An improved and general synthesis of monomers for incorporating trityl linker groups into polystyrene synthesis supports

Article abstract of DOI:10.1016/j.tet.2004.01.027

A straightforward synthesis of trityl alcohols in which one of the aryl rings is substituted with a vinyl group is presented. The synthesis of the alcohols involves the direct addition of the Grignard reagent prepared from 4-bromostyrene to substituted be

Full text of DOI:10.1016/j.tet.2004.01.027

Tetrahedron 60 (2004) 2903–2907
An improved and general synthesis of monomers
for incorporating trityl linker groups
into polystyrene synthesis supports
*
Matthew Kwok Wai Choi and Patrick H. Toy
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China
Received 23 October 2003; revised 20 December 2003; accepted 5 January 2004
Abstract—A straightforward synthesis of trityl alcohols in which one of the aryl rings is substituted with a vinyl group is presented. The
synthesis of the alcohols involves the direct addition of the Grignard reagent prepared from 4-bromostyrene to substituted benzophenones.
These compounds are used to incorporate trityl linker groups into polystyrene-based organic synthesis supports. Both non-cross-linked and
cross-linked (JandaJele) polystyrene have been prepared using these monomers.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Therefore, in order to prepare better defined polymers with
easily controllable levels of trityl group incorporation, the
functional monomer, (4-ethenylphenyl)diphenyl methanol
(1a) (Scheme 1), has been prepared and co-polymerized
with styrene and divinylbenzene under suspension
polymerization conditions to afford polystyrene trityl resin
by Kurth et al.19 The first reported synthesis of 1a involved
the addition of t-BuLi to 4-bromostyrene followed by
reaction of the thus formed aryl lithium species with
benzophenone.19a The same authors also reported a
procedure involving the use of potassium, potassium iodide
and anhydrous magnesium chloride to activate 4-bromo-
styrene.19b Later, Rimmer et al. reported that the first
synthesis of 1a was not reproducible due to anionic
polymerization of the starting material, and that an inverse
addition procedure (4-bromostyrene added to t-BuLi)
afforded acceptable and reproducible yields of 1a.20 Most
recently, Janda et al. have reported the only other method
for the preparation of 1a which involves a four-step
synthetic sequence starting with 4-vinylbenzyl alcohol.21
While these reported syntheses do produce the desired
product, they are less than optimal, especially when
considering the reported difficulty in reproducing the
results, the costs and hazards associated with using t-BuLi
and potassium, and the length of the most recent synthesis.
Furthermore, they have not been demonstrated to be general
methods for the preparation of substituted trityl monomers,
as they only report the synthesis of 1a.
In polymer-supported synthesis, linker moieties are required
for the attachment of the synthesis substrate to the polymer
support. Commonly these linker groups are based on
standard protecting groups used in traditional solution-
phase synthesis.1 Trityl groups2 are often used in this
context since they can be prepared with various substituents
on the aryl rings that modulate their cleavage and because
they can serve as protecting groups for alcohols,3 acids,4
amides,5 amines,6 amino acids,7 hydroxamic acids,8 imida-
zoles,9 nucleotides,10 thiols,11 and thioureas.12 The most
common trityl group functionalized polymers used in
this regard are cross-linked unsubstituted trityl resin13 and
2-chlorotrityl resin.14
The polymer-bound trityl alcohol groups of such resins are
usually introduced by one of three methods: (1) The
sequence of lithiation of a halogentated phenyl group of a
preformed polymer, followed by treatment with a benzo-
phenone.15 (2) The sequence of Friedal–Crafts acylation of
a preformed polymer with a benzoyl chloride followed by
the addition of an aryl Grignard reagent.10,16 (3) Direct
lithiation of cross-linked polystyrene using a 1:1 complex of
n-BuLi and TMEDA, followed by reaction with a
benzophenone.17 However, a significant drawback of all
of these methods is that since they derivatize preformed
polymers, it is difficult to determine the final composition of
the product polymer and to accurately control its homo-
geneity and loading level.18
We are interested in the preparation and applications of
polymers that incorporate monomers derivatized with
various functional groups22 and have successfully used the
Grignard reagent formed from 4-bromostyrene to prepare
monomers containing sulfide23 and phosphine24 groups.
