Polymer-supported triphenylphosphine: application in organic synthesis and organometallic reactions

This comprehensive review highlights the diverse chemistry and applications of polymer-supported triphenylphosphine (PS-TPP) in organic synthesis since its inception. Specifically, the review describes applications of the preceding reagent in functional group interconversions, heterocycle synthesis, metal complexes and their application in synthesis, and total synthesis of natural products. Many examples are provided from the literature to show the scope and selectivity (regio, stereo, and chemo) in these transformations.


Introduction
One of the latest advances in recent years has been the utility of solid-phase synthesis as a strategy to prepare chemical libraries, 1 biologically active molecules, and natural products. 2,3 Adaptation of solution phase synthetic techniques to use on solid supports offers some key advantages over solution-phase chemistry such as ease of purication, recyclability of the solid matrix, and use of excess reagents to achieve complete reaction conversion.
Consequently reagents have found many applications in synthetic organic chemistry. As such, the use of supported reagents in medicinal chemistry has been nicely showcased by Ley in the multi-step synthesis of drug targets and natural products such as silde-nal (Viagra), 4 epimaritidine 5 and epibatidine. 6 One of the most useful reagents to which many chemical transformations can be credited is polymer-supported triphenylphosphine (diphenylpolystyrylphosphine or polystyryldiphenylphosphine (1), PS-PPh 2 ), an analogue of the ubiquitous triphenylphosphine (PPh 3 ). The latter is a common reagent used in many chemical transformations where in many cases it gets oxidized to triphenylphosphine oxide (Ph 3 PO). Removal of Ph 3 PO from the product requires tedious chromatographic separation and/or crystallization processes which renders PPh 3 impractical. As an alternative, polystyrene-supported triphenylphosphine was introduced. This reagent has an advantage over the its soluble counterpart because it can be separated along with any oxidation byproduct by ltration. The reagent can be easily prepared in one step and for convenience is commercially available from several chemical suppliers (100-200 mesh, extent of labeling: $3 mmol g À1 triphenylphosphine loading). The immobilized reagent was rst reported in 1971 and has been extensively used ever since. 7 However, the full synthetic potential of the reagent and variations thereof is still being established and several research groups around the globe are still aggressively pursuing such endeavors as demonstrated by the recent surge of research articles published by various groups on a wide range of transformations mediated by this reagent. The PS-PPh 2 reagent has not yet been thoroughly reviewed in the literature except in some instances where it was briey featured as a part of reviews of much wider scope. [8][9][10] Thus, in this comprehensive review, an attempt to give an overall detailed picture of the synthetic utility of PS-PPh 2 has been made by taking many examples from the literature covering almost 50 years. The review focuses on the preparation of PS-PPh 2 and its utility in functional group interconversions, transition metal complexes and their reactions, heterocyclic synthesis, and preparation of natural products. Special focus has been dedicated to the impact of the structural framework of the substrate, substitution pattern, and conguration on reaction times and conditions, as well as on the stereo-, chemo, and regiochemical outcome of the reaction. Therefore we have discussed the synthetic schemes and entries in every table for the various transformations in detail. The scope of the review will be limited to PS-PPh 2 and its reactions.

Preparation of polystyryldiphenylphosphine (1)
Generally, one of the simplest approaches to immobilize a phosphine ligand on a polymer support involves direct reaction of the desired ligand with a functionalised polymer such as bromopolystyrene or Merrield's resin. Polystyrene resins are commercial available in a variety types, cross-link densities, and particle sizes. The cross-linked diphenyl-polystyrylphosphine (PS-PPh 2 , 1) can be prepared from bromopolystyrene (2) via a lithium-halogen exchange process by initial lithiation of the polymer support 2 to form lithiated polystyrene (Scheme 1), followed by reaction with chlorodiphenylphosphine (PPh 2 Cl). 7,[11][12][13] There are however drawbacks associated with this approach. Reaction of cross-linked bromopolystyrene with butyllithium oen leads to unwanted side-reactions involving the C]C bonds of the divinylbenzene crosslinking. Consequently, the product resin becomes contaminated and shows poor swelling properties. More efficient preparation of the polystyryl-lithium species that precludes attack of the divinylbenzene crosslinking moiety involves reaction of cross-linked polystyrene with the 1 : 1 complex of n-butyl-lithium and N,N,N 0 N 0 -tetramethylethylenediamine (TMEDA). 14 An alternative preparation of PS-PPh 2 (1) involves reaction of cross-linked bromopolystyrene (2) with lithium diphenylphosphide (3). 7,12,13,15 This method represents the more common route for the attachment of monodentate phosphines to polymer resins. PS-PPh 2 is insoluble in all typical organic solvents and is readily available through several chemical vendors as 2% divinylbenzene crosslinked polystyrene beads (100-400 mesh size) with loading ranges from 1.0 mmol P per g to over 3.0 mmol P per g. The reagent can be handled like a typical solid and is amenable to long term storage, although preferably under inert atmosphere to avoid aerial oxidation. Since 2010, he was appointed as a full-time professor of organic chemistry (photochemistry) at Assiut University, Egypt. As of October 2012, Prof. Saleh has been on a sabbatical leave as a full-time professor at Umm Al-Qura University, Makkah, Saudi Arabia. His current research interests include synthesis and photophysical properties of novel organic compounds such as material-based gels, electronic devices and solar energy conversion, uorescent materials and antimicrobial agents. Also, part of his research interests include the developments of synthetic methodologies for the synthesis of novel organic compounds with unprecedented properties with unique applications.

Polystyryldiphenylphosphinemediated functional group interconversions
3.1. Wittig reagents 3.1.1. Carbonyl olenation with p-polystyryldiphenylbenzyl-phosphonium chloride. The Wittig reaction 16 represents on of the most used chemical methods for olen synthesis involving phosphines in solution. Not surprisingly, the rst reported application of PS-TPP involved a Wittig reaction. Castells was the rst to report the use of polymer-bound triphenylphosphine in this capacity to synthesize stilbene (40-60% yield) from the reaction of benzaldehyde with ppolystyryldiphenyl-benzyl-phosphonium chloride, prepared by reacting PS-TPP with neat benzyl chloride. 7 A concurrent investigation by Heitz and Michels 17 on polymer-supported Wittig synthesis of olens using polystyrene crosslinked with 0.5 and 2.0 wt% of divinylbenzene (DVB) found that higher yields were possible with a 0.5% crosslinked polystyrene support. This was because only about 75% of the pore volume in a swollen polymer crosslinked with 2% DVB was accessible to substrates with molar masses 300-400, according to gelchromatographic studies. Heitz and Michels 18 also investigated steric control of the Wittig reaction on triphenylphosphane resins. They found that the adduct formed from the reaction of the aldehyde with the ylide can be selectively converted either to the trans-or cis-olen as the major product in the mixture. The formation of the cis-olen is kinetically controlled and favored in salt-free medium while the trans-olen is thermodynamically controlled and predominates if the adduct is formed at low temperature (À78 C) as the lithium salt is generated by adding lithium perchlorate as a Lewis acid. The study was, however, very limited in scope as the diastereoselectivity was poor and only reported for three olens. Another concurrent study on the preparation and application of polymeric phosphoranes in the Wittig reaction was reported by Mckinley and Rakshys using the standard 2% crosslinked polystyryldiphenyl phosphine. 19 Although the carbonyl-olenation reactions proceeded with methylene, ethylene, and benzylidene polymeric ylides using aromatic and aliphatic aldehydes and ketones, the conversion of the carbonyl compound was incomplete and yields were generally low (24-72%). It is noteworthy that these earlier papers reported syntheses of alkenes in uctuating yields, depending on the polymer used and particular reaction conditions. Thus, further improvements were required for a useful methodology of general applicability.
3.1.2. Polymer-supported phase transfer catalysed Wittig reaction. Phase transfer catalysed reactions 20 have been used extensively in organic synthesis, although they have been used to a much lesser extent in polymer chemistry. Thus, chemical reactions that combine the advantages of both experimental techniques are of interest. Hodge et al. described a phase transfer catalysed Wittig reaction between aldehydes 6 and polymer-bound phosphonium salt residues 5, prepared from PS-TPP and various organic halides 4 (Scheme 2). 21,22 The reaction proceeds at room temperature and the small molecules are tethered to the polymer with bonds which are stable to both acid and base. The Wittig reaction was carried out in CH 2 Cl 2 with 50% aqueous NaOH and a phase transfer catalyst (tetrabutylammonium iodide (TBAI) or cetyltrimethylammonium bromide (CTAB)). These conditions offered the highest reported olen 7 yields compared to those reported by earlier work on polymer-supported Wittig reagents. [17][18][19]23,24 As shown in Table 1, high yields of essentially pure alkenes were obtained from arylalkylphosphonium salts and various aldehydes (entries 1-9). However, while the alkylphosphonium salt (entry 10) reacted with a moderate yield with a reactive aldehyde, alkylphosphonium salts did not react with any aldehydes (entry 11). The Wittig reactions were performed with both, crosslinked and linear PS-TPP, although the former was more convenient since the resulting oxidized byproduct could be directly removed by ltration whilst the latter and it oxide were soluble and required precipitation workup. This renders linear polymers generally unsuitable. The isomeric ratios (cis : trans) were not determined for all olens, although the measured ones were comparable to those obtained under conventional phase transfer catalysed conditions (entry 1; E : Z (100 : 0); entry 3; E : Z (57 : 43); entry 4; E : Z (44 : 56)). A point that merits comment is that the Wittig reaction can take place without any added catalyst, albeit more slowly, producing much lower yields as well. Ketones also failed to react with the phosphonium salts.
3.1.3. Wittig reagents bound to crosslinked polystyrenes with variable crosslinking densities. Building on the earlier work describing polymer-supported Wittig reagents, Ford et al. reported a detailed study on the impact of varying the extent of crosslinking of the polystyrene support on yields of Wittig products. 13 The polymer-supported reagents with 0.5% and 2% cross-linked polystyrenes that had been used earlier were too gelatinous and unsuitable for large-scale ltration. 17 Thus, more highly crosslinked and rigid polystyrene supports were being sought out, although on the expense of lower Wittig yields, since penetration of reagents into all of the functional sites and out of the more highly cross-linked polymer matrices would be expected to be poor especially with large substrates. Ford described the use of Wittig reagents supported on polystyrenes with up to 20% cross-linking and with reactants as bulky as 10-nonadecanone ( Table 2, entries 8 and 9) and the 3keto steroid, cholest-4-en-3-one (Table 2, entries 10 and 11). The Wittig reagents were prepared on 2%, 8%, and 20% DVB crosslinked polystyrene from the reaction of crosslinked PS-TPP and either MeI (8a) or BnBr (8b), to afford the methyl-(9a) and benzylphosphonium (9b) salts, respectively (Scheme 3).
As shown in Scheme 3 and Table 2, Wittig reactions of the methylidenephosphoranes, generated from phosphonium salts 9 under basic conditions, were complete aer 6 h at room temperature, followed by heating for 24 h at 60 C. The chemical yields in all cases depended on the polymer as follows: 2% crosslinked polymer produced higher yields than >20% crosslinked polymer >8% crosslinked polymer. A similar trend was observed for olens generated from polymer-bound benzylphosphonium salts. In this case, E/Z diastereomeric ratios ranged from 72/28 to 43/57. In general, reactions of the phosphoranes 9 with aldehydes and ketones afforded olens in 73-96% yields with the 2% crosslinked polymer, 52-77% yields with the 8% cross-linked polymer, and 72-87% yields with the 20% cross-linked macroporous polymer. Ford showcased the utility of phosphonium salts on 2% cross-linked polystyrene and on 20% cross-linked macroporous polystyrene in the synthesis of ethyl retinoate. 25 The preparation of olens from polymer-supported phosphonium salts derived from PS-TPP (1) and various carbonyl compounds and elaboration thereaer has also been exploited by Ley for the synthesis of bhydroxyamines. 26 Table 1 Reactions of polymer-bound phosphonium salts 5 derived from PS-TPP (1) and aldehydes 6 under phase-transfer conditions
3.1.5. Preparation of vinyl ethers and thioethers via Wittig reagents.

