Amides from transamidation

In a later development by Bedenbaugh et methylamine was used as solvent and lithium as electron donor. No proton donor was required, suggesting that the lithium salt (28) of hemiaminal (27) is stable under the reaction conditions (both aldehydes and aldimines are reduced by the reagent cf. the analogous reduction of carboxylic acids, Section 1.12.2 and Scheme 2). Yields of aldehydes produced by this method are shown in Table 8. It is notable that only tertiary amides are reduced satisfactorily. A major limitation of the reaction is the substantial formation of side products resulting from transamid-ation by the methylamine solvent (/. e. RCONHMe from RCONR 2). 

Carboxylic acid amides from carboxylic acids by transamidation... 

MPD-1 fibers may be obtained by the polymeriza tion of isophthaloyl chloride and y -phenylenediamine in dimethyl acetamide with 5% lithium chloride. The reactants must be very carefully dried since the presence of water would upset the stoichiometry and lead to low molecular weight products. Temperatures in the range of 0 to —40° C are desirable to avoid such side reactions as transamidation by the amide solvent and acylation of y -phenylenediamine by the amide solvent. Both reactions would lead to an imbalance in the stoichiometry and result in forming low molecular weight polymer. Fibers are dry spun direcdy from solution. 

Another degradation reaction observed in suspension was the formation of covalent insulin dimers [134][136], These involve isopeptide links between two insulin molecules, that result from a transamidation reaction mainly between the B-chain N-terminus of one insulin molecule, and one of the four amide side chains in the A-chain (principally AsnA21) of the second insulin molecule. 

NH3 or RNH2 or R2NH Amide formation from carboxylic acid derivatives (mild) or from carboxylic acids (A technical synthesis of nylon-6,6) transamidation [capro-lactame —> nylon-6 (perlon)] Peptide synthesis (Section 6.4.3)... 

The NH2 group of carboxamides, particularly if unsubstituted, can be exchanged for residues from other amines, hydrazines, etc. Thus A-formyl-amines are often obtained quite smoothly by heating the amine with form-amide in a vacuum at as low as 70°.1144 Higher carboxamides react analogously at temperatures of 150-200°.1145 Transamidation occurs more readily if the carboxamide is melted with the amine hydrochloride 692,1146 and diacyl-amides, including cyclic dicarboximides such as succinimide and phthalimide are more reactive than simple carboxamides.1147... 

In summarizing, it must be realized that most of all acidic conditions to remove a synthetic peptide from its gel phase support include the possibility for undesired attacks on either protected or free peptide side functions as well as on the backbone, causing fissions and conversions also during work-up manipulations of already detached raw products. This is the case because most of the usually employed protecting principles — urethanes, esters, and ethers as well as some functional sites of a peptide such as alcoholic, thioUc, and amide side chain groups — can be involved in proton catalyzed eliminations, transesterification, transamidations, and cyclol formations, though some of these side reactions usually are rather feared under basic conditions. 

Transamidation of primary amides (10) by amines (11) may be carried out highly efficiently by heating equimolar amounts of each in the presence of 10mol% L-proline under solvent-free conditions (Scheme 4). In the proposed mechanism, L-proline condenses with an amide to form intermediate (A), which undergoes nucleophilic addition of an amine to generate a TI (B), loss of ammonia from which yields intermediate (C). In the final step, hydrolysis yields the transamidation product and regenerates L-proline (Scheme 5). ... 

Amino-alkyl amides form amidines reversibly on heating and under acidic conditions. In the latter case amidines are proposed as intermediates in transamidation reactions. A full paper on a modified Shapiro reaction of hydrazones derived from secondary or-keto-amides has appeared. Ultra sound is reported to produce improvements in the heterogeneous reaction between amides and P4Sio. °... 

The amide transfer reactions can be distinguished from the transamidation reactions studied by Fruton et al. as follows. The enzyme is not a peptidase or protease. The amide (or hydroxylamine) transfer is restricted to the /3-carboxyl of aspartic acid or the y-carboxyl of glutamic acid the transfer is not associated with hydrolysis of the amide it does depend on ATP or ADP, arsenate or phosphate, and Mn++, but this dependence notwithstanding, it shares with the peptidase-protease type of transamidation its independence of energy or phosphate transfer. 

On this basis the extent to which an enzyme-catalyzed transamidation will occur will depend on the relative concentration of water and the replacement reagent, and the relative affinity of the replacement agent for the ES-complex. Durell and Fruton (51) have studied papain-catalyzed hydroxamic acid formation from o-benzoyl-L-argininamide. Their calculations show that hydroxylamine is about 420 times more efficient in its reaction with the enzyme-substrate complex than is water. Preliminary observations suggest that when amino acid amides or peptides are the attacking molecule the efficiency is even greater. Moreover, papain is a much more effective catalyst for transamidation than trypsin. 

Aside from the outstanding and reliable diastereoselectivity, two more advantageous features helped the method to success the easy, one-step preparation of various N-acylated derivatives from the parent oxazolidinones and the cleavage of the auxiliary by hydrolysis, transamidation to the Weinreb amide, esterification, and reduction, as outlined in Section 4.1. A typical Evans aldol procedure with phenylalanine-derived oxazolidinone (S)-47, including the preparation of propionic imide 73 and cleavage of the auxiliary, is shown in Scheme 4.47. Typically, the boron aldolate resulting from the addition to the aldehyde has to be cleaved by an oxidative work-up. The hydrolysis of the aldol adduct 211 occurs without detectable epimerization that liberates diastereomerically and enantiomerically pure carboxylic acid 212 besides the auxiliary (S)-47 [110]. 

Altering the iV-substitution of an amide by the introduction of an amine is termed transamidation it offers an interesting approach to the construction of functionalised amide bonds. It can allow alternative disconnection pathways that may suffer from decarboxylation if carboxylic acids are... 

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