Cycloaddition Of Isatins Research Articles

Engaging Isatins and Amino Acids in Multicomponent One-Pot 1,3-Dipolar Cycloaddition Reactions-Easy Access to Structural Diversity.

Multicomponent reactions (MCRs) have undoubtedly emerged as the most indispensable tool for organic chemists worldwide, finding extensive utility in the synthesis of intricate natural products, heterocyclic molecules with significant bioactivity, and pharmaceutical agents. The multicomponent one-pot 1,3-dipolar cycloaddition reactions, which were initially conceptualized by Rolf Huisgen in 1960, find extensive application in contemporary heterocyclic chemistry. In terms of green synthesis, the multicomponent 1,3-dipolar cycloaddition is highly favored owing to its numerous advantages, including high step- and atom-economies, remarkable product diversity, as well as excellent efficiency and diastereoselectivity. Among the numerous pieces of research, the most fascinating reaction involves the utilization of azomethine ylides generated from isatins and amino acids that can be captured by various dipolarophiles. This approach offers a highly efficient and convenient method for constructing spiro-pyrrolidine oxindole scaffolds, which are crucial building blocks in biologically active molecules. Consequently, this review delves deeper into the dipolarophiles utilized in the 1,3-dipolar cycloaddition of isatins and amino acids over the past six years.

Yb(OTf)3 Anchored on Crosslinked Chitosan Microsphere: A Green Heterogenized Catalyst for the Synthesis of Bispiro‐Fused Heterocycles

AbstractUsing renewable biomass chitosan as a raw material, crosslinked chitosan microsphere (CCM) was prepared by inverse suspension, which was then immersed in the ethanol solution of Yb(OTf)3 to fabricate CCM‐supported Yb(OTf)3 (Yb(OTf)3@CCM). The three‐component [3+2] cycloaddition of isatins, tetrahydroisoquinolines and 5‐alkenyl rhodanines was developed with Yb(OTf)3@CCM as a green heterogeneous catalyst, which gave access to a suite of architecturally complex bispiro‐fused heterocycles merging four pharmacophores with moderate to excellent yields (50–96 %) and diastereoselectivities (up to 99 : 1 dr). The reaction mechanism was preliminarily clarified by controlled experiments and dynamic high‐resolution mass spectrometry studies. The synthetic potential of this protocol was proved by a gram‐scale reaction which furnished the product with comparable results (85 % yield and 72 : 28 dr). Moreover, the catalyst could be recovered just through filtering, washing and drying process, and reused five times with the catalytic activity remaining in an acceptable range (from 93 % to 73 % yield).

DFT Studies on the Molecular Structure, Regioisomerism, Ground and Excited state Charge Transfer Properties of Spiro‐heterocycles

AbstractThe electronic structure, stereochemical aspects and charge transfer properties of the spiro compound (5S,8S) spiro‐{6‐phenyl‐1‐aza‐3‐oxa‐7‐thia‐bicyclo[3,3,0]‐octene‐8,3’(2’H)‐indol}‐2’‐one (spiro bicyclo adduct) synthesized using the multi‐component reaction via 1,3‐dipolar cycloaddition of isatin and thioproline with the dipolarophile phenylacetylene have been studied. The two lowest energy regio‐isomers of the spiro heterocycle formed from the stereospecific dipolar reaction have been analysed along with the electron‐withdrawing and releasing substituents using DFT method at the CAM‐B3LYP/6‐311++G(d,p) level of theory. The atomic charges and the stabilization energy due to the intramolecular charge delocalization process calculated using the natural orbitals at the different molecular sites reveal the different donor‐acceptor interactions occurring in the system. The intramolecular electronic transitions (specifically n to π* and π to π*) is found to occur from the localized donor end component to the acceptor end components in the multi‐component system. The hole produced by the ionization of the entities is found to migrate from the thioproline component to the phenyl acetylene part in a time scale of around 4 fs. The electron‐withdrawing and donating substituents on the spirobicyclo adduct have been proven to tune the excited and ground state charge transfer properties uniquely. The results can shed light on how multi‐component reactions can be directed to produce spiro adducts with versatile applications.

