Part 10 Pd 催化的偶联反应

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
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:
Ligand: triphenylphosphine; dppf
Key point of reaction:
1. Oxygen free 2. Temperature
Synthesis of organoboron Reagent
A. Synthesis from Organolithium or Magnesium Reagent
same with the aryl compounds
O O N Br O2N B(OH) 2 Pd(PPH3)4 O aq. Na2CO 3, benzene N
J. Org. Chem. 1984, 49, 5237
O NO2
3-pyridine-diethylborane is stable under air and H2O, which could get good yield of suzuki coupling.
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
O N O Pd(PPh3) 4, K 2CO 3
OTf BocHN CO 2Me ArB(OH) 2 Pd(PPH3)4 BocHN K2 CO 3, toluene, 90 CO 2Me
J. Org. Chem.; EN; 57; 1; 1992; 379-381
Ar
The coupling with triflates often fails to proceed due to the decomposition of catalysts, precipitating palladium black at the early stage of reaction. Addition of 1 equiv of lithium or potassium bromide is effective in preventing such a decomposition of the catalyst.
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.
Application of Suzuki coupling
1.3 coupling with Aryl boronic acid having functionality
If there is function group are sensitive with H2O, such as –CN or Ester. The reaction can be dealed with in anhydrous solvent.
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%
Oxidation addition
Reductive elimination
2.
3.
Transmetalation
Reductive elimination diaryl- > (alkyl)aryl- > diethylpalladium(II)
transmetalation
General cycle for cross 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
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.
Suzuki Reaction
Reaction condition:
Catalyst: Pd(PPh3)4, Pd(dppf)Cl2;Pd(PPh3)2Cl2;Pd(AcO)2; PEPPSI-IPR Base: Na2CO3; NaOC2H5; triethylamine; K3PO4, CsF, TBAF, TBAC,TBAI,etc
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
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.
+
Cl F
B
Boc N
N Boc
dioxane:H 2O(4:1) 120° C
wenku.baidu.com
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.
Pd催化的偶联反应
欧成武
Pd-catalyzed C-C Coupling
1. Suzuki-Miyaura Coupling 2. Sonogashira Coupling 3. Heck Reaction 4. Stille Coupling 5. Hiyama Coupling 6. Negishi Coupling 7. Kumada-Corriu Coupling 8. Cyanation
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
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.
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
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