M.C.

White, Chem 253 Cross Coupling -84- Week of October4, 2004

C-C Bond Formation

Csp-Csp2 Csp2-Csp2 Bonds Csp3-Csp2 Bonds

R R
R
R R Alkyl Ar
R R R Ar Alkyl
R

Csp3-Csp3 Bonds
General Mechanism A paradigm shift:
Cl Cl nucleophilic substitution
Pd(II) (or Ni(II) ) at an sp2 hybridized
Cl Cl Alkyl Alkyl
carbon is made routine
R2-M by using transition metal
R = aryl, vinyl
mediated catalysis.
R2 R2 X = I, Br, OTf, Cl
Classifications based on the main group metal
1 2 (0) 1
R R LnPd R -X used to transfer R2 in the transmetalation event.
reductive oxidative Kumada Coupling Negishi Coupling
elimination addition Ni(0) or Pd(0)
Ni(0) or Pd(0)
M = MgX, Li M = Al(i-Bu)2
R1 R1 Zr(Cl)Cp2
LnPd(II) LnPd (II)
ZnX
R2 X
Stille Reaction Hiyama Coupling
Pd(0) Pd(0)
M = SnR3 M = SiR3

Suzuki Reaction Sonogashira

X-M R2-M R2= aryl, vinyl, alkyl Pd(0) Pd(0)
transmetalation M = BX2 M = Cu (in situ)
M.C. White, Chem 253 Cross-Coupling -85- Week of October 4, 2004

Kumada pushes the frontier

Ph2 All the pieces of the catalytic cycle were in the literature...
P Cl
Ni(II)
Transmetallation: Chatt and Shaw J. Chem. Soc. 1960 1718.
Report the synthesis of alkyl and aryl nickel(II) complexes
Cl P Cl
Ph 2 0.7 mol% from the corresponding nickel(II) halides.
Cl n-BuMgBr (2 eq)
94%
Br PPh3 R PPh3
2 RMgBr
Ni(II) Ni(II)
Ph 2 Ph3P Br
P Cl Ph3P R
(II)
Ni
P Cl
Ph 2 0.7 mol% R= R'
Cl MgBr
80%

Reductive elimination/Oxidative addition: Yamamoto JOMC

Kumada JACS 1972 (94) 4374. 1970 (24) C63. "Preparation of a phenyl-nickel complex, phenyl
(dipyridyl)nickel chloride, an olefin dimerization catalyst.
Cl
LnNi(II) Cl
Cl
R2-MgX R2= aryl, vinyl, alkyl N N
R2 R2 Ni(II) Ni(II)
R1 = aryl, vinyl + butane
R1 R2 L nNi(0) R1-X X = Cl > Br> I N N Cl
reductive oxidative
elimination addition

R1 R1
L nNi(II) L nNi(II) Cl
R2 X Cl
N N
(II)
Ni Ni(0)
transmetalation N N
MgX 2 R2-MgX
M.C. White, Chem 253 Cross-Coupling -86- Week of October 4, 2004

Kumada Coupling
Common Bidentate Phosphines R2
Effect of the ligand: P Cl
(II)
Ni
P Cl
Cl R2
( )n 0.7 mol%
P P n-BuMgBr (2 eq)

Ligand % yield

dppp 100 · Bidentate phosphine ligands

dppm, n=0, bis(diphenylphosphino)methane exhibit higher catalytic activity
dmpf 94
dppe, n=1, bis(diphenylphosphino)ethane than monodentate phosphines
dppp, n=2, bis(diphenylphosphino)propane Ph3P (2eq) 84 with dppp being optimal for a
dppb, n=3, bis(diphenylphosphino)butane wide range of aryl and vinyl
dppe 79 halides.
dmpe 47
P P dppb 28

dmpe, bis(dimethylphosphino)ethane Ph2

Reactivity of aryl halide: P Cl
(II)
Ni
P Cl
P X Ph 2
0.7 mol%

Fe n-BuMgBr (2 eq)

P X % yield · Unlike other cross-coupling

methods, aryl and vinyl chlorides
F 31 (2h) exhibit higher reactivities than
dmpf, bis(dimethylphosphino)ferrocene Cl 95 (3h) their Br or I analogs. It is
Br 54 (4.5h) noteworthy that even aryl
I 80 (3h) fluorides undergo the nickel
Kumada Bull. Chem. Soc. Jpn. 1976 (49) 1958. catalyzed cross-coupling.
M.C. White, Chem 253 Cross-Coupling -87- Week of October4 , 2004

Kumada Coupling: Applications

· Industrial production of p-substituted styrene derivatives (Hokka Chemical Industry, Japan)
Ph 2
Ph 2 P Cl
P Cl
Ni(II)
Ni(II)
P Cl
MgCl P Cl Ph2
Ph2
Cl + 0.1 mol%
Strem 2001-2003 catalog
t-BuO t-BuO $7.6/g (very cheap)

Banno JOMC 2002 (653) 288.

