Exploiting poly(ethylene glycol) as a matrix for liquid-phase organic synthesis

Article abstract of DOI:10.3390/50801018

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.

Full text of DOI:10.3390/50801018

Molecules 2000, 5, 1018-1032
molecules
ISSN 1420-3049
2000 by MDPI
http://www.mdpi.org
©
Exploiting Poly(ethylene glycol) as a Matrix for Liquid-Phase
Organic Synthesis
,
1
,2
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, U.S.A.
1Tel.: (858)-784 2576, Fax: (858) 784 2590, E-mail: paulw@scripps.edu
2Tel.: (858)-784 2515, Fax: (858) 784 2595, E-mail: kdjanda@scripps.edu
Received:14February2000; revised form: 31 July 2000 / Accepted:1August 2000 / Published: 20 August 2000
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 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.
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 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 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 [9-11], 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.

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Molecules 2000, 5
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 func-
tionalized polymers as reagent supports [16-18]. 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 be-
tween 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 be-
came 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 triaryl-
phosphine 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&ꢀꢁDꢁQHDWꢁVROXWLRQꢁRIꢁ3(*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 mix-
ture into degassed diethyl ether, followed by filtration and sequential washing of the polymeric precipi-
tate 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.
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3
1
The oxidation state of the phosphine termini of 2 was routinely quantified by 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.
1
The derivatization level of the polymer is also determined by inspection of the 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 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 pro-
1
tons δ 3.64 ppm). Inspection of the 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 triarylphos-
-1
phine residues (ca. 0.5 mmol g ). The ease of NMR-characterization of soluble polymer reagent 2 of-
fers 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 tech-
niques [23].
Liquid-Phase Ozonide Reduction
1
31
1
31
Figure 2. A) H and P NMR spectra of PEG-supported triarylphosphine 2. B) H and P NMR spec-
tra of PEG-supported triarylphosphine 9.

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Molecules 2000, 5
As an entry level into the utility of 2 in organic chemistry, the mild chemical decomposition of ozon-
ides 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
tion-phase chemistry however, because of the problems of removing both the excess PPh
byproduct, triphenylphosphine oxide, from the reaction mixture. The use of polystyrene-supported PPh
3
is an excellent alternative [24]. It has received only limited use in solu-
3
and reaction
3
as a stoichiometric reagent for this reaction has been reported as an alternative and gives good to ex-
cellent yields of aldehydes [25]. Therefore an important part of this study was a direct comparison be-
tween this new liquid-phase approach with 2, and a solid-phase approach with commercially available
PPh
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 , polystyrene-supported
PPh , or PEG-supported PPh (2). The results are shown below (Table 1).
3
.
3
3
3
Table 1. Direct comparison of ozonide hydrolysis between solution-phase,
solid-phase and liquid-phase triphenylphosphine.
a
Yield, %
Entry
Alkene
Product
b
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2
PPh
3
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1
2
94
80
58
98
1
0a
11a
2
2
3
4
73
92
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1
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2
d
d
d
2
84
60
97
77
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0c
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11d
0
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0H2
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51
56
0H2
1
0d
2
5
72
62
63
1
1
1
0e
11e
a
Reaction conditions: The respective triphenylphosphine (2eq.) was added to the ozonide
(
1eq.) of the alkene in CH
2
Cl
2
and left to stir for 2 h. Yields based on HPLC comparison
b
to authentic product standards; Commercially available PPh
3
(Aldrich Chem. Co.);
c
d
Commercially available polystyrene-PPh
3
resin (Aldrich Chem. Co.); Isolated yield.

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Molecules 2000, 5
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. Pas-
sage 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 ex-
and the byproduct PPh O.
cess PPh
3
3
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 p-
ethoxyether functionality which links the reagent to the soluble polymer support, the homogeneous na-
ture 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 consider-
able efforts in recent years [26-28]. The Wittig olefination reaction has also been much studied
throughout the evolution of crosslinked polymer-supported reagents and considerable success has been
achieved [29-34]. Bernard and Ford [34] noted an inverse correlation between the yield of alkene ob-
tained 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 sug-
gested that a soluble polymer-supported phosphonium salt may give excellent yields in the Wittig reac-
tion.
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Molecules 2000, 5
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 polymer-
supported Wittig olefination reactions in aqua. Treatment of PEG-supported phosphine 2 with benzyl-
bromide, followed by precipitation into diethyl ether yielded the soluble polymer-supported benzyl tri-
arylphosphonium salt 12 in 81% yield (based on the weight of polymer obtained). This polymeric phos-
phonium 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).
Table 2. Aqueous Wittig reactions phosphonium salt 12 and aldehydes (11a-13a-d).
a
b
Conditions
Entry
Aldehyde
13a
Yield % (E/Z ratio)
1
2
3
4
5
6
7
8
1 N NaOH, r.t.
1 N NaOH, 90Û&
1 N NaOH, r.t.
1 N NaOH, 90Û&
1 N NaOH, r.t.
1N NaOH, r.t.
1 N NaOH, 90Û&
1 N NaOH, r.t.
65 (56:44)
62 (75:25)
80 (46:54)
78 (75:25)
95 (48:52)
38 (49:51)
49 (47:53)
63 (54:46)
13b
13c
11a
13d
a
b
Yields of isolated stilbenes (14a-e).
1
Measured by H NMR of crude mixture.
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. Iso-
lation of the stilbenes (14a-e) was achieved by partitioning the reaction mixture with CH Cl , followed
2
2
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&ꢀꢁ UHVXOWHGꢁ LQꢁ 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 phos-
phine 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-polymer-
interactions 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-

