Enantioselective reductive multicomponent coupling reactions between isatins and aldehydes

A metal-free stereoselective reductive coupling reaction between isatins and aldehydes is reported. The reaction relies on commercial diethyl phosphite (∼€70 kg^–1) as the stoichiometric reductant. Base-catalyzed Pudovik addition and phosphonate/phosphate rearrangement achieved polarity inversion on the isatin, and the derived carbanions were trapped by aldehydes with subsequent dialkoxyphosphinyl migration. Chiral iminophosphoranes were used as basic catalysts to achieve high diastereo- and enantioselectivities with excellent yields.     

Novel Sterically Crowded and Conformationally Constrained α-Aminophosphonates with a Near-Neutral pKa as Highly Accurate 31P NMR pH Probes. Application to Subtle pH Gradients Determination in Dictyostelium discoideum Cells

In order to discover new ³¹P NMR markers for probing subtle pH changes (<0.2 pH unit) in biological environments, fifteen new conformationally constrained or sterically hindered α-aminophosphonates derived from diethyl(2-methylpyrrolidin-2-yl)phosphonate were synthesized and tested for their pH reporting and cytotoxic properties in vitro. All compounds showed near-neutral pK_as (ranging 6.28–6.97), chemical shifts not overlapping those of phosphorus metabolites, and spectroscopic sensitivities (i.e., chemical shifts variation Δδ_ab between the acidic and basic forms) ranging from 9.2–10.7 ppm, being fourfold larger than conventional endogenous markers such as inorganic phosphate. X-ray crystallographic studies combined with predictive empirical relationships and ab initio calculations addressed the inductive and stereochemical effects of substituents linked to the protonated amine function. Satisfactory correlations were established between pK_as and both the 2D structure and pyramidalization at phosphorus, showing that steric crowding around the phosphorus is crucial for modulating Δδ_ab. Finally, the hit ³¹P NMR pH probe 1b bearing an unsubstituted 1,3,2-dioxaphosphorinane ring, which is moderately lipophilic, nontoxic on A549 and NHLF cells, and showing pK_a = 6.45 with Δδ_ab = 10.64 ppm, allowed the first clear-cut evidence of trans-sarcolemmal pH gradients in normoxic Dictyostelium discoideum cells with an accuracy of <0.05 pH units.     

Phosphomethylation of p-substituted anilines

Conclusions The phosphomethylation of p-substituted anilines in three-component systems (amine-paraformaldehyde-trialkyl phosphite, diethyl phosphite, or diethyl thiophosphite) proceeds best with trialkyl phosphites, and the yields are 55–95%.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 178–180, January, 1982.     

Mechanisms of Rebaudioside A Degradation and Ingredient-Sweetener Interactions in Beverages during Storage

The instability of rebaudioside A (Reb A) in food product applications during storage challenges their utilization. The pathways of Reb A degradation in aged acidic beverages were investigated. Three Reb A degradation compounds of known sensory importance were monitored, consisting of (1) a rearrangement, (2) a hydration, and (3) an epoxidation/rearrangement product. Using deuterium-labeled water (D₂O) experiments, compounds 1–2 were reported to be generated by acid-catalyzed mechanisms involving the formation of a carbocation on carbon position 16, followed by either deprotonation via E₁ elimination on C15 to form the more thermodynamically stable trisubstituted alkene (compound 1), or by the Markovnikov addition of water via SN₁ substitution to form a tertiary alcohol (compound 2). Compound 3 was generated by epoxidation of the exomethylene at the C16–17 positions, followed by the opening and rearrangement of the ring to form a new alkene bond between C15–C16 and a primary alcohol on C17. Further analysis of the effect of beverage ingredients indicated the addition of caramel color significantly increased (p < 0.0001) the concentrations of compounds 1–2 compared to the aged control by 89 and 83%, respectively, whereas a specific coffee flavor and caramel color were reported to significantly reduce (p < 0.0001) the formation of compound 3 compared to the aged control during storage by 90 and 79%, respectively.     

