Mannich reaction in the synthesis of n,s-containing heterocycles. 13. one-pot method for preparing pyrimido[4,3-b]-[1,3,5]thiadiazines by reaction of aldehydes, cyanothioacetamide, formaldehyde, and primary amines

Article abstract of DOI:10.1007/s10593-012-1038-7

Successive reaction of cyanothioacetamide with aliphatic or aromatic aldehydes, formaldehyde, and primary amines gives the corresponding 3,7-disubstituted 3,4,7,8-tetrahydro-2H,6H-pyrimido-[4,3-b][1,3,5]thiadiazine-9- carbonitriles.

Full text of DOI:10.1007/s10593-012-1038-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 4, July, 2012 (Russian Original Vol. 48, No. 4, April, 2012)
MANNICH REACTION IN THE SYNTHESIS OF
N,S-CONTAINING HETEROCYCLES. 13*. ONE-POT
METHOD FOR PREPARING PYRIMIDO[4,3-b]-
[1,3,5]THIADIAZINES BY REACTION OF ALDEHYDES,
CYANOTHIOACETAMIDE, FORMALDEHYDE,
AND PRIMARY AMINES
V. V. Dotsenko1**, K. A. Frolov1, and S. G. Krivokolysko1
Successive reaction of cyanothioacetamide with aliphatic or aromatic aldehydes, formaldehyde, and
primary amines gives the corresponding 3,7-disubstituted 3,4,7,8-tetrahydro-2H,6H-pyrimido-
[4,3-b][1,3,5]thiadiazine-9-carbonitriles.
Keywords: cyanothioacetamide, pyrimido[4,3-b][1,3,5]thiadiazines, aminomethylation, Mannich
reaction, multicomponent condensation.
The double aminomethylation of different N,S-dinucleophiles including dithiocarbamates, primary
thioamides, and 2-mercaptoazoles(azines) can be deservedly considered as one of the most simple and
convenient methods for constructing the 1,3,5-thiadiazine system [2-4]. This route was used successfully in the
synthesis of condensed thiadiazines including substituted bis(pyrido[2,1-b][1,3,5]thiadiazin-7-yl)methanes [5],
1,2,4-triazolo[3,4-b][1,3,5]thiadiazines [6], imidazo[2,1-b][1,3,5]thiadiazines [7-16], 1,2,4-triazino[3,2-b][1,3,5]thia-
diazines [15], thiazolo[3',4':1,5][1,2,4]triazolo[3,4-b][1,3,5]thiadiazines [17], 1,3,5-thiadiazino[3,2-a]benzimid-
azoles [18], cyclopenta[g]pyrido[2,1-b][1,3,5]thiadiazines [19], pyrimido[2,1-b][1,3,5]thiadiazines [20], and
pyrido[2,1-b][1,3,5]thiadiazines [21].
We have previously reported the preparation of 8-aryl-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b]-
[1,3,5]thiadiazine-9-carbonitriles 1 by treatment of 3-aryl-2-cyanoprop-2-enethioamides 2 with primary amines
and HCHO [22] (method A), by recyclization of 4H-thiopyrans 3 under the Mannich reaction conditions [23]
(method B), or by the aminomethylation of tetrahydropyridine-2-thiolates 4 [24] (method C). The said methods
are not free from limitations and drawbacks. Method A allows preparation of pyrimidothiadiazines 1 with
acceptable yields (up to 65%) but is limited to a range of products consisting only of 8-aryl derivatives of
compound 1 since the 3-alkyl analogs of the starting ,-unsaturated thioamides 2 are unknown at this time.
_______
*For Communication 12, 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/7 Molodezhny Kv., Lugansk
91034, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 689-697, April, 2012. Original
article submitted August 30, 2011.
642
0009-3122/12/4804-0642©2012 Springer Science+Business Media, Inc.

This limitation is removed with the preparation of thiadiazines 1 by the aminomethylation of 4H-thiopyrans 3
using method B, but, in this case, the yields of the target products are lower and the route itself is atom
inefficient. Method C gives the lowest yields of thiadiazines 1 (up to 28%) and seems the least rational.
In the earlier study [23], we declared the possible preparation of pyrimido[4,3-b][1,3,5]thiadiazines 1 by
a multicomponent condensation of aromatic aldehydes, cyanothioacetamide 5, p-toluidine, and HCHO (method D).
In searches for the optimum approach to the pyrimido[4,3-b][1,3,5]thiadiazines 1 synthesis, we have studied and
summerized in the present work the overall possibilities for a multicomponent approach and, in particular, the
possibility of varying the substituents in the 8 position of the pyrimido[4,3-b][1,3,5]thiadiazine system 1 and the
introduction of aliphatic aldehydes into this reaction.
