2-Polystyrylsulfonyl ethanol supports for the solid-phase syntheses of hydantoins and ureas

Article abstract of DOI:10.1016/S0040-4039(01)00057-0

Reaction of sodium polystyrylsulfinate 1 with 2-chloroethanol gave the 2-arylsulfonyl ethanol resin 2, which was converted to the polymer-supported amine 5. Amine 5 was coupled with an isocyanate or an isothiocyanate to give the polymer-supported urea der

Full text of DOI:10.1016/S0040-4039(01)00057-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1973–1974
2-Polystyrylsulfonyl ethanol supports for the solid-phase
syntheses of hydantoins and ureas
Wenqiang Huang,* Shaoling Cheng and Weimin Sun
The State Key Laboratory of Functional Polymer Materials for Adsorption and Separation, Institute of Polymer Chemistry,
Nankai University, Tianjin 300071, PR China
Received 9 November 2000; revised 3 January 2001; accepted 10 January 2001
Abstract—Reaction of sodium polystyrylsulfinate 1 with 2-chloroethanol gave the 2-arylsulfonyl ethanol resin 2, which was
converted to the polymer-supported amine 5. Amine 5 was coupled with an isocyanate or an isothiocyanate to give the
polymer-supported urea derivatives 6. Treatment of the resin 6 with 6N HCl gave hydantoins 7, while reaction of the same resin
with 4N NaOH then HCl gave the urea derivatives 8. © 2001 Elsevier Science Ltd. All rights reserved.
Efforts have been made towards the discovery of novel
tethers for connecting hydroxyl groups to polymer sup-
ports and the materials obtained are useful for deriva-
tization to ether and ester resins.1–6 Hydroxyl groups
can be attached directly to polymers via ‘unfunctional-
ized’ tethers and examples are the Wang resin,2 Sasrin
resin,3 and Rink acid resin.4 Alternatively, tethers with
functional groups can be inserted between hydroxyl
groups and supports, and these functional groups offer
an additional handle for releasing the desired molecules
from the polymers. For example, 2-polystyrylsulfonyl
ethanol 2 has been used in the solid-phase synthesis of
oligonucleotides.5 Bramdstetter and co-workers have
explored the use of a polystyrene-supported b-hydroxy-
lethylene thioether, which can be released by thioether
oxidation and alkaline treatment. Tesser and co-work-
ers prepared 2-polystyrylmethylenesulfonylethanol resin
by the reaction of the Merrifield resin with thioethanol
followed by the oxidization with MCPBA.6 We report
an efficient method for the synthesis of 2 by the direct
coupling of 2-chloroethanol with resin 1.7 The resin 2
can easily couple with carboxylic acids to form ester
linkages, which can be cleaved by using both aqueous
basic and acidic conditions.
2-Polystyrylsulfonylethanol 2 was prepared by treat-
ment of polystyrylsulfinate resin 1 with 2-chloroethanol
in DMF in the presence of tetrabutylammonium iodide
and potassium iodide.8 The efficiency of hydroxyl
group attachment on the resin was 1.59 mmol/g, which
was determined by using 3,5-dinitrobenzoyl chloride.
Reaction of 2 with Boc-protected glycine under general
DCC/DMAP coupling conditions gave resin 3,9 which
was converted to 4 by the treatment with 6N hydro-
* Corresponding author. E-mail: wenqhuang@hotmail.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00057-0

