Benzyl Azide Research Articles

Preparation of Benzyl Azide Complexes of Iridium(III)

Hydride complexes IrHCl(2)(PiPr(3))P(2) (1) and IrHCl(2)P(3) (2) [P = P(OEt)(3) and PPh(OEt)(2)] were prepared by allowing IrHCl(2)(PiPr(3))(2) to react with phosphite in refluxing benzene or toluene. Treatment of IrHCl(2)P(3), first with HBF(4).Et(2)O and then with an excess of ArCH(2)N(3), afforded benzyl azide complexes [IrCl(2)(eta(1)-N(3)CH(2)Ar)P(3)]BPh(4) (3, 4) [Ar = C(6)H(5), 4-CH(3)C(6)H(4); P = P(OEt)(3), PPh(OEt)(2)]. Azide complexes reacted in CH(2)Cl(2) solution, leading to the imine derivative [IrCl(2){eta(1)-NH=C(H)C(6)H(5)}P(3)]BPh(4) (5). The complexes were characterized by spectroscopy and X-ray crystal structure determination of [IrCl(2)(eta(1)-N(3)CH(2)C(6)H(5)){P(OEt)(3)}(3)]BPh(4) (3a) and [IrCl(2){eta(1)-NH=C(H)C(6)H(5)}{P(OEt)(3)}(3)]BPh(4) (5a). Both solid-state structure and (15)N NMR data indicate that the azide is coordinated through the substituted Ngamma [Ir]-Ngamma(CH(2)Ar)NNalpha nitrogen atom.

Synthesis of 1,3,4‐Trisubstituted Isoquinolines by Iodine‐Mediated Electrophilic Cyclization of 2‐Alkynyl Benzyl Azides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Design and Synthesis of a Tag‐Free Chemical Probe for Photoaffinity Labeling

AbstractThe novel aromatic diazirine‐containing benzoic acid 22 was prepared via the diazirine 11 as the key intermediate. After formylation of the aryl ring and cleavage of the methyl ether function of aldehyde 12, the phenolic hydroxy group was converted into the ether 21 terminating in an alkyne function. Oxidation of the aldehyde to the carboxylic acid provided the chemical probe 22 designed for tag‐free photoaffinity labeling. In a proof‐of‐concept study it could be shown that irradiation of the simple ester 23 indeed yields the methanol insertion product 24. A subsequent click reaction with benzyl azide 20 led to the triazole 25. A more complicated example was realized with the esterification of bafilomycin A1 (27) with acid 22. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Metal‐Free Triazole Formation as a Tool for Bioconjugation

The development of selective and site-specific bio-orthogonal conjugation methods is an important topic in chemical biology. A wide range of methods, such as the Staudinger ligation, native chemical ligation, genetic incorporation, expressed-protein ligation, Huisgen azide–alkyne cycloaddition, and the Diels–Alder ligation are currently employed in the selective modification of proteins and other biomolecules. In recent years, the Cu-catalyzed variant of the Huisgen 1,3-dipolar cycloaddition, also referred to as “click reaction”, has been increasingly applied in various fields of chemistry as a versatile and mild ligation method. This method allows for the synthesis of complex materials, which include bioconjugates, glycopeptides, functionalized polymers, virus particles, and therapeutics. However, due to the toxicity of the copper catalyst to both bacterial and mammalian cells applications that involve in vivo ligation are limited. In order to circumvent the use of copper ions, Bertozzi and co-workers have devised a strain-promoted [3+2] cycloaddition reaction that involves azides and a strained cyclooctyne derivative. Recent reports by Ju et al. have also shown successful applications of copper-free 1,3-dipolar cycloaddition by using either elevated temperatures or electron-deficient alkynes. We envisioned that the combination of ring strain and electron deficiency, as occurs in oxa-bridged bicyclic systems 2a and 2b, could also lead to an increased reactivity toward [3+2] cycloaddition reactions. Here, we report a spontaneous tandem [3+2] cycloaddition–retro-Diels–Alder ligation method that results in a stable 1,2,3-triazole linkage. This methodology can be applied to biomacromolecules that contain various functional groups under physiological conditions. The oxabridged bicyclic systems 2a and 2b were prepared by a Diels– Alder reaction of substituted propiolates with furan (Scheme 1). Subsequent hydrolysis provided the desired carboxylic acid derivatives 3a and 3b, in excellent yield. To compare the reactivity of Diels–Alder products 2a and b with the corresponding alkynes, [3+2] cycloaddition reactions were performed under ambient conditions by using benzyl azide, and monitored over time with H NMR spectroscopy (Figure 1). The oxanorbornadienes 2a and 2b and their respective alkynes provided identical 1,4,5-substituted triazoles to the products.

