8
Tetrahedron
RP (15 x 0.46 cm), water/methanol (10-80%), 1.00 mL/min,
water/methanol (30-90%), 1.00 mL/min, 20 °C, tR= 9.917 min,
ACCEPTED MANUSCRIPT
20 °C, tR= 4.916 min, purity >99.99%. Mass: calc. for
[M+H]+ (C17H17N2O2) requires m/z: 281.13 (open), 263.12
(closed); found: 263.15. Spectral data is in accordance with
literature data.24
purity >99.99%. Mass: calc. for [M+H]+ (C16H13N2O) requires
m/z: 249.10; found: 249.05. Spectral data is in accordance with
literature data.24
4.1.6. 13-Methyl-13,13a-dihydro-5H-
isoquinolino[1,2-b]quinazolin-8(6H)-one (15)
4.1.4. 13-Methyl-8-oxo-6,8-dihydro-5H-
isoquinolino[1,2-b]quinazolin-13-ium chloride (4a)
The synthesis was carried out according to the procedure used
by F. H. Darras, et al. with 1-Methyl-1H-benzo[d][1,3]oxazine-
2,4-dione (0.32 g, 1.15 mmol, 1.0 eq), 3,4-dihydroisoquinoline
(0.21 g, 1.18 mmol, 1.02 eq) in dry toluene (10 mL). This yielded
the title compound as pale yellow solid (3.93 mmol, 87%).32
Compound 4b was dissolved in CH2Cl2 and 1 M HCl in iso-
propanol (8.0 eq) was added. The mixture discolored
immediately and was stirred for 15 min at rt prior to removal of
the solvent in vacuo. This yielded the quinazolinium form 4a in
quantitative yield and no further purification was necessary.
Rf = 0.11 – 0.39 (tailing) (SiO2, methanol/dichloromethane/NH3
1
Rf = 0.39 (SiO2, PE/EA 3:1). Mp = 128.2 – 129.6 °C. H-NMR
(400 MHz, CDCl3, 300 K): δ = 8.07 – 8.04 (m, 1H, Ar-HD-ring),
7.48 – 7.39 (m, 1H, Ar-HA-ring), 7.42 – 7.37 (m, 1H, Ar-HA-ring),
7.31 – 7.29 (m, 2H, Ar-HA-ring and Ar-HD-ring), 7.23 – 7.21 (m, 1H,
Ar-HD-ring), 7.13 – 7.05 (m, 2H, Ar-HA-ring and Ar-HD-ring), 5.76 (s,
1H, NCHN), 4.69 – 4.64 (m, 1H, NCHHCH2), 3.28 – 3.21 (m,
1H, NCHHCH2), 3.08 – 2.97 (m, 1H, NCH2CHH), 2.88 – 2.82
(m, 1H, NCH2CHH), 2.59 (s, 3H, CH3) ppm. 13C{1H}-NMR (101
MHz, CDCl3, 300 K): δ = 164.39 (s, C=O), 150.55 (s, Cquart.),
137.15 (s, Cquart.), 133.20 (s, Ar-CA-ring), 132.49 (s, Cquart.), 128.99
(s, Ar-CD-ring), 128.84 (s, Ar-CA-ring), 128.51 (s, Ar-CD-ring), 128.06
(s, Ar-CA-ring or Ar-CD-ring), 127.04 (s, Ar-CA-ring or Ar-CD-ring),
122.35 (s, Ar-CA-ring or Ar-CD-ring), 122.06 (s, Cquart.), 119.87 (s,
Ar-CA-ring or Ar-CD-ring), 72.06 (s, NCHN), 39.36 (s, NCH2CH2),
36.45 (s, CH3), 28.62 (s, NCH2CH2), ppm. IR: ν = 2865w, 1649s,
1601m, 1465m, 1451m, 1418m, 1402m, 1364w, 1341m, 1302m,
1285m, 1240w, 1167m, 1144m, 1119m, 1076m, 1051w, 1031m,
955m, 928m, 905w, 876w, 858w, 807w, 796w, 781s, 761s, 702s,
661w, 651w cm-1. HPLC: Synergi 4U fusion-RP (15 x 0.46 cm),
water/methanol (30-90%), 0.1% formic acid, 1.00 mL/min,
20 °C, tR= 9.870 min, purity >99.99%. Mass: calc. for [M+H]+
(C17H17N2O) requires m/z: 265.13; found: 265.10. Spectral data is
in accordance with the literature.32
(25%
aq-solution)
10:1:0.1%).
