Organocatalytic Oxidative Dimerization of Alcohols to Esters

Abstract

2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) catalyzes the direct oxidation of primary alkyl alcohols to symmetric ­esters at 1–2 mol% loadings. These rapid reactions take place at room temperature to afford the products in yields of 55–99%.

Key words

catalysis - dimerization - alcohols - esters - oxidation

• References

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General references for TEMPO:
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• 10 The mechanism is consistent with the generally accepted mechanism for TEMPO oxidations under basic conditions, see: Bailey WF, Bobbitt JM, Wiberg KB. J. Org. Chem. 2007; 72: 4504
• 11 It has been reported that aldehydes are oxidized by 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate and pyridine via acyl-pyridinium salts, see: Bartelson AL, Bobbitt JM, Bailey WF. Chem. Abstr. 2009; 985377
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• 13 Oxidation shuttles in TEMPO-mediated chemistry have been reported by others see ref. 9 and see also: Rychnovsky SD, Vaidyanathan R. J. Org. Chem. 1999; 64: 310
• 14 All reactions were carried out using oven-dried (120 °C) glassware. Acetonitrile was dried by passage over activated alumina under a nitrogen atmosphere (water content <20 ppm, Karl–Fischer titration). Pyridine was distilled from calcium hydride. All other commercially available reagents were used without further purification. Chromatographic purification of products (flash chromatography) was performed on silica 32–63, 60 Å. NMR spectra were recorded with a Bruker Avance I 300 spectrometer operating at 300 MHz and 75 MHz for ¹H and ¹³C acquisitions, respectively, or with Bruker Avance III 400 spectrometers operating at 400 MHz (¹H) and 101 MHz (¹³C) or with a Bruker DPX200 spectrometer operating at 200 MHz (¹H) and 50 MHz (¹³C). Chemical shifts (δ) are reported in ppm with the solvent resonance as the internal standard relative to chloroform (δ = 7.26 ppm for ¹H, and δ = 77.0 ppm for ¹³C). IR spectra were recorded with a Bruker FTIR. High-resolution mass spectra APCI were recorded with a Waters Micromass LCT premier instrument operating at 70 eV (acetonitrile–water, 70%; flowrate 0.2 mL). All known pure compounds showed NMR spectra consistent with those reported in the literature.General Procedure: The alcohol (2 mmol), TEMPO (3.1 mg, 0.02 mmol, 1 mol%) and pyridine (0.322 mL, 4.0 mmol, 2 equiv) were dissolved in acetonitrile (2 mL). A stock solution of TCCA (156 mg/mL, 0.32 mmol/mL, 0.32 equiv/mL) in acetonitrile (3 mL) is added dropwise over 0.5–1 h until no more starting material was observed by TLC (usually 2–3 mL stock solution, 0.65–1.3 equiv of TCCA). Sat. NaHCO₃ (25 mL) was added and the reaction was extracted with diethyl ether (4 × 20 mL). The combined extracts were dried over Na₂SO₄ and the product was purified by flash chromatography (EtOAc–hexane).3-Phenylpropyl 3-Phenylpropanoate (3a): ¹⁵ The product was purified by flash chromatography (EtOAc–hexane, 14%) as an oil (252 mg, 94%). R _f = 0.57 (EtOAc–hexane, 20%). ¹H NMR (200 MHz, CDCl₃): δ = 7.23 (m, 10 H), 4.09 (t, J = 6.5 Hz, 2 H), 2.96 (t, J = 7.6 Hz, 2 H), 2.63 (t, J = 7.6 Hz, 4 H), 1.93 (dt, J = 13.2, 6.5 Hz, 2 H).2-(Benzyloxy)ethyl 2-(Benzyloxy)acetate (3b): ³ The product was purified by flash chromatography (EtOAc–hexane, 30%) as an oil (191 mg, 64%). R _f = 0.83 (EtOAc–hexane, 50%). ¹H NMR (300 MHz, CDCl₃): δ = 7.44–7.27 (m, 10 H), 4.66 (s, 2 H), 4.56 (s, 2 H), 4.35 (t, J = 4.7 Hz, 2 H), 4.14 (s, 2 H), 3.69 (t, J = 9.5 Hz, 2 H).2-Phenoxyethyl 2-Phenoxyacetate (3c): ³ The product was purified by flash chromatography (EtOAc–hexane, 30%) as an oil (234 mg, 86%). R _f = 0.82 (EtOAc–hexane, 80%). ¹H NMR (200 MHz, CDCl₃): δ = 7.33–7.13 (m, 5 H), 6.90–6.74 (m, 5 H), 4.65 (s, 2 H), 4.56 (t, J = 4.8 Hz, 2 H), 4.20–4.12 (t, J = 4.5 Hz, 2 H).2-Butoxyethyl 2-Butoxyacetate (3d): ³ The product was purified by flash chromatography (EtOAc–hexane, 18%) as an oil (250.7 mg, 99%). R _f = 0.51 (EtOAc–hexane, 20%). ¹H NMR (200 MHz, CDCl₃): δ = 4.25 (t, J = 4.5 Hz, 2 H), 4.05 (s, 2 H), 3.59 (t, J = 4.9 Hz, 2 H), 3.54–3.36 (m, 4 H), 1.66–1.21 (m, 8 H), 0.87 (td, J = 7.1, 1.6 Hz, 6 H).