Asymmetric [2 + 2] cycloaddition of isatin with ketene catalyzed by N, N'-dioxide-Sc(III) complex: Mechanism and selectivity

• [2 + 2] cycloaddition of ketene occurred via a concerted [ π 2 s +( π 2 s + π 2 s )] mechanism. • Bulky substituent induced the re -face of ketene to attack the si -face of isatin, enhancing ee % and dr . • N -benzylisatin coordinated to Sc 3+ ion in bidentate fashion, forming reactive species. The mechanism and stereoselectivity of the phenylethylketene with isatin catalyzed by a chiral N,N′- dioxide-Sc(III) complex were studied at the B3LYP-D3(BJ)/6–311G(d,p)//B3LYP-D3(BJ)/def2-SVP(SMD,CH 2 Cl 2 ) theoretical level. The calculations indicated that the reaction occurred in a one-step but asynchronous manner. The four-membered product was formed by nucleophilic attack of the electron-rich O(2) atom in the N -benzylisatin toward the electron-deficient C(β) atom in ketene in the initial stage of reaction, which was responsible to the high regioselectivity of the cycloaddition. The π-π stacking interaction between two deformed reactants stabilized the corresponding transition state, affording the enantiomer with S,R -configuration as major product in background reactions. The N -benzylisatin coordinated to the Sc 3+ in bidentate manner, forming a hexacoordinated scandium-complex reactive species in the catalytic process. Different from the non-catalytic reaction, the C α -C 1 bond was formed prior to the construction of C β -O 2 bond. The ortho - i Pr in the aniline of chiral N,N′- dioxide ligand shielded re -face of isatin, and induced the ketene to attack the isatin from less hindered si -face, leading to good enantioselectivity of product. Suffering from the steric repulsion from benzyl group in N -benzylisatin, the phenylethylketene substrate preferred to approach the si- face of N -benzylisatin with its re -face, affording predominant product with S,S -configuration. Variation of substituent in reactants and ligand structure would modify the shielding degree of ortho - i Pr toward prochiral face of isatin, adjusting the stereoselectivity. Steric hindrance from bulky substituents in chiral N, N ’-dioxide ligand and the Bn group in isatin as well as Et group in ketene contributed to high enantio‑ and diastereoselectivity of product.

Synthesis of spiro(indoline‐3,1′‐pyrazolo[1,2‐a]pyrazoles) by 1,3‐dipolar cycloadditions of isatin N,N′‐cyclic azomethine imines with alkynes

Abstract1,3‐Dipolar cycloaddition of isatin N,N′‐cyclic azomethine imine catalyzed by CuCO3 has been developed. Structurally interesting heterocyclic spiro(indoline‐3,1′‐pyrazolo[1,2‐a]pyrazoles) have been synthesized as single regioisomers in good yields and high functional group compatibility.

1,3-Dipolar cycloaddition of isatin N,N'-cyclic azomethine imines with α,β-unsaturated aldehydes catalyzed by DBU in water.

A simple and green procedure was established by [3 + 3] cycloaddition reaction of isatin derived cyclic imine 1,3-dipoles with α,β-unsaturated aldehydes, giving the desired spiro heterocyclic oxindoles with aza-quaternary centers in good yields and diastereoselectivities. It should be noted that water can be employed as a suitable solvent for the improvement of diastereoselectivity.

Rapid abnormal [3+2]-cycloaddition of isatin N,N′-cyclic azomethine imine 1,3-dipoles with chalcones

More than 35 new compounds were prepared rapidly in moderate to excellent yields with high diastereoselectivities by K2CO3-promoted abnormal 1,3-diploar cycloaddition of isatin N, N′-cyclic azomethine imines with chalcones.

Synthesis of dispiro[1-benzothiophene-2,3'-pyrrolidine-2',3”-indoline]-2”,3-diones in cycloaddition reaction

The 1,3-dipolar cycloaddition of azomethine ylides derived from isatin and sarcosine to (Z)-2-(arylmethylidene)-1-benzothiophen-3(2H)- ones afforded novel dispiro[1-benzothiophene-2,3'-pyrrolidine-2',3”-indoline]-2”,3-diones in moderate yields. The structures of all the products were characterized by NMR, IR, HRMS together with X-ray crystallographic analysis. The reaction gives two diastereomeric products. This result is different from the cycloaddition of isatin, sarcosine, and other exocyclic olefins which generally afford only one product.

