Mannich reaction in the synthesis of N,S-containing heterocycles. 16.*Synthesis of derivatives of tetra-hydropyrido[1,2-a][1,3,5]triazine and 5,6,12,13-tetra-hydro-1H,8H-dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocine

Article abstract of DOI:10.1007/s10593-013-1339-5

The aminomethylation of 6-amino-4-aryl-2-thioxo-1,2-dihydropyridine-3,5- dicarbonitriles by the action of primary amines and an excess of formaldehyde under conditions of base catalysis was studied. It was found that the structure and yields of the products depend largely on the structure of the initial amine and also on the ratio of the reagents and reaction conditions. In the case of alkyl- or arylalkylamines, 8-aryl-3-alkyl(arylalkyl)-6-thioxo-1,3,4,6- tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitriles were obtained, whereas when aromatic amines were used 3,10-diaryl-1,8-dithioxo-5,6,12,13- tetrahydro-1H,8H-dipyrido[1,2-a:1′,2′-e][1,3,5,7]tetrazocine-2,4,9, 11-tetracarbonitriles or their mixtures with the above-mentioned pyrido[1,2-a][1,3,5]triazines were obtained. Dipyrido[1,2-a:1′2′-e]- [1,3,5,7]tetrazocine derivatives were also synthesized by direct condensation of 6-amino-4-aryl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitriles with formaldehyde.

Full text of DOI:10.1007/s10593-013-1339-5

Chemistry of Heterocyclic Compounds, Vol. 49, No. 7, October, 2013 (Russian Original Vol. 49, No. 7, July, 2013)
MANNICH REACTION IN THE SYNTHESIS OF N,S-CONTAINING
HETEROCYCLES. 16.* SYNTHESIS OF DERIVATIVES OF TETRA-
HYDROPYRIDO[1,2-a][1,3,5]TRIAZINE AND 5,6,12,13-TETRA-
HYDRO-1H,8H-DIPYRIDO[1,2-a:1',2'-e][1,3,5,7]TETRAZOCINE
V. V. Dotsenko1**, S. Yu. Suikov2, T. M. Pekhtereva2, and S. G. Krivokolysko1
The aminomethylation of 6-amino-4-aryl-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitriles by the action
of primary amines and an excess of formaldehyde under conditions of base catalysis was studied. It was
found that the structure and yields of the products depend largely on the structure of the initial amine
and also on the ratio of the reagents and reaction conditions. In the case of alkyl- or arylalkylamines,
8-aryl-3-alkyl(arylalkyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitriles
were obtained, whereas when aromatic amines were used 3,10-diaryl-1,8-dithioxo-5,6,12,13-tetrahydro-
1H,8H-dipyrido[1,2-a:1′,2′-e][1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitriles or their mixtures with the
above-mentioned pyrido[1,2-a][1,3,5]triazines were obtained. Dipyrido[1,2-a:1′2′-e]-[1,3,5,7]tetrazocine
derivatives were also synthesized by direct condensation of 6-amino-4-aryl-2-thioxo-1,2-dihydro-
pyridine-3,5-dicarbonitriles with formaldehyde.
Keywords: 6-amino-4-aryl-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitriles, dipyrido[1,2-a:1'2'-e][1,3,5,7]-
tetrazocines, pyrido[1,2-a][1,3,5]triazines, double Mannich reaction, multicomponent cyclo-
condensation.
It is well known that pyrido[1,2-a][1,3,5]triazine derivatives have high biological activity. Thus, being
antagonists of serotonin receptors 5-HT2 and 5-HT2a, they exhibit hypotensive [2, 3] and antithrombotic [4]
activity. Pyrido[1,2-a][1,3,5]triazines also have anthelmintic activity [5-7]. The most popular methods of
constructing the pyrido[1,2-a][1,3,5]triazine system are cyclodimerization of pyrid-2-yl iso(thio)cyanates
[8-13], the aza-Wittig reaction of (triphenylphosphoranylidene)aminopyridines with isocyanates [14], and the
reaction of 2-aminopyridine derivatives with various nucleophilic reagents: ethoxycarbonyl iso(thio)cyanate
[15, 16], diethylimino dicarboxylate [16], chlorocarbonyl isocyanate [17], ethoxymethyleneurethane [18],
chloroalkyl isocyanates [19], and N-(1-chloroalkylidene)carbamoyl chlorides [20].
_______
*For communication 15, see [1].
**To whom correspondence should be addressed, e-mail: Victor_Dotsenko@bigmir.net.
1"ChemEx" Laboratory, Vladimir Dal' East Ukrainian National University, 20-A Molodyozhnyi Kv., Lugansk
91034, Ukraine.
2L. M. Litvinenko Institute of Physical-Organic Chemistry and Coal Chemistry, National Academy of Sciences
of Ukraine, 70 R. Luxemburg St., Donetsk 83114, Ukraine; e-mail: pechtereva@i.ua.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1082-1097, July, 2013. Original
article submitted May 16, 2012; revision submitted January 9, 2013.
0009-3122/13/4907-1009©2013 Springer Science+Business Media New York
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While continuing a cycle of researches on the aminomethylation of cyclic S,N-bis-nucleophiles our
attention was focussed on 6-amino-4-aryl-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitriles 1 as possible
substrates for the preparation of pyrido[1,2-a][1,3,5]triazine derivatives under the Mannich reaction conditions.
The pyridines 1 are fully accessible compounds and can be synthesized easily by several methods starting from
malononitrile and/or cyanothioacetamide [21-24]. Earlier we did a preliminary report [25] on the possibility of
producing pyrido[1,2-a][1,3,5]triazine derivatives upon the aminomethylation of compounds 1. In the present
work, we present the results from a detailed investigation of the behavior of 6-amino-4-aryl-2-thioxo-
1,2-dihydropyridine-3,5-dicarbonitriles 1 and the corresponding thiolates under Mannich conditions.
Ar
Ar
Ar
CN
S
NC
CN
S
NC
CN
NC
Et3N
EtOH
Method B
Method А
N
H2N
N
H
1a–d
H2N
S
N
H2N
NMM+
Et3NH+
4a–d
4e,f
RNH2
EtOH, 
HCHO
Ar
Ar
Ar
CN
S
NC
CN
S
NC
HN
CN
NC
HN
N
N
R
S
N
N
HO
H
B
N
R
N
2a–x
H
A
S
CN
H
4
N
8
7
N
NC
Ar
6
5
HCHO, Et3N
9
3
1c,d, 4e
N
EtOH or DMF, 
12
N
H
13
10
2
Ar
CN
1
11
CN
S
3a–f
NMM+ = N-methylmorpholinium; 1, 3, 4 a Ar = 4-MeC6H4, b Ar = 4-ClC6H4, c Ar = 3,4-(MeO)2C6H3,
d Ar = 4-MeOC6H4, e Ar = 2-thienyl, f Ar = 4-EtOC6H4; 2 a Ar = 4-MeC6H4, R = CH2Ph; b Ar = 4-MeC6H4,
R = furfuryl; с Ar = 4-MeC6H4, R = 4-EtC6H4; d Ar = R = 4-MeC6H4; e Ar = 4-ClC6H4, R = CH2Ph; f Ar = 4-ClC6H4,
R = 4-MeC6H4; g Ar = 4-ClC6H4, R = 4-EtOC6H4; h Ar = 3,4-(MeO)2C6H3, R = CH2Ph; i Ar = 3,4-(MeO)2C6H3,
R = 4-MeC6H4; j Ar = 4-MeOC6H4, R = 4-O2NC6H4; k Ar = 4-MeOC6H4, R = CH2CH2Ph;
l Ar = 4-MeOC6H4, R = t-Bu; m Ar = 4-MeOC6H4, R = 4-MeC6H4; n Ar = 2-thienyl, R = CH2Ph;
o Ar = 2-thienyl, R = CH2CH2Ph; p Ar = 4-EtOC6H4, R = CH2Ph; q Ar = 4-EtOC6H4, R = Me;
r Ar = 4-EtOC6H4, R = CH2CO2Et; s Ar = 4-EtOC6H4, R = Ph; t Ar = 4-EtOC6H4,
R = 4-HOOCC6H4; u Ar = 4-EtOC6H4, R = 4-MeC6H4; v Ar = 4-EtOC6H4, R = CH2COPh;
w Ar = 4-EtOC6H4, R = 4-BrC6H4; x Ar = 4-EtOC6H4, R = furfuryl
It was established that the structure of the products from the reaction of 6-aminopyridine-2(1H)-thiones
1 with an excess of HCHO and primary amines depends substantially on the structure of the amine component.
Thus, after successive treatment with Et3N in refluxing alcohol, 2 equiv. of a highly nucleophilic primary amine,
and then with an excess (20-25 equiv.) of HCHO, compounds 1a-d are aminomethylated smoothly at the N-1
and 6-NH2 nitrogen atoms with the formation of the expected pyrido[1,2-a][1,3,5]triazine derivatives
2a,b,e,h,k,l (method A) with up to quantitative yields. However, the introduction of aromatic amines into the
reaction leads either to the formation of a mixture of pyridotriazines 2c,d,f,g,i,m and dipyrido[1,2-a:1′,2′-e]-
[1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile derivatives 3a-d in various ratios (Table 1) or to the exclusive
1010

