Azide Coupling Research Articles

An aryl thiol-vinyl azide coupling reaction and a thiol-vinyl azide coupling/cyclization cascade: efficient synthesis of β-ketosulfides and arene-fused 5-methylene-2-pyrrolidinone derivatives.

The addition reaction of thiol to vinyl azide has been extensively studied. Variously substituted aryl thiols are all viable for this coupling process. The scope of the other partner is successfully expanded from α-aryl vinyl azide to α-alkyl vinyl azide. A thiol-vinyl azide coupling/cyclization cascade is realized with substituted aryl vinyl azides carrying a 2-methoxycarbonyl group. The value of β-ketosulfide products was demonstrated by its application in S-heterocycle synthesis.

Synthesis and Anti proliferative Activity of New N‐Pentylquinoxaline carboxamides and Their O‐Regioisomer

AbstractWe have designed a series of quinoxalinepeptidomimetic derivatives based on our previous reported scaffold in attempt to find a promising lead compound. Quinoxaline derivatives; N‐alkyl‐3‐(3‐oxo‐4‐pentyl‐3,4‐dihydro‐quinoxalin‐2‐yl)‐propanamides and methyl 2‐[3‐(3‐oxo‐4‐pentyl‐3,4‐dihydro‐quinoxalin‐2‐yl)propanamido]alkanoates and their O‐regioisomers were prepared by alkylation of the ambient nucleophile methyl 3‐(3‐oxo‐3,4‐dihydroquinoxalin‐2‐yl)propanoate with pentyl bromide to give the corresponding N‐ and O‐pentylquinoxaline ester derivatives. The N‐ and O‐pentyl‐quinoxaline ester derivatives gave the desired products by the reaction with amines and amino acid esters via azide coupling method. We have examined the anti proliferative activity of the 35 different synthesized compounds on human HCT‐116 and HEK‐293 cell lines. Out of 35 screened derivatives, 14 active compounds exhibited inhibitory action on the HCT‐116 cells with IC50 values ranging from 0.43 mM to 2.62 mM. We have also examined the impact of these active compounds on cancer cells nucleus and caspase 3 activity, we have the found that active compounds also increased in the caspase 3 activity which led to programmed cell death of cancer cells. We have also examined the impact of 35 compounds on the normal and non‐cancerous cells (HEK‐293) and we have found these active compounds did not cause any cytotoxic effect on the normal cells.

Metal‐Free Electrochemical Coupling of Vinyl Azides: Synthesis of Phenanthridines and β‐Ketosulfones

We reported an efficient and environmentally benign electrochemical synthesis of phenanthridines by oxidative coupling of vinyl azides with sodium azide or benzenesulfonyl hydrazides, for the first time. The reaction conditions are mild, and no additional metal‐catalyst or exogenous oxidants are needed. The protocol has broad substrate scope and high functional group tolerance. Furthermore, this green electrochemical procedure can be readily extended to the synthesis of β‐ketosulfones. Gram scale reactions further demonstrate the practicability.

An expeditious one-pot synthesis of thiourea derivatives of carbohydrates from sugar azides

A facile and practical route for the high-yielding synthesis of various thiourea derivatives of carbohydrates has been accomplished through the coupling of carbohydrate-based azides and amines under Staudinger condition (PPh3/CS2). Structures of all the developed compounds have been elucidated using various spectroscopic techniques, including NMR, IR, and MS. Weak interactions within compound 3a have also been discussed through the analysis of its single crystal X-ray data.

Synthesis and Biological Activities of Some New Benzotriazinone Derivatives Based on Molecular Docking; Promising HepG2 Liver Carcinoma Inhibitors.

