Design and synthesis of [1,2,4]-triazolo isoquinoline derivatives via 1, 3-dipolar [3 + 2] cycloaddition: Reaction of azomethine imine with ethyl cyanoformate as unknown protocol

A series of novel 1, 2, 4-triazolo isoquinoline derivatives (8a-8p) were synthesized starting from 2-phenylethan-1-ol derivative (1) in a 7 step synthetic sequence. The key step in the scheme involves 1, 3-dipolar [3?+?2] cycloaddition of azomethine imine and ethyl cyanoformate as unknown reaction protocol. We have demonstrated the hydrolysis of both ester and benzoyl group in a single step and the corresponding carboxylic acid derivatives were coupled with various amines to generate unknown 1, 2, 4-triazolo isoquinoline derivatives The structures of the compounds (8a-8p) were characterized by ¹H NMR, ¹³C NMR and HRMS analysis.     

Nickel-catalyzed [2 + 2] cycloaddition reaction using bisallenes

A nickel-catalyzed [2 + 2] cycloaddition of bisallenes has been described. Simple bisallenes are employed for the formation of “head to head” cycloadducts in the presence of Ni(0) with xantphos. The dienyl moiety in a product were applicable for various [4 + 2] cycloaddition reactions. Allene-allenamides under Ni-xantphos system gave the tricyclic compounds through sequential [2 + 2]–[4 + 2] cycloaddition reaction in highly stereoselective manner.     

Diversity-oriented one-pot multicomponent synthesis of chromanone-based 3,3′-pyrrolidinyl-spirooxindoles via a 1,3-dipolar cycloaddition reaction

A new methodology was developed for the highly efficient one-pot multicomponent synthesis of chromanone-based 3,3′-pyrrolidinyl-spirooxindoles via a 1,3-dipolar cycloaddition reaction of chromones 1 with azomethine ylides (thermally generated in situ from isatins and proline or thioproline). Another valuable application of this method was for the less reactive chromone through a carboxylic acid-activation and then decarboxylation strategy, which enabled diversity-oriented synthesis of complex pirooxindoles bearing four contiguous stereocenters (one of which is a spiro quaternary stereocenter) with high efficiency and stereoselectivity (up to 90% yield and 20:1 d.r.). This protocol could provide libraries of stereochemically rich and multiple pharmecore collections, that will help in search for new drug-like molecules.     

One-pot multicomponent construction of chromanone-fused pyrrolidinyl spirooxindole collections through a decarboxylative 1,3-dipolar [3 + 2] cycloaddition reaction

Abstract

A new method was developed for the facile one-pot multicomponent construction of heterocycle-fused spiro compounds containing chromanone and pyrrolidinyl spirooxindoles, two potential pharmacophores, in one molecule through a decarboxylative 1,3-dipolar [3?+?2] cycloaddition reaction of carboxylic acid group-activated chromones 1 with isatin-derivated azomethine ylides based on molecular hybridization strategy. A wide variety of products with three contiguous stereocenters including a spiro quaternary stereocenter were smoothly prepared with high efficiency (up to 87% yield and 20:1?diastereomeric ratio). This method could offer libraries of architecturally diverse and multiple pharmacore collections, potentially useful in medicinal chemistry.     

Urea mediated 5-substituted-1H-tetrazole via [3 + 2] cycloaddition of nitriles and sodium azide

A simple, new and convenient metal free procedure for the synthesis of 5-substituted 1H-tetrazoles using various nitriles and sodium azide in the presence of urea and acetic acid with good to high yields is developed. The reaction plausibly proceeds through in situ formation of urea azide active complex without toxic and/or expensive metal catalysts.     

A practical synthesis of functionalized isoindolinones via [3 + 3] benzannulation of 1,3-bissulfonylpropenes and 4-arylmethylene-2,3-dioxopyrrolidines

A straightforward synthesis of isoindolinones has been developed via a [3?+?3] benzannulation of 4-arylmethylene-2,3-dioxopyrrolidines and 1,3-bissulfonylpropenes (or 4-sulfonylcrotonates). A series of functionalized isoindolinones were obtained in excellent yields. The reaction could be carried out under mild conditions without transition metal catalyst. The finding provides a practical approach for the preparation of isoindolinone derivatives with potential biological activities.     

