Oxygen Nucleophiles Research Articles

Palladium-Catalyzed Dearomative syn-1,4-Oxyamination.

A palladium-catalyzed dearomative syn-1,4-oxyamination protocol using non-activated arenes has been developed. This one-pot procedure utilizes arenophile chemistry, and the corresponding para-cycloadducts are treated with oxygen nucleophiles via formal allylic substitution, providing direct access to syn-1,4-oxyaminated products. The reaction conditions permit a range of arenes, as well as different O-nucleophiles, such as oximes and benzyl alcohols. Moreover, this process was established in an asymmetric fashion, delivering products with high enantioselectivity. The dearomatized products are amenable to a multitude of further derivatizations ranging from olefin chemistry to C-H activation, giving rise to a diverse set of new functionalities. Overall, this dearomative functionalization offers rapid and controlled formation of molecular complexity, enabling straightforward access to functionalized small molecules from simple and readily available arenes.

Mechanism and Origins of Enantioselectivities in Spirobiindane-Based Hypervalent Iodine(III)-Induced Asymmetric Dearomatizing Spirolactonizations.

The work of Kita et al. on asymmetric oxidative dearomatization of naphthol carboxylic acids to spirolactones mediated/catalyzed by a novel, conformationally rigid μ-oxo-bridged hypervalent iodine(III) species is a landmark discovery in enantioselective iodine(III) catalysis [Kita, Y.; et al. Angew. Chem., Int. Ed. 2008, 47, 3787. DOI: 10.1002/anie.200800464 ; J. Am. Chem. Soc. 2013, 135, 4558. DOI: 10.1021/ja401074u ]. We have investigated the detailed mechanism of this important transformation using density functional theory. Calculations revealed that proton transfer from the pendant carboxylic acid of naphthols to the bridging oxygen atom or the ligand of iodine(III) species, which enhances the nucleophilicity of the carboxylic oxygen and the nucleofugality of the iodoarene, is crucial for the dearomatizing spirolactonization. Halogen bonding between the resulting carboxylate and the electron-deficient iodine(III) center further stabilizes the dearomatizing spirolactonization transition states. Calculations also revealed a long-neglected cleaved μ-oxo iodine(III) species that is more reactive but less selective than the μ-oxo-bridged hypervalent iodine(III) species itself for the oxidative dearomatization of naphthols. The coexistence of two sequential dearomatizing spirolactonization processes in the reaction system results in a lower enantioselectivity. A new stereochemical model that is able to reproduce and rationalize the observed apparent enantioselectivities is proposed.

Site Selectivity of Halogen Oxygen Bonding in 5- and 6-Haloderivatives of Uracil

Seven 5-and 6-halogenated derivatives of uracil or 1-methyluracil (halogen = Cl, Br, I) were studied by single crystal X-ray diffraction. In contrast with pure 5-halouracils, where the presence of N-H⋯O and C-H⋯O hydrogen bonds prevents the formation of other intermolecular interactions, the general ability of pyrimidine nucleobases to provide electron donating groups to halogen bonding was confirmed in three crystals and cocrystals containing uracil with the halogen atom at the C6 position. In the latter compounds, among the two nucleophilic oxygen atoms in the C=O moiety, only the urea carbonyl oxygen O1 can act as halogen bond acceptor, being not saturated by conventional hydrogen bonds. The halogen bonds in pure 6-halouracils are all rather weak, as supported by Hirshfeld surface analysis. The strongest interaction was found in the structure of 6-iodouracil, which displayed the largest (13%) reduction of the sum of van der Waals (vdW) radii for the contact atoms. Despite this, halogen bonding plays a role in determining the crystal packing of 6-halouracils, acting alongside conventional hydrogen bonds.

