Electrophilic aromatic substitution lithiation

The first preparations of diaryliodonium salts have been reported in the 19th century, but refinements and improvements keep appearing to date. In most cases an iodoaryl species containing iodine(III) is coupled with an arene or a derivative of it in a typical electrophilic aromatic substitution. Lithiated, stannylated or silylated aryls and arylboronic acids or borates have been introduced recently in order to avoid harsh conditions and to improve yields. The iodoaryl species may be also formed in situ from arenes and iodine(III) reagents. 

Probably the best modem method for introduction of OF by electrophilic aromatic substitution is lithiation, reaction with a boronate ester, and oxidation.4 These are the same boron compounds that are used in Suzuki coupling (chapter 18) and are made the same way. In this example, selective mono-lithiation by Br/Li exchange on available tribromoanisole 39 (easily prepared by bromination of anisole or phenol) occurs ortho to the MeO group and reaction of aryl-lithium 39 with trimethyl borate gives the boronic ester 40. Peroxyacids such as peracetic acid are usually used for the final oxidation. 

The widespread applications of polystyrene derived resins is due to the fact that styrene consists of a chemically inert aUcyl backbone carrying chemically reactive aryl side chains that can be easily modified. As discussed earlier, a wide range of different types of polystyrene resins exhibiting various different physical properties can be easily generated by modification of the crosslinking degree. In addition, many styrene derived monomers are commercially available and fairly cheap. Polystyrene is chemically stable to many reaction conditions while the benzene moiety, however, can be funtionalised in many ways by electrophilic aromatic substitutions or lithiations. As shown in Scheme 1.5.4.1 there are principally two different ways to obtain functionalised polystyrene/DVB-copolymers. 

As shown so far many functionalised resins were obtained by electrophilic aromatic substitution reactions. A very valuable route to other functionalised resins constitute lithiation reactions on polystyrenes as shown by Frechet and FarralF and depicted in Scheme 1.54.9. 

Substituted benzyl alcohols can be prepared by o-lithiation of the corresponding benzyl alcohol with 2 moles of Bu Li in TMEDA-pentane followed by reaction with an electrophile. Similarly, the sulphonates (16) are further lithi-ated to (17, X = Li), and (17, X = E) are obtained with electrophiles (E ). Subsequent desulphonation thus leads to a new methodology for electrophilic aromatic substitution. 

A point of interest in lithiation mediated aromatic substitution reaction is, how to effect substitution at a less active position (in lithiation reactions) in presence of the more active. In one approach, after effecting lithiation at the more active position, the metallation mixture is treated with ClSiMe, which introduces — SiMcj at that point. Further lithiation now occurs at the second position. After reacting with a suitable electrophile, the SiMcj group is replaced by H by acid cleavage of the C—Si bond. The following example illustrates the approach... 

C-substitution of nitrogen heterocycles , Vorbriiggen, H. and Maas, M., Heterocycles, 1988, 27, 2659 (discusses electrophilic and radical substitutions, lithiations and the use of iV-oxides) Regioselective substitution in aromatic six-membered nitrogen heterocycles , Comins, D. L. and O Connor, S., Adv. Heterocycl. Chem., 1988, 44, 199 (discusses electrophilic, nucleophilic and radical substitution, and metallation). 

Electrophilic quench of aryllithium species with carbonyl electrophiles is particularly efficient. However, alkyl halides (other than iodomethane) are poor electrophiles, probably owing to competing elimination reactions (see Section 2.1). The formation of alkyl-substituted aromatic compounds can be achieved, however, by using epoxide electrophiles or by lithiation and reaction of 2-methylbenzamides, themselves generated by orr/ o-lithiation. For example, the benzamide 128 can be deprotonated at the benzylic position and treated with a variety of electrophiles. Addition of aromatic aldehydes gives, after lactonization, 3-aryl-3,4-dihydroisocoumarins (1.119). 

As shown in Scheme 2, our first approach for construction of the labile iso-chromanone core 3 relied on an innovative orf/io-lithiation strategy. It was envisioned that in conjunction with an appropriate chiral-directing group, a suitable electrophile (5) might be introduced in the orf/io-position of the meta-lated aromatic 4. The resulting product would then be further transformed into the desired heterocycle 3. Notably, this route is very flexible by allowing the addition of various electrophiles in a modular fashion. Also, it starts from a 3-methylsalicylic acid derivative (4) that already contains almost the complete aromatic substitution pattern of the ajudazols. 

A variety of optically active 4,4-disubstituted allenecarboxylates 245 were provided by HWE reaction of intermediate disubstituted ketene acetates 244 with homochiral HWE reagents 246 developed by Tanaka and co-workers (Scheme 4.63) [99]. a,a-Di-substituted phenyl or 2,6-di-tert-butyl-4-methylphenyl (BHT) acetates 243 were used for the formation of 245 [100]. Addition of ZnCl2 to a solution of the lithiated phos-phonate may cause binding of the rigidly chelated phosphonate anion by Zn2+, where the axially chiral binaphthyl group dictates the orientation of the approach to the electrophile from the less hindered si phase of the reagent. Similarly, the aryl phosphorus methylphosphonium salt 248 was converted to a titanium ylide, which was condensed with aromatic aldehydes to provide allenes 249 with poor ee (Scheme 4.64) [101]. 

For synthesis of disubstituted compounds of type 14, the starting compounds are carbon substituted aromatic compounds and the electrophiles are also carbon derivatives. The same lithiation directing groups and electrophiles, as mentioned earlier, are used. 

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