Investigations on regio‐ and stereoselectivities in cycloadditions involving α‐ (3‐pyridyl)‐N‐phenylnitrone: Development of an efficient route to novel nicotine analogs

Thermal reactions of hitherto α‐(3‐pyridyl)‐N‐phenylnitrone ( 1 ) with mono‐substituted electron‐rich and electron‐neutral dipolarophiles are regio‐, and stereo‐selective (exo‐selective), controlled by LUMO ‐ dipole ‐ HOMO‐ dipolarophile interaction, and furnish syn‐5‐substituted‐3‐(3‐pyridyl)‐isoxazolidines ( 5 ) in high yields. With electron deficient dipolarophiles such as acrylonitrile there is observed a loss of regioselectivity as well as stereoselectivity and the regioselectivity is reversed in reactions with methyl vinyl ketone and methyl acrylate, due to intervention of HOMO‐dipole ‐ LUMO‐dipolarophile interaction, affording 4‐substi‐tuted‐3‐(3‐pyridyl)‐isoxazolidines ( 7 ) as major products. Reactions of nitrone ( 1 ) with disubstituted dipolarophiles such as methyl methacrylate and ethyl coronate furnish methyl syn‐5‐methy‐3‐pyridyl‐1‐phenyl‐isoxazolidine‐5‐carboxylate ( 8 ) and ethyl anti‐5‐methy‐3‐pyridyl‐1‐phenyl‐isoxazolidine‐4‐carboxylate ( 10 ), respectively, in high yields. Reaction with N‐Phenylmaleimide affords novel isoxazolidino‐pyrro‐lidinediones bearing a 3‐pyridyl moiety ( 11, 12 ). A mechanistic rationalization of the obtained results in terms of electronic, steric and secondary interactions is proffered.     

N-(2-pyridylmethyl)imines as azomethine precursors in catalytic asymmetric [3 + 2] cycloadditions

An efficient Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition of N-(2-pyridylmethyl) imines has been developed. In the presence of a Cu(CH(3)CN)(4)PF(6)/bisoxazoline catalyst system, high levels of enantioselectivity (up to 97% ee) and moderate to high exo selectivity were achieved with a wide variety of substituted dipolarophiles, including maleimides, fumarates, fumarodinitrile, enones, and nitroalkenes. The reaction with unsymmetrically substituted dipolarophiles is completely regioselective.     

Highly enantioselective nitrone cycloadditions with 2-alkenoyl pyridine N-oxides catalyzed by Cu(II)-BOX complexes

Enantioselective nitrone cycloadditions with 2-alkenoyl pyridine N-oxides as dipolarophiles have been reported. The reaction is catalyzed by Cu(II)-BOX complexes to give the expected isoxazolidine products with high diastereo- and enantioselectivity.     

1,3-Dipolar Cycloaddition Reactions of C-(2-Nitro)-styryl-N-phenyl Nitrone Leading to the Regiospecific and Stereospecific Synthesis of New Isoxazolidine Derivatives

New substituted isoxazolidine derivatives have been synthesized through regiospecific and stereospecific 1,3-dipolar cycloadditions of C-(2-nitro)-styryl-N-phenyl nitrone with reactive dipolarophiles in excellent yields and effects of substituents have been noted.     

Synthesis of Some Novel Class of Regioselective Spiro Isoxazolidine Derivatives via 1,3‐Dipolar Cycloaddition Reaction of N‐Benzyl‐C‐fluoro‐substituted Phenyl Nitrones in Ionic Liquid

Synthesis of some new class of regioselective spiro isoxazolidine derivatives have been described using N‐benzyl‐C‐fluoro substituted‐phenyl nitrones with new dipolarophiles via 1,3‐dipolar cycloaddition reaction in ionic liquid. The novel spiro cycloadducts found to exhibit good synthetic potentiality as they could be converted into synthetically more important spiro 1,3‐amino alcohols. Simple reaction methodology, noninvolvent of catalysts, good to excellent yields, and greener approaches are the important features noticed in this syntheses.     

Organocatalytic enantioselective (3+2) cycloaddition using stable azomethine ylides

We have developed a highly efficient procedure for carrying out the catalytic enantioselective (3+2) cycloaddition between enals and stable azomethine ylides such as isoquinolinium and phthalizinium methylides. Under the optimized reaction conditions highly substituted chiral pyrroloisoquinolines and pyrrolophthalazines have been obtained in high yields and excellent diastereo- and enantioselectivities.     

Cobalt-catalyzed reductive coupling of activated alkenes with alkynes

Cobalt complex/Zn systems effectively catalyze the reductive coupling of activated alkenes with alkynes in the presence of water to give substituted alkenes with very high regio- and stereoselectivity in excellent yields. While the intermolecular reaction of acrylates, acrylonitriles, and vinyl sulfones with alkynes takes place in the presence of CoI2(PPh3)2/Zn, the reaction of enones and enals with alkynes requires the use of the CoI2(dppe)/Zn/ZnI2 system. The intramolecular reductive coupling of activated alkenes (enones, enals, acrylates, and acrylonitriles) with alkynes also works efficiently. Further a variety of cyclic lactones and lactams were prepared using this methodology. Possible mechanistic pathways are proposed based on a deuterium-labeling experiment carried out in the presence of D2O.     

