Part 10 Pd 催化的偶联反应
钯催化交叉偶联反应
钯催化的交叉偶联反应一、偶联反应综述1．交叉偶联反应偶联反应，从广义上讲，就是由两个有机分子进行某种化学反应而生成一个新有机分子的过程。
狭义的偶联反应是涉及有机金属催化剂的碳－碳键生成的反应，根据类型的不同，又可分为自身偶联反应和交叉偶联。
交叉偶联反应是一个有机分子与另一有机分子发生的不对称偶联反应。
2．碳碳键形成的重要性新碳－碳键的形成在有机化学中是极其重要的。
人们了解了天然有机物质的结构和性能，并根据有机物质的结构，通过碳原子组装成链，建立有机分子，最终实现天然有机物质的人工合成。
目前为止，人类已经利用有机合成化学手段创造出几千万种物质，且越来越多的有机物质已经广泛应用到制药、建材、食品、纺织等人类生活领域，我们的生活也几乎离不开有机物了。
合成药物、塑料等有机物质时，需要用小的有机分子将碳原子连接在一起构建新的复杂大分子，因而有机合成中高效的连接碳－碳键的方法是有机合成化学中的重要工具。
从以往该领域诺贝尔化学奖的授予情况也可以看出合成新碳－碳键的重要性:1912年维克多·格林尼亚因发明格林尼亚试剂——有机镁试剂获奖，1950年迪尔斯和阿尔德因发明双烯反应迪尔斯－阿尔德反应获奖，1979年维蒂希与布朗因发明维蒂希反应共同获奖，2005年伊夫·肖万、罗伯特·格拉布、理查德·施罗克因在有机化学的烯烃复分解反应研究方面作了突出贡献获奖。
3．有机合成中的钯催化交叉偶联反应随着时代发展，合成有机化学的研究愈加深入，20世纪后半期，科学家们发现了大量通过过渡金属催化来创造新有机分子的反应，促使有机合成化学快速发展。
特别是赫克、根岸英一和铃木章发现的钯催化交叉偶联反应，为化学家们提供了一个更为精确有效的工具。
三位科学家发现的钯催化交叉偶联反应中都使用了金属钯作为反应的催化剂，当碳原子与钯原子连在一起时，钯原子唤醒了“懒惰”的碳原子但又不至于使它太活泼，于是形成温和的碳－钯键，在反应过程中，钯原子又可以把别的碳原子吸引过来，形成另一个金属－碳键，此时两个碳原子都连接在钯原子上，它们的距离足够接近而发生反应，生成新的碳－碳单键。
钯催化交叉偶联反应
钯催化交叉偶联反应什么是钯催化交叉偶联反应？钯催化交叉偶联反应(Palladium-Catalyzed Cross-Coupling Reaction)是一种重要的有机合成反应。
它是一类碳-碳键构造的反应，是通过将两种不同的碳基官能团或碳碳键连接在一起，以形成新的C-C化合物。
反应机理在钯催化交叉偶联反应中，两个分子的有机基团进行偶联，然后由钯离子起催化作用，生成新的碳碳键。
催化剂形式上是Pd(0)配合物，反应机理如下：1.钯催化剂先通过脱对氢化学计量通常分配Pdcatalyst (I)。
2.钯催化剂进一步和配体形成配合物(PdL2)。
3.配合物和卤代烃发生交换生成过渡态PdL2(RX)。
过渡态中，钯离子与亲电吸引剂的卤素原子形成键；此过程中C-X钩体断裂，形成第一级碳中间体。
4.结合第二个有机基团生成PdL2(RY)介于新的物种。
5.最后的反应产物通常通过还原反应，将钯催化剂还原为Pd(0)。
应用钯催化交叉偶联反应已经成为有机合成中的重要反应之一，广泛应用于制药、化工、材料科学等领域。
其重要应用包括:•制备非对映选择性或对映选择性的C-C连接化合物。
•制备有机材料。
•合成复杂天然产物的合成方法研究。
反应类型钯催化交叉偶联反应可以根据反应物和类型进行分类。
最常用的交叉偶联反应类型是官能团反应 (Functional Group Coupling) 和碳-碳双键偶联反应 (Carbon-Carbon Double Bond Coupling)，这些反应分类包括下列:1.骨架化反应 (Fragmentation Reaction)2.偶联反应 (Cross-Coupling Reaction)3.代换反应 (Substitution Reaction)4.重排反应 (Rearrangement Reaction)反应优点由于钯催化交叉偶联反应具有高效性、选择性、重复性和收率高的特点，它已经成为有机化学领域极为重要的反应之一。
钯催化的偶联反应（1）
钯催化的偶联反应（1）背景五十年前，钯刚刚进入有机化学家的视野，当时的C-C键形成还主要依赖化学计量的反应——活泼的亲核试剂与亲电试剂反应。
上世纪六十年代末，Richard Heck 首先将钯引入了有机化学反应，在催化量的二价钯存在下完成了芳香化合物的偶联，这标志着在钯催化C-C键形成反应这一领域取得的引人注目的突破。
在接下来的很多年中，研究人员报道了更多钯介导的C-C偶联反应。
如今，钯催化的偶联反应为有机合成提供了很有用并且应用广泛的工具，其中有代表性的有Heck反应，Negishi反应和Suzuki反应，2010年的诺贝尔化学奖肯定了这种发现的重要性。
# 研究进展钯催化具有与众不同的特点与优势。
温和的反应条件减小了副产物的生成，因此可以完成高的立体选择性。
并且，钯催化的反应对于底物的官能团都有很好的耐受性，因此，相比于传统的化学计量的反应，利用钯催化可以用更少的步骤构建复杂的有机分子。
此外，配体和助催化剂可以对反应活性进行微调。
有机钯化合物对水和空气的高稳定性(除一些磷配合物外)使反应更容易加工，并且降低了成本。
那么，钯催化的偶联反应应用广泛也是情理之中的。
事实上，除了在均相溶液中的钯催化剂外，衍生出一系列全新的、高选择性的催化剂，近年来已经出现了高效的的多相（负载）钯催化剂，他们可以重复使用，因此在偶联反应中有很好的经济效益。
显然，很多交叉偶联反应已经足够高效地在工业上进行吨量级的合成，在过去的二十年中，这些钯催化的偶联反应已经从实验室中的克级合成转变为制药、农化和精细化工行业的吨级生产。
和所有钯催化的C-C偶联反应一样，Heck 反应与Heck-Matsuda 反应(Scheme 1.2)始于芳基卤化物对钯的氧化加成，但是如果另一个底物是烯烃，Heck反应的机理明显不同。
通常的偶联反应都在均相条件下进行，使用的膦配体要求隔绝氧气，而Matsuda 和 Kikukawa 将芳基卤化物替换为芳香重氮盐，这一优化条件使Heck反应能够兼容含氧的条件，不需要使用对氧气敏感的有机膦配体。
Pd 催化偶联反应
DOI:10.1002/anie.200602761Palladium-Based Catalytic Systems for the Synthesis of Conjugated Enynes by Sonogashira Reactions and Related AlkynylationsHenri Doucet*and Jean-Cyrille Hierso*AngewandteChemieKeywords:alkynes ·cross-coupling ·heterogeneous catalysis ·palladium ·sonogashira reactions8342007Wiley-VCH Verlag GmbH &Co.KGaA,WeinheimAngew.Chem.Int.Ed.2007,46,834–8711.IntroductionThe palladium-catalyzed cross-coupling between sp 2-hybridized carbon atoms (C(sp 2))aryl,heteroaryl,and vinyl halides and sp-hybridized carbon atoms of terminal acety-lenes (C(sp))pertains to the family of modern and extremely powerful synthetic methods for the synthesis of important organic intermediates.The conjugated p systems resulting from alkynylation reactions—conducted either with alkynyl-metal reagents or directly with terminal alkynes—are build-ing blocks often encountered within natural products,phar-maceutical molecules,synthetic agrochemicals,and molecular materials.The palladium/copper co-catalyzed alkynylation of aryl and vinyl halides is probably the most widely employed methodology to yield enynes;a simpler version of the reaction requires exclusively a palladium catalyst (widely known as copper-free alkynylation).Collectively,the seminal works by Stephens and Castro (1963),[1]Dieck and Heck (1975),[2]Cassar (1975),[3]and Sonogashira,Tohda,and Hagihara (1975)[4]have initiated an outstanding number of studies in the fields of organic chemistry,organometallic chemistry and catalysis,total syn-thesis,and material science.[5–8]The original reactions and their experimental conditions,as disclosed by the pioneering authors (Scheme 1),reveal both a straightforward applicabil-ity and a very large substrate range,which is probably at the origin of their success.Sonogashira and related alkynylation reactions have been covered in the last few years by several relevant reviews,inresearch.[5–19]Table 1lists these and other pertinent review articles related to the palladium-catalyzed synthesis of con-jugated enynes and the various applications of these reactions.In 2006Tykwinski and Shi Shun reviewed the synthetic efforts directed towards the synthesis of polyyne natural products,together with a highlight of the natural sources and biological relevance of some selected examples.[9]The impor-tant role of palladium-catalyzed alkynylations in total syn-thesis has been covered in a recent review by Nicolaou et al.[7]The performances of the current palladium catalysts with the highest turnover numbers (TONs)or turnover frequen-cies (TOFs)in homogeneous phase cross-coupling,including Sonogashira and related reactions,were critically examined by Farina in 2003;[10]Fu and Littke had previously covered the palladium-catalytic systems able to activate the relatively inert chloride substrates.[11]Several reviews have surveyed the results obtained for alkynylation reactions carried out in the presence of carbene ligands [12–15]or palladacyle com-plexes.[13,16]Conceptual advances by Tykwinski,[17]cross-coupling in water by GenÞt and Savignac,[18]and advances on mechanistic aspects by Jutand [19]have also been covered.In light of these recent reviews it appears that a critical discussion specifically devoted to all the different classes of catalytic systems proposed to date for homogenous andC onjugated alkynes are recurring building blocks in natural products,a wide range of industrial intermediates,pharmaceuticals and agro-chemicals,and molecular materials for optics and electronics.The palladium-catalyzed cross-coupling between sp 2-hybridized carbon atoms of aryl,heteroaryl,and vinyl halides with sp-hybridized carbon atoms of terminal acetylenes is one of the most important develop-ments in the field of alkyne chemistry over the past 50years.The seminal work of the 1970s has initiated an intense search for more general and reliable reaction conditions.The interest in the catalytic activation of demanding substrates,the need to minimize theconsumption of depletive resources,and the search for easy access to an increased variety of functionalized enynes has led to the current generations of high-turnover catalysts.This Review gives an overview of the highly efficient palladium catalyst systems for the direct alky-nylation of C(sp 2)halides with terminal alkynes,both in homogeneous and heterogeneous phases.From the Contents1.Introduction 8352.Sonogashira–Heck Alkynylations in the Homogeneous Phase 8363.Recyclable Systems for Sonogashira–Heck Alkynylations8504.Miscellaneous and Connected Studies8615.Summary and Outlook868[*]Dr.H.DoucetInstitut Sciences Chimiques de Rennes UMR 6226CNRS-UniversitØde Rennes “Catalyse et Organometalliques”Campus de Beaulieu,35042Rennes (France)Fax:(+33)2-23-23-69-39E-mail:henri.doucet@univ-rennes1.frDr.J.