In one-pot strategy, diazotization of methyl anthranilate 5 followed by addition of amino acid ester hydrochloride, we have prepared methyl-2-(4-oxobenzotriazin-3(4H)-yl)alkanoates 6a–c. Starting with hydrazides 7a,b, N-alkyl-2-(4-oxobenzotriazin-3(4H)-yl)alkanamides 9–10(a–h) and methyl-2-(2-(4-oxobenzotriazin-3(4H)-yl)alkanamido)alkanoates 11–12(a–e) were prepared via azide coupling. Hydrazones 13–15 were prepared via condensation of hydrazides 7a,b with 4-methoxybenzaldehyde, 4-dimethylaminobenzaldehyde, and/or arabinose. Molecular docking was done for synthesized compounds using MOE 2008-10 software. The compounds 9a, 12a, 12c, 13a, 13b, and 14b have the most pronounced strong binding affinities toward the target E. coli Fab-H receptor, whereas compounds 3, 11e, 12e, and 13a have the most pronounced strong binding affinities toward the target vitamin D receptor. The in vitro antibacterial activities of the highest binding affinity docked compounds were tested against E. coli, Staphylococcus aureus, and Salmonella spp. Majority of the tested compounds showed effective positive results against E. coli, while they were almost inactive against Staphylococcus aureus and Salmonella spp. The in vitro cytotoxic activities of the highest binding affinity-docked compounds were tested against the human liver carcinoma cell line (HepG2). Some compounds showed potent cytotoxic activity with low IC50 values, especially for 3 (6.525 μM) and 13a (10.97 μM) than that for standard drug doxorubicin (2.06 μM).

Unexpected Reactions of Terminal Alkynes in Targeted "Click Chemistry'' Coppercatalyzed Azide-alkyne Cycloadditions.

High efficiency in terms of reaction yield and purity has led to the extensive utilization of copper-catalyzed azide-alkyne cycloaddition (CuAAC) in various fields of chemistry. Its compatibility with low molecular weight alcohols promotes the application in surfactant synthesis to tackle the miscibility constraints of the reactants. For the tuning of surfactant properties, double click coupling of the antipode precursors was attempted. Failure of the CuAAC to provide the targeted product in combination with unexpected reaction outputs led to an investigation of the side reaction. The CuAAC-based coupling of sugar azide with propargyl building block in the presence of copper- (I) catalyst exclusively led to the mono-coupling product in a respectable yield of almost 80%. Besides the unexpected incomplete conversion, the loss of the remaining propargyl group, as indicated by both NMR and MS. On the other hand, application of substantial amounts of CuSO4 under reducing conditions in refluxing toluene/water furnished the alkyne dimer in a moderate yield of 43%, while no change of azide compound was noticed. The Cu(I)-catalyst applied for azide-alkyne cycloadditions enables the homo-coupling of certain terminal alkynes at a higher temperature. Moreover, aromatic propargyl ethers may be cleaved to furnish the corresponding phenol. The copper-catalyzed coupling appeared highly sensitive towards the alkyne compound. Only selected derivatives of propargyl alcohol were successfully dimerized. The observed failure of the Huisgen reaction for the synthesis of sugar-based surfactants may indicate non-recognized constrains of the reaction, which could affect its wide application in bioconjugation. The temperature requirement for the alternative dimerization of terminal alkynes renders this side reaction nonrelevant for typical click couplings, while narrow substrate diversity and moderate yield limit its synthetic application.

Regioselective Synthesis of Diverse Thio-, Seleno-substituted 1,2,3-Triazoles

: Thio-, seleno-substituted triazoles are useful scaffolds employed in the fields of organic synthesis, medicinal chemistry, and material science. A number of synthetic approaches to efficient formation of thio- and seleno-triazoles have been disclosed, including the interception of copper(I) triazolides generated in-situ, cycloaddition of internal alkynes (thio-, halo-, and metalated alkynes) to azides, and the coupling of azides and nonalkyne substrates. This mini-review intends to summarize the synthetic methods toward thio-, seleno-1,2,3-triazoles and the relative reaction mechanisms.

Newly synthesized 3-(4-chloro-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid methyl ester derivatives selectively inhibit the proliferation of colon cancer cells.

