Solid-phase synthesis of functionalized 1,2,4-triazin-6-ones

Article abstract of DOI:10.1016/S0040-4039(02)01956-1

The solid supported synthesis of functionalized 1,2,4-triazin-6-ones from resin bound amino acids and acid chlorides is described. A thioamide intermediate is generated with Lawesson's reagent, and the final products are cyclized and cleaved from resin with hydrazine. The products are obtained in good yield and purity.

Full text of DOI:10.1016/S0040-4039(02)01956-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8165–8167
Solid-phase synthesis of functionalized 1,2,4-triazin-6-ones
Benjamin E. Blass,a,* Keith R. Coburn,a Amy L. Faulkner,a Song Liu,a Adam Ogden,a
David E. Portlocka and Anil Srivastavab
aProcter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, OH 45040, USA
bChembiotek Research International, Salt Lake, Block BN, Sector V, Kolkata 700091, India
Received 19 July 2002; accepted 4 September 2002
Abstract—The solid supported synthesis of functionalized 1,2,4-triazin-6-ones from resin bound amino acids and acid chlorides is
described. A thioamide intermediate is generated with Lawesson’s reagent, and the final products are cyclized and cleaved from
resin with hydrazine. The products are obtained in good yield and purity. © 2002 Published by Elsevier Science Ltd.
Over the last decade, combinatorial chemistry has
become an important tool in the drug discovery pro-
cess. The synthesis of vast libraries of structurally
diverse compounds based on heterocyclic scaffolds,
including imidazoles, benzodiazepines, diketopiperazi-
nes, oxazolidinones, and quinolones have been dis-
closed.1 Our efforts in this area have led to an
investigation of the solid-phase synthesis of several
types of heterocycles, including aminohydantoins,2
1,2,3-triazoles,3 and 1,2,4-triazin-6-ones. As a class,
1,2,4-triazin-6-ones have been shown to posses a wide
range of biological activity, including antibacterial,
antifungal, antihypertensive, antiasthmatic, CCK
antagonist, bronchodilatory, and lipoxygenase inhibi-
tion.4 A brief examination of the literature revealed
that the solid-phase preparation of this class of com-
pounds had not yet been reported. We felt that
the previously disclosed methods for the solution-phase
synthesis5 of this interesting class of compounds could
be adapted to solid-phase synthesis for the preparation
of screening libraries from commercially available resin
bound amino acids and acid chlorides. Preparation
of the critical thioamide on solid support, however,
has not been reported, and the application of
Lawesson’s reagent to solid-phase synthesis has been
limited.6
Commercially available Merrifield resin bound, Boc-
protected amino acids (1) were readily converted to the
requisite amide (2) by deprotection under standard
conditions and condensation with an appropriate acid
chloride. Conversion to the thioamide (3) was then
accomplished by treating the resin with Lawesson’s
reagent in toluene at 75°C. Progress of the reaction can
be easily monitored by IR, as the characteristic amide
peak IR at 1675 cm−1 is lost as the reaction proceeds.
The reaction conditions tolerate a wide range of sol-
vents including 1,4-dioxane, acetonitrile, THF,
dichloroethane, and 1,2-dimethoxyethane, allowing this
procedure to be preformed in a variety of plastic vessels
that are useful for the preparation of large combinato-
rial libraries. The solid by-products generated from the
Lawesson’s reagent, normally removed by filtration in a
solution phase reaction, are easily eliminated by thor-
ough washing of the resin with excess DMSO. Resin
cleavage and cyclization with a 2% solution of hydra-
Scheme 1. Solid-phase synthesis of 1,2,4-triazin-6-ones. Reagents and conditions: (a) i. TFA, CH2Cl2, rt 1 h, ii. TEA, CH2Cl2, rt
1 h; (b) R2COCl, DIPEA, CH2Cl2, rt 24 h; (c) Lawesson’s reagent, toluene, 75°C, 5 h; (d) 2% hydrazine in isopropanol, 75°C,
24 h.
Keywords: solid-phase synthesis; 1,2,4-triazin-6-ones; Lawesson’s reagent.
* Corresponding author. Fax: 513-622-3797; e-mail: blass.be@pg.com
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01956-1

