Synthesis and reactions of 3-methylthiazolo[3,2-a]benzimidazole-2- carboxylic acid hydrazide: Synthesis of some new pyrazole, 1,3-thiazoline, 1,2,4-triazole and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives pendant to thiazolo[3,2-a]benzimidazole moiety

Article abstract of DOI:10.1002/jccs.200700222

The reaction of 3-methylthiazolo[3,2-a]benzimidazole-2-carboxylic acid ethyl ester (1) with hydrazine hydrate gives the hydrazide 2 which reacts with CS₂/KOH to afford the potassiumsalt 3. Treatment of 3 with l-aryl-2-bromoethanones 4a,b afforded the 1,3-thiazoline derivatives 6a,b, respectively, while the reaction of 3 with hydrazine hydrate afforded 1,2,4-triazole-3-thione derivative 9. The reaction of 9 with l-aryl-2-bromoethanones 4a,b and with hydrazonyl chlorides 11a,b gave the 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives 10a,b and 12a,b, respectively. Treatment of hydrazide 2 with phenyl isothiocyanate in refluxing benzene gave the thiosemicarbazide derivative 16. The latter reaction gave 1,3,4-oxadiazole derivative 17 when benzene was replaced by DMF. Cyclization of the thiosemicarbazide derivative 16 with NaOH resulted in the formation of the 1,2,4-triazole-3-thione derivative 18.

Full text of DOI:10.1002/jccs.200700222

Journal of the Chinese Chemical Society, 2007, 54, 1573-1582
1573
Synthesis and Reactions of
3-Methylthiazolo[3,2-a]benzimidazole-2-carboxylic Acid Hydrazide:
Synthesis of Some New Pyrazole, 1,3-Thiazoline, 1,2,4-Triazole and
1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazine Derivatives Pendant to
Thiazolo[3,2-a]benzimidazole Moiety
Hatem A. Abdel-Aziz,a,* Nehal A. Hamdy,a Ahmad M. Faragb and Issa M. I. Fakhra
aApplied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt
bDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
The reaction of 3-methylthiazolo[3,2-a]benzimidazole-2-carboxylic acid ethyl ester (1) with hydra-
zine hydrate gives the hydrazide 2 which reacts with CS2/KOH to afford the potassium salt 3. Treatment of
3 with l-aryl-2-bromoethanones 4a,b afforded the 1,3-thiazoline derivatives 6a,b, respectively, while the
reaction of 3 with hydrazine hydrate afforded 1,2,4-triazole-3-thione derivative 9. The reaction of 9 with
l-aryl-2-bromoethanones 4a,b and with hydrazonyl chlorides 11a,b gave the 1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazine derivatives 10a,b and 12a,b, respectively. Treatment of hydrazide 2 with phenyl isothiocya-
nate in refluxing benzene gave the thiosemicarbazide derivative 16. The latter reaction gave 1,3,4-
oxadiazole derivative 17 when benzene was replaced by DMF. Cyclization of the thiosemicarbazide de-
rivative 16 with NaOH resulted in the formation of the 1,2,4-triazole-3-thione derivative 18.
Keywords: Thiazolo[3,2-a]benzimidazole; Pyrazoles; 1,3,4-Oxadiazoles; 1,3-Thiazolidines;
1,2,4-Triazoles; 1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazines; Hydrazonyl chlorides.
INTRODUCTION
RESULTS AND DISCUSSION
The utility of hydrazides as key intermediates for the
synthesis of several series of heterocyclic compounds and
the broad spectrum of biological activities of their cyclized
products have been reported1-4 and aroused our interest in
exploring the utility of hydrazides as versatile precursors
for the synthesis of a variety of substituted heterocycles,5-9
in addition to the interesting biological activities of thi-
azolo[3,2-a]benzimidazole derivatives such as antibacte-
rial,10,11 anti-inflammatory,12 antiulcer,13,14 antiviral15,16
and immunomodulatory17,18 activities. Also, some thi-
azolo[3,2-a]benzimidazole derivatives are used for treat-
ment of cancer,19 neurogenic pain20 and bone diseases.21
The above observations prompted us to prepare a new se-
ries of heterocycles incorporating thiazolo[3,2-a]benzimi-
dazole moiety starting from the unreported 3-methylthi-
azolo[3,2-a]benzimidazole-2-carboxylic acid hydrazide
(2) for biological screening.
