Simple Silyl Linker for the Solid Phase Organic Synthesis of Aryl-Containing Molecules

Article abstract of DOI:10.1021/jo9620472

We have designed a simple (dimethylsilyl)propionic acid linker for the solid phase synthesis of aryl-containing organic compounds. The linker is cleaved smoothly with trifluoroacetic acid either in solution or in the vapor phase to release the unsubstituted aryl moiety. Using this linker, we have successfully demonstrated the solid phase synthesis of a test compound which involved alkylation, acylation, and Mitsunobu reactions.

Full text of DOI:10.1021/jo9620472

6726
J . Org. Chem. 1997, 62, 6726-6732
Sim p le Silyl Lin k er for th e Solid P h a se Or ga n ic Syn th esis of Ar yl-
Con ta in in g Molecu les
Kenneth A. Newlander, Balan Chenera, Daniel F. Veber, Nelson C. F. Yim, and
Michael L. Moore*
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals,
King of Prussia, Pennsylvania 19406
Received November 1, 1996
We have designed a simple (dimethylsilyl)propionic acid linker for the solid phase synthesis of
aryl-containing organic compounds. The linker is cleaved smoothly with trifluoroacetic acid either
in solution or in the vapor phase to release the unsubstituted aryl moiety. Using this linker, we
have successfully demonstrated the solid phase synthesis of a test compound which involved
alkylation, acylation, and Mitsunobu reactions.
Ch a r t 1. Silyl Lin k er s
In tr od u ction
There has been increasing interest in the application
of solid phase synthesis to the preparation of organic
compounds, especially in the contexts of combinatorial
chemistry and multiple simultaneous synthesis. One of
the limitations in the solid phase approach involves the
linker by which the organic molecule is attached to the
solid support. Most linkers are based on protecting group
chemistry and require the presence of an appropriate
functional group in the target molecules being synthe-
sized. Recently Plunkett and Ellman1 and Chenera et
al.2 have described arylsilane resin linkers (1 and 2,
respectively, where PS represents the polystyrene matrix
and R represents the rest of the organic molecule
synthesized on the resin; Chart 1) which are designed to
release the unsubstituted aryl moiety. Linker 1 is
cleaved with hydrogen fluoride but is stable to TFA.
Linker 2 is cleaved with either TFA at room temperature
or cesium fluoride at elevated temperature.
We were interested in the solid phase synthesis of
molecules of the general structure represented by 5 as a
potential combinatorial library, and the use of an aryl-
silane linker provided an attractive synthetic route as
shown in Scheme 1. We focused on linker 2 since we felt
TFA cleavage would be more desirable than HF cleavage.
We modified the design of linker 2, which is attached to
Merrifield resin via an ether linkage, to introduce a
carboxylic acid functionality which could be coupled to
benzhydrylamine (BHA) resin to give 3. This strategy
affords us several advantages. The silyl linker carboxylic
acid 6 can be prepared in solution and can be rigorously
purified and characterized before attachment to the resin.
Attachment to the BHA resin is via an amide bond
formation reaction, a highly optimized solid phase reac-
tion which can easily be monitored by ninhydrin test3 and
can be driven to completion. The resulting resin con-
struct should therefore be both homogeneous and of
known loading, both of which facilitate analysis of the
subsequent synthetic reactions performed.
mediates after neat TFA cleavage from the resin and in
fact were unable to isolate either benzyl alcohol from
cleavage of 7a or benzaldehyde from cleavage of 7b.
Since TFA cleavage offers considerable advantages in
combinatorial synthesis, we investigated the cleavage
chemistry in more detail. These results led us to design
the simplified silyl linker 4, on which we have success-
fully demonstrated all the requisite chemistry shown in
Scheme 1.
Resu lts a n d Discu ssion
In order to evaluate cleavage conditions, we prepared
the model compound 15 as shown in Scheme 2. 4-Bro-
mobenzyl alcohol was protected as the triisopropylsilyl
ether 9, which was then converted to the Grignard
reagent and reacted with (bromomethyl)chlorodimethyl-
silane to give the (bromomethyl)silane 10. Treatment of
10 with methyl 3-(4-hydroxyphenyl)propionate and po-
tassium carbonate in refluxing 2-butanone gave the
silylmethyl phenyl ether 11, which was deprotected to
During initial synthetic experiments, we encountered
unexpected difficulties in isolating the expected inter-
X Abstract published in Advance ACS Abstracts, September 1, 1997.
(1) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1995, 60, 6006-
6007.
(2) Chenera, B.; Finkelstein, J . A.; Veber, D. F. J . Am. Chem. Soc.
1995, 117, 11999-12000.
(3) Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Anal.
Biochem. 1970, 34, 594-598.
S0022-3263(96)02047-6 CCC: $14.00 © 1997 American Chemical Society

Silyl Linker for Synthesis of Aryl Molecules
J . Org. Chem., Vol. 62, No. 20, 1997 6727
Sch em e 1
Sch em e 2
Sch em e 3
oxygen bond in the linker, was instead isolated in
quantitative yield along with a second product which has
been tentatively assigned the structure 17 based on H
1
NMR and mass spectral data. This cleavage pattern and
distribution of products were unanticipated based on the
previously published work2 but has in fact been observed
in the analogous cleavage of silylmethyl methyl ethers
with trimethylsilyl iodide4 and, in work reported subse-
quently to this investigation, in a related arylsilane
linker.5
The use of TFA as a cleavage reagent is quite attractive
for combinatorial or multiple simultaneous synthesis due
to the ease of workup, especially compared with alterna-
tives like HF or CsF. We therefore undertook to modify
the silyl linker such that we could perform the cleavage
with neat TFA.6
give the benzyl alcohol 12. Oxidation of 12 with man-
ganese dioxide to the aldehyde 13 followed by reductive
amination with tyramine and acetylation with acetic
anhydride gave the desired model compound 15. Com-
pound 15 was then subjected to several different cleavage
reactions. The results are summarized in Scheme 3.
Treatment of 15 with neat TFA at room temperature
did not give the desired compound 18. The phenol 16,
which arises from an alternative cleavage of the carbon-
Since the presence of the heteroatom in the silylmethyl
ether moiety provided a competing cleavage pathway, we
decided to design a linker which did not contain a
(4) Cunico, R. F.; Gill, H. S. Organometallics 1982, 1, 1-3.
(5) Han, Y.; Walker, S. D.; Young, R. N Tetrahedron Lett. 1996, 37,
2703-2706.
(6) Subsequent experiments demonstrated that the desired product
18 could be obtained from 15 using conditions less suitable for
combinatorial synthesis, such as HF or CsF (see ref 2).

