A recyclable fluoroalkylated 1,4-disubstituted [1,2,3]-triazole organocatalyst for aldol condensation of aldehydes and ketones

A new fluoroalkylated 1,4-disubstituted [1,2,3]-triazole was prepared and acted as an organocatalyst for aldol condensation of different ketones with various aldehydes. Aldol condensation proceeded efficiently in the presence of catalytic amount of fluoroalkylated [1,2,3]-triazole. The catalyst could be easily recovered by fluorous solid-phase extraction with excellent purity and reused for three runs with slightly decrease in its activity.     

Regioselective synthesis of 1-(2,6-dichloro-4-trifluoromethylphenyl)- 4-alkyl-1H-[1,2,3]-triazoles

A new and efficient method for the synthesis of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-alkyl-1H-[1,2,3]-triazoles by the room temperature 1,3-dipolar cycloaddition of (2-azido-1,3-dichloro-5-trifluoromethyl)benzene with terminal alkynes in the presence of Cu (I) salt as catalyst is reported. All the reactions gave 1,4-disubstituted products with high regioselectivity, as no 1,5-disubstituted product was formed. The structures of all the title compounds have been confirmed by elemental analysis, 1H- and 13C-NMR and in addition, the structure of compound 5a was investigated by X-ray crystallography.     

NMR and mass spectral analysis of step-growth polymers from azide alkyne cycloaddition and regioselectivity afforded by copper(I) and ruthenium(II) catalysts

Azide alkyne cycloaddition was applied to step growth polymerization of the diazido monomer, di(3-azido-2-hydroxypropyl) ether of bisphenol-A (DAHP-BPA) with either tetraethyleneglycol dipropargyl ether (TEGDPE) or tetraethyleneglycol dipropiolate (TEGDP). Polymerizations were conducted without catalyst and in the presence of Cu(I) or Ru(II) complex. The resulting oligomers and polymers were characterized using ¹H- and ¹³C-NMR spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), with an emphasis on the relative abundance of 1,4- vs. 1,5-disubstituted regioisomeric 1,2,3-triazoles. Uncatalyzed reaction of DAHP-BPA/TEGDPE at 70°C yielded a 55/45 mixture of 1,4/1,5-disubstituted triazoles; reaction was slow and residual alkyne end groups were observed, suggesting attritional loss of azide. Catalyzed with Cu(PPh₃)₃Br, the same system yielded 93/7, 1,4/1,5-disubstituted triazoles, and few residual end groups were detected, consistent with higher molecular weight and controlled 1:1 depletion of azide and alkyne. Cp*RuCl(COD) catalyst was not soluble in the bulk system, necessitating solution polymerization in THF. Ru(II) yielded 6/94, 1,4/1,5-disubstituted triazoles, and MALDI-TOF-MS showed an end group composition similar to that observed with Cu(I). Uncatalyzed reaction of the DAHP-BPA/TEGDP system, involving the more reactive propiolate, yielded a high proportion (85%) of 1,4-disubstituted triazole linkages, and MALDI-TOF-MS revealed a controlled 1:1 depletion of azide and alkyne groups.     

Quick and highly efficient copper-catalyzed cycloaddition of organic azides with terminal alkynes

Good to excellent yields of 1,4-disubstituted 1,2,3-triazoles were obtained within 2-25 min when the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was carried out under solvent-free conditions, with [Cu(phen)(PPh(3))(2)]NO(3) (1mol%) as the catalyst.     

Efficient synthesis of allylic azides and one-pot regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles from homoallyl alcohols

This protocol is for an expedient and operationally simple synthesis of allylic azides and one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from homoallyl alcohols. Synthesis of allylic azides involves the palladium-catalyzed hydroazidation of unactivated olefins with migration of double bond. This hydroazidation can be coupled to Cu(I) promoted 1,3-dipolar cycloaddition to afford the corresponding 1,4-disubstituted 1,2,3-triazoles.     

Synthesis of functionalized organotrifluoroborates via the 1,3-dipolar cycloaddition of azides

[reaction: see text] We have successfully prepared potassium azidoalkyltrifluoroborates from the corresponding halogen compounds in 94-98% yields through a nucleophilic substitution reaction with NaN(3). In the presence of various alkynes and Cu(I) as a catalyst, these azidotrifluoroborates easily formed 1,4-disubstituted organo-[1,2,3]-triazol-1-yl-trifluoroborates in 85-98% yields. This method was then developed into a facile one-pot synthesis for the preparation of various organo-[1,2,3]-triazol-1-yl-trifluoroborates using haloalkyltrifluoroborates as the starting materials.     

Regioselective synthesis of [1,2,3]-triazoles catalyzed by Cu(I) generated in situ from Cu(0) nanosize activated powder and amine hydrochloride salts

A straightforward and efficient method for the regioselective synthesis of functionalized 1,4-disubstituted [1,2,3]-triazoles, from terminal alkynes and azides, has been established utilizing Cu(0) as the source of the catalytic species. The presumed catalytic Cu(I) species is generated by the combination of 10 mol % copper nanosize activated powder and 1 equiv of an amine hydrochloride salt. The addition of an amine hydrochloride salt into the reaction mixture enhanced the dissolution of copper metal, and subsequently facilitated the formation of the Cu(I)-acetylide intermediate required for the regioselective cycloaddition.     

