3-Halo-5,6-dihydro-4H-1,2-oxazine N-oxides as synthetic equivalents of unsaturated nitrile oxides in the [3 + 2]-cycloaddition with arynes: synthesis of substituted 3-vinyl-1,2-benzisoxazoles.

The reaction of 3-halo-5,6-dihydro-4H-1,2-oxazine N-oxides with arynes was studied. Arynes were generated from o-silylaryl triflates and underwent consecutive [3 + 2]-cycloaddition/[4 + 2]-cycloreversion with N-oxides leading to substituted 3-vinyl-benzisoxazoles in high yields. In the presented sequence, 1,2-oxazine N-oxides act as surrogates of rarely employed unsaturated nitrile oxides. A broad substrate scope was demonstrated. The influence of the substitution pattern of an aryne on the reaction outcome was determined. In the presence of bulky substituents, polycyclic 4,4a-dihydro-3H-benzofuro[3,2-c][1,2]oxazines were selectively formed. Mechanistic schemes for the observed reaction pathways were proposed. The synthetic utility of the products was demonstrated by their follow-up modifications.

An Intramolecular Nitroso-Meerwein-Ponndorf-Verley-Oppenauer Reaction to Access Fused Pyrrolidine Scaffolds.

δ-Hydroxy chloronitroso compounds generated in situ from 1,2-oxazine N-oxides undergo a 1,5-hydride transfer related to the Meerwein-Ponndorf-Verley-Oppenauer reaction. Based on the process discovered, a three-step access to fused pyrrolidine scaffolds containing up to four contiguous stereogenic centers starting from simple nitrostyrenes and cycloalkenes or cyclodienes has been developed. The suggested reaction mechanism was confirmed by in situ UV-vis and ATR FT-IR monitoring and DFT calculations.

Catalytic Reductive Recyclization of Functionalized Isoxazoline N-Oxides to Pyrrolizidine-3-ones.

Pyrrolizidine is among the saturated N-heterocyclic scaffolds most frequently found in natural products and pharmaceutically relevant substances. Herein, a strategy for the synthesis of polysubstituted pyrrolizidine-3-ones by catalytic reductive domino-type recyclization of properly functionalized isoxazoline N-oxides was developed. The process is diastereoselective, and one diastereomer (out of four possible ones) is predominant in many of the studied cases. Using the developed method, modifications of potent GSK's PDE4 inhibitor and MSD's potent hNK1 antagonist were prepared.

Crown-hydroxylamines are pH-dependent chelating N,O-ligands with a potential for aerobic oxidation catalysis.

Despite the rich coordination chemistry, hydroxylamines are rarely used as ligands for transition metal coordination compounds. This is partially because of the instability of these complexes that undergo decomposition, disproportionation and oxidation processes involving the hydroxylamine motif. Here, we design macrocyclic poly-N-hydroxylamines (crown-hydroxylamines) that form complexes containing a d-metal ion (Cu(II), Ni(II), Mn(II), and Zn(II)) coordinated by multiple (up to six) hydroxylamine fragments. The stability of these complexes is likely to be due to a macrocycle effect and strong intramolecular H-bonding interactions between the N-OH groups. Crown-hydroxylamine complexes exhibit interesting pH-dependent behavior where the efficiency of metal binding increases upon deprotonation of the hydroxylamine groups. Copper complexes exhibit catalytic activity in aerobic oxidation reactions under ambient conditions, whereas the corresponding complexes with macrocyclic polyamines show poor or no activity. Our results show that crown-hydroxylamines display anomalous structural features and chemical behavior with respect to both organic hydroxylamines and polyaza-crowns.

Building Up a Piperazine Ring from a Primary Amino Group via Catalytic Reductive Cyclization of Dioximes.

Piperazine is one of the most frequently found scaffolds in small-molecule FDA-approved drugs. In this study, a general approach to the synthesis of piperazines bearing substituents at carbon and nitrogen atoms utilizing primary amines and nitrosoalkenes as synthons was developed. The method relies on sequential double Michael addition of nitrosoalkenes to amines to give bis(oximinoalkyl)amines, followed by stereoselective catalytic reductive cyclization of the oxime groups. The method that we developed allows a straightforward structural modification of bioactive molecules (e.g., α-amino acids) by the conversion of a primary amino group into a piperazine ring.

Michael addition of P-nucleophiles to azoalkenes provides simple access to phosphine oxides bearing an alkylhydrazone moiety.

