聚乙二醇支持的CuI催化Huisgen环加成反应合成三氮唑

20314年3月安徽师范大学学报(自然科学版)Journal of Anhui Normal University ( Natural Science)May.201Synthesis of Triazoles by PEG Supported CuI CatalyzedHuisgen Cycloaddition ReactionZHENG Cai-yun' ,HU Jin-song2 ,YU Shu-yan2，SHANG Yong jia2(1. Guangzhou Panyu Polytechnic, Guangzhou 511483, China; 2. Collge of Chermistry and Materials Science, Anhui Normal University, Wuhu241000，China)Abstract: An efficient synthetic method for aromatic triazoles accelerated by rpolymer -supported Culas catalyst between organic azides and terminal alkynes has developed. Treatment of terminal alkyneswith benzyl axide or aryl azides in water smoothly gave the Huisgen 1, 3-dipolar cycloadditionproducts, triazoles. The novel Cu(I) complex has shown good activity and stability after eightcatalytic cycles.Key words: huisgen 1,3-dipolar cycloaddition; triazoles; polymer -supported CulClassification No. :0621.3 Document code: A Paper No. : 1001 - 2443(2011)03 - 0244-06IntroductionThe Huisgen 1, 3-dipolar eycloaddition reaction of organic azides and alkynest1] has gained considerableattention in recent years due to the introduction in 2001 of Cu(I) catalysis by Tornoe and Meldal(2}, leading toa major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldaland the Sharpless laboratoriesls.4. The great success of the Cu (I) catalyzed alkyne azide cyecloaddition(CuAAC) is rooted in the fact that it is a virtually quantitative, very robust, insensitive," general, andorthogonal ligation reaction， suitable for even bimolecular ligationfs) and in vivo taggingl6,7] or as apolymerization reaction for synthesis of long linear polymers81. All these advantages, combined with thepotentially favorable physicochemical properties of the resulting triazoles9! , have propelled the Cu( I)- catalyzedHuisgen cycloaddition to be one of the most popular and efficient reactions within the concept of click chemistry;asa result, a burst in the number of publications on the topic has occurred in past few yearslo,11.Recently, the techniques of soluble polymer support to synthesize small molecule libraries were appliedsuesfully to combinatorial chemistry and parall synthesis. Synthetic approaches that utilized soluble polymerstermed liquid phase chemistry12], c∞ouple the advantages of homogeneous solution chemistry (high reactivity,lack of diffusion phenomena and ease of analysis) with those of solid phase methods (use of excess reagents andeasy isolation and purification of products) , and thus have attracted the attention of synthetic chermists. Amongthem, polymer-supported organic catalysts, with the aim of facilitating catalyst recovery and its recycling use,have proved to be the powerful synthetic tools readily available to the chermical community in organicchemistrylis. Of the polymers, polyethylene glycol is the most frequently used soluble resin in liquid-phasesynthesis-14]. Herein, we developed an eficient synthetic method for aromatic triazoles accelerated by rpolymer-supported CuI as catalyst between organic azides and terminal alkynes.Received date:2011-02 - 20Foundation item: Supported by National Natural Science Foundation of China (20872001) and the Naturel Science Foundation of EducationAdninistration of Anbui Province (KJ2008A064).Author' s brief: ZHENG Cai-yun(1967 - ), femnale, bom in Qian' an, Hebei Province, sociate peoessor.中国煤化工MHCNMHG34卷第3期郑彩云,胡劲松,余述燕,等:聚乙二醇支持的 Cul催化Huisgen环加成反应合成三氮唑2451 Results and DiscussionAs part of our ongoing research into the liquid-phase synthesishi5 8，we chose to perform our reactions onthe soluble polymer supported poly ethyene glyol(PEG) with an average moleular weight of 4000 for its uniquenaturel19]. As depicted in scheme 1, the novel PEG supported-Cux are readily accessible in three steps startingwith PEG and a,a'-Dichloro-p xylol. Treatment of dihydroxy-PEG 4000 with NaH in THF in the presence ofNal, fllowed by addition of 1, 4-bis ( chloromethy!1) benzene could afford the polymeric benzyl chloride 3 innearly quantitatively yield. The polymeric benzy| chloride was