Synthesis of Oxindoles by Palladium-catalyzed C–H Bond Amidation

经典化学合成反应标准操作1。

前言 (1)2. 分子内的Heck反应 (2)2.1 生成烯基取代的反应 (2)2。

1。

1 分子内Heck反应化生成环外双键示例 (3)2。

2 形成季碳中心的反应 (4)2.2。

1 分子内不对称Heck反应示例 (5)2。

3 多烯大环的合成 (5)2.2。

1 Heck反应用于合成大环多烯示例 (6)3。

分子间的Heck 反应 (7)3。

1 常规分子间Heck反应 (7)3。

1.1 Pd(OAc)2—P（o-tol)3体系用于不饱和羧酸酯的Heck反应标准操作三 (8)3.1.2 不饱和酮的Heck反应标准操作 (9)3.1。

3 杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作一 (9)3。

1。

4 杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作二 (9)3.1。

5 芳香卤代物和不饱和羧酸的Heck反应合成反式3-芳基不饱和酸示例103。

1.6 非共轭双键Heck反应示例 (10)3.2 不对称分子间Heck反应 (11)3。

3 非常用离去基团的Heck反应(Irina P。

Beletskaya Chem。

Rev. 2000，100，3009—3066） (11)3。

3。

1 重氮盐参与的Heck反应示例 (12)3.3.2 酰氯参与的Heck反应示例 (14)1。

前言通常把在碱性条件下钯催化的芳基或乙烯基卤代物和活性烯烃之间的偶联反应称为Heck反应。

自从20世纪60年代末Heck 和Morizoki独立发现该反应以来，通过对催化剂和反应条件的不断改进使其的应用范围越来越广泛,使该反应已经成为构成C-C 键的重要反应之一。

另外，Heck反应具有很好的Trans选择性R XPd(0)Z RZX = I, Br, OTf, etcZ = H, R, Ar, CN, CO2R, OR, OAc, NHAc, etc研究表明，Heck反应的机理有一定的规律,通常认为反应共分四步:（a)氧化加成（Oxidative addition）: RX (R为烯基或芳基，X=I > TfO 〉Br >〉Cl)与Pd0L2的加成，形成PdⅡ配合物中间体；（b）配位插入(Cordination—insertion):烯键插入Pd—R键的过程；（c）β—H的消除；（d)催化剂的再生：加碱催化使重新得到Pd0L2。

