c-c bond formation - harvard universitypeople.fas.harvard.edu/~chem253/notes/2004wk3.pdf · jomc...
TRANSCRIPT
M.C. White, Chem 253 Cross Coupling -84- Week of October4, 2004
C-C Bond Formation
A paradigm shift:nucleophilic substitutionat an sp2 hybridizedcarbon is made routineby using transition metalmediated catalysis.
R
R
ArR R
R
Alkyl
R
Alkyl Ar
Csp2-Csp2 Bonds Csp3-Csp2 Bonds
R
R
R
Csp-Csp2
Alkyl Alkyl
Csp3-Csp3 Bonds
Kumada Coupling
Ni(0) or Pd(0)M = MgX, Li
Stille Reaction
Pd(0)M = SnR3
Negishi Coupling
Ni(0) or Pd(0)M = Al(i-Bu)2 Zr(Cl)Cp2 ZnX
Suzuki Reaction
Pd(0)M = BX2
Classifications based on the main group metal
used to transfer R2 in the transmetalation event.
Hiyama Coupling
Pd(0)M = SiR3
Sonogashira
Pd(0)M = Cu (in situ)
R = aryl, vinyl
X = I, Br, OTf, Cl
Pd(II)
LnPd(0) R1-X
LnPd(II)R1
X
R2-M
LnPd(II)R1
R2
oxidative addition
transmetalation
X-M
R1 R2
General Mechanism
reductiveelimination
R2= aryl, vinyl, alkyl
R2-M
R2 R2
Cl
Cl(or Ni(II)
Cl
Cl
)
M.C. White, Chem 253 Cross-Coupling -85- Week of October 4, 2004
Kumada pushes the frontier
PPh2
Ni(II)
Ph2P Cl
ClCl
Cl n-BuMgBr (2 eq)
PPh2
Ni(II)
Ph2P Cl
Cl
Cl MgBr
Kumada JACS 1972 (94) 4374.
0.7 mol%
94%
0.7 mol%
80%
Reductive elimination/Oxidative addition: Yamamoto JOMC1970 (24) C63. "Preparation of a phenyl-nickel complex, phenyl (dipyridyl)nickel chloride, an olefin dimerization catalyst.
N
N
Ni(II)
Cl
N
N
Ni(II)
Cl
+ butane
N
N
Ni(II)
Cl
N
N
Ni(0)
Cl
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.
Ph3P
Ni(II)Br PPh3
Br
2 RMgBr
Ph3P
Ni(II)R PPh3
R
R = R'
All the pieces of the catalytic cycle were in the literature...
LnNi(II)
LnNi(II)R1
XLnNi(II) R1
R2
MgX2
R1R2
R2 R2
Cl
Cl
R1 = aryl, vinyl
X = Cl > Br> ILnNi(0)R1-X
R2-MgX
oxidative addition
transmetalation
reductiveelimination
R2= aryl, vinyl, alkylR2-MgX
M.C. White, Chem 253 Cross-Coupling -86- Week of October 4, 2004
Kumada Coupling
P P
( )n
dppm, n=0, bis(diphenylphosphino)methanedppe, n=1, bis(diphenylphosphino)ethanedppp, n=2, bis(diphenylphosphino)propanedppb, n=3, bis(diphenylphosphino)butane
P P
dmpe, bis(dimethylphosphino)ethane
P
P
Fe
dmpf, bis(dimethylphosphino)ferrocene
Common Bidentate Phosphines
Kumada Bull. Chem. Soc. Jpn. 1976 (49) 1958.
P
Ni(II)P Cl
ClCl
n-BuMgBr (2 eq)
0.7 mol%
R2
R2
Ligand
dppp
dmpf
Ph3P (2eq)
dppe
dmpe
dppb
% yield
100
94
84
79
47
28
Effect of the ligand:
· Bidentate phosphine ligandsexhibit higher catalytic activity than monodentate phosphineswith dppp being optimal for awide range of aryl and vinylhalides.
Reactivity of aryl halide:
P
Ni(II)P Cl
ClX
n-BuMgBr (2 eq)
0.7 mol%
Ph2
Ph2
X % yield
FClBrI
31 (2h)95 (3h)54 (4.5h)80 (3h)
· Unlike other cross-couplingmethods, aryl and vinyl chlorides exhibit higher reactivities thantheir Br or I analogs. It isnoteworthy that even arylfluorides undergo the nickelcatalyzed cross-coupling.
M.C. White, Chem 253 Cross-Coupling -87- Week of October4 , 2004
Kumada Coupling: Applications
P
Ni(II)P Cl
ClMgCl
Ph2
Ph2
t-BuO
Cl
t-BuO
P
Ni(II)P Cl
Cl
Ph2
Ph2
N Br
P
Ni(II)P Cl
Cl
Ph2
Ph2
S MgBr
Me3SiCH2MgCl
BuMgBr
N
S
NNSiMe3
0.1 mol%
· Industrial production of p-substituted styrene derivatives (Hokka Chemical Industry, Japan)
Strem 2001-2003 catalog$7.6/g (very cheap)
Banno JOMC 2002 (653) 288.
· Functionalization of heterocyclic halides
0.5-1 mol%
71%72%78%
· Formation of sterically hindered biaryls
Kumada Tetrahedron 1982 (38) 3347.
