C-H鍵活化,chemical review

1、Carboxylate-Assisted Transition-Metal- Catalyzed C-H Bond Functionalizations: Mechanism and ScopeLutz Ackermann*, Chem. Rev.2011, 111, 13151345New words and phrases：stoichiometricarenecomplexeswith respect todimericoptically activeortho-slopeentropyacetatecrystallographicprecursoragosticinteractiona

2、cidityfacilehencec.p.exceedingly化學(xué)計(jì)量的芳烴復(fù)合物關(guān)于，就而言二聚的光學(xué)活性鄰位斜率熵乙酸鹽結(jié)晶的前體抓氫鍵相互作用酸度溫和的，靈巧的因此，今后化學(xué)純非常，及其mildambientpyrroleproceedreadilyfavorableanalogousdisplacementin situdualdimersodiumtriflatebicarbonatecarbonatenoteworthyheteroatomhydrocarbonimido溫和周圍環(huán)境吡咯開始，繼續(xù)進(jìn)行容易地有利的類似的取代，移位在反應(yīng)過程中雙重的二聚體鈉三氟甲磺酸碳酸氫鹽碳酸鹽值

3、得注意的雜原子烴類酰亞胺New words and phrases：deuteriumfacilitatepyrazoleboratepronouncedcarbazoleisotopicubiquitousbe restricted tocesiumstand outalkali metalpivalatediastereoseletiveendothermicexothermicformatealkyneannulation氘促進(jìn)吡唑硼酸鹽明顯的咔唑同位素的普遍存在的局限于銫突出堿金屬三甲基乙酸鹽非對映選擇性的吸熱的放熱的甲酸鹽炔烴環(huán)化hydroxamicmain grouprcedoxp

4、redominatlyunravelelectron-withdrawingisoproypylbidentatepiralicbiarylpotassiumrevisitazoleelusiverobustnesstriazoleortho-meta-para-異羥肟酸主族氧化還原反應(yīng)占據(jù)主導(dǎo)闡明 吸電子異丙基雙齒的特戊酸聯(lián)芳鉀再論唑難懂的穩(wěn)健性三唑鄰位的間位的對位的1. Introduction 2. Stoichiometric C-H Bond Metalation 2.1. Intermolecular Metalation 2.2. Stoichiometric Cyclometa

5、lations 2.3. Related Assisted Metalations with Monodentate Bases3. Catalytic C-H Bond Functionalizations 3.1. Key Observations with Stoichiometric Amounts of Carboxylates 3.1.1. Aryl Halides as Arylating Reagents 3.1.2. Dehydrogenative Arylations 3.2. Catalytic Amounts of Carboxylates 3.2.1. Palladi

6、um 3.2.2. Ruthenium 4. ConclusionsCONTENTS1.INTRODUCTION Key to success was generally a detailed mechanistic understanding of the elementary C-H bond metalation step, which depending on the nature of the metal fragment can proceed via several distinct reaction pathways. 3 Traditional modes: oxidativ

7、e addition with electronrich latetransition metals -bond metathesis with early transition metals electrophilic activation with electrondeficient late transition metals（C-H鍵的金屬化有多種反應(yīng)模型，以下是三種經(jīng)典模型，分別是后過渡金屬的氧化加成；前過渡金屬鍵的復(fù)分解；缺電后過渡金屬的親電激活）1.INTRODUCTION oxidative addition with electronrich latetransition m

8、etals -bond metathesis with early transition metals electrophilic activation with electrondeficient late transition metals1.INTRODUCTION Within a continuum, detailed experimental and computational analysis provided strong evidence for novel C-H bond metalation mechanisms relying on the assistance of

9、 a bifunctional ligand bearing an additional Lewis-basic heteroatom, such as that found in (heteroatom-substituted) secondary phosphine oxides or most prominently carboxylates. Base-assisted metalation（經(jīng)過詳細(xì)的實(shí)驗(yàn)和計(jì)算分析，目前有一個(gè)雙官能團(tuán)配體和堿參與 的反應(yīng)機(jī)理為普遍承認(rèn)的C-H鍵金屬化的機(jī)理）1.INTRODUCTIONThis review contains: Summary of

