Transcript Synthesis of Optically Pure Non Proteogenic Amino Acids

Palladium Assisted Coupling Reactions
Outline
Introduction
The Mechanisms of Palladium Assisted Coupling
The Phosphine Ligands
The Coupling Reactions
Metal Catalysts Applications in Organic Chemistry
Precious Metal Catalysed Reactions Have Expanded the
Toolbox of Organic Chemists and Are Widely Used
Some Prominent Examples of Modern Catalytic Reactions
Carbon-Carbon Coupling Reactions
Asymmetric Hydrogenation
Selective Oxidations
Alkene Metathesis
Hydrosilylations
Carbonylations and Decarbonylations
Carbon Heteroatom Coupling Reactions
This Overview will Cover the Most Common Carbon-Carbon
and Coupling Reactions
Palladium Assisted Couplings



1)
The various Pd Assisted Coupling Reactions Have Closely Related Mechanisms1
The Initial Step of a Coupling Reaction is Formation of an Organopalladium Salt
Four Basic Methods Are Used for This Step:
Direct Metallation of a Hydrocarbon, usually with a Pd(II) Salt:
RH
2)
+
PdX2
R Pd X
+
HX
Exchange of an Anion with an Organometallic Reagent such as a Grignard:
RM
+
PdX2
R Pd X
+
MX
Palladium Assisted Couplings
3)
Oxidative Addition of an Organic Halide, Acetate etc to a Pd(0) Species
RX
4)
+
R Pd X
Pd(0)
Addition of a Pd(II) Salt to an Alkene, Diene or Acetylene
PdX2
+
R
R
X
XPd
R
R
Palladium Assisted Couplings
The Organopalladium Species so formed May Then Form Coupling
Products by One of Three Routes:
1) Disproportionation Followed by Reductive Elimination of the Coupled
Product
R Pd R
2 R Pd X
R Pd R
R R
+
+
PdX2
Pd
2) Alkylation or Arylation by an Organometallic Reagent Followed
by Reductive Elimination
R Pd X
R Pd
+
R1
R Pd
R1M
R
R1
+
R1
Pd
+
MX
Palladium Assisted Couplings
3)
Insertion into an Alkene, Diene or Acetylene Followed by
b Hydride or Reductive Elimination
H
R Pd X
H
+
R
PdX
R
+
XPdH
1) Heck Richard F., Palladium Reagents in Organic Synthesis, Academic Press 1985 p 179
Coupling Reactions
R
B
OH
R
R
Br
R
Pd (0)
Heck
R
Mg
+
Suzuki
OH
Palladium Assisted Coupling Reactions Have
Been Developed for a Variety Of Substrates
X
R
nBU
R Sn nBU
nBU
Kumada
R
Stille
R
X = Hal, Tosylate
R
Sonagashira
CH3
R Si CH3
CH3
R
Hyama
R
R
N
H
R
N
R
Buchwald-Hartwig
Coupling Reactions: The Catalytic Cycle
Most of These Coupling Reactions Have a Similar Catalytic Cycle
R X
Pd (0)
L
L
R
Oxidative Addition
Rate Determining Step
I > OSO2CF3 > Br > Cl
Pd +2
L
L
X
R1 M
R1
Transmetalation
M = H or Metal
R
X M
L
R
L
R
Pd +2
Pd +2
R1
L
L
Reductive Elimination
R1
Cis Trans Isomerization
Phosphine Ligands
The Use of Phosphine Ligands is Necessary for Nearly All Homogeneous
Catalysis with Precious Metals1.
Choice of the Ligand can Influence:
Solubility of the Active Species
Shielding and Steric Properties of the Catalyst
Electron Density at the Metal Center
Reactivity of the Catalyst
Lifetime and Turnover
The Enantioselectivity
Phosphine Ligands
Electron Rich Metal Centers Tend to Accelerate the Key
Oxidative Addition Step
 Effect Increased with Electron Donating Group in R
Phosphine Ligands Usually Strong  Donors and Weak  Acceptors
Electron Withdrawing Groups Favour  Acceptor Backbonding
 Acceptor
R
R
P
M
R
-Donor
Cone Angle
Tolman Coined the Name Cone Angle to Indicate the Approximate Amount of
“Space” that the Ligand Consumed About the Metal Center as Determined from 3-D
Space-Filling Models of the Phosphine Ligands2.