-C.HiersoLaboratoire de Synth se et Electrosynth se OrganomØtalliques associØau CNRS (UMR 5188)FacultØdes sciences Mirande UniversitØde Bourgogne9avenue Alain Savary,21078Dijon (France)Fax:(+33)3-8039-3682E-mail:jean-cyrille.hierso@u-bourgogne.frHomepage:http://www.u-bourgogne.fr/LSEO/Equipes/PagesEquipes/EquipeMEUNIER/JeanCyrHIERSO.html835Angew.Chem.Int.Ed.2007,46,834–871 2007Wiley-VCH Verlag GmbH &Co.KGaA,Weinheimheterogeneous Sonogashira–Heckalkynylation reactions would be timely and useful.Herein we compare the highly efficient palladium catalyst systems reported for the direct alkynylation of C(sp 2)halides with terminal alkynes in the presence (Sonogashira—Tohda–Hagihara reaction)and without (Dieck–Heck–Cassar alky-nylation)a copper co-catalyst.The advantages of the reactions being carried out in a homogeneous phase are covered in the first part,notably:1)high turnover numbers,2)the coupling of the widely available and low-cost aryl chlorides,3)milder reaction conditions and the minimization of the consumption of depletive resources.The second part isdevoted to the recyclable catalytic systems both in homoge-neous and heterogeneous phases:1)biphasic (and/or ther-momorphic)systems,2)colloidal and solid-supported cata-lysts,and 3)systems using unusual solvents,such as ionic liquids.The last part is a discussion on other closely related research in this field,especially:1)new activation processes (microwaves and sonication),2)catalytic systems using other metals and the so-called “metal-free”systems,and 3)recently disclosed unusual coupling partners.The remaining chal-lenges in the field as well as the desirable developments are outlined in the conclusion.In this Review,the literature cut-off on this very productive topic in organic chemistry and catalysis was the beginning of 2006.2.Sonogashira–Heck Alkynylations in the Homogeneous PhaseIn the last three decades a large number of palladium–ligand complexes (and even ligand-free catalytic systems)have been tested on homogeneous-phase Sonogashira–Heck–Cassar reactions.These studies have shown that virtually any palladium source is capable of reaching high TONs for facile reactions—such as the coupling of aryl iodides with phenyl-acetylene—provided appropriate reaction conditions are found.On the other hand,with less-reactive substrates—such as electron-rich or sterically congested aryl bromides,aryl chlorides,propargyl alcohols,or propargylamines—much lower TONs are generally obtained,and the ligands have a large influence on the outcome of the reactions.Therefore,the systematic study of TONs in palladium-catalyzed C ÀC bond-formation processes is an important area of research for future industrial applications.For this reason the focus herein is placed upon the TONs of the reactions rather than on the yields,which are generally high.The factors that affect the rates of the Sonogashira reaction are not completely understood,however,the steric and electronic properties of the ligands and catalysts are determining parameters.In the following,we discuss succes-sively the results of studies carried out on systems incorpo-rating either monophosphanes,carbenes,and di-,tri-,and tetradentate ligands,as well as palladacycles;herein emphasis is placed upon the alkynylation reactions which employed vinyl and aryl bromides or chloride substrates.Henri Doucet was born in Paris in 1967.He received his PhD in chemistry with Prof.P.H.Dixneuf and Dr.C.Bruneau at Rennes University.After postdoctoral positions at Oxford University (J.M.Brown)andNagoya University (R.Noyori),he moved to the University of Marseille as a CNRS researcher.His research interests include organic synthesis by metal-catalyzed process-es and ligand synthesis.At the end of 2006he joined Rennes University.Jean-Cyrille Hierso was born in Toulouse in 1971.He studied physical chemistry at the UniversitØP.Sabatier,where he worked on Pd nanochemistry (MS 1994,Dr.B.Chau-dret,LCC-CNRS)and on CVD for heteroge-neous catalysis (PhD 1997,Prof.P.Kalck).After postdoctoral research on scorpionate organometallic complexes (Prof.M.Etienne,LCC)and paints chemistry (Prof.J.Reedijk,Netherlands),in 2001he was appointed Maître de ConfØrences in Dijon.In 2006he was awarded his Habilitation on the syn-thesis of ferrocenyl polyphosphanes and their application in homogeneous catalysis.Scheme 1.Original conditions reported in pioneering works on alkynylation reactions of C(sp 2)halides.2007Wiley-VCH Verlag GmbH &Co.KGaA,Weinheim Angew.Chem.Int.Ed.2007,46,834–8712.1.High-Turnover Palladium–Ligand Catalyst Systems2.1.1.Palladium–Monophosphane SystemsThe Sonogashira–Heck coupling was originally carried out using amines as solvents.Thorand and Krause found that good yields were obtained when this reaction was carried out using2mol%[PdCl2(PPh3)2],4mol%CuI,and1.5equiv-alents of triethylamine in THF(Scheme2).For example,4-bromobenzaldehyde or4-bromoacetophenone gave the expected products with yields of99%and92%,respectively, when trimethylsilylacetylene was used.Moreover,these reactions were performed at room temperature.[20]Two years later,Fu,Buchwald,and co-workers deter-mined that[PdCl2(PhCN)2]/P(t Bu)3serves as an efficient and a versatile catalyst for a wide range of Sonogashira reactions of electron-poor or electron-rich aryl bromides at room temperature(Scheme3):4-bromoanisole couples with high efficiency,even the very electron-rich4-bromo-N,N-dimethylaniline reacts cleanly at room temperature,and Sonogashira couplings of sterically hindered aryl bromides can be achieved at room temperature.This study provided evidence of the usefulness of bulky,electron-rich phosphanes in palladium-catalyzed Sonogashira reactions.[21]The efficiency of the[Pd2(dba)3]/P t Bu3system in the absence of a copper co-catalyst was reported concomitantly by Böhm and Herrmann(Scheme4).[22]This system promotes the alkynylation of electron-rich,electron-poor,and sterically congested aryl bromides equally at room temperature,with-out the need for a CuI co-catalyst.This catalyst is highly active—only0.5mol%palladium and ligand are required. Both Et3N and THF can be employed as the solvent;Et3N plays an additional role of an organic base.The practical utility of trialkylphosphanes such as P t Bu3 can be compromised by their sensitivity to oxidation,which can render them difficult to handle.To address this problem, Netherton and Fu examined the conversion of air-sensitive trialkylphosphanes into storable,air-stable phosphonium salts by protonation of the phosphorus atom(Scheme5).The authors demonstrated that these robust salts can serve as direct alternatives to the corresponding phosphanes:a simple deprotonation by a Brønsted base under the reaction conditions releases the trialkylphosphane.