Reaction of isothiourea with 2,3-diaza-3-pentenedioic anhydride. A solid-phase synthesis of 3-amino-1,2,4-triazin-5(4H)-ones

Article abstract of DOI:10.1016/S0040-4039(01)00766-3

The first reported solid-phase synthesis of 3-amino-1,2,4-triazin-5(4H)-ones is described. Reactions of polymer-bound isothiourea with 2,3-diaza-3-pentenedioic anhydride forms 3-amino-1,2,4-triazin-5(4H)-ones in good yields and high purity.

Full text of DOI:10.1016/S0040-4039(01)00766-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4433–4435
Reaction of isothiourea with 2,3-diaza-3-pentenedioic anhydride.
A solid-phase synthesis of 3-amino-1,2,4-triazin-5(4H)-ones
Rui-Yang Yang* and Alan P. Kaplan
ArQule Inc., 19 Presidential Way, Woburn, MA 01801, USA
Received 19 April 2001; accepted 30 April 2001
Abstract—The first reported solid-phase synthesis of 3-amino-1,2,4-triazin-5(4H)-ones is described. Reactions of polymer-bound
isothiourea with 2,3-diaza-3-pentenedioic anhydride forms 3-amino-1,2,4-triazin-5(4H)-ones in good yields and high purity.
© 2001 Elsevier Science Ltd. All rights reserved.
Solid-phase syntheses of small, organic molecules have
received widespread attention during the last decade.1
In particular, a large number of heterocycles have been
synthesized using many of these solid-phase
approaches.2 1,2,4-Triazin-5-one is a very important
class of heterocyclic compounds that show a wide vari-
ety of applications in both the pharmaceutical and
agrochemical industries. As potential human therapies,
Examples of herbicidal 1,2,4-triazin-5-ones include
metribuzin (1) and metamitron (2).10
O
O
t-Bu
NH2
Ph
NH2
Me
N
N
N
N
N
SMe
N
Metribuzin (1)
Metamitron (2)
1,2,4-triazin-5-ones
have
exhibited
anticancer,3
antiulcer4 and antiinflammatory5 effects. Within the
agrochemical field, this class of compound has shown
activity as herbicides,6–8 desiccants,7 defoliants,7 plant-
growth regulators7 and insecticides.8 There is also a
report of this compound class increasing crop yields.9
Despite the importance of this compound class, there
are no published reports of a solid-phase synthesis of
1,2,4-triazin-5-ones. Recently, we reported a concise
and efficient solid-phase synthesis of 2-amino-4(3H)-
quinazolinones via the reaction of polymer-bound
NH2+ . Cl-
DMF, 80oC
S
Cl
S
+
R1
HN R1
N
H
NH2
5
4
3
O
Ar
O
O
O
N
6
Ar
N
Ar
N
N
H
O
NH
S
N
N
R1
NH
R1
N
H
i-Pr2NEt, DMF, 100oC
H2N
7
Scheme 1.
Keywords: solid-phase synthesis; thioformamidines; triazinones.
* Corresponding author. Tel.: 1-781-9940358; fax: 1-781-3766019; e-mail: ruiyang@arqule.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00766-3

4434
R.-Y. Yang, A. P. Kaplan / Tetrahedron Letters 42 (2001) 4433–4435
isothiourea 5 with isatoic anhydride.11 As part of our
continuing interest in the synthesis of biologically rele-
vant heterocycles from polymer-bound isothiourea,
herein we report a convenient traceless solid-phase syn-
thesis of 3-amino-1,2,4-triazin-5(4H)-ones.
612 in DMF in the presence of diisopropylethylamine at
100°C. The expected product, 3-amino-1,2,4-triazin-
5(4H)-one 7, is obtained (Scheme 1). The products are
formed via a similar mechanism as we described previ-
ously,11 i.e. acylation of isothiourea 5 with 2,3-diaza-3-
pentenedioic anhydride 6 followed by release of the
resulting product 7 via an intramolecular cyclization.
The results summarized in Table 1 indicate that the
reaction is general for N-alkyl-substituted isothioureas.
N-Phenyl-substituted isothiourea, though, fails to
provide the desired product in good purity (entry 13 in
The polymer-bound isothiourea 5, prepared quantita-
tively from the reaction of thiourea 3 and chloromethyl
polystyrene resin 4 (2% DVB Merrifield resin, 2.3
mmol/g) in DMF at 80°C,11 is reacted with a stoichio-
metric amount of 2,3-diaza-3-pentenedioic anhydride
Table 1. Solid-phase synthesis of 3-amino-1,2,4-triazin-5-ones 7

