Solid-phase synthesis of 1,2,4-triazolidine-3,5-diones

Article abstract of DOI:10.1016/S0040-4039(02)00701-3

A traceless synthesis of 1,2,4-triazolidine-3,5-diones has been achieved through cyclo-elimination from solid-phase. This traceless cyclo-elimination release step is induced by catalytic amount of base or by simply refluxing the urea carbamate intermediat

Full text of DOI:10.1016/S0040-4039(02)00701-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3899–3901
Solid-phase synthesis of 1,2,4-triazolidine-3,5-diones
Kyung-Ho Park* and Linda J. Cox
DuPont Central Research and Development, Chemical Science and Engineering, Experimental Station, PO Box 80328,
Wilmington, DE 19880-0328, USA
Received 15 March 2002; accepted 2 April 2002
Abstract—A traceless synthesis of 1,2,4-triazolidine-3,5-diones has been achieved through cyclo-elimination from solid-phase. This
traceless cyclo-elimination release step is induced by catalytic amount of base or by simply refluxing the urea carbamate
intermediate. © 2002 Elsevier Science Ltd. All rights reserved.
Recently urazole and substituted urazoles (1,2,4-triazo-
lidine-3,5-diones) have become an important structural
motif both in biological systems1 and in polymeric
materials.2 They also have been shown to exhibit some
anticonvulsant3a or fungicidal activities3b as well as
catalytic activity in radical polymerization.3c Although
much attention has been directed towards solid-phase
method development for the synthesis of numerous
heterocycles for use in biological discovery efforts,4 it is
surprising that there are no reports of solid-phase
routes to urazoles. As part of our efforts towards the
preparation and biological evaluation of urazole deriva-
tives, we disclose here an efficient route for the prepara-
tion of urazole derivatives and its synthetic strategy
applicable to solid-phase combinatorial approaches.
gies were applied.5 Thus, a carbamate linker6 system
was introduced to release the intact target in the final
step of the reaction sequence. Our preliminary solution-
phase reaction to the target proved the validity of this
linker system (Scheme 1). The reaction of benzyl chlo-
roformate with phenylhydrazine in the presence of
Et3N afforded benzyl 3-phenylcarbazate 1, which upon
treatment with phenylisocyanate gave urea intermediate
2. In the presence of base such as K2CO3 or Et3N,
cyclized diphenyl urazole 3a was obtained from 2 in
good yield.
Our solid-phase approach to 1,2,4-triazolidine-3,5-
diones began with the coupling of hydroxymethyl
polystyrene or Wang resin with p-nitrophenyl chloro-
formate to afford p-nitrophenyl carbonate resin 4
(Scheme 2).7 Subsequent reaction of the carbonate resin
4 with hydrazine derivatives afforded polymer bound
For our solid-phase approach to the traceless 1,2,4-tria-
zolidine-3,5-diones 3, cyclo-elimination release strate-
O
O
NHNH2
Ph-N=C=O
N N
O
Cl
O
CH2Cl2
H H
Et3N, CH2Cl2
-5oC - OoC
70%
rt
1
93%
O
NH
N
O
O
N
NH
K2CO3
O
H
N
NH
N
N
N
O
+
R2
R1
3a
CH3CN
80oC
O
88%
O
OH
3
2
Scheme 1.
* Corresponding author. Tel.: (302)-695-1784; e-mail: kyung-ho.park@usa.dupont.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00701-3

