Huisgen Reaction Research Articles

Copper‐Catalyzed Huisgen and Oxidative Huisgen Coupling Reactions Controlled by Polysiloxane‐Supported Amines (AFPs) for the Divergent Synthesis of Triazoles and Bistriazoles

An interesting example of a divergent catalysis with a copper(I) and amine-functional macromolecular polysiloxanes system was successfully presented in click chemistry. In this manuscript, we demonstrate the remarkable ability of the secondary amine-functional polysiloxane to induce oxidative coupling in the copper-mediated Huisgen reactions of azides and alkynes, thereby achieving good yields and selectivities. The click reactions mediated by a polysiloxane-supported secondary amine allow the preparation of novel heterocyclic compounds, that is, bistriazoles. Comparably, it is also surprising that the use of a diamine-functional polysiloxane as ligand led to a classic Huisgen [3+2] cycloaddition in excellent yields. From the results of the present amine-functional polysiloxanes-controlled Huisgen reaction or oxidative Huisgen coupling reaction to divergent products and the proposed mechanism, we suggested that the mononuclear bistriazole-copper complex stabilized and dispersed by the secondary amine-functional polysiloxane was beneficial to prevalent the way to oxidative coupling.

Investigation of regioselectivity in the synthesis of spiro [pyrrolidine-2,3′-oxindoles] by use of the Huisgen reaction

The Huisgen reaction has been used to synthesize five-membered heterocyclic compounds in high yield and with high regio and stereoselectivity. In the synthesis of spiro [pyrrolidine-2,3'-oxindole] derivatives from isatin, alpha-amino acids, and (E)-beta-phenyl nitroolefins, two regioisomers were obtained in each reaction. The regioselectivity of the major product was found to be different from that in reported work, and was investigated at the B3LYP/6-311G* level of theory. On the basis of this new finding, several conditions, for example molar ratio, solvent, and temperature, which affect the regioselectivity of this reaction were investigated; the results obtained are discussed. It was found that the regioselectivity of this reaction was affected by solvent and temperature, irrespective of the ratio of the reactants. Low temperature and high solvent polarity leads to high regioselectivity, and protic solvents result in higher yield and regioselectivity. These results are of benefit for regioselective synthesis of some compounds.

Synthesis of Bicyclic Imidazoles via [2 + 3] Cycloaddition between Nitriles and Regioselectively Generated α-Imino Gold Carbene Intermediates

The cyclic α-imino gold carbene intermediate B is most likely generated in situ via regioselective nitrene transfer from an azido group to a tethered terminal alkyne in the presence of a gold catalyst and at ambient temperature. This highly electrophilic intermediate can react with a weakly nucleophilic nitrile, which is used as the reaction solvent, to deliver a bicyclic imidazole rapidly in an overall bimolecular [2 + 2 + 1] cycloaddition and in mostly serviceable yield. The competing intramolecular Huisgen reaction, although likely also catalyzed by gold, is minimized by using AuCl(3) as the catalyst.

Theoretical study of the regioselectivity of the Huisgen reaction

From the structure of a series of spiro (pyrrolidine-2,3'-oxindole) derivatives synthesized by Huisgen reaction of isatin, alpha-amino acids, and different olefins, different regioselectivities were found. The possible mechanism of the Huisgen reaction of oxindole azomethine ylide and the substituent of olefins was investigated using a B3LYP/6-311G* level of theory, and the results show that the regioselection depends on the energy barrier between the stacking state and the regioisomer. This mechanism can also be applied to the illumination of other Huisgen reactions.

Construction of chlorophyll assemblies based on zinc complexes of triazole–chlorin conjugates

A series of triazole–chlorin conjugates were prepared by Huisgen reactions of a C3–ethynylated chlorophyll derivative with azido compounds. Dimerization behaviour of their zinc complexes was investigated based on UV–vis, circular dichroism, and 1H NMR spectroscopies as well as molecular modelling calculation.

