Aldol isatins

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). 

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 following exemplify reactions of the aldol type. 3-Hydroxythiophene with benzaldehyde forms (269). Anions derived from oxindole (270 Z = NH) and indoxyl (271) react with isatin (272) to give isoindigo (273) and indirubin (274). 

The reactive 3-carbonyl group in compounds of type (279) undergoes aldol condensation with active methylene compounds such reactions of isatin with indoxyl, oxindole (Section 3.3.2.5.4) and with thiophenes (Section 3.3.1.5.7.ii) have already been mentioned. These compounds also react with Grignard reagents and phosphorus halides as expected, e.g. isatin (279 Z = NH) with MeMgBr and PC13 yields (285) and (286), respectively. 

A well-known method for the synthesis of 4-quinolinecarboxylic acid derivatives involves the aldol condensation of isatins with ketones having an activated CH2 group in the presence of bases, followed by recyclization of the condensation products (or some of their subsequent transformations) to the desired compounds. Thus, the ketols 164 are formed with good yields from the ketones 163 and isatin 7 in the presence of ammonia and are transformed into 2-substituted quinolinecarboxylic acids 165 when heated in an acidic medium [23, 76],... 

The isatins 7 and 54 react with the imines 203 in boiling dioxane with the formation of the products from aldol condensation 204, which recyclize when heated in ethylene glycol or glycerol to the amides of 4-quinolinecarboxylic acids 205 [179],... 

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... 

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... 

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 formation of indigo by oxidation of indoxyl in alkaline solution might be formulated as involving formation of isatin and condensation of this substance with indoxyl in the aldol manner,... 

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],... 

Isatins 72 reacted with a-methyl aldehydes (77a) catalyzed efficiently by tetrazole 90a (15 mol%) in the presence of 1 equiv. of water and using phosphoric acid (15 mol%) as co-catalyst at 0°C in isopropanol, to afford the corresponding aldol... 

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... 

The proline-catalyzed aldol addition of acetone (1) to isatin 143 affords desired product 144 within 4 days in quantitative yield but with very low enantiomeric excess [158]. Other simple proline derivatives gave disappointing results. However, di- and pseudopeptides 145-147 generate useful levels of selectivity (Chart 3.19) [89b, 159, 160]. 

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. 

While targeting isosteric analogues of natural spirobrassinin and phytoalexin, Wang and co-workers [54] synthesized spirooxindoles in almost optically pure form through an intramolecular aldol/cyclization reaction of a-isothiocyanato imides with isatins catalyzed by a rosin-derived organocatalyst (Scheme 16.27). 

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 ... 

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