Synthesis of Some New Optically Active Octahydro-6H-pyrido[4,3-b]-carbazole Derivatives

Abstract

An optically active octahydro-6H-pyrido[4.3-b]carbazole derivative was obtained by Fischer indolization of a decahydroisoquinolone with phenylhydrazine. The reaction proceeded with quantitative regioselectivity; no angular annulation products could be observed. The tetracyclic product was derivatized by sulfonamide, urea or carboxamide formation. Its linear constitution as well as relative and absolute configuration were established by single crystal X-ray crystallography of a derivative.

Key words

indoles - carbazoles - heterocycles - piperidines - amides

References and Notes

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8

(4aS,11aR)-Methyl 1,2,3,4,4a,5,11,11a-octahydro-6H-pyrido[4.3-b]carbazole-11a-carboxylate (2). TFA (1.0 mL, 1.5 g, 14 mmol) was added dropwise to the cooled (ice-water bath) isoquinolone 1 (347 mg, 1.11 mmol). The resulting solution was stirred for 15 h at 50 ˚C and then for 6.5 h at 100 ˚C. After cooling to ambient temperature, glacial AcOH (3 mL) and phenylhydrazine (240 mg, 2.22 mmol) were added. The mixture was again heated for 30 h at 100 ˚C and then poured onto ice (ca. 45 g). Aqueous KOH (5 mL, 50%) was added to the mixture until pH 14. Subsequently, CH₂Cl₂ (100 mL) was added and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 100 mL). The combined organic layers were washed with water (100 mL) and dried (MgSO₄). After filtration, the solvent was evaporated and the residue was purified by chromatography (SiO₂; CH₂Cl₂-MeOH, 2:1; R _f  = 0.23) to yield the title compound 2 (170 mg, 0.60 mmol, 54%) as a yellow solid; mp 170-180 ˚C (dec.). ^¹H NMR (CDCl₃, 300 MHz): δ = 1.64 (d, J = 12.5 Hz, 1 H, 4-H), 1.93-2.21 (m, 1 H, 4a-H), 2.12 (dq, J = 4.5 Hz, J = 15.6 Hz, 2 H, 4-H and 2-NH), 2.47 (d, J = 15.7 Hz, 1 H, 11-H), 2.65 (d, J = 12.7 Hz, 2 H, 1-H and 5-H), 2.76 (dt, J = 12.3 Hz, J = 3.0 Hz, 1 H, 3-H), 3.08 (dd, J = 11.6 Hz, J = 14.9 Hz, 1 H, 5-H), 3.21 (d, J = 15.7 Hz, 2 H, 3-H and 11-H), 3.56 (s, 3 H, OCH₃), 3.60 (d, J = 12.4 Hz, 1 H, 1-H), 7.05-7.12 (m, 2 H, 8-H and 9-H), 7.23-7.26 (m, 1 H, 7-H), 7.42 (d, J = 7.0 Hz, 1 H, 10-H), 8.05 (s, 1 H, 6-NH). ^¹³C{^¹H} NMR (CDCl₃, 126 MHz): δ = 27.90 (CH₂, C-4), 29.73 (CH₂, C-5 or C-11), 30.26 (CH₂, C-11 or C-5), 40.13 (CH, C-4a), 46.89 (CH₂, C-3), 47.14 (C, C-11a), 51.66 (CH₃), 56.75 (CH₂, C-1), 107.17 (C, C-10b), 110.44 (CH, C-7), 117.66 (CH, C-10), 119.14 (CH, C-9), 121.16 (CH, C-8), 127.39 (C, C-10a), 133.26 (C, C-5a), 135.89 (C, C-6a), 174.72 (CO). IR (ATR): 3345 (m), 3140 (w), 3049 (w), 2922 (s), 2852 (m), 1705  (s), 1589 (m), 1451 (s), 1324 (m), 1194 (s), 741 (vs) cm^-¹. MS (EI, 70 eV): m/z (%) = 284 (100) [M⁺], 252 (40), 241 (12), 225 (50), 208 (70), 194 (60), 180 (54), 167 (56), 157 (20), 143 (52). HRMS (EI, 70 eV): m/z [M⁺] calcd for C₁₇H₂₀N₂O₂: 284.1525; found: 284.1523. [α]_D ^²0 +81 (c 1.3, CHCl₃).

9

(4aS,11aR)-Methyl 2-(4-bromobenzenesulfonyl)-1,2,3,4,4a,5,11,11a-octahydro-6H-pyrido[4.3-b]carbazole-11a-carboxylate (5). Et₃N (57 mg, 0.56 mmol) and 4-BrC₆H₄SO₂Cl (142 mg, 0.56 mmol) were subsequently added to a cooled (ice-water bath) solution of the carbazole 2 (79 mg, 0.28 mmol) in CH₂Cl₂ (0.6 mL). The resulting mixture was stirred for 2 h at 23 ˚C and then diluted with water (2 mL) and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 1 mL). The combined organic layers were dried (MgSO₄) and the solvent was evaporated after filtration. Two-fold chromatography of the residue (SiO₂; hexane-MTBE, 1:2; R _f  = 0.36; then hexane-EtOAc, 1:2) gave the title compound 5 (100 mg, 0.200 mmol, 71%) as a brown solid; mp 165-175 ˚C (dec.). Single crystals were obtained by slow evaporation of a solution in CHCl₃. ^¹H NMR (CDCl₃, 500 MHz): δ = 1.72-1.82 (m, 2 H), 2.23 (d, J = 11.5 Hz, 1 H), 2.30-2.48 (m, 3 H), 2.64-2.70 (dd, J = 5.4 Hz, J = 16.0 Hz, 1 H), 3.18-3.39 (m, 2 H), 3.58 (s, 3 H), 3.90-3.94 (m, 1 H), 4.35 (dd, J = 1.7 Hz, J = 11.5 Hz, 1 H), 7.04-7.08 (m, 1 H), 7.08-7.13 (m, 1 H), 7.23-7.27 (m, 1 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.63-7.66 (m, 2 H), 7.70-7.71 (m, 2 H), 7.74 (s, 1 H). ^¹³C{^¹H} NMR (CDCl₃, 126 MHz): δ = 27.05 (CH₂), 28.35 (CH₂), 29.91 (CH₂), 39.27 (CH), 46.63 (C), 47.05 (CH₂), 51.93 (CH₃), 55.76 (CH₂), 106.00 (C), 110.54 (CH), 117.55 (CH), 119.26 (CH), 121.39 (CH), 127.03 (C), 127.90 (C), 129.11 (2 × CH), 132.42 (2 × CH), 132.96 (C), 135.56 (C), 135.89 (C), 172.61 (C). IR (ATR): 3370 (s), 2953 (w), 2915 (m), 2853 (m), 1719  (s), 1575  (m), 1469 (m), 1454 (m), 1389 (m), 1339 (s), 1324 (m), 1234 (vs), 1159 (vs), 1090 (s), 1011 (m), 943 (m), 916 (vs), 747 (vs), 732 (vs) cm^-¹. MS (EI, 70 eV): m/z (%) = 502 (42) [M⁺], 283 (69), 251 (100), 223 (29), 194 (58), 143 (38), 97 (27). HRMS (EI, 70 eV): m/z [M⁺] calcd for C₂₃H₂₃BrN₂O₄S: 502.0562; found: 502.0566. [α]_D ^²0 -46 (c 0.9, CH₂Cl₂).

11

CCDC 742770 (5) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone]