Activation of N-containing olefins and alkynes with superacids

Alkynes are one of the most abundant chemicals in organic chemistry, and therefore the development of catalytic reactions to transform alkynes into other useful functionalities is of great value. In recent decades, extraordinary advances have been made in this area with transition-metal catalysis, and silver-based reagents are ideal for the activation of alkynes. This high reactivity is probably due to the superior π-Lewis acidic, carbophilic behavior of silver(I), allowing it to selectively activate carbon-carbon triple bonds (C≡C) through the formation of a silver-π complex. Within this field, we have been interested in the activation and subsequent reactions of readily accessible terminal alkynes for the synthesis of nitrogen-containing compounds, which has generally received less attention than methods involving internal alkynes. This is possibly due to the lack of suitable reactive reaction partners that are compatible under transition metals. Therefore, a thorough understanding of the factors that influence homogeneous silver catalysis and the identification of the appropriate reaction partners can provide a powerful platform for designing more efficient silver-catalyzed reactions of terminal alkynes. In this context, we envisioned that using readily available, environmentally benign, and inexpensive trimethylsilyl azide (TMSN3) or an isocyanide as the nitrogen-donor would be the key to develop novel reactions of terminal alkynes.This Account describes our efforts since 2013 toward the development of novel silver-catalyzed tandem reactions of terminal alkynes with either TMSN3 or isocyanides for the assembly of various nitrogen-containing compounds. The first section of this Account discusses the initial developments in the silver-catalyzed hydroazidation of terminal alkynes with TMSN3 and the subsequent advances made in our laboratory. We first describe the discovery and experimental and computational mechanistic investigations of silver-catalyzed hydroazidation reactions, which is the most efficient strategy reported to date for accessing vinyl azides. Mechanistic study of this hydroazidation reaction provides an alternative activation mode for terminal alkyne conversion in transition metal catalysis. We then present the chemistry of in situ generated vinyl azides, including one-pot tandem radical addition/cyclization or migration reactions of terminal alkynes to access a variety of nitrogen-containing molecules. Finally, we discuss the one-pot, multistep tandem hydroazidation and 1,2-azide migratory gem-difluorination of terminal alkynes for the synthesis of β-difluorinated alkyl azides. The second section describes the silver-catalyzed coupling reactions between terminal alkynes and isocyanides, which offer a straightforward method for accessing synthetically useful building blocks, such as pyrroles, allenamides, benzofuran, vinyl sulfones, indazolines, propiolonitriles, and pyrazoles. The high efficiency, mild conditions, low cost, broad substrate scope, high chemo- and regioselectivity, step economy, and ecofriendliness of the developed approaches make them attractive and practical. The progress in this area provides guiding principles for designing new reactions of terminal alkynes that can be extended to various nitrogen-containing molecules of interest to medicinal and materials chemists.

Metal silylamides [MN(SiMe3)2, M = Li, Na, and K] are widely used Brønsted bases and have become among the most prevalent bases in organic research owing to their commercial availability and low cost. MN(SiMe3)2 exhibits strong basicity and high stability, making it a common deprotonation reagent for C-H bond activation. Nitrogen-containing compounds are ubiquitous in pharmaceuticals and natural products, rendering the synthesis of bioactive nitrogen-containing compounds a research priority. Traditionally, the synthesis of these compounds has relied on amines, but the importance of sustainable chemistry is increasing, and the development of efficient and atom-economical synthetic methodologies without compromising compound selectivity and environmental safety is a major theme of research today. In this review, we comprehensively summarize recent advances in the tandem synthesis of nitrogen-containing compounds mediated by MN(SiMe3)2 under transition-metal-free conditions. Based on distinct reaction mechanisms, the tandem reactions are classified into two categories: those proceeding via imine intermediates and those involving silylamide intermediates. Moreover, the reaction conditions, functional group universality, reaction mechanism, and applications are discussed in detail, and the prospects and limitations of development in this field are also critically analyzed.

Imidoyl radicals (R1N=C.R2) are very attractive intermediates that can be readily produced by several methods, i.e. hydrogen atom abstraction from aldimines, homolytic fragmentation of certain imidoylic precursors, and addition of both carbon- and heteroatom-centered radicals to isonitriles and isothiocyanates. As far as their synthetic potential is concerned, they have been shown to perform smooth intra- and intermolecular additions to double and triple carbon-carbon bonds, as well as cyclizations onto aromatic rings, sulfur atoms, and cyano groups. They have been therefore efficiently employed in cyclizations, annulations, and cascade reactions leading to the construction of various nitrogen-containing heterocyclic compounds, e.g. indoles, phenanthridines, pyrrolidines, quinolines, quinoxalines, and fused polycyclic derivatives. They have been also used as key intermediates in the synthesis of carbonyl compounds, amides, and nitriles and as precursors of alkyl radicals in tin-free reactions. In this review we discuss thoroughly the generation methods, the structural features, and, above all, the reactivity of imidoyl radicals, with particular attention devoted to their synthetic applications.

