Next Article in Journal
Claisen, Cope and Related Rearrangements in the Synthesis of Flavour and Fragrance Compounds
Previous Article in Journal
Synthesis of Potassium (1,1-Dioxothiolan-3-yl)-dithiocarbamate
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 5
Issue 8
10.3390/50801018
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Frank Sieber
,
Paul Wentworth, Jr.
* and
Kim D. Janda
*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA
*
Authors to whom correspondence should be addressed.
Molecules 2000, 5(8), 1018-1032; https://doi.org/10.3390/50801018
Submission received: 14 February 2000 / Revised: 31 July 2000 / Accepted: 1 August 2000 / Published: 20 August 2000
Browse Figures
Versions Notes

Abstract

:
Soluble polymer-supported chemistry is a technology that allows the blending of the benefits of polymer-supported synthesis and solution-phase chemistry. Herein, we describe 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 phosphine and for the Stille reaction.

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.

Results and Discussion

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 (50°C) a neat solution of PEG3400 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.
Molecules 05 01018 g001 550
Figure 1.
Figure 1.
Molecules 05 01018 g001
The oxidation state of the phosphine termini of 2 was routinely quantified by 31P 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 1H 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 PEG3400, 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 1H 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].

Liquid-Phase Ozonide Reduction

Molecules 05 01018 g002 550
Figure 2. A) 1H and 31P NMR spectra of PEG-supported triarylphosphine 2. B) 1H and 31P NMR spectra of PEG-supported triarylphosphine 9.
Figure 2. A) 1H and 31P NMR spectra of PEG-supported triarylphosphine 2. B) 1H and 31P NMR spectra of PEG-supported triarylphosphine 9.
Molecules 05 01018 g002
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 PPh3 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 PPh3 and reaction byproduct, triphenylphosphine oxide, from the reaction mixture. The use of polystyrene-supported PPh3 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 PPh3.
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: PPh3, polystyrene-supported PPh3, or PEG-supported PPh3 (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 CH2Cl2. The solution-phase reactions were purified by silica gel chromatography to remove the excess PPh3 and the byproduct PPh3O.
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.
Molecules 05 01018 sch001 550
Scheme 2.
Scheme 2.
Molecules 05 01018 sch001
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 CH2Cl2, 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 90°C) resulted in improved 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 (AlH3) [38] in THF as determined by 31P 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-PEG5000 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 1H NMR spectroscopic analysis of 15a-b.
Molecules 05 01018 sch002 550
Scheme 3.
Scheme 3.
Molecules 05 01018 sch002
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 1H 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 80°C. The results show that DMF is the most superior of the solvents tested for the PEGsupported Stille reaction. Similar to the case with THF, PdCl2(PPh3)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 PdCl2(PPh3)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-PEG5000-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-PEG5000, 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 15a-b in a parallel fashion, furnishing the library of biaryl, heterobiaryl and styryl derivatives 18a-b and 28a-b 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.

Experimental

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 F254 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 F254 plates repectively. 1H-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. 31P 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 PPh3

2-Formylbenzenepropanal (11c)

A solution of 1,2-dihydronaphthalene (10c) (100 mg, 0.77 mmol) in CH2Cl2 (30 mL) was cooled to - 78°C. A stream of ozone-enriched oxygen was introduced until a blue color persisted. After 5 min a stream of dry nitrogen or argon was bubbled through the reaction mixture until the blue color disappeared. PPh3 (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. Rf (Et2O / hexane 9:1) = 0.56; RT 4.4 min; 1H NMR (250 MHz, CDCl3) δ 10.16 (s, 1H), 9.82 (d, J =1.0 Hz, 1H, Ar-H), 7.82 (dd, J = 7.4 Hz, 1H, Ar-H), 7.56-7.25 (m, 3H, Ar-H), 3.35 (t, J = 7.5 Hz, 2H), 2.79 (dt, 2H); 13C (101 MHz, CDCl3) δ 201.3, 192.9, 147.9, 142.7, 135.4, 134.5, 131.3, 127.0, 102.0, 45.2, 25.6; FABHRMS calcd. for C10H10O2 (M+) 162.1852, found 162.1854.