Xenon Trioxide Adducts of O‐Donor Ligands; [(CH3)2CO]3XeO3, [(CH3)2SO]3(XeO3)2, (C5H5NO)3(XeO3)2, and [(C6H5)3PO]2XeO3

Xenon trioxide (XeO3 ) forms adducts with triphenylphosphine oxide, dimethylsulfoxide, pyridine-N-oxide, and acetone by coordination of the ligand oxygen atoms to the XeVI atom of XeO3 . The crystalline adducts were characterized by low-temperature, single-crystal X-ray diffraction, and Raman spectroscopy. Unlike solid XeO3 , which detonates when mechanically or thermally shocked, solid (C5 H5 NO)3 (XeO3 )2 , [(C6 H5 )3 PO]2 XeO3 , and [(CH3 )2 SO]3 (XeO3 )2 are insensitive to mechanical shock. The [(CH3 )2 SO]3 (XeO3 )2 adduct slowly decomposes over several days to (CH3 )2 SO2 , Xe, and O2 . All three complexes undergo rapid deflagration when ignited by a flame. Both [(C6 H5 )3 PO]2 XeO3 and (C5 H5 NO)3 (XeO3 )2 are room-temperature stable and the [(CH3 )2 CO]3 XeO3 complex dissociates at room temperature to form a stable solution of XeO3 in acetone. The xenon coordination sphere of [(C6 H5 )3 PO]2 XeO3 , a distorted square-pyramid, provides the first example of a five-coordinate XeO3 complex with only two Xe- - -O adduct bonds. The xenon coordination spheres of the remaining adducts are distorted octahedra, comprised of three Xe- - -O secondary bonds that are approximately trans to the primary Xe-O bonds of XeO3 . Quantum-chemical calculations were used to assess the nature of the Xe- - -O adduct bonds, which are described as predominantly electrostatic bonds between the nucleophilic oxygen atoms of the bases and the σ-holes of the electrophilic xenon atoms.

Cu(I)-Catalyzed Oxygen and Nitrogen Nucleophiles Triggered Regioselective Synthesis of Furo/Pyrrolo-Annulated Quinolines.

Cu(I)-catalyzed intramolecular annulation of o-ethynylquinoline-3-carbaldehydes leads to the synthesis of alkoxy/imidazole-substituted 1,3-dihydrofuro[3,4-b]quinolines via C-O and C-N bond formation. The scope of the reaction was further extended to o-ethynylquinoline-3-carbonitriles for the synthesis of alkoxy-substituted 3H-pyrrolo[3,4-b]quinolines using alcohols as nucleophiles. These reactions are regioselectively favoring the 5-exo-dig cyclizations in all the annulation processes.

The Carboxylate Ligand as an Oxide Relay in Catalytic Water Oxidation.

Carboxylate groups have diverse functionalities in ligands of transition metal catalysts. Here we present a conceptually different function of the carboxylates: the oxide relay. It functions by providing an intramolecular nucleophilic oxygen close to the oxo group to facilitate O-O bond formation and at a later stage a remote electrophilic center to facilitate OH- nucleophilic attack. Empirical valence bond-molecular dynamics (EVB-MD) models were generated for key bond forming steps, diffusion coefficients and binding free energies from potential of mean force estimations were calculated from molecular dynamics (MD) simulations, activation free energies of chemical steps were calculated using density functional theory (DFT). The catalyst studied is the extremely active Ru(tda)(py)2 water oxidation catalyst. The combination of simulation methods allowed for estimation of the turnover frequencies, which were within 1 order of magnitude from the experimental results at different pH values. From the calculated reaction rates we find that at low pH the OH- anion nucleophilic attack is the rate-limiting step, which changes at high pH to the O-O bond formation step. Both steps are extremely rapid, and key to the efficiency is the oxide relay functionality of a pendant carboxylate group. We cannot exclude all alternative mechanisms and suggest isotope experiments using 18O-labeled water to support or invalidate the oxide relay mechanism. The functionality was discovered for a ruthenium catalyst, but since there is nothing in the mechanism restricting it to this metal, the oxide relay functionality could open new ways to design the next-generation water oxidation catalysts with improved activity.

Recent Developments in Peptidyl Diaryl Phoshonates as Inhibitors and Activity-Based Probes for Serine Proteases.

