AbstractPalladium is known to be able to catalyse a wide variety of cross coupling reactions. One of these reactions is known as “Stille coupling” named after John Kenneth Stille. This reaction couples an organic compound containing a leaving group and an organotin compound using a palladium catalyst.The first mentioned compound usually contains a sp2 hybridized carbon and the leaving groups are usually halides or triflates.IntroductionThere are a lot of applications for Palladium catalysts.
Cross coupling reactions are a very important part of organic synthesis and Pd is the basis of some of the catalysts used (e.g. the coupling of phenylboronic acid and haloarenes using a Pd(PPh3)4 catalyst 1).Historically, Palladium catalysts were already used for cross coupling reactions in the late 1970s. Toshihiko Migita was one of the researchers that worked on these reactions and set the basis for the development of the Stille coupling. He used Palladiumcomplexes (Pd(PPh3)4) led to the best yields) to catalyse coupling reactions containing tin reagents in 1983.
2Migita ended up coupling arryl and acyl halides with allyl tin compounds at low temperatures with high yields and Stille carried on to using different tin reagents at milder conditions and higher yields. 3The Stille coupling is nowadays used in synthetic organic chemistry. One example is the synthesis of the anticancer compound Cotylenin which includes the coupling of an allylic tin reagent and a triflate 4MechanismThe Stille coupling relies on a catalytic cycle containing an oxidative addition, transmetalation,isomerization and lastly reductive elimination.In the first step is the oxidative addition of the organic electrophile to the Pd0 complexfollowed by the addition of the leaving anion to form the a PdII complex. This leads to a cisaddition as shown.
Whereas the cis product is formed initially, the trans product is more stable and hence formedby isomerization. This can be prevented by using a bidentate ligand.The driving force for the transmetalation is the formation of an 18-electron transition state.The organotin compound is added to the formed trans PdII complex and a four-membered ringis formed. The high ring tension leads to a ring opening followed by leaving of the tin halide.In the end, both organic rests stay bonded to the Pd.After that, both of the R groups must isomerize back to the cis conformation. If a bidentateligand was used, this step is obviously not necessary.
The cis R-groups can then undergo areductive elimination that leads to the formation of the desired coupled product and a Pd0complex.There are two proposed mechanisms for the elimination. Either one more ligand is introducedinto the complex to form a trigonal bipyramidal structure. This leads to R and R’ being forcedinto an equatorial position which favours the formation of the desired C-C bond.
The other possible mechanism is that one ligand will dissociate leading to a T-shapedintermediate. This intermediate has 14 valence electrons and hence is very reactive andeliminates the product readily.AdditivesThe addition of CuI to the reaction will accelerate the Stille coupling. It is able to scavenge freeligand and hence speed up the transmetalation if a predissociative mechanism is assumed.
Therefore, if soft ligands are used the effect of CuI is very small because soft ligands easilydissociate from PdII. With hard ligands, the effect is stronger. According to the research ofFarina and Liebeskind 5 who used CuI in their experiment, the copper does not acceleratethe dissociation of ligand from the PdRXL2 complex but it scavenges the released ligand andtherefore speed up the transmetalation.Another way to accelerate the reaction is the addition of fluoride ions. The coupling of trans-(p-CN-C6H4)PdBr(PPh3)2 with (2- thienyl)SnBu3 for example does not work at roomtemperature. Even large excess and a long reaction do not show the desired product. Afterthe addition of Bu4NF however, the reaction quickly leads to 93% yield of product.
Too highconcentrations of fluoride result in the formation of the unreactive species 2-ThSnFBu3–though. The ideal ratio of F- to (2- thienyl)SnBu3 is smaller than 1. The mechanism of thecatalysis can be explained by the addition of the fluoride anion to the PdII complex to form ananionic pentacoordinated complex which is more prone to the reductive elimination. 6Another possible additive is LiCl. It improves the oxidative addition by stabilizing the transitionstate.
It also accelerates the transmetalation because of its effect on the polarity of thesolvent.Ligand effectsThe ligands of the used palladium complex have a severe impact on the reaction. Bidentateligands seem to accelerate the oxidative addition of aryl iodides are used for the couplingreaction. The bite angle also shows an impact. Switching from1,3-bis(diisopropropylphosphanyl)propane to 1,4-bis(diisopropropylphosphanyl)butane ledto a slower addition of phenyl iodide. The rate of the reductive elimination also depends onthe biting angle if bidentate ligands are used. Smaller angles seem to have a positive impactand eliminate the product more readily.
This is probably due to the higher ring tension andhence easier cleavage of one of the coordination sites of the ligand. The formed T-shapedcomplex intermediate is more prone to the elimination as described earlier. Complexes withmore stable chelates however do not undergo elimination at mild conditions. 7Alternative MechanismsAlthough the mechanism of the Stille coupling seems to be known (oxidative addition,isomerization, transmetalation and reductive elimination) there are a few other proposedmechanisms.For the coupling of sterically hindered alkenyl stannanes there probably is another mechanismincluding a palladium carbene intermediate. It includes a migration reaction as shown belowand the product is a 1,2-disubstituted alkene.
8Another possible pathway of the reaction may starts with the oxidative addition of theorganotin compound. Alkynyl stannanes can react with some Pd0 complexes via oxidativeaddition and with a certain ligand of the Pd0 complex the reaction works in following way. 9There maybe is also the possibility of a PdII/PdIV catalysis of the reaction. PdII complexes canbe oxidized to PdIV by oxidative addition of alkyl halides, aryl halides however are less reactivein that way. Nevertheless, this possibility should be kept in mind for future research.
Thereare in fact known MII/MIV catalysed reactions, even with Ni which is also a group 10 elementsame as Pd. It couples Alkyl halides or tosylates with Grignard reagents but the proposedmechanism is very similar to the Stille coupling and hence may also be applied to a possiblePdII/PdIV mechanism.ConclusionThe reaction is widely used because of its versatility. The used organotin compounds are toxicbut on the other hand air stable and mostly commercially available. Organic molecules withleaving groups are also commercially available or easy to synthesize.
So in the end it is a verysimple coupling reaction that also works under mild conditions. Only bulky or heavilysubstituted reagents sometimes react slowly. But this issue may be solved by adding copperiodide as described earlier.