Convenient synthesis of ferrocenyl β-C-glycosydic spiropyrrolidines and pyrrolizidines through 1,3-dipolar cycloaddition reaction

An expedient method for the synthesis of ferrocene grafted β-C-glycosydic spiroheterocycles is reported through 1,3-dipolar cycloaddition reaction (1,3-DC reaction). The novel C-glycosyl dipolarophiles derived from d-glucose, d-mannose, and d-ribose underwent neat [3+2] cycloaddition reaction with the azomethine ylides generated from 1,2-diketones and secondary amino acids to give the corresponding β-C-glycosidic heterocycles in good yields. The electrochemical behavior of the cycloadducts is also described.     

Synthesis of bicyclo[3.1.0]hexanones via 1,3-dipolar cycloaddition of diazoalkanes to homochiral α-sulfinyl-2-cyclopentenones

The reactions of diazomethane, diazoethane, and (trimethylsilyl)diazomethane with (S)-2-p-tolylsulfinylcyclopent-2-en-1-one have been studied. The sulfinyl group increases the reactivity and controls the π-facial and endo/exo selectivities. The π-facial selectivity can be inverted in the presence of Yb(OTf)₃, which makes possible the stereodivergent synthesis of both diastereoisomeric pyrazolines. Completely stereoselective denitrogenation of optically pure pyrazolines into cyclopropanes was achieved under substoichiometric Yb(OTf)₃ catalysis.     

A facile regio- and stereoselective synthesis of novel dispirooxindolyl-[acridine-2′,3-pyrrolidine/thiapyrrolizidine]-1′-ones via 1,3-dipolar cycloaddition of azomethine ylides

A facile regio- and stereoselective synthesis of novel dispirooxindolyl-[acridine-2′,3-pyrrolidine]-1′-ones and dispirooxindolyl-[acridine-2′,3-thiapyrrolizidine]-1′-ones have been accomplished via 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from the reaction of sarcosine/1,3-thiazolane-4-carboxylic acid and substituted isatins, to a series of (E)-2-[arylmethylidene]-3,4-dihydro-1(2H)-acridinones in good yields.     

Synthesis of novel dispiro[indoline-3,2'-pyrrolidine-3',10”-thiazolo[3',2':1,2]pyrimido[5,4-g]indolizine] derivatives by 1,3-dipolar cycloaddition reaction

Chemistry of Heterocyclic Compounds - A number of 7-aryl-5,6-dihydro-7H-thiazolo[3',2':1,2]pyrimido[5,4-g]indolizines were synthesized by the reaction of...     

A facile regio- and stereoselective synthesis of novel spiro[indolin-3,2′-pyrrolidin]-2-one’s via 1,3-dipolar cycloaddition of azomethine ylides

A facile regio and stereoselective synthesis of novel spiro[indolin-3,2′-pyrrolidin]-2-one’s have been accomplished through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of isatin and benzyl amine with quinoline bearing dipolarophiles in good yields. The synthesized compounds were well characterized through different spectroscopic techniques, such as single crystal XRD, FTIR, NMR, and mass spectral analysis.     

A tactical approach for the synthesis of novel β-lactam-substituted,polycyclic-fused isoxazolidine derivatives via an intramolecular [3+2] cycloaddition reaction

The synthesis of functionalized β-lactam-substituted, tricyclic chromenoisoxazolidine and tetracyclic naphthopyranoisoxazolidine derivatives by intramolecular nitrone cycloaddition reaction is described. The O-allyl hydroxyaldehyde derivatives, obtained from Baylis–Hillman adducts (BHA) derived from β-lactam aldehyde underwent intramolecular cycloaddition reaction to give β-lactam-substituted, polycyclic isoxazolidine derivatives in good yield. All the products were confirmed by spectral analysis. The products with a β-lactam substituent may find good applications in biological chemistry.     

Multisubstituted pyrazole synthesis via[3+2]cycloaddition/rearrangement/N-H insertion cascade reaction of α-diazoesters and ynones

The cascade reactions of alkyl α-diazoesters and ynones using Al(OTf)₃ as the catalyst are described.A series of 4-substituted pyrazoles were obtained via [3+2] cycloaddition,1,5-ester shift,1,3-H shift,and N-H insertion process.Deuterium labelling experiments,kinetic studies and control experiments were carried out for the rationalization of the mechanism.     

Catalyst-free synthesis of 3-hydroxyimidazo[1,2-a]pyridine zwitterion derivatives via the three-component reaction of ethyl glyoxalate, 2‑aminopyridines and cyclic 1,3-dicarbonyls

The three-component reaction of ethyl glyoxalate, 2-aminopyridines, and cyclic 1,3-dicarbonyl compounds such as 4-hydroxycoumarin, N,N-dimethylbarbituric acid and 4-hydroxy-6-methyl-2H-pyran-2-one is described for the synthesis of 3-hydroxyimidazo[1,2-a]pyridine zwitterion derivatives.     

