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.

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.

Recent Advances in the Catalytic Enantioselective Reformatsky Reaction

This paper reviews the present state of the catalytic enantioselective Reformatsky reaction. Advancements in asymmetric versions of this reaction have recently led to a considerable extension of its scope and applicability, principally due to the use of highly active chiral ligands and very specific reaction conditions.

Solvent-Free Enantioselective Friedländer Condensation with Wet 1,1′-Binaphthalene-2,2′-diamine-Derived Prolinamides as Organocatalysts

Wet unsupported and supported 1,1′-binaphthalene-2,2′-diamine (BINAM) derived prolinamides are efficient organocatalysts under solvent-free conditions at room temperature to perform the synthesis of chiral tacrine analogues in good yields (up to 93%) and excellent enantioselectivies (up to 96%). The Friedländer reaction involved in this process takes place with several cyclohexanone derivatives and 2-aminoaromatic aldehydes, and it is compatible with the presence of either electron-withdrawing or electron-donating groups at the aromatic ring of the 2-aminoaryl aldehyde derivatives used as electrophiles. The reaction can be extended to cyclopentanone derivatives, affording a regioisomeric but separable mixture of products. The use of the wet silica gel supported organocatalyst, under solvent-free conditions, for this process led to the expected product (up to 87% enantiomeric excess), with its reuse being possible at least up to five times.

Solvent-Free Enantioselective Organocatalyzed Aldol Reactions

The use of proline as catalyst for the aldol process has given a boost to the development of organocatalysis as a research area. Since then, a plethora of organocatalysts of diverse structures have been developed for this and other organic transformations under different reaction conditions. The use of an organic molecule as catalyst to promote a reaction meets several principles of Green Chemistry. The implementation of solvent-free methodologies to carry out the aldol reaction was soon envisaged. These solvent-free processes can be performed using conventional magnetic stirring or applying ball milling techniques and are even compatible with the use of supported organocatalysts as promoters, which allows the recovery and reuse of the organocatalysts. In addition, other advantages such as the reduction of the required amount of nucleophile and the acceleration of the reaction are accomplished by using solvent-free conditions leading to a “greener” and more sustainable process.

Enantioselective aldol reactions with aqueous 2,2-dimethoxyacetaldehyde organocatalyzed by binam-prolinamides under solvent-free conditions

Aqueous 2,2-dimethoxyacetaldehyde (60% wt solution) is used as an acceptor in aldol reactions, with cyclic and acyclic ketones and aldehydes as donors, organocatalyzed by 10 mol % of N-tosyl-(Sa)-binam-l-prolinamide [(Sa)-binam-sulfo-l-Pro] at rt under solvent-free conditions. The corresponding monoprotected 2-hydroxy-1,4-dicarbonyl compounds are obtained in good yields and with high levels of diastereo- and enantioselectivity mainly as anti-aldols. In the case of 4-substituted cyclohexanones a desymmetrization process takes place to mainly afford the anti,anti-aldols. 2,2-Dimethyl-1,3-dioxan-5-one allows the synthesis of a useful intermediate for the preparation of carbohydrates in higher yield, de and ee than with l-Pro as the organocatalyst.

Chiral rhodium complexes covalently anchored on carbon nanotubes for enantioselective hydrogenation

Chiral rhodium hybrid nanocatalysts have been prepared by covalent anchorage of pyrrolidine-based diphosphine ligands onto functionalized CNTs. This work constitutes the first attempt at covalent anchoring of homogeneous chiral catalysts on CNTs. The catalysts, prepared with two different chiral phosphines, were characterized by ICP, XPS, N2 adsorption and TEM, and have been tested in the asymmetric hydrogenation of two different substrates: methyl 2-acetamidoacrylate and α-acetamidocinnamic acid. The hybrid nanocatalysts have shown to be active and enantioselective in the hydrogenation of α-acetamidocinnamic acid. A good recyclability of the catalysts with low leaching and without loss of activity and enantioselectivity was observed.

Efficient Diastereo- and Enantioselective Synthesis of exo-Nitroprolinates by 1,3-Dipolar Cycloadditions Catalyzed by Chiral Phosphoramidite⋅Silver(I) Complexes

Chiral complexes formed by privileged phosphoramidites and silver triflate or silver benzoate are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides generated from α-amino acid-derived imino esters and nitroalkenes affording with high dr the exo-cycloadducts 4,5-trans-2,5-cis-4-nitroprolinates in high ee at room temperature. In general, better results are obtained using silver rather than copper(II) complexes. In many cases the exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. The mechanism and the justification of the experimentally observed stereodiscrimination of the process are supported by DFT calculations. These enantiomerically enriched exo-nitroprolinates can be used as reagents for the synthesis of nitropiperidines, by ester reduction and ring expansion, which are inhibitors of farnesyltransferase.

Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantio­selective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the N-Tosyl-(S a)-binam-l-prolinamide-Organocatalyzed Aldol Reaction

N-Tosyl-(S a)-binam-l-prolinamide is an efficient catalyst for the aqueous aldol reaction between ketones and glyoxylic acid, as the monohydrate or as an aqueous solution, or a 50% toluene solution of ethyl glyoxylate. These reactions led to the formation of chiral α-hydroxy-γ-keto carboxylic acids and esters in high levels of diastereo- and enantioselectivities (up to 97% ee), providing mainly anti aldol products. Only cyclopentanone and cyclohexane-1,4-dione afforded an almost 1:1 mixture of the syn/anti-diastereoisomers; however, the reaction between 4-phenylcyclohexanone and ethyl glyoxylate gave the corresponding syn,syn-product as the major diastereoisomer.

Aqueous Enantioselective Aldol Reaction of Methyl- and Phenylglyoxal Organocatalyzed by N-Tosyl-(S a)-binam-l-prolinamide

The direct aldol reaction between methylglyoxal (40% aqueous solution) or phenylglyoxal monohydrate and ketones or aldehydes is catalyzed by N-tosyl-(S a)-binam-l-prolinamide to afford the corresponding chiral γ-oxo-β-hydroxy carbonyl compounds, mainly as anti isomers with enantioselectivities up to 97%.

Enantioselective Synthesis of exo-4-Nitroprolinates from Nitro­alkenes and Azomethine Ylides Catalyzed by Chiral Phosphor­amidite·Silver(I) or Copper(II) Complexes

Chiral complexes formed by privileged phosphoramidites derived from chiral binol and optically pure Davies’ amines, and copper(II) triflate, silver(I) triflate or silver(I) benzoate are excellent catalysts for the general 1,3-dipolar cycloaddition between nitroalkenes and azomethine ylides generated from α-amino acid derived imino esters. These three methods can be conducted at room temperature to afford the exo-cycloadducts (4,5-trans-2,5-cis-4-nitroprolinates) with high diastereoselectivity and high enantioselectivity. In general, the three procedures are complementary but silver catalysts are more versatile and less sensitive to sterically congested starting materials.

Pyrimidine-Derived Prolinamides as Recoverable Bifunctional Organocatalysts for Enantioselective Inter- and Intramolecular Aldol Reactions under Solvent-Free Conditions

Chiral L-prolinamides 2 containing the (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine scaffold and a 2-pyrimidinyl unit are synthesized and used as general organocatalysts for intermolecular and intramolecular aldol reactions with 1,6-hexanedioic acid as a co-catalyst under solvent-free conditions. The intermolecular reaction between ketone–aldehyde and aldehyde–aldehyde must be performed under wet conditions with catalyst (S,S)-2b at 10 °C, which affords anti-aldols with high regio-, diastereo-, and enantioselectivities. For the Hajos–Parrish–Eder–Sauer–Wiechert reaction, both diastereomers of catalyst 2 give similar results at room temperature in the absence of water to give the corresponding Wieland–Miescher ketone and derivatives. Both types of reactions were scaled up to 1 g, and the organocatalysts were recovered by extractive workup and reused without any appreciable loss in activity. DFT calculations support the stereochemical results of the intermolecular process and the bifunctional role played by the organocatalyst by providing a computational comparison of the H-bonding networks occurring with catalysts 2a and 2b.

Binap-silver-catalyzed enantioselective multicomponent 1,3-dipolar cycloaddition of azomethines ylides derived from ethyl glyoxylate

The enantioselective binap–silver catalyzed multicomponent 1,3-dipolar cycloaddition using ethyl glyoxylate, phenylalanine ethyl ester, and maleimides is described. The employment of basic silver carbonate allows the reaction to take place in the absence of an extra base giving high yields and ee. In addition, low-level calculations regarding the importance of the benzyl substituent at the α-position of the amino ester justify the expected absolute configuration of the final cycloadducts and the observed high enantiodiscrimination.

Enantioselective Solvent-Free Synthesis of 3-Alkyl-3-hydroxy-2-oxoindoles Catalyzed by Binam-Prolinamides

BINAM-prolinamides are very efficient catalyst for the synthesis of non-protected and N-benzyl isatin derivatives by using an aldol reaction between ketones and isatins under solvent-free conditions. The results in terms of diastereo- and enantioselectivities are good, up to 99% de and 97% ee, and higher to those previously reported in the literature under similar reaction conditions. A high variation of the results is observed depending on the structure of the isatin and the ketone used in the process. While 90% of ee and 97% ee, respectively, is obtained by using (Ra)-BINAM-l-(bis)prolinamide as catalyst in the addition of cyclohexanone and α-methoxyacetone to free isatin, 90% ee is achieved for the reaction between N-benzyl isatin and acetone using N-tosyl BINAM-l-prolinamide as catalyst. This reaction is also carried out using a silica BINAM-l-prolinamide supported catalyst under solvent-free conditions, which can be reused up to five times giving similar results.