· Functionalization of heterocyclic halides

Ph 2
P Cl
Ni(II)
P Cl
Ph2
0.5-1 mol% SiMe3
N Br Me3SiCH2MgCl N N N
BuMgBr S
S MgBr 78% 72% 71%
Kumada Tetrahedron 1982 (38) 3347.

· Formation of sterically hindered biaryls Nucleophilic N-heterocyclic carbenes are

used as a phosphine mimics that (unlike
monodentate phosphines) do not
BF4- dissociate from the metal
BF4-
O O N N
II
Ni + N N
Cl O O
3 mol%
3 mol% R

R imidazolium salt
Br Mg RMgX
R = CF 3, H, CH3, OCH3 R= CF3, 91%
H, >99% BF4-
CH3, 95%
steric hinderance tolerated OCH3, 98% N N
only on the Grignard

Herrmann ACIEE 2000 (39) 1602.

M.C. White, Chem 253 Cross-coupling -88- Week of October 4, 2004

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: PPh3 I

Ph3P
R2
P Cl Pd Pd(II)
Ni(II) Ph3P PPh3 Ph3P I
P Cl Ph3P
Ph Br R2 Ph Me

MeMgBr
Palladium (0) shown to be an effective, stereospecific catalyst for
96% (Z)-β-bromostyrene 96% (Z)-stilbene
cross-coupling of alkenyl halides with Grignard reagents.
Murahashi JOMC 1975 (91) C39.
R2
P Cl PPh3
Ni(II)
Ph Ph Pd
P Cl
R2 Ph3P PPh3
Ph Br 3 mol% Ph Me
Br Me Ph3P
MeMgBr
MeMgI
>99% (E)-β-bromostyrene >99% (E)-stilbene
99% cis-β-bromostyrene 99% cis-stilbene
>99% yield
R2
P Cl Palladium (0) shown to be stereospecific for alkenyl Grignards
Ni(II) reagents. Linstrumelle TL 1978, 191.
BrMg Me P Cl Ph Me
R2
PPh3
96% Z 27% Z: 73% E n-C6H13 Pd n-C6H13
Br
Ph3P PPh3
Ph3P 5 mol%
Note: Nickel catalysis may involve radical pathways I
(E)-1-iodo- BrMg Me
Kumada TL 1975 1719. 1-octene >97%, (2Z,4E)-2,4-undecadiene
Kumada Pure & Appl. Chem. 1980 (52) 669. 87% yield
(Z)-1-propenyl-1
Note: Pd catalysts can also transmetallate with organolithium Pd(0): I>Br>>Cl magnesium bromide
reagents: Murahashi JOMC 2002 (653) 27.
M.C. White, Chem 253 Cross-Coupling -89- Week of October 4, 2004

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
(PPh3)2Ni(0) n-C4H9
Al(i-Bu)2 I
5 mol%
Pd: 74%, >99% (E,E)
* PdCl 2(PPh 3)2 + 2 eq. DIBAL Ni: 70%, 95% (E,E), 5% (E,Z)
Ni(acac)2 + 2 eq. DIBAL
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 +
O o
50 C, 4h
MeO
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 Pd Et Et
Ph3 P PPh3
Ph3 P 5 mol%
i-Bu2Al
No rxn after 1 wk w/out ZnCl2
(or ZrCp2Cl)
ZnCl2, 1h, 25 oC, 88%
Negishi Acc. Chem. Res. 1982 (15) 340.
 M.C. White, Chem 253 Cross Coupling -90- Week of October 4, 2004

Negishi Coupling: Csp3-Csp2 and Csp3-Csp3

Formation of Csp2-Csp3 bonds using alkylzinc reagents.
n-BuMgCl n-BuZnCl
β-hydride H
51% 2%
elimination
PPh3
Pd(PPh3)4 n-C 4H9
Pd II
I n-BuZnCl
PPh3
reductive
or n-BuMgCl elimination
n-C 4H9 n-C 4H9 25% 76%
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 F3C
NiII
O O O O
10 mol% O
I
Bu NiII O Bu
O
Pent2Zn Pent
50 mol% Bu
F3C 70% yield, 1h
possible intermediate
w/out π-acid: 20%, 15h

Knochel ACIEE 1998 (37) 2387.

M.C. White/Q. Chen, Chem 253 Cross-Coupling -91- Week of October 4, 2004

Negishi Coupling: Csp3-Csp2

Note: β-hydride present in alkyl zinc. Ph3 P PPh3
transmetalation I Pd II

I ZnCl2, t-BuLi (3 eq) Zn OTBS

O O OTBS
O O OTBS Et2O, -78 °C to rt O O OTBS PMP
PMP PMP OPMB
-PPh3
transmetalation II
+
oxidative
addition Ph3 P PPh3
I PdII PPh3
OTBS 5% Pd(PPh 3) 4 I
Pd II
OTBS
Et2O, rt
O O OTBS OTBS
OPMB
OPMB PMP
OPMB

Ligand dissociation to the

trigonal planar intermediate reductive
is thought to favor reductive elimination
elimination from square
O O OH OH planar complexes.
Yamamoto OM 1989 (8) 180.
NH2

HO O O OTBS OTBS
13 steps
O PMP

O 66% OPMB

(+)-Discodermolide

Smith JACS 2000 (8654).