Transition-Metal-Free Synthesis of Isoquinolines

Reported is an efficient synthesis of 1,3,4-trisubstituted isoquinolines involving an iodine-mediated, intramolecular electrophilic heteroannulation of 2-alkynyl benzyl azides. Cyclization with I2 is achieved in excellent yields for substrates bearing bulky R1 = aryl or alkenyl substituents which stabilize the cationic iodonium intermediate formed upon alkyne activation by I2. The reaction failed for R1 = coordinating substituent or H. Formation of side product 3 was minimized by the use of iodine electrophiles having less nucleophilic counterions (i.e. Py2IBF4/HBF4 and NIS) The preliminary investigation of functional group compatibility suggests a dependence of reaction outcome on the iodine reagent and reaction conditions. However, the availability of neutral, basic, or acidic reaction conditions provides options for sensitive substrates, and the method shows promise for the construction of substituted naphthyridines.

Stabilization of Parallel Triplexes by Twisted Intercalating Nucleic Acids (TINAs) Incorporating 1,2,3‐Triazole Units and Prepared by Microwave‐Accelerated Click Chemistry

A highly efficient method for postsynthetic modification of unprotected oligonucleotides incorporating internal insertions of (R)-1-O-(4-ethynylbenzyl)glycerol has been developed through the application of click chemistry with water-insoluble pyren-1-yl azide and water-soluble benzyl azide and acceleration by microwave irradiation. The twisted intercalating nucleic acids (TINAs) obtained in these reactions, possessing bulged insertions of (R)-3-O-{4-[1-(pyren-1-yl)-1H-1,2,3-triazol-4-yl]benzyl}glycerol (7), formed parallel triplexes with thermal stabilities of 20.0, 34.0, and 40.0 degrees C at pH 7.2 in the cases of one, two, or three insertions of 7, respectively, separated by three nucleic bases. An oligonucleotide with four insertions of 7--each between three nucleic bases in the sequence--was unable to form complexes with complementary single- or double-stranded DNAs, as a result of self-aggregation of the pyrene moieties. This assumption was supported by the formation of a very strong excimer band at 460 nm in the fluorescence spectra. Molecular modeling of the parallel triplex with bulged insertion of the monomer 7 in the triplex-forming oligonucleotide (TFO) showed that only the pyrene moiety was stacking between the bases of the dsDNA, whereas 1,2,3-triazole did not participate in the triplex stabilization. Thermal denaturation studies of the duplexes and triplexes, as well as the fluorescence properties of TINA-triazole 7, are discussed and compared with previous studies on TINA.

Synthesis of 1,3,4‐Trisubstituted Isoquinolines by Iodine‐Mediated Electrophilic Cyclization of 2‐Alkynyl Benzyl Azides

Synthesis of 1,3,4‐Trisubstituted Isoquinolines by Iodine‐Mediated Electrophilic Cyclization of 2‐Alkynyl Benzyl Azides

Synthesis of 1,3,4‐Trisubstituted Isoquinolines by Iodine‐Mediated Electrophilic Cyclization of 2‐Alkynyl Benzyl Azides

Das richtige „I“ macht's: Eine Reihe von 2-Alkinylbenzylaziden konnte mithilfe einer Iodonium-vermittelten Synthese glatt und mit akzeptablen bis ausgezeichneten Ausbeuten in 1,3,4-trisubstituierte Isochinoline überführt werden (siehe Schema). Abhängig von der Substratstruktur wurden Iod, das Barluenga-Reagens (Py2IBF4/HBF4) oder N-Iodsuccinimid als I+-Quelle eingesetzt.

Alkynyl polysaccharides: synthesis of propargyl potato starch followed by subsequent derivatizations

Potato starch propargyl ethers (PgS) with degrees of substitution (DS) from 0.1 to 2.2 have been prepared by etherification of starch with sodium hydroxide or Li dimsyl in Me 2SO and propargyl bromide. DS values and substituent distribution were determined after hydrolysis and acetylation by GC–MS. The order of reactivity was 2 > 6 ≫ 3, with O-3 substitution being preferably observed in the trisubstituted units. Repeated analysis of the starch derivatives revealed that propargyl residues were lost during storage, a phenomenon that was not fully understood until now. Selected PgS were further functionalized: (a) O- and C-methylated to O-(2-butynyl)- O-methyl starch (BMS), (b) in a Mannich type reaction with diethylamine and formaldehyde to yield O-(4-diethylamino)-2-butinyl starch (DEABiS), (c) in a 1,3-dipolar cycloaddition with benzyl azide (‘click-chemistry’) to a N-benzyltriazole derivatized starch (BTrS), and (d) with carbon dioxide to O-(3-carboxy)-2-butinyl starch (CBiS). While the yield of carboxylation was only poor, conversion was high or nearly quantitative for reactions a–c. Thus, it is demonstrated that starch propargyl ethers are valuable intermediates for the preparation of functional polysaccharides.