Bulkier Ligands with Larger Cone Angles Have higher Dissociation Rates Thereby
Accelerating the Key Oxidative Addition Step
M
cone angle 
Preparation of Phosphine Ligands
Two Major Routes5: Radical Addition of Alkenes to Phosphines
H2C
R
H2P
PH3
R
Radical Initiator
R
PH
R
Radical Initiator
R
R
P
Radical Initiator
R
Nucleophilic Substitution of Phosphine Halogenides with Grignard or Organo Lithium
Compounds
R
M
R1
P
Cl
R2
3
R1
P
R3
R2
Typical Examples
Phosphine Ligands
Cone
Angle
 -Donor
Stability
Triphenylphosphine
145o
Medium
Air Stable
Tricyclohexylphosphine
170o
Strong
Air Sensitive
Tri-(tert-butyl) Phosphine
182o
Strong
Air Sensitive
Trimesitylphosphine
212o
Medium Strong
Air Stable
Trimethylphosphine
118o
Medium Strong
Air Sensitive
Phosphine Ligands References
1)
2)
3)
4)
5)
H.U. Blasé, A. Indolese, A. Schnyder, Curr. Science. 78 2000 1336
C.A. Tolman, Chem Rev. 1977 77, 313
A.F. Littke, G.C. Fu, Angew.Chem. 1999 111, 2568.
J.P. Wolfe, H Tomori, J.P Sadghi, J. Jin, S.L. Buchwald, J. Org Chem. 2000 65, 1158
J.P. Wolfe, Angew. Chem. 1999 111, 2570
D.H.Valentine, J.H. Hillhouse, Synthesis 2003 16 2437
The Heck Reaction
X
R
Pd-(PPh3)4
R
+
R
Base -HX
X
+
Pd-(PPh3)4
R1
Base -HX
R
R1
Discovered in the Late 1960’s the Heck Reaction1 Has Become Very Widely Used
An Alkene is Coupled With a Aryl- or Alkenyl-Halogenide2 to Give Vinylarenes or
Dienes3
Catalysed by Palladium(0)Complexes with Tertiary Phosphine-Ligands
The Catalyst is Either Added Directly, i.e. as Tetrakistriphenylphosphine Palladium(0)
or the Catalyst is Produced in situ by Reduction of Palladium-Salts in the Presence of a
Suitable Phosphine-Ligand
Heck Reaction Catalytic Cycle
The Heck Reaction Differs2
Step 1: Oxidative addition
R-X
L
X
L
Pd2+
R
L
Pd
L
Step 2: Olefin Insertion
R1
Base
H2C
Step 4: Reductive elimination
L
X
Pd
L
L
X
2+
Pd2+
HH
L
H
R1 H
R1
R
Step 3: b-Hydride elimination
R
The Heck Reaction
Terminal Alkenes Good Substrates for Heck-Reaction and React
at the Non-Substituted Carbon.
Nonterminal 1,2-Disubstituted Alkenes Give Usually Product
Mixtures, With a Preference for the Less Sterically Hindered
Carbon5.
The Choice of the Right Amine-base6 and Especially the Right
Phosphine-Ligand has Great Influence on the Selectivity and
Reactivity in the Heck Reaction
Chiral Ligands Like (R)- or (S)- BINAP Have Been Used for a
Enantioselective Heck-Reaction 6,7,8.
OTriflate
+
O
Pd(OAc)2
O
R-BINAP
71% Yield, 93% ee
Heck Reaction References
1) R.F. Heck, J.am.chem..soc. 1968, 90 5518.
2) A. deMeijere, F.E. Meyer, Angew.Chem. Int.Ed.Engl. 1994, 33, 2379.
3) Either the olefin or the amine-base act as reducing agent
4) J.K. Stille, Angew.Chem.Int.Ed.Engl. 1986 25, 508
5) Organikum, 21st edition, Wiley-VCh, Weinheim 2000
6) T.Hayashi, A. Kubo, F. Ozawa Pure&Appl.Chem. 1992, 64, 421.
7) T. Hayashi et.al. Tetrahedron Lett. 1993, 34, 2505.
8) A.B.Dounay, K.Hatakana, J.J.Kodanko, M.Oestreich, L.E.Overmann,
L.A.Pfeifer, M.M.Weiss, J.am.chem..soc. 2003,125, 6261
Useful Acros Chemicals for the Heck Reaction
Tetrakis(triphenylphosphine)palladium(0) 99%
20238
1g5g
Palladium(II) acetate 47.5% Pd
19518
2 g 10 g
Palladium(II) chloride 59% Pd
19520
5g
Palladium(II) chloride 99,999%
36967
1g5g
Bis(triphenylphosphine)palladium(II) chloride 15% Pd
19732
1g5g
Bis(triphenylphosphine)palladium(II) chloride 98%
29925
250 mg 5 g
Tris(dibenzylideneacetone)dipalladium(0) 97%
1877
500 mg 5 g
Bis(dibenzylideneacetone)palladium
29197
1g5g
Bis(triphenylphosphine)palladium(II) acetate 99%
20927
1g5g
(R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl 99+%
26553
250 mg
(S)-(-)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl 99+%
26554
250 mg
(±)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl
36864
5g
Bis(tri-t-butylphosphine)palladium(0) 98%
36350
100 mg
Bis(tricyclohexylphosphine)palladium(0)
36351
100 mg
Tri-m-tolylphosphine 98%
31728
5g
Tri-p-tolylphosphine 95%
42233
5g
Tri-o-tolylphosphine 99%
42232
5g
Tris(4-methoxyphenyl)phosphine 95%
42224
10 g
Tris(4-chlorophenyl)phosphine 97%
42221
2g
Triisopropylphosphine 98%
31733
1g5g
Tri-tert-butylphosphine 95%
36098
1g 5 g
Trimesitylphosphine 97%
32113
1g
Tris(2,6-dimethoxyphenyl)phosphine
36496
5 g 25 g
Tricyclohexyl phosphine 97%
42161
5g
Acros offers currently more than 160 Aryl iodides and over 550 Aryl bromides .
