Ambident amide

RA-410(OH) 21, 2 Ambident s. Anions, ambident Amidals s. l,l-Di(acylamines) C-Amidatiou with hydroxamic... 

Amberlyst resin 538 Amberlyst-15 (H+) 762 f. ambident electrophile 456, 478 ambident nucleophile 78 amides... 

HSAB is particularly useful for assessing the reactivity of ambident nucleophiles or electrophiles, and numerous examples of chemoselective reactions given throughout this book can be explained with the HSAB principle. Hard electrophiles, for example alkyl triflates, alkyl sulfates, trialkyloxonium salts, electron-poor car-benes, or the intermediate alkoxyphosphonium salts formed from alcohols during the Mitsunobu reaction, tend to alkylate ambident nucleophiles at the hardest atom. Amides, enolates, or phenolates, for example, will often be alkylated at oxygen by hard electrophiles whereas softer electrophiles, such as alkyl iodides or electron-poor alkenes, will preferentially attack amides at nitrogen and enolates at carbon. 

Phenanthridones and benzophenanthridones undergo ready alkylation on treatment with dialkyl sulfates in alkali.113, 126 As in the case of other, similar, ambident nucleophiles, V-alkylation normally predominates, although with diethyl sulfate 2-nitrophenanthridone gives a significant amount (27%) of 6-ethoxy-2-nitrophenanthri-dine,126 and, more recently, O-methylation has been observed in the reactions between both the methyl ester and the pyrrolidine amide of phenanthridone-4-carboxylic acid with methyl iodide in the presence... 

A variation of the alkylation of imines has been developed188,189. The imine is first converted to the ambident ion by sodium hydride, sodium amide or lithium diisopropy-lamide and an alkylating agent is then added. 

According to Bredereck et al.,17,18 the reaction of carboxylic acid amides with dialkyl sulfates proceeds via the intermediate ambident cation such as (5). In the case of caprolactam, when excess dialkyl sulfate is taken, the A,(9-dialkyl derivative (6) is formed, which with base forms 3 (Scheme 1). 

The synthesis of the allyl ethers in nitrogen heterocyclic systems presents an element of complication in that the allylation could occur on the oxygen atom or the basic nitrogen atom. This is a feature of alkylation of ambident anions.3 However, this applies only when the allylation is effected by reacting the oxo or hydroxy derivative of the compound with an allyl halide in the presence of a base.3 The alternative method is to react the appropriate halo derivative with sodium allyloxide in allyl alcohol. The latter approach provides not only better yields of the allyl ethers but also certainty of the constitution of the ethers obtained. A diagnostic tool in deciding between the 1-allyl derivative and the O-allyl compound that has commonly been employed is the infrared absorption of the amide carbonyl in the case of the former which is clearly absent in the latter. 

A major distinction for nucleophilic reactions with ambident anions is whether they proceed with kinetic or thermodynamic control.80 N-Substituted saccharins (10) should be thermodynamically more stable because of amide character than the isomeric pseudosaccharin (3) of imidate structure. In fact 3 may be rearranged thermally to 10 in an irreversible reaction.96 The threshold for thermodynamic control appears to be lowered for electrophiles with multiple bonds, e.g., formaldehyde, reactive derivatives of carboxylic acids, but also quaternary salts of N-heterocyclic compounds.80 It will be seen that in those cases substitution indeed occurs at the nitrogen, not necessarily through thermodynamic control. 

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

Pyridazinones have been reported to undergo a number of reactions with substitution on oxygen or nitrogen of the amide group. They can react as ambident anions in alkylations, but in view of the complexity of some such reactions this theory seems not to be so simply explainable when applied to pyridazinones. 

Deprotonation of alkylnitriles with LDA or lithium hexamethyldisilazide (LHMDS" ) and treatment of the resultant ambident a-nitrile anions with 1° and 2°-alkyl halides affords C-alkylated products in good yield. However, the a-anions of highly substituted nitriles may undergo N-alkylation to give amides on aqueous workup. 

The addition of alcohols to nitrilium salts gives rise to formation of alkoxymethyleneiminium salts, which react with bases to yield imido esters (231 Scheme 33). - By deprotonation of carboxylic acid amides ambident anions are formed, which can be alkylated in the presence of silver ions to give imido esters, e.g. (232). " Secondary amides react with trifluoroacetic acid anhydride or trifluorosulfonic acid anhydride to give mixed anhydrides of imidic acids (233). ... 

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