Ar
CN
HCHO,
RNH2
HCHO,
RNH2
NC
CN
Ar
NH2
R
Ar
S
Method B
Method А
N
N
N
S
H2N
S
3
NH2
2
CN
O
Ar
S
CN
ArCHO
RNH2
HCHO,
RNH2
CN
S
R
EtOH, B:
Method D
NH2
+
R
5
1
Method C
HO
N
H
4
HCHO
R
NMMH+
NMMH+ = N-methylmorpholinium
It was found that successive reaction of cyanothioacetamide (5) with aldehydes, primary amines, and
formaldehyde occurs under mild conditions (short term heating in aqueous EtOH in the presence of catalytic
amounts of base) and leads to the pyrimido[4,3-b][1,3,5]thiadiazine-9-carbonitriles 1a-o in 11-70% yield
(Table 1). Both aromatic and aliphatic aldehydes can be used in the reaction.
R1
R1NH2,
HCHO
EtOH,
base
R
S
NH
R
CN
RCHO
+
S
NH2
HN
CN
5
CN
NH2
S
R1
N
R1
R1
R
R1
R1NH2
HCHO
R1
R
N
N
N
N
N
HCHO
N
H
HN
S
R
HS
CN
CN
1a–o
CN
SH
a R = Et; b–e R = i-Pr, f–h R = 3,4-(OCH2O)C6H3CH2CH(Me), i–k R = 4-МеC6H4,
l R = 2-ClC6H4, m R = 4-Me2NC6H4, n R = 4-O2NC6H4, o R = 3-O2NC6H4;
a,c,g,k–о R1 = 4-МеC6H4, b R1 = Ph, d R1 = 4-AcNHC6H4,
e,f R1 = 4-МеOC6H4, h,j R1 = Bn, i R1 = 3-МеC6H4
In the latter case, the previously unknown 8-alkylpyrimido[4,3-b][1,3,5]thiadiazine-9-carbonitriles 1a-g are
formed in low yields (up to 40%). The use of aromatic aldehydes in this reaction usually gives higher yields of the
target products 1i-o when compared with yields using aliphatic aldehydes. Compound 1h could not be prepared in
a pure state. In this case, synthesis by the general method gives an uncrystallizable oil which contains about 73% of
the target product according to HPLC-MS and 1H NMR spectroscopy. Attempts to purify the
643

TABLE 1. Physicochemical and Spectroscopic Characteristics of
Compounds 1a-p
Found, %
——————
Calculated, %
IR spectrum,
Com-
pound
Empirical
formula
Yield,
%
Mp, °С
, cm-1
С
Н
N
1a
1b
1c
1d
C23H26N4S
C22H24N4S
C24H28N4S
70.65 6.75 14.50 175-176 (decomp.) 2165 (C≡N)
70.73 6.71 14.35 (Ме2СО)
69.88 6.39 14.99 140-142 (decomp.) 2173 (C≡N)
70.18 6.42 14.88 (Me2CO-EtOH)
71.08 7.09 14.00 171-173 (decomp.) 2164 (C≡N)
71.25 6.98 13.85 (Me2CO)
17
29
39
19
C26H30N6О2S 63.23 6.20 17.26 169-171 (decomp.) 2167 (C≡N)
63.65 6.16 17.13 (Me2CO)
1675 (С=О)
3300 (NH)
1e
1f
C24H28N4О2S 65.65 6.52 12.53 152-153 (decomp.) 2172 (C≡N)
26
30
37
-
66.03 6.46 12.38 (Me2CO-EtOH)
C31H32N4О4S 66.40 5.81 10.14 164-165 (decomp.) 2167 (C≡N)
66.89 5.79 10.06 (DMF-Me2CO)
1g
1h
1i
C31H32N4О2S 70.53 6.18 10.79 185-187 (decomp.) 2170 (C≡N)
70.96 6.15 10.68 (Me2CO)
—
—
—
—
—
2170 (C≡N)
2176 (C≡N)
2176 (C≡N)
2172 (C≡N)
C28H28N4S
C28H28N4S
C28H28N4S
74.03 6.28 12.49 177-179
74.30 6.24 12.38 (DMF-EtOH)
62
65
70
1j
74.14 6.22 12.50 128-131 (DMF)
74.30 6.24 12.38 (125-128 [22])
74.16 6.25 12.53 177-176
74.30 6.24 12.38 (DMF-EtOH)
(178-181 [22])
1k
1l
C27H25ClN4S 68.32 5.27 12.01 210-212
68.56 5.33 11.84 (DMF-EtOH)
(210-211 [22])
2167 (C≡N)
66
1m
1n
1o
C29H31N5S
72.11 6.50 14.73 165-167 (decomp.) 2165 (C≡N)
26
36
33
72.32 6.49 14.54 (DMF-Me2CO)
C27H25N5O2S 66.75 5.25 14.69 213-215 (decomp.) 2167 (C≡N)
67.06 5.21 14.48 (DMF-EtOH)
C27H25N5O2S 66.88 5.22 14.65 205-207 (decomp.) 2168 (C≡N)
67.06 5.21 14.48 (DMF-EtOH)
1p
С21Н22N4S
69.37 6.15 15.55 195-197 (decomp.) 2158 (C≡N)
69.58 6.12 15.46 (DMF-Me2CO)
11 (А)
13 (В)
compound 1h or to separate it from the mixture using column chromatography were unsuccessful. In the case of
aliphatic aldehydes it was found that morpholine is preferred to tertiary amine catalysts such as
N-methylmorpholine or triethylamine.
