Kinetic study of thermal 1,3-dipolar cycloaddition of azomethine ylides using differential scanning calorimetry as monitoring window

Kinetics of 1,3-dipolar cycloaddition involving azomethine ylides, generated from thermal [1,2]-prototropy of the corresponding imino ester, employing differential scanning calorimetry (DSC), is surveyed. Glycine and phenylalanine derived imino esters have different behavior. The first one prefers reacting with itself at 75 ºC, rather than with the dipolarophile. However, the α-substituted imino ester gives the cycloadduct at higher temperatures. The thermal dynamic analysis by 1H NMR of the neat reaction mixture of the glycine derivative reveals the presence of signals corresponding to the dipole in very small proportion. The non-isothermal and isothermal DSC curves of the cycloaddition of phenylalaninate and diisobutyl fumarate are obtained from freshly prepared samples. The application of known kinetic models and mathematical multiple non-linear regressions (NLR) allow to determine and to compare Ea, lnA, reaction orders, and reaction enthalpy. Finally a rate equation for each different temperature can be established for this particular thermal cycloaddition.

2-Aminobenzimidazole Organocatalyzed Asymmetric Amination of Cyclic 1,3-Dicarbonyl Compounds

The use of a trans-cyclohexanediamine benzimidazole derivative as a hydrogen-bond catalyst for the electrophilic amination of cyclic 1,3-dicarbonyl compounds is herein presented. High yields and enantioselectivities varying from moderate to excellent are generally obtained using mild reaction conditions and as low as 1 mol% of catalyst loading.

Binap-gold (I) versus Binap-silver trifluoroacetate complexes as catalysts in 1,3-dipolar cycloadditions of axomethine ylides

The 1,3-dipolar cycloaddition between azomethine ylides and alkenes is efficiently catalysed by [{(Sa)-Binap-Au(tfa)}2] (Binap=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; tfa=trifluoroacetyl). Maleimides, 1,2-bis(phenylsulfonyl)ethylene, chalcone and nitrostyrene were suitable dipolarophiles even when using sterically hindered 1,3-dipole precursors. The results obtained in these transformations improve the analogous ones obtained in the same reactions catalysed by [Binap–Ag(tfa)]. In addition, computational studies have also been carried out to demonstrate both the high enantioselectivity exhibited by the chiral gold(I) complex, and the non-linear effect observed in this transformation.

Enantioselective 1,3-dipolar cycloadditions of azlactones and electrophilic alkenes catalyzed by dimeric BinapAuTFA complexes

Glycine-derived azlactones react with maleimides using (S)- or (R)-dimeric BinapAuTFA complexes affording the corresponding cycloadducts in good yields and high enantioselections (up to 99% ee). The intermediate carboxylic acids are treated with trimethylsilyldiazomethane and isolated as Δ¹-pyrroline methyl esters. These cycloadducts are transformed into exo-proline derivatives by reduction with NaBH3CN in acidic media. On the other hand, N-benzoylalanine-derived oxazolone reacts with tert-butyl acrylate providing the cycloadduct with the ester group at the 3-position with a trans-relative configuration with respect to the methyl ester group.

Selective hydrosilylation of 1,3-diynes catalyzed by titania-supported platinum

Titania-supported platinum (mainly as Pt(II)) has been found to effectively catalyze the hydrosilylation of 1,3-diynes at 70 °C with low catalyst loading (0.25 mol %) under solvent-free conditions. Monohydrosilylation was achieved for diaryl-substituted diynes, whereas dialkyl-substituted diynes were transformed into the corresponding dihydrosilylated products in good yields. In every case, the process was proven to be highly stereoselective, with syn addition of the silicon–hydrogen bond, and regioselective, with the silicon moiety exclusively bonded to the most internal carbon atom of the 1,3-diyne (β-E product), as confirmed by X-ray crystallography.

Binap-silver salts as chiral-catalysts for the enantioselective 1,3-dipolar cycloaddition of azomethine ylides and alkenes

Binap-AgSbF6 catalyzed 1,3-dipolar cycloadditions between azomethine ylides and electrophilic alkenes are described and compared with analogous transformations mediated by other Binap-silver(I) salt complexes. Maleimides and 1,2-bis(phenylsulfonyl)ethylene are suitable dipolarophiles for obtaining very good enantioselectivities, even better values are generated by a multicomponent version. There are some very interesting applications of the disulfonylated cycloadducts in the total synthesis of cis-2,5-disubstituted pyrrolidines, precursors of natural products, or valuable intermediates in the synthesis of antiviral compounds.

Microwave-assisted multicomponent diastereoselective 1,3-dipolar cycloaddition of ethyl glyoxylate derived azomethine ylides

The thermal multicomponent 1,3-dipolar cycloaddition (1,3-DC) of diethyl aminomalonate or α-amino esters (derived from glycine, alanine, phenylalanine, and phenylglycine) with ethyl glyoxylate and the corresponding dipolarophile such as maleimides, methyl acrylate, methyl fumarate, (E)-1,2-bis(phenylsulfonyl)ethylene, and electron deficient alkynes allows the diastereoselective synthesis of new polysubstituted pyrrolidine derivatives. Microwave-assisted heating processes give better results than conventional heating ones, affording endo-cycloadducts as major stereoisomers. In general, 2,5-cis-cycloadducts are preferentially formed according to the previous formation of the W-shaped dipole. Only in the 1,3-DC of the disulfone with phenylglycine and ethyl glyoxylate the corresponding exo-trans-cycloadduct was isolated. The compound endo-cis-4b, derived from phenylalanine, ethyl glyoxylate and N-benzylmaleimide, has been further transformed into a very complex diazabicyclo[2.2.1]octane skeleton with potential biological activity.