The reaction of 3-methylthiazolo[3,2-a]benzimida-
zole-2-carboxylic acid ethyl ester (1) with hydrazine hy-
drate in refluxing ethanol gave the hydrazide 2. Its IR spec-
trum showed the appearance of three absorption bands due
to NH2 and NH functions in addition to the carbonyl ab-
sorption band. Its mass spectrum showed a peak corre-
sponding to its molecular ion at m/z 246 (M+) (Scheme I).
The hydrazide 2 reacts with carbon disulfide in ethanol in
the presence of potassium hydroxide to give the potassium
salt 3, which reacts with l-aryl-2-bromoethanones 4a and
4b to give the 1,3-thiazolidine derivatives 6a and 6b, re-
1
spectively. Their structures were confirmed by IR, H
NMR and mass spectra. For example, The 1H NMR spec-
trum of 6a showed a singlet signal (D2O-exchangeable) at d
10.97 due to NH function, in addition to a singlet signal of
thiazoline moiety at d 5.08, whereas its mass spectrum
showed a peak corresponding to its molecular ion at m/z
* Corresponding author. E-mail: hatem_741@yahoo.com

1574 J. Chin. Chem. Soc., Vol. 54, No. 6, 2007
Abdel-Aziz et al.
Scheme I
Me
COOEt
N
N
S
1
NH2NH2.H2O
Me
CONHNH2
N
N
S
2
CS2 / KOH
RCHO
O
Me
- +
CONHNHCSSK
Me
R
N
N
H
N
N
N
N
S
S
3
O
7a-d
Br
Ar
4a-b
7a-d
R
O
O
Me
a
H
N
S
N
H
Ar
N
N
S
S
S
b
5
H
H
H
OH
- H2O
OH
OH
Ar
CH2OH
O
c
ribosyl
S
Me
N
N
H
HO
H
S
N
N
HO
H
H
S
OH
OH
H
CH2OH
6a-b
mannosyl
d
a, Ar = Ph
b, Ar = 4-BrC6H4

Heterocycles Pendant to Thiazolo[3,2-a]benzimidazole
J. Chin. Chem. Soc., Vol. 54, No. 6, 2007 1575
422 (M+).
corresponding to its molecular ion at m/z 288 (M+) [cf.
Experimental part].
On the other hand, treatment of compound 2 with the
appropriate aldehydes in refluxing ethanol yielded the cor-
responding hydrazones 7a-d (Scheme I). The structures of
the latter products were established on the basis of the ap-
pearance of an NH absorption band in the region of 3236-
3138 cm-1 and a band of carbonyl function in the region of
1660-1639 cm-1 in their IR spectra, whereas their 1H NMR
spectra revealed the appearance of a signal due to the
-CH=N- proton in the region of 8.05-8.32 ppm and a D2O-
exchangeable signal (NH) in the region of 11.65-11.96
ppm [cf. Experimental part].
Moreover, treatment of the potassium salt 3 with hy-
drazine hydrate in a mixture of ethanol and water afforded
4-amino-5-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-
4H-1,2,4-triazole-3-thione (9). Its 1H NMR spectrum re-
vealed two signals (D2O-exchangeable) at d 5.85 (NH2)
and d 8.75 (NH), whereas its mass spectrum showed a peak
corresponding to its molecular ion at m/z 302 (M+) (Scheme
II). The structure of compound 9 was further confirmed by
an independent synthesis outlined in Scheme II. Thus,
treatment of 1,3,4-oxadiazole-2-thione derivative 8 with
hydrazine hydrate in refluxing ethanol resulted in the for-
mation of a product identical to compound 9 that was ob-
tained above.