The aim of the study is to demonstrate the synthetic potential of organometallic compounds in the synthesis of acyclic and cyclic sulfur-containing compounds, which are characterized by wide practical application. Particular interest in sulfur compounds is primarily due to their use as inhibitors of the development of pathogenic microorganisms – viruses, bacteria, fungi, which are capable of mutating and developing resistance to the drugs used. In this regard, a wide arsenal of biologically active S-containing compounds is needed. An analysis of studies in the field of S-functionalization of halogen derivatives, thiones, unsaturated compounds under the action of organometallic reagents is carried out, and studies of the Ufa school of chemists, namely the scientific group of Professor A.G. Ibragimov, in which methods of synthesis of sulfur-containing compounds under the action of metal complex catalysis were actively studied

Iridium and copper supported on silicon dioxide as chemoselective catalysts for dehydrogenation and borrowing hydrogen reactions

The saturated nitrogen-containing heterocyclic compounds include many drugs and compounds that may be used as synthons for the synthesis of other pharmacologically active substances. The need for new derivatives of saturated nitrogen-containing heterocycles for organic synthesis, biotechnology and the pharmaceutical industry, including optically active derivatives, has increased interest in microbial synthesis. This review provides an overview of microbial technologies that can be valuable to produce new derivatives of saturated nitrogen-containing heterocycles, including hydroxylated derivatives. The chemo-, regio- and enantioselectivity of microbial processes can be indispensable for the synthesis of new compounds. Microbial processes carried out with fungi, including Beauveria bassiana, Cunninghamella verticillata, Penicillium simplicissimum, Aspergillus niger and Saccharomyces cerevisiae, and bacteria, including Pseudomonas sp., Sphingomonas sp. and Rhodococcus erythropolis, biotransform many substrates efficiently. Among the biological activities of saturated nitrogen-containing heterocyclic compounds are antimicrobial, antitumor, antihypertensive and anti-HIV activities; some derivatives are effective for the treatment and prevention of malaria and trypanosomiasis, and others are potent glycosidase inhibitors.

The results of studies on the application of elemental phosphorus for the synthesis of important organophosphorus compounds are surveyed and summarized. Currently, this trend represents a synthetically, environmentally and technologically attractive alternative to classical organophosphorus chemistry based on toxic and corrosive phosphorus chlorides. Direct phosphination and phosphinylation of organic compounds with elemental phosphorus (discussed in the first part of the review) basically extend the range of available phosphines, phosphine chalcogenides and phosphinic acids and provides further development of their synthetic potential (discussed in the second part of the review). It is shown that the breakthrough in this area is largely due to the discovery of reactions of elemental phosphorus (white and red) with various electrophiles in superbasic suspensions and emulsions derived from alkali metal hydroxides and to the development of electrochemical, electrocatalytic and catalytic activation of white phosphorus.The bibliography includes 299 references.

A novel strategy for the synthesis of imidazo-fused polycyclic compounds under mild, base-free, and silver-free conditions by a rhodium(III)-catalyzed C-H annulation of alkenyl or arylimidazoles and (hetero)cyclic 1,3-dicarbonyl compounds is reported here. Such a step-economic protocol features the selective cleavage of two different C-H bonds in one step, featuring easy operation, readily available starting materials, gram-scale synthesis, broad functional group tolerance, and no requirement to presynthesize carbene precursors. Notably, the synthetic potential is showcased by the structural modification of drug and the highly step-economic synthesis of Janus kinase inhibitor in only three steps with a satisfactory 26% total yield (previous method: in nine steps with 0.6% yield).

