Solid-phase approaches toward cyclic oligomers

Article abstract of DOI:10.1016/S0040-4020(01)00930-9

Strategies were sought to effect cyclizations of oligo(m-phenylene ethynylene) by exploiting pseudo-high dilution effects on polymer supports. Using Pd/Cu-catalyzed coupling protocols, Merrifield's resin (1% crosslinked chloromethylated polystyrene) proved inadequate for site isolation; inter-site couplings ensued on the flexible support. Conversely, use of the Argopore resin, a more highly crosslinked polystyrene, inhibited inter-site interactions, and no identifiable final product could be separated from the resin. Spectroscopic and mass spectrometric methods indicated that the product from the Argopore resin might be a threaded catenane.

Full text of DOI:10.1016/S0040-4020(01)00930-9

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 9055±9065
Solid-phase approaches toward cyclic oligomers
David B. Shortell,a Liam C. Palmera and James M. Tourb,p
aDepartment of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
bDepartment of Chemistry and Center for Nanoscale Science and Technology, Rice University, MS 222, 6100 Main Street,
Houston, TX 77005, USA
Received 21 August 2001; accepted 21 September 2001
AbstractÐStrategies were sought to effect cyclizations of oligo)m-phenylene ethynylene) by exploitingpseudo-high dilution effects on
polymer supports. UsingPd/Cu-catalyzed couplingprotocols, Merri®eld's resin )1% crosslinked chloromethylated polystyrene) proved
inadequate for site isolation; inter-site couplings ensued on the ¯exible support. Conversely, use of the Argopore resin, a more highly
crosslinked polystyrene, inhibited inter-site interactions, and no identi®able ®nal product could be separated from the resin. Spectroscopic
and mass spectrometric methods indicated that the product from the Argopore resin might be a threaded catenane. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Supramolecular synthesis
has several potential advantages over conventional solution-
phase organic syntheses including simpli®ed puri®cation of
intermediates, use of easily ®lterable excess reagents to
drive reactions, minimization of orthogonal protection
group protocols, and simple adaptation to combinatorial
and automated approaches.14±18,25,26 While targeting the
cyclic oligo)m-phenylene ethynylene) 1, we considered a
resin-supported strategy as illustrated by Fig. 1. We were
emboldened by Moore's success in obtaininghigher yields
usingresin based-macrocyclic synthesis versus the solution
phase.27
Over the last two decades, there has been a surge of
development in the ®eld of supramolecular chemistry. The
preparation of well-de®ned molecular architectures has
played a large role in the exploration of this discipline.1±5
Both the creation of exactly speci®ed chemical structures
and the methodologies to their syntheses are crucial for
the advancement of supramolecular and materials
chemistry.6±13 The controlled incorporation of moieties
that de®ne the steric, electronic, and chemical properties
of the supramolecular frameworks has been critical for
7
effectingthe syntheses. Some speci®c methods include
step-wise divergent/convergent syntheses,14±18 templated
approaches,19±21 and geometrically controlled routes.22,23
Initially we sought to improve the synthesis of cyclic
oligo)m-phenylene ethynylene)s by employinga resin-
supported route for a pseudo-high dilution effect. However,
as we will show, lightly crosslinked resins did not provide
the needed site isolation due to their inherent ¯exibilities.24
While the more rigid resins did inhibit inter-site inter-
actions, we were not able to separate identi®able products,
and spectroscopic and mass spectrometric methods indi-
cated that the ®nal product might be a threaded catenane.3
3. Attempted coupling of resin-bound pentamer with
1,3-diethynylbenzene
Speci®cally, a resin-immobilized oligomer could be con-
structed )Scheme 1), affordinga diiodo-functionalized
pentamer that could be reacted with 1,3-diethynylbenzene
to form a cyclic hexamer 1. Accordingly, 1,3-diiodobenzyl
alcohol )2) was prepared by borane reduction of the known
1,3-diiodobenzoic acid. 3, a resin suitable for immobilizing
alcohol functionalized molecules,28 was prepared from
commercially available Merri®eld's resin )1% crosslinked
polystyrene with chloromethylation at 1.00 mequiv./gCl).
Treatment with the sodium salt of 2-)hydroxymethyl)-3,4-
dihydro-2H-pyran in dimethylacetamide gave the desired
resin with 100% expected mass gain after drying. 2 was
bound to the resin by heatingat 60 8C in the presence of
p-toluenesulfonic acid in 1,2-dichloroethane28 to give 4.
The yield of 67% was determined by mass increase and
by cleavinga small sample from the polymer support
under literature conditions28 to measure the loading. This
diiodo-functionalized resin 4 is the startingmaterial for the
two-directional oligomer growth.
2. Bene®ts of solid-supported chemistry
Solid-supported chemistry in the preparation of oligomers
Keywords: supramolecular; macrocycle; pseudo-high dilution.
Correspondingauthor. Address: Department of Chemistry and Center for
p
Nanoscale Science and Technology, Rice University, MS 222, 6100 Main
St., Houston, TX 77005, USA. Tel.: 11-713-348-6246; fax: 11-713-348-
6250; e-mail: tour@rice.edu
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00930-9

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D. B. Shortell et al. / Tetrahedron 57 .2001) 9055±9065
Figure 1. Strategy 1 for the preparation of resin-immobilized cyclic oligo)m-phenylene ethynylene)s.
Scheme 1. Preparation of a resin-immobilized pentamer.

D. B. Shortell et al. / Tetrahedron 57 .2001) 9055±9065
9057
Figure 2. Strategy 2 for the preparation of resin-immobilized cyclic oligo)m-phenylene ethynylene)s.
ꢀ1†
Reaction of 4 with trimethylsilylacetylene under palladium-
catalyzed cross-couplingconditions 29,30 gave 5 )Scheme 1).
Resin 5 shows a stronginfrared absorbance at 2156 cm
appearance of the infrared absorbance at 3292 cm21. This
entire transformation resulted in only 20% of the expected
mass gain.