Heating of the potassium salt 3 in an aqueous solution
of potassium hydroxide afforded a product identified as
5-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-1,3,4-oxad
iazole-2-thione (8) on the basis of its spectral data (Scheme
II). Its IR spectrum revealed an absorption band at 3218
cm-1 due to NH function. Its mass spectrum showed a peak
On the other hand, treatment of compound 9 with l-
aryl-2-bromoethanone 4a and 4b in refluxing ethanol
yielded the 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine deriva-
Scheme II
H
N
N
Me
- +
CONHNHCSSK
Me
S
O
N
N
S
KOH
S
N
N
8
3
NH2NH2.H2O
NH2NH2.H2O
Cl
H
N
H
N
O
H C
3
N
N
Ar
Br
Me
S
Ar
11a-b
O
4a-b
N
N
N
NH2
S
9
N
N
N
N
N
N
Me
S
Me
HN
Ar
S
N
N
N
N
N
N
N
S
S
Me
Ar
12a-b
a, Ar =Ph
b, Ar = 4-ClC6H4
10a-b
a, Ar = Ph
b, Ar = 4-BrC6H4

1576 J. Chin. Chem. Soc., Vol. 54, No. 6, 2007
Abdel-Aziz et al.
tives 10a and 10b, respectively (Scheme II). The latter
products were established on the basis of their spectral
data: For example, the lack of amino bands in their IR spec-
tra and the appearance of the characteristic signals due to
methylene protons of thiadiazine moiety in the region of
4.54-4.57 ppm in their 1H NMR spectra [cf. Experimental
part].
(Scheme III), while the reaction of the hydrazide 2 with
ethoxymethylene-malononitrile (14a) or with ethoxymeth-
ylene-ethyl cyanoacetate (14b) in ethanol afforded, in each
case, a single product. The reaction products were identi-
fied as 5-amino-1-(3-methylthiazolo[3,2-a]benzimidazol-
2-oyl)-1H-pyrazole-4-carbonitrile (15a) and 5-amino-1-
(3-methylthiazolo[3,2-a]benzimidazol-2-oyl)-1H-pyra-
zole-4-carboxylic acid ethyl ester (15b), respectively
(Scheme III). The structures of 15a,b were established on
the basis of their spectral data. For example, the IR spec-
trum of 15a revealed a band of the amino group at 3425,
3283 cm-1 in addition to absorption bands at 2226 and 1675
cm-1 corresponding to nitrile and carbonyl functions, re-
spectively, while its 1H NMR showed a broad singlet signal
(D2O-exchangeable) at d 8.16 due to the amino group in ad-
dition to a multiplet at d 7.31-8.16 due to aromatic protons.
Its mass spectrum showed a peak corresponding to its mo-
lecular ion at m/z 322 [cf. Experimental part].
Similarly, the treatment of 9 with hydrazonyl halides
11a and 11b in ethanol afforded the 1,2,4-triazolo[3,4-
b]-1,3,4-thiadiazine derivatives 12a and 12b, respectively,
on the basis of their spectral data. Their 1H NMR spectra
showed the D2O-exchangeable signal corresponding to the
NH of hydrazone function in the region of 11.68-11.85
ppm and their mass spectra showed, in each case, a peak
corresponding to the molecular ion (Scheme II).
