M.C. White, Chem 153
Cross Coupling -84-
Week of October1, 2002
C-C Bond Formation
Csp-Csp2
Csp3-Csp2 Bonds
Csp2-Csp2 Bonds
R
R
R
R
Alkyl
R
R
Pd(II)
Cl
(or Ni(II)
Cl
R2
R
R
LnPd
Cl
R2
R = aryl, vinyl
X = I, Br, OTf, Cl
(0)
1
R -X
oxidative
addition
reductive
elimination
LnPd(II)
)
Cl
R2-M
2
R
Ar
R1
(II)
LnPd
R2
R1
X
A paradigm shift:
nucleophilic substitution
at an sp2 hybridized
carbon is made routine
by using transition metal
mediated catalysis.
R2-M
transmetalation
R2= aryl, vinyl, alkyl
Alkyl
Alkyl
Classifications based on the main group metal
used to transfer R2 in the transmetalation event.
Negishi Coupling
Kumada Coupling
Stille Reaction
Ni(0) or Pd(0)
M = Al(i-Bu)2
Zr(Cl)Cp2
ZnX
Hiyama Coupling
Pd(0)
M = SnR3
Pd(0)
M = SiR3
Ni(0) or Pd(0)
M = MgX, Li
Suzuki Reaction
X-M
Alkyl
Csp3-Csp3 Bonds
General Mechanism
1
R
R
Pd(0)
M = BX2
Sonogashira
Pd(0)
M = Cu (in situ)
Ar
M.C. White, Chem 153
Cross-Coupling -85-
Week of October 1, 2002
Kumada pushes the frontier
Ph2
P
All the pieces of the catalytic cycle were in the literature...
Transmetallation: Chatt and Shaw J. Chem. Soc. 1960 1718.
Report the synthesis of alkyl and aryl nickel(II) complexes
from the corresponding nickel(II) halides.
Cl
Ni(II)
Cl
P
Ph 2
Cl
n-BuMgBr (2 eq)
Cl
0.7 mol%
94%
Ph 2
P
Br
PPh3
Ni(II)
Ph3P
Cl
R
2 RMgBr
Br
Ni(II)
Ph3P
PPh3
R
(II)
Ni
Cl
0.7 mol%
P
Ph 2
Cl
R=
R'
MgBr
80%
Reductive elimination/Oxidative addition: Yamamoto JOMC
1970 (24) C63. "Preparation of a phenyl-nickel complex, phenyl
(dipyridyl)nickel chloride, an olefin dimerization catalyst.
Kumada JACS 1972 (94) 4374.
LnNi(II)
Cl
Cl
Cl
R2-MgX
R2
R1
R2= aryl, vinyl, alkyl
R2
L nNi(0)
R2
R1-X
N
Ni(II)
Ni(II)
N
N
+ butane
Cl
oxidative
addition
reductive
elimination
L nNi(II)
R1 = aryl, vinyl
X = Cl > Br> I
N
R1
R2
L nNi(II)
R1
Cl
X
Cl
N
N
(II)
Ni(0)
Ni
transmetalation
MgX 2
R2-MgX
N
N
M.C. White, Chem 153
Cross-Coupling -86-
Week of October 1, 2002
Kumada Coupling
Common Bidentate Phosphines
Effect of the ligand:
R2
P
Cl
Ni
P
P
0.7 mol%
n-BuMgBr (2 eq)
dppm, n=0, bis(diphenylphosphino)methane
dppe, n=1, bis(diphenylphosphino)ethane
dppp, n=2, bis(diphenylphosphino)propane
dppb, n=3, bis(diphenylphosphino)butane
P
Cl
P
R2
Cl
( )n
(II)
P
Ligand
% yield
dppp
100
dmpf
94
Ph3P (2eq)
84
dppe
79
dmpe
47
dppb
28
dmpe, bis(dimethylphosphino)ethane
Reactivity of aryl halide:
· Bidentate phosphine ligands
exhibit higher catalytic activity
than monodentate phosphines
with dppp being optimal for a
wide range of aryl and vinyl
halides.
Ph2
P
Cl
(II)
Ni
X
P
P
Ph 2
Cl
0.7 mol%
n-BuMgBr (2 eq)
Fe
P
dmpf, bis(dimethylphosphino)ferrocene
Kumada Bull. Chem. Soc. Jpn. 1976 (49) 1958.
X
% yield
F
Cl
Br
I
31 (2h)
95 (3h)
54 (4.5h)
80 (3h)
· Unlike other cross-coupling
methods, aryl and vinyl chlorides
exhibit higher reactivities than
their Br or I analogs. It is
noteworthy that even aryl
fluorides undergo the nickel
catalyzed cross-coupling.
M.C. White, Chem 153
Cross-Coupling -87-
Week of October1 , 2002
Kumada Coupling: Applications
· Industrial production of p-substituted styrene derivatives (Hokka Chemical Industry, Japan)
Ph 2
P
Ph 2
P
Cl
P
Ph2
MgCl
Cl
+
Cl
Ni(II)
Ni(II)
Cl
P
Ph2
Cl
0.1 mol%
t-BuO
Strem 2001-2003 catalog
$7.6/g (very cheap)
t-BuO
Banno JOMC 2002 (653) 288.
· Functionalization of heterocyclic halides
Ph 2
P
Cl
Ni(II)
P
Ph2
N
Br
Cl
0.5-1 mol%
MgBr
78%
72%
· Formation of sterically hindered biaryls
Ni
Cl
O
N
O
II
+
O
3 mol%
N
3 mol%
steric hinderance tolerated
only on the Grignard
N
R
imidazolium salt
RMgX
Br Mg
R = CF 3, H, CH3, OCH3
71%
BF4-
N
R
Herrmann ACIEE 2000 (39) 1602.
N
Nucleophilic N-heterocyclic carbenes are
used as a phosphine mimics that (unlike
monodentate phosphines) do not
dissociate from the metal
BF4O
SiMe3
S
S
Kumada Tetrahedron 1982 (38) 3347.
N
N
Me3SiCH2MgCl
BuMgBr
R= CF3, 91%
H, >99%
CH3, 95%
OCH3, 98%
BF4N
N
M.C. White, Chem 153
Cross-coupling -88-
Week of October 1, 2002
Pd Kumada Coupling: stereospecific transmetallation
Oxidative addition to Pd(0) had been reported: Fitton Chem.
