B. Gabriele et al.
FULL PAPER
3.16ϫ 10–2 mmol, or 28.6 mg, 7.94ϫ 10–2 mmol, see Table 2), KI
(52.5 mg, 0.31 mmol, or 131.8 mg, 0.79 mmol, see Table 2), and
crude (2-alkynylbenzylidene)(tert-butyl)amine 2 (prepared as de-
scribed above, formally derived from 1.58 mmol of starting 1) dis-
solved in 8 mL of a 3:1 mixture of HC(OR)3 and anhydrous ROH
(R = Me or Et). The autoclave was sealed and, while stirring, the
autoclave was pressurized with CO (16 atm) and air (up to 20 atm).
After stirring at 80 or 100 °C (see Table 2) for 15 h, the autoclave
was cooled, degassed and opened. The solvent was evaporated, and
the products were purified by column chromatography on silica gel.
Methyl 3-Butyl-7-methoxyisoquinoline-4-carboxylate (3c): Purified
by column chromatography on silica gel (hexane/acetone, 98:2).
Yield: 231 mg (53% based on starting 1c). Yellow solid. M.p. 65–
67 °C. IR (KBr): ν = 1727 (s), 1579 (m), 1501 (m), 1385 (w), 1221
˜
1
(s), 1161 (w), 1135 (w), 1028 (m), 833 (m), 746 (s) cm–1. H NMR
(300 MHz, CDCl3): δ = 9.15 (s, 1 H, 1-H), 7.73 (d, J = 8.9 Hz, 1
H, 5-H), 7.36 (dd, J = 8.9, 2.4 Hz, 1 H, 6-H), 7.21 (distorted d, J
= 2.4 Hz, 1 H, 8-H), 4.04 (s, 3 H, CO2Me), 3.94 (s, 1 H, OMe),
2.96–2.88 (m,
2 H, CH2CH2CH2CH3), 1.85–1.72 (m, 2 H,
CH2CH2CH3), 1.49–1.35 (m, 2 H, CH2CH3), 0.95 (t, J = 7.3 Hz,
3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.3, 158.1,
152.1, 151.6, 128.8, 127.7, 125.5, 124.4, 122.8, 105.0, 55.5, 52.4,
36.1, 32.4, 22.7, 13.9 ppm. GC–MS: m/z (%) = 273 (5) [M]+, 258
(16), 244 (12), 231 (100), 216 (56), 214 (44), 198 (6), 187 (6), 173
(74), 158 (15), 141 (6), 130 (11), 128 (11), 115 (10), 102 (6), 89 (5),
77 (5). C16H19NO3 (273.33): calcd. C 70.31, H 7.01, N 5.12; found
C 70.39, H 7.03, N 5.10.
Methyl 3-Butylisoquinoline-4-carboxylate (3a): Purified by column
chromatography on silica gel (hexane/AcOEt, 9:1). Yield: 222 mg
(58% based on starting 1a). Yellow oil. IR (film): ν = 2952 (m),
˜
2931 (m), 1735 (s), 1622 (m), 1576 (m), 1497 (m), 1435 (m), 1379
(m), 1278 (m), 1229 (s), 1139 (m), 1037 (m), 869 (w), 757 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.25 (s, 1 H, 1-H), 7.96 (dd, J =
8.1, 1.2 Hz, 1 H, 5-H), 7.81 (distorted dd, J = 8.5, 1.2 Hz, 1 H, 8-
H), 7.71 (distorted ddd, J = 8.5, 6.9, 1.2 Hz, 1 H, 7-H), 7.57 (dis-
torted ddd, J = 8.1, 6.9, 1.2 Hz, 1 H, 6-H), 4.06 (s, 3 H, CO2Me),
Methyl 3-Butyl-6-nitroisoquinoline-4-carboxylate (3d): Purified by
column chromatography on silica gel (hexane/AcOEt, 95:5). Yield:
274 mg (60% based on starting 1d). Yellow solid. M.p. 68–71 °C.
