Type II Anion Relay Chemistry: Exploiting Bifunctional Weinreb Amide Linchpins for the One‐Pot Synthesis of Differentiated 1,3‐Diketones,Pyrans, and Spiroketals

The design, synthesis, and validation of new highly effective bifunctional linchpins for type II anion relay chemistry (ARC) has been achieved. The mechanistically novel negative‐charge migration that comprises the Brook rearrangement is now initiated by a stabilized tetrahedral intermediate, which is generated by nucleophilic addition to a Weinreb amide, rather than by a simple oxyanion that is generated from an epoxide. As a result, the linchpin preserves the carbonyl functionality in the ARC adducts, thus permitting access to functionally complex systems in a single flask without the need for further chemical manipulations. This tactic was validated with the one‐pot preparation of monoprotected 1,3‐diketones as well as pyran and spiroketal scaffolds, depending on the choice of nucleophile, electrophile, and work‐up conditions.     

Through‐Bond/Through‐Space Anion Relay Chemistry Exploiting Vinylepoxides as Bifunctional Linchpins

The development of new bifunctional linchpins that permit the union of diverse building blocks is essential for the synthetic utility of anion relay chemistry (ARC). The design, synthesis, and validation of three vinylepoxide linchpins for through‐bond/through‐space ARC are now reported. For negative charge migration, this class of bifunctional linchpins employs initial through‐bond ARC by an S_N2′ reaction, followed by through‐space ARC exploiting a 1,4‐Brook rearrangement. The trans‐disubstituted vinylepoxide linchpin yields a mixture of E/Z isomers, whereas the cis‐disubstituted and the trans‐trisubstituted vinylepoxide linchpins proceed to deliver three‐component adducts with excellent E selectivity.     

Fragmentation pathways of deprotonated amide‐sulfonamide CXCR4 inhibitors investigated by ESI‐IT‐MSn,ESI‐Q‐TOF‐MS/MS and DFT calculations

Amide‐sulfonamides provide a potent anti‐inflammatory scaffold targeting the CXCR4 receptor. A series of novel amide‐sulfonamide derivatives were investigated for their gas‐phase fragmentation behaviors using electrospray ionization ion trap mass spectrometry and quadrupole time‐of‐flight mass spectrometry in negative ion mode. Upon collision‐induced dissociation (CID), deprotonated amide‐sulfonamides mainly underwent either an elimination of the amine to form the sulfonyl anion and amide anion or a benzoylamide derivative to provide sulfonamide anion bearing respective substituent groups. Based on the characteristic fragment ions and the deuterium–hydrogen exchange experiments, three possible fragmentation mechanisms corresponding to ion‐neutral complexes including [sulfonyl anion/amine] complex ( INC‐1 ), [sulfonamide anion/benzoylamide derivative] complex ( INC‐2 ) and [amide anion/sulfonamide] complex ( INC‐3 ), respectively, were proposed. These three ion‐neutral complexes might be produced by the cleavages of S–N and C–N bond from the amide‐sulfonamides, which generated the sulfonyl anion (Route 1), sulfonamide anion (Route 2) and the amide anion (Route 3). DFT calculations suggested that Route 1, which generated the sulfonyl anion (ion c ) is more favorable. In addition, the elimination of SO₂ through a three‐membered‐ring transition state followed by the formation of C–N was observed for all the amide‐sulfonamides.     

Electro‐Oxidation of 3,4‐Dihydroxybenzoic Acid in the Presence of 6‐Methyl‐1,2,4‐Triazine‐3‐Thione‐5‐One: Unique Synthesis of 7H‐Thiazolo[3,2‐b]‐1,2,4‐Triazin‐7‐One Derivative in Aqueous Media

The electrochemical oxidation of 3,4‐dihydroxy benzoic acid ( 1 ) has been studied in the presence of 6‐methyl‐1,2,4‐triazine‐3‐thione‐5‐one ( 2 ) in aqueous solution. The oxidation mechanism of 1 and its reaction in the presence of 2 was offered. It was confirmed that 1 is converted to 7H‐thiazolo[3,2‐b]‐1,2,4‐triazin‐7‐one derivative 5 through Michael addition reaction of 2 to anodically generated o‐benzoquinone. The results of the research were used for electrochemical synthesis of 5 in an undivided cell in good yield and purity.     

