Electron Deficient Dienes 3: [1] Rapid Access to 2-Hydroxybenzophenones
via Inverse Electron Demand Diels-Alder-Driven Domino Reactions of a
Chromone-Fused Electron Deficient Diene with Enamines

Abstract

Horner-Wadsworth-Emmons reaction of 3-formylchromone affords an electron deficient 1,3-diene that undergoes domino inverse electron demand Diels-Alder/elimination/intramolecular elimination reactions with enamines to afford functionalized 2-hydroxybenzophenones.

Key words

domino reactions - inverse electron demand Diels-Alder - chromones - enamines - benzophenones

References

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8

( E )-3-(4-Oxo-4 H -chromen-3-yl)acrylic acid ethyl ester(7): To a stirred room temperature suspension of NaH [2.07 g (60% dispersion in mineral oil), 51.7 mmol] in anhydrous THF (50 mL) under N₂ was added dropwise triethylphosphonoacetate (12.4 g, 55.1 mmol) to give a clear colorless solution. The resulting solution was then added dropwise to a stirred solution of 3-formylchromone 6 (6.00 g, 34.5 mol) in dry THF (200 mL). The resulting orange solution was stirred at room temperature for 48 h. The solvent was removed under reduced pressure. The resulting orange solid was dissolved in CH₂Cl₂ (50 mL) and washed with saturated aqueous NaHSO₃ solution (4 × 20 mL), dried over MgSO₄ and filtered. The solvent was removed under reduced pressure and the residue was subjected to column chromatography (silica gel, 2% EtOAc/CH₂Cl₂) to afford 7 (6.64 g, 79%) as a yellow solid. Mp = 96-98 °C (Lit. [7] mp not reported); ¹H NMR (500 MHz, CDCl₃) δ = 8.29 (dd, J = 8.2 Hz, 1.7 Hz, 1 H), 8.12 (s, 1 H), 7.74-7.68 (m, 1 H), 7.49-7.43 (m, 2 H), 7.40 (d, J = 15.8 Hz, 1 H), 7.32 (d, J = 15.8 Hz, 1 H), 4.26 (q, J = 7.1 Hz, 2 H), 1.33 (t, J = 7.0 Hz, 3 H).

9

A stepwise mechanism, i.e. Michael addition followed by an intramolecular Mannich reaction cannot be ruled out. We will comment further on this topic in forthcoming publications.

10

General procedure for the reaction of diene 7 with enamines: A solution of diene 7 (0.500 g, 2.05 mmol) and the enamine (1.5 equivalents) in CH₂Cl₂ (12.5 mL) was stirred at room temperature under N₂ until the starting material had been consumed or no further reaction was evident (according to TLC analysis). The mixture was washed with 1 M aqueous HCl solution (4 × 10 mL). The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The product was purified by column chromatography on silica gel. The products obtained from chromatography did not require further purification for analysis. All new compounds were characterized by melting point, ¹H NMR, ¹³C NMR, EIMS and HRMS and/or elemental analysis. For example: 6-(2-Hydroxybenzoyl)indan-4-carboxylic acid ethyl ester(13a): Diene 7 and 1-(cyclopent-1-enyl)pyrrolidine 12a (0.422 g, 3.07 mmol) were reacted for 0.25 h according to the general procedure to afford after chromatography (CH₂Cl₂) 13a (0.493 g, 78%) as a yellow solid. Mp = 90-92 °C; ¹H NMR (500 MHz, CDCl₃) δ = 11.99 (s, 1 H), 8.15 (s, 1 H), 7.71 (s, 1 H), 7.60-7.50 (m, 2 H), 7.08 (d, J = 8.1 Hz, 1 H), 6.91-6.88 (m, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 3.38 (t, J = 7.5 Hz, 2 H), 3.02 (t, J = 7.5 Hz, 2 H), 2.16 (quint, J = 7.6 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H); ¹³C NMR (500 MHz, CDCl₃) δ = 201.1, 166.4, 163.4, 151.2, 146.7, 136.5, 136.4, 133.6, 129.6, 128.7, 127.0, 119.3, 118.9, 118.6, 61.2, 34.3, 32.6, 25.2, 14.5; EIMS (70 eV) m/z (%) = 310 (28, M⁺), 282 (26), 237 (50), 121 (100), 114 (15); HRMS calcd for C₁₉H₁₈O₄ 310.1205, found 310.1203; Anal. calc’d for C₁₉H₁₈O₄, C 73.55, H 5.85, found C 73.27, H 6.10. Experimental details and charaterization data for the other compounds may be obtained upon request from the authors. Standard 2D NMR experiments were used to unambiguously assign the structures of the products.