Exploiting Poly(ethylene glycol) as a Matrix for Liquid-Phase Organic Synthesis

Tel.: (858)-784 2515, Fax: (858) 784 2595, E-mail: kdjanda@scripps.eduReceived: 14 February 2000; revised form: 31 July 2000 / A ccepted: 1 August 2000 / Published: 20 A ugust 2000Abstract: Soluble polymer-supported chemistry is a technology that allows the blending ofthe benefits of polymer-supported synthesis and solution-phase chemistry. Herein, we de-scribe our recent efforts in this area targeted at exploring the scope of poly(ethylene glycol)(PEG) as the matrix. Specifically we describe the use of PEG as a support for triphenyl phos-phine and for the Stille reaction.Keywords: soluble polymer, synthesis, poly(ethylene glycol), triphenyl phosphine, Wittig re-action, Stille reaction.IntroductionFor many years solid polymers have been dominant both as supports for organic reagents and incombinatorial synthesis [1,2]. However, there are concerns associated with the use of insoluble poly-meric derivatives such as lowered reactivity, site-site interactions, extended reaction times and diffusion-limited reactivity. The use of soluble matrices [3] such as poly(ethylene glycol) [4] circumvents theseproblems while also allowing for routine monitoring of reaction progress [5,6].Our efforts in this field have included the development of soluble polymer-supported combinatoriallibraries [7], catalysts [8], reagents [9-11], linker strategies [12,13] and synthetic methodology [14,15].This report details the development and application of a poly(ethylene glycol) bound triarylphosphinereagent and the optimization of a liquid-phase Stille cross-coupling reaction with subsequent generationof a small library of biaryl, heterobiaryl and styryl derivatives in high yields and purity.


Introduction
For many years solid polymers have been dominant both as supports for organic reagents and in combinatorial synthesis [1,2].However, there are concerns associated with the use of insoluble polymeric derivatives such as lowered reactivity, site-site interactions, extended reaction times and diffusionlimited reactivity.The use of soluble matrices [3] such as poly(ethylene glycol) [4] circumvents these problems while also allowing for routine monitoring of reaction progress [5,6].
Our efforts in this field have included the development of soluble polymer-supported combinatorial libraries [7], catalysts [8], reagents [9][10][11], linker strategies [12,13] and synthetic methodology [14,15].This report details the development and application of a poly(ethylene glycol) bound triarylphosphine reagent and the optimization of a liquid-phase Stille cross-coupling reaction with subsequent generation of a small library of biaryl, heterobiaryl and styryl derivatives in high yields and purity.

Development and Application of a Poly(ethylene glycol)-Supported Triarylphosphine Reagent (2)
Our group recently communicated an extension of PEG-supported chemistry into the field of functionalized polymers as reagent supports [16][17][18].We prepared a novel triarylphosphine derivative of PEG (1) and showed that, when compared to a heterogeneous commercially available counterpart, it possesses favorable reaction kinetics in both the Staudinger and Mitsunobu etherification reactions.The present study expands on those preliminary investigations.

