11The Stille Reaction哈佛有机化学讲义Word格式文档下载.docx

1、 L L cis transCasado, A. L.; Espinet, P. Organometallics 1998, 17, 954-959. p-hydride elimination can be a serious side reaction within alkyl palladium intermediates.i HVyd（II）L2X = = + HPd（II）L2XI Oxidative addition and reductive elimination steps occur with retention of configuration for sp2-hybri

2、dized substrates. Transmetalation is proposed to be the rate determining step with most substrates. Relative order of ligand transfer from Sn: alkynyl alkenyl aryl allyl = benzyl a-alkoxyalkyl alkyl The details of the mechanism are still being elucidated, and the mechanism may change with different

3、reaction conditions: Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978-8985. Stille Reaction conditions: Catalyst: Commercially available Pd（II） or Pd（0） sources. Examples: Pd（PPh3）4 Pd（OAc）2 Pd2（dba）3 O dba = Ligands: Phosphine （PR3） ligands are often added when the Pd source doesnt contain strong liga

4、nds.Large rate enhancements （102-103） occur with poorly electron-donating ligands: A general Stille cross-coupling employing aryl chlorides （which are more abundant and less expensive than aryl iodides, aryl bromides, and aryl triflates） has been developed.tri-2-furylphosphineQAsCP O Astriphenylarsi

5、neCH3OClBu3SnOEt Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595.Pd2（dba）3 （1.5 mol %）P（f-Bu）3 （6.0 mol %） *CsF （2.2 equiv）dioxane, 100 C98% Additives: CuI can increase the reaction rate by 102.Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1999, 38, 2411-2413.SSnBusPd2（dba）3 （5 mol %）PPh

6、3 （20 mol %） Adioxane, 50 1-substituted vinylstannanes can be poor substrates for the Stille reaction, probably due to steric constraints. However, conditions have been discovered that afford the desired Stille coupling product in excellent yields.mol % CuIrelative rateOH CH3OMOM（1.2 equiv）CH310114

7、The rate increase is attributed to the free ligand scavenging ability of CuI; strong ligands in solution are known to inhibit the rate-limiting transmetalation step.OCTPd（PPh3）4 （10 mol %）LiCl （6 equiv）, CuCl （5 equiv）/PH3DMSO, 60 C, 45 h Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org

8、. Chem. 1994, 59, 5905-5911.；Nf = n-CqFgSO?92% Stoichiometric Cu itself can mediate cross-coupling reactions under mild conditions, without Pd.SnBugO（1.5 equiv）CuONMP, 23 C, 15 min89% Transmetalation of Bu3Sn with CuCl is proposed to increase the rate of this reaction.Isolation of the homocoupling p

9、roduct in the following experiment was taken as evidence for a transmetalation event.n-PentylOHAllred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-2749.NMPN-CH3CuCl （5 equiv）, CuCl2 （2 equiv）C, 2 h84%Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605. Alkenes

10、as coupling partners:+OTBDMSPhPd2（dba）3 （20 mol %）CdC* （1.8 equiv）（j-Pr）2NEt, NMP40C, 53 h69%+ BugSn 1OTBSPd（PPh3）4 （10 mo l%）LiCl, THF80 C, sealed tube100%N（cH3）2CHOCH3I3Ph :（+）-A83543A, （+）-Lepicidin CdCl2 serves as a transmetalation cocatalyst. Without it, homodimerization of both coupling partne

11、rs was observed.Evans, D. A.; Black, W. D. J. Am. Chem. Soc. 1993, 115, 4497-4513.CH34HO2C HIndanomycin （X-14547A）Burke, S. D.; Piscopio, A. D.; Kort, M. E.; : Matulenko, M. A.; Parker, M. H.; Armistead, D. M.;Shankaran, K. J. Org. Chem. 1994, 59, 332-347.:Han, Q; Wiemer, D. F. J. Am. Chem. Soc. 199

12、2, 114, 7692-7697.Smith, A. B.; Condon, S. M.; McCauley, J. A.Leazer, J. L.; Leahy, J. W.; Maleczka, R. E. J. Am. Chem. Soc. 1995, 117, 5407-5408.Rapamycin1. （2-furyl）3PbPdCl2 （20 mol %） （j-Pr）2NEt, DMF, THF, 23 C, 7 h74%2. TBAF, AcOH, 0 3. HFPy, Py, THF, 23 61%Andrew Haidle,SnBugPd（CH3CN）2Cl2（20 mo

13、l %）（j-Pr）2NEt DMF, THF 25 C, 24 h28% 1 Allylic, benzylic halides:CH”.AcerosolideCHCI3, reflux, 48 h65%CH3 OCH3CH3 CH3 :Rapamycin :Nicolaou, K. C.; Chakraborty, T. K; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. : 1993, 115, 4419-4420. Acid chlorides can be used as coupling reagents （the Stille react

14、ion, as first reported, used ； acid chlorides）. :Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636-3638.O BnPdCI（PPh3）2 （2.5 mol %） oCHCl + 3H C 5%）A CHoj3 H2n4、O THF, 50 c 15 min 3 :93% H2N OPaquette, L. A.; Astles, P. C. J. Org. Chem. 1993, 58, 165-169.TBSOHO八 OCH3PdCl2（CH3CN）2 （3 mol

