Job/Unit: O21408
/KAP1
Date: 18-12-12 16:45:03
Pages: 8
Synthesis of 3,4-Dihydroisoquinolin-1-ones
2 H), 4.51 (br. s, 1 H), 5.91 (s, 2 H), 6.60–6.66 (m, 2 H), 6.72 (d, J (s, 6 H), 4.21 (d, J = 5.3 Hz, 2 H), 4.79 (br. s, 1 H), 6.74–6.83 (m,
= 7.9 Hz, 1 H) ppm. HRMS (FAB): calcd. for C14H20NO4 [M +
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.31 (3 C), 44.42,
H]+ 266.1392; found 266.1395.
55.72, 55.83, 79.27, 110.79, 111.09, 119.55, 131.56, 148.20, 148.99,
155.77 ppm. IR (CHCl ): ν
= 3352, 2975, 2934, 1725 cm–1.
˜
tert-Butyl (3-Methoxyphenethyl)carbamate (19d):[20] Colorless oil.
1H NMR (300 MHz, CDCl3): δ = 1.42 (s, 9 H), 2.75 (t, J = 7.0 Hz,
2 H), 3.33–3.37 (m, 2 H), 3.78 (s, 3 H), 4.52 (br. s, 1 H), 6.72–6.77
(m, 3 H), 7.20 (t, J = 7.8 Hz, 1 H) ppm. HRMS (FAB): calcd. for
C14H22NO3 [M + H]+ 252.1600; found 252.1603.
3
max
HRMS (FAB): calcd. for C14H22NO4 [M + H]+ 268.1549; found
268.1553.
tert-Butyl [3-(3,4-Dimethoxyphenyl)propyl]carbamate (19m): White
solid, m.p. 69.5–72.0 °C. 1H NMR (300 MHz, CDCl3): δ = 1.42 (s,
9 H), 1.77 (quint., J = 7.4 Hz, 2 H), 2.57 (t, J = 7.8 Hz, 2 H), 3.05–
3.20 (m, 2 H), 3.83 (s, 3 H), 3.85 (s, 3 H), 4.50 (br. s, 1 H), 6.68–
6.78 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.39 (3 C),
31.92, 32.68, 40.19, 55.81, 55.92, 79.11, 111.31, 111.74, 120.13,
tert-Butyl Phenethylcarbamate (19e):[21] White solid, m.p. 56.4–
1
57.2 °C (lit.: 56.1–56.4 °C). H NMR (300 MHz, CDCl3): δ = 1.45
(s, 9 H), 2.83 (t, J = 7.3 Hz, 2 H), 3.35–3.45 (m, 2 H), 4.57 (br. s,
1
H), 7.16–7.38 (m, 5 H) ppm. HRMS (FAB): calcd. for
C13H20NO2 [M + H]+ 222.1494; found 222.1490.
134.19, 147.27, 148.89, 155.95 ppm. IR (CHCl ): ν
= 3374,
˜
3
max
2974, 2935, 1709 cm–1. HRMS (FAB): calcd. for C16H26NO4 [M +
H]+ 296.1862; found 296.1862.
tert-Butyl (4-Chlorophenethyl)carbamate (19f): White solid, m.p.