羊蜡酸插层制备介观层状羟基磷灰石赵大洲【摘要】羊蜡酸作为一种典型的有机脂肪酸，因具有良好的生物键合能力而受到医学界的广泛关注．本文作者在醇／水混合溶剂中，通过羊蜡酸插层制备了介观层状羟基磷灰石，并采用红外光谱、X 射线衍射以及透射电镜进行了相应的表征．分析结果显示，羊蜡酸在形成层状介观结构中起着重要的作用，所制备的样品层间距约为3．1 nm ，羊蜡酸层与羟基磷灰石层呈现交替叠加的层状结构．%As a typical organic fatty acid ,capric acid has been widely concerned in the medical community because of its good biological bonding ability .In this paper ,mesoscopic lamellar hydroxyapatite (ML-HA) was prepared by capric acid intercalation .The products were charac-terized by infrared spectroscopy ,X-ray diffraction and transmission electron microscopy .The analysis results reveal that capric acid played a decisive role in the formation of lamellar meso-structures .The lamellar spacing of the sample is about 3 .1 nm with the layered structure of capric acid layer and hydroxyapatite layer alternately superimposed .【期刊名称】《化学研究》【年(卷),期】2016(027)002【总页数】4页(P246-249)【关键词】羊蜡酸;羟基磷灰石;介观;插层【作者】赵大洲【作者单位】陕西学前师范学院化学与化工系，陕西西安 710100【正文语种】中文【中图分类】O611.4有机脂肪酸是生物机体能量来源的主要物质之一，通式为CnH2n+1COOH，在氧气充足的情况下可被氧化为二氧化碳和水，释放出大量能量，在生物医学领域有着潜在的应用价值. 除此之外，有机脂肪酸还可应用于日用化学工业中，包括化妆品、洗涤剂以及涂料等[1-4]. 羊蜡酸又叫癸酸，是一种人体必需脂肪酸，不仅在降血脂和防治冠心病方面有着重要的作用，而且还能促进儿童的生长发育和智力发育. 羟基磷灰石 (HA)是一种生物相容性较好的活性材料，被广泛应用于牙齿和骨骼的修复领域[5-12]. 介观羟基磷灰石具备可调控的纳米结构，成为近年来研究者们关注的热点. 例如，利用不同浓度的聚醚 F127 制备具有两类介观孔径尺寸的羟基磷灰石[13]. 介观羟基磷灰石的形态和结构决定了其不同的应用价值，其中层状羟基磷灰石因具有可调节的纳米级层间距而备受关注[14-15]. 本文作者在醇/水混合溶剂中，采用羊蜡酸插层，成功制备了介观层状羟基磷灰石，并进行了机理探讨.1.1 实验仪器及药品样品的红外谱图采用 Nicolet Impact-410 型 FTIR 红外光谱仪进行表征；样品的小角扫描采用 D8 FOCUS 型粉末X射线衍射仪进行表征；样品的广角扫描采用SHIMADZU XRD-6000型X射线衍射仪进行测定；采用 HITACHI H-8100 型透射电子显微镜观测样品的形貌.硝酸钙、磷酸氢二铵、氢氧化钠和无水乙醇均购自北京化工厂；羊蜡酸购自国药集团化学试剂有限公司. 以上所有化学药品均属于分析纯.1.2 实验过程样品的制备过程均在体积比为1∶1的醇水混合溶剂中进行. 配制下述3种溶液：溶液A：将 1.9 g磷酸氢二铵加入到 30 mL 醇水混合溶剂中，均匀搅拌30 min，静置，记为溶液A.溶液B：将 3.2 g 羊蜡酸和 5.9 g 硝酸钙依次加入到30 mL的醇水混合溶剂中，均匀搅拌30 min，静置，记为溶液B.溶液C：将 8 g 氢氧化钠固体溶解于100 mL 醇水混合溶剂中，均匀搅拌 30 min，记为溶液C.将溶液A与溶液B混合，持续搅拌 1 h，向混合液中加入 20 mL 溶液 C，所得混合液在 35 ℃继续搅拌 4 h后得到悬浊液，调节其 pH为 10；将反应液全部转入到 100 mL 的不锈钢反应釜中，在 100 ℃下处理1 d；所得产物经过冷却、过滤、洗涤、干燥，最终得到由羊蜡酸插层合成的介观层状羟基磷灰石，标记为 ML-HA.2.1 红外光谱分析图1是样品 ML-HA 的红外光谱图. 从图中既可以观察到羟基磷灰石的特征吸收峰，又可以观察到羊蜡酸的特征吸收峰. 其中，在 1 032 cm-1，850 cm-1 和 565 cm-1 处出现的 PO43-吸收峰与 3 150-3 650 cm-1 范围内出现的 -OH 振动峰均为羟基磷灰石的特征吸收峰. 在 1 581 cm-1 和 1 542 cm-1处出现的 -COO- 的伸缩振动峰以及在 2 950 cm-1 和 2 880 cm-1处出现的 -CHx的伸缩振动峰归属于羊蜡酸的特征吸收峰，说明羊蜡酸与羟基磷灰石已经成功复合.2.2 X射线粉末衍射谱图分析图2是样品 ML-HA 的小角X射线衍射谱图. 由图可知在2θ为2.98°、5.98°和8.96°处出现衍射峰，分别标记为 (001)、(002) 和 (003)，说明样品 ML-HA 属于介观层状结构.相应的小角衍射数据见表1，依据布拉格方程λ= 2d sin θ(其中λ = 1.541 8 nm，d 为层间距，θ是布拉格角) 计算出样品 ML-HA 的周期性层间距是2.97 nm. 同时，为了进一步研究在形成介观层状结构的过程中羊蜡酸所起的重要作用，我们做了对比实验，制备出未加羊蜡酸的样品 HA，其方法与1.2相同. 图 3 是样品 ML-HA 和 HA的广角X射线衍射谱图. 二者相比较，其衍射峰位基本一致，然而HA 在小角衍射区域并未出现衍射峰. 上述实验结果说明羊蜡酸在形成介观层状结构中起着极为重要的作用.2.3 透射电镜分析透射电镜照片可以更加直观的观察到样品的微观结构. 图 4a 是样品 ML-HA 的透射电镜照片，从图中能清晰地观察到样品呈现黑白相间的层状结构，其中白色区域为羊蜡酸层，黑色区域为羟基磷灰石层，进一步说明样品 ML-HA 是羊蜡酸与羟基磷灰石交替叠加的层状结构. 图 4b 为样品 ML-HA 的高分辨透射电镜照片，从图中可以计算出样品的周期性层间距约为 3.1 nm.2.4 机理分析介观层状羟基磷灰石的形成过程属于协同模板法. 首先，在反应初期，呈现阴性的羊蜡酸与无机 Ca2+阳离子通过静电作用结合在一起；然后，在反应体系中加入 PO43- 与 OH-，使体系中的 Ca2+与 PO43-结合形成更稳定的以羊蜡酸为中间层的介观层状磷酸三钙，其介观层状结构由小角 XRD 谱图 (图5) 分析得知. 最后，经过水热处理，由图5 分析得知，样品介观层状磷酸三钙按照阴离子电荷密度和形态需求自发的重组转化为羊蜡酸层与HA层交替排列的层状结构 ML-HA. 本文作者以生物相容性较好的羊蜡酸插层制备了有序的介观层状羟基磷灰石. XRD 与TEM表征分析表明，样品层间距约为3.1 nm. 该研究成果在工业催化氧化、水质监测以及药物缓释等领域具有一定的应用前景.【相关文献】[1] SONG S K, DONG L J, CHEN S, et al. Stearic-capric acid eutectic/activated attapulgiate composite as form-stable phase change material for thermal energy storage [J]. Energy convers Manage, 201 4, 81: 306-311.[2] SAN A. Thermal reliability test of some fatty acids as PCMs used for solar thermal laten t heat storage applications [J]. Energy convers Manage, 2003, 44 (14): 2277-2287.[3] 付路军, 董发勤, 杨玉山, 等. 二元脂肪酸/SiO2 复合相变储能材料的制备与表征[J]. 功能材料, 2013, 44 (4): 1-4.[4] 陈江, 江纪修, 李炜坪. 抗癌药物载体——磁流体的制备及其性质研究[J]. 中国医院药学杂志, 1997, 17 (4): 163-166.[5] LEGEROS R. Effect of carbonate on the lattice parameters of apatite [J]. Nature, 1965, 2 06: 403-404.[6] KIKUCHI M, ITOH S, ICHINOSE S, et al. Self-organization mechanism in a bone-like hydroxyapatite/collagen nanocomposite synthesized in vitro and its biological reactio n in vivo [J]. Biomaterials, 2001, 22: 1705-1711.[7] JALOTA S, BHADURI S B, TAS A C. A new rhenanite (beta-NaCaPO4) and hydroxyapatite biophasic biomaterial for skeletal repair [J]. J Biomed Mater Res Part B, 2007, 80B: 304-316.[8] NARAYAN R J, HOBBS L W, JIN C M, et al. The use of functionally gradient materials in medicine [J]. Jom 2006, 58: 52-56.[9] WATARI F, YOKOYAMA A, OMORI M, et al. Biocompatibility of materials and developm ent to functionally graded implant for bio-medical application [J]. Compos Sci Technol, 2004, 64: 893-908.[10] FRAKENBURG E, GOLDSTEIN S, BAUER T, et al. Biomechanical and histological evaluat ion of a calcium phosphate cement [J]. Journal of Bone & Joint Surgery 1998, 80: 1112-1114.[11] YUAN H P, LI Y B, DE BRUIJN J D, et al. Tissue responses of calcium phosphate cemen t: a study in dogs [J]. Biomaterials, 2000, 21: 1283-1290.[12] THOMPSON J B, KINDT J H, DRAKE B, et al. Bone indentation recovery time correlates with bond reforming time [J]. Nature, 2001, 414: 773-776.[13] ZHAO Y F, MA J. Triblock co-polymer templating synthesis of mesostructured hydroxyapatite [J]. Micropor Mesopor M ater, 2005, 87 (2): 110-117.[14] 黄占杰. 磷酸钙陶瓷生物降解研究的进展[J]. 功能材料, 1997, 28: 1-4.[15] KASTEN P, LUGINBUHL R, VAN GRIENSVEN M, et al. Comparison of human bone mar row stromal cells seeded on calcium-deficient hydroxyapatite, beta-tricalcium phosphate and demineralized bone matrix [J]. Biomaterials, 2003, 24: 2593-2603.。

