Concerning Tishchenko-Like Side Products in Oxidation of Hydroxymethyl to Formyl Groups

Abstract

Oxidation of a hydroxymethyl group to an aldehyde sometimes gives a dimeric ester reminiscent of a Tishchenko aldehyde-ester disproportionation. This process has been observed only with Cr(VI)/pyridine based reagents, and can be avoided most notably by using Dess-Martin and Swern (DMSO/COCl₂) reagents.

Tishchenko - Cr(VI)/pyridine based reagents - oxidation

References

1 Ermolenko L. Sasaki NA. Potier P. Synlett  2001,  1565 

2 Yunker MB. Fraser-Reid B. J. Chem. Soc., Chem. Commun.  1975,  61 

3

Synthesis of Ester 7b from 5b with PCC: To a stirred mixture of PCC (129.4 g), sodium acetate (49.2 g), molecular sieves (120 g) in CH₂Cl₂ (600 mL) at ambient temperature was added a solution of alcohol 5b (38.8 g) in 100 mL of CH₂Cl₂. After 5 h, the mixture was filtered through a pad of Celite and washed with CH₂Cl₂. The combined filtrate and washings was passed through a pad of celite and a pad of silica gel. Removal of the solvent by rotatory evaporation gave 50 g crude product mixture with a 6b:7b ratio of 1:19 estimated by ¹H NMR. Pure 7b (5.2 g) was obtained from 10 g of the crude product mixture by flash chromatography eluted with hexane-EtOAc (7:3). ¹H NMR (CDCl₃): δ = 7.2-7.3 (m, 10 H), 5.3-5.5 (2 s, 2 H), 3.6-4.6 (m, 10 H), 1.2-2.2 (m, 6 H) ppm. ¹³C NMR (CDCl₃): δ = 170.5, 139.0, 138.5, 129.5 (2 C), 129.38 (2 C), 128.74 (2 C), 126.85 (2 C), 126.68 (2 C), 101.78, 101.69, 75.95, 75.16, 67.49, 67.13, 67.03, 28.75, 28.00 ppm. GC-MS: 384 (M).

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14

Synthesis of Aldehyde 6b from 6b with Dess-Martin Periodinane: To a stirred mixture of alcohol 5b (35 g), pyridine (87 mL) and anhyd DCM (500 mL) was added a cooled solution of DMP (15 wt% in CH₂Cl₂, 1000 mL) in 20 min. The mixture was stirred at ambient temperature for 22 h. The reaction mixture was concentrated to 500 mL under reduced pressure, then diluted with 2 L of EtOAc followed by 100 mL of aq 2 M NaOH. After stirred for 1 h, the white precipitate was removed by filtration through a pad of Celite and washed with EtOAc. The combined filtrate and washings was washed with 100 mL of sat. NaHCO₃ and 100 mL of brine, dried over Na₂SO₄ (200 g) overnight, filtered, concentrated to dryness under reduced pressure. The residue was purified on 350 g of silica gel eluted with hexane-EtOAc 1/0 to 7/3 to give 24.8 g of aldehyde 6b in 72% yield. ¹H NMR (CDCl₃): δ = 9.62 (s, 1 H), 7.2-7.6 (m, 5 H), 5.50 (s, 1 H), 4.1-4.3 (m, 2 H), 3.75-3.85 (m, 1 H), 1.6-2.0 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = 200.68, 138.52, 129.69, 128.86 (2 C), 126.77 (2 C), 101.63, 80.88, 66.94, 26.40. GC-MS: 192 (M).