Cl
R
R = CF3, H, CH3, OCH3
O
NiIIO O
O3 mol%
+
3 mol%
NN
BF4-
NN
BF4-
imidazolium salt
RMgX
Nucleophilic N-heterocyclic carbenes are used as a phosphine mimics that (unlikemonodentate phosphines) do notdissociate from the metal
BrMg
steric hinderance toleratedonly on the Grignard
+
R
NN
BF4-
R= CF3, 91% H, >99% CH3, 95% OCH3, 98%
Herrmann ACIEE 2000 (39) 1602.
M.C. White, Chem 253 Cross-coupling -88- Week of October 4, 2004
Pd Kumada Coupling: stereospecific transmetallation
The nickel catalyzed Kumada coupling is stereospecific for vinyl mono-halides (complete retention of geometric configuration)but non-stereospecific for alkenyl Grignards:
Ph Br
MeMgBr
P
Ni(II)P Cl
Cl
R2
R2Ph Me
96% (Z)-stilbene
Ph
MeMgBr
Ph
>99% (E)-stilbene
Br Me
96% (Z)-β-bromostyrene
>99% (E)-β-bromostyrene
P
Ni(II)P Cl
Cl
R2
R2
BrMg Me
96% Z
P
Ni(II)P Cl
Cl
R2
R2
Br
Ph Me
27% Z: 73% E
Kumada TL 1975 1719.Kumada Pure & Appl. Chem. 1980 (52) 669.
Oxidative addition to Pd(0) had been reported: Fitton Chem. Comm. 1968, 6.
PPh3
PPh3
Pd
Ph3P
Ph3P
I
Ph3P
Pd(II)Ph3P
I
Palladium (0) shown to be an effective, stereospecific catalyst for cross-coupling of alkenyl halides with Grignard reagents.Murahashi JOMC 1975 (91) C39.
Ph Br
MeMgI
Ph Me
99% cis-stilbene>99% yield
99% cis-β-bromostyrene
PPh3
PPh3
Pd
Ph3P
Ph3P
Palladium (0) shown to be stereospecific for alkenyl Grignards reagents. Linstrumelle TL 1978, 191.
I
n-C6H13
BrMg Me
3 mol%
PPh3
PPh3
Pd
Ph3P
Ph3P5 mol%
(E)-1-iodo-1-octene
(Z)-1-propenyl-1magnesium bromide
n-C6H13
>97%, (2Z,4E)-2,4-undecadiene 87% yield
Note: Pd catalysts can also transmetallate with organolithiumreagents: Murahashi JOMC 2002 (653) 27.
Pd(0): I>Br>>Cl
Note: Nickel catalysis may involve radical pathways
M.C. White, Chem 253 Cross-Coupling -89- Week of October 4, 2004
Negishi Coupling: towards FG tolerance
Negishi Acc. Chem. Res. 1982 (15) 340.
n-C5H11
Al(i-Bu)2
n-C4H9
I5 mol%
n-C5H11
n-C4H9
or
(PPh3)2Pd(0)*
(PPh3)2Ni(0)
Pd: 74%, >99% (E,E)Ni: 70%, 95% (E,E), 5% (E,Z)
+
* PdCl2(PPh3)2 + 2 eq. DIBAL Ni(acac)2 + 2 eq. DIBAL
Negishi JACS 1976 (98) 6729.
ZrCp2Cl
O
O
Br
O
MeO
+(PPh3)2Pd(0)*
50oC, 4h
O
O
O
MeO
70%
Negishi TL 1978 (12) 1027.
I
EtEt
i-Bu2Al(or ZrCp2Cl)
PPh3
PPh3
Pd
Ph3P
Ph3P
5 mol%
ZnCl2, 1h, 25oC, 88%
EtEt
No rxn after 1 wk w/out ZnCl2
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 catalyzedcross-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.
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.
The addition of ZnCl2 increased the reactivity of the transmetalating reagent making the cross coupling of sterically hindered substrates possible. It is thought that thealkenylzirconium, alkenylalane undergo in situ transmetalations with ZnCl2 to form alkenylzinc, a more reactive transmetalating reagent.
M.C. White, Chem 253 Cross Coupling -90- Week of October 4, 2004
n-C4H9
IPdII
PPh3
PPh3
n-C4H9
β-hydride elimination
reductiveelimination
n-C4H9
n-C4H9
H
n-BuZnCl
or n-BuMgCl
n-BuMgCl
51%
25%
n-BuZnCl
2%
76%
Pd(PPh3)4
Formation of Csp2-Csp3 bonds using alkylzinc reagents.
O
BuI
O
NiII
O
Bu
O
F3C
Pent2Zn
possible intermediateF3C 50 mol%
O
NiII
O O
O
10 mol%
O
Bu
Pent
70% yield, 1h
w/out π-acid: 20%, 15h
Recall: formation of Csp3-Csp3 bonds using alkylzinc reagents.
Negishi JACS 1980 (102) 3298.
Knochel ACIEE 1998 (37) 2387.
Negishi Coupling: Csp3-Csp2 and Csp3-Csp3
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.
