Solid-phase synthesis of phenylacetylene oligomers utilizing a novel 3-propyl-3-(benzyl-supported) triazene linkage

Article abstract of DOI:10.1021/jo961250u

Sequence-specific phenylacetylene oligomers consisting of functionalized monomers (hexyl benzoate, hexyl phenyl ether, benzonitrile, and tert-butylphenyl) are synthesized in gram quantities using solid-phase methods. Growing oligomers are attached to a divinylbenzene cross-linked polystyrene support by the 1-aryl-3-propyl-3-(benzyl-supported) triazene moiety. This linkage is obtained by reaction of arenediazonium tetrafluoroborate salts with a n-propylamino-modified Merrifield resin. Condensation strategies are described, producing oligomers with higher yields and simplified procedures compared to solution-phase methods. Terminal acetylene is protected with a trimethylsilyl group. After deprotection of the resin-bound terminal acetylene, an aryl iodide monomer or an aryl iodide-terminated oligomer is coupled to the supported oligomer using a palladium(O) catalyst. The cycle can be repeated to produce sequence-specific oligomers of varying length and functionality. The resulting oligomers are liberated from the polymer support by cleavage of the 1-aryl-3-propyl-3-(benzyl-supported) triazene group by reaction with iodomethane producing an aryl iodide.

Full text of DOI:10.1021/jo961250u

8160
J . Org. Chem. 1996, 61, 8160-8168
Solid -P h a se Syn th esis of P h en yla cetylen e Oligom er s Utilizin g a
Novel 3-P r op yl-3-(ben zyl-su p p or ted ) Tr ia zen e Lin k a ge
J ames C. Nelson, J ames K. Young, and J effrey S. Moore*
Departments of Chemistry, Materials Science, and Engineering and The Beckman Institute for Advanced
Science and Technology, University of Illinois, Urbana, Illinois 61801
Received J uly 2, 1996X
Sequence-specific phenylacetylene oligomers consisting of functionalized monomers (hexyl benzoate,
hexyl phenyl ether, benzonitrile, and tert-butylphenyl) are synthesized in gram quantities using
solid-phase methods. Growing oligomers are attached to a divinylbenzene cross-linked polystyrene
support by the 1-aryl-3-propyl-3-(benzyl-supported) triazene moiety. This linkage is obtained by
reaction of arenediazonium tetrafluoroborate salts with a n-propylamino-modified Merrifield resin.
Condensation strategies are described, producing oligomers with higher yields and simplified
procedures compared to solution-phase methods. Terminal acetylene is protected with a trimeth-
ylsilyl group. After deprotection of the resin-bound terminal acetylene, an aryl iodide monomer or
an aryl iodide-terminated oligomer is coupled to the supported oligomer using a palladium(0)
catalyst. The cycle can be repeated to produce sequence-specific oligomers of varying length and
functionality. The resulting oligomers are liberated from the polymer support by cleavage of the
1-aryl-3-propyl-3-(benzyl-supported) triazene group by reaction with iodomethane producing an
aryl iodide.
In tr od u ction
have been utilized in combinatorial and automated
strategies involving the simultaneous preparation of as
many as 106 different peptides.13,14 When the combina-
torial approach is combined with an effective screening
protocol, a wide variety of substrates can be tested for a
desired property or activity. Because this approach has
yielded rich rewards in the biomolecular field, it is
reasonable to expect analogous benefits when it is applied
to the study of more broadly defined supramolecular
interactions. To this end, we describe solid-phase meth-
odology for the preparation of phenylacetylene oligomers.
In this article we present full details and describe
further developments in the solid-phase synthesis of
phenylacetylene oligomers including a novel 3-propyl-3-
(benzyl-supported) triazene linkage. We report the prepa-
ration and characterization of the polymeric support,
methods for attaching substrates, repetitive methods
involved in oligomeric growth, liberation of the oligomer
from the support to produce aryl iodide terminated
oligomers, and a nondestructive IR method for tracking
oligomer synthesis. Finally, we compare and contrast the
yields and purities of oligomers obtained by this solid-
phase method with oligomers produced by solution
methods.
Well-defined phenylacetylene oligomers are valuable
as precursors to shape-persistent macrocycles1 and as
linear chain molecules with extended conjugation.2 The
phenylacetylene construction has been used to produce
molecules which exhibit a variety of interesting proper-
ties such as liquid crystallinity, nanoporosity, conforma-
tional bistability, and solution aggregation.3-6 The phe-
nylacetylene construction is unique in that it allows for
the production of monodisperse site-specifically function-
alized oligomers comprised of an all carbon backbone. We
have reported solution-based synthetic routes to precisely
defined phenylacetylene oligomers7 as well as com-
municated the solid-phase preparation of these oligo-
mers.8 Here we present full details of the solid-phase
method.
Solid-phase synthetic methods are utilized extensively
for the synthesis of oligopeptides, oligonucleotides, and
recently, many small molecules.9-12 Solid-phase applica-
tions are widespread owing to the ease of workup,
purification, and to their natural incorporation into
repetitive coupling schemes. Solid-phase methodologies
* Author to whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) Zhang, J .; Pesak, D. J .; Ludwick, J . L.; Moore, J . S. J . Am. Chem.
Soc. 1994, 116, 4227-4239.
Resu lts a n d Discu ssion
The synthesis of oligomers utilizes a polymer-bound
terminal acetylene that is masked with a trimethylsilyl
group. After removal of the trimethylsilyl protecting
group, an aryl iodide is coupled to the polymer-supported
terminal acetylene using a palladium(0) catalyst. This
cycle is repeated producing oligomers of varying length
and functionality. The resulting oligomer is liberated
from the polymer support by cleavage of the 1-aryl-3-
propyl-3-(benzyl-supported) triazene group by reaction
with iodomethane to produce an oligomer terminated at
one end by an aryl iodide and at the other end by
(2) Tour, J . M. Chem. Rev. 1996, 96, 537-553.
(3) Venkataraman, D.; Lee, S.; Zhang, J .; Moore, J . S. Nature 1994,
371, 591-593.
(4) Bedard, T. C.; Moore, J . S. J . Am. Chem. Soc. 1995, 117, 10662-
10671.
(5) Shetty, A. S.; Zhang, J .; Moore, J . S. J . Am. Chem. Soc. 1996,
118, 1019-1027.
(6) Zhang, J .; Moore, J . S. J . Am. Chem. Soc. 1994, 116, 2655-2656.
(7) Zhang, J .; Moore, J . S.; Xu, Z.; Aguirre, R. A. J . Am. Chem. Soc.
1992, 114, 2273-2274.
(8) Young, J . K.; Nelson, J . C.; Moore, J . S. J . Am. Chem. Soc. 1994,
116, 10841-10842.
(9) Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. Tetrahedron
1996, 52, 4527-4554.
(10) Fru¨chtel, J . S.; J ung, G. Angew. Chem., Int. Ed. Engl. 1996,
35, 17-42.
(11) Lloyd-Williams, P.; Albericio, F.; Giralt, E. Tetrahedron 1993,
49, 11065-11133.
(13) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J .;
Steele, J . Tetrahedron 1995, 51, 8135-8173.
(14) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555-600.
(12) Merrifield, R. B. J . Am. Chem. Soc. 1963, 85, 2149-2154.
