The First Organocatalytic Hetero-Domino Knoevenagel-Diels-Alder-Epimerization Reactions: Diastereoselective Synthesis of Highly Substituted Spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones

Abstract

l-Proline and pyrrolidine catalyzed the three component hetero-domino Knoevenagel-Diels-Alder-Epimerization reactions of readily available precursors enones 1a-i, arylaldehydes 2a-i and 1,3-indandione 3 to furnish highly substituted prochiral spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones 5a-i in a highly diastereo­selective fashion with excellent yields. We demonstrate the first l-proline and pyrrolidine catalyzed epimerization reactions of trans-spiranes 6a-i to cis-spiranes 5a-i. Prochiral spiranes 5a-i are excellent­ starting materials for the synthesis of benzoannelated centro­polyquinanes.

2-amino-1,3-butadiene - Diels-Alder reaction - domino reactions - organocatalysis - organic Lewis acid

References

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9

General Experimental Procedure for the Preparation of Prochiral Spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones by Using l -Proline and Pyrrolidine Catalyzed Hetero-Domino Knoevenagel-Diels-Alder-Epimerization Reaction: Method A. In an ordinary glass vial equipped with a magnetic stirring bar, to 0.5 mmol of the aldehyde and 0.5 mmol of 1,3-indandione was added 1.0 mL of solvent, and then the catalyst l-proline (0.1 mmol) or pyrrolidine (0.15 mmol) was added and the reaction mixture was stirred at ambient temperature for 15-30 min. When the reaction mixture solidified, more solvent was added, 0.5 mL. Then 0.5 mmol of the enone was added and the reaction stirred at 70 °C for 1-2 h (Table [2] ). The crude reaction mixture was treated with saturated aq NH₄Cl solution, the layers were separated, and the organic layer was extracted three to four times with CH₂Cl₂ (10 mL), dried with anhyd Na₂SO₄, and evaporated. The pure Domino products were obtained by flash column chromatography (silica gel, mixture of hexane/EtOAc). Method B. In an ordinary glass vial equipped with a magnetic stirring bar, to 0.5 mmol of aldehyde, 0.5 mmol of enone, 0.5 mmol of 1,3-indandione was added 1.0 mL of solvent, and then the catalyst l-proline (0.1 mmol) or pyrrolidine (0.15 mmol) was added and the reaction mixture was heated slowly to 70 °C with stirring for 1-h. the Domino products were isolated as in Method A. Both methods gave identical results. (2β,6β)-2,6-Diphenylspiro[cyclohexane-1,2′-indan]-1′,3′,4-trione(5aa). Plane of symmetry with chair conformation. ¹H NMR (399 MHz, CDCl₃): δ = 7.64 (1 H, td, J = 7.6 and 1.2 Hz), 7.48 (1 H, m), 7.41 (2 H, m), 7.08-6.90 (10 H, m, 2 × Ph-H), 3.81 (4 H, m), 2.66 (2 H, ABq, J = 17.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 208.4 (C, C=O), 203.4 (C, C=O), 201.8 (C, C=O), 142.7 (C, C-8′), 141.9 (C, C-9′), 137.3 (2 × C), 135.2 (2 × CH), 128.3 (4 × CH), 128.0 (4 × CH), 127.6 (2 × CH), 122.4 (CH), 122.0 (CH), 62.0 (C, C-1 or C-2′), 48.7 (2 × CH), 43.4 (2 × CH₂). HRMS (MALDI-FTMS): m/z = 381.1492 [M + H⁺], calcd for C₂₆H₂₀O₃H⁺ 381.1485. (2β,6α)-2,6-Diphenyl-spiro[cyclohexane-1,2′-indan]-1′,3′,4-trione(6aa).
C₂-Symmetry with twist conformation. ¹H NMR (399 MHz, CDCl₃): δ = 7.57 (2 H, m), 7.52 (2 H, m), 7.08-6.90 (10 H, m, 2 × Ph-H), 3.99 (2 H, dd, J = 13.5 and 3.2 Hz, H-2 and 6), 3.62 (2 H, dd, J = 16.3 and 13.5 Hz, H-3β and 5β), 2.78 (2 H, dd, J = 16.7 and 3.2 Hz, H-3α and 5α). ¹³C NMR (100 MHz, CDCl₃): δ = 210.0 (C, C=O), 202.8 (2 × C, C=O), 142.0 (2 × C, C-8′ and 9′), 137.2 (2 × C), 135.3 (2 × CH,
C-7′ and 4′), 128.3 (4 × CH), 128.1 (4 × CH), 127.3 (2 × CH), 122.4 (2 × CH, C-5′ and 6′), 61.5 (C, C-1 or 2′), 43.4 (2 × CH, C-6 and 2), 41.5 (2 × CH₂, C-3 and 5). HRMS (MALDI-FTMS): m/z = 403.1300 [M + Na⁺], calcd for C₂₆H₂₀O₃Na⁺ 403.1305.

10

Formation of the kinetic product, trans-spirane 6aa as the major isomer in ionic liquids, as opposed to the cis-spirane 5aa through the endo-transition state in the classical Diels-Alder route is likely explained by unique solvation in the ionic liquid of the 2-amino-1,3-butadiene 9a and dienophile 8a in the transition states shown below. Asymmetric solvation in the ionic liquids may produce a steric hindrance with the phenyl group on the dienophile, in the endo-transition state, thereby disfavoring it (Figure [1] ).

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