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The reaction of cyclic nitronic esters (isoxazoline- and 5,6-dihydro-4

A facile synthesis of [5,5]-annulated N-fused heterocycles – pyrrolo[2,1-b]thiazoles and pyrrolo[1,2-b]indazoles via Cu(II)-mediated oxidative [3+2]-annulation between nitroalkenes and azolium ylides was developed. The reaction proceeds in mild conditions with copper (II) trifluoroacetate/2,6-lutidine system as a promoter. The method is applicable to a broad range of nitroalkenes and azolium salts, providing target N-fused heterocycles in moderate to good yields. In the case of α-fluoronitroalkenes unique fluorinated derivatives were accessed via this methodology.

In this review, the advances made over the last 6 years in [4 + 1]-annulation reactions involving sulfonium, sulfoxonium and ammonium ylides, as well as diazo compounds and carbenes are summarized.

Novel reactivity of pyridinium ylides in reaction with 4-oxothiazolidin-5-ylidenes as electron-deficient alkenes involving a tandem Michael addition/elimination process was developed to give double bond functionalization products in mild conditions.

A “renewed isoxazoline route” toward densely functionalized ketones avoiding the use of unstable and hazardous nitrile oxide intermediates has been developed.

Reaction of six-membered cyclic nitronates with disubstituted ketenes affords hitherto unknown saturated oxazolo[3,2-b][1,2]oxazines possessing up to four contiguous stereogenic centers. The process involves a tandem of [3+2]-cycloaddition across the C═O bond of ketene, followed by a spontaneous [1,3]-rearrangement of transient vinylidene-substituted bicyclic nitrosoacetals. DFT calculations of the mechanism suggest that the [1,3]-O,C-shift proceeds through a recyclization of a biradical intermediate formed by an unusually mild homolytic cleavage of the N-O bond. The resulting products can be utilized as precursors of other fused 1,2-oxazines derivatives, in particular 1,2-oxazino-1,2,4-triazin-3-ones.

A novel approach to conjugated enone oximes from aliphatic nitro compounds deals with double silylation of N,N-bis(silyloxy) enamines followed by a stereoselective reaction with an ester-stabilized sulfur ylide. The proposed mechanism involves the generation of labile nitrosoalkenes as intermediates, which react with the sulfur ylide to give target enone oximes.

The Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic 1,3-dienes was investigated. A series of novel monofluorinated norbornenes was prepared in up to 97% yield. The reaction with 1,3-cyclohexadiene permits the preparation of monofluorinated bicyclo[2.2.2]oct-2-enes. The kinetic data of the reactions with 1,3-cyclopentadiene and 1,3-cyclohexadiene were used to calculate activation parameters. Furthermore, the synthetic utility of the cycloadducts obtained was demonstrated.

An efficient route for the synthesis of multifunctionalized pyrrolidines based on copper-catalyzed diastereoselective [3 + 2]-cycloaddition of nitroalkenes with azomethine ylides was developed. Novel fluorinated heterocycles - β-fluoro-β-nitropyrrolidines - were accessed via this method. The products can be prepared in good to excellent yields and with high diastereoselectivity. Subsequent transformations of pyrrolidines including oxidative aromatization into fluorinated pyrrolines and medicinally attractive β-fluoro-NH-pyrroles as well as chemoselective reduction reactions were demonstrated. Application of the developed procedures for the non-fluorinated analogues was demonstrated to lead to various β-substituted pyrrole derivatives.

An asymmetric total synthesis of Merck's hNK1 antagonist and three of its stereoisomers was accomplished in 10 steps. The synthesis involves a stereoselective assembly of 1,2-oxazine N-oxide by the [4 + 2]-cycloaddition, site-selective C-H oxygenation using a novel tandem acylation/[3,3]-rearrangement process and the reductive 1,2-oxazine ring contraction into a pyrrolidine ring as key stages. Using this strategy, the fused pyrrolidine subunit was constructed with exceptionally high regio- and stereoselectivities. The approach described here can be used to access enantiopure 3,4-disubstituted prolinols, which are frequently found in pharmaceutically relevant molecules and organocatalysts.

Chlorination of conjugated nitroalkenes with iodobenzene dichloride or sulfuryl chloride to give target α-chloronitroalkenes in good yields is described. Details of the procedure depend on the donating ability of the nitroalkene substituents. The activity of the described chlorinating agents increases in order ‘PhICl2/Py’ < ‘SO2Cl2’ < ‘SO2Cl2/HCl’ with the former producing the best yields for highly donating substrates and the latter for non-activated groups. An autocatalytic role of hydrogen chloride and the chemoselectivity of chlorination were also demonstrated.

