Polystyrene-supported triphenylphosphine

[603-35-0]P

(reagent used in a variety of substitution and condensation reactions)

Solubility: insoluble in all typical solvents.

Form Supplied in: tan to dark brown 2% divinylbenzene crosslinked polystyrene beads 100-400 mesh in diameter; available from Aldrich/Fluka, Polymers Labs, NovaBiochem, Argonaut Technologies. Loading ranges from ~ 1.0 mMol P g-1 to > 3.0 mMol  P g-1.

Purification: washed with dichloromethane, dimethylformamide, and methanol and dried under vacuum.

Handling, Storage, and Precautions: can be handled like a typical solid taking precaution not to breathe dust, should be stored under inert atmosphere in a tightly sealed container to avoid oxidation. Toxic properties have not been fully examined.

Introduction and Background

Triphenylphosphine is a common chemical used for numerous organic transformations. During the reaction it is often oxidized to triphenylphosphine oxide. Since it is a true reagent, and not a starting material, excess reagent and oxidized by-products are generally removed following a synthetic sequence. Removal often requires tedious chromatographic and/or crystallization techniques. Polystyrene-supported triphenylphosphine (PS-TPP) was developed in the mid-1970s. It can be prepared from chlorodiphenylphosphine and lithiated polystyrene (from lithium-halogen exchange of bromopolystyrene) or by the reaction between lithium diphenylphosphine and bromopolystyrene. Polystyrene-supported triphenylphosphine has distinct advantages over its soluble counterpart since it can be filtered from reaction mixtures along with any oxidation by-product formed in the process. This simple removal can be performed in parallel fashion making it a useful reagent for combinatorial chemistry. Some of the documented uses of commercially available polystyrene-supported triphenylphosphine are highlighted here.

Mitsunobu Reactions

The condensation of alcohols with moderately acidic functional groups via triphenylphosphine-azodicarboxylate activation is one of the most common and reliable methods for alkylation. Products from the Mitsunobu reaction are often difficult to purify since stoichiometric quantities of triphenylphosphine oxide and hydrazine dicarboxylates lead to impurities that require difficult chromatographic purification of desired products. Easier methods for the removal of contaminants, such as filtration and/or conversion of impurities to substances more easily removed, have been developed. Polystyrene-supported triphenylphosphine was first used in the Mitsunobu reaction in 1983.1 Several years passed before its obvious utility in this transformation resurfaced. Recently, aryl ethers were prepared from phenols and alcohols. Good regioselectivity could be obtained with phenols bearing additional hydroxyl groups.2 The same researchers also showed that polystyrene-supported triphenylphosphine was useful for inversion of stereochemistry of alcohols.3 Others have improved the process by using polystyrene-supported triphenylphosphine as well as azodicarboxylates that are destroyed in situ. In the first instance, commercially available t-butylazodicarboxylate by-products were destroyed in situ upon treatment with trifluoroacetic acid (TFA). Filtration to remove phosphine oxide and excess phosphine followed by standard work-up led to products of > 95% purity in some cases. This protocol was used to generate a small parallel library which was free of phosphine/hydrazine impurities (1).4 In a similar development, cocaine analogs were prepared from benzoic acid and a tropane derivative.5 The product was isolated after removal of excess acid with a solid-phase scavenger, filtration, and TFA treatment for destruction of the azodicarboxylate. Barrett demonstrated the use of polystyrene-supported triphenylphosphine and an olefinic azodicarboxylate to obtain Mitsunobu products. Upon completion, the hydrazine by-product was converted to a solid via ring opening metathesis-polymerization (ROMP). This procedure, termed impurity annihilation, allowed most reagent-derived impurities to be filtered from the reaction mixture.6 Although the convenience of using polymer-supported triphenylphosphine in the Mitsunobu reaction has been demonstrated, reaction rates are known to be significantly decelerated.7 The rate loss presumably occurs from the increased diffusion time of reagents and starting materials into the polymer matrix.

Polymer-Supported Halophosphorane Complexes

Polymer-supported dichlorophosphorane was first prepared in 1974 from polymer-supported phosphine which was oxidized to the phosphine oxide and then treated with phosgene to provide the desired product.8 The reagent proved useful in a variety of transformations including conversion of acids to acid chlorides, alcohols to alkyl chlorides, primary amides to nitriles, secondary amides to imidoyl chlorides, and ketones to olefinic chlorides (2). The phosphine oxide by-product was recycled back to the dichlorophosphorane reagent by phosgene treatment following removal by filtration. Likewise, the bromine and carbon tetrabromide adducts have been prepared and used for brominations.9 The authors reported cleaner products and milder conditions with the tetrabromide reagent since HBr is not a by-product. Others have prepared similar bromine and iodine reagents in combination with imidazole.10 These reagents provide products and yields similar to their solution-phase counterparts.

Polymer-supported phosphine-halogen complexes have also been used for condensation reactions. Amides and small peptides were prepared from the corresponding acids and amines when reacted with polymer-supported phosphine and carbon tetrachloride.11,12 The procedure was amenable to a number of different protecting groups, racemization did not occur to any appreciable extent, and yields were high. The method also avoids the need for chromatography of products. One procedure involved activation via 2,2-dipyridyl disulfide and the reaction was followed by a filtration and standard work-up to provide good yields of pure products.13 Similarly, acids and alcohols were condensed to esters with iodine/bromine-phosphine reagents.14 Again, yields of products are high and chromatography is generally not required. The condensations occur via acid halides formed in situ.