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Molecules 2000, 5
phine from the polymer. However, quantitative reduction of 9 was achieved with freshly prepared alane
3
1
(
AlH ) [38] in THF as determined by P NMR vide supra. The polymer was isolated in 75% yield fol-
3
lowing 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 reiso-
lation.
Table 3. Regeneration of PEG-supported triarylphosphine 2.
a
Entry
Reagent
Conditions
CH Cl / r.t.
P(V) to P(III) /%
b
1
2
3
4
5
PMHS , CH
2
Cl
2
2
2
20
33
40
56
PMHS
Benzene/ reflux 20 h
THF/ reflux 20 h
PMHS
c
HSiCl
3
Benzene/ reflux 20 h
AlH •THF
3
THF/ r.t. 30 min
100
a
31
b
c
Measured by P NMR of the reaction mixtures. Polymethylhydrosiloxane. With tri-
ethylamine.
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 or-
ganometallic 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 reac-
tion within the sphere of polymer-supported chemistry has been demonstrated with the recent emer-
gence of solid- [41-43] 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 rea-
gents are to some extent outweighed by the problems associated with their removal after reaction com-
pletion. 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 re-
quired 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 polymer-
supported products by a simple precipitation of the support into a suitable solvent and recovery by fil-
tration.
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
1
being > 95% [46]. The conversion was quantitative based upon H NMR spectroscopic analysis of 15a-
b.

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Molecules 2000, 5
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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 [49-51]. Initially therefore, we had serious concerns
that the PEG-backbone may serve to either retard or completely inhibit the Stille reaction via com-
plexation of either the palladium catalyst, the alkali metal halide or the organostannane reagent.
Table 4. Optimization of the Stille cross-coupling reaction parameters between 15a and 16.
a
Û
b
b
Entry Catalyst
Solvent conc./mM T/ C LiCl Time/h Yield 18a/% Yield 19a/%
c
1
2
3
4
5
6
7
8
9
Pd(PPh
Pd(PPh
Pd(PPh
3
)
)
)
2
2
Cl
Cl
Cl
2
toluene
THF
20
20
20
20
20
20
20
20
10
110
reflux
80
+
+
+
+
+
+
-
24
24
24
24
24
24
24
48
24
22
68
89
53
7
-
-
-
-
c
c
c
3
2
3
2
2
DMF
toluene
THF
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
)
4
4
4
110
reflux
80
3
)
)
73
58
12
0
3
DMF
DMF
DMF
DMF
10
86
97
98
3
)
2
2
2
Cl
Cl
Cl
2
80
3
)
)
2
80
+
+
3
2
80
0
a
b
c
Based on the concentration of PEG-bound substrate 15a.
Isolated yields after workup.
Not determined.

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Molecules 2000, 5
1
The efficiency of the initial series of experiments was determined both by H NMR analysis of the
PEG-biaryl adduct 17a and, following transesterification, by the isolated yields of the biaryl methyl ester
1
8a 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 PEG-
supported 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&ꢂꢁ7KHꢁUHVXOWVꢁVKRZꢁWKDWꢁ'0)ꢁLVꢁWKHꢁPRVWꢁVXSHULRUꢁRIꢁWKHꢁVROYHQWVꢁWHVWHGꢁIRUꢁWKHꢁ3(*ꢃ
supported Stille reaction. Similar to the case with THF, PdCl (PPh is the best catalyst (Table 4, en-
2
)
3 2
tries 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 re-
action concentration of 20 mM for 48 h, or 10 mM for 24 h, gives excellent yields for the monometh-
oxy-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 coun-
terpart. The toxic tributyl tin derivatives are easily separated from the PEG-biaryl adduct 17a by pre-
cipitation 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
7a, because the homocoupling side-reaction takes place in solution and thus the contaminant is re-
1
moved 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
3
4a-b) were each isolated in > 95% purity.

