New Synthetic Methodology Toward Azaspiro-γ-Lactones by Oxidative C–H Spirocyclization

Abstract

A new synthetic methodology for azaspiro-γ-lactones is reported. The key C–H spirolactonization was accomplished by employing iodobenzene diacetate and potassium bromide to afford a variety of azaspiro-γ-lactones in high yields. The reaction was also applicable to the preparation of a bislactone derivative.

Key words

C–H spirolactonization - hypervalent iodine - azaspiro-γ-lactone - spiroheterocyclic compound - N,O-spirocycle

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When the reaction was performed under the classical C–H oxidation conditions (PIDA, I₂, hν) developed by Suárez, only 13% of product was obtained along with 43% yield of recovered starting material and a substantial amount of an unidentified side product. For Suárez’s conditions, see:
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• 18 General procedure for spirolactonization: To a solution of 1 (21.9 mg, 0.100 mmol) in CH₂Cl₂ (1.0 mL) was added iodobenzene diacetate (PIDA, 38.7 mg, 0.120 mmol) and potassium bromide (11.9 mg, 0.100 mmol) at room temperature under an argon atmosphere. After stirring the suspension for 24 h, the reaction was quenched by addition of saturated aqueous NaHCO₃ (5 mL). The resulting mixture was extracted with EtOAc (5 mL × 3), washed with brine (5 mL), dried with Na₂SO₄, filtered, and concentrated in vacuo to give a crude material. This material was purified by column chromatography on silica gel by using hexane/EtOAc as the eluent.
• 19 Compound 2a: White solid; mp 230–232 °C; IR (KBr): 1774 (C=O), 1702 (C=O) cm^–1; ¹H NMR (300 MHz, CDCl₃): δ 7.83 (m, 1 H, ArH), 7.66–7.49 (m, 3 H, ArH), 3.05 (s, 3 H, CH ₃), 3.04–2.98 (m, 2 H, CH ₂), 2.77 (ddd, J = 7.5, 9.9, 14.1 Hz, 1 H, CH ₂), 2.60 (ddd, J = 7.5, 8.7, 14.1 Hz, 1 H, CH ₂); ¹³C NMR (75 MHz, CDCl₃): δ 174.3 (C), 166.6 (C), 143.9 (C), 132.9 (CH), 130.7 (CH), 123.7 (CH), 121.4 (CH), 97.4 (C), 29.3 (CH₂), 29.2 (CH₂), 23.7 (CH₃). Anal. Calcd for C₁₂H₁₁NO₃: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.12; H, 4.88; N, 6.24.
• 20 The addition of 2,2,6,6-tetramethylpiperide 1-oxyl (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) to the reaction mixture of 1a completely shut down the formation of 2a, indicating that these reactions should be a radical process. Hydrogen abstraction from the substrate would occur at the potentially reactive C–H bond adjacent to the nitrogen atom. In the case of 2d, hydrogen abstraction on the endocyclic carbon atom would be favored because the generated radical species could be much more stabilized by the conjugated system of isoindolinone the benzylic radical on the exocyclic position.