Synthesis and tautomeric structure of 7-arylhydrazono-7H-[1,2,4]triazolo[3,4-b]-[1,3,4]thiadiazines

Article abstract of DOI:10.1080/10426500210251

Two synthetic approaches were developed for the title compounds 8a-g via coupling of diazotized anilines with 7-acetyl-6-methyl-3-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 7, and reaction of N-aryl 2-oxopropanehydrazonoyl chlorides 9 with 4-omino

Full text of DOI:10.1080/10426500210251

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis and Tautomeric Structure of 7-
Arylhydrazono-7H-[1,2,4]Triazolo[3,4-b]
[1,3,4]Thiadiazines
Mosselhi A. N. Mosselhi a , Magda A. Abdallah a , Yassin F. Mohamed a & Ahmad S. Shawali a
a Department of Chemistry, Faculty of Science , University of Cairo , Giza, Egypt
Published online: 27 Oct 2010.
To cite this article: Mosselhi A. N. Mosselhi , Magda A. Abdallah , Yassin F. Mohamed & Ahmad S. Shawali (2002) Synthesis and
Tautomeric Structure of 7-Arylhydrazono-7H-[1,2,4]Triazolo[3,4-b][1,3,4]Thiadiazines, Phosphorus, Sulfur, and Silicon and the
Related Elements, 177:2, 487-496, DOI: 10.1080/10426500210251
To link to this article: http://dx.doi.org/10.1080/10426500210251
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Phosphorus, Sulfur and Silicon, 2002, 177:487–496
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
SYNTHESIS AND TAUTOMERIC STRUCTURE
OF 7-ARYLHYDRAZONO-7H-[1,2,4]TRIAZOLO[3,4-b]-
[1,3,4]THIADIAZINES
Mosselhi A. N. Mosselhi, Magda A. Abdallah,
Yassin F. Mohamed, and Ahmad S. Shawali
Department of Chemistry, Faculty of Science,
University of Cairo, Giza, Egypt
(Received March 18 2001.)
Two synthetic approaches were developed for the title compounds
8a–g via coupling of diazotized anilines with 7-acetyl-6-methyl-3-
phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 7, and reaction of
N-aryl 2-oxopropanehydrazonoyl chlorides 9 with 4-amino-3-mercapto-
5-phenyl-1,2,4-triazole 1. The tautomeric structures of 8 were eluci-
dated by their spectral analyses and correlation of their acid disso-
ciation constants with Hammett equation.
Keywords: 1,2,4-triazole-3-thione; [1,2,4]triazolo[3,4-b][1,3,4]thiadia-
zines; hydrazonoyl halides; tautomerism; thiohydrazonates
INTRODUCTION
In spite of the enormous body of literature dealing with the chem-
istry of [1,2,4]triazolo[3,4-b]thiadiazine derivatives, nothing has been
reported about the arylazo derivatives of such ring system. This is sur-
prising in terms of the wide range of biological activities reported for
various [1,2,4]triazolo[3,4-b]thiadiazine derivatives against gram nega-
tive bacteria,1 gram positive bacteria,2 antiinflammatory activity,3 and
the well known industrial and pharmaceutical uses of arylazo com-
pounds. In light of these considerations, it was thought interesting to
explore the synthesis of a series of the hitherto unknown 3-phenyl-
6-methyl-7-arylazo-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines. In con-
tinuation of previous studies on reactions of azolethiones 2-4
(Chart 1) with hydrazonoylhalides and the synthesis of arylazo
heterocycles,4 8 we envisaged that the title compounds or their arylazo
Address correspondence to Ahmad S. Shawali, Department of Chemistry, Faculty of
Science, University of Cairo, Giza, Egypt.
487

