Cu-catalyzed N-3-Arylation of Hydantoins Using Diaryliodonium Salts

A general Cu-catalyzed, regioselective method for the N-3-arylation of hydantoins is described. The protocol utilizes aryl(trimethoxyphenyl)iodonium tosylate as the arylating agent in the presence of triethylamine and a catalytic amount of a simple Cu-salt. The method is compatible with structurally diverse hydantoins and operates well with neutral aryl groups or aryl groups bearing weakly donating/withdrawing elements. It is also applicable for the rapid diversification of pharmaceutically relevant hydantoins.


Single crystal X-ray diffraction data for 3a
Single crystals of 3a were grown by recrystallization from hot toluene. Around 50 mg of 3a was added to a 4 mL screw cap vial equipped with a magnet together with a few drops of toluene and heated (on a heating block) to around 105 o C. Upon heating, more toluene was added dropwise until full dissolution. The vial was fitted with a screw cap and left over night for slow cooling to room temperature.

Single crystal X-ray diffraction data for 3f
Single crystals of 3f were grown by slow evaporation from acetonitrile. In a 4 mL screw cap vial, 44 mg of 3f was dissolved in acetonitrile (1-2 mL). The vial was left open, and the solution was allowed to slowly evaporate over days at room temperature.

Single crystal X-ray diffraction data for 3p
Single crystals of 3p were grown by slow evaporation from deuterated chloroform. In a 4 mL screw cap vial, 53 mg of 3p was dissolved in deuterated chloroform (0.5 mL). The vial was left open, and the solution was allowed to slowly evaporate over night at room temperature.

Single crystal X-ray diffraction data for 3r
Single crystals of 3r were grown by slow evaporation from deuterated chloroform. In a 4 mL screw cap vial, 56 mg of 3r was dissolved in deuterated chloroform (0.5 mL). The vial was left open, and the solution was allowed to slowly evaporate over night at room temperature.

Preparation of chiral hydantoins 1e and 1g
Hydantoins 1e and 1g were prepared according to literature 2 with slight modifications.

General procedure
Chiral amino acid (10.0 mmol, 1.0 eq), potassium cyanate (10.0 mmol, 1.0 eq) and water (3 mL) were added to a 10 mL round-bottom flask. The reaction mixture was refluxed for 1 h, and allowed to cool to room temp. Hydrochloric acid (35% (v/v), 1.5 mL) was added and the reaction was refluxed for an additional 15 min. The mixture was cooled in an ice bath, affording colorless crystals, which were filtered off, washed with cold water (2-3 mL) and cold ethanol (0.5 mL).

Preparation of aryl(2,4,6-trimethoxyphenyl)iodonium salts
Aryl(TMP)iodonium salts 2a-s were prepared according to literature procedures. 5,6 General procedure A: preparation of aryl(2,4,6-trimethoxyphenyl)iodonium tosylates 4 Aryl iodide (5.00 mmol, 1.00 eq) and acetonitrile (5 mL) were added to a 50 mL round-bottom flask and equipped with a magnetic stir bar. p-Toluenesulfonic acid monohydrate (TsOH · H2O) (5.05 mmol, 1.01 eq) was added in one portion at room temperature, followed by m-chloroperbenzoic acid (mCPBA) 5.05 mmol, 1.01 eq). The flask was lowered into a pre-heated heating block set at 77°C, and stirred for 30 minutes. 1,3,5-trimethoxybenzene (TMP-H) (5.05 mmol, 1.01 eq) was then added and the resulting solution was stirred for 5 minutes at 77 °C. The flask was cooled to ambient temperature before acetonitrile was removed under reduced pressure. The resulting crude oil was triturated with diethyl ether (40 mL). The precipitate was isolated by vacuum filtration with a fritted funnel and rinsed with diethyl ether (3 x 20 mL), then dried further under high vacuum to obtain the product in analytic purity.
General procedure B: preparation of aryl(2,4,6-trimethoxyphenyl)iodonium tosylates 6 Aryl iodide (2.50 mmol, 1.0 eq) and dichloromethane (19 mL) were added to a 50 mL round-bottom flask equipped with a magnetic stir bar. m-Chloroperbenzoic acid (mCPBA) (2.75 mmol, 1.1 eq) was added and the solution was stirred at rt for 4h. p-Toluenesulfonic acid monohydrate (TsOH · H2O) (2.75 mmol, 1.1 eq) and 1,3,5-trimethoxybenzene (TMP-H) (3.75 mmol, 1.5 eq) were then added. The resulting solution was stirred at rt for 30 minutes, and evaporated under reduced pressure. The resulting crude oil was triturated with diethyl ether (20 mL). The precipitate was isolated by vacuum filtration with a fritted funnel and rinsed with diethyl ether (3 x 20 mL), then dried further under high vacuum to obtain the product in analytic purity. The spectroscopic data is in accordance with previously reported ones. 5

General procedure
Hydantoin or imide (0.2 mmol, 1.0 eq), aryl(TMP)iodonium tosylate (0.6 mmol, 3.0 eq) and Cu(NO3)2 · 2.5 H2O (4.7 mg, 0.02 mmol, 0.1 eq) were added to a 7 mL screw cap vial equipped with a magnetic stir bar. Toluene (2 mL) was added and the vial was placed in a pre-heated vial insert heating block set to 70 o C. Triethylamine (42 µL, 0.3 mmol, 1.5 eq) was added via a syringe, and the suspension was stirred for 24 hours at 70 o C. The resulting mixture (typically colored orange, brown or black) was allowed to cool to room temperature before it was concentrated under reduced pressure.
The crude mixture was purified by column chromatography using silica gel and eluent system as specified. In certain cases, co-elution of a strongly colored impurity during column chromatography was observed. This impurity was removed by trituration in a small amount of either toluene or methanol as specified. The desired product was dried under high vacuum for several hours.