Synthesis of Liquid-Phase Phosphine Reagent (2)
A concern with the original reagent 1 was the carbamate ester moiety incorporated as a linker between the triarylphosphine and the PEG support.The known base and acid sensitivity of the urethane linkage, coupled with worries about its lability in the presence of Lewis acids and metallating reagents, linked any further exploitation of PEG-supported triarylphosphines to an immediate replacement of this carbamate ester group.An aryl-alkyl ether moiety was chosen as the replacement linker, the chemical stability of which is comparable to that of the poly(ethylene oxide) backbone, therefore reagent 2 became the functionalized polymer of choice [19].
The synthetic strategy towards 2 involves an initial concise preparation of the key hydroxyphosphine 3 [20], followed by its attachment to PEG via the dimesylate 4 [21].4-Bromo-phenol 5 was protected as the TBDMS ether 6, that was then phosphinylated under standard conditions [22] to give the triarylphosphine 7. The silyl ether was removed and the resultant hydroxyphosphine 3 was obtained in 87% yield for the three steps.Mesylate 4 was obtained by heating (50Û& D QHDW VROXWLRQ RI 3(* 3400 8 in methanesulfonyl chloride.No base was required under these conditions, which had the benefit that the purification of 6 was simplified from its original preparation [21].Etherification between 4 and 3 was performed in rigorously degassed DMF.Phosphine 2 was then isolated by addition of the reaction mixture into degassed diethyl ether, followed by filtration and sequential washing of the polymeric precipitate with i-Pr alcohol (to remove salts) followed by diethyl ether to give reagent 2 in 92% yield, based on the weight of polymer isolated.
The oxidation state of the phosphine termini of 2 was routinely quantified by 31 P NMR after certain periods of storage.This revealed that even after prolonged exposure to air (2-3 weeks) little oxidation to the phosphine oxide (< 5%) occurs.
The derivatization level of the polymer is also determined by inspection of the 1 H NMR of 2. The chemical shift of α-methylene protons of PEG and its derivatives is a function of the moiety attached to the termini hydroxyl groups.For underivatized PEG 3400 , the chemical shift of these α-protons is δ 3.8 ppm, for PEG-mesylate 4, this changes to δ 4.35 ppm (also detectable are the β-methylene protons δ 3.74 ppm) and for the phosphine terminated polymer 2 this changes to δ 4.16 ppm (β-methylene protons δ 3.64 ppm).Inspection of the 1 H NMR of 2 shows that no mesylate 4 remains.Therefore there is high confidence that the polymeric phosphine 2 is quantitatively substituted with terminal triarylphosphine residues (ca.0.5 mmol g -1 ).The ease of NMR-characterization of soluble polymer reagent 2 offers a considerable advantage over its solid-phase homologue which, in order to determine the oxidation state of the phosphine center, must involve either gel-or solid-phase NMR, or single-bead FTIR techniques [23].As an entry level into the utility of 2 in organic chemistry, the mild chemical decomposition of ozonides was selected.Ozonolysis of alkenes has a broad scope of application in organic chemistry, and the range of methods for destruction of the intermediary ozonides is equally broad.However, the two major methods of choice: Zn/acetic acid or dimethyl sulfide have limitations, a result of potential chemical substituent sensitivity in the former case, or noxious reagents and high-boiling point byproducts in the latter.For these reasons PPh 3 is an excellent alternative [24].It has received only limited use in solution-phase chemistry however, because of the problems of removing both the excess PPh 3 and reaction byproduct, triphenylphosphine oxide, from the reaction mixture.The use of polystyrene-supported PPh 3 as a stoichiometric reagent for this reaction has been reported as an alternative and gives good to excellent yields of aldehydes [25].Therefore an important part of this study was a direct comparison between this new liquid-phase approach with 2, and a solid-phase approach with commercially available PPh 3 .

Liquid-Phase Ozonide Reduction
A range of alkenes 10a-e were treated with ozone.The incipient ozonides were then decomposed into the product aldehydes (11a-e) by addition of one of three reagents: PPh 3 , polystyrene-supported PPh 3 , or PEG-supported PPh 3 (2).The results are shown below (Table 1).The isolation procedure for the PEG-supported reagent involved a simple precipitation of the spent reagent into ether, and concentration.This consistently removed > 99% of the polymer byproduct.Passage of the ether concentrate through a short silica pad completely removed the remaining polymer traces, giving the product aldehydes in analytically pure form.The solid-phase reagent was separated from the reaction mixture by filtration.The product was isolated by then washing the resin with volumes of CH 2 Cl 2 .The solution-phase reactions were purified by silica gel chromatography to remove the excess PPh 3 and the byproduct PPh 3 O.
In all cases studied, the yields of aldehyde were highest with the soluble polymer-supported reagent 2 and with the exception of 11d the soluble reagent gave higher yields than the solid-phase reagent.This result may be a composite of three factors; increased reducing power of the soluble polymer-supported phosphine 2 when compared to both the solid-and solution-phase reagents, a result of the pethoxyether functionality which links the reagent to the soluble polymer support, the homogeneous nature of the ensuing chemical process when compared to the hetereogeneous resin reagent and the ease of isolation and purification of the products when compared with solution-phase strategy.

