Methylbenzylamines aminations

Isobutylamine and 2 phenylethylamine can be prepared by the Gabriel synthesis ten butyl amine N methylbenzylamine and aniline cannot... 

Preparation of Amines. Amines are prepared by heating aUphatic, aromatic, or cycHc ketones with ammonium formate, formamide, or an A/-substituted ammonium formate at 165—190°C (Leuckart reaction). For example, cx-methylbenzylamine is prepared by the reaction of acetophenone with ammonium formate. 

Addition of p-tert-butylthiophenol 178 to the racemic furanone 168 in dry toluene, and in the presence of quinidine as a chiral catalyst, provided (/ )-168 together with the Michael adduct 179. The enantiomeric excess of the recovered furanone (R)-168 was determined via the addition of (/)-Q -methylbenzylamine This amine addition showed complete diastereofacial control to give the adduct 180 in quantitative yield (Scheme 50) (94T4775). 

The synthesis starts by condensation of readily available optically active (R)-(+)-alpha-methylbenzylamine with 4-phenyl-2-butanone to form an imine which is itself reduced by hy-drogenolysis (Raney nickel) to give a 9 1 mixture of the (R,R)-amine and the (R,S)-amine (4). 

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. 

A reaction that involves dehydrogenation to an imine, which then reacts further is the reaction of primary or secondary amines with palladium black. The imine initially formed by the dehydrogenation reacts with another molecule of the same or a different amine to give an aminal, which loses NH3 or RNH2 to give a secondary or tertiary amine. An example is the reaction between V-methylbenzylamine and... 

As 29 had been recognized as the most accessible starting-material for the synthesis of racemic carba-sugars, its resolution was successfully achieved with optically active a-methylbenzylamine as chiral reagent. Reaction of 29 with (-l-)-a-methylbenzylamine gave a mixture of two diastereoisomeric salts [(+)-amine, (—)-29 and (+)-amine, (-l-)-29], which were well separated, and the former salt was converted into (—)-29, [a] -111.8° (ethanol). Analogously, (+)-29, [a] +110.7° (ethanol), was obtained. ... 

Evidently this is a hydrogenation and the source of the hydrogen is benzylamine as indicated by the production of benzaldehyde and ammonia in equivalent amounts presumably the benzylamine is dehydrogenated to the imine C,HjCH =NH, which is then hydrolysed. In the absence of hexamine, the maximum yield of benzaldehyde is 50 per cent. When hexamine is added to the reaction mixture, the yield of aldehyde is increased and that of methylbenzylamine is decreased, and methyl-amine is present at the end of the reaction. Hexamine reacts as the methylene derivative of ammonia, CH2=NH, which is hydrogenated to methylamine. The fundamental stage of the Sommelet reaction may be written as ... 

The use of dissociable diastereomers for enantiomer resolution may be illustrated by the case where racemic mandelic acid is resolved using en-antiomerically pure a-methylbenzylamine. The n and p salts of a-methylbenzyl-amine mandelate have aqueous solubilities of 49.1 and 180 g/L, respectively, at 25°C [153], A more recent example, which focuses on the crystallographic origin of the solubility differences, is provided by the resolution of ( )-mandelic acid with (-)-ephedrine in water or methanol solution [154], In general, the relative solubilities of the n and p salt pairs are strongly influenced by the choice of solvent medium and temperature, which provide considerable flexiblity in optimizing the crystallization conditions and the efficiency of resolution. This process may be facilitated by the development of a full solubility phase diagram. 

Mechanisms involving axial coordination of the optically active amine have also been invoked, and crystal structure data on RCo(DMG)2B complexes, where R is alkyl or (R)-l-(methoxycarbonyl)ethyl, and B is (R )-a-methylbenzylamine, were obtained (316, 317). Because deuteration of the (R)-methoxycarbonyl complex gave (5)-methylpropionate-2-d, it was concluded that Co—C bond cleavage occurred with inversion of configuration at the carbon (317). It would be useful to know the mechanistic details of this step, which could involve attack by D+, DCo(III), or coordinated D, as well as D2, for it is an unusual, if not unique, observation [contrast with the usual retention mechanism outlined in Eq. (39)]. 

With the same methodology, it was possible to quantify the gas-phase exchange equilibria of the (/f)-enantiomer of the chiral amines (M/ ), sec-butylamine, 1-cyclohexylethylamine, a-methylbenzylamine, and 1-(1-naphthyljethylamine with protonated (S,S)-3 ([Uss] ) or protonated (R,R)-3 ([U/ / ] ). One among the selected amines was introduced together with a reference achiral amine (Mjef), i e., isopropylamine or cyclohexylamine, into the FT-ICR cell, where they react with [Uss] or to form the corresponding [Uss M/ ]" and [U/j/j M/ ]" adducts. The... 

