Myers The Stille Reaction Chem 115

Recent Reviews:
• Oxidative addition initally gives a cis complex that can rapidly isomerize to the trans isomer:
Williams, R. Org. Synth. 2011, 88, 197–201.
Selig, R.; Schollmeyer, D.; Albrecht, W.; Laufer, S. Tetrahedron 2011, 67, 9204–9213. R fast L
PdL2
Tietze, L. F.; Dufert, A. Pure Appl. Chem., 2010, 82, 1375–1392. R–I L Pd I R Pd I

L L
Generalized Cross-Coupling: cis trans

Typically: R–X R'–M catalyst R–R' M–X Casado, A. L.; Espinet, P. Organometallics 1998, 17, 954–959.
2 • M = Sn, B, Zr, Zn
• R and R' are sp –hybridized
• !-hydride elimination can be a serious side reaction within alkyl palladium intermediates.
This typically requires a syn coplanar alignment of hydride and palladium:

• X = I, OSO2CF3, Br, Cl • catalyst = Pd (sometimes Ni)

H Pd(II)L2X
+ HPd(II)L2X

Mechanism:

• A specific example: • Oxidative-addition and reductive-elimination steps occur with retention of configuration

Pd catalyst 2
for sp -hybridized substrates.
p-Tol–Br + n-Bu3Sn–Ph p-Tol–Ph + n-Bu3Sn–Br

Pd(II) • Transmetalation is proposed to be the rate-determining step with most substrates.

• Relative order of ligand transfer from Sn:

p-Tol–Ph Pd(0)Ln p-Tol–Br
alkynyl > alkenyl > aryl > allyl = benzyl > "-alkoxyalkyl > alkyl

reductive elimination oxidative addition

• Electron-rich and sterically hindered aryl halides undergo slower oxidative addition and
p-Tol–Pd(II)Lm–Ph p-Tol–Pd(II)Lm–Br are often poor substrates as a result.

• Electron-poor stannanes undergo slower transmetallation and are often poor substrates
n-Bu3Sn–Br n-Bu3Sn–Ph
as a result.
transmetalation

• Many functional groups are tolerated (e.g., CO2R, CN, OH, CHO).

Andrew Haidle, Jeff Kohrt, Fan Liu

1
 Myers The Stille Reaction Chem 115
Stille Reaction conditions: Cl

• Catalyst: Commercially available Pd(II) or Pd(0) sources. Examples: Ph Ph

N N
Pd(PPh3)4 Pd(OAc)2 Pd2(dba)3 N
N Ph OCH3 N OCH3
O
N OCH3 Pd(OAc)2 (8 mol%)
dba = 4 (24 mol%) F
dioxane Ph
Sn(n-Bu)3
F N N
microwave
o OCH3
101 C, 94%
• Ligand Additives: Sterically hindered, electron-rich ligands typically accelerate coupling.

This catalyst system and microwave heating limited the formation of a destannylated byproduct.
NR Cy
Selig, R.; Schollmeyer, D.; Wolfgang, A.; Saufer, S. Tetrahedron 2011, 67, 9204 - 9213
P P Cy
N N R iPr iPr
t-Bu 2
N R • Additives: CuI can increase the reaction rate by >10 :
t-Bu P
I Pd2(dba)3 (5 mol %)
iPr t- Bu
n-Bu3Sn PPh3 (20 mol %)
1 tris-N-iso-butyl Ar-Cl 4 "X-Phos" 5
dioxane, 50 °C
2 N-iso-butyl-bis-N-benzyl Ar-Cl, Ar-Br
3 tris-N-benzyl Ar-Cl, Ar-Br, Ar-OTf, vinyl-Cl mol % CuI relative rate
(leading references in examples below) 0 1
• Examples:
10 114

• The rate increase is attributed to the ability of CuI to scavenge free ligands; strong ligands
Cl n-Bu3Sn in solution are known to inhibit the rate-limiting transmetalation step.

