Formal Enone α-Arylation via I(III)-Mediated Aryl Migration/Elimination

A formal enone α-arylation is described. This metal-free transformation relies on the I(III)-mediated skeletal reorganization of silyl enol ethers and features mild conditions, good yields, and high stereoselectivities for β-substituted enones.


Preparation of aryl ketones
The precursors for the synthesis of the silyl enol ethers were prepared following either of the procedures shown above. The Weinreb amides were synthesized according to a known procedure. [1] A) Grignard addition: To a solution of the appropriate Weinreb amide in anhydrous tetrahydrofuran (0.2 M) at 0 °C was added the aryl Grignard reagent (2 equiv) dropwise. The reaction was kept stirring at 0 °C for 2 h. After this time, a saturated aqueous solution of ammonium chloride was cautiously added to the reaction mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate (three times). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography on silica gel to afford the desired products.

B) Phenyllithium addition:
To a solution of the appropriate Weinreb amide in anhydrous tetrahydrofuran (0.2 M) at -40 °C was added phenyllithium (1.9 M in dibutyl ether, 1.2 equiv) dropwise.
The reaction was kept stirring at -40 °C for a further 15 min. After this time, an excess of methanol was added dropwise, so as not to raise the temperature of the solution. The resulting mixture was poured onto a saturated aqueous solution of ammonium chloride and the layers were separated. The aqueous layer was extracted with ethyl acetate (three times). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure.
The crude mixture was purified by flash column chromatography on silica gel to afford the desired products.
With the exception of ketone 1u (see below), all ketones have been reported in the literature, for which reason the data is not reproduced here.

Synthesis of silyl enol ethers General Procedure A
To a cooled solution of lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 1.5 equiv) at 0 °C in a flame-dried Schlenk flask, the ketone in anhydrous tetrahydrofuran (0.5 M) was added dropwise. After stirring at the same temperature for 30 min, chlorotrimethylsilane (1.5 equiv) was added dropwise and the resulting solution was allowed to warm to ambient temperature and stirred for another 2 h. After this time, the reaction mixture was transferred to a round-bottom flask using dichloromethane and the solvents were removed under reduced pressure. The crude residue was subsequently filtered through a short column of silica gel. Inseparable TMSOTMS was then removed under high vacuum over the course of several hours to afford the pure product.

General Procedure B
Copper cyanide (10 mol%) was added to a flame-dried Schlenk flask followed by anhydrous tetrahydrofuran (0.3 M) and the mixture was stirred at room temperature for 10 min. The mixture was cooled to -78°C and subsequently the appropriate Grignard reagent (1.5 equiv) was added dropwise.
The reaction mixture was stirred at -78°C for an additional 10 min. After this time, a solution of trans-chalcone (1.0 equiv) in anhydrous tetrahydrofuran (1 M) was added dropwise over 1 h. The reaction mixture was stirred for 6 h and the resulting enolate was quenched by the addition of chlorotrimethylsilane (2 equiv), allowing the system to reach room temperature while stirring for additional 1 h. After this time, saturated aqueous solution of ammonium chloride was added to the reaction mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate (three times). The combined organic layers were dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure.
Purification by filtration over silica gel (heptane/ethyl acetate 95:5) gave the title compound in quantitative yield. All analytical data were in good accordance with those reported in the literature. [2]
Purification by flash column chromatography over silica gel (heptane/ethyl acetate 98:2) gave the title compound in 92% yield. All analytical data were in good accordance with those reported in the literature. [4]
Purification by flash column chromatography over silica gel (heptane/ethyl acetate 98:2) gave the title compound in 61% yield.
Purification by flash column chromatography over silica gel (heptane/ethyl acetate 98:2) gave the title compound in quantitative yield.
Purification by flash column chromatography over silica gel (heptane/ethyl acetate 98:2) gave the title compound in 75% yield. All analytical data were in good accordance with those reported in the literature. [4]
All analytical data were in good accordance with those reported in the literature. [9]
All analytical data were in good accordance with those reported in the literature. [9]
Purification by flash column chromatography over silica gel (heptane/ethyl acetate 98:2) gave the title compound in 94% yield.
Purification by flash column chromatography over silica gel (heptane/ethyl acetate 98:2) gave the title compound in quantitative yield. All analytical data were in good accordance with those reported in the literature. [4]
Purification by flash column chromatography over silica gel (heptane/ethyl acetate 98:2) gave the title compound in 63% yield. All analytical data were in good accordance with those reported in the literature. [4]

General procedure for 5 mmol scale of 7a
Iodosobenzene diacetate (1.99 g, 6 mmol, 1.2 equiv) was placed in a flame-dried Schlenk tube and dichloromethane (0.1 M with respect to the silyl enol ether) was added. The suspension was cooled to 0 °C, after which trimethylsilyl trifluoromethanesulfonate (1.29 mL, 7 mmol, 1.4 equiv) was added in one portion (addition was performed swiftly, while ensuring that no TMSOTf adhered to the wall of the Schlenk tube). After a clear solution had formed (ca. 5 min), the mixture was cooled to -78 °C. After cooling, 6a (5 mmol, 1 equiv) was added as a solution in dichloromethane (2 x 1 M solution) and the resulting colourless solution was stirred at the same temperature for 30 min. After this time, triethylamine (2.79 mL, 20 mmol, 4 equiv) was added in one portion and the resulting solution was brought to ambient temperature after 5 min. Stirring was continued for 1 h, after which time the reaction mixture was transferred to a round-bottom flask using dichloromethane, followed by direct concentration using a rotary evaporator. The crude material was subsequently directly purified by flash column chromatography on silica gel (heptane/toluene 50:50) to afford 7a in 75% yield (785 mg, 3.77 mmol).

Nazarov reaction
A solution of 7a (41.7 mg, 0.2 mmol, 1 equiv) in 0.5 mL of sulfuric acid (H2SO4, 98%) was heated (oil bath) at 60 °C for 1 h. After allowing the system reach ambient temperature, the mixture was diluted by addition of ethyl acetate (1 mL), followed by the careful addition of a saturated aqueous solution of sodium bicarbonate (1 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 1 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography on silica gel (toluene) to give the title compound in 59% yield (24 mg, 0.12 mmol). All analytical data were in good accordance with those reported in the literature. [21] S27