M.C White, Chem 253 Cross-Coupling-92- Week of October 4, 2004

Stille Coupling
The original report: Catalyst
Ph3P Cl
PdII Palladium(0)
P h3P
1 mol% Ph PPh3 Pd 2(dba)3
Br + Me4Sn Me
HMPA, 62oC O
Pd
+ Me 3SnCl Ph3P PPh3
Stille JACS 1979 (101) 4992. Ph3P
dibenzylideneacetone (dba)
Strem 2001-2003
Transfer from tin:
$53/g Strem 2001-2003
alkynyl>alkenyl>aryl>benzyl>allyl>alkyl. $28/g
Allows for simple alkyl groups (Me, Bu) to
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.
O O
H3CCN Cl Pd II
II
Pd
Cl O O
Cl NCCH3
Ln Pd (II)
Cl
Strem 2001-2003 Strem 2001-2003
2
R2-Sn(R3)3 R = alkynyl, aryl, vinyl, alkyl $39/g $52/g

R2 R2
R 1 = aryl, vinyl, alkynyl
R1 R2 Ln Pd(0) R1-X X = I>Br>OTf>>Cl Ligands

reductive oxidative Monodentate phosphines are added to palladium sources with poorly
elimination addition coordinating ligands to prevent catalyst decomposition ("plating out")to metallic
Pd(0). Bidentate phosphines result in low reaction rates and poor yields.
R1 R1
L nPd(II) L nPd(II)
R2 X

PPh3 O
transmetalation

The rate-determining step in P O As

Stille-couplings with reactive
XSn(R3)3 2 3
R -Sn(R )3 O
electrophiles (i.e. R 1-X=
unsaturated iodides, triflates)
tri-2-furylphosphine triphenylarsine
M.C. White/M.W. Kanan Chem 253 Cross-Coupling -93- Week of October 4, 2004

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.
oxidation

(n-Bu 3Sn)(Bu)CuLi.LiCN 3 eq. SO3 Py, 3eq. Et3N,

OH Bu3Sn OH CH 2Cl2/DMSO
96%

HWE condensation

CO2Et

PO(EtO)2
CHO CO2Et
Bu3Sn Bu3Sn
i) n-BuLi, DMPU, THF, 0°C
ii) aldehyde, -78°C-> -20°C
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 253 Cross-Coupling -94- Week of October 4, 2004

Stille: Ligand Effects

Pd2dba3 + Ligand Relative
Ligand Pd:L θ rate
I
Bu3Sn
THF, 50 oC PPh3 1:2 145o 1

It has been observed experimentally that increasing the concentration of (2-furyl)3 P 1:2 ND 20
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 AsPh3 1:2 142o 78
be electronic in nature where phosphines that are poor σ-donors promote
the cross-coupling more effectively than those that are strong σ-donors.
Farina JACS 1991 (113) 9585.

Kinetics studies support a mechanism Relative

involving fast oxidative addition followed Ligand k1/k-1 kobs
by a rate-determining transmetalation event
PPh3 <5 x 10 -5 1
which requires initial solvent/ligand
exchange. This predissociation event is
(2-furyl)3 P 6 x 10 -3 105
disfavored thermodynamically with strong
donor ligands such as PPh3, and more
AsPh3 0.86 1100
favored with weak donor ligands such as
AsPh3.
L [S]
k1 Bu3Sn
I Pd 2(dba)3,L (1:4) Pd I Pd I + L + Bu3SnI
50oC, THF k-1 k2
L L
1 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 253 Cross-Coupling -95- Week of October 4, 2004

Stille: Mechanism of Pd/Sn Transmetalation

SE2 (open) SE2 (cyclic) SE2 (cyclic, pentacoordinate)

δ−
Cl
H H Sn R' Sn R'
δ+ δ+
R Pd C SnR3
X Pd R X Pd R
R'
L
L L L

favored in highly polar favored in non-polar solvents

and/or nucleophilic 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 253 Cross-Coupling -96- Week of October 4, 2004

Stille: Copper Effects

Pd:L:CuI Relative HPLC
molar ratio rate Yield (%)
I Pd 2dba3 , PPh3, +/- CuI
1:4:0 1 85
1:4:1 5 85
Bu3 Sn 1:4:2 114 >95
dioxane, 50 oC 1:4:4 197 45
1:2:0 64 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.