Mp = 237 – 239 °C
(decomposition). 1H-NMR (400 MHz, MeOD, 300 K): δ = 8.53 –
8.45 (m, 1H, Ar-H), 8.23 – 8.12 (m, 3H, Ar-H), 7.91 – 7.82 (m,
2H, Ar-H), 7.70 – 7.67 (m, 2H, Ar-H), 4.42 (t, J = 6.2 Hz, 2H,
NCH2CH2), 4.35 (s, 3H, CH3), 3.26 (t, J = 6.3 Hz, 2H,
NCH2CH2) ppm. 13C{1H}-NMR (101 MHz, MeOD, 300 K): δ =
159.92 (s, C=O), 159.05 (s, C=N), 144.27 (s, Cquart.), 141.67 (s,
Cquart.), 138.12 (s, Ar-C), 137.32 (s, Ar-C), 133.48 (s, Ar-C),
130.66 (s, Ar-C), 129.84 (s, Ar-C), 129.32 (s, Ar-C), 128.63 (s,
Ar-C), 124.12 (s, Cquart.), 120.44 (s, Ar-C), 120.22 (s, Cquart.),
64.75 (s, Ar-C), 45.08 (s, CH3), 42.85 (s, NCH2CH2), 28.03 (s,
NCH2CH2) ppm. IR: ν = 3353brw, 1693s, 1615s, 1600s, 1578w,
1545s, 1490s, 1461m, 1422s, 1334m, 1307m, 1282s, 1248m,
1213w, 1149m, 1102m, 1040w, 1000m, 977w, 953w, 903w,
815w, 791w, 763s, 745m, 687m, 666w cm-1. HPLC: Synergi 4U
fusion-RP (15 x 0.46 cm), water/methanol (30-90%), 1.00
mL/min, 20 °C, tR= 2.454 min, purity= 98.27%. Mass: calc. for
[M]+ (C17H15N2O) requires m/z: 263.12; found: 263.10.
4.1.5. 5H-Isoquinolino[1,2-b]quinazolin-8(6H)-one
(8)
3,4-Dihydroisoquinolin-1(2H)-one
(190 mg,
1.28 mmol,
4.1.7. 14-Methyl-7,8,13b,14-
tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-
5(13H)-one (16)
1.0 eq) was dissolved in dry THF (15 mL) and POCl3 (0.15 mL,
1.54 mmol, 1.2 eq) added at 60 °C. The mixture was stirred under
Ar atmosphere for 40 min. Methyl 2-aminobenzoate (340 mg,
2.25 mmol, 1.8 eq) was dissolved in dry THF (3 mL) and added
dropwise to the reaction mixture over 5 min. The temperature
was increased to 75 °C and the solution stirred for 113 h. The
solution was cooled to rt and 25% NH3 solution (6 mL) was
added until the aqeous phase reached pH = 9. The yellow
mixture was stirred vigorously for 30 min. The mixture was
extracted with CH2Cl2 (4 x 50 mL), washed with brine and the
combined organic layers were dried over Na2SO4. Evaporation of
solvent yielded 0.38 g of crude product. Parts of the crude
product (220 mg) were purified by column chromatography
(SiO2, 30 x 2 cm, petrolether/ethyl acetate 2:1, F 8-15) to yield
off-white crystals (84.7 mg, 0.302 mmol, 24%). Rf = 0.50 (SiO2,
The synthesis was carried out according to the procedure used
by G. Huang, et al. with 1-methyl-1H-benzo[d][1,3]oxazine-2,4-
dione (0.82 g, 4.61 mmol, 1.0 eq), 4,9-dihydro-3H-pyrido[3,4-
b]indole (0.80 g, 4.70 mmol, 1.02 eq) in dry CH2Cl2 (15 mL)