[23]Table1:Review articles relating to the synthesis and application of enynes and polyynes,as well as to the catalytic systems developed for the alkynylation of halides(published after1999).Title Authors Ref. Synthesis of Naturally Occurring Polyynes R.R.Tykwinski,A.L.K.Shi Shun[9] Palladium-Catalyzed Cross-Coupling Reactions in Total Synthesis K.C.Nicolaou,P.G.Bulger,D.Sarlah[7] High-Turnover Palladium Catalysts in Cross-Coupling and Heck Chemistry:A Critical Overview V.Farina[10] Recent homogeneous catalytic applications of chelate and pincer N-heterocyclic carbenes E.Peris,R.-H.Crabtree[12] Dual role of nucleophiles in palladium-catalyzed Heck,Stille,and Sonogashira reactions A.Jutand[19] Palladium-Catalyzed Alkynylation E.-I.Negishi,L.Anastasia[6] Evolution in the Palladium-Catalyzed Cross-Coupling of sp-and sp2-Hybridized Carbon Atoms R.R.Tykwinski[17]Phospha-palladacycles and N-heterocyclic carbenes palladium complexes: efficient catalysts for CÀC coupling reactions W.A.Herrmann,K.Öfele,D.von Preysing,S.K.Schneider[13]N-Heterocyclic Carbenes:A New Concept in Organometallic Catalysis W.A.Herrmann[14] Palladium-Catalyzed Coupling Reactions of Aryl Chlorides A.F.Littke,G.C.Fu[11] Catalytic cross-coupling reactions mediated by palladium/nucleophilic carbene systems S.Nolan et al.[15] Development of Pd/Cu-catalyzed cross-coupling of terminal acetylenes with sp2carbon halides K.Sonogashira[5] Poly(arylethynylene)s:Syntheses,Properties,Structures,and Applications U.H.F.Bunz[8] Application of palladacycles in Heck-type reactions W.A.Herrmann,V.P.W.Böhm,C.-P.Reisinger[16] Recent developments of palladium(0)catalyzed reactions in aqueous medium J.-P.GenÞt,M.Savignac[18]Scheme2.Alkynylations of aryl bromides in THF.Scheme3.Sonogashira coupling of aryl bromides using a Pd/P t Bu3system.Scheme4.Heck coupling(copper-free)of aryl bromides using aPd/P t Bu3system.dba=trans,trans-dibenzylideneacetone.837Angew.Chem.Int.Ed.2007,46,834–871 2007Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim Following the reports by Fu,Buchwald,and Herrmann (Schemes 3and 4)Soheili et al.developed a copper-free alkynylation procedure for aryl bromides with P t Bu 3at room temperature (Scheme 6).With acetonitrile as the solvent and1,4-diazabicyclo[2.2.2]octane (DABCO)as the base,the reaction of activated and electron-rich aryl bromides with aromatic and aliphatic acetylenes proceeded in good yields.A lower conversion was obtained using 4-chloroacetophe-none.[24]The efficiency of bulky,electron-rich phosphane ligands was also developed by Köllhofer and Plenio.They obtained high TONs for the alkynylation of a wide variety of aryl bromides at higher temperatures than those employed before;Na 2[PdCl 4]/P t Bu 3was used as the catalyst while HN i Pr 2was used as the solvent and the base (Scheme 7).For example,a TON of 18600was obtained for the reaction of the deactivated aryl bromide N ,N -dimethyl-4-bromoaniline with phenylacetylene at 808C.[25]By using this catalytic system,the sterically congested 1-bromo-2,6-dimethylbenzene reacted with phenylacetylene to give the expected product with a TON of 16800.They also explored the potential of (1-Ad)2PBn (1-Ad =1-adamantyl)as the ligand for this coupling instead of P t Bu 3.The coupling of various aryl bromides with phenylacetylene at catalyst loadings as low as 0.005mol %occurred in excellent yields;P t Bu 3was found to be the superior ligand for most of the substrate combinations.These two sterically hindered and electron-rich phos-phane ligands were also found to be efficient for the coupling of aryl chlorides (Scheme 8).A variety of electron-poor,electron-rich,and sterically congested aryl chlorides were successfully alkynylated in good yields and TONs using 2mol %of the catalyst.The choice of the base was decisive for the success of this reaction.While alkynes and aryl bromides couple efficiently in the presence of HN i Pr 2,reactions with aryl chlorides were troublesome.The best solvents were toluene,xylene,and DMSO,and the best base Na 2CO 3.[26]The recycling possibilities using modified ligands of this kind has also been examined (see Section 3.1.1).[27–31]Probably the most impressive results for the activation of aryl have been reported by Gelman and Buchwald using dicyclohexyl(2’,4’,6’-triisopropylbiphenyl-2-yl)phos-phane as the ligand.They have developed a general protocol for the coupling of aryl chlorides and alkynes using a low catalyst loading in the presence of this sterically congested electron-rich ligand (Scheme 9).This method requires only 0.1mol %catalyst,moderate temperatures (70–958C),and tolerates electron-rich,electron-poor,and sterically con-gested aryl chlorides.They have also observed that the addition of CuI as a co-catalyst can inhibit the coupling reaction or lead to a decrease in the yield.A good functional group compatibility and a broad range of compatible alkynes characterize this new catalytic system.[32]For example,the reaction of 2-chloroanisole with phenylacetylene gave the coupling product with a TON of 950and in 95%yield.A sulfonated version of this ligand for a Sonogashira reaction in water has also been described (see Section 2.3).[33]A few other bulky and electron-rich phosphane ligands have been prepared and tested in the Sonogashira reaction.A palladium complex of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane has been shown to beanScheme 5.Air-stable phosphonium salts used in Sonogashira alkynyl-ations of arylbromides.Scheme 6.Heck alkynylation of aryl bromides and chlorides using a Pd/P t Bu 3system.Scheme 7.Sonogashira coupling of aryl bromides using Pd/P t Bu 3and Pd/(1-Ad)2PBnsystems.Scheme 8.Sonogashira alkynylation of aryl chlorides using Pd/P t Bu 3and Pd/(1-Ad)2PBn systems.2007Wiley-VCH Verlag GmbH &Co.KGaA,WeinheimAngew.Chem.Int.Ed.2007,46,834–871effective catalyst for the alkynylation of aryl bromides, including electron-rich or sterically congested ones(Scheme10).[34]Capretta and co-workers have also demonstrated that the phosphorinane family of trialkylphosphane ligands can be used in the Sonogashira reaction of aryl bromides (Scheme11).[35]The reactions were performed at room temperature in dioxane with HN(i Pr)2as the base and CuI as the co-catalyst.Wolf and Lerebours developed a combination of a palladium source and a phosphinous acid as the catalyst for a Sonogashira reaction that proceeds in water and in air without the need for an organic cosolvent(Scheme12,see also Section2.3).Disubstituted alkynes have been prepared in up to91%yield by the coupling of various aryl halides in the presence of tetrabutylammonium bromide and pyrroli-dine or NaOH using10mol%catalyst.[36]Zhang and co-workers have developed a copper-and amine-free Sonogashira reaction using readily prepared,air-stable aminophosphane ligands.The mild reaction conditions and the utilization of an inorganic base are the most attractive features of this reaction(Scheme13).The use of electron-rich and bulky ligands might make both the oxidative addition and the reductive elimination steps easier.However,these ligands have not yet been tested in the activation of aryl chlorides.