Palladium-Catalyzed Intramolecular Cyclization of 2-Iodobenzamides: ­An Efficient Synthesis of 3-Acyl Isoindolin-1-ones and 3-Hydroxy-3-acyliso­indolin-1-ones

Abstract

Palladium-catalyzed intramolecular cyclization of 2-iodo­benzamides with a 2-oxoethyl function group on the nitrogen atom moiety is presented, providing an efficient method for the synthesis of 3-acyl isoindolin-1-ones and 3-hydroxy-3-acylisoindolin-1-ones under mild conditions in moderate yields.

Key words

intramolecular cyclization - palladium-catalyzed - 3-acyl isoindolin-1-ones - 3-hydroxy-3-acylisoindolin-1-ones - ­2-iodobenzamides

• References and Notes

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For the synthesis of 3-hydroxy isoindolin-1-one derivatives, see:
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• 20 General Procedure for the Synthesis of 2:2-Iodobenzamide 1 (0.3 mmol), Pd₂(dba)₃·CHCl₃ (0.0075 mmol), Xantphos (0.015 mmol), and i-PrOH (1 mL) were added into a Schlenk tube at r.t. under N₂. After stirring for 5 min, Et₃N (1 mL) was added. The reaction mixture was stirred at 70 °C until the reaction was complete, as monitored by TLC (usually 2–5 h). Then the reaction mixture was cooled and the solvent was removed under reduced pressure. Dilute HCl (15 mL) was added, the aqueous layer was extracted with EtOAc (3 × 15 mL) and dried over MgSO₄. After filtration and removal of the solvent in vacuo, the residues were purified by flash chromatography (silica gel; PE–EtOAc, 5:1 → 4:1) to afford 2.3-Benzoyl-2-phenylisoindolin-1-one (2a): solid (mp 178–180 °C). ¹H NMR (500 MHz, CDCl₃): δ = 7.99 (d, J = 7.4 Hz, 1 H), 7.95 (d, J = 7.5 Hz, 2 H), 7.69 (d, J = 8.0 Hz, 2 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.47–7.54 (m, 4 H), 7.33 (t, J = 8.2 Hz, 2 H), 7.29 (d, J = 7.5 Hz, 1 H), 7.13 (d, J = 7.4 Hz, 1 H), 6.65 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 193.3, 167.7, 138.8, 138.1, 135.1, 134.2, 132.4, 132.3, 129.4, 129.2, 129.1, 128.7, 125.1, 124.8, 122.5, 121.0, 67.0. IR: 3056, 1687, 1372, 752 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₆NO₂: 314.1181; found: 314.1177.

It has been reported that carbonyl compounds can react with molecular oxygen under basic conditions:
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• 22 General Procedure for the Synthesis of 3:2-Iodobenzamides 1 (0.3 mmol), Pd₂(dba)₃·CHCl₃ (0.0075 mmol), Xantphos (0.015 mmol), and i-PrOH (1 mL) were added into a Schlenk tube at r.t. under N₂. After stirring for 5 min, Et₃N (1 mL) was added. The reaction mixture was stirred at 70 °C until the reaction was complete, as monitored by TLC (usually 2–5 h). Then the reaction mixture was stirred continuously under O₂ for 24 h. The reaction mixture was cooled and the solvent was removed under reduced pressure. Saturated NaCl (15 mL) was added, the aqueous layer was extracted with EtOAc (3 × 15 mL) and dried over MgSO₄. After filtration and removal of the solvent in vacuo, the residues were purified by flash chromatography (silica gel; PE–EtOAc, 5:1 → 4:1) to afford 3.3-Benzoyl-3-hydroxy-2-phenylisoindolin-1-one (3a): solid (mp 124–126 °C). ¹H NMR (500 MHz, CDCl₃): δ = 8.05–8.07 (m, 1 H), 7.61–7.67 (m, 2 H), 7.47–7.51 (m, 3 H), 7.40–7.41 (m, 1 H), 7.24–7.29 (m, 5 H), 7.19–7.21 (m, 2 H), 6.02 (br s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 195.7, 167.8, 144.1, 134.7, 134.2, 133.6, 132.4, 131.4, 130.8, 129.3, 129.0, 128.8, 127.6, 126.8, 124.8, 122.7, 91.8. IR: 3254, 1684, 1386, 741 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₆NO₃: 330.1130; found: 330.1142.