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η 3-Allyl Palladium Chemistry
G. Poli
On the Polarization of Allyl-Complexes
Pd
L
LL
E
aldehydeimineMichael acceptor
E
PdLL
Nu
Nuactive methyleneaminealcoolate
nucleophilic
electrophilic
G. Poli
Unless in the presence of special bulky ligands (see later the “memory effect” section)
palladium usually prefers η3-allyl structures, whereas other transition metals (i.e. Rh) prefer η1,η2-olefin type structures.
L -L
[Pd]X
R R
M
R
M
η3-allyl η1,η2-olefin
or
PdA
B
R1
R3
R2
PdA
BR2
R3R1
PdA
B
R1 R3
R2
η3 → η1
PdA
BR3
R2
R1
rotation
PdA
B
R3
R2
R1
η1 → η3
++
+ +
+
η3-Allyl-Pd Complexes are Fluxional Compounds
Syn-anti equilibration via η3-η1-η3 rearrangement / C-C rotation
Pregosin, P.S. Togni, A. et al. J. Am. Chem. Soc. 1994, 116, 4067
During the syn-anti equilibration switch of the face coordinated to the metal takes place. The
process does not bring about switch between the allylic C1 and C3 carbons with respect to the ancillary ligands A and B, but it involves inversion of the C2 orientation with respect to the
palladium atom.
These processes may occur on the same time scale as other steps in the catalytic cycle and can lead to a loss of stereochemical information
G. Poli
η3-Allyl-Pd Complexes are Fluxional Compounds
The process involves η3 → η1 rearrangement, rotation about the C-Pd bond, geometry
change around the metal, η1 → η3 rearrangement. Addition of chloride anions can accelerate the apparent allyl rotation via pentacoordination and pseudorotation.
Alternatively, ligand dissociation is another possible pathway for apparent allyl rotation.
Apparent allyl rotation via η3-η1-η3 rearrangement / Pd-C rotation
PdB
A
R1 R2
PdB A
R2R1
PdB
A
R2R1
PdA B
R2R1
PdA
B
R1 R2
η3 → η1
rotation
η1 → η3
++
+ + +
G. Poli
Generation of η3-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
HBase, PdX2
HPd
XX
Base [Pd]X
Base XH
X
Via
Pd(
0)V
ia P
d(II)
G. Poli
[Pd(0)]ArAr[Pd]X
[Pd]X
Ar
[Pd]X
C[Pd(0)]
ArX[Pd]
Ar
[Pd]X
[Pd(0)]ArX
OAcCy3P Pd PCy3
rt 12h
Pd PCy3
OAcCy3P+ AcO-
43% 43%
OAc(Ph3P)4Pd
80°Cno reaction
Pd PCy3
OAc
CO / rt
OAc
The oxidative addition of allyl acetate to Pd is a reversible process
OAc
D D(Ph3P)4Pd
rt OAc
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 π-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
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
NR
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
η3-allyl-Pd complex. This reaction is usually reversible and the extent of its equilibrium depends on the nature of the leaving group.
