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 L
PdL2 fast
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

R–X R'–M catalyst R–R' M–X Casado, A. L.; Espinet, P. Organometallics 1998, 17, 954–959.

• !-hydride elimination can be a serious side reaction within alkyl palladium intermediates. This
typically requires a syn coplanar alignment of hydride and palladium:
Typically: • R and R' are sp2–hybridized • M = Sn, B, Zr, Zn

• 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 for

Pd catalyst sp2-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 are
p-Tol–Pd(II)Lm–Ph p-Tol–Pd(II)Lm–Br often poor substrates as a result.

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

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

Andrew Haidle, Jeff Kohrt, Fan Liu

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 Myers The Stille Reaction Chem 115
Stille Reaction conditions: Cl

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

Ph
N Ph
Pd(PPh3)4 Pd(OAc)2 Pd2(dba)3 N
N
Ph OCH3 N OCH3
O N
OCH3 Pd(OAc)2 (8 mol%)
N 4 (24 mol%)
dba = F
Ph
Sn(n-Bu)3 dioxane N
F N
microwave
OCH3
101 oC, 94%
• Ligand Additives: Sterically hindered, electron-rich ligands typically accelerate coupling.
This catalyst system and microwave heating limited the formation of a destannylated byproduct.
R Cy Selig, R.; Schollmeyer, D.; Wolfgang, A.; Saufer, S. Tetrahedron 2011, 67, 9204 - 9213
N
P P Cy
N R iPr iPr
N N R • Additives: CuI can increase the reaction rate by >102:
t-Bu t-Bu
P Pd2(dba)3 (5 mol %)
t-Bu I PPh3 (20 mol %)
iPr
n-Bu3Sn
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
mol % CuI relative rate
3 tris-N-benzyl Ar-Cl, Ar-Br, Ar-OTf, vinyl-Cl
(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 in
n-Bu3Sn solution are known to inhibit the rate-limiting transmetalation step.
Cl
Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905–5911.
N Pd2(dba)3 (1.5 mol%) N
3 (3.5 mol%) • Stoichiometric Cu itself can sometimes mediate cross-coupling reactions under mild conditions,
CsF, Dioxane, 110 oC without Pd:
97% O

CuO S (1.5 equiv)

Verkade, J.G.; Su, W.; Urgaonkar, S.; McLaughlin, P.A. J. Am. Chem. Soc. 2004, 126, 16433- CH3 O
16439 Sn(n-Bu)3 CH3 O
CH3
H3C CH3 Cl I CH3 NMP, 23 °C, 15 min
Pre-milled Cl
Cl H3C CH3
Pd(OAc)2, 4
(1–2 mol%) 89%
MeO2C n-Bu3Sn CH3 O
CH3 CsF, DME MeO2C
80 oC, 96% NMP = N CH3

Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-2749.

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

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 Myers The Stille Reaction Chem 115
• Additives: fluoride can coordinate to the organotin reagent to form a hypervalent tin species that • A general Stille cross-coupling reaction employing aryl chlorides (which are more abundant and
is believed to undergo transmetallation at a faster rate: less expensive than aryl iodides, aryl bromides, and aryl triflates) has been developed:

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

Pd(PPh3)4 (2 mol %) Cl OEt P(t-Bu)3 (6.0 mol %)
n-Bu3Sn n-Bu3Sn
THF, 62 °C 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 product
• Examples: in excellent yields:
OMOM
(1.2 equiv)
10% Pd/C (5 mol%) n-Bu3Sn CH3
I LiF, Air O OMOM
OH CH3
n-Bu3Sn O ONf
MeO NMP, 140 ºC MeO Pd(PPh3)4 (10 mol %) CH3
96% OH CH3
LiCl (6 equiv), CuCl (5 equiv)
DMSO, 60 °C, 45 h

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

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
NO2 N OMe
NO2 PdCl2 (2 mol%) O O O H
Br
Pt-Bu3 (4 mol%) N OMe
N Br H N
N N
MeO OMe n-Bu3Sn H H
CuI (4 mol%), CsF
MeO OMe n-Bu3Sn
DMF, 45 ºC
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