HPLC When weakly coordinating ligands such as ArPh3 are used, an enhancement in the
Pd:L:CuI Relative
Ligand Yield (%) rate cross-coupling is still observed upon addition of CuI, although to a lesser
molar ratio rate
extent. To account for this the authors propose an initial transmetalation from an
PPh3 1:4:0 1 85 organostannane to an organocuprate, followed by more facile transmetalation of
AsPh3 1:4:0 2710 >95 the alkenylcuprate with the palladium catalyst. This proposal is supported by the
AsPh3 1:4:1 3459 >95 change in selectivity of the group transfered from the organostannane in the
AsPh3 presence of CuI.
1:4:2 3624 >95 CuI
Bu3 Sn LnCu
Farina& Liebeskind JOC 1994 (59) 5905. -ISnBu3

t-Bu
Group transfer selectivity
OTf PdCl2(PhCN)2
AsPh3 +/- CuI Bu
NMP, 80 oC A : B
+
t-Bu - CuI 90 : 10
O + CuI >98 : 2
A B
Bu3Sn O O
M.C. White, Chem 253 Cross-Coupling -97- Week October 4, 2004
Stille reaction: "the copper effect"
a general coupling system for sterically congested substrates
ONf
n-C5H11
Pd(PPh3)4
+ n-C5H11
Bu3Sn CuX, LiCl
OH
solvent
OH ~ 40 h
Nf = n-C4 F9SO2
Conditions optimized yield

X = I, solvent = DMA 38 %

X = Cl solvent = DMSO 88 %
Proposed catalytic cycle
DMA = dimethylacetamide

R Ar LnPd(0) Ar-X

reductive oxidative
elimination addition

Ar Ar The authors propose that the greater electrophilicity of CuCl

LnPd(II) LnPd(II)
R X 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.
transmetalation II

RCuLiCl

-Bu 3SnCl

RSnBu 3 + CuCl + LiCl transmetalation I Corey, E.J. JACS 1999 121 7600-7605.
M.C. White, Chem 253 Cross-Coupling -98- Week of October 4, 2004

Stille: nucleophilically-accelerated transmetalation

Br Me
Pd(PPh3)4
+ Me4 Sn
PhMe, 75 oC, 7h
MeO MeO
<5% yield

Br Me
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+ δ+
Sn Sn

CH3 H3C Br

L [S]
Pd Pd
Ar δ- Br L
Ar [S] or L

S E2 (open) SE2 (cyclic)

Farina Pure & Appl. Chem. 1996 68:1 pp 73-78.
M.C. White/M.W. Kanan Chem 253 Cross-Coupling -99- Week of October 4, 2004

Stille: Extraordinary FG Tolerance

H H
O
H
O H H
O
Bu3Sn OTIPS H H H
HO
I O
OR H H
HO
CH3
OH
OH Pd2(dba)3 (0.2 eq.) H 3C
H 3C H
H Ph3As (0.8 eq.) O
O CuTC (1.5 eq.)
NMP, 35°C 50% key intermediate in
total synthesis of
oxidative addition (Ph3As)2Pd 0 (+)-Amphidinolide
reductive elimination

AsPh3 H H
O
transmetalation II H
I Pd AsPh3 II O
H 3C PdLn OTIPS H H
CH3 H HO
OH
H 3C
H CH3
O
O
OH
H H H H
O O
H LnCuTC H
O O + ISnBu3
Bu3Sn OTIPS H H LnCu OTIPS H H
HO transmetalation I HO CuTC
Cu(I) thiophene-
2-carboxylate
S
The successful cross-coupling in the presence of an epoxide, alcohol, Cu
carboxylic acid and several olefins illustrates the compatability of the Stille
O
cross-coupling with nearly all functional groups.
Williams, JACS, 2001, (123), 765.
M.C. White/ M.W. Kanan Chem 253 Cross-Coupling -100- Week of October 4, 2004

Stille: Double Couplings

NMeTs
O
OTf Bn SnBu3 N
I
H H N H H
N N OTf Bn N N
O
NMeTs Key intermediate in
Quadrigemine C
Pd2(dba)3 CHCl3, P(2-furyl)3 ,
N N OTf Bn N N
H H CuI, NMP, rt H H
I N

O
NMeTs
oxidative addition 71%
(PR 3) 2Pd 0

PR3 OTf
II reductive elimination
I Pd PR3
transmetalation II N Bn
H H
N N O II
PdLn + CuI(L)n
H H
N N
TsMeN

transmetalation I OTf Bn Cu(L)n

OTf Bn SnBu3
CuI(L) n N
N
O
O NMeTs
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 253 Cross-Coupling-101- Week of October 4, 2004

Stille: Macrocyclization
SnBu3

TfO
Pd(CH3CN)2Cl 2, 5 mol% highly unsaturated
O
LiCl, DMF, 20°C polycyclic ring systems
O
O O 48%

oxidative addition
O2
SnBu3
OTf- The Stille coupling has proven to be an effective H
strategy for macrocyclization through diene or eneyne
+
LnPd formation. In this case, the product is a substrate for a H
transannular 4+2 cycloaddition, which proceeds
spontaneously to afford the polycyclic product.
O
O O O

Cl- substitution for OTf often

referred to as the "LiCl effect" is
thought to promote the rate-limiting [4+2]
transmetalation event
SnBu3 Stille JACS 1986 (108) 3033.

Cl
Pd Pd
Ln Ln

O O
O O transmetalation O O reductive elimination

Suffert Org. Lett. 2002 (4) 3391.

