Cyclic Dipolarophiles Research Articles

Convenient generation of 1,3-dipolar nitrilimines and [3 + 2] cycloaddition for the synthesis of spiro compounds

In the presence of 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as an oxidizer, the domino [3 + 2] cycloaddition reaction of aldohydrazones with 2-arylidene-1,3-indnaediones or 5-arylidene-1,3-dimethylbarbituric acids in acetonitrile at 80 °C afforded functionalized spiro[indene-2,4′-pyrazoles]-1,3-diones or 2,3,7,9-tetraazaspiro[4.5]dec-1-ene-6,8,10-triones in satisfactory yields. This reaction was believed to proceed with in situ generation of reactive 1,3-dipolar nitrilimine and its sequential 1,3-dipolar cycloaddition reaction with cyclic dipolarophiles. Thus, a new convenient synthetic method for the active dipolar nitrilimine was successfully developed.

Diastereoselective synthesis of benzo[d]chromeno[3′,4′:3,4]pyrrolo[2,1-b]thiazoles via cycloaddition reaction of benzothiazolium salts with 3-nitrochromenes

Diastereospecific synthesis of benzo[d]chromeno[3′,4′:3,4]pyrrolo[2,1-b]thiazoles via cycloaddition reaction of benzothiazolium salts with 3-nitrochromenes.

Chromanyl–isoxazolidines as Antibacterial agents: Synthesis, Biological Evaluation, Quantitative Structure Activity Relationship, and Molecular Docking Studies

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(chrom-4-one-3-yl)-N-phenylnitrones (N) with different mono-substituted, disubstituted, and cyclic dipolarophiles were carried out to obtain substituted N-phenyl-3'-(chrom-4-one-3-yl)-isoxazolidines (1-40). All the synthesized compounds were assayed for their in vitro antibacterial activity and display significant inhibitory potential; in particular, compound 32 exhibited good inhibitory activity against Salmonella typhymurium-1 & Salmonella typhymurium-2 with minimum inhibitory concentration value of 1.56 μg/mL and also showed good potential against methicillin-resistant Staphylococcus aureus with minimum inhibitory concentration 3.12 μg/mL. Quantitative structure activity relationship investigations with stepwise multiple linear regression analysis and docking simulation studies have been performed for validation of the observed antibacterial potential of the investigated compounds for determination of the most important parameters regulating antibacterial activities.

Polycyclic aromatic azomethine ylides: a unique entry to extended polycyclic heteroaromatics.

Based on polycyclic aromatic azomethine ylides (PAMYs), a metal-free "cycloaddition-planarization-sequence" is proposed, providing a unique entry to extended nitrogen-containing polycyclic aromatic hydrocarbons (N-PAHs). This method is highly versatile, as the structure of unprecedented N-PAHs can be tailored by the dipolarophile in the crucial 1,3-cycloaddition-reaction. Linear, as well as five- and six-membered cyclic dipolarophiles are successfully used. The geometric and optoelectronic nature of N-PAHs are investigated by UV-vis absorption and single crystal structure analysis. Remarkably, the newly synthesized N-PAHs demonstrate varying absorption profiles, covering the whole visible light range with rich photophysical properties, for example, fluorescent quantum yields up to 54%.

ChemInform Abstract: Catalytic Enantioselective 1,3‐Dipolar Cycloadditions of Azomethine Ylides for Biology‐Oriented Synthesis

AbstractReview: 37 refs.

Catalytic enantioselective 1,3-dipolar cycloadditions of azomethine ylides for biology-oriented synthesis.

