The Mannich reaction in the synthesis of N, S-containing heterocycles Recyclization of stable cyclic Michael adducts, N-methylmorpholinium 6-R-6-hydroxy-1, 4, 5, 6-tetrahydropyridine-2-thiolates, to pyrimido[4, 3-b][1, 3, 5]thiadiazines under conditions of aminomethylation reaction

Article abstract of DOI:10.1007/s11172-009-0199-8

5-Substituted N-methylmorpholinium 4-aryl-6-R-3-cyano-6-hydroxy-1, 4, 5, 6-tetrahydro-pyridine-2-thiolates upon the action of primary amines and HCHO in ethanol undergo recy-clization to 3, 7-disubstituted 8-aryl-3, 4, 7, 8-tetrahydro-2H, 6H-pyrimido[4, 3-b][1, 3, 5]thia-diazine-9-carbonitriles in low yields (5-28%). The latter were also obtained by alternative method, viz., by sequential condensation of cyanothioacetamide with aromatic aldehydes, primary amines, and HCHO.

Full text of DOI:10.1007/s11172-009-0199-8

Russian Chemical Bulletin, International Edition, Vol. 58, No. 7, pp. 1479—1483, July, 2009
1479
The Mannich reaction in the synthesis of N,Sꢀcontaining heterocycles
10*. Recyclization of stable cyclic Michael adducts,
Nꢀmethylmorpholinium 6ꢀRꢀ6ꢀhydroxyꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolates,
to pyrimido[4,3ꢀb][1,3,5]thiadiazines under conditions of aminomethylation reaction
V. V. Dotsenko,a,b K. A. Frolov,a S. G. Krivokolysko,a and V. P. Litvinovc†
aV. Dal’ EastꢀUkrainian National University, ChemEx Laboratory,
20a Molodezhnyi kv., 91034 Lugansk, Ukraine.
Eꢀmail: Victor_Dotsenko@bigmir.net
bState Enterprise Luganskstandardmetrology,
50 ul. Timiryazeva, 91021 Lugansk, Ukraine
cN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation
5ꢀSubstituted Nꢀmethylmorpholinium 4ꢀarylꢀ6ꢀRꢀ3ꢀcyanoꢀ6ꢀhydroxyꢀ1,4,5,6ꢀtetrahydroꢀ
pyridineꢀ2ꢀthiolates upon the action of primary amines and HCHO in ethanol undergo recyꢀ
clization to 3,7ꢀdisubstituted 8ꢀarylꢀ3,4,7,8ꢀtetrahydroꢀ2H,6Hꢀpyrimido[4,3ꢀb][1,3,5]thiaꢀ
diazineꢀ9ꢀcarbonitriles in low yields (5—28%). The latter were also obtained by alternative
method, viz., by sequential condensation of cyanothioacetamide with aromatic aldehydes,
primary amines, and HCHO.
Key words: the Mannich reaction, pyridineꢀ2ꢀthiolates, aminomethylation, pyrimido[4,3ꢀb]ꢀ
[1,3,5]thiadiazines, recyclization, the retro Michael reaction.