21
due to the trimethylsilyl-terminated alkynes. Upon treat-
ment with tetrabutylammonium ¯uoride, this absorbance
was replaced by the absorbance at 3292 cm21 of resin 6.
These infrared bands have been used previously to deter-
mine the ef®cacy of polystyrene-supported reactions.15,18,24
Cyclization was attempted with 1,3-diethynylbenzene
)Eq. )1)). However, the desired cyclic hexamer 1 was not
obtained upon cleavage from the polymer support with
pyridinium p-toluenesulfonate in n-butanol and 1,2-di-
chloroethane.24,28 Analysis of the cleaved material suggests
that inter-site reactions had taken place duringthe oligomer
growth; this behavior has been previously reported.24,31,32
The occurrence of reactions between the resin-supported
oligomers also explains the low mass increase of later
reactions in the sequence.
Treatment with 1,3-diiodobenzene, again under palladium-
29,30
catalyzed cross-couplingconditions,
gave 7. Assuming
that the dialkyne was site-isolated while bindingto the
support, there was no danger of oligomerization. The mass
increase was only 34% of the expected increase, but the
terminal alkyne proton infrared absorbance disappeared,
indicatingthat the startingmaterial had been con-
sumed.15,18,24 Reaction of 7 with trimethylsilylacetylene
under palladium catalyzed cross-couplingconditions gave
8, which was desilylated to give 9, again accompanied by
the expected infrared signatures. Finally, treatment with
1,3-diiodobenzyl alcohol gave 10 as indicated by the dis-
4. Attempted coupling of a,v-diethynyl pentamer to
resin-bound diiodoarene
Turning to a different strategy, as depicted in Fig. 2, an
Scheme 2. Preparation of functionalized pentamer.

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D. B. Shortell et al. / Tetrahedron 57 .2001) 9055±9065
Scheme 3. Preparation of functionalized heptamer.
oligomer would be prepared by solution-phase two-direc-
tional synthesis and reacted with a resin-immobilized small
molecule containingthe appropriate diiodo-functionality.
latter compounds with 1,3-diethynylbenzene, even with
slow addition of the dialkyne to a solution of excess
dihalide, gave polymeric products. The resulting trimer 13
was treated with excess mono-silylated 1,3-diethynyl-
benzene24,33 to give pentameric material 14 that was depro-
tected with potassium carbonate in methanol to give 15.
Strategy 2 would enjoy the same streamlined synthetic route
as in the ®rst method; however, because the oligomer would
not be bound to a polymer support duringgrowth reactions,
suitably protected functionalities would be required in order
to avoid polymerization.
In addition to the pentamer 15, we sought a heptamer in the
hope of polymer-supported cyclization to form a cyclic
octamer since previously used methods were ineffective.22,23
As we wished to target a cyclic hexamer, efforts turned to
the preparation of an appropriately functionalized pentamer
)Scheme 2).
Treatment of ethyl 3,5-diiodobenzoate with excess mono-
silylated 1,3-diethynylbenzene in the presence of palladium
and copper gave 16 )Scheme 3). Desilylation34 gave 17,
which was coupled with excess 12 to give pentamer 18.
Treatment with excess mono-silylated 1,3-diethynyl-
benzene in the presence of palladium and copper gave the
desired heptamer 19. Reaction with methanolic potassium
Couplingof an excess of the known methyl 3-bromo-5-
iodobenzoate )12) with 1,3-diethynylbenzene gave 13. 12
rather than the dibromo- or diiodo-derivative was required
in order to avoid polymerization; experiments usingthe
ꢀ2†

D. B. Shortell et al. / Tetrahedron 57 .2001) 9055±9065
9059
ꢀ3†
carbonate gave the desired desilylated material as the
trimethyl triester 20.
5. Use of the Argopore resin
Due to the side-reaction between resin-functionalities, truly
site-isolated reactions to form cyclic oligomers are dis-
favored with this solid-support. Therefore, we turned our
attention to a more highly cross-linked system, namely the
Argopore resin. This highly cross-linked chloromethylated
polystyrene has been previously used to maximize site iso-
lation, although the precise crosslinking level is not
disclosed by the manufacturer.31,32 Our preliminary experi-
ments have shown that the material swells very little in
Attempts to react oligomer 15 with resin-immobilized
diiodide 4 did not result in the desired cyclic hexamer, 21
)Eq. )2)). As in our previous strategy, it seems that in the
resin-supported compounds molecules are not truly site-
isolated, resultingin reaction between separate resin-
bound functionalities.31,32 We instead obtained 22 as con-
®rmed by treatment with acid to afford 23 )Eq. )3)). Like-
wise cyclic octamer derived from 4 and 20 did not form.
Scheme 4. Preparation of the cyclic hexamer on the Argopore resin.

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D. B. Shortell et al. / Tetrahedron 57 .2001) 9055±9065
Scheme 5. Attempted cleavage reactions to liberate cyclic hexamer.
solvents such as THF )which greatly swell Merri®eld's
resin) thereby attestingto the hihg crosslink density. It
was hoped that this rigid resin would minimize the
probability of inter-site reactions of the resin-supported
oligomers.
further subjected to sonication for 24 h in dimethylforma-
mide; some physical decomposition of the polymer was
observed, but no product was isolated.
We then theorized that the material, once cyclized, was
physically entangled with the highly cross-linked polymer
in a threaded )catenane) structure )Scheme 6).
As shown in Scheme 4, resin-immobilized diiodobenzyl
alcohol )40) was prepared on the Argopore resin. Reaction
of the pentamer 15 with the functionalized Argopore resin 40
gave a bright yellow resin with the expected mass increase
and an infrared absorbance at 1733 cm21, indicatingthat
ester functionality had indeed been incorporated in the
polymer support. Oddly, standard cleavage conditions did
not provide the desired cyclic oligomer, 24 )Scheme 5),
which is a precursor to 1. In fact, no oligomeric material
could be cleaved from the resin. The only spectroscopically
observable product was a small amount of 2. Since cyclics
similar to 24 are generally soluble,22,23,27 we did not believe
we had a simple solubility problem in product isolation.
