2,4-difluorobenzene-1,3-diol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,4-difluororesorcinol (Compound 4, 0.15 g, 1.0 mmol) and ethyl stearoylacetate (354 mg, 1.03 mmol) in methanesulfonic acid (4 mL) is stirred at room temperature overnight. The reaction mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is washed with brine (1×) and dried over sodium sulfate, then concentrated to 0.67 g of a pale brown solid, which is purified by silica gel chromatography to give 49 mg of Compound 30 as a colorless powder: Rf =0.64 (EtOAc/hexanes 3:2). 1H NMR (CDCl3) δ 7.12 (dd, 1H), 6.22 (s, 1H), 1.7-0.7 (m, 70H). 19F NMR (CDCl3) Φ 139.8 (t, 1F), 153.5 (d, 1F). The reaction mixture is partitioned between ethyl acetate and water The ethyl acetate layer is washed with brine (1×) dried over sodium sulfate concentrated to 0.67 g of a pale brown solid, which is purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,4-difluororesorcinol (Compound 4, 0.20 g, 1.37 mmol) and ethyl 4-chloroacetoacetate (0.29 g, 1.75 mmol) in 2 mL methanesulfonic acid is kept at room temperature for 2.5 hours, then diluted with 25 mL water. The resulting precipitate is collected on a Buchner funnel and dried to give 134 mg of dimly fluorescent Compound 28 as a colorless powder. This product is purified further by chromatography (silica gel, ethyl acetate/hexanes): Rf =0.45 (EtOAc/hexanes 3:2); 1H NMR (CDCl3 -CD3OD) δ 7.13 (dd, 1H), 6.41 (s, 1H), 4.52 (s, 2H); 19F NMR (CDCl3 -CD3OD) Φ 136.38 (t, 1F), 153.26 (d, 1F). The resulting precipitate is collected on a Buchner funnel dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Compound 4 (0.46 g, 3.1 mmol) and methyl-4,4,4-trifluoroacetoacetate (0.55 g, 3.2 mmol) in 7 mL CH3 SO3H is stirred at 20° C. for 48 hours. The reaction mixture is poured into 70 mL ice water, and the resulting precipitate is collected by filtration, washed with water, dried in vacuo at 60° C. for 16 hours to yield 240 mg (30%) of Compound 20 as an off-white powder. 1 H-NMR (DMSO-d6) δ 7.33 (d, 1 H), 6.99 (s, 1H). 19F-NMR (DMSO-d6) Φ 59.38 (s, 3F), 129.93 (t, J=9.9 Hz, 1H), 147.78 (d, J=9.3 Hz, 1F). the resulting precipitate is collected by filtration washed with water dried in vacuo at 60° C. for 16 hours

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,4-difluororesorcinol (0.50 g, 3.4 mmol) and hexamethylenetetraamine (0.96 g, 6.8 mmol) in 4 mL trifluoroacetic acid is heated to reflux for 24 hours. After cooling, the reaction is quenched by the addition of 2 mL 20% H2SO4, and then stirred for an additional hour. The reaction mixture is then poured into 50 mL water and extracted with EtOAc (50 mL×2), washed with brine (30 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The residue is purified by sublimation to yield 0.35 g (59%) of Compound 13 as a colorless powder. Mp. 141°-143° C. 1H-NMR (DMSO-d6) δ 9.7 (s, 1H), 7.21 (dd, J=9.8; 6.5 Hz, 1H). 19 F-NMR(DMSO-d6) Φ 143.78 (t, J=9.8 Hz, 1F), 158.31 (d, J=6.5 Hz, 1F). Anal. calcd for C7H4F3O3 : C, 48.29; H, 2.32. Found: C, 47.87, H, 2.62. to reflux for 24 hours After cooling the reaction is quenched by the addition of 2 mL 20% H2SO4 The reaction mixture is then poured into 50 mL water extracted with EtOAc (50 mL×2) washed with brine (30 mL) dried over anhydrous MgSO4 concentrated in vacuo The residue is purified by sublimation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl acetylsuccinate (2.4 g, 11.1 mmol) is added to a solution of Compound 4 (1.3 g, 8.9 mmol) in 20 mL methanesulfonic acid at 20° C. The reaction is stirred for 16 hours and poured into 200 mL ice water. The product is extracted with EtOAc (80 mL×2), washed with brine (40 mL), dried over anhydrous MgSO4, and concentrated in vacuo to yield a brown oil. The crude oil is purified by column chromatography on silica gel eluted with CHCl3 /MeOH (95:5 to 90:10) to yield 1.06 g (40%) of Compound 10 as an off-white solid. 