6728 J . Org. Chem., Vol. 62, No. 20, 1997
Newlander et al.
Sch em e 4
Sch em e 5
F igu r e 1. Time course of TFA vapor cleavage of 25.
product was quite clean, with no detectable impurities
or contamination by starting material.
In addition to neat TFA, TFA vapor has also been used
to cleave compounds from acid-labile resins and repre-
sents an effective method for interfacing bead-based
combinatorial synthesis with subsequent biological screen-
ing.7 The time course of vapor phase TFA cleavage of
25 is shown in Figure 1. Weighed aliquots of 25 were
cleaved for various times and extracted with 2% MeOH
in CHCl3, and the amount of 18 obtained was quantitated
by HPLC. The time course for vapor phase cleavage is
quite similar to the solution cleavage results, with a t1/2
of about 13 h and nearly quantitative cleavage occurring
by 40 h at room temperature.
The time course of cleavage and the relatively sub-
stantial amount of cleavage, approximately 30%, which
had occurred in the first 6 h of reaction suggested that
this resin might be useful for controlled partial release
of compound from the resin. Partial release is useful in
single-bead-associated combinatorial screening.7,8 A por-
tion of the compound can be released from a single bead,
eluted, and assayed as soluble material. Sufficient
compound remains on the bead for subsequent identifica-
tion.9,10 Partial cleavage has been achieved in a rigorous
fashion by the simultaneous use of orthogonally cleavable
heteroatom in the chain. Since the precedent for TFA-
mediated cleavage of aryl-silyl bonds generally involve
simple trialkylsilanes, we designed linker 4 (Chart 1),
in which the linker is formally a (dimethylsilyl)propionate
moiety. This would afford the same strategic advantages
in being able to prepare, purify, and characterize the
arylsilyl linker by traditional methods and then attaching
it to an amine-containing resin using a high-yielding,
easily monitored acylation step.
The model compound 23 was readily prepared accord-
ing to Scheme 4. The benzyl alcohol silylpropionate 20
was prepared from the corresponding 4-bromobenzyl
alcohol in six steps. Treatment of 10 with the sodium
salt of dimethyl malonate gave 19, which was deprotected
to the benzyl alcohol and then demethoxycarbonylated
with lithium chloride in DMSO and water to give 20.
Oxidation to the benzaldehyde 21 with MnO2, reductive
amination with tyramine, and acetylation of the second-
ary amine with acetic anhydride gave the silyl-linked
model compound 23. Gratifyingly, treatment of 23 with
neat TFA for 24 h produced the desired model product
compound 18 cleanly, with no evidence of any side
reactions including reattachment of the linker to the
unprotected phenol.
(7) J ayawickreme, C. K.; Graminski, G. F.; Quillan, J . M.; Lerner,
M. R. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 1614-1618.
(8) Salmon, S. E.; Lam, K. S.; Lebl, M.; Kandola, A.; Khattri, P. S.;
Wade, S.; Patek, M.; Kocis, P.; Krchnak, V.; Thorpe, D.; Felder, S. Proc.
Natl. Acad. Sci. U.S.A. 1993, 90, 11708-11712.
(9) Zambias, R. A.; Boulton, D. A.; Griffin, P. R. Tetrahedron Lett.
1994, 35, 4283-4286.
(10) Krebs, J . F.; Siuzdak, G.; Dyson, H. J .; Stewart, J . D.; Benkovic,
S. J . Biochemistry 1995, 34, 720-723.
In order to evaluate the cleavage on the solid support,
23 was saponified and the resulting free acid 24 was
coupled to BHA resin to give 25 as shown in Scheme 5.
Treatment of 25 with neat TFA for 40 h at room
temperature gave a quantitative yield of 18. As is often
the case with solid phase cleavage reactions, the crude

Silyl Linker for Synthesis of Aryl Molecules
J . Org. Chem., Vol. 62, No. 20, 1997 6729
Sch em e 6
dialkylated tyramines. Using an excess of tyramine and
a resin-bound alkylating agent, dialkylation is effectively
suppressed and the desired product is obtained cleanly.
Acetylation with acetic anhydride to give 29 followed by
Mitsunobu reaction with (dimethylamino)ethanol using
diisopropyl azidodicarboxylate (DIAD) instead of DEAD
to avoid formation of any ethyl ether11 gave the resin-
bound model compound 30. The final product 31 was
obtained in quantitative yield based on starting resin 26
after cleavage with TFA vapor.
Con clu sion
F igu r e 2. Repetitive partial cleavages of 25 with TFA vapor.
We have designed a simplified arylsilyl linker for solid
phase organic synthesis which cleanly releases the aryl
moiety upon treatment with neat trifluoroacetic acid, in
either the liquid or vapor phase, making it highly suitable
for practical combinatorial or multiple synthesis. The
amount of cleavage can be controlled by varying the
reaction time, making controlled partial cleavage feasible.
Finally, we have demonstrated the synthesis of a model
compound for a combinatorial library, involving alkyla-
tion, acylation, and Mitsunobu reactions using our de-
signed linker on a solid support.
linkers, but it has also been effected by limited exposure
of acid-labile linkers to TFA vapor.
In order to evaluate the utility of the silylpropionate
linker for partial cleavage, an aliquot of 25 was subjected
to several rounds of treatment with TFA vapor. After
each partial cleavage, the released 18 was eluted from
the resin and quantified by HPLC. The results are
shown in Figure 2. Approximately 25% of the available
18 was released from the resin in each of the first two
6-h exposures to TFA vapor, and an additional 10% was
released in the third partial cleavage. These numbers
are in good agreement with the time course of cleavage
in Figure 1 and indicate that this linker would perform
suitably in a partial release strategy.
Having demonstrated the desired cleavage properties
in the silylpropionate linker, we undertook a model
synthesis, as shown in Scheme 6, incorporating all the
chemistry which we had envisioned in Scheme 1. The
chemistry was monitored by elemental analysis and
magic angle spinning (MAS) proton NMR. The benzyl
alcohol linker 20 was saponified, coupled to BHA resin,
and smoothly converted to the benzyl bromide 27 with
CBr4 and triphenylphosphine. This resin-bound benzyl
bromide was then used to alkylate tyramine to produce
the secondary amine 28. This reaction demonstrates the
power of solid phase synthesis. In a solution reaction,
one would expect to obtain a mixture of mono- and
Exp er im en ta l Section
Reagent grade solvents and commercial reagents were used
without additional purification. THF was distilled from
sodium benzophenone ketyl. BHA resin (200-400 mesh,
substitution 1.11 mmol/g) was prepared as previously re-
ported.12 Proton NMR spectra were obtained at 250 and 400
MHz. Magic angle spinning (MAS) proton NMR was obtained
at 500 MHz on a spectrometer equipped with a magic angle
spinning nanoprobe. Chemical shifts are reported relative to
TMS.
