“Click” Synthesis of Nonsymmetrical Bis(1,2,3-triazoles)

Aizpurua, J. M.; Azcune, Itxaso; Fratila, Raluca M.; Balentová, Eva; Sagartzazu‐Aizpurua, Maialen; Miranda, José I.

doi:10.1021/ol1003127

Cited by 47 publications

(27 citation statements)

References 30 publications

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“…This 32CA reaction is presents a very low regioselectivity, as TS-m1 is only 0.34 kcal mol−1 lower in energy than , indicating that this 32CA reaction is only under kinetic control. These results are in disagreement with the meta regioselectivity observed experimentally [8].…”

Section: Kinetic Study Of the 13-dipolar Cycloaddition Reaction Of Tcontrasting

confidence: 67%

“…It was recently reported that is possible to impart some regioselectivity into these thermal cycloadditions by utilizing sterically or catalyze or electronically biased alkynes [6,7]. Herein, we used new theory recently proposed by Domingo named a Molecular Electron Density Theory (MEDT) to study the cycloaddition reaction of the Prop-2-yn-1-ol with azides 1, 2 and 3 experimentally studied by Jesus MA et al [8] (Scheme 1). Our aim is to explain the regioselectivity experimentally found.…”

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confidence: 99%

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2017

OAJTMR

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The mechanism the regioselectivity of prop-2-yn-1-ol 4 with Azido-benzene, 4-Azido-benzonitrile and 1-Azido-4-nitro-benzene in [3+2] cycloaddition, have been theoretically studied using DFT methods at the B3LYP/6-311 G (d,p) computational level. The possible ortho/meta regioselective channels were explored and characterized. Analysis of the free energies associated with the different reaction pathways indicates that the 32CA reactions of the between prop-2-yn-1-ol 4 and azides 1, 2 and 3 are highly meta regioselectivities, in agreement with the experimental results.

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Section: Kinetic Study Of the 13-dipolar Cycloaddition Reaction Of Tcontrasting

confidence: 67%

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confidence: 99%

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2017

OAJTMR

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“…The formation of the triazole products was monitored by HPLC and mass spectrometry using selected ion recording (SIR) detection (LC/MS-SIR) after 24 h at 25°C. After analysis of each reaction mixture, only azide 8 42) was sufficiently accelerated in its cycloaddition with alkyne 4a in the presence of the hDAO enzymes to yield a detectable amount of triazole 9 (at this point not distinguished as to whether a syn-and/or anti-substituted triazole) in the background with great reproducibility by LC/ MS-SIR measurement (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

Toguchi

Hirose

Yorita

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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In situ click chemistry is a target-guided synthesis approach for discovering novel lead compounds by assembling organic azides and alkynes into triazoles inside the affinity site of target biogenic molecules such as proteins. We report in situ click chemistry screening with human D-amino acid oxidase (hDAO), which led to the identification of a more potent hDAO inhibitor. The hDAO inhibitors have chemotherapeutic potential as antipsychotic agents. The new inhibitor displayed competitive inhibition of hDAO and showed significantly increased inhibitory activity against hDAO compared with that of an anchor molecule of in situ click chemistry.Key words fragment-based lead discovery; templated reaction; ligand-binding site; drug discovery; triazole formation; ligand affinity Although D-amino acids exist in a wide range of organisms, they are nonetheless often called unnatural amino acids. D-Serine is abundant in the forebrain and acts as an endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptors to enhance neurotransmission. 1) D-Amino acid oxidase (DAO) was the first flavoenzyme to be identified, in 1935 by Krebs,2) and catalyzes the oxidative deamination reaction of D-amino acids. This reaction by human DAO (hDAO) in the brain primarily converts D-serine to hydroxypyruvate to regulate the concentration of D-serine. The overexpression of hDAO in the brain therefore causes neuropsychiatric disorders such as schizophrenia, a serious public health problem that affects nearly 0.8% of the global population, by reducing the amount of D-serine below the level required for adequate neuronal function.3,4) Furthermore, a protein from the human gene G72 has been identified as an interacting partner to activate hDAO, and the association of both DAO and gene G72 with schizophrenia together with activation of hDAO activity by a G72 protein product points to the involvement of the regulation of NMDA receptor. 5) Thus, hDAO inhibitors have potential to be lead compounds to the development of therapeutic agents for schizophrenia.Within the realm of click chemistry research, triazole formation between organic azide and alkyne is widely recognized. Triazole formation includes the 1,3-dipolar reaction known as the Huisgen cycloaddition, [6][7][8][9] and catalytic reactions that selectively afford the corresponding 1,4-substituted triazole or 1,5-substituted triazole using monovalent copper 10,11) or ruthenium reagents, 12,13) respectively. In situ click chemistry is a target-guided synthesis (TGS) method for the fast and efficient production of potential inhibitors against target biomolecules such as enzymes. Using this approach, complementary alkyne and azide building are assembled at binding sites and then accelerate the Huisgen 1,3-dipolar cycloaddition reaction to afford the corresponding conventional triazole, as illustrated in Fig. 1.To date, in situ click chemistry research has garnered success in inhibitor explorations where acetylcholinester-

