Friedel-Crafts, alkylation ketone synthesis

Figure 7-11 shows a Friedel-Crafts acylation reaction. The reaction produces an aryl ketone, which is useful in synthesis because it makes it relatively easy to convert the ketone (RCOR) group to an alkyl (R) group. The procedure involves the catalytic hydrogenation of the aryl ketone, and it s particularly useful when the electrophile in a Friedel-Crafts alkylation is susceptible to rearrangement. 

The synthesis of alkylbenzenes may be classified under (a) the Wurtz-Fittig reaction (b) the reduction of aryl aldehydes and ketones and (c) and Friedel-Crafts alkylation reaction. 

Corey1 wanted to make the ketone 2 as an intermediate in the synthesis of the marine allomone 1 (a substance exuded by an organism and used by a predator). Disconnection 2a (Friedel-Crafts alkylation) would be easy to realise as it occurs para to the powerful o,p-directing OMe group. But disconnection 2b is more difficult as it must occur meta to OMe. So we should make the formation of bond b a cyclisation and disconnect it first. 

The Friedel-Crafts alkylation of arenes with lactones provides a convenient method for the synthesis of arylalkanoic acids. However, depending on the nature of the arene, catalyst, temperature and reaction time, the resulting arylalkanoic acids can undergo partial or complete cyclization to the corresponding cyclic ketones (Scheme 10). Equations (65) to (68) show examples of Friedel-Crafts alkylations using lactones as the alkylating agents." "" ... 

Michael reaction of an oc,p-unsaturated ketone with a silyl enol ether (Scheme 26) and a Diels-Alder reaction of an oxazolidinone derivative with cy-clopentadiene (Scheme 27) also worked well using MC Sc(OTf)3. Moreover, a Friedel-Crafts acylation proceeded smoothly to produce an aromatic ketone in a good yield (Scheme 28). Friedel-Crafts alkylation and acylation reactions are fundamental and important processes in organic synthesis as well as in indus-... 

Since 1972, updates on Friedel-Crafts alkylation, aromatic aldehyde synthesis, nitration, etc., were regularly published in books and extensive reviews. However, improvements in Friedel-Crafts acylations were scantly considered, despite the great practical application of the aromatic ketones in different fields of the fine and pharmaceutical chemistry. 

The approach to haplophytine proposed by Fukuyama and Tokuyama et al. did not rely on the synthesis of aspidophytine previously reported [75]. One of the main synthetic problems was the connection of the left-hand segment to the indole moiety of aspidophytine. Retrosynthetically, Fischer indole synthesis of the fully elaborated left-hand fragment 186 and the tricychc ketone 187 gave haplophytine. 186 was generated through oxidative skeletal rearrangement from precursor 188, which was accessible from indole 189 by Friedel-Crafts alkylation. Optically active ketone 187 was assembled through a stereoselective intramolecular Mannich reaction from aldehyde 190 (Scheme 33). 

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. 

Synthesis of Tetralin compound (121. The tetralin (12) has already been described. It was synthesised as shown in Figure 6. Friedel-Crafts alkylation of tetralin gave the i-butyltetralin (13) which was oxidised to a mixture of the two ketones (14) and (15) which were... 

The synthesis of alltyl-bridged poly(p-phenylene)s is based on typical poly(p-phenylene) chemistry, followed by a second reaction in which the rigidifying bridge is created. Scherf et al. [314, 315,704,705] used Suzuki coupling to create a ketone-substituted poly(p-phenylene). In a next step, the ketone functions in this polymer were reduced and, finally, the ladder polymer was obtained by Friedel-Crafts alkylation (Fig. 43). 

In 2008, Chi et al. reported a tandem reaction of indoles, a,P-unsaturated aldehydes, and methyl vinyl ketone (MVK) for the synthesis of chiral indole derivatives with two stereogenic centers [ 19]. To avoid the interference of the two secondary amine catalysts and cocatalyst acid, the soluble star polymer-based site isolatbn method was adopted, whereby the supported imidazolidinone catalyst promoted initial Friedel-Crafts alkylation and the supported pyrrolidine derivative promoted the following Michael addition to MVK (Scheme 9.19). Notably, simple combination of these catalysts in one pot didn t mediate the cascade reaction efficiently despite the fact that the MacMillan imidazolidinone and pyrrolidine catalyst can efficiently promote separate Friedel-Crafts reaction and Michael addition, respectively. Moreover, when the pyrrolidine catalyst was replaced by its enantiomer, a diaste-reomer of the product could be obtained with high enantioselectivity. This smdy presented a novel solution to the efficient combination of incompatible substrates and catalysts. 

A similar strategy was used by Fehr and co-workers to achieve the enantioselective (5,5)-vulcanolide (5, 5)-26 synthesis (Scheme 31.12). Li-enolate of ketone 33 was protonated by ( )-//-E affording the enantioenrichied ketone 34. Then, Friedel-Craft alkylation of o-xylene followed by reduction provides the secondary alcohol 35. The trans cyclohexyl derivative 36 was easily obtained under acidic conditions in 44% over three steps. Then, a monooxidation affords the (5,5)-vulcanolide (S,5)-26) in ca. 29% yield over five steps with 83% ee. 

The ehiral phosphoiie aeid (i )-(231) has been shown as an efficient Bronsted aeid eatalyst in asymmetrie synthesis of various acyclic and endo exocyclic p-hydroxyenones (230) through a regiospecific aldol condensation between a,p- unsaturated ketones (228) and ethyl glyoxalate (229) (Seheme 60). Enantioseleetive synthesis of 3-indolyl-substituted isoindolin-l-ones (234) through the ehiral phosphoric add (235) catalysed asymmetric Friedel-Crafts alkylation of indoles (232) with 3-hydroxyisoindolin-l-ones (233) in excellent ehemieal yields (up to 99%) and with moderate to good enantioselectivities (up to 99% ee), has been described by Zhou et al. (Scheme 61). ... 

The most important method for the synthesis of aromatic ketones 3 is the Friedel-Crafts acylation. An aromatic substrate 1 is treated with an acyl chloride 2 in the presence of a Lewis-acid catalyst, to yield an acylated aromatic compound. Closely related reactions are methods for the formylation, as well as an alkylation procedure for aromatic compounds, which is also named after Friedel and Crafts. 

The synthesis of the right-hand fragment of ziprasidone started with a Wolff-Kishner reduction of isatin 43 to give the oxmdole 44 (Scheme 14). Friedel-Crafts acylation with chloroacetyl chloride afforded aryl ketone 45, which was reduced with triethylsilane in trifluoroacetic acid to the phenethyl chloride 46. The two fragments were joined by alkylation of 40 with 46 in the presence of Nal and Na2CO3 to give ziprasidone (4) in low yield. The yield of the coupling step was improved dramatically when the reaction was conducted in water (Scheme 15). 

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