Organocatalytic Asymmetric Cascade Reactions of 7‐Vinylindoles: Diastereo‐ and Enantioselective Synthesis of C7‐Functionalized Indoles

The first catalytic asymmetric cascade reaction of 7‐vinylindoles has been established by the rational design of such substrates. Cascade reactions with isatin‐derived 3‐indolylmethanols in the presence of a chiral phosphoric acid derivative allow the diastereo‐ and enantioselective synthesis of C7‐functionalized indoles as well as the construction of cyclopenta[b]indole and spirooxindole frameworks (all >95:5 d.r., 94–>99 % ee). This approach not only addresses the great challenge of the catalytic asymmetric synthesis of C7‐functionalized indoles, but also provides an efficient method for constructing biologically important cyclopenta[b]indole and spirooxindole scaffolds with excellent optical purity. Investigation of the reaction pathway and activation mode has suggested that this cascade reaction proceeds through a vinylogous Michael addition/Friedel–Crafts process, in which dual H‐bonding activation of the two reactants plays a crucial role.     

Efficient One‐Pot Synthesis of Novel Spirooxindole‐Fused Phosphorous Heterocycle Derivatives by a Three‐Component Domino Reaction

A highly efficient, catalyst‐free, and regioselective synthesis of structurally diverse spirooxindole‐fused phosphorous heterocycle derivatives was constructed in good yields by means of a three‐component domino reaction of isatins, dichlorophenylphosphine or phenyl phosphorodichloridite, and o‐aminophenol in tetrahydrofuran reflux. The advantages of this method include high efficiency, mild reaction conditions, and environmentally benign reagents. These spirooxindole‐fused phosphorous heterocycles are promising candidates for drug discovery.     

Catalytic Asymmetric Construction of 3,3′‐Spirooxindoles Fused with Seven‐Membered Rings by Enantioselective Tandem Reactions

The first catalytic asymmetric construction of a spirooxindole scaffold incorporated with a seven‐membered benzodiazepine moiety has been established by a three‐component (isatin, 1,2‐phenylenediamine, cyclohexane‐1,3‐dione) tandem reaction catalyzed by a chiral phosphoric acid. Structurally complex spirobenzodiazepine oxindoles with one quaternary stereogenic center are obtained in high yield with excellent enantioselectivity (up to 99 % yield, enantiomeric ratio>99.5:0.5). This approach takes advantage of organocatalytic asymmetric tandem reactions to efficiently construct the structurally rigid spirobenzodiazepine oxindole architecture with high enantiopurity in a single transformation, which involves a cascade enamine–imine formation/intramolecular Mannich reaction sequence.     

An efficient one‐pot three‐component reaction for synthesis of spirooxindole derivatives in water media under catalyst‐free condition

An efficient, clean, and environmentally benign synthesis of spirooxindole derivatives by one‐pot three‐component reaction of isatins, malononitrile, and carbonyl compound in the absence of catalysis in water was described. A variety of spirooxindole derivatives were obtained with excellent yields within short reaction time. This novel protocol has the advantages of convenient operation, low cost, and environmental benign. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:673–677, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20723     

Construction of Spirocyclic Oxindoles through Regio‐ and Stereoselective [3+2] or [3+2]/[4+2] Cascade Reaction of α,β‐Unsaturated Imines with 3‐Isothiocyanato Oxindole

On the basis of asymmetric regioselective [3+2] or [3+2]/[4+2] cascade reaction of 3‐isothiocyanato oxindoles with C=C and C=N bonds of α,β‐unsaturated methanesulfonamides, diversified S‐containing heterocyclic spirooxindole derivatives could be obtained in high yields along with good to excellent diastereo‐ and enantioselectivities under mild conditions in the presence of cinchona alkaloid‐derived organocatalysts.     

Synthesis of Spirooxindoles through Cyclocondensation of Isatin and Cyclic 1,3‐Diones

A simple, clean, and efficient method for the synthesis of spirooxindole derivatives via condensation of isatin with enolizable cyclic β‐diketones has been developed. The use of water as a solvent allows avoiding the use of toxic organic solvents, which makes this reaction safe and environmentally friendly. The mechanism of the condensation reaction has been investigated using first‐principles‐based density functional theory calculations.     

