(DPEPhos)Ni(mesityl)Br: An Air-Stable Pre-Catalyst for Challenging Suzuki–Miyaura Cross-Couplings Leading to Unsymmetrical Biheteroaryls

Abstract

The successful application of (DPEPhos)Ni(mesityl)Br (C1) as a pre-catalyst in the Suzuki–Miyaura cross-coupling of heteroaryl chlorides or bromides and heteroaryl boronic acids is reported. The use of C1 in this context allows for such reactions to be conducted under mild conditions (2 mol% Ni, 25 °C), including cross-couplings leading to unsymmetrical biheteroaryls. Successful transformations of this type involving problematic pyridinyl boronic acid substrates (10 mol% Ni, 60 °C) are also described.

Key words

Suzuki–Miyaura - nickel - biheteroaryls - heteroaryl boronic acids - heteroaryl halides

• References and Notes

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• 20 General Procedure for Cross-coupling (GP1) Unless otherwise specified, under an inert atmosphere C1 (12.7 mg, 0.016 mmol, 2 mol %), aryl halide (0.8 mmol), boronic acid (1.6 mmol), and K₃PO₄ (679 mg, 3.2 mmol) were added to an oven-dried 4 dram vial containing a magnetic stir bar. 1,4-Dioxane (1.3 mL) and benzene (700 μL) were added, the vial was sealed with a screwcap featuring a PTFE/silicone septum and was removed from the glovebox. Degassed water (86 μL) was added via a gas-tight syringe. The reaction mixture was magnetically stirred for 16 h at room temperature. Note: On several occasions the base became clumpy and stuck to the bottom of the reaction vial; in these cases it was noted that reactions were more successful if efficient stirring was maintained. After 16 h, the reaction mixture was taken up in EtOAc (ca. 10 mL) and extracted with distilled water (3 × 10 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated with the aid of a rotary evaporator.
• 21 General Procedure for Cross-Coupling Using Pyridinyl Boronic Acids (GP2) Unless otherwise specified, under an inert atmosphere C1 (31.9 mg, 0.04 mmol, 10 mol %), aryl halide (0.4 mmol), boronic acid (1.2 mmol), and KOtBu (157.1 mg, 1.4 mmol), were added to an oven-dried 4 dram vial containing a magnetic stir bar. 1,4-Dioxane (4 mL) and EtOH (101.7 μL) were added. The vial was sealed with a screwcap featuring a PTFE/silicone septum and was removed from the glovebox. The reaction mixture was magnetically stirred for 16 h in a temperature-controlled aluminum heating block set to 60 °C. After 16 h, the reaction mixture was cooled to room temperature, taken up in EtOAc (ca. 10 mL), and extracted with distilled water (3 × 10 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated with the aid of a rotary evaporator.
• 22 Representative Synthesis A: Preparation of 2b Following GP1 (aryl halide 127.2 mg, boronic acid 337.6 mg), the title product was obtained via flash chromatography using silica and 30% EtOAc in hexanes. The product was isolated as white solid (74%). ¹H NMR (500.1 MHz, CDCl₃): δ = 9.15 (s, 1 H), 8.76 (s, 2 H), 7.49–7.48 (m, 1 H), 6.36–6.32 (m, 2 H), 1.46 (s, 9 H). ¹³C{¹H} NMR (125.8 MHz, CDCl₃): δ = 156.9, 156.3, 148.7, 128.6, 127.5, 124.1, 116.5, 111.2, 84.7, 27.7. HRMS (ESI⁺): m/z calcd for C₁₃H₁₅N₃NaO₂: 268.1056; found: 268.1067 [M + Na]⁺.
• 23 Representative Synthesis B: Preparation of 3d Following GP2 (aryl halide 54.4 mg, boronic acid 249.6 mg), the title product was obtained via flash chromatography using silica and 70% EtOAc in hexanes. The product was isolated as a white solid (88%). ¹H NMR (300.1 MHz, CDCl₃): δ = 9.16 (d, J = 2.2 Hz, 1 H), 8.61 (d, J = 2.4 Hz, 1 H), 8.25 (d, J = 2.1 Hz, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 7.91–7.89 (m, 2 H), 7.75–7.72 (m, 1 H), 7.62–7.59 (m, 1 H), 6.81 (d, J = 8.8 Hz, 1 H), 3.89 (t, J = 4.7 Hz, 4 H), 3.64 (t, J = 5.0 Hz, 4 H). ¹³C{¹H} NMR (125.8 MHz, CDCl₃): δ = 159.0, 149.2, 147.1, 146.5, 136.2, 131.7, 131.1, 129.2, 129.1, 128.1, 127.7, 127.0, 123.3, 106.8, 66.7, 45.5; HRMS (ESI⁺): m/z calcd for C₁₈H₁₈N₃O: 292.1444; found: 292.1443 [M + H]⁺.