Next, the reaction of hydrazide 2 with pentan-2,4-
dione in refluxing ethanol afforded 2-(3,5-dimethyl-pyr-
azol-1-oyl)-3-methylthiazolo[3,2-a]benzimidazole (13)
Scheme III
Me
O
NH2
O
Me
H3C
N
R
N
N
N
S
N
N
S
Me
N
13
R
N
15a-b
O
O
EtO
CN
a, R = CN
b, R = COOEt
14a-b
Me
Me
Me
CONHNH2
Me
CONHNHCSNHPh
N
N
S
PhNCS
benzene
N
N
S
16
2
KI / I2
DMF PhNCS
NaOH
H
N
N
N
N
Me
Me
NHPh
S
O
N
N
N
N
Ph
S
S
N
17
18

Heterocycles Pendant to Thiazolo[3,2-a]benzimidazole
J. Chin. Chem. Soc., Vol. 54, No. 6, 2007 1577
Treatment of the hydrazide 2 with phenyl isothio-
cyanate in refluxing benzene gave the thiosemicarbazide
derivative 16 (Scheme III). The IR spectrum of compound
16 showed three bands due to three NH functions in addi-
ods.
3-Methylthiazolo[3,2-a]benzimidazole-2-carboxylic
acid hydrazide (2)
1
tion to a carbonyl absorption band at 1650 cm-1. Its H
A mixture of the ester 1 (2.6 g, 10 mmol) and hydra-
zine hydrate (0.6 mL, 99%) in 50 mL of absolute ethanol
was refluxed for 5 h. The separated white solid was filtered
off and recrystallized from EtOH/DMF to give the title
compound 2 as white powder in 76% yield, mp. 235-237
°C; IR (KBr) nmax/cm-1 3310, 3222, 3145 (NH, NH2), 1631
(C=O), 1588 (C=N); 1H NMR (DMSO-d6) d 2.99 (s, 3H,
CH3), 7.26-8.04 (m, 4H, ArH), 9.02 (br. s, 2H, NH2, D2O-
exchangeable), 9.85 (br. s, 1H, NH, D2O-exchangeable);
MS m/z (%) 247 (M++1, 99%), 246 (M+, 100%), 187
(64.6%), 115 (82.0%), 51 (91.4%). For C11H10N4OS
(246.29). Calcd.: C, 53.64; H, 4.09; N, 22.75; S, 13.02%.
Found: C, 53.96; H, 4.22; N, 22.40; S, 13.15%.
NMR spectrum revealed three signals (D2O-exchangeable)
at d 8.86, 9.98 and 10.43 assigned to three NH protons. In
addition, its mass spectrum showed a peak corresponding
to its molecular ion at m/z 381 (M+).
Interestingly, when the latter reaction of the hydra-
zide 2 with phenyl isothiocyanate was carried out in re-
fluxing DMF instead of benzene, the reaction gave 2-(3-
methylthiazolo[3,2-a]benzimidazol-2-yl)-5-phenylamino-
1,3,4-oxadiazole (17) (Scheme III). The structure of com-
pound 17 was confirmed on the basis of its elemental analy-
sis and spectral data; its IR spectrum revealed the presence
of one absorption band due to NH function and the lack of
carbonyl absorptions. Its mass spectrum showed a peak
corresponding to its molecular ion at m/z 347 (M+). On the
other hand, the structure of compound 17 was further con-
firmed by an independent synthesis by treatment of the
thiosemicarbazide derivative 16 with potassium iodide and
iodine in the presence of sodium hydroxide (Scheme III).
Furthermore, the intramolecular cyclization of thio-
semicarbazide derivative 16 takes place upon heating with
sodium hydroxide to produce the 1,2,4-triazole derivative
18 (Scheme III). Its mass spectrum revealed a peak corre-
sponding to the molecular ion at m/z 363 (M+) and its IR
was free of NH and carbonyl functions (Scheme III).
Potassium 3-(3-methylthiazolo[3,2-a]benzimidazol-2-
yl)dithiocarbazate (3)
To a solution of hydrazide 2 (2.5 g, 10 mmol) in etha-
nol (100 mL), a solution of potassium hydroxide [0.84 g,
15 mmol; in water (10 mL)] and carbon disulfide (3 mL)
were added. The reaction mixture was heated under reflux
for 3 h, then left to cool. The resulting solid was collected
by filtration, washed with ether and dried to give the potas-
sium salt 3 as a pale brown solid in 63% yield which was
used directly in the next reactions without further purifica-
tion, mp. >300 °C; IR (KBr) nmax/cm-1 3340, 3202 (2 NH),
1658 (C=O), 1624 (C=N).
