Methylamines from formamides

Preparation of formamides from COz and a non-tertiary amine by homogeneous hydrogenation has been well studied and is extremely efficient (Eq. (12)). Essentially complete conversions and complete selectivity can be obtained (Table 17.3). This process seems more likely to be industrialized than the syntheses of formic acid or formate esters by C02 hydrogenation. The selectivity is excellent, in contrast to the case for alkyl formates, because the amine base which would stabilize the formic acid is used up in the synthesis of the formamide consequently little or no formic acid contaminates the product. The only byproducts that are likely to crop up in industrial application are the methylamines by overreduction of the formamide. This has been observed [96], but not with such high conversion that it could constitute a synthetic route to methylamines. 

Group contribution method of Andersen, Beyer, and Watson [51,52] In this method, a given compound is constructed from abase group (methane, cyclopentane, benzene, naphthalene, methylamine, dimethylamine, trimethylamine, or formamide) with known enthalpies of formation, which is then modified by appropriate substitutions to yield the desired molecule. 

Aside from the N-compounds listed above, a number of low-molecular-weight N compounds were also identified. [17] These included ammonia, hydrogen cyanide, dinitrogen (N2), nitric oxide (NO), methylamine, nitrous oxide (N20), formamide, acetamide, and N, N-dimethylmethanamine. 

EXTENSIONS AND COMMENTARY N-Methyltryptamine (monomethyltryptamine, NMT) is an alkaloid that has been found in the bark, shoots and leaves of several species of Virola, Acacia and Mimosa. However, the major snuffs associated with these plant have been shown to also contain 5-MeO-DMT and are discussed there. NMT has been synthesized in a number of ways. One can react 3-(2-bromoethyl)indole with methylamine. NMT can be isolated as the benzoyl derivative from the methylation of tryptamine with methyl iodide followed by reaction with benzoyl chloride, with the hydrolysis of this amide with alcoholic KOH. It can also be synthesized from indole with oxalyl chloride, with the resulting glyoxyl chloride reacting with methylamine in ether to give indol-3-yl N-methylglyoxalylamide (mp 223-224 °C from IPA) which is obtained in a 68% yield, which is reduced to NMT to give the amine hydrochloride (mp 175-177 °C from ) in a 75% yield. The most simple and direct synthesis is the formamide reduction given above. 

In an initial step, 2-chloroacetic acid ethyl ester is reacted with formamide to give 5-methylimidazole-4-carboxylic acid ethyl ester. Then sodium in ammonia is used to convert that to 4-hydroxymethyl-5-methylimidazole-hydrochloride. Cysteamine HCI (HSCH2CH2NH2-HCI) is then reacted to give 4-(2-aminomethyl)-thiomethyl-5-methyl-imidazole dihydrochloride. Then N-cyanamido-5,5-dimethyl-dithio-carbonate (from cyanamid, KOH, CS2 and ((CH3)2S04) is reacted to give a further intermediate which is finally reacted with methylamine to give cimetidine. 

Racemic 2-aminobutan-l-ol (1) is a cheap chemical which can be easily resolved into both its enantiomers on an industrial scale. The asymmetric synthesis of chiral amines from hydrazines derived from (7 )-(—)-2-aminobutan-l-ol [(R)-(—)-l], using the general strategy disclosed in early works, is summarized here. The title hydrazine (4) is prepared as follows (eq 1). Treatment of the amino alcohol [(7 )-(—)-l] with excess ethyl formate followed by LAH reduction of the intermediate formamide gives the N-methylamine [(7 )-(—)-2]. IV-Nitrosation of the latter afforded (R)-(+)-3 which is next reduced to the hydrazine [( )-(—)-4] by means of LAH. Being unstable, the hydrazine (4) must be used immediately without purification. 

At least two reaction pathways may be postulated for the formation of INMF. The first (Scheme B, path a) involves initial reaction of CO with ammonia to give formamide, followed by methylation with Me-Ru generated via ruthenium-catalyzed CO hydrogenation. An alternative pathway would proceed via initial formation of methanol from CO/H2, to be followed by the production of methylamines and subsequent carbonylation (path b). 

Potassium permanganate acetic acid N-Demethylation via formamides Formamides from methylamines with and without simultaneous oxidation of methylene to keto groups... 

Two reactions which should lend themselves to the synthesis of pyrrolidines with a wide variety of substituents have been published this year. In the first method Blake and co-workers have improved the versatility of a well known pyrrolidine synthesis from arylcyclopropyl ketones. By reaction with formamide in the presence of MgCl2, alkylcyclopropyl ketones (105) give good yields of pyrrolidines (106). The second method details the reaction of Schiff s bases of trimethylsilyl methylamine with acyl halides in the presence of alkenes and... 

Dinitrobenzamides are very suitable derivatives for paper chromatography. The derivatives of primary and secondary aliphatic amines behave quite differently on chromatograms. As tertiary amines do not react with the reagent, the method offers a good opportunity for the differentiation of primary, secondary, and tertiary amines. In the solvent system 25% dimethylformamide/hexane the primary amines from methylamine to amylamine remain at the start, while higher amines, up to C14, separate well (Fig. 34). Lower secondary amines also remain at the start. Only di-n-propylamine and di-n-butylamine move. The formamide/hexane... 

---