Phosphoramidite-Cu(OTf)2 complexes as chiral catalysts for 1,3-dipolar cycloaddition of iminoesters and nitroalkenes

Chiral complexes formed by phosphoramidites such as (Sa,R,R)-9 and Cu(OTf)2 are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted proline esters mainly as exo-cycloadducts in high er at room temperature. The exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. DFT calculations support the stereochemical results.

Multicomponent synthesis of unnatural pyrrolizidines using 1,3-dipolar cycloaddition of proline esters

The synthesis of unnatural pyrrolizidines has been studied using a multicomponent-domino process involving proline or 4-hydroxyproline esters, an aldehyde and a dipolarophile. The formation of the iminium salt promotes the 1,3-dipolar cycloaddition affording highly substituted pyrrolizidines under mild conditions and high regio- and diastereoselectivities.

Synthetic scope and DFT analysis of the chiral binap-gold (I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

The 1,3-dipolar cycloaddition between glycine-derived azlactones with maleimides is efficiently catalyzed by the dimeric chiral complex [(Sa)-Binap·AuTFA]2. The alanine-derived oxazolone only reacts with tert-butyl acrylate giving anomalous regiochemistry, which is explained and supported by Natural Resonance Theory and Nucleus Independent Chemical Shifts calculations. The origin of the high enantiodiscrimination observed with maleimides and tert-butyl acrylate is analyzed using DFT computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF) level. Several applications of these cycloadducts in the synthesis of new proline derivatives with a 2,5-trans-arrangement and in the preparation of complex fused polycyclic molecules are described.

Adición conjugada de compuestos 1,3-dicarbonílicos a maleimidas catalizada por 2-aminobencimidazoles quirales

En la presente memoria se describe la síntesis y aplicación de diversos organocatalizadores quirates derivados de 2-aminobencimidazol en reacciones de adición Michael de compuestos 1,3-discarbonílicos a maleimidas. En este trabajo se ha preparado un organocatalizador quiral y reciclable con simetría C₂ derivado de bencimidazol y (1R,2R)-ciclohexano-1,2-diamina y se ha utilizado con éxito en la adición conjugada de β-dicetonas, β-cetoésteres y malonatos de dialquilo a maleimida y maleimidas N-sustituidas. La adición, que se lleva cabo en tolueno y a temperatura ambiente, conduce a las correspondientes succinimidas quirales con buenos rendimientos, moderadas diastereoselectividades y excelentes excesos enantioméricos. También se han realizado estudios mecanísticos mediante cálculos computacionales DFT y estudios de difusión por resonancia magnética nuclear para determinar el modo de actuación del catalizador y el estado de transición de la reacción de adición conjugada de compuestos 1,3-dicarbonílicos a maleimidas que han confirmado el estado de transición y mecanismo propuestos.

Domino 1,3-Dipolar Cycloadditions of N-Alkyl-α-Amino Esters with Paraformaldehyde: A Direct Access to α-Hydroxymethyl α-Amino Acids

N-Alkyl-α-amino esters undergo a domino reaction, based on the iminium cation generation, with paraformaldehyde, followed by a 1,3-dipolar cycloaddition of the stabilized azometh­ine ylide with another equivalent of formaldehyde. The resulting products are oxazolidines, which can be transformed after hydrolysis into α-hydroxymethyl α-amino acid or its derivatives. The diastereoselective 1,3-dipolar cycloaddition was performed using sarcosine (–)-menthyl or (–)-8-phenylmenthyl esters affording the cyclic product with moderate enantiomeric ratio.

Coinage Metal Complexes as Chiral Catalysts for 1,3-Dipolar Cycloadditions

In this account, we describe the experience of our research group in the implementation of chiral coinage metal complexes into the efficient enantioselective 1,3-DC of azomethine ylides derived from α-amino acids and azlactones with different dipolarophiles. The corresponding chiral metallodipoles were generated in situ and next focused on the synthesis of highly substituted prolines. For this purpose, privileged ligands such as phosphoramidites and binap with silver(I), gold(I) and copper(II) salts are described. Depending from the ligand and mainly from the metal salt it can be possible to control the facial endo/exo-diasteroselectivity and the enantioselectivity of these types of processes. The synthetic processes are also supported by DFT calculations in order to elucidate the most plausible mechanism and the stereochemical results.

Asymmetric 1,3-Dipolar Cycloadditons of Stabilized Azomethine Ylides with Nitroalkenes

This review highlights the biological importance of many polysubstituted nitro-prolines and -pyrrolidines. Their preparation using asymmetric 1,3-dipolar cycloadditions of azomethine ylides with nitroalkenes using diastereoselective and enantioselective strategies is described remarking the scope and main features of each one.