A series of 24 compounds were synthesized based on structure modification of the model methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as potent HDACIs. Saponification and hydrazinolysis of the model ester afforded the corresponding acid and hydrazide, respectively. The model ester was transformed into the corresponding trichloroacetimidate or acetate by the reaction with trichloroacetonitrile and acetic anhydride, respectively. N-Alkyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropan-amides and methyl-2-[(3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoyl)amino] alkanoates were obtained by the reaction of corresponding acid or hydrazide with amines and amino acid esters via DCC and azide coupling methods. Methyl-3-aryl-3-(4-chlorophenyl)-2,2-dimethylpropanoates were obtained in good yields and short reaction time from the corresponding trichloroacetimidate or acetate by the reaction with C-active nucleophiles in the presence of TMSOTf (0.1 eq.%) via C–C bond formation. The antiproliferative and apoptotic activity were further studied with molecular docking. The 48 post-treatments showed that out of 24 compounds, 12 compounds showed inhibitory actions on HCT-116 cells, we have calculated the inhibitory action (IC50) of these compounds on HCT-116 and we have found that the IC50 values were in between 0.12 mg mL−1 to 0.81 mg mL−1. The compounds (7a & 7g) showed highest inhibitory activity (0.12 mg mL−1), whereas compound 7d showed the lowest inhibitory activity (0.81 mg mL−1). We have also examined inhibitory action on normal and non-cancerous cells (HEK-293 cells) and confirmed that action of these compounds was specific to cancerous cells. The cancerous cells were also examined for nuclear disintegration through staining with DAPI, (4′,6-diamidino-2-phenylindole) is a blue-fluorescent DNA stain, and we have found that there was loss of DAPI staining in the compound treated cancerous cells. The compounds were found to potentially act through the HSP90 and TRAP1 mediated signaling pathway. Compounds 7a and 7g showed the highest selectivity to TRAP1 which explained its superior activity.

Organocatalyzed preparation of 1,4,5-trisubstituted-glycosyl-1,2,3-triazole derivatives.

Organocatalytic coupling of glycosyl azides with enolates of active ketones and esters through azide-enolate [3 + 2] cycloaddition in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) furnished 1,4,5-trisubstituted-glycosyl-1,2,3-triazole derivatives in excellent yield. The reaction condition is simple and can be scaled-up. Graphical abstract Coupling of glycosyl azides with active ketones through azide-enolate [3 + 2] cycloaddition in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) furnished 1,4,5-trisubstituted-glycosyl-1,2,3-triazole derivatives in excellent yield.

Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylsulfonamides via Regioselective Acylation.

N-Acylsulfonamides represent an important bioisostere of carboxylic acids that allow for greater molecular elaboration and enhanced hydrogen bonding capabilities. Herein, we present a mild and convenient palladium(0)-catalyzed synthesis of N-acylsulfonamides via the carbonylative coupling of sulfonyl azides and electron-rich heterocycles. The reaction proceeds via in situ generation of a sulfonyl isocyanate followed by regioselective acylation of an indole or pyrrole nucleophile. This approach has been used to synthesize 34 indole- and pyrrole-substituted N-acylsulfonamides in yields of up to 95%. Importantly, this process is ligand-free and compatible with an ex situ solid CO source and requires only slightly elevated temperatures, making it a highly attractive method for the preparation of this important class of compounds. This study further investigated the possibility of labeling N-acylsulfonamides with carbon-11 to facilitate biological evaluation and in vivo studies with positron emission tomography.

Convenient Synthesis of Some Novel Pyridazinone‐Bearing Triazole Moieties

The chemoselective reactions of 2‐(5‐mercapto‐4‐phenyl‐4H‐[1,2,4]triazol‐3‐ylmethyl)‐6‐p‐tolyl‐4,5‐dihydro‐2H‐pyridazin‐3‐one (3) with different electrophiles were evaluated. Triazole 3 reacted with alkyl halides in the presence of triethylamine in alcohol to give the corresponding S‐substituted derivatives. On the basis of S‐chemoselective reactions of triazole 3, a series of amino acid 10a–d and dipeptide derivatives 12a–d were prepared via azide coupling of the corresponding hydrazides 9 and 15 with amino acid ester hydrochlorides, respectively. N‐Substituted triazoles 6a–c or 7a–d attached to pyridazin‐3‐one moiety were successfully formed by the reaction of 3 with activated acrylic acid derivatives or with amines. Antibacterial activities of the synthesized derivatives were investigated through correlation with Escherichia coli FabH inhibitory activities using molecular modeling docking software. The antimicrobial activity of synthesized compounds was evaluated, showing best inhibition zone for N‐substituted carboxylic acid 5a and N‐substituted nitrile 5c parallel to the molecular modeling studies.

Small-angle scattering study of tetra-poly(acrylic acid) gels.

