Synthesis, acidity constants and tautomeric structure of 7-Arylhydrazono[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines in ground and excited states

Article abstract of DOI:10.1002/jccs.200100012

7-Arylhydrazono[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 4 were synthesized from the reactions of 4-amino-5-phenyl-4H-[1,2,4]triazole-3-thiol 2 and 2-(2-naphthyl)-2-oxoethanehydrazonoyl bromides 1 and their acid dissociation constants pK and pK*, in the ground and excited states, respectively, were determined. Both pK and pK* constants were correlated by Hammett equation. The pK and the spectral data presented indicate that the title compounds exist predominantly in the hydrazone tautomeric form.

Full text of DOI:10.1002/jccs.200100012

JournaloftheChineseChemicalSociety, 2001, 48, 65-72
65
Synthesis, Acidity ConstantsandTautomericStructureof
7-Arylhydrazono[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines in Ground and
Excited States
Ahmad S. Shawali*, Ibrahim F. Zeid, Mahmoud H. Abdelkader,
Alsayed A. Elsherbini and Farag M. A. Altalbawy
DepartmentofChemistry,FacultyofScience,UniversityofCairo,Giza,Egypt
7-Arylhydrazono[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 4were syn the sized from the re ac tions of
4-amino-5-phenyl-4H-[1,2,4]triazole-3-thiol 2 and 2-(2-naphthyl)-2-oxoethanehydrazonoyl bro mides 1 and
theiraciddissociationconstantspKandpK*,inthegroundandexcitedstates,respectively,weredetermined.
Both pK and pK* con stants were cor re lated by Hammett equa tion. The pK and the spec tral data pre sented in-
dicatethatthetitlecompoundsexistpredominantlyinthehydrazonetautomericform.
INTRODUCTION
Manyderivativesofthe[1,2,4]triazolo[3,4-b][1,3,4]-
and/orlaserproduction.5 On the other hand, as they can ex-
hibitazo-hydrazonetautomerism,weaimedtoelucidatetheir
actualtautomericstructureinbothgroundandexcitedstates.
thiadiazineringsystemhaveattractedconsiderableattention
ofmanyresearchgroupsbecauseoftheirdiverseandinterest-
ingbiologicalandpharmacologicalactivities.1-3 However,
the arylazo de riv a tives of such a ring sys tem have been hith-
ertounreported, althoughthearylazogroupingisknowntobe
importantinpromotinganti-neoplasticactivity.4 In view
oftheimportantbiologicalactivitiesdisplacedby[1,2,4]-
triazolo[3,4-b][1,3,4]thiadiazines and azo groups, it was con-
sid ered worth while to syn the size a se ries of the ti tle com-
pounds 4(Scheme I) and de ter mine their acid dis so ci a tion
con stants pK and pK* in the ground and ex cited states, re-
spec tively. Such arylazo com pounds are of in ter est to us due
to the fol low ing. On the one hand, some of them might be
usefulaspotentialprecursorstonovelphotographiccouplers
RESULTS AND DISCUSSION
TherequiredhithertounreportedN-aryl2-(2-naphthyl)-
2-oxoethanehydrazonoyl bro mides 1a-c, f-jwere pre pared
by the cou pling of dimethyl 2-naphthoylmethylsulfonium
bromidewiththeappropriatediazotizedanilinesinethanolin
the pres ence of so dium ac e tate trihydrate. Their struc tures
weresubstantiatedbytheirspectra(MS,IRand1H NMR) and
el e men tal anal y ses (Ta ble 1 and 4). The other bro mides 1d
and 1ewerepreparedaspreviouslyreported.18
Reaction of 4-amino-5-phenyl-4H-1,2,4-triazole-3-
thiol2 with 2-Aryl-2-oxoethanehydrazonoyl bro mides 1a-g
inethanolinthepresenceofsodiumethoxideaffordedthere-
spec tive thiohydrazonate es ters 3a-g,respectively(Scheme
I).Similarreactionsof2 with1h-j underthesameconditions,
directlyafforded, however, therespective7-arylhydrazono-
3,6-diaryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine4h-j, prob-
ablyviain situ dehydrative cyclization of the ini tially formed
thiohydrazonates 3h-j (Scheme I). The con ver sion of3a-g
into the re spec tive triazolothiadiazines4a-g was af fected by
their treat ment with ace tic acid. The struc tures of the prod-
ucts 4a-j and their thiohydrazonate pre cur sors3a-j were es-
tablishedonthebasisoftheirelementalanalysisandspecral
data (MS, 1H NMR, IR and UV) (Ta bles 1-4).
Scheme I
Attentionwasthenturnedtothetautomericstructureof
the prod ucts4a-jas they can ex ist in the tau to meric hydra-
zone form 4A or the arylazoenamine form 4B (Scheme I).
Unfortunately, their IR spectra (Ta ble 2) which were re-

66 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Shawali et al.
Table 1. IR and Mass Spectral Data of the New Compounds 1 and 3
Compd. No.
(KBr) cm-1 / m/e (%)
1a
3290, 1650, 1615 /
384(4), 383(5), 239(14), 155(100), 127(75), 122(63), 95(11), 77(14), 65(7)
3270, 1655, 1615 /
367(3), 366(5), 323(23), 155(100), 127(55), 91(4), 77(20)
3270, 1655, 1615 /
367(15), 366(19), 156(16), 155(100), 127(87), 91(2), 77(15)
3242, 1654, 1527 /
1b
1c
1f
383(2), 387(2), 155(100), 127(79), 99(13), 77(12)
3224, 1649, 1625 /
1g
1h
399(3), 397(4), 353 (M+ - NO2)(16), 155(100), 127(83), 95(11), 77(13)
3220, 1670, 1645, 1625 /
396(10), 395(3), 352(10), 351(34), 350(91), 154(4), 127(100), 119(20),
77(10)
3a
3b
3c
3d
3e
3f
3375, 3300, 3060, 1708, 1614 /
496(30), 391(58), 355(45), 283(61), 262(62), 193(32), 180(79),
155(94), 127(60), 102(87), 86(100), 77(26)
3379, 3301, 3060, 1703, 1616 /
479(5), 478(4), 461(35), 422(75), 208(25), 191(1), 155(100), 127(75),
103(44), 91(55), 77(32)
3210, 3186, 3043, 1700, 1616 /
479(5), 478(3), 461(35), 432(13), 343(17), 257(9), 191(1), 188(27), 171(7),
155(26), 126(25), 103(44), 91(100), 77(31).
3215, 3150, 1695, 1649 /
465(8), 464(10), 415(15), 414(18), 375(12), 251(18), 191(28), 180(37),
155(100), 127(91), 103(21), 91(14), 77(65)
3330, 3205, 3058, 1650, 1620 /
497(1.0), 449(3), 409(8), 361(4), 299(10), 270(41), 214(24), 155(100),
127(55), 105(8), 77(6)
3274, 3186, 3060, 1650, 1618 /
497(3), 449(9), 409(24), 388(8), 299(32), 270(100), 214(75), 167(18),
155(10), 108(11), 79(9)
3g
3245, 3185, 1695, 1616 /
464(M+ - NO2)(28), 432(21), 328(25), 299(19), 289(11), 281(18), 250(11),
226(13), 192(7), 188(25), 177(19), 171(48), 164(12), 153(80), 155(58),
127(94), 103(100), 91(22), 77(68)
cordedinpotassiumbromidewerenotoftoomuchhelptode-
cidewhichistheactualtautomericformofthecompoundsin
question. Thisproblemwassolvedbyexaminingboththe1H
NMR and UV spec tra of4a-j andcorrelationoftheiracidity
constantsbyHammettequation.
The 1H NMR spec tra of 4a-jin deuterated chlo ro form
re vealed, in each case, the pres ence of only one NH pro ton
sig nal near 10.34-10.91 (Ta ble 3). The ap pear ance of only
the lat ter sig nal in the re gion 10.0-12.0 in di cates that the
stud ied com pounds4a-j ex ist pre dom i nantly in the hydra-
zone form 4A. This is be cause the 1H NMR spec tra of com-
pounds that ex ist as an equi lib rium mix ture of hydrazone and
azo tautomers were re ported to show in each case two ex-
change able singlets at 10.12 and 11.50correspondingto-
gether to one pro ton as sign able to the NH pro ton res o nances
of the hydrazone and arylazoenamine forms, re spec tively.7
The elec tronic ab sorp tion spec tra of the com pounds
4a-j in dioxane (Ta ble 2) are also com pat i ble with the hydra-
zone form4A. As shown in Ta ble 2, each com pound ex hib its
in dioxane two bands in the re gions 270-350 and 350-440 nm.
