Iron-Catalyzed Coupling of Alkenes and Enones: Sakurai–Michael-type Conjugate Addition of Catalytic Allyliron Nucleophiles

The iron-catalyzed coupling of alkenes and enones through allylic C(sp3)–H functionalization is reported. This redox-neutral process employs a cyclopentadienyliron(II) dicarbonyl catalyst and simple alkene substrates to generate catalytic allyliron intermediates for 1,4-addition to chalcones and other conjugated enones. The use of 2,4,6-collidine as the base and a combination of triisopropylsilyl triflate and LiNTf2 as Lewis acids was found to facilitate this transformation under mild, functional group-tolerant conditions. Both electronically unactivated alkenes as well as allylbenzene derivatives could be employed as pronucleophilic coupling partners, as could a range of enones bearing electronically varied substituents.


General procedures
General procedure A for the synthesis of ketones 3 through the coupling of alkenes and enones A reaction tube (13 mm × 100 mm, Fisherbrand, part # 14-959-35C) equipped with an olive shaped magnetic stir bar (10 mm) was capped with a Teflon/silicone septum (Thermo/National part # C4015-66A) screw cap, flame dried under vacuum, and transferred into an argon-filled glovebox. In the glovebox were added Michael acceptor (1, 0.3 mmol, 1.0 equiv), dry toluene (0.2 mL, 1.5 M), and alkene (2, 0.9 mmol, 3.0 equiv). The solution was briefly stirred. Then collidine (0.6 mmol, 80 µL, 2.0 equiv) and TIPSOTf (0.45 mmol, 139 µL, 1.5 equiv) were sequentially added with brief stirring after each addition. LiNTf2 (0.11 mmol, 30.1 mg, 0.35 equiv) was added and the reaction vial was capped and shaken to ensure complete mixing. Finally, [Cp*Fe(CO)2(thf)] + [BF4] -(20 mol %, 24.6 mg) was added and the reaction tube was again capped and shaken. The reaction tube was then removed from the glovebox and placed in an oil bath at 80 °C for 16 h at 400 rpm. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a short plug of silica gel using ethyl acetate. A 4 N solution of HCl in dioxane (0.6 mmol, 150 µL, 2.0 equiv) was added to the crude solution at room temperature and the mixture was stirred for 30 min at room temperature. The crude mixture was concentrated in vacuo. The diastereomeric ratio (dr) was then determined by 1 H NMR analysis of a portion of the crude material. After concentration in vacuo, the crude mixture was purified by flash column chromatography to provide the desired product.

Large scale synthesis and synthetic applications of products Large scale synthesis of 1-(4-chlorophenyl)-4-(4-methoxyphenyl)-3-phenylhex-5-en-1-one (3ob)
S25 5 mmol scale reaction: A 25 mL round bottom flask equipped with a magnetic stir bar and condenser was flame dried under vacuum and transferred into an argon-filled glovebox. In the glovebox were added 4'chlorochalcone (1o, 1.21 g, 5 mmol, 1.0 equiv), dry toluene (3.3 mL, 1.5 M), and 4-allylanisole (2b, 2.3 mL, 15 mmol, 3.0 equiv) and solution was briefly stirred. Then collidine (10 mmol, 1.33 mL, 2.0 equiv), TIPSOTf (7.5 mmol, 2.32 mL, 1.5 equiv), LiNTf2 (1.75 mmol, 501.8 mg, 0.35 equiv), and [Cp*Fe(CO)2(thf)] + [BF4] -(15 mol %, 308.4 mg), were sequentially added with brief stirring after each addition. The flask was then removed from the glovebox and placed in an oil bath at 80 °C with water cooled condenser for 16 h at 400 rpm. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a silica plug using ethyl acetate. A 4 N solution of HCl in dioxane (10 mmol, 2.5 mL, 2.0 equiv) was added at room temperature and the mixture was stirred for 30 min at room temperature. The crude mixture was concentrated in vacuo. The diastereomeric ratio (dr) was then determined by 1 H NMR analysis of a portion of the filtrate. After concentration in vacuo, the crude mixture was purified by flash column chromatography (hexanes/ethyl acetate = 100:1) to afford the title compound as an off white solid (1.78 g, 91%). The diastereomeric ratio (dr 1.6:1) was determined by NMR analysis of the crude product.

Synthesis of 1-chloro-4-(3-(4-methoxyphenyl)-4-phenylcyclopent-1-en-1-yl)benzene (4)
A flame dried round bottom flask with stir bar was transferred into the glove box. Methyltriphenylphosphonium bromide (267.9 mg, 0.75 mmol, 1.5 equiv) and potassium tert-butoxide (84.2 mg, 0.75 mmol, 1.5 equiv) were transferred into the flask and subsequently dissolved in anhydrous THF (2.5 mL) at room temperature. The resulting yellow solution was stirred at room temperature for 1 h. Ketone 3ob (195.4 mg, 0.5 mmol, 1.0 equiv) was added to the reaction mixture. The flask was sealed, removed from the glove box, and stirred at rt for 16 h. The reaction is quenched by the addition of water and ethyl acetate. The crude reaction mixture is extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by flash chromatography (hexanes/ethyl ether = 100:3) to give the pure product S3 as a yellow oil (167.8 mg, 86% yield).   The following reaction was based on a literature procedure. 19 A reaction tube equipped with a magnetic stir bar was capped with a Teflon/silicone septum screw cap and flame dried under vacuum. S3 (50.3 mg, 0.46 mmol, 1.0 equiv), Grubb's second generation catalyst (39.1 mg, 0.046 mmol, 10 mol %), and anhydrous DCE (5.0 mL) were added into the reaction tube in the glovebox. The reaction tube was sealed, removed from the glove box, and was stirred for 18 h at 80 °C. The reaction mixture was cooled to room temperature and filtered through a plug of silica gel and washed with CH2Cl2 (ca. 30 mL). The crude product was purified by flash chromatography (hexanes/ethyl ether = 100:1) to give the pure product 4 as a yellow oil (57.5 mg, 90% yield). 1 H NMR (300 MHz, CDCl3) δ 7.56 -6.86 (m, 9H* + 11H'), 6.85 -6.78 (m, 2H'), 6.75 -6.70 (m, 2H*), 6.63 -6.56 (m, 2H*), 6.35 -6.29 (m, 1H*), 6

Synthesis of 2,4,5-triphenyl-4H-pyran (6)
Ketone 3aa (32.6 mg, 0.1 mmol, 1.0 equiv) was dissolved in CH2Cl2 (10 mL) in a round bottom flask and cooled to -78 °C. A stream of O3 is bubbled through the solution until a blue/gray color persists (ca. 45 min). The reaction is quenched by adding dimethyl sulfide (1 mL) to the flask and allowing the reaction mixture to slowly warm to room temperature. Volatiles were evaporated under reduced pressure, and the resulting residue was used directly in the next step.
The following reaction was based on a literature procedure. 20 The crude residue was transferred to a reaction tube equipped with a magnetic stir bar and dissolved in 1.6 mL of anhydrous toluene. MgSO4 (ca. 100 mg) and catalytic phosphoric acid (85% aq. solution, ca. 10 drops) were added under air. The reaction tube was capped with a Teflon/silicone septum screw cap and was stirred at 110 °C for 6 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by flash chromatography (hexanes/ethyl acetate = 100:1) to give the pure product 6 as a white solid (13.9 mg, 45% yield).

X-Ray determination of diastereomer assignments
Sample 3aa was diastereomerically enriched through repeated recrystallization from diethyl ether and hexanes.