O-(Tr iisop r op ylsilyl)-4-br om oben zyl Alcoh ol (9). To a
solution of 4-bromobenzyl alcohol (50.07 g, 268 mmol) in DMF
(500 mL) was added with stirring, under argon, imidazole (40
(11) Krchnak, V.; Flegelova, Z.; Wiechsel, A. S.; Lebl, M. Tetrahedron
Lett. 1995, 36, 6193-6196.
(12) Bryan, W. M. J . Org. Chem. 1986, 51, 3371-3372.

6730 J . Org. Chem., Vol. 62, No. 20, 1997
Newlander et al.
g, 588 mmol) followed by triisopropylsilyl chloride (TIPS-Cl;
57.3 mL, 268 mmol). After stirring for 24 h at room temper-
ature the reaction mixture was evaporated to dryness, taken
up in hexane (500 mL), washed with aq 1 N hydrochloric acid
(500 mL) and brine (500 mL), dried (MgSO4), and evaporated
to give 9 as a clear oil (91.72 g, 99%): TLC Rf 0.71 (silica gel,
50:1 hexane:ethyl acetate); GC tR 2.98 min (HP 530 µm × 20
m methylsilicone column, He carrier flow 20 mL/min, 150 °C
initial temp, rate 10 °C/min, 250 °C final temp, 2 min final
time); 1H NMR (400 MHz, CDCl3) δ 1.08 (18H, d, J ) 6.4 Hz),
1.14 (3H, m), 4.78 (2H, s), 7.22 (2H, d, J ) 8.4 Hz), 7.45 (2H,
d, J ) 8.4 Hz). Anal. Calcd for C16H27SiOBr: C, 55.97; H,
7.93; Br, 23.37. Found: C, 55.82; H, 7.82; Br, 23.61.
[Dim e t h yl[4-[[(t r iisop r op ylsilyl)oxy]m e t h yl]p h e n -
yl]silyl]m eth yl Br om id e (10). To a stirred mixture of Mg
turnings (2.22 g, 91 mmol) in THF (100 mL) was added 1,2-
dibromoethane (300 µL, 3.5 mmol). The mixture was stirred
under argon and heated to 70 °C (reflux). After 5 min the
reaction mixture was cooled to room temperature, and a
solution of 9 (30 g, 87.4 mmol) in THF (100 mL) was added in
one portion. The reaction mixture was then slowly heated to
reflux (slightly exothermic) and allowed to stir for another 5
h until all the Mg was consumed. The resultant pale brown
solution was then cooled to -78 °C, and a solution of (bro-
momethyl)chlorodimethylsilane (15 mL, 110 mL) in THF (50
mL) was added slowly over 5 min. After stirring for 1 h the
reaction mixture was allowed to warm to room temperature
and stirred for an additional 16 h. The reaction mixture was
evaporated to dryness, taken up in hexane (500 mL), washed
with cold aq 1 N hydrochloric acid (500 mL) and brine (500
mL), dried (MgSO4), and evaporated. Purification by Kugel-
rohr distillation (140-150 °C, 1 Torr) gave 10 as a clear oil
(23.54 g, 65%): TLC Rf 0.53 (silica gel, 50:1 hexane:ethyl
acetate); GC tR 8.27 min (HP 530 µm × 20 m methylsilicone
column, He carrier flow 20 mL/min, 150 °C initial temp, rate
10 °C/min, 250 °C final temp, 2 min final time); 1H NMR (400
MHz, CDCl3) δ 0.43 (6H, s), 1.12 (18H, d, J ) 6.6 Hz), 1.18
(3H, m), 2.63 (2H, s), 7.38 (2H, d, J ) 8.0 Hz), 7.51 (2H, d, J
) 8.0 Hz). Anal. Calcd for C19H35Si2OBr: C, 54.91; H, 8.49;
Br, 19.23. Found: C, 54.88; H, 8.29; Br, 19.09.
mmol). The suspension was heated to reflux under argon and
stirred for 16 h. After cooling to room temperature the reaction
mixture was filtered through a pad of Celite and rinsed with
CH2Cl2 (50 mL). The filtrate was evaporated to give 13 as a
white crystalline solid (3.74 g, 94%): TLC Rf 0.47 (silica gel,
30% ethyl acetate/hexane); 1H NMR (400 MHz, CDCl3) δ 0.46
(6H, s), 2.59 (2H, t), 2.89 (2H, t), 3.66 (3H, s), 3.77 (2H, s),
6.88 (2H, d, J ) 8.5 Hz), 7.09 (2H, d, J ) 8.5 Hz), 7.78 (2H, d,
J ) 7.9 Hz), 7.86 (2H, d, J ) 7.9 Hz), 10.03 (1H, s). Anal.
Calcd for C20H24O4Si: C, 67.38; H, 6.68. Found: C, 68.31; H,
6.68.
Met h yl 3-[[[Dim et h yl[4-[N-[2-(4-h yd r oxyp h en yl)et h -
y l ]a m i n o m e t h y l ]p h e n y l ]s i l y l ]m e t h o x y ]p h e n y l ]-
p r op ion a te (14). To a stirred solution of 13 (1.03 g, 2.9 mmol)
in dry methanol (30 mL) were added tyramine (0.5 g, 3.6 mmol)
and acetic acid (0.22 mL, 3.6 mmol). The reaction mixture
was stirred for 2 h; then NaBH3CN (0.23 g, 3.6 mmol) was
added portionwise over 15 min (foaming). After stirring for
16 h the reaction mixture was evaporated to dryness, taken
up in CHCl3 (100 mL), washed with brine (100 mL), dried
(Na2SO4), and evaporated. Purification by flash chromatog-
raphy (silica gel, 3-5% methanol/CHCl3) gave 14 as a clear
oil (1.02 g, 74%): TLC Rf 0.20 (silica gel, 5% methanol/CHCl3);
1H NMR (400 MHz, CDCl3) δ 0.40 (6H, s), 2.59 (2H, t), 2.75
(2H, t), 2.87 (4H, 2t), 3.66 (3H, s), 3.72 (2H, s), 3.80 (2H, s),
6.69 (2H, d, J ) 8.4 Hz), 6.87 (2H, d, J ) 8.6 Hz), 7.01 (2H, d,
J ) 8.4 Hz), 7.08 (2H, d, J ) 8.6 Hz), 7.27 (2H, d, J ) 7.8 Hz),
7.53 (2H, d, J ) 7.8 Hz); MS(ES) m/z 478.3 [M + H]+. Anal.