Synthesis of New Spirooxindole‐Fused Isoxazoline/Triazole and Isoxazoline/Isoxazole Derivatives from Three‐Component 1,3‐Dipolar Cycloaddition

A series of diverse heterocycles containing spirooxindole, isoxazoline/triazole, and isoxazole rings has been synthesized via an efficient three‐component reaction of (E )‐2‐(1‐propargyl‐2‐oxoindoline‐3‐ylidene)acetophenones 1 , arylnitrile oxides 2 , and arylazides 3 using Cu(I) as catalyst. The regiochemistry and stereochemistry of cycloadducts 4a and 5a have been confirmed by X‐ray diffraction studies. The heterocycles were screened against Gram‐positive and Gram‐negative bacteria and fungi. Several compounds exhibit moderate to excellent activities comparable to those of established standard drugs.     

Efficient Synthesis of Spirooxindole Pyrrolones by a Rhodium(III)‐Catalyzed C−H Activation/Carbene Insertion/Lossen Rearrangement Sequence

A rhodium(III)‐catalyzed domino annulation of simple olefins with diazo oxindoles to give spirooxindole pyrrolone products is described. This reaction can be formally viewed as the result of an anomalous tandem C?H activation, carbene insertion, Lossen rearrangement, and a nucleophilic addition process. The potential utility of this reaction was further demonstrated by the late‐stage diversification of drug molecules.     

Facile Synthesis of Spirooxindole‐Cyclohexenes via Phosphine‐Catalyzed [4 + 2] Annulation of α‐Substituted Allenoates

A phosphine‐catalyzed [4 + 2] annulation of α ‐substituted allenoate with exocyclic alkene moiety of oxindoles or indan‐1,3‐diones has been developed. Thus, under the catalysis of PPh₃ (20 mol%), a series of spirooxindole‐ or spiroindan‐1,3‐dione‐cyclohexenes have been obtained in moderate to excellent yields and regioselectivity from the annulations of α ‐methyl allenoates with 3‐methyleneoxindoles or 2‐methyleneindan‐1,3‐diones. This method offers an easy access to structurally novel spirocyclohexenes.     

Application of Sulfonic Acid Functionalized SBA‐15 as a New Nanoporous Acid Catalyst in the Green One‐Pot Synthesis of Spirooxindole‐4H‐pyrans

Sulfonic acid functionalized SBA‐15 (SBA‐Pr‐SO₃H) as a new nanoporous solid acid catalyst was applied in the green one‐pot synthesis of spirooxindole‐4H‐pyrans via condensation of isatins, malononitrile or methyl cyanoacetate or ethyl cyanoacetate, and 4‐hydroxycoumarin in water solvent. SBA‐Pr‐SO₃H was proved to be an efficient heterogeneous nanoporous solid acid catalyst with a pore size of 6 nm that could be easily handled and removed from the reaction mixture by simple filtration and can be recovered and reused for several times without any loss of activity. The significant merits of present methodology are its simplicity, short reaction time, good yields, and environmentally benign mild reaction condition as water was used as a green solvent.     

Catalytic Asymmetric 1,2‐Addition of α‐Isothiocyanato Phosphonates: Synthesis of Chiral β‐Hydroxy‐ or β‐Amino‐Substituted α‐Amino Phosphonic Acid Derivatives

α‐Amino phosphonic acid derivatives are considered to be the most important structural analogues of α‐amino acids and have a very wide range of applications. However, approaches for the catalytic asymmetric synthesis of such useful compounds are very limited. In this work, simple, efficient, and versatile organocatalytic asymmetric 1,2‐addition reactions of α‐isothiocyanato phosphonate were developed. Through these processes, derivatives of β‐hydroxy‐α‐amino phosphonic acid and α,β‐diamino phosphonic acid, as well as highly functionalized phosphonate‐substituted spirooxindole, can be efficiently constructed (up to 99 % yield, d.r. >20:1, and >99 % ee). This novel method provides a new route for the enantioselective functionalization of α‐phosphonic acid derivatives.     