More rigorous cleavage conditions28 were attempted, as
shown in Scheme 5. Usingtri¯uoroacetic acid±methanol
)95:5), followed by overnight continuous extraction with
THF gave no product. Additionally, treatment with p-tolue-
nesulfonic acid in CH2Cl2 also failed to remove product
from the polymer support.
6. Some evidence for a resin-threaded catenane
Thus we performed matrix-assisted laser-desorption ioni-
zation mass spectrometry )MALDI-MS) on the suspected
resin/catenane )25) with the hope of cleavingeither the
resin or the macrocycle, and detectingthe macrocycle's
fragments.35 We assumed that the material had been trans-
esteri®ed to the di)butyl) ester duringthe attempted
cleavage reaction conditions )n-butanol and acid). Thus,
the product alcohol di)butyl) ester has a predicted mass
spectrometric distribution for C59H42O5 of 830.3 )100%
intensity), 831.2 )65% intensity), and 832.3 )20% inten-
sity) amu. Ions from the MALDI-MS of 25 )Rˆn-butyl)
were centered at 815, 774, 756, 712, 694, and 692 amu
that must correspond to our oligomeric material; control
experiments with the matrix alone, as well as the resin 40
prior to reaction with pentamer 15, did not show these frag-
ments. Note that peak differences of a few mass units are
dif®cult to distinguish in this MALDI-MS since intense
energy was required to decompose the host resin. Moreover,
the insoluble beads' macroscopic contour contributed to the
need for averaging over 200 scans.35 The observed peak at
815 corresponds to loss of methyl from the parent ion. The
peak at 774 )256 amu) corresponds to the ion formed by a
First assumingthat the material was physically entrapped in
the pores of the polymer matrix, we attempted to mech-
anically liberate the macrocycle. By coolingthe solid
resin with liquid N2 and pulverizingwith an agate mortar
and pestle, we reduced the resin to a ®ne paste. This paste
was then treated again with the above extraction conditions,
resultingin no observed oligomer. The pulverized resin was
Scheme 6. Effect of the cleavage reaction on the Argopore resin-bound cyclic hexamer.

D. B. Shortell et al. / Tetrahedron 57 .2001) 9055±9065
9061
McLafferty rearrangement )loss of C4H8). The peak
centered at 756 corresponds to the ion formed by loss of a
butoxy group )±OC4H9). As each of these ions are higher in
molecular weight than that of the starting pentamer 15 )or
even its di)butyl) ester derivative), we concluded that 15
had reacted with functionality on resin 40 to produce a
compound that could fragment under the MALDI conditions
to give the observed species. The spectrometric information,
coupled with the clear 1733 cm21 IR signature for the ester
and our inability to remove the product from the resin using
vigorous conditions suggested that the catenane 25 had
formed. Further work is needed to con®rm this interesting
result.
successively in the funnel with THF )3£250 mL), DMF
)3£250 mL), 1:1 DMF±water )3£250 mL), acetone )3£
250 mL), CH2Cl2 )3£250 mL), and Et2O )3£250 mL). The
resin was allowed to pre-dry in the funnel, followed by
rigorous drying in a vacuum oven for 8 h )608C at
,2.5 mmHgpressure).
8.3. General procedure for cleavage of immobilized
compounds from polymer resin28
Approximately 0.50 gof the loaded polymer was added to a
¯ask containingC 6H5N±TsOH )0.15 g, 0.60 mmol), 1-buta-
nol )50 mL), and CH2ClCH2Cl )50 mL). The reaction was
stirred overnight at 608C. The reaction mixture was then
poured through a fritted funnel and the ®lter cake was
washed extensively with CH2Cl2. The ®ltrate was washed
with water )3£) and the organics concentrated in vacuo to
give the cleaved compound. The loading was determined
from isolated product; yield was calculated from the loading
compared to the theoretical loadingbased on Merri®eld's
resin )1.00 mequiv./g).
7. Conclusions
In summary, we initiated a study to mimic high dilution
conditions for macrocycle formation by conductingthe
cyclization step on a polymer support. However, the lightly
crosslinked Merri®eld's resin was inadequate to provide the
desired site isolation. Use of the Argopore resin, a more
highly crosslinked polystyrene, inhibited inter-site inter-
actions; some evidence that the cyclized products were
threaded by the resin to form resin/macrocycle catenanes
was obtained. Although a resin that could be decomposed
after reaction could likely be used to achieve the desired
macrocyclization with site isolation and subsequent libera-
tion, the resin/macrocycle structures provide a unique
avenue to catenanes,5 should our preliminary conclusion
be con®rmed with further work. It is possible that a
functionalized, decomposable resin could be used to provide
a general synthesis to such threaded catenanes.
8.3.1. 3,5-Diiodobenzyl alcohol /2). To a dry ¯ask at 08C
containing3,5-diiodobenzoic acid )0.10 g, 0.27 mmol) was
slowly added BH3±THF )3.0 mL, 3.0 mmol) via syringe.
This was stirred for 1 h, then allowed to warm to room
temperature. The reaction was quenched with 15:1 THF±
water. The crude mixture was extracted with ether )3£
20 mL), dried over MgSO4, and concentrated in vacuo.
This was dissolved in CH2Cl2 and ®ltered through a silica
gel plug and reconcentrated to yield 0.10 g )100%) of a
1
white solid. FTIR )KBr) 3422, 3213, 1638, 1386 cm21. H
NMR )400 MHz, CDCl3) d 7.95 )s, 1H), 7.66 )s, 2H), 4.60
)s, 2H), 1.57 )s, 1H plus additional water). 13C NMR
)100 MHz, CDCl3) d 144.6, 144.0, 134.8, 94.8, 63.5.
HRMS Calcd for C7H6I2O: 359.8508. Found: 359.8504.