Ab Initio Molecular Dynamics Simulations of the Interaction between Organic Phosphates and Goethite

Today’s fertilizers rely heavily on mining phosphorus (P) rocks. These rocks are known to become exhausted in near future, and therefore effective P use is crucial to avoid food shortage. A substantial amount of P from fertilizers gets adsorbed onto soil minerals to become unavailable to plants. Understanding P interaction with these minerals would help efforts that improve P efficiency. To this end, we performed a molecular level analysis of the interaction of common organic P compounds (glycerolphosphate (GP) and inositol hexaphosphate (IHP)) with the abundant soil mineral (goethite) in presence of water. Molecular dynamics simulations are performed for goethite–IHP/GP–water complexes using the multiscale quantum mechanics/molecular mechanics method. Results show that GP forms monodentate (M) and bidentate mononuclear (B) motifs with B being more stable than M. IHP interacts through multiple phosphate groups with the 3M motif being most stable. The order of goethite–IHP/GP interaction energies is GP M < GP B < IHP M < IHP 3M. Water is important in these interactions as multiple proton transfers occur and hydrogen bonds are formed between goethite–IHP/GP complexes and water. We also present theoretically calculated infrared spectra which match reasonably well with frequencies reported in literature.     

X-ray Structures and Computational Studies of Two Bioactive 2-(Adamantane-1-carbonyl)-N-substituted Hydrazine-1-carbothioamides

Two biologically active adamantane-linked hydrazine-1-carbothioamide derivatives, namely 2-(adamantane-1-carbonyl)-N-(tert-butyl)hydrazine-1-carbothioamide) 1 and 2-(adamantane-1-carbonyl)-N-cyclohexylhydrazine-1-carbothioamide 2, have been synthesized. X-ray analysis was conducted to study the effect of the t-butyl and cyclohexyl moieties on the intermolecular interactions and conformation of the molecules in the solid state. X-ray analysis reveals that compound 1 exhibits folded conformation, whereas compound 2 adopts extended conformation. The Hirshfeld surface analysis indicates that the contributions of the major intercontacts involved in the stabilization of the crystal structures do not change much as a result of the t-butyl and cyclohexyl moieties. However, the presence and absence of these contacts is revealed by the 2D-fingerprint plots. The CLP–Pixel method was used to identify the energetically significant molecular dimers. These dimers are stabilized by different types of intermolecular interactions such as N–H···S, N–H···O, C–H···S, C–H···O, H–H bonding and C–H···π interactions. The strength of these interactions was quantified by using the QTAIM approach. The results suggest that N–H···O interaction is found to be stronger among other interactions. The in vitro assay suggests that both compounds 1 and 2 exhibit urease inhibition potential, and these compounds also display moderate antiproliferative activities. Molecular docking analysis shows the key interaction between urease enzyme and title compounds.     

Transition Metal–(μ-Cl)–Aluminum Bonding in α-Olefin and Diene Chemistry

Olefin and diene transformations, catalyzed by organoaluminum-activated metal complexes, are widely used in synthetic organic chemistry and form the basis of major petrochemical processes. However, the role of M–(μ-Cl)–Al bonding, being proven for certain >C=C< functionalization reactions, remains unclear and debated for essentially more important industrial processes such as oligomerization and polymerization of α-olefins and conjugated dienes. Numerous publications indirectly point at the significance of M–(μ-Cl)–Al bonding in Ziegler–Natta and related transformations, but only a few studies contain experimental or at least theoretical evidence of the involvement of M–(μ-Cl)–Al species into catalytic cycles. In the present review, we have compiled data on the formation of M–(μ-Cl)–Al complexes (M = Ti, Zr, V, Cr, Ni), their molecular structure, and reactivity towards olefins and dienes. The possible role of similar complexes in the functionalization, oligomerization and polymerization of α-olefins and dienes is discussed in the present review through the prism of the further development of Ziegler–Natta processes and beyond.     

Preparation of Complexes η<Superscript>4</Superscript>-4-(1,3-Diphenyl-2-propen-1-one)-η<Superscript>3</Superscript>-3-(1,3,5-triorganyl-1,3,5-triazacyclohexane)carbonyltungsten(0) and Their Reactions with Diethyl Phosphite

New tungsten complexes were prepared of a composition η³-[(1,3,5-triorganyl)-1,3,5-triazacyclohexane]-tricarbonyltungsten(0) where a tridentate coordination of the triazinane fragment to the metal center was found. The reaction of tricarbonyltriazinane tungsten complexes with 1,3-diphenyl-2-propen-1-one (chalcone) under thermochemical activation resulted in replacement of two carbon monoxide molecules in the coordination sphere of tungsten by a chalcone molecule linked to the transition metal atom through a system of π-bonds C=C and C=O. The phosphorylation of η⁴-(1,3-diphenyl-2-propen-1-one)-η³-[(1,3,5-triphenyl)-1,3,5-triazacyclohexane]-monocarbonyltungsten(0) with diethyl phosphite occurred at the carbonyl group of the coordinated heterodiene; the phosphonate thus formed underwent intracomplex phosphonate-phosphate rearrangement affording an organometallic phosphate.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005, pp. 793–797.Original Russian Text Copyright © 2005 by Kuramshin, Asafyeva, Cherkasov.     