Standard Procedure B: Ozonide Reduction With Liquid-Phase PPh3 reagent 2

2-Formylbenzenepropanal (11c)

A solution of the ozonide of 1,2-dihydronaphthalene (10c) (100 mg, 0.77 mmol) in CH2Cl2 (30 mL) was prepared as described in standard procedure A. PEG-PPh3 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 PPh3 reagent

2-Formylbenzenepropanal (11c)

A solution of the ozonide of 1,2-dihydronaphthalene (10c) (100 mg, 0.77 mmol) in CH2Cl2 (30 mL) was prepared as described in standard procedure A. Resin-bound PPh3 (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 CH2Cl2 (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

4-Nitrostilbene (14a)

Wittig salt 12 (200 mg, 0.10 mmol) and 13a (70 mg, 0.46 mmol) were dissolved in a solution of 1 N NaOH (4.6 mL) and water (1 mL). The reaction mixture was then stirred at either room temperature (Table 2, entry 1) or 90°C (Table 2, entry 2). The reaction mixture was then diluted with CH2Cl2 (100 mL) and anhydrous MgSO4 was added with vigorous stirring. The desiccant was then removed by filtration and washed with CH2Cl2. The combined filtrate and washings were concentrated in vacuo (to 3 mL) and then added dropwise to vigorously stirring diethyl ether (100 mL). The precipitate was removed by filtration and washed with diethyl ether (20 mL). The filtrate and washings were then concentrated (2 mL) in vacuo and passed through a pad of silica gel (1cm × 2cm). The eluant was evaporated to dryness to give a mixture of the E:Z stilbenes 14a (Table 2, entry 1; 45 mg, 65%. Table 2, entry 2; 43 mg, 62%) as a pale yellow oil.

Regeneration of PEG-(OPhPPh2)2 (2)

PEG-phosphine oxide 9 (200 mg, 0.1 mmol) was dissolved in THF (2.5 mL) and cooled (0°C). Freshly prepared alane [44] 0.5 M in THF (0.25 mL) was added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred for 30 min. The reaction mixture was then cooled (0°C) and quenched with MeOH (0.3 mL). The crude mixture was filtered through a short pad of Celite, the clear filtrate was then concentrated in vacuo (to 4 mL) and added dropwise into vigorously stirring degassed diethyl ether (50 mL). The precipitate was collected by filtration, washed with diethyl ether (30 mL) and dried in vacuo to give reagent 2 (150 mg, 75%) as an ivory solid.

Standard Procedure E: Stille Coupling of PEG-bound iodo benzoate and Transesterification with KCN/MeOH

Stille Coupling

In a typical procedure MeO-PEG5000 bound para-iodobenzoate 15a (1.0 g, 191 µmol) was dissolved in a degassed anhydrous solution of LiCl (79 mg, 1.91 mmol) in DMF (5 mL). Dichlorobis(triphenyl phosphine)-palladium(II) (13 mg, 19 µmol) and tributyl-phenylstannane (187 µL, 574 µmol) were then added. The reaction mixture was stirred under nitrogen at 80°C for 24 h. The dark suspension was cooled to room temperature, diluted with CH2Cl2, filtered through a glass fritted funnel and concentrated in vacuo to 8 mL. This clear solution was added into vigorously stirred diethyl ether (120 mL). The precipitate was isolated by filtration and washed with i-Pr alcohol and diethyl ether to give the polymeric biaryl product 3a as a white solid (980 mg, 99%).
MeO-PEG5000-(4-phenylbenzoate) (18a). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.1 Hz, 2 H), 7.65-7.59 (m, 4 H), 7.44 (t, J = 7.56 Hz, 2 H), 7.37 (t, J = 7.28 Hz, 1 H), 4.47 (t, J = 4.56 Hz, 2 H, PEG-α-methylenes), 3.81 (m, PEG-β-methylenes), 3.62 (m, PEG-methylenes).

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 (CH2Cl2 or hexane-10% diethyl ether as the eluant), to give the methyl ester 18a as a white solid (40 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.1 Hz, 2 H), 7.67-7.61 (m, 4 H), 7.44 (t, J = 7.56 Hz, 2 H), 7.39 (t, J = 7.32 Hz, 1 H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.94, 145.55, 139.90, 133.81, 130.04, 128.87, 128.09, 127.21, 126.97, 52.07; FABHRMS calcd. for C14H13O2 (MH+) 213.0916, found 213.0922.