converted to PEG-supported piperazine 4 byadding excess piperazine in the presence of K2CO3 in CH2Ch.And then the evaluation of its catalytic activity in Huisgen 1 ,3-dipolar cycloadditon was carried out.OoH.cCcme-oUaHNC NHgaNH_CuxCHgCN,tKxCO3 DCM, efu_CuXx=I.Br.CIScheme 1 The synthesis of the polymer supported-CuXInitially, screening of proper Cu complex was made in a model reaction of octyne and phenyl azide indichloromethane at 60C for 4 hours by using 5mol% catalyst (relative to octyne) (Table 1).N=5mol% catalystCH2Clz，60CTable 1 Screening of Cu complexes for the reaction of octyne and phenyl azideAzideAlkyneTime/hYielde.(5mol%)4)6zCuBrO)-Ns9<-Ns87Cul>-Nomnva. All the reactions were crried out in N. alkyme(1mmo), azide(1. 1mmo)b. Yields of isolated yield after flash chromatographyAs shown, in contrast with unmodified Cul, the polymer-supported-CuX showed more satistactory catalyticproperty, even for commonly deactivated CuBr and CuC, the resuling triazole were formed with 90% and 87%yields (entry 2, 3), respectively. Notably, the polymer-supported-CuI provided the desired product with thebest yield (entry 1). The unprecedented activity may be attributed to itsIn order to中国煤化工optimize this transformation, different reaction parameters (solvent, tempeTHCNM H G2.catalyst)were examined with the polymer -supported-CuI as catalyst. Some selected r246安徽师范大学学报(自然科学版)2011年After setle down with polymer- supported-CuI as catalyst, we further optimized this reaction, and theresults are summarized in Table 2. This reaction can be carried out in a variety of solvents, such as THF, DMF,DCM, benzene, dioxane and water. To our delight, water turns out to be the best solvent for this reaction,which is a choice for its safety, nontoxicity, economical availability and environmentally friendly. Although atroom temperature, the desired product was obtained in 87% yield in water, the elevating of the temperature to0C increased the yield to 96% . Further increasing the temperature to 100C gave a comparable result. Thus,we eventually settle down the optimized reaction conditions to be the combinationof 5 mol % of polymer-supported-Cul as catalyst, water as solvent.Utilizing the optimal reaction conditions, variousTable 2 The investigation of the optimized conditiontriazoles and alkynes were used to test the versatilityof the cycloaddition reactionof this reaction, and the results were summarized in_Entry_ Catalyst/% Solvent__ Time/h T/C Conversion/%bTable 3. We found that the reaction of benzyl azide orDCM6(96DMF6086aryl azide with electron-donating groups proceededTHF82well to give the corresponding 1, 4-disubsituted triazolesCHzCNDioxane .87with excellent yields (entry 5一10 and 16 - 19).H2OUnexpectedly， for most aryl azide with electron-Benzene6[withdrawing groups (such as nitro group, formyl25group), the major product was alkynes instead ofl20triazoles, which were obtained throughHO97Sonogashira- coupling of azides and alkynes(entry 1 -)6_4and 11 - 15). As we know, the lascal Sonogashira-coupling reactions betweenaryl halides and terminalalkynes were catalyzed by Pd complexes, the aryl azides as substrate and polymer supported-Cul as catalyst wasseldom seen, it probably provided us a new research thought.Table 3 Polymer-supported-CuI catalyzed the reactions of alkynes and azides*N=NOHO2N- -NsO2N-90O2N-<)7O2N-<>-Ns W OHTrace .O2N-7-iV^OHO2N-<)5 Hxc-<~>-NsHsc-<7>i599trace1.c->-=6 Hgc-》>-NsHsc-<>-NJOH98中国煤化工YHCNMHG34卷第3期郑彩云,胡劲松,余述燕,等:聚乙二醇支持的Cul催化Huisgen环加成反应合成三氮唑2477 Hc--NsVV cIH4.C- -riyma95Hsc-->=人 ,Cltrace9 Hsc-~)>-Ns oH4zC-)810HgC-NswNOTBSH2C)6H2C-个oTBS11OHC--Ng MOTBSOHC- -OTBSTrace~OTBS120HC-N3orc0--0913DHC-oHOHc--iV_oHOHC-》-=E,OH14 0HC-,OH .OHCNNCoH0Hc-1)HC-NaNN=N16(>-Ns__t<>-NOH口>=^oH7>-No心>-=)718(>Ns96O=M19<>-Nsw 0H中国煤化工a. Reaction conditions: alksyne( lmmol), azide(1. 1mmol), catalyst(5mol%) in H2CMYHCNMHGb. Yields of isolated yield after flash chromatography.