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DOI: 10.1055/s-0031-1290655
Synthesis of Isoquinoline Alkaloids via Oxidative Amidation-Bischler-Napieralski Reaction
Publication History
Publication Date:
28 March 2012 (online)
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
- Supporting Information for this article is available online:
- Supporting Information
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References and Notes
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].
(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].
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.
(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].