Keywords: Trityl alcohols; Monomers; Peptide synthesis.
*
Corresponding author. Tel.: þ852-2859-2167; fax: þ852-2857-1586;
e-mail address: phtoy@hkucc.hku.hk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.027

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M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2903–2907
Scheme 1. Synthesis of monomers 1a–f.
Herein we report our results using this reagent to prepare 1a
and derivatives of it and the incorporation of these into both
cross-linked and, for the first time, non-cross-linked
polystyrene polymers.
We next examined the use of our monomers in the
preparation of both non-cross-linked and cross-linked
polystyrenes (Scheme 2). Co-polymerization of 1a with
styrene in the presence of AIBN afforded soluble polymer
2a, which is reported here for the first time. In order to
determine the efficiency of incorporation of the functional
monomers in this polymerization process, monomer 1c was
co-polymerized with styrene to afford 2b. Analysis of 2b by
1H NMR shows that reaction of a 10:1 ratio of styrene/1c
results in the observed incorporation of these monomers in
a ratio of 8.8:1. This indicates that the monomers with
electron donating substituents are slightly more reactive
than styrene in the polymerization process.
2. Results and discussion
Obviously, the most direct method for preparing com-
pounds 1 is via the nucleophilic addition of a styrene
equivalent to a substituted benzophenone. Hence this was
the method used in the first reported synthesis of such
compounds.19a However, the nucleophile used was an aryl
lithium and the reagents used in the preparation of such a
species can readily initiate anionic polymerization of
styrene molecules and makes this method low yielding
and unreliable.20 Therefore we chose to examine the
addition of the relatively less nucleophilic and more
easily prepared styrene Grignard reagent, prepared simply
from 4-bromostyrene and magnesium,25 to a series of
benzophenones (Scheme 1).
Suspension co-polymerization of 1a, 1e and 1f with styrene
and the JandaJel cross-linker, 1,4-bis(4-vinylphenoxy)-
butane, afforded JJ-Tr-OH (3a), JJ-2-Cl-Tr-OH (3b), and
JJ-4-Cl-Tr-OH (3c), respectively (Scheme 2).27–29 It is
important to note that the loading levels of 3b and 3c, based
on elemental analysis of chlorine, are slightly lower than
expected (theoretical 1.5 mmol/g loading each, observed
1.3 mmol/g (3b), and 1.1 mmol/g (3c)). This implies that, in
contrast to 1c, monomers 1e and 1f react more slowly than
styrene during polymerization. These differences in reac-
tivity must therefore be taken into account when preparing
polymers with specific loading levels. In order to determine
the rate of incorporation of 1a into 3a, we treated 3a
sequentially with TBDMSCl/DMSO16c,30 and BnNH2 to
form 4 and 5, respectively. Elemental analysis of both 4
(chlorine, 5.4%) and 5 (nitrogen, 2.1%) indicates that 3a has
a loading level close to the theoretical 1.5 mmol/g.
Gratifyingly, these reactions afforded good yields (65–
82%) of the desired products (1a–g), even when the
benzophenones were substituted with deactivating electron
donating groups. As might be expected, the benzophenones
substituted with electron withdrawing substituents afforded
slightly higher yields (1e–g). In all of these reactions,
4-bromostyrene was used in excess of the benzophenone
since any unreacted Grignard reagent was converted to
easily removable styrene. When it was used as the limiting
reagent, the excess benzophenone was more tedious to
separate from the desired alcohol. It should be noted that the
synthesis of only monomer 1a has been previously reported
and that monomer 1d represents a new linker group. To our
knowledge, no previously used trityl linker in solid-phase
synthesis contained more than one electron donating group
in addition to the alkyl group from the polystyrene
backbone, to modulate the electron density at the incipient
carbocation center.26 Therefore the use of these types of
more highly substituted linkers may allow for the synthesis
substrates to be more selectively or mildly cleaved from the
polymers.