M.C. White, Chem 253 Cross Coupling -102- Week of October 4, 2004

Hiyama Coupling

"ligandless system" Cl
Pd Pd The F- reagent believed to first attack the organosilicon compound to generate a
Cl pentacoordinate silicate. This has the effect of enhancing the anionic character of
2.5 mol% the typically non-polar organosilicon bond , thereby promoting transmetalation.
I + _
SiMe3 TASF* (1.3 eq) Me Me
1.3 eq HMPA, 50 C o [(CH 3) 2N]3S+
89% Si TASF Si Me
Me Me
Me
TASF = tris(diethylamino)sulfonium F
No reaction in absence of TASF
difluorotrimethylsilicate
good source of F-

Reaction is stereospecific. It proceeds w/complete retention of db geometry.

Cl
Pd Pd
Cl
SiMe3
2.5 mol%
n-C6H13
I P(OEt)3 5 mol%
n-C6H13 78%
TASF* (1.1 eq)
THF, 50oC

Essentially complete FG tolerance: esters, ketones, free hydroxyls, aldehydes

HO Cl
Pd Pd
SiMe3 Cl
HO
2.5 mol%
Br TASF* (1.1 eq)
Ph Ph
THF, 50oC

Hayama JOC 1988 (53) 918.

M.C. White, Chem 253 Cross-Coupling -103- Week of October 4, 2004

Hiyama Coupling
Exclusive γ substitution of allyltrifluorosilanes

β I Pd(PPh3)4, 5 mol%
SiF3 TBAF (1.0 eq), THF enhanced nucleophilicity of the γ
γ α 100oC (sealed tube) carbon of the intermediate
Br Br pentacoordinate allylic silicate is
37 h
78%
used to rationalize regoiselectivity
of substition.
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)

20

F3CO2SO C(O)Me C(O)Me

%ee
SiF3 Pd(PPh3 )4 , 5 mol% 0
TBAF (2 eq), THF
50o C 20
(S)-1-phenyl-1- 2 eq 41% (S)-1-phenyl-1-
(trifluorosilyl) retention (4 formylphenyl) (R) 40
ethane (34% ee) ethane (32-34% ee)
40 50 60 70 80 90 100
o
‡ temperature ( C)
F Pd(Ar)Ln ‡
F F Since reductive elimination is known to
F Ph
F go with retention of configuration at the
Ph
F Si Si Pd(Ar)Ln alkyl center, the observed
F stereochemical outcome of the
FF H F H cross-coupling reaction is thought to be
reflective of the transition state for
SE2 (open): inversion transmetalation.
SE2 (cyclic): retention Hiyama JACS 1990 (112) 7794
 M.C. White, Chem 253 Cross-Coupling -104- Week of October 4, 2004

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 CO2Me
CO2Et
Pd2dba3, 3 mol%
Br CO2Et
Sn N(TMS) 2 PPh 3, Toluene, 90oC
Substrate assisted N(TMS) 2
transmetalation: Br 71%

_
EtO
C Ph
O
PPh3
N(TMS)2 + MeO2C Pd II
Sn
N(TMS)2 Br PPh3
Br
hypervalent tin
possible transmetalation intermediates

· like silicon, tin is fluorophilic Fouquet JOC 1997 (62) 5242

N(TMS) 2 I Pd(PPh ) , 1 mol%

Sn N(TMS) 2
3 4
Br
1 step TBAF (3 eq)
Br
Sn[N(TMS)2]2 t-Bu dioxane, 110oC t-Bu
76%
F- assisted "Lampert's stannylene" 12h
transmetalation:
Lampert Chem. Commun. 1974, 895.
_
F
N(TMS) 2 Sn N(TMS) 2
Sn TBAF N(TMS) 2
In contrast to tetraorganotins, monoorganotins N(TMS) 2
can be used transfer value added alkyl substituents. Br F

proposed transmetalating
reagent: hypervalent tin species
M.C. White, Chem 253 Cross-Coupling -105- Week of October 4 , 2004

General method for Stille

cross- coupling with aryl chlorides
1.5% [Pd2(dba)3]
Cl 6% Pt-Bu3 Additive (1.1 eq) % GC Yield
+ Bu3Sn
dioxane, 100 o C Me none 12
Me NEt3 16
12% CsCO3 40
NaOH 42
Bulky, electron rich phosphines are are known to sucessfully promote the oxidative TBAF 24
addition of Pd(0) to aryl chlorides in the Suzuki reaction (presumably via the
formation of highly nucleophilic, coordinatively unsaturated (14e-) palladium(0) KF 28
complexes). The poor reactivity of this system in promoting the Stille coupling of aryl CsF 50
chlorides to simple vinyltributyltin prompted Fu to hypothesize that the problematic CsF (2.2) 59
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).
Synthesis of sterically hindered biaryls Csp 3-Csp2 Stille couplings

3.0 % Pd(P(t-Bu)3) 2 1.5% [Pd 2(dba)3]

2.2 eq. CsF 6% Pt-Bu3
Cl Bu3Sn MeO Cl MeO Bu
dioxane, 100 oC 2.2 eq. CsF
89% dioxane, 100 oC
Bu3Sn-Bu

