Dimethylamine, reaction with acetone

Tritiated formaldehyde is also useful in Mannich reactions. Examples of such applications include the preparation of the topoisomerase-1 inhibitor 364 by condensation of tritiated formaldehyde and dimethylamine with 10-hydroxycamptothecin 1363). the reaction with acetone and diethylamine to give 4-diethylamino-4-[ H2]butan-2-one 365 which was further converted upon heating with thebaine (366) to the morphine derivative 367 (specific activity of 46 Ci/mol). Furthermore, condensation of aqueous deuterated formaldehyde with allyltrimethylsilane to prepare the 2,6-doubly labeled piperidine 368. as indicated , would be expected to work equally well with tritiated formaldehyde. 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

The Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

Elimination of R NH. Cardwell showed that the Mannich reaction of acetone with formaldehyde and dimethylamine gives the unsymmetrical product (1), and that... 

A mixture of acetophenone 58 (60.0 g, 0.5 mmol), dimethylamine hydrochloride (52.7 g, 0.65 mmol), and paraformaldehyde 2 (19.8 g, 0.22 mmol) with cone. HCl (1 mL) in 80 mL of 95% EtOH was heated at reflux for 2 h. The reaction mixture was diluted with 400 mL of acetone and allowed to cool to room temperature before storing in the refrigerator overnight. The resultant crystals were filtered, washed with acetone and dried to afford 72-77 g (68-72%). 

In a 500 cc. round-bottomed flask attached to a reflux condenser are placed 60 g. (58.5 cc., 0.5 mole) of acetophenone (Note 1), 52.7 g. (0.65 mole) of dimethylamine hydrochloride, and 19.8 g. (0.22 mole) of paraformaldehyde. After the addition of 1 cc. of concentrated hydrochloric acid (sp. gr. 1.19) in 80 cc. of 95 per cent ethyl alcohol, the mixture is refluxed on a steam bath for two hours (Note 2). The yellowish solution is filtered, if it is not clear (Notes 3 and 4), and is transferred to a 1-1. wide-mouthed Erlenmeyer flask. While still warm, it i6 diluted by the addition of 400 cc. of acetone (Note 5), allowed to cool slowly to room temperature, and then chilled overnight in the refrigerator. The large crystals are filtered and washed with 25 cc. of acetone. After it has been dried for two and one-half hours at 40-50°, this crude product weighs 72-77 g. (68-72 per cent of the theoretical amount) and melts at 138-141° (Notes 6 and 7) it is suitable for many reactions. 

Another example is the reaction of l-(17f-benzotriazol-l-yl)-l-(arylhydrazono)acetones 263 with DMFDMA. The intermediate 264 undergoes Michael addition followed by elimination of dimethylamine yielding pyridazin-4(l//)-ones 265 (Scheme 66) <2000JHC167>. 

Place 26.5 g (0.326 mol) of dry dimethylamine hydrochloride, 10 g (0.33 mol) of powdered paraformaldehyde and 30 g (29.3 ml, 0.25 mol) of acetophenone 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 transfer the filtrate to a 500-ml wide-mouthed conical flask and, while still warm, add 200 ml of acetone. Allow to cool to room temperature and leave in a refrigerator overnight. Filter the crystals at the pump, wash with 10 ml of acetone and dry for 6 hours at 40-50 °C the yield of crude product, m.p. 152-155 °C, is 38 g (71%). Recrystallise the crude product by dissolving in 45 ml of hot rectified spirit and slowly adding 225 ml of acetone to the solution collect the solid which separates by suction filtration and dry at 70 °C. The purified material melts at 155-156 °C and the recovery is about 90 per cent. 

Co-solvent or solvent is generally used to oxidize these water insoluble alkenes efficiently [12]. Among the different solvents described in the literature (dimethyl sulfoxide, acetone, tetrahydrofuran, dioxane, acetonitrile), dimethylformamide appears to be the most suitable one for the oxidation. Indeed, by employing a water/dimethylformamide mixture, oxidation of 1-dodecene to 2-dodecanone can be achieved with yields greater than 80%. However, hydrolysis of dimethylformamide is also possible during the reaction, yielding dimethylamine which can lead to the formation of inactive complexes. 

The homologues of 2,4-DMA that were iodinated (or occasionally fluor-inated) were mono- or di-alkylated on the nitrogen, and the precursor that was common to all was the corresponding acetone. The above nitrostyrene, 1-(2,4-dimethoxyphenyl)-2-nitropropene, was reduced in acetic acid with elemental iron, and the base-washed extracts stripped of solvent and distilled (125-145 deg C at 0.5 mm/Hg) to give 2,4-dimethoxyphenylacetone as a water-white oil. The principal reductive amination product of this, the one that was most thoroughly explored with various halogenation schemes, was obtained by the reaction of 2,4-dimethoxyphenylacetone with dimethylamine and sodium cyanoborohydride. This product,... 

Reactions of dimethylamine and foimaldehyde with hydrogen cyanide , isobutanoP, phenol , and acetone are typical ... 

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