Isatin, aldol reactions

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. 

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... 

Chiral 3-hydroxyoxindoles can he synthesized from isatin hy an asymmetric aldol reaction. The prolinamide 68 possesses just the right attrihutes of a catalyst to meet the demand. 

The preparation of 76 began with phenol 65. A key TiCLj-mediated coupling with isatin 67 afforded a tertiary alcohol, which was reduced to form 78 via the chloride. Ester reduction followed by p-TsOH-catalyzed reaction with 2,2-dimethoxypropane afforded acetonide 79. Oxindole silylation and an aldol reaction with HCHO provided an equimolar mixture of both CIO stereoisomers 80. A two-step protection followed by 9-BBN reduction of the lactam gave fragment 76 in good yield (Scheme 13). 

Table 2.38 Asymmetric Aldol Reaction of Isatins and Acetone ...

Scheme 4.22 Aldol reaction between isatins and ketones...

Finally, sulfonamide 79f (5 mol%) has shown to be effective in the aldol reaction between acetone (3a, 200 equiv.) and isatins (72) in the presence of 10 equiv. of water at 25°C, yielding the corresponding aldol products 89 in good results (59-99% yield, 92-97% ee), with exception for product 73a which was obtained in high yield (99%) but nearly as racemic mixture [155],... 

In particular, the use of isatin 143 as an electrophile in aldol reactions is attractive since the reaction affords chiral oxyindole derivatives of type 144, which are... 

SCHEME 3.25. The aldol reaction of isatin (143) with acetone (1). 

CHART 3.21. Bifunctional catalyst for the aldol reaction of isatins with ketones. 

Chen J-R, Liu X-P, Zhu X-Y, Qiao Y-F, Zhang J-M, Xiao W-J (2007) Organocatalytic Asymmetric Aldol Reaction of Ketones with Isatins Straightfmward Stereoselective Synthesis of 3-Alkyl-3-hydroxyindolin-2-ones. Tetrahedron 63 10437... 

Itoh T, Ishikawa H, Hayashi Y (2009) Asymmetric Aldol Reaction of Acetaldehyde and Isatin Derivatives for the Total Syntheses of ent-Convolutamydine E and CPC-1 and a Half Fragment of Madindoline A and B. Org Lett 11 3854... 

Catalysts derived from readily available D-glucosamine catalyse asymmetric aldol reactions/ including amino alcohols derived from the sugar that catalyse reaction of isatin (58) with ketones in high yield and good delee ... 

Pyruvic aldehyde dimethyl acetal, MeCO-CH(OMe)2, undergoes enantioselective direct aldol reaction with isatin derivatives, using a bifimctional organocatalytic combination of a cinchona-derived primary amine and trichloroacetic acid. Glycosyl-a-aminotetrazoles efficiently catalyse enantioselective aldol reactions DPT calculations have been used to identify the origin of the selectivity. ... 

A bifunctional amine/thiourea catalyst gives high ee in a direct vinylogous aldol reaction of allyl ketones with isatins, giving biologically important 3-hydroxy-2-oxindoles. ... 

Br0nsted Base Catalyzed Aldol Reactions of Isatins... 

Scheme 28.17 Cinchona-thiourea catalyzed aldol reactions of isatins.

The 3-hydroxyindole structure can be found in many natural products, as exemphlied by convolutamydines, madindolines, and CPC-1 93. Hayashi and co-workers reported on an asymmetric catalytic direct aldol reaction of isatin 90 with acetaldehyde in the presence of a proline-derived organocatalyst (Scheme 27.16). In this reaction. 

A similar type of direct aldol reaction, i.e., reaction of isatin and ketone, was reported by Xiao and co-work-ers by the use of an L-proline-derived bifunctional orga-nocatalyst 99. The catalytic activity of 99 is quite high, and aldol reaction of isatin 97 with acetone proceeded at low temperature (below zero) to give the aldol adduct (5)-convolutamydine A 100 in high yield (Scheme 27.17). 

Chen JR, Liu XP, Zhu XY, Li L, Qiao YF, Zhang JM, Xiao WJ. Organocatalytic asymmetric aldol reaction of ketones with isatins straightforward stereoselective synthesis of 3-alkyl-3-hydroxyindolin-2-ones. Tetrahedron 2007 63 10437-10444. 

Itoh, T., Ishikawa, H., and Hayashi, Y. (2009) Asymmetric aldol reaction of acetaldehyde and isatin derivatives for the total syntheses of eut-convolutamydine E and CPC-1 and a half fragment of madindoline A and B. Org. Lett., 11, 3854—3857. 

Chen, W.-B., Du, X.-L., Cun, L.-F., Zhang, X.-M., and Yuan, W.-C. (2010) Highly enantioselective aldol reaction of acetaldehyde and isatins only with 4-hydroxydiarylprolinol as catalyst concise stereoselective synthesis of (R)-convolutamydines B and E, (-)-donaxridine and (R)-chimonamidine. Tetrahedron, 66, 1441-1446. 

Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds has been reviewed and their modularly designed thioamide 0 derivatives have been applied successfully to direct cross-aldol reactions between aldehydes and ketones, reactions of activated carbonyl compounds (isatins) with acetylphosphonate as the enol precursor, and C( 1) functionalization of 1,3-dicarbonyl compounds by aldehydes and ketones. Cross-aldol addition to C(3) of isatins by the methyl group of 4-aryl-tra 5 -cf, -unsaturated methyl ketones has also been promoted... 

The Yamamoto vinylogous aldol reaction, in which bulky aluminium-based Lewis acids activate the aldehyde and also become part of the enolate, is stereodirected by 2,3-syn and 2,3-anti disubstitution of the aldehydes bulky -substituents favour 1,3-syn diol formation, whereas alkynyl groups lead to 1,3-anti products. The reaction of (g) a-branched enals with isatins may switch from vinylogous aldolization to a pericyclic pathway depending on the nature of the a-branch. °... 

Aldol reactions of unactivated ketones (164) with isatins (165) are catalyzed by the quinidine-thiourea bifunctional catalyst 166 through an ammonium enolate... 

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