3. Conclusions
In summary, we have developed an improved, general and
reproducible method for the synthesis of a variety of
substituted triphenyl methanols that contain a vinyl group.
These compounds can be used to directly introduce trityl
linker groups into both soluble and insoluble polystyrene
polymers. Given the wide range of substituted benzo-
phenones that are commercially available or easily synthe-
sized, our methodology allows access to a great number of

M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2903–2907
2905
Scheme 2. Synthesis of polymers 2–5. Reagents and conditions: (a) AIBN, toluene, 80 8C. (b) Chlorobenzene, benzoyl peroxide, water, acacia gum, NaCl,
85 8C. (c) TBDMSCl, DMSO, CH2Cl2, rt. (d) BnNH2, THF, rt.
new trityl linkers having varying acid sensitivities, which
should further enhance the applicability of such linkers. The
utility of such linkers in the new non-cross-linked polymers
2a–b in polymer-supported peptide/organic synthesis is
currently being assessed.
(500 mL) and brine (500 mL). The organic layer was
dried over MgSO4, filtered and concentrated in vacuo. The
crude product was purified by silica gel chromatography
(5% EtOAc/hexanes) to afford 1a as a white solid (12.6 g,
44 mmol, 65%). Mp 72–73 8C. 1H NMR (300 MHz,
CDCl3) d 2.77 (s, 1H, exchangeable with D2O), 5.24 (dd,
1H, J¼10.9, 0.9 Hz), 5.74 (dd, 1H, J¼17.6, 0.9 Hz), 6.68
(dd, 1H, J¼17.6, 10.9 Hz), 7.17–7.36 (m, 14H). 13C NMR
(75 MHz, CDCl3) d 81.9, 114.1, 125.8, 127.3 (2C), 127.9
(4C), 128.0 (4C), 128.2 (2C), 128.7 (2C), 136.4, 144.3,
146.8 (2C). HR EI-MS: calcd for C21H18O, 286.1358; found
286.1356.
4. Experimental
4.1. General
All reagents were obtained from the Aldrich, Lancaster or
Acros chemical companies and were used without further
purification. All moisture sensitive reactions were carried
out in dried glassware under a N2 atmosphere. Tetrahydro-
furan was distilled under a N2 atmosphere over sodium and
benzophenone. Dichloromethane was distilled under a N2
atmosphere over calcium hydride Merck silica gel 60
(230–400 mesh) was used for chromatography. Thin layer
chromatography analysis was performed using glass plates
coated with silica gel 60 F254. The NMR spectra were
recorded using a Bruker DRX 300 spectrometer. Chemical
shift data are expressed in ppm with reference to TMS.
EI-MS data were recorded on a Finnigan MAT 96 mass
spectrometer.
4.1.2. (4-Ethenylphenyl)-(4-methylphenyl)phenyl metha-
nol (1b). This was prepared by procedure A using
4-methylbenzophenone (1.4 g, 6.9 mmol) to afford 1b as a
pale yellow solid (1.3 g, 4.5 mmol, 65%). Mp 74–76 8C. 1H
NMR (300 MHz, CDCl3) d 2.34 (s, 3H), 2.73 (s, 1H,
exchangeable with D2O), 5.40 (dd, 1H, J¼10.9, 0.9 Hz),
5.73 (dd, 1H, J¼17.6, 0.9 Hz), 6.68 (dd, 1H, J¼17.6,
10.9 Hz), 7.10–7.36 (m, 13H). 13C NMR (75 MHz, CDCl3)
d 21.0, 81.8, 114.0, 125.7 (2C), 127.2, 127.8 (2C), 127.90
(2C), 127.92 (2C), 128.1 (2C), 128.7 (2C), 136.38, 136.44,
137.0, 143.9, 146.6, 146.9. HR EI-MS: calcd for C22H20O,
300.1514; found 300.1512.
