Novel synthesis of 1,3,4-thiadiazine derivatives and their cycloaddition reactions

Article abstract of DOI:10.1002/ardp.200600111

4-Phenyl-3-thiosemicarbazide 1 reacted with the α-halocarbonyl compounds 2a, b to give the thiosemicarbazone derivatives 3a, b. The latter compounds underwent cyclization to the 1,3,4-thiadiazine derivatives 4a, b which underwent [2 + 4] cycloaddition rea

Full text of DOI:10.1002/ardp.200600111

608
Arch. Pharm. Chem. Life Sci. 2006, 339, 608–615
Full Paper
Novel Synthesis of 1,3,4-Thiadiazine Derivatives and Their
Cycloaddition Reactions
Wagnat W. Wardakhan
National Organization for Drug Control and Research, Cairo, A. R. Egypt
4-Phenyl-3-thiosemicarbazide 1 reacted with the a-halocarbonyl compounds 2a, b to give the
thiosemicarbazone derivatives 3a, b. The latter compounds underwent cyclization to the 1,3,4-
thiadiazine derivatives 4a, b which underwent [2 + 4] cycloaddition reactions to give the 4H-thio-
pyran derivatives 7a, b. The chemistry of these thiopyrans was studied. Some of the fused deriv-
atives among them compounds 20a, 20b, 21a, 21b allowed good mycelial growth and sporula-
tion by the two fungi. This indicates that the two fungi can use the N-containing heterocyclic
ring as a nitrogen source.
Keywords: Thiadiazine / Thiopyran / Thiosemicarbazide / Toxicity /
Received: July 9, 2006; accepted: July 25, 2006
DOI 10.1002/ardp.200600111
Introduction
Results and discussion
As a part of our continuing program towards the reactiv-
ity and the synthesis of potentially pharmaceutically
active heterocycles, we have now investigated the reac-
tion of 4-phenyl-3-thiosemicarbazide [18] with a-haloke-
tons to form acyclic derivatives that undergo cyclization
to thiadiazine derivatives. The reaction of thiosemicarba-
zide 1 with a-halocarbonyl compounds 2a, b in ethanol at
room temperature gave the condensed products 3a, b.
Structures of the latter products are based on analytical
and spectral data. The 1H-NMR spectrum of 3a, for exam-
ple, showed the presence of a singlet at d 2.89 correspond-
ing to CH3, a singlet at d 5.21 for CH2, a multiplet at d
7.32–7.45 for aromatic protons, and two singlets (D2O
exchangeable) at d 8.36, 8.49 for two NH groups. Com-
pounds 3a, b underwent ready cyclization when heated
in sodium ethoxide solution in a boiling water bath to
give the 6H-1,3,4-thiadiazine derivatives 4a and 4b,
respectively. The analytical and spectral data are consis-
tent with the proposed structures. Thus, the 13C-NMR of
compound 4a showed d: 23.9 (CH3), 28.8 (thiadiazine
CH2), 116.9, 118.7, 129.9, 131.4, 134.5, 140.2, 144.8 (C6H5,
C6H4), 162.9, 164.4 (2 C=N).
Heterocycles containing nitrogen or sulfur are common
building blocks both incorporated in natural products
and pharmaceutical compounds; and the development
of simple and effective ways to synthesize heterocycles is
a point of major concern in medicinal chemistry [1–5].
In this regards, the utilization of the hetero Diels-Alder
reaction undoubtedly represents one of the most attrac-
tive routes for preparing these heterocycles with maxi-
mum atom economy and high selectivity [6–9]. Our
laboratory has a long-standing interest in the synthesis
of heterocyclic compounds beginning with readily avail-
able starting materials [10–13]. The importance of these
groups of compounds is due to their diverse biological
and pharmaceutical interest, some of which are known
as potent and specific inhibitors of carrier-mediated
transport [14], others as antimalarial drugs [15], and yet
others possess cytotoxic activity against cells of human
bladder cancer cell [16, 17].
Correspondence: Wagnat W. Wardakhan, National Organization for
Drug Control and Research, P.O. 29, Cairo, A. R. Egypt.
E-mail: wagnatward@hotmail.com
In spite of the rich chemistry with thiopyran deriv-
atives, it is surprising that there is no report, to the best
of our knowledge, of the uses of 1,3,4-thiadiazine deriv-
Fax: +20 2 762-6368
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Arch. Pharm. Chem. Life Sci. 2006, 339, 608–615
Novel Synthesis of 1,3,4-Thiadiazine Derivatives
609
Scheme 1. Synthesis of Michael adducts 9a–d.
atives that take part in asymmetric hetero Diels-Alder
reaction. In this work, we are using 1,3,4-thiadiazine
derivatives as precursors for thiopyran derivatives in a
one-pot reaction. Thus, compounds 4a, b underwent [4 +
2] cycloaddition when treated with either acrylonitrile
(5a) or ethyl acrylate (5b) in 1,4-dioxan/acetic acid mix-
ture to give the 4H-thiopyran derivatives 7a, b via the
intermediate formation of 6a, b. The structures of com-
pounds 7a, b are based on analytical and spectral data.
Thus, the 13C-NMR spectrum of 7a showed d 29.2, 98.6,
117.3, 140.6 (thiopyran C), 116.8 (CN), 118.3, 119.6, 120.7,
126.5, 129.8, 129.9, 130.4, 136.7 (two phenyl C). Further
structure elucidations were obtained through studying
the reactivity of 7a, c towards some chemical reagents.
