giovanni poli master paris centre ue nc 843 2013-2014...
TRANSCRIPT
I
Giovanni Poli
Master Paris Centre
UE NC 843 2013-2014
Organometallic Catalysis Directed Toward Organic
Synthesis (block A)1
http://www.edu.upmc.fr/chimie/MC843-blocA/
.
Teachers: Giovanni Poli, Julie Oble
1 Scientific apparatus in the alchemist's workshop (1580), Chemical Heritage Foundation.
II
Program
1 The catalytic chemistry of palladium (0): [Pd(0) Pd(II) Pd(0)]
1.1 Pd(0) sources and generation of Pd(0) from Pd(II) complexes
1.2 Syn carbopalladations:
1.3 C-C Cross-couplings reactions
1.4 C-N / C-O Cross couplings
1.5 3-Allylpalladium Chemistry
1.6 Additions toY[Pd(II)]X-activated alkenes and alkynes (Y = C, N, O)
2 The catalytic chemistry of palladium (II):
2.1 Non-organometallic Pd(II) sources
2.2 Addition of Nucleophiles to Alkenes: General Reactivity
2.3 Oxidative processes [Pd(II) Pd(0) [Oxidant] Pd(II)]
2.4 Isohypsic processes [Pd(II) that stays Pd(II)]
3 A Selection among: Sequential Pd-catalyzed Reactions and Synthetic Applications
3.1 Kaneda / Sonogashira, Kaneda / Suzuki
3.2 Allylic alkylation / Pauson Khand
3.3 Sequential carbopalladations
3.3.1 Zip closures
3.4 Suzuki / Mizoroki-Heck
3.5 Carbopalladation / oxypalladation
3.6 Palladium-ene / carbopalladation
3.7 N-arylation / aryl-aryl coupling
3.8 Allylation / Mizoroki-Heck
3.9 The synthesis of N-acetyl clavicipitic acid methyl ester
3.10 The synthesis of strychnine
Pre-required Notions for NC 843 Essentially the first two chapters of UE NC741 course (UPMC Master Chimie)
1. The Transition Metal-Ligand bond: an introduction 1.1 Formal oxidation state, d
n configuration, oxidation number, coordinative unsaturation
1.2 Hapticity and electron count
1.3 Geometry of Transition Metals
1.4 Common ligands for transition-metal complexes (Phosphines, CO, carbenes)
2 The Elementary Steps in TM Catalysis 2.1 Ligand substitution
2.2 Oxidative addition
2.3 Reductive elimination
2.4 Oxidative coupling
2.5 Transmetalation
2.6 Migratory insertion
2.7 Dehydrometalation ( H-elimination)
III
Suggested Bibliographic References for Consultation
1 J. F. Hartwig, Organotransition Metal Chemistry: From Bonding to Catalysis, University Science
Books, 2010.
2 M. Bochmann, Organometallics 1, Complexes with Transition Metal-Carbon -Bonds, Oxford
University Press, Oxford, 1992.
3 L. S. Hegedus, Transition Metals in the Synthesis of Complex Organic Molecules, University
Science Books, Sausalito, California, USA, 1999.
4 M. Schlosser Ed. Organometallics in Synthesis: A Manual, J. Wiley & Sons, 2002.
5 F. Mathey, A. Sevin, Chimie Moléculaire des Eléments de Transition, Les éditions de l’École
Polytechnique, 2000.
6 J. Tsuji, Palladium Reagents and Catalysts, J. Wiley & Sons, 2004.
7 J. M. Campagne; D. Prim, Les Complexes de Palladium en Synthèse Organique, CNRS ed. 2001.
8 J. Tsuj Ed., Palladium in Organic Synthesis, Springer, 2005.
9 E-I Negishi Ed. Handbook of Organopalladium Chemistry for Organic Synthesis, J. Wiley & Sons,
2002.
10 C. Elschenbroich, Organometallics, Wiley-VH, Weinheim, 2005.
11 E. C. Constable, Metals and Ligand Reactivity, VCH, Weinheim, 1996.
12 R. Toreki, Organometallic Hypertext Book, http://www.ilpi.com/organomet
The Catalytic Chemistry of Palladium (0)
Pd(0) _____ Pd(II) ____ Pd(0)
Negishi, E.-i., Ed. Handbook of Organopalladium Chemistry for Organic Synthesis; Wiley-Interscience: New
York, 2002
G. Poli
1
Pd(0) Sources
[Pd(II)]X2 H[Pd(II)]X [Pd(0)] + XHdehydropallad.
H2C CH2 H2C CH2
X[Pd]X-coordination halopalladation X[Pd]
X
H
H2CX
Amines
Alkenes
[Pd(II)]X2
NEt3N [Pd(II)]X
Me
Me
Me X
HH
N MeMe
Me
H[Pd(II)]X
NEt3 XHNEt3
[Pd(0)]dehydropalladation reductive elimination
G. Poli
Throughout this course, brackets around palladium atom in the notation of a generic complex intend to
render implicit the dative ligands.
2
Pd(0) Sources
Ammonium formate or CO + H2O
Organometallics
G. Poli
Kammerer, C.; Prestat, G.; Madec, D.; Poli, G. Chem. Eur. J. 2009, 15, 4224
Cl[Pd]Cl
[Pd(0)]
dehydropalladation reductive elimination
H OH
ONEt3
[Pd]O
O
H
ligandsubstitutionNEt3HCl
CO2
[Pd]
Cl H
NEt3
Cl
NEt3HCl
H2O
Cl[Pd]ClCO Cl[Pd]Cl
C
O
Pd NN
Cl
Cl
C MeCMe
nBuLi (2.0 equiv.)nBu4NBr (2.0 equiv.)NaH, DMSO, 55°C Pd SS
O
Me
Me
O
Me
Me
Pd S
S
O
Me
O
Me
(0) (0)and/ or
possible in situ formed Pd(0) species
[Pd(II)]X2[Pd(0)]
2 n-BuLi 2 LiX
[Pd] Bu-n
Bu-nligand subst. reductive elim.
n-octane
NB: Also Dibal or hydrazine can also effect Pd(II) to Pd(0) reduction.
Remias, J. E.; Sen, A. J. Mol. Cat. A: 2002, 189 , 33
Related to car chemistry !
CO-to-CO2 conversion
3
Pd(0) Sources
Phosphine Pd(OAc)2 + 4 PPh3 + H2O -----> (PPh3)3Pd + O=PPh3 + 2AcOH
Ozawa, F.; Kubo, A.; Hayashi, T.; Chem. Lett. 1992, 2177
Amatore, C.; Carre, E. Jutand, A.; M’Barke, M.A. Organometallics, 1995, 14, 1818
G. Poli
4
Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S.L. Org. Lett. 2008,10, 3505.
Pd(0) Sources
Protocols for forming a highly active Pd(0) catalysts
NMe2
P
Bu-t
Bu-t
NaOBu-t
Pd
Cl
Pd
ClOBu-t NaCl
NMe2
P
Bu-t
Bu-t
Pd(0)solvent, heat
probable structure of the veryactive Pd(0) catalyst
1 Pd(OAc)2 + 4 H2O + 3 Pr-ii-Pr
PBu-t
Bu-t t-BuOH 110°C1.5 min
Pr-ii-Pr
Pr-i
PBu-t
Bu-tPd(0)
+ Pr-ii-Pr
Pr-i
P
Bu-t
Bu-tO
probable structure of the veryactive Pd(0) catalyst
+ AcOH
Pr-i
Lundgren RJ, Sappong-Kumankumah A, Stradiotto M. Chem. Eur. J. 2010, 16, 1983
Phosphine
Add of nucleophiles to π-allyl complexes
G. Poli
5
Pd(0) Sources
PdPd
Cl
Pd
Cl
Na PMe(tBu3)2, heatPd PP
Step 1: Tatsuno, Y.; Yoshida, T.; Otsuka, S. Inorg. Synth. 1990, 28, 342.
Step 2: Netherton, Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 3910.
Reductive elimination of Cp(η3-allyl)Pd
2 Na2PdCl4 + 2 CO + 2 H2OCl
2 Pd
Cl
Pd
Cl
4 NaCl + 2 CO2 +4 HCl
Cl Pd
Cl
Cl
C
1- Na+
Na2PdCl4 + CO-NaCl H2O
O Cl Pd
Cl
C
O
O-HCl
1- Na+
H
-CO2-HCl
ClPd(0)1- Na+
OH
HCl
ClPd(0)1- Na+
Cl
Pd
Cl
Pd
Cl
1/2
-NaCl
Preparation of [allylPdCl]2
G. Poli
6
Pd(0) Sources
Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073
See also: Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686.
In contrast to PPh3 ,these
phosphines do not reduce
Pd(OAc)2 to Pd(0), and use of
Pd(dba)2 gives unsatisfactory
results. This trick allows to
generate the active monoligated
XPhosPd(0) in situ.
Overall, o-phenyl aniline is
oxidized to carbazole and Pd(II) is
reduced to Pd(0).
G. Poli
Oxidation of o-phenyl aniline
7
NH2
Pd(OAc)2,
tol, 60°C
NH2
Pd
AcO
2
LiCl, acetone, rt (83%)
Cy2P
i-Pr
i -Pr i-Pr
Cy2P
i-Pr
i -Pr
i -PrN
PdClXPhos
HH
THFK2CO3 aq. rt
Cy2P
i-Pr
i -Pr
i -PrNH
Pd
P
i -Pr i -Pr
i-Pr
NH
Pd(0)
Cy Cycarbazole
amino-to-amido
reductive elimination
base
-0.5 CO2, -0.5 H2O, - KCl
o-phenyl aniline
Tetrakis(triphenylphosphine)palladium(0)
J. Chem. Soc. 1957
G. Poli
Pd(Ph3)4: The seminal paper
Malatesta, L.; Angoletta, M. J. Chem. Soc., 1957, 1186 8
Tetrakis(triphenylphosphine)palladium(0)
Crystal structure
Andrianov, V. G.; Akhrem, I.S.; Chistovalova, N. M.; Struchkov, Y. T. J. Struct. Chem. 1976, 17, 111
Pd(0) d10: tetrahedric
G. Poli
9
Tetrakis(triphenylphosphine)palladium(0)
O2 (air)
PdO
O
PPh3
PdPh3P
PPh3
PPh3
- PPh3
PPh3
PdPh3P PPh3
PPh3PdPh3P- PPh3(0)
(0)(0)
18e- 16e- 14e-
Ph3P
Ph3P
- 2PPh3
(II)
G. Poli
bright yellow crystals
Coulson;, D. R.; Satek, L. C.; Grim, S. O. Inorg. Synth. 1972, 13: 121
2007, Vol. 28 (ed R. J. Angelici), Wiley Ed.Hoboken, NJ, USA.
Pd
Cl
Ph3P
PPh3
Cl
2 PPh32.5 N2H4
- 0.5 N2- 2 N2H4HCl
Pd(PPh3)4PdCl2
PPh3
10
Pd2(dba)3.CHCl3
Pd(dba)2
cryst.CHCl3
PdCl2
Ph
O
Ph
NaOAc / MeOH ref lux nPPh3
(dba)(0)
(0)Ph
O
Ph
Pd(PPh3)n
Dibenzylideneacetonepalladium(0) Complexes
G. Poli
Ph
O
Ph
Ph
O
Ph
Ph
O
Ph
Pd Pd
Ph
OPh
Ph
O
Ph
Pd
O
Ph
PhPd2(dba)3 Pd(dba)3
In Pd(dba)3 each dba has one s-cis and one s-trans configured double bond. Pd is almost in a
planar geometry. Only the s-trans double bonds are involved in complexation to Pd 11
Syn Carbopalladations:
The Mizoroki-Heck Reaction
G. Poli
12
The Seminal Papers
Bull. Chem. Soc. Jap.
G. Poli
13
The Seminal Papers
G. Poli
14
The Mizoroki-Heck Reaction
a) The Mizoroki-Heck Reaction; Oestreich, M., Ed.; Wiley: Chichester, 2009.
b) b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev., 2000, 100, 3009-3066.
c) c) Whitecomb, N. J.; Hii, K. K.; Gibson, S.E. Tetrahedron, 2001, 57, 7449 -7476.
XR
Pd(0) catbase
R R
and / or
base.HX
aryl, vinyl, benzyl (no - sp3 H, otherwise: dehydropalladation !)
X: N2BF4, COCl, I, OTf, Br, Cl
R : an alkene (neutral, rich, or poor)
Pd cat: a Pd(0) cat. or a Pd(II) cat. which is reduced in situ to Pd(0)
base: usually: NEt3, AcOK, Na2CO3...
G. Poli
15
The Mechanism of the Mizoroki-Heck Reaction
Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314
Bissember, A. C. Levina, A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 14232 G. Poli
16
PdPh3P PPh3
OAc
Hnot a competentintermediate
Pd(OAc)2
2 PPh3
{PPh3 + H2O + NEt3}{Ph3P O
16 VE
+ AcOH}
- XHNEt3
14 VE
oxidativeadditionHX trapping
carbopalladation
reductiveelimination
tls
R R
ArPd(OAc)2 cat NEt3ArX
Ar
PdH PPh3
OAc
R
Ar
PdPPh3
OAc
R
H
+ conf change
NEt3
- AcOHNEt3Pd
PPh3
OAc
PPh3
HNEt3(0)
Pd
PPh3
OAc
PPh3
AcO
Pd
PPh3
OAc
PPh3
Ar
Pd
PPh3OAc
PPh3
Ar
Pd
PPh3
Ar
R
- PPh3
R
OAc PPh3
PPh3
Et3N
PPh3
Choice of the Ancillary Ligand
In difficult cases electron-rich and bulky phosphines perform better. Electron richness is expected to favor
oxidative addition (with these phosphines the very difficult oxidative addition to aryl chlorides is possible).