Comm. 1968, 6.
The nickel catalyzed Kumada coupling is stereospecific for vinyl
mono-halides (complete retention of geometric configuration)
but non-stereospecific for alkenyl Grignards:
R2
P
Br
Cl
P
R2
Ph3P
Ph
Me
MeMgBr
96% (Z)-β-bromostyrene
96% (Z)-stilbene
R2
P
P
R2
Br
PPh3
Cl
Palladium (0) shown to be an effective, stereospecific catalyst for
cross-coupling of alkenyl halides with Grignard reagents.
Murahashi JOMC 1975 (91) C39.
Ph
MeMgBr
Ph
Pd
Ph3P
PPh3
3
mol%
Ph3P
Br
99% cis-β-bromostyrene
Me
P
R2
Cl
Me
99% cis-stilbene
>99% yield
Palladium (0) shown to be stereospecific for alkenyl Grignards
reagents. Linstrumelle TL 1978, 191.
Cl
Ni(II)
BrMg
Ph
MeMgI
>99% (E)-stilbene
R2
P
I
Ph3P
PPh3
Me
>99% (E)-β-bromostyrene
Pd(II)
Ph3P
Cl
Ni(II)
Ph
Ph3P
Pd
Cl
Ni(II)
Ph
I
PPh3
Ph
Me
PPh3
27% Z: 73% E
96% Z
Br
Note: Nickel catalysis may involve radical pathways
Kumada TL 1975 1719.
Kumada Pure & Appl. Chem. 1980 (52) 669.
Note: Pd catalysts can also transmetallate with organolithium
reagents: Murahashi JOMC 2002 (653) 27.
n-C6H13
I
(E)-1-iodo1-octene
Pd(0): I>Br>>Cl
Pd
PPh3
Ph3P
Ph3P 5 mol%
BrMg
Me
(Z)-1-propenyl-1
magnesium bromide
n-C6H13
>97%, (2Z,4E)-2,4-undecadiene
87% yield
M.C. White, Chem 153
Cross-Coupling -89-
Week of October 1, 2002
Negishi Coupling: towards FG tolerance
Negishi demonstrates for the first time that metals less electropositive than Mg or Li can act as effective transmetalation reagents in the Kumada Ni and Pd catalyzed
cross-coupling reaction. The stereospecificity observed in the Pd catalyzed reaction confirms that it is the preferred metal for alkenyl-alkenyl couplings to form 1,3-dienes.
n-C5H11
n-C5H11
+
n-C 4H9
(PPh3)2Pd(0)*
or
I
Al(i-Bu)2
(PPh3)2Ni(0)
n-C4H9
5 mol%
* PdCl 2(PPh 3)2 + 2 eq. DIBAL
Ni(acac)2 + 2 eq. DIBAL
Pd: 74%, >99% (E,E)
Ni: 70%, 95% (E,E), 5% (E,Z)
Negishi JACS 1976 (98) 6729.
The lack of functional group compatibility in both the alkyne hydroalumination and of the resulting alkenylalane prompted a shift to alkenylzirconium transmetalating reagents
(generated via hydrozirconation of terminal alkynes) which can tolerate such functionalities as ethers, ketones and esters, etc... Problems still exist with highly electrophilic
(e.g. aldehydes) and protic functionality (e.g. alcohols). In addition, these intermediates are moisture sensitive.
Br
O
O
(PPh3)2Pd(0)*
+
O
O
MeO
O
o
50 C, 4h
70%
ZrCp2Cl
O
MeO
Negishi TL 1978 (12) 1027.
The addition of ZnCl2 increased the reactivity of the transmetalating reagent making the cross coupling of sterically hindered substrates possible. It is thought that the
alkenylzirconium, alkenylalane undergo in situ transmetalations with ZnCl2 to form alkenylzinc, a more reactive transmetalating reagent.
PPh3
I
Et
Et
i-Bu2Al
(or ZrCp2Cl)
Negishi Acc. Chem. Res. 1982 (15) 340.
Pd
PPh3
Ph3 P
Ph3 P
5 mol%
ZnCl2, 1h, 25 oC, 88%
Et
Et
No rxn after 1 wk w/out ZnCl2
M.C. White, Chem 153
Cross Coupling -90-
Week of October 1, 2002
Negishi Coupling: Csp3-Csp2 and Csp3-Csp3
Formation of Csp2-Csp3 bonds using alkylzinc reagents.
H
β-hydride
elimination
Pd(PPh3)4
I
Pd II
n-BuZnCl
or n-BuMgCl
PPh3
n-BuMgCl n-BuZnCl
2%
25%
76%
n-C 4H9
reductive
elimination
PPh3
n-C 4H9
n-C 4H9
51%
n-C 4H9
Negishi JACS 1980 (102) 3298.
Q: β-hydride elimination and reductive elimination presumably go through a similar Pd organometallic intermediate formed after the
transmetalation event. Develop a hypothesis for why less β-hydride elimination product is observed when a zinc versus magnesium
transmetalating reagent is used.
Recall: formation of Csp3-Csp3 bonds using alkylzinc reagents.
O
O
NiII
O
O
O
10 mol%
I
F3C
O
O
NiII
Bu
O
Bu
O
Pent2Zn
F3C
Pent
Bu
50 mol%
possible intermediate
70% yield, 1h
w/out π-acid: 20%, 15h
Knochel ACIEE 1998 (37) 2387.
M.C. White/Q. Chen, Chem 153
Cross-Coupling -91-
Week of October 1, 2002
Negishi Coupling: Csp3-Csp2
Note: β-hydride present in alkyl zinc.
transmetalation I
I
O
O
Zn
ZnCl2, t-BuLi (3 eq)
OTBS
Ph3 P
O
Et2O, -78 °C to rt
O
PMP
O
OTBS
O
Pd II
OTBS
OTBS
PMP
PMP
Ph3 P
I
PPh3
Pd II
OTBS
Et2O, rt
OPMB
PPh3
I
5% Pd(PPh 3) 4
OTBS
PdII
-PPh3
transmetalation II
+
oxidative
addition
PPh3
O
O
OTBS
OTBS
OPMB
PMP
OPMB
OPMB
O
O
OH
OH
NH2
HO
13 steps
O
O
(+)-Discodermolide
Smith JACS 2000 (8654).
Ligand dissociation to the
trigonal planar intermediate
is thought to favor reductive
elimination
from
square
planar complexes.
