Benzyhc position

The benzyhc position m alkylbenzenes is analogous to the allyhc position m alkenes Thus a benzyhc C—H bond like an allyhc one is weaker than a C—H bond of an alkane as the bond dissociation energies of toluene propene and 2 methylpropane attest... 

ALkoxyalkyl-substituted arenechromium complexes have been lithiated enantioselec-tively in the benzylic position without control over planar chirahty and the tendency for lithium amides to lithiate at a benzyhc position rather than on the ring itself poses a problem with some substrates. In the lithiation of 433, an element of planar stereochemistry is introduced during a benzyhc lithiation (Scheme 176) . Exploiting... 

While not strictly a directed metallation, an important early example of enantioselective lithiation in a benzyhc position was the lithiation of the achiral biaryl 598 using n-BuLi-(—)-sparteine. The product 599 of unknown configuration was obtained in moderate ee (Scheme 236) . ... 

Besides hydroxylation of exogeneous phenol to the corresponding catechol, some imine and xylene-based Ugand systems have been shown to undergo (partial) hydroxylation of a central benzene-ring to yield a phenolate fragment in an intramolecular hydroxylation reaction [179,183-189]. Somewhat related reactivity was observed in the intramolecular hydroxylation at a benzyhc position of a sidearm on a specific aminopyridine ligand (compare Sect. 4.1). 

The nucleus of the one-time widely prescribed prescribed COX-2 inhibitor, rofecoxib, better known by its trade name Vioxx , actually comprises a butenolide rather than a classical heterocycle. The drug was withdrawn from the market at full flood due to an unexpectedly high incidence of adverse cardiovascular side effects. The compound is included at this point to emphasize the breadth of the SAR for COX-2 anti-inflammatory agents. Reaction of phenylacetic acid (35-1) with ethyl bro-moacetate in the presence of triethylamine leads to the formation of the ester (35-2). Treatment of that intermediate with a strong base generates a carbanion at the benzyhc position in an intramolecular reaction, this attacks the terminal ester carbonyl to yield the butenolide (35-3). Reaction of that compound with triflic anhydride converts the... 

The Y-T equation (2) has been used extensively in studies of electrophilic substitution in the aromatic ring, and aliphatic nucleophilic substitution and related reactions forming a carbocation or a carbocationic (electron-deficient) centre at the conjugative position (mostly benzyhc position) in the side chain. 

The Hammett p value of -4.1 suggests a carbocation intermediate as does the regioselectivity of the reaction (MeOH attacks the benzyhc position) but the stereochemistry (the reaction occurs with inversion) and a modest negative entropy of activation (AS = -48 JmoH K ) suggest rather an Sn2 reaction with a loose transition state having substantial positive charge at the benzylic carbon. Neither piece of evidence alone would be enough to define the mechanism. 

Side-chain bromination at the benzylic position occurs when an alkylben-zene is treated with iV-bromosuccinimide (NBS). For example, propylbenzene gives (l-bromopropyl)benzene in 97% yield on reaction with NBS in the presence of benzoyl peroxide, (PhC02)2, as a radical initiator. Bromination occur exclusively in the benzyhc position and does not give a mixture of product ... 

The new radical abstracts hydrogen atoms from the benzyhc positions to make stable delocalized radicals. These react with bromine to give the benzylic bromide and release a bromine atom. 

The mixture t-BuIi/t-BuOK is known as Schlosser s base, and is one of the most powerful bases known. It will abstract protons from allylic and benzyhc positions, and will even deprotonate benzene. Similar a-eliminations may occur from trihaloacetate anions (Scheme 5.10). 

Both products are presumably generated via a common intermediate, the seven-membered oxapalladacycle 136, from the domino Pd-catalyzed/norbornene-mediated reaction sequence. In the presence of a benzyhc C-H, an intramolecular redox process takes place by hydrogen migration from the benzyhc position to the aromatic position, aHbrding the aldehyde products 134. When using tertiary benzyl alcohols, C-O couphng is the predominant pathway leading to the dibenzopyran products 135. It was found that cesium pivalate was the base of choice in the former process and potassium carbonate was suitable for the latter. 

In a follow-up study, the same group applied a similar approach to another tandem biocatalyst system. Therein, activated methylene groups (benzyhc positions) were transformed into the corresponding achiral ketones by double oxidation (Scheme 3.8) [27]. 

The acid hydrolysis of (+)-styrene oxide yields a totally racemic diol, whereas the acid methanolysis of (+)-styrene oxide yields a product with 89% inversion of configuration at the benzyhc position. 

Aromatic donors form the largest class of substrates fragmentable by electron transfer in view of their accessible oxidation potential and the easy cleavage at the benzyhc position. Pioneering work by Nicholas and Arnold demonstrated the high acidity of the toluene radical cation. The process has been extended... 

Selective bromination at the benzyhc position generates a new chirality center. The intermediate benzyhc radical is expected to be attacked from either face of the planar radical with equal likelihood, giving rise to a racemic mixture of enantiomers ... 

The carboxylic acid group can be made via oxidation of the benzyhc position. A methyl group can certainly be oxidized to a carboxylic acid group, however, we choose a larger, sterically hindered alkyl group, as will soon be explained. 

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