Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013 Electronic Supplementary Information Regioselective prenylation of bromocarbazoles by palladium(0)- catalysed cross-coupling – synthesis of O-methylsiamenol, O-methylmicromeline and carquinostatin A Claudia Thomas, Olga Kataeva, Arndt W. Schmidt and Hans-Joachim Knölker* Department Chemie, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden, Germany. E-mail: [email protected] Materials and methods All reactions were carried out in oven-dried glassware using dry solvents under an argon atmosphere unless stated otherwise. Tetrahydrofuran was dried using a solvent purification system (MBraun-SPS). Other chemicals were used as received from commercial sources. All reactions were carried out in a MBraun MB 150B-G-II glove box under an argon atmosphere. Flash chromatography was performed on a Büchi Sepacore system equipped with an UV monitor using silica gel from Acros Organics (0.035–0.070 mm). Thin layer chromatography was performed with TLC plates from Merck (60 F254) using UV-light for visualisation. Melting points were measured on a Gallenkamp MPD 350 melting point apparatus. Ultraviolet spectra were recorded on a Perkin Elmer 25 UV/VIS spectrometer. Infrared spectra were recorded on a Thermo Nicolet Avatar 360 FT-IR spectrometer using the ATR method (Attenuated Total Reflectance). NMR spectra were recorded on Bruker Avance II 300 and DRX 500 spectrometers. Chemical shifts d are reported in parts per million with the non- deuterated solvent as internal standard. The following abbreviations have been used: s: singlet, d: doublet, t: triplet, quint: quintet, m: multiplet and br: broad. Mass spectra were recorded on a Finnigan MAT-95 spectrometer (electron impact, 70 eV) or by GC/MS-coupling using an Agilent Technologies 6890 N GC System equipped with a 5973 Mass Selective Detector (electron impact, 70 eV). Elemental analyses were measured on an EuroVector EuroEA3000 elemental analyser. 3-Prenylcarbazole (3-(3-methyl-but-2-enyl)carbazole) (6) The tert-prenylstannane 9 (90.0 mg, 251 µmol) and caesium fluoride (50.0 mg, 329 µmol) were added at room temperature to a solution of 3-bromocarbazole (5) (51.1 mg, 208 µmol), Pd(dba)2 (12 mg, 21 µmol) and P(t-Bu)3 (9.0 mg, 49 µmol) in dry DMF (3 mL) under an argon atmosphere. The mixture was stirred under an argon atmosphere for 24 h (TLC control showed complete conversion). The mixture was diluted with diethyl ether and washed with a saturated aqueous solution of potassium fluoride, water (2 ×) and brine. The water washings were extracted with diethyl ether and the Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013 combined organic layers were dried over sodium sulfate. The solvent was evaporated and the crude product was further purified by column chromatography on silica gel (petroleum ether– dichloromethane 50:1) provide 3-prenylcarbazole (6) (40.0 mg, 82%) as a colourless solid; mp 128129 °C. UV (MeOH): λ = 230, 237, 248 (sh), 260, 284 (sh), 290 (sh), 296, 328, 341 nm. Fluorescence (MeOH): λex = 296 nm, λem = 352, 364 nm. IR (ATR): = 3411, 3078, 3054, 2960, 2923, 2869, 2030, 1817, 1631, 1603, 1575, 1458, 1411, 1360, 1333, 1287, 1239, 1136, 1113, 1083, –1 1 1040, 1002, 904, 886, 812, 770, 751, 734, 701, 684, 630 cm . H NMR (500 MHz, acetone-d6): δ = 1.75 (d, J = 1.0 Hz, 3 H), 1.78 (s, 3 H), 3.50 (d, J = 7.4 Hz, 2 H), 5.42 (tquint, J = 7.4, 1.4 Hz, 1 H), 7.14 (br t, J = 7.5 Hz, 1 H), 7.22 (dd, J = 8.3, 1.6 Hz, 1 H), 7.35 (br t, J = 7.6, 1 H), 7.41 (d, J = 8.2 Hz, 1 H), 7.47 (d, J = 8.3 Hz, 1 H), 7.91 (d, J = 0.7 Hz, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 10.21 (br. s, 1 13 H). C NMR and DEPT (75 MHz, acetone-d6): δ = 17.90 (CH3), 25.92 (CH3), 35.01 (CH2), 111.49 (CH), 111.61 (CH), 119.41 (CH), 120.11 (CH), 120.79 (CH), 123.87 (C), 124.11 (C), 125.52 (CH), 126.22 (CH), 127.18 (CH), 131.92 (C), 133.02 (C), 139.35 (C), 141.20 (C). MS (EI): m/z (%) = 235 (67) [M+], 220 (100), 205 (26), 204 (21), 180 (21), 167 (19). 