ORGANOMETALLIC COMPOUNDS

IN ORGANIC SYNTHESIS
UNIT 4
TRANSITION METAL ORGANOMETALLIC CATALYSTS
WITH / n / -DONOR LIGANDS

4.1 INTRODUCTION

4.2 DIHYDROGEN COMPLEXES

4.3 THE WILKINSON CATALYST. HYDROGENATION OF OLEFINS

4.4 HYDROFORMYLATION OF OLEFINS

4.5 CARBONYLATION OF METHANOL

4.6 METATHESIS

4.7 HECK AND CROSS-COUPLING REACTIONS

 Unit 4
Bibliography

Organometallics 1 Complexes with Transition Metal-Carbon

-Bonds (Manfred Bochmann)
Chapter 1: A few basics pp. 1- 7

Transition Metals for Organoc Synthesis. Building Blocks

and Fine Chemicals (Matthias Beller, Carsten Bolm Eds.)

Chapter 1.1: Basic Aspects of Organic Synthesis with

Transition Metals pp. 3- 14

Chapter 1.2: Concepts for the Use of Transition Metals in

Industrial Fine Chemical Synthesis pp. 15- 25
 Unit 4
Bibliography

The Organometallic Chemistry of the Transition Metals 4th

Ed. (Robert H. Crabtree)
Chapter 1: Introduction pp. 1- 28
Chapter 2: General Properties of Organometallic Complexes
pp. 29- 52

Fundamentals of Organometallic Catalysis

(Dirk Steinborn)
 Unit 4
4.7 Heck and cross-coupling reactions

In the presence of CO atmosphere, these reactions can be carbonylative

publications
 Unit 4
4.7 Heck and cross-coupling reactions
General mechanism
Favoured by:
Coupling partners with opposite electronic properties
Presence of bulky ligands to destabilize rearranged complex

Favoured by:
Electron poor E+
Strong σ-donating L
l > Br ~ OTf >> Cl
Favoured by:
C: electron rich group
Lack of steric hindrance on R-Pd-R’
 Unit 4
4.7 Heck and cross-coupling reactions
General mechanism. Reduction of Pd (II)
 Unit 4
4.7 Heck and cross-coupling reactions
General mechanism. Reduction of Pd (II)

Ozawa, F.; Kubo, A.; Hayashi, T.; Chem. Lett. 1992, 2177
Amatore, C.; Carre, E. Jutand, A.; M’Barke, M.A. Organometallics, 1995, 14, 1818
 Unit 4
4.7 Heck and cross-coupling reactions
General mechanism. Reduction of Pd (II)

Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S.L. Org. Lett. 2008,10, 3505
 Unit 4
4.7 Heck and cross-coupling reactions
Kumada-Tamao-Corriu coupling
 Unit 4
4.7 Heck and cross-coupling reactions
Kumada-Tamao-Corriu coupling. Mechanism
4.7 Heck and cross-coupling reactions Unit 4

Kumada-Tamao-Corriu coupling. Conditions

Best results with diphosphine ligands (best dppp) and
aryl or vinyl chlorides

PhBr

Steric hindrance is acceptable only on the Grignard component

The reaction is limited to halide partners that do not react with organomagnesium compounds

Pd catalysis is also effective: Pd(OAc)2/PCy3 coupling of alkyl halides (Beller, M. et al. ACIE 2002, 114, 4218-4221)
4.7 Heck and cross-coupling reactions Unit 4

Negishi coupling

Baba S.; Negishi, E-.i. J. Am. Chem. Soc., 1976, 98, 6729-6731
Negishi, E-I.; Hu, Q.; Huang, Z.; Qian, M.; Wang, G.; Aldrichimica Acta, 2005, 38, 71-88.
Lessene, G. Aust. J. Chem. 2004, 57, 107-117.
4.7 Heck and cross-coupling reactions Unit 4

Negishi coupling. First report

Baba S.; Negishi, E-.i. J. Am. Chem. Soc., 1976, 98, 6729-6731
4.7 Heck and cross-coupling reactions Unit 4

Negishi coupling. Organozincs

Pihko, P. M.; Koskinen, A. M. P. Synlett 1999, 1966-1968

Organozincs are the most reactive organometals for TM-catalyzed cross-coupling

reactions.
They are usually generated via transmetalation from other organometals (Li, Mg,
Al, Zr…) in the presence of ZnCl2 or ZnBr
4.7 Heck and cross-coupling reactions Unit 4

Negishi coupling. Csp2-Csp3 Couplings

In contrast to what happens with Grignard reagents, when using -H containing
organozincs dehydropalladation does not compete with reductive elimination

Negishi J. Am. Chem. Soc. 1980, 102, 3298

4.7 Heck and cross-coupling reactions Unit 4

Negishi coupling. Csp2-Csp3 Couplings

4.7 Heck and cross-coupling reactions Unit 4

Negishi coupling. Csp3-Csp3 Couplings

Great challenge, since dehydropalladation can become competitive!!