[37] Martensson and co-workers have attempted to optimize the copper-free alkynylation reaction through careful choice of the solvent and base.Several reactions were conducted using4-trifluoromethyliodobenzene to examine the depend-ence of the alkynylation on the solvent,base,and ligand(such as AsPh3or P(OEt)3,Scheme14;see also Section4.3).[38][PdCl2(PCy3)2]showed high catalytic activity in the cross-coupling of aryl chlorides with a variety of terminal alkynes in DMSO at100–1208C under copper-free conditions and with Cs2CO3as the base(Scheme15).The advantages of this copper-free procedure include the availability and ease of handling of the catalyst,and a high catalytic activity for bothScheme9.Heck alkynylation(copper-free)of aryl chlorides using a Pd/PCy2(triisopropylbiphenylyl)system.Scheme10.Heck alkynylation of aryl bromides using a Pd/phospha-adamantane system.Scheme11.Sonogashira coupling of aryl bromides using a Pd/phos-phorinane system.Scheme12.Alkynylation in water employing a palladium–phosphinousacid complex as catalyst.Scheme13.Palladium/aminophosphane-catalyzed alkynylation of aryl bromides.Scheme14.Coupling of an aryl iodide using Pd/AsPh3and Pd/P(OEt)3 systems.839Angew.Chem.Int.Ed.2007,46,834–871 2007Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim electron-poor and electron-rich aryl chlorides.[39]A variety of functional groups including alcohols,esters,and ketones were tolerated under these conditions.Of the relevant useful procedures,a low temperature (À208C)Sonogashira reaction of aryl iodides has also been described in which tris(2,4,6-trimethylphenyl)phosphane was used as the ligand.[40]Catalytic protocols involving a combination of a palla-dium source and monophosphane ligands emerged as very powerful systems in the Sonogashira–Heck–Cassar alkynyl-ation reactions of demanding aryl bromide and chlorides.Some of the ligands in this category,especially the sterically congested and electron-rich P t Bu 3,(1-Ad)2PBn,dicyclo-hexyl(2’,4’,6’-triisopropylbiphenyl-2-yl)phosphane,and PCy 3have led to reactions with impressive TONs,even with deactivated aryl bromides or aryl chlorides.These palladium catalysts will likely play a leading role in the development of Sonogashira–Heck alkynylation reactions in the coming years;particularly if properties such as air-and moisture-insensitivity are developed,they could replace traditional systems with PPh 3ligands.2.1.2.Systems Incorporating CarbenesCarbene ligands have also been employed for homoge-neous-phase Sonogashira–Heck reactions (Schemes 16-18).[41–48]In all cases the alkynylation products were obtained,however,generally with low TON values.The highest TON of 540was reported by McGuiness and Cavell using a carbene–pyridine ligand for the coupling of 4-bromoacetophenone with phenylacetylene (complex A in Scheme 16).[41]Bulky phenanthracenyl-substituted imidazolium-derived carbene ligands have been investigated for the copper-free alkynylation of aryl bromides and iodides (Scheme 17).A remarkable dependence on the size of the ligand was found.[44]Palladium complexes of acyclic diaminocarbenes ligands were also found to catalyze the alkynylation of aryl bromides such as 2-bromotoluene or 2-bromoanisole in high yields (Scheme 18).[45]A palladium/imidazolium chloride system has been used to mediate the coupling reaction of aryl halides with alkynylsilanes.The combination of 3mol %Pd(OAc)2and 6mol %imidazolium chloride in the presence of Cs 2CO 3as the base proved to be an efficient system for the coupling of para -and ortho -substituted aryl bromides with alkynylsilanes in high yields and with TONs of 14to 33(Scheme 19).[46]It is noteworthy that the coupling of primary and secondary alkyl bromides with terminal alkynes using palla-dium–carbene complexes as catalysts has also recently been described (see Section 4.3).[47,48]Scheme 15.Copper-free alkynylation of aryl chlorides using the complex [PdCl 2(PCy 3)2].Cy =cyclohexyl.Scheme 16.Alkynylation reactions of 4-bromoacetophenone using Pd/carbenesystems.Scheme 17.Phenanthracenylimidazolium-derived carbene ligands for the Heck alkynylation of arylbromides.Scheme 18.Heck alkynylation of ortho -substituted bromoarenes with a Pd/diaminocarbene acyclicligand.Scheme 19.A palladium/imidazolium chloride system for the coupling of aryl bromides and alkynylsilanes.2007Wiley-VCH Verlag GmbH &Co.KGaA,WeinheimAngew.Chem.Int.Ed.2007,46,834–871To date,carbene ligands do not appear to be highly efficient catalysts for the coupling of aryl chlorides.In addition,more mechanistic studies are needed to reach a better understanding of the only moderate efficiency of these catalytic systems for aryl alkynylation reactions.2.1.3.Chelating Diphosphanes,Diamines,and P,N LigandsDidentate ligands such as diphosphanes or diamines are also efficient at catalyzing Sonogashira–Heck alkynylation reactions.A polymer-supported copper-free system with a bispyrimidine ligand resulted in the efficient alkynylation of aryl iodides with high TONs(Scheme20).The use of the less reactive bromobenzene gave a satisfactory yield of up to 85%,even with Pd amounts as low as0.006mol%.The reaction of chlorobenzene can be accelerated effectively by the addition of n Bu4NBr to the reaction mixture.Under these conditions the TON was similar to those obtained with iodo-or bromobenzene.[49]A di(pyridin-2-ylmethyl)amine-derived palladium chlo-ride complex is also an efficient catalyst for the coupling of aryl iodides or bromides with alkynes(Scheme21,see also Section2.3).With this catalyst,the alkynylation can be performed under copper-free conditions in N-methylpyrroli-dine(NMP),with TONs up to200000and TOFs up to67000 for aryl iodides,and TONs up to900for aryl bromides.[50,51] The coupling of2-bromothiophene with phenylacetylene in the presence of0.1mol%catalyst led to the product in90% yield.This ligand was also anchored to a polymer for heterogeneous catalysis studies(see Section3.2.2).[51,52]The efficiency of bulky electron-rich diphosphane ligands for Sonogashira reactions with iodobenzene,bromobenzene, or activated aryl chlorides has been investigated by Astruc and co-workers(Scheme22).A TON of100was obtained for the reaction of bromobenzene with phenylacetylene.How-ever,these catalysts gave low TONs of0–15and yields of0–30%with aryl chlorides.A bis(tert-butylphosphane)was generally found to be more efficient than a bis(cyclohexyl-phosphane)ligand.[53]The efficiency of a dendrimer deriva-tive of this catalyst and a resin-supported bis(diphenylphos-phanylmethyl)aminopolystyrene complex have also been tested(see Section3.1.1).