Iridium‐Catalyzed α‐Selective Arylation of Styrenes by Dual C−H Functionalization

Abstract An IrI‐system modified with a ferrocene derived bisphosphine ligand promotes α‐selective arylation of styrenes by dual C−H functionalization. These studies offer a regioisomeric alternative to the Pd‐catalyzed Fujiwara–Moritani reaction.


1,1'-Bis(dichlorophosphino)ferrocene
The title compound was prepared following a literature procedure. 4  General Procedure A for the preparation of ligands; L-2 -L-5: An oven-dried multi-neck flask fitted with a condenser was charged with Mg turnings (500 mol%) and purged with nitrogen. One iodine bead was added and the solids were suspended in dry Et 2 O (4.50 mL/mmol of Mg). To activate the magnesium, the solution was heated to reflux with a heatgun. Once cooled to ambient temperature, the fluorinated aryl bromide (600 mol%) was added via syringe and the solution was heated at reflux for 1 h. The solution was cooled to ambient temperature, before 1,1'bis(dichlorophosphino)ferrocene (100 mol%) dissolved in dry Et 2 O (6.00 mL/mmol of 1,1'bis(dichlorophosphino)ferrocene) was added dropwise. The solution was stirred overnight. Unreacted Grignard reagent was quenched by the addition of water (15 mL/mmol). The resulting solution was extracted with CH 2 Cl 2 (3 × 25 mL/ mmol). The organic extracts were combined, dried over Na 2 SO 4 and concentrated in vacuo. The resulting oil was dissolved in CH 2 Cl 2 and filtered through Celite ® to afford the crude product as an orange oil. Purification by FCC (hexane/EtOAc 0-5%) followed by recrystallization with cyclohexane afforded the pure products.
Ligands L-1 and L-6 were purchased from commercial sources (Aldrich, Strem) and used without any further purification.
Substrates 1k (quantitative), 1m (quantitative) and 1p (quantitative) were synthesized following General Procedure B. The spectroscopic properties of these compounds were consistent with the data available in the literature: 1k 13 , 1m 14 , 1p 15 .
Substrate 1r was synthesised following General Procedure D. The spectroscopic properties of this compound were consistent with the literature. 16 Styrenes 2a-2i were purchased from commercial sources (Aldrich, Strem).
General Procedure B for the preparation of acetanilide substrates 1k, 1m, 1p: To an ice cooled (0 °C) solution of aniline (100 mol%) and pyridine (60 mol%) in CH 2 Cl 2 (0.7 M) was added dropwise acetic anhydride (110 mol%). The reaction was warmed to ambient temperature and stirred until consumption of the starting material (monitored by TLC). Water (2 mL/mmol) was added and the mixture was extracted with CH 2 Cl 2 (3 × 5 mL/mmol). The organic extracts were combined, washed with saturated aq. NaHCO 3 (3 × 2 mL/mmol) and brine (2 mL/mmol), dried over Na 2 SO 4 and concentrated in vacuo to provide the crude product. Purification by FCC afforded pure acetanilide.

General Procedure C for the preperation of acetanilide substrates 1e and 1h:
To an oven-dried flask was added EDCI (110 mol%) and DMAP (1 mol%) under nitrogen. CH 2 Cl 2 (0.2 M), aniline (100 mol%) and the relative carboxylic acid (105 mol%) were added. The resulting solution was stirred at ambient temperature until full consumption of aniline was observed by TLC. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution before being dried over Na 2 SO 4 and concentrated in vacuo. Purification by FCC afforded pure acetanilide.
General Procedure D for the preparation of acetanilides 1r, 1s, 1t and 1v: To a stirred solution of the corresponding aniline (5.00 mmol) and triethylamine (0.732 mL, 5.25 mmol) in dry EtOAc (8 mL) at 0 °C was added cyclopentanecarbonyl chloride (0.638 mL, 5.25 mmol) dropwise over 5 minutes. The solution was then allowed to warm to ambient temperature and stirred until completion (as monitored by TLC). The resulting slurry was taken up in EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL), before being dried over Na 2 SO 4 and concentrated in vacuo. Purification of the residues by recrystallisation (hexane/EtOAc) afforded the title compounds.  The title compound was prepared following a literature procedure. 17 To a flame-dried round-bottomed flask was added estrone ( 17-oxo-7,8,9,11,12,13,14,15,16,17-

Selected Reaction Optimization Tables:
Optimization of reaction with regard to the oxidant:

General Procedure E for branch-selective Heck-like reaction on acetanilide substrates:
An oven-dried re-sealable tube, fitted with a magnetic stirrer, was charged with substrate (0.143 mmol, 100 mol%), [Ir(cod) 2 ]OTf (7.5 -10 mol%) and L-4 (7.5 -10 mol%). The tube was fitted with a rubber septum and purged with nitrogen. Styrene derivative (450 mol%) and t-butylethylene (200 mol%) in anhydrous 1,4-dioxane (0.5-1.0 M concentration with respect to substrate) were added and the tube was fitted with a Young's tap. The reaction mixture was then heated at 130 °C for 72-96 h, before being cooled to ambient temperature and concentrated in vacuo. Purification of the residues by FCC afforded the pure products. Note that the alkenylation and hydroarylation products were easily separated by FCC. In some cases, a second column was performed to remove an impurity associated with degradation of the ligand.

N-(2-(1-(4-(Tert-butyl)phenyl)vinyl)phenyl)cyclopentanecarboxamide (4ff)
General Procedure E: The reaction was carried out with Ir(cod) 2 OTf (7.5 mol%), L-4 (7.5 mol%) and 1,4-dioxane (1.0 M with respect to substrate) and was run for 96 h. The crude material was purified by The title compounds were prepared by adaptation of a literature procedure. 23 A 3-necked, oven-dried flask, fitted with a condensor was charged with the corresponding alkene (100 mol%) and purged with nitrogen. MeCN (0.03 M with respect to alkene) and POCl 3 (1000 mol%) were added and the solution was heated at reflux and stirred overnight. The reaction was cooled to ambient temperature and diluted with water (2.0 mL). Aqueous 1 M NaOH solution was added until pH 8 was reached and the resulting solution was extracted with ethyl acetate (3 × 5 mL). The organic extracts were combined, dried over Na 2 SO 4 and concentrated in vacuo. Purification of the residues by FCC afforded the title compounds.

Phenylcinnoline (9)
The title compound was prepared following a literature procedure. 28 To a Schlenk tube was added 8 (100 mg, 0.512 mmol) and aq. HCl (2 M, 1.4 mL) under nitrogen and the reaction was cooled to -5 °C.
NaNO 2 (88.3 mg, 1.28 mmol) was added and the solution was stirred for 15 mins. Aq. H 3 PO 2 (50%, 1 mL) was added and the resulting solution was stirred for 3 h at -5 °C before the reaction was warmed to ambient temperature and stirred for a further 3 h. The reaction was quenched by the addition of water (15 mL) and extracted with Et 2 O (3 × 15 mL). The organic extracts were combined, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by FCC (hexane/Et 2 O 50%) to afford the title compound (106 mg, quantitative) as a yellow oil. 1 6, 144.6, 135.2, 134.3, 131.3, 130.5, 130.2, 129.9, 129.3, 129.1, 124.7, 124.5. The spectroscopic properties for this compound were consistent with the data available in the literature. 29