PS-TPP halophosphorane complexes
3.2.1. Polymer-supported dichlorophosphorane. Polymersupported dichlorophosphoranes (26 and 28) were rst prepared in 1974 from PS-TPP (1) and its related benzyl analogue 27 by initial oxidation with peracetic acid to the corresponding polymer-bound phosphine oxides, followed by treatment with carbon oxychloride (phosgene) to provide the desired halophosphorane complexes 26, and 28 (Scheme 6). 28 Reagents 26 and 28 were used successfully for the synthesis of acid chlorides from carboxylic acids ( Table 3, entries 1-3 and 5-7), a nitrile from a primary amide (entry 4), a chloroalkene from a ketone (entry 10), an imidoyl chloride from an anilide (entry 8), and an alkyl chloride from an alcohol (entry 9). The recovered resin-bound phosphine oxide was rephosgenated back to the halophosphorane reagent for reuse.
3.2.2. Condensation of N-alkoxycarbonyl a-amino acids with primary amines using PS-TPP and CCl 4 . The combination of PS-TPP and carbon tetrachloride comprises a convenient coupling system for the amidation of N-alkoxycarbonyl a-amino acids and primary amines. 29 Such a process is oen beset with shortcomings associated with epimerization of the N-terminal residue and purication of the product. However, the preceding method reported by Landi and Brinkman is not afflicted by the aforementioned problems. The reagent system proved effective for N-Boc (t-butoxycarbonyl) and N-Fmoc (9-uorenylmethoxycarbonyl) amino acids, as well as N-CBz (benzyloxycarbonyl) substrates (Table 4). Typically, the procedure involved reuxing an equimolar mixture of the N-protected amino acid and the amine with 4-methylmorpholine (29) (1.1 equiv. or 2.2 equiv. if the amine was an acid salt) and PS-TPP (2 equiv.) in a binary solvent mixture of CH 2 Cl 2 and CCl 4 (2 : 1). Interestingly, although earlier work of Relles 28 and Hodge 30 described the formation of acid chlorides from the reaction of polymersupported dichlorotriphenylphosphorane with carboxylic acids, these intermediates were not present or involved in the current condensation. The active electrophile was found to be a resin-bound mixed phosphinic anhydride.