formation of dipyridotetrazocines 3. The latter are the products of the concurrent reaction in which the
6-aminopyridine-2(1H)-thiones 1a-d act simultaneously as substrate and as amine component of the Mannich
reaction. The dipyridotetrazocines 3c-e were also obtained by direct treatment of the thiones 1c,d and the
thiolate 4e with formalin in the absence of the amines. The formation of the tetrazocine 3f in the case where
α-aminoacetophenone is used is probably due to removal of the latter from the reaction zone as a result of self-
condensation side processes.
It was established that the aminomethylation of 6-aminopyridine-2(1H)-thiones 1a-d is facilitated in the
presence of Et3N. The catalytic effect of the base is obviously due to increase in the nucleophilicity of the
substrate as a result of the formation of the corresponding triethylammonium pyridine-2-thiolates 4a-d and also
to the higher solubility of the latter in EtOH compared with compounds 1a-d. The N-methylmorpholinium
thiolates 4a,f can also be brought directly into the reaction (method B), leading to the eventual formation of
analogous products. If secondary amines and piperidine in particular are used as base it is in principle possible
to obtain the expected products but with smaller yields, evidently as a result of aminomethylation side reactions
involving the base. For example, with piperidine as catalyst the pyridotriazine 2d was obtained in a yield of
only 25%.
The effect of the reagent ratio (pyridinethione 1d:amine) and the conditions on the product yields and
on the direction of the reaction was demonstrated for the case of the interaction of 6-aminopyridine-2(1H)-
thione 1d with para-toluidine and formalin. Thus, under model conditions (method A, refluxing, 2 equiv. of the
amine) a mixture of pyrido[1,2-a][1,3,5]triazine 2m and dipyridotetrazocine 3d in a ratio of ~3:1 was formed
(according to 1H NMR spectroscopy). With an equimolar ratio of the reagents the proportion of the tetrazocine
component increased regularly, and a mixture of compounds 2m and 3d in a ratio of ~8:7 was obtained as
product (according to HPLC/MS 7:8). On the other hand, realization of the reaction under milder conditions
(1 equiv. of the amine, 30-40°C) promoted aminomethylation involving the more active para-toluidine, and the
ratio of the products changed in favor of the pyridotriazine 2m (~9:1). The use of an excess of the amine
(2.5 equiv.) under these conditions gave a product containing only trace quantities of the dipyridotetrazocine 3d.
However, an appreciable decrease in the total yield of the aminomethylation products was observed if the
reaction was carried out without heating. It is thus possible to achieve a high degree of regioselectivity in the
process by varying the reaction conditions and the reagent ratio. Study of the possibilities for regioselective
synthesis of the pyridotriazines 2 and pyridotetrazocines 3 will form the subject of our future investigations.
The obtained compounds 2a-x are finely crystalline powders with colors from light-yellow to yellow-
orange. They are insoluble in ethanol, moderately soluble in acetone and DMF, and soluble in dimethyl
sulfoxide. The tetrazocines 3a-f are beige or pale-yellow powders insoluble in CHCl3, EtOH, and acetone and
poorly soluble in DMF and DMSO. The substantial differences in the solubility of compounds 2a-x and 3a-f
make it possible to separate their mixtures into the individual components. Thus, the appreciably less soluble
dipyridotetrazocines can be separated by recrystallization, as was demonstrated for the case of the mixture of
compounds 2u and 3f. As shown above it is, however, clear that a highly selective regiodirected path for the
preparation of compounds 2 and 3 has better prospects.
The structure of the synthesized compounds was confirmed by elemental analysis and by spectral
investigations (Table 1). Thus, the IR spectra of pyrido[1,2-a][1,3,5]triazines 2a-x contain absorption bands
corresponding to the stretching vibrations of the NH bond (3355-3180 cm-1) and two conjugated cyano groups
with maxima in the regions of 2229-2219 and 2216-2205 cm-1. In the IR spectra of compounds 2a-x there are
broad singlets for the protons of the methylene groups 2-CH2 and 4-CH2 resonating at 4.42-5.20 ppm and 5.38-
6.19 ppm and also broad singlets for the NH protons at 9.06-9.60 ppm. It should be noted that the signals of the
3
2-CH2 and NH protons do not reveal splitting, which is obviously due to the small value of the JNH,C(2)H spin-
spin coupling constant. We observed a similar phenomen earlier [25, 26] in the series of annelated
tetrahydro[1,3,5]triazines of similar structure.
1011

