Cinzia Chiappe*a, Giovanni Imperatoa, Elio Napolitanob and Daniela Pieraccinia
aDipartimento di Bioorganica e Biofarmacia, via Bonnanno 33, Pisa, Italy. E-mail: cinziac@farm.unipi.it; Fax: +39 050 43321; Tel: +39 050 44074
bScuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, Pisa, Italy. E-mail: eliona@farm.unipi.it
First published on 8th December 2003
The Stille cross-coupling reaction has been investigated in ten different ILs to evaluate how the different physico-chemical properties of the medium can affect the transfer of vinyl and alkyl groups, as well as the efficiency of the extraction processes. The possibility of working in the absence of ligand has been also evaluated.
Fig. 1 ILs used. |
We considered the reaction of tributylvinylstannane, tetramethylstannane and tetrabutylstannane with iodobenzene in presence or in absence of AsPh3 (“ligandless” coupling). When AsPh3 was present, Pd2(dba)3 was the source of catalyst; otherwise Pd(OAc)2 was adopted in the ligandless reaction. Although palladium catalysts rapidly dissolve in the ionic media at the reaction temperature, reagents and products are only slightly soluble, so a biphasic system resulted. In these cases cross-coupling products could, in principle, be isolated by decantation. Only in the very lipophilic [bmim][C8H17SO4] did the reaction occur in a homogeneous phase. In order to obtain comparable data, however, products were isolated in all cases by n-pentane extraction.
The data summarized in Table 1 show that [bmim][C8H17SO4] is the best solvent for the Stille coupling of vinylstannane and iodobenzene both in terms of yield of reaction and extraction from the reaction medium (entry 4), followed by bis(trifluoromethylsulfonyl)imide salts ([bmim][Tf2N], [HPy][Tf2N], [bpyrr][Tf2N], entries 1, 9, 10, respectively). In contrast, significantly lower yields of styrene were obtained in nucleophilic solvents like [bmim][Br] and [emim][OTs]. Modification of the structure of the cation determines appreciable variations in the coupling rate only for hexafluorophosphate derivatives (compare entries 2 and 7 with 1, 8, 9, 10). The difference seems related to a different hydrogen-bond acidity; the cation which is unable to form a hydrogen bond performs better than the other one.
The ligandless Stille coupling was significantly less effective, as compared to the reaction with AsPh3 complexed catalyst, in all ionic liquids: up to 24 hours (as compared to 4 h) were necessary to achieve quantitative coupling. It is worth of note that under these conditions the reduction of Pd(II) to Pd(0) is immediate, therefore the reduced efficiency of the ligandless coupling cannot be attributed to this step. The data, summarized in Table 2, show that [Tf2N] derivatives give the highest reaction rates. It is worth noting that, in absence of AsPh3, the reaction seems to be more sensitive to the cation, so that ILs unable to give hydrogen bonding ensure the highest percentage of conversion (entries 8–7 vs. 1–2).
The reuse of catalyst was briefly investigated for the reaction in [bmim][C8H17SO4], [bmim][Tf2N], [bpyrr][Tf2N], and [HPy][Tf2N]: the data reveal a modest decrease in activity for Pd(II) in [bpyrr][Tf2N] (20%) and a complete loss of activity of the catalyst in the remaining ILs; the loss of catalytic activity is probably due to the precipitation of Pd(0) at the end of the extraction process.
The transfer of alkyl groups from simple tetraorganotin to iodobenzene still remains difficult in the ionic medium and, in the case of methyl introduction, it is generally accompanied by the formation of biphenyl (Table 3). When Me4Sn was used as reactant and [bmim][C8H17SO4] as solvent, the introduction of the alkyl group also proceeded with the uncomplexed catalyst, although a slightly higher amount of biphenyl was detected (entries 1, 2). Once again, [bmim][C8H17SO4] and [bmim][Tf2N] are the best choice solvents for this Stille cross-coupling.
Solvent | Catalyst | Ligand | R | Time/h | Mass balancea [%] | Ph–Rb [%] | Biphenylb [%] | |
---|---|---|---|---|---|---|---|---|
a Determined using benzonitrile as internal standard.b Determined by GC and GM analysis.c The unreacting material was always represented by iodobenzene. | ||||||||
1 | [bmim]C8H17SO4 | Pd2(dba)3 | AsPh3 | –CH3 | 24 | 100 | 31c | n.d |
2 | [bmim]C8H17SO4 | Pd(OAc)2 | — | –CH3 | 24 | 100 | 48c | 6 |
3 | [bmim]Tf2N | Pd2(dba)3 | AsPh3 | –CH3 | 24 | 90 | 62c | 27 |
5 | [bmim]Tf2N | Pd(OAc)2 | — | –CH3 | 24 | 70 | 12c | 30 |
4 | [bmim]PF6 | Pd2(dba)3 | AsPh3 | –CH3 | 24 | 87 | 54c | 28 |
6 | [bmim]C8H17SO4 | Pd2(dba)3 | AsPh3 | –C4H9 | 48 | 50 | 15c | <1 |
7 | [bmim]C8H17SO4 | Pd(OAc)2 | — | –C4H9 | 48 | 52 | 21c | n.d. |
8 | [bmim]Tf2N | Pd2(dba)3 | AsPh3 | –C4H9 | 48 | 70 | 60c | n.d. |
9 | [bmim]OTs | Pd2(dba)3 | AsPh3 | –C4H9 | 48 | 30 | 20c | n.d. |
10 | [bmim]Br | Pd2(dba)3 | AsPh3 | –C4H9 | 48 | 30 | 8c | n.d |
11 | [HPy]Tf2N | Pd2(dba)3 | AsPh3 | –C4H9 | 48 | 55 | 9c | n.d |
On the other hand, the introduction of n-butyl was extremely slow and always stopped before completion. Moreover product extraction with n-pentane was particularly ineffective as compared with previous examples. It is however worth noting that, when [bmim][Tf2N] was used as solvent, 60% of butylbenzene was obtained without the formation of the side product.