Preparation of dipeptides using PS-TPP and CCl 4 .
Polymer-supported triphenylphosphine and carbon tetrachloride have also been successfully used for the synthesis of dipeptides. Appel described the synthesis of three small peptides from N-protected amino acid and amino acid ester salts using PS-TPP and CCl 4 . The reaction was heated at 40 C in acetonitrile as solvent to afford the peptides in 70-76% yields ( Table 5). 31 3.2.4. Preparation of acid chlorides and alkyl chlorides using PS-TPP and CCl 4 . The PS-TPP-CCl 4 reagent system has also been applied successfully to convert carboxylic acids into acid chlorides, 30,32 and thiols 32 as well as alcohols 15,30,32 into alkyl chlorides (Scheme 7). The reactions do not generate HCl and thus the conditions are essentially neutral.
Some representative examples of the conversion of carboxylic acids into acid chlorides, and alcohols/thiols into alkyl chlorides are summarized in Table 6. Generally, a carbon tetrachloride solution of the carboxylic acid, alcohol, or thiols in the presence of excess PS-TPP (1.3-2 molar equiv.) was heated at reux for 1-5 h and the oxidized polymer resin was removed at the end of reaction period by ltration. Carbon tetrachloride was used as a co-reagent and as a solvent. A range of aliphatic and aromatic carboxylic acids, thiols, and alcohols were suitable substrates and gave good yields (50-98%), except for the secondary alcohol, cyclohexanol (entry 13). In this case, some elimination occurred, giving a mixture of chlorocyclohexane and cyclohexene. The acetonide protecting group (entry 12) remained intact, underscoring the advantage of neutral conditions. Interestingly, substrate selectivity based on size was not a factor in determining the reaction rate considering that substrates need to diffuse into the polymer to react. For instance, 5b-cholan-24-ol (entry 14), which represents a relatively large substrate, reacted satisfactorily with the reagent. Mechanistically, the polymer-supported reactions involving the conversion of alcohols into alkyl chlorides seem to follow similar pathways to those observed for the free Ph 3 P reagent as judged by the quantity of phosphine (2 equiv.) consumed per mole of alkyl chloride and by the quantity of chloroform produced at the end of the reaction. Formation of the polymeric chlorinating species appears to be the slow step, although the PS-TPP reactions have been shown to be faster than those using Ph 3 P due to a microenvironmental effect. 32,33 The suggested mechanism also required that polymer supported phosphine residues react together. 33 This is consistent with Sherrington's work in which the conversion of alcohols into alkyl chlorides was retarded or even inhibited when highly crosslinked PS-TPP (>15% crosslink ratio of styrene to DVB) was utilized. 34 Although highly crosslinked polymers favour the formation of chloroalkanes because the alcohol penetrates the matrix more easily, the inherent rigidity and lack of backbone mobility hinders the approach and reaction of non-adjacent phosphine residues, and therefore inhibit the preceding transformation. As a result, the aforementioned chlorination reactions are best carried with Ph 3 P supported on polystyrene of low crosslink ratio (1-2%). 35 3.2.5. Synthesis of amides from carboxylic acids and amines using PS-TPP and CCl 4 . Hodge et al. also demonstrated that carboxylic acids could be directly converted into amides by treatment with carbon tetrachloride and PS-TPP in the presence of at least 2 molar equivalents of the amine (Table 7). 32 The reaction was reminiscent to that reported earlier by Appel and Willms whereby several peptides were prepared using the same reagent. 31 Amides were prepared in 1,2-dichloroethane (DCE) containing 10% CCl 4 by volume (entries 1, 2 and 5) or in CCl 4 under reux for 3 h to afford the amides in 57-94% yield. The same system was used by Hodge to convert primary carboxamides and oximes into nitriles or imidoyl chlorides in good yields.
3.2.7. Synthesis of dibromoalkenes by reaction of carbonyl compounds with PS-TPP and CBr 4 . Aldehydes and ketones react with dibromomethylene ylides 32, generated from the reaction of carbon tetrabromide with Ph 3 P (Scheme 8, reaction 1), to give 1,1-dibromoalkenes 34 (reaction 2). Additionally, the carbonyl group may react with the accompanying triphenylphosphine  Undec-10-en-1-o1 11-Bromoundec-1-ene 89 7 Cinnamyl alcohol Cinnamyl bromide 89 8 Octan-2-o1 2-Bromooctane 76 9 Adamantanol 1-Bromoadamantane 97 10 Trinorbornan-endo-2-ol Trinorbornan-exo-2-yl bromide  are semi-crystalline solids which are easy to handle, stable at room temperature, and amenable to storage for weeks. However, they undergo rapid decomposition if they are exposed to moisture giving the corresponding hydrogen halide and phosphine oxide. The halogen complexes were prepared by treating PS-TPP with an equimolar amount of bromine (1 M) or iodine (1 M) solution, or by bubbling gently gaseous chlorine through the suspended polymer resin in CH 2 Cl 2 . The halogens got consumed immediately and the formation of the complexes was almost instantaneous. Epoxide-ring opening reactions proceeded in high yields (Table 9) and maintained regio-and stereo-selectivity when compared to the same transformation carried out with Ph 3 P-X 2 complexes.  4-Nitro-benzyl alcohol 4-Nitro-benzyl iodide 96 5 3-Chloro-benzyl alcohol 3-Chloro-benzyl iodide 95 6 4-Chloro-benzyl alcohol 4-Chloro-benzyl bromide 91 7 4-Bromo-benzyl alcohol 4-Bromo-benzyl bromide 92 8 3-Phenylpropan-1-ol (3-Bromopropyl)benzene 81 9 Octan-1-ol 1-Iodooctane 92 10 3-Methylbut-2-en-1-ol 1-Iodo-3-methylbut-2-ene 87 11 Cyclohexanol  (Table 10). 41 The complexes were prepared as before 40 and the procedure involved adding the acid to an equimolar amount of the complex, followed by stirring at room temperature for 10-15 min. Subsequent addition of the alcohol and warming up to 40-50 C gave the desired ester in high yield within 1-3 h. The halogen complexes act both as condensating agents and acid catalysts. The reaction was assumed to involve protonated acyl halides as the key intermediates that react with the added alcohol. The advantage of this protocol include rapid ester formation, directly from the acid, broad range of alcohol and carboxylic acid substrates, and simple workup. The iodine complex (PS-TPP-I 2 ) was most practical, among the three halogen complexes, as the formation of esters with PS-TPP-Cl 2 was slow, whereas the use of PS-TPP-Br 2 resulted in some bromination of double bonds for unsaturated substrates. 3.2.10. Microwave assisted conversion of alcohols to alkyl halides with PS-TPP-X 2 complexes. Microwave assisted organic synthesis has been implemented as a technology in organic Table 13 Acetalization reactions of ketones and aldehydes catalysed by PS-TPP-I 2 complex a chemistry since the mid-1980's. 42 Recently, a microwave assisted procedure for the conversion of allylic, benzylic and aliphatic alcohols to the corresponding alkyl bromides and iodides using polymer-supported triphenylphosphine and iodine or bromine was described by Rokhum et al. 43 The iodination and bromination reactions were complete within 7 minutes under microwave irradiation conditions and gave alkyl halides in yields ranging from 76-96% (Table 11). Primary alcohols converted to the corresponding halides at a faster rate than secondary alcohols and preference of secondary over tertiary substitution was observed with unsymmetrical diols (entry 13). In case of symmetrical diols (entry 14), the monoiodinated products were obtained in very high yields (88-93%). The methodology features high chemo-and regioselectivity behaviour, short reaction times, product isolation requiring only ltration and solvent removal.
3.2.11. Formylation of primary and secondary alcohols using PS-TPP and iodine. The conversion of alcohols into formic acid esters is a well known protection strategy. 44 Unfortunately, many of the methods used to prepared formate esters use drastic conditions and suffer from serious limitations which include heating the alcohol in 85% formic acid or employing uncommon reagents. Palumbo et al. exploited PS-TPP-halogen complexes in the synthesis of formic acid esters from various primary and secondary alcohols (Table 12). 45 It is noted that tertiary alcohols under the same conditions failed to give the desired formate esters and instead afforded the alkyl halides. Both iodine and chlorine complexes (PS-TPP-I 2 and PS-TPP-Cl 2 ) were suitable, whereas the bromine complex (PS-TPP-Br 2 ) was not tolerated at least with unsaturated alcohols due the co-occurrence of a side reaction involving some bromination of double bonds. The iodine complex was the most convenient considering the ease of handling compared with chlorine.
3.2.12. Acetalization of carbonyl compounds with PS-TPP-I 2 complex. Cyclic and acyclic acetals, dithioacetals, and oxathioacetals are very common groups used to protect the  carbonyl function of aldehydes and ketones. 46 One drawback of acetalization, besides using alcoholic media and Brønsted acid catalysts, is the generation of water during the reaction and the need to remove it by physical or chemical means to drive the equilibrium forward. Thus, a strategy to prepare acetals from carbonyl compounds and alcohol, diols, dithiols, or hydroxythiols under anhydrous conditions and devoid of water formation has been described using the combination of PS-TPP and I 2 . 47 In this approach, the carbonyl compound in anhydrous acetonitrile is treated with a pre-formed PS-TPP-I 2 complex, followed by the desired protecting reagent. An adduct is formed between the positively charged phosphorus atom and carbonyl oxygen, thus activating the carbonyl carbon center for nucleophilic addition by a molecule of the protecting reagent (Scheme 9). A subsequent non-equilibrium step involves the elimination of PS-TPPO and generation of an oxygen-stabilized carbocation which undergoes further reaction with a second reagent molecule or a tethered nucleophile on the same reagent to afford the nal product. The devised procedure for acetalization tolerates aliphatic and aromatic aldehydes and ketones, as shown in Table 13. It is noted that in order to avoid acidic medium for certain substrates, anhydrous Et 3 N was added in portions throughout the reaction.
3.2.13. Polymer-supported triphenylphosphine dibromide (PS-TPP-Br 2 -imiH) and diiodide (PS-TPP-I 2 -imiH): conversion of alcohols into alkyl iodides. Building on Hodge's earlier work regarding the use of polymer-supported triphenylphosphine dibromide (PS-TPP-Br 2 ) in the conversion of alcohols into alkyl bromides, 36 Classon prepared a similar polymer-supported phosphine-halogen complex using iodine in combination with imidazole (PS-TPP-I 2 -imiH). 48 The addition of imidazole enhanced reactivity and neutralized liberated HI, resolving reactivity and yield issues encountered earlier by Hodge et al. in the bromination of alcohols using the related PS-TPP-Br 2 complex. 36 Other bases such as pyridine or Et 3 N were examined, although much lower yields were generally obtained. The halogenation reactions were performed in heated toluene which provided a two phase liquid-liquid reaction system and promoted faster reactivity than other solvents because the nonpolar character of the solvent appears to destabilize the charged phosphonium halide intermediate and drive decomposition to the uncharged alkyl iodide and phosphine oxide byproduct. The iodinations examined involved the synthesis of iodides from alcohols, using various carbohydrates as substrates. Acid-sensitive groups such as acetals, glycosidic linkages, and triphenylmethyl ethers remained intact under reaction conditions (Scheme 10). However unprotected polyhydroxy sugars were unsuitable as substrates and gave complicated reaction mixtures.
3.2.14. Synthesis of (E)-nitroalkenes from aldehydes and nitroalkanes PS-TPP and I 2 . Bez et al. described the rst solid phase one-pot procedure for the synthesis of (E)-nitroalkenes 38 (ref. 49) by reacting diverse aromatic, aliphatic, and a,b-unsaturated aldehydes (36) with nitroalkanes (37) in the presence of polymer-bound triphenylphosphine, iodine and imidazole     (Table 14). Although the same transformation proceeded with similar efficiency using triphenylphosphine instead of its polymer-bound analogue, easy removal of the unwanted polymer-bound triphenylphosphine oxide provided the edge for practical application of the protocol. The reaction generally gave good yields except with less electrophilic aldehydes such as 3,4dimethoxybenzaldehyde (entry 8) and 3,4-methylenedioxybenzaldehyde (entry 9) which also required longer reaction time (3 h) for complete conversion.
3.2.15. Preparation of N-protected b-iodoamines from bamino alcohols using PS-TPP-I 2 complex. Enantiomerically pure N-protected b-iodoamines are important synthetic precursors used for the preparation of D-or L-b-amino acids, which themselves represent challenging synthetic targets. 50 One approach to the preparation of b-amino acids consists of homologating the requisite a-aminoacid, whereby the acarboxyl group gets converted into an alkyl halide in preparation for the subsequent homologation step. Longobardo et al. developed a general synthesis of chiral N-protected b-iodoamines 40, possessing either D-or L-conguration, by treating the precursor chiral N-protected b-aminols 39 with PS-TPP-I 2 complex. 51 The b-aminoalcohols were accessed from N-protected a-aminoacid or commercial b-aminols. As shown in Table 15, the conversion was effective for b-aminols protected with the most frequently used N-protecting groups (Cbz, Boc, Fmoc) without any detectable racemization of the stereocenter. The utility of this methodology was later demonstrated by Longobardo et al. in the synthesis of enantiopure N-and Cprotected homo-b-amino acids by direct homologation of aaminoacid. 52 The devised process involved reducing the carboxyl group of N-protected a-amino acids and converting the resulting N-protected b-amino alcohols into the corresponding b-iodoamines with PS-TPP-I 2 , which represented the key step of the strategy. Subsequent cyanation and acidic hydrolysis of the b-amino cyanides afforded enantiopure homo-b-amino acids.
3.2.16. Peptide synthesis using PS-TPP-I 2 complex. The utility of the polystyryl diphenylphosphine-iodine complex (PS-TPP-I 2 ) has also been showcased in peptide synthesis. 53 The action of the complex involves converting the free carboxylic acid group of a N-protected a-amino acid into an acyl donor intermediate, followed by nucleophilic substitution by the amino function of a second, C-protected a-amino acid, affording fully protected dipeptides. Using this approach, Longobardo and coworkers were able to couple various N-protected a-amino acid with a-aminoacyl esters, by using PS-TPP-I 2 , in high yields and without detectable racemization of the reacting substrates (Table 16). 53 Neutral reaction conditions were secured by the addition of excess imidazole to neutralize the released hydrogen iodide. Thus, the process was effective for substrates carrying the common N-protecting groups (Fmoc, Boc, Cbz) and tolerated acid sensitive S-and O-protecting groups like the trityl (entry 3), methyl (entries 2 and 3), tert-butyl (entry 4), and benzyl groups (entry 5).
3.2.17. Monoesterication of symmetric diols using PS-TPP-I 2 complex. The preparation of carboxylic acid esters from di-or polyhydroxylated substrates is a challenging synthetic task and the introduction of reliable strategies towards the selective monoesterication of such alcohols is useful. 54 Rokhum and Pathak reported the use of PS-TPP/iodine in coupling reactions between carboxylic acids and alcohols or amines to produce esters and amides, respectively. 55 More importantly, the PS-TPP-I 2 reagent has been shown to affect the monoesterication of symmetrical diols without resorting to high dilution or slow addition conditions. As shown in Table 17, the monoesterication of 1,6-hexanediol (entries 1-5) and 1,8hexanediol (entries 6-8) with various carboxylic acids was achieved in high yields (84-92%) in the presence of DMAP and preformed PS-TPP-I 2 complex.
3.2.18. Iodination, bromination, and chlorination of alcohols with PS-TPP/X 2 and PS-TPP/NCS imidazole systems. Building on the previous reports describing the use of PS-TPP and iodine for the conversion of a-amino acids and sugars into the corresponding iodides, 48,52,56 Kita et al. extended the methodology to the halogenation of alcohols under new conditions. 57 The reagent system was prepared by treating a suspension of PS-TPP in CH 2 Cl 2 at room temperature with imidazole and iodine, bromine, or N-chlorosuccinimide (NCS). Subsequent addition of various allylic, benzylic, and primary alcohols gave the halogenated products in very high yields (88-98%) ( Table 18). The reactions worked well with ortho, meta, para-, and multisubstituted benzylic alcohols (entries 2-9), as well as allylic (entries 10-12) and simple alcohols (entries 1, 13 and 14). While the iodination and bromination reactions were complete within 2 h in all cases, the chlorination reaction (entry 14) required 24 h for complete conversion. Finally, when the reagent system was tested on secondary alcohols, the reaction was very slow and unpractical for such systems.

