The Stille reaction is a chemical reaction widely used in organic synthesis. The reaction involves the coupling of two organic groups, one of which is carried as an organotin compound (also known as organostannanes). A variety of organic electrophiles provide the other coupling partner. The Stille reaction is one of many palladium-catalyzed coupling reactions.Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010. Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508–524. (Review)Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1998, 50, 1–652. (Review)
R'-X + R''-SnR3 ->[\ce{Pd}] R'-R'' + XSnR3
These organostannanes are also stable to both air and moisture, and many of these reagents either are commercially available or can be synthesized from literature precedent. However, these tin reagents tend to be highly toxic. X is typically a halide, such as Cl, Br, or I, yet pseudohalides such as triflates and sulfonates and phosphates can also be used.Scott, W. J.; Crisp, G. T.; Stille, J. K. Organic Syntheses, Coll. Vol. 8, p. 97 (1993); Vol. 68, p. 116 (1990). (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). (Article) Several reviews have been published.Kurti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier: Burlington, 2005.Mitchell, T. N. J. Organomet. Chem., 1986, 304, 1–16.Mitchell, T. N. Synthesis, 1992, 803–815. ()Farina, V. Pure Appl. Chem., 1996, 68, 73–78. ().Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction; Wiley: Online, 2004. ().Espinet, P.; Echavarren, A. M. Angew. Chem. Int. Ed., 2004, 43, 4704–4734.()Pattenden, G.; Sinclair, D. J. J.Organomet. Chem., 2002, 653, 261–268.Kosugi, M.; Fugami, K. J. Organomet. Chem., 2002, 19, 10–16.Pierre Genet, J.; Savignac, M. J. Organomet. Chem., 1999, 576, 305–317.Cordova, C.; Bartolomé, C.; Martínez-Ilarduya, J.M..; Espinet, P. ACS Catal., 2015, 5, 3040–3053.().
History The first example of a palladium catalyzed coupling of aryl halides with organotin reagents was reported by Colin Eaborn in 1976.Azarian, D.; Dua, S. S.; Eaborn, C.; Walton, D. R. M. J. Organomet. Chem., 1976, 117, C55-C57. () This reaction yielded from 7% to 53% of diaryl product. This process was expanded to the coupling of acyl chlorides with alkyl-tin reagents in 1977 by Toshihiko Migita, yielding 53% to 87% ketone product.Kosugi, M.; Shimizu, Y.; Migita, T. Chem. Lett., 1977, 6, 1423–1424. ()
In 1977, Migita published further work on the coupling of allyl-tin reagents with both aryl (C) and acyl (D) halides. The greater ability of allyl groups to migrate to the palladium catalyst allowed the reactions to be performed at lower temperatures. Yields for aryl halides ranged from 4% to 100%, and for acyl halides from 27% to 86%.Kosugi, M.; Sasazawa, K.; Shikizu, Y.; Migita, T. Chem. Lett., 1977, 6, 301–302. ()Kosugi, M.; Shimizu, Y.; Migita, T. J. Organomet. Chem., 1977, 129, C36-C38. () Reflecting the early contributions of Migita and Kosugi, the Stille reaction is sometimes called the Migita–Kosugi–Stille coupling.
John Kenneth Stille subsequently reported the coupling of a variety of alkyl tin reagents in 1978 with numerous aryl and acyl halides under mild reaction conditions with much better yields (76%–99%).Milstein, D.; Stille, J. K. Journal of the American Chemical Society, 1978, 100, 3636–3638. () Stille continued his work in the 1980s on the synthesis of a multitude of ketones using this broad and mild process and elucidated a mechanism for this transformation.Milstein, D.; Stille, J. K. Journal of the American Chemical Society, 1979, 101, 4992–4998. ()Milstein, D.; Stille, J. K. J. Org. Chem., 1979, 44, 1613–1618. ()
By the mid-1980s, over 65 papers on the topic of coupling reactions involving tin had been published, continuing to explore the substrate scope of this reaction. While initial research in the field focused on the coupling of alkyl groups, most future work involved the much more synthetically useful coupling of vinyl, alkenyl, aryl, and allyl organostannanes to halides. Due to these organotin reagent's stability to air and their ease of synthesis, the Stille reaction became common in organic synthesis.
Mechanism The mechanism of the Stille reaction has been extensively studied.Casado, A. L.; Espinet, P.; Gallego, A. M. J. Am, Chem. Soc., 2000, 122, 11771-11782. () The catalytic cycle involves an oxidative addition of a halide or pseudohalide (2) to a palladium catalyst (1), transmetalation of 3 with an organotin reagent (4), and reductive elimination of 5 to yield the coupled product (7) and the regenerated palladium catalyst (1).Crabtree, R. H. The Organometallic Chemistry of the Transition Metals, 5th ed.; Wiley: New York, 2009.
However, the detailed mechanism of the Stille coupling is extremely complex and can occur via numerous reaction pathways. Like other palladium-catalyzed coupling reactions, the active palladium catalyst is believed to be a 14-electron Pd(0) complex, which can be generated in a variety of ways. Use of an 18- or 16- electron Pd(0) source , can undergo ligand dissociation to form the active species. Second, phosphines can be added to ligandless palladium(0). Finally, as pictured, reduction of a Pd(II) source (8) , , , , etc.) by added phosphine ligands or organotin reagents is also common
Oxidative addition Oxidative addition to the 14-electron Pd(0) complex is proposed. This process gives a 16-electron Pd(II) species. It has been suggested that anionic ligands, such as OAc, accelerate this step by the formation of [Pd(OAc)(PR3)n]−, making the palladium species more nucleophillic.Perez-Temprano, M. H.; Gallego, A. M.; Casares, J. A.; Espinet, P. Organometallics, 2011, 30, 611–617. (). In some cases, especially when an sp3-hybridized organohalide is used, an SN2 type mechanism tends to prevail, yet this is not as commonly seen in the literature. However, despite normally forming a cis-intermediate after a concerted oxidative addition, this product is in rapid equilibrium with its trans-isomer.Minniti, D. Inorg. Chem, 1994, 33, 2631–2634.().Casado, A. L.; Espinet, P. Organometallics, 1998, 17, 954–959. ().
