Synthesis of new derivatives of pyrido[1,2-a]triazine [7]

Full text of DOI:10.1007/s10593-007-0080-3

Chemistry of Heterocyclic Compounds, Vol. 43, No. 4, 2007
SYNTHESIS OF NEW DERIVATIVES OF PYRIDO[1,2-a]TRIAZINE
V. V. Dotsenko1, S. G. Krivokolysko1, and V. P. Litvinov2
Keywords: 6-amino-4-(het)aryl-2-thioxopyridine-3,5-dicarbonitriles, 1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-
[1,3,5]triazines, the Mannich reaction.
One of the most useful methods for the annelation of the 1,3,5-thiadiazine ring is the double Mannich
aminomethylation of 2-mercaptoazoles and -azines. This reaction is of a general nature and has been used
successfully for the synthesis of derivatives of sym-triazolo[3,4-b][1,3,5]thiadiazine [1], thiazolo-
[3',4':1,5][1,2,4]triazolo[3,4-b][1,3,5]thiadiazine [2], imidazo[2,1-b][1,3,5]thiadiazine [3,4], 1,2,4-triazino[3,2-b]-
[1,3,5]thiadiazine [4], and 1,3,5-thiadiazino[3,2-a]benzimidazole [5]. In the case of derivatives of pyridine-
2-thiolate the Mannich reaction does not proceed uniquely but leads to derivatives of pyrido[2,1-b]-
[1,3,5]thiadiazine [6], 3,7-diazabicyclo[3.3.1]nonane (bispidine) [7], or 3,5,7,11-tetraazatricyclo-
[7.3.1.02.7]tridec-2-ene [8] depending on the structure of the aminomethyl substrate. We have studied the
behavior of 6-amino-4-(het)aryl-2-thioxopyridine-3,5-dicarbonitriles 1 which are readily accessible by the
reaction arylmethylenemalonitriles with cyanothioacetamide under Mannich reaction conditions. It was
established that thione 1 readily and under mild conditions underwent aminomethylation with primary amines
and HCHO to give pyrido[1,2-a]triazines 2. Thus the presence of an amino group in position 6 is region-
directing , and the thione 1 behaves as an N,N-binucleophile rather than an N,S-binucleophile under Mannich
1
conditions. The structures of compounds 2 were confirmed spectroscopically. Characteristic signals in the H
NMR spectra are the broad peak of the N(1)H proton at 9.61-9.16 ppm and the signals of protons H-4
(6.04-5.36) and H-2 (5.06-4.44 ppm) which are resolved at 200 MHz as a pair of broadened pseudosinglets.
Antihelminthics, fungicides [9], and antagonists of 5-hydroxytryptamine receptors [10] are found among
the pyrido[1,2-a][1,3,5]triazines, but only a limited number of methods for the synthesis of derivatives of these
heterocyclic systems is known.
R
S
N
N
N
4
1
6
5
N
3
N
R
R1NH2, HCHO
7
2
H2N
N
H
S
8
R
N
H
1
9
1a,b
N
2a,b
1, 2 a R = 4-ClC6H4, R1 = 4-MeC6H4; b R = fur-2-yl, R1 = CH2Ph
1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded on a Varian
Mercury VX-200 (200 MHz) spectrometer. IR spectra of nujol mulls were recorded with an IKS-29 spectrometer
and elemental analyses were carried out with a Perkin-Elmer CHN analyzer.
__________________________________________________________________________________________
1"ChemEx" Laboratory, Vladimir Dal' East-Ukrainian National University, Lugansk 91034, Ukraine;
2
e-mail: ksg@lep.lg.ua. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow
117913; e-mail: vpl@mail.ioc.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.4, 621-622,
April, 2007. Original article submitted September 28, 2006.
0009-3122/07/4304-0517©2007 Springer Science+Business Media, Inc.
517

Pyrido[1,2-a][1,3,5-triazines 2. A suspension of a thione, 1a,b, (2 mmol) in EtOH (20 ml) was heated
until solution was complete, filtered through paper, and a primary amine (2 mmol) and an excess of 37% CH2O
(3.5 ml) were added to the filtrate. The mixture was boiled for 2-3 min with intense stirring. The precipitate was
separated and recrystallized from a suitable solvent.
8-(4-Chlorophenyl)-3-(4-methylphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-
7,9-dicarbonitrile (2a). Yellow crystals, yield 48%; mp 238-240°C (dec) (from DMF–EtOH, 1 : 1). IR spectrum,
1
ν, cm-1: 2206, 2225 (2C≡N), 3200 (NH). H NMR spectrum, δ, ppm (J , Hz): 9.61 (1H, br. s, NH); 7.56 (4H, q,
3J = 8.4, 4-ClC6H4); 7.05 (4H, q, 3J = 8.3, 4-MeC6H4); 6.04 (2H, br. pseudo s, H-4); 5.06 (2H, br. pseudo-s, H-2);
2.21 (3H, s, CH3). Found, %: C 62.94; H 3.87; N 16.80. C22H16ClN5S. Calculated, %: C 63.23; H 3.86; N 16.76.
3-Benzyl-8-(2-furyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5-triazin-7,9-dicarbaldehyde (2b).
Yellow crystals, 64% yield; mp 300°C (from DMF-EtOH, 1 : 1). IR spectrum, ν, cm-1: 2203, 2215(2 C≡N), 3210
1
(NH). H NMR spectrum, δ, ppm: 9.16 (1H, br. s, NH); 8.10 (1H, m, H-5furyl); 7.38 (1H, m, H-3furyl); 7.32 (5H,
m, C6H5); 6.82 (1H, m H-1furyl); 5.36 (2H, br. pseudo s, H-4); 4.44 (2H, br. pseudo s, H-2); 3.85 (2H, br. s,
CH2C6H5). Found, %: C 63.89; H 4.06; N 18.80. C20H15N5OS. Calculated, %: C 64.43; H 4.05; N 18.75.
This work was carried out as part of an agreement for scientific and technical cooperation between the
Vladimir Dal' East-Ukrainian National University and the N. D. Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences and an Russian Fundamental Research Fund project (No. 05-03-32031).
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