Diacyl amides

N-t-butyl derivatives (e.g., 58) can give satisfactory results but are prone to a number of side reactions, including that just mentioned.173-175 Diacyl-amides (63) may arise as by-products from the ketoketenimine via an imino-anhydride (as shown in Scheme 11) rather than from the enol ester.176 Tetrahydrobenzisoxazolium ions (59) and related compounds are promising as far as freedom from rearrangement and lack of promotion of racemiza-tion are concerned, but they do not appear to have been evaluated in actual peptide syntheses.171 Although beyond the scope of this review, benzisox-azolium salts have also been applied as reagents for peptide synthesis.177,178... 

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... 

Diacyl-amide werden bevorzugt im sauren Medium hydrolysiert, vgl. z.B. Lit.417 und Tab. 40, S. 258, Beispiele fur die alkalische Hydrolyse sind ebenfalls bekannt (vgl. Tab. 41, S. 259). 

The product of this reaction is an imide (Section 20 16) a diacyl derivative of an amine Either aqueous acid or aqueous base can be used to hydrolyze its two amide bonds and liberate the desired primary amine A more effective method of cleaving the two amide bonds is by acyl transfer to hydrazine... 

Aromatic copoly(amide—imide)s with Atriazine rings in the repeating unit of the backbone are also possible from a diacyl chloride reacting with preformed imide groups and diamines containing Atriazine rings (15). 

Carboxylic acid hydiazides are prepared from aqueous hydrazine and tfie carboxylic acid, ester, amide, anhydride, or halide. The reaction usually goes poody with the free acid. Esters are generally satisfactory. Acyl halides are particularly reactive, even at room temperature, and form the diacyl derivatives (22), which easily undergo thermal dehydration to 1,3,4-oxadiazoles (23). Diesters give dihydtazides (24) and polyesters such as polyacrylates yield a polyhydrazide (25). The chemistry of carboxyhc hydrazides has been reviewed (83,84). 

The similarity between the cryptands and the first of these molecules is obvious. Compound 7 7 is a urethane equivalent of [2.2.2]-cryptand. The synthesis of 7 7 was accomplished using a diacyl halide and l,10-diaza-18-crown-6 (shown in Eq. 8.13). Since amidic nitrogen inverts less rapidly than a tertiary amine nitrogen, Vogtle and his coworkers who prepared 7 7, analyzed the proton and carbon magnetic resonance spectra to discern differences in conformational preferences. Compound 7 7 was found to form a lithium perchlorate complex. 

The low condensation of diacyl chloride and bis-orf/zo-aminophenol gave a polyhydroxy amide that was submitted to a thermal dehydration.185 187 The two functions of an aminophenol could be acylated, and the question of chemose-lective acylation has been discussed.188 The problem is not O-acylation versus N-acylation because the N-acylated product is tire more stable isomer, but the question is how to control N-monoacylation versus diacylation that could reduce the molecular weight. It has been shown that the condensation in the presence of inorganic salt (LiCl) in NMP gives selectively the N-monoacylated... 

Hydrazides (RCONHNH2) are highly useful starting materials and intermediates in the synthesis of heterocyclic molecules.2 They can be synthesized by hydrazinolysis of amides, esters and thioesters.3 The reaction of hydrazine with acyl chlorides or anhydrides is also well known,4 but it is complicated by the formation of 1,2-diacylhydrazines, and often requires the use of anhydrous hydrazine which presents a high thermal hazard. Diacylation products predominate when hydrazine reacts with low molecular weight aliphatic acyl chlorides, which makes the reaction impractical for preparatory purposes.5... 

Formally related reactions are observed when anthracene [210] or arylole-fines [211-213] are reduced in the presence of carboxylic acid derivatives such as anhydrides, esters, amides, or nitriles. Under these conditions, mono- or diacylated compounds are obtained. It is interesting to note that the yield of acylated products largely depends on the counterion of the reduced hydrocarbon species. It is especially high when lithium is used, which is supposed to prevent hydrodimerization of the carboxylic acid by ion-pair formation. In contrast to alkylation, acylation is assumed to prefer an Sn2 mechanism. However, it is not clear if the radical anion or the dianion are the reactive species. The addition of nitriles is usually followed by hydrolysis of the resulting ketimines [211-213]. 

