Modern Synthetic Methods - uni-muenchen.de€¦ · Modern Synthetic Methods Dr. Dorian Didier [email protected]. R-M R-X-R’ R-X-M R-B(R’) 2 R-Si(R’) 3 Cross-Coupling

Modern Synthetic Methods

Dr. Dorian Didier

[email protected]

mailto:[email protected]

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


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


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


Generalities

R-M

R’-XR-R’

4

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3


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



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



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



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



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



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



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




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




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




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



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



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



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


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



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



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



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



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



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



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



Compatibility


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



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



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



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



R-M

R’-XR-R’

28

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’

29

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



Mechanism ?

Radicals ?

R-M

R’-XR-R’

30

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



Initiation

Propagation

R-M

R’-XR-R’

31

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



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



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





MgCl

MgCl

R-M

R’-XR-R’

34

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3





R-M

R’-XR-R’

35

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3





R-M

R’-XR-R’

36

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



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



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



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




R-M

R’-XR-R’

40

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3




R-M

R’-XR-R’

41

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



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



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



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



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



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



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



R-M

R’-XR-R’

48

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



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



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



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



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



R-M

R’-XR-R’

regioselectivities ?

53

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



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



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



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



R-M

R’-XR-R’

57

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



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



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



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



R-M

R’-XR-R’

61

F. Y. Kwong et al. Org. Lett. 2007, 9, 3469.

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’

62

Remote Arylation

J. F. Hartwig et al. Angew. Chem. Int. Ed. 2010, 49, 5757.


Documents

Modern Synthetic Methods - uni-muenchen.de€¦ · Modern Synthetic Methods Dr. Dorian Didier [email protected]. R-M R-X-R’ R-X-M R-B(R’) 2 R-Si(R’) 3 Cross-Coupling