The reaction of 7a or 7c with either malononitrile (8a) or
ethyl cyanoacetate (8b) gave the Michael adducts 9a–d,
respectively (Scheme 1). The analytical and spectral data
are in agreement with the proposed structures (see
Experimental, section 3). Compounds 9c and 9d under-
went ready cyclization in sodium ethoxide solution to
give the benzo[c]thiopyran derivatives 10a, b.
Scheme 2. Synthesis of 5-phenylamino-7H-thiopyrano[3,4-
d]pyridazine derivatives 16a and 16b.
The reaction of 7a or 7c with either hydrazine hydrate
(11a) or phenylhydrazine (11b) gave the amidrazone
derivatives 12a and 12b, respectively. Structures of the
latter products were based on analytical and spectral
data (see Experimental, section 3). The reaction of either
12a or 12c with ethyl orthoformate in concentrated sul-
furic acid in a boiling water bath afforded the 7H-thiopyr-
ano[3,4-d]pyridazine derivatives 14a and 14b, respec-
tively. Similarly, the reaction of either 12a or 12c with
benzoyl chloride (15) gave the 5-phenylamino-7H-thiopyr-
ano[3,4-d]pyridazine derivatives 16a and 16b, respec-
tively (Scheme 2). The analytical and spectral data of com-
pounds 14a, b and 16a, b are the basis of their structure
elucidations (see Experimental, section 3).
The reaction of 7a or 7c with 2-amino-1,1,3-tricyano-
propene (17) gave the 2-(4H-thiopyran-4-yl)-pyridine deriv-
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Arch. Pharm. Chem. Life Sci. 2006, 339, 608–615
plant pathogen causing tomato wilt in Egypt, was iso-
lated from infected tomato plants. The latter organism
was isolated from infected rice plants.
The newly synthesized products were dissolved in
aqueous ethanol to give a logarithmic series of concen-
trations from 2 to 256 mg/L upon tenfold dilution with
the growth medium and spore suspension of the test
fungi. The toxicity of compounds was determined by
sporeling growth bioassay described by Spendley and
Ride [19] which is based on the technique of Skipp and
Bailey [20], a suspension of fungal spores was prepared in
water and pipetted into the wells of multi-well slides, fol-
lowed with 25 lL of the culture medium. The inoculated
slides were then incubated at 258C until short germ tubes
appeared; approximately 50 lm in length was calculated
(at 0 h). 5 lL volumes of the prepared compound test solu-
tions were added to the inoculated wells, one control
well on each slide being treated with solvent only. The
slides were then returned to the incubator until germ
tubes 400 l 50 lm in length were visible in the control
wells. Further growth was arrested by the addition of lac-
tophenol aniline blue to each of the wells. Based on these
assays, the percent inhibition of germ-tube growth (with
respect to the controls) was plotted against the logarithm
of concentration of each compound. From this, the con-
centrations producing 50% inhibition (ED50) and 100%
inhibition (MLD) were directly obtained. When the ED50
or MLD values exceeded the maximum concentrations of
the compound used, extrapolation was performed when
the last point was within 5% of the ED50 or MLD line,
otherwise the result was expressed as A256 mg/L.
Scheme 3. New procedure for the synthesis of thiopyranyltria-
zole derivatives.
Growth
atives 19a and 19b, respectively. The reaction took place
through the intermediate formation of 18a, b followed
by Michael addition. On the other hand, the reaction of
either 7a or 7c with 4-phenyl-3-thiosemicarbazide (1)
gave the 4-phenyl-3-thiosemicarbazone derivatives 20a
and 20b, respectively. The latter products readily under-
went cyclization when heated under reflux in 1,4-dioxan
containing triethylamine to afford the 4H-thiopyrano-4-
yl-1,3,4-triazole derivatives 21a and 21b, respectively. The
reaction shows a new procedure for the synthesis of thio-
pyranyltriazole derivatives (Scheme 3). The structures
were confirmed on the basis of 1H- and 13C-NMR analyses
(see Experimental, section 3).
Since some compounds are lethal at relatively high doses
and others at lower doses, comparison of the effect of
compound on the growth, sporulation, and nucleic acid
synthesis of the test fungi was undertaken at a concentra-
tion of 64 mg/L.
A series of conical flasks (250 mL capacity) containing
50 mL Czapek-Dox liquid medium were used for each
fungus. Each of three flasks was supplemented with
64 mg/L of each compound. The flasks were inoculated
with a 5 mm-diameter agar disc cut from the margin of
actively growing colonies. The flasks were incubated at
288C for seven days after which the produced mycelial
felts were collected, washed several times with distilled
water and oven-dried at 808C to constant mass.
Bioassay
Materials and methods: test organisms
Sporulation
The fungi selected for this study were Fusarium oxysporum
f.sp. Lycoperici (SACC) and Helminthosporium oryea (Cochlio-
bolus miyabeanus). The former organism, an important
Plates of Czapek-Dox agar supplemented with 64 mg/L of
each compound were inoculated with a 5 mm-diameter
agar disc of the used fungus. The plates were then incu-
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Arch. Pharm. Chem. Life Sci. 2006, 339, 608–615
Novel Synthesis of 1,3,4-Thiadiazine Derivatives
611
bated for seven days at 288C. A 1 cm2 section was cut from Compound 3a
White crystals from ethanol, yield 68% (2.46g), m. p. 1488C; Anal-
ysis for C16H16BrN3S (362.29). Anal. Calcd.: C, 53.04; H, 4.45; N,
11.60; S, 8.85. Found: C, 53.43; H, 4.21; N, 11.94; S, 8.58. IR (t/cm–
1): 3478-3321 (2 NH), 3058 (CH aromatic), 1663 (C=N), 1638 (C=C),
1204–1194 (CS); 1H-NMR (d ppm): 2.89 (s, 3H, CH3), 5.21 (s, 2H,
CH2), 7.32–7.45 (m, 9H, C6H5, C6H4), 8.36, 8.49 (2s, 2H, 2NH).
the margin of the colony and transferred to a vial con-
taining 10 mL sterile distilled water. The suspension was
spontaneously shaken for 5 min and the concentration
of spores per mL was counted in a hemocytometer. Three
plates were used for each treatment.
