An efficient Mannich-type synthesis of bis(pyrido[2,1-b][1,3,5]thiadiazin- 7-yl)-methanes

Article abstract of DOI:10.1007/s00706-007-0809-9

Morpholinium 3-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-thiolate upon treatment with primary amines and a formaldehyde excess under mild conditions produces bis(pyrido[2,1-b][1,3,5]thiadiazin-7-yl)methane derivatives in good yields (67-87%).

Full text of DOI:10.1007/s00706-007-0809-9

Monatsh Chem 139, 657–661 (2008)
DOI 10.1007/s00706-007-0809-9
Printed in The Netherlands
An efficient Mannich-type synthesis of bis(pyrido[2,1-b][1,3,5]thiadiazin-7-yl)-
methanes
Victor V. Dotsenko1;2, Sergey G. Krivokolysko2, Victor P. Litvinov3;y;z
1
State Enterprise ‘‘Luganskstandartmetrology’’, Lugansk, Ukraine
2
Vladimir Dal’ East Ukrainian National University, Lugansk, Ukraine
3
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation
Received 12 August 2007; Accepted 21 September 2007; Published online 19 May 2008
# Springer-Verlag 2008
Abstract Morpholinium 3-cyano-4-methyl-6-oxo-1,6-
dihydropyridine-2-thiolate upon treatment with pri-
mary amines and a formaldehyde excess under mild
conditions produces bis(pyrido[2,1-b][1,3,5]thiadiaz-
in-7-yl)methane derivatives in good yields (67–87%).
sis inhibiting effect [11, 12] and suppressor of insect
egg-laying [13]. 2-Thioxotetrahydro-1,3,5-thiadi-
azines (‘‘carbothialdines’’) also posess antidermato-
phytic [14], hypolipidemic [15], anti-leishmanial,
parasiticidal [16], and antihelmintic [17] types of
activity. 3,5-Dimethyl-2-thioxotetrahydro-1,3,5-thia-
dizine (DTTT, carbothialdine, Dazomet, Basamid+,
in former USSR known under the name ‘‘thiazon’’)
is highly effective soil fungicide and slimicide [18]
and produces a total ovicidal effect on the helminth
eggs in soil [19]. DTTT also behaves as a monoden-
tate ligand towards some metal carbonyls [20].
One of the most concise and effective approaches
to the ring-fused 1,3,5-thiadiazines based on the
double Mannich-type condensation of 2-mercaptoa-
zole or -azine derivatives with primary amines and a
formaldehyde excess. In fact, the related syntheses
of s-triazolo[3,4-b][1,3,5]thiadiazines [21], thiazolo-
[30,40:1,5][1,2,4]triazolo[3,4-b][1,3,5]thiadiazines
[22], 1,3,5-thiadiazino[3,2-a]benzimidazoles [23],
imidazo[2,1-b][1,3,5]thiadiazines [24], 1,2,4-triazino-
[3,2-b][1,3,5]thiadiazines [25], pyrido[2,1-b][1,3,5]-
thiadiazines [26], and pyrimido[6,1-b][1,3,5]thiadi-
azines [27] have been reported in literature to date.
In continuation of our efforts on the application of
3-cyanopyridine-2(1H)-chalcogenones in heterocyclic
synthesis [28], and to develop the above Mannich-
type method for 1,3,5-thiadiazine ring construction,
studies have been taken up on the aminomethylation
Keywords Heterocycles; Mannich reaction; Michael adducts;
Pyridine-2-thiolates; 1,3,5-Thiadiazines.
Introduction
1,3,5-Thiadiazines are known to be the compounds
of a great practical interest [1]. Thus, 1,3,5-thiadi-
azines constitute new classes of insecticides [2]. They
exhibit antileukemic [3], antifungal and antimicro-
bial activity [3, 4], and they are usefully applied as
herbicides [5], miticides [6], antibacterial [7], anti-
tumoral [8] and antitubercular agents [9]. Further-
more, these compounds are promising prodrugs for
amino acids and similar compounds [10]. Buprofezin
(Applaud+, 2-tret-butylimino-3-isopropyl-5-phenyl-
perhydro-1,3,5-thiadiazine) is widely known as an
insect growth regulator with strong chitin biosynthe-
y
z
Deceased
This paper is dedicated to the blessed memory of our
colleague, Prof. Victor Petrovich Litvinov (December 24,
1932–February 26, 2007)
Correspondence: Victor V. Dotsenko, State Enterprise
‘‘Luganskstandartmetrology’’, 91021 Lugansk, Ukraine.
E-mail: Victor_Dotsenko@bigmir.net