A very unexpected result was obtained in the condensation of acetaldehyde, thioamide 5, p-toluidine, and
formaldehyde. Instead of the expected 8-methyl-3,7-di(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido-
[4,3-b][1,3,5]thiadiazine-9-carbonitrile its 8-unsubstituted analog 1p was formed. Compound 1p was also found
1
as an admixture (up to 20% according to H NMR data) in unpurified samples of compounds 1a,c. Clearly
formation of the pyrimidothiadiazine system precedes the N-aminomethylation and retro-Knoevenagel reaction.
A possible reason for the anomalous reaction course is the ease of the retro-reaction and the comparable rate of
the reaction of the cyanothioacetamide with formaldehyde and aliphatic aldehydes. Compound 1p was also
obtained by the direct aminomethylation of the cyanothioacetamide (5).
S
CN
CN
CN
+
Ar
Ar
ArNH2
HCHO
N
N
N
S
NHAr
2HCHO
ArNH2
EtOH
NH2
5
HCHO
S
N
S
N
N
N
– R2NH
H
R2NH
Ar
Ar
R2N+H2
R2N+H2
1p
CN
Ar = 4-MeC6H4; R2NH = morpholine
644

Finally, attempts to broaden the boundaries of the use of this route and to exchange the
cyanothioacetamide (5) in this reaction for cyanoacetamide or to introduce into the reaction 3-aryl-2-cyano-
prop-2-enamides 6a,b in place of compounds 2 were not successful. Hence under the said conditions only the
perhydro-1,3,5-triazine 7 (a known product of p-toluidine condensation with formaldehyde [25]) was isolated in
place of the 3-(2-chlorophenyl)-2-cyanoprop-2-enamide (6a) aminomethylation products. Polycomponent
condensation of furfural, cyanoacetamide, HCHO, and p-toluidine gives a mixture of the unsaturated amide 6b
(R = 2-furyl) and the perhydro-1,3,5-triazine 7.
CN
Ar
Ar
N
N
N
R
NH2
Ar
O
6a,b
7
6 a R = 2-ClC6H4, b 2-furyl; 7 Ar = 4-MeC6H4
Hence the 3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-9-carbonitriles can be success-
fully prepared by condensation of cyanothioacetamide with aliphatic or aromatic aldehydes, formaldehyde, and
primary amines. A similar route, in contrast to other methods, allows the preparation of pyrimido[4,3-b]-
[1,3,5]thiadiazines unsubstituted in position 8 or with alkyl substituents in this position in acceptable yields.
Cyanoacetamide and its arylmethylidene derivatives do not take part in a Mannich reaction under these
conditions.
EXPERIMENTAL
IR spectra were recorded on an IKS-29 spectrophotometer in nujol. 1H NMR spectra were recorded on
Varian Unity Plus (400 MHz) and Bruker DRX-500 (500 MHz) spectrometers and 13C NMR spectra on a
Bruker DRX-500 (125 MHz) using DMSO-d6 with TMS as internal standard. HPLC-MS analysis was carried
out on an Agilent 1100 liquid chromatograph with DAD and Sedex 75 ELSD detectors combined with an
Agilent LC/MSD VL mass spectrometer in electrospray ionization mode. Elemental analysis was performed on
a Carlo-Erba 1106 Elemental Analyzer with an accuracy of measurement of ± 0.25%. Monitoring of the purity
of the compounds obtained was carried out by TLC using Silufol UV-254 plates with acetone–hexane (1:1) as
eluent and visualized by UV light or iodine vapor. Melting points for the prepared compounds were determined
on a Kofler hot bench and are not corrected.
