Strain‐Promoted Azide–Alkyne Cycloaddition with Ruthenium(II)–Azido Complexes

The reactivity of an exemplary ruthenium(II)–azido complex towards non‐activated, electron‐deficient, and towards strain‐activated alkynes at room temperature and low millimolar azide and alkyne concentrations has been investigated. Non‐activated terminal and internal alkynes failed to react under such conditions, even under copper(I) catalysis conditions. In contrast, as expected, rapid cycloaddition was observed with electron‐deficient dimethyl acetylenedicarboxylate (DMAD) as the dipolarophile. Since DMAD and related propargylic esters are excellent Michael acceptors and thus unsuitable for biological applications, we investigated the reactivity of the azido complex towards cycloaddition with derivatives of cyclooctyne (OCT), bicyclo[6.1.0]non‐4‐yne (BCN), and azadibenzocyclooctyne (ADIBO). While no reaction could be observed in the case of the less strained cyclooctyne OCT, the highly strained cyclooctynes BCN and ADIBO readily reacted with the azido complex, providing the corresponding stable triazolato complexes, which were amenable to purification by conventional silica gel column chromatography. An X‐ray crystal structure of an ADIBO cycloadduct was obtained and verified that the formed 1,2,3‐triazolato ligand coordinates the metal center through the central N2 atom. Importantly, the determined second‐order rate constant for the ADIBO cycloaddition with the azido complex (k₂=6.9 × 10^?2 M ^?1 s^?1) is comparable to the rate determined for the ADIBO cycloaddition with organic benzyl azide (k₂=4.0 × 10^?1 M ^?1 s^?1). Our results demonstrate that it is possible to transfer the concept of strain‐promoted azide–alkyne cycloaddition (SPAAC) from purely organic azides to metal‐coordinated azido ligands. The favorable reaction kinetics for the ADIBO‐azido‐ligand cycloaddition and the well‐proven bioorthogonality of strain‐activated alkynes should pave the way for applications in living biological systems.     

Silicium dioxide nanoparticles as carriers for photoactivatable CO-releasing molecules (PhotoCORMs)

Silicium dioxide nanoparticles of about 20 nm diameter containing azido groups at the surface were prepared by emulsion copolymerization of trimethoxymethylsilane and (3-azidopropyl)triethoxysilane and studied by transmission electron microscopy (TEM). A photoactivatable CO-releasing molecule (PhotoCORM) based on [Mn(CO)(3)(tpm)](+) (tpm = tris(pyrazolyl)methane) containing an alkyne-functionalized tpm ligand was covalently linked to the silicium dioxide nanoparticles via the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC "click" reaction). The surface functionalization of the particles with azido groups and manganese CORMs was analyzed by UV-vis, IR, (1)H and (13)C CP-MAS NMR spectroscopies as well as energy-dispersive X-ray spectroscopy (EDX). The myoglobin assay was used to demonstrate that the CORM-functionalized nanoparticles have photoinducible CO-release properties very similar to the free complex. In the future, such functionalized silicium dioxide nanoparticles might be utilized as delivery agents for CORMs in solid tumors.     

Tuning the optical properties of BODIPY dye through Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC) reaction

Borondipyrromethenes(BODIPY) are a class of fluorescent dyes whose fluorescence quantum yields are generally high and independent of the solvent.In this paper,we report the synthesis of a new type of BODIPY compound that carries an azido group on the 3-position of the pyrrole core.The azido group quenches the fluorescence of the dye due to its weak electron-donating effect.The fluorescence of the BODIPY dye can be switched on after reacting with alkynes via a Cu(Ⅰ) catalyzed azide-alkyne cycloaddition(CuAAC) reaction.We further demonstrate that this azido-BODIPY compound can be used in the cell imaging applications.     