Nucleic acids
Compound 3b
The nucleic acids (RNA and DNA) of each fungus were
estimated in the mycelia harvested from liquid Czapek-
Dox medium amended with 64 mg/L of each thiophene
derivative after seven days of incubation at 288C. The
method used for quantitative determination of RNA is
that of Ashwell [21]. It depends on a colorimetric analysis
of ribose, using the oreintol reaction. The quantitative
estimation of DNA depends on measuring the color devel-
oped after treating the extracted DNA with diphenyla-
mine reagent.
Most of the tested compounds showed significant toxi-
city which is dependent on their chemical structure. The
toxicity pattern of the compounds toward the two fungi
is similar although the levels of compounds that were
required to produce ED50 and MLD for Helminthosporium
oryzae were higher than those required for Fusarium oxy-
porum f. sp. Lycopersici.
Colorless crystals from ethanol, yield 73% (1.76 g), m. p. 1808C.
Analysis for C10H12ClN3S (241.74). Anal. Calcd.: C, 49.68; H, 5.00;
N, 17.38; S, 13.26. Found: C, 49.91; H, 4.68; N, 17.05; S, 12.94. IR
(t/cm-1): 3466-3319 (2 NH), 3050 (CH aromatic), 1660 (C=N), 1639
(C=C), 1208-1196 (CS); 1H-NMR (d ppm): 3.04 (s, 3H, CH3), 5.09 (s,
2H, CH2), 7.33-7.39 (m, 5H, C6H5), 8.32, 8.47 (2s, 2H, 2NH).
2-Phenylamino-5-(4-methylphenyl)-6H-1,3,4-
thiadiazine 4a; and 2-Phenyl-amino-5-methyl-6H-
1,3,4-thiadiazine 4b
General procedure: A suspension of either 3a (3.62 g, 0.01 mol)
or 3b (2.41 g, 0.01 mol) in sodium ethoxide solution (0.02 mol)
[obtained by dissolving sodium metal (0.46 g, 0.01 mol) in abso-
lute ethanol (40 mL)] was heated in a boiling water bath for 8 h,
then left to cool. The solid product, formed in each case,
obtained upon pouring onto ice/water containing a few drops of
hydrochloric acid (till pH 7) was collected by filtration.
Compound 4a
The effect of all tested compounds on growth, sporula-
tion was tested at a concentration of 64 mg/L. Com-
pounds 20a, 20b, 21a, 21b allowed good mycelial growth,
sporulation by the two fungi. This indicates that the two
fungi can use the N-containing heterocyclic ring as a
nitrogen source.
Yellow crystals from 1,4-dioxan, yield 5% (1.54 g), m. p. 223–
2268C. Analysis for C16H15N3S (281.38). Anal. Calcd.: C, 68.30; H,
5.37; N, 14.93; S, 11.40. Found: C, C, 68.52; H, 5.77; N, 15.41; S,
11.82. IR (t/cm–1): 3466–3328 (NH), 3056 (CH aromatic), 1636
(C=C); 1H-NMR (d ppm): 2.72 (s, 3H, CH3), 3.44 (s, 2H, thiadiazine
CH2), 7.30–7.43 (m, 9H, C6H5, C6H4); 13C-NMR d: 23.9 (CH3), 28.8
(thiadiazine CH2), 116.9, 118.7, 129.9, 131.4, 134.5, 140.2, 144.8
(C6H5, C6H4), 162.9, 164.4 (2 C=N).
The toxicity of the newly synthesized products were measured
by Professor S. A. Ouf, his kind help is greatly appreciated.
Compound 4b
Pale yellow crystals from 1,4-dioxan, yield 60% (1.23 g),
m. p. >3008C. Analysis for C10H11N3S (205.28). Anal. Calcd.:
C, 58.51; H, 5.40; N, 20.47; S, 15.62. Found: C, 58.22; H,
5.27; N, 20.56; S, 15.98. IR (t/cm-1): 3456-3312 (NH), 3058
(CH aromatic), 1641 (C=C); 1H-NMR (d ppm): 2.89 (s, 3H,
CH3), 3.46 (s, 2H, thiadiazine CH2), 7.33-7.38 (m, 5H, C6H5).
Experimental
All melting points were determined in open capillaries and are
uncorrected. IR spectra were measured using KBr discs on a Pye
Unicam SP-1000 spectrophotometer (Pye Unicam Ltd. Cam-
bridge, England). 1H-NMR and 13C-NMR spectra was measured on
a Varian EM390-200 MHz instrument (Varian Inc., Palo Alto, CA,
USA) in CD3SOCD3 as solvent using TMS as internal standard, and
chemical shifts are expressed as d ppm.
