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Patented July 15, 1952 Dog +H:0 Patented July 15, 1952 2,603,661 2,603,661 LEUCKART syNTHESIS William F. Bruce, Havertown, Pa., and Wincent J. Webers, Racine, Wis., assignors to Wyeth Incorporated, Philadelphia, Pa., a corporation. of Delaware Application August 19, 1948, Serial No. 45,207 Claims. (C. 260-562) 2 The invention relates to the preparation of The reaction may be postulated by the follow formylamino and amino derivatives and more ing equations: . ". particularly involves a catalytic process for ob R R. taining formylamino compounds by the reaction of a ketOne and a formamide. 5 c=o + NERCHO Dog . The preparation of certain commercially im R77 ; : R N+HRCHIO (i) portant amines has heretofore depended to a great extent on the utilization of the Well-known R oH R oH . Leuckart reaction. This reaction, as first re Nc4 ' , , -m--> c ported in the literature, involved the use of am 10 R? YHRCHO R?. monium formate, which with benzophenone R OF formed. N-benzhydryl formamide. The latter compound when hydrolyzed formed the corre Yo +NHR-Cho - sponding amine. Subsequent to the disclosure of R?. YRCHO this reaction a great many ketones have been 5 . R. H. - - - - - - - - tried and found to proceed as with benzophe - So +NH.R+ co, none. The Leuckart reaction has therefore been R?. YRCho (3) adapted to the preparation of important physiol ogically active amines, such as the Sympatho 20 R H Hydrolysis mimetic amines, by selecting the proper ketone Dog +H:0 "..." for the reaction. As an example, if one starts R. NRCHO - With phenylacetone, the final hydrolysis of the . R E formamide product will yield the central ner Y/ " . vous stimulating compound, amphetamine. An 25 R? YHRacid + HcooH important advantage of the Leuckart reaction is . (4) essentially in the relative simplicity of the reac - In the above formulae, R is intended to repre tion. However, certain inherent difficulties in sent either hydrogen or lower alkyl radicals, pref carrying out this reaction have been a spur to erably a methyl or ethyl group, while R and R' seeking other methods for preparing important 30 may represent either alkyl, aryl, -aralkyl or Sub amines. stituted aryl or aralkyl radicals. Substituents The primary disadvantage of the Leuckart for hydrogen atoms in the latter case may be process and the chief reason for seeking other alkyl, alkoxy, nitro or halogen radicals as de methods of amine preparation is the requirement 35 sired, or in fact any substituent which does not for ammonium formate. Because of its insta interfere in the reaction. bility, this reagent is not known to be commer The reaction for the formation of formyl cially available and therefore is prepared only for amino products, as indicated above, is catalyzed immediate use. Moreover, the preparation of in the presence of a selected salt of a relatively ammonium formate is involved and difficult to 40 strong acid and moderately strong to a relatively weak base. Thus, bases of the group I metals carry out on a relatively large scale. are excluded because they are strong bases in This invention involves the discovery of a contradistinction to the bases of the group II. method for reacting ketones with commercially metals which form moderately strong bases. available and easily obtainable formamide or 45 The cation component of the catalyst may be simple formamide derivatives and completely either metallic or non-metallic but preferably it avoiding the necessity for using ammonium for is a di- and tri-valent metal and more preferably, mate, by carrying out the reaction catalytically. a di- and tri-valent metal selected from the The yields obtained by following this newly dis Second or third groups of the periodic table. The covered process are in many cases as high or 50 effectiveness of the catalyst is believed to be higher than that achieved by the standard based on its ability to furnish either a proton Leuckart reaction. In some cases where the or the equivalent of it, such as single or multiple yields are somewhat lower, the benefits derived positively charged metallic or non-metallic ions. by avoiding the use of ammonium formate more However it should be clearly understood that than adequately compensate for the lower yields. 