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Synthetic approaches to previously unknown 4-OR-2-methyltetrahydroquinazoline N-oxides were elaborated. 4-Alkoxy- and 4-aryloxy-2-methyltetrahydroquinazoline N-oxides were investigated in the condensation reactions with aromatic aldehydes to give a series of novel π-conjugated structures with fluorescent properties.

An efficient protocol for the straightforward functionalization of the isoxazole ring via the reactions of aromatic nucleophilic substitution of the nitro group with various nucleophiles has been elaborated. The method features excellent chemical yields, easy operability of the reaction, mild reaction conditions and a broad scope of both 5-nitroisoxazoles and nucleophiles. A synthetic approach to 3,5- and 3,4,5-substituted isoxazoles via the sequential functionalization of the isoxazole ring has been developed based on the excellent regioselectivity of the reaction of 3,5-dinitroisoxazoles with nucleophiles.

The Ritter-type reaction of alkyl perchlorates with nitriles of various structures was systematically studied. The reaction has a wide scope and proceeds under extremely mild conditions without any catalysts or special activation of reagents. A structural diversity of the obtained by the Ritter-type reaction N-alkyl amides bearing small ring, double bonds, additional functional groups, aromatic and adamantane fragments, was demonstrated.

1,2,3-Triazoles bearing additional functional groups have found applications as the ligands in catalysis of a broad scope of reactions, synthesis of transition metals complexes for various practicable purposes, and design of metal-based drugs. Triazolyl ligands accelerating CuAAC reactions, such as TBTA and TTTA, are nowadays commonly used in organic synthesis, and the search for novel ligands with a less complicated structure represents an important task. In the present work a series of hydroxyalkyltriazoles, containing a cyclooctane core, were synthesized via cycloaddition of readily available individual diastereomers of azidoalcohols or diazidodiols with phenylacetylene. The obtained hydroxyalkyltriazoles were probed as ligands for CuAAC reactions of benzyl azide with acetylenes, and 1-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]cyclooctanol was demonstrated to act as an effective ligand for these processes. The complex salt of the abovementioned triazole and CuCl2 was readily obtained. According to X-ray diffraction analysis data, the complex contained two molecules of triazole, in which only N1-atoms of the triazole ring acted as coordination centers. Such a molecular structure correlates well with the efficiency of 1-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]cyclooctanol as a ligand in CuAAC reactions: it is able to coordinate copper ions and, at the same time, it forms a sufficiently labile complex to not withdraw copper ions from the catalytic cycle.

Two dispiro[cyclopropane-1,3’-bicyclo[3.3.1]nonane-7′,1″-cyclopropanes] were treated with various oxidative systems. The conditions providing mono- or dioxidation of the CH2 groups neighbouring to spiro-annulated cyclopropane moieties to afford the corresponding mono- or diketones were found.

New 8-arylidene-4-cyanotetrahydroquinazoline N-oxides were obtained via the condensation of readily available 4-cyanotetrahydroquinazoline N-oxides with aromatic aldehydes. Some of the synthesized compounds revealed fluorescent properties and moderate cytotoxic activity.

4-Azido-2-methyltetrahydroquinazoline N-oxide cleanly undergoes the copper( i )-catalyzed azide–alkyne cycloaddition (CuAAC) reaction with alkynes to give new conjugates with pyrimidine N-oxide and triazole moieties. Its deoxygenated analogue, 4-azido-2-methyltetrahydroquinazoline, is inert in CuACC process due to the shift of imidoyl azide–tetrazole equilibrium towards the tetrazole tautomer.

5-Aminoisoxazoles bearing 3-positioned electron-withdrawing group react chemoselectively with trifluoroacetyl nitrate (generated from ammonium nitrate and trifluoroacetic anhydride) to give the corresponding 4-nitro derivatives in yields up to 80%. The results were rationalized by computation studies. Several 5-amino-4-nitroisoxazole-3-carboxilic acid derivatives revealed moderate antibacterial activity.

A straightforward approach for the synthesis of 4-nitroisoxazoles has been developed via heterocyclization of aryl/hetaryl-substituted α,β-unsaturated ketones upon treatment with tetranitromethane-triethylamine (TNM-TEA) complex or t-BuONO. This strategy features high efficiency and wide substrate tolerance under simple reaction conditions.