4.1.1. (4-Ethenylphenyl)diphenyl methanol (1a). Pro-
cedure A. Benzophenone (12.4 g, 68 mmol) was added
dropwise at 0 8C to a solution of the Grignard reagent
prepared from 4-bromostyrene (14.0 g, 76 mmol) and Mg
(2.2 g, 92 mmol) in dry THF (250 mL). After TLC analysis
indicated electrophile consumption was complete, the
reaction mixture was diluted with diethyl ether (1 L), and
then washed sequentially with water (500 mL), 10%
aqueous HCl (500 mL), saturated aqueous NaHCO3
4.1.3. (4-Ethenylphenyl)-(4-methoxyphenyl)phenyl
methanol (1c). This was prepared by procedure A using
4-methoxybenzophenone (6.5 g, 31 mmol) to afford 1c as a
pale yellow liquid (6.5 g, 21 mmol, 67%). 1H NMR
(300 MHz, CDCl3) d 2.76 (s, 1H, exchangeable with
D2O), 3.78 (s, 3H), 5.23 (dd, 1H, J¼10.9, 0.9 Hz), 5.73
(dd, 1H, J¼17.6, 0.9 Hz), 6.68 (dd, 1H, J¼17.6, 10.9 Hz),
6.81–7.35 (m, 13H). 13C NMR (75 MHz, CDCl3) d 55.3,
81.6, 113.3 (2C), 114.0, 125.8 (2C), 127.2, 127.8 (2C),

2906
M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2903–2907
127.9 (2C), 128.0 (2C), 129.2 (2C), 136.4, 136.5, 139.1,
146.7, 147.0, 158.8. HR EI-MS: calcd for C22H20O2,
316.1463; found 316.1459.
58H). Polymers 2 are soluble in THF, EtOAc, CH2Cl2, DMF.
They are not soluble in methanol, ethanol, ether, and water.
4.1.9. Poly(styrene-co-[4-ethenylphenyl]-[4-methoxy-
phenyl]phenyl-methanol) (2b). This was prepared by
procedure B using styrene (16.5 g, 158 mmol), 1c (5.0 g,
16 mmol) and AIBN (0.3 g, 1.6 mmol) in toluene (100 mL)
4.1.4. Bis(4-methoxyphenyl)phenyl methanol (1d). This
was prepared by procedure A using 4,40-dimethoxybenzo-
phenone (1.5 g, 6.1 mmol) to afford 1d as a pale yellow
liquid (1.6 g, 4.6 mmol, 75%). 1H NMR (300 MHz, CDCl3)
d 2.71 (s, 1H, exchangeable with D2O), 3.79 (s, 6H), 5.23
(dd, 1H, J¼10.9, 0.9 Hz), 5.73 (dd, 1H, J¼17.6, 0.9 Hz),
6.67 (dd, 1H, J¼17.6, 10.9 Hz), 6.81–7.36 (m, 12H). 13C
NMR (75 MHz, CDCl3) d 55.4 (2C), 81.4, 113.3 (4C),
114.1, 125.8 (2C), 128.1 (2C), 129.2 (4C), 136.47, 136.51,
139.5 (2C), 147.0, 158.8 (2C). HR EI-MS: calcd for
C23H22O3, 346.1569; found 346.1545.
1
to afford 2b as a white powder (8.8 g, 45%). H NMR
(300 MHz, CDCl3) d 1.25–2.16 (bm, 33H), 3.74 (bs, 3H),
6.47–7.48 (bm, 57H). The ratio of monomer incorporation
into 2b was determined by 1H NMR to be 8.8:1 (styrene/1c).
This corresponds to a loading level of 0.8 mmol/g of
polymer.