Solution: inhibition of the -elimination using appropriate L [P(c-C5H9)3,…] that fill the
vacant coordination site needed for the -elimination, or speeding up the transmetallation
and reductive elimination steps.
Cardenas, D. J. Angew. Chem. Int. Ed. 1999, 38, 3018-3020.
Luh, T.-Y.; Leung, M.-k.; Wong, K.-T. Chem. Rev. 2000, 100, 3187-3204.
Cardenas, D. J. Angew. Chem. Int. Ed. 2003, 42, 384-387.
Frisch, A. C.; Beller, M. Angew. Chem. Int. Ed. 2005, 44, 674-688.
4.7 Heck and cross-coupling reactions Unit 4

Migita-Kosugi-Stille coupling

Main drawback: toxicity low polarity, poorly soluble in water (RSnR3)

Transfer scale : alkynyl > alkenyl > aryl > benzyl > alkyl (Me and Bu groups are
normally the non-transferable groups)

Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652.
4.7 Heck and cross-coupling reactions Unit 4

Migita-Kosugi-Stille coupling. Mechanism

As the rds is the ligand dissociation, Ph3As, a weaker donor than phosphines, gives faster
rates and generally better yields

Amatore, C.; Jutand, et al. Chem.Eur.J. 2001, 2134; J. Am. Chem. Soc. 2003, 125, 4212
4.7 Heck and cross-coupling reactions Unit 4

Migita-Kosugi-Stille coupling. Conditions (Cu and LiCl effects)

4.7 Heck and cross-coupling reactions Unit 4

Mizoroki-Heck reaction.

Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev., 2000, 100, 3009; in Transition Metal Catalyzed Reactions,
Eds Murahashi, S.-I. Davies, S. I. Blackwell Science, Oxford, 1999, p. 29;
Whitecomb, N. J.; Hii, K. K.; Gibson, S.E. Tetrahedron, 2001, 57, 7449.
Martin Oestreich Ed. The Mizoroki-Heck Reaction, Wiley, 2009
4.7 Heck and cross-coupling reactions Unit 4

Mizoroki-Heck reaction. Mechanism

Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314

4.7 Heck and cross-coupling reactions Unit 4

Mizoroki-Heck reaction. Cationic/neutral mechanism

4.7 Heck and cross-coupling reactions Unit 4

Mizoroki-Heck reaction. Catalysts

Deactivated substrates: electron-rich and bulky phosphines perform better.

Very reactive iodides, diazonium salts and acyl chlorides can be used without ligands.
N-heterocyclic carbenes are known to mimic phosphines. They are very good -donors
4.7 Heck and cross-coupling reactions Unit 4

Mizoroki-Heck reaction. Catalysts

t-Bu3P is malodorous and pyrophoric.

Solution: t-Bu3P.HBF4

Bedford, R. Coord Chem Rev. 2004, 248, 2283.

Littke, A. E.; Fu, G. Angew. Chem. Int. Ed., 2002, 41, 4176.
4.7 Heck and cross-coupling reactions Unit 4

Mizoroki-Heck reaction. Ligand-less conditions

The system KHCO3 / Bu4NCl in DMF without ligands is very effective. Under these
conditions,1 known as the Jeffery’s ligand-less conditions, R4N+X--stabilized Pd colloids are
formed and function as active catalysts.2

1. Jeffery, T. Tetrahedron, 1996, 52, 10113.

2. Reets, M. T., Westermann, E. Angew. Chem. Int. Ed. 2000, 39, 165.
4.7 Heck and cross-coupling reactions Unit 4

Mizoroki-Heck reaction. Ligand-less conditions

4.7 Heck and cross-coupling reactions Unit 4

Mizoroki-Heck reaction. Ligand-less conditions

Matsuda-Heck
4.7 Heck and cross-coupling reactions Unit 4

Mizoroki-Heck reaction. Regioselectivity

4.7 Heck and cross-coupling reactions Unit 4

Suzuki-Miyaura reaction

Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457

4.7 Heck and cross-coupling reactions Unit 4

Suzuki-Miyaura reaction. Mechanism

4.7 Heck and cross-coupling reactions Unit 4

Suzuki-Miyaura reaction. Nucleophiles

Me
BF3K

Me
Pd(OAc)2 (2 mol% Pd) Me
SPhos (4 mol%)
K2CO3, MeOH
Me
50 ºC, 20 h
Cl Me
92%
Pd(OAc)2 (1 mol% Pd) OH
Me
SPhos (2 mol%) Me
K3PO4, THF
100 ºC, 0.5 h
OH Me
94%

