Polystyrene resins containing 1,3-propanedithiol functions for solid-phase organic syntheses

Article abstract of DOI:10.1055/s-2003-38735

A completely odourless reliable synthesis of styrenic resins containing 1,3-propanedithiol functions able to form 1,3-dithiane derivatives with carbonyl compounds and back up the chemistry of thioacetals and thioketals is reported. The degree of functionalisation of the resin can be easily determined through the composition of the copolymerising mixture and confirmed by titration. The resins show good accessibility to various reagents and are effective for solid-phase synthesis being exploitable in the field of combinatorial chemistry.

Full text of DOI:10.1055/s-2003-38735

864
LETTER
Polystyrene Resins Containing 1,3-Propanedithiol Functions for Solid-Phase
Organic Syntheses
1
, 3-Propanedithiol
i
Resins
n
for Solid-P
h
c
ase Synthe
e
ses nzo Bertini,*a Marco Pocci,a Francesco Lucchesini,a Silvana Alfei,a Angela De Munnob
a
Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, Università di Genova, Via Brigata Salerno, 16147 Genova, Italy
b
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
Fax +39(010)3532684; E-mail: bertini@dictfa.unige.it
Received 23 December 2002
Styrene (9 mol)
DVB (2%), BPO (2%),
Abstract: A completely odourless reliable synthesis of styrenic
resins containing 1,3-propanedithiol functions able to form 1,3-
dithiane derivatives with carbonyl compounds and back up the
chemistry of thioacetals and thioketals is reported. The degree of
functionalisation of the resin can be easily determined through the
composition of the copolymerising mixture and confirmed by titra-
tion. The resins show good accessibility to various reagents and are
effective for solid-phase synthesis being exploitable in the field of
combinatorial chemistry.
Benzene/monomers = 1/1 v/w
Water/organic phase = 20/1 v/v
Stabilizers, 80 °C, 7h, 800 rpm
OSO2C6H5
OSO2C6H5
1
1) DMF
Key words: solid-phase synthesis, polymeric dithiols, polymeric
dithianes, umpolung reactions, ketones
2) CH3COSK (2.5 mol)
65 °C, 6h; r.t., 18h
OSO2C6H5
OSO2C6H5
R1
R2
In the continuously expanding field of polymer supported
organic synthesis1–3 the examples of carbon-carbon bond
forming reactions are rapidly growing.4,5 Our contribution
in this area has led to new soluble polystyrene reagents
containing 1,3-propanedithiol functions as odourless pre-
cursors of polymeric 1,3-dithiane systems useful in vari-
ous syntheses through umpolung reactions.6,7 Though the
use of soluble polymeric reagents has some advantages8
allowing reaction conditions of solution chemistry and
easy analysis by NMR of the chemical transformations,
proper solvent/non-solvent couples for the polymer pre-
cipitation are necessary and this can represent a limitation.
In view of general applications, as well as in the field of
combinatorial chemistry, we herein report the completely
odourless synthesis of styrene resins in the form of cross-
linked beads containing 1,3-propanedithiol functions
which ensure easy separation and purification simply by
filtering and washing. The resins prove useful for many
applications, such as synthesis, protection and reduction
of carbonyl compounds and production of difunctional
systems, particularly in automated procedures. In this
communication they are tested in the transformation of
benzaldehyde into ketones and compared with the previ-
ously prepared soluble polymeric reagents.7
1) THF
2) 1 M LAH (4 mol)
SCOCH3
SCOCH3
r.t., 18h
0 °C
SH
SH
R3
Scheme 1
This approach was chosen because 1 can be prepared on a
large scale and easily purified by crystallisation from eth-
anol,6 and the reactions involved in the transformations
R1→R2 and R2→R3 are reported to be almost quantita-
tive in soluble systems.6,7 The copolymerisation of styrene
and 1 was carried out in an aqueous suspension9 formed
by vigorously stirring, in a round-bottom cylindrical
flanged reactor equipped with an anchor type mechanical
stirrer, an excess of aqueous solution of stabilisers with a
solution composed of the monomers, divinylbenzene
(DVB) as cross-linker, dibenzoyl peroxide (BPO) as rad-
ical initiator and benzene as hydrophobic solvent and
porogen. The monomer molar ratio 1/styrene in the copo-
lymerisation feed was nominally 1/9, such a ratio in solu-
ble systems7 having been found fully satisfactory for
general applications. The cross-linker DVB was fixed to
2% by weight of the monomers after observations that
higher concentrations afforded beads of R1 with only
The 1,3-propanedithiol resins R3 were synthesised by co-
polymerising styrene with 2-(4-ethenylphenyl)methyl-
1,3-propanediol bisbenzenesulfonate6 (1) in the presence
of a cross-linker followed by chemical transformation of
the intermediate resins R1 and R2 as shown in Scheme 1.
Synlett 2003, No. 6, Print: 05 05 2003.
Art Id.1437-2096,E;2003,0,06,0864,0866,ftx,en;D29202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
1,3-Propanedithiol Resins for Solid-Phase Syntheses
865