ConspectusCycloaddition reactions are among the most powerful methods for the synthesis of complex compounds. In particular, the development and application of the 1,3-dipolar cycloaddition, an important member of this reaction class, has grown immensely due to its powerful ability to efficiently build various five-membered heterocycles. Azomethine ylides are commonly used as dipoles for the synthesis of the pyrrolidine scaffold, which is an important motif in natural products, pharmaceuticals, and biological probes. The reaction between azomethine ylides and cyclic dipolarophiles allows access to polycyclic products with considerable complexity. The extensive application of the 1,3-dipolar cycloaddition is based on the fact that the desired products can be obtained with high yield in a regio- and stereocontrolled manner. The most attractive feature of the 1,3-dipolar cycloaddition of azomethine ylides is the possibility to generate pyrrolidines with multiple stereocenters in a single step. The development of enantioselective cycloadditions became a subject of intensive and impressive studies in recent years. Among many modes of stereoinduction, the application of chiral metal–ligand complexes has emerged as the most viable option for control of enantioselectivity.In chemical biology research based on the principle of biology-oriented synthesis (BIOS), compound collections are prepared inspired by natural product scaffolds. In BIOS, biological relevance is employed as the key criterion to generate hypotheses for the design and synthesis of focused compound libraries. In particular, the underlying scaffolds of natural product classes provide inspiration for BIOS because they define the areas of chemical space explored by nature, and therefore, they can be regarded as “privileged”. The scaffolds of natural products are frequently complex and rich in stereocenters, which necessitates the development of efficient enantioselective methodologies.This Account highlights examples, mostly from our work, of the application of 1,3-dipolar cycloaddition reactions of azomethine ylides for the catalytic enantioselective synthesis of complex products. We successfully applied the 1,3-dipolar cycloaddition in the synthesis of spiro-compounds such as spirooxindoles, for kinetic resolution of racemic compounds in the synthesis of an iridoid inspired compound collection and in the synthesis of a nitrogen-bridged bicyclic tropane scaffold by application of 1,3-fused azomethine ylides. Furthermore, we performed the synthesis of complex molecules with eight stereocenters using tandem cycloadditions. In a programmable sequential double cycloaddition, we demonstrated the synthesis of both enantiomers of complex products by simple changes in the order of addition of chemicals. Complex products were obtained using enantioselective higher order [6 + 3] cycloaddition of azomethine ylides with fulvenes followed by Diels–Alder reaction. The bioactivity of these compound collections is also discussed.

Microwave-Assisted Synthesis of Spiro-Isoxazolidines

Solvent-free synthesis of spiro-isoxazolidines (exclusively endo-diastereoisomers) through [3 + 2] cycloaddition of N-cyclohexylidene N-phenyl nitrones with cyclic dipolarophiles under microwave irradiation is described.

Diastereoselective Synthesis of Novel Spiro-Isoxazolidines via [3 + 2] Cycloaddition

In this protocol, synthesis of novel 2,5-diphenyl-3,3-spiropentamethylene-5H-2,3,3a,6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones through [3 + 2] cycloaddition of N-cyclohexylidene N-phenyl nitrones with cyclic dipolarophiles is described. 1,3-Dipolar cycloaddition of nitrones with substituted N-arylmaleimides gives exclusively endo-diastereoisomers of spiro-isoxazolidines and their stereochemistry was assigned using 1H NMR and 1H-1H correlation spectroscopic studies.

Synthesis and cytotoxicity evaluation of regioisomeric substituted N-phenyl-3′-(chrom-4-one-3-yl)-isoxazolidines: induction of apoptosis through a mitochondrial-dependent pathway

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(chrom-4-one-3-yl)-N-phenylnitrones (5) with different mono-substituted, disubstituted and cyclic dipolarophiles were carried out to obtain substituted N-phenyl-3′-(chrom-4-one-3-yl)-isoxazolidines (7a–p, 10a–c and 12a–c). Some of the obtained isoxazolidines display significant cytotoxicity against several human cancer cell lines. The preliminary bioassay results revealed that compound 10c showed higher cytotoxicity than paclitaxel against the A549 cell line with an IC50 value of 0.7 μM. Compound 10c induces apoptosis through a mitochondrial-dependent pathway in human promyelocytic leukemia (HL-60) cells as revealed by induced apoptotic bodies' formation, DNA ladder, increased Sub-G0 DNA fraction and loss of mitochondrial membrane potential (ΔΨm) in HL-60 cells.

