Convenient Method for Preparation of Aza‐Crown Ethers

A convenient method for the preparation of peraza crown ethers in a one‐pot synthesis in the presence of KF/Al₂O₃ is presented.     

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.     

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.     

A Convenient and Versatile Method for the Preparation of α‐Hydroxymethyl Ketone Derivatives from the Corresponding Allyl Silyl Ethers or Allyl Carboxylates

The ozonolysis of 1‐substituted allyl silyl ethers or 1‐substituted allyl carboxylates followed by treatment with bases gave the corresponding α‐silyloxymethyl‐ or α‐acyloxymethyl‐ketones in good yields. It is proposed to proceed via the corresponding α‐silyloxy‐ or α‐acyloxyaldehydes intermediates followed by 1,4‐group migration. The results of theoretical calculations are applicable to explain the experimental results.     

The Trifluoromethyl Anion: Evidence for [K(crypt‐222)]+

[K(crypt‐222)]⁺ ( 1 ) and [K(crypt‐222)]⁺ ( 3 ) are isostructural, displaying nearly identical unit cell parameters. The two structures are similar to the extent that the previously reported [K(crypt‐222)]⁺ model can be refined against the new data for [K(crypt‐222)]⁺ , with extra electron density being observed from the fourth fluorine atom of the . In agreement with experimental observations, theoretical calculations suggest that deprotonated [K(crypt‐222)]⁺ is highly unstable even at as low as 195 K. The previously considered 1:1 CHF ₃ clathrate of deprotonated [K(crypt‐222)]⁺ (crystallographically indistinguishable from 1 ) is ruled out on the basis of all available data.     

Kinetic Study of the Oxidation of Catechols in the Presence of Some Aza‐crown Ethers by Digital Simulation of Cyclic Voltammograms

The electrochemical oxidation of catechols ( 1 ) have been studied in the presence of diaza‐18‐crown‐6 (DA18C6) ( 3a ), diaza‐15‐crown‐5 (DA15C5) ( 3b ), and aza‐15‐crown‐5 (A15C5) ( 3c ) as nucleophiles in aqueous solution, by means of cyclic voltammetry and controlled‐potential coulometry. The results indicate the participation of electrochemically generated o‐benzoquinones ( 2 ) in Michael‐type reaction with aza‐crown ethers ( 3 ) to form the corresponding new o‐benzoquinone‐aza‐crown ether adducts ( 5 ). Based on ECE mechanism, the observed homogeneous rate constants (k_obs) of the reaction of o‐bezoquinones ( 2 ) with aza‐crown ethers ( 3 ) were estimated by comparing the experimental cyclic voltammograms with the digital simulated results. The calculated observed homogeneous rate constants (k_obs) was found to vary in the order DA18C6>DA15C5>A15C5.     

Synthesis of Some Novel Thioxanthenone‐Fused Azacrown Ethers,and Their Use as New Catalysts in the Efficient,Mild, and Regioselective Conversion of Epoxides to β‐Hydroxy Thiocyanates with Ammonium Thiocyanate

The regioselective ring‐opening reactions of some epoxides with ammonium thiocyanate in the presence of a series of new 9H‐thioxanthen‐9‐one‐fused azacrown ethers, i.e., 7 – 11 (Scheme 1), and also of dibenzo[18]crown‐6 ( 12 ), Kryptofix^® 22 ( 13 ), and benzo[15]crown‐5 ( 14 ) were studied (Tables 1 and 2). The epoxides were subjected to cleavage by NH₄SCN in the presence of these catalysts under mild conditions in various aprotic solvents. Reagents and conditions were identified for the synthesis of individual β‐hydroxy thiocyanates in high yield and with more than 90% regioselectivity. The results can be discussed in terms of a four‐step mechanism (Scheme 2): 1) formation of a complex between catalyst and NH₄SCN, 2) release of SCN^? from the complex, 3) reaction of the released SCN^? at the sterically less hindered site of the epoxide, and 4) regeneration of the catalyst. The major advantages of this method are the high regioselectivity, the simple regeneration of the catalyst, the reuse of it through several cycles without a decrease of activity, and the ease of workup of the reaction mixtures.     

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.     