ꢀ
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Molecules 2000, 5
Table 5. Parallel liquid-phase Stille couplings of iodides 15a-b with tributyl
a
stannanes 16 and 21-27 .
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Molecules 2000, 5
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 p-
anisaldehyde as appropriate. Liquid chromatography was performed using compressed air (flash chro-
matography) with the indicated solvent system and silica gel 60 (230-400 mesh). Preparative and semi-
preparative TLC was performed using Merck 1 mm or 0.5 mm coated silica gel Kieselgel 60 F254 plates
1
repectively. 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 mil-
1
3
lion (ppm) on the δ scale from an internal standard. C NMR spectra were recorded on either a Bruker
3
1
AMX 500 spectrometer at 125 MHz or a Bruker AMX 400 spectrometer at 100 MHz. P NMR spec-
tra were recorded on a Bruker AMX 400 spectrometer at 162 MHz. Infra-red spectra were run on a
-1
Nicolet 510 FT-IR spectrometer from 4000-600 cm . 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 (30 mL) was cooled to -
2
7
8Û&ꢂꢁ$ꢁVWUHDPꢁRIꢁR]RQHꢃHQULFKHGꢁR[\JHQꢁZDVꢁLQWURGXFHGꢁXQWLOꢁDꢁEOXHꢁFRORUꢁSHUVLVWHGꢂꢁ$IWHUꢁꢄꢁPLQꢁD
stream of dry nitrogen or argon was bubbled through the reaction mixture until the blue color disap-
peared. PPh (403 mg, 1.54 mmol) was added in one portion and the resulting solution was allowed to
3
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 4.4
T
1
min; H NMR (250 MHz, CDCl
3
) δ 10.16 (s, 1H), 9.82 (d, J =1.0 Hz, 1H, Ar-H), 7.82 (dd, J = 7.4 Hz,
1
3
1
2
H, Ar-H), 7.56-7.25 (m, 3H, Ar-H), 3.35 (t, J = 7.5 Hz, 2H), 2.79 (dt, 2H); C (101 MHz, CDCl ) δ
3
01.3, 192.9, 147.9, 142.7, 135.4, 134.5, 131.3, 127.0, 102.0, 45.2, 25.6; FABHRMS calcd. for
+
C
10
H
10
O
2
(M ) 162.1852, found 162.1854.

ꢀ
ꢁꢅꢂ
Molecules 2000, 5
Standard Procedure B: Ozonide Reduction With Liquid-Phase PPh
-Formylbenzenepropanal (11c)
3
reagent 2
2
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 2 (3.08 g, 1.54 mmol) was added in one
3
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
was prepared as described in standard procedure A. Resin-bound PPh (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 Cl (250 mL). The filtrate and washings were
2
Cl
2
(30 mL)
3
2
2
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 90Û&ꢁꢅ7DEOHꢁꢆꢇꢁHQWU\ꢁꢆꢀꢂꢁ7KHꢁUHDFWLRQꢁPL[WXUHꢁZDVꢁWKHQꢁGLOXWHGꢁZLWKꢁ&+
Cl (100
mL) and anhydrous MgSO was added with vigorous stirring. The desiccant was then removed by fil-
tration and washed with CH Cl
. The combined filtrate and washings were concentrated in vacuo (to 3
(
2
2
4
2
2
mL) and then added dropwise to vigorously stirring diethyl ether (100 mL). The precipitate was re-
moved by filtration and washed with diethyl ether (20 mL). The filtrate and washings were then con-
centrated (2 mL) in vacuo and passed through a pad of silica gel (1cm × 2cm). The eluant was evapo-
rated 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-(OPhPPh (2)
2 2
)
PEG-phosphine oxide 9 (200 mg, 0.1 mmol) was dissolved in THF (2.5 mL) and cooled (0Û&ꢀꢂ
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

ꢀ
ꢁꢆꢁ
Molecules 2000, 5
cooled (0Û&ꢀꢁDQGꢁTXHQFKHGꢁZLWKꢁ0H2+ꢁꢅꢈꢂꢉꢁP/ꢀꢂꢁ7KHꢁFUXGHꢁPL[WXUHꢁZDVꢁILOWHUHGꢁWKURXJKꢁDꢁVKRUWꢁSDG
of Celite, the clear filtrate was then concentrated in vacuo (to 4 mL) and added dropwise into vigor-
ously 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 80Û&ꢁIRUꢁ ꢆꢊꢁ Kꢂꢁ 7KHꢁ GDUNꢁ VXVSHQVLRQꢁ ZDV
cooled to room temperature, diluted with CH
2
Cl , filtered through a glass fritted funnel and concen-
2
trated 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%).
1
MeO-PEG5000-(4-phenylbenzoate) (18a). H NMR (400 MHz, CDCl
3
) 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 (CH
2
Cl
2
or hexane-10% diethyl ether as the eluant), to give the methyl ester 18a as
1
a white solid (40 mg, 98%). H NMR (400 MHz, CDCl
3
) δ 8.11 (d, J = 8.1 Hz, 2 H), 7.67-7.61 (m, 4
1
3
H), 7.44 (t, J = 7.56 Hz, 2 H), 7.39 (t, J = 7.32 Hz, 1 H), 3.94 (s, 3H); C NMR (100 MHz, CDCl
3
) δ
1
66.94, 145.55, 139.90, 133.81, 130.04, 128.87, 128.09, 127.21, 126.97, 52.07; FABHRMS calcd. for
+
C
14
H
13
2
O (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
2
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Molecules 2000, 5
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(
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Sample Availability: Available from the authors.
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2000 by MDPI (http://www.mdpi.org).