Synthesis of glycosyl iodides.
A new and stereoselective synthesis of a-D-glycosyl iodides obtained by the replacement of the free anomeric hydroxyl functional group of fully protected sugars using PS-TPP-iodine complex was reported by Caputo and co-workers. 56 Thus, the addition of various protected sugars to a mixture of PS-TPP, iodine, and imidazole, at room temperature, resulted in the rapid conversion to the a-glycosyl iodide anomer (Table 19). No traces of the b-anomers were observed in any of the examples, suggesting that the process is thermodynamically controlled.
3.2.20. Esterication of alkylphosphonic acids. Alkylphosphonates have many synthetic and pharmaceutical applications. 58 In addition, methyl, ethyl, i-propyl and n-propyl esters of alkyl phosphonic acids are registered chemical warfare agents (CWAs). 59 The related O,O 0 -dialkyl alkylphosphonates (DAPs) are very useful reference chemicals that have been used as markers of nerve agents. 60 However, since they are also classied as CWAs, they are not available commercially and access to this class of compounds becomes inevitable during verication analysis. Dubey et al. reported a procedure for the preparation of DAPs by esterication of alkylphosphonic acids using primary alcohols, iodine, imidazole, and PS-TPP (Table  20). 61 Pure phosphonate esters were obtained by vacuum distillation in 83-94% yield following removal of PS-TPP oxide and imidazolium iodide by ltration.
3.2.21. Acetonation of sugars (protection of diols) with triphenylphosphine polymer-bound/iodine complex. The triphenylphosphine polymer-bound/iodine complex is a strong Lewis acid and a dehydrating agent as shown by the many transformations presented thus far. 62 Palumbo et al. exploited this feature to prepare O-isopropylidene derivatives of various sugars by condensing the sugar with acetone. 63 The isopropylidene function has been widely used in carbohydrate chemistry to protect diols and in certain cases sugar derivatives incorporating such a group have shown antipyretic and anti-inammatory activities. 64 The synthesis of the reagent complex involved adding a solution of iodine to an equimolar amount of polystyryl diphenylphosphine suspension at room temperature under dry N 2 atmosphere and dark conditions. Subsequent addition of an acetone solution of the sugar to the suspension then afforded the thermodynamically more stable acetonides within 30 minutes in very high purity and yields (Table 21).
3.2.22. Conversion of alcohols to alkyl halides with catalytic amounts of PS-TPP. As shown earlier, Kita et al. 57 had already reported a convenient method of iodination of alcohols using PS-TPP/iodine/imidazole reagent system. Rokhum reported a modication of Kita's method, switching imidazole with DMAP. 65 However in both approaches the catalyst (imidazole/DMAP) was used in excess and the recovery and reuse of the reagent system was not possible. A major drawback of using equimolar amounts of PS-TPP for the halogenation of alcohols is the formation of polymer-supported triphenylphosphine oxide byproduct as the end of the reaction, which in principle may be recycled using reducing conditions. 66,67 However, in order to avoid the inconvenience associated with recovering and recycling the polymer through reduction, Rokhum described a clever approach to the selective halogenation of alcohols using catalytic amounts of polymersupported triphenylphosphine-methylacrylate complex 41. 68 The protocol involves reactions of PS-TPP and methylacrylate in dichloromethane (10 mL) at room temperature for two minutes to generate in situ the triphenylphosphine-methylacrylate complex 42 (40 mol%). Subsequent addition of iodine and polymer supported triphenylphosphine, followed by the alcohol afforded the desired iodide products in 78-93% yields. The procedure was successful with primary aliphatic alcohols, as well as secondary and tertiary ones, although the latter took longer time from complete conversion. Allyl alcohols were also converted into the corresponding iodides without affecting the olenic bonds. Direct bromination using the reported reaction conditions proceeded as well to afford the desired bromides in high yields (87-91%) (Scheme 11).

Application of polymer-supported phosphonium salts derived from PS-TPP as traceless linkers for solid phase synthesis of alkenyl, alkyl and heterocyclic products
Solid-phase synthesis of small organic molecule libraries for drug discovery programs has been one of the key driving forces responsible for the rapidly expanding eld of combinatorial chemistry. 69 Consequently, a large number of polymeric supports have been devised to immobilise compounds via polar functional groups such as alcohols, amides, and carboxylic acids. 69 With the growing need to access a diverse range of small molecules, additional linker groups were required to meet the demand. One particular type, termed "traceless" linkers, leave no remnants in the cleaved product of the functionality utilized to tether the substrate to its support. Hughes showcased the utility of polymer-bound phosphonium salts derived from PS-TPP as traceless linkers for the solid-phase synthesis of small molecules. 70 Thus, as shown in Scheme 12, the phosphonium salt 44 was prepared from 2-nitrobenzyl bromide (43) and PS-TPP, followed by reduction of the nitro group to generate the polymer-bound aniline 45. Finally, the aniline was acylated with 4-methoxybenzoyl chloride to afford anilide 46. The polymersupported substrate 46 was elaborated and cleaved, via hydrolysis or an intramolecular Wittig/cyclization reaction in a traceless manner, to afford alkenyl, heteroaryl, and alkyl products (47)(48)(49) in 78-82% yield.

Staudinger reaction
3.4.1. Reduction of nucleoside azides to amines. Functionalization of nucleosides by converting the sugar moiety into an aminosugar has been extensively studied. 71,72 Reducing an azido function attached to the carbohydrate part represents one of the most convenient means for the preparation of the amine group. 72 Building on this early work, Holletz and Cech described the reduction of nucleoside azides to amines under mild conditions and good yields using PS-TPP (Table 22). 73 The  reaction was executed in two steps using pyridine or dioxane as solvents. In the rst step, reaction of PS-TPP with the azido nucleoside afforded an iminophosphorane, which upon subsequent hydrolysis in the second step with water or concentrated ammonia, led to the formation of the amine. While water hydrolysis le the base protecting group intact (entries 1, 2 and 3), ammonia was used in cases where simultaneous hydrolysis and N-deprotection was desired (entries 5 and 6). The reaction workup required only ltration of the suspended PS-TPPO and evaporation of the ltrate in vacuo to afford pure products in nearly quantitative yields (89-100%).  74 and have been utilized in the synthesis of various functional groups as well as heterocyclic rings. 75 Azides comprise convenient precursors as means to introduce the isothiocyanate group to sugars via a tandem Staudinger-aza-Wittig reaction of the azide with Ph 3 P and carbon disulde. 75 Fernández et al. demonstrated the utility of PS-TPP in lieu of Ph 3 P in the one-step preparation of nonanomeric sugar isothiocyanates from primary and secondary sugar azides (Table 23). 76 While primary azidodeoxy sugars afforded the corresponding primary deoxyisothiocyanato in high yields (entries 1-3), secondary azides, especially those with the azide group located at an endocyclic carbon atom, gave much lower yields (entries 5 and 6). Mono-and disaccharides, including pyranose and furanose derivatives, protected with a variety of labile and sensitive O-protecting groups underwent successful functional group interconversion, illustrating the scope of the method. This strategy was not successful with glycosyl azides because of the higher reactivity of the anomeric isothiocyanate. Prior to the work of Fernández et al., a similar reduction reaction of a 3 0 -azidonucleoside using PS-TPP was reported by Cech and Zehl as a technical improvement to the preparation of isothiocyanato derivatives. 77 The proposed mechanism of these reactions involve initial formation of a polymer-supported iminophosphorane intermediate, followed by a cyclization reaction with carbon disulde to give a four-membered ring, and subsequent cycloreversion of the ring to afford the isothiocyanate.
3.4.3. A one-pot aza-Wittig based polymer supported route to primary and secondary amines. Azides have been employed as the nitrogen source for the preparation of primary amines by converting the azide into an iminophosphorane (the Staudinger reaction), followed by hydrolysis. 78 This approach, however, can not be used to access secondary amines because imine intermediates are not involved. Hemming and co-workers disclosed a study describing the conversion of azides 50 into a-unsubstituted primary amines 51 or a-branched secondary amines 52 via the intermediacy of polymer-supported iminophosphoranes and imines (Table 24). 79 Their strategy involved a Staudinger reaction between PS-TPP and various azides (R 1 -N 3 ), affording polymer-supported iminophosphoranes. Subsequent in situ aza-Wittig reaction of the resulting iminophosphorane with aromatic or alkyl aldehydes (R 2 CHO) gave imine intermediates, which were either reduced in situ to the corresponding aunsubstituted primary amines (path a), or functionalized via 1,2-addition of organometallic reagents (R 3 MgX or R 3 Li) to afford a-branched secondary amines (path b). The use of trimethylsilyl azides (R 1 ¼ TMS, entries 11-13) permitted synthesis of primary amines following in situ N-desilylation, whilst using benzyl azides allowed access to N-benzyl protected amines (entry 1, 6, 9 and 10). On the other hand, the wide range of suitable organometallic reagents allowed the preparation of synthetically useful homoallylic amines (entries 10 and 11). The yields ranged from 52-99% for most substrates except when the hindered pivalaldehyde was used (entry 6).