Tetra-poly(acrylic acid) (tetra-PAA) gels were fabricated by cross-end coupling of azide (-N3) and alkyne (-C≡CH) terminated tetra-arm poly(tert-butyl acrylate)s. The structures of the tetra-PAA gels and their sols (tetra-PAA sols, i.e., tetra-PAA macromer solutions obtained by deprotection of tert-butyl groups) were investigated by small-angle X-ray and small-angle neutron scattering experiments in methanol, salt-free aqueous media, and salt solutions. The scattering functions, I(q), of the tetra-PAA sols in methanol were described by the Ornstein-Zernike (OZ) function, , whereas those of the gels were represented by the sum of the OZ function and a power-law function, . Here, ξ is the correlation length, q is the magnitude of the scattering vector, A is a constant, and b is the scattering exponent. The OZ and the power-law functions represent the concentration fluctuations and cross-link inhomogeneities characteristic of gels, respectively. In salt-free aqueous media, there appeared a characteristic polyelectrolyte peak in the scattering functions, and the polymer concentration, C, dependence of the peak was similar for both sols and gels. In the presence of salt, both the scattering upturn for gels and the polyelectrolyte peak for both gels and sols were suppressed. Upon increasing the salt concentration, C s, the scattering intensity increased in the low q regions and the scattering functions were well fitted by the OZ function for both gels and sols.

Oxidative nitrene transfer from azides to alkynes via Ti(ii)/Ti(iv) redox catalysis: formal [2+2+1] synthesis of pyrroles.

Catalytic oxidative nitrene transfer from azides with the early transition metals is rare, and has not been observed without the support of redox noninnocent spectator ligands. Here, we report the formal [2+2+1] coupling of azides and alkynes via TiII/TiIV redox catalysis from simple Ti halide imido precatalysts. These reactions yield polysubstituted N-alkyl pyrroles, including N-benzyl protected pyrroles and rare examples of very electron rich pentaalkyl pyrroles. Mechanistic analysis reveals that [2+2+1] reactions with bulky azides have different mechanistic features from previously-reported reactions using azobenzene as a nitrene source.

Cu‐Catalysed Mild Synthesis of N‐Imidoyl and N‐Oxoimidoyl Sulfonimidamides through the Three‐Component Coupling of Sulfonimidamides, Azides, and Alkynes

Hitherto unknown N‐imidoyl sulfonimidamides have been synthesized by a Cu‐catalysed mild one‐pot multicomponent reaction of sulfonimidamides, azides, and alkynes in THF at room temperature under air in moderate to good yield. Furthermore, in the presence of molecular oxygen, the N‐imidoyl sulfonimidamides were further oxidized to give N‐oxoimidoyl sulfonimidamides.

Convenient Synthesis of Piperazine Substituted Quinolones

A series of 1‐[(4‐hydroxy‐2‐oxo‐1‐phenyl‐1,2‐dihydroquinolin‐3‐yl)carbonyl]‐4‐(substituted) piperazines 3a–c and methyl 2‐[(4‐hydroxy‐2‐oxo‐1‐phenyl‐1,2‐dihydroquinolin‐3‐yl)carbonylamino] alkanoates 5a–d has been developed by the direct condensation of ethyl [4‐hydroxy‐2‐oxo‐1‐phenyl‐1,2‐dihydro‐3‐quinoline] carboxylate 2 with N1‐monosubstituted piperazine hydrochlorides or amino acid ester hydrochloride in the presence of triethyl amine. The quinolone amino acid esters 5a–d were the key intermediate for the preparation of a series of 1‐[2‐((4‐hydroxy‐2‐oxo‐1‐phenyl‐1,2‐dihydroquinolin‐3‐yl)carbonylamino)alkylcarbony]‐4‐substituted piperazine derivatives 8–11 (a‐d) via azide coupling method with amino acid ester hydrochloride.