The efficient synthesis of organic compounds is an important field of research, which sets the basis for numerous applications in medicine or materials science. Based on the polarity induced by functional groups, logical bond disconnections can be deduced for the elaboration of organic compounds. Nevertheless, this classical approach makes synthesis rigid, as not all bond disconnections are possible. The concept of Umpolung has been therefore introduced: by inverting the normal polarity of functional groups, new disconnections become possible. Among the tools for achieving Umpolung, hypervalent iodine reagents occupy a privileged position. The electrophilicity of the iodine atom and the reactivity of the hypervalent bond allow access to electrophilic synthons starting from nucleophiles. Nevertheless, some classes of hypervalent iodine reagents can be too unstable for many applications, in particular involving metal catalysis. In this context, cyclic hypervalent iodine reagents, especially benziodoxolones (BXs), have been known for a long time to be more stable than their acyclic counterparts, yet their synthetic potential had not been fully exploited. In this Account, we report our efforts since 2008 on the use of BX reagents in the development of new transformations in organic synthesis, which showed for the first time their versatility as synthetic tools. Our work started with electrophilic alkynylation, as alkynes are one of the most important functional groups in organic chemistry, but are usually introduced as nucleophiles. We used ethynylbenziodoxolones (EBXs) in the direct alkynylation of nucleophiles, such as keto esters, thiols, or phosphines. The reagents could then be applied to the gold- and palladium-catalyzed alkynylation of C-H bonds on (hetero)arenes, leading to a more efficient alternative to the Sonogashira reaction. More complex reactions were then developed with formations of several bonds in a single transformation. Gold- and platinum-catalyzed cyclization/alkynylation domino processes gave access to new types of alkynylated heterocycles. Multifunctionalization of olefins became possible through intramolecular oxy- and amino-alkynylations. (Enantioselective) copper-catalyzed oxy-alkynylation of diazo compounds led to stereocenters with perfect atom economy. Finally, EBXs were also used for the alkynylation of radicals generated under photoredox conditions. Since 2013, we then extended the use of BX reagents to other transformations. Azidobenziodoxol(on)ess (ABXs) were used in the azidation of keto esters, enol silanes, and styrenes. New more stable derivatives were introduced. Cyanobenziodoxolones (CBXs) enabled the cyanation of stabilized enolates, thiols, and radicals. Finally, new BX reagents were developed for the Umpolung of indoles and pyrroles. They could be used in metal-catalyzed directed C-H functionalizations, as well as in Lewis acid mediated oxidative coupling to give functionalized bi(hetero)arenes. In the past decade, our group and others have shown that BX reagents are not only "structural beauties", but also extremely useful reagents in synthetic chemistry. A toolbox of cyclic hypervalent iodine reagents is now available to achieve Umpolung-based disconnections. We are convinced that the field is still in its infancy, and many new reagents and transformations still remain to be discovered.

A method for sequential introduction of two organic groups on the same or the different α-carbons of nitrogen has been developed based on a combination of the concept of electroauxiliary and the cation pool method. Selective introduction of two carbon nucleophiles into 2,5- or 2,2-position of pyrrolidine has been accomplished via sequential electrochemical oxidation of pyrrolidine derivatives containing two silyl groups as the electroauxiliaries. Introduction of two carbon nucleophiles into 2,6-position of piperidine was also successful. The products having two olefinic groups were effectively converted to nitrogen-containing spiro compounds using ring closing metathesis, and an application to formal synthesis of cephalotaxine was also carried out. These results clearly illustrate the synthetic utility and potential of the present approach, and open a new aspect of the synthesis of nitrogen-containing compounds.

The synthesis and characterization of new cluster compounds represented by the series Ir(4)(CO)(12-x)L(x) (L = tert-butyl-calix[4]-arene(OPr)(3)(OCH(2)PPh(2)); x = 2 and 3) is reported using ESI mass spectrometry, NMR spectroscopy, IR spectroscopy and single-crystal X-ray diffraction. Thermally driven decarbonylation of the cluster compound series represented by x = 1-3 according to the formula above is followed via FTIR and NMR spectroscopies, and dynamic light scattering in toluene solution. The propensity of these clusters to decarbonylate in solution is shown to be directly correlated with number density of adsorbed calixarene phosphine ligands and controlled via Pauli repulsion between metal d and CO 5σ orbitals. The tendency for cluster aggregation unintuitively follows a trend that is exactly opposite to the cluster's propensity to decarbonylate. No cluster aggregation is observed for clusters consisting of x = 3, even after extensive decarbonylation via loss of all bridging CO ligands and coordinative unsaturation. Some of the CO lost during thermal treatment via decarbonylation can be rebound to the coordinatively unsaturated cluster consisting of x = 3. In contrast, the clusters consisting of x = 1 and x = 2 both aggregate into large nanoparticles when treated under identical conditions. Clusters in which the calixarene phosphine ligand is replaced with a sterically less demanding PPh(2)Me ligand 6 lead to significantly less coordinative unsaturation upon thermal treatment. Altogether, these data support a mechanical model of accessibility in coordinatively unsaturated metal clusters in solution, which hinges on having at least three sterically bulky organic ligands per Ir(4) core.