S0022-3263(96)01250-9 CCC: $12.00 © 1996 American Chemical Society

Solid-Phase Synthesis of Phenylacetylene Oligomers
J . Org. Chem., Vol. 61, No. 23, 1996 8161
Sch em e 1. A Step w ise Ad d ition Ap p r oa ch to Oligom er ic Ch a in Gr ow th a
a
Reagents: (a) tetrabutylammonium fluoride, THF, rt, 5 min; (b) Pd2(dba)3, CuI, PPh3, triethylamine, 65 °C, 12 h; (c) MeI, 110 °C,
6-48 h.
Sch em e 2. F r a gm en t Ad d ition Ap p r oa ch a
a
Reagents: (a) tetrabutylammonium fluoride, THF, rt, 5 min; (b) Pd2(dba)3, CuI, PPh3, triethylamine, 65 °C, 12 h; (c) MeI, 110 °C,
6-48 h.
(trimethylsilyl)acetylene. Overviews of the repetitive
monomer coupling, oligomers are prepared in a sequen-
tial fashion. This stepwise addition of monomers is
useful in the preparation of small nonrepeating oligo-
mers. Alternatively, a fragment condensation strategy
may be useful for the preparation of large repeating
oligomers (Scheme 2). Fragment condensation strategies
chemistry used for oligomer synthesis are shown in
Schemes 1 and 2. As shown in Scheme 1, the polymer-
supported trimethylsilyl monomer is deprotected and
then coupled with monomer to produce a trimethylsilyl
dimer. By repeating trimethylsilyl deprotection and

8162 J . Org. Chem., Vol. 61, No. 23, 1996
Nelson et al.
Sch em e 3. Con ver sion of Ch lor om eth yla ted
P olystyr en e to Resin (8)
neat n-propylamine in a sealed vessel under nitrogen at
70 °C for 3 days (Scheme 3). The resulting resin is
washed according to a literature procedure to remove
noncovalently bound material.15 Characterization of the
resin includes gel-phase 13C NMR, IR, elemental analysis
(C, H, N, and Cl), and swelling ratios. A comparison of
the 13C NMR spectra of the chloromethyl polymer and
resin 8 indicate complete substitution of the benzyl
chloride for the benzylpropylamino group. Elemental
analyses data show a chlorine null and approximately
1% nitrogen incorporation, consistent with the expected
value based on the chloride loading of the unmodified
support. Swelling ratios in dichloromethane of the
starting polymer and resin 8 are identical, indicating that
no significant cross-linking occurs during the propylami-
nation.16
F igu r e 1. Functionalized monomers.
Determination of the degree of substitution σï (mequiv/g
of resin) of the resin is accomplished by two methods:
(1) elemental analysis (eq 1), where A is the percent of
chlorine or nitrogen obtained from combustion analysis
and MA is atomic weight of chlorine or nitrogen, (2)
recording the weight change of resin after a particular
reaction (eq 2), where W is weight of resin in grams and
∆M is change in molecular weight for the added frag-
ment. Method 1 is utilized to determine the substitution
of resin 8. This method is only accurate to within ca. 20%
due to the small percentage of chlorine or nitrogen
measured (Cl, 2.5%, and N, 1%), as a result the substitu-
tion of resin 8 varies from 0.5 mequiv/g to 0.7 mequiv/g
of nitrogen using method 1. Method 2 is used to
determine the substitution of resin-bound aryl bromide
monomers. Method 2 is accurate to within 1%, because
weight increases of up to 15% are associated with the
linkage reaction. All subsequent substitutions (σ) are
calculated based on σï (obtained from method 2 for resin-
bound aryl bromide monomers) using eq 3. Constants
are added in order to obtain the units of mequiv/g of
support.
F igu r e 2. Chemical structures of triazene tethers. 5: peptide
linkage of acid triazene. 6: ether linkage of alcohol triazene.
7: direct triazene linkage of benzenediazonium tetrafluorobo-
rate.
enhance the overall yield and purity of an oligomer by
reducing the number of coupling and deprotection steps
required during the synthesis, relative to the sequential
strategy.
The difunctional monomers are based on aryl iodides
and terminal acetylenes protected as their corresponding
trimethylsilyl derivatives and aryl iodides. The mono-
mers used in this investigation are summarized in Figure
1 and abbreviated hexyl phenyl ether (A), hexyl benzoate
(B), tert-butylphenyl (C), benzonitrile (D), aryl bromide
(Br), aryl iodide (I), and (trimethylsilyl)acetylene (TMS).
All four monomers are readily synthesized from com-
mercially available materials as described in the sup-
porting information.
Lin k a ge. Three separate linkages to the polymer
support are shown in Figure 2. Peptide coupling of a
triazene derivative of nipecotic acid to p-aminomethyl
polystyrene:1% divinylbenzene copolymer beads gives 5.
Etherification of a triazene derivative of 3-piperidinemeth-
anol to chloromethyl polystyrene:1% divinylbenzene co-
polymer beads gives 6. Direct triazene link to propy-
laminomethyl polystyrene:1% divinylbenzene copolymer
beads gives 7.8 Linkage 7 is preferred as it allows for
facile infrared monitoring at every reaction step, can
easily be adapted to base sensitive functionality, and
eliminates the need to synthesize the triazene derivatives
required for the other two linking strategies.
σï ) 10A/MA
(1)
(2)
(3)
σï ) 1000∆Wconversion/∆MconversionWsupport
σ ) 1000σï/(σï∆Mconversion + 1000)
Functionalized aryl bromide monomers are linked to
the resin by reaction of the corresponding benzenedia-
zonium tetrafluoroborate salts with resin 8 suspended
in DMF containing finely ground potassium carbonate
at 0 °C (Scheme 4). The functionalized benzenediazo-
nium tetrafluoroborate salts 9, 10, and 11 are prepared
analytically pure in high yield from the corresponding
anilines using the method of Doyle et al.17 The linkage
(15) Patterson, J . A. Biochemical Aspects of Reactions on Solid
Supports; Academic Press: New York, 1971.
Propylaminomethyl polystyrene:1% divinylbenzene co-
polymer beads (resin, 8) are prepared by heating a
suspension of chloromethylated polystyrene resin with
(16) Rich, D. H.; Gurwara, S. K. J . Am. Chem. Soc. 1975, 97, 1575-
1579.
(17) Doyle, M. P.; Bryker, W. J . J . Org. Chem. 1979, 44, 1572-1574.

Solid-Phase Synthesis of Phenylacetylene Oligomers
J . Org. Chem., Vol. 61, No. 23, 1996 8163
Sch em e 4. Atta ch m en t of Ben zen ed ia zon iu m
Sa lts to Resin (8)
F igu r e 3. Portionwise addition of solid benzenediazonium salt
to the DMF/resin suspension followed by removal of an aliquot
of this solution and quenching with diethylamine produces a
3,3-diethyltriazene that can be analyzed by GC. When the
concentration of triazene increases (ca. 200 mg addition), the
reaction is complete.
reaction is accomplished by the portionwise addition of
solid benzenediazonium to the DMF suspension.
