Stille-coupling
Comprehensive catalytic cycle and mechanistic factors

2014. 10. 11. M2 Hanada

1Index1.
2.

Introduction
Initial mechanistic approach
2-1. Original mechanistic proposal
2-2. Opposite two results

3.

Comprehensive catalytic cycle
3-1.Dual pathway
3-2. kinetic transmatalation analysis
3-3. Triflate (1) solvent effect
3-4.Short summary
3-5. Triflate (2) LiCl
3-6. additive study : Copper effect4.
5.

Summary
Perspective
5-1.Future direction of this field
5-2. What to overcome21. Introduction

OutlineStille coupling (Migita-Kosugi-Stille coupling)
R X+R'SnR"3PdLn

R R'+

X SnR"3(X = halide, OTf)
Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 301.
Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636.

Feature・Organostannane
・Mild condition → Broad substrate scope, synthetic applycation
John Kenneth Stille (1930-1989)
He received B.A and M.A. degrees from the University of
Arizona and received his Ph.D. from the University of Illinois,
where he studied under Carl Marvel.
Stille began his independent career at the University of Iowa
in 1957 before moving to Colorado State University in 1977.
.

3

1. Introduction

Organostannane Featured-d+CSnc (electronegativity) 2.55

1.96

◯ Air and moisture stable, tolerant of many functional groups.
→Due to low polarity of the C-Sn bond
◯ Synthesized under mild condition
× Highly toxic (and stannane byproduct is often inseparable .)Similar polarity bondHigh polarity bondd-d+d-d+d-d+

C Mg

C Zn

C Si

2.55 1.31

2.55 1.65

2.55 1.90

Grignard reagent Negishi coupling
Kumada couplingHiyama coupling

d-d+C B

2.55 2.04

Suzuki coupling

Espinet, P. ; Echavarren, A. M. Angew. Chem. Int. Ed. 2004, 43, 4704. 4

1. Introduction

Synthetic applications

Mild reaction condition and functional group tolerance→ Applicable to the late stage of total synthesis
Intermediate of Dynemicin A

The last step of Ganbierol
OH
MeO

MeH

O

H

I
IO

H
O H

HOH

O

H

H

O

H

O
H MeH

SnBu3

OH
MeO

MeO

HO
H

N

MeOAc
OOAc
HBrOH

OTBS

Pd(PPh 3)4, CuCl, LiCl
1:1 DMSO/THF, 60 °C, 43%O

MeHO

H

Me 3SnSnMe3
Pd(PPh 3)4,DMF, 75 °C, 78%

HO H

HOHO

HHO

HHO
H MeMeO

HOO

HMeOH

O

NOAc
OOAc
H

Sasaki, M. et al., J. Am. Chem. Soc. 2002, 124, 14983.
OTBS

Danishefsky, S. J. et al., J. Am. Chem. Soc. 1996, 118, 9509. 5

Index1.
2.

Introduction
Initial mechanistic approach
2-1. Original mechanistic proposal
2-2. Opposite two results

3.

Comprehensive catalytic cycle
3-1.Dual pathway
3-2. kinetic transmatalation analysis
3-3. Triflate (1) solvent effect
3-4.Short summary
3-5. Triflate (2) LiCl
3-6. additive study : Copper effect4.
5.

Summary
Perspective
5-1.Future direction of this field
5-2. What to overcome
62-1. original mechanistic proposal

Original mechanistic proposal
1986 StillePhL

L

Pd ClPdPhL

nBu 3SnCl

2n-Bu
1

nBu 3SnPh

PdL 2

Ph+PhPh3detectedOOClPhPh

PdL 2

reductiveelimination

L = PPh 3Phoxidativeaddition

31 and 4 are only detectable Pdcompound.(31P NMR)
It is suggested thattransmetalation is the ratedetermining.
detectedOL

OPdPhLPdLPhPhL

4nBu 3SnPh6
isomerizationOPhtransmetaration

LPdCl

rate-detemining?

PhL
5nBu 3SnCl

Stille, J.K. Angew. Chem. Int. Ed. 1986, 25, 508.

7

2-1. original mechanistic proposal

Stereochemistry of transmetalation

CldPhCOPd d+H D
C

Snd+R 3

L

Labadie, J. W. Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129.

8

2-2. Opposite two results

Retention? Inversion?
ClH DO

SnnBu 3

PhCH 2Pd(PPh 3)2Cl(4mol%)

D H

HMPA, 65 °C> 65% inversion

OLabadie, J. W. Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129.