658
V. V. Dotsenko et al.
of accessible morpholinium 3-cyano-4-methyl-6-
oxo-1,6-dihydropyridine-2-thiolate (1). The latter can
be easily obtained by reaction of ethyl 3-morphol-
inocrotonate with cyanothioacetamide [29, 30], or
by the ternary condensation of cyanothioacetamide,
acetoacetic ester and morpholine [31]. Due to the
presence of various functional groups thiolate 1 is
expected to be a good starting point for the synthesis
of pyrido[2,1-b][1,3,5]thiadiazine derivatives under
double Mannich-type reaction conditions.
the stronger field at ꢀ ¼ 3.66–3.76 ppm. It seems rea-
sonable to accept the assumption that these peaks
must be assigned to the H2C-protons of 7,70-methy-
lene bridge of dipyridylmethane structure 3, while
other resonances in the spectra fit the two sets of
magnetically equal protons. The plausible assump-
tion that the peaks at ꢀ ¼ 3.66–3.76 ppm were that of
the H2C-bridge protons resonances agreed well with
chemical shifts (generally in the range ꢀ ¼ 3.5–
5.0 ppm) reported for related dihetarylmethane spe-
cies (for instance, see [32, 33]). There have been a
number of tandem Knoevenagel-Michael-type reac-
tions with aldehydes to form 3,30-dipyridylmethane
species reported for a variety of C(3)-nucleophilic
2-pyridones [32–36]. So, both a survey of literature
and our interpretation of 1H NMR data were consis-
tent with the structure for products 3a–3f given in
the Scheme 1.
Results and discussion
We have found that thiolate 1 readily reacts with
primary amines and a formaldehyde excess under
short-time heating in DMF to form Mannich-type
condensation products. The latter were supposed
first to have a pyrido[2,1-b][1,3,5]thiadiazine struc-
1
It is strongly supposed that the reaction procced
through the formation of non-isolable intermediate
4. Presumably, the former resulted from the conden-
sation of formaldehyde with pyridine-2-thiolate 1
occurred at C(5) atom followed by the Michael ad-
dition. Adduct 4, in turn, undergo S,N-bis-amino-
ture 2. Surprisingly, the H NMR spectra of all the
obtained compounds lacked the characteristic peaks
at ꢀ ¼ 5.36–6.51 ppm corresponding to C(5)H pyri-
dine protons [29–31]. Instead of it, the broadened
singlets with total integral values of 1H in ratio to
the values of aromatic or H3C-protons appeared in
Scheme 1