Yamamoto OM 1989 (8) 180.
reductive
elimination
O
O
OTBS
OTBS
PMP
66%
OPMB
M.C White, Chem 153
Cross-Coupling-92-
Week of October 1, 2002
Stille Coupling
The original report:
Catalyst
Ph3P
PdII
Cl
Palladium(0)
P h3P
Br +
Ph
1 mol%
Me4Sn
Pd 2(dba)3
PPh3
Me
HMPA, 62oC
O
Pd
+ Me 3SnCl
Ph3P
Stille JACS 1979 (101) 4992.
PPh3
Ph3P
dibenzylideneacetone (dba)
Strem 2001-2003
$53/g
Transfer from tin:
alkynyl>alkenyl>aryl>benzyl>allyl>alkyl.
Allows for simple alkyl groups (Me, Bu) to
Strem 2001-2003
$28/g
serve as"dummy" R3 substituents thereby
avoiding using four identical expensive and/or
Palladium(II)
difficult to synthesize R 2 groups. Alkyl
transfers are only practical for methyl or butyl.
H3CCN
Ln
Pd (II)
Cl
Cl
Cl
R1
R2
Ln
Pd(0)
R2
oxidative
addition
reductive
elimination
L nPd(II)
R 1 = aryl, vinyl, alkynyl
X = I>Br>OTf>>Cl
R1-X
R1
R2
L nPd(II)
O
Cl
O
NCCH3
Pd II
O
O
Strem 2001-2003
$52/g
Strem 2001-2003
$39/g
2
R2-Sn(R3)3 R = alkynyl, aryl, vinyl, alkyl
R2
Pd
II
Ligands
Monodentate phosphines are added to palladium sources with poorly
coordinating ligands to prevent catalyst decomposition ("plating out")to metallic
Pd(0). Bidentate phosphines result in low reaction rates and poor yields.
R1
X
PPh3
O
transmetalation
XSn(R3)3
The rate-determining step in
Stille-couplings with reactive
2
3
R -Sn(R )3
electrophiles (i.e. R 1-X=
unsaturated iodides, triflates)
P
O
As
O
tri-2-furylphosphine
triphenylarsine
M.C. White/M.W. Kanan Chem 153
Cross-Coupling -93-
Week of October 1, 2002
Unmatched stability and low cross-reactivity of organotins
Organotin reagents are:
· Highly functional group tolerant
· Readily synthesized via a variety of methods*
· Air and moisture stable (often distillable)
· Stable to the vast majority of organic reagents.
OH
oxidation
3 eq. SO3 Py, 3eq. Et3N,
(n-Bu 3Sn)(Bu)CuLi.LiCN
Bu3Sn
OH
CH 2Cl2/DMSO
96%
HWE condensation
CO2Et
CHO
Bu3Sn
PO(EtO)2
i) n-BuLi, DMPU, THF, 0°C
ii) aldehyde, -78°C-> -20°C
Bu3Sn
CO2Et
73%
Stille Coupling
OTf
CO2Et
2.5 mol% Pd2(dba)3
20 mol% AsPh3, NMP
62%
retinoic acid precursor
Dominguez Tetrahedron 1999 (55) 15071
* For comprehensive review of synthesis of aryl and vinyl stannanes see A.G
Myers/A. Haidle Chem 115: "The Stille Reaction".
M.C. White, Chem 153
Cross-Coupling -94-
Week of October 1, 2002
Stille: Ligand Effects
Pd2dba3 + Ligand
I
Relative
rate
Ligand
Pd:L
θ
PPh3
1:2
145o
1
(2-furyl)3 P
1:2
ND
20
AsPh3
1:2
142o
78
Bu3Sn
THF, 50 oC
It has been observed experimentally that increasing the concentration of
monodentate phosphine ligands decreases the rate of the Stille reaction.
No correlation exists between cone angles (θ) and observed rates indicating
that the ligand effect is not of steric origin. The ligand effect is thought to
be electronic in nature where phosphines that are poor σ-donors promote
the cross-coupling more effectively than those that are strong σ-donors.
Kinetics studies support a mechanism
involving fast oxidative addition followed
by a rate-determining transmetalation event
which requires initial solvent/ligand
exchange. This predissociation event is
disfavored thermodynamically with strong
donor ligands such as PPh3, and more
favored with weak donor ligands such as
AsPh3.
L
I
Pd 2(dba)3,L (1:4)
Pd
50oC, THF
L
1
k1
Ligand
k-1
Relative
kobs
k1/k-1
PPh3
<5 x 10 -5
1
(2-furyl)3 P
6 x 10 -3
105
0.86
1100
AsPh3
[S]
Pd
I
Farina JACS 1991 (113) 9585.
L
Bu3Sn
I + L
+ Bu3SnI
k2
2
The existence of this pre-equilibrium in the transmetalation mechanism is a subject of much debate in the literature. An alternative proposal
involves a tin-mediated associative substitution where transmetalation occurs via a pentacoordinate Pd intermediate. Espinet JACS 2000
(122) 11771 and Espinet JACS 1998 (120) 8978.
M.C. White/M.W. Kanan Chem 153
Cross-Coupling -95-
Week of October 1, 2002
Stille: Mechanism of Pd/Sn Transmetalation
SE2 (open)
SE2 (cyclic)
SE2 (cyclic, pentacoordinate)
δ−
Cl
δ+
R
Pd
L
H H
C
δ+
SnR3
Sn
R'
X
Pd
R
Sn
R'
X
Pd
R
R'
favored in highly polar
and/or nucleophilic solvents
L
L
L
favored in non-polar solvents
Farina Pure & Appl. Chem. 1996 68:1 pp 73-78.
The mechanism for Pd/Sn transmetalation is highly dependent on reaction conditions, and the subject of ongoing debate in the literature.
Stille JACS 1983 105 669-670, 6129-6137.
Epsinet JACS 1998 120 8978-8985, 2000 122 11771-11782.
M.C. White, Chem 153
Cross-Coupling -96-
Week of October 1, 2002
Stille: Copper Effects
I
Pd 2dba3 , PPh3, +/- CuI
Bu3 Sn
dioxane, 50 oC
Pd:L:CuI
molar ratio
Relative
rate
HPLC
Yield (%)
1:4:0
1:4:1
1:4:2
1:4:4
1:2:0
1
5
114
197
64
85
85
>95
45
91
To explain the observed rate enhancements in the presence of the cocatalyst CuI, the authors propose that CuI acts as a ligand
scavenger, binding to free PPh3 and thereby promoting ligand dissociation. This proposal is supported by 31P NMR studies where
Cu complexed phosphine is detected.
