1-benzofuran-3-yl acetate

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

Procedure: To a solution of benzofuran-3-yl acetate (8) (100 g, 1.42 mol) in methanol (350 mL) was added diluted (7.5%) H2SO4 (500 mL) at ambient temperature followed by heating to reflux for 1-3 h. The progress of the reaction was monitored by HPLC analysis. Upon completion of the reaction, the reaction mixture was cooled, filtered, and the slurry was washed with water, and vacuum dried to obtain the product meeting the desired specifications. Yield—83-100%. by heating to reflux for 1-3 h Upon completion of the reaction the reaction mixture was cooled filtered the slurry was washed with water, and vacuum dried to obtain the product

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To acetic anhydride (300 mL) was added 2-(carboxymethoxy)benzoic acid (7) (100 g, 0.510 mol) at ambient temperature and heated to 130-140° C. The reaction temperature was maintained for 14-20 h under stirring. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, the reaction mixture was cooled to 50-80° C., acetic anhydride was recovered at 50-80° C. at reduced pressure and the crude product was extracted with dichloromethane (500 mL). The dichloromethane layer was recovered completely to obtain the product meeting the desired specifications. Yield—76-85%. The reaction temperature was maintained for 14-20 h Upon completion of the reaction the reaction mixture was cooled to 50-80° C. acetic anhydride was recovered at 50-80° C. at reduced pressure the crude product was extracted with dichloromethane (500 mL) The dichloromethane layer was recovered completely to obtain the product

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To acetic anhydride (300 mL) was added 2-(carboxymethoxy)benzoic acid (7) (100 g, 0.510 mol) at ambient temperature and heated to 130-140° C. The reaction temperature was maintained for 14-20 h under stirring. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, the reaction mixture was cooled to 50-80° C., acetic anhydride was recovered at 50-80° C. at reduced pressure and the crude product was extracted with dichloromethane (500 mL). The dichloromethane layer was recovered completely to obtain the product meeting the desired specifications. Yield—76-85%. The reaction temperature was maintained for 14-20 h Upon completion of the reaction the reaction mixture was cooled to 50-80° C. acetic anhydride was recovered at 50-80° C. at reduced pressure the crude product was extracted with dichloromethane (500 mL) The dichloromethane layer was recovered completely to obtain the product

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

Procedure: Another synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2B. According to the synthesis, methyl salicylate reacts with ethyl chloroacetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield exclusively or predominantly (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide and 2-haloethanol, the (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) may form (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A), which may undergo potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).

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

Procedure: Another synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2B. According to the synthesis, methyl salicylate reacts with ethyl chloroacetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield exclusively or predominantly (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide and 2-haloethanol, the (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) may form (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A), which may undergo potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).

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

Procedure: A synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2A. According to the synthesis, methyl salicylate reacts with ethyl chloro acetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide, (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) opens ethylene oxide resulting (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A) that undergoes potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).

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

Procedure: To a solution of benzofuran-3-yl acetate (8) (100 g, 1.42 mol) in methanol (350 mL) was added diluted (7.5%) H2SO4 (500 mL) at ambient temperature followed by heating to reflux for 1-3 h. The progress of the reaction was monitored by HPLC analysis. Upon completion of the reaction, the reaction mixture was cooled, filtered, and the slurry was washed with water, and vacuum dried to obtain the product meeting the desired specifications. Yield—83-100%. by heating to reflux for 1-3 h Upon completion of the reaction the reaction mixture was cooled filtered the slurry was washed with water, and vacuum dried to obtain the product

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To acetic anhydride (300 mL) was added 2-(carboxymethoxy)benzoic acid (7) (100 g, 0.510 mol) at ambient temperature and heated to 130-140° C. The reaction temperature was maintained for 14-20 h under stirring. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, the reaction mixture was cooled to 50-80° C., acetic anhydride was recovered at 50-80° C. at reduced pressure and the crude product was extracted with dichloromethane (500 mL). The dichloromethane layer was recovered completely to obtain the product meeting the desired specifications. Yield—76-85%. The reaction temperature was maintained for 14-20 h Upon completion of the reaction the reaction mixture was cooled to 50-80° C. acetic anhydride was recovered at 50-80° C. at reduced pressure the crude product was extracted with dichloromethane (500 mL) The dichloromethane layer was recovered completely to obtain the product

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

Procedure: Another synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2B. According to the synthesis, methyl salicylate reacts with ethyl chloroacetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield exclusively or predominantly (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide and 2-haloethanol, the (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) may form (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A), which may undergo potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).

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

Procedure: A synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2A. According to the synthesis, methyl salicylate reacts with ethyl chloro acetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide, (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) opens ethylene oxide resulting (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A) that undergoes potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).