Heck反应及金属催化偶联反应

J.Org.Chem.1989,54,5846
像天然产物physostigmine的合成，成功 的运用和Heck反应构成手性的季碳中心。
MeO
I O
N Me
OTIPS Pd2(dba)3-CHCl3 (10 mol%) (S)-BINAP (23 mol%)
PMP, DMA, 100°C
MeO
OTIPS
CO2Me
H 74% (46% ee)
J.Org.Chem. 1989, 54, 4738
同一年，Overman及其工作组首先利用Heck 反应合 成了手性季碳原子。
OTf O
Pd(OAc)2 (10 mol%) (R,R)-DIOP (10 mol%)
Et3N, C6H6, rt
O 90% (45% ee)
O N Me
3 M HCl THF, rt
MeO
CHO O N Me
84% (95% ee)
MeNH3Cl, Et3N LiAlH4, THF, reflux
(88%)
MeO
NMe NH Me (-)-esermethole
1) BBr3, CH2Cl2, rt 2) Na, Et2O, MeNCO
总的说来，Heck反应可以分为两大类：分子内反应 和分子间反应。第一篇该反应的报道是Heck 在1972年 发表的。
I +
Pd(OAc)2 (20 mol%) nBu3N (1 eq)
NMP, 100°C, 2h
Nolley, J.P.; Heck, R. F.; Tetrahedron 1972, 37, 2320
RX
Pd(0) Z
R Z
X = I, Br, OTf, etc
Z = 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PdR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。
Heck reaction
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
MeCN, 80°C, 10h
OMe
OMe
MeO O
O N
NCO2Me
90%
Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 6094
该反应还被Danishefsky应用到全合成Taxol上。
OTf
OTBS
O OH O
Pd(PPh3)4 (1.1 eq) K2CO3, MeCN, 85°C
2.2 形成季碳中心的反应
从20世纪80年代早期研究以来得到了广泛的应用。 1989年，Shibasaki 和Overman 首先报道不对称Heck反 应。
CO2Me I
Pd(OAc)2 (3 mol%) (R)-BINAP (9 mol%) cyclohexene (6 mol%)
Ag2CO3 (2 eq) NMP, 60°C
Heck 反应
汝杰
南京航空航天大学 仿生结构与材料防护研究所
过渡金属催化的交叉偶联反应
Transition Metal Catalyzed Cross Coupling
Organic Chemist
A
B
A
B
The formation of carbon–carbon bonds is a fundamental reaction in organic synthesis the efficiency of which has interested organic chemists for a long time ago. Aryl–aryl bond formation has been known for more than a century and was one of the first reactions involving a transition metal.1 Modern synthetic chemistry is also sustained by the use of transition-metal catalysts as powerful tools for carbon– carbon bond-forming processes.2 Among these, carbon–carbon coupling reactions through the activation of carbon–hydrogen bonds,3 as well as addition reactions,4 have experienced an increasing interest in the preparation of molecules, the access to which is not so straightforward using other methodologies. On the other hand, the transition-metal catalysed carbon–carbon bond formation developed in the 1970s represented a milestone in synthetic organic chemistry that allowed the cross coupling of substrates in ways that would have previously been thought impossible
Kumada reaction
The Kumada Coupling was the first Pd or Ni-catalyzed cross coupling reaction, developed in 1972.
Negishi reaction
Fukuyama Coupling
Glaser (Hay) Coupling
Suzuki Coupling
[Pd] or [Ni]
+ R1 X 2R
B(OH)2
Base
1R
R2
Sonogashira Reaction
R1 X + R2
H Pd-Complex, CuI
Amine
R2
R1
Amination Reaction
Stille reaction
Mori, M.; Ban, K.; Tetrahedron 1977, 12, 1037
2. 分子内的Heck反应
2.1 生成烯基取代的反应
该类反应主要用于生成环外双键。环外双键是合 成上一大难题，该反应成功的应用具有重大意义。
目前已有合成的报道。
MeO O
OMe I
OMe
O N
NCO2Me
Pd(PPh3)4 (cat) NEt3 (12 eq)
Mori 和 Ban于1977年首次报道了分子内的Heck反应：
CO2Me Br
N Ac
Pd(OAc)2 (2 mol%) PPh3, DMF
TMEDA (2 equaiv) 125°C, 5h
CO2Me
N Ac 43%
Indole product formed as result of Pd-H isomerization of product clefin
1
OMe
OMe
O N
NCO2Me
2
A stirred solution of 1, triethylmine and catalytic tetrakispalladium(0) in 2.4 mL of acetonitrile was heated at 80 ℃ in a sealed tube under an argon atmosphere for 10 h. The reaction mixture turned dark orange after ca10 minand the catalyst plated out on the walls of the tube as a shiny layer of palladium metal upon completion of the reactionThe reaction mixture was cooled to room temperaturethe reaction was quenched with aqueous NaHCO3andthe mixture was extracted with EtOAc The organic extracts were washed with aqueous NaHSO3 water and brine and dried over MgSO4 Filtrationconcentrationand purification of the orange residue by flash column chromatography gave 66mg of19 as acolorless solidmp 193-194 ℃Rf = 0.29
(31%)
MeNHCO2
NMe NH Me
(-)-physostigmine
Matsuura, T.; Overman, L.E. J.Am.Chem.Soc. 1998, 120, 6500
2.2.1 分子内不对称Heck反应
MeO
I
OTIPS
O
10 % Pd2(dba)3, 23 % (s)-BINAP, CHCl3 MeO
O
OTBS
H OO
O 49%
O
（紫杉醇）
Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 2843
分子内Heck反应化生成环外双键
MeO O
OMe I
OMe
Pd(PPh3)4 , NEt3(12eq)
NO NCO2Me
MeCN, 80℃, 10h
MeO O
OTIPS
O
N H
1,2,2,6,6-pentamethylpiperidine, DMA, 100 oC
N
H
1
2
A mixture of Pd2(dba)3·CHCl3 (360 mg, 0.347 mol), (s)-BINAP (504 mg, 0.809 mol), and N,N-dimethylacetamide (DMA, 21 mL) was stirred at room temperature for 65 min. To the resulting orange solution was added a solution of compound 1 (1.82 g, 3.51 mol), 1,2,2,6,6-pentamethylpiperidine (3.2 mL, 18 mmol), and DMA (18 mL), and the reaction was heated at 100 ℃ for 90 min. The result dark solution was poured into half-saturated aqueous NaHCO3 (100 mL) and extracted with ether (3 × 150 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4), and concentrated, and the residue was purified by sgc (9:1 → 1:1 hexane-EtOAc) to give oxindole enoxysilane compound 2 (1.29 g, 94%) as a 98:2
X
Ha
CO2Et
Hb
Hc
PdLn
Hb
CO2Et
Hc
X PdLn
Ha Hb
a PdLnX HcCO2Et
b
Ha
PdLnX
Hb
HcCO2Et
A
Hb
PdLnX
Ha
HcCO2Et
B
Hb
CO2Et
Hc
E
Ha PdLnX
Hc Ph
Hb CO2Et
CO2Et Ha Hc
Z
Hb PdLnX
Hc Ha
ຫໍສະໝຸດ BaiduPh CO2Et
2010 Nobel prize
瑞典皇家科学院说，这三名科学家因在有机合成领域中钯催化交叉偶 联反应方面的卓越研究获奖。这一成果广泛应用于制药、电子工业和先 进材料等领域，可以使人类造出复杂的有机分子。
赫克,79岁，美国特拉华大学名誉教授；根岸荣一,75岁,美国普渡大 学化学教授；铃木彰,80岁,日本札幌北海道大学教授。