1H-NMR (DMSO-d6) δ 7.56 (d, 1H), 4.08 (q, 2H), 3.67 (s, 2H), 2.34 (s, 3H), 1.19 (t, 3H). 19F-NMR (DMSO-d6) Φ 130.13 (t, 1F), 148.87 (d, 1F). Also isolated from the column is 0.50 g (20%) of 6,8-difluoro-7-hydroxy-4-methylcoumarin 3-acetic acid (Compound 11). The product is extracted with EtOAc (80 mL×2) washed with brine (40 mL) dried over anhydrous MgSO4 concentrated in vacuo to yield a brown oil The crude oil is purified by column chromatography on silica gel eluted with CHCl3 /MeOH (95:5 to 90:10)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,4-difluororesorcinol (Compound 4; 1.00 g, 8.76 mmol) and ethyl acetoacetate (1.14 g, 8.76 mmol) in 5 mL methanesulfonic acid is kept at room temperature for 24 hours, then poured into water (75 mL). The resulting precipitate is collected, rinsed with water and dried, giving 0.91 g of Compound 5 as a tan powder. An analytical sample is prepared by crystallization from light petroleum ether/methanol, giving the Compound 5 as colorless needles. UV-vis (pH 7 buffer): 358 nm, ε=17,700 cm-1M-1 ; ex/em 358/452 nm. 1H NMR (CDCl3) δ7.12 (dd, 1H), 6.27 (s, 1H), 2.38 (s, 3H). 19F NMR (CDCl3) Φ 136.5 (t, 1F), 152.8 (t, 1F). The resulting precipitate is collected rinsed with water dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Compound 3 (0.64 g, 3.7 mmol) in dichloromethane (0.3M, anhydrous) at room temperature under nitrogen is treated with boron tribromide solution (3.0 equivalents, 1.0M in dichloromethane, Aldrich or Fluka) via syringe over five minutes. The reaction is monitored by TLC, and takes 24-48 hours to reach completion; an additional 0.5 equivalents of boron tribromide solution is sometimes necessary to drive the reaction to completion. The reaction mixture is carefully quenched with water, and the resulting mixture is stirred until all precipitate dissolves. The resulting solution is extracted twice with ether. The ether extract is washed twice with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure and purified by sublimation to yield 0.49 g (90%) of Compound 4 as a colorless crystalline solid: m.p. 100°-101° C.; 1H NMR (CDCl3) 8.99 (s, 1H), 8.62 (s, 1H), 6.32 (td, 1H), 6.05 (m, 1H); 19F (CDCl3) 145.4 (m, 1F), 156.0 (m, 1F). Anal. calc. for C6H4O2F2 ; C, 49.33; H, 2.76. Found: C, 48.96; H, 3.21; N, 0.028. the reaction to completion The reaction mixture is carefully quenched with water dissolves The resulting solution is extracted twice with ether The ether extract is washed twice with brine dried over anhydrous sodium sulfate concentrated under reduced pressure purified by sublimation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,4-difluororesorcinol (0.8 g) in 8 mL of methyl sulfonic acid is introduced into a flask and then 1.3 equivalents (963 μL) of ethyl 4-chloroacetoacetate are added dropwise. After 3 hours of stirring at room temperature, the mixture is cooled to 0° C. and then 100 mL of water are added. The residue is then filtered, dried and washed with diethyl ether in order to obtain 0.34 g (25%) of the compound 1. the mixture is cooled to 0° C. The residue is then filtered dried washed with diethyl ether in order