Calcd for C28H35NO4Si: C, 70.40; H, 7.39; N, 2.93. Found: C,
68.45; H, 7.19; N, 2.60.
Met h yl 3-[[[Dim et h yl[4-[N-[2-(4-h yd r oxyp h en yl)et h -
yl]a c e t a m id om e t h yl]p h e n yl]silyl]m e t h oxy]p h e n yl]-
p r op ion a te (15). To a stirred solution of 14 (2.0 g, 4.2 mmol)
in CH2Cl2 (50 mL) was added acetic anhydride (0.47 mL, 5
mmol) followed by pyridine (0.81 mL, 10 mmol). After stirring
for 16 h the reaction mixture was evaporated to dryness.
Purification by flash chromatography (silica gel, 1-5% metha-
nol/CHCl3) gave 15 as a white solid (1.53 g, 70%): TLC Rf 0.41
(silica gel, 5% methanol/CHCl3); HPLC (Altex Ultrasphere SI,
4.6 × 250 mm) 1-10% iPrOH/CHCl3 linear gradient over 25
min, UV 280 nm, tR 8.15 min, k′ 2.2; 1H NMR (400 MHz,
MeOH-d4) (amide rotamers) δ 0.37, 0.38 (6H, 2s), 1.91, 2.09
(3H, 2s), 2.55 (2H, t), 2.70, 2.74 (2H, 2t), 2.81 (2H, t), 3.43,
3.45 (2H, 2t), 3.61 (3H, s), 3.74, 3.75 (2H, 2s), 4.44, 4.57 (2H,
2s), 6.69, 6.70 (2H, 2d), 6.83 (2H, d, J ) 8.6 Hz), 6.96, 6.97
(2H, 2d), 7.05 (2H, d, J ) 8.7 Hz), 7.17, 7.24 (2H, 2d), 7.57,
7.60 (2H, 2d); MS(ES) m/z 520.2 [M + H]+. Anal. Calcd for
C30H37NO5Si: C, 69.33; H, 7.18; N, 2.70. Found: C, 69.06; H,
7.13; N, 2.41.
Meth yl 3-[[[Dim eth yl[4-[[(tr iisop r op ylsilyl)oxy]m eth -
yl]p h en yl]silyl]m eth oxy]p h en yl]p r op ion a te (11). To a
stirred solution of 10 (29.57 g, 71 mmol) and methyl 3-(4-
hydroxyphenyl)propionate (12.80 g, 71 mmol) in 2-butanone
(200 mL) was added K2CO3 (9.8 g, 71 mmol). The suspension
was stirred under argon at reflux (80 °C) for 72 h, cooled to
room temperature, and evaporated to dryness. The residue
was taken up in ethyl acetate (500 mL), washed with aq 1 N
HCl (500 mL) and brine (500 mL), dried (MgSO4), and
evaporated to dryness. Purification by flash chromatography
(silica gel, 5% ethyl acetate/hexane) gave 11 (22.06 g, 60%) as
a clear oil along with recovered starting material (10.43 g,
TF A Solu tion Clea va ge Rea ction of 15. To an aliquot
of compound 15 (300 mg, 0.58 mmol) was added TFA (10 mL).
The reaction mixture was stirred for 16 h at room temperature
and evaporated to dryness. HPLC analysis (Altex Ultrasphere
SI, 4.6 × 250 mm, 1-10% iPrOH/CHCl3 gradient over 25 min,
1.5 mL/min, UV at 280 and 254 nm) showed only trace
amounts of starting material with two major products at tR
3.89 and 15.15 min. The two major products were then
isolated by flash chromatography (silica gel, 2% methanol/
CHCl3). The earlier eluting peak (tR 3.89 min) was identified
as methyl 3-(4-hydroxyphenyl)propionate (16) (95 mg, 91%):
1H NMR (400 MHz, CDCl3) δ 2.50 (2H, t), 2.89 (2H, t), 3.68
(3H, s), 5.78 (1H, br s), 6.76 (2H, d), 7.04 (2H, d). Anal. Calcd
for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.83; H, 6.58. The
later eluting peak (tR 15.15 min) was isolated as a white solid
and has a structure consistant with the siloxane dimer 17 (135
mg, 70%): MS(ES) m/z 669.4 [M + H]+; IR (Nujol) 3162, 1616,
1
35%): TLC Rf 0.49 (silica gel, 10% ethyl acetate/hexane); H
NMR (400 MHz, CDCl3) δ 0.41 (6H, s), 1.09 (18H, d, J ) 6.5
Hz), 1.17 (3H, m), 2.58 (2H, t), 2.88 (2H, t), 3.66 (3H, s), 3.73
(2H, s), 4.84 (2H, s), 6.88 (2H, d, J ) 8.7 Hz), 7.09 (2H, d, J )
8.7 Hz), 7.37 (2H, d, J ) 8.0 Hz), 7.56 (2H, d, J ) 8.0 Hz).
Anal. Calcd for C29H46O4Si2: C, 67.65; H, 9.01. Found: C,
66.85; H, 8.36.
Met h yl 3-[[[Dim et h yl[4-(h yd r oxym et h yl)p h en yl]sil-
yl]m et h oxy]p h en yl]p r op ion a t e (12). To compound 11
(29.76 g, 57.8 mmol) was added a solution of acetic acid:THF:
water (3:1:1) (500 mL). The resulting mixture was stirred at
45 °C for 24 h under an Ar atmosphere, cooled to room
temperature, and evaporated to dryness. Purification by flash
chromatography (silica gel, 30% ethyl acetate/hexane) gave 12
as a white crystalline solid (16.47 g, 79%): TLC Rf 0.29 (silica
1252, 1045 cm-1 1H NMR (400 MHz, MeOH-d4) (amide
;
1
gel, 30% ethyl acetate/hexane); H NMR (400 MHz, CDCl3) δ
rotomers) δ 0.29, 0.30 (6H, 2s), 1.91, 2.09 (3H, 2s), 2.71, 2.72
(2H, 2t), 3.45, 3.46 (2H, 2t), 4.43, 4.56 (2H, 2s), 4.86 (2H, s),
6.69, 6.71 (2H, d, J ) 7.8 Hz), 6.95, 6.97 (2H, 2d, J ) 7.8 Hz),
7.13, 7.20 (2H, 2d, J ) 7.7 Hz), 7.47, 7.50 (2H, 2d, J ) 7.7
Hz). Anal. Calcd for C38H48N2O5Si2•1/4H2O: C, 67.77; H, 7.26;
N, 4.16. Found: C, 67.70; H, 7.26; N, 3.95.