6‐Azido‐6‐deoxy‐l‐idose as a Hetero‐Bifunctional Spacer for the Synthesis of Azido‐Containing Chemical Probes

The design of 6‐azido‐6‐deoxy‐l ‐idose for use as a hetero‐bifunctional spacer is reported. The hemiacetal at one terminus is an equivalent of an aldehyde and can react with nucleophiles, such as amino groups and electron‐rich aromatics. The azido group at the other terminus bio‐orthogonally undergoes a Hüisgen [3+2] cycloaddition with an acetylene. The idose derivative exhibited a higher level of reactivity towards oxime formation than a corresponding glucose derivative. The ¹³C NMR spectrum of the uniformly ¹³C‐labeled 6‐azido‐idose indicated that the acyclic forms of the sugar totaled 0.3 % of all the isomers, whereas those of glucose totaled 0.01 %. The larger population of the acyclic forms of the idose derivative would result in higher reactivity towards electrophilic addition in comparison with glucose derivatives. Finally, we prepared a C‐idosyl epigallocatechin gallate (EGCG) that bears an azido group through C‐glycosylation of EGCG with 6‐azido‐idose. This glycosyl form of the C‐idosyl EGCG exhibited a cytotoxicity against U266 cells that was comparable to that of EGCG. These results suggested that the EGCG derivative could be used as an effective chemical probe for the elucidation of EGCG biological functions.     

Tethered Blatter Radical for Molecular Grafting: Synthesis of 6-Hydroxyhexyloxy,Hydroxymethyl, and Bis(hydroxymethyl) Derivatives and Their Functionalization

Synthetic access to 7-CF₃-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl radicals containing 4-(6-hydroxyhexyloxy)phenyl, 4-hydroxymethylphenyl or 3,5-bis(hydroxymethyl)phenyl groups at the C(3) position and their conversion to tosylates and phosphates are described. The tosylates were used to obtain disulfides and an azide with good yields. The Blatter radical containing the azido group underwent a copper(I)-catalyzed azide–alkyne cycloaddition with phenylacetylene under mild conditions, giving the [1,2,3]triazole product in 84% yield. This indicates the suitability of the azido derivative for grafting Blatter radical onto other molecular objects via the CuAAC “click” reaction. The presented derivatives are promising for accessing surfaces and macromolecules spin-labeled with the Blatter radical.     

Surface modification of magnetic nanoparticle via Cu(I)-catalyzed alkyne-azide [2 + 3] cycloaddition

The Cu(I)-catalyzed alkyne-azide [2 + 3] cycloaddition has been demonstrated to be an effective and orthogonal conjugation reaction to covalently immobilize biomolecules on magnetic nanoparticles (MNPs). The azido group on the MNP surface provides better conjugation efficiency with alkynated molecules. Moreover, the C-terminal alkynated protein was site-specifically immobilized on MNP. The protein binding activity presented by site-specific immobilization is higher than that by random amide bond formation.     

Total syntheses of (+)-australine and (-)-7-epialexine

Three approaches were examined for the synthesis of 3-(hydroxymethyl)pyrrolizidines, a class of compounds that includes the polyhydroxylated pyrrolizidine alkaloids alexine (1), australine (2), and various stereoisomers of thereof. In the first approach, the intramolecular cycloaddition of an azide onto an electron-rich 1, 3-diene bearing a terminal alkoxymethyl substituent (i.e., 21) afforded the dehydropyrrolizidines 22a and 22b, with 22a predominating. A rationale for this stereoselectivity was proposed. Transformation of the major diastereomer 22a into a natural 3-(hydroxymethyl)pyrrolizidine was not possible due to difficulties encountered in transforming the phenyl vinyl sulfide functionality into other useful functional groups. A second approach was examined, wherein the intramolecular cycloaddition of an azide with an optically pure S-t-Bu-substituted diene (i.e., 30) was found to produce the pyrrolizidine 31. In this case, the alkoxymethyl substituent was incorporated into the tether between the azide and the diene, rather than on the diene itself. A key transformation in the synthesis of the diene 30 was the use of the allylic borane R(2)BCH(2)CH=C(TMS)(StBu) for the stereoselective conversion of the D-arabinose-derived azido aldehyde 28 to the E-isomer of 30. The cyclization of 30 to 31 also produced the bicyclic triazene 32, the result of 1,3-dipolar cycloaddition of the azide onto the distal double bond of the diene. Again, difficulties in transformation of the vinyl sulfide functionality of 31 into useful oxygen functionality limited this approach to naturally occurring 3-(hydroxymethyl)pyrrolizidines. A third approach to these compounds was successful. The transformation of L-xylose into the azido epoxy tosylate 46 was accomplished using two Wittig reactions and an epoxidation, in addition to other standard functional group manipulations. Reductive double-cyclization of 46 afforded the pyrrolizidines 47a and 47b, which were debenzylated to afford (+)-australine 2 and (-)-7-epialexine 4, respectively. In the preliminary report of this work, erroneous spectroscopic data in the original literature on the structural assignment of australine led to the conclusion that the synthetic material obtained herein was actually (+)-7-epiaustraline. Recently corrected spectroscopic data have appeared which verify that (+)-australine 2 was indeed synthesized for the first time.     