4-Cyano-2-phenylamino-5-(4-methylphenyl)-4H-
thiopyran 7a; Ethyl 2-phenylamino-5-(methylphenyl)-
4H-thiopyran-4-carboxylate 7b; 4-Cyano-2-
1-x-Bromo(4-methyl-acetophenone)-4-phenyl-3-
thiosemicarbazone 3a; and 1-a-chloroacetone-4-
phenylamino-5-methyl-4H-thiopyran 7c; and Ethyl 2-
phenylamino-5-methyl-4H-thiopyran-4-carboxylate
phenyl-3-thiosemicarbazone 3b
7d
General procedure: To a solution of compound 1 (1.67 g,
0.01 mol) in absolute ethanol (40 mL) either 2a (2.0 g, 0.01 mol)
or 2b (0.92 g, 0.01 mol) was added. The reaction mixture was stir-
red at room temperature over night. The solid product, formed
upon pouring onto ice/water, was collected by filtration.
General procedure: To a solution of either 4a (2.81 g, 0.01 mol)
or 4b (2.05 g, 0.01 mol) in 1,4-dioxan (50 mL) containing glacial
acetic acid (10 mL) either acrylonitrile (0.53 g, 0.01 mol) or ethyl
acrylate (1.00 g, 0.01 mol) was added. The reaction mixture in
each case was heated under reflux for 8 h, then left to cool. The
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Arch. Pharm. Chem. Life Sci. 2006, 339, 608–615
solid product formed after evaporating around 60% of the sol-
vent and cooling was collected by filtration.
Compound 9a
Pale brown crystals from 1,4-dioxan, yield 80% (2.96 g), m. p.
180–1848C. Analysis for C22H18N4S (370.47). Anal. Calcd.: C,
71.32; H, 4.90; N, 15.12; S, 8.66. Found: C, 71.64; H, 5.32; N, 15.06;
S, 8.41. IR (t/cm-1): 3440–3312 (NH2, NH), 3050 (CH aromatic),
2222, 2220 (2 CN), 1638 (C=C); 1H-NMR (d ppm): 2.83 (s, 3H, CH3),
4.22 (s, 2H, NH2), 4.46 (m, 1H, thiopyran H-4), 6.36–6.65 (m, 2H,
thiopyran H-3, H-6), 7.22-7.37 (m, 9H, C6H5, C6H4), 8.32 (s, 1H, NH).
Compound 7a
Yellow crystals from acetic acid, yield 70% (2.13 g), m. p. 187–
1918C. Analysis for C19H16N2S (304.41). Anal. Calcd.: C, 74.97; H,
5.30; N, 9.20; S, 10.53. Found: C, 75.33; H, 5.20; N, 8.95; S, 10.44.
IR (t/cm–1): 3462–3318 (NH), 3062 (CH aromatic), 2225 (CN),
1640 (C=C); 1H-NMR (d ppm): 2.82 (s, 3H, CH3), 4.38 (m, 1H, thio-
pyran H-4), 6.23–6.70 (m, 2H, thiopyran H-3, H-6), 7.30–7.48 (m,
9H, C6H5, C6H4)), 8.36 (s, 1H, NH); 13C NMR d: 29.2, 98.6, 117.3,
140.6 (thiopyran C), 116.8 (CN), 118.3, 119.6, 120.7, 126.5, 129.8,
129.9, 130.4, 136.7 (two phenyl C).
Compound 9b
Yellowish orange crystals from 1,4-dioxan, yield 68% (2.84 g), m.
p. 211–2148C. Analysis for C24H23N3O2S (417.52). Anal. Calcd.: C,
69.04; H, 5.55; N, 10.06; S, 7.68. Found: C, 68.73; H, 5.28; N, 9.84;
S, 7.29. IR (t/cm–1): 3454–3322 (NH2, NH), 3052 (CH aromatic),
1641 (C=C); 1H-NMR (d ppm): 1.13 (t, 3H, J = 7.04 Hz, CH3), 2.96 (s,
3H, CH3), 4.20 (s, 2H, NH2), 4.26 (q, 2H, J = 7.04 Hz, CH2), 4.50 (m,
1H, thiopyran H-4), 6.33–6.67 (m, 2H, thiopyran H-3, H-6), 7.20–
7.42 (m, 9H, C6H5, C6H4), 8.38 (s, 1H, NH).
Compound 7b
Yellow crystals from acetic acid, yield 72% (2.57 g), m. p. 180–
1848C, Analysis for C21H21NO2S (351.46). Anal. Calcd.: C, 71.76; H,
6.02; N, 3.99; S, 9.12. Found: C, 72.05; H, 5.83; N, 4.21; S, 8.89. IR
(t/cm-1): 3464–3337 (NH), 3056 (CH aromatic), 1687 (CO), 1638
(C=C); 1H-NMR (d ppm): 1.14 (t, 3H, J = 6.77 Hz, CH3), 2.79 (s, 3H,
CH3), 4.23 (q, 2H, J = 6.77 Hz, CH2), 4.41 (m, 1H, thiopyran H-4),
6.32-6.67 (m, 2H, thiopyran H-3, H-6), 6.82-7.38 (m, 9H, C6H5,
C6H4), 8.30 (s, 1H, NH).
Compound 9c
Yellow crystals from acetic acid, yield 73% (2.14 g), m. p. 1778C.
Analysis for C16H14N4S (294.37). Anal. Calcd.: C, 65.28; H, 4.79; N,
19.03; S, 10.89. Found: C, 64.98; H, 4.66; N, 18.87; S, 11.26. IR (t/
cm–1): 3466–3320 (NH2, NH), 3055 (CH aromatic), 2225 (CN),
1638 (C=C); 1H-NMR (d ppm): 2.99 (s, 3H, CH3), 4.36 (s, 2H, NH2),
4.55 (m, 1H, thiopyran H-4), 6.31–6.64 (m, 2H, thiopyran H-3, H-
6), 7.31–7.38 (m, 5H, C6H5), 8.36 (s, 1H, NH).