0.41 (6H, s), 1.78 (1H, br s), 2.58 (2H, t), 2.88 (2H, t), 3.65
(3H, s), 3.74 (2H, s), 4.69 (2H, s), 6.88 (2H, d, J ) 8.6 Hz),
7.08 (2H, d, J ) 8.6 Hz), 7.38 (2H, d, J ) 7.8 Hz), 7.60 (2H, d,
J ) 7.8 Hz); MS(ES) m/z 381.2 [M + Na]+. Anal. Calcd for
C20H26O4Si: C, 67.01; H, 7.31. Found: C, 66.86; H, 7.41.
Met h yl
3-[[[Dim et h yl(4-for m ylp h en yl)silyl]m et h -
HF Clea va ge Rea ction of 15. To compound 15 (300 mg,
0.58 mmol) in an HF reaction vessel containing anisole (1 mL)
was distilled HF (9 mL) while cooling at -78 °C. The mixture
oxy]p h en yl]p r op ion a te (13). To a stirred solution of 12 (4.0
g, 11.2 mmol) in CH2Cl2 (150 mL) was added MnO2 (5.0 g, 57.5

Silyl Linker for Synthesis of Aryl Molecules
J . Org. Chem., Vol. 62, No. 20, 1997 6731
was stirred for 1 h at 0 °C in an ice bath and then evaporated
under vacuum to dryness. The residue was placed under high
vaccum for several hours to remove excess anisole and
analyzed by HPLC. HPLC (Altex Ultrasphere SI, 4.6 × 250
mm, 1-10% iPrOH/CHCl3 gradient over 25 min, 1.5 mL/min,
UV at 280 and 254 nm) showed a major product with a
retention time of 8.87 min as well as small amounts of the
two products 16 and 17 isolated in the previous TFA reaction.
Purification by flash chromatography (silica gel, 2% methanol/
CHCl3) gave the major product as a white solid, identified as
the desired cleavage product 18 and identical with authentic
material by TLC, HPLC, MS(ES), and 1H NMR (108.5 mg,
69%): MS(ES) m/z 270.4 [M + H]+; 1H NMR (400 MHz, CDCl3)
(amide rotomers) δ 1.88, 2.12 (3H, 2s), 2.74, 2.78 (2H, 2t), 3.41,
3.58 (2H, 2t), 4.39, 4.63 (2H, 2s), 6.78 (2H, 2d), 7.95, 7.01 (2H,
2d), 7.11-7.35 (5H, m). Anal. Calcd for C17H19NO2: C, 75.81;
H, 7.11; N, 5.20. Found: C, 75.72; H, 7.01; N, 5.03.
Dim eth yl [Dim eth yl[4-[[(tr iisop r op ylsilyl)oxy]m eth -
yl]p h en yl]silyl]m eth ylm a lon a te (19). To a stirred solution
of 0.5 M sodium methoxide in methanol (88 mL, 44 mmol) was
added dimethyl malonate (10 mL, 85 mmol) followed by 10
(18.30 g, 44 mmol). The reaction mixture was heated at reflux
to 70 °C, under argon, and stirred for 24 h. After cooling to
room temperature, the reaction mixture was evaporated to
dryness, taken up in ethyl acetate (250 mL), washed with cold
aq 1 N hydrochloric acid (250 mL) and brine (250 mL), dried
(MgSO4), and evaporated. Purification by flash chromatog-
raphy (silica gel, 5% ethyl acetate/hexane) gave 19 as a clear
oil (14.37 g, 70%): TLC Rf 0.34 (silica gel, 10% ethyl acetate/
hexane); 1H NMR (400 MHz, CDCl3) δ 0.29 (6H, s), 1.09 (18H,
d, J ) 6.5 Hz), 1.18 (3H, m), 1.41 (2H, d, J ) 7.9 Hz), 3.36
(1H, t), 3.61 (6H, s), 4.83 (2H, s), 7.35 (2H, d, J ) 7.9 Hz), 7.46
(2H, d, J ) 7.9 Hz); MS(ES) m/z 489.2 [M + Na]+. Anal. Calcd
for C24H42Si2O5: C, 61.76; H, 9.07. Found: C, 61.84; H, 8.75.
mmol). After the mixture stirred for 2 h at room temperature,
NaBH3CN (0.32 g, 5 mmol) was added in portions. The
reaction mixture was stirred for 16 h and evaporated to
dryness. Purification by flash chromatography (silica gel, 95:5
to 90:10 CHCl3:MeOH) gave 22 as an oil (0.94 g, 61%): TLC
Rf 0.25 (silica gel, 95:5 CHCl3:MeOH); 1H NMR (400 MHz,
CDCl3) δ 0.28 (6H, s), 1.08 (2H, ddd), 2.28 (2H, ddd), 2.77 (2H,
t), 2.89 (2H, t), 3.64 (3H, s), 3.81 (2H, s), 6.71 (2H, d, J ) 8.4
Hz), 7.03 (2H, d, J ) 8.4 Hz), 7.27 (2H, d, J ) 7.8 Hz), 7.44
(2H, d, J ) 7.8 Hz); MS(ES) m/z 372.3 [M + H]+. Anal. Calcd
for C21H29NO3Si: C, 67.89; H, 7.87; N, 3.77. Found: C, 67.23;
H, 7.69; N, 3.66.
Meth yl 3-[Dim eth yl[4-[N-[2-(4-hydroxyphenyl)ethyl]ace-
tamidomethyl]phenyl]silyl]propionate (23). To a stirred solu-
tion of 22 (0.94 g, 2.4 mmol) in CH2Cl2 (25 mL) was added
pyridine (250 µL, 3.1 mmol) followed by acetic anhydride (229
µL, 2.4 mmol). After stirring for 16 h the reaction mixture
was taken up in CHCl3 (50 mL), washed with cold aq 1 N HCl
(50 mL) and brine (50 mL), dried (MgSO4), and evaporated.