R.-Y. Yang, A. P. Kaplan / Tetrahedron Letters 42 (2001) 4433–4435
4435
Table 1). We have found that the reactions work well in
References
DMSO too. For example, reaction of N-ethylisothiourea
with 1-(4-biphenyl)-2,3-diaza-3-pentenedioic anhydride
in DMSO gives the desired product in 72% yield with
85% purity (entry 9). All the products are fully charac-
terized by 1H NMR and mass spectrometric techniques.
1. For excellent reviews on solid-phase synthesis, see: (a)
Special issue on combinatorial chemistry, Chem. Rev.
1997, 97, 349; (b) Acc. Chem. Res. 1996, 29, No. 3; (c)
Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D.
Tetrahedron 1996, 52, 4527; (d) Hermkens, P. H. H.;
Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1997, 53,
5643; (e) Booth, S.; Hermkens, P. H. H.; Ottenheijm,
H. C. J.; Rees, D. Tetrahedron 1998, 54, 15385; (f)
Lebl, M. J. Comb. Chem. 1999, 1, 3.
2. Franzen, R. G. J. Comb. Chem. 2000, 2, 195.
3. Vuddhakul, V.; Jacobsen, N. W.; Rose, S. E.; Ioan-
noni, B.; Seow, W. K.; Thong, Y. H. Cancer Lett.
1988, 42, 29.
In summary, we have disclosed a novel reaction of
polymer-bound isothiourea with 2,3-diaza-3-pentene-
dioic anhydride, which provides a very convenient solid-
phase synthesis of 3-amino-1,2,4-triazin-5(4H)-ones.
This is the first reported solid-phase synthesis of 1,2,4-tri-
azin-5-one class of compounds. The products formed
using this method are devoid of any residual functionality
due to resin attachment (i.e. traceless). Unlike the most
commonly used solution-phase methods reported in
literature,13 which liberate methylthiol as a by-product
from the reaction of amine with 3-methylthio-1,2,4-tri-
azin-5(4H)-one, this solid-phase method releases poly-
mer-bound thiol, thus providing a better working
environment, especially for library production.
4. Hirai, K.; Sugimoto, H.; Mizushima, T. Jpn. Kokai
Tokkyo Koho 1986, JP 61134389 A2.
5. Bierowska-Charytonowicz, D.; Konieczny, M. Rocz.
Chem. 1973, 47, 2199.
6. (a) Oettmeier, W.; Hilp, U.; Draber, W.; Fedtke, C.;
Schmidt, R. R. Pestic. Sci. 1991, 33, 399; (b) Sane-
mitsu, Y.; Shiroshita, M.; Hashimoto, S.; Kato, H.;
Matsumoto, H. Eur. Pat. Appl. 1982, EP 44696 A2.
7. Kranz, E.; Santel, H. J.; Luerssen, K.; Schmidt, R. R.;
Krauskopf, B. Ger. Offen. 1990, DE 3917043 A1.
8. Boehner, B.; Tobler, H. Eur. Pat. Appl. 1985, EP
150677.
9. Kralovic, J.; Beska, E. Czech. 1984, CS 212151 B.
10. Draber, D.; Fedtke, C. Advances in Pesticide Science,
Part 3; Geissbuhler, Ed.; Pergamon Press: Oxford,
1978; p. 475.
General procedure: The mixture of polymer-bound isoth-
iourea 5 (0.18 mmol) and 2,3-diaza-3-pentenedioic anhy-
dride 6 (0.15 mmol) was heated in anhydrous DMF (1.0
mL) in the presence of diisopropylethylamine (0.07 mL,
0.4 mmol) at 100°C for 24 h. The resin was filtered and
washed with hot DMF (0.5 mL×3), and the combined
filtrate was concentrated to give a solid residue. The
desired product, 3-amino-1,2,4-triazin-5(4H)-ones 7, was
obtained by washing the residue with water (0.5 mL×3).
11. Yang, R.-Y.; Kaplan, A. Tetrahedron Lett. 2000, 41,
7005.
12. Hurd, C. D.; Mori, R. I. J. Am. Chem. Soc. 1955, 77,
5359.
Acknowledgements
13. (a) Jacobsen, N. W.; Rose, S. E. Aust. J. Chem. 1988,
41, 609; (b) Eid, M. M.; Hassan, R. A.; Kadry, A. M.
Pharmazie 1988, 43, 166.
The authors would like to thank the Analytical Depart-
ment for the mass spectrometric analysis.
.