A. Nakagawa et al. / Bioorg. Med. Chem. 16 (2008) 7046–7054
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chloroform. Mp 158–159 °C; 1H NMR (500 MHz, CDCl3) d 8.26 (d,
J = 7.7 Hz, 1H), 7.66 (t, J = 6.8 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H),
7.46–7.43 (m, 2H), 7.36 (d, J = 7.7 Hz, 1H), 7.29–7.23 (m, 2H),
4.28 (d, J = 22.7 Hz, 1H), 4.22 (d, J = 22.7 Hz, 1H). MS m/z 256
(MH+); HRMS calcd for C15H11FNO2 (MH+) 256.0774; found:
256.0785. Anal. Calcd for C15H10FNO2: C, 70.58; H, 3.95; N, 5.49.
Found: C, 70.30; H, 4.21; N, 5.32. Reaction of PIQ-2F (189 mg,
0.739 mmol) with methyl iodide gave DMPIQ-2F (17, 107 mg,
0.376 mmol, 50.9%) as a colorless oil, which later became a white
solid. DMPIQ-2F (17) was recrystallized from n-hexane–chloro-
which was recrystallized from n-hexane–chloroform. Mp 106–
109 °C; 1H NMR (500 MHz, CDCl3) d 8.26 (d, J = 7.7 Hz, 1H), 7.66
(t, J = 7.5 Hz, 1H), 7.56 (m, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.44–7.41
(m, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.27 (m, 1H), 4.29 (d, J = 22.7 Hz,
1H), 4.22 (d, J = 22.2 Hz, 1H); MS m/z 272 (MH+); HRMS calcd for
C
C
15H11ClNO2 (MH+) 272.0478; found: 272.0484. Anal. Calcd for
15H10ClNO2: C, 66.31; H, 3.71; N, 5.16. Found: C, 66.29; H, 3.88;
N, 5.13. Reaction of PIQ-2C (114 mg, 0.418 mmol) with methyl io-
dide gave DMPIQ-2C (20, 26 mg, 0.0871 mmol, 20.8%) as a colorless
oil, which later became a white solid. DMPIQ-2C (20) was recrys-
tallized from n-hexane–ethyl acetate. Mp 123–125 °C; 1H NMR
(500 MHz, CDCl3) d 8.27 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H),
7.57–7.55 (m, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42–7.40 (m, 2H),
7.27–7.25 (m, 1H), 1.77 (s, 3H), 1.76 (s, 3H); MS m/z 300 (MH+);
HRMS calcd for C17H15ClNO2 (MH+) 300.0791; found: 300.0823.
Anal. Calcd for C17H14ClNO2: C, 68.12; H, 4.71; N, 4.67. Found: C,
67.90; H, 4.86; N, 4.61.
form. Mp 98–100 °C; 1H NMR (500 MHz, CDCl3)
d 8.27 (d,
J = 7.3 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.48
(t, J = 7.7 Hz, 1H), 7.49–7.43 (m, 2H), 7.29–7.21 (m, 2H), 1.76 (s,
3H), 1.74 (s, 3H); MS m/z 284 (MH+); HRMS calcd for C17H15FNO2
(MH+) 284.1087; found: 284.1098. Anal. Calcd for C17H14FNO2: C,
72.07; H, 4.98; N, 4.94. Found: C, 72.11; H, 4.78; N, 5.16.
4.3.4. 2-(3-Fluorophenyl)-4,4-dimethylisoquinoline-
1,3(2H,4H)-dione (DMPIQ-3F, 18)
4.3.7. 2-(3-Chlorophenyl)-4,4-dimethylisoquinoline-
Reaction of m-fluoroaniline (216 mg, 1.94 mmol) with homoph-
thalic anhydride (294 mg, 1.81 mmol) gave 2-(3-fluorophenyl)iso-
quinoline-1,3(2H,4H)-dione (PIQ-3F, 289 mg, 1.13 mmol, 62.4%) as
a light yellow powder which was recrystallized from n-hexane–
chloroform. Mp 125–128 °C; 1H NMR (500 MHz, CDCl3) d 8.24 (d,
J = 8.1 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.49–7.47 (m, 2H), 7.36 (d,
J = 7.7 Hz, 1H), 7.16 (dt, J = 8.6, 2.6 Hz, 1H), 7.01 (d, J = 7.7 Hz,
1H), 6.96 (td, J = 9.0, 2.1 Hz, 1H), 4.23 (s, 2H). MS m/z 256 (MH+);
HRMS calcd for C15H11FNO2 (MH+) 256.0774; found: 256.0814.
