Synthesis of novel silylated 1,2,4-triazin-5-ones

Article abstract of DOI:10.1016/j.tetlet.2005.04.021

The reaction of various α-silyl-α-keto esters with thiosemicarbazide at 50°C in ethyl acetate was found to give α-silyl-substituted thiosemicarbazone-acetic acid esters in good yield. These may then be converted to their corresponding silyl-substituted 1,2,4-triazin-5-ones by cyclization under basic conditions.

Full text of DOI:10.1016/j.tetlet.2005.04.021

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4049–4051
Synthesis of novel silylated 1,2,4-triazin-5-ones
Carsten Bolm,a,* Andrey Kasyanb and Sandra Saladinc
aInstitute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany
bProBioGen AG, Goethestr. 50-54, D-13086 Berlin, Germany
cBeiersdorf AG, Unnastr. 48, D-20245 Hamburg, Germany
Received 7 March 2005; accepted 5 April 2005
Available online 20 April 2005
Abstract—The reaction of various a-silyl-a-keto esters with thiosemicarbazide at 50 ꢀC in ethyl acetate was found to give a-silyl-
substituted thiosemicarbazone-acetic acid esters in good yield. These may then be converted to their corresponding silyl-substituted
1,2,4-triazin-5-ones by cyclization under basic conditions.
ꢁ 2005 Elsevier Ltd. All rights reserved.
Our interest is focused on exploring the reactivity of
a-silyldiazo carbonyl compounds, and we have recently
used them to generate a-silyl amino acids and peptides,1
a-silyl esters and their corresponding hydroxyacetic
acids,2 as well as a-silyl-substituted dioxolanones.3 We
now report the synthesis of novel 1,2,4-triazin-5-ones,
utilizing a base-mediated intramolecular cyclization of
a-silyl-substituted thiosemicarbazone-acetic acid esters.
The latter compounds are obtained by condensation of
a-silyl keto esters with thiosemicarbazide.4
similar concept was envisioned for silyl-substituted
1,2,4-triazin-5-ones.
As shown in Table 1, various a-silyl-substituted thio-
semicarbazone-acetic acid esters 3 were obtained in
good yields (up to 84% yield) by condensation of
a-silyl-a-keto esters 1 with thiosemicarbazide (2).10
We found that the cyclization11 of the a-triorganylsilyl-
thiosemicarbazone-acetic acid esters 3 under basic
1,2,4-Triazin-5-ones are attractive compounds, parti-
cularly because of their potent biological activities.5
Synthetic contributions for the generation of these
compounds include palladium-catalyzed polyhetero-
Claisen rearrangements of 3-(allylthio)-1,2,4-triazin-
5(4H)-ones,6 the reaction of diethyl oxomalonate with
thiosemicarbazide, followed by methylation,7 and 1,5-
electrocyclizations of nitrilimines.8 Hence, we were
interested in synthesizing analogous silyl-substituted
1,2,4-triazin-5-ones, which have potential biological
activity, due to the presence of the hydrophobic and ste-
rically-demanding triorganylsilyl substituent. For exam-
ple, derivatives and analogues of natural amino acids
that incorporate organosilanes have been developed
since the 1950s, and it is known that peptides containing
silyl alanine likewise show potent biological activity.9 A
Table 1. Synthesis of silylated thiosemicarbazones 3 by condensation
of a-silyl keto esters 1 with thiosemicarbazide (2)
3
3
R
R
2
2
R
R
H NNHC(S)NH (2)
Si CO R
Si CO R
2
2
2
2
1
1
R
R
EtOAc, 50 ˚C, 1 h
O
NNHC(S)NH
2
1
3
Entry
R
R1/2
R3
Product
Yielda (%)
1
Me
Me
Me
Et
Me
Et
Me
Et
3a
3b
3c
3d
3e
3f
65
71
76
69
78
79
74
84
82
73
81
79
2
3
Me
Me
Et
t-Bu
Me
Et
4
5
Et
Et
6
Me
Me
Et
t-Bu
Me
Et
7
Bn
Bn
Bn
Bn
Bn
Bn
3g
3h
3i
8
9
Me
Me
Ph
t-Bu
Ph
10
11
12
3j
Keywords: a-Silyl-a-keto esters; Iminations; 1,2,4-Triazin-5-ones; Thi-
osemicarbazones; Intramolecular cyclization.
Me
Ph
3k
3l
Ph
*
Corresponding author. Tel.: +49 241 8094 675; fax: +49 241 8092
391; e-mail: carsten.bolm@oc.rwth-aachen.de
a After column chromatography.
0040-4039/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.021

4050
C. Bolm et al. / Tetrahedron Letters 46 (2005) 4049–4051
3
3
conditions is dependent on the size of the substituted
silicon moiety present in the molecule. Hence, silyl-
substituted thiosemicarbazones containing substituents
larger than the trimethylsilyl group cyclized effectively
to the desired 6-triorganylsilyl-3-thioxo-3,4-dihydro-
2H-1,2,4-triazin-5-ones 4 in up to 88% yield, as shown
in Table 2.12
R
R
O
O
2
1
2
1
R
R
MeI, Na CO
Si
Si
2
3
NH
N
R
R
MeOH / H O
2
80-90 ˚C, 2 h
N
N
N
H
4
S
N
H
6
SCH
3
Scheme 2. Methylation of silyl-substituted 1,2,4-triazin-5-ones 4.
In the case of the a-trimethylsilyl-substituted thiosemi-
carbazone derivatives 3a, 3d, and 3g, however, the tri-
methylsilyl moiety is lost in the course of the reaction,
a-keto esters with thiosemicarbazide in up to 84% yield.
Cyclization of these precursors under basic conditions
allows for the ready synthesis of the corresponding sil-
ylated 1,2,4-triazin-5-ones in up to 88% yield. Future
work toward the synthesis of silylated nitrogen-contain-
ing heterocycles will be reported in due course.
generating
5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-
carboxylic acid esters 5 in up to 50% yield, as shown
in Scheme 1.13 The yields are low, since the cyclization
did not go to completion, leaving unreacted starting
material lacking the trimethylsilyl group in the reaction
mixture. In the absence of Na2CO3, cyclization of TMS-
substituted 3 to 5 also occurred in a solution of ethyl
acetate at room temperature, although only after a few
weeks. Compounds 3 also cyclized when they were left
3–4 months standing in air.
Acknowledgements
We are grateful to the Deutsche Forschungsgemeins-
chaft (SPP 1118, Graduiertenkolleg 440) and the Fonds
der Chemischen Industrie for financial support. We also
acknowledge the highly stimulating discussions with
Professor Dr. Drauz (DEGUSSA AG) and financial
support from DEGUSSA AG for a postdoctoral fellow-
ship for A.K.
Finally, methylation of 6-triorganylsilyl-3-thioxo-3,4-
dihydro-2H-1,2,4-triazin-5-ones 4 was successfully car-
ried out with iodomethane14 to afford pharmaceutically
relevant
6-triorganylsilyl-3-methyl-sulfanyl-2H-1,2,4-
triazin-5-ones 6 in up to 89% yield, as shown in Scheme
2. When an excess of MeI (3:1) was used, the N–H bond
of 6 was also methylated. Examples of 2-methyl-3-meth-
ylsulfanyl-2H-1,2,4-triazin-5-ones are well known in the
literature.8,15
References and notes
1. Bolm, C.; Kasyan, A.; Drauz, K.; Gunther, K.; Raabe, G.
¨
Angew. Chem., Int. Ed. 2000, 39, 2288.
2. (a) Bolm, C.; Kasyan, A.; Heider, P.; Saladin, S.; Drauz,
K.; Gunther, K.; Wagner, C. Org. Lett. 2002, 4, 2265; (b)
In summary, we have shown that silylated thiosemicar-
bazones are easily obtained by condensation of a-silyl-
¨
Bolm, C.; Saladin, S.; Claßen, A.; Kasyan, A.; Veri, E.;
Raabe, G. Synlett 2005, 16, 461.
Table 2. Cyclization of silylated thiosemicarbazone-acetic acid esters 3
to their corresponding 1,2,4-triazin-5-ones 4
3. Bolm, C.; Saladin, S.; Kasyan, A. Org. Lett. 2002, 4, 4631.
4. (a) Labib, G. H.; Rahman, M. A.; El-Kilany, Y.; El-
Massry, A. I.; El-Ashry, E. S. H. Bull. Chem. Soc. Jpn.
1988, 61, 4427; (b) Just, G.; Kim, S. Can. J. Chem. 1977,
55, 427; (c) Watanabe, U. Chem. Pharm. Bull. 1963, 11,
1551; (d) Slouka, J. Pharmazie 1979, 34, 796; (e) Slouka, J.
Pharmazie 1960, 15, 317; (f) Brody, F.; Westheimer, J.
J. Biol. Chem. 1979, 254, 4238.
3
3
R
R
O
2
1
2
R
Na CO or K CO
3
R
R
2
3
2
Si CO R
2
Si
NH
1
R
MeOH / H O
2
NNHC(S)NH
N
2
80 ˚C, 1 h
N
H
S
3
4
5. (a) Draber, W.; Dickore, K.; Buchel, K. H.; Trebst, A.;
¨
Entry
R
R1/2
R3
Product
Yielda (%)
Pistorius, E. Naturwissenschaften 1968, 55, 446; (b)
Mamolo, M. G.; Falagiani, V.; Zampieri, D.; Vio, L.;
Banfi, E. Il Farmaco 2000, 55, 590; (c) Garg, N. K.; Stoltz,
B. M. Tetrahedron Lett. 2005, 46, 1997.
1
2
3
4
5
6
Et, Bn
Et
Bn
Et
Et
4a
4b
4b
4c
4d
4e
81
84
77
72
88
79
Me
Me
Me
Ph
Ph
t-Bu
t-Bu
Ph
6. Mizutani, M.; Sanemitsu, Y. J. Org. Chem. 1983, 48, 4585.
7. Huang, J. J. J. Org. Chem. 1985, 50, 2293.
Bn
Bn
Me
Ph
8. Shawali, A. S.; Gomha, S. M. Tetrahedron 2002, 58, 8559.
9. (a) Weidmann, B. Chimia 1992, 46, 312; (b) Weinand, A.;
Ehrhardt, C.; Metternich, R.; Tapparelli, C. Bioorg. Med.
Chem. 1999, 7, 1295; (c) Tacke, R.; Merget, M.; Berter-
mann, R.; Bernd, M.; Beckers, T.; Reissmann, T. Organo-
metallics 2000, 19, 3486.
Bn
a After column chromatography.
H
N
Na CO or K CO
3
S
2
3
2
Me Si CO R
3
2
10. General procedure of the condensation reaction: To a
solution of the corresponding a-silyl keto ester 1
MeOH / H O
2
80 ˚C, 1 h
CO R
2
HN
NNHC(S)NH
N
2
(10 mmol) in ethyl acetate (100 mL) was added thio-
semicarbazide (2) (1.82 g, 20 mmol). The suspension was
stirred for 1 h at 50 ꢀC, after which unreacted 2 was
filtered off. The solvent was removed under reduced
pressure, and the residue was purified by flash column
chromatography (silica gel, petroleum ether/ethyl acetate,
10:1 up to 3:1, Rf 0.15–0.25). All products were obtained
3a: R = Me
3d: R = Et
3g: R = Bn
5
40-50 %
Scheme 1. Cyclization of a-trimethylsilyl-thiosemicarbazone-acetic
acid esters to give novel 1,2,4-triazole carboxylic acid ester
derivatives 5.
3

