Preparation of a novel polystyrene-based urea resin

Article abstract of DOI:10.1016/j.tetlet.2005.02.029

A urea-functionalized polystyrene-resin with a Rink linker was prepared by adaptation of a solution-phase synthesis to solid-phase chemistry. Thereby, a resin-bound acylurea was formed by reacting a Rink-amide resin with trichloroacetyl isocyanate, followed by the thermal removal of the trichloroacetyl group and thus generating the unsubstituted solid-supported urea.

Full text of DOI:10.1016/j.tetlet.2005.02.029

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2231–2233
Preparation of a novel polystyrene-based urea resin
Manuela Meusel and Michael Gutschow*
¨
Pharmaceutical Institute Poppelsdorf, University of Bonn, D-53115 Bonn, Germany
Received 22 July 2004; revised 31 January 2005; accepted 4 February 2005
Abstract—A urea-functionalized polystyrene-resin with a Rink linker was prepared by adaptation of a solution-phase synthesis to
solid-phase chemistry. Thereby, a resin-bound acylurea was formed by reacting a Rink-amide resin with trichloroacetyl isocyanate,
followed by the thermal removal of the trichloroacetyl group and thus generating the unsubstituted solid-supported urea.
Ó 2005 Elsevier Ltd. All rights reserved.
Solid-phase organic synthesis (SPOS) has revolutionized
organic synthesis in the past decade. Successful solid-
phase chemistry requires careful selection of the solid
support, the linker technology and the solvents em-
ployed. During our efforts toward the solid-phase syn-
thesis of nitrogen-containing heterocycles, there was a
pressing need for a resin-bound unsubstituted urea.
Ureas have been important reagents and building blocks
in numerous syntheses of mono- and bicyclic azahetero-
cycles,1 for example, 2-azetidinones,2 3,1-benzoxazin-
4-ones,3 barbituric acids,4 and hydantoins.5 Herein, we
describe the preparation of a polystyrene (PS)-based
urea resin as a valuable material to be used in SPOS.
ammonia (Scheme 1). We performed the reaction con-
trol via IR spectroscopy by observing the disappearance
of the NCO signal at 2250 cmꢀ1. However, the concept
of these scavenger resins includes that they should perma-
nently catch excess electrophilic (e.g., bromomethylcar-
bonyl compounds7) or nucleophilic reagents (e.g.,
amines8) in solution reactions, and are therefore not
designed to release the formed products. Thus, neither
urea 3 could be released from the resin 2, nor any prod-
ucts that might be generated from 2 by SPOS.
It was our primary objective to provide a resin contain-
ing a urea moiety connected to a suitable linker for
cleavage of intermediates and products. We therefore
chose the frequently used Rink linker, which is easy-
to-handle, stable under non-acidic conditions and
moderately priced. In order to explore this strategy, a
solution synthesis applicable to the polymer support
was developed. Mimicking the Rink amide backbone,
the benzhydryl group was selected. The idea was to pre-
pare a N-acyl-N0-benzhydrylurea, where the acyl func-
tionality should be cleaved by nucleophilic attack in
the following step. Benzhydrylamine 4 was reacted with
A methylthiourea PS-resin and methyliso(thio)cyanate
PS-resins are commercially available as nucleophilic
and electrophilic scavengers, respectively. Bra¨se and
Dahmen described some resin-bound ureas, all of them
being terminally substituted.6 To the best of our knowl-
edge, there are no reports on the existence of a termi-
nally unsubstituted urea moiety. Such a resin could
easily be synthesized, when starting from the mentioned
methylisocyanate resin and treating it with gaseous
no
cleavage
a
H
N
PS
PS
H2N
NH2
N C O
NH2
1
O
O
2
3
PS
= polystyrene resin
Scheme 1. Reagents and conditions: (a) excess gaseous ammonia, dry dichloromethane, 1 h, rt.
Keywords: Solid-phase synthesis; Urea resin; Rink linker; Trichloroacetyl isocyanate.
*
Corresponding author. Tel.: +49 228 73 2317; fax: +49 228 73 2567; e-mail: guetschow@uni-bonn.de
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.029