(S)-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl 2,2-Dimethyl-1,3-dioxolane-4-carboxylate (3e): ³ The product was purified by flash chromatography (EtOAc–hexane, 30%) as an oil (143 mg, 55%). R _f = 0.95 (EtOAc–hexane, 50%). ¹H NMR (400 MHz, CDCl₃): δ = 4.56 (t, J = 7.0 Hz, 1 H), 4.31–3.97 (m, 6 H), 3.69 (dd, J = 8.4, 5.9 Hz, 1 H), 1.44 (s, 3 H), 1.37 (s, 3 H), 1.34 (s, 3 H), 1.29 (s, 3 H).(Tetrahydrofuran-2-yl)methyl Tetrahydrofuran-2-carboxylate (3f): ³ The product was purified by flash chromatography (EtOAc–hexane, 80%) as an oil (166 mg, 83%). ¹H NMR (400 MHz, CDCl₃): δ = 4.47 (m, 1 H), 4.17 (m, 1 H), 4.05 (m, 3 H), 3.86 (m, 2 H), 3.76 (dd, J = 14.3, 7.2 Hz, 1 H), 2.22 (m, 1 H), 1.92 (m, 6 H), 1.58 (m, 2 H).(Tetrahydro-2H-pyran-2-yl)methyl Tetrahydro-2H-pyran-2-carboxylate (3g): ³ The product was purified by flash chromatography (EtOAc–hexane, 80%) as an oil (171 mg, 75%). ¹H NMR (400 MHz, CDCl₃): δ = 4.09 (m, 1 H), 3.48 (m, 1 H), 1.96 (m, J = 11.6 Hz, 1 H), 1.87 (m, J = 7.4 Hz, 1 H), 1.56 (m, 2 H), 1.32 (m, 1 H).2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) Acetate (3h): The product was purified by flash chromatography (EtOAc–hexane, 50%) as a solid (310 mg, 82%). R _f = 0.49 (EtOAc–hexane, 50%). ¹H NMR (400 MHz, CDCl₃): δ = 7.89–7.80 (m, J = 6.3, 3.1 Hz, 4 H), 7.77–7.70 (m, 4 H), 4.44–4.38 (m, 4 H), 3.98 (t, J = 5.3 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 167.99, 167.29, 167.16, 134.16, 134.07, 132.08, 131.96, 123.60, 123.47, 62.96, 38.80, 36.65. IR (thin film): 3024, 1763, 1722, 1633, 1520, 1404, 1215, 1014 cm^–1. HRMS (APCI): m/z [M + 1] calcd for C₁₉H₁₂N₂O₆: 379.0930; found: 379.0929.1,4-Dioxan-2-one (3i): ^4g The product was purified by flash chromatography (EtOAc–hexane, 80%) as an oil (103 mg, 100%). Yields varied from 70 to 100% due to the inherent instability of the product. ¹H NMR (400 MHz, CDCl₃): δ = 4.50 (t, J = 4.7 Hz, 2 H), 4.38 (s, 2 H), 3.87 (t, J = 4.7 Hz, 2 H).Tetrahydro-2H-pyran-2-one (3j): ^4b The product was purified by flash chromatography (EtOAc–hexane, 80%) as an oil (86 mg, 86%). ¹H NMR (400 MHz, CDCl₃): δ = 4.34 (t, J = 5.5 Hz, 2 H), 2.56 (t, J = 6.9 Hz, 2 H), 2.01–1.79 (m, 4 H).Hexyl Hexanoate (3k): ^2d The product was purified by flash chromatography (EtOAc–hexane, 20%) as an oil (137 mg, 68%). R _f = 0.5 (EtOAc–hexane, 20%). ¹H NMR (200 MHz, CDCl₃): δ = 4.03 (t, J = 6.7 Hz, 2 H), 2.26 (t, J = 7.5 Hz, 2 H), 1.68–1.49 (m, 4 H), 1.37–1.18 (m, 10 H), 0.86 (t, J = 6.6 Hz, 6 H).Decyl Decanoate (3l): ^2d The reaction was carried out using t-BuOCl (2 equiv) as the oxidant instead of TCCA. The product was purified by flash chromatography (EtOAc–hexane, 10%) as an oil (234 mg, 75%). ¹H NMR (400 MHz, CDCl₃): δ = 4.05 (t, J = 6.7 Hz, 2 H), 2.29 (t, J = 7.5 Hz, 2 H), 1.68–1.55 (m, 4 H), 1.40–1.16 (m, J = 13.6 Hz, 26 H), 0.88 (t, J = 6.6 Hz, 6 H).Cyclobutylmethyl Cyclobutanecarboxylate (3m): ¹⁶ The product was purified by flash chromatography (Et₂O–pentane, 8%) as an oil (135 mg, 80%). R _f = 0.5 (Et₂O–pentane, 20%). ¹H NMR (400 MHz, CDCl₃): δ = 3.99 (d, J = 6.7 Hz, 2 H), 3.07 (pent., J = 8.5 Hz, 1 H), 2.55 (sept., 1 H), 2.17 (m, 4 H), 1.98 (m, 2 H), 1.84 (m, 4 H), 1.71 (m, 2 H).
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