8. Experimental
8.1. General procedure
8.3.2. Dihydropyran functionalized resin /3).28 To a dry
N2-purged ¯ask containing 2-)hydroxymethyl)-3,4-dihydro-
2H-pyran )6.85 g, 60.0 mmol) and THF )100 mL) was
slowly added NaH )1.67 g, 66.0 mmol). Vigorous bubbling
accompanied the addition, and the reaction was stirred
for 2 h at room temperature. The resultingsolution was
concentrated and dissolved in dimethylacetamide )300
mL). Merri®eld's resin was then added to the solution,
and the reaction was stirred for 12 h. The product was
isolated and puri®ed by the general resin washing procedure
accordingto Section 8.2. A total of 22.1 g)100% of
expected mass change) of white powder was obtained.
FTIR )CCl4) 3411.5, 3029.7, 2921.0, 1947.2, 1600.4,
All operations, unless otherwise noted, were carried out
under a dry, oxygen-free, atmosphere. Infrared spectra of
resin-immobilized compounds were obtained by swelling
the polymer with CCl4 and pressingthe sample between
two NaCl plates. THF and Et2O were distilled under N2
over sodium benzophenone ketyl. Reagent grade CH2Cl2
was distilled under N2 from CaH2. Bulk grade hexanes
were distilled prior to use. Column chromatography was
carried out on silica gel )230±400 mesh from EM Science).
Merri®eld resin )1% crosslinked, 200±400 mesh, 1.00
mequiv./gCl, Aldrich #22,148-1) and Arogpore resin
)highly crosslinked, 200±400 mesh, 0.96 mequiv./g Cl,
Aldrich #45,250-1) were purchased from Aldrich Chemical
Co. and used without additional puri®cation. When refer-
ringto the approximate number of mmol on a resin, it refers
to the active synthetic component. Flash chromatography
refers to column chromatography with a N2 head pressure
as described by Still.36
1445.6, 1380.6, 1380.6, 1238.9 cm21
.
8.3.3. Diiodoarene-functionalized resin /4). A method
analogous to that of Thompson was used.28 To a dry
N2-purged ¯ask containing resin 3 )11.5 g, 10 mmol
DHP), CH2ClCH2Cl )200 mL), and TsOH±H2O )1.00 g,
5.26 mmol) was added 3,5-diiodobenzyl alcohol )7.75 g,
21.5 mmol). The reaction was heated to 608C for 12 h.
Afterwards, the product was isolated accordingto the
general resin washing procedure according to Section 8.2.
A total of 13.9 g)67% of expected mass change) of product
was obtained as a pale yellow powder. FTIR )CCl4) 3398.5,
8.2. General resin washing procedure
The solvent-suspended resin was isolated by ®ltration
through a dry pre-weighed sintered glass funnel. The mother
liquor was set aside, and the ®ltrant was then washed

9062
D. B. Shortell et al. / Tetrahedron 57 .2001) 9055±9065
3032.7, 2922.4, 2320.6, 1949.4, 1871.6, 1597.3, 1443.8,
1368.5 cm21
)1.0 mL, 5.7 mmol) was sealed, and the reaction was stirred
at room temperature for 12 h. The reaction mixture was
poured into water, extracted with CH2Cl2, washed with
water, and concentrated in vacuo to give a crude solid.
The product was further puri®ed by ¯ash column chroma-
tography )silica, 2:1 hexane±CH2Cl2) to yield 0.8822 g
)95%) of the desired trimer as a white solid. FTIR )®lm)
3075.3, 2999.4, 2952.2, 2847.8, 1727.9, 1597.4, 1583.0,
1478.8, 1439.0, 1267.0, 1195.3, 1165.1, 1130.7, 997.7,
.
8.4. General coupling procedures 1 and 2
The resin was loaded into a ¯ame-dried, N2-purged screw-
cap tube containing ,0.008 mol equiv. [)C6H5)3P]2PdCl2,
,0.06 mol equiv. CuI, ,3.25 mol equiv. iPr2NEt and 100
mL THF. ,3 mol equiv. of trimethylsilylacetylene )pro-
cedure 1) or diiodoarene )procedure 2) was added, the
tube was sealed and the mixture was stirred at room
temperature for 12 h. The product was isolated by the
general resin washing procedure according to Section 8.2.
1
952.7, 907.8, 829.9, 792.9, 765.4, 731.6, 676.9 cm21. H
NMR )CDCl3, 400 MHz) d 8.06 )t, Jˆ1.5 Hz, 2H), 8.04
)t, Jˆ1.5 Hz, 2H), 7.75 )t, Jˆ1.6 Hz, 2H), 7.63 )s, 1H),
7.45 )dd, Jˆ7.7, 1.3 Hz, 2H), 7.30 )t, Jˆ7.7 Hz, 1H), 3.90
)s, 6H). 13C NMR )CDCl3, 100 MHz) d 166.0, 139.2, 135.9,
133.5, 133.1, 133.0, 132.4, 129.8, 126.3, 124.0, 123.4, 91.8,
88.9, 53.9. HRMS Calcd for C26H16Br2O4: 549.9415.
Found: 549.9424.
8.4.1. 1,3-Bis/trimethylsilylethynyl)arene-functionalized
resin /5). Usingcouplingprocedure 1, 4 )12.63 g, 8.79
mmol) gave 12.11 g )100% of expected mass change) of
product that as a yellow powder. FTIR )CCl4) 3025.8,
2909.3, 2156.3, 1598.1, 1488.0, 1446.8, 1360.3, 1250.7,
8.4.8. Bis-silylated pentamer 14. To a ¯ame-dried,
N2-purged screw-cap tube containing trimer 13 )0.78 g,
1.42 mmol), [)C6H5)3P]2PdCl2 )20 mg, 0.029 mmol), CuI
)20 mg, 0.11 mmol), and a 3:1 mixture of mono- and
disilyl-1,3-diethynylbenzene )0.91 g, 3.0 mmol monosilyl)
was added iPr2NEt )1.0 mL, 5.7 mmol) and THF )10 mL)
via syringe. The tube was evacuated and back-®lled with dry
N2 )3£) then sealed, and the reaction was stirred at 808C for
2 d. The reaction mixture was poured into water, extracted
with CH2Cl2, washed with water, and concentrated in vacuo
to give a crude solid. The product was further puri®ed by
¯ash column chromatography )silica, 2:1 hexane±CH2Cl2)
to yield 0.78 g)70%) of the desired pentamer as a pale
yellow solid. FTIR )®lm) 3066.9, 2956.8, 2158.6, 1727.6,
1595.6, 1478.1, 1441.3, 1355.1, 1263.2, 1112.5, 1001.5,
1032.1, 851.3, 795.4, 740.6, 682.6 cm21
.