3900
K.-H. Park, L. J. Cox / Tetrahedron Letters 43 (2002) 3899–3901
O
O
NO2
Cl
O
*
OH
O
O
NO2
N-methyl morpholine
CH2Cl2
NMP
THF
0oC - rt
4
R1 NHNH2
* Hydroxymethyl polystyrene
or Wang resin
rt
O
O
O
R2-N=C=O
rt
NH
N
R1
THF, 60oC
with or without
Et3N (cat.)
overnight
O
H
N
NH
N
O
NH
HN
N
R2
R2
THF
R1
R1
O
5
O
3
6
Scheme 2.
carbazate 5. Treatment of 5 with isocyanate gave urea
bound resin intermediate 6, and subsequent cyclo-elimi-
nation reaction of 6 in the presence or absence of base
(Et3N) delivered 1,2,4-triazolidine-3,5-diones 3 (Table
1).
Acknowledgements
We thank Drs. Steven W. Shuey and Eric M. Smith for
comments on the manuscript.
The reactivity difference of the cyclo-elimination step
between Merrifield and Wang resin is noteworthy.8
Thus, Merrifield-based resin 6 (R1, R2=Ph) released
urazole 3a (35% overall yield) even without base; on the
other hand Wang-based carbamate linker 6 needed a
base (2 days of reflux) to afford 3a (26% overall yield).
Previously reported cyclization/cleavage steps of hetero-
cycles from carbamate linkers require an excess of base
(10–14 equiv.).9 However, in the presence of base the
released urazole derivatives (pKa=4.3–5.3)10 are present
as a salt, which necessitates an acid work-up to get the
final product. Therefore, it is advantageous to employ
hydroxymethyl polystyrene in the preparation of ura-
zoles in the solid-phase reaction.
References
1. (a) Paparin, J.-L.; Hwang, S.-H.; Nguyen, M.; Zheng, Y.;
Ruan, F.; Little, T.; Blaskovich, M. A. Abstracts of
Papers, 222nd ACS National Meeting (August 26–30,
2001), Chicago, IL, ORGN-495; (b) Boldi, A. M.; John-
son, C. R.; Eissa, H. O. Tetrahedron Lett. 1999, 40, 619;
(c) Kolb, V. M.; Dworkin, J. P.; Miller, S. L. J. Mol.
Evol. 1994, 38, 549.
2. (a) Mallakpour, S. E.; Nasr-Isfahani, H. J. Appl. Polym.
Sci. 2001, 82, 3177; (b) Mallakpour, S. E.; Sheik-
holeslami, B. Polym. Int. 1999, 48, 41.
3. (a) Jacobson, C. R.; D’Adamo, A.; Cosgrove, C. E. US
Patent, 3,663,564, 1972; (b) Shigematsu, T.; Tomita, M.;
Shibahara, T.; Nakazawa, M.; Munakata, S. JP
52,083,562, 1977; (c) Baumgartner, E.; Blumenstein, U.;
Bueschl, R.; Rieber, N. EP 390,026, 1990.
4. (a) Sammelson, R. E.; Kurth, M. J. Chem. Rev. 2001,
101, 137; (b) Dolle, R. E. J. Comb. Chem. 2000, 2, 383;
(c) Lorsbach, B. A.; Kurth, M. J. Chem. Rev. 1999, 99,
1549.
In summary, we have established a viable route for the
synthesis of traceless 1,2,4-triazolidine-3,5-diones via
solid-phase organic chemistry. Production of a large
library of these heterocycles via parallel solid-phase
synthesis and evaluation of biological activities is cur-
rently under investigation.
5. Park, K.-H.; Kurth, M. J. Drugs Fut. 2000, 25, 1265.
6. Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetra-
hedron Lett. 1996, 37, 937.
Table 1. 1,2,4-Triazolidine-3,5-diones (3) from solid-phase
Compound
R1
R2
% Yielda,b (purity)c
7. Typical procedure (Table 1, 3b): p-Nitrophenyl chloro-
formate (0.338 g, 1.68 mmol) was added to a stirring
solution of hydroxymethyl polystyrene (0.3 g, 0.84 mmol,
2.8 mmol/g) and N-methyl morpholine (0.17 g, 1.68
mmol) at 0°C. The reaction mixture was warmed to rt,
and stirred for 2 days. The resin was filtered, washed with
DCM, and dried under a vacuum to afford the resin 4
(FTIR (KBr): 1770 cm−1). The resultant resin was treated
with phenylhydrazine (0.45 g, 4.2 mmol) and N-methyl
morpholine (1 mL) in NMP (N-methylpyrrolidinone)/
THF (10 mL/10 mL) solvent. After stirring the reaction
mixture for 30 h at rt under nitrogen, the resin was
filtered, washed (DMF, THF), and dried under a vacuum
to give the resin 5 (R1=Ph, FTIR (KBr): 1733 cm−1).
3a
3b
3c
3d
3e
3f
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
CH3-
C6H5-
35 (\95%)
44 (\95%)
37 (\95%)
19 (45%)
p-Cl-C6H4-
p-F-C6H4-
m-Cl-C6H4-
o-Tolyl-
Benzyl-
p-Cl-C6H4-
p-F-C6H4-
20 (71%)
18 (\95%)
25 (\95%)
27 (\95%)
3g
3h
CH3-
a Overall yield from hydroxymethyl polystyrene.
b Purified from column chromatography.
c By LC MS at 254 nm after simply removing urea impurity by short
silica column.

K.-H. Park, L. J. Cox / Tetrahedron Letters 43 (2002) 3899–3901
3901
Resin 5 (R1=Ph) was treated with p-chlorophenyliso-
cyanate (0.258 g, 1.68 mmol) at rt overnight, filtered,
washed (DMF, THF), and dried to deliver resin 6 (R1=
Ph, R2=p-Cl-C6H4-, FTIR (KBr): 1746, 1715 cm−1).
Resin 6 (R1=Ph, R2=p-Cl-C6H4-) was stirred by reflux
in the presence of Et3N (8 mg, 0.084 mmol) in THF
overnight. Filtration of the resin, concentration of the
filtrate under reduced pressure, and short silica column
afforded urazole 3b (107 mg) as a white solid. Yield
Hz). 13C NMR (300 MHz, DMF-d7): l 153.1, 150.2,
137.7, 133.5, 131.7, 129.7, 129.6, 128.7, 125.6, 119.1.
Anal. calcd for C14H10ClN3O2: C, 58.45; H, 3.50; Cl,
12.32; N, 14.61. Found: C, 58.49; H, 3.22; Cl, 12.32; N,
14.48%.
8. Park, K.-H.; Kurth, M. J. Tetrahedron Lett. 2000, 41,
7409.
9. (a) Ref. 6; (b) Gouilleux, L.; Fehrentz, J. A.; Winternitz,
F.; Martinez, J. Tetrahedron Lett. 1996, 37, 7031.
10. Bausch, M. J.; David, B.; Dobrowolski, P.; Gaudalupe-
Fasano, C.; Gostowski, R.; Selmarten, D.; Prasad, V.;
Vaughn, A.; Wang, L.-H. J. Org. Chem. 1991, 56, 5643.
(overall): 44%, mp: 245°C, FTIR (KBr): 1766, 1704 cm−1
,
1H NMR (300 MHz, DMF-d7): l 7.94–7.90 (m, 4H),
7.83–7.81 (m, 2H), 7.71–7.68 (m, 2H), 7.36 (t, 1H, J=6.4