假耧斗菜中化学成分的研究目的研究假耧斗菜中的化学成分。

方法运用多种方法对其化学成分进行纯化和鉴定，并运用3-（4，5-二甲基吡啶-2）-5-（3-羧基甲氧基苯基）-2-（4-磺苯基）-2-氢-四唑盐（MTS）比色法考察了化合物Ⅰ和Ⅱ的对肺癌细胞H460、人乳腺癌细胞MCF-7和人肝癌细胞Hep G2的体外抗肿瘤活性。

结果共分离得到7个化合物，分别为：Paraquinin A（Ⅰ）、Praquinin B（Ⅱ）、小檗碱（Ⅲ）、Menisdaurin（Ⅳ）、3，4-二甲基苯甲酸（Ⅴ）、对羟基苯甲酸（Ⅵ）、己内酰胺（Ⅶ），抗肿瘤活性结果显示化合物Ⅰ和Ⅱ均无细胞毒活性。

结论化合物Ⅲ～Ⅶ为首次从该植物中分离得到，并首次测试了化合物Ⅰ和Ⅱ的抗肿瘤活性。

[Abstract] Objective To investigate the chemical constituents of Paraquilegia microphylla. Methods The constituents were separated and purified by chromatographic methods，and their structures were elucidated by spectroscopic methods，compounds Ⅰand Ⅱwere evaluated for their cytotoxicity against human H460 non-small cell lung cancer cells （H460），the breast cancer cell line MCF-7 （MCF-7）and human hepatocellular cell line Hep G2 （Hep G2）by [3-（4，5-dimethylthiazol-2-yl）-5-（3-carboxymethoxyphenyl）-2-（4-sulfophenyl）-2H-tetrazolium （MTS）method. Results Seven known compounds were obtained and1identified as Paraquinin A （Ⅰ），Praquinin B （Ⅱ），Berberine （Ⅲ），Menisdaurin （Ⅳ），3，4-dimethyl benzoic acid （Ⅴ），4-hydroxybenzoic acid （Ⅵ）and caprolactam （Ⅶ），the results of the cytotoxicity about compounds Ⅰand Ⅱwere inactive against several human cancer cells. Conclusion Compounds Ⅲ-Ⅶare isolated from this plant for the first time，the cytotoxicity of compounds Ⅰand Ⅱagainst several human cancer cells were tested for the first time.[Key words] Paraquilegia microphylla；Chemical composition；Flavonoid C-glycoside；Cyanogenic glycoside假耬斗菜Paraquilegia microphylla （Royle）Drunmm.Et Hutch.为毛茛科的假耧斗菜属植物，主要分布于西藏、四川、甘肃、云南、青海等地。

