[CONTRIBUTION FROM THE
NATIONAL INSTITUTE
OF HEALTH]
OBSERVATIONS ON THE MANNICH REACTION EDWARD M. FRY Received March 86, 1945
The Mannich reaction, the condensation of compounds having a reactive hydrogen atom with formaldehyde and the hydrochlorides of primary amines, secondary amines, or ammonia has heretofore been effected in aqueous media, methanol, ethanol, isoamyl alcohol, or an excess of one of the reactants (1). The use of nitrobenzene and benzene as solvents has also proved effective, giving satisfactory yields in a relatively short reaction time. Although the condensations reported in this paper were made with the purpose of getting the compound rather than to test the effectiveness of the method, a few comparison runs in alcohol indicated that the new solvents may be superior in some cases to the old, and as no further investigation along these lines is contemplated, the results are submitted as they stand. Identity of new compounds was established in most cases by analyses of the corresponding amino alcohols which will be reported later (2). The symmetrical dialkylamine hydrochlorides from dimethyl- to dihexylamine hydrochloride were condensed with paraformaldehyde and the ketones P-acetotetrah, methyl a-naphthyl ketone, methyl P-naphthyl ketone, acetophenone, 9-acetylanthracene, indanone-l , and 9- or 10-bromo-3-acetylphenanthrene. The apparatus used was a two-neck flask equipped with a sealed stirrer and a condenser with a cooling jacket extending to its tip. This construction facilitated scraping back into the reaction the distilled formaldehyde polymer which often collected in the early stages of a condensation. In order to prevent this condensation on the other neck of the Bask, the condenser neck was a t a lower level. Equivalent amounts of the ketone and secondary amine hydrochloride with an excess of paraformaldehyde and a small amount of concentrated hydrochloric acid (based on the paraformaldehyde) were refluxed in the solvent (bath temperature about 110"); the course of the reaction was marked by solution of the components and in certain cases by the cessation of polymer condensation. Prolonged refluxing may result in decomposition of the amino ketone hydrochloride and the liberated amine hydrochloride may recrystallize from the solution. This was an effect observed with the higher amine salts. The amine hydrochlorides lower than dibutylamine hydrochloride were condensed in a 1:1 benzene-nitrobenzene mixture. The nitrobenzene has valuable solvent properties and may aid in the formation of a complex between the amine hydrochloride and formaldehyde. (See the dimethylamine indanone condensation below.) These lower amino ketone hydrochlorides were stable under the conditions of the reaction and were water-soluble, hence it was desirable to distill the water a t the end of the reaction. This was done by inserting 259
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EDWARD M. FRY
a small water collector between the flask and condenser, and raising the bath temperature to about 145". In the case of amines higher than &butylamine hydrochloride, it was found disadvantageous to use nitrobenzene in the solvent. Its solvent action is no longer needed as these amine hydrochlorides are moderately soluble in hot benzene. Its use also seems to favor the amine splitting which takes place fairly easily with the higher amino ketone hydrochlorides. [The yield of 1-(3-dihexyIamino-1-oxo-propy1)naphthalenedropped from 40% in benzene to 8% in nitrobenzene.] Because of the inadvisbility of heating any longer than necessary due to this splitting-tendency [see 2-(3-dihexylamino-l-oxo-propyl)naphthalene hydrochloride below], water was not removed a t the end of these condensations. It cannot be removed as it forms because of the accompanying removal of formaldehyde. I n one case [see 9-(3-diainylamino-l-oxo-propyl)anthracene below], the yield was improved by heating for only 15 minutes, unreacted components being recovered. On cooling the solution, any amine hydrochloride present usually crystallized first, the product being subsequently forced out by further chilling and by the addition of dry ether, or in some cases by removing the solvent under reduced pressure before inducing crystallization of the product. EXPERIMENTAL