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“…Due to overlap with other bands the analysis of the triazole band at 1400-1500 cm − 1 [ 28 ] was impossible, allowing only a quantifi cation of the amount of the azide band during the reaction. As seen in Figure 1 a, the azide band (red arrow) decreases continuously with time until complete disappearance, thus allowing the determination of azideconversion during the reaction progress.…”

Section: 35-tris(prop-2-ynyloxymethyl)benzene (5)mentioning

confidence: 99%

Low‐Temperature Cu(I)‐Catalyzed “Click” Reactions for Self‐Healing Polymers

Schunack

Gragert

Döhler

et al. 2011

Macro Chemistry & Physics

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Systematic investigations on the Cu(I)-catalyzed "click" reaction between a three-arm star polymer and low-molecular-weight alkynes are described. Liquid trivalent alkynes ( 2 -7 ) are reacted either with monovalent azidotelechelic polyisobutylene 1b ( M n = 1900 g mol − 1 , PDI = 1.3) in solution, or with the trivalent azidotelechelic polyisobutylene 1a ( M n = 4000 g mol − 1 , PDI = 1.3). A signifi cant autoacceleration is observed leading to increased reaction rates of the mono-, di-, and trisubstituted alkynes. Reaction in the solvent-free state proved to be signifi cantly faster than reaction in solution. Upon testing various Cu(I) catalysts, CuBr(PPh 3 ) 3, tripropargylamine 2 emerges as the ideal component for a room-temperature "click" reaction with the threearm star polyisobutylene 1a .components displaying suffi cient (high) molecular mobility to allow subsequent formation of a supramolecular or covalent network. Thus, liquid components (DCPD or derivatives, liquid epoxides) or molecules with low molecular weights (corresponding to high mobility) are used preferentially, in order to keep the time scale of diffusion suffi ciently short as to allow physical contact between the interacting molecules. We recently have reported [ 13 ] on a chemical self-healing polymer (see Figure 1 ), where two reactive liquid (polymeric) components are embedded into separate capsules, subsequently reacting after rupture of the capsule by mechanical deformation and destruction. In contrast to similar systems reported in the literature, our approach uses the azide/alkyne "click" reaction [14][15][16] as the underlying chemical "addition" reaction to effect crosslinking between a multivalent (polymeric) liquid azide 1a and the trivalent alkynes 2 and 6 (see Scheme 1 ). To effect the encapsulation of polymer 1a , an emulsion method was developed, generating urea/formaldehyde capsules with incorporated (fl uorescently) labeled polymer. The two different capsules were then embedded into a polymeric matrix containing added Cu(I) catalyst and base, leading to effect a separate location of the capsules in the matrix, which release their contents after mechanically induced rupture and subsequent crosslinking reaction. The so-induced "click" reaction leads to a measureable reaction rate of several days at temperatures of 40 ° C. The present

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“Click” Synthesis of Nonsymmetrical Bis(1,2,3-triazoles)

Cited by 47 publications

References 30 publications

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<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

Low‐Temperature Cu(I)‐Catalyzed “Click” Reactions for Self‐Healing Polymers

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