3- hydroxy-2-oxindoles

The Martinet procedure for the synthesis of indole-2,3-diones involves the reaction of an aminoaromatic compound and either an oxomalonate ester or its hydrate in the presence of an acid to yield a 3-(3-hydroxy-2-oxindole)carboxylic acid derivative which after oxidative decarboxylation yields the respective isatin. This method was applied with success for the synthesis of 5,6-dimethoxyisatin from 4-aminoveratrole whereas the use of 2,4-dimethoxyaniline was less successful40 (Scheme 9). 

Additional examples of synthetic applications of hypervalent iodine-induced heterocyclizations include the following the metal-free one-pot synthesis of 2-acylbenzothiazoles by oxidative cyclization of multiform substrates [434], iodine(III)-mediated tandem oxidative cyclization for construction of 2-nitrobenzo[ ]furans [435], hypervalent iodine mediated oxidative cyclization of o-hydroxystilbenes into benzo- and naphthofu-rans [436], PhI(OCOCF3)2-mediated synthesis of 3-hydroxy-2-oxindoles and spirooxindoles from anilides [437], synthesis of isoxazoles by hypervalent iodine-induced cycloaddition of nitrile oxides to alkynes [438],... 

The first example of direct enantioselective addition of a C—H bond to a ketone was reported by Shibata and co-workers in 2009 using the cationic Ir/ (S)-Hg-BINAP as the catalyst in the synthesis of a chiral 4-acetyl-3-hydroxy-3-methyl-2-oxindole with 72% ee. Recently, Yamamoto and co-workers developed a cationic Ir/(R,R)-Me-BIPAM catalyzed asymmetric intramolecular direct hydroarylation of a-keto amides 178 affording the chiral 3-substi-tuted 3-hydroxy-2-oxindoles 179 in high yields with complete regioselectivity and high enantioselectivity (84-98% ee). In their proposed reaction mechanism, the aryl iridium complex formed via C—H bond activation is coordinated with the two carbonyl groups of the amide (Scheme 5.65). 

In 2010, Franz and co-workers found chiral pybox complex Sc Vl7 as an efficient catalyst for the direct addition of indoles to N-Me isatin 15 to afford 3-hydroxy-2-oxindole derivatives 16 (Table 6.1). This chiral catalytic system... 

An interesting enantioselective copper-catalyzed coupling of pyrroles 261 with isatins 260 was reported for the synthesis of 3-substituted-3-hydroxy-2-oxindoles 262. This reaction proceeds in moderate to high yield with high ee (140L3192). 

Scheme 2.8 The total synthesis of the 3-hydroxy-2-oxindole derivatives.

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 MBH reaction of acrylates CH2=CHC02R with isatins, employing the bifunctional phosphinothiourea catalysts (198), afforded the corresponding 3-hydroxy-2-oxindole derivatives with moderate enantioselectivity (<69% ee). orf/io-Mercaptobenzoic acid and ort/io-mercaptophenols 2-X-QH4SH (X = CO2H or OH) have been shown to act as multifunctional Lewis basic catalysts for both the intramolecular MBH and Rauhut-Currier reaction in aqueous solutions. The catalytic activity of these protic nucleophiles is believed to originate from a Brpnsted acid-induced destabilization of the intermediate thioethers. ... 

Chen T-Y, Krische MJ (2013) Regioselective ruthenium-catalyzed hydrohydroxyalkylation of dienes with 3-hydroxy-2-oxindoles prenylation, geranylation and beyond. Org Lett 15 2994-2997... 

Yamaguchi E, Mowat J, Luong T, Krische MJ (2013) Regio- and diastereoselective C-C coupling of a-olefins and styrenes to 3-hydroxy-2-oxindoles by Ru-catalyzed hydrohydroxyalkylation. Angew Chem Int Ed 52 8428-8431... 

Hypervalent iodine reagents have successfully been employed in the oxidative functionalization of enolizable carbonyl compounds over the years [6]. This methodology has allowed the construction of diverse C-C bonds in the context of heterocychc synthesis and has enriched the otherwise rare repertoire of such chemistry. Zhao, Du, and coworkers [37] have recendy realized a metal-free PIFA-mediated synthesis of 3-hydroxy-2-oxindoles 34 and spirooxindoles 35 starting from anilide derivatives 33 (Scheme 8 (1)). These processes showcase an oxidative cross coupling between an aromatic carbon and a pendant aliphatic carbon, followed by further oxidative hydroxylation or spirocycUzation. Later, the authors extended the same concept to achieve C(sp )-C(sp ) bond formation, where anilide derivatives possessing terminal enol functionality underwent PIDA-... 

Formaldehyde f-butyl hydrazone, H2C=N-NH-Bu has been used as a formyl anion equivalent it reacts with isatins to give functionalized 3-hydroxy-2-oxindoles. 

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. ... 

The catalytic effect of alkylmethylimidazolium ionic liquids as solvents for the Baylis-Hillman reaction has been investigated by DFT, using benzaldehyde, substrate and DABCO as base. 3-Substituted 3-hydroxy-2-oxindoles (76, n = 0, 1) have been prepared in water via an MBH reaction of unprotected isatins with cyclic enones. Bicyclic imidazolyl alcohol (77) is a particularly good catalyst, with its hydroxyl group proposed to stabilize the betaine intermediate. 

Catalyst 3 was also used in the construction of substituted 3-hydroxy-2-oxindoles by the reaction of 5-methoxy substituted isatins with various indoles [28]. Up to 91% ee could be obtained in 1,4-dioxane as the solvent and benzoic acid as an additive. Similarly, 3 was apphed as catalyst for the formation of spiro[4H-pyran-3,3 -oxindoles] via a one-pot domino Knoevenagel, conjugate addition, cyclization sequence (Scheme 6.12) [29]. 

Three years later, two groups independently described the asymmetric addition of indoles to isatins to give, in a straightforward manner, 3-indolyl-3-hydroxy-2-oxindole derivatives 61 and 62 (Scheme 35.13) [19, 20]. In these examples, quaternary stereogenic centers are created in high yields and excellent enantioselectivities (up to 99% ee). 

Peddibhotla S. 3-Substituted-3-hydroxy-2-oxindole, an emerging new scaffold for drug discovery with potential anticancer and other biological activities. Curr. Bioact. Comp. 2009 5 20-38. 

Nakamura et al. established the stereoselective synthesis of 3-hydroxy-2-oxindols by using 1,7-asymmetric induction. Scheme 8.51 shows the enantioselective synthesis of convo-lutamydine B 310, an antitumor agent. The vinylogous aldol reaction with dienolate 303 and enf-303 was found to be effective to yield 3-hydroxy-2-oxindols stereoselectively. 

Recently, Lu s group reported almost the same P-lCD-catalyzed asymmetric MBH reaction of isatin derivatives with acrylates [41]. They also demonstrated that P lCD was an efficient catalyst for this reaction, affording 3-substituted 3-hydroxy-2-oxindoles 87 in good yields with high enantioselectivities (Scheme 31.27). They pointed out that the C6 -OH group of P-ICD probably facilitates the key proton transfer step in the MBH reaction, via an intramolecular proton relay process. 

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