Ligand
PPh3
AsPh3
AsPh3
AsPh3
Pd:L:CuI
molar ratio
1:4:0
1:4:0
1:4:1
1:4:2
Relative
rate
HPLC
Yield (%)
1
2710
3459
3624
85
>95
>95
>95
Farina& Liebeskind JOC 1994 (59) 5905.
When weakly coordinating ligands such as ArPh3 are used, an enhancement in the
rate cross-coupling is still observed upon addition of CuI, although to a lesser
extent. To account for this the authors propose an initial transmetalation from an
organostannane to an organocuprate, followed by more facile transmetalation of
the alkenylcuprate with the palladium catalyst. This proposal is supported by the
change in selectivity of the group transfered from the organostannane in the
presence of CuI.
CuI
LnCu
Bu3 Sn
-ISnBu3
t-Bu
OTf
PdCl2(PhCN)2
AsPh3 +/- CuI
NMP, 80 oC
Bu
+
t-Bu
O
Bu3Sn
Group transfer selectivity
O
A
O
B
A : B
- CuI
+ CuI
90 : 10
>98 : 2
M.C. White, Chem 153
Cross-Coupling -97-
Week October 1, 2002
Stille reaction: "the copper effect"
a general coupling system for sterically congested substrates
ONf
+
n-C5H11
CuX, LiCl
solvent
~ 40 h
Bu3Sn
OH
Nf = n-C4 F9SO2
n-C5H11
Pd(PPh3)4
OH
Conditions
Proposed catalytic cycle
R
X = I, solvent = DMA
38 %
X = Cl solvent = DMSO
88 %
DMA = dimethylacetamide
LnPd(0)
Ar
Ar-X
oxidative
addition
reductive
elimination
LnPd(II)
optimized yield
Ar
LnPd(II)
R
Ar
X
transmetalation II
The authors propose that the greater electrophilicity of CuCl
relative to CuI (expected from the greater electronegativity of Cl
relative to I) leads to faster and more efficient transmetalation of
the hindered vinylstannane to the corresponding vinyl Cu(I)
species.
RCuLiCl
-Bu 3SnCl
RSnBu 3
+
CuCl
+
LiCl
transmetalation I
Corey, E.J. JACS 1999 121 7600-7605.
M.C. White, Chem 153
Cross-Coupling -98-
Week of October 1, 2002
Stille: nucleophilically-accelerated transmetalation
Me
Br
Pd(PPh3)4
+
Me4 Sn
MeO
PhMe, 75 oC, 7h
MeO
<5% yield
Me
Br
N
Pd(PPh3)4
Sn
PhMe, 75 oC, 7h
+
MeO
MeO
Me
67% yield
Vedejs JACS 1992 114 6556-6558.
The authors propose that using the reagent 1-aza-5-stannabicyclo[3.3.3]undecane accelerates
the Pd/Sn transmetallation event, possibly via one of the following transition states:
N
N
δ+
Sn
δ+
Sn
CH3
L
[S]
Pd
Ar δ- Br
S E2 (open)
Farina Pure & Appl. Chem. 1996 68:1 pp 73-78.
H3C Br
Pd
L
Ar [S] or L
SE2 (cyclic)
M.C. White/M.W. Kanan Chem 153
Cross-Coupling -99-
Week of October 1, 2002
Stille: Extraordinary FG Tolerance
H
O
H
H
O
H
OTIPS H
HO
Bu3Sn
H
H
H
HO
OH
OR
CH3
H
O
(Ph3As)2Pd 0
oxidative addition
Pd
O
50%
key intermediate in
total synthesis of
(+)-Amphidinolide
H
transmetalation II
AsPh3
O
H
H
O
II
H
PdLn OTIPS H
HO
H 3C
H
CH3
H 3C
H
reductive elimination
AsPh3
I
H 3C
Pd2(dba)3 (0.2 eq.)
Ph3As (0.8 eq.)
CuTC (1.5 eq.)
NMP, 35°C
OH
H
O
I
H 3C
H
O
OH
H
CH3
O
O
OH
H
H
H
O
H
O
Bu3Sn
OTIPS H
H
HO
LnCuTC
transmetalation I
O
H
H
O
LnCu
H
OTIPS H
HO
+ ISnBu3
CuTC
Cu(I) thiophene2-carboxylate
S
The successful cross-coupling in the presence of an epoxide, alcohol,
carboxylic acid and several olefins illustrates the compatability of the Stille
cross-coupling with nearly all functional groups.
Williams, JACS, 2001, (123), 765.
Cu
O
M.C. White/ M.W. Kanan Chem 153
Cross-Coupling -100-
Week of October 1, 2002
Stille: Double Couplings
O
OTf Bn
I
H H
N
N
SnBu3
O
H H
N
N
Key intermediate in
Quadrigemine C
NMeTs
Pd2(dba)3 CHCl3, P(2-furyl)3 ,
CuI, NMP, rt
N
N
H H
I
N
OTf Bn
N
OTf Bn
N
N
N
H H
O
oxidative addition
I
Pd
(PR 3) 2Pd 0
OTf
PR3
H H
N
N
reductive elimination
N Bn
transmetalation II
O
II
PdLn
TsMeN
transmetalation I
OTf Bn
N
O
SnBu3
NMeTs
71%
PR3
II
NMeTs
CuI(L) n
OTf Bn
N
O
NMeTs
+ CuI(L)n
H H
N
N
Cu(L)n
NMeTs
The cross-coupling is effected at the aryl iodide positions in the presence of aryl triflates. This generates a product that is a substrate for
a intramolecular Heck reaction, which is the next step in the sequence. Also of note is the steric hindrance of the stannane due to the
adjacent protected amide.
Overman JACS 2002 (124)9008.
M.C. White/M.W. Kanan Chem 153
Cross-Coupling-101-
Week of October 1, 2002
Stille: Macrocyclization
SnBu3
TfO
Pd(CH3CN)2Cl 2, 5 mol%
O
LiCl, DMF, 20°C
O
O
O
highly unsaturated
polycyclic ring systems
48%
oxidative addition
O2
SnBu3
OTf+
LnPd
The Stille coupling has proven to be an effective
strategy for macrocyclization through diene or eneyne
formation. In this case, the product is a substrate for a
transannular 4+2 cycloaddition, which proceeds
spontaneously to afford the polycyclic product.
