Carboxamide derivatives nucleophiles

An intramolecular ring expansion of aziridine esters can be accomplished by installing an appropriate nucleophilic entity in these substrates. Conversion of the ester moiety into carboxamides derived from aminomalonate ester gives compounds 44 containing the requisite nucleophilic site in the malonate moiety (Scheme 35). 

Reaction via unstable acidic or basic intermediates can be promoted by proton transfer to a base or from an acid, respectively, thus giving rise to base or acid catalysis. The concept is illustrated for nucleophilic attack on carboxamide derivatives (Scheme 11.6). With base catalysis, deprotonation of the first-formed intermediate promotes the forward reaction, as does protonation of the first-formed intermediate with acid catalysis. 

Scheme 11.6 Proton transfer in nucleophilic substitution in carboxamide derivatives.

The Ugi Reaction is the one-pot condensation of an amine, aldehyde or ketone, isocyanide, and a nucleophile to afford a-substituted carboxamide derivatives. Also known as the Ugi Four-Component Reaction (U-4CR) or Ugi Four-Component Coupling (or Condensation) (U-4CC), this reaction is recognized as a reliable tool for the construction of peptide bonds and for its applications within combinatorial chemistry. ... 

In contrast with carboxyl-derived enolates, few general, highly stereoselective methods for the asymmetric alkylation of aldehyde and ketone enolates are available [15, 20]. Some of the key problems associated with these are widely appreciated. The aldehyde and ketone counterparts are more weakly nucleophilic than carboxamide-derived enolates. In addition, the ease with which the products undergo epimerization under relatively mild acidic or alkaline conditions can provide a practical limit to the isolation of pure adducts. 

Nucleophilic attack by carbanion occurs in the reaction of 2-nitrobenzamides 154 treated with sodium ethoxide (72JCS(P1)835). The reaction mixtures usually contain small amounts of nitrile 155 and carboxamide 156, the product of decarboxylation 158 being usually the principal product (Scheme 24). The corresponding bromo derivatives under the used conditions did not react. 

Because of partial deactivation of many catalysts by aliphatic amines, less nucleophilic derivatives such as carboxamides or carbamates are usually used as substrates for carbene N-H insertion. 

From A(-substituted carboxamides, the 3-unsubstituted derivatives were formed, with loss of the corresponding amine. This reaction is to be expected from the mechanism of the ring closure amidine formation and subsequent nucleophilic attack of the amidine nitrogen on the carbonyl group. 

The resistance of the furoxan ring to chemical attack allows derivatives to be prepared via the reactions of the substituents (Section 4.22.3.4). Carboxylic acids are available by permanganate oxidation of methyl derivatives or by hydrolysis of the corresponding esters reaction with ammonia affords carboxamides. Acylfuroxans provide a source of hydroxyalkyl compounds by reduction, and oximes, for example, via nucleophilic addition. Acylation and oxidation of aminofuroxans allows the amide and nitro derivatives to be prepared. Nucleophilic displacements of nitro substituents can take place, but can be somewhat hazardous on account of the explosive nature of these compounds. Alkoxy derivatives are formed with sodium alkoxide, while reaction with thiolate anions yields sulfides, from which sulfones can be synthesized by peracid oxidation. Nitrofuroxans have also been reduced to... 

The carboxamide moiety was then examined, preparing several 2,4-dichlorophenoxy compounds in solution (9.37-9.43, Fig. 9.20). Replacement of the primary amide with small N-nucleophile-derived groups (9.41-9.43) maintained activity, as did the methyl ester-substituted 9.39 while the free acid 9.38, the deletion compiound 9.37, and more complex secondary amide analogues lost inhibitory activity. The hydroxamate function significantly increased the solubihty profile of 9.43 thus it was considered relevant for the optimization of the chemical series (Fig. 9.20). 

Fluoro-l-phenylpyrazole-4-carboxamides 304 have been formed by condensation of the 5-fluoro-l-phenylpyrazole-4-carboxylic acid 303 with amines (Equation 58) <2000EJ0823>. 4-Benzoyl-l-(4-nitrophenyl)-5-phenyl-l//-pyrazole-3-carboxylic acid 305 was converted via reactions of its acid chloride with alcohols or N-nucleophiles, into the corresponding ester or amide derivatives 306 (Equation 59) <2004CHE1039>. Resin-bound pyrazole-4-carboxylic... 

Reactions of selenazadienes with chloroacetyl chloride (2 equiv) then alcohols or amines gave 2-amino-l,3-selena-zole-5-carboxylates 8 or 2-amino-l,3-selenazole-5-carboxamides 10, respectively. The reaction is initiated by the nucleophilic displacement by selenium of chloride from the a-position of the chloroacetyl chloride, eventually affording the 1,3-selenazole derivatives (Scheme 8) <2005JHC831, 2004S233>. 

Bicyclo[4.1.0]heptane-7,7-diyl)dimorpholine reacted with oxazol-5(47/)-one derivatives in a nucleophilic substitution reaction. - A 1 2 ratio of the reagents was necessary since morpholine as leaving group consumes one mole of oxazol-5(4//)-one to give a carboxamide. 

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