10、the development and scope of carboxylates as cocatalysts in transition-metal-catalyzed C-H functionalizations until autumn 2010. Discussion of experimental and computational studies on stoichiometric metalation reactions being of relevance to the mechanism of these catalytic processes. （截止至2010年秋季的羧

11、化物作為助催化劑的發(fā)展和使用范圍的總結(jié)；化學(xué)計(jì) 量金屬化反應(yīng)在催化過程中與機(jī)理的關(guān)系，并進(jìn)行了實(shí)驗(yàn)與計(jì)算討論） Some acronyms：（本文反復(fù)出現(xiàn)的三個(gè)重要縮寫詞） CMD : concerted metalation deprotonation （協(xié)同的金屬化與去質(zhì)子化） IES : internal electrophilic substitution（分子內(nèi)親電取代） AMLA : ambiphilic metal ligand activation （親電和親核金屬配體的活化）2.STOICHIOMETRIC C-H BOND METALATION2.1. Intermolec

12、ular MetalationSEAr-type mechanismSEi-type mechanismsynchronous bond fission and bond formation protodemercuration of diphenylmercurymercuration（汞化） protodemercuration（去汞化） （鍵分裂和形成同步進(jìn)行的過渡態(tài)）（二苯基汞的去汞化）2.1. Intermolecular Metalation（SEAr-type mechanism） In 1980, Roberts and co-workers performed detaile

13、d kinetic studies on the mercuration of arenes by Hg(O2CCF3)2. Among others, large primary kinetic isotope effects (KIE) of kH/kD6 disclosed in 1967 by Kresge and Brennan already indicated the proton transfer to be rate determining . While previous mechanistic proposals had favored a SEAr-type manif

14、old with discrete -complexes,Roberts and co-workers rationalized their observations with transition state 1 featuring a synchronous bond fission and bond formation as illustrated in Figure 1; a SEAr-type mechanism could not completely be ruled out.The kinetic isotope effect (KIE) is the change in th

15、e rate of a chemical reaction when one of the atoms in the reactants is substituted with one of its isotopes. Formally, it is the ratio of rate constants for the reactions involving the light (kL) and the heavy (kH) isotopically substituted reactants:kIE=kL/kH （維基百科）KIE：動力學(xué)同位素效應(yīng) Notably, this mode o

16、f action resembled the previously proposed mechanism for the reverse reaction, that is, the protodemercuration of diphenylmercury, for which Winstein and Traylor had put forward a concerted SEi-type mechanism in 1955 . A related beneficial effect of stoichiometric amounts of pivalic acid in a gold-m

17、ediated C-H bond activation of electron-deficient arenes was disclosed by Larrosa and co-workers in 2010. 2.1. Intermolecular Metalation（SEi-type mechanism）Cytolysis of Diphenylmercury 2.STOICHIOMETRIC C-H BOND METALATION2.2. Stoichiometric Cyclometalation 1960s : Stoichiometric cyclometalation reac

18、tions of arenes bearing Lewis-basic directing groups were realized with complexes of various transition metals. 1970s : Additive NaOAc can accelerate cyclometalation reactions with iridium, platinum, or palladium complexes.Effect of NaOAc on the Cyclopalladation of Amine 2 Disclosed by Shaw (1972-19

19、75) no additive: -NaOAc (1.0equiv): 84%（醋酸鈉的加入能催化銥、鉑和鈀復(fù)合物的環(huán)金屬化反應(yīng)，下圖中加入 醋酸鈉后，產(chǎn)率增至84%）2.2. Stoichiometric Cyclometalation Importantly, it was proposed that the C-H bond metalation occurred via a carboxylate-assisted intramolecular deprotonation in a concerted fashion, as was illustrated by transition-

20、state structure 4. As a consequence, the authors proposed a mechanistic model in which the deprotonation occurred through assistance of a coordinated acetate. On the basis of crystallographic data on related palladium precursors, Ryabov and co-workers also considered the possibility of agnostic inte

