Design and synthesis of pyrido[2,1- b ][1,3,5]thiadiazine library via uncatalyzed mannich-type reaction

Article abstract of DOI:10.1021/co5000807

This Research Article describes the synthesis of an over 700-member library of (8R/8S)-3-R-8-aryl-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-9-carbonitriles by uncatalyzed Mannich-type reaction of N-methylmorpholinium (4R/4S)-4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-2-thiolates with a set of primary amines and excessive HCHO. The scope and limitations of the reaction were studied. Starting thiolates were obtained in yields of 53-82% by multicomponent reaction of aromatic aldehydes, cyanothioacetamide, 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid), and N-methylmorpholine, followed by heterocyclization of the resulting Michael adducts.

Full text of DOI:10.1021/co5000807

Research Article
pubs.acs.org/acscombsci
Design and Synthesis of Pyrido[2,1‑b][1,3,5]thiadiazine Library via
Uncatalyzed Mannich-Type Reaction
Victor V. Dotsenko,*,†,§ Konstantin A. Frolov,† Tatyana M. Pekhtereva,‡ Olena S. Papaianina,‡
Sergey Yu. Suykov,‡ and Sergey G. Krivokolysko†
†ChemEx Laboratory, Vladimir Dal’ East Ukrainian National University, 91034 Lugansk, Ukraine
§Kuban State University, 350040 Krasnodar, Russian Federation
‡L. M. Litvinenko Institute of Physical-Organic Chemistry and Coal Chemistry NAS of Ukraine, 83114 Donetsk, Ukraine
S
* Supporting Information
ABSTRACT: This Research Article describes the synthesis of
an over 700-member library of (8R/8S)-3-R-8-aryl-6-oxo-
3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-9-car-
bonitriles by uncatalyzed Mannich-type reaction of N-
methylmorpholinium (4R/4S)-4-aryl-3-cyano-6-oxo-1,4,5,6-
tetrahydropyridin-2-thiolates with a set of primary amines
and excessive HCHO. The scope and limitations of the reaction were studied. Starting thiolates were obtained in yields of 53−
82% by multicomponent reaction of aromatic aldehydes, cyanothioacetamide, 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s
acid), and N-methylmorpholine, followed by heterocyclization of the resulting Michael adducts.
KEYWORDS: uncatalyzed Mannich-type reaction, cyanothioacetamide, Meldrum’s acid, tetrahydropyridine-2-thiolates,
aminomethylation, pyrido[2,1-b][1,3,5]thiadiazines
prostaglandin E2 biosynthesis34 and by inhibition of chitin
INTRODUCTION
■
biosynthesis and integumentary cuticule deposition.35,36 Re-
1,3,5-Thiadiazines have attracted considerable attention over
cently, buprofezin has been found to be an acetylcholinesterase
the years because of their biological activities and applications
in medicine and agriculture (for reviews on the 1,3,5-thiadiazine
chemistry, see refs 1−3). 1,3,5-Thiadiazines are known as
inhibitor in B-biotype Bemisia tabaci.37 Another widely used
compound is tetrahydro-3,5-dimethyl-1,3,5-thiadiazine-2-thi-
antidermatophites,4,5 antifungal and fungistatic agents,6−14
one, also known under names Dazomet, Basamid, Mylone,
antimicrobials and bactericides,15−23 antifibrinolytic
Thiazone, Carbothialdine, or DMTT (Figure 1), which is a soil
agents,24−27 tuberculostatics,28−31 etc. Thiadiazines are widely
fumigant and used as a powerful insecticide, papermaking
used as insecticides.32 2-tert-Butylimino-3-isopropyl-5-phenyl-
3,4,5,6-tetrahydro-2H-l,3,5-thiadiazin-4-one, also known as
slimicide and nematicide, fungicide, and herbicide for cabbage,