German Edition:DOI:10.1002/ange.201607177Heterocycle SynthesisInternational Edition:DOI:10.1002/anie.201607177Transition-Metal-Free Synthesis of N -Hydroxy Oxindoles by an Aza-Nazarov-Type Reaction Involving Azaoxyallyl CationsWenzhi Ji,Yahu A.Liu,and Xuebin Liao*Abstract:A novel transition-metal-free method to constructN-hydroxy oxindoles by an aza-Nazarov-type reaction involv-ing azaoxyallyl cation intermediates is described.A variety of functional groups were tolerated under the weak basic reaction conditions and at room temperature.A one-pot process was also developed to make the reaction even more practical.This method provides alternative access to oxindoles and their biologically active derivatives.O xindoles are widely present in natural products,[1]and alsoin pharmacologically active compounds such as NMDA antagonists,[2]calcium channel blockers,[3]and agents with anti-angiogenic,[4]anticancer,[5]and analgesic effects [6](Figure 1).Past decades have seen the development ofnumerous methods to synthesize oxindoles containing a vari-ety of functionalities,[7]and these methods include the derivatization of either isatin or indoles,[8]radical cyclizations of aniline derivatives,[9]Friedel–Crafts-type cyclizations,[10]and transition-metal-mediated reactions,[11,9n]among others.One of the most efficient modes to construct oxindoles is their conversion from a -halo anilides (Scheme 1).As early as the 1930s,Stoll Øet ed AlCl 3to promote cyclization froma -halo anilides,[10a,b]but the reaction conditions were very harsh and problematic with some substrates (Scheme 1a).Some of the other preparations of oxindoles from a -halo anilides include Buchwald s synthesis of oxindoles by a palla-dium-catalyzed C ÀH functionalization [11a]and Lei s nickel-catalyzed cyclization.[11p]Recently,Yu and co-workers reported another method to convert 2-bromoanilides,con-taining two electron-withdrawing substituents,into 3,3-dis-ubstituted oxindoles by visible-light-promoted photoredox catalysis.[9t]However,most of these reactions require costly metal catalysts which can contaminate products.Transition-metal-free reactions have emerged in recent years as important methods for the formation of C ÀC,C ÀN,C ÀO,and even C ÀS bonds.[12]Although typical examples of metal-free cyclizations to prepare oxindoles are processes involving radicals,[9a–e]a potassium tert -butoxide promoted synthesis of oxindoles reported by the group of Bolm was believed to proceed through an S N Ar reaction.[13]Addition-ally,both the groups of Zhu [14]and Zhao [15]developed metal-free approaches to oxindoles using a hypervalent iodine(III)reagent,but the reaction has limited scope and requires an external oxidant.Herein,we describe a transition-metal-free and oxidant-free access to oxindoles under mild reaction conditions.Azaoxyallylic cations are reactive intermediates which have not yet been studied extensively.In the 1960s,the azaoxyallyl cation was first suggested as an intermediate when Sheehan studied a -lactam chemistry.[16]In 1993,the group of Kikugawa showed evidence for azaoxyallyl cation intermedi-ates,[17]but there had not been much progress until Jeffrey and co-workers reported the first practical [4+3]cycloaddition involving azaoxyallyl cations.[18,19]Very recently,the groups of Jeffrey [20]and Wu,[21]and ourselves [22]reported a dearomative [3+2]cycloaddition of azaoxyallyl cationic intermediates.Our group has also explored the application of azaoxyallyl cations as synthons in synthetic approaches towards (Æ)-minfien-sine.[22]Considering that this intermediate could be trappedbyFigure 1.Representative natural products and pharmacologically active compounds containing oxindolecore.Scheme 1.Access to oxindoles from a -halo anilides.[*]W.Ji,Prof.Dr.X.LiaoSchool of Pharmaceutical Sciences,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases Tsinghua University (China)E-mail:************************ Dr.Y .A.LiuMedicinal Chemistry,Genomics Institute of the Novartis Research Foundation,San Diego,CA 92121(USA)Supporting information and the ORCID identification number(s)for the author(s)of this article can be found under:/10.1002/anie.201607177.132862016Wiley-VCH Verlag GmbH &Co.KGaA,WeinheimAngew.Chem.Int.Ed.2016,55,13286–13289a benzene ring to construct an oxindole skeleton,we initiated our screenings to generate azaoxyallyl cations from anilides under mild reaction conditions:a KHCO 3/1,1,1,3,3,3-hexa-fluoro-2-propanol (HFIP)system.It was found that the substituent on the anilide nitrogen atom is a key factor,as no reaction occurred when the substituent was H,methyl,methoxy,or benzyl (Table 1,entries 1–4).To our delight,when a -bromo-N -hydroxy anilide (7,R =OH)was subjected to the system,[20–22]the desired oxindole 8(R =OH)was obtained in 90%yield (entry 5).Thus,7(R =OH)was chosen as the model substrate for the initial survey.Replacing KHCO 3with either K 2CO 3or Et 3N as the base resulted in lower yield (entries 6and 7).The solvent was so crucial that the reaction conducted in common solvents gave the elimination product 9as the main product without forming 8(entries 8–11).Having identified the optimized reaction conditions,we next explored the substrate scope.A variety of N-hydroxy anilides were subjected to the KHCO 3/HFIP reaction system (Scheme 2).Functional groups such as methyl,methoxy,halogens,ester,nitrile,or hydroxy were found to be well tolerated in the system (11a –m ).The position of substituents at the para,meta ,or ortho positions did not affect the reaction.The substituted