Synthesis and application of polytetrahydrofuran-grafted polystyrene (PS-PTHF) resin supports for organic synthesis

Article abstract of DOI:10.1016/j.tet.2005.08.121

Cross-linked polystyrene (PS) with polytetrahydrofuran (PTHF) chains were prepared for use in solid phase organic synthesis (SPOS). The resins were prepared from styrene, styrene-PTHF macromonomers and cross-linkers 1,4-bis[4-vinylphenoxy]butane or divinylbenzene by suspension polymerization. The styrene-PTHF macromonomers were prepared by cationic polymerization of 4-vinylbenzyl bromide and 4-(4-vinylphenoxy)butyl iodide activated by silver hexafluoroantimonate and 4-(5-hydroxypentyl)styrene activated by triflic anhydride. Alternatively, polytetrahydrofuran-grafted polystyrene (PS-PTHF) resins could also be directly prepared from 5-hydroxypentyl JandaJel by cationic polymerization using triflic anhydride as the initiator. These PS-PTHF resins exhibited good swelling characteristics across a wide spectrum of polar and non-polar solvents. These resins were used in the synthesis of 3-methyl-1-phenyl-2-pyrazolin-5-one, which requires β-ketoester formation at low temperature (-78°C), resulting in good yield and product purity; whereas the same synthesis carried out on PEG-grafted PS (PS-PEG) resin resulted in incomplete synthesis.

Full text of DOI:10.1016/j.tet.2005.08.121

Tetrahedron 61 (2005) 12160–12167
Synthesis and application of polytetrahydrofuran-grafted
polystyrene (PS–PTHF) resin supports for organic synthesis
a,b,†
a,†
Byoung Se Lee, Sergio Meth, Hiroki Suzuki,
a
b
Osamu Shimomura,
a
Suresh Mahajan, Ryoki Nomura and Kim D. Janda
b
a,
*
a
Departments of Chemistry and Immunology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
0550 North Torrey Pines Road, La Jolla, CA 92037, USA
Department of Applied Chemistry, Osaka Institute of Technology, 1 6-1, Omiya 5-chome, Ashahi-ku, Osaka 535-8585, Japan
1
b
Received 13 July 2005; revised 11 August 2005; accepted 11 August 2005
Available online 26 October 2005
Abstract—Cross-linked polystyrene (PS) with polytetrahydrofuran (PTHF) chains were prepared for use in solid phase organic synthesis
SPOS). The resins were prepared from styrene, styrene–PTHF macromonomers and cross-linkers 1,4-bis[4-vinylphenoxy]butane or
divinylbenzene by suspension polymerization. The styrene–PTHF macromonomers were prepared by cationic polymerization of
-vinylbenzyl bromide and 4-(4-vinylphenoxy)butyl iodide activated by silver hexafluoroantimonate and 4-(5-hydroxypentyl)styrene
activated by triflic anhydride. Alternatively, polytetrahydrofuran–grafted polystyrene (PS–PTHF) resins could also be directly prepared from
-hydroxypentyl JandaJel by cationic polymerization using triflic anhydride as the initiator. These PS–PTHF resins exhibited good swelling
characteristics across a wide spectrum of polar and non-polar solvents. These resins were used in the synthesis of 3-methyl-1-phenyl-
-pyrazolin-5-one, which requires b-ketoester formation at low temperature (K78 8C), resulting in good yield and product purity; whereas
(
4
5
2
the same synthesis carried out on PEG–grafted PS (PS–PEG) resin resulted in incomplete synthesis.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
chlorinated hydrocarbons, as well as DMF. Because of the
excellent swelling of JandaJel resins (e.g., 8–10 ml/g in
THF depending on resin functionalization), the environment
of the resins becomes more ‘solution-like’ and thus provides
easy access to the reactive sites, and therefore solution phase
Solid-phase organic synthesis (SPOS) continues to be
important in the development of libraries of new mol-
ecules. As more complex syntheses are investigated,
1
3
specialized solid-phase supports are needed to allow facile
library development. In essence, the research chemist needs
to have a ‘menu’ of resins to choose from so as to adapt
solution-phase synthesis with little or no modification to the
solid-phase. The physical and chemical properties of the
solid support play an important role in successful
implementation of a SPOS strategy. Commercially avail-
able Merrifield and JandaJel resins have proven to be robust
supports and allow access to reactive sites because of their
good swelling characteristics. These resins are lightly cross-
linked styrene-based polymers. JandaJels (JJ) have
improved swelling when evaluated against Merrifield Resins
synthesis conditions can readily be adapted to SPOS.
However, polar protic solvents such as alcohols and water
do not swell these resins and therefore limits their
application, especially in terms of on-bead screening.
Complex multi-step synthesis requires a solid support that
can function in both polar and non-polar solvents. Any new
solid support needs to provide access to reactive sites in
polar as well as non-polar solvents and be robust in severe
4
chemical environments. PEG–grafted polyacrylamide
(
PAM–PEG; e.g., PEGA) polymer beads as well as
5
PEG–grafted polystyrene (PS–PEG; e.g., TentaGel (TG),
ArgoGel) resins have been designed to have utility in
polar solvents and have limited swelling in non-polar
solvents. However, PEG–grafted polyacrylamide resins
have intrinsic limitations since these are not compatible
with some common reagents because of the vulnerable
amide bond. The grafted PEG chains provide a hydrophilic
component to the hydrophobic polystyrene backbone, and
exhibit more uniform swelling in both polar and non-polar
(MF) by virtue of the more flexible cross linker 1,4-bis[4-
vinylphenoxy] butane (7) compared to the divinylbenzene
2
cross-linker for Merrifield resin. These resins swell well in
low polarity solvents such as benzene, toluene, THF, and
Keywords: Organic synthesis; Cross-linked polystyrene; Macromonomers.
*
Corresponding author. Tel.: C1 858 784 2515; fax: C1 858 784 2592;
e-mail: kdjanda@scripps.edu
O.S. and B.S.L. contributed equally to this work.