2.99–2.89 (m,
2 H, CH2CH2CH2CH3), 1.86–1.74 (m, 2 H,
CH2CH2CH3), 1.49–1.35 (m, 2 H, CH2CH2CH2CH3), 0.95 (t, J = IR (KBr): ν = 1725 (s), 1585 (m), 1535 (s), 1384 (m), 1348 (s), 1239
˜
7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = (m), 1092 (w), 1033 (w), 842 (m) cm–1. 1H NMR (300 MHz,
169.1, 153.6, 153.5, 133.2, 131.4, 127.9, 126.9, 126.4, 123.8, 122.9,
52.4, 36.2, 32.3, 22.7, 13.9 ppm. GC–MS: m/z (%) = 243 (1) [M]+,
228 (22), 214 (17), 201 (100), 186 (65), 184 (62), 168 (17), 167 (13),
154 (15), 143 (81), 129 (19), 128 (15), 127 (16), 115 (36), 101 (9),
CDCl3): δ = 9.41 (s, 1 H, 1-H), 8.81–8.78 (m, 1 H, 5-H), 8.35 (dd,
J = 9.1, 2.1 Hz, 1 H, 7-H), 8.16 (distorted d, J = 9.1 Hz, 1 H, 8-
H), 4.13 (s, 3 H, CO2Me), 3.07–2.97 (m, 2 H, CH2CH2CH2CH3),
1.90–1.75 (m, 2 H, CH2CH2CH3), 1.52–1.36 (m, 2 H, CH2CH3),
89 (10), 77 (11). C15H17NO2 (243.30): calcd. C 74.05, H 7.04, N 0.96 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz,
5.76; found C 74.03, H 7.05, N 5.74.
CDCl3): δ = 167.8, 156.4, 153.7, 149.0, 132.7, 129.9, 127.7, 123.8,
120.7, 120.5, 53.0, 36.4, 32.1, 22.7, 13.9 ppm. GC–MS: m/z (%) =
288 (absent) [M]+, 273 (20), 259 (13), 246 (100), 231 (62), 229 (65),
213 (15), 199 (11), 188 (39), 185 (17), 158 (10), 142 (17), 128 (13),
115 (16), 114 (16), 101 (8), 88 (6), 77 (9). C15H16N2O4 (288.30):
calcd. C 62.49, H 5.59, N 9.72; found C 62.52, H 5.57, N 9.73.
Ethyl 3-Butylisoquinoline-4-carboxylate (3aЈ): Purified by column
chromatography on silica gel (hexane/acetone, 95:5). Yield: 240 mg
(59% based on starting 1a). Yellow oil. IR (film): ν = 2958 (m),
2929 (m), 1725 (s), 1622 (w), 1577 (m), 1497 (w), 1466 (m), 1378
(m), 1280 (m), 1226 (s), 1139 (m), 1037 (m), 867 (w), 757 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.24 (s, 1 H, 1-H), 7.99–7.93 (m,
˜
Methyl 3-Butyl-6-methylisoquinoline-4-carboxylate (3e): Purified by
1 H, 5-H), 7.87–7.80 (m, 1 H, 8-H), 7.71 (distorted ddd, J = 8.5, column chromatography on silica gel (hexane/AcOEt, 95:5). Yield:
6.9, 1.6 Hz, 1 H, 7-H), 7.58 (distorted ddd, J = 8.1, 6.9, 1.2 Hz, 1
H, 6-H), 4.55 (q, J = 7.3 Hz, 2 H, CO2CH2CH3), 3.00–2.90 (m, 2
203 mg (50% based on starting 1e). Yellow oil. IR (film): ν = 1728
˜
(s), 1628 (w), 1497 (w), 1437 (m), 1232 (m), 1147 (w), 1036 (m),
H, CH2CH2CH2CH3), 1.87–1.75 (m, 2 H, CH2CH2CH3), 1.50–1.36 805 (m) cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.17 (s, 1 H, 1-
(m, 2 H, CH2CH2CH3), 1.47 (t, J = 7.3 Hz, 3 H, CO2CH2CH3),
H), 7.85 (d, J = 8.5 Hz, 1 H, 8-H), 7.57–7.53 (m, 1 H, 5-H), 7.41
0.96 (t, J = 7.3 Hz, 3 H, CH2CH2CH3) ppm. 13C NMR (75 MHz, (dd, J = 8.5, 1.6 Hz, 1 H, 7-H), 4.06 (s, 3 H, CO2Me), 2.96–2.87
CDCl3): δ = 168.7, 153.5, 153.2, 133.2, 131.3, 127.9, 126.8, 126.4,
123.7, 123.2, 61.7, 36.3, 32.3, 22.8, 14.3, 14.0 ppm. GC–MS: m/z
(%) = 257 (1) [M]+, 228 (13), 215 (11), 200 (8), 186 (51), 184 (23),
168 (13), 154 (21), 143 (100), 130 (19), 115 (34), 102 (16), 89 (11),
(m, 2 H, CH2CH2CH2CH3), 2.54 (s, 3 H, Me at C-6), 1.85–1.71
(m, 2 H, CH2CH2CH3), 1.49–1.34 (m, 2 H, CH2CH3), 0.94 (t, J =
7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
169.4, 153.4, 153.1, 142.0, 133.4, 129.2, 127.7, 124.9, 122.6, 122.4,
77 (10), 76 (10), 63 (19). C16H19NO2 (257.33): calcd. C 74.68, H 52.4, 36.3, 32.3, 22.7, 22.4, 13.9 ppm. GC–MS: m/z (%) = 257 (1)
7.44, N 5.44; found C 74.63, H 7.45, N 5.44.