H
H
O
O
O
O
Cl- substitution for OTf often
referred to as the "LiCl effect" is
thought to promote the rate-limiting
transmetalation event
SnBu3
[4+2]
Stille JACS 1986 (108) 3033.
Cl
Pd
Ln
O
O
Pd
Ln
transmetalation
O
O
reductive elimination
O
O
Suffert Org. Lett. 2002 (4) 3391.
M.C. White, Chem 153
Cross Coupling -102-
Week of October1, 2002
Hiyama Coupling
"ligandless system"
Pd
Cl
The F- reagent believed to first attack the organosilicon compound to generate a
pentacoordinate silicate. This has the effect of enhancing the anionic character of
the typically non-polar organosilicon bond , thereby promoting transmetalation.
Pd
Cl
I +
2.5 mol%
SiMe3
1.3 eq
TASF* (1.3 eq)
HMPA, 50 C
TASF = tris(diethylamino)sulfonium
difluorotrimethylsilicate
good source of F-
_
Me
o
89%
Si
Me
Me
Me
TASF
Si
F
No reaction in absence of TASF
Reaction is stereospecific. It proceeds w/complete retention of db geometry.
Pd
SiMe3
I
n-C6H13
Cl
Pd
Cl
2.5 mol%
n-C6H13
P(OEt)3 5 mol%
78%
TASF* (1.1 eq)
THF, 50oC
Essentially complete FG tolerance: esters, ketones, free hydroxyls, aldehydes
HO
Pd
SiMe3
Br
Ph
Hayama JOC 1988 (53) 918.
Cl
Pd
Cl
2.5 mol%
TASF* (1.1 eq)
THF, 50oC
HO
Ph
[(CH 3) 2N]3S+
Me
Me
M.C. White, Chem 153
Cross-Coupling -103-
Week of October 1, 2002
Hiyama Coupling
Exclusive γ substitution of allyltrifluorosilanes
Pd(PPh3)4, 5 mol%
TBAF (1.0 eq), THF
I
β
SiF3
γ
α
100oC (sealed tube)
37 h
Br
enhanced nucleophilicity of the γ
carbon of the intermediate
pentacoordinate allylic silicate is
used to rationalize regoiselectivity
of substition.
Br
78%
I
Pd(PPh3)4, 5 mol%
SiF3
Hiyama JACS 1991 (113) 7075.
TBAF (1.0 eq), THF
100oC (sealed tube)
46 h
O
70%
O
Temperature dependent retention of stereochemistry during transmetalation event
40
(S)
F3CO2SO
C(O)Me
SiF3
C(O)Me
Pd(PPh3 )4 , 5 mol%
TBAF (2 eq), THF
2 eq
0
20
50o C
(S)-1-phenyl-1(trifluorosilyl)
ethane (34% ee)
%ee
20
41%
retention
(S)-1-phenyl-1(4 formylphenyl)
ethane (32-34% ee)
(R) 40
40
‡
Pd(Ar)Ln
F
F
F
Ph
F
Si
FF
F
H
SE2 (cyclic): retention
60
70
80
o
‡
F
50
Ph
Si
F
F
Pd(Ar)Ln
H
SE2 (open): inversion
temperature ( C)
Since reductive elimination is known to
go with retention of configuration at the
alkyl
center,
the
observed
stereochemical outcome of
the
cross-coupling reaction is thought to be
reflective of the transition state for
transmetalation.
Hiyama JACS 1990 (112) 7794
90
100
M.C. White, Chem 153
Cross-Coupling -104-
Week of October 1, 2002
Hypervalent Organotin
· monoorganotins are less reactive to Stille coupling than traditional tetraorganotins
· the reactivity of monoorganotins towards transmetalation with organopalladium compounds
can be increased by nucleophilic assistance that procedes via hypervalent tin intermediates
CO2Me
CO2Et
Sn
Substrate assisted
transmetalation:
CO2Me
Pd2dba3, 3 mol%
PPh 3, Toluene, 90oC
Br
N(TMS) 2
N(TMS) 2
CO2Et
71%
Br
_
EtO
C
Ph
O
Sn
N(TMS)2 + MeO2C
N(TMS)2
Br
Pd II
PPh3
PPh3
Br
hypervalent tin
possible transmetalation intermediates
Fouquet JOC 1997 (62) 5242
· like silicon, tin is fluorophilic
Br
Sn
1 step
Sn[N(TMS)2]2
F- assisted
transmetalation:
I Pd(PPh ) , 1 mol%
3 4
TBAF (3 eq)
N(TMS) 2
N(TMS) 2
Br
dioxane, 110oC
t-Bu
t-Bu
76%
12h
"Lampert's stannylene"
Lampert Chem. Commun. 1974, 895.
_
F
In contrast to tetraorganotins, monoorganotins
can be used transfer value added alkyl substituents.
Sn
Br
N(TMS) 2
N(TMS) 2
TBAF
Sn
N(TMS) 2
N(TMS) 2
F
proposed transmetalating
reagent: hypervalent tin species
M.C. White, Chem 153
Cross-Coupling -105-
Week of October1 , 2002
General method for Stille
cross- coupling with aryl chlorides
1.5% [Pd2(dba)3]
6% Pt-Bu3
Cl
+
Bu3Sn
Additive (1.1 eq)
dioxane, 100 o C
Me
none
NEt3
CsCO3
NaOH
TBAF
KF
CsF
CsF (2.2)
Me
12%
Bulky, electron rich phosphines are are known to sucessfully promote the oxidative
addition of Pd(0) to aryl chlorides in the Suzuki reaction (presumably via the
formation of highly nucleophilic, coordinatively unsaturated (14e-) palladium(0)
complexes). The poor reactivity of this system in promoting the Stille coupling of aryl
chlorides to simple vinyltributyltin prompted Fu to hypothesize that the problematic
step was transmetallation. In order to test this hypothesis, he began to screen additives
known enhance the reactivity of organotins towards transmetalation (Lewis bases and
fluoride additives).
