‘Click Synthesis’ of 1H‐1,2,3‐Triazolyl‐Based Oxiconazole (=(1Z)‐1‐(2,4‐Dichlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone O‐[(2,4‐Dichlorophenyl)methyl]oxime) Analogs

The ‘click synthesis’ of some oxiconazole analogs 5a – 5v having 1H‐1,2,3‐triazolyl residues by Huisgen cycloaddition was achieved in four steps (Scheme 1). Oximation of phenacyl chloride ( 1 ) followed by azidation of 2‐chloro‐1‐phenylethanone oxime ( 2 ) provided azido ketoxime 3 . The CuI‐catalyzed Huisgen cycloaddition of 3 with terminal alkynes gave the 4‐substituted (at the triazole) 2‐(1H‐1,2,3‐triazol‐1‐yl)‐1‐phenylethanone oximes 4a – 4i . The O‐alkylation of 4a – 4i with various alkyl halides resulted in the formation of the target molecules 5a – 5v in good yields.     

A Novel ‘Domino‐Click Approach’ to Unsymmetrical Bis‐1H‐1,2,3‐triazoles

Aryl azides 1 were treated with allenylmagnesium bromide ( 2 ) to generate 1,5‐disubstituted butynyl‐1H‐1,2,3‐triazoles 3 in a domino fashion, which upon Cu^I‐catalyzed 1,3‐dipolar cycloaddition with aryl azides 4 afforded novel bis‐1H‐1,2,3‐triazoles 5 in quantitative yields (Scheme 1 and Table).     

‘Click Synthesis’ of Some Novel Benzimidazol Oxime Ethers Containing Heterocycle Residues as Potential ß‐Adrenergic Blocking Agents

The ‘click synthesis’ of some novel O‐substituted oximes, 5a – 5j , which contain heterocycle residues, as new analogs of ß‐adrenoceptor antagonists is described (Scheme 1). The synthesis of these compounds was achieved in four steps. The formation of (E)‐2‐(1H‐benzo[d]imidazol‐1‐yl)‐1‐phenylethanone oxime, followed by their reaction with 2‐(chloromethyl)oxirane, afforded mixture of oil compounds 3 and 4 , which by a subsequent tetra‐n‐butylammonium bromide (TBAB)‐catalyzed reaction with N H heterocycle compounds (Scheme 1), led to the target compounds 5a – 5j in good yields.     

A Copper‐Catalyzed Multicomponent Reaction and ‘Click Strategy’ for the Stereoselective Synthesis of a New Series of Oxazolone Peptidomimetics with α‐Acylamino Amide and β‐Amido Ketone Structures

A novel ‘click ligation’ strategy for the stereoselective synthesis of a medium‐size library of structurally complex and functionally diverse oxazolone peptidomimetics, which contain α‐acylamino carboxamide or β‐amido ketone residues, is presented. Most of these molecules have lipophilicity constant values (log P) in the qualifying range for cell permeability, and that indicates the possibilities of these new molecules to be used in the search for potential inhibitors for a broad spectrum of enzymes.     

Oligonucleotides Containing 7‐Deaza‐2′‐deoxyinosine as Universal Nucleoside: Synthesis of 7‐Halogenated and 7‐Alkynylated Derivatives,Ambiguous Base Pairing,and Dye Functionalization by the Alkyne–Azide ‘Click’ Reaction

Oligonucleotides containing 7‐deaza‐2′‐deoxyinosine derivatives bearing 7‐halogen substituents or 7‐alkynyl groups were prepared. For this, the phosphoramidites 2b – 2g containing 7‐substituted 7‐deaza‐2′‐deoxyinosine analogues 1b – 1g were synthesized (Scheme 2). Hybridization experiments with modified oligonucleotides demonstrate that all 2′‐deoxyinosine derivatives show ambiguous base pairing, as 2′‐deoxyinosine does. The duplex stability decreases in the order C_d>A_d>T_d>G_d when 2b – 2g pair with these canonical nucleosides (Table 6). The self‐complementary duplexes 5′‐d(F⁷c⁷I‐C)₆, d(Br⁷c⁷I‐C)₆, and d(I⁷c⁷I‐C)₆ are more stable than the parent duplex d(c⁷I‐C)₆ (Table 7). An oligonucleotide containing the octa‐1,7‐diyn‐1‐yl derivative 1g , i.e., 27 , was functionalized with the nonfluorescent 3‐azido‐7‐hydroxycoumarin ( 28 ) by the Huisgen–Sharpless–Meldal cycloaddition ‘click’ reaction to afford the highly fluorescent oligonucleotide conjugate 29 (Scheme 3). Consequently, oligonucleotides incorporating the derivative 1g bearing a terminal C?C bond show a number of favorable properties: i) it is possible to activate them by labeling with reporter molecules employing the ‘click’ chemistry. ii) Space demanding residues introduced in the 7‐position of the 7‐deazapurine base does not interfere with duplex structure and stability (Table 8). iii) The ambiguous pairing character of the nucleobase makes them universal probes for numerous applications in oligonucleotide chemistry, molecular biology, and nanobiotechnology.     