Wittig Reagents

One of the more frequently used transformations involving phosphines in solution is the Wittig reaction. Several literature reports exist where polymer-supported triphenylphosphine has been used in this capacity to prepare olefins from relatively small starting materials.15-18 Ford was the first to prepare carbon-carbon double bonds on molecules as large as steroids with this reagent in the early 1980s.19 Good yields were obtained from carbonyl compounds and a modest excess of the resin-bound phosphonium salt. The excess polymeric reagent was filtered off along with the oxide by-product. The process represents one of the earliest examples of product cleavage from a resin in a traceless manner. In another example, a polymer-bound benzylphosphonium resin with an ortho-benzamide substituent was treated with a base and heated to provide the corresponding indole in the solution phase through an intramolecular Wittig/cyclization-cleavage method.20 The author also reacted the phosphonium-linked intermediates with aldehydes to generate conventional Wittig products with simultaneous product cleavage from the resin (3). Others have made use of the pseudo-high-dilution environment of polymer-supported phosphonium salts and selectively reacted them with dialdehydes to provide the monoolefinic product.15 A recent publication also described the preparation of olefins from resin-bound phosphonium salts and their elaboration to 1,2-aminoalcohols.21

Staudinger Reaction

Another useful transformation in which phosphines play a pivotal role is the Staudinger reaction and its modified versions. Phosphines react with azides to form iminophosphoranes which can be hydrolyzed to amines or reacted with carbonyl compounds to form imines and amides. Only a few examples exist in which polymer-supported triphenylphosphine has been used. Holletz and Cech converted azido nucleosides to amines by reacting the azide with polymer-supported triphenylphosphine and then hydrolyzing the intermediate with aqueous ammonia.22 The method did not affect other protecting groups and required no chromatography for pure products. In another example, iminophosphoranes prepared from resin-bound triphenylphosphine and soluble azides were reacted with aldehydes to provide the corresponding solution-phase imines which were reduced in situ with either sodium cyanoborohydride or resin-bound cyanoborohydride (4). Generally, good yields of the corresponding secondary amines were obtained.23 When trimethylsilylazide was used as the starting material, the process yielded primary amines following hydrolysis of the silyl nitrogen bond. Recently, b-azidovinylpyridines were converted to resin-bound iminophosphoranes and further reacted with isocyanates to provide solution-phase carbodiimides which spontaneously cyclized to pyridopyrimidines.24 Target compounds were prepared in parallel fashion.

Polymer-Bound Phosphine-Metal Complexes

Soluble phosphines are probably the most widely used ligands for catalysis mediated by heavy metals. It is not surprising that polymer-bound phosphine was used for this purpose shortly after its initial appearance in the literature. Soluble derivatives of heavy metals are often difficult to remove from organic reactions so the notion of an insoluble version of an active catalyst was attractive. Air stability of many catalysts was another feature attracting research in this area. A review on the subject was published in 1983.25 Several more recent metal-polystyrene-bound phosphine complexes and their reactions are mentioned here.

An insoluble version of tris(triphenylphosphine)ruthenium dichloride was recently prepared and evaluated for hydrogen transfer-oxidation capabilities.26 Ketones were reduced in the presence of isopropanol (hydrogen transfer reagent) under conditions similar to the soluble catalyst. Likewise, alcohols were successfully oxidized to ketones in the presence of peracetic acid and the insoluble ruthenium catalyst.

Cobalt has also been immobilized on PS-TPP. Its activity in the Pauson-Khand reaction has recently been explored.27 The same resin was used to immobilize acetylenes on resin through a Nicholas reaction.28

Rhodium complexes with polystyrene-supported phosphine were also used for oxidation of alcohols to aldehydes.29 The reagent could also be used to catalyze aldehyde addition to olefins.

Miscellaneous Uses for Polystyrene-supported Triphenylphosphine

The title reagent has been utilized occasionally as a linker for solid-phase synthesis. Following the reaction with a solution-phase azide the resin-bound iminophosphorane product can be treated and handled as many resin-bound starting materials are.24 Likewise, resin-bound phosphonium salts can be cleaved via hydrolysis or Wittig reaction.20 In all cases the cleavage from the resin is traceless.

E/Z mixtures of nitro olefins can be isomerized to E nitro olefins via resin-bound triphenylphosphine. Only catalytic amounts of the resin were necessary and the nucleophilic, nonbasic nature of the catalyst resulted in fewer nonconjugated side products than were obtained with triethylamine (5).30

The reagent has also proven valuable in the reduction of steroid ozonides.31 Products that were always contaminated to some degree with triphenylphosphine when it was used as the reducing agent, were isolated in pure form when the resin-bound reagent was used in its place.

Related Reagents.

Triphenylphosphine.


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Jeffrey C. Pelletier

Wyeth Pharmaceutical, Collegeville, PA, USA



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