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Synlett 2006(4): 0624-0626  
DOI: 10.1055/s-2006-932469
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of s-Indacene Derivatives by Robinson-Type Cyclopentene Annulation

Jens Christoffers*a,b, Yawei Zhanga, Wolfgang Freyb, Peter Fischerb
a Institut für Reine und Angewandte Chemie der Universität Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26111 Oldenburg, Germany
b Institut für Organische Chemie der Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: +49(711)6854269; e-Mail: jchr@oc.uni-stuttgart.de;
Further Information

Publication History

Received 16 December 2005
Publication Date:
20 February 2006 (online)

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Abstract

s-Indacene derivatives are obtained as single diastereo­isomers by a Robinson-type annulation of 2,5-cyclohexandione-1,4-dicarboxylates with methyl vinyl ketone. Hydrogenative debenzylation and subsequent decarboxylation yields tricyclic products with a central aromatic ring.

Key words

annulation - indacene - cyclopentene - aldol reaction - conjugate addition - hydrogenation

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Dimethyl cis -1,4-Bis(3-oxobutyl)-2,5-cyclohexanedione-1,4-dicarboxylate ( 2a). A mixture of 290 mg FeCl3·6H2O (1.07 mmol), 2.00 g (8.76 mmol) diester 1a, and 7.3 mL (6.14 g, 87.6 mmol) methyl vinyl ketone in 5 mL CH2Cl2 was stirred for 2 d at 60 °C. The reaction mixture was filtered through SiO2, the residue was washed with tert-butyl methyl ether, and the solvent was stripped off to yield the crude product 2a (3.00 g, 8.14 mmol, 93%) as a red solid, as a mixture of two diastereoisomers (cis/trans 12: 1). Recrystallization of the crude product from PE-EtOAc (90 mL, 1: 2) furnished colorless crystals (1.94 g, 5.27 mmol, 60%) of the pure cis diastereoisomer (single NMR signal set), mp 145 °C. 1H NMR (500 MHz, CDCl3): δ = 2.07-2.10 (m, 2 H), 2.14 (s, 6 H), 2.20-2.26 (m, 2 H), 2.36-2.52 (m, 4 H), 2.65 (d, J = 15.5 Hz, 2 H), 3.20 (d, J = 15.5 Hz, 2 H), 3.72 (s, 6 H) ppm. 13C{1H}-NMR (62 MHz, CDCl3): δ = 28.68 (CH2), 29.94 (CH3), 38.21 (CH2), 44.90 (CH2), 53.28 (CH3), 59.27 (C), 170.00 (C=O), 201.26 (C=O), 206.67 (C=O) ppm. IR (ATR): ν = 1746 (m), 1708 (vs), 1429 (s), 1373 (m), 1303 (s), 1262 (s), 1200 (s), 1168 (s), 1136 (m), 1101 (s), 1022 (m), 976 (s), 809 (m), 752 (m) cm-1. MS (EI, 70 eV): m/z (%) = 368 (5) [M+], 166 (100). Anal. Calcd for C18H24O8 (368.38): C, 58.69; H, 6.57. Found: C, 58.47; H, 6.61.

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Dimethyl cis -1,5-Dimethyl-4,8-dioxo-2,3,3a,4,6,7,7a,8-octahydro- s -indacene-3a,7a-dicarboxylate ( 3a). Ice-cold concd H2SO4 (3 mL) was added dropwise at 0 °C to 280 mg (760 µmol) Michael adduct 2a. The reaction mixture was stirred for 1 h at 0 °C and for 16 h at 23 °C, and then added dropwise to 20 mL sat. NaHCO3 solution. The aqueous phase was extracted with CH2Cl2 (5 × 50 mL), and the combined organic layers were dried over MgSO4. After filtration, the solvent was stripped off, and the residue was purified by chromatography on SiO2 (PE-EtOAc, 2:1, R f = 0.35), yielding 3a as yellowish crystals (143 mg, 430 µmol, 57%), mp 92 °C. Recrystallization from EtOAc afforded single crystals suitable for X-ray diffraction analysis. 1H NMR (500 MHz, CDCl3): δ = 2.30-2.34 (m, 2 H, CHH), 2.32 (s, 6 H, CH3), 2.44-2.53 (m, 4 H, CH2), 2.76-2.78 (m, 2 H, CHH), 3.68 (s, 6 H, CH3) ppm. 13C{1H}-NMR (62 MHz, CDCl3): δ = 17.25 (CH3), 31.67 (CH2), 38.98 (CH2), 52.99 (CH3), 70.77 (C), 130.21 (C), 165.44 (C), 171.76 (C=O), 191.93 (C=O) ppm. IR (ATR): ν = 2949 (m), 1728 (vs), 1688 (vs), 1607 (vs), 1425 (vs), 1370 (s), 1329 (m), 1245 (m), 1161 (m), 1071 (s), 998 (s), 837 (s), 803 (s), 755 (s) cm-1. MS (EI, 70 eV): m/z (%) = 332 (39) [M+], 304 (3) [M+ - CO], 273 (25) [M+ - CO2Me], 166 (100). Anal. Calcd for C18H20O6 (332.35): C, 65.05; H, 6.07. Found: C, 64.65; H, 6.14.