Anal. Calcd for C15H10FNO2: C, 70.58; H, 3.95; N, 5.49. Found: C,
70.67; H, 4.17; N, 5.46. Reaction of PIQ-3F (272 mg, 1.07 mmol)
with methyl iodide gave DMPIQ-3F (18, 194 mg, 0.684 mmol,
63.9%) as white crystals. DMPIQ-3F (18) was recrystallized from
n-hexane–ethyl acetate. Mp 113–114 °C; 1H NMR (500 MHz,
CDCl3) d 8.26 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.54 (d,
J = 7.7 Hz, 1H), 7.49–7.44 (m, 2H), 7.15 (dt, J = 7.9, 2.1 Hz, 1H),
7.00 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 1.74 (s, 6H); MS
m/z 284 (MH+); HRMS calcd for C17H15FNO2 (MH+) 284.1087;
found: 284.1060. Anal. Calcd for C17H14FNO2: C, 72.07; H, 4.98;
N, 4.94. Found: C, 72.20; H, 4.89; N, 5.24.
1,3(2H,4H)-dione (DMPIQ-3C, 21)
Reaction of m-chloroaniline (237 mg, 1.86 mmol) with homoph-
thalic anhydride (269 mg, 1.66 mmol) gave 2-(3-chlorophenyl)iso-
quinoline-1,3(2H,4H)-dione (PIQ-3C, 284 mg, 1.05 mmol, 63.4%) as
a white powder, which was recrystallized from n-hexane–chloro-
form. Mp 154–155 °C; 1H NMR (500 MHz, CDCl3) d 8.24 (d,
J = 8.1 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.46–
7.43 (m, 2H), 7.36 (d, J = 7.7 Hz, 1H), 7.26–7.24 (m, 1H), 7.13–7.11
(m, 1H), 4.23 (s, 2H); MS m/z 272 (MH+); HRMS calcd for
C
C
15H11ClNO2 (MH+) 272.0478; found: 272.0501. Anal. Calcd for
15H10ClNO2: C, 66.31; H, 3.71; N, 5.16. Found: C, 66.14; H, 3.99;
N, 5.15. Reaction of PIQ-3C (166 mg, 0.612 mmol) with methyl io-
dide gave DMPIQ-3C (21, 45 mg, 0.148 mmol, 24.3%) as a colorless
oil, which later became a white solid. DMPIQ-3C (21) was recrystal-
lized from n-hexane–chloroform. Mp 139–142 °C; 1H NMR (500
MHz, CDCl3) d 8.26 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.54
(d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.45–7.43 (m, 2H), 7.24–
7.22 (m, 1H), 7.11–7.09 (m, 1H), 1.74 (s, 6H); MS m/z 300 (MH+);
HRMS calcd for C17H15ClNO2 (MH+) 300.0791; found: 300.0746.
Anal. Calcd for C17H14ClNO2: C, 68.12; H, 4.71; N, 4.67. Found: C,
67.87; H, 4.89; N, 4.63.
4.3.5. 2-(4-Fluorophenyl)-4,4-dimethylisoquinoline-
1,3(2H,4H)-dione (DMPIQ-4F, 19)
4.3.8. 2-(4-Chlorophenyl)-4,4-dimethylisoquinoline-
Reaction of p-fluoroaniline (212 mg, 1.89 mmol) with homoph-
thalic anhydride (303 mg, 1.87 mmol) gave 2-(4-fluorophenyl)iso-
quinoline-1,3(2H,4H)-dione (PIQ-4F, 181 mg, 0.706 mmol, 37.8%)
as a light yellow powder which was recrystallized from n-hexane–
chloroform. Mp 198–200 °C; 1H NMR (500 MHz, CDCl3) d 8.24 (d,
J = 7.6 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.36
(d, J = 7.6 Hz, 1H), 7.20–7.18 (m, 4H), 4.23 (s, 2H); MS m/z 256
(MH+); HRMS calcd for C15H11FNO2 (MH+) 256.0774; found:
