Synthetic Studies Towards the Synthesis of 6-Substituted 3-Fluoro-5,6-dihydropyran-2-ones^[1]

Abstract

The synthesis of 6-substituted 3-fluoro-5,6-dihydropyran-2-ones under mild conditions is described. The key step of the synthesis involves a Julia–Kocienski olefination.

Key words

fluorosulfones - lactones - dihydropyranones - Julia–Kocienski olefination

• References and Notes

• 1 Presented at the NEHU (ETC-2016) and KU (NSCTC-VII-2016) conference: S. K. Mandal and A. P. Chattopadhyay, An Approach for the Synthesis of Fluorinated 6-Substituted 5,6-Dihydropyran-2-one Analogues. Also presented at the VB (RTCR-2017) conference: S. K. Mandal and A. Sarkar, Synthesis of Fluorinated 6-Substituted 5,6-Dihydropyran-2-one Analogues.
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• 24 3-Hydroxy-3-phenylpropanal (4a); Typical Oxidation Procedure To a solution of 1-phenylbut-3-en-1-ol (5a; 150 mg, 1.01 mmol) in 3:1 1,4-dioxane/H₂O (10 mL) at r.t. were successively added 2.5% OsO₄ in t-BuOH (0.18 mL; 0.022 mmol) and 2,6-lutidine (0.24 mL, 2.02 mmol). NaIO₄ (864 mg, 4.04 mmol) was then added in portions over 30 min, and the mixture was stirred at r.t. for 2 h. The reaction was quenched by addition of H₂O (10 mL), and the mixture was diluted with Et₂O (20 mL). The layers were separated, and the aqueous layer was extracted with Et₂O (2 × 50 mL). The organic layers were combined, washed with H₂O (2 × 25 mL) and brine (25 mL), then dried (Na₂SO₄), filtered, and concentrated in vacuo to give the crude product, which was used directly in the condensation reaction.
• 25 Ethyl (2E)-2-Fluoro-5-hydroxy-5-phenylpent-2-enoate (2a) and Ethyl (2Z)-2-Fluoro-5-hydroxy-5-phenylpent-2-enoate (IIa); Typical Condensation Procedure Cs₂CO₃ (780 mg, 2.4 mmol) was added to a stirred solution of the crude 4a and sulfone 3 (366 mg, 1.2 mmol) in CH₂Cl₂ (10 mL) at r.t., and the mixture was stirred overnight. The solids were removed by filtration, and the solvent was removed in vacuo. The crude product was purified by column chromatography [silica gel (100–200 mesh) EtOAc/PE (4:1)] to give a mixture of 2a and IIa; yield: 147 mg (62%)
• 26 3-Fluoro-6-phenyl-5,6-dihydro-2H-pyran-2-one (1a): Typical Lactonization Procedure The mixture of 2a and IIa obtained from the condensation reaction was treated with CSA (5 mg, 2 mol%) in CH₂Cl₂ (10 mL) at r.t. overnight. The resulting mixture was concentrated and purified by column chromatography [silica gel (100–200 mesh), CH₂Cl₂] to give a white solid; yield: 63 mg (33% overall); mp 82 °C. IR (KBr) 1743, 1674, 1164, 769 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.66–2.74 (m, 1 H), 2.83–2.93 (m, 1 H), 5.54 (dd, J = 4.0, 12.0 Hz, 1 H), 6.36–6.40 (m, 1 H), 7.36–7.48 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 30.6 (d, ³ J _CF = 4.0 Hz), 80.0, 118.0 (d, ² J _CF = 13.0 Hz), 126.1 (2 C), 128.9 (2 C), 129.1, 137.4, 147.6 (d, ¹ J _CF = 258.0 Hz), 158.9 (d, ² J _CF = 31.0 Hz). HRMS: m/z [M + H] calcd for C₁₁H₁₀FO₂: 193.0665; found: 193.0668.