Halogen Bonding of N-Halosuccinimides with Amines and Effects of Brønsted Acids in Quinuclidine-Catalyzed Halocyclizations

An arguable expectation in halogen chemistry is that an amine will react oxidatively with an N-halosuccinimide (NXS) to form an N-halogenated species bearing a covalent N−X bond. While likely for NCS under most conditions, we find this expectation simply not true for NIS and largely inaccurate for NBS. Herein, we disclose evidence through systematic NMR and X-ray studies that non-covalent halogen bonded amine complexes of NIS predominate over covalent N-halogenated species, even with primary and secondary amines. For example, during the catalytic electrophilic halocyclization of gem-disubstituted alkenes by cinchona-like amines, the quinuclidine complexes of NIS and NBS display lower reactivity than their parent N-halosuccinamides and require the presence of an appropriate Brønsted acid. Specifically, a Brønsted acid and quinuclidine jointly catalyze the halo-cycloetherification of γ-alkenyl alcohols with NIS or NBS, while only quinuclidine acts as a catalyst in the halolactonization of γ-alkenoic acids. Although our evidence confirms a transient N-halogenated quaternary ammonium salt as the halonium species, it is important to note that NIS predominantly forms ‘off-cycle’ halogen bonded amine complexes in solution.     

B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1

B-RafV600E mutant is found in 40–70% of papillary thyroid carcinoma (PTC) and has an important role in the pathogenesis of PTC. The sodium iodide symporter (NIS) is an integral plasma membrane glycoprotein that mediates active iodide transport into the thyroid follicular cells, and B-RafV600E has been known to be associated with the loss of NIS expression. In this study, we found that B-RafV600E inhibited NIS expression by the upregulation of its promoter methylation, and that specific regions of CpG islands of NIS promoter in B-RafV600E harboring PTC were highly methylated compared with surrounding normal tissue. Although DNA methyltransferase 3a and 3b (DNMT3a,3b) were not increased by B-RafV600E, DNMT1 expression was markedly upregulated in PTC and B-RafV600E expressing thyrocytes. Furthermore, DNMT1 expression was upregulated by B-RafV600E induced NF-κB activation. These results led us to conclude that NIS promoter methylation, which was induced by B-RafV600E, is one of the possible mechanisms involved in NIS downregulation in PTC.     

Ring opening of activated cyclopropanes with NIS/NaN3: synthesis of C-1 linked pseudodisaccharides

NIS/NaN₃ mediated ring opening of various donor–acceptor cyclopropanes has been investigated. The study shows the necessity of the donor oxygen lone pair in such ring opening reactions. This methodology has been utilized in the synthesis of C-1 linked pseudodisaccharides through the use of click chemistry.     

Iodination of alpha-Phosphino Enolate Complexes of Palladium(II) and Platinum(II). Synthesis and Crystal Structures of [(dmba)Pd{Ph(2)PC(I)C(O)Ph}] and of the Dipalladium(II) Complex [(dmba)Pd{Ph(2)PCC(O)Ph}Pd(I)(tmeda)] Obtained by Palladium(0) Insertion into the Carbon-Iodine Bond