†
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.121

O. Shimomura et al. / Tetrahedron 61 (2005) 12160–12167
12161
1
3
solvents, but the swelling is low compared to the Merrifield
and JandaJel resins, especially in non-polar solvents.
PS–PEG resins have superior performance in reactions
involving salts and in peptide synthesis. However, studies
conducted by Li et al. indicate that the PS resins have
superior or equivalent kinetics in many chemical reactions
silver (I) hexafluoroantimonate (Scheme 1a). The cationic
polymerization of THF was carried out in THF at K10 8C,
and then terminated by quenching with dilute sodium
hydroxide solution, resulting in macromonomers with
1
4
hydroxyl end groups in quantitative yield.
6
compared to PS–PEG resins. Furthermore, these PS–PEG
resins generally have low loading capacity, tend to
aggregate and have poor stability in some chemical
environments, for example, in acidic media.
(
a)
b)
1) THF, AgPF
6
, -10 o
C
2
) NaOH, H O
2
OH
Br
O
1
2
n
In considering new resins that could be adapted to SPOS, we
chose to focus on tetrahydrofuran-based resins since
tetrahydrofuran is a good organic solvent and is partially
miscible with water. Therefore, we speculated that styrene-
based resins containing PTHF chains could therefore provide
resins with good swelling in a broad spectrum of solvents and
increased chemical resistance compared to the PS–PEG
resins. Polymerization of THF has been studied over the last
, -10 o
C
(
1) THF, AgPF
6
2
) NaOH, H O
2
O
O
OH
I
O
3
4
n
1
) THF, Tf
O, DTBP, -10 o
C
2
5
0 years and an extensive body of literature is available on
(c)
polymeric techniques for preparing THF-based polymers.
Based on the literature, two approaches to preparing
PS–PTHF resins can be formulated: (1) preparation of
macromonomers of styrene–PTHF, followed by suspension
polymerization, and (2) grafting of PTHF chains to pre-
formed resins similar to the preparation of PS–PEG resins.
Evidence for the implementation of the second approach is
the reported successful partial graft polymerization of PTHF
on polyvinyl chloride (PVC), brominated poly-butadiene and
2) NaOH, H O
2
OH
OH
O
5
6
n
Scheme 1. Preparation of macromonomers.
The number of PTHF chains, n, was found to be directly
proportional to the reaction time and macromonomers of
specific chain length were obtained by controlling the
reaction times. Two macromonomers of average chain
lengths of nZ7.1 and 13.6 were obtained. The average
number of PTHF chains in the macromonomers was
calculated by analysis of H NMR spectra (Fig. 1), through
comparison of the peak ratio of benzyl protons (a:
.48 ppm) and methylene protons (c: 1.62 ppm). Although
the NMR measurement gives an average chain length, these
macromonomers contain a statistical distribution of macro-
monomers with varying chain length (verified by a GPC
analysis) and a polydispersity of 1.1 for nZ7.1 was
calculated from the measured distribution.
7
random polymers of styrene and methacryloyl chloride.
Styrene–PTHF macromonomers of varying chain length also
have been prepared, and successfully used in suspension
8
–11
polymerizations.
These macromonomers are prepared by
1
cationic ring opening polymerization using initiators prepared
from styrene derivatives or end capping of the living
polymerization of THF with a styrene compound. For
example, vinyl phenoxide PTHF macromonomers have
been prepared with low polydispersity by the living
polymerization of THF initiated by triethyloxonium tetra-
fluoroborate and then terminated by end capping with sodium
4
8
vinyl phenoxide. In another example, macromonomers were
prepared by polymerizing THF from vinyl benzyl halides
activated by reacting with silver (I) hexafluoroantimonate.
PTHF macromonomers have also been prepared from triflic
Since the benzylic carbon of 2 might be susceptible to attack
under acidic conditions, two other macromonomers were also
prepared, 4-(4-vinylphenoxy)butyl–PTHF 4 and 5-(4-vinyl-
phenyl)pentanoxy–PTHF 6. Using AgPF or AgBF acti-
1
2
esters of butyl or allyl alcohols.
6
4
vation, 4-(4-vinylphenoxy)butyl iodide was readily converted
to the corresponding macromonomers (Scheme 1b). Macro-
monomers containing nZ17.0 and 34.0 were prepared using
this procedure. However, we were unsuccessful in preparing
macromonomer 6 by silver (I) activation from either 4-(5-
bromopentyl)styrene or 4-(5-iodopentyl)styrene as precur-
sors, presumably due to lower activity of these aliphatic type
halides. Wesucceededinmakingmacromonomer6from4-(5-
hydroxypentyl) styrene 5 activated with triflic anhydride
(Scheme 1c). A macro monomer of number-average
Herein, we report the preparation of macromonomers
-vinylbenzyloxy–PTHF 2, 4-(4-vinylphenoxy)butyl–
4
PTHF 4, 5-(4-vinylphenyl)pentanoxy–PTHF 6 and suspen-
sion polymerization with styrene and styrene-based
cross-linkers to produce PS–PTHF resins. We also report
the preparation of PS–PTHF resins by a grafting protocol.
The synthesis of 3-methyl-1-phenyl-2-pyrazolin-5-one 18
using these resins was used as a test case to evaluate these
resins as a support for organic synthesis, particularly to
examine the stability of these resins in acidic medium and
metallation chemistry at low temperatures (K78 8C).
molecular weight (M
weightof (M ) 747, and polymerizationdispersity (M /M ) of
) of 689, weight-average molecular
n
w
w
n
1.1 was prepared (obtained by ESI-TOF, previously calibrated
2
. Results and discussion
with polyethylene glycol (PEG)) by controlling the reaction
time, resulting in a macromonomer with an average chain
length of nZ6.9. All the macromonomers were generally
unstable even at low temperature having a shelf life of a few
Macromonomers of 4-vinylbenzyloxy PTHF 2 were
prepared from 4-vinylbenzyl bromide 1 activated with

12162
O. Shimomura et al. / Tetrahedron 61 (2005) 12160–12167
1
Figure 1. H NMR Spectrum of macromonomer 2.
of the macromonomer 4; alternatively, resins 8 and 10 were
isolated as free flowing powders.