Synthesis and cytotoxic evaluation of substituted 3-(3′-indolyl-/3′-pyridyl)-isoxazolidines and bis-indoles

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(3-indolyl)-N-phenylnitrone (10) were carried out with different mono-substituted, disubstituted and cyclic dipolarophiles under mono-mode microwave irradiation to obtain substituted 3-(indol-3′-yl)-N-phenyl-isoxazolidines (16–22). Reactions of nitrone (10) with allenic esters under similar conditions afforded, via a domino process, bis-indole derivatives (23a–c) along with compounds 24 and 25. Similarly, reactions of C-(3-pyridyl)-N-phenylnitrone (26) with mono-substituted, disubstituted and cyclic dipolarophiles were carried out in refluxing dry toluene to obtain substituted 3-(3′-pyridyl)-N-phenylisoxazolidines (27–34). Some of the compounds (16f, 18b, 23a, 23c, 27c and 29f) display significant cytotoxicity against a number of human cancer cell lines.

Asymmetric Synthesis of Pyrrolo[2,1-a]isoquinoline Derivatives by 1,3-Dipolar Cycloadditions of Stabilized Isoquinolinium N-Ylides with Sulfinyl Dipolarophiles

Enantiomerically pure pyrrolo[2,1-a]isoquinoline derivatives are obtained by 1,3-dipolar reactions of isoquinolinium azomethine ylides with enantiopure 3-p-tolylsulfinylacrylonitriles, tert-butyl (2E)-4,4-diethoxy-2-p-tolylsulfinylbut-2-enoate, and 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones. Reactions evolve through the anti conformation of the ylide with complete regioselectivity. The facial selectivity is completely controlled by the configuration of the sulfinyl sulfur for acyclic dipolarophiles, whereas it is high (dr 83/17 or 89/11) but controlled by the C-5 configuration for sulfinylfuranones. Complete endo selectivity is observed with cyclic dipolarophiles and substituted acrylonitriles, but it is low with butenoate. The sulfinyl group also exerts a positive influence on the dipolarophilic reactivity toward these ylides.

ChemInform Abstract: 1,3-Cycloaddition of Nitrile Oxides to Cyclic and Open-Chain 4-Oxo-2-sulfinylbut-2-enoic Acid Derivatives.

Abstract The reactions of tert-butyl (E)-4,4-diethoxy-2-p-tolylsulfinylbut-2-enoate with benzonitrile, acetonitrile, and bromoformonitrile oxides yield isoxazoles. However, (S5,SS)- and (R5,SS)-5-ethoxy-3-p-tolylsulfinylfuranones with benzonitrile oxide afford isoxazolines. The reactivity of the double bond as a dipolarophile is strongly increased by the sulfinyl group. This is also the case of the regioselectivity, which usually is opposite to that exhibited by dipolarophiles lacking the sulfinyl group. Electrostatic interactions seemingly explain this behaviour. The π-facial selectivity of the reactions with the cyclic dipolarophiles is dependent on steric effects, but some role seems to be exerted by electrostatic attraction.

Antibacterial Activity, Quantitative Structure–Activity Relationship and Diastereoselective Synthesis of Isoxazolidine Derivatives Via 1,3‐Dipolar Cycloaddition of d‐glucose Derived Nitrone with Olefin

The diastereoselectivity of the intermolecular 1,3-dipolar cycloaddition reaction of d-glucose-derived nitrones with both cyclic and acyclic dipolarophiles were studied. The reaction of nitrone with acyclic dipolarophiles resulted in the formation of the endo adduct exclusively whereas with cyclic dipolarophiles endo adduct was obtained as the major product. Antibacterial activity was evaluated for these eighteen isoxazolidine derivatives against Staphylococcus aureus NCIM5021, Escherichia coli NCIM 2931 and Pseudomonas aeruginosa NCIM 5029 by twofold dilution technique using resazurin as the indicator dye. Quantitative structureactivity relationships were developed with fourteen and the model was validated with four data. Electronic and spatial descriptors were the major contributors in all the three quantitative structureactivity relationship equations and the statistical parameters r(2), r(2)(adj) , F-ratio and q(2) were found to be satisfactory.