ß-Hydrazonophosphine oxides are precursors of useful organophosphorus compounds, including phosphorylated N-heterocycles, α-aminophosphonates, and vinylphosphonates. In this work, a general transition metal-free synthesis of ß-hydrazonophosphine oxides was developed. The method relies on the Michael addition of phosphine oxides R2P(O)H to reactive azoalkenes (1,2-diaza-1,3-butadienes), which are generated in situ from α-halohydrazones and Hunig's base. The reaction stereoselectively leads to Z-isomers of ß-hydrazonophosphine oxides that are stabilized by intramolecular hydrogen bonding. The conversion of the products thus obtained into potential chelating ligands was showcased.

Nitronate-aryne cycloaddition as a concise route to stereochemically complex fused benzisoxazolines and amino alcohols.

The reaction of cyclic nitronates (isoxazoline N-oxides and 5,6-dihydro-4H-1,2-oxazine N-oxides) with Kobayashi's aryne precursors affords tricyclic benzene-fused nitroso acetals as a result of [3 + 2]-cycloaddition. The process is regio- and stereoselective in most cases and produces the target cycloadducts possessing up to four contiguous stereogenic centers. These nitroso acetals were shown to be convenient precursors of valuable polysubstituted aminodiols through catalytic hydrogenolysis of the N-O bonds. Also, the action of protic acids resulted in an unusual fragmentation of the cyclic nitroso acetal moiety through heterolytic N-O bond cleavage and Beckmann-type reaction. Using this acid-mediated reaction, the synthesis of a hitherto unknown hexahydrobenzo[4,5]isoxazolo[2,3-a]azepine scaffold was accomplished.

Interrupted Nef and Meyer Reactions: A Growing Point for Diversity-Oriented Synthesis Based on Nitro Compounds.

The Nef reaction (nitro to carbonyl group conversion) and related Meyer reaction are among the key transformations of aliphatic nitro compounds. The interrupted versions of these reactions in which the normal pathway is redirected to a different end product by an external nucleophile are much less common, albeit these processes substantially increase the synthetic potential of nitro compounds. In this review, examples of interrupted Nef and Meyer reactions are summarized, and the prospects of this methodology in diversity-oriented organic synthesis are analyzed. The bibliography contains 90 references.

Interrupted Nef Reaction of Cyclic Nitronates: Diastereoselective Access to Densely Substituted α-Chloronitroso Compounds.

The reaction of cyclic nitronic esters (isoxazoline- and 5,6-dihydro-4H-1,2-oxazine-N-oxides) with hydrochloric acid affords geminal chloronitroso compounds bearing a distant hydroxyl group. The reaction is usually diastereoselective, and in some cases stereodivergent formation of isomers at different temperatures is observed. The discovered process represents the first example of an interrupted Nef reaction of nitronic esters. DFT calculations support the initial formation of N,N-bis(oxy)iminium cations (key intermediates in the Nef reaction), which are intercepted by the chloride anion followed by ring opening. The synthetic utility of the resulting functionalized chloronitroso compounds in the Diels-Alder reaction with cyclopentadiene was demonstrated.

1,4,6,10-Tetraazaadamantanes (TAADs) with N-amino groups: synthesis and formation of boron chelates and host-guest complexes.

A synthetic route to 1,4,6,10-tetraazaadamantanes (TAADs) bearing free and protected amino groups at the bridge N-atoms has been developed via intramolecular cyclotrimerization of C=N units in the corresponding tris(hydrazonoalkyl)amines. In a similar fashion, unsymmetrically substituted TAADs having both amino and hydroxy groups at the bridge N-atoms were prepared via a hitherto unknown co-trimerization of oxime and hydrazone groups. The use of N-TAAD derivatives as potential ligands and receptors was showcased through forming boron chelates and host-guest complexes with water and simple alcohols.

Regio- and diastereoselective access to densely functionalized ketones via the Boekelheide rearrangement of isoxazoline N-oxides.

In this work, the classical "isoxazoline route" toward aldols involving the [3 + 2]-cycloaddition of nitrile oxide to alkenes and hydrogenolysis of the oxime group was revisited. To avoid regioselectivity issues, [4 + 1]-annulation of nitroalkenes with sulfonium ylides was used to construct the isoxazoline ring bearing an N-oxide moiety. Subsequent deoxygenative C-H functionalization using the Boekelheide rearrangement and hydrogenolysis of the isoxazoline ring afforded α'-acyloxy-substituted aldols, which are difficult to access both by the classical aldol reaction and the "isoxazoline route". The products are formed in good to high overall yields and as single diastereomers in most cases. The synthetic use of these aldols was showcased by their smooth transformation into diastereomerically pure triols and a 2,3-diaryl-4-hydroxy-substituted tetrahydrofuran derivative, which is structurally related to cinncassin B.

Deoxygenative Arylation of 5,6-Dihydro-4H-1,2-oxazine-N-oxides with Arynes.

