Olefinic Dipolarophiles Research Articles

An Ultrasound-assisted Three Component Protocol for the Regio and Stereo-selective Synthesis of Some Novel Dispiroheterocycles and Their Biological Evaluation as Anti-inflammatory, Anti-obesity Agents

Background: The increasing utilization of spiro compounds in drug discovery, led us to design and synthesize regioselectively some novel dispiroheterocycles, by a standard 1,3-dipolar cycloaddition reaction between 6-hydroxyaurone and in situ generated azomethine ylides, using ultra-sonication as green energy source. These results are first of its kind in the literature reported so far for the similar conditions. After confirmation of the proposed structures spectroscopically, using 1H NMR, 13C NMR and FT-IR spectral data, all the compounds are screened for their potential biological activities. Methods: Three component protocol, that contain (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one, sarcosine and unsubstituted isatin. In which azomethine ylides react with olefinic dipolarophiles through 1,3-dipolar cycloaddition, which is highly regio- and stero-selective way in situ. Structures of the proposed products have been confirmed using 1H NMR, 13C NMR and FT-IR spectral data. Results: In order to screen the potential biological activities of the synthesized compounds, their effect was observed on trypsin, amylase and lipase activities. Differential effect has been observed. Trypsin was substantially activated whereas an inhibitory effect was observed for amylase and lipase supported by insilico studies. Conclusion: Synthesis of six novel 6-hydroxy-1'-methyl-4'-phenyl-3H-dispiro[benzofuran-2,3'- pyrrolidine-2',3''-indoline]-2'',3-dione derivatives have been made using a multicomponent greener protocol. These synthesized compounds have exhibited differential effects toward trypsin, amylase and lipase well supported by in-silico studies. Thus, the present study highlights their potential use as antiinflammatory and anti-obesity agents.

Mechanistic studies of 1,3-dipolar cycloadditions of bicyclic thioisomünchnones with alkenes. A computational rationale focused on donor-acceptor interactions.

This paper describes a mechanistic study, with the interplay of experiment and theory, on the cycloadditions of a bicyclic mesoionic 1,3-dipole versus a series of representative symmetrical (1-phenyl-1H-pyrrole-2,5-dione and dimethyl maleate) and asymmetrical [(E)-(2-nitrovinyl)benzene, acrylonitrile, and but-3-en-2-one] olefinic dipolarophiles. These results allow a comparative analysis with monocyclic dipoles and open further avenues to structurally diversified heteroatom-rich rings. The unichiral version of the bicyclic dipole leads to adducts containing up to five chiral centers, whose formation proceeds with high levels of facial stereoinduction in reactions involving bulky dipolarophiles. The second and largest part of this study provides a theoretical interrogation on the pericyclic mechanism with DFT-methods [M06-2X/6-311++G(d,p)]. In order to get further mechanistic insights, we have also explored charge transfers between reaction partners using NBO analysis, which satisfactorily justifies the stereochemical outcome.

Synthesis of 3D-Rich Heterocycles: Hexahydropyrazolo[1,5-a]pyridin-2(1H)-ones and Octahydro-2H-2a,2a1-diazacyclopenta[cd]inden-2-ones

Two cyclic azomethine imines, 7-methyl- and 7-phenyl-2-oxo-Δ7-hexahydropyrazolo[1,5-a]pyridin-8-ium-1-ide, were prepared in seven steps from the respective commercially available δ-keto acids. The addition of Grignard reagents followed by N-alkylation at position 1 afforded the 1,7,7-trisubstituted hexahydropyrazolo[1,5-a]pyridin-2(1H)-ones, whereas 1,3-dipolar cycloadditions of these dipoles to typical acetylenic and olefinic dipolarophiles gave 4a-substituted 2a,2a1-diazacyclopenta[cd]indene derivatives as the first representatives of a novel heterocyclic system. Regio- and stereoselectivity as well as the mechanism of these [3 + 2]-cycloadditions were evaluated using computational and experimental methods. The data obtained were in agreement with the polar concerted cycloaddition mechanism via the energetically favorable syn/endo-transition states.

