Awuah and Capretta
JOCArticle
107.4, 105.3, 56.4, 56.1; HRMS (ES) calcd for C17H16NO3 (M þ 1)
282.1130, found 282.1291
δ 8.29 (s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 4.07 (s, 3H), 4.02 (s, 3H);
13C NMR (CDCl3, 50 MHz) δ 154.5, 151.6, 148.5, 141.6, 132.9,
123.3, 117.4, 105.0, 104.7, 56.4; HRMS (ES) calcd for C11H10Br-
ClNO2 (M þ 1) 301.9583, found 301.9609.
6,7-Dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile (25):
To solution of 4-bromo-6,7-dimethoxyisoquinolin-1(2H)-one
(23) (0.96 mmol, 270.7 mg) in N-methyl-2-pyrrolidone (4 mL)
was added (193.8 mg, 2 mmol) CuCN. The mixture was irra-
diated in a microwave for 40 min at 200 °C. The reaction mixture
was concentrated under a reduced pressure and the residue was
purified by flash column chromatography on silica gel with a
gradient of 50% ethyl acetate in hexane to 100% ethyl acetate.
Compound 25 was obtained in 86% yield (198 mg, 0.86 mmol):
1H NMR (DMSO-d6, 200 MHz) δ 8.08 (s, 1H), 7.58 (s, 1H),
7.02 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H); 13C NMR (DMSO-d6,
50 MHz) δ 160.5, 154.2, 149.6, 138.4, 129.2, 118.7, 116.7, 107.4,
103.9, 87.9, 56.0, 55.8; HRMS (CI) calcd for C12H11N2O3 (M þ 1)
231.0725, found 231.0773.
1-Bromo-6,7-dimethoxy-4-phenylisoquinoline (26): To a mix-
ture of 6,7-dimethoxy-4-phenylisoquinolin-1(2H)-one (24) (80 mg,
0.28 mmol) and POBr3 (253.7 mg, 0.84 mmol) in a microwave
vial was added DCM (3 mL). The mixture was irradiated in a
microwave for 30 min at 120 °C. The reaction mixture was dilu-
tedwithDCM(10mL) andwashedwithsaturatedaqueoussodium
bicarbonate solution (5 mL), then with brine (5 mL). The organic
extract was dried over Na2SO4 and concentrated under reduced
pressure to give 1-bromo-6,7-dimethoxy-4-phenylisoquinoline
(26) (98%), which was used for the synthesis of 27 and 28 with-
out further purification.
4-Bromo-1-ethoxy-6,7-dimethoxyisoquinoline (30): To a solu-
tion of 4-bromo-1-chloro-6,7-dimethoxyisoquinoline (29) (50 mg,
0.17 mmol) in ethanol (2 mL) was added NaOEt (46.7 mg, 0.33
mmol). The reaction mixture was irradiated in a microwave for
30 min at 90 °C. The mixture was diluted with DCM (10 mL) and
washed with distilled water (5 mL). The DCM was dried over
Na2SO4. Removal of the solvent and purification by flash column
chromatography on silica gel with 20% ethyl acetate in hexane
yielded 30 in 87% yield (45 mg, 0.144 mmol): 1H NMR (CDCl3,
200 MHz) δ 8.04 (s, 1H), 7.5 (s, 1), 7.31 (s, 1H), 4.52 (q, J=6.6
Hz, 2H), 4.06 (s, 3H), 4.04 (s, 3H), 1.50 (t, J=6.6 Hz, 3H); 13
C
NMR (CDCl3, 50 MHz) δ 159.1, 153.6, 150.1, 139.8, 132.7, 115.6,
110.3, 105.1, 103.3, 62.4, 56.3, 14.8; HRMS (EI) calcd for C13H14-
BrNO3 311.0157, found 311.0154.