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 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
Sn(n-Bu)3
Br Et O Et O is extremely low. The following examples show methods by which residual tin can be minimized:
N N
O S O S
O S S O
HN HN
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% Sn(n-Bu)3 + I
VEGFR2 Kinase Inhibitor N
N DMF, 95 oC N
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.; Liu,
W.; Crosby, R. M.; Johnson, J. H.; Epperly, A. H.; Kumar, R.; Luttrell, D. K.; Stafford, J. A. J. Med. H
N
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 100 ºC, 52%
O
NC
Sn(CH3)3 O N
H H
N N
O
CO2Me H CH3
I O HN
NH CO2Me CH3
NH N S
Pd2(dba)3, AsPh3
H3C CH3
CuI, DMF N
H3C CH3 N
60 ºC, 55%
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 Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.; Munchhof, M. J.; Marx, M.
N N Sn(n-Bu)3 N
A.; Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Proc. Res. Dev. 2003, 7, 676 - 683
S N
Br N N
NH S NH
O CH3 Pd(PPh3)4, CuI O CH3
H3C OH DMF, 80 ºC H3C OH
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

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 Myers The Stille Reaction Chem 115
Alkyl Stille Coupling Reactions - sp2-sp3:

TESO TESO • Initially, "alkyl" Stille couplings were mostly limited to the transfer of Me, Allyl and Benzyl groups.
H H CH3 H H CH3
H3C Tf2O H3C • Coupling of higher n-alkyl groups was limited by !-hydride eliminations. This limitation has been
O OTf overcome by innovations in the ligand and Pd sources.
N N
O TMP, DIEA O
CO2PNB CO2PNB • sp2-sp3 coupling: alkyl-Br + vinyl-SnR3
used crude
O
n-Bu3Sn OH [(allyl)PdCl]2 (2.5 mol%) O
O CH3 CH3
Pd(dba)2 (13 mol%) [HP(t-Bu)2Me]+ BF4– (15%)
n-Bu3Sn
O +
P(2-furyl)3 (32 mol%)
Me4NF, 3 Å MS
ZnCl2, HMPA, 70 ºC Br THF, 23 ºC
OTHP OTHP
53%

Fu, G.C.; Menzel, K. J. Amer. Chem. Soc. 2003, 125, 3718.

N -OTf TESO CH3
H H
N OH
H3C • using the electron-rich PCy(pyrrolidinyl)2 ligand allows couplings of both vinyl and aryl stannanes
TESO CONH2 N with higher alkyl bromides:
H H CH3 O
N SO2 CO2PNB n-Bu3Sn
H3C
N 47% 2-steps
O OMe
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 Me4NF, 3 Å MS O
OMe
MTBE, 23 ºC 71%

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
60 oC, 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:

CH3
• Alkenes as coupling partners: O
Pd(PPh3)4 (10 mo l%)
OTIPS O + CH3
O CH3 O Bu3Sn LiCl, THF
Pd2(dba)3 (20 mol %) H3C
OTES O N OTf CH3 80 °C, sealed tube
CH3 CH3 I CdCl2 (1.8 equiv) OTBS
+
O Ph (i-Pr)2NEt, NMP 100%
H
O 40˚C, 53 h
SnBu3 OTBDMS 69%
CH3 CH3
O O
CH3
CH3 CH3
O O CH3 O
O N(CH3)2 OTIPS CH3 H3C
CH3
O OTES O
CH3 CH3 CH3 CH3 CH3
H CH3
O O O OTBS
O Jatrophone
O H H H
O O N
H Han, Q; Wiemer, D. F. J. Am. Chem. Soc. 1992, 114, 7692–7697.
Ph
H O CH3
H OTES
O CH3
OCH3 OTBDMS O O
OCH3 CH3
CH3O
OCH3 O N
H
(+)-A83543A, (+)-Lepicidin
Bu3Sn
O
I O
• CdCl2 serves as a transmetalation cocatalyst. Without it, homodimerization of both CH3 H
OCH3
coupling partners was observed. O OTBS
CH3
Evans, D. A.; Black, W. D. J. Am. Chem. Soc. 1993, 115, 4497–4513. O OTIPS
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 74%
H H CH3
CH3 DMF, 23 ˚C, 72 h H3C H OH
O I O 2. TBAF, AcOH, 0 °C
H H H H O
HO2C HO2C O 3. HF•Py, Py, THF, 23 °C
CH3 61% H3C
H CH3 CH3
OCH3 O N 61%
+ H
Indanomycin (X-14547A)
O
HN O
H
O CH3 OCH3 Smith, A. B.; Condon, S. M.; McCauley, J. A.;
O OH
H H Leazer, J. L.; Leahy, J. W.; Maleczka, R. E.
Bu3Sn CH3
Burke, S. D.; Piscopio, A. D.; Kort, M. E.; O OH J. Am. Chem. Soc. 1995, 117, 5407–5408.
Matulenko, M. A.; Parker, M. H.; Armistead, D. M.; CH3 OCH3 CH3 CH3
H 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
O O SnBu3 (20 mol %) CO2CH3
CH3
OCH3 O (i-Pr)2NEt Br
N Bu3Sn O CH3
I H DMF, THF Pd(PPh3)4 (10 mol %)
(CH3)3Sn
25 ˚C, 24 h CH3 +
I O CHCl3, reflux, 48 h
O OTHP
H 28%
CH3 OCH3 O 65%
O OH
CH3 O OTDS
O OH
CH3 OCH3 CH3 CH3
CH3
H OH CO2CH3 CO2CH3
O
O
CH3
CH3 O O
OCH3 O
N
CH3 CH3 OTHP
H
CH3
O H O O
O O
H
CH3 OCH3 OTDS
O OH O O
Acerosolide
CH3
O OH
CH3 OCH3 CH3 CH3
Paquette, L. A.; Astles, P. C. J. Org. Chem. 1993, 58, 165–169.
Rapamycin

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

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

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

CH3 CH3
I Bu3Sn O CH3 CH3
I O
Pd2(dba)3•CHCl3 (15 mol %) CH3 CH3
O O O AsPh3 (0.6 equiv) O O O HO
CH3 CH3 SnBu3
iPr2NEt (10 equiv) CH3 O OH
NH O O H NH O O H
N N
N CH3 NH
O DMF, 25 °C, 36 h N O
NH CH3 (2 equiv)
NH CH3 O
CH3 62% CH3
CH3
OH OH

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

O CH3
HO OH HO

CH3 O OH O O OH CH3 O OH O O O
CH3 CH3
CH3 NH 2 N H2SO4 (2.0 equiv) CH3 NH
H CH3 NH O O H
NH O O N N
O THF : H2O 4 : 1, 25 °C, 7 h O N
N O O O
NH CH3 NH CH3
CH3 33% (plus 50% starting material) 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 palladium • Liebeskind's copper(I) thiophene-2-carboxylate promoted coupling reaction was used for the total
catalysis failed. Note the selective transformation of the vinyl triflate to the vinyl stannane in the synthesis of concanamycin F. This reaction failed intramolecularly when the two coupling
presence of the vinyl bromide. partners had already been joined via the ester linkage.

CH3
OTf I
CH3 CH3 Et CH3
OTES O
H CH3
CH3 TESO OCH3
TBSO H Br Pd(Ph3)4 (2 mol %)
CH3 CH3 CH3 OCH3
CH3 CH3
LiCl (6 equiv)
(CH3)3SnSn(CH3)3 (2 equiv)
THF, reflux, 16 h Bu3Sn OCH3
OR OBz
R = DEIPS
HO CH3
Sn(CH3)3 CH3 CH3
O
CH3 CH3 CuO S

H CH3
CH3
TBSO H Br NMP, 20 °C, 1 h
CH3
CuCl (3 equiv) CH3 CH3 89%
DMF, 60 °C, 1 h

CH3 OCH3
CH3 CH3 OR OBz
Et CH3
OTES HO CH3 R = DEIPS
O
CH3 CH3
TESO OCH3
CH3 CH3 CH3 CH3 OCH3
H CH3
TBSO TBAF (2.5 equiv)
H
CH3 CH3 THF, 50 ° C, 14 h
55%, three steps
CH3