Suchanabsorptionpatternissimilartothatoftypicalhydra-
zones.8 Fur ther more the spec tral data of the unsubstituted de-
rivative4d, taken as a rep re sen ta tive ex am ple of the se ries
stud ied, in dif fer ent sol vents (Ta ble 2) show small shifts in
max. Such small shifts in
of 4din dif fer ent sol vents are
max
due to sol vent-solute in ter ac tion and are con sis tent with the
assignedtautomericform4A. In agree ment with this con clu-
sion is the ob ser va tion that the spec tra of arylhydrazones de-

7-Arylhydrazono[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 67
Table 2. Electronic Absorption and IR Spectral Data of the
4a-jweredeterminedbyspectrophotometricmethodin80%
(v/v) dioxane-water mix ture at 27 oC and ionic strength of
0.1. In acid me dium each of the com pounds un der study
shows a maximum (band A) in the region 350-450 nm,
whereas in al ka line me dium it ex hib its an other max i mum
(band-B) in the re gion 450-590 nm. As the pH in creases, the
height of the for mer band-A de creases and si mul ta neously
that of the sec ond band-B in creases and the spec tra show, in
each case, one isobestic point in di cat ing the pres ence of at
least two spe cies in equi lib rium. This spec tral be hav iour is
characteristicofasimpleone-stageprotolyticequilibrium.In
each case, plots of absorbance val ues at ei ther one of the two
char ac ter is tic wave lengths ex hibit sig moid curves with in-
flec tion point at a given pH value that cor re sponds to the ap-
par ent pK value of the com pound un der study. From the pH-
absorbance data the respective acidity constants in the
ground state were cal cu lated and the re sults are sum ma rized
inTa ble 5.
Compounds 4a-j
Compd.
No.
max (Dioxane) (Log )
(cm-1)
NH, C=N, C=O
4a
4b
4c
4d+
4e
4f
4g
4h
4i
408 (3.86), 300 (4.29)
392 (3.88), 305 (4.23)
398 (4.02), 312 (4.26)
394 (4.13), 310 (4.35)
390 (4.06), 304 (4.23)
389 (4.01), 302 (4.22)
379 (4.16), 307 (4.36)
397 (4.40), 319 (4.42)
393 (4.31), 318 (4.38)
406 (4.51), 325 (4.29)
3150, 1602
3190, 1612
3170, 1614
3120, 1608
3150, 1609
3100, 1620
3110, 1620
3147, 1618, 1670
3159, 1610, 1706
3160, 1610
4j
+ Solvent: max (Log ) Ethanol: 400 (4.11), 305 (4.32);
Chloroform: 395 (4.06), 316 (4.26); Acetic acid: 389 (3.69), 310
(4.01); Cyclohexane: 401 (3.80), 305 (4.07); Pyridine: 404 (3.90),
331 (4.02); Ether: 396 (3.90), 307 (sh) (4.23).
rived from the re ac tion of qui nones with N-alkyl-N- aryl-
hydrazines, un like those of o-hydroxy and p-hydroxy-azo
compounds,arelargelyindependentofthesolventpolarity.9
Re cently, it has been shown that LFER cor re la tion of
the acid ity con stants of a se ries of com pounds that can ex ist
in the azo and/or the hydrazone tau to meric forms can be used
to iden tify their ac tual tau to meric form(s).10 Accordingly, in
the pres ent work, the acid ity con stants, pK’s , of the se ries
As shown in the lat ter Ta ble 5, the acid ity con stants of4
are influenced by the substituents present in the phenyl
group, be ing in creased by elec tron with draw ing substituent
anddecreasedbyelectrondonatinggroups.Correlationofthe
-
pKa data with the Hammett substituent con stants and
x
x
resultedinthefollowingequations:
pK = 10.88 - 3.03 x; r = 0.967; s = 0.10
(1)
Table 3. Characteristic Mass Spectral Data of the New Products 4a-j
Compd.
No.
m/e (%)
4a
4b
4c
4d
4e
4f
477(15), 476(22), 449(31), 416(14), 310(19), 342(39), 282(46), 273(15), 266(33),
153(53), 134(28), 127(57), 122(70), 103(78), 77(100)
461(34), 460(22), 433(390), 400(11), 343(26), 258(18), 153(36), 126(12), 91(100),
77(42)
461(5), 460(34), 431(17), 342(32), 257(20), 188(27), 153(40), 139(14), 127(46),
103(72), 91(100), 77(47)
447(30), 446(22), 418(13), 342(24), 244(9), 188(20), 153(33), 139 (8), 127(39),
103(70), 92(12), 77(100)
481(22), 480(38), 453(21), 420(20), 342(20), 286(16), 277(13), 238(15), 196(15),
188(37), 171(26), 153(63), 127(55), 111(41), 103(100), 99(26), 77(55)
481(48), 480(20), 343(36), 238(14), 188(37), 154(65), 153(100), 127(68), 125(23),
111(46), 103(88), 99(26), 77(84)
4g
4h
4i
492(61), 491(56), 464(50), 432(16), 431(14), 355(12), 341(18), 311(13), 288(14),
196(16), 188(62), 171(24), 153(76), 139(15), 127(62), 103(100), 91(13), 77(47)
489(81), 488(44), 343(36), 328(16), 296(21), 286(20), 188(54), 165(21), 153(82),
137(20), 127(70), 119(66), 103(100), 91(37), 77(70)
520(10), 519(22), 459(17), 342(29), 297(25), 264(17), 228(11), 196(14), 188(34),
171(26), 165(20), 153(83), 149(28), 127(87), 103(100), 92(18), 77(92)
492(27), 491(26), 328(26), 312(26), 298(15), 188(36), 171(68), 153(100), 139(25),
127(60), 103(93), 91(18), 77(36)
4j

68 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Shawali et al.