1
61.2–62.5 °C. H NMR (400 MHz, CDCl3): δ = 1.39 (s, 9 H), 2.72
(t, J = 6.9 Hz, 2 H), 3.23–3.36 (m, 2 H), 4.63 (br. s, 1 H), 7.08 (d,
J = 8.3 Hz, 2 H), 7.20–7.25 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 28.28 (3 C), 35.47, 41.56, 79.14, 128.52 (2 C), 130.05
Synthesis of Methyl [2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)ethyl]-
carbamate (12): NEt3 (2.9 mL, 20.5 mmol, 2.0 equiv.), DMAP
(125 mg, 1.03 mmol, 0.1 equiv.), and methyl chloroformate
(0.9 mL, 11.3 mmol, 1.1 equiv.) were added to a solution of 2-(7-
methoxybenzo[d][1,3]dioxol-5-yl)ethanamine[15] (2.0 g, 10.3 mmol,
1.0 equiv.) in CH2Cl2 (52 mL) at 0 °C. After stirring for 3 h at room
temperature, the reaction was quenched by the addition of brine
at 0 °C. The mixture was then extracted twice with CH2Cl2. The
combined organic layers were washed with a saturated NH4Cl solu-
tion and brine, dried with MgSO4, and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (hexane/
EtOAc, 2:1) to give methyl carbamate 12 (2.5 g, 95%) as a pale-
(2 C), 132.05, 137.39, 155.73 ppm. IR (CHCl ): νmax = 3348, 2976,
˜
3
2932, 2869, 1689 cm–1. HRMS (FAB): calcd. for C13H19ClNO2 [M
+ H]+ 256.1104; found 256.1109.
tert-Butyl [2-(1H-Indol-3-yl)ethyl]carbamate (19g):[22] White solid,
1
m.p. 89.5–90.5 °C (lit.: 88–90 °C). H NMR (300 MHz, CDCl3): δ
= 1.42 (s, 9 H), 2.94 (t, J = 6.8 Hz, 2 H), 3.38–3.51 (m, 2 H), 4.60
(br. s, 1 H), 6.98–7.13 (m, 1 H), 7.10 (dt, J = 1.0, 7.4 Hz, 1 H),
7.19 (dt, J = 1.2, 7.6 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.59 (d,
J = 7.7 Hz, 1 H), 8.07 (br. s, 1 H) ppm. HRMS (FAB): calcd. for
C15H21N2O2 [M + H]+ 261.1603; found 261.1608.
1
yellow solid, m.p. 100.2–101.5 °C. H NMR (400 MHz, CDCl3): δ
tert-Butyl [2-(1-Methyl-1H-indol-3-yl)ethyl]carbamate (19h):[16]
White solid, m.p. 64.3–65.5 °C. H NMR (300 MHz, CDCl3): δ =
1.42 (s, 9 H), 2.93 (t, J = 6.8 Hz, 2 H), 3.42 (br. s, 2 H), 3.74 (s, 3
H), 4.57 (br. s, 1 H), 6.87 (s, 1 H), 7.07–7.11 (m, 1 H), 7.19–7.30
(m, 2 H), 7.57 (d, J = 7.7 Hz, 1 H) ppm. HRMS (FAB): calcd. for
C16H23N2O2 [M + H]+ 275.1760; found 275.1765.
= 2.69 (t, J = 6.8 Hz, 2 H), 3.33–3.42 (m, 2 H), 3.64 (s, 3 H), 3.86
(s, 3 H), 4.69 (br. s, 1 H), 5.91 (s, 2 H), 6.31 (s, 1 H), 6.34 (s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 36.18, 42.28, 52.03,
56.53, 101.29, 102.64, 107.90, 133.19, 133.75, 143.56, 148.93,
1
156.91 ppm. IR (CHCl ): νmax = 3340, 2942, 2890, 2843, 1697 cm–1.
˜
3
HRMS (FAB): calcd. for C12H16NO5 [M + H]+ 254.1028; found
254.1025.
tert-Butyl [2-(Thiophen-3-yl)ethyl]carbamate (19i): White solid, m.p.
