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Synlett 2008(12): 1870-1876  
DOI: 10.1055/s-2008-1078508
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Transition Metals in Organic Synthesis, Part 87: [¹] An Efficient Palladium-­Catalyzed Route to 2-Oxygenated and 2,7-Dioxygenated Carbazole Alkaloids - Total Synthesis of 2-Methoxy-3-methylcarbazole, Glycosinine, Clausine L, Mukonidine, and Clausine V

Ronny Forke, Micha P. Krahl, Frank Däbritz, Anne Jäger, Hans-Joachim Knölker*
Department Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax: +49(351)46337030; e-Mail: hans-joachim.knoelker@tu-dresden.de;
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Publication History

Received 7 April 2008
Publication Date:
02 July 2008 (online)

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Abstract

Optimization of the palladium(II)-catalyzed oxidative cyclization of N,N-diarylamines opens up the way to an efficient synthesis of 2-oxygenated and 2,7-dioxygenated carbazole alkaloids including 2-methoxy-3-methylcarbazole, glycosinine, clausine L, mukonidine, and clausine V.

Key words

alkaloids - antibiotics - catalysis - cyclizations - palladium

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Characteristic Spectroscopic Data of the 2-Oxygenated and 2,7-Dioxygenated Carbazole Alkaloids2-Methoxy-3-methylcarbazole (4)
Colorless crystals; mp 221 ˚C (lit.¹¹ 223 ˚C). UV (MeOH): λmax = 230, 237, 257, 264 (sh), 301, 331 nm. IR (ATR): ν = 3402, 2992, 2919, 2851, 1631, 1609, 1496, 1455, 1340, 1304, 1230, 1194, 1175, 1139, 1109, 1038, 1014, 1003, 885, 819, 766, 749, 725 cm-¹. ¹H NMR (500 MHz, acetone-d 6): δ = 2.32 (s, 3 H), 3.89 (s, 3 H), 7.02 (s, 1 H), 7.12 (t, J = 7.8 Hz, 1 H), 7.27 (t, J = 7.8 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1 H), 7.82 (s, 1 H), 7.97 (d, J = 7.8 Hz, 1 H), 10.05 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d 6): δ = 16.87 (CH3), 55.68 (CH3), 93.35 (CH), 111.27 (CH), 116.73 (C), 118.95 (C), 119.43 (CH), 119.79 (CH), 121.94 (CH), 124.14 (C), 124.60 (CH), 140.61 (C), 140.74 (C), 158.20 (C). MS (EI): m/z (%) = 211 (100) [M+], 210 (11), 196 (77), 180 (7), 168 (25), 167 (35), 166 (10). Anal. Calcd (%) for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.12; H, 6.64; N, 6.13.
Glycosinine ( O -Methylmukonal) (5)
Colorless crystals; mp 196-198 ˚C (lit.¹² 189.0-189.5 ˚C, lit.¹³ 185 ˚C). UV (MeOH): λmax = 235, 243 (sh), 276, 295, 351 nm. IR (ATR): ν = 3323, 2922, 2851, 1664, 1603, 1575, 1487, 1460, 1436, 1412, 1381, 1345, 1328, 1309, 1259, 1244, 1200, 1169, 1145, 1030, 974, 917, 901, 854, 841, 764, 744, 724 cm-¹. ¹H NMR (500 MHz, acetone-d 6): δ = 4.02 (s, 3 H), 7.16 (s, 1 H), 7.22 (t, J = 7.8 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 8.51 (s, 1 H), 10.46 (s, 1 H), 10.66 (br s, 1 H). ¹³C NMR and DEPT (75 MHz, acetone-d 6): δ = 56.32 (CH3), 93.78 (CH), 111.89 (CH), 117.95 (C), 119.58 (C), 120.74 (CH), 120.95 (CH), 121.35 (CH), 124.38 (C), 126.37 (CH), 141.61 (C), 146.43 (C), 162.37 (C), 188.57 (CHO). MS (EI): m/z (%) = 225 (100) [M+], 224 (26), 210 (9), 209 (14), 208 (22), 196 (8), 180 (21), 179 (42), 168 (21), 154 (28). Anal. Calcd (%) for C14H11NO2: C, 74.65; H, 4.92; N, 6.22. Found: C, 74.77; H, 4.98; N, 6.19.
