Synthesis and tautomeric structure of 2-arylazo-4H-imidazo[2,1-b][1,3,4] thiadiazines

Article abstract of DOI:10.3184/030823407X237885

Two series of the title compounds were prepared via reaction of N-aryl 2-oxohydrazonoyl halides with 1-amino-4-phenylimidazoline-2-thione. Their tautomeric structure was elucidated by spectral analysis, and the correlation of their acid dissociation const

Full text of DOI:10.3184/030823407X237885

JOURNAL OF CHEMICAL RESEARCH 2007
AUGUST, 479–483
RESEARCH PAPER 479
Synthesis and tautomeric structure of 2-arylazo-4H-imidazo[2,1-b][1,3,4]
thiadiazines
Ahmad S. Shawali*, Mosselhi A.N. Mosselhi and Thoraya A. Farghaly
Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
Two series of the title compounds were prepared via reaction of N-aryl 2-oxohydrazonoyl halides with 1-amino-4-
phenylimidazoline-2-thione. Their tautomeric structure was elucidated by spectral analysis, and the correlation of
their acid dissociation constants with the Hammett equation, to be as the hydrazone form.
Keywords: imidazoles, fused imidazoles, 1,3,4-thiadiazines, azo-hydrazone tautomerism, hydrazonoyl halides, thiohydrazonates
N
S
Hydrazonoyl halides (1) have demonstrated their potential
for the synthesis of various types of fused heterocycles.
Considerable effort has been made therefore during the
past three decades to study their synthesis and reactions.1-5
Furthermore, a literature search revealed that although
several imidazo[2,1-b][1,3,4]thiadiazine derivatives have
been prepared by the action of α-halocarbonyl compounds
upon either 2-amino-1,3,4-thiadiazines6-8 or 1-amino-2-
imidazolinethione derivatives,7-9 the 2-arylazo derivatives of
this fused-ring system have not been reported previously.5
In continuation of our recent studies on the reactions of
hydrazonoyl halides with heterocyclic thiones,10-17 we now
describe a new one-pot method for the preparation of 3-
substituted 2-arylazo-7-phenyl-4H-imidazo[2,1-b][1,3,4]thia-
diazines 4. Our interest in the synthesis of these compounds
is owing to the increasing utility of arylazo heterocycles in
various sectors of industry including hair dyeing, thermal
transfer printing, nonlinear optics, disperse dyes, pigments
and ink-jet inks.18 Furthermore, as compounds 4 can exist in
one or more of the three tautomeric forms I–III (Fig. 1), it
was thought worthwhile to elucidate their actual tautomeric
structure. This is a necessary preliminary to an intended
exploration of their nonlinear optical properties.
R
N
Ph
N-NHAr
N
H
N
I
R
N
Ph
R
N=NAr
N
S
II
N
S
N
H
Ph
N
N=NAr
III
Fig. 1
carbon atom of the S-C=N-NH group.10 Refluxing the esters
3Bc and 3Cd in acetic acid for 24 h resulted in dehydrative
cyclisation and the formation of products that proved identical
with compounds 4Bc and 4Cd, respectively (Scheme 1).
The assignment of structure 4 for the isolated products was
further confirmed by alternative syntheses of 4Ac, 4Bb and
4Bc as typical examples of the two series prepared. Thus,
treatment of 2 with phenacyl bromide in ethanol in the presence
of triethylamine afforded 3,7-diphenylimidazo[2,1-b][1,3,4]
thiadiazine (6, Scheme 2). Similarly, treatment of 2 with 3-
chloro-2,4-pentanedione in ethanolic potassium hydroxide
Results and discussion
Treatment of the hydrazonoyl halides 1A and 1B with
1-amino-4-phenylimidazole-2-thiol (1-amino-4-phenyl-1,3-
dihydro-2H-imidazole-2-thione, 2) in ethanol in the presence
of sodium ethoxide at room temperature afforded, in each
case, only one isolable material as evidenced by TLC analysis
of the crude products. Both microanalysis and spectral data
(1)
R-CO-C(Cl)=NNHAr
EtONa/EtOH
NH2
1
(MS, IR and H and 13C NMR) indicated that the isolated
N
products are the respective 3,7-disubstituted 2-arylhydrazono-
imidazo[2,1-b][1,3,4]thiadiazines 4A and 4B, respectively
(Scheme 1). This finding indicates that the initially formed
thiohydrazonate esters 3A and 3B undergo in situ dehydrative
cyclisation as soon as they are formed to give the respective 4
directly as end products. The involvement of intermediates 3
was evidenced by their isolation in two cases. Thus, reaction
of 2 with the hydrazonoyl halides 1Bc and 1Cd, respectively,
yielded the thiohydrazonates 3Bc and 3Cd.