Transformations of diethyl phosphite in the presence of Mn2(CO)10

Upon heating with Mn₂(CO)₁₀-BrR systems, diethyl phosphite is partially converted to (EtO)₃P(O). Evidence is given for a radical complex mechanism for these transformations.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1903–1905, August, 1989.     

Conjugative Stabilization versus Anchimeric Assistance in Carbocations

In this study, an old concept of anchimeric assistance is viewed from a different angle. Primary cations with two different heteroatomic substituents in the α-position to the cationic carbon atom CHXY–CH₂⁺ (X, Y = Me₂N, MeO, Me₃Si, Me₂P, MeS, MeS, Br) can be stabilized by the migration of either the X or Y group to the cation center. In each case, the migration can be either complete, resulting in the transfer of the migrating group to the adjacent carbon atom and the formation of a secondary carbocation stabilized by the remaining heteroatom, or incomplete, leading to an anchimerically assisted iranium ion. For all combinations of the above groups, these transformations have been studied by theoretical analysis at the MP2/aug-cc-pVTZ level and were shown to occur depending on the ability of anchimeric assistance by X and Y, as well as the conformation of the starting primary carbocation. In the conformers of α-amino cations with the p-orbital, C–N bond and the nitrogen lone pair in one plane, the Me₂N group migrates to the cationic center to give aziranium ions. Otherwise, the second heteroatom is shifted to give iminium ions, without or with very slight anchimeric assistance. In the α-methoxy cations, the MeO group can be shifted to the cationic center to give the O-anchimerically assisted ions as local minima, the global minima being the ions anchimerically assisted by another heteroatom. The electropositive silicon tends to migrate towards the cationic center, but with the formation of a π-complex of the Me₃Si cation with the C=C bond rather than a Si-anchimerically assisted cation. The phosphorus atom can either fully migrate to the cationic center (X = P, Y = S, Se) or form anchimerically stabilized phosphiranium ions (X = P, Y = O, Si, Br). The order of the anchimeric assistance for the heaviest atoms decreases in the order Se >> S > Br.     

In(OTf)3 catalysed simple one-pot synthesis of α-amino phosphonates

A new efficient one-pot synthesis of α-amino phosphonates derived from nitro substituted anilines, aldehydes and diethyl phosphite has been carried out by employing 5 mol% of In(OTf)₃. The method is equally effective for the generation of α-amino phosphonates from various carbonyl compounds and other amines.     

In Vitro Bioaccessibility of Bioactive Compounds from Citrus Pomaces and Orange Pomace Biscuits

The present investigation aimed to provide novel information on the chemical composition and in vitro bioaccessibility of bioactive compounds from raw citrus pomaces (mandarin varieties Clemenule and Ortanique and orange varieties Navel and Valencia). The effects of the baking process on their bioaccessibility was also assessed. Samples of pomaces and biscuits containing them as an ingredient were digested, mimicking the human enzymatic oral gastrointestinal digestion process, and the composition of the digests were analyzed. UHPLC-MS/MS results of the citrus pomaces flavonoid composition showed nobiletin, hesperidin/neohesperidin, tangeretin, heptamethoxyflavone, tetramethylscutellarein, and naringin/narirutin. The analysis of the digests indicated the bioaccessibility of compounds possessing antioxidant [6.6–11.0 mg GAE/g digest, 65.5–97.1 µmol Trolox Equivalents (TE)/g digest, and 135.5–214.8 µmol TE/g digest for total phenol content (TPC), ABTS, and ORAC-FL methods, respectively; significant reduction (p < 0.05) in Reactive Oxygen Species (ROS) formation under tert-butyl hydroperoxide (1 mM)-induced conditions in IEC-6 and CCD-18Co cells when pre-treated with concentrations 5–25 µg/mL of the digests], anti-inflammatory [significant reduction (p < 0.05) in nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages], and antidiabetic (IC₅₀ 3.97–11.42 mg/mL and 58.04–105.68 mg/mL for α-glucosidase and α-amylase inhibition capacities) properties in the citrus pomaces under study. In addition, orange pomace biscuits with the nutrition claims “no-added sugars” and “source of fiber”, as well as those with good sensory quality (6.9–6.7, scale 1–9) and potential health promoting properties, were obtained. In conclusion, the results supported the feasibility of citrus pomace as a natural sustainable source of health-promoting compounds such as flavonoids. Unfractionated orange pomace may be employed as a functional food ingredient for reducing the risk of pathophysiological processes linked to oxidative stress, inflammation, and carbohydrate metabolism, such as diabetes, among others.     

