Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents.

Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces challenges in current synthetic methods to address inefficiencies and environmental concerns. The traditional synthesis of this drug involves a process that generates a large amount of waste and other by-products that need disposal. This study presents a one-pot DES-based sustainable protocol for synthesizing atenolol. The use of the DES allowed the entire process to be conducted with no need for additional bases or catalysts, in short reaction times, under mild conditions, and avoiding chromatographic purification. The overall yield of atenolol was 95%. The scalability of the process to gram-scale production was successfully demonstrated, emphasizing its potential in industrial applications. Finally, the 'greenness' evaluation, performed using the First Pass CHEM21 Metrics Toolkit, highlighted the superiority in terms of the atom economy, the reaction mass efficiency, and the overall process mass intensity of the DES-based synthesis compared with the already existing methods.

Enantioselective Catalytic Aldol Reactions in the Presence of Knoevenagel Nucleophiles: A Chemoselective Switch Optimized in Deep Eutectic Solvents Using Mechanochemistry.

In the presence of different nucleophilic Knoevenagel competitors, cyclic and acyclic ketones have been shown to undergo highly chemoselective aldol reactions with aldehydes. In doing so, the substrate breadth for this emerging methodology has been significantly broadened. The method is also no longer beholden to proline-based catalyst templates, e.g., commercially available O-t-Bu-L-threonine is advantageous for acyclic ketones. The key insight was to exploit water-based mediums under conventional (in-water) and non-conventional (deep eutectic solvents) conditions. With few exceptions, high aldol-to-Knoevenagel chemoselectivity (>10:1) and good product profiles (yield, dr, and ee) were observed, but only in DESs (deep eutectic solvents) in conjunction with ball milling did short reaction times occur.

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.

Replacing the Z-phenyl Ring in Tamoxifen® with a para-Connected NCN Pincer-Pt-Cl Grouping by Post-Modification †.

Post-modification of a series of NCN-pincer platinum(II) complexes [PtX(NCN-R-4)] (NCN = [C6H2(CH2NMe2)2-2,6]-, R = C(O)H, C(O)Me and C(O)Et), X = Cl- or Br-) at the para-position using the McMurry reaction was studied. The synthetic route towards two new [PtCl(NCN-R-4)] (R = C(O)Me and C(O)Et) complexes used above is likewise described. The utility and limitations of the McMurry reaction involving these pincer complexes was systematically evaluated. The predicted "homo-coupling" reaction of [PtBr(NCN-C(O)H-4)] led to the unexpected formation of 3,3',5,5'-tetra[(dimethylamino)methyl]-4,4'-bis(platinum halide)-benzophenone (halide = Br or Cl), referred to hereafter as the bispincer-benzophenone complex 13. This material was further characterized using X-ray crystal structure determination. The applicability of the pincer complexes in the McMurry reaction is shown to open a route towards the synthesis of tamoxifen-type derivatives of which one phenyl ring of Tamoxifen® itself is replaced by an NCN arylplatinum pincer fragment. The newly synthesized derivatives can be used as potential candidates in anti-cancer drug screening protocols. Two NCN-arylpincer platinum tamoxifen type derivatives, 5 and 6, were successfully synthesized and of 5 the separation of the diastereomeric E-/Z-forms was achieved. Compound 6, which is the pivaloyl protected NCN pincer platinum hydroxy-Tamoxifen® derivative, was obtained as a mixture of E-/Z-isomers. The new derivatives were further analyzed and characterized with 1H-, 13C{1H}- and 195Pt{1H}-NMR, IR, exact mass MS and elemental analysis.

Enantioselective Michael Addition of Aldehydes to Maleimides Organocatalyzed by a Chiral Primary Amine-Salicylamide.

A primary amine-salicylamide derived from chiral trans-cyclohexane-1,2-diamine was used as an organocatalyst for the enantioselective conjugate addition of aldehydes, mainly α,α-disubstituted to N-substituted maleimides. The reaction was performed in toluene as a solvent at room temperature. The corresponding enantioenriched adducts were obtained with high yields and enantioselectivities up to 94%. Theoretical calculations were used to justify the stereoinduction.

