Nucleophilic arylation with tetraarylphosphonium salts

Organic phosphonium salts have served as important intermediates in synthetic chemistry. But the use of a substituent on the positive phosphorus as a nucleophile to construct C–C bond remains a significant challenge. Here we report an efficient transition-metal-free protocol for the direct nucleophilic arylation of carbonyls and imines with tetraarylphosphonium salts in the presence of caesium carbonate. The aryl nucleophile generated from phosphonium salt shows low basicity and good nucleophilicity, as evidenced by the successful conversion of enolizable aldehydes and ketones. The reaction is not particularly sensitive to water, shows wide substrate scope, and is compatible with a variety of functional groups including cyano and ester groups. Compared with the arylmetallic reagents that are usually moisture sensitive, the phosphonium salts are shelf-stable and can be easily handled.


General Information
All solvents were obtained from commercial available and were extra dry grade. All glassware used was dried in a 120 °C oven and cooled in a desiccator before use. 1 H, 19 F, 31 P and 13 C NMR spectra were recorded on a 400 MHz NMR or 500 MHz NMR spectrometer. 1 H NMR chemical shifts were determined relative to internal (CH 3 ) 4 Si (TMS) at δ 0.0 or to the signal of a residual protonated solvent: CDCl 3 δ 7.26. 13 C NMR chemical shifts were determined relative to internal TMS at δ 0.0. 19 F spectra were referenced to CFCl 3 .The following abbreviations were used to explain the multiplicities: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad.
Materials. All reagents were used as received from commercial sources, unless specified otherwise, or prepared as described in the literature.

Synthesis of the teraarylphosphonium salts 1
General procedure for the synthesis of teraarylphosphonium salts (2b-2i) 1 Under argon atmosphere, the mixture of Ar 3 P (45 mmol, 1.5 equiv), Ar'I (30 mmol, 1.0 equiv) and Pd 2 (dba) 3 (275 mg, 0.3 mmol, 1%) was stirred at 140 o C for 10 h. Then the mixture was cooled to room temperature. After filtration, the residue was washed with THF (20 mL × 3) and then dried under reduced pressure to afford the pure product as a solid.

General procedure for the synthesis of teraarylphosphonium salts (2e'-2i')
Into the solution of (2e-2i) (10 mmol) in DCM (20 mL) was added the aqueous solution of lithium bis((trifluoromethyl)sulfonyl)amide (1 M, 20 mL). The resulting mixture was stirred for 1 min, and then extracted with DCM (20 mL × 3). The combined organic phase was concentrated to 20 mL. This anion metathesis procedure was further repeated twice. The final organic phase was dried over anhydrous MgSO 4 . After filtration, the solvent was removed under vacumm to give the pure product (2e'-2i') as solid.

General procedure for the synthesis of triphenyl(pyridin-2-yl)phosphonium iodide (2j)
Under argon atmosphere, the mixture of Ph 3 P (11.8g, 45 mmol, 1.5 equiv), 2-Iodopyridine (6.15g, 30 mmol, 1.0 equiv) was stirred at 140 o C for 10 h. Then the mixture was cooled to room temperature. After filtration, the residue was washed with THF (20 mL × 3) and then dried under reduced pressure to afford the pure product (2j) as white solid.

General procedure for phenylation of aldehydes
Under N 2 atmosphere, the mixture of aldehyde (0.50 mmol), tetraphenylphosphonium iodide (583.0 mg, 1.25 mmol) and Cs 2 CO 3 (488.7mg, 1.50 mmol) in THF (4 mL) and stirred at 65 o C for 12 h. The reaction was quenched by 3 N HCl (0.5 mL). The resulting mixture was extracted with DCM (3 × 30 mL). The combined organic phase was dried over Na 2 SO 4 . After filtration, the solvent was removed by concentration, and the residue was subjected to column chromatography to afford the pure product.

General procedure for phenylation of ketones
Under N 2 atmosphere, the mixture of ketone (0.40 mmol), tetraphenylphosphonium iodide (745.8 mg, 1.60 mmol) and Cs 2 CO 3 (586.4 mg, 1.80 mmol) in THF (4 mL) was stirred at 65 o C for 24 h. The reaction was quenched by 4.5 N HCl (1.5 mL). The resulting mixture was extracted with DCM (3 × 30 mL). The combined organic phase was dried over Na 2 SO 4 . After filtration, the solvent was removed by concentration, and the residue was subjected to column chromatography to afford the pure product.

General procedure for the synthesis of imines 23
All imines were synthesized according to the procedure reported in literature The mixture of aldehyde (31.5 mmol, 1.05 equiv), sulfonamide (30.0 mmol, 1.0 equiv) and tetraethyl orthosilicate (120 mmol, 25 g, 4.0 equiv) was stirred at 160°C until no ethanol was produced. After the reaction system was cooled to room temperature, ethyl acetate/n-hexane (1:3) was added to precipitate the crude product. After filtration, the solid was washed by ethyl acetate/n-hexane(1:3) followed by ethanol to give the pure product.

The procedure for the synthesis of Ph 5 P 31
Under N 2 atmosphere, into a suspension of 2a (4.66g, 10 mol) in dry diethyl ether (10 mml) was added the solution phenyl-lithium in diethyl ether (1 M, 11 mL). The mixture was stirred at room temperature for 8 days. The solvent was decanted and the solid was washed with dry diethyl ether (5 ml X 3) under nitrogen. The solid was then dissolved with dry THF (10 ml). After fast filtration, the solvent was removed under vaccum to give the product as a white solid.
Pentaphenylphosphorane: 60% yield, white solid. 1 (4 mL) and stirred at 65 o C for 6 h. The reaction was quenched by 3 N HCl (0.5 mL). The resulting mixture was extracted with DCM (3 × 30 mL). The combined organic phase was dried over Na 2 SO 4 . After filtration, the solvent was removed by concentration, and the residue was subjected to column chromatography to afford the pure 3a in 11% yield.
The use of Ph 5 P instead of salt 2a for the phenylation of aldehyde 1a was also examined. Although Ph 5 P can react with the aldehyde, the desired product was not detected at all without the presence of Cs 2 CO 3 . Even with Cs 2 CO 3 present, the yield obtained was very low (11%), meaning that Ph 5 P should not be an important intermediate for this arylation reaction.

Determination of CO 2 by GC-MS spectroscopy
In a glove box under N 2 atmosphere, [1,1'-biphenyl]-4-carbaldehyde (1a, 92.2 mg, 0.5 mmol), tetraphenylphosphonium iodide (583.2 mg, 1.25 mmol), Cs 2 CO 3 (489.0 mg, 1.5 mmol) and DMF (4 ml) were added into a 25 mL Schlenk tube. The tube was sealed and taken out from the glove box. After being stirred at 65 o C for 12 h, the mixture was cooled to room temperature. In the gas phase, CO 2 was detected by GC-MS spectroscopy. In this gas phase, N 2 and benzene were also detected, which is reasonable because the reaction was performed under N 2 atmosphere, and the in situ generated phenyl anion equivalent might be readily trapped by proton to give benzene.