Purification by flash chromatography (silica gel, 98:2 to 95:5
CHCl3:MeOH) gave 23 as a clear oil (1.00 g, 95%): TLC Rf
0.41 (silica gel, 95:5 CHCl3:MeOH); 1H NMR (400 MHz, CDCl3)
(amide rotamers) δ 0.27, 0.28 (6H, 2s), 1.07 (2H, m), 1.73 (1H,
s), 1.89, 2.11 (3H, 2s), 2.27 (2H, ddd), 2.76, 2.79 (2H, 2t), 3.41,
3.57 (2H, 2t), 3.62, 3.63 (3H, 2s), 4.38, 4.61 (2H, 2s), 6.76, 6.79
(2H, 2d, J ) 8.4 Hz), 6.96, 7.01 (2H, 2d, J ) 8.4 Hz), 7.11,
7.23 (2H, 2d, J ) 7.9 Hz), 7.44, 7.46 (2H, 2d, J ) 7.9 Hz);
MS(ES) m/z 414.2 [M + H]+. Anal. Calcd for C23H31NO4Si:
C, 66.79; H, 7.56; N, 3.39. Found: C, 63.37; H, 7.25; N, 2.97.
N-[2-(4-Hyd r oxyp h en yl)eth yl]-N-ben zyla ceta m id e (18)
fr om Clea va ge of 23. To compound 23 (300 mg, 0.7 mmol)
was added trifluoroacetic acid (20 mL). The reaction mixture
was stirred at room temperature for 36 h and concentrated to
dryness. HPLC analysis (Zorbax SIL, 4.6 × 250 mm, 1-10%
iPrOH/CHCl3 gradient over 25 min, UV 280 nm) showed <8%
starting material remained. The major product was purified
by flash chromatography (silica gel, 98:2 CHCl3:MeOH) to give
18 (172 mg, 91%): TLC Rf 0.36 (silica gel, 95:5 CHCl3:MeOH);
HPLC tR 10.75 min, k′ 4.4 (Zorbax SIL, 4.6 × 250 mm), 1-10%
iPrOH/CHCl3 over 20 min, UV 254 and 280 nm; MS(ES) m/z
270.4 [M + H]+; 1H NMR (400 MHz, CDCl3) (amide rotamers)
δ 1.88, 2.12 (3H, 2s), 2.74, 2.78 (2H, 2t), 3.41, 3.58 (2H, 2t),
4.39, 4.63 (2H, 2s), 6.78 (2H, 2d), 7.95, 7.01 (2H, 2d), 7.11-
7.35 (5H, m).
Met h yl
3-[Dim et h yl[4-(h yd r oxym et h yl)p h en yl]sil-
yl]p r op ion a te (20). Compound 19 (14.37 g, 30.8 mmol) was
added to a solution of 3:1:1 acetic acid:water:THF (200 mL)
and heated to 45 °C. The reaction mixture was stirred for 24
h, cooled, and evaporated to dryness. Purification by flash
chromatography (silica gel, 35% ethyl acetate/hexane) gave the
benzyl alcohol as a clear oil (8.31 g, 87%): TLC Rf 0.40 (silica
1
gel, 40% ethyl acetate/hexane); H NMR (400 MHz, CDCl3) δ
0.30 (6H, s), 1.42 (2H, d, J ) 7.7 Hz), 1.66 (1H, br s), 3.35 (1H,
t), 3.62 (6H, s), 4.69 (2H, s), 7.36 (2H, d, J ) 7.9 Hz), 7.49 (2H,
d, J ) 7.9 Hz); MS(ES) m/z 333.2 [M + Na]+. Anal. Calcd for
C15H22O5Si: C, 58.04; H, 7.14. Found: C, 57.49; H, 7.03.
To a stirred solution the above alcohol (8.31 g, 26.8 mmol)
in DMSO (50 mL) were added LiCl (2.27 g, 54 mmol) and water
(1.4 mL). After flushing with argon the reaction mixture was
heated to 140 °C and stirred for 24 h. The reaction mixture
was then cooled to room temperature, taken up in ethyl acetate
(250 mL), washed with brine (500 mL), dried (MgSO4), and
evaporated. Purification by flash chromatography (silica gel,
30% ethyl acetate/hexane) gave 20 as a clear oil (5.02 g, 74%):
3-[Dim eth yl[4-[N-[2-(4-h yd r oxyp h en yl)eth yl]a ceta m i-
d om eth yl]p h en yl]silyl]p r op ion ic Acid (24). To a stirred
solution of 23 (0.67 g, 1.6 mmol) in dioxane (10 mL) was added
aq 1 N NaOH (3.5 mL). After stirring for 16 h the reaction
mixture was acidified with aq 1 N HCl (3.5 mL) and partially
evaporated. The remaining material was taken up in CHCl3
(75 mL), washed with brine (75 mL), dried (MgSO4), and
evaporated to give 22 as a white solid foam (0.66 g, 100%):
1
TLC Rf 0.23 (silica gel, 95:4:1 CHCl3:MeOH:HOAc); H NMR
(400 MHz, CDCl3) (amide rotamers) δ 0.27, 0.28 (6H, 2s), 1.07
(2H, m), 1.94, 2.12 (3H, 2s), 2.28 (2H, ddd), 2.74, 2.77 (2H,
2t), 3.40, and 3.53 (2H, 2t), 4.36, 4.58 (2H, 2s), 6.76, 6.79 (2H,
2d, J ) 8.4 Hz), 6.93, 6.99 (2H, 2d, J ) 8.4 Hz), 7.10, 7.21
(2H, 2d, J ) 7.9 Hz), 7.43, 7.46 (2H, 2d, J ) 7.9 Hz); MS(ES)
m/z 400.2 [M + H]+. Anal. Calcd for C22H29NO4Si: C, 66.13;
H, 7.32; N, 3.51. Found: C, 65.94; H, 7.46; N, 3.23.
3-[Dim eth yl[4-[N-[2-(4-h yd r oxyp h en yl)eth yl]a ceta m i-
dom eth yl]ph en yl]silyl]pr opion yl Ben zh ydr ylam in e Resin
(25). To BHA resin (1.0 g, 1.06 mmol), which was washed with
a solution of 10% Et3N in CH2Cl2 followed by CH2Cl2 in a
shaker vessel,13 was added a solution of 24 (0.66 g, 1.59 mmol)
in DMF (20 mL) followed by HOBt (0.42 g, 3.1 mmol) and DCC
(0.36 g, 1.7 mmol). The reaction mixture was shaken for 16
h, washed with DMF (2 × 25 mL), 1:1 CHCl3:MeOH (2 × 25
mL), and CH2Cl2 (2 × 25 mL), and dried under vacuum for 24
h to give 23 (1.36 g): EA %N ) 2.3 found, 2.4 calcd (0.81 mmol/
g).
