Isatins, arylation

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

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). 

The reaction of isatin cr-chloride (160a) with electron-rich aryl compounds, in the presence of a Lewis acid, gives indolone salts (161) from which the indolones (162) can be liberated on treatment with base.49, 108, 109 The reaction of 160a with various amines, under these conditions, has been reported108 to give the unstable indolones (163) although later attempts to repeat the synthesis were unsuccessful.49... 

Isatin and its derivatives have reacted with both aryl and alkyl Grignard reagents to give 3-alkyl (or aryl) dioxindoles (178).232,497-500 Use of an excess of phenylmagnesium bromide with A-benzyl501 and... 

The ketone carbonyl of a series of isatins (63) undergoes enantioselective addition of aryl- and alkenyl-boronic acids, using a rhodium catalyst and a chiral phosphine.180... 

Smith, K. El-Hiti, G. A. Hawes, A. C. Carbonylation of doubly lithiated N -aryl-N,N-dimethylureas a novel approach to isatins via intramolecular trapping of acyllithiums. Synthesis 2003, 2047-2052. 

The present review covers all the available published data on the Pfitzinger reaction beginning from the time of its discovery. The investigated material has been classified on the basis of the structure of the initial ketones separate sections cover the reactions of isatins with dialkyl ketones, keto acids, alkyl aryl ketones, and alkyl hetaryl ketones and also with cyclic ketones. Papers describing the synthesis of 4-quinolinecarboxylic acids by methods related to the Pfitzinger reaction are discussed in a separated section. 

REACTIONS OF ISATINS WITH ALKYL ARYL KETONES... 

Aryl-4-quinolinecarboxylic acids 78 (Table 3) were synthesized by the condensation of isatin 7 with monosubstituted acetophenones 77 [24, 63, 69, 71-80],... 

The schemes presented below illustrate investigations into the reaction of acetophenone 74 [18, 19, 68, 86, 87] and more complex methyl aryl ketones [19, 88] with annelated isatins 10, 12, 32, 83, and 84, leading to various polycyclic systems 85-88. 

When the isatins 1 and the acetates of a-hydroxy ketones 95 are heated in the presence of potassium hydroxide [99] or sodium hydroxide [100] in water and alcohol, hydrolysis of the OAc group occurs in addition to recyclization, and the reaction products are 2-aryl-3-hydroxy-4-quinolinecarboxylic acids 96, recommended as antiarhythmic agents and immunodepressants. 

The synthesis of derivatives of quinoline from isatins and carboxylic acid anhydrides can also be realized without isolating the intermediate N-acyl derivatives. Thus, unsubstituted 2-quinolonecarboxylic acid containing the 14C isotope at position 3 was synthesized by the condensation of isatin 7 with the anhydride (H314CC0)20 [172], The unsubstituted acid 168 [163] and its 3-aryl derivatives 195 [173, 174] were obtained by heating the isatin 7 directly with the respective anhydrides. 

This method has been used for the synthesis of 1-aryl and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine as well as indoline. In the case of dimethoxyanilines, spontaneous cyclization to yield dimethoxyisatins in the absence of a Lewis acid has been observed, as exemplified in the synthesis of melosatin A, albeit in very low yield (Scheme 8). 

A -Arylisatin can be obtained from isatin in quantitative yields by reaction with Ph3Bi(OAc)2 and Cu° under an inert atmosphere93 or from aryl bromides and cupric oxide94. 

Hann, R.M. The condensation of rhodanic acids with Isatin 3-Aryl-rhodanal-... 

Pyrazolo[3,4-Z)]pyridines, the 7-chloro-6-fluoro-2,4-dimethylquinoline and its mercapto-thiadiazolyl or oxadiazolyl quinolines 21 were prepared via Diels-Alder reaction conversion of methyl 2-(3-oxo-3-phenylpropenylamino)benzoate into 3-benzoyl-l.S -quinolin-4-one 22 . A mixture of aniline derivatives and malonic ester gave a variety of 3-aryl-4-hydroxyquinolin-2(l//)-ones 23. Condensation of isatins with ketones afforded quinoline-4-carboxylic acids. 2-Aryl-l,2,3,4-tetrahydro-4-quinolinones 22 and carbazolylquinolone were also prepared. The substitution of 2-chloroquinoline gave the 2-substituted quinolines. Basic alumina has catalyzed the C-C bond formation between 2-hydroxy-1,4-naphthoquinone and 2-chloroquinoline derivative to give 21. Reaction of organic halides with 8-hydroxyquinolines gave the respective ethers. The azodye derivatives of 21 were prepared in the absence of solvent. Silica gel catalyzed the formation of 2-ketomethylquinolines from reaction of 2-methylquinolines with acyl chlorides. 

Condensation of o-phenylenediamine with methylglyoxal, aldohexoses and aryl or alkyl acyloins gave the corresponding quinoxalines 76. Indoloquinoxalines were obtained from isatin. Carbethoxymethylation of isatin and then reaction with o-phenylenedimine gave the respective indoloquinoxalines 77, whereas hydrazide was condensed with aromatic aldehydes and monosaccharides. L-Ascorbic acid or D-isoascorbic acid were oxidized with iodine and then reacted with o-phenylenediamine and phenylhydrazine to give quinoxalinones 78, which were cyclized to pyrazolyl-quinazolinones . ... 

This conversion employs a boronic acid with a copper(ll) catalyst. The method was developed for reactions of heterocycles, including the V-arylation of isatin ° and of pyrazole, imidazole and their benzo derivatives (1,2,3-triazole, 1,2,4-triazole and 5-phenyltetrazole gave only very modest yields). These conditions also apply to the V-arylation of 2-pyridone (and various fused derivatives), 3-pyridazinones, indole-2-carboxylates and pyrrole-2-carboxylates. ... 

The synthesis of 86 commenced with oxazole carboxylic acid 87. Base-catalyzed lithiation and coupling with isatin 88 followed by methyl ester formation and Boc deprotection provided tertiary alcohol 89. A second coupling of the amine 89 with carboxylic acid 90 followed by chlorination afforded chloride 91. Treatment of 91 with TBAF gave a 1 1 mixture of O-aryl ether 92 (CIO) in excellent yield. Refluxing 92 in chloroform resulted in the formation of 93 (70%, with 30% of the isomer), which was subjected to a three-step reaction sequence to furnish intermediate 86 (Scheme 16). 

The Scheidt group reported a highly enantioselective NHC-catalyzed addition of a,p-unsaturated aldehydes to isatins activated by lithium cations (up to 93% yield, >20 1 dr, 97% ee). The addition of lithium chloride as a Lewis acid with p-aryl substituted enals generates lactone products with high enantioselectivity (up to 93% ee) which result from an organized transition... 

By using an N-heterocyclic carbene catalyst bearing a hydroxyl moiety, the Ma group reported an asymmetric cyclization of aryl 3-bromoenals and isatins. A series of chiral spirooxindole butenolides, including an alkenyl-substituted compound, were produced in excellent yields and enan-tioselectivity (up to 99% yield, 92% ee). The authors demonstrated that the hydrogen bonding between the free hydroxyl group of the catalyst and the isatin substrates would enhance the reactivity and selectivity. However, the Cs ion may also be involved as a Lewis acid to facilitate this transformation (Scheme 7.44). 

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