Copper/Graphene/Clay Nanohybrid: A Highly Efficient Heterogeneous Nanocatalyst for the Synthesis of Novel 1,2,3‐Triazolyl Carboacyclic Nucleosides via ‘Click’ Huisgen 1,3‐Dipolar Cycloaddition

A very mild and highly efficient synthesis of some novel 1H‐1,2,3‐triazolyl carboacyclic nucleosides via a ‘Click’ Huisgen cycloaddition of N‐propargyl nucleobases and azido alcohols using Cu/aminoclay/reduced graphene oxide nanohybrid (Cu/AC/r‐GO nanohybrid) as nanocatalyst is described. The preparation and characterization of Cu/AC/r‐GO nanohybrid are discussed. This catalyst was characterized by X‐ray diffraction, FT‐IR, TEM, and energy‐dispersive analysis of X‐ray techniques. Cu/AC/r‐GO nanohybrid is a stable and highly efficient heterogeneous nanocatalyst that can be easily prepared, used, and restored from the reaction mixture by simple filtration, and reused for many consecutive trials without significant decrease in activity.     

Synthesis of 1,4‐Diazabutadienes (=N,N′‐Ethane‐1,2‐diylidenebis[amines]) by Grinding

A simple and convenient method for the synthesis of 1,4‐diazabutadienes (=N,N′‐ethane‐1,2‐diylidenebis[amines]) by grinding glyoxal (=ethanedial) or an α‐diketone and anilines (=benzenamines) in the presence of TsOH in a mortar with a pestle is described. By this way, 1,4‐diazabutadienes were obtained in good to excellent yields.     

Reactions of Polycyclic Ketones with Dimethoxycarbene; a Convenient Route for a ‘One‐Pot’ Preparation of Some α‐Hydroxycarboxylic Acid Esters

Polycyclic ‘cage’ ketones, such as pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecan‐8‐one ( 10 ), pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane‐8,11‐dione ( 11 ), and adamantan‐2‐one ( 16 ) were treated with the nucleophilic dimethoxycarbene (DMC; 1 ), which was generated thermally from 2,5‐dihydro‐2,2‐dimethoxy‐5,5‐dimethyl‐1,3,4‐oxadiazole ( 4a ) in boiling toluene. In this ‘one‐pot’ procedure, the α‐hydroxycarboxylic acid ester 12 or a corresponding derivative 15 or 17 was obtained (Schemes 4–7). Additionally, ‘cage’ thione 21 was treated with DMC under the same conditions yielding dimethoxythiirane 22 (Scheme 8). Subsequent hydrolysis or desulfurization (followed by hydrolysis on silica gel) of 22 gave α‐mercaptocarboxylate 25 and the corresponding desulfurized ester 24 , respectively. In all cases, the addition of DMC occurred stereoselectively, and the addition from the exo‐face is postulated to explain the structures of the isolated products.     

A rapid and sensitive LC–MS/MS method for quantification of quercetin‐3‐O‐β‐d‐glucopyranosyl‐7‐O‐β‐d‐gentiobioside in plasma and its application to a pharmacokinetic study

A rapid and sensitive LC–MS/MS method with good accuracy and precision was developed and validated for the pharmacokinetic study of quercetin‐3‐O‐β‐d ‐glucopyranosyl‐7‐O‐β‐d ‐gentiobioside (QGG) in Sprague–Dawley rats. Plasma samples were simply precipitated by methanol and then analyzed by LC–MS/MS. A Venusil® ASB C₁₈ column (2.1 × 50 mm, i.d. 5 μm) was used for separation, with methanol–water (50:50, v/v) as the mobile phase at a flow rate of 300 μL/min. The optimized mass transition ion‐pairs (m/z) for quantitation were 787.3/301.3 for QGG, and 725.3/293.3 for internal standard. The linear range was 7.32–1830 ng/mL with an average correlation coefficient of 0.9992, and the limit of quantification was 7.32 ng/mL. The intra‐ and inter‐day precision and accuracy were less than ±15%. At low, medium and high quality control concentrations, the recovery and matrix effect of the analyte and IS were in the range of 89.06–92.43 and 88.58–97.62%, respectively. The method was applied for the pharmacokinetic study of QGG in Sprague–Dawley rats. Copyright © 2016 John Wiley & Sons, Ltd.     