M.C. White/Q. Chen, Chem 253 Cross-Coupling -91- Week of October 4, 2004
Negishi Coupling: Csp3-Csp2
O O
PMP
I
OTBS O O
PMP
Zn
OTBS
O O
PMP
OTBS
OPMB
OTBS
OPMB
OTBS
I
O
NH2
OH OH
O
O
HO
O
Ph3P
O O
PMP
OTBS
PdIIPPh3
OPMB
OTBSZnCl2, t-BuLi (3 eq)
Et2O, -78 °C to rt
5% Pd(PPh3)4
Et2O, rt
66%
(+)-Discodermolide
Note: β-hydride present in alkyl zinc.
13 steps
transmetalation I
Ph3PPdII
PPh3
OPMB
OTBS
I
oxidativeaddition
+ transmetalation II-PPh3
O O
PMP
OTBS
PdII
OPMB
OTBS
PPh3
reductive elimination
Ligand dissociation to the trigonal planar intermediateis thought to favor reductiveelimination from squareplanar complexes.Yamamoto OM 1989 (8) 180.
Smith JACS 2000 (8654).
M.C White, Chem 253 Cross-Coupling-92- Week of October 4, 2004
P O
O
O
Catalyst
PPh3
PPh3
Pd
Ph3P
Ph3P
Palladium(0)
Palladium(II)
Pd2(dba)3
O
dibenzylideneacetone (dba)Strem 2001-2003
$53/g Strem 2001-2003$28/g
Cl
PdIIH3CCN Cl
NCCH3
Strem 2001-2003$39/g
O
PdIIO O
O
Strem 2001-2003$52/g
Monodentate phosphines are added to palladium sources with poorlycoordinating ligands to prevent catalyst decomposition ("plating out")to metallic Pd(0). Bidentate phosphines result in low reaction rates and poor yields.
PPh3
As
tri-2-furylphosphine triphenylarsine
Ligands
Stille Coupling
Stille JACS 1979 (101) 4992.
LnPd(II)
LnPd(II) R1
XLnPd(II)
R1
R2
XSn(R3)3
R1 R2
R2 R2
Cl
Cl
R1 = aryl, vinyl, alkynyl
X = I>Br>OTf>>ClLnPd(0)R1-X
R2-Sn(R3)3
oxidative addition
transmetalation
reductiveelimination
R2= alkynyl, aryl, vinyl, alkylR2-Sn(R3)3
Transfer from tin:
alkynyl>alkenyl>aryl>benzyl>allyl>alkyl.
Allows for simple alkyl groups (Me, Bu) to
serve as"dummy" R3 substituents thereby
avoiding using four identical expensive and/or
difficult to synthesize R2 groups. Alkyl
transfers are only practical for methyl or butyl.
Br Me4Sn
Ph3PPdII
Ph3P Cl
Ph
HMPA, 62oC
Me
Me3SnCl
The original report:
+1 mol%
+
The rate-determining step in
Stille-couplings with reactive
electrophiles ( i.e. R1-X=
unsaturated iodides, triflates)
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.
OH OHBu3Sn
CHOBu3Sn Bu3Sn
CO2Et
OTf
CO2Et
PO(EtO)2
CO2Et
i) n-BuLi, DMPU, THF, 0°Cii) aldehyde, -78°C-> -20°C
2.5 mol% Pd2(dba)320 mol% AsPh3, NMP
Dominguez Tetrahedron 1999 (55) 15071
3 eq. SO3 Py, 3eq. Et3N,
CH2Cl2/DMSO
96%
73%
62%
oxidation
HWE condensation
retinoic acid precursor
Stille Coupling
(n-Bu3Sn)(Bu)CuLi.LiCN
* For comprehensive review of synthesis of aryl and vinyl stannanes see A.GMyers/A. Haidle Chem 115: "The Stille Reaction".
M.C. White, Chem 253 Cross-Coupling -94- Week of October 4, 2004
Stille: Ligand EffectsPd2dba3 + Ligand
Bu3Sn
Ligand Pd:LRelative
rate
PPh3
(2-furyl)3P
AsPh3
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 tobe electronic in nature where phosphines that are poor σ-donors promote the cross-coupling more effectively than those that are strong σ-donors.
θ
145o
ND
142o
1:2
1:2
1:2
1
20
78
I
THF, 50oC
Farina JACS 1991 (113) 9585.
Pd
L
L
I Pd
[S]
L
IBu3Snk1
+ L + Bu3SnI
1 2
I Pd2(dba)3,L (1:4)
50oC, THF k-1 k2
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.
Ligand k1/k-1
PPh3
(2-furyl)3P
AsPh3
Relativekobs
1
105
1100
<5 x 10-5
6 x 10 -3
0.86
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.
M.C. White/M.W. Kanan Chem 253 Cross-Coupling -95- Week of October 4, 2004
Stille: Mechanism of Pd/Sn Transmetalation
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.
Pd C
H H
R'
SnR3R
ClR'Sn
X Pd R
L L
δδδδ++++δδδδ++++
δδδδ−−−−
L
SE2 (open) SE2 (cyclic, pentacoordinate)
R'Sn
X Pd R
SE2 (cyclic)
L
favored in highly polar and/or nucleophilic solvents
favored in non-polar solvents
Farina Pure & Appl. Chem. 1996 68:1 pp 73-78.