The literature data2—8 show that 2ꢀmercaptopyridines,
tautomeric to them pyridineꢀ2(1H)ꢀthiones, or the correꢀ
sponding thiolates extremely ready undergo the Mannich
reaction, however, in most cases it is a nontrivial problem
to predict the product structures and direction of the amiꢀ
nomethylation reaction. Decisive factors influencing regiꢀ
oselectivity of the process are the medium рH and espeꢀ
cially the structure of mercaptopyridine substrate. For inꢀ
stance, the following compounds were described as amiꢀ
nomethylation products: 2ꢀ(aminomethyl)thiopyridines,2
pyrido[2,1ꢀb][1,3,5]thiadiazines,3 pyrido[1,2ꢀa][1,3,5]ꢀ
triazines,4 3,7ꢀdiazabicyclo[3.3.1]nonane,5 3,5,7,11ꢀtetraꢀ
azatricyclo[7.3.1.02,7]tridecꢀ2ꢀenes,6 8ꢀthioxospiroꢀ
[3,5,7,11ꢀtetraazatricyclo[7.3.1.02,7]tridecꢀ2ꢀenꢀ13,4´ꢀ
piperidine]ꢀ1,9ꢀdicarbonitriles,7 bis(pyrido[2,1ꢀb][1,3,5]ꢀ
thiadiazinꢀ7ꢀyl)methanes.8 In continuation of our research
in the field of aminomethylation of functionally substitutꢀ
ed pyridineꢀ2ꢀthiolates, we decided to study behavior of
piperidinium (4R*,5R*,6R*)ꢀ5ꢀbenzoylꢀ4ꢀ(2ꢀchloropheꢀ
nyl)ꢀ3ꢀcyanoꢀ6ꢀhydroxyꢀ6ꢀmethylꢀ1,4,5,6ꢀtetrahydropyꢀ
ridineꢀ2ꢀthiolate (1) under conditions of the "double"
Mannich condensation.
Thiolate 1 is easily synthesized by polycomponent conꢀ
densation of cyanothioacetamide, 2ꢀchlorobenzaldehyde,
benzoylacetone, and piperidine; the reaction is regiospeꢀ
cific.9 Being a stable Michael adduct, thiolate 1 is potenꢀ
tially capable of both further dehydration and transformaꢀ
tion to 1,4ꢀdihydropyridine derivative and the retro Michaꢀ
el reaction with the liberation of benzoylacetone and
(E)ꢀ3ꢀarylꢀ2ꢀcyanopropꢀ2ꢀenethioamide (2). In fact, this
is the latter version which is implemented under aminomꢀ
ethylation conditions. Treatment of thiolate 1 with 2 equiv.
of pꢀtoluidine and excess formaldehyde leads to pyrimiꢀ
do[4,3ꢀb][1,3,5]thiadiazine (5a) as the only isolable reacꢀ
tion product instead of expected bispydine derivatives 3 or
pyrido[2,1ꢀb][1,3,5]thiadiazine (4) (Scheme 1). In favor
of the intermediate formation of thioamide 2 testifies the
fact that compound 5 and its analogs can be easily syntheꢀ
sized by aminomethylation of unsaturated thioamides 2
(see Ref. 10), as well as by polycomponent reaction of
aromatic aldehydes, cyanothioacetamide, primary amines,
and formaline in weakly basic medium and by recyclizaꢀ
tion of 2,6ꢀdiaminoꢀ3,5ꢀdicyanoꢀ4Hꢀthiopyrans in the
presence of RNH2/HCHO.11 To sum up, the aminomeꢀ
thylation of thiolate 1 initially gives thioamides 2 through
the retro Michael reaction, which are further aminomethꢀ
ylated to pyrimido[4,3ꢀb][1,3,5]thiadiazines 5. When benꢀ
* For Part 9, see Ref. 1.
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1436—1440, July, 2009.
1066ꢀ5285/09/5807ꢀ1479 © 2009 Springer Science+Business Media, Inc.

1480
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Dotsenko et al.
Table 1. Dependence of the yields of compound 5d on the reacꢀ
tion conditions and the ratio substrate : amine in the recyclizaꢀ
tion reaction of thiolate 7b
zylamine is involved into the reaction instead of pꢀtoꢀ
luidine, a tarꢀlike product of complex composition
was obtained, in which pyrimidothiadiazine (5b) and
perhydroꢀ1,3,5ꢀtriazine (6) were identified by TLC (see
Scheme 1).
Com
pꢀToluidine
Conditions
Yield of 5d
pound
7b/mmol
/mmol equiv.