A well-defined biodegradable 1,2,3-triazolium-functionalized PEG-b-PCL block copolymer: facile synthesis and its compatibilization for PLA/PCL blends

A novel biodegradable 1,2,3-triazolium-functionalized PEG-b-PCL copolymer (TAPEC) was synthesized by the “click” coupling of methoxypolyethylene glycol azide and α-propargyl-ω-hydroxyl-poly(e-caprolactone), followed by the quaternization of the 1,2,3-triazole moiety with iodomethane. All the intermediates and TAPEC were characterized by 1H NMR, FT-IR, and gel permeation chromatography (GPC). Taking advantage of the characteristics of ionic liquid and block copolymer, this ion-containing diblock copolymer is expected to be used as a novel compatibilizer in mixed biopolyester for regulating the interface and crystallization behaviors. Hence, the TAPEC was evaluated as a compatibilizer and an interface emulsifier in the blends of polylactic acid (PLA) and poly(e-caprolactone) (PCL). Non-isothermal crystallization experimental results showed that the TAPEC with the higher amount of e-caprolactone units induces a plasticization and nucleate effect that increased the crystallization ability of the PLA phase; meanwhile, in the PCL phase, the agminated ionic cluster acting as a nucleating agent significantly increased the crystalline of PCL.

Synthesis of methyl 2-[(1,2-dihydro-4-hydroxy-2-oxo-1-phenylquinolin-3-yl)carbonylamino] alkanoates and methyl 2-[2-((1,2-dihydro-4-hydroxy-2-oxo-1-phenylquinolin-3-yl)carbonyl-amino)alkanamido] alkanoate

A series of methyl 2-[(1,2-dihydro-4-hydroxy-2-oxo-1-phenylquinolin-3-yl)carbonyla mino] alkanoates 7a-f has been developed by the direct condensation of ethyl [4-hydroxy-2-oxo--1-phenyl-1,2-dihydro-3-quinoline] carboxylate 4 with amino acid ester hydrochloride in the presence of triethylamine. The quinoline amino acid esters 7a-f were the key intermediate for the preparation of a series of methyl 2-[2-((1,2-dihydro-4-hydroxy-2- oxo-1-phenylquinolin-3-yl)carbonylamino)alkanamido] alkanoate 10-13(a-f) via azide coupling method with amino acid ester.

Regioselective synthesis of o-triazolyl-1,5-benzodiazepin-2-ones and o-isoxazolyl-1,5-benzodiazepin-2-ones via copper-catalyzed 1,3-dipolar cycloaddition reactions

A series of novel O -triazolyl-1,5-benzodiazepin-2-ones 6a – o and O -isoxazolyl-1,5-benzodiazepin-2-ones 7a – o was synthesized via a Cu(I)-catalyzed 1,3-dipolar alkyne–azide coupling reaction of N-substituted-1,5-benzodiazepine–alkyne derivatives 3a – c with various aromatic azides 4a – e and nitrile oxides 5a – e , respectively. The chemical structures of synthesized compounds were determined using 1 H NMR, 13 C NMR, heteronuclear multiple bond correlation (HMBC), high-resolution mass spectra, as well as elemental analysis and was further confirmed by an X-ray diffraction analysis for compound 7d .

Tandem Coupling of Azide with Isonitrile and Boronic Acid: Facile Access to Functionalized Amidines

AbstractAmidine is a notable nitrogen‐containing structural motif found in bioactive natural products and pharmaceuticals. Herein, a novel rhodium(I)‐catalyzed tandem reaction of readily accessible azides with isonitriles and boronic acids via a carbodiimide intermediate is achieved. This protocol offers an alternative approach toward N‐sulfonyl‐, N‐acyl‐, and N‐ phosphoryl‐functionalized, as well as general N‐aryl and N‐alkyl amidines with broad substrate scope. In addition, functionalized guanidines can also been synthesized when amines are used instead. The accomplishment of estrone‐derived amidine and glibenclamide bioisosteres further reveals the practical utility of this strategy.

Tandem Coupling of Azide with Isonitrile and Boronic Acid: Facile Access to Functionalized Amidines.

Amidine is a notable nitrogen-containing structural motif found in bioactive natural products and pharmaceuticals. Herein, a novel rhodium(I)-catalyzed tandem reaction of readily accessible azides with isonitriles and boronic acids via a carbodiimide intermediate is achieved. This protocol offers an alternative approach toward N-sulfonyl-, N-acyl-, and N- phosphoryl-functionalized, as well as general N-aryl and N-alkyl amidines with broad substrate scope. In addition, functionalized guanidines can also been synthesized when amines are used instead. The accomplishment of estrone-derived amidine and glibenclamide bioisosteres further reveals the practical utility of this strategy.