Table 4. 1H NMR Spectra Data of the Compounds 1, 3 and 4
Compd. No.
(multiplicity, number of protons)+
1a
1b
1c
1f
3.7 (s, 3H), 7.2-8.25 (m, 11H), 8.92 (s, 1H)
2.25 (s, 3H), 6.7-8.1 (m, 11H), 8.7 (s, 1H)
2.31 (s, 3H), 7.0-8.4 (m, 11H), 8.65 (s, 1H)
7.07-8.08 (m, 11H), 8.62 (s, 1H)
1g
1h
3a
3b
3c
3d
3e
3g
4a
4b
4c
4d
4e
4f
6.76-8.16 (m, 11H), 8.56 (s, 1H)
2.55 (s, 3H), 7.19-8.65 (m, 11H), 8.87 (s, 1H)
3.69 (s, 3H), 6.22 (s, 2H), 6.7-8.4 (m, 16H), 10.8 (s, 1H)
2.20 (s, 3H), 5.97 (s, 2H), 7.0-8.5 (m, 16H), 10.7 (s, 1H)
2.40 (s, 3H), 6.41 (s, 2H), 6.92-8.11 (m, 16H), 11.14 (s, 1H)
5.96 (s, 2H), 7.05-8.52 (m, 17H), 10.71 (s, 1H)
5.94 (s, 2H), 7.19-8.49 (m, 16H), 10.80 (s, 1H)
6.16 (s, 2H), 7.19-8.10 (m, 16H), 10.80 (s, 1H)
3.36 (s, 3H), 6.99-8.10 (m, 16H), 10.34 (s, 1H)
2.16 (s, 3H), 7.56-8.38 (m, 16H), 10.51 (s, 1H)
2.14 (s, 3H), 7.72-8.43 (m, 16H), 10.59 (s, 1H)
6.92-8.40 (m, 17H), 10.59 (s, 1H)
7.08-8.41 (m, 16H), 10.69 (s, 1H)
7.9-8.43 (m, 16H), 10.70 (s, 1H)
4g
4h
4i
7.47-8.44 (m, 16H), 10.95 (s, 1H)
2.30 (s, 3H), 7.05-8.53 (m, 16H), 10.71 (s, 1H)
1.72 (t, J = 7 Hz, 3H), 4.22 (q, J = 7 Hz, 2H), 7.14-8.43 (m, 16H), 10.91 (s,
1H)
4j
7.19-8.12 (m, 16H), 11.17 (s, 1H)
+ in CDCl3 or DMSO-d6
pK = 10.89 - 2.35 x-; r = 0.985; s = 0.06
(2)
azo forms 4A and 4B,respectively,theformertautomeric
formpredominantlyexistsinsolution.Thisisbecauseif4 ex-
istsasequilibriummixtureofsay4A and 4B (Scheme II), the
ef fec tive acid dis so ci a tion con stant K will be given by the
equation:
whererandsarethecorrelationcoefficientandthestandard
de vi a tion, re spec tively. From the val ues of r and s, it is ob vi-
ous that the pK val ues are better cor re lated with the ex alted
-
Hammett substituent con stant
.
x
TheobservedlinearcorrelationbetweenpKand - in-
K = K1/(KT +1) = K2KT/(1 + KT)
(3)
x
di cates that among the pos si ble tau to meric hydrazone and
where K1 and K2 are the acid dis so ci a tion con stants of the
hydrazone and azo tautomers, re spec tively, and KT is the tau-
Table 5. Acid Dissociation Constants of 4a-j in Ground and
Excited States
Scheme II
Compd.
