Friedel-Crafts reaction Functionalisation

We used this strategy in chapter 6 under two-group C-X disconnections where bromination of ketones was the usual functionalisation. More relevant here are conversions of carbonyl compounds into 1,2-dicarbonyl compounds by reaction with selenium dioxide SeC>2 or by nitrosation. So acetophenone 57 gives the ketoaldehyde10 58 with SeC>2. These 1,2-dicarbonyl compounds are unstable but the crystalline hydrate 59 is stable and 58 can be reformed on heating. Since aromatic ketones such as 57 would certainly be made by a Friedel-Crafts reaction the disconnection 58a is not between the two carbonyl groups and offers an alternative strategy. 

We have already seen how anisole 1 may be functionalised by using a Friedel-Crafts reaction. Anisole is a simple, perhaps the most simple, functionalised benzene ring that can be lithiated by o/ t/to-lithiation. We use it here to introduce the reaction. 

The Heck reaction makes a C-C bond and adds a highly functionalised fragment that can be elaborated into many other functional groups. The same is true of the Friedel-Crafts reaction that generally works well with azoles or other heterocycles able to do electrophilic substitution. As usual, it is best to have only one free position so that no regioselectivity problems arise. In the Heck reaction, the site of attack is marked by the iodine atom, but the Friedel-Crafts can occur at any free position. Our example is a pyrazole that acylates cleanly with Lewis acid catalysts to give eventually the herbicide pyrazolate 196. 

Numerous synthetic approaches to anthracyclines are based on carbanion mediated cyclisations. These reactions often occur under mild conditions, allowing incorporation of highly functionalised precursors. Some approaches follow an initial base-catalysed coupling of two fragments by cyclisation under Friedel-Crafts conditions (previous section), while other strategies bring about both condensation and cyclisation under basic conditions. Syntheses based on closure of rings C, B or A have been described. 

Many functionalised aromatic units are commercially available or reasonably easy to synthesize directly through electrophilic substitution reactions (e.g., Friedel-Crafts acylation, bromination and nitration) subsequent functional group interconversions allow access to those groups that carmot be directly introduced (e.g., -CO H, -NH2, -CN and... 

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