Bz O, DME
2
+
+
macromonomer NaCl, acacia gum
PS-PTHF
8a, b macromonomer = 2
9a, b. macromonomer = 4
2
or 4 or 6
H O
2
O
O
85°C, 20 h
Even though we succeeded in producing resin 10 from 5-(4-
vinylphenyl)pentoxy PTHF 6, precautions were necessary
in the preparation of the resin due to the instability of
macromonomer 6. Therefore, we searched for an alternative
procedure for making this resin. Since we were successful in
activating 4-(5-hydroxypentyl)styrene 6 using triflic anhy-
dride, we hypothesize that this approach could be applied to
7
1
0, macromonomer = 6
or DVB
Scheme 2. Preparation of macromonomers.
days, however, macromonomer 6 was found to be more
unstable and had to be used immediately in resin preparation.
Having the three macromonomers in hand, we prepared
PS–PTHF resins 8a,b, 9a,b and 10 (Scheme 2) by
suspension polymerization of styrene, PTHF macromono-
mers 2, 4 and 6, and cross linkers divinylbenzene (DVB)
and 7.
The polymers were filtered and washed to obtain the resins in
6
9, 70, 48, 57 and 40% yield, respectively. In order to avoid
problems with emulsions, a 10% higher concentration of
NaCl was used with DVB as the cross-linker in the production
of the resin 10. The presence of PS and PTHF in resin 8a was
1
3
confirmed by C NMR. The NMR spectrum of 8a (Fig. 2)
shows the presence of the methylene protons neighboring the
hydroxyl group, the protons labeled as e and f can be
attributed to the peaks at 62.6 and 30.3 ppm, respectively,
1
5
confirming the presence of both PS and PTHF in the resin.
1
Similarly, magic angle spinning (MAS) H NMR of resin 10
showed very defined peaks at 3.4 and 1.6 ppm, corresponding
to the PTHF backbone, confirming the formation of
PS–PTHF resins. The loading of the resins 8a,b, 9a,b
and 10 was determined to be 0.55, 0.35, 0.29, 0.17 and
0
.34 mmol/g, respectively, by Fmoc-glycine loading and
quantitation of dibenzofulvene release. Resins 9a,b obtained
from 4-(4-vinylphenoxy)butyl PTHF were found to be sticky,
presumably because of the long chain lengths (nZ17.0, 34.0)
1
3
Figure 2. C NMR of PS–PTHF resin 8a.

O. Shimomura et al. / Tetrahedron 61 (2005) 12160–12167
12163
graft PTHF macromer to 5-hydroxypentyl JandaJel resin
5-HPJJ resin), a resin previously prepared in our
laboratory. Gratifyingly, we were successful in activating
this resin with triflic anhydride, and this method proved to
be reproducible, reliable and easy to use (Scheme 3).
PTHF grafted 5-HPJJ-OH
(
25
20
1
6
y = 0.5207x
2
R = 0.9598
1
5
0
5
0
OH Tf O, DTBP
OTf
2
1
11
2
CH Cl2
12
rt, 15 min
1) THF
rt, 10-35 min
OH
n
O
13a-f
2) TBAOH (40%)
rt, 1 h
n = 4.4 - 20.8
0
10
20
Time, min
30
40
1
) oxetane/CH Cl2 (1:1)
rt, 15 min
2
OTf
O
OH
n
12
2) TBAOH (40%)
rt, 1 h
14
n = 13.1
Figure 3. Kinetics for the preparation of PTHF–grafted 5-HPJJ resins.
Scheme 3. Preparation of PTHF–grafted polystyrene from 5-hydroxypentyl
JandaJel.
The procedure for the preparation of the PTHF–grafted
polystyrene (PS–PTHF) required activation of 5-hydro-
xypentyl JandaJel (11) with triflic anhydride and in the
presence of 2,6-di-tert-butylpyridine (DTBP) to give triflate
resin 12. The terminal triflate acts as an active intermediate
for living polymerization of THF. The activated 5-HPJJ
complex 12 was isolated and the grafting of PTHF
macromer was achieved by adding anhydrous THF to
the isolated complex. A series of PTHF–grafted polystyrene
resins 13a–f with varying number of PTHF chain length
were prepared by adjusting the reaction time from 10 to
Figure 4. Microscopic images of resins.
shown in optical microscopic images (Fig. 4), demons-
trating that the resins were spherical and free-flowing.
3
5 min (Table 1). However, when the same procedure was
The stability of the PS–PTHF resins was examined under
severe acidic and basic conditions, and the stability of these
resins compared with commercially available hydroxy-
methyl Merrifield (MF), hydroxymethyl JandaJel (JJ) and
hydroxyl-TentaGel (TG) resins. All resins were stable under
strong basic conditions as measured by weight loss (Table 2).
However, PEG or PTHF grafted resins were not stable under
acidic conditions. Merrifield resin was shown to be inert under
all conditions. Among the PTHF derived resins, the pentyl
resins 13b,e were found to be more stable than the benzyl
resin 8 in TFA (condition C). The IR spectrum of the treated
resins confirmed the findings based on weight loss.
applied to hydroxymethyl polystyrene resins, grafting of
PTHF did not take place and PS–PTHF resins were not
obtained.
The chain lengths of 13a–f were calculated from the weight
increase, and verified by measuring the hydroxyl loading by
0
17
,4 -dimethoxytrtyl chloride (DMT) titration. The number
4
of grafted PTHF units were found to have a linear
correlation with reaction time (Fig. 3), resulting in zero
order kinetics, suggesting that the number of PTHF units did
not have an effect on the reactivity of the activated triflate
end unit. IR spectra of the grafted resin showed two new
K1
peaks (C–O bond stretching) at 1028 and 1103 cm
one enhanced peak (aliphatic C–H bond stretching) at
and
The swelling property of resin supports is an essential
feature for site accessibility in solid-phase organic
synthesis. We measured swelling of these resins in several
common solvents used in organic synthesis (Table 3).