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.

Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes.

The asymmetric conjugate addition of carbon and heteroatom nucleophiles to nitroalkenes is a very interesting tool for the construction of highly functionalized synthetic building blocks. Thanks to the rapid development of asymmetric organocatalysis, significant progress has been made during the last years in achieving efficiently this process, concerning chiral organocatalysts, substrates and reaction conditions. This review surveys the advances in asymmetric organocatalytic conjugate addition reactions to α,ß-unsaturated nitroalkenes developed between 2013 and early 2017.

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.

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.

Enantioselective direct aldol reaction of α-keto esters catalyzed by (S(a))-binam-D-prolinamide under quasi solvent-free conditions.

(S(a))-Binam-D-prolinamide (20 mol%), instead of (S(a))-binam-L-prolinamide, in combination with chloroacetic acid (100 mol%) is an efficient organocatalyst for the direct aldol reaction between α-keto esters as electrophiles and alkyl and α-functionalised ketones, under quasi solvent-free conditions, providing access to highly functionalised chiral quaternary γ-keto α-hydroxyesters with up to 92% ee.

New guidelines for testing "Deep eutectic solvents" toxicity and their effects on the environment and living beings.

Deep eutectic solvents (DESs) were described at the beginning of this century as an alternative to ionic liquids (ILs) in green chemistry. Despite their obvious sustainable advantages as reaction media, there is still controversy about their potential toxicity. Most of the ecotoxicity assays done up to now involving DESs are based on antibiograms. This is not a good approach due to the high density and viscosity of most DESs already described. Additionally, antibiograms do not allow continuous monitoring of neither cellular growth nor changes on physicochemical parameters like culture acidification due to cellular growth or DESs metabolization. This work starts by displaying advantages and disadvantages of the DESs toxicity assays already reported. Then, using a new DES recently described and Escherichia coli as a model microorganism, liquid cultures with continuous monitoring of pH, temperature, shaking and optical density have been used, for the first time, to quantify potential toxicity of the DES as well as the degree of the cellular tolerance (in preadapted and non-preadapted cells). The results obtained show that this new DES is not toxic for E. coli at concentrations up to 300 mM and cellular preadaptation was crucial for the cells to grow. At concentrations between 300 mM and 450 mM, cells can tolerate this DES. Above 600 mM, the DES is toxic causing complete inhibition of growth. This toxicity is not only due to the chemical composition of the DES, but also due to the high acidification of the media caused by the DES hydrolysis during cellular growth. The consequences of sterilization procedures on the DES stability are also analysed into detail, finding that sterilization by autoclave promotes DES hydrolysis. From these results, new guidelines are proposed for furthers studies aiming to characterize and quantify DESs toxicity.

Palladium Mesoionic Carbene Pre-catalyst for General Cross-Coupling Transformations in Deep Eutectic Solvents.

A strong σ-donor mesoionic carbene ligand has been synthesized and applied to four different palladium-catalyzed cross-coupling transformations, proving the catalyst/medium compatibility and the increased activity of this system over previous reports in Deep Eutectic Solvent medium. Some cross-coupling processes could be carried out at room temperature and using aryl chlorides as starting materials. The possible implementation of multistep synthesis in eutectic mixtures has also been explored. The presence of palladium nanoparticles in the reaction media has been evaluated and correlated to the observed activity.

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 (S(a))-binam-L-prolinamide in combination with benzoic acid is used as catalysts in the direct aldol reaction between cycloalkyl, alkyl, and alpha-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.

Alcohols as electrophiles in C--C bond-forming reactions: the hydrogen autotransfer process.

The hydrogen autotransfer process involves an initial oxidative hydrogen elimination, followed by different types of reactions, and is completed with a reductive hydrogen addition to give the final product. The sequence allows the alkylation of different nucleophilic agents using environmentally benign alcohols as electrophiles, mild conditions, and soft bases, with water produced as the only waste material. Recent examples of modulating the organometallic catalyst have also lent themselves to expansion of the range of available substrates, as described in this Minireview.

