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Total Synthesis of RS-42358 and Analogs Using Lateral Lithiation
1115
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Anal. Calcd for C16H21NO2 0.2 H2O: C, 73.08; H, 8.20; N, 5.33.
Found: C, 73.13; H, 8.01; N, 5.52.
3.79 (d, J = 7, 2H), 6.79 (t, J = 1, 1H), 7.35-7.43 (m, 2H), 8.25-
8.31 (m, 1H).
13C NMR (75 MHz, CDCl3): d = 20.08 (2 ¥ CH3), 22.88 (CH2),
27.06 (CH2), 28.33 (CH), 29.98 (CH2), 56.36 (CH2), 113.24 (C),
125.86 (CH), 126.02 (C), 126.27 (CH), 127.51 (CH), 130.80 (CH),
133.87 (C), 135.29 (C), 162.11 (C).
5,6-Dihydro-1H,4H-naphtho[1,8-cd]pyran-1-one (2)
A mixture of aldehyde 8 (6.95 g, 26.8 mmol) and 1 M HCl (200 mL)
was refluxed for 45 min. The solution was cooled to r.t. and extract-
ed with EtOAc (2 ¥ 250 mL). The extracts were combined and con-
centrated in vacuo to a solid. The solid was purified by flash
chromatography (CH2Cl2/toluene, 20/80) to give 2 (3.86 g, 77%) as
a white crystalline solid.
MS (EI): m/z = 241 (M+).
Anal. Calcd for C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C,
79.79; H, 7.96; N, 6.02.
Mp: 101.1-102.0 °C (toluene/hexanes).
IR (KBr): n = 1723 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.91-1.99 (m, 2H), 2.64 (dt,
J = 1.5, 6, 2H), 2.92 (t, J = 6, 2H), 7.09 (t, J = 1.5, 1H), 7.42 (dd,
J = 8, 8, 1H), 7.51 (dd, J = 1, 8, 1H), 8.12 (dd, J = 1, 8, 1H).
13C NMR (75 MHz, CDCl3): d = 22.29 (CH2), 24.48 (CH2), 29.30
(CH2), 114.15 (C), 121.27 (C), 127.43 (CH), 127.89 (CH), 133.84
(C), 133.89 (CH), 135.59 (C), 139.05 (CH), 162.84 (C).
2-(1-Methylethyl)-2,4,5,6-tetrahydro-1-oxo-1H-benz[de]iso-
quinoline (10c)
Mp: 87.4-88.2 °C (EtOAc/CH2Cl2).
IR (KBr): n = 1595, 1613, 1657 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.37 (d, J = 7, 6H), 1.92-2.02 (m,
2H), 2.76 (dt, J = 1, 6, 2H), 2.96 (t, J = 6, 2H), 5.36-5.50 (m, 1H),
6.89 (t, J = 1, 1H), 7.35-7.41 (m, 2H), 8.26-8.32 (m, 1H).
13C NMR (75 MHz, CDCl3): d = 21.85 (2 ¥ CH3), 22.90 (CH2),
27.38 (CH2), 29.97 (CH2), 45.48 (CH), 114.02 (C), 121.77 (CH),
125.87 (C), 126.00 (CH), 126.28 (CH), 130.77 (CH), 133.36 (C),
135.16 (C), 161.47 (C).
MS (EI): m/z = 186 (M+).
Anal. Calcd for C12H10O2: C, 77.40; H, 5.41. Found: C, 77.46; H,
5.39.
MS (EI): m/z = 227 (M+).
2-Substituted-2,4,5,6-tetrahydro-1-oxo-1H-benz[de]isoquino-
lines 10a-e; General Procedure
Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C,
79.35; H, 7.48; N, 6.39.
In a 5 mL Wheaton vial were combined the amine (see Table for
equiv) and lactone 2 (0.248 g, 1.33 mmol). The vial was placed in
an oil bath (see Table for time and temp). The vial was cooled and
the contents were dissolved out with i-PrOH (10 mL) with, if nec-
essary, the aid of CH2Cl2 (1 mL). To the solution was added concd
HCl (0.42 g, 4.3 mmol) dropping the pH to <2. The solution was
concentrated in vacuo removing most of the solvent. The residue
was mixed with 1M HCl (10 mL). The solution was extracted with
CH2Cl2 (2 ¥ 15 mL). The extracts were combined, dried (MgSO4),
and concentrated in vacuo. The residue was purified by flash chro-
matography (CH2Cl2 followed by EtOAc/CH2Cl2, 5/95) to give
10a-e. The yields are listed in the Table.