The Suzuki Reaction
Amongst the Growing Number of Palladium-Catalysed C-C-Coupling
Reactions the Suzuki-Miyaura-Reaction1,2 Plays a Leading Role.
In This Reaction an Aryl-Halogenide is Coupled With an Arylor Vinyl-Boronic acid or Boronic-Ester to Unsymmetrical Biaryls
OH
B
X
Pd-Catalyst
OH
Base
R1
R2
R2
R1
Scheme 1
Tetrakis(triphenylphosphine)palladium is most common
Other Homogeneous Catalysts as Well as Immobilised or Heterogeneous8
Palladium-Compounds Have Been Used.
Advantages of the Suzuki-Reaction
The Stability of the Boron-Reagents3
Boronic Acids and Esters are Crystalline, Easy to Handle, Thermally
stable, Non-Toxic and Relatively Inert to Water and Oxygen
The Tolerance for Different Functional Groups
The Simple Experimental Conditions.
The Suzuki-Miyaura-Reaction Was Also Extended to B-alkyl
Compounds6.
Boronic Acids
The Easy Access to a Broad Variety Boronic-Acids Through Different
Synthetic Pathways
4,5 >160
Boronic Acids and Esters Available from Acros
CH3
Si CH3
CH3
BB
r3 /C
H
H
2 Cl
2O
2
H3C
X
+
O
H3C
H3C
B
HO
M
OH
B
CH3
CH3
O
CH3
CH3
B
O
H3C
t
lys
a
t
a
O
AO 33057
-C
Pd
se
Ba
B(OMe)3
Scheme 2
H2O
Pd
-C
ata
Ba
lys
se
t
H3C
X
2
/I
Al
BC
l
3
/C
H
3I
M=MgX or Li
+
H3C
H3C
H3C
AO 37163
O
BH
O
Suzuki Reaction References
[1] N.Miyaura, Advances in Metal-Organic Chemistry, JAI Press Inc. 1998
[2] Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483. N. Miyaura et al.,
Tetrahedron Letters 1979, 3437; N. Miyaura, A. Suzuki, Chem. Commun. 1979, 866
[3] Boronic acids and esters are crystalline, easy to handle, thermally stable, non-toxic and
relatively inert to water and oxygen
[4] synthesis of arylboronic esters: T.Ishiyama, M.Murata, N. Miyaura J.Org.Chem. 1995 60, 7508;
T.Ishiyama, N. Miyaura, J.Organometal.Che,. 611 (2000) 392.
[5] synthesis of vinyl-boronate esters by diboration or hydroboration:
T.B.Marder, N.C.Norman, Topics in Catalysis 5 (1998) 63.
[6] N.Miyaura, T.Ishiyama, M.Ishikawa, A.Suzuki, Tetrahedron Lett. 1986 27, 6369;
a review in: S.R.Chemler, D. Trauner, S.J. Danishefsky, Angew.Chem. Int.Ed.Engl 2001, 40, 4544.
[7] For a synthesis without phosphine-ligands; Org.Synthesis Vol 75, 61
[8] R. Heidenreich, K.Köhler, J.G.E.Krauter, J.Pietsch Synlett 7 (2002) 1118.
More Literatur: Littke, Fu, Angew. Chem 1998, 110, 3586.