The assigned structures of the thiohydrazonates 3Bc and
3Cd were supported by their mass spectra. Characteristic
peaks were observed corresponding to the fragments (M+
– RCOC=NNHAr). This finding supports the thiohydrazonate
structure 3, because the mass spectra of both aryl and heteroaryl
thiohydrazonates have been reported to be characterised by
elimination of the elements of the corresponding arenethiol
and heteroaryl thiol from their molecular ions, respectively.10
Further evidence in support of structure 3 for the isolated
products was provided by the 13C NMR spectra which
revealed the presence of a signal near d 147 attributable to the
Ph
S
N
H
2
R-CO
C
N
NAr
NH2
S
COR
N-NHAr
AcOH, ∆
(-H2O)
N
Ph
N
N
3
N
S
R
N
Ph
N-NHAr
4
R = A, CH3; B, Ph; C, 2-thienyl
Ar = C6H4X; X: a, 4-OMe; b, 4-Me; c, H; d, 4-Cl, e, 3-Cl;
f, 3-NO2; g, 4-NO2; h, 4-CO2Et; i, 4-COCH3; j, 4-CN
* Correspondent. E-mail: as_shawali@mail.com
Scheme 1
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480 JOURNAL OF CHEMICAL RESEARCH 2007
N
Table
1
Electronic absorption spectra of imidazo[2,1-b]
Ph
NH2
N
[1,3,4]thiadiazines 4Aa–j and 4Ba–j in dioxan
N
PhCOCH2Br
Et3N
Cpd no
lmax (log e)
Ph
Ph
N
S
S
N
H
4Aa
4Ab
4Aca
4Ad
4Ae
4Af
414 (3.98), 324 (4.03), 244 (4.22)
404 (4.08), 379 (4.18), 268 (4.30)
390 (4.08), 270 (4.35)
392 (4.15), 271 (4.27)
389 (4.00), 272 (4.21)
6
2
KOH
ClCH(COCH3)2
NH2
XC6H4N2Cl
OH
393 (4.07), 310 (4.37), 241 (4.34)
414 (4.30), 270 (4.24)
4Ag
4Ah
4Ai
COCH3
N
4Bb,c
X = b, 4-Me; c, H
394 (4.24), 286 (4.22)
H
396 (4.15), 286 (4.19)
Ph
Ph
S
4Aj
393 (4.15), 286 (4.19)
COCH3
N
4Ba
4Bb
4Bcb
4Bd
4Be
4Bf
415 (3.81), 282 (3.97)
7
429 (3.70), 251 (4.00)
- H2O
406 (3.80), 279 (4.02), 234 (4.04)
409 (3.72), 252 (4.28)
N
CH3
424 (3.77), 321 (4.15), 245 (4.02)
406 (3.80), 279 (4.02), 246 (4.04)
418 (3.87), 305 (3.80)
N
PhN2Cl, OH
- CH3CO2H
4Ac
4Bg
4Bh
4Bi
H
408 (4.14), 321 (4.17)
N
S
COCH3
407 (3.89), 325 (3.96)
4Bj
406 (4.25), 288 (4.48)
8
aSolvent, lmax (log e): EtOH 392 (4.05), 270 (4.13); acetone 389
(4.07); chloroform 383 (4.22); cyclohexane 394 (4.23); acetic
acid 382 (4.27); DMSO 398 (4.10); acetonitrile 387 (4.49);
dichloromethane 390 (4.35); DMF 393 (4.24); toluene 392 (4.51).
bSolvent, lmax (log e): EtOH 408 (3.59), 279 (3.80), 230 (3.84);
acetone 405 (3.80); chloroform 407 (3.76); cyclohexane 410
(3.80); acetic acid 405 (3.63); DMSO 413 (3.86); acetonitrile 404
(3.99); dichloromethane 407 (3.71), DMF 409 (3.90), toluene
408 (3.80).
Scheme 2
yielded 2-acetyl-3-methyl-7-phenylimidazo[2,1-b][1,3,4]thia-
diazine (8), probably via cyclisation of the initially formed
substitution intermediate, 3-[(1-amino-4-phenyl-imidazol-
2-yl)thio]-2,4-pentanedione (7, Scheme 2). The structures of
the isolated products 6 and 8 were assigned on the basis of
1
their spectral data (mass, IR, H NMR) and microanalyses.
was tested.20-24 The pK values for the series 4Aa-j and 4Ba-j
For example, the PMR spectrum of 8 revealed characteristic
signals at d 2.26 (s, 3H), 2.33 (s, 3H), 4.99 (s, 1H), 7.35 –
7.75 (m, 5H), 8.08 (s, 1H); whereas the pmr spectrum of 6
showed signals at d 4.40 (s, 2H), 7.73 – 7.99 (m, 10H), 8.24
(s, 1H). Reaction of 8 with diazotised aniline in ethanol in
the presence of sodium acetate yielded a product in overall
good yield that was identified as the phenylhydrazone 4Ac,
formed via a Japp-Klingemann reaction19 (Scheme 2). The
latter product proved identical with that obtained above from
1Ac and 2. Similar coupling of 6 with diazotised p-toluidine
and aniline in pyridine yielded products that were found to be
identical with compounds 4Bb and 4Bc, respectively.
Next, the tautomerism of 4 was studied. As shown in
Fig. 1, the products 4 can exist in one or more of three
possible tautomeric structures, viz. the iminohydrazone, the
azo-enamine and the CH-azo forms, I – III, respectively.
Of these forms, structure I seems to be the form of choice,
as it is consistent with the electronic absorption and 1H
NMR spectra. For example, like typical hydrazones,20,21
the electronic absorption spectra of 4 in dioxan revealed in
each case two characteristic absorption bands in the regions
429–389 and 286–234 nm (Table 1), and the spectra of the
unsubstituted derivatives 4Ac and 4Bc, taken as representative
examples of the series prepared, each in different solvents,
exhibit little if any solvent dependence (Table 1). On the
basis of such absorption patterns, it can be concluded that the
studied compounds 4 have in solution one tautomeric form,
namely the hydrazone tautomer I.
a
were determined potentiometrically at 27°C in 80% dioxan-
water mixture (v/v). In all determinations 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) and the results are summarised
in Table 2.