安徽师范大学学报(自然科学版)2011年The recycling of poly( ethylene -glyool)-supported catalyst 5 was performed in the reaction and the resultsare shown in Table3 (entries 1 一4). Poly( ethylene-glyo)-supported catalyst 5 was readily recovered byprecipitation with diethyl ether followed by filtraton (average recovery yields ranged from 80 to 90%), and maybe re-used at least two times without loss of chemical efficiency.2 ConclusionIn summary, we designed a new class of poly( ethyleneglycol) -supprted Cul based on piperazine, Using5mol% of the catalyst, the triazoles of 1, 3-dipolar addition between terminal alkynes with electron-donatinggroups and azides were obtained in g∞od yields, while the alkynes of Sonogashir- -∞oupling reactions betweenaryl azides containing electron-withdrawing groups and terminal alkynes were obtained in major product. Itenvironmentally friendly since the polymers can be recycled and it should be amenable to use in medicinalchemistry parallel synthesis procedures where small quantities of highly pure products are desired with minimalpurification necessary.3 ExperimentMelting points were determined on an XT-4 apparatus and were uncorrected. IR spectra were taken on aBruker Vector-22 spectrometer in KBr pellets and reported in cm -1. IHNMR spectra were recorded at 300 MHzon a Bruker Avance 300 spectrometer in CDCI3 and DMSO-d6 with chemical shifts (d) given in parts per millionrelative to TMS as an internal standard. 13C NMR spectra were recorded ona Bruker Avance -300(75.5 MHz)spectrometer with complete proton decoupling.4 General procedure for the synthesis of compounds 54.1 Synthesis of PEG- supported chlor-p-xylol 3Toa solution of PEG(10 g, 5 mmol) in 50 mL THF were added a,a' -Dichloro P xylol (3.5 g,20 mmol),Nal(1.5 g,10 mmol), NaH(0. 24 g, 10 mmo). The mixture was strred at room temperature for 5 days underNz atomsphere. After filtration, 300 mL absolute ether was added into the filtrate slowly. The PEG supportedchloro p-xylol 3 was gained as educt.H NMR (300MHz, CDCI3) δ: 7.37(m, 4H, ArH), 4. 61(s, 2H, CH2C), 4. 58(s, 2H, OCH2), 3.35- 3.90(m, PEG) ppm.4.2 Synthesis of PEG-supported piperazine 4Piperization(1.72 g, 20 mmol) and K2CO3(0.345 g, 2. 5 mmol) were added into PEG-supported chloro-p-xylol (10 g, 5 mmol) in 50 mL DCM. The mixture was thout any particular protection, and remained euallyactive over eight cycles. As solvent, water is the best choice for its perfect stirred in reflux for 8h, then themixture was cooled to room temperature. The insoluble substance was filtrated, the polymner was precipitated byaddition of 300 mL absolute ether.'H NMR(300MHz, CDCIg) 8:7.37(m, 4H, ArH), 4.61(s, 2H, -CH2C), 4. 58(s, 2H, -0CH2-),3.35 - 3. 90(m, PEG) ppm.4.3 Synthesis of PEG-supported copper (I) salts 5Copper(I) sats (6 mmol) and PEG supprted piperazine 4 (10 g, 5 mmol) were added to 35mlL CH3CN,then the mixture was stirred at room temperature for 10h. The insoluble substance was filtrated, the polymerwas precipitated by addition of 200 mL absolute ether, for completion of the precipitation, the suspension wasleft at 0 for another 30 min. The polymer was filtered, rinsed with 0.1 L of diethyl ether, and dried for5 hat 0.5 Torr in vacuo. Thus, the PEG supported copper(I) salts were obtained中国煤化工4.4 General procedure for the synthesis of triazoles and alkynesCNMHGInto a two-necked bottle, aromatic azides(1. 1 mmol) and terminalcatalyst34卷第3期郑彩云,胡劲松,余述燕,等:聚乙二醇支持 的Cul催化Huisgen环加成反应合成三氮唑249(3 mol%) and H2O(5 mL) were added consecutively, the mixture was stirred at 60C under N2 for 3 - 4h.After cooled to room temperature, the mixture was extracted with ethyl acetate for three times and dried withanhydrous Na2SO4. The fitrate was concentrated, and the resulting residue was purified by flashchromatography (hexane -ethyl acatate) to provide the desired products.References[1] HUISGEN R. Kinetics and reaction mechanisms: selected examples from the experience of forty years[J]. Pure Appl Chem, 1989,61:613.2] TORNoE C w, MELDAL M. Pepidriaols: Copper (1)-atalyzed 1.3-dipolar cyladditions on slid-phase[J]. 2001 ,263 - 264.3] TORNoE C W, CHRISTENSEN C, MELDAL M. 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