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Phenylpropanolamines from Propenylbenzenes

A. W. Langman and D. R. Dalton
Erythro-Bromohydrins from Alkenes and N-Bromosuccinimide in Dimethyl Sulfoxide
Organic Syntheses, Coll. Vol. 6, p. 184

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Propenylbenzene to 1-Phenyl-2-Bromo-1-Propanol

Place in 1 L RB flask 37 ml (35 g) propenylbenzene (bp 69°C at 13mmHg), then 250 ml of DMSO, add 15 ml H2O, and with stirring, add 106 g of N-bromosuccinimide* in small portions during 15 min. A yellow color appears when NBS is added, and by the time the addition is complete, the color is bright-orange. During the addition temp rose up to 50°C. Stir another 15 min, then pour into 1 L of cold water and 3-5 times extract with 100-ml portions of ether. The combined etheral extracts washed water, then NaCl soln, extract dried over MgSO4 and ether was distilled off. Obtained 70 g of the bromohydrin as a yellow oil.

trans-Propenylbenzene yields (S*,S*)-erythro-1-phenyl-2-bromo-1-propanol (92%), and cis-propenylbenzene yields (R*,S*)-threo-1-phenyl-2-bromo-1-propanol (95%)


1-Phenyl-2-Bromo-1-Propanol to Phenylpropanolamine (PPA)

(Assholium's voice:) Dissolve the bromohydrin in 100 ml of methanol. Saturate 400 ml of methanol with ammonia at -10°C (bubble ammonia until volume grows with 50%, up to 550-600 ml). Mix methanolic soln of bromohydrin with ammonia soln, place it in sealed bomb and heat at 110-120°C 4-5 hrs. After cooling open it carefully (ammonia evolution!), pour in 1 L glass (careful, please - mixture foamy as freshly-opened champagne) and allow main quantities of ammonia evolve on a slowly heated water bath. Distill off methanol and obtained semi-cryst oil dissolve in 300 ml of 20% HCl. Wash milky soln twice with hexane, basify and extract PPA with methylene chloride (3x100 portions). Dry with Na2SO4, and remove solvent. Result - about 42 g of oil, cryst on chilling with mp 53-55°C. Conversion is 92%.

* Commercial N-Bromosuccinimide was used without purification. If the purity of the N-bromosuccinimide is in doubt, it should be titrated before use by the standard iodide–thiosulfate method and purified, if necessary, by recrystallization from 10 times its weight of water [Fieser & Fieser, "Reagents for Organic Synthesis," Vol. 1, p. 78 (1967)]. Solutions of N-bromosuccinimide in dimethyl sulfoxide cannot be stored, since the solvent is oxidized by the brominating reagent.