When the pK values for each series were plotted vs.
a
Hammett substituent constants s ,25 all the substituents fall
x
on the correlation line except the substituents with –R effect,
namely the p-Ac, p-CN, p-NO2 and p-CO2Et groups, which
are capable of direct interaction with the negatively charged
–
reaction site. When the pK data were plotted versus s
a
x
constants,25 better correlations were obtained. The equations
of the regression lines obtained are:
pK (4A) = 7.49 - 2.51 s –; r = 0.993; s = ± 0.10
a
x
pK (4B) = 8.56 - 2.31 s –; r = 0.992; s = ± 0.10
a
x
–
Theseexcellentcorrelationsindicatethattheparameterr inthe
o
Yukawa–Tsuno equation: pK = pK + r[s + r– (s – – s )],
a
a
x
x
x
which gives the contribution of the resonance effect of the
substituent varied, is close to unity for the two series 4Aa–j
and 4Ba–j studied.26
The linear correlation between pK values and s – constants,
a
x
–
and the determined values of r and r , provide further
evidence that the studied compounds 4 exist predominantly
in the hydrazone form I. This is because the values of r (2.51
1
This conclusion was confirmed by the H NMR spectra
–
and 2.31) and r = 1.00 are similar to those reported for the
of the studied compounds 4. Thus, their spectra showed
hydrazone NH proton signals in the region δ 9.85–10.89
(see Experimental), and the absence of signals at δ 11.7
and 5.3 which would be characteristic for the NH and CH
protons of the azo-enamine and CH-azo forms II and III,
respectively.22,23
To obtain further evidence for the assignment of structure
I for the products 4, their acid dissociation constants were
determined and their correlation by the Hammett equation
–
ionisation of phenols (r = 2.67; r = 1.00) and anilinium
–
ions (r = 2.77; r = 1.00) in 50% ethanol–water mixture.27-29
If either II or III were the predominant form for the studied
compounds, the r values would be expected to be less than
2.0 and to be similar to that reported for the ionisation of
–
2-arylazophenols (r = 1.223; r = 0.286),27 since the bridge
between the substituent and the (deprotonation) reaction site
in forms II and III is longer than in I. Thus, it is reasonable
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JOURNAL OF CHEMICAL RESEARCH 2007 481
Table 2 Acid dissociation constantsa of 4Aa–j and 4Ba–j
–
Cpd No.
pKa ( s)
Cpd No.
pKa ( s)
σX
σX
4Aa
4Ab
4Ac
4Ad
4Ae
4Af
8.30 (0.05)
7.91 (0.03)
7.42 (0.02)
6.80 (0.02)
6.50 (0.02)
5.76 (0.04)
4.30 (0.03)
5.90 (0.01)
5.50 (0.03)
5.10 (0.02)
4Ba
4Bb
4Bc
4Bd
4Be
4Bf
9.20 (0.03)
8.90 (0.03)
8.50 (0.04)
8.10 (0.03)
7.60 (0.03)
7.05 (0.04)
5.50 (0.03)
7.17 (0.02)
6.70 (0.02)
6.40 (0.04
–0.27
–0.17
0.00
0.23
0.37
0.71
0.78
0.45
0.50
0.66
–0.27
–0.17
0.00
0.23
0.37
0.71
1.28
0.68
0.84
0.88
4Ag
4Ah
4Ai
4Bg
4Bh
4Bi
4Aj
4Bj
aIn dioxan–water (4:1 v/v) at 27oC and μ = 0.10.
(M+ + 1, 14), 363 (M+, 45), 228 (9), 187 (19), 174 (7), 142 (2), 135
(35), 122 (100), 116 (10), 107 (97), 103 (14), 95 (20), 77 (20). Anal.
Calcd. for C19H17N5OS (363.44): C, 62.79; H, 4.71; N, 19.27. Found:
C, 62.80; H, 4.57; N, 19.00%.
3-Methyl-7-phenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one
2-(4-methylphenyl)hydrazone (4Ab): Yellow solid (0.65 g, 75%),
m.p. 236–238°C (EtOH-dioxan). IR: νmax 3163. NMR: δH 2.08 (s,
3H, CH3), 2.39 (s, 3H, CH3), 7.24–7.31 (m, 5H, ArH), 7.33 (d, J
= 8 Hz, 2H, ArH), 7.73 (d, J = 8 Hz, 2H, ArH), 8.08 (s,1H, ArH),
10.06 (s, 1H, NH). MS m/z (%) 349 (M+ + 2, 6), 348 (M+ + 1, 22),
347 (M+, 82), 346 (61), 228 (7), 187 (31), 183 (16), 174 (21), 119
(11), 116 (17), 106 (17), 103 (27), 91 (100), 77 (27). Anal. Calcd. for
C19H17N5S (347.44): C, 65.68; H, 4.93; N, 20.16. Found: C, 65.70;
H, 4.53; N, 20.32%.
3-Methyl-7-phenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one
2-phenylhydrazone (4Ac): Pale yellow crystals (0.67 g, 80%),
m.p. 218–220°C (EtOH-dioxan). IR: νmax 3425 cm-1. NMR: δH 2.45
(s, 3H, CH3), 6.93–7.81 (m, 10H, ArH), 8.16 (s, 1H, ArH), 10.10 (s,
1H, NH). MS: m/z (%) 335 (M+ + 2, 9), 334 (M+ + 1, 22), 333 (M+,
100), 228 (9), 187 (64), 183 (64), 174 (24), 147 (14), 142 (9), 116
(27), 105 (22), 103 (56), 92 (20), 77 (95). Anal. Calcd. for C18H15N5S
(333.42): C, 64.84; H, 4.53; N, 21.00. Found: C, 64.77; H, 4.47;
N, 21.02%.
3-Methyl-7-phenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one
2-(4-chlorophenyl)hydrazone (4Ad): Yellow solid (0.72 g, 78%),
m.p. 260–262°C (EtOH-dioxan). IR: νmax 3440 cm-1. NMR: δH 2.45
(s, 3H, CH3), 7.20–7.35 (m, 5H, ArH), 7.39 (d, J = 8 Hz, 2H, ArH),
7.79 (d, J = 8 Hz, 2H, ArH), 8.17 (s,1H, ArH), 10.06 (s, 1H, NH):
δC 20.4, 115.8, 116.7, 120.9, 124.4, 125.3, 127.1, 127.3, 128.5, 128.9,
132.8, 139.1, 143.2, 149.1. MS: m/z (%) 370 (M+ + 2, 11), 369 (M+
+ 1, 30), 368 (M+, 26), 367 (100), 188 (14), 187 (89), 183 (44), 174
(31), 147 (16), 142 (12), 139 (24), 126 (23), 117 (13), 113 (20),
111 (68), 103 (87), 77 (18), 76 (25). Anal. Calcd. for C18H14ClN5S
(367.86): C, 58.77; H, 3.84; N, 19.04. Found: C, 58.83; H, 3.74; N,
19.32%.