1974
W. Huang et al. / Tetrahedron Letters 42 (2001) 1973–1974
Table 1. The results of solid-phase synthesis of (thio)hydantoins and (thio)urea from 6
Compound
Mp (°C)a
Elemental analysis (%)
Yield (%)b
Found
Calc.
C
H
N
C
H
N
7a
7b
8a
8b
158–158.5 (154–156)
196–197 (195–196)
247–250 (dec.) (245–248 (dec.))
140–141 (141)
61.2
55.1
55.7
51.0
4.62
5.02
4.20
4.98
15.5
13.8
14.6
12.3
61.4
55.7
56.2
51.4
4.54
5.15
4.17
4.76
15.9
14.4
14.6
13.3
29
20
30
21
a Literature melting point in parentheses.
b Isolated overall yield.
chloric acid in dioxane. The ester group in 4 appears to
survive under these conditions probably due to the
formation of ammonium salts. The resin obtained was
treated with benzoyl chloride/pyridine in DCM to mask
the uncoupled hydroxyl groups.
4. Rink, H. Tetrahedron Lett. 1987, 28, 3787.
5. Bramdstetter, F.; Schott, H.; Bayer, E. Tetrahedron Lett.
1970, 35, 867.
6. Tesser, G. I.; Buis, J. T. A. R. M.; Wolters, E. T. M.;
Bothe-Helmes, E. G. A. M. Tetrahedron 1976, 32, 1069.
7. Resin 1, which is available from Hecheng Co. of Nankai
University, PRC, has the following properties: 1% DVB
cross-linked, 1.88 mmol SO2Na/g.
8. Resin 1 (5 g) was suspended in a mixture of DMF (10
mL) and THF (20 mL) for 30 min with mechanical
stirring. To the suspension were added 2-chloroethanol (6
mL), tetrabutylammonium iodide (0.8 g), and potassium
iodide (4.4 g). The mixture was refluxed at 90°C under an
N2 atmosphere for 48 h. After filtration, the resin was
washed sequentially with DMF, H2O, EtOH, acetone,
DCM, and Et2O, and then dried under reduce pressure
over P2O5 at 40°C.
9. Resin 2 (0.50 g) was swelled in DMF (5 mL) for 30 min.
To the resulting suspension were added Boc-Gly (0.35 g),
DCC (0.41 g) and DMAP (0.245 g). The mixture was
mechanically shaken at 30°C for 4 h. The resin was
filtered out and washed twice in succession with DMF,
EtOH, DCM, and Et2O, and then dried over P2O5 at
40°C overnight.
10. To urea resin 6a (0.50 g) was added HCl (6N) in dioxane
(5 mL). After the suspension was stirred at 80°C for 6 h,
the resin was filtered out and washed three times with
methanol. The combined aqueous and organic phases
were neutralized with sodium carbonate and then evapo-
rated to dryness. The residue was dissolved in DCM.
After removal of insoluble materials, the solvent was
evaporated to give a crude product. 3-Phenylhydantoin
(white needles) can be obtained by recrystallization from
water.
Resin 5 was obtained by neutralization of 4 with Et3N
in DCM, the amount of triethylamine (<2 equiv.) being
minimized to reduce alcohol elimination. The corre-
sponding vinyl sulfone resin was obtained from resin 5.
Polymer-supported urea 6a was prepared by the treat-
ment of 5 in DMF with phenyl isocyanate (5 equiv.,
based on the loading of amine) under a nitrogen atmo-
sphere at room temperature for 8 h. Reaction of 5 with
phenyl isothiocyanate required an elevated temperature
(90°C) to give polymer-supported thiourea 6b. Direct
treatment of compounds 6a and b with 6N aqueous
hydrochloric acid in dioxane released the corresponding
hydantoin 7a and thiohydantoin 7b, respectively.10 Base
treatment (4N NaOH in dioxane) of the same polymer
resin 6a or b produced compounds 8a or b after acid
neutralization.11 The results are summarized in Table 1.
To summarize, 2-polystyrylsulfonylethanol resin 2 can
be easily prepared by an SN2 displacement of 2-
chloroethanol with sulfinic acid resin 1. This resin is
useful for its conversion to the urea 6, which can release
both 7 and 8 using simple acidic and basic reagents.
Acknowledgements
This project was supported financially by NNSFC
(2960415).
11. To urea resin 6a (0.50 g) was added a mixture of NaOH
(4N), dioxane, and methanol (v/v/v=1:30:9, 5 mL). The
suspension was mechanically shaken at room temperature
for 15 min. Resin materials were filtered out and washed
several times with methanol. The combined aqueous and
organic phases were neutralized with aqueous HCl, and
then evaporated to dryness. The residue was dissolved in
methanol. The filtered organic phase was dried to give 8a,
which can be recrystallized from water.
References
1. For a review, see: Blackburn, C. Biopolymers 1998, 47,
311.
2. Wang, S. S. J. Am. Chem. Soc. 1973, 95, 1328.
3. Mergler, M.; Tanner, R.; Gosteli, J.; Grogg, P. Tetra-
hedron Lett. 1998, 20, 4005.
.