Modification of methyl O-propargyl- d-glucosides: model studies for the synthesis of alkynyl based functional polysaccharides

Methyl 4,6- O-benzylidene-2,3-di- O-propargyl-α- d-glucoside ( 2) has been prepared and its structure determined, including its X-ray structural analysis. For comparison the structure of the corresponding allyl derivative has also been determined by X-ray crystallography. Glucoside 2 is a versatile starting material for numerous novel derivatives such as diols, a diester, a diacid, and a dialdehyde. Subjecting 2 to a Mannich reaction leads to a (bis)amine in excellent yields. The click reaction between 2 and benzyl azide furnishes a (bis)triazole as the main product. Deprotection of 2 furnishes a (bis)propargyl ether, which can be converted by the methodology developed for 2 to the corresponding (bis)acetylenes; click reaction with benzyl azide converts 2 into a (bis)triazole.

Cu/C Catalyst for Click Chemistry

A copper-in-charcoal catalyst for click chemistry was demonstrated. Thus, the Cu/C was prepared from activated wood charcoal and Cu(NO3)2 with ultrasonic agitation. Highly efficient click chemistry of benzyl azide and 2-methyl-but-3-yn-2-ol by using Cu/C catalyst (10 mol%) was performed at 60 °C in dioxane to give a 1,4-triazole derivative in 99% yield. The click cycloaddition was significantly accelerated with stoichiometric Et3N or by microwave irradiation. This Cu/C catalyst was reused without loss of activity under air (1st-3rd use: 99% yield).

Reactions of manganese and rhenium complexes with organic azides: preparation of tetraazabutadiene derivatives

Azide complexes [M(RN(3))(CO)(3)P(2)]BPh(4)[M = Mn, Re; R = C(6)H(5)CH(2), 4-CH(3)C(6)H(4)CH(2), C(6)H(5), 4-CH(3)C(6)H(4), C(5)H(9); P = PPh(OEt)(2), PPh(2)(OEt)] were prepared by allowing tricarbonyl MH(CO)(3)P(2) hydride complexes to react first with Brønsted acid (HBF(4), CF(3)SO(3)H) and then with organic azide in the dark. In sunlight the reaction yielded tetraazabutadiene [M(eta(2)-1,4-R(2)N(4))(CO)(2)P(2)]BPh(4) complexes or, with benzyl azide, imine [M{eta(1)-NH[double bond, length as m-dash]C(H)Ar}(CO)(3)P(2)]BPh(4)(Ar = C(6)H(5), 4-CH(3)C(6)H(4)) derivatives. Tetraazabutadiene [M(eta(2)-1,4-R(2)N(4))(CO)(2)P(2)]BPh(4) complexes were also prepared by reacting dicarbonyl MH(CO)(2)P(3) species first with Brønsted acid and then with an excess of organic azide. Complexes were characterised spectroscopically (IR, (1)H, (31)P, (13)C, (15)N NMR data) and by the X-ray crystal structure determination of complex [Re{eta(2)-1,4-(C(6)H(5)CH(2))(2)N(4)}(CO)(2){PPh(OEt)(2)}(2)]BPh(4)(). Strong evidence for coordination of the organic azide was obtained from the (15)N NMR spectra of labelled [M(C(6)H(5)CH(2)(15)NN(15)N)(CO)(3)P(2)]BPh(4) derivatives.

Dissociative electron attachment and electron energy-loss spectra of phenyl azide

Electron-induced chemistry—dissociative electron attachment (DEA)—was studied for phenyl azide. The major fragment corresponded to the loss of N2 and formation of the phenylnitrene anion. This process has an onset already at zero kinetic energy of the incident electron and is interpreted as proceeding via the A″π* electronic ground state of the phenyl azide anion. Other fragments, N3− and CN−, were observed at higher energies and interpreted as proceeding via low-lying shape resonances or higher lying core-excited resonances. The interpretation of the dissociative attachment spectra was supported by an investigation of the excited electronic states of neutral phenyl azide by electron energy-loss spectroscopy and DFT/MRCI calculations, and a study of shape and core-excited resonances of the phenyl azide anion by means of electron transmission spectroscopy and of cross sections for vibrational and electronic excitation by electron impact. Interesting parallels and differences are found by comparing DEA of phenyl and benzyl azides with the corresponding chloro compounds.