N N Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905–5911.
Pd2(dba)3 (1.5 mol%)
3 (3.5 mol%) • Stoichiometric Cu itself can sometimes mediate cross-coupling reactions under mild
o
CsF, Dioxane, 110 C conditions, without Pd:
97%
O
Verkade, J.G.; Su, W.; Urgaonkar, S.; McLaughlin, P.A. J. Am. Chem. Soc. 2004, 126, 16433-
Sn(n-Bu)3 CH3 O CuO S CH3 O
(1.5 equiv)
16439
Cl Pre-milled CH3
H3C CH3 H3C CH3 I CH3 NMP, 23 °C, 15 min
Cl Cl
Pd(OAc)2, 4
89% O
(1–2 mol%)
MeO2C n-Bu3Sn CsF, DME CH3
CH3 MeO2C Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-2749. NMP = N CH
3
o
80 C, 96%

Buchwald, S.L.; Naber, J.R. Adv. Synth. Catal. 2008, 350, 957-961
Andrew Haidle, Jeff Kohrt

2
 Myers The Stille Reaction Chem 115
• Additives: fluoride can coordinate to the organotin reagent to form a hypervalent tin species • A general Stille cross-coupling reaction employing aryl chlorides (which are more abundant

that is believed to undergo transmetallation at a faster rate: and less expensive than aryl iodides, aryl bromides, and aryl triflates) has been developed:

OTf Cl OEt Pd2(dba)3 (1.5 mol %) OEt

n-Bu3Sn Pd(PPh3)4 (2 mol %) P(t-Bu)3 (6.0 mol %)

THF, 62 °C n-Bu3Sn CsF (2.2 equiv)
CH3O CH3O
t-Bu t-Bu dioxane, 100 °C
Salt (equiv) relative rate yield 98%
LiCl (3) 1 >95
Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1999, 38, 2411–2413.
Bu4NF•H2O (1.3) 3 87

Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033–3040. • 1-substituted vinylstannanes can be poor substrates for the Stille reaction, probably due to steric
effects. However, conditions have been discovered that provide the desired Stille coupling
• Examples: product in excellent yields:
OMOM
n-Bu3Sn (1.2 equiv)
10% Pd/C (5 mol%) CH3
I LiF, Air O OH CH OMOM
n-Bu3Sn O 3
NMP, 140 ºC ONf
MeO MeO Pd(PPh3)4 (10 mol %) CH3
96% LiCl (6 equiv), CuCl (5 equiv) OH CH3
DMSO, 60 °C, 45 h

Nf = n-C4F9SO2 92%
Sajiki, H.; Yabe, Y.; Maegawa, T.; Monguchi, Y. Tetrahedron 2010, 66, 8654–8660

Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600–1605.
• The following difficult coupling between an electron-rich aryl halide and electron-poor
aryl stannane was accomplished using both copper and fluoride additives:
• Examples of Stille coupling in drug discovery:

O
Br NO2 PdCl2 (2 mol%) NO2 N OMe
O O H
O
Pt-Bu3 (4 mol%) N Br H
N

OMe N N
MeO OMe n-Bu3Sn N
CuI (4 mol%), CsF MeO OMe H H

DMF, 45 ºC n-Bu3Sn
89% N
N
Pd(PPh3)2Cl2 (7 mol%)
CuO, DMF, 130 ºC
NC microwave, 89% NC

Baldwin, J. E.; Mee, S. P.H.; Lee, V. Chem. Eur. J. 2005, 11, 3294–3308
Smallheer, J. M.; Quan, M. L.; Wang, S.; Bisacchi, G. S. Patent: US2004/220206 A1, 2004

Andrew Haidle, Jeff Kohrt

3
 Myers The Stille Reaction Chem 115
• Industrial examples of the Stille Reaction in Large-Scale Process Chemistry

• Many organostannanes are toxic and therefore tolerance for residual tin in pharmaceutical products is
Br N Et O Sn(n-Bu)3 O
NEt extremely low. The following examples show methods by which residual tin can be minimized:
O S S O S
HN O S HN O
Pd(PPh3)4 (10 mol%) CH3 Cl CH3 Cl
MeO n-Bu4NCl, DMF MeO N S Pd(PPh3)4 (5 mol%) N S
110 ºC, 52% VEGFR2 Kinase Inhibitor Sn(n-Bu)3 + I
N N o N
DMF, 95 C N
(672 g) (535 g) 67%
Harris, P. A.; Cheung, M.; Hunter III, R. N.; Brown, M. L.; Veal, J. M.; Nolte, R. T.; Wang, L.;
H
Liu, W.; Crosby, R. M.; Johnson, J. H.; Epperly, A. H.; Kumar, R.; Luttrell, D. K.; Stafford, J. A.
N
J. Med. Chem. 2005 , 48, 1610–1619
CH3
H2N
• Both AsPh3 and CuI are required to provide the coupled product in the following example:
t-BuOH, DCE

