Dimethylamine hydrochloride, reaction

The Mannich Reaction involves the condensation of formaldehyde with ammonia or a primary or secondary amine and with a third compound containing a reactive methylene group these compounds are most frequently those in which the methylene group is activated by a neighbouring keto group. Thus when acetophenone is boiled in ethanolic solution with paraformaldehyde and dimethylamine hydrochloride, condensation occurs readily with the formation of... 

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. 

The addition product of ethyl acetoacetate and methyl a-methoxyacrylate was hydrolyzed, and the resulting dicarboxylic acid was treated with dimethylamine hydrochloride and aqueous formaldehyde. The product of the Mannich reaction was decarboxylated, reesterifed, and finally treated with methyl iodide to supply quaternary salt 469 as the main product. During the above one-pot process, elimination also took place, yielding unsaturated ketone 470, which was later utilized as its hydrogen bromide adduct 471. Reaction of 3,4-dihydro- 3-car-boline either with 469 or 471 furnished the desired indolo[2,3-a]quinolizine derivative 467 as a mixture of two diastereomeric racemates. 

In a similar transformation, 74 was synthesized from the reaction of 72 with 73 <99JHC501>. It was assumed that this reaction also proceeds via the Michael addition of 72 to the in situ generated double bond produced by the elimination of dimethylamine hydrochloride from 73. 

If the metlij lamine hydrochloride iu solution from the previous reaction be heated with a further quantity of formalin at 115° dimethylamine hydrochloride (dimethylammonium chloride) may be isolated ... 

The formation of a-naphthols of type 189 from 1-alkyl-substituted salts 30, on heating with dimethylamine hydrochloride in ethanol, occurs by another mechanism and will be explained in Section III,C,4,b,i. The interaction of l-aryl-3-carboxy-substituted salts 62 with secondary amines in benzene is initiated probably as in the reaction of these salts with primary amines, and the attack by the secondary amine on position 3 is the primary step of this reaction. However, since protonation of the intermediate anion 190, a masked acyl anion, becomes difficult, an interaction of this anion with the carbonyl group of the benzophenone fragment occurs (86KGS125). The enamines 191 thus formed are usually hydrolyzed on purification, yielding five-membered cyclic acyloins 192. 

The mechanism of the reaction is considered in Section 6.12.7, p. 1050, where acetophenone, which can only enolise in one direction, reacts with the formaldehyde equivalent (17) formed from formaldehyde and dimethylamine hydrochloride, to give the Mannich base (18), which in this case is isolated as the hydrochloride. The free Mannich bases are obtained by treatment with base and solvent extraction or crystallisation (e.g. gramine, Expt 6.147). 

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. 

Reaction of 2-(A/,N-disubstituted amino)-4//-pyrido[l,2-a]pyrimidin-4-ones 371 (R = H) with an excess of paraformaldehyde and dimethylamine hydrochloride in Dowtherm A at 100-105°C for 90 minutes afforded a mixture of the corresponding Mannich base 711 and 3,3 -methylene bis compound 712 in 12-54% yield, respectively (93FES1225). 

About 55.5 g of p-chloroethyl-di-n-butylcarbamate and about 22.6 g of dimethylamine are placed in a container, firmly sealed, and heated at about 95°C for about 16 hours. To the resulting crude mixture is added ethyl ether and the mixture filtered to remove dimethylamine hydrochloride formed during the course of the reaction. The ethereal solution is then extracted with 12 N hydrochloric acid. Under a fresh layer of ether and at a temperature under 10°C the aqueous acid extract is first neutralized with sodium carbonate and then made strongly alkaline with sodium hydroxide. The supernatant ethereal solution is then separated and dried over potassium hydroxide. The ethereal solution is finally concentrated and the residue obtained is fractionally distilled under vacuum. The p-dimethylaminoethyl-di-n-butylcarbamate is found to distill undecomposed at about 128°C to 130°C under approximately 2 mm pressure. 

N,N-Dimethyldesacetyl vincaleukoblastine (VLB) glycinate Five hundred milligrams of desacetyl VLB chloroacetate (were dissolved in 10 ml of tetrahydrofuran. Four milliliters of a 25% solution of dimethylamine in tetrahydrofuran were added, and the resulting mixture was allowed to remain overnight at room temperature. A precipitate of dimethylamine hydrochloride, produced as a by-product of the reaction, was removed by filtration and the... 

The Mannich reaction proceeded in nearly quantitative yield for the pyrrolopyridines (1) and (4). A somewhat lower yield was obtained from the isomer (3). A number of derivatives of compound (1) have also been subjected to the Mannich reaction. The typical reaction conditions include treatment with excess paraformaldehyde and dimethylamine hydrochloride in butanol. Results are summarized in Table 41 <69TL1909>. 

Selenophene and its homologs are dialkylaminomethylated by dimethylamine hydrochloride and paraformaldehyde in anhydrous alcohol 62 the reaction gives hydrochlorides of the respective a-(N-dimethylaminomethyl)selenophenes. 

