582 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2
Griffin et al.
The combined aqueous layer was neutralized with saturated
aqueous NaHCO3, and the solid which was deposited was
collected and washed with water to give 79 as a pale yellow
solid: 1H NMR δ 6.17 (2H, br s, NH2), 6.93 (2H, d, Ar-H), 7.00
(1H, s, H-3), 7.87-8.81 (8H, m, Ar-H); MS (ESI+) m/z 288 (M
+ 1).
g, 1 mmol) and thiomorpholine (0.38 mL, 4 mmol) as pale
yellow crystals: 1H NMR (CDCl3) δ 2.63-2.68 (4H, m, CH2S),
4.03-4.08 (4H, m, CH2N), 5.62 (1H, s, 3-H), 7.01 (1H, d, J )
7.8 Hz, 7-H), 7.51-7.72 (3H, m, Ar-H), 8.60 (1H, d, J ) 7.8
Hz, 6-H), 8.75 (1H, d, J ) 8.5 Hz, 11-H); MS (EI) m/z 298 (M
+ 1).
2-(3-Aminophenyl)benzo[h]chromen-4-one (80). The
title compound was prepared from 77 (0.32 g, 1.0 mmol) as
for 79: 1H NMR δ 5.61 (2H, br s, NH2), 6.93 (1H, m, Ar-H),
7.11 (1H, s, H-3), 7.32-7.46 (2H, m, Ar-H), 7.55 (1H, m, Ar-
H), 7.89-8.26 (5H, m, Ar-H), 8.75-8.82 (1H, m, Ar-H); MS
(ESI+) m/z 288 (M + 1).
2-(Pyrrolidin-1-yl)pyrimido[2,1-a]isoquinolin-4-one (89)
was synthesized from 86 (0.23 g, 1 mmol) and pyrrolidine (0.34
mL, 4 mmol) in accordance with method VII, to give white
crystals: 1H NMR (CDCl3) δ 1.98-2.11 (4H, m, CH2CH2),
3.51-3.61 (4H, m, NCH2), 5.49 (1H, s, 3-H), 7.04 (1H, d, J )
7.6 Hz, 7-H), 7.54-7.69 (3H, m, Ar-H), 8.65 (1H, d, J ) 7.6
Hz, 6-H), 8.85-8.88 (1H, m, Ar-H); MS (ESI+) m/z 266 (M +
1).
2-(2,5-Dihydropyrrol-1-yl)pyrimido[2,1-a]isoquinolin-
4-one (90). Reaction of 86 (0.35 g, 1.5 mmol), 3-pyrroline (0.14
mL, 1.8 mmol), and NEt3 (0.25 mL, 1.8 mmol) following method
VII gave the title compound as beige crystals: 1H NMR
(CDCl3) δ 4.11 (2H, br s, NCH2), 4.53 (2H, br s, NCH2), 5.35
(1H, s, 3-H), 5.90 (2H, br s, CHdCH), 6.98 (1H, d, J ) 7.6 Hz,
7-H), 7.52-7.76 (3H, m, Ar-H), 8.64 (1H, d, J ) 7.6 Hz, 6-H),
8.80-8.85 (1H, m, Ar-H); MS (ESI+) m/z 264 (M + 1).
2-(2-Aminophenyl)benzo[h]chromen-4-one (81). The
title compound was prepared from 76 (1.25 g, 3.94 mmol)
analogously to 79: 1H NMR δ 7.16 (1H, s, H-3), 7.81-8.37
(12H, m, Ar-H + NH2); MS (ESI+) m/z 288 (M + 1).
2-(3-Pyridyl)benzo[h]chromen-4-one (82) was prepared
following the procedure described in method VI, from 1-hy-
droxy-2-acetonaphthone and pyridine-3-carbonyl chloride: IR
(KBr) 3089, 3068, 3059, 3025, 2961, 2900, 1652, 1600, 1593
1
cm-1; H NMR (CDCl3) δ 6.58 (1H, s, H-3), 7.00-8.86 (10H,
m, Ar-H); MS (EI) m/z 273 (M+).
2-(4-Pyridyl)benzo[h]chromen-4-one (83) was prepared
following the procedure described in method VI, from 1-hy-
droxy-2-acetonaphthone and pyridine-4-carbonyl chloride: IR
(KBr) 3082, 3058, 3021, 3004, 1652, 1585, 1571 cm-1; 1H NMR
(CDCl3) δ 6.95 (1H, s, H-3), 7.48-9.27 (10H, m, Ar-H); MS (EI)
m/z 273 (M+).
