Palladium-Catalyzed Synthesis of Isoquinolinones via Sequential Cyclization and N–O Bond Cleavage of N-Methoxy-o-alkynylbenzamides

Abstract

A palladium-catalyzed controlled 6-endo-dig cyclization process has been developed for the chemoselective synthesis of isoquinolin-1-ones from N-alkoxy-o-alkynylbenzamides. The mechanism and scope of the reaction have also been investigated. Deuterium-labeling studies were used to confirm the intramolecular 1,5-hydrogen shift as a key step in the transformation.

Key words

alkynes - regioselectivity - palladium - cyclization - ­amides

• References and Notes

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• 14 General Procedure for the Palladium-Catalyzed Synthesis of Isoquinolinone To a solution of N-alkoxy-o-alkynylbenzamide 1 (0.20 mmol) in DCE (4 mL) was added i-PrOH (0.6 mmol), p-benzoquinone (1.0 mmol), and PdCl₂(PPh₃)₂ (0.04 mmol) under O₂ atmosphere. After being refluxed for 24 h, the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with EtOAc–hexane (1:3) and/or toluene–Et₂O (3:1). Representative spectroscopic data of selected products are as follows. 2-Methyl-3-phenylisoquinolin-1(2H)-one (2a) Yellow solid; mp 66–67 °C (EtOAc–hexane; lit.^5f 63 °C). ¹H NMR (300 MHz, CDCl₃): δ = 8.45 (br d, J = 7.5 Hz, 1 H), 7.64 (br t, J = 8.1 Hz, 1 H), 7.51–7.39 (m, 7 H), 6.46 (s, 1 H), 3.44 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.3, 143.8, 136.3, 136.1, 132.2, 128.8, 128.7, 128.5, 127.7, 126.5, 125.7, 124.7, 107.5, 34.1. IR (KBr): ν_max = 1652, 1619 cm^–1. ESI-HRMS: m/z calcd for C₁₆H₁₃NO [M + H]⁺: 236.1069; found: 236.1066. 3-(4-Fluorophenyl)-2-methylisoquinolin-1(2H)-one (2b) Yellow solid; mp 135–137 °C (EtOAc–hexane). ¹H NMR (300 MHz, CDCl₃): δ = 8.44 (d, J = 7.8 Hz, 1 H), 7.64 (t, J = 7.8 Hz, 1 H), 7.51–7.45 (m, 2 H), 7.42–7.37 (m, 2 H), 7.17 (t, J = 8.4 Hz, 2 H), 6.44 (s, 1 H), 3.41 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 164.6, 163.3, 161.3, 142.7, 136.2, 132.3, 132.2, 130.7, 130.6, 127.8, 126.7, 125.8, 124.9, 115.9, 115.6, 107.7, 34.1. IR (KBr): ν_max = 1650, 1619 cm^–1. ESI-HRMS: m/z calcd for C₁₆H₁₃ONF [M + H]⁺: 254.0976; found: 254.0967. 7-Chloro-2-methyl-3-phenylisoquinolin-1(2H)-one (2h) White solid; mp 148–150 °C (EtOAc–hexane). ¹H NMR (300 MHz, CDCl₃): δ = 8.37 (d, J = 8.4 Hz, 1 H), 7.49–7.45 (m, 4 H), 7.42–7.37 (m, 3 H), 6.36 (s, 1 H), 3.40 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 162.8, 145.4, 138.6, 137.6, 135.8, 129.7, 129.2, 128.7, 128.6, 127.1, 124.9, 123.2, 106.4, 34.1. IR (KBr): ν_max = 1649, 1624 cm^–1. ESI-HRMS: m/z calcd for C₁₆H₁₃ONCl [M + H]⁺: 270.0680; found: 270.0673.