G. Poli
Facial Exchange in the π-Allyl Complex
Displacement of palladium from the π-allyl complex by Pd(0)
MeO2C
Pd
PPh3Ph3P
+
Pd(PPh3)4THF -15 °C
Pd
L L
MeO2C
Pd
PPh3Ph3P
+TfO-
TfO-
Kurosawa H. et al. Chem. Lett. 1990, 1745; Organometallics, 1993, 12, 2869; Granberg, K. L. Backvall J.-E. J. Am. Chem. Soc. 1992, 114, 6858Stary I. et al. Tetrahedron, 1992, 48, 7229; J. Am. Chem. Soc. 1989, 111, 4981Bosnich B. et al. J. Am. Chem. Soc. 1985, 107, 2046
Rapid isomerization to a 45 : 55 equilibrium mixture is observed even at -15°C starting from either complex
G. Poli
Oxidative Addition of Pd(0) on Allyl Systems
Me Ph
OAc
58% ee
Pd(dppe)
NaBF4Me Ph
PdP P
Ph
Ph
Ph
Ph
+
BF4-
47% ee
T. Hayashi et al.J.Am.Chem.Soc. 1983, 105, 7767T. Hayashi et al. J.Chem.Soc. Chem.Commun. 1984, 107
Inversion mechanism: Pd(0) approaches anti with respect to the acetate moiety
G. Poli
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
Reactions of η3-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
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 π-allyl complex) and nucleophilic attack are notsimilar processes.Pd(0)Ln approaches the alkene anti to the leaving group, to generate the π-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-olefinπ-coordination
nucleophilic addition to the metal
reductive elimination
decoordination
X = leaving group
ionization retention
retention
reversible
reversible
G. Poli
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
v i a r e a r r a n g e m e n t
Me Ph
[Pd]Ph
-Zn(OAc)Br
Me Ph
[Pd]OAc
Me Ph
[Pd]Ph
-Zn(OAc)Br
oxidativeaddition
transmetalation reductiveelimination
G. Poli
Stabilized Nucleophiles (pKa < 25)
X
Pd(II)L L
Nu
X
Pd(0)L L
Pd(0)
L L
Nu
Pd(0)L L
*
X-+
Nu*
Ionization and nucleophilic attack 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 π-allyl complex. Then, the nucleophile approaches the π−allyl moiety anti to Pd(II)Ln. (outer sphere). Thus, starting from a sterogenic substrate overall retention (via double inversion) is observed.
metal-olefin
π-coordination
ionizationnucleophilic attack
decoordination
When Nu is an active methylene the reaction is named allylic alkylation or Tsuji-Trost reaction.
reversible
reversible
irreversible
η3-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.
X = leaving group
G. Poli
The Seminal Paper
NaCH(CO2Et)2Pd
Cl
PdCl CO2Et
CO2Et
CO2Et
CO2Et++
Pd
Cl
PdCl
+
N O
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
σ → π
π → σ
Pd
PhPh
Ph
Ph PP
Me Ph
AcO-Me
Ph
PhPh
Ph
Ph PP
Pd
H(inversion)
AcO-
+Pd
P PPh
Ph
PhPh
Me
PhPd(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
PhPh
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
Ionization of the Allylic System to the η3-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
Complete Transfer of the Stereoinformation
O
O
Me
MeO2C
Me
H
OP
OOEt
OEt
1. Pd(PPh3)4 / THF2. LiCl / THF
OO
H
Ziegler F.E. et al. J. Am. Chem. Soc., 1988, 110, 5434Ziegler F.E. et al. J. Am. Chem. Soc., 1988, 110, 5442
No appreciable racemization of the transient η3-allyl-Pd complex
Starting from a stereogenic acetate
G. Poli
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 π-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
Allylic Alkylations via Titanated Nucleophiles
Poli, G.; Giambastiani, G.; Mordini, A. J. Org. Chem. 1999, 64, 2962-2965G. 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 ORRO OR
Ph
Pd(PPh3)2
pre-catalyst
Ph OAc
PhPd
PPh3
PPh3
AcO
O
OMe
O OMeTi
RO
RO
RO
OR H
HTi(OR)4
MeO2C CO2Me
R'OH
OO
OMe
MeO
Ti
RO ORRO OR
Ph
R' = OAc or i-PrO
start here
and here
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
PdCl
2.5 mol %
tppts (22 mol%) H2O/AcOEtNa2CO3, rt, 13h, 75%
P
NaO3S
SO3NaNaO3S
NaO3S
SO3Na
SO3Na
tppts (hydrosoluble)
It is proposed that water activates the allylalcohol via hydration of the hydroxy group and stabilizes the resulting hydroxide ion by strong solvation.