A
convenient way to monitor this reaction is by indirect
analysis of the supernatant DMF solution. Removal of
an aliquot of this solution followed by quenching with
diethylamine produces a 3,3-diethyltriazene which is
analyzed by GC. Once 3,3-diethyltriazene is detected,
no more benzenediazonium is added and the reaction is
complete. Figure 3 shows the 3,3-diethyltriazene con-
centration after each addition of benzenediazonium. The
end point is apparent by the jump in concentration of
the triazene. This method allows for the minimization
of reaction time as well as the efficient use of the
benzenediazonium tetrafluoroborate. The product resin
is filtered, washed with DMF to remove excess benzene-
diazonium, washed with water to remove excess carbon-
ate, and then washed with methanol to collapsed the
resin to an easily transferable form. IR analysis of the
resin-bound aryl bromides (P ) resin) P-A-Br (12), P-B-
Br (13), P-D-Br (14) in all cases reveals a weak band at
1405 cm-1 which is assigned to the triazene NdN
stretch.18 Resin 13 reveals a band at 1721 cm-1 which
is assigned to the carbonyl stretch of the COOnC6H13
group, and resin 14 reveals a band at 2233 cm-1 which
is assigned to the carbon-nitrogen stretch of the CN
group.
Resin-bound aryl bromides 12-14 are coupled with
(trimethylsilyl)acetylene to produce resin-bound “start-
monomers” P-A-TMS (15), P-B-TMS (16), P-D-TMS (17)
using a Pd2(dba)3 (2.5 mM)/PPh3 (20 mM)/CuI (4 mM)
catalyst solution in triethylamine. This catalyst solution
is prepared oxygen free and heated with stirring at 70
°C for 2 h prior to use. The supernate of the resulting
heterogeneous mixture (some undissolved palladium and
copper iodide remains) is cannula transferred under an
inert atmosphere onto the resin-bound aryl bromide
followed by addition of oxygen free (trimethylsilyl)-
acetylene. The resulting suspension is heated in a sealed
vessel in an oven at 65 °C without stirring and is agitated
periodically to remix resin beads stuck to the side of the
reaction vessel. A typical coupling reaction proceeds in
24-48 h at 65 °C.19 In our original report, the catalyst
was prepared homogeneously in a 1:1 DMF:triethylamine
solution.8 The problem associated with this catalyst
system was its instability, resulting in palladium metal
deposition and darkening of the resin. At the completion
of the coupling reaction, the resin-bound monomer is
filtered, washed with CH2Cl2 (to remove the catalyst
components, excess (trimethylsilyl)acetylene, and tri-
ethylamine hydroiodide byproduct), washed with DMF
(in preparation for the next wash), washed with a 0.05
M solution of sodium diethyl dithiocarbamate in 99/1
DMF/diisopropylethylamine (to remove any Cu(I), Cu-
(II) or Pd(II) trapped in the resin),20 washed with DMF
(to remove excess sodium diethyl dithiocarbamate from
the previous wash), washed with CH2Cl2 (to remove DMF
from previous wash), washed with methanol to collapsed
the resin to an easily transferable, and dried to a constant
mass in vacuo. The (trimethylsilyl)acetylene coupling
reaction is monitored by liberating a small portion of the
resin-bound monomer with iodomethane followed by GC
analysis of the resulting aryl iodide.
Resin-bound monomers P-A-TMS (15), P-B-TMS (16),
P-D-TMS (17) are deprotected by treatment of the resin-
bound (trimethylsilyl)acetylene group with a solution of
tetrabutylammonium fluoride in wet (5 wt % H2O)
tetrahydrofuran at room temperature. This deprotection
reaction was originally accomplished by treatment of the
resin with a suspension of potassium hydroxide, metha-
nol, and tetrahydrofuran at 75 °C for 1-24 h. These
initial conditions, in addition to being slow, were unsuit-
able for resin-bound monomers 16 and 17, resulting in
the formation of hydrolysis products. When using tet-
rabutylammonium fluoride, the trimethylsilyl group of
2 is removed cleanly, whereas under the potassium
hydroxide conditions transesterification and hydrolysis
of the hexyl benzoate of 2 occurred. When the tetrabu-
tylammonium fluoride method is applied to the depro-
tection of resin-bound monomers 16 and 17, no hydrolysis
was observed as evidenced by infrared analysis of resin-
bound deprotected monomers (no additional band was
observed in 3200-3450 cm-1 region). The resin-bound
terminal acetylene is filtered, washed with THF to
remove excess tetrabutylammonium fluoride, washed
with methanol to collapse the resin to an easily transfer-
able form, and dried to a constant mass in vacuo.
(Trimethylsilyl)acetylene deprotection is monitored by
infrared analysis of the dried resin, as described below.
Nu ll-to-Nu ll In fr a r ed Mon itor in g. A simple, non-
destructive method was developed to monitor oligomer
synthesis. Infrared analysis of the resin is accomplished
by placing approximately 1 mg of the resin between two
(18) Zimmermann, F.; Lippert, T.; Beyer, C.; Stebani, J .; Nuyken,
O.; Wokaun, A. Appl. Spectrosc. 1993, 47, 986-993.
(19) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 6403-6406.
(20) Briscoe, G. B.; Humphries, S. Talanta 1969, 16, 1403-1419.

8164 J . Org. Chem., Vol. 61, No. 23, 1996
Nelson et al.
F igu r e 4. Infrared spectra used to monitor cross-coupling and deprotection reactions on the resin-bound oligomer. Observation
of a null at 3311 cm-1 and 2156 cm-1 corresponds to complete acetylene coupling and (trimethylsilyl)acetylene deprotection,
respectively.
Ta ble 1. Yield s a n d P u r ity of Mon om er s
NaCl plates, swelling the beads by adding a drop of
polymer
isolated
carbon tetrachloride, and immediately recording an FTIR
spectrum. Failure to swell the beads yields no useful
signal. The resulting IR spectra have the characteristic
polystyrene absorptions in addition to the diagnostic
bands, assigned as follows, to the resin-bound functional
groups: 3311 cm-1 (strong) terminal acetylenic carbon-
hydrogen stretch; 2109 cm-1 (weak) terminal acetylenic
carbon-carbon stretch; 2156 cm-1 (medium) carbon-
carbon stretch of acetylene with trimethylsilyl group;
2233 cm-1 (medium) benzonitrile carbon-nitrogen triple
bond stretch; 1721 cm-1 (strong) benzoate carbonyl
stretch; 1405 cm-1 (weak) triazene (NdN) stretch.18,21 The
trimethylsilyl deprotection step is monitored by the
complete disappearance (null signal) of the 2156 cm-1
band and the appearance of the 3311 cm-1 band (Figure
4). The coupling of resin-bound terminal acetylene
(described below) is monitored by the complete disap-
pearance (null signal) of the 3311 cm-1 band and the
appearance of the 2156 cm-1 band. The reliability of this
“null-to-null” infrared monitoring was confirmed by
removal and characterization of a trimethylsilyl depro-
tected product and is believed to be sensitive to a level
of detection of at least 5% unreacted material. Liberation
of resin-bound oligomers (described below) is monitored
by the disappearance of IR bands attributed to the
oligomer.
Treatment of resin-bound aryl bromide monomers 12
and 13 and resin-bound monomers 15 and 16 with
iodomethane in a sealed reaction flask at 110 °C for 12
h affects the liberation of monomers 18, 19, 1, and 2. As
shown in Table 1 all monomers are recovered in greater
then 90% yield with a greater than 90% purity. The
liberated monomers are recovered from the resin by
filtration and repeated washing with CH2Cl2. The com-
pleteness of this reaction is assessed by infrared analysis.