cucumber, maize, potato, and tomato plants.38−44 Dazomet also
behaves as a monodentate ligand toward some metal
carbonyls.45 In addition, Dazomet have been reported to
possess an ovicidal effect on helminths eggs.46 Another
bioactive 1,3,5-thiadiazine, NIP-200 (3,5-dimethyl-4,6-diphen-
yl-tetrahydro-2H-1,3,5-thiadiazine-2-thione, Figure 1) is a
potent hypolipidemic agent increasing the synthesis of bile
acids as a result of the activation of cholesterol 7α-hydroxylase,
the rate-limiting enzyme in the conversion of cholesterol to bile
acids.47 3,5-Dibenzyltetrahydro-2H-1,3,5-thiadiazine-2-thione
(D47, Dibenzthion) is an antimycotic agent useful for
treatment of dermatomycoses.48−51
buprofezin or Applaud (Figure 1), was found to be the most
active growth regulator on the greenhouse whitefly (Trialeur-
odes vaporariorum) and the brown planthopper (Nilaparvata
lugens), which is regarded as one of the most serious insect
pests in rice fields.33 Buprofezin acts on the insects by strong
suppression of oviposition because of the inhibition of
One of the most effective approaches to 1,3,5-thiadiazines is
based on the double Mannich-type reaction of thioamides,
dithiocarbamates or related S,N-binucleophilic species with
primary amines and formaldehyde.1−3 Cyclic thioamides (γ-
and δ-thiolactams, 2-mercaptoazoles, -azines, or their 2-
Received: May 16, 2014
Revised: August 1, 2014
Published: September 5, 2014
Figure 1. Biologically active 1,3,5-thiadiazines.
© 2014 American Chemical Society
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ACS Combinatorial Science
Research Article
thioxotautomers) can also be successfully employed in this
reaction, giving rise to a variety of ring-condensed 1,3,5-
thiadiazines. In fact, the related syntheses of 1,2,4-triazolo[3,4-
b][1,3,5]thiadiazines,52−60 imidazo[2,1-b][1,3,5]-
thiadiazines,61,62 1,2,4-triazino[3,2-b][1,3,5]thiadiazines,61
thiazolo[3′,4′:1,5][1,2,4]triazolo[3,4-b][1,3,5]thiadiazines,63
1,3,5-thiadiazino[3,2-a]benzimidazoles,64 cyclopenta[g]pyrido-
[2,1-b][1,3,5]thiadiazines,65 bis(pyrido[2,1-b][1,3,5]thiadiazin-
7-yl)methanes,66 pyrimido[2,1-b][1,3,5]thiadiazines,67 and
pyrimido[4,3-b][1,3,5]thiadiazines68−70 have been reported
(Scheme 1).
cides.78−80 Recently we found that pyrido[2,1-b][1,3,5]-
thiadiazine 6 and related compounds showed significant
inhibition against tick-borne encephalitis virus and Powassan
virus.81 Encouraged by this success, we turned our attention to
the synthesis of related pyrido[2,1-b][1,3,5]thiadiazines in
regard to library construction.
As we have shown in preliminary communications,82,83 these
pyrido[2,1-b][1,3,5]thiadiazines could be easily prepared by
Mannich-type reaction of N-methylmorpholinium 4-aryl-6-oxo-
3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates 7 with primary
amines and excess formaldehyde (Scheme 2). This effective and
Scheme 2. Synthesis of Pyrido[2,1-b][1,3,5]thiadiazines 8
Scheme 1. Diversity of Ring-Condensed 1,3,5-Thiadiazines
time-saving protocol is based on the use of inexpensive, readily
available building blocks. In contrast to related double Mannich
reactions,52−60 no catalyst is required for this process. In most
cases, the obtained pyrido[2,1-b][1,3,5]thiadiazines 8 were
pure enough for analytical purposes that allowed us to exclude
any purification steps. These results prompted us to study the
scope and limitations of the reaction.