Bulkiness is expected to favor the reductive elimination (in the cross-coupling reactions). 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 s-donors.
Some special ligands
are more expensive
than palladium !
CH3
P
Pd
O O
Pd
OO P
CH3
H3C
H3C
H3C
CH3
P
MeMe Me
Me
Me Me Me
MeMe
P
P
Pd
Me MeMe
Me
MeMe
Me
Me
PPh2
PPh2
PPh2
Ph2P
OMeMeO
PCy2 PCy2
Me
MeMe
Me
Me Me
Tedicyp(Santelli, Parrain)
Sphos (Buchwald)Herrmann's palladacycle (Fu)
PCP Pincer (Milstein)
Xphos (Buchwald)
NC
N
Me
Me
MeMe
Me
Me
Me Me
NHC IMes(Nolan)
O
P
P
Pd
R
RMe
Me Me
Me
Me Me R RR
(Bedford)
G. Poli
17
Hermann Beller Catalyst
Beller, M.; Fischer, H.; Herrmann, W. A.; Öfele, K.; Brossmer, C. Angew. Chem. Int. Ed. 1995, 34, 1848-1849.
d'Orlyé, F.; Jutand, A. Tetrahedron 2005, 61, 9670-9678.
P
Pd
O O
Pd
OO P
CH3
H3C o-Tol o-Tol
o-Tolo-Tol
+ AcO
P
OAc
Pd0
o-Tolo-Tol
OAc1/2
G. Poli
18
Some Useful Corollary Information
P
MeMe Me
Me
Me Me Me
MeMe
P
pKa Cone angle
11.4 182°
2.7 145°
P 9.7 170°
Reviews dealing with ligands in cross-couplings and Heck reactions:
a) Bedford, R. Coord Chem Rev. 2004, 248, 2283. b) Littke, A. E.; Fu, G. Angew. Chem. Int. Ed.,
2002, 41, 4176.
t-Bu3P is malodorous and pyrophoric. However,
it is possible to buy the corresponding
tetrafluoborate salt t-Bu3P.HBF4, and generated
the free phosphine in situ by addition of a
Brønsted base.
G. Poli
19
The Ligandless Conditions
Very reactive iodides, diazonium salts and acyl chlorides can be used without ligands.
The system KHCO3 / Bu4NCl in DMF without ligands is very effective. Under these conditions,1 known as the
Jeffery’s ligandless 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.
Pd(OAc)2 + R4N X
X= Cl, Br
heat
stabilize Pd(0)nanoparticules
R4N X
R4N X
R4N X
R4N X
R4N X
R4N X
R4N X
R4N X
PhI
Leaching,Oxidativeaddition
PhPdIX
PhPdX3
2
G. Poli G. Prestat
20
The Ligandless Conditions
MeO
Br
MeO2CCO2Me
Pd(OAc)2 cat.Me(Cy)2N (1.5 eq)NEt4Cl (1 eq)95°C (72%)
MeO
MeO2CCO2Me
E : Z 11 : 1
Gürtler, C.; Buchwald, S.L. Chem. Eur., 1999, 5, 3107
G. Poli
21
Halides and Pseudohalides
Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989
Cl
OMe
Ph
Pd2(dba)3 (1.5 mol%)P(t-Bu)3 (6 mol%)Cy2NMe (1.1 eq)dioxane, 120°C, 72%
OMe
Ph
Cl
O Me
Ph
Pd2(dba)3 (1.5 mol%)P(t-Bu)3 (3 mol%)Cy2NMe (1.1 eq)dioxane, rt, 78% O Me
Ph
Iodides react smoothly even in the absence of a ligand, and bromides in the presence or the absence
of a phosphine ligand. Chlorides react only in the presence of bulky electron-rich phosphines.
NCbz
CO2R
Pd(OAc)2 (10 mol%)(o-Tol)3P (20 mol%)BuN4Cl (77%)
NCbz
CO2R
OTf
These reactions conditions do not
racemize aminoacid derivatives.
Triflates are conveniently obtained
from the corresponding ketones or
phenols.
Crisp, G. T. Tetrahedron, 1992, 48, 3541
G. Poli
22
Halides and Pseudohalides
Sengupta, S.; Sadhukhan, S. K.; Tetrahedron Lett., 1998, 39, 715
The diazonium salts are very conveniently obtained from the corresponding anilines (via
diazotation), which in turn may derive from the nitro derivatives. The diazonium salts are the most
reactive reaction partners. K. Kikukawa, T. Matsuda, Chem. Lett. 1977, 159 – 162; b) K.
Kikukawa, K. Nagira, F. Wada, T. Matsuda, Tetrahedron 1981, 37, 31 – 36.
Pd(OAc)2 cat.EtOH, 80°C
NH2Me
I
NaNO2HBF4
NMe
I
NBF4
Ph Me
I
Ph
CN
Pd(OAc)2 cat.NaHCO3 nBu4ClDMF, 80°C(Jeffery)
Me
Ph
NC
61%
Order of reactivity in the oxidative addition: N2 >> I >> OTf > Br >> Cl
Jutand, A.; Mosleh, A., Organometallics, 1995, 14, 1810.
G. Poli
23
Neutral vs Cationic Mechanism
Ar-OTf +
PdP
PPd
P
P
ArPd
P
P
(s)
Ar
or ArX + AgOTf
Ar-X +
PdP
P
PdP
X
Ar
PdP
P
X
ArP
Pd XPP
Ar
G. Poli
24
Regioselectivity of the Mizoroki-Heck
CN
MeO
I
Pd(OAc)2 catAcOKBu4NBr, DMF (84%)
CN
MeO
Br
Me2N
OBu-n
Pd2(dba)3 (5 mol%)P(Bu-t)3 (1 mol%)Cy2NMe (1.1 eq)dioxane, rt (97%)
Me2N
OBu-n
Me2N
OBu-n
4 : 1 (E : Z 3 : 1)
Masllorens, J.; Moreno-Manas, M.; Pla-Quintana, A.; Pleixats, R.; Roglans, A. Synthesis, 2002, 48, 1903
Littke, A. F.; Fu, G. J. Am. Chem. Soc., 2001, 123, 6989
Cabri, W. Acc. Chem. Res. 1995, 2-7
EWG Donor
[Pd] X
EWG
[Pd] X
majoronly
[Pd]X [Pd]X
Donor
electron poor alkenes
Pd X
EWG
Pd goes to the more electron rich carbon
PdX
Donor
electron rich alkenes
G. Poli
25
Allylic Alcohols as Alkenes
Br [Pd(0)]Me
OH+
Me
CHO
Melpolder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41, 265. Buntin, S. A.; Heck, R. F. Org.
Synth. Coll. Vol. 1990, 7, 361.
When allylic alcohols are used as alkenes dehydropalladation occurs from an oxygen-
bearing carbon. As a result, carbonyl compounds are generated rather than -arylated
allylic alcohols.
MeOH
[Pd]Br
H
Me
OH
Me
OH
CC
CHO X
OH
Mizoroki-HeckThus, a dihydrocinnamaldehyde
target can be retrosynthetically
disconnected via a Mizoroki-Heck
reaction.
G. Poli
26
Intramolecular Mizoroki-Heck Reactions
G. Poli
27
Formation of 5 and 6-Membered Rings
Huwe, C. M.; Blechert, S. Tetrahedron Lett., 1994, 35, 9537
The 5-exo and 6-exo intramolecular variation has been extensively applied in synthesis
Pilger, G. et al. Synlett, 2000, 1163
Parsons, P. J. et al. Tetrahedron Lett., 2001, 42, 2209 No problem for C-C formation
at quaternary center
CHO
OMe
I
O
O
NMe2
OMeO
CHOO
NMe2
Pd(OAc)2 catAg2CO3dppe, DMF (75%) galantamine
alkaloid
N
Ph
Br
OTBDMS
Pd(OAc)2 (10 mol%)PPh3 (20 mol%)K2CO3 (68%)
N
Ph
OTBDMS
G. Poli
28
Formation of 6-Membered Rings
Hines, J. Jr; Overman, L. E. Nasser, T.; Rucker, P. V. Tetrahedron Lett., 1998, 39, 4647
No problem for C-C formation
at quaternary center
TfO
PhS
OH
O
O
Pd(dppb) cat.AcOK, DMA (70%)
PhS
OHO
O
cardenonide
Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 11028
MeO
OBn
I
NR
H
Pd(CF3CO2)2PMP, tol, 120°C(60%)
NR
OBn
OMe
morphine
PMP: NMe
MeMe
Me
Me
G. Poli
29
Halo-1,6-Dienes
apparent 6-endo cyclization
6-exo cyclization
EtO2C
EtO2C I
EtO2C
EtO2C
Type I substrates: 1-halo-1,6-dienes
Type II substrates: 2-halo-1,6-dienes
[Pd(0)], base
[Pd(0)], base
OHOH
I
Owczarczyk, Z.; Lamaty, F.; Vawter, E. J. Negishi, E.-I. J. Am. Chem. Soc. 1992, 114, 10091
G. Poli
30
1-Halo-1,6-Dienes
EtO2C
EtO2C I
EtO2C
EtO2C
Pd(PPh3)4 cat or Cl2Pd(PPh3)2 cat, HNEt2
EtO2C
EtO2C [Pd]I
6-exocarbopalladation EtO2C
EtO2C [Pd]I
3-exocarbopalladation
tail-biting
EtO2C
EtO2C
[Pd]I
dehydropalladation[Pd(0)]
oxidativeaddition
G. Poli
31
2-Halo-1,6-Dienes
I
OH
PdCl2(PPh3)2, NEt3, DMF, 80°C, NEt2H (69%)
OH
OH
[Pd]X5-exocarbopalladation OH
[Pd]I
H
3-exocarbopalladation
[Pd]I
OH
[Pd]I
OH
cyclopropylcarbinyl-homoallylrearrangement
dehydropalladationoxidativeaddition
[Pd(0)]
Owing to its mechanism the cyclopropylcarbinyl-to-homoallyl rearrangement can take place
only if the two red bonds (C-C and C-Pd) can become syncoplanar. It can be understood as
an unusually facile retro-carbopalladation. Notice that the double bond configuration of the
final product is reversed with respect to that of the starting material.
Apparent 6-exo cyclization
G. Poli
32
Asymmetric Mizoroki-Heck Reactions
G. Poli
33
Intermolecular Asymmetric Reactions
O
Pd(OAc)2 catL*, 40°C (65%)
O
OTf
+
98% ee
P
MeO
MeO
PL*:
Gilbertson, S. R.; Fu, Z. Org. Lett, 2001, 3, 161
Trabesinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.; Pregosin, P. S.; Tschoerner, M. J. Am. Chem.
Soc. 1997, 119, 6315
O
Pd2dba3 catL*i-Pr2NEt, PhH70°C (100% conv)
O
OTf
+
96% ee
PPh2ON
Bu-t
L*:
The non-coordinating triflate anion is crucial
G. Poli G
34
Intermolecular Asymmetric Reactions
The selectivity of this reaction is highly dependent on the nature of the (pseudo)halide and of
the ligand.
Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi, K.; Moriguchi, K. Organometallics
1993, 12, 4188
O
[Pd]X
O
[Pd]X
O
O
H[Pd]X
O
H
[Pd]X
OO
H
X[Pd]
O
H
HH
H
H[Pd]X
H[Pd]XH[Pd]X
+
L
G. Poli
35
Intramolecular Asymmetric Reactions
neutralcationic
iii
i: Pd2(dba)3 5%; (R)-BINAP 11%; DMA; Ag3PO4, 80°C, (81%)
ii: Pd2(dba)3 5%, (R)-BINAP 11%, DMA; PMP, 110°C (71%)
O
NMe
IO
O
NO
Me
O
O
(S) 71% ee
NO
Me
O
O
(R) 66% ee
Overman, L. E.; Poon, D. J. Angew. Chem. Int. Ed. Engl. 1997, 36, 518
The importance of non-coordinating anions
PPh2
PPh2
(R)-BINAP
G. Poli
36
Intramolecular Asymmetric Reactions
Tietze, L. F.; Schimpf, R. Angew. Chem. Int. Ed. Engl. 1994, 33, 1089
The presence of the silicon atom in the precursor directs the dehydropalladation thereby
avoiding -H elimination from the undesired side.
MeO
Me I
SiMe3Pd2(dba)3, (R)-BINAPAg3PO4, DMF, 80°C(91%, 92% ee)
MeO
Me
MeO
Me
SiMe3
[Pd]
[Pd(0)]
[Pd]SiMe3
G. Poli
37
Related Process Involving
Carbopalladations
G. Poli
38
Palladium-ene Cyclizations
[Pd] [Pd] [Pd]
Oppolzer, W. In Comprehensive Organometallic Chemistry II, Vol. 12, Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds. Pergamon, Oxford, 1995, p. 905.
AcOH
[Pd(0)]
OAc
[Pd]OAc [Pd]OAc
H[Pd]OAc
H[Pd]OAc
[Pd(0)]
oxid. add.
insertion
dehydropallad.
red. elim.
