Preparation of soluble polymeric supports with a functional group for liquid-phase organic synthesis

Article abstract of DOI:10.1055/s-2002-19762

Soluble copolymers of styrene with functional groups were prepared by radical co-polymerization of styrene with various substituted styrenes. They were characterized by NMR spectroscopy and their molecular weight was determined by size exclusion chromatography.

Full text of DOI:10.1055/s-2002-19762

316
LETTER
Preparation of Soluble Polymeric Supports with a Functional Group for
Liquid-Phase Organic Synthesis
Preparation of
f
unc
a
tionalized
r
Polymer
i
ic Supp
n
orts
G
roup f
e
or Liquid-Phase
O
M
rganic
S
ynthesis alagu,a Philippe Guérin,b Jean-Claude Guillemin*a
a
Laboratoire de Synthèses et Activations de Biomolécules, UMR CNRS 6052, ENSCR, Avenue du Général Leclerc, 35700 Rennes,
France
b
Laboratoire de Recherche sur les Polymères, UMR CNRS 7581, 2-8, rue Henri Dunant, 94320 Thiais, France
Fax +33(223)238108; E-mail: jean-claude.guillemin@ensc-rennes.fr
Received 8 October 2001
Abstract: Soluble copolymers of styrene with functional groups
were prepared by radical co-polymerization of styrene with various
substituted styrenes. They were characterized by NMR spectrosco-
py and their molecular weight was determined by size exclusion
chromatography.
Key words: polymerization, soluble copolymer, polystyrene, func-
tional group
The use of solid polymeric supports, dedicated to organic
synthesis, affords the advantage of a simplified purifica-
tion of the products, based on the facile separation of the
support from the reaction mixture. However, the broadly
employed solid polystyrene beads, initially developed by
Merrifield,1 have shown some limitations. Consequently,
some attempts to develop alternatives to these resins have
recently been made. Particularly, polymers with higher
loading, specific solubility,2 swelling properties,3 or in-
creased chemical and mechanical stability4 have been
used. Thus, Janda et al. have shown that soluble supports
were readily applicable to small organic molecule synthe-
sis in liquid-phase methodology.5,6 The use of soluble
polymeric supports affords the application of homoge-
neous reaction conditions, as well as the product charac-
terization by routine analytical methods. These soluble
supports have proven to be convenient polymeric materi-
als for applications dealing with supported reagents7 and
catalysts.8 Such copolymers are easily prepared by radical
polymerization (Scheme 1) and with glassware usually
used for organic synthesis. The analysis of polymers by
routine NMR spectroscopy is easily performed in various
deuterated solvents. However, these polymers can present
the disadvantages of reticulation in some experimental
conditions and consequently lose their specific physical
properties. So, they are mainly useful in quite short se-
quences, usually of less than six steps.5,6
Scheme 1
corresponds to an economy of several steps. However,
such an approach is only interesting when a variety of
monomer can be used in the polymerization step without
reticulation of the polymer or lose of the functional
groups. We report here the preparation of copolymers of
styrene with substituted styrenes bearing one or two func-
tional groups and show the compatibility of the functional
groups with the co-polymerization reaction.
Preparation of the monomers.