There are multiple reasons why isomerization is favored here. First, a bulky ligand set is usually used in these processes, such as phosphines, and it is highly unfavorable for them to adopt a cis orientation relative to each other, resulting in isomerization to the more favorable trans product. An alternative explanation for this phenomenon, dubbed antisymbiosis or transphobia, is by invocation of the sdn model.Landis, C. R.; Firman, T. K.' Root, D. M.; Cleveland, T. Journal of the American Chemical Society, 1998, 120, 1842–1854. (). Under this theory, palladium is a hypervalent species. Hence R1 and the trans ligand, being trans to each other, will compete with one palladium orbital for bonding. This 4-electron 3-center bond is weakest when two strong donating groups are present, which heavily compete for the palladium orbital. Relative to any ligand normally used, the C-donor R1 ligand has a much higher trans effect. This trans influence is a measure of how competitive ligands trans to each other will compete for palladium's orbital. The usual ligand set, phosphines, and C-donors (R1) are both soft ligands, meaning that they will form strong bonds to palladium, and heavily compete with each other for bonding.Vicente, J.; Arcas, A.; Bautista, D. Organometallics, 1997, 16, 2127–2138. ().Pearson, R. G. Inorg. Chem, 1973, 12, 712–713.(). Since halides or pseudohalides are significantly more electronegative, their bonding with palladium will be highly polarized, with most of the electron density on the X group, making them low trans effect ligands. Hence, it will be highly favorable for R1 to be trans to X, since the R1 group will be able to form a stronger bond to the palladium.
Transmetallation The transmetallation of the trans intermediate from the oxidative addition step is believed to proceed via a variety of mechanisms depending on the substrates and conditions. The most common type of transmetallation for the Stille coupling involves an associative mechanism. This pathway implies that the organostannane, normally a tin atom bonded to an allyl, alkenyl, or aryl group, can coordinate to the palladium via one of these double bonds. This produces a fleeting pentavalent, 18-electron species, which can then undergo ligand detachment to form a square planar complex again. Despite the organostannane being coordinated to the palladium through the R2 group, R2 must be formally transferred to the palladium (the R2-Sn bond must be broken), and the X group must leave with the tin, completing the transmetalation. This is believed to occur through two mechanisms.Garcia-Melchor, M.; Braga, A. A. C.; Lledos, A.; Ujaque, G.; Maseras, F. Acc. Chem. Res., 2013, 46, 2626–2634. ()
First, when the organostannane initially adds to the trans metal complex, the X group can coordinate to the tin, in addition to the palladium, producing a cyclic transition state. Breakdown of this adduct results in the loss of R3Sn-X and a trivalent palladium complex with R1 and R2 present in a cis relationship. Another commonly seen mechanism involves the same initial addition of the organostannane to the trans palladium complex as seen above; however, in this case, the X group does not coordinate to the tin, producing an open transition state. After the α-carbon relative to tin attacks the palladium, the tin complex will leave with a net positive charge. In the scheme below, please note that the double bond coordinating to tin denotes R2, so any alkenyl, allyl, or aryl group. Furthermore, the X group can dissociate at any time during the mechanism and bind to the Sn+ complex at the end. Density functional theory calculations predict that an open mechanism will prevail if the 2 ligands remain attached to the palladium and the X group leaves, while the cyclic mechanism is more probable if a ligand dissociates prior to the transmetalation. Hence, good leaving groups such as triflates in polar solvents favor the cyclic transition state, while bulky phosphine ligands will favor the open transition state.
A less common pathway for transmetalation is through a dissociative or solvent assisted mechanism. Here, a ligand from the tetravalent palladium species dissociates, and a coordinating solvent can add onto the palladium. When the solvent detaches, to form a 14-electron trivalent intermediate, the organostannane can add to the palladium, undergoing an open or cyclic type process as above.
Reductive elimination step In order for R1-R2 to reductively eliminate, these groups must occupy mutually cis coordination sites. Any trans-adducts must therefore isomerize to the cis intermediate or the coupling will be frustrated. A variety of mechanisms exist for reductive elimination and these are usually considered to be concerted.Gillie, A.; Stille, J. K. Journal of the American Chemical Society, 1980, 102, 4933–4941. ().Brown, J. M.; Cooley, N. A. Chem. Rev., 1988, 88, 1031–1046. ().
First, the 16-electron tetravalent intermediate from the transmetalation step can undergo unassisted reductive elimination from a square planar complex. This reaction occurs in two steps: first, the reductive elimination is followed by coordination of the newly formed sigma bond between R1 and R2 to the metal, with ultimate dissociation yielding the coupled product.
The previous process, however, is sometimes slow and can be greatly accelerated by dissociation of a ligand to yield a 14-electron T shaped intermediate. This intermediate can then rearrange to form a Y-shaped adduct, which can undergo faster reductive elimination.