亚洲免费av电影一区二区三区,日韩爱爱视频,51精品视频一区二区三区,91视频爱爱,日韩欧美在线播放视频,中文字幕少妇AV,亚洲电影中文字幕,久久久久亚洲av成人网址,久久综合视频网站,国产在线不卡免费播放

        ?

        A one-pot protocol for copper-mediated azide–alkyne cycloaddition using alkenyl tri fl ate precursors

        2019-02-15 02:28:44YuChenLianchaoLiuDiminWuYuPengHeAngLi
        Chinese Chemical Letters 2019年1期

        Yu Chen,Lianchao Liu,Dimin Wu,Yu-Peng He*,Ang Li,*

        a College of Chemistry,Chemical Engineering and Environmental Engineering,Liaoning Shihua University,Fushun 113001,China

        b State Key Laboratory of Bioorganic and Natural Products Chemistry,Center for Excellence in Molecular Synthesis,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China

        Key words:Click chemistry Azide–alkyne cycloaddition Alkenyl tri fl ates Lithium chloride

        ABSTRACT On the basis of the mild transformation of alkenyl tri fl ates into alkynes promoted by LiCl,a one-pot protocol using alkenyl tri fl ate precursors was developed for copper-mediated azide–alkyne cycloaddition.This protocol may provide an opportunity of sequentially click reactions for the construction of bifunctional probes in chemical biology studies.

        The emergence and evolution of click chemistry have greatly facilitated the development of the fields of chemical biology and material science[1].Thecopper catalyzed azide–alkynecycloaddition(Cu AAC)pioneered by Sharplessand co-workers[2]remainsoneof the most powerfultoolsofclick chemistry,despitenumerousendeavorsto develop various click reactions[1c,d,g].CuAACprovidesan expedient and modular approach to prepare small molecule probesof biological interest;biotin,photoactivatable groups,and fluorophores can be readily installed onto the small molecule core at a late stage [23_TD DIFF1b].In recent years,sequential click reactions have received increasing attention[3].The programmed reaction sequence allows rapid construction of multifunctional small molecule probesand polymers.For instance,an af fi nity-based bifunctional probe for cellular target identi fi cation usually contain a photoactivatable group(such as a diazirine)for crosslinking with the target protein and a biotin tag for pull-dow n[4],and it is more practical to introduce the photoactivatable group by aclick reaction at a late stage rather than to carry on the fairly labile functionality through ade novo synthesis.In this case,sequential click reactionsare highly desired.Although one can envision a variety of combinations of click reactions,the most attractive and straightforw ard strategy of using double Cu AAC reactions to install different functionalities is hampered by the narrow w indow for differentiation of the substrate reactivity.Recently,we reported the LiCl mediated elimination of alkenyl tri fl ates for the preparation of alkynes under mild conditions[5],which permits a strategy of masking terminal alkynes as alkenyl tri fl ates in a click process.Thus,we envision a programmed sequence of tw o copper mediated cycloaddition reactions starting from asubstrate containing a terminal alkyne and an alkenyl tri fl ate which can beeasily converted into an terminal alkyne.The fi rst click event should occur under standard Cu AAC conditions,while the second step requiresan efficient one-pot protocolon thebasisof our previous discovery[5].Herein,we describe such a protocol for copper-mediated azide–alkyne cycloaddition using alkenyl tri fl ate precursors.

        We investigated the conditions for the one-pot elimination/azide formation/cycloaddition sequence,using readily available alkenyl tri fl ate 1[5]as a precursor.The resultswere summarized in Table 1.In the presence of LiCl,elimination of 1 proceeded in DMF at ambient temperature to give the desired terminal alkyne[5].Benzyl azidewasthen generated in situ from NaN3and Bn Br through an SN2 reaction;DMFalso served as a good solvent for the substitution.Thus,weneeded a suitable copper salt or complex asa promoter for the cycloaddition,which had to be compatible to the reaction system.The commonly used Cu I[6]proved to be ineffective under these conditions(entry 1).Interestingly,copper(I)thiophene-2-carboxylate(CuTC)[5,7]led to formation of asmall amount of 1,2,3-triazole2(entry 2).Increasing theequivalentsof Cu TCimproved the yield of 2 to 30%,which was still unsatisfactory from a synthetic perspective.To our delight,Et3N was found to be a crucial additive for this one-pot process,and 2 was obtained in 78%isolated yieldfrom 1.Et3N presumably buffered the acid generated through the elimination processand might promotetheformation of thecopper acetylide intermediate as well.Of note,the amine can be added before the SN2 reaction;this order change had no bearing on the overall ef fi ciency.

        Table 1 Studies of the conditions for the one-pot tri fl ate elimination/azide formation/cycloaddition sequence.