G. Poli
39
Palladium-ene Cyclizations
OMe
Pd(PPh3)4 cat AcOH
OAc
OMe
Oppolzer, W.; Swenson, R. E.; Pachinger, W. Helv. Chim. Acta, 1989, 72, 14
Trost, B. M.; Luengo, J.I. J. Am. Chem. Soc. 1988, 110, 8239
OAc
R
E
E
Pd2(dba)3CHCl3AcOH / AcOLiMeCN
R
E
E OAc
G. Poli
40
Reversible vs Irreversible Oxidative Addition
Lautens, M.; Tayama, E.; Herse, C. JACS, 2005, 127, 72-73
See also: Sinou et al. Eur. J. Org. Chem. 2000, 4071
oxidative addition / carbopalladation / deacetoxypalladation / Pd(II) reduction
G. Poli
41
Ph
HN
Me
OAc
I Cl
Pd2(dba)3 (5mol %)(o-Tol)3P (22 mol %)n-BuNMe2 (2.0 eq.)MeCN-H2O 10:1reflux 6h (88% y)
N
H
Me
Ph
Ph
HN
Me
OAc
[IPd] Cl
OA
N
H
Me
Ph
[IPd]
AcO
intra-CP
deacetoxyPd
[Pd(0)]
n-BuNMe2 or (o-Tol)3P
Ph
HN
Me
I Cl
[Pd]OAc
[Pd(II)][Pd(I0]
OA
Cl
Cl
Pd Catalyzed C-C Cleavage
- Carbon Elimination
Pd - Carbon elimination is the microscopic reverse reaction of carbopalladation.
Although carbopalladation is usually the thermodynamically favored step, some
particular cases (i.e. strain release and the impossibility of dehydropalladation) may
drive the equilibrium in favor of Pd - Carbon elimination.
C
C Y
[Pd]X
C Y
RR
-carbon elimin
carbopallad
C [Pd]X
Y = CR2, O
C
C Y
[Pd]X
R
G. Poli
42
Cleavage of CPC-Pd and CP-Pd
The different modes
R[Pd]X
[Pd]X
R
CPC-Pd
decarbo-pd
R[Pd]X
R[Pd]X
CPC-Pd
decarbo-pdX[Pd] R
X[Pd]
R
carbo-pd
carbo-pd
[|Pd]X
R
CP-Pd
less frequent decarbo-pdR
R
[Pd]X[Pd]X
CPC-Pd : cyclopropylcarbinylpalladium
CP-Pd : cyclopropylpalladium
G. Poli
43
From Methylenecyclopropane
Fournet, G.; Balme, G.; Goré, J. Tetrahedron, 1988, 44, 5809
[Pd(0)]
[Pd]Br
[Pd]Br
intermolec.carbo-pd
oxid.add.
Br[Pd]
C-C-C-Pd syncoplanar
intramolec.decarbo-pd
Br[Pd]
H[Pd]Br
H migration(dehydro-Pd +hydro-Pd)
CO2Me
CO2Me
cyclopropylcarbinyl Pd(CPC-Pd)
Br
CO2Me
CO2Me
Pd(dba)2 dppe, THF 80°C 40h (55%)
CO2Me
CO2Me
MeO2C
MeO2C
+
70 : 30
G. Poli
44
From Tertiary Cyclopropanols [Pd(II)]
OAcO[Pd]
CPC-Pd
[Pd(0)]
decarbo-pdAcO[Pd]
Ph
H[Pd]OAcligandexchange
OTIPS
O
less substituted
bond is preferentially cleaved
dehydro-pd
AcOH
O2, DMSO[Pd(OAc)2]
AcOH
reductiveelimination
Park, S-.B.; Cha, J. K.; Org. Lett. 2000, 2, 147
HO
OTIPS
Pd(OAc)2 10%DMSOTol MS 4A, O2, 80°C OTIPS
O
major regioisomer75% (+ 18% other regioisomer)
G. Poli
45
Dehydropalladation versus Decarbopalladation
To obtain decarbopalladation, competitive dehydropalladation must be forbidden in the substrate (tertiary
substituent) and strain release must operate. Indeed, dehydropalladation of oxypalladium intermediates
is a key step in Pd-mediated oxidations.
X[Pd]O C
HH
O C
H
+ H[Pd]X
aldehyde
X[Pd]O C
HC
O C
C
+ H[Pd]X
ketone
X[Pd]O C
CC
dehydropalladation
dehydropalladation
decarbopalladation
C O
C
C
C [Pd]X
CPC-Pd
G. Poli
46
From Tertiary Cyclopropanols [Pd(0)]
Okumoto, H.; Jinnai, T.; Shimizu, H.; Harasa, Y.; Mishima, H.; Suzuki, A. Synlett, 2000, 629
HO Ph
Pd(dba)2 5%MeCN 50°C (94%)
O
Ph
O
Phtraces
+
O PhH[Pd]
CPC-Pd
oxidativeaddition
[Pd(0)]
decarbo-pdH[Pd] Ph
O
H[Pd]H
H2
H
G. Poli
47
Arylative Fragmentation , -Disubstituted Arylmethanols
Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M.; J. Am. Chem. Soc. 2001, 123, 10407
Terao, Y.; Wakui, H.; Nomoto, M.; Satoh, T.; Miura, M.; Nomura, J. Org. Chem. 2003, 68, 5236
OH
Cl
Pd(OAc)2, PCy3
Cs2CO3
o-xylene reflux (97%)+ +
O
No strain
release in this
case
Bulky
phosphines
are necessary
RR
R O [Pd] Ar
the more electronrich R migrates
[Pd]Cl
[Pd(0)]
O [Pd]
ligandexchange
[Pd]
O
reductiveelimination
HCl
decarbopalladation
G. Poli
48
Arylative Fragmentation of 2,2-Disubstituted 3-Allen-1-ols
Ph[Pd]I
[Pd(0)]reductiveelimination
decarbopalladation
OHPh
I[Pd]
PhOH
Ph
[Pd]I
Ph
OHPh
I[Pd]
H[Pd]I
HIoxidadd
alleneinsertion
dehydr o
- pd
No dehydropalladation is possible here
Oh, C. H.; Jung, S. H.; Bang, S. Y.; Park, D. I. Org. Lett. 2002, 4, 3325
C
OHPh
Pd(PPh3)4 3%K2CO3 dioxane reflux
+ PhI
Ph
PhCHO +
87% 82%
G. Poli
49
TM-Catalyzed Cross-Coupling Reactions
Relevant references:
- Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F.,
Eds.; Wiley-VCH: Weinheim, 2004.
- Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley: New York, 2002.
- Cross-Coupling Reactions. A Practical Guide; Miyaura, N., Ed. Top. Curr. Chem.
2002, 219.
- Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. 2005, 44, 4442-4489
- Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651-2710.
- Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417-1492
- van Leeuwen, P. W. N. M. and Chadwick, J. C. 2011, Metal-Catalyzed Cross-
Coupling Reactions (chapt 9), in Homogeneous Catalysts: Activity - Stability -
Deactivation, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany
G. Poli
50
Cross-Coupling Reactions
Bolm, C. J. Org. Chem. 2012, 77, 5221-5223
http://pubs.acs.org/JACSbeta/jvi/issue15.html
51
G. Poli
TM-Catalyzed Cross-Coupling Reactions
In the presence of CO atmosphere these reactions can be carbonylative
R1 SnR3 + R2-X R1-R2
R1-BY2 + R2-X
[Pd(0)] cat
R1 + R2-X R1 R2
R1 ZnR + R2-X
R1-R2
R1-R2
[Pd(0)] cat
[Pd(0)] cat
[Pd(0)] cat
Stille
Suzuki
Cassar Sonogashira
Negishi
base
base, CuX cat
R1 MgX + R2-X R1-R2
[Ni(0)] cat or [Pd(0)] cat
Kumada Corriu(Murahashi if organolithiums)
R1 SiR3 + R2-X R1-R2[Pd(0)] cat
Hiyamabase/nucleophile
52
G. Poli
General Mechanism
53
G. Poli
The Kumada-Corriu Coupling
Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374–4376.
Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun. 1972, 144. 54
G. Poli
The Pd(II) Reduction
55
G. Poli
Mechanism
G. Poli G. Prestat
56
The Kumada Corriu Coupling
ClP
Ni
P
Ph Ph
Ph Ph
Cl
Cl0.7%
n-BuMgBr 2.0 eq.
Kumada, M.
Bull. Chem.
Soc. Jpn. 1976,
49, 1958.
- Best results with diphosphine ligands (best dppp) and aryl or vinyl chlorides.
- The Ni pre-catalyst is commercially available
- Steric hindrance is acceptable only on the Grignard component
-The reaction is limited to halide partners that do not react with organomagnesium compounds.
- Typically used in the industrial-scale production of styrene derivatives and the synthesis of
unsymmetrical biaryls.
- Alkynyl Grignard (with Pd cat.) can also be cross coupled Org. Lett., 2004, 6, 1461-1463
- Under particular and mild conditions [Pd(OAc)2/PCy3 cat, NMP/THF, rt] coupling of alkyl halides is also
possible: Frisch, A. C. Shaikh, N. Zapf, A. Beller, M. Angew. Chem., 2002, 114, 4218-4221
57
G. Poli
Configuration of the Vinyl Residues
P
Ni
P
Ph Ph
Ph Ph
Cl
Clcat.
MeMgBr
Ph Br Ph Me
P
Ni
P
Ph Ph
Ph Ph
Cl
Clcat.
MeMgBr
Ph
Br
Ph
Me
P
Ni
P
Ph Ph
Ph Ph
Cl
Clcat.
BrMg Me Ph Me
PhMgBrZ:E 27:73
Vinyl halides cross couple with total
retention of configuration.
In contrast, alkenyl Grignard reagents
lose their configuration in the coupling
58
G. Poli
Improved Functional Group Tolerance
NC I
ClMg Cl
Pd(dba)2 0.02 eq.
PCy2Me2N
0.03 eq.
THF, -50°C
NC Cl
86%
I Cl
i-PrMgCl LiClTHF -20°C
The Grignard reagent is prepared in situ via the Knochel method (I/Mg exchange
between an aryl iodide and isopropylmagnesium chloride/ lithium chloride).
Martin, R.; Buchwald S. L. J. Am. Chem. Soc., 2007, 129, 3844–3845A.
Krasovskiy, A.; Knochel, P. 2004, Angew. Chem. Int. Ed. Engl, 43, 3333–3336 59
G. Poli
The Negishi Coupling
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.
In the seventies, Negishi’s group published several seminal papers on the Pd- or Ni-
catalyzed cross-coupling disclosing:
- The Pd- or Ni-catalyzed coupling between alkenylalanes and aryl halides, and the
related alkenyl-alkenyl coupling.
- The Pd-catalyzed coupling of organozinc chlorides with alkenyl and aryl halides.
- The Pd- or Ni-catalyzed coupling of organozirconiums with aryl or alkenyl halides
- The Pd-catalyzed carboalumination-cross-coupling tandem reaction in the
presence of ZnCl2 or ZnBr2 for the coupling step.
These findings established for the first time that the Pd- or Ni-catalyzed cross-coupling
could be achieved with main group organometals less electropositive than Li or Mg such
as Zn, B, and Sn. Subsequently, Negishi focused his studies on the coupling of
organozincs, whereas coupling of organoboranes and organostannanes was
subsequently developed by Suzuki and Stille, respectively.
The major drawback of the Negishi coupling is the incompatibility of the organozinc
reagents with many common functional groups, together with their relative sensitivity
towards oxygen and water.
60
G. Poli
Baba S.; Negishi, E-.i. J. Am. Chem. Soc., 1976, 98, 6729-6731
The Seminal Paper
61
G. Poli
The 1st Report
n-PentAl(i-Bu)2
n-Pent
AlH(i-Bu)2
PdCl2(PPh3)2
DIBAL
Pd(0)(PPh3)2 catn-Pent
Bu-n
Bu-nI
74% (E,E)
Baba S.; Negishi, E-.i. J. Am. Chem. Soc., 1976, 98, 6729-6731
Cross coupling via alkenylZr, in turn obtained via hydrozirconation of terminal alkynes,
tolerates more functional groups
62
G. Poli
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 ZnBr2.
Bu3SnSnBu3
Bu3SnZnCl
BrCO2Me
Pd(PPh3)40°C
Bu3SnCO2Me
95%
BuLiBu3Sn
Li
ZnCl2
63
G. Poli
Csp2-Csp3 Couplings
Negishi J. Am. Chem. Soc. 1980, 102, 3298
In contrast to what happens with Grignard reagents, when using -H containing
organozincs dehydropalladation does not compete with reductive elimination.
n-BuI Pd(PPh3)4 cat
n-Bu4ZnCl or n-Bu4MgCl
n-Bu n-Bu
76% 2% n-Bu4ZnCl25% 51% n-BuMgCl
64
G. Poli
oxidativeaddition
reductiveelimination
Pd(0)(PPh3)2
n-Bu4ZnCl orn-Bu4MgCl
ZnIClorMgICl
transmetallation
cis-transisomerization
n-BuI
n-BuPd
Ph3P
PPh3
I
n-BuPd
PPh3
PPh3
n-Bu
n-Bu
H
cis
n-BuPd
PPh3
H PPh3
n-Bu
Pd
Ph3P
PPh3
trans
-H elimination
reductiveelimination
2% n-Bu4ZnCl51% n-BuMgCl
76% n-Bu4ZnCl25% n-BuMgCl
start here
Csp2-Csp3 Couplings
65
G. Poli
Csp3-Csp3 Couplings
Coupling of Csp3 residues, especially from the halide partner, is a great challenge, since
dehydropalladation can become competitive. The solution: inhibition of the -elimination using
appropriate ligands that fill the vacant coordination site needed for the -elimination, or speeding up the
transmetallation and reductive elimination step..
