 4.11 (s, 3H), 4.09 (s, 3H), 4.05 (s, 3H), 3.78 (s, 3H),
3.60 (s, 3H); 13C NMR (100 MHz) (CDCl3) d 161.7, 157.9, 153.8,
148.4, 145.6, 140.6, 140.5, 136.0, 135.9, 129.6, 128.8, 127.5,
127.1, 127.0, 125.1, 122.9, 119.5, 114.1, 102.5, 63.2, 61.5, 60.9,
59.7, 57.4, 57.2, 44.5; HRMS (ESI) Calcd for C34H34INO5 (MꢀI)+
536.2437. Found 536.2418.
7.7.3. 2,3-Dimethoxy-5-(6,7,8-trimethoxy-1-methylisoquinolin-
3-yl)phenol
3-(3-(Benzyloxy)-4,5-dimethoxyphenyl)-6,7,8-trimethoxy-1-
methylisoquinoline (2.3 g, 4.84 mmol) was suspended in MeOH
(250 mL) followed by addition of Pd/C (10% wt.) (200 mg). The
reaction flask was sealed with septum and purged with N2 (3x) fol-
lowed by H2 (3x). Reaction mixture was then stirred at RT under H2
balloon for 3 h. Reaction was monitored by TLC and stopped once
the starting material was consumed. Reaction mixture was then
passed through a pad of Celite and washed with MeOH. The filtrate
was concentrated yielding the crude product as a grey foam which
was taken forward without further purification (1.67 g, 90% yield);