Formal β‐C−H Arylation of Aldehydes and Ketones by Cooperative Nickel and Photoredox Catalysis

Abstract α‐C−H‐functionalization of ketones and aldehydes has been intensively explored in organic synthesis. The functionalization of unactivated β‐C−H bonds in such carbonyl compounds is less well investigated and developing a general method for their β‐C−H arylation remains challenging. Herein we report a method that uses cooperative nickel and photoredox catalysis for the formal β‐C−H arylation of aldehydes and ketones with (hetero)aryl bromides. The method features mild conditions, remarkable scope and wide functional group tolerance. Importantly, the introduced synthetic strategy also allows the β‐alkenylation, β‐alkynylation and β‐acylation of aldehydes under similar conditions. Mechanistic studies revealed that this transformation proceeds through a single electron oxidation/Ni‐mediated coupling/reductive elimination cascade.


General information
All reactions involving air-or moisture-sensitive reagents or intermediates were carried out in flame-dried glassware under an argon atmosphere using standard Schlenk techniques. Acetonitrile, (CH3CN 99.9%, Extra Dry over Molecular Sieves) were purchased from Acros Organics. Otherwise noted, other commercially available reagents were purchased from TCI, Sigma-Aldrich, Alfa Aesar, Acros, ABCR or BLD pharm in the highest purity grade and used directly without further purification. Thin layer chromatography (TLC) was performed on Merck silica gel 60 F-254 plates and visualized by fluorescence quenching under UV light (254/366 nm). Column chromatography was performed on Merck or Fluka silica gel 60 (40-63 μm) using a forced flow of 0.5 bar. 1 H NMR (300 MHz and 400 MHz), 13 C NMR (76 MHz and 100 MHz) and 19 F NMR (282 MHz) spectra were measured on a Bruker DPX 300 and Bruker AV 400 spectrometer at 300 K. The multiplicity of all signals was described as s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). Chemical shifts (δ in ppm) were referenced on the residual peak of CDCl3 ( 1 H NMR: δ = 7.26; 13  Kessil blue LED. IR spectra were recorded on a Digilab 3100 FT-IR Excalibur Series spectrometer and the position of the absorption bands is given in wave numbers ν (cm -1 ).

General procedure A to obtain -arylated aldehydes and ketones.
To an oven-dried 10 mL Schlenk tube, 4-CzIPN (2.0 mg, 2.5 mol, 2.5 mol%), [Ni(dtbbpy)(H2O)4]Cl2 (4.7 mg, 0.010 mmol, 10 mol%) and aryl bromide (0.10 mmol, 1.0 eq.) were added. The reaction tube was evacuated and backfilled with argon four times. Next, MeCN (1.0 mL) was added, which was followed by the addition of a silyl enol ether (0.20 mmol, 2.0 eq.) and 2,4,6collidine (18.2 mg, 0.15 mmol, 1.5 eq.). The resulting mixture was stirred for three minutes before irradiating with a 45 W blue LED at room temperature for 24 hours. After removal of the solvent under reduced pressure, THF (2.0 mL) was added to the residue, followed by the addition of TBAF (1.0 M in THF, 0.25 mL, 0.25 mmol) and HOAc (24.8 mg, 0.40 mmol, 4.0 eq.) at 0 o C. The resulting mixture was slowly allowed to warm to room temperature and stirred for 2 h. After addition of aqueous NH4Cl solution and extraction with DCM, the organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of pentane and diethyl ether as eluent to get the desired product 3.

The fluorination of 4b to produce α-fluoro--arylated ketone 5c
To a solution of 4b (38.8 mg, 0.1 mmol) in MeCN (1.0 mL), Selectfluor (38.9 mg, 0.11 mmol) was added at 0 °C, and the resulting reaction mixture was allowed to warm to room temperature. After stirring for 3 h, the solvent was removed under reduced pressure.

Luminescence quenching experiments
Emission intensities were recorded using a Jasco FP-8300 spectrofluorometer.

UV-visible spectroscopy
UV-visible absorption spectra were recorded on a Jasco V-650 spectrophotometer, equipped with a temperature control unit at 25 °C. The samples were measured in Starna Fluorometer Microquartz cuvettes (volume: 3.0 ml, path length: 10 mm) equipped with a PTFE-stopper. The spectra were aquired from 400 to 700 nm using 0.5 nm steps. All measurements were performed in dry MeCN at one quarter of concentrations used for the standard reaction. Note: Due to substantial insolubility of the Ni(II) complex, in some instances the baseline appears deviating from the zero value, owing to scattering effects.
UV−vis analysis of the individual reaction components and the reaction system showed the 4-CzIPN to be the only absorbing species in the visible range, indicating that only the organic photocatalyst should be activated by the light. UV-Vis spectrometer. The above procedure was repeated three more times, and the average absorption was used for the calculation of photon flux. A nonirradiated sample was also prepared and the absorbance at 510 nm was measured.

