R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Functionnalized Organometallic Reagents
C-N, C-O and C-S Bond Formation
Introduction to Organoboron Chemistry
Introduction to Organosilicon Chemistry
Carbometallation Reactions
R-M
R’-XR-R’
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Functionnalized Organometallic Reagents
C-N, C-O and C-S Bond Formation
Introduction to Organoboron Chemistry
Introduction to Organosilicon Chemistry
Carbometallation Reactions
R-M
R’-XR-R’
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
Generalities
Cross-Coupling Reactions with R-BF3K Reagents
Stille Cross-Coupling Reactions
Negishi Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Sonogashira Cross-Coupling Reactions
Arylation of Enolates
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Generalities
Very slow Slow Fast Fast Very slow
I >> Br > OTf > Cl
R-M
R’-XR-R’
5
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
High tolerance of functionnal grougs
T. Heh et al. Tetrahedron Lett. 2005, 46, 3573.
R-M
R’-XR-R’
6
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
A. E. Thompson et al. J. Org. Chem. 2005, 70, 388.
M. Uesugi et al. J. Am. Chem. Soc. 2009, 131, 4774.
R-M
R’-XR-R’
7
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
C. M. Crudden et al. J. Am. Chem. Soc. 2009, 131, 5024.
S. L. Buchwald et al. J. Am. Chem. Soc. 2005, 127, 4685
Works with hindered substrates
R-M
R’-XR-R’
8
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
Iterative Cross-Coupling Reactions
M. D. Burke et al. J. Am. Chem. Soc. 2007, 129, 6716.J. Am. Chem. Soc. 2009, 131, 6961.
R-M
R’-XR-R’
9
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
M. Suginome et al. J. Am. Chem. Soc. 2007, 129, 758.Org. Lett. 2008, 10, 377.Org. Lett. 2009, 11, 1899.
Iterative Cross-Coupling Reactions
R-M
R’-XR-R’
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
Better Understanding of the Mechanism
R-M
R’-XR-R’
11
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
Better Understanding of the Mechanism
Oxidative Addition
Csp3-X usually slow
Favoured by
Electronically Rich LigandsBulky Ligands
Can lead to b-H elimination
R-M
R’-XR-R’
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
Better Understanding of the Mechanism
J. A. Soderquist J. Org. Chem. 1998, 63, 461.
Y. Kishi J. Am. Chem. Soc. 1987, 109, 4756.
G. A. Molander Angew. Chem. Int. Ed. 2009, 48, 9240.
TM is accelerated by a base
R-M
R’-XR-R’
13
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Suzuki-Miyaura Cross-Coupling Reactions
Better Understanding of the Mechanism
Avoiding b-HElimination
BulkyLigands
ChelatingLigands
R-M
R’-XR-R’
14
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Cross-Coupling Reactions with R-BF3K Reagents
G. Molander et al. J. Org. Chem. 2005, 70, 3950.
G. Molander et al. J. Org. Chem. 2002, 67, 8416.
R-M
R’-XR-R’
15
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Cross-Coupling Reactions with R-BF3K Reagents
G. A. Molander et al. J. Am. Chem. Soc. 2008, 130, 9257.
G. A. Molander et al. J. Org. Chem. 2008, 73, 7481
R-M
R’-XR-R’
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Cross-Coupling Reactions with R-BF3K Reagents
Mechanism
G. A. Molander et al. J. Am. Chem. Soc. 2010, 132, 17108.
R-M
R’-XR-R’
16
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Overview of Different (pre)Catalytic Systems and Common Ligands
R-M
R’-XR-R’
17
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Stille Cross-Coupling Reactions
G.C. Fu et al. Angew. Chem. Int. Ed. 1999, 38, 2411.G.C. Fu et al. J. Am Chem. Soc. 2003, 125, 3718.