Various functional groups can be easily introduced onto a
styrene, by some well-known organic reactions. Accord-
ing to the literature, 4-vinylbenzylalcohol,9 4-vinylbenzy-
lamine,10 but-3-enyl-4-vinylbenzene,11 4-vinylbenzoic
acid,12 the styrenic monomer bearing the Wang linker13
and isopropyl 4-styrenesulfonate14 have been prepared as
reported. 4-Vinylbenzyl azide 2 has been synthesized by
nucleophilic substitution of 4-vinylbenzylchloride with
sodium azide, in dimethylsulfoxide, at 80 °C.15 From p-
styrenesulfonylchloride,16 allylamine and and triethyl-
amine in dichloromethane, the sulfonamide 3 has been
prepared,17 then converted to the sulfonamide 4 with pro-
pargyl bromide in the presence of cesium carbonate
(Scheme 2).18
Although several co-polymerizations with amino group
substituents have been reported,8 most of the work was fo-
calized on the modification of the polystyrene bearing a
chloromethyl substituent. The co-polymerization of sty-
rene with a monomer bearing the desired functionality
Preparation of copolymers
To study the co-polymerization of styrene with substitut-
ed styrenes, we used the experimental conditions reported
by Janda et al.5 in the preparation of copolymer 1. For
most experiments, the reactions were performed with 33
equiv. of styrene and 1 equiv. of the substituted styrene
and were carried out twice in order to evaluate the repro-
ducibility of the molecular weight, the loading and the
chemical yield.19 The radical co-polymerization of mono-
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0316,0318,ftx,en;G30801ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Preparation of Functionalized Polymeric Supports for Liquid-Phase Organic Synthesis
317
Table Preparation of Copolymers 1, 5–13
Sample
Mw (D)a
I = Mw/Mn Loading
(mmol/g)
Yield
(%)
52
52
40
37
25
44
35
20
55
49
1
5
39000
47000
33300
19000
29000
35000
45000
45000
40000
44000
1.4
2.1
1.6
1.4
1.6
1.5
1.5
1.1
2.0
1.5
0.32b
0.24b
0.18b
0.30b
0.28b
0.50c
0.37b
1.1c
6
7
8
9
10
11
12
13
0.32b
0.32b
a SEC determination in THF.
b Ratio 33.
c Ratio 10.
Scheme 2
to design the requisite monomer with much more synthet-
ic tools than those afforded by the subsequent chemical
modification of polystyrene 1.
mer with substituted styrenes has been achieved success-
fully in all the cases, even in the presence of other
unsaturations (Scheme 3). Copolymers 5–13 are readily
Acknowledgement
soluble in most of commonly used organic solvents, and We are grateful to Synthelabo-Sanofi for financial support and to
Drs Jean-Bernard Ducep and Luc Van Hifte for helpful suggestions.
easily recovered by precipitation in methanol. Molecular
weights have been determined by size exclusion chroma-
tography (SEC) (Table).
References
Apart from the sample containing a primary amine 7, the
average molecular weight of the synthesized copolymers
(2) (a) Bergbreiter, D. E.; Case, B. L.; Liu, Y.-S.; Caraway, J.
(1) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
is in the same range as the molecular weight of the refer-
ence sample 1. The polydispersity is good for most of the
samples (1, 6–11, 13). The yields range between 20% and
55% and, in most cases, the loading is not dependent on
the nature of the functional group.
W. Macromolecules 1998, 31, 6053. (b) Gravert, D. J.;
Datta, A.; Wentworth, P. Jr.; Janda, K. D. J. Am. Chem. Soc.
1998, 120, 9481.
(3) (a) Buchardt, J.; Meldal, M. Tetrahedron Lett. 1998, 39,
8695. (b) Toy, P. H.; Janda, K. D. Tetrahedron Lett. 1999,
40, 6329.
(4) Liu, S.; Akhtar, M.; Gani, D. Tetrahedron Lett. 2000, 41,
4493.
(5) Chen, S.; Janda, K. D. J. Am. Chem. Soc. 1997, 119, 8724.
(6) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489.
(7) (a) Bertini, V.; Lucchesini, F.; Pocci, M.; De Munno, A.
Tetrahedron Lett. 1998, 39, 9263. (b) Enholm, E. J.;
Gallagher, M. E.; Moran, K. M.; Lombardi, J. S.; Schulte, J.
P. Org. Lett. 1999, 1, 689. (c) Toy, P. H.; Reger, T. S.;
Janda, K. D. Org. Lett. 2000, 2, 2205.
(8) Giffels, G.; Beliczey, J.; Felder, M.; Kragl, U. Tetrahedron:
Asymmetry 1998, 9, 691.
(9) Letsinger, R. L.; Kornet, M. J.; Mahadevan, V.; Jerina, D. M.
J. Am. Chem. Soc. 1964, 86, 5163.
Scheme 3 1: X = CH2Cl, 5: X = CH2OH, 6: X = CH2N3, 7: X =
CH2NH2, 8: X = CH2OpC6H4CH2OH, 9: X = (CH2)2CH=CH2, 10: X
= CO2H, 11: X = SO3 Pr, 12: X = SO2N(H)CH2CH=CH2, 13: X =
i
SO2N(CH2CH=CH2)-(CH2C CH)
The radical co-polymerization reaction conditions are
thus compatible with various functional groups. Alcohol,
carboxylic acid, azide, alkene or sulfonamide groups can
be incorporated into the macromolecular chain as pendant
groups during the step of co-polymerization. Such prep-
arations of various functionalized soluble supports enable
(10) Itsuno, S.; Koisumi, T.; Okumura, C.; Ito, K. Synthesis 1995,
2, 150.