(%)
It should be noted that this reaction has a general charꢀ
acter: for instance, other cyclic Michael adducts, such as
Nꢀmethylmorpholinium 4ꢀarylꢀ3ꢀcyanoꢀ5ꢀethoxycarboꢀ
nylꢀ6ꢀhydroxyꢀ6ꢀphenylꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthioꢀ
lates (7a,b) (see Ref. 12) and Nꢀmethylmorpholinium
5ꢀbenzoylꢀ4ꢀ(2ꢀchlorophenyl)ꢀ3ꢀcyanoꢀ6ꢀhydroxyꢀ6ꢀpheꢀ
nylꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolate (8) (see Ref. 13),
under the Mannich reaction conditions undergo similar
recyclization with elimination of 1,3ꢀdicarbonyl comꢀ
ponent and formation of the same pyrimido[4,3ꢀb]ꢀ
[1,3,5]thiadiazines 5 (Scheme 2). The yields in this reacꢀ
tion are rather low and do not exceed 28%; no additional
amount of the product was obtained from the mother soꢀ
lution. Using transformation of thiolate 7b to comꢀ
pound 5d as an example, it was shown that the ratio subꢀ
strate : primary amine of 1 : 4 (with constant excess of
НСНО
/mmol
Т/°C
1.02
1.10
1.22
1.00
1.00
1.23
1.02/1
2.2/2
4.9/4
4.0/4
4.0/4
27
27
27
34
34
65
→20*
→20*
→20*
20
**
→20*
4.1
7.3
17.5
0
0
16.4
7.65/6.2
* Heating to 20 °C.
** Reflux for 3 h.
formaline) was the optimum from the point of the recyꢀ
clization product yield (Table 1).
It seems quite probable that some primary amine and
HCHO are consumed in aminomethylation of 1,3ꢀdicarꢀ
Scheme 1
B =
;
R = 4ꢀMeC6H4 (5a), R = CH2Ph (5b); Ar = 2ꢀClC6H4

Pyrimido[4,3ꢀb][1,3,5]thiadiazines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1481
Scheme 2
5a,d were characterized by spectroscopic methods and
proved identical to the samples obtained by aminomethyꢀ
lation10 of unsaturated thioamides 2. The structures of
compounds 5c,d were confirmed by alternative synthesis
from corresponding aromatic aldehyde, cyanothioacetꢀ
amide (9), primary aromatic amine, and formaldehyde with
the yields of pyrimido[4,3ꢀb][1,3,5]thiadiazines being 19
and 58%, respectively. It should be especially noted
that the synthesis of 3,7,8ꢀtriphenylꢀ3,4,7,8ꢀtetrahydroꢀ
2H,6Hꢀpyrimido[4,3ꢀb][1,3,5]thiadiazineꢀ9ꢀcarbonitrile
(5c) by aminomethylation of the corresponding 2ꢀcyanoꢀ
thioacetamide according to the method described in the
literature10 is hindered due to the difficulties in the prepaꢀ
ration of the latter and its tendency to dimerization by the
type of [4+2]ꢀcycloaddition.16
The IR spectra of pyrimidothiadiazines 5 exhibit inꢀ
tensive absorption bands related to the stretching vibraꢀ
tions of the conjugated cyano group (ν = 2175—2161 cm–1).
1
In the H NMR spectra of compounds 5, in addition to
characteristic signals for the aromatic substituents there
are present a singlet for the protons C(8)H at δ 5.17—5.24,
a set of the signals for three methylene groups, two pairs of
doublets N—CH2—N in the region δ 4.70—5.29, two
doublets for the protons N—CH2—S shifted toward the
upꢀfield region (δ 4.02—4.67).
In conclusion, Nꢀmethylmorpholinium 4ꢀarylꢀ5ꢀcyꢀ
anoꢀ6ꢀhydroxyꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolates
upon the action of a primary amine and formaline underꢀ
go recyclization to form 3,7ꢀdisubstituted 8ꢀarylꢀ3,4,7,8ꢀ
tetrahydroꢀ2H,6Hꢀpyrimido[4,3ꢀb][1,3,5]thiadiazineꢀ9ꢀ
carbonitriles. The method cannot be used for preparative
purposes due to the low yields and availability of more
convenient and efficient methods for obtaining the target
pyrimido[4,3ꢀb][1,3,5]thiadiazines. In particular, such
a method consists in the sequential oneꢀpot condensation
of an aldehyde, cyanothioacetamide, a primary amine,
and formaline.