P. Espinet et al. J. Am. Chem. Soc. 1998, 120, 8978.J. Am. Chem. Soc. 2000, 122, 11771.
J. F. Hartwig et al. J. Am. Chem. Soc. 2001, 123, 1232.
On the Mechanism
R-M
R’-XR-R’
18
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Stille Cross-Coupling Reactions
E. J. Corey et al. J. Am. Chem. Soc. 1999, 121, 7600.
G. Guillaumet et al. Org. Lett. 2003, 5, 803.L. S. Liebeskind et al. Org. Lett. 2003, 5, 801.
R-M
R’-XR-R’
19
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Negishi Cross-Coupling Reactions
High Tolerance of Functionnal Groups
P. Knochel et al. Org. Lett. 2005, 7, 4871.
R-M
R’-XR-R’
20
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Negishi Cross-Coupling Reactions
S. L. Buchwald et al. J. Am. Chem. Soc. 2004, 126, 13028.
G. C. Fu et al. J. Am. Chem. Soc. 2001, 123, 2719.
« Quinoxaline »
R-M
R’-XR-R’
21
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Negishi Cross-Coupling Reactions
Alkenyl-Zinc
Alkyl-Zinc
G. C. Fu et al. J. Am. Chem. Soc. 2001, 123, 2719.J. Am. Chem. Soc. 2002, 124, 6343.
M. G. Organ et al. J. Org. Chem. 2005, 70, 8503.Org. Lett. 2005, 7, 3805.
R-M
R’-XR-R’
22
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Negishi Cross-Coupling Reactions
Alkynyl-Zinc
E. Negishi et al. Org. Lett 2003, 5, 1597.
J. A. Miller et al. Tetrahedron Lett. 2004, 45, 4989.
Tetrahedron Lett. 2005, 46, 2927. (benzylic electrophiles)Org. Lett 2001, 3, 3111. (aryl electrophiles)
R-M
R’-XR-R’
23
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Negishi Cross-Coupling Reactions
Compatibility
P. Knochel et al. Org. Lett. 2008, 10, 2765.
P. Knochel et al. Chem. Eur. J. 2009,15, 1324.
R-M
R’-XR-R’
24
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
S. Buchwald et al. J. Am. Chem. Soc. 2007, 129, 3844.
R-M
R’-XR-R’
25
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
E. Nakamura et al. J. Am. Chem. Soc. 2005, 127, 17979.
W. A. Herrmann et al. Angew. Chem. Int. Ed. 2000, 39, 1602.
With -Cl and -FPh-MgBr
R-M
R’-XR-R’
26
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Preparation
Acceleration Effect
Same observation in the presence of :
P. Knochel Angew. Chem. Int. Ed. 2009, 48, 205.
R-M
R’-XR-R’
27
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
R-M
R’-XR-R’
28
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
R-M
R’-XR-R’
29
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Mechanism ?
Radicals ?
R-M
R’-XR-R’
30
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Initiation
Propagation
R-M
R’-XR-R’
31
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Variation of Electrophiles
J. A. Miller et al. Tetrahedron Lett. 2001, 42, 6991.
J. W. Dankwardt Angew. Chem. Int. Ed. 2004, 43, 2428.
V. Snieckus et al. Angew. Chem. Int. Ed. 2004, 43, 888.
R-M
R’-XR-R’
32
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Copper-Catalyzed CKT Cross-Coupling
N. Kambe et al. Angew. Chem. Int. Ed. 2007, 46, 2086.
R-M
R’-XR-R’
33
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Copper-Catalyzed CKT Cross-Coupling
N. Kambe et al. Angew. Chem. Int. Ed. 2007, 46, 2086.
MgCl
MgCl
R-M
R’-XR-R’
34
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Copper-Catalyzed CKT Cross-Coupling
N. Kambe et al. Angew. Chem. Int. Ed. 2007, 46, 2086.
R-M
R’-XR-R’
35
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Copper-Catalyzed CKT Cross-Coupling