M.C. White, Chem 253 Cross-Coupling -96- Week of October 4, 2004
Stille: Copper Effects
I
Bu3Sn
Pd2dba3, PPh3, +/- CuI
dioxane, 50 oC
Pd:L:CuImolar ratio
Relativerate
HPLCYield (%)
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
LigandPd:L:CuI
molar ratioRelative
rate
HPLCYield (%)
PPh3 1:4:0 1 85AsPh3 1:4:0 2710 >95AsPh3 1:4:1 3459 >95AsPh3 1:4:2 3624 >95 CuI
-ISnBu3
Bu3Sn LnCu
OTf
O
Bu3Sn
t-Bu
PdCl2(PhCN)2
t-Bu
O O
Bu
Group transfer selectivity
A B
A : B
- CuI 90 : 10
+ CuI >98 : 2
NMP, 80 oCAsPh3 +/- CuI
+
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 lesserextent. To account for this the authors propose an initial transmetalation from anorganostannane to an organocuprate, followed by more facile transmetalation ofthe alkenylcuprate with the palladium catalyst. This proposal is supported by thechange in selectivity of the group transfered from the organostannane in thepresence of CuI.
To explain the observed rate enhancements in the presence of the cocatalyst CuI, the authors propose that CuI acts as a ligandscavenger, binding to free PPh3 and thereby promoting ligand dissociation. This proposal is supported by 31P NMR studies where Cu complexed phosphine is detected.
Farina& Liebeskind JOC 1994 (59) 5905.
M.C. White, Chem 253 Cross-Coupling -97- Week October 4, 2004
ONfPd(PPh3)4
Nf = n-C4F9SO2
Bu3Sn
n-C5H11
OH
+n-C5H11
OHCuX, LiCl
~ 40 hsolvent
Conditions optimized yield
X = I, solvent = DMA 38 %
X = Cl solvent = DMSO 88 %
DMA = dimethylacetamide
LnPd(II)Ar
XLnPd(II)
Ar
R
R Ar LnPd(0)
oxidative addition
transmetalation II
reductiveelimination
Ar-X
RSnBu3 + CuCl + LiCl
-Bu3SnCl
RCuLiCl
transmetalation I
Proposed catalytic cycle
The authors propose that the greater electrophilicity of CuClrelative to CuI (expected from the greater electronegativity of Cl relative to I) leads to faster and more efficient transmetalation ofthe hindered vinylstannane to the corresponding vinyl Cu(I)species.
Corey, E.J. JACS 1999 121 7600-7605.
Stille reaction: "the copper effect"a general coupling system for sterically congested substrates
M.C. White, Chem 253 Cross-Coupling -98- Week of October 4, 2004
Stille: nucleophilically-accelerated transmetalation
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:
Sn
N
CH3
Pd[S]
BrAr
L
δ+
δ-
Sn
N
H3C
Pd
δ+
Br
L[S] or LAr
SE2 (open) SE2 (cyclic)
Farina Pure & Appl. Chem. 1996 68:1 pp 73-78.
Br
MeO
+ Me4Sn
Me
MeO
Pd(PPh3)4
PhMe, 75 oC, 7h
Br
MeO
Pd(PPh3)4
Me
MeOPhMe, 75 oC, 7h
<5% yield
Sn
N
Me
+
67% yield
M.C. White/M.W. Kanan Chem 253 Cross-Coupling -99- Week of October 4, 2004
Stille: Extraordinary FG Tolerance
Williams, JACS, 2001, (123), 765.
O
O
H
HOHOTIPS
H
Bu3Sn
H
H
OH
O
CH3
I
H3CH
O
O
H
HOHOR
HH
H
OH
O
H3CH
OH
O
CH3
Pd
H3CH
I AsPh3
AsPh3
O
O
H
HOHOTIPS
H
Bu3Sn
H
H
O
O
H
HOHOTIPS
H
H
HLnCu
O
O
H
HOHOTIPS
HH
H
OH
O
CH3
PdLnH3CH
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.
(Ph3As)2Pd0
Pd2(dba)3 (0.2 eq.)Ph3As (0.8 eq.)CuTC (1.5 eq.)NMP, 35°C 50%
LnCuTC+ ISnBu3
II
oxidative addition
transmetalation II
reductive elimination
transmetalation ICuTC
Cu(I) thiophene-2-carboxylate
Cu
O
S
key intermediate in total synthesis of(+)-Amphidinolide
M.C. White/ M.W. Kanan Chem 253 Cross-Coupling -100- Week of October 4, 2004
Stille: Double Couplings
Overman JACS 2002 (124)9008.
HN N
I
NH
N
I
H
H
OTf
N
ONMeTs
SnBu3Bn
Pd2(dba)3 CHCl3, P(2-furyl)3, CuI, NMP, rt
HN N
NH
N
H
HOTf
N
ONMeTs
Bn
OTf
N
ONMeTs
Bn
HN N
HPdI PR3
PR3
II
(PR3)2Pd0
HN N
HPdLn
OTf
N
O
TsMeN
Bn
OTf
N
ONMeTs
SnBu3BnOTf
N
ONMeTs
Cu(L)nBn
CuI(L)n
oxidative addition
+ CuI(L)n
transmetalation I
transmetalation II
reductive elimination
71%
II
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 theadjacent protected amide.