Pyrimidine N-oxide moiety for the first time was used as a heterocyclic core for the construction of π-conjugated molecules with fluorescent properties. For the synthesis of the title compounds a simple two-step protocol starting from readily available 4-fluoro-2-methylpyrimidine N-oxides was elaborated. A series of 17 novel pyrimidine N-oxide derivatives containing various functional substituents and π-conjugated systems of different length were obtained. The title compounds revealed fluorescent properties in visible region, possessing emission maximum up to 575 nm. Deoxygenation of the N-oxide group led to the loss of visible fluorescence. The chemosensor properties towards TFA and a number of metal cations were demonstrated for 3a, the first representative of the title series. Cytotoxic activity against breast adenocarcinoma cell line was found for three pyrimidine N-oxide derivatives 3b,i,n. Pyrimidine N-oxide 3a was shown to possess excellent biocompatibility and capability to enter cells, that makes it a promising structure for development of bioimaging fluorescent probes.

Tick-borne encephalitis is an important human arbovirus neuroinfection spread across the Northern Eurasia. Inhibitors of tick-borne encephalitis virus (TBEV) strain Absettarov, presumably targeting E protein n-octyl-β-d-glucoside (β-OG) pocket, were reported earlier. In this work, these inhibitors were tested in vitro against seven strains representing three main TBEV subtypes. The most potent compound, 2-[(2-methyl-1-oxido-5,6,7,8-tetrahydroquinazolin-4-yl)amino]-phenol, showed EC50 values lower than 22 µM against all the tested strains. Nevertheless, EC50 values for virus samples of certain strains demonstrated a substantial variation, which appeared to be consistent with the presence of E protein not only in infectious virions, but also in non-infectious and immature virus particles, protein aggregates, and membrane complexes.

1-Aminospiro[2.3]hexane-1,5-dicarboxylic and 1-ammo-5-(ammomethyl)spiro[2.3]hexane-1-carboxylic acids, which are the conformationally rigid analogues of glutamic acid and lysine, respectively, were synthesized from 3-methylidenecyclobutanecarbonitrile. The synthetic route includes a catalytic [1+2]-cycloaddition of ethyl 2-diazo-2-nitroacetate to a double bond of the unsaturated nitrile, a subsequent chemoselective reduction of the nitro and cyano groups, and a hydrolysis of the ester moiety.

Nitro-substituted isoxazoles are of utmost interest both as versatile intermediates for targeted organic synthesis and as perspective bioactive compounds for drug development. Nevertheless, the existing approaches to them usually lack generality and strongly depend on the position of the nitro group and on the presence of other substituents in the isoxazole ring. This review provides the first systematization of all available data concerning synthetic approaches to 3-, 4-, and 5-nitroisoxazoles. There are a number of preparative approaches to 4-nitroisoxazoles based on classical heterocyclization reactions of nitro-substituted compounds and the nitration of isoxazoles. 3-Nitro- and, especially, 5-nitroisoxazoles are much less readily available. A few methods affording 3-nitroisoxazoles have been reported, often employing the heterocyclization of unsaturated compounds by treatment with sodium nitrite. The sole general preparative method for 5-nitroisoxazoles, containing a variety of functional groups, employs the heterocyclization of electrophilic alkenes by treatment with tetranitromethane activated with triethylamine.1 Introduction2 Synthesis of 4-Nitroisoxazoles2.1 Nitration of Isoxazoles2.2 Condensations of α-Nitro Ketones or Their Oximes2.3 1,3-Dipolar Cycloaddition of Nitrile Oxides to Acetylenes and Their Synthetic Equivalents2.4 Heterocyclization of Acetylene Derivatives by Treatment with Sodium Nitrite2.5 Heterocyclization of Nitro Derivatives of 1,3-Diketones and Their Synthetic Equivalents2.6 Miscellaneous Methods3 Synthesis of 3-Nitroisoxazoles3.1 Heterocyclization of Acetylene Derivatives or 1,3-Dihalogenoalkenes by Treatment with Sodium Nitrite3.2 Heterocyclization of Morita–Baylis–Hillman Acetates by Treatment with Sodium Nitrite3.3 1,3-Dipolar Cycloadditions4 Synthesis of 5-Nitroisoxazoles4.1 1,3-Dipolar Cycloadditions4.2 Synthesis Using Polynitro Compounds5 Conclusion