A DFT study of 1,3-dipolar cycloaddition reactions of 5-membered cyclic nitrones with α,β-unsaturated lactones and with cyclic vinyl ethers: Part 1

The 1,3-dipolar cycloaddition of cyclic nitrones with electron-poor and electron-rich cyclic dipolarophiles (α,β-unsaturated lactones and vinyl ethers) is studied. The energies of the cycloaddition reactions have been investigated through molecular orbital calculations at the B3LYP/6-31+G(d) level theory. Different reaction channels and reactants approaches, effective in regio- and stereochemical preferences are discussed. The results were compared with experimental data to find a good agreement.

1,3-cycloaddition of nitrile oxides to cyclic and open-chain 4-oxo-2-sulfinylbut-2-enoic acid derivatives

The reactions of tert-butyl ( E)-4,4-diethoxy-2- p-tolylsulfinylbut-2-enoate with benzonitrile, acetonitrile, and bromoformonitrile oxides yield isoxazoles. However, ( S 5, S S)- and ( R 5, S S)-5-ethoxy-3- p-tolylsulfinylfuranones with benzonitrile oxide afford isoxazolines. The reactivity of the double bond as a dipolarophile is strongly increased by the sulfinyl group. This is also the case of the regioselectivity, which usually is opposite to that exhibited by dipolarophiles lacking the sulfinyl group. Electrostatic interactions seemingly explain this behaviour. The π-facial selectivity of the reactions with the cyclic dipolarophiles is dependent on steric effects, but some role seems to be exerted by electrostatic attraction.

ChemInform Abstract: X=Y‐ZH Compounds as Potential 1,3‐Dipoles. Part 44. Asymmetric 1,3‐ Dipolar Cycloaddition Reactions of Imines and Chiral Cyclic Dipolarophiles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

X=y-ZH compounds as potential 1,3-dipoles. part 44. 1 asymmetric 1,3-dipolar cycloaddition reactions of imines and chiral cyclic dipolarophiles

Metallo 1,3-dipoles generated in situ from both aryl and aliphatic imines of α-amino esters by the action of silver salts and tertiary amines undergo cycloaddition at room temperature to 5R-(1′R, 2′S, 5′R-menthyloxyl)-2(5H)-furanone and to N-acetyl-5R-isopropoxy-2(5H)pyrrolone giving homochiral cycloadducts in good yield in all cases. π-Interaction between the dipolarophile carbonyl group and the aryl group in the aryl imines is not required for good induction. The stronger the base the faster the cycloaddition with 2-t-butyl-1,1,3,3tetramethylguanidine > DBU > NEt 3. X-Ray crystal structures of representative cycloadducts establish the absolute configuration of the pyrrolidine stereocentres.

ChemInform Abstract: π‐Facial Selectivity of the 1,3‐Dipolar Cycloaddition of the Parent Azomethine Ylide to Homochiral Dipolarophiles.

The 1,3-dipolar cycloaddition of the azomethine ylide (2) with homochiral cyclic dipolarophiles proceeds with high facial selectivity, whereas for homochiral acyclic dipolarophiles, the π-facial selectivity and mode of cycloaddition is dependent on the structure of the dipolarophile.

π-Facial selectivity of the 1,3-dipolar cycloaddition of the parent azomethine ylide to homochiral dipolarophiles

The 1,3-dipolar cycloaddition of the azomethine ylide (2) with homochiral cyclic dipolarophiles proceeds with high facial selectivity, whereas for homochiral acyclic dipolarophiles, the π-facial selectivity and mode of cycloaddition is dependent on the structure of the dipolarophile.

ChemInform Abstract: X=Y‐ZH Systems as Potential 1,3‐Dipoles. Part 8. Pyrrolidines and δ5‐Pyrrolines (3,7‐Diazabicyclo(3.3.0)octenes) from the Reaction of Imines of α‐Amino Acids and Their Esters with Cyclic Dipolarophiles. Mechanism of Racemization of α‐Amino Acids and Their Esters in the Presence of Aldehydes.

AbstractHeating of the imines (I) in toluene generates azomethine ylides by a prototropic shift; these undergo cycloaddition with the maleimide (IIa) or the anhydride (IIb) to give the racemic, single diastereoisomeric adducts (III).