Oxindole reaction with aldehydes

Due to the presence of these resonance forms in azomethine ylids, reaction with alkenes often leads to mixtures of regioisomeric cycloadducts. Resonance stabilizing substituents are usually employed to enhance the regioselectivity. Intramolecular reactions usually favor only one mode of addition. An example of an intermolecular reaction is taken from Williams synthesis of spirotryprostatin B,372 in which 5,6-diphenylmor-pholin-2-one (473) reacted with the aldehyde shown to give a mixture of ( )- and (Z)-azomethine ylids (474). This product was generated in situ with oxindole 475, and [3-i-2]-cycloaddition product 476 was obtained in 82% yield. 

The easy condensation of aldehydes with 3-monosubstituted oxindoles has been further exploited by Ban and co-workers, who synthesized several 3-spirooxindole derivatives 48). The approach was used in the stereospecific synthesis of racemic iV-methylrhynchophyllane (Chart X). The Iraws-diethylcyclopentanone CVIIIa was subjected to Baeyer-Villiger oxidation to yield the threo lactone CIX, which was converted to the chloroaldehyde CXI, by successive reaction with phosphorus... 

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

A mechanistic rationalization for this reaction is presented in Scheme 5.48. Domino process is initiated with generation of key intermediate 152, which undergoes a 1,4-addition of a deprotonated oxindole to form 153. After H-migration and following aldol reaction with another molecule of alkynyl aldehyde, intermediate 155 is formed. Subsequent lactonization delivers prodnct 66 and regenerates NHC for the next catalytic cycle. The stereochemistry of the products may be determined by the most sterically favored chair transition state in 155. 

These ligands were initially tested in the nickel(ll)-catalyzed enantioselec-tive fluorination of oxindoles and P-ketoesters, yielding the corresponding products with enantioselectivities of up to >99% ee and high yields. Application of the chiral pincer ligands in the chromium-catalyzed enantioselective Nozaki-Hiyama-Kishi reaction of aldehydes gave the corresponding alcohols with a maximum enantioselectivity of 93% [34]. 

The spirocyclic oxindole core structure was constructed by an asymmetric 1,3-dipolar cycloaddition in the total synthesis of (—)-spirotryprostatin B. A reaction of oxazi-none 137 with aldehyde 138 and oxindole 139 resulted in spirooxindole 141 via the chiral azomethine yhde 140, simultaneously creating three bonds and four stereogenic centers in one step (Scheme 16.20). ... 

Oxindole exists as the carbonyl-tautomer, the hydroxy 1-tautomer ( 2-hydroxyindole ) being undetectable. There is nothing remarkable about the reactions of oxindole for the most part it is a typical 5-membered lactam, except that deprotonation at the p-carbon (pA a 18) occurs more readily than with simple amides, because the resulting anion is stabilised by an aromatic indole resonance contributor. Such anions will react with electrophiles like alkyl halides and aldehydes at the p-carbon, the last with dehydration and the production of aldol condensation products. Oxindoles can be oxidised to isatins (20.13.3) via easy 3,3-dibromination, then hydrolysis. Bromination of oxindole with A -bromosuccinimide gives... 

Wittig reaction on ketone 300 was followed by acidic hydrolysis of the vinyl ether to provide aldehyde 290. Reduction of the aldehyde group with NaBHa resulted in the synthesis of (—)-affinisine oxindole (118) in 34% yield (over three steps). Consequently, the stereospecific total synthesis of the sarpagine-related (—)-affinisine oxindole (118) was accomplished in 11 steps and in 10% yield from d-(+)-tryptophan (155). 

Recently, there has been considerable progress in the synthesis of nitrogen-containing heterocycles based on (ox)indole skeleton. Oxindole derivatives serve as useful reaction partners in various domino transformations. Michael addition of aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral intermediates, which were further combined with diverse activated olefins or imines to afford spirocyclic oxindoles with high molecular complexity (Scheme 8.27). Spiro-oxindole derivatives were also assembled by a Michael/Michael/aldol cascade of oxindole and two equivalents of enal. " ... 

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). 

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