Synthesis of 4‐Aryl‐1,7‐naphthyridine‐2(1H)‐thiones by the Electrocyclic Reaction of 4‐(1‐Arylalk‐1‐enyl)‐3‐isothiocyanatopyridines Generated in situ from the Corresponding Isocyanides

A convenient synthis for 4‐substituted and 3,4‐disubstituted 1,7‐naphthyridine‐2(1H)‐thiones 7 has been developed. The method is based on the electrocyclic reaction of 4‐(1‐arylalk‐1‐enyl)‐3‐isothiocyanatopyridines 6 , generated in situ by the treatment of the respective isocyanides 5 with S₈ in the presence of a catalytic amount of selenium. The isocyanides 5 can be easily prepared from commercially available pyridin‐3‐amine by conventional organic reactions.     

A novel optically active diblock copolymer composed of poly(ethylene glycol) and poly[N‐{o‐(4‐phenyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl}maleimide]: Synthesis,micellization behavior,and chiroptical property

A series of optically active amphiphilic block copolymers were synthesizedby using potassium alkoxide of poly(ethylene glycol) monomethyl ether (MeOPEGO^?K⁺) to initiate the anionic polymerization of N‐{o‐(4‐phenyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl}maleimide [(R)‐PhOPMI]. The PEG‐macroinitiators generated in situ in the reaction between MeOPEGOH and potassium naphthylide in tetrahydrofuran. The synthetic procedure may provide the PEG‐b‐PPhOPMI copolymers with well‐defined structure, as evidenced by gel permeation chromatography, ¹H NMR, FTIR, and elemental analysis. In particular, the preparation of block copolymers having a laevorotation or dextrorotation activity was accomplished by changing the feed composition. The micellization was examined for the amphiphilic block copolymers in aqueous milieu by fluorescence spectroscopy, dynamic light scattering, and circular dichroism. The results indicate that the copolymers could form regular spherical micelles with core‐shell structure when the hydrophilic component was long enough; in contrast, the copolymers containing shorter PEG segments formed aggregates in large dimension due to the considerable interaction between hydrophobic PPhOPMI components. Also, it was found that the aggregated structure of the polymeric micelles is strongly dependent on the medium nature and the polymer concentration. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1025–1033, 2008     

Nano‐emulsion use for the synthesis of polyaniline nano‐grains or nano‐fibers

We report that nano‐emulsions can be creatively used as a morphology selective synthesis method to prepare not only nano‐grains but also nano‐fibers with high selectivity. Synthesis of the two different morphological materials was demonstrated using polyaniline synthesis as a model case. Polyaniline nano‐grains were synthesized from aniline molecules in nano‐size aqueous droplets as polymerization sites whose droplets were generated by inverse water‐in‐oil nano‐emulsion use, and polyaniline nano‐fibers were synthesized from aniline in aqueous nano‐dimensional channels as polymerization sites whose channels were generated by direct oil‐in‐water nano‐emulsion use containing high population of oil droplets. Using the approaches, we successfully synthesized nano‐fibers of 60 nm diameter with 0.5 µm length and also nano‐grains having diameter of 60–80 nm. The two different polymerization sites of nano‐scale dimension were made by changing the ratio among surfactant, aqueous aniline/HCl solution, and oil, i.e. organic solvent. We found the nano‐fibers synthesized from the channels formed by the direct oil‐in‐water nano‐emulsion have higher bulk electrical conductivity than the nano‐grains which were synthesized from the droplets formed by the inverse water‐in‐oil emulsion. We also found that the emulsion use allows us to use a room temperature synthesis unlike conventional synthesis methods which require to use ice bath temperature. Physical properties of both nano‐fibers and nano‐grains synthesized were characterized by Fourier transform infrared (FTIR), UV–Vis spectra, scanning electron microscopy (SEM), and four probes conductivity measurement. Copyright © 2009 John Wiley & Sons, Ltd.     

Poly(2‐hydroxyethyl methacrylate‐co‐N,O‐dimethacryloylhydroxylamine) particles by dispersion polymerization

Poly(2‐hydroxyethyl methacrylate‐co‐N,O‐dimethacryloylhydroxylamine) particles were prepared by dispersion polymerization in toluene/2‐methylpropan‐1‐ol medium using cellulose acetate butyrate and dibenzoyl peroxide (BPO) as a steric stabilizer and initiator, respectively. The particle size was reduced with decreasing solvency of the reaction medium (more nuclei were generated) because the critical chain length of the precipitated oligomers decreased with an increasing toluene content, which is a poorer solvent for the polymer than 2‐methylpropan‐1‐ol. There is an optimum initiator concentration (2 wt % BPO relative to monomers) for producing low‐polydispersity particles under given conditions. Additionally, discrete spherical particles were obtained at a low monomer concentration and/or higher polymerization temperature. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1625–1632, 2002     

In Situ Solid‐State Generation of (BN)2‐Pyrenes and Electroluminescent Devices

New BN‐heterocyclic compounds have been found to undergo double arene photoelimination, forming rare yellow fluorescent BN‐pyrenes that contain two B? N units. Most significant is the discovery that the double arene elimination can also be driven by excitons generated electrically within electroluminescent (EL) devices, enabling the in situ solid‐state conversion of BN‐heterocycles to BN‐pyrenes and the use of BN‐pyrenes as emitters for EL devices. The in situ exciton‐driven elimination (EDE) phenomenon has also been observed for other BN‐heterocycles.     