[54,55]Among the ligands used for Sonogashira–Heck alkynyl-ations,bulky phosphanes with poor s-donating ability have attracted much less attention.Their efficiency is a pleasant surprise since poor s-donor ligands would not be expected to facilitate the oxidative addition step,but rather would be assumed to be powerful inhibitors.The didentate ligand1,1’-bis[di(5-methyl-2-furyl)phosphanyl]ferrocene catalyzed the arylation of phenylacetylene efficiently(Scheme23).4-Bro-moacetophenone and4-bromoanisole were employed as the activated and deactivated substrates,respectively.The reac-tion of4-bromoacetophenone in the presence of10À4mol% catalyst gave a TON of920000,which is among the highest reported TONs for aryl bromides.4-Bromoanisole was also quantitatively converted,but with a lower TON of1000.[56] As the authors noted,a decisive advantage of the ferrocenylphosphane ligands such as1,1’-bis[di(5-methyl-2-furyl)phosphanyl]ferrocene is their robustness towards air,Scheme20.Coupling of aryl halides to phenylacetylene using a supported palladium–bispyrimidine complex.Scheme21.Alkynylation of aryl halides using a palladium–bispyridine complex.Scheme22.Alkynylations of aryl halides using palladium and anelectron-rich aminobisphosphane.Scheme23.A Pd/[bis(furyl)phosphanyl]ferrocene system for thealkynylation of aryl bromides at low concentration.841Angew.Chem.Int.Ed.2007,46,834–871 2007Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim moisture (no phosphorus oxidation),and elevated reaction temperatures,which allows them to be used in substantially lower concentration.The palladium(II)complex of a ferrocene-based phosphinimine-phosphane ligand was also applied to the amine-and copper-free Sonogashira coupling of aryl iodides and aryl bromides with terminal alkynes by using one equivalent of tetrabutylammonium acetate as an activator (Scheme 24).The corresponding disubstituted alkynes were obtained in high yields and good TONs by using 0.1mol %of the Pd catalyst.[57]The combination of an iminophosphane ligand and Pd-(OAc)2was found to be more effective than a Pd(OAc)2/PPh 3complex for the coupling of some aryl bromides with alkynes (Scheme 25).[58]The efficiency of a Pd(OAc)2/pyrimidine catalyst has also been evaluated (Scheme 26).This system gave satisfactory results in terms of yields of product,however,low TONs were reported.[59]A dinuclear palladium–tetraphenyl oxalic amidinate com-plex has been used as a precatalyst in the copper-free Sonogashira reaction of 4-bromoacetophenone with phenyl-acetylene,and gave moderate TONs (Scheme 27).[60]Yoshifuji and co-workers have reported the use of didentate P ,P [61]and P ,S ligands [62]with 1,3-diphosphapropene skeletons for the coupling of iodobenzene with phenylacety-lene using 2.5mol %catalyst.The P ,P ligand was inactive for the coupling of bromobenzene.Several didentate ligands provided efficient catalytic systems for the alkynylation of aryl substrates.Three of them led to very good TONs:22300(bispyrimidine ligand,Scheme 20),200000(bipyridine ligand,Scheme 21),and 71000(bis-tert -butylphosphane ligand,Scheme 22)in the coupling of simple aryl iodide substrates.Some were even efficient at activating more demanding aryl bromides:the bispyrimidine and bipyridine ligands (Schemes 20and 21)allow the coupling of aryl bromides (TONs of 15500and 700,respectively),while the ferrocene-based didentate ligands (Schemes 23and 24)gave the arylated alkynes in fairly good to remarkably high TONs (920000and 990,respectively).Conversely,most of these ligands were found to be less efficient in the activation of aryl chlorides.2.1.4.Tri-and Tetradentate LigandsOnly a few multidentate ligands (tri-,tetradentate,or more)have been tested for Sonogashira–Heck alkynylations.This is all the more surprising since,most of the time,a threefold or more excess of the monodentate ligands are used under conventional conditions.Thus,multidentate ligands might be of great interest in the future development of catalytic alkynylations.The potential of a tridentate C,N,C-dicarbene pincer ligand has been evaluated in the reaction of iodobenzene and 4-bromoacetophenone with phenylacetylene (Scheme 28).Iodobenzene and phenylacetylene can be coupled in 92%yield in pyrrolidine using 1mol %of this catalyst and CuI as a promoter.On the other hand,a 10%yield was obtained after 19h from 4-bromoacetophenone.[63]Recently,this complex has been immobilized onto clays (see Section 3.2.3).[64]Scheme 24.A ferrocene-based phosphinimine-phosphane ligand for the copper-free alkynylation of arylbromides.Scheme 25.Coupling of aryl bromides to phenylacetylene using a Pd/iminophosphanesystem.Scheme 26.Coupling of aryl halides to phenylacetylene using a palladium–pyrimidinesystem.Scheme 27.Coupling of 4-bromoacetophenone to phenylacetylene using a dinuclear [Pd(acac)]complex.Scheme 28.Sonogashira alkynylation with the palladium complex of a tridentate C,N,C-dicarbene pincer ligand.2007Wiley-VCH Verlag GmbH &Co.KGaA,WeinheimAngew.Chem.Int.Ed.2007,46,834–871。
Pd催化交叉偶联反应研究进展
第32卷 第2期华侨大学学报(自然科学版)Vo l.32 No.2 2011年3月Jo ur nal of H uaqiao U niversity(Natur al Science)M ar.2011文章编号: 1000 5013(2011)02 0121 04Pd催化交叉偶联反应研究进展熊兴泉(华侨大学材料科学与工程学院,福建泉州362021)摘要: 综述以H eck反应、N eg ishi反应和Suzuki反应为主导的Pd催化交叉偶联技术,着重阐述以磁性纳米粒子(M N Ps)、高分子为载体的负载型Pd催化剂的研究进展及其在有机化学中的应用.关键词: P d催化剂;交叉偶联反应;Heck反应;N eg ishi反应;Suzuki反应中图分类号: O643.32;T Q426.81文献标志码: A目前,Pd催化交叉偶联反应主要包括卤代芳香烃与烯烃之间的H eck反应[1-4]、与有机锌试剂之间的Negishi反应[5-6],以及与有机硼酸之间的Suzuki反应[7-9].由于有着反应选择性好、催化效率高、反应条件温和及反应原料来源丰富等优点,该类型的反应已经成为有机合成化学和催化化学领域研究的热点,在天然产物、高分子材料、功能材料和液晶材料的合成及医药生产中得到广泛应用[10-11].就催化机理而言,Pd催化交叉偶联反应有3个相似的历程:(1)氧化加成,即Pd催化剂氧化插入卤代物形成中间体R2-Pd( )-X;(2)金属转移 即过渡金属化产生R1-Pd( )-R2中间体;(3)还原消除,即生成偶联产物R1-R2,同时Pd催化剂重新进入催化循环 Pd催化交叉偶联反应是以贵金属Pd作催化剂的,但由于Pd有毒且在使用过程中易析出极细的Pd粉,不仅使催化剂的使用寿命短、实用性差,也使产物的纯化困难.因此,如何提高催化剂的使用寿命成为降低反应成本一个非常关键的因素.1 磁性纳米粒子负载Pd催化剂磁性纳米粒子(MNPs)由于制备方法多样,工艺相对容易控制,具有结构和功能的可调控性,以及其在磁性、催化等多方面的良好特性,日渐成为研究热点.将M NPs作为Pd催化剂的载体,可以使催化剂易从反应体系中分离和回收.文献[12]利用叠氮与炔基之间的 点击 反应,将外围为叠氮功能化的M NPs与炔基功能化的二吡啶基甲醇连接起来;然后,利用吡啶与Pd之间的配位作用,制备出负载Pd催化剂的M NPs,并利用红外光谱(IR)和透射电子显微镜(TEM)等手段对其进行表征.磁性纳米粒子负载Pd催化剂能很好地催化芳基硼酸与芳基溴之间的Suzuki反应,合成含有取代基的联苯型芳香化合物的产率为85%~99%.实验表明,该类催化剂在外加磁场作用下容易回收,并具有较好的重复使用性能.2009年,韩国仁荷大学的Taher等[13]分别将含有咪唑基团的三甲氧基硅烷及氮杂Pd卡宾键合到外围为羟基功能化的MNPs上,制备出具有磁性的氮杂Pd卡宾纳米粒子.同时,在以水作溶剂的反应体系中,将该催化剂用于催化芳基硼酸与芳基溴之间的Suzuki反应,以92%~98%的高产率合成联苯型芳香化合物.实验表明,该类催化剂表现出优良的催化性能及较高的稳定性能,且连续使用5次后,仍显示出好的催化特性(Suzuki反应产率仍能维持在93%).2 高分子负载Pd催化剂高分子载体材料可以分为天然高分子载体和合成高分子载体.一般而言,作为高分子载体应该具有 收稿日期: 2010 11 22通信作者: 熊兴泉(1980 ),男,博士,主要从事 点击 化学及结构可控聚合物的研究.E mail:x x qluli@. 基金项目: 国家自然科学基金资助项目(21004024);福建省青年科技人才创新项目(2008F3067)122华侨大学学报(自然科学版) 2011年以下3个特点:(1)容易进行化学修饰,即一般可以利用功能性单体进行聚合或在聚合完成后再进行功能化,使-OH,-NH2或-COOH功能化的高分子载体能与Pd催化剂的配体(如三芳基膦)结合;(2)较大的比表面积,即可提高Pd催化剂的分散度,从而可提高催化剂的催化效率;(3)具有一定的强度及较好的化学稳定性,可达到延长催化剂使用寿命并使其易于分离和回收的目的.2.1 天然高分子载体天然高分子材料,例如淀粉、田菁胶、壳聚糖等,由于原料价廉易得,表面官能团丰富(分子中含有大量羟基或氨基),是负载Pd的理想载体材料.2004年,H dary等[14]以天然高分子壳聚糖为载体,制备出壳聚糖Pd配合物催化剂,并成功将该催化剂用于Sukuzi和H eck偶联反应中.实验表明,该催化剂催化取代型卤代芳烃与苯硼酸之间的Suzuki反应效果很好,短时间就可以获得较高的产率 特别对于有供电子基团(如-OM e)的底物,其产率会更高一些;含吸电子基团(如-NO2或-CN)的产率很低,并且催化剂会分解成黑色固体.溴代和碘代芳烃均有明显活性,但氯代苯在反应18h后产率仅为3%,基本无活性.催化剂用极性溶剂,如甲醇洗涤后可以重复使用.将此催化剂用于碘代苯和丙烯酸正丁酯、苯乙烯等的H eck反应中,催化活性也很高,分别以87%和88%的产率合成出肉桂酸丁酯和反式的1,2-二苯乙烯.Calo等[15]也以壳聚糖为原料制备出壳聚糖负载的纳米Pd催化剂,并在离子液体中系统研究该催化剂对卤代苯与丙烯酸正丁酯之间H eck反应的催化性能.