NC O 100 ºC, 52%

NC H
Sn(CH3)3 O N
N
H

O N
CO2Me H O CH3 HN CH3
NH I CO2Me
H3C CH3 Pd2(dba)3, AsPh3 NH N S
CuI, DMF N
H3C CH3
60 ºC, 55% N

VEGFR Kinase Inhibitor

Kohrt, J. T.; Filipski, K. J.; Rapundalo, S. T.; Cody, W. L.; Edmunds, J. J. Tetrahedron Lett. 2000,
41, 6041–6044
• The Stille reaction was the only reliable coupling method at > 50-g scale.

• Note the presence of both OH and NH groups is tolerated under Stille coupling conditions: • Residual tin was minimized by slurring the coupling product in MTBE followed by
recrystallization from ethyl acetate.

SEM SEM
N
N N Sn(n-Bu)3 N N
Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.; Munchhof, M. J.; Marx, M. A.;
Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Proc. Res. Dev. 2003, 7, 676 - 683
BrN S N N

O NH CH3 Pd(PPh3)4, CuI S O NH CH3

OH DMF, 80 ºC OH
H3C H3C
CH3 84% CH3

Hendricks, R. T.; Hermann, J. C.; Jaime-Figueroa, S.; Kondru, R. K.; Lou, Y.; Lynch, S. M.; Owens,
T. D.; Soth, M.; Yee, C. W. Patent: WO2011/144585
Jeff Kohrt

4
 Myers The Stille Reaction Chem 115
2 3
Alkyl Stille Coupling Reactions - sp -sp :

TESO Tf2O TESO • Initially, "alkyl" Stille couplings were mostly limited to the transfer of Me, Allyl and Benzyl groups.
H H CH3 H H CH3
H3C O H3C OTf • Coupling of higher n-alkyl groups was limited by !-hydride eliminations. This limitation has
N TMP, DIEA N been overcome by innovations in the ligand and Pd sources.
O CO2PNB O CO2PNB 2 3
• sp -sp coupling: alkyl-Br + vinyl-SnR3
used crude
O
n-Bu3Sn OH O CH3 [(allyl)PdCl]2 (2.5 mol%) O CH3
+ –
O [HP(t-Bu)2Me] BF4 (15%)
Pd(dba)2 (13 mol%)
P(2-furyl)3 (32 mol%)
+ n-Bu3Sn Me4NF, 3 Å MS
Br
ZnCl2, HMPA, 70 ºC THF, 23 ºC OTHP
OTHP
53%

N -OTf TESO OH Fu, G.C.; Menzel, K. J. Amer. Chem. Soc. 2003, 125, 3718.
H H CH3
N H3C • using the electron-rich PCy(pyrrolidinyl)2 ligand allows couplings of both vinyl and aryl
CONH2 N stannanes with higher alkyl bromides:
TESO H H CH3 O

H3C N SO2
CO2PNB n-Bu3Sn

N 47% 2-steps OMe

O CO2PNB 1.54 kg, 80% pure
[(allyl)PdCl]2 (2.5 mol%)
EtO PCy(pyrrolidinyl)2 (10%) EtO
L-786,392, a "carbapenem" antibiotic candidate with activity against Br
methicillin-resistant Staphylococcus aureus (MRSA). O O 71% OMe
Me4NF, 3 Å MS
MTBE, 23 ºC

Fu, G.C.; Menzel, K.; Tang, H. Angew. Chem. Int. Ed. 2003, 42, 5079.
• HMPA, a somewhat toxic ligand, was essential for successful coupling.
• Secondary Alkyl Couplings: secondary alkyl halides are also prone to undergo !-hydride
• Tin residues were minimized by silica-gel chromatography followed by recrystallization
from hexane. elimination in Stille coupling. This limitation has been overcome by using a Ni catalyst:

Yasuda, N.; Yang, C.; Wells, K. M.; Jensen, M. S.; Hughes, D. L. Tetrahedron Lett. 1999, 40,
427– 430. NiCl2 (10 mol%)
Br
+ 2,2'-bipyridine (15%)

