Highly Chemoselective and Regioselective Dehydrogenative Cross-Coupling Reaction between Pyridines and Ethers

Abstract

A highly chemoselective and regioselective dehydrogenative cross-coupling (DCC) reaction of unactivated pyridines with cyclic or acyclic ethers has been developed to give the corresponding 2- or 4-coupled pyridines in satisfactory yields. The DCC reaction affords an efficient and greener synthesis for a range of new pyridines. A possible mechanism involving radical substitution is also proposed.

Key words

dehydrogenative - cross-coupling - pyridine - ether - synthesis

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• 9 General Procedure of the DCC Reaction between Pyridine 1 and Ether 2 for the Synthesis of Monocoupled Pyridine 3 In a Teflon cap sealed tube, a mixture of Sc(OTf)₃ (24.6 mg, 0.05 mmol), pyridine 1 (0.5 mmol), and DTBP (146 mg, 1.0 mmol, 2 equiv) in ether 2 (2 mL) was stirred at 140 °C for 8 h. Then the mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, PE–EtOAc as eluent) to give monocoupled pyridine 3. Characterization of Typical Monocoupled Pyridines 3 2-(1,4-Dioxan-2-yl)pyridine (3ab) Oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (d, J = 4.0 Hz, 1 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.14 (t, J = 6.0 Hz,1 H), 4.67 (dd, J = 2.4, 10.0 Hz, 1 H), 4.07 (dd, J = 2.6, 11.4 Hz, 1 H), 3.92–3.84 (m, 2 H), 3.75–3.63 (m, 2 H), 3.45 (t, J = 10.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 157.9, 149.0, 136.6, 122.7, 120.7, 78.1, 71.2, 66.4, 66.3 ppm. HRMS (EI-TOF): m/z [M⁺] calcd for C₉H₁₁NO₂: 165.0790; found: 165.0790. 2-(1,2-Dimethoxyethyl)pyridine (3af) Oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.51 (d, J = 4.4 Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.13 (t, J = 6.2 Hz, 1 H), 4.44 (t, J = 5.2 Hz, 1 H), 3.58 (d, J = 5.6 Hz, 1 H), 3.32 (s, 3 H), 3.31 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃), δ = 159.0, 149.2, 136.5, 122.6, 121.2, 83.9, 75.7, 59.2, 57.6 ppm. HRMS (EI-TOF): m/z [M⁺] calcd for C₉H₁₃NO₂: 167.0946; found: 167.0947. 2-Phenyl-4-(tetrahydrofuran-2-yl)pyridine (3ea) Oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.56 (d, J = 4.8 Hz, 1 H), 7.91 (d, J = 7.2 Hz, 2 H), 7.62 (s, 1 H), 7.41–7.31 (m, 3 H), 7.12 (d, J = 5.2 Hz, 1 H), 4.90 (t, J = 7.2 Hz, 1 H), 4.05 (q, J = 7.3 Hz, 1 H), 3.91 (q, J = 7.3 Hz, 1 H), 2.39–2.30 (m, 1 H), 1.98–1.91 (m, 2 H), 1.79–1.70 (m, 1 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 157.5 153.7, 149.5, 139.4, 128.9, 128.7, 127.0, 119.0, 117.4, 79.2, 68.9, 34.3, 25.8 ppm. HRMS (EI-TOF): m/z [M⁺] calcd for C₁₅H₁₅NO: 225.1154; found: 225.1158. 4-(1-Ethoxyethyl)-2-phenylpyridine (3ee) Oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.58 (d, J = 5.2 Hz, 1 H), 7.92 (d, J = 7.2 Hz, 2 H), 7.61 (s, 1 H), 7.43–7.33 (m, 3 H), 7.12 (d, J = 6.0 Hz, 1 H), 4.40 (q, J = 6.4 Hz, 1 H), 3.40–3.32 (m, 2 H), 1.40 (d, J = 6.8 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 157.7, 154.1, 149.8, 139.4, 128.9, 128.7, 126.9, 119.6, 117.8, 76.8, 64.5, 23.8, 15.4 ppm. HRMS (EI-TOF): m/z [M⁺] calcd for C₁₅H₁₇NO: 227.1310; found: 227.1312.