RESULTS AND DISCUSSION
■
In the current study, we report an optimized protocol for the
synthesis of 700+ membered library of 3-R-8-aryl-6-oxo-3,4,7,8-
tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carboni-
triles 8{1−47,1−31}, employing a small library of N-
methylmorpholinium 4-aryl-6-oxo-3-cyano-1,4,5,6-tetrahydro-
pyridine-2-thiolates 7{1−47} (Table 1), 37% aq. HCHO and
a set of various primary amines 9{1−31} (Figure 3). The
required thiolates 7{1−47} are easily accessible by one-pot
condensation of aromatic aldehydes, cyanothioacetamide 10
and Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) 11 in
the presence of N-methylmorpholine following the consequent
cyclization of the isolable Michael adduct, N-methylmorpholi-
nium 5-(3-amino-1-aryl-2-cyano-3-thioxopropyl)-2,2-dimethyl-
4-oxo-4H-1,3-dioxin-6-olate 12, as outlined in Scheme 3.81−90
As the starting 1,4,5,6-tetrahydropyridine-2-thiolates 7 have
been prepared as racemic mixtures of (4R)- and (4S)-
enantiomers, all the pyrido[2,1-b][1,3,5]thiadiazine-9-carbon-
itriles 8 also were obtained as mixtures of (8R)- and (8S)-
isomers.
However, despite the diversity and availability of ring-
condensed 1,3,5-thiadiazines, their use and applicability is much
less studied.3 Thus, pyrazolo[1,5-c][1,3,5]thiadiazine-2-diones
1 (Figure 2) have been reported as effective fungicides71−73 and
photosynthetic electron transport inhibitors.74,75 1,2,4-Triazolo-
[3,4-b][1,3,5]thiadiazines 2 were recognized as antibacterial
agents,52−55 while their oxo-analogs 3 showed moderate
insecticidal activity.76 In addition, 3-azacephalosporins 4
showed antibacterial activity,77 and imidazo- and pyrimido-
[2,1-b][1,3,5]thiadiazines 5 were recognized as insecti-
We found that 1,4,5,6-tetrahydropyridine-2-thiolates 7{1−
47} easily react with primary amines 9{1−31} and excess 37%
aqueous formaldehyde under short-term heating in EtOH to
give 3-R-8-aryl-6-oxo-3,4,7,8-2H,6H-pyrido[2,1-b][1,3,5]-
thiadiazine-9-carbonitriles 8{1−47,1−31} (Scheme 3). Presum-
ably, the reaction proceeds through the formation of non-
isolable intermediate 13. The order of mixing of the reactants
does not exert a noticeable influence on the yields of the final
products. Thus, when a suspension of thiolate 7{2} in EtOH
was treated consecutively with 4.2 equiv of 37% HCHO and 1.1
equiv of PhCH2NH2 9{ 3}, thiadiazine 8 {2,3} was obtained in
83% yield. Alternatively, when a hot solution of thiolate 7{2} in
aq. EtOH was added to the mixture of HCHO and
benzylamine in EtOH, thiadiazine 8 {2,3} yielded in 77%.
EtOH is the solvent of choice since thiolates 7 were found to be
Figure 2. Biologically active ring-condensed 1,3,5-thiadiazines.