Useful Chemicals from Acros for Suzuki Chemistry
Bis(pinacolato)diboron
Bis(triphenylphosphine)palladium(II) chloride
33057
29925
Pinacolborane
Catecholborane
9-Borabicyclo[3.3.1]nonane
Palladium(II)acetate
Tetrakis(triphenylphosphine)palladium
Tris(dibenzylideneacetone)dipalladium(0)
Tetrakis(acetonitril)palladium(II) BF4(1,1'Bis-(diphenylphosphino)-ferrocene) Palladiumdichloride “Pd(dppf)Cl2”
Palladium(II)chloride, 99.995%
Borontribromide 1 M in Methylenchoride
Borontrichloride 1 M in Methylenchloride
Bis(dibenzylideneacetone)palladium
1,2-Bis(diphenylphosphino)ethane
1,3-Bis(diphenylphosphino)propane
1,4-Bis(diphenylphosphino)butane
Triphenylphosphine, polymer supported
Triphenylphosphine, polymer supported
Bis(neopentylglycolato)diboron
Bis(Hexylene glycolato)diboron
Borontribromide 99,9%
Borontribromide 99+%
Borontrichloride 1 M in Hexane
37163
18290
34634
19518
20238
37071
36352
34868
36967
19890
17668
29197
14791
31005
29646
36684
36687
35889
36634
19892
Sonogashira Coupling
The Sonogashira-Reaction1 is the Palladium-Catalysed Coupling of CopperAcetylides and Aryl-Halogenides to Yield Alkynylarenes2,3
X
Pd-Catalyst
+
HC
R
Cu(I)-salt
R
Scheme 1
Sonogashira Coupling
This Reaction is One of the Most Important Reactions to Produce Alkenyl- and
Aryl-acetylenes4, which Have Recently Got a Lot of Attention as EndiynAntibiotics5,6
HC
SiMe 3
(Ph3P)2PdCl2
O
Et
O
Br
CuI, Et 3N
O
Et
O
SiMe 3
Br
Scheme 2
SiMe 3
TMS Acetylene in Sonogashira Coupling
The Use of Silylated Acetylene Avoids Coupling at Both Positions
The Silyl-Protecting Group can be Removed in-situ, to Enable the Second Coupling
Reaction i.e. for the Synthesis of Un-Symmetric bis-Arylethynes7
R1
HC
SiMe 3
SiMe 3
X
Pd-Cat. Cu(I)-salt, Base
R1
R2
Scheme 3
Sonogashira Coupling
The Sonogashira-Reaction has a Broad Scope, Tolerating Several Functional
Groups.
 It Can be Performed with Ammonia as Base in Aqueous Solution8
Works with Palladium on Carbon as Catalyst9
Recent Improvements of the Reaction Are the Development of Efficient Catalysts
for the Use of Arylchlorides10 and Copper-Free Protocols11.
Sonogashira Coupling References
[1] K.Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975, 4467-4470.
[2] C. E. Castro, R. D. Stephens, J. Org. Chem. 28, 2163 (1963). C. E. Castro, R. D. Stephens, J. Org.
Chem. 28, 3313 (1963).
[3] Organikum 21st ed. Wiley-VCH-Verlag Weinheim 2001.
[4] R.R.Tykwinsky, Angew. Chem.Int.Ed.Engl. 2003, 42, 1566
[5] G.Pratviel, J.Bernadou, B. Meunier. Angew. Chem.Int.Int.Ed.Engl. 1995, 34, 746; K.C. Nicolaou, W.-M.
Dai, Angew. Chem. Int.Ed.Engl. 1991, 30, 1387.
[6] A.G.Myers, P.M.Harrington, E.Y.Kuo, J.Am.Chem.Soc. 113 (1991) 694; A.G.Myers, M.M.Alauddin,
M.A.M.Fuhry, Tetrahedron Lett. 30 (1989) 6997.
[7] Y.Nishihara,, K.Ikegashira, K. Hirabayashi, J.Ando, A.Mori, T. Hiyama, J.Org.Chem. 2000, 65, 1780.
[8] A.Mori, M.S.M.Ahmed, A.Sekiguchi, K.Masui, T.Koike Chem.Lett. 2002, 756.
[9] R.G.Heidenreich, K.Köhler, J.G.E. Krauter, J.Pietsch, Synlett 2002, 1118
[10] A. Köllhofer, T. Pullmann, H. Plenio, Angew. Chem. 2003 115, 1086
[11] D. Gelman, S.L.Buchwald, Angew.Chem 2003, 115, 6176.
Useful Chemicals From Acros for Sonogashira Chemistry
(Triethylsilyl)acetylene
Trimethylsilylacetylene 98%
1-(Trimethylsilyl)-1-propyne 98%
1,4-Bis(trimethylsilyl)-1,3-butadiyne 98%
3-Trimethylsilyl-2-propyn-1-ol 99%
4-(Trimethylsilyl)-3-butyn-2-one 98%
36873
20357
22353
22539
31389
36780
1g5g
5 g 25 g
1g5g
5g
1g
5g
(Triisopropylsilyl)acetylene 97%
Bis(triphenylphosphine)palladium(II)chloride 98%
Tetrakis(triphenylphosphine)palladium(0) 99%
Palladium(II)acetate
Palladium (5%) on Carbon
Palladium (10%) on Carbon
36874
29925
20238
19518
19502
19503
5 g 25 g
2,5 g 5 g
1g5g
2 g 10 g
10 g 100 g
10 g 50 g
Acros Also Offers Over 70 Terminal Alkynes
The Stille Coupling Reaction
The Stille-coupling 1,2 is the Palladium-Catalyzed Reaction Between
Organo-Stannanes and Organic Halides3.
