Stille reaction

The Stille reaction is a chemical reaction coupling an organotin compound with an sp²-hybridized organic halide catalyzed by palladium. [ 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 a pseudohalide such as a triflate, 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 by John Kenneth Stille and David Milstein, a Post-doc in his laboratory. Stille reactions were used in 50% of all cross-coupling reactions published in 1992. 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 this catalytic cycle is the reduction of the palladium catalyst (1) to the active Pd(0) species (2). The oxidative addition of the organohalide (3) gives a cis intermediate which rapidly isomerizes to the trans intermediate 4.Ref|Casado1998B Transmetalation with the organostannane (5) forms intermediate 7, which produces the desired product (8) and the active Pd(0) species (2) after reductive 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 or dioxane.

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 their radical cations ["The Mechanism of the Stille Reaction Investigated by Electrospray Ionization Mass Spectrometry"Leonardo S. Santos, Giovanni B. Rosso, Ronaldo A. Pilli, and Marcos N. Eberlin J. 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 as mannitol, a urea such as dimethylurea and a salt such as ammonium 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 is tris(dibenzylideneacetone)dipalladium(0) with triphenylarsine:

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