结果表明,当以四丁基溴化铵为溶剂、四丁基乙酸铵为碱时,该催化剂的活性较高.在130 条件下反应15m in,溴代苯生成酯的产率高达98%;而在100 下,仅反应5m in,碘代苯的产率也达95%,并且在该条件下重复使用10次以上,催化剂仍能保持明显的催化活性.2.2 合成高分子载体合成高分子载体一般分为可溶性高分子载体与不溶性高分子载体.研究表明,不溶性高分子载体存在负载量低、传质困难、催化活性中心与底物接触几率小等缺陷;而可溶性高分子载体可克服以上不溶性高分子载体的缺点.通过将催化剂负载在可溶性载体上可以实现 均相反应,两相分离 的目的.目前,常见的合成高分子载体材料主要有聚酰亚胺、聚苯乙烯、聚苯乙烯-聚乙二醇接枝共聚物、聚醚型树状分子等聚合物材料.Seokin等[16]通过二酐单体与含Pd的二胺单体之间的缩聚反应,合成了一种新型的含Pd的聚酰亚胺催化剂 在极性溶剂中,以Cs2CO3做缚酸剂,可以高效催化苯乙烯与卤代芳烃的H eck反应.实验表明,在80 条件下反应2h,碘代苯与苯乙烯反应产率可达93%.在相似条件下,该催化剂也能高效催化卤代苯与苯硼酸之间的Suzuki反应,反应2h后的Suzuki反应产率也可达93%.研究表明,该类催化剂能有效克服有机膦,特别是富电子的苯基膦导致的在大规模制备中存在的高价格、低反应速率及空气敏感等缺陷.Dahan等[17]以羟基功能化的聚苯乙烯树脂为原料,将其与羧酸功能化的苯基膦进行缩合反应,合成了不同代数且固定于聚苯乙烯树脂上的树枝状载体负载Pd催化剂.将其用于溴代苯和丙烯酸正丁酯、苯乙烯等的H eck反应中,表现出良好的催化活性.研究表明,树状分子代数越高,对H eck反应的催化活性和选择性越高,代数增加一代,可以使其中一些反应产率增加5倍.3 Pd催化交叉偶联反应在有机合成中的应用Pd催化交叉偶联反应已经被广泛应用于许多物质,特别是一些抗癌药物及抗炎症药物的合成研究和工业化生产[18-20].在天然产物合成方面,分子间或分子内的Pd催化交叉偶联反应被用作合成中的关键步骤.值得一提的是,1996年,Danishefsky等[21]成功地将H eck反应应用在紫杉醇全合成的关键步骤中,并取得良好的效果.另外,H eck反应也被成功应用于另一新的绿色抗肿瘤药物 白藜芦醇的全合成中.Guiso等[22]以Pd(OAc)2作催化剂,以3,5-二乙酰酯基取代的苯乙烯与对乙酰基碘苯进行H eck反应,以70%的收率制备出全乙酰化白藜芦醇,最后几乎以定量的产率去掉乙酰基后得到白藜芦醇.Andrus等[23]用3,5-二羟基苯甲酸为起始原料进行4步反应,以52%的总产率合成出白藜芦醇,其中H eck反应一步收率可达73%.Menche 等[24]在H 2O 与M eCN 的混合体系中,以三乙胺做缚酸剂,二(三苯基膦)二氯化Pd 作为催化剂,催化烯基碘化物与乙烯衍生物之间的H eck 反应,合成具有抑制癌细胞生长活性的药物活性分子Archazo lid A.结果表明,该反应以55%的收率合成出关键中间体,并有较好的选择性(E/Z =6 1).Neg ishi 反应也被成功应用于药物及天然产物的合成中.Chacko 等[25]以二(三叔丁基膦)Pd 作催化剂,以碘代核苷衍生物及多种有机锌试剂进行N eg ishi 反应,以34%~65%的收率制备出一系列具有生物活性和药物活性的5-氟烷基嘧啶核苷衍生物.另外,Neg ishi 等[26]利用两步Neg ishi 反应成功合成出 -胡萝卜素和其相关衍生物.N eg ishi 反应也可以方便地合成一些具有药物活性的海洋天然产物,如Discoderm olide,Nakienone A 的关键结构片段[27 28].与金属有机化合物相比,芳基硼酸对热、空气、水不敏感,具有廉价、低毒等优点.因此,苯硼酸与芳基溴代物之间的Suzuki 反应也成为合成具有生物活性天然产物的常用方法.例如,具有调节钙和磷代谢作用的维生素D 3的合成就采用了Suzuki 反应[29].4 研究展望Pd 催化交叉偶联反应是现代有机合成中构成C-C 键的重要方法之一 由于该类型的反应具有选择性好、产率高、官能团耐受性好,以及对底物的兼容性较好等优点,因而受到人们越来越多的关注,并已经在在医药以及天然产物合成中得到了广泛的应用.然而,到目前为止,Pd 催化交叉偶联反应还存在以下3个关键问题:(1)Pd 催化剂价格昂贵且有毒,使其在医药合成工业上的应用受到限制;(2)如何研究出高活性负载型Pd 催化剂,使其既保持活性又易于分离和回收;(3)如何进一步拓宽Pd 催化交叉偶联反应的应用范围.2010年的诺贝尔化学奖颁发给了长期从事于Pd 催化交叉偶联反应的H eck,Negishi 和Suzuki 等3位化学家,这将进一步激发越来越多研究者关注这一领域,并解决以上问题.实践证明,将Pd 催化剂以化学或物理的方式负载于无机或有机高分子载体,如M NPs 或聚合物等上,不仅可以延长其使用寿命,而且催化剂也易于分离和回收.参考文献:[1] H ECK R F,NO L LEY J P.Palladium-catalyzed viny lic hydrog en substitution r eactions w ith ar yl,benzyl,and sty ryl halides[J].J O rg Chem,1972,37(14):2320-2322.[2] HECK R F.Palladium-cataly zed reactions of organic halides with olefins[J].Acc Chem Res,1979,12(4):146-151.[3] BEL ET SK AY A I P,CHEP RA KO V A V.T he Heck reactio n as a shar pening sto ne o f palladium catalysis[J].ChemRev ,2000,100(8):3009-3066.[4] N EGI SH I E,COP ER ET C,M A S,et al.Cyclic carbopalladat ion:A ver satile synthetic methodolog y for the co nstr uctio n o f cyclic o rg anic co mpo unds[J].Chem Rev,1996,96(1):365-394.[5] N EGISH I E,K IN G A O,OK U K ADO N Selectiv e carbon-carbon bo nd fo rmation v ia transitio n metal catalysis(3):A hig hly selectiv e sy nthesis of unsymmetr ical biar yls and diary lmethanes by the nickel-o r palladium-catalyzed re action of a ryl-and benzylzinc derivativ es w ith ar yl halides[J].J O rg Chem,1977,42(10):1821-1823.[6] N EGISH I E,H U Q ian,H U A N G Zhi-hong,et al.Palladium-cat aly zed alkeny latio n by the negishi coupling [J].A ldr ichimica A cta,2005,38(3):71-88.[8] SU ZU K I A O rg ano bo rates in new synthetic r eactions[J].Acc Chem Res,1982,15(6):178-184.[9] M IY A U RA N,Y AN A GA T ,SU ZU K I A T he palladium-catalyzed cr oss-coupling reactio n of pheny lbor onic acidw ith halo arenes in the presence of bases[J].Sy nthetic Co mmunicatio ns,1981,11(7):513-519.[10] NICO LA O U K C,BU L GER P G ,SA RL A H D Palladium-catalyzed cr oss-co upling reactions in total synthesis[J].Ang ew Chem I nt Ed Eng l,2005,44(29):4442-4489.[11] T O RBO RG C,BELL ER M R ecent a pplicat ions o f palladium -catalyzed coupling r eactions in the harmaceutical,ag r ochemical,and fine chemical indust ries[J].A dv anced Synthesis &Cataly sis,2009,351(18):3027-3043.[12] L G uang-hua,M AI W en-peng,JI N R i-zhe,et al.Immobilizatio n of dipyr idyl co mplex to mag net ic nano par ti cle via click chemistr y as a recy clable catalyst for Suzuki cross-coupling r eact ions[J].Synlett,2008,19(9):1418-123第2期 熊兴泉:Pd 催化交叉偶联反应研究进展124华侨大学学报(自然科学版) 2011年1422.[13] T A HER A,K IM J B,JU N G J Y H ig hly activ e and mag netically r ecover able P d-NH C catalyst immobilized onF e3O4nano par ticle-ionic liquid matrix fo r Suzuki r eaction in water[J].Synlett,2009(15):2477-2482.[14] H A RDY J J E,HU BERT S,M A CQ U AR RIE D J,et al.Chitosan-based hetero geneous cataly st s for Suzuki andH eck reactio ns[J].G reen Chem,2004(6):53-56.[15] CA L O V,NA EEI A,M O N OP OL I A,et al.Heck reactio n cataly zed by nanosized palladium on chit osan in ionic liquids[J].Og ranometallics,2004,23(22):5154-5158.[16] SE KI N T,K Y T EP E L,DEM IR S,et al.N ov el ty pe o f metal-containing po ly imides for the heck and Suzuki-m iyaura cr oss-co upling reactio ns as hig hly active cata lysts[J].Journal o f Ino rg anic and O rganometa llic P olymers, 2003,13(4):223-235.[17] D AH A N A,PO RT N O Y M Remarkable dendritic effect in the po ly mer-suppor ted catalysis of the Heck ary lationo f olefins[J].O rg anic L et ters,2003,5(8):1197-1200.[18] BEL L ER M,BOL M C.T r ansition metals fo r or ganic sy nt hesis:Building blocks and fine chemicals[M].Weinheim:W iley-V CH,2004.[19] D IEDER ICH F,ST A N G P J.M etal-catalyzed cr oss-co upling r eactions[M].Weinheim:Wiley-VCH,1998.[20] M EI JERE A,DI ED ER ICH F.M etal-cata lyzed cr oss-coupling r eact ions[M].W einheim:Wiley-VCH,2004.[21] D AN ISH EFSK Y S J,M A ST ERST ER S J,Y OU N G W B,et al.T o tal synthesis of baccat in III and tax ol[J].J A mChem Soc,1996,118(12):2843-2859.[22] G U ISO M,M A RR A C,F ARI NA A A new efficient resverat rol sy nthesis[J].T etr ahedro n L et ters,2002,43(4):597-598.[23] AN DRU S M B,L IU J,M EREDIT H E L,et al.Sy nthesis of resver atro l using a dir ect decar bo ny lat ive Heck a ppro ach fr om r eso rcylic acid[J].T etr ahedro n L etters,2003,44(26):4819-4822.[24] M ENCH E D,H ASSF EL D J,L I J,et a l.T otal synthesis o f ar chazolid A[J].J A m Chem So c,2007,129(19):6100-6101.[25] CH A CK O A M,Q U W C,KU N G H F.Synthesis of5-fluor oalky lated pyrimidine nucleosides via neg ishi cross-co upling[J].Journal o f Or ganic Chemistry,2008,73(13):4874-4881.[26] ZENG F X,N EGISH I E A No vel,select ive and efficient route to caro teno ids and related natur al pro ducts v ia zr-catalyzed car bo aluminatio n and pd-and zn-catalyzed cro ss coupling[J].Or ganic L etters,2001,3(5):719-722.[27] SM I T H A B,BEAU CH A M P T J,LA M A RCH E M J,et al.Evo lutio n of a g ram-sca le synthesis of(+)-discodermo lide[J].J Am Chem Soc,2000,122(36):8654-8664.[28] PO U R M,N EGISH I E.An eff icient and selective synthesis of nakienone a Invo lving a novel pro toco l fo r -alkenylation o f keto nes via palladium-cataly zed alkenyI-alkeny l co upling[J].T etrahedr on L etters,1997,38(4):525-528,[29] HA N A ZA WA T,K OY A M A A,W A DA T,et a l.Efficient converg ent synthesis o f1 ,25-dihydrox y vitamin D3andits analog ues by suzuki-miy aura coupling[J].Or ganic L et ters,2003,5(4):523-525.Recent Advances in Pd-Catalyzed Cross-Coupling ReactionXIO NG Xing-quan(College of M aterial Science and Engin eering,H uaqiao University,Quanzh ou362021,China)Abstract: Recent advances in the palladium-catalyzed cro ss-coupling reactions,w hich mainly exemplified by H eck re actio n,N egishi reaction and Suzuki r eact ion,ar e discussed her ein.A t the same time,it em phasizes the pr og ress o f mag netic nano par ticles(M N Ps)o r polymer-suppo rted Pd cataly st s and its applications in or ganic chemistry.Keywords: palladium-cat aly zed;cro ss-coupling reactio n;H eck reaction;N egishi reaction;Suzuki reaction(责任编辑:陈志贤 英文审校:熊兴泉)。