3.0 % Pd(P(t-Bu)3) 2
2.2 eq. CsF
Bu3Sn
MeO
dioxane, 100 oC
89%
Br
Fu ACIEE 1999 (38) 2411
Fu JACS 2002 (124) 6343
Bu3Sn
MeO
dioxane, 100 oC
Bu3Sn-Bu
0.5% [Pd 2(dba)3]
1.1% Pt-Bu3
toluene, rt
88%
Cl
1.5% [Pd 2(dba)3]
6% Pt-Bu3
2.2 eq. CsF
Room temperature aryl bromide Stille couplings
O
12
16
40
42
24
28
50
59
Csp 3-Csp2 Stille couplings
Synthesis of sterically hindered biaryls
Cl
% GC Yield
O
the air-sensitivity of P(t-Bu)3 is a
drawback to this methodology:
Pd(P(t-Bu)3)2, a more air-stable,
crystalline complex is more easily
handled and is now commercially
available from Strem.
Bu
M.C. White, Chem 153
Cross-Coupling -106-
Week of October 1, 2002
Negishi-Suzuki Coupling?
I
M
"(PPh3)2 Pd(0)"
generated in situ from
Cl2 Pd(PPh3)2 and DIBAL
THF
Negishi's metal counterion screen:
M
Negishi chose to pursue this
lead, rather than the organoborane and organotin results
temp (oC)
time (h)
Product
yield %
Li
25
24
3
MgBr
25
24
49
ZnCl
25
1
91
Al(Bu-i)2
25
3
49
HgCl
25
1
trace
BBu3Li
reflux
1
92
SnBu3
25
6
83
ZrCp2Cl
25
1
0
Negishi JOMC 2002 (653) 34.
M.C. White, Chem 153
Cross-Coupling -107-
Week of October 1, 2002
Suzuki Cross Coupling
Representative Suzuki Cross Coupling
O
HB
C 4H 9
H
O
O
catecholborane
B O
regiospecific
syn hydroboration
C 4H 9
R
(0)
2
1
Ln Pd
R
R -X
R1 = aryl, vinyl, alkynyl
X = I>OTf>Br>>Cl
oxidative
addition
reductive
elimination
LnPd (II)
R
1
L nPd(II)
R2
L nPd(II)
R3
BY2
OR2
NaOEt, benzene
reflux
Ph
Br
C4H 9
Organoboranes
A variety of different organoboron reagents can be
used to effect transfer of the R2 group via
transmetalation. Generally, electron rich unhindered
organoboranes are most reactive towards
transmetalation. Organoboranes are non-toxic and
air and moisture stable.*
O
R
R1
2
R
B(Oi-Pr)2
2
B
O
X
R2OM
BY2OR2
R1
Pd(Ph3 )4 (1 mol%)
86%
Catalytic Cycle:
1
100% stereospecific the
configurations of the
vinylborane and vinyl
halide are retained.
Excellent method for
the construction of
conjugated dienes.
Ph
R2 = alkynyl, aryl, vinyl, alkyl
XM
transmetalation
The rate-determining step in
Suzuki-couplings
with
reactive electrophiles (i.e.
R1 -X= unsaturated iodides)
*See: Chem 115 Suzuki Handout for comprehensive review of synthesis of
organoboron compounds (A.G. Meyers/A. Haidle)
B R2
O
M = Na, K, Tl
R2
B
O
pinacolborane
9-BBN
(9-Borabicyclo[3.3.1]nonane)
Palladium Catalysts
Pd(0)
Pd(PPh3)4
(most common)
Pd2(dba)3 + phosphine
Pd(II)
Pd(OAc)2 + phosphine
PdCl2(dppf) (for sp3-sp2)
M.C White, Chem 153
Cross-Coupling-108-
Week of October 1, 2002
Suzuki Coupling: Role of the Base
The boron-carbon bonds in most organoboron compounds are considered to be highly covalent/non-ionic. As a result, organoboron
compounds are generally insensitive to water and related solvents, and highly compatible with most organic functionality. However, for the
same reason, these intermediates do not readily undergo transmetalation.
Organoboron compounds can be activated to undergo
transmetalation by adding a nucleophilic base. This
effect is thought to be due, at least in part, to the
formation of a hypervalent, anionic boron "ate"
complex, which undergoes transmetalation more
readily and can coordinate the Pd metal.
It is also proposed that a nucleophilic base can
displace the Pd-bound halide that results from
oxidative addition, to generate a metal center that
is capable of coordinating the organoborane.
RO
B R
R
O B
R
O B
R
R
R'L2Pd
boron ate-complex
R'L2Pd X
RO
B R
R
R'L2Pd O
R'L2Pd
‡
Soderquist has proposed a µ2-hydroxo-bridged,
4-centered cyclic transition state for the
transmetalation event, which has been shown
to proceed with retention of configuration for
both coupling partners.
Soderquist J. Org. Chem. 1998 63 461-470
R
O
H
O
R'L2Pd
B
C
B
R
M.C White, Chem 153
Cross-Coupling-109-
Week of October 1, 2002
Suzuki: Ligand Effects for Csp3-Csp2 couplings
Ph
PdCl2(dppf) is often found to be a superior catalyst for Suzuki cross coupling reactions between
boron-alkyl derivatives (possessing β-hydrogens) and vinyl/aryl halides/triflates. This ligand is
thought to favor reductive elimination vs. competitive β-hydride elimination for at least two
reasons:
· The bidentate phosphine ligand enforces a cis geometry between the alkyl and
vinyl/aryl substituents; this cis geometry is required for reductive elimination
Ph
P
Cl
Pd
Fe
Cl
P
· The large bite angle for this bidentate phosphine ligand results in a smaller angle
between the alkyl and vinyl/aryl substituents. Recall that minimization of the angle
between two metal-bound substituents is thought to promote reductive elimination
event by increasing orbital overlap:
Ph Ph
dppf, bis(diphenylphosphino)ferrocene
Suzuki JACS 1989 (111) 314
see also Hayashi JACS 1984 (106) 158; Brown Inorg. Chimica Acta, 1994 (220) 249.
Danishevsky ACIEE 2001 (40) 4544.
CO2Me
OH
Me
S
Me
1. 9-BBN-H
S
2.PdCl 2(dppf), K 2CO3
S
CO2Me
Me
Me
Me
O
S
Me
HO
OAc Me
Br
OAc Me
OH Me
dihydroxyserrulatic acid
Urema JACS 1991 113 5402-5410.