Unfortunately, none of the PTHF-derived resins showed any
swelling in water, whereas TentaGel swells in water. When
swelling of resins 13a–f was examined, it was generally
found to mirror the swelling obtained in 5-HPJJ. The best
swelling results were obtained in resins 13b and 13e (nZ
6.9, 13.8, respectively). In methanol and diethyl ether resins
K1
2
852 cm
resin 14 from oxetane, with nZ13.1 and an –OH loading of
.57 mmol/g, to determine if these resins may have
in comparison to 5-HPJJ. We also prepared
0
properties similar to PS–PEG resins. Unlike TentaGel
where several ethylene oxide units (more than 30) can be
grafted onto the polystyrene polymer, PTHF and oxetane
grafted resins with nO13 were found to be sticky in
consistency. The morphology of PTHF derived resins is
Table 1. Loading and chain lengths of grafted 5-HPJJ resins
Resin
11
13a
13b
13c
13d
13e
13f
Time (min)
n
Weight increase (%)
PTHF (wt%)
0
10
4.4
31.8
24.1
0.76
15
6.9
50.1
33.4
0.67
0.67
20
9.1
65.5
39.6
0.60
25
28
35
—
—
—
—
1.00
12.2
88.3
46.9
13.8
99.5
49.9
0.50
0.44
20.8
150.3
60.0
–OH loading (mmol/g)
Calculated
a
Measured
0.53
0.40
a
Measured by a DMT protocol.

12164
O. Shimomura et al. / Tetrahedron 61 (2005) 12160–12167
Table 2. Stability test (weight change (%))
Conditions
MF
TG
JJ
PTHF–grafted JJ
8
a
11
13b
13e
A
B
C
D
E
10% TBAOH (40%)/THF, 60 8C, 3.5 h
3% NaH/THF, room temperature, 3.5 h
50% TFA/toluene, room temperature, 5 h
—
—
C10
—
—
—
—
C4
K25
K10
—
—
—
—
—
—
—
—
—
—
a
b
b
C10
K24
K10
C6
C6
c
e
d
d
x
d
d
d
1 M BBr
1 M SnCl
3
/CH
/CH
2
Cl
Cl
2
, room temperature, 3 h
, room temperature, 3 h
x
—
x
—
x
K30
x
K36
b
b
4
2
2
K30
a
Hydroxyl groups were protected with trifluoroacetyl group.
All PTHF units were cleaved.
All PEG units were cleaved.
Resin dissolved.
Partial cleavage of PEG units.
b
c
d
e
Table 3. Swollen volume (mL/g) of various resins
CH
Cl
2 2
THF
Dioxane
Toluene
DMF
MeOH
Acetone
Et
2
O
n-Hexane
2
H O
5
-HPJJ
11
8.9
8.9
6.3
9.1
6.8
5.1
9.4
7.4
7.7
5.9
6.9
8.2
8.7
8.7
6.1
8.6
6.1
4.5
8.8
6.8
7.1
6.7
5.1
8.1
8.3
7.8
5.6
7.9
5.3
4.1
7.3
5.9
6.2
6.5
5.5
8.0
7.6
8.3
7.0
7.9
6.0
4.4
8.0
6.6
4.8
4.5
4.6
7.1
6.8
5.2
4.1
5.3
3.5
2.8
4.4
3.4
4.2
5.7
5.1
6.3
2.4
2.4
2.6
3.0
2.6
2.2
2.8
2.5
2.3
2.7
3.7
2.2
4.3
4.1
3.5
4.1
3.3
2.8
3.8
3.3
4.0
3.7
4.0
4.1
4.6
4.7
3.7
4.9
3.7
2.2
5.1
4.1
4.6
3.2
2.0
3.9
2.4
2.6
2.5
3.0
2.6
2.5
3.2
3.2
3.1
2.1
—
—
—
—
—
—
—
—
—
—
—
8
1
1
1
a
3a
3b
3c
PS–PTHF
13d
1
1
1
3e
3f
4
MF
TG
JJ
3.0
—
—
1
5
3b and 13e exhibited slightly higher swelling compared to
-HPJJ and JJ. Resin 14 prepared from oxetane showed
reagent to afford 15, which was reacted with LiHMDS at
K78 8C and treated with acetyl chloride to afford
1
8
similar behavior as the PTHF derived resins. We also
measured swelling of resins 13b, 13e and TG at K78 8C in
THF. Compared to swelling at room temperature, a
significant reduction in swelling volume (w40%) was
found for TG at K78 8C, whereas the PTHF derived resins
retained the same degree of swelling obtained at room
temperature. Resin 10 exhibited swelling behaviour equiv-
alent to resin 13b, whereas, resins 9a and 9b swelling could
not be determined precisely because of the stickiness of the
resins. Even though PS–PTHF resins exhibited only a
marginal improvement in swelling especially in polar
solvents, nevertheless, we decided to test these new resins
in a synthetic application.
b-ketoester 16. Treatment of 16 with phenylhydrazine
afforded 17, which was cleaved with TFA in acetonitrile at
room temperature to obtain 18. No reaction was obtained
with TentaGel, however, with all three PS–PTHF resins 18
was obtained in 42–48% yield with a purity ranging
between 91 and 96% (Table 4). PEG-based resins proved
ineffective under these conditions, probably due to low
solubility of PEG in organic solvents, and as discussed
previously, TentaGel was shown to have much lower
swelling at low temperature, presumably resulting in
inaccessibility of reactive sites for this reaction. The fact
that successful synthesis of 18 was achieved suggests that
PS–PTHF resins are capable of generating carbanions at low
temperatures.