3-tert-Prenylcarbazole (3-(2-methyl-but-3-en-2-yl)carbazole) (7) A solution of 3-bromocarbazole (5) (88.9 mg, 361 µmol), Pd(dba)2 (33.1 mg, 57.6 µmol) and P(t-Bu)3 (22.4 mg, 111 µmol) in a mixture of dry DMF (3 mL) and dry THF (3 mL) was stirred at room temperature under an argon atmosphere for 5 min (the colour had then changed from purple to olive). The prenylboronate 10 (106 mg, 541 µmol) and caesium fluoride (220 mg, 1.45 mmol) were added and the mixture was stirred under an argon atmosphere for 5 days (TLC control showed complete conversion). The mixture was diluted with diethyl ether, poured into water and the layers were separated. The aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with water and brine and dried over sodium sulfate. The solvent was evaporated and the crude product was further purified by column chromatography on silica gel (petroleum ether– dichloromethane 10:1) to provide 3-tert-prenylcarbazole (7) (75.9 mg, 89%) as a colourless solid; mp 110113 °C. UV (MeOH): λ = 229 (sh), 236, 246 (sh), 259, 284 (sh), 288 (sh), 295, 325, 338 nm. Fluorescence (MeOH): λex = 295 nm, λem = 354, 364 nm. IR (ATR): = 3417, 3080, 3052, 2961, 2924, 2869, 1635, 1604, 1493, 1478, 1459, 1410, 1389, 1377, 1359, 1287, 1245, 1137, 1113, 1041, –1 1 1004, 996, 907, 815, 750, 735, 631 cm . H NMR (500 MHz, acetone-d6): δ = 1.50 (s, 6 H), 5.04 (dd, J = 10.6, 1.4 Hz, 1 H), 5.10 (dd, J = 17.5, 1.4 Hz, 1 H), 6.15 (dd, J = 17.5, 10.6 Hz, 1 H), 7.15 (br t, J = 7.5 Hz, 1 H), 7.35 (br t, J = 7.6 Hz, 1 H), 7.415 (d, J = 1.7 Hz, 1 H), 7.424 (s, 1 H), 7.48 (d, J = 8.1 Hz, 1 H), 8.11 (d, J = 7.5 Hz, 1 H), 8.12 (s, 1 H), 10.23 (br s, 1 H). 13C NMR and DEPT (125 MHz, acetone-d6): δ = 29.21 (2 CH3), 41.75 (C), 110.49 (CH2), 111.25 (CH), 111.69 (CH), 117.83 (CH), 119.45 (CH), 120.75 (CH), 123.75 (C), 124.18 (C), 125.33 (CH), 126.18 (CH), 139.34 (C), 139.83 (C), 141.40 (C), 149.97 (CH). MS (EI): m/z (%) = 235 (53) [M+], 220 (100), 205 (28), 204 (235), 180 (13), 167 (11). Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013 (R)-2′-O-Acetyl-4-O-methylneocarazostatin B [(R)-1-(2-acetoxypropyl)-3,4-dimethoxy-2-methyl- 6-(3-methylbut-2-enyl)carbazole] (13) Method A: The tert-prenylstannane 9 (56.0 mg, 156 µmol) and caesium fluoride (22.0 mg, 145 µmol) were added at room temperature to a solution of (R)-6-bromo-1-(2-acetoxypropyl)-3,4-dimethoxy-2- methylcarbazole (12) (51.0 mg, 121 µmol), Pd(dba)2 (11 mg, 19 µmol) and P(t-Bu)3 (9.0 mg, 44 µmol) in dry DMF (2.5 mL) under an argon atmosphere. The mixture was stirred under an argon atmosphere for 24 h (TLC control showed complete conversion). The mixture was diluted with diethyl ether and washed with a saturated aqueous solution of potassium fluoride, water (2 ×) and brine. The water washings were extracted with diethyl ether and the combined organic layers were dried over sodium sulfate. The solvent was evaporated and the crude product was further purified by column chromatography on silica gel (petroleum ether–acetone 100:1) to provide (R)-2′-O-acetyl-4-O- 1 methylneocarazostatin B (13) (38.5 mg, 78%) as beige crystals. H NMR (300 MHz, CDCl3): δ = 1.29 (d, J = 6.3 Hz, 3 H), 1.78 (s, 3 H), 1.80 (s, 3 H), 2.16 (s, 3 H), 2.41 (s, 3 H), 3.02 (dd, J = 13.7, 10.0 Hz, 1 H), 3.25 (dd, J = 13.7, 3.1 Hz, 1 H), 3.51 (d, J = 7.3 Hz, 2 H), 3.89 (s, 3 H), 4.11 (s, 3 H), 5.04 (m, 1 H), 5.45 (m, 1 H), 7.21 (dd, J = 8.3, 1.6 Hz, 1 H), 7.40 (d, J = 8.3 Hz, 1 H), 8.01 (s, 1 H), 9.47 (br s, 1 H). MS (EI): m/z (%) = 410 (28), 409 (100) [M+], 394 (33), 349 (23), 335 (18), 334 (71), 323 (18), 322 (79), 306 (8), 278 (10), 174 (10), 167 (9), 159 (7), 69 (16). For further spectroscopic data, see: W. Fröhner, K. R. Reddy, H.-J. Knölker, Heterocycles, 2007, 74, 895. Method B: A solution of (R)-6-bromo-1-(2-acetoxypropyl)-3,4-dimethoxy-2-methylcarbazole (12) (40.0 mg, 95.2 µmol), Pd(dba)2 (11.3 mg, 19.7 µmol) and P(t-Bu)3 (8.0 mg, 40 µmol) in dry DMF (2 mL) was stirred at room temperature under an argon atmosphere for 5 min (the colour had then changed from purple to olive).