Direct C(sp2)–H alkylation of unactivated arenes enabled by photoinduced Pd catalysis

Despite the fundamental importance of efficient and selective synthesis of widely useful alkylarenes, the direct catalytic C(sp2)–H alkylation of unactivated arenes with a readily available alkyl halide remains elusive. Here, we report the catalytic C(sp2)–H alkylation reactions of unactivated arenes with alkyl bromides via visible-light induced Pd catalysis. The reaction proceeds smoothly under mild conditions without any skeletal rearrangement of the alkyl groups. The direct syntheses of structurally diverse linear and branched alkylarenes, including the late-stage phenylation of biologically active molecules and an orthogonal one-pot sequential Pd-catalyzed C–C bond-forming reaction, are achieved with exclusive chemoselectivity and exceptional functional group tolerance. Comprehensive mechanistic investigations through a combination of experimental and computational methods reveal a distinguishable Pd(0)/Pd(I) redox catalytic cycle and the origin of the counter-intuitive reactivity differences among alkyl halides.


I. Experimental section 1. General information
Unless otherwise stated, all reactions were carried out using standard Schlenk techniques or in an argon-filled glove box. All anhydrous solvents were purchased from Aldrich and used without further purification. All 1D NMR spectroscopy experiments were conducted with a Varian 400 and 500 MHz. NMR spectra were processed with MestReNova. Chemical shifts are reported in ppm and referenced to residual solvent peaks (CHCl3 in CDCl3: 7.26 ppm for 1 H, 77 ppm for 13 C). Coupling constants are reported in Hertz. GC analyses were carried out with a 7980A GC system from Agilent Technologies, equipped with an HP-5 column and FID detector using dodecane as internal standard. FT-IR spectra were recorded on a PerkinElmer FT-IR spectrometer. Transmission electron microscopy (TEM) image was acquired on a Hitachi 7600 operating at 100 kV. Elemental analyses were conducted at the National Center for Inter-University Research Facilities of Seoul National University (NCIRF) using a Thermo Scientific Flash 2000 elemental analyzer and a Bruker Avance-600, respectively. All starting materials and reagents were purchased from Acros, Aldrich, Alfa Aesar, TCI, and Strem Chemical Inc., and used without further purification unless otherwise stated. S3

Procedure for KIE experiments
The KIE was determined by comparing the initial reaction rates of the reactions with benzene and benzene-d6. Both reactions were conducted using the above general procedure with the following modifications. After adding all the reagents, 3bromotoluene (0.20 mmol) and dodecane (0.20 mmol) as an internal standard were added to a 10 mL Schlenk tube, and each tube was heated to 80 °C in an oil bath. At the required time period, each tube was immediately placed into an ice bath, and a small aliquot was withdrawn. Each aliquot was filtered through Celite and then analyzed by GC.

Order in [ArBr]
The order in [ArBr] was determined by obtaining the initial rate of the C-H arylation with varying concentrations of 3-bromotoluene. Each reaction was conducted using the general procedure with the following modifications. After adding all the reagents, varying amounts of 3-bromotoluene and dodecane (0.20 mmol) as an internal standard were added to a 10 mL Schlenk tube, and each tube was heated to 80 °C in an oil bath. At the required time period, each tube was immediately placed into an ice bath, and then a small aliquot was withdrawn. Each aliquot was filtered through Celite and then analyzed by GC.  Figure S5.

Gram-scale reaction General procedure for arylation reaction with ammonium salt
A Schlenk tube (500 mL) was charged with 3-bromotoluene (10 mmol), cesium fluoride (2.5 equiv), cesium pivalate (0.80 equiv), palladium acetate (5.0 mol%), pivalic acid (30 mol%), tetra-n-butylammonium bromide (0.80 equiv), and benzene (75 mL) in an argon-filled glove box. The reaction vessel was placed in an oil bath and heated to 80 °C. After 18 h, the reaction was cooled to room temperature, and the crude reaction mixture was concentrated using a rotary evaporator. The residue was purified by column chromatography to afford the desired product.
Scheme S3. Gram-scale reaction of direct C-H arylation S16

Resin-ArBr (4)
The synthesis was conducted by modifying a procedure used for an analogous complex. [2] A 50 mL Schlenk tube was charged with Wang resin (

3-methylbiphenyl (3aa)
Colorless oil. The compound was identified by spectral comparison with literature data. [

4-methylbiphenyl (3ab)
White solid. The compound was identified by spectral comparison with literature data. [

3-fluorobiphenyl (3ap)
Colorless oil. The compound was identified by spectral comparison with literature data. [ The yields and selectivities of arene substrate scopes were determined by GC using dodecane as an internal standard.