Reaction of six-membered cyclic nitronates with disubstituted ketenes affords hitherto unknown saturated oxazolo[3,2

Currently, the chemistry of organofluorine compounds is a leading and rapidly developing area of organic chemistry. Fluorine present in a molecule largely determines its specific chemical and biological properties. This thematic issue covers the trends of organofluorine chemistry that have been actively developed in Russia the last 15 – 20 years. The review describes nucleophilic substitution and heterocyclization reactions involving fluorinated arenes and quinones and skeletal cationoid rearrangements in the polyfluoroarene series. The transformations involving CF3-substituted carbocations and radical cations are considered. Heterocyclization and oxidative addition reactions of trifluoroacetamide derivatives and transformations of the organic moiety in polyfluorinated organoboranes and borates with retention of the carbon – boron bond are discussed. Particular attention is devoted to catalytic olefination using freons as an efficient synthetic route to fluorinated compounds. The application of unsymmetrical fluorine-containing N-heterocyclic carbene ligands as catalysts for olefin metathesis is demonstrated. A variety of classes of organofluorine compounds are considered, in particular, polyfluorinated arenes and 1,2-diaminobenzenes, 1-halo-2-trifluoroacetylacetylenes, α-fluoronitro compounds, fluorinated heterocycles, 2-hydrazinylidene-1,3-dicarbonyl derivatives, imines and silanes. The potential practical applications of organofluorine compounds in fundamental organic chemistry, materials science and biomedicine are outlined. The bibliography includes 1019 references.

A new tandem double acylation/rearrangement reaction of nitro compounds is described. It has a broad substrate scope allowing the mild and efficient synthesis of α-acyloxy oxime esters in high yields and regioselectivity. According to the obtained data, the mechanism for transformation was proposed. The utility of the obtained α-hydroxy oxime esters was demonstrated.

Aerobic reactions of iron(III), nickel(II), and manganese(II) chlorides with formaldoxime cyclotrimer (tfoH3) and 1,4,7-triazacyclononane (tacn) produce indefinitely stable complexes of general formula [M(tacn)(tfo)]Cl. Although the formation of formaldoxime complexes has been known since the end of 19th century and applied in spectrophotometric determination of d-metals (formaldoxime method), the structure of these coordination compounds remained elusive until now. According to the X-ray analysis, [M(tacn)(tfo)]+ cation has a distorted adamantane-like structure with the metal ion being coordinated by three oxygen atoms of deprotonated tfoH3 ligand. The metal has a formal +4 oxidation state, which is atypical for organic complexes of iron and nickel. Electronic structure of [M(tacn)(tfo)]+ cations was studied by XPS, NMR, cyclic (CV) and differential pulse (DPV) voltammetries, Mossbauer spectroscopy, and DFT calculations. Unusual stabilization of high-valent metal ion by tfo3- ligand was explained by the donation of electron density from the nitrogen atom to the antibonding orbital of the metal-oxygen bond via hyperconjugation as confirmed by the NBO analysis. All complexes [M(tacn)(tfo)]Cl exhibited high catalytic activity in the aerobic dehydrogenative dimerization of p-thiocresol under ambient conditions.

An asymmetric total synthesis of Merck's hNK

A new four-stage algorithm for the reactivity umpolung of aliphatic nitro compounds has been proposed and experimentally confirmed. Bis(trialkylsilyloxy)iminium cations, which are key intermediates in the new scheme, have been qualitatively and quantitatively determined by the method of double nuclear magnetic resonance. Their thermodynamic parameters have been determined. The kinetics of coupling of these cations with π-nucleophiles has been measured experimentally, and the stereodynamics of the interaction of these cations has been discussed using a general model involving anomeric assistance. The utility and novelty of the proposed approach for the development of modern methodology of organic synthesis using available aliphatic nitro compounds as initial reagents have been demonstarted.

Acylation of nitronates affords α-acyloxyoxime derivatives via an umpolung functionalization of the α-position. This transformation involves generation of hitherto unknown N-acyloxy, N-oxyenamines and their fast [3,3]-sigmatropic rearrangement driven by the cleavage of the weak N-O bond. The reaction has a broad scope, and it is regioselective in the case of nitronates possessing nonsymmetrically substituted α-positions. Application to the formal total synthesis of clausenamide and cis-clausenamide is presented.

A novel strategy for the synthesis of stereochemically defined 3,4,5-trisubstituted 2-pyrrolidones was developed. The suggested approach involves reductive domino-type recyclization of 3-aminomethyl-substituted isoxazolines as a key stage. The latter are prepared via α-C–H functionalization of readily available isoxazoline-N-oxides.