Key intermediate in Quadrigemine C
M.C. White/M.W. Kanan Chem 253 Cross-Coupling-101- Week of October 4, 2004
Stille: MacrocyclizationSnBu3
TfO
O OO
O
OO
H
H
Pd(CH3CN)2Cl2, 5 mol%
LiCl, DMF, 20°C
SnBu3
PdLn
O O
Cl
PdLn
O OO O
48%
[4+2]
oxidative addition
transmetalation reductive elimination
The Stille coupling has proven to be an effectivestrategy for macrocyclization through diene or eneyneformation. In this case, the product is a substrate for a transannular 4+2 cycloaddition, which proceedsspontaneously to afford the polycyclic product.
SnBu3
LnPd
O O
+
OTf-
Cl- substitution for OTf oftenreferred to as the "LiCl effect" isthought to promote the rate-limitingtransmetalation event
O2
Suffert Org. Lett. 2002 (4) 3391.
highly unsaturatedpolycyclic ring systems
Stille JACS 1986 (108) 3033.
M.C. White, Chem 253 Cross Coupling -102- Week of October 4, 2004
Hiyama Coupling
SiMe3
In-C6H13
THF, 50oC
PdCl
PdCl
n-C6H13
Reaction is stereospecific. It proceeds w/complete retention of db geometry.
2.5 mol%
TASF* (1.1 eq)
P(OEt)3 5 mol%78%
I
HMPA, 50oC
+2.5 mol%
SiMe3
PdCl
PdCl
TASF* (1.3 eq)
TASF = tris(diethylamino)sulfonium difluorotrimethylsilicate good source of F-
No reaction in absence of TASF
"ligandless system"
1.3 eq89%
The F- reagent believed to first attack the organosilicon compound to generate apentacoordinate silicate. This has the effect of enhancing the anionic character of the typically non-polar organosilicon bond , thereby promoting transmetalation.
Si
Me
MeMe
TASF Si
Me
MeMe
F
_
[(CH3)2N]3S+
Hayama JOC 1988 (53) 918.
SiMe3
Essentially complete FG tolerance: esters, ketones, free hydroxyls, aldehydes
THF, 50oC
PdCl
PdCl
BrPh
HO
HO
Ph
2.5 mol%
TASF* (1.1 eq)
M.C. White, Chem 253 Cross-Coupling -103- Week of October 4, 2004
Hiyama Coupling
enhanced nucleophilicity of the γcarbon of the intermediatepentacoordinate allylic silicate isused to rationalize regoiselectivity of substition.
Hiyama JACS 1991 (113) 7075.
SiF3
F3CO2SO C(O)Me C(O)MePd(PPh3)4, 5 mol%
TBAF (2 eq), THF
2 eq(S)-1-phenyl-1-(trifluorosilyl)ethane (34% ee)
50oC
41% (S)-1-phenyl-1-(4 formylphenyl)
ethane (32-34% ee)retention
(S)
(R)
0
20
40
20
40
%ee
40 50 60 70 80 90 100
temperature (oC)
SiF3
I
Br Br
SiF3
I
OO
Pd(PPh3)4, 5 mol%
TBAF (1.0 eq), THF
100oC (sealed tube)
37 h
78%
Pd(PPh3)4, 5 mol%
TBAF (1.0 eq), THF
100oC (sealed tube)
46 h
70%
α
β
γ
Exclusive γ substitution of allyltrifluorosilanes
Hiyama JACS 1990 (112) 7794
Temperature dependent retention of stereochemistry during transmetalation event
Since reductive elimination is known togo with retention of configuration at the alkyl center, the observedstereochemical outcome of thecross-coupling reaction is thought to bereflective of the transition state fortransmetalation.
SiPh
HF
F
F
F
Pd(Ar)LnF‡
SE2 (cyclic): retention
Si
Ph
H
SE2 (open): inversion
F
F
FF
Pd(Ar)Ln
F‡
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
· like silicon, tin is fluorophilic
Substrate assistedtransmetalation:
C
Sn
Br
N(TMS)2
N(TMS)2
Br
CO2Me
O
EtO
CO2Me
CO2Et
CO2Et
Sn
Br
N(TMS)2
N(TMS)2
BrPdII
PPh3
PPh3
MeO2C
Ph
Pd2dba3, 3 mol%
PPh3, Toluene, 90oC
71%
possible transmetalation intermediates
_
+
hypervalent tin
ISn
Br
N(TMS)2
N(TMS)2Br
Sn[N(TMS)2]2 t-Bu t-Bu
Sn
Br
N(TMS)2
N(TMS)2 Sn
F
N(TMS)2
N(TMS)2
F
TBAF
"Lampert's stannylene"
1 step
Lampert Chem. Commun. 1974, 895.
Pd(PPh3)4, 1 mol%
TBAF (3 eq)
dioxane, 110oC
12h 76%
_
In contrast to tetraorganotins, monoorganotinscan be used transfer value added alkyl substituents.
proposed transmetalating reagent: hypervalent tin species
F- assisted transmetalation:
Fouquet JOC 1997 (62) 5242
M.C. White, Chem 253 Cross-Coupling -105- Week of October 4 , 2004
General method for Stillecross- coupling with aryl chlorides
Me
ClBu3Sn
Me
Additive (1.1 eq) % GC Yield
none
NEt3CsCO3
NaOH
TBAF
KF
CsF
CsF (2.2)
Bulky, electron rich phosphines are are known to sucessfully promote the oxidativeaddition of Pd(0) to aryl chlorides in the Suzuki reaction (presumably via theformation 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 problematicstep was transmetallation. In order to test this hypothesis, he began to screen additivesknown enhance the reactivity of organotins towards transmetalation (Lewis bases andfluoride additives).