Liquid-Phase Wittig Reactions in aqua
Reagent 2 was subsequently transformed into the polymer-supported phosphonium salt 12 suitable for Wittig olefination in aqueous solution.Organic chemistry in water has been the focus of considerable efforts in recent years [26][27][28].The Wittig olefination reaction has also been much studied throughout the evolution of crosslinked polymer-supported reagents and considerable success has been achieved [29][30][31][32][33][34].Bernard and Ford [34] noted an inverse correlation between the yield of alkene obtained from polymer-supported Wittig reagents with aldehydes and ketones in solution and the degree of divinylbenzene (DVB) cross-linking in the resin.Progressing from 0.5-20% DVB crosslinking, i.e. from gel to macroporous resins, can result in a fall of 20% in the yield of alkenes.These results suggested that a soluble polymer-supported phosphonium salt may give excellent yields in the Wittig reaction.

6FKHPH
The physical properties of the PEG backbone are such that the PEG-supported phosphonium salt 12 is eminently water soluble and offer the tantalizing prospect of facilitating the first soluble polymersupported Wittig olefination reactions in aqua.Treatment of PEG-supported phosphine 2 with benzylbromide, followed by precipitation into diethyl ether yielded the soluble polymer-supported benzyl triarylphosphonium salt 12 in 81% yield (based on the weight of polymer obtained).This polymeric phosphonium salt 12 is completely soluble in water at pH 7. The reaction of this novel Wittig salt (12) was then studied with a range of aldehydes (11a and 13a-d) in aqueous sodium hydroxide solution (Scheme 2, Table 2).The isolated yields of the alkenes 14a-e by this method were good to excellent, proving that the rate of reaction of the ylide with the substrate aldehydes is indeed much faster than decomposition to 9. Isolation of the stilbenes (14a-e) was achieved by partitioning the reaction mixture with CH 2 Cl 2 , followed by removal of the water by addition of anhydrous magnesium sulfate, and then precipitation of the polymer supported triphenylphosphine oxide byproduct 9 into diethyl ether and concentration of the etheric solution to dryness.
To explore the scope of this reaction two components were varied: base strength and temperature.Increasing the base-strength (from 1 N to 2 N NaOH) neither affected the yield of stilbenes (14a-e) nor the E:Z isomer distribution.However, elevating the temperature (up to 90Û& UHVXOWHG LQ LPSURYHG yields of 14d and as to be expected an increase in the E:Z ratio for the stilbene products.

Regeneration of Spent Reagent 9
A number of standard methods were employed to regenerate the oxidized polymer-supported phosphine 9 (Table 3).Only poor to moderate reduction of 9 to 2 occurred with polymethylhydrosiloxane (PMHS) [35] using various conditions.The reason is perhaps due to unfavorable polymer-polymerinteractions between the polymeric reductant and the PEG-backbone.Trichlorosilane [36,37], while leading to a significant reduction of the phosphine group (56%), completely cleaved the terminal phos-phine from the polymer.However, quantitative reduction of 9 was achieved with freshly prepared alane (AlH 3 ) [38] in THF as determined by 31 P NMR vide supra.The polymer was isolated in 75% yield following the usual precipitation into degassed ether.The incomplete polymer recovery is attributed to problems associated with the byproduct aluminium salts either complexing to the polymer support and thus preventing precipitation or polymer-backbone hydrolysis during the reduction process.Thus, the utility of this reagent was made complete by its facile regeneration by quantitative reduction and reisolation.

