An Improved Synthesis of Pyridoxine via [2+2+2] Cyclization of Acetylenes and Nitriles

Abstract

An improved synthesis of pyridoxine (vitamin B₆) is reported. The key step involves the light-promoted [2+2+2] cyclization of 3,3-bissilyl-di-2-propynyl ethers and acetonitrile in the presence of [cpCo(cod)] (1 mol%) as a catalyst. Convenient oxidation and iodination procedures are elaborated to transfer 3-silyl­pyridines into corresponding 3-hydroxy- and 3-iodo-derivatives.

Key words

pyridines - alkynes - nitriles - cyclizations - vitamins

References

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7

3,3-Bis(dimethylisopropoxysilyl)-di-2-propynyl ether (1, 9.1 g, 10 mL, 27.85 mmol) and MeCN (5 mL) were dissolved in hexane (130 mL). Then, [cpCo(cod)] (65 mg, 0.28 mmol, 1 mol%) was added to the solution, and the reaction mixture was stirred under reflux for 20 h under two 460 W Phillips HPM 12 lamps’ irradiation. The reaction mixture was evaporated in vacuum, and the residue was distilled. A fraction with bp 119-122 °C (2·10^-3 mbar) was collected to give 8.29 g (81% yield) of compound 3 as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 5.06 (m, 2 H), 5.04 (m, 2 H), 4.03-3.94 (m, 2 H), 2.55 (s, 3 H), 1.09 (d, J = 6.1 Hz, 6 H), 1.07 (d, J = 6.1 Hz, 6 H), 0.31 (s, 6 H), 0.28 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.24, 157.46, 152.28, 136.75, 123.03, 73.42, 71.28, 64.84, 64.68, 25.75, 24.92, 0, -2.23. MS (70 eV): m/z (%) = 368 (2) [M⁺], 352 (11), 325 (100), 312 (34), 294 (24), 74 (28), 43 (23).

8

Bissilylated pyridine 3 (5.565 g, 15.14 mmol) was stirred for 12 h at 70 °C in absolute i-PrOH (10 mL). The solvent was evaporated, and the residue was distilled in vacuo to give 2.85 g (75% yield) of the product 4 with bp 74-77 °C (8·10^-3 mbar). ¹H NMR (400 MHz, CDCl₃): δ = 8.29 (s, 1 H), 5.09 (m, 2 H), 4.96 (m, 2 H), 4.03-3.97 (m, 1 H), 2.56 (s, 3 H), 1.12-1.1 (m, 6 H), 0.33 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.09, 155.04, 141.61, 130.98, 124.11, 74.1, 70.19, 64.84, 25.38, 24.98, 0.003. MS (70 eV): m/z (%) = 251 (5) [M⁺], 236 (10), 208 (100), 194 (37), 176 (18), 75 (18).

10

KH (1.575 g, 39.26 mmol) was suspended in DMF (20 mL) at 0 °C. Then, t-BuOOH (6.5 mL, 39 mmol, 6 M solution in nonane) was added dropwise to the slurry within 10 min so that the reaction temperature did not exceed 5 °C. After the addition, the mixture was stirred additionally for 10 min at 5 °C until the evolution of hydrogen ceased. The solution of 6-methyl-7-(dimethylisopropoxysilyl)-1,3-dihydrofuro[3,4-c]pyridine (4, 3.23 g, 12.86 mmol) in DMF (3 mL) was added dropwise to the reaction mixture within 30 min at 5 °C under vigorous stirring. The reaction mixture was stirred for additional 30 min. At this point the color turned to brown, and the reaction mixture was evaporated to dryness in high vacuum. The remaining solids were dissolved in hot HOAc (10 mL) followed by addition of HBr (25 mL, 48% in H₂O). The solution was brought to reflux, and 13 mL of liquids were distilled off at atmospheric pressure. The remaining solution was left overnight at 5 °C. The precipitated hydrobromide was filtered off, washed with acetone, and then air dried. The crude salt was recrystallized from HOAc (8 mL) to give 1.68 g (35% yield) of the product 6 as beige crystals with mp 228 °C. ¹H NMR (400 MHz, CD₃OD): δ = 8.34 (s, 1 H), 4.74 (s, 2 H), 4.73 (s, 2 H), 2.61 (s, 3 H). ¹³C NMR (100 MHz, CD₃OD): δ = 154.8, 145.2, 143.3, 137.1, 134.4, 25.5, 21.2, 16.3. MS (70 eV): m/z (%) = 296 (4) [M⁺ - Br], 248 (2), 215 (37), 134 (67), 106 (100), 80 (50), 65 (50), 39 (74).

11

The solution of the pyridine 7 (228 mg, 1.1 mmol), dried KF (198 mg, 3.4 mmol), nitrobenzene (0.35 mL, 3.4 mmol) in DMF (3 mL) was treated with iodine (863 mg, 3.4 mmol), and the mixture stirred for 10 h at 80 °C. Then reaction was quenched by addition of 5% solution of Na₂SO₃ in H₂O after cooling and extracted with Et₂O. The organic phase was dried over Na₂SO₄, solvents were removed in vacuum, and the oily residue was purified on silica (Et₂O) to give 206 mg (72% yield) of the iodide 8 as colorless crystals. ¹H NMR (400 MHz, CDCl₃): δ = 8.21 (s, 1 H), 5.21 (s, 2 H), 4.92 (s, 2 H), 2.70 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 158.1, 155.1, 141.2, 133.4, 89.6, 78.3, 73.7, 28.1. MS (70 eV): m/z (%) = 261 (100) [M⁺], 233 (50), 205 (15), 133 (11), 106 (51), 77 (29), 63 (12), 51 (16).