moderate swelling in DMF, the solvent for their transfor- Loadings of the resins R2 were determined readily in CO2
mation into R2. A good swelling of the resins in the sol- free air (where the thiol functions can form disulfide
vents where they are generated or employed is an bridges) by hydrolysis of the thioacetate units with NaOH
important prerequisite of supports for solid-phase synthe- 0.2 N in water/dioxane 1/4 at reflux for 4.5 hours, and ti-
sis.10
tration of the residual base with HCl in presence of phe-
nolphthalein. Controls carried out under nitrogen afforded
similar results, the experimental error being within 1%.
The R2 loading values (Table 1) always resulted in good
agreement with the monomer feed compositions used to
prepare the R1 progenitors, proving that the R1→R2
transformations are practically quantitative and that the
growing radical chain, under the suspension conditions,
has no significant kinetic preference for monomer 1 or
styrene, in analogy to observations in dioxane solution co-
polymerisation.7 The content of SH groups in the resins
R3 determined by iodimetric titration confirmed that the
transformation R2→R3 can be considered quantitative,
so a practical procedure for a supported organic synthesis
can start from a known weight of R2, achieving formation
and utilisation of R3 with stoichiometry based on the de-
termined loading of R2 or on the copolymerisation feed
composition.
As stabilisers three different types of water soluble poly-
mers, such as poly(N-vinylpyrrolidone) (PVP), polyvinyl-
alcohol (PVA) and acacia gum (AG), were employed in
connection with sodium chloride, which was preferred to
calcium salts due to its easier removal from R1 by wash-
ing with water, methanol and acetone, before drying in
vacuo.
The stability of the benzenesulfonate functions during the
preparation of R1 by prolonged heating with water under
the copolymerisation conditions was confirmed in tests
performed either with monomer 1 in the absence of BPO
or with a sample of soluble copolymer 1/styrene. The na-
ture and concentration of the stabiliser significantly af-
fected swelling and shape of the R1 beads, which are
granular with PVP 2.0%, shapeless with PVP 0.2% and
acacia gum 3.3%, and rather regular spheres with PVA
2.0%.
The transformations R1→R2→R3 were in agreement
with the following observed changes of the IR spectra:
complete disappearance of the strong benzenesulfonate
bands at 1365 and 1188 cm–1 and appearance of the strong
carbonyl band at 1695 cm–1 in the conversion R1→R2
and complete disappearance of the band at 1695 cm–1 and
appearance of the weak but evident S-H band at 2560
cm–1 in the conversion R2→R3.
The effectiveness of the resins R3a–d as 1,3-pro-
panedithiol polymeric reagents was tested in the synthesis
of 1-phenyl-1-pentanone (2) and 1-phenyl-1-heptanone
(3) using an excess of substrates according to Scheme 2.
Resins R1 were transformed into R2 by swelling for one
hour in DMF (10 mL/g of resin) and treatment with a so-
lution of potassium thioacetate in DMF (50 mg/mL) at
65 °C for 6 hours, followed by 18 hours of gentle stirring
at room temperature, filtering, washing with DMF, water,
acetone and drying in vacuo to constant weight. Resins R2
were transformed into R3 by swelling for one hour in THF
(15 mL/g of resin) and treatment at 0 °C with a 1 M THF
solution of LAH, followed by 18 hours stirring at room
temperature, washing with deoxygenated HCl 0.83 M in
water/THF 1/5, methanol, THF and drying in vacuo. If not
immediately used the R3 resins can be stored under nitro-
gen for months without decrease of their efficiency. The The resins R4 were washed with CHCl3, THF, aqueous
resins R1 and R2 appear perfectly stable in the air and are K2CO3 (5%), CH3OH, THF, R5 with anhydrous THF
suitable for unlimited storage. The swelling abilities in (when any unreacted butyl lithium could react with the
various solvents and ease of filtration are quite good for added alkyl halide to produce mixtures of electrophiles)
all the R1, R2, R3 samples as well as for the derivatives and R6 with CH3OH.
R4 and R6.
Table 2 compares swelling data in some common solvents
Table 1 lists synthesis data and properties of some repre- of R1d and resins derived from it.
sentative R1 resins, and loading of their derivatives R2.
Table 1 Copolymerisation Dataa and Properties of the Resins R1a–d and Loading of R2a–d
Resin
Stabilisers
Polymer%b NaCl%b
1 In the feed
Yield
%
% Swelling
in DMFd
R2 Loadinge
mmol/gc
mmol/g
R1a
R1b
R1c
R1d
PVP 2.0
PVP 0.2
AG 3.3
2.0
1.3
2.0
2.0
0.6941
0.6964
0.6962
0.6955
85.4
77.9
96.2
80.9
410
220
230
265
R2a
R2b
R2c
R2d
0.788
0.788
0.786
0.784
PVA 2.0
a Nominal feed molar ratio 1/styrene = 1/9, cross-linker 2% DVB by weight of monomers.
b By weight of water.
c Of monomers and cross-linker.
d Calculated from the formula 100(Vs-Vd)/Vd where Vs and Vd are the volumes of the swollen and dry resin, respectively.
e Determined by acidimetric titration of the alkali hydrolysed thioacetate units.
Synlett 2003, No. 6, 864–866 ISSN 0936-5214 © Thieme Stuttgart · New York