Compound 7c
Yellow crystals from acetic acid, yield 68% (1.96 g), m. p. 266-
2698C. Analysis for C13H12N2S (228.31). Anal. Calcd.: C, 68.39; H,
5.30; N, 12.27; S, 14.04. Found: C, 68.66; H, 5.02; N, 12.52; S,
13.78. IR (t/cm–1): 3470–3323 (NH), 3060 (CH aromatic), 2220
Compound 9d
Yellow crystals from ethanol, yield 76% (2.59 g), m. p. 222–
2258C. Analysis for C18H19N3O2S (341.43). Anal. Calcd.: C, 63.32;
H, 5.61; N, 12.31; S, 9.39. Found: C, 63.11; H, 5.78; N, 12.09; S,
9.56. IR (t/cm–1): 3457–3318 (NH2, NH), 3058 (CH aromatic), 1633
(C=C);1H-NMR (d ppm): 1.14 (t, 3H, J = 6.77 Hz, CH3), 4.23 (q, 2H, J =
6.77 Hz, CH2), 2.87 (s, 3H, CH3), 4.40 (s, 2H, NH2), 4.58 (m, 1H, thio-
pyran H-4), 6.33–6.62 (m, 2H, thiopyran H-3, H-6), 7.33–7.39 (m,
5H, C6H5), 8.34 (s, 1H, NH).
1
(CN), 1641 (C=C); H-NMR (d ppm): 2.78 (s, 3H, CH3), 4.29 (s, 1H,
thiopyran H-4), 6.30-6.77 (m, 2H, thiopyran H-3, H-6), 7.33-7.38
(m, 5H, C6H5), 8.26 (s, 1H, NH).
Compound 7d
Orange crystals from 1,4-dioxan, yield 60% (1.65 g), m. p. 1448C.
Analysis for C15H17NO2S (275.37). Anal. Calcd.: C, 65.43; H, 6.22;
N, 5.09; S, 11.64. Found: C, 65.07;H, 5.97; N, 5.17;S, 11.62. IR (t/
cm–1): 3458–3322 (NH), 3054 (CH aromatic), 1689 (CO), 1636
(C=C); 1H-NMR (d ppm): 1.15 (t, 3H, J = 7.03 Hz, CH3), 2.79 (s, 3H,
CH3), 4.24 (q, 2H, J = 7.03 Hz, CH2), 4.43 (m, 1H, thiopyran H-4),
6.34-6.64 (m, 2H, thiopyran H-3, H-6), 6.88-7.37 (m, 5H, C6H5), 8.29
(s, 1H, NH).
5-Cyano-4,6-Diamino-2-phenylamino-8H-
benzo[d]thiopyran 10a and Ethyl-4-amino-2-
phenylamino-8H-benzo[d]thiopyran-6-carboxylate
10b
A suspension of either 9c (2.94 g, 0.01 mol) or 9d (3.41 g,
0.01 mol) in sodium ethoxide (0.02 mol) [obtained by dissolving
sodium metal (0.46 g, 0.02 mol) in absolute ethanol (40 mL)] was
heated in a boiling water bath for 5 h. The solid product formed
upon pouring onto ice/water containing few drops of hydrochlo-
ric acid (till pH 6) was collected by filtration.
4-(b-Amino-a-cyanoacrylonitrilo)-2-phenylamino-5-
(4-methylphenyl)-4H-thiopyran 9a, 4-(Ethyl-amino-a-
cyanoacrylate)-2-phenylamino-5-(4-methylphenyl)-
4H-thiopyran 9b, 4-(ß-Amino-a-cyanoacrylonitrilo)-2-
phenyl-amino-5-methyl-4H-thiopyran 9c; and 4-
(Ethyl-ß-Amino-a-cyanoacrylate)-2-phenylamino-5-
Compound 10a
Pale yellow crystals from DMF, yield 76% (2.23 g), m. p. A3008C.
Analysis for C16H14N4S (294.37), Anal. Calcd.: C, 65.28; H, 4.79; N,
19.03; S, 10.89. Found: C, 65.44; H, 5.14; N, 18.82; S, 10.68. IR (t/
cm–1): 3462–3332 (2 NH2), 3056 (CH aromatic), 2222 (CN), 1633
(C=C);1H-NMR (d ppm): 4.22, 4.83 (2s, 4H, 2NH2), 4.37 (m, 2H, thio-
pyran CH2), 5.99, 6.88 (2s, 2H, thiopyran H-3, benzene CH), 7.28–
7.38 (m, 5H, C6H5), 8.66 (s, 1H, NH); 13C-NMR: 44.8 (thiopyran
CH2), 80.4 (thiopyran C-3) 116.2 (CN), 118.9, 119.2, 120.5, 129.3,
134.1, 135.7, 142.6, 143.8, 144.6, 148.8 (aromatic C).
methyl-4H-thiopyran 9d
General procedure: A solution of either 7a (3.04 g, 0.01 mol) or
7c (2.28 g, 0.01 mol) in 1,4-dioxan (50 mL) containing triethyl-
amine (0.50 mL) either malononitrile (0.66 g, 0.01 mol) or ethyl
cyanoacetate (1.07 g, 0.01 mol) was added. The reaction mixture
was heated under reflux for 2 h then evaporated in vacuo. In
each case, the remaining product was triturated with ethanol
and the formed solid product was collected by filtration.
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Novel Synthesis of 1,3,4-Thiadiazine Derivatives
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Hz, thiopyran H-3), 7.21–7.42 (m, 11H, 2C6H5, thiopyran H-6),
8.33, 8.41 (2s, 2H, 2NH).