Catalytic,three-component assembly reaction for the synthesis of pyrrolidines

[reaction: see text] Copper(I) salts catalyze the three-component assembly reaction between an alpha-diazo ester, an imine, and various alkenes and alkynes to form substituted pyrrolidines with excellent to good diastereoselectivities in high yields. The transition metal-catalyzed decomposition of the alpha-diazo compound in the presence of the imine likely generates a transient azomethine ylid that undergoes addition with various dipolarophiles in a highly convergent manner.     

Catalytic highly enantioselective 1,3-dipolar cycloaddition reaction of nitrones with 3-alkenoyl-2-oxazolidinones by use of a bidentate chiral bis(imine) ligand–Cu(II) triflate complex

A copper(II) triflate complex with bidentate, chiral C₂-symmetric cyclohexane-1,2-bis[(2,6-dichlorophenylmethylene)amine] catalyzed the 1,3-dipolar cycloaddition reactions of nitrones with electron-deficient dipolarophiles, 3-(2-alkenoyl)-1,3-oxazolidin-2-ones to give isoxazolidine cycloadducts with extremely high endo- and enantioselectivities.     

Photoactivated 1,3-dipolar cycloaddition for the rapid preparation of F labelled radiotracers

An ¹⁸F-labelled 2,5-diaryl tetrazole reagent has been prepared and reacted with substituted alkene dipolarophiles through a photoactivated 1,3-dipolar cycloaddition reaction. The radiobioconjugation reaction furnished the desired product in 5 min with radiochemical conversions of 85-95% at room temperature. Remarkably, for the activated dipolarophiles, these results were obtained in highly dilute solutions (10-100 μM).     

From imidates to vinyl-1,2,4-triazoles: Synthesis,mechanistic aspects and first issues of their reactivity

The reaction of variously substituted acylimidates with hydrazine derivatives represents an efficient and easy to set synthetic entry towards 5-vinyl-1,2,4-triazole derivatives. The construction of the triazole ring allows the installation of variety of substituent combination at the N(1), C(3) and C(5) positions of the five-membered heterocycle in good to high yields. The method reveals selective towards 5-vinyl-1,2,4-triazoles avoiding the potential formation of seven- and five-membered side-products as supported by theoretical calculations and NMR experiments. First lines of Pd-catalyzed arylation of the vinyl fragment towards 5-styryl-1,2,4-triazoles and Cu-catalyzed arylation at the N(1) site are finally described.     

Asymmetric Synthesis of Highly Substituted β‐Lactones through Oxidative Carbene Catalysis with LiCl as Cooperative Lewis Acid

The reaction of enals with β‐diketones, β‐ketoesters, and malonates bearing a β‐oxyalkyl substituent at the α‐position by oxidative NHC catalysis to provide highly substituted β‐lactones is described. Reactions occur with excellent diastereo‐ and enantioselectivity. The organo cascade comprises two C? C bond formations and one C? O bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed in the cascade.     

Morita-Baylis-Hillman adducts as effective dipolarophiles in copper(I)-catalyzed 1,3-dipolar cycloaddition with azomethine ylides: asymmetric construction of pyrrolidine derivatives containing quaternary stereogenic center

The first catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with easily accessible Morita-Baylis-Hillman adducts as the dipolarophiles has been developed successfully and provides the highly substituted pyrrolidines bearing a unique quaternary and two tertiary stereogenic centers in excellent diastereoselectivity and up to 97% ee.     

Synthesis of bis‐pyrrole tetra esters and alcohols as novel mimetics of the anticancer mitomycin

Open‐chain bis‐Reissert compounds 1 were converted to the corresponding bis‐oxazolium intermediates via acid‐catalyzed intramolecular cyclization. These oxazolium compounds exist in a variety of tautomeric structures in which the meso‐ionic form can be intercepted by reaction with dipolarophiles in a 1,3‐dipolar‐cycloaddition reaction to produce a variety of highly functionalized bis‐pyrrole esters 2 . In turn, the bis‐pyrrole esters could be converted to the corresponding bis‐pyrrole tetrols 3 in high yields. J. Heterocyclic Chem., 2011.     