Bis(2‐(6‐methylpyridin‐2‐yl)‐benzimidazolyl)titanium dichloride and titanium bis(6‐benzimidazolylpyridine‐2‐carboxylimidate): Synthesis,characterization, and their catalytic behaviors for ethylene polymerization

A series of 6‐(benzimidazol‐2‐yl)‐N‐organylpyridine‐2‐carboxamide were synthesized and transformed into 6‐benzimidazolylpyridine‐2‐carboxylimidate as dianionic tridentate ligands. Bis(2‐(6‐methylpyridin‐2‐yl)‐benzimidazolyl)titanium dichloride ( C1 ) and titanium bis(6‐benzimidazolylpyridine‐2‐carboxylimidate) ( C2 – C8 ) were synthesized in acceptable yields. These complexes were systematically characterized by elemental and NMR analyses. Crystallographic analysis revealed the distorted octahedral geometry around titanium in both complexes C1 and C4 . Using MAO as cocatalyst, all complexes exhibited from good to high catalytic activities for ethylene polymerization. The neutral bis(6‐benzimidazolylpyridine‐2‐carboxylimidate)titanium ( C2 – C8 ) showed high catalytic activities and good stability for prolonged reaction time and elevated reaction temperature; however, C1 showed a short lifetime in catalysis as being observed at very low activity after 5 min. The elevated reaction temperature enhanced the productivity of polyethylenes with low molecular weights, whereas the reaction with higher ethylene pressure resulted in better catalytic activity and resultant polyethylenes with higher molecular weights. At higher ratio of MAO to titanium precursor, the catalytic system generated better activity with producing polyethylenes with lower molecular weights. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 3411–3423, 2008     

Anilinic N‐Oxides Support Cytochrome P450‐Mediated N‐Dealkylation through Hydrogen‐Atom Transfer

The mechanism of N‐dealkylation mediated by cytochrome P450 (P450) has long been studied and argued as either a single electron transfer (SET) or a hydrogen atom transfer (HAT) from the amine to the oxidant of the P450, the reputed iron–oxene. In our study, tertiary anilinic N‐oxides were used as oxygen surrogates to directly generate a P450‐mediated oxidant that is capable of N‐dealkylating the dimethylaniline derived from oxygen donation. These surrogates were employed to probe the generated reactive oxygen species and the subsequent mechanism of N‐dealkylation to distinguish between the HAT and SET mechanisms. In addition to the expected N‐demethylation of the product aniline, 2,3,4,5,6‐pentafluoro‐N,N‐dimethylaniline N‐oxide (PFDMAO) was found to be capable of N‐dealkylating both N,N‐dimethylaniline (DMA) and N‐cyclopropyl‐N‐methylaniline (CPMA). Rate comparisons of the N‐demethylation of DMA supported by PFDMAO show a 27‐fold faster rate than when supported by N,N‐dimethylaniline N‐oxide (DMAO). Whereas intermolecular kinetic isotope effects were masked, intramolecular measurements showed values reflective of those seen previously in DMAO‐ and the native NADPH/O₂‐supported systems (2.33 and 2.8 for the N‐demethylation of PFDMA and DMA from the PFDMAO system, respectively). PFDMAO‐supported N‐dealkylation of CPMA led to the ring‐intact product N‐cyclopropylaniline (CPA), similar to that seen with the native system. The formation of CPA argues against a SET mechanism in favor of a P450‐like HAT mechanism. We suggest that the similarity of KIEs, in addition to the formation of the ring‐intact CPA, argues for a similar mechanism of Compound I (Cpd I) formation followed by HAT for N‐dealkylation by the native and N‐oxide‐supported systems and demonstrate the ability of the N‐oxide‐generated oxidant to act as an accurate mimic of the native P450 oxidant.     