anilides with electron-withdrawing groups tended to have poor yields (11i ,j ).Spiro-oxindoles (11n ,o )with five-membered or six-membered rings were readily prepared in this method.Both 3-monosubstituted and 3,3-disubstituted substrates gave oxindoles in good yields (11p –t ),but the former (11p –s )reacted more slowly (12h)than did the latter (11t ).Besides a -bromo-N -hydroxy ani-lides,a -chloro-N -hydroxy anilide (11r )also reacted smoothly.Since N-hydroxy anilides can be prepared readily by reacting phenylhydroxylamine (12)with either acyl chloride or bromide,[23]we turned our attention to testing the possibility of a one-pot process for the synthesis of 11and 8(Scheme 3).In the one-pot process,2-bromo-2-methylpropa-noyl bromide (13;R 2=R 3=Me,X 1=X 2=Br)was added dropwise to a mixture of 12and KHCO 3in ether,withsubsequent evaporation of the ether solvent and addition of HFIP .The reaction mixture was then stirred for another 5hours at room temperature,thus resulting in the desired product 8a in 68%yield.Because various phenylhydroxyl-amines and acyl halides are either commercially available or can be prepared readily,this one-pot procedure is more practical than the two-step method,albeit in lower,but acceptable yield (11g ,11q ,11r ,11u –z ).Given the versatility of the one-pot process,it was applied to the synthesis of the progesterone receptor antagonist 5[24](Scheme 4).The synthesis began with treatment of N -(4-bromophenyl)hydroxylamine (14)with the acyl bromide 15in a one-pot process to give the oxindole 11f in 55%yield.The oxindole 11f was then reacted with the boronic acid 16under Suzuki coupling conditions to afford the precursor 17in 72%yield.[25]Cleavage of the N ÀO bond of 17afforded 5in 81%yield.[26]It was found that when the substituent on the anilide nitrogen atom was either H,methyl,benzyl,or methoxy,the reaction did not afford the desired product 8.In addition,an attempt with N -benzyl-2-bromo-N -hydroxy-2-methylpropa-namide (18)under the standard reaction conditions to prepare the six-membered ring compound 19gave the olefin 20in almost quantitative yield without even trace amount of 19formed (Scheme 5).Thus,the reactivity of 7can possibly be ascribed to the nitrogen atom attached directly to the benzene ring.Based on these results and previous mechanistic studies of azaoxyally cations,[17–21]we herebyTable 1:Optimization of the reaction conditions.[a]Entry R Base Solvent Yield [%][b]1H KHCO 3HFIP n.r.2Me KHCO 3HFIP n.r.3Bn KHCO 3HFIP n.r.4OMe KHCO 3HFIP n.r.5OH KHCO 3HFIP 906OH Et 3N HFIP 837OH K 2CO 3HFIP 528OH KHCO 3THF no 9OH KHCO 3CH 2Cl 2no 10OH KHCO 3MeCN no 11OHKHCO 3tolueneno[a]Reaction conditions:7(0.3mmol,1.0equiv)and base (1.1equiv)in solvent (2mL)at room temperature (RT)for 5h.[b]The yield is that of isolated product.n.r.=no reaction,no =no desired product 8,THF =tetrahydrofuran.Scheme 2.Substrate scope for the reaction.Yield is that of the isolated product.X =Br.Reaction conditions:10(0.3mmol,1.0equiv),and KHCO 3(1.1equiv)in HFIP (2mL)at room temperature (RT)for 5h.[a]Reaction time:12h.[b]X =Cl.12h.13287Angew.Chem.Int.Ed.2016,55,13286–132892016Wiley-VCH Verlag GmbH &Co.KGaA,Weinheimpropose one possible pathway in Scheme 6.Dehydrohaloge-nation of 7a leads to the azaoxyallyl cation 21,which is further stabilized by delocalization of positive charge to generate the more stable form 22.Then,a 4p electrocycliza-tion occurs to afford the final product 8a .[28]In the azaoxyallyl cation,the lone pair of electrons on the hydroxy played a pivotal role in stabilizing the cation.[17–21]Additionalevidence to support this proposed mechanism is that the anilides substituted with electron-withdrawing groups [EtOC-(O)and CF 3]formed the desired products in poor yields (Scheme 2;11i ,j ).In addition,use of HFIP as the solvent is the key,since it presumably stabilizes the transition state through hydrogen-bond interactions with the oxygen atom of the azaoxyallyl cation.[18–21,27]To conclude,we developed a transition-metal-free method to construct oxindoles by an aza-Nazarov-type reaction involving azaoxyallyl cation intermediates.The reaction can be carried out under very mild reaction conditions and has broad functional-group tolerance.In addition,a one-pot procedure was developed to make the method yet more practical.This reaction provides an alter-native access to oxindoles and their biologically active derivatives.More detailed mechanistic studies are ongoing and will be reported in due course.AcknowledgmentsThis work was supported by the Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,the Tsinghua-Peking Centre for Life Sciences and “1000Talents Recruitment Program”.Keywords:azaoxyallylic cations ·cyclizations ·heterocycles ·oxindoles ·synthetic methodsHow to cite:Angew.Chem.Int.Ed.2016,55,13286–13289Angew.Chem.2016,128,13480–13483[1]a)C.V .Galliford,K.A.Scheidt,Angew.Chem.Int.Ed.2007,46,8748;Angew.Chem.2007,119,8902;b)C.Marti,E.M.Carreira,.Chem.2003,2209.[2]T.H.Kang,Y.Murakami,K.Matsumoto,H.Takayama,M.Kitajima,N.Aimi,H.Watanabe,Eur.J.Pharmacol.2002,455,27.[3]A.M.Swensen,J.Herrington,R.M.Bugianesi,G.Dai,R.J.Haedo,K.S.Ratliff,M.M.Smith,V .A.Warren,S.P .Arneric,ljee,D.Parker,T.P .Snutch,S.B.Hoyt,C.London,J.L.Duffy,G.J.Kaczorowski,O.B.McManus,Mol.Pharmacol.2012,81,488.[4]J.L.Whatmore, E.Swann,P 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海洋生物海绵中溴吡咯生物碱的研究进展高荔【期刊名称】《《药学研究》》【年(卷),期】2019(038)010【总页数】8页(P600-607)【关键词】海绵; 溴吡咯生物碱; 分离; 合成【作者】高荔【作者单位】山东省体检办公室山东济南250014【正文语种】中文【中图分类】R282.77这个美丽的蓝色星球上，海洋面积十分广大，占地球的四分之三。

