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Scalable asymmetric synthesis of non-proteinogenic (S)-aminoacids and their derivatives based on an organocatalyzed Mannich-type reaction involving allomaltol applicable to subsequent RuIII-catalyzed oxidative cleavage has been developed.

This highlight gives an overview of recent advances in production of crystalline materials for high energy density applications for rechargeable batteries and solar cells or energetic compounds in supercritical carbon dioxide medium.

A bifunctional tertiary amine-squaramide-catalyzed enantioselective Mannich-type addition of available allomaltol to

Proline-histidine dipeptide laid the foundation for the construction of three new ion-tagged organocatalysts, utilising the imidazole moiety of histidine for generating the quaternary species. A brief comparative investigation of the catalysts in the enamine-mediated direct asymmetric aldol reaction brought out their contrasting features, particularly under aqueous conditions. The best among them was also utilised in preparing some derivatives and effecting a desymmetrisation.

Three-component Strecker reaction of aldehydes, amines and KCN has been performed for the first time in supercritical carbon dioxide. In the proposed procedure non-toxic and non-flammable carbon dioxide acts not only as an environmentally benign reaction medium but also as the reaction promoter via in situ formation of carbonic acid which provides a gradual release of the true cyanating agent (HCN) from available KCN. The reaction conditions (pressure, temperature, concentrations of reagents) were optimized, and various aromatic and aliphatic amines and aldehydes were transformed into valuable α-amino nitriles including perspective pharmacological substances. The equimolar amount of used cyanogen reagent, carrying out the process in a sealed autoclave in ‘green’ solvent medium under mild conditions (90 bar, 35 °C) along with the high yields of products and the scalability of the developed procedure make it suitable for sustainable industrial applications.

2-Nitroallylic carbonates, a new class of "green" 1,3-bielectrophilic reagents for organic synthesis and catalysis, have been prepared. The bifunctional tertiary amine-catalyzed asymmetric [3 + 3] annulations of cyclic enols with these reagents occur much faster than corresponding reactions with 2-nitroallylic esters and produce no acidic by-products poisoning the catalyst. Furthermore, 2-nitroallylic carbonates enable highly enantioselective one-pot synthesis of a variety of fused dihydropyrane derivatives from available precursors bearing pharmacophoric fragments.

A convenient synthesis of chiral N-nitro-oxazolidin-2-ones by nitration of α-amino acid derived 1,3-oxazolidin-2-ones containing one or two stereogenic centers with dinitrogen pentoxide in liquefied 1,1,1,2-tetrafluoroethane medium has been developed. The obtained N-nitroheterocycles were converted into enantiomerically pure O-(β-nitraminoalkyl) carbamates by treatment with ammonia or amines in the same solvent. The synthesized N-nitro compounds are slightly toxic in vitro to Human Embryonic Kidney 293 (HEK293) cells.

Liquid and supercritical CO2 and TFE have been systematically studied as media for CL-20 recrystallization to estimate their potential for the selective preparation of ultrafine particles. It has been found that the polymorphic composition of produced microcrystals can be efficiently controlled by the alteration of the solvent system and the micronization method used. Thus, the application of CO2 as an anti-solvent in both SAS and GAS methods results in the formation of α-CL-20–CO2 solvates, regardless of the process conditions. The use of TFE as an active medium for the GAS and RESS methods allows for selective preparation of uniform ultrafine β- or e-CL-20 particles under mild conditions. The developed e-CL-20 production method favorably differs from the known analogues by its tolerance to the quality of the initial substrate (crude CL-20), increased environmental and industrial safety, ease of product isolation, and the ability to control the particle morphology and crystalline phase.

Screening of four Buchwald ligands for the cross-coupling of isomeric di-, tri- and tetrachlorobenzenes with arylboronic acids revealed that good yields of exhaustive substitution can be best provided by 2-dicyclohexylphosphino-2′-(dimethylamino) biphenyl (DavePHOS).

Regardless of the sustainable development path, today, there are highly demanded chemical productions still operating that bear environmental and technological risks inherited from the previous century. The fabrication of nitro compounds, and nitroarenes in particular, is traditionally associated with acidic wastes formed in nitration reactions exploiting mixed acids. However, nitroarenes are indispensable for industrial and military applications. We faced the challenge and developed a greener, safer, and yet effective method for the production of nitroaromatics. The proposed approach comprises the application of an eco-friendly nitrating agent, namely dinitrogen pentoxide (DNP), in the medium of liquefied 1,1,1,2-tetrafluoroethane (TFE) – one of the most non-hazardous Freons. Importantly, the used TFE is not emitted into the atmosphere but is effortlessly recondensed and returned into the process. DNP is obtained via the oxidation of dinitrogen tetroxide with ozone. The elaborated method is characterized by high yields of the targeted nitro arenes, mild reaction conditions, and minimal amount of easy-to-utilize wastes.