The starting cyanothioacetamide (5) was prepared by a known method [26].
3,4,7,8-Tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-9-carbonitriles (1a-o) (General Method).
The base (2-3 drops, morpholine in the case of the aliphatic aldehydes, N-methylmorpholine or Et3N in the case
of aromatic aldehydes) was added to a mixture of cyanothioacetamide (5) (0.5 g, 5.0 mmol) and the
corresponding aldehyde (5.0 mmol) in EtOH (15-20 ml). The product was stirred for 10-20 min at 20ºC and the
corresponding amine (10.5 mmol) and 37% formalin, free from paraformaldehyde admixture (2.5-3.0 ml, 34-40
mmol) were added. The mixture was then refluxed with vigorous stirring for 1-3 min, a further 15 ml of EtOH
added, and stirring continued for 3-5 h at 20ºC. The precipitate formed after 24 h was filtered off (in the case of
tar formation the solution was decanted) and immediately recrystallized from acetone, a mixture of acetone–
EtOH (1: 1), or dissolved in hot DMF with subsequent reprecipitation using EtOH or acetone.
8-Ethyl-3,7-di(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-9-car-
1
3
bonitrile (1a). Colorless crystals. H NMR spectrum (400 MHz), , ppm (J, Hz): 1.00 (3Н, t, J = 7.3,
3
3
СH2CH3); 1.62-1.75 (2Н, m, СH2CH3); 2.25 (3Н, s, CH3); 2.26 (3Н, s, CH3); 3.70 (1Н, dd, J = 9.1, J = 9.1,
Н-8); 4.39 (1Н, d, J = 12.9) and 4.62 (1Н, d, J = 12.9, NСН2N); 4.75 (1Н, d, J = 12.9) and 4.88 (1Н, d,
2
2
2
645

2
2
3
2J = 12.9, NСH2N); 4.99 (1Н, d, J = 12.6) and 5.17 (1Н, d, J = 12.6, SСН2N); 6.80 (2Н, d, J = 7.9, H Ar);
6.95 (2Н, d, 3J = 8.2, H Ar); 6.96 (2Н, d, 3J = 7.9, H Ar); 7.00 (2Н, d, 3J = 8.2, H Ar).
8-Isopropyl-3,7-diphenyl-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-9-carbo-
1
3
nitrile (1b). Beige powder. H NMR spectrum (400 MHz), , ppm (J, Hz): 1.01 (3Н, d, J = 6.2, СH3); 1.09
3
3
2
(3Н, d, J = 6.2, СH3); 1.94-1.96 (1Н, m, СH(СH3)2); 3.45 (1H, d, J = 9.1, H-8); 4.48 (1Н, d, J = 12.9) and
2
2
2
4.74 (1Н, d, J = 12.9, NСH2N); 4.82 (1Н, d, J = 12.9) and 5.07 (1Н, d, J = 12.9, NСH2N); 5.03 (1Н, d,
2J = 12.6) and 5.25 (1Н, d, 2J = 12.6, SСH2N); 6.83-7.26 (10H, m, Н Ph).
8-Isopropyl-3,7-di(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-
1
3
9-carbonitrile (1c). Colorless crystals. H NMR spectrum (400 MHz), , ppm (J, Hz): 1.00 (3Н, d, J = 6.3,
СH3); 1.07 (3Н, d, 3J = 6.3, СH3); 1.83-1.87 (1Н, m, СH(СH3)2); 2.25 (6Н, br. s, 2ArCH3); 3.30 (1H, d, 3J = 8.6,
2
2
2
H-8); 4.40 (1Н, d, J = 13.0) and 4.56 (1Н, d, J = 13.0, NСН2N); 4.72 (1Н, d, J = 13.5) and 4.82 (1Н, d,
2J = 13.5, NСН2N); 4.92 (1Н, d, 2J = 13.1) and 5.16 (1Н, d, 2J = 13.1, SСH2N); 6.70–6.94 (8H, m, H Ar).