Synthesis,Structural Determination,and Antioxidant Activities of Acyclic and Substituted Heterocyclic Phosphonates Linearly Linked 4-hydroxy-2(1H)-quinolinone

The chemical reactivity of 3-[(E)-3-(dimethylamino)-2-propenoyl]-4-hydroxy-1-methy-2(1H)-quinolinone (1) towards some phosphorus reagents was studied. The enaminone 1 was cyclized into pyranoquinolinylphosphonate 2 via treatment with diethyl phosphite in basic medium. However, its reaction with triethoxy phosphonoacetate gave the substituted oxopyranylphosphonate 3. Using the same reaction conditions, both thioxopyridinylphosphonate 4 and oxopyranylphosphonate 5 were produced via a reaction of enaminone 1 with both diethyl 2-amino-2-thioxoethylphosphonate and diethyl vinylphosphonate, respectively, in low yields. In addition, the two novel oxopyridinylphosphonates 6 and 7 were obtained by treatment of enaminone 1 with a diethyl cyanomethylphosphonate reagent. Two oaxathiaphosphininyl derivatives, 8 and 9, were obtained by treatment of the enaminone 1 with O, O-diethyl dithiophosphoric acid under different reaction conditions. Diazaphosphininyl 11 and oxazaphosphininyl 12 derivatives were obtained in excellent yields using a P-phenylphosphonic diamide reagent under different reaction conditions. The treatment of the enaminone 1 with phosphorus pentasulfide produced the non-phosphorylated product thioxothiopyranoquinolinone 13. Finally, the enaminone was turned into oxathiaphosphininyl 14 using Lawesson’s reagent. The possible reaction mechanisms of the formation of these products were discussed. The structures of newly isolated products were established by elemental analysis and spectral tools. The compounds were evaluated for their antioxidant activities.     

1,1,3,3,3-Pentafluoro-2-pentafluorophenylpropene oxide. Precursor for novel phosphonates and ylides

1,1,3,3,3-Pentafluoro-2-pentafluorophenylpropene oxide reacted with triethyl phosphite to give the ylide C₆F₅(CF₃)C=P(OEt)₃. Hydrolysis yielded the phosphonate C₆F₅(CF₃)CHP(O)(OEt)₂, which was dehydrofluorinated using Et₃N · BF₃ to form the vinyl phosphonate C₆F₅(CF₂=)CP(O)(OEt)₂, a compound available also directly from the starting epoxide and diethyl trimethylsilyl phosphite. The vinyl phosphonate and diethyl trimethylsilyl phosphite furnished a 2:1 mixture of (Z) and (E) bisphosphonates together with fluorotrimethylsilane. Thermolylsis of the ylide gave diethyl phosphorofluoridate and 1,1-difluoro-2-pentafluorophenyl-but-1-ene. © 1997 John Wiley & Sons, Inc.     

Perturbating Intramolecular Hydrogen Bonds through Substituent Effects or Non-Covalent Interactions

An analysis of the effects induced by F, Cl, and Br-substituents at the α-position of both, the hydroxyl or the amino group for a series of amino-alcohols, HOCH₂(CH₂)_nCH₂NH₂ (n = 0–5) on the strength and characteristics of their OH···N or NH···O intramolecular hydrogen bonds (IMHBs) was carried out through the use of high-level G4 ab initio calculations. For the parent unsubstituted amino-alcohols, it is found that the strength of the OH···N IMHB goes through a maximum for n = 2, as revealed by the use of appropriate isodesmic reactions, natural bond orbital (NBO) analysis and atoms in molecules (AIM), and non-covalent interaction (NCI) procedures. The corresponding infrared (IR) spectra also reflect the same trends. When the α-position to the hydroxyl group is substituted by halogen atoms, the OH···N IMHB significantly reinforces following the trend H < F < Cl < Br. Conversely, when the substitution takes place at the α-position with respect to the amino group, the result is a weakening of the OH···N IMHB. A totally different scenario is found when the amino-alcohols HOCH₂(CH₂)_nCH₂NH₂ (n = 0–3) interact with BeF₂. Although the presence of the beryllium derivative dramatically increases the strength of the IMHBs, the possibility for the beryllium atom to interact simultaneously with the O and the N atoms of the amino-alcohol leads to the global minimum of the potential energy surface, with the result that the IMHBs are replaced by two beryllium bonds.     