One‐Pot,Three‐Component Synthesis of 1‐(2‐Hydroxyethyl)‐1H‐1,2,3‐triazole Derivatives by Copper‐Catalyzed 1,3‐Dipolar Cycloaddition of 2‐Azido Alcohols and Terminal Alkynes under Mild Conditions in Water

A safe, efficient, and improved procedure for the regioselective synthesis of 1‐(2‐hydroxyethyl)‐1H‐1,2,3‐triazole derivatives under ambient conditions is described. Terminal alkynes reacted with oxiranes and NaN₃ in the presence of a copper(I) catalyst, which is prepared by in situ reduction of the copper(II) complex 4 with ascorbic acid, in H₂O. The regioselective reactions exclusively gave the corresponding 1,4‐disubstituted 1H‐1,2,3‐triazoles in good to excellent yields. This procedure avoids the handling of organic azides as they are generated in situ, making this already powerful click process even more user‐friendly and safe. The remarkable features of this protocol are high yields, very short reaction times, a cleaner reaction profile in an environmentally benign solvent (H₂O), its straightforwardness, and the use of nontoxic catalysts. Furthermore, the catalyst could be recovered and recycled by simple filtration of the reaction mixture and reused for ten consecutive trials without significant loss of catalytic activity. No metal‐complex leaching was observed after the consecutive catalytic reactions.     

Two‐Step Synthesis of 1,3‐Disubstituted 3,4‐Dihydro‐4‐thioxoquinazolin‐2(1H)‐ones from 1‐Bromo‐2‐fluorobenzenes

An efficient synthesis of 3‐alkyl‐3,4‐dihydro‐4‐thioxobenzoquinazolin‐2(1H)‐ones 3 has been accomplished in two steps and in satisfactory yields from 1‐bromo‐2‐fluorobenzenes 1 . Thus, the reaction of 1‐fluoro‐2‐lithiobenzenes, generated by the Br/Li exchange between 1 and BuLi, with alkyl isothiocyanates, gives N‐alkyl‐2‐fluorobenzothioamides 2 , which, in turn, react with a series of isocyanates in the presence of NaH to give the desired products 3 .     

A Convenient Synthesis of 2,3‐Dihydro‐3‐methylidene‐1H‐isoindol‐1‐ones by Reaction of 2‐Formylbenzo­nitriles with Dimethyloxosulfonium Methylide

A facile method for the synthesis of 2,3‐dihydro‐3‐methylidene‐1H‐isoindol‐1‐one and its derivatives carrying substituent(s) at C(5) and/or C(6) has been developed. The reaction of 2‐formylbenzonitrile ( 1a ) with dimethyloxosulfonium methylide, generated by the treatment of trimethylsulfoxonium iodide with NaH in DMSO/THF at 0°, resulted in the formation of 2,3‐dihydro‐3‐methylidene‐1H‐isoindol‐1‐one ( 2a ) in 77% yield. Similarly, six 2‐formylbenzonitriles carrying substituent(s) at C(4) and/or C(5), i.e., 1b – 1g , also gave the corresponding expected products 2b – 2g in comparable yields.     

G‐Quartet‐Based Nanostructure for Mimicking Light‐Harvesting Antenna

Artificial light‐harvesting systems have received great attention for use in photosynthetic and optoelectronic devices. Herein, a system involving G‐quartet‐based hierarchical nanofibers generated from the self‐assembly of guanosine 5′‐monophosphate (GMP) and a two‐step Förster resonance energy transfer (FRET) is presented that mimics natural light‐harvesting antenna. This solid‐state property offers advantages for future device fabrication. The generation of photocurrent under visible light shows it has potential for use as a nanoscale photoelectric device. The work will be beneficial for the development of light‐harvesting systems by the self‐assembly of supramolecular nanostructures.     

One Ligand in Dual Roles: Self‐Assembly of a Bis‐Rhomboidal‐Shaped,Three‐Dimensional Molecular Wheel

A facile high yield, self‐assembly process that leads to a terpyridine‐based, three‐dimensional, bis‐rhomboidal‐shaped, molecular wheel is reported. The desired coordination‐driven supramolecular wheel involves eight structurally distorted tristerpyridine (tpy) ligands possessing a 60° angle between the adjacent tpy units and twelve Zn²⁺ ions. The tpy ligand plays dual roles in the self‐assembly process: two are staggered at 180° to create the internal hub, while six produce the external rim. The wheel can be readily generated by mixing the tpy ligand and Zn²⁺ in a stoichiometric ratio of 2:3; full characterization is provided by ESI‐MS, NMR spectroscopy, and TEM imaging.     