ChemInform Abstract: Synthesis of Spiropyrrolidines via Five‐Component 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Olefinic Dipolarophiles Generated in situ Simultaneously.

AbstractThe introduced method allows 1,3‐dipole azomethine ylides and olefinic dipolarophiles to be simultaneously generated in situ, which makes this novel annulation strategy both practical and attractive with the advantages of direct use of commercially available and inexpensive reagents, simple experimental and work‐up procedures, and mild reaction conditions.

A green, multicomponent, regio- and stereo-selective 1,3-dipolar cycloaddition of azides and azomethine ylides generated in situ with bifunctional dipolarophiles using PEG-400

A series of novel dispiropyrrolidine-linked 1,2,3-triazole derivatives have been prepared by one-pot, four-component protocol that employed 5-arylidene-3-(prop-2-ynyl)thiazolidine-2,4-dione, isatin, sarcosine and substituted azides using Cu(I) generated in situ as catalyst in PEG-400 as a highly efficient and green media. This is the first report of a four-component reaction involving a classical Huisgen reaction, in which the two dipolar moieties (substituted azides and in situ generated azomethine ylides) react with acetylenic and olefinic dipolarophiles, respectively. The 1,3-dipolar cycloaddition proceeds in a highly regio- and stereo-selective manner. This methodology can be an ideal tool for the preparation of biologically important five-membered heterocyclic compounds in one pot.

ChemInform Abstract: Expeditious Construction of Spiro‐Pyrrolidines by an Autocatalytic One‐Pot, Five‐Component, 1,3‐Dipolar Cycloaddition of in situ Generated Azomethine Ylides and Olefinic Dipolarophiles.

AbstractThe title compounds are prepared by a solvothermal synthesis in a highly regio‐ and stereoselective manner involving a classical Huisgen reaction in which the azomethine ylide and olefinic dipolarophiles are simultaneously generated in situ without the need to isolate the intermediates.

Expeditious Construction of Spiro‐Pyrrolidines by an Autocatalytic One‐Pot, Five‐Component, 1,3‐Dipolar Cycloaddition of in situ Generated Azomethine Ylides and Olefinic Dipolarophiles

AbstractTwo series of previously unknown spiro‐pyrrolidine derivatives were prepared by a five‐component reaction that employed ninhydrin, 1,2‐phenylenediamine, sarcosine, aldehydes, and malononitrile or cyanoacetic ester in a solvothermal synthesis. This is the first report of an autocatalytic five‐component reaction involving a classical Huisgen reaction, in which the dipole – an azomethine ylide – and the dipolarophile were simultaneously generated in situ. The 1,3‐dipolar cycloaddition reaction was found to proceed in a highly regio‐ and diastereoselective manner. The methodology for the preparation of the spiro‐pyrrolidines could be an ideal tool for green chemistry and the synthesis of alkaloids.

A selective synthesis of enamines versus aziridines

Abstract The reaction of 10‐azidoacetyl‐10H‐phenothiazine with olefinic dipolarophiles depends on the reaction temperature. In refluxing toluene, a mixture of enamine and aziridine is formed in 3:1 ratio. The reaction mechanism appears to involve a Michael‐type addition of the nucleophilic N1 azide atom to the olefinic double bond. In chloroform, a cycloaddition reaction takes place with the formation of a 4,5‐dihydro‐1,2,3‐triazole. The heating of dihydrotriazoles in toluene is accompanied by nitrogen elimination leading to a mixture of enamine and aziridine in 1:3 ratio. J. Heterocyclic Chem., 2011.

ChemInform Abstract: Generation of Nitrile Oxides from Oxime Derivatives by the Oxidation with Ammonium Hexanitratocerate(IV).

Aromatic and aliphatic nitrile oxides are generated by the oxidation of α-hydroxyimino carboxylic acid with ammonium hexanitratocerate(IV). They react with olefinic and acetylenic dipolarophiles to give the corresponding cycloaddition products in good yield. The oxidation of α-oxo aldoximes also affords α-oxo carbonitrile oxides.