Acknowledgments 

Financial support for this work was supplied by the NIH (GM 56154, KDJ) and The Skaggs Institute for Chemical Biology.

References and Notes

  1. Shuttleworth, S.J.; Allin, S.M.; Sharma, P.K. Synthesis 1997, 27, 1217–1239.
  2. Sherrington, D.C.; Hodge, P. Synthesis and Separations Using Functional Polymers; John Wiley & Sons, Inc.: New York, 1988. [Google Scholar]
  3. Gravert, D.J.; Janda, K.D. Chem Rev. 1997, 97, 489–509. [PubMed]
  4. Geckeler, K.E. Adv. Polym. Sci. 1995, 121, 31–79.
  5. Wentworth, P., Jr.; Janda, K.D. Curr. Opin. Biotech. 1998, 9, 109–115.
  6. Booth, R.J.; Hodges, J.C. Acc. Chem. Res. 1999, 32, 18–26.
  7. Han, H.; Wolfe, M.M.; Brenner, S.; Janda, K.D. Proc. Natl. Acad. Sci. USA 1995, 92, 6419–6423. [PubMed]
  8. Han, H.; Janda, K.D. J. Am. Chem. Soc. 1996, 118, 7632–7633.
  9. Sieber, F.; Wentworth, P., Jr.; Toker, J.D.; Wentworth, A.D.; Metz, W.A.; Reed, N.N.; Janda, K.D. J. Org. Chem. 1999, 64, 5188–5192.
  10. Wentworth, P., Jr.; Vandersteen, A.M.; Janda, K.D. Chem. Commun. 1997, 759–760.
  11. Hori, M.; Janda, K.D. J. Org. Chem. 1998, 63, 889–894. [PubMed]
  12. Zhao, X.-Y.; Janda, K.D. Tetrahedron Lett. 1997, 38, 5437–5440.
  13. Zhao, X.-Y.; Janda, K.D. Bioorg. & Med. Chem. Lett. 1998, 8, 2439–2442.
  14. Chen, S.; Janda, K.D. J. Am. Chem. Soc. 1997, 119, 8724–8725.
  15. Chen, S.; Janda, K.D. Tetrahedron Lett. 1998, 39, 3943–3946.
  16. Wentworth, P., Jr.; Vandersteen, A.M.; Janda, K.D. Chem. Commun. 1997, 759–760.
  17. Wipf, P.; Venkatraman, S. Tetrahedron Lett. 1996, 37, 4659–4663.
  18. Harris, J.H.; Liu, Y.; Chai, S.; Andrews, M.D.; Vederas, J.C. J. Org. Chem. 1998, 63, 2407–2409.
  19. A recent report attempts the synthesis of 2 for use as a macroinitiator in block copolymer synthesis (Choi, Y.K.; Bae, Y.H.; Kim, S.W. Macromolecules 1995, 28, 8419-8421). However, the authors observed significant oxidation of the phosphine end-groups during its isolation which they did not isolate in pure form.
  20. A recent report descibes a one step route to phosphine 6 in moderate yield (63% yield). [Herd, H.; Heßler, A.; Hingst, W.; Tepper, M.; Stelzer, O. Journal of Organometallic Chemistry 1996, 522, 69-76.] However, in our hands the obtained yields were even lower (38%). Therefore we adopted a three step approach to 6 the overall yield being 83% (Scheme 1).
  21. Zhao, X.-Y.; Janda, K.D. Tetrahedron Lett. 1997, 38, 5437–5440.
  22. Relles, H.M.; Schluenz, R.W. J. Am. Chem. Soc. 1974, 96, 6469–6475.
  23. Yan, B. Acc. Chem. Res. 1998, 31, 621–630.
  24. Feiser, M.; Feiser, L.F. Reagents for Organic Synthesis; Mir: Moscow, 1978; pp. 1238–1239. [Google Scholar]
  25. Ferraboshi, P.; Gambero, C.; Azadani, M.N.; Santaniello, E. Synth. Commun. 1986, 16, 667–672.
  26. Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; John Wiley & Sons, Inc.: New York, 1997. [Google Scholar]
  27. Li, C.-J. Chem. Rev. 1993, 93, 2023–2035.
  28. Lubineau, A.; Augé, J.; Queneau, Y. Synthesis 1994, 741–760.