Cl3Sn KOt-Bu
t-BuOH, i-BuOH
o
60 C, 72%

The use of PhSnCl3 facilitated the removal of toxic by-products during reaction work-up.
Fu, G.C.; Maki, T.; Powell, D.A. J. Amer. Chem. Soc. 2005, 127, 510 Jeff Kohrt

5
Examples:
• Alkenes as coupling partners: O CH3 Pd(PPh3)4 (10 mo l%)

OTIPS O O + CH3
Pd2(dba)3 (20 mol %) O
CH3 Bu3Sn LiCl, THF
H3C
OTES O N CH3 OTBS 80 °C, sealed tube
OTf
CH3 CH3 CdCl2 (1.8 equiv)
+I 100%
O H Ph (i-Pr)2NEt, NMP
O CH3 CH3
O 40˚C, 53 h

SnBu3 OTBDMS 69%

CH3 O
CH3
CH3 O CH3 CH3 O
O O N(CH3)2 OTIPS H3 C
CH3
H O OTES CH3 O CH3
CH3 CH3 CH3 CH3
O OTBS
O O O Jatrophone
H H H
O O N Han, Q; Wiemer, D. F. J. Am. Chem. Soc. 1992, 114, 7692–7697.
O
H
H CH3
H O Ph
CH3 OTES
O OTBDMS CH3 O O
OCH3
OCH3

CH3O OCH3 ON
H O
(+)-A83543A, (+)-Lepicidin Bu3Sn
I O
H
• CdCl2 serves as a transmetalation cocatalyst. Without it, homodimerization of CH3 OTBS OCH3
O CH
both coupling partners was observed. OTIPS
O 3

Evans, D. A.; Black, W. D. J. Am. Chem. Soc. 1993, 115, 4497–4513.

CH3 OCH3 CH3 CH3 1. [(2-furyl)3P]2PdCl2 (20 mol %)
HN (i-Pr)2NEt, DMF, THF, 23 ˚C, 7 h
CH3 Pd(PPh3)4 (10 mol %) CH3 O CH3 74%
CH3 O I DMF, 23 ˚C, 72 h H3C H H H 2. TBAF, AcOH, 0 °C
O H OH
O O 3. HF•Py, Py, THF, 23 °C
HO2C H H 61% HO2C H
CH3 H3 C H CH3 N 61%
CH3 OCH3 O
+
Indanomycin (X-14547A) H O
CH3 O H OCH3 Smith, A. B.; Condon, S. M.; McCauley, J. A.;
O HN O OH

H H Burke, S. D.; Piscopio, A. D.; Kort, M. E.; CH OH Leazer, J. L.; Leahy, J. W.; Maleczka, R. E.
Bu3Sn O 3 J. Am. Chem. Soc. 1995, 117, 5407–5408.
H Matulenko, M. A.; Parker, M. H.; Armistead, D. M.; CH3 OCH3 CH3 CH3

CH3 Shankaran, K. J. Org. Chem. 1994, 59, 332–347. Rapamycin

Andrew Haidle

6
Further Examples:
CH3 • Allylic, benzylic halides:
H OH Pd(CH3CN)2Cl2 CO2CH3
O O SnBu3 (20 mol %)
CH3
OCH3 O O Br CH3
N Bu Sn (i-Pr)2NEt
I H 3 DMF, THF Pd(PPh ) (10 mol %)
(CH ) Sn
34

I O O 25 ˚C, 24 h CH3 + 3 3 OTHP CHCl3, reflux, 48 h

CH3 O OH H OCH3 28%
O 65%
O CH OH O OTDS
3
CO2CH3 CO2CH3
CH3 OCH3 CH3 CH3 CH3
H OH
O O
O O CH3
CH3 OCH3 O
N CH3 CH3 CH3 OTHP
H
O O H O
O
O OH H O OTDS
CH3 OCH3 O O
Acerosolide
O CH OH
3

CH3 OCH3 CH3 CH3 Paquette, L. A.; Astles, P. C. J. Org. Chem. 1993, 58, 165–169.
Rapamycin

CH3
Nicolaou, K. C.; Chakraborty, T. K; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. TBSO O
HO O PdCl2(CH3CN)2 (3 mol %)
1993, 115, 4419–4420. O + H PPh3 (5 mol %)
TBSO Cl H DME, reflux
• Acid chlorides can be used as coupling reagents (the Stille reaction, as first reported, used Bu3Sn O OCH3
75%
acid chlorides).

Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636–3638.