488
M. A. N. Mosselhi et al.
tautomers could be prepared directly from 5-substituted-4-amino-
3-mercapto-1,2,4-triazole 1. Herein, we report full details of two alter-
native convenient approaches for synthesis of the target compounds 8
and elucidation of their tautomeric structures as they can exist in one
or more of the three tautomeric forms 8A–C (Scheme 1).
CHART 1
SCHEME 1
RESULTS AND DISCUSSION
The starting 4-amino-3-mercapto-5-phenyl-1,2,4-triazole 1 and 3-
chloro-2,4-pentanedione 5 used in this study were prepared as

Thiadiazines
489
previously described.9,10 Treatment of 1 with 3-chloro-2,4-penta-
nedione 5 in ethanolic potassium hydroxide yielded 7-acetyl-6-methyl-
(7H)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 7, probably via cyclization
of the initially formed substitution intermediate, namely 3-[(4-amino-5-
phenyl-4H-1,2,4-triazol-3-yl)thio]-2,4-pentanedione 6 (Scheme 1). The
structure of the isolated product 7 was elucidated on the basis of its
spectral data (mass, IR, 1H NMR) and microanalyses. For example, its
PMR spectrum revealed characteristic signals at 2.39 (s, 3H), 2.45 (s,
3H), 4.20 (s, 1H), 7.26–8.02 (m, 5H).
Reaction of 7 with diazotized anilines in ethanol in the presence of
sodium acetate, yielded products that were identified as 7-arylazo-6-
methyl-3-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 8 in over-
all good yields via Japp-Klingemann reaction29 (Scheme 1). The struc-
ture of the isolated products was deducted on the basis of their spectral
(MS, IR and 1H NMR) and elemental analysis data in addition to their
alternate synthesis outlined below. For example, their IR spectra re-
vealed the absence of the acetyl carbonyl group and they showed NH
absorption in the region 3160–3190 cm 1. Also, their 1H NMR spectra
revealed the absence of the signal of CH3CO protons which is present
in the spectrum of 7. Moreover they exhibit a hydrazone NH proton
signal in the region 10.1–10.6 which is extinguished by addition of
deuterium oxide (Table I).
The structure of the products 8 have been further established by
their alternate synthesis. Thus, reaction of 1 with each of N-aryl 2-
oxopropanehydrazonoyl chlorides 9a–g in ethanol in the presence of
sodium ethoxide in a 1:1 molar ratio at room temperature afforded in
each case a single product identical in all respects (m.p., IR, PMR, MS)
with the respective 8. The direct formation of 8 from 1 and 9 indicates
that the initially formed substitution products, namely the thiohydra-
zonates 10 (Scheme 1) underwent in situ dehydrative cyclization, under
the employed reaction conditions, to give 8 as the end products. The in-
termediacy of 10 was confirmed by their isolation and conversion into 8.
For example, in our hands when the reaction of 1 with 9 was carried out
in benzene in the presence of triethylamine at room temperature, the
respective thiohydrazonates 10a–f were obtained, respectively, in 85–
90% yield. When the latter esters were refluxed in glacial acetic acid,
they were converted into the corresponding triazolothiadiazine deriva-
tives 8 (Scheme 1). The structures of the thiohydrazonates 10a–f were
evidenced by their mass spectra and other spectral data (see Experi-
mental section). For example, the mass spectra of the isolated products
10a–f revealed in each case a peak at m/z 192 corresponding to the
thiol 1 cleaved from the molecular ions. The mass spectra of both aryl
and heteroaryl thiohydrazonates were reported to be characterized by