O
B
O
4.7 Heck and cross-coupling reactions Unit 4

Suzuki-Miyaura reaction. Nucleophiles

9-BBN Ar X Ar
n
BF3K n BF3K
Pd(OAc)2 /XPhos
KF,THF, t.a.

Pd(OAc)2 /DavePhos
Ar' X Cs2CO3,THF/H2O,
PCy2 80 ºC
PCy2
i-Pr i-Pr
NMe2
Ar
Ar'
n
i-Pr

XPhos DavePhos

Orthogonal synthesis
4.7 Heck and cross-coupling reactions Unit 4

Suzuki-Miyaura reaction. Electrophiles

Cl Me2N
R Pd2(dba)3/L : 1/2 Ar
R P(t-Bu)3
+
PCy2
Ar-B(OH)2
DavePhos
Me
Ph
Me Me
Me Me
Me Me
0.05% Pd, P(t-Bu)3 1% Pd, 4% P(t-Bu)3 1% Pd, P(t-Bu)3
94% 96% 88%

Ph Ph
Me
CN
MeO O
N
1% Pd, DavePhos 1.5% Pd, DavePhos 1% Pd, DavePhos
96% 92% 94%
4.7 Heck and cross-coupling reactions Unit 4

Sonogashira-Hagihara reaction. Cu-cocatalyzed mechanism

Amatore, C.; Jutand, A.; Le Duc, G. Chem. Eur. J. 2011, 17, 2492.
Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116.
Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
4.7 Heck and cross-coupling reactions Unit 4

Sonogashira-Hagihara reaction. Cu-free mechanism

L L
R' Pd X

H R
L L
(F)
R' Pd X

H R
Carbapalladation
(G)
mechanism
R H
R' Pd X
2L L (E)
R R'
(C) Pd0L2
R'X
L

L Deprotonation
L R H
L Pd R mechanism
R' Pd X
R' (B) (A)
L

R H
+ -
H-base X R H
R' Pd X
base + L L (E) L

García‐Melchor, M.; Pacheco, M. C.; Nájera, C.; Lledós, A.; Ujaque, G. ACS Catal. 2012, 2, 135.
4.7 Heck and cross-coupling reactions Unit 4

Sonogashira-Hagihara reaction. Cu-free mechanism

PdL2 + R R' Cationic mechanism

(C)
+
base L X-
R' Pd L
H-base+
H R L
(H)
L
R' Pd L R H
R' Pd X
(B) L (E)
-
R
R'
L Pd X base
X-

(I) H-base+
L
R
Anionic mechanism

Ljungdahl, T.; Bennur, T.; Dallas, A.; Emtenäs, H.; Martensson J. Organometallics 2008, 27, 2490.
4.7 Heck and cross-coupling reactions Unit 4

Sonogashira-Hagihara reaction. Catalysts and conditions

Huang, H.; Liu, H.; Jiang, H.; Chen, K. J. Org. Chem. 2008, 73, 6037.

Yi, C.; Hua, R. J. Org. Chem. 2006, 71, 2535.

4.7 Heck and cross-coupling reactions Unit 4

Sonogashira-Hagihara reaction. Catalysts and conditions

Choy, P. Y.; Chow, W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y. Chem. Eur. J. 2010, 16, 9982.

Alonso, D. A.; Nájera, C.; Pacheco, M. C. Adv. Synth. Catal. 2003, 345, 1146.

Brown, W. S.; Boykin, D´A. D.; Sonnier Jr, M. Q.; Clark, W. D.; Brown, F. V.; Shaughnessy, K. H. Synthesis 2008, 1965
4.7 Heck and cross-coupling reactions Unit 4

Hiyama coupling

RO also activates Si !

4.7 Heck and cross-coupling reactions Unit 4

Buchwald-Hartwig coupling
4.7 Heck and cross-coupling reactions Unit 4

Buchwald-Hartwig coupling

Guram, A.; Rennels, R.; Buchwald, S. ACIE, 1995 , 34, 1348

Louie, J.; Hartwig, J. Tet. Lett., 1995 , 3609