Electrophilicity benzylating agents

The cyclizations of 85 to 86 and of 87 to 88 represent the simple cases in which the internal nucleophile is the OH group of an alcohol [64,65]. An in situ generated hydroxy group, as in the addition of alcohols to carbonyl compounds, can also participate in phenylseleno-etherification reactions. This is examplified by the conversion of 89 into 90 in the presence of benzyl alcohol [66]. Another type of OH, which gives rise to these reactions is the enolic OH of /1-dicarbonyl compounds. Thus, Ley reported that compounds like 91 and 93 can be transformed into the cyclic derivatives 92 and 94 by treatment with N-PSP 11 in the presence of zinc iodide [67]. The cyclization of 95 to 96 represents a simple example of the selenolactonization process [68, 69]. It is interesting to note that the various cyclization reactions indicated in Scheme 14, which require different electrophilic selenenylating agents, can all be effected with phenyselenyl sulfate [70]. 

Electrophilic catalysis may play an important role in the case of the similar benzylic carbon, too. For an O-benzyl system, it was found in a 1997 experiment that palladium oxide is a much more effective catalyst than palladium metal when the catalyst has been prereduced with chemical reducing agents. This finding shows very clearly that the electrophilic character of the unreduced metal ions plays an important role in the hydrogenolysis of the benzyl C—O bonds. Additional support for this mechanism is the fact that a small amount of butylamine can inhibit the hydrogenolysis of the benzyl C—O bond. 

Anomeric alkylation has been extensively studied by Schmidt and co-workers,62 and the main alkylating agents used were dialkyl sulphates, benzyl bromide, allyl bromide63 or various O-triflates, allowing the synthesis of disaccharides.64 The stereochemical outcome of anomeric alkylation is known to depend on many parameters such as the base, the solvent and its effect on solubility and concentration, the temperature, chelation effects, presence of additives, and nature of the electrophilic species.62 65... 

R = Me R = R = R = H, R = Me and R = R = H, R = R = Me) were reacted with the carbon electrophiles n-butyl, isopropyl and benzyl bromides, and isobutenyl chloride, in each case the alkylating agent attacked mainly at the carbon remote from the nitrogen, thus giving the conjugated product 82 (R = electrophile) with the double bond cis. Eth-oxide-catalyzed isomerization of 83 converted it to 84. °... 

The cathodic substitution of halides has been applied in the synthesis of antiinflammatory agents. Arylpropionic acids are formed by reductive dehalogenation of the corresponding benzylic halides in the presence of carbon dioxide as electrophile [22] ... 

More reactive anions such as the 2-lithio-l,3-dithiane derivatives, phenyllithium and r-butyllithium do not require a special solvent and proceed in high yield in THF. While HMPA is known to suppress the migratory insertion to CO in anionic complexes,127 it does not deter the CO insertion in these cases no example of direct alkylation is reported. The only electrophile which adds without CO insertion is the proton, as discussed above. Good alkylating agents (primary iodides and triflates, ally bromide, benzyl... 

The O-alkylation of carboxylates is a useful alternative to the acid-catalyzed esterification of carboxylic acids with alcohols. Carboxylates are weak, hard nucleophiles which are alkylated quickly by carbocations and by highly reactive, carbocation-like electrophiles (e.g. trityl or some benzhydryl halides). Suitable procedures include treatment of carboxylic acids with alcohols under the conditions of the Mitsunobu reaction [122], or with diazoalkanes. With soft electrophiles, such as alkyl iodides, alkylation of carboxylic acid salts proceeds more slowly, but in polar aprotic solvents, such as DMF, or with non-coordinating cations acceptable rates can still be achieved. Alkylating agents with a high tendency to O-alkylate carboxylates include a-halo ketones [42], dimethyl sulfate [100,123], and benzyl halides (Scheme 6.31). 

A global electrophilicity index of common benzylating and acylating agents has been established from MO calculations and it shows a quantitative linear correlation with the experimental substrate selectivity index from a series of benzylation and acylation reactions.21 The values of relative rate coefficients predicted from the index may be accurate to within 10%. The reaction of /-butyl chloride with anisole catalysed by /Moluenesulfonic acid in supercritical difluoromethane has been subject to kinetic analysis.22 The proportions of substitution at the ortho -position and disubstitution increase at lower pressures, attributed to the decrease in the hydrogen-bonding ability of the solvent. 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

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