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Research Article
Table 1. Diversity and Yields of 4-Aryl-6-oxo-3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates 7
entry
compound
Ar
yield
entry
compound
Ar
2-NO2C6H4
yield
a
d
1
7{1}
Ph
67
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
7{24}
7{25}
7{26}
7{27}
7{28}
7{29}
7{30}
7{31}
7{32}
7{33}
7{34}
7{35}
7{36}
7{37}
7{38}
7{39}
7{40}
7{41}
7{42}
7{43}
7{44}
7{45}
7{46}
7{47}
57
b
2
7{2}
2-MeC6H4
71
3-NO2C6H4
64
73
83
a
3
7{3}
4-MeC6H4
71
4-NO2C6H4
4
7{4}
4-EtC6H4
68
70
4-MeSC6H4
g
5
7{5}
4-i-PrC6H4
3-PhCH2OC6H4
4-PhCH2OC6H4
5-Br-2-MeOC6H3
3-Br-4-MeOC6H3
2-furyl
68
g
c
6
7{6}
2-ClC6H4
73
78
7
7{7}
4-ClC6H4
79
76
69
76
73
8
7{8}
2-FC6H4
f
9
7{9}
3-FC6H4
55
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
7{10}
7{11}
7{12}
7{13}
7{14}
7{15}
7{16}
7{17}
7{18}
7{19}
7{20}
7{21}
7{22}
7{23}
4-FC6H4
71
5-Me-2-furyl
53
e
3-BrC6H4
61
75
62
2-thienyl
71
2-Cl-6-FC6H3
2,6-Cl2C6H3
2-MeOC6H4
4-MeOC6H4
2-EtOC6H4
3-Me-2-thienyl
57
76
82
69
74
69
4-HO-3-MeOC6H3
4-HO-3-EtOC6H3
4-EtO-3-MeOC6H3
3-Br-4-HO-5-MeOC6H2
3-Br-4-HO-5-EtOC6H2
1-naphthyl
h
78
e
72
f
80
a
3,4-(MeO)2C6H3
2,5-(MeO)2C6H3
2,4-(MeO)2C6H3
2,3-(MeO)2C6H3
3,4-(OCH2O)C6H3
2,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
70
a
a
70
72
d
82
2-MeO-1-naphthyl
4-(4-ClC6H4CH2O)C6H4
4-PhCH2O-3-MeOC6H3
4-(2-ClC6H4CH2O)C6H4
4-EtOC6H4
65
g
70
77
a
g
79
75
71
57
a
a
67
65
3-MeOC6H4
68
a
b
c
d
e
f
g
h
Ref 89. Ref 82. Ref 84. Ref 83. Ref 85. Ref 90. Ref 81. Ref 86.
Figure 3. Diversity of primary amines 9.
less soluble in higher alcohols, whereas lower yields of
thiadiazines 8 were obtained with MeOH. Both aliphatic and
aromatic primary amines reacted under these conditions.
However, we did not succeed to obtain pyridothiadiazines 8
from anilines bearing strong electron-withdrawing substituents
(e.g., NO2, CN, Ac, PhC(O)) in ortho- or para-position to
amino group, heterocyclic amines (e.g., Gewald’s 2-amino-
thiophenes, 2-aminopyridines, 2-aminothiazoles) and amino
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Scheme 3. Synthesis of Starting Thiolates 7 and Pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitriles 8
acids (α- and β-alanines). Unsatisfactory results were also
obtained in the case of most sterically hindered amines, such as
2,6-dimethylaniline 9{14}, 2-MeOC6H4NH2 9{21}, 5-Cl-2-
MeOC6H3NH2 9{23}, 2-CF3C6H4NH2, tert-butylamine, and 2-
ethyl-6-methylaniline. Meanwhile, 2-EtOC6H4NH2 9{7}, mesi-
dine 9{22}, and 2-alkylanilines 9{11,16,17,18} showed good
reactivity.
Scheme 5. Aminomethylation of C-5 Substituted 1,4,5,6-
Tetrahydropyridine-2-thiolates
The scope of the reaction is limited to the use of
formaldehyde only. Under these conditions, aliphatic aldehydes
are known to react in different ways: thus, as we have shown
before,91 the reaction of thiolates 7 with primary amines 9 and
isobutyraldehyde leads to thiazolo[3,2-a]pyridines 14 (Scheme
4). The reaction of thiolate 7{6} with acetaldehyde and alkyl
amounts. We were a bit surprised by the fact that the yields of
pyrido[2,1-b][1,3,5]thiadiazines 8 are dependent on the nature
of an aromatic substituent at C-4 position of starting thiolate 7.