O
O O
CH3
CH TBSO O HO O
O Bu3Sn O BnPdCl(PPh3)2 (2.5 mol %) O HO 3
O H H
CuI (2.5 mol %) O O
+ CH3
CH Cl TBSO O OCH3
3
O THF, 50 ˚C, 15 min OH
H2N O
H2N
93%
Monocillin I

Lampilas, M.; Lett, R. Tetrahedron Lett. 1992, 33, 777–780.

Liebeskind, L. S.; Yu, M. S.; Fengl, R. W. J. Org. Chem. 1993, 58, 3543–3549. Andrew Haidle

7
Further Examples:
I

I CH3 Bu Sn O CH3 CH3 O CH

I
3
Pd2(dba)3•CHCl3 (15 mol %) 3 CH3 CH3
O O O 3 HO
CH3 AsPh3 (0.6 equiv) O O CH O
SnBu3
NH O O H iPr2NEt (10 equiv) H
NH O CH3 O OH
N
O N
N O DMF, 25 °C, 36 h N O CH3 NH
NH NH CH 3 (2 equiv)
CH3 CH3
62% O
CH3
OH OH CH3

Pd2(dba)3•CHCl3 (10 mol %)

AsPh3 (0.2 equiv)
iPr2NEt (10 equiv)
DMF, 40 °C, 5 h

45%

CH3 CH3 CH3 CH3 CH3 CH3

HO OH HO O CH3
O OH O O OH O OH O O O
CH3 CH3
CH 3 NH CH3 2 N H2SO4 (2.0 equiv) CH NH CH3
NH
OO H
3
H CH3
O NHO O N O N
N O O THF : H2O 4 : 1, 25 °C, 7 h N NH O
NH
CH3 CH3 33% (plus 50% starting material) CH3 CH3
CH3
CH3
OH OH

Sanglifehrin A

• In the first Stille coupling, none of the regioisomeric coupling product was isolated.

Nicolaou, K. C.; Murphy, F.; Barluenga, S.; Ohshima, T.; Wei, H.; Xu, J.; Gray, D. L. F.; Baudoin, O. J. Am. Chem. Soc. 2000, 122, 3830–3838.
Andrew Haidle

8
Examples involving copper(I):
• The copper(I)-mediated coupling of a vinyl stannane and a vinyl bromide succeeded when • Liebeskind's copper(I) thiophene-2-carboxylate promoted coupling reaction was used for the
palladium catalysis failed. Note the selective transformation of the vinyl triflate to the vinyl total synthesis of concanamycin F. This reaction failed intramolecularly when the two coupling
stannane in the presence of the vinyl bromide. partners had already been joined via the ester linkage.

CH3 I
OTf
CH3 CH3 Et CH3 O
OTES
H CH TESO
TBSO 3 Br OCH3
CH3 Pd(Ph3)4 (2 mol %)
H CH3

CH3 CH3 LiCl (6 equiv) CH3 CH3 OCH3

Bu Sn OCH3
(CH3)3SnSn(CH3)3 (2 equiv)
THF, reflux, 16 h
3 OR OBz
Sn(CH3)3 R = DEIPS
HO CH3
O CH3 CH3
S
CH3 CH3 CuO
H CH3 NMP, 20 °C, 1 h
CH3
TBSO H Br CH3
CuCl (3 equiv) 89%
CH3 CH3
DMF, 60 °C, 1 h CH3 OCH3 OBz

CH3 CH3 Et CH3 OR

HO CH3
OTES R = DEIPS
O

TESO CH3 CH3

OCH3
CH3 CH3
CH3 CH3 OCH3
H CH3 TBAF (2.5 equiv)
TBSO H
THF, 50 ° C, 14 h
CH3 CH3
55%, three steps
CH3
CH3 CH3
CH3 OCH3 O •CH3
Aegiceradienol CH3 CH3
Et CH3 OH
O OH
OH
HO O OH
CH3 CH 3
H CH3
CH3 CH3 OCH3
HO H
Concanamycin F
CH3 CH3
Paterson, I.; Doughty, V. A.; McLeod, M. D.; Trieselmann, T. Angew. Chem., Int. Ed. Engl. 2000,
Huang, A. X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999–10003.
39, 1308–1312. Andrew Haidle