3,7-Di(4-acetamidophenyl)-8-isopropyl-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-
1
9-carbonitrile (1d). Colorless amorphous powder. H NMR spectrum (500 MHz), , ppm (J, Hz): 0.99 (3Н, d,
3J = 6.2, СH3); 1.06 (3Н, d, 3J = 6.2, СH3); 1.90-1.95 (1Н, m, СH(СH3)2); 2.02 (3Н, s, NНCOCH3); 2.04 (3Н, s,
3
2
2
NНCOCH3); 3.42 (1H, br. d, J = 9.3, H-8); 4.47 (1Н, d, J = 13.2) and 4.67 (1Н, d, J = 13.2, NСН2N); 4.79
(1Н, d, J = 12.7) and 4.98 (1Н, d, J = 12.7, NСН2N); 5.09 (1Н, d, J = 12.7) and 5.25 (1Н, d, J = 12.7,
2
2
2
2
3
3
3
SСН2N); 6.85 (2Н, d, J = 8.8, H Ar); 7.10 (2H, d, J = 8.8, H Ar); 7.36 (2H, d, J = 8.8, H Ar); 7.47 (2H, d,
3J = 8.8, H Ar); 9.75 (1Н, s, NHAc); 9.82 (1Н, s, NHAc).
8-Isopropyl-3,7-di(4-methoxyphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-
1
9-carbonitrile (1e). White amorphous powder. H NMR spectrum (400 MHz), , ppm (J, Hz): 1.00 (3Н, d,
3J = 6.6, СH3); 1.07 (3Н, d, 3J = 6.6, СН3); 1.84-1.88 (1Н, m, СН(СН3)2); 3.20 (1H, d, 3J = 9.4, H-8); 3.71 (3Н,
2
2
s, ОCH3); 3.74 (3Н, s, ОCH3); 4.43 (1Н, d, J = 13.2) and 4.47 (1Н, d, J = 13.2, NСН2N); 4.74-4.76 (2H, m,
NСH2N); 4.93 (1H, d, 2J = 12.6) and 5.21 (1H, d, 2J = 12.6, SСH2N); 6.68-6.98 (8H, m, H Ar).
8-[2-(1,3-Benzodioxol-5-yl)-1-methylethyl]-3,7-di(4-methoxyphenyl)-3,4,7,8-tetrahydro-2H,6H-pyri-
mido[4,3-b][1,3,5]thiadiazine-9-carbonitrile (1f). White amorphous powder. 1H NMR spectrum (500 MHz), ,
3
ppm (J, Hz) (ratio of main and minor diastereomers 3:1): 0.81 (2.25Н, d, J = 6.4, СНСH3); 0.89 (0.75Н, d,
2
3
3J = 6.8, СНСH3)*; 1.97-2.05 (1Н, m, СНСH3)*2; 2.18-2.26 (1Н, m)*2, 2.99 (0.75H, dd, J = 13.2, J = 3.4),
and 3.05 (0.25H, dd, 2J = 13.1, 3J = 3.0, ArCH2CH)*; 3.41 (0.25Н, d, 3J = 8.8, H-8)*; 3.46 (0.75Н, d, 3J = 8.3,
Н-8); 3.71 (2.25Н, s, ОСH3); 3.72 (0.75Н, s, ОСH3)*; 3.73 (0.75Н, s, ОСH3)*; 3.74 (2.25Н, s, ОСH3); 4.51
2
2
2
2
(0.75Н, d, J = 13.2) and 4.55 (0.75Н, d, J = 13.2, NСH2N); 4.63 (0.5Н, dd, J = 13.2, J = 13.2, NСН2N)*;
4.79-4.88 (2Н, m, NСН2N)*2; 5.00 (0.25Н, d, 2J = 12.7)* and 5.27 (0.25Н, d, 2J = 12.7, NСH2S)*; 5.04 (0.75Н,
d, 2J = 12.7) and 5.29 (0.75Н, d, 2J = 12.7, NСH2S); 5.98 (1.5Н, s, ОСH2O); 5.99 (0.5Н, s, ОСH2O)*; 6.60-7.05
(11Н, m, Н Ar)*2. 13C NMR spectrum, , ppm: 16.0 (СHCH3)*; 16.2 (СHCH3); 38.8 (CHCH3); 39.0 (CHCH3)*
42.8 (ArCH2); 43.4 (ArCH2)*; 53.4 (ArOCH3)*; 55.7 (ArOCH3); 61.9 (C-8)*; 62.3 (C-8); 64.0 (NCH2N)*; 61.1
(NCH2N); 64.5 (NCH2N); 64.6 (NCH2N)*; 73.6 (SCH2N); 73.7 (SCH2N)*; 101.1 (OCH2O); 108.5; 109.6 (C-9);
109.8 (С-9)*; 114.6 (C≡N); 114.7 (C≡N)*; 119.6 (C Ar)*; 119.9 (C Ar); 120.7 (C Ar)*; 120.9 (C Ar); 121.5 (C
Ar); 122.3 (C Ar); 122.5 (C Ar)*; 134.9 (C Ar); 135.0 (C Ar)*; 139.1 (C Ar); 143.9 (C Ar); 145.7 (C Ar); 151.7
(C-9a)*; 151.9 (C-9a); 154.3 (C Ar)*; 154.6 (C Ar)*2.