Radical telomerization of vinyltrimethylsilane with diethyl phosphite

Telomerization of vinyltrimethylsilane with diethyl phosphite was carried out in the presence of tert-butyl peroxide (TBP), affording a series of regular telomers (EtO)₂P(O)(CH₂CHSiMe₃)_nH (n=1–3)(T_n) and the compounds Me₃Si· (CH₂)₂CH(CH₃)OP(O)(OEt)(CH₂)₂SiMe₃(T₂). Arguments are presented which support a rearrangement with 1,5-H migration in the first propagating radical along a chain including P and O atoms. The partial chain-transfer constant C₁ (6.2) was evaluated.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1883–1887, August, 1990.     

The Kabachnik–Fields and Pudovik Reactions on the Basis of E,Z‐Citral and Its Imines and (R,S)‐Citronellal

The Kabachnik–Fields reaction of E,Z‐citral with diethyl phosphite in the presence of isobutylamine has been found to form α‐aminophosphonates. The Pudovik reactions of diethyl phosphite with prenyl imines prepared on the basis of E,Z‐citral with isobutylamine also allowed us to obtain the same α‐aminophosphonates. We have managed to synthesize α‐aminophosphonates by the reaction of O,O‐dialkyl trimethylsilyl phosphites with prenyl imines in the presence of water or diethylamine. α‐Aminophosphonates were also synthesized by the reaction of diethyl phosphite with (R,S)‐citronellal in the presence of alkylamines. α‐Aminophosphonates obtained showed bacteriostatic activity against Staphylococcus aureus and Bacillus cereus. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:36–42, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21060     

The Synthesis of Hypodiphosphoric Acid and Derivatives with P-P Bond,including Esters and Diphosphine Dioxides: A Review

The synthesis of hypodiphosphoric acid and its related compounds began in 1877, but no summary of the synthetic efforts has been reported. This review includes published papers related to the molecules containing the >P(=O)-P(=O)< fragment, which notably resembles the structure of the >P(=O)-O-P(=O)< moiety, the essential building block of many important molecules found in nature and in the field of medicinal chemistry. This review covers the strategies related to the synthesis of hypodiphosphoric acid (former name hypophosphoric acid), its ester form, and diphosphine dioxides. Finally, some properties and applications of these structures studied during this period are presented.     

Packed-Fiber Solid Phase-Extraction Coupled with HPLC-MS/MS for Rapid Determination of Lipid Oxidative Damage Biomarker 8-Iso-Prostaglandin F2α in Urine

The 8-iso-prostaglandin F_2α (8-iso-PGF_2α) biomarker is used as the gold standard for tracing lipid oxidative stress in vivo. The analysis of urinary 8-iso-PGF_2α is challenging when dealing with trace amounts of 8-iso-PGF_2α and the complexity of urine matrixes. A packed-fiber solid-phase extraction (PFSPE)–coupled with HPLC-MS/MS–method, based on polystyrene (PS)-electrospun nanofibers, was developed for the specific determination of 8-iso-PGF_2α in urine and compared with other newly developed LC-MS/MS methods. The method, which simultaneously processed 12 samples within 5 min on a self-made semi-automatic array solid-phase extraction processor, was the first to introduce PS-electrospun nanofibers as an adsorbent for the extraction of 8-iso-PGF_2α and was successfully applied to real urine samples. After optimizing the PFSPE conditions, good linearity in the range of 0.05–5 ng/mL with R² > 0.9996 and a satisfactory limit of detection of 0.015 ng/mL were obtained, with good intraday and interday precision (RSD < 10%) and recoveries of 95.3–103.8%. This feasible method is expected to be used for the batch quantitative analysis of urinary 8-iso-PGF_2α.     

Nucleophilic Addition to Carbonyl Compounds. Competition Between Hard (Amine) and Soft (Phosphite) Nucleophile

Abstract

In the reaction mixture of carbonyl compound, amine and diethyl phosphite several different reactions are observed. The formation of aminophosphonate (Kabachnik- Fields reaction) is frequently accompanied with the formation of hydroxyphosphonate (Pudovik reaction) or product of its rearrangement. ^1–3 This is due to the presence of one electrophile (carbonyl compound) and two nucleophiles (amine and phosphite) in the reaction mixture, which may compete for the electrophilic center.