C. Bolm et al. / Tetrahedron Letters 46 (2005) 4049–4051
4051
as slightly yellow solids upon evaporation of the solvents
and dried in high vacuum.
uct was then purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate, 10:1 up to 3:1, Rf
values 0.15–0.25), to afford 4 as a slightly yellow solid.
13. The stability of a-silyl amino acid derivatives has recently
been investigated, and there also, trimethylsilyl-substituted
compounds proved to be the least stable ones Liu, G.;
McN. Sieburth, S. Org. Lett. 2005, 7, 665.
11. (a) Hishmat, O. H.; Fawzy, N. M.; Farrag, D. S.; El-All,
A. S. Rev. Roum. Chim. 1999, 44, 161; (b) Hlavac, J.;
Slouka, J.; Hradil, P.; Lemr, K. J. Heterocycl. Chem. 2000,
37, 115; (c) Wasti, K.; Joullie, M. M. J. Chem. Soc., Perkin
Trans. 1 1976, 2521.
12. General procedure for the cyclization of 3 to give silylated
1,2,4-triazin-5-ones 4: A solution of the corresponding
14. (a) Slouka, J.; Stransky, Z. Pharmazie 1973, 28, 309; (b)
Taylor, E. C.; Pont, J. L. J. Org. Chem. 1987, 52, 4287; (c)
Slouka, J. Pharmazie 1980, 35, 744; (d) Andreichikov, Yu.
S.; KolÕtsova, S. V.; Zhikina, I. A.; Nekrasov, D. D. Russ.
J. Org. Chem. 1999, 35, 1538; (e) Aliev, Z. G.; Atovmyan,
L. O.; Andreichikov, Yu. S.; KolÕtsova, S. V.; Nekrasov,
D. D. Russ. Chem. Bull. 1999, 47, 682; (f) Eid, M. M.;
Hassan, R. A.; Kadry, A. M. Pharmazie 1988, 43, 166.
15. Heravi, M. M.; Oskooi, H. A.; Mafi, M. Synth. Commun.
1997, 27, 1725.
a-triorganylsilylthiosemicarbazone-acetic acid esters
3
(3 mmol) in methanol (20 mL) was added to a solution
of 1 g of Na2CO3 or K2CO3 in water (20 mL). This
mixture was stirred for 1 h at 80 ꢀC under reflux, cooled to
ambient temperature, and the product was extracted twice
with ethyl acetate (2 · 30 mL). The combined organic
layers were dried over MgSO4, and removal of the solvent
afforded the crude silylated 1,2,4-triazin-5-one. The prod-