G. Poli
OH BEt3, Pd(OAc)2 cat., PPh3THF, NaH, rt, 74%CO2ET
CO2Et
CO2Et
CO2EtO
H
BEt3+
Generation of the η3-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, 8107Larock, R. C.; Lu, Y.; Bain, A. C.; Russel, C. E. J. Org. Chem., 1991, 56, 4589.
484 discrete mechanistic steps !!!
G. Poli
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
CO2MeO
OAc
OH
OCO2Mert, 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%
+
CO2MeO
Pd2(dba)3, Ph3P
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 OAcCOMe
CO2Et+
Pd(PPh3)4, PPh3, 69%
CH2Cl2, 11hPh
CO2Et
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%
pKa Scale of Pro-nucleophiles
G. Poli
The Memory Effect
D OAc+
THF, rt, 95%
NaCMe(CO2Me)2
Pd
Cl
PdCl
cat D
Me CO2Me
CO2MeD
MeCO2Me
CO2Me
(R)-MeO-MOP
83 : 17
D+
THF, rt, 85%
NaCMe(CO2Me)2
Pd
Cl
PdCl
cat D
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 π-allyl intermediates is slow when bulky ligands are used such as MeO-MOP or t-Bu3P
G. Poli
Regioselectivity of Addition and the Memory Effect
Normally, Pd-catalyzed allylation of nucleophiles with substituted π-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 π-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 π-allyl-Pdintermediates are implicated as a function of the starting regioisomeric substrate used.
G. Poli
Regioselectivity of Addition and the Memory Effect
X
[Pd(0)]
R
[Pd(II)]XLn
RX
R Ph Nu
Nu
R
Nu
common intermediate
linear
branched
linear
branched
L
X
[Pd(0)]
R
[Pd(II)]XL
R
X
R Ph 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
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
PdCl
cat Ph
CO2Me
CO2MeMe
Ph
MeO2C CO2MeMe
L = 91 9
Ph
OAc
+
L, THF, rt
NaCMe(CO2Me)2
Pd
Cl
PdCl
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
Rationale for the Memory Effect
When L is a bulky monophosphine the generated π-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, 822-836Poli, G. Scolastico C. Chemtracts - Org.Chem. 1999, 12, 837-845
RX
PdL
R
PdLX
Nu
R
PdXL
Nu
R
H
slow or disfavored
fast
G. Poli
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, 4369G. 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 =
Allylation of Nitrogen Nucleophiles (Allylic Amination)
Several nitrogen-based nucleophiles attack η3-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 η3-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
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
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, K2CO355°C, 20h, 96%
Pd
Cl
PdCl
cat+
N
O
HPPh2Ph2P
PPh2Ph2P(TEDICYP)
N
O
Fe
OAc
Me Me NNaCHO
CHO
Pd
Cl
PdCl
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
OO
OO
Li N
Boc
BocNH2
hydrolysis
OAc
Pd(PPh3)4 THF, H2O 88% N
NH2
Ph N N N NN
AcONaNa
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
Terminal Versus Central Attack in η3-Allyl Systems
σ-donor ligands raise the antisymmetrical MO and slightly lower the symmetrical one, while
π-acceptor ligands, owing to back-donation, lower the antisymmetrical MO.
Thus, under frontier orbital control, σ-donor ligands favor central carbon atom addition, while π-acceptor ligands direct the addition to the terminal position.
