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H. Tang et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 360–366
C19H28N2O N HCl: C, 67.74; H, 8.68; N, 8.32. Found: C, 67.68; H,
2-(4-Fluorobenzyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]
8.73; N, 8.30.
isoquinolin-4(11bH)-one 8a
Yellowish solid; yield: 87.5%; m.p.: 278.18C; 1H-NMR (300 MHz,
CDCl3) d: 2.81–2.96 (m, 4H, CH2), 3.36–3.62 (m, 2H, CH2),3.92–
4.09 (m, 2H, CH2), 4.11–4.28 (m, 2H, CH2), 5.81–5.88 (m, 1H, CH),
7.11–7.31 (m, 4H, Ar-H), 7.65–7.78 (m, 4H, Ar-H); MS (ESI) m/z:
311.4 [M + H]. Anal. calcd. for C19H19FN2O N HCl: C, 65.80; H, 5.81;
N, 8.08. Found: C, 65.1.6; H, 5.78; N, 8.01.
2-Heptyl-2,3,6,7-tetrahydro-9,10-dimethoxy-1H-
pyrazino[2,1-a]isoquinolin-4(11bH)-one 6b
White solid; yield: 89.5%; m.p.: 260.48C; 1H-NMR (300 MHz,
CDCl3) d: 0.85–0.95 (t, J = 6 Hz, 3H, CH3), 1.22–1.41 (m, 8H, CH2),
1.73–2.08 (m, 2H, CH2), 2.69–2.94 (t, 4H, CH2), 3.14–3.33 (t, 2H,
CH2), 3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 4.13–4.19 (m, 2H,
CH2), 4.85 (m, 2H, CH2), 5.72–5.76 (dd, J = 9.3 Hz, 1H, CH), 6.64 (s,
1H, Ar-H), 6.71 (s, 1H, Ar-H); MS (ESI) m/z: 361.5 [M + H]. Anal.
calcd. for C21H32N2O3 N HCl: C, 63.54; H, 8.38; N, 7.06. Found: C,
61.97; H, 8.21; N, 7.03.
2-(4-Fluorobenzyl)-2,3,6,7-tetrahydro-9,10-dimethoxy-
1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one 8b
Yellowish solid; yield: 90.1%; m.p.: 301.28C; 1H-NMR (300 MHz,
CDCl3) d: 2.35–2.62 (m, 2H, CH2), 2.82–2.94 (m, 3H, CH2), 3.42–
3.52 (m, 3H, CH2), 3.52–3.55, 3.64–3.71 (m, 2H, CH2), 3.82 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 4.72–4.85 (m, 1H, CH), 6.49 (s, 1H, Ar-
H), 6.632 (s, 1H, Ar-H), 7.01–7.08 (t, J1 = 2.1 Hz, J2 = 4.8 Hz, 2H, Ar-
H), 7.26–7.38(t, J1 = 2.1 Hz, J2 = 4.8 Hz, 2H, Ar-H); MS (ESI) m/z:
371.4 [M + H]. Anal. calcd. for C21H23FN2O3 N HCl: C, 61.99; H, 5.95;
N, 6.88. Found: C, 61.67; H, 6.76; N, 6.84.
2-Heptyl-2,3,6,7-tetrahydro-10-fluoro-1H-pyrazino[2,1-a]
isoquinolin-4(11bH)-one 6c
Yellow solid; yield: 79.9%; m.p.: 270.68C; 1H-NMR (300 MHz,
CDCl3) d: 0.86–0.96 (t, J = 6.5 Hz, 3H, CH3), 1.25–1.42 (m, 8H, CH2),
1.87–2.03 (t, 2H, CH2), 2.80–3.05 (t, 4H, CH2), 2.99–3.08 (m, 2H,
CH2), 3.42–3.49 (m, 2H, CH2), 4.00–4.24 (m, 2H, CH2), 5.81–5.85
(m, 1H, CH), 6.94–7.00 (m, 2H, Ar-H), 7.17–7.19 (m, 1H, Ar-H); MS
(ESI) m/z: 319.4 [M + H]. Anal. calcd. for C19H27FN2O N HCl: C, 64.30;
H, 7.95; N, 7.89. Found: C, 64.25; H, 7.81; N, 7.74.
2-(4-Fluorobenzyl)-2,3,6,7-tetrahydro-10-fluoro-1H-
pyrazino[2,1-a]isoquinolin-4(11bH)-one 8c
1
Yellowish solid; yield: 81.5%; m.p.: 315.38C; H-NMR (300 MHz,
CDCl3) d: 2.74–3.02 (m, 4H, CH2), 3.32–3.52 (m, 2H, CH2), 3.90–
4.48 (m, 2H, CH2), 4.72–4.85 (m, 2H, CH2), 5.84 (m, 1H, CH), 6.84
(s, 2H, Ar-H), 6.72 (s, 1H, Ar-H), 7.15–7.22 (m, 1H, Ar-H), 7.26 (s,
1H, Ar-H), 7.56–7.78 (t, 2H, Ar-H); MS (ESI) m/z: 330.6 [M + H]. Anal.
calcd. for C19H18F2N2O N HCl: C, 62.55; H, 5.25; N, 7.68. Found: C,
61.45; H, 5.21; N, 7.61.
