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

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.

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

References and Notes

1 Booker-Milburn KI. Sharpe A. J. Chem. Soc., Perkin Trans. 1  1998,  983 

2a Rapson WS. Robinson R. J. Chem. Soc.  1935,  1285 

Reviews:

2b Gawley RE. Synthesis  1976,  777 

2c Jung ME. Tetrahedron  1976,  32:  3 

3 Christoffers J. In Encyclopedia of Catalysis   Vol. 5:  Horvath I. Wiley; New York: 2003.  p.99 

Reviews:

4a Ramaiah M. Synthesis  1984,  529 

4b Hudlicky T. Price JD. Chem. Rev.  1989,  89:  1467 

5 Review: Tius MA. Eur. J. Org. Chem.  2005,  2193 

6 Review: Yamago S. Nakamura E. Org. React.  2002,  61:  1 

7 Buchanan GL. Kennedy WB. Lawson AM. J. Chem. Soc., Perkin Trans. 1  1977,  32 

8a LeGoff E. LaCount RB. Tetrahedron Lett.  1964,  1161 

8b Birladeanu L. Chamot E. Fristad WE. Paquette LA. Winstein S. J. Org. Chem.  1977,  42:  3260 

9a Bauer M. Kauf T. Christoffers J. Bertagnolli H. Phys. Chem. Chem. Phys.  2005,  7:  2664 

9b Pelzer S. Kauf T. van Wüllen C. Christoffers J. J. Organomet. Chem.  2003,  684:  308 

9c Review: Christoffers J. Synlett  2001,  723 

10 Moore JA. Org. Prep. Proced. Int.  1972,  4:  31 

11 Christoffers J. Oertling H. Önal N. J. Prakt. Chem.  2000,  342:  546 

12

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.

13 Christoffers J. Schuster K. Chirality  2003,  15:  777 

14

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.

15

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: [phone]; email: [e-mail]].

16

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-H_ax), 1.76 (ddt, J = 12.4, 3.2, 6.7 Hz, 2 H, 2,6-H_eq), 1.87 (ddd, J = 13.7, 7.2, 3.2 Hz, 2 H, 3,7-H_eq), 2.20 (ddquint, J = 10.0, 9.2, 6.5 Hz, 2 H, 1,5-H_eq), 2.48 (ddd, J = 13.7, 11.0, 6.9 Hz, 2 H, 3,7-H_ax), 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.

17

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.

18

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.

19 Christoffers J. Mann A. Eur. J. Org. Chem.  2000,  1977 

20

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.