众多的海洋生物在海洋中共生共存，相互依赖，它们在这样相对稳定的环境中繁衍生息。

随着科学技术的不断进步，人类把探索的触角伸向了广阔无垠的海洋。

科学家从众多的海洋生物中提取到了许多有效成分，这些成分与陆地生物中所提取的成分截然不同。

因此，海洋生物的次级代谢产物在化学结构和药理活性方面也与陆生生物有着较大的差别，在医药领域有着无限的开发潜力和巨大的研究价值[1]海洋生物品种多、数量大，海绵就是其中非常重要的一种。

作为最原始多细胞动物的海绵，细胞已经发生分化，但仍未形成组织。

因为机体表面存在很多小孔，所以在动物分类学上属于多孔动物门，海绵大多生活在海洋中一些非常坚硬的物质(如：礁石、珊瑚等)上。

在长期的生物进化过程中，海绵与放线菌等微生物形成了极其密切的共生关系,进而产生了许多化学结构新颖且多种多样、药理活性丰富且良好的次级代谢产物[2]。

长期以来，来自各个国家和地区的科学家们通过不断的努力，已经研究了地球上不同海域海绵的活性化学化学成分。

对于那些有明确药理活性的化合物，科学家们还对其生物合成途径进行进一步探究，试图找到该类化合物的人工合成方法，造福人类。

海水中含有大量的盐分，即具有丰富的氯离子(Cl-)。

同时，还含有大量的溴离子(Br-)和较少量的碘离子(I-)。

这些卤素离子，广泛参与海洋生物的生物合成过程中的各种卤化反应，最终产生大量带有卤素原子的化合物。

含有卤素原子的天然药物，例如抗生素金霉素和氯霉素、抗真菌药灰黄霉素等，它们均具有较为独特的生物活性。

由此可见，含有特殊结构的生物碱成分也可能含有某种特别的药理活性，非常具有研究价值。

化学试剂,2007,29(1),53～54吲唑的简便合成蔡可迎3,宗志敏,魏贤勇(中国矿业大学化工学院,江苏徐州　221008)摘要:以邻硝基甲苯为原料,在乙醇钠催化下与草酸二乙酯缩合,然后经水解、双氧水氧化、盐酸酸化得到邻硝基苯乙酸,收率62%。

邻硝基苯乙酸用8%硫化铵溶液在回流温度下还原2h 后再进行重氮化反应,将得到的重氮盐溶液于室温放置24h 得到吲唑,收率71%。

两步总收率44%。

关键词:吲唑;邻硝基苯乙酸;合成中图分类号:O626 文献标识码:A 文章编号:025823283(2007)0120053202收稿日期:2006205225基金项目:江苏省高新技术产业发展项目(J H B05233)。

作者简介:蔡可迎(19702),男,江苏沛县人,博士生,讲师,从事有机中间体的合成研究。

吲唑是重要的有机合成中间体,其许多衍生物具有药物活性[123]。

例如,吲唑环在Cu (Ⅱ)催化下与芳基硼酸反应可得12芳基吲唑[4],12芳基吲唑可作避孕药[5];吲唑与酸酐或酰氯反应可得N 2酰基吲唑[6],其中一些N 2酰基吲唑具有驱虫活性。

吲唑的合成方法主要有:1)以吲唑232羧酸为原料进行脱羧反应得到[7];2)以32腈基吲唑为原料进行脱腈基反应得到[7];3)以32氯吲唑为原料经脱氯得到[8];4)邻甲基苯胺与乙酐、醋酸钾和亚硝酸异戊酯的混合物料反应得到[9];5)42醛基吡唑与丁二酸二乙酯在叔丁醇钾催化下缩合得到[10]。

方法1)、2)和3)的问题是原料不易获得;方法4)的反应体系复杂,导致后处理困难,收率低;方法5)需在强碱催化下进行,条件苛刻。

以价廉易得的邻硝基甲苯为原料,在乙醇钠催化下与草酸二乙酯进行缩合反应,再经水解、氧化及酸化制得邻硝基苯乙酸,后者通过还原、重氮化、环合及脱羧可得到吲唑:1　实验部分111　主要仪器与试剂惠普HP 6890/5973型气相色谱/质谱联用仪;美国Nicolet 公司Magna 2IR 560红外光谱仪。