N. Kambe et al. Angew. Chem. Int. Ed. 2007, 46, 2086.
R-M
R’-XR-R’
36
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Manganese-Catalyzed CKT Cross-Coupling
G. Cahiez et al. Org. Lett. 2008, 10, 5255.
Stereoretention
R-M
R’-XR-R’
37
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Silver-Catalyzed CKT Cross-Coupling
K. Oshima Org. Lett. 2008, 10, 969.
Specially on Bulky Electrophiles
R-M
R’-XR-R’
38
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Special Case of N-tosylhydrazones
P. Aznar et al. Angew. Chem. Int. Ed. 2007, 46, 5587.
R-M
R’-XR-R’
39
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Special Case of N-tosylhydrazones
R-M
R’-XR-R’
40
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Corriu-Kumada-Tamao Cross-Coupling Reactions
Special Case of N-tosylhydrazones
R-M
R’-XR-R’
41
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Sonogashira Cross-Coupling Reactions
From terminal alkynes
Can be catalyzed by few transition metal complexes
R-M
R’-XR-R’
42
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Sonogashira Cross-Coupling Reactions
R-M
R’-XR-R’
43
R-M
R’-X
R-M
R-X-R’
R-X-M
R-R’
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Sonogashira Cross-Coupling Reactions
S. L. Buchwald et al. Org.Lett. 2000, 2, 1729.
C.-G. Cho et al. Org. Lett. 2002, 4, 1171.44
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Sonogashira Cross-Coupling Reactions
Copper-Catalyzed, Paladium-Free
M. Taillefer et al. Org. Lett. 2008, 10, 3203.
R-M
R’-XR-R’
45
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Sonogashira Cross-Coupling Reactions
M. Taillefer et al. Org. Lett. 2008, 10, 3203.
R-M
R’-XR-R’
46
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Sonogashira Cross-Coupling Reactions
M. Nakamura et al. Angew. Chem. Int. Ed. 2011, 50, 10973.
Iron-Catalyzed
R-M
R’-XR-R’
47
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
48
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
I. Beletskaya et al. Chem. Rev. 2000, 100, 3009. (review)
G. C. Fu et al. J. Org. Chem. 1999, 64, 10.
49
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
S. Cacchi et al. Org. Lett. 2003, 5, 777.
T. Tu et al. Synlett, 2011, 951.50
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
M. Santelli et al. Synthesis 2008, 1142.
T. Skydstrup et al. Angew. Chem. Int. Ed. 2006, 45, 3349.51
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
M. Santelli, Synthesis, 2006, 3495
J. Xiao, Angew. Chem. Int. Ed., 2006, 45, 4152 52
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
regioselectivities ?
53
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
J. Zhou et al. J. Am. Chem. Soc. 2014, 136, 650.
54
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
Decarboxylative Heck
A. G. Myers et al. J. Am. Chem. Soc. 2002, 124, 11250.
55
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Heck Cross-Coupling Reactions
R-M
R’-XR-R’
Decarboxylative Heck
A. G. Myers et al. Org. Lett. 2004, 6, 433. 56
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Arylation of Enolates
R-M
R’-XR-R’
58
J. F. Hartwig et al. J. Org. Chem. 1998, 63, 6546.
Lloyd-Jones et al. Angew. Chem. Int. Ed. 2002, 41, 953.
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Arylation of Enolates
R-M
R’-XR-R’
59
S. L. Buchwald et al. J. Am. Chem. Soc. 2000, 122, 1360.J. F. Hartwig et al.J. Am. Chem. Soc. 2002, 124, 9330.
S. L. Buchwald et al. J. Org. Chem. 2002, 67, 106.
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Arylation of Enolates
R-M
R’-XR-R’
60
J. F. Hartwig et al. J. Am. Chem. Soc. 2005, 127, 15824.
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Arylation of Enolates
R-M
R’-XR-R’
61
F. Y. Kwong et al. Org. Lett. 2007, 9, 3469.