Clausine L (6)
Colorless crystals; mp 172-173 ˚C (lit.8 133-135 ˚C; lit.9 204-205 ˚C). UV (MeOH): λmax = 235, 241, 269, 282 (sh), 319, 333 nm. IR (ATR): ν = 3264, 2951, 2922, 2852, 1690, 1632, 1608, 1574, 1486, 1462, 1427, 1392, 1348, 1313, 1278, 1239, 1201, 1163, 1115, 1082, 1035, 979, 950, 909, 875, 825, 789, 775, 766, 750, 727 cm-¹. ¹H NMR (500 MHz, acetone-d 6): δ = 3.85 (s, 3 H), 3.92 (s, 3 H), 7.15 (s, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.54 (s, 1 H), 10.53 (br s, 1 H). ¹³C NMR and DEPT (75 MHz, acetone-d 6): δ = 51.77 (CH3), 56.44 (CH3), 94.85 (CH), 111.83 (CH), 113.76 (C), 116.97 (C), 120.47 (CH), 120.63 (CH), 124.19 (C), 124.99 (CH), 126.00 (CH), 141.53 (C), 144.70 (C), 159.83 (C), 167.45 (C=O). MS (EI): m/z (%) = 255 (100) [M+], 240 (5), 224 (89), 209 (18), 194 (9), 181 (7), 166 (14), 153 (15), 139 (11). HRMS: m/z calcd for C15H13NO3 [M+]: 255.0895; found: 255.0889.
Mukonidine (3) Colorless crystals; mp 189 ˚C (lit.8 168-170 ˚C; lit.¹0 188 ˚C). UV (MeOH): λmax = 235, 243, 270 (sh), 276 (sh), 284, 325, 338 nm. IR (ATR): ν = 3347, 2952, 2922, 2852, 1644, 1627, 1582, 1481, 1464, 1432, 1373, 1363, 1329, 1258, 1236, 1189, 1165, 1118, 1093, 1014, 991, 949, 898, 871, 821, 784, 762, 740, 719 cm-¹. ¹H NMR (500 MHz, acetone-d 6): δ = 4.00 (s, 3 H), 6.93 (s, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.47 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.62 (s, 1 H), 10.52 (br s, 1 H), 11.07 (s, 1 H). ¹³C NMR and DEPT (75 MHz, acetone-d 6): δ = 52.60 (CH3), 97.70 (CH), 105.95 (C), 111.79 (CH), 117.85 (C), 120.58 (CH), 120.89 (CH), 123.41 (CH), 124.30 (C), 126.51 (CH), 141.96 (C), 146.62 (C), 161.62 (C), 172.22 (C=O). MS (EI): m/z (%) = 241 (46) [M+], 209 (100), 181 (20), 153 (33), 126 (10), 104 (10).
Isomukonidine (13)
Colorless crystals; mp 226 ˚C (decomp.) (‘Chakraborty’s mukonidine’, lit.7 245 ˚C). UV (EtOH): λmax = 235, 241, 269, 278 (sh), 281, 320, 334 nm. IR (ATR): ν = 3206, 3180, 2922, 2851, 1702, 1625, 1608, 1582, 1492, 1459, 1439, 1357, 1328, 1303, 1246, 1224, 1192, 1159, 1078, 1024, 1010, 968, 914, 874, 819, 778, 764, 751, 716 cm-¹. ¹H NMR (500 MHz, acetone-d 6): δ = 4.13 (s, 3 H), 7.24 (t, J = 7.8 Hz, 1 H), 7.27 (s, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.51 (d, J = 7.8 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 8.77 (s, 1 H), 10.62 (br s, 1 H), 10.88 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d 6): δ = 57.08 (CH3), 94.56 (CH), 111.62 (C), 111.88 (CH), 118.10 (C), 120.72 (CH), 120.84 (CH), 123.97 (C), 126.24 (CH), 126.37 (CH), 141.58 (C), 145.02 (C), 158.90 (C), 166.56 (C=O). MS (EI): m/z (%) = 241 (100) [M+], 226 (5), 224 (9), 194 (5), 182 (11), 168 (6), 154 (14), 153 (6). Anal. Calcd (%) for C14H11NO3: C, 69.70; H, 4.60; N, 5.81. Found: C, 69.84; H, 4.81; N, 5.92.
3-Cyano-7-hydroxy-2-methoxycarbazole (19)
