第9章钯催化C-C键交叉偶联反应的机理

1、耙催化cc键交叉偶联反应及其机理+ mXm= B (Suzuki-Miyaura) Sn (Stille) Zn (Negishi) Si (Hiyama).M= Fe, Rh, Ni, Pd .X=l, Br, Cl, OTf.Acc. Chem. Res. 2013, 46, 2626-2634.1.锂催化cc键交叉偶联反应Alfred NobelorCross-Coupling ProductHalide3rd WaveV l be卜sa如jwiO Th? Nohel IviundAtkQ The Nobel FcmrdUkvnHeckNegishiSuzukiLigand3rd Wav

2、eMetal Catalyst1st WaveCoupling Partner2nd WaveNanjing University of Science and TechnologyNanjing University of Science and Technology7000 -6000 -5000 -4W0 -3000Suzuki HeckKumada NegishiSonogashiraStille Buchwald-HartwigHlyamaAlpha ketone arylation1000 -0Pre 19711fl71 -1 flfifl 1fi81-1RftO20007001-

3、2010Angew. Chem. I nt. Ed. 201 乙 51, 5062-5085.Nanjing Universrtji of Science and Technology19001910CuGteser18$9：Ullman 1901NO2XCu (3.7 equiv)200 °C. neatUllmann 1901PdHalide3rd WaveR2-YCouplingPartner2nd Wave19401950MeerweinlOk J)KhdrasiclZnCIOCl76% (X 二 Br)+ Me4SnTMetaf Catalyst fst WaveBrftB

4、u H wLigandCross-Coupling1960广丫 I 广5丫 Pd(OAc)2 (1.0 mol%)Pd(allyl)CI2 (2.5 mol%)19001910的 Z Ri = AlkylUyl Hartwl» 1995R2 = Alkyl. Arylr AlkynyliHPBuch wa Id 19951920193(1194Q195019601970Cul (1 mol%)HrPrffPPhoLUI mcl%'PdCI2P(otoly1)32 (5 mol%)HMDS, toluene. 100 °C2nd WavePdChlPCo-tolyl)

5、 (2 mol%)NaOfBu, toluene, 100 986%19701990PdCMPPhh (5 mol%)/BnaAIHfIQmol%)；HartwEg199SPhCH2Pd(PPh3)2CI(0.05 mol%)PdC以 PPhJ(0.5 mol%)PhDenmark 1999I 用 ura 19934Such wa Id 199?Nanjing Universrtji of Science and Technology2.反应机理LBP%1氧化加成2转移金属化3还原消除Nanjing Universrtji of Science and Technology存在问题：1缺乏更为

6、具体深入的理论和验证研究。2对于具体的因素和条件对于反应的影响缺乏明确 和系统解释和依据，如配体、金属和底物的类型 对于反应的影响。Nanjing Universrtji of Science and Technology2.1氧化加成LnpdNanjing Universrtji of Science and TechnologyNanjing Universrtji of Science and TechnologyLnPdXRPdLnNanjing Universrtji of Science and TechnologyNanjing Universrtji of Science an

7、d TechnologySn2机理： 1构型反转 2液相反应协同机理：1构型保持2气相反应3某些极性溶剂Nanjing Universrtji of Science and TechnologyLnPd +(3KDOxidative AdditionReductive EliminationNanjing Universrtji of Science and TechnologyNanjing Universrtji of Science and TechnologyBrPd/LupR1LUP = Unhindered PhosphineLHP = Hindered PhosphineR1B(

8、OH)2Pd/Sp9Nanjing Universrtji of Science and TechnologyNanjing Universrtji of Science and Technology1位阻小的磷配体，按SQ机理进行，在烷基位置反应。2位阻大的磷配体，按协同机理进行，在芳基位置反应。Chem. Eur. J. 2010,16f 13390-13397.Nanjing Universrtji of Science and Technology22转移金属化TransmetalationA+ m-(x)Suzuki couplings+ X-B(OH)2R1-Pd-X+R2-B(O

9、H)2R1-Pd-X + R2B(OH)Ppathway 府pathway 0)b(oh)3 + x°a R1Pd卜R?HO°Pathway B)1 Pathway 0.没有碱反应不能进行。2 PathwayA.主要的反应途径，碱首先活化 硼酸。3 PathwayR与丹仍于竞争反应，碱* *1 %i /1 Cm 1 , xoR1-Pd-OH + R2-B(OH)2 + X0B(OH)3Nanjing Universrtji of Science and TechnologyNanjing Universrtji of Science and TechnologyStille

10、 coupli ngs(RX + -SnR3晒十 (gg) + x-SnR3L-Pd-LIX+R2SnR3Cyclic Mecbanjsfn)L-Pd-R2R1XSnR3cis1环合机理A:锂过渡态上只有一个配体配位B:有利于配体离去的特性（大位阻的磷配体）C :环合步骤为决速步（F取代CI降低能垒，Au降低环合过 渡态的位阻）Y= L or solve ntQpen MechanisrriR2SnR3 XSnRsR1L-Pd-LR2trans2线性机理A:锂过渡态上有两个配体配位B :有利于X基团离去的特征（极性溶剂、三氟磺酸基） C :锡试剂取代X基团是最高能垒OR LPdR2ILcisN

11、anjing Universrtji of Science and TechnologyMe-Pd-CIZnM eCiIZn MeCIPdL2 + Me-MecisLtransNegishi coupli ngs咬X + -ZnY _+ X-ZnY(Y = R2 or halide)1反式(trans )过渡态比顺式(cis )的更容易生成 2两者是相互竞争的反应3只有顺式过渡态可以转化为最终产物4顺反式不会直接相互转换Nanjing Universrtji of Science and TechnologyNanjing Universrtji of Science and Technolo

12、gySonogashira couplings &x + H = Base ()>r + H_Basx°R1= aryl, hetaryl, alkenyl, alkyl, SiR$R2= aryl, hetaryl, vinylX= I, Br, Cl, OTfPdL2 + R1-X +1 Cu(l)可以活化烘婭生成烘基铜Cationic/ R PX *AnionicMechanismMechanism2根据脱质子和配体交换的顺序，可以将机理分为阳离子型机理和阴离子型机理。LR1-Pd-LHt-R2R1PdX3离子型机理与前两种机理存在竞争关系，可以有效提高 反应速率

13、。4离子型机理中碱有两个作用:结合质子和卤素(吸电基 有利于反应进行)BaseH-Base5BaseH-R2L=” a RJd-LH-Bas/X0IIOXR2(/o 门 jc Mechanism)R2Nanjing Universrtji of Science and Technology1转移金厲化过程是反应的决速步2锂不与氢原子直接作用，碱与质子结合后形成卡宾可以 与锂结合形成稳定的环状过渡态3 Concerted metalation deprotonation (CMD)IS2.3还原消除Reductive EliminationtransPdLn +1只有顺式产物会进行还原消除2还原消除过程不可逆3 过渡态能垒大小：vinyl < Ph < ethynyl < Me