8-[2-(1,3-Benzodioxol-5-yl)-1-methylethyl]-3,7-di(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyri-
1
mido[4,3-b][1,3,5]thiadiazine-9-carbonitrile (1g). White amorphous powder. H NMR spectrum (400 MHz),
, ppm (J, Hz) (ratio of main and minor diastereomers 10:1): 0.86 (2.73Н, d, 3J = 6.4, СНСH3); 0.95 (0.27Н, d,
3J = 6.7, СНСH3)*; 1.93-2.03 (1Н, m, СHCH3)*2; 2.18-2.24 (1Н, m, ArCH2CH)*2; 2.28 (3Н, s, ArCH3)*2; 2.30
3
(3Н, s, ArCH3)*2; 2.96-3.04 (1H, m, ArCH2CH)*2; 3.47 (0.09Н, d, J = 7.7, H-8)*; 3.52 (0.91Н, d, 3J = 8.1, Н-
8); 4.46 (1Н, d, 2J = 12.9)*2 and 4.54 (1Н, d, 2J = 12.9, NСH2N)*2; 4.77-4.79 (2Н, m, NСH2N)*2; 4.96 (1Н, d,
2
2J = 12.6)*2 and 5.19 (1Н, d, J = 12.6, NСH2S)*2; 5.92 (0.18Н, s, ОСH2O)*; 5.93 (1.82Н, s, ОCH2O); 6.57
646

(1Н, d, 3J = 7.6, Н Ar)*2; 6.64-6.68 (2Н, m, Н Ar)*2; 6.76 (2H, d, 3J = 8.0, Н Ar)*2; 6.90-6.95 (4Н, m, Н Ar)*2;
6.99 (2H, d, 3J = 8.4, Н Ar)*2.
8-[2-(1,3-Benzodioxol-5-yl)-1-methylethyl]-3,7-dibenzyl-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b]-
[1,3,5]thiadiazine-9-carbonitrile (1h). Yellow tar, glassifies on prolonged standing. According to HPLC-MS
and 1H NMR data the content of the main material is about 73%. 1H NMR spectrum (400 MHz), , ppm (J, Hz)
3
3
(ratio of main and minor diastereomers 10:9): 0.72 (1.41H, d, J = 6.3, CHCH3)*; 0.81 (1.59H, d, J = 6.8,
CHCH3); 1.90-2.12 (2H, m, CHCH3, ArCHHCH)*2; 2.93-2.97 (0.47H, m, ArCHHCH)*; 3.08-3.12 (0.53H, m,
ArCHHCH); 3.33-3.39 (4H, m, 2CH2Ph)*2; 3.43-4.87 (7H, m, H-8, 2NCH2N, NCH2S)*2; 5.92-5.97 (2H, m,
OCH2O)*2; 6.53-7.42 (13H, m, H Ar)*2. Mass spectrum (ESI), m/z (Irel, %): 525 [M+H]+ (37), 406 [M+H-
PhCH2N=CH2]+ (100), 120 [PhCH2NH=CH2]+ (16).
3,7-Di(3-methylphenyl)-8-(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazi-
1
ne-9-carbonitrile (1i). Pale-yellow amorphous powder. H NMR spectrum (400 MHz), , ppm (J, Hz): 2.30
(6H, br. s, 2 CH3); 2.36 (3H, s, CH3); 4.14 (1H, d, 2J = 13.0) and 4.63 (1H, d, 2J = 13.0, NCH2N); 4.81 (1H, d,
2
2
2J = 13.0) and 4.97 (1H, d, J = 13.0, NCH2N); 5.13 (1H, s, H-8); 5.08 (1H, d, J = 12.9) and 5.27 (1H, d,
2J = 12.9, SCH2N); 6.69-7.28 (12H, m, H Ar).
3,7-Dibenzyl-8-(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-9-carbo-
1
nitrile (1j). Beige amorphous powder. H NMR spectrum (400 MHz), , ppm (J, Hz): 2.30 (3H, s, CH3); 3.49
(1H, d, 2J = 12.3) and 3.70 (1H, d, 2J = 12.3, NCH2N); 3.90 (2H, br. s, PhCH2); 4.00 (1H, d, 2J = 12.4) and 4.11
(1H, d, 2J = 12.4, NCH2N); 4.19 (2H, br. s, PhCH2); 4.23 (1H, s, H-8); 4.51 (1H, d, 2J = 12.1) and 4.74 (1H, d,
2J = 12.1, SCH2N); 7.09-7.45 (14H, m, H Ar).