Synthesis of 1,2,3-triazoles from heterocyclic α-nitro azides

Noncatalytic and Cu(I)-catalyzed dipolar cycloadditions of heterocyclic a-nitro azides to substituted alkynes were studied. Catalytic cyclization gave 1,4-disubstituted triazoles only. The effect of the substituents in alkynes and that of the nature of the starting heterocycles on the isomer ratio of triazoles were examined. New representatives of 1,2,3-triazoles were obtained; their physicochemical properties were studied. A comparative analysis of the spectral characteristics of the resulting regioisomeric triazole derivatives was performed.     

Reaction of substituted sulfenes with N,N-disubstituted α-amino-methyleneketones. II. Synthesis of N,N-disubstituted cis and trans 4-amino-3-chloro-3,4,5,6,7,8-hexahydro-1,2-benzoxathiin 2,2-dioxides,and 4-amino-5,6,7,8-tetrahydro-1,2-benzoxathiin 2,2-dioxides

The polar 1,4-cycloaddition of chlorosulfene (generated in situ from chloromethanesulfonyl chloride and triethylamine) to N,N-disubstituted (E)-2-aminomethylenecyclohexanones I gave mixtures of N,N-disubstituted cis and trans 4-amino-3-chloro-3,4,5,6,7,8-hexahydro-1,2-benzoxathiin 2,2-dioxides III and IV, except for N,N-diphenyl enaminone which did not react. Only compounds IV could be separated from these mixtures by silica gel chromatography, with the exception of the piperidino adducts (III + IV)d, from which also IIId could be obtained pure. Compounds IV or mixtures III + IV were dehydrochlorinated with DBN in refluxing benzene to afford N,N-disubstituted 4-amino-5,6,7,8-tetrahydro-1,2-benzoxathiin 2,2-dioxides V in satisfactory yields. Structural and conformational features of compounds III, IV and V were determined from uv, ir and nmr spectral data.     

A stereospecific synthesis of (+/-)-5,8-disubstituted indolizidines and (+/-)-1,4-disubstituted quinolizidines found in poison frog skins

An efficient, high-yield stereospecific route to three (+/-)-5, 8-disubstituted indolizidines, (209B (I), 209I (II), 223J (III)) and two (+/-)-1,4-disubstituted quinolizidines (207I (IV), 233A (V)), racemates of alkaloids found in the skins of neotropical and Madagascan poison frogs is reported. The structures of the natural alkaloids were thereby established by chiral GC comparison with the exception of indolizidine 209B (I) for which a natural 209B could no longer be detected.     

Cu(I)- and Ru(II)-mediated "click" cyclization of tripeptides toward vancomycin-inspired mimics

Structural mimics comprising 1,4- and 1,5-disubstituted triazole-containing cyclic tripeptides with excellent resemblance toward the DE-ring of vancomycin are conveniently accessible using Cu(I)- or Ru(II)-assisted "click" cyclization.     

Sonochemical synthesis of fluorescent 1,4-disubstituted triazoles using l-phenylalanine as an accelerator ligand in aqueous media

A green sonochemical protocol using l-phenylalanine as a water soluble promotor ligand has been developed for the regioselective synthesis of fluorogenic 1,4-disubstituted triazoles (3a-o) via well-known click reaction at 40?°C. l-Phenylalanine is a biocompatible, economical, commercially available and non-toxic ligand which not only serves to stabilize Cu(I) oxidation state but also prevents its disproportion to enhances and modulate the rate of reaction. The designed catalytic system exhibits broad substrate compatibility and can be recycled up to 5 cycles without appreciable loss in the yield of desired product. Gram scale synthesis was successfully accomplished with 92% yield.     

Zinc-mediated chain extension reaction of 1,3-diketones to 1,4-diketones and diastereoselective synthesis of trans-1,2-disubstituted cyclopropanols

[reaction: see text] A variety of 1,3-diketones can be efficiently converted into the corresponding 1,4-diketones and trans-1,2-disubstituted cyclopropanols by using organozinc species in one-pot reactions. It was found that 2.3 equiv of CF3CO2ZnCH2I was effective to give the corresponding chain-extended products in 44-85% yields, while a mixture of organozinc species formed from 4.0 equiv of Et2Zn, 2.0 equiv of CF3CO2H, and 4.0 equiv of CH2I2 resulted in the formation of trans-1,2-disubstituted cyclopropanols with quite good yields and diastereoselectivity.     

