Monofluoro-substituted azomethine ylides in fluorocarbene reactions with imines. Synthesis and transformations of monofluoroaziridines

N-Arylmethylene and N-benzhydrylideneamines react with fluorocarbene yielding fluoro-substituted azomethine ylides that undergo 1,3-π-cyclization into aziridines. Generation of fluoroylides in the presence of dipolarophiles (dimethyl maleate or dimethyl acetylenedicarboxylate) led to the reaction of 1,3-dipolar cycloaddition resulting in substituted 2-pyrrolines or pyrroles. 2-Fluoroaziridines, products of N-alkyl-N-benzhydrylideneamines 1,3-π-cyclization, in the presence of acid catalysts suffer isomerization into α-fluoroimines and 1,3-disubstituted indoles.     

Stereoselective synthesis of functional derivatives of 2-(2-carboxyethyl)pyrrolidine-2-carboxylic acid

Azomethine ylides generated from dimethyl 2-(arylmethylideneamino)pentanedioates by the action of AgOAc and Et₃N reacted with dipolarophiles in regio-and stereoselective fashion to form 5-aryl-2-(2-carboxyethyl)pyrrolidine-2-carboxylic acid derivatives. 1,3-Dipolar cycloaddition of divinyl sulfone to the azomethine ylide generated from the Schiff base derived from methyl (S)-2-phthalimido-4-oxobutanoate and dimethyl glutamate gave chiral simplified kaitocephalin analogs.     

Synthesis and thermal transformations of spiro-fused N-phthalimidoaziridines

Oxidation of N-aminophthalimide in the presence of 2-arylideneinden-1,3-diones with electron-withdrawing substituents gives the corresponding 3-aryl-1-phthalimidospiro[aziridine-2,2′-indene]-1′,3′-diones in good yields. Heating these aziridines with standard dipolarophiles (N-phenylmaleimide, dimethyl acetylenedicarboxylate, maleate, and fumarate) leads, in most cases, to spiro[inden-2,2′-pyrrole] derivatives as products of 1,3-dipolar cycloaddition of the intermediate azomethine ylides with up to 70–95% yields in the case of N-phenylmaleimide. As is typical for 2-acylaziridines, the competing rearrangement into 2-aryl-4H-indeno[2,1-d][1,3]oxazol-4-ones prevails for less active dipolarophiles. Increasing the electron-releasing properties of the 3-aryl ring allows the observation of the push–pull effect of electron-donating and electron-withdrawing substituents on the ease of the three-membered ring-opening.     

1,3-Dipolar cycloadditions with azomethine ylide species generated from aminocyclopropanes

Two types of bicyclic N-cyclopropyl glycine ester derivatives have been prepared and put under scrutiny as possible precursors of azomethine ylides. The results demonstrate that they can indeed participate in 1,3-dipolar cycloaddition reactions with dipolarophiles, as illustrated in the cases of phenyl vinyl sulfone, N-phenylmaleimide, diethyl fumarate and diethyl maleate. The relative configurations of the major diastereoisomers produced are consistent with the predicted generation of azomethine ylide species, reacting in concerted cycloaddition processes. This unprecedented way of generating such 1,3-dipoles provides access to functionalised pyrrolizidine and pyrrolidine derivatives, that would be difficult to make directly by more classic methods. It was also found that using phenyl vinyl sulfone or N-phenylmaleimide as the dipolarophile reactant, a domino nucleophilic conjugate addition/1,3-dipolar cycloaddition process may operate competitively.     

A novel Fe(II)/diaryl prolinol catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with alkenes

A novel Fe(II)/diaryl prolinol catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with alkenes has been developed. In the presence of FeCl₂ (10 mol %) and α,α-bis(3,5-bistrifluoromethylphenyl)prolinol L1 (10 mol %), [3+2] cycloaddition of azomethine ylides with electronic-deficient olefins underwent smoothly in CH₃CN at room temperature to generate the desired endo-adducts in moderate to good yields and enantioselectivities. This is the first example of Fe(II)/N,O-ligand (L1) catalyzed 1,3-dipolar enantioselective cycloaddition reaction of azomethine ylides.     

Thermal transformations of alk-1-enyl-N-phthalimidoaziridines

Thermolysis of alk-1-enyl-N-phthalimidoaziridines leads to products of 1,5-electrocyclization of intermediate azomethine ylides with participation of C=C bonds. If acyl or alkoxycarbonyl substituent is present in the aziridine ring, the C=O bond is also involved. Thermolysis of the title compounds in the presence of N-phenylmaleimide or dimethyl acetylenedicarboxylate under analogous conditions gives products of 1,3-dipolar cycloaddition of azomethine ylides to the double or triple bond of the dipolarophile.     

Silver acetate-catalysed asymmetric 1,3-dipolar cycloadditions of imines and chiral acrylamides

N-Metallated azomethine ylides were generated by the reaction of arylidene glycine imines with AgOAc and triethylamine. These azomethine ylides undergo cycloaddition to chiral acrylamides with excellent diastereoselectivity. The configuration of two of the cycloadducts was confirmed by X-ray crystallography.     

