Deep Eutectic Solvents as à-la-Carte Medium for Transition-Metal-Catalyzed Organic Processes

Our society is facing a tremendous challenge to become more sustainable in every sphere of life. Regarding the chemical industry, one of the most significant issues to be addressed is the use of volatile organic compounds (VOCs) as solvents because they are petrol-derived and most of them are toxic and flammable. Among the possible solutions, deep eutectic solvents (DESs) have emerged as sustainable alternatives to VOCs in organic catalyzed transformations and other fields. The advantages of these new reaction media are not only related to their more benign physical and chemical properties and, for most of them, their renewable sources but also due to the possibility of being recycled after their use, increasing the sustainability of the catalyzed process in which they are involved. However, their use as media in catalytic transformations introduces new challenges regarding the compatibility and activity of known catalysts. Therefore, designed catalysts and “à-la-carte” DESs systems have been developed to overcome this problem, to maximize the reaction outcomes and to allow the recyclability of the catalyst/media system. Over the last decade, the popularity of these solvents has steadily increased, with several examples of efficient metal-catalyzed organic transformations, showing the efficiency of the catalysts/DES system, compared to the related transformations carried out in VOCs. Additionally, due to the inherent properties of the DES, unknown transformations can be carried out using the appropriated catalyst/DES system. All these examples of sustainable catalytic processes are compiled in this review.This research has been made possible with the financial support received from the University of Alicante (VIGROB-316FI), the Spanish Ministerio de Ciencia e Innovación (PID2021-127332NB-I00) and the Valencian Department of Innovation, Universities, Science and Digital Society (APOSTD/2020/235 and AICO/2021/013)

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.This research was supported by the Ministerio de Ciencia Innovación (MICINN: Projects CTQ2007-62771/BQU, CTQ2010-20387, and Consolider Ingenio 2010 CSD2007-00006), FEDER, the Generalitat Valenciana (Project PROMETE0/2009/039), the University of Alicante and the EU (ORCA action CM0905). A.B.C. thanks the Spanish ME for a predoctoral fellowship (FPU AP2009-3601)

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%.This work was financially supported by the Ministerio de Economia y Competitividad (MINECO: Projects: CTQ2010-20387 and Consolider INGENIO CSD2007-0006), FEDER, the Generalitat Valenciana (Prometeo/2009/039), the University of Alicante and the EU (ORCA action CM0905)

Bio-renewable enantioselective aldol reaction in natural deep eutectic solvents

Among the deep eutectic solvents (DES), natural deep eutectic solvents (NADES) formed by D-glucose and racemic malic acid are suitable media to perform the enantioselective L-proline catalyzed intermolecular aldol reaction, creating simultaneously and selectively a C–C bond and a new stereocenter. The scope of the reaction was found to be broad, with products being obtained with good levels of diastereo- and enantioselectivities. Furthermore, when the reaction was performed at a large scale, the catalyst together with the reaction media can be recovered by simple water extraction and reused at least three times affording similar results. Therefore, the use of NADES as reaction media to carry out a VOC-free selective process has been demonstrated for the first time. The process is clean, cheap, simple and scalable and meets most of the criteria to be considered as a sustainable and bio-renewable process, with the reaction media and catalyst arising directly from Nature.This work was supported by the University of Alicante (VIGROB-173 and UAUSTI13-09)

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.This work was financially supported by the Ministerio de Economia y Competitividad (MINECO: Projects: CTQ2010-20387 and Consolider INGENIO CSD2007-0006), FEDER, the Generalitat Valenciana (Prometeo/2009/039, the University of Alicante and the EU (ORCA action CM0905). A.B.-C. thanks the Spanish MICINN for a predoctoral fellowship (FPU AP2009-3601)

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.This work was financially supported by the Ministerio de Economia y Competitividad (MINECO: Projects: CTQ2010-20387 and Consolider INGENIO CSD2007-0006), FEDER, the Generalitat Valenciana (Prometeo/2009/039), the University of Alicante, and the EU (ORCA action CM0905)

Indium-mediated allylation of carbonyl compounds in deep eutectic solvents

This study describes, for the first time, the in situ generation of indium organometallic reagents in environmentally friendly deep eutectic solvents (DESs). The allylation process of different carbonyl compounds is achieved mediated by indium metal and using cheap allyl chloride derivatives. The unique DES properties allow to perform the reaction at room temperature and under air, obtaining yields ranging from 45% to 99%. It is possible to recycle the reaction medium for at least four consecutive cycles without much decrease of the observed results. Also, a linear correlation between the yield of the reaction and the density of the DESs is observed.This work was supported by the University of Alicante (VIGROB-316FI and VIGORB20-170) and the Spanish Ministerio de Economia, Industria y Competitividad (PGC2018-096616-B-100). NGG and BS thank Generalitat Valenciana (ACIF/2020/186 and ACIF/2017/211, respectively) for their fellowships

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.We thank the financial support from the Spanish Ministerio de Economía y Competitividad (MINECO, Projects CTQ2010-20387 and Consolider Ingenio 2010, CSD2007-00006), FEDER, the Generalitat Valenciana (Prometeo/2009/039), the University of Alicante and the European Commission (ORCA action CM0905). A.B.-C. thanks Spanish MINECO for a predoctoral fellowship (FPU AP2009-3601)

Deep Eutectic Solvents as Reaction Media for the Palladium-Catalysed C−S Bond Formation: Scope and Mechanistic Studies

A unique jigsaw catalytic system based on deep eutectic solvents and palladium nanoparticles where C−S bonds are formed from aryl boronic acids and sodium metabisulfite, is introduced. The functionalization step is compatible with a broad spectrum of reagents such as nucleophiles, electrophiles or radical scavengers. This versatile approach allows the formation of different types of products in an environmentally friendly medium by selecting the components of the reaction, which engage one with another as pieces in a jigsaw. This simple procedure avoids the use of toxic volatile organic solvents allowing the formation of complex molecules in a one-pot reaction under mild conditions. Despite the fact that only 1 mol % of metal loading is used, the recyclability of the catalytic system is possible. Kinetic experiments were performed and the reaction order for all reagents, catalyst and ligand was determined. The obtained results were compared to palladium nanocrystals of different known shapes in order to shed some light on the properties of the catalyst.This work was supported by the University of Alicante (UAUSTI16-10, VIGROB-173), and the Spanish Ministerio de Economía, Industria y Competitividad (CTQ2015-66624-P). X.M. thanks Generalitat Valenciana (ACIF/2016/057) for fellowship

Visible-Light-Mediated Amide Synthesis in Deep Eutectic Solvents

In the present study, for the first time environmentally friendly deep eutectic solvents (DESs) are used as reaction media to perform an efficient, simple and straightforward photocatalytic amide synthesis at room temperature using thioacids and amines. This method features mild conditions, a broad substrate scope, high yields (≤99%) under ambient conditions with air and moisture tolerance. Moreover, the applied operationally mild reaction conditions tolerate the presence of several different functional group substituents on the amine counterpart. Finally, the developed approach allows the recycling of the reaction medium and catalyst for at least three consecutive cycles without a significant decrease in the reaction yield.This research has been made possible thanks to the financial support received from the University of Alicante (VIGROB-316FI), the Spanish Ministerio de Ciencia e Innovación (PID2021-127332NB-I00) and the Valencian Department of Innovation, Universities, Science and Digital Society (APOSTD/2020/235 and AICO/2021/013). The authors thank the Department of Pharmacy, Health and Nutritional Sciences (Department of Excellence funded according to the Law 232/2016) of the University of Calabria (Italy)