The Stille Reaction Chem 115

Home , Reductive elimination, Stille reaction

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

• Electron-poor stannanes undergo slower transmetallation and are often poor substrates as n-Bu Sn–Br n-Bu Sn–Ph 3 3 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 Ph OCH3 N OCH3 O N Pd(OAc)2 (8 mol%) N OCH3 dba = 4 (24 mol%) F Ph Sn(n-Bu) dioxane F 3 N N microwave OCH 101 oC, 94% 3 • 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 2 N N R • Additives: CuI can increase the reaction rate by >10 : t-Bu t-Bu P Pd2(dba)3 (5 mol %) t-Bu I iPr PPh3 (20 mol %) 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 solution are known to inhibit the rate-limiting transmetalation step. Cl n-Bu3Sn 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 S Verkade, J.G.; Su, W.; Urgaonkar, S.; McLaughlin, P.A. J. Am. Chem. Soc. 2004, 126, 16433- CuO (1.5 equiv) CH3 O 16439 Sn(n-Bu) 3 CH3 O CH3 H C CH I CH Pre-milled 3 3 Cl 3 NMP, 23 °C, 15 min Cl Cl H3C CH3 Pd(OAc)2, 4 (1–2 mol%) 89% n-Bu Sn O MeO2C 3 CH3 MeO2C CH3 CsF, DME 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

2 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 Cl OEt Pd(PPh3)4 (2 mol %) P(t-Bu)3 (6.0 mol %) n-Bu Sn 3 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 product • Examples: in excellent yields: OMOM (1.2 equiv) 10% Pd/C (5 mol%) n-Bu3Sn CH3 I LiF, Air OMOM O OH CH3 n-Bu Sn 3 O NMP, 140 ºC MeO ONf Pd(PPh ) (10 mol %) MeO 3 4 CH3 96% LiCl (6 equiv), CuCl (5 equiv) OH CH3 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 NO PdCl (2 mol%) 2 O N OMe Br NO2 2 O O H Pt-Bu (4 mol%) 3 N Br N OMe N N H N n-Bu Sn H MeO OMe 3 CuI (4 mol%), CsF H 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

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 Sn(n-Bu)3 Br O is extremely low. The following examples show methods by which residual tin can be minimized: N Et O N Et O S O S O S S O HN HN Pd(PPh ) (10 mol%) Cl 3 4 CH3 Cl CH3 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 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.; 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 O N CO2Me H CH3 O NH I HN CO2Me CH3 NH N S Pd (dba) , AsPh H C CH 2 3 3 3 3 CuI, DMF N H C CH N 60 ºC, 55% 3 3 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 Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.; Munchhof, M. J.; Marx, M. N N N Sn(n-Bu) N N 3 A.; Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Proc. Res. Dev. 2003, 7, 676 - 683 N Br N S N NH S NH O CH3 Pd(PPh3)4, CuI O 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

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

Fu, G.C.; Menzel, K. J. Amer. Chem. Soc. 2003, 125, 3718. N -OTf TESO H H CH3 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 CO PNB N SO 2 n-Bu3Sn H3C 2 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 Me NF, 3 Å MS O 4 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. NiCl (10 mol%) Br 2 + 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 CH O Bu3Sn LiCl, THF Pd (dba) (20 mol %) 3 H C 2 3 3 CH OTES O N OTf 3 OTBS 80 °C, sealed tube CH3 CH3 + I CdCl2 (1.8 equiv) O Ph (i-Pr) NEt, NMP 100% H 2 O 40˚C, 53 h

SnBu3 OTBDMS 69% CH CH3 O 3 O CH3 CH CH 3 O 3 O O N(CH ) CH3 O 3 2 OTIPS CH3 H3C CH3 O OTES O CH3 CH3 CH3 CH3 CH3 H CH3 O O O OTBS O Jatrophone H H O H O O N H Han, Q; Wiemer, D. F. J. Am. Chem. Soc. 1992, 114, 7692–7697. Ph H O CH3 H OTES CH O 3 O OCH3 OTBDMS O OCH3 CH3O CH3 OCH3 O N H (+)-A83543A, (+)-Lepicidin Bu Sn 3 O I O • CdCl2 serves as a transmetalation cocatalyst. Without it, homodimerization of both H CH3 OCH coupling partners was observed. O OTBS 3

