Here is a reference that might interest somebee's?
Synthesis of alkyl-substituted 1-(alkyloxyphenyl)ethylamines.
McCoubrey, A.
J. Pharm. and Pharmacol. (1956), 8 648-52.
Abstract
cf. C.A. 46, 9068f. Me, Et, and Pr derivs. of 1-(p-cyclohexyloxyphenyl)ethylamine (I) were readily prepd., but amyl and hexyl derivs. could not be synthesized. The allyl ether of dihydromorphine (prisms from petr. ether, m. 77-8°) was rearranged by boiling in diethylaniline, the alkali-sol. product was hydrogenated to 2-propyldihydromorphine (95%), prisms from petr. ether, m. 99°. 4-Hydroxy-3-methylacetophenone gave the cyclohexyl ether (16%), b0.4 145-50°; 2,4-dinitrophenylhydrazone, red needles from EtAcO-EtOH, m. 181°. Huang-Minlon reduction of 5-bromo-2-hydroxyacetophenone gave 4-bromo-2-ethylphenol (II) (75%), b22 160-70°; a-naphthylurethan deriv., red needles from C6H6, m. 140°. The cyclohexyl ether (16%), b16 210-12°, of II was converted to the Grignard reagent and added to Ac2O at -70° to give 4-cyclohexyloxy-3-ethylacetophenone, b3 190-2° (2,4-dinitrophenylhydrazone, red needles from EtAcO, m. 152°). The same ketone was prepd. by acetylation of o-ethylphenol. The product yielded on fractional distn. 3-ethyl-4-hydroxyacetophenone, b1 170-80°, m. 95°. 3-Allyl-4-hydroxyacetophenone reduced over Pd-C gave 4-hydroxy-3-propylacetophenone, prisms from C6H6EtOH, m. 89-90°; the cyclohexyl ether (14%), b0.3 145-50° (2.4-dinitrophenylhydrazone, red needles from EtOAcEtOH, m. 141°). 3-Cyclohexyloxy-4-hydroxyacetophenone formed an allyl ether which rearranged to 3-allyl-5-cyclohexyloxy-4-hydroxyacetophenone (69%), b0.6 170-80°, needles from petr. ether, m. 58°. 4-Benzyloxy-3-hydroxyacetophenone gave the n-hexyl ether (77%), plates from petr. ether, m. 74°, which was debenzylated (Pd-C) to 3-n-hexyloxy-4-hydroxyacetophenone (III) (89%), needles from petr. ether, m. 48°. The crude allyl ether of III heated 35 min. at 200° gave 3-allyl-5-n-hexyloxy-4-hydroxyacetophenone (47%) b0.9 175-80°, needles from petr. ether then EtOH, m. 83°. p-Bromophenyl caproate (5 g.), b2 125-30° mixed with AlCl3 (5 g.) in tetrachloroethane, then heated 30 min. at 120° gave 4-bromo-2-caproylphenol (80%), b1 145-50°, plates from petr. ether, m. 58-9° (2,4-dinitrophenylhydrazone, orange needles from EtOAc, m. 206°), was reduced with hydrazine to 4-bromo-2-n-hexylphenol (86%), b1 125-45°, needles from petr. ether, m. 52%. 2-Bromo-4-n-hexylphenylcyclohexyl ether (16%), b0.5 195-200° slowly treated with Mg in boiling Et2O, then treated with Ac2O at -70° gave a trace of ketone isolated as the 2,4-dinitrophenylhydrazone (not purified). p-Bromophenylvalerate gave 4-bromo-2-valeroylphenol (45%), b1 120-1° (2,4-dinitrophenylhydrazone, red plates from EtOAc, m. 231°). 2-n-Amyl-4-bromophenol, needles from petr. ether, m. 30°. Amines were prepd. by reduction of the corresponding acetophenone oximes. The following 3,4,5-RR'R''C6H2C(:NOH)Me (IV) and 3,4,5-RR'R''C6H2CHMeNH2 (V) were prepd. (R, R', R'', m.p. of IV, and m.p. of V.HCl given): cyclohexyloxy, HO, allyl, 107°, 175°; n-hexyloxy, OH, allyl, 85°, 148°; H, cyclohexyloxy, Me, 100°, 202° (free base, b1 140-5°); H, cyclohexyloxy, Et, 121°, 226° (free base, b2 150-60°); H, cyclohexyloxy, Pr, 114°, 169°. Introduction of alkyl groups into the C6H6 ring of 1-(p-cyclohexyloxyphenyl)ethylamine or of dihydromorphine abolished their analgesic activity. 1-(3-Cyclohexyloxy-4-hydroxy-5-propylphenyl)ethylamine had analgesic activity in rats, but was very toxic.
Do Your Part To Win The War
