Friedel-Crafts reactions aromatic carbonylation

The three-component synthesis of benzo and naphthofuran-2(3H)-ones from the corresponding aromatic alcohol (phenols or naphthols) with aldehydes and CO (5 bar) can be performed under palladium catalysis (Scheme 16) [59,60]. The mechanism involves consecutive Friedel-Crafts-type aromatic alkylation and carbonylation of an intermediate benzylpalla-dium species. The presence of acidic cocatalysts such as TFA and electron-donating substituents in ortho-position (no reaction with benzyl alcohol ) proved beneficial for both reaction steps. 

Friedel-Crafts aromatic substitution reactions have been widely explored in polymer chemistry [29,30] and generally proceed with Lewis acids such as AICI3 with elimination of hydrogen halides. In superacid solutions, however, the Friedel-Crafts reactions take place with dehydration from the oxygen of the carbonyl group and the proton of aromatics. The reactivity of the pro-tonated carbonyl group in the superacid can be further increased by the... 

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. 

The heteroaromatic substitution reflects the Friedel-Crafts reaction with the opposite reactivity and selectivity. The synthetic advantages and disadvantages are also opposite to those of concern for the selectivity of monosubstitution - whereas introduction of a carbonyl group deactivates the aromatic ring toward further substitution in the electrophilic process, in contrast it activates the heteroaromatic... 

One of the most attractive features of the Friedel-Crafts acylation is the deactivation of the product toward further substitution. The acylbenzene has a carbonyl group (a deactivating group) bonded to the aromatic ring. Since Friedel-Crafts reactions do not occur on strongly deactivated rings, the acylation stops after one substitution. 

This product is worth a close look. The three-atom chain joining the two aromatic rings has the ketone on the middle carbon atom and t is therefore on C2 ([3) with respect to both rings. This is the difficult position for a carbonyl group and so this product cannot be made by a Friedel-Crafts reaction on either ring. 

Haworth reaction A reaction in which an aryl compound is treated with a cyclic anhydride, such as succinic anhydride, and the intermediate Friedel-Crafts product is reduced and then cyclised via an internal Friedel-Crafts reaction to give a 1,2-disubstituted aromatic compound with a carbonyl group in the new ring. The whole sequence is called the Haworth reaction. 

The asymmetric Friedel-Crafts reaction of trifluoromethyl pyruvate 53 with aromatic compounds is catalyzed by cationic Pd(II) complexes with BINAP or SEGPHOS [184]. The reaction proceeded at -30 °C to afford the product 63 in 89% ee with (S)-BINAP and in 82% ee with (S)-SEGPHOS (Scheme 45). In sharp contrast to the situation of the carbonyl-ene reaction, the BINAP ligand provides higher enantioselectivity than the SEGPHOS ligand. 

The Friedel-Crafts reaction was one of the first to be attempted in ionic liquids (for typical examples, see Scheme 20. Friedel-Crafts acylation, which allows easy functionalization of aromatic compounds to ketones, is of significant commercial importance. The electrophilic substitution with an acylating agent is catalyzed by an acid, typically AICI3. Since this catalyst can form a stable adduct with the carbonyl of the product, an excess of AICI3 is required, which gives rise to a copious amount of inorganic waste. 

The key step is the selective C—H bond activation of two methyl groups of an ortho-tert-hutyl in the Schiff base 434. Treatment of 434 with Pd(OAc)2 afforded the palladacycle 435 in 75 % yield by the help of rather strong coordination to N and O functions. The first functionalization was achieved by the reaction with the alkenylboronic acid to yield the alkylated product 436 in 86 % yield, which was converted to 437 by the Friedel-Crafts reaction. Then the second palladacycle formation from 437 provided two diastereomers 438, which were, without isolation, subjected to carbonylation (40 atm) at room temperature. Treatment of crude reaction mixture with silica gel cleaved the Schiff base and spontaneous lactonization occurred to give a mixture of the lactones 439 and 440 (6 1). The main product was N-alkylated to yield 441. Finally, the fourth ring was constructed by a Heck-type reaction on the aromatic ring to give the desired compound. 

The Friedel-Crafts reaction of electron-rich aromatic and heteroaromatic compounds with carbonyl acceptors is one of the fundamental reactions for forming carbon-carbon bonds. In recent years, several enantioselective approaches have been described utiMzing copper and scandium complexes as catalysts. In addition, the use of organocatalytic approaches has been considerably expanded. 

Wittig reaction. Another option is to consider disconnecting at the aromatic ring and utilizing a Friedel-Crafts reaction. Since the alkyl group would require an unstable 1° carbocation, synthesis via Friedel-Crafts alkylation is impossible. Instead, an FGI that installs a carbonyl at the benzylic position gives an aromatic ketone that can undergo a Friedel-Crafts acylation disconnection. 

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