No.
pK
pK*
max
max
(a)
(b)
(cm-1)
4a
4b
4c
4d
4e
4f
4g
4h
4i
11.55
11.30
11.22
11.14
10.06
9.68
9.30
8.94
9.22
8.02
405
402
400
400
405
390
384
397
393
410
500
496
499
504
504
505
496
526
514
576
4691
4714
4959
5158
4850
5839
5880
6176
5990
7029
1.79
1.43
0.91
0.41
-0.028
-2.46
-2.93
-3.91
-3.24
-6.60
4j
(a) in acid medium; (b) in alkaline medium

7-Arylhydrazono[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines
tomericequilibriumconstant.Accordingtothislastequation
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 69
ues ob tained shows that they are larger than the cor re spond-
ing ground state val ues. These re sults em pha size the im por-
tance of res o nance ef fects in ex cited states, which are, of
course, ex pected since ionic res o nance struc tures make much
larger con tri bu tion in the ex cited state than to ground state. In
addi tion, such linearcorre la tionsindi cate that the stud ied
com pounds ex ist pre dom i nantly in the ex cited state in one
tautomericform,namelythehydrazonetautomerA.
a lin ear cor re la tion be tween pK and - would be ob served
x
only if K T isindependentofthesubstituentandthiswillnever
be the case.11 Fur ther more, the value of = 2.35 seems to be
in fa vor of the hydrazone tau to mer4A as it is in good agree-
ment with those re ported for sim i lar hy dra zones and not
arylazo derivtives.12 If the azo form 4B werethepredominant
tautomerforthestudiedcompounds4a-j, the value of the re-
actionconstant would have been not more than 0.75. This is
be cause the transmissive fac tor for the bridge -C=C-N=N- in
the azo form4B is ex pected to be 0.32 as the transmissive fac-
tors of the -C=C- and -N=N- bridges were re ported to be 0.47
and0.69,respectively.13
EXPERIMENTAL
Melting points were determined on a Gallenkamp
electrothermalapparatusandtheyareuncorrected.IRspectra
of all new compunds were re corded in KBr us ing Fou rier
Trans form and Pye Unicam SP300 In fra red spec tro pho tom-
eters. 1HNMRspectrawererecordedindeutratedchloroform
or dimethylsulfoxide us ing a Varian Gem ini 200 NMR spec-
trom e ter. Mass spec tra were re corded on a GCMS-Q P1000-
EXVarianMAT711andSSQ7000spectrometers.Theultra-
violetspectrawererecordedusingaPerkinElmerLambda40
spectrophotometer. El e men tal anal y ses were car ried out at
the Microanalytical Cen ter of Cairo Uni ver sity, Giza, Egypt.
4-Amino-5-phenyl-4H-1,2,4-triazole-3-thiol 2 and N-
aryl 2-oxo-2-(2-naphthyl)ethanehydrazonoyl bro mides1b,
d,e,i,j werepreparedaspreviouslydescribed.17,18
To shed some light on the pre dom i nant tauomeric form
of the prod ucts4a-jin the ex cited state, we ex am ined the cor-
re la tion of their acid ity con stants pK* in the sin glet ex cited
-
state with the Hammett con stants x and x . At pres ent there
are three meth ods avail able for the de ter mi na tion of the acid
dis so ci a tion con stant pK* of a sin glet ex cited state. These
are:(a)measurementoffluorescenceintensityasafunction
ofpH;(b)measurementoffluorescencefrequencyoftheacid
and its con ju gate base; and (c) mea sure ment of ab sorp tion
frequencyofbothspecies.14 As method-c is rather gen eral, it
was adopted in the pres ent work to de ter mine the ex cited
state pK* val ues for the re ac tion se ries 4a-jun der study. Ac-
cord ing to this method, which uti lizes the so-called Forster
energycycle,15 the value of pK, thedifferencebetweenthe
val ues of the acid ity con stants pK* and pK of a given com-
pound in the ex cited state and ground states, re spec tively, is
usuallyevaluatedbytheequation:
N-aryl 2-oxo-2-(2-naphthyl)ethanehydrazonoyl bro mides
1a,c and 1f-h
General Procedure
A sus pen sion of dimethyl (2-naphthoylmethyl) sul fon-
ium bro mide (3.1 g, 0.01 mol) and so dium ac e tate trihydrate
(1.3 g, 10 mmol) in eth a nol (100 mL) was cooled to 0-5oC in
an ice-bath while be ing stirred. To the re sult ing cold mix ture
was added the ap pro pri ate arenediazonium chlo ride, pre-
pared by diazotizing the re spec tive aryla mine (0.01 mol) in
theusualway. Aftertheadditionwascompleted(20min), the
re ac tion mix ture was left in an ice-box for 3 h. The solid prod-
uct that pre cip i tated was fil tered off, washed with wa ter and
crys tal lized from the ap pro pri ate sol vent to give the re spec-
tive hydrazonoyl bro mide 1. The com pounds pre pared are
listedtogetherwiththeirphysicalconstantsinTable6.
pK = pK* - pK = 0.625 ( )/T
(4)
where
representsthefrequencydifference(inwavenum-
ber)betweentheabsorption max of the neu tral com pound and
its con ju gate acid or base.14,16 The val ues of pK*, cal cu lated
forthereactionseries4a-j usingthisequationaregiveninTa-
ble 5.
