Isatins ketones

PUtzing erReaction. Quinoline-4-carboxyhc acids are easily prepared by the condensation of isatin [91-56-5] (16) with carbonyl compounds (50). The products may be decarboxylated to the corresponding quinolines. The reaction of isatin with cycHc ketones has been reported, eg, the addition of cyclohexanone gives the tricycHc intermediate (17) [38186-54-8] which upon oxidation produces quinoline-2,3,4-tricarboxyhc acid [16880-83-4] (51). 

Isatin (190) is a compound with interesting chemistry. It can be iV-acetylated with acetic anhydride, iV-methylated via its sodium or potassium salt and O-methylated via its silver salt. Oxidation of isatins with hydrogen peroxide in methanolic sodium methoxide yields methyl anthranilates (81AG(E)882>. In moist air, O-methylisatin (191) forms methylisatoid (192). Isatin forms normal carbonyl derivatives (193) with ketonic reagents such as hydroxylamine and phenylhydrazine and the reactive 3-carbonyl group also undergoes aldol condensation with active methylene compounds. Isatin forms a complex derivative, isamic acid (194), with ammonia (76JCS(P1)2004). 

In 1903 Walther and co-workers recognized that imino-nitriles show parallel reactivity to that for the corresponding ketones in the presence of isatin under Pfitzinger conditions/... 

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... 

Condensation of Isatin 3 with Ethyl Methyl Ketone 39/... 

A mixture of 60 g (0.408 mol) of isatin, 200 mL of 34% potassium hydroxide in diluted alcohol solution, 88 g (1.22 mol) of ethyl methyl ketone and 375 mL of water were stirred and heated under reflux for 72 hours. About 125 mL of liquid was removed by distillation the residue was made slightly acidic and filtered. The filtrate was made strongly acidic to precipitate the reaction product, which was collected by filtration, washed, dried, weighed 70 g (85% yield). 

The Pfitzinger reaction consisting in the alkaline condensation of isatin or 6-bromoisatin with ketones has been applied extensively by Buu-Hoi et af.211.279.310.316,525,553 Cagniant, to acetylthio-... 

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]. 

Virus replication comprises numerous biochemieal transformations that might provide suitable targets for antiviral therapy. The antiviral effect of thiosemicarbazones was first demonstrated by Hamre et al. [53, 54], who showed that p-aminobenzaldehyde-3-thiosemicarbazone and several of its derivatives were active against vaccinia virus in mice. These studies were extended to include thiosemicarbazones of isatin, benzene, thiophene, pyridine, and quinoline derivatives, which also showed activity against vaccinia-induced encephalitis. The nature of the aldehyde/ketone moiety was not as significant as the presence of the thiosemicarbazide side chain the latter was deemed essential for antiviral activity. 

A more highly oxidized indole relative is isatin (47). The ketonic carbonyl group is nonenolizable and has interesting properties. In strong acid it... 

Reaction of isatin or thioisatin 263 with (R)-(—)-thiaproline afforded thiazolo-oxazolidinones 264 as precursor of azomethine ylides, obtained by decarboxylation, for 1,3-dipolar cycloadditions (Equation 116) <2002SC435, 2004PS2549>. Condensation of 5-(alkylamino)methyl-2-pyrazolines 265 with ketones or aldehydes led to tetrahy-dro-imidazo[l,5-7]pyrazoles 266 (Equation 117) <1998JCCS375>. 

The word enamine was coined in 1927 by Wittig [27], However, at that time, enamines were usually not considered as reactive intermediates. An early example of enamine catalysis that was not explicitly recognized as enamine-based reaction was the reaction of isatin with ketone nucleophiles (acetone and acetophenone), first pnblished by Lindwall and coworkers in 1932 [28, 31]. Later, the interconversion of imininm ions and enamines in enzymatic reactions was recognized by Westheimer [32, 354]. The first person to propose a modem enamine-based... 

Ketones cannot generally be used as acceptors, at least not directly, due to unfavorable equilibrium between the aldol product and the starting ketones. However, highly reactive ketones [87, 88], such as isatin 2 [95] (Fig. 3) and a-keto phosphonates (e.g. 112) [110] can readily be used as acceptors. 

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). 

Under mildly basic conditions, such as with piperidine or diethylamine as catalyst, isatins condense with a wide variety of ketone to give compounds of the type 171.144,145,150,169,232,471-490 These compounds have frequently been used to prepare substituted tryptamines476,484,485,487 and also some 9//-pyridazino[3,4-6]indole... 

Ketones of the type 200 (where R is not CH3 or CH2) react with isatin to give cinchoninic acids of the type 201.557 572-593 In a number of... 

Cycloalkanones also react with isatin 27 32 207-471,552,557,567,573 B99 612 for example, cyclohexanone and isatin gave 203.609 Steroidal ketones have also been used.590,G12a Resorcinol and phloroglncinol appear to react analogously613 resorcinol gave 204. 

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... 

Similarly, hydroxyalkylation with aldehydes or ketones is best accomplished with activated aromatic compounds, such as phenols.7 However, reaction even with chlorobenzene has been carried out with either para-banic acid or isatin using triflic acid (eqs 6-7).8,9... 

Keywords isatin, isatin derivatives, ketones, 4-quinolinecarboxylic acid derivatives, condensation, cyclization, Pfitzinger reaction, recyclization. 

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. 

The reaction of isatins with ketones leading to 4-quinolinecarboxylic acids is carried out in the presence of strong nucleophiles (sodium hydroxide or potassium hydroxide). For this reason the generally accepted mechanism of the process is the following. The isatins 1 are converted by the action of alkalis into the salts of... 

Subsequently only the initial isatins and ketones and also the final products will be presented in the texts and in the schemes without mention of the intermediate formation of the salts 2-4. As a rule the conditions and the yields of the reactions will be indicated in the schemes and in the tables. 

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