3-(Arylamino)-1,2,4-triazin-5-one: A novel synthesis and its use

Article abstract of DOI:10.1002/ejoc.201000242

An optimized procedure is given for the synthesis of novel 3-(arylamino)-1,2,4-triazin-5-one building blocks from commercially available material. By employing these building blocks, a practical protocol is described for the functionalization of the 5-position of the triazine core with anilines or phenols.

Full text of DOI:10.1002/ejoc.201000242

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000242
3-(Arylamino)-1,2,4-triazin-5-one: A Novel Synthesis and Its Use[‡]
Ruben Leenders,*[a] Jan Heeres,[b] Dirk Vandenput,[a] Remco Zijlmans,[a]
Jérôme Guillemont,[c] and Paul Lewi[b]
Dedicated to the memory of Dr. Paul Janssen
Keywords: Nitrogen heterocycles / Medicinal chemistry / Antiviral agents
An optimized procedure is given for the synthesis of novel 3-
(arylamino)-1,2,4-triazin-5-one building blocks from com-
mercially available material. By employing these building
blocks, a practical protocol is described for the functionaliza-
tion of the 5-position of the triazine core with anilines or
phenols.
route to 3-(arylamino)-1,2,4-triazin-5-ones. These building
blocks were further functionalized in the 5-position with
either anilines or phenols (see Scheme 2) to furnish prod-
ucts that act as non-nucleoside reverse transcriptase inhibi-
tors (NNRTIs). In this paper we present a practical synthe-
sis of triazines A and B with X = 4-CN.[9] (Scheme 1) and
further functionalization of the 5-position.
Introduction
3-(Arylamino)-1,2,4-triazin-5-ones of general structure C
(Figure 1) are useful building blocks for further elaboration
on the triazine core, analogousely to the standard repertoire
in the chemistry of 2-hydroxy-N-heterocycles.[2]
Figure 1. 1,2,4-triazin-5-ones.
These 3-(arylamino)-1,2,4-triazin-5-ones with general
structure A or B (Figure 1), or their tautomeric forms, are
not described in the literature,[3] whereas triazines of general
structure C, where the R group is not H or Me, are very
scarcely described, mainly in papers dating back more than
35 years.[4] One letter reports a solid-phase synthesis of
structures C with various R groups being aryl.[5]
Results and Discussion
As part of our continuing interest in HIV-inhibiting pyr-
imidines,[6] triazines,[1,7] and purines,[8] we devised a novel
Scheme 1. Synthesis of 1,2,4-triazin-5-one 5.
[‡] See Ref.[1]
In the first step, commercial thiourea 1 is S-methylated
in 92% yield to give the hydroiodide salt 2,[10] which pre-
cipitates from the reaction mixture and is filtered off. For
the next step it is essential to keep the isourea in its salt
form as use of the free base gave a yield at least 10 times
lower. From 2 in an optimized procedure, intermediate hy-
drazinecarboximidamide 3 was prepared, and in a one-pot
process with the appropriate oxo ester 4a or 4b, 5-hydroxy-
1,2,4-triazines 5a and 5b were synthesized and purified by
trituration. Triazines 5a and 5b were thus obtained in 90+%
[a] Mercachem BV,
Kerkenbos 10–13, 6546 BB Nijmegen, The Netherlands
Fax: +31-24-372-3305
E-mail: ruben.leenders@mercachem.com
www.mercachem.com
[b] Janssen Research Foundation, Center for Molecular Design,
Antwerpsesteenweg 37, 2350 Vosselaar, Belgium
[c] Johnson and Johnson Pharmaceutical Research and Develop-
ment, Medicinal Chemistry Department,
Campus de Maigremont BP315, 27106 Val de Reuil Cedex,
France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000242.
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2852–2854