[M]+, 256 (2), 242 (21), 228 (16), 226 (11), 215 (100), 200 (66), 198
(50), 182 (14), 157 (90), 142 (13), 129 (13), 128 (13), 115 (18), 102
(4), 89 (3), 77 (8). C16H19NO2 (257.33): calcd. C 74.68, H 7.44, N
5.44; found C 74.62, H 7.42, N 5.45.
Methyl 3-Butyl-7-nitroisoquinoline-4-carboxylate (3b): Purified by
column chromatography on silica gel (hexane/AcOEt, 95:5). Yield:
300 mg (66% based on starting 1b). Yellow solid. M.p. 55–56 °C.
IR (KBr): ν = 1724 (s), 1625 (m), 1534 (m), 1384 (s), 1347 (s), 1223
Methyl 3-(Tetrahydropyran-2-yloxymethyl)isoquinoline-4-carboxyl-
ate (3f): Purified by column chromatography on silica gel (hexane/
acetone, 98:2). Yield: 244 mg (51% based on starting 1f). Yellow
˜
(m), 1091 (w), 1032 (w), 840 (m), 731 (w) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 9.44 (s, 1 H, 1-H), 8.92 (d, J = 2.3 Hz, 1
H, 8-H), 8.46 (dd, J = 9.2, 2.3 Hz, 1 H, 6-H), 8.00 (d, J = 9.2 Hz,
oil. IR (film): ν = 2948 (m), 1730 (s), 1685 (m), 1576 (w), 1437 (m),
˜
1
H, 5-H), 4.10 (s,
3
H, CO2Me), 3.05–2.95 (m,
2
H,
1363 (m), 1221 (s), 1121 (m), 1065 (m), 1033 (m), 975 (w), 905 (w),
CH2CH2CH2CH3), 1.88–1.75 (m, 2 H, CH2CH2CH3), 1.51–1.36
755 (m) cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.26 (s, 1 H, 1-
(m, 2 H, CH2CH3), 0.96 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C H), 7.90 (br. d, J = 7.9 Hz, 1 H, 5-H), 7.85 (distorted dd, J = 8.5,
NMR (75 MHz, CDCl3): δ = 168.0, 158.0, 155.1, 145.8, 135.8,
126.1, 125.0, 124.5, 124.4, 123.0, 52.9, 36.6, 32.1, 22.7, 13.9 ppm.
GC–MS: m/z (%) = 288 (absent) [M]+, 273 (20), 259 (14), 246 (100),
231 (58), 229 (52), 213 (14), 199 (10), 188 (50), 185 (22), 167 (10),
0.9 Hz, 1 H, 8-H), 7.66 (distorted ddd, J = 8.5, 7.0, 1.5 Hz, 1 H,
7-H), 7.54 (distorted ddd, J = 7.9, 7.0, 0.9 Hz, 1 H, 6-H), 5.03
(distorted d, J = 12.9 Hz, 1 H, CHHOTHP), 4.83 (distorted d, J =
12.9 Hz, 1 H, CHHOTHP), 4.63 (t, J = 3.2 Hz, 1 H, OCHOCH2),
142 (17), 128 (10), 115 (15), 101 (6), 91 (6). C15H16N2O4 (288.30): 4.04 (s, 3 H, CO2Me), 3.86–3.72 (m, 1 H, OCHOCHH), 3.50–3.40
calcd. C 62.49, H 5.59, N 9.72; found C 62.40, H 5.58, N 9.75. (m, 1 H, OCHOCHH), 1.65–1.36 (m, 6 H, CH2CH2CH2CH2) ppm.
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Eur. J. Org. Chem. 2011, 5626–5635