Benzylamides reactions

Reaction mechanism Detailed mechanistic studies have been conducted on this reaction. While the stoichiometric protonolysis reaction of [ (ArNCMe)2CH Mg" Bu]2 with benzylamine, 2-methoxyethylamine, and pyrrolidine to yield the corresponding dimeric magnesium amides and methane proceeds rapidly and non-reversibly at room temperature [88], the reaction of [ (ArNCMe)2CH Ca N (SiMe3)2 (THF)] with benzylamine forms a quantifiable equilibrium between monomeric bis(trimethylsilyl)amide and dimeric benzylamide reaction products. A van t Hoff analysis of this equilbrium mixture allowed derivation of AG°(298 K) as —2.7 kcal mol consistent with facile precatalyst activation via protonolysis with a primary amine [76, 87]. 

A- [(Acy loxy )methyl] derivatization was also examined for its potential to improve the biological stability of peptides. For example, the peptide-like model A-[(benzyloxy )carbonyl]glycine benzylamide (8.171, R = H) was de-rivatized to a few N-/Yacyloxy)methyl] derivatives whose chemical and enzymatic hydrolysis was investigated [225], The results compiled in Table 8.13 indicate a fast chemical hydrolysis, the mechanism of which is depicted as Reaction b in Fig. 8.21. Enzymatic hydrolysis also occurs in human plasma, resulting in short half-lives, with the exception of the pivaloyl analogue. 

General methods for the preparation of a.jS-unsaturated iron-acyl complexes are deferred to Section D 1.3.4.2.5.1.1. examples of the alkylation of enolates prepared via Michael additions to ii-0 ,/ -unsaturated complexes prepared in situ are included here. Typical reaction conditions for these one-pot processes involve the presence of an excess of alkyllithium or lithium amide which first acts as base to promote elimination of alkoxide from a /f-alkoxy complex to generate the -a,)S-unsaturated complex which then suffers 1,4-nucleophilic addition by another molecule of alkyllithium or lithium amide. The resulting enolate species is then quenched with an electrophile in the usual fashion. The following table details the use of butyllithium and lithium benzylamide for these processes44,46. 

Figure 3.18. Acidolytic cleavage of aryl benzyl ethers as competing reaction during the acidolysis of N-benzylamides [212],...

In neutral medium the deuterium solvent isotope effect, (A h2o/ D2o) in the hydrolysis of diaryldiacyloxyspirosulphuranes483, 404-407 has been found to be 1.66. In acidic medium the ratio of catalytic rate constants has been found to be 0.56. Heterocondensed imidazoles 408, are produced in the reaction of N-benzylamides, 409, of nitrogen heterocyclic carboxylic acids with phosphorus pentachloride. Deuterium labelling experiments have been carried out to understand the mechanism of this reaction involving a nitrile ylide species484. 

Reflux a mixture of 1 g of the ester, 3 ml of benzylamine and 0.1 g of powdered ammonium chloride for 1 hour in a Pyrex test tube fitted with a short condenser. Wash the cold reaction mixture with water to remove the excess of benzylamine. If the product does not crystallise, stir it with a little water containing a drop or two of dilute hydrochloric acid. If crystallisation does not result, some unchanged ester may be present boil with water for a few minutes in an evaporating dish to volatilise the ester. Collect the sold AT-benzylamide on a filter, wash it with a little petroleum, b.p. 100-120 °C, and recrystallise it from dilute ethanol, ethyl acetate or acetone. 

Hydroxylation of benzylamides The reaction of N-benzylamides with K02 and 18-crown-6 results in o- and />-hydroxylation (equation I). 

Cleavage of imidazoles dehydroamino acids,3 2,4-Disubstituted imidazoles4 undergo a Diels-Alder-like reaction with singlet oxygen in the presence of DBU (1-2 equiv.) to provide imine diamides, which isomerize to dehydroamino acid derivatives in the presence of base. Hydrogenation in the presence of catalysts with chiral phosphine ligands results in optically active amino acid diamides. The overall process is illustrated for the synthesis of the N-benzylamide of N-acetylleucine (equation I). 

The reaction of a primary amide and benzaldehyde, in the presence of a silane and trifluoroacetic acid, leads to the corresponding A -benzylamide. This transformation is a reductive alkylation. A-Alkynyl amides have been prepared by the cop-... 

A 1-phenylethylamino moiety is used for diastereomeric control not only in addition of nucleophiles to A-(l-phenylethyl)imines but also in diasteroselective Michael addition to a,P-unsaturated esters. Thus, lithium A-(l-phenylethyl)-A-benzylamide 148 is employed for a one-pot tandem Michael addition-fluorination reaction (see Scheme 9.32) [58]. The reaction provides a/i/f-3-amino-2-fluoroesters 149 exclusively, whose diastereoselectivi-ties (64-66% de) to the chiral carbon of the 1-phenylethyl-group are good enough. 

As expected, 1 is more active than 4, and is recovered in quantitative yield by extraction with perfluoromethylcyclohexane. Although 2 and 3 are more active than 4, they cannot be recovered by extraction with any fluorous solvents. The amide condensation proceeds cleanly in the presence of 5 mol% of 1 the desirable amide has been obtained in 95% yield by azeotropic reflux for 15 h. In addition, the corresponding N-benzylamide has been obtained in quantitative yield by heating 4-phenylbutyric acid with benzylamine in the presence of 2 mol% of 1 under azeotropic reflux conditions for 4 h. Based on these results, the re-use of 1 has been examined for the direct amide condensation reaction of cyclohexanecarboxylic add and benzylamine in a 1 1 1 mixture of o-xylene, toluene, and perfluorodecalin under azeotropic reflux conditions with removal of water for 12 h [ Eq. (2) and Table 2] [5]. After the reaction has been completed, the homogeneous solution is cooled to ambient temperature to be separated in the biphase mode of o-xylene-toluene/ perfluorodecalin. The corresponding amide is obtained in quantitative yield from the organic phase. Catalyst 1 can be completely recovered from the fluorous phase and re-used in the recyclable fluorous immobilized phase. 

Grether and Waldmann [15] developed an enzyme-labile safety catch linker 1 tested in intermolecular Mizoroki-Heck reactions (Scheme 14.1). This linker releases alcohols and amines through enzymatic cleavage of the benzylamide moiety followed by snbsequent lactam formation. After a Mizoroki-Heck reaction performed on an immobilized iodoarene... 

Wolff rearrangement has also been applied for the synthesis of silylketenes 25 from silyl diazoketones 24. The ketenes 25 upon further reaction with BnNH2 afforded the corresponding a-silyl benzylamides 26 in good yields. 

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