UPLC‐HR‐MS/MS‐based determination study on the metabolism of four synthetic cannabinoids,ADB‐FUBICA,AB‐FUBICA,AB‐BICA and ADB‐BICA,by human liver microsomes

Since 2012, several cannabimimetic indazole and indole derivatives with valine amino acid amide residue have emerged in the illicit drug market, and have gradually replaced the old generations of synthetic cannabinoids (SCs) with naphthyl or adamantine groups. Among them, ADB‐FUBICA [N‐(1‐amino‐3,3‐dimethyl‐1‐oxobutan‐2‐yl)‐1‐(4‐fluorobenzyl)‐1H–indole‐3‐carboxamide], AB‐FUBICA [N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐(4‐fluorobenzyl)‐1H–indole‐3‐carboxamide], AB‐BICA [N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐benzyl‐1H‐indole‐3‐carboxamide] and ADB‐BICA [N‐(1‐amino‐3,3‐dimethyl‐1‐oxobutan‐2‐yl)‐1‐benzyl‐1H‐indole‐3‐carboxamide] were detected in China recently, but unfortunately no information about their in vitro human metabolism is available. Therefore, biomonitoring studies to screen their consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated their phase I metabolism by incubating with human liver microsomes, and the metabolites were identified by ultra‐performance liquid chromatography–high resolution–tandem mass spectrometry. Metabolites generated by N‐dealkylation and hydroxylation on the 1‐amino‐alkyl moiety were found to be predominant for all these four substances, and others which underwent hydroxylation, amide hydrolysis and dehydrogenation were also observed in our investigation. Based on our research, we recommend that the N‐dealkylation and hydroxylation metabolites are suitable and appropriate analytical markers for monitoring their intake.     

One‐Pot Synthesis of Dispiro[oxindole‐3,3′‐pyrrolidines] by Three‐Component [3+2] Cycloadditions of in situ‐Generated Azomethine Ylides with 3‐Benzylidene‐2,3‐dihydro‐1H‐indol‐2‐ones

An efficient one‐pot, three‐component synthesis of novel dispiro[oxindole‐3,3′‐pyrrolidines] by 1,3‐dipolar cycloaddition of azomethine ylides, in situ generated by reaction of 1,2‐diones with sarcosine and subsequent decarboxylation, with a series of (E)‐3‐benzylidene‐2,3‐dihydro‐1H‐indol‐2‐ones is reported. Molecular complexity is generated in only one synthetic step. All reactions proceed with excellent regioselectivity and in good‐to‐excellent yields. The workup is easy, the reaction times are short, and no catalyst is required.     

Rapid sampling of all‐atom peptides using a library‐based polymer‐growth approach

We adapted existing polymer growth strategies for equilibrium sampling of peptides described by modern atomistic forcefields with a simple uniform dielectric solvent. The main novel feature of our approach is the use of precalculated statistical libraries of molecular fragments. A molecule is sampled by combining fragment configurations—of single residues in this study—which are stored in the libraries. Ensembles generated from the independent libraries are reweighted to conform with the Boltzmann‐factor distribution of the forcefield describing the full molecule. In this way, high‐quality equilibrium sampling of small peptides (4–8 residues) typically requires less than one hour of single‐processor wallclock time and can be significantly faster than Langevin simulations. Furthermore, approximate, clash‐free ensembles can be generated for larger peptides (up to 32 residues in this study) in less than a minute of single‐processor computing. We discuss possible applications of our growth procedure to free energy calculation, fragment assembly protein‐structure prediction protocols, and to “multi‐resolution” sampling. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011     

Formation of activation‐free,selectively bioconjugatable poly(N‐acryloxysuccinimide‐co‐oligoethylene glycol methyl ether methacrylate) films by surface‐initiated ARGET ATRP

Activation‐free copolymeric films possessing high selectivity to target proteins and low biofouling background are prepared via controlled radical polymerization. The copolymeric films are generated by surface‐initiated activators regenerated by electron transfer atom transfer radical polymerization (SI‐ARGET ATRP) of N‐acryloxysuccinimide (NAS) and oligo(ethylene glycol) methyl ether methacrylate (OEGMEMA) by controlling the molar feed ratio of the two monomers. The formation of copolymeric films is characterized by ellipsometry, contact angle goniometry, FTIR spectroscopy, and X‐ray photoelectron spectroscopy. The prepared copolymeric films are biotinylated without an activation step. Biotin–streptavidin association is employed as a model system to investigate both selective binding and the relevant signal‐to‐noise (S/N) ratio. When the molar feed ratio of NAS and OEGMEMA is 2:8, the copolymeric film is optimized to give the highest S/N ratio (339.8) according to surface plasmon resonance studies. The highly selective bioconjugation is used to generate micropatterns of rhodamine‐conjugated streptavidin on the copolymeric film. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 329–337