8.4.2. 1,3-Bis/ethynyl)arene-functionalized resin /6). To a
dry ¯ask containingresin 5 )11.4 g, 8.79 mmol) and THF
)250 mL) was added )C4H9)4NF )25.0 mL, 25.0 mmol,
1.0 M in THF). The resultant black solution was stirred at
room temperature for 1 h. Afterwards, the product was
isolated accordingto the general resin washingprocedure
accordingto Section 8.2. A total of 10.30 g)90% of
expected mass change) of product was obtained as an
orange powder. FTIR )CCl4) 3291.9, 3026.8, 2912.4,
1551.9, 1360.3, 1244.9, 994.6, 784.0 cm21
.
8.4.3. Resin 7. Usingcouplingprocedure 2,
6 )9.72 g,
1
887.9, 847.6, 794.2, 763.9, 732.0, 682.3, 646.5 cm21. H
7.90 mmol) and 1,3-diiodobenzene gave 10.79 g )34% of
expected mass change) of product as a yellow powder.
FTIR )CCl4) 3021.3, 2926.0, 1596.3, 1448.2, 1112.2,
NMR )CDCl3, 400 MHz) d 8.11 )d, Jˆ1.7 Hz, 2H), 8.10
)d, Jˆ1.5 Hz, 2H), 7.79 )s, 2H), 7.70 )s, 1H), 7.65 )s, 2H),
7.50±7.42 )m, 6H), 7.33 )t, Jˆ7.7 Hz, 1H), 7.28 )t, Jˆ
7.8 Hz, 2H), 3.93 )s, 6H), 0.27 )s, 18H). 13C NMR
)CDCl3, 100 MHz) d 166.6, 139.3, 136.2, 135.9, 133.4,
133.1, 132.9, 132.7, 131.9, 129.8, 129.6, 125.1, 125.0,
124.8, 124.3, 124.0, 105.2, 96.4, 91.3, 91.2, 89.5, 89.3,
53.7, 1.3. HRMS Calcd for C52H42O4Si2: 786.2622.
Found: 786.2651.
789.8 cm21
.
8.4.4. Resin 8. Usingcouplingprocedure 1,
7 )9.45 g,
5.77 mmol), gave 9.41 g )100% of expected mass change)
of product as a yellow powder. FTIR )CCl4) 3054.6, 2912.8,
2155.5, 1596.8, 1449.6, 785.6 cm21
.
8.4.5. Resin 9. To a dry ¯ask containingresin 8 )8.4 g,
5.2 mmol) and THF )150 mL) was added )C4H9)4NF
)20.0 mL, 20.0 mmol, 1.0 M in THF). The resultant black
solution was stirred at room temperature for 1 h. After-
wards, the product was isolated accordingto the general
resin washingprocedure accordingto Section 8.2. A total
of 8.07 g)105% of expected mass change) of product was
obtained as an orange powder. FTIR )CCl4) 3291.7, 3030.6,
8.4.9. Pentamer 15. To a dry ¯ask containingpentamer 14
)124 mg, 0.158 mmol), MeOH )50 mL), and CH2Cl2
)50 mL) was added K2CO3 )100 mg, 0.724 mmol) at room
temperature. The suspension was stirred at room tempera-
ture for 3 h, at which time the startingmaterial had been
completely consumed by TLC analysis. The crude mixture
was ®ltered through a silica gel plug and concentrated in
vacuo. The concentrate was dissolved in CH2Cl2, washed
with water, and reconcentrated to give the desired pentamer
as 80 mg)79%) of a pale yellow solid. FTIR )®lm) 3292.1,
2924.9, 2854.5, 1726.6, 1596.2, 1476.8, 1441.2, 1355.0,
2921.7, 1594.4, 1451.3, 787.8 cm21
.
8.4.6. Resin 10. Usingcouplingprocedure 2,
9 )7.4 g,
5 mmol), and 1,3-diiodobenzyl alcohol gave 7.85 g )20%
of expected mass change) of product was obtained as a
yellow powder. FTIR )CCl4) 3420 )br), 3034.6, 2916.3,
1264.3, 1199.8, 1111.4, 1001.5, 895.1, 793.8, 766.3 cm21
.
1H NMR )CDCl3, 400 MHz) d 8.14 )t, Jˆ1.7 Hz, 2H), 8.13
)t, Jˆ1.7 Hz, 2H), 7.83 )t, Jˆ1.5 Hz, 2H), 7.72 )t, Jˆ1.1 Hz,
1H), 7.66 )t, Jˆ1.3 Hz, 2H), 7.52±7.45 )m, 6H), 7.36 )t,
Jˆ7.7 Hz, 1H), 7.31 )t, Jˆ7.7 Hz, 2H) 3.95 )s, 6H), 3.12
)s, 2H). 13C NMR )CDCl3, 100 MHz) d 166.7, 139.3, 136.3,
135.9, 133.5, 133.3, 133.0, 132.9, 132.0, 129.8, 129.7,
125.0, 124.3, 124.1, 123.8, 91.2, 91.1, 89.5, 89.4, 83.9,
1599.6, 1447.5, 1370.0, 1034.6, 790.1 cm21
.