55 the invention is not to be limited to this theo 2,603,661 3 4. rical reason for the mode of action advanced carbonate sublimed into the reflux condenser, as a possible explanation. and ammonia, and carbon dioxide were evolved. It has been found that best results are Ob At exactly four hours after boiling started, the tained if the catalyst selected is appreciably flask was removed from the oil bath, allowed to Soluble in the reactants and does not completely 5 cool to about 140, and cautiously poured into precipitate out of Solution during the reaction. The preferred, catalytic salts may be obtained about 200 cc. of cold water. (If it was cooled by reacting a di- or tri-Valent metal or metal salt much below 1308; the formyl; derivative crystal or hydroxide With strong mineral or organic lized, and removal from the flask was difficult.) acids such as the halogen acids, as for example, 10, andThe theflask mixture was washed of benzophenone, out with a N-benzhydryl little water, hydrochloric, hydrobromic, hydroiodic acids; the formamide, and water soluble Substances was strong sulfur acids such as sulfuric, chlorosult - - cooled, seeded with a crystal of benzophenone, fonic and sulfamic acids; and such strong or and the mixture of solids collected on a Buchner ganic acids as formic, the mono-dir..and tric * funnel, washed with a little water, and dried. halogenated acetic acids, citric, etc. 3. The amount of benzophenone and of N-benz The ketonic reactant selected for the reaction hydryl formamide in the mixture of Solids was depends in large measure on the-particular amino. determined by distillation in vacuo without a col compound desired as the final product, the ke umn. Benzophenone boils at 114 at 1.2 mm., but tone being represented by the general: formula . was collected at 120-130° in order to speed up the 20 distillation. When the benzophenone was all R-CO-R.' gone, the boiling point rose rapidly, at 160 the where R', and R' represent the radicals as indi receiver changed, and then the remaining formyl cated previously. Among the particular ketones derivative was distilled with strong enough heat which may be reacted and from which one may ing to prevent.crystallization in the side arm of obtain substantial yields of the formyl deriva the flask. The amide boils. at 173 at.1.2 mm., tives may be mentioned benzophenone; benzyl but as before, it saved, time to collect.it at 185 acetophenone; 4-methylpentanone-2; 4-methyl 1909. A small amount of tar. (about a gram) re hexanone-2; 4-ethylhexanone-2; heptanone-2; mained in the Claisen flask. A yield of 95.6% 4- and 6-methylheptanone-2; phenylacetone; benzhydrylformamide was thus obtained. fluorenone; camphor; 1-methyl-1-phenylace 30 . EXAMPEI. tone; and in fact any ketone can be used which has been. Successfully reacted by the standard A reaction as described in Example. I was car Leuckart reaction depending-on ammonium for ried out with pure formamide (99%) but without mate as the reactant. a catalyst, 45 grams, of benzophenone and 55 cc. The temperature: conditions for the reaction 35 of formamide being used. The temperature was may range from about 120° to about 200° C. with held at about 200° C. (bath temperature) with a temperature of about 170-190° C. preferred. an inside temperature-of-187° C. The yield-of Concerning the amounts of reactants, an excess benzhydrylformamide was found to be 21.7%. of the formamide is preferred, with a ratio of about 6 moles of the formamide to about one mol 40 EXAMPLE III . of the ketone particularly preferred. The reac 110 cc. formamide-and-53.g. of methyl isobutyl tion is generally carried out under atmospheric ketone were placed in a 200 cc. acetylation flask preSSure conditions although higher pressures having an air-condenser. To the flask was also. may of course be used if desired. Pressures added 0.4.g. of magnesium-carbonate mixed with higher than atmospheric are required if the ke 0.8 g. of chloroacetic acid (equivalent to 1 gram tone used boils below the reaction temperature. of magnesium chloroacetate). The flask was In order to avoid degradation of the reactants heated in a wax bath and air was displaced with and the product, -oxygen must be substantially inert gas. Refluxing became vigorous at 160°C. completely excluded from the reaction. This is and-the-temperature was slowly raised to 1908. C. best done by passing an inert gas such as nitros, 50 over about 4 hours. The reaction mixture was gen, hydrogen, carbon monoxide or carbon diox washed with ether, and the ether was evaporated ide-continuously.through the reaction:zone dur-, on a steam bath. The ether extract was now, vacuum...distilled. Some, ketone still remaining ing the heating operation: It has been found that substantial yields. may be 3 obtained. With a distilled over at 30-35 C. at 6 mm. The main reaction time of about, 2 to about 24 hours: Ehe 55 fraction distilled oyer, at 75-81. C. at 4 mm. This amount of catalyst necessary; for the reaction is was 2-formanidor 4-methylpentane. Its refrac-. not critical. Thus,.a.s.little as 0.05mol; of cata tive-index at 20° C. was 14528. It was then mixed lyst has-been used permol of ketone reactant, but with hydrochloric acid which resulted in the for larger amounts have also been used effectively..
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