M.C. White, Chem 153
Cross-coupling -110-
Week of October 1, 2002
Suzuki Couplings: Ligand Effects
First report of effective Suzuki cross-coupling of
unactivated aryl chlorides:
Cl
Bidentate ligands are ineffective. The optimal phosphine to
ligand ratio is between 1 and 1.5. Both pieces of data suggest
that the active catalyst has a single phosphine attached.
B(OH)2
1.5% [Pd2(dba)3]
3.6% phosphine
Phosphine
2 eq. Cs2CO 3
dioxane, 80oC
Fu ACIEE 1998 (37) 3387.
Aryl chlorides are traditionally unreactive towards Suzuki cross
couplings (recall: I> OTf > Br >>>Cl). This is thought to be due
in part to the strength of the Ar-Cl bond (i.e. Ph-X: Cl (96
kcal/mol), Br (81 kcal/mol), I (65 kcal/mol)). Reports of
reactivity were limited to reactions using activated substrates (i.e.
aryl chlorides with electron withdrawing substituents). The low
cost and high availability of aryl chlorides, however makes them
very attractive substrates. Fu was the first to discover that bulky,
electron rich ligands could overcome this reactivity issue.
B(OH)2
none
BINAP
dppf
Ph2P(CH2)3PPh 2
Cy2P(CH 2)2 PCy2
PPh3
PCy 3
PtBu3
P(o-tol)3
0.5% [Pd2 (dba)3]
1.2% P(t-Bu)3
OTf
3.3 eq. KF
THF, rt
OMe
% GC Yield
----------2069
2056
2056
2066
0
0
0
0
0
0
75
86
10
B(OH)2
1.5% [Pd2(dba)3]
3.0% P(t-Bu)3
3.3 eq. KF
THF, rt
98%
OMe
Full paper: Fu JACS 2000 (122) 4020.
----------145
170
182
194
CO v, cm -1
Chemoselective Suzuki couplings: first example of Pd-catalyzed crosscoupling that demonstrates higher selectivity for aryl chlorides than for
aryl triflates
Room temperature Suzuki couplings with aryl bromides
Br
θ
Cl
95%
OTf
M.C. White, Chem 153
Cross-Coupling -111-
Week of October 1, 2002
Bulky, electron-rich phosphines
P(t-Bu)3
o
94
PdII
109.9o
164.6o
I
T-shaped monomer
Ph
I
t-Bu
O
Pd(dba)2 + 1 P(t-Bu)3
Pd0 P
PdII
t-Bu
t-Bu
dba
Ph
dba
Hartwig JACS 2002 (124) 9346.
14e-
P(t-Bu)3
I
M.C. White, Chem 153
Cross Coupling -112-
Week of October 1, 2002
Suzuki: Ligand Effects for Csp3-Csp3 couplings
Br
4 % Pd(OAc)2
8% ligand
n-Dec
+
n-Hex
n-Dec
n-Hex
9BBN
1.2 eq. K3PO4
THF, rt
Subtle Ligand Effects
θ
Ligand
BINAP
dppf
P(OPh)3
P(n-Bu)3
PPh3
AsPh3
P(2-furyl)3
PCy3
P(i-Pr)3
PtBu3
P(o-tol)3
CO v, cm -1
% GC Yield
----2085
2060
2069
----2056
2059
2056
2066
<2
<2
<2
9
<2
<2
<2
85
68
<2
<2
----128
132
145
142
--170
160
182
194
R
oxidative
addition
H
R
Pd
X
β -hydride
elimination
L Pd0 PR3
H
PR3
Pd
R
· It is thought that the inability of palladium to effectively
mediate cross couplings between alkyl halides and alkyl
boranes is due to slow oxidative addition of the alkyl
halides/triflates to palladium and facile β-hydride
elimination of the Pd alkyl intermediates. In the majority
of cases when oxidative addition occurs it is followed by
β-hydride elimination rather than the desired
transmetalation event. Fu does not present any data that
indicates β-hydride elimination occurs after the
transmetalation event (would expect see 1-hexene). The
appearance of 1-decene as a bi-product indicates that
β-hydride elimination competes with transmetalation after
oxidative addition.
Fu JACS 2001 (123) 10099.
<2
12
<2
27
<2
<2
<2
<2
6
21
14
PR3
X
L = solvent
or OAc
n-Dec
X
transmetalation
R'BR3
R'
R
PR3
Pd
X
reductive
elimination
R
R'
·electron rich, bulky phosphines may promote oxidative addition by
increasing electron density at the metal center and by promoting the
formation of a coordinatively and electronically unsaturated complex.
· electron rich, bulky phosphines may disfavor β-hydride elimination
both by making the metal less electrophilic and blocking open
coordination sites at the metal center.
M.C. White, Chem 153
Cross-Coupling -113-
Week of October 1, 2002
Suzuki: Ligand Effects II
Buchwald Ligands (commercially available from Strem).
General features: electron rich and bulky. Buchwald speculates that
the electron rich nature of the phosphines promotes oxidative addition
and tight binding to the metal (prevents Pd black formation).
Moreover, the steric bulk of the ligand promotes reductive
elimination. Subtle feature: o-phenyl may be oriented such that
π-interaction with the metal occurs. It is not clear why this feature is
important.
Room temperature Suzuki cross-coupling of
unactivated aryl chlorides:
Cl
B(OH)2
1.5% Pd(OAc)2
3.0% 4
3 eq. KF
THF, rt
92%
Pt-Bu2
PCy2
Suzuki Csp2-Csp3 Coupling
Me2N
Me2N
1
2
PCy2
P(t-Bu)2
C6H14
Cl
0.5% Pd(OAc)2
1.0% 4
B
3
nC6H14
3.3 eq. KF
THF, 65 oC
83%
CO2Me
4
Exceptionally high TON
O
B(OH)2
Br
Buchwald ACIEE 1999 (38) 2413.
Buchwald JACS 1999 (121) 9550
Pd(OAc)2 : 4 (1:2)
3.3 eq. KF
100oC
100,000,000 TN in 24h*
Note: only observed for this substrate
O
Ph
CO2Me
M.C. White, Chem 153
Cross-Coupling -114-
Week of October 1, 2002
Suzuki: An alternative to phosphines
Me
Me
L =
N
Me
N
Me
Me
Me
Nucleophilic N-heterocyclic carbenes (imidazol-2-ylidenes):
these so called "phosphine mimics" do not dissociate from
the metal center, and thus an excess of ligand is not required
to prevent agregation of the catalys to yield the bulk metal.
generated in situ from the corresponding Cl salt
MeO2C
Cl
MeO2C
+ (HO)2B
99% yield
General conditions
Me
Cl
(HO)2B
+
OMe
Me
Pd2(dba)3 (1.5 mol%)
L (3.0 mol%)
Cs2CO 3 (2 equiv.)
dioxane, 80 oC, 1.5 h
Me
91% yield
Me
Cl
+
(HO)2B
Me
Me
89% yield
Nolan J. Org. Chem. 1999 64 3804-3805.