The worst results were obtained with thiolates 7{24−26,32,34}
(Ar = 2-NO2Ph, 3-NO2Ph, 4-NO2Ph, 2-furyl, 2-thienyl).
Overall, pyridothiadiazines 8 were obtained in yields ranging
from poor to excellent, depending mostly on the nature of
primary amine and thiolate. Table S1 (Supporting Information)
gives a few representative examples of how the yields of
pyridothiadiazines 8 depend on the nature of the reagents.
N-Methylmorpholinium 4-aryl-6-oxo-3-cyano-1,4,5,6-tetrahy-
dropyridine-2-thiolates 7{1−47} are yellow or orange crystal-
line solids, soluble in hot aqueous EtOH but insoluble in
acetone and cold EtOH. Pyridothiadiazines 8 are colorless or
slightly yellowish crystalline solids, stable in neutral media,
soluble in hot acetone, EtOAc, DMF or DMSO, but sparingly
soluble in ether or alcohols. Compounds 8 are quite stable but
decompose when treated with AcOH or diluted strong acids to
form a complex mixture of retro-Mannich products. On the
other hand, 1,3,5-thiadiazine ring may be cleaved with
hydrazine hydrate to give after further heterocyclization the
known95 pyrazolopyridines of general structure 17. Thus, when
compound 8{6,9} was reacted with excessive N2H4·H2O in hot
EtOH, pyrazolopyridine 17a (Ar = 2-ClC6H4) was obtained in
36% yield (Scheme 6).
Scheme 4. Reaction of Thiolates 7 with Amines 9 and
Various Aldehydes
amines led to appearance of cherry red coloration and resulted
in the formation of tars, probably due to aldol-type
condensations of CH3CHO promoted by amines. The product
of the reaction of thiolate 7{15} with p-toluidine and
benzaldehyde consists of a red tarry mass, while the reaction
with benzylamine and 4-ClC6H4CHO, 4-MeOC6H4CHO or
furfural afforded colorless crystalline solids, which appeared to
be the same compound, benzylammonium salt 15. The
prolonged heating did not result in the formation of any
Mannich-type products with thiolates 7.
Scheme 6. Reactions of Pyridothiadiazines 8
The structure of thiolate component is another key factor
which has strong influence on the reaction outcome. As we
have reported earlier,92−94 those 1,4,5,6-tetrahydropyridine-2-
thiolates that bear an electron-withdrawing group (CN,
CO2R) at C-5 position under the same conditions gave no
1,3,5-thiadiazine derivatives but readily underwent the double
Mannich-type reaction at C-3 and C-5 to afford 3,7-
diazabicyclo[3,3,1]nonanes 16 (Scheme 5). In contrast, the
aminomethylation of thiolates 7 proceeds with high regiose-
lectivity to give no C-3 attacked products, even in trace
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Starting 1,4,5,6-tetrahydropyridine-2-thiolates 7 and pyrido-
[2,1-b][1,3,5]thiadiazines 8 were characterized by H NMR
pyrazolopyridine 17a were recorded on an IKS-29 IR-
spectrometer (LOMO, USSR).
1
LCMS analyses were obtained on a PE SCIEX API 150EX
mass spectrometer (API-ES) following separation on a
Shimadzu LC-10AD liquid chromatography system with
Waters XBridge C18 3,5 μm (4.6 × 150 mm) column,
equipped with Shimadzu SP D-10A UV−vis detector (220 and
254 nm) and Sedex 75 ELSD detector.
and IR spectroscopy. In the IR spectra of compounds 8, strong
absorptions at 1675−1690 and 2190−2205 cm−1 were detected
because of the CO and conjugated CN groups,
respectively. 1D NMR (1H NMR, 13C NMR, 13C DEPT
1
NMR) and 2D NMR experiments (1H−1H COSY, H,13C-
1
HMBC, and H,13C-HSQC) were used for the complete and
unambiguous 1H and 13C chemical shift assignments for
selected compound, 3-(2-furylmethyl)-8-(2,3-dimethoxyphen-
yl)-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]-
thiadiazine-9-carbonitrile 8{20,4} (Figure 4). Full set of data of
homo- and heteronuclear correlations is given in the
Supporting Information, Table S2.