In the pyrazine series, the Mannich reaction was applied first to 2,5-dimethyl-pyrazine by Linder and Spoerri (715). Of the amines tried, positive reactions were obtained only with dime thy lamine, piperidine, and morpholine, and it was found that one, or more usually two, of the hydrogen atoms of each of the methyl groups could be substituted. Thus 2,5-dimethylpyrazine, dimethylamine hydrochloride, and formalin in refluxing isopentyl alcohol gave 2,5-bis[bis(dimethylaminomethyl)-methyl]pyrazine and 2,5-bis(j3-dimethylaminoethyl)pyrazine. Reaction of 2-methyl-pyrazine with formalin and diethylamine hydrochloride gave 2- 3-diethylamino-ethylpyrazine (716) similarly dimethylamine hydrochloride gave 2-dimethyl-aminoethylpyrazine (17) and some 2-[bis(dimethylaminomethyl)]methylpyrazine (18) (657). 

The reaction of amine hydrochlorides with thioxoesters affords amidinium salts (155 equation 91). Formamidinium salts (156 equation 92) with bulky substituents at the nitrogens can be obtained by oxidation of AA A/ -trisubstituted or AA -disubstitut thioureas with peracetic acid. - Byproducts in this reaction can be ureas and thiourea trioxides. -Dimethylaminoacrolein reacts with dimethylamine hydrochloride to give (157 equation 93), the parent compound of the vinylogous amidinium salt series. - From AA -dimethylthiobenzamide and Al-sulfinyldimethylammonium tetrafluoroborate the benzamidin-ium salt (158 equation 94) was prepared. ... 

As dihydrocodeinone contains the system —CO—CH2— it was expected to undergo the Mannich reaction, and indeed after heating with dimethylamine hydrochloride and formaldehyde no dihydrocodeinone could be recovered, and only 40 per cent, of the product was crystalline. Under the same conditions 1-bromodihydrocodeinone (in which the reactive position of the aromatic nucleus is blocked, thus preventing any nuclear condensation) gave a 90 per cent, yield of crystalline material, also obtained when diethylamine hydrochloride was used in the reaction. The product cannot be sublimed, evidently boing dimolecular, and has been allotted the structure [lxvi, R = Br], i.e. 7 7 -methylenebis-(l-bromodihydrocodeinone). It is converted to 7 7 -methylenebis-(dihydrocodeinone) [lxvi, R = H] by catalytic reduction, and this is identical with the crystalline material obtained from dihydrocodeinone. A 5 5 or 5 7 -linkage is of course also possible, but the 7 7 union was considered to be most likely as it is the least hindered. No reaction occurs if triethylamine is substituted for the secondary amine, so that formation of a complex between the latter and... 

Dimethylamine hydrochloride (1 equivalent) was prepared by evaporation of a mixture of aqueous dimethylamine (45 g, 1.0 mol, as 25% aqueous solution) and excess concentrated hydrochloric acid under reduced pressure. To the solid residue was added an aqueous solution of the cyclohexanone (224 g, 2.0 mol) and formaldehyde (30 g, 1.0 mol, 40% aqueous solution). The two-phase mixture was heated carefully (reaction is exothermic) to boiling under a long reflux condenser, boiled for about 5 min, and then cooled to room temperature. Water (200 mL) was added, the layers separated, the aqueous layer saturated with sodium chloride, washed with ether (4 x 50 mL), and then made basic with 30% aqueous potassium hydroxide (1.3 equivalents). The Mannich base separated as a yellow upper layer with a strong amine odor. The layers were separated, the aqueous layer extracted with ether (5 x 100 mL), the combined organic layer and ether extracts dried over magnesium sulfate, and the solvent was distilled to provide the amino ketone (118 g, 70%). 

He takes the filtered reaction mixture and pours it in a 1000 ml sep funnel. The reaction mixture contains dimethylamine hydrochloride and some other garbage, and he wants to remove some of this unwanted material before he proceeds to get the rest of the methylamine hydrochloride. He adds 200 ml of chloroform to the sep funnel, and shakes it with the reaction mixture for 30 seconds. He lets it set for a couple of minutes. The chloroform layer should be on the bottom. It has a lot of dimethylamine hydrochloride and other garbage dissolved in it. He drains out the chloroform layer and throws it out. 

He pours the reaction mixture into a 1000 ml round bottom flask and again sets up the glassware as shown in Figure 3. He reattaches the vacuum and continues boiling off the water and formic acid under a vacuum. When the volume of the mixture reaches 500 ml, he removes the flask from the hot oil and places it in cool water. As it cools off, more crystals of methylamine hydrochloride appear. He filters the cold reaction mixture to obtain these crystals. He transfers them to a beaker and adds 200 ml of cold chloroform to the beaker. He stirs the crystals around in the chloroform for a few minutes, breaking up any chunks. This dissolves any dimethylamine hydrochloride in the product. He filters the crystals in the beaker, then puts them in the 1000 ml, 3-necked flask along with his first crop of methylamine hydrochloride crystals. He throws away the chloroform and returns the reaction mixture to the 1000 ml flask. 

In an alternative synthesis,3 a methoxycarbonyl lactone, for example (5), is treated successively with formaldehyde-dimethylamine hydrochloride (Mannich reaction), methyl iodide, and finally heated in dimethylformamide. The final step... 

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