An efficient Mannich-type synthesis
659
binder – starch) in the acetone–heptane (1:1) system; spots
were visualized with iodine vapors and UV light. The starting
thiolate 1 was prepared according to the general method
reported in Refs. [29, 30].
methylation to afford bis(pyrido[2,1-b][1,3,5]thiadi-
azin-7-yl)methanes 3 in high yields (67–87%). Both
aliphatic and aromatic primary amines reacted under
these conditions, but the synthesis is not so variable
since sterically unhindered primary amines should
be employed only. For instance, we failed to carry
out the reaction with 2,6-dimethylaniline, o-pheneti-
dine, tert-butylamine, or 2-ethyl-6-methylaniline. All
efforts to use amines with strong electron-accepting
substituents such as o-nitroaniline also gave unsatis-
factory results.
Bis(3-R-9-cyano-8-methyl-6-oxo-3,4-dihydro-2H,6H-
pyrido[2,1-b][1,3,5]thiadiazin-7-yl)methanes (3a–3f).
General procedure
To the solution of thiolate 1 (1.0g, 4 mmol) in 5–6 cm3 DMF,
corresponding primary amine (4mmol) and an excess of 37%
aqueous formaldehyde solution (4cm3, 53 mmol) were added.
The mixture was refluxed for 1–2 min, cooled, filtered through
a paper filter and left to stand for 24h at ambient temperature.
The colorless crystals of 3a–3f were filtered off, washed twice
with hot EtOH and recrystallized from an appropriate solvent.
All the obtained 3a–3f are fine colorless crystals,
readily soluble in DMSO or hot DMF, but insoluble
in alcohols, dioxane, or acetone. The structures of
1
Bis(9-cyano-8-methyl-6-oxo-3-phenyl-3,4-dihydro-2H,6H-
pyrido[2,1-b][1,3,5]thiadiazin-7-yl)methane
3a–3f were confirmed by IR- and H NMR-spectra,
1
as well as elemental analysis data. The H NMR
(3a, C31H26N6O2S2)
spectra revealed the signals of C(8)CH3 protons as
singlets at ꢀ ¼ 2.09–2.30 ppm and broadened sin-
glets at ꢀ ¼ 3.66–3.76 ppm corresponding to methy-
lene bridge protons. The protons of SCH2NCH2N
system appeared as two broadened singlets in the
lower field (ꢀ ¼ 4.85–5.67 ppm) that agreed well
with the values of ꢀ ¼ 4.50–5.32 ppm as we reported
prior for related compounds [24, 26]. The IR spectra
of 3a–3f showed typical lactam C¼O band ab-
sorption (ꢁꢀ¼ 1630–1650 cmꢀ1) and the peaks at
ꢁꢀ¼ 2205–2216 cmꢀ1 attributed to conjugated cyano
group, but revealed a lack of any NH group stretch-
ing bands.
Finally, it should be noted that 3,30-dipyrido-
methanes, being a relatively rare class of compounds,
are of practical interest due to their inhibitory effects
on the growth of a wide range of cancer cell lines
[34, 36]. In this paper, we proposed an effective
approach for synthesis of previously unknown dipy-
ridomethanes containing a biologically active 1,3,5-
thiadiazine fragment, that may therefore be expected
to have a biological role needs to be examined.
Yield 67%; mp 247–250ꢂC (dec, from acetone:DMF ¼ 1:1);
1H NMR (200MHz, DMSO-d6): ꢀ ¼ 2.12 (br s, 2C(8)CH3),
3.67 (s, CH2), 5.53, 5.67 (both br s, each 4H, 2SCH2NCH2),
6.96–7.26 (m, 2Ph) ppm; IR (nujol): ꢁꢀ¼ 2205 (2CꢃN), 1650
(2C¼O) cmꢀ1
.
Bis{9-cyano-8-methyl-3-(4-methylphenyl)-6-oxo-3,4-dihydro-
2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-7-yl}methane
(3b, C33H30N6O2S2)
Yield 84%; mp 265ꢂC (dec, from EtOH:DMSO ¼ 1:1); 1H
NMR (200MHz, DMSO-d6): ꢀ ¼ 2.08 (br s, 2Ar–CH3), 2.19
(br s, 2C(8)CH3), 3.70 (s, CH2), 5.47, 5.64 (both br s, each
3
4H, 2SCH2NCH2), 6.98 (q, J ¼ 8.2 Hz, 2C6H4CH3) ppm; IR
(nujol): ꢁꢀ¼ 2216 (2CꢃN), 1647 (2C¼O) cmꢀ1
.
Bis{9-cyano-3-(4-fluorophenyl)-8-methyl-6-oxo-3,4-dihydro-
2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-7-yl}methane
(3c, C31H24F2N6O2S2)
Yield 70%; mp 270–272ꢂC (dec, from DMF); 1H NMR
(200MHz, DMSO-d6): ꢀ ¼ 2.14 (br s, 2C(8)CH3), 3.66 (s,
CH2), 5.49, 5.64 (both br s, each 4H, 2SCH2NCH2), 7.01–
7.20 (m, 2C6H4F) ppm; IR (nujol): ꢁꢀ¼ 2205 (2CꢃN), 1642
(2C¼O) cmꢀ1
.
Bis{3-(4-chlorophenyl)-9-cyano-8-methyl-6-oxo-3,4-dihydro-
2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-7-yl}methane
(3d, C31H24Cl2N6O2S2)
Experimental
Melting points were measured on a Kofler hot stage apparatus.
Elemental analyses for C, H, and N were conducted using
a Perkin-Elmer C, H, and N Analyzer; their results were found
to be in good agreement with the calculated values (ꢁ0.2%).
IR spectra were recorded on an IKS-29 spectrophotometer in
Nujol mulls. The 1H NMR spectra were performed on Varian
Mercury VX-200 (199.97 MHz) spectrometer on DMSO-d6
solutions with Me4Si as the internal standard. The purity of
all obtained compounds was checked by TLC on Silufol+ UV
254 plates (sorbent – Silpearl, large-pore silicagel after Pitra
with luminiscent indicator for UV 254 on the aluminium foil,
Yield 87%; mp 272–275ꢂC (dec, from DMF); 1H NMR
(200 MHz, DMSO-d6): ꢀ ¼ 2.13 (br s, 2C(8)CH3), 3.66 (s,
CH2), 5.50, 5.67 (both br s, each 4H, 2SCH2NCH2), 7.18 (q,
3J ¼ 8.6 Hz, 2C6H4CH3) ppm; IR (nujol): ꢁꢀ¼ 2205 (2CꢃN),
1650 (2C¼O) cmꢀ1
.
Bis(3-benzyl-9-cyano-8-methyl-6-oxo-3,4-dihydro-2H,6H-
pyrido[2,1-b][1,3,5]thiadiazin-7-yl)methane
(3e, C33H30N6O2S2)
Yield 84%; mp 220–222ꢂC (dec, from DMF:EtOH¼ 2:1); 1H
NMR (200MHz, DMSO-d6): ꢀ ¼ 2.30 (br s, 2C(8)CH3), 3.61