3,7,8-Tri(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-9-carbo-
nitrile (1k). White finely crystalline powder. 1H NMR spectrum (400 MHz), , ppm (J, Hz): 2.25 (3H, s, CH3);
2
2.28 (3H, s, CH3); 2.30 (3H, s, CH3); 4.28 (1H, d, J = 13.0) and 4.53 (1H, d, 2J = 13.0, NCH2N); 4.87 (1H, d,
2
2
2J = 12.7) and 4.94 (1H, d, J = 12.7, NCH2N); 5.12 (1H, s, H-8); 5.10 (1H, d, J = 12.5) and 5.32 (1H, d,
2J = 12.5, SCH2N); 7.00-7.20 (12H, m, H Ar).
8-(2-Chlorophenyl)-3,7-di(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadia-
1
zine-9-carbonitrile (1l). White finely crystalline powder. H NMR spectrum (400 MHz), , ppm (J, Hz): 2.27
2
2
(3H, s, CH3); 2.31 (3H, s, CH3); 4.20 (1H, d, J = 13.0) and 4.49 (1H, d, J = 13.0, NCH2N); 4.68 (1H, d,
2J = 13.1) and 4.94 (1H, d, 2J = 13.1, NCH2N); 5.12 (1H, d, 2J = 12.6) and 5.23 (1H, d, 2J = 12.6, SCH2N); 5.28
(1H, s, H-8); 6.80-7.20 (8H, m, H Ar); 7.25-7.45 (4H, m, 2-ClC6H4).
8-(4-Dimethylaminophenyl)-3,7-di(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]-
1
thiadiazine-9-carbonitrile (1m). Bright-yellow crystals. H NMR spectrum (400 MHz), , ppm (J, Hz): 2.31
(3H, s, ArCH3); 2.32 (3H, s, ArCH3); 2.95 (6H, s, (CH3)2N); 4.15 (1H, d, 2J = 12.6) and 4.46 (1H, d, 2J = 12.6,
2
2
NCH2N); 4.77-4.78 (2H, m, NCH2N); 4.94 (1H, s, H-8); 5.01 (1H, d, J = 12.5) and 5.21 (1H, d, J = 12.5,
SCH2N); 6.64 (2H, d, 3J = 8.1, H Ar); 6.90-7.02 (8H, m, 2MeC6H4); 7.09 (2H, d, 3J = 8.1, H Ar).
3,7-Di(4-methylphenyl)-8-(4-nitrophenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thia-
diazine-9-carbonitrile (1n). Bright-yellow crystals. 1H NMR spectrum (500 MHz), , ppm (J, Hz): 2.27 (3H, s,
2
2
2
CH3); 2.28 (3H, s, CH3); 4.03 (1H, d, J = 13.2) and 4.68 (1H, d, J = 13.2, NCH2N); 4.89 (1H, d, J = 12.7)
and 4.95 (1H, d, 2J = 12.7, NCH2N); 5.15 (1H, d, 2J = 12.2) and 5.31 (1H, d, 2J = 12.2, SCH2N); 5.37 (1H, s, H-
8); 7.00-7.05 (8H, m, 2MeC6H4); 7.60 (2H, d, 3J = 8.1, H Ar); 8.25 (2H, d, 3J = 8.1, H Ar).
3,7-Di(4-methylphenyl)-8-(3-nitrophenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadia-
1
zine-9-carbonitrile (1o). Bright-yellow crystals. H NMR spectrum (400 MHz), , ppm (J, Hz): 2.26 (3H, s,
CH3); 2.27 (3H, s, CH3); 4.05 (1H, d, 2J = 12.9) and 4.68 (1H, d, 2J = 12.9, NCH2N); 4.87 (1H, d, 2J = 13.3) and
4.94 (1H, d, 2J = 13.3, NCH2N); 5.14 (1H, d, 2J = 12.5) and 5.32 (1H, d, 2J = 12.5, SCH2N); 5.37 (1H, s, H-8);
_______
* Signals of the minor diastereomers.
*2 Overlapping of the signals of the main and minor diastereomers.
647

3
3
3
6.97 (2H, d, J = 7.9, H Ar); 7.03 (2H, d, J =7.9, H Ar); 7.04-7.08 (4H, m, H Ar); 7.71 (1H, dd, J = 7.5,
3J = 7.9, H-5'); 7.80 (1H, d, 3J = 7.5, H-6'); 8.18 (1H, s, H-2'); 8.22 (2H, d, 3J = 7.9, H-4').
