Synthesis of Isoquinoline Alkaloids via Oxidative Amidation-Bischler-Napieralski Reaction

Abstract

A straightforward synthesis of α-keto amides by coupling primary amines with aryl dibromoethanones under oxidative amidation conditions has been developed. The α-keto amides were then subjected to heterocyclodehydration reaction under Bischler-Napieralski conditions followed by aromatization with DBU provided 1-benzoyl isoquinolines in a two-stage process. Utilizing this methodology, isoquinoline alkaloids such as thalmicrinone, papavaraldine, and pulcheotine A were synthesized in excellent yields.

Key words

oxidative amidation - Bischler-Napieralski cyclization - aromatization - isoquinoline alkaloids - thalmicrinone - papavaral­dine - pulcheotine A

References and Notes

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17

2-Oxo- N -phenethyl-2-phenylacetamide (7a) Pale yellow liquid; yield 2.76 g (50.0%). IR(neat): 1216, 1282, 1318, 1364, 1449, 1497, 1520, 1579, 1597, 1668, 2857, 2930 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.92 (t, J = 7.0 Hz, 2 H), 3.66 (q, J = 6.8 Hz, 2 H), 7.10 (br s, 1 H, NH), 7.23-7.27 (m, 5 H), 7.33 (t, J = 7.2 Hz, 2 H), 7.47 (t, J = 7.8 Hz, 2 H), 7.62 (t, J = 7.4 Hz, 1 H) 8.31 (d, J = 7.6 Hz, 2 H). ^¹³C NMR (400MHz, CDCl₃): δ = 40.5, 35.4, 126.6, 128.6, 128.4, 131.0, 134.0, 138.2, 161.7, 187.6. MS: m/z (%) = 254.10 [M + 1].
N -(3,4-Dimethoxyphenethyl)-2-oxo-2-phenylacetamide (7b)
Yellow oil; yield 1.83 g (48.0%). IR(neat): 665, 846, 964, 1005, 1123, 1232, 1317, 1508, 1599, 1644, 2952, 3277 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.84 (t, 2 H, J = 6.8 Hz), 3.60 (q, 2 H, J = 6.8 Hz), 3.84 (s, 3 H), 3.86 (s, 3 H), 6.76-6.82 (m, 2 H), 6.95 (m,1 H), 7.2 (br, NH), 7.40-7.60 (m, 3 H) 8.28 (m, 2 H). ^¹³C NMR (200 MHz, CDCl₃): δ = 34.9, 40.5, 55.7, 55.8, 111.3, 111.8, 120.5, 128.3, 130.7, 130.9, 133.1, 134.2, 147.7, 148.9, 161.8, 187.7. MS: m/z (%) = 314.2 [M + 1].
N -(2-{Benzo[ d ][1,3]dioxol-5-yl}ethyl)-2-(4-methoxy-phenyl)-2-oxoacetamide (7c) Yellow solid; yield 2.64 g (51.0%); mp 86-88 ˚C. IR (KBr): 517, 620, 722, 803, 849, 1038, 1171, 1265, 1296, 1357, 1527, 1598, 1638, 1683, 2939, 3376 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.82 (t, 2 H, J = 6.8 Hz), 3.60 (q, 2 H, J = 6.8 Hz), 3.88 (s, 3 H), 5.93 (s, 2 H), 6.66-6.76 (m, 3 H), 6.92-6.95 (m, 2 H), 7.2 (br, NH), 8.37-8.40 (m, 2 H). ^¹³C NMR (200 MHz, CDCl₃): δ = 35.1, 40.6, 55.4, 100.8, 108.3, 108.9, 113.7, 121.6, 126.2, 132.0, 133.8, 146.2, 147.8, 162.2, 164.6, 185.6. MS: m/z (%) = 328.2 [M + 1].
