Synthesis of Hydroxy-7H-benzo[c]fluoren-7-ones

Abstract

An efficient synthesis of 2-, 3- and 4-hydroxy-7H-benzo[c]fluoren-7-ones, useful intermediates for the synthesis of photochromic naphthopyrans, is described. The synthetic approach involves the use of oxazolines as activating groups for aromatic ­nucleophilic substitution and starts with readily available di­methoxynaphthaldehydes.

Key words

phenols - fused-ring systems - nucleophilic aromatic substitutions - hydroxy-7H-benzo[c]fluoren-7-ones

References

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10

Procedure for the Synthesis of 2a-c: A solution of sodium chlorite (3.12 g, 80% purity, 27.6 mmol) in 7 mL of H₂O was added rapidly to a warm solution of dimethoxynaphth-aldehyde 1a-c (4.10 g, 19.0 mmol), resorcinol (2.83 g, 21.6 mmol), t-butanol (18.5 mL), HOAc (a few drops) and p-dioxane (16 mL). The reaction mixture was heated 10 min at 85 °C then cooled and concentrated under reduced pressure. CH₂Cl₂ (20 mL) were added and the organic phase extracted with aq NaOH (2%). The aqueous phase was separated, acidified with HCl and extracted 3 times with CH₂Cl₂. The organic phases were combined, washed with H₂O, sat. NaCl, dried (Na₂SO₄) and then the solvent was evaporated under reduced pressure to give pure dimethoxynaphthoic acids 2a-c.
1,5-Dimethoxy-2-naphthoic acid (2a): 65% yield, mp 128-130 °C. IR (KBr): 3100-2600, 1697, 1255 cm^-1. ¹H NMR (CDCl₃): δ = 8.14 (d, J = 8.7 Hz, 1 H), 8.05 (d, J = 9.0 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 1 H), 7.53 (t, J = 8.5 Hz, 1 H), 6.97 (d, J = 8.5 Hz, 1 H), 4.15 (s, 3 H), 4.03 (s, 3 H). MS (EI): m/z (%) = 232 (100), 217 (20), 187 (30), 115 (40).
1,6-Dimethoxy-2-naphthoic acid (2b): 70% yield, mp 146-147 °C. IR (KBr): 3100-2400, 1697, 1238 cm^-1. ¹H NMR (CDCl₃): δ = 8.09 (m, 2 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.20 (s, 1 H), 4.16 (s, 3 H), 3.98 (s, 3 H). MS (EI): m/z (%) = 232 (100), 215 (30), 159 (31).
1,7-Dimethoxy-2-naphthoic acid (2c): 75% yield, mp 114-116 °C. IR (KBr): 3100-2500, 1687, 1257 cm^-1. ¹H NMR (CDCl₃): δ = 7.88 (dd, J = 8.5 and 2.5 Hz, 1 H), 7.74 (d, J = 7.0 Hz, 1 H), 7.59 (d, J = 7.0 Hz, 1 H), 7.35 (s, 1 H), 7.24 (d, J = 8.5 Hz, 1 H), 4.08 (s, 3 H), 3.92 (s, 3 H). MS (EI): m/z (%) = 232 (100), 217 (49), 173 (50).

11

Data for oxazolines: 3a: 42% yield. IR (neat): 2965, 1643, 1376 cm^-1. ¹H NMR (CDCl₃): δ = 7.99 (d, J = 8.8 Hz, 1 H), 7.80 (m, 2 H), 7.41 (t, J = 7.8 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 4.16 (s, 2 H), 3.97 (s, 6 H), 1.43 (s, 6 H).
3b: 91% yield. IR (neat): 2958, 1637, 1621, 1359 cm^-1. ¹H NMR (CDCl₃): δ = 8.14 (d, J = 9.1 Hz, 1 H), 7.80 (d, J = 8.7 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.16 (dd, J = 2.5 and 9.0 Hz, 1 H), 7.10 (d, J = 2.5 Hz, 1 H), 4.14 (s, 2 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 1.41 (s, 6 H).
3c: 65% yield. IR (neat): 2965, 1631,1625, 1224 cm^-1. ¹H NMR (CDCl₃): δ = 7.71 (d, J = 9.0 Hz, 1 H), 7.67 (d, J = 8.6 Hz, 1 H), 7.52 (m, 2 H), 7.19 (d, J = 9.0 Hz, 1 H), 4.16 (s, 2 H), 3.98 (s, 3 H), 3.93 (s, 3 H), 1.43 (s, 6 H).