3-Methyl-7-phenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one
2-(3-chlorophenyl)hydrazone (4Ae): Yellow solid (0.67 g, 73%),
m.p. 256–258°C (EtOH–dioxan). IR: νmax 3417 cm-1. NMR: δH 2.43
(s, 3H, CH3), 6.95–7.81 (m, 8H, ArH), 8.18 (s, 1H, ArH), 10.11 (s,
1H, NH). MS: m/z (%) 370 (M+ + 2, 5), 369 (M+ + 1, 22), 368 (M+,
13), 367 (55), 210 (18), 188 (14),187 (100), 174 (35), 142 (16), 117
(13), 113 (18), 111 (57), 102 (21), 91 (11), 77 (19). Anal. Calcd. for
C18H14ClN5S (367.86): C, 58.77; H, 3.84; N, 19.04. Found: C, 58.70;
H, 3.62; N, 19.00%.
3-Methyl-7-phenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one
2-(3-nitrophenyl)hydrazone (4Af): Yellow solid (0.64 g, 68%),
m.p. 244–246°C (EtOH-dioxan). IR: νmax 3417 cm-1. NMR: δH 2.39
(s, 3H, CH3), 7.24 (m, 9H, ArH), 8.20 (s, 1H, ArH), 10.41 (s, 1H,
NH). MS: m/z (%) 380 (M+ + 2, 7), 379 (M+ + 1, 22), 378 (M+, 100),
187 (37), 183 (17), 174 (18), 147 (10), 116 (20), 103 (31), 76 (8).
Anal. Calcd. for C18H14N6O2S (378.42): C, 57.13; H, 3.73; N, 22.21.
Found: C, 56.73; H, 3.77; N, 22.10%.
3-Methyl-7-phenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one 2-
(4-nitrophenyl)hydrazone (4Ag): Orange solid, (0.68 g, 72%), m.p.
272–274°C (EtOH-dioxan). IR: νmax 3247 cm-1. NMR: δH 2.49 (s, 3H,
CH3), 7.08 (d, J = 9 Hz, 2H, ArH), 7.10–7.67 (m, 5H, ArH), 7.68 (d,
J = 9 Hz, 2H, ArH), 8.01 (s, 1H, ArH), 10.02 (s, 1H, NH). MS: m/z
(%) 380 (M+ + 2, 9), 379 (M+ + 1, 30), 378 (M+, 100), 348 (13),
228 (12), 210 (19), 189 (13), 187 (60), 174 (35), 147 (20), 142 (16),
122 (12), 116 (38), 107 (32), 104 (19), 92 (18), 77 (13), 76 (24).
Anal. Calcd. for C18H14N6O2S (378.42): C, 57.13; H, 3.73; N, 22.21.
Found: C, 57.11; H, 3.51; N, 21.92%.
to conclude that the observed linear correlation of the
dissociation constants with the Hammett equation indicates
that the hydrazone tautomeric form I prevails under the
conditions of the pK measurement.
a
Experimental
All melting points were determined on a Gallenkamp Electrothermal
apparatus. Solvents were generally distilled and dried by standard
literature procedures prior to use. The IR spectra were measured
on a Pye-Unicam SP300 instrument in potassium bromide discs.
1H and 13C NMR spectra were recorded on a Varian Mercury
1
VXR-300 spectrometer (300 MHz for H and 75 MHz for 13C) and
the chemical shifts were related to that of the solvent (DMSO-d6
throughout). Mass spectra were recorded on a GCMS-Q1000-EX
Shimadzu and GCMS 5988-A HP spectrometers; the ionising voltage
was 70 eV. Electronic absorption spectra were recorded on a Perkin-
Elmer Lambada 40 spectrophotometer. Elemental analyses were
carried out by the Microanalytical Centre of Cairo University, Giza,
Egypt. The hydrazonoyl halides 1Aa–j, 1Ba–j14,30-34 and 1Cd,35a and
1-amino-4-phenylimidazole-2-thiol 2,35b were prepared by literature
methods.
Synthesis of 3,7-disubstituted 2-arylhydrazonoimidazo[2,1-b][1,3,4]
thiadiazines (4)
To sodium ethoxide solution, prepared from sodium metal (0.06 g,
2.5 mmole) and absolute ethanol (15 ml) was added compound 2
(0.48 g, 2.5 mmole) and the mixture was stirred for 10 min. To the
resulting solution was added the appropriate hydrazonoyl chloride 1A
(2.5 mmole) and the reaction mixture was stirred overnight at room
temperature. The solid that precipitated was filtered off, washed with
water, dried and finally crystallised from an appropriate solvent to
give the respective 3,7-disubstituted 2-arylhydrazonoimidazo[2,1-b]
[1,3,4]thiadiazine 4A.
Repetition of the above procedure using 1B and 1Cd each in
place of 1A gave in all cases the respective fused system 4 except
in the cases of 1Bc and 1Cd, where the isolated products were the
thiohydrazonates 3Bc and 3Cd, respectively.
(1-Amino-4-phenylimidazol-2-yl) N-phenyl-2-oxo-2-phenylethane-
thiohydrazonate (3Bc): Pale yellow solid (0.74 g, 72%), m.p. 160–
162°C (EtOH-dioxan). IR: νmax 3317, 3186, 1643 cm-1. NMR: δH 6.35
(s, 2H, NH2), 7.23-7.80 (m, 15H, ArH), 8.30 (s, 1H, ArH), 11.0 (s,
1H, NH). MS: m/z (%) 413 (M+, 3), 250 (15), 234 (30), 191 (39), 176
(13), 131 (18), 118 (21), 117 (29), 105 (100), 103 (24), 77 (80). Anal.