Electrophilic attack of 1 equiv of I(2) on a PC(sp)2 carbon of the Pt(II) complex (1) afforded (2) in 90% yield. Complex 2 was subsequently deprotonated by NaOEt in ethanol to give the bis(enolato) complex (3). This alpha-phosphino, alpha-iodo enolato complex was obtained directly and quantitatively by the reaction of 1 with 1 equiv of N-iodosuccinimide (NIS). When 2 equiv of NIS was used, the symmetrical complex (4) was formed selectively. In contrast to I(2), NIS was also able to functionalize the phosphino enolate ligand of complexes to give the corresponding iodo derivatives (C N = dmba (5) or 8-mq (6)). These represent the first examples in which a phosphino enolate C-H bond has been directly functionalized, i.e. replaced by a C-X bond. Attempts to use this procedure with or with were unsuccessful. Reaction of 5 with Pd(dba)(2) in the presence of tetramethylenediamine (tmeda) or 2,2'-bipyridine (bipy) afforded (7) and (8), respectively. The solid state structures of complexes 5 and 7.CH(2)Cl(2) have been determined by single-crystal X-ray diffraction: 5 crystallizes in the monoclinic space group P2(1)/n with Z = 4 in a unit cell of dimensions a = 12.867(3) ?, b = 10.625(3) ?, c = 19.509(6) ?, and beta = 102.23(2) degrees; 7.CH(2)Cl(2) crystallizes in the monoclinic space group C2/c with Z = 8 in a unit cell of dimensions a = 35.906(3) ?, b = 13.565(3) ?, c = 15.775(2) ?, and beta = 95.099(10) degrees. Complex 7 contains two palladium(II) centers, in a square-planar environment, connected by the P-C unit of a phosphino enolate ligand which adopts an unprecedented &mgr;-eta(2)(P,C):eta(2)(P,O) bonding mode. The two coordination planes are almost orthogonal and make a dihedral angle of 88.0(2) degrees, which minimizes the steric hindrance between the ligands.     

Solution Phase Chemistry of Lanthanide Complexes. 12. 1:1 and 1:2 Lanthanide Complexes with s-Carboxymethoxysuccinic Acid

Abstract

The solution phase coordination chemistry associated with 1:1 and 1:2 complexes of lanthanide ions with S-carboxymethoxysuccinic acid (CMOS) has been studied by spectroscopic means. The Tb(III) luminescence intensities and lifetimes were found to be sensitive towards the solution phase properties, as were the circularly polarized luminescence spectra of these complexes. It was found that below pH 6, Ln(CMOS) complexes were monomeric in nature and contained an average of 6 molecules of coordinated water. Above neutral pH, the Ln(CMOS)₂ complexes became self-associated into hydroxy-bridged, oligomeric species. The Ln(CMOS)₂ complexes were found to be oligomeric at all pH values, with ligand bridging taking place below neutral pH and hydroxy bridging taking place above neutral pH.     

A computational study of 1:1 and 1:2 complexes of nitryl halides (O2NX) with HCN and HNC

Quantum calculations at the MP2/cc-pVTZ have been used to examine 1:1 and 1:2 complexes between O₂NX (X = Cl, Br) with HCN and HNC moieties. The interaction of the lone pair of the HCN(HNC) with the σ-hole and π-hole of O₂NX molecules and hydrogen bonding between lone pairs of X and O of O₂NX with H of HCN and HNC have been considered in 1:1 complexes. The 1:1 complexes can easily be differentiated using the stretching frequency of the N–X bond. Thus, those complexes with σ-hole and H···O₂NX interactions show a blue shift of the N-X bond stretching while a red shift is observed in the complexes along the π-hole and H···XNO₂ interactions. In the 1:2 complexes, the cooperative and diminutive energetic effects have been analyzed using the many-body interaction energies. The nature of the interactions has been characterized with the Atoms in Molecules (AIM) and Natural Bond Orbital (NBO) methodologies. Stabilization energies of 1:1 and 1:2 complexes including the variation of the zero-point vibrational energy (ΔZPVE) are in the range 3–9 kJ mol^?1 and 21–40 kJ mol^?1, respectively.     

Gold-catalyzed cycloisomerizations of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols to 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols

A method to prepare 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols by gold(I)-catalyzed cycloisomerization of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols with N-iodosuccinimide (NIS) is reported. The reactions were shown to be operationally simplistic and proceed efficiently for a wide variety of substrates, affording the corresponding products in good to excellent yields (70-99%). The mechanism is suggested to involve activation of the alkyne moiety of the substrate by the gold(I) catalyst. This triggers intramolecular addition of the tethered aniline moiety to give a vinyl gold intermediate, which undergoes iododeauration with NIS to give the (E)-2-(iodomethylene)indolin-3-ol adduct. Subsequent 1,3-allylic alcohol isomerization (1,3-AAI) followed by formylation of this vinyl iodide intermediate then gives the 1H-indole-2-carbaldehyde.     