A convenient method for arylation of mono- and disubstituted 1,2,3-triazoles by copper-catalyzed Chan-Lam coupling was developed. The method is applicable for the regioselective synthesis of fluorescent 4-halogen-substituted (Hal = F, Cl, Br) 2,5-diaryl-1,2,3-triazoles in high yields. Comparative study of their fluorescent properties revealed that 4-fluorosubstituted triazoles possess the highest quantum yield (up to 0.69) among halogenated triazoles possessing Cl and Br in the position 4.

Nucleophilic addition of thiols to N,N-bis(oxy)enamines (nitrosoalkene acetals) produce valuable α-thiooximes in a highly efficient manner. The reaction was found to be solvent-dependent, likely because of distinct mechanisms operating in nonpolar and basic solvents (involving either Brønsted acid or Lewis base catalysis). By performing a series of competition experiments, the relative reactivity of S-, N-, and O-nucleophiles in reaction with N,N-bis(oxy)enamines was determined for the first time. Interestingly, the relative nucleophilicity was found to be highly dependent on the solvent, which allows regioselective control of these reactions by using an appropriate medium.

A one-pot three-component route towards fluorinated five/five-annulated nitroso acetals bearing two fused isoxazolidine rings is described. Target nitroso acetals were obtained with complete regioselectivity and high stereoselectivity. The mechanism of this tandem [4 + 1]/[3 + 2] cycloaddition was proposed to include the intermediate formation of elusive 3-fluoro-isoxazoline-N-oxides as key intermediates. This method is applicable for the synthesis of a broad scope of nitroso acetals starting from various fluoronitroalkenes, halogenated dicarbonyl compounds and dipolarophiles of different electronic nature.

Reaction of N-Alk-N′-(trimethylsilyl)carbodiimides (Alk = Me, But) with nitrating agents (N2O5, (NO2)2SiF6) affords alkyl(nitro)cyanamides and N-alkyl-N′-nitrocarbodiimides. The product ratio depends on the reaction conditions. N-(tert-butyl)-N′-nitrocarbodiimide can be obtained in almost pure form. This compound is stable at temperatures below 10 °C. Its structure was confirmed by 1Н, 13C, and 14N NMR. The reaction of N-(tert-butyl)-N′-nitrocarbodiimide with amines provides a new route to N-alkyl(aryl)-substituted N′-(tert-butyl)-N″-nitroguanidines.

Michael addition of malonic esters to azoalkenes generated in situ from α-bromo- and α-chlorohydrazones was accomplished. Both aliphatic and aromatic substrates bearing different functional groups are tolerated. The use of a strong base (sodium hydride) for generation of azoalkenes and deprotonation of malonate was found to be essential for a successful coupling. Synthetic potential of the obtained β-hydrazonoalkylmalonates was demonstrated by their smooth conversion into five- and six-membered N-heterocycles, functionalized hydrazides, 2-(2-oxo-2-arylethyl)malonates and 2-arylethylmalonates.

New efficient synthesis of 4-fluoro-5-aryl-1,2,3-NH-triazoles was elaborated. The reaction of NaN3 with arylsubstituted α fluoronitroalkenes resulted in domino construction of target fluorinated triazoles. Sulfamic acid was found to be an effective promoter for this heterocyclization. It was demonstrated that subsequent functionalization of obtained triazoles proceeds highly regioselectively at the N-2 position. The observed regioselectivity was supported by DFT calculations.

The regioselectivity of the addition of HO-acids to the activated π bond in N,N-bis(oxy)enamines has been found to be dramatically dependent upon the solvent. Mechanistic investigations and quantum-chemical calculations revealed that solvent affects the reaction pathway. In basic solvents (DMF, NMP, DMSO), N,N-bis(oxy)enamines were converted into nitrosoalkenes by a Lewis base promoted process followed by oxy-Michael addition of the HO-acid. In non-polar solvents (toluene, CH2Cl2), the reaction occurs by an acid-promoted SN′ substitution of the N-oxy-group via a highly reactive N-vinyl-N-alkoxynitrenium species. Based on these studies, general and efficient protocols for the oximinoalkylation of various HO-acids (carboxylic acids, phenols, hydroxamic, phosphoric and sulfonic acids) employing readily available N,N-bis(oxy)enamines were developed. These methods proved to be applicable to the post-modification of natural molecules bearing acidic OH groups (such as steroidal hormones, bile acids, protected amino acids and peptides) and ligands (BINOL). The resulting α-oxyoximes were demonstrated to be useful precursors of valuable 1,2-amino alcohol or 1,2-hydroxylamino alcohol derivatives, including the antiarrhythmic drug Mexiletine and a potent matrix metalloproteinase inhibitor.