yielding the title compound as beige solid (1.37 g, 4.52 mmol,
98%).41 Rf = 0.70 (SiO2, PE/EA 1:1). Mp = 254 – 256 °C
(decomposition). 1H-NMR (400 MHz, DMSO-d6, 300 K): δ
= 11.05 (s, 1H, NH), 7.79 (dd, J = 7.8, 1.6 Hz, 1H, Ar-H), 7.50 –
7.45 (m, 2H, Ar-H), 7.38 – 7.35 (m, 1H, Ar-H), 7.14 – 6.87 (m,
4H, Ar-H), 6.12 (d, J = 1.5 Hz, 1H, Ctert.-H), 4.65 – 4.61 (m, 1H,
NCHHCH2), 3.24 – 3.17 (m, 1H, NCHHCH2), 2.97 – 2.89 (m,
1H, NCH2CHH), 2.88 (s, 3H, CH3), 2.84 – 2.75 (m, 1H,
NCH2CHH) ppm. 13C{1H}-NMR (101 MHz, DMSO-d6, 300 K):
δ = 164.28 (s, C=O), 148.78 (s, Cquart.), 136.50 (s, Cquart.), 133.48
(s, Ar-C), 130.63 (s, Cquart.), 128.01 (s, Ar-C), 125.98 (s, Cquart.),
121.88 (s, Ar-C), 120.29 (s, Ar-C), 119.24 (s, Cquart.), 118.93 (s,
Ar-C), 118.24 (s, Ar-C), 117.46 (s, Ar-C), 111.68 (s, Ar-C),
111.53 (s, Cquart.), 69.80 (Ctert.-H), 40.92 (NCH2CH2), 36.47
(CH3), 19.51 (NCH2CH2) ppm. IR: ν = 3211w, 2943w, 2914w,
2845w, 1627s, 1604s, 1508m, 1494w, 1472w, 1447m, 1406w,
1389m, 1343w, 1323w, 1308m, 1280m, 1262m, 1227m, 1201w,
1164m, 1145w, 1129w, 1109w, 1028w, 1011w, 941w, 879w,
844w, 745s, 733s, 689m cm-1. HPLC: Synergi 4U fusion-RP (15
1
petrolether/ethyl acetate 2:1). Mp = 158.0 – 158.7 °C. H-NMR
(400 MHz, CDCl3, 300 K): δ = 8.56 – 8.41 (m, 1H, Ar-HD-ring),
8.42 – 8.24 (m, 1H, Ar-HA-ring), 7.86 – 7.63 (m, 2H, Ar-HA-ring),
7.54 – 7.41 (m, 3H, Ar-HD-ring (2H) and Ar-HA-ring (1H)), 7.33 –
7.25 (m, 1H, Ar-HD-ring), 4.47 – 4.37 (m, 2H, NCH2CH2), 3.11 (t,
J = 6.4 Hz, 2H, NCH2CH2) ppm. 13C-NMR (101 MHz, CDCl3,
300 K): δ = 161.85 (s, C=O), 149.51 (s, Cquart.), 147.97 (s, C=N),
137.19 (s, Cquart.), 134.35 (Ar-CA-ring), 131.84 (Ar-CA-ring), 129.74
(s, Cquart.), 128.18 (Ar-CD-ring), 127.77 (2 Ar-CA-ring), 127.64 (Ar-
CD-ring), 127.01 (Ar-CD-ring), 126.66 (Ar-CD-ring), 120.91 (s, Cquart.),
39.76 (s, NCH2CH2), 27.63 (s, NCH2CH2) ppm. IR: ν = 3070w,
3031w, 2928w, 2901w, 2850w, 2359w, 2120w, 1921w, 1668s,
1608m, 1589s, 1557s, 1470s, 1457s, 1395s, 1334s, 1308m,
1265m, 1253m, 1173m, 1149s, 1108m, 1065w, 1030w, 1013w,
980m, 958w, 947m, 905m, 876m, 840m, 795w, 760s, 737s, 705s,
691s, 669m cm-1. HPLC: Synergi 4U fusion-RP (15 x 0.46 cm),
x
0.46 cm), water/methanol (30-90%), 0.1% formic acid,
1.00 mL/min, 20 °C, tR= 9.965 min, purity= 94.44%. Mass: calc.
for [M+H]+ (C19H18N3O) requires m/z: 304.14; found: 304.10.
Spectral data is in accordance with the literature.43