Improved synthesis of (4-ethenylphenyl)diphenyl methanol and its application in the preparation of trityl functionalized polystyrene resin containing tetrahydrofuran derived cross-linker

Article abstract of DOI:10.1016/S0040-4039(00)01529-X

An improved and straightforward synthesis of (4-ethenylphenyl)diphenyl methanol is described. This monomer was used in the preparation of trityl functionalized polystyrene containing a flexible tetrahydrofuran cross-linker, giving rise to a suitable support for solid-phase organic synthesis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01529-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8417–8420
Improved synthesis of (4-ethenylphenyl)diphenyl methanol
and its application in the preparation of trityl functionalized
polystyrene resin containing tetrahydrofuran derived
cross-linker
Raffaella Manzotti, Thomas S. Reger and Kim D. Janda*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037 USA
Received 31 August 2000; accepted 11 September 2000
Abstract
An improved and straightforward synthesis of (4-ethenylphenyl)diphenyl methanol is described. This
monomer was used in the preparation of trityl functionalized polystyrene containing a flexible tetra-
hydrofuran cross-linker, giving rise to a suitable support for solid-phase organic synthesis. © 2000
Elsevier Science Ltd. All rights reserved.
Polymer-immobilized trityl alcohol and chloride moieties are useful protecting groups for
solid-phase organic synthesis (SPOS). Furthermore, they allow the attachment of a variety of
bifunctional building blocks such as amino acids, amino alcohols, and diamines via the
carboxyl, hydroxyl, or amino groups, respectively. In the field of the base-stable anchor groups
for linking substrates to solid support, trityl functionalized resins such as the chlorotrityl-PS/
DVB resin1–3 are widely used as platforms for the immobilization of nucleophiles.
We recently reported the synthesis of a new class of resins (termed JandaJels4) for SPOS
containing a flexible tetrahydrofuran derived cross-linker 1 (Fig. 1) that offered several advan-
tages over the other commercially available polystyrene resins.5 These resins were prepared with
a variety of common functionalities such as chloromethyl,5 hydroxymethyl,6,7 aminomethyl,8 and
the Wang-type linker.9 Due to the interesting features of the trityl linker and its usefulness in
SPOS, we decided to copolymerize (4-ethenylphenyl)diphenyl methanol 2 with styrene and with
2 mol% of our flexible tetrahydrofuran derived cross-linker 1 (Fig. 1).5
* Corresponding author. Fax: (+1)-858-784-2595; e-mail: kdjanda@scripps.edu
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01529-X

8418
Figure 1.
The preparation of trityl monomer 2 was first performed by adding 4-bromostyrene to
tert-butyllithium followed by the slow addition of benzophenone, as described by Rimmer et
al.10 In the literature, an isolated yield of 55% was reported; however, in our hands it was not
possible to obtain pure 2 either by crystallization or chromatography with a chemical yield
better than 41%. Furthermore, the chromatographic purification of monomer 2 from unreacted
benzophenone was troublesome and tedious (especially for scale-up) and always afforded mixed
fractions besides the desired compound 2.
An alternative route to the functional monomer 2 was therefore investigated (Scheme 1). The
previously reported 4-vinyl-benzyl alcohol 311 was quantitatively oxidized to the corresponding
aldehyde 4 using Swern’s methodology.12,13 Grignard reaction with phenyl magnesium bromide
gave alcohol 5,14 which underwent Swern oxidation to provide ketone 6 in 100% yield for the
two steps. Finally, monomer 2 was obtained in 74% yield by another Grignard reaction with
phenyl magnesium bromide. Although our synthetic route to 2 is longer than that reported by
Rimmer,10 it is more convenient in terms of chemical yield and ease of purification. In fact, the
first three steps of the synthesis did not require any purification and the only chromatography
was performed at the last step, giving rise to pure monomer 2 as white needles (mp, 55°C).
Scheme 1. (a) DMSO-(COCl)2, −60°C, Et3N, 20 min then rt. (b) PhMgBr, Et2O, rt, 10 min
Trityl alcohol-functionalized resin
7
was obtained in 89% yield by suspension
copolymerization5 of styrene, trityl monomer 2, and 2 mol% of cross-linker 1. Conversion to the
trityl chloride 8 was accomplished by refluxing resin 7 with acetyl chloride in benzene (Scheme
2).2 Chloride content determination indicated that the bead loading was quite low (0.3 mmol/g)
in comparison to the theoretically calculated value (ꢀ1 mmol/g, based on the amount of
monomer 2 used in the polymerization reaction).

8419
Scheme 2. (a) CH3COCl, benzene, reflux, 48 h. (b) 9, THF, rt, 48 h
As the trityl chloride functionality is prone to hydrolysis, chlorine content determination
might not give a reliable result. Therefore, resin 8 was converted into 10 by reaction with
4-nitrophenethylamine 9 in THF at room temperature for 48 h (Scheme 2). Resin 10 contained
a more stable amine moiety and nitrogen content analysis indicated that the bead loading was
0.68 mmol/g, which corresponds to a loading capacity of 0.75 mmol/g for resin 8. The swelling
properties of resin 7 were measured in solvents typically used for organic synthesis and were
compared with those measured for commercially available trityl alcohol-functionalized
Merrifield-type resin that is cross-linked with divinylbenzene (Table 1).
Table 1
Volumes of swollen resins
Volume of swollen resin (mL/g)a
Resin
Dioxane
THF
DMF
Benzene
DCM
Merrifield-1%b
JandaJel-Trt-OH-2% (7)
5.8
10.6
6.0
11.0
5.6
8.0
5.4
10.2
6.6
9.6
a Volumes were measured in syringes equipped with a sintered frit after equilibrating for 1 h.15
b Resin with a loading capacity of 1.1 mmol/g was purchased from Advanced Chemtech and was used as received.
From Table 1, it is clear that our resin 7 has outstanding swelling properties in comparison
to the commercially available Merrifield trityl functionalized resin. It is noteworthy that our 2%
cross-linked resin swells nearly twice as much as the 1% DVB cross-linked analogue. As the
degree to which a given resin absorbs a particular solvent and swells is considered to be
indicative of site accessibility and consequently resin functionalization,15 resin 7 might constitute
a suitable support for reactions which require basic or neutral conditions. As such, we are
currently utilizing 7 in the SPOS of other organic reactions of interest to our laboratory.
In summary, we have provided a new high-yielding entry to the functional monomer 2 which
allows for its large scale preparation in pure form. Monomer 2 was used in the preparation of
a polystyrene resin containing a flexible tetrahydrofuran cross-linker and showed excellent
swelling properties compared to the commercially available Merrifield-type resin. This combina-
tion of support and linker should find application in solid-phase organic synthesis and
investigations along these lines will be reported in due course.

8420
Acknowledgements
This work was supported by funding from The Skaggs Institute for Chemical Biology and the
National Institutes of Health (GM-56154). K.D.J. is an Arthur C. Cope Scholar and R.M. is a
Fulbright Fellow.
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