Aza Wittig synthesis of pyrido[1,2-c]pyrimidine heterocycles.
Pyrido[1,2-c] pyrimidines comprise a promising class of heterocycles which may potentially provide novel superoxide scavengers and anti-inammatory agents. 80 Molina and co-workers designed a solid-phase synthesis of these fused azaheterocycles via an aza Wittig reaction under mild reaction conditions. Their strategy for the synthesis of pyrido[1,2-c] pyrimidines 55 and 56 is outlined in Scheme 13. Staudinger reaction between PS-TPP (1) and ethyl a-azido-b-(2-pyridyl) acrylate (53) in dry CH 2 Cl 2 at room temperature gave the polymer-bound iminophosphorane 54. Subsequent reaction of 3.4.5. Synthesis of secondary amines from alkyl azides and alkyl halides. The most popular methods for the synthesis of secondary amines use either reductive aminations or alkylation procedures on primary amines. However, overalkylation leading to the formation of the corresponding tertiary or quaternary ammonium salts is difficult to avoid. Classon et al. described a one-pot, two-step procedure that delivers only secondary amines from the corresponding azides and reactive alkyl halides using polymer-bound, triphenylphosphine-supported synthesis (Table 25). 81 The solid-phase method involves a Staudinger reaction between PS-TPP (1) and the azide to afford the corresponding phosphoazide which rapidly eliminates nitrogen   to give an iminophosphorane intermediate. Subsequent alkylation with alkyl (entries 1 and 6), allyl (entry 4), or benzyl (entries, 2, 3, 5 and 7) halides produced the corresponding resin-bound disubstituted aminophosphonium salts. Finally, the secondary amines were freed from the solid support by hydrolytic cleavage using methanolic KOH. The yields obtained were good in all examples (78-87%) except when phenylazide was used (21%) (entry 5). The low yield was attributed to its reduction to the corresponding aniline. 3.4.6. Synthesis of glucopyranosyl amides using PS-TPP. The presence of the glycosyl amide motif in naturally occurring biomolecules like glycoproteins and nucleic acids has inspired interest in the synthesis of compounds containing such structural feature. 82 In particular, glycosyl amides have been synthetically targeted because they have been suggested as potential inhibitors of glycosyl hydrolases 83 and the binding of broblast growth factor (FGF-2) to heparin. 84 Norris et al. devised a method for the introduction of the glycosyl amide by way of a Staudinger process in which a glycosyl azide reacts with PS-TPP, followed by reaction of the resulting iminophosphorane with an acid chloride (Scheme 14). 85 Norris et al. reacted 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide with PS-TPP and various acid chlorides (Table 26, entries 1-9) using a parallel synthesizer to prepare a small library of glucopyranosyl amides. The excess acid chloride was removed at the end of the reaction by treatment with polymer-supported tris(2-aminoethyl) amine. Optimum yield was observed with pnitrobenzoyl chloride, underscoring the preference of the polymer-bound iminophosphorane for highly electrophilic acid chlorides (entry 1). On the other hand, the highly hindered pivaloyl chloride inhibited the reaction between the iminophosphorane intermediate and acid chloride (entry 8).

The Mitsunobu reaction
3.5.1. Esterication using PS-TPP. The condensation of alcohols with carboxylic acids via triphenylphosphineazodicarboxylate activation is one of the most reliable and common methods for esterication (the Mitsunobu reaction). 86 However, byproducts from the Mitsunobu reaction and excess reagents are non-volatile and soluble in organic solvents necessitating difficult chromatographic separation of the desired product almost always. PS-TPP was rst utilized in the Mitsunobu reaction by Amos et al. in 1983 for the preparation of esters from alcohols and carboxylic acids (Table 27). 87 The use of PS-TPP conferred convenience in terms of purication of the ester product. The method worked well with aliphatic and aromatic acids and tolerated a variety of functional groups as shown in Table 27. The yield was unaffected in the series of benzoic acids substituted with electron-donating and electronwithdrawing groups (entries 1 and 4-7). As anticipated, secondary alcohols (entries 3, 4 and 11) gave consistently lower yields than primary alcohols (entries 1, 2 and 5-10) and tertiary alcohols were too hindered and remained unreacted. When an optically pure alcohol was used (entry 11), inversion of the chiral center was observed.

Synthesis of aryl ethers from phenols and alcohols.
Georg and co-workers 88 reported the rst example of a Mitsunobu reaction 86 using PS-TPP in the synthesis of aryl ethers. The group prepared a library of aryl ethers from phenols with electron releasing and electron withdrawing groups and various alcohols (Table 28). 88 In a typical experiment, PS-TPP, diethyl azodicarboxylate (DEAD), the alcohol, and the phenol in dichloromethane were stirred at room temperature for 4-12 hours. Filtration of the resin, followed by evaporation of the solvent in vacuo and purication by column chromatography afforded pure aryl ethers in 59-94% yields. It is noted that presence of electron withdrawing substituents at the aromatic ring of the phenol (Cl and CN) accelerated the reaction rate, whereas electron donating substituent (OMe) generally reduced the reaction rate, resulting in a slower reaction progress.
3.5.2.1. Stereochemical inversion of secondary alcohols. Georg et al. found that polymer-supported triphenylphosphine can replace triphenylphosphine in the Mitsunobu reaction to form stereochemically inverted secondary alcohols. 89 The procedure addresses the most signicant drawback associated with the Mitsunobu reaction which includes removal of excess triphenylphosphine and its oxide by-product. The protocol is very comparable to the standard Mitsunobu reaction in regards to yield, stereochemical inversion, reaction time, and even inversion of sterically hindered secondary alcohols. As shown in Table 29, benzylic, alkyl, and cyclic secondary alcohols underwent successful inversion of conguration, although yields were slightly lower with the former two types of substrates (entries 3 and 5) and much lower for sterically hindered ones (entry 6). It is noted that no racemisation was observed for substrates bearing an acidic proton at the stereocenter (entries 2 and 4). The yields reported were in general comparable to those obtained when the inverted products were prepared using standard homogeneous Mitsunobu conditions, suggesting that the reactivity of PS-TPP is similar to its free form. Many of the inverted esters were hydrolyzed to the corresponding alcohols with LiOH which were isolated in 95-97% yields. Optical rotation analysis of the alcohols showed complete inversion of conguration when compared with the starting material. 3.5.3. Synthesis of aryl ethers from aminoalcohols. Building on the method of Georg et al. who described earlier the preparation of aryl-alkyl ethers from phenols and alcohols using a solution-based Mitsunobu coupling strategy with PS-TPP, 88 Shuttleworth et al. discovered an improvement to the etherication reaction and reported optimum conditions. 90 Thus, when Shuttleworth and co-workers treated a collection of phenols with N-protected aminoalcohols under Georg's conditions, poor conversion to the ether products was observed (16-49% yields). It was shown that the progress of this reaction could be signicantly enhanced when a tertiary amine base is used and the order of reagent addition is modied. The improved procedure calls for the treatment of a slight excess of PS-TPP with DEAD at 0 C for 5 min, followed by the addition a premixed solution of the aminoalcohol, phenol, and Et 3 N. It was suggested that the base enhances the overall rate of reaction as it plays a role in the formation of the phenolate required for the S N 2 nucleophilic displacement of the alkoxyphosphonium salt derived from the aminoalcohols. The modied approach was successfully applied to the synthesis of a range of aryl ethers from phenols and N-protected aminoalcohols (Table 30).
3.5.4. Scavenging the hydrazinedicarboxylate ester byproduct in the Mitsunobu reaction with PS-TPP (solid phase scavenger). The Mitsunobu reaction is a four component process that utilizes an alcohol, nucleophile, phosphine, and azodicarboxylate ester. Furthermore, upon reaction completion, two side products, the hydrazinedicarboxylate ester and phosphine oxide, are generated. In their quest for impurity annihilation and to add further improvement to the Mitsunobu process, Barrett et al. employed PS-TPP (1) and an olenic azodicarboxylate (bis(5-norbornenyl-2-methyl) azodicarboxylate, DNAD, 59) to obtain Mitsunobu products in 43-100% yields (86-96% purity) from alcohols and carboxylic acids or their nucleophilic equivalents (phthalimides, or Nhydroxyphthalimides). 91 Ring opening metathesispolymerization (ROMP) of the hydrazine by-product (DNADH 2 ) using Grubbs catalyst (Cl 2 (Cy 3 P) 2 Ru]CHPh) converted it to a poly(DNADH 2 ) solid which was conveniently removed by ltration alongside PS-TPPO. In addition to its role in the Mitsunobu reaction, PS-TPP was added during reaction work-up to form a complex with excess DNAD so it may be ltered out (Scheme 15).
3.5.5. The Mitsunobu reaction with PS-TPP and di-t-butylazodicarboxylate. Others groups have also described alternative methods to improved the Mitsunobu process by using PS-TPP with azodicarboxylates that can be destroyed in situ. Pelletier et al. reported a protocol in which PS-TPP and commercially available di-t-butylazodicarboxylate (DBAD, 60) were used in the Mitsunobu reaction whereby the latter and its expected hydrazide byproduct 61 were destroyed in situ upon treatment with triuoroacetic acid (TFA) at the completion of the reaction (Scheme 16). 92 Both of these compounds provide volatile gaseous byproducts (2-methylpropene) and water-soluble hydrazine ditriuoroacetate. Filtration to remove the phosphine oxide resin and excess PS-TPP followed by standard aqueous work-up afforded products in high purity (>95%) in certain cases. This approach was employed to prepare a 3 Â 5 parallel library which was free of phosphine and hydrazine impurities without recourse to chromatography. The methodology was successfully applied to the alkylation of a wide range of nucleophiles containing many representative and moderately acidic functional groups (sulphonamide, phenol, imide, hydantoin, and carboxylic acid) with a variety of alcohols  (methanol, isopropanol, benzyl alcohol). A similar protocol using TFA for the destruction and removal of DBAD was used by Aberle et al. during PS-TPP-mediated esterication and inversion of carbinol stereochemistry of a tropane alkaloid. 93 3.6. Conversion of carboxylic acids to amides Buchstaller et al. reported a two-step procedure for the conversion of carboxylic acids into amides at ambient temperature under neutral conditions. 94 Initially, the acid was converted into the acid chloride using PS-TPP and trichloroacetonitrile. The reaction was carried out in dichloromethane at room temperature for 3 h. Subsequent treatment with various types of amines (aromatic, benzylic, primary, and secondary) and polymer-bound morpholine as a base afforded the desired amides in 42-99% yields (Table 31).

