Dimethylamine 3-Dimethylaminopropiophenone

PP-Dimethylacrylic acid, 460 Dimethylamine hydrochloride, 414, 416 Dimethylaminomethylindole, 1012,1013 P-Dimethylaminopropiophenone hydrochloride, 910, 911... 

Condensation of the active methyl group in acetophenone with formaldehyde and dimethylamine (in the form of its hydrochloride) is an example of the Mannich reaction (e.g. the synthesis of dimethylaminopropiophenone, Expt 6.147). The probable mechanism of the reaction involves the intermediate formation of the hydroxymethyldimethylamine which eliminates water to form the reactive species (1). This condenses with the a-carbon atom of acetophenone reacting in its enol form. 

To a mixture of 21.4g (0.1 mol) of dimethylaminopropiophenone hydrochloride and 13.0g (0.2 mol) of potassium cyanide in a 500-ml flask, add 260 ml of boiling water heat the heterogeneous mixture under reflux for 30 minutes. Part of the dimethylamine, which is eliminated in the reaction, distils collect this in dilute hydrochloric acid. Cool the reaction mixture in ice the oil solidifies and crystals form in the aqueous layer. Collect the solid [crude 3-benzoylpropionitrile, 10.5 g (66%)] by suction filtration and recrystallise it from benzene-light petroleum (b.p. 40-60 °C) the product separates as almost colourless blades, m.p. 76 °C. 

P-Dimethylaminopropiophenone hydrochloride. Place 26 5 g. of dry dimethylamine hydrochloride, 10 g. of powdered paraformaldehyde and 30 g. (29-3 ml.) of acetophenone (Section IV,136) in a 250 ml. round-bottomed flask attached to a reflux condenser. Introduce 40 ml. of 95 per cent, ethanol to which 0-5 ml. of concentrated hydrochloric acid has been added, and reflux the mixture on a water bath for 2 hours the reaction mixture should ultimately be almost clear and homogeneous. Filter the yellowish solution (if necessary) through a hot water funnel ... 

Ethyl 5-amino-4-oxo-3-p-tolyl-3,4-dihydrothieno [3,4-d] pyridazin-l-carboxylate (295) and p-dimethylaminopropiophenone (presumably converted by loss of dimethylamine into phenyl vinyl ketone under the reaction conditions) probably gave the intermediate adduct (296) that lost H2S to afford ethyl 5-amino-7-benzoyl-4-oxo-3-p-tolyl-3,4-dihydro-1 -phthalazinecarboxylate (298) (Mc2NCHO, trace AcOH, reflux, 2h 61%) the same substrate (295) with p-methoxy-p-nitrostyrene likewise gave ethyl 5-amino-7-p-methoxyphenyl-6-nitro-4-oxo-3-p-tolyl-3,4-dihydro-l-phthalazinecarboxylate (297) (80%) and many analogs were made similarly. ... 

Dimethylamine hydrodiloride dissolved in aq. 40%-formaldehyde soln., after 0.5 hr. acetic anhydride added, warmed with shaking until a gently refluxing clear soln. results, o-nitroacetophenone added, and heated 0.5 hr. on a water bath -> o-nitro- -dimethylaminopropiophenone. Y 64.2%. - This procedure minimizes reaction of the product with the remaining formaldehyde. F. e. s. W. Back, Ardi. Pharm. 303, 491 (1970). 

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