490
M. A. N. Mosselhi et al.
TABLE I Spectral Data of Triazolothiadiazines 8 and the
Thiohydrazonates 10
1
Compd
IR(KBr), (cm
3180 (NH)
)
1H NMR (CDCl3),
8a
2.24 (s, 3H), 2.51 (s, 3H), 7.10–8.09 (m, 9H),
10.21 (s, 1H).
8b
3191 (NH)
2.30 (s, 3H), 2.51 (s, 3H), 6.79–8.10 (m, 9H),
10.19 (s, 1H).
8c
8d
8e
8f
3168 (NH)
3168 (NH)
3165 (NH)
3155 (NH), 1672 (CO)
3170 (NH), 1703 (CO)
2.51 (s, 3H), 7.36–8.07 (m, 10H), 10.40 (s, 1H).
2.51 (s, 3H), 7.34–8.08 (m, 9H), 10.37 (s, 1H).
2.47 (s, 3H), 6.98–8.10 (m, 9H), 10.37 (s, 1H).
2.50 (s, 6H), 7.4–8.07 (m, 9H), 10.62 (s, 1H).
1.31 (t, 3H), 2.5 (s, 3H), 4.28 (q, 2H),
7.41–8.08 (m, 9H), 10.59 (s, 1H).
8g
10a
10b
10c
10d
10e
10f
3120, 3272 (NH), 1643 (CO) 2.33 (s, 3H), 2.48 (s, 3H), 5.74 (s, 2H),
7.15–8.1 (m, 9H), 10.42 (s, 1H).
3317, 3247, 3209 (NH),
1666 (CO)
2.33 (s, 3H), 3.32 (s, 3H), 6.31 (s, 2H),
6.87–8.03 (m, 9H), 10.93 (s, 1H).
3161, 3273 (NH), 1662 (CO) 2.48 (s, 3H), 5.75 (s, 2H), 7.11–8.18 (m, 10H),
10.52 (s, 1H).
3278, 4141 (NH), 1664 (CO) 2.4 (s, 3H), 5.7 (s, 2H), 7.2–7.4 (m, 9H),
10.7 (s, 1H).
3317, 3248, 3209 (NH),
1666 (CO)
3.34 (s, 3H), 6.32 (s, 2H), 7.09–8.04 (m, 9H),
11.12 (s, 1H).
3240, 3163 (NH), 1651 (CO) 1.77 (s, 3H), 3.3 (s, 3H), 6.72 (s, 2H),
7.23–8.04 (m, 9H), 9.89 (s, 1H).
the loss of the elements of the corresponding arenethiol and heteroaryl
thiol from their molecular ions, respectively.11
Next, the tautomerism of 8 was examined. As shown in Scheme 1,
the products 8 can have one or more of the three possible tautomeric
structures namely the iminohydrazone, the azo-enamine and the CH-
azo forms, A–C respectively. Of these forms, structure A seems to be the
form of choice as it is consistent with their electronic absorption and 1H
NMR spectra. For example, like typical hydrazones,12,13 the electronic
absorption spectra of 8 in dioxane revealed in each case three absorp-
tion bands in the regions 385–370, 300–280, and 250–240 nm (Table II)
and the spectra of the unsubstituted derivative 8c, taken as a repre-
sentative example of the series prepared, in different solvents exihibit
little, if there is any, solvent dependence (Table II). On the basis of such
absorption patterns, it can be concluded that the studied compounds 8
have in solution one tautomeric form namely the hydrazone tautomer
A. Such a conclusion is substantiated by the spectra of 8c at different
pH’s. In acid medium, the spectrum revealed a maximum (band-A) in