1,3-Dipolar Cycloaddition of Difluoro-Substituted Azomethine Ylides. Synthesis and Transformations of 2-Fluoro-4,5-dihydropyrroles

2-Fluoro-4,5-dihydropyrrole-3,4-dicarboxylic acid derivatives were obtained by reaction of difluorocarbene with N-substituted ketone imines in the presence of fumaronitrile, maleonitrile, or dimethyl maleate. The reaction involves intermediate formation of azomethine ylides and their subsequent cycloaddition at the double bond. 11H-Dibenz[b,e]azepine and 3,4-dihydroisoquinolines react with difluorocarbene in the presence of fumaronitrile to give fluoro-substituted dibenzo[c,f]pyrrolo[1,2-a]azepine and pyrrolo[2,1-a]-isoquinoline derivatives. Treatment of 2-fluoro-4,5-dihydropyrrole-3,4-dicarbonitrile with amines and alkoxides affords the corresponding 2-amino- and 2-alkoxy derivatives, while its reactions with hydrazine hydrate and benzimidamide lead to formation of substituted pyrrolo[2,3-c]pyrazole and pyrrolo[2,3-d]-pyrimidine derivatives.     

Thermolysis of dimethyl <Emphasis Type="Italic">cis</Emphasis>- and <Emphasis Type="Italic">trans</Emphasis>-1 pthalimidoaziridine-2,3-dicarboxylates in the presence of dipolarophiles

Thermolysis of dimethyl esters of stereoisomeric phthalimidoaziridine-2,3-dicarboxylic acids in the presence of dimethyl fumarate, dimethyl maleate, and N-phenylmaleimide occurred stereo-specifically and stereoselectively led to the formation of derivatives of 1-phthalimidopyrrolidine, products of 1,3-dipolar additrion of intermediately arising azomethine ylides. In keeping with the rules of the conservation of orbital symmetry the thermal opening of the 2,3-disubstituted 1-phthalimidoaziridines into azomethine ylides occurred conrotatory. The relative positions of the substituents in the dipolarophiles is retained in the reaction products indicating the concerted addition mechanism.     

Reactivity of allenoates towards aziridines: synthesis of functionalized methylenepyrrolidines and pyrroles

The reactivity of buta-2,3-dienoates towards aziridines is reported. Typically, allenoates react as the 2π-component in the [3+2] cycloaddition with azomethine ylides generated from aziridines, affording 4-methylenepyrrolidines in a site-, regio- and stereoselective fashion. However, N-cyclohexyl- or N-tert-butyl-2-benzoyl-3-phenylaziridines showed a different reactivity in the reaction with buta-2,3-dienoates. Pyrrole derivatives were obtained as single or major products resulting from a formal [3+2] cycloaddition via C-N bond cleavage of the three-membered ring heterocycle leading to functionalized pyrroles. From the reaction with allenoates bearing bulkier C-4 substituents 4-methylenepyrrolidines were also formed as minor products.     

Multicomponent domino protocol for the stereoselective synthesis of novel pyrrolo[3,2-c]quinolinone hybrid heterocycles

A series of structurally intriguing novel pyrrolo[3,2-c]quinolinone heterocyclic hybrids have been synthesized for the first time via a one-pot multicomponent domino reaction sequence that involves a 1,3-dipolar cycloaddition and two subsequent annulation steps. Baylis-Hillman adducts derived from various substituted benzaldehyde and methyl acrylate in presence of DABCO were used as a dipolarophiles, while the 1,3-dipole components were azomethine ylides, formed in situ from isatin derivatives and l-phenylalanine. The reaction generated five new bonds, three new rings and four contiguous stereocenters, which were created with full diastereomeric control.     

Proline-mediated dimerization of cinnamaldehydes via 1,3-dipolar cycloaddition reaction with azomethine ylides. A rapid access to highly functionalized hexahydro-1H-pyrrolizine

1,3-Dipolar cycloaddition reaction of cinnamaldehyde with azomethine ylides generated through decarboxylation of iminium or oxazolidinone intermediate formed by the reaction of l-proline with cinnamaldehydes is reported. The stereoselective reaction provides an efficient access to the highly functionalized hexahydro-1H-pyrrolizine.     

Stereoselective synthesis of cis- and trans-2′,5′-disubstituted N-arylpyrrolo[3′,4′:1,9](C60-I h )[5,6]fullerenes by the 1,3-dipolar cycloaddition of azomethine ylides from dialkyl aziridinedicarboxylates to fullerene C60

A stereoselective method for the synthesis of 2′,5′-disubstituted N-arylpyrrolofullerenes from anilines, alkyl glyoxylates, alkyl diazoacetates, and fullerene C₆₀ was proposed. The key step of the synthesis is the 1,3-dipolar cycloaddition reaction of fullerene with azomethine ylides generated by heating of dialkyl aziridinedicarboxylates. The thermal opening of the aziridine ring to azomethine ylide and the cycloaddition of the latter to C₆₀ at 100 °C are nearly completely stereoselective: only trans-adducts are formed from cis-aziridines, whereas trans-aziridines give exclusively cis-adducts.     