Compound 10b
Orange crystals from 1,4-dioxan, yield 70% (2.06 g), m. p. 245–
2478C. Analysis for C16H13N3OS (295.36). Anal. Calcd.: C, 65.06; H,
4.44; N, 14.23; S, 10.86. Found: C, 64.69; H, 4.28; N, 13.86; S,
11.19. IR (t/cm–1): 3520–3330 (NH2, OH), 3057 (CH aromatic),
2220 (CN), 1640 (C=C); 1H-NMR (d ppm): 4.23 (s, 2H, NH2), 4.57 (m,
2H, thiopyran CH2), 5.99, 6.39 (2s, 2H, thiopyran H-3, benzene
CH), 7.25-7.40 (m, 5H, C6H5), 8.78 (s, 1H, NH), 10.88 (s, 1H, OH).
1-Amino-5-phenylamino-8-(4-methylphenyl)-7H-
thiopyrano[d]pyridazine 14a; 1-Amino-5-
phenylamino-4-methyl-7H-thiopyrano[d]pyridazine
14b
General procedure: To a solution of either 12a (3.36 g, 0.01 mol)
or 12c (2.60 g, 0.01 mol) in concentrated sulfuric acid (10 mL),
ethyl orthoformate (0.58 g, 0.01 mol) was added. The reaction
mixture was heated in a boiling water bath for 40 min then left
to cool. The whole mixture was poured onto ice/water and the
formed solid product was collected by filtration.
4-Amidrazono-2-phenylamino-5-(4-methylphenyl)-
4H-thiopyran 12a; 4-Phenyl-amidrazono-2-
phenylamino-5-(4-methylphenyl)-4H-thiopyran 12b;
4-Amidrazono-2-phenylamino-5-methyl-4H-thiopyran
12c; and 4-Phenylamidrazono-2-phenylamino-5-
Compound 14a
methyl-4H-thiopyran 12d
Buff crystals from DMF, yield 75% (2.61 g), m. p. 1668C. Analysis
for C20H18N4S (346.45). Anal. Calcd.: C, 69.34; H, 5.24; N, 16.17; S,
9.26. Found: C, 69.22; H, 5.54; N, 16.08; S, 8.93. IR (t/cm–1): 3448–
3312 (NH2, NH), 3056 (CH aromatic), 1662 (C=N), 1632 (C=C); 1H-
NMR (d ppm): 2.81 (s, 3H, CH3), 2.88 (d, 1H, J = 2.76 Hz, thiopyran
H-4), 4.34 (s, 2H, NH2), 7.21–7.42 (m, 11H, C6H5, C6H4, pyridazine
H-3, thiopyran H-6), 8.22 (s, 1H, NH).
General procedure: To a solution of either 7a (3.04 g, 0.01 mol)
or 7c (2.28 g, 0.01 mol) in dimethylformamide (30 mL) either
hydrazine hydrate (0.50 mL, 0.01 mol) or phenylhydrazine
(1.08 g, 0.01 mol) was added. The reaction mixture was heated
under reflux for 6 h then poured onto ice/water containing few
drops of hydrochloric acid. The precipitated solid product was
collected by filtration.
Compound 14b
Compound 12a
Pale brown crystals from DMF, yield 56% (1.51 g), m. p. 222–
2258C. Analysis for C14H14N4S (270.35). Anal. Calcd.: C, 62.20; H,
5.22; N, 20.72; S, 11.86. Found: C, 62.56; H, 5.43; N, 20.92; S,
11.67. IR (t/cm–1): 3466–3329 (NH2, NH), 3055 (CH aromatic),
2879 (CH3), 1656 (C=N), 1640 (C=C); 1H-NMR (d ppm): 2.84 (s, 3H,
CH3), 2.83 (d, 1H, J = 2.81 Hz, thiopyran H-4), 4.09 (s, 2H, NH2),
7.20–7.34 (m, 7H, C6H5, pyridazine H-3, thiopyran H-6), 8.30, (s,
1H, NH).
Pale yellow crystals from 1,4-dioxan, yield 80% (2.68 g), m. p.
244–2478C. Analysis for C19H20N4S (336.45). Anal. Calcd.: C,
67.83; H, 5.99; N, 16.65; S, 9.53. Found: C, 67.77; H, 6.11; N, 16.35;
S, 9.53. IR (t/cm–1): 3455–3329 (2 NH2, NH), 3054 (CH aromatic),
2986 (CH3), 1670 (C=N), 1636 (C=C); 1H-NMR (d ppm): 2.74 (s, 3H,
CH3), 2.90 (d, 1H, J = 2.84 Hz, thiopyran H-4), 4.20, 5.31 (2s, 4H,
2NH2), 6.01 (d, 1H, J = 2.84 Hz, thiopyran H-3), 7.28–7.38 (m, 10H,
C6H5, C6H4, thiopyran H-6), 8.32 (s, 1H, NH).
1-Amino-4-phenyl-5-phenylamino-8-(4-
methylphenyl)-7H-thiopyrano-[d]pyridazine 16a; and
1-Amino-4-phenyl-5-phenylamino-4-methyl-7H-
Compound 12b
Reddish brown crystals from 1,4-dioxan, yield 69% (2.84 g), m. p.
