A Versatile Approach for the Synthesis of para-Substituted Arenes via Palladium-Catalyzed C–H Functionalization and Protodecarboxylation of Benzoic Acids

Abstract

While a great number of ortho C–H functionalization reactions have been developed and several breakthroughs have been achieved in meta C–H activation, para C–H functionalization is still in its infancy stage. In this article, a versatile strategy for the synthesis of para-substituted arenes has been developed via a tandem process consisting of palladium-catalyzed C–H functionalization and subsequent copper-catalyzed protodecarboxylation of benzoic acids. Both electron-withdrawing and electron-donating functionalities can be introduced into the para positions of arenes bearing a variety of substituents.

Key words

C–H activation - palladium - decarboxylation - arenes - regio­selectivity

• References and Notes


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• 19 Synthesis of para-Arylated Arenes A mixture of m-toluic acid (68.0 mg, 0.50 mmol), iodobenzene (167.2 μL, 1.50 mmol), Ag₂CO₃ (76.0 mg, 0.28 mmol), K₂CO₃ (35.0 mg, 0.25 mmol), and Pd(OAc)₂ (2.3 mg, 0.01 mmol) in AcOH (130.0 μL) was heated under an atmosphere of N₂ at 120 °C for 24 h. After cooling down to r.t., the reaction mixture was quenched by addition of 2.0 M aq HCl (10 mL), diluted with EtOAc (10 mL), and then filtered through a pad of Celite. The filtrate was washed with brine, dried over Na₂SO₄, and concentrated in vacuo, yielding crude 2-phenylbenzoic acid derivatives. A mixture of the crude product, Cu₂O (3.6 mg, 0.025 mmol), and 1,10-phenanthroline (9.0 mg, 0.050 mmol) in a solution of NMP (1.5 mL) and quinoline (0.5 mL) was heated under an atmosphere of N₂ at 170 °C for 24 h. The reaction mixture was quenched by addition of 0.2 M aq HCl (10 mL), diluted with EtOAc (10 mL), and then filtered through a pad of Celite. The filtrate was washed with brine (10 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel preparative TLC to give 4-methylbiphenyl. ¹H NMR (400 MHz, CDCl₃): δ = 7.59–7.57 (m, 2 H), 7.51–7.49 (m, 2 H), 7.45–7.41 (m, 2 H), 7.34–7.31 (m, 1 H), 7.26–7.24 (m, 2 H), 2.40 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 141.14, 138.34, 136.99, 129.45, 128.68, 126.97, 126.95, 21.08. HRMS (ESI-TOF): m/z calcd for C₁₃H₁₃ ⁺: 169.1012 [M + H]⁺; found: 169.0938.
• 20 Synthesis of para-Benzoylated Arenes A mixture of m-toluic acid (27.2 mg, 0.20 mmol), benzoylformic acid (90.1 mg, 0.60 mmol), Pd(TFA)₂ (6.6 mg, 0.020 mmol), and Ag₂CO₃ (165.5 mg, 0.60 mmol) in DME (2 mL) was heated at 150–165 °C for 24–48 h. After cooling down to r.t., the reaction mixture was diluted by addition of EtOAc (10 mL) and then filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford 2-benzoylbenzoic acid derivatives. A mixture of the crude product, Cu₂O (1.4 mg, 0.010 mmol), and 1,10-phenanthroline (3.6 mg, 0.020 mmol) in a solution of NMP (1.5 mL) and quinoline (0.5 mL) was heated under an atmosphere of N₂ at 170 °C for 24 h. The reaction mixture was quenched by addition of 0.2 M aq HCl (10 mL), diluted with EtOAc (10 mL), and then filtered through a pad of Celite. The filtrate was washed with brine (10 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel preparative TLC to give phenyl(p-tolyl)methanone. ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 7.1 Hz, 2 H), 7.72 (d, J = 8.1 Hz, 2 H), 7.58 (t, J = 7.4 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.28 (d, J = 7.9 Hz, 2 H), 2.44 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196.50, 143.22, 137.95, 134.87, 132.13, 130.29, 129.91, 128.95, 128.18, 21.64. HRMS (ESI-TOF): m/z calcd for C₁₄H₁₂NaO⁺: 219.0780 [M + Na]⁺; found: 219.0774.
• 21 Synthesis of para-Hydroxylated Arenes A 50 mL Schlenk-type tube (with a Teflon high-pressure valve and side arm) was charged with m-toluic acid (68.0 mg, 0.50 mmol), benzoquinone (54.0 mg, 0.50 mmol), KOAc (98.0 mg, 1.00 mmol), Pd(OAc)₂ (11.2 mg, 0.050 mmol), and N,N-dimethyl­acetamide (1.5 mL). The reaction tube was evacuated and back-filled with O₂ (3×, ballon). After the reaction mixture was stirred at 115 °C for 15 h, it was allowed to cool down to r.t. The reaction mixture was diluted with EtOAc (10 mL) and then filtered through a pad of Celite. The filtrate was concentrated in vacuo to yield crude 2-hydroxylbenzoic acid. A mixture of the crude product, Cu₂O (3.6 mg, 0.025 mmol), and 1,10-phenan­throline (9.0 mg, 0.050 mmol) in a solution of NMP (1.5 mL) and quinoline (0.5 mL) was heated under an atmosphere of N₂ at 220 °C for 12 h. The reaction mixture was quenched by addition of 0.2 M aq HCl (10 mL), diluted with EtOAc (10 mL), and then filtered through a pad of Celite. The filtrate was washed with brine (10 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel preparative TLC to give p-cresol. ¹H NMR (400 MHz, CDCl₃): δ = 7.05 (d, J = 8.3 Hz, 2 H), 6.75 (d, J = 8.3 Hz, 2 H), 4.95 (br, 1 H), 2.29 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 153.18, 130.03, 129.92, 115.06, 20.43. HRMS (ESI-TOF): m/z calcd for C₇H₉O⁺: 109.0648 [M + H]⁺; found: 109.0657.