Identification and structural characterization of the synthetic cannabinoid 3‐(1‐adamantoyl)‐1‐pentylindole as an additive in ‘herbal incense’

Since the end of 2010, more than 20 synthetic cannabimimetics have been identified in ‘Spice’ products, demonstrating the enormous dynamic in this field. In an effort to cope with the problem, many countries have already undertaken legal measures by putting some of these compounds under control. Nevertheless, once a number of compounds were scheduled, they were soon replaced by other synthetic cannabinoids. In this article, we report the identification of a new – and due to its substitution pattern rather uncommon – cannabimimetic found in several ‘herbal incense’ products. The GC–EI mass spectrum first led to misidentification as the alpha‐methyl‐derivative of JWH‐250. However, since both substances show different retention indices, thin‐layer chromatography was used to isolate the unknown compound. After application of nuclear magnetic resonance spectroscopy, high‐resolution MS and GC–MS/MS techniques, the compound was identified as 3‐(1‐adamantoyl)‐1‐pentylindole, a derivative of JWH‐018 carrying an adamantoyl moiety instead of a naphthoyl group. This finding supports that the listing of synthetic cannabinoids as prohibited substances triggers the appearance of compounds with uncommon substituents. Moreover, it emphasizes the necessity of being aware of the risk of misidentification when using techniques sometimes providing only limited structural information like GC–MS. Copyright © 2012 John Wiley & Sons, Ltd.     

Copper Supported on the SiO2 Nanoparticle in Click Chemistry: An Alternative Catalytic System for Regioselective and One‐Pot Synthesis of 1,2,3‐Triazoles and β‐Hydroxytriazoles

In this work, readily prepared copper supported on the SiO₂ nanoparticles has been found to effectively catalyze the 1,3‐dipolar cycloaddition of a variety of azides, alkynes, epoxides and sodium azide, furnishing the corresponding 1,2,3‐triazoles and β‐hydroxytriazoles. Click reaction proceeds in short reaction times and under mild reaction conditions, and the resulting products are obtained in good yields at ambient temperature.     

A One‐Pot Tandem Ugi Multicomponent Reaction (MCR)/Click Reaction as an Efficient Protecting‐Group‐Free Route to 1H‐1,2,3‐Triazole‐Modified α‐Amino Acid Derivatives and Peptidomimetics

By a one‐pot tandem Ugi multicomponent reaction (MCR)/click reaction sequence not requiring protecting groups, 1H‐1,2,3‐triazole‐modified Ugi‐reaction products 6a – 6n (Scheme 1 and Table 2), 7a – 7b (Table 4), and 8 (Scheme 2) were synthesized successfully. i.e., terminal, side‐chain, or both side‐chain and terminal triazole‐modified Ugi‐reaction products as potential amino acid units for peptide syntheses. Different catalyst systems for the click reaction were examined to find the optimal reaction conditions (Table 1, Scheme 1). Finally, an efficient Ugi MCR+Ugi MCR/click reaction strategy was elaborated in which two Ugi‐reaction products were coupled by a click reaction, thus incorporating the triazole fragment into the center of peptidomimetics (Scheme 3). Thus, the Ugi MCR/click reaction sequence is a convenient and simple approach to different 1H‐1,2,3‐triazole‐modified amino acid derivatives and peptidomimetics.     

Synthesis of β‐Haloketones by β‐Addition Reactions of α,β‐Unsaturated Ketones with BX3 (X = Br,Cl) as Halide Source

A series of β‐bromoketones and β‐chloroketones were synthesized by the addition reactions of α,β‐unsaturated ketones under BX₃ (X = Br, Cl) and ethylene glycol reaction system. The α,β‐unsaturated ester also was successfully converted to its corresponding β‐bromoester under the reaction condition.     

Synthesis of new optically active α,α′,β‐trisubstituted‐β‐lactones as monomers for stereoregular biopolyesters

Various optically active (4R)‐alkyloxycarbonyl‐3,3‐dialkyl‐2‐oxetanones as monomers were synthesized from L‐(S)‐malic acid in six steps to prepare a new family of stereopolyesters for biomedical applications. The synthesis began with an esterification followed of a dialkylation in the aim to introduce hydrophobic groups as methyl or reactive group as allyl. Then, a saponification has permitted to obtain the corresponding diacids that reacted with appropriate alcohols to furnish different monoesters. The last and most important step was activation of hydroxyl group of monoesters with the asymmetric carbon configuration inversion according to the Mitsunobu reaction. Thus, this reaction has provided lactones from monoesters with 100% enantiomeric excess which was confirmed by ¹H NMR and by the synthesis of corresponding isotactic and semicrystalline homopolyesters. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2586–2597     

New Convenient Five‐Component One‐Pot Synthesis of 3‐Alkyl‐6‐amino‐1,4‐dihydro‐4‐{[(1,2,3‐triazol‐4‐yl)methoxy]phenyl}pyrano[2,3‐c]pyrazole‐5‐carbonitrile Derivatives

3‐Alkyl‐6‐amino‐1,4‐dihydro‐4‐{[(1,2,3‐triazol‐4‐yl)methoxy]phenyl}pyrano[2,3‐c]pyrazole‐5‐carbonitrile derivatives were synthesized through a one‐pot five‐component condensation reaction.     

1,2,3‐Triazole Bridge as Conformational Constrain in β‐Hairpin Peptides: Analysis of Hydrogen‐Bonded Positions

Conformational constrained β‐hairpin peptides are useful tool to modulate protein–protein interactions. A triazole bridge in hydrogen‐bonded positions between two antiparallel strands induces a conformational stabilization of the β‐hairpin peptide. The entity of the stability of the β‐hairpin peptide depends on the length of the bridge.