L L
Nu
L L
Nu
SymmetricalLower with σ-donor ligands
Low-lying unoccupied MO‘s in (η3-allyl)PdL2 complex
AntisymmetricalLower with π-acceptor ligands
G. Poli
Terminal Versus Central Attack in η3-Allyl Systems
Cl
PdL L
ClMe CO2Et
CO2Et
Pd
L L
Cl
Me CO2Et
CO2Et
PdL L
Me CO2Et
CO2EtMeEtO2C
CO2EtMe
CO2Et
CO2Et
A
B
+
- Cl-
+
σ-donorligands
π-acceptorligands
- PdL2
- PdL2 - NaCl
L = PPh3 A:B 98 : 2
L = TMEDA A:B <1 : > 99BF4-
-NaBF4
Cl-
MeNaC(CO2Et)2
MeNaC(CO2Et)2
However, competition between terminal and central addition may be present only with rather hard nucleophiles.If the energy level of the nucleophile is too low (i.e. if the nucleophile is too stabilized) charge control may override frontier orbital control, and terminal attack is restored
G. Poli
Enantiodiscrimination in the Allylic Alkylation
G. Poli
Types of Enantiodiscriminationη3-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
σ
R R
[Pd(0)]Ln*[Pd(0)]Ln*
[Pd(II)]Ln*
enantiotopic allylic sitesof the meso π-allyl-moietyin the Pd allyl complexes
σ
R
[Pd(II)]Ln*
enantiotopic faces of the π-allyl moietyin the Pd allyl complexes
σ
σ
Nu Nu
O
R
σ
forming stereogenic center
X R
X
[Pd(0)]Ln*
enantiotopic geminal allylic leaving groups
Hσ
enantiotopic faces of the nucleophile
G. Poli
Which is the Best Chiral Catalyst?
Phosphines: good σ-donors and π-acceptors.They stabilize the monomeric species while providing control over the steric and electronic properties of the system. The different properties of the donor atoms are transmitted to the π-system through the metal, thus allowing the fine tuning of the reactivity of the substrate.
Phosphites: strong back bonding
Amines: pure σ-donors
Bonds trans to P are expected to be longer than bonds trans to N.
Predictions are very difficult because: 1) information on the olefinic complexes is not available 2) In palladium catalyzed allylic alkylations, allyl-palladium complexes are often in dynamic equilibrium. On the time scale of the catalytic cycle ligands can dissociate, reassociate, and change their conformations
and geometry. When a stabilized nucleophile attacks a π-allyl-Pd-complex, bond reorganization is also occurring between the ligands and the allylic moiety as the substrate undergoes a change in hapticity. Interactions between the chiral ligands and the allyl fragment during the η3-η2 reorganization may be just as important as interactions between the allyl fragment and the incoming nucleophile.
G. Poli
Some Chiral Ligands for Pd-cat Allylic Alkylations
N
O
RR
O
N
R
O
N PPh Ph
Ph
R = t-Bu, Bn R = t-Bu, Ph, i-Pr
Ph
NOH)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
PhPh
OO
PhPh
P
HN
Two different concepts: • Envelopment of the π-allyl moiety by creating a chiral pocket.• Interaction with the incoming nucleophile.
NH NHO O
P PPh
Ph
PhPh
G. Poli
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 η3-Allyl Complexes
G. Poli
Discrimination of Enantiotopic Faces
O
O
OMe
NaCH(CO2Me)2
Pd(dba)2R-(+)-BINAPdioxane, rt.
CO2Me
CO2MeH
90% ee
Fiaud J. C. et al. J. Org. Chem. 1990, 55, 4840; Tetrahedron, 1994, 50, 465.
PPh2
PPh2
R-(+)-BINAP
The reaction is dependent on solvent and counterion. For example, yields and enantioselectivities dropped with toluene as the solvent or in the presence of crown ethers. The enantioselectivity correlates roughly with the leaving group ability: better leaving groups gave poorer enantioselectivities.
Pd(dba)2dppedioxane, rt.
NaCH(CO2Me)2OAc
60% ee 56% ee
CO2Me
CO2Me Enantioface exchange is not occurring during the reaction. Enantiomeric purity is preserved.