Poly(ethylene glycol) as a Soluble Polymer Matrix for the Stille Cross Coupling Reaction
The Stille [39,40] cross-coupling reaction possesses wide scope and functional group tolerance.In addition, the requisite tin reagents are easily prepared and relatively stable when compared to most organometallic reagents.These properties make this particular process very attractive as a route to many carbon-carbon bond forming reactions under relatively ambient conditions.The importance of this reaction within the sphere of polymer-supported chemistry has been demonstrated with the recent emergence of solid- [41][42][43] and fluorous-phase [44,45] approaches.
The defining feature of the Stille coupling is the use of a trialkyltin reagent in a palladium-catalyzed coupling with either a halide or triflate.As with all tin chemistry, the benefits associated with these reagents are to some extent outweighed by the problems associated with their removal after reaction completion.The tri-n-butyl derivatives are more difficult to remove from a reaction mixture than the methyl congeners due to their low volatility and poor water solubility.Therefore there is an increasing need for methodologies which facilitate the separation of the side-product tributyltin derivatives from the required adducts following the Stille reaction.Our aim was to study the potential of poly(ethylene glycol) as a soluble matrix for the electrophile component of the reaction.The tributyltin derivative and 'other' components of the reaction being in solution could, theoretically, be separated from the polymersupported products by a simple precipitation of the support into a suitable solvent and recovery by filtration.
MeO-PEG 5000 was initially esterified with either para-or ortho-iodobenzoic acid using DCC and DMAP to give para-and ortho-polymer-supported iodides, 15a-b respectively, with polymer recoveries being > 95% [46].The conversion was quantitative based upon 1 H NMR spectroscopic analysis of 15ab.A number of efficient reaction conditions for solution-phase Stille couplings have been developed [39,40,47,48] and initially we utilized a number of these for the reaction between PEG-iodide 15a and tributyl phenyltin (16) to explore the viability of PEG as a soluble polymer support for this reaction and then to identify the optimal conditions necessary for the PEG-supported Stille variant (Scheme 3 and Table 4).Previous work has revealed conflicting evidence regarding the potential for coordination of the PEG polyether backbone to transition metals [49][50][51].Initially therefore, we had serious concerns that the PEG-backbone may serve to either retard or completely inhibit the Stille reaction via complexation of either the palladium catalyst, the alkali metal halide or the organostannane reagent.The efficiency of the initial series of experiments was determined both by 1 H NMR analysis of the PEG-biaryl adduct 17a and, following transesterification, by the isolated yields of the biaryl methyl ester 18a and monoaryl ester 19a (resulting from no cross-coupling with 15a).Reactions were conducted in toluene, THF or DMF, with either a Pd(0) or Pd(II) catalyst (0.1 equiv.) in the presence or absence of LiCl (10 equiv.).A three-fold excess of tributyl phenylstannane 16 was used relative to the PEGsupported electrophile 15a.Additional parameters that were modified included temperature, reaction time and reaction concentration.solvent (Table 1, entries 3 and 6-9) under standard conditions of 15a (20 mM) and 80Û&7KHUHVXOWVVKRZWKDW'0)LVWKHPRVWVXSHULRURIWKHVROYHQWVWHVWHGIRUWKH3(* supported Stille reaction.Similar to the case with THF, PdCl 2 (PPh 3 ) 2 is the best catalyst (Table 4, entries 3 and 6) with considerable amounts of the transesterified iodide 19a being recovered after reaction with Pd(0) (58%).In addition, by leaving the reaction to run for 48 h rather than the preliminary 24 h, a considerable increase in the observed biaryl adduct 18a is achieved (89 and 97% respectively) (Table 4, entries 3 and 8).
In a recent fluorous-phase approach to the Stille reaction, between aryl tin reagents and aryl halides, it was observed that by using LiCl as an additive that the cross-coupling efficiencies were significantly enhanced [44].However, the positive effect of LiCl on our PEG-supported Stille variant seems to be only marginal (compare Table 4, entries 3 and 7).This result is more in line with previous reports which found that LiCl does not usually enhance the reaction between trialkyl tin reagents with aryl halides, but is generally more useful with aryl triflate electrophiles [52,53].
The summary of these results is that the use of PdCl 2 (PPh 3 ) 2 in the presence of LiCl in DMF at a reaction concentration of 20 mM for 48 h, or 10 mM for 24 h, gives excellent yields for the monomethoxy-PEG 5000 -supported variant of the Stille cross-coupling reaction (97 and 98% respectively).
This liquid-phase approach imparts a number of significant advantages over its solution-phase counterpart.The toxic tributyl tin derivatives are easily separated from the PEG-biaryl adduct 17a by precipitation of the polymer-support into either iso-propyl alcohol or diethyl ether.Polymer recovery was >99% in each case.In addition, the homocoupled biaryl side-product 20, an incontrovertible product in the solution-phase reaction [39,40], does not contaminate the soluble-polymer supported biaryl product 17a, because the homocoupling side-reaction takes place in solution and thus the contaminant is removed during the precipitation step.Having optimized the liquid-phase Stille reaction conditions on monomethoxy-PEG 5000 , we then sought to examine the scope of this cross coupling process in a parallel format.A range of tributyl stannanes, 16 and 21-28, were reacted with the PEG-supported iodides 15ab in a parallel fashion, furnishing the library of biaryl, heterobiaryl and styryl derivatives 18a-b and 28ab to 34a-b (Table 5).
The isolated yields of all library members were good to excellent (69 -99%) showing that under our pre-optimized conditions vide supra, that the scope of the PEG-supported variant of the Stille reaction is quite broad.Following passage down a short pad of silica gel, the library members (18a-b, 28a-b to 34a-b) were each isolated in > 95% purity.In each case (Table 5, entries 1-8) the yield of the ortho-isomer was lower than its corresponding para-congener.We rationalize that this phenomenon may be a result, at least in part, of the steric effect imparted by the PEG-backbone polymer chain during ligand transfer.However this effect followed no definitive trend related to the size of the moiety being transferred.suggests that the process involved may be more complex than simple steric retardation.While, in this report, no attempt has been made to re-optimize the reaction conditions to improve the yield of the ortho-isomers, it is speculated that future studies directed to resolve this issue would involve simply increasing the number of equivalents of the stannane and/or palladium catalyst, whilst perhaps using more dilute reaction conditions.

