Synlett 2004(15): 2705-2708  
DOI: 10.1055/s-2004-835646
LETTER
© Georg Thieme Verlag Stuttgart · New York

Transition Metal Complexes in Organic Synthesis, Part 74: [1] Total Synthesis of the Marine Alkaloid 6-Chlorohyellazole

Hans-Joachim Knölker*, Wolfgang Fröhner, Renate Heinrich
Institut für Organische Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax: +49(351)46337030; e-Mail: hans-joachim.knoelker@chemie.tu-dresden.de;
Weitere Informationen

Publikationsverlauf

Received 15 September 2004
Publikationsdatum:
08. November 2004 (online)

Abstract

A considerably improved iron-mediated synthesis leads to the marine carbazole alkaloid hyellazole on large scale in eight steps and 63% overall yield from 2,6-dimethoxytoluene. The first conversion of hyellazole into 6-chlorohyellazole has been achieved along with remarkably regiospecific halogenation reactions.

24

Synthesis of 6-Bromohyellazole (12) by Oxidative Cyclization of the Iron Complex 10 with Concomitant Bromination Using NBS: Na2CO3 (27 mg, 255 µmol) was added to a solution of the iron complex 10 (109 mg, 253 µmol) in MeCN (5 mL). Subsequently, a solution of NBS (135 mg, 758 µmol) in MeCN (2 mL) was added dropwise at r.t. to the intensely stirred light yellow suspension. The resulting dark brown mixture was stirred at r.t. for 1 h. After that period, conc. HBr (48%, 12.8 µl, 19 mg, 113 µmol) and a solution of NBS (54 mg, 303 µmol) in MeCN (4 mL) were added, and the reaction mixture was stirred for additional 2.5 h. To this mixture Na2CO3 (27 mg, 255 µmol) and silica gel (3 g) were added. Removal of the solvent in vacuum and purification of the residue by flash chromatography (hexane-EtOAc, 7:1) on silica gel afforded 6-bromohyellazole (12) as colorless crystals; yield: 64 mg (69%); mp 168-169 °C (cyclohexane). UV (MeOH): λ = 218, 242, 270 (sh), 310, 347, 360 nm. IR (DRIFT): ν = 3356 (br), 1585, 1503, 1485, 1457, 1414, 1286, 1204, 1145, 1126, 1023, 841, 801, 703 cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.21 (s, 3 H), 3.99 (s, 3 H), 7.16 (d, J = 8.6 Hz, 1 H), 7.39-7.42 (m, 3 H), 7.44-7.47 (m, 2 H), 7.54 (m, 2 H), 7.62 (br s, 1 H), 8.15 (d, J = 1.7 Hz, 1 H). 13C NMR and DEPT (125 MHz, CDCl3): δ = 13.78 (CH3), 56.14 (CH3), 100.07 (CH), 111.62 (C), 112.06 (CH), 119.39 (C), 122.69 (CH), 124.89 (C), 125.52 (C), 125.78 (C), 127.71 (CH), 127.77 (CH), 129.06 (2 CH), 129.82 (2 CH), 133.72 (C), 137.23 (C), 138.04 (C), 153.00 (C). MS (110 °C): m/z (%) = 365 (100) [M+], 350 (13), 286 (4), 271 (51), 270 (27), 242 (12), 241 (19). Anal. Calcd for C20H16BrNO: C, 65.59; H, 4.40; N, 3.82. Found: C, 65.57; H, 4.46; N, 3.75.

26

Transformation of 6-Bromohyellazole (12) into 6-Chlorohyellazole (2):
DMF (25 mL) was added to a mixture of 6-bromohyellazole (12) (505 mg, 1.38 mmol) and cuprous chloride (546 mg, 5.52 mmol). The resulting suspension was heated under reflux for 6 h. The reaction mixture was cooled to r.t., H2O (50 mL) and conc. HCl (25 mL) were added, and the aqueous layer was extracted with Et2O (2 × 50 mL). The combined organic layers were washed with H2O (2 × 50 mL) and dried over Na2SO4. Evaporation of the solvent in vacuum and purification of the residue by flash chromatography (hexane-EtOAc, 4:1) on silica gel provided 6-chloro-hyellazole (2) as colorless crystals, which were subsequently recrystallized from MeOH at -30 °C; yield: 425 mg (96%); mp 162-163 °C. UV (EtOH): λ = 211 (sh), 221, 242, 265 (sh), 302 (sh), 310, 347, 361 nm. IR (DRIFT): ν = 3358 (br), 1586, 1503, 1486, 1452, 1416, 1286, 1205, 1145, 1064, 1023, 842, 803, 705 cm-1. 1H NMR (500 MHz, acetone-d 6): δ = 2.14 (s, 3 H), 3.99 (s, 3 H), 7.27 (dd, J = 8.7, 2.1 Hz, 1 H), 7.40 (m, 3 H), 7.45 (m, 1 H), 7.53 (m, 2 H), 7.75 (s, 1 H), 8.13 (d, J = 2.1 Hz, 1 H), 9.66 (br s, 1 H). 13C NMR and DEPT (125 MHz, acetone-d 6): δ = 14.06 (CH3), 56.31 (CH3), 101.13 (CH), 113.28 (CH), 120.21 (CH), 120.55 (C), 124.12 (C), 124.97 (C), 125.44 (CH), 125.64 (C), 126.87 (C), 128.39 (CH), 129.70 (2 CH), 130.77 (2 CH), 135.16 (C), 138.41 (C), 139.63 (C), 153.62 (C). MS (105 °C):
m/z (%) = 321 (100) [M+], 306 (16), 271 (37), 270 (14), 242 (6), 241 (11). Anal. Calcd for C20H16ClNO: C, 74.65; H, 5.01; N, 4.35. Found: C, 74.71; H, 5.17; N, 4.32.