Pyrimidine N-oxides Research Articles

The Boekelheide Rearrangement of Pyrimidine N-oxides as a Case Study of Closed or Open Shell Reactions - Experimental and Computational Evidence for the Participation of Radical Intermediates.

In a case study, the acetic anhydride-promoted reaction of a model pyrimidine N-oxide to the corresponding 4-acetoxymethyl-substituted pyrimidine derivative (Boekelheide rearrangement) was investigated in detail by experiment and quantum chemical calculations. The reaction conditions were varied and several side products formed in low to moderate yields were identified. These experiments indicate that a (pyrimidin-4-yl)methyl radical is one of the key species of the rearrangement. This interpretation was supported by the fact that rearrangements performed in solvents which can easily lose hydrogen atoms, afford considerable quantities of products incorporating the solvent. With TEMPO the key radical could be trapped. Other carboxylic acid anhydrides confirm the conclusion that the Boekelheide rearrangement of the model pyrimidine N-oxide proceeds, at least in part, via radical intermediates. The high level closed and open shell quantum chemical calculations show that concerted [3,3]-sigmatropic rearrangements or stepwise processes, either via ion pairs or via radicals, are energetically feasible.

A new mechanism for resonance Rayleigh scattering detection of minoxidil based on catalytic oxidation of silver nanoparticles

This work presents a new method for minoxidil detection based on silver nanoparticle (AgNP) oxidation. Minoxidil, which is a pyrimidine N-oxide, can be reduced to its corresponding pyrimidine via a redox reaction. In this system, acetate buffer serves as a proton source. AgNPs act as electron donors that contribute electrons to the reaction, producing Ag+. Consequently, the sizes and numbers of AgNPs in the system decrease, which results in a decline in their resonance Rayleigh scattering (RRS). By monitoring the RRS intensity at 409 nm, a change in intensity was linearly related to the minoxidil concentration over a concentration range of 0.5 – 5.0 mM. The detection limit was 0.35 mM. This approach is simple and rapid. It is done by directly mixing the drug and AgNPs in an acidic buffer. The reaction was completed within 2 min. This proposed method was successfully utilized for quantification of minoxidil in topical hair-growth formulations.

Access to Highly Substituted Pyrimidine N-Oxides and 4-Acetoxymethyl-Substituted Pyrimidines via the LANCA Three-Component Reaction–Cyclocondensation Sequence

AbstractThe LANCA three-component reaction of lithiated alkoxy­allenes (LA), nitriles (N), and carboxylic acids (CA) smoothly provides β-alkoxy-β-ketoenamides in broad structural variety. The subsequent cyclocondensation of these compounds with hydroxylamine hydrochloride afforded a large library of pyrimidine N-oxides under mild conditions and in good yields. Their synthetic utility was further increased by the Boekelheide rearrangement leading to 4-acetoxymethyl-substituted pyrimidines. With trifluoroacetic anhydride the rearrangement proceeds even at room temperature and directly furnishes 4-hydroxymethyl-substituted pyrimidine derivatives. The key reactions are very robust and work well even in the presence of sterically demanding substituents.

4-Azidotetrahydroquinazoline derivatives in CuAAC reaction

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.

The LANCA three-component reaction to highly substituted β-ketoenamides - versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives.

The LANCA three-component reaction of lithiated alkoxyallenes LA, nitriles N and carboxylic acids CA leads to β-ketoenamides KE in good to excellent yields. The scope of this reaction is very broad and almost all types of nitriles and carboxylic acids have successfully been used. The alkoxy group introduced via the allene component is also variable and hence the subsequent transformation of this substituent into a hydroxy group can be performed under different conditions. Enantiopure nitriles or carboxylic acids can also be employed leading to chiral KE with high enantiopurity and dinitriles or dicarboxylic acids also lead to the expected bis-β-ketoenamides. β-Ketoenamides incorporate a unique combination of functional groups and hence a manifold of subsequent reactions to highly substituted heterocyclic compounds is possible. An intramolecular aldol-type condensation reaction efficiently furnishes pyridin-4-ols PY that can be further modified by palladium-catalyzed reactions, e.g., to specifically substituted furopyridine derivatives. Condensations of β-ketoenamides with ammonium salts or with hydroxylamine hydrochloride afford pyrimidines PM or pyrimidine N-oxides PO with a highly flexible substitution pattern in good yields. The functional groups of these heterocycles also allow a variety of subsequent reactions to various pyrimidine derivatives. On the other hand, acid-labile alkoxy substituents such as a 2-(trimethylsilyl)ethoxy group are required for the conversion of β-ketoenamides into 5-acetyl-substituted oxazoles OX, again compounds with high potential for subsequent functional group transformations. For acid labile β-ketoenamides bearing bulky substituents the acid treatment leads to acylamido-substituted 1,2-diketones DK that could be converted into quinoxalines QU. All classes of heterocycles accessed through the key β-ketoenamides show a unique substitution pattern – not easily accomplishable by alternative methods – and therefore many subsequent reactions are possible.

