Phenacylamine hydrochloride

Checked by William E. Parham, Norman Newman and R. M. Dodson. 

In a thoroughly dry 500-ml., three-necked, round-bottomed flask fitted with a mechanical stirrer, dropping funnel, and a Y-tube containing a calcium chloride drying tube and a thermometer (Note 1) are placed 24.2 g. (26 ml., 0.20 mole) of a-phenyl-ethylamine (Note 2) and 50 ml. of dry benzene (Note 3). The solution is cooled in an ice-salt bath to 5°, and a solution of 44.5 g. (50 ml., 0.41 mole) of lerl-butyl hypochlorite2 (Note 4) in 50 ml. of dry benzene (Note 3) is added at such a rate as to maintain the temperature below 10° (Note 5). After the addition of the tert-butyl hypochlorite solution is complete, the reaction mixture is stirred at room temperature 1-4 hours (Note 6). 

The submitters used di-a-phenylethylamine obtained either from the Eastman Kodak Company or Matheson, Coleman and Bell without further purification. The preparation of dl-a-phenylethylamine has been described previously in Organic Syntheses.14, 

Reagent grade dry benzene is dried by simple distillation, the first 10% of the distillate being discarded. 

The submitters did not redistil the tert-butyl hypochlorite. If it is desired to avoid the use of fer/-butyl hypochlorite, an equivalent quantity of dichloramine B (N,N-dichlorobenzene-sulfonamide, Arapahoe Chemical Co., Boulder, Colorado) may be substituted. This material is soluble in benzene but the benzene-sulfonamide is not therefore the reaction mixture must be filtered just before the addition of the sodium methoxide solution. Using this technique, the submitters obtained 44-52% of phenacylamine hydrochloride. 

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Alternatively, imidazotriazine 491 was prepared [89JCR(S)206] by the thermal cyclization of carbethoxy hydrazone 490, which was prepared from carbaldehyde acetal 489. The latter was prepared by cyclocondensation of the respective phenacylamine hydrochloride with diethoxy acetonitrile in the presence of sodium methoxide. 

Peroxides, test for, 41, 92 Peroxy acids from carboxylic acids and 70% hydrogen peroxide, 43, 96 Peroxybenzoic acid, 43,93 iodometric analysis of, 43, 94 Peroxystearic acid, 43,96 Phenacylamine hydrochloride, 41, 82... 

Phenacylamine hydrochloride has been prepared by (1) the hydrolysis of the quaternary salt obtained from phenacyl bromide and hexamethylenetetramine (the Delepine reaction),6-11 (2) the hydrolysis of N-phenacylphthalimide (the Gabriel reaction),12-14... 

Of the procedures cited in Section 3, procedures (1), (3), and (4) have been examined by the submitters for comparison with the present procedure. Of these, the present procedure and that based on the Delepine reaction (1) appeared to be the most satisfactory for preparative purposes. Yields by the two procedures were comparable however, the Delepine reaction could be run somewhat more conveniently on a larger scale (provided that one was willing to accept a tedious extraction of the product from the copious quantity of ammonium salts with which it is mixed). The Delepine reaction also makes a lesser demand on the skill and technique of the operator. On the other hand, attempts in the submitters laboratory to extend the Delepine reaction to sec-bromides have been unsuccessful therefore the Delepine reaction appears to lack the generality of the present procedure, which shares such generality, apparently, with procedures (2), (3), (7). and (8). Furthermore, the Delepine reaction gives a mixture of phenacylamine hydrochloride and hydrobromide M0 (although the submitters have found that by careful fractional crystallization from isopropyl alcohol-hydrochloric acid solution about 50% of the pure hydrochloride can be obtained). 

Taking advantage of an intramolecular Wittig reaction, the a-amidoketones 316 underwent annulation to the 3-pyrrolines 317 upon treatment with the ylide 318 <199581151>. These intermediates could be further elaborated to the pyrroles 319 by base-induced elimination of benzenesulfinic acid (Scheme 37) <2000TL8969>. It should also be mentioned that a set of unusual 3-pyrroline-2-ones have been synthesized by Ugi s four-component reactions from phenacylamine hydrochloride, cyanoacetic acid, cyclohexyl isocyanide, and aldehydes, involving final formation of the C(3)-C(4) bond <1999H(50)463>. 

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