1
9
We chose the synthesis of a b-ketoester to demonstrate the
application of these new resins in SPOS and compare their
performance to the PEG based resin. The synthesis involves
the use of LiHMDS at K78 8C and these conditions have
been shown to be problematic for SPOS. Scheme 4 shows
the synthesis using TentaGel and PS–PTHF resins 8b, 13b
and 13e. The resins were reacted with acetic acid by using
3. Conclusion
In summary, styrene-based PTHF macromonomers were
prepared from the cationic polymerization of THF from
styrene-based precursors activated with either silver (I) or
1
,3-diisopropylcarbodiimide (DIC) as a condensation
Table 4. Yields and purity of 3-methyl-1-phenyl-2-pyrazolin-5-one 18
O
LiHDMS/THF
O
O
TG
PS–PTHF
AcOH, DIC, DMAP
CH Cl
-78 °C, 15 min
OH
O
O
8b
13b
13e
0.50
AcCl
2
2
15
16
a
rt, 3 h
-78 °C, 15 min
OH loading
mmol/g)
Theoretical
0.44
0.67
~
rt, 3 h
(
b
NHPh
N
Measured
0.32
—
1
0.35
94
48
0.67
96
47
0.44
91
42
O
TMOF, PhNHNH2
THF
2% TFA/MeCN
rt, 30 min
N
Purity (%)
Yield (%)
O
O
N
18
17
50 °C, 3 h
a
Loading for TG based on reported value from manufacturer and for 13b
and 13e by weight increase.
Measured by a DMT protocol.
b
Scheme 4. Preparation of 3-methyl-1-phenyl-2-pyrazolin-5-one 18.

O. Shimomura et al. / Tetrahedron 61 (2005) 12160–12167
12165
triflic anhydride. PS resins with PTHF graft chains were
synthesized by suspension polymerization of styrene,
macromonomer and cross-linkers. Alternatively a reprodu-
cible procedure was developed for production of resins by
grafting PTHF chains to pre-formed 5-hydroxypentyl
JandaJel. These resins were used successfully for the
synthesis of 3-methyl-1-phenyl-2-pyrazolin-5-one 18 in
good yield and purity, whereas Tentagel was shown to be
ineffective in this synthesis. These resins had good chemical
stability and swelling characteristics, and compared to
commercially available resins should provide equal or better
solid supports in SPOS.
was poured into water and extracted with ethyl acetate,
dried with MgSO The ethyl acetate layer was evaporated
and distilled under vacuum to obtain 4-vinylbenzyl alcohol
4
.
1
(92.3 g, 97% yield). H NMR (600 MHz, CDCl ) d 4.66 (s,
3
2H), 5.24 (d, 1H, JZ10.5 Hz), 5.75 (d, 1H, JZ17.7 Hz),
6.71 (dd, 1H, JZ17.4, 10.8 Hz), 7.31 (d, 2H, JZ7.8 Hz),
1
3
7.40 (d, 2H, JZ7.8 Hz); C NMR (125 MHz, CDCl ) d
3
65.0, 113.8, 126.3, 127.1, 136.4, 136.9, 140.4.
4.1.2. Synthesis of 4-vinylbenzyl bromide 1. 4-Vinyl-
benzyl bromide 1 was prepared by slight modification of the
procedure for preparation of 4-styrylbenzyl bromide from
2
1
4
-styrylbenzyl alcohol. Phosphorous tribromide PBr3
18.4 g, 6.4 ml, 68 mmol) in Et O (10 ml) was added to
(
4-vinylbenzyl alcohol (5.9 g, 44.3 mmol) in Et O (500 ml)
2
4
. Experimental
2
at 0 8C under N . After 1 h, additional PBr (18.4 g, 6.4 ml,
2
3
4
.1. General methods
68 mmol) was added. The reaction mixture was stirred for
h at room temperature. After the reaction, the reaction
mixture was cooled to 0 8C and water (100 ml) was added
1
Unless otherwise noted, materials were obtained from
Aldrich and were used without further purification. TG
and MF resins were purchased from Novabiochem.
slowly to control the temperature. The solution was
extracted with Et
aqueous NaHCO
O, and the Et
, brine and dried with MgSO
4
O layer was washed with
2
2
1
JandaJel-OH (JJ) was purchased from Aldrich. H and
C NMR spectra were recorded in CDCl on a Bruker
3
. The crude
1
3
product was purified by vacuum distillation (0.65 mmHg) at
60 8C to obtain 1. Yield 6.8 g (78%). H NMR (500 MHz,
3
1
DRX-600, DRX-500, AMX-400 or a Varian Unity-300
spectrometer using tetramethylsilane (TMS) as an internal
standard. FT-IR spectra were obtained with a Nicolet Avatar
CDCl
) d 4.48 (s, 2H), 5.26 (dd, 1H, JZ11.0, 1.0 Hz), 5.75
3
(dd, 1H, JZ17.6, 1.0 Hz), 6.69 (dd, 1H, JZ17.6, 11.0 Hz),
1
3
3
(
60 FT-IR spectrometer equipped with a Nicolet Smart Gate
ZnSe). Gel permeation chromatographic analyses (GPC)
7.35 (m, 4H); C NMR (125 MHz, CDCl
126.6, 129.2, 136.1, 137.2, 137.7.
) d 33.4, 114.6,
3
were carried out on a Shimadzu LC-6A preparative liquid
chromatograph with a Shimadzu CR-501A integrator andwa
Shimadzu SPD-10AV UV–vis detector (254 nm) (Styragel
HR2, HR3, and HR4, THF as eluent) using polystyrene
standards. GC–MS analyses were carried out on a Shimadzu
QP-5000 equipped with GC-17A gas chromatography
instrument using DB-1 (J&W scientific 30 m!0.25 mm!
4.1.3. Synthesis of macromonomer 2 (nZ7.1). A solution
of 4-vinylbenzyl bromide 1 (2.96 g, 15 mmol) in THF
(10 ml) was added to a solution of silver hexafluoropho-
sphate (4.55 g, 18 mmol) in THF (500 ml) at K10 8C and
stirred for 8 min. After the reaction, NaOH (3 g, 75 mmol)
in water (50 ml) was added to the reaction mixture. The
solution was filtered to remove AgBr and the solution was
concentrated to a volume of ca. 200 ml. The solution was
then added drop-wise into water and extracted with ethyl
acetate. The organic ethyl acetate layer was washed with
NH Cl, brine, and dried with MgSO . Evaporation of the
0
.25 mm) column. Gas chromatography (GC) analyses were
carried out on Shimadzu GC-17A instrument using Ultra
Alloy-7 (15 m!0.25 mm!0.25 mm) column. UV analyses
were carried out on a Shimadzu UV mini 1240 UV–vis
spectrophotometer. Microscope pictures were obtained
using a BioRad Rainbow Radiance 2100 Confocal Laser
Scanning Microscope (CLSM) attached to a Nikon
TE2000U Eclipsed Inverted Fluorescence Microscope
equipped with Differential Interference Contrast Optics
4
4
solvents afforded 2 (10.46 g, quant.) as a clear viscous oil
that solidified upon standing at 4 8C, was pure according to
NMR analysis, and was used without further purification
1
(nZ7.1 calculated by H NMR). Macromonomer 2
1
(
20! Plan Apo 0.75 na). Electron spray ionization–time-of-
(nZ13.1) was prepared by a similar procedure. H NMR
flight determinations were obtained using an Agilent ESI-
TOF mass spectrometer. MAS data was collected on a
Varian Inova spectrometer at 400 MHz using Varian’s
nanoprobe. The polymer was suspended in solution and
sample spinner was set at 2000 RPM.