经典化学合成反应标准操作Heck 反应目录1. 前言 (2)2. 分子内的Heck反应 (3)2.1 生成烯基取代的反应 (3)2.1.1 分子内Heck反应化生成环外双键示例 (4)2.2 形成季碳中心的反应 (5)2.2.1 分子内不对称Heck反应示例 (6)2.3 多烯大环的合成 (6)2.2.1 Heck反应用于合成大环多烯示例 (7)3. 分子间的Heck 反应 (8)3.1 常规分子间Heck反应 (8)3.1.1 Pd(OAc)2-P(o-tol)3体系用于不饱和羧酸酯的Heck反应标准操作三 (9)3.1.2 不饱和酮的Heck反应标准操作 (10)3.1.3 杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作一 (10)3.1.4 杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作二 (10)3.1.5 芳香卤代物和不饱和羧酸的Heck反应合成反式3-芳基不饱和酸示例 .. 113.1.6 非共轭双键Heck反应示例 (11)3.2 不对称分子间Heck反应 (12)3.3 非常用离去基团的Heck反应（Irina P. Beletskaya Chem. Rev. 2000, 100,3009-3066） (12)3.3.1 重氮盐参与的Heck反应示例 (13)3.3.2 酰氯参与的Heck反应示例 (15)1. 前言通常把在碱性条件下钯催化的芳基或乙烯基卤代物和活性烯烃之间的偶联反应称为Heck反应。

自从20世纪60年代末Heck 和Morizoki独立发现该反应以来,通过对催化剂和反应条件的不断改进使其的应用范围越来越广泛,使该反应已经成为构成C-C键的重要反应之一。

另外，Heck反应具有很好的Trans选择性R XPd(0)Z RZX = I, Br, OTf, etcZ = H, R, Ar, CN, CO2R, OR, OAc, NHAc, etc研究表明，Heck反应的机理有一定的规律，通常认为反应共分四步：（a）氧化加成（Oxidative addition）: RX (R为烯基或芳基，X=I > TfO > Br >> Cl)与Pd0L2的加成，形成PdⅡ配合物中间体；（b）配位插入（Cordination-insertion）:烯键插入Pd-R键的过程；（c）β-H的消除；（d）催化剂的再生：加碱催化使重新得到Pd0L2。

通过1,3-偶极环加成反应合成3-吡咯螺环氧化吲哚的研究进展周英;张文会;张敏;彭礼军;黄俊飞;杨超;刘雄利;余章彪【摘要】作为一种重要的天然生物碱,吡咯螺环氧化吲哚骨架一直是天然产物化学和药物化学领域里的研究热点.由于含吡咯螺环氧化吲哚骨架分子广泛具有抗氧化、抗肿瘤等生物活性,近年来对其进行全合成和衍生化合成研究也持续升温.以各种取代的氨基酸为原料和各种取代羰基原位产生亚胺叶立德,然后再和α,β-不饱和烯烃发生1,3-偶极[3+2]环加成反应是合成各种吡咯螺环氧化吲哚类化合物的一种有效方法.本文对这一合成方法在近几年的研究进展进行了综述.【期刊名称】《山地农业生物学报》【年(卷),期】2015(034)002【总页数】6页(P9-13,46)【关键词】亚胺叶立德;1,3-偶极环加成反应;吡咯螺环氧化吲哚;综述【作者】周英;张文会;张敏;彭礼军;黄俊飞;杨超;刘雄利;余章彪【作者单位】贵州大学药学院贵州省中药民族药创制工程中心,贵州贵阳550025;贵州大学药学院贵州省中药民族药创制工程中心,贵州贵阳550025;贵州大学药学院贵州省中药民族药创制工程中心,贵州贵阳550025;贵州大学药学院贵州省中药民族药创制工程中心,贵州贵阳550025;贵州大学药学院贵州省中药民族药创制工程中心,贵州贵阳550025;贵州大学药学院贵州省中药民族药创制工程中心,贵州贵阳550025;贵州大学药学院贵州省中药民族药创制工程中心,贵州贵阳550025;贵州大学药学院贵州省中药民族药创制工程中心,贵州贵阳550025【正文语种】中文【中图分类】R914.51 引言由于吡咯螺环氧化吲哚类化合物具有明确或潜在的生物和药物活性，近年来已被大家广泛关注［1］。

例如，spirotryprostatin A(1)［2］，pteropodine(2)［3］，alstonisine(3)［4］，elacomine(4)［5］，horsfiline(5)［6］，formosanine(6)［7］，rychnophylline(7)［8］等都是经典的含具有吡咯螺环氧化吲哚骨架的天然生物碱(见图1)。