866
V. Bertini et al.
LETTER
Table 3 Synthesis of the Ketones 2 and 3 from Weighed R2 Using
Excess of Benzaldehyde and Alkyl Halides RBr
1) CHCl3 1 h
R2
BTA units mmol
0.3416
R
Ketone Yield%a
2) PhCH=O (3.5 mol)
SH
SH
.
R2a
R2b
R2c
R2d
R2a
R2b
R2c
R2d
Butyl
Butyl
Butyl
Butyl
Hexyl
Hexyl
Hexyl
Hexyl
2
2
2
2
3
3
3
3
80
79
89
91
93
88
77
76
BF3·Et2O (1mol)
r.t., 2 h
R3
0.3792
0.3389
0.3390
1) THF 1h
2) 1.67 N BuLi (3 mol)
–30 °C, 4 h
0.3341
S
Ph
0.3655
R4
S
H
0.3337
0.3315
3) RBr (5 mol)
a Referred to the moles of BTA units.
–30 °C
r.t., 18 h
S
Ph
R5
S
Li
Acknowledgement
This work was financially supported by MIUR (Programmi di
Ricerca di Rilevante Interesse Nazionale 2002) and University
Funds.
1) THF 1h
2) H5IO6 (3 mol)
S
S
r.t., 3 h
0 °C
References
Ph
R6
R
(1) Brown, R. C. D. J. Chem. Soc., Perkin Trans. 1 1998, 3293.
(2) Blackburn, C. Biopolymers 1998, 47, 311.
(3) Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000, 100,
2091.
O
2 (R = butyl)
3 (R = hexyl)
Ph
R
(4) Lorsbach, B. A.; Kurth, M. J. Chem. Rev. 1999, 99, 1549.
(5) Sammelson, R. E.; Kurth, M. J. Chem. Rev. 2001, 101, 137.
(6) Bertini, V.; Lucchesini, F.; Pocci, M.; De Munno, A.
Tetrahedron Lett. 1998, 39, 9263.
(7) Bertini, V.; Lucchesini, F.; Pocci, M.; De Munno, A. J. Org.
Chem. 2000, 65, 4839.
(8) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489.
(9) Arshady, R.; Ledwith, A. React. Polymer 1983, 1, 159.
(10) Andrew, R. V.; Janda, K. D. J. Comb. Chem. 2000, 2, 579.
(11) (a) The Aldrich Library of FT-IR Spectra, Vol. 2; Pouchert,
C. J., Ed.; Aldrich Chemical Company: USA, 1985, 9C.
(b) Taber, D. F.; Amedio, J. C. Jr.; Yung, K. Y. J. Org.
Chem. 1987, 52, 5621.
Scheme 2
The crude ketones 2 and 3 in presence of the residual resin
were treated with aqueous Na2SO3 (10%), filtered, ex-
tracted with Et2O, dried with anhydrous Na2SO4, evapo-
rated in vacuo and verified by IR11a,b and GC-MS.12a,b
The preparations of 2 and 3 afforded samples in high pu-
rity and yield (Table 3), based on the loading of 2-(4-ethe-
nylphenyl)methyl-1,3-propanediol bisthioacetate (BTA)
units. The conversions are comparable with those based
on reaction of the same aldehydes with excess of soluble
1,3-propanedithiol polymers.7 This indicates good acces-
sibility of the various reagents to the dithiol functions in-
side the resin.
(12) John Wiley MS Library, 7th Edition, (a) ID: 485116;
(b) ID: 551046.
Table 2 Swelling Data in Various Solvents of R1d–R4d and R6d/Bu
Resin
% Swellinga
Hexane
Toluene
95
CHCl3
170
CH2Cl2
100
THF
40
Dioxane
140
DMF
265
200
65
R1d
0
0
0
0
0
R2d
190
365
360
345
120
300
250
315
R3d
200
310
200
110
R4d
285
700
345
240
115
275
R6d/Bu
255
225
305
185
a Calculated from the formula 100(Vs-Vd)/Vd where Vs and Vd are the volumes of the swollen and dry resin, respectively.
Synlett 2003, No. 6, 864–866 ISSN 0936-5214 © Thieme Stuttgart · New York