1
TLC Rf 0.41 (silica gel, 30% ethyl acetate/hexane); H NMR
(400 MHz, CDCl3) δ 0.28 (6H, s), 1.09 (2H, ddd), 1.85 (1H, br
s), 2.26 (2H, ddd), 3.62 (3H, s), 4.68 (2H, s), 7.36 (2H, d, J )
8.0 Hz), 7.50 (2H, d, J ) 8.0 Hz); MS(ES) m/z 275.1 [M + Na]+.
Anal. Calcd for C13H20O3Si: C, 61.87; H, 7.99. Found: C,
62.16; H, 7.81.
Meth yl 3-[Dim eth yl(4-for m ylp h en yl)silyl]p r op ion a te
(21). To a stirred solution of 20 (1.16 g, 4.6 mmol) in CH2Cl2
(50 mL) was added MnO2 (2.0 g, 23 mmol). The reaction
mixture was heated to reflux and stirred for 16 h. After cooling
to room temperature the reaction mixture was filtered through
a pad of Celite and washed with CH2Cl2, and the filtrate was
evaporated to dryness to give 21 as a clear oil (1.03 g, 89%):
1
TLC Rf 0.74 (silica gel, 30% ethyl acetate/hexane); H NMR
(400 MHz, CDCl3) δ 0.35 (6H, s), 1.12 (2H, ddd), 2.32 (2H, ddd),
3.62 (3H, s), 7.68 (2H, d, J ) 7.9 Hz), 7.85 (2H, d, J ) 7.9 Hz),
10.02 (1H, s). Anal. Calcd for C13H18O3Si: C, 62.36; H, 7.25.
Found: C, 61.89; H, 7.07.
N-[2-(4-Hyd r oxyp h en yl)eth yl]-N-ben zyla ceta m id e (18)
fr om th e Solu tion P h a se TF A Clea va ge of 25. To resin
Met h yl
3-[Dim et h yl[4-[N-[2-(4-h yd r oxyp h en yl)et h -
yl]am in om eth yl]ph en yl]silyl]pr opion ate (22). To a stirred
solution of 21 (1.00 g, 4 mmol) in MeOH (25 mL) was added
tyramine (0.70 g, 5 mmol) followed by HOAc (0.30 mL, 5
(13) Stewart, J . M.; Young, J . D. Solid Phase Peptide Synthesis;
Pierce Chemical Co.: Rockford, IL, 1984.

6732 J . Org. Chem., Vol. 62, No. 20, 1997
Newlander et al.
25 (301.5 mg, 244 µmol) was added TFA (20 mL). The reaction
mixture was stirred for 40 h at room temperature, filtered
through a sintered glass funnel, and washed with CHCl3 (3 ×
5 mL). The filtrate was evaporated to dryness and dried under
vacuum for 24 h to give 21 as an off-white solid identical to
the authentic material made in solution (77.6 mg, 100%, 96%
by N analysis of recovered resin): TLC Rf 0.36 (silica gel, 95:5
CHCl3:MeOH); HPLC tR 10.75 min, k′ 4.4 (Zorbax SIL, 4.6 ×
250 mm), 1-10% iPrOH/CHCl3 over 20 min, UV 254 and 280
nm; MS(ES) m/z 270.4 [M + H]+; 1H NMR (400 MHz, CDCl3)
(amide rotomers) δ 1.88, 2.12 (3H, 2s), 2.74, 2.78 (2H, 2t), 3.41,
3.58 (2H, 2t), 4.39, 4.63 (2H, 2s), 6.78 (2H, 2d), 7.95, 7.01 (2H,
2d), 7.11-7.35 (5H, m).
Va p or P h a se TF A Clea va ge Rea ction Stu d ies. To each
of four 2-mL sintered glass funnels was placed 100 mg of dried
resin 25. The samples were each washed with CH2Cl2 to swell
the resin and then drained mostly dry by vacuum aspiration.
Each was then placed into a 50-mL beaker, within a TLC
chamber containing a layer of TFA on the bottom. At selected
time periods (6, 16, 24, and 40 h) a sintered glass funnel with
resin was removed and dried under vacuum to remove residual
TFA. The resin in each sintered glass funnel was then washed
twice with a 1-mL solution of 2% methanol in CHCl3 filtered
directly into separate vials under vacuum. A 5-µL aliquot of
each filtrate was then injected into an HPLC, and the peak
area of the product was obtained to determine the amount
cleaved. The conversion factor for the peak area to percent
cleaved was obtained from the peak area of the 40-h resin
sample and the percent cleaved obtained from nitrogen
analysis. For multiple TFA cleavages the washed resin after
the 6-h reaction was reintroduced into the TFA chamber for
another 6 h and reanalyzed as above. This was repeated a
third time for another 6 h (see Figures 1 and 2).
added DMF (20 mL), tyramine (1.7 g, 12.4 mmol), and Et3N
(1.8 mL, 12.9 mmol). The reaction mixture was shaken for
16 h, washed with DMF (2 × 20 mL), MeOH (2 × 20 mL),
CH2Cl2 (2 × 20 mL), and hexane (20 mL), and dried under
vacuum for 16 h to give resin 28 (1.52 g, 0.72 mmol/g): EA
%N found 2.01, calcd 2.33; MAS 1H NMR (500 MHz) δ 0.20
(6H), 1.10 (2H), 2.20 (2H), 2.70 (2H), 2.82 (2H), 3.74 (2H), 6.71,
6.90, 7.18, 7.40 (8H).
3-[Dim eth yl[4-[N-[2-(4-h yd r oxyp h en yl)eth yl]a ceta m i-
dom eth yl]ph en yl]silyl]pr opion yl Ben zh ydr ylam in e Resin
(29). To resin 28 (1.0 g, 0.72 mmol) in a shaker vessel were
added CH2Cl2 (20 mL), pyridine (60 µL, 0.74 mmol), and acetic
anhydride (70 µL, 0.74 mmol). The reaction mixture was
shaken for 16 h, washed with CH2Cl2 (2 × 20 mL), MeOH (2
× 20 mL), CH2Cl2 (20 mL), and hexane (20 mL), and dried
1
under vacuum for 16 h to give resin 29 (1.07 g): MAS H NMR
(500 MHz) (amide rotamers) δ 0.19 (6H), 1.02 (2H), 1.80, 1.95
(3H), 2.15 (2H), 2.63, 2.70 (2H), 3.29, 3.45 (2H), 4.22, 4.49 (2H),
6.70, 6.81, 6.89, 7.3 (8H). TFA vapor cleavage of this resin 29
for 72 h at room temperature gave a 72% isolated yield of 12,
1
identical by HPLC, TLC, MS(ES), and H NMR with authentic
material. A small amount (<5%) of the diacetylated material
was also obtained after cleavage.