Typically the Stannane is sp2 or sp-Hybridised (Aryl, Alkenyl, Alkynyl) but
also Alkyl-, Allyl- and Benzyl-Stannanes4 Have Also Been Used.
SnBu3
+
Pd-cat
H2C
X
CH2
Reactivity order: Alkynyl > Alkenyl > Aryl > Allyl ~ Benzyl>Alkyl.
The Organic Halides May be Aryl, Vinyl- and Acyl1,6,7 Substituted2
The Stille Coupling Reaction
The Halides Are Usually Bromides or Iodides (and Also Triflates)
Tf O
SnBu3
Pd(PPh3)4 O
LiCl, 75%
O
H3C
CH3
H3C
CH3
The Stille-Coupling Can be Influenced by Additives Like Copper8-and
Silver9-Salts and Lithium Chloride10
The Stille Couping Reaction
The Pathway of the Reaction Has Been Studied11 and the Catalytic Cycle is
Similar to Other Palladium-Catalyzed Cross-Coupling Reactions2.
The Stille Coupling Has Found Many Applications in Organic Synthesis,
Due to the Broad Scope and Good Tolerance with Many Functional Groups.
Some Recent Examples in Total Synthesis: Synthesis of Amphidinolide A12,
Synthesis of Sanglifehrin13,14, Synthesis of Callipeltoside A15,
Partial Synthesis of Maitotoxine16.
Stille Reaction References
[1] D. Milstein, J. K. Stille, J. Am. Chem. Soc. 100, 3636 (1978).
[2] J. K.Stille, Angew.Chem. Int. Ed, 1986, 25, 508-524.
[3] Acetate and triflate are also possible.
[4] for an overview over different substituents see: T.N.Mitchell, Synthesis 1992 803
[5] A.F.Littke, G.C.Fu, Angew.Chem. 1999 111 2568
[6] Organic Syntheses, CV 8, 268
[7] J.A.Soderquist, I. Rosado, Y. Marrero, C. Burgos, Arkivoc 2001, 12
[8] V.Farina, S.Kapadia, B. Krishnan, C. Wang, L.S.Liebeskind, J.Org.Chem. 1994 59, 5905
[9] S. Gronowitz, P.Björk, J.Malm, A.-B. Hörnfeld, J.Organometal.Chem. 460 (1993) 127.
[10] W.J. Scott, J.K.Stille, J.Am.Chem.Soc. 108 (1986) 3033.
[11] H.Nakamura, M.Bao, Y. Yamamoto, Angew. Chem. 2001 113, 3308.
[12] H.W.Lam, G.Pattenden, Angew.Chem. 2002 114, 526.
[13] K.C.Nicolau, J.Xu, F.Murphy, S. Barluenga, O.Baudoin, H.Wei, D.L.F. Grey, T.Ohshima,
Angew. Chem 1999 111 2599
[14] M.Duan, L.Paquette, Angew. Chem 2001 113 3744.
[15] B.M.Trost, O.Dirat, J.L.Gunzner, Angew.Chem 2002 114 869.
[16] K.C.Nicolau, M.Sato, N.D.Miller, J.L. Gunzner, J.Renaud, E.Untersteller, Angew.Chem 1996 108 952.
[17] R.Franzén, Can.J.Chem. 78 957 (2000).
[18] S.T.Handy, X. Zhang Org.Lett. 2001, 3 233.
Acros Products for Stille Reactions
Acros offers a wide range of palladium-catalysts,
phosphine-ligands and organo-tin-compounds for the
Stille-coupling:
Bis(tri-n-butyltin) oxide, stabilized
Tetra-n-butyltin 96%
Tri-n-butyltin chloride , tech. 90%
Bis(triphenyltin) oxide
Tetramethyltin 99%
Trimethyltin chloride 99%
Dibutyltin oxide 98%
Butyltin trichloride 97%
Dibutyltin dichloride 97%
Tetraethyltin 97%
Tri-n-butyltin hydride 97%
Tri-n-butyltin cyanide 97%
Triphenyltin hydride 95%
Allyltributyltin 97%
O-Neopentyl-S-triphenylstannyl xanthate 95%
10651
13798
13935
15113
16398
16399
17936
19120
19487
21207
21573
21602
22378
26555
29333
Hiyama Coupling Reaction
The Hiyama-Coupling 1,2 is the Palladium-Catalysed Reaction Between
Aryl- and Alkenyl- Halogenides or Triflates with Organo-Silanes.
Cl
Pd
CH2 -
Pd
CH2 -
I
Cl
Si
+
TASF, HMPA, 50 oC
O
O
Cl
0.5% PdCl2(PiPr3)2
+
O
6 Eq KF, DMF, 120oC
Cl
Si
Cl
O
The Hiyama-Coupling is Comparable with the Stille-Coupling with the
Advantage of Avoiding Toxic Tin Compounds in the Reaction.