2232
M. Meusel, M. Gu¨tschow/ Tetrahedron Letters 46 (2005) 2231–2233
H
N
H
N
a
O
O
5
H
c
N
NH2
NH2
O
Cl
H
N
H
N
Cl
Cl
4
7
b
O
O
6
Scheme 2. Reagents and conditions: (a) PhCONCO (1.5 equiv), dry THF, 24 h, rt; (b) CCl3CONCO (1.5 equiv), dry THF, 24 h, rt; (c) MeOH, 16 h,
reflux.
benzoyl- and trichloroacetyl isocyanate in dry THF for
24 h at room temperature (Scheme 2). Heating the prod-
uct 6 in methanol9 for 16 h generated the desired benz-
hydrylurea 710 in 63% yield after purification by
column chromatography,14 whereas N-benzhydryl-N0-
benzoylurea 5 did not react similarly. It could be con-
cluded that the benzoyl compound 5 would require
much stronger conditions to form 7.
three different NH signals at 7.28, 7.52 and 10.99 ppm.
As known from the literature data,13 the first two sig-
nals, belonging to the NH2 group, nearly coalesce, due
to the formation of an intramolecular hydrogen bond
in 12 (Fig. 1).
To obtain the urea resin 11 (Scheme 3), the trichloroace-
tyl group had to be removed. This could be managed by
refluxing the resin 10 for 48 h in a mixture of equal por-
tions of methanol and dioxane containing 0.1% water.
In contrast to the solution reaction, the addition of diox-
ane as a solvent, which causes good swelling of the PS-
resin, was necessary when applying that method to solid
phase. Indeed, urea itself was finally detached from the
resin 11. The solid (yield of crude product: 94%)11 was
identified as urea 3 (purity: 56%)15 and the structure
With a sound solution-phase strategy in hand, we now
extended our methodology to polymer supported syn-
thesis. Fmoc-protected Rink-amide resin 8 (Scheme 3)
was deprotected with 20% piperidine in DMF and
washed. Fmoc removal was indicated by a positive
TNBS- (trinitrobenzol sulfonic acid) or Kaiser test.
The resin 9 was reacted with trichloroacetyl isocyanate
as described above for the solution reaction to generate
the resin-bound trichloroacetylurea 10. The TNBS and
Kaiser test performed after the washing procedure were
negative if the reaction was complete. For reaction con-
trol, the product could then be cleaved from the solid
support under standard TFA conditions. Best yields re-
sulted when 5% TFA in dichloromethane was applied, in
comparison to 10% or 20% TFA. After evaporation of
the solvent, trichloroacetylurea 12 was obtained in good
yield (72%)11 and excellent purity (96%).12
1
13
was confirmed by means of H, C NMR and EIMS.14
In summary, an urea-functionalized PS-resin with a
Rink linker was prepared by adaptation of a solution-
phase synthesis to solid phase. Thereby, trichloroacetyl
isocyanate was used to generate a resin-bound acylurea,
Cl
H
N
Cl
Cl
O
H
O
N
H
Evidence for structure 12 was obtained from 1H and 13
C
1
NMR spectroscopy.14 The H spectrum of 12 displayed
Figure 1.
Cl
H
H
N
H
N
H
Cl
Cl
c
a
b
N
NH2
N
NH2
Fmoc
R
9
R
R
R
R
O
O
d
O
10
8
11
d
= Rink-amide resin
Cl
H2N
NH2
H
N
Cl
Cl
H2N
O
O
O
3
12
Scheme 3. Reagents and conditions: (a) 20% piperidine/DMF, 1 h, rt; (b) CCl3CONCO (10 equiv), dry THF, 24 h, rt; (c) MeOH/dioxane (1:1), 48 h,
67 °C; (d) 5% TFA/dichloromethane, 2 h, rt.