Regio- and stereoselectivity of captodative olefins in 1,3-dipolar cycloadditions. A DFT/HSAB theory rationale for the observed regiochemistry of nitrones

Captodative olefins 1-acetylvinyl carboxylates proved to be highly regioselective dipolarophiles in 1,3-dipolar cycloadditon to propionitrile oxide, arylphenylnitrile imines, diazoalkanes, and nitrones to yield the corresponding 5-substituted heterocycles. The addition of the latter was also stereoselective, being slightly susceptible to steric demand of the carboxylate substituent in the olefin. All atempts to cleave the isoxazolidine N-O bond under reductive conditions failed, providing diverse products with side-group reduction. FMO theory was unsuccessful to explain the regioselectivity observed with nitrones, since the opposite orientation was predicted. The recently formulated DFT/HSAB theoretical model was able to rationalize this regioselectivity, identifying the nucleophilic and electrophilic atoms involved in the process via calculation of interaction energies, suggesting the specific direction of the electronic process at each of the reaction sites.     

Alpha-oximono-esters as precursors to heterocycles--generation of oxazinone N-oxides and cycloaddition to alkene dipolarophiles

Preparation of a series of terminally and internally substituted delta-alkenyl and delta-alkynyl esters 6, 7 and 9, potential precursors to oxazin-2-one nitrones, has been attempted. Condensation between pyruvic or benzoylformic acid and the appropriate alcohol proceeded smoothly in some cases whilst allylic transposition was a major feature in other cases--most especially during reactions with alpha-vinylbenzyl alcohol. Oximation of pyruvic acid derivatives furnished E-oxime isomers whilst benzoylformic acid derivatives afforded mixed geometrical isomers. The E-oxime of 4a1 carrying an internal Me group undergoes facile thermal cyclisation affording nitrones 1c and 1d in good yield. Oximes E-5a,b with a terminal methyl substituent on the alkene moiety furnish nitrone only under the influence of an external electrophile [PhSeBr/AgBF4]. A terminal Ph substituent on 5c,d prohibits formation of the cyclic dipole irrespective of reaction conditions, and whilst 5d reacts to afford a bicyclic isoxazolofuranone 13 by an IOOC reaction (intramolecular oxime olefin cyclisation) 5c remains thermally inert. Finally delta-alkynyl oximes 9c,d also failed to cyclise. The regio- and stereochemical characteristics of the cycloadditions between the new dipoles and electron poor olefinic dipolarophiles have been investigated. The conditions needed for reaction were rather forcing since the dipoles are somewhat stabilised by the adjacent alkoxycarbonyl group. All reactions proceeded regiospecifically to give adducts with 5-substituted isoxazolidine rings whilst diastereoselectivity varied with the choice of dipolarophile and the steric demands of the nitrone substituents. The phenylselenyl dipole 10a could not be trapped by any dipolarophiles bar dimethyl acetylenedicarboxylate.     

Synthesis of Two 6-N-Protected 9-N-Vinyladenines as Dipolarophiles in the Synthesis of Modified Nucleosides

A new class of potential antiviral drugs is represented by isoxazolidine nucleosides. The paper reports on the synthesis of protected adenines useful as dipolarophiles in the preparation of analogues of dideoxyadenosine by 1,3-dipolar cycloaddition processes.     

Origins of the Reactivity in 1,3-Dipolar Cycloadditions of Acyl Isocyanide Ylides

1,3-Dipolar cycloadditions are the preferred method to generate five-membered heterocyclic rings. Surprisingly, cycloadditions based on acyl-isocyanide ylides have remained underexplored by the chemical community. Acyl-isocyanide ylides readily react with dipolarophiles, such as substituted alkenes, to yield Δ¹-pyrroline derivatives. As an explanation for the observed reactivity of this reaction is lacking, extensive density functional theory calculations were performed to scrutinize the mechanistic features of the transformation. Herein we explain the experimental outcome of the reaction using a variety of reactivity theories and predict opposed regioselectivity for electron-poor and electron-rich dipolarophiles. With the insights obtained, we hope to incentivize the design of new cycloaddition reactions based on the acyl-isocyanide ylides motif.     

New zinc(II)-based catalyst for asymmetric azomethine ylide cycloaddition reactions

[reaction: see text] A new chiral aziridino alcohol ligand for zinc(II)-catalyzed azomethine ylide cycloadditions is described. In the presence of this catalyst, N-arylidene glycine methyl esters react with a variety of dipolarophiles to give substituted pyrrolidines in very good to excellent chemical yields and up to 95% ee. The absolute sense of asymmetric induction appears to be dipolarophile-dependent.     

Photo- and thermoinduced generation of 1,3-diaryl carbonyl ylides from 2,3-diaryloxiranes 1,3-dipolar cycloadditions to dipolarophiles

A group of symmetrically substituted 2,3-diaryloxiranes have been studied as photoprecursors for carbonyl ylides. The stereochemistry of the adducts obtained upon interception of these 4n pi-transient systems with a variety of dipolarophiles provides information on the mode(s) of electrocyclic opening of the oxiranes to carbonyl ylides, as well as the mechanism of the 4n + 2 cycloaddition process. The stereochemistry of the dipolarophiles is preserved in the cycloadducts, which is consistent with a concerted addition process; however, solvent effects, steric hindrance, and possibly secondary orbital overlap factors all may play a role in determining the product distribution.