Ultrasound-mediated esterication of carboxylic acids catalyzed by polymer-supported triphenylphosphine
Very recently, Pattarawarapan et al. described a sonochemical method for the methyl esterication of carboxylic acids catalyzed by polymer-supported triphenylphosphine. 95 Thus, using 1 : 2 : 0.1 molar ratio of 2,4,6-trichloro-1,3,5-triazine (TCT)/ Na 2 CO 3 /PS-Ph 3 P, various carboxylic acids containing reactive hydroxyl groups as well as acid-and base-sensitive moieties were converted to methyl esters in one step without the need to preactivate the acid (Table 32). The products were obtained in 70-99% yield within 10-30 minutes and in most cases did not require purication by column chromatography. It is noted that in the absence of PS-Ph 3 P catalyst, the reaction gave complex mixture of products containing only 27-35% of the corresponding ester. Therefore, a signicant increase in both the reaction rate and product yield was observed by using catalytic quantities of PS-Ph 3 P under ultrasonic irradiation conditions. The proposed mechanism of esterication involves formation of triazinephosphonium chloride, subsequent displacement with a carboxylate anion to give an acyloxytriazine, and an ensuing attack by methanol to afford the ester product with concomitant elimination of the hydroxyl derivative of TCT.

Reductive amination of aldehydes and ketones
Aldehydes and ketones have been shown to undergo indirect reductive amination using polymer-supported triphenylphosphine-palladium acetate complex PS-TPP-Pd(OAc) 2 (10 mol% loading) as a heterogeneous and recyclable catalyst and sodium formate as a reducing agent (Table 33). 96 The catalyst was easily prepared and isolated quantitatively as a yellowish solid by heating a mixture of PS-TPP and Pd(OAc) 2 (P/Pd ratio of 4 : 1) in DMF to 45-50 C for 4 h. The protocol involved two stages where the imine or iminium ion is rst formed from the aldehyde or ketone, respectively, followed by PS-TPP-Pd(OAc) 2 -mediated catalytic reduction with sodium formate. Aromatic aldehydes and ketones gave higher yields than the corresponding aliphatic substrates and the catalyst was reusable over four consecutive cycles without any profound loss of catalytic activity.

Synthesis of (E)-nitroalkenes by isomerisation of (E/Z)nitro olen mixtures
Treatment of (E/Z) mixture of nitroolens with catalytic amounts of PS-TPP (0.1 equiv.) has been reported to produce pure (E)-nitroalkenes in a number of cases (Table 34). 97 The mechanism of isomerisation involves addition of nucleophilic Scheme 16 Mitsunobu reaction with PS-TPP and removal of byproducts. PS-TPP to the activated double bond, interconversion to the appropriate intermediate, and subsequent elimination reaction to afford the nitroalkene. The stereoselectivity of the E/Z-isomerisation was retained in all cases (entries 1-4) except when a phenyl group was introduced in a-position (entry 5) or a phenylthio group in the b-position (entry 6). In these examples, an E/Z-ratio of 90 : 10 and 65 : 35 was observed, respectively.

Debromination of a-bromo ketones
An effective method for the debromination of various a-bromo ketones using PS-TPP was described by Salunkhe et al. 98 The debromination reaction proceeded in high yields (85-97%) in anhydrous benzene using equimolar amounts of the resinbound polymer. Pure ketones were isolated ( Table 35) following ltration of the polymeric phosphine oxide byproduct and solvent removal in vacuo.

Henry reaction of aldehydes with nitroalkanes
Polymer-supported triphenylphosphine was found to react with ethyl acrylate in a stoichiometric ratio to generate an ethyl acrylate conjugated polystyryldiphenylphosphine (PDPP-EA) complex in situ. 68 The complex was used to catalyze the synthesis of 2-nitroalcohols from the reaction of various nitroalkanes and aldehydes (Henry reaction) under solvent-free conditions (Table 36). 99 The catalyst was easily prepared in under 10 min by stirring an equimolar mixture of PS-TPP and ethyl acrylate. Although the ensuing Henry reaction proceeded well in a number of solvents, the highest yields were obtained without solvent and optimum efficiency of the method required 10 mol% of the catalyst. Resin-bound triphenylphosphine could be recovered from the reaction and reused up to ve times without loss of activity. The reaction protocol was applied for the reaction of primary and secondary niroalkanes with aliphatic aldehydes and aromatic aldehydes bearing various electron-donating and electron-withdrawing substituents (Table 36). Good yields were observed with all types of substrates, including those with some degree of steric hindrance (entry 5).

Hydroperoxide reduction
Reduction of hydroperoxides into alcohols with PS-TPP represents a very mild approach to such a transformation especially in complex synthetic settings. Galal et al. described the reduction of hydroperoxide 62 using PS-TPP (Scheme 17). 100 The reaction was carried out rapidly (50 min) at room temperature and afforded the alcohol product 63 in 92% yield.

Ozonide reduction
One of the most popular approaches for the preparation of carbonyl compounds from alkenes involves ozonolysis of a double bond, followed by reductive cleavage of the resulting ozonide with a reducing agent. 101 Santaniello et al. used PS-TPP to reduce ozonides to the corresponding carbonyl products (Table 37). 102 Various aldehydes and ketones were obtained in high yields (80-92%) and were virtually pure.
3.14. Stereoselective isomerization of a,b-ynones to (E,E)a,b-g,d-dienones using PS-TPP PS-TPP has been successfully used as an organocatalyst for the stereoselective isomerization of a,b-ynones to (E,E)-a,b-g,ddienones. 103 The amount of PS-TPP (20 mol%) and the reaction temperature (80 C) were critical to the isomerization process. Thus, under these optimized conditions, the conversion of several ynones to the corresponding dienones was accomplished in moderate to good yields (Table 38). Ynones with aromatic and heteroaromatic substituents could be isomerized in good yields (entries 1-3) whilst aliphatic ynones showed lower yields (entries 4-6). The recovered PS-TPP was reused several times as it retained its catalytic activity, although the catalytic capacity was reduced signicantly aer repeated use as reected by a steady decrease in product yield. 3.15. g-Addition of pronucleophiles to alkynoate Some years ago, Trost et al. discovered the ability of triphenylphosphine to redirect the conjugate addition of various carbon nucleophiles from the normal b-position to the g-position of 2alkynoates 104 and applied the new method to the construction of tetrahydrofuran and tetrahydropyran rings 105 which show widespread occurrence in many classes of natural products. Nitrogen pronucleophiles also underwent successful g-addition reactions in the same manner to afford nitrogen-containing products. 106 In these transformations, the nucleophilic triphenylphosphine, which was used in catalytic amounts, rst added to the triple bond of an a,b-unsaturated system and nally was eliminated from the reaction product aer a series of transformations. As an improvement to the g-addition reactions which require tertiary phosphine homogeneous catalysts, regarded as the major limitation of the methodology, Li et al. efficiently carried out Trost's g-addition of various carbon pronucleophiles to methyl 2-butynoate catalyzed by PS-TPP. 107 The  reactions were run in aqueous media using water : toluene (5 : 1) under microwave irradiation conditions (Table 39) and conventional heating as well. The polymer catalyst was recovered and reused in subsequent reactions without loss of activity. In general, high yields were obtained with all pronucleophiles for which pK a < 16, although increased steric hindrance or lowered kinetic acidity of the pronucleophile compromised the yield (entries 5 and 6).