21、ractions.（C-H鍵金屬化經(jīng)歷了羧化物輔助的分子內(nèi)去質(zhì)子化過程）（該段重點(diǎn)討論了乙酸鹽輔助下的金屬化機(jī)理模型） Proposed transition state 6 for ortho-palladation of DMBA-H.2.2. Stoichiometric Cyclometalation Transition state 4 of a carboxylate-assisted cyclopalladation as proposed by Sokolov and Reutov (1979). This agostic interaction enhances the ac

22、idity of the ortho-proton, which enables a subsequent facile intramolecular deprotonation by the coordinated acetate.（抓氫鍵增強(qiáng)了鄰位氫的酸性，隨后發(fā)生了乙酸鹽的輔助下的溫和的分子內(nèi)去 質(zhì)子化過程）2.2. Stoichiometric Cyclometalation b:initial agostic C-H bond interaction （抓氫鍵的相互作用） c:barrierless proton transfer（位阻較小的氫轉(zhuǎn)移） 8:six-membered t

23、ransition（六元過渡態(tài)）2.2. Stoichiometric Cyclometalation Cyclometalation reactions with iridium （銥催化的環(huán)金屬化反應(yīng)） Stoichiometric Cyclometalation of Pyrrole 10 in the presence of NaOAc 2.2. Stoichiometric Cyclometalation Cyclometalation reactions with iridium The mechanism of these transformations was explored

24、 through computational studies by Davies, Macgregor, and co-workers, which provided strong evidence for AMLA(6) transition state 11a, while the corresponding four-membered AMLA(4) transition state 11b turned out to be less favorable.（六元過渡態(tài)與四元過渡態(tài)相比更易形成）2.2. Stoichiometric Cyclometalation Cyclometalat

25、ion reactions with ruthenium（釕的環(huán)金屬化反應(yīng)） Both aryl- and alkyl-substituted imines reacted readily with Cp*RhCl22, solely N-alkyl-substituted imines provided the desired ruthenacycles with RuCl2(p-cymene) at ambient reaction temperature. （烷基和芳基取代的亞胺均可與Cp*RhCl22 發(fā)生金屬化反應(yīng)） Cycloruthenation in the Presence

26、of NaOAc 2.2. Stoichiometric Cyclometalation Cyclometalation reactions with ruthenium A proton abstraction mechanism（去質(zhì)子機(jī)理） was calculated to be more facile. Here, coordination of bicarbonate was calculated to yield structure12. Complex 12 evolved to formal ruthenium(III) complex 14 through transiti

27、on state 13 within a cyclometalation that was determined to be exothermic by 13.9 kcal mol-1. Calculated Mechanism for a Cycloruthenation 13 : three-membered transition state 14 : ruthenium(III) complex 2.STOICHIOMETRIC C-H BOND METALATION2.3. Related Assisted Metalations with Monodentate Bases It w

28、as experimentally observed that anionic monodentate ligands would enable efficient iridiations or ruthenations, respectively. The intermolecular metalation of benzene was shown to occur by assistance of the hydroxo ligand. （陰離子單原子螯合配體能催化銥和釕的金屬化反應(yīng)） Notably, complexes TpRu(PMe3)2(OH) and TpRu(PMe3)2(N

29、HPh) facilitated hydrogen/deuterium exchange. The mechanism of this transformation was shown to involve initial ligand dissociation and ruthenium(II)-mediated activation of an aromatic C-D bond.（ TpRu(PMe3)2(OH) and TpRu(PMe3)2(NHPh) 復(fù)合物能促進(jìn)氫-氘交換，該轉(zhuǎn)化的 機(jī)理包括開始的配體分解和二價(jià)釕介導(dǎo)的芳香C-D鍵的活化） Proposed Mode of Act

30、ion for C-H Bond Metalation with an Iridium(III)-Hydroxide Complex 2.3. Related Assisted Metalations with Monodentate Bases2.3. Related Assisted Metalations with Monodentate BasesProposed Mechanism for Deuterium-Hydrogen Exchange with TpRu(PMe3)2(OH) 3.CATALYTIC C-H BOND FUNCTIONALIZATIONS3.1. Key o