This review presents current achievements in peptidyl diaryl phosphonates as covalent, specific mechanism-based inhibitors of serine proteases. Along three decades diaryl phosphonates have emerged as invaluable tools in fundamental and applicative studies involving these hydrolases. Such an impact has been promoted by advantageous features that characterize the phosphonate compounds and their use. First, the synthesis is versatile and allows comprehensive structural modification and diversification. Accordingly, reactivity and specificity of these bioactive molecules can be easily controlled by appropriate adjustments of the side chains and the leaving groups. Secondly, the phosphonates target exclusively serine proteases and leave other oxygen and sulfur nucleophiles intact. Synthetic accessibility, lack of toxicity, and promising pharmacokinetic properties make them good drug candidates. In consequence, the utility of peptidyl diaryl phosphonates continuously increases and involves novel enzymatic targets and innovative aspects of application. For example, conjugation of the structures of specific inhibitors with reporter groups has become a convenient approach to construct activity-based molecular probes capable of monitoring location and distribution of serine proteases.

Chemoselective, Regioselective, and Enantioselective Allylations of NH2OH under Iridium Catalysis.

The utilization of unprotected NH2OH, which is not only an oxygen nucleophile but also a nitrogen nucleophile, in iridium-catalyzed allylic substitution is realized under mild conditions. The chemoselectivity, stereoselectivity, and multiple allylation are controlled by adjusting the reaction conditions. This method produces the N-(1-allyl)hydroxylamines in good to high yields with high level of chemoselectivities, regioselectivities, and enantioselectivities. The application of allylated hydroxylamine (R)-3a in the synthesis of diallylated hydroxylamine 6 is achieved, along with an excellent diastereomeric ratio.

Unexpected intramolecular nucleophilic cyclization of ureidoacetamide: A novel route towards the synthesis of 2,4,5-trisubsituted oxazoles

A variety of N, 2-diaryl-2-ureidoacetamide prepared from the condensation of N-aryl-α-aminoamide with potassium cyanate (KOCN) undergo efficient Hendrickson’s reagent-mediated nucleophilic cyclization to afford 2,5-diamine-4-aryloxazoles. The two-step synthesis provides seven target products in yields of 61–78% under mild conditions. This reaction involves an unusual pathway in which the electrophilic amide carbonyl carbon is activated by Hendrickson’s reagent and attacked by a nucleophilic ureido oxygen in a 5-exo-trig O-cycloisomerization.

General Synthetic Approach for the Laurencia Family of Natural Products Empowered by a Potentially Biomimetic Ring Expansion.

The Laurencia family of C15-acetogenins is Nature's largest collection of halogenated natural products, with many of its members possessing a brominated 8-membered cyclic ether among other distinct structural elements. Herein, we demonstrate that a bromonium-induced ring expansion, starting from a common tetrahydrofuran-containing bicyclic intermediate and using the highly reactive bromenium source BDSB (Et2SBr·SbCl5Br), can lead to concise asymmetric total syntheses of microcladallenes A and B, desepilaurallene, laurallene, and prelaureatin. Key advances in this work include (1) the first demonstration that the core bromonium-induced cyclization/ring-expansion can be initiated using an enyne with an internal ether oxygen nucleophile, (2) that reasonable levels of stereocontrol in such processes can be achieved both with and without appended ring systems and stereogenic centers, (3) that several other unique chemoselective transformations essential to building their polyfunctional cores can be achieved, and (4) that a single, common intermediate can lead to five different members of the class encompassing two distinct 8-membered cyclic ether ring collections. Considering this work along with past efforts leading to two other natural products in the collection, we believe the breadth of structures prepared to date affords strong evidence for Nature's potential use of similar processes in fashioning these unique molecules.