alpha-selective sialylations at -78 degrees C in nitrile solvents with a 1-adamantanyl thiosialoside

Novel 1-adamantanylthio sialosides were synthesized and coupled to acceptors under NIS/TfOH promotion conditions. These donors showed higher reactivity than the phenylthio sialosides and could be activated by NIS/TfOH in nitrile solvents at -78 degrees C to afford improved alpha-sialylations. With the N-acetyl-5-N,4-O-oxazolidinone-protected 1-adamantanylthio sialyl donor high alpha-selectivities could be achieved in the sialylations of both primary and sterically hindered secondary acceptors, including the important galactose 3-OH acceptors.     

An efficient synthesis of highly substituted furans via the electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones

The electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones offers an efficient and straightforward route to highly substituted furans under extremely mild reaction conditions. Iodine, NIS, and PhSeBr have proven successful as electrophiles in this process.     

Semiempirical MO approach to the mechanism of the NIS-mediated nucleophilic addition to glycals: multicomponent intermediates as models to tackle reactivity in organic chemistry

A proposition for the nucleosidation mechanism of five-membered glycals promoted by N-iodo-succinimide (NIS), leading to 2′-deoxy-2′-iodo-β-nucleosides, is presented herein supported by semiempirical MO calculations. The proposed mechanism goes through the formation of multicomponent molecular intermediates that drastically diminish the total energy values when compared to charged intermediates (via iodonium species). The nucleosidation step was performed establishing either bicomponent (dihydrofuran–NIS) or tricomponent (dihydrofuran–NIS–silylated nucleobase) intermediates. The latter possibility has been shown to be the most likely (according also to DFT calculations), and suggests that the mechanism should take place in a concerted fashion. According to the tricomponent pathway, we have studied the stereoselectivity of the process, finding that the activation energy for the β-nucleosidation step is between ∼6 kcal/mol (AM1) and ∼10 kcal/mol (PM3) more favorable than that of the corresponding α-anomer, in agreement with the experimental results. The final step consists in an intramolecular silyl-transfer process accompanied by the NIS cleavage (in a different way depending on the calculation method employed), giving rise to the ultimate formation of N-silyl-succinimide.     

The application of HPLC‐MS/MS to studies of pharmacokinetics and interconversion of isoliquiritigenin and neoisoliquiritigenin in rats

A specific and sensitive HPLC‐MS/MS method was developed and validated for the simultaneously quantification of isoliquiritigenin (ISL) and neoisoliquiritin (NIS) in rat plasma by oral administration. Analytes were analyzed on an Agilent 6460 LC‐MS/MS system (Agilent, USA) using an Agilent Zorbax SB‐C₁₈ column (4.6 × 150 mm, 5 μm). Gradient elution was applied for the analyte separation using a mobile phase composed of 0.1% formic acid aqueous solution and methanol at a flow rate of 1.0 mL/min with a total running time of 12 min. The calibration curves for ISL and NIS showed good linearity in the concentrations ranging from 0.001 to 4.000 μg/mL with correlation coefficients >0.998. The precision, accuracy, recovery and stability were deemed acceptable. The method was applied to the pharmacokinetics study of ISL and NIS in rats by single and combination administration. The result showed that C_max and AUC_0→t of ISL were markedly increased from 0.53 to 1.20 μg/mL, and from 69.63 to 200.74 min μg/mL by combination administration. The mean t_1/2 value was also prolonged from 64.55 to 203.74 min in the combination group. These results indicated that NIS may have been metabolized to ISL which increased the absorption and extended the elimination of ISL. However, little difference was found for NIS pharmacokinetics parameters between single NIS and the combination group, which suggested that there was no significant biotransformation of ISL to NIS. Copyright © 2015 John Wiley & Sons, Ltd.     