+
1.5% [Pd2(dba)3]6% Pt-Bu3
dioxane, 100 oC
12%
12
16
40
42
24
28
50
59
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.
Cl Bu3Sn
BrO
Bu3SnO
Csp3-Csp2 Stille couplings
ClMeO
Bu3Sn-Bu
BuMeO
Synthesis of sterically hindered biaryls
3.0 % Pd(P(t-Bu)3)2
2.2 eq. CsF
dioxane, 100 oC
89%
Room temperature aryl bromide Stille couplings
0.5% [Pd2(dba)3]1.1% Pt-Bu3
toluene, rt88%
1.5% [Pd2(dba)3]6% Pt-Bu3
2.2 eq. CsF
dioxane, 100 oC
Fu ACIEE 1999 (38) 2411Fu JACS 2002 (124) 6343
M.C. White, Chem 253 Cross-Coupling -106- Week of October 4, 2004
Negishi-Suzuki Coupling?
M
I "(PPh3)2Pd(0)"
generated in situ fromCl2Pd(PPh3)2 and DIBAL
THF
M
Li
MgBr
ZnCl
Al(Bu-i)2
HgCl
BBu3Li
SnBu3
ZrCp2Cl
temp (oC)
25
25
25
25
25
reflux
25
25
Product yield %
24
24
1
3
1
1
6
1
time (h)
3
49
91
49
trace
92
83
0
Negishi's metal counterion screen:
Negishi JOMC 2002 (653) 34.
Negishi chose to pursue thislead, rather than the organo-borane and organotin results
M.C. White, Chem 253 Cross-Coupling -107- Week of October 4, 2004
Suzuki Cross Coupling
B
C4H9
O
OHB
O
O
catecholboraneHC4H9
regiospecificsyn hydroboration
Br Ph
Pd(Ph3)4 (1 mol%)
NaOEt, benzenereflux
C4H9
Ph100% stereospecific the configurations of thevinylborane and vinylhalide are retained.Excellent method forthe construction ofconjugated dienes.86%
Representative Suzuki Cross Coupling
Catalytic Cycle:
LnPd(II)R1
XLnPd(II)
R1
R2
R1R2
R1 = aryl, vinyl, alkynyl
X = I>OTf>Br>>ClLn Pd(0)R1-X
oxidative addition
transmetalation
reductiveelimination
R2= alkynyl, aryl, vinyl, alkyl
The rate-determining step in
Suzuki-couplings with
reactive electrophiles (i.e.
R1-X= unsaturated iodides)
LnPd(II)R1
OR2
R2OMM = Na, K, Tl
XM
BY2
R3
BY2OR2
A variety of different organoboron reagents can beused to effect transfer of the R2 group viatransmetalation. Generally, electron rich unhindered organoboranes are most reactive towardstransmetalation. Organoboranes are non-toxic andair and moisture stable.*
R2 B(Oi-Pr)2
R2 B
O
O
pinacolborane
R2 B
O
O
B R2
9-BBN(9-Borabicyclo[3.3.1]nonane)
Organoboranes
*See: Chem 115 Suzuki Handout for comprehensive review of synthesis of organoboron compounds (A.G. Meyers/A. Haidle)
Palladium Catalysts
Pd(PPh3)4(most common)
Pd2(dba)3 + phosphinePd(0)
Pd(II)
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
B R
ROO B
R
RO B
R
R
boron ate-complexR'L2Pd
Organoboron compounds can be activated to undergo transmetalation by adding a nucleophilic base. Thiseffect is thought to be due, at least in part, to theformation of a hypervalent, anionic boron "ate"complex, which undergoes transmetalation morereadily and can coordinate the Pd metal.
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.
It is also proposed that a nucleophilic base candisplace the Pd-bound halide that results fromoxidative addition, to generate a metal center that is capable of coordinating the organoborane.
XRO
O
RB R
O
R
B
R
R'L2Pd R'L2Pd
R'L2Pd
O B
R'L2Pd C
HSoderquist has proposed a µ2-hydroxo-bridged, 4-centered cyclic transition state for thetransmetalation event, which has been shownto proceed with retention of configuration forboth coupling partners.
‡
Soderquist J. Org. Chem. 1998 63 461-470
M.C White, Chem 253 Cross-Coupling-109- Week of October 4, 2004
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 isthought to favor reductive elimination vs. competitive β-hydride elimination for at least tworeasons:
· The bidentate phosphine ligand enforces a cis geometry between the alkyl and vinyl/aryl substituents; this cis geometry is required for reductive elimination
· The large bite angle for this bidentate phosphine ligand results in a smaller anglebetween the alkyl and vinyl/aryl substituents. Recall that minimization of the angle between two metal-bound substituents is thought to promote reductive eliminationevent by increasing orbital overlap:
Suzuki JACS 1989 (111) 314see also Hayashi JACS 1984 (106) 158; Brown Inorg. Chimica Acta, 1994 (220) 249.Danishevsky ACIEE 2001 (40) 4544.