1012

1013

1014

The IR spectra of the products from reaction of pyridines 1a-d and 4e,f with HCHO contain absorption
bands corresponding to the stretching vibrations of the N–H bond at 3350-3310 cm-1 and also a single broad
absorption band at 2215-2205 cm-1 (C≡N). The 1H NMR spectra of compounds 3a-f contain a set of signals for
the NHCH2N fragment in the form of three doublets of doublets (or unresolved multiplets) at 4.63-4.86 and
6.85-7.11 ppm (CH2) and also at 8.53-8.97 ppm (NH) (2JНСН = 10.3-13.4, 3JNH,CH = 2.0-3.4, 3JNH,CH = 8.3-9.8 Hz).
The mass spectra contain a molecular ion peak indicating that the molecules of compounds 3a-f contain two
2-aminopyridine fragments linked by two methylene bridges. On the basis of these data, four alternative
structures A-D can be proposed for compounds 3a-f (Fig. 1).
Ar
Ar
Ar
Ar
CN
CN
S
NC
HN
CN
S
CN
NH
S
NC
NC
NC
HN
S
N
N
N
N
N
N
HN
HN
S
NH
CN
N
H
N
HN
S
N
S
S
NC
NC
NC
CN
CN
CN
Ar
NC
Ar
Ar
Ar
A
B
C
D
Fig. 1. Alternative structures for the products of the reaction of pyridines 1 with HCHO.
1
1
A choice in favor of structure A was made on the basis of the results from H–1H COSY and H–13C
HSQC experiments for compound 3d. The presence of the corresponding cross peaks in the H–1H COSY
1
spectrum indicates spin-spin coupling between the NH protons and the protons of the methylene bridges
(Fig. 2). In the 13C NMR spectrum of compound 3d there is a single peak at 42.4 ppm corresponding to the
1
carbons of the methylene bridges. In the H–13C HSQC spectrum, this signal gives two cross peaks with the
Fig. 2. Fragment of the 1H–1H COSY spectrum of compound 3d.
1015

Fig. 3. Fragment of the 1H–13C HSQC spectrum of compound 3d.
protons of the CH2 group in the form of a broad doublet at 4.74 ppm and a doublet of doublets at 7.03 ppm
3
(2J = 11.4 Hz, JNH,CH = 9.0 Hz). The upfield shift of the signals for one of the protons of the methylene bridge
(4.63-4.86 ppm) observed in the spectra of compounds 3a-f is probably due to the effect of the magnetic
anisotropy of the surrounding groups in the relatively rigid cyclic structure. The presence of the signal at 189.8
ppm (C=S) in the 13C NMR spectrum of compound 3d makes it possible to exclude structures C and D from
consideration.
Therefore, it was thus established that the result of the aminomethylation of 6-amino-2-thioxo-1,2-di-
hydropyridine-3,5-dicarbonitriles by the action of HCHO and primary amines depends substantially on the
structure of the latter: in the case of highly nucleophilic aliphatic amines pyrido[1,2-a][1,3,5]triazine derivatives
were obtained, whereas the products of the competing reaction of 6-aminopyridine-2(1H)-thiones with HCHO,
i.e., dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocines, or their mixtures with pyrido[1,2-a][1,3,5]tri-azines, were
formed when less active aromatic amines were used. In general, the ratio of the products in the mixture is
affected by the ratio of the reagents and the nucleophilicity of the amine, whereas the steric factor (the steric
arrangement of the substituents Ar and R) does not play a significant role. The products from aminomethylation
involving the S-nucleophilic centers are not formed under the given conditions. The aminomethylation of
6-aminopyridine-2(1H)-thiones is regiocontrolled; by varying the ratio of the reagents and reaction temperature
it is possible to change the ratio of the products in the mixtures over a wide range right up to full
regioselectivity. The dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocine derivatives can also be obtained by direct
condensation of 6-amino-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitriles with formaldehyde.
EXPERIMENTAL
The IR spectrum of compound 3d was recorded in pellets with KBr on an Infralum FT-801 Fourier
spectrometer; the spectra of the other compounds were recorded in vaseline oil on an IKS-29
1
spectrophotometer. The H NMR spectra were recorded on Varian Gemini 200 (200 MHz, compounds 2a,b,e,
mixtures 2с+3а, 2f+3b, 2g+3b), Bruker DRX-400 (400 MHz, compounds 2k,l,x, 3с-е, mixtures 2d+3а,
1016