Re face preferred
G. Poli
Discrimination of Enantiotopic Faces
P
NO
Ph Pd
Ph
R
Ph
Ph
NuH
R Yield % ee %
Me 95 95
Ph 88 99
ClC6H4- 91 >95
2-Py 89 92
1-Naphth 96 >96
Mesityl 91 98
Williams, J. M. J. et al. Tetrahedron: Asymmetry 1995, 6, 2535
Ph R
Ph OAc2.5 % [Pd(allyl)Cl]2NaCH(CO2Me)2Ligand 10 %
Ph R
PhMeO2C CO2Me
P N
O
Ph Ph
G. Poli
Discrimination of Enantiotopic Faces
π-σ-π Pd/C rotation may bring about apparent allyl rotation. In contrast to what happens with symmetrical allyl fragments (see later), only complex A has the less
substituted allyl terminus trans to P atom of the ligand. This may explain the lower reactivity of these non symmetrical complexes with respect to the symmetrical
ones. The nucleophile has to “wait” for the allyl group to arrange itself in the more
sterically crowded isomer.
P
N
O
Ph Pd
Ph
R
Ph
+
H
Ph Nu
reactive
Brown, J. Oxford
A B
P
N
O Ph
Pd
Ph
R
Ph
Ph
Nu
+
G. Poli
Discrimination of Enantiotopic Faces
Ph R
Ph OAc
Ph R
Ph
MeO2C CO2Me
Ph R
Ph[Pd]
R
Ph OAc
Ph R
Ph
MeO2C CO2Me
Ph R
Ph
[Pd]
Ph
Ph R
Ph[Pd]
π-σ-π C/C rot. accounts for generation of the same reactive intermediate from the two enantiomeric acetates (enantioface exchange).
G. Poli
OAcNu
Nu
Desymmetrization of Meso η3-Allyl Complexes
This substrate is often taken as a model to test new chiral ligands in
asymmetric allylic alkylation.With this substrate the ionization step produces a meso form, and
the nucleophile is directly involved in the enantiodiscriminating step.
A wide variety of bidentate ligands are capable of inducing high ee’s.
G. Poli
The Oxaxoline P/N Ligand
Helmchen G. et al. Tetrahedron Lett. 1994, 35, 1523
ligand / Pd ratio: 1.2
0.02 equiv.
yield 98%e.e.: 98%
Ph Ph
OAc
H2C(CO2Me)2 3 equiv.1/2 [C3H5PdCl]2 cat.BSA 3 equiv.AcOK 0.01 equiv.THF / rt
Ph Ph
MeO2C CO2Me
N P
2.24 Å
2.12 Å
Major and more reactive complexAttack trans to P atomi-Pr is pseudo-axial
Ph Ph
HH
+OPh
PPdN Ph
Nu
X-ray structure
G. Poli
Oxaxoline Ligands do not Exchange Enantiofaces during Rxn
Pfalz, A. Pregosin, P. et al. Helv. Chim. Acta, 1995, 78, 265.
A B
L = PPh3 58 : 42L = A 99 : 1L = B 1 : 99L = C 93 : 7
SR
CH2(CO2Me)2AcOK, 23 °C2% (allylPdCl)2ligand
CO2MeMeO2COAc MeO2C CO2Me
enantiopure enantiopure enantiopure
Enantiofaces are not exchanged during the reaction
Ph Tol
PdL L
Ph TolPd
L L
Nu
O
NN
O
PhCH2 CH2Ph
C
O
N
Ph
P
PhPh
O
N
Ph
P
PhPh
P/N Oxazoline ligands BOX ligand
G. Poli
H
H
H
H
Ph Ph
HH
SbF6-SbF6
-
++N
HO
PdP
PhPh
Ph Ph
HH
HOPh
PPdN Ph
PF6-PF6
-
++N
HO
PdP
Ph
PhH
H H
H
SbF6-
+
HOPh
PPdN Ph
PhPh
H H
PF6-
+N
HO
PdP
Ph
PhH
HH
H
PhPh
PPd
HO
Nη1→η3 η3→η1
η1→η3 η3→η1
3 1
31
11
8 1
d.r.:
d.r.:
Facial Exchange in π-Allyl Complexes (η3-η1-η3)
Via NOESY ROESY cross peaks: A: 1-Hs/1Ha; 1-Ha/1Hs; 3-Hs/3Hs. B: 3-Ha/3-Ha
Under the conditions of the allylic alkylation the two conformations interconvert at least 50 times faster than nucleophilic attack.Attack trans to the weaker (and longer) Pd-P bond is easier than trans to the Pd-N bond. The major conformer turns out to be also the more reactive one.