12

Data for oxazolines 4a: 30% yield. ¹H NMR (CDCl₃): δ = 8.33 (d, J = 8.7 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.48-7.34 (m, 5 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.23 (t, J = 8.5 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 4.03 (s, 3 H), 3.72 (s, 2 H), 1.21 (s, 6 H).
4b: 36% yield. ¹H NMR (CDCl₃): δ = 7.75 (m, 2 H), 7.54 (d, J = 9.0 Hz, 1 H), 7.45-7.32 (m, 5 H), 7.17 (d, J = 2.5 Hz, 1 H), 7.04 (dd, J = 2.5 and 9.5 Hz, 1 H), 3.92 (s, 3 H), 3.69 (s, 2 H), 1.19 (s, 6 H).
4c: 39% yield. ¹H NMR (CDCl₃): δ = 7.79 (m, 2 H), 7.63 (d, J = 8.5 Hz, 1 H), 7.45-7.35 (m, 5 H), 7.17 (d, J = 2.5 and 9.1 Hz, 1 H), 6.94 (d, J = 2.5 Hz, 1 H), 3.71 (s, 2 H), 3.68 (s, 3 H), 1.19 (s, 6 H).

13

Procedure for the Synthesis of 5a-c: A solution of oxazoline 4a-c (0.69 g, 2.08 mmol) in MeI (10 mL) was stirred at r.t. overnight and the excess of MeI removed under reduced pressure. To the crude MeI salt, were added MeOH (12 mL) and NaOH 20% (12 mL) and the mixture heated to reflux for 12 h. The solution was extracted with Et₂O and the organic layer discarded. The aqueous layer was acidified with HCl (aq), extracted with Et₂O, dried (Na₂SO₄) and concentrated to give the corresponding methoxy-1-phenyl-2-naphthoic acid. Without further purification, H₂SO₄ (5 mL) was added. After stirring for 5 min at r.t. the resulting dark colored solution was poured into ice (50 g) and then extracted with Et₂O (3 × 50 mL). The organic layer was dried (Na₂SO₄) and the solvent was evaporated under reduced pressure to give pure ketone 5a-c as red solids.
5a: 97% yield, mp 192-193 °C. IR (KBr): 1706, 1263 cm^-1. ¹H NMR (CDCl₃): δ = 8.27 (d, J = 8.5 Hz, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.67 (d, J = 7.5 Hz, 1 H), 7.54-748 (m, 2 H), 7.28 (t, J = 7.5 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 4.02 (s, 3 H). MS (EI): m/z (%) = 260 (100), 245 (20), 217 (53), 189 (50).
5b: 86% yield, mp 146-147 °C. IR (KBr): 1708, 1272 cm^-1. ¹H NMR (CDCl₃): δ = 8.36 (d, J = 9.0 Hz, 1 H), 7.93 (d, J = 7.5 Hz, 1 H), 7.68-7.59 (m, 2 H), 7.47 (m, 1 H), 7.22 (m, 2 H), 7.11 (d, J = 2.5 Hz, 1 H), 3.92 (s, 3 H). MS (EI): m/z (%) = 260 (100), 217 (45), 189 (50).
5c: 78% yield, mp 126-128 °C. IR (KBr): 1725, 1274 cm^-1. ¹H NMR (CDCl₃): δ = 7.92 (d, J = 7.5 Hz, 1 H), 7.78 (d, J = 9.0 Hz, 1 H), 7.72-7.67 (m, 2 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.54-7.50 (m, 2 H), 7.31-7.24 (m, 2 H), 4.02 (s, 3 H). MS (EI): m/z (%) = 260 (100), 217 (60), 189 (45).