  29. McKinley, S.V.; Rakshys, J.W. J. Chem. Soc. Chem. Commun. 1972, 134–135.
  30. Heitz, W.; Michels, R. Angew. Chem. Int. Ed. Engl. 1972, 11, 298–299.
  31. Heitz, W.; Michels, R. Justus Liebigs Ann. Chem. 1973, 227–230.
  32. Clarke, S.D.; Harrison, C.R.; Hodge, P. Tetrahedron Lett. 1980, 21, 1375–1378.
  33. Hodge, P.; Waterhouse, J. Polymer 1981, 22, 1153–1154.
  34. Bernard, M.; Ford, W.T. J. Org. Chem. 1983, 48, 326–332.
  35. Lipowitz, J.; Bowman, S.A. J. Org. Chem. 1973, 38, 162–165.
  36. Horner, L.; Balzer, W.D. Tetrahedron Lett. 1965, 3, 1157–1158.
  37. Cremer, S.E.; Chorvat, R.J. J. Org. Chem. 1967, 32, 4066–4070.
  38. Griffin, S.; Heath, L.; Wyatt, P. Tetrahedron Lett. 1998, 39, 4406.
  39. Stille, J.K. Pure & Appl. Chem. 1985, 57, 1771–1780.
  40. Stille, J.K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508–524.
  41. Deshpande, M.S. Tetrahedron Lett. 1994, 35, 5613–5614.
  42. Forman, F.W.; Sucholeiki, I. J. Org. Chem. 1995, 60, 523–528.
  43. Plunkett, M.J.; Ellman, J.A. J. Am. Chem. Soc. 1995, 117, 3306–3307.
  44. Hoshino, M.; Degenkolb, P.; Curran, D.P. J. Org. Chem. 1997, 62, 8341–8349. [PubMed]
  45. Curran, D.P.; Hoshino, M. J. Org. Chem. 1996, 61, 6480–6481. [PubMed]
  46. Blettner, C.G.; König, W.A.; Stenzel, W.; Schotten, T. Synlett 1998, 295–297.
  47. Mitchell, T.N. Synthesis 1992, 803–815.
  48. Farina, V. Pure & Appl. Chem. 1996, 68, 73–78.
  49. Bergbreiter, D.E.; Liu, Y.-S. Tetrahedron Lett. 1997, 38, 3703–3706.
  50. Blettner, C.G.; König, W.A.; Stenzel, W.; Schotten, T. Synlett 1998, 803–815.
  51. Blaskovich, M.A.; Kahn, M. J. Org. Chem. 1998, 63, 1119–1125.
  52. Scott, W.J.; Stille, J.K. J. Am. Chem. Soc. 1986, 108, 3033–3037.
  53. Chen, Q.-Y.; He, Y.-B. Chin. J. Chem. 1990.
  • Sample Availability: Available from the authors.
Table
Table 1. Direct comparison of ozonide hydrolysis between solution-phase, solid-phase and liquid-phase triphenylphosphine.
Table 1. Direct comparison of ozonide hydrolysis between solution-phase, solid-phase and liquid-phase triphenylphosphine.
EntryAlkeneProductYield,a %
PPh3b Molecules 05 01018 i0012
1 Molecules 05 01018 i002 Molecules 05 01018 i003945898
2 Molecules 05 01018 i004 Molecules 05 01018 i005807392
3 Molecules 05 01018 i006 Molecules 05 01018 i00784d60d97d
4 Molecules 05 01018 i008 Molecules 05 01018 i009515677
5 Molecules 05 01018 i010 Molecules 05 01018 i011726263
aReaction conditions: The respective triphenylphosphine (2eq.) was added to the ozonide (1eq.) of the alkene in CH2Cl2 and left to stir for 2 h. Yields based on HPLC comparison to authentic product standards; bCommercially available PPh3 (Aldrich Chem. Co.); cCommercially available polystyrene-PPh3 resin (Aldrich Chem. Co.); d Isolated yield.
Table
Table 2. Aqueous Wittig reactions phosphonium salt 12 and aldehydes (11a-13a-d).
Table 2. Aqueous Wittig reactions phosphonium salt 12 and aldehydes (11a-13a-d).
EntryAldehydeConditionsYield %a (E/Z ratio)b