15、%）PPh3 （5 mol %）DME, reflux75%Liebeskind, L. S.; Yu, M. S.; Fengl, R. W. J. Org. Chem. 1993, 58, 3543-3549.Monocillin I.、OO OCH3Lampilas, M.; Lett, R. Tetrahedron Lett. 1992, 33, 777-780.Pd2（dba）3-CHCl3 （15 mol %） AsPhg （0.6 equiv） /Pr2NEt （10 equiv）DMF, 25 C, 36 h62%Pd2（dba）3CHCl3 （10 mol %）AsPh3 （

16、0.2 equiv）/PrzNEt （10 equiv）DMF, 40 C, 5 h45%2 N H2SO4 （2.0 equiv）THF : H2O 4 : 1, 25 33% （plus 50% starting material） In the first Stille coupling, none of the regioisomeric coupling product was isolated. Murphy, F.; Barluenga, S.; Ohshima, T.; Wei, H.; Xu, J.; Gray, D. L. F.; Baudoin, O. J. Am. Ch

17、em. Soc. 2000, 122, 3830-3838.Examples involving copper（I）: The copper（I）-mediated coupling of a vinyl stannane and a vinyl bromide succeeded when palladium catalysis failed. Note the selective transformation of the vinyl triflate to the vinyl stannane in the presence of the vinyl bromide. Liebeskin

18、ds copper（I） thiophene-2-carboxylate promoted coupling reaction was used for the total synthesis of concanamycin F. This reaction failed intramolecularly when the two coupling partners had already been joined via the ester linkage.OTfCH3 CH3CuCl （3 equiv）DMF, 60 C, 1 hPd（Ph3）4 （2 mol %）LiCl （6 equiv

19、）（CH3）3SnSn（CH3）3 （2 equiv）THF, reflux, 16 hSn（CH3）3L-CH3BrEtTESOCH3 CH3 OCH3”otCSConcanamycin FR = DEIPSHuang, A. X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999一10003.Paterson, I.; Doughty, V. A.; McLeod, M. D.; Trieselmann, T. Angew. Chem., Int. Ed. Engl. 2000, 39, 1308-1312. Andrew

20、 HaidleSynthesis of Aryl and Vinyl Stannanes:Bu3SnCl （0.85 equiv） BugSn，Li NH2CH2CH2NH2 THF, 0 C t 25 C, 18 h33% Directed ortho metalation followed by addition of a stannyl chloride is a standard method.Snieckus, V. Chem. Rev. 1990, 90, 923-924.Bu3SnH （1.2 equiv）AIBN （2.4 mol %） 90 C, 6 hBu3Sn，SnBu3

21、t-BuLi （3.8 equiv）Et2。，23 C, 2 h; Bu3SnCl （4.3 equiv）SnBu90%Renaldo, A. F.; Labadie, J. W.; Stille, J. K. Org. Synth. 1988, 67, 86-97.Tius, M. A.; Gomez-Galeno, J.; Gu, X.; Zaidi, J. H. J. Am. Chem. Soc. 1991, 113, 5775-5783.Bu3SnsnBu3CH3Li （1.2 equiv）, THF, -78 ClCO2Et （1.2 equiv）, 2.5 h; CH3OH（CH3

22、）3Sn2Pd（PPh3）4 （5 mol %）DME, 80 C, 15 h97%（CH3）3Sn59%Benaglia, M.; Toyota, S.; Woods, C. R.; Siegel, J. S. Tetrahedron Lett. 1997, 38, 4737-4740.CH3 OHI人OBu3SnOCH3, Et2O, 23 C;OTHPR SnR3Bu3SnH （1.1 equiv）AIBN （3 mol %）95 C, 3 h+ r：YCH3BugSn OTHP92% 85 : 15 The addition of stannyl radicals to alkynes

23、 is reversible under these conditions. The product ratio reflects the thermodynamic equilibrium.Corey, E. J.; Ulrich, P.; Fitzpatrick, J. M. J. Am. Chem. Soc. 1976, 98, 222-224.Bu3SnSsnBu3PdCl2（CH3CN）2 （5 mol %）BugSn OThibonnet, J.; Abarbi, M.; Parrain, J.-L.; Duchene, A. Synlett 1997, 771-772.Bu3Sn

24、（Bu）CuCNLi2THF, -40 C, 20 min;NHQSnBu395%97:3 E:ZAksela, R.; Oehlschlager, A. C. Tetrahedron 1991, 47, 1163-1176.CH3（2-Th）CuCNLi2 （1 equiv） -10 C t 23 C, THF, Et2。, 30 minBu3Sn CuCNLi26CrCZ/BusSnCHZC, 2.5 h; H2OSriBug82%1998, 39, 6419-6420.Hodgson, D. M.; Foley, A. M.; Lovell, P. J. Tetrahedron Lett.n-BuHB（ c-C6H“）26 12 n-Bu B（c-Hex）2THFNaOH （1 equiv）, THF, 23 C, 0.5 h;Cu（acac）2 （5 mol %）;BusSnCI,-15 n-Bu SnBu3Behling, J. R.; Ng, J. S.; Babiak, K. A.; Campbell, A. L.; Elsworth, E.;