Palladium-Catalyzed Synthesis of Biaryl Ketones via tert-Butyl Isocyanide Insertion

Abstract

A simple and efficient palladium-catalyzed carbonylative Suzuki coupling via tert-butyl isocyanide insertion has been developed, which demonstrates the utility of isocyanides in intermolecular C–C bond construction. This methodology provides a novel pathway for the synthesis of diaryl ketones in moderate to good yields. The approach is tolerant to a wide range of substrates and applicable to library synthesis. A possible reaction mechanism was proposed based on the experimental results.

Key words

isocyanide - carbonylative Suzuki coupling - palladium catalyst - diaryl ketone - insertion reaction

• References and Notes

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Coupling reactions via isocyanide insertion to form intramolecular C–N bonds:
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Coupling reactions via isocyanide insertion to form intermolecular C–N bonds:
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• 19 General Experimental Procedure In a 15 mL sealed tube equipped with a magnetic stirring bar were added iodobenzene (1.0 mmol, 112 μL), phenylboronic acid (1.2 mmol, 146 mg), tert-butyl isocyanide (1.2 mmol, 136 μL), PdCl₂ (0.03 mmol, 5 mg), Ph₃P (0.06 mmol, 16 mg), K₃PO₄ (2.0 mmol, 424 mg), and anhydrous toluene (4.0 mL). The tube was purged with N₂, and the contents were stirred at 110 °C for 4 h. After completion of the reaction as indicated by TLC, the mixture was filtered through neutral Al₂O₃, and the solvent was removed under vacuum. Then, the residue was stirred in THF (10 mL) and HCl (1 M, 3 mL) for 2 h. Then, the mixture was extracted with EtOAc, dried with Na₂SO₄, and evaporated. The residue was purified on a silica gel column using PE–EtOAc (100:1) as the eluent to give the pure product 3a. Benzophenone (3a) White solid; mp 48–50 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.79–7.82 (m, 4 H), 7.55–7.60 (m, 2 H), 7.45–7.49 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 196.7, 137.6, 132.4, 130.1, 128.3. ESI-MS: m/z = 183.0 [M + H]⁺.
• 20 Intermediate 8 HRMS (CI): m/z calcd for C₁₇H₁₉N [M]⁺: 237.1517; found: 237.1517. HRMS (CI): m/z calcd for C₁₃H₉N [M – C₄H₉]⁺: 180.0813; found: 180.0810.