660
V. V. Dotsenko et al.
(s, CH2), 3.76 (br s, CH2C6H5), 4.85, 4.96 (both br s, each 4H,
2SCH2NCH2), 7.20–7.28 (m, 2Ph) ppm; IR (nujol): ꢁꢀ¼ 2203
7. Dhonde MG, Deshmukh GP (2005) Chem Heterocycl
Compd 41:787
´ ´ ´ ´
8. Perez R, Rodrıguez H, Perez E, Suarez M, Reyes O,
(2CꢃN), 1630 (2C¼O) cmꢀ1
.
´
´
´
Gonzalez LJ, Lopez de Cerain A, Ezpeleta O, Perez C,
Ochoa C (2000) Arzneim-Forsch (Drug Research) 50:
854
Bis{9-cyano-3-(4-ethoxyphenyl)-8-methyl-6-oxo-3,4-
dihydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-7-yl}methane
(3f, C35H34N6O4S2)
9. Katiyar D, Tiwari VK, Tripathi RP, Srivastava A,
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Yield 68%; mp 250–253ꢂC (dec, from DMF:EtOH ¼ 1:1);
1H NMR (200MHz, DMSO-d6): ꢀ ¼ 1.25 (t, 3J ¼ 7.0 Hz,
OCH2CH3), 2.09 (br s, 2C(8)CH3), 3.67 (s, CH2), 3.91 (q,
3J ¼ 7.0 Hz, OCH2CH3), 5.45, 5.60 (both br s, each 4H,
2SCH2NCH2), 6.88 (q, 3J ¼ 8.9 Hz, 2Ar) ppm; IR (nujol):
ꢁꢀ¼ 2211 (2CꢃN), 1648 (2C¼O) cmꢀ1
.
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Acknowledgements
Authors are grateful to Dr. Nataliya V. Lyutenko (Clemson
University, SC, USA) for a SciFinder literature search
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