31、bservations with Stoichiometric Amounts of carboxylates Effect of Bases on Palladium-Catalyzed Sequential Direct Arylation 3.1.1. Aryl Halides as Arylating Reagents（芳基鹵化物作為芳基化試劑） Larock and co-workers observed that the nature of stoichiometrically used carboxylate bases exerted a pronounced effect o

32、n palladium catalyzed C-H bond functionalizations. （以羧酸鹽作為堿對鈀催化的C-H鍵的官能團(tuán)化有顯著影響） The elegant synthesis of carbazole 18 through “palladium migration”proceeded efficiently only when using CsOPiv as the base. （咔唑18的鈀遷移過程只有在使用CsOPiv作為堿時(shí)才可發(fā)生）3.1.1. Aryl Halides as Arylating ReagentsbaseyieldNEt30%Na2CO30%

33、NaOActraceCsOPiv60% Site-selective direct C-2 arylations of indoles were achieved under remarkably mild reaction conditions, with aryl iodides as arylating reagents and Ag2O as the base. Here, a pronounced effect of stoichiometrically added carboxylic acids was observed. Site-Seletive Palladium-Cata

34、lyzed Direct Arylation （鈀催化的直接芳基化的位置選擇） 3.1.1. Aryl Halides as Arylating Reagents With o-nitrobenzoic acid (19) providing optimal results for reactions at ambient temperature.additiveConversion(GC)-12%CH3CO2H49%o-MeOC6H4CO2H13%p-O2NC6H4CO2H81%o-O2NC6H4CO2H（19）99% CsOPiv clearly stood out as the base

35、 of choice in this site-selective transformation and carbonates or phosphates of alkali metals turned out to be ineffective. Detailed mechanistic studies revealed rhodium(III) pivalate 20 to be the resting state in the catalytic cycle. （CsOPiv仍是位置選擇轉(zhuǎn)化中較好的堿，堿金屬的碳酸鹽和磷酸鹽都被證明是無效的， 實(shí)驗(yàn)證明，三價(jià)銠復(fù)合物20是該催化循環(huán)中的過

36、渡態(tài)）3.1.1. Aryl Halides as Arylating Reagents The beneficial effect of stoichiometric carboxylate bases was not restricted to palladium-catalyzed transformations. Indeed, Sames and co-workers observed that particularly cesium carboxylates enabled efficient, rhodium-catalyzed direct C-2 arylations of

37、free (NH) pyrroles and indoles.（以羧酸鹽作為堿并不局限于鈀催化的轉(zhuǎn)化，也可用于銠催化的吡咯和吲哚的芳基化） The authors proposed that the pivalate ligand assists the C-H bond dissociation as an internal base, as was recently illustrated by Beck and Gaunt with transition state21. （特戊酸配體作為分子內(nèi)的堿是使C-H鍵裂解，其中間體為過渡態(tài)21）3.1.1. Aryl Halides as Ar

38、ylating Reagents CsOPiv as the Base in Rhodium-Catalyzed Direct Arylations3.CATALYTIC C-H BOND FUNCTIONALIZATIONS3.1. Key observations with Stoichiometric Amounts of carboxylates3.1.2. Dehydrogenative Arylations The palladium catalyzed direct oxidative coupling of arenes with alkenes, During the las

39、t decades, this process has matured to being a highly useful tool for diastereoselective syntheses of substituted alkenes, which is, for example, reflected by efficient oxidative arylations at ambient reaction temperature. Palladium-Catalyzed Fujiwara-Moritani Reaction at Ambient Temperature（鈀催化的烯烴對

40、芳烴的氧化偶聯(lián)反應(yīng)被廣泛用于取代烯烴的非對映選擇性 合成，下圖的反應(yīng)為室溫下鈀催化的Fujiwara-Moritani反應(yīng)。）3.1.2. Dehydrogenative Arylations The palladation with Pd(2-O2CH)2 was determined to occur through,-complex (R = Ph) 22 as intermediate, which gives rise to six-membered transition 23. The exothermic nature of this process was attributed