Preparation of two series of VxSiBeta zeolite catalysts with V centres in framework and extra-framework positions and their application in selective oxidation of methanol

Two series of V-containing Beta zeolites have been prepared by contacting of the aqueous NH4VO3 solution with two SiBeta zeolites at pH = 2.5 and 6, respectively. Because of the presence in NH4VO3 solution at pH = 2.5 mainly monomeric VO2+ ions, vanadium have been easily incorporated into framework of SiBeta zeolite as pseudo-tetrahedral non hydroxylated (SiO)3V = O and hydroxylated (SiO)2(OH)V = O species. The moderate nucleophilicity of the basic vanadyl oxygen of the latter species play important role in methanol oxidation toward formaldehyde. The selectivity toward formaldehyde on this series of VxSiBeta(I) increases with the amount of pseudo-tetrahedral hydroxylated (SiO)2(HO)V = O species, which act as either redox or acidic and basic centres. In contrast at pH = 6, the aqueous NH4VO3 solution is expected to contain both mononuclear and polynuclear V ions, thus it is more difficult to incorporate V species in SiBeta at this condition as shown by FT-IR and NMR data. The absence of pseudo-tetrahedral V species in framework position of V0.6SiBeta(II) is probably responsible for lack of activity of this catalyst in methanol oxidation. The appearance of this species in the series of VxSiBeta(II) zeolites for high V content leads to their activity in methanol oxidation toward formaldehyde.

Vanadium-Catalyzed Coupling of Allenols with Electrophilic Halide Sources for the Formation of α-Halo-α′,β′-unsaturated Ketones

A vanadium-catalyzed coupling of allenylic alcohols with electrophilic halide sources to form α-halo-α',β'-unsaturated ketones is described. The process proceeds through a metal enolate formed from the 1,3-transposition of an allenol that is initiated by a cheap and earth-abundant vanadium oxo catalyst. Fluorine, chlorine, and bromine electrophiles can be utilized, and the resulting products can give rise to the introduction of nitrogen, oxygen, sulfur, and iodine nucleophiles α to the ketone through substitution chemistry.

Nucleophile-intercepted Beckmann fragmentation reactions.

We describe the first examples of nucleophile-intercepted Beckmann fragmentations of indoline oximes. This reaction uses MsCl as a promoter to give cyano chlorides and is believed to proceed through an aziridinium intermediate via a double stereoinvertive process. Mechanistic insights have led to the further discovery that oxygen, nitrogen, and bromide nucleophiles can be employed for this fragmentation by the use of other promoters. We envision that these products may be useful in the syntheses of members of the akuammiline and koumine families of indoline alkaloids.

Copper-Catalyzed Modular Amino Oxygenation of Alkenes: Access to Diverse 1,2-Amino Oxygen-Containing Skeletons

Copper-catalyzed alkene amino oxygenation reactions using O-acylhydroxylamines have been achieved for a rapid and modular access to diverse 1,2-amino oxygen-containing molecules. This transformation is applicable to the use of alcohols, carbonyls, oximes, and thio-carboxylic acids as nucleophiles on both terminal and internal alkenes. Mild reaction conditions tolerate a wide range of functional groups, including ether, ester, amide, carbamate, and halide. The reaction protocol allows for starting with free amines as the precursor of O-benzoylhydroxylamines to eliminate their isolation and purification, contributing to broader synthetic utilities. Mechanistic investigations reveal the amino oxygenation reactions may involve distinct pathways, depending on different oxygen nucleophiles.

Rhodium-Catalyzed Tandem Reaction of Isocyanides with Azides and Oxygen Nucleophiles: Synthesis of Isoureas.

A novel rhodium-catalyzed tandem reaction of isocyanides with azides and various oxygen nucleophiles has been developed. The reaction provides a simple and highly efficient one-pot synthesis of various N-sulfonyl/acylisoureas with broad substrate scope in an atom-economical manner from readily available starting materials in a highly stereoselective manner.

Utility of 3-benzylidenefuran-2(3H)-one and 3-benzylideneisobenzofuran-1(3H)-one as precursors of biologically active novel heterocycles

In the present work, 3-benzylidenefuran 2 and 3-benzylideneisobenzofuran 3 derivatives were investigated in a comparative study in which they were utilized as building blocks to construct different heterocyclic compounds. Therefore, they were allowed to react with different nitrogen and oxygen nucleophiles under the same conditions to afford some novel compounds 4–16. All the structures of the synthesized compounds 2–16 were elucidated based on their elemental analyses and spectral measurements. The bioactivities of the synthesized compounds were evaluated, where some of tested compounds exhibited promising antimicrobial, antitumor, and antioxidant activities.