H6OBz
SnBu3
94% eeClO

Ph(PPh 3)2Cl 2, CuCN
toluene, 75 °C, 74%
98% retention

H OBz
6O

Falck, J. R. et al., J. Am. Chem. Soc. 1994, 116, 1.
9

2-2. Opposite two results

Additive effect?
LiCl effect is different depending on ligand.

Espinet, P. et al. J. Am. Chem. Soc. 2000, 122, 11771.

Index1.
2.

Introduction
Initial mechanistic approach2-1. Original mechanistic proposal
2-2. Opposite two results

3.

Comprehensive catalytic cycle
3-1.Dual pathway
3-2. Kinetic transmatalation analysis
3-3. Triflate (1) solvent effect
3-4.Short summary
3-5. Triflate (2) LiCl
3-6. Additive study : Copper effect4.
5.

Summary
Perspective
5-1.Future direction of this field
5-2. What to overcome
113-1. Dual pathway

Dual pathway

Prof. Pablo Espinet(Spain)Prof. Espinet is founder (in 2007) anddirector of the Institute CINQUIMA(Center of Innovation in Chemistry andAdvanced Materials).
Research topics : molecular dynamics insolution, mechanism of the Stillereaction, other metal-catalyzed
reactions (Negishi, Sonogashira),
molecular materials.
Espinet, P. ; Echavarren, A. M. Angew. Chem. Int. Ed. 2004, 43, 4704. 12

3-2. Kinetic transmetalation analysis

Kinetics study of transmetalation
by 19F NMR monitoring

Solvent = THF, temperature = 322.6 K

ln([1] 0 - [1]1) = kobs t

The concentration of 1 is stoichiometrically linked to that of 2.
kobs-1 vs [AsPh3] and kobs vs [3a] : good linear dependence eachrobs = kobs [2a] =a = (2.32±0.09) ×10-5 s-1a [3a][AsPh 3] + b[2a]b = (6.9±0.3) ×10-4 mol L-1

Casado, A. L. Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978. 13

3-2. Kinetic transmetalation analysis

Dissociative pathway theory
Dissociative pathway :Ligand dissociation occurs previous to transmetalation.

Associativepathway

Dissociative
pathway

Experimental consistence
・Excess ligand retards the reaction.
・Modest donicity (AsPh3) ligand iseffective. (than PPh3)
・The first-order dependence on stannane(Slow transmetalation from C)

Casado, A. L. Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978.

143-2. Kinetic transmetalation analysis

Experimental inconsistency of thedissociative pathway
Experimental result

Theoritical equation
If : Late dissociation (rate-determining)robs = kobs [2a] =a [3a][AsPh 3] + b[2a]inconsistent→ zeroth order with respect to [2a]If: Fast dissociationrobs = kobs [2a] =k'2Kdis [3a] total→ 12% of 3a should be dissociated as C,= 1.3 ´ 10 -4 mol L-1 but it was not detected.

Kdis + [AsPh 3]

k'2 = 1.8 ´ 10-1 s-1 Kdis
Kdis = k'1/k'-1[2a]Casado, A. L. Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978.

15

3-2. Kinetic transmetalation analysis

Associative (cyclic) transmetalation
Cyclic pathway equation
d [IV]/dt = k1[2a][3a] - k-1[IV][AsPh 3]-k2[IV] = 0[IV] =

k1[2a] [3a]robs = k2 [IV]k-1[AsPh 3] + k2

k1k2 [3a]robs = kobs [2a] =k-1[AsPh 3] + k2[2a]k1 = 0.034 mol-1 L s-1

Stereochemistry
Retention

k2/k-1 = 6.9 ´ 10 -4 mol L -1

Reasonable

Experimental resultrobs = kobs [2a] =a [3a][AsPh 3] + ba = (2.32±0.09) ×10-5 s-1[2a]b = (6.9±0.3) ×10-4 mol L-1(trans-[PdR1R2L] was not observed,
so cis addition was proposed.)
Casado, A. L. Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978.

16

3-3. Triflate (1) solvent effect

Triflate : (1) Solvent coordinating
Neutral intermediate : Previously proposed solvent coordinatng intermediate
LR PdL(S)(S)X

R Pd
S = solvent

XLFarina, V. Pure & Appl. Chem. 1996, 68, 73.

Cationic intermediates were characterized by Espinet et al.
CDCl3, CH2Cl2, PhCl : non-coordinating

THF: coordinating

Espinet, P. et al. J. Am. Chem. Soc. 2000, 122, 11771.