41、 to formation of the strong O-H bond through assistance of the coordinated formate ligand. Calculated Intermolecular Palladation within the Fujiwara-Moritani Reaction（已經(jīng)證明了Pd(2-O2CH)2參與的鈀化反應(yīng)經(jīng)歷了-復(fù)合物過渡態(tài)，該中間體 是六元過渡態(tài)。在甲酸配體的輔助下，C-O鍵形成后放出熱量，因此該過程 為放熱過程。）3.CATALYTIC C-H BOND FUNCTIONALIZATIONS3.2. Catalyti

42、c Amounts of Carboxylates3.2.1. Palladium . Carbonate-Assisted C-H Bond Functionalizations Transition-metal-catalyzed direct arylations with aryl halides are economically attractive alternatives to conventional cross-coupling reactions with prefunctionalized organometallic or main-group eleme

43、nt arylating reagents. Contrary to oxidative direct arylations, these overall redox-neutral processes do not require stoichiometric metal salts as terminal oxidant and can ensure regioselectivity through The use of easily accessible yet ecologically benign halides as leaving groups. （與氧化直接芳基化相比，這種介于

44、氧化還原之間的過程不需要化學(xué)計(jì)量的金屬 鹽作為終端氧化劑，并且有較好的區(qū)域選擇性，反應(yīng)較易發(fā)生，使用廉價(jià)的鹵 化物作為離去基團(tuán)，經(jīng)濟(jì)性較好。）. Carbonate-Assisted C-H Bond FunctionalizationsMerits :Not requiring stoichiometric metal salts as terminal oxidant. Ensuring regioselectivity. Ecologically benign as leaving group.. Carbonate-Assisted C-H Bond Fun

45、ctionalizations Two distinct mechanisms were put forward to account for this observation, namely, a -bond metathesis and an intermolecular deprotonation by a noncoordinated carbonate base.R=OMe 10:1R=Me 15:1R=t-Bu or CF3 30:1R=CO2Me 30:1R=Cl 3.2:1R=F 1:4.3羧化物輔助的C-H鍵官能團(tuán)化反應(yīng)有兩個(gè)可能的機(jī)理： （1）-鍵復(fù)分解機(jī)理（鍵復(fù)分解機(jī)理（

46、2）分子內(nèi)去質(zhì)子化機(jī)理）分子內(nèi)去質(zhì)子化機(jī)理. Carbonate-Assisted C-H Bond Functionalizations Intermolecular competition experiments unravelled the increased reactivity of pyridine N-oxides bearing electron-withdrawing groups, indicating a non-SEAr reaction manifold.（通過分子內(nèi)競爭實(shí)驗(yàn)，闡明了當(dāng)吡啶N-氧化物連有吸電子基團(tuán)時(shí)，活性增加） A complete in

47、version of reactivity as compared to reactions via traditional SEAr-type mechanisms was noted in that the less electron-rich arene reacted preferentially.. Carbonate-Assisted C-H Bond FunctionalizationsElectron-rich biphenyl monophosphine ligand S-PhosIsopropyl acetate as solventA lower react

48、ion temperature of 80oCThe optimum reaction condition: （實(shí)驗(yàn)結(jié)果與傳統(tǒng)的SEAr-type不同，芳烴的電子云密度越低，反應(yīng)活性越好。）. Carbonate-Assisted C-H Bond Functionalizations Palladium-Catalyzed Direct Arylations of Electron-Deficient Oligofluoro-Substituted (Hetero)Arenes. Carbonate-Assisted C-H Bond Functionalizat

49、ions Intramolecular competition experiments with Dave-Phos as the ligand highlighted a significant rate acceleration by electronegative groups exerting a negative inductive effect, such as fluorine, chlorine, or trifluoromethyl substituents. Intramolecular Competition Experiment（以Dave-Phos為配體進(jìn)行的分子內(nèi)競

50、爭實(shí)驗(yàn)表明，連有吸電誘導(dǎo)作用的 電負(fù)性基團(tuán)會增加反應(yīng)活性，比如氟、氯或三氟甲基取代。） These experimental observations, along with DFT calculations reported by Echavarren, Maseras, and co-workers, suggested a concerted deprotonative C-H bond metalation via carbonate assistance to be operative.. Carbonate-Assisted C-H Bond Functionaliz