General
Unless otherwise stated, all reactions were performed under an inert atmosphere using dry reagents and solvents and flame-dried glassware.Analytical thin-layer chromatography (TLC) was performed using 0.25 mm pre-coated silica gel Kieselgel 60 F 254 plates.Visualisation of the chromatogram was by UV absorbance, iodine, dinitrophenylhydrazine, ceric ammonium molybdate, iron(III) chloride or panisaldehyde as appropriate.Liquid chromatography was performed using compressed air (flash chromatography) with the indicated solvent system and silica gel 60 (230-400 mesh).Preparative and semipreparative TLC was performed using Merck 1 mm or 0.5 mm coated silica gel Kieselgel 60 F 254 plates repectively. 1 H-NMR spectra were recorded on a Bruker AMX-600, AMX-500, AMX-400 or AC-250 spectrometers at 600, 500, 400 or 250 MHz respectively.Chemical shifts are reported in parts per million (ppm) on the δ scale from an internal standard. 13C NMR spectra were recorded on either a Bruker AMX 500 spectrometer at 125 MHz or a Bruker AMX 400 spectrometer at 100 MHz. 31 P NMR spectra were recorded on a Bruker AMX 400 spectrometer at 162 MHz.Infra-red spectra were run on a Nicolet 510 FT-IR spectrometer from 4000-600 cm -1 .Mass spectra were recorded on a VG ZAB-VSE instrument.Optical rotations were measured using a Perkin-Elmer 241 polarimeter.
Standard Procedure A: Ozonide Reduction With Solution-Phase PPh 3