9
Synthesis of Aryl and Vinyl Stannanes:

Bu3SnCl (0.85 equiv) Bu3Sn H

SnR3 H Li • NH2CH2CH2NH2 THF, 0 °C → 25 °C, 18 h

33%

Bu3SnH (1.2 equiv)

• Directed ortho metalation followed by addition of a stannyl chloride is a standard method.
Snieckus, V. Chem. Rev. 1990, 90, 923–924. AIBN (2.4 mol %) Bu3Sn
Bu3Sn H SnBu
90 °C, 6 h 3

OMOM OMOM 90%

t-BuLi (3.8 equiv)
Et2O, 23 °C, 2 h;
SnBu3 Renaldo, A. F.; Labadie, J. W.; Stille, J. K. Org. Synth. 1988, 67, 86–97.
Bu3SnCl (4.3 equiv)
OMOM OMOM
74%

Tius, M. A.; Gomez-Galeno, J.; Gu, X.; Zaidi, J. H. J. Am. Chem. Soc. 1991, 113, 5775-5783. CH3Li (1.2 equiv), THF, –78 °C, 2 h;
ClCO2Et (1.2 equiv), 2.5 h; CH3OH
Bu3Sn Bu Sn
SnBu3 3 CO2Et
[(CH3)3Sn]2 59%

Pd(PPh3)4 (5 mol %)
BrN (CH3)3Sn N
Renaldo, A. F.; Labadie, J. W.; Stille, J. K. Org. Synth. 1988, 67, 86–97.
OCH3 DME, 80 °C, 15 h OCH3
97%

Benaglia, M.; Toyota, S.; Woods, C. R.; Siegel, J. S. Tetrahedron Lett. 1997, 38, 4737-4740. CH3 OH Bu3SnOCH3, Et2O, 23 °C; CH3 OH

I O Bu3Sn O
Bu3Sn SnBu3

PdCl2(CH3CN)2 (5 mol %)
R' SnR3
69%

Thibonnet, J.; Abarbi, M.; Parrain, J.-L.; Duchêne, A. Synlett 1997, 771–772.
Bu3SnH (1.1 equiv)
CH3 AIBN (3 mol %) Bu3Sn CH3 + CH3
OTHP 95 °C, 3 h OTHP Bu3Sn OTHP
92% 85:15 Bu3Sn(Bu)CuCNLi2
CH CH
3 THF, –40 °C, 20 min; 3

SnBu3
• The addition of stannyl radicals to alkynes is reversible under these conditions. The product ratio
NH4Cl
reflects the thermodynamic equilibrium. 97:3 E:Z
95%
Corey, E. J.; Ulrich, P.; Fitzpatrick, J. M. J. Am. Chem. Soc. 1976, 98, 222–224.
Aksela, R.; Oehlschlager, A. C. Tetrahedron 1991, 47, 1163–1176.
Andrew Haidle

10
 O H CrCl2/Bu3SnCHI2 O
Bu3Sn CH3(2-Th)CuCNLi2 (1 equiv) Bu3Sn CH3O SnBu3
CH3O DMF, 25 °C, 2.5 h; H2O
SnBu3 –10 °C ! 23 °C, THF, Et2O, 30 min CuCNLi2
O
S
82%

Hodgson, D. M.; Foley, A. M.; Lovell, P. J. Tetrahedron Lett. 1998, 39, 6419–6420.

Bu3Sn
CuCNLi2
n-Bu HB(c-C6H11)2 B(c-Hex)2
O CH S HO CH3
3
THF n-Bu NaOH (1 equiv), THF, 23 °C, 0.5 h;
CH3 Bu3Sn CH3
Cu(acac)2 (5 mol %);
–78 °C ! 0 °C, THF, 2 h
SnBu3 Bu3SnCl, –15 °C ! 23 °C
74%
n-Bu
86% overall

Hoshi, M.; Takahashi, K.; Arase, A. Tetrahedron Lett. 1997, 38, 8049–8052.
Behling, J. R.; Ng, J. S.; Babiak, K. A.; Campbell, A. L.; Elsworth, E.; Lipshutz, B. H.
Tetrahedron Lett. 1989, 30, 27–30.
SnR3
R'

EtO Bu3Sn(Bu)CuCNLi2, THF EtO SnBu3

–78 °C ! –50 °C; CH3OH SnBu

OEt OEt Bu3Sn(CH3)CuCNLi2 3

H H HO
95%
THF, –78 °C ! 0 °C;
O

Marek, I.; Alexakis, A.; Normant, J.–F. Tetrahedron Lett. 1991, 32, 6337–6340. 93%

Barbero, A.; Cuadrado, P.; Fleming, I.; Gonzalez, A. M.; Pulido, F. J. J. Chem.

