Dimethylamine.hydrochloride

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... 

Note. Dimethylamine hydrochloride is a deliquescent substance the sample if damp must be dried in a vacuum desiccator and then rapidly weighed before use. 

Add 5 ml. (5 g.) of acetophenone, 1-25 g. of finely powdered paraformaldehyde, and 3 5 g. of dry dimethylamine hydrochloride to 8 ml. of absolute ethanol, and then boil the mixture under reflux for 1-5 hours. Filter the solution (which is now almost entirely clear) through a preheated filter-funnel, and cool the filtrate in ice-water with stirring. The propiophenone hydrochloride rapidly separates as white crystals filter oflF the crystals at the pump and recrystallise from a small quantity of ethanol m.p. 155-156°. Yield, 2 5 g. 

If the metlijlainiiie hydrochloride in solution from the previous re.action be heated with a further quantity of formalin at 115° dimethylamine hydrochloride (dimethylammonium chloride) may be isolated ... 

Transfer the filtrate to a ceramic evaporating dish and heat on a water bath until a crystalline scum forms on the top. Cool the dish quickly then filter the mess on the vacuum Buchner to yield 96g of Methylamine Hydrochloride. Concentrate the filtrate once again to obtain a second crop of crystals, -IQg. Concentrate the filtrate a third time as far as possible using the water bath, then store the dish in a vacuum dessicator loaded with Sodium Hydroxide in the bottom for 24 hours. Add Chloroform to the residue left in the crucible to dissolve out Dimethylamine Hydrochloride (distill off the Chloroform to recover - good stuff) then filter on the venerable old vacuum Buchner funnel to yield an additional 20g of Methylamine Hydrochloride, washing the crystals in the funnel with a small poiiion of Chloroform ( 10mL). 

Dimethylamine hydrochloride [506-59-2] M 81.6, m 171 . Crystd from hot CHCI3 or abs EtOH. Also recrystd from MeOH/ether soln. Dried in a vacuum desiccator over H2SO4, then P2O5. Hygroscopic. 

Methylamine hydrochloride [593-51-1] M 67.5, m 231.8-233.4°, h 225-230°/15mm, pK 10.62. Crystd from n-butanol, absolute EtOH or MeOH/CHCls. Washed with CHCI3 to remove traces of dimethylamine hydrochloride. Dried under vacuum first with H2SO4 then P2O5. Deliquescent, stored in a desiccator over P2O5. 

The procedure described above is a modification of that of Hauser, Taylor, and Ledford2 and of Luten which avoids use of anhydrous dimethylamine. It is related to the procedure of Goodson and Christopher that employs benzaldehyde, aqueous dimethylamine hydrochloride, and potassium cyanide. 

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. 

Acetophenone, m.p. 19-20°, and a practical grade of dimethylamine hydrochloride were used. 

The excess dimethylamine hydrochloride is held in solution by the acetone. 

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. 

Names of the salts formed upon condensation with an acid are added after the chemical names. For instance, [3-(2-chloropheno-thiazine-10-yl)propyl]dimethylamine hydrochloride [4. ... 

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. 

The total yield of crude centrifuged methylamine hydrochloride is 830-850 g. This product contains, as impurities, water, ammonium chloride, and some dimethylamine hydrochloride. In order to obtain a pure product, the crude methylamine hydrochloride is recrystallized from absolute alcohol (Note 4). The crude salt is placed in a 5-I. round-bottom flask fitted with a reflux condenser protected at the top with a calcium chloride tube 2 1. of absolute alcohol is added and the mixture heated to boiling. After about half an hour the undissolved material is allowed to settle and the clear solution is poured off. When the alcoholic solution is cooled, methylamine hydrochloride crystallizes out. It is filtered off and centrifuged, and the alcohol used for another extraction. The process is repeated until the alcohol dissolves no more of the product (about five extractions are necessary). In the flask 100-150 g. of ammonium chloride remains, making the total recovery of ammonium chloride 850-950 g. The yield of recrystallized methylamine hydrochloride is 600-750 g. (45-51 per cent of the theoretical amount, based on the ammonium chloride used up in the process). 

---