Background: Increasing use of the three-membered ring in drug development initiates the search for efficient methods of transformations of cyclopropane derivatives. Oxidation of methylene group activated by an adjacent cyclopropane represents a direct approach towards carbonylcyclopropanes, allows avoiding unnecessary synthetic stages and meets the requirements of atom economy. Objective: In this review all available data concerning the oxidation of cyclopropane-containing hydrocarbons and their functionally substituted derivatives are systematized, and the general regularities between the structure of the starting compound, the oxidant employed and the reaction outcome are underlined. Conclusion: The following regularities were distinguished for the oxidation of cyclopropane-containing compounds into cyclopropylketones. The main structural parameters of the starting compounds, which influence the distribution of the oxidation products, are the followings: the presence of competing C-H bonds, flexibility or rigidity of structure, electron and sterical substituents effects. A number of preparative methods of activated C(sp3)-H bonds oxygenation were elaborated, employing such powerful oxidants as ozone, dioxiranes, CrO3 and a variety of catalytic systems, based on transition metals. For the oxidation of cyclopropane derivatives all these oxidants may be employed. RuO4, generated in situ, usually behaves as selective and soft oxidant. TFDO often demonstrates lesser selectivity, but it may be the best choice when several activated CH2 groups should be oxidised. In the case of dihalocyclopropanes the use of CrO3 is preferable. Summarily, the oxidation of methylene group adjacent to cyclopropane has been undoubtedly developed into a reliable preparative approach to cyclopropylketones, which should find an active use in synthetic organic chemistry.

A series of polycyclic hydrocarbons containing cyclopropane moieties 1,2-annelated or spiro-condensed with cyclooctane ring were investigated under oxidative conditions. Four oxidizing systems (O3 on SiO2, dioxirane derived from trifluoroacetone, CrO3 and RuO4, generated in situ), were employed to evaluate and compare their reactivity and usefulness. RuO4 was found to be the best one, considering its oxidative power together with a simple preparative procedure. The conditions for specific oxidation of polycyclic hydrocarbons were found. Novel cyclooctane derivatives containing cyclopropyl carbonyl moieties were obtained.

The heterocyclization of gem-dichlorocyclopropanes upon treatment with nitronium triflate in organic nitriles was studied and the influence of the medium on the reaction pathway was shown. While in anhydrous solvent 5-chloroisoxazole was the only product, the admixture with water promoted a three-component heterocyclization affording 4-chloropyrimidine N-oxides. This phenomenon was rationalized using DFT calculations.

Novel N-(1-oxidopyrimidin-4-yl)- and N,N′-bis(1-oxidopyrimidin-4-yl)diamines were prepared from 4-fluoropyrimidine N-oxides and diamines basing on SNAr reaction. One compound from this series possessed antiviral activity against tick-borne encephalitis virus (TBEV).

A convenient approach to novel symmetric bispyrimidine diamines comprises SNAr reactions of 4-fluoropyrimidine N-oxide with alkane-α,ω-diamines with subsequent reduction of N-oxide function. The obtained substances were tested in patch-clamp experiments for the influence on the kainateinduced currents in Purkinje neurons and showed negative modulating effect.

The first example of a novel class of AMPA receptor positive allosteric modulators of the bis(pyrimidine) series having a hydroquinone linker has been obtained and showed a potency to increase kainate-induced currents at subnanomolar concentrations.

Tricyclic bis-adducts of cyclohexa-1,4-diene with bromofluorocarbene and non-symmetric adducts with both bromofluoro- and dichlorocarbenes were synthesised selectively. The treatment of the bis-adducts with nitrating reagents in acetonitrile affords the products of heterocyclization of a sole dihalogenocyclopropane into 4-fluoropyrimidine N-oxide. The difference in the reactivity of bis-cyclopropanes with different sets of halogen substituents leads to selective heterocyclization of bromofluorocyclopropanes without affecting the dichlorocyclopropane moiety.

A novel reaction of tetranitromethane with electrophilic alkenes in the presence of triethylamine affording substituted 5-nitroisoxazoles is described. Triethylamine reacts with tetranitromethane to generate N-nitrotriethylammonium and trinitromethanide. This process provides the heterocyclization of electrophilic alkenes. A variety of α,β-unsaturated aldehydes, ketones, esters, amides, phosphonates, nitro, and sulfur compounds was involved in the heterocyclization reaction, and a wide range of functionalized 5-nitroisoxazoles was obtained in good to high yields. The scope and limitations of the reaction and the mechanistic proposal are discussed.