Comꢀ
pound
Ar
R
5a
5c
5d
7a
7b
2ꢀClC6H4
Ph
4ꢀClC6H4
Ph
4ꢀМеC6H4
Ph
B =
;
4ꢀМеC6H4
—
—
4ꢀClC6H4
bonyl compounds, dibenzoylmethane and ethyl benzoylꢀ
acetate, eliminating in the reaction course. For the recyꢀ
clization to be a success, it is optimum to perform the
reaction under mild conditions (a shortꢀtime heating to
20 °C), since both a prolonged reflux of the mixture of
thiolate 7b, pꢀtoluidine, and HCHO in EtOH and keeping
the starting reactants in EtOH at 20 °C lead to resinificaꢀ
tion of the reaction mixture.
Finally, it is also necessary to note that for the analogs
of cyclic adducts 1, 7, and 8, there are described only
separate examples of transformations leading to recyclizaꢀ
tion/destruction of the tetrahydropyridine ring. For inꢀ
stance, in a number of cases there was found abnormal
recyclization of 6ꢀalkylꢀ3ꢀcyanoꢀ6ꢀhydroxyꢀ1,4,5,6ꢀtetꢀ
rahydropyridineꢀ2ꢀthiolates to (E)ꢀ3ꢀarylꢀ2ꢀ(thiazolꢀ2ꢀ
yl)acrylonitriles during attempted alkylation with αꢀhaꢀ
loketones.14,15
Experimental
1
H NMR spectra were recorded on a Bruker Avance II 400
spectrometer (399.97 MHz) (for compound 1, Bruker AMꢀ300
(300 MHz)) in DMSOꢀd6 with Me4Si as an internal standard.
IR spectra were recorded on a IKSꢀ29 spectrophotometer in
Nujol. Elemental analysis was performed on a PerkinꢀElmer
C,H,NꢀAnalyzer. The individuality of compounds synthesized was
monotored by TLC on Silufol UV 254 plates in acetone—nꢀhepꢀ
tane (1 : 1) solvent system, visualization was performed by iodine
vapors or UV detector. Melting points were measured on a Kofꢀ
ler stage and uncorrected. The starting Nꢀmethylmorpholinium
4ꢀarylꢀ3ꢀcyanoꢀ5ꢀethoxycarbonylꢀ6ꢀhydroxyꢀ6ꢀphenylꢀ1,4,5,6ꢀ
tetrahydropyridineꢀ2ꢀthiolates 7a,b and Nꢀmethylmorpholiniꢀ
um 5ꢀbenzoylꢀ4ꢀ(2ꢀchlorophenyl)ꢀ3ꢀcyanoꢀ6ꢀhydroxyꢀ6ꢀpheꢀ
nylꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolate (8) were obtained acꢀ
cording to the known procedures.12,13 Perhydroꢀ1,3,5ꢀtriazine 6
for comparative analysis was obtained by condensation of forꢀ
maline with benzylamine.17
Pyrimido[4,3ꢀb][1,3,5]thiadiazines 5 are colorless or
pale yellow finely crystalline substances virtually insoluble
in EtOH, moderately soluble in acetone, and readily soluꢀ
ble in warm DMF or DMSO. The recyclization products

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Dotsenko et al.
Piperidinium (4R*,5R*,6R*)ꢀ5ꢀbenzoylꢀ4ꢀ(2ꢀchlorophenyl)ꢀ
3ꢀcyanoꢀ6ꢀhydroxyꢀ6ꢀmethylꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthioꢀ
late (1) was obtained according to the procedure given in the
Dr. Sci. Thesis:9 cyanothioacetamide (2.0 g, 20 mmol), benzoyꢀ
lacetone (3.25 g, 20 mmol) (after 5 min), and piperidine (2.5 mL,
25 mmol) were sequentially added to a mixture of 2ꢀchlorobenꢀ
zaldehyde (2.3 mL, 20 mmol) and piperidine (3 drops) in EtOH
(30 mL) (temperature, 20 °C) with stirring. After 3 h, a preciꢀ
pitate formed was filtered off and washed with acetone to obꢀ
tain thiolate 1 (7.7 g, 82%) as a white finely crystalline powder,
m.p. 165—167 °C. Found (%): C, 63.66; H, 5.94; N, 8.91.