P
P
PhPh
Ph Ph
Fe
dppf, bis(diphenylphosphino)ferrocene
Pd
Cl
Cl
Suzuki: Ligand Effects for Csp3-Csp2 couplings
Me
MeOAc
S
SCO2Me
Me
Br
Me
MeOAc
S
S
Me
CO2Me
Me
MeOH
O
HO
Me
OH
1. 9-BBN-H
2.PdCl2(dppf), K2CO3
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
Cl B(OH)2
First report of effective Suzuki cross-coupling ofunactivated aryl chlorides:
Fu ACIEE 1998 (37) 3387.
1.5% [Pd2(dba)3]3.6% phosphine
2 eq. Cs2CO3
dioxane, 80oC
Aryl chlorides are traditionally unreactive towards Suzuki crosscouplings (recall: I> OTf > Br >>>Cl). This is thought to be duein part to the strength of the Ar-Cl bond (i.e. Ph-X: Cl (96kcal/mol), Br (81 kcal/mol), I (65 kcal/mol)). Reports ofreactivity were limited to reactions using activated substrates (i.e. aryl chlorides with electron withdrawing substituents). The lowcost and high availability of aryl chlorides, however makes themvery 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
Br B(OH)20.5% [Pd2(dba)3]
1.2% P(t-Bu)3
3.3 eq. KFTHF, rt
98%OMe
OMe
Chemoselective Suzuki couplings: first example of Pd-catalyzed cross-coupling that demonstrates higher selectivity for aryl chlorides than for aryl triflates
OTf
Cl
B(OH)21.5% [Pd2(dba)3]
3.0% P(t-Bu)3
3.3 eq. KFTHF, rt
95%
OTf
Phosphine % GC Yield
none
BINAP
dppf
Ph2P(CH2)3PPh2
Cy2P(CH2)2PCy2
PPh3
PCy3
PtBu3
P(o-tol)3
0
0
0
0
0
0
75
86
10
θ
---
---
---
---
---
145
170
182
194
CO v, cm-1
---
---
---
---
---
2069
2056
2056
2066
Bidentate ligands are ineffective. The optimal phosphine toligand ratio is between 1 and 1.5. Both pieces of data suggest that the active catalyst has a single phosphine attached.
Full paper: Fu JACS 2000 (122) 4020.
M.C. White, Chem 253 Cross-Coupling -111- Week of October 4, 2004
PdII
P(t-Bu)3
I
T-shaped monomer
164.6o
109.9o
94o
Bulky, electron-rich phosphines
Hartwig JACS 2002 (124) 9346.
Pd(dba)2 + 1 P(t-Bu)3Pd0 PO
t-Bu
t-Bu
t-Bu
Ph
Ph14e-
I
dba
dba
PdII
P(t-Bu)3
I
M.C. White, Chem 253 Cross Coupling -112- Week of October 4, 2004
Suzuki: Ligand Effects for Csp3-Csp3 couplings
n-DecBr
9BBNn-Hex
n-Decn-Hex
4 % Pd(OAc)28% ligand
1.2 eq. K3PO4THF, rt
+
Ligand % GC Yield
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
<2
<2
<2
9
<2
<2
<2
85
68
<2
<2
θ
---
---
128
132
145
142
---
170
160
182
194
CO v, cm-1
---
---
2085
2060
2069
---
---
2056
2059
2056
2066
Subtle Ligand Effects
Fu JACS 2001 (123) 10099.
n-Dec
<2
12
<2
27
<2
<2
<2
<2
6
21
14
· It is thought that the inability of palladium to effectivelymediate cross couplings between alkyl halides and alkylboranes is due to slow oxidative addition of the alkylhalides/triflates to palladium and facile β-hydrideelimination of the Pd alkyl intermediates. In the majorityof cases when oxidative addition occurs it is followed byβ-hydride elimination rather than the desiredtransmetalation event. Fu does not present any data thatindicates β-hydride elimination occurs after thetransmetalation event (would expect see 1-hexene). Theappearance of 1-decene as a bi-product indicates thatβ-hydride elimination competes with transmetalation after oxidative addition.
·electron rich, bulky phosphines may promote oxidative addition byincreasing electron density at the metal center and by promoting theformation of a coordinatively and electronically unsaturated complex.· electron rich, bulky phosphines may disfavor β-hydride eliminationboth by making the metal less electrophilic and blocking opencoordination sites at the metal center.
Pd0 PR3L
L = solvent or OAc
R
X
R Pd
H
X
PR3oxidative addition
PdX
PR3H
R
β-hydrideelimination
transmetalation R PdX
PR3R'
R'BR3
reductiveelimination
R
R'
M.C. White, Chem 253 Cross-Coupling -113- Week of October 4, 2004
Suzuki: Ligand Effects IIBuchwald Ligands (commercially available from Strem).General features: electron rich and bulky. Buchwald speculates thatthe 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 reductiveelimination. Subtle feature: o-phenyl may be oriented such thatπ-interaction with the metal occurs. It is not clear why this feature isimportant.