钯催化的偶联反应和脱羰基化偶联反应用于合成杂环化合物的开题报告
钯催化的偶联反应和脱羰基化偶联反应用于合成杂环化合物的开题报告一、研究背景杂环化合物是具有重要生物活性和药理活性的有机分子之一。
在合成杂环化合物的过程中，钯催化的偶联反应和脱羰基化偶联反应是常用的重要方法之一。
在这两种反应中，钯金属催化剂能够通过亲核取代反应、氧化加成反应、还原消除反应等多种途径实现杂环化合物的构建。
通过钯催化合成杂环化合物可以提高化合物的生物利用度，从而实现设计和发现新的药物。
二、钯催化偶联反应钯催化偶联反应是由钯金属催化剂催化的有机合成反应。
这种反应可以将两个具有亲电性的反应物进行偶联反应，并形成新的化学键。
钯催化偶联反应可以用于构建碳-碳、碳-氮、碳-硫、碳-氧等各种类型的化学键。
在钯催化偶联反应中，常见的反应类型包括Suzuki偶联、Stille偶联、Heck偶联、Negishi偶联等。
苯基取代物、芳基卤化物、膦化合物、乙烯基化合物是钯催化偶联反应中常见的反应底物。
三、钯催化脱羰基化偶联反应钯催化脱羰基化偶联反应是通过钯金属催化剂催化的羰基化合物的去除羰基团和与其他底物发生偶联反应而构建新化学键的反应。
这种反应广泛应用于不对称合成、卡宾化合物的制备和天然产物的全合成中。
在钯催化脱羰基化偶联反应中，常用的反应底物包括羰基化合物，硫醇和芳香醛酮类化合物。
通过钯催化脱羰基化偶联反应，可以有效地构建含有杂环结构的化合物。
四、总结钯催化的偶联反应和脱羰基化偶联反应是合成杂环化合物的重要方法，能够实现杂环化合物的高效合成。
这些反应已经证明在合成许多具有生物活性的天然产物和药物中是非常有效的。
因此，这些反应的发展与应用具有重要的理论和实践意义。
药明康德Pd催化的偶联反应MA070818精品PPT课件
在钯催化下，有机硼化合物与有机卤素化合物进行的 偶联反应，称之为Suzuki偶联反应，或Suzuki-Miyaura 偶联反应。
R1 BY2
+
R2 X
[P d ] base
R1 R2
BY2 = B(OR)2, 9-BBN, B(CHCH3CH(CH3)2) X = I, Br, Cl, OSO2(CnF2n+1), n = 0,1,4
合成反应讲座(五)
Pd催化的偶联反应
化学合成部执行主任:
药明康德版权所有
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内容简介
Pd 催化的偶联反应有较多类型，目前用途最广泛 的主要有以下三类:
1. Suzuki 反应 2. Heck 反应 3. Sonogashira 反应
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第一部分： Suzuki 反应
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1. 前 言
1.1 Suzuki反应的通式
TMS 1.nBuLi,THF -78oC, 15min
TMS
2. B(OMe)3
I
-78oC-25oC,30min (HO)2B
3. H+/HCl
Chem. Eur. J. 2003, 9, 4430-4441
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2. 有机硼试剂的合成
2.2 通过二硼烷频哪酯制备芳基硼酸酯
对于分子中带有酯基、氰基、硝基、羰基等官能团的芳香卤代物来 说, 无法通过有机金属试剂来制备相应的芳基硼酸。1995年由 Ishiyama率先取得了突破: 通过二硼烷频哪酯和芳基卤发生偶联反应 制备相应的芳基硼酸酯 (yield: 60-98%)。这个方法还有一个突出的优 点就是还可以原位制备硼酸酯, 然后“一锅法”和芳基卤反应用于芳基芳基偶联反应。
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1. 前 言
钯催化交叉偶联反应
钯催化交叉偶联反应钯催化交叉偶联反应2010-10-26 17：32钯催化交叉偶联反应摘要钯催化交叉偶联反应是一类用于碳碳键形成的重要反应，在有机合成中应用十分广泛。
钯催化交叉偶联反应-简介为制造复杂的有机材料，需要通过化学反应将碳原子集合在一起。
但是碳原子在有机分子中与相邻原子之间的化学键往往非常稳定，不易与其他分子发生化学反应。
以往的方法虽然能令碳原子更加活跃，但是，过于活跃的碳原子却又会产生大量副产物。
而用钯作为催化剂则可以解决这个问题。
钯原子就像"媒人"一样，把不同的碳原子吸引到自己身边，使碳原子之间的距离变得很近，容易结合--也就是"偶联"。
这样的反应不需要把碳原子激活到很活跃的程度，副产物比较少，因此更加精确而高效。
赫克、根岸英一和铃木章通过实验发现，碳原子会和钯原子连接在一起，进行一系列化学反应。
这一技术让化学家们能够精确有效地制出他们需要的复杂化合物。
钯催化交叉偶联反应-应用如今，"钯催化交叉偶联反应"被应用于许多物质的合成研究和工业化生产。
例如合成抗癌药物紫杉醇和抗炎症药物萘普生，以及有机分子中一个体格特别巨大的成员--水螅毒素。
科学家还尝试用这些方法改造一种抗生素--万古霉素的分子，用来灭有超强抗药性的细菌。
此外，利用这些方法合成的一些有机材料能够发光，可用于制造只有几毫米厚、像塑料薄膜一样的显示器。
科学界一些人士表示，依托"钯催化交叉偶联反应"，一大批新药和工业新材料应运而生，这三名科学家的科研成果如今已经成为支撑制药、材料化学等现代工业文明的巨大力量。
钯催化交叉偶联反应-诺贝尔奖2010年10月6日在瑞典皇家科学院举行的新闻发布会上，瑞典皇家科学院常任秘书诺尔马克首先宣读了获奖者名单。
他说，赫克、根岸英一和铃木章在"钯催化交叉偶联反应"研究领域作出了杰出贡献，其研究成果使人类能有效合成复杂有机物。
浅议钯催化的偶联反应
图 3 Suzuki 偶联及其反应机理
由于 Suzuki 偶联反应条件温和，可以在水中进 行，原料低毒易得，区域选择性好等诸多优点，该反 应获得了广泛的认同和应用，随着水相反应、微波合 成、固相合成等绿色合成方法的发展，该反应在材料 合成及 天 然 产 物 的 合 成 中 获 得 了 更 为 广 泛 的 应 用［5］。 3 Negishi 偶联反应
参考文献
［1］ HeckR F ． Acylation ，methylation ，and carboxyalkylation of olefins by group VIII metal derivatives ［J ］． J Am Chem Soc，1968，90 （ 20） ： 5518 － 5526．
（ 本文文献格式： 何 林，杜广芬，顾承志，等． 浅议 钯催化的偶联反应［J］． 山东化工，2011，40（ 11） ： 55 － 58． ）
Heck 偶联、Suzuki 偶联、Negishi 偶联反应是有 机合成中最常用的碳 － 碳键形成反应，经过几十年 的发展，这类钯催化的偶联反应适用范围广，用途广 泛，将诺贝尔化学奖授予钯催化偶联反应的重要发 现者，也充分说明了这类反应的重要意义。当然，钯 催化的反应还有很多工作要做，比如活泼性差的羧 酸酯参与的偶联反应，最近北大施章杰小组已经取 得重要进展［10］，再如活泼性差的氯代烃参与的偶联 及不对称偶联反应，还需要做大量的工作。
图 4 Negishi 偶联反应
Negishi 偶联反应的机理与 Suzuki 偶联反应极 其类似，同样经过氧化加成、转金属化、还原消除三 个主要的步骤。与 Heck 偶联和 Suzuki 偶联不同的
钯催化交叉偶联反应
钯催化的交叉偶联反应一、偶联反应综述1．交叉偶联反应偶联反应，从广义上讲，就是由两个有机分子进行某种化学反应而生成一个新有机分子的过程。
狭义的偶联反应是涉及有机金属催化剂的碳－碳键生成的反应，根据类型的不同，又可分为自身偶联反应和交叉偶联。
交叉偶联反应是一个有机分子与另一有机分子发生的不对称偶联反应。
2．碳碳键形成的重要性新碳－碳键的形成在有机化学中是极其重要的。
人们了解了天然有机物质的结构和性能，并根据有机物质的结构，通过碳原子组装成链，建立有机分子，最终实现天然有机物质的人工合成。
目前为止，人类已经利用有机合成化学手段创造出几千万种物质，且越来越多的有机物质已经广泛应用到制药、建材、食品、纺织等人类生活领域，我们的生活也几乎离不开有机物了。
合成药物、塑料等有机物质时，需要用小的有机分子将碳原子连接在一起构建新的复杂大分子，因而有机合成中高效的连接碳－碳键的方法是有机合成化学中的重要工具。
从以往该领域诺贝尔化学奖的授予情况也可以看出合成新碳－碳键的重要性:1912年维克多·格林尼亚因发明格林尼亚试剂——有机镁试剂获奖，1950年迪尔斯和阿尔德因发明双烯反应迪尔斯－阿尔德反应获奖，1979年维蒂希与布朗因发明维蒂希反应共同获奖，2005年伊夫·肖万、罗伯特·格拉布、理查德·施罗克因在有机化学的烯烃复分解反应研究方面作了突出贡献获奖。
3．有机合成中的钯催化交叉偶联反应随着时代发展，合成有机化学的研究愈加深入，20世纪后半期，科学家们发现了大量通过过渡金属催化来创造新有机分子的反应，促使有机合成化学快速发展。
特别是赫克、根岸英一和铃木章发现的钯催化交叉偶联反应，为化学家们提供了一个更为精确有效的工具。
三位科学家发现的钯催化交叉偶联反应中都使用了金属钯作为反应的催化剂，当碳原子与钯原子连在一起时，钯原子唤醒了“懒惰”的碳原子但又不至于使它太活泼，于是形成温和的碳－钯键，在反应过程中，钯原子又可以把别的碳原子吸引过来，形成另一个金属－碳键，此时两个碳原子都连接在钯原子上，它们的距离足够接近而发生反应，生成新的碳－碳单键。
钯催化的偶联反应
AgNO3/KF作用下的Pd催化2-溴噻吩S原子邻位上的C-H键选择性偶联反应摘要：溴噻吩的衍生物与芳基碘在加入了钯的硝酸银/氟化钾催化剂的催化下发生C—H键的偶联反应，而C—Br键未发生变化。
这些含有C —Br键的偶联产物在钯的进一步催化下使溴噻吩和芳基碘的C—C键相连接从而得到理想的产量。
引言：狭义上的偶联反应是涉及由基金属催化剂的C-C键生成的反应，根据类型不同，可分为交叉偶联反应和自身偶联反应。
交叉偶联反应是一个有机分子与另一有机分子发生的不对称偶联反应。
例如：烯丙基锂与2-氯辛烷可以发生交叉偶联反应生成4-甲基-1-癸烯。
格利雅试剂、有机铝、有机锌、有机锡、有机铜、有机铅、有机汞等多种有机金属化合物也都可以与卤化烷等烃基化试剂发生交叉偶联反应，生成相应的不对称烃，是合成不对称烃，特别是单烷基芳烃和含有三级碳原子的链烃的有效方法。
交叉偶联反应的范围很广，像芳烃重氮盐与苯酚或N,N-二甲基苯胺的偶联反应，也属于交叉偶联反应。
正文：芳香族化合物与有机卤化物的C-H键取代反应和那些含金属试剂与相同的有机卤化物的偶联反应相比，在有机合成中更有前景。
【1】相比之下，C-H键上的直接反应将有利于含有不同种类的官能团的衍生物的合成，并且，反应也会加强合成中原子的效应。
我们注意到噻吩衍生物的偶联反应是发生在C-H键上，从而形成了联噻吩。
在添加了AgF后，反应效率得到了提高。
【2】当噻吩与2-溴噻吩反应生成正联溴噻吩时，仍然是C-H键发生偶联，而C-Br键未发生变化。
我们的注意力集中到溴噻吩衍生物C-H键的交叉耦合上,来介绍噻吩环上的取代基。
【3】溴噻吩上的C-H键偶联，如果可以通过C-Br键的反应而进一步改变偶联产物，那么C-H键和C-Br键的偶联反应的相互结合将得到一种新的合成取代噻吩的方法。
这将把人们的注意力都吸引到设计更先进的有机金属材料来揭示液晶、光发射和有机半导体的特点。
【4】在此，我们报告一个新的催化剂系统—AgNO3/KF，它有助于提高钯催化下溴噻吩衍生物C-H键的取代反应发的效率。
钯催化交叉偶联反应及其在有机合成中的应用
第16卷第12期江苏技术师范学院学报JOURNAL OF JIANGSU TEACHERS UNIVERSITY OF TECHNOLOGY Vo l.16,No.12Dec .,20102010年12月0引言2010年的诺贝尔化学奖颁发给了三个有机化学家，理查德·海克（Richard Heck ）、根岸英一（Ei-ichi Negishi）和铃木章（Akira Suzuki ），他们发现的钯催化交叉偶联反应具有高度的选择性，在相对温和的条件下，形成碳-碳单键。
在过去的40年里，这些反应成为有机化学家主要的非常有效的工具。
该反应作为五个被授予诺贝尔化学奖反应之一，其重要性已不言而喻。
前四个反应分别是Grignard 反应（1912），Diels-Alder 反应（1950），Wittig 反应（1979）和烯烃复分解（olefin metathesis ）反应（2005）。
由Heck 、Negishi 和Suzuki 研究的钯催化碳-碳单键的成键反应给有机合成带来了巨大的影响，在靶向合成方面有很多的应用。
这三个反应之所以被广泛应用于合成大量的天然化合物和具有生物活性的复杂分子结构的物质，主要是因为反应条件温和，大量的官能团在如此温和的条件下，能够不被破坏而保留下来。
这三个反应同样也广泛应用于精细化学品工业和制药工业中。
1钯催化交叉偶联反应———Heck 反应的发现20世纪50年代过渡金属开始在有机化学中发挥了相当大的作用，出现了大量的由过渡金属催化的构建有机化合物分子的反应。
一家德国公司Wacker Chemie AG 以钯作为催化剂，以空气氧化乙烯生成乙醛，这一重要的方法在工业上称为Wacker 法[1]。
Richard Heck 当时就职于美国Delaware 的一家化学公司，由于受到对化学生产中Wacker 法成功应用的日渐强烈的好奇心的驱使，他开始使用钯作为催化剂进行实验。
1968年，Heck 就其成功的研究工作，以唯一作者的身份发表了一系列研究论文[2-6]。
有机合成钯催化交叉偶联反应(精选文档)
1.格氏试剂——拉开钯催化交叉偶联反应的序幕
有机合成化学所构造出来的物质大部分都是以碳胳为骨架所构建起来的,然而碳原子本身十分稳定,在化学反应中并不活泼。因此化学家们希望通过各种化学反应,来激活碳原子,使其更容易参与到反应中并与其它碳原子相连,构造更
复杂的有机物。通过多年的尝试与努力, Grignard (格林尼亚发明了有机镁试剂(即格氏试剂,并利用其活化了碳原子,成功将碳原子连接在一起。以下为利用格氏试剂所进行的烷基化反应:
赫克反应与格氏反应相比,具有更好的化学选择性,减少反应的副产物,而且赫克反应在常温下进行,反应条件温和,对于工业生产具有重要的应用价值。不过赫克反应的局限之处在于,它往往只能用于有机合成中碳碳单键的合成,在合成一些更大的分子时会显示出其缺陷及产生较多的副产物。化学家们并不满足于停留在当前的成果中,而是孜孜不倦地进一步改进钯催化交叉偶联反应。
为铃木反应。
铃木反应与根岸反应相
似,均经历了三个过程:氧
构建单键最重要的反应之
一,并以他自己的名字赫克对
