Regioselective Benzylation of Azido-Containing Monosaccharides

Abstract

A regioselective benzylation or p-methoxybenzylation of diols in azido-containing monosaccharide derivatives was reported, and the reaction was performed under the conventional reaction conditions (NaH/BnBr in DMF). The hydroxyl functionality adjacent to the azido group was benzylated selectively in good yields.

Key words

selective benzylation - alkylation - azido-containing monosaccharides - protection - hydroxyl group

References and Notes

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14

The reaction conditions such as solvents, temperature, and ratio of reagents were investigated. The optimized reaction conditions: molar ratio of NaH/BnBr/substrates (1.3:1.3:1), DMF as solvent, reaction temperature (-15 °C to r.t.).

15

General Experimental Procedure.
To a solution of p-methylphenyl 2,3-dideoxy-2,3-diazido-1-thio-β-d-mannopyranoside (0.2 mmol) in anhyd DMF (4 mL) was added NaH (1.3 equiv) at -15 °C, after stirring for 5 min BnBr (1.3 equiv) was added, then the mixture was warmed to r.t. for 30 min. The reaction mixture was quenched with H₂O and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (PE-EtOAc, 12:1 to 6:1) to afford products 1a (71%), 1b (7%) and 1c (16%). Compound 1a: ¹H NMR (500 MHz, CDCl₃): δ = 7.38-7.31 (m, 7 H), 7.13 (d, 2 H, J = 8.0 Hz), 4.85 (d, 1 H, J = 10.5 Hz, -CH₂Ph), 4.77 (d, 1 H, J = 1.5 Hz, H-1), 4.66 (d, 1 H, J = 10.5 Hz, -CH₂Ph), 4.09 (dd, 1 H, J = 1.5, 3.5 Hz, H-2), 3.90-3.86 (m, 2 H, H-4, H-6a), 3.76-3.74 (m, 2 H, H-3, H-6b), 3.32-3.29 (m, 1 H, H-5), 2.34 (s, 3 H, -SPhCH₃), 2.07 (d, 1 H, J = 7.0 Hz, 6-OH). ¹³C NMR (125 MHz, CDCl₃): δ = 138.53, 136.97, 132.29, 130.01, 129.49, 128.58, 128.35, 128.27, 86.95, 80.54, 75.28, 73.72, 66.75, 64.83, 61.70, 21.10. MS (ESI-TOF): m/z = 444 [M + NH₄]⁺, 449 [M + Na]⁺. Anal. Calcd for C₂₀H₂₂N₆O₃S: C, 56.32; H, 5.20; N, 19.70. Found: C, 56.51; H, 5.38; N, 19.56.
Compound 1b: ¹H NMR (500 MHz, CDCl₃): δ = 7.39-7.30 (m, 7 H), 7.10 (d, J = 8.5 Hz, 2 H), 4.74 (d, J = 1.5 Hz, 1 H), 4.58 (dd, J = 8.5, 14.5 Hz, 2 H), 4.03-3.99 (m, 2 H), 3.81 (dd, J = 5.0, 10.0 Hz, 1 H), 3.75 (dd, J = 7.0, 10.0 Hz, 1 H), 3.63 (dd, J = 4.0, 10.0 Hz, 1 H), 3.45-3.41 (m, 1 H), 3.21 (d, J = 1.5 Hz, 1 H), 2.33 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 138.69, 137.33, 132.74, 130.17, 129.90, 128.86, 128.40, 128.19, 87.33, 78.02, 74.24, 71.34, 69.93, 66.50, 64.41, 21.38. MS (ESI-TOF): m/z = 444 [M + NH₄]⁺, 449 [M + Na]⁺. Anal. Calcd for C₂₀H₂₂N₆O₃S: C, 56.32; H, 5.20; N, 19.70. Found: C, 56.11; H, 5.30; N, 19.51.
Compound 1c: ¹H NMR (500 MHz, CDCl₃): δ = 7.43-7.41 (m, 2 H), 7.35-7.30 (m, 7 H), 7.26-7.24 (m, 2 H), 7.07 (d, J = 8.5 Hz, 2 H), 4.79 (d, J = 12.0 Hz, 1 H), 4.73 (d, J = 1.5 Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.58-4.54 (m, 2 H), 4.73 (dd, J = 1.0, 3.5 Hz, 1 H), 3.85 (t, J = 10.0 Hz, 1 H), 3.73-3.71 (m, 3 H), 3.43-3.39 (m, 1 H), 2.32 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 138.12, 137.98, 137.02, 132.18, 129.89, 129.82, 128.45, 128.30, 128.28, 128.10, 127.89, 127.60, 86.84, 80.37, 75.06, 74.20, 73.54, 68.64, 66.90, 64.79, 21.05. MS (ESI): m/z = 516 [M]⁺. Anal. Calcd for C₂₇H₂₈N₆O₃S: C, 62.77; H, 5.46; N, 16.27. Found: C, 62.70; H, 5.40; N, 16.25.