2-(3-(R)-Hydroxypyrrolidin-1-yl)pyrimido[2,1-a]iso-
quinolin-4-one (91). The title compound was prepared by
method VII, from 86 (0.23 g, 1 mmol) and 3-(R)-pyrrolidinol
(0.36 mL, 4 mmol), as a cream solid: 1H NMR δ 1.98-2.19
(2H, m, CH2CH(OH)), 3.41-3.55 (2H, m, NCH2), 3.81-3.96
(2H, m, NCH2), 4.48-4.55 (1H, m, CH(OH)), 5.17 (1H, s, 3-H),
7.36 (1H, d, J ) 7.6 Hz, 7-H), 7.77-7.83 (1H, m, Ar-H), 7.91-
7.99 (2H, m, Ar-H), 8.63 (1H, d, J ) 7.6 Hz, 6-H), 8.86 (1H, d,
J ) 8.0 Hz, 11-H); MS (ESI+) m/z ) 282 (M + 1).
2-(4-Methylpiperazin-1-yl)pyrimido[2,1-a]isoquinolin-
4-one (92) was prepared by method VII, from 86 (0.23 g, 1.00
mmol) and N-methylpiperazine (0.44 mL, 4.00 mmol), as a
white solid: 1H NMR δ 2.91 (3H, s, NCH3), 3.39-3.47 (8H, m,
piperazine CH2), 5.95 (1H, s, 3-H), 7.49 (1H, d, J ) 7.6 Hz,
7-H), 7.84-7.99 (1H, m, Ar-H), 8.00-8.04 (2H, m, Ar-H), 8.67
(1H, d, J ) 7.6 Hz, 6-H), 8.99 (1H, d, J ) 8.0 Hz, 11-H); MS
(ESI+) m/z 295 (M + 1).
2-(2,5-Dimethylpiperidin-1-yl)pyrimido[2,1-a]isoquin-
olin-4-one (93). The title compound was synthesized by
method VII, from 86 (0.23 g, 1.00 mmol) and 2,5-dimethylpi-
peridine (0.52 mL, 4.00 mmol) as white crystals: 1H NMR
(CDCl3) δ 0.89 (3H, s), 0.93 (3H, s), 1.65 (4H, m), 4.42 (2H, s),
5.62 (1H, s), 6.96 (1H, d), 7.61 (3H, m), 8.59 (1H, d), 8.76 (1H,
m); MS (ESI+) m/z 308 (M + 1).
2-(cis-2,6-Dimethylmorpholin-4yl)pyrimido[2,1-a]iso-
quinolin-4-one (94). The title compound was prepared as
detailed in method VII from 86 (0.12 g, 0.50 mmol) and cis-
2,6-dimethylmorpholine (0.25 mL, 2 mmol) as white crystals:
1H NMR (CDCl3) δ 1.29 (6H, d), 2.68 (2H, dd), 3.70 (2H, m),
4.30 (2H, m), 5.63 (1H, s), 7.06 (1H, d), 7.67 (3H, m), 8.65 (1H,
d), 8.81 (1H, d); MS (ESI+) m/z 310 (M + 1).
2-(2,2-Dimethylmorpholin-4-yl)-pyrimido[2,1-a]isoquin-
olin-4-one (95) was prepared from 86 (0.12 g, 1.00 mmol),
2,2-dimethylmorpholine (0.12 mL, 1.04 mmol), and NEt3 (0.17
mL, 1.22 mmol) according to method VII, to give a pale yellow
solid: 1H NMR (CDCl3) δ 1.23 (6H, s, Me), 3.48 (2H, s, NCH2C-
(Me2)), 3.65-3.82 (4H, m, NCH2CH2O), 5.58 (1H, s, 3-H), 7.03
(1H, d, J ) 7.7 Hz, 7-H), 7.51-7.74 (3H, m, Ar-H), 8.61 (1H,
d, J ) 7.7 Hz, 6-H), 8.77 (1H, d, J ) 7.8 Hz, 11-H); MS (ESI+)
m/z 310 (M + 1).