Analyses of amino alcohols derived from most of the previously unreported amino ketones described below will be given i n another paper (2). 3-(Piperidino-1-oxo-propylbenzenehydrochloride. Three and one-tenth grams of acetophenone, 3 g. of piperidine hydrochloride, 1.5 g. of paraformaldehyde (2 molecular equivalents), and 0.1 cc. of concentrated hydrochloric acid in 7.5cc. of nitrobenzene and 7.5 cc. of benzene were brought t o reflux. I n 10 minutes almost all of the solid had gone into solution and a crystalline precipitate began t o form. The total reaction time waa 53 minutes, water being removed the last 23 minutes. The purified product weighed 5.45 g. (83%); m.p. 190192". The yield is 80% using alcohol as the solvent (3). 6-(3-Dimethylamino-l-oxo-propyl)-l,8, I,&-tetrahydronaphthalene hydrochloride. Four and thirty-five hundredths grams of 6-aceto-l,2,3,4-tetrahydronaphthalene, 2.05 g. of dimethylamine hydrochloride, 0.9 g. of paraformaldehyde (1.2molecular equivalents), and 0.05 cc. of concentrated HC1 in 7 cc. of nitrobenzene and 7 cc. of benzene were refluxed for 45 minutes, water being removed during the last 15 minutes. Purified from absolute ethanol-ether, the product weighed 3.9 g. (59%) and melted at 158-163'. Prepared in alcohol according t o Mannich (4) i t was obtained i n 47y0yield, m.p. 160-168'. The original paper gives the m.p. 170" but states no yield. 6-(S-Diethylame'~~-l-oxo-propyl)-l,8,I,/t-tetrahydronaphthraEene hydrochloride. The crude product was obtained crystalline from a n acetone solution in 86% yield. It was prepared as above with a 60 minute reaction time. When this condensation was run i n alcohol for 3.5 hours at reflux temperature, 52% of the starting ketone was recovered. The yield was 65% crude product batied on the unrecovered ketone, 2-(3-Dimethylamino-1-oxo-propy1)naphthalenehydrochloride. Sixteen and one-tenth grams of methyl @-naphthyl ketone, 7.72 g. of dimethylamine hydrochloride, 3.13 g. of paraformaldehyde (1.1 molecular equivalents), and 0.16 cc. of concentrated HCl in 20 cc. of benzene and 20 cc. of nitrobenzene were refluxed for 63 minutes, water being collected during the last 35 minutes. The product was recrystallized from absolute ethanol; wt. 18.4 g. (73.6%), m.p. 171-172.5'. Previously reported (5) in 69% yield, m.p. 153-154'.
OBSERVATIONS ON THE ErfANNICH REACTION
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2-(3-Diamylanaino-l-ozo-propyl)naphthalent? hydrochloride. Thirteen and six-tenths grams of methyl 6-naphthyl ketone, 15.4 g. of: diamylamine hydrochloride, 2.63 g. of paraformaldehyde (1.1 molecular equivalents), and 0.13 cc. of concentrated HCl i n 30 cc. of benzene were refluxed 70 minutes. Water was not removed. One and eight-tenths grams of amine hydrochloride and approximately 2 g. of the starting ketone were recovered. The product was recrystallized by adding dry ether t o a benzene solution; wt. 20.8 g. (69.3'%), m.p. 11C118". 2-(3-Dihexylamino-l-oxo-propyl)naphthalen~ hydrochloride. Seven and seven-tenths grams of dihexylamine hydrochloride, 5.92 g. of methyl 8-naphthyl ketone, 1.15 g. of paraformaldehyde (1.1 molecular equivalents), and 0.06 cc. of concentrated HC1 i n 25 cc. of benzene were refluxed for 32 minutes. Two and nine-tenths grams of amine hydrochloride and 2.45 g. of starting ketone were recovered. The product was purified by adding dry ether t o a benzene solution; wt. 6.75 g., m.p. 1.10-113". On the basis of ketone reacted the yield is S270. Judging from recovered dihexylamine hydrochloride, this amino ketone hydrochloride was 64y0 decomposed by refluxing for 145 minutes in benzene. TWOand three-tenths grams of methyl &naphthyl ketone, 3 g. of dihexylamine hydrochloride, 0.6 g. of paraformaldehyde (1.5 n~olecularequivalents), and 0.03 cc. of concentrated €IC1 in solution in i o cc. of absolute ethanol were refluxed for 3 hours; 2.55 g. of amine hydrochloride and 1.5 g. of starting ketone were recovered. S o amino ketone hydrochloride was isolated. 