In the literature, there is insufficient information on the synthesis of compounds in a series of pyrimidine-2-thiol derivatives containing a five-membered nitrogen-containing heterocyclic fragment; at the same time, there are a sufficient number of examples, demonstrating the synthetic and biological potential for compounds of this kind. The relevance of the study “structure – acute toxicity” relationship in a number of newly synthesized derivatives of 1,2,4-triazole-3(2H)-thione with pyrimidine-2-thiol is due to the synthesis of potential low molecular weight interferon inducers and antitumor agents, the search for molecular descriptors of their structure, important for establishing “structure – acute toxicity” laws, as a system for evaluating the biological effects of compounds. Therefore, it is strategically and economically justified to conduct a study of the acute toxicity of synthesized compounds as a priority. The aim of the work is targeted synthesis of a number of S-derivatives (1,2,4-triazole-3(2H)-yl)methyl)thiopyrimidines and the establishment of the “structure – acute toxicity” relationship. Materials and methods. A modern set of physical-chemical research methods was used to study the compounds. The study of the acute toxicity of the synthesized compounds was performed on adult Danio rerio. During the experiments, the fish were kept on a diet for a test period of 96 hours, and their mortality was checked every 24, 48, 72 and 96 hours with the test compounds in each mini-aquarium containing at least 7 individuals of Danio rerio. Results. Results 1H NMR spectra confirm that the alkylation reaction occurs specifically on the sulfur atom. Thus, after analyzing LC50 data, we found that the least toxic among the studied compounds is 2-(((4-methyl-5-(octylthio)-4H-1,2,4-triazole-3-yl )methyl)thio)pyrimidine with an acute toxicity value of 49.66 mg/l. The most toxic compound is 2-(((4-methyl-5-(methylthio)-4H-1,2,4-triazole-3-yl)methyl)thio)pyrimidine with an LC50 value of 8.29 mg/l. The low toxicity of the compound 2-(((4-methyl-5-(octylthio)-4H-1,2,4-triazole-3-yl)methyl)thio)pyrimidine is most likely due to the presence of an octyl substituent, which sufficiently penetrates through biological membranes and does not have a strong toxic effect on organ systems. Furthermore, it does not accumulate but is metabolized in the cell. Conclusions. New hybrids of 1,2,4-triazole-3(2H)-yl)methyl)thiopyrimidines were obtained using the heterocyclization reaction of the intermediate carbothioamide. To reduce the indicators of acute toxicity and increase their biological activity, synthesized S-derivatives of this series were created. It was established that S-derivatives of 1,2,4-triazole-3(2H)-yl)methyl)thiopyrimidines belong to moderately toxic to low-toxic compounds according to the classification of D. R. Passino. 2-(((4-Methyl-5-(octylthio)-4H-1,2,4-triazole-3-yl)methyl)thio)pyrimidine has an acute toxicity value of 49.66 mg/l. The most toxic compound is 2-(((4-methyl-5-(methylthio)-4H-1,2,4-triazole-3-yl)methyl)thio)pyrimidine with an LC50 value of 8.29 mg/l.

In this report, we describe the catalytic activation of terminal alkynes using TpRuPPh 3 (MeCN) 2 X (X = PF 6 and SbF 6 ) complexes. These ruthenium species enable transformation of terminal alkynes into π-alkyne, vinylidene, and allenylidene intermediates, and provide new catalytic reactions via three different pathways. Due to the cationic nature and the coordinative unsaturation around the ruthenium center, we observed the formation and scission of new types of C-X (X = O, N, C) bonds occurring in the catalytic transformations of terminal alkynes, as well as structurally reorganized products. This review summarizes some important examples. 1 Introduction 2 Allenylidene Intermediate 2.1 Internal Redox Reaction 2.2 Cleavage of Carbon-Carbon Triple Bond 3 Vinylidene Intermediate 3.1 Cyclization of CIS-3-En-1-ynes 3.2 Cyclization of CIS-3-Eny-1-nyl Epoxides 3.3 Cyclization of 3,5-Dien-1-ynes 3.4 Cyclization of 3,5-Dien-1-ynes with Skeletal Rearrangement 3.5 Cyclization of 2′,2′-Disubstituted (o-ethynyl)styrenes 4 π-Alkyne Intermediates 4.1 Cyclization of Acyclic 6,6-Disubstituted 3,5-Dien-1-ynes 4.2 Aromatization of Enediynes with Catalytic Nucleophilic Additions 4.3 Aromatization of Endiynes with Catalytic C-H Bond Insertion 5 Concluding Remarks

Soluble aluminum hydrides function as catalysts in deprotonation, insertion, and activation reactions

Aza-fluorocyclization of nitrogen-containing unsaturated compounds