2-(2-Ethylmorpholin-4-yl)pyrimido[2,1-a]isoquinolin-
4-one (96). Reaction of 86 (0.12 g, 1.00 mmol) with 2-ethyl-
morpholine (0.12 mL, 1.04 mmol) and NEt3 (0.17 mL, 1.22
mmol) according to method VII gave the title compound as a
pale brown solid: 1H NMR (CDCl3) δ 0.98 (3H, t, J ) 7.5 Hz,
CH3), 1.49-1.63 (2H, m, CH2), 2.72-2.77 (1H, m), 3.06-3.11
(1H, m), 3.35-3.40 (1H, m), 3.59-3.65 (1H, m), 3.98-4.01 (1H,
m), 4.21-4.26 (1H, m), 5.62 (1H, s, 3-H), 7.06 (1H, d, J ) 7.6
Hz, 7-H), 7.63-7.74 (3H, m, Ar-H), 8.61 (1H, d, J ) 7.6 Hz,
6-H), 8.83 (1H, d, J ) 8.2 Hz, 11-H); MS (ESI+) m/z 310 (M +
1).
2-(4-tert-Butylphenyl)benzo[h]chromen-4-one (84) was
prepared following the procedure described in method VI, from
1-hydroxy-2-acetonaphthone and 4-tert-butylbenzoyl chlo-
ride: IR 3059, 2962, 2903, 2868, 1645, 1631, 1613, 1571 cm-1
;
1H NMR (CDCl3) δ 1.45 (9H, s, C(CH3)3), 7.27 (1H, s, H-3),
7.72-8.29 (9H, m, Ar-H), 8.76-8.81 (1H, m, Ar-H); MS (EI)
m/z 328 (M+).
Pyrimido[2,1-a]isoquinoline-2,4-dione (85). 2-Aminoiso-
quinoline (5.16 g, 35.79 mmol) was dissolved in diethyl
malonate (5.43 mL, 35.79 mmol). EtOH (20 mL) was added,
and the solution was heated to 170 °C for 4 h. EtOH was
removed by distillation and, after cooling, the dark residue was
triturated with EtOAc (10 mL). The residual pale solid was
collected by filtration and washed with EtOAc to furnish the
title compound as a pale brown solid (4.43 g, 24.89 mmol,
1
70%): mp 294-296 °C; H NMR (CDCl3) δ 3.39 (2H, s, CH2),
6.10-6.14 (1H, m, Ar-H), 7.21-7.42 (5H, m, Ar-H); MS (ESI+)
m/z 213 (M+).
2-Chloropyrimido[2,1-a]isoquinolin-4-one (86). A solu-
tion of 85 (4.43 g, 24.89 mmol) in POCl3 (20 mL) was heated
under reflux for 5 h, cooled, and poured carefully into ice water
(∼250 mL). The aqueous solution was adjusted to pH 7 with
saturated Na2CO3 solution, and the solid that deposited was
collected and washed thoroughly with water. The crude
product was purifed by chromatography on silica, eluting with
DCM, to provide the title compound as pale yellow crystals.
1
(5.21 g 91%) mp 197-199 °C; H NMR (CDCl3) δ 6.12-6.17
(1H, m, Ar-H), 6.81 (1H, s, CH), 7.24-7.45 (5H, m, Ar-H); MS
(ESI+) m/z 231.5 (M+).
2-Amine-Substituted Pyrimido[2,1-a]isoquinolin-4-
ones (13, 88-108): General Method VII. To a solution of
86 (1 mol equiv) in boiling EtOH (20 mL) was added the
appropriate amine (4 mol equiv), and the solution was stirred
vigorously under reflux for 16 h. The solid that crystallized
upon cooling of the reaction mixture was collected and washed
with cold EtOH (30 mL) to furnish the title compound.
2-(Morpholin-1-yl)pyrimido[2,1-a]isoquinolin-4-one (13)
was prepared according to method VII from 86 (0.23 g, 1 mmol)
and morpholine (0.35 mL, 4 mmol). White crystals: IR (KBr)
3070, 2983, 2945, 2911, 2864, 1701, 1641, 1574, 1546, 1522
1
cm-1; H NMR δ 3.82 (8H, m, morpholine), 5.73 (1H, s, H-3),
7.37 (1H, d, Ar-H), 7.75 (1H, m, Ar-H), 7.77 (1H, d Ar-H), 7.91
(1H, d Ar-H), 8.62 (1H, d, Ar-H), 8.88 (1H, d, Ar-H); MS (EI)
m/z 281 (M+).
2-(Thiomorpholin-4-yl)pyrimido[2,1-a]isoquinolin-4-
one (88) was prepared as outlined in method VII from 86 (0.23