A palladium-catalyzed C–H functionalization route to ketones via the oxidative coupling of arenes with carbon monoxide†

We describe the development of a new palladium-catalyzed method to generate ketones via the oxidative coupling of two arenes and CO. This transformation is catalyzed by simple palladium salts, and is postulated to proceed via the conversion of arenes into high energy aroyl triflate electrophiles. Exploiting the latter can also allow the synthesis of unsymmetrical ketones from two different arenes.

S2 grinding with calcium oxide for 10 min before allowing to sit overnight; then sublimed and immediately stored under nitrogen at -36 °C. All other reagents were purchased from commercial suppliers and used as received after thoroughly drying to remove all traces of water. This was typically done by either dissolving solids and storing over 4 Å molecular sieves overnight before filtration and removal of solvent to yield solid that is dried under vacuum overnight, or by removing oxygen from liquids via freeze-pump-thaw techniques and subsequent storage over 4 Å molecular sieves. 1 H nuclear magnetic resonance (NMR) characterization was performed on 400 and 500 MHz spectrometers (101 and 126 MHz for 13 C NMR). High-resolution mass spectra were obtained using a quadrupole-time of flight and an orbitrap detector by direct infusion in positive ESI mode or by atmospheric pressure chemical ionization.

Stoichiometric Reaction of PdCl 2 with Carbon Monoxide in Benzene (Scheme 1):
In a glove box, silver triflate (184 mg, 0.72 mmol) was added to a 50 mL thick-walled, glass reaction vessel sealable with a Teflon stopcock and equipped with a stir bar. PdCl 2 (44 mg, 0.25 mmol) was dissolved in 10 mL benzene and added to the reaction vessel. The vessel was sealed, removed from the glove box, evacuated and backfilled three times with carbon monoxide, and finally pressurized with 4 atm carbon monoxide. The contents of the reaction vessel were stirred and heated at 100 °C for 22 h, after which the carbon monoxide was released in a fume hood.
Hexamethylbenzene (5 mg, 0.033 mmol) was then added to the reaction vessel as a standard, the mixture was filtered through a pad of silica to remove any solids, and the reaction vessel was thoroughly rinsed with CHCl 3 followed by ethyl acetate. The solvents were removed in vacuo to yield ketone 1a in 71% yield as determined by 1 H NMR spectral analysis relative to the external standard.

Typical Procedure for Catalyst Development in Neat Benzene (Table 1, Entries 1-4):
In a glove box, silver triflate (198 mg, 0.77 mmol) and iodine (63 mg, 0.25 mmol) were dry transferred into a 50 mL thick-walled, glass reaction vessel sealable with a Teflon stopcock and equipped with a stir bar. PdCl 2 (4 mg, 0.025 mmol) and the residual iodine left after dry transferring were dissolved in 1 mL of benzene and added to the reaction vessel. The vessel was S4 sealed, removed from the glove box, evacuated and backfilled three times with carbon monoxide, and finally pressurized with 4 atm carbon monoxide. The contents of the reaction vessel were stirred and heated at 100 °C for 22 h, after which the carbon monoxide was released in a fume hood. Hexamethylbenzene (6 mg, 0.036 mmol) was then added to the reaction vessel as a standard, the mixture was filtered through a pad of silica to remove any solids, and the reaction vessel was thoroughly rinsed with CHCl 3 followed by ethyl acetate. The solvents were removed in vacuo to yield ketone 1a in 79% yield as determined by 1 H NMR spectral analysis relative to the external standard.

Typical Procedure for Catalyst Development in 1,2-Dichloroethane (Table 1, Entries 5-12):
In a glove box, silver triflate (182 mg, 0.71 mmol) and iodine (63 mg, 0.25 mmol) were dry transferred into a 50 mL thick-walled, glass reaction vessel sealable with a Teflon stopcock and equipped with a stir bar. [Pd(allyl)Cl] 2 (2 mg, 0.0066 mmol) and the residual iodine left after dry transferring was dissolved in 1 mL of 1,2-dichloroethane and added to the reaction vessel followed by tert-butylbenzene (81 µL, 0.52 mmol). The vessel was sealed, removed from the glove box, evacuated and backfilled three times with carbon monoxide, and finally pressurized with 1 atm carbon monoxide. The contents of the reaction vessel were stirred and heated at 60 °C for 22 h, after which the carbon monoxide was released in a fume hood. Hexamethylbenzene (8 mg, 0.046 mmol) was then added to the reaction vessel as a standard, the mixture was filtered through a pad of silica to remove any solids, and the reaction vessel was thoroughly rinsed with CHCl 3 followed by ethyl acetate. The solvents were removed in vacuo to yield ketone 1b in 87% yield as determined by 1 H NMR spectral analysis (CDCl 3 ) relative to the external standard. Table 2:

Procedure for the Synthesis of Ketones in
All compounds in Table 2 were prepared according to the procedure detailed below. See the tabulated NMR data for any adjustments to the procedure employed or reaction temperature. For compounds 1m, 1n, 1o, and 1p, 2,6-di-tert-butylpyridine (258 µL, 1.15 mmol) was also added to quench in situ generated triflic acid and prevent side reactions.

S5
Representative Procedure: In a glove box, silver triflate (350 mg, 1.36 mmol) and iodine (126 mg, 0.50 mmol) were dry transferred into a 50 mL thick-walled glass reaction vessel sealable with a Teflon stopcock and equipped with a magnetic stir bar. [Pd(allyl)Cl] 2 (5 mg, 0.013 mmol) and the residual iodine left after dry transferring were dissolved in 2 mL of 1,2-dichloroethane and added to the reaction vessel. Benzene was added to the reaction vessel via micropipette (134 µL, 1.50 mmol). The vessel was sealed, removed from the glove box, evacuated and backfilled three times with carbon monoxide, and finally pressurized with 4 atm carbon monoxide. The reaction mixture was stirred and heated at 60 °C for 22 h, after which the carbon monoxide was released in a fume hood. The reaction mixture was filtered through a pad of silica, and the reaction vessel was thoroughly rinsed with CHCl 3 followed by ethyl acetate. The solvents were removed in vacuo and the product was purified via column chromatography (silica gel, gradient hexane / ethyl acetate 0% to 20%) affording pure benzophenone 1a as a white solid in 78% yield (70 mg, 0.38 mmol). Table 3: Table 3 were prepared according to the procedure detailed below. See the tabulated NMR data for any adjustments to the procedure employed or reaction temperature. For compounds 2k, 2m, and 2n, 2,6-di-tert-butylpyridine (258 µL, 1.15 mmol) was also added together with the heterocycle to quench in situ generated triflic acid and prevent side reactions.

All compounds in
Representative Procedure: In a glove box, silver triflate (339 mg, 1.32 mmol) and iodine (126 mg, 0.49 mmol) were dry transferred into a 50 mL thick-walled glass reaction vessel sealable with a Teflon stopcock and equipped with a magnetic stir bar. [Pd(allyl)Cl] 2 (5 mg, 0.013 mmol) and the residual iodine left after dry transferring were dissolved in 2 mL of 1,2-dichloroethane and added to the reaction vessel. Benzene was added to the reaction vessel via micropipette (89 µL, 1.00 mmol). The vessel was sealed and the reaction mixture was allowed to stir at room temperature for 4.5 h in the glove box, upon which the vessel was opened and tert-butylbenzene was added to the reaction mixture via micropipette (232 µL, 1.50 mmol). The vessel was sealed, removed from the glove box, evacuated and backfilled three times with carbon monoxide, and finally pressurized with 4 atm carbon monoxide. The reaction mixture was stirred and heated at S6 filtered through a pad of silica and the reaction vessel was thoroughly rinsed with CHCl 3 followed by ethyl acetate. The solvents were removed in vacuo and the product was purified via column chromatography (silica gel, gradient hexane / ethyl acetate 0% to 20%) affording pure ketone 2d as a white solid in 92% yield (109 mg, 0.46 mmol).

