One-Pot 2-O-Alkylation of l-Ascorbic Acid

Abstract

One-pot 2-O-alkylation of l-ascorbic acid involving an in situ 3-O-silylation and desilylation sequence was investigated. Initially the 3-OH group was masked with a t-butyldimethylsilyl (TBDMS) group followed by alkylation of the 2-OH group. Removal of the TBDMS group using 20% sulfuric acid also resulted in hydrolysis of the 5,6-O-isopropylidene to give 2-O-alkyl derivatives of l-ascorbic acid. Selective removal of the 3-O-TBDMS with tetrabutylammonium fluoride (TBAF) gave 5,6-O-isopropylidene-2-O-alkyl derivatives of l-ascorbic acid in good overall yields. Through the application of this protocol, 5,6-O-isopropylidene 2-O-alkyl derivatives of l-ascorbic acid as well as 2-O-alkyl derivatives of l-ascorbic acid may be easily accessed.

Key words

l-ascorbic acid - alkylation - one-pot synthesis - silylation - desilylation

• References and Notes

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• 10 Selected analytical data of novel compounds: Compound 2a: Viscous liquid; [α]_D ²⁵ +21.60 (c 0.5, MeOH); IR: 3400, 2951, 1770, 1675, 1352, 1145, 759 cm^–1; ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.47–3.57 (m, 2 H), 3.71–3.76 (m, 1 H), 4.12 (s, 3 H), 4.73–4.85 (br m, 3 H); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 58.9, 61.9, 68.6, 74.6, 119.5, 150.8, 170.7; MS: m/z = 213.2 [M + Na]⁺. Compound 2b: Viscous liquid; ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.30 (t, J = 3.2 Hz, 3 H), 3.47–3.57 (m, 2 H), 3.72–3.76 (m, 1 H), 4.18 (m, 3 H), 4.43–4.49 (m, 3 H); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 15.2, 61.7, 66.5, 68.8, 74.70, 118.8, 150.0, 170.7. Compound 2c: White solid; mp 100–102 °C; [α]_D ²⁵ +69.72 (c 0.5, MeOH); IR: 3423, 2987, 1749, 1681, 1373, 1074, 910 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 1.28 (m, 6 H), 2.90 (br s, 3 H), 3.79–3.85 (m, 2 H), 3.96 (dd, J = 6.2, 2.4 Hz, 1 H), 4.65 (d, J = 2.4 Hz, 1 H), 5.10–5.18 (m, J = 5.7 Hz, 1 H); ¹³C NMR (75 MHz, DMSO-d ₆): δ = 23.3, 23.4, 62.1, 68.7, 73.1, 74.8, 118.1, 149.2, 170.8. Compound 2g: Viscous liquid; IR: 3332, 3155, 2949, 1739, 1681, 1537, 1340, 1161, 731 cm^–1; ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.47 (m, 2 H), 3.75 (dd, J = 13, 6.4 Hz, 1 H), 4.86 (s, 2 H), 5.05 (d, J = 6.2 Hz, 1 H), 5.98 (AB q, J = 12.6 Hz, 2 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.90 (d, J = 7.6 Hz, 1 H), 8.21 (d, J = 7.6, 1.5 Hz, 1 H), 8.31 (s, 1 H), 9.02 (br s, 1 H); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 61.7, 68.5, 70.5, 74.6, 119.9, 122.1, 122.9, 129.7, 134.0, 138.8, 147.8, 149.5, 170.2; MS: m/z = 333.8 [M + Na]⁺. Compound 2h: Yellow solid; mp 118–120 °C; IR: 3385, 3238, 2960, 1743, 1685, 1543, 1336, 1163, 732 cm^–1; ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.50 (m, 2 H), 3.78 (m, 1 H), 4.20–4.35 (br s, 2 H), 4.73 (s, 1 H), 5.6 (m, 2 H), 7.72 (m, 2 H), 8.20–8.27 (m, 2 H), 9.04 (br s, 1 H); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 61.7, 68.5, 70.5, 74.6, 119.9, 122.9, 129.8, 138.8, 147.7, 149.4, 170.2; MS: m/z = 333.9 [M + Na]⁺. Compound 3b: White solid; mp 92–93 °C; [α]_D ²⁵ +15.52 (c 0.5, MeOH); IR: 3348, 2928, 1775, 1602, 1411, 1390, 707 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 1.35–1.40 (m, 9 H), 4.03 (dd, J = 8.5, 6.7 Hz, 1 H), 4.15 (dd, J = 8.5, 6.7 Hz, 1 H), 4.24–4.28 (m, 1 H), 4.51–4.58 (m, 3 H); ¹³C NMR (75 MHz, CDCl₃): δ = 15.3, 25.5, 25.8, 65.2, 68.1, 74.2, 75.6, 110.7, 118.8, 148.8, 171.3. Compound 3e: White solid; mp 122–124 °C; [α]_D ²⁵ +12.56 (c 0.5, MeOH); IR: 3289, 2988, 