113a1 N NaOH, r.t.65 (56:44)
2 1 N NaOH, 90°C62 (75:25)
313b1 N NaOH, r.t.80 (46:54)
4 1 N NaOH, 90°C78 (75:25)
513c1 N NaOH, r.t.95 (48:52)
611a1N NaOH, r.t.38 (49:51)
7 1 N NaOH, 90°C49 (47:53)
813d1 N NaOH, r.t.63 (54:46)
a Yields of isolated stilbenes (14a-e).b Measured by 1H NMR of crude mixture.
Table
Table 3. Regeneration of PEG-supported triarylphosphine 2.
Table 3. Regeneration of PEG-supported triarylphosphine 2.
EntryReagentConditionsP(V) to P(III)a/%
1PMHSb, CH2Cl2CH2Cl2/ r.t.20
2PMHSBenzene/ reflux 20 h33
3PMHSTHF/ reflux 20 h40
4HSiCl3cBenzene/ reflux 20 h56
5AlH3•THFTHF/ r.t. 30 min100
aMeasured by 31P NMR of the reaction mixtures. bPolymethylhydrosiloxane. cWith triethylamine.
Table
Table 4. Optimization of the Stille cross-coupling reaction parameters between 15a and 16.
Table 4. Optimization of the Stille cross-coupling reaction parameters between 15a and 16.
EntryCatalystSolventconc./mMaT/ CLiClTime/hYield 18a/%bYield 19a/%b
1Pd(PPh3)2Cl2toluene20110+2422-c
2Pd(PPh3)2Cl2THF20reflux+2468-c
3Pd(PPh3)2Cl2DMF2080+2489-c
4Pd(PPh3)4toluene20110+2453-c
5Pd(PPh3)4THF20reflux+24773
6Pd(PPh3)4DMF2080+241058
7Pd(PPh3)2Cl2DMF2080-248612
8Pd(PPh3)2Cl2DMF2080+48970
9Pd(PPh3)2Cl2DMF1080+24980
a Based on the concentration of PEG-bound substrate 15a. b Isolated yields after workup. c Not determined.
Table
Table 5. Parallel liquid-phase Stille couplings of iodides 15a-b with tributyl stannanes 16 and 21-27a.
Table 5. Parallel liquid-phase Stille couplings of iodides 15a-b with tributyl stannanes 16 and 21-27a.
Molecules 05 01018 i012
aReactions were conducted under the conditions described vide supra. bCompound descriptors a and b represent the para- and ortho-isomers respectively. All the products were characterized by 1H, 13H NMR spectroscopy and HRFABMS and gave satisfactory spectroscopic data when compared to authentic samples or to literature data. See the supporting information for more detail. clsolated yields after the two steps. dYields of ortho-product 30b was not determined because instability of the stannanes 23 precluded its efficient synthesis.

Share and Cite

MDPI and ACS Style

Sieber, F.; Wentworth, P., Jr.; Janda, K.D. Exploiting Poly(ethylene glycol) as a Matrix for Liquid-Phase Organic Synthesis. Molecules 2000, 5, 1018-1032. https://doi.org/10.3390/50801018

AMA Style

Sieber F, Wentworth P Jr., Janda KD. Exploiting Poly(ethylene glycol) as a Matrix for Liquid-Phase Organic Synthesis. Molecules. 2000; 5(8):1018-1032. https://doi.org/10.3390/50801018

Chicago/Turabian Style

Sieber, Frank, Paul Wentworth, Jr., and Kim D. Janda. 2000. "Exploiting Poly(ethylene glycol) as a Matrix for Liquid-Phase Organic Synthesis" Molecules 5, no. 8: 1018-1032. https://doi.org/10.3390/50801018

APA Style

Sieber, F., Wentworth, P., Jr., & Janda, K. D. (2000). Exploiting Poly(ethylene glycol) as a Matrix for Liquid-Phase Organic Synthesis. Molecules, 5(8), 1018-1032. https://doi.org/10.3390/50801018

Article Metrics

Back to TopTop