180–1828C. Analysis for C25H24N4S (412.55). Anal. Calcd.: C,
72.78; H, 5.86; N, 13.58; S, 7.77. Found: C, 72.69; H, 6.11; N, 13.47;
S, 8.09. IR (t/cm–1): 3473–3321 (NH2, 2NH), 3060 (CH aromatic),
2877 (CH3), 1667 (C=N), 1643 (C=C); 1H-NMR (d ppm): 2.79 (s, 3H,
CH3), 2.89 (d, 1H, J = 2.77 Hz, thiopyran H-4), 4.21 (s, 2H, NH2),
6.12 (d, 1H, J = 2.77 Hz, thiopyran H-3), 7.22-7.48 (m, 10H, C6H5,
C6H4, thiopyran H-6), 8.30, 8.51 (2s, 2H, 2NH).
thiopyrano[d]pyridazine 16b
General procedure: To a solution of either 12a (3.36 g, 0.01 mol)
or 12c (2.60 g, 0.01 mol) in pyridine (50 mL) in an ice bath (0–
58C), benzoyl chloride (1.45 g, 0.01 mol) was added drop-wise
with continuous stirring for 20 min. The whole reaction mix-
ture was heated under reflux for 1 h then poured onto ice/water
containing few drops of hydrochloric acid.
Compound 12c
Yellow crystals from acetic, yield 70% (1.82 g), m. p. 1608C. Anal-
ysis for C13H16N4S (260.36). Anal. Calcd.: C, 59.97; H, 6.19; N,
21.52; S, 12.32. Found: C, 60.33; H, 6.08; N, 21.36; S, 12.22. IR (t/
cm–1): 3467–3318 (2 NH2, NH), 3051 (CH aromatic), 1663 (C=N),
1639 (C=C); 1H-NMR (d ppm): 2.76 (s, 3H, CH3), 2.86 (d, 1H, thio-
pyran H-4), 4.23, 5.35 (2s, 4H, 2NH2), 6.17 (d, 1H, thiopyran H-3),
7.24–7.37 (m, 6H, C6H5, thiopyran H-6), 8.30 (s, 1H, NH).
Compound 16a
Buff crystals from 1,4-dioxan, yield 80% (3.37 g), m. p. 222–
2268C. Analysis for C26H22N4S (422.54). Anal. Calcd.: C, 73.90; H,
5.25; N, 13.26; S, 7.59. Found: C, 74.26; H, 5.01; N, 13.31; S, 7.82.
IR (t/cm–1): 3472–3334 (NH2, NH), 3050 (CH aromatic), 1658
(C=N), 1639 (C=C); 1H-NMR (d ppm): 2.88 (s, 3H, CH3), 2.91 (d, 1H, J
= 2.79 Hz, thiopyran H-4), 4.32 (s, 2H, NH2), 7.20–7.40 (m, 15H,
2C6H5, C6H4, thiopyran H-6), 8.28 (s, 1H, NH).
Compound 12d
Compound 16b
Orange crystals from DMF, yield 56% (2.22 g), m. p. 1408C. Anal-
ysis for C19H20N4S (336.45). Anal. Calcd.: C, 67.83; H, 5.99; N,
16.65; S, 9.53. Found: C, 67.67; H, 6.21; N, 16.89; S, 9.45. IR (t/
cm–1): 3462–3324 (NH2, 2 NH), 3055 (CH aromatic), 2880 (CH3),
1668 (C=N), 1633 (C=C);1H-NMR (d ppm): 2.69 (s, 3H, CH3), 2.82 (d,
1H, J = 3.01 Hz, pyran H-4), 4.25 (s, 2H, NH2), 6.09 (d, 1H, J = 3.01
Brown crystals from 1,4-dioxan, yield 66% (2.28 g), m. p. 190–
1938C. Analysis for C20H18N4S (346.45). Anal. Calcd.: C, 69.34; H,
5.24; N, 16.17; S, 9.26. Found: C, 69.22; H, 5.09; N, 16.35; S, 9.52.
IR (t/cm–1): 3456–3333 (NH2, NH), 3058 (CH aromatic), 1660
(C=N), 1637 (C=C); 1H-NMR (d ppm): 2.88 (s, 3H, CH3), 2.80 (d, 1H, J
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Arch. Pharm. Chem. Life Sci. 2006, 339, 608–615
= 2.80 Hz, thiopyran H-4), 4.13 (s, 2H, 2NH2), 7.25–7.44 (m, 11H,
2C6H5, thiopyran H-6), 8.37 (s, 1H, NH).
Compound 20b
Yellow crystals from acetic acid, yield 82% (3.24 g), m. p. 1208C.
Analysis for C20H21N5S2 (396.54). Anal. Calcd.: C, 60.73; H, 5.35; N,
17.71; S, 16.21. Found: C, 60.47; H, 5.82; N, 18.09; S, 16.34. IR (t/
cm–1): 3474–3338 (NH2, 3NH), 3057 (CH aromatic), 2888 (CH3),
1657 (C=N), 1641 (C=C); 1H-NMR (d ppm): 2.65 (s, 3H, CH3), 2.90 (d,
1H, J = 2.57 Hz, thiopyran H-4), 4.30 (s, 1H, NH), 5.36 (d, 1H, J =
2.57 Hz, thiopyran H-3), 5.45 (s, 2H, NH2), 7.25–7.37 (m, 11H,
2C6H5, thiopyran H-6), 8.26, 8.37 (2s, 2H, 2NH).
2,4-Diamino-3,5-dicyano-6-(2-phenylamino-5-(4-
methylphenyl)-4H-thiopyran-4-yl)-pyridine 19a; and
2,4-Diamino-3,5-dicyano-6-(2-phenylamino-5-methyl-
4H-thiopyran-4-yl)-pyridine 19b
General procedure: To a solution of either 7a (3.04 g, 0.01 mol)
or 7c (2.28 g, 0.01 mol) in dimethylformamide (30 mL) contain-
ing triethylamine (0.50 mL), compound 17 was added. The reac-
tion mixture was heated under reflux for 3 h then poured onto
ice/water. In each case, the formed solid product was collected
by filtration.