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CCDC-290724 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; email: deposit@ccdc.cam.ac.uk].

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Dimethyl 1,5-Dimethyl-4,8-dioxo-1,2,3,3a,4,4a,5,6,7,7a, 8,8a-dodecahydro- s -indacene-3a,7a-dicarboxylate ( 4a).
A suspension of 150 mg ester 3a (451 µmol) and Pd (5% on carbon, 50 mg) in 2 mL i-PrOH was degassed and stirred for 16 h at 80 °C under 1 atm of H2. After filtration, the solvent was stripped off, and the residue was purified by chromatography on SiO2 (PE-EtOAc, 2: 1, R f = 0.41), yielding compound 4a as a colorless solid (106 mg, 315 µmol, 70%), mp 68 °C. 1H NMR (500 MHz, CDCl3): δ = 1.16 (d, J = 6.5 Hz, 6 H, 1,5-CH3), 1.24 (ddt, J = 12.4, 7.2, 10.6 Hz, 2 H, 2,6-Hax), 1.76 (ddt, J = 12.4, 3.2, 6.7 Hz, 2 H, 2,6-Heq), 1.87 (ddd, J = 13.7, 7.2, 3.2 Hz, 2 H, 3,7-Heq), 2.20 (ddquint, J = 10.0, 9.2, 6.5 Hz, 2 H, 1,5-Heq), 2.48 (ddd, J = 13.7, 11.0, 6.9 Hz, 2 H, 3,7-Hax), 3.54 (d, J = 9.2 Hz, 2 H, 4a,8a-H), 3.80 (s, 6 H, OCH3) ppm. 13C{1H}-NMR (62 MHz, CDCl3): δ = 19.67 (CH3), 32.48 (CH2), 32.89 (CH2), 36.74 (CH), 53.57 (CH3), 61.41 (CH), 67.96 (C), 172.59 (C=O), 202.41 (C=O) ppm. IR (ATR): ν = 2962 (s), 2875 (m), 1733 (vs), 1706 (vs), 1449 (m), 1428 (m), 1374 (s), 1231 (vs), 1130 (m), 1068 (s), 999 (s), 943 (vs), 895 (s), 802 (m), 685 (m) cm-1. MS (EI, 70 eV): m/z (%) = 336 (35) [M+], 304 (100), 277 (32) [M+ - CO2Me]. Anal. Calcd for C18H24O6 (336.38): C, 64.27; H, 7.19. Found: C, 64.41; H, 7.56.

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The vicinal coupling constant between the bridgehead proton 8a-H and 1-H is 9.1 Hz, which, in a five-membered ring, is compatible only with a close to ideal antiperiplanar, i.e. trans orientation of these two hydrogens. This configuration is confirmed unequivocally by a detailed analysis of the 13C,1H multiple bond coupling correlation (HMBC).
The HMBC correlation plot displays prominent cross-peaks between 1-H and C-2, C-8a, and the methyl carbon; these 2 J correlations are independent, of course, of any torsional angle. For the three possible 3 J correlations, the 2D plot shows an equally pronounced cross-peak only to the C-8 carbonyl resonance while no cross-peaks at all appear for the 1-H/C-3 and the 1-H/C-3a correlations. With an all-cis configuration of both CH3 and both COOCH3 groups, and a boat or tub conformation of the central six-membered ring, dihedral angles of ca. 90° between 1-H and both C-3 and C-3a, and of ca. 30° between 1-H and C-8 can be read off a molecular model.

