Friedel Crafts isatin

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). 

Isatins fail to yield Knoevenagel condensation products with malonic acid419. However, malonic acid can be condensed with isatin in a mixture of ethanol and pyridine, in which the initial condensation product suffers decarboxylation, furnishing an acetic acid derivative. This can be converted to the acid chloride and submitted to a Friedel-Crafts acylation reaction, yielding acetophenone derivatives420. Alternatively the oxoindolinylidene acetic acid derivative can be treated with an arene in the presence of AICI3 to yield. sy />o[indoline-3,3 -indan]-2,l-dione derivatives. ... 

When isatins are used in the Friedel-Crafts alkylation of /w-cresol in an acidic medium at high temperature, the adduct formed suffers dehydration, furnishing a spiro dibenzopyran derivative458 (Scheme 110). 

Whereas closely related catalysts allowed the Friedel-Crafts-type additions to be expanded to other carbonyl acceptors, such as isatins, the same reactions depicted in Schemes 14.17 and 14.18 have also been achieved in an environmentally more benign solvent, namely Solkane 365 mfc, a liquid hydrofluorocarbon (CF3CH2CF2CH3) that is nontoxic with no impact on the ozone layer, and is used as an insulating and blowing agent for polyurethane foams. To achieve useful yields and enantioselectivities in this fluorinated reaction medium, perfluorinated CPN and CPD Cinchona alkaloid derivatives, able to dissolve in it, were designed and synthesised by Shibata and coworkers (Figure 14.4). 

Activation of the oxime of 6 through protonation induces a Friedel-Crafts type acylation. After re-aromatization to 14, loss of water yields imine 15, which hydrolyzes upon workup to yield isatin (4). 

The Stolle reaction is thought to occur via a typical mechanism for amide formation from an amine and acid chloride, followed by Friedel-Crafts alkylation or acylation. No definitive mechanistic work has been performed on this reaction, but incorporating the mechnistic understandings of two steps provides a firm basis for understanding the mechanism of this reaction. Formation of the mono-amide from oxalyl chloride and aniline provides intermediate 4, which in the presence of AICI3 undergoes intramolecular electrophilic aromatic substitution to the desired 2,3-dioxindole (isatin) 7 via intermediates 5 and 6. 

Alternatively, isatins 1784 can be synthesized from secondary aromatic amines with oxalyl chloride followed by a Friedel-Crafts cyclization [1311]. 

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