Anionic ortho-Fries Rearrangement, a Facile Route to Arenol-Based Mannich Bases

Abstract

Phenol and 1-naphthol-based carbamates undergo the anionic ortho-Fries rearrangement to their corresponding amides. Bulky substitution at position 8 of 1-naphthol-based carbamates makes the rearrangement an exclusive reaction, even at -90 ˚C, under a variety of conditions. The amides can be efficiently reduced to the corresponding Mannich bases. A novel route to 7-[(dialkylamino)methyl]-8-hydroxy-1-naphthaldehydes is presented.

Key words

rearrangements - reductions - Mannich bases - carb­a­mates - ortho-Fries rearrangement

References and Notes

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  Sigma-Aldrich cat. no. 644234.

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13

Conversion of Carbamates to Amides (Table 1); General Procedure: n-BuLi (3.8 mL, 1.6 M sol in hexane) was added dropwise to a stirred solution of diisopropylamine (0.607 g, 6 mmol), in anhyd THF (6 mL) at -78 ˚C under a nitrogen atmosphere. After 20 min at -78 ˚C a solution of the appropriate carbamate (5 mmol) in anhyd THF (6 mL) was added. The reaction mixture was stirred for 30 min at -78 ˚C, allowed to warm to r.t., stirred for a further 6 h and then quenched with sat. NH₄Cl (5 mL). The reaction mixture was extracted with Et₂O (3 × 20 mL) and the combined organic extracts were washed with brine (25 mL) and then dried (Na₂SO₄). The solvent was removed in vacuo and the crude product was purified by silica flash column chromatography (hexane-Et₂O, 6:4) to give the corresponding amide. The structures of the products were confirmed by comparison of their mp, TLC, IR or ^¹H NMR data with authentic samples obtained commercially or prepared by literature methods.
N , N -Diethyl-1-hydroxy-2-naphthamide (Table 1, entry 8): Obtained as colourless microcrystals (EtOAc-hexane); yield: 0.87 g (72%); mp 50-52 ˚C; R _f 0.48 (hexane-Et₂O, 3:7). IR (KBr): 3443, 3067, 2982, 2934, 1635 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.29 (t, J = 7.2 Hz, 6 H), 3.54 (q, J = 7.2 Hz, 4 H), 7.25-7.33 (m, 2 H), 7.45-7.58 (m, 2 H), 7.78 (d, J = 6.8 Hz, 1 H), 8.41 (d, J = 7.6 Hz, 1 H), 11.41 (br s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.6, 42.4, 110.6, 117.7, 123.7, 123.8, 125.7, 125.8, 127.4, 128.4, 135.6, 157.8, 172.8. ES-MS: m/z = 244.66 [M + 1]⁺. Anal. Calcd for C₁₅H₁₇NO₂: C, 74.05; H, 7.04; N, 5.76. Found: C, 73.78; H, 7.20; N, 5.69.

17

Sigma-Aldrich cat. no. 642932.

21

Conversion of Amides to Mannich Bases (Table 2); General Procedure: A solution of appropriate amide (1.25 mmol) in anhyd THF (50 mL) was added to a stirred solution of LiAlH₄ (0.244 g, 6.25 mmol) in anhyd THF (25 mL) at 0 ˚C. The reaction mixture was allowed to warm to r.t., stirred for 3 h and then treated successively with H₂O (10 mL), 15% aq NaOH (10 mL) and H₂O (40 mL). The reaction mixture was extracted with Et₂O (3 × 30 mL) and the combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. The crude product was purified by silica flash column chromatography eluting with Et₂O to give the corresponding Mannich base. The structure of the products was confirmed by comparison of their mp, TLC,
IR or ^¹H NMR data with authentic samples obtained commercially or prepared by literature methods.
2-[(Diethylamino)methyl]-1-naphthol (Table 2, entry 8): Obtained as a dark red oil; yield: 0.18 g (65%), mp 149-150 ˚C (as HCl salt); R _f 0.14 (hexane-Et₂O, 3:7). IR (KBr): 3330 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.16 (t, J = 7.2 Hz, 6 H), 2.69 (q, J = 7.2 Hz, 4 H), 3.92 (s, 2 H), 7.07 (d, J = 8.0 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.41-7.49 (m, 2 H), 7.74 (m, 1 H), 8.22-8.28 (m, 1 H), 11.15 (br s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 11.3 (2 × C), 46.5 (2 × C), 57.2, 114.4, 118.0, 122.0, 124.7, 125.0, 125.8, 126.4, 127.3, 133.8, 154.0. ES-MS: m/z = 230.24 [M + 1]⁺. Anal. Calcd for C₁₅H₁₉NO: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.25; H, 8.64; N, 5.74.

33

2-[(Diethylamino)methyl]-8-(1,3-dioxolan-2-yl)-1-naphthol (8b): Prepared by reducing 8-(1,3-dioxolan-2-yl)-N,N-diethyl-1-hydroxy-2-naphthamide (7b) with LiAlH₄ according to the general procedure.^²9 Obtained as a colourless semi-solid; yield: 42 mg (74%); R _f 0.38 (hexane-Et₂O, 1:4). IR (KBr): 3330 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.26 (t, J = 7.2 Hz, 6 H), 3.50 (q, J = 7.2 Hz, 4 H), 3.82 (s, 2 H), 4.08-4.18 (m, 5 H), 7.27-7.90 (m, 5 H), 11.45 (br s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.22, 41.75, 42.10, 65.09, 102.16, 114.00, 119.06, 124.16, 126.84, 129.50. ES-MS: m/z = 302.3 [M + 1]⁺. Anal. Calcd for C₁₈H₂₃NO₃: C, 71.73; H, 7.69; N, 4.65. Found: C, 71.48; H, 7.54; N, 4.51.

34

7-[(Diethylamino)methyl]-8-hydroxy-1-naphthaldehyde (9b): Compound 8b (0.04 g, 0.13 mmol) was dissolved in a mixture of 10% aq HCl (10 mL) and THF (10 mL) and heated under reflux for 1 h. After cooling, 10% aq K₂CO₃ was added dropwise to the reaction mixture until pH 5, followed by extraction with Et₂O (3 × 10 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. The crude material was purified by crystallisation from hexane-EtOAc (6:1) to give colourless microcrystals; yield: 26 g (88%); mp 128-130 ˚C; R _f 0.54 (hexane-Et₂O, 3:2). IR (KBr): 3335, 1710 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.26 (t, J = 7.2 Hz, 6 H), 3.52 (q, J = 7.2 Hz, 4 H), 3.84 (s, 2 H), 7.25-8.10 (m, 5 H), 9.93 (s, 1 H), 11.85 (br s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 41.39, 41.90, 117.54, 124.56, 131.59, 136.89, 192.12. ES-MS: m/z = 258.12 [M + 1]⁺. Anal. Calcd for C₁₆H₁₉NO₂: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.49; H, 7.31; N, 5.26.