C25H28ClN3O2S (M = 470.04). Calculated (%): C, 63.88;
H, 6.00; N, 8.94. IR (Nujol), ν/cm–1: 3450, 3214 (OH, NH, NH2+),
2173 (CN), 1697 (C=O). 1H NMR (DMSOꢀd6), δ: 1.58 (m, 6 H,
(CH2)3); 1.75 (s, 3 H, CH3); 3.01 (m, 4 H, CH2NCH2); 4.13 and
and 37% aq. HCHO (2.5 mL, 34 mmol) (free of paraformaldeꢀ
hyde) in EtOH (20 mL) was brought to boiling, the solution
formed was filtered through a paper filter. The mixture was kept
for 4 days at 20 °C, a precipitate was filtered off and washed with
hot EtOH to obtain pyrimido[4,3ꢀb][1,3,5]thiadiazine 5a (0.24 g,
28%). Analytically pure sample was obtained by recrystallization
from acetone—EtOH (1 : 1) solvent mixture.
Synthesis of pyrimido[4,3ꢀb][1,3,5]thiadiazines (5c,d) by seꢀ
quential condensation of aldehyde, cyanothioacetamide, primary
amine, and formaldehyde. A mixture of cyanothioacetamide 9
(0.3 g, 3 mmol), Nꢀmethylmorpholine (2 drops), and pꢀchloꢀ
robenzaldehyde (0.42 g) (or freshly distilled PhCHO (0.31 mL,
3 mmol)) in EtOH (15 mL) was stirred for 30 min, after that 37%
aq. formaline (2 mL, 27 mmol) (free of paraformaldehyde) and
primary amine (6.6 mmol) (freshly distilled aniline (0.6 mL) for
5c or pꢀtoluidine (0.71 g) for 5d) were added to the reaction
mixture. The mixture obtained was refluxed for 3—5 min with
intensive stirring, kept for 48 h at 20 °C, the solvent was decantꢀ
ed, and a tarꢀlike residue was treated with boiling ethanol. The
product was filtered off, washed with water and hot EtOH and
recrystallized from suitable solvent to obtain analytically pure
pyrimido[4,3ꢀb][1,3,5]thiadiazines 5c,d.
3
4.27 (both d, 1 H each, C(4)H and C(5)H, J = 11.8 Hz); 6.08
(m, 10 H, Ph, 2ꢀClC6H4, OH); 8.32 (br.s, 1 H, NH). The relaꢀ
tive configuration (4R*,5R*,6R*) was assigned to thiolate 1 based
on the Xꢀray diffraction data for the Sꢀalkylation product.9
Reaction of piperidinium (4R*,5R*,6R*)ꢀ5ꢀbenzoylꢀ4ꢀ(2ꢀ
chlorophenyl)ꢀ3ꢀcyanoꢀ6ꢀhydroxyꢀ6ꢀmethylꢀ1,4,5,6ꢀtetrahydroꢀ
pyridineꢀ2ꢀthiolate (1) with primary amines and HCHO. Excess
of 37% aqueous HCHO (3 mL, 40 mmol) (free of paraformaldeꢀ
hyde) and pꢀtoluidine (0.3 g, 2.8 mmol) (or benzylamine (0.3 mL,
2.8 mmol)) were added to a suspension of pyridineꢀ2ꢀthiolate 1
(0.6 g, 1.28 mmol) in EtOH (15 mL), the mixture obtained was
heated until it was homogenized, filtered through a folded filter,
and kept at 20 °C. In the case of pꢀtoluidine, already after 15 min
a pale yellow precipitate of pyrimido[4,3ꢀb][1,3,5]thiadiazine
5a was formed, which after 48 h was filtered off and washed with
EtOH. In the case of benzylamine, an oil obtained crystallized to
a yellow tarꢀlike substance on prolonged (1 month) standing,
which was (TLC, NMR) a complex multicomponent mixture.