OMe
M.C. White, Chem 153
Cross-Coupling -115-
Week of October 1, 2002
Suzuki: the “TlOH effect”
O
O
O
O
RO
RO
O
ZOCOHN
OR
OY
O
OY
YO
OR
RO
75
OR
OR
76
OR
OR
OR
75
O
I
OR
OR
Pd(PPh3)4
+
(HO) 2B
76
Base
RO
O
RO
R = CH2PhOMe(p)
Y = Si(Me)2(t-Bu)
Z = CH 2CH2Si(Me)3
(MeO)2
Conditions
P
O
OR
OR
OR
O
Yield
KOH, 70 oC, 18 h
0%
TlOH, rt, 25 min
63%
Further studies demonstrated that with TlOH, this coupling can be achieved almost
instantaneously even at 0 oC, allowing its application to substrates with fragile functional
groups as well as with large molecular weights.
Kishi, JACS. 1987, 109, 4756-4758.
M.C. White, Chem 153
Cross-Coupling -116-
Week October 1, 2002
Suzuki: TlOH vs. TlOEt
OTBDPS
OTBDPS
Me
Me
Me
Me
HO
B(OH)2
TBSO
TBSO
TBDPSO
O
O
TlX, Pd(PPh3) 4
THF, H2O
Me
Me
Reagent age
TlX source
I
Me
Me
Me
Yield
Me
OH
---
TlOH (10% stock solution)
1 month old
83%
71%
TlOH (10% stock solution)
5 month old
50%
TlOH (from solid))
12 month old
52%
TlOEt
OTBDPS
The use of TlOEt in place of TlOH has advantages in terms of commercial availability, stability, and ease of use. Roush and
coworkers found that thallium(I) ethoxide promotes rapid Suzuki cross couplings for a range of vinyl- and arylboronic acids
with vinyl and aryl coupling partners in good to excellent yields.
t-BuO2C
t-BuO2C
CO2t-Bu
(HO) 2B
CO2t-Bu
OH
Pd(PPh3)4, TlOEt
THF/H2O : 3/1 97% yield
THF (anhydrous) 92% yield
I
CO2Me
CO2Me
HO
The presence of water does not appear to be necessary for effective cross couplings with
Pd(PPh3)4/TlOEt, challenging the assumption that TlOH is an obligatory intermediate
Roush, Org. Lett. 2000, 17, 2691-2694.
M.C. White/M.S. Taylor Chem 153
Cross-Coupling -117-
Week of October 1, 2002
Suzuki : Formation of Hindered Aryl-Aryl Bonds
N
N
B(OH)2
O
NCO2t-Bu
TfO
O
OMe
O
Pd(dppf)Cl2, K3PO4
THF, 65°C
O
NCO2t-Bu
O
OMe
O
63%
1:1 mixture of atropisomers
OTf -
N
P
+
reductive elimination
N
O
transmetalation
O
Pd
Pd 0(dppf)
Pd 0(dppf)
oxidative addition
Intermediate en route
to Diazonamide A
O
NCO2t-Bu
OMe P P O
Pd
NCO2t-Bu
P
B(OH)2
O
OMe
O
The aryl triflate used in this coupling is highly hindered as a result of the oxazole substituent in the 3-position of the indole. The ability to
reliably couple such an electrophile to a similarly hindered 2-substituted arylboronic acid highlights the utility of the Suzuki cross-coupling for
the formation of challenging bonds. Furthermore, the tolerance of lactone, protected indole, and the Lewis basic oxazole functionality is notable.
Vedejs OL 2000 (2) 1033.
M.C. White/M.S. Taylor Chem 153
Cross-Coupling -118-
Week of October 1, 2002
Suzuki: reliable method for late-stage macrocyclization
OTBS
O
I
O
TBS
O
B
O
O
OTBS
O
TBS
O
O
PdCl 2(MeCN)2
O
TBS
O
O
TBS
O
Ph 3As, AgO, THF
Desilylation yields
Rutamycin b.
O
O
O
O
O
OTBS
Pd(Ph3As)n
oxidative addition
O
70%
Pd(Ph 3As)n
OTBS
reductive elimination
OTBS
O
O
AsPh3
Ph3As
TBS
B
Pd
O
O I
O
O
TBS
O
OTBS
transmetalation
O
AsPh3 TBSO
Pd AsPh3
O
O
TBS
O
O
O
O
O
O
OTBS
O
OTBS
Demonstration of the utility of the Suzuki coupling as an efficient macrocyclization method.
Spiroketal, ketone, and enone functionalities are all well tolerated. The efficiency of this reaction
compares well with more conventional methods such as macrolactonization or olefination. (Note
that in this case, the corresponding Stille macrocyclization was not successful)
White, J. Org. Chem. 2001, 66, 5217.
M.C. White, Chem 153
Cross-Coupling -119-
Week of October 1, 2002
Hydroboration/Suzuki coupling sequence
sets a new stereocenter and effects macrocyclization
OPMB
OMe O
OMOM
O
1. 9-BBN, THF
O
2. (dppf)PdCl2 (20 mol%)
Benzene / H2O, NaOH
80°C, 12 h (48%)
I
OPMB
OMe O
Pd 0(dppf)
hydroboration
H B
OPMB
OMe O
oxidative addition
OMOM
O
OPMB
OMe O
OMOM
O
Pd 0(dppf)
I
BR2
Pd I
P
P
BR2
transmetalation
OMOM
Synthetic studies towards
Salicylihamide A
reductive elimination
OPMB
OMe O
OMOM
O
Pd
PP
The well-documented diastereoselectivity of hydroboration reactions with 1,1-disubstituted olefins provides an opportunity to
control stereochemistry as part of the coupling strategy. Alternative cyclization via macrolactonization is rendered difficult in
this instance by the bulky ortho-substituted carboxylic acid.
Maier, Org. Lett. 2002, 4, 13, 2205.