Isatin alkylation

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... 

Sect. 3.2). However, this approach is limited to the few trialkylboranes that are easily available and cheap since only one of the three alkyl group is transferred. By using a triethylborane as a chain transfer reagent, the reaction could be extended to alkyl iodides as radical precursors. Bertrand [94,114] and Naito [95,97] reported both the use of triethylborane for the tin-free addition of alkyl iodides to imines. A typical example for a tentative of asymmetric addition to a glyoxylate imine is depicted in Scheme 50 (Eq. 50a). More recently additions to isatin imines were reported (Eq. 50b) as well as addition to 2H-aziridine-3-carboxylates by Lemos [100] and Somfai [101] (Eq. 50c). 

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... 

Although the metal ions promoted macrocycle formation, in some cases the free macrocycles could be synthesized in non-template conditions of high dilution. The free macrocycles have sometimes been prepared by means of template reactions involving zinc(II) acetate. The dialdehydes (68) were prepared by a sequence of reactions involving a poor initial alkylation step, but a superior approach has been developed (Scheme 26).156-158 Alkylation of isatin compounds can be carried out in high yield and substituted isatins are readily available. 

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-... 

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... 

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],... 

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. 

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

Reactivity of isatin and derivatives towards electrophiles 3.1 /V-alkylation... 

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. 

Heating in orr/zo-dichlorobenzene results in a retro-aldol reaction and the obtention of the N-alkylated isatin. More recently the use of CaH2 in DMF has been reported and this method was used for the synthesis of both mono and bis-iV-alkylisatins. These latter compounds have been previously prepared using dihaloalkanes and NaH in dioxane or DMF or by the use of LiH82 Some of these alkylation methodologies were evaluated for the synthesis of isatins... 

An alternative method for preparing 1-alkylisatins consists in the reaction of isatin and alkyl halides in a benzene-chloroform/50% aq. KOH biphasic system, employing tetrabutylammonium hydrogensulfate as the phase transfer catalyst. ... 

Isatins can be chemoselectively alkylated at positions 1 or 3. Subsequent reduction of... 

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,... 

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). 

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