8.4.7. Trimer 13. An oven-dried, N2-purged screw-cap tube
containing1,3-diethynylbenzene )213 mg, 1.69 mmol), 12
)1.15 g, 3.37 mmol), [)C6H5)3P]2PdCl2 )20 mg, 0.029
mmol), CuI )20 mg, 0.11 mmol), THF )5.0 mL) and iPr2NEt

D. B. Shortell et al. / Tetrahedron 57 .2001) 9055±9065
9063
79.3, 53.8. HRMS Calcd for C46H26O4: 642.1831. Found:
642.1843.
pink solid. FTIR )®lm) 3073.1, 2952.2, 2215.2, 1726.0,
1596.8, 1563.9, 1478.0, 1439.2, 1369.4, 1317.6, 1266.7,
1111.1, 1000.4, 905.2, 794.7, 765.0, 731.0, 676.9 cm21
.
8.4.10. Bis-silylated trimer 16. To an oven-dried,
N2-purged screw-cap tube containing ethyl 3,5-diiodo-
benzoate )0.80 g, 2.0 mmol), [)C6H5)3P]2PdCl2 )70 mg,
0.10 mmol), CuI )70 mg, 0.37 mmol), THF )20 mL), and a
3:1 mixture of mono- and disilyl-1,3-diethynylbenzene
)1.21 g, 4.03 mmol monosilyl) was added iPr2NEt )1.0
mL, 5.7 mmol) via syringe. The tube was sealed, and the
reaction was stirred at room temperature for 12 h. The crude
mixture was then dissolved in Et2O, washed with water,
dried over anhydrous MgSO4, passed through a short silica
gel plug, and concentrated in vacuo. The crude product was
further puri®ed by ¯ash column chromatography )silica, 3:1
hexane±CH2Cl2) to yield 0.80 g)74%) of the desired trimer
as a yellow solid. FTIR )®lm) 3066.7, 2961.8, 2158.4,
1948.1, 1724.5, 1593.8, 1475.5, 1442.9, 1406.7, 1368.5,
1258.5, 1217.8, 1140.6, 1111.4, 1025.4, 990.9, 960.0,
1H NMR )CDCl3, 400 MHz) d 8.15 )d, Jˆ1.5 Hz, 2H),
8.13 )t, Jˆ1.7 Hz, 2H), 8.11 )t, Jˆ1.5 Hz, 2H), 7.85 )t,
1.4 Hz, 1H), 7.83 )t, Jˆ1.6 Hz, 2H), 7.72 )s, 2H), 7.52
)app td, Jˆ7.8, 1.3 Hz, 4H), 7.37 )t, Jˆ7.7 Hz, 2H), 4.41
)q, Jˆ7.1 Hz, 2H), 3.94 )s, 6H), 1.43 )t, Jˆ7.1 Hz, 3H). 13C
NMR )CDCl3, 100 MHz) d 165.05, 164.97, 138.1, 134.8,
132.3, 132.0, 131.9, 131.8, 131.3, 131.2, 128.7, 125.2,
123.8, 123.1, 122.8, 122.3, 90.6, 89.8, 88.4, 87.6, 61.6,
52.7, 14.5. HRMS Calcd for C45H28Br2O6: 822.0253.
Found: 822.0235.
8.4.13. Bis-silylated heptamer 19.
A
¯ame-dried,
N2-purged screw-cap tube containing pentamer 18 )0.59 g,
0.71 mmol), [)C6H5)3P]2PdCl2 )100 mg, 0.143 mmol), CuI
)100 mg, 0.53 mmol), THF )20.0 mL), and a 3:1 mixture of
mono- and disilyated 1,3-diethynylbenzene )1.00 g, 3.33
mmol monosilylated) was evacuated and back-®lled with
dry N2 )3£). To this solution was added iPr2NEt )1.0 mL,
5.7 mmol) via syringe. The tube was sealed, and the reaction
was heated at 808C for 3 d. The reaction mixture was poured
into water, extracted with CH2Cl2, washed with water,
®ltered through a silica gel plug, and concentrated in
vacuo to give a black tar. The product was further puri®ed
by ¯ash column chromatography )silica, 1:1 hexane±
CH2Cl2) to yield 0.45 g)60%) of the desired heptamer as
a brown semi-solid. FTIR )®lm) 3065.5, 2955.8, 2158.5,
1729.5, 1597.9, 1478.0, 1441.5, 1357.8, 1265.3, 1240.5,
1206.7, 1169.3, 1137.2, 1111.1, 1026.1, 1004.0, 894.9,
1
848.5, 794.4, 763.0, 730.9, 685.3, 646.5 cm21. H NMR
)CDCl3, 400 MHz) d 8.12 )d, Jˆ1.6 Hz, 2H), 7.80 )t, Jˆ
1.5 Hz, 1H), 7.67 )td, Jˆ1.4, 0.6 Hz, 2H), 7.47 )dt, Jˆ7.7,
1.3 Hz, 2H), 7.44 )dt, Jˆ8.0, 1.4 Hz, 2H), 7.29 )td, Jˆ7.7,
0.6 Hz, 2H), 4.40 )q, 7.1 Hz, 2H), 1.42 )t, Jˆ7.1 Hz, 3H),
0.27 )s, 18H). 13C NMR )CDCl3, 100 MHz) d 166.2, 139.2,
136.3, 133.4, 133.1, 132.7, 132.4, 129.6, 125.0, 124.8,
124.0, 105.2, 96.4, 91.2, 89.4, 62.8, 15.7, 1.3. HRMS
Calcd for C35H34O2Si2: 542.2097. Found: 542.2039.
8.4.11. Trimer 17. To a dry ¯ask containingtrimer 16
)0.80 g, 1.5 mmol) and THF )15 mL) was slowly added
)C4H9)4NF )6.0 mL, 6.0 mmol, 1.0 M in THF) via syringe
at room temperature. The reaction was stirred at room
temperature for 30 min, and the crude mixture was ®ltered
through a silica gel plug and concentrated in vacuo. The
concentrate was dissolved in CH2Cl2, washed with water,
and re-concentrated before further puri®cation by ¯ash
column chromatography )silica, 2:1 hexane±CH2Cl2) to
give 0.40 g )68%) of the desired trimer as a golden oil.