Room temperature aryl bromide Stille couplings the air-sensitivity of P(t-Bu)3 is a

drawback to this methodology:
0.5% [Pd 2(dba)3] Pd(P(t-Bu)3)2, a more air-stable,
Br 1.1% Pt-Bu3 crystalline complex is more easily
Bu3Sn
O O handled and is now commercially
toluene, rt
88% available from Strem.
Fu ACIEE 1999 (38) 2411
Fu JACS 2002 (124) 6343
M.C. White, Chem 253 Cross-Coupling -106- Week of October 4, 2004

Negishi-Suzuki Coupling?
I "(PPh3)2 Pd(0)"
generated in situ from
M Cl2 Pd(PPh3)2 and DIBAL

THF

Negishi's metal counterion screen:

Product
M temp (oC) time (h) yield %
Li 25 24 3
MgBr 25 24 49
Negishi chose to pursue this
lead, rather than the organo- ZnCl 25 1 91
borane and organotin results
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 253 Cross-Coupling -107- Week of October 4, 2004

Representative Suzuki Cross Coupling Suzuki Cross Coupling

O 100% stereospecific the
Ph
HB O Pd(Ph3 )4 (1 mol%) configurations of the
O vinylborane and vinyl
B O NaOEt, benzene halide are retained.
catecholborane
C 4H 9 H reflux Excellent method for
regiospecific C 4H 9 Br Ph C4H 9 the construction of
syn hydroboration conjugated dienes.
86%

Catalytic Cycle: Organoboranes

A variety of different organoboron reagents can be
used to effect transfer of the R2 group via
transmetalation. Generally, electron rich unhindered
R1 = aryl, vinyl, alkynyl organoboranes are most reactive towards
R 1
R 2 Ln Pd (0)
R -X1 X = I>OTf>Br>>Cl transmetalation. Organoboranes are non-toxic and
air and moisture stable.*
reductive oxidative
elimination addition O
1 2 2
R R1 R B(Oi-Pr)2 R B
LnPd (II) L nPd(II) O
R2 X

R2OM
M = Na, K, Tl O B R2
BY2OR2
R2 B
R1 R2 = alkynyl, aryl, vinyl, alkyl
L nPd(II) XM O 9-BBN
R3 OR2 pinacolborane (9-Borabicyclo[3.3.1]nonane)
BY2
transmetalation
Palladium Catalysts
The rate-determining step in
Suzuki-couplings with Pd(0)
reactive electrophiles (i.e. Pd(PPh3)4 Pd2(dba)3 + phosphine
R1 -X= unsaturated iodides) (most common)
Pd(II)
*See: Chem 115 Suzuki Handout for comprehensive review of synthesis of
organoboron compounds (A.G. Meyers/A. Haidle) Pd(OAc)2 + phosphine PdCl2(dppf) (for sp3-sp2)
M.C White, Chem 253 Cross-Coupling-108- Week of October 4, 2004

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 RO R R
effect is thought to be due, at least in part, to the B R O B O B
formation of a hypervalent, anionic boron "ate" R R
complex, which undergoes transmetalation more R'L2Pd
readily and can coordinate the Pd metal. boron ate-complex

It is also proposed that a nucleophilic base can B R

displace the Pd-bound halide that results from R R
RO
oxidative addition, to generate a metal center that R'L2Pd X R'L2Pd O O B
is capable of coordinating the organoborane. R'L2Pd R

‡
H
Soderquist has proposed a µ2-hydroxo-bridged,
4-centered cyclic transition state for the O B
transmetalation event, which has been shown
to proceed with retention of configuration for R'L2Pd C
both coupling partners.

Soderquist J. Org. Chem. 1998 63 461-470

M.C White, Chem 253 Cross-Coupling-109- Week of October 4, 2004

Suzuki: Ligand Effects for Csp3-Csp2 couplings

Ph PdCl2(dppf) is often found to be a superior catalyst for Suzuki cross coupling reactions between
Ph boron-alkyl derivatives (possessing β-hydrogens) and vinyl/aryl halides/triflates. This ligand is
P thought to favor reductive elimination vs. competitive β-hydride elimination for at least two
Cl
reasons:
Fe Pd · The bidentate phosphine ligand enforces a cis geometry between the alkyl and
vinyl/aryl substituents; this cis geometry is required for reductive elimination
Cl
P · The large bite angle for this bidentate phosphine ligand results in a smaller angle
Ph Ph between the alkyl and vinyl/aryl substituents. Recall that minimization of the angle
between two metal-bound substituents is thought to promote reductive elimination
dppf, bis(diphenylphosphino)ferrocene event by increasing orbital overlap:

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 Me

Me 1. 9-BBN-H
S Me Me
S O
2.PdCl 2(dppf), K 2CO3
S
CO2Me S HO
Me
OAc Me
OAc Me OH Me
Br
dihydroxyserrulatic acid

Urema JACS 1991 113 5402-5410.