Colorless crystals; mp 251-252 ˚C. UV (MeOH): λmax = 220, 244, 282, 322, 336 nm. IR (ATR): ν = 3529, 3385, 3364, 3324, 3205, 2923, 2841, 2219, 1612, 1574, 1474, 1450, 1429, 1400, 1357, 1322, 1283, 1263, 1243, 1202, 1143, 1115, 1026, 954, 899, 845, 819, 810, 721 cm-¹. ¹H NMR (500 MHz, acetone-d 6): δ = 3.97 (s, 3 H), 6.79 (dd, J = 8.4, 2.1 Hz, 1 H), 6.94 (d, J = 2.1 Hz, 1 H), 7.14 (s, 1 H), 7.89 (d, J = 8.4 Hz, 1 H), 8.21 (s, 1 H), 8.47 (br s, 1 H), 10.45 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d 6): δ = 56.43 (CH3), 93.45 (C), 94.23 (CH), 97.72 (CH), 110.21 (CH), 116.10 (C), 118.26 (C), 118.47 (C), 121.41 (CH), 125.36 (CH), 142.88 (C), 144.55 (C), 157.40 (C), 159.90 (C). Anal. Calcd (%) for C14H10N2O2: C, 70.58; H, 4.23; N, 11.76. Found: C, 70.99; H, 4.71; N, 11.30.
3-Cyano-2,7-dihydroxycarbazole (20)
Colorless crystals; mp >260 ˚C (decomp.). UV (MeOH): λmax = 220, 244, 277, 282, 323, 337 nm. IR (ATR): ν = 3349, 3315, 2921, 2851, 2218, 1613, 1475, 1448, 1420, 1393, 1326, 1283, 1216, 1190, 1145, 987, 953, 882, 844, 822, 806, 789, 752, 724 cm-¹. ¹H NMR (500 MHz, acetone-d 6): δ = 6.77 (dd, J = 8.4, 2.1 Hz, 1 H), 6.91 (d, J = 2.1 Hz, 1 H), 7.05 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 8.16 (s, 1 H), 8.46 (br s, 1 H), 9.44 (br s, 1 H), 10.29 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d 6): δ = 92.51 (C), 97.62 (CH), 97.82 (CH), 110.06 (CH), 116.31 (C), 118.45 (C), 118.80 (C), 121.34 (CH), 124.87 (CH), 143.15 (C), 144.93 (C), 157.49 (C), 157.92 (C).
7-Hydroxy- O -methylmukonal (22) Light yellow crystals; mp >240 ˚C (decomp.). UV (MeOH): λmax = 223, 242, 284 (sh), 300, 348 nm. IR (ATR): ν = 3384, 3310, 2920, 2846, 1655, 1603, 1583, 1498, 1469, 1400, 1364, 1320, 1236, 1199, 1157, 1104, 1036, 953, 921, 907, 860, 842, 817, 800, 745, 735 cm-¹. ¹H NMR (500 MHz, acetone-d 6): δ = 3.99 (s, 3 H), 6.79 (dd, J = 8.4, 2.1 Hz, 1 H), 6.94 (d, J = 2.1 Hz, 1 H), 7.08 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 8.35 (s, 1 H), 8.45 (br s, 1 H), 10.41 (br s, 1 H), 10.44 (s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d 6): δ = 56.26 (CH3), 93.69 (CH), 98.04 (CH), 110.15 (CH), 117.14 (C), 118.49 (C), 119.25 (C), 119.79 (CH), 121.49 (CH), 143.23 (C), 146.54 (C), 157.47 (C), 161.59 (C), 188.56 (CHO). Anal. Calcd (%) for C14H11NO3: C, 69.70; H, 4.60; N, 5.81. Found: C, 69.89; H, 4.84; N, 5.44.
Clausine V (9)
Colorless crystals; mp >270 ˚C (decomp.) (lit.¹5 228-230 ˚C; lit.³³ 272-274 ˚C). UV (MeOH): λmax = 224 (sh), 227, 231, 236 (sh), 238, 259, 311, 319 nm. IR (ATR): ν = 3378, 2937, 2837, 1607, 1573, 1502, 1453, 1323, 1263, 1230, 1198, 1156, 1118, 1025, 934, 823, 803, 728 cm-¹. ¹H NMR (500 MHz, acetone-d 6): δ = 3.84 (s, 6 H), 6.76 (dd, J = 8.5, 2.2 Hz, 2 H), 6.98 (d, J = 2.2 Hz, 2 H), 7.84 (d, J = 8.5 Hz, 2 H), 10.07 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d 6): δ = 55.66 (2 CH3), 95.55 (2 CH), 108.37 (2 CH), 117.97 (2 C), 120.59 (2 CH), 142.27 (2 C), 159.11 (2 C). MS (EI): m/z (%) = 227 (100) [M+], 212 (92), 184 (19), 169 (17), 141 (6). Anal. Calcd (%) for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.55; H, 6.16; N, 6.68.

