Palladium and organocatalysis: an excellent recipe for asymmetric synthesis

The dual activation of simple substrates by the combination of organocatalysis and palladium catalysis has been successfully applied in a variety of different asymmetric transformations. Thus, the asymmetric a-allylation of carbonyl compounds, a-fluorination of acyl derivatives, decarboxylative protonation of β-dicarbonyl compounds, cyclization reactions of alkynyl carbonyl compounds and β-functionalization of aldehydes have been efficiently achieved employing this double-catalytic methodology.

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.

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.

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.

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.

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.

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%.

Bis(2-aminobenzoimidazole)-Organocatalyzed Asymmetric Alkylation of Activated Methylene Compounds with Benzylic and Allylic Alcohols

The first organocatalyzed asymmetric alkylation of activated methylene compounds using benzylic and allylic alcohols as alkylating agents through dual hydrogen bond activation in an SN1-type reaction is reported. This green protocol employs a bis(2-aminobenzoimidazole) in combination with an achiral Brønsted acid as a bifunctional catalytic system and gives the alkylation products with moderate to good enantioselectivities. Although the scope of the reaction is limited, this methodology can be considered as complementary to existing metal-catalyzed processes. In addition, modest results were obtained in a first attempt to perform a metal-free asymmetric Tsuji–Trost reaction using allylic alcohols. Finally, the recovery and reusability of the organocatalyst is also achieved.

Solvent-dependent enantioswitching in the Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by mono-N-Boc-protected cyclohexa-1,2-diamines

Enantiomerically pure mono-N-Boc-protected trans-cyclohexa-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. Using a single enantiomer of the organocatalyst, both enantiomeric forms of the resulting Michael adducts bearing a new quaternary stereocenter are obtained in high yields, by only changing the reaction solvent from chloroform (up to 86% ee) to aqueous DMF (up to 84% ee).

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.