Tri-2-furylphosphine (TFP)1

[5518-52-5]  · C12H9O3P  · (MW 232.175)

(phosphine ligand used in palladium-catalyzed cross-coupling and related transition metal-catalyzed reactions)

Physical Data: mp 63 °C;2 64-65 °C;3 bp 136 °C/4 mmHg;2 114 °C/0.6 mmHg.4

Solubility: soluble in most common organic solvents. Only sparingly soluble in hydrocarbons (e.g. pentane, hexanes).

Form Supplied in: white crystalline solid.

Analysis of Reagent Purity: extensive 1H, 13C, and 31P NMR analysis of TFP has been reported.3,5,6

Preparative Methods: commercially available. TFP can be prepared by reacting 2-furyllithium (formed in situ by lithiation of furan with n-BuLi or PhLi) with PCl3.2,4 Pre-forming the CeCl3 adduct has been shown to lead to much better yield.7 A simple procedure is reported below:8 In a three-necked round-bottom flask equipped with mechanical stirrer, addition funnel and nitrogen inlet, was placed furan (20.0 g, 0.294 mol), and anhydrous diethyl ether (100 mL) was added. From the addition funnel, n-BuLi (1.57 M in hexanes, 128 mL, 0.20 mol) was added at room temperature over 1 h. The resulting slurry was stirred another hour at room temperature, then cooled in ice, and a solution of PCl3 (5.50 g, 0.040 mol) in anhydrous toluene (45 mL) was added over 40 min. The ice bath was removed and the slurry was refluxed for 3 h. Upon cooling, aqueous ammonium chloride (10%, 140 mL) was added dropwise over 1 h. The phases were separated, the aqueous was extracted with diethyl ether (2 × 50 mL) and the organics combined, dried, and evaporated in vacuo. Distillation (bp 81-91 °C at 0.03 mmHg) gave a semisolid mass, which was further recrystallized from benzene/hexanes, to give white crystals with mp 63 °C.

Purification: TFP can be distilled in vacuo and/or recrystallized from benzene/hexanes or cyclohexane.2,3,4,8

Handling, Storage, and Precautions: TFP is quite stable to oxygen and can be stored under normal laboratory conditions. Traces of the oxide form on prolonged storage. No toxicological data are known for this phosphine.

Properties of the Ligand and Derived Catalysts

TFP is a ligand whose steric properties, as expressed by the cone angle parameter, differ very little from those of triphenylphosphine (TPP).1 Its electronic properties are, however, drastically different. That this is the case was suggested by the work of Allen et al., who showed that some tri-2-furylphosphonium salts were hydrolyzed by alkali up to 1010 times faster than the corresponding triphenylphosphonium salts.4 Allen went on to use these tri-2-furylphosphonium salts in the Wittig reaction,9 where they displayed unremarkable properties. From these studies, the electron-withdrawing properties of the TFP moiety are clear, and one would surmise that TFP should be much less basic than TPP, and therefore a ligand of much lower s-donicity than TPP. This is confirmed by the 1J(31P-77Se) coupling constants for the corresponding phosphine selenides.10 Infrared CO stretching of the corresponding Pd(II)-acyl complexes confirms that TFP is a poorer s-donor than TPP.11 More recent IR data on Ru(0) complexes confirm this view.12 Due to its much lower s-donicity, TFP dissociates from Pd(II) species more readily than TPP, as shown by direct equilibration experiments,11 and it is therefore expected to be a useful ligand in reactions where pre-coordination of the substrate to Pd(II), via ligand loss, is part of the rate-determining step.

Although cis-(TFP)2PdCl2 has been isolated and crystallized,13 all applications of this ligand in palladium chemistry have employed a simple Pd(0) or Pd(II) source and free TFP in variable proportions. Although Pd(OAc)2 is often used in conjunction with 2-4 equiv TFP, the most common palladium source is now constituted by the Pd-dba complexes. The original study on the use of TFP reported that TFP is much more associated with Pd(0) than TPP is, on the basis of low-temperature 31P NMR studies.11 It was postulated that this may be due p-back-bonding with the electron rich Pd(0). Amatore et al. studied the Pd/dba/TFP system in more detail and also concluded that TFP is more associated to Pd(0) than TPP is. They measured oxidative addition rates for both TPP and TFP complexes and, although they found differences that can be ascribed both to the different level of association and the intrinsic reactivity of the Pd(0) complexes, the rate difference is only minor and not enough to explain the tremendous acceleration noted in some Pd/TFP-catalyzed reactions.14 Evidence for p-back-bonding of TFP to Ru(0) complexes has also been presented.13 This back-bonding was invoked as the main reason for the increased catalyst stability observed with Pd(0)-TFP complexes versus the corresponding TPP species. Regardless of the resting state, qualitative observations have shown that TFP complexes are more robust and yield higher turnover numbers than those containing TPP.11

