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A new method of obtaining secondary amines, based on the Leuckart synthesis, is described. It has been applied to the preparation of several old and new amines.
The Leuckart synthesis1 of primary amines by heating ketones with formamide or ammonium formate has been improved by Ingersoll and co-workers2. Needing several secondary ß-phenylethylamines for pharmacological assays, we varied the Ingersoll adaptation by using the corresponding alkylformamides, and obtained the desired amines, as formyl derivatives, by the general equation:
RCOR' + 2 HCONHR" → NH2R" + RCH(NR"COH)R' + CO2
This method has been applied by Wallach3 to certain alicyclic and terpenoid ketones, but, curiously enough, has been used very little by others. The advantages of simplicity and economy are evident, but possibly have been outweighed, as Ingersoll suggests, by the troublesome procedure, low yields, and formation of secondary and tertiary amines as by-products.
We have found that this method of obtaining secondary amines is general and satisfactory, giving 50-80% yields based on the ketone, taken in 0.01 to 1 mole lots. Excess of alkylformamide is used (4 moles to 1 of ketone) but the excess is recovered. The secondary amines are obtained directly as hydrochlorides, and are very pure, with no tertiary derivative.
| Ketones | Amines |
Secondary amine obtained | Yield |
mp°C (HCl) |
| Acetophenone | Methyl |
dl-Methyl-α-phenethyla | 60% | 178-179 |
| p-Methylacetophenone | Methyl | dl-Methyl-α-p-methylphenethyl | 50% | 159-160 |
| p-Chloroacetophenone | Methyl | dl-Methyl-α-p-chlorophenethyl | 70% | 199-200 |
| p-Bromoacetophenone | Methyl | dl-Methyl-α-p-bromophenethyl | 70% | 196-197 |
| Acetophenone | Ethyl |
dl-Ethyl-α-phenethylb | 70% | 199-200 |
| p-Methylacetophenone | Ethyl | dl-Ethyl-α-p-methylphenethyl | 60% | 217-218 |
| p-Chloroacetophenone | Ethyl | dl-Ethyl-α-p-chlorophenethyl | 80% | <250 |
| p-Bromoacetophenone | Ethyl | dl-Ethyl-α-p-bromophenethyl | 60% | <250 |
| Acetophenone | Butyl | dl-Butyl-α-phenethyl | 70% | 154-155 |
| p-Methylacetophenone | Butyl | dl-Butyl-α-p-methylphenethyl | 50% | 159-160 |
| p-Chloroacetophenone | Butyl | dl-Butyl-α-p-chlorophenethyl | 80% | 174-175 |
| p-Bromoacetophenone | Butyl | dl-Butyl-α-p-bromophenethyl | 70% | 174-175 |
a. As the N-alkyl-formamides. b. Lit.4 mp 173°C. c. Lit.4 mp 201°C.
In this paper we describe a number of newly prepared amines and some others previously made only by more complicated procedures. The methyl and ethyl derivatives of phenethylamine were obtained by Busch and Lefhelm4 from benzalmethyl- amine and methyl- or ethylmagnesium iodide.
The formyl derivatives were not isolated but were hydrolyzed directly by refluxing with hydrochloric acid. In later papers we hope to discuss the little known mechanism of the Leuckart synthesis and describe a new series of secondary amines from ß-phenylethylamines.
Table I summarizes the melting points and analyses of the various hydrochlorides.
General Method
In a distilling flask fitted with a cork bearing a thermometer extending nearly to the bottom is placed 4 moles of alkylammonium formate prepared by adding the proper amine to cold formic acid. The temperature is raised slowly to 180-190°C and this temperature maintained as long as water distils. After cooling, 1 mole of ketone is added and the mixture heated until boiling begins; water, carbon dioxide, and amine distil and are collected in concentrated hydrochloric acid. In case any ketone distils over, it is returned to the flask at intervals. The temperature of the boiling mixture is 190-230°C, which is maintained for four to eight hours, after which the mixture is cooled and diluted with 3-4 volumes of water, giving oily and aqueous layers. The aqueous layer, mixed with the hydrochloric acid used in collecting the distilled amine, is concentrated to give the hydrochloride of the excess of amine used. The oil is refluxed for several hours with 150-200mL of hydrochloric acid per mole of ketone taken, and after the hydrolysis is complete water is added, the solution filtered through moist paper to separate resinified material and the filtrate, if not clear, extracted once or twice with ether. In some experiments the amine hydrochloride crystallizes on cooling. The aqueous solution is made alkaline with ammonia, extracted with ether, the ether solution dried with sodium sulfate and saturated with hydrogen chloride to give the amine hydrochloride. The product is purified further by dissolving in absolute alcohol and precipitating with absolute ether.