Catalytic diastereoselective construction of multiple contiguous quaternary carbon stereocenters via [2 + 2] cycloaddition and mechanistic insight

Multiple contiguous quaternary carbon stereocenters (CQS) are highly challenging, yet important structural motifs in organic synthesis. Here, we describe a visible light induced catalytic [2 + 2] cycloaddition approach that constructed up to four CQS in a pentacyclic fused ring system diastereoselectively, from the readily accessible dienamides with pendent heteroaryls. Variously substituted dienamides have been cyclized with heteroaryls to provide a range of novel CQS-containing scaffolds (26 examples, up to 96% yield and >20:1 dr ratio). Mechanistic studies revealed that it may proceed through an uncommon β-C radical initiated 7-endo cyclization from the biradical intermediate.     

Direct construction of novel exo′-selective spiropyrrolidine bisoxindoles via a three-component 1,3-dipolar cycloaddition reaction

An efficient synthesis of novel exo′-selective spiropyrrolidine bisoxindoles has been achieved via a three-component 1,3-dipolar cycloaddition reaction. The azomethine ylides generated in situ from substituted isatin and primary α-amino acid methyl ester (or primary α-amino acids) reacted with the Knoevenagel adducts of substituted isatin to furnish novel spiropyrrolidine bisoxindoles in high yields (up to 99%). The structure and relative stereochemistry of cycloadducts were confirmed by single crystal X-ray diffraction. The possible mechanism was proposed and the cycloaddition proceeded via exo′-transition state.     

Molecular hybridization-guided one-pot multicomponent synthesis of chromanone-fused 3,3′-pyrrolidinyl-dispirooxindoles through a 1,3-dipolar cycloaddition reaction

A new methodology was developed for the synthesis of 3,3′-pyrrolidinyl-dispirooxindoles 3 through a 1,3-dipolar cycloaddition event of isatylidenyl-chromanones 2 with azomethine ylides (thermally generated in situ from isatins and sarcosine). The method gives an easy access to a series of highly functionalized products containing three consecutive stereocenters and vicinal spiroquaternary stereocenters fused in one ring structure with 15 examples in high yields (up to 82% yield) and good diastereoselectivity (up to >20:1), which makes possible the synthesis of libraries under similar circumstances. Moreover, the current method provides a convenient approach for the efficient incorporation of two biologically important scaffolds (chromanone and 3,3′-pyrrolidinyl-dispirooxindoles). X-ray diffraction studies of one of the cycloadducts proved the structure and regiochemistry of the cycloaddition. In particular, their biological activity against human leukemia cells K562 and normal L929 cells has been evaluated. These results suggested that 3,3′-pyrrolidinyl-dispirooxindoles 3 may be potential leads for further biological screenings.     

Synthesis of new β- and γ-aminopyrrolidinephosphonates via 1,3-dipolar cycloaddition of substituted vinylphosphonates

Synthesis of α- and β-(aminomethyl)vinylphosphonates was achieved from vinyl bromide via a cross-coupling reaction with triethyl phosphite and by cross-metathesis of allyl bromide and vinylphosphonate, respectively. The 1,3-dipolar cycloaddition of these vinylphosphonates with a dipole in the presence of trifluoroacetic acid afforded selectively the β-aminopyrrolidinephosphonates. Syntheses of cis- and trans-γ-aminopyrrolidinephosphonates are also described.     

Facile synthesis and functionalization of fluoranthenes via intramolecular [4 + 2] annulations between thiophenes and alkynes

Fluoranthenes have attracted tremendous attention due to their unique optoelectronic properties and extensive applications. Although several synthetic methodologies have been developed for the preparation of fluoranthene derivatives, it is still unfavorable to functionalize the fluoranthene framework at different positions due to the relatively low selectivity and reactivity. Herein, a catalyst-free intramolecular [4 + 2] annulation between thiophenes and alkynes is developed towards the synthesis of fluoranthenes. Altogether 20 examples have been demonstrated using this method. Various functional groups can be precisely introduced into the fluoranthene skeleton at different positions by simply tuning the substituents on the thiophenes and alkynes. The conjugation of the fluoranthene can be facilely extended through different directions. Furthermore, the feasibility of this [4 + 2] annulation reaction is also investigated by density functional theory calculations. Therefore, this protocol provides not only a synthetic methodology towards fluoranthenes with substituents functionalized at different positions, but also an effective pathway to construct large polycyclic aromatic hydrocarbons containing fluoranthene moieties.