Procedures for quantum yield determination
The photon flux was calculated as follows: where V is the total volume (0.96 L) of the solution that was analyzed, ΔA (0.208) is the difference between the average absorption of irradiated and non-irradiated solutions at 510 nm, Ɩ is the path length (1.00 cm), and ε is the molar absorptivity of the ferrioxalate actinometer at 510 nm (11,100 L . mol -1. cm -1 ).
The photon flux was calculated as follows: where Φ is the quantum yield for the ferrioxalate actinometer (approximated as 0.845, which was reported at λ = 457.9 nm) 11 The average photon flux was thus calculated to be 1.06 × 10 -6 einsteins . s -1 .
The quantum yield was calculated as follows: where flux is the photon flux determined by ferrioxalate actinometry (1.06 × 10 -6 Einstein/s), t is the time (7200 s), and f is the fraction of light absorbed by the reaction mixture at 456 nm. This value is calculated using eq. 3 where A (456 nm) is the orption of the ferrioxalate solution at 456 nm. An absorption spectrum gave an A(456 nm) value of > 3, indicating that the fraction of absorbed light ( ) is > 0.999.
Thus, the reaction quantum yield () was determined to be  = 0.0014.

Light on-off experiments
Four parallel reactions were performed between triisopropyl silyl enol ether 1a (45.6 mg, 0.20 mmol, 2.0 eq.) and methyl 4-bromobenzoate 2a (21.4 mg, 0.10 mmol, 1.0 eq.) according to the General Procedure. The yield of 4a was determined by GC with biphenyl as the internal standard at the given times. The white area indicates the light irradiation, while the grey area indicates time in the dark.

Synthesis of the Ni(II) complex
Ar-Ni II -Br complex was synthesized according to a reported procedure. 12 In an argon filled glove box, a 50 mL round bottom flash containing a stirring bar was charged with Ni(COD)2 (138 mg, 0.500 mmol, 1.0 eq.), 4,4'-di-tert-butyl-2,2'-bipyridine (134 mg, 0.500 mmol, 1.0 eq.) and dry THF (5 mL). The dark purple mixture was stirred overnight at room temperature. Then, 4-bromo-1,2dichlorobenzene (1.12 g, 5.00 mmol, 10 eq.) was added and the mixture was stirred for additional 2 h. Dry pentane (10 mL) was added to the orange mixture and filtered. The resulting precipitate was washed with dry pentane (3  10 mL) and dried under vacumm to obtain the Ni(II) complex as a brown solid, which was used without further purification.

Stoichiometric amount reactions of Ni(II) complex
To an oven-dried 10 mL Schlenk tube, 4-CzIPN (2.0 mg, 2.5 mol, 2.5 mol%) and Ni(II) complex (55.0 mg, 0.10 mmol, 1.0 eq.) were added. The reaction tube was evacuated and backfilled with argon four times. Next, MeCN (1.0 mL) was added, which was followed by the addition of 2,4,6collidine (18.2 mg, 0.15 mmol, 1.5 eq.). The resulting mixture was stirred for three minutes before irradiating with a 45 W blue LED at room temperature for 24 hours. After removal of the solvent under reduced pressure, THF (2.0 mL) was added to the residue, followed by the addition of TBAF (1.0 M in THF, 0.25 mL, 0.25 mmol) and HOAc (24.8 mg, 0.40 mmol, 4.0 eq.) at 0 o C. The resulting mixture was slowly allowed to warm to room temperature and stirred for 2 h. After addition of aqueous NH4Cl solution and extraction with DCM, the organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Only trace amount of product was obtained by silica gel chromatography using a mixture of pentane and diethyl ether as eluent.
The resulting mixture was stirred for three minutes before irradiating with a 45 W blue LED at room temperature for 24 hours. After removal of the solvent under reduced pressure, THF (2.0 mL) was added to the residue, followed by the addition of TBAF (1.0 M in THF, 0.25 mL, 0.25 mmol) and HOAc (24.8 mg, 0.40 mmol, 4.0 eq.) at 0 o C. The resulting mixture was slowly allowed to warm to room temperature and stirred for 2 h. After addition of aqueous NH4Cl solution and extraction with DCM, the organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. 56% yield of targeted product was obtained by silica gel chromatography using a mixture of pentane and diethyl ether as eluent.