Calcd. for C23H19N5OS (413.44): C, 66.81; H, 4.63; N, 16.94. Found:
C, 66.41; H, 4.53; N, 16.60%.
(1-Amino-4-phenyl-imidazol-2-yl)
N-(4-chlorophenyl)-2-oxo-2-
thienyl-ethane-thiohydrazonate (3Cd): Yellow solid (0.62 g, 55%),
m.p. 182–184°C (EtOH-dioxan). IR: νmax 3277, 3181, 1630 cm-1.
NMR: δH 5.74 (s, 2H, NH2), 6.76 (d, J = 9 Hz, 2H, ArH), 7.20–7.65
(m, 8H, ArH), 7.67 (d, J = 9 Hz, 2H, ArH), 8.23 (s,1H, ArH), 10.82
(s, 1H, NH); δC 113.9, 115.3, 123.6, 123.8, 125.0, 126.1, 127.4,
128.2, 128.6, 128.8, 129.0, 137.2, 139.0, 147.4, 159.0, 161.3, 189.0.
MS: m/z (%) 456 (M+ + 3, 1), 455 (M+ + 2, 2), 453 (M+, 2), 286 (3),
191 (55), 174 (5), 171 (8), 137 (16), 117 (19), 111 (100), 104 (11), 78
(27). Anal. Calcd. for C21H16ClN5OS2 (453.98): C, 55.56; H, 3.55; N,
15.43. Found: C, 55.40; H, 3.77; N, 15.25%.
3-Methyl-7-phenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one
2-(4-methoxyphenyl)hydrazone) (4Aa): Pale yellow solid (0.64 g,
70%), m.p. 220–222°C (EtOH-dioxan). IR: νmax 3150 cm-1. NMR:
δH 2.44 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 6.91 (d, J = 9 Hz, 2H,
ArH), 7.28–7.39 (m, 5H, ArH), 7.79 (d, J = 9 Hz, 2H, ArH), 8.17
(s,1H, ArH), 9.85 (s, 1H, NH). MS: m/z (%) 365 (M+ + 2, 4), 364
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482 JOURNAL OF CHEMICAL RESEARCH 2007
2-[(4-Ethoxycarbonylphenyl)hydrazono]-3-methyl-7-phenyl-2H-
imidazo[2,1-b][1,3,4]thiadiazine (4Ah): Yellow solid (0.70 g, 70%),
m.p. 240–242°C (EtOH-dioxan). IR: νmax 3386, 1701 cm-1. NMR:
δH 1.30 (t, J = 7 Hz, 3H, CH3), 2.45 (s, 3H, CH3), 4.27 (q, J = 7 Hz,
2H, CH2), 7.26–7.41 (m, 5H, ArH), 7.79 (d, J = 7 Hz, 2H, ArH), 7.88
(d, J = 7 Hz, 2H, ArH), 8.18 (s,1H, ArH), 10.40 (s, 1H, NH). MS: m/z
(%) 406 (M+ + 1, 20), 405 (M+, 76), 189 (11), 187 (100), 174 (37),
149 (74), 121 (39), 103 (82), 91 (29), 77 (19), 73 (44). Anal. Calcd.
for C21H19N5O2S (405.48): C, 62.21; H, 4.72; N, 17.27. Found: C,
62.01; H, 4.55; N, 17.10%.
1H, ArH), 10.89 (s, 1H, NH). MS: m/z (%) 441(M+ + 1, 2), 440 (M+,
8), 186 (20), 122 (12), 116 (19), 105 (100), 103 (33), 91 (15), 76 (34).
Anal. Calcd. for C23H16N6O2S (440.49): C, 62.72; H, 3.66; N, 19.08.
Found: C, 62.97; H, 3.68; N, 19.20%.
2-[(4-Ethoxycarbonylphenyl)hydrazono]-3,7-diphenyl-2H-
imidazo[2,1-b][1,3,4]-thiadiazine (4Bh): Orange solid (0.81 g,
69%), m.p. 180°C (EtOH-dioxan). IR: νmax 3155, 1708 cm-1. NMR:
δH 1.29 (t, J = 7 Hz, 3H, CH3), 4.25 (q, J = 7 Hz, 2H, CH2), 7.26–7.85
(m, 14H, ArH), 8.31 (s, 1H, ArH), 10.57 (s, 1H, NH). MS: m/z (%)
468 (M+ + 1, 9), 467 (M+, 27), 439 (23), 295 (5), 291 (25), 205 (6),
187 (88), 174 (17), 161 (11), 150 (12), 137 (35), 121 (25), 116 (80),
103 (100), 77 (99), 74 (10). Anal. Calcd. for C26H21N5O2S (467.55):
C, 66.79; H, 4.53; N, 14.98. Found: C, 66.64; H, 4.30; N, 14.90%.
2-[(4-Acetylphenyl)hydrazono]-3,7-diphenyl-2H-imidazo[2,1-b]
[1,3,4]thiadiazine (4Bi): Yellow solid (0.76 g, 70%), m.p. 224°C
(EtOH-dioxan). IR: νmax 3220, 1662 cm-1. 1H NMR (DMSO-d6)
δ 2.47 (s, 3H, COCH3), 7.13 (d, J = 8 Hz, 2H, ArH), 7.25-7.86 (m,
10H, ArH), 7.77 (d, J = 8 Hz, 2H, ArH), 8.32 (s, 1H, ArH), 10.59
(s, 1H, NH). MS: m/z (%) 439 (M+ + 2, 6), 438 (M+ + 1, 17), 437
(M+, 53), 409 (12), 290 (24), 245 (19), 244 (32), 211 (12), 187 (100),
173 (21), 147 (29), 129 (13), 119 (61), 116 (56), 105 (33), 103 (86),
91 (37), 77 (67). Anal. Calcd. for C25H19N5OS (437.53): C, 68.63;
H, 4.38; N, 16.01. Found: C, 69.00; H, 4.70; N, 16.40%.