2-(4-Methoxyphenyl)-2-oxo- N -(2,3,4-trimethoxy-phenethyl)acetamide (7d)
Yellow oil; yield 2.85 g (53.0%). IR(neat): 669, 850, 1169, 1215, 1420, 1598, 1660, 2400, 3019 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.84 (t, 2 H, J = 6.8 Hz), 3.57 (q, 2 H, J = 6.8 Hz), 3.84 (s, 3 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 3.97 (s, 3 H), 6.61 (d, 1 H, J = 8.4 Hz), 6.85 (d, 1 H, J = 8.4 Hz), 6.92 (d, 2 H, J = 8.8 Hz), 7.35 (br, NH), 8.35-8.38 (m, 2 H). ^¹³C NMR (200 MHz, CDCl₃): δ = 29.5, 40.2, 55.4, 55.9, 60.6, 60.8, 107.3, 113.7, 124.3, 126.4, 133.7, 142.2, 151.9, 152.7, 162.4, 164.5, 185.8. MS: m/z (%) = 374.2 [M + 1].
2-(4-Methoxyphenyl)-2-oxo- N -(3,4,5-trimethoxy-phenethyl)acetamide (7e)
Yellow solid; yield 2.95 g (50.0%); mp 85-87 ˚C. IR (KBr): 665, 846, 1005, 1123, 1232, 1444, 1599, 1644, 1925, 2120, 2925, 2969, 3276 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.84 (t, 2 H, J = 6.8 Hz), 3.60 (q, 2 H, J = 6.8 Hz), 3.83 (s,
3 H), 3.85 (s, 6 H), 3.89 (s, 3 H), 6.40 (s, 2 H), 6.74-6.95 (m, 2 H), 7.20 (br, NH), 8.23-8.40 (m, 2 H). ^¹³C NMR (200 MHz, CDCl₃): δ = 35.8, 40.4, 55.4, 56.0, 60.7, 105.5, 113.7, 126.1, 133.7, 134.0, 136.6, 153.2, 162.3, 164.6, 185.6. MS: m/z (%) = 374.2 [M + 1].
2-(3,4-Dimethoxyphenyl)-2-oxo- N -(3,4,5-trimethoxy-phenethyl)acetamide (7f) Off white solid; yield 3.19 g (48.0%); mp 96-98 ˚C. IR (KBr): 666, 872, 1015, 1126, 1276, 1421, 1514, 1591, 1648, 2025, 2836, 2935, 3311 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.85 (br, 2 H), 3.60 (br, 2 H), 3.83 (s, 3 H), 3.85 (s, 6 H), 3.94 (s, 3 H), 3.97 (s, 3 H), 6.45 (s, 2 H), 6.91 (d, 1 H, J = 8.4 Hz), 7.20 (br, NH), 7.86 (s, 1 H), 8.20 (d, 1 H, J = 7.6 Hz). ^¹³C NMR (200 MHz, CDCl₃): δ = 35.8, 40.4, 55.9, 56.0, 60.7, 105.5, 110.1, 112.5, 126.2, 127.2, 133.9, 136.6, 148.7, 153.2, 154.6, 162.2, 185.4. MS: m/z (%) = 404.2 [M + 1].
N -(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-2-oxoacetamide (7g) Yellow solid; yield 2.93 g (53.0%); mp 78-79 ˚C. IR (KBr): 657, 766, 868, 1029, 1141, 1267, 1416, 1513, 1591, 1651, 2835, 2935, 3332 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.85 (t, 2 H, J = 7.2 Hz), 3.64 (q, 2 H, J = 6.0 Hz), 3.86 (s,
3 H), 3.88 (s, 3 H), 3.94 (s, 3 H), 3.97 (s, 3 H), 6.75 (s, 1 H), 6.78-6.93 (m, 3 H), 7.20 (br, NH), 7.86 (d, 1 H, J = 2.0 Hz), 8.23 (dd, 1 H, J = 8.8, 2.0 Hz). ^¹³C NMR (200 MHz, CDCl₃): δ = 34.9, 40.5, 55.8, 55.9, 56.0, 110.0, 111.3, 111.8, 112.4, 120.5, 126.2, 127.1, 130.7, 374.2 [M + 1].