反应命名。
赫克反应的反应机理如
下(见右图:反应开始,活泼
的钯Pd(0催化剂与卤代烃发
生被称为氧化-加成的反应,
在这步反应中,生成了R-Pd-X ,钯的氧化态形式上从(0转化为(Ⅱ ,也就意味着生成了Pd-C键;第二步,烯烃与钯配位,此时烯烃和R基团同时与钯连接,这样就使它们能够相互发生反应;第三步, R基团迁移到烯烃的碳原子上,而钯同时与烯烃的另一个碳原子相连,这一步称为迁移-插入,结果生成了C-C键;第四步, R替换了底物烯烃上的一个氢原子,即通过消除烯烃的β-H得到了一个新的取代烯烃,同时还生成了HPdX ,它随即失去HX得到Pd(0,进入另一次催化循环。
贵金属钯Pd催化的偶联反应
通过调整钯催化剂的反应条件(温度、溶剂、配体、碱和其他添加剂)，可使钯催化成为有机化学合成中用途广泛的工具。
其中，钯催化的交叉偶联反应彻底改变了分子的构造方式。
从有机合成和药物化学领域，到材料科学和聚合物化学，交叉耦合已经影响到多个科学领域。
在偶联反应中，钯催化剂不但可以形成C-C、C-O、C-N和C-F等碳键，而且对各种官能团具有很高的耐受性，通常能够提供良好的空间和区域特异性，可以不用引入保护基团。
常用的偶联反应包括Heck偶联、Suzuki偶联、Stille偶联、Hiyama偶联、Sonogashira偶联、Negishi偶联、Buchwald-Hartwig胺化等等。
具体反应如下所示：1、Negeshi偶联反应(C-C) [1]（其中，R/R’可以是烷基、烯基、芳基、烯丙基、炔基或炔丙基，X/X’可以是氯、溴、碘或其他基团，催化剂是钯）2、Suzuki偶联反应(C-C) [2](其中，R可以是烯基，芳基或烷基，R’可以是烯基，芳基、炔基或烷基，Y可以是烷基，羟基或者氧烷基，X可以是氯、溴、碘或三氟甲磺酸)3、Stille偶联反应(C-C) [3]（其中，R可以是烯基、芳基、酰基，R’可以是烯基、芳基或者烷基，R’’可以是烷基，X可以是氯、溴、碘或者三氟甲磺酸）4、Buchwald–Hartwig偶联反应(C-N/C-O)[4]（其中，R是芳基，R’可以是邻、间芳基或烷基，R”可以是烷基或芳基，X可以是氯、溴、碘或者三氟甲磺酸）5、Heck偶联反应(C-C) [5]（其中，R可以是烯基、芳基和不含有β氢的烷基，R’可以是烯基，芳基和烷基，X可以是氯、溴、碘、三氟甲磺酸、对甲基苯磺酰氯或者N2+）6、Sonogashira偶联反应(C-C) [6]（其中，R可以是烯基或者芳基，R’可以是H、炔基、芳基、烷基或者硅烷基，X可以是氯、溴、碘或者三氟甲磺酸）。
有机合成中钯催化下的交叉偶联反应
有机合成中钯催化下的交叉偶联反应－2010年诺贝尔化学奖简介陈明华( 兴义师范学院化学生物系，贵州兴义 562400)摘要:介绍了2010年诺贝尔化学奖的科学背景，即“有机合成中钯催化下的交叉偶联反应”的产生、发展和应用，体现了有机化学已经发展成为一门艺术形式，在这个形式下，科学家们在试管里创造性的产生出不可思议的化学物质的过程。
关键词:钯催化剂；交叉偶联反应；赫克反应；铃木反应；根岸反应Palladium-Catalyzed Cross Couplings in Organic SynthesisCHEN Ming-Hua(Department of Chemistry and Biological, Xingyi Normal College, Xingyi, Guizhou 562400)Abstract: This paper introduces scientific background of the Nobel Prize in Chemistry for 2010, it’s palladium-catalyzed cross couplings in organic synthesis.And this fack had been presents that “Organic chemistry has developed into an art form where scientists produce marvelous chemical creations in their test tubes”.Key words: palladium catalyst; cross-coupling reaction; heck reaction; suzuki reaction; negishi reaction2010年10月6日，瑞典皇家科学院决定授予美国特拉华大学(University of Delaware) 理查德-赫克(Richard F. Heck), 普渡大学(Purdue University)根岸荣一(Ei-ichi Negishi)和日本北海道大学(Hokkaido University)的铃木彰(Akira Suzuki)三位教授2010年的诺贝尔化学奖，以表彰他们在“有机合成中钯催化下的交叉偶联反应”作出的贡献[1]。
PdC催化suzuki偶联
PdC催化suzuki偶联昨天介绍的是无配体水相suzuki, 复习下条件: Pd(OAc)2(0.25% or 5%), K3PO4, H2O, 100 ℃今天介绍下Pd/C催化的suzuki反应，催化剂一直是我们关注的点，什么样的催化剂受人喜欢？便宜高效污染少，最起码Pd/C价格便宜，有负载，反应完后直接过滤，Pd残留少，所以要是能用Pd/C做suzuki，也是很有诱惑力的。
先把条件列出来，Pd/C suzuki，就用这个条件： Pd/C, Na2CO3, 醇类溶剂（异丙醇或者MeOH/H2O），含水反应标配，就是这样的固定搭配先试试。
最近更新的文献，一定要让你的头脑建立条件反射，先锁死反应条件，无水Pd/C suzuki，不用思考就可以先开出这么个条件，此条件不行再优化。
介绍下大致情况首先在1994年， Buchecker, R.在 T etrahedron letter(1994, 35, 3277)上的一篇文章上介绍了Pd/C催化的suzuki反应，这是很小规模的案例。
反应规模：几百mg，大致3mmol级别，5%Pd/C, 95% EtOH, 80℃。
OTf一般条件下不反应(entry 10)，用CN活化以后仍然不行（entry 16）,把碱从Na2CO3换成NaHCO3以后，有50%收率。
接下来介绍点量大点的OPRD, 1997, 1, 163-164作者称这是首例COOH在suzuki偶联里面兼容。
这里可以采用一锅法，硼酸制备完以后，直接加催化剂进去做suzuki偶联。
最后使用异丙醇，Na2CO3水溶液，60℃，5% Pd/C，合成了几公斤的联苯（X=F）OPRD 1999, 3,248-252化合物2是合成SB-245570 (1)的中间体，2的合成需要用到6 和7的suzuki偶联，一开始使用的是Pd（PPh3）4体系，但是Pd （PPh3）4比较贵，考虑使用便宜的Pd/C最终条件：6（1eq），7（1.06eq），Na2CO3 (1.92 eq)，Pd/C (1.18%), MeOH/H2O (1:1),回流5h。
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Oxidation addition
Reductive elimination
2.
3.
Transmetalation
Reductive elimination diaryl- > (alkyl)aryl- > diethylpalladium(II)
transmetalation
General cycle for cross coupling
Pd(0)Ln ROTf [R-Pd( Ⅱ)][TfO]Ln PPh3 LiBr R-Pd-BrnL2
[Ph3PR] [Tfo]
Pd(0)
Application of Suzuki coupling
1.5 coupling with Aryl iodide
For Aryl idiode, the reaction could be performed under mild condition without ligand of phosphine. Such as PdCl2, Pd(OAc)2, Pd/C which makes the purification easier.
HO ArB(OH)2 I 0.3% mol%Pd/C, 3 equiv K2CO3 H2O, r.t., 12h, 77-99%
J. Org. Chem.; 2002, 67, 2721
HO
OH B OH I OMe
Pd(OAc) 2 K2 CO 3, acetone/H2O
OMe
Org. Syn., Coll.V ol. 10, P501; vOL. 75, P61
Pd/C N O I (HO)2B COOH Na2CO3, MeOH/H2O, reflux, 91% O
Org. Process Res. Dev. 1999, 3, 248
N
COOH
Application of Suzuki coupling
1.6 coupling with heterocycle aryl compounds
Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 888.
Application of Suzuki coupling
1.2 coupling with bulky arylboronic acid
Low yields are resulted in when using ortho-disubstituted arylboronic acids. The order of reactivity for mesitylboronic acids corresponds to the basic strength: Ba(OH)2 > NaOH > K3PO4>Na2CO3>NaHCO3.
O O Br N BEt2 aq. NaOH/Bu4NCl, THF Pd(PPh3)4 O N O
Synthesis 1984, 936
Application of Suzuki coupling
1.7 Coupling with Aryl chloride
using tricyclohexyl phosphine and P(t-Bu)3 as ligand could lead to high yield for the coupling with Aryl chloride.
F Br O O F OH B Pd(dppf )Cl2 OH Na2 CO 3, DCM, reflux O O
Patent: US2002/55631 A1 (2002/05/09)
Application of Suzuki coupling
1.4 coupling with Triflate
cross-coupling reactions
R R' R R' Si R' Y R' HY R'
Y= N, O, S, P
R
R' R' Mg R'
R R'
R
Sn R'
X
B R'
R R'
Zn R' R R'
R R'
R R'
Introduction
The cross-coupling reaction now accessible via a variety of organometallic reagents may provide a fundamentally common synthetic methodology.
a. Using toxic TlOH or Tl2CO3 as base.
b. Using potassium methyl trifluroboronate to do the coupling, which the reagent is easy to be prepared and is stable under air.
B. Hydroboration of Alkenes and Alkynes
CF3 Br O O S O 2 36 g, 90% N H N B(i-PrO)3 n-BuLi, -78oC
HO HO B
CF3 TFA salt O O S O N H N
WUXI-AU-167-01 13 g, 37%
CF3 Br O O S O N H N n-BuLi, -78oC B(i-PrO)3
HO HO B
CF3 O O S O N H
TFA salt N
2' 40 g, 93%
WUXI-AU-167-02 13 g, 33%
Application of Suzuki coupling
1.1 Microwave activated reaction biaryl coupling:
1.3 coupling with Aryl boronic acid having functionality
O B O O ArX K3PO4, DMF, 80 O
Organomet allics 1984, 3, 1392-1395.
Pd(PPH 3) 4
Ar
Aryl boronic acid 39% yield Aryl boronic ester 89% yield
But mostly weak base often get more clean reaction.
Pd(PPH 3) 4 B(OH) 2 ArX aq. Ba(OH) 2, DME, 80 Ar
J. Am. Chem. Soc.; 120; 28; 1998; 6920-6930
Application of Suzuki coupling
Ligand: triphenylphosphine; dppf
Key point of reaction:
1. Oxygen free 2. Temperature
Synthesis of organoboron Reagent
A. Synthesis from Organolithium or Magnesium Reagent
+
Cl F
B
Hale Waihona Puke Boc NN Boc
dioxane:H 2O(4:1) 120° C
F
N
92%
Application of Suzuki coupling
2.0 synthesis of Alkyl-Aryl
A. A combination of PdCl2(dppf) and aqueous NaOH in THF works nicely for most cases. Although strong bases accelerate the coupling reaction, more weak bases and aprotic conditions are desirable for functionalized alkylboranes.(K2CO3 or K3PO4 in DMF) B. There is often low yield for Aryl chloride and methyl boronic acid coupling.
Mechanism for cross-coupling
Rate-determination step
1. • • •
Oxidative addition addition rate: I > OTf > Br >>Cl Aryl halides with electron-withdrawing groups are more reactive than those with donating groups Alkyl halides having ß-hydrogen may compete with ß –hydride elimination
Application of Suzuki coupling
1.5 coupling with Aryl iodide
D.S.Ennis using Pd/C as catalyst to do Suzuki-coupling and synthesize the antidepressive drug SB-245570.
OH Cl O O B OH Pd(Cy 3)Cl2 CsF, NMP O
Tetrahedron Letter, 1997, 38(22), 5575
O
Application of Suzuki coupling
1.7 Coupling with Aryl chloride