3-(Arylamino)-1,2,4-triazin-5-one: A Novel Synthesis and Its Use
14.29 mmol, 1.2 equiv.) and methanol (50 mL). The reaction mix-
ture was stirred at room temp. for 2 d, in a flask with a gas outlet
to release the formed thiomethanol. After that time, LCMS indi-
cated 98% conversion to 3. To the methanolic solution of interme-
diate 3 was added ethyl glyoxalate (4a) (50% in toluene, 4.72 mL,
23.81 mmol, 2 equiv.), and the reaction mixture was stirred at room
temp. overnight. The MeOH was evaporated, and the residue was
stripped twice with dry toluene (50 mL). Dry DMF (100 mL) was
added, and the mixture was heated at 80 °C over 48 h. The DMF
was evaporated (40 °C, 2.0 mbar). The yellow-orange solid residue
purity in 34% and 41% overall yield, respectively, without
the need of column chromatography.[11]
In a further modification towards our products, triazin-
5-ones 5a and 5b were functionalized with 2,4,6-trisubsti-
tuted anilines and phenols. The very reactive 5-chloro-1,2,4-
triazines 8 were prepared and coupled to a deprotonated
phenol to yield products 10 (Scheme 2). In the aniline series,
however, intermediates 8 did not react with 6. In an alterna-
tive one-pot process, however, where the aniline is added to
a stirred suspension of 5 in neat phosphoryl chloride, prod- was stirred in methanol (30 mL), filtered off and dried. Yield:
0.868 g (4.07 mmol) of triazine 5a, 34.2% from intermediate 2. An
analytical sample was prepared by dissolving the compound in hot
DMSO and precipitating it in water. 1H NMR (400 MHz, [D6]-
DMSO, 22 °C): δ = 7.50 (1 H, triazine-H), 7.77 (d, J = 8.9 Hz, 2
H, ArH), 7.81 (d, J = 8.9 Hz, 2 H, ArH), 9.86 (br. s, 1 H, NH),
12.57 (br. s, 1 H, OH) ppm. 13C NMR (100 MHz, [D6]DMSO,
22 °C): δ = 162.4, 152.7, 142.4, 140.1, 133.1, 120.4, 119.0,
104.7 ppm. M.p. 351–353 °C. HRMS: calcd. for [MH+] 214.0729,
ucts 7 were obtained from 8 generated in situ. A detailed
general procedure for these transformations is given in the
Supporting Information.
found 214.0718 (–4.89 ppm). FT-IR: ν = 665.4, 713.6, 736.7, 842.8,
˜
1180.4, 1340.4, 1506.3, 1519.8 cm–1.
6-Methyl-3-[(4-cyanophenyl)amino]-1,2,4-triazin-5-one (5b): To HI
salt 2 (3.80 g, 11.91 mmol) was added hydrazine hydrate (0.69 mL,
14.29 mmol, 1.2 equiv.) and methanol (50 mL). The reaction mix-
ture was stirred at room temp. for 2 d, in a flask with a gas outlet to
release the formed thiomethanol. After that time, LCMS indicated
97.5% conversion to 3. To the methanolic solution of intermediate
3 was added methyl pyruvate (4b) (2.15 mL, 23.8 mmol, 2 equiv.),
and the reaction mixture was stirred at 20 °C overnight. The
MeOH was evaporated, and the residue was stripped twice with
dry toluene (50 mL). Dry DMF (100 mL) was added, and the mix-
ture was heated at 80 °C over 48 h. The DMF was evaporated
(40 °C, 2.0 mbar). The sticky brown residue was stirred in methanol
(50 mL), filtered off and dried. Yield: 1.121 g, 4.93 mmol of triazine
5b, 41.4% from intermediate 2. An analytical sample was prepared
by dissolving the compound in hot DMSO and precipitating it in
1
water. H NMR (400 MHz, [D6]DMSO, 22 °C): δ = 2.10 (s, 3 H,
Me), 7.78 (t, J = 9.9 Hz, 4 H, ArH), 9.75 (br. s, 1 H, NH), 12.31
(br. s, 1 H, OH) ppm. 13C NMR (100 MHz, [D6]DMSO, 22 °C): δ
= 152.9, 147.8, 142.7, 133.1, 120.0, 119.1, 104.3, 16.9 ppm. M.p.
Ͼ380 °C (dec.). HRMS: calcd. for [MH+] 228.0885, found
Scheme 2. Coupling of anilines 6 and phenoles 9 to 1,2,4-triazines
5.
228.0877 (–3.81 ppm). FT-IR: ν = 1126.4, 1178.4, 1199.6, 1517.9,
˜
1635.5 cm–1.
Conclusions
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data for compounds 5a and 5b (1H NMR,
13C NMR, FT-IR and HRMS); general procedure to prepare prod-
ucts 7 and 10; table of all products 7 and 10 prepared this way and
their yields.
We have described an optimized procedure for the syn-
thesis of 1,2,4-triazine building blocks 5a and 5b without
the need for column chromatography and their functionali-
zation of the 5-position with anilines and phenols.
[1] Some of the compounds in this paper were claimed in: P. J.
Lewi, P. A. J. Janssen, M. R. de Jonge, L. M. H. Koymans,
H. M. Vinkers, F. F. D. Daeyaert, J. Heeres, R. G. G. Leenders,
G. J. C. Hoornaert, A. Kilonda, D. W. Ludovici, WO2004/
074266, 2004.
Experimental Section
Intermediate 2: 1-(4-Cyanophenyl)thiourea (1) (4.81 g, 27.2 mmol)
was suspended in acetone (100 mL), and MeI (1.78 mL, 28.5 mmol,
1.05 equiv.) was added. The reaction mixture was stirred at room
temp. for 2 d, then placed in a cooler for 2 h, and then the solid
was filtered off. The filtrate was washed with acetone and dried.
Yield: 8.26 g (25.9 mmol 95.3%) of intermediate 2 as its HI salt.
1H NMR (400 MHz, [D6]DMSO, 22 °C): δ = 2.71 (s, 3 H, SMe),
7.55 (d, J = 8.6 Hz, 2 H, ArH), 8.00 (d, J = 8.6 Hz, 2 H, ArH),
9.67 (br. s, 3 H, 2 NH + HI) ppm.
[2] This hydroxy function can be functionalized after chlorination,
triflation, mesylation etc. with or without palladium catalysis;
alkylated; used in the Mitsunobu reaction etc.
[3] Except in our work; see ref.[1]
[4] a) T. Ueda, M. Furukawa, Chem. Pharm. Bull. 1964, 12, 100–
103; b) A. K. Mansour, S. B. Awad, S. Antoun, Z. Naturforsch.,
Teil B 1974, 29, 792–796; c) A. K. Mansour, Y. A. Ibrahim, J.
Prakt. Chem. (Leipzig) 1973, 315, 221–226.
[5] R.-Y. Yang, A. P. Kaplan, Tetrahedron Lett. 2001, 42, 4433–
4435.
3-[(4-Cyanophenyl)amino]-1,2,4-triazin-5-one (5a): To HI salt 2
(3.80 g, 11.91 mmol) was added hydrazine hydrate (0.69 mL,
Eur. J. Org. Chem. 2010, 2852–2854
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2853

