3-chloro-2-methylbenzaldehyde

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

Procedure: A warm solution of 1.5 gm. (0.01 mole) of 6-chloro-o-tolualdehyde in 15 ml. of ethanol was stirred into a solution of 1.1 gm. (0.010 equiv.) of carboxymethoxylamine hemihydrochloride and 1.3 gm. (0.016 equivs.) of anhyd. sodium acetate in 15 ml. water. After heating a half hour on the steam bath, the reaction mixture was cooled and adjusted to pH 8 with 5% aqueous sodium hydroxide. The mixture was extracted with ether, and the ether extract was discarded. The alkaline-aqueous phase was then adjusted to pH 5 with hydrochloric acid and was evaporated to 25 ml. volume. It was then acidified to pH 1.5-2.0 with cooling in ice bath. The solid was removed by filtration, was washed with cold water, and was dried in air to obtain 1.5 gm. (68%) of crude product melting at 121°-6° C. Recrystallization from aqueous-ethanol yielded 1.4 gm. of product melting at 124°-7° C. (dried at 65° C. in vacuo). After heating a half hour on the steam bath the reaction mixture was cooled The mixture was extracted with ether the ether extract was evaporated to 25 ml with cooling in ice bath The solid was removed by filtration was washed with cold water was dried in air to obtain 1.5 gm Recrystallization from aqueous-ethanol yielded 1.4 gm

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

Procedure: A warm solution of 1.5 gm. (0.01 mole) of 6-chloro-o-tolualdehyde in 15 ml. of ethanol was stirred into a solution of 1.1 gm. (0.010 equiv.) of carboxymethoxylamine hemihydrochloride and 1.3 gm. (0.016 equivs.) of anhyd. sodium acetate in 15 ml. water. After heating a half hour on the steam bath, the reaction mixture was cooled and adjusted to pH 8 with 5% aqueous sodium hydroxide. The mixture was extracted with ether, and the ether extract was discarded. The alkaline-aqueous phase was then adjusted to pH 5 with hydrochloric acid and was evaporated to 25 ml. volume. It was then acidified to pH 1.5-2.0 with cooling in ice bath. The solid was removed by filtration, was washed with cold water, and was dried in air to obtain 1.5 gm. (68%) of crude product melting at 121°-6° C. Recrystallization from aqueous-ethanol yielded 1.4 gm. of product melting at 124°-7° C. (dried at 65° C. in vacuo). After heating a half hour on the steam bath the reaction mixture was cooled The mixture was extracted with ether the ether extract was evaporated to 25 ml with cooling in ice bath The solid was removed by filtration was washed with cold water was dried in air to obtain 1.5 gm Recrystallization from aqueous-ethanol yielded 1.4 gm

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

Procedure: The title compound was prepared from 3-chloro-2-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 1.

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

Procedure: A mixture of (2-methoxy-2-oxoethyl)triphenylphosphonium bromide (10.0 g, 24.08 mmol) in 100 mL DCM, 50 mL water and NaOH (10 N) (4.82 ml, 48.2 mmol) was vigorously shaken in a separatory funnel. The organic layer was separated and the aqueous phase was extracted with DCM. The combined organic layers were dried (MgSO4) and concentrated to give methyl 2-(triphenylphosphoranylidene)acetate (7.5 g, 93% yield) as a white solid. A solution of 3-chloro-2-methylbenzaldehyde (0.7 g, 4.53 mmol) and 2-(triphenylphosphoranylidene)acetate (1.817 g, 5.43 mmol) in MeOH (22.6 ml) was stirred at room temperature for 2 h. The mixture was concentrated and purified by flash chromatography (0-30% ethyl acetate:hexanes) to afford the title compound (0.23 g, 24% yield) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=15.9 Hz, 1H), 7.47-7.40 (m, 2H), 7.17-7.15 (m, 1H), 6.33 (d, J=15.9 Hz, 1H), 3.83 (s, 3H), 2.48 (s, 3H). The mixture was concentrated purified by flash chromatography (0-30% ethyl acetate:hexanes)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyltriphenylphosphonium bromide (6.9 g, 0.019M) was suspended in dry tetrahydrofuran (100 ml) at -40° C. under an atmosphere of dry nitrogen. n-Butyllithium (13.5 ml. of a 1.55M solution in hexane, 0.021M) was added dropwise during 10 minutes and the mixture was stirred at -40° C. for 30 minutes. 3-Chloro-2-methylbenzaldehyde (3.0 g, 0.019M) in dry tetrahydrofuran (10 mls) was then added. The mixture was maintained at -40° C. for 30 minutes and then allowed to warm to room temperature. Hexane (150 ml) was added and the mixture was filtered. The hexane was evaporated to give crude 3-chloro-2-methylstyrene which was used directly without further purification. The mixture was maintained at -40° C. for 30 minutes to warm to room temperature the mixture was filtered The hexane was evaporated

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

Procedure: A warm solution of 1.5 gm. (0.01 mole) of 6-chloro-o-tolualdehyde in 15 ml. of ethanol was stirred into a solution of 1.1 gm. (0.010 equiv.) of carboxymethoxylamine hemihydrochloride and 1.3 gm. (0.016 equivs.) of anhyd. sodium acetate in 15 ml. water. After heating a half hour on the steam bath, the reaction mixture was cooled and adjusted to pH 8 with 5% aqueous sodium hydroxide. The mixture was extracted with ether, and the ether extract was discarded. The alkaline-aqueous phase was then adjusted to pH 5 with hydrochloric acid and was evaporated to 25 ml. volume. It was then acidified to pH 1.5-2.0 with cooling in ice bath. The solid was removed by filtration, was washed with cold water, and was dried in air to obtain 1.5 gm. (68%) of crude product melting at 121°-6° C. Recrystallization from aqueous-ethanol yielded 1.4 gm. of product melting at 124°-7° C. (dried at 65° C. in vacuo). After heating a half hour on the steam bath the reaction mixture was cooled The mixture was extracted with ether the ether extract was evaporated to 25 ml with cooling in ice bath The solid was removed by filtration was washed with cold water was dried in air to obtain 1.5 gm Recrystallization from aqueous-ethanol yielded 1.4 gm

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

Procedure: The title compound was prepared from 3-chloro-2-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 1.