3-[Dim e t h yl[4-[N -[2-[4-[(N ′,N ′-d im e t h yla m in o)e t h -
o x y ]p h e n y l]e t h y l]a c e t a m i d o m e t h y l]p h e n y l]s i ly l]-
p r op ion yl Ben zh yd r yla m in e Resin (30). To resin 29 (0.87
g, 0.58 mmol) in a shaker vessel were added dry THF (15 mL),
(N,N-dimethylamino)ethanol (0.58 mL, 5.8 mmol), Ph3P (0.76
g, 2.9 mmol), and DIAD (0.57 mL, 2.9 mmol). The reaction
mixture was shaken under an argon atmosphere for 4 h and
filtered to dryness under argon. The reaction was repeated
an additional time for 16 h; the mixture was washed with THF
(2 × 15 mL), MeOH (2 × 15 mL), CH2Cl2 (2 × 15 mL), and
hexane (15 mL) and dried under vacuum for 16 h to give resin
30 (0.94 g, 0.67 mmol/g): MAS 1H NMR (500 MHz) (amide
rotamers) δ 0.21 (6H), 1.08 (2H), 1.95, 2.05 (3H), 2.19 (2H),
2.32 (6H), 2.72 (2H), 2.80 (2H), 3.36, 3.52 (2H), 4.02 (2H), 4.30,
4.58 (2H), 6.80, 6.90, 7.14, 7.47 (8H).
N-[2-[4-N′,N′-Dim eth yla m in o)eth oxy]p h en yl]eth yl]-N-
ben zyla cet a m id e (31). Resin 30 (200 mg, 134 µmol) was
exposed to TFA vapor at room temperature for 72 h and dried
under vacuum. Extraction with 1:1 CHCl3:MeOH (4 × 2 mL),
evaporation of the filtrate, and drying under vacuum for 24 h
gave 31 as its TFA salt (67.2 mg, 100%): TLC Rf 0.23 (silica
gel, 9:1 CHCl3:MeOH); MS(ES) m/z 341.0 [M + H]+; 1H NMR
(400 MHz, CDCl3) (amide rotamers) δ 1.92, 2.12 (3H, 2s), 2.77,
2.82 (2H, 2t), 2.98 (6H, s), 3.49 (2H, t), 3.58 (2H, m), 4.33 (2H,
t), 4.53, 4.60 (2H, 2s), 6.94, 6.97 (2H, 2d, J ) 8.5 Hz), 7.13,
7.14 (2H, 2d, J ) 8.5 Hz), 7.19-7.38 (5H, m). Anal. Calcd
for C21H28N2O2: C, 74.08; H, 8.29; N, 8.23. Found: C, 73.78;
H, 8.15; N, 8.29.
3-[Dim e t h yl[4-(h yd r oxym e t h yl)p h e n yl]silyl]p r op -
ion ic Acid . To a solution of 20 (2.50 g, 9.9 mmol) in dioxane
(30 mL) was added aq 1 N NaOH (15 mL). After stirring for
4 h the reaction mixture was acidified with aq 1 N hydrochloric
acid (15 mL) and evaporated to near dryness. The residue was
taken up in ethyl acetate (100 mL), washed with cold aq 1 N
HCl (100 mL) and brine (100 mL), dried (MgSO4), and
evaporated to give the free acid as a clear oil (2.36 g, 100%):
1
TLC Rf 0.45 (silica gel, 95:4:1 CHCl3:MeOH:HOAc); H NMR
(250 MHz, CDCl3) δ 0.30 (6H, s), 1.08 (2H, ddd), 2.30 (2H, ddd),
4.68 (2H, s), 7.36 (2H, d, J ) 7.9 Hz), 7.50 (2H, d, J ) 7.9 Hz).
Anal. Calcd for C12H18O3Si: C, 60.47; H, 7.61. Found: C,
59.72; H, 7.42.
3-[Dim e t h yl[4-(h yd r oxym e t h yl)p h e n yl]silyl]p r op -
ion yl Ben zh yd r yla m in e Resin (26). To BHA resin (7.0 g,
7.77 mmol), washed first with 10% Et3N in CH2Cl2 followed
by CH2Cl2, was added a solution of the above 3-[dimethyl[4-
(hydroxymethyl)phenyl]silyl]propionic acid (2.36 g, 9.9 mmol)
in DMF (30 mL). To this were added 1-hydroxybenzotriazole
(HOBt; 2.7 g, 20 mmol) and DCC (2.1 g, 9.9 mmol). The
reaction mixture was shaken for 16 h, washed with DMF (2 ×
30 mL), 1:1 CHCl3:MeOH (2 × 30 mL), CH2Cl2 (2 × 30 mL),
and hexane (30 mL), and dried under vacuum for 24 h to give
resin 26 (8.66 g, 0.90 mmol/g): negative ninhydrin test;3 MAS
1H NMR (500 MHz) δ 0.20 (6H), 1.05 (2H), 2.10 (2H), 2.80 (1H),
4.52 (2H), 7.22, 7.40 (4H).
3-[Dim et h yl[4-(b r om om et h yl)p h en yl]silyl]p r op ion yl
Ben zh yd r yla m in e Resin (27). To resin 25 (1.60 g, 1.44
mmol) in a shaker vessel were added THF (30 mL), CBr4 (0.96
g, 2.88 mmol), and Ph3P (0.76 g, 2.88 mmol). The reaction
mixture was shaken for 16 h, washed with THF (2 × 30 mL),
ethanol (2 × 30 mL), CH2Cl2 (2 × 30 mL), and hexane (30 mL),
and dried under vacuum for 16 h to give resin 27 (1.76 g, 0.84
mmol/g): EA %N found 1.18, calcd 1.22; %Br found 6.62, calcd
6.95.
Ack n ow led gm en t. We would like to thank Ms.
Edith Reich for performing the elemental analyses, Dr.
Steven Carr and Ms. Mary Metzger for performing the
MS(ES) analyses, and Drs. Susanta Sarkar and J acques
1
Briand for their assistance in obtaining MAS H NMR
spectra, all of whom are in the Department of Analytical
and Physical Sciences. We would also like to thank Drs.
William Miller and Dirk Heerding for valuable discus-
sions.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for all
compounds described (22 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of this journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
3-[Dim et h yl[4-[N-[2-(4-h yd r oxyp h en yl)et h yl]a m in o-
m eth yl]p h en yl]silyl]p r op ion yl Ben zh yd r yla m in e Resin
(28). To resin 27 (1.50 g, 1.26 mmoL) in a shaker vessel were
J O9620472