天然产物化学常用参考文献一、图书（一）天然产物化学一般理论1. 林启寿编著, 中草药成分化学, 科学出版社, 19772. 徐任生主编, 天然产物化学, 科学出版社, 19973. 姚新生主编. 天然药物化学(第三版). 人民卫生出版社, 20024. 杨其菖编. 天然药物化学,中国医药科技出版社, 19975. R. D. H. Murray. Progress in the Chemistry of Organic Natural Products. Springer Wien New York, 2002（二）成分提取分离1. 上海药物研究所编著. 中草药有效成分提取与分离. 上海科学技术出版社, 19832. Richard J. P. Cannell. Natural Products Isolation.Humana Press, 19983. Raphael Ikan. Natural Products -- A Laboratory Guide (Second Edition). Academic Press, 19914. J. B. Harborne. Phytochemical Methods -- A Guide to Modern Techniques of Plant Analysis (Three edition). Chapman & Hall, UK, 1998（三）化合物结构解析1. 梁晓天. 核磁共振. 科学出版社,19762. 洪山海. 光谱解析法在有机化学中的应用. 科学出版社, 19803. 赵天增. 核磁共振氢谱. 北京大学出版社, 19834. 沈其丰. 核磁共振碳谱. 北京大学出版社, 19885. 姚新生主编. 有机化合物波谱解析. 中国医药科技出版社, 20016. Dudley H. Willeams等著. 王剑波, 施卫峰译. 有机化学中的光谱方法. 北京大学出版社, 20017. 苏克曼, 潘铁英, 张玉兰. 波谱解析法. 华东理工大学出版社, 20028. E. Pretsch, P. Buhlmann, C. Affolter. 荣国斌译. 波谱数据表--有机化合物的结构解析. 华东理工大学出版社, 20029. 宁永成编著. 有机化合物结构鉴定与有机波谱学. 科学出版社, 199910. 于德泉, 杨峻山主编. 分析化学手册第七分册核磁共振波谱分析. 化学工业出版社, 199911. 丛浦珠. 质谱学在天然有机化学中的应用. 科学出版社, 198712. Biemann K. Tables of Spectral Data for Structure Determination of Organic Compounds (Second edition). Berlin; New York : Springer-Verlag, 198913. Crews, Phillip. Organic structure analysis. New York : Oxford University Press, 1998.14. Robert M. Silverstein and Francis X. Webster.Spectrometric identification of organic compounds. (6th ed.) New York : Wiley, 1998.15. Joseph B. Organic structural spectroscopy.Prentice Hall, 1998.16. Laurence M. H., Timothy D.W. Introduction to organic spectroscopy. New York : Oxford University Press, 1997.17. Meier, Bernd Zeeh. Spectroscopic methods in organic chemistry. New York : G. Thieme,1997.18. EberhardBreitmaier ; translated by Julia Wade. Structure elucidation by NMR in organic chemistry : a practical guide. New York : Wiley, 1993.19. Field L. D., Sternhell S., Kalman J.R. Organic structures from spectra. (2nd ed.) New York : John Wiley, 1995.20. ErnoPretsch. Spectra interpretation of organic compounds. New-York: Cambridge: VCH, 1997.21. Pretsch. [et al. translated from the German by K. Biemann]. Tables of spectral data for structure determination of organic compounds (2nd ed.) New York: Springer-Verlag, 1989.22. Robert V. Hoffman. Organic chemistry : an intermediate text. Oxford University Press, 1997.23. Gerhard Quinkert, Ernst Egert, Christian Griesinger. Aspects of organic chemistry : structure. Cambridge : VCH, 1996.（四）化合物查询1. 江纪武、肖庆祥编著. 植物药有效成分手册. 人民卫生出版社(1986年2. 中国科学院上海药物研究所植化室编译. 黄酮体化合物鉴定手册, 科学出版社(1981)3. 中国医学科学院药物研究所编著. 中草药有效成分的研究. 北京人民卫生出版, 19724. 黄天守编. 化学化工药学大辞典. 台北市大学图书公司出版, 19825. Dictionary of Natural Products on CD-ROM.（五）生物活性检测药理实验H. G. 沃格尔, W. H. 沃格尔编著.杜冠华, 李学军, 张永祥等译. 药理学实验指南——新药发现和药理学评价. 科学出版社, 2001（六）中药材1. 江苏新医学院编. 中药大辞典(上, 下册), 上海科学技术出版社, 20002. 全国中草药汇编编写组编. 全国中草药汇编(上, 下册), 人民卫生出版社, 19733. 刘寿山编著. 中药研究文献摘要(共四册). 科学出版社4. 中国科学院南海海洋研究所编著. 中国海洋药用生物. 科学出版社, 19785. 候宽昭编著. 中国种子植物科属词典. 科学出版社, 1982（七）其他王北婴、李仪奎编. 中药新药研制开发技术与方法. 上海科学技术出版社, 2001二、期刊1. Journal of Asian Natural Product Research, 中国医学科学院药物研究所主办2. 中国药理学报, 中国药学会主办3. 药学学报, 中国药学会主办4. 中国药学杂志, 中国药学会主办5. 中国中药杂志, 中国药学会主办6. 中草药, 中草药信息中心站、天津药物研究院主办7. 天然产物研究与开发, 中国科学院成都分院主办8. 国外医学植物药分册, 国家医药管理局中草药情报中心站(天津)主办9. 国外医学中医中药分册, 中国中医研究所情报研究室主办10. Phytochemistry11. PlantaMedica12. Journal of Natural Product13. Chemical & Pharmaceutical Bulletin14. Natural Product Letter15. Natural Product Peport16. Chemistry of Natural Compounds17. Journal of American Chemical Society18. Lipid19. Sterol三、检索工具1. 中文科技资料目录中草药2. 中国药学文摘3. Chemical Abstracts4. The Merck Index5.Dictionary of Organic Compounds6.CRC Handbook of Data Organic Compounds7.Index Chemicus8. The Sadtler Standard Spectra Total Spectra Indes。