8166
B. E. Blass et al. / Tetrahedron Letters 43 (2002) 8165–8167
Table 1. Representative examples of the solid-phase synthesis of 1,2,4-triazin-6-ones7
zine in 2-propanol at 75°C for 24 h provides the desired
1,2,4-triazin-6-ones (4) in excellent yield and purity
(Scheme 1 and Table 1). It should be noted that
aliphatic acid chlorides failed to give the desired 1,2,4-
triazin-6-one. While formation of the requisite
thioamide was readily accomplished, cyclization did not
occur under the condition described, and only the ring
open product from hydrazine-mediated resin cleavage
was obtained.
4. (a) Abdel-Hamide, S. G. J. Indian Chem. Soc. 1997, 74,
613–618; (b) Chan, P. S. US Patent 4743586, 1988; (c)
Freidinger, R. M.; Lansdale, P. A.; Evans, B. E.; Lans-
dale, P. A.; Bock, M. G.; Hatfield, P. A. US Patent
5177071, 1993; (d) Kutscher, B.; Engel, J.; Metzenauer, P.;
Achterrath-Tuckermann, U.; Szelenyi, S. European Patent
599152, 1994.
5. (a) Andersen, T. P.; Ghattas, A. G.; Lawesson, S. O.
Tetrahedron 1983, 39, 3419–3727; (b) Collins, D. J.;
Hughes, T. C.; Johnson, W. M. Aust. J. Chem. 1996, 49,
463–468.
In summary, we have developed a method for the
solid-phase synthesis of functionalized 1,2,4-triazin-6-
ones. The products are obtained in good yield and the
procedures are amenable to the production of combina-
torial libraries.
6. (a) Pons, J. F.; Mishir, Q.; Nouvet, A.; Brookfield, F.
Tetrahedron Lett. 2000, 41, 4965–4968; (b) Majer, Zs.;
Zewdu, M.; Hollosi, M.; Seprodi, J.; Vadasz, Zs.; Teplan,
I. Biochem. Biophys. Res. Commun. 1988, 150, 1017–1020.
7. Representative procedure: Boc-protected phenylalanine
Merrifield resin (5 g, loading 0.8 mmol/g) was treated with
trifluoroacetic acid in methylene chloride (50%, 50 mL) for
2 h at rt. The resin was then filtered and washed succes-
sively with methylene chloride (three times), and methanol
(three times). This was followed by neutralization of the
salt with triethyl amine in methylene chloride (50%, 50
mL, 1 h). The resin was then filtered, washed as previously
described, and dried under vacuum. 200 mg of the resin
(0.16 mmol) was then placed in a 10 mL reaction vessel of
a Quest™ 210. A solution of DIPEA (140 mL, 0.8 mmol),
and p-tert-butyl benzoyl chloride (125 mL, 0.64 mmol) in 6
mL of methylene chloride was added, and the reaction was
agitated overnight at rt. The vessel was drained and the
resin washed as previously described, and dried under
vacuum. The acylated resin (167.5 mg, 0.17 mmol) was
References
1. (a) Gordon, E. W.; Gallop, M. A.; Barret, R. W.; Dower,
W. J.; Fodor, S. P. A. J. Med. Chem. 1994, 37, 1233–1252,
1386–1401; (b) Terret, N. K.; Gardner, M.; Gordon, D.
W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51,
8135–8173; (c) Bunin, B. A. The Combinatorial Index;
Academic Press, 1998; (d) Czarnik, A. W.; DeWitt, S. H.
A Practical Guide to Combinatorial Chemistry; American
Chemical Society, 1997.
2. Wilson, L. J.; Li, M.; Portlock, D. E. Tetrahedron Lett.
1998, 39, 5135–5138.
3. Blass, B. E.; Coburn, K. R.; Faukner, A. L.; Hunn, C. L.;
Natchus, M. G.; Parker. M. S.; Portlock, D. E.; Tullis, J.
S.; Wood, R. Tetrahedron Lett. 2002, in press.