R. Leenders et al.
SHORT COMMUNICATION
[6]
[9] We also successfully used anilines with X = 4-CH=CHCN; 4-
CH2CH2CN, 4-CH2CN.
[10] D. W. Ludovici, M. J. Kukla, P. G. Grous, S. Krishnan, K.
Andries, M.-P. de Béthune, H. Azijn, R. Pauwels, E. de Clercq,
E. Arnold, P. A. J. Janssen, Bioorg. Med. Chem. Lett. 2001, 11,
2225–2228.
See: R. Leenders, J. Heeres, J. Guillemont, P. Lewi, Tetrahedron
Lett. 2010, 51, 543–544 and the literature cited there under
references [1] and [2].
[7] G. J. C. Hoornaert, A. Kilonda, J. Heeres, P. J. Lewi, M. R.
de Jonge, F. F. D. Daeyaert, H. M. Vinkers, L. M. H. Koymans,
P. A. J. Janssen, WO2006015985, 2006.
[8] P. J. Lewi, M. R. de Jonge, L. M. H. Koymans, F. F. D. Daeya-
ert, J. Heeres, H. M. Vinkers, R. G. G. Leenders, D. A. L. Van-
denput, WO 2005/028479, 2005.
[11] These compounds have a very adverse solubility making col-
umn chromatography impossible.
Received: February 22, 2010
Published Online: April 9, 2010
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2852–2854