Synthesis of substituted 2-phenylbenzothiazoles
Substituted 2-phenylbenzothiazoles are of tremendous importance to medicinal chemistry and are considered as privileged pharamacophore. 112 Several 2-phenylbenzothiazole derivatives have been shown to exhibit selective and potent biological activities, culminating in their clinical evaluation against certain types of tumours. For instance, 2-(4-amino-3methylphenyl)-5-uorobenzothiazole emerged as a lead compound against breast and ovarian cancer and had undergone phase 1 clinical trial in the U.K. in the form of its water soluble L-lysyl amide prodrug (Phortress). 113,114 2-(3,4-Dimethoxyphenyl)-5-uorobenzothiazole (PMX 610) is another clinical candidate with selective cytotoxicity prole reminiscent of the related 2-(4-aminophenyl)benzothiazole series. 115 In addition, the radioactive 11 C-labelled 6-hydroxy-4-(methylaminophenyl)benzothiazole known as Pittsburgh compound B has been developed for use in positron emission tomography (PET) scans to image beta-amyloid plaques in neuronal tissue as a non-invasive method of investigating Alzheimer's disease and other neurodegenerative conditions. 2-Phenylbenzothiazoles can be synthetically accessed via condensation of 2-aminophenol with benzaldehydes or benzoic acid derivatives, followed by oxidation of the resulting dihydrobenzothiazole. However, the synthesis of substituted 2phenylbenzothiazoles is challenging because the requisite substituted 2-aminothiophenols are prone to oxidation.   Westwell et al. developed an approach to substituted 2-phenylbenzothiazoles where PS-TPP and p-TSOH were used to promote a reaction between stable 2-aminothiophenol disuldes and benzaldehydes (Table 41). 116 The procedure features a variety of substituents on both the benzothiazole and phenyl rings with yields ranging between 80-97%.

Synthesis of 1,2,4-oxadiazoles
1,2,4-Oxadiazole are biologically interesting heterocycles that act as bioisosteres for amides or esters in medicinal chemistry. 117 These compounds comprise an important structural motif and have been incorporated into muscarinic 118 and benzodiazepine 119 receptor agonists, serotoninergic (5-HT3)  antagonists, 120 as well as antirhinovirals. 117 They have also found applications as peptide mimetics. 121 Because of their biological properties, Wang et al. developed a polymer-assisted solution phase reaction protocol for the synthesis of 1,2,4-oxadiazole in an expeditious manner. 122 They found that under microwave heating conditions at 100 C for 5 min, various carboxylic acids are converted into the corresponding acid chlorides in nearly quantitative yields by treatment with trichloroacetonitrile and PS-PPh 3 . Thus, in the rst step, the preparation of 1,2,4-oxadiazoles involved generating the acid chlorides in situ from the corresponding carboxylic acids using PS-PPh 3 /CCl 3 CN. Subsequent addition of the amidoxime and DIEA in THF and heating in the microwave at 150 C for 15 min afforded the desired 1,2,4-oxadiazole in excellent yield (Table  42). It is noteworthy that the PS-PPh 3 resin from the rst step did not interfere with the reaction in the second step, thereby allowing the transformation to be performed in on pot.

Synthesis of vinylthio-, vinylsulnyl-, vinylsulfonyl-and vinylketo-benzofuroxans and benzofurazans
Vinylthio-, vinylsulnyl and vinylsulfonyl-benzofuroxan heterocycles possess remarkable in vitro activities against different Trypanosoma cruzi strains, 123 which is a protozoan parasite responsible for causing Chagas' disease, a potentially lifethreatening disease of the heart and gastrointestinal tract. The parasite infects a population of nearly 30 million yearly and In addition, PS-TPP was used as a mild reducing agent to render benzofurozan derivatives 78 in excellent yields by deoxygenating a number of the benzofuroxan products 77 for the purpose of verifying the role played by the N-oxide group in the trypanosomicidal activity (Scheme 20).  b-lactams by reacting a-bromo carboxylic acids and imines was described by Kikuchi and Hashimoto 127 (Scheme 21). This coupling reaction was mediated by Ph 3 P or PS-TPP to afford the b-lactams with high trans-selectivity and high yields in most cases.

Peptide synthesis
5.1. Peptide synthesis with polymeric triphenylphosphine/ 2,2 0 -dipyridyl disulde Horiki described the synthesis of dipeptides by the Mukaiyama procedure 128 using PS-TPP and 2,2 0 -dipyridyl disulde (Scheme 22). 129 The procedure involved reuxing a mixture of PS-TPP, PySSPy, N-protected valine, ethyl glycinate, and Et 3 N in CH 2 Cl 2 for 1 d. Best results were obtained when 2 equiv. of PS-TPP and 1.5 equiv. PySSPy to each amino acid were employed. Next, methylation (entry 1) or benzylation (entry 2) of 82a (Table 43), followed by oxidative cleavage afforded the peptidal diketones (entries 1 and 2) in good yields. For the preparation of peptidyl ketones, 82b was directly hydrolyzed under basic conditions with NaHCO 3 in THF/water (entries 3 and 4) or under acidic conditions in the case of its methylated phosphorane 82a (entry 5).

Synthesis of a small library of palmarumycin CP 1 analogs
Wipf and co-workers 132 utilized PS-TPP for the synthesis of a small library of palmarumycin CP 1 (83) analogs aer developing an efficient synthetic approach for the preparation of palmarumycin CP 1 , a natural product and an antifungal agent. 131 The library was obtained by a Mitsunobu coupling reaction of palmarumycin CP 1 with a total of 13 alcohols using PS-TPP (Table 44). 132 The reaction was performed on a very small scale (2-7 mg) to afford the ether products 84 in high purity and reasonable yields.

Total synthesis of epothilone A
The epothilones 133,134 belong to a class of natural products that exhibit extraordinary cytotoxicity and are potential cancer drugs. As such, they prevent cancer cells from dividing by promoting GTP-independent tubulin polymerization, thus   inducing mitotic arrest and inhibiting tumor growth. 134 Mechanistic investigation into the mode of action showed that the epothilones bind competitively to the same sites in b-tubulin as taxol, although the former appear to have better efficacy, and milder adverse effects than taxol. 135 Moreover, certain epothilones exhibit cytotoxic biological activity against multiple-drugresistant cells, and are relatively more soluble in water than the analogous taxanes, making them interesting synthetic drug targets. Ley  7. PS-TPP-metal complexes and their application in synthesis

Cobalt immobilization on PS-TPP
The Pauson-Khand (P-K) reaction was rst reported in 1971 138 and inspired many investigations in the ensuing years. 139 The reaction is used for the synthesis of cyclopentenones via a cobalt carbonyl-mediated cyclization of an alkene, an alkyne, and carbon monoxide. Challenges associated with handling the very labile Co 2 (CO) 8 spurred the development of a PS-TPP cobalt carbonyl complex as a catalyst for the Pauson-Khand reaction. 140 The catalyst (92) was prepared by reacting equimolar amounts of PS-TPP and Co 2 (CO) 8 142 In a typical experiment, the alcohol reacted with an equimolar amount of 1-alkene in the presence of PS-TPP (15 mol%), Ph 3 P (5 mol%), RhCl 3 $xH 2 O (5 mol%), and 2-amino-4-picoline (100 mol%) as co-catalyst (Table 45) in toluene at 130 C for 72 h. The catalytic activity of the recovered catalyst did not decrease aer reusing it for four cycles and electronwithdrawing substituents (entries 2 and 4) afforded ketones in higher yields than electron-donating groups (entries 3 and 5).
The yield was also negatively impacted with sterically hindered olenic substrates (entries 6 and 7). This polymer-supported Rh(I) catalyst could also be generated in situ from other Rh(I) complexes via a ligand exchange reaction.

PS-TPP-supported ruthenium catalyst for use in transfer hydrogenation and hydrocarbon oxidation
Chloro-ruthenium complexes such as RuCl 2 (PPh 3 ) 3 (100) have been used frequently in metal-mediated transformations which include transfer hydrogenation and hydrocarbon oxidation. 143 Soluble phosphines have been widely used as ligands for catalysis employing heavy metals. Unfortunately, removal of soluble derivatives of heavy metals from organic reactions is challenging. Besides providing ease of separation from the product mixture at the end of the reaction, attaching a metal complex to a polymer lowers toxicity and air sensitivity of such species and precludes contamination of the product with heavy metals. Leadbeater reported an insoluble version of RuCl 2 (-PPh 3 ) 3 (101) and described its capabilities in transfer hydrogenation and hydrocarbon oxidation. Immobilization of the ruthenium complex was carried out by stirring an equimolar mixture of PS-TPP and RuCl 2 (PPh 3 ) 3 in toluene at room temperature overnight. 144 The resulting polymer-bound ruthenium complex, which was isolated by ltration, was stable in air and amenable to prolonged storage under an atmosphere of nitrogen. Using catalytic amount of the immobilized complex (0.15%), selective hydrogen transfer from 2-propanol to various ketones (Table 46, entries 1-4) occurred rapidly, delivering the product alcohols in yields (40-83%) comparable to those obtained with the unsupported RuCl 2 (PPh 3 ) 3 complex. Similarly, the oxidation of a range of alcohols (entries 5 and 6) and hydrocarbons (entries 7-10) using a catalytic amount of the polymer-supported ruthenium complex and t-BuOOH gave the desired ketones in good  3-Furyl 50 10 2-Pyridyl 43 11 3-Pyridyl 29 12 4-Pyridyl 17 13 HC]CH 2 71 a Reagents and conditions: 1 : 5 : 5 : 5 molar ratios of palmarumycin CP 1 : PS-TPP : alcohol : DEAD, CH 2 Cl 2 , 0 C, 24 h. yields (47-100%). It was shown that the catalyst could be recycled and reused a number of times without losing activity.