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.
oxidativeaddition
reductiveelimination
transmetalation
Pd(0)X
R1
M
MX
R2
R1
R2
dehydro-palladationR1
R2
R1
[Pd]R1
+ H[Pd]X
R2
[Pd]XR1
-dehydropalladation
H[Pd]X +
start here
66
G. Poli
Synthesis of -Carotene
Negishi, E-I.; Xeng, F. Org. Lett., 2001, 3, 719-722.
AlMe3Cp2ZrCl2
Me
AlMe2
ZnCl2Pd2(dba)3 catP(2-furyl)3 catDMF rt
Me
ZnCl
SiMe3
MeSiMe3
70%
X
MeK2CO3, MeOH
[Zr --> Al] [Al --> Zn]
[Zn --> Pd]
AlMe3Cp2ZrCl2
[Zr --> Al]
Me MeAlMe2
ZnCl2Pd2(dba)3 catP(2-furyl)3 catDMF rt
Me Me
BrI
0.5 equiv.
MeMe-carotene
[Al --> Zn --> Pd]
67
G. Poli
Zr-Catalyzed Alkene Carboalumination
Cl
ZrCp
Cp Cl
MeZr
Cp
Cp Cl
R
ZrCp
CpCl
R
Me
AlMe2R
Me
AlMe3
AlMe2Cl
Negishi Ei-i, et al J. Am. Chem. Soc., 1996, 118 (40), 9577–9588 68
G. Poli
Synthesis of Discodermolide
Smith III, A. B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654 - 8664;
Smith III, A. B.; Kaufman, M. D.; Beauchamp, T. J.; LaMarche, M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823
- 1826.
I
TBSO O O
PMP
t-BuLi 3.0 equiv, ZnCl2Et2O to rt
Zn
TBSO O O
PMP
Pd(PPh3)4 catEt2O rt
PMBOI
OTBS
PMBO
OTBS
TBSO O O
PMP
[Li --> Zn]
[Zn --> Pd]
66%
O
O
HO
Me
OH
OH
OH O O
NH2
discodermolide (microtubule stabilizing agent)
14 15
14
15
14
15
69
G. Poli
Li Zn Transmetalation with t-BuLi
R I
t-BuLi
R Li
t-BuI
ZnCl2
R ZnCl
LiCl
t-BuLi
R Zn
LiCl
t-Bu
t-BuLi
t-BuH + isobutene
This sequence would account for the need of 3.0 equivalents of t-BuLi
70
G. Poli
The Migita-Kosugi-Stille Coupling
The Stille Coupling is a flexible C-C bond forming reaction between stannanes and
halides or pseudohalides.
The main drawback is the toxicity of the tin compounds, and their low polarity, which
makes them poorly soluble in water.
Stannanes are stable, functional group tolerant and readily synthesizable.
Me and Bu groups are normally the non-transferable groups.
Transfer scale : alkynyl > alkenyl > aryl > benzyl > alkyl
R1 SnR3 + R2-X R1-R2[Pd(0)] cat
Stille
Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652. 71
G. Poli
The Seminal Paper
72
G. Poli
The First Reports
PhBr + MeSn4
PdPh3P
Ph3P
ClPh
HMPA, 62°CPh-Me
cat.
The seminal papers
Milstein, D.; Stille J. K. J. Am. Chem. Soc. 1978, 100:3636-3638.
Milstein, D.; Stille J. K. J. Am. Chem. Soc. 1979, 101:4992-4998
Kosugi, M. ; Sasazawa, K. ; Shimizu, Y. Migita, T. Chem. Lett. 1977, 301 - 302.
Kosugi, M. Sasazawa, K. Migita, T. Chem. Lett. 1977, 1423 - 1424.
Kosugi and his group pioneered the coupling
PhBr +PhH, reflux (96%)
SnBu3Ph
Pd(PPh3)4 cat
73
G. Poli
Mechanism of the Migita-Kosugi-Stille Coupling
Amatore, C.; Jutand, et al. Chem.Eur.J. 2001, 2134; J. Am. Chem. Soc. 2003, 125, 4212
As the rds is the ligand dissociation, Ph3As, a weaker donor than phosphines, gives faster rates
and generally better yields. V. Farina, J.Am.Chem.Soc. 1991, 113, 9585.
For a different interpretation see: Espinet, J.Am.Chem.Soc. 2000, 122, 11771; J.Am.Chem.Soc.
1998, 120, 8978.
74
G. Poli
Examples
The presence of Cu(I) salts (CuCl better than CuI) is beneficial, especially when phosphines (instead of
arsines) are used. It is believed that a first transmetallation from the organostannane to the
organocuprate takes place, followed by a more facile transmetallation of the alkenylcuprate with the
palladium catalyst. Also LiCl is beneficial and is believed to accelerate the transmetallation step.
Nicolaou, K. C. et al. Angew. Chem. Ed. Engl. 1996, 36, 889-891
The copper and the LiCl effect
O OTf
TBSO
TBSOOMe3Sn
OBn
OBn
Pd(PPh3)4 catCuCl (2 equiv.)THF rt+
O
TBSO
TBSOO
OBn
OBn
OTsSnBu3
Pd(Ph3)4 cat.LiCl, THF
V. Farina, J.Am.Chem.Soc. 1991, 113, 9585
75
G. Poli
Examples
Piers, E. Tetrahedron, 1991, 47, 4555.
TfO
Bu3Sn
CO2Me
R R
CO2Me50-90%
Pd(Ph3)4 cat
OTf
OSiR3
OSiR3
Bu3Sn
OSiR3
Pd(Ph3)4 cat OSiR3
Hirama, M. Synlett, 1991, 651
76
G. Poli
Use of Aryl Chlorides
In difficult cases, addition of a fluoride salt can enhance the reactivity. Since these salts are expected
to enhance the reactivity of the stannanes, it was postulated that, at least in these cases, the
transmetalation is the slow step.
Fu, G., et al. ACIE. 1999, 38, 2411; J.Am.Chem.Soc. 2002, 124, 6343
Me
Cl
SnBu3
Pd2(dba)3 (1.5%)P t -Bu3 (6%)CsF (2.2 equiv)
Medioxane 100°C
59%
without CsF (12% y)
OMe
Cl
SnBu4
Pd2(dba)3 (1.5%)P t -Bu3 (6%)CsF (2.2 equiv)
Me
Me
dioxane 100°C
Csp3 Csp2 coupling
77
G. Poli
Problems with Electron Rich Components
Kong, K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113, 6313-6315;
Segelstein, B. E.; Butler, T. W.; Chenard, B. L. J. Org. Chem. 1995, 60, 12-13.
If there is not a special phosphine, problems may arise in coupling electron rich components
Bu3Sn
OMeBr
OMe
MeO
OMe
MeO
22%
55%
Pd(PPh3)4 catDMF
Pd
Ph3P Br
PPh3
MeO
P
MeO
Br
- Pd(0)(PPh3)2
Pd
Ph2P Br
PPh3
OMe
Bu3Sn
OMe Pd
Ph2P
PPh3
OMeOMe
[Pd(0)]
Pd(0)PPh3
oxid. add.
red. elim.
transmetalation
red. elim.
oxid. add.
desired
undesired
- Bu3SnBr
PPh3
Ph Ph
Bu3Sn
OMe
transmetalation - Bu3SnBrnormal desired reactivity
undesired reactivity
78
G. Poli
Application to Rapamycin Synthesis
K. C. Nicolaou, et al. Chem. Eur. J. 1995, 1, 318-333.
A. B. Smith III, et al. J. Am. Chem. Soc. 1995, 117, 5407-5408. 79
G. Poli
Application to Dynemicin Synthesis
S. J. Danishefsky et al., J. Am. Chem. Soc. 1996, 118, 9509-9525;
80
G. Poli
Suzuki Coupling
R1-BY2 + R2-X R1-R2
[Pd(0)] cat
base
Base is essential for the transmetalation step
Ag(OH)>Tl(OH)~Ba(OH)~CsCO3>NaOH>K3PO4>Na2CO3>NaHCO3
General case: R2X no C-H on sp3 carbon at the position
Reviews: a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483. b) Hayashi, T. Synlett 2001, 879.
c) Hayashi, T. Yamasaki, K. Chem. Rev. 2003, 103, 2829–2844. c) Darses, S.; Genet, J. P. Chem. Rev.
2008, 108, 288–325. d) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286
R1 B
Oi-Pr
Oi-PrR1 B
O
O
R1 B
O
O
pinacolboraneB(pin)
BR1
9-Borabicyclo[3,3,1]nonane9-BBN
R1 B
OH
OH
Organoboranes :non-toxic,air and moistrure stable
R1 B
O
O
catecholborane
boronic acids boronic esters
boranes
R1 BF3K
trifluoroborates
81
G. Poli
The Seminal Paper
82
G. Poli
The germs of the growth of the Suzuki coupling can be found in earlier work by the Heck’s and
Negishi group.
Taken from: Nicoaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 1998, 37, 3387-
3388
“The Heck group reported, at a conference in November 1973, the coupling of (Z)- and (E)-1-
hexenylboronic acids with methyl acrylate with stoichiometric amounts of Pd(OAc)2 in Et3N,
resulting in carbon–carbon bond formation to afford methyl (E,Z)-2,4-nonadienoate and methyl
(E,E)-2,4-nonadienoate, respectively: a) R. F. Heck in Proceedings of the Robert A. Welch
Foundation Conferences on Chemical Research XVII. Organic-Inorganic Reagents in Synthetic
Chemistry (Ed.W. O. Milligan), 1974, p. 53–98; see also: b) H. A. Dieck, R. F. Heck, J. Org.
Chem. 1975, 40, 1083 –1090.”
“Negishi reported, first at the 174th National Meeting of the American Chemical Society (New
Orleans, March 1977), and then in a table within a chapter in a book published in 1978, an
example of a coupling between an alkynyl borate species and an aryl iodide under palladium-
catalyzed conditions: E. Negishi in Aspects of Mechanism and Organometallic Chemistry (Ed.:
J. H. Brewster), Plenum, New York, 1978, p. 285.”
On the “Seeds” of the Suzuki Coupling
83
G. Poli
Stereoselectivity
Miyaura, N.; Suzuki, A. Org. Synth., 1993, Coll. Vol. 8, 532; 1990, 68, 130.
84
G. Poli
Organoborane Synthesis
Dennis G. Hall Ed.: Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine,
Wiley-VCH, Weinheim, 2005.
R-B(OMe)2
a) Mgb) B(OMe)3
(RO)2B-B(OR)2PdCl2dppf cat.AcOK
DMSO, 90°C
R-Hal
H+, H3O+
R-B(OH)2
R-Hal R-B(OR)2Miyaura reaction
85
G. Poli
Organoborane Synthesis
R R
BY2
R
R
BY2
R
1) HBBr2.SMe2
2) i-PrOH
X
X
B(Oi -Pr)2
R
B(Oi -Pr)2
H
R
B(Oi -Pr)2
R'
R
R'
B(Oi -Pr)2
R
KHB(Oi -Pr)3
R'Li
R'ZnX[Pd(0)]
InversionSn2 likemechanism
Retention
HBY2
HBY2
86
G. Poli
Mechanism Suzuki
Amatore, C.; Jutand, A.; Le Duc, G. Chem. Eur. J. 2011, 17, 2492-2503
Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116-2119
See also:Braga, : A. A. C.; Morgon, N. H.; Ujaque, G.; Lledó,. A.; Maseras, F. J. Organomet. Chem.
2006, 691, 4459.
Pd-O bond: (O: hard Lewis
base; Pd: soft Lewis acid)
G. Poli
oxidativeaddition
reductiveelimination
Pd(0)L2
Hal
ArPd
Hal
L
L
R
transmetallation
R-B(OH)2, base, Pd(0)Ln cat
ArPd
OH
L
L
OH R-B(OH)2
OR'
BR'O
OR''
R
M
ArPd
R
L
L
ArPd
L
L
R
R''O-M
B(OR)3
ate complex
path when with weakaqueous bases
possible path with strong andnucleophilic bases (t-BuOK) R-B(OR')2
Ar Ar
R-B(OH)3
- Hal
OH-
less reactive
slowOH
ROH
ROMB(OR)4
87
The Transmetalation Step
Concerted four-center mechanism, Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461
Order of transmetallation reactivity: Cl > Br > I
Aryl iodides undergo oxidative addition more rapidly than do aryl
bromides (and irreversibly). Nevertheless, bromides react faster
than iodides. This suggests that transmetalation is the turnover-
limiting step. That is: transmetalation of Pd(P(t-Bu)3)(Ar)(I) is less
rapid than that of Pd(P(t-Bu)3)(Ar)(Br).
Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020
Pd O
C B
OR
OR
R
R
L
RC
PdO
C B
OR
OR
R
R
L
C
Pd O
C B
OR
OR
R
R
L
H
C
L
Pd OR
C B
RO ORRR
L
C
L strongbond
concerted four-center TS
X
Pd
C B
OR
OR
R
R
L
C
X Nucl
OH
tBuONa
L
88
G. Poli
Aryl Bromide / Triflate Selectivity
OTf
Br
PhZnBr,Cl2Pd(dppp) (4 mol %)THF, 60°C, 11h (90%)
Br2HC=CHSnBu3LiCl (3 equiv.)Cl2Pd(dppp)DMF, 25°C, 39h (25%)
Br
PhB(OH)2KF (3 equiv)Pd(dba)2 (1.5 mol %)PtBu3 (3.6 mo%)THF, 25°C, 4h, (80%)
OTf
Negishi
Stille
Suzuki
In Kumada, Negishi, or Stille cross couplings, the bromide site reacts preferentially over
the triflate, at least using chelating diphosphines such as dppp. However, this trend
reverses in Suzuki coupling, where an anomalous preference for the bromide site is
observed, independently of the phosphine used. Consider that the intrinsic order of
oxidative addition rate to Pd(0) is: TfO > I > Br > OTs > Cl. The reason of this behavior
remains for moment obscure.
Espino, G.; Kurbangalieva, A.; Brown, J. M. Chem. Commun. 2007, 1742
OTf
Br
Pd
L
L
irrev.
OTf
Br
Pd-L
B
OH
HO
?
irrev.
89
G. Poli
Stereochemistry of The Transmetallation
Csp3 organoboranes give complete retention of configuration with respect to Csp3 carbon
Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461
tBu
1. 9-BBN-D2. CD3CO2D
tBu
D D 9-BBN-HB
H D
DH
tBu
Ph
H D
DH
tBu
PhBr, NaOHPd(PPh3)4 cat
1. 9-BBN-H2. CD3CO2D
tBu
H D
H
9-BBN-DB
D H
DH
tBu
Ph
D H
DH
tBu
PhBr, NaOHPd(PPh3)4 cat
J = 4.8 Hz J = 4.8 Hz
J = 12.3 Hz J = 12.5 Hz
90
G. Poli
The Miyaura Reaction
Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem., 1995, 60, 7508-7510 91
G. Poli
Aryl Chlorides and the Ligands
Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 1998, 37, 3387-3388.
Wolfe, J. P.; Buchwald, S. L. Angew. Chem. Int. Ed. 1999, 38, 2413-2416.
92
G. Poli
This protocol is particularly suited for boronic acids that quickly deboronate under
basic conditions, such as polyfluorophenylboronic acid and five membered 2-
heteroaromatic boronic acids.
The rate of the Suzuki coupling reaction under the described conditions decreases in the
order ArCl > ArBr > ArI, in accord with a rate detrmining transmetalation step.
XPhos
N
PdCl
H
H
F
F
B(OH)2
MeO
Cl
2 mol%
THF, aq. K3PO4, rt, 30 min (95%)
F
F
OMe
Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073
See also: Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686.
Generation of the Catalytically Active XPhosPd(0) in Situ
G. Poli
93
Csp3-Csp3 Coupling
Bulkiness may disfavor -hydride elimination by lowering the
electrophilicity of the metal and blocking open coordination sites.
Depending on the phosphine β-hydride elimination (dehydropalladation)
may compete with transmetalation but not with reductive elimination.
Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am. Chem; Soc 2001, 123, 10099-10100. 94
G. Poli
Suzuki Coupling: Selected Examples
Br
N
N
Cl
OH
B(OH)2
N
N N
N
Tr
Pd(OAc)2, PPh3, K2CO3,
DEM, H2O, THF, 75°C
N
N
Cl
OH
N
N N
N
Tr
trityl losartan
Losartan (Merck) is an angiotensin II receptor antagonist
Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1994,
59, 8151-8156.
95
G. Poli
Suzuki Coupling: Selected Examples
Tsukano, C.; Sasaki, M. J. Am. Chem. Soc. 2003, 125, 14294-14295.
96
G. Poli
Suzuki Coupling: selected examples
White, J. D.; Hanselmann, R.; Jackson, R. W.; Porter, W. J.; Ohba, Y.; Tiller, T.; Wang, S. J. Org.
Chem. 2001, 66, 5217-5231.
Suzuki coupling is very efficient for
macrocyclization and is compatible
with highly functionalized precursors.
97
G. Poli
The Problem of Electron Rich Components
Kwong, F. Y.; Lai, C. W.; Yu, M.; Chan, K. S. Tetrahedron 2004, 60, 5635-5645
OMe
MeO
MeO
B(OH)2
Br
O
O
+
Pd(PPh3)4 cat.Na2CO3
OMe
MeO
MeO
OO
OMe
MeO
MeO
54 % 27%
O'Keefe, D. F.; Dannock, M. C.; Marcuccio, S. M. Tetrahedron Letters 1992, 33, 6679-6680.
Same scrambling problems as in the Migita-Kosugi-Stille coupling may arise…
Pd
Ph3P
Ph3P
Ar X
Pd(0)(PPh3)
P ArPh
PhX
Pd
P
Ph3P
X
Ph Ar
Ph
reductive elim. oxidative addition
98
G. Poli
The Problem of Proto-deboronation
B(OR)2 H
B(OH)2
EWG
B(OH)2
RR
B(OH)2
S
B(OH)2
S B(OH)2
1 71000 850000
B(OR)2(OR)'
R'O
borate
protic source
o-EWG and steric hindrance at the ortho position
raise the proto-deboronation. In this case excess
borane is used.
protodeboronation rate
Protodeboronation may be an
undesired side reaction
99
G. Poli
Potassium Trifluoroborates
a) Molander, G. A.; Canturk, B. Angew.Chem. Int. Ed. 2009, 48, 9240-9261. b) Darses, S.; Genêt, J.-P.
Eur. J. Org. Chem. 2003, 4313.
Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S. Schrimpf M. R. J. Org. Chem., 1995, 60, 3020-3027
K Trifluoroborates are slowly hydrolyzed in the reactions to give back the same starting boronic acid. This
avoids the extensive generation of undesired phenolic and oxidative homocoupling side products.
Butters M.; Harvey, J. N.; Jover, J.; Lennox, A.J.J; Lloyd-Jones G.C., Murray, P.M. Angew. Chem. Int. Ed.
2010, 49, 5156–5160 100
G. Poli
Rehybridization of the boron center from sp2 to sp3 via complexation with N-
methyliminodiacetic acid (MIDA) protects the boronic acid function from
transmetallation, thereby allowing to perform sequential Suzuki-Miyaura reactions. If
desired, under aqueous basic conditions MIDA boronates undergo Suzuki coupling
through an in situ slow-release of the boronic acid.
MIDA Boronates
Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.
OBr
BO
N
O
Me
OO
MeB(OH)2
[Pd(0)] cat
Cylohexyl JohnPhos,
K3PO4, THF, 65°C, 15h, (80%)(anhydrous conditions)
OB
O
N
O
Me
OO
Me
1. aq. NaOH, THF
23°C, 10 min (93%)
2. Pd(dba)2
Cylohexyl JohnPhos,K3PO4, THF, 80°C,
28h, (73%)
(anhydrous conditions)
OMe
Br
MeO OMOM
B O
N OMe
OO
MeO
OMOM
BO
N
OMe
O
O
MOMOO
OMe
Br
1. aq. NaOH, THF
23°C, 10 min (99%)
2. Pd(dba)2
Cylohexyl JohnPhos,K3PO4, THF, 65°C,
20h, (81%)
OMe
MeO
OMOM
MOMO
OO
Me
OBr
B
HO
N
O
HOO
OH
OHPhH, DMSO13h reflux
101
G. Poli
Homocouplings
Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.;
Lakmini, H. J. Am. Chem. Soc., 128, 6829-6836.
2 Ar-BY2 Ar-Ar + ArOH
[Pd(0)] cat
base
Oxidative homocoupling of the boronic acid
Ar-X[Pd(0)] Ar-[Pd]-X
Ar-[Pd]-X
s-bond metathesis Ar-[Pd]-Ar
+ PdX2
Ar-Ar- [Pd(0)]
r=k[Pd] [Pd] solve the problem !
Homocoupling of the halide
102
G. Poli
Hiyama Coupling
Silanes are not toxic !!!
Polarization of vinyl silane is low.
Activation by a fluoride source is required
Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 920-923.
S SiF
F
N
N
TASF = N
103
G. Poli
Sore, H. S. Galloway W. R. D. Sping, D. R. Chem. Soc. Rev., 2012, 41, 1845-1866
Denmark S. E. Regens, C. S. Acc. Chem. Res. 2008, 41, 1486-1499
Mechanism
Formation of the pentacoordinated species is difficult when non transferable groups
other than methyl are used. A number of functional groups have been introduced on
the silicon atom to facilitate this step.
104
G. Poli
Fuoro- and Alkoxy-Silanes
SiMe(3-n)Fn
[PdCl(-C3H5)]2
(2.5%)
TASF (1 equiv.)
THF, 50°C
n-Hex
n-HexI
n time (h) Yield (%)
0 24 0
1 10 81
2 48 79
3 24 0
[PdCl(-C3H5)]2
(2.5%)
TBAF (1.5 equiv.)
THF, 50°C
n-BuI
n Yield (%)
1 95
2 96
3 54
SiMe(3-n)(OEt)n
n-Bu n-Bu
P(OEt)3 (5%)
n-Bu
Fluorosilanes
Alkoxysilanes
Tamao, K.; Kobayashi, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 6051-6054.
a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1989, 54, 268-270. b) Hatanaka, Y.; Hiyama, T. Tetrahedron
Lett. 1990, 31, 2719-2722.
105
G. Poli
Silanols and Silacyclobutanes
Silanols
Silacyclobutanes
Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821-5822.
Denmark, S. E.; Wehrli, D. Org. Lett. 2000, 2, 565-568.
n-HexSi
R R
OH
Pd(dba)2 (5%)
TBAF (2 equiv.)
THF, rt, 10 min
74-95 %
Ar I
Z or E
R = Me or i-Pr
n-HexAr
Z starting with ZE starting with E
Ar = C6H5, 1-naphtyl, 2-thienyl, (4-CH3CO)-C6H4, (4-CH3O)-C6H4
Z starting with ZE starting with E
RSi
Pd(dba)2 (5%)
TBAF (3 équiv.)
THF, T.A., 10 min
84-94 %
Ar I
Z or E
R = H or n-Hex
RAr
Ar = C6H5, 1-naphtyl, 2-thienyl, (4-CH3CO)-C6H4, (4-CH3O)-C6H4
106
G. Poli
Pyridyl- Thienyl- and Benzyl-Silanes
Pyridylsilanes
Thienylsilanes
Hosoi, K.; Nozaki, K.; Hiyama, T. Chem. Lett. 2002, 2, 138-139.
a) Itami, K.; Nokami, T.; Yoshida, J.-I. J. Am. Chem. Soc. 2001, 123, 5600-5601. b) Itami, K.; Nokami, T.;
Ishimura, Y.; Mitsudo, K.; Kamei, T.; Yoshida, J.-I. J. Am. Chem. Soc. 2001, 123, 11577-11585
RSi Pd(OAc)2 (5%)
TBAF (2.4 equiv.)
THF, rt
Ar X RAr
Ar-I = C6H5, (4-EtO2C)-C6H4, (4-MeO)-C6H4,(4-F3C)-C6H4 90-98 %
(1.2 equiv.)
S
R = H, n-Hex, Ph
Ar-Br = (4-F3C)C6H5 96 %
Benzylsilanes
Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org Lett. 2003, 5, 1895-1898. 107
G. Poli
Terminal Alkyne-Csp2 Cross-Couplings
R H XR'+
[Pd(0)]Cu(I)Base R
R
Csp-Csp2 coupling : Allows the formation of enynes and arylacetylenes
Totally stereospecific
Palladium source : Pd(II) is used as precatalyst, PdCl2L2
Pd-cat: Heck-Cassar coupling, Pd/Cu cat: Sonogashira coupling
Base : Amine
I Br
I
Cl
Br
> > >
Rate order for Csp2-X
Chinchilla, R.; Nájera, C.; Chem. Rev. 2007, 107, 874–922 108
G. Poli
About the Terminology
Taken from: Plenio, H. Angew. Chem. Int. Ed. 2008, 47, 6954 –6956
The terminology of coupling reactions involving sp-hybridized carbon centers is not applied
uniformly in the literature. The term “Sonogashira coupling” or (less often) “Sonogashira-
Hagihara coupling” now includes the various types of C(sp) C(sp2) and C(sp)C(sp3) cross-
coupling reactions, regardless of the catalytically active metal used. However, traditionally,
the term “Sonogashira coupling” corresponded exclusively to the Pd/Cu-catalyzed coupling
protocol, whereas the related copper-free reaction was termed “Heck(Cassar) coupling”.
Although the name “Stephens-Castro reaction” corresponded originally to the stoichiometric
use of copper acetylides, reactions catalyzed exclusively by copper are referred to as either
Sonogashira reactions or catalytic Stephens–Castro (or just Castro) reactions.
a) Cassar, L. J. Organomet. Chem. 1975, 93, 253 – 259.; b) H. A. Dieck, F. R. Heck, J. Organomet. Chem.
1975, 93, 259 - 263. c) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4467 – 4470. 109
G. Poli
The Seminal Paper
110
G. Poli
Mechanism of the Sonogashira Coupling
R HR'-X + R R'
PdR' X
PPh3
PPh3
R Cu
CuX
PdR' PPh3
PPh3
R
R H
H2XNEt2NEt2H
Pd(0)(PPh3)2
PdR
R
PPh3
PPh3
PdCl
PPh3
Cl
PPh3
R Cu
CuX
2
2
2
2
H2XNEt2
NEt2H
R R
PdCl2(PPh3)2, / CuI cat, NEt2H solvent
Sonogashira, K. J. Organomet. Chem. 2002, 653, 46– 49 111
G. Poli
The Cu-Pd Transmetalation Step
PdL
X
L
PdLL
transmetallation
R HR3N + R3NHX
R CuCuX
R
Catalytic in Copper
Stochiometric in base
R H
pKa 23 10.75
Et3NH
R H
CuI-complexationincrease the acidty
G. Poli G. Prestat
112
Mechanism of the Heck-Cassar Coupling
Copper free Pd-Cat
Sonogashira have been
reported. The exact
mechanism is under debate.