2-Formylbenzenepropanal (11c)
A solution of 1,2-dihydronaphthalene (10c) (100 mg, 0.77 mmol) in CH 2 Cl 2 (30 mL) was cooled to -78Û& $ VWUHDP RI R]RQHHQULFKHG R[\JHQ ZDV LQWURGXFHG XQWLO D EOXH FRORU SHUVLVWHG $IWHU PLQ D stream of dry nitrogen or argon was bubbled through the reaction mixture until the blue color disappeared.PPh 3 (403 mg, 1.54 mmol) was added in one portion and the resulting solution was allowed to warm to room temperature and stirred for 2 h.The reaction mixture was then concentrated in vacuo and the crude residue was purified by silica gel chromatography, using 25% hexanes-ethyl ether as the eluant, to give the aldehyde 11c (105 mg, 84%) as a colorless oil.R f (Et 2 O / hexane 9:1) = 0.56; R T 4.4 min; 1

2-Formylbenzenepropanal (11c)
A solution of the ozonide of 1,2-dihydronaphthalene (10c) (100 mg, 0.77 mmol) in CH 2 Cl 2 (30 mL) was prepared as described in standard procedure A. PEG-PPh 3 2 (3.08 g, 1.54 mmol) was added in one portion and the resulting solution was allowed to warm to room temperature and stirred for 2 h.The reaction mixture was then concentrated (to 5 mL) in vacuo and added dropwise to vigorously stirring diethyl ether (200 mL).The precipitate was removed by filtration and washed with diethyl ether (50 mL).The filtrate and washings were then concentrated (10 mL) in vacuo and passed through a pad of silica gel (1cm × 2cm).The eluant was evaporated to dryness to give the dialdehyde 11c (121 mg, 97%) as a colorless oil.
Standard Procedure C: Ozonide Reduction With Solid-Phase PPh 3 reagent

2-Formylbenzenepropanal (11c)
A solution of the ozonide of 1,2-dihydronaphthalene (10c) (100 mg, 0.77 mmol) in CH 2 Cl 2 (30 mL) was prepared as described in standard procedure A. Resin-bound PPh 3 (513 mg, 1.54 mmol) was added in one portion and the resulting solution was allowed to warm to room temperature and stirred for 2 h.The resin was removed by filtration and washed with CH 2 Cl 2 (250 mL).The filtrate and washings were then concentrated (10 mL) in vacuo and passed through a pad of silica gel (1cm × 2cm).The eluant was evaporated to dryness to give the dialdehyde 11c (75 mg, 60%) as a colorless oil.
Standard Procedure D: Wittig reactions in aqua with Liquid-Phase Phosphonium Salt 3
Standard Procedure E: Stille Coupling of PEG-bound iodo benzoate and Transesterification with KCN/MeOH

Transesterification
The PEG-bound biphenyl 3a (980 mg, 189 µmol) and potassium cyanide (100 mg, 1.5 mmol) were dried at room temperature under high vacuum for 1 h.Anhydrous methanol (10 mL) was added under a nitrogen atmosphere.The reaction mixture was stirred at room temperature for 24 h and then added to diethyl ether (150 mL).The precipitate was collected by filtration and washed twice with diethyl ether.The filtrate was concentrated in vacuo and the crude residue was purified by passage through a short column of silica gel (CH 2 Cl 2 or hexane-10% diethyl ether as the eluant), to give the methyl ester 18a as a white solid (40 mg, 98%). 1

Table 1 .
Direct comparison of ozonide hydrolysis between solution-phase, solid-phase and liquid-phase triphenylphosphine.
a Yields of isolated stilbenes (14a-e).b Measured by 1 H NMR of crude mixture.

Table 3 .
Regeneration of PEG-supported triarylphosphine 2. Measured by 31 P NMR of the reaction mixtures.

Table 4 .
Optimization of the Stille cross-coupling reaction parameters between 15a

and 16. Entry Catalyst Solvent conc./mM a T/ Û C LiCl Time/h Yield 18a/% b Yield 19a/% b
aBased on the concentration of PEG-bound substrate 15a.b Isolated yields after workup.c Not determined.