(500 MHz, CDCl ) d 1.55–1.66 (br, 29.7H), 3.39–3.56 (br,
29.7H), 4.48 (s, 2H), 5.22 (d, 1H, JZ11.0 Hz), 5.80 (dd, 1H,
JZ17.6, 1.0 Hz), 6.75 (dd, 1H, JZ17.6, 11.0 Hz), 7.32 (d,
3
1
3
2H, JZ8.1 Hz), 7.45 (d, 2H, JZ17.6, 8.1 Hz); C NMR
(500 MHz, CDCl ) d 27.2, 62.3, 70.7, 71.0–71.2, 72.8,
113.9, 126.9, 128.5, 137.5, 137.6, 139.8.
3
4.1.1. Synthesis of 4-vinylbenzyl alcohol. 4-Vinylbenzyl
alcohol was prepared by slight modification of the reported
4.1.4. Synthesis of of 4-[4-(vinyl)phenoxy]butyliodide 3.
A mixture of NaOH (0.40 g, 10 mmol) and 4-acetoxy-
styrene (0.91 ml, 5 mmol) in DMSO (15 ml) was stirred at
60 8C for 2 h. The mixture was cooled to room temperature
and 1,4-diiodobutane (1.32 ml, 10 mmol) in DMSO (15 ml)
was added gradually. After 30 min, water (100 ml) was
added and the solution extracted with ethyl acetate
(100 ml!3). Ethyl acetate layer was washed with dilute
2
0
method. A mixture of 4-vinylbenzyl chloride (100 ml,
.71 mmol) and potassium acetate (80 g, 0.84 mmol) in
0
DMSO (300 ml) was stirred at 40 8C for 48 h. The reaction
mixture was poured into water (300 ml) and extracted three
times with ethyl acetate (300 ml). The collected ethyl
acetate layer was dried with MgSO . The ethyl acetate was
4
evaporated to afford 4-vinylbenzyl acetate and used without
further purification. Sodium hydroxide (50 g, 1.25 mol) was
added to the crude 4-vinylbenzyl acetate in EtOH (300 ml)/
water (50 ml) and refluxed for 1.5 h. The reaction mixture
HCl, aqueous NaHCO , and brine. The organic ethyl acetate
3
layer was dried over Na SO , and filtered. After evaporation
4
2
of the solvent, the residue was washed with methanol to

12166
O. Shimomura et al. / Tetrahedron 61 (2005) 12160–12167
extract the 1,4-bis[4-(vinyl)phenoxy)]butane. The extract
was evaporated and separated by column chromatography
on silica gel to provide the desired compound in 41% yield
under N at 45 8C. The temperature of the reaction mixture
2
was raised to 85 8C and stirring was continued for 20 h. The
suspension was filtered to recover the polymer beads and
washed with hot water. The resin was washed with THF in a
soxhlet extractor for 20 h. The recovered beads 8a were
washed with ether and hexane and dried under vacuum for
24 h. Yield 9.39 g (69%). Sieve separation: 100–200 mesh:
5.03 g, 40–100 mesh: 1.41 g, !40 mesh: 1.54 g. Resins 8b,
1
(
solvent: hexane). H NMR (300 MHz, CDCl ) d 7.33 (d,
3
JZ8.7 Hz, 2H), 6.84 (d, JZ8.7 Hz, 2H), 6.65 (dd, JZ17.4,
1.0 Hz, 1H), 5.60 (dd, JZ17.7, 1.0 Hz, 1H), 5.12 (dd,
JZ10.8, 1.1 Hz, 1H), 3.98 (t, JZ6.0 Hz, 2H), 3.26
t, JZ6.6 Hz, 2H), 1.85–2.08 (m, 4H).
1
(
9
a, and 9b were prepared using a similar procedure.
C NMR (150 MHz, CDCl ) d 26.0–27.0, 30.3, 40.3,
2.0–45.0, 62.6, 70.0–72.0, 125.0–134.0.
1
3
3
4
4
.1.5. Synthesis of macromonomer 4. The monomer
-[4-(vinyl)phenoxy]butyliodide 3 (1.86 g, 6.0 mmol) in
4
THF (25 ml) was added in the solution of silver
hexafluorophosphate (8.99 g, 30 mmol) in THF (250 ml)
at K10 8C. After 1 h, NaOH (1.5 g, 38 mmol) in water
4
.2. Preparation of 10 by suspension polymerization
Resin 10 was prepared using the same procedure as for resin
, but using a higher concentration of NaCl (10%) in water
(
30 ml) was added in the reaction mixture. The generated
8
solid material (AgI) was separated by filtration and
evaporated to ca. 150 ml. Ethyl acetate (200 ml) was
added to the reaction mixture, and ethyl acetate layer was
washed with NH Cl, brine, and dried with MgSO . The
and divinyl benzene as the cross-linker to minimize
problems of emulsion formation.
4
4
organic layer was filtered and evaporated. The residue was
separated by column chromatography on silica gel (hexane/
EtOAc: 95:5 to THF) to obtain 4 in 81% yield. The
polymerization degree of PTHF was nZ17.0 determined by
4
.3. Measurement of swelling volume
Resins (100–200 mesh, 50 mg) were placed in a 1 ml
syringe with filter and 0.8 ml of the desired solvent was
added. The syringe was placed in a shaker for 1 h and the
volume of the resin was measured.