2m+3d, and 2w+3f), and Bruker DRX-500 (500 MHz, compounds 2h,n-r, mixtures 2i+3c, 2s+3f, 2t+3f, 2u+3f)
1
1
spectrometers. Solvent was DMSO-d6, TMS was an internal standard. The 13С, H–1H COSY, and Н–13С
HSQC NMR spectra of compound 3d were recorded on a Bruker Avance II 400 spectrometer (400 MHz for 1H
nuclei and 100 MHz for 13C nuclei) at 60°C in DMSO-d6, with internal standard TMS. The HPLC-MS analysis
of compounds 2k,l,x, 3d,e and of the mixtures 2d+3a and 2m+3d was conducted on a Shimadzu
LC-10AD liquid chromatograph with Shimadzu SP D-10A UV-Vis (254 nm) and Sedex 75 ELSD detectors in
conjunction with a PE SCIEX API 150EX mass spectrometer with electrospray ionization at atmospheric
pressure. Elemental analysis was performed on a Carlo-Erba 1106 Elemental Analyzer with ±0.40% error. The
melting points were determined on a Kofler hot bench and were not corrected. The purity of the synthesized
compounds was monitored by TLC on Silufol UV-254 plates in the 1:1 acetone–hexane system with
visualization by iodine vapor and a UV detector. The starting 6-aminopyridine-2(1H)-thiones 1a-d [27] and the
thiolates 4e,f [28] were obtained by known methods.
Preparation of Pyrido[1,2-a][1,3,5]triazines 2a-m and/or Dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazoci-
nes 3a-d from 2-Aminopyridines 1a-d (General Method). A. Et3N (0.14 ml, 1.0 mmol) was added to a
suspension of the corresponding 6-aminopyridinethione 1a-d (0.7-0.8 mmol) in EtOH (10 ml). The mixture was
heated with vigorous stirring until completely dissolved; the corresponding primary amine (2 equiv.) and an
excess of 37% formalin free from paraform impurity (1.5 ml, 20 mmol) were added to the obtained solution.
The mixture was refluxed with vigorous stirring for 3-5 min, stirred at ~20°C for 6 h, and left overnight. The
finely crystalline yellow precipitate of the corresponding compound 2a-m, 3a-d or their mixtures was filtered
off, washed with water and alcohol, and recrystallized when necessary from the indicated solvent.
Preparation of Pyrido[1,2-a][1,3,5]triazines 2n-x and/or Dipyrido[1,2-a:1′,2′-e][1,3,5,7]tetra-
zocines 3e,f from Pyridine-2-thiolates 4e,f (General Method). B. N-methylmorpholinium pyridine-2-thiolate
4e,f (~0.7-0.8 mmol) was dissolved by heating in EtOH (10 ml); the corresponding primary amine (2 equiv.)
and an excess of 37% formalin free from paraform impurity (1.5 ml, 20 mmol) were added. The obtained
mixture was refluxed with stirring for 2-3 min, and the product usually began to crystallize. The reaction
mixture was maintained at 20°C for 24-48 h, and the precipitate was filtered off and washed successively with
EtOH, water, and EtOH.
Reaction of 6-Amino-4-(4-methylphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1a)
with Benzylamine and Formalin. The reaction of pyridine 1a (208 mg, 0.78 mmol) and PhCH2NH2 (0.17 ml,
1.56 mmol) by method A gave 3-benzyl-8-(4-methylphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-
[1,3,5]triazine-7,9-dicarbonitrile (2a). Yield 261 mg (84%), finely crystalline light-yellow powder, mp 215-
1
220°C (decomp.). The product was obtained in analytically pure form and according to H NMR spectroscopy
did not contain the tetrazocine 3a as impurity. Found, %: C 69.24; H 4.85; N 17.46. C23H19N5S. Calculated, %:
C 69.50; H 4.82; N 17.62.
Reaction of 6-Amino-4-(4-methylphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1a) with
Furfurylamine and Formalin. The reaction of pyridine 1a (220 mg, 0.83 mmol) and furfurylamine (0.15 ml,
1.70 mmol) by method A gave 3-furfuryl-8-(4-methylphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-
[1,3,5]triazine-7,9-dicarbonitrile (2b). Yield 288 g (90%), finely crystalline light-yellow powder, mp 225-230°C
(decomp.). The product was obtained in analytically pure form and according to 1H NMR spectroscopy did not
contain the tetrazocine 3a as impurity. Found, %: C 65.29; H 4.44; N 18.00. C21H17N5ОS. Calculated, %:
C 65.10; H 4.42; N 18.07.
Reaction of 6-Amino-4-(4-methylphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1a) with
4-Ethylaniline and Formalin. The reaction of pyridine 1a (210 mg, 0.79 mmol) and 4-ethylaniline (0.20 ml,
1
1.58 mmol) by method A gave a mixture that according to H NMR spectroscopy consisted of ~87 mol% of
3-(4-ethylphenyl)-8-(4-methylphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbo-
nitrile (2c) and ~13 mol% of 3,10-di(4-methylphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido-
[1,2-a;1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3a). Total yield 202 mg (corresponds to a ~52% yield
of pyridotriazine 2c and ~16% of tetrazocine 3a of the theoretically calculated on the pyridine 1a), yellow powder.
1017