Organoplatinum(II) complexes as a color biomarker in solid-phase peptide chemistry and screening.

[reaction: see text] A novel organoplatinum(II) biomarker is introduced to facilitate the solid-phase screening of combinatorial libraries for substrates and inhibitors of enzymes and receptors. The robust organoplatinum(II) biomarker can be incorporated, on amine functions, in peptides using standard peptide coupling techniques. The chemistry, stability, and (reversible) coloration process with KI(3) of the organoplatinum(II) biomarker was investigated.

SPR studies of carbohydrate-protein interactions: signal enhancement of low-molecular-mass analytes by organoplatinum(II)-labeling.

The relatively insensitive surface plasmon resonance (SPR) signal detection of low-molecular-mass analytes that bind with weak affinity to a protein--for example, carbohydrate-lectin binding--is hampering the use of biosensors in interaction studies. In this investigation, low-molecular-mass carbohydrates have been labeled with an organoplatinum(II) complex of the type [PtCl(NCN-R)]. The attachment of this complex increased the SPR response tremendously and allowed the detection of binding events between monosaccharides and lectins at very low analyte concentrations. The platinum atom inside the organoplatinum(II) complex was shown to be essential for the SPR-signal enhancement. The organoplatinum(II) complex did not influence the specificity of the biological interaction, but both the signal enhancement and the different binding character of labeled compounds when compared with unlabeled ones makes the method unsuitable for the direct calculation of biologically relevant kinetic parameters. However, the labeling procedure is expected to be of high relevance for qualitative binding studies and relative affinity ranking of small molecules (not restricted only to carbohydrates) to receptors, a process of immense interest in pharmaceutical research.

Lipase active-site-directed anchoring of organometallics: metallopincer/protein hybrids.

The work described herein presents a strategy for the regioselective introduction of organometallic complexes into the active site of the lipase cutinase. Nitrophenol phosphonate esters, well known for their lipase inhibitory activity, are used as anchor functionalities and were found to be ideal tools to develop a single-site-directed immobilization method. A small series of phosphonate esters, covalently attached to ECE "pincer"-type d8-metal complexes through a propyl tether (ECE=[C6H3(CH2E)(2)-2,6]-; E=NR2 or SR), were designed and synthesized. Cutinase was treated with these organometallic phosphonate esters and the new metal-complex/protein hybrids were identified as containing exactly one organometallic unit per protein. The organometallic proteins were purified by membrane dialysis and analyzed by ESI-mass spectrometry. The major advantages of this strategy are: 1) one transition metal can be introduced regioselectively and, hence, the metal environment can potentially be fine-tuned; 2) purification procedures are facile due to the use of pre-synthesized metal complexes; and, most importantly, 3) the covalent attachment of robust organometallic pincer complexes to an enzyme is achieved, which will prevent metal leaching from these hybrids. The approach presented herein can be regarded as a tool in the development of regio- and enantioselective catalyst as well as analytical probes for studying enzyme properties (e.g., structure) and, hence, is a "proof-of-principle design" study in enzyme chemistry.

Covalently bonded platinum(II) complexes of alpha-amino acids and peptides as a potential tool for protein labeling.

Arylplatinum(II) complexes have been covalently bonded to the N and C termini and to the alpha-carbon of various amino acid derivatives. These organometallic-functionalized amino acid compounds can be converted into the corresponding free amino acids under both basic and acidic conditions; this demonstrates the excellent stability properties of these biomolecules. Due to the NMR activity displayed by the 195Pt nucleus (natural abundance 33.8%, I = 1/2) these compounds are functional bio-markers. Furthermore, the ability of the arylplatinum functional group to bind SO2 gas, selectively and reversibly as indicated by changes in the spectroscopic properties (1H, 13C, 195Pt NMR and UV spectra) of these compounds, allows for the potential use of these complexes as in vitro biosensors.