Diastereoselective construction of pyrrolo[2,1-a]isoquinoline-based bispirooxindoles through a three-component [3 + 2] cycloaddition.

An efficient three-component one-pot [3 + 2] cycloaddition of isatins, 1,2,3,4-tetrahydroisoquinolines and methyleneindolinones has been developed. This reaction proceeded in a highly diastereoselective manner to afford a wide range of pyrrolo[1,2-a]isoquinoline-based bispirooxindoles in up to 91% yields. Additionally, a gram-scale experiment and some chemical transformations were conducted.

Diversity-driven and facile 1,3-dipolar cycloaddition to access dispirooxindole-imidazolidine scaffolds.

A diversity-driven three-component 1,3-dipolar cycloaddition of isatins, amino acids and isatin-derived ketimines was developed to facilely assemble dispirooxindole-imidazolidine skeletons bearing vicinal quaternary carbon centers. This protocol features additive-free, minimal solvent usage (0.1 mL DMSO/0.2 mmol scale), wide substrate scope (34 examples), mild reaction conditions (room temperature) and high chemical yield (up to 99%).

ChemInform Abstract: Green Synthesis of Spirooxindole‐Pyrrolidine/Piperidine Fused Nitrochromane: One Pot Three Component Stereo and Regioselective Cycloaddition.

AbstractThe title compounds are stereo‐ and regioselectively prepared in nontoxic solvent by 1,3‐dipolar cycloaddition of isatin, prolin/pipecolic acid, and nitrochromenes.

Highly diastereoselective synthesis of imidazolidine-dispirooxindoles via three-component [3 + 2] cycloadditions of isatins, 2-(aminomethyl)pyridine and isatin-based imines

In the presence of Et3N, the [3 + 2] cycloaddition of isatins, 2-(aminomethyl)pyridine and isatin-based imines proceeded readily, and furnished novel imidazolidine-dispirooxindoles in up to 84% yield with up to >99 : 1 diastereoselectivity.

ChemInform Abstract: Phosphine‐Catalyzed Domino Reaction: An Efficient Method for the Synthesis of Highly Functionalized Spirooxazolines.

AbstractA new class of spirocyclic oxindole derivatives is obtained in good to high yields and stereoselectivity by a novel phosphine‐catalyzed intermolecular [3 + 2]cycloaddition of isatins and ynones.

A facile synthetic approach to novel spiro-oxindoles/acenaphthylen-1-ones containing benzo[1,4]thiazin-3-one ring via 1,3-dipolar cycloaddition

A series of spiro-oxindole derivatives containing spirobenzo[1,4]thiazin-3-one ring were synthesized regioselectively via a multicomponent 1,3-dipolar cycloaddition of isatin, 2-(4-methyl-benzylidene)-4H-benzo[1,4]thiazin-3-one and sarcosine or l-proline in toluene under reflux condition. Also spiro-acenaphthylen-1-ones containing spirobenzo[1,4]thiazin-3-one ring have been synthesized using 2-(4-methyl-benzylidene)-4H-benzo[1,4]thiazin-3-one as dipolarophile. The methodology affords high yields of products in short reaction time.

An Easy Access to Novel Spiro-Fused Pyrrolo Benzo[b]thiophene 1,1-Dioxide Derivatives via 1,3-Dipolar Cycloaddition Using Benzo[b]thiophene 1,1-Dioxide

A series of spirooxindoles containing tri- and tetracyclic fused pyrrolo benzo[b]thiophene 1,1-dioxide derivatives was synthesized regioselectively via a multicomponent 1,3-dipolar cycloaddition of isatin, benzo[b]thiophene 1,1-dioxide and sarcosine or L-proline in methanol under reflux condition. Also a series of spiro frameworks having tri- and tetracyclic fused pyrrolo benzo[b]thiophene 1,1-dioxide derivatives was synthesized from ninhydrin, 11H-indeno[1,2-b]quinoxalin-11-one and acenaphthene-quinone using benzo[b]thiophene 1,1-dioxide as a dipolarophile. The methodology affords high yields of products in short reaction time.