In all cases, small amounts (approximately 5%) of
monomer remain attached to the resin. Complete re-
moval of the monomer can be achieved by increasing the
reaction time; however, products obtained after long
oligomer
support (mg) product (mg) yielda
purityb
I-A-Br (18)
I-B-Br (19)
I-A-TMS (1)
I-B-TMS (2)
610.4
597.2
647.1
651.1
85.0
83.8
93.3
90.3
98
90
94
98
98
95
97
94
a
Overall yield calculated from weight increase of initial polymer-
b
supported aryl bromide monomer. Purity assessed by GC after
filtration through silica gel.
reaction times (48 -72 h) are less pure. The resin
obtained at the end of the reaction is dark brown in color
and partially decomposed, as evidenced by examination
of the spent resin under an optical microscope. Treat-
ment of unmodified chloromethylated polystyrene with
iodomethane at 110 °C also results in partially decom-
posed polymer beads.
Oligom er Syn th esis. Dimers I-A-B-TMS (20) and
I-B-B-TMS (21) are prepared by coupling monomer 2 to
resin-bound monomers 15 and 16, respectively, followed
by liberation from the support. Dimers I-A-A-TMS (22)
and I-B-A-TMS (23) are prepared by coupling monomer
1 to resin-bound monomers 15 and 16, respectively,
followed by liberation from the support. The couplings
are accomplished using the palladium(0) catalyst system
described above. The triethylamine supernatant is added
to the resin/aryl halide mixture with the aryl halide in
10% excess. The resulting suspension is heated in a
sealed vessel in an oven at 65 °C without stirring and is
agitated periodically to remix resin beads stuck to side
of the vessel. A typical coupling reaction proceeds in 12
h at 65 °C. The product resin is washed as above and
excess monomer is recovered from the first CH2Cl2 wash.
As shown in Table 2 all dimers are obtained in greater
than 75% yield with a purity greater than 91%. All cross-
coupling and (trimethylsilyl)acetylene deprotection reac-
tions were monitored by IR analysis. As before, the resin
obtained after liberation with iodomethane is dark brown,
and small amounts (approximately 5%) of dimer remain
resin bound.
The synthesis of the hexameric oligomer I-B-B-B-A-A-
A-TMS (24) is accomplished by the stepwise addition of
single monomer units (Scheme 1). Two repetitive cycles
(21) Grindley, T. B.; J ohnson, K. F.; Katritzky, A. R.; Keogh, H. J .;
Thirkettle, C.; Topsom, R. D. J . Chem. Soc., Perkin Trans. 2 1974, 3,
282-288.

Solid-Phase Synthesis of Phenylacetylene Oligomers
J . Org. Chem., Vol. 61, No. 23, 1996 8165
Ta ble 2. Yield s a n d P u r ity of Dim er s a n d Hexa m er s
Ta ble 3. HP LC of Cr u d e Oligom er ic P r od u cts
of deprotection and coupling using monomer 2 to resin-
bound monomer 16 followed by three repetitive cycles of
deprotection and coupling with monomer 1 and finally
liberation with iodomethane gave 24 in overall yield of
48%. All stages of this 10-step sequence are monitored
by IR analysis. All cross-coupling reactions were com-
plete after 12 h at 65 °C and all (trimethylsilyl)acetylene
deprotection reactions were finished within 5 min at room
temperature. During the synthesis, small portions (5 mg)
of the intermediate dimer, trimer, tetramer, and pen-
tamer were liberated from the resin and analyzed by
HPLC. As can be seen in Table 3, the purity of inter-
mediate dimer 26, trimer 27, tetramer 28, pentamer 29,
and hexamer 24 are all similar. This constant qualitative
purity level suggests that most of the impurities arise
from the liberation step rather than being a result of the
repetitive couplings or (trimethylsilyl)acetylene depro-
tections, as this would result in a decrease in purity with
each repetitive cycle. Included in Table 3 is the HPLC
trace of methyl benzoate trimer 30 (R ) methyl) prepared
by solution-phase methods. As can be seen, the purity
of trimer 30 is similar to trimer 27 which was prepared
with the solid-phase method. The hexameric oligomer
24 prepared on a 2 g scale by the solid-phase method was
compared with authentic sample synthesized in solution.
The solid-phase method resulted in an overall yield of
48% as compared to 39% using the solution-phase
method. The solid-phase method from monomer to
hexamer required 11 synthetic steps taking 6 days to
complete. The solution-phase method from the monomer
required 13 synthetic steps taking approximately 14 days
to complete.
Hexamer I-B-B-B-A-A-A-TMS (24) prepared using the
solid-phase method was cyclized to the corresponding
phenylacetylene macrocycle using previously described
methods.1 The macrocycle derived from the hexamer
prepared using the solid-phase method was compared to
authentic macrocycle derived from a hexamer prepared
by solution-phase methods. Both HPLC and 1H NMR
data were identical for both macrocycles. Thus, in the
hexyl benzoate/hexyl phenyl ether system, the solid-
phase method is far less laborious and is superior to the
solution-phase method, giving enhanced yields and re-
sulting in products of similar purity. In addition, this
solid-phase method allows for simplified workup and
purification by allowing for filtration and washing of
insoluble intermediates.
The synthesis of the hexameric oligomer I-D-C-D-C-
D-C-TMS (25) is accomplished by the repetitive process
of coupling and deprotection with alternate addition of
monomer 3 and monomer 4 to resin-bound monomer 17.
Liberation of 25 from the support was relatively slow due
to the electron-withdrawing nature of the nitrile group
on resin-bound monomer 17. The purity of hexamer 25
was found to be greatly effected by the reaction time of
cleavage. If the reaction was allowed to proceed for 48
h, a product was obtained which contained 20% of a
relatively polar impurity as assessed by HPLC. If the

8166 J . Org. Chem., Vol. 61, No. 23, 1996
Nelson et al.
chromatography (TLC) was performed on precoated sheets of
silica gel 60, and flash column chromatography was carried
out with silica gel 60 (230-400 mesh). Dry triethylamine was
obtained by vacuum transfer from calcium hydride. Dry
tetrahydrofuran (THF) was obtained by vacuum transfer from
sodium and benzophenone. The 1H, 13C, and gel-phase 13C
NMR spectra were recorded at 400 and 100 MHz. Gel-phase
13C NMR samples were prepared by swelling the polymer
support in CDCl3 and removing excess solvent by evaporation.
Chemical shifts are expressed in parts per million (δ) using
residual solvent protons as internal standard. Low and high
resolution electron impact mass spectra were obtained operat-
ing at 70 eV. Low and high resolution fast atom bombardment
(FAB) mass spectra were obtained on VG ZAB-SE and VG 70-
SE-4F spectrometers. Gas-liquid chromatography (GC) was
performed with a 12.5 m x 0.2 mm x 0.5 µm HP-1 methyl
silicone column, with helium carrier gas, and a flame ioniza-
tion detector. Elemental analyses were performed by the
University of Illinois Micro Analytical Service Laboratory.