Hiyama Coupling Reaction
The Reaction Rate is Increased by Activating the Silane with Fluoride and
by Using Chloro and Fluorosilanes instead of Trimethylsilanes3
Microwaves Have Been Used to Accelerate the Reaction Rate4.
Recently the use of Siloxanes5 and of Silacyclobutanes6 in the
Hiyama Coupling Have Been Reported
CH3
10 mol % Pd(OAc)
Br
CH3
20 mol % PPh3
2 Eq. PhSi(OMe)3
CH3
2 Eq TBAF, DMF, 85°C
85% yield
CH3
The Reaction Tolerates Several Functional Groups and Also Different
Aromatic or Vinylic Systems Can be Transferred7.
Hiyama Reaction References
[1] Y. Hatanaka, and T. Hiyama, J. Org. Chem., 1988, 53, 918, Y. Hatanaka, and T. Hiyama,
Pure.Appl.Chem. 1994, 66, 1471.
[2] A.F.Littke, G.C.Fu, Angew.Chem. 2002, 114, 4350
[3] K. Gouda, E.Hagiwara, Y.Hatakana, T.Hiyama, J.Org.Chem. 1996 61, 7232.
[4] U.S.Sørensen, J.Wede, E.Pombo-Villar, ECSOC-5, September 2001.
[5] P.DeShong, C.J.Handy, M.E.Mowery, Pure.Appl.Chem. 9 2000 1655, M.E.Mowery, P.DeShong,
Org.Lett, 1999 2137.
[6] S.E.Denmark, J.Y.Choi, J.Am.Chem.Soc., 1999, 121, 5821.
[7] K. Hosoi, K. Nozaki, T. Hiyama, Proc. Japan Acad., 78, Ser. B (6), 154-160 (2002), K. Hosoi, K. Nozaki,
and T.Hiyama, Chem.Lett, 2002, 138.
Acros Products for Hiyama Chemistry
Vinyltrimethylsilane 97%
Tetravinylsilane 97%
Triethylvinylsilane 97%
1,1-Bis(trimethylsilyloxy)2-trimethylsilylethene
Allyldichloromethylsilane 97%
Triphenylvinylsilane 95%
(1-Bromovinyl)trimethylsilane 97%
Triethoxyvinylsilane 97%
Vinyl tris(2-methoxyethoxy) silane 96%
Vinyltriacetoxysilane, monomer 90%
Vinyltris(trimethylsilyloxy)silane 95%
Phenyltrimethoxysilane
Dichloromethylphenylsilane 98%
20033
31373
31377
33101
33819
35099
40328
17461
25051
25056
33847
37064
14738
Palladium catalysts
Bis(triphenylphosphine)palladium(II)chloride 98% 29925
Allylpalladium chloride, dimer ,98%
Tetrakis(triphenylphosphine)palladium(0),99%
20683
20238
Tetrabutylammoniumfluoride,
1 M in tetrahydrofurane
Tetrabutylammoniumfluoride,
trihydrate, 99%
Dichloromethylvinylsilane 97%
Phenyltrichlorosilane 95%
Vinyltrimethoxysilane 98%
20195
22108
14743
13100
21652
and many more silanes, chlorosilanes and siloxanes
Kumada Coupling Chemistry
The Kumada-Coupling1,2,3 is the Nickel4or Palladium-Catalysed Reaction
Between Aryl and Vinyl-Halogenides or Triflates and Aryl, Alkenyl or Alkyl- GrignardReagents5,6
Heteroaryl7 and Alkyl8-Halides Can Also be Coupled with Grignard Reagents.
Kumada Coupling Chemistry
X
Mg
Br
Pd or Ni
+
catalyst
R1
R1
R2
R2
Cl
+
2 n-Butyl-MgBr
(dppe)NiCl 2
CH3
Cl
H3C
Mg
+
CH3
Br
Pd(OAc)2
PCy3
Cl
CH3
Kumada Coupling Chemistry
The Reactivity of the Halogenides Follows the Order I > Br > Cl
When Palladium is Used as Catalyst, Whereas with Certain Nickel Catalysts
the order is: Cl > I > Br5.
(Z)-Alkenyl-Grignards Couple non-Stereospecific with Nickel Catalysts2,
but the Reaction is Stereospecific (“Retention of Configuration”)
with Palladium-Catalysts9.
The Phosphine-Ligand has a Strong Influence on the Yield with Bidentate
Ligands Having Greater Activity than Monodentate Phosphines.
Bis(diphenylphosphino)propane (AO 31005) is Optimal for Most reactions2
The Kumada-Coupling is Somewhat Limited Because of the Incompatibility
of Grignard-Reagents with Certain Functional Groups.
Kumada Coupling Chemistry
Murahashi et al11,12 Have Used Numerous Organo Lithium Compounds instead of
Grignard-Reagents for a Kumada-Like Coupling Reaction.