M.C. White, Chem 253 Cross-coupling -110- Week of October 4, 2004

Suzuki Couplings: Ligand Effects

First report of effective Suzuki cross-coupling of
unactivated aryl chlorides:
Bidentate ligands are ineffective. The optimal phosphine to
ligand ratio is between 1 and 1.5. Both pieces of data suggest
Cl B(OH)2 that the active catalyst has a single phosphine attached.
1.5% [Pd2(dba)3]
3.6% phosphine
2 eq. Cs2CO 3 Phosphine θ CO v, cm -1 % GC Yield
dioxane, 80oC none --- --- 0
BINAP --- --- 0
Fu ACIEE 1998 (37) 3387.
dppf --- --- 0
Aryl chlorides are traditionally unreactive towards Suzuki cross Ph2P(CH2)3PPh 2 --- --- 0
couplings (recall: I> OTf > Br >>>Cl). This is thought to be due Cy2P(CH 2)2 PCy2 --- --- 0
in part to the strength of the Ar-Cl bond (i.e. Ph-X: Cl (96 PPh3 0
145 2069
kcal/mol), Br (81 kcal/mol), I (65 kcal/mol)). Reports of
PCy 3 170 2056 75
reactivity were limited to reactions using activated substrates (i.e.
aryl chlorides with electron withdrawing substituents). The low PtBu3 182 2056 86
cost and high availability of aryl chlorides, however makes them P(o-tol)3 194 2066 10
very attractive substrates. Fu was the first to discover that bulky,
electron rich ligands could overcome this reactivity issue.

Room temperature Suzuki couplings with aryl bromides Chemoselective Suzuki couplings: first example of Pd-catalyzed cross-
coupling that demonstrates higher selectivity for aryl chlorides than for
Br B(OH)2
aryl triflates
0.5% [Pd2 (dba)3] OTf B(OH)2
1.2% P(t-Bu)3 1.5% [Pd2(dba)3]
3.3 eq. KF 3.0% P(t-Bu)3
THF, rt 3.3 eq. KF
98% THF, rt
OMe
OMe Cl 95%
Full paper: Fu JACS 2000 (122) 4020. OTf
M.C. White, Chem 253 Cross-Coupling -111- Week of October 4, 2004

Bulky, electron-rich phosphines

P(t-Bu)3
o
94
164.6o
PdII

109.9o I

T-shaped monomer

Ph

I P(t-Bu)3
t-Bu
O Pd0 P t-Bu PdII
Pd(dba)2 + 1 P(t-Bu)3
t-Bu I
dba
14e-
Ph
dba

Hartwig JACS 2002 (124) 9346.

M.C. White, Chem 253 Cross Coupling -112- Week of October 4, 2004

Suzuki: Ligand Effects for Csp3-Csp3 couplings

Br 4 % Pd(OAc)2
n-Dec 8% ligand n-Hex
+ n-Dec
n-Hex 1.2 eq. K3PO4
9BBN THF, rt
Subtle Ligand Effects

Ligand θ CO v, cm -1 % GC Yield n-Dec

· It is thought that the inability of palladium to effectively
BINAP --- --- <2 <2 mediate cross couplings between alkyl halides and alkyl
dppf --- --- <2 12 boranes is due to slow oxidative addition of the alkyl
P(OPh)3 128 2085 <2 <2 halides/triflates to palladium and facile β-hydride
P(n-Bu)3 132 2060 9 27 elimination of the Pd alkyl intermediates. In the majority
PPh3 of cases when oxidative addition occurs it is followed by
145 2069 <2 <2
β-hydride elimination rather than the desired
AsPh3 142 --- <2 <2 transmetalation event. Fu does not present any data that
P(2-furyl)3 --- --- <2 <2 indicates β-hydride elimination occurs after the
PCy3 170 2056 85 <2 transmetalation event (would expect see 1-hexene). The
P(i-Pr)3 160 2059 68 6 appearance of 1-decene as a bi-product indicates that
PtBu3 182 2056 <2 21 β-hydride elimination competes with transmetalation after
P(o-tol)3 194 2066 <2 14 oxidative addition.
Fu JACS 2001 (123) 10099.

R
oxidative H PR3 reductive R
R R' PR3
addition Pd transmetalation R elimination
X X Pd
R'BR3 X R'
β -hydride
·electron rich, bulky phosphines may promote oxidative addition by
L Pd0 PR3 elimination
increasing electron density at the metal center and by promoting the
L = solvent H PR3 formation of a coordinatively and electronically unsaturated complex.
or OAc · electron rich, bulky phosphines may disfavor β-hydride elimination
Pd
R both by making the metal less electrophilic and blocking open
X
coordination sites at the metal center.
M.C. White, Chem 253 Cross-Coupling -113- Week of October 4, 2004

Suzuki: Ligand Effects II

Buchwald Ligands (commercially available from Strem). Room temperature Suzuki cross-coupling of
General features: electron rich and bulky. Buchwald speculates that unactivated aryl chlorides:
the electron rich nature of the phosphines promotes oxidative addition
and tight binding to the metal (prevents Pd black formation). Cl B(OH)2
Moreover, the steric bulk of the ligand promotes reductive
1.5% Pd(OAc)2
elimination. Subtle feature: o-phenyl may be oriented such that
3.0% 4
π-interaction with the metal occurs. It is not clear why this feature is
important. 3 eq. KF
THF, rt
PCy2 Pt-Bu2 92%