Tetraspiro[2.1.2(5).1.2(9).1.2(13).1(3)]hexadecane-1,3,5,7-tetraone 4, a unique tetraketone containing a cyclooctane core and four spiroannelated cyclopropane moieties, represents the previously unknown cyclotetramer of carbonylcyclopropane. For this purpose oxidation of the parent polyspirocyclic hydrocarbon was examined under various oxidative conditions, and the reactivity of oxidants towards methylene groups of the eight-membered cycle, activated by adjacent spirocyclopropane rings, was evaluated and contrasted. Whereas the treatment of tetraspirohexadecane with ozone resulted in monooxidation, its reaction with methyl(trifluoromethyl)dioxirane afforded the product of four-fold oxidation, triketoalcohol 10. Subsequent oxidation of the latter with Dess-Martin periodinane gave the target tetraketone 4.

A number of nitrosonium and nitronium salts were probed as reagents for the heterocyclization of 1-bromo-1-fluorocyclopropanes in the presence of organic nitriles to give pyrimidine N -oxides. Nitronium triflate, either preformed or generated in situ from nitric and triflic acids, was shown to be the most efficient reagent for this reaction, affording a mild and convenient procedure for the synthesis of 4-halogenopyrimidine derivatives. X-ray crystallography was used to confirm the ionic structure of nitronium triflate (NO 2 + )(CF 3 SO 3 − ).

Tick-borne encephalitis virus (TBEV) belonging to Flavivirus genus causes severe infection in humans. The search for therapeutically relevant compounds targeting TBEV requires the exploration of novel chemotypes. A versatile synthesis of previously unknown 4-aminopyrimidines and 4-aminopyrimidine N-oxides based on a fluorosubstituted heterocyclic core is described. A representative series of 4-aminotetrahydroquinazoline derivatives, containing aliphatic and aromatic substituents as well as the adamantane framework, was obtained and their activity against tick-borne encephalitis virus reproduction was studied. Nine compounds were found to inhibit TBEV entry into the host cells. A bulky hydrophobic adamantyl group was identified to be important for the antiviral activity. The developed synthetic route allowed an easy access to a consistent compound library for further structure-activity relationship studies.

An unusual condensation reaction of 2-methyltetrahydroquinazoline N-oxides with aromatic aldehydes was found. The reaction of 4-cyano substituted heterocycles as well as the use of microwave irradiation for 4-morpholinyl substituted heterocycles resulted in the condensation engaging the methylene group of the tetrahydroquinazoline fragment with simultaneous deoxygenation of the N-oxide. A preparative approach towards previously unknown pyrimidine-containing conjugated molecules was developed based on this process.

The review covers methods of synthesis of amino acids of the cyclopropylglycine series published in the past decade. Main methods of synthesis of cyclopropylglycines are based on the carbene and ylide addition to alkenes, enzymatic reactions, the Kulinkovich cyclopropanation of esters and amides, MIRC reactions, the modification of cyclopropanecarbaldehydes by the Strecker reaction, and other transformations of functional groups of cyclopropanes. Particular attention is given to 2-carboxycyclopropylglycines and 3,4-methanoprolines. These compounds have attracted interest as conformationally rigid cyclopropane-containing analogs of glutamic acid and proline and also as components of physiologically active peptides. The physiological properties of cyclopropylglycines are briefly characterized.

Novel three-component heterocyclization involving gem-bromofluorocyclopropanes, nitrosyl tetrafluoroborate, and a molecule of the solvent (nitrile) yielding previously unknown fluorinated pyrimidine N-oxides is described. A two-step synthetic approach to 4-fluoropyrimidine N-oxides from alkenes under mild conditions is developed using this reaction. Mechanistic aspects of the heterocyclization are discussed.

A number of new alkoxy- and phenylsulfanyl-substituted 1,1-dihalospiro[2.2]pentanes bearing different halogen atoms were synthesized. 1,1-Dihalo-4-tert-butoxyspiro[2.2]pentanes reacted with methyllithium at −55 to −10°C to give exclusively 1-tert-butoxy-2-vinylidenecyclopropane. The reaction of 1-bromo-1-fluoro-4-phenylsulfanylspiro[2,2]pentane with methyllithium resulted in replacement of the fluorine atom by methyl group.

A skeletal carbenoid rearrangement of the gem-bromochlorospiropentanes in the presence of methyllithium has been studied. The synthetic and mechanistic aspects of this rearrangement as well as the influence of the halogen atom nature on the reaction pathway are discussed.