256.0791. Anal. Calcd for C15H10FNO2: C, 70.58; H, 3.95; N, 5.49.
Found: C, 70.49; H, 4.22; N, 5.33. Reaction of PIQ-4F (187 mg,
0.739 mmol) with methyl iodide gave DMPIQ-4F (19, 98 mg,
0.345 mmol, 57.9%) as light yellow crystals. DMPIQ-4F (19) was
recrystallized from n-hexane–chloroform. Mp 161–162 °C; 1H
NMR (500 MHz, CDCl3) d 8.26 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.3 Hz,
1H), 7.54 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.19–7.17 (m,
4H), 1.74 (s, 6H); MS m/z 284 (MH+); HRMS calcd for C17H15FNO2
(MH+) 284.1087; found: 284.1101. Anal. Calcd for C17H14FNO2: C,
72.07; H, 4.98; N, 4.94. Found: C, 72.22; H, 5.18; N, 4.78.
1,3(2H,4H)-dione (DMPIQ-4C, 22)
Reaction of p-chloroaniline (268 mg, 2.10 mmol) with homoph-
thalic anhydride (312 mg, 1.92 mmol) gave 2-(4-chlorophenyl)iso-
quinoline-1,3(2H,4H)-dione (PIQ-4C, 331 mg, 1.22 mmol, 63.5%) as
a white powder, which was recrystallized from n-hexane–chloro-
form. Mp 173–175 °C; 1H NMR (500 MHz, CDCl3) d 8.24 (d,
J = 7.3 Hz, 1H), 7.66 (t, J = 6.9 Hz, 1H), 7.51–7.47 (m, 3H), 7.36 (d,
J = 7.7 Hz, 1H), 7.15 (d, J = 6.4 Hz, 2H), 4.23 (s, 2H); MS m/z 272
(MH+); HRMS calcd for C15H11ClNO2 (MH+) 272.0478; found:
272.0500. Anal. Calcd for C15H10ClNO2: C, 66.31; H, 3.71; N, 5.16.
Found: C, 66.12; H, 3.77; N, 5.17. Reaction of PIQ-4C (148 mg,
0.545 mmol) with methyl iodide gave DMPIQ-4C (22, 61 mg,
0.202 mmol, 37.1%) as white crystals. DMPIQ-4C (22) was recrys-
tallized from n-hexane–chloroform. Mp 171–172 °C; 1H NMR
(500 MHz, CDCl3) d 8.26 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.7 Hz,
1H), 7.54 (d, J = 7.7 Hz, 1H), 7.49–7.46 (m, 3H), 7.14 (d, J = 9.0 Hz,
2H), 1.73 (s, 6H); MS m/z 300 (MH+); HRMS calcd for C17H15ClNO2
(MH+) 300.0791; found: 300.0754. Anal. Calcd for C17H14ClNO2: C,
68.12; H, 4.71; N, 4.67. Found: C, 67.74; H, 4.73; N, 4.67.
4.3.6. 2-(2-Chlorophenyl)-4,4-dimethylisoquinoline-
1,3(2H,4H)-dione (DMPIQ-2C, 20)
Reaction of o-chloroaniline (287 mg, 2.25 mmol) with homoph-
thalic anhydride (302 mg, 1.86 mmol) gave 2-(2-chlorophenyl)iso-
quinoline-1,3(2H,4H)-dione (PIQ-2C, 351 mg, 1.29 mmol, 69.5%)
4.3.9. 4-(3,4-Dihydro-4,4-dimethyl-1,3-dioxoisoquinolin-2(1H)-
yl)benzonitrile (DMPIQ-4CN, 23)
Reaction of 4-aminobenzonitrile (203 mg, 1.72 mmol) with
homophthalic anhydride (303 mg, 1.87 mmol) gave 4-(3,4-dihy-