2-chloro-4-methoxyphenol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 2-chloro-4-methoxyphenol (10 g, 63 mmol) and K2CO3 (9.7 g, 69.4 mmol) in N,N-dimethyl formamide (120 mL) was added 2-bromothiazole (11.4 g, 69.4 mmol). The suspension was heated at 150° C. for 4 hours, cooled to ambient temperature, and poured into water (1000 mL). The mixture was extracted with ether (2×300 mL) and the combined ether layers were dried (MgSO4), filtered and concentrated. The resulting black oil was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 25% ethyl acetate in hexanes to provide 12.3 g of the title compound (81%) as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.81 (s, 3H) 7.01 (dd, J=9.01, 3.13 Hz, 1H) 7.18-7.21 (m, 1H) 7.23 (t, J=3.13 Hz, 2H) 7.47 (d, J=9.19 Hz, 1H); MS (ESI) m/z 241.9 (M+H)+. cooled to ambient temperature The mixture was extracted with ether (2×300 mL) the combined ether layers were dried (MgSO4) filtered concentrated The resulting black oil was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 25% ethyl acetate in hexanes

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-4-methoxy-phenol (7.93 g, 0.05 mol), 2-bromothiazole (9.0 g, 0.055 mol) and potassium carbonate (7.6 g, 0.055 mol) in dimethyl sulfoxide was heated at 160° C. under nitrogen for 4 hours. The solution was cooled and treated with water, and the aqueous phase was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give 30 g of the crude material, which was purified on a silica gel (ethyl acetate/hexane 5-35%) to afford 10.62 g of the product as a light yellow oil (88% yield), 1H NMR (300 MHz, CDCl3) δ ppm 3.81 (s, 3H) 6.80 (d, J=4.04 Hz, 1H) 6.85 (dd, J=9.19, 2.94 Hz, 1H) 7.01 (d, J=2.94 Hz, 1H) 7.19 (d, J=3.68 Hz, 1H) 7.27 (d, J=8.82 Hz, 1H). MS (ESI), m/z 241.9 (M+H)+. The solution was cooled the aqueous phase was extracted with dichloromethane The organic layer was washed with brine dried concentrated to give 30 g of the crude material, which was purified on a silica gel (ethyl acetate/hexane 5-35%)

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

Procedure: The dinitro precursor was prepared by reacting 2-chloro-4-methoxyphenol (Aldrich Chemical Co., Milwaukee, Wis.) as the potassium 2-chloro-4-methoxyphenolate with methyl 4-chloro-3,5-dinitrobenzoate, as described in Example 1.2.1. The methyl 3,5-dinitro-4-(2′-chloro-4′-methoxyphenoxy)benzoate product (66% yield) was crystallized from ethanol to give orange crystals. Melting point: 116-119° C.

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

Procedure: Combine the product of step (b) (2.5 g) with 2-chloro-4-methoxyphenol (5.2 g) and potassium carbonate (10 g) in acetone (100 ml) and relux for 48 hours. Evaporate the solvent, extract the resultant residue with dichloromethane and purify on a silica gel column, eluting with 100% CH2Cl2 →10% CH3OH/CH2Cl2. Evaporate the solvent extract the resultant residue with dichloromethane purify on a silica gel column eluting with 100% CH2Cl2