Hydrogen‐Bonding Network Promoted [3+2] Cycloaddition: Asymmetric Catalytic Construction of Spiro‐pseudoindoxyl Derivatives

The enantioselective construction of a spirocyclic quaternary stereogenic carbon center at the C2 position of indole has long been an elusive problem in organic synthesis. Herein, by employing a rationally designed hydrogen‐bonding network activation strategy, for the first time, 2,2′‐pyrrolidinyl‐spirooxindole, which is a valuable and prevalent indole alkaloid scaffold, was directly obtained through a catalytic asymmetric [3+2] cycloaddition reaction with high yields and excellent stereoselectivities.     

Facile Synthesis of Chiral Spirooxindole‐Based Isotetronic Acids and 5‐1H‐Pyrrol‐2‐ones through Cascade Reactions with Bifunctional Organocatalysts

Unprecedented organocatalyzed asymmetric cascade reactions have been developed for the facile synthesis of chiral spirooxindole‐based isotetronic acids and 5‐1H‐pyrrol‐2‐ones.The asymmetric 1,2‐addition reactions of α‐ketoesters to isatins and imines by using an acid–base bifunctional 6′‐OH cinchona alkaloid catalyst, followed by cyclization and enolization of the resulting adducts, gave chiral spiroisotetronic acids and 5‐1H‐pyrrol‐2‐ones, respectively, in excellent optical purities (up to 98 % ee). FT‐IR analysis supported the existence of hydrogen‐bonding interaction between the 6′‐OH group of the cinchona catalyst and an isatin carbonyl group, an interaction that might be crucial for catalyst activity and stereocontrol.     

Chiral Iodine‐Catalyzed Dearomatizative Spirocyclization for the Enantioselective Construction of an All‐Carbon Stereogenic Center

The first enantioselective dearomatizative spirocyclization of 1‐hydroxy‐N‐aryl‐2‐naphthamide derivatives has been accomplished by chiral organoiodine catalysis to stereoselectively create an all‐carbon stereogenic center, providing a straightforward approach to access spirooxindole derivatives in good yields and with high to excellent levels of enantioselectivity. Chiral hypervalent phenyl‐λ³‐iodanes generated in situ from the oxidation of the chiral phenyl iodine actually participate in the asymmetric oxidative dearomatizative spirocyclization reaction.     

Enantioselective Synthesis of 2‐Oxindole Spirofused Lactones and Lactams by Heck/Carbonylative Cylization Sequences: Method Development and Applications

An efficient one‐pot assembly of all‐carbon spiro‐oxindole compounds from non‐oxindole‐based materials has been developed through a palladium‐catalyzed asymmetric Heck/carbonylative lactonization and lactamization sequence. Diversified spirooxindole γ‐and δ‐lactones/lactams were accessed in high yields with good to excellent enantioselectivities (up to 99 % ee) under mild reaction conditions. The natural product coixspirolactam A was conveniently synthesized by applying the current methodology, and thus its absolute configuration was elucidated for the first time. Asymmetric synthesis of an effective CRTH2 receptor antagonist has also been demonstrated utilizing this method in the key step.     

Efficient Enantioselective Total Synthesis of (−)‐Horsfiline

A new efficient and concise enantioselective synthetic method for (?)‐horsfiline is reported. (?)‐Horsfiline could be obtained from diphenylmethyl tert‐butyl malonate in 9 steps (32 %,>99 % ee) by using the enantioselective phase‐transfer catalytic allylation (91 % ee) as the key step. This approach can be applied as a practical route for the large‐scale synthesis of spirooxindole natural products, which enables a systematic investigation of their biological activity to be performed.     

