- Stille reaction
The Stille reaction is a
chemical reaction coupling anorganotin compound with an sp2-hybridized organichalide catalyzed bypalladium . [ Kosugi, M. "et al." "Chem. Letters" 1977, 301.] [ Milstein, D.; Stille, J. K. "J. Am. Chem. Soc. " 1978, "100", 3636. (DOI|10.1021/ja00479a077)] The reaction is widely used in organic synthesis.X is typically a
halide , such as Cl, Br, I. Additionally, X can be apseudohalide such as atriflate , CF3SO3-. [ Scott, W. J.; Crisp, G. T.; Stille, J. K. "Organic Syntheses ", Coll. Vol. 8, p.97 (1993); Vol. 68, p.116 (1990). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv8p0097 Article] )] [ Stille, J. K.; Echavarren, A. M.; Williams, R. M.; Hendrix, J. A. "Organic Syntheses ", Coll. Vol. 9, p.553 (1998); Vol. 71, p.97 (1993). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv9p0553 Article] )]The Stille reaction was discovered in
1977 byJohn Kenneth Stille and David Milstein, a Post-doc in his laboratory. Stille reactions were used in 50% of all cross-coupling reactions published in1992 . The reaction continues to be exploited industrially, especially for pharmaceuticals.The reaction is usually performed under inert atmosphere using dehydrated and degassed solvent. This is because oxygen causes the
oxidation of the palladium catalyst and promotes homo coupling of organic stannyl compounds, and these side reactions lead to a decrease in the yield of the desired cross coupling reaction.As the organic tin compound, a trimethylstannyl or tributylstannyl compound is normally used. Although trimethylstannyl compounds show higher reactivity compared with tributylstanny compounds, the toxicity of the former is about 1000 times larger than that of the latter. Therefore it is better to avoid using trimethylstannyl compounds unless necessary.
Several reviews have been published. [ Stille, J. K. "
Angew. Chem. Int. Ed. Engl. " 1986, "25", 508–524. ( [http://dx.doi.org/10.1002/anie.198605081 Review] )] [ Farina, V.; Krishnamurthy, V.; Scott, W. J. "Org. React." 1998, "50", 1–652. ( [http://www.mrw2.interscience.wiley.com/ordb/articles/or050.01/abstract-fs.html Review] )] [ Mitchell, T. N. "Synthesis" 1992, 803-815. ( [http://dx.doi.org/10.1055/s-1992-26230 Review] )]Reaction mechanism
The
reaction mechanism of the Stille reaction has been well studied. [ Casado, A. L.; Espinet, P. "Organometallics" 1998, "17", 954–959.] [ Casado, A. L.; Espinet, P. "J. Am. Chem. Soc. " 1998, "120", 8978–8985. (DOI|10.1021/ja9742388)] The first step in thiscatalytic cycle is the reduction of thepalladium catalyst (1) to the active Pd(0) species (2). Theoxidative addition of the organohalide (3) gives a cis intermediate which rapidly isomerizes to the trans intermediate 4.Ref|Casado1998BTransmetalation with the organostannane (5) forms intermediate 7, which produces the desired product (8) and the active Pd(0) species (2) afterreductive elimination . The oxidative addition and reductive elimination retain the stereochemical configuration of the respective reactants.Rate of ligand transfer (transmetalation) from tin::alkynyl > alkenyl > aryl > allyl = benzyl > α-alkoxyalkyl > alkyl
The low reactivity of alkyl stannanes is a serious drawback but can be remedied by the use of strongly polar solvents such as
HMTP , DMF ordioxane .In 2007 the Stille reaction was subjected to a special type of
mass spectroscopy allowing for the first time the direct experimental observation of a Pd(0)(PPh3)2 species (always assumed to exist but never before actually detected) and a cyclic transmetallation intermediate -Pd(II)-X-Sn-C- both through theirradical cation s ["The Mechanism of the Stille Reaction Investigated by Electrospray Ionization Mass Spectrometry"Leonardo S. Santos, Giovanni B. Rosso, Ronaldo A. Pilli, and Marcos N. EberlinJ. Org. Chem. ; 2007; 72(15) pp 5809 - 5812; (Note) DOI|10.1021/jo062512n] .Variations
To improve the yield of the reaction,
lithium chloride is often added to the reaction mixture. This reagent stabilizes the intermediate complex formed by the oxidative addition of a catalyst and accelerates the reaction.Reactivity and specificity of the Stille reaction can be improved by the addition of stoichiometric amounts of Cu(I) or Mn(II) salts. [ Liebeskind, L. S.; Peña-Cabrera, E. "
Organic Syntheses ", Coll. Vol. 10, p.9 (2004); Vol. 77, p.135 (2000). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=v77p0135 Article] )] [ Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. "J. Org. Chem. " 1994, "59", 5905.] [ Liebeskind, L. S.; Fengl, R. W. "J. Org. Chem. " 1990, "55", 5359.]The cross-coupling reaction can be inhibited by ligands of a high
donor number .In the presence of Cu(I) salts,
palladium-on-carbon has been shown to be an effective catalyst. [ Roth, G. P.; Farina, V.; Liebeskind, L. S.; Peña-Cabrera, E. "Tetrahedron Lett. " 1995, "36", 2191.] [Renaldo, A. F.; Labadie, J. W.; Stille, J. K. "Organic Syntheses ", Coll. Vol. 8, p.268 (1993); Vol. 67, p.86 (1989). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv8p0268 Article] )]In the realm of
green chemistry a Stille reaction is reported taking place in a low melting and highly polar mixture of a sugar such asmannitol , aurea such as dimethylurea and a salt such asammonium chloride Note|Vasold2006 ["Stille Reactions with Tetraalkylstannanes and Phenyltrialkylstannanes in Low Melting Sugar-Urea-Salt Mixtures"Giovanni Imperato, Rudolf Vasold, Burkhard König Advanced Synthesis & Catalysis Volume 348, Issue 15 , Pages 2243 - 2247 2006 DOI|10.1002/adsc.2006] [cite journal
title = The Mechanisms of the Stille Reaction
author = P. Espinet, A. M. Echavarren
journal =Angewandte Chemie International Edition
volume = 43
issue = 36
year = 2004
pages = 4704–4734
doi = 10.1002/anie.200300638] . The catalyst system istris(dibenzylideneacetone)dipalladium(0) withtriphenylarsine :References
ee also
*
Heck reaction
*Hiyama coupling
*Suzuki reaction External links
* [http://www.chem.harvard.edu/groups/myers/handouts/Stille.pdf Stille reaction handout] from the Myers group.
* [http://www.organic-chemistry.org/namedreactions/stille-coupling.shtm Stille reaction] at organic-chemistry.org
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