EXPERIMENTAL
Reaction of potassium salt (3) with a-haloketones 4a,b
General procedure
To a solution of the potassium salt 3 (1.8 g, 5 mmol) in
ethanol (20 mL), the appropriate l-phenyl-2-bromoeth-
anone (4a) or l-(4-bromophenyl)-2-bromoethanone (4b) (5
mmol) was added. The reaction mixture was heated under
reflux for 2 h. The precipitated solid was collected by filtra-
tion, washed with ethanol and dried. Crystallization from
EtOH/DMF afforded compounds 6a,b, respectively.
Melting points were measured with a Gallenkamp ap-
paratus and are uncorrected. IR spectra were recorded on a
Shimadzu FT-IR 8101 PC infrared spectrophotometer. The
1H NMR spectra were determined in DMSO-d6 at 300 MHz
on a Varian Mercury VX 300 NMR spectrometer using
TMS as an internal standard. Mass spectra were measured
on a GCMS-QP1000 EX spectrometer at 70 eV. Elemental
analyses were carried out at the Microanalytical Center of
Cairo University. 3-Methylthiazolo[3,2-a]benzimidazole-
2-carboxylic acid ethyl ester (1)22 and hydrazonyl chlo-
rides 11a,b,23 were prepared according to reported meth-
3-Methylthiazolo[3,2-a]benzimidazole-2-carboxylic
acid (4-phenyl-2-thioxo-thiazol-3-yl)amide (6a)
White crystals, Yield 76%, mp. 185-187 °C; IR (KBr)

1578 J. Chin. Chem. Soc., Vol. 54, No. 6, 2007
Abdel-Aziz et al.
nmax/cm-1 3414 (NH), 1678 (C=O), 1616 (C=N); 1H NMR
(DMSO-d6) d 3.02 (s, 3H, CH3), 5.08 (s, 1H, thiazoline),
7.28 -8.06 (m, 9H, ArH), 10.97 (br. s, 1H, NH, D2O-ex-
changeable); MS m/z (%) 423 (M++1, 36.9%), 422 (M+,
54.2%), 239 (47.3%), 296 (35.8%), 185 (31.7%), 156
(100%), 77 (45.1%). For C20H14N4OS3 (422.55). Calcd.: C,
56.85; H, 3.34; N, 13.26; S, 22.76%. Found: C, 56.56; H,
3.12; N, 12.88; S, 22.94%.
3-Methylthiazolo[3,2-a]benzimidazole-2-carboxylic
acid [1-(thien-1-yl)methylidene] hydrazide (7b)
White solid, Yield 83%, mp. 279-81 °C (EtOH/DMF),
IR (KBr) nmax/cm-1 3181 (NH), 1660 (C=O), 1586 (C=N);
1H NMR (DMSO-d6) d 3.22 (s, 3H, CH3), 7.14-8.10 (m,
7H, 4 ArH and 3H, thiophene), 8.30 (s, 1H, -CH=N-),
11.96 (br. s, 1H, NH, D2O-exchangeable); MS m/z (%) 341
(M++1, 16.0%), 340 (M+, 43.5%), 261 (7.3%), 242
(74.1%), 162 (100%), 111 (82.3%), 65 (64.8%). For
C16H12N4OS2 (340.43). Calcd.: C, 56.45; H, 3.55; N, 16.46;
S, 18.84%. Found: C, 56.74; H, 3.68; N, 16.31; S, 18.82%.