14

Procedure for the Synthesis of 6a-c: A mixture of ketone 5a-c (0.34 g, 1.31 mmol), HOAc (2.5 mL) and HBr 47% (5 mL) was heated under reflux for 5 h. After cooling the reaction mixture was poured into 100 mL of H₂O and extracted with Et₂O (3 × 50 mL). The combined organic layers were extracted 3 times with NaOH (5%, 20 mL) and the organic phase discarded. The aqueous phase was acidified with HCl 10%, and extracted with Et₂O (3 × 50 mL). The combined organic layers were dried (Na₂SO₄) and the solvent evaporated under reduced pressure giving the pure hydroxybenzofluorenones 6a-c.
4-Hydroxy-7H-benzo[c]fluoren-7-one (6a): 63% yield, mp 258-260 °C. IR (KBr): 3280, 1691 cm^-1. ¹H NMR (acetone-d ₆): δ = 9.39 (s, 1 H), 8.34 (d, J = 8.5 Hz, 1 H), 8.23 (d, J = 7.5 Hz, 1 H), 8.17 (d, J = 8.5 Hz, 1 H), 7.68 (d, J = 8.5 Hz, 1 H), 7.66-7.62 (m, 2 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 1 H), 7.11 (d, J = 7.5 Hz, 1 H). ¹³C NMR (CDCl₃/CD₃OD): δ = 195.4, 153.9, 145.2, 142.3, 134.5, 134.2, 131.7, 129.8, 129.5, 128.3, 128.2, 124.1, 123.7, 123.3, 118.1, 115.8, 110.4. MS (EI): m/z (%) = 246 (100), 218 (22), 189 (70). HRMS: Calcd for C₁₇H₁₀O₂: 246.0681; found: 246.0673.

3-Hydroxy-7H-benzo[c]fluoren-7-one (6b): 93% yield, mp 264-265 °C. IR (KBr): 3230, 1685 cm^-1. ¹H NMR (acetone-d ₆): δ = 9.21 (s, 1 H), 8.61 (d, J = 9.0 Hz, 1 H), 8.23 (d, J = 7.5 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.62 (m, 3 H), 7.40 (t, J = 7.5 Hz, 1 H), 7.37 (dd, J = 2.5 and 9.1 Hz, 1 H), 7.34 (d, J = 2.5 Hz, 1 H). ¹³C NMR (CDCl₃/CD₃OD): δ = 194.9, 157.2, 144.7, 143.3, 140.3, 134.8, 134.2, 129.0, 128.5, 127.6, 126.5, 123.6, 123.4, 123.1, 120.3, 120.1, 110.7. MS (EI): m/z (%) = 246 (100), 218 (15), 189 (45). HRMS: Calcd for C₁₇H₁₀O₂: 246.0681; found: 246.0676.
2-Hydroxy-7H-benzo[c]fluoren-7-one (6c): 91% yield, mp 263-265 °C. IR (KBr): 3276, 1685 cm^-1. ¹H NMR (acetone-d ₆): δ = 8.11 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 2.2 Hz, 1 H), 7.93 (d, J = 8.5 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.63 (m, 2 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 7.32 (dd, J = 2.3 and 8.9 Hz, 1 H). ¹³C NMR (CDCl₃/CD₃OD): δ = 195.3, 156.5, 145.4, 141.5, 134.5, 134.3, 133.2, 131.9, 131.0, 130.1, 129.7, 128.1, 123.8, 122.8, 120.8, 116.9, 106.4. MS (EI): m/z (%) = 246 (100), 217 (5), 189 (40). HRMS: Calcd for C₁₇H₁₀O₂: 246.0681, found: 246.0678.