1 - (3-Dihexylamino-l-oxo-propyl)naphthalent~ hydrochloride. Twelve and sixty-five hundredths grams of methyl a-naphthyl ketone, 16.45 g. of dihexylamine hydrochloride, 2.45 g. (1.I molecular equivalents) of paraformaldehyde, and 0.12 cc. of concentrated HCl were refluxed for 55 minutes i n 30 cc. of benzene. Three and six-tenths grams of amine hydrochloride was recovered. The product was recrystallized by adding dry ether t o a benzene solution; wt. 11.9 g. (39.77,); m.p. 80-83". When this condensation was run in nitrobenzene at 100-107" for 24 minutes (amine hydrochloride began t o separate from solution a t this time), the recovered amine hydrochloride amounted to 67% and t,he amino ketonc hydrochloride to 7.676. Dirnefh~lann.inometliy1-2-indr;none-1.Five and eighty-five hundredt,hs grams of indanone-!, 3.61 g. of dimethylamine hydrochloride, 1.16 g. of paraformaldehyde (1.1 molecular equivalents), and 0.07 cc. of concentrated HCI in 8 cc. of benzene and 8 cc. of nitrobenzene were refluxed for 31 minutes, water being removed during the last 12 minutes. The aniino ketone hydrochloride \vas recrystallized by adding ether t o its so1ut)ionin alcohol; a't. 3.75 g. (37.59&),m.p. 143-145.5". This condensation was repeated. The amine hydrochloride, paraformaldehyde, and acid were refluxed in the benzene-nitrobenzene solvent. A heavy, oily solid first formed, changing t o a light-bodied oil in about 10 minutes. I n 10 more minutes the indanone was added. Within 3 minutes after the resumption of refluxing, an oil separated and soon crystallized. Refluxing was continued for 30 lfiinutes after adding the indanone, water being removed during the last 12 minutes. Bfter purificat,ion the product weighed 6.4 g. (G49:,), m.p. 144-145". 9- (9-Dinrethylamino-1-oxo-propy1)anthracene hydrochloride. One and three-tenths grams of dimethylamine hydrochloride, 0.53 g. of paraformaldehyde (1.1 molecular equivalents), and 0.03 cc. of concentrated HCI were refluxed i n 7 cc. of nitrobenzene and 7 cc. of benzene until a light-bodied oil had formed in the solvent. Three and five-tenths grams of 9-acetylanthracene was added and refluxing continued for 2 hours, water being removed during t h e last 8 minutes. Some amine hydrochloride was removed. The product was recrystallized by adding dry ether t o its solution in absolute ethanol; n t . 2.0 g. (4ooj0), m.p. 156-160". 9-(S-Diamylamino-l-oxo-propyZ)anthracenehydrochloride. Seventy-seven and fourtenths grams of 9-acetylanthracene, 68.0 g. of diamylamine hydrochloride, 11.6 g. of parnformaldehyde (1.1 molecular equivalents), and 0.58 cc. of concentrat'ed HCl i n 230 cc. of benzene were refluxed for 15 minutes, foaming badly; the mixture was then rapidly cooled.
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Sixty-three and six-tenths grams of crude amine hydrochloride (containing some paraformaldehyde), and 58.7 g. (after purification) of 9-acetylanthracene were recovered. The product was crystallized by adding water t o a solution in alcohol; wt. 17.8 g. (49.2V0 on basis of the ketone used). It appears t o sinter a t 130") remaining unmelted below 200°, but if placed i n t h e bath a t 140") i t melts t o a clear solution which solidifies in a few seconds. Probably decomposition into the high-melting diamylamine hydrochloride occurs. 5-(S-DimethyEamino-l-oxo-propyl)-9, or- 10-bromophenanthrene hydrochloride. Two and one-tenth grams of dimethyhmine hydrochloride, 0.84 g. of paraformaldehyde (1.1 molecular equivalents), and 0.04 cc. of concentrated HC1 were refluxed i n 8 cc. of benzene and 8 cc. of nitrobenzene until the light oily complex formed. Seven and six-tenths grams of the ketone was added and refluxing continued for 8 minutes when a voluminous precipitate necessitated t h e addition of 8 cc. more benzene. The suspension was refluxed for 15 minutes longer, during which time water was collected. The product was recrystallized from alcohol; wt. 7.2 g. (72%); m.p. 193-199°. BETKESDA,MD.
REFERENCES (1) (2) (3) (4) (5)
Organic Reactions, Vol. 1, p. 327. FRYAND MOSETTIG,unpublished results. Organic Reactions, Vol. 1, p. 329. MANNICHAND LAMMERINC:, Ber., 55, 3524. BLICKE AND MAXWELL, J . A m . Chem. Soc., 64,431 (1942).