Efficient and widely applicable method of constructing neo-proteoglycan utilizing copper(I) catalyzed 1,3-dipolar cycloaddition

Efficient constructions of two types of neo-proteoglycan are described. Enzymatically prepared alkyne containing chondroitin 6-sulfate chains and chemically synthesized azido group having compounds are linked by utilizing the copper(I) catalyzed 1,3-dipolar cycloaddition.     

Efficient microwave-assisted synthesis of multivalent dendrimeric peptides using cycloaddition reaction (click) chemistry

Multivalent dendrimeric peptides were synthesized via a microwave-assisted Huisgen 1,3-dipolar cycloaddition between azido peptides and dendrimeric alkynes in yields ranging from 46 to 96%.     

C2-symmetric macrocyclic carbohydrate/amino acid hybrids through copper(I)-catalyzed formation of 1,2,3-triazoles

An efficient method was developed for the preparation of macrocyclic carbohydrate/amino acid hybrids by macrocyclization with copper(I)-catalyzed 1,2,3-triazole formation. Methyl 2-amino-6-azido-3,4-di-O-benzoyl-2,6-dideoxy-beta-D-glucopyranoside was prepared and coupled to two different N-propiolyl dipeptides (propiolyl-Tyr-Tyr-OH and propiolyl-Arg(Mtr)-Tyr-OH) to obtain bifunctional molecules carrying one azido group and one terminal alkyne. These bifunctional molecules were cyclodimerized using Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes to form macrocycles containing two 1,2,3-triazoles. Various cyclization methods were evaluated, and the most efficient conditions were found to be CuI and N,N-diisopropylethylamine in CH3CN.     

Tridentate complexes of 2,6-bis(4-substituted-1,2,3-triazol-1-ylmethyl)pyridine and its organic azide precursors: an application of the copper(II) acetate-accelerated azide-alkyne cycloaddition

Rapid coupling reactions between 2,6-bis(azidomethyl)pyridine and terminal alkynes in the presence of 5 mol% Cu(OAc)(2)·H(2)O without the addition of a reducing agent afford tridentate ligands for first-row transition-metal ions. The chelation between Cu(II) and alkylated nitrogen atoms of the azido groups of 2,6-bis(azidomethyl)pyridine, as observed in the solid state, is credited for the acceleration of the azide-alkyne cycloaddition reactions.     

Binding of pi-acceptor ligands to (triamine)iron(II) complexes

A series of (Me3TACN)FeII derivatives with soft coligands have been investigated, where Me3TACN is N,N',N"-trimethyl-1,4,7-triazacyclononane. Treatment of Me3TACN with FeCl2 afforded a compound with the empirical formula (Me3TACN)FeCl2 (1). Compound 1, which is a versatile precursor reagent, was shown by single-crystal X-ray diffraction to be the salt [(Me3TACN)2Fe2Cl3][(Me3TACN)FeCl3], containing isolated [(Me3TACN)2Fe2Cl3]+ and [(Me3TACN)FeCl3]- subunits. Treatment of 1 with NaBPh4 gave the known [(Me3TACN)2Fe2Cl3]BPh4, while the addition of Me3TACN to FeCl4(2-) gave [(Me3TACN)FeCl3]-. Oxygenation of 1 afforded [(Me3TACN)FeCl2]2(mu-O), which was shown crystallographically to be centrosymmetric with a pair of distorted octahedral Fe centers. The Fe-N bond trans to the Fe-O bond is elongated by 02 A relative to the other Fe-N distances. Solutions of 1 and thiolates absorb CO to give [(Me3TACN)Fe(SPh)(CO)2]BPh4 and (Me3TACN)Fe(S2C2H4)(CO) (nu CO = 1896 cm-1). Treatment of 1 with excess CN- afforded [(Me3TACN)Fe(CN)3]-, isolated as its PPh4+ salt 5. Crystallographic and spectroscopic studies show that 5 is low spin with a C3v structure; its Fe-N distances contracted by 023 A relative to those in [(Me3TACN)FeCl3]-. Aqueous solutions of 1 bind CO upon the addition of CN- to produce (Me3TACN)Fe(CN)2(CO) (6) Analogous to 6 is (Me3TACN)Fe(CN)2(CNMe), prepared by methylation of 5. The metastable dicarbonyl [(Me3TACN)FeI(CO)2]I was prepared by treatment of FeI2(CO)4 with Me3TACN and was crystallographically characterized as its BPh4- salt. Values of E1/2 for [(Me3TACN)FeCl3]-, 5, and 6 are -0409, -0640, and 0533 V vs Fc/Fc+, respectively.     

Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides

The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.     

DFT investigation of the tri(amino)amine N(NH(2))(3)(2+) and the tri(azido)amine N(N(3))(3)(2+) dications and related mixed amino(azido)ammonium ions (N(3))(x)N(NH(2))(4-x)(+) (x = 0-4)(1)

Structures of the tri(amino)amine N(NH(2))(3)(2+) and the tri(azido)amine N(N(3))(3)(2+) dications were calculated at the density functional theory (DFT) B3LYP/6-311+G level. The tri(amino)amine dication (NH(2))(3)N(2+) (1) was found to be highly resonance stabilized with a high kinetic barrier for deprotonation. The structures of diamino(azido)amine dication (NH(2))(2)N(N(3))(2+) (2), amino(diazido)amine dication (NH(2))N(N(3))(2)(2+) (3), and tri(azido)amine dication (N(3))(3)N(2+) (4) were also found to be highly resonance stabilized. The structures and energetics of the related mixed amino(azido)ammonium ions (N(3))(x)N(NH(2))(4-x)(+) (x = 0-4) were also calculated.     

1,3-Cycloaddition synthesis of 1,2,3-triazole conjugates of betulonic acid with peptides

1,2,3-Triazole conjugates of betulonic acid with peptides were synthesized by 1,3-dipolar cycloaddition of azido peptides to N-(3-oxolup-20(29)-en-28-oyl)-4-ethynylaniline.     

Unveiling the synthesis of spirocyclic,tricyclic, and bicyclic triazolooxazines from intramolecular [3 + 2] azide-alkyne cycloadditions with a molecular electron density theory perspective

Structural Chemistry - The intramolecular [3+2] cycloaddition (32CA) reactions of azido alkynes leading to spirocyclic, tricyclic, and bicyclic triazolooxazines has been studied within the...     

Synthesis of a constrained polyfunctional bicyclic iminocyclitol scaffold from l-sorbose via a tandem sequence including stereoselective intramolecular Huisgen cycloaddition

The synthesis of a functionalized (azido, amino, and hydroxy) 8-oxa-3-azabicyclo[3.2.1]octane framework and its conversion into a protected sugar amino acid and a tricyclic framework is described. The sequence includes a one-pot Huisgen 1,3-dipolar cycloaddition, with decomposition to an aziridine and subsequent ring opening by azide. The stereoselectivity observed in the Huisgen cycloaddition reaction is attributed to minimization of allylic strain.     

Crystal structures and magnetic properties of 2,3,5,6-tetrakis(2-pyridyl)pyrazine (tppz)-containing copper(II) complexes