As shown, the val ues of pK*, like those of pK of the
ground state, are in flu enced by the substituent in the hydra-
zonemoiety.CorrelationofthesepK*datawiththeHammett
substituent con stants, x and - us ing the method of least
x
squaresgavethefollowinglinearequations:
3-(4-Amino-5-phenyl-1,2,4-triazolyl)thio hydrazonates, 3
Method A
Toamixtureofequimolarquantitiesoftheappropriate
hydrazonoyl bro mide1 and triazolethiol2 (10 mmol each) in
dry ben zene (40 mL) was added triethylamine (1.4 mL, 10
mmol).Themixturewasstirredfor15hatroomtemperature,
pK* = 0.407 - 6.76 x; r = 0.939; s = 0.14
pK* = 0.439 - 5.28 x-; r = 0.985; s = 0.06
(5)
(6)
Such data in di cate that pK* are also better cor re lated
with - con stants. Fur ther more, a sin gle glance at the val-
x

70 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Shawali et al.
Table 6. N-Aryl 2-(2-Naphthyl)-2-oxoethanehydrazonoyl bromides, 1a-j
Compd.
No.
Yield,
%
M.p.,oC
(solvent)
Molecular
formula
Anal. Calcd./Found
C,%
H,%
N,%
1a
1b
1c
1d
1e
1f
85
95
90
75
95
90
90
80
95
95
145 (a)
164 (a)i
142 (a)
150 (a)ii
209 (a)iii
198 (b)
220 (c)
208 (b)
184 (b)iv
212 (b)v
C19H15BrN2O2
(383.2)
C19H15BrN2O
(367.2)
C19H15BrN2O
(367.2)
C18H13BrN2O
(353.2)
C18H12BrClN2O
(387.7)
C18H12BrClN2O
(387.7)
C18H12BrN3O3
(398.2)
C20H15BrN2O2
(395.3)
C21H17BrN2O3
(425.3)
59.55
59.1
62.14
62.4
62.14
62.0
3.95
3.7
4.12
4.0
4.12
4.0
7.31
7.3
7.63
7.6
7.63
7.5
55.77
55.6
54.29
54.2
60.78
60.4
3.12
3.5
3.04
3.0
3.83
4.0
7.23
7.2
10.55
10.5
7.09
7.0
1g
1h
1i
1j
C18H12BrN3O3
(398.2)
Solvent of crystallization: (a) Ethanol; (b) Acetic acid; (c) Dioxane.
o
i Lit.18b mp. 166-167 oC; ii Lit.18a m.p. 149-150 C; iii Lit.18b mp. 208-210 oC; iv Lit.18b mp. 184-
185 oC; v Lit.18b mp. 211-213 oC.
thenthesolventwasdistillledunderreducedpressureinaro-
ta tory evap o ra tor. The solid left was col lected, washed with
waterandfinallycrystallizedfromtheappropriatesolventto
give the re spec tive thiohydrazonate es ter3. The com pounds
3a-g prepared, togethertheirphysicalconstants, arelistedin
Table7.
The prod ucts iso lated from sim i lar re ac tions of2 with
1h-j, proved to be the triazolothiadiazines 4h-j,respectively
(Table8).
Method B
To an ethanolic so dium ethoxide so lu tion, pre pared
from so dium metal (0.11 g, 0.005 g.atom) and ab so lute eth a-
Table 7. 3-(4-Amino-5-phenyl-1,2,4-triazolyl)thio hydrazonates, 3a-g
Compd.
No.
Yield,
%
M.p.,oC
(solvent)
Molecular
formula
Anal. Calcd./Found
C,%
H,%
N,%
3a
3b
3c
3d
3e
3f
80
75
75
80
75
75
85
198 (a)
165 (a)
167 (a)
170 (a)
190 (a)
180 (b)
160 (b)
C27H22N6O2S
(494.6)
C27H22N6OS
(478.6)
C27H22N6OS
(478.6)
C26H20N6OS
(464.5)
C26H19ClN6OS
(499.0)
C26H19ClN6OS
(499.0)
65.57
65.4
67.76
67.6
67.76
67.4
67.22
67.2
62.58
62.5
62.58
62.2
4.48
4.5
4.63
4.1
4.63
4.7
4.34
4.2
3.84
3.4
3.84
4.0
16.99
16.5
17.56
17.4
17.56
17.8
18.09
18.0
16.84
16.4
16.84
16.8
3g
C26H19N7O3S
(509.6)
61.1
59.9
3.76
3.4
19.24
19.3
Solvent of crystallization: (a) Ethanol; (b) Dioxane-water.