Asymmetric aldol reactions of isatin and 4,6-dibromoisatin with acetone are efficiently catalyzed by β-amino alcohols derived from α-pinene and 3-carene. The target compounds can be isolated by crystallization from toluene, which eliminates the need for using chromatography and makes the asymmetric synthesis of (R)-convolutamydine A (up to 94% ee and yield 75%) simple and convenient.

A correlation between the equilibrium ratio of tautomeric products generated by the asymmetric Michael reactions of cyclic carbon acids with β,γ-unsaturated α-keto esters and the chemical shift of ...

A very simple and highly efficient C2-symmetric tertiary amine-squaramide organocatalyst for asymmetric Michael reactions has been elaborated. In the presence of only 1 mol % of this catalyst, kojic acid derivatives and β-dicarbonyl compounds reacted with nitroolefins, affording the corresponding adducts in a nearly quantitative yield with an enantioselectivity up to 99% ee. The kojic acid-derived adducts could be efficiently produced under "green" conditions (in 96% EtOH or pure water). Moreover, due to the very low solubility in organic solvents, the developed nonsupported catalyst could be readily recovered and reused in catalytic reactions up to 7 times. Utmost availability (one-step synthesis without chromatographic purification), high level of stereoinduction, low efficient loading, and recyclability make it attractive for industrial application in the pharmaceutical industry.

The first ever installation for continuous nitration in a liquefied gas mobile phase was developed. The installation was used to convert 2-ethylhexan-1-ol, diethylene glycol, and glycerol into their corresponding nitro esters. The starting compounds were treated with a 10% excess of dinitrogen pentoxide in liquefied 1,1,1,2-tetrafluoroethane (TFE) medium. The flow reactions proceeded at room temperature and ≤10 bar pressure with excellent conversion and selectivity. An important feature of the developed procedure is TFE recycling which prevents its release into the atmosphere. The proposed approach for nitro esters flow production outperforms the known batch-type analogs in terms of having a far better specific productivity (by two orders of magnitude), reduced fire and explosion risks, and less pronounced negative impact on the environment. The enumerated advantages along with equipment availability lay the foundation for the development of a highly efficient nitration technology, which is characterized by reduced amounts of waste by employing a TFE medium.

The continuous need for energetic materials with increased performance and improved safety characteristics stimulates synthetic efforts as well as physical modification of existing compounds. The present study reports the fabrication of 1,3,5,7-tetranitro-1,3,5,7-tetrazoctane (HMX)-based composites with common commercial polymers, polymethyl acrylate (PMA), acrylonitrile butadiene styrene rubber (ABS), ethyl cellulose (EC), polylactide (PLA), and polyethylene terephthalate glycol (PETG). To precipitate the polymer on the HMX particles, the supercritical CO2-based anti-solvent method was employed. Surface state studies with various modes of scanning probe microscopy show that the polymers at less than 3 wt% content do not form a continuous layer but precipitate as globular islands. Nevertheless, the coating effectively absorbs the mechanical stress, resulting in a much lower sensitivity to impact and a considerable improvement of the HMX friction sensitivity. Specifically, for HMX@3PMA composite the impact and friction sensitivities are 54 J and 240 N, as compared to 7 J and 150 N for neat HMX. Additionally, the beneficial improvement of flowability is observed for the fabricated composites, and evidenced by small-scale flow cup studies. Importantly, the suggested procedure affords the safe and easy-to-handle energetic material powder containing only 1–3 wt% of the polymer additive.

Simple C2-symmetric chiral tertiary amines bearing squaramide fragments along with the 1,2-di(pyridin-2-yl)ethane spacer group have been synthesized. Among them, amine 8b with a different configuration of stereocenters in 1,2-di(pyridin-2-yl)ethane and 1,2-diaminocyclohexane units efficiently catalyzed asymmetric additions of β-dicarbonyl compounds to nitroolefins and domino reaction of ortho-(tosylamino)chalcone with β-nitrostyrene in wet (20 equiv. of H2O) DCM, affording corresponding adducts in up to 99% yield and 94% ee. The developed procedure is scalable. Due to poor solubility in organic solvents and water, the catalyst could be readily separated from the reaction mixture and over 10 times reused in the reaction without compromising enantiomeric enrichment and yield of product.

