Oxindoles electrophilic substitution

Silica sulfuric acid efficiently catalyzed the electrophilic substitution reaction of indoles with varions isatins in dichloromethane to afford the corresponding oxindole derivatives in high yields at room temperature. The catalyst exhibited ranarkable reusable activity (Scheme 2.11) (Azizian et al. 2006). 

The acid-catalysed Fischer indole synthesis is an electrophilic substitution, and the evidence suggests that it occurs less readily with pyridylhydrazones than with benzene derivatives. Some failures with derivatives of 2-pyridyl-hydrazine have been recorded but cyclohexanone and desoxybenzoin 2-pyridylhydrazones were cyclized in about 50 per cent yields with poly-phosphoric acid. Zinc chloride has been used successfully with methyl isopropyl ketone 2-pyridylhydrazone 82, The Brunner oxindole synthesis worked... 

NBS reacts with the indole nucleus following the normal pattern of electrophilic substitution attack at the 3-position is favored. When this position is blocked substitution occurs at the 2-position. Indole and 3-alkylated indoles exposed to one mole of NBS under anhydrous conditions yield 3-bromoindole and 2-bromo-3-alkylindoles respectively 175,394). By contrast, halogenation in hydroxylic solvents often leads directly to oxindoles and both 2- and 3-halo-indoles readily form... 

The oxidation of 3-substituted indole to oxindoles can also be done with a mixture of DMSO and cone, hydrochloric acid[6-9]. This reaction probably involves a mechanism similar to the halogenation with a protonated DMSO molecule serving as the electrophile[10]. 

S02-extrusion affords the electrophilic radical 49 (Scheme 10). Intramolecular homolytic substitution eventually gives tetrahydronaphthalene 50 (92%). Beckwith showed that the A-(o-bromophenyl)amide 51 can be transformed into the corresponding oxindole 54 (70%) at high temperatures using BusSnH via tandem radical translocation of the initially formed aryl radical 52 to form 53 with subsequent intramolecular homolytic substitution [77]. The nucleophilic a-aminomethyl radical 55 reacted in a tandem addition/homolytic aromatic substitution reaction via radical 56 to tetrahydroquinoline 57 [78]. Radical 55 can either be prepared by oxida-... 

Silvani and coworkers have converted isatin to the chiral imines 94 and 97 that were employed as electrophiles for the diastereoselective addition of Grignard reagents [60]. As illustrated in Scheme 26, addition of allyl Grignard to 94 or 97 afforded the amino-substituted quaternary oxindoles 95 or 98 with good diastereos-electivity (80 20 and 89 11 dr, respectively). Grignard adducts 95 and 98 were further manipulated to afford the enantiomeric pair of 3-amino-3-allyloxindoles (5)-96 and (R)-99, respectively. 

The Barbas group has employed a cinchona alkaloid to direct an enantioselective a-amination of oxindoles using diethyl azodicarboxylate as the electrophilic species (Scheme 27) [61]. In one example, A-benzyl protected 3-methyloxindole 100 was transformed to the amino-substituted oxindole 102 in 91% ee using (DHQD)2PHAL... 

In one approach reported by Nicolaou and colleagues, the CIO quaternary center was constructed via aromatic substitution using an oxindole C3 electrophile (the tosyl derivative of 169) as illustrated in Scheme 42. The all-carbon quaternary center of 170 was set in 47% yield as a 1 1 mixture of oxindole C3 epimers. 

An aryne multicomponent reaction involving isoquinoline and 5-bromo-1-methylisatin resulted in spirooxazino isoquinolines (Scheme 66).The reaction occurs with a number of iV-substituted isatins. Quinoline can replace the isoquinoline as well. Carbonyls other than the isatins can trap the anion as well. A variety of aromatic, aliphatic, and heteroaromatic aldehydes can function as the electrophile. When pyridine replaces isoquinoUne as the nucleophilic trap, the reaction forms an oxindole but not an oxazino pyridine derivative (14SL608). 

The group subsequently found that trifloromethyl ketones and isatins were suitable electrophiles for the NHC-catalysed [2 + 2] cycloaddition reaction of ketenes, ° giving the eorresponding trifluoromethyl-substituted p-lactones 165 and spiroeyelie oxindole-p-laetones 167, respectively, in good yields with high enantioselectivities (Scheme 20.69). 

Further applications of P-ICD as catalyst were extended to asymmetric BH reaction employing isatins as electrophiles. Shi and co-workers [97a], Zhou and co-workers [97c], and Lu and co-workers [97b] independently reported the BH reactions of isatins with HFIP acrylates, acrolein, and MVK, leading to 3-substituted-3-hydroxy-2-oxindoles in good yields and high enantioselectivities regardless of configuration difference (Scheme 9.27). Furthermore, P-ICD-derivatived catalyst 44 was synthesized and turned out to be an efficient catalyst in the asymmetric aza-BH reaction [98]. 

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