FTIR )®lm) 3293.5, 3068.5, 2982.3, 1723.1, 1595.8,
1476.4, 1442.4, 1369.9, 1258.1, 1204.5, 1111.2, 1025.0,
1
844.8, 793.4, 767.4, 733.0, 682.8, 647.3 cm21. H NMR
)CDCl3, 400 MHz) d 8.15 )t, Jˆ1.2 Hz, 2H), 8.14 )t, Jˆ
1.5 Hz, 2H), 8.12 )t, Jˆ1.5 Hz, 2H), 7.85 )t, Jˆ1.3 Hz, 1H),
7.83 )t, Jˆ1.7 Hz, 1H), 7.73 )s, 2H), 7.66 )s, 2H), 7.53 )t,
Jˆ1.5 Hz, 2H), 7.51 )t, Jˆ1.8 Hz, 2H), 7.48±7.43 )m, 4H),
7.36 )t, Jˆ7.9 Hz, 2H), 7.29 )t, Jˆ7.7 Hz, 2H), 4.41 )q,
Jˆ7.2 Hz, 2H), 3.95 )s, 6H), 1.44 )t, Jˆ7.2 Hz, 3H), 0.27
)s, 18H). 13C NMR )CDCl3, 100 MHz) d 165.4, 164.9,
138.1, 138.0, 135.0, 134.6, 132.21, 132.18, 131.9, 131.7,
131.4, 131.1, 130.7, 128.5, 128.3, 123.8, 123.73, 123.69,
123.5, 123.0, 122.7, 103.8, 95.1, 90.0, 89.9, 89.8, 88.3,
88.2, 88.0, 61.5, 52.6, 52.5, 14.4, 0.0. HRMS Calcd for
C71H54O6Si2: 1058.3459. Found: 1058.3480.
1
896.0, 795.1, 768.5, 733.0, 879.3 cm21. H NMR )CDCl3,
400 MHz) d 8.10 )d, Jˆ1.0 Hz, 2H), 7.78 )s, 1H), 7.66 )s,
2H), 7.48 )td, Jˆ7.7 Hz, 2H), 7.45 )d, Jˆ7.8 Hz, 2H), 7.28
)t, Jˆ7.7 Hz, 2H), 4.38 )q, Jˆ7.1 Hz, 2H), 3.13 )s, 2H), 1.41
)t, Jˆ7.1 Hz, 3H). 13C NMR )CDCl3, 100 MHz) d 165.0,
138.1, 135.1, 132.3, 132.2, 131.9, 131.1, 128.5, 123.7,
123.0, 122.6, 89.9, 88.3, 82.7, 78.2, 61.6, 14.5. HRMS
Calcd for C29H18O2: 398.1307. Found: 398.1316.
8.4.14. Heptamer 20. To a dry ¯ask containingheptamer 19
)0.26 g, 0.25 mmol), MeOH )25 mL), and CH2Cl2 )25 mL)
was added K2CO3 )0.25 g, 1.8 mmol) at room temperature.
The suspension was stirred at room temperature for 90 min,
at which time the startingmaterial had been completely
consumed by TLC analysis. The crude mixture was ®ltered
through a silica gel plug and concentrated in vacuo. The
concentrate was dissolved in CH2Cl2, washed with water,
and re-concentrated to give 0.22 g )99%) of the desired
heptamer as a yellow solid. FTIR )®lm) 3293.4, 2951.1,
1725.3, 1595.8, 1476.9, 1440.2, 1355.6, 1264.1, 1112.5,
8.4.12. Pentamer 18. To an oven-dried, N2-purged screw-
cap tube containingtrimer 17 )0.38 g, 0.95 mmol), 12
)0.65 g, 1.91 mmol), [)C6H5)3P]2PdCl2 )14 mg, 0.020
mmol), and CuI )14 mg, 0.074 mmol) was added THF
)10 mL) and iPr2NEt )1.0 mL, 5.7 mmol) via syringe.
Upon addition of the amine, the clear pale yellow solution
darkened to orange-brown within 10 min. The tube was
sealed, and the reaction was stirred at room temperature
for 12 h. The reaction mixture was poured into water,
extracted with CH2Cl2, and concentrated in vacuo to give
a crude brown solid. The product was further puri®ed by
¯ash column chromatography )silica, 2:1 hexane±CH2Cl2)
to yield 0.72 g)92%) of the desired pentamer as a slightly
1002.2, 902.2, 793.4, 731.5 cm21 1H NMR )CDCl3,
.
400 MHz) d 8.13 )m, 4H), 8.12 )t, Jˆ1.1 Hz, 2H), 7.84 )t,
Jˆ1.6 Hz, 1H), 7.82 )t, Jˆ1.5 Hz, 2H), 7.72 )t, Jˆ1.6 Hz,
2H), 7.66 )t, Jˆ1.5 Hz, 2H), 7.52±7.45 )m, 8H), 7.35 )t,
Jˆ8.1 Hz, 2H), 7.30 )t, Jˆ7.8 Hz, 2H), 3.95 )s, 3H), 3.94
)s, 6H). 13C NMR )CDCl3, 100 MHz) d 165.5, 138.1, 135.1,
134.7, 132.3, 132.2, 131.8, 131.7, 130.8, 128.6, 128.5,

9064
D. B. Shortell et al. / Tetrahedron 57 .2001) 9055±9065
123.8, 123.1, 122.9, 122.6, 90.0, 89.9, 88.3, 88.2, 82.7, 78.1,
52.6.
A method analogous to that of Thompson was used.28 To
a dry N2-purged ¯ask containing resin 30 )3.00 g,
,2.76 mmol DHP), CH2ClCH2Cl )100 mL), and C6H5N±
TsOH )0.50 g) was added 3,5-diiodobenzyl alcohol )3.00 g,
8.33 mmol). The reaction was heated to 608C for 12 h.