        Having established the optimal conditions,we examined a series of azides(generated in situ from NaN3and corresponding alkyl bromides)for the one-pot process,as show n in Table 2.1,2,3-Triazoles 3–11 were obtained in good to excellent yields(entries1–9).Substituted benzyl azides with electron-rich(entry 1)or electron-de fi cient(entries 2 and 3)aromatic rings all performed well under the standard conditions.α-Azido carbonyl compounds(entries 4–7)were suitable substrates as well,which w ould allow facile incorporation of a photoactivatable group or a biotin tag.To our delight,the reactions of allyl azides(entries 8 and 9)proceededwith good ef fi ciency,which may offer an alternative type of linkers of improved stability compared with esters and amides.

        Table 2 Scope of the azides(generated in situ)suitable for the one-pot sequence.

        A general procedure for the one-pot sequence is described below.To a stirred solution of alkenyl tri fl ate 1 (34.2 mg,0.090 mmol)in DMF(300 m L)was added anhydrous LiCl(15.3mg,0.361 mmol)at 22?C.The mixture was allowed to stir at that temperature for 1.5h before Et3N(9.1 mg,12.5 m L,0.090 mmol),NaN3(8.8 mg,0.135 mmol),and the bromide(0.135 mmol)were sequentially added.The resultant mixture was stirred at 22[13_TD DIFF]?Cfor 2.5 h,and Cu TC(34.3 mg,0.180 mmol)wasadded.The mixture was allowed to stir at that temperature for 2h before it was quenched with saturated aq.NaHCO3(2m L)and extracted with EtOAc(5?2 m L).The combined organic phases were washed with brine(5m L),dried over anhydrous Na2SO4,fi ltered,and concentrated under vacuum.The residue was subjected to preparative thin layer chromatography for puri fi cation using EtOAc/petroleum ether(1:3)as eluent to give the 1,2,3-triazole.Characterization of compounds 2–11 is included in the Supporting information.

        In summary,we have developed an efficient protocol for copper-mediated azide–alkyne cycloaddition using alkenyl tri fl ate precursors.Three sequential reactions,namely the LiCl-promoted elimination for alkyne formation,the nucleophilic substitution for azide formation,and the cycloaddition for the triazole formation,proceeded smoothly in one pot.This protocol may fi nd further use in the construction of bifunctional small molecule probesfor target identi fi cation,imaging,and other chemical biology studies.

        Acknow ledgm ents

        We thank Xiaowen Yang and Dr.Wenhao Zhang for helpful discussions.Financial support was provided by the National Natural Science Foundation of China(Nos.21525209,21621002,21772225,and 21761142003),the Chinese Academy of Sciences(Strategic Priority Research Program(No.XDB20000000)and Key Research Program of Frontier Sciences(No.QYZDB-SSW-SLH040)),Shanghai Science and Technology Commission(Nos.15JC1400400 and 17XD1404600),the National Program for Support of Top-Notch Young Professionals of China,and the K.C.Wong Education Foundation.

        Appendix A.Supplem entary data

        Supplementary material related to thisarticle can be found,in the online version,at doi:https://doi.org/10.1016/j.cclet.2018.06.001.

        北岛玲中文字幕人妻系列| 人妻在线有码中文字幕| 精品人妻av中文字幕乱| 午夜久久久久久禁播电影| 色老板精品视频在线观看| 久久99国产伦精品免费| 91亚洲国产成人久久精品网站| 国产熟女一区二区三区不卡| 一边摸一边抽搐一进一出视频| 真人作爱免费视频| 男人j进女人p免费视频| 亚洲国产综合久久精品| 亚洲国产婷婷香蕉久久久久久| 大屁股人妻女教师撅着屁股| 男人添女人下部高潮全视频| 色爱无码A V 综合区| 久久精品韩国日本国产| 亚洲二区精品婷婷久久精品| 久久精品亚洲熟女av麻豆| 久久精品国产免费观看三人同眠| 国产美女自慰在线观看| 日韩最新在线不卡av| 亚洲国产精品激情综合色婷婷 | 妇女bbbb插插插视频| 日韩久久一级毛片| 久久精品国产亚洲AV古装片| 日韩精品免费在线视频一区| 国产成人综合亚洲看片| 欧美激情五月| 亚洲中文字幕在线精品2021| 亚洲av香蕉一区二区三区av| 中文字幕乱码一区av久久不卡| 欧美在线区| 久久精品日韩免费视频| h视频在线播放观看视频| 国自产拍偷拍精品啪啪一区二区| 久久久久亚洲av无码专区| 国产精品综合久久久久久久免费| 在线免费观看亚洲天堂av| 韩国一区二区三区黄色录像| 亚洲精品久久久www小说|