Helmchen G. et al. Tetrahedron Lett. 1994, 35, 1523
Via C-C rotation(syn-anti equilibration)k = 0.65 s-1 -23 °C
Via Pd-C rotation(apparent allyl rotation)k = 1.6 s-1 +25 °C
A1 A2
B1 B2
The complexed allyl face is exchanged
The complexed allyl face is not exchanged
P/N Oxazoline ligands
G. Poli
Rationalization of the Enantioselectivity
The enantioselectivity is determined by the regioselectivity of the nucleophilic attack
Ar Ar
Pd CH2PhPhCH2
O
N N
O
+
PF6-
Pd
N N
68°108°
85°99°
2.17
2.13
2.12
2.11
According to 1H-NOESY the allyl complex exists in at least two rapidly interconvertingconformations.
The coordination at Pd is pseudo-square planar and the central chelated 6-membered ring
system is in a boat-like conformation. The C-Pd distance of the two allylic termini is different.The nucleophile attacks preferentially the allylic terminus associated to the longer, and thus
more reactive, C-Pd bond.
NuX-ray structure
G. Poli
Rationalization of the Enantioselectivity
R
R
R
R
R
RPhPh
H H
Ph
Nu
Ph
Ph
Nu
Ph
CH2(CO2Me)2AcOK, 23 °C2% (allylPdCl)2
Ar Ar
OAcCO2MeMeO2C
Ar ArO
NN
O
PhCH2 CH2Ph
favored disfavored
The different energies of the two possible diastereomeric Pd(0) complexes resulting from the nucleophilic attack, or of the corresponding transition states leading to them, may be the
factors dictating the selectivity (a pseudo square planar geometry is assumed for Pd).
BOX ligand
G. Poli
C1 vs C2 Symmetric Ligands
1,3-syn-disubstituted Pd π-allyl complexes may interconvert only via π−σ−π (C-Pd rot)
mechanism (apparent allyl rotation), as shown above. An alternative π−σ−π (C-C rot) mechanism, which would bring about syn/anti interconversion, is usually at work only
with terminal π-allyl complexes, where the syn/anti interconversion is hidden.
If R1 = R2, the π-allyl fragment has C2h symmetry, and the two allylic termini become enantiotopic. Now, if the chiral bischelating ligand has C1 symmetry, complexes A and B
are different diastereoisomers. The two isomers, usually referred to as endo and exo,
can be distinguished spectroscopically, in fact, their interconversion in solution is slow
with respect to NMR time scale.If, on the other hand, the ligand has C2 symmetry (L1 = L2), the above interconversion
becomes hidden, since it would re-generate the same diastereoisomer (A = B).
A B
C-Pd rot σ→ππ→σR1 R2
PdL2 L1*
PdL2 L1
R1 R2
*Pd
L1 L2
R1 R2
*R1 R2
PdL1 L2*+ + + +
G. Poli
C2 vs C1 Symmetric Ligands
Apparent allyl rotation
PdR
R
Ph
PhPN
OPh
OPh
N
PdR
R
P Ph
Ph
RR
NO
NO
PdPh
Ph
RR
Ph
PhPd
ON
ON
+
+ +
+
G. Poli
C2
C1
The Syn/Anti Exchange may be Selective
With Josiphos the allylic carbon attached to the Cy2P group always remains trans to this group. Only the bond trans to Ph2P group is broken during the syn/anti exchange process.