(11) Greber, E. Makromol. Chem. 1962, 54, 119.
(12) Dalton, A. I.; Tidwell, T. T. J. Polym. Sci. Polym. Chem. Ed.
1974, 12, 2957.
(13) Wang, S.-S. J. Am. Chem. Soc. 1973, 95, 1328.
Synlett 2002, No. 2, 316–318 ISSN 0936-5214 © Thieme Stuttgart · New York

318
K. Malagu et al.
LETTER
(14) Shirai, M.; Nakanishi, J.; Tsunooka, M.; Matsuo, T.; Endo,
M. J. Photopolymer Sci. Techn. 1998, 4, 641.
and then dried with magnesium sulfate. After evaporation of
the solvent, the residue was purified by chromatography on
silica gel (CH2Cl2). The monomer 4 was obtained as a
colorless oil (123 mg, Yield 92%). 1H NMR (CDCl3): 7.84
(d, 2 H, J = 8.3, Ar-H); 7.53 (d, 2 H, J = 8.3, Ar-H); 6.76 (dd,
1 H, J = 10.9, 17.6, (Ar)-CH=CH2); 5.88 (d, 1 H, J = 17.6,
(Ar)-CH=CH2); 5.74 (ddt, 1 H, J = 17.3, 10.2, 5.6,
CH=CH2); 5.44 (d, 1 H, J = 10.9, (Ar)-CH=CH2); 5.29 (d, 1
H, J = 17.3, CH=CH2); 5.07 (d, 1 H, J = 10.2, CH=CH2);
4.05 (d, 2 H, J = 2.6, CH2-CCH); 3.60 (d, 2 H, J = 5.6, CH2);
1.63 (t, 1 H, J = 2.6, CCH).
(15) 4-Vinylbenzyl Azide 2: A mixture of 2 g (13 mmol) of 4-
vinylbenzylchloride, 1.7 g (26 mmol) of sodium azide and
0.2 g (1.3 mmol) of sodium iodide in 25 mL of DMSO was
stirred at 80 °C for 15 h, cooled, and treated with 25 mL of
water and 75 mL of ether. The organic phase was separated,
washed with water and then dried with magnesium sulfate.
Yield 90%. 1H NMR (CDCl3): 7.41 (d, 2 H, J = 8.1, Ar-H);
7.25 (d, 2 H, J = 8.1, Ar-H); 6.71 (dd, 1 H, J = 10.7, 17.8,
CH=C); 5.75 (d, 1 H, J = 17.8, C=CH2); 5.25 (d, 1 H, J =
10.7, C=CH2); 4.29 (s, 2 H, CH2N3). 13C NMR (CDCl3):
138.3, 136.9, 135.4, 129.1, 127.3, 115.1, 55.2.
(16) Kamogawa, H.; Kanzawa, A.; Kadoya, M.; Naito, T.;
Nanazawa, M. Bull. Chem. Soc. Jpn. 1983, 56, 762.
(17) Sulfonamide 3: Allylamine (1.1 mL, 14.2 mmol) was added
to a solution of p-styrene-sulfonylchloride (1.44 g, 7.11
mmol) in a solution of dichloromethane–triethylamine (13
mL, 10:3). The mixture was stirred for 15 h at room
temperature, and then acidified by a 0.25 N aqueous HCl
solution (10 mL). The organic products were extracted with
ethyl acetate (3 20 mL). The combined organic layers were
washed with brine and dried with magnesium sulfate. After
evaporation of the solvent, the residue was purified by
chromatography on silica gel (CH2Cl2). The monomer was
isolated as a colorless oil (1.25 g, Yield 79%). 1H NMR
(CDCl3): 7.83 (d, 2 H, J = 8.4, Ar-H); 7.52 (d, 2 H, J = 8.4,
Ar-H); 6.75 (dd, 1 H, J = 10.9, 17.5, (Ar)-CH=C); 5.88 (d, 1
H, J = 17.5, (Ar)-C=CH2); 5.72 (m, 1 H, J = 17.3, 10.2, 5.6,
CH=CH2); 5.42 (d, 1 H, J = 10.9, (Ar)-CH=CH2); 5.16 (d, 1
H, J = 17.3, CH=CH2); 5.07 (d, 1 H, J = 10.2, CH=CH2);
4.83 (s, 1 H, NH); 3.60 (m, 2 H, CH2). 13C NMR (CDCl3):
142.4, 139.3, 135.9, 133.5, 128.1, 127.4, 118.3, 118.0, 46.3.
