Electrophilic aromatic benzylation

Novolacs are prepared with an excess of phenol over formaldehyde under acidic conditions (Fig. 7.6). A methylene glycol is protonated by an acid from the reaction medium, which then releases water to form a hydroxymethylene cation (step 1 in Fig. 7.6). This ion hydroxyalkylates a phenol via electrophilic aromatic substitution. The rate-determining step of the sequence occurs in step 2 where a pair of electrons from the phenol ring attacks the electrophile forming a car-bocation intermediate. The methylol group of the hydroxymethylated phenol is unstable in the presence of acid and loses water readily to form a benzylic carbo-nium ion (step 3). This ion then reacts with another phenol to form a methylene bridge in another electrophilic aromatic substitution. This major process repeats until the formaldehyde is exhausted. 

Organolithium reagent 35 was added to aldehyde 31 (Scheme 7.6) to obtain alcohol 36 as an inconsequential 1 1 mixture of diastereomers. The benzylic alcohol was removed using a Barton two-step radical deoxygenation protocol, followed by electrophilic aromatic bromination to provide the desired coupling partner 37. 

As a simple example, note that the major products obtained as a result of addition of HBr to the alkenes shown below are not always those initially expected. For the first alkene, protonation produces a particularly favourable carbocation that is both tertiary and benzylic (see Section 6.2.1) this then accepts the bromide nucleophile. In the second alkene, protonation produces a secondary alkene, but hydride migration then leads to a more favourable benzylic carbocation. As a result, the nucleophile becomes attached to a carbon that was not part of the original double bond. Further examples of carbocation rearrangements will be met under electrophilic aromatic substitution (see Section 8.4.1). 

C-H activation at a primary benzylic site was the key step in very short syntheses of lig-nans 206 and 207 (Scheme 14.27) [138]. Even though both the substrate 203 and the vinyl-diazoacetate 204 contain very electron-rich aromatic rings, C-H activation to form 205 (43% yield and 91% ee) is still possible because the aromatic rings are sterically protected from electrophilic aromatic substitution by the carbenoid. Reduction of the ester in (S)-205 followed by global deprotection of the silyl ethers completes a highly efficient three-step asymmetric total synthesis of (-i-)-imperanene 206. Treatment of (R)-205 in a more elaborate synthetic sequence of a cascade Prins reaction/electrophilic substitution/lacto-nization results in the total synthesis of a related lignan, (-)-a-conidendrin 207. 

Phenol-formaldehyde prepolymers, referred to as novolacs, are obtained by using a ratio of formaldehyde to phenol of 0.75-0.85 1, sometimes lower. Since the reaction system is starved for formaldehyde, only low molecular weight polymers can be formed and there is a much narrower range of products compared to the resoles. The reaction is accomplished by heating for 2 1 h at or near reflux temperature in the presence of an acid catalyst. Oxalic and sulfuric acids are used in amounts of 1-2 and <1 part, respectively, per 100 parts phenol. The polymerization involves electrophilic aromatic substitution, first by hydroxymethyl carboca-tion and subsequently by benzyl carbocation—each formed by protonation of OH followed by loss of water. There is much less benzyl ether bridging between benzene rings compared to the resole prepolymers. 

The regioselectivity by electrophilic aromatic substitution is conserved when switching to acidic reaction conditions. Thus 2-substituted pyrazole 1-oxide 123 was nitrated regio and monoselectively at C3 by HN03-H2S04 to give 124 in quantitative yield (1992ACSA972). Further nitration takes place first at the benzyl 4-position, and then at the pyrazole 5-position (Scheme 39). 

A second acid-catalysed electrophilic aromatic substitution now occurs to link a second phenol to the first. The rather stable benzylic cation makes a good intermediate. 

Representative couplings of aromatic hydrocarbons are summarized in Table 1. Alkyl-substituted aromatic hydrocarbons can be coupled to diphenyls and/or diphenylmethanes depending on their substitution pattern (Table 1, numbers 1-6). The initially formed radical cation I [Eq. (3)] reacts with the starting compound to the diphenyl (II) (Eq. (3), path a] or loses a proton to form a benzyl radical [Eq. (3), path b], which after oxidation to the cation undergoes an electrophilic aromatic substitution at the starting compound to form the diphenylmethane (III). A low charge density on an unsubstituted carbon atom of I favors path a, whereas a low charge density on a substituted carbon atom favors path b[4]. 

With silver salts, 1-bromocyclopropyl 2-phenylethyl sulfide [60, R = (CH2)2Ph] and 1-bromo-cyclopropyl benzyl sulfide (60, R = Bn) produce relatively stable thiocyclopropyl cations, which undergo intramolecular electrophilic aromatic substitution to afford spiro compounds 61 and 62.1 ... 

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