Most applications of TFP center around cross-coupling and related reactions. More recently, olefin insertion reactions of different kinds have also seen the application of TFP. In a few cases, even nickel- and ruthenium-catalyzed reactions have been carried out with TFP as ligand. Sometimes the reduced donicity of TFP can also be exploited in order to avoid reactions normally promoted by phosphines: for example, an alloc group deprotection using Pd(0) and HSnBu3 in the presence of a reactive azide moiety could not be carried out with TPP-derived catalysts, because of the competing Staudinger reaction. Due to the reduced reactivity of TFP in this reaction,15 a Pd(0)-TFP catalyst has been employed successfully.16

In view of the recent publication of an excellent and comprehensive review on the properties of tri-2-furylphosphines in transition metal-mediated synthesis,1 only the most useful applications of TFP will be briefly highlighted here, and the emphasis will be on the scope of the ligand, citing only those cases where the authors have reported that TFP shows synthetic advantage over more traditional ligands.

Use of TFP in the Stille Cross-Coupling Reaction

Historically, the first application of TFP as a ligand in a catalytic reaction came in a Stille coupling,17 and this still represents the most common area of application for TFP. In the synthesis of a variety of 3-substituted cephalosporins, it was shown that TFP could enhance the rate of cross-coupling between cephem derivatives and organostannanes by 1-2 orders of magnitude, therefore avoiding the side reactions normally observed with this class of sensitive substrates (b-lactam scission, d3-d2 double bond migration, etc.). This resulted in a general and stereospecific approach to a variety of substituted cephems (1).18-22

This protocol was then extended to a number of nucleoside derivatives.23,24 The milder conditions allowed by TFP were used to avoid double-bond isomerization or double-bond migration.11 In later work, a mechanistic rationale was proposed in order to account for the enhanced rates observed with TFP and AsPh3.11,25-27 In order to account for the measured inhibition of coupling rate by excess ligand, it was postulated that the rate-determining transmetalation is a stepwise process (2).

Pre-dissociation of a ligand molecule from intermediate 1 is needed, because another intermediate is observed kinetically before the transmetalation per se takes place. Such an intermediate, where unsaturated stannanes are involved, is likely to be 2,11 or any other species bearing one less phosphine coordinated to Pd(II) (the geometry of 1 is well characterized, for 2 and 3 the geometry shown is only tentative). Under this scenario, it is the dissociability of TFP from Pd(II) that makes it such a useful ligand. TFP has also been used in conjunction with CuI as co-catalyst,28 although the effect of CuI in conjunction with electron-withdrawing phosphines is known to be minor.29

Many applications have followed these initial reports. Dussault et al. have shown that a palladium complex containing TFP can effect cross-coupling under mild conditions on substrates bearing sensitive peroxide moieties (3).30,31

Mathey and co-workers have applied TFP as a ligand in order to effect regioselective cross-coupling on dibromophosphinines (4). A rationale for the regioselectivity was presented.32

Siesel and Staley have shown that sensitive cyclooctatetraene bromides couple efficiently with stannanes using TFP as a ligand (5).33 Later the same authors found the combination Pd/dba/TPP and CuI superior for this coupling.34

Gennari et al. have shown that the kinetic advantage of TFP extends to carbonylative Stille couplings (6).35 Under all conditions employed, the E/Z isomerization of the alkenyl triflate double bond could not be suppressed.

The regioselectivity of the coupling with unsymmetrical allylstannes has been studied, and it was shown that TFP has opposite selectivity to AsPh3 but similar to that of TPP (7).36

Recently, TFP has been found to be the ligand of choice in the Stille coupling of a new class of substrates, the benzylic sulfonium salts (8).37 The following example highlights the high reactivity of the sulfonium moiety, whereas an aryl bromide moiety is left untouched.

A new version of the Stille reaction which is catalytic in tin (in conjunction with a stoichiometric amount of a polysilane) was recently described by Maleczka et al. These authors found TFP to be the optimal ligand in this version as well (9).38 Note that two palladium catalysts were used, for reasons that are unclear.

Terminal gem-dibromoolefins can be coupled selectively at the E-bromo substituent using a TFP-based catalyst (10).39 Note that the same coupling fails with TPP, whereas AsPh3 tends to promote double coupling.