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,4-difluororesorcinol (Compound 4, 0.15 g, 1.0 mmol) and ethyl stearoylacetate (354 mg, 1.03 mmol) in methanesulfonic acid (4 mL) is stirred at room temperature overnight. The reaction mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is washed with brine (1×) and dried over sodium sulfate, then concentrated to 0.67 g of a pale brown solid, which is purified by silica gel chromatography to give 49 mg of Compound 30 as a colorless powder: Rf =0.64 (EtOAc/hexanes 3:2). 1H NMR (CDCl3) δ 7.12 (dd, 1H), 6.22 (s, 1H), 1.7-0.7 (m, 70H). 19F NMR (CDCl3) Φ 139.8 (t, 1F), 153.5 (d, 1F). The reaction mixture is partitioned between ethyl acetate and water The ethyl acetate layer is washed with brine (1×) dried over sodium sulfate concentrated to 0.67 g of a pale brown solid, which is purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,4-difluororesorcinol (Compound 4, 0.20 g, 1.37 mmol) and ethyl 4-chloroacetoacetate (0.29 g, 1.75 mmol) in 2 mL methanesulfonic acid is kept at room temperature for 2.5 hours, then diluted with 25 mL water. The resulting precipitate is collected on a Buchner funnel and dried to give 134 mg of dimly fluorescent Compound 28 as a colorless powder. This product is purified further by chromatography (silica gel, ethyl acetate/hexanes): Rf =0.45 (EtOAc/hexanes 3:2); 1H NMR (CDCl3 -CD3OD) δ 7.13 (dd, 1H), 6.41 (s, 1H), 4.52 (s, 2H); 19F NMR (CDCl3 -CD3OD) Φ 136.38 (t, 1F), 153.26 (d, 1F). The resulting precipitate is collected on a Buchner funnel dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Compound 4 (0.46 g, 3.1 mmol) and methyl-4,4,4-trifluoroacetoacetate (0.55 g, 3.2 mmol) in 7 mL CH3 SO3H is stirred at 20° C. for 48 hours. The reaction mixture is poured into 70 mL ice water, and the resulting precipitate is collected by filtration, washed with water, dried in vacuo at 60° C. for 16 hours to yield 240 mg (30%) of Compound 20 as an off-white powder. 1 H-NMR (DMSO-d6) δ 7.33 (d, 1 H), 6.99 (s, 1H). 19F-NMR (DMSO-d6) Φ 59.38 (s, 3F), 129.93 (t, J=9.9 Hz, 1H), 147.78 (d, J=9.3 Hz, 1F). the resulting precipitate is collected by filtration washed with water dried in vacuo at 60° C. for 16 hours

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,4-difluororesorcinol (0.50 g, 3.4 mmol) and hexamethylenetetraamine (0.96 g, 6.8 mmol) in 4 mL trifluoroacetic acid is heated to reflux for 24 hours. After cooling, the reaction is quenched by the addition of 2 mL 20% H2SO4, and then stirred for an additional hour. The reaction mixture is then poured into 50 mL water and extracted with EtOAc (50 mL×2), washed with brine (30 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The residue is purified by sublimation to yield 0.35 g (59%) of Compound 13 as a colorless powder. Mp. 141°-143° C. 1H-NMR (DMSO-d6) δ 9.7 (s, 1H), 7.21 (dd, J=9.8; 6.5 Hz, 1H). 19 F-NMR(DMSO-d6) Φ 143.78 (t, J=9.8 Hz, 1F), 158.31 (d, J=6.5 Hz, 1F). Anal. calcd for C7H4F3O3 : C, 48.29; H, 2.32. Found: C, 47.87, H, 2.62. to reflux for 24 hours After cooling the reaction is quenched by the addition of 2 mL 20% H2SO4 The reaction mixture is then poured into 50 mL water extracted with EtOAc (50 mL×2) washed with brine (30 mL) dried over anhydrous MgSO4 concentrated in vacuo The residue is purified by sublimation