18

(4-Methoxyphenyl)(5,6,7-trimethoxy-3,4-dihydroiso-quinolin-1-yl)methanone (6d) 2-(4-Methoxyphenyl)-2-oxo-N-(2,3,4-trimethoxyphenethyl)-acetamide (7d, 1.62 g, 4.34 mmol) in POCl₃ (16 mL) was taken in the round-bottom flask under nitrogen atmosphere, and the mixture was heated at 80 ˚C for 12 h under N₂. The mixture was then cooled to 0 ˚C and quenched into sat. NaHCO₃ solution (160 mL) below 10 ˚C. The product was then extracted with CH₂Cl₂ (25 mL). The organic layer was washed with 10% NaHCO₃ solution (25 mL) and dried over anhyd Na₂SO₄. The organic layer was distilled off under vacuum. Hexane was added hexane (10 mL), and the mixture was filtered to obtain the product as a pale yellow color solid (1.36 g, 88%); mp 143-145 ˚C.

19

6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(phenyl)-methanone (6b)
Yellow color low melting solid; yield 1.05 g (87.0%). IR(neat): 609, 756, 844, 921, 1010, 1173, 1319, 1421, 1572, 1597, 1668, 1847, 2367, 2944, 3735 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.82 (t, 2 H, J = 7.6 Hz), 3.78 (s, 3 H), 3.90 (t, 2 H, J = 7.6 Hz), 3.93 (s, 3 H), 6.76 (s, 1 H), 6.95 (s, 1 H), 7.28-7.46 (m, 2 H), 7.58 (m, 1 H), 8.00 (t, 2 H, J = 7.2 Hz). ^¹³C NMR (200 MHz, CDCl₃): δ = 25.3, 47.1, 55.9, 56.0, 109.6, 110.4, 119.2, 128.4, 130.3, 131.0, 133.7, 135.4, 147.5, 151.6, 164.3, 193.7. MS: m/z (%) = 296.3 [M + 1].

{7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl}(4-methoxyphenyl)methanone (6c)
Yellow solid; yield 1.26 g (90.0%); mp 139-141 ˚C. IR (KBr): 509, 607, 768, 932, 1039, 1172, 1255, 1387, 1505, 1600, 1650, 2912, 3376 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.78 (t, 2 H, J = 7.6 Hz), 3.87 (s, 3 H), 3.89 (t, 2 H, J = 6.4 Hz), 5.95 (s, 2 H), 6.76 (s, 1 H), 6.84 (s, 1 H), 6.93-6.95 (m, 2 H), 7.99-8.02 (m, 2 H). ^¹³C NMR (200 MHz, CDCl₃): δ = 25.8, 47.0, 55.4, 101.3, 106.9, 108.1, 113.7, 120.4, 128.2, 132.6, 132.8, 146.3, 149.7, 164.1, 164.5, 192.4. MS: m/z (%) = 310.1 [M + 1].
(4-Methoxyphenyl)(5,6,7-trimethoxy-3,4-dihydroiso-quinolin-1-yl)methanone (6d)
Pale yellow solid; yield 1.36 g (88.0%); mp 143-145 ˚C. IR (KBr): 634, 724, 881, 983, 1018, 1133, 1264, 1316, 1417, 1595, 167, 2840, 2937 cm^-¹. ^¹H NMR (400 MHz, CDCl₃):