CH3 CH3
CH3 OCH3 • CH3
OH O
Et CH3
OH O OH
CH3 CH3 OH
Aegiceradienol CH3 CH3
HO O
H CH3
CH3 CH3 OCH3
HO H
CH3 CH3
Concanamycin F

Huang, A. X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999–10003. Paterson, I.; Doughty, V. A.; McLeod, M. D.; Trieselmann, T. Angew. Chem., Int. Ed. Engl. 2000,
39, 1308–1312. Andrew Haidle

9
Synthesis of Aryl and Vinyl Stannanes:

Bu3SnCl (0.85 equiv)

H Li • NH2CH2CH2NH2 Bu3Sn H
SnR3 THF, 0 °C → 25 °C, 18 h
33%

• Directed ortho metalation followed by addition of a stannyl chloride is a standard method. Bu3SnH (1.2 equiv)
Snieckus, V. Chem. Rev. 1990, 90, 923–924. AIBN (2.4 mol %)
Bu3Sn
Bu3Sn H SnBu3
90 °C, 6 h

OMOM OMOM 90%

t-BuLi (3.8 equiv)
Et2O, 23 °C, 2 h;
Renaldo, A. F.; Labadie, J. W.; Stille, J. K. Org. Synth. 1988, 67, 86–97.
Bu3SnCl (4.3 equiv) SnBu3
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 Bu3Sn
SnBu3 CO2Et
59%
[(CH3)3Sn]2
Pd(PPh3)4 (5 mol %)
Br N (CH3)3Sn N Renaldo, A. F.; Labadie, J. W.; Stille, J. K. Org. Synth. 1988, 67, 86–97.
DME, 80 °C, 15 h
OCH3 OCH3
97%

CH3 OH CH3 OH
Benaglia, M.; Toyota, S.; Woods, C. R.; Siegel, J. S. Tetrahedron Lett. 1997, 38, 4737-4740. Bu3SnOCH3, Et2O, 23 °C;
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
Bu3Sn(Bu)CuCNLi2
92% 85 : 15 CH3 THF, –40 °C, 20 min; CH3

SnBu3
NH4Cl
• The addition of stannyl radicals to alkynes is reversible under these conditions. The product ratio
97:3 E:Z
reflects the thermodynamic equilibrium. 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 CrCl2/Bu3SnCHI2 O
CH3(2-Th)CuCNLi2 (1 equiv) Bu3Sn H
Bu3Sn CuCNLi2 CH3O CH3O SnBu3
SnBu3 DMF, 25 °C, 2.5 h; H2O
–10 °C ! 23 °C, THF, Et2O, 30 min O
S
82%

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

Bu3Sn
CuCNLi2

S HB(c-C6H11)2
CH3 HO CH3 B(c-Hex)2
O n-Bu n-Bu NaOH (1 equiv), THF, 23 °C, 0.5 h;
CH3 Bu3Sn CH3 THF
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'

Bu3Sn(Bu)CuCNLi2, THF
EtO EtO SnBu3
–78 °C ! –50 °C; CH3OH SnBu3
Bu3Sn(CH3)CuCNLi2
OEt OEt 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)
THF–HMPA, 0 °C; CH3 SnBu3
H3C THF, 23 °C, 15 min
CH3 O CH3 O
SnBu3 SnBu3 CH3O
CH3OH 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
 1. (Bu3Sn)2CuCNLi 2
Bu3SnH, ZrCl4 (20 mol %), hexane, 0 °C, 1 h; SnBu3
n-Hex THF, –78 °C
n-Hex H H 3C O H 3C O
Et3N (1 equiv), 0 °C → 23 °C
2. CH 3OH 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
Pd(PPh3 )4 (5 mol %)
THF, 0 °C, 3 h n-C10H 21
Bu3SnCl (0.83 equiv) n-C10H 21 H
+
Mg (1 equiv) 2. H3O , 0 °C, 10 min SnBu3
PbBr 2 (5 mol %)
Br • SnBu3 70% (NMR) >95:5 E:Z
THF, 23 °C, 1 h

99%
Matsubara, S.; Hibino, J.–I.; Morizawa, Y.; Oshima, K.; Nozaki, H. J. Organomet. Chem. 1985, 285,

Tanaka, H.; Abdul Hai, A. K. M.; Ogawa, H.; Torii, S. Synlett 1993, 835–836. 163–172.

