Benzaldehyde → 2-Amino-5-ethylphenol hydrochloride

Participants

Reaction Conditions

Reaction Steps

In a 500-mL 3-necked round bottom flask equipped with a stirrer, thermometer, and 15°-20° C. water bath was placed 40 g (0.264 moles, 1.0 equiv.) of 4-ethylnitrobenzene, 230 mL of methanol, 30 mL of water, 30.8 g (0.2904 moles, 1.1 equiv.) of benzaldehyde, and 36.6 g (0.561 moles, 4.25 equiv.) of zinc powder. The reaction mixture, with vigorous stirring, was cooled to 15°-20° C. and the dropwise addition of 79.2 (1.32 moles, 5.0 equiv.) of acetic acid was begun. The reaction mixture was allowed to exotherm to 34°-36° C., and the temperature was held there throughout the 30 minute addition period. When the addition was complete, the reaction temperature was held at 35° C. with a steam pot for 1 hour. The reaction flask was placed under full aspirator vacuum and the reaction mixture was stripped to about 1/3 volume. Xylene (100 mL) was added to the reaction mixture to azeotrope water from the reaction mixture. This azeotrope step was repeated 2 more times with fresh xylene. The zinc acetate salts were filtered off. The xylene/product liquors were stripped to an oil under aspirator vacuum. Dichloromethane (250 mL) was added to the product oil and cooled to 0° C. Via an addition funnel, 49.6 g (0.273 moles, 1.033 equiv.) of trichloroacetyl chloride was added maintaining the reaction temperature below 20° C. The resulting dark solution was warmed to 25° C. and held here for 15 minutes to form a compound of this invention having Formula (I). Acetic acid (44 mL) was added in one portion, followed by 27 g (0.32 moles, 1 equiv.) of concentrated hydrochloric acid. The reaction mixture was heated, and the low boiling liquid (lower than 50° C.) was distilled off. When the pot temperature reached 78°-80° C. and no more volatile liquids distilled, the reaction was allowed to reflux for 3 hours (at 78°-85° C.). The reaction was cooled to 50° C. and 600 mL of ethyl acetate was added in one portion. The dark solution was stirred and cooled to 15°-20° C. The 2-amino-5-ethylphenol hydrochloride came out of solution slowly. The mixture was stirred at 15°-20° C. for 30 minutes then collected and washed with ethyl acetate and heptane. The fluffy yellow-orange crystals were dried in a warm air oven overnight. The 24.4 g yield of 15 was 53.2% of the theoretical: MP 218° C.±2° C.; HPLC (area %) 78.0%; IR (KBr)16 (OH) 3.0μ and 7.0μ, (--NH2.HCl) 3.9μ and 5.25μ; NMR (DMSO-D6, Me4Si) δ1.1 (t,3H), 2.5 (q,2H), 6.65 (d, 1H), 6.9 (S, 1H), 7.3 (T, 2H), 10 (S, 2H), 10.7 (S, 1H); TLC (1 BuOAc, 2 PhCH3, 4 CHCl3), silica-gel-coated plates, viewed under short-wave UV light, major spot for 15, Rf =0.18.

Provenance & Evidence