Thioether-Catalysed Tandem Synthesis of Furans and Cyclic Ethers or Lactones

Abstract

Acyclic conjugated ynenediones tethered to an alcohol or carboxylic acid are converted into furanyl-substituted cyclic ethers or lactones in a single step by treatment with the tetrahydrothiophene. Modest levels of diastereocontrol can be achieved in some cases where the presence of a substituent on the tether results in the creation of a second stereogenic centre upon formation of the cyclic ether or lactone.

Key words

organocatalysis - thioether - furans - lactones - cyclic ethers - tandem cyclisation

• References and Notes

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• 16 General Procedure for the Cyclisation of Simple Primary Alcohols and Carboxylic Acids such as Substrates 12, 13, 16, and 17 A solution of tetrahydrothiophene (1.0 mL of a 0.5 M solution in CH₂Cl₂) was added to the ynenedione (1 mmol), and the reaction mixture was stirred at 40 °C for 48 h. The mixture was then concentrated under reduced pressure and the residue purified by flash column chromatography on silica gel. 1-​(2-Methyl-5-tetrahydrofuranyl-3-furanyl)ethanone (14) R_f = 0.20 (PE–EtOAc, 5:2). ¹H NMR (400 MHz, CDCl₃): δ = 6.64 (1 H, s, CH-furan), 4.81 (1 H, dd, J = 6.7, 6.7 Hz, CHO), 3.97–3.92 (1 H, m, CH₂O), 3.86–3.81 (1 H, m, CH₂O), 2.53 (3 H, s, CH₃C), 2.34 (3 H, s, CH₃C=O), 2.20–2.13 (1 H, m, CH ₂CHO), 2.09–1.99 (2 H, m, CH ₂CHO, CH ₂CH₂O), 1.98–1.92 (1 H, m, CH ₂CH₂O). ¹³C NMR (101 MHz, CDCl₃): δ = 194.1, 158.3, 153.0, 121.9, 107.2, 73.6, 68.4, 30.3, 29.1, 26.0, 14.5. IR (film): v _max = 2941, 1668, 1565, 1406, 1231, 1028 cm^–1. HMRS (EI): m/z calcd for C₁₁H₁₄O₃ [M]⁺: 194.0943; found: 194.0938. 1-(2-Methyl-5-tetrahydropyranyl-3-furanyl)ethanone (15) R_f = 0.20 (PE–EtOAc, 5:1). ¹H NMR (500 MHz, CDCl₃): δ = 6.47 (1 H, s, CH-furan), 4.33 (1 H, dd, J = 10.3, 3.1 Hz, CHO), 4.07 (1 H, dddd, J = 11.4, 3.7, 1.8, 1.8 Hz, CH₂O), 3.59 (1 H, ddd, J = 11.4, 11.4, 2.3 Hz, CH₂O), 2.56 (3 H, s, CH₃C), 2.37 (3H, s, CH₃C=O), 1.97–1.93 (1 H, m, CH ₂CH₂CH₂O), 1.87–1.76 (2 H, m, CH₂ CHO), 1.69–1.55 (3 H, m, CH₂ CH₂O, CH ₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃): δ = 194.3, 158.2, 153.2, 121.9, 107.0, 72.8, 68.9, 29.6, 29.3, 25.8, 23.3, 14.6. IR (film): v _max = 2937, 1676, 1566, 1406 cm^–1. HMRS (EI): m/z calcd for C₁₂H₁₆O₃ [M]⁺: 208.1099; found: 208.1103. Dihydro-5-​(4-acetyl-5-methyl-2-​furanyl)​-2(3H)​-​furanone (18) R_f = 0.18 (PE–EtOAc, 1:1); mp 63–65 °C. ¹H NMR (400 MHz, CDCl₃): δ = 6.63 (1 H, s, CH-furan), 5.41 (1 H, t, J = 7.2 Hz, CHO), 2.76–2.57 (2 H, m, CH ₂CH ₂), 2.56 (3 H, s, CH₃C), 2.54–2.42 (2 H, m, CH ₂CH ₂), 2.37 (3 H, s, CH₃C=O). ¹³C NMR (101 MHz, CDCl₃): δ = 193.7, 176.2, 159.4, 148.8, 122.2, 110.0, 74.0, 29.2, 28.5, 26.5, 14.5. IR (film): v _max = 1767, 1674, 1231, 1146 cm^–1. ESI-HMRS: m/z calcd for C₁₁H₁₂NaO₄ [M + Na]⁺: 231.0628; found: 231.0619. Tetrahydro-6-​(4-acetyl-5-methyl-2-​furanyl)​-2H-​pyran-​2-​one (19) R_f = 0.27 (PE–EtOAc, 1:1). ¹H NMR (400 MHz, CDCl₃): δ = 6.59 (1 H, s, CH-furan), 5.31 (1 H, dd, J = 9.6, 4.2 Hz, CHO), 2.69–2.50 (2 H, m, CH₂CO), 2.56 (3 H, s, CH₃C), 2.37 (3 H, s, CH₃C=O), 2.19–1.87 (4 H, m, CH ₂CH ₂CHO). ¹³C NMR (126 MHz, CDCl₃): δ = 193.8, 170.3, 158.9, 149.6, 122.1, 108.9, 74.6, 29.6, 29.2, 26.2, 18.4, 14.5. IR (film): v _max = 1732, 1674, 1564 cm^–1. ESI-HMRS: m/z calcd for C₁₂H₁₄O₄ [M + Na]⁺ 245.0784; found: 245.0781.
• 17 General Procedure for the Cyclisation of Secondary Alcohols and Aryl Substrates such as 24–28 and 35–38 A solution of tetrahydrothiophene (1.0 mL of a 0.5 M solution in CH₂Cl₂) was added to the ynenedione (1 mmol) and phenylphosphonic acid (0.1 mmol), and the reaction mixture was stirred at 40 °C for 48 h. The mixture was then concentrated under reduced pressure and the residue purified by flash column chromatography on silica gel.
• 18 Diastereomers were assigned by the use of two-dimensional nuclear Overhauser spectroscopy (NOESY) in order to establish the spatial relationship between the ring-junction protons of the tetrahydrofuran or tetrahydropyran.