2-Decyl-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]
isoquinolin-4(11bH)-one 7a
White solid; yield: 82.9%; m. p.: 275.68C; 1H-NMR (300 MHz,
CDCl3) d: 0.83–0.87 (t, J = 6.9 Hz, 3H, CH3), 1.23–1.43 (m, 12H,
CH2), 1.68–1.85 (m, 2H, CH2), 2.68–2.86 (t, 2H, CH2), 2.94–3.36 (t,
4H, CH2), 3.77–3.94, 3.97–4.08 (dd, 2H, CH2), 4.31–4.72 (t, 2H,
CH2), 5.24–5.33 (t, 1H, CH), 7.22–7.28 (m, 3H, Ar-H), 7.37–7.40 (t, J
= 9 Hz, 1H, Ar-H); MS (ESI) m/z: 343.4 [M + H]. Anal. calcd. for
C22H34N2O N HCl: C, 69.72; H, 9.31; N, 7.39. Found: C, 69.67; H,
9.27; N, 7.32.
General procedure of the preparation of 9a–12c
To a solution of 5a–8c (3.89 mmol) in THF, LiAlH4 (15.5 mmol)
was added with stirring. After stirring for 3.5 h, the excess of the
reducing agent was decomposed with water. The organic layer
was decanted and the solid material was extracted with THF. The
combined organic extracts were dried over anhydrous Na2SO4.
After removal of the solvent, the residue was taken up in ether
and treated with 1 M HCl in ether. The salt was filtered and dried
to afford 9a–12c.
2-Decyl-2,3,6,7-tetrahydro-9,10-dimethoxy-1H-
pyrazino[2,1-a]isoquinolin-4(11bH)-one 7b
White solid; yield: 88.6%; m.p.: 276.48C; 1H-NMR (300 MHz,
CDCl3) d: 0.78–0.93 (t, J = 6 Hz, 3H, CH3), 1.18–1.41 (m, 14H, CH2),
1.86 (s, 2H, CH2), 2.64–3.01 (t, 4H, CH2), 3.20–3.24 (t, 2H, CH2),
3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 4.11–4.25 (m, 2H, CH2), 4.87
(m, 2H, CH2), 5.73–5.76 (dd, J = 9.3 Hz, 1H, CH), 6.64 (s, 1H, Ar-H),
6.69 (s, 1H, Ar-H); MS (ESI) m/z: 403.6 [M + H]. Anal. calcd. for
C24H38N2O3 N HCl: C, 65.66; H, 8.95; N, 6.38. Found: C, 64.63; H,
8.81; N, 6.27.
2-Pentyl-2,3,6,7,11b-hetrahydro-1H-pyrazino[2,1-a]
isoquinolin hydrochloride 9a
White solid; yield: 94.1%; m.p.: 234.58C; 1H-NMR (300 MHz,
CDCl3) d: 0.89–0.94 (t, J = 6.1 Hz, 3H, CH3), 1.30–1.37 (m, J = 21.9
Hz, 4H, CH2), 1.74–1.85 (m, 2H, CH2), 3.14–3.20 (m, 4H, CH2),
3.61–3.89 (m, 8H, CH2), 3.90–3.94 (m, 1H, CH), 7.21–7.48 (m, 4H,
Ar-H); MS (ESI) m/z: 259.4 [M + H]. Anal. calcd. for C17H26N2 N 2 HCl:
C, 61.63; H, 8.53; N, 8.45. Found: C, 61.52; H, 8.49; N, 8.37.
2-Decyl-2,3,6,7-tetrahydro-10-fluoro-1H-pyrazino[2,1-a]
2-Pentyl-2,3,6,7,11b-hetrahydro-9,10-dimethoxy-1H-
isoquinolin-4(11bH)-one 7c
pyrazino[2,1-a]isoquinolin hydrochloride 9b
Yellow solid; yield: 80.1%; m.p.: 216.18C; 1H-NMR (300 MHz,
CDCl3) d: 0.88–0.91 (t, J = 6.5 Hz, 3H, CH3), 1.17–1.40 (m, 14H,
CH2), 1.87–2.03 (m, 2H, CH2), 2.86–3.01 (m, 4H, CH2), 3.11–3.22
(m, 2H, CH2), 3.91–4.04 (m, 2H, CH2), 4.79–4.84 (m, 2H, CH2),
5.82–5.85 (m, 1H, CH), 6.91–7.00 (s, 2H, Ar-H), 7.17–7.21 (t, 1H, Ar-
H); MS (ESI) m/z: 361.5 [M + H]. Anal. calcd. for C22H33FN2O N HCl:
C, 66.56; H, 8.63; N, 7.06. Found: C, 66.02; H, 8.52; N, 7.04.
White solid; yield: 89.3%; m.p.: 262.58C; 1H-NMR (300 MHz,
CDCl3) d: 0.91–0.97 (t, J = 6.1 Hz, 3H, CH3), 1.30–1.38 (m, J = 22.8
Hz, 4H, CH2), 1.63–1.78 (m, 2H, CH2), 3.11–3.21 (t, 2H, CH2), 3.71–
3.77 (m, 8H, CH2), 3.78–3.80 (m, 1H, CH), 3.71 (s, 3H, OCH3), 3.73
(s, 3H, OCH3), 6.83 (m, 2H, Ar-H), 6.89 (m, 2H, Ar-H); MS (ESI) m/z:
319.5 [M + H]. Anal. calcd. for C19H30N2O2 N 2 HCl: C, 58.31; H,
8.24; N, 7.16. Found: C, 58.26; H, 8.21; N, 7.19.
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