Isatins alkylation with

The use of triflic acid in the alkylation with other dicarbonyl compounds, such as isatins,258 parabanic acid,259 and ninhydrin,260 has also been explored. A significant acidity dependence was found in the reaction of isatin with benzene.258 Alkylation does not take place in the presence of trifluoroacetic acid (Ho = —2.7) at 25°C in 12 h. Adding 22% of triflic acid (//0 10.6) brings about a 90% yield of the 3,3-... 

By the reaction of isatins with alkyl hetaryl ketones it is possible to obtain various 2-hetaryl-substituted 4-quinolinecarboxylic acids. Thus, in the presence of aqueous solutions of alkalis ketones of the furan series 103 react with isatins 59 with the formation of acids 104 containing a furyl substituent [12, 103, 104],... 

Alkyl-substituted 4-quinolinecarboxylic acids 197 were synthesized by the condensation of isatin 7 with the aldoximes 198 [176],... 

State formed by coordination of a lithium cation with the enol oxygen atom of the NHC-bound homoenolate and the 1,2-dicarbonyl of the isatin. Interestingly, with p-alkyl enals, lithium chloride was disadvantageous, owing to the promotion of a competing pathway. The trends in enantioselectivity observed upon variation of the alkali metal and counterion are presumably due to the oxophilicity and coordination states of lithium compared to sodium or potassium and fine tuning of the Lewis acidity upon variation of the lithium counterion (Scheme 7.39). 

Scheme 35.13 F-C alkylation with isatins creation of quaternary stereogenic centers.

Buu-Hoi has shown that n-alkyl methyl ketones excluding ethyl methyl ketone, yield primarily 2-monosubstituted cinchoninic acids. It has been demonstrated that the products of the condensation of isatin with aryloxyketones are the corresponding 3-aryloxy-4-quinoline carboxylic acids rather than the isomeric 2-aryloxymethylcinchoninic acids.In the case of simple a-alkoxyketones such as 1-alkoxyethyl methylketones, the preferred products are the 2-alkoxyalkylcinchoninic... 

The enantioselective hydrogenation of isatine derivatives has also been performed with high ee-values (up to 94%) using the alkyl-substituted oxoProNOP ligands (15 j). 

Mix 32.8 g (0.217M) methyl-6-methylnicotinate (other alkyl groups can replace either methyl group) with 45.2 g (0.2M) 5-bromoisatin (apparently 4-Br or 4 or 5 Cl isatin will also work) in a 250 ml flask at 100° in an oil bath and raise the temperature of the... 

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). 

Isatin sodium or potassium salts react with dimethyl34 56,143-146 and diethyl147 sulfate, a variety of alkyl halides,11,48,54,148 162 acyl... 

The most frequently reported oxidation reaction of isatins is the oxidation with alkaline hydrogen peroxide to give anthranilic acids. This procedure has been both as a proof of structure of isatins and as a method of synthesis of anthranilic acids. The oxidation has been applied to alkyl 8"10 11 23 33>38-40>46 49>50>118halo n.18.35.36-38-40.47.10 .11 . 119,136,240 alkoxy,26,a8 39,47,75.io7,ii8,i36 trifluoromethyl,33,38,137 and nitro8,120,217 isatins. Use of N-substituted isatins led to N-substituted anthranilic acids.66,71,125,158,169,243 In the oxidation of 5-bromo-l-(y-carbethoxypropyl)-7-ethylisatin, 60 was isolated after treatment with ethanol and acid.11 Oxidation of isatin derivatives 61 led, after treatment with diazomethane, to the acridine derivatives 62.67 Application of this oxidation method to 7-hydroxyisatins gave rise to benzoxazo-lones (63).2,41... 

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 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. 

It was found that from the ketones R3CH2COCH2R4 30, in which R3 < R4, and the isatins 9 only one compound 31 is formed in each case, i.e., the reaction takes place through the groups with smaller molecular mass CH2R3 [16, 24], Such a reaction path can clearly be explained by steric factors and, to some degree, by the inductive effect of the alkyl radicals. 

Unsymmetrical ketones containing Ar and OAr substituents in the alkyl radicals behave differently in the Pfitzinger reaction. Thus, methyl p-phenylethyl ketone reacts with isatin 7 in the presence of potassium hydroxide in water and alcohol through the methyl group - a single product 2-(P-phenylethyl)-4-quinolinecarboxylic acid is formed with a yield of 79% [22, 32],... 

REACTIONS OF ISATINS WITH ALKYL ARYL KETONES... 

During study of the behavior of alkyl 2,5-dimethylthienyl ketones 107 in the Pfitzinger reaction it was found that their reaction with isatin 7 under normal conditions, leading to compounds 108, only takes place with R = Me, Ph with R = Pr, Bu the corresponding products could not be isolated [107], This is clearly due to steric hindrances brought about by the groups 2-Me and R containing two or more carbon atoms. 

Many methods have been devised for the /V-alkylation of isatins. These derivatives are commonly synthesized from the reaction of the sodium salt of isatin with alkyl halides or sulphates . Various methods for the preparation of this salt have been reported, and include the reaction of isatin with sodium hydride, either in toluene under reflux74 or in DMF75. Other methods include the use of potassium carbonate in DMF76,77 or in acetone78. In the latter case an aldol reaction of the solvent also occurs with the C-3 carbonyl of the isatin derivative. 

Isatin and 1-alkylisatins furnish condensation products at the C-3 position when reacted with hydrazine, alkyl and arylhydrazines , heteroarylhydrazines derived from pyrimidine240, pyrazine241, thiazole242, 1,2,4-triazine243, quinazoline244 245,... 

The most frequently reported oxidation reaction of isatins is the oxidation with alkaline hydrogen peroxide to give anthranilic acids. This procedure has been both as a proof of structure of isatins and as a method of synthesis of anthranilic acids. The oxidation has been applied to alkyl b.33,38-40,48,49,so,11,18,35,36,33-40,47,106,118, 119,136,240 25,38,39,47,75,107,118,136 trifluoromethyl, and... 

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 . ... 

Reaction of aromatic or heterocyclic amines with formaldehyde and urea or phenylthioureas gave 2-(oxo)thioxohexahydro-l,3,5-triazines 90. Regioselective cyclization and isomerization of propargylthio-l,2,4-triazinones were achieved to give the fused heterocycles 91-93. Cyclization of isatin 3-thiosemicarbazones gave 94 which can be alkylated to 95 . The imidazotriazepines 96 were obtained from heating a mixture of hydrazide and ortho-ester. 

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