Substitution reactions at tetracoordinate boron: synthesis of N-heterocyclic carbene boranes with boron-heteroatom bonds

Boryl halide, carboxylate and sulfonate complexes of 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (dipp-Imd-BH(2)X, X = halide or sulfonate) have been prepared from the parent borane dipp-Imd-BH(3) by (1) substitution reactions with R-X (X = halide or sulfonate), (2) reactions with electrophiles (like I(2) or NIS), or (3) acid/base reactions with HX (provided that HX has a pK(a) of about 2 or less). Dipp-Imd-BH(2)I is most conveniently prepared by reaction with diiodine while dipp-Imd-BH(2)OTf is best prepared by reaction with triflic acid. These and other less reactive complexes behave as electrophiles and can be substituted by a wide range of heteroatom nucleophiles including halides, thiolates and other sulfur-based nucleophiles, isocyanate, azide, nitrite, and cyanide. The resulting products are remarkably stable, and many have been characterized by X-ray crystallography. Several are members of very rare classes of functionalized boron compounds (boron azide, nitro compound, nitrous ester, etc.).     

Palladium catalyzed C-H functionalization of O-arylcarbamates: selective ortho-bromination using NBS

A series of cyclometalated palladium complexes derived from O-phenylcarbamates has been synthesized by the reaction of the respective carbamates with Pd(OAc)(2) in the presence of acids, CF(3)CO(2)H, CF(3)SO(3)H, and p-TsOH. The palladacycles were observed to coordinate amines and electron rich anilines but not sulfonamides or carboxamides. Analysis of the (t)Bu-NH(2) adduct of the palladacycle 2b (2b·(t)Bu-NH(2)) by NMR spectroscopy (NOE) revealed a cis-coordination of the amine. However, the amine adducts failed to undergo ortho-amination (C-N bond formation) under varied reaction conditions. Notably, the palladacycle 1d was found to react efficiently with N-iodosuccinimide (NIS) to yield the ortho-iodinated carbamate, 1e. More significantly, this reaction can be extended to a palladium-catalyzed ortho C-H bromination of aryl-O-carbamates even at 5 mol % loading of Pd(OAc)(2) using N-bromosuccinimide (NBS).     

Intramolecular Diamination and Alkoxyamination of Alkenes with N-Sulfonyl Ureas With N-Iodosuccinimide

Reaction of N-δ-alkenyl-N'-sulfonyl urea 1 with N-iodosuccinimde (NIS; 2 equiv) and a catalytic amount of AgOTf (20 mol %) at room temperature led to intramolecular alkoxyamination to form bicyclic isourea 2a in 95% isolated yield. In comparison, reaction of 1 with NIS and sodium bicarbonate (1 equiv) at room temperature led to isolation of bicyclic imidazolidin-2-one 2b in 91% yield. These NIS-mediated alkoxyamination and diamination protocols were effective for a range of N-δ-alkenyl-N'-sulfonyl ureas to form the corresponding heterobicyclic compounds in good yield with high chemoselectivity and good to excellent diastereoselectivity.     

Spectroscopic, semi-empirical and antimicrobial studies of a new amide of monensin A with 4-aminobenzo-15-crown-5 and its complexes with Na cation at 1:1 and 1:2 ratios

A new amide of monensin A with 4-aminobenzo-15-crown-5 (M-AM3) was synthesised and its ability to form complexes with Na⁺ cations was studied by ESIMS, ¹H, ¹³C and ²³Na NMR, FTIR and PM5 semi-empirical methods. ESI mass spectrometry indicates that in the gas phase M-AM3 amide forms complexes of 1:1 and 1:2 stoichiometry with Na⁺ cations. The formation of such complexes is also confirmed in the acetonitrile solution, in which the existence of equilibrium between two structures A and B is found, of which B structure is dominant. The structures of M-AM3 and its 1:1 and 1:2 complexes with Na⁺ cations are stabilised by various intramolecular hydrogen bonds, which are discussed in detail. The in vitro biological tests have demonstrated that the new M-AM3 amide shows good activity towards some strains of Gram-positive bacteria (MIC 25-50 μg/ml).     

Structure of 1 : 1 and 2 : 1 complexes of 3,5-dimethylpyrazole with HCl and HO3SCF3

3,5-Dimethylpyrazole complexes with HCl (an 1 : 1 complex) and trifluoromethanesulfonic acid (1 : 1 and 2 : 1 complexes) were structurally studied using X-ray crystallography.     