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 CH H C 3 O I DMF, 23 ˚C, 72 h 3 O H OH 2. TBAF, AcOH, 0 °C H H H H O HO C HO2C O 2 CH 61% H C 3. HF•Py, Py, THF, 23 °C 3 3 H CH CH3 3 OCH3 O N 61% + H Indanomycin (X-14547A) O O HN H CH OCH Smith, A. B.; Condon, S. M.; McCauley, J. A.; O 3 O OH 3 H H Leazer, J. L.; Leahy, J. W.; Maleczka, R. E. Bu Sn CH3 3 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 CH 3 Shankaran, K. J. Org. Chem. 1994, 59, 332–347. Rapamycin Andrew Haidle

6 Further Examples: • Allylic, benzylic halides: CH3 H OH Pd(CH CN) Cl O 3 2 2 O SnBu3 (20 mol %) CO2CH3 CH3 OCH 3 O N (i-Pr) NEt Br Bu3Sn 2 O H CH3 Pd(PPh ) (10 mol %) I DMF, THF (CH ) Sn 3 4 + 3 3 I O 25 ˚C, 24 h CH3 CHCl , reflux, 48 h O OTHP 3 H 28% CH OCH O 65% 3 O OH 3 CH OTDS O 3 OH O

CH3 OCH3 CH3 CH3 CH3 H OH CO2CH3 CO2CH3 O O CH3 CH3 O O OCH 3 O N CH CH OTHP H 3 3 CH3 O H O O O H O CH OCH OTDS 3 O OH 3 O O Acerosolide CH O 3 OH CH OCH CH CH 3 3 3 3 Paquette, L. A.; Astles, P. C. J. Org. Chem. 1993, 58, 165–169. Rapamycin

CH Nicolaou, K. C.; Chakraborty, T. K; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. TBSO O 3 PdCl2(CH3CN)2 (3 mol %) 1993, 115, 4419–4420. O HO O PPh (5 mol %) + H 3 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 O O CH3 CH TBSO O HO HO 3 O BnPdCl(PPh3)2 (2.5 mol %) H O Bu Sn O O O H 3 CuI (2.5 mol %) O + O CH Cl CH3 3 THF, 50 ˚C, 15 min TBSO OOCH3 H2N O OH H N O 93% 2 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:

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

Pd2(dba)3•CHCl3 (10 mol %)

AsPh3 (0.2 equiv)

iPr2NEt (10 equiv) DMF, 40 °C, 5 h

45%

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

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.

CH OTf 3 I CH3 CH3 Et CH3 OTES O H CH3 CH TESO OCH TBSO Br 3 3 H CH Pd(Ph3)4 (2 mol %) CH CH 3 CH3 CH3 OCH3 3 3 LiCl (6 equiv)

(CH3)3SnSn(CH3)3 (2 equiv) OCH THF, reflux, 16 h Bu3Sn 3 OR OBz R = DEIPS HO CH3 CH3 CH3 Sn(CH3)3 O CH3 CH3 CuO S H CH 3 CH TBSO Br 3 H CH3 NMP, 20 °C, 1 h CuCl (3 equiv) CH3 CH3 89% DMF, 60 °C, 1 h

CH3 OCH3 OR OBz CH3 CH3 Et CH3 OTES HO CH O 3 R = DEIPS CH3 CH3 TESO OCH3 CH3 CH3 CH3 CH3 OCH3

H CH3 TBAF (2.5 equiv) TBSO H CH3 CH3 THF, 50 ° C, 14 h 55%, three steps CH3

CH3 CH3 CH3 OCH3 • CH3 OH O Et CH3 OH O OH CH CH OH 3 3 CH CH Aegiceradienol HO O 3 3 H CH3 CH3 CH3 OCH3 HO H CH CH 3 3 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) Bu3Sn H H Li • NH2CH2CH2NH2 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 %) Bu Sn Bu Sn H 3 SnBu 3 90 °C, 6 h 3