Elementary analyses were taken on a Carlo Erba
Strumentazione 1106 Analyzer.
Melting points were measured on a Koefler hot stage and are
uncorrected. The purity of the compounds were checked by
TLC (thin layer chromatography) on Silufol UV 254 plates
(sorbent, Silpearl, large-pore silicagel after Pitra with
luminiscent indicator for UV 254 on the aluminum foil; binder,
starch) in the acetone−hexane (1:1) system; spots were
visualized with iodine vapors and UV light.
Synthesis of Starting N-Methylmorpholinium 4-Aryl-
3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates
7{1−47}. General Procedure. The thiolates 7{1−47} were
obtained in a manner analogous to reported procedures81−90 as
follows: A 0.5 L round-bottom flask fitted with an overhead
stirrer was charged with the corresponding aromatic aldehyde
(0.1 mol), cyanothioacetamide 10 (10.0 g, 0.10 mol) and EtOH
(100 mL). N-Methylmorpholine (0.8−1.0 mL) was added, and
the mixture was stirred for 1 h at 20 °C (yellow/orange
crystalline 3-aryl-2-cyanoprop-2-enethioamides may precipitate
from the solution). Then Meldrum’s acid (2,2-dimethyl-1,3-
dioxane-4,6-dione) 11 (15.0 g, 0.104 mol) and N-methyl-
morpholine (16.5 mL, 0.15 mol) were added, and the solution
was stirred vigorously until the mixture became pale yellow and
a white solid of the Michael adduct 12 precipitated. (If the
precipitate does not appear within 20 min, the mixture was
refluxed for 2−4 h and worked up as shown below.) The
obtained slurry was stirred for 0.5 h. Then the flask was fitted
with a reflux condenser. The mixture was refluxed to complete
dissolution of the Michael adduct 12 and until evolution of
CO2 ceased (∼2−4 h). The solution was evaporated to a
syrupy consistency and treated with dry acetone (100 mL). The
crystalline precipitate of the corresponding thiolate 7 separates
upon cooling to 15 °C and stirring (or seeding). The mixture
was allowed to stand overnight, after which the solid was
filtered off, washed with cold EtOH and acetone to give N-
methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydro-
pyridine-2-thiolates 7{1−47} in 53−83% yields. The com-
pounds were used without further purification.
Synthesis of (8R/8S)-3-R-8-Aryl-6-oxo-3,4,7,8-tetrahy-
dro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-9-carbonitriles
8{1−47,1−31}. General Procedure. Pyrido[2,1-b][1,3,5]-
thiadiazines 8 were prepared as follows: the corresponding
thiolate 7{1−47} (2.5 mmol) was dissolved in 15−20 mL of
warm EtOH; water (3−5 mL) may be added if appropriate.
The obtained solution may be filtered through a paper filter to
remove trace solids. To the solution, a primary amine 9{1−31}
(2.6−2.7 mmol, 1.04−1.08 equiv) and an excess of 37% aq.
HCHO (5.0 mL, d = 1.08 g/mL, 66.6 mmol) were added, and
the mixture was refluxed for 2−4 min under vigorous stirring
until the product began to separate from the boiling solution. If
no solid separated, the solution was allowed to cool to room
temperature and left for 24−72 h. The crystalline solid was
collected and washed with water, cold EtOH, ether, and then
purified (if appropriate) by recrystallization. Selected data on
the yields of pyrido[2,1-b][1,3,5]thiadiazines 8 are given in
1
Figure 4. Assignment of signals and key H−13C HMBC correlations
for compound 8{20,4}.
