Phenols, direct acylation

Graphite can promote the Friedel-Crafts acylation reaction of active aromatic compounds such as anisoles and polymethylbenzenes with acyl halides to afford the corresponding aromatic ketones [101]. In a typical experiment, graphite is added to a mixture of anisole and benzoyl bromide in benzene, and the mixture is heated under reflux for 8h to afford para-methoxybenzophenone in 80% yield. Different acyl halides and several anisoles and polymethylbenzenes are utilized to give the corresponding products in high yields (60-92%). 

Hydroxylated aromatic ketones represent valuable intermediate compounds in the synthesis of important fragrances and pharmaceuticals. For example, the resorcinol acylation products are employed for the production of valuable fine chemicals such as 4-0-octyl-2-hydroxybenzophenone (UV light absorbent for polymers) and ipriflavone (antiosteopenic drug). a-Hydroxyacetophenone (o-HAP) and p-hydroxyacetophenone (p-HAP) are widely used for the synthesis of aspirin and paracetamol (4-acetaminophenol), respectively [103]. a-HAP represents also a key intermediate for the production of 4-hydroxycoumarin and warfarin, which are both used as anticoagulant drugs in the therapy of thrombotic disease [104], and it is also employed for the synthesis of flavo-nones [105,106]. 

SCHEME 3.16 Hypothesized mechanism for the ort/jo-functionalization of phenol promoted by a heterogeneous catalyst. 

It must also be observed that the mode of p-HAP formation is probably different form that of o-HAP the ortho isomer is a primary product, while the para-one seems to be a secondaiy product. Of course, other ways for the formation of o-HAP can result from the acylation of phenol with phenyl acetate, which is a better acylating agent than acetic acid. 

Mechanistic differentiation between direct phenol C-acylation and 0-acylation followed by Fries rearrangement is often difficult Therefore, in this section are included synthetic processes where both reagents, the phenol substrate and the acylating agent, and the catalyst are mixed together in the starting reaction mixture aside from the specific reaction mechanism. 

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The remaining discussion is organized in three sections dealing, respectively, with the use of homogeneous catalysts, heterogeneous catalysts, and direct phenol acylation. Each section contains various subtopics based on the nature and role of each class of catalysts. 

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