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. SnBu3 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 Bu3Sn SnBu3 CO Et 59% 2 [(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;

IO 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) CH AIBN (3 mol %) Bu Sn CH CH 3 3 3 + 3 95 °C, 3 h OTHP OTHP Bu3Sn OTHP Bu3Sn(Bu)CuCNLi2 92% 85 : 15 CH3 THF, –40 °C, 20 min; CH3 SnBu NH Cl 3 • The addition of stannyl radicals to alkynes is reversible under these conditions. The product ratio 4 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 O CrCl2/Bu3SnCHI2 CH (2-Th)CuCNLi (1 equiv) H Bu Sn 3 2 Bu3Sn 3 CuCNLi CH3O CH3O SnBu3 SnBu3 2 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 CH B(c-Hex)2 O 3 HO CH3 n-Bu n-Bu NaOH (1 equiv), THF, 23 °C, 0.5 h; CH Bu Sn CH THF 3 3 3 Cu(acac) (5 mol %); –78 °C ! 0 °C, THF, 2 h 2 Bu SnCl, –15 °C 23 °C SnBu3 3 ! 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 SnBu Bu3Sn(CH3)CuCNLi2 3 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. Cp Zr(H)Cl (1.15 equiv) 2 CH SnBu THF–HMPA, 0 °C; H C 3 3 CH O CH O 3 THF, 23 °C, 15 min 3 3 SnBu SnBu 3 3 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. (Bu Sn) CuCNLi SnBu 3 2 2 Bu3SnH, ZrCl4 (20 mol %), hexane, 0 °C, 1 h; 3 n-Hex THF, –78 °C n-Hex H H3C O H3C O 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

Pd(PPh3)4 (5 mol %)

THF, 0 °C, 3 h n-C H Bu SnCl (0.83 equiv) 10 21 3 n-C10H21 H + Mg (1 equiv) 2. H3O , 0 °C, 10 min SnBu3

PbBr2 (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.

R3Sn ((CH3)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 HCO2Et PhH, 23 °C, 10 min CO2Et 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) Et N+HBr – (1 equiv) n-Pentyl 4 2 n-Pentyl CO2Et CH3 CO2Et Br THF, –78 °C –48 °C, 4 h; CH OH → 3 (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 Bu Sn CH CuSC H Li CH CO Et Bu SnCl 3 3 6 5 3 2 3 > –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.

[(CH ) Sn] (1 equiv) 3 3 2 CO CH R'' CO2CH3 2 3 Pd(PPh3)4 (1 mol %) 85 °C R Ph (CH3)3Sn Ph CO2CH3 Sn(CH ) SnR Sn(CH3)3 3 3 3 THF, reflux, 3 h 84% Sn(CH3)3 Ph 67%

Pd (dba) (2 mol %) OH 2 3 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)

CH CH3OH (1.7 equiv) DCl, CD3OD, 23 °C 3 (CH3)3Sn CH CO Et 3 CH CO2Et 2 Sn(CH3)3 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.

• frequently are unstable to chromatography on silica gel (addition of triethylamine to the CO CH CO2CH3 2 3 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 –78 °C → –50 °C; OEt 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 Bu SnMgCH (3 equiv) 3 3 H3C Pd(PPh3)2Cl2 (10 mol %) CuCN (5 mol %), EtI (excess) Bu3SnH (1.5 equiv) I2 (1 equiv) BnO SnBu3 BnO TBSO TBSO TBSO THF, 20 min, 0 °C CH2Cl2, 0 °C, 10 min CH2Cl2, 0 °C, 2 min TBSO TBSO SnBu3 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