17

3-3. Triflate (1) solvent effectPolar solvents

Stablew/o PPh3 w/ PPh3
62.5%

53%

w/o PPh3 w/ PPh3

w/o PPh3 w/ PPh3

17.5%

20%

0%

47%

In polar coordinating solvents, solvent coordinating complex is stable eventhough X is halide.
(NMP(less coordinative than HMPA) is able to displace triflate and PPh3trans to R, but cannot displace halides trans to R or PPh3 cis to R)
Espinet, P. et al. J. Am. Chem. Soc. 2000, 122, 11771.

18

3-3. Triflate (1) solvent effectSE2 open pathway:
reasonable mechanism for inversion
ClH D
SnnBu 3O

PhCH 2Pd(PPh 3)2Cl(4mol%)

HMPA, 65 °C> 65% inversion

First stille proposed intermediate
CldPhCOPd d+D H

OEspinet et al. proposed intermediate

H DC

Snd+R 3

L・Associative pathway
・HMPA coordinated intermediate
・The bridging ability of HMPA is poor.
Espinet, P. et al. J. Am. Chem. Soc. 2000, 122, 11771.

19

3-4. short summary

Short summary
Cyclic:
X = Halide
Stereochemistry: retention
Solvent: non-coordinatingOpen:
X = Halide, or –Otf
Stereochemistry: inversion
Solvent: coordinating(non-coordinating(-OTf)

20

3-5. Triflate (2) LiCl

Triflate : (2) Role of LiCl
LiCl effect is different depending on ligand.

Espinet, P. et al. J. Am. Chem. Soc. 2000, 122, 11771.
21

3-5. Triflate (2) LiCl

Oxidative addition speedClFFOTf
Cl+SnBu3

F
(1)

(2)

PdL 4, (LiCl)

ClFClFF(3a)

AsPh3 is less coordinating ligand than PPh3. Thus, it is supposed effective.

PPh3:
Oxidative addition is fast.

AsPh3:
Oxidative addition is slow.
Espinet, P. et al. J. Am. Chem. Soc. 2000, 122, 11771.

22

Difference between ligands

3-5. Triflate (2) LiCl

PPh3:
Oxidative addition is fast.

AsPh3:
Oxidative addition is slow.

PPh3 in THF:
LiCl retards the reaction.
AsPh3 in THF:
LiCl accelerates the reaction.
Espinet, P. et al. J. Am. Chem. Soc. 2000, 122, 11771.

23

3-5. Triflate (2) LiCl

Mechanistic explanation
L = PPh3 (rds is transmetalation.)

L = AsPh3 (rds is oxidative addition.)
slow

fast

Fast transmetalation

accelerate

Slowtransmetalation=Retarded

LiCl is effective in only slow oxidative addition reaction.
(In some reactions, other effect is also suggested.)
Espinet, P. et al. J. Am. Chem. Soc. 2000, 122, 11771.

24

Additive study : copper effect

3-6. Additive study :Copper effect

Copper effect: Cu(I) salt accelerate the reaction
I Pd 2dba3, dioxane
SnBu3
CuI, 50 °C, ligand

In the absence of CuI

In the presence of CuI

Liebeskind, J. S. et al. J. Org. Chem. 1994, 59, 5905.

25

3-6. Additive study :Copper effect

Kinetic study of copper effect
ClF

F
ClFL
Pd I
L

(5 mol%)ClF

F

ClCuI, L(10 mol% each)
I+R 2 SnBu3

F
R2F
THF

ClF

L = PPh 3, AsPh3
SE2 cyclic reaction

k0obs ® Pd onlyClF

Characterized by 19F NMR.

k'obs ® Pd : L : Cu =1 : 2 : 0k''obs ® Pd: L : Cu = 1 : 2 : 2(k"obs - k'obs)/(k0obs - k'obs) ® the fraction of autoretardation compensated by CuI
Casado, A. L.; Espinet, P. Organometallics, 2003, 22, 1305. 26

Evaluation of the copper effect

3-6. Additive study :Copper effect

19F NMR.
Nonewby=1
Pd : L : Cu: 2: 0k0obs® PdPd species
only k'wereobs ®observed→CuI
did not react with Pd complex directly nor promote the dissociation of''k obs
® Pd: L : Cu = 1 : 2 : 2
theligand.