Pregosin, P. S. Togni, A. et al. J. am. Chem. Soc. 1994, 116, 4067
Fe Pd
CyCy
Ph
P
P
Ph
Pd
CyCy
Ph
P
P
Ph
Fe
P
PPh
Ph
CyCy
PdFe
P
PPh
Ph
CyCy
PdFe+ +
+ +
G. Poli
Trost B.M.et al. Angew. Chem.,Int.Ed.1995, 34, 2386,
PdP
HN O
O
P
NH
The π-allyl unit sits in a chiral pocket defined by the propeller arrangements of the aryl rings which orient in edge-face relationships.
The P-Pd-P bite angle is 110.5°, considerably larger than the normal (~90°) bite agle of square planar complexes.
PdP P
PhPh
Ph
Phϑ
The Trost Ligands
X-ray structure
G. Poli
The Trost Ligands: Concept
XO
P
OX
P
Pd
ON
Pd
P P
NO
H H
SCAFFOLD SCAFFOLD
2-diphenylphosphinoaniline (DPPA) L12-(diphenylphosphino)benzoic acid (DPPBA) L2
For both series opening of the bite angle (P-Pd-P) is believed to enhance the depth of the
chiral pocket in which the substrate must reside. This is expected to create a chiral space that controls enantioselectivity.
B. M. Trost et al. Angew. Chem Int. Ed. Engl. 1992, 31, 228; J. Am. Chem. Soc. 1992, 114, 9327
G. Poli
Discrimination of Enantiotopic Leaving Groups
SCAFFOLD
X Y
P
Y X
P
Pd
O OTsHN NHTs
O O
O
NO
Ts
O
NO
Ts2.5 mol% (Pd2(dba)37.5 mol% Ligand THF rt
SCAFFOLD
XY
P
YX
P
Pd
Clockwise Counterclockwise
Clockwise Counterclockwise
intramolecular
G. Poli
A Mnemonic Device...
N
O
O
Ts
2.5 mol% Pd2(dba)3 CHCl37.5 mol% ligandTHF / rt
(-)clockwise ionization
PhPh
P
ONH
PhPh
P
ONH
PPh2
PPh2
chiral scaffold
linker
clockwise ligand L2
pro-R pro-S
HNS
O OO O
OO
SNH
O O
PdP
P
Clockwise ligand induces a clockwise motion of the catalyst with respect to the substrate, thereby preferentially ionizing the pro-R leaving group.
…to correlate absolute stereochemistry with the chirality of the ligand
Enantioselective ionization of enantiotopic leaving groups
G. Poli
PhCO2 O2CPh PhCO2 NuNu / ligand
Nu O2CPhNu / ligand
NH NHO O
P PPh
Ph
PhPh
NH NHO O
P PPh
Ph
PhPh
L3 counterclockwiseL4 clockwise
Nu ligand A:B yield %
NaCH(CO2Me)2 L3 96.5 : 3.5 80
NaCH(CO2Me)2 L4 4 : 96 68
PhCH2NHMe L3 89 : 11 75
PhCH2NHMe L4 <1 : >99 77
Discrimination of Enantiotopic Leaving Groups
ABclockwise counter-clockwise
Trost, B. M. Van Vranken, D. L. Chem. Rev. 1996, 96, 395
intermolecular
G. Poli
Discrimination of Enantiotopic π-Allyl Faces
PhPh
P
ONH
PhPh
P
ONH
H H
Trost, B. M. Bunt, R. C. Angew. Chem. Int. Ed. Engl. 1996, 35, 99
CH2Cl2: 98% eeTHF: 68% ee
<1>75
NO O
OH
PdL L
O-
PdL L
O-
NO O
OH
Ligand (7.5%)K2CO3 (5%)(allyl)PdCl/2 (2.5%)(99%)
N
O
O
H
O
The epimerization (deracemization) has to occur faster than alkylation so that one of the two complexes reacts faster than the other. In the ligand, rotation of the carboxylate bond is restricted owing to the peri interactions. The nature of the chiral cavity is different with respect to the parent phenyl-type ligand.
faster reacting
regio + enantiocontrol + starting material deracemization
G. Poli
Interaction Between η3-Allyl Pd-Complexes and Allenes
[Pd]O2Ct-Bu
t-BuCO2
.