An efficient synthesis of [1,2,5]oxadiazolo[3,4-d]pyridazine 1,5,6-trioxides (1) from 3,4-bis(hydroxyimino)methyl)-1,2,5-oxadiazole 2-oxides using a mixture of concentrated nitric and trifluoroacetic acids has been developed. The scope of the unconventional reaction was established. The 4,7-dinitro[1,2,5]oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide 1f represents a new high energy compound, unfortunately with low thermal stability. The parent [1,2,5]oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide 1c was studied by single-crystal X-ray diffraction analysis which revealed a planar molecule with an unusually long intracyclic N N bond of 1.668(5) A and unexpected exo-cyclic bond angles at the nitroxyl nitrogen atoms. In the crystal, the molecules of 1c are bound to each other by strong π-π stacking and C H⋯O hydrogen bonding interactions into a three-dimensional framework that results in a high crystal density of 1.833 gcm−3.

A highly efficient, safe, and sustainable procedure was developed for the synthesis of various pharmacology-relevant and/or energy-rich nitroesters. It is based on nitration of corresponding alcohols with dinitrogen pentoxide in the liquid 1,1,1,2-tetrafluoroethane medium. The proposed approach is attractive for commercial applications because it offers significant advantages such as mild and clean reaction conditions, low operation pressure, available equipment, scalability, and facile fluid recycling. Structure–NO donor activity correlations were elucidated by an in vitro Griess assay for synthesized nitroesters and the obtained data may be useful for further in vivo experiments.

Novel C2-symmetric N,N'-bis(2-amino-1,2-diphenylethyl)squaramides with 1,2-di(pyridin-2-yl)ethane and 1,2-diphenylethane spacer groups were designed and applied as organocatalysts in asymmetric additions of 4-hydroxycoumarin and 4-hydroxy-6-methyl-2H-pyran-2-one to α,β-unsaturated ketones. Both enantiomers of the anticoagulant warfarin and its analogs were prepared in up to 96% yield and with 96% ee. Recyclability of the developed catalysts and synthetic utility of the prepared Michael adducts for asymmetric synthesis of potential chiral medications via acylation reactions were demonstrated.

Novel pseudo-enantiomeric bifunctional tertiary amine-squaramides modified with long-chained alkoxy or polyfluoroalkoxy groups, have been synthesized. They catalyzed the asymmetric double-Michael cascade reactions of o-N-tosylaminophenyl α,β-unsaturated ketones with α-nitroolefins in carbon dioxide medium at significantly lower pressure (75 bar) and temperature (35 °C), than known less lipophilic catalysts. Both enantiomers of the pharmacologically valuable methoxy-substituted tetrahydroquinoline derivatives can be prepared in moderate to high yield with promising enantioselectivity (up to 98% ee) under the optimized conditions.

An efficient sterically hindered C2-symmetric bifunctional tertiary amine-squaramide organocatalyst for the asymmetric Michael addition/hemiketalization domino reaction of kojic acid derivatives with β,γ-unsaturated α-ketoesters has been designed. Pharmacology-relevant functionalized 2,3,4,8-tetrahydropyrano[3,2-b]pyran derivatives were produced over the catalyst in as low as 1 mol% with up to 99% yield and 99% ee. The procedure is at least 30-fold scalable and the catalyst is readily reusable in the catalytic reaction via acid-base extraction. Acylation of the products with (S)- or rac-ibuprofen and with undec-10-enoic acid afforded the corresponding chiral esters containing two privileged pharmacophoric motifs.

Simple enantiomerically pure C2-symmetric quinoline (isoquinoline)-derived 1,2-diamines were synthesized from the corresponding aldehydes via stereospecific diaza-Cope rearrangement with 2,2′-(1,2-diaminoethane-1,2-diyl)diphenol (HPEN). Efficient green synthesis of both enantiomers of the anticoagulant Warfarin and rodenticide Coumachlor was achieved in an aqueous medium via the asymmetric iminium-type Michael reaction in the presence of the catalysts 8e and (ent)-8e in combination with (R)- or (S)-mandelic acid, respectively. This procedure provides high enantioselectivity (up to 91% ee), which has never been attained for these bioactive compounds with the known catalysts under aqueous conditions. Nearly optically pure Warfarin (∼99% ee) was prepared via a green isolation procedure, which included acidic precipitation of the crude product from a basic aqueous solution followed by single recrystallization. Furthermore, unlike the known primary amine-derived organocatalysts, the developed aqueous catalytic system does not produce parasitic byproducts and can be recovered and reused in the asymmetric reaction.

