Synthesis of pyrido[2,1-b][1,3,5]thiadiazines by the aminomethylation of 4-methyl-6-oxo-2-thioxopiperidine-3-carbonitrile

Full text of DOI:10.1007/s10593-012-1109-9

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
SYNTHESIS OF PYRIDO[2,1-b][1,3,5]THIADIAZINES
BY THE AMINOMETHYLATION OF 4-METHYL-
6-OXO-2-THIOXOPIPERIDINE-3-CARBONITRILE
K. A. Frolov1**, V. V. Dotsenko1, S. G. Krivokolysko1, and V. P. Litvinov2*
Keywords: 4-methyl-6-oxo-2-thioxopiperidine-3-carbonitrile, pyrido[2,1-b][1,3,5]thiadiazines, amino-
methylation, Mannich reaction.
Pyrido[2,1-b][1,3,5]thiadiazines are a rather rare type of condensed heterocyclic system [1-3], and only
isolated studies reporting the preparation of this bicyclic system have been reported [4-6]. We have shown that
treatment of the previously synthesized 4-methyl-6-oxo-2-thioxopiperidine-3-carbonitrile 1 [7] with primary
amines in the presence of excess HCHO gives the previously unknown pyrido[2,1-b][1,3,5]thiadiazines 2a,b.
1
The structure of compounds 2a,b was confirmed from H NMR and IR spectroscopy and from elemental
analysis data. The potential of the method and its optimization will be the subject of further investigations.
O
O
R
N
HN
N
RNH2, 2HCHO
EtOH, 
Me
Me
S
S
CN
CN
1
2a,b
2 a R = 4-MeC6H4, b R = Ph
1
IR spectra were obtained on an IRS-29 spectrophotometer using vaseline oil. H NMR spectra were
recorded on a Bruker Avance II 400 instrument (400 MHz) using DMSO-d6 with TMS as internal standard.
Elemental analysis was performed on a Perkin Elmer CHN analyzer. Melting points for the compounds prepared
were determined on a Kofler hot stage and are not corrected. The reaction course and purity of the synthesized
compounds was monitored by TLC on Silufol UV-254 plates using acetone–hexane (1:1) as eluent and visualized
with iodine vapor or in UV light.
Pyrido[2,1-b][1,3,5]thiadiazines 2a,b (General Method). A mixture of compound 1 (0.20 g,
1.2 mmol), a primary amine (1.8 mmol), and an excess of 37% formaldehyde (1.0 ml, 13.3 mmol) in EtOH
_______
*Deceased
**To whom correspondence should be addressed, e-mail: ka.frolov@inbox.ru.
1"ChemEx" Laboratory, Vladimir Dal' East-Ukrainian National University, 20-A/7 Molodezhny kv., Lugansk
91034, Ukraine.
2N. D. Zelinsky Institute of Organic Chemistry, 47 Lenin Ave., Moscow 117913, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1197-1198, July, 2012. Original
article submitted June 1, 2011.
0009-3122/12/4807-1117©2012 Springer Science+Business Media New York
1117

(10 ml) was refluxed to complete dissolution of the starting reagents (1-2 min), filtered through a paper filter,
and left for 24 h at 20ºC. The precipitate formed was filtered off, then washed with EtOH and hexane.
8-Methyl-3-(4-methylphenyl)-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-
9-carbonitrile (2a). Yield 0.18 g (50%); mp 143-145ºC (EtOH). IR spectrum, , cm-1: 1698 (C=O), 2192
1
3
(C≡N). H NMR spectrum, , ppm (J, Hz): 1.10 (3H, d, J = 6.6, 8-CH3); 2.27-2.33 (4H, m, H-8, ArCH3);
2.60-2.68 (2H, m, 7-CH2); 5.22 (2H, br. pseudo-s, NCH2N); 5.25 (1H, d, 2J = 13.8) and 5.45 (1H, d, 2J = 13.8,
SCH2N); 6.89 (2H, d, J = 8.2) and 7.06 (2H, d, J = 8.2, H Ar). Found, %: C 63.88; H 5.79; N 13.92.
C16H17N3OS. Calculated, %: C 64.19; H 5.72; N 14.03.
3
3
8-Methyl-6-oxo-3-phenyl-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitrile
1
(2b). Yield 0.21 g (61%); mp 159-161ºC (EtOH). IR spectrum, , cm-1: 1688 (C=O), 2190 (C≡N). H NMR
spectrum, , ppm (J, Hz): 1.10 (3H, d, 3J = 6.4, 8-CH3); 2.28-2.35 (1H, m, H-8); 2.62-2.67 (2H, m, 7-CH2); 5.26
2
2
(2H, br. pseudo-s, NCH2N); 5.29 (1H, d, J = 13.9) and 5.49 (1H, d, J = 13.9, SCH2N); 6.91-7.29 (5H, m,
H Ph). Found, %: C 62.88; H 5.35; N 14.64. C15H15N3OS. Calculated, %: C 63.13; H 5.30; N 14.72.
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