R'

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

OTf Sn(CH3)3
Pd(PPh3)4 (2 mol %)
CH3 CH3
LiCl, THF, 60 °C, 10 h
(CH3 )3SnCu•S(CH3)2 (2 equiv) 74%
TBSO TBSO
CH3OH (60 equiv), THF
Sn(CH3)3
–63 °C, 12 h 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.
82%

• 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 CO 2Et
CO 2Et
PhH, 23 °C, 10 min
TBSO Cu•S(CH3)2
(CH3)3Sn δ+ 83%

Miyake, H.; Yamamura, K. Chemistry Lett. 1989, 981–984.

Piers, E.; Chong, J. M. Can. J. Chem. 1988, 66, 1425–1429.
Andrew Haidle

12
• An alternate route:

C6H5S((CH3)3Sn)CuLi (1.2 equiv)

CH3 CH3OH (1.7 equiv)
Et4N+HBr2– (1 equiv) CO2Et CH3 CO2Et
n-Pentyl n-Pentyl
Br THF, –78 °C → –48 °C, 4 h; CH3OH (CH3)3Sn
OH CH2Cl2, 23 °C OH
76% 98:2 E:Z
62%

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.

t–BuLi (3 equiv) CO2Et CuSC6H5Li

n-Pentyl n-Pentyl
Br Bu3Sn CH3 CuSC6H5Li CH3 CO2Et
Bu3SnCl
OH OH (CH3)3Sn > –78 °C (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
R Ph (CH3)3Sn
Ph CO2CH3 Sn(CH3)3 Sn(CH3)3
SnR3 THF, reflux, 3 h
Sn(CH3)3 84% Ph
67%

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 %)
CO2CH3
HO CH3 Bu3SnH, PhH, 23 °C
Bu3Sn CH3
CO2CH3 H
87% HCl (1 equiv)
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
 Vinylstannanes:
R'
R''
• are sensitive to acids, undergoing protodestannylation with retention of stereochemistry.
SnR3

Seyferth, D. J. Am. Chem. Soc. 1957, 79, 2133–2136.

C6H5S((CH3)3Sn)CuLi (2.5 equiv)

CH3 CH3OH (1.7 equiv) (CH3)3Sn DCl, CD3OD, 23 °C
CH3 CH3
CO2Et CO2Et Sn(CH3)3 D
THF, –100 °C, 6h
CH3
79%
Cochran, J. C. et al. Organometallics 1982, 1, 586–590.
Piers, E.; Morton, H. E. J. Org. Chem. 1980, 45, 4263–4264.

CO2CH3 CO2CH3 • frequently are unstable to chromatography on silica gel (addition of triethylamine to the
CuCl (1 mol %)
n–Pentyl n–Pentyl eluent can prevent decomposition during chromatography).
Sn(CH3)3 H
DMF, H2O, 23 °C, 2 h
Sn(CH3)3 Sn(CH3)3
91%
• can be purified by a chromatographic technique that uses C-18 silica, which has been made

Piers, E.; McEachern, E. J.; Romero, M. A. J. Org. Chem. 1997, 62, 6034–6040. hydrophobic by capping the silanol residues with octadecyldimethylsilyl groups.

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

R'

R''
• can be difficult to separate from unwanted tin by-products after the reaction. For leading

references on the work-up of tin reactions, see:

Bu3Sn(Bu)CuCNLi2, THF
EtO EtO SnBu3

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:

OH OH OH
Bu3SnMgCH3 (3 equiv) H3C Pd(PPh3)2Cl2 (10 mol %)
CuCN (5 mol %), EtI (excess) Bu3SnH (1.5 equiv) I2 (1 equiv)
BnO SnBu3
BnO TBSO
THF, 20 min, 0 °C TBSO
CH2Cl2, 0 °C, 10 min CH2Cl2, 0 °C, TBSO
TBSO TBSO SnBu3 2 min TBSO I
73%
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

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