δ = 2.81 (t, 2 H, J = 7.6 Hz), 3.76 (s, 3 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 3.92 (s, 3 H), 3.93 (br s, 2 H), 6.70 (s, 1 H), 6.95 (d, 1 H, J = 8.8 Hz), 8.01-8.03 (m, 2 H). ^¹³C NMR (200 MHz, CDCl₃): δ = 18.7, 47.0, 55.5, 56.1, 60.9, 61.0, 106.4, 113.8, 123.8, 128.4, 132.0, 132.8, 145.0, 150.1, 151.9, 164.2, 192.4. MS: m/z (%) = 356.2 [M + 1].
(4-Methoxyphenyl)(6,7,8-trimethoxy-3,4-dihydroiso-quinolin-1-yl)methanone (6e)
Pale yellow solid; yield 1.72 g (88.0%); mp 175-177 ˚C. IR (KBr): 669, 928, 1008, 1174, 1215, 1436, 1598, 1691, 1740, 2853, 2925 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.12 (br s, 2 H), 3.58 (s, 3 H), 3.76 (s, 3 H), 3.89 (s, 3 H), 4.01 (s, 3 H), 4.20 (br, 2 H), 6.70 (s, 1 H), 6.99 (d, 2 H, J = 8.8 Hz), 7.87 (d, 2 H, J = 8.8 Hz). ^¹³C NMR (200 MHz, CDCl₃): δ = 26.4, 42.6, 56.4, 57.7, 61.4, 61.6, 109.5, 112.2, 115.9, 127.2, 133.0, 138.9, 141.4, 156.0, 165.0, 167.0, 171.1, 187.1. MS: m/z (%) = 356.2 [M + 1].
(3,4-Dimethoxyphenyl)(6,7,8-trimethoxy-3,4-dihydro-isoquinolin-1-yl)methanone (6f) Cream color solid; yield 1.23 g (86.0%); mp 165-167 ˚C. IR (KBr): 609, 724, 801, 983, 1107, 1132, 1264, 1361, 1405, 1595, 1668, 2840, 2937 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.74 (t, 2 H, J = 7.6 Hz), 3.58 (s, 3 H), 3.77 (s, 3 H), 3.84 (br, 2 H), 3.91 (s, 3 H), 3.94 (s, 3 H), 3.95 (s, 3 H), 6.55 (s, 1 H), 6.88 (d, 1 H, J = 8.4 Hz, 2.0 Hz), 7.54 (dd, 1 H, J = 8.2 Hz), 7.66 (d, 1 H, J = 1.6 Hz). ^¹³C NMR (200 MHz, CDCl₃): δ = 25.9, 46.8, 55.9, 56.0, 60.2, 60.5, 106.2, 109.9, 110.8, 115.2, 125.5, 128.3, 134.7, 140.1, 148.9, 150.8, 153.3, 156.4, 163.7, 192.4. MS: m/z (%) = 386.2 [M + 1].
(6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(3,4-dimethoxyphenyl)methanone (1)
Brown color solid; yield 1.08 g (85.0%); mp 188-190 ˚C. IR (KBr): 631, 866, 1024, 1134, 1269, 1278, 1361, 1460, 1515, 1583, 1660, 2833, 2969 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.82 (t, 2 H, J = 8.0 Hz), 3.78 (s, 3 H), 3.92 (br, 2 H), 3.93 (s, 3 H), 3.94 (s, 3 H), 3.95 (s, 3 H), 6.75 (s, 1 H), 6.88 (d, 1 H, J = 8.4 Hz), 6.91 (s, 1 H), 7.60 (dd, 1 H, J = 8.4, 1.6 Hz), 7.67 (d, 1 H, J = 1.6 Hz). ^¹³C NMR (200 MHz, CDCl₃): δ = 25.3, 47.1, 55.9, 56.0, 109.6, 109.9, 110.4, 111.2, 119.4, 126.4, 128.5, 130.9, 147.5, 149.0, 151.5, 154.0, 164.5, 192.6. MS: m/z (%) = 356.2 [M + 1].