4.1.10. Poly(styrene-co-[4-ethenylphenyl]diphenyl metha-
nol-co-1,4-bis[4-vinylphenoxy]butane) (JandaJel-Tr-
OH, 3a). Procedure C. A solution of acacia gum (6.0 g)
and NaCl (2.75 g) in warm deionion water (45 8C, 150 mL)
was placed in a 150 mL flanged reaction vessel equipped
with a mechanical stirrer and deoxygenated by purging with
N2 for 2 h.31 A solution of 1a (4.3 g, 15.0 mmol), styrene
(6.3 mL, 57 mmol), cross-linker (0.4 g, 1.5 mmol), AIBN
(0.2 g) in chlorobenzene (10 mL) was injected into the
rapidly stirred aqueous solution. This mixture was heated at
85 8C for 20 h. The crude polymer was collected and
washed with hot water (3£100 mL) and then placed in a
Soxhlet extractor and washed with THF for one day. The
beads were recovered, washed with methanol, diethyl ether
and hexanes. The shrunken beads 3a (8.0 g, 80%) were dried
in vacuo.Polymers3 were isolatedasbeadsthatmostlyranged
in size between 100 and 200 mesh. They exhibit good swelling
in solvents such as THF, benzene and CH2Cl2.. They exhibit
poor or no swelling in solvents such as acetonitrile, dimethyl
formamide, ethanol and water.
4.1.5. (2-Chlorophenyl)-(4-ethenylphenyl)phenyl metha-
nol (1e). This was prepared by procedure A using
2-chlorobenzophenone (7.5 g, 35 mmol) to afford 1e as a
colourless liquid. (8.5 g, 27 mmol, 77%). 1H NMR
(400 MHz, CDCl3) d 4.39 (s, 1H, exchangeable with
D2O), 5.20 (dd, 1H, J¼10.9, 0.8 Hz), 5.71 (dd, 1H, J¼
17.6, 0.8 Hz), 6.69 (dd, 1H, J¼17.6, 10.9 Hz), 6.74–7.34
(m, 13H). 13C NMR (100 MHz, CDCl3) d 82.4, 114.1, 125.9
(2C), 126.4, 127.4, 127.7 (2C), 127.96 (2C), 128.0 (2C),
129.1, 131.3, 131.4, 133.2, 136.4, 136.6, 143.6, 145.2,
145.5. HR EI-MS: calcd for C21H17ClO, 320.0968; found
320.0971.
4.1.6. (4-Chlorophenyl)-(4-ethenylphenyl)phenyl metha-
nol (1f). This was prepared by procedure A using
4-chlorobenzophenone (7.5 g, 35 mmol) to afford 1f as a
pale yellow liquid (8.0 g, 25 mmol, 72%). 1H NMR
(300 MHz, CDCl3) d 2.75 (s, 1H, exchangeable with
D2O), 5.25 (dd, 1H, J¼10.9, 0.7 Hz), 5.76 (dd, 1H, J¼
17.6, 0.7 Hz), 6.69 (dd, 1H, J¼17.6, 10.9 Hz), 7.13–7.41
(m, 13H). 13C NMR (75 MHz, CDCl3) d 81.6, 114.4, 126.0
(2C), 127.6 (2C), 127.9 (2C), 128.1 (2C), 128.2 (2C), 129.4
(2C), 130.2, 133.3, 136.3, 136.8, 145.4, 146.1, 146.4. HR
EI-MS: calcd for C21H17ClO, 320.0968; found 320.0960.
4.1.11. Poly(styrene-co-[2-chlorophenyl]-[4-ethenylphe-
nyl]phenyl methanol-co-1,4-bis[4-vinylphenoxy]butane)
(JandaJel-2-Cl-Tr-OH, 3b). This was prepared by pro-
cedure C using of 1e (4.8 g, 15.0 mmol), styrene (5.7 mL,
50 mmol), cross-linker (0.4 g, 1.5 mmol), and AIBN (0.2 g)
in chlorobenzene (10 mL) to afford 3b (7.3 g, 73%).
Elemental analysis was used to determine the chlorine
content (4.6%) and thus the loading level of 1.3 mmol Cl/g
of 3b.