Four new copper(II) complexes of formula [Cu(2)(tppz)(dca)(3)(H(2)O)].dca.3H(2)O (1), [Cu(5)(tppz)(N(3))(10)](n)() (2), [[Cu(2)(tppz)(N(3))(2)][Cu(2)(N(3))(6)]](n)() (3), and [Cu(tppz)(N(3))(2)].0.33H(2)O (4) [tppz = 2,3,5,6-tetrakis(2-pyridyl)pyrazine and dca = dicyanamide anion] have been synthesized and structurally characterized by X-ray diffraction methods. The structure of complex 1 is made up of dinuclear tppz-bridged [Cu(2)(tppz)(dca)(3)(H(2)O)](+) cations, uncoordinated dca anions, and crystallization water molecules. The copper-copper separation across bis-terdentate tppz is 6.5318(11) A. Complex 2 is a sheetlike polymer whose asymmetric unit contains five crystallographically independent copper(II) ions. These units are building blocks in double chains in which the central part consists of a zigzag string of copper atoms bridged by double end-on azido bridges, and the outer parts are formed by dinuclear tppz-bridged entities which are bound to the central part through single end-on azido bridges. The chains are furthermore connected through weak, double out-of-plane end-on azido bridges, yielding a sheet structure. The intrachain copper-copper separations in 2 are 6.5610(6) A across bis-terdentate tppz, 3.7174(5) and 3.8477(5) A across single end-on azido bridges, and from 3.0955(5) to 3.2047(7) A across double end-on azido bridges. The double dca bridge linking the chains into sheets yields a copper-copper separation of 3.5984(7) A. The structure of 3 consists of centrosymmetric [Cu(2)(tppz)(N(3))(2)](2+) and [Cu(2)(N(3))(6)](2)(-) units which are linked through axial Cu.N(azido) (single end-on and double end-to-end coordination modes) type interactions to afford a neutral two-dimensional network. The copper-copper separations within the cation and anion are is 6.5579(5) A (across the bis-terdentate tppz ligand) and 3.1034(6) A (across the double end-on azido bridges), whereas those between the units are 3.6652(4) A (through the single end-on azido group) and 5.3508(4) A (through the double end-to-end azido bridges). The structure of complex 4 is built of neutral [Cu(tppz)(N(3))(2)] mononuclear units and uncoordinated water molecules. The mononuclear units are grouped by pairs to give a rather short copper-copper separation of 3.9031(15) A. The magnetic properties of 1-4 have been investigated in the temperature range 1.9-300 K. The magnetic behavior of complexes 1 and 4 is that of antiferromagnetically coupled copper(II) dimers with J = -43.7 (1) and -2.1 cm(-)(1) (4) (the Hamiltonian being H = -JS(A).S(B)). An overall ferromagnetic behavior is observed for complexes 2 and 3. Despite the structural complexity of 2, its magnetic properties correspond to those of magnetically isolated tppz-bridged dinuclear copper(II) units with an intermediate antiferromagnetic coupling (J = -37.5 cm(-)(1)) plus a ferromagnetic chain of hexanuclear double azido-bridged copper(II) units (the values of the magnetic coupling within and between the hexameric units being +61.1 and +0.0062 cm(-)(1), respectively). Finally, the magnetic properties of 3 were successfully analyzed through a model of a copper(II) chain with regular alternating of three ferromagnetic interactions, J(1) = +69.4 (across the double end-on azido bridges in the equatorial plane), J(2) = +11.2 (through the tppz bridge), and J(3) = +3.4 cm(-)(1) (across the single end-on azido bridge).     

Ionic liquids based on FeCl(3) and FeCl(2). Raman scattering and ab initio calculations

We have prepared ionic liquids by mixing either iron(II) chloride or iron(III) chloride with 1-butyl-3-methylimidazolium chloride (BMIC). Iron(II) chloride forms ionic liquids from a mole ratio of 1 FeCl(2)/3 BMIC to almost 1 FeCl(2)/1 BMIC. Both Raman scattering and ab initio calculations indicate that FeCl(4)(2-) is the predominant iron-containing species in these liquids. Iron(III) chloride forms ionic liquids from a mole ratio of 1 FeCl(3)/1.9 BMIC to 1.7 FeCl(3)/1 BMIC. When BMIC is in excess, Raman scattering indicates the presence of FeCl(4-). When FeCl(3) is in excess, Fe(2)Cl(7-) begins to appear and the amount of Fe(2)Cl(7-) increases with increasing amounts of FeCl(3). Ionic liquids were also prepared from a mixture of FeCl(2) and FeCl(3) and are discussed. Finally, we have used both Hartree-Fock and density functional theory methods to compute the optimized structures and vibrational spectra for these species. An analysis of the results using an all-electron basis set, 6-31G, as well as two different effective core potential basis sets, LANL2DZ and CEP-31G is presented.     

Peptide ligation through click chemistry for the generation of assembled and scaffolded peptides

The synthesis of [1,2,3]-triazoles through copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition was examined for its utility to generate assembled and scaffolded peptides from peptide and scaffold precursors, which were N-terminally modified with azido and alkyne moieties, respectively.