1
49.5–50.5 °C. H NMR (300 MHz, CDCl3): δ = 1.42 (s, 9 H), 2.80
General Procedure for the Optimization of the Friedel–Crafts-Type
Cyclization Reaction (Table 1): The specified amount of base
(DMAP, pyridine, or 2-chloropyridine) and triflic anhydride (1.0 m
in CH2Cl2) was added to a stirred solution of N-Boc-carbamate 11
(89 mg, 0.30 mmol, 1.0 equiv.) in CH2Cl2 (10 mL) at the specified
temperature (0 or –78 °C). After 30 min, the reaction mixture was
warmed to room temperature and stirred for the indicated dura-
tion. (In the case of entries 5–7 of Table 1, a Lewis acid was added
after 20 min, stirred for another 10 min, and then warmed to room
temperature.) Then the reaction was quenched by the addition of
a saturated NaHCO3 solution at 0 °C. This solution was diluted
with CH2Cl2, washed with brine, dried with MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (CH2Cl2/MeOH, 20:1) to give the cy-
clized products 13 and 14 as a white solid. [When DMAP was re-
placed by the less basic pyridine or 2-chloropyridine (Table 1, en-
tries 2 and 3), N-triflated derivatives 16 and 17 were also gener-
ated.] Isocyanate 18 could be obtained by quenching the reaction
mixture with aqueous NaHCO3 solution before the addition of the
Lewis acid.
(t, J = 6.9 Hz, 2 H), 3.30–3.41 (m, 2 H), 4.54 (br. s, 1 H), 6.92–6.98
(m, 2 H), 7.25–7.27 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 28.35 (3 C), 30.65, 40.99, 79.21, 121.25, 125.75, 128.05, 139.23,
155.80 ppm. IR (CHCl ): ν
= 3350, 2977, 2931, 1694 cm–1.
˜
3
max
HRMS (FAB): calcd. for C11H18NO2S [M + H]+ 228.1058; found
228.1063.
tert-Butyl (3Ј,5Ј-Dimethoxy-1,1Ј-biphenyl-2-yl)carbamate (19j):[23]
White solid, m.p. 88.5–89.6 °C (lit.: 88.0–88.8 °C). 1H NMR
(300 MHz, CDCl3): δ = 1.45 (s, 9 H), 3.80 (s, 6 H), 6.48 (s, 3 H),
6.60 (br. s, 1 H), 7.06 (dt, J = 1.2, 7.5 Hz, 1 H), 7.20 (dd, J = 1.7,
7.5 Hz, 1 H), 7.32 (dt, J = 1.7, 8.4 Hz, 1 H), 8.10 (d, J = 8.3 Hz,
1 H) ppm. HRMS (FAB): calcd. for C19H24NO4 330.1705; found
330.1709.
tert-Butyl (3Ј,4Ј-Dimethoxy-1,1Ј-biphenyl-2-yl)carbamate (19k):
1
Colorless oil. H NMR (300 MHz, CDCl3): δ = 1.45 (s, 9 H), 3.88
(s, 3 H), 3.93 (s, 3 H), 6.54 (br. s, 1 H), 6.85–6.98 (m, 3 H), 7.06
(dt, J = 1.2, 7.5 Hz, 1 H), 7.20 (dd, J = 1.7, 7.5 Hz, 1 H), 7.30 (dt,
J = 1.4, 7.1 Hz, 1 H), 8.10 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 28.30 (3 C), 55.88, 55.91, 80.40, 111.51,
112.30, 119.55, 121.46, 122.87, 128.15, 130.05, 130.70, 130.97,
4-Methoxy-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one
(13): White solid, m.p. 163.0–165.0 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.79 (t, J = 6.4 Hz, 2 H), 3.37 (dt, J = 3.6, 6.3 Hz, 2
H), 4.03 (s, 3 H), 5.94 (s, 2 H), 6.38 (s, 1 H), 6.51 (br. s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 30.38, 39.69, 60.76, 101.37,
102.29, 115.68, 134.50, 137.04, 144.74, 151.26, 164.68 ppm. IR
135.34, 148.53, 149.09, 152.84 ppm. IR (CHCl ): ν
= 3345,
˜
3
max
2977, 2934, 1730 cm–1. HRMS (FAB): calcd. for C19H24NO4 [M +
H]+ 330.1705; found 330.1704.
tert-Butyl (3,4-Dimethoxybenzyl)carbamate (19l): White solid, m.p.
1
65.0–66.5 °C. H NMR (300 MHz, CDCl3): δ = 1.48 (s, 9 H), 3.84
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5