Benzaldehyde with methylamine

One problem with reductive amination as a method of amine synthesis is that by-products are sometimes obtained. For example, reductive amination of benzaldehyde with methylamine leads to a mixture of iV-methylbenzylamine and i -methyldibenzylarnine. How do you suppose the tertiary amine byproduct is formed Propose a mechanism. 

Depending on the reaction conditions, two different imines of formula CgHgN might be formed by the reaction of benzaldehyde with methylamine. Explain, and give the structures of the two imines. 

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

Pyruvate decarboxylase (PDC, E.C. 4.1.1.1) accepts other substrates besides pyruvate, its natural reactant As early as 1921, Neubergand Hirsch described the reaction of yeast with benzaldehyde and pyruvate to phenylacetylcarbinol (2-keto-3-hydroxy-propylbenzene) (Neuberg, 1921) in a carboligase side reaction which yields ephedrine after reaction with methylamine and catalytic hydrogenation (Figure 7.37). 

The irans-benzylidene derivative (188), obtained as the major product of condensation of 3-methylpiperazine 2,5-dione and benzaldehyde in the presence of acetic anhydride, undergoes photoisomerization to the cis isomer (191) on irradiation in methanol. Both isomers have been converted into tetrahydropyrazine imino ethers (189) and (192) by treatment with triethyloxonium fluoroborate. The trans compound reacts more slowly and gives a lower yield of imino ether and this is attributed to steric hindrance. Compounds 188 and 191 are de-acetylated on treatment with methanolic 2 N potassium hydroxide. The trans and cis isomers (187) and (190), so produced are converted into 3-benzyl-2,5-dihydroxy-6-methylpyrazine (144) when heated at 100° with sodium hydroxide.384 Treatment of the dichloroacetyl derivative of phenylalanine with methylamine gives l-methyl-3-benzylidenepiperazine 2,5-dione with the stereochemistry shown.384a... 

Benzaldehyde first reacts with methylamine and NaBHsCN in the usual way to give the reductive amination product /V-methylbenzylamine. This product then reacts further with benzaldehyde in a second reductive amination to give Af-methyldibenzylamine. 

Normal nucleophilic substitution reactions of alkyl and aryl chloropyrazines have been examined as follows 2-chloro-3-methyl- and 3-chloro-2,5-dimethyl(and diethyl)pyrazine with ammonia and various amines (535, 679, 680) 2-chloro-3(and 6)-methylpyrazine with methylamine and dimethylamine (681, 844), piperidine and other amines (681, 921) 2-chloro-5(and 6)-methylpyrazine with aqueous ammonia (362) alkyl (and phenyl) chloropyrazines with ammonium hydroxide at 200° (887) 2-chloro-3-methylpyrazine with aniline and substituted anilines (929), and piperazine at 140° (759) 2-chloro-3-methyl(and ethyl)pyrazine with piperidine (aqueous potassium hydroxide at reflux) (930,931) [cf. the formation of the 2,6-isomer( ) (932)] 2-chloro-3,6-dimethylpyrazine with benzylamine at 184-250° (benzaldehyde and 2-amino-3,6-dimethylpyrazine were also produced) (921) 2-chloro-3,5,6-trimethylpyrazine with aqueous ammonia and copper powder at 140-150° (933) and with dimethylamine at 180° for 3 days (934,935) 2-chloro-6-trifluoromethylpyrazine with piperazine in acetonitrile at reflux (759) 2-chloro-3-phenylpyrazine with aqueous ammonia at 200° (535) 2-chloro-5-phenylpyrazine with liquid ammonia in an autoclave at 170° (377) 2-chloro-5-phenylpyrazine with piperazine in refluxing butanol (759) but the 6-isomer in acetonitrile (759) 5-chloro-2,3-diphenylpyrazine and piperidine at reflux (741) and 5-chloro-23-diphenylpyrazine with 2-hydroxyethylamine in a sealed tube at 125° for 40 hours (834). 

A very ingenious direct synthesis of i-ephedrine, avoiding the laborious resolution of the racemic mixture, has been devised by Hildebrandt and Klavehn (271) and described by Kamlet (272). Neuberg and Hirsch (273) in 1921 demonstrated that when equal mols of acetaldehyde and benzaldehyde are added to a carbohydrate solution actively fermenting by yeast, levorotatory l-phenyl-2-ketopropanol-l, C H5-CH(OH)CO-CHi, is formed. This compound on reaction with methylamine and catalytic reduction yields 1-ephedrine directly. 

Scheme 38.2 Synthesis of ephedrine by fermentation reaction on benzaldehyde, followed by reductive condensation with methylamine...

A -Chloromethylamine attacks ketones in alkaline solution with formation of oxaziranes with cyclohexanone, compound 17 is produced in 50% yield. The reaction with aldehydes with zV-chloromethyl-amine yields predominantly acid amides. However, oxaziranes are also produced here as by-products. From benzaldehyde and A -chloro-methylamine, 2-raethyl-3-phenyloxazirane (15) was obtained in 10% yield. 

Raja and Perumal reported the synthesis of novel 2,6-diaryl-3-(arylthio)piperidin-4-ones via a four-component reaction consisting of arylthioacetones, 2-substituted aromatic aldehydes and methylamine or ammonium acetate <06CPB795>. Further elaboration of this four component reaction to a novel five component tandem Mannich-enamine-substitution sequence involving the reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, two equivalents of a substituted aromatic aldehyde, and two equivalents of ammonium acetate is shown below <06T4892>. When this five-component tandem reaction involves para-substituted benzaldehydes, the cis (193) and trans (194) diastereomers of thiazones are obtained. Alternatively, orf/zo-substituted benzaldehydes form only the trans (194) diastereomer along with an air-oxidized product 195. 

To a solution of 41.6 g. (0.25 mole) of purified 2,3-dimethoxy-benzaldehyde (Note 1) in 150 ml. of 95% ethanol is added 23.4 g. (0.75 mole) of methylamine in 50 to 75 ml. of water (Note 2). The mixture is heated to boiling and placed in a 500-ml. heavy-walled bottle (Note 3), and 6 g. of Raney nickel catalyst is added (Note 4). The bottle is connected to a low-pressure hydrogenation apparatus, the system is flushed with hydrogen, and the mixture is shaken with hydrogen at an initial pressure of 45 lb. until 0.25 mole of hydrogen is absorbed and the absorption ceases (Note 5). 

Anyway, MADAM-6 is not active. And the equally intriguing positional isomer, the easily made MADAM-2, will certainly contribute to these speculations. A quiz for the reader Will 2,N-dimethyl-3,4-methylenedioxyamphetamine (MADAM-2) be (1) Of much reduced activity, akin to MADAM-6, or (2) Of potency and action similar to that of MDMA, or (3) Something unexpected and unanticipated I know only one way of finding out. Make the Schiffs base between piperonal and cyclohexylamine, treat this with butyl lithium in hexane with some TMEDA present, add someN-methylformanilide, convert theformed benzaldehyde toanitrostyrenewith nitroethane, reduce this with elemental iron to thephenylacetone, reduce this in the presence of methylamine with sodium cyanoborohydride, then taste the result. 

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