Methylcyclopropanone hemiacetal (4) undergoes an asymmetric Strecker reaction to give IR, 25 )-(- -)-a/to-norcoronic acid (5) in good yield and high de. The induction depends on the use of a chiral amine [e.g. (5 )-a -methylbenzylamine] to control the face on which the intermediate iminium cation (6) is attacked. 

A kinetic smdy has been reported of substituent effects on the reactions of 2-phenoxy- and 2-(4-nitrophenoxy)-3-nitro-5-X-thiophenes with benzylamine and with A-methylbenzylamine in benzene as solvent. The intramolecularly hydrogen-bonded intermediate (14) is postulated. Reactions of the 5-unsubstimted thiophenes (X = H) are not base-catalysed, indicating that nucleophilic attack is rate limiting, and the more basic secondary amine shows higher reactivity than the primary... 

The N-alkylation of secondary amines was also examined under the same catalytic conditions. Reactions of N-methylaniline and N-methylbenzylamine with benzyl alcohol gave the corresponding tertiary amines in good yields (Scheme 5.20). 

Amination of phenylhthium with Af,Af,0-trimethylhydroxylamine Ik did not lead to the formation of the expected tertiary amine instead A-methylbenzylamine was isolated (equation 4). 

It was of interest to extend this synthetically interesting procedure to the production of chiral amines such as ot-methylbenzylamine (58) 188). Unfortunately, the enzymes display somewhat low activity toward substrates of this kind. 

NCA polymerization by secondary amines may involve the amine or activated monomer mechanisms or both mechanisms simultaneously. Unhindered secondary amines such as dimethylamine and piperidine react like primary amines, and polymerization occurs by the amine mechanism. Polymerization by slightly hindered amines such as diethylamine, N-methylbenzylamine, and di-n-propylamine involves a combination of the amine and activated monomer mechanisms. More hindered secondary amines, such as di-n-isopropylamine and dicyclohexylamine, react almost exclusively via the activated monomer mechanism. 

The group of Turner has reported the deracemization of amines [79]. The wild type of Type II monoamine oxidase from Aspergillus niger possesses very low but measurable activity toward the oxidation of L-a-methylbenzylamine. The oxidation of the D enantiomer is even slower. In vitro evolution led to the identification of a mutant with enhanced enantioselectivity, showing high E values (>100) for a variety of primary and secondary amines. An example is shown in Scheme 5.39. 

The integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100% yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz, in 1996, first reported the DKR of rac-2-methylbenzylamine using Candida antarctica lipase B and vinyl acetate with palladium on carbon as the racemization catalyst [20]. The reaction was carried out at 50°C over 8 days to give the (S)-amide in 99% ee and 64% yield. Rather surpris-... 

IH NMR Characteristics of the nuclear magnetic resonance spectra of amines may be illustrated by comparing 4-methylbenzylamine (Figure 22.8a) with 4-methylbenzyl... 

Phthalimidines (isoindolin-l-ones) can be valuable intermediates for the synthesis of isoindoles and some natural products, and there has been recent interest in the development of simple methods for the direct conversion of o-phthalaldehyde into /V-substituted phthalimidines. Condensation of o-phthalaldehyde with primary aliphatic amines using acetonitrile as solvent gives disappointing yields with a-methylbenzylamine, for example, the yield of the phthalimidine 1 is only 21%. By contrast, treatment of o-phthalaldehyde with a-amino acids in hot acetonitrile gives generally excellent yields of the corresponding phthalimidines. With L-valine, for example, 2 is formed in 87% yield. 

In lieu of 19F NMR spectroscopy, a second method for determining loading involves the reaction of an accurately weighed sample of resin with a known quantity of a reactive amine, e.g., 2-methylbenzylamine. The reaction product is evaluated by 1H NMR and LC/MS. Loading is determined by integration and comparison of the aromatic methyl protons and the o-methylene protons of the product amide relative to the starting amine. 

When 33 was mixed with an equimolar amount of (R)-(+)-a-methylbenzylamine in ethanol, a mixture of two crystalline salts, [(+)-amine+ (—)-adduct ] and [(+)-amine+ (+)-adduct ] was obtained. Fractional crystallization of the mixture from ethanol gave the former salt [(+)-amine+ (—)-adduct ] (84) in 42% yield as an opti-... 

TV-Methylbenzylamine (two carbon substituents on nitrogen a secondary amine)... 

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