Tougerti, A.; Negri, S.; Jutand, A.; Chem. Eur. J. 2007, 13, 666. Ljungdahl, T.; Bennur, T.; Dallas, A.;
Emten, H.; Mårtensson, J. Organometallics, 2008, 27, 2490–2498. 113
G. Poli
Sonogashira : Functional Group Compatibility
114
G. Poli
Carbonylative Cross-Couplings
Ishiyama, T.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc Jpn., 1991, 64, 1999
Dewey, T. M.; Mundt, A.; Crouch, G. J.; Zyzniewski, M. C.; Eaton, B. E. J. Am. Chem. Soc. 1995, 117, 8474-8475
CO insertion is usually faster than transmetalation
Suzuki
Migita-Kosugi-Stille
115
G. Poli
-Arylation of Carbonyl Compounds
R
O+ Ar-X
BasePd(0)Ligand
R
O
Ar
Palucki, M.; Buchwald, S.L. J.Am.Chem.Soc. 1997, 119, 11108.
For a review see Culkin, D.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234-245.
Pd(0) source : Pd(dba)2
Base : t-BuONa or KN(SiMe3)2
Ligand : Ferrocenylphosphine, Binap, NHC…
Solvent : THF
Br OMe
PhMe
O BINAP
NaOBu-t
OMe
Me
Ph
O
91%
116
G. Poli
The Seminal Papers
117
G. Poli
Mechanism
oxidativeaddition
reductiveelimination
Pd(0)L4
Pd(0)L2 ArX
ArPd
L
X
L
LPd
O
Ar
L
ligand substitution
R
O
B-M
R
O
MX
B-HM
R
LPd
Ar
L
OR
O
RAr
118
G. Poli
Ketones: An Asymmetric Version
Åhman, ; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald S. L.; J. Am. Chem. Soc., 1998,
120, 1918–1919.
119
G. Poli
Ketones: Intramolecular Versions
Br
O
Br
O
Br
O
Br
O
Br
O
Br O
10 mol % PdCl2(Ph3P)2, 3 mol. equiv. Cs2CO3, THF or toluene at reflux.
Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581
120
G. Poli
Amides
K. H. Shaughnessy, B. C. Hamann, and J. F. Hartwig, J. Org. Chem., 1998, 63, 6546.
121
G. Poli
Aromatic Aminations (Buchwald-Hartwig Coupling)
Pd(0) precursor : Pd(OAc)2 PdCl2 Pd(dba)2
Nucleophiles: primary and secondary amines, amides, imines…
Leaving groups: I, Br, Cl, TfO
Bases : t-BuONa or LiN(SiMe3)2
Ligand : dppf, Binap, tBu3P, NHC…
Migita, T. Chem Lett. 1983, 927.
Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116: 5969–5970.
Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901–7902.
Wolfe, J. P.; Buchwald, S. L. 2004, Org. Synth. Coll. Vol. 10, 423.
For the first example of Pd-catalyzed C-N coupling on activated chloroarenes see: Kondratenko, N. B.; Kolomejcev, A.
A.; Mogilevskaya, B. O.; Varlamova, N. M.; Yagupolskii L. M. Zh. Org. Khim. (Rus.) 1986, 22, 1721-1729.
Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534-1544.
This reaction was first reported by Migita in 1983, who used aminostannanes as nucleophiles. The
reaction was later developed independently by the groups of Buchwald and Hartwig. As in the Migita
paper, the first publications needed the use (or the in situ generation ) of the corresponding
aminostannes. However, in the second-generation variant, the aminostannane could be replaced by a
free amine and a strong base.
122
G. Poli
The Seminal Papers
123
G. Poli
The Seminal Papers
124
G. Poli
Mechanism
Choice of the proper ligand allows
to favor reductive elimination over
dehydropalladation
Ar X Ar NR
RHN
R
R+
[Pd(0)] cat, base (BM)
Pd(0) L
Pd(0)L2PdX2L2
Pd
Ar
X
L
PdL
Ar
X Pd
X
Ar
L
HNR
RPd
Ar
X
L NR
RH
BMPd
Ar
LN
R
R
- BH, - MX
H
NR
R
Pd
Ar
L HArHPd(0) L +
oxidativeaddition
ligand coordination exit of X ligand
reductiveelimination
dehydropalladation
Amine coordination acidifies amine proton
125
G. Poli
Examples
Amides
Imines
Amines
Louie, J.; Hartwig, J. F. Tetrahedron Letters 1995, 36, 3609–3612
126
G. Poli
Aromatic Etherification
ROH + Base : t-BuONa , ArONa, R3SiONa
Pd(0) precursor : Pd(OAc)2 PdCl2 Pd(dba)2
Ligand : FerrocenylPhosphine, Binap, tBu3P NHC…
Less developed than the corresponding amination
Br
FG + HOR
Pd(0)LigandBase
O
FG
R
Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc., 1997, 119, 3395–339
Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem. Soc., 2001, 123, 10770–10771
127
G. Poli
-Allyl Palladium Chemistry
G. Poli
[Pd(II)]YX
Nu
R
[Pd(II)]YXNu
R
nucleophilic attack to -complexed allyl moieties
128
On the Polarization of Allyl-Complexes
Pd
L
LL
E
aldehydeimineMichael acceptor
E
PdL
L
Nu
Nuactive methyleneaminealcoolate
nucleophilic
electrophilic
G. Poli
Unless in the presence of special bulky ligands (see later the “memory effect” section)
palladium usually prefers 3-allyl structures, whereas other transition metals (i.e. Rh)
prefer 1,2-olefin type structures.
L -L
[Pd]X
R R
M
R
M
3-allyl 1,2-olefin
or
129
T.Hayashi et al.
J. Am. Chem. Soc., 1989, 111, 6301
H. Yang et al.
Organometallics, 1993, 12, 3485
G.Helmchenet al.
Tetrahedron Lett., 1994, 35, 1523
M.Yamaguchi et al.
Chem.Lett.,1996, 241
A.Pfaltz et al.
Acta Crystallogr.,Sect.C, 1995, 51, 1109
2.24 Å
2.12 Å
X-ray Structures of Some 3-Allyl Pd Complexes
G. Poli
130
PdL1
L2 R
PdL1
L2R
PdL2
L1 R
D1 ent-D1
PdL2
L1R
ent-D2
PdL1
L2
B
PdL1
L2
ent-B
PdL
L R
C
PdL
LR
ent-C
D2
PdL
L
Eendo
R
PdL
L
Eexo
R
PdL
L
A
no stereogenic unit one stereogenic unit: axis
one stereogenic unit: Pd atom one stereogenic unit: allyl plane
two stereogenic units: Pd atom, allyl plane
Stereogenic Units in a η3-Allylpalladium Complex
131
G. Poli
Pd
L2L1
PdL2
L1
Pd
L1
Pd
L2L1X
3-1
ligandassociation
liganddissociation
nucleophilicdisplacement
Pd
LL
Pd(0)L2
X- L2
Equilibria in a Generic η3-Allylpalladium Complex
132
G. Poli
3-Allyl-Pd Complexes are Fluxional Compounds
Syn-anti equilibration via 3-1-3 rearrangement / C-C rotation
Pregosin, P.S. Togni, A. et al. J. Am. Chem. Soc. 1994, 116, 4067
η3-η1 Isomerization followed by C-C bond rotation and η1-η3 equilibration leads to a global
syn-anti exchange of the substituent pair concerned in the rotation, with concomitant
exchange of the complexed allyl face. This equilibrium is very facile when R1 = R2 = H,
and normally displaced toward the syn isomer side in the case of monosubstitution.
G. Poli
R1
R2
PdX L
R1
R2 PdX
L
R2
R1
1
3 C-C rot R2
R1 Pd
X
L
PdX L
syn position
anti position
133
PdL
L
Eendo
R
PdL
L
PdL
L R
PdL1
L2 R
PdL1
L2
A
C D1
A B ent-Bregeneration enantiomerization
PdL
L
PdL1
L2
PdL
LR
enantiomerization ent-C
PdL1
L2R
enantiomerization ent-D1
PdL
L
REexodiastereomerization
Consequences of the syn-anti isomerization
134
G. Poli
Pd
A B
PdB
XA
Pd Pd
A
A
A
B A
dissociative
associative
1-3
Pd
PdPd Pd
XB
- B B
X - X
1 31 3
1 3
1 3
1 3
1 3
1 3
3-1C-Pd rot
1 3
B
A
A
B
Apparent Allyl Rotation
Apparent allyl rotation (AAR) involves the formal rotation of the allyl moiety around
the imaginary Pd-allyl bond axis.
Three possible pathways: a) dissociative mechanism b) associative mechanism,
c) η3-η1 isomerization / C-Pd rotation / η1-η3 isomerization 135
G. Poli
Consequences of the Apparent Allyl Rotation
G. Poli
PdL
L
Eendo
R
PdL
L
Eexo
R
PdL
L
PdL
L R
PdL1
L2 R
PdL1
L2
A
C D1
A B ent-B
C
PdL
LPd
L1
L2
PdL
L
RPd
L1
L2
R
regeneration enantiomerization
regeneration D2epimerization
diastereomerization
AAR AAR
AAR AAR
AAR
Such a movement can bring about inversion of the stereogenic palladium center, (like in B
and D), or of the stereogenic axis (like in E), but never of the stereogenic plane, which
sticks complexed to the metal via the same side.
136
Palladium(0)-catalyzed allyl exchange
As π-allylpalladium(II) complexes are electrophilic and palladium(0) complexes
nucleophilic, the two species can react with each other leading to exchange of the
complexed π-allyl face.
Kurosawa H. et al. Chem. Lett. 1990, 1745; Organometallics, 1993, 12, 2869
Granberg, K. L. Backvall J.-E. J. Am. Chem. Soc. 1992, 114, 6858-6863
Stary I. et al. Tetrahedron, 1992, 48, 7229; J. Am. Chem. Soc. 1989, 111, 4981
Bosnich B. et al. J. Am. Chem. Soc. 1985, 107, 2046
CO2Me
PdPh3P PPh3
CO2Me
PdPh3P PPh3
TfO
Keq. = 1.22 (THF)
45% 55%
+ Pd(0)(PPh3)2
TfO
+ Pd(0)(PPh3)2
137
G. Poli
Generation of 3-Allyl Palladium Complexes
X = leaving group
X [Pd(0)]
R [Pd(II)]X
R
X
RX
R
[Pd(0)]
[Pd(0)]
X
R
[Pd(0)]
Nu, PdX2 PdX X Nu [Pd]X
Nu
H
Base, PdX2
H
Pd
X
X
Base [Pd]X
Base XH
X
Via
Pd
(0)
Via
Pd
(II)
G. Poli
[Pd(0)]ArAr[Pd]X
[Pd]X
Ar
[Pd]X
C
ArX[Pd]
Ar
[Pd]X
[Pd(0)]ArX
Trost B. M. et al.
J. Am. Chem. Soc. 1973, 95, 292 138
OAc
Cy3P Pd PCy3
rt 12h
PdPCy3
OAcCy3P
+AcO
-
43% 43%
OAc(Ph3P)4Pd
80°Cno reaction
PdPCy3
OAc
CO / rt
OAc
The oxidative addition of allyl
acetate to Pd is a reversible
process
OAc
D D(Ph3P)4Pd
rtOAc
D D+
OAcD
D
Oxidative Addition of Allyl Acetates to Pd(0)
Yamamoto A. et al. J. Am. Chem. Soc. 1981, 103, 5600
Generation of -
allyl-Pd complexes
from allylic
acetates is
reversible and
thermodynamically
disfavored
G. Poli
The oxidative addition of
allyl acetate to Pd(0) is a
reversible process
139
On the Nature of the Allylic Leaving Groups
O
O O
O
O
NHR
O
O
O
CH3O
O OH Cl NO2 SO2Ph
NR2NR3X SR2X
EWGEWG
N
R
O
O
CF3
CCl3
O
OMe
OP
O
OEt
OEt
Many allylic systems undergo oxidative addition in the presence of Pd(0) to generate a
-allyl-Pd complex. This reaction is usually reversible and the extent of its equilibrium
depends on the nature of the leaving group.
G. Poli
140
Oxidative Addition of Pd(0) on Allyl Systems
Me Ph
OAc
58% ee
Pd(dppe)
NaBF4Me Ph
Pd
P P
Ph
Ph
Ph
Ph
+
BF4-
47% ee
T. Hayashi et al.J.Am.Chem.Soc. 1983, 105, 7767
T. Hayashi et al. J.Chem.Soc. Chem.Commun. 1984, 107
Inversion mechanism: Pd(0) approaches anti with respect to the acetate moiety
G. Poli
141
Oxidative Addition of Pd(0) on Allyl Systems
OAc
OAc
Pd(PPh3)4 5%
NaCH(CO2Me)23 : 2
OAc
CO2Me
CO2Me
unreactive
Stereoelectronic effects are important.