7-Arylhydrazono[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 71
Table 8. 7-Arylazo-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, 4a-j
Compd.
No.
Yield,
%
M.p.,oC
(solvent)
Molecular
formula
Anal. Calcd./Found
C,%
H,%
N,%
4a
4b
4c
4d
4e
4f
60
65
55
70
65
60
75
75
80
85
280 (a)
264 (b)
260 (a)
270 (b)
290 (c)
300 (b)
308 (d)
268 (b)
250 (b)
305 (d)
C27H20N6OS
(476.6)
C27H20N6S
(460.6)
C27H20N6S
(460.6)
C26H18N6S
(446.5)
C26H17ClN6S
(480.9)
C26H17ClN6S
(480.9)
C26H17N7O2S
(491.5)
C28H20N6OS
(488.6)
C29H22N6O2S
(518.6)
C26H17N7O2S
(491.5)
68.05
68.0
70.41
70.4
70.41
69.5
69.94
69.3
64.93
65.0
64.93
64.3
63.53
63.5
68.84
68.5
67.11
66.8
63.53
63.2
4.23
4.0
4.38
4.2
4.38
4.1
4.06
4.3
3.56
3.5
3.56
3.5
3.49
3.4
4.13
4.3
4.27
4.6
3.49
3.4
17.63
17.6
18.25
18.2
18.25
18.5
18.82
18.8
17.47
17.5
17.47
17.3
19.95
20.0
17.20
17.2
16.19
15.8
19.95
19.8
4g
4h
4i
4j
Solvent of crystallization: (a) Ethanol; (b) Acetic acid; (c) Dioxane, (d) DMF.
nol (20 mL) was added the triazolethione 2 (0.96 g, 5 mmol).
Af ter stir ring the mix ture for 15 min, the ap pro pri ate hydra-
zonoylbromide1 (5 mmol) was added and stir ring con tin ued
for 4-6 h. Dur ing this pe riod, the hydrazonoyl bro mide dis-
solvedandnewprecipitatewasformed.Thereactionmixture
wasthenleftovernightatroomtemperature. Thecrudeprod-
uct that pre cip i tated was fil tered off, washed with wa ter and
weredeterminedspectrophotometricallyin80vol%dioxane-
o
wa ter mix ture at 27 oC 0.1 C and ionic strength 0.1. An
Orion 420A pH me ter fit ted with com bined glass elec trode
type 518635 was em ployed for mea sure ment of pH val ues.
The in stru ment was ac cu rate to 0.01 pH unit. It was cal i-
brated us ing two stan dard Beckman buffer so lu tions of pH
4.01 and 7.00. The pH me ter read ings (B) re corded in dioxane-
finallycrystallizedfromtheappropriatesolvent.Theisolated w atersolutionswereconvertedtohydrogenionconcentra-
prod ucts proved iden ti cal in all re spects with those ob tained
above by Method A.
tion [H+] by means of the widely used re la tion of van Uitert
and Haas19 namely:
Here too the re ac tions of 2 with 1h-j, when car ried out
asabove,affordeddirectlythetriazolothiadiazinederivatives
4h-j,respectively(Table8).
-log [H+] = B + log UH
where log U H isthecorrectionfactorforthesolventcomposi-
tion and ionic strength used for which B is read. The value
wasdeterminedbyrecordingthepHvaluesforaseriesofso-
lu tions con tain ing known amounts of hy dro chlo ric acid and
so dium chlo ride such that the ionic strength is 0.1 in 80 vol %
dioxane-water at 27 oC. The value of log UH was found to be
-0.48.
7-Arylhydrazono[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines,
4a-g
A solution of the appropriate thiohydrazonate 3 (2
mmol) in ace tic acid (10 mL) was refluxed for 1 h and then
cooled.Thesolidthatprecipitatedwascollectedbyfiltration,
washedwithwater, driedandfinallycrystallizedfromtheap-
pro pri ate sol vent to give the re spec tive triazolothiadiazine
derivative4. The com pounds pre pared to gether with their
physicalconstantsaregiveninTable8.
Theexperimentalprocedurefollowedinthedetermina-
tion of pK con stants and their cal cu la tions from the absorb-
ance - pH data are as pre vi ously de scribed (8). The pK val ues
obtainedwerereproducibletowithin 0.02 pK unit. The re-
sultsaresummarizedinTable5.
pK Determination
Theaciddissociationconstantsofthecompounds 4a-j

72 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Shawali et al.