(k"obs - k'obs)/(k0obs - k'obs) ® the fraction of autoretardation compensated by CuICuI compensates 30% autoretardation for PPh3, and 1% for AsPh3. (R2 = aryl)
In the presence of CuI[AsPh3]free = 1.5 × 10-2 mol L-1 → CuI captured 25% released AsPh3.
[PPh3]free = 2.1 × 10-4 mol L-1 → CuI captured 99% released PPh3.

Copper salt is more effective scavenger when the ligand is PPh3.
Casado, A. L.; Espinet, P. Organometallics, 2003, 22, 1305.

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Index1.
2.

Introduction
Initial mechanistic approach
2-1. Original mechanistic proposal
2-2. Opposite two results

3.

Comprehensive catalytic cycle
3-1.Dual pathway
3-2. Kinetic transmatalation analysis
3-3. Triflate (1) solvent effect
3-4.Short summary
3-5. Triflate (2) LiCl
3-6. Additive study : Copper effect4.
5.

Summary
Perspective
5-1.Future direction of this field
5-2. What to overcome
284. Summary

Summary

Dual pathway catalytic cycle
・Open pathway → inversion products
・Cyclic pathway→ retention ones.
・Coordinative solvent gives openpathway products.
・Rate-determining step:
usually transmetalation, but in somecases it is oxidative addition.
(ex. X = OTf, L=AsPh3)
・LiCl: effective only slow oxidativeaddition (ex. X = OTf,L = AsPh3)
・CuI: scavenger of free ligand (forespecially PPh3 rather than AsPh3)

29

Index1.
2.

Introduction
Initial mechanistic approach
2-1. Original mechanistic proposal
2-2. Opposite two results

3.

Comprehensive catalytic cycle
3-1.Dual pathway
3-2. kinetic transmatalation analysis
3-3. Triflate (1) solvent effect
3-4.Short summary
3-5. Triflate (2) LiCl
3-6. additive study : Copper effect4.
5.

Summary
Perspective
5-1.Future direction of this field
5-2. What to overcome30

5. Perspective

Perspective
0. The author suggests that this dual reaction pathways
might be found in reactions like Suzuki-Miyaura coupling.
(Due to similarity of the polarity of boron compound)
1. Furture direction of this field・New cocatalyst - Development of the current reaction
paradigm
・Giving to an explain to some phenomenon (selectivity etc.)
・Changing from Palladium to another metal
2. What Stille coupling (or other reaction) should overcome
next?
31

5-1. Future direction of this field

New cocatalyst: Gold

Gold cocatalyst improves the yieldeven in some reaction which
doesn’t proceed at all without gold.

Espinet, P. et al. Angew. Chem. Int. Ed. 2013, 52, 2189.

32

5-1. Future direction of this field

Giving explanation to some phenomena
・Regiocontrolled oxidative addition with CuIOOBr+BrO

PdL 2Br

Br5a: X = Br, 5b: X=I・Cu transmetalation possibility
SnBu3

PdL 2X

Oconditions
L = PPh 3

1OOPd(PPh 3)4
Br (5 mol%)

6Cho, C. –G. et al. J. Am. Chem. Soc. 2003, 125, 14288.

CuI
NMP, 16 h

Bu 3SnI (+ SM + Bu 3SnOH)※Only in polar solvents
Liebestkind, et al. J. Org. Chem. 1994, 59, 5905. 33

5-1. Future direction of this field

Changing from Pd to another metal
・CuTC
RI+1.5 equiv CuTCR'SnBu3

CuTC =R R'NMPCu OSO
Alled, G. D.; Liebeskind, L. S J. Am. Chem. Soc. 1996, 118, 2748.
Wang,M; Lin, Z.; Organometallics 2010, 29, 3077.

Total Synthesis of Formamicinone

Roush, W. R. et al. Org. Lett. 2003, 5, 377.
34

5-2. What to overcome

What Stille coupling (or other reaction)
should overcome? (just my view)✕Sn toxicity – high toxicity, stoichiometric amount
Possible answer
1. Reducing Sn →catalytic amountof tin?
R X2LX Pd R 2

R 33Sn R1

M XLin situ
Organostannane
generation ?

PdL 2L

M R1

L Pd R 2

R 33Sn X

R1

R1 R 2

2. Some other metals replace tin?
(cf: C-H sililation, C-H borylation )d-d+CSnc (electronegativity) 2.55

1.96

Or others?

d-d+

C Si

2.55 1.90

d-d+

C B

2.55 2.04

Thank you for your kind attention.

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