Recyclable clay supported Cu (II) catalyzed tandem one-pot synthesis of 1-aryl-1,2,3-triazoles

Montmorillonite KSF clay supported CuO nanoparticles efficiently catalyzes one-pot aromatic azidonation of aryl boronic acids followed by regioselective azide–alkyne 1,3-dipolar cycloaddition (CuAAC) reaction producing corresponding 1-aryl-1,2,3-triazole derivatives at room temperature in excellent yields without use of any additives. Investigations on mechanism of CuAAC revealed that sodium azide, which is used as azidonating reagent in one-pot protocol reduces Cu(II) to click-active Cu(I). The catalytic efficiency of another Cu(II) source CuSO₄ in combination with NaN₃ for this one-pot CuAAC protocol, further supported our mechanism. This is the first report for use of Cu(II)/NaN₃ catalytic system for CuAAC protocol. The clay–Cu(II) catalyst being ligand-free, leaching-free, easy to synthesize from inexpensive commercially available precursors, recyclable, and environmentally friendly will be highly useful for economical synthesis of 1,4-disubstituted 1,2,3-triazoles.     

A convenient synthesis of fluoroalkylated γ-butyrolactones from polyfluoroalkyl iodides and 4-pentenoic acid catalyzed by Pd(PPh3)4

A convenient synthesis of fluoroalkylated γ-butyrolactones was realized through the reaction of fluoroalkyl iodides with 4-pentenoic acid in the presence of catalytic amounts of tetrakis(triphenylphosphine)palladium and sequential treatment with triethylamine in 79-85% yields.     

New 1,2,3-Triazoles from (R)-Carvone: Synthesis,DFT Mechanistic Study and In Vitro Cytotoxic Evaluation

Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide–alkyne cycloaddition reaction using CuSO₄,5H₂O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu (I). All the newly synthesized 1,2,3-triazoles 9a–h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC₅₀ values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC₅₀ value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.     

Diverse reactions of 1,4-dilithio-1,3-dienes with nitriles: facile access to tricyclic Delta1-bipyrrolines, multiply substituted pyridines, siloles, and (Z,Z)-dienylsilanes by tuning of substituents on the butadienyl skeleton

Addition cyclization of 1,2,3,4-tetrasubstituted 1,4-dilithio-1,3-dienes (Type I) with four equivalents of various aromatic nitriles in the presence of hexamethylphosphoramide (HMPA) gives exclusively fully substituted pyridines in moderate to good yields. Similarly, trisubstituted pyridines can be prepared by the reaction of 2,3-dialkyl- or diaryl-substituted 1,4-dilithio-1,3-dienes (Type II) with nitriles. However, five- or six-membered-ring fused 2,3-disubstituted 1,4-dilithio-1,3-dienes (Type III) reacted with various aromatic and aliphatic nitriles without alpha-hydrogen atoms to afford tricyclic Delta1-bipyrrolines in high yields. The reaction of six-membered-ring fused 2,3-disubstituted 1,4-dilithio-1,3-diene (Type III) with 2-cyanopyridine afforded the corresponding pyridine, and no tricyclic Delta1-bipyrroline was observed. Seven-membered-ring fused dilithiodienes reacted with PhCN or trimethylacetonitrile to afford the corresponding pyridines in good yield. When 1,2,3,4-tetrasubstituted dilithio reagents (Type I) were treated with Me3SiCN, a tandem silylation/intramolecular substitution process readily occurred to yield siloles, whereas the reaction of 2,3-disubstituted dilithio reagents (Types II and III) with Me3SiCN gave rise to (Z,Z)-dienylsilanes with high stereoselectivity. These results revealed that the formation of tricyclic Delta1-bipyrrolines, pyridines, siloles, and (Z,Z)-dienylsilanes are strongly dependent on the substitution patterns of the dilithio butadienes and the nature of the nitriles employed.     

Substitution reactions involving the 2,6-methyl groups of 1,4-dihydropyridines

4,4-Disubstituted 1,4-dihydropyridines (I) are brominated with bromine in chloroform to give 2,6-bis(bromomethyl)-4,4-disubstituted 1,4-dihydropyridines (II), whereas 2,6-bis(dibromomethyl)-4,4-disubstituted 1,4-dihydropyridines (III) are obtained in the case of bromination of I in acetic acid. The bromine atoms in II and III are labile and readily undergo nucleophilic substitution.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1519–1524, November, 1978.     

Copper(I)-doped Wyoming’s montmorillonite for the synthesis of disubstituted 1,2,3-triazoles

A new catalytic system based on copper(I)-doped Wyoming’s montmorillonite was elaborated. This system was studied and was found to catalyze the formation of 1,4-disubstituted 1,2,3-triazoles when starting from azides and alkynes. It was used for the synthesis of a few triazole derivatives to show its usefulness.     

A facile and regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles using click chemistry

The reaction of α-tosyloxy ketones, sodium azide, and terminal alkynes in presence of copper(I) in aqueous polyethylene glycol afforded regioselectively 1,4-disubstituted 1,2,3-triazoles in good yield at ambient temperature. The one-pot exclusive formation of 1,4-disubstituted 1,2,3-triazoles involves in situ formation of α-azido ketones, followed by cycloaddition reaction with terminal alkyne. The generality of this one-pot method was demonstrated by synthesizing an array of diverse 1,4-disubstituted 1,2,3-triazoles.