3,7-Di(4-methylphenyl)-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-9-carbonitri-
le (1p). A. Obtained by condensation of acetaldehyde, thioamide 5, p-toluidine, and HCHO. A mixture of
cyanothioacetamide (5) (0.5 g, 5.0 mmol), acetaldehyde (0.5 ml, 8.9 mmol) and N-methylmorpholine (3 drops)
was stirred in EtOH (15-20 ml) for 30 min at 20ºC. p-Toluidine (1.1 g, 10.3 mmol) and 37% formalin free from
paraformaldehyde (3.0 ml, 40.0 mmol) were added. The mixture was refluxed for 2-3 min and then stirred at
20ºC. The precipitate formed after 24 h was filtered off, washed with EtOH, and immediately recrystallized
from a mixture of acetone and DMF (1:1). Compound 1p (200 mg, 11%) was obtained as a light-yellow, finely
crystalline powder.
B. Obtained from thioamide 5, formalin, and toluidine. A mixture of the cyanothioacetamide (5) (1.00 g,
10.0 mmol), p-toluidine (1.38 g, 12.9 mmol), and 37% formalin (3.0 ml, 40.0 mmol) was refluxed for 2-3 min in
EtOH (30 ml) with stirring. After 24 h the precipitate was filtered off and recrystallized from a mixture of
ethanol and DMF (1:1). Yield 480 mg (13%). 1H NMR spectrum (400 MHz), , ppm (J, Hz): 2.25 (3H, s, CH3);
2.27 (3H, s, CH3); 3.96 (2H, br. s, 8-CH2); 4.65 (2H, br. s) and 4.78 (2H, br. s, 4,6-CH2); 5.08 (2H, br. s,
3
SCH2N); 6.87-6.91 (4H, m, 2H-3',5'); 6.98 (4H, d, J = 7.6, 2H-2',6'). Mass spectrum (ESI), m/z (Irel, %): 364
[M+H]+ (100), 245 [M+H-ArN=CH2]+ (76), 120 [ArNH=CH2]+ (81).
1,3,5-Tri(4-methylphenyl)-1,3,5-perhydrotriazine (7). 3-(2-Chlorophenyl)-2-cyanoacrylamide (6a)
(0.564 g, 2.73 mmol), p-toluidine (0.658 g, 6.14 mmol), and 37% HCHO (2.5 ml, 33.30 mmol) were refluxed in
DMF (4 ml) for 3-4 min and then held for 72 h at 20ºC. Yield 205 mg (28%). Colorless needle like crystals; mp
1
125ºC (mp 127.9ºC [25], 126-127ºC [27]), Rf = 0.81 (acetone–hexane, 1:1). H NMR spectrum (500 MHz), ,
3
3
ppm (J, Hz): 2.21 (9H, s, 3CH3); 4.77 (6H, br. s, 3CH2); 7.05 (12H, dd, J = 8.1, J = 8.1, H Ar). Found, %:
C 80.56; H 7.65; N 11.79. C24H27N3. Calculated, %: C 80.63; H 7.61; N 11.75.
Multicomponent Condensation of Furfural, Cyanoacetamide, Formalin, and p-Toluidine. A
mixture of cyanoacetamide (0.5 g, 6.0 mmol), furfural (0.5 ml, 6.0 mmol), and morpholine (1 drop) was stirred
in EtOH (20-25 ml) for 30 min at 20ºC. p-Toluidine (0.71 g, 6.6 mmol) and 37% formalin free from an
admixture of paraformaldehyde (2.0 ml, 26.6 mmol,) were added. The mixture was refluxed for 2-3 min, filtered
through a plaited filter, and held for 48 h at 20ºC. The precipitate formed was filtered off and washed with
1
EtOH to give the sandy-gray product (0.34 g). According to H NMR data (400 MHz) this product is the (E)-
2-cyano-3-(2-furyl)prop-2-enamide (6b) (35% yield) with an admixture of about 2% of the perhydrotriazine 7. 1H
NMR spectrum (400 MHz), , ppm (J, Hz): 6.70 (1H, dd, 3J = 3.4, 3J = 1.6, H-4 furyl); 7.33 (1H, br. d, 3J = 3.4,
H-3 furyl); 7.47 (1H, br. s) and 7.56 (1H, br. s, CONH2); 7.92 (1H, d, 3J = 1.6, H-5 furyl); 7.96 (1H, s, –CH=).
3
Proton signals of the perhydrotriazine 7: 2.23 (9H, s, 3CH3); 4.72 (6H, br. s, 3CH2); 6.90 (12H, dd, J = 8.1,
3J = 8.1, H Ar).
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