Alkylation of isatins

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. 

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. 

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). 

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 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... 

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. 

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],... 

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... 

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. ... 

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). 

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. 

Microwave irradiation has been used to accelerate the conversion of isatins to their thiosemicarbazones, which were cyclized into l,2,4-triazino[5,6-fo]indole-3-thiols. Selective alkylation of these tricyclic systems with different alkylating agents has also been achieved under microwave irradiation conditions [125]. 

The use of bifunctional catalyst 60d (10 mol%) has permitted the synthesis of several 3-alkyl-3-hydroindolin-2-ones (73) by reaction of acetone (13.6 equiv.) or butanone with a variety of isatins 72 (Scheme 4.22). The addition of acetic acid (20 mol%) as co-catalyst was required to achieve good results. For the case of the reaction with butanone, the process was highly regioselective affording mainly product 73d and 73e. Convolutamydine A, an alkaloid isolated from floridian marine bryozoan Amathia convolute, was prepared by reaction of acetone (3a) with 4,6-dibromoisatin (R =4,6-Brj and =H in 72) catalyzed by compound 60d under similar conditions, with product of type 73 being isolated in practical quantitative yield and 60% ee [134]. 

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