Generation of functionalized azomethine ylides and their application to stereoselective heterocycle synthesis: an equivalent process of C-unsubstituted nitrile ylide cycloaddition reaction

The synthetic process equivalent to C-unsubstituted (CH) nitrile ylides cycloaddition reaction is achieved via cycloaddition of NH-azomethine ylide and the following fission reaction of the cycloadducts under acidic conditions. Cycloaddition of NH-azomethine ylide generated by a thermal 1,2-prototropy in 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde system with maleimides provides proline derivatives under extremely mild conditions. Heating their adducts in AcOH at 85 °C causes a cleavage of C-C bond between the proline and heterocyclic moiety to give the parent heterocyclic system and dehydroproline derivatives, which is regarded as a cycloadduct of C-unsubstituted (CH) nitrile ylide. This cycloaddition-fission reaction sequences can be applied to one-pot three-component reaction.     

gem-Difluorosubstituted NH-azomethine ylides in the synthesis of 4-fluorooxazolines via the three-component reaction of imines, trifluoroacetophenones and CF2Br2

A simple one-step synthesis of a new class of fluorinated heterocycles, 4-fluoro-3-oxazolines, from diarylmethanimines, trifluoroacetophenones and CF₂Br₂ is described. The reaction proceeds via the sequential formation of difluorocarbene and a gem-difluorosubstituted NH-azomethine ylide, followed by 1,3-dipolar cycloaddition with a ketone.     

A convenient one-pot approach to Paclitaxel (Taxol) side chain via 1,3-dipolar cycloaddition of carbonyl ylides and N-benzoylbenzyl imines

An efficient cascade approach to α-hydroxy-β-amino acid derivatives is reported, which goes through a 1,3-dipolar cycloaddition of carbonyl ylides and N-benzoylbenzyl imines and followed by hydrolysis under acidic conditions. This is the first example of using N-benzoylbenzyl imine as dipolarophile for 1,3-dipolar cycloaddition with carbonyl ylide, which provides a direct and convenient access for the one-pot synthesis of paclitaxel side chain and its derivatives.     

1,3-Dipolar Cycloaddition of Azomethine Ylides Generated from Ketimines and Difluorocarbene to Symmetrically Substituted Olefins

Iminiodifluoromethanides generated from difluorocarbene and benzophenone or fluorenone imines enter into reaction of 1,3-cycloaddition with electron-deficient alkenes to furnish pyrrolidone derivatives. The generation of iminiodifluoromethanides from alkyl N-benzhydrylidene glycinates in the presence of dipolarophiles is liable to complication by a concurrent proton shift in the initial imine giving NH-azomethine ylide also capable of 1,3-dipolar cycloaddition resulting in a side product of pyrrolidone series. The use of active lead instead of lead powder as reductant for dibromodifluoromethane in generation of difluorocarbene permits suppressing formation of the side products in these reactions.     

Catalytic Asymmetric [ 2,3 ] -Sigmatropic Rearrangement of Sulfur Ylides Generated from Carbenoids

The catalytic asymmetric reactions of oxygen or sulfur ylides generated from carbenoids have attracted consider able attention in recent years. High enantioselectivities have been achieved in the 1,3-dipolar cycloaddition reactions and [ 2,3 ]-sigmatropic rearrangement of oxygen ylides. In contrast to the oxygen ylide, the corresponding catalytic asymmetric reaction of sulfur ylide is less developed. Compared to oxygen ylides, the sulfur ylides are more stable and experimental evidence supports a free ylide rather than a metal-bound ylide as reaction intermediate. That means the enantio-control must be in the step of the ylide formation. If the subsequent reaction such as [ 2,3 ]-sigmatropic rearrangement or 1,3-dipolar cycloaddition is a concerted process and is faster than the racemization of the chiral ylide intermediate, then the catalytic asymmetric sulfur ylide reaction will be possible.     

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.     

Synthesis of Novel Dispiro 1,4-Benzothiazine Hybrid Heterocycles Through 1,3-Dipolar Cycloaddition

The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of acenaphthylene-1,2-dione or isatins and α-amino acids to (E)-methyl/ethyl 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-ylidene)acetate led to the stereoselective formation of novel dispiro 1,4-benzothiazine hybrid heterocycles in good yields.     

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.     

The first example of the generation of azomethine ylides from a fluorocarbene: 1,3-cyclization and 1,3-dipolar cycloaddition

The reaction of Schiff bases with fluorocarbene, generated by reduction of dibromofluoromethane with active lead in the presence of Bu₄NBr under ultrasound irradiation, involves the formation of fluoro-substituted azomethine ylides which undergo cyclization into aziridines. 1,3-Cyclization of ylides, generated from N-arylimines of benzaldehyde, proceeds stereoselectively. When carrying out the reaction of Schiff bases with fluorocarbene in the presence of dimethyl maleate or dimethyl acetylenedicarboxylate, the products of dehydrofluorination of the primary adducts of the 1,3-dipolar cycloaddition of fluoro-substituted azomethine ylides to multiple bonds of dipolarophiles were obtained. In the case of the reaction of N-alkylimines of benzaldehyde the cycloaddition of ylides to dimethyl maleate completely suppressed the cyclization to aziridines.     