2-[(4-Cyanophenyl)hydrazono]-3,7-diphenyl-2H-imidazo[2,1-b]
[1,3,4]thiadiazine (4Bj): Orange solid (0.77 g, 73%), m.p. 272°C
(dioxan). IR: νmax 3236, 2221 cm-1. NMR: δH 7.15 (d, J = 7 Hz, 2H,
ArH), 7.28–7.76 (m, 10H, ArH), 7.83 (d, J = 7 Hz, 2H, ArH), 8.33 (s,
1H, ArH), 10.65 (s, 1H, NH). MS: m/z (%) 422 (M+ + 2, 6), 421 (M+
+ 1, 18), 420 (M+, 62), 290 (22), 244 (27), 187 (100), 173 (21), 146
(17), 117 (32), 115 (52), 105 (28), 103 (85), 91 (35), 77 (52). Anal.
Calcd. for C24H16N6S (420.50): C, 68.55; H, 3.84; N, 19.99. Found:
C, 68.45; H, 4.12; N, 19.81%.
2-[(4-Acetylphenyl)hydrazono]-3-methyl-7-phenyl-2H-
imidazo[2,1-b][1,3,4]thiadiazine (4Ai): Dark red solid (0.62 g, 66%),
m.p. 268–269°C (EtOH). IR: νmax 3244, 1658 cm-1. NMR: δH 2.46
(s, 3H, CH3), 2.50 (s, 3H, COCH3), 7.26–7.43 (m, 5H, ArH), 7.79 (d,
J = 8 Hz, 2H, ArH), 7.91 (d, J = 8 Hz, 2H, ArH), 8.2 (s, 1H, ArH), 10.40
(s, 1H, NH). MS: m/z (%) 377 (M+ + 2, 10), 376 (M+ + 1, 29), 375
(M+, 100), 256 (11), 228 (15), 187 (61), 183 (17), 174 (18), 147 (14),
119 (42), 103 (31), 77 (15). Anal. Calcd. for C20H17N5OS (375.46): C,
63.98; H, 4.56; N, 18.65. Found: C, 64.21; H, 4.32; N, 18.75%.
2-[(4-Cyanophenylhydrazono]-3-methyl-7-phenyl-2H-
imidazo[2,1-b][1,3,4]thiadiazine (4Aj): Yellow solid (0.63 g,
1
70%), m.p. 260–262°C (EtOH). IR: νmax 3386, 2218 cm-1. H NMR
(DMSO-d6) δ 2.44 (s, 3H, CH3), 7.23–7.44 (m, 5H, ArH), 7.71 (d,
J = 8 Hz, 2H, ArH),, 7.78 (d, J = 8 Hz, 2H, ArH), 8.19 (s, 1H, ArH),
10.46 (s, 1H, NH). MS: m/z (%) 360 (M+ + 2, 7), 359 (M+ + 1, 24),
358 (M+, 100), 187 (65), 177 (26), 147 (18), 142 (12), 116 (37), 103
(67), 90 (39), 77 (10). Anal. Calcd. for C19H14N6S (358.43): C, 63.67;
H, 3.94; N, 23.45. Found: C, 63.54; H, 3.65; N, 23.20%.
3,7-Diphenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one2-(4-methoxy-
phenyl)hydrazone (4Ba): Dark red solid, (Yield 0.64 g, 60%),
m.p.108–110°C (EtOH). IR: νmax 3140 cm-1. NMR: δH 3.68 (s, 3H,
OCH3), 6.82 (d, J = 9 Hz, 2H, ArH), 7.02 (d, J = 9 Hz, 2H, ArH),
7.27–7.85 (m, 10H, ArH), 8.27 (s, 1H, ArH), 10.08 (s, 1H, NH).
MS: m/z (%) 427 (M+ + 2, 16), 426 (M+ + 1, 20), 425 (M+, 73), 365
(11), 290 (28), 268 (4), 236 (3), 213 (6), 187 (45), 160 (7), 147 (6),
135 (43), 122 (73), 107 (100), 77 (35), 76 (13). Anal. Calcd. for
C24H19N5OS (425.52): C, 67.75; H, 4.50; N, 16.46. Found: C, 67.42;
H, 4.23; N, 16.32%.
Cyclisation of the open-chain intermediates 3Bc and 3Cd
A solution of 3Bc or 3Cd (0.0025 mole) in glacial acetic acid
(30 ml) was refluxed for 5 hours, then poured onto ice with stirring.
The solid that precipitated was filtered off, dried and crystallised from
the ethanol to give the respective 4Bc or 4Cd.
3,7-Diphenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one 2-(4-methyl-
phenyl)hydrazone (4Bb): Dark red solid (0.66 g, 65%), m.p. 110–
112°C (EtOH). IR: νmax 3218 cm-1. NMR: δH 2.21 (s, 3H, CH3), 6.97
(d, J = 9 Hz, 2H, ArH), 7.02 (d, J = 9 Hz, 2H, ArH), 7.28–7.85 (m,
10H, ArH), 8.28 (s, 1H, ArH), 10.13 (s, 1H, NH). MS: m/z (%) 411
(M+ + 2, 8), 410 (M+ + 1, 21), 409 (M+, 58), 290 (19), 245 (11),
244 (21), 187 (60), 137 (6), 119 (20), 116 (27), 103 (35), 91 (100),
77 (25). Anal. Calcd. for C24H19N5S (409.52): C, 70.39; H, 4.68; N,
17.10. Found: C, 70.34; H, 4.52; N, 17.40%.
3,7-Diphenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one 2-(4-chloro-
phenyl)hydrazone (4Bd): Yellow solid (0.77 g, 72%), m.p.158–160°C
(EtOH). IR: νmax 3417 cm-1. NMR: δH 7.06–7.55 (m, 10H, ArH), 7.74
(d, J = 9 Hz, 2H, ArH), 7.82 (d, J = 9 Hz, 2H, ArH), 8.30 (s, 1H,
ArH), 10.33 (s, 1H, NH); δC 113.7, 115.3, 118.1, 122.5, 123.5, 125.3,
125.9, 126.1, 126.7, 127.0, 127.7, 128.1, 130.7, 132.8, 137.5, 140.9,
148.5. MS: m/z (%) 432 (M+ + 3, 13) 431 (M+ + 2, 39), 430 (M+ +
1, 33), 429 (M+, 100), 290 (46), 244 (27), 187 (96), 173 (16), 139
(16), 116 (26), 111 (30), 103 (41), 89 (12), 77 (15). Anal. Calcd. for
C23H16ClN5S (429.93): C, 64.26; H, 3.75; N, 16.29. Found: C, 64.42;
H, 3.58; N, 16.13%.