51、ationsTwo mechanisms were calculated to be viable:(i)A concerted deprotonation through a coordinated carbonate in an intramolecular fashion.(ii) An intermolecular deprotonation through the action of an external noncoordinated carbonate base.（在大量實(shí)驗(yàn)的基礎(chǔ)上，經(jīng)過密度泛函理論計(jì)算，證明了羧化物輔助的C-H鍵 官能團(tuán)化的機(jī)理為伴有去質(zhì)子化的C-H鍵金屬化的

52、過程。）. Carbonate-Assisted C-H Bond FunctionalizationsComputed Mechanisms for C-H Bond Palladation in Intramolecular Direct Arylations. Carbonate-Assisted C-H Bond Functionalizations Interestingly, subsequent optimization studies revealed bidentate phosphine ligands, such as dppf, dppm,

53、dppe, or Xantphos, to be superior in intramolecular palladium-catalyzed direct arylations with aryl bromides. Monodentate phosphine ligands Bidentate ligands Monodentate versus Bidentate Phosphine Ligands in Palladium-Catalyzed Intramolecular Direct Arylations（單齒膦配體反應(yīng)活性好于雙齒配體）3.CATALYTIC C-H BOND FU

54、NCTIONALIZATIONS3.2. Catalytic Amounts of Carboxylates3.2.1. Palladium . Direct Arylations with Carboxylic Acids as Cocatalysts. C(sp2)-H Bond Functionalizations. With the aim of increasing the amount of available soluble base, Fagnou and Lafrance probed different carboxylic acids as cocataly

55、sts in palladium-catalyzed direct arylations of unactivated arenes. Effect of Base and Additive on an Intermolecular Palladium-Catalyzed Direct Arylation（為了考察鍵和羧酸的反應(yīng)活性，F(xiàn)agnou和Lafrance進(jìn)行了對比實(shí)驗(yàn)）. Direct Arylations with Carboxylic Acids as Cocatalysts. C(sp2)-H Bond Functionalizations Here, both

56、the quantity and the nature of the acid strongly affected the yield of the desired products.baseadditiveYield(GC-MS)K2CO3-0%KOPiV-41%K2CO3AcOH11%K2CO3i-PrCO2H13%K2CO3PivOH82% To rationalize the remarkable reactivity of the palladium catalyst derived from PivOH, the authors suggested that the potassi

57、um pivalate acts as a proton shuttle within concerted metalation-deprotonation (CMD) transition state.（上表可以看出，以特戊酸作為催化劑是產(chǎn)率最高。根據(jù)實(shí)驗(yàn)所表現(xiàn)出的這 種高反應(yīng)活性，作者提出了伴隨著金屬化-去質(zhì)子化過渡態(tài)的質(zhì)子穿梭機(jī)理）. Direct Arylations with Carboxylic Acids as Cocatalysts. C(sp2)-H Bond Functionalizations. Direct Arylations with C

58、arboxylic Acids as Cocatalysts. C(sp2)-H Bond Functionalizations An illustrative application of carboxylate-assisted palladium catalyzed direct arylations of arenes is represented by the efficient reaction of nitrobenzenes with aryl halides, which set the stage for an atom-economical preparation of

59、biaryl 29, an intermediate in the synthesis of the commercial agrochemical product Boscalid.（由芳基鹵化物對硝基苯進(jìn)行的鈀催化的直接芳基化是聯(lián)芳基化合物的原子經(jīng)濟(jì)性 合成方法，下圖所合成的產(chǎn)物是商用農(nóng)藥Boscalid的中間體）. Direct Arylations with Carboxylic Acids as Cocatalysts. C(sp2)-H Bond FunctionalizationsThe mechanism of palladium-catalyzed direct

60、 arylations of electron-deficient.. Direct Arylations with Carboxylic Acids as Cocatalysts. C(sp2)-H Bond FunctionalizationsPd(t-Bu)3(Ar)Brpalladium(II) speciessix-membered inner-sphere CMD transition state Subsequently, the acetic acid is likely deprotonated by the stoichiometric carbonate b