Six-membered cyclic nitronates (5,6-dihydro-4H-1,2-oxazine-N-oxides) react with Kobayashi's aryne precursors producing 3-(2-hydroxyaryl)-substituted 1,2-oxazines via deoxygenative C-H arylation. The process involves a hitherto unknown 1,3-dipolar cycloaddition of nitronate to the aryne to give an unusual tricyclic nitroso acetal, in which the N-O bond of the isoxazoline ring is selectively cleaved upon the action of a base (CsF) or an acid (TFA). The transient cycloadducts were isolated and characterized in some cases. The synthetic potential of the obtained 3-(2-hydroxyaryl)-substituted 1,2-oxazines was demonstrated by their stereoselective reduction to 1,4-amino alcohols and reductive 1,2-oxazine ring contraction to tetrahydrofuran derivatives.

Iron(IV) complexes with tetraazaadamantane-based ligands: synthesis, structure, applications in dioxygen activation and labeling of biomolecules.

4,6,10-Trihydroxy-1,4,6,10-tetraazaadamantane (TAAD) has been shown to form a stable Fe(IV) complex having a diamantane cage structure, in which the metal center is coordinated by three oxygen atoms of the deprotonated ligand. The complex was characterized by X-ray diffraction analysis, HRMS, NMR, FT-IR, Mössbauer spectroscopy and DFT calculations, which supported the d4 configuration of iron. The Fe(IV)-TAAD complex showed excellent performance in dioxygen activation under mild conditions serving as a mimetic of the thiol oxidase enzyme. The nucleophilicity of the bridgehead nitrogen atom in TAAD provides a straightforward way for the conjugation of Fe(IV)-TAAD complexes to various functional molecules. Using this approach, steroidal and peptide molecules having an iron(IV) label have been prepared for the first time. In addition, the Fe(IV)-TAAD complex was covalently bound to a polystyrene matrix and the resulting material was shown to serve as a heterogeneous catalyst for aerobic oxidation of thiols to disulfides.

Construction of Saturated Oxazolo[3,2-b][1,2]oxazines via Tandem [3+2]-Cycloaddition/[1,3]-Rearrangement of Cyclic Nitronates and Ketenes.

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.

Revealing the Structure of Transition Metal Complexes of Formaldoxime.

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, Mössbauer 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.

Merging Boron with Nitrogen-Oxygen Bonds: A Review on BON Heterocycles.

Cyclic boronate esters play important roles in organic synthesis, pharmacology, supramolecular chemistry and materials science owing to their stability in air and versatile reactivity. Most of these compounds contain a B-O-C linkage with an alkoxy- or carboxylate group bound to the boron atom (e.g. boronate-diol esters, MIDA boronates). Boron chelates comprising a B-O-N motif (BON heterocycles) are much less explored, although first representatives of this class were prepared in the early 1960s. In recent years, there has been a growing interest in BON heterocycles as new chemotypes for drug design. The exocyclic B-O-N linkage, which is readily formed under mild conditions, shows surprising hydrolytic and thermal resistance. This allows the formation of BON heterocycles to be used as click-type reactions for the preparation of bioconjugates and functionally modified polymers. We believe that BON heterocycles are promising yet underrated organoboron derivatives. This review summarizes the scattered information about known types of BON heterocycles, including their synthesis, reactivity and structural data. Available applications of BON heterocycles in materials science and medicinal chemistry, along with their prospects, are also discussed. The bibliography contains 289 references.

The Cyclic Nitronate Route to Pharmaceutical Molecules: Synthesis of GSK's Potent PDE4 Inhibitor as a Case Study.

An efficient asymmetric synthesis of GlaxoSmithKline's potent PDE4 inhibitor was accomplished in eight steps from a catechol-derived nitroalkene. The key intermediate (3-acyloxymethyl-substituted 1,2-oxazine) was prepared in a straightforward manner by tandem acylation/(3,3)-sigmatropic rearrangement of the corresponding 1,2-oxazine-N-oxide. The latter was assembled by a (4 + 2)-cycloaddition between the suitably substituted nitroalkene and vinyl ether. Facile acetal epimerization at the C-6 position in 1,2-oxazine ring was observed in the course of reduction with NaBH3CN in AcOH. Density functional theory (DFT) calculations suggest that the epimerization may proceed through an unusual tricyclic oxazolo(1,2)oxazinium cation formed via double anchimeric assistance from a distant acyloxy group and the nitrogen atom of the 1,2-oxazine ring.

Asymmetric Synthesis of Merck's Potent hNK1 Antagonist and Its Stereoisomers via Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine N-Oxides.

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.