1
H NMR. Macromonomer 4 (nZ34.0) was prepared by a
1
similar procedure. H NMR (300 MHz, CDCl ) d 7.32 (d,
3
JZ8.4 Hz, 2H), 6.84 (d, JZ9.0 Hz, 2H), 6.65 (dd, JZ17.7,
11.0 Hz, 1H), 5.60 (d, JZ17.7 Hz, 1H), 5.11 (d, JZ
12.0 Hz, 1H), 3.98 (t, JZ6.3 Hz, 2H), 3.64 (t, JZ6.0 Hz,
2H), 3.50–3.49 (br), 1.73–1.86 (m, 2H), 1.56–1.70 (br).
4.4. Determination of the loading of 8a,b, 9a,b, and 10
The PTHF resin (100 mg), DIC (100 mL), DMAP (2 mg),
and Fmoc-glycine (300 mg) in anhydrous CH Cl (2 ml)
2
2
4.1.6. Synthesis of macromonomer 6. 4-(5-Hydroxypen-
tyl)styrene 5 was prepared using literature procedure.
was placed in screw-top vial, and shaken at room
temperature for 1 h. The mixture was filtered and washed
three times with CH Cl . The filtrate was returned to a
1
6
A
solution of 5 (490 mg, 2.79 mmol) in CH Cl (10 ml) was
added slowly to a solution of di-tert-butyl pyridine (0.80 g,
2
2
2
2
screw-top vial and the reaction was carried out again. The
mixture was washed three times each with CH Cl , THF,
MeOH, Et O and hexanes. The produced resin was dried in
4
3
.19 mmol) and trifluoromethanesulfonic anhydride (1.04 g,
.69 mmol) at room temperature. The solution was stirred
2
2
2
for 1 h and then cooled to K20 8C. THF (50 ml) was then
added with strong stirring for 10 min. After the reaction,
NaOH (3 g, 75 mmol) was added to the reaction mixture.
The resulting solution was evaporated to 20% of the initial
volume. Water (25 ml) was added to the solution, followed
by three extractions with ethyl acetate. The combined
organic phase was washed with brine (2!25 ml) and dried
vacuo overnight. Approximately 15 mg of each resin was
added into 2 vials and 20% piperidine/DMF (3 ml) was
added to the vial and shaked at room temperature for 1 h. A
1
00 ml aliquot of this solution was diluted to 3 ml with 20%
piperidine/DMF and the UV adsorption at 290 nm
measured.
over MgSO . Evaporation of the solvent afforded the
4
4.5. Preparation of PTHF–grafted 5-hydroxypentyl
JandaJel 13a–f
macromonomer 6 (1.87 g, 93.7% as a typical result) as a
clear viscous oil. Small amounts of the solvent remained in
the product and the material was used without further
purification immediately for resin synthesis (nZ6.9, as
5
-Hydroxypentyl JandaJel 11 (1.00 g, 1.07 mmol OH
1
1
loading) was placed in a cylindrical reaction vessel, with
sintered glass filter and a stopcock at one end and with a
rubber-sealed screw-cap at the other end. The reaction
vessel was charged with argon gas and sealed by closing the
stopcock. The resin was swollen with anhydrous dichloro-
methane (20 ml). 2,5-Di-tert-butylpyridine (0.72 ml,
3.21 mmol) and trifluoromethanesulfonic anhydride
(0.54 ml, 3.21 mmol) were added through syringe in
sequence. The suspension was shaken for 15 min at room
temperature. The solution containing excess reagents was
drained through the sintered glass filter and the resin was
dried by flowing argon gas. The resin was washed three
times with anhydrous dichloromethane (10 ml) and dried by
flowing argon gas for 5 min. THF (15 ml) was then added
calculated by H NMR and ESI). H NMR (500 MHz,
acetone-d ) d 7.59 (d, 2H), 7.35 (d, 2H), 6.70 (dd, 1H), 5.15
6
(
d, 1H), 3.39 (m, 30H), 1.58–1.60 (m, 30H).
4.1.7. Preparation of 8a,b, 9a,b by suspension polymer-
ization. Suspension polymerization was carried out by
2
slight modification of the reported method. A solution of
styrene (6.8 ml, 60 mmol), 2 (6.90 g, 10.3 mmol, nZ7.1),
and 7 (406 mg, 1.4 mmol) in DME (16.1 ml) was heated to
4
5 8C until a homogeneous solution was obtained. The
initiator (benzoyl peroxide, 120 mg) was added to the
organic solution and the solution was added by syringe to
aqueous phase (142 ml prepared by reported method )
2

O. Shimomura et al. / Tetrahedron 61 (2005) 12160–12167
12167
into the reaction vessel via a syringe and the reaction vessel
was shaken for 10–35 min at room temperature. Tetra-n-
References and notes
butylammonium hydroxide (40% in H O, 1 ml) was then
2
1. (a) Chaiken, I. M.; Janda, K. D. Molecular Diversity and
Combinatorial Chemistry; American Chemical Society:
Washington, DC, 1996. (b) Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound
Libraries; Obrecht, D., Villalgordo, J. M., Eds.; Pergamon:
New York, 1998. (c) Bunin, B. A. The Combinatorial Index;
Academic: London, 1998.
added to terminate the living polymerization. After
additional shaking for 1 h, the resulting resin was collected
into a syringe equipped with polypropylene filter and
washed several times with dichloromethane, Et O and
2
n-hexane in sequence, and dried under reduced pressure to
give a series of poly-THF-grafted JandaJel (13a–f).
2
. (a) Toy, P. H.; Janda, K. D. Tetrahedron Lett. 1999, 40,
329–6332. (b) Toy, P. H.; Reger, T. S.; Garibay, P.; Garno,
J. C.; Malikayil, J. A.; Liu, G.; Janda, K. D. J. Comb. Chem.
001, 3, 117–124. (c) JandaJel resins are commercially
6
4.6. Preparation of polyoxetane–grafted 5-hydroxy-
pentyl JandaJel 14
2
available from Aldrich Chemical Co.