Reaction of 6-Amino-4-(4-methylphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1a)
with para-Toluidine and Formalin. The reaction of pyridine 1a (210 mg, 0.79 mmol) and para-toluidine
(170 g, 1.59 mmol) by method A gave a mixture consisting, according to 1H NMR spectroscopy, of ~90 mol%
of 3,8-di(4-methylphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitrile (2d)
and ~10 mol% of 3,10-di(4-methylphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido[1,2-a:1′,2′-e]-
[1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3a). Total yield 230 mg (corresponds to ~64% of the
pyridotriazine 2d and ~14% of the tetrazocine 3a of the theoretically calculated on the pyridine 1a), bright-
yellow powder. Mass spectrum, m/z: 398.4 (2d [М+H]+), 556.5 (3a [М+H]+) According to HPLC-MS, the
2d:3a ratio amounts to 96:4.
Reaction of 6-Amino-4-(4-chlorophenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1b) with
Benzylamine and Formalin. The reaction of pyridine 1b (215 mg, 0.75 mmol) and PhCH2NH2 (0.17 ml, 1.56
mmol) by method
A
gave 3-benzyl-8-(4-chlorophenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-
[1,3,5]triazine-7,9-dicarbonitrile (2e). Yield 279 mg (89%), finely crystalline light-yellow powder, mp > 200°C
(decomp.). The product was obtained in analytically pure form and according to 1H NMR spectroscopy did not
contain the tetrazocine 3b as impurity. Found, %: C 63.04; H 3.90; N 16.56. C22H16ClN5S. Calculated, %:
C 63.23; H 3.86; N 16.76.
Reaction of 6-Amino-4-(4-chlorophenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1b) with
para-Toluidine and Formalin. The reaction of pyridine 1b (211 mg, 0.74 mmol) and para-toluidine (158 mg,
1
1.47 mmol) by method A gave a mixture that consisted, according to H NMR spectroscopy, of ~90 mol% of
8-(4-chlorophenyl)-3-(4-methylphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbo-
nitrile (2f) and ~10 mol% of 3,10-di(4-chlorophenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido-
[1,2-a:1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3b). Total yield 187 mg (corresponds to a ~52%
yield of pyridotriazine 2f and ~12% of tetrazocine 3b of the theoretically calculated on the pyridine 1b), yellow
powder.
Reaction of 6-Amino-4-(4-chlorophenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1b) with
4-Ethoxyaniline and Formalin. The reaction of pyridine 1b (204 mg, 0.71 mmol) and 4-ethoxyaniline (0.18
1
ml, 1.40 mmol) by method A gave a mixture that, according to H NMR spectroscopy, consisted of ~40 mol% of
8-(4-chlorophenyl)-3-(4-ethoxyphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbo-
nitrile (2g) and ~60 mol% of 3,10-di(4-chlorophenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido-
[1,2-a:1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3b). Total yield 178 mg (corresponds to a ~19% yield of
pyridotriazine 2g and ~56% of tetrazocine 3b of the theoretically calculated on the pyridine 1b), yellow powder.
Reaction of 6-Amino-4-(3,4-dimethoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile
(1c) with Benzylamine and Formalin. The reaction of pyridine 1c (228 mg, 0.73 mmol) and PhCH2NH2
(0.20 ml, 1.83 mmol) by method A gave 3-benzyl-8-(3,4-dimethoxyphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-
pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitrile (2h). Yield 235 mg (73%), finely crystalline yellow powder, mp
1
>250°C, Rf 0.40. The product was obtained in analytically pure form and according to H NMR spectroscopy
did not contain tetrazocine 3c as impurity. Found, %: C 64.84; H 4.80; N 15.90. C24H21N5O2S. Calculated, %:
C 64.99; H 4.77; N 15.79.
Reaction of 6-Amino-4-(3,4-dimethoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile
(1c) with para-Toluidine and Formalin. The reaction of pyridine 1c (214 mg, 0.69 mmol) and para-toluidine
1
(147 mg, 1.37 mmol) by method A gave a mixture that, according to H NMR spectroscopy, consisted of
~75 mol% of 8-(3,4-dimethoxyphenyl)-3-(4-methylphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-
[1,3,5]triazine-7,9-dicarbonitrile (2i) (Rf 0.54) and ~25 mol% of 3,10-di(3,4-dimethoxyphenyl)-1,8-dithioxo-
5,6,12,13-tetrahydro-1H,8H-dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3c) (Rf 0.10).
Total yield 190 mg (corresponds to a ~44% yield of the pyridotriazine 2i and ~29% of the tetrazocine 3c of the
theoretically calculated on the pyridine 1c), yellow powder.
Reaction of 6-Amino-4-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1d)
with 4-Nitroaniline and Formalin. The reaction of pyridine 1d (225 mg, 0.80 mmol) with 4-nitroaniline
1018

(150 mg, 1.09 mmol) by method A gave 3,10-di(4-methoxyphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-
dipyrido[1,2-a:1',2'-e] [1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3d) not containing the pyridotriazine 2j as
impurity. The analytically pure product was obtained by recrystallization from DMSO. Yield 70 mg (30%), beige
powder, mp >300°C. Found, %: C 61.48; H 3.45; N 18.90. C30H20N8O2S2. Calculated, %: C 61.21; H 3.42; N 19.03.
Reaction of 6-Amino-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1d)
with 2-Phenylethylamine and Formalin. The reaction of pyridine 1d (306 mg, 1.08 mmol) and Ph(CH2)2NH2
(0.27 ml, 2.15 mmol) by method A gave 8-(4-methoxyphenyl)-3-(2-phenylethyl)-6-thioxo-1,3,4,6-tetrahydro-
2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitrile (2k). Yield 390 mg (~84%), finely crystalline yellow powder,
mp >220°C (decomp.), Rf 0.53. The product was obtained in analytically pure form and, according to 1H NMR
spectroscopy, did not contain the tetrazocine 3d as impurity. Mass spectrum, m/z: 134.3 [H2C=N(CH2)2Ph+H]+,
307.3 [M-Ph(CH2)2NH2+H]+, 428.3 [М+H]+, 855.3 [2М+H]+. Found, %: C 67.20; H 5.02; N 16.52. C24H21N5OS.
Calculated, %: C 67.43; H 4.95; N 16.38.
Reaction of 6-Amino-4-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1d)
with tert-Butylamine and Formalin. The reaction of pyridine 1d (320 mg, 1.13 mmol) and t-BuNH2 (0.5 ml,
4.76 mmol) by method A gave 3-(tert-butyl)-8-(4-methoxyphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-
[1,3,5]triazine-7,9-dicarbonitrile (2l). Yield 337 mg (78%), finely crystalline light-yellow powder, mp >250°C,
1
Rf 0.61 (acetone–hexane, 1:1). The product was obtained in analytically pure form and according to H NMR
spectroscopy did not contain tetrazocine 3d as impurity. Mass spectrum, m/z: 380.1 [М+H]+, 759.5 [2М+H]+.
Found, %: C 63.07; H 5.62; N 18.54. C20H21N5OS. Calculated, %: C 63.30; H 5.58; N 18.45.
Reaction of 6-Amino-4-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1d)
with 2 equiv. of para-Toluidine and Formalin. The reaction of pyridine 1d (318 mg, 1.13 mmol) and para-
toluidine (241 mg, 2.25 mmol) by method A gave a mixture, that, according to 1H NMR spectroscopy, consisted
of ~75 mol% of 3-(4-methylphenyl)-8-(4-methoxyphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-
[1,3,5]triazine-7,9-dicarbonitrile (2m) (Rf 0.58) and ~25 mol% of 3,10-di(4-methoxyphenyl)-1,8-dithioxo-
5,6,12,13-tetrahydro-1H,8H-dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3d) (Rf 0.17).
Total yield 212 mg (corresponds to a ~31% yield of pyridotriazine 2m and ~21% of tetrazocine 3d of the
theoretically calculated on pyridine 1d), yellow powder.
Reaction of 6-Amino-4-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1d) with
1 equiv. of para-Toluidine and Formalin. Et3N (0.35 ml, 2.52 mmol) was added to a suspension of pyridine 1d
(330 mg, 1.17 mmol) and para-toluidine (125 mg, 1.17 mmol) in EtOH (12 ml), and the mixture was heated with
vigorous stirring until completely dissolved. An excess of 37% formalin free from paraform impurity (1.5 ml,
20 mmol) was added to the obtained solution. The obtained mixture was refluxed with vigorous stirring for 3-5 min,
while the product began to crystallize. The mixture was stirred for 2 h at ~50°C, cooled, and left overnight. The
finely crystalline yellow precipitate that formed was filtered off and washed with water, alcohol, and petroleum ether. A
1
mixture that, according to H NMR spectroscopy, contained ~53 mol% of 8-(4-methoxyphenyl)-3-(4-methylphenyl)-
6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitrile (2m) (Rf 0.55) and ~47 mol% of 3,10-di-
(4-methoxyphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido-[1,2-a:1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-
tetracarbonitrile (3d) (Rf 0.14) was obtained. Total yield 176 mg (corresponds to a ~16% yield of pyridotriazine 2m
and ~28% of tetrazocine 3d of the theoretically calculated on the pyridine 1d), yellow powder. 1H NMR spectrum, δ,
ppm (J, Hz): 2.23 (1.59Н, s, ArCH3); 3.83 (1.59H, s, ОCH3); 3.84* (2.82Н, s, 2ОCH3); 4.74* (0.94Н, dd, 2J = 13.1,
3
3J = 2.4, NHCH2N); 5.07 (1.06Н, br. s, 2-СН2); 6.05 (1.06Н, br. s, 4-СН2); 6.98 (1.06H, d, J = 8.3, H Ar);
7.00-7.04* (0.94H, м, NHCH2N); 7.07 (1.06H, d, 3J = 8.6, H Ar); 7.11* (1.88H, d, 3J = 8.5, H Ar); 7.16 (1.06H, d,
3J = 8.3, H Ar); 7.46 (1.06H, d, 3J = 8.6, H Ar); 7.51* (1.88H, d, 3J = 8.5, H Ar); 8.79* (0.94Н, dd, 3J = 2.4, 3J = 8.7,
2NH); 9.54 (0.53Н, br. s, NH). Mass spectrum, m/z: 120.1 (2m, [ArN=CH2+H]+), 295.5 (3d, [1/2M+H]+), 414.0 (2m
[М+H]+), 428.0 (2m [М+15]+), 589.0 (3d [M+H]+), 827.0 (2m [2М+H]+). According to HPLC-MS, the sample
contained compounds 3m and 3d in a ratio of ~7:8 (47 and 53%).
_______
*Signals of tetrazocine 3d.
1019