In conformationally locked cyclohexanes: the equatorial isomer is unreactive
Fiaud, J.C. Aribi-Zouioueche, L. J. Chem. Soc. Chem. Commun. 1986, 390
G. Poli
142
Reactions of 3-Allyl Palladium Complexes
In all these cases Pd(0) is regenerated and transformation can be catalytic in Pd
[Pd]X
Nu (C, O, N) R NuR
MR'
R R'
CO, ROHR CO2R
R'MMR'
R MR'
H-
R H
R''
R = R"CH2
allylation of nucleophiles(if Nu is a soft carbanion: Tsuji-Trost reaction)
transmetalationdehydropalladation
carbonylation
metalation hydrogenolysis
G. Poli
143
Non-stabilized Nucleophiles (pKa > 25)
X
Pd(II)
L L Nu
X
Pd(0)
L L
Pd(0)
L L
X-
Nu*
+
X-
Pd(II)
L Nu
L
Nu*
Pd(0)
L L
ionization (formation of the -
allyl complex) and nucleophilic
attack are not similar
processes.
Pd(0)Ln approaches the alkene
anti to the leaving group, to
generate the -allyl complex.
Subsequently, the nucleophile
first attacks palladium (inner
sphere, transmetalation), then
it undergoes reductive
elimination. The two latter
steps proceed with retention
mechanism. Thus, starting
from a sterogenic substrate
overall inversion is observed.
Yamamoto A. et al. Organometallics, 1991, 10, 1221
metal-olefin
-coordination
nucleophilic
addition to the
metal
reductive
elimination
decoordination
X = leaving group
ionization retention
retention
reversible
reversible
G. Poli
144
Phenylzinc: A Non-stabilized Nucleophile
T. Hayashi, A. Yamamoto, T. Hagitara, J. Org. Chem. 1986, 51, 723.
Global inversion of configuration is observed
Me Ph
OAc
(S)-E68% ee
Me
PhOAc
61% ee(R)-Z
PhZnBr
Pd(PPh3)4
Me Ph
Ph
PhZnBr
Pd(PPh3)4
Me Ph
Ph
(R)-E44% ee
(R)-E30% ee
Me Ph
[Pd]OAc
via rearrangement
Me Ph
[Pd]Ph
-Zn(OAc)Br
Me Ph
[Pd]OAc
Me Ph
[Pd]Ph
-Zn(OAc)Br
oxidativeaddition
transmetalationreductiveelimination
G. Poli
145
The Seminal Paper
NaCH(CO2Et)2Pd
Cl
Pd
Cl CO2Et
CO2Et
CO2Et
CO2Et++
Pd
Cl
Pd
Cl
+
NO
G. Poli
146
Stabilized Nucleophiles (pKa < 25)
Ionization and nucleophilic
substitution are similar
processes. However, the
former step is usually
reversible (as metal-alkene
coordination), whereas the
latter is normally irreversible.
Pd(0)Ln approaches the
alkene anti to the leaving
group, to generate the -allyl
complex. Then, the
nucleophile approaches the
allyl moiety anti to Pd(II)Ln.
(outer sphere). Thus, starting
from a sterogenic substrate
overall retention (via double
inversion) is observed.
When Nu is an active methylene the reaction is named allylic alkylation or Tsuji-Trost reaction.
3-allyl-Pd complexes are generated from acetates only in very small amounts. However,
the irreversible reaction with the nucleophile gradually drives the reaction to completion.
G. Poli
Nucleophilicsubstitution
[Pd(0)]
Oxidativeaddition
product-to-substratePd(0) trans-coordination
Nu-Y
X
R
R
[Pd(0)]
Nu
R
Nu
R
[Pd]X
- YX
[Pd]XR
B
[Pd(0)]
X
R
A C D
147
The Double Inversion Mechanism
[Pd(0)] cat.NaCH(CO2Me)2
OAc
CO2Me CO2Me
CO2Me
CO2MeCO2Me
[Pd]OAc
inversion inversion
overall retention
Trost ,B.M.; Verhoeven, T.R. J. Org. Chem., 1976, 41, 3215-3216
148
G. Poli
Active Methylenes: Typical Soft Nucleophiles
Hayashi, T.; Yamamoto, A.; Hagitara, T. J. Org. Chem. 1986, 51, 723.
Bosnich, B. ;MacKenzie, P. B. Pure Appl. Chem. 1982, 54, 189
O
O
MeO
MeO
Na
+
90 : 10
92 : 8(S)-E
(S)-E
Me Ph
CO2MeMeO2C
(R)-Z
73% ee(S)-E
Me Ph
MeO2C CO2Me
73% ee
s
s
Pd
Ph
Ph
Ph
PhPP
Me Ph
AcO-Me
Ph
Ph
Ph
Ph
PhPP
Pd
H(inversion)
AcO-
+Pd
P PPh
Ph
Ph
Ph
Me
Ph
Pd(0) dppe
Me
PhOAc
+
Me Ph
CO2MeMeO2C
30% ee(S)-E
Me Ph
MeO2C CO2Me
O
O
MeO
MeO
Na
(inversion)AcO-
+Pd
P PPh
Ph
Ph
Ph
Me PhPd(0) dppe
38% ee
Me Ph
OAc
+
+AcO-
syn, syn
anti, syn
syn, syn
Double inversion mechanism (with or without anti-syn equilibration)
G. Poli
149
Ionization of the Allylic System to the -Allyl Complex
Fiaud, J.C. Legros, J. Y. J. Org. Chem. 1987, 52, 1907
Proof of the mechanism with this particular allylic acetate
OAc
H
[Pd(0)]
no reaction
H
AcO
[Pd(0)][Pd]OAc
non-stabilizednucleophile Nu
H
stabilizednucleophile
no reaction
hindered
hindered
G. Poli
150
Complete Transfer of the Stereoinformation
O
O
Me
MeO2C
Me
H
OP
OOEt
OEt
1. Pd(PPh3)4 / THF
2. LiCl / THF
O
O
H
Ziegler F.E. et al. J. Am. Chem. Soc., 1988, 110, 5434
Ziegler F.E. et al. J. Am. Chem. Soc., 1988, 110, 5442
No appreciable racemization of the transient 3-allyl-Pd complex
Starting from a stereogenic acetate
G. Poli
151
Complete Transfer of the Stereoinformation
CO2Me
Pent
O
OCO2Me
CO2Me
Pent
O
NaH / DMSO
PdL L+
CO2Me
Pent
O
Pent
O
NaI / HMPA
CO2Me
Pent
O
PdL L
+
61% ee
Pd2(dba)3TMPP
Complete transfer of the stereochemical information can be obtained if the transiently
formed -allyl-Pd complex can be trapped before it can equilibrate. The degree of transfer
of the stereochemical information depends, inter alia, on the concentration of the Pd
catalyst: the higher the Pd concentration the lower the transfer of the stereochemical
information.
G. Poli
152
Exercise
PivO
OH OPiv
CO2R Pd(PPh3)4 cat
THF, rt, (76%)
N N
O CO2RPivO
PivO
OH OPiv CO2R
Pd(PPh3)4 cat
THF, 65°C, (79%)
N N
O CO2RPivO
Find a rational for the different stereochemical outcome of the two transformations
depicted here below.
Vares, L. Rein, T. Org. Lett. 2000, 2, 2611 G. Poli
153
OSiMe3
NSiMe3
O
NSiMe3
O
NHSiMe3AcO
Nu
AcOSiMe3 NuH
[Pd]OAc
[Pd(0)]
OAc Nu
The BSA/cat AcO- Enolizing System
Trost, B.M .; Murphy, D. J. Organometallics, 1985, 4, 1143-1145
Giambastiani, G.; Poli, G. J. Org. Chem. 1998, 63, 9608-9609
CO2Et
CO2Et+Ph OAc
Pd2(dba)3 (0.05 equiv),PPh3 (0.5 equiv)BSA : AcOK catTHF reflux (83% y)
PhCO2Et
CO2Et
154
G. Poli
Allylic Alkylations via Titanated Nucleophiles
Poli, G.; Giambastiani, G.; Mordini, A. J. Org. Chem. 1999, 64, 2962-2965 G. Poli
CO2Et
CO2Et+Ph OAc
Pd2(dba)3 (0.05 eq).PPh3 (0.05 eq.)Ti(OPr-i)4 (1.3 eq.)
CH2Cl2 reflux 9h(86%)
PhCO2Et
CO2Et
PdPPh3
PPh3
O O
OMeMeO
Ti
RO OR
RO OR
Ph
Pd(PPh3)2
pre-catalyst
Ph OAc
PhPd
PPh3
PPh3
AcO
O
OMe
O OMeTi
RO
RO
RO
OR H
H
Ti(OR)4
MeO2C CO2Me
R'OH
OO
OMe
MeO
Ti
RO OR
RO OR
Ph
R' = OAc or i-PrO
start here
and here
155
Direct Use of Allylic Alcohols
Horino, Y.; Naito, M.; Kimura, M.; Tanaka, S.; Tamaru, Y. Tetrahedron Lett. 2001, 42, 3113
Kinoshita, H.; Shinokubo, H.; Oshima, K, Org. Lett. 2004, 22, 4085-4088
O
CO2Et OH
O
CO2Et
Pd
Cl
Pd
Cl
2.5 mol %
tppts (22 mol%) H2O/AcOEt
Na2CO3, rt, 13h, 75%
P
NaO3S
SO3NaNaO3S
NaO3S
SO3Na
SO3Na
tppts (hydrosoluble)
It is proposed that water activates the allyl
alcohol via hydration of the hydroxy group
and stabilizes the resulting hydroxide ion
by strong solvation.
G. Poli
OH BEt3, Pd(OAc)2 cat., PPh3
THF, NaH, rt, 74%CO2ET
CO2Et
CO2Et
CO2EtO
H
BEt3+
156
Generation of the -Allyl Pd Complex after a Carbopalladation
52%
E = CO2Et
"PdH" migration
[Pd]I
Ph Ph
[Pd]I
Ph
[Pd]I
PhPh
[Pd]I
Ph
E
E
E
E
i+ +
H[Pd]I
H[Pd]I
i : Pd(dba)2, NaHCO3, NBu4Cl, DMSO, 80° C
PhI
Ph
Larock, R. C.; Wang, Y.; Lu, Y.; Russel, C. E. J. Org. Chem., 1994, 59, 8107
Larock, R. C.; Lu, Y.; Bain, A. C.; Russel, C. E. J. Org. Chem., 1991, 56, 4589.
484 discrete mechanistic steps !!!
G. Poli
157
Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981, 22, 2575
Tsuji, J.; Shimizu, I.; Minami, I. Tetrahedron Lett. 1982, 23,4809
In Situ Generation of Base
+
89 : 11
OAc
OH
CO2Me
O
OAc
OH
O
CO2Mert, 72%
+
CO2Me
O
O
OAc Pd2(dba)3, TMPP
With allylic oxiranes, carbonates, and phenates (see next sheet) as substrates use of a base
can be avoided since the anion generated during ionization can deprotonate the pro-
nucleophile.
G. Poli
AcO
CO2Me
O
AcOOCO2Me
77%
+
CO2Me
OPd2(dba)3, Ph3P
158
In Situ Generation of Base In Situ Generation of Base
With allylic acetates use of the base can be also avoided if the pro-nucleophile is sufficiently
acidic (pKa DMSO ≤12).
Poli, G., Giambastiani, G. J. Org. Chem. 1998, 63, 9608-9609
SO2Ph
SO2Ph
+Cl(CH2)2Cl, 12h
Pd2(dba)3, PPh3, 95%Ph OAc
SO2Ph
SO2PhPh
Ph OAc
COMe
CO2Et+
Pd(PPh3)4, PPh3, 69%
CH2Cl2, 11h
PhCO2Et
COMe
Tsuji, J.; Okumoto, H.; Kobayashi, Y.; Takahashi, T. Tetrahedron Lett. 1981, 22, 1357
G. Poli
CO2Me
OPh
O
CO2Me
O
Pd(OAc)2, Bu3P
MeCN, 85%
159
O2N SO2Ph
O2N CO2Me
NC CN
PhO2S SO2Ph
PhO2S CO2MeCO2Et
O
EtO2C CO2Et
17
16
15
14
13
12
11
10
9
8
7
pka in DMSO
7.17.3
8.08.4
11.0
12.2
14.0
14.2
16.4
NH
NH
O
O
O
O
O
O
O
a) B
ord
well, F
. G.; A
cc. C
hem
. Res. 1
988, 2
1, 4
56. b
) Hashid
a,
Y.; K
ob
aya
sh
i, M.; M
ats
ui, K
.; Bull. C
he
m. S
oc. J
pn. 1
97
1, 4
4,
25
06. c
) Pe
ars
on, R
. G.; D
illon
, R. L
. J. A
m. C
he
m. S
oc. 1
95
3,
75, 2
493
. d) h
ttp://w
ww
.ch
em
.wis
c.e
du
/are
as/re
ich
/pka
tab
le/
pKa of some Carbon Pro-nucleophiles
G. Poli
160
OAc
Y
[Pd(C3H5)Cl]2 / PPh3 cat.LiCH(CO2Et)2
THF
Y
EtO2C CO2Et
(87%) 10 : 1 Y = SMe
(76%) 19 : 1 Y = NMe2
Y
CO2Et
EtO2C
Si
OAc
N Si
CO2EtEtO2C
NSi N
CO2Et
EtO2C
(92%) 95 : 5
[Pd(C3H5)Cl]2 cat.P(C6F5)3 cat.LiCH(CO2Et)2
THF
PdR3P
Nu
AcOY
Intramolecularly-Directed Regioselectivity
Krafft, M.E.; Lucas, M.C. Chem Commun, 2003, 1232-1233
Itami K et al. J. Am. Chem. Soc., 2001, 12, 6957-6958
trans influence of the chelated η3-allyl intermediate, wherein the nucleophile
preferentially attacks the longer and, more reactive Pd-C bond
161
G. Poli
The Memory Effect
D OAc
+
THF, rt, 95%
NaCMe(CO2Me)2
Pd
Cl
Pd
Cl
catD
Me CO2Me
CO2MeD
MeCO2Me
CO2Me
(R)-MeO-MOP
83 : 17
D
+
THF, rt, 85%
NaCMe(CO2Me)2
Pd
Cl
Pd
Cl
catD
Me CO2Me
CO2MeD
MeCO2Me
CO2Me
(R)-MeO-MOP
17 : 83
OAc
Hayashi, T.; Kawatsura, M.; Uozumi, Y.; J. Am. Chem. Soc. 1998, 120, 1681
Isomerization of the -allyl intermediates is slow when bulky ligands are used such as
MeO-MOP or t-Bu3P
G. Poli
162
Regioselectivity of Addition and the Memory Effect
Normally, Pd-catalyzed allylation of nucleophiles with substituted -allyl systems occurs
with preference at the less substituted alllylic terminus to give the linear product as the
major compound. The bulkier the nucleophile, the higher the preference for the linear
product. In line with the fact that a common -allyl-Pd intermediate is involved, the final
product ratio is independent of the regiochemistry of the chosen starting substrate.