TFP was also found to be the ligand of choice when carrying out the Stille reaction in supercritical carbon dioxide.40 Its solubility in the medium may be an additional reason for its success. Polymers have been prepared by TFP-promoted Stille couplings,41-43 and the Stille reaction on polymer supports has also benefited from the use of TFP.44 The Ni(0) version of the Stille reaction is not appreciably promoted by TFP.45 The use of TFP in conjunction with carbene ligands has been shown not to be especially effective.46

Many applications of the TFP-promoted Stille coupling have been made to the synthesis of complex natural products, due mostly to the much milder conditions employable with this ligand.1 In conclusion, TFP is broadly applicable to most, if not all, Stille couplings with reactive electrophiles, i.e. in those cases where transmetalation is rate determining.

As most phosphines, TFP is thermally labile when bound to palladium, and subject to a P-Pd aryl exchange reaction.47 This was highlighted by some studies carried out at temperatures in excess of 100 °C. Incorporation of the furan ring into the product during attempted Stille couplings has been reported.48

Use of TFP in other Cross-Coupling Reactions

Unfortunately and perhaps surprisingly, a detailed and quantitative ligand study for other cross-coupling reactions has not been reported, and the assumption that all cross-coupling reactions follow the same mechanism would be a dangerous one. In any case, a lack of detailed mechanistic knowledge has not prevented applications of TFP-based catalysts to other metal systems. One of the most effective coupling methods consists in reacting organozinc derivatives under palladium catalysis, and this is generally known as Negishi coupling.

An interesting example (11) highlights the mildness of the TFP-based protocol, whereby a normally reactive boronate moiety is left untouched under the conditions, although other ligands such as AsPh3 also performed well in this reaction.49

Judicious ligand choice allowed Knochel and co-workers to selectively couple an aryl iodide moiety, leaving a triflate group unreacted, by using a TFP-based Pd(0) catalyst. The triflate can be easily coupled after switching the ligand to dppf (12).50

Also interesting is a recent application of a gem-dizinc reagent, which can homologate electrophiles by one carbon atom. TFP as ligand allows selective mono-coupling, and the resulting organozinc derivatives can be treated in situ with a variety of electrophiles (13).51

Allylic acetates have also been coupled in high yields with organozincs using TFP,52 and applications to nucleoside chemistry have also been recorded.53

The cross-coupling of organoboron derivatives (Suzuki reaction)54 has also been carried out with TFP as ligand, with apparent benefit. Once again, since the ligand dependence of the Suzuki coupling is not known, it is premature to conclude that TFP is a really useful ligand for Suzuki couplings. An investigation of the coupling of aryl boronic acids with aryl iodides concludes that TlOH is necessary to carry out the reaction at room temperature in DMA/water. Under these conditions, TFP affords no yield advantage over TPP. The authors conclude that the Suzuki transmetalation does not involve ligand dissociation and it follows instead a traditional substitution reaction via penta-coordinated palladium.55 This conclusion is premature, given that the use of Tl(I) may labilize the iodide, therefore affording a different type of tetracoordinate palladium intermediate. This would parallel the situation in the Stille reaction, which benefits from labile ligands only if the Pd(II) intermediate is strongly coordinated to a halide moiety.25

Shen showed that TFP aids in the selective Suzuki coupling of gem-dibromo olefins,56 and the homo-coupling of aryl boronic acids also works best with TFP-based palladium catalysts.57

A recent application of the TFP catalyst is the elegant new ketone synthesis described by Liebeskind et al., an example of which is shown below (14).58

The use of TFP in the coupling of organosilicon reagents (Hiyama reaction)59 has also not been studied in detail. A recent example found TFP to be an effective ligand, but inferior to others, including tri(tert-butyl)phosphine.60

The palladium-catalyzed coupling of acetylenes, named the Sonogashira coupling, has also been carried out with TFP-based catalysts.61 A couple of applications to nucleoside62 and carbohydrate chemistry63 have appeared.