Thiadiazines
491
TABLE II Electronic Absorption Spectra and Acidity Constants (pKa’s) of
7H-3-phenyl-6-methyl-7-arylhydrazono[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazines, 8
Compd
(log ε) (dioxane) f a
pKa (
s)b
max
X
8a
8b
8c
8d
8e
8f
379 (4.41), 288 (4.24), 248 (4.37)
376 (4.39), 291 (4.22), 250 (4.37)
374 (4.40), 288 (4.29), 248 (4.35)
375 (4.38), 290 (4.26), 249 (4.30)
372 (4.47), 290 (4.35), 251 (4.42)
376 (4.51), 296 (4.35), 246 (4.29)
379 (4.46), 303 (4.23), 242 (4.17)
9.62 0.03
9.18 0.06
9.14 0.05
8.65 0.05
8.09 0.03
7.48 0.07
6.83 0.05
0.17
0.07
0.00
0.23
0.37
0.68
0.84
8g
af
(log ε) of 8c in different solvents: Ethanol: 381 (4.43), 291 (4.29), 249 (4.37);
max
Chloroform: 374 (4.36), 289 (4.19), 251 (4.32): Acetonitrile: 372 (4.38), 288 (4.25), 250
(4.94); Cyclohexane: 381 (4.44), 287 (4.33), 250 (4.43).
b
s, standard deviation.
the region 350–420 nm, whereas in alkaline medium it exhibits another
maximum (band-B) in the region 470–530 nm. As the pH increases,
the intensity of band-A decreases and simultaneously that of band-B
increases and one isobestic point is recorded indicating the presence
of an equilibrium between the hydrazone form and its anion. This
spectral behavior, while characteristic of a simple one-stage protolytic
equilibrium, is also similar to that reported for typical hydrazones.12
1
This conclusion was also evidenced by the H NMR spectra of the
studied compounds 8. Thus, while the latter spectra showed hydrazone
NH proton signal in the region 10.2–10.6 (Table I), they revealed the
absence of signals at 11.6927 and 5.2728 which are characteristic for
the NH and CH protons of the azo-enamine and CH-azo forms B and C
respectively.
To provide further evidence for the assignment of structure A for the
products 8, their acid dissociation constants, pKa’s, were determined
and their correlation by Hammett equation was tested.12,14 18 The acid
dissociation constants for the series 8a–g were determined potentio-
metrically at 25 C in 80% dioxane-water mixture (v/v). In all determi-
nations the ionic strength was kept constant at 0.1. From the pH-titrant
volume data, the acid dissociation constants of the compounds studied
were calculated (see Experimental section) and the results are summa-
rized in Table II.
When these pKa values were plotted against Hammett substituent
constants X, all the substituents fall on the correlation line except the
substituents with -R effect, namely the p-Ac and p-EtOCO groups which

492
M. A. N. Mosselhi et al.
are capable of direct interaction with the negatively charged reaction
site. However, when the pKa data were plotted versus constants,
X
a better correlation was obtained. The equation of the regression line
obtained is:
pKa = 9.13 2.63 X ; r = 0.990; s = 0.10
This excellent correlation indicates that the parameter r in the
Yukawa-Tsuno equation: pKa = pKOa + [ X + r (
X)], and which
gives the contribution of the resonance effect of theXsubstituent varied,
is close to unity for the series 8a–g studied.19
The foregoing linear correlation between pKa values and
con-
X
stants and the values of and r found provide further evidence that
the studied compounds 8 exist predominantly in the hydrazone form
A. This is because the values of (2.63) and r = 1.00 are similar to
those reported for ionization of phenols ( = 2.67; r = 1.00) (20, 21)
and anilinium ions ( = 2.77; r = 1.00) (22) in 50% ethanol-water mix-
ture. If either form B or C were the predominant form for the studied
compounds, the values would have been less than 2.0 and will be
similar to that reported for ionization of 2-arylazophenols ( = 1.223;
r
= 0.286),20 since the bridge between the substituent and the reac-
tion site in such forms B and C is longer than in A. Thus, it is not
unreasonable to conclude that the observed linear correlation of the
dissociation constants with Hammett equation indicates that the tau-
tomeric form A prevails under the conditions of the measurement of
pKa’s.
EXPERIMENTAL
Melting points were determined on a Gallenkamp electrothermal ap-
paratus and are uncorrected. Elemental analyses were performed by
the Microanalytical Laboratory (Cairo University, Giza, Egypt). IR
spectra were recorded on Fourier Transform and Pye Unicam SP 300
infrared spectrophotometers. 1H NMR spectra were recorded on a
Varian Gemini 200 spectrometer in deuterated chloroform with use
of tetramethylsilane as an internal standard. Electronic absorption
spectra were recorded on Pye-Unicam AR55 and Cary spectrophotome-
ters. Mass spectra were obtained on a GCMS-OQ 1000-EX Varian Mat
711 and SSQ 7000 spectrometers. The reagents 4-amino-5-phenyl-1,2,
4-triazole-3-thione 110 and 3-chloro-2,4-pentanedione 59 were prepared
by literature methods.

