Shotgun Process through Differentiation of Aliphatic and Aromatic Aldehyde Functions: The First Synthesis of Ferulic Acid Hexan-3-onyl Ether

Abstract

A shotgun process was explored which enables one-pot allylation of aliphatic aldehyde and aldol reaction of aromatic aldehyde. This protocol was applied to the first synthesis of ferulic acid hexan-3-onyl ether.

Key words

shotgun process - allylation - aldol reaction - aldehydes - ferulic acid

References

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7

When benzaldehyde was employed in place of p-anisaldehyde, a shotgun process did not take place because the reaction of benzaldehyde with the ketene silyl acetal became slow due to the decreased coordinating ability of this substrate and parallel reactions alternatively occurred.

8

The substrate was prepared as follows. To a suspension of vanillin (1.52 g, 10.0 mmol) and K₂CO₃ (4.15 g, 30.0 mmol) in DMF (20 mL) was added 3-bromopropionaldehyde dimethyl acetal (1.64 mL, 12.0 mmol) at room temperature, and then the mixture was heated to 100 °C for 12 h. After addition of water (20 mL) at 0 °C and usual workup (EtOAc-water), the combined organic layer was washed with water and brine. After drying over Na₂SO₄ and filtration, the organic layer was concentrated under reduced pressure. The crude mixture was subjected to column chromatography on silica gel to afford 9 (7:3 hexane-EtOAc, 2.42 g, 95% yield). To a solution of 9 (2.42 g, 9.50 mmol) in THF (10 mL) was added 6 N HCl aq (4 mL) at 0 °C, and then the mixture was warmed to room temperature. The mixture was stirred for 2 h, and NaHCO₃ aq was added until pH 8 at 0 °C. After usual workup (EtOAc/water), the organic layer was washed with brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Recrystallization of the crude mixture from Et₂O afforded 4 (415 mg, 21% yield). 4: ¹H NMR (300 MHz, CDCl₃) δ 3.07 (dt, J = 1.1 Hz, 6.3 Hz, 2 H), 3.91 (s, 3 H), 4.44 (t, J = 6.3 Hz, 2 H), 7.03 (d, J = 8.1 Hz, 1 H), 7.41 (d, J = 1.8 Hz, 1 H), 7.46 (dd, J = 1.8, 8.1 Hz, 1 H), 9.86 (s, 1 H), 9.90 (t, J = 1.1 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ 42.9, 55.9, 62.5, 109.3, 111.7, 126.6, 130.4, 149.7, 153.3, 190.9, 199.4. HRMS (EI) calcd for C₁₁H₁₂O₄: 208.0736; found: 208.0740.

9

Shotgun process for 5 (Scheme [8] ): To a solution of 2 (0.10 mL, 0.40 mmol), 3 (223 mg, 1.10 mmol) and 4 (208 mg, 1.00 mmol) in CH₂Cl₂ (5 mL) was added a 0.5 M CH₂Cl₂ solution of TMSOTf (0.20 mL, 0.10 mmol) at -78 °C under Ar. After the mixture had been stirred for 5 h, NaHCO₃ aq (10 mL) was added. After usual workup (EtOAc-water), the organic layer was washed with 1 N HClaq, NaHCO₃ aq and brine. After drying over Na₂SO₄ and filtration, the organic layer was concentrated under reduced pressure. The crude mixture was subjected to column chromatography on silica gel to afford 5 (17:3 hexane-EtOAc, 358 mg, 79% yield). 5 (diastereomer mixture): ¹H NMR (300 MHz, CDCl₃) δ -0.15 (s, 3 H), 0.02 (s, 3 H), 0.85 (s, 9 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.91-2.02 (m, 2 H), 2.32 (t, J = 6.7 Hz, 2 H), 2.52 (dd, J = 4.0 Hz, 14.5 Hz, 1H), 2.70 (dd, J = 9.4 Hz, 14.5 Hz, 1 H), 3.08 (br, 1 H), 3.84 (s, 3 H), 3.93-4.01 (m, 1 H), 4.05-4.31 (m, 4 H), 5.07-5.17 (m, 3 H), 5.80-5.94 (m, 1 H), 6.82 (s, 2 H), 6.92 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ -5.4, -4.7, 14.1, 18.0, 25.6, 35.4, 35.5, 41.9, 46.6, 55.7, 60.4, 67.6, 67.7, 69.9, 71.9, 108.8, 112.3, 117.6, 117.8, 134.7, 137.4, 147.2, 149.1, 171.2. HRMS (EI) calcd for C₂₄H₄₀O₆Si: 452.2594; found: 452.2584.

10

1: ¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J = 7.3 Hz, 3 H), 1.65 (sext, J = 7.3 Hz, 2 H), 2.49 (t, J = 7.3 Hz, 2 H), 2.98 (t, J = 6.6 Hz, 2 H), 3.88 (s, 3 H), 4.33 (t, J = 6.6 Hz, 2 H), 6.32 (d, J = 15.9 Hz, 1 H), 6.92 (d, J = 8.3 Hz, 1 H), 7.07 (d, J = 1.7 Hz, 1 H), 7.12 (dd, J = 1.7 Hz, 8.3 Hz, 1 H), 7.72 (d, J = 15.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ 13.6, 17.1, 41.8, 45.4, 55.9, 64.0, 110.3, 112.7, 115.0, 123.0, 127.4, 146.9, 149.5, 150.6, 172.3, 208.5. HRMS (EI) calcd for C₁₆H₂₀O₅: 292.1311; found: 292.1308.

11

1′: ¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J = 7.4 Hz, 3 H), 1.65 (sext, J = 7.4 Hz, 2 H), 2.50 (t, J = 7.4 Hz, 2 H), 2.97 (t, J = 6.5 Hz, 2 H), 3.87 (s, 3 H), 4.32 (t, J = 6.5 Hz, 2 H), 6.32 (d, J = 15.9 Hz, 1 H), 6.87 (d, J = 8.8 Hz, 1 H), 7.13-7.16 (m, 2 H), 7.71 (d, J = 15.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ 13.6, 17.0, 41.9, 45.4, 55.9, 64.2, 111.4, 112.2, 115.0, 123.4, 127.0, 146.7, 148.3, 151.8, 172.4, 208.7.