Stille reaction

The Stille reaction (also known as Stille Coupling) is a chemical reaction coupling an organotin compound with an sp2-hybridized organic halide catalyzed by palladium.[1][2] 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-.[3][4]

The Stille reaction was discovered in 1977 by John Kenneth Stille and David Milstein, a post-doctorate 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, as 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 tributylstannyl 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.[5][6][7]

Contents

Reaction mechanism

The reaction mechanism of the Stille reaction has been well studied.[8][9] 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.[1] 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 spectrometry 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.[10]

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.[11][12][13]

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.[14][15]

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 [16] .[17] The catalyst system is tris(dibenzylideneacetone)dipalladium(0) with triphenylarsine:

See also

References

  1. ^ Kosugi, M. et al. Chem. Letters 1977, 301.
  2. ^ Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. (doi:10.1021/ja00479a077)
  3. ^ Scott, W. J.; Crisp, G. T.; Stille, J. K. Organic Syntheses, Coll. Vol. 8, p.97 (1993); Vol. 68, p.116 (1990). (Article)
  4. ^ 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). (Article)
  5. ^ Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508–524. (Review)
  6. ^ Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1998, 50, 1–652. (Review)
  7. ^ Mitchell, T. N. Synthesis 1992, 803-815. (Review)
  8. ^ Casado, A. L.; Espinet, P. Organometallics 1998, 17, 954–959.
  9. ^ Casado, A. L.; Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978–8985. (doi:10.1021/ja9742388)
  10. ^ 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
  11. ^ Liebeskind, L. S.; Peña-Cabrera, E. Organic Syntheses, Coll. Vol. 10, p.9 (2004); Vol. 77, p.135 (2000). (Article)
  12. ^ Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905.
  13. ^ Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359.
  14. ^ Roth, G. P.; Farina, V.; Liebeskind, L. S.; Peña-Cabrera, E. Tetrahedron Lett. 1995, 36, 2191.
  15. ^ Renaldo, A. F.; Labadie, J. W.; Stille, J. K. Organic Syntheses, Coll. Vol. 8, p.268 (1993); Vol. 67, p.86 (1989). (Article)
  16. ^ Stille Reactions with Tetraalkylstannanes and Phenyltrialkylstannanes in Low Melting Sugar-Urea-Salt MixturesGiovanni Imperato, Rudolf Vasold, Burkhard König Advanced Synthesis & Catalysis Volume 348, Issue 15 , Pages 2243 - 2247 2006 doi:10.1002/adsc.2006
  17. ^ P. Espinet, A. M. Echavarren (2004). "The Mechanisms of the Stille Reaction". Angewandte Chemie International Edition 43 (36): 4704–4734. doi:10.1002/anie.200300638. PMID 15366073. 

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