O
Li PdCl , PPh
2
3
O
Br
Br
O
Li PdCl , PPh
2
3
O
In a Recent Example the Kumada Coupling Was Used for an
Intermediate Step in the Total Synthesis of (+)-Ambrucitin13.
CH3
H2C
Mg
CH3
Br
O
O
I
CH3
CH3
Pd(PPh3)4
CH2
CH3
CH3
Kumada Reaction References
[1] M.Kumada, J.Am.Chem.Soc. 1972 94 4374.
[2] M.Kumada, Pure Appl. Chem 1980 52, 669.
[3] G.C.Fu, A.F.Littke, Angew.Chem. 2002, 114, 4363.
[4] V.P.K.Böhm, T. Weskamp, C.W.K. Gstöttmayr, W.A. Herrmann Angew. Chem. 2000, 112, 1672
[5] K.Tamao, K.Sumitano, Y.Kiso, M.Zemayashi, A.Fujioka, S.-I. Komada, I. Nakajima, A. Minato, M.Kumada,
Bull.Soc.Chim.Jap. 49 (1976) 1958
[6] M. Kumada, K. Tamao, and K. Sumitani, Organic Syntheses, CV 6, 407
[7] K.Tamao, S.Komada, I.Nakajima, M.Kumada, A.Minato, K.Suzuki, Tetrahedron 38 (1982) 3347.
[8] A.C.Frisch, N. Shaikh, A.Zapf, M.Beller, Angew.Chem. 2002, 114, 4218.
[9] S.I.Murahashi, J.Organometal.Chem. 653 (2002) 27.
[10] Kumada-coupling with „sensitive“ Grignard-reagents: V.Bonnet, F. Mongin, F.Trécourt, G.Quéguiner, P.Knochel,
Tetrahedron Lett. 42 2001, 5717.
[11] M. Yamamura, I.Moritani, S.-I. Murahashi, J.Organometal.Chem. 1975 91 C39; S.-I. Murahashi,
M.Yamamura, K.Yanagisawa, N.Mita, K.Kondo, J.Org.Chem. 1979, 44 2408.
[12] S.I.Murahashi, T.Naota, Y. Tanigawa, Organic Syntheses, CV 7, 712.
[13] P.Liu, E.N.Jacobsen, J.Am.Chem.Soc. 2001, 123, 10772.
Acros Products for Kamada Chemistry
Nickel & Palladium Catalysts and Ligands
[1,3-Bis-Diphenylphosphino-propane] nickel(II)chloride
Nickel acetylacetonate 96%
Bis(triphenylphosphine)nickel(II)chloride 98%
Tetrakis(triphenylphosphine)nickel(0) 95%
[1,2-Bis-Diphenylphosphino-ethane] nickel (II) chloride
29159
12826
21750
22398
36323
Bis(triphenylphosphine)nickel(II)bromide 99%
Nickel(II) chloride hexahydrate , 99.9999%
Nickel(II) chloride hexahydrate , p.a.
1,2-Bis(dicyclohexylphosphino)ethane nickel(II) chloride
31632
19357
27051
30116
1,1’-Bis-(diphenylphosphino)ferrocene
1,2- Bis-(diphenylphosphino)ethane
1,3-Bis(diphenylphosphino)propane
1,4-Bis-(diphenylphosphino)butane
34801
14791
31005
29646
Bis(triphenylphosphine)palladium(II)chloride 98%
Tetrakis(triphenylphosphine)palladium(0) , 99%
1,1’-Bis(diphenylphosphino)ferrocene palladium(II) chloride,
complex with dichloromethane
29925
20238
34868
Acros Also Offers Large Collection of Grignard and Organo Lithium Compounds
Buchwald Hartwig Chemistry
The Transition Metal Catalyzed Cross-Coupling Between Aryl-halogenides1,2,3
and –Triflates4 and Primary or Secondary Amines to Anilines is Called the
Buchwald-Hartwig5 Reaction.
.
R1
Hal
R
+
N
R
Pd Catalyst
HN
R1
Base
By Replacing the Amines with Alcohols or Phenols the Reaction Leads to
Arylethers6,7 Although the “Reductive Elimination” Step is Somewhat More
Difficult8
Buchwald Hartwig Chemistry
The Buchwald-Hartwig Reaction Has Been Used in the Synthesis of
Acridones15 and Other Heterocycles
The Chemo and Regioselectivity of the Buchwald-Hartwig Reaction was
Shown in the Total Synthesis of Isocryptolepine16
Buchwald Hartwig Chemistry
Yields Can be Strongly Improved by Using Sterically Hindered Phosphine Ligands1,9,10,11 or the
Very Potent N-Heterocyclic Carbenes12,13, Made From Imidazolium Salts
Scheme 2
P
CH3
P
N
H3C
AO 35621
AO 35622
H3C CH3
CH3
P
H3C
Cl
CH3
CH3
CH3
H3C
N
+
N
H3C
CH3
CH3
AO 35623
-
H3C
AO 35619
Buchwald Hartwig Chemistry References
1) J.F.Hartwig, Angew. Chem. Int. Ed.,Engl. 1998, 37, 2046-2067.