4-Phenylamino-3-(2-phenylamino-5-(4-
methylphenyl)-4H-thiopyran-4-yl)-1,2,4-triazole 21a;
and 4-Phenylamino-3-(2-phenylamino-5-methyl-4H-
thiopyran-4-yl)-1,2,4-triazole 21b
General procedure: A solution of either 20a (4.71 g, 0.01 mol) or
20b (3.96 g, 0.01 mol) in 1,4-dioxan (40 mL) containing triethyl-
amine (1.0 mL) was heated under reflux for 5 h then poured
onto ice water. The formed solid product was collected by filtra-
tion.
Compound 19a
Pale yellow crystals from 1,4-dioxan, yield 70% (3.05 g), m. p.
1308C. Analysis for C25H20N6S (436.53). Anal. Calcd.: C, 68.78; H,
4.62; N, 19.25; S, 7.35. Found: C, 68.66; H, 4.93; N, 18.90; S, 7.48.
IR (t/cm–1): 3460–3329 (2 NH2, NH), 3053 (CH aromatic), 2225,
2220 (2 CN), 1658 (C=N), 1634 (C=C); 1H-NMR (d ppm): 2.86 (s, 3H,
CH3), 2.89 (d, 1H, J = 2.78 Hz, thiopyran H-4), 4.30, 4.87 (2s, 4H, 2
NH2), 5.42 (d, 1H, J = 2.78 Hz, thiopyran H-3), 7.25-7.38 (m, 10H,
C6H5, C6H4, thiopyran H-6), 8.09 (s, 1H, NH).
Compound 21a
Pale yellow crystals from acetic acid, yield 77% (2.59 g), m. p.
A3008C. Analysis for C26H23N5S (437.56). Anal. Calcd.: C, 71.37; H,
5.30; N, 16.01; S, 7.33. Found: C, 71.66; H, 5.47; N, 15.98; S, 7.05.
IR (t/cm–1): 3477–3341 (3 NH), 3063 (CH aromatic), 1660 (C=N),
1640 (C=C); 1H-NMR (d ppm): 2.83 (s, 3H, CH3), 2.90 (d, 1H, J = 2.39
Hz, thiopyran H-4), 4.36 (s, 1H, NH), 5.30 (d, 1H, J = 2.39 Hz, thio-
pyran H-3), 7.29–7.57 (m, 15H, 2C6H5, C6H4, thiopyran H-6), 8.28,
8.34 (2s, 2H, 2NH); 13C-NMR: 26.7 (CH3), 44.6 (thiopyran C-4), 92.7
(thiopyran C-3), 117.0, 118.9, 119.2, 122.7, 126.5, 127.8, 129.0,
133.3, 134.7, 136.2, 143.8, 144.9 (2 C6H5, C6H4, thiozole C-3, C-5,
thiopyran C-2, C-6), 159.9, 164.7 (2 C=N).
Compound 19b
Yellow crystals from 1,4-dioxan, yield 76% (2.73 g), m. p. 240–
2458C. Analysis for C19H16N6S (360.44). Anal. Calcd.: C, 63.31; H,
4.47; N, 23.32; S, 8.90. Found: C, 63.20; H, 4.89; N, 23.64; S, 9.11.
IR (t/cm–1): 3450–3322 (2 NH2, NH), 3053 (CH aromatic), 2891
(CH3), 2227, 2221 (2 CN), 1664 (C=N), 1632 (C=C); 1H-NMR (d ppm):
2.91 (s, 3H, CH3), 2.83 (d, 1H, J = 2.80 Hz, thiopyran H-4), 4.16,
4.78 (2s, 4H, 2NH2), 5.44 (d, 1H, J = 2.80 Hz, thiopyran H-3), 7.23–
7.38 (m, 6H, C6H5, thiopyran H-6), 8.37 (s, 1H, NH).
Compound 21b
Yellow crystals from acetic acid, yield 50% (1.80 g), m. p. 188–
1938C. Analysis for C20H19N5S (361.46). Anal. Calcd.: C, 66.46; H,
5.30; N, 19.37; S, 8.87. Found: C, 66.45, H, 5.21; N, 19.32; S, 8.45.
IR (t/cm– 1): 3456–3323 (3 NH), 3055 (CH aromatic), 2980 (CH3),
1655 (C=N), 1643 (C=C);1HNMR ((d ppm): 2.74 (s, 3H, CH3), 2.93 (d,
1H, thiopyran H-4), 4.33 (s, 1H, NH), 5.32 (d, 1H, thiopyran H-3),
7.27–7.45 (m, 11H, 2C6H5, thiopyran H-6), 8.29, 8.33 (2s, 2H,
2NH).
2-Phenylamino-4-(formamido-4-phenyl-3-
thiosemicarbazono)-5-(4-methylphenyl)-4H-
thiopyran 20a; and 2-Phenylamino-4-(formamido-4-
phenyl-3-thiosemicarbazono)-5-methyl-4H-thiopyran
20b
General procedure: To a solution of either 7a (3.04 g, 0.01 mol)
or 7c (2.28 g, 0.01 mol) in 1,4-dioxan (30 mL) containing triethyl-
amine (0.50 mL), 4-phenyl-3-thiosemicarbazide (1.67 g, 0.01 mol)
was added. The reaction mixture was heated under reflux for 6 h
then evaporated under vacuum. The remaining product was tri-
turated with diethyl ether and the formed solid product was col-
lected by filtration.
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