Reaction of 6-Amino-4-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (1d)
with 1 equiv. of para-Toluidine and Formalin without Refluxing. Et3N (0.4 ml, 2.87 mmol) was added to a
suspension of pyridine 1d (301 mg, 1.07 mmol) and para-toluidine (115 mg, 1.07 mmol) in EtOH (12 ml), and the
mixture was heated with vigorous stirring until completely dissolved. An excess of 37% formalin free from paraform
impurity (1.5 ml, 20 mmol) was added to the obtained solution. The mixture was stirred at 30-40°C, and after
2-3 min a precipitate began to form. The mixture was stirred for a further 20 min and maintained at 20°C for
24 h. The precipitate was filtered off and washed with water, EtOH, and petroleum ether. A mixture that
according to 1H NMR spectroscopy contained ~90 mol% of 8-(4-methoxyphenyl)-3-(4-methylphenyl)-6-thioxo-
1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]tri-azine-7,9-dicarbonitrile (2m) and ~10 mol% of 3,10-di(4-
methoxyphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-di-pyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-
tetracarbonitrile (3d) was obtained. Total yield 143 mg (corresponds to a ~28% yield of pyridotriazine 2m and
~6% of tetrazocine 3d of the theoretically calculated on the pyridine 1d), finely crystalline light-yellow powder.
1H NMR spectrum, δ, ppm (J, Hz): 2.23 (0.27Н, s, ArСН3); 3.80-3.85* (3Н, m, ОСН3); 4.74-4.79** (0.2Н, m,
NHCH2N); 5.07 (1.8Н, br. s, 2-СН2); 6.05 (1.8Н, br. s, 4-СН2); 6.98 (1.8H, d, 3J = 8.1, H Ar); 7.00-7.16* (4.2Н,
m, NHCH2N (3d), H Ar); 7.46 (1.8H, d, 3J = 8.0, H Ar); 7.51** (0.4H, d, 3J = 8.3, H Ar); 8.76-8.83** (0.2Н, m,
2NH); 9.46 (0.9Н, br. s, NH).
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(2-thienyl)pyridine-2-thiolate (4e)
with Benzylamine and Formalin. The reaction of the thiolate 4e (307 mg, 0.85 mmol) and PhCH2NH2
(0.18 ml, 1.65 mmol) by method B gave 3-benzyl-(2-thienyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-
[1,3,5]triazine-7,9-dicarbonitrile (2n). Yield 331 mg (~100%), finely crystalline yellow powder, mp >250°C,
1
Rf 0.61. The product was obtained in analytically pure form and according to H NMR spectroscopy did not
contain tetrazocine 3e impurity. Found, %: C 61.74; H 3.90; N 18.05. C20H15N5S2. Calculated, %: C 61.67;
H 3.88; N 17.98.
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(2-thienyl)pyridine-2-thiolate (4e)
with 2-Phenylethylamine and Formalin. The reaction of the thiolate 4e (201 mg, 0.56 mmol) and
Ph(CH2)2NH2 (0.14 ml, 1.12 mmol) by method B gave 3-(2-phenylethyl)-8-(2-thienyl)-6-thioxo-1,3,4,6-tetra-
hydro-2H-pyrido[1,2-a]-[1,3,5]triazine-7,9-dicarbonitrile (2o). Yield 223 mg (~99%), finely crystalline yellow-
orange powder, mp 168-171°C (decomp.), Rf 0.65. The product was obtained in analytically pure form and
according to 1H NMR spectroscopy did not contain tetrazocine 3e impurity. Found, %: C 62.77; H 4.22; N 17.45.
C21H17N5S2. Calculated, %: C 62.51; H 4.25; N 17.36.
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(4-ethoxyphenyl)pyridine-2-thiolate
(4f) with Benzylamine and Formalin. The reaction of the thiolate 4f (300 mg, 0.76 mmol) and PhCH2NH2
(0.16 ml, 1.51 mmol) by method B gave 3-benzyl-8-(4-ethoxyphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-
pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitrile (2p). Yield 294 mg (91%), pale-yellow powder, mp >250°C. The
product was obtained in analytically pure form and according to 1H NMR spectroscopy did not contain tetrazocine 3f
impurity. Found, %: C 67.61; H 4.96; N 16.25. C24H21N5OS. Calculated, %: C 67.43; H 4.95; N 16.38.
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(4-ethoxyphenyl)pyridine-2-thiolate
with Methylamine and Formalin. The reaction of the thiolate 4f (295 mg, 0.74 mmol) and 40% aqueous
MeNH2 solution (0.15 ml, 1.74 mmol) by method B gave 8-(4-ethoxyphenyl)-3-methyl-6-thioxo-1,3,4,6-tetra-hydro-
2H-pyrido[2,1-a][1,3,5]triazine-7,9-dicarbonitrile (2q). Yield 230 mg (88%), yellow powder, mp >250°C. The
product was obtained in analytically pure form and according to 1H NMR spectroscopy did not contain tetrazocine 3f
impurity. Found, %: C 61.68; H 4.86; N 19.85. C18H17N5OS. Calculated, %: C 61.52; H 4.88; N 19.93.
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(4-ethoxyphenyl)pyridine-2-thiolate
(4f) with Ethyl 2-Aminoacetate and Formalin. The reaction of the thiolate 4f (315 mg, 0.79 mmol), ethyl
aminoacetate hydrochloride (0.209 g, 1.5 mmol), and Et3N (0.25 ml, 1.8 mmol) by method B gave ethyl [7,9-di-
______
*Multiplets formed by superimposition of the signals for compounds 2m and 3d.
**Signals of tetrazocine 3d.
1020