Structure of 1:1 and 1:2 complexes formed by aromatic NH and OH proton donors with aliphatic amines. Possibility of homoconjugated NHN cation formation

Structure of the complexes with NHN hydrogen bond formed by bis(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-amine ((4-CF₃C₆F₄)₂NH, FA) as proton donor with aliphatic amines (dibutyl-, tributyl- and trimethylamines) as proton acceptors in aprotic solvents (isooctane and methylene chloride) in a wide range of concentrations and temperatures have been studied by IR and UV spectra. Quantitative treatment of the spectra by a computer program based on factor analysis reveals the equilibrium between free molecules and FA–aliphatic amine complexes of 1:1 and 1:2 composition, the latter having an ionic structure with proton transferred from FA to the aliphatic amine. Thermodynamic characteristics of the 1:1 and 1:2 complexes for FA+dibutylamine system have been measured. Appearance of IR bands indicating formation of NHN⁺ homoconjugated cation has been detected in FA+trimethylamine solution in methylene chloride at temperatures 190–150 K. Spectral manifestations of the complexes containing the (trimethylamine-H-trimethylamine)⁺ cation, formed by FA and OH proton donor (pentachlorophenol) are compared.     

Glycosidation with a disarmed glycosyl iodide: promotion and scope

[reaction: see text] Glucuronyl iodide 1 has been studied in detail as a "disarmed" glycosyl donor. In a model reaction, using N-iodosuccinimide (NIS) as a promoter and 2-phenylethanol as acceptor, best results were obtained using NIS with I(2), followed by trimethylsilyltrifluoromethanesulfonate (TMSOTf). When a series of primary and secondary alcohols was glycosylated using these conditions, yields of 60-83% of beta-glucuronides were obtained. Various "nonheavy" metal salts also effectively catalyzed the model reaction but led to significant amounts of alpha-product with less reactive secondary alcohols.     

Determining binding constants for 1:1 and 1:2 inclusion complexes of ester betulin derivatives with (2-hydroxypropyl)-β-cyclodextrin by affinity capillary electrophoresis

The complexation of ester betulin derivatives with (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) was studied by mobility shift affinity CE. Electrophoretic mobility for triangular peaks was calculated using the parameter a₁ of the Haarhoff–Van der Linde function instead of the peak top time. Dependences of the viscosity corrected electrophoretic mobility on HP-β-CD concentration were not described on the basis of only complexes with 1:1 stoichiometry due to the fact that these binding curves did not reach a plateau. However, the dependences were well described taking into account both 1:1 and 1:2 complexes. The presence of higher order equilibria was also revealed by x-reciprocal plots. The values of apparent binding constant logarithm, obtained for the first time, for 1:1 and 1:2 HP-β-CD complexes of betulin 3,28-diphthalate and betulin 3,28-disuccinate with 95% confidence interval limits in brackets are the same within error and are equal to 4.85 (4.73–4.95), 8.56 (7.75–8.82), 4.92 (4.86–4.97), and 8.54 (8.23–8.72) at 25°C, respectively. These values for 1:1 and 1:2 HP-β-CD complexes of betulin 3,28-disulfate at 25°C are 4.61 (4.57–4.64) and 7.11 (6.57–7.34), respectively. The binding constants for betulin 3,28-disulfate agree with the previously obtained results from the separation in the thermostatted capillary segment.     

Novel 4,5-bis(trifluoromethyl)-1H-pyrazoles through a concise sequential iodination-trifluoromethylation reaction

An efficient protocol for the assembly of a new series of 1,3-disubstituted 4,5-bis(trifluoromethyl)-1H-pyrazoles – through a concise sequential iodination-trifluoromethylation reaction at the C-4 position of an initial series of 1-aryl-3-(alkyl/aryl)-5-trifluoromethyl-1H-pyrazoles (electronically deactivated heterocycles), using NIS and MFSDA, at good conversion yields and in short reaction times – is reported.