Design and synthesis of spiro bis(1,2,3-triazolium) salts as chiral ionic liquids

Room temperature chiral spiro ionic liquids 1 and 2 based on 1,2,3-triazolium salts, were synthesized via an intramolecular double Huisgen reaction. The preparation of the enantiomerically pure spiro triazolium salts was achieved by resolution by HPLC using a chiral stationary phase column and subsequent N-dialkylations of spiro triazoles 6 and 10.

Synthesis of novel oligoester-block-polyacrylate-block-oligoester ABA triblock copolymers by coupling methods

An original approach based on coupling methodology was used to prepare novel well-defined ABA triblock copolymers, made of polyester-type chain ends (A) associated with a polyacrylate midblock (B). Poly(ethylene terephthalate)-block-poly(lauryl acrylate)-block-poly(ethylene terephthalate) (PET-b-PLAc-b-PET) copolymers were achieved from poly(ethylene terephthalate)-b-poly(lauryl acrylate) (PET-b-PLAc) diblock ones. The first step consisted in the synthesis of diblock copolymers by atom transfer radical polymerization of lauryl acrylate starting from PET segment as a macroinitiator. In the second step, the coupling of diblock copolymers was achieved using four different methods, which were evaluated and compared: atom transfer radical coupling, “click” chemistry using the Huisgen's reaction, and coupling via a dithiol reagent or a diisocyanate molecule. Coupling using the Huisgen's reaction or a diisocyanate spacer proved to be the most efficient techniques. Even if these methods showed limitation and were only adapted for copolymers with low molecular weights, we managed to successfully prepare ABA triblock copolymers involving a polyester segment as end blocks and a polyacrylate moiety as midblock. To our knowledge, such kind of chemical structure has never been reported before and would be useful, possibly affording physical networks leading to rheological modification, for instance. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Synthesis of Triazole-Linked Fluorescent Saccharides and Glycosyl Amino Esters

Synthesis of fluorescent carbohydrates and glycopeptides has been emerging as an attractive research field because of various biological roles of carbohydrates and glycoproteins. Fluorescent glycosides and C-glycosides were synthesized by copper(I)-catalyzed Huisgen reaction between 6- O -(2-azidoacetyl) glycopyranosides and alkyne-functionalized fluorophores. For the fluorescent disaccharides as well as glycosyl amino acids derivatives, glycosylation of azido-functionalized thioglycosides, followed by click reaction with corresponding fluorophores is preferred than the inversed procedure (click reaction before the glycosylation). Fluorophores like dansyl, NBD, or rhodamine have been successfully introduced on the sugar ring. All the newly synthesized fluorescent glycosides and glycoconjugates showed similar photophysical properties to the native fluorophores, with a higher quantum yield for the dansyl derivatives.

New Cross-Linkable Polymers with Huisgen Reaction Incorporating High μβ Chromophores for Second-Order Nonlinear Optical Applications

We report herein the synthesis, the functionalization, and the successful radical polymerization of very nonlinear optical (NLO) active push–pull polyene chromophores (CPO). Second, the thermal Huisgen cyclo-addition cross-linking reaction was implemented, and it proved to be fully compatible with a polyene-based push–pull chromophore. Toward this goal, PMMA-co-CPO-3 and two cross-linkable polymers (PCC1-CPO-3 and PCC2-CPO-3) were first prepared and characterized by a modified Teng and Man technique performed in transmission. These first series of polymers were not compatible with the applied poling conditions because an irreversible film degradation was systematically observed at a temperature significantly lower than the cross-linking temperature. Consequently, a second series of polymers was prepared, in which the cross-linking temperature was decreased by functionalizing acetylenic moieties with ester electron withdrawing groups, which decrease the activation energy of the thermal Huisgen cyclo-addition. These new polymers were stable until the cross-linking reaction, and they exhibit bulk electro-optic coefficients (r33) until 41 pm/V at 1.5 μm. Furthermore, it was shown that the Huisgen cross-linking reaction is compatible with such push–pull polyene-based chromophores, and it systematically enhances the stability of the electro-optic activity because chromophore orientation was maintained up to 96 °C against 70 °C for the same uncross-linked polymer.