Despite continnons progress in amide bond formation, the acylation of hydroxylamine nnder carbodiimide promotion is often contaminated by Af,0-diacylation even with sub-stoichiometric amounts of acids. Appendino and colleagues have developed a practical solution to the problem by combining the in situ activation of carboxylic acids 102 with the cyclic phosphonic anhydride PPAA (103), and the generation of hydroxylamine from its corresponding hydrochloride to form 104 (Scheme 54). 

The amide carbonyl vibrational frequencies of A-acyloxy-Af-alkoxyamides are similar to that observed for the twisted l-aza-2-adamantanone (98, 1731 cm ) . It is apparent from the extensive data available for both A-chlorohydroxamic esters (Table 2, Section in.B.2) and Af-acyloxy-A-alkoxyamides that when an amide nitrogen lone pair loses conjugation with the carbonyl (either through twisting/pyramidalization or, in the case of anomeric amides, pyramidalization alone), the configuration is analogous to an ester rather than a ketone. As with esters, acid halides and anhydrides or diacyl peroxides , the carbonyl stretch frequency is higher than that of ketones and aldehydes... 

Shtamburg and coworkers have reported that A,A -dialkoxy-A,A -dicarboalkoxyhydra-zines (219) have lower barriers to amide isomerization and weaker anomeric interactions . They measured a barrier to amide isomerization of only 9.8 kcalmoD. Furthermore, benzylic methylenes in A-benzyloxy systems were isochronous down to at least —90°C. These results are in line with observations for the A,A -diacyl-A,A -dialkoxyhydrazines since, in the carboalkoxy systems, the nitrogen lone pairs are lowered in energy by the additional electron demand, thereby reducing both amide conjugation and anomeric overlap. 

The reaction of iV-acyloxy-iV-alkoxyamides and aromatic amines, the thermal decomposition of iV,iV -diacyl-iV,iV -dialkoxyhydrazines as well as the base-induced decomposition of azodicarboxyiates are examples of the HERON reaction, one of the newest-named reactions in the chemical literature , but one that seems to be common for these as well as a range of other bisheteroatom-substituted amides . No doubt new examples will be discovered and it is entirely predicated upon the configurational and conformational properties of anomeric amides, attributes arising directly as a consequence of the dual electron demands of the heteroatoms at nitrogen. 

The highest flexibility for a variation of the functional group and the chains X and Y (i.e. the size of the rim of the lamp shade) will be realiad when the synthesis of 3 is convergent and modular (Scheme 1). Amide bonds can easily be formed in macrocyclizations [13], therefore macrocyclic diamines 7 and diacyl dichlorides 8 had to be prepared. For the synthesis of macrocyclic diamines 7, also a large number of reactions are known. However, in this case a reduction of a macrocyclic diamide could not be achieved [11]. Therefore, another route was used the formation of macrocyclic diimines 6 (bis-Schiff bases) followed by NaBH4 reduction to the macrocyclic diamines 7. This approach has the advantage that for the construction of macrocyclic diimines 6, the metal ion template effect [14] may be exploited. 

The degradation of support-bound a-amino acid amides has been used to prepare retro-inverso peptide mimetics ([226], second equation in Figure 10.6). These compounds are of interest because of their potentially improved metabolic stabilities, selectivities, and biological activities compared with peptides [226], Although retro-inverso peptides are aminals susceptible to acid-catalyzed hydrolysis, N,N -diacylated aminals can be sufficiently stable to withstand the conditions of Boc-group removal [227] or of acidolytic cleavage of peptides from Wang resin [226]. 

Even though the resulting amide has an unshared electron pair on nitrogen, it does not react with a second mole of acetic anhydride to become diacylated ... 

This same polyamide can be prepared by reaction of the diacyl chloride of adipic acid with hexamethylenediamine. In Section 19.6 we saw that the conversion of the salt of a carboxylic acid and an amine to an amide could be accomplished by heating but that this method was not often used in the laboratory because of the rather vigorous conditions that must be employed. However, in an industrial setting, cost is a more important factor. Because the reaction starting only with the diacid and the diamine is much less expensive than first converting the diacid to its acyl chloride, the former method is the one used to prepare nylon 6,6. 

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