CuII-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with a chiral ferrocene-derived P,N-ligand

A ferrocene-derived P,N-heterodonor ligand was effectively used in a Cu(OAc)₂·H₂O-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with maleate derivatives, affording cycloadducts with high yields (up to 96%), diastereoselectivities (>99 dr), and enantioselectivities (up to 99% ee).     

Stereoselective synthesis of 5-(4-azetidinyl)-proline esters via 1,3-dipolar cycloaddition reaction of N-metalated azomethine ylides

The conformationally locked s-trans enone functionality present in the (E)-3-arylidene-4-chromanones undergo regioselective 1,3-dipolar cycloaddition reaction with N-metalated azomethine ylides derived from β-lactam imines of glycine methyl ester in the presence of silver acetate to give spiropyrrolidines in moderate to good yield. The regio and stereochemistry of the cycloadducts have been established by single crystal X-ray structure and spectroscopic techniques.     

Synthesis of novel dispiro-oxindoles via 1,3-dipolar cycloaddition reactions of azomethine ylides

The 1,3-dipolar cycloaddition of 1-allyl-5-haloisatin derivatives as dipolarophiles with the azomethine ylides generated in situ from N-allylisatin and l-proline to furnish novel dispiro-oxindoles has been investigated. The structures and relative stereochemistry of both types of cycloadducts were confirmed by single crystal X-ray diffraction, ¹H and ¹³C NMR spectroscopy and mass spectrometry.     

New Tandem Reactions of Metal Carbenoids. Intermolecular Formation of Azomethine Ylide from Methyl 2-Diazo-2-phenylacetate and Schiff Base: Intramolecular 1,3-Dipolar Cycloaddition

Rhodium acetate-catalyzed decomposition of methyl 2-diazo-2-phenylacetate in the presence of substituted N-methylbenzylideneamines possessing an activated alkenyl fragment (dipolarophile) in the side chain gives products of intramolecular cycloaddition of intermediate Z,E- and E,Z-azomethine ylides. The cycloaddition is regioselective, and the products are hexahydrochromeno[4,3-b]pyrrole derivatives. The stereoselectivity of the process depends on the temperature. In the temperature range from 20 to 80°C, the major stereoisomer is that with cis junction of the tetrahydropyran and pyrrolidine rings. N-Phenylazomethine ylides generated from methyl 2-diazo-2-phenylacetate and alkyl 4-[2-(phenyliminomethyl)phenoxy]-2-butenoates at 40°C undergo cyclization to aziridines at a higher rate, as compared to the rate of cycloaddition to the internal dipolarophile. N-Phenylazomethine ylides generated by thermolysis of the corresponding aziridine or by the “deprotonation” method react with equal regio- and stereoselectivity to give intramolecular cycloaddition products, hexahydrochromeno[4,3-b]pyrrole derivatives with trans-fused tetrahydropyran and pyrrolidine rings. Analysis of the experimental and calculation data suggests preference of the endo transition state in the cycloaddition of the examined azomethine ylides.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 6, 2005, pp. 939–949.Original Russian Text Copyright © 2005 by Khlebnikov, Novikov, Bespokoev, Kostikov, Kopf, Starikova, Antipin.     

1,3-Dipolar cycloaddition reactions of benzo[b]thiophene 1,1-dioxide with azomethine ylides

New pyrrolo derivatives of benzo[b]thiophene 1,1-dioxide have been synthesised via 1,3-dipolar cycloaddition reactions. Reaction of benzo[b]thiophene 1,1-dioxide with stabilised azomethine ylides gave products in low yield but high stereoselectivity whereas reaction with non-stabilised azomethine ylides gave high overall yields but low stereoselectivity.     

Intermolecular cycloaddition of nonstabilized azomethine ylides generated from 1,3-thiazolidine-4-carboxylic acids: synthesis of 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazoles

The 1,3-dipolar cycloaddition of dimethyl acetylenedicarboxylate with nonstabilized azomethine ylides, generated via the decarboxylative condensation of 1,3-thiazolidine-4-carboxylic acids with aldehydes, afforded 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazole derivatives. 2-Substituted-1,3-thiazolidine-4-carboxylic acids led to the stereoselective formation of 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazoles. Quantum-chemistry calculations were carried out allowing the rationalization of the observed stereoselective formation of the anti-dipole.     

A new chiral phosphine oxide ligand for enantioselective 1,3-dipolar cycloaddition reactions of azomethine ylides

A new set of phosphorus-containing chiral ligands has been synthesized and used with silver(I) for the catalytic asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides. One of these ligands (POFAM6) was found to produce an effective catalyst for the asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides with electron deficient dipolarophiles to form pyrrolidines in up to 97% yield and 89% ee.