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.     

X=y-zh systems as potential 1,3-dipoles—5 : Intramolecular cycloadditions of imines of α-amino acid esters

Azomethine ylides are readily generated from imines of α-amino acid esters by a formal 1,2-H shift. A suitably positioned unactivated double or triple bond in either of the two precursors of the imines (aldehyde or α-amino ester) leads to an intramolecular cycloaddition generating fused ring systems in good yield. Cis stereochemistry is assigned to the newly created ring junction of the cycloadducts based on NOE difference spectroscopy and, in the case of 8a, by a single crystal X-ray structure. Equilibration of the kinetically formed dipole leads to mixtures of epimeric cycloadducts for imines of phenylglycine methyl ester but equilibration is not observed for other imines. Reasons for this are discussed. The intramolecular cycloaddition is sensitive to ring size with 6/5 and 5/5 cis-fused systems being most easily formed depending in which moiety (aldehyde or amino acid) the dipolarophile is located. Intramolecular trapping of the azomethine ylide by an alkyne is accompanied by variable amounts of aromatized pyrrolic products.     

Regioselective synthesis of mono- and bis-decahydrobenzocarbazoles via tandem reactions of α-diazo ketones

Regioselective intermolecular 1,3-dipolar cycloaddition reactions of rhodium generated carbonyl ylides with indoles are reported in this paper. Intermolecular 1,3-dipolar cycloaddition reactions of five-membered-ring cyclic carbonyl ylides with indole and substituted indoles afforded hexahydro-2H-carbazol-2-ones in a regioselective manner. Similarly, reactions of cyclic carbonyl ylides were carried out to afford decahydrobenzo[c]carbazoles or decahydrocyclopenta[c]carbazoles with high regioselectivity. Interestingly, the other possible regioisomer decahydrobenzo[a]carbazoles were also obtained by the reaction of cyclic carbonyl ylides and indoles having electron withdrawing substituents. The structure and stereochemistry of regioisomers 6,11c-epoxy-1,2,3,4,4a,5,6,6a,11b,11c-decahydro-4a-methyl-5-oxo-7H-benzo[c]carbazole and 11-benzenesulfonyl-6,11b-epoxy-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-4a-methyl-5-oxo-1H-benzo[a]carbazole were unequivocally corroborated by single-crystal X-ray analyses. To advance this study, regioselective double 1,3-dipolar cycloaddition reaction of five-membered-ring cyclic carbonyl ylides has been demonstrated for the first time with biindoles having various aryl and alkyl spacers. This process constructed up to eight stereocenters, four carbon-carbon and two carbon-oxygen bonds in a single step with an excellent molecular complexity and stereoselectivity.     

Generation of NH-azomethine imine intermediates through the 1,2-hydrogen shift of hydrazones and their intermolecular cycloaddition reaction with olefinic dipolarophiles

The thermal 1,2-hydrogen shift of the hydrazone generates the NH-azomethine imine intermediate in the 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde system under mild conditions. Therein, the resulting NH-azomethine imine should be stabilized by forming an internal hydrogen bond with the carbonyl oxygen at the 4-position. Its smooth stereoselective intermolecular cycloaddition reaction with olefinic dipolarophiles giving pyrazolidine derivatives is discussed.     

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.     

Binaphthol-derived bisphosphoric acids serve as efficient organocatalysts for highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides to electron-deficient olefins

A variety of chiral bisphosphoric acids derived from binaphthols have been evaluated for enantioselective 1,3-dipolar cycloaddition reactions, revealing that the feature of the linker in the catalysts exerted great impact on the stereoselectivity. Among them, the oxygen-linked bisphosphoric acid 1a provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction tolerating a wide range of substrates including azomethine ylides, generated in situ from a broad scope of aldehydes and α-amino esters, and various electron-deficient dipolarophiles such as maleates, fumarates, vinyl ketones, and esters. This reaction actually represents one of the most enantioselective catalytic approaches to access structurally diverse pyrrolidines with excellent optical purity. Theoretical calculations with DFT method on the formation of azomethine ylides and on the transition states of the 1,3-dipolar cycloaddition step showed that the dipole and dipolarophile were simultaneously activated by the bifunctional chiral bisphosphoric acids through the formation of hydrogen bonds. The effect of the bisphosphoric acids on reactivity and stereochemistry of the three-component 1,3-dipolar cycloaddition reaction was also theoretically rationalized. The bisphosphoric acid catalyst 1a may take on a half-moon shape with the two phosphoric acid groups forming two intramolecular hydrogen bonds. In the case of maleates, one phosphate acts as a base to activate the 1,3-dipole, and simultaneously, the two hydroxyl groups in the catalyst 1a may respectively form two hydrogen bonds with the two ester groups of maleate to make it more electronically deficient as a much stronger dipolarophile to participate in a concerted 1,3-dipolar cycloaddition with azomethine ylide. However, in the cases involving acrylate and fumarate dipolarophiles, only one hydroxyl group forms a hydrogen bond with the ester functional group to lower the LUMO of the C-C double bond and another one is remained to adjust the acidity and basicity of two phosphoric acids to activate the dipole and dipolarophile more effectively.     