According to the comparative TLC data, in addition to unidentiꢀ
fied products, the mixture contained pyrimido[4,3ꢀb][1,3,5]ꢀ
thiadiazine10 5b (Rf 0.60) and 1,3,5ꢀtribenzylperhydroꢀ1,3,5ꢀtriꢀ
azine17 6 (Rf 0.73). We failed in our attempts to separate this
mixture by recrystallization or chromatography.
Reaction of Nꢀmethylmorpholinium 4ꢀarylꢀ3ꢀcyanoꢀ5ꢀethꢀ
oxycarbonylꢀ6ꢀhydroxyꢀ6ꢀphenylꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀ
thiolates (7a,b) with primary amines and HCHO. Excess of 37%
aq. HCHO (2 mL, 27 mmol) (free of paraformaldehyde) and
corresponding primary amine (4 equiv., 4.8—5.2 mmol) were
added to a suspension of pyridineꢀ2ꢀthiolate 7a,b (1.2—1.3 mmol)
in EtOH (15 mL), the mixture obtained was refluxed for 1—2 min
until the starting reactants were completely dissolved, filtered
through a folded filter, and kept for 4—5 days at 20 °C. The
solvent was decanted, a tarꢀlike product was treated with boiling
EtOH (8—10 mL). An insoluble precipitate of the corresponding
pyrimido[4,3ꢀb][1,3,5]thiadiazine 5c,d was filtered off, washed
with EtOH, and recrystallized from suitable solvent. The reacꢀ
tions of thiolate 7b with HCHO and pꢀtoluidine (1 equiv.,
2 equiv., and 6 equiv.) were performed similarly. The results are
given in Table 1. Reflux (3 h) of a mixture of thiolate 7b,
pꢀtoluidine (4 equiv.) and excess HCHO in ethanol led to resinꢀ
ification of the reaction mixture, from which we failed to isolate
compound 5d.
8ꢀ(2ꢀChlorophenyl)ꢀ3,7ꢀdi(4ꢀmethylphenyl)ꢀ3,4,7,8ꢀtetrahyꢀ
droꢀ2H,6Hꢀpyrimido[4,3ꢀb][1,3,5]thiadiazineꢀ9ꢀcarbonitrile
(5a). A pale yellow finely crystalline powder, the yield was 5%
on thiolate 1, 28% on thiolate 8. M.p. 209—210 °C (decomp.,
from acetone : EtOH = 1 : 1) (cf. Ref. 10: 210—211 °C (DMF)).
Found (%): C, 67.95; H, 5.30; N, 12.01. C27H25ClN4S (M =
= 473.04). Calculated (%): C, 68.56; H, 5.33; N, 11.84. IR
(Nujol), ν/cm–1: 2165 (C≡N). 1H NMR (DMSOꢀd6), δ: 2.26
and 2.30 (both s, 3 H each, 2 MeC6H4); 4.07 and 4.57 (both d,
1 H each, SCH2N, 2J = 13.0 Hz); 4.70 and 4.86 (both d, 1 H
2
each, NCH2N, J = 13.2 Hz); 5.06 and 5.26 (both d, 1 H each,
NCH2N, 2J = 12.4 Hz); 5.24 (s, 1 H, C(8)H); 6.78 and 6.91
(both d, 2 H each, 4ꢀMeC6H4, 3J = 8.5 Hz); 7.00 and 7.05
(both d, 2 H each, 4ꢀMeC6H4, 3J = 8.6 Hz); 7.21—7.32 (m, 4 H,
2ꢀClC6H4).