PCy2
Me2N
Pt-Bu2
Me2N
PCy2 P(t-Bu)2
1 2
3 4
Cl B(OH)2
Room temperature Suzuki cross-coupling of unactivated aryl chlorides:
1.5% Pd(OAc)23.0% 4
3 eq. KFTHF, rt
92%
Suzuki Csp2-Csp3 Coupling
Cl0.5% Pd(OAc)2
1.0% 4
3.3 eq. KF
THF, 65oC
C6H14
83%CO2Me
CO2Me
B nC6H14
Exceptionally high TON
B(OH)2O
Br
Pd(OAc)2 : 4 (1:2)
3.3 eq. KF
100oC
100,000,000 TN in 24h*
O
Ph
Note: only observed for this substrateBuchwald ACIEE 1999 (38) 2413.Buchwald JACS 1999 (121) 9550
M.C. White, Chem 253 Cross-Coupling -114- Week of October 4, 2004
Cl
Cl
Cl
MeO2C
Me
Me
Me
(HO)2B
(HO)2B
(HO)2B
OMe
MeO2C
Me
Me
Me
OMe
General conditions
Pd2(dba)3 (1.5 mol%)
L (3.0 mol%)
Cs2CO3 (2 equiv.)
dioxane, 80 oC, 1.5 h
+
+
+
99% yield
91% yield
89% yield
Nolan J. Org. Chem. 1999 64 3804-3805.
N N
Me
Me
Me
Me
Me
Me
Nucleophilic N-heterocyclic carbenes (imidazol-2-ylidenes): these so called "phosphine mimics" do not dissociate fromthe metal center, and thus an excess of ligand is not requiredto prevent agregation of the catalys to yield the bulk metal.
L =
generated in situ from the corresponding Cl salt
Suzuki: An alternative to phosphines
M.C. White, Chem 253 Cross-Coupling -115- Week of October 4, 2003
Suzuki: the “TlOH effect”
O
ORZOCOHN
O
O
O
RO OR
OR
O
O
OR
RO
RO
YO
OY
OY
OR
O
OR
OR
OR
OR
RO
OOR
OR
O
OR
RO
I
(HO)2B
+75
76
7576
R = CH2PhOMe(p)Y = Si(Me)2(t-Bu)Z = CH2CH2Si(Me)3
P
O
(MeO)2
Conditions Yield
KOH, 70 oC, 18 h
Pd(PPh3)4
Base
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
Roush, Org. Lett. 2000, 17, 2691-2694.
TlX source Yield
TlOEt
TlOH (10% stock solution)
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.
OTBDPS
O
Me
Me
I
TBSO
Me HO B(OH)2
Me Me
TBDPSO
TlX, Pd(PPh3)4
THF, H2O
OTBDPS
O
Me
Me
TBSO
Me
OTBDPS
Me Me
OHReagent age
--- 83%
1 month old 71%
TlOH (10% stock solution) 5 month old 50%
TlOH (from solid)) 12 month old 52%
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
I
CO2Me
t-BuO2C CO2t-Bu(HO)2B OH
Pd(PPh3)4, TlOEt
THF/H2O : 3/1 97% yieldTHF (anhydrous) 92% yield
CO2Me
t-BuO2C CO2t-Bu
HO
M.C. White/M.S. Taylor Chem 253 Cross-Coupling -117- Week of October 4, 2004
Suzuki : Formation of Hindered Aryl-Aryl Bonds
OMe
B(OH)2O
ONCO2t-Bu
N
O
TfO
NCO2t-Bu
N
O
Pd+
P
P
NCO2t-Bu
N
O
OMeO
O
OMeO
O
NCO2t-Bu
N
O
PdP P
Pd(dppf)Cl2, K3PO4
THF, 65°C
1:1 mixture of atropisomers Intermediate en route to Diazonamide A
Pd0(dppf)
OTf -
Pd0(dppf)oxidative addition
63%
OMe
B(OH)2O
O
transmetalation
reductive elimination
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 toreliably couple such an electrophile to a similarly hindered 2-substituted arylboronic acid highlights the utility of the Suzuki cross-coupling forthe 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
O O OO
B
O
O
O
O OTBS
O O
I
OTBS
TBS TBS PdCl2(MeCN)2
OO OO
B
O
O
O
O OTBS
O OPd
OTBS
TBSI
Ph3AsAsPh3
TBS
Pd(Ph3As)n Pd(Ph3As)n
OO OO
O
O
O
O OTBS
Pd
OTBS
TBSAsPh3
AsPh3
TBS
O O OO
O
O
O
O OTBS
OTBS
TBS TBS
Ph3As, AgO, THF Desilylation yields Rutamycin b.
70%
oxidative addition reductive elimination
transmetalation
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. (Notethat 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
O
I
OMe O
OMOM
OPMB
O
I
OMe O
OMOM
OPMB
BR2
O
Pd
OMe O
OMOM
OPMB
PP
I BR2
BH
O
OMe O
OMOM
OPMB
O
Pd
OMe O
OMOM
OPMB
P P
1. 9-BBN, THF
2. (dppf)PdCl2 (20 mol%)
Benzene / H2O, NaOH
80°C, 12 h (48%)
Synthetic studies towards Salicylihamide A
Pd0(dppf)
Pd0(dppf)hydroboration
oxidative additiontransmetalation
reductive elimination
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.