Isatins domino reactions

Kumar RS, Rajesh SM, Perumal S et al (2010) Novel three-component domino reactions of ketones, isatin and amino acids synthesis and discovery of antimycobacterial activity of highly functionalised novel dispiropyrrolidines. Eur J Med Chem 45 411 22... 

The use of sulfur ylides as versatile reactants in these domino reactions was also reported by Briere and co-workers [53]. They developed a highly diastereoselective synthesis of spiro epoxyoxindoles from reaction between in s/Yw-generated sulfur ylides and isatin derivatives. Moderate enantioselectivity (30% ee) could be achieved with a C2-symmetrical chiral sulfur ylide. 

In related work, the same researchers described a four-component domino reaction that allows the one-pot synthesis of highly complex spiro systems, i.e. spiro[indoline/acenaphthylene-3,4-pyrazolo[3,4-6]pyridine derivatives 59 and 60 from phertylhydrazine, 3-aminocrotononitrile, isatin or acenaphthylene-1,2-dione and cyclic 1,3-dicarbonyl compoimds, including cyclohexane-l,3-diones and barbituric or thiobaibituric acid, in the presence of ( )-camphor-10-sulphonic acid (CSA) as catalyst (Scheme 1.30). 

Wang and coworkers reported the highly enantioselective domino reaction between isatin derivatives 54c and a-isothiocyanato imides 102 catalyzed by a... 

A four-component domino reaction of isatin 58, phenylhydrazine, 3-aminocrotononitrile 117, and cyclic 3-diketones/amide/thioamide 118 in an aqueous medium in the presence of ( )-camphor-10-sulfonic acid on heating at 100 °C for 2-3 h afforded the spiro-fused 2-oxindoles 119 (Scheme 39) [94]. The reaction was successfully extended to 5-chloro- and 5-nitroisatins. According to the proposed mechanism, an acid-catalyzed reaction of phenylhydrazine with nitrile 117 affords the 5-amino-3-methyl-l-phenyl pyrazole 111 that adds to the carbonyl carbon of isatin giving rise to an intermediate product 120. The acid-catalyzed reaction of this intermediate (that has been isolated) with carbonyl compounds 118 affords another intermediate compound 121, which eventually furnishes the final products 119 by cyclodehydration forming tetrahydropyridine ring followed by subsequent dehydration (Scheme 40). 

SCHEME 39 A four-component domino reaction of isatin, phenylhydrazine, 3-aminocrotononitrile, and cyclic p-diketones/amide/thioamide. 

Further organocatalytic three-component reactions forming heterocyclic spirooxin-doles have featured combination of isatins, malononitrile and isocyanoacetates, and NHC-catalysed domino reaction of alkynyl aldehydes with oxindoles. Silylstannation of a, -unsaturated aldehydes occurs in an NHC-catalysed three-component condensation to form iyn-diols. ... 

This strategy was used to synthesize spirocyclopenteneoxindoles, as well as stereodefined cyclopentenes. Likewise, Hu reported a [3 -f 2] annulation reaction of 2-atylideneindane-l,3-diones with MBH carbonates that proceeded smoothly in the presence of a multifunctional thiourea-phosphine catalysts to produce the corresponding quaternary carbon centered spirocyclic cyclopentenes. A phosphine-triggered tandem [3 + 4] annulation reaction between MBH carbonates and 1,4-diheteroatom dinucleophiles was described, which provided access to saturated seven-membered 1,4-heterocycles. Analogously, MBH carbonates were used as C3 synthons in asymmetric [3 + 2] annulation reactions for the asymmetric synthesis of 3-spirocyclopentene-2-oxindoles. Another kind of annulation reaction for the construction of highly functionalized stereodefined cyclopentene skeletons involved a Rauhut-Currier Domino Reaction. Finally, an efficient asymmetric [3 + 2] cycloaddition reaction between MBH carbonates of isatins and... 

The domino three-component reaction of isatins, aminoacids and cyclic ketones provided novel dispiropyrrolidines 240-243 (Scheme 42) [86]. The compounds were... 

A catalytic asymmetric isatin-involved Povarov reaction was utilized by Shi and colleagues to prepare 251 in a diastereo- and enantioselective manner. During the three-component coupling, two chiral quaternary centers are formed in >99 1 dr and up to 97% ee (130L128). Complex polyhet-erocyclics 252 and 253 were prepared by a highly selective four-component domino multicyclization with an isatin, an enamineone, and two acetylenes. Four new rings and four stereocenters are created in a one-pot operation, with the reactions complete within 30 min in up to 64% yield (13OL1540). 

The mechanism proposed to explain this domino sequence of reactions is summarized in Scheme 1.31 for the case of the reactions with isatin, and was proposed to be initiated by the formation of 5-amino-3-methyl-l-phenylpyrazole from phen-ylhydrazine and 3-aminocrotononitrile. Its acid-catalyzed reaction with isatin leads to 61, which was proved to be an intermediate of the reaction by its isolation by reducing the reaction time and its transformation in the final products under the standard reaction conditions. The combination of 61 with the starting cyclic 1,3-dicarbonyl compounds, again under acidic catalysis, would then afford intermediate 62, and then the observed product 59 after a final cyclocondensation step with loss of a molecule of water [45],... 

In 2012, a chiral cinchona alkaloid-derived primary amine was associated by Wang et al. to a (R)-BINOL-derived phosphoric acid to induce a three-component domino Knoevenagel-Michael reaction between isatins, malononitrile, and acetone, providing the corresponding domino products in generally excellent yields and enantioselectivities, as shown in Scheme 2.13. A hypothetic cooperative catalysis can be envisaged to explain these excellent results. 

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]. 

A three-component reaction related to the Hantzsch-synthesis of dihydropyrid-ines was recently reported by Yuan and colleagues who developed a domino cascade Knoevenagel/Michael/cyclization sequence converting isatin derivatives 182, malonitrile (183), and symmetrical acyclic 1,3-diketones or (3-ketoesters 184... 

Scheme 42.42 Enantioselective domino Hantzsch-like synthesis of dihydropyrans starting from isatin derivatives, malonitrile, and 1,3-dicarbonyl compounds. The reaction was efficiently catalyzed by cupreine.

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