Regioselective Trapping of Terminal Di-, Tri-, and Tetraynes with Benzyl Azide

[Structure: see text] The reaction of benzyl azide with terminal di-, tri-, and tetraynes appended with a range of functional groups has been explored. Standard reaction conditions for BnN3 catalyzed by CuSO4.5H2O gave alkynyl, butadiynyl, and hexatriynyl triazoles in moderate to good yields. The reaction proceeds regioselectively as determined by the X-ray crystallographic analysis of three derivatives (1c, 1d, and 3c), and no evidence of multiple azide addition to the polyyne framework is observed.

Synthesis of N-benzylated indole-, indazole- and benzotriazole-4,7-diones

The benzylation of 4,7-dimethoxy-1 H-indole ( 5) followed by an oxidative demethylation led to 1-benzyl-1 H-indole-4,7-dione ( 2) with a 73% overall yield. From the commercially available 7-nitro-1 H-indazole ( 7), a three-step pathway was developed to access 1-benzyl-1 H-indazole-4,7-dione ( 3). Two of these steps were investigated in order to improve the process. The direct synthesis of 1-benzyl-1 H-benzotriazole-4,7-dione ( 4), through a 1,3-dipolar cycloaddition between benzyl azide and para-benzoquinone ( 13), was also studied. The simplicity of the methodologies described offers wide perspectives in obtaining 1-alkylated indole-, indazole- and benzotriazole-4,7-diones.

Synthesis of Fluorine‐Containing N‐Benzyl‐1,2,3‐triazoles and N‐Methyl‐pyrazoles from Conjugated Alkynes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Facile syntheses of surface‐functionalized micelles and shell cross‐linked nanoparticles

AbstractBlock copolymer micelles and shell cross‐linked nanoparticles (SCKs) presenting Click‐reactive functional groups on their surfaces were prepared using two separate synthetic strategies, each employing functionalized initiators for the controlled radical polymerization of acrylate and styrenic monomers to afford amphiphilic block copolymers bearing an alkynyl or azido group at the α‐terminus. The first route for the synthesis of the azide‐functionalized nanostructures was achieved via sequential nitroxide‐mediated radical polymerization (NMP) of tert‐butyl acrylate and styrene, originating from a benzylic chloride‐functionalized initiator, followed by deprotection of the acrylic acids, supramolecular assembly of the block copolymer in water and conversion of the benzylic chloride to a benzylic azide. In contrast, the second strategy utilized an alkynyl‐functionalized reversible addition fragmentation transfer (RAFT) agent directly for the RAFT‐based sequential polymerization of tetrahydropyran acrylate and styrene, followed by selective cleavage of the tetrahydropyran esters to give the α‐alkynyl‐functionalized block copolymers. These Click‐functionalized polymers, with the functionality located at the hydrophilic polymer termini, were then self‐assembled using a mixed‐micelle methodology to afford surface‐functionalized “Clickable” micelles in aqueous solutions. The optimum degree of incorporation of the Click‐functionalized polymers was investigated and determined to be ca. 25%, which allowed for the synthesis of well‐defined surface‐functionalized nanoparticles after cross‐linking selectively throughout the shell layer using established amidation chemistry. Functionalization of the chain ends was shown to be an efficient process under standard Click conditions and the resulting functional groups revealed a more “solution‐like” environment when compared to the functional group randomly inserted into the hydrophilic shell layer. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 5203–5217, 2006

Theoretical study of the molecular properties of benzyl azide, 2-, 3- and 4-methyl benzyl azide

Ab initio and density functional calculations have been performed to study the benzyl azide, 2-, 3- and 4-methyl benzyl azides. Several molecular properties, such as conformational equilibrium, optimal geometry, and vibrational frequencies, have been computed for these molecules. Ionisation energies were also computed.

Synthesis of fluorine containing N‐benzyl‐1,2,3‐triazoles and N‐methyl‐pyrazoles from conjugated alkynes

Abstractmagnified image1, 3‐Dipolar‐cycloaddition reaction of fluoro substituted 3‐aryl‐propynenitriles 1 with benzyl azide 2 afforded the expected 3‐benzyl‐5‐aryl‐3H‐[1,2,3]triazole‐4‐carbonitrile 3 and 1‐benzyl‐5‐aryl‐1H‐[1,2,3]‐triazole‐4‐carbonitrile 4 in good yield. However, 1,3‐dipolar cycloaddition of diazomethane 5 with 3‐aryl‐propynenitriles 1 resulted in the exclusive formation of N‐methyl‐pyrazole derivatives 6 and 7.

Facile Synthesis of Fréchet Type Dendritic Benzyl Azides and Dendrimer via Cycloaddition Reaction with Tripodal Core

Frechet-type dendritic benzyl azides were efficiently synthesized using 5-(azidomethyl)-1,3-dihydroxybenzene as an azide focal point functionalized unit by adding a generation to the existing dendron and applied for the construction of dendrimers containing 1,2,3-triazole rings as connectors via click chemistry with a tripodal acetylene core.