Thiadiazines
493
N-Aryl 2-oxopropanehydrazonoyl Chlorides, 9
The hydrazonoyl chlorides 9a–g were prepared by coupling of
3-chloro-2,4-pentanedione 5 with diazotized anilines as previously
described.23,24 The physical constants of the known compounds 9a–e
are similar to those reported in literature. Those of the new derivatives
9f and 9g are as follows.
Compound 9f: Yield 85%; m.p. 184 C (EtOH); (cm 1) 3227 (NH),
1693, 1654 (CO). 1H NMR 2.49 (s, 3H), 2.53 (s, 3H), 7.51–7.99 (m, 4H),
11.01 (s. 1H). Anal. Calcd. for C11H11ClN2O2 (238.6): C, 55.36; H, 4.65;
N, 11.74. Found: C, 55.5; H, 4.4; N, 11.9%.
Compound 9g: Yield 80%, m.p. 170 C (EtOH), (cm 1) 3242 (NH),
1
1697, 1700 (CO); H NMR 1.24 (t, 3H), 4.18 (q, 2H), 2.44 (s, 3H),
7.22–7.89 (m, 4H), 9.59 (s, 1H). Anal. Calcd. for C12H13ClN2O3 (268.7):
C, 53.64; H, 4.88; N, 10.43; Found: C, 53.3; H, 4.7, N, 10.2%.
Synthesis of 7H-3-phenyl-6-methyl-7-acetyl-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 7
To a solution of 1 (1.92 g, 0.01 mol) in ethanol was added an aque-
ous solution of potassium hydroxide (0.75 mL, 75%) and the mixture
was warmed for 10 min at 80 C and cooled. To the resulting clear
solution was added 3-chloro-2,4-pentanedione 5 (1.2 mL, 0.01 mol)
dropwise while stirring the reaction mixture. After the addition of
5 was completed, the mixture was stirred for further 18 h at room
temperature. The solid that precipitated was filtered off, washed with
water, dried, and finally crystallized from benzene to give pure 7 in
65% yield, m.p. 142–143 C; (cm 1) 1705 (CO): 1H NMR 2.39 (s,
3H), 2.40 (s, 3H), 4.24 (s, 1H), 7.26–8.11 (m, 5H). Anal. Calcd. for
C13H12N4OS: C, 57.34; H 4.44; N, 20.57; Found: C, 57.1: H, 4.7; N,
20.3%.
Synthesis of Thiohydrazonate Esters 10
To a mixture of equimolar quantities of the hydrazonoyl chloride 9 and
triazolthione 1 (10 mmol each) in dry benzene (40 mL) was added tri-
ethylamine (1.4 mL, 10 mmol). The mixture was stirred for 15 h at room
temperature, then the excess solvent was distilled under reduced pres-
sure. The solid left was collected and crystallized from ethanol to give
10 in 92% yield. The physical constants of the latter products are given
in Table III.

