Isatins 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). 

Keywords Aromaticity Bromination Diels-Alder reaction Electrophilic substitution Furan Indophenine Isatin Metallatimi Palladium(O) catalysis Pyrrole S-oxidation Sulfur lone pair Thiophene numbering Viktor Meyer TT-System... 

Electrophilic reactions of phenols a variety of substituted isatins and phenols. 

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. 

Although a good start, these reports underscored the fact that attaching two disparate aromatics to isatin in a single step based on electrophilic aromatic substitution would be quite challenging to accomplish in a reasonable yield. Moreover, since an oxazole and a phenol have far different reactivities, this approach might not work at all. How, then, should one proceed on the basis of this information The answer that these researchers devised was based on the hypothesis that if they could form a compound such as 38 first, then perhaps the second aromatic moiety could be introduced through this same acid-catalyzed eletrophilic aromatic substitution process that Baeyer and Olah had used so productively. As shown in Scheme 3, this idea translated into the initial nucleophilic addition of a dianion derived from oxazole 34 to the more reactive... 

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]. 

The Stolle reaction is thought to occur via a typical mechanism for amide formation from an amine and acid chloride, followed by Friedel-Crafts alkylation or acylation. No definitive mechanistic work has been performed on this reaction, but incorporating the mechnistic understandings of two steps provides a firm basis for understanding the mechanism of this reaction. Formation of the mono-amide from oxalyl chloride and aniline provides intermediate 4, which in the presence of AICI3 undergoes intramolecular electrophilic aromatic substitution to the desired 2,3-dioxindole (isatin) 7 via intermediates 5 and 6. 

In 2011, Ye et al. reported that NHCs can be used as effective catalysts for the conventional [4 + 2] cycloaddition reactions of ketenes. NHC 46, created in situ from its common precursor 46 in the presence of CS2CO3, catalyzed the reaction of a, d-unsaturated acyl chlorides 43 and activated trifluoromethyl ketones 44, promoted by Et3N to afford the corresponding optically active trifluoromethyl substituted 5-lactones 45 (Scheme 16) (2011MI1943). Activated ketones as isatin and its derivatives have been fruitfully employed as electrophiles in this reaction. This reaction is... 

When N-substituted formanilides 1780 are treated briefly and sequentially with oxalyl chloride, Hunig s base, and bromine, isatins 1784 are rapidly formed, many in good yields. The reaction involves deprotonation of the Vilsmeier reagent, dimerization of the carbene thus formed, and electrophilic cyclization of the dimer by the action of bromonium ion followed by aqueous hydrolysis [1309, 1310]. The reaction sequence has been developed into a simple and efficient one-pot isatin synthesis from formanilides. 

Vinyl carbanions derived from acrylic esters and their jS-phenyl derivatives react with several carbon electrophiles to give a-substituted and a,/8-disub-stituted derivatives. While /8>alkyl substituted acrylates have been shown to dimerize in the presence of potassium catalyst at 110 C. Three simple unsaturated esters undergo palladium(0)-catalysed codimerization with methylenecyc-lopropane to furnish methylenecyclopentanecarboxylic esters in reasonable yield. An efficient procedure for the oxidation of isatins to anthranilic acid esters has appeared. Methyl 2,4,6-tri-isopropylbenzoate forms a dipole-stabilized carbanion on reaction with Bu Li, which then reacts with carbon electrophiles [e.g. E = Bui, (CH3)2C0, or CH3CHO] to give a range of ester derivatives in good yield (Scheme 52). ... 

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