Synthesis and DNA-binding properties of 1,2,3-triazole-linked H-pin pyrrole- and imidazole-containing polyamides formed by the Huisgen reaction

Abstract Covalently linked pyrrole (Py)- and imidazole (Im)-containing H-pin polyamides bind in the minor groove of specific DNA sequences with high affinity. The synthesis of 1,2,3-triazole-linked and heterodimeric H-pin polyamides 13a,b formed from the Huisgen reaction of an alkyne-containing f-PyPyPy (6) with an azide-containing f-ImPyIm (7) is reported. The reaction proceeded smoothly under thermal conditions to give an inseparable mixture of 1,4- and 1,5-isomers (13a and 13b, respectively) by column chromatography. When the reaction was conducted under ‘click’ or Cu(I)-catalyzed conditions or in the presence of the cognate DNA sequence, no desired product was observed. Preliminary results from DNA thermal denaturation and circular dichroism titration studies provided evidence of mixture 13a,b binding to the target DNA sequence 5′-TCTCAA-3′.

Development of convergent synthetic method for saccharide-linked ethynylpyridine foldamers by Huisgen reaction

Based on ‘click chemistry’, the new convergent synthesis to a variety of saccharide-linked 2,6-pyridylene ethynylene ‘ethynylpyridine’ foldamers was developed. Ethynylpyridine 6-, 9-, and 12-meric blocks were linked with 1,7-octadiyne linker block by Sonogashira reaction, and joined with azido group-introduced glucoside, galactoside, and mannoside templates by Huisgen reaction. The resulting saccharide-linked ethynylpyridine foldamers exhibited typical circular dichroism to indicate the formation of a helical structure by intramolecular hydrogen bonds.

医薬品製造におけるフローマイクロリアクターの役割：反応条件スクリーニングとサンプル合成

In the last decade, rapidly evolving microreaction technology based on tiny microchannels has attracted broad attention in organic synthesis. The new technology has also a great potential even for pharmaceutical production because time-saving optimization of flow reaction conditions can be accomplished using an automated microreactor system and the optimal condition can readily be applied to large scale production. A microreaction system also guarantees the quality of products, the operational safety, and the low energy cost. Herein, we report the synthesis of a key intermediate of myriceric acid A, an endothelin receptor antagonist (S-0139) and a matrix metalloproteinase inhibitor (S-3304) using a flow microreactor as model cases. The intermediate of S-0139 was synthesized by Barton reaction using a photo-microreactor and a compact light source, such as a black light or a UV-LED, with high energy efficiency. Using an automated microreactor system, MiChS System X-1, quick optimization of the reaction conditions and the 100 g scale synthesis of the S-3304 by Sonogashira coupling reaction was achieved. We also demonstrate that the flow reaction system using ionic liquid as catalyst support allowed facile separation of products from the catalyst. Large scale synthesis of a key intermediate of S-3304 was also achieved in combination with a micro-extraction/catalyst recycling system, in which the ionic liquid containing the Pd catalyst was continuously recycled. Moreover, parallel synthesis of triazoles by azidation using MiChS System X-1 followed by Huisgen reaction using a batch reactor was successfully carried out.

High-temperature continuous flow synthesis of 1,3,4-oxadiazoles via N-acylation of 5-substituted tetrazoles

Applying continuous flow processing in a high-temperature/high-pressure regime (200–220 °C, 11–14 bar) 2,5-disubstituted-1,3,4-oxadiazoles are prepared in high yields within 5–10 min residence time by treatment of 5-substituted-1 H-tetrazoles with anhydrides or acid chlorides as electrophiles (Huisgen reaction).