Soc., Chem. Commun. 1992, 351–353.

(Bu3Sn)2CuCNLi2
1. Cp2Zr(H)Cl (1.15 equiv) SnBu3
CH3 O THF–HMPA, 0 °C; CH3
H3C THF, 23 °C, 15 min
CH3 O
SnBu3 CH3O
CH3OH SnBu3
CH3O 2. H2O
94% (NMR) 95:5 E:Z
99%

Cabezas, J. A.; Oehlschlager, A. C. Synthesis 1994, 432–442. Lipshutz, B. H.; Kell, R.; Barton, J. C. Tetrahedron Lett. 1992, 33, 5861–5864.

Andrew Haidle

11
 Bu 3SnH, ZrCl 4 (20 mol %), hexane, 0 °C, 1 h; 1. (Bu3Sn)2CuCNLi2
SnBu3
H3C O THF, –78 °C H3C O
n-Hex H n-Hex
Et3N (1 equiv), 0 °C → 23 °C 2. CH3OH SnBu3
89% >95:5 Z:E
95% (NMR)

Asao, N.; Liu, J.–X.; Sudoh, T.; Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1995, 2405–2406. Cabezas, J. A.; Oehlschlager, A. C. Synthesis 1994, 432–442.

• SnBu3
1. (Bu3Sn)2Zn
Bu3SnCl (0.83 equiv) Pd(PPh3)4 (5 mol %)
THF, 0 °C, 3 h n-C10H21
n-C10H21 H +
Mg (1 equiv) 2. H O , 0 °C, 10 min SnBu 3
Br 3
PbBr (5 mol %)
2 • SnBu3 70% (NMR) >95:5 E:Z
THF, 23 °C, 1 h
99%

Tanaka, H.; Abdul Hai, A. K. M.; Ogawa, H.; Torii, S. Synlett 1993, 835–836. Matsubara, S.; Hibino, J.–I.; Morizawa, Y.; Oshima, K.; Nozaki, H. J. Organomet. Chem. 1985,

285, 163–172.

R'

R3Sn ((CH3)3Sn)2 (0.9 equiv)

OTf Sn(CH3)3
Pd(PPh3)4 (2 mol %)
(CH3)3SnCu•S(CH3)2 (2 equiv)
CH3 CH3
LiCl, THF, 60 °C, 10 h

TBSO TBSO 74%

CH3OH (60 equiv), THF Sn(CH3)3
–63 °C, 12 h
82% Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.; Gilbertson, S.
R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J. Org. Chem. 1986, 51, 277–279.

• The addition of the cuprate reagent is reversible. The authors attribute the observed
regioselectivity to the higher stability of the polarized carbon-copper bond when
copper is attached to the less electronegative terminal carbon.
Bu3SnH (1.3 equiv) SnBu3
– Pd(PPh3)4 (2 mol %)
δ H
CO2Et
TBSO Cu•S(CH3)2 PhH, 23 °C, 10 min CO2Et
+ 83%
(CH3)3Sn δ

Piers, E.; Chong, J. M. Can. J. Chem. 1988, 66, 1425–1429. Miyake, H.; Yamamura, K. Chemistry Lett. 1989, 981–984.
Andrew Haidle

12
• An alternate route:
C6H5S((CH3)3Sn)CuLi (1.2 equiv)
3
CH CO2Et CH3OH (1.7 equiv) CH3 CO2Et
n-Pentyl + –
Et4N HBr2 (1 equiv) n-Pentyl
Br THF, –78 °C → –48 °C, 4 h; CH3OH (CH ) Sn
OH CH2Cl2, 23 °C 33
OH
62% 76% 98:2 E:Z

Marshall, J. A.; Sehon, C. A. Org. Synth. 1999, 76, 263–270. • The initially formed cis adduct is stable at –100 °C, but at higher temperatures (–48 °C), the
equilibrium favors the Cu/Sn trans isomer.

