Ambident electrophiles compounds

The presence of two electrophilic reaction centers in the molecule of o -unsaturated carbonyls is responsible for their ability to participate in the synthesis of heterocycles. Such compounds can react as ambident electrophiles owing to delocalization of electron density in a C=C-C=0 system. The addition of nucleophiles to these molecules can proceed in one of two main directions—via attack of the carbonyl group (1,2-addition) or involving the / -carbon (1,4-addition). 

These compounds are characterized by their tautomerism, and they exhibit ambident electrophilic reactivity. 

The main feature of these compounds is their tautomerism and resultant ambident electrophilic reactivity. Their reactivity is therefore highly dependent upon the electron distribution within the ring. Electrophilic attack occurs P to either the ring nitrogen or sulfur, whereas nucleophilic attack tends to take place at the a-position, normally C-2. Nucleophiles can also deprotonate the heterocycle, acting as bases. 

A reaction in which perchloryl fluoride functions as an ambident electrophile, somewhat analogous to Neeman s oxofluorination, was discovered by Kende and MacGregor on passing FCIOj into a suspension of sodium 2,6-dimethylphenoxide in pentane or toluene at 0°. Workup and chromatography gave 2,6-dimethylphenol, 2,6-dimethylbenzoquinone, 2,2, 6,6 -tetramethyl-4,4 -diphenoquinone and, in about 20% yield, a new compound characterized as the dimer (3) of 6-fluoro-2,6-dimethyl-... 

Dialkyl triselenocarbonates have been characterized as ambident electrophiles by Henriksen and Kristiansen on the basis of their study of the reaction of these compounds with amines. In general, this reaction resulted in the formation of various products, a fact that was rationalized by the application of Pearson s principle of hard and soft acids and bases. Thus the selenocarbonyl carbon atom was found to represent the harder centre of acidity, combining principally with the harder amine base added, whereas the selenium atom of the alkylseleno-group appeared to represent a softer centre of acidity, combining preferentially with the softer alkyl selenide ion liberated by the former process. 

NH form e.g. 505). Most 4- and 5-hydroxy compounds of types (500) and (502) exist largely in these non-aromatic azolinone forms, although the hydroxyl form can be stabilized by chelation e.g. 506). The derived ambident anions react with electrophiles at O or C. Replacement of the hydroxyl group is sometimes possible provided electron-withdrawing groups are present as, for example, in 5-substituted 4-hydroxypyrazoles. 

Besides direct nucleophilic attack onto the acceptor group, an activated diene may also undergo 1,4- or 1,6-addition in the latter case, capture of the ambident enolate with a soft electrophile can take place at two different positions. Hence, the nucleophilic addition can result in the formation of three regioisomeric alkenes, which may in addition be formed as E/Z isomers. Moreover, depending on the nature of nucleophile and electrophile, the addition products may contain one or two stereogenic centers, and, as a further complication, basic conditions may give rise to the isomerization of the initially formed 8,y-unsaturated carbonyl compounds (and other acceptor-substituted alkenes of this type) to the thermodynamically more stable conjugated isomer (Eq. 4.1). 

In a mechanistically similar process, the neutral palladium(II) dipyridylamine complex (24), obtained by deprotonation of complex (23), underwent reaction with benzoyl chloride to give the substituted complex (25) together with some free ligand (Scheme 8).33 This particular reaction sequence could not be generalized because of the relative instability of other metal complexes related to compound (24). However, a more extensive series of electrophilic substitutions could be carried out on the neutral complex (26), which displayed ambident nucleophilic behaviour by reaction with benzyl chloride and benzoyl chloride at nitrogen and reaction with benzenediazonium fluoroborate at carbon (Scheme 9). 

Apart from their fundamental role in sulfur ylide chemistry, sulfonium salts have found applications as soft electrophiles. In alkylation of ambident nucleophiles such as the enolates of [3-dicarbonyl compounds they led to selective C-alkylation [205],... 

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. 

Crotyllithium reagents are ambident nucleophiles and can react with electrophiles either at the a- or y-carbon. The regiochemistry of attack depends on many factors, such as structure, the electrophile, and the solvent. Generally, unhindered carbonyl compounds preferentially add to crotyllithiums at the y-position. 

Dihydro-3//-pyrazol-3-ones are also CH-acids. The pKa value of the unsubstituted compound is 7.94. They react with bases to give ambident anions which are stabilized by conjugation and can be attacked by electrophiles at C-4, at N-1, or at the 0-atom. Thus 2,4-dihydro-3//-pyrazol-3-ones undergo aldol condensations and react with nitrous acid to give isonitroso compounds, e.g. ... 

Enolates of carbonyl compounds are ambident anions. Although the negative charge resides predominantly at the oxygen, reactions of enolates with electrophiles can take place at the carbon terminus. C-Monoalkylation of enolates is usually accompanied by di- and polyalkylation owing to a rapid... 

Azlactone is commonly utilized as a precursor of a-quatemary a-amino acids and various heterocyclic compounds [28-30]. Because the enol form of azlactone has aromatic character, facile deprotonation from the C4-position affords the corresponding enolate under the influence of various bases. Interestingly, the enolate ion shows ambident reactivity and attacks the electrophile at either the C4-position (a-addition) or the C2-position (y-addition), thus acting as an a-amino enolate or an acyl anion equivalent, respectively (Fig. 1). The site-selectivity associated with this enolate seems to be heavily dependent on its stereoelectronic characteristics, and introduction of a bulky substituent into the Cl- or C4-position suppresses the nucleophilicity at the particular position. 

Homopropargylic alcohols are important intermediates, as these structural units are present in a variety of natural products and biologically active compounds [1]. Synthesis of these compounds is generally accomplished by reactions of their organometallic equivalents using an array of metals (Mg, Li, Ti, Zn, Al, Sn, Si) [2]. However, their utility is limited due to their ambident nucleophilic nature, which makes them to react with electrophiles unselectively to produce a mixture of products. 

Further, enamines (38) or allylamines (39) are deprotonated to give ambident 1-aminoallyl anions which react with chlorotrimethylsilane with high regio-selectivity to yield the versatile silylated enamines (40) only, and which may be hydrolysed, or further deprotonated and subsequently alkylated to give enamines (41), which themselves may be isolated or hydrolysed without further purification (Scheme 54). Similarly, the silylated enamines (43) are derived from (42). Surprisingly, compounds (43) react with a variety of carbon electrophiles in the presence of TiCU to give products derived from substitution at the y-position (Scheme 55). A(,iV-Bis(silyl)enamines react with carbonyl compounds in the presence of fluoride ion to provide an interesting route to 2-aza-l,3-dienes, Enamine products also result from the rearran ment of thioimidates derived... 

Each resonance form contributes to the characteristics of the enolate ion and thus to the chemistry of carbonyl compounds. The resonance hybrid possesses partial negative charges on both carbon and oxygen as a result, it is nucleophilic and may attack electrophiles at either position. A species that can react at two different sites to give two different products is called ambident ( two fanged from ambi, Latin, both dens, Latin, tooth). The enolate ion is thus an ambident anion. Its carbon atom is normally the site of reaction, undergoing... 

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