M. Meusel, M. Gu¨tschow/ Tetrahedron Letters 46 (2005) 2231–2233
2233
11. Calculated on the basis of the initial loading of the Rink-
amide resin.
12. Determined by RP18-HPLC on the basis of relative areas,
eluent acetonitrile:water = 24:76 as described in: Eichel-
baum, M.; Sonntag, B.; Von Unruh, G. Arch. Toxicol.
1978, 41, 187–193.
from which the desired resin-bound urea could be gener-
ated by simple heating in methanol/dioxane. Investiga-
tions are in progress to utilize this resin in our studies
toward the solid-phase synthesis of certain small organic
molecules. In general, the urea resin promises to be a
versatile starting material for various SPOSs.
13. Masiero, S.; Fini, F.; Gottarelli, G.; Spada, G. P. J. Chem.
Res. (S) 1998, 634–635.
14. Following are 1H NMR, 13C NMR, MS spectral and
other analytical data of compounds:
Acknowledgments
1
Compound 5: white, crystalline solid; mp 202–203 °C; H
NMR (500 MHz, DMSO-d6) d 6.12 (d, 1H, J = 7.55 Hz,
CH), 7.25–7.99 (m, 15H, Ph), 9.58 (d, 1H, J = 7.55 Hz,
CHNH), 10.88 (s, 1H, NH); 13C NMR (125 MHz,
DMSO-d6) d 57.18 (CH), 126.89, 127.39, 128.35, 128.63,
128.86, 132.52, 133.03, 142.33 (Ph), 152.86 (NHCONH),
168.98 (CO). EIMS (m/z, 70 eV): 330 (M+, 40), 182
(Ph2C@NHþ2 , 100).
The authors are grateful to the Deutsche Forschungs-
gemeinschaft for financial support (Graduiertenkolleg
804). M.M. wants to thank the Boehringer Ingelheim
Fonds, Germany, and the National Science Foundation,
USA, for supporting this project by a travel grant.
1
Compound 6: white, crystalline solid; mp 110–115 °C; H
References and notes
NMR (500 MHz, DMSO-d6) d 6.01 (d, 1H, J = 7.65 Hz,
CH), 7.25–7.38 (m, 10H, Ph), 8.53 (d, 1H, J = 7.60 Hz,
CHNH), 11.10 (s, 1H, NH); 13C NMR (125 MHz,
DMSO-d6) d 57.56 (CH), 92.32 (CCl3), 127.45 (C-40, C-
400), 127.04, 128.78 (CH–Ph), 141.88 (C-10, C-100), 150.47
(NHCONH), 160.60 (CO). EIMS (m/z, 70 eV): 370 (M+,
4), 208 (Ph2C@N–CO+, 100).
1. Bakibaev, A. A.; Yu Yagovkin, A.; Vostretsov, S. N. Russ.
Chem. Rev. 1998, 67, 295–314.
2. Kohmoto, S.; Kreher, T.; Miyaji, Y.; Yamamoto, M.;
Yamada, K. J. Org. Chem. 1992, 57, 3490–3492.
3. Gutschow, M. J. Org. Chem. 1999, 64, 5109–5115.
´
uchowska, M. H. Adv. Heterocycl. chem. 1985, 38, 229–
¨
4. Bojarski, J. T.; Mokrosz, J. L.; Barton, H. J.; Pal-
1
Compound 7: white, crystalline solid; mp 128–131 °C; H
NMR (500 MHz, DMSO-d6) d 5.52 (s, 2H, NH2), 5.86 (d,
1H, J = 8.51 Hz, CH), 6.93 (d, 1H, J = 8.51 Hz, CHNH),
7.19–7.34 (m, 10H, Ph); 13C NMR (125 MHz, DMSO-d6)
d 56.87 (CH), 126.81 (C-40, C-400), 127.08, 128.44 (CH–
Ph), 143.88 (C-10, C-100), 157.89 (CO). EIMS (m/z, 70 eV):
226 (M+, 100), 182 (Ph2C@NH2þ, 82).
297.
5. (a) Meusel, M.; Gutschow, M. Org. Prep. Proced. Int.
¨
2004, 36, 391–443; (b) Meusel, M.; Ambrozak, A.; Hecker,
_
T. K.; Gutschow, M. J. Org. Chem. 2003, 68, 4684–4692.
¨
6. Bra¨se, S.; Dahmen, S. Handbook of Combinatorial
Chemistry: Drugs, Catalysts, Materials. In Linkers for
Solid-phase Synthesis; Nicolaou, K. C., Hanko, R.,
Hartwig, W., Eds.; Wiley–VCH: Weinheim, 2002; pp
140–141.
7. Warmus, J. S.; Ryder, T. R.; Hodges, J. C.; Kennedy, R.
M.; Brady, K. D. Bioorg. Med. Chem. Lett. 1998, 8, 2309–
2314.
8. Baindur, N.; Chadha, N.; Player, M. R. J. Comb. Chem.
2003, 5, 653–659.
9. (a) Zobova, N. N.; Nazyrova, A. Z. Zh. Org. Khim. 1993,
29, 1906–1908; (b) Schnell, B.; Krenn, W.; Faber, K.;
Kappe, O. J. Chem. Soc., Perkin Trans. 1 2000, 4382–
4389.
Compound 12: white, crystalline solid; mp 152–153 °C,
lit.16 mp 150 °C; 1H NMR (500 MHz, DMSO-d6) d 7.28 (s,
1H, NH2), 7.52 (s, 1H, NH2), 10.99 (s, 1H, NH); 13C
NMR (125 MHz, DMSO-d6) d 92.39 (CCl3), 152.25
(NHCONH), 161.19 (CO). EIMS (m/z, 70 eV): 205
(MH+, 2) 87 (MH+ ꢀ CCl3, 100).
1
Compound 3: brownish solid; mp 110–113 °C; H NMR
(500 MHz, DMSO-d6) d 4.79 (s, br, 4H, NH2); 13C NMR
(125 MHz, DMSO-d6) d 160.00 (CO). EIMS (m/z, 70 eV):
60 (M+, 100).
15. Determined by RP18-HPLC on the basis of a calibration
curve obtained from four different concentration of urea,
eluent water:acetonitrile = 95:5, k = 210 nm, flow: 1 mL/
min.
16. Pearl, I. A.; Dehn, W. M. J. Am. Chem. Soc. 1939, 61,
1377–1378.
10. Bakibaev, A. A.; Akhmedzhanov, R. R.; Filimonov, V.
D.; Novocheeva, T. P.; Saratikov, A. S.; Tignibidina, L.
G.; Pustovoitov, A. V. Pharm. Chem. J. 1993, 27, 631–634.