Scheme 1 |
The strong cation–anion interaction present in [bmim][Br] could reduce the ability of this anion to nucleophilically assist the transmetallation and could therefore explain the low rate of the Stille cross-coupling reaction performed in this solvent, as compared1c to other Pd-mediated reaction performed in tetrabutylammonium bromide. Competing equilibria have been proposed by Welton to explain the effect of hydrogen bonding in Diels–Alder reaction and in recent polarity mesurements.8,9 Though in Diels–Alder reaction it is the ability of the cation to act as a hydrogen bond donor that determine the endo selectivity, in the Stille cross-coupling it is the hydrogen bond acceptance of the anion that can influence the result of the reaction. Therefore, it seems that both in hydrogen bond donation and acceptance, competition between the solute and the proper counterpart of the ionic liquid can be important in determining the result of a given reaction.
On the other hand, the high efficiency of the reaction in [bmim][C8H17SO4] might be related to more favorable intrinsic properties of this new ionic liquid or to the fact that reaction occurs in a homogeneous phase.
The structure of the cationic counterpart has little effect on the vinyl transfer from tetraorganotin to iodobenzene. The data reported in Table 1 show that, mantaining the anion, ionic liquids derived from different classes of organic compounds, that is imidazolium, pyridinium and pyrrolidinium salts, give almost identical results. The ability of the cation to form hydrogen bonds seems, however, to have some consequences. In particular, the introduction of a methyl group between the two nitrogen atoms in imidazolium derivatives, that should suppress the hydrogen bond acidity of the solvent, has a different effect depending on the nature of the negative counterpart: it enhances the rate of cross-coupling in the hexafluorophosphate series, whereas it has no effect on the bis(trifluoromethylsulfonyl)imide derivatives.
The data seem also to demonstrate that the reaction rates are not dependent on viscosity: comparable results are obtained for the homologous [bmim][Tf2N] and [bm2im][Tf2N], which at least at room temperature have quite different viscosities.10,11 Therefore, although the reactions occur under heterogeneous conditions, mass transfer is not the rate determining step. However, this physical property is probably more important during the isolation of the product; because of the poor material balance, the three most viscous ILs, namely [bm2im][PF6], [emim][OTs], and [bmim][Br], cannot be advantageously used as solvent for the Stille reaction (entries 5, 6, 7 from Table 1).
As shown in Table 2, ILs can effectively replace toxic solvents like HMPA in ligandless Stille cross-coupling.12 As with Pd(AsPh3)2, non nucleophilic ionic liquids having bis(trifluoromethylsulfonyl)imide as the anion are the best choice for the ligandless cross-coupling reactions (entries 1, 8, 9, 10). Apparently, when ligands are not present, the possibility of N–Sn intermolecular interactions enhances the reactivity of the system so that the coupling is complete in reasonably short times (4 hours). Furthermore, under these conditions the rate of the reaction is more sensitive to cationic structure, so that ILs incapable of forming H-bonds are preferred (compare entries 1 and 2 with 7 and 8). As in conventional solvents, the lack of coordinating ligands negatively affects the stability of the catalyst, so that recycling of the system is often difficult.
Much of the discussion of Pd catalyzed reactions in ionic liquids has focused on the possible formation of imidazolidene complexes either by deprotonation of the imidazolium cation1b,13 or by oxidative addition of the cation to the metal centre.14 As the Stille cross-coupling under investigation is sensitive to the presence of AsPh3 and the yields of conversion in [bpyrr][Tf2N] and [HPy][Tf2N] are very similar to those obtained in [bmim][Tf2N], we believe that the involvement of a metal carbene complex formed in situ is unlikely under our conditions. However, our data do not give information about the nature of the really reactive palladium species, so it is not possible to exclude the presence of Pd nanoparticles.15
Finally, although with a lower efficiency, ILs can also be used to transfer alkyl groups using simple commercial tetraalkylstannanes. Besides, the yields for methyl and butyl transfer are similar to or higher than those reported in conventional organic solvents.16 Anyway, the use of ionic liquids as the reaction media cannot be considered a variant to the use of stannatranes17 which, although not easy to synthesize, remain the reagents capable of significantly improving the alkyl transfer in Stille coupling.
Reactions were carried out in a screw cup with Teflon-faced rubber septum vials under magnetic stirring. To a suspension of Pd2(dba)3 (0.025 mmol) and Ph3As (0.05 mmol) or Pd(OAc)2 (0.025 mmol) in 1 ml of ionic liquid were added iodobenzene (0.5 mmol) and the organostannane (0.6 mmol). The mixtures were stirred at 80 °C for the times reported in Tables 1, 2 and 3. The products were extracted with n-pentane (10 × 1 ml), the organic layers were dried over MgSO4 and diluted to an exactly known volume. A portion of this solution, exactly measured, was analyzed by GC-MS and the remaining by GC, after the addition of an appropriate amount of an internal standard (benzonitrile).
Footnote |
† Electronic supplementary information (ESI) available: Stille coupling of iodobenzene with tributylvinylstannane in ionic liquids with complexed palladium catalyst. See http://www.rsc.org/suppdata/gc/b3/b313221h/ |
This journal is © The Royal Society of Chemistry 2004 |