Synthesis of β-Substituted Chalcones from Phenones via Conjugated Nucleophilic Substitution of Propargylic Alcohols

Abstract

Phenones can be efficiently transformed into β-substituted chalcones in a two-step process. First, propargylic alcohols were obtained by addition of ethoxyacetylene anion to aromatic ketones. Activation of the propargylic alcohols using a catalytic amount of acid in the presence of an electron-rich aromatic ketone affords the title enones in moderate to good yields.

Key words

electrophilic aromatic substitution - ketones - olefination - propargylic alcohols - chalcones

• References and Notes

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• 11 Preparation of Propargylic Alcohols; Typical Procedure: At –78 °C, n-BuLi (2.5 M in hexanes, 400 μL, 1.00 mmol) was added dropwise to a solution of ethoxyacetylene (40% in hexanes, 240 μL, 1.00 mmol) in anhydrous THF (3 mL). The solution was stirred for 5 min, warmed slowly to 0 °C over 1 h and stirred for 30 min. After cooling to –78 °C, acetophenone (50 μL, 0.43 mmol) was added in one portion. The solution was warmed to r.t. over 1 h and stirred for 1.5 h. Saturated aqueous NH₄Cl was added, the aqueous phase was extracted with EtOAc, and the combined organic layers were dried with MgSO₄ and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (hexanes–EtOAc, 95:5→75:25) to afford the desired compound 3a (65 mg, 80%) as a yellow oil
• 12 Preparation of β-Substituted Chalcones; Typical Procedure: To a solution of propargylic alcohol (3a; 26.6 mg, 0.140 mmol) in anhydrous acetonitrile (0.7 mL), indole (49 mg, 0.42 mmol) and FeCl₃ (1 mg, 0.007 mmol) were added. The solution was stirred for 24 h, then the solvent was evaporated under vacuum. Analysis of the crude reaction mixture by NMR indicated an E/Z ratio of 1.2:1. The crude mixture was purified by flash chromatography on silica gel (hexanes–EtOAc, 90:10→60:40) to afford the corre-sponding β-substituted chalcones (E)-10a (14.3 mg, 39%) and (Z)-10a (11.9 mg, 33%), respectively, as white and yellowish solids
• 13 Stereochemistry was established by NOE experiments
• 14 The regioisomers were separable by chromatography; see the Supporting Information