20

1-Benzoyl Isoquinoline (5a)
To a stirred solution of 1-benzoyl dihydroisoquinoline (6a, 14, 1.15 g, 4.89 mmol) in CH₂Cl₂ (12 mL) was added DBU (2.2 mL, 14.6 mmol), and the mixture was stirred at 25 ˚C for 12 h. The mixture was concentrated in vacuo, and the obtained residue was purified by column chromatography (silica gel, PE-EtOAc = 7:3) to give 5a as a light yellow color solid (0.91 g, 80%); mp 75-77 ˚C.

22

(6,7-Dimethoxyisoquinolin-1-yl)(phenyl)methanone (5b)
Light brown color solid; yield 0.54 g (78.0%); mp 131-133 ˚C. IR (KBr): 637, 866, 1140, 1231, 1421, 1675, 2838, 2936, 3077 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.97 (s, 3 H), 4.06 (s, 3 H), 7.15 (s, 1 H), 7.48 (t, 2 H, J = 7.6 Hz), 7.58-7.66 (m, 3 H), 7.96 (d, 2 H, J = 7.6 Hz,), 8.47 (d, 1 H, J = 5.5 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 56.0, 56.1, 104.2, 104.9, 105.0, 121.5, 123.0, 128.3, 130.8, 133.3, 134.1, 137.2, 140.0, 151.3, 153.1, 153.4, 195.2. MS:
m/z (%) = 294.1 [M + 1].
[1,3]-Dioxolo[4,5- g ]isoquinolin-5-yl(4-methoxy-phenyl)methanone (4)
Off white color solid; yield 0.71 g (80.0%); mp 156-158 ˚C. IR (KBr): 518, 605, 843, 950, 1263, 1463, 1596, 1652, 1920, 2913 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.87 (s, 3 H), 6.09 (s, 2 H), 6.92-6.96 (m, 2 H), 7.14 (s, 1 H), 7.48 (s, 1 H), 7.60 (d, 1 H, J = 5.6 Hz), 7.92-7.95 (m, 2 H), 8.43 (d, 1 H, J = 5.2 Hz). ^¹³C NMR (200 MHz, CDCl₃): δ = 55.5, 101.7, 102.2, 102.6, 113.6, 121.7, 123.8, 129.5, 133.1, 135.4, 140.3, 149.2, 151.0, 154.7, 163.9, 193.5. MS: m/z (%) = 308.1 [M + 1].
(4-Methoxyphenyl)(5,6,7-trimethoxyisoquinolin-1-yl)-methanone (3)
Cream color solid; yield 0.72 g (80.0%); mp 146-148 ˚C. IR (KBr): 647, 740, 832, 934, 1030, 1053, 1127, 1257, 1479, 1601, 2944, 3735 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.88 (s, 3 H), 3.93 (s, 3 H), 4.02 (s, 3 H), 4.07 (s, 3 H), 6.95 (d, 2 H, J = 8.8 Hz), 7.36 (s, 1 H), 7.93-7.99 (m, 2 H), 8.48 (d, 1 H, J = 5.2 Hz). ^¹³C NMR (400 MHz, CDCl₃): δ = 55.4, 56.0, 61.1, 61.5, 100.3, 113.6, 116.4, 123.7, 129.1, 129.7, 133.2, 139.5, 114.1, 146.6, 154.0, 154.4, 163.9, 193.7. MS: m/z (%) = 354.2 [M + 1].
(4-Methoxyphenyl)(6,7,8-trimethoxyisoquinolin-1-yl)-methanone (5c)
Ash color solid; yield 0.88 g (82.0%); mp 118-120 ˚C. IR (KBr): 669, 928, 1008, 1174, 1215, 1436, 1598, 1691, 1740, 2853, 2925 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.67 (s, 3 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 4.01 (s, 3 H), 6.63-6.92 (m, 3 H), 7.54 (d, 1 H, J = 4.8 Hz), 7.72 (d, 2 H, J = 7.6 Hz), 8.43 (d, 1 H, J = 4.4 Hz). ^¹³C NMR (400 MHz, CDCl₃): δ = 55.3, 56.1, 60.5, 60.9, 100.9, 113.7, 117.7, 119.3, 129.6, 131.8, 134.7, 141.7, 141.9, 148.2, 155.8, 157.3, 163.5, 193.7. MS: m/z (%) = 354.2 [M + 1].
(3,4-Dimethoxyphenyl)(6,7,8-trimethoxyisoquinolin-1-yl)methanone (5d)
Light brown color solid; yield 0.58 g (77.0%); mp 216-218 ˚C. IR (KBr): 635, 722, 756, 991, 1018, 1116, 1271, 1348, 1420, 1584, 1667, 2837, 2936, 3078 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 3.51 (s, 3 H), 3.78 (s, 3 H), 3.81 (s, 3 H), 3.82 (s, 3 H), 3.99 (s, 3 H), 6.95 (q, 2 H, J = 8.4 Hz), 7.34 (s, 1 H), 7.40 (s, 1 H), 7.79 (d, 1 H, J = 5.6 Hz) 8.40 (d, 1 H, J = 5.6 Hz). ^¹³C NMR (400 MHz, CDCl₃): δ = 55.5, 55.7, 56.2, 60.3, 60.6, 101.8, 109.8, 110.7, 116.7, 119.5, 125.0, 129.1, 134.1, 141.3, 147.2, 148.8, 153.1, 154.8, 157.0, 192.6. MS: m/z (%) = 384.2 [M + 1].
(6,7-Dimethoxyisoquinolin-1-yl)(3,4-dimethoxyphenyl)-methanone (2)
Yellow color solid; yield 0.48 g (79.0%); mp 203-205 ˚C. IR (KBr): 631, 860, 1024, 1140, 1269, 1324, 1512, 1584, 1656, 2836, 2934, 3070, 3403 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.95 (s, 3 H), 3.96 (s, 6 H), 4.00 (s, 3 H), 6.87 (d, 1 H, J = 8.4 Hz), 7.14 (s, 1 H), 7.43 (dd, 1 H, J = 8.4, 1.6 Hz), 7.54 (s, 1 H), 7.65 (d, 1 H, J = 5.2 Hz), 7.71 (d, 1 H, J = 2.0 Hz), 8.45 (d, 1 H, J = 5.2 Hz). ^¹³C NMR (400 MHz, CDCl₃): δ = 56.0, 56.1, 104.1, 104.8, 109.9, 112.0, 121.2, 122.8, 126.8, 129.9, 133.9, 140.0,149.0, 151.0, 153.2, 153.7, 153.8, 193.9. MS: m/z (%) = 354.4 [M + 1].