ChemInform Abstract: Novel Generation and Cycloaddition of N-Silylated Azomethine Ylides from α-Silylimidates and Trifluorosilane.

Abstract The Generation of N-silylated azomethine ylides was achieved by the reaction of α-silylimidates and trifluorophenylsilane. The generated azomethine ylides can be regarded as synthetic equivalents of nitrile ylides since they have an alkoxy group which may serve as a leaving group. Cycloaddition with acetylenic or olefinic dipolarophiles proceeded smoothly to give pyrrole or pyrroline derivatives in good to excellent yields. For example, α-silylimidate 1 was treated with 1.2 equiv of trifluorophenylsilane in the presence of 1 equiv of dimethyl acetylenedicarboxylate to give pyrrole 2 in 97% yield. Furthermore, when starting with a secondary α-silylamide, the one-pot synthesis of N-unsubstituted azomethine ylides could be achieved by the successive treatment with alkylation and desilylation agents.

Investigations on synthesis of indole based constrained mimetic scaffolds through 1,3-dipolar cycloadditions of the C-(3-indolyl)- N-phenylnitrone with a variety of olefinic and allenic dipolarophiles under microwave irradiation

Monomode microwave assisted regio- and stereo-selective 1,3-dipolar cycloadditions of C-(3-indolyl)- N-phenylnitrone ( 19) with a number of olefinic dipolarophiles ( 20a– f) afford isoxazolidines ( 21– 26) in high yields, which are conformationally constrained mimetics of indole-3-propionic acid of biological significance. Similar cycloadducts derived from addition of nitrone ( 19) to allenic esters ( 27a– c) undergo domino reorganization to afford potentially biologically active bis-indole derivatives ( 28, 29). The observed regio- and stereo-selectivities are analysed, inter alia, in terms of HOMO-dipole–LUMO-dipolarophile and involved secondary orbital/steric interactions in the transition states intervening these cycloadditions.

1,3-Dipolar cycloadditions of 5-(4-methoxyphenyl)- and 5-(1H-indol-3-yl)-substituted (1Z,4R*,5R*)-1-(arylmethylidene)-4-benzamido-3-oxopyrazolidin-1-ium-2-ides to olefinic dipolarophiles

1,3-Dipolar cycloadditions of (1Z,4R*,5R*)-1-(arylmethylidene)-4-benzamido-5-(4-methoxyphenyl)-3-oxopyrazolidin-1-ium-2-ides 6a–6f and their 5-(1H-indol-3-yl) analogues 6g–6j to olefinic dipolarophiles 7–9 were studied. Stereochemistry was controlled by the structure of dipoles 6 and dipolarophiles 7–9. Reactions of ortho-unsubstituted dipoles 6a–6c, 6g gave the major isomers 10 and 14 with syn-oriented protons H-3 and H-5, whilst ortho-disubstituted dipoles 6d, 6e, 6j gave cycloadducts 11 and 12 with anti-oriented protons H-3 and H-5. In comparison with their 5-phenyl-substituted analogues, dipoles 6a–6e, 6g, 6j were less reactive in cycloadditions to olefinic dipolarophiles 7–9. This was reflected in longer reaction times, lower yields, and sometimes in lower selectivity as well. The relative configurations of cycloadducts were determined by NMR.

1,3‐Dipolar cycloadditions of (4R*,5R*)‐1‐alkylidene‐4‐(benzoylamino)‐5‐phenyl‐3‐pyrazolidinon‐1‐azomethine imines

Abstractmagnified image1,3‐Dipolar cycloadditions of azomethine imines 3a and 3b, available by acid‐catalyzed treatment of 3‐pyrazolidinone 1 with acetone (2a) and butyraldehyde (2b), respectively, were studied. Reactions of 3a with DMAD (4) afforded a mixture of products 9 and 10a, whilst treatment of 3b with DMAD (4) gave a mixture of compound 9 and epimeric cycloadducts 10/10′b. On the other hand, cycloadducts 13a,b‐16a,b were isolated as single diastereomers in 9–37% yields upon reactions of 3a,b with olefinic dipolarophiles 5–8. The structures of cycloadducts 9, 10a, 10/10′b, and 13a,b‐16a,b were determined by 1H nmr and NOESY spectroscopy. The structure of compound 13a was confirmed by X‐ray diffraction.