Br n-Pentyl t–BuLi (3 equiv) CO2Et CuSC6H5Li

Bu3Sn n-Pentyl
CH3 CuSC6H5Li CH3 CO2Et
Bu3SnCl > –78 °C
OH OH (CH3)3Sn (CH3)3Sn
67%

Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600–7605. Piers, E.; Morton, H. E. J. Org. Chem. 1980, 45, 4263–4264.

[(CH3)3Sn]2 (1 equiv) CO2CH3 CO2CH3

R''
Pd(PPh3)4 (1 mol %) 85 °C (CH ) Sn
33
R Ph CO2CH3 Ph Sn(CH ) Sn(CH3)3
SnR3 THF, reflux, 3 h 33
84% Ph
67% Sn(CH3)3

Pd2(dba)3 (2 mol %) OH
Piers, E.; McEachern, E. J.; Romero, M. A. J. Org. Chem. 1997, 62, 6034–6040.
CO2CH3 PPh3 (16 mol %)

HO CH3 Bu3SnH, PhH, 23 °C CO2CH3

87% Bu3SnCH3 HCl (1 equiv) H
CO2CH3

TBSO Sn(CH3)3 TBSO CO2CH3

DMF, H2O, 23 °C, 5 min
Sn(CH3)3 Sn(CH3)3
85%
• The regiochemistry of the addition is explained as the result of hydride addition to the
more electron-deficient terminus of the acetylene.

Piers, E.; McEachern, E. J.; Romero, M. A. J. Org. Chem. 1997, 62, 6034–6040.
Trost, B. M.; Li, C–J. Synthesis 1994, 1267–1271.
Andrew Haidle

13
 R' Vinylstannanes:
R''
• are sensitive to acids, undergoing protodestannylation with retention of stereochemistry.
SnR3

C6H5S((CH3)3Sn)CuLi (2.5 equiv) Seyferth, D. J. Am. Chem. Soc. 1957, 79, 2133–2136.

CH CH3OH (1.7 equiv) (CH ) Sn CH3 DCl, CD3OD, 23 °C

3
CO Et D
33

CO2Et
2 Sn(CH3)3 CH3
THF, –100 °C, 6h
CH3
79%
Piers, E.; Morton, H. E. J. Org. Chem. 1980, 45, 4263–4264. Cochran, J. C. et al. Organometallics 1982, 1, 586–590.

n–Pentyl CO2CH3 CuCl (1 mol %) n–Pentyl CO2CH3

• frequently are unstable to chromatography on silica gel (addition of triethylamine to the

Sn(CH3)3 H eluent can prevent decomposition during chromatography).

DMF, H2O, 23 °C, 2 h
Sn(CH3)3 Sn(CH3)3
91%
Piers, E.; McEachern, E. J.; Romero, M. A. J. Org. Chem. 1997, 62, 6034–6040. • can be purified by a chromatographic technique that uses C-18 silica, which has been made

hydrophobic by capping the silanol residues with octadecyldimethylsilyl groups.

SnR3 Farina, V. J. Org. Chem. 1991, 56, 4985–4987.

R'
R''

EtO EtO • can be difficult to separate from unwanted tin by-products after the reaction. For leading
Bu3Sn(Bu)CuCNLi2, THF SnBu3
references on the work-up of tin reactions, see:

OEt –78 °C → –50 °C; OEt

Renaud, P.; Lacôte, E.; Quaranta, L. Tetrahedron Lett. 1998, 39, 2123–2126.
Br

78% • react cleanly and efficiently with I2 to form vinyl iodides with retention of stereochemistry.

Marek, I.; Alexakis, A.; Normant, J.–F. Tetrahedron Lett. 1991, 32, 6337–6340. For example:

HC OH OH OH
Bu3SnMgCH3 (3 equiv) Pd(PPh3)2Cl2 (10 mol %)
CuCN (5 mol %), EtI (excess) 3 I2 (1 equiv)
BnO SnBu3 Bu3SnH (1.5 equiv)
BnO TBSO TBSO
THF, 20 min, 0 °C TBSO CH2Cl2, 0 °C, 10 min CHCl ,0°C,
2 2
73% TBSO 2 min TBSO I
TBSO SnBu3
83%

Matsubara, S.; Hibino, J.-I.; Morizawa, Y.; Oshima, K.; Nozaki, H. J. Organomet. Chem. 1985,
Smith, A. B.; Ott, G.R. J. Am. Chem. Soc. 1998, 120, 3935–3948.
285, 163–172.
Andrew Haidle

14