2) M.H.Ali, S.L.Buchwald, J. Org. Chem. 2001, 66 2560– 2565.
3) J.F.Hartwig, M.Kawatsura, S.H.Hauck, K.H.Shaughnessy, L.M.Alcazar-Roman, J.Org.Chem. 1999 64, 5575.
4) J.Louie, M.S.Driver, B.C.Hamann, J.F.Hartwig, J.Org.Chem.1997, 62, 1268.
5) The first examples have been reported independently in 1995: A.S.Guram, R.A. Rennels, S.L.Buchwald,
Angew.Chem, Int Ed.Engl. 1995, 34, 1348; J.Louie, J.F.Hartwig, Tetrahedron Lett. 1995, 36, 3609.
6) M.Palucki, J.P.Wolfe, S.L.Buchwald, J.Am.Chem.Soc. 1996 118, 10333.
7) A.Aranyos, D.W.Old, A.Kiyomori, J.P.Wolfe, J.P.Sadighi, S.L.Buchwald, J.A.Chem.Soc, 1999 121, 4369
8) B.S.Williams, K.I.Goldberg, J.Am.Chem.Soc. 2001 123, 2576.
9) J.P.Wolfe, S.L.Buchwald, Angew.Chem. 1999 111 2570.
10) S.Urgaonkar, M.Nagarajan, J.G.Verkade, J.Org.Chem. 2003 68,452.
Buchwald Hartwig Chemistry References
11) J.P.Wolfe, H.Tomori, J.P.Sadighi, J.Yin, S.L.Buchwald J.Org.Che,. 2000 65, 1158
12) G.A.Grasa, M.S.Viciu, J.Huang, S.P.Nolan, J.Org.Chem. 2001, 66, 7729.13
W.A.Herrmann, Angew.Chem.Int.Ed.Engl. 2002 41, 1290.
14) B.H.Lipshutz, H.Ueda, Angew.Chem.Int.Ed.Engl. 2000 39 4492.
15) S.Mc.Neill, M.Gray, L.E.Briggs, J.J.Li, V.Snieckus, Synlett 1998 4, 419.
16) B.U.W.Maes, T.H.M.Jonkers, G.L.F.Lemière, G.Rombouts,
N Heterocyclic Carbenes
N-Heterocyclic Carbenes (NHC) Have Emerged as a New Class of ó-Donor Ligands with
Similar and Even Superior Electronic Characteristics as Phosphine-Ligands1.
The NHC’s A and B Can be Easily Prepared From the Corresponding Imidazolium-ions and
Imidazolidinium ions with Base 2,3,4,5.
R
R
N
N
:B
A:
N
N
R
R
Base
R
N
Cl
_
R
N
+
Cl
+
C H
C H
N
N
R
R
_
NHC Metal Complexes
In the Presence of a Suitable Metal the NHC form Complexes6 Which are
Very Useful as Catalysts for Cross-Coupling Reactions7 (i.e. with Palladium) or
Methatesis-8,9,10 Reactions (with Ruthenium).
Compared with Phosphine Ligands, the NHC-Metal Complexes Have a
Very High Catalytic Activity Combined with Improved Stability and
Endurance.
NHC References
1) W.A.Herrmann, Angew.Chem.Int.Ed.Engl, 2002, 41, 1290
2) W.A.Herrmann, Ch.Köcher, L.J.Gooßen, G.R.J.Artus, Che,Eur.J.1996, 1627.
3) M.Regitz, Angew.Chem. 1996,108,791.
4) W.A.Herrmann, Ch. Köcher, Angew.Chem. 1997, 109, 2256
5) O.V.Starikova, G.V.Dolgushin, L.I.Larina, T.N.Komarova, V.A.Lopyrev, Arkivoc 2003 119124.
6) W.A.Herrmann, M.Elison, J.Fischer, Ch. Köcher, G.R.J. Artus, Chem.Eur.J. 1996 2, 772.
7) A.C.Hillier, G.A.Grasa, M.S.Viciu, MH.M.Lee, C.Yang, S.P.Nolan, J.Organometal.Chem.
653 2002 69.
8) M.Scholl, T.M.Trnka, J.P.Morgan, R.H.Grubbs, Tetrahedron Lett. 1999 40, 2247.
9) L.Ackermann, A.Fürstner, T.Weskamp, J.F.Kohl, W.A.Herrmann, Tetrahedron Lett. 1999 40
4787.
10) A.Fürstner, Angew.Chem. 2000, 112, 3140ROS ORGANICS