4.1.7. Bis(4-chlorophenyl)phenyl methanol (1g). This was
prepared by procedure A using 4,40-dichlorobenzophenone
(1.7 g, 6.8 mmol) to afford 1g as a pale yellow liquid (2.0 g,
5.6 mmol, 82%). 1H NMR (300 MHz, CDCl3) d 2.72 (s, 1H,
exchangeable with D2O), 5.27 (dd, 1H, J¼10.9, 0.7 Hz),
5.75 (dd, 1H, J¼17.6, 0.7 Hz), 6.69 (dd, 1H, J¼17.6,
10.9 Hz), 7.14–7.35 (m, 12H). 13C NMR (75 MHz, CDCl3)
d 81.2, 114.6, 126.0 (2C), 127.9 (2C), 128.2 (4C), 129.2
(4C), 133.5 (2C), 136.1, 137.0, 144.8 (2C), 145.5. HR
EI-MS: calcd for C21H16Cl2O, 354.0578; found 354.0576.
4.1.12. Poly(styrene-co-[4-chlorophenyl]-[4-ethenylphe-
nyl]phenyl methanol-co-1,4-bis[4-vinylphenoxy]butane)
(JandaJel-4-Cl-Tr-OH, 3c). This was prepared by pro-
cedure C using of 1f (4.8 g, 15.0 mmol), styrene (5.7 mL,
50 mmol), cross-linker (0.4 g, 1.5 mmol), and AIBN (0.2 g)
in chlorobenzene (10 mL) to afford 3c (7.2 g, 72%).
Elemental analysis was used to determine the chlorine content
(3.7%) and thus the loading level of 1.1 mmol Cl/g of 3c.
4.1.8. Poly(styrene-co-[4-ethenylphenyl]diphenyl-metha-
nol) (2a). Procedure B. To a solution of styrene (18.2 g,
175 mmol) and 1a (5.0 g, 17 mmol) in toluene (100 mL)
was added AIBN (0.3 g, 1.7 mmol). The mixture was
purged with N2 for 30 min and the solution was stirred at
90 8C for 24 h. The solution was concentrated in vacuo
and then the residue was taken up in 10 mL of THF. This
solution was added dropwise to vigorously stir cold methanol
(200 mL). The white precipitate was filtered and dried to
afford 2a as a white powder (11.6 g, 50%). 1H NMR
(300 MHz, CDCl3) d 1.25–2.16 (bm, 33H), 6.47–7.48 (bm,
4.1.13. Poly(styrene-co-[4-ethenylphenyl]diphenyl chlor-
ide-co-1,4-bis[4-vinylphenoxy]butane) (JandaJel-Tr-Cl,
4). To a magnetically stirred suspension of 3a (2.0 g)
in anhydrous CH2Cl2 (20 mL) at rt and under a N2
atmosphere was added tert-butyldimethylsilyl chloride
(2.3 g, 15.0 mmol) and dimethyl sulfoxide (0.5 g,
6.0 mmol). Stirring was continued for 3 h at rt, at which
time the resin was filtered off, and washed sequentially with
dichloromethane, diethyl ether, and hexanes. The shrunken

M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2903–2907
2907
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beads 4 (2.2 g) were dried in vacuo. Elemental analysis was
used to determine the chlorine content (5.4%) and thus the
loading level of 1.5 mmol Cl/g of 4.
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4.1.14. Poly(styrene-co-[4-ethenylphenyl]diphenyl benzyl-
amine-co-1,4-bis[4-vinylphenoxy]butane) (JandaJel-Tr-
NHCH2Ph, 5). To a magnetically stirred suspension of
4 (0.2 g, 0.3 mmol) in THF (5 mL) at rt was added
benzylamine (0.2 g, 1.5 mmol). Stirring was continued for
24 h at rt, at which time the resin was filtered off, and
washed sequentially with dichloromethane, methanol,
diethyl ether, and hexanes. The shrunken beads 5 (0.2 g)
were dried in vacuo. Elemental analysis was used to
determine the nitrogen content (2.1%) and thus the loading
level of 1.5 mmol N/g of 5.
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This research was supported financially by the University of
Hong Kong, the Hung Hing Ying Physical Sciences
Research Fund and the Research Grants Council of the
Hong Kong Special Administrative Region, People’s
Republic of China (Project No. HKU 7112/02P). We also
wish to thank Mr. Chris Ka Wo Ng for his assistance in
preparing some of the starting materials and Mr. Bob
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many of the reagents used in this study.
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