In conclusion, an efficient and simple method for the
preparation of 3-R-8-aryl-6-oxo-3,4,7,8-tetrahydro-2H,6H-
pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitriles 8{1−47,1−31}
using readily available starting materials by Mannich-type
reaction is reported. A small library of N-methylmorpholinium
4-aryl-6-oxo-3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates
7{1−47}, 37% aq. HCHO and primary amines 9{1−31} were
used as starting compounds. The developed method requires
no catalyst and usually gives acceptable yields of pure
pyridothiadiazines.
EXPERIMENTAL PROCEDURES
■
The 1H NMR and 13C NMR spectra of thiolates 7 and
pyridothiadiazines 8 were performed on Bruker DRX-500
instrument (500.13 and 125.76 MHz for 1H and 13C,
respectively) in DMSO-d6 using residual solvent peak (δ 2.49
ppm; 39.50 ppm for H and 13C, respectively) as reference or
1
1
with Me4Si as the internal standard. The H NMR spectra of
benzylammonium salt 15 were recorded on a Bruker DRX-400
instrument (400.40 MHz) and 1H NMR spectrum of
pyrazolopyridine 17a was recorded on a Varian Gemini 200
instrument (199.975 MHz) in DMSO-d6. NMR experiments
for compound 8{20,4} were performed on a Bruker Avance II
400 instrument (400.13 and 100.62 MHz for H and 13C
1
respectively) in DMSO-d6 or CCl4−DMSO-d6 with Me4Si as
the internal standard. Data are reported as follows: chemical
shift, multiplicity (s = singlet, br. s = broad singlet, d = doublet,
dd = doublet of doublets, t = triplet, q = quartet, m =
multiplet), coupling constants (Hz), integration and assign-
ment of peak.
FT-IR spectra of thiolates 7 were recorded in KBr pellets
using Thermo Nicolet Avatar 370 FT-IR Spectrometer. IR
spectra of thiadiazines 8, benzylammonium salt 15, and
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Research Article
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Table S1 (Supporting Information). Spectra of selected
pyridothiadiazines 8 are given as PDF files in the archive
(Supporting Information).
ASSOCIATED CONTENT
* Supporting Information
■
S
Further details on the experimental procedures and spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Victor_Dotsenko@bigmir.net.
(16) Sarac, S.; Ertan, M.; Balkan, A.; Yulug, N. Synthesis and
antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-
thione derivatives of cefadroxil. Arch. Pharm. 1991, 324, 449−453.
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thione derivatives as potential antimicrobial agents. Arch. Pharm.
2000, 333, 281−286.
■
Author Contributions
The study was initiated and designed by V.V.D. Compounds
were synthesized and characterized by V.V.D. and K.A.F. NMR
study was performed by S.Y.S., T.M.P., and O.S.P.; V.V.D.
wrote the manuscript and Supporting Information. The study
was supervised by S.G.K. All authors discussed and approved
the publication of the manuscript.
(19) Deohate, P. P.; Berad, B. N. Synthesis and antimicrobial activity
of 1,3,5-thiadiazines and their isomerism into 1,3,5-triazines. Indian J.
Chem. 2005, 44B, 638−642.
Notes
(20) Ilhan, E.; Capan, G.; Ergenc, N.; Uzun, M.; Kiraz, M.; Kaya, D.
Synthesis and antimicrobial activity of new tetrahydro-2H-1,3,5-
thiadiazine-2-thione derivatives. Farmaco 1995, 50, 787−790.
(21) Ertan, M.; Sarac, S.; Yulug, N. Synthesis and antimicrobial
activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thione
derivatives of amoxicillin. Arzneim. Forsch. 1990, 40, 790−795.
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antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-
thione derivatives of cephalexin. Arzneim. Forsch. 1990, 40, 1246−
1249.
The authors declare no competing financial interest.
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