However, in the presence of special bulky monophosphine ligands, allylation takes
place preferentially on the C atom originally occupied by the leaving group. Such a
behavior, which is more pronounced with the branched substrate, is named “memory
effect”, and indicates that, in contrast to the previous case, different -allyl-Pd
intermediates are implicated as a function of the starting regioisomeric substrate used.
G. Poli
163
Regioselectivity of Addition and the Memory Effect
X
[Pd(0)]
R
[Pd(II)]XLn
RX
RPh Nu
Nu
R
Nu
common intermediate
linear
branched
linear
branched
L
X
[Pd(0)]
R
[Pd(II)]XL
R
X
RPh Nu
Nu
R
linear
branched
linear
branched
L
[Pd(0)]
L[Pd(II)]XL
R
Nu
Nu
No memory effect (no bulky monophosphines as ligands)
Memory effect (special bulky monophosphines as ligands)
G. Poli
164
Regioselectivity of Addition and the Memory Effect
Hayashi, T.; Kawatsura, M.; Uozumi, Y.; J. Am. Chem. Soc. 1998, 120, 1681
Ph
OAc L, THF, rt
NaCMe(CO2Me)2
Pd
Cl
Pd
Cl
catPh
CO2Me
CO2MeMe
Ph
MeO2C CO2MeMe
L = 91 9
Ph
OAc
+
L, THF, rt
NaCMe(CO2Me)2
Pd
Cl
Pd
Cl
catPh
CO2Me
CO2MeMe
Ph
MeO2C CO2MeMe
+
L = 92 8
PPh2
OMe L = (R)-MeO-MOP
PPh3
79 21
(R)-MeO-MOP
PPh3
L = (R)-MeO-MOP 23 77
+
+
G. Poli
165
Rationale for the Memory Effect
When L is a bulky monophosphine the generated -allyl complex features L and R in
anti positions. Furthermore, apparent allyl rotation is slow compared to the addition of
the nucleophile.
Poli, G. Scolastico C. Chemtracts - Org.Chem. 1999, 12, 822-836
Poli, G. Scolastico C. Chemtracts - Org.Chem. 1999, 12, 837-845
R
X
PdL
R
PdLX
Nu
R
PdXL
Nu
R
H
slow or disfavored
fast
G. Poli
166
Allylation of Oxygen Nucleophiles
Pd-catalyzed allylation of oxygen-based nucleophiles is also possible. However, good
results in intermolecular O-allylations can be obtained only by enhancing the
nucleophilicity of these coupling partners via their transformation into metal (i.e. Zn or
Sn) alkoxides.
Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369 G. Poli
CO2Me
OAc
Ph OH
ZnEt2 (0.5 eq.) THFCO2Me
O Ph
CO2Me
O Ph
++
Pd(OAc)2 / L
P
> 40 : 1 (70%)
1 : 2 (20%)Pd(PPh3)4
[Pd(0)] cat.
L =
167
Allylation of Nitrogen Nucleophiles (Allylic Amination)
Several nitrogen-based nucleophiles attack 3-allylpalladium complexes thereby
generating allylic amines or amine derivatives. These nucleophiles include primary (but
not ammonia) and secondary amines, carboxamides, sulfonamides, and azides. The
reaction proceeds under conditions similar to the Pd-catalyzed allylic alkylation (Tsuji-
Trost reaction). The allylic amination reaction may be a reversible step. In other words,
the resulting allylic amine may, in the presence of Pd(0), give back the parent 3-
allylpalladium complex.
Primary and secondary amines can add as such, whereas the less nucleophilic
carboxamides or sulfonamides usually need prior deprotonation.
Cl
OAc
HN
OAcPd2dba3
.CHCl3 cat.
PPh3, THF, rt, 12h, 95%Ph NH2
Ph
Lemaire, S. Giambastiani, G. Prestat, G. Poli G. Eur. J. Org. Chem. 2004, 2840-2847
G. Poli
168
Allylation of Nitrogen Nucleophiles
N
N
O
s-Bu
Ts
Ph
NOAc
O
s-Bu NH
Ts
Ph
5% Pd(OAc)2, 10% dppe, DMF, 80°C, 3 h
N
N
O
R
Ts
Ph
N
N
O
R
Ts
Ph
N
N
O
Ph
Ts
Ph
[Pd]
Pd(0) Pd(0)
cis : trans 95 : 5
more stableless stable
quant.
Ferber, B.; Lemaire, S.; Mader, M. M.; Prestat, G.; Poli, G. Tetrahedron Lett. 2003, 44, 4213-4216
G. Poli
169
Allylation of Nitrogen Nucleophiles (Allylic Amination)
Feuerstein, M.; Laurenti, D.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2001, 42, 2313
Chiusoli, G. P.; Costa, M.; Pallini, L.; Terenghi, G. Transition Met. Chem. 1981, 6, 317; 1982, 7,
304.
The latter example shows that even allylic alkylation, in special cases, can be a reversible process
CO2Me
CO2Me
+ Et2NH
Pd(PPh3)4 THF, 95%
NEt2
CO2Me
CO2Me
CO2Me
CO2Me[Pd]
G. Poli
OAc
H2O, K2CO3
55°C, 20h, 96%Pd
Cl
Pd
Cl
cat+
N
O
HPPh2Ph2P
PPh2Ph2P(TEDICYP)
N
O
170
Fe
OAc
Me Me NNaCHO
CHO
Pd
Cl
Pd
Cl
cat
PPh2
PPh2
(DPPF)
N
Me Me
CHOOHCMeCN79%
+hydrolysis
NH2
Me Me
Indirect Preparation of Primary Allylic Amines
OAc +
Pd2(dba)3 dppe, 93%
N
O
O
O
OLi N
Boc
BocNH2
hydrolysis
OAc
Pd(PPh3)4 THF, H2O 88% N
NH2
PhN N N N
N
AcONa
Na
sodium azide allyl azide
PPh3 NH2OHPh Ph
+
Ph3PO, N2
Murahashi, S.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y. J. Org. Chem. 1989, 54, 3292
Connel, R. D.; Rein, T.; Åkermark, B.;Helquist, P. J. Org. Chem. 1988, 53, 3845
Wang, Y.; Ding, K. J. Org. Chem. 2001, 66, 3238
The direct Pd-cat allylation of ammonia is not a clean reaction. However, indirect preparation of
primary allylic amines via Pd-catalysis is possible using ammonia “surrogates”.
G. Poli
171
SS PhPh
O O
Pd (10 mol%)
O2N-CH2-CO2MeDMBQ (1.5 equiv.)AcOH (0.5 equiv.)dioxane:DMSO (4:1)45°C, 24 h
86%linear : branched = 4:1
CO2Me
NO2
AcO OAc
Direct Allylic Alkylation
Allylic CH activation
Young, A.J. White, M.C. 2008, J. Am. Chem. Soc. 130,14090-14091
172
G. Poli
Enantiodiscrimination in the Allylic Alkylation
(AAA)
G. Poli
Topics in Organometallic Chemistry, vol 38, Transition Metal Catalyzed Enantioselective Allylic
Substitution in Organic Synthesis, Kazmaier, U. (ed), 2011, Springer. ISBN 978-3-642-22748-6
Pfaltz A, Lautens M,1999, Allylic substitution reactions. In: Jacobsen, E.N.; Pfaltz, A.; Yamamoto, H.
(eds) Comprehensive Asymmetric Catalysis. Springer: Heidelberg.
Helmchen, G.; Kazmaier, U. Förster, S. 2010, Enantioselective allylic substitutions with carbon
nucleophiles In: Ojima I (ed) Catalytic Asymmetric Synthesis. 3rd ed. Wiley: New Jersey. p 497-641. 173
Types of Enantiodiscrimination
3-Allyl complex formation (ionization)
Product formation
[Pd(II)]Ln*
X
R
enantiotopic faces of the starting alkene
X
enantiotopic allylic leaving groupsin the starting meso substrates
X
s
R R
[Pd(0)]Ln*
[Pd(0)]Ln*
[Pd(II)]Ln*
enantiotopic allylic sites
of the meso -allyl-moiety
in the Pd allyl complexes
s
R
[Pd(II)]Ln*
enantiotopic faces of the -allyl moiety
in the Pd allyl complexes
s
s
Nu Nu
O
R
s
forming stereogenic center
X R
X
[Pd(0)]Ln*
enantiotopic geminal allylic leaving groups
Hs
enantiotopic faces of the nucleophile
G. Poli Trost, B.M.; VanVranken, D.L. Chem. Rev. 1996, 96, 395
174
Some Chiral Ligands for Pd-cat Allylic Alkylations
N
O
RR
O
N
R
O
N P
Ph Ph
Ph
R = t-Bu, Bn R = t-Bu, Ph, i-Pr
Ph
N
OH)n
PhPFe
P Ph
Ph
(O
OHO2C
Ph2P PPh2
B.M. Trost G. Helmchen, A. Pfaltz, J.M.J. Williams
T. Hayashi K. Achiwa
NH
P
Ph
Ph
OO
Ph
Ph
P
HN
Two different concepts:
• Envelopment of the -allyl moiety
by creating a chiral pocket.
• Interaction with the incoming
nucleophile.
NH NH
O O
P P
Ph
Ph
Ph
Ph
G. Poli
175
About the Enantiodeterminant Step in AAA
RC ent-2
E
3-allyl-1
3-allyl-2
ent-1(major)
ent-2(minor)
RC ent-1
coord
/oxid
.a
dd.
nucl
.su
bs t
.
RC ent-2
E
3-allyl-1
3-allyl-2
ent-1(major)
ent-2(minor)
RC ent-1
substrate substrate
profile a profile b
coord
/oxid
.add
.
nucl
.s u
bst
.
nucl
.s u
bs t
.
coord
/oxid
.a
dd.
coord
/oxid
.a
dd.
nucl
.su
bs t
.
The starred paths are the rate- and enantiodetermining steps.
176
G. Poli
OBoc
OBoc
HNBr CO2Me+
OBoc
N CO2Me
Br
[Pd(C3H5)Cl]2 (1.25 mol%)Ligand (1.9 mol %)
Cs2CO3CH2Cl2, rt
HNNH
O O
PPh2 Ph2P
Ligand :
83% (92% ee)
Oxidative Addition is the Enantiodeterminant Step
Trost, B.M.; Dong, G. J. Am. Chem. Soc., 2006, 128, 6054-6055
Ionization of enantiotopic leaving groups. Total synthesis of agelastatin A
177
G. Poli
Oxidative Addition is the Enantiodeterminant Step
Nucleophilic addition is fast compared to the interconversion of diastereomeric
η3-allyl complexes: i.e.: slowly -σ- equilibrating η3-allylpalladium complexes
[Pd]*X
RR X R R
NuSlow Fast[Pd(0)]*[Pd]*X
Nu, - [Pd(0)]*
-X
OH
OCO2CH3
BnO BnO
O
Pd2dba3·CHCl3 (1 mol%)Ligand (3 mol %)
NEt3 (1.5 equiv.)CH2Cl2, rt
HNNH
O O
PPh2 Ph2P
Ligand :
89% (86% ee)
Trost, B.M.; Asakawa, N. Synthesis, 1999, 1491-1494.
Synthesis of vitamin E core
178
G. Poli
Nucleophilic Attack is the Enantiodiscriminating Step
R R
X
R R
R R
[Pd]*X
X
R R
Nu
R R
Nu+
[Pd(0)]*
Nua
a
bb
-[Pd(0)]*, - X
CO2Me
TsHN OCO2Me
Pd2(dba)3·CHCl3 (2.5 mol%)Ligand (7.5 mol%)
CH2Cl2, 0°C
NH HN
OO
NPPh2
Ligand:
TsN
MeO2C
90% (88% ee)
Trost, B.M.; Oslob, J.D. J. Am. Chem. Soc. 1999, 121, 3057-3064
Synthesis of (-)-Anatoxin-a
179
G. Poli