Protecting‐Group‐Free Total Synthesis and Biological Investigation of Cabucine Oxindole A†

Owing to their challenging structures and promising biological profiles, spirooxindole alkaloids have long attracted much attention from the synthetic community. Herein, we wish to describe a concise, protecting‐group‐free total synthesis of cabucine oxindole A, a putative natural spirooxindole alkaloid and a possible biosynthetic congener of cabucine and palmirine. Key transformations of our approach include a one‐step, organocatalytic and enantioselective construction of the spiro[pyrrolidine‐3,3’‐oxindole] moiety and a Korte rearrangement to furnish the final dihydropyran motif. Biological investigation of 1 and its synthetic intermediates revealed lactone 2 as a mild MOLT‐4 and MCF7 cell line inhibitor.     

Task‐specific Ionic Liquid Mediated Eco‐compatible Approach for the Synthesis of Spirooxindole Derivatives and Their DNA Cleavage Activity

Guanidine‐based task‐specific ionic liquid 1,1,3,3‐tetramethylguanidine acetate [TMG][Ac]was found to be a very effective solvent for the synthesis of pharmaceutically important spirooxindole derivatives through one‐pot multicomponent reaction of substituted isatin, thiazolidine‐4‐carboxylic acid and naphthoquinone followed by the spontaneous dehydrogenation in excellent yields without using any reagent and catalyst. The TMG‐based ionic liquid could be recovered and used at least four times without considerable reduction in its activity. The advantageous features of the developed synthetic protocol are high atom economy, operational simplicity, shorter reaction time, easily handling, and environmentally benign. The structure and relative stereochemistry of final products was established by single crystal X‐ray structure and spectroscopic techniques. The synthesized compounds were subjected for DNA cleavage activity.     

Synthesis and characterization of MgO nanoparticles supported on ionic liquid‐based periodic mesoporous organosilica (MgO@PMO‐IL) as a highly efficient and reusable nanocatalyst for the synthesis of novel spirooxindole‐furan derivatives

The synthesis and catalytic application of a novel MgO containing periodic mesoporous organosilica with ionic liquid framework (MgO@PMO‐IL) is described. The prepared MgO@PMO‐IL was characterized by Fourier transform‐infrared spectroscopy, N₂ adsorption/desorption, transmission electron microscopy, field emission‐scanning electron microscopy, thermogravimetric and inductively coupled plasma analyses. This nanocatalyst was successfully applied as a highly efficient and recoverable catalyst for the synthesis of novel spirooxindole‐furan derivatives via the three‐component reaction of 1,3‐dicarbonyl compounds, N‐phenacyl pyridinium salts and isatin derivatives. The products were achieved in high to excellent yields with a simple work‐up procedure and short reaction times, and the catalyst could be recovered through a simple filtration process and successfully reused seven times without any significant decrease in its efficiency.     

Brominated Trihalomethylenones as Versatile Precursors to 3‐Ethoxy, ‐Formyl, ‐Azidomethyl, ‐Triazolyl,and 3‐Aminomethyl Pyrazoles

5‐Bromo[5,5‐dibromo]‐1,1,1‐trihalo‐4‐methoxy‐3‐penten[hexen]‐2‐ones are explored as precursors to the synthesis of 3‐ethoxymethyl‐5‐trifluoromethyl‐1H‐pyrazoles from a cyclocondensation reaction with hydrazine monohydrate in ethanol. 3‐Ethoxymethyl‐carboxyethyl ester pyrazoles were formed as a result of a substitution reaction of bromine and chlorine by ethanol. The dibrominated precursor furnished 3‐acetal‐pyrazole that was easily hydrolyzed to formyl group. In addition, brominated precursors were used in a nucleophilic substitution reaction with sodium azide to synthesize the 3‐azidomethyl‐5‐ethoxycarbonyl‐1H‐pyrazole from the reaction with hydrazine monohydrate. These products were submitted to a cycloaddition reaction with phenyl acetylene furnishing the 3‐[4(5)‐phenyl‐1,2,3‐triazolyl]5‐ ethoxycarbonyl‐1H‐pyrazoles and to reduction conditions resulting in 3‐aminomethyl‐1H‐pyrazole‐5‐carboxyethyl ester. The products were obtained by a simple methodology and in moderate to good yields.