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1,5-Dimethyl-1,2,3,5,6,7-hexahydro- s -indacene-4,8-diol ( 5). A suspension of 200 mg ester 3c (413 µmol) and Pd (5% on carbon, 40 mg) in 4 mL i-PrOH was degassed and stirred for 16 h at 80 °C under 1 atm of H2. After filtration, the solvent was stripped off, and the residue was purified by chromatography on SiO2 (PE-EtOAc, 3: 1, R f = 0.42), yielding compound 5 as a mixture of two diastereoisomers (A/B 2:1) as a yellowish solid (66 mg, 302 µmol, 73%), mp 158 °C. 1H NMR (500 MHz, acetone-d 6): δ = 1.16 (d, J = 6.9 Hz, 6 H, isomer B), 1.19 (d, J = 6.9 Hz, 6 H, isomer A), 1.64-1.70 (m, 2 H, isomers A and B), 2.16-2.23 (m, 2 H, isomers A and B), 2.68-2.75 (m, 2 H, isomers A and B), 2.78-2.87 (m, 2 H, isomers A and B), 3.27-3.32 (m, 2 H, isomers A and B), 6.73 (s, 2 H, isomers A and B) ppm. 13C{1H}-NMR (125 MHz, acetone-d 6): δ (isomer A) = 19.66 (CH3), 27.50 (CH2), 34.36 (CH2), 37.46 (CH), 129.01 (C), 134.39 (C), 142.69 (C) ppm; δ (isomer B) = 19.59 (CH3), 27.50 (CH2), 34.31 (CH2), 37.40 (CH), 128.96 (C), 134.44 (C), 142.69 (C) ppm. IR (ATR): ν = 3267 (w, br), 2929 (m), 2864 (m), 1701 (m), 1646 (s), 1444 (vs), 1368 (m), 1223 (s), 1187 (m), 955 (m), 933 (vs), 898 (s), 646 (m) cm-1. MS (EI, 70 eV): m/z (%) = 218 (71) [M+], 203 (100) [M+ - Me], 175 (9). HRMS: m/z calcd for C14H18O4 (218.30): 218.1307; found: 218.1306.

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4,8-Diacetoxy-1,5-dimethyl-1,2,3,5,6,7-hexahydro- s -indacene ( 6). A suspension of 60 mg hydroquinone 5 (275 µmol), 90 mg anhyd NaOAc (1.10 mmol), and 270 mg zinc dust (4.13 mmol) in 3 mL AcCl was stirred for 2 h at 60 °C and 16 h at 23 °C. The reaction mixture was poured into ice water (50 mL), and the aqueous phase was extracted with CH2Cl2 (4 × 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on SiO2 (PE-EtOAc, 5:1, R f = 0.35) to yield 6 as a mixture of two diastereoisomers (A/B 2:1) as a yellowish oil (63 mg, 208 µmol, 76%) that solidifies at 5 °C; mp 70 °C. 1H NMR (500 MHz, CDCl3): δ = 1.19 (d, J = 6.9 Hz, 6H, isomer B), 1.20 (d, J = 6.9 Hz, 6 H, isomer A), 1.58-1.73 (m, 2 H, isomers A and B), 2.25-2.33 (m, 2 H, isomers A and B), 2.29 (s, 6 H, isomers A and B), 2.58-2.69 (m, 2 H, isomers A and B), 2.73-2.83 (m, 2 H, isomers A and B), 3.23-3.27 (m, 2 H, isomers A and B) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ (isomer A) = 19.49 (CH3), 20.69 (CH3), 28.13 (CH2), 34.27 (CH2), 38.13 (CH), 136.53 (C), 140.09 (C), 141.12 (C) 168.66 (C=O) ppm; δ (isomer B) = 19.48 (CH3), 20.70 (CH3), 28.12 (CH2), 34.31 (CH2), 38.19 (CH), 136.53 (C), 140.11 (C), 141.13 (C) 168.67 (C=O) ppm. IR (ATR): ν = 2954 (m), 2929 (m), 2867 (m), 1763 (m), 1463 (m), 1447 (m), 1369 (s), 1323 (m), 1228 (s), 1182 (vs), 1039 (w), 1014 (m), 960 (m) cm-1. HRMS (EI, 70 eV): m/z calcd for C18H22O4: 302.1518; found: 302.1517 [M+]. Anal. calcd for C18H22O4 (302.37): C, 71.50; H, 7.33. Found: C, 71.17; H, 7.48.