1757, 1697, 1757, 1697, 1372, 1117, 810 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 1.35 (s, 3 H), 1.37 (s, 3 H), 3.99–4.14 (m, 2 H), 4.27 (m, 1 H), 4.58 (d, J = 2.9 Hz, 1 H), 5.48 (s, 2 H), 6.51 (s, 1 H), 7.35 (m, 4 H); ¹³C NMR (75 MHz, CDCl₃): δ = 25.5, 25.8, 65.2, 72.5, 73.9, 75.6, 110.3, 119.7, 128.8, 129.5, 134.1, 134.6, 148.4, 171.2; MS: m/z = 341.3 [M + H]⁺. Compound 3f: White solid; mp 136–138 °C; [α]_D ²⁵ +82.84 (c 0.5, MeOH); IR: 3981, 2987, 1753, 1678, 1334, 1038, 806 cm^–1; ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (s, 3 H), 1.30 (s, 3 H), 3.93 (dd, J = 8.4, 6.4 Hz, 1 H), 4.08 (dd, J = 8.4, 6.4 Hz, 1 H), 4.22 (dt, J = 6.4, 3.3 Hz, 1 H), 4.64 (m, 1 H), 5.44 (s, 2 H), 7.32 (m, J = 8.2 Hz, 2 H), 7.51 (m, 2 H), 9.05 (br s, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 25.6, 64.7, 71.2, 73.5, 74.4, 109.1, 120.1, 121.6, 129.4, 130.8, 135.5, 148.3, 169.7; MS: m/z = 385.0 [M + H]⁺. Compound 3g: Viscous liquid; IR: 3502, 2987, 1745, 1687, 1529, 1346, 1115, 729 cm^–1; ¹H NMR (400 MHz, CDCl₃): δ = 1.32 (s, 3 H), 1.34 (s, 3 H), 4.03 (m, J = 8.6, 6.8 Hz, 1 H), 4.15 (dd, J = 8.6, 6.8 Hz, 1 H), 4.31–4.35 (m, 1 H), 4.61 (d, J = 3 Hz 1 H), 5.56–5.63 (AB q, J = 12.6 Hz, 2 H), 7.56 (m, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 8.20 (m, 1 H), 8.25 (d, J = 1.5 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 25.4, 25.8, 65.3, 71.8, 73.6, 75.5, 110.5, 120.1, 122.6, 123.5, 124.7, 129.7, 133.7, 137.9, 148.0, 171.0. Compound 3h: Yellow solid; mp 152 °C; [α]_D ²⁵ +59.96 (c 0.5, MeOH); IR: 3266, 2996, 1758, 1701, 1523, 1339, 1164 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 1.36 (s, 3 H), 1.37 (s, 3 H), 4.06 (dd, J = 8.5, 6.7 Hz, 1 H), 4.14 (dd, J = 8.5, 6.7 Hz, 1 H), 4.33 (dt, J = 6.7, 3.3 Hz, 1 H), 4.64 (d, J = 3.3 Hz, 1 H), 5.60 (AB q, J = 13 Hz, 2 H), 6.37 (br s, 1 H), 7.58 (d, J = 8.6 Hz, 2 H), 8.25 (d, J = 8.6 Hz, 2 H); ¹³C NMR (75 MHz, CDCl₃): δ = 25.5, 25.8, 65.2, 71.8, 73.7, 75.4, 110.4, 119.8, 123.8, 128.1, 142.9, 147.8, 147.9, 170.8; MS: m/z = 373.9 [M + Na]⁺ .
• 11 One-Pot Synthesis of 2-O-Alkyl Derivatives of l-Ascorbic Acid; General Procedure: A solution of 5,6-O-isopropylidene-l-ascorbic acid (1; 2.00 g, 9.25 mmol) and Et₃N (1.2 equiv, 11.12 mmol) in anhydrous CH₂Cl₂ (10.0 mL) was cooled to 0 °C. To this reaction mixture was added a solution of TBDMSCl (1.53 g, 10.18 mmol) in anhydrous CH₂Cl₂ (5.0 mL). The reaction mixture was allowed to warm to r.t. and stirred for 2 h. After completion of the reaction (TLC), Et₃N (1.2 mL, 11.12 mmol) was added followed by the requisite alkylating agent (1.1 equiv 10.18 mmol) and the mixture was stirred for a further 1–2 h at r.t. The reaction mixture was then treated with 20% aq H₂SO₄ (10.0 mL) and stirred at r.t. for 1.5 h. After completion of the reaction as indicated by TLC, the reaction mixture was neutralized with solid NaHCO₃ and the product was extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (hexane–EtOAc).
• 12 One-Pot Synthesis of 2-O-Alkyl Derivatives of 5,6-O-Isopropylidene l-Ascorbic Acid; General Procedure: The same experimental procedure as described in ref. 11 was employed with minor modifications. Selective deprotection of TBDMS group was achieved by the addition of TBAF (1.0 equiv, 9.25 mmol) instead of H₂SO₄. The reaction mixture was stirred at r.t. for 0.5 h. After completion of reaction (monitored by TLC), the mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined extracts were dried over anhydrous Na₂SO₄, filtered, and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (hexane–EtOAc).