Infrared spectra were recorded on an Mattson, galaxy series
F igu r e 5. Isolated impurity 31 produced during the cleavage
of oligomer 25 after 48 h reaction time.
reaction time was minimized to 8-12 h at 110 °C a
product which was 98% pure resulted (Table 2). A small
quantity (3 mg) of impurity 31 was isolated by prepara-
tive HPLC. Characterization by mass spectrometry and
1H NMR indicated 31 to be a result of the (trimethylsilyl)-
acetylene moiety reacting with advantageous HI pro-
duced under cleavage conditions (Figure 5). Attempts
to quench HI, in situ, by the addition of propylene oxide
or potassium carbonate resulted in slow or no reaction.
This observation supports an acid-catalyzed mechanism
for the decomposition of aryl triazenes in iodomethane
at 110 °C.22 It is believed that the primary source of
impurities come from the side reaction with HI. Hex-
amer 25 was also synthesized utilizing solution-phase
methods, thus providing a comparison. The solid-phase
method resulted in an overall yield of 58% as compared
to 40% using solution-phase methods, with both methods
giving products of similar purity. The solid-phase method
from monomer to hexamer required 11 synthetic steps
taking 6 days to complete. The solution-phase method
from the monomer required 9 synthetic steps taking
approximately 14 days to complete.
FTIR 5000 Spectrometer; absorptions are reported in cm-1
.
Infrared analysis of the polymer support was accomplished by
placing approximately 1 mg of the support between two NaCl
plates, swelling the beads by adding a drop of carbon tetra-
chloride and immediately recording an FTIR spectrum. HPLC
analysis was accomplished using an UV absorbence detector
and a silica column (4.6 mm × 25 cm). Swelling ratios were
measured by using an optical microscope fitted with a camera
and video recorder. The beads were repeatedly swollen and
shrunk to obtain a statistical average of change in bead
diameter. 3-tert-Butyl-5-(2-(trimethylsilyl)ethynyl)iodoben-
zene (3) was prepared following the reported procedure.1
P r op yla m in om eth yla ted P olystyr en e (0.7 m equ iv/g of
n itr ogen , 1% cr osslin k ed w ith d ivin ylben zen e, 200-400
m esh ) (8). A suspension of chloromethyl polystyrene:1%
divinylbenzene copolymer beads (20.0 g, 0.700 mequiv/g of
chlorine, 200-400 mesh) and n-propylamine (100 mL, 1.22
mol) were degassed and heated at 70 °C for 3 days in a sealed
tube and agitated periodically. The polymer was transferred
to a coarse sintered glass filter using CH2Cl2 and washed with
CH2Cl2 (400 mL). The resin was thoroughly washed according
to the following protocol to remove noncovalently-bound mate-
rial:15 the resin was placed in a 1-L round-bottom flask and
fitted with a magnetic stirrer and reflux condenser at 70 °C.
The resin was stirred slowly with dioxane/2 N NaOH (1/1, v/v,
400 mL) for 30 min, and the solvent was removed by aspiration
through a coarse sintered glass filter. This was repeated once
more with dioxane/2 N NaOH (1/1, v/v, 400 mL), twice each
with dioxane/H2O (1/1, v/v, 400 mL), DMF (400 mL), methanol
(400 mL), and finally benzene (400 mL). The resin was then
rinsed with hot methanol (400 mL), hot benzene (400 mL), hot
methanol (400 mL), hot CH2Cl2 (400 mL), and 200 mL of
methanol and dried in vacuo to a constant mass to give 19.58
g of propylaminomethyl polystyrene:1% divinylbenzene co-
polymer beads (8) (0.689 mequiv/g of nitrogen, 200-400 mesh).
Anal. Found: C, 90.44; H, 7.87; N, 0.95; Cl, 0.01. Swelling
ratio using CH2Cl2, chloromethyl polystyrene:1% divinylben-
zene copolymer beads (4.64, σ ) 0.50), propylaminomethyl
polystyrene:1% divinylbenzene copolymer beads (8) (4.25, σ )
0.13).
3-Br om o-5-(h exyloxy)b en zen ed ia zon iu m Tet r a flu o-
r obor a te (9). To a three-neck round-bottom flask fitted with
addition funnel and nitrogen inlet was added boron trifluoride
etherate (8.1 mL, 66.2 mmol) which was then chilled in an
ice-acetone bath (-20 °C). To the reaction flask was added
dropwise over 5 min a solution of 3-bromo-5-(hexyloxy)aniline
(32, 4.5 g, 16.5 mmol) in dry THF (67 mL). To the chilled
reaction mixture was added dropwise over 30 min a solution
of tert-butyl nitrite (6.9 mL, 57.9 mmol) in dry THF (54 mL).
The chilled mixture was stirred an additional 10 min, and the
cold bath was allowed to warm to 5 °C over 20 min (during
which time a white solid precipitated). To the mixture was
added diethyl ether (300 mL), and the mixture was chilled in
an ice-bath for 15 min. The solid was collected by filtration,
washed with chilled (0-5 °C) diethyl ether (20 mL), and dried
in vacuo to give 5.62 g, (15.22 mmol, 92%) of 3-bromo-5-
Con clu sion
The 3-propyl-3-(benzyl-supported) triazene linkage can
be used for a variety of functionalized monomers (e.g.,
esters, ethers, nitriles). This linkage is achieved by direct
reaction of benzenediazonium salts with resin 8. Oligo-
mers consisting of functionalized monomers have been
synthesized in gram quantities, in higher yields, and
employing simplified procedures as compared to solution-
phase methods. Purity levels are comparable or better
than those obtained using solution-phase methods. Us-
ing tetrabutylammonium fluoride to deprotect resin-
bound (trimethylsilyl)acetylene results in facile removal
(5 min) of the silyl group in the presence of base sensitive
functionality such as benzoate and benzonitrile. By
utilizing a premade catalyst solution in triethylamine
decomposition of the palladium(0) catalyst, which results
in the decomposition of palladium metal on the support,
can be avoided. The development of this solid-phase
method is the first step toward the combinatorial syn-
thesis of phenylacetylene oligomers and is the first report
to describe direct attachment of benzenediazonium salts
producing a triazene linker.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, all starting materials
were obtained from commercial suppliers and were used
without further purification. Melting points were obtained in
open capillary tubes and are uncorrected. Analytical thin layer
(22) Moore, J . S.; Weinstein, E. J .; Wu, Z. Tetrahedron Lett. 1991,
32, 2465-2466.

Solid-Phase Synthesis of Phenylacetylene Oligomers
J . Org. Chem., Vol. 61, No. 23, 1996 8167
(hexyloxy)benzenediazonium tetrafluoroborate (9) as a yellow
powder. Anal. Calcd for C12H16N2BBrF4O: C, 38.85; H, 4.35;
N, 7.55. Found: C, 39.21; H, 4.53; N, 7.31.
3-Br om o-5-(h exyloxyca r bon yl)ben zen ed ia zon iu m Tet-
r a flu or obor a te (10). Using the procedure for 9, 6.35 g (15.93
mmol, 95%) of 3-bromo-5-(hexyloxycarbonyl)benzenediazonium
tetrafluoroborate (10) was produced as a white powder from
hexyl 3-bromo-5-aminobenzoate (33, 5.0 g, 16.7 mmol). Anal.
Calcd for C13H16N2BBrO2F4: C, 39.13; H, 4.04; N, 7.02.