Suzuki Csp2-Csp3 Coupling

Me2N
Me2N
C6H14
1 2 Cl
0.5% Pd(OAc)2
PCy2 P(t-Bu)2 1.0% 4
B nC6H14
3.3 eq. KF
THF, 65 oC
CO2Me
CO2Me
83%
3 4

Exceptionally high TON

O B(OH)2 O
Pd(OAc)2 : 4 (1:2)
3.3 eq. KF
100oC
Br Ph
100,000,000 TN in 24h*
Buchwald ACIEE 1999 (38) 2413.
Buchwald JACS 1999 (121) 9550 Note: only observed for this substrate
M.C. White, Chem 253 Cross-Coupling -114- Week of October 4, 2004

Suzuki: An alternative to phosphines

Me Me
Nucleophilic N-heterocyclic carbenes (imidazol-2-ylidenes):
N Me these so called "phosphine mimics" do not dissociate from
L = Me N
the metal center, and thus an excess of ligand is not required
Me to prevent agregation of the catalys to yield the bulk metal.
Me
generated in situ from the corresponding Cl salt

MeO2C Cl + (HO)2B MeO2C

99% yield

General conditions
Pd2(dba)3 (1.5 mol%)
Me Cl + (HO)2B L (3.0 mol%) Me
Cs2CO 3 (2 equiv.)
OMe dioxane, 80 oC, 1.5 h 91% yield OMe

Me Me

Cl + (HO)2B

Me Me

89% yield

Nolan J. Org. Chem. 1999 64 3804-3805.

M.C. White, Chem 253 Cross-Coupling -115- Week of October 4, 2003

Suzuki: the “TlOH effect”

O
O
O O RO OY
RO OY
O
ZOCOHN OR
O YO
OR
76
RO OR 75
OR OR
OR
OR

O
I OR
75 Pd(PPh3)4
+ OR
Base
(HO) 2B 76
RO
OR
O
RO
OR
R = CH2PhOMe(p)
Y = Si(Me)2(t-Bu) (MeO)2
P OR
Z = CH 2CH2Si(Me)3
O O

Conditions 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 253 Cross-Coupling -116- Week October 4, 2004

Suzuki: TlOH vs. TlOEt

OTBDPS
OTBDPS
Me Me Me
Me Me
Me HO B(OH)2
TBSO
TBSO TBDPSO
O
O
TlX, Pd(PPh3) 4
THF, H2O
Me
Me
Reagent age Yield Me Me
I TlX source
OH
TlOEt --- 83%
OTBDPS
TlOH (10% stock solution) 1 month old 71%

TlOH (10% stock solution) 5 month old 50%

TlOH (from solid)) 12 month old 52%

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 CO2t-Bu

t-BuO2C CO2t-Bu
(HO) 2B OH

Pd(PPh3)4, TlOEt
THF/H2O : 3/1 97% yield
I CO2Me
THF (anhydrous) 92% yield
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 253 Cross-Coupling -117- Week of October 4, 2004

Suzuki : Formation of Hindered Aryl-Aryl Bonds

N
N B(OH)2
O OMe O
O O NCO2t-Bu
TfO NCO2t-Bu Pd(dppf)Cl2, K3PO4
O OMe
THF, 65°C
O
63%
1:1 mixture of atropisomers Intermediate en route
to Diazonamide A

Pd 0(dppf) Pd 0(dppf)
oxidative addition reductive elimination

OTf -
N N
O
transmetalation
P
O
O OMe P P O
Pd + NCO2t-Bu 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 253 Cross-Coupling -118- Week of October 4, 2004

Suzuki: reliable method for late-stage macrocyclization

OTBS OTBS
O O O O O O O O
I TBS TBS PdCl 2(MeCN)2 TBS TBS
B O O
O O Ph 3As, AgO, THF Desilylation yields
O O Rutamycin b.

O O
O OTBS 70% O OTBS

Pd(Ph3As)n Pd(Ph 3As)n

oxidative addition reductive elimination

OTBS OTBS
O
AsPh3 O O O O
B
Ph3As TBS TBS AsPh3 TBSO O O
Pd transmetalation TBS
O O I O Pd AsPh3
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 253 Cross-Coupling -119- Week of October 4, 2004

Hydroboration/Suzuki coupling sequence

sets a new stereocenter and effects macrocyclization
OPMB
OPMB OMe O
OMe O
1. 9-BBN, THF OMOM
OMOM O
O Synthetic studies towards
2. (dppf)PdCl2 (20 mol%)
Benzene / H2O, NaOH Salicylihamide A
80°C, 12 h (48%)
I

hydroboration Pd 0(dppf) reductive elimination

H B

OPMB OPMB
OPMB OMe O transmetalation OMe O
OMe O oxidative addition
OMOM OMOM
OMOM O O
O

Pd 0(dppf)
Pd I BR2 Pd
I BR2
P
P 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.