Carboxamido groups

Alteration of positional selectivity will result from built-in solvation of the transition state by an adjacent carboxyl-related function.Aminations will be so affected by carboxyl, carboxylate ion, carboalkoxy and less so by carboxamido groups (cf. Section I,D,2,b, structure 12.) Other substitutions such as alkoxylations can be so affected by carboxamido and amidino groups (cf. Section I,D, 2,b, structure 14). The effect of the cyclic hydrogen-bonded form (63) of 2-carboxamidopyridine on the reactivity of a leaving group is not known. 

Aliphatic amines proved to be more reactive than aromatic amines with EMME [e.g., 76JCS(P1) 1331 ]. Aromatic amines react more easily than the amino portion of the carboxamido group (e.g., 75IJC1275) (Scheme 8). 

Antibacterial sulfonamides contain two N-atoms, the sulfonamido (N1) and the para primary amino (N4). The sulfonamido group, in contrast to a carboxamido group, is chemically and metabolically stable. In other words, hydrolytic cleavage of sulfonamides to produce a sulfonic acid and an amine has never been observed. We, therefore, focus our discussion on the primary amino group, acetylation of which is one of the major metabolic pathways for some sulfonamides. Hydrolysis of the N4-acety luted metabolites back to the parent sulfonamide can occur in the liver, kidney, and intestinal tract. The reaction is strongly influenced by the structure of the parent amine e.g., N4-acetylsulfisoxazole (4.121) was deacetylated by intestinal bacteria whereas /V4-acctyIsulI anilamide (4.122) under identical conditions was not [78][79],... 

The simplest degradation displayed by asparagine and glutamine is direct hydrolytic deamidation of the side-chain carboxamido group (Fig. 6.29, Pathway d). Such a reaction, however, is seen only at low pH values, and its biological significance appears negligible. Its product is the Asp peptide (6.62) whose further reactions have been presented in Fig. 6.27. 

While the examples outlined in the previous section all pertain to attack by a basic N-atom, another possibility is intramolecular attack by an acidic N-atom, i.e., a deprotonated amide. For example, in AT-(2-carbamoylphe-nyljcarbamalcs of model phenols (8.135, X = H, Cl, or MeO, Fig. 8.11), the deprotonated carboxamido group attacks the carbamate carbonyl C-atom to form a quinazoline-2,4-dione with release of the phenol [173]. In acidic media, formation of the quinazoline-2,4-dione is decreased by competitive breakdown of the intermediate to an anthranilate and C02 in addition to the phenol (not shown). 

With Aralkyl- or Wacylpyridinium salts, the addition of isonitriles takes place efficiently when a carboxamido group is present in the 3-position. The outcome of the reaction involves the stabilization of the nitrilium intermediates by the amide, which suffers a mild dehydration providing 3-cyano-4-carbamoyl-l,4-dihydropyridines. This method also works with the corresponding Wacylquinolinium and Wacylisoquinolinium salts (Equation 58) <2006OL5789, 2004JOC3550>. 

The fusion of a pyrimidine onto an existing thiophene has also been described. The thiophene with ortho-amino and ester functions (i.e. (280 R = C02Et)) is treated first with a series of elaborate primary amines, which form the 4-carboxamido group. Subsequent reaction with trimethyl-aluminum leads to the dioxothienopyrimidine (281) in which the desired variation occurs at R4 (Equation (99)) <90JHC1761>. 

Zhu and coworkers implemented a family of Ugi-type MCRs, based on intramolecular trapping of the intermediate nitrilium ion by a carboxamido group, to prepare diversely substituted oxazoles as versatile synthetic intermediates [192-194], They later reported an interesting example of the Ugi-Reissert process using this feature (237, Scheme 34a) [195], This strategy enabled the direct addition of isocyanides to the Ai-alkyl nicotinamide salts 239. However, the different substitution pattern of the carboxamido group, led to a different outcome isomerization of the putative bis-iminofurane intermediate to the cyano-carbamoyl derivative 240. Remarkably, the process is also efficient in a Reissert-type reaction (Scheme 34b, c) [196]. 

First to be checked was a set of methanofullerene derivatives 289a-c, readily available via addition of substituted diarylcarbenes (generated in situ) to one of the double bonds of fullerene 59 followed by a conventional transformation of the carboxamido groups of the side chains (Scheme 4.88). Bis-succinoyl-... 

Reduction of the carboxamido group of ceramide to a methylene group... 

The participation of an isolated double bond in a five-membered ring in displacement reactions is apparently difficult or impossible, but fortunately becomes very easy when the double bond is conjugated with an imino group and in the 7,5-position relative to a carboxamido group, as in tryptophan peptides. 

In human plasma, two groups of compounds were seen. In most cases, the reaction in plasma (i.e., chemical plus enzymatic activation) was approximately twofold faster than in buffer. This indicates that enzymatic hydrolysis in human plasma, if any, was modest at best. Only for the three prodrugs with an unsubstituted carboxamido group (R = H) was the enzymatic reaction several-fold faster than was intramolecular catalysis, suggesting these compounds to be substrates of plasmatic hydrolases. Thus, the A -(2-carbamoylphenyl)carbamate promoiety allowed a highly modulatable intramolecular activation with little enzymatic activation. 

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