3,7,8ꢀTriphenylꢀ3,4,7,8ꢀtetrahydroꢀ2H,6Hꢀpyrimido[4,3ꢀb]ꢀ
[1,3,5]thiadiazineꢀ9ꢀcarbonitrile (5c). A beige finely crystalline
powder, the yield was 12% on thiolate 7a, in the condensation
reaction of thioamide 9 with PhCHO, PhNH2, and HCHO, the
yield was 19%. M.p. 176—178 °C (acetone—EtOH = 2 : 1).
Found (%): C, 72.49; H, 5.34; N, 13.80. C25H22N4S (M = 410.54).
Calculated (%): C, 73.14; H, 5.40; N, 13.65. IR (Nujol), ν/cm–1
:
2161 (C≡N). 1H NMR (DMSOꢀd6), δ: 4.17 and 4.67 (both d,
1 H each, SCH2N, 2J = 13.1 Hz); 4.86 and 4.96 (both d,
1 H each, NCH2N, 2J = 12.9 Hz); 5.10 and 5.29 (both d,
1 H each, NCH2N, 2J = 12.5 Hz); 5.18 (s, 1 H, C(8)H); 6.89—7.36
(m, 15 H, 3 Ph).
8ꢀ(4ꢀChlorophenyl)ꢀ3,7ꢀdi(4ꢀmethylphenyl)ꢀ3,4,7,8ꢀtetrahyꢀ
droꢀ2H,6Hꢀpyrimido[4,3ꢀb][1,3,5]thiadiazineꢀ9ꢀcarbonitrile
(5d). A snowꢀwhite finely crystalline powder, the yield was 17.5%
on thiolate 1 and 58% on thioamide 9, 4ꢀClC6H4CHO,
4ꢀMeC6H4NH2, and HCHO. M.p. 208—210 °C (decomp., from
a DMF—EtOH = 1 : 1 solvent mixture; cf. Ref. 10: 213—215 °C
(EtOH)). Found (%): C, 68.05; H, 5.31; N, 11.98. C27H25ClN4S
(M = 473.04). Calculated (%): C, 68.56; H, 5.33; N, 11.84. IR
(Nujol), ν/cm–1: 2175 (C≡N). 1H NMR (DMSOꢀd6), δ: 2.23
and 2.24 (both s, 3 H each, 2 MeC6H4); 4.02 and 4.61 (both d,
1 H each, SCH2N, 2J = 13.0 Hz); 4.83 and 4.92 (both d, 1 H
each, NCH2N, 2J = 13.2 Hz); 5.17 (s, 1 H, C(8)H); 5.10 and
Reaction of Nꢀmethylmorpholinium 5ꢀbenzoylꢀ4ꢀ(2ꢀchloꢀ
rophenyl)ꢀ3ꢀcyanoꢀ6ꢀhydroxyꢀ6ꢀphenylꢀ1,4,5,6ꢀtetrahydropyriꢀ
dineꢀ2ꢀthiolate (8) with formaline and pꢀtoluidine. A mixture of
thiolate 8 (1.0 g, 1.8 mmol), pꢀtoluidine (0.39 g, 3.65 mmol),

Pyrimido[4,3ꢀb][1,3,5]thiadiazines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1483
5.28 (both d, 1 H each, NCH2N, 2J = 12.2 Hz); 6.94—7.10
(m, 8 H, two groups of signals for pꢀtolyl substituents 4ꢀH3CC6H4
are overlapped); 7.32 and 7.42 (both d, 2 H each, 4ꢀClC6H4,
3J = 8.5 Hz).
7. (a) V. V. Dotsenko, S. G. Krivokolysko, V. P. Litvinov, Khim.
Geterotsikl. Soedin., 2007, 1709 [Chem. Heterocycl. Compd.
(Engl. Transl.), 2007, 43, 1455]; (b) V. V. Dotsenko, S. G.
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8. V. V. Dotsenko, S. G. Krivokolysko, V. P. Litvinov, Moꢀ
natsh. Chem., 2008, 139, 657.
9. S. G. Krivokolysko, Dr. Sci. Thesis, MSU, Moscow, 2001
(in Russian).
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Received February 4, 2009