‘Click Synthesis’ of Some Novel O‐Substituted Oximes Containing 1,2,3‐Triazole‐1,4‐diyl Residues as New Analogs of β‐Adrenoceptor Antagonists

The ‘click synthesis’ of some novel O‐substituted oximes, 7a – 7t , which contain 1,2,3‐triazolediyl residues, as new analogs of β‐adrenoceptor antagonists is described (Schemes 1–4). The synthesis of these compounds was achieved in four to five steps. The formation of oximes of 9H‐fluoren‐9‐one and benzophenone, i.e., 9a and 9b , respectively, followed by their reaction with propargyl bromide, afforded O‐propargyl oximes 10a and 10b , respectively, which by a subsequent CuI‐catalyzed Huisgen cycloaddition with prepared β‐azido alcohols 11a – 11j (Schemes 2 and 3), led to the target compounds 7a – 7t in good yields.     

Preparation of 8‐Aza‐7‐deazaaristeromycin and ‐neplanocin A and Their 5′‐Homologs

The synthesis of new members of the aristeromycin and neplaoncin A families of carbocyclic nucleosides possessing the 1H‐pyrazolo[3,4‐d]pyrimidine ring is reported. For this purpose, an adapted route to 4‐amino‐1H‐pyrazolo[3,4‐d]pyrimidine is described.     

Facile One‐Pot Synthesis of Monosubstituted 1‐Aryl‐1H‐1,2,3‐triazoles from Arylboronic Acids and Prop‐2‐ynoic Acid (=Propiolic Acid) or Calcium Acetylide (=Calcium Carbide) as Acetylene Source

The synthesis of monosubstituted 1‐aryl‐1H‐1,2,3‐triazoles was achieved in a one‐pot reaction from arylboronic acids and prop‐2‐ynoic acid or calcium acetylide (=calcium carbide), respectively, as a source of acetylene, with yields ranging from moderate to excellent (Scheme 1, Table 2). The reaction conditions were successfully applied to arylboronic acids, including analogs with various functionalities. Unexpectedly, the 1,2,3‐triazole moiety promoted a regioselective hydrodebromination (Scheme 2).     

Regio‐ and Enantioselective Aza‐Diels–Alder Reactions of 3‐Vinylindoles: A Concise Synthesis of the Antimalarial Spiroindolone NITD609

An asymmetric aza‐Diels–Alder reaction of 3‐vinylindoles with isatin‐derived ketimines has been developed. A series of spiroindolone derivatives were thus obtained in good to excellent yields with excellent enantioselectivity (up to 96 % yield and 99 % ee). Furthermore, the antimalarial compound NITD609 could be obtained in three steps with an overall yield of 40.6 %. Control experiments and operando IR experiments imply a concerted reaction pathway. The regioselectivity and exo selectivity result from π–π interactions between the two indoline rings of the two reactants.     

Convenient Synthesis of 1H‐Indol‐1‐yl Boronates via Palladium(0)‐Catalyzed Borylation of Bromo‐1H‐indoles with ‘Pinacolborane’

An atom‐economic Pd⁰‐catalyzed synthesis of a series of pinacol‐type indolylboronates 3 from the corresponding bromoindole substrates 2 and pinacolborane (pinBH) as borylating agent was elaborated. The optimal catalyst system consisted of a 1 : 2 mixture of [Pd(OAc)₂] and the ortho‐substituted biphenylphosphine ligand L‐3 (Scheme 4, Table). Our synthetic protocol was applied to the fast, preparative‐scale synthesis of 1‐substituted indolylboronates 3a – h in the presence of different functional groups, and at a catalyst load of only 1 mol‐% of Pd.     

A Convenient Method for the Preparation of 1,5‐Diaryl‐3‐(arylamino)‐1H‐pyrrol‐2(5H)‐ones

A simple and eco‐friendly method for the preparation of 1,5‐diaryl‐3‐(arylamino)‐1H‐pyrrol‐2(5H)‐ones via the cyclo‐condensation reaction of aldehydes, amines and ethyl pyruvate in the presence of silica supported ferric chloride (SiO₂‐FeCl₃) as reusable heterogeneous catalyst is described. The present methodology offers several advantages such as excellent yields, simple procedure and short reaction times.     

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/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.     

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.     

One‐Step Synthesis of Dialkyl 2‐[(4‐Methylphenyl)sulfonyl]‐1H‐pyrrole‐3,4‐dicarboxylates by Reaction of Acetylenedicarboxylates with ‘Tosylmethyl Isocyanide’ (TsMIC) and Triphenylphosphine

The reactive 1 : 1 adducts in the reaction between Ph₃P and dialkyl acetylenedicarboxylates have been trapped with ‘tosylmethyl isocyanide’ (TsMIC ; 1 ) to yield dialkyl 2‐[(4‐methylphenyl)sulfonyl]‐1H‐pyrrole‐3,4‐dicarboxylates 3 (Scheme 1). The structures of the highly functionalized compounds 3 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this type of cyclization is proposed (Scheme 2).