Found: C, 39.19; H, 3.90; N, 6.99.
3-Br om o-5-cya n ob en zen ed ia zon iu m Tet r a flu or ob o-
r a te (11). Using the procedure for 9, 7.23 g (24.4 mmol, 96%)
of 3-bromo-5-cyanobenzenediazonium tetrafluoroborate (11)
was produced as a white powder from 3-bromo-5-aminoben-
zonitrile (34, 5.0 g, 25.4 mmol): 172-174 °C dec. Anal. Calcd
for C7H3N3BBrF4: C, 28.42; H, 1.02; N, 14.20. Found: C,
28.76; H, 1.13; N, 14.12.
1-(3-(Hexyloxyca r bon yl)-5-(2-(tr im eth ylsilyl)eth yn yl)-
p h en yl)-3-p r op yl-3-(ben zyl-su p p or ted ) Tr ia zen e (16). Us-
ing the procedure for 15, 1-(3-bromo-5-(hexyloxycarbonyl)-
phenyl)-3-propyl-3-(benzyl-supported) triazene (13, 5.45 g,
0.452 mequiv/g) and (trimethylsilyl)acetylene (1.0 mL, 7.2
mmol) were allowed to react to produce 5.24 g (0.448 mequiv/
g) of 1-(3-(hexyloxycarbonyl)-5-(2-(trimethylsilyl)ethynyl)phe-
nyl)-3-propyl-3-(benzyl-supported) triazene (16) as light yellow
polymer beads.
1-(3-Cya n o-5-(2-(tr im eth ylsilyl)eth yn yl)p h en yl)-3-p r o-
p yl-3-(ben zyl-su p p or ted ) Tr ia zen e (17). Using the proce-
dure for 15, 1-(3-bromo-5-cyanophenyl)-3-propyl-3-(benzyl-
supported) triazene (14, 9.00 g, 0.351 mequiv/g) and (tri-
methylsilyl)acetylene (3.0 mL, 21.6 mmol) were allowed to
react to produce 8.99 g (0.349 mequiv/g) of 1-(3-cyano-5-(2-
(t r im et h ylsilyl)et h yn yl)ph en yl)-3-pr opyl-3-(ben zyl-su p-
ported) triazene (17) as light yellow polymer beads.
3-Br om o-5-(h exyloxy)iod oben zen e (18). A suspension
of 1-(3-bromo-5-(hexyloxy)phenyl)-3-propyl-3-(benzyl-supported)
triazene (12, 610.4 mg, 0.389 mequiv/g) and iodomethane (6.1
mL) was degassed and heated at 110 °C in a sealed tube for
24 h. After the iodomethane was removed in vacuo, the
product was extracted from the resin using hot CH2Cl2. The
resulting solution was cooled and filtered through a plug of
silica gel, and the CH2Cl2 was removed in vacuo to give a
brown oily residue. The residue was purified by filtration
through a plug of silica gel in hexanes to give 85 mg (0.23
mmol, 98%) of 3-bromo-5-(hexyloxy)iodobenzene (18) as a
colorless oil: Rf 0.53 (hexanes); MS (EI) m/ e 384 (21), 382 (22),
300 (67), 298 (70). Anal. Calcd for C12H16BrIO: C, 37.63; H,
4.21. Found: C, 37.70; H, 4.42.
Hexyl 3-Br om o-5-iod oben zoa te (19). Using the proce-
dure for 18, 1-(3-bromo-5-(hexyloxycarbonyl)phenyl)-3-propyl-
3-(benzyl-supported) triazene (13, 597.2 mg, 0.411 mequiv/g)
and iodomethane (6.0 mL) were allowed to react to give a
brown residue. The residue was purified by filtration through
a plug of silica gel in hexanes to give 83.8 mg (0.22 mmol, 90%)
of hexyl 3-bromo-5-iodobenzoate (19) as a white solid: mp
43.1-45.0 °C; Rf 0.34 (20:80 (v/v), dichloromethane: hexanes);
MS (EI) m/ e 412 (9), 410 (10), 328 (98), 326 (100). Anal. Calcd
for C13H16BrIO2: C, 37.98; H, 3.92. Found: C, 37.98; H, 4.11.
3-(H e xyloxy)-5-(2-(t r im e t h ylsilyl)e t h yn yl)iod ob e n -
zen e (1). Using the procedure for 18, 1-(3-(hexyloxy)-5-(2-
(t r im et h ylsilyl)et h yn yl)ph en yl)-3-pr opyl-3-(ben zyl-su p-
ported) triazene (15, 11.0 g, 0.316 mequiv/g) and iodomethane
(95 mL) were allowed to react to give a brown residue. The
residue was purified by flash chromatography (hexanes) to give
1.31 g (3.26 mmol, 94%) of 3-(hexyloxy)-5-(2-(trimethylsilyl)-
ethynyl)iodobenzene (1) as a white solid: mp 28.3-30.1 °C;
Rf 0.40 (hexanes); MS (EI) m/ e 400 (58), 385 (60). Anal. Calcd
for C17H25IOSi: C, 51.00; H, 6.29. Found: C, 51.22; H, 6.04.
Hexyl 3-Iod o-5-(2-(tr im eth ylsilyl)eth yn yl)ben zoa te (2).
Using the procedure for 18, 1-(3-(hexyloxycarbonyl)-5-(2-
(t r im et h ylsilyl)et h yn yl)ph en yl)-3-pr opyl-3-(ben zyl-su p-
ported) triazene (16, 10.0 g. 0.300 mequiv/g) and iodomethane
(90 mL) were allowed to react to give a brown residue. The
residue was purified by flash chromatography (25/75, dichlo-
romethane/hexanes) to give 1.26 g (2.90 mmol, 98%) of hexyl
3-iodo-5-(2-(trimethylsilyl)ethynyl)benzoate (2) as a white
solid: mp 46.9-48.3 °C; Rf 0.28 (25:75 (v/v), dichloro-
methane: hexanes); MS (EI) 428 (38), 413 (100), 344 (16), 329
(20). Anal. Calcd for C18H25IO2Si: C, 50.47; H, 5.88. Found:
C, 50.74; H, 6.05.
1-(3-Br om o-5-(h exyloxy)p h en yl)-3-p r op yl-3-(b en zyl-
su p p or ted ) Tr ia zen e (12). To a chilled (0 °C) suspension of
propylaminomethyl polystyrene:1% divinylbenzene copolymer
beads (8, 4.32 g, 0.522 mequiv/g of nitrogen, 200-400 mesh),
finely ground potassium carbonate (590 mg, 4.5 mmol), and
DMF (50 mL) was added 3-bromo-5-(hexyloxy)benzenediazo-
nium tetrafluoroborate (9, 1.0 g, 2.69 mmol) in portions over
1 h. After each addition, an aliquot of the DMF supernatant
was diluted in diethylamine and analyzed by GC. After
diethyltriazene was detected, the additions were ceased and
the suspension was transferred to a fritted filter using DMF
and washed sequentially with 120 mL of the following sol-
vents: MeOH, H2O, MeOH, THF, MeOH, and dried in vacuo
to a constant mass to give 4.85 g (0.389 mequiv/g, 84%) of 1-(3-
bromo-5-(hexyloxy)phenyl)-3-propyl-3-(benzyl-supported) tria-
zene (12) as light yellow polymer beads.