The enantiomers (up to 99% ee) of both geraniol- and nerol-derived 2-cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid, the active ingredient of the wound healing medication Cygerol, were prepared via a low-temperature alkylation, basic hydrolysis, derivatization with (S)-4-benzyloxazolidin-2-one and chromatographic separation steps. The absolute configuration of stereocenters in the antipodes having an (E)- or (Z)-geometry of the internal double bond was determined based on characteristic 1H NMR signals of the corresponding (S)-4-benzyloxazolidin-2-one-derived imides and on conversion to the known diethyl (S)-2-cyclohexylsuccinate and (S)-2-cyclohexylbutane-1,4-diol with reported specific rotations.

Current trends and characteristic examples of recent advances in syntheses of practically important compounds bearing semi-polar nitrogen–oxygen bonds (NO-systems) are considered. Their applications for the preparation of pharmaceutically relevant molecules, energetic materials and some other useful products are briefly discussed with a focus on original reports published in the period 2015–2017.

Organic systems still dominate several traditional areas of chemical science and well-known applications, such as the synthesis of pharmaceutical compounds and drugs. However, a fascinating trend has appeared recently to combine pure organic systems into advanced molecular architectures and to create hybrid molecular systems. These interdisciplinary areas, where possible connections between organic and hybrid systems may be developed, are the focus of the present review to develop valuable practical applications.

The undesirable side-processes responsible for the fast deactivation of primary amino acid derived organocatalysts in asymmetric aldol reactions are identified. A new ionic-liquid-supported (S)-valine-/(S)-α,α-diphenylserinol-derived catalyst (9) is designed on the basis of these results and exhibits much better recyclability in asymmetric syn-aldol reactions between hydroxyacetone and aldehydes. Furthermore, this catalyst appeared to be useful for the stereoselective synthesis of the naturally occurring 1(3H)-isobenzofuran-1-one scaffold through an asymmetric syn-aldol/lactonization cascade reaction.

Chiral tertiary amine-derived ionic liquid-supported squaramide was synthesized from available precursors and applied as an efficient organocatalyst for asymmetric Michael additions of β-dicarbonyl compounds to α-nitroolefins in the presence of water. Corresponding Michael adducts were generated under proposed conditions in nearly quantitative yield with high enantioselectivity (up to 99% ee). Useful precursors to pharmaceutically important chiral β-amino acids and anticonvulsant Pregabalin were conveniently prepared using the developed “on water” protocol. The catalyst is readily recoverable and reusable over 30 times without a significant decrease of catalytic reaction activity and selectivity.

The Nazarov reaction (cyclization) is one of the most useful synthetic tools for the stereoselective preparation of various cyclopentenone scaffolds. This review summarizes recent applications of this reaction to the synthesis of natural compounds and their usefulness to pharmacology analogs published over 2005-2016. Modern protocols for the facile generation of key cationic intermediates and efficient catalytic, in particular asymmetric, versions of Nazarov cyclization are considered. Available literature data are for the first time classified according to the chemical structures of the products, which include relatively simple non-annulated functionalized cyclopentenoids and complex polynuclear cyclopentenone derivatives annulated with one or more non-aromatic, aromatic or heteroaromatic rings. This classification is convenient for specialists in organic synthesis and for researchers working in the area of medicinal and biomolecular chemistry.

A correlation between the equilibrium ratio of tautomeric products generated by the asymmetric Michael reactions of cyclic carbon acids with β,γ-unsaturated α-keto esters and the chemical shift of the α-proton in starting nucleophilic substrates was revealed which makes equilibration predictable. New tetrahydropyran-fused benzo[

The prevalence of nitrogen containing heterocycles in natural products and pharmaceuticals is a doubtless fact. In this review, recent applications of a stereoselective aza-Michael reaction as an efficient tool for the asymmetric synthesis of naturally occurring nitrogen-containing heterocyclic scaffolds and their usefulness to pharmacology are reviewed and summarized. The available data are for the first time classified according to types of heterocyclic products and subdivided in accordance with synthetic methodologies used as key stereocontrolling steps (diastereoselective or enantioselective reactions, single bond-forming or cascade reactions, etc.). This classification is convenient for organic chemists and for researchers working in the areas of natural product synthesis and medicinal chemistry. Specific attention is paid to organocatalytic asymmetric versions of the aza-Michael reaction developed over the past decade.

