Heterocyclic carbene–metal-catalyzed Csp2–Csp2 and Csp–Csp2 couplings using nonmetallic substrates

The use of carbene ligands for transition-metal complexes has been developed in the last decades, being of special interest those carbenes derived from a nitrogen-containing heterocyclic system. An interesting variety of carbene-metal complexes has been tested in the Mizoroki-Heck reaction. In comparison, few examples can be found for the Matsuda-Heck version of this coupling reaction. Additionally, the Sonogashira coupling has been also catalyzed with different carbene-metal catalysts.

A Highly Efficient Solvent-Free Asymmetric Direct Aldol Reaction Organocatalyzed by Recoverable (s)-Binam-L-Prolinamides. ESI-MS Evidence of the Enamine-Iminium Formation

Recoverable (Sa)-binam-l-prolinamide in combination with benzoic acid is used as catalysts in the direct aldol reaction between cycloalkyl, alkyl, and α-functionalized ketones and aldehydes under solvent-free reaction conditions. Three different methods are assayed: simple conventional magnetic stirring, magnetic stirring after previous dissolution in THF and evaporation, and ball mill technique. These procedures allow one to reduce not only the amount of required ketone to 2 equiv but also the reaction time to give the aldol products with regio-, diastereo-, and enantioselectivities comparable to those in organic or aqueous solvents. Generally anti-isomers are mainly obtained with enantioselectivities up to 97%. The reaction can be carried out under these conditions also using aldehydes as nucleophiles, yielding after in situ reduction of the aldol products the corresponding chiral 1,3-diols with moderate to high enantioselectivities mainly as anti-isomers. The aldol reaction has been studied by the use of positive ESI-MS technique, providing the evidence of the formation of the corresponding enamine−iminium intermediates.

Aqueous organocatalyzed aldol reaction of glyoxylic acid for the enantioselective synthesis of α-hydroxy-γ-keto acids

N-Tosyl-(Sa)-binam-L-prolinamide is an efficient catalyst for the aqueous aldol reaction, between glyoxylic acid, as monohydrate or aqueous solution, and ketones. This reaction led to the formation of chiral α-hydroxy-γ-keto carboxylic acids in high levels of diastereo- and enantioselectivities achieving mainly anti aldol products.

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.

Enantioselective Michael addition of isobutyraldehyde to nitroalkenes organocatalyzed by chiral primary amine-guanidines

Primary amine-guanidines derived from trans-cyclohexane-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of isobutyraldehyde to arylated and heteroarylated nitroalkenes. The reaction was performed in the presence of imidazole as the additive in aqueous DMF as the solvent at 0 °C. The corresponding Michael adducts bearing a new stereocenter were obtained in high yields and with enantioselectivities of up to 80%. Theoretical calculations are used to justify the observed sense of the stereoinduction.

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.

Enantioselective Michael addition of aldehydes to maleimides organocatalysed by chiral 1,2-diamines: an experimental and theoretical study

Simple and commercially available chiral 1,2-diamines were used as organocatalysts for the enantioselective conjugate addition of aldehydes, including α,α-disubstituted, to maleimides. The reaction was carried out in the presence of hexanedioic acid as an additive in aqueous solvents at room temperature. By employing (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine as organocatalysts, the corresponding Michael adducts bearing new stereocenters were obtained in high or quantitative yields with enantioselectivities of up to 92%, whereas the use of (1S,2S)-1,2-diphenylethane-1,2-diamine gave a much lower ee. Theoretical calculations were used to justify the observed sense of the stereoinduction.

Polymer-supported l-prolinol-based catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines

l-Prolinol-based ligands anchored to Merrifield or Wang-type resins have been shown to form efficient catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines. The enantioselectivity achieved with the polymeric catalyst (ee up to 88%) is slightly lower than the one obtained with the homogeneous ligand N-benzyl-l-prolinol, but the polymer-supported ligand presents the advantage of its recyclability: it can be recovered and used in up to six consecutive catalytic cycles with only a slight decrease in the enantiomeric excess. The phosphinamides obtained as addition products can be transformed into the corresponding enantiomerically enriched α-branched primary amines under mild acidic conditions.

Recoverable silica-gel supported binam-prolinamides as organocatalysts for the enantioselective solvent-free intra- and intermolecular aldol reaction

Silica-gel supported binam-derived prolinamides are efficient organocatalysts for the direct intramolecular and intermolecular aldol reaction under solvent-free conditions using conventional magnetic stirring. These organocatalysts in combination with benzoic acid showed similar results to those obtained under similar homogeneous reaction conditions using an organocatalyst of related structure. For the intermolecular process, the aldol products were obtained at room temperature and using only 2 equiv of the ketone with high yields, regio-, diastereo- and enantioselectivities. Under these reaction conditions, also the cross aldol reaction between aldehydes is possible. The recovered catalyst can be reused up to nine times providing similar results. More interestingly, these heterogeneous organocatalysts can be used in the intramolecular aldol reaction allowing the synthesis of the Wieland–Miescher and ketone analogues with up to 92% ee, with its reused being possible up to five times without detrimental on the obtained results.

Copper-Free Oxime–Palladacycle-Catalyzed Sonogashira Alkynylation of Deactivated Aryl Bromides and Chlorides in Water under Microwave Irradiation

Palladium-catalyzed Heck alkynylation cross-coupling reactions between terminal alkynes and deactivated aryl chlorides and aryl bromides can be performed in the absence of copper cocatalyst with water as solvent at 130 °C under microwave irradiation. An oxime-derived chloro-bridged palladacycle is an efficient precatalyst for this transformation with 2-dicyclohexylphosphanyl-2′,4′,6′-triisopropylbiphenyl (XPhos) as ancillary ligand, pyrrolidine as base, and SBDS as surfactant. All of the reactions can be performed under air and with reagent-grade chemicals under low loading conditions (0.1–1 mol-% Pd).

Enantioselective Synthesis of Succinimides by Michael Addition of Aldehydes to Maleimides Organocatalyzed by Chiral Primary Amine-Guanidines

The monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine affords chiral primary amine-guanidines that are used as chiral organocatalysts in the enantioselective Michael addition of aldehydes, particularly α,α-disubstituted aldehydes, to maleimides. The reaction is carried out in the presence of imidazole, as an additive, in aqueous N,N-dimethylformamide, as the solvent, and affords the corresponding enantioenriched succinimides in high or quantitative yields with enantioselectivities up to 96 % ee. Theoretical calculations (DFT and M06–2X) suggest a different hydrogen-bonding coordination pattern between the maleimide (C=O) and the catalyst (NH groups) is responsible for the enantioinduction switch that is observed when the reaction is carried out using primary amine-guanidines versus primary amine-thioureas as the organocatalysts.

Enantioselective Synthesis of Succinimides by Michael Addition of 1,3-Dicarbonyl Compounds to Maleimides Catalyzed by a Chiral Bis(2-aminobenzimidazole) Organocatalyst

A wide variety of chiral succinimides have been prepared in high yields and enantioselectivities by asymmetric conjugate addition of 1,3-dicarbonyl compounds to maleimides under very mild reaction conditions using a bifunctional benzimidazole-derived organocatalyst. Computational and NMR studies support the hydrogen-bonding activation role of the catalyst and the origin of the stereoselectivity of the process.