Heterocycles. 13. synthesis of [1,2-d]triazolo steroids

Reaction of 1,2-epoxy-5α-3-ketosteroids with sodium azide produces a mixture of expected 2-azido-5α-δ¹-3-ketosteroids and novel [1,2-d]triazolosteroids. A possible pathway for formation of the latter involving 1,3-dipolar cycloaddition of sodium azide is discussed.     

Efficient catalytic effects of Lewis acids in the 1,3-dipolar cycloaddition reactions of carbonyl ylides with imines

[reactions: see text] 1,3-Dipolar cycloaddition reactions between imines and carbonyl ylides generated by tandem intramolecular carbenoid-carbonyl cyclizations were found to be effectively catalyzed by Lewis acids (10 mol %). The Rh2(OAc)4-catalyzed reactions of o-(methoxycarbonyl)-alpha-diazoacetophenone with imines such as N-[2-(benzyloxy)benzylidene]aniline in the absence of Lewis acid gave no 1,3-dipolar cycloaddition products, but rather the dimeric product of the corresponding carbonyl ylide. In contrast, in the presence of Lewis acids such as Yb(OTf)3, the 1,3-dipolar cycloaddition reactions of the corresponding 1-methoxy-2-benzopyrylium-4-olate proceeded smoothly with several imines, giving in most cases exo-selectivity and no formation of the dimeric product. When Yb(OTf)3 was used as a Lewis acid catalyst, a fundamental catalytic effect was also observed in the cycloaddition reactions of imines with carbonyl ylides generated from 1-diazo-5-phenyl-2,5-pentanedione, 1-diazo-2,5-hexanedione and diazomethyl 2,3,4,5-tetrachloro-6-methoxycarbonylphenly ketone. This efficient catalytic effect can be satisfactorily explained in terms of energetics of the cycloaddition in the absence and the presence of Lewis acid by calculations using the ONIOM (B3LYP/6-31G(d):PM3) method.     

Synthesis of Polysubstituted Pyrrolizidines from Proline Derivatives and Conjugated Nitroolefins

The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and i-proline alkyl esters with several nitroolefins was investigated. Cyclic and acyclic nitroolefins add to the anti form of the ylide in a highly diastereoselective but poorly regioselective manner to give pyrrolizidine derivatives. In a few cases, the stereochemical results strongly support a stepwise mechanism.     

New Cycloadditon Reaction of 2-Chloroprop-2-enethioamides with Dialkyl Acetylenedicarboxylates: Synthesis of Dialkyl 2-[4,5-bis(alkoxycarbonyl)-2-(aryl{alkyl}imino)-3(2H)-thienylidene]-1,3-dithiole-4,5-dicarboxylates

The 1,3-dipolar cycloaddition of 1,2-dithiole-3-thiones with alkynes to form 1,3-dithioles is one of the most studied reactions in this class of polysulfur-containing heterocycles. Nucleophilic substitution of chlorine atoms in dimethyl 2-(1,2-dichloro-2-thioxoethylidene)-1,3-dithiole-4,5-dicarboxylate, which was obtained by addition one molecules of DMAD to 4,5-dichloro-3H-1,2-dithiole-3-thione, led to a series of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides. Cycloaddition reaction of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides with activated alkynes led to the unexpected formation of 2-(thiophen-3(2H)-ylidene)-1,3-dithioles via new intermediate, 1-(1,3-dithiol-2-ylidene)-N-phenylethan-1-yliumimidothioate. Structure of dimethyl 2-(4,5-bis(methoxycarbonyl)-2-(phenylimino)thiophen-3(2H)-ylidene)-1,3-dithiole-4,5-dicarboxylate was finally proven by single crystal X-ray diffraction study. Optimized reaction conditions and a mechanistic rationale for the 1,3-dipolar cycloaddition of novel intermediate are presented.     

An expedient diastereoselective synthesis of pyrrolidinyl spirooxindoles fused to sugar lactone via [3+2] cycloaddition of azomethine ylides

Synthesis of pyrrolidinyl-spirooxindoles fused to sugar lactone has been achieved by a one pot three component 1,3-dipolar cycloaddition (1,3-DC) reaction. A unique dipolarophile (α,β-unsaturated lactone) derived from d-glucose/d-galactose reacted with azomethine ylide generated in situ from isatin/N-substituted isatin and secondary amino acids (sarcosine/proline/piperidine-2-carboxylic acid) to give the corresponding cycloadducts in good yield. The cycloaddition was found to be highly regio- and diastereoselective.