PS-TPP-arene-ruthenium complex for use in enol formate synthesis and the cyclopropanation of olens
Arene-ruthenium complex 103 is another analog of a homogeneous metal complex that has been immobilized on PS-TPP by Leadbeater. 145 The free complex [Ru-(p-cumene)Cl 2 (Ph 3 P)] is among many other arene ruthenium catalysts that have been frequently used in a plethora of metal-mediated reactions such as enol formate synthesis 146 and cyclopropanation of alkenes. 147 The air-stable polymer-bound complex 103 was prepared via a thermolysis reaction of the dimer 102 with two molar equivalents of PS-TPP (1) in CH 2 Cl 2 (Scheme 27). The ruthenium polymer-supported complex 103 was used catalytically (1 mol%) for the regioselective addition of formic acid to terminal alkynes and diynes to generate the corresponding enol formates in 76-95% yields (Table 47, entries 1-5). Reactions were conducted in toluene since it produced optimum yields even though resin swelling is not as marked as in other solvents. The catalyst was similarly active in alkene cyclopropanation reactions (entries 6 and 7). 7.6. Catalytic oxidation of benzylic and allylic alcohols and acid anhydride synthesis with PS-TPP-cobalt complex PS-TPP has also been used by Leadbeater to attach the homogeneous transition metal catalyst CoCl 2 (PPh 3 ) 2 (104) and assess its ability in the catalytic oxidation of alcohols to aldehydes and ketones and the synthesis of acid anhydrides ( Table 48). Immobilization of the cobalt catalyst was achieved by agitating a mixture of CoCl 2 (PPh 3 ) 2 and the functionalized phosphine resin 1 (1 : 1.7 molar ratio) in CH 2 Cl 2 overnight. 148 The catalyst loading was estimated to be approximately 2.4 mmol g À1 of resin. The resulting complex 105 (1 mol%) was used to selectively oxidize primary and secondary benzylic alcohols as well as allylic alcohols using tert-butylhydroperoxide as oxidant (entries 1-4). Aliphatic alcohols remained unaffected under the reaction conditions. The group demonstrated that the polymeric support had little effect on the product yield compared to the homogeneous cobalt complex. The supported catalyst was also investigated in the coupling of acid chlorides and carboxylic acids. Several asymmetrically substituted acid anhydrides were prepared in good yields (entries 5-7).

Polystyrene-bound triphenylphosphine gold(I) catalysts; synthesis of furans, pyrroles, and oxazolidines
Cationic gold(I) complexes exhibit signicant affinity to carboncarbon multiple bonds and have become particularly attractive catalysts because they are resistant to moisture and air.     cyclohexene (112) with Et 2 NH, the cis substitution product 109 was produced with net retention of stereochemistry due to steric steering (Scheme 29). However, the use of non-supported Pd(PPh 3 ) 4 afforded a mixture of cis-3-diethylamino-5-carbomethoxy-L-cyclohexene (113) and its trans diastereomer 114 which had inverted conguration. Apparently, the pathway leading to a Reagents and conditions: PS-Ph 3 P (3 mol%), Pd(OAc) 2 (7 mol%), Zn(CN) 2 (1 molar equivalent), DMF, microwave irradiation (2-3 min for aryl triates; 30-50 min for aryl halides at 140 C); thermal heating conditions (1.5-3 h). inversion of conguration was not possible due to the inability of the amine nucleophile to co-ordinate to the polymer supported palladium complex 111. Trost exploited the availability of this clean retention pathway for nitrogen nucleophiles for the development of a convenient isoquinuclidine synthesis. 152 7.8.2. Hallberg 's PS-PPh 2 -Pd(Cl) 2 PPh 3 catalyst; Heck arylation. Hallberg and co-workers 153 have reported supported analogues of PdCl 2 (PPh 3 ) 2 from PS-PPh 2 and PdCl 2 (PhCN) 2 by reacting the two components (Scheme 30). Interestingly, the group prepared supported complexes with Pd : P ratios of 1 : 1, 1 : 2, 1 : 3 and 1 : 4 and discovered that coordination of the metal to the resin changes with metal loading, complex 115 being formed at low metal loading. The complexes were investigated in the Heck arylation of methyl acrylate and styrene with iodo-and bromobenzene (Scheme 30). The supported complex 115 with low PS-PPh 2 : Pd ratio was found to be most effective for the arylation reactions of the aryl iodide substrates, whereas the complexes with high PS-PPh 2 : Pd ratios worked best with the aryl bromoanalogues. In general, the rates of reaction of the latter analogues were reported to be much slower than those obtained with homogeneous analogues, reaction durations being days rather than hours. 7.8.3. Palladium-catalyzed cyanation of aryl triates and aryl halides using polymer-supported triphenylphosphine. A method for the expeditious cyanation of aryl triates and aryl halides using a heterogeneous palladium catalyst prepared from PS-TPP as the ligand and palladium(II) acetate has been demonstrated by Srivastava et al. 154,155 In this methodology, a variety of aryl triates and aryl halides bearing both electronwithdrawing and electron-donating groups were successfully cross-coupled with zinc cyanide under microwave as well as under conventional heating conditions (Table 50). While both reaction conditions offered similar yields for aryl triates (91-98%), microwave-induced cyanation required much shorter times (2-3 minutes) for the completion of reaction whereas thermal conditions needed 1.5-3 hours. On the other hand, aryl halides required relatively longer microwave heating (30-50 min) time for complete reaction. It is noted that complete conversion of the triate to the corresponding nitrile product was possible with as little as 3 mol% of PS-TPP catalyst and 1 equivalent of Zn(CN) 2 . This is noteworthy since similar transformations require much higher loading of both catalyst and cyanation reagent. By comparison, aryl halides required 7 mol% of PS-TPP catalyst. 7.8.4. Allylation of carboxylic acids, alcohols, and amines using PS-TPP-palladium complex. Allyl esters, allyl ethers, and allyl amines are useful functional groups with wide utility in organic synthesis. 156 Bhanage et al. reported an effective heterogeneous catalytic methodology for the allylation of various N-and O-pronucleophiles with 1-phenyl-1-propyne as the allylating agent and PS-TPP-Pd as the heterogeneous catalyst (Table 51). 157,158 Preparation of the PS-TPP-Pd complex involved reuxing a mixture of PS-TPP (5 molar equivalents) as the heterogeneous ligand and Pd(OAc) 2 as the catalyst precursor in toluene for 20 min. Various reaction parameters for the allylation reaction such as catalyst loading, time, temperature, solvent, and molar ratio of reagents were investigated and optimized. Highest yields were obtained when the allylating agent (1-phenyl-1-propyne), the pronucleophile (amine, alcohol, carboxylic acid), benzoic acid, and Pd(OAc)/PS-TPP were used in a 1 : 1.2 : 10 mol% : 10 mol% and reuxed for 6-18 h in toluene. As shown in Table 51, the allylation protocol was successful with various N-and O-pronucleophiles. Interestingly, carboxylic acids (entries 6-8) were more effective as substrates for the allylation reaction than alcohols (entries 4 and 5). Weaker Npronucleophiles such as those containing electron decient anilines (entries 1 and 2) or are sterically hindered (entry 3) were well tolerated giving the desired allyl amines in good to high yields.

Conclusion
Solid-phase synthesis continues to evolve as it offers important features such as removal of the product by ltration of the solid resin, easy handling, reduced side reactions, and recyclability of the solid matrix for repeated use. Although Ph 3 P is ranked as one of the worst atom-economic reagents known, polymersupported triphenylphosphine has found many applications. This is because the commonly encountered problems in solution-phase chemistry involving Ph 3 P such as removal of excess Ph 3 P, Ph 3 P-complexes, and the by-product Ph 3 PO can be easily avoided with PS-TPP. Moreover, the byproduct PS-TPPO can be reduced to PS-TPP by treatment with trichlorosilane. In the past few decades since its rst preparation in 1971, PS-TPP (1) has demonstrated wide applicability and its many proven applications have been well documented. Surprisingly, no comprehensive review has been dedicated to the versatile reagent as it has been oen briey mentioned in reviews of wider scope. The reagent has since been successfully used in the Mitsunobu reactions, the Staudinger reaction, and for the preparation of PS-TPP-halophosphorane complexes, Wittig reagents, and as a ligand for palladium, cobalt, ruthenium, gold, and rhodium complexes. The heavy metal catalysts proved more air stable and were utilized in transfer hydrogenation and hydrocarbon oxidation reactions, Pauson-Khand-, Nicholas-, and Heck reactions. Others have also used it for the mono-olenation of symmetrical dialdehydes, preparation of vinyl ethers, thioethers, isocyanates, dipeptides, acid chlorides, alkyl halides, amides, amines, dibromoalkenes, halohydrins, and esters. Furthermore, formylation of primary and secondary alcohols, as well as acetalization of carbonyl compounds has been demonstrated. The reagent has also been useful in the synthesis of heterocycles such as 2-phenylbenzothiazoles, 3aminoindole-2-carbonitriles, 1,3,4-thiadiazole-2,5dicarbonitrile, thiazole-2,4,5-tricarbonitrile, 1,2,4-oxadiazoles, vinylthio-, vinylsulnyl-, vinylsulfonyl-and vinylketobenzofuroxans and benzofurazans, and b-lactams. The reagent also has proven valuable for the reduction of steroidal ozonides, isomerization of E/Z mixtures of nitro olens, and has been used occasionally as a linker for solid phase synthesis. Finally, the reagent was elegantly applied in the total synthesis of a small library of palmarumycin CP 1 analogs and the total synthesis of epothilone A. PS-TPP demonstrated high success in a wide range of reaction types and rendered the purication process much more facile because the liberated phosphine oxide byproduct remains attached to the resin. Based on its past performance, it is likely that the reagent will make its debut in yet to be seen novel transformations.

Conflicts of interest
There are no conict of interest to declare.