2-Cyclohexyl-2,4,5,6-tetrahydro-1-oxo-1H-benz[de]isoquino-
line (10d)
The general procedure was used except that the eluent for chroma-
tography was MeOH/CH2Cl2, (5/95). Compound 10d was obtained
as an oil.
IR (KBr): n = 1597, 1618, 1655 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.19-1.29 (m, 1H), 1.46-1.62 (m,
5H), 1.72-1.81 (m, 1H), 1.87-2.01 (m, 5H), 2.74 (dt, J = 1, 6, 2H),
2.95 (t, J = 6, 2H), 4.97-5.05 (m, 1H), 6.91 (br s, 1H), 7.34-7.41
(m, 2H), 8.26-8.32 (m, 1H).
13C NMR (75 MHz, CDCl3): d = 22.82 (CH2), 25.51 (CH2), 25.86
(2 ¥ CH2), 27.27 (CH2), 29.89 (CH2), 32.33 (2 ¥ CH2), 53.31 (CH),
113.56 (C), 122.53 (CH), 125.74 (C), 125.96 (CH), 126.13 (CH),
130.65 (CH), 133.25 (C), 135.04 (C), 161.42 (C).
2-Butyl-2,4,5,6-tetrahydro-1-oxo-1H-benz[de]isoquinoline
(10a)
The general procedure was used except that the eluent for chroma-
tography was EtOAc/CH2Cl2 (10:90).
HRMS (EI): m/z calc 267.1623. Found: 267.1618 (M+).
Mp: 71.1-72.3 °C (CH2Cl2).
IR (KBr): n = 1597, 1614, 1655 cm-1.
Anal. Calcd for C18H21NO.0.25 H2O: C, 79.52; H, 7.97; N, 5.15.
Found: C, 79.42; H, 7.87; N, 5.50.
1H NMR (300 MHz, CDCl3): d = 0.96 (t, J = 7, 3H), 1.34-1.46 (m,
2H), 1.70-1.80 (m, 2H), 1.93-2.01 (m, 2H), 2.73 (dt, J = 1, 6, 2H),
2.96 (t, J = 6, 2H), 3.97 (t, J = 7, 2H), 6.83 (t, J = 1, 1H), 7.35-7.41
(m, 2H), 8.25-8.31 (m, 1H).
13C NMR (75 MHz, CDCl3): d = 13.79 (CH3), 20.07 (CH2), 22.87
(CH2), 27.06 (CH2), 29.98 (CH2), 31.49 (CH2), 48.92 (CH2), 113.69
(C), 125.76 (CH), 126.01 (C), 126.29 (CH), 126.94 (CH), 130.76
(CH), 133.88 (C), 135.29 (C), 161.87 (C).
2-(1,1-Dimethylethyl)-2,4,5,6-tetrahydro-1-oxo-1H-
benz[de]isoquinoline (10e)
The general procedure was used except that the HCl treatment was
unnecessary.
Mp: 91-94 °C (EtOAc/CH2Cl2).
IR (KBr): n = 1597, 1618, 1649 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.73 (s, 9H), 1.93-2.01 (m, 2H),
2.72 (dt, J = 1, 6, 2H), 2.95 (t, J = 6, 2H), 7.14 (t, J = 1, 1H), 7.32-
7.39 (m, 2H), 8.22-8.27 (m, 1H).
13C NMR (75 MHz, CDCl3): d = 23.06 (CH2), 27.59 (CH2), 28.82
(3 ¥ CH3), 29.87 (CH2), 60.35 (C), 112.63 (C), 123.48 (CH), 125.73
(CH), 126.06 (CH), 127.41 (C), 130.47 (CH), 133.39 (C), 134.76
(C), 162.96 (C).
MS (EI): m/z = 241 (M+).
Anal. Calcd for C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C,
79.41; H, 7.90; N, 6.00.
2-(2-Methylpropyl)-2,4,5,6-tetrahydro-1-oxo-1H-benz[de]iso-
quinoline (10b)
Mp: 89.5-91.4 °C (EtOAc/CH2Cl2).
IR (KBr): n = 1595, 1618, 1653 cm-1.
MS (EI): m/z = 241 (M+).
1H NMR (300 MHz, CDCl3): d = 0.96 (d, J = 7, 6H), 1.93-2.01 (m,
2H), 2.14-2.28 (m, 1H), 2.73 (dt, J = 1, 6, 2H), 2.96 (t, J = 6, 2H),
Anal. Calcd for C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C,
79.40; H, 7.88; N, 5.96.
Synthesis 2000, No. 8, 1113–1116 ISSN 0039-7881 © Thieme Stuttgart · New York