Thermally stable polymers containing 1,3,4-oxadiazole units obtained from Huisgen reaction

Thermally stable polymers containing 1,3,4-oxadiazole units have been synthesized through Huisgen reaction of the aromatic/aliphatic bis-tetrazole compounds with the aromatic/aliphatic bis-acid chlorides in pyridine as solvent. The obtained polymers are insoluble or slightly soluble even in polar aprotic solvents such as DMSO and DMF. Relatively high inherent viscosity values (0.61–1.33 dL/g, in 0.125% H2SO4 at 25°C) were observed for these compounds. Thermal analyses of the polymers using DSC and TGA techniques showed that the polymers have improved thermal stabilities. The glass transition temperature has not been observed in the fully aromatic polymers, but the polymers obtained from 5-[6-(1H-tetrazol-5-yl)hexyl]-1H-tetrazole (IV) showed very clear Tg. A model reaction was also investigated and the resulting bis-1,3,4-oxadiazole compound was characterized by conventional spectroscopy methods.

ChemInform Abstract: Synthesis and anti‐HIV Evaluation of 3′‐Triazolo Nucleosides.

AbstractA series of title compounds of type (I) and (II) are tested for their anti‐HIV activities.

Synthesis and second-order nonlinear optical properties of a crosslinkable functionalized hyperbranched polymer

A new implementation of copper-free thermal Huisgen 1,3-dipolar crosslinking reaction into a high T g hyperbranched polyimide polymer in order to stabilize the electro-optic (EO) activity of second-order non linear materials is reported. Towards this goal, two different synthetic approaches were explored. The first strategy is based on the post-functionalization of the polymer with mixtures of DR1 azido derivative and propargylic alcohol, whereas, the second consists in the preparation of two complementary functionalized hyperbranched polymers that are mixed just before the preparation of films. Materials exhibit good second-order nonlinear optical coefficients ( d 33) close to 30 pm/V at the fundamental wavelength of 1064 nm. Moreover, the thermal stability of the NLO properties of these materials reaches temperatures as high as 150 °C, and probably higher. This represents the highest thermal stability of crosslinkable EO polymers based on the crosslinking Huisgen reaction.

Synthesis of spiro bis(1,2,3-triazolium) salts as chiral ionic liquids

Unique chiral spiro ionic liquids based on 1,2,3-triazolium salts were synthesized via an intramolecular double Huisgen reaction. The optical resolution of the liquid precursors and subsequent dialkylations leads to chiral spiro triazolium salts on a gram scale.

ChemInform Abstract: Expeditious Construction of Spiro‐Pyrrolidines by an Autocatalytic One‐Pot, Five‐Component, 1,3‐Dipolar Cycloaddition of in situ Generated Azomethine Ylides and Olefinic Dipolarophiles.

AbstractThe title compounds are prepared by a solvothermal synthesis in a highly regio‐ and stereoselective manner involving a classical Huisgen reaction in which the azomethine ylide and olefinic dipolarophiles are simultaneously generated in situ without the need to isolate the intermediates.

Expeditious Construction of Spiro‐Pyrrolidines by an Autocatalytic One‐Pot, Five‐Component, 1,3‐Dipolar Cycloaddition of in situ Generated Azomethine Ylides and Olefinic Dipolarophiles

AbstractTwo series of previously unknown spiro‐pyrrolidine derivatives were prepared by a five‐component reaction that employed ninhydrin, 1,2‐phenylenediamine, sarcosine, aldehydes, and malononitrile or cyanoacetic ester in a solvothermal synthesis. This is the first report of an autocatalytic five‐component reaction involving a classical Huisgen reaction, in which the dipole – an azomethine ylide – and the dipolarophile were simultaneously generated in situ. The 1,3‐dipolar cycloaddition reaction was found to proceed in a highly regio‐ and diastereoselective manner. The methodology for the preparation of the spiro‐pyrrolidines could be an ideal tool for green chemistry and the synthesis of alkaloids.

ChemInform Abstract: Bitriazolyl Acyclonucleosides Synthesized via Huisgen Reaction Using Internal Alkynes Show Antiviral Activity Against Tobacco Mosaic Virus.

AbstractNew bitriazolyl acyclonucleosides (II) are prepared via one‐step Huisgen reaction as structural isomers of previously identified potential antiviral agents.