The series of 2-phenyl- and 2,2-diphenyl gem-dihalogeno-spiropentanes were employed as model compounds to study the carbenoid rearrangement with the use of methyllithium. The scope and limitations of this skeletal rearrangement are outlined and its mechanism is discussed.

A series of novel gem-bromofluorospiropentanes were synthesized and investigated in the reaction with methyllithium. Either substitution of the fluorine atom for a methyl group or rearrangement into methylated cyclobutene derivatives occurred under these conditions.

A series of new substituted gem-dibromospiropentanes was studied in a reaction with methyllithium at −55...−50°C. This reaction is a carbenoid rearrangement that leads to the formation of monomeric and dimeric bromocyclobutenes and also to the products of cyclobutylidene insertion into a C-H bond of the solvent depending on the character of substituents in the dibromospiropentane fragment.

A number of nitrosonium and nitronium salts were probed as reagents for the heterocyclization of 1-bromo-1-fluorocyclopropanes in the presence of organic nitriles to give pyrimidine N -oxides. Nitronium triflate, either preformed or generated in situ from nitric and triflic acids, was shown to be the most efficient reagent for this reaction, affording a mild and convenient procedure for the synthesis of 4-halogenopyrimidine derivatives. X-ray crystallography was used to confirm the ionic structure of nitronium triflate (NO 2 + )(CF 3 SO 3 − ).

A skeletal rearrangement of dihalogenospiropentanes in the presence of alkyllithium reagents has been systematically studied using a number of gem-dibromospiropentanes. The scope and limitations of this carbenoid rearrangement are outlined and its mechanism is discussed.

A series of 4-fluoropyrimidine 1-oxides, obtained via three-component heterocyclization, was studied under various reduction conditions. An effective preparative method for the synthesis of 4-fluoropyrimidines from readily available starting materials was elaborated. 4-Fluoro-substituted tetrahydroquinazolines and tetrahydroquinazoline N-oxides were demonstrated to be highly reactive in aromatic nucleophilic substitution.

A straightforward gram-scale synthesis of 1,3,5,7-tetrakis(methylidene)cyclooctane (TMCO) from commercial adamantane-1,3-dicarboxylic acid has been developed. TMCO exhibits high reactivity toward a number of carbenes and epoxidizing reagents, undergoing multiple cyclopropanations, dihalocyclopropanations, or epoxidations of four double bonds to yield polyspirocyclic products. Stereochemical features of polyspirocyclopropanated compounds have been thoroughly examined in experimental (NMR) and theoretical (DFT) studies. Comprehensive stereochemical assignment of TMCO adducts with dihalocarbenes and spiroepoxy products was achieved. The conditions of the formation of 1-methyl-3,7-bis(methylidene)bicyclo[3.3.1]nonane from the adamantane derivative were optimized, and diadducts of this diene with dihalocarbenes were isolated and characterized.

It is demonstrated, that 4-fluoropyrimidines can be synthesized in a two-step process involving heterocyclization of gem-bromofluorocyclopropanes followed by reduction of the resulting N-oxides with PCl3.

The review covers methods of synthesis of amino acids of the cyclopropylglycine series published in the past decade. Main methods of synthesis of cyclopropylglycines are based on the carbene and ylide addition to alkenes, enzymatic reactions, the Kulinkovich cyclopropanation of esters and amides, MIRC reactions, the modification of cyclopropanecarbaldehydes by the Strecker reaction, and other transformations of functional groups of cyclopropanes. Particular attention is given to 2-carboxycyclopropylglycines and 3,4-methanoprolines. These compounds have attracted interest as conformationally rigid cyclopropane-containing analogs of glutamic acid and proline and also as components of physiologically active peptides. The physiological properties of cyclopropylglycines are briefly characterized.

A series of novel gem-bromofluorospiropentanes were synthesized and investigated in the reaction with methyllithium. Either substitution of the fluorine atom for a methyl group or rearrangement into methylated cyclobutene derivatives occurred under these conditions.

A series of new substituted gem-dibromospiropentanes was studied in a reaction with methyllithium at −55...−50°C. This reaction is a carbenoid rearrangement that leads to the formation of monomeric and dimeric bromocyclobutenes and also to the products of cyclobutylidene insertion into a C-H bond of the solvent depending on the character of substituents in the dibromospiropentane fragment.