. (a) Vaino, A. R.; Janda, K. D. J. Comb. Chem. 2000, 2, 579–596.
The procedure is similar to the preparation of 13a–f, except
a 50/50 mixture of oxetane–dichloromethane (15 ml) was
used instead of 15 mL of THF for grafting the activated
complex.
3
(b) Gambs, C.; Dickerson, T. J.; Mahajan, S.; Pasternack, L. B.;
Janda, K. D. J. Org. Chem. 2003, 68, 3673–3678.
4
5
. Meldal, M. Tetrahedron Lett. 1992, 33, 3077–3080.
. (a) Gooding, O. W.; Baudart, S.; Deegan, T. L.; Heisler, K.;
Labadie, J. F.; Newcomb, W. S.; Porco, J. A.; Eikeren, P.
J. Comb. Chem. 1999, 1, 113–122. (b) Kita, R.; Svec, F.;
Fr e´ chet, J. M. J. J. Comb. Chem. 2001, 3, 564. (c) Bayer, E.
Angew. Chem., Int. Ed. 1991, 30, 113–129.
4
.6.1. Synthesis of 5-methyl-2-phenyl-2,4-dihydro-
2
2
pyrazol-3-one 18. TentaGel (0.32 mmol/g), and PTHF
reins 8b (0.35 mmol/g), 13b (0.67 mmol/g), and 13e
(
0.44 mmol/g)) were swollen in CH Cl (12 ml) and treated
2 2
with DIC (5 equiv), DMAP (1 equiv) and acetic acid
5 equiv). After shaking at room temperature for 3 h, these
resins were filtered, and washed with CH Cl , MeOH and
6
. Li, W.; Yan, B. J. Org.Chem. 1998, 63, 4092–4097.
. Franta, E.; Riebel, L.; Lehmann, J. J. Polym. Sci. 1976, 56,
(
7
2
2
1
39–148.
. Asami, R.; Takai, M. Macromol. Chem. Suppl. 1985, 12,
63–173.
. Asami, R.; Takai, M.; Kyuda, K.; Asakura, E. Polymer J.
983, 2, 139–144.
0. Asami, R.; Takai, M.; Kita, K.; Asakura, E. Polym. Bull. 1980,
, 713–718.
Et O and dried in vacuo. Under argon, 5 equiv of LiHMDS
2
8
9
(
1 M solution in THF, prepared from solid LiHMDS) was
1
slowly added via syringe to a pre-cooled suspension at
K78 8C of acetyl resin in THF, and stirred for 15 min at
K78 8C. Acetyl chloride (5 equiv) was added dropwise, and
the mixture was stirred for 15 min at K78 8C and then
allowed to warm to room temperature. After 3 h, the resin was
filtered, and washed with THF, CH Cl , MeOH and Et O, and
dried in vacuo. These resulting resins were treated with
phenylhydrazine (10 equiv) in THF (4 ml) and trimethyl
orthoformate (4 ml) at 50 8C for 12 h, and filtered, and washed
with THF, CH Cl , MeOH and Et O, and dried under
vacuum. The desired product 18 was obtained by treating
with 2% TFA/acetonitrile (7 ml) at room temperature for
30 min. The resulting filtrate was concentrated under reduced
pressure, and purified by preparative TLC to give 18;
TentaGel (!1 mg, 1%), 8b (15 mg, 48%), 13b (27 mg,
4
1
1
1
1
1
1
2
1. Rempp, P.; Lutz, P.; Masson, P.; Franta, E. Macromol. Chem.
Suppl. 1984, 8, 3–15.
2. Dubreuil, M. F.; Goethals, E. J. Macromol. Chem. Phys. 1997,
2
2
2
1
98, 3077–3087.
3. Burgess, F. J.; Cunliffe, A. V.; Richerds, D. H.; Thompson, D.
Polymer 1978, 19, 334–340.
2
2
2
4. The chain length can be controlled by adjusting the
polymerization time. Use of p-vinylbenzyl chloride instead
of p-vinylbenzyl bromide as a chain initiator resulted in low
reactivity.
1
7%), 13e (16 mg, 42%). H NMR (400 MHz, CDCl ) d 2.13
15. Lorg e´ , F.; Wagner, A.; Mioskowski, C. J. Comb. Chem. 1999,
, 25–27.
3
1
(
s, 3H), 3.37 (s, 2H), 7.13 (t, JZ7.6 Hz, 1H), 7.35 (t, JZ
1
3
16. Lee, S.-H.; Clapham, B.; Koch, G.; Zimmerman, J.; Janda,
K. D. J. Comb. Chem. 2003, 5, 188–196.
8
CDCl ) d 16.9, 17.0, 42.9, 43.0, 43.1, 118.7, 118.8, 125.0,
.0 Hz, 2H), 7.81 (d, JZ7.6 Hz, 2H); C NMR (100 MHz,
3
K1
28.7, 137.9, 156.3, 170.4; FTIR (cm ): 3064, 2924, 2852,
17. Lee, B. S.; Suresh, M.; Clapham, B.; Janda, K. D.
J. Org.Chem. 2004, 69, 3319–3329.
1
C
1
714, 1594, 1561, 1498; MS (ESI) m/zZ175 [MCH] .
1
8. Synthesis of 16 from 15 was modified slightly for the
preparation of ethyl acetoacetate from ethyl acetate. See,
Townsend, C. A.; Christensen, S. B.; Davis, S. G. J. Chem.
Soc., Perkin Trans. 1 1988, 839–861.
Acknowledgements
1
9. Chen, S.; Janda, K. D. J. Am. Chem. Soc. 1997, 119, 8724–8725.
We gratefully acknowledge financial support from The
Skaggs Institute for Chemical Biology and Jason Moss for a
critical reading of the manuscript. We also thank Bruce
Clapham for supplying 5-HPJJ and for critical suggestions
for preparation of the resins.
20. Bamford, C. H.; Lindsay, H. Polymer 1973, 14, 330–332.
21. Sellner, H.; Faber, C.; Rheiner, P. B.; Seebach, D. Chem. Eur.
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