cyano-8-(4-ethoxycarbonyl)-6-thioxo-1,6-dihydro-2H-pyrido[1,2-a][1,3,5]triazin-3(4H)-yl]acetate (2r). Yield
327 mg (98%5), finely crystalline yellow powder, mp >250°C. The product was obtained in analytically pure
1
form and according to H NMR spectroscopy did not contain tetrazocine 3f impurity. Found, %: C 59.78;
H 4.96; N 16.66. C21H21N5O3S. Calculated, %: C 59.56; H 5.00; N 16.54.
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(4-ethoxyphenyl)pyridine-2-thiolate
(4f) with Aniline and Formalin. The reaction of the thiolate 4f (303 mg, 0.76 mmol) and aniline (0.14 ml,
1.54 mmol) by method B gave a mixture that, according to 1H NMR spectroscopy, consisted of ~87 mol% of
8-(4-ethoxyphenyl)-3-phenyl-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitrile (2s)
and ~13 mol% of 3,10-di(4-ethoxyphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido[1,2-a:1',2'-e]-
[1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3f). Total yield 266 mg (corresponds to a ~69% yield of
pyridotriazine 2s and ~21% of tetrazocine 3f of the theoretically calculated on the thiolate 4f), yellow powder.
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(4-ethoxyphenyl)pyridine-2-thiolate
(4f) with 4-Aminobenzoic Acid and Formalin. The reaction of the thiolate 4f (294 mg, 0.74 mmol) and
4-aminobenzoic acid (200 mg, 1.46 mmol) by method B gave a mixture that according to 1H NMR spectroscopy
consisted of ~43 mol% of 4-[7,9-dicyano-8-(4-ethoxycarbonyl)-6-thioxo-1,6-dihydro-2H-pyrido-[1,2-a]-
[1,3,5]triazin-3(4H)-yl]benzoic acid (2t) and ~57 mol% of 3,10-di(4-ethoxyphenyl)-1,8-dithioxo-5,6,12,13-tetra-
hydro-1H,8H-dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3f). Total yield 70 mg
(corresponds to a mixture of ~7% of pyridotriazine 2t and ~20% of tetrazocine 3f of the theoretically calculated
on the thiolate 4f), light-yellow powder.
Reaction of N-methylmorpholinium 6-Amino-3,5-dicyano-4-(4-ethoxyphenyl)pyridine-2-thiolate
(4f) with para-Toluidine and Formalin. The reaction of the thiolate 4f (315 mg, 0.79 mmol) with para-
toluidine (0.17 g, 1.59 mmol) by method B gave a mixture that, according to 1H NMR spectroscopy, consisted of
~50 mol% of 8-(4-ethoxyphenyl)-3-(4-methylphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]-
triazine-7,9-dicarbonitrile (2u) and ~50 mol% of 3,10-di(4-ethoxyphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-
1H,8H-dipyrido-[1,2-a:1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3f). Total yield 282 mg (corresponds
to a mixture of ~42% of the pyridotriazine 2u and ~56% of the tetrazocine 3f of the theoretically calculated on
the thiolate 4f), light-yellow powder. During an attempt at separation of the sample by crystallization from a 1:3
DMF–EtOH mixture, 120 mg (49%) of the tetrazocine 3f containing trace quantities of the pyridotriazine 2u
(<2%) was obtained. Flesh-colored powder.
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(4-ethoxyphenyl)pyridine-2-thiolate (4f)
with α-Aminoacetophenone and Formalin. The reaction of the thiolate 4f (310 mg, 0.78 mmol),
α-aminoacetophenone hydrochloride (336 mg, 1.56 mmol) and Et3N (0.25 ml, 1.8 mmol) by method B gave
3,10-di(4-ethoxyphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocine-
2,4,9,11-tetracarbonitrile (3f) containing trace quantities of the pyridotriazine 2v (~2%). The analytically pure
product was obtained by recrystallization from DMF followed by precipitation with acetone. Yield 110 mg
(46%), beige powder, mp >250°C. Found, %: C 61.98; H 3.95; N 18.26. C32H24N8O2S2. Calculated, %: C 62.32;
H 3.92; N 18.17.
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(4-ethoxyphenyl)pyridine-2-thiolate
(4f) with 4-Bromoaniline and Formalin. The reaction of the thiolate 4f (300 mg, 0.76 mmol) and
1
4-bromoaniline (152 mg, 0.88 mmol) by method B gave a mixture that according to H NMR spectroscopy
consisted of ~10 mol% of 3-(4-bromophenyl)-8-(4-ethoxyphenyl)-6-thioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-
[1,3,5]triazine-7,9-dicarbonitrile (2w) and ~90 mol% of 3,10-di(4-ethoxyphenyl)-1,8-dithioxo-5,6,12,13-tetra-
hydro-1H,8H-dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3f). Total yield 137 mg
(corresponds to a mixture of ~3% of pyridotriazine 2w and ~54% of tetrazocine 3f of the theoretically
calculated on the thiolate 4f), pale-yellow powder.
Reaction of N-Methylmorpholinium 6-Amino-3,5-dicyano-4-(4-ethoxyphenyl)pyridine-2-thiolate
(4f) with Furfurylamine and Formalin. The reaction of the thiolate 4f (300 mg, 0.76 mmol) and furfurylamine
(0.14 ml, 1.52 mmol) by method B gave 8-(4-ethoxyphenyl)-3-furfuryl-6-thioxo-1,3,4,6-tetra-hydro-2H-
1021

pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitrile (2x). Yield 280 mg (88%), finely crystalline yellow powder, mp
>230°C (decomp.). The product was obtained in analytically pure form and according to 1H NMR spectroscopy
did not contain tetrazocine 3f impurity. Mass spectrum, m/z: 418.3 [М+H]+, 835.2 [2М+H]+. Found, %:
C 63.51; H 5.03; N 16.75. C22H19N5OS. Calculated, %: C 63.29; H 4.59; N 16.77.
Preparation of Dipyrido[1,2-a:1',2'-e][1,3,5,7]tetrazocines 3c,d by Reaction of 2-Aminopyridines
1c,d with Formalin (General Method). An excess of Et3N (0.5 ml, 3.6 mmol) was added to a suspension of the
corresponding 6-aminopyridinethione 1c,d (1.3 mmol) in DMF (4-5 ml), and the mixture was heated with
vigorous stirring until completely dissolved. An excess of 37% formalin free from paraform impurity (1.0 ml,
13.3 mmol) was added to the obtained solution. The obtained mixture was refluxed with vigorous stirring for
3-5 min, while after 1-2 min a precipitate began to form. The suspension was stirred at ~20°C for 6 h and left
overnight. The finely crystalline precipitate of the dipyridotetrazocine 3c,d was washed with water and with
acetone. Instead of DMF it is possible to use EtOH (10 ml) as solvent, but the yields here are reduced to
41-49%.
3,10-Di(3,4-dimethoxyphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido[1,2-a:1',2'-e]-
[1,3,5,7]tetrazocine-2,4,9,11-tetracarbonitrile (3c). Yield 232 mg (55%) (in EtOH 173 mg (41%)), pale-
1
yellow powder, mp >300°C. IR spectrum, ν, cm-1: 2205-2215 (C≡N), 3260-3310 (N–H) H NMR spectrum, δ,
2
3
ppm (J, Hz): 3.78 (6Н, s, 2ОСН3); 3.84 (6Н, s, 2ОСН3); 4.76 (2Н, dd, J = 13.2, J = 2.9, NHCH2N); 7.06
2
3
(2Н, dd, J = 13.2, J = 9.4, NHCH2N); 7.11-7.14 (4Н, m, H Ar); 7.21-7.24 (2Н, m, H Ar); 8.80 (2Н, dd,
3
3J = 2.9, J = 9.4, 2NH). Found, %: C 59.38; H 3.75; N 17.16. C32H24N8O4S2. Calculated, %: C 59.25; H 3.73;
N 17.27.
3,10-Di(4-methoxyphenyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido[1,2-a:1',2'-e][1,3,5,7]-
tetrazocine-2,4,9,11-tetracarbonitrile (3d). Yield 256 mg (67%) (in EtOH 187 mg (49%)), beige powder,
1
mp >300°C (DMSO). IR spectrum, ν, cm-1: 1183 (С=S), 2215 (C≡N), 3341 (N–H). Н NMR spectrum, , ppm
2
3
2
3
(J, Hz): 3.86 (6Н, s, 2ОСН3); 4.71 (2Н, dd, J = 13.2, J = 3.0, NHCH2N); 7.04 (2Н, dd, J = 13.2, J = 9.2,
3
3
3
3
NHCH2N); 7.09 (4Н, d, J = 8.5, H Ar); 7.45 (4Н, d, J = 8.5, H Ar); 8.75 (2Н, dd, J = 3.0, J = 9.2, 2NH).
13C NMR spectrum, δ, ppm: 41.9 (NCH2); 55.1 (OСН3); 113.9 (C-3,5 Ar); 114.6 (C≡N); 114. 8 (C≡N); 125.4
(C-i Ar); 129.9 (C-2,6 Ar); 155.7 (C Py); 157.6 (C Py); 160.8 (С-4 Ar); 164.5 (C Py); 167.4 (C Py); 189.8 (C=S).
Mass spectrum, m/z: 588.8 [М+Н]+. Found, %: C 61.40; H 3.45; N 18.91. C30H20N8O2S2. Calculated, %:
C 61.21; H 3.42; N 19.03.
3,10-Di(2-thienyl)-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido[1,2-a:1',2'-e][1,3,5,7]tetra-
zocine-2,4,9,11-tetracarbonitrile (3e). An excess of 37% formalin (1.2 ml, 16 mmol), free from paraform
impurity, was added to a suspension of N-methylmorpholinium 6-amino-3,5-dicyanopyridine-4-(2-thienyl)-
3-thiolate (4e) [27] (95 mg, 0.264 mmol) in EtOH (5 ml). The mixture was heated to boiling with vigorous
stirring and quickly filtered through a folded filter. Crystallization began in 1-3 min, and after 6 h the precipitate
was filtered off and washed with EtOH and with acetone. Yield 51 mg (71%), finely crystalline light-yellow
powder, mp >250°C. 1H NMR spectrum, δ, ppm (J, Hz): 4.74 (2Н, dd, 2J = 13.4, 3J = 3.4, NHCH2N); 7.00 (2Н,
2
3
3
3
3
dd, J = 13.4, J = 9.1, NHCH2N); 7.28 (2Н, dd, J = 3.8, J = 4.8, Н-4 thienyl); 7.56 (2Н, d, J = 3.8, Н-3
3
3
3
thienyl); 7.95 (2Н, d, J = 4.8, Н-5 thienyl); 8.84 (2Н, dd, J = 3.4, J = 9.1, 2NH). Mass spectrum, m/z: 540.8
[М+Н]+. Found, %: C 53.70; H 2.35; N 20.95 Calculated, %: C 53.70; H 2.35; N 20.95.
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