Synlett 2009(17): 2777-2782  
DOI: 10.1055/s-0029-1217991
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Nikos Assimomytisa, Yiannis Sariyannisb, Georgios Stavropoulosb, Petros G. Tsoungas*c, George Varvounisd, Paul Cordopatisa
a Department of Pharmacy, University of Patras, 26500 Patras, Greece
b Department of Chemistry, University of Patras, 26500 Patras, Greece
c Department of Research and Technology, Ministry of Development, 14-18 Messogion Ave., 11510 Athens, Greece
Fax: +30(210)7713810; e-Mail: pgt@gsrt.gr;
d Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, 45110 Ioannina, Greece
Further Information

Publication History

Received 31 July 2009
Publication Date:
24 September 2009 (online)

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.

    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. 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. 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. 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. 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.