Swern Oxidation of Alcohols with Ion-Supported Methyl Sulfoxide and Oxalyl Chloride

Abstract

The oxidation of primary and secondary alcohols with ion-supported methyl sulfoxide and oxalyl chloride in the presence of triethylamine in dichloromethane efficiently proceeded to give the corresponding aldehydes and ketones, respectively, in good yields with high purity. Isolation of the product was achieved very easily by simple diethyl ether extraction of the reaction mixture and subsequent removal of solvent from the extract. The reaction did not produce any unpleasant odor. Furthermore, ion-supported methyl sulfide was recovered in good yield and could be re-oxidized to ion-supported methyl sulfoxide for reuse in the same oxidation.

Swern oxidation - ion-supported methyl sulfoxide - ­alcohol - aldehyde - ketone - reuse

References and Notes

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9a

Preparation of 6-mercaptohexan-1-ol: Thiourea (270 mmol) and KI (90 mmol) were added to a solution of 6-chlorohexan-1-ol (180 mmol) in EtOH (150 mL) at r.t., and the mixture was heated at reflux for 14 h. Then, aq NaOH (2.7 m, 270 mmol, 100 mL) was added to the mixture, which was then heated at reflux for 3 h. The reaction mixture was cooled to r.t., and neutralized with aq HCl (1 M, 200 mL). The mixture was extracted with Et₂O (2 × 300 mL) and the combined organic layer was dried over Na₂SO₄, filtered, and evaporated in vacuo. The residue was dissolved in Et₂O (200 mL) and the mixture was filtered. The filtrate was concen-trated to give 6-mercaptohexan-1-ol as an oil. IR (neat): 3348, 2555, 1054 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 1.34-1.47 (m, 5 H), 1.54-1.67 (m, 4 H), 1.84 (s, 1 H), 2.54 (q, J = 7.4 Hz, 2 H), 3.64 (t, J = 6.6 Hz, 2 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 24.49, 25.17, 28.05, 32.53, 33.86, 62.76.

9b

Preparation of 6-(methylthio)hexan-1-ol: MeI (189 mmol) was added to a solution of 6-mercaptohexan-1-ol (180 mmol) and K₂CO₃ (198 mmol) in DMF (160 mL) at 0 ˚C, and the mixture was stirred for 2 h. The reaction mixture was filtered and concentrated, then H₂O (150 mL) was added to the residue, which was extracted with EtOAc (3 × 200 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the residue by distillation (85-95 ˚C/1.0 mmHg) gave 6-(methylthio)hexan-1-ol (66% yield from 6-chlorohexan-1-ol) as an oil. IR (neat): 3365, 1055 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 1.34-1.47 (m, 4 H), 1.55-1.67 (m, 5 H), 2.10 (s, 3 H), 2.50 (t, J = 7.4 Hz, 2 H), 3.64 (t, J = 6.6 Hz, 2 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 15.47, 25.32, 28.49, 29.01, 32.57, 34.14, 62.76.

9c

Preparation of 6-(methylthio)hexyl 4′-methyl-benzenesulfonate: p-TsCl (72 mmol) in CH₂Cl₂ (60 mL) was added to a solution of 6-(methylthio)hexan-1-ol (60 mmol), Et₃N (90 mmol) and Me₃N˙HCl (6.0 mmol) in CH₂Cl₂ (60 mL) at 0 ˚C, and the obtained mixture was stirred for 1 h. H₂O (100 mL) was added to the reaction mixture, which was neutralized with 1 M HCl and extracted with EtOAc (2 × 200 mL). The combined organic layer was washed with H₂O, brine, dried over Na₂SO₄, and concen-trated in vacuo. The residue was purified by column chromatography on silica gel (hexane-EtOAc, 4:1; R _f = 0.4) to give 6-(methylthio)hexyl p-toluenesulfonate (95% yield) as an oil. IR (neat): 1360, 1175 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 1.31-1.37 (m, 4 H), 1.51-1.68 (m, 4 H), 2.07
(s, 3 H), 2.44 (t, J = 7.3 Hz, 2 H), 2.45 (s, 3 H), 4.02 (t, J = 6.5 Hz, 2 H), 7.35 (d, J = 8.1 Hz, 2 H), 7.79 (d, J = 8.1 Hz, 2 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 15.39, 21.52, 24.89, 27.92, 28.60, 28.72, 33.93, 70.41, 127.75, 129.72, 133.05, 144.60.