CO2MeMeO2CMeO2C
MeO2C .MeO2C CO2Me
Pd(0)
anti allene-attackto η3-allylPdoxydative add.
Franzén, J.; Löfstedt, J.; Dorange, I.; Bäckvall, J.-E. J. Am. Chem. Soc. 2002, 124, 11246Franzén, J.; Löfstedt, J.; Falk, J.; Bäckvall, J.-E. J. Am. Chem. Soc. 2003, 125, 14140
Allenes can intramolecularly syn carbopalladate with a π-allyl Pd complex to generate a new π-allyl Pd complex, which can in turn be trapped to give a cyclized allylic ester.
a) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067. b) Doi, T.; Yanagisawa, A.; Nakanishi, S.; Yamamoto, K.; Takahashi, T. J. Org. Chem. 1996, 61, 2602. (c) Takahashi, T.; Doi, T.; Yamamoto, K. In Transition Metals for Organic Synthesis, Beller, M.; Bolm, C., Eds. Wiley-VCH: Weinheim, 1998; Vol. 1, pp 265-274
AcO
.
[Pd]OAc
.
OAc
[Pd]OAcoxidativeaddition
Pd(0)
syn carbopd
[Pd(0)]
nu add to η3-allyl
However, allenes are also able to act as π-nucleophiles, giving trans attack on a (π-allyl)Pd complex instead of cis insertion.
Pd(0)-Catalyzed Cyclization of 1,3-Dienyl Allenes
Löfstedt, J.; Franzén, J.; Bäckvall, J. E. J. Org. Chem. 2001, 66, 8015Joakim Löfstedt, Katja Närhi, Ismet Dorange and Jan-E. Bäckvall, J. Org. Chem. 2003, 68, 7243-7248
.
MeO2C CO2MePd(dba)2 (5 mol%) Li2CO3, CH2Cl2Nu (10 equiv.)
MeO2CCO2MeRCO2
10 examplesNu: RCO2H, ROH, RSH
.
MeO2C CO2Me Pd(dba)2, LiOAc, AcOH(D)(65%)
MeO2CCO2MeAcO
H(D)
Possible Mechanisms of the Cyclization
1st hypothesis
oxidativecoupling
external attackon π-allylPd
.
MeO2C CO2Me MeO2CCO2Me
[Pd]
[Pd]CO2Me
CO2Me
H-Nu
MeO2CCO2Me
H[+Pd]
MeO2CCO2Me
H
NuPd(dba)2
Nu-[Pd(0)]
-LL
[Pd(0)]
bis-allyl-Pdrearrangement
protonation
A palladacycle is formed by oxidative cycloaddition to Pd(0). This species rearranges to a bis-(η3,η1-allyl)Pd complex, which in turn can be protonated by the protic nucleophile at the γ-position of the σ-allylligand, to give a new (η3-allyl)Pd complex. An external nucleophilic attack on this (η3-allyl)Pd complex would give the products and regenerate Pd(0).
.
MeO2C CO2Me
[Pd]
MeO2C CO2Me MeO2CCO2Me
[Pd+]
MeO2CCO2MeNu
Nu-[Pd]-H
Nu-[Pd(0)]
[Pd(0)] + NuH
HH H
oxidativeaddition
syn hydropdto allene
syn caropdto alkene
external attckon π-allylPd
The Pd-hydride species, generated by oxidative addition of NuH to Pd(0), hydropalladates the distal allenicdouble bond thereby forming a vinyl-Pd species. The latter intermediate would then undergo intramolecularcarbopalladation to give an (η3-allyl)Pd complex. Subsequent external nucleophilic attack would give the products.
2nd hypothesis