Received June 3, 2000.
Baumeister, U.; Stroehl, D.; Danz, H. Heterocycles 1997,
45, 1183.
Key Words
7. Amer, A.; Elmassry, A. M.; Awad, L.; Rashed, N.;
Elashry, E. S.; Ho, D. M. J. Chem. Soc. Perkin Trans. I
1990, 2513.
Hydrazonoyl halides; 1,2,4-Triazole-3-thione;
Thiohydrazonate esters; Forster cycle; Hammett
equation; Tautomerism.
8. Shawali, A. S.; Khattab, S. A.; Farag, A. J. Chem. Eng.
Data 1977, 22, 104.
9. Jones, R.; Ryan, A. J.; Sternhell, S.; Wright, S. E. Tet ra-
hedron 1963, 19, 1497.
REFERENCES
10. Mosselhi, M. A.; Abdallah, M. A.; Riyadh, S. M.;
Harhash, A. E.; Shawali, A. S. J. Prakt. Chem. 1998, 340,
160 and the ref er ences cited there in.
1. (a) Bala, S.; Gupta, R. P.; Sachdeva, M. L.; Singh, A.;
Pujari, H. K. Indian J. Chem. 1978, 16B, 481. (b) Mohan,
J. ibid. 1983, 22B, 270.
2. (a) Prasad, A.; Ramalingam, R. J.; Rao, A. B.; Diwan, P.
V.; Sattur, P. B. Eur. J. Med. Chem. 1989, 24, 199. (b)
El-Khawass, S. M.; Habib, N. S. J. Heterocycl. Chem.
1989, 26, 177.
11. Kurasawa, Y.; Hosaka, T.; Takada, A. H. S.; Kim, H. S.;
Okamoto, Y. J. Heterocycl. Chem. 1994, 31, 1661.
12. (a) Tsuno, Y.; Ibata, J.; Yukawa, Y. Bull. Chem. Soc. Jpn.
1959, 32, 960. (b) Socha, J.; Horska, J.; Vecera, M. Coll.
Czech. Chem. Commun. 1969, 34, 2982.
3. Chande, M. S; Karnik, B. M.; Ganguly, N. J. In dian
Chem. Soc. 1990, 67, 695.
13. (a) Shawali, A. S.; Altahou, B. M. Tetrahedron 1977, 33,
1625. (b) Jaffe’, H. H. Chem. Rev. 1953, 53, 191.
14. Jaffe’, H. H.; Jones, H. L. J. Org. Chem. 1965, 30, 964.
15. Forster, T. Z. Elektrochem. 1950, 54, 42.
16. Weller, A. In ProgressinReactionKinetics; Por ter, G.,
Ed.; Pergamon Press: Lon don, 1961, 187.
4. Garg, H. G.; Prakash, C. J. Med. Chem. 1971, 14, 175. (b)
Ross, W. C. J.; Warweek, G. P. J. Chem. Soc. 1956, 1364.
(c) Harrman, E.; Gabliko, J. J. Can cer Chemother. Rep.
1961, 14, 85. (d) Jain, R.; Pardasani, H. K. Indian J.
Heterocycl. Chem. 1991, 1, 79.
5. (a) Onda, H.; Mizukura, N. Jpn. Kokai Tokkyo Koho JP
0421, 683; Chem. Abstr. 1992, 116: 257383g. (b) Kato,
M.; Kita, H.; Mizukura, N. Jpn. Kokai Tokkyo Koho JP
0441,488, Chem. Abstr. 1992, 117: 9837v. (c) Hanami,
A.; Kita, H.; Ooya, H.; Onodera, A. Jpn. Kokai Tokkyo
Koho JP 07,179,468; Chem. Abstr. 1995, 123: 340150u.
6. (a) Frohberg, P.; Wiese, M.; Nuhn, P. Arch. Pharm.
Pharm. Med. Chem. 1997, 330, 47. (b) Frohberg, P.;
17. Reid, J. R.; Heindel, N. D. J. Heterocycl. Chem. 1976, 13,
925.
18. (a) Hassaneen, H. M.; Shawali, A. S.; Elwan, N. M.;
Abunada, N. M. SulfurLett. 1992, 14, 41. (b) Hassaneen,
H. M.; Shawali, A. S.; Elwan, N. M.; Abunada, N. M.
SulfurLett. 1992, 13, 273.
19. van Uitert, L. G.; Haas, C. G. J. Am. Chem. Soc. 1953, 75,
451.