Afterwards, the product was isolated accordingto the
general resin washing procedure according to Section 8.2.
A total of 3.50 g)50% of expected mass change) of product
was obtained as a pale yellow powder. The resin showed an
identical infrared spectrum to that of compound 4.
8.4.15. Resin-immobilized heptamer 22. A ¯ame-dried
N2-purged screw-cap tube containing resin 4 )0.500 g,
0.225 mmol arene, 0.45 mequiv./gresin), bis)dibenzyl-
ideneacetone)palladium)0) )5.8 mg, 0.010 mmol), CuI
)10.0 mg, 0.0525 mmol), )C6H5)3P )5.3 mg, 0.020 mmol),
and pentamer 15 )70.0 mg, 0.109 mmol) was evacuated
and back-®lled with dry N2 )3£). To this solution was
added iPr2NEt )1.0 mL, 5.7 mmol) and THF )5.0 mL).
Upon addition of the amine, the clear red solution became
a brownish-tan suspension over ca. 1 min. The tube was
sealed, and the reaction was stirred at 808C for 36 h. After-
wards, the product was isolated accordingto the general
resin washingprocedure accordingto Section 8.2. A total
of 546.2 mg)550.8 mgtheory ˆ91% of expected mass
change) of product was obtained as a bright yellow powder.
FTIR )CCl4) 3026.0, 2918.8, 1944.6, 1874.0, 1804.9,
1729.4, 1593.6, 1549.5, 1489.4, 1447.2, 1359.8, 1252.7,
8.4.19. Argopore-resin-immobilized hexamer 210. A
¯ame-dried N2-purged screw-cap tube containing resin 40
)1.19 g, 0.454 mmol arene, 0.38 mequiv./g resin), bis-
)dibenzylideneacetone)palladium)0) )25 mg, 0.043 mmol),
CuI )25 mg, 0.13 mmol), )C6H5)3P )25 mg, 0.10 mmol),
and pentamer 15 )145 mg, 0.226 mmol) was evacuated
and back-®lled with dry N2 )3£). To this solution was
added iPr2NEt )1.0 mL, 5.7 mmol) and THF )20.0 mL).
Upon addition of the amine, the suspension darkened to
brown over ca. 1 min. The tube was sealed, and the reaction
was stirred at 808C for 2 d. Afterwards, the product was
isolated accordingto the general resin washingprocedure
accordingto Section 8.2. A total of 1.24 g)1.30 gtheory,
43% of expected mass change) of product was obtained as a
yellow powder. FTIR )KBr) 3025.6, 2927.5, 1733.8, 1600.8,
1491.2, 1449.3, 1384.7, 1262.9, 1117.1, 1036.4, 898.5,
834.4, 795.9, 763.9, 704.9 cm21. MALDI-MS )The sample
was suspended in 100% MeCN and then placed atop a dried
layer of matrix made from a-cyano-4-hydroxycinnamic
acid in 70% MeCN and 0.1% tri¯uoroacetic acid. The
sample was run in positive ion mode and the data was
calibrated by external calibration with peptide standards
Angiotensin I and Bovine Insulin.) 815.89 )6.4%), 774.16
)3.2%), 756.03 )16.0%), 712.02 )11.2%), 694.04 )100%),
692.07 )94.4%).
1109.3, 789.8 cm21
.
8.4.16. Heptamer 23. Resin-immobilized heptamer 22
)546 mg) was suspended in a solution of C6H5N±TsOH
)50 mg, 0.20 mmol) in CH2ClCH2Cl )25 mL) and n-butanol
)25 mL). The suspension was heated at 708C for 24 h. The
polymer was removed by ®ltration and the crude ®ltrant was
concentrated in vacuo to give a crude solid. The crude mass
was further puri®ed by ¯ash column chromatography
)silica, 9:1 CH2Cl2/acetone) to obtain a small amount of
residual 3,5-diiodobenzyl alcohol and 92 mg)0.083 mmol,
0.15 mequiv./gresin, 0.22 mequiv./gresin theory, 69% of
expected mass) of the expected heptamer as a yellow ®lm.
FTIR )®lm) 3401.1, 2925.2, 2854.5, 1726.8, 1597.3, 1556.1,
1478.3, 1440.6, 1354.3, 1253.8, 1198.5, 1110.5, 1003.3,
1
907.4, 792.8, 768.1, 732.1, 681.5 cm21. H NMR )CDCl3,
400 MHz) d 8.16 )m, 4H), 7.86 )t, Jˆ1.7 Hz, 2H), 7.80 )t,
Jˆ1.5 Hz, 2H), 7.74 )t, Jˆ1.6 Hz, 1H), 7.70 )m, 4H), 7.54±
7.48 )m, 8H), 7.38 )t, Jˆ8.4 Hz, 1H), 7.36 )t, Jˆ7.8 Hz,
2H), 4.67 )s, 4H), 3.96 )s, 6H), 1.25 )br s, 2H1H2O). 13C
NMR )CDCl3, 100 MHz) d 165.7, 143.0, 139.2, 138.3,
135.8, 134.8, 134.8, 132.4, 131.8, 131.8, 131.7, 130.9,
129.1, 128.7, 125.0, 123.9, 123.2, 123.10, 123.05, 93.9,
89.95, 89.92, 89.7, 88.3, 88.2, 63.9, 52.5. HRMS Calcd
for C60H36I2O6: 1106.0601. Found: 1106.0640.
Acknowledgements
This work was funded by the National Science Foundation.
The trimethylsilylacetylene was kindly provided by Dr I.
Chester of the FAR Research Inc.
References
8.4.17. Dihydropyran functionalized Argopore resin
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THF )25 mL) was slowly added NaH )0.45 g, 18.80
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the reaction was stirred for 2 h at room temperature. The
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to the solution, and the reaction was stirred for 12 h. The
product was isolated and puri®ed by the general resin
washingprocedure accordingto Section 8.2. A total of
5.20 g)96% of expected mass change) of white powder
was obtained. The resin showed an identical infrared
spectrum to that of compound 3.
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