3,7-Diphenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one 2-phenyl-
hydrazone (4Bc): Yellow solid (0.68 g, 69%), m.p.100°C (EtOH).
IR: νmax 3417 cm-1. NMR: δH 6.48-8.14 (m, 15H, ArH), 8.17 (s, 1H,
ArH), 10.00 (s, 1H, NH). MS: m/z (%) 397 (M+ + 2, 6), 396 (M+
+ 1, 24), 395 (M+, 71), 290 (19), 244 (20), 187 (63), 173 (16), 147
(12), 116 (27), 105 (24),103 (48), 77 (100), 76 (16). Anal. Calcd. for
C23H17N5S (395.49): C, 69.85; H, 4.33; N, 17.71. Found: C, 69.62;
H, 4.35; N, 17.35%.
7-Phenyl-3-(2-thienyl)-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one
2-(4-chlorophenyl)hydrazone (4Cd): Dark red solid (0.65 g, 60%),
m.p.140°C (EtOH). IR: νmax 3150 cm-1. NMR: δH 7.25–7.38 (m, 8H,
ArH), 7.41 (d, J = 7 Hz, 2H, ArH), 7.83 (d, J = 7 Hz, 2H, ArH), 8.32
(s, 1H, ArH), 10.39 (s, 1H, NH). MS: m/z (%) 439 (M+ + 3, 4), 438
(M+ + 2, 5), 437 (M+ + 1, 26), 436 (M+, 17), 269 (13), 250 (15), 178
(100), 174 (11), 139 (23), 116 (49), 113 (11), 103 (37), 99 (21), 89
(18), 77 (16), 76 (18). Anal. Calcd. for C21H14ClN5S2 (435.96): C,
57.86; H, 3.24; N, 16.06. Found: C, 57.52; H, 3.10; N, 15.94%.
Synthesis of 2-acetyl-3-methyl-7-phenyl-2H-imidazo-[2,1-b][1,3,4]
thiadiazine (8)
3,7-Diphenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one 2-(3-chloro-
phenyl)hydrazone (4Be): Dark red solid (0.73 g, 68%), m.p.120–
122°C (EtOH). IR: νmax 3358 cm-1. NMR: δH 6.92-7.85 (m, 14H,
ArH), 8.32 (s, 1H, ArH), 10.38 (s, 1H, NH). MS: m/z (%) 432 (M+ +
3, 12), 431 (M+ + 2, 39), 430 (M+ + 1, 31), 429 (M+, 74), 290 (31),
272 (19), 244 (22), 187 (100), 173 (16), 147 (12), 139 (11), 116 (28),
111 (25), 103 (42), 89 (15), 77 (19). Anal. Calcd. for C23H16ClN5S
(429.93): C, 64.26; H, 3.75; N, 16.29. Found: C, 64.09; H, 3.58; N,
16.14%.
3,7-Diphenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one 2-(3-nitro-
phenyl)hydrazone (4Bf): Dark red solid (0.72 g, 65%), m.p.160°C
(EtOH). IR: νmax 3293 cm-1. NMR: δH 7.28–7.91 (m, 14H, ArH),
8.33 (s, 1H, ArH), 10.62 (s, 1H, NH). MS: m/z (%) 442 (M+ + 2, 10),
441(M+ + 1, 35), 440 (M+, 100), 290 (28), 277 (18), 245 (27),
174 (15), 118 (32), 103 (44), 89 (12), 77 (21). Anal. Calcd. for
C23H16N6O2S (440.49): C, 62.72; H, 3.66; N, 19.08. Found: C, 62.53;
H, 3.80; N, 19.00%.
To a solution of 2 (0.96 g, 5 mmole) in ethanol was added an aqueous
solution of potassium hydroxide (0.4 ml, 75%) and the mixture was
warmed for 10 min. at 80°C and then cooled. To the resulting clear
solution was added 3-chloro-2,4-pentanedione (0.6 ml, 5 mmol)
dropwise with stirring. After the addition was complete the mixture
was stirred for a further 18 h at room temperature. Petroleum ether
was added and the mixture was left in a refrigerator over night.
A solid which separated was filtered off and crystallised from
petroleum ether to give pure 8 as a pale yellow solid (0.75 g, 55%),
m.p.128–130°C. IR: νmax 1712 cm-1. NMR: δH 2.26 (s, 3H, CH3),
2.33 (s, 3H, COCH3), 4.99 (s, 1H, CH), 7.35–7.75 (m, 5H, ArH), 8.08
(s,1H, ArH). MS: m/z (%) 272 (M+ + 1, 10), 271 (M+, 49), 228 (100),
201 (34), 188 (77), 116 (97), 102 (93), 89 (56), 76 (76). Anal. Calcd.
for C14H13N3OS (271): C, 61.99; H, 4.80; N, 15.50. Found: C, 62.10;
H, 4.63; N, 15.32%.