Novel π-conjugated systems based on pyrimidine N-Oxide

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.

Preparation and Reactions of Trichloromethyl-Substituted Pyridine and Pyrimidine Derivatives

The three-component reaction of lithiated methoxyallene, nitriles and trichloroacetic acid gave three model β-keto enamides that were starting materials for the synthesis of trichloromethyl-substituted pyridine and pyrimidine N-oxide derivatives. Upon treatment with acetic anhydride, the methyl group of the prepared pyrimidine N-oxides was converted into an acetoxymethyl group by a Boekelheide rearrangement. A few typical experiments also revealed that the trichloromethyl group of the prepared pyrimidine N-oxides can be replaced by an alkoxy or a hydroxy group, or transformed into an arylthiomethyl group. An alternative approach to β-keto enamides via the corresponding β-keto enamines was also examined and provided the expected 4-hydroxy-6-(trichloromethyl)pyridine derivative in good yield.

Substituent effects on stereoselectivity of dihalocarbene reactions with cyclohexadiene and on the reactivity of bis-dihalocyclopropanes in electrophilic nitrations en route to pyrimidine N-oxides.

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.

Near-Infrared Photoluminescence in Hexacyanido-Bridged Nd–Cr Layered Ferromagnet

Hexacyanidochromate(III) anion is here explored as the building block for the construction of bimetallic 3d-4f coordination polymers that combine spin ordering and luminescence. We report the two-dimensional cyanido-bridged {[NdIII(pmmo)2(H2O)3][CrIII(CN)6]} (1) layered framework obtained by the spontaneous crystallization from the aqueous solution of Nd3+, pyrimidine N-oxide (pmmo), and [CrIII(CN)6]3–. 1 crystallizes as light green plates in the orthorhombic Pbca space group and reveals a topology of a square grid built of nine-coordinated [NdIII(μ-NC)4(H2O)3(pmmo)2]− complexes of a nearly capped square antiprism geometry, and six-coordinated octahedral [CrIII(CN)6]3– moieties. Because of the presence of cyanide-mediated ferromagnetic coupling between paramagnetic NdIII (J = 9/2) and CrIII (S = 3/2) centers, 1 exhibits a long-range ferromagnetic ordering below Curie temperature of 2.8 K, with a tiny magnetization-field hysteresis loop detected at 1.8 K. Under the UV light irradiation, 1 shows the near-in...

Bis(gem-dihalocyclopropanes): synthesis and heterocyclization upon treatment with nitronium triflate

A reaction of octa-1,7and deca-1,9-dienes with an excess of bromofluorocarbene proceeds predominantly with the formation of a monoadduct, whereas the bis-adduct can be prepared by repeated cyclopropanation. The [1+2] cycloaddition of dichlorocarbene to the monoadduct of bromofluorocarbene with deca-1,9-diene gave a new bis(cyclopropane) containing gem-dichloro- and gem-bromofluorocyclopropane fragments in one molecule. The bis-adducts obtained were subjected to the heterocyclization with nitronium triflate: in the case of bis(gem-bromofluorocyclopropane) the reaction proceeded with retention of one dihalocyclopropane fragment and gave mononuclear pyrimidine N-oxide.

Nitronium salts as novel reagents for the heterocyclization of gem-bromofluorocyclopropanes into pyrimidine derivatives

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 (NO2+)(CF3SO3−).

Elucidating the Mechanism of Cytochrome P450–Mediated Pyrimidine Ring Conversion to Pyrazole Metabolites with the BACE1 Inhibitor GNE-892 in Rats

We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one), a β-secretase 1 inhibitor. Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the (14)C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for <5% of the administered dose, their unique nature prompted us to conduct further investigations. The pyrazole-containing metabolites were formed in vitro with rat hepatocytes and liver microsomes, which supported that they were formed during hepatic metabolism. Further, their generation was inhibited by 1-aminobenzotriazole, indicating involvement of cytochrome P450s. Studies with rat recombinant enzymes identified that CYP2D2 generated the N-hydroxypyrazole metabolite from GNE-892. This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide. On the basis of these data, we propose a mechanism in which the pyrimidine is activated via N-oxidation, followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate. After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazole ring. This article highlights a mechanistic approach for determining the biotransformation of the pyrimidine to a pyrazole for GNE-892.