Helical chirality of pyrrolo[1,2-a][4,5]diazafluoren-5-one derivatives

The treatment of the N-phenacyl-4,5-diazafluorenium-9-one bromides 4a,b and the diesters of acetylenedicarboxylic acid with Et3N in methylene chloride at room temperature gave trans- 9,10-dihydro-pyrrolo(1,2-a)(4,5)diazafluoren-5-one derivatives 7 along with the corresponding aromatized compounds 8. The non-planarity of the diethyl (8c,e) and diisopropyl (8d,f) pyrrolodiazafluorenone esters was deduced by H-NMR spectroscopy. The 1,3-dipolar cycloaddition between diazafluorenonium N-ylides, generated from 4, and an activated olefinic dipolarophile (acrylonitrile) is reported for the first time. The optical properties of pyrrolodiazafluorenone 8 were also investigated.

Reaction of Functionalized Azomethine Ylides with Olefinic Dipolarophiles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Construction of C-nucleosides diversified by [3+2] cycloaddition from a sugar-based mesoionic ring

A mesoionic acyclic C-nucleoside (4), serves as the starting chiron to construct highly functionalized 2-aza-7-thiabicyclo[2.2.1]heptanes and heptenes by means of a [3+2] cycloaddition with acetylenic and olefinic dipolarophiles. Further elimination of either sulfur or hydrogen sulfide leads to acyclic C-nucleosides bearing a heterocyclic moiety of 2-pyridone.

Reaction of Functionalized Azomethine Ylides with Olefinic Dipolarophiles

N-Unsubstituted pyrrolidine derivatives are prepared by the cycloaddition of an N-unsubstituted azomethine ylide in the pyrido[1,2-a]pyrimidin-4(4H)-one system and olefinic dipolarophiles. The acid treatment of the cycloadducts, pyrrolidines, caused a fission reaction to give pyrroline derivatives and the parent heterocyclic system.

Intramolecular Cycloaddition of Geminal Dichloroazomethine Ylides to Multiple Carbon-Carbon Bonds

Geminal dichloroazomethine ylides generated by reaction of dichlorocarbene with Schiff bases derived from O-alkenyl- or O-alkynylsalicylaldehyde undergo intramolecular [3 + 2]-cycloaddition with participation of the olefinic or acetylenic dipolarophile to afford chromeno[4,3-b]pyrrole and chromeno[4,3-b]pyridine derivatives. The greatest yields of the intramolecular cycloaddition products were obtained from N-methyl-substituted dichloroazomethine ylides, whereas the main stabilization path of N-phenyl and N-tert-butyl derivatives was cyclization to geminal dichloroaziridines.

Stereocontrol in cycloadditions of (1 Z,4 R*,5 R*)-1-arylmethylidene-4-benzoylamino-5-phenylpyrazolidin-3-on-1-azomethine imines

Cycloadditions of (1 Z,4 R*,5 R*)-4-benzoylamino-5-phenylpyrazolidin-3-on-1-azomethine imines to olefinic dipolarophiles were studied. Stereochemistry of cycloadditions to azomethine imines 3 was found to be controlled by stereodirecting phenyl group at position 3, as well as by the ortho-substituents at the aromatic ring at position 1′. The structures of dipoles and products were confirmed by NMR and X-ray diffraction.

Intramolecular Cycloadditions of Silacarbonyl Ylides Tethered to Unactivated Dipolarophiles: A New Route to Bicyclosilaoxolanes.

Abstract The intramolecular 1,3-dipolar cycloaddition of silacarbonyl ylides derived from a silylene and unsaturated aldehydes tethered to unactivated olefinic or acetylenic dipolarophiles successfully proceeded to directly afford bicyclosilaoxolane derivatives in good yields.