Palladium-Catalyzed Olefin Insertion Reactions

The Heck reaction,64 which presumably requires pre-complexation of the reactive olefin to a Pd(II) intermediate, may be expected to benefit from TFP-based catalysts, and indeed several applications of TFP in insertion reactions have appeared. A recent one highlights both the high turnover frequency and the catalyst stability when TFP is used as ligand, which allows catalyst loads as low as 0.1%. Also the complete lack of desilylation, a common problem with vinylsilanes, is noteworthy (15).65

TFP was shown to be the ideal ligand, in conjunction with Pd(OCOCF3)2, or other fluorinated Pd sources, for Heck reactions in supercritical carbon dioxide.66 Use of TFP in conjunction with 2,5-dihydropyrroles gave products in good yield without double-bond migration, a common problem with these substrates (16).67

In the intramolecular arylation of enamidines from tetrahydropyridines, TFP was found to be a superior ligand, but in this case it was unsuccessful at preventing double-bond migration around the ring.68 A study of the regiochemistry of the Heck reaction with complex vinyl ethers showed no major difference between TFP and other common ligands.69

Use of TFP in Tandem Palladium-Catalyzed Synthetic Sequences

Given the synthetic versatility of palladium catalysis and the ability of TFP to enhance cross-coupling and olefin insertion rates, it is no surprise that TFP has found extensive application in tandem sequences. Liebeskind has systematically investigated the coupling of cyclobutenone electrophiles with unsaturated stannanes.70,71,72 This is usually followed in situ by thermal electrocyclic ring-opening/ring-closure to yield annulated benzene derivatives. TFP is needed only to promote the palladium step. An example is shown in 17.73

The combination Heck cyclization/cross-coupling reaction has been exploited extensively by Grigg in a variety of cascade reactions.74 An example is shown in 18.75

Generally, the intermediate alkyl-palladium should not have any b-hydrogen atoms, otherwise fast b-elimination would ensue. A carbonylation can also be inserted before the Stille capping step.76 In some cases, both the Heck insertion and the Stille capping are intramolecular.77 Use of an alkyne in the insertion followed by Stille coupling is shown in 19.78

Trapping by Suzuki coupling in a TFP-based process has also been described.79 Some examples where even alkyl-palladium intermediates with b-hydrogens can be trapped with stannanes have been reported. In one of them, Oppolzer reported that a catalytic system consisting of TFP as a ligand and ZnCl2 co-catalyst was the key to avoiding formation of 5 and directing the reaction toward 6 (20).80

Another report is apparently at odds with the one above, because TFP is reported to lead to b-elimination exclusively.81 Obviously, more work needs to be carried out on these tandem processes before generalizations can be made. An easier way to avoid b-elimination is to use norbornene as the olefin acceptor, where no syn co-planar hydrogens are present for the alkyl-palladium intermediate to eliminate, and therefore trapping with stannanes is possible in high yields. Here as well, TFP has proven very useful.82,83 Oppolzer has extended his approach to double olefin insertion reactions.84 He has also extended the range of electrophiles to propargyl acetates, which lead to vinylcyclopropanes via a TFP-promoted process.85 A palladium-catalyzed three-component one-pot condensation of alkynes with allyl bromide and stannanes uses TFP as ligand, but the yields are too low for the process to be synthetically useful.86

An interesting ‘umpolung’ approach was recently reported by Grigg, where insertion is across an allene, and the resulting palladium complex is `switched' to a nucleophilic reactivity mode by the use of Indium metal, followed by trapping with aldehydes (21).87

A different type of process employs a reactive electrophile, generated by oxidative addition of an unsaturated halide and Pd(0). This complex can apparently coordinate with an isolated alkyne, triggering formation of a C-C bond and a C-O bond. An example utilizing TFP is shown in 22.88 A variation on this theme using an endocyclic trapping process also uses TFP as ligand.89

A mechanistically related cyclization affording oxazolidinones, which uses a nitrogen-based nucleophile instead, was reported recently by the same group.90 Note that the TFP-based catalyst allows the reaction to proceed at room temperature, whereas an analogous method, independently developed, uses TPP and requires 60 °C.91

Among other applications in palladium chemistry, TFP has also been used in conjunction with regioselective silylstannations (23).92

Grigg has shown that TFP favors intramolecular attack on the central carbon of p-allyl-Pd moieties, yielding cyclopropanes among other products.93

Regioselective internal alkoxycarbonylation of terminal alkynes has also employed TFP as ligand, although superior results were obtained with a similar catalyst based on 2-diphenylphosphinopyridine.94 An isolated report on intramolecular amidation has described the use of TFP-based palladium catalysts.95

Among the non-palladium based synthetic methods utilizing TFP, the clever catalytic cycloisomerization/oxidation of homopropargyl alcohols developed by Trost and co-workers stands out. In this case also, TFP is described as providing superior results (24).96

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Vittorio Farina

Boehringer Ingelheim Pharmaceuticals, Ridgefield Connecticut, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.