1-Ethoxy-6,7-dimethoxy-4-phenylisoquinoline (31): By using
4-bromo-1-ethoxy-6,7-dimethoxyisoquinoline (30) (30 mg, 0.096
mmol) and phenylboronic acid (17.9 mg, 0.144 mmol) and the
procedure as described for compound 24, 1-ethoxy-6,7-dimethoxy-
4-phenylisoquinoline (31) was obtained in 93% yield (29 mg,
0.092 mmol): 1H NMR (CDCl3, 200 MHz) δ 7.81 (s, 1H), 7.58
(s, 1H), 7.47 (s, 5H), 7.10 (s, 1H), 4.58 (q, J=6.8 Hz, 2H), 4.03
(s, 3H), 3.83 (s, 3H), 1.52 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3,
50 MHz) δ 159.1, 152.7, 149.3, 138.3, 138.1, 132.7, 130.0, 128.6,
127.3, 126.9, 114.2, 103.7, 103.1, 62.0, 56.1, 55.9, 14.9; HRMS
(ES) calcd for C19H20NO3 (M þ 1) 310.1443, found 310.1437.
1-Bromo-6,7-dimethoxyisoquinoline-4-carbonitrile (32): To a
mixture of 6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carbo-
nitrile (25) (150.1 mg, 0.652 mmol) and POBr3 (0.59 g, 1.956
mmol) was added dicholoromethane (4 mL). The reaction
mixture was irradiated in a microwave for 30 min at 150 °C.
The anisole was removed under reduced pressure and the residue
was added slowly to ice then extracted with CH2Cl2 (3ꢀ10 mL).
The combined organic fractions were washed with saturated
aqueous bisodium carbonate solution (5 mL), then with brine
(5 mL). The organic extract was dried over Na2SO4 then concen-
trated under reduced pressure and the residue was purified by
flash column chromatography on silica gel with CH2Cl2 to yield
6,7-Dimethoxy-1,4-diphenylisoquinoline (27): To a mixture of
1-bromo-6,7-dimethoxy-4-phenylisoquinoline (26) (0.107 mmol,
36.7 mg), phenylboronic acid (0.161 mmol, 16.6 mg), Cs2CO3
(0.24 mmol, 78.2 mg), Pd2(dba)3 CHCl3 (2.3 mg, 0.0021 mmol,
3
2 mol %), and PA-Ph, (1.3 mg. 0.0043 mmol, 4 mmol %) was
added toluene (1.5 mL). The mixture was degassed, placed
under an argon atmosphere, then irradiated in a microwave
for 30 min at 90 °C. Toluene was removed and the residue was
purified by flash column chromatography on silica gel with ethyl
1
acetate to give 27 in 95% yield (35 mg, 0.10 mmol): H NMR
(CDCl3, 200 MHz) δ 8.43 (s, 1H), 7.73 (d, J = 1.2 Hz, 2H),
7.45-7.57 (m, 8H), 7.25 (d, J = 1.2 Hz, 2H), 3.88 (s, 6H); 13C
NMR (CDCl3, 50 MHz) δ 157.8, 152.7, 149.9, 141.5, 140.2,
137.9, 132.1, 131.6, 130.1, 129.8, 128.9, 128.6, 128.0, 122.6,
106.0, 103.6, 56.1; HRMS (ES) calcd for C23H19NO2 (M þ 1)
342.1494, found 342.1482.
1
32 in 89% yield (169 mg, 0.58 mmol): H NMR (CDCl3, 200
MHz) δ 8.49 (s, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 4.12 (s, 3H), 4.10
(s, 3H); 13C NMR (CDCl3, 50 MHz) δ 155.9, 152.6, 147.4, 145.7,
133.0, 124.4, 116.1, 107.5, 104.8, 103.0, 57.0, 56.6; HRMS (CI)
calcd for C12H10BrN2O2 (M þ 1) 292.9881, found 292.9902.