(18) Sulfonamide 4: A 80% w/w solution of propargyl bromide
(97 mg, 0.65 mmol) in toluene was added to a mixture of
allyl p-styrenesulfonamide (120 mg, 0.48 mmol) and cesium
carbonate (213 mg, 0.65 mmol) in DMF (1.2 mL). The
mixture was stirred for 15 h at room temperature, then 9 mL
of ethyl acetate was added. The mixture was washed with a
saturated ammonium chloride aqueous solution and the
organic products were extracted with ethyl acetate (3 10
mL). The combined organic layers were washed with brine
(19) General Procedure for the Preparation of Copolymers
5–13: AIBN (11.6 mg, 0.07 mmol) was added to a solution
of styrene (1.43 g, 13.8 mmol) and monomer (0.42 mmol) in
toluene (5.3 mL), and the mixture was stirred for 40 h at 70
°C under inert atmosphere. After evaporation of the solvent,
dichloromethane (4.5 mL) was added to the residue and the
solution was dropped into methanol (23 mL) with strong
stirring, at room temperature, to precipitate the polymer. The
resulting suspension was filtered, washed with methanol and
dried under vacuum.
Copolymers 5–13. Selected data. For all the copolymers 5–
13: 1H NMR (CDCl3): 7.3–6.2 (brd signal, Ar-H PS); 2.2–
1.2 (brd signal, -CH-CH2- PS). 13C NMR (CDCl3): 147.0–
145.0, 129.1–126.0, 47.0–40.5. 5: 1H NMR (CDCl3): 4.60
(s, 2 H, CH2O). 13C NMR (CDCl3): 66.0 (CH2OH). 6: 1H
NMR (CDCl3): 4.21 (s, 2 H, CH2N3). 13C NMR (CDCl3):
133.1, 55.2. 7: 1H NMR (CDCl3): 3.74 (s, 2 H, CH2NH2).
8: 1H NMR (CDCl3): 4.97 (s, 2 H, CH2O); 4.61 (s, 2 H,
CH2OH). 13C NMR (CDCl3): 159.2, 134.6, 133.9, 129.7,
115.5, 70.6, 65.6. 9:1H NMR (CDCl3): 5.89 (brd s, 1 H,
CH=CH2); 5.02 (brd s, 2 H, CH=CH2); 2.65 (s, 2 H, Ph-
CH2), 2.35 (brd s, 2 H, CH2-CH=CH2). 13C NMR (CDCl3):
139.0, 115.4, 36.3, 35.7. 11: 1H NMR (CDCl3): 7.52 (brd
s, 2 H, Ar-H); 4.65 (brd s, 1 H, CH); 2.2-1.2 (CH3). 12: 1H
NMR (CDCl3): 7.54 (brd s, 2 H, Ar-H); 5.71 (brd s, 1 H,
CH=CH2); 5.14 (m, 2 H, CH=CH2); 3.52 (brd s, 2 H, CH2-
CH=C). 13: 1H NMR (CDCl3): 7.46 (brd s, 2 H, Ar-H);
5.72 (brd s, 1 H, CH=CH2); 5.28 (m, 2 H, CH=CH2); 4.03
(brd s, 2 H, CH2-CCH); 3.78 (brd s, 2 H, CH2-CH=CH2);
2.2-1.2 (-C CH). 13C NMR (CDCl3): 136.4, 132.5, 120.7,
78.7, 74.4, 49.6, 36.4.
Synlett 2002, No. 2, 316–318 ISSN 0936-5214 © Thieme Stuttgart · New York