Alternative synthesis of 4Ac
3,7-Diphenyl-2H-imidazo[2,1-b][1,3,4]thiadiazin-2-one 2-(4-nitro-
phenyl)hydrazone (4Bg): Orange solid (0.74 g, 67%), m.p. 250–
252°C (EtOH). IR: νmax 3375 cm-1. NMR: δH 7.18 (d, J = 9 Hz, 2H,
ArH), 7.26–7.85 (m, 10H, ArH), 8.12 (d, J = 9 Hz, 2H, ArH), 8.34 (s,
To a solution of 8 (0.68 g, 2.5 mmol) in ethanol (20 ml) was added
sodium acetate trihydrate (0.34 g, 2.5 mmol) and the mixture was
cooled to 0–5°C in an ice-bath. A solution of benzenediazonium
chloride, prepared as usual by diazotising (2.5 mmol) in hydrochloric
PAPER: 07/4686

JOURNAL OF CHEMICAL RESEARCH 2007 483
acid (6 M, 1.5 ml) with sodium nitrite (1M, 2.5 ml) was added
dropwise over a period of 20 min. The whole was then left in
a refrigerator overnight. The precipitated solid was collected,
washed with water and finally crystallised from ethanol to give 4Ac
The isolated product 4Ac was found to be identical with that obtained
above from the reaction of 2 with 1Ac.
75.38 The pKa values obtained were reproducible to within ± 0.02 pKa
unit. The results are recorded in Table 2.
Received 6 June 2007; accepted 16 August 2007
Paper 07/4686 doi: 10.3184/030823407X237885
References
Synthesis of 3,7-diphenyl-imidazo[2,1-b][1,3,4]thiadiazine (6)
Triethylamine(0.35ml, 2.5mmole)wasaddedtoamixtureof1-amino-
4-phenylimidazole-2-thiol (2) (0.48 g, 2.5 mmole) and phenacyl
bromide (0.50 g, 2.5 mmole) in ethanol (20 ml). The whole was
refluxed for 5 hours. Excess of solvent was evaporated off and the
residue was cooled and poured into cold water. The precipitated
solid was filtered off and recrystallised from methanol to give 3,7-
diphenylimidazo[2,1-b][1,3,4]thiadiazine (6) as a yellow solid (0.44 g,
60%), m.p.146°C (MeOH) (Lit.35b m.p. 140°C). NMR: δH 4.40 (s,
2H, CH2), 7.73-7.99 (m, 10H, ArH), 8.24 (s,1H, ArH). MS: m/z (%)
293 (M+ + 2, 5), 292 (M+ + 1, 17), 291 (M+, 82), 188 (77), 186 (64),
160 (18), 149 (11), 130 (11), 117 (26), 116 (45), 103 (69), 89 (22),
77 (100). Anal. Calcd. for C17H13N3S (291.38): C, 70.08; H, 4.50; N,
14.42. Found: C, 70.40; H, 4.23; N, 14.52%.
1
2
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19 R.R. Phillip, Organic Reactions, Adams, R., ed., John Wiley & Sons,
New York, 1959, Vol. 10, Chap. pp. 143.
Preparation of authentic samples of 4Bb and 4Bc
A solution of p-methylbenzenediazonium chloride, prepared by
diazotising p-toluidine (2.5 mmol) in hydrochloric acid (6M, 1.5 ml)
with sodium nitrite (1M, 2.5 ml) was added dropwise over a period of
20 min to a cold stirred solution of 6 (0.73 g, 2.5 mmol) in pyridine
(10 ml), cooling in an ice bath. The whole was then left in a refrigerator
overnight. The solution was poured onto ice and hydrochloric acid.
The precipitated solid was collected, washed with water and finally
crystallised from ethanol to give 4Bb. Repetition using diazotised
aniline in lieu of the diazotised p-toluidine gave 4Bc. The isolated
products 4Bb and 4Bc were found to be identical with those obtained
via cyclisation of 3Bc as described above.
20 A.S. Shawali, N.M.S. Harb and K.O. Badahdah, J. Heterocyclic Chem.,
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21 R. Jones, A.J. Ryan, S. Sternhell and S.E. Wright, Tetrahedron, 1963, 19,
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pKa determination of compounds 4Aa–j and 4Ba–j
The acid dissociation constants of the compound series 4A and 4B
were determined potentiometrically in 80% dioxan–water mixture
at 25 + 0.1°C and ionic strength (KNO3) of 0.1. A Meetrohm
686 titroprocessor equipped with 665 Dosimat was employed.
The electrode and the titroprocessor were calibrated with standard
Beckman buffer solutions of pH 4.01 and 7.00. The pH meter reading
B recorded in dioxan–water solution was converted to hydrogen ion
concentration [H+] by means of the widely relation of van Uitert and
Hass36, 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. A carbonate-free sodium hydroxide titrant was
prepared and standardised against potassium hydrogen phthalate
solution.
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:
32 A.S. Shawali and A.O. Abdelhamid, Bull. Chem. Soc. Jpn., 1976, 49, 321.
33 A.S. Shawali, M.H. Abdel Kader and M.A. Eltalbawy, Tetrahedron, 2002,
58, 2875.
34 D.B. Sharp, J. Am. Chem. Soc., 1949, 71, 1106.
35 (a) A.M. Farag and M.S. Algharib, Org. Prep. Proc. Int., 1988, 20, 521;
(b) T. Pyl, F. Waschk and H. Beyer, Liebigs Ann. Chem., 1963, 663, 113.
36 L.G. Van Uitert and C.G. Haas, J. Am. Chem. Soc. 1953, 75, 451.
37 A. Albert and E.P. Serjeant, The Determination of Ionisation Constants,
Chapman and Hall Ltd., London, 1971, pp. 9 – 39.
38 P. Gans, A. Sabatini and A. Vacca, Inorg. Chim. Acta, 1976, 18, 237.
pKa = pHi – log V/(V – V)
i
e
i
where pHi is the corrected pH value of the solution when the volume
of the added titrant is V and V is the volume of the titrant at the
i
equivalence point as previously edescribed.37 The calculations of the
pKa values were carried out using the computer program MINIQUAD-
PAPER: 07/4686