Three-Component Ring-Opening Reactions of Cyclic Ethers, α-Diazo Esters, and Weak Nucleophiles under Metal-Free Conditions.

A protocol for three-component reactions of cyclic ethers, α-diazo esters, and weak nitrogen, oxygen, carbon, and sulfur nucleophiles (p Ka = 2.2-14.8) to afford a variety of structurally complex α-oxyalkylated esters is reported. These reactions involve intermolecular activation of the cyclic ether (present in excess) by the α-diazo ester to form an oxonium ylide under metal-free conditions, followed by ring opening by the nucleophile.

Regioselectivity, stereoselectivity, and molecular mechanism of [3\u2009+\u20092] cycloaddition reactions between 2-methyl-1-nitroprop-1-ene and (Z)-C-aryl-N-phenylnitrones: a DFT computational study

Reaction paths for [3 + 2] cycloaddition (32CA) between 2-methyl-1-nitroprop-1-ene and (Z)-C-aryl-N-phenylnitrones were explored in detail at the B3LYP/6-31G(d) level of theory. All of the 32CA processes considered were found to be initiated by the attack of the most nucleophilic oxygen atom in the nitrone molecule on the most electrophilic carbon atom (Cβ) in the nitroethylene moiety. This type of interaction favors the formation of 4-nitro-substituted cycloadducts. Additionally, based on a molecular electron density theory (MEDT) study, the 32CA processes of interest should be considered polar processes with asynchronous transition states (TSs). However, the asynchronicity of the localized TSs is unexpectedly low and clearly insufficient to enforce a stepwise zwitterionic mechanism.

Mechanism and Origins of Chemo- and Stereoselectivities of Aryl Iodide-Catalyzed Asymmetric Difluorinations of β-Substituted Styrenes.

The mechanism of the aryl iodide-catalyzed asymmetric migratory geminal difluorination of β-substituted styrenes ( Banik et al. Science 2016, 353, 51 ) has been explored with density functional theory computations. The computed mechanism consists of (a) activation of iodoarene difluoride (ArIF2), (b) enantiodetermining 1,2-fluoroiodination, (c) bridging phenonium ion formation via SN2 reductive displacement, and (d) regioselective fluoride addition. According to the computational model, the ArIF2 intermediate is stabilized through halogen-π interactions between the electron-deficient iodine(III) center and the benzylic substituents at the catalyst stereogenic centers. Interactions with the catalyst ester carbonyl groups (I(III)+···O) are not observed in the unactivated complex, but do occur upon activation of ArIF2 through hydrogen-bonding interactions with external Brønsted acid (HF). The 1,2-fluoroiodination occurs via alkene complexation to the electrophilic, cationic I(III) center followed by C-F bond formation anti to the forming C-I bond. The bound olefin and the C-I bond of catalyst adopt a spiro arrangement in the favored transition structures but a nearly periplanar arrangement in the disfavored transition structures. Multiple attractive non-covalent interactions, including slipped π···π stacking, C-H···O, and C-H···π interactions, are found to underlie the high asymmetric induction. The chemoselectivity for 1,1-difluorination versus 1,2-difluorination is controlled mainly by (1) the steric effect of the substituent on the olefinic double bond and (2) the nucleophilicity of the carbonyl oxygen of substrate.

Safe Synthesis of 4,7-Dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine and Its SNAr Reactions.

A safe and efficient synthesis of 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine from the commercial diaminomaleonitrile is reported. Conditions for selective aromatic nucleophilic substitution of one or two bromine atoms by oxygen and nitrogen nucleophiles are found, whereas thiols formed the bis-derivatives only. Buchwald-Hartwig or Ullmann techniques are successful for incorporation of a weak nitrogen base, such as carbazole, into the [1,2,5]thiadiazolo[3,4-d]pyridazine core. The formation of rather stable S…η2-(N=N) bound chains in 4,7-bis(alkylthio)-[1,2,5]thiadiazolo[3,4-d]pyridines makes these compounds promising for the design of liquid crystals.