Nucleophilicity, ambident amides

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 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. 

Amides, carbamates, and ureas are rapidly alkylated, usually on carbonyl oxygen (see the section on ambident nucleophiles). Alkylation of amides with MeOTSf in CH2CI2 followed by reduction of the salts provides a route for the selective reduction of amides esters, nitriles, acetals, and double bonds are left unaffected by this procedure. Alkylation of isoindolin-l-ones and subsequent deprotonation can provide routes to methoxyisoindoles. ... 

Ambident Nucleophiles. Amides and related functional groups can be alkylated on oxygen or nitrogen and, as has been noted already, alkylation on carbonyl oxygen normally predominates. In the case of carbamates, 0-alkylation by Me0S02F can be faster, but W-alkylation predominates at equilibrium. It has been noted that methylation of secondary amides and thioamides occurs at the protonless heteroatom in the major tautomer. The ionic products of these reactions can be deprotonated to give synthetically useful products, e.g. imidates, but excess Me0S02F should be removed before treatment with base. ... 

Amides are alkylated largely on oxygen, as expected (see below), although some N-alkylation can be seen by NMR. N-Alkylation is more apparent with carbamates (see the section on ambident nucleophiles). Al,N-Dimethylmethanesulfonamides can be N-alkylated (Me0S02p) to provide salts which are effective reagents for mesylation. A/,N-Dimethylsulfamate esters react... 

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