Novel di- and tetra(pyrazolyl)bipyridine ligands have been prepared from available bipyridine N-oxide and N,N′-dioxide nitro derivatives via nucleophilic substitution reactions. The ligands were converted to the corresponding homoleptic octahedral cobalt (II) complexes with PF6− anions which are of interest as potential redox components for electrochemical applications.

A convenient one-pot synthesis of primary aliphatic N-nitramines, which includes the nitration of available N,N′-dialkyloxalamides or N-alkylcarbamates with dinitrogen pentoxide in the 1,1,1,2-tetrafluoroethane media followed by ammonolysis of intermediate N-nitroamides in the same solvent has been developed. The method is environmentally safe, and affords target N-nitramines in up to 94% overall yield.

A short and efficient synthesis of 1-(2-oxido-1,2,5-oxadiazol-3-yl)alkyl nitrates from 3-alkyl-1,2,5-oxadiazole 2-oxides, using a mixture of nitric and sulfuric acids in chloroform, has been developed. The scope of the unconventional reaction was established; its mechanism likely included a new Grob-type fragmentation.

The rapid development of organic chemistry and catalysis has provided outstanding chemical tools to build complex molecular architectures that were never possible before. In spite of amazing progress in studying individual molecules and reactions, practical applications are limited due to the high cost of newly developed technologies and the difficulty in understanding the processes at the molecular level. Herein, we summarize our first steps and experiences carrying out an ongoing project on organic and hybrid molecular systems that highlights new fascinating opportunities and identifies future challenges.

A convenient protocol for the synthesis of natural isoprenoid-derived carboxylic esters via reaction of allylic terpenols with triethyl orthoacetate (propionate) in the presence of 1-butyl-3-methylimidazolium hexafluorophosphate, [bmim][PF6] (10 mol%), has been developed. The desired terpene derivatives were prepared in moderate to high yield. The ionic liquid (IL) can be easily separated from the products and repeatedly used up to ten times without reduction in the product yield. Experimental data evidence that HF, generated in situ from the IL, most likely acts as a true catalyst in the Johnson–Claisen rearrangement.

A primary amine-based aqueous ionic liquid-supported recyclable catalytic system for asymmetric Michael addition of aldehydes to maleimides has been developed. The best enantioselectivity (up to 84% ee ) was attained at the [bmim]BF 4 /water 2 : 1 (v/v) ratio.

An efficient sterically hindered C2-symmetric bifunctional tertiary amine-squaramide organocatalyst for the asymmetric Michael addition/hemiketalization domino reaction of kojic acid derivatives with β,γ-unsaturated α-ketoesters has been designed. Pharmacology-relevant functionalized 2,3,4,8-tetrahydropyrano[3,2-b]pyran derivatives were produced over the catalyst in as low as 1 mol% with up to 99% yield and 99% ee. The procedure is at least 30-fold scalable and the catalyst is readily reusable in the catalytic reaction via acid-base extraction. Acylation of the products with (S)- or rac-ibuprofen and with undec-10-enoic acid afforded the corresponding chiral esters containing two privileged pharmacophoric motifs.

Novel C2-symmetric N,N'-bis(2-amino-1,2-diphenylethyl)squaramides with 1,2-di(pyridin-2-yl)ethane and 1,2-diphenylethane spacer groups were designed and applied as organocatalysts in asymmetric additions of 4-hydroxycoumarin and 4-hydroxy-6-methyl-2H-pyran-2-one to α,β-unsaturated ketones. Both enantiomers of the anticoagulant warfarin and its analogs were prepared in up to 96% yield and with 96% ee. Recyclability of the developed catalysts and synthetic utility of the prepared Michael adducts for asymmetric synthesis of potential chiral medications via acylation reactions were demonstrated.

The review is devoted to the application of C2-symmetric diamines and their derivatives as organocatalysts for asymmetric reactions (aldol, Michael, Mannich, Diels–Alder reactions, desymmetrization, allylation, etc.). Amino acid derivatives, di- and polyamides (sulfamides), bisureas, bisthioureas, bisamidines and bisguanidines are considered. Significant attention is given to the effect of the catalyst structure on the mechanism of catalytic action. Successful applications of such catalysts in enantioselective synthesis of chiral biologically active compounds are summarized. The bibliography includes 181 references.