One-Step Conversion of Azine N-Oxides to α-N-Aryltriflamidoazines

Various pyridine, quinoline, isoquinoline, and pyrimidine N-oxides were converted to their corresponding α-N-aryltriflamidoheteroarenes in good yield by treatment with N-aryltriflimides, both neat and in solution, at temperatures ranging from rt to 100 °C.

Three-Component Heterocyclization of gem-Bromofluorocyclopropanes with NOBF4: Access to 4-Fluoropyrimidine N-Oxides

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.

Experimental and theoretical molecular and electronic structures of the N-oxides of pyridazine, pyrimidine and pyrazine

The structures of pyridazine N-oxide, pyrimidine N-oxide and pyrazine N-oxide have been determined by X-ray diffraction for the first time. Comparison with theoretical predictions of the equilibrium structures using the B3LYP method together with a cc-pVTZ basis set, show close agreement with the structural parameters observed, and experimental dipole moments, which suggests that the charge distribution is realistic. An ‘atoms in molecules’ (AIM) analysis of the computed wave-functions shows total electron densities rather different from the classical picture of a dative bond, whereas the same wave-functions subjected to Mulliken analysis show a more conventional view of the electron distribution. This latter procedure allows a bond dipole analysis of the N-oxide charge distribution.

Synthesis of Lead(II) Minoxidil Coordination Polymer: A New Precursor for Lead(II) Oxide and Lead(II) Hydroxyl Bromide

A new lead(II) coordination polymer, [PbBr2(C9H15N5O)]n (1), where C9H15N5O is (2,4-diamino-6-piperidine-1-yl) pyrimidine N-oxide (minoxidil) is synthesized and characterized. Polymer 1 is synthesized in methanol by sonochemical and hydrothermal methods from lead(II) acetate, KBr and the minoxidil ligand. The crystal structure of [PbBr2(C9H15N5O)]n indicates a syndiotactic coordination polymer. The Pb(II) atom lies on a mirror plane; the mirror plane is perpendicular to the pyrimidine ring bisecting the piperidine ring. N–H···O intramolecular and C–H···Br, N–H···N strong intermolecular interactions were observed. Micro-rods of PbO and nano-plates of PbOHBr were prepared by thermal decomposition of the nano-structured [PbBr2(C9H15N5O)]n as a precursor. Characterization of the products was carried out using X-ray crystallography, elemental analysis, FTIR spectroscopy, scanning electron microscopy, energy dispersive X-ray analysis and thermal analysis. The sonochemical method resulted in a significant reduction of reaction time, reaction temperature and particle sizes of the products.

One-Step Conversion of Azine N-Oxides to α-1,2,4-Triazolo-, 1,2,3-Triazolo, Imidazolo-, and Pyrazoloheteroarenes

Pyridine, quinoline, isoquinoline, azaindole, and pyrimidine N-oxides were converted to their alpha-triazole and alpha-diazole derivatives by treatment with the corresponding p-toluenesulfonylazoles and Hunig's base at elevated temperatures.

One-Step Synthesis of Imidazolo-Heteroarenes from Heteroarene N-Oxides

A one-step procedure for the introduction of an imidazole unit into unsubstituted, mono-, and disubstituted heteroarene N-oxides is described. Thus treatment of various pyridine, quinoline, isoquinoline, pyrimidine N-oxides with sulfuryl diimidazole at elevated temperatures leads to the corresponding α-imidazoloheteroarenes in fair to excellent yields. Electron-rich N-oxides led to optimum yields under mild conditions, whereas electron-poor, sterically encumbered substrates required longer reaction times and higher temperatures. A mechanism is proposed.

Preparation of Biphenylene‐ and Benzocyclooctene‐Fused Heterocycles.

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Cross-Coupling Reactions of DiazineN-Oxides with Aryl Halides

A reasonably efficient Pd-catalyzed cross-coupling of diazine N-oxides with aryl­halides to afford aryl diazines is reported. In view of the absence of metalated (B, Zn, Mg, Sn) partners, the process may be formally categorized in the C-H-activation group of reactions. The reaction proceeds with pyrazines, pyrimidines, and pyridazine N-oxides to introduce aryl substituents ortho to the N-oxide function. The scope of hetero­cycle substitutent R1 received inadequate attention whereas that of R2, the aryl halides (bromides, iodides, and even chlorides), has been thoroughly investigated in terms of electron-donating and -withdrawing groups. An interesting catalyst inhibitory effect in the coupling reactions of pyrimidine N-oxides was noted but not elucidated.