N-Benzylamides

D) N-Benzylamides. Ammonium salts are readily converted into the... 

N-Benzylamides are recommended when the corresponding acid is liquid and/or water-soluble so that it cannot itself serve as a derivative. Phe benzylamides derived from the simple fatty acids or their esters are not altogether satisfactory (see Table below) those derived from most hydroxy-acids and from poly basic acids or their esters are formed in good yield and are easily purified. The esters of aromatic acids yield satisfactory derivatives but the method must compete with the equally simple process of hydrolysis and precipitation of the free acid, an obvious derivative when the acid is a solid. The procedure fails with esters of keto, sul phonic, inorganic and some halogenated aliphatic esters. 

The melting points of the N-benzylamides are collected in the following Table ... 

N-Benzylamides of acids from esters. Esters are converted into the. N -benzylamides of the corresponding acids by heating with benzylamine in the presence of a little ammonium chloride as catalyst ... 

N-Benzylamides 22 and 23 (R = PhCH2) are isolated as stable cyclic isomers 22B and 23B, whereas N-r-butylamides possess open-chain structures 22A and 23A (R = f-Bu) in the solid state (86KGS80). The hydrochloride of the amide 22A (R = r-Bu) retains the open-chain structure in the... 

Beckmann rearrangement of, 729,741 p-Benzoquinone, 745 Benzoylacetone, 865 o-Benzoylbenzoic acid, 728, 739 Benzoyl chloride, 791, 792 Benzoyl glycine, 584 Benzoyl peroxide, 807 determination of, 809 Benzoyl piperidine, 489, 492 P-Benzoylpropionic acid, 728, 737 P-Benzoylpropionitrfle, 911, 912 Benzoyl-p-toluidide, 582, 583 Benzyl acetate, 780, 783 Benzylacetophenone, 726, 734 Benzyl alcohol, 706,711, 811,812,884 N-Benzylamid es 394 table of, 395 ... 

Several different types of linker have been developed that yield amides upon cleavage. These linkers can often also be used to prepare sulfonamides, carbamates, or ureas. There are essentially three different strategies for the release of amides from insoluble supports (a) cleavage of the benzylic C-N bond of resin-bound N-alkyl-N-benzylamides (backbone amide linkers, BAL linkers), (b) nucleophilic cleavage of resin-bound acylating agents with amines, and (c) acylation/debenzylation of resin-bound /V-benzyl-/V,A -dialkylamines. 

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. 

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

The isoquinolines 70 are an important subclass of the tertiary N-benzylamides, and their lithiation and benzylation is an important way of synthesising a range of benzylisoquinoline alkaloids.4849... 

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 N-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. 

The N-H bond of amides has a pKa of 15-18, an acidity comparable to alcohols and protection of the N-H bond by JV-benzylation is a common ploy. Schemes 8.181 and 8.182 exemplify catalytic hydrogenolyses of N-benzylamides, which were steps in syntheses of Huperzine A71 and AI-77-B (gastroprotective agent),385 respectively. However a number of authors have commented that N-benzylamide groups can be difficult to hydrogenolyse (see below) and therefore these examples may represent particularly favourable cases,... 

An alternative common method uses sodium in liquid ammonia to cleave N-benzylamides under conditions mild enough to tolerate -lactam rings. 

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). 

RCOOCHj + HaNNHj —> RCONHNHj + CHjOH The hydrazides are often crystalline and then serve as useful derivatives. Esters of higher alcohols should be converted first to the methyl esters by boiling with sodium methoxide in methanol (see under N-benzylamides). 

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. 

The most common derivative of the acid is the N-benzylamide derivative. 

Dermer OC, King J (1943) N-benzylamides as derivatives for identifying the acyl groups in esters. J Org Chem 8 138-173... 

In a 2005 paper published by Prof Kappe s group describing palladium[Pg.100]

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