494
M. A. N. Mosselhi et al.
TABLE III Physical Constants of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 8
and Thiohydrazonate esters 10
Anal. Calcd./Found
Compd
Yield (%)
76
m.p. Ca
252
Molecular formula
C%
H%
N%
8a
C18H16N6S
(348.4)
62.05
62.3
4.63
4.2
24.12
23.8
8b
8c
85
85
80
90
86
89
85
85
91
85
88
92
270-2
300
276
290
280
300
180
182
165
178
192
184
C
18H16N6S
(348.4)
62.05
62.4
61.06
61.1
55.36
55.6
55.36
55.2
60.62
60.9
59.10
58.9
59.00
59.0
59.02
59.0
57.94
57.8
52.78
52.6
52.78
52.7
57.85
58.0
4.63
4.4
4.22
4.1
3.55
3.4
3.55
3.4
4.28
4.5
4.46
4.5
4.95
4.8
4.92
4.8
4.58
4.5
3.91
3.9
3.91
3.9
4.60
4.6
24.12
24.2
25.13
24.9
22.78
22.9
22.78
22.8
22.32
22.1
20.68
20.6
22.93
22.8
22.95
22.8
23.85
23.6
21.72
21.5
21.72
21.6
21.31
21.0
C17H14N6S
(334.4)
C17H13ClN6S
(368.8)
8d
8e
C
17H13ClN6S
(368.8)
8f
C
19H16N6OS
(376.4)
8g
C20H18N6O2S
(406.4)
C18H18N6OS
(366.4)
10a
10b
10c
10d
10e
10f
C
18H18N6OS
(366)
C17H16N6OS
(352.4)
C17H15ClN6OS
(386)
17H15ClN6OS
(386)
C19H18N6O2S
(394)
C
aSolvent of crystallization is dioxane.
Synthesis of 7H-3,6-disubstituted 7-Arylhydrazono-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 8
Method A: To a solution of 7H-3-phenyl-6-methyl-7-acetyl-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazine 7 (10 mmol) in ethanol (40 mL) was
added sodium acetate trihydrate (1.36 g) and the mixture was cooled
to 0–5 C in an ice bath. To the resulting cold solution was added por-
tionwise a cold solution of the appropriate diazonium salt, prepared
by diazotizing the appropriate aniline derivative (10 mmol) dissolved
in hydrochloric acid (6 ml, 6 M) with a solution of sodium nitrite
(0.7 g, 10 mmol) in water (10 mL). After the addition of the diazo-
nium salt was completed, the mixture was stirred for further 30 min in

Thiadiazines
495
the ice bath. The solid precipitated during this period was filtered off,
washed with water, dried, and crystallized from dioxane to give pure 8.
The physical constants of the compounds 8a–g prepared are listed in
Table III.
Method B: To a stirred solution of 4-amino-5-phenyl-1,2,4-triazole-
3-thione 1 (10 mmol) in ethanolic sodium ethoxide solution, pre-
pared by adding sodium metal (0.23 g, 10 mmol) to absolute
ethanol (20 mL), was added the appropriate hydrazonoyl chloride 9
(10 mmol). The mixture was stirred for 15 h at room temperature.
The solid that precipitated was collected by filtration and crystal-
lized from dioxane to give the respective pure 8. The products iso-
lated proved identical in all respects with those obtained above by
method A.
Method C: A solution of the appropriate thiohydrazonate 10
(2 mmol) in acetic acid (10 mL) was heated under reflux for 1 h and
cooled. The solid that precipitated was filtered off, washed with water,
and finally crystallized from dioxane to give the respective 8. The phys-
ical constants of the products prepared are identical to those obtained
above.
pKa Determination: The acid dissociation constants of the com-
pounds 8a–g were determined potentiometrically in 80% dioxane-water
mixture at 25 0.1 C and ionic strength (KNO3) of 0.1. An Orion 420A
pH-meter fitted with combined glass electrode type 518635 was em-
ployed for measurement of pH values. The instrument was accurate to
0.01 pH unit. It was calibrated using two standard Beckman buffer
solutions of pH 4.01 and 7.00. The pH meter reading (B) recorded in
dioxane-water solution was converted to hydrogen ion concentration
[H+] by means of the widely relation of van Uitert and Haas25 namely:
log [H+] = B + log UH, where log UH is the correction factor for the
solvent composition and ionic strength used for which B is read. The
value of log UH was found to be 0.48.
The experimental procedure followed in the determination of pKa
values and their calculations, by the method of least squares, from the
titrant volume—pH data using the relation:
pKa = pHi logVi/(Vc Vi)
where pHi is the corrected pH value of the solution when the volume of
the added titrant is Vi and Vc is the volume of the titrant at the equiv-
alence point, as previously described.26 The pKa values obtained were
reproducible to within 0.02 pKa unit. The results are summarized in
Table II.

496
M. A. N. Mosselhi et al.
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