Procedure for the Synthesis of Crystal Violet 3 (Scheme 2):
In a glove box, iodine (61 mg, 0.24 mmol) was dry transferred into a 50 mL thick-walled glass reaction vessel sealable with a Teflon stopcock and equipped with a magnetic stir bar.
[Pd(allyl)Cl] 2 (2 mg, 0.0066 mmol) and the residual iodine left after dry transferring were dissolved in 1 mL of 1,2-dichloroethane and added to the reaction vessel. N,N-dimethylaniline was added to the reaction vessel via micropipette (193 µL, 1.52 mmol). The vessel was sealed, removed from the glove box, evacuated and backfilled three times with carbon monoxide, and finally pressurized with 4 atm carbon monoxide. The reaction mixture was stirred and heated at 100 °C for 22 h, after which the pressure was released in a fume hood. The reaction mixture was filtered with added 300 mL acetonitrile to remove solids. 1,3,5-trimethoxybenzene (13 mg, 0.079 mmol) was added to the reaction solution as an NMR standard, followed by 0.2 mL triethylamine to quench acid generated during the reaction. A 1 mL aliquot of the reaction mixture was taken from the solution and 1 H NMR analysis revealed the formation of 3 together with its demethylated isomer in 41% yield (ratio of 1:1.2 of R = Me : H).
For isolation of 3, the procedure above was repeated on a larger scale [iodine (126 mg, 0.50 mmol), [Pd(allyl)Cl] 2 (5 mg, 0.012 mmol), and N,N-dimethylaniline (387 µL, 3.05 mmol) in 2 mL 1,2-dichloroethane]. Upon release of CO at the end of the reaction, the reaction mixture was filtered through a pad of basic alumina and the reaction vessel was thoroughly rinsed with acetonitrile. The solvents were removed in vacuo and the product was purified via column chromatography (basic alumina, gradient CHCl 3 / MeCN 0% to 30%). The products elute close together and care must be taken to very slowly increase the solvent gradient (some overlap in products is unavoidable) to afford pure Crystal Violet 3 (R = Me) as a green solid in 21% yield (52 mg, 0.10 mmol) and pure Methyl Violet 6B 3' (R = H) as a green solid in 7% yield (16 mg, 0.034 mmol). Both of these products are sparingly soluble in many solvents (most notably prior S7 to removal of the acid), and require polar solvents such as acetonitrile or methanol for quantitative dissolution.

III. Mechanistic Studies
Monitoring Catalysis with 1 H NMR in Figure 2b: In a glove box, silver triflate (34 mg, 0.13 mmol) and iodine (12 mg

S8
In situ iodobenzene 1 H and 13 C NMR spectra:

S9
In situ Benzophenone 1 H and 13 C NMR spectra:

Reaction of tert-Butylbenzene, AgOTf, and I 2 (Figure 2c):
In a glove box, iodine (63 mg, 0.25 mmol) and cyclooctane standard (6 mg, 0.057 mmol) were added to a vial containing silver triflate (114 mg, 0.44 mmol) and a stir bar using 1 mL 1,2dichloroethane. To this mixture, tert-butylbenzene (81 µL, 0.52 mmol) was added. The reaction mixture was stirred for 30 min at room temperature, after which the stirring was halted, and the S10 precipitate allowed to settle. 1 ml of this mixture was transferred to an NMR tube, and 1 H NMR analysis shows the formation of 4-tert-butyliodobenzene in >99% yield. In Situ 4-iodo-tert-butylbenzene 1 H NMR Spectrum:

Temperature (Figure 2c):
In a glove box, silver triflate (118 mg, 0.46 mmol) was dry transferred into a 50 mL thick-walled glass reaction vessel sealable with a Teflon stopcock and equipped with a magnetic stir bar.
[Pd(allyl)Cl] 2 (3 mg, 0.0071 mmol) and 4-tert-butyliodobenzene (65 mg, 0.25 mmol) were dissolved in 1 mL of 1,2-dichloroethane and added to the reaction vessel. tert-butylbenzene was added to the reaction vessel via micropipette (77 µL, 0.50 mmol). The vessel was sealed, removed from the glove box, evacuated and backfilled three times with carbon monoxide, and finally pressurized with 4 atm carbon monoxide. The reaction mixture was stirred at room temperature for 22 h and afterward the CO was removed on a Schlenk line before the vessel was S11 brought into the glove box. Cyclooctane standard (7 mg, 0.061 mmol) was then added to the reaction vessel. A 1 mL sample of the mixture was added to a J. Young NMR tube and 1 H NMR analysis revealed the formation of ketone 1b in 23% yield.