1-(3-Br om o-5-(h exyloxyca r b on yl)p h en yl)-3-p r op yl-3-
(ben zyl-su p p or ted ) Tr ia zen e (13). Using the procedure for
12, 3-bromo-5-(hexyloxycarbonyl)benzenediazonium tetrafluo-
roborate (10, 2.06 g, 5.16 mmol), potassium carbonate (1.13 g,
8.60 mmol), propylaminomethyl polystyrene:1% divinylben-
zene copolymer beads (8, 8.30 g, 0.522 mequiv/g of nitrogen,
200-400 mesh) and DMF (60 mL) were allowed to react to
produce 9.66 g (0.452 mequiv/g, 100%) of 1-(3-bromo-5-(hexy-
loxycarbonyl)phenyl)-3-propyl-3-(benzyl-supported) triazene
(13) as light yellow polymer beads.
1-(3-Br om o-5-cya n op h en yl)-3-p r op yl-3-(b en zyl-su p -
p or ted ) Tr ia zen e (14). Using the procedure for 12, 3-bromo-
5-cyanobenzenediazonium tetrafluoroborate (11, 1.85 g, 6.26
mmol), potassium carbonate (1.37 g, 10.4 mmol), propylami-
nomethyl polystyrene:1% divinylbenzene copolymer beads (8,
10.03 g, 0.522 mequiv/g of nitrogen, 200-400 mesh), and DMF
(75 mL) were allowed to react to produce 10.82 g (0.351, 73%)
of 1-(3-bromo-5-cyanophenyl)-3-propyl-3-(benzyl-supported) tri-
azene (14) as light yellow polymer beads.
1-(3-(Hexyloxy)-5-(2-(tr im eth ylsilyl)eth yn yl)p h en yl)-3-
p r op yl-3-(ben zyl-su p p or ted ) Tr ia zen e (15). To a heavy-
walled flask equipped with nitrogen inlet was added 1-(3-
bromo-5-(hexyloxy)phenyl)-3-propyl-3-(benzyl-supported)
triazene (12, 3.00 g, 0.389 mequiv/g). The flask was evacuated
and back-filled with dry nitrogen three times. In a separate
flask a catalyst solution consisting of tris(dibenzylideneac-
etone)dipalladium(0) (2.5 mM), copper(I) iodide (4 mM), and
triphenylphosphine (20 mM) in dry triethylamine was de-
gassed and stirred at 70 °C for 2 h. The supernatant from
this catalyst (18 mL) was transferred via cannula to the
reaction flask containing the resin-bound aryl bromide. To
the mixture was added dry, degassed (trimethylsilyl)acetylene
(1.0 mL, 7.2 mmol). The flask was sealed and kept at 65 °C
for 48 h and agitated periodically to remix polymer beads stuck
on flask walls. The polymer was transferred to a fritted filter
using CH2Cl2 and washed sequentially with 30 mL of the
following solvents: CH2Cl2, DMF, 0.05 M solution of sodium
diethyl dithiocarbamate in 99/1 DMF/diisopropylethylamine,20
DMF, CH2Cl2, MeOH, and dried in vacuo to constant mass to
give 2.96 g (0.386 mequiv/g) of 1-(3-(hexyloxy)-5-(2-(trimeth-
ylsilyl)ethynyl)phenyl)-3-propyl-3-(benzyl-supported) triazene
(15) as light yellow polymer beads.
Dep r otection of Resin -Bou n d (Tr im eth ylsilyl)a cety-
len es. To a suspension of resin-bound (trimethylsilyl)acety-
lene (1.0 equiv) and THF (9 mL/g of polymer) was added a
solution of tetrabutylammonium fluoride (1.0 M) in wet (5 wt
% H2O) THF (2.0 equiv). The suspension was stirred periodi-
cally for 5 min. The polymer was transferred to a fritted filter
using THF and washed sequentially (30 mL/g of polymer) with
THF followed by MeOH and dried in vacuo to constant mass
to give the resin-bound terminal acetylene as light yellow
polymer beads.
Cr oss-Cou p lin g of Resin -Bou n d Ter m in a l Acetylen es
w ith Ar yl Ha lid e Mon om er s. To a heavy-walled flask
equipped with nitrogen inlet side arm were added resin-bound

8168 J . Org. Chem., Vol. 61, No. 23, 1996
Nelson et al.
terminal acetylene (1.0 equiv) and aryl iodide (1.1 equiv). The
flask was evacuated and back-filled with dry nitrogen three
times. In a separate flask a catalyst solution consisting of tris-
(dibenzylideneacetone)dipalladium(0) (2.5 mM), copper(I) io-
dide (4 mM), and triphenylphosphine (20 mM) in dry trieth-
ylamine was degassed and stirred at 70 °C for 2 h. The
supernatant from this catalyst (6 mL/g of resin) was trans-
ferred via cannula to the reaction flask containing the resin-
bound terminal acetylene. The flask was sealed and kept at
65 °C for 12 h and agitated periodically to remix polymer beads
stuck on flask walls. The polymer was transferred to a fritted
filter using CH2Cl2 and washed with CH2Cl2 (30 mL/g of resin).
Excess aryl iodide can be recovered from the first CH2Cl2 wash.
The resin was washed sequentially (30 mL/g of resin) with the
following solvents: DMF, 0.05 M solution of sodium diethyl
dithiocarbamate in 99/1 DMF/diisopropylethylamine, DMF,
CH2Cl2, MeOH, and dried in vacuo to constant mass to give
resin-bound oligomer as light yellow to brown polymer beads.
I-A-B-TMS (20). Using the above procedures, monomer 2
was coupled with deprotected monomer 15 (0.386 mequiv/g)
to produce polymer-supported dimer P-A-B-TMS. Using the
procedure for 18, polymer-supported dimer P-A-B-TMS (596.7
mg, 0.355 mequiv/g) and iodomethane (5.0 mL) were allowed
to react to give a brown residue. The crude residue was
filtered through a plug of silica eluting with 25/75 (v/v),
dichloromethane/hexanes, to give 116.9 mg (0.19 mmol, 88%)
of I-A-B-TMS (20) as a clear oil: Rf 0.24 (25:75 (v/v), dichloro-
methane: hexanes); MS (EI) 628 (100), 613 (10). Anal. Calcd
for C32H41IO2Si: C, 61.14; H, 6.57. Found: C, 61.47; H, 6.47.
I-B-B-TMS (21). Using the above procedures, monomer 2
was coupled with deprotected monomer 16 (0.448 mequiv/g)
to produce polymer-supported dimer P-B-B-TMS. Using the
procedure for 18, polymer-supported dimer P-B-B-TMS (674.0
mg, 0.407 mequiv/g) and iodomethane (5.0 mL) were allowed
to react to give a brown residue. The crude residue was
filtered through a plug of silica eluting with 40/60 (v/v),
dichloromethane/hexanes, to give 134.4 mg (0.20 mmol, 75%)
of I-B-B-TMS (21) as a white solid: mp 51.2-53.3 °C; Rf 0.42
(40:60 (v/v), dichloromethane:hexanes); MS (EI) m/ e 659 (3),
658 (13), 657 (43), 656 (100), 572 (12). Anal. Calcd for
C33H41IO4Si: C, 60.36; H, 6.29. Found: C, 60.43; H, 6.47.