General Procedure for Coupling of 1-Bromo-6,7-dimethoxy-
isoquinoline-4-carbonitrile with Aldehydes via Nucleophilic Aroy-
lation. To a stirred solution of 1-bromo-6,7-dimethoxyisoquino-
line-4-carbonitrile (32) (30.1 mg, 0.102 mmol), aldehyde (0.15
mmol), and (0.15 mmol) of 1,3-dimethylimidazolium iodide in
DMF (1.5 mL) was added (0.15 mmol) NaH. The mixture was
stirred at room temperature. After 2 h, water (4 mL) was added
and the reaction mixture was extracted with chloroform (3 ꢀ
8 mL). The organic layer was dried over Na2SO4, then con-
centratedandthe residuewas purifiedbyflashcolumn chromato-
graphy on silica gel with a gradient of CH2Cl2 to 50% ethyl
acetate in CH2Cl2 to afford the coupled product. 6,7-Dimethoxy-
1-(4-methoxyphenylcarbonyl)isoquinoline-4-carbonitrile (33): Using
1-bromo-6,7-dimethoxyisoquinoline-4-carbonitrile (32) (30.1 mg,
0.102 mmol) and 4-methoxybenzaldehyde (20 mg, 0.15 mmol) and
the procedure described above yielded 33 in 99% yield (35 mg,
0.102 mmol): 1H NMR (CDCl3, 200 MHz) δ 8.79 (s, 1H), 7.91 (d,
J=8.8 Hz, 2H), 7.50 (s, 1H), 7.44 (s, 1H), 6.97 (d, J=8.8 Hz, 2H),
4.12 (s, 3H), 3.96 (s, 3H), 3.89 (s, 3H); 13C NMR (CDCl3, 50 MHz)
δ 192.7, 164.7, 157.2, 155.7, 152.2, 150.2, 145.2, 133.4, 128.9, 122.0,
116.5, 114.1, 105.6, 104.8, 102.7, 56.8, 56.5, 55.8; HRMS (CI) calcd
for C20H17N2O4 (M þ 1) 349.1144, found 349.1153.
6,7-Dimethoxy-4-phenyl-1-(piperidin-1-yl)isoquinoline (28):
To a mixture of 1-bromo-6,7-dimethoxy-4-phenylisoquinoline
(26) (36 mg, 0.1 mmol), Pd2(dba)3 CHCl3 (2.3 mg, 0.0021 mmol,
3
2 mol %), PA-Ph (1.3 mg. 0.0043 mmol, 4 mmol %), and NaOtBu,
(14.4 mg, 0.15) in a microwave vial was added toluene (2 mL).
The mixture was degassed with and placed under an atmosphere
of argon. Piperidine (15 μL, 0.15 mmol) was added and the mix-
ture was irradiated in a microwave for 30 min at 180 °C. Toluene
was evaporated under reduced pressure and the residue was
purified by flash column chromatography on silica gel with 2%
MeOH in DCM to yield 28 in 64% yield (22 mg, 0.064 mmol):
1H NMR (CDCl3, 200 MHz) δ 8.01 (s, 1H), 7.50 (s, 5H), 7.14 (s,
2H), 4.04 (s, 3H), 3.84 (s, 3H), 3.33 (t, J = 5 Hz, 4H), 1.86 (m,
4H), 1.72 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 160.9, 152.3,
149.0, 139.9, 138.3, 132.9, 130.1, 128.7, 127.8, 127.4, 117.4, 104.8,
104.1, 55.8, 52.7, 26.6, 25.0; HRMS (ES) calcd for C22H25N2O2
(M þ 1) 349.1916, found 349.1935.
4-Bromo-1-chloro-6,7-dimethoxyisoquinoline (29): 4-Bromo-
6,7-dimethoxyisoquinolin-1(2H)-one (23) (283 mg, 1 mmol) was
treated with POCl3 (2 mL, 20 mmol) and then irradiated in a
microwave for 30 min at 100 °C. The solvent was removed under
reduced pressure and the residue was poured onto ice, made
basic to pH 8, and extracted with DCM (3ꢀ10 mL). The DCM
extract was dried over Na2SO4 and concentrated to give 29 in
1
98% yield (296 mg, 0.98 mmol): H NMR (CDCl3, 200 MHz)
J. Org. Chem. Vol. 75, No. 16, 2010 5633