B. E. Blass et al. / Tetrahedron Letters 43 (2002) 8165–8167
8167
NMR, 300 MHz, CD3OD): l 1.03 (d, J=6.60 Hz, 6H),
1.60 (m, 2H), 1.94 (m, 1H), 4.05 (t, J=5.34 Hz, 1H),
7.45–7.70 (m, 5H). (M+H) 232. Entry 2 (1H NMR, 300
MHz, CD3OD): l 1.00 (d, J=6.60 Hz, 6H), 1.55 (m, 2H),
1.90 (m, 1H), 4.00 (t, J=5.60 Hz, 1H), 6.57 (s, 1H), 6.90
(s, 1H), 7.65 (s, 1H). (M+H) 222. Entry 3 (1H NMR, 300
MHz, CD3OD): l 1.03 (d, J=6.72 Hz, 6H), 1.59 (m, 2H),
2.10 (m, 1H), 4.02 (t, J=5.37 Hz, 1H), 7.12 (br s, 1H),
7.48 (d, J=4.86 Hz, 1H), 7.53 (d, J=6.12 Hz, 1H). (M+H)
238. Entry 4 (1H NMR, 300 MHz, CD3OD): l 1.02 (d,
J=6.60 Hz, 6H), 1.36 (s, 9H), 1.66 (m, 2H), 1.94 (m, 1H),
4.12 (t, J=5.40 Hz, 1H), 7.47–7.57 (m, 4H). (M+H) 288.
Entry 5 (1H NMR, 300 MHz, CD3OD): l 3.15 (m, 2H),
4.42 (t, J=4.59 Hz, 1H), 7.29–7.60 (m, 10H). (M+H) 266.
Entry 6 (1H NMR, 300 MHz, CD3OD): l 3.08 (m, 2H),
4.31 (t, J=4.59 Hz, 1H), 6.53 (s, 1H), 6.77 (s, 1H), 7.21 (br
s, 5H), 7.61 (s, 1H). (M+H) 256. Entry 7 (1H NMR, 300
MHz, CD3OD): l 3.09 (m, 2H), 4.36 (t, J=4.93 Hz, 1H),
7.15 (br s, 1H), 7.31 (m, 5H), 7.42 (d, J=2.68 Hz, 1H),
7.56 (d, J=4.06 Hz, 1H). (M+H) 272. Entry 8 (1H NMR,
300 MHz, CD3OD): l 1.34 (s, 9H), 3.04 (m, 2H), 4.36 (t,
J=4.68 Hz, 1H), 7.23–7.45 (m, 9H). (M+H) 322. Entry 9
(1H NMR, 300 MHz, CD3OD): l 1.43 (d, J=6.75 Hz,
3H), 4.13 (q, J=6.72 Hz, 1H), 7.42–7.50 (m, 5H). (M+H)
190. Entry 10 (1H NMR, 300 MHz, CD3OD): l 3.25 (m,
2H), 4.40 (t, J=4.46 Hz, 1H), 6.96–7.63 (m, 10H). (M+H)
305. Entry 11 (1H NMR, 300 MHz, CD3OD): l 2.08 (m,
2H), 2.11 (s, 3H), 2.68 (t, J=5.22 Hz, 2H), 4.21 (t, J=5.73
Hz, 1H), 7.47–7.70 (m, 5H). (M+H) 250. Entry 12 (1H
NMR, 300 MHz, CD3OD): l 2.18 (q, J=7.50 Hz, 2H),
2.62 (t, J=7.62 Hz, 2H), 4.21 (t, J=5.70 Hz, 1H), 5.11 (s,
2H), 7.33–7.73 (m, 10H). (M+H) 338. Entry 13 (1H NMR,
300 MHz, CD3OD): l 4.07 (s, 2H), 7.46–7.73 (m, 5H).
(M+H) 176. Entry 14 (1H NMR, 300 MHz, CD3OD): l
3.80 (m, 2H), 4.20 (m, 1H), 4.55 (s, 2H), 7.23–7.62 (m,
10H). (M+H) 296. Entry 15 (1H NMR, 300 MHz,
CD3OD): l 1.05 (dd, J=6.85 Hz each, 6H), 2.22 (m, 1H),
4.01 (d, J=4.08 Hz, 1H), 7.38–7.77 (m, 5H). (M+H) 218.
then suspended in 8 mL of toluene, 82.5 mg of Lawesson’s
reagent (0.20 mmol, 1.2 equiv.) was added, and the reac-
tion was agitated at 75°C for 5 h. The reaction was cooled,
the vessel was drained and the resin was washed succes-
sively with methylene chloride (3×6 mL), dimethyl sulfox-
ide (3×6 mL), and methanol (3×6 mL). The yellow resin
was then dried under vacuum. The resin was then sus-
pended in 8 mL of 2-propanol, and 160 mL of hydrazine
was added. After agitating at 75°C for 24 h, the reaction
was cooled, drained of solvent and washed with methylene
chloride (three times), and methanol (three times). The
solvent was collected and evaporated to yield the crude
product. Purification by HPLC provided 34.9 mg (68%) of
the desired product. Spectral data for Table 1: entry 1 (1H