I-A-A-TMS (22). Using the above procedures, monomer 1
was coupled with deprotected monomer 15 (0.386 mequiv/g)
to produce polymer-supported dimer P-A-A-TMS. Using the
procedure for 18, polymer-supported dimer P-A-A-TMS (751.4
mg, 0.359 mequiv/g) and iodomethane (5.0 mL) were allowed
to react to give a brown residue. The crude residue was
filtered through a plug of silica eluting with 10/90 (v/v),
dichloromethane/hexanes, to give 135.7 mg (0.23 mmol, 84%)
of I-A-A-TMS (22) as a white solid: mp 39.3-40.8 °C; Rf 0.24
(10:90 (v/v), dichloromethane:hexanes); MS (EI) m/ e 603 (1),
(v/v), dichloromethane:hexanes, to give I-B-B-B-A-A-A-TMS
(24) as a white powder. The crude powder was purified by
precipitation from CH2Cl2 using MeOH to give 1.587 g (1.07
mmol, 48%) of I-B-B-B-A-A-A-TMS (24) as a white solid. To
a solution of 24 (611 mg, 0.41 mmol) in THF (16 mL) was
added a solution of tetrabutylammonium fluoride (1.0 M) in
wet (5 wt % H2O) THF (0.8 mL), and the mixture was stirred
at room temperature for 5 min. The mixture was diluted with
diethyl ether (100 mL) and washed with water (3 × 50 mL)
and brine (2 × 50 mL). The organic phase was dried over
MgSO4, filtered, and concentrated in vacuo to give a light
yellow solid residue. The residue was purified by flash
chromatography (40:60 (v/v), dichloromethane:hexanes) to give
580 mg (0.41 mmol, 99%) of I-B-B-B-A-A-A-H (36) as a white
solid: mp >250 °C dec; Rf 0.28 (40:60 (v/v), dichloromethane:
hexanes); MS (FAB) 1413.6 (100). Anal. Calcd for C87H97
IO9: C, 73.92; H, 6.92. Found: C, 73.81; H, 6.99.
-
Oligom er s 26 th r ou gh 30. Oligomers (I-B-B-TMS (26),
I-B-B-B-TMS (27), I-B-B-B-A-TMS (28), I-B-B-B-A-A-TMS
(29)) were prepared on a 5 mg scale by liberation of the
corresponding resin-bound oligomers and analyzed by HPLC
(Table 2). Methyl benzoate trimer 30 (I-B-B-B-TMS (30), R
) methyl) was prepared by solution-phase methods and was
analyzed by HPLC (Table 2).
I-D-C-D-C-D-C-TMS (25). Using the above procedures,
monomer 3 and monomer 4 were coupled with deprotected
monomer 17 (0.349 mequiv/g) to produce polymer-supported
hexamer P-D-C-D-C-D-C-TMS. Using the procedure for 18,
polymer-supported hexamer P-D-C-D-C-D-C-TMS (2.71 g,
0.279 mequiv/g) and iodomethane (27.0 mL) were allowed to
react for 12 h to give a brown residue. The crude residue was
filtered through a plug of silica eluting with dichloromethane
to give 459.8 mg (0.44 mmol, 58%) of I-D-C-D-C-D-C-TMS (25)
as a white powder: mp 306.0-309.0 °C; Rf 0.25 (1:1 (v/v),
dichloromethane:hexanes); MS (FAB) m/ e 1044.8 (10). Anal.
Calcd for C66H54N3ISi: C, 75.92; H, 5.21; N, 4.02. Found: C,
76.15; H, 5.61; N, 3.77.
3-Iod o-5-(2-(tr im eth ylsilyl)eth yn yl)ben zon itr ile (4). To
a sealed tube was added 1-(3-(2-(trimethylsilyl)ethynyl)-5-
cyanophenyl)-3,3-diethyltriazene (35, 7.26 g, 24.3 mmol),
iodine (1.24 g, 4.9 mmol), and iodomethane (50 mL). The
mixture was degassed three times by evacuation, sealed, and
kept at 110 °C for 29 h. The excess iodomethane was removed
by vacuum transfer leaving a brown residue. The residue was
dissolved in CH2Cl2 (100 mL) and filtered through a plug of
silica gel. The organic layer was washed with a half saturated
solution of sodium meta bisulfite (100 mL), and brine (100 mL),
dried over anhydrous MgSO4, filtered, and concentrated in
vacuo to give a light brown residue. The residue was purified
by flash chromatography (20/80, dichloromethane/hexanes) to
give 7.19 g (22.1 mmol, 91%) of 3-iodo-5-(2-(trimethylsilyl)-
ethynyl)benzonitrile (4) as a white solid: mp 64.2-65.3 °C; Rf
0.24 (20:80 (v/v), dichloromethane:hexanes); MS (EI) m/ e 327
(1), 326 (4), 325 (20), 310 (100). Anal. Calcd for C12H12NISi:
C, 44.32; H, 3.72; N, 4.31. Found: C, 44.35; H, 3.82; N, 4.17.
602 (6), 601 (22), 600 (55), 585 (5). Anal. Calcd for C31H41
IO2Si: C, 61.99; H, 6.88. Found: C, 61.78; H, 6.86.
-
I-B-A-TMS (23). Using the above procedures, monomer 1
was coupled with deprotected monomer 16 (0.448 mequiv/g)
to produce polymer-supported dimer P-B-A-TMS. Using the
procedure for 18, polymer-supported dimer P-B-A-TMS (560.6
mg, 0.412 mequiv/g) and iodomethane (5.0 mL) were allowed
to react to give a brown residue. The crude residue was
filtered through a plug of silica eluting with 25/75 (v/v),
dichloromethane/hexanes, to give 110.7 mg (0.18 mmol, 76%)
of I-B-A-TMS (23) as a white solid: mp 45.5-47.5 °C; Rf 0.22
(25:75 (v/v), dichloromethane:hexanes); MS (EI) m/ e 631 (1),
630 (5), 629 (17), 628 (41). Anal. Calcd for C32H41IO3Si: C,
61.14; H, 6.57. Found: C, 61.29; H, 6.55.
I-B-B-B-A-A-A-TMS (24) a n d I-B-B-B-A-A-A-H (36). Us-
ing the above procedures, monomer 1 and monomer 2 were
coupled with deprotected monomer 16 (0.448 mequiv/g) to
produce polymer-supported hexamer P-B-B-B-A-A-A-TMS.
Using the procedure for 18, polymer-supported hexamer P-B-
B-B-A-A-A-TMS (7.37 g, 0.304 mequiv/g) and iodomethane
(50.0 mL) were allowed to react to give a brown residue. The
crude residue was filtered through a plug of silica in 50:50
Ack n ow led gm en t. This work was supported by the
National Science Foundation (CHE-94-23121), the 3M
Company, and the Camille Dreyfus Teacher-Scholar
Awards Program. We gratefully acknowledge Scott D.
Schneider for the synthesis of monomer 4, and Peng
Zhang for the solution synthesis of hexamer 25.
Su p p or tin g In for m a tion Ava ila ble: Listings of 1H NMR,
13C NMR, and IR spectra; preparative procedures for com-
pounds 32-35 and precursors (12 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O961250U