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Crystal Data for Glycosinine (5)
C14H11NO2, crystal size: 0.34 × 0.21 × 0.09 mm³, M = 225.24 g mol-¹, monoclinic, space group: P21/c, λ = 0.71073 Å, a = 11.235 (1), b = 13.717 (1), c = 7.259 (2) Å, β = 106.38 (1)˚, V = 1073.3 (3) ų, Z = 4, D calcd = 1.394
g cm-³, µ = 0.094 mm-¹, T = 198 (2) K, θ range = 3.28-30.00˚; reflections collected: 26896, independent: 3108 (R int = 0.0999), 159 parameters. The structure was solved by direct methods and refined by full-matrix least-squares on F ²; final R indices [I > 2σ(I)]: R1 = 0.0514, wR2 = 0.1018; maximal residual electron density: 0.273 e Å-³. CCDC-686500 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.uk/data_request/cif.

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Crystal Data for Isomukonidine (13)
C14H11NO3, crystal size: 0.32 × 0.29 × 0.28 mm³, M = 241.24 g mol-¹, monoclinic, space group: C2/c, λ = 0.71073 Å, a = 16.423 (3), b = 7.5231 (15), c = 18.548 (4) Å, β = 96.25 (3)˚, V = 2278.1 (8) ų, Z = 8, D calcd = 1.407 g cm-³, µ = 0.100 mm-¹, T = 298 (2) K, θ range = 3.13-30.02˚; reflections collected: 34016, independent: 3328 (R int = 0.0590), 168 parameters. The structure was solved by direct methods and refined by full-matrix least-squares on F ²; final R indices [I > 2σ(I)]: R1 = 0.0430, wR2 = 0.1125; maximal residual electron density: 0.316 e Å-³. CCDC-686501 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.uk/data_request/cif.

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Experimental Procedure for the Microwave-Assisted Palladium(II)-Catalyzed Oxidative Cyclization The diarylamine 16 (400 mg, 1.01 mmol), Pd(OAc)2 (46.3 mg, 0.21 mmol), Cu(OAc)2 (458 mg, 2.52 mmol), and pivalic acid (4.7 g) were heated in a 10 mL microwave vessel for 2 h at 130 ˚C. The reaction mixture was extracted with a sat. solution of K2CO3 until the aqueous layer showed no further blue color. The aqueous layer was extracted with Et2O and the combined organic layers were dried with MgSO4. Removal of the solvent in vacuum and flash chromatography (PE-Et2O, gradient elution from 4:1 to 1:1) of the crude product on SiO2 provided 3-cyano-7-triiso-propylsilyloxy-4-methoxycarbazole (18) (yield 17.0 mg, 4%) as colorless crystals (mp 141-143 ˚C), then the diarylamine 16 (yield 28.2 mg, 7%) as colorless crystals, and, as the most polar fraction, 3-cyano-7-triisoprop-ylsilyloxy-2-methoxycarbazole (17) (yield 266.0 mg, 67%) as colorless crystals (mp 180-181 ˚C).