9d

Preparation of 1-Methyl-3-[6′-(methylthio)hexyl]-1 H -imidazol-3-ium p -Toluenesulfonate (Ion-Supported Methyl Sulfide): 1-Methylimidazole (33 mmol) was added to a solution of 6-(methylthio)hexyl p-toluenesulfonate (30 mmol) in MeCN (30 mL) at r.t., and the mixture was stirred at 60 ˚C for 48 h. The reaction mixture was concentrated in vacuo, and the residue was washed with Et₂O (3 × 100 mL) to give ion-supported methyl sulfide (99% yield) as an oil. IR (neat): 1191, 1034 cm^-¹; ^¹H NMR (400 MHz, CDCl₃):
δ = 1.19-1.38 (m, 4 H), 1.48-1.56 (m, 2 H), 1.73-1.81 (m, 2 H), 2.07 (s, 3 H), 2.34 (s, 3 H), 2.43 (t, J = 7.3 Hz, 2 H), 3.93 (s, 3 H), 4.14 (t, J = 7.6 Hz, 2 H), 7.15 (d, J = 7.8 Hz, 2 H), 7.31 (t, J = 1.8 Hz, 1 H), 7.41 (t, J = 1.8 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 2 H), 9.59 (s, 1 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 15.41, 21.20, 25.64, 27.87, 28.62, 29.95, 33.89, 36.25, 49.63, 121.81, 123.52, 125.71, 128.61, 137.51, 139.36, 143.56.

9e

Preparation of 3-Methyl-1-[6′-(methylsulfinyl)-hexyl]-1 H -imidazolium p -Toluenesulfonate (Ion-Supported Methyl Sulfoxide): H₂O₂ (30% in H₂O, 1.47 mL, 48 mmol) was added dropwise to a solution of ion-supported methyl sulfide {1-methyl-3-[6′-(methylthio)hexyl]-
1H-imidazol-3-ium p-toluenesulfonate; 7.69 g, 20 mmol} in AcOH-THF (2:1, 45 mL) at 0 ˚C, and the mixture was stirred at r.t. for 2 h. The reaction mixture was quenched with aq sat. Na₂SO₃, and concentrated in vacuo. The obtained mixture was dissolved in CH₂Cl₂, dried over Na₂SO₄, and filtered. After removal of the solvent, ion-supported methyl sulfoxide was obtained (99% yield) as an oil; IR (neat): 1034 cm^-¹; ^¹H NMR (500 MHz, CDCl₃): δ = 1.28-1.49 (m, 4 H), 1.67-1.86 (m, 4 H), 2.34 (s, 3 H), 2.55 (s, 3 H), 2.68 (t, J = 7.6 Hz, 2 H), 3.93 (s, 3 H), 4.19 (t, J = 7.4 Hz, 2 H), 7.15 (d, J = 7.9 Hz, 2 H), 7.36-7.38 (m, 2 H), 7.74 (d, J = 8.2 Hz, 2 H), 9.63 (s, 1 H); ^¹³C NMR (125 MHz, CDCl₃): δ = 21.21, 22.06, 25.37, 27.59, 29.59, 36.25, 38.30, 49.49, 53.79, 121.96, 123.38, 125.71, 128.64, 137.63, 139.48, 143.43; HMRS (APPI): m/z [M⁺] calcd for C₁₁H₂₁ON₂S: 229.1369; found: 229.1357

10

General Procedure for the Swern Oxidation using Ion-Supported Methyl Sulfoxide: Oxalyl chloride (0.34 mL) was added dropwise to a solution of ion-supported methyl sulfoxide (1.60 g, 4.0 mmol) in CH₂Cl₂ (6 mL) at -70 ˚C and the mixture was stirred for 30 min at the same temperature. A solution of alcohol (2.0 mmol) in CH₂Cl₂ (3 mL) was added dropwise at -70 ˚C and the obtained mixture was stirred for 30 min. Triethylamine (1.66 mL, 12 mmol) was added dropwise at -70 ˚C and the mixture was stirred for
1 h at the same temperature. The resulting mixture was warmed to -60 ˚C and stirred for 1.5 h at the same temperature. The mixture was warmed to -50 ˚C and stirred for 1 h at the same temperature. Finally, the mixture was warmed to r.t. by removing the cooling bath and stirred for
2 h at the same temperature. The reaction mixture was quenched with H₂O (10 mL), neutralized (pH 6-7) with aq 1 M HCl, and extracted with Et₂O (2 × 40 mL). The organic layer was washed with H₂O (10 mL), dried over Na₂SO₄, and filtered. After removal of the solvent, aldehyde or ketone was obtained. The purity was estimated by ^¹H NMR analysis.
Most of the aldehydes and ketones obtained in this study are commercially available and were identified by comparison with the authentic materials (see the Supporting Information; mp, IR, ^¹H NMR, and ^¹³C NMR).
The aqueous layer was concentrated in vacuo. After the addition of aq sat. NaHCO₃, ion-supported methyl sulfide was extracted with CHCl₃ (3 × 40 mL). The organic layer was dried over Na₂SO₄ and filtered. After removal of the solvent, the residue was washed with Et₂O (2 × 10 mL), and concentrated in vacuo to provide ion-supported methyl sulfide (˜73% yield). The recovered ion-supported methyl sulfide was quantitatively oxidized to the corresponding ion-supported methyl sulfoxide with hydrogen peroxide in a mixture of AcOH and THF, as described above.