3-Methylthiazolo[3,2-a]benzimidazole-2-carboxylic
acid [4-(4-bromophenyl)-2-thioxothiazol-3-yl]amide
(6b)
White crystals, Yield (78%), mp. 231-233 °C; IR
(KBr) nmax/cm-1 3406 (NH), 1670 (C=O), 1616 (C=N); 1H
NMR (DMSO-d6) d 3.07 (s, 3H, CH3), 5.14 (s, 1H, thiazoli-
dine), 7.34-8.09 (m, 8H, ArH), 10.55 (br. s, 1H, NH, D2O-
exchangeable); MS m/z (%) 505 (M++4, 6.4%), 503 (M++2,
3.3%), 501 (M+, 6.7%), 240 (31.6%), 167 (19.6%), 166
(22.0%), 156 (100%), 81 (82.5%). For C20H13BrN4OS3
(501.45). Calcd.: C, 47.91; H, 2.61; N, 11.17; S, 19.18%.
Found: C, 47.72; H, 2.46; N, 10.88; S, 19.34%.
N¢-D-Aldehydoribosyl-(3-methylthiazolo[3,2-a]benzimi-
dazol-2-yl)carbohydrazide (7c)
White solid, Yield 56%, mp. 158-160 °C (H2O); IR
(KBr) nmax/cm-1 3530-3085 (4OH, NH), 1639 (C=O), 1616
1
(C=N); H NMR (DMSO-d6) d 2.89 (s, 3H, CH3), 2.99-
3.27 (m, 3H, ribose), 3.40-3.58 (m, 2H, ribose), 4.35-5.29
(m, 4H, 4OH, D2O-exchangeable), 7.26-8.01 (m, 5H, ArH),
8.08 (s, 1H, -CH=N-), 11.65 (br. s, 1H, NH, D2O-ex-
changeable); MS m/z (%) 364 (M++2, 5.9%), 363 (M++1,
13.6%), 362 (M+, 8.5%), 189 (100%), 64 (19.4%). For
C16H18N4O4S (362.41). Calcd.: C, 53.03; H, 5.01; N, 15.46;
S, 8.85%. Found: C, 52.76; H, 5.25; N, 15.42; S, 8.64%.
Reaction of 3-methylthiazolo[3,2-a]benzimidazole-2-
carboxylic acid hydrazide (2) with aldehydes
General procedure
A mixture of the hydrazide 2 (2.5 g, 10 mmol) and the
appropriate aldehyde namely (Benzaldehyde, 2-Thiophen-
aldehyde, D-(+)-Ribose, D-(+)-Mannose) (10 mmol) in
ethanol (30 mL) was refluxed for 3 h (refluxing for 8 h in
case of 7c,d). The solid formed product was collected by
filtration, washed with ethanol (with H2O in case of 7c,d)
and dried. Recrystallization from the proper solvent to af-
ford the corresponding hydrazones 7a-d.
N¢-D-Aldehydomannosyl-(3-methylthiazolo[3,2-a]benz-
imidazol-2-yl)carbohydrazide (7d)
White solid, Yield 49%, mp. 200-203 °C (H2O); IR
(KBr) nmax/cm-1 3520-3060 (5OH, NH), 1656 (C=O), 1546
1
(C=N); H NMR (DMSO-d6) d 3.01 (s, 3H, CH3), 2.75-
3.22 (m, 3H, mannose), 3.34-3.60 (m, 3H, mannose), 4.09-
5.32 (m, 5H, 5OH, D2O-exchangeable), 7.18-8.00 (m, 5H,
ArH), 8.05 (s, 1H, -CH=N-), 11.88 (br. s, 1H, NH, D2O-ex-
changeable); MS m/z (%) 395 (M++3, 16.4%), 394 (M++2,
23.5%), 393 (M++1, 26.0%), 392 (M+, 100%), 116 (8.8%),
84 (9.2%). For C17H20N4O5S (392.44). Calcd.: C, 52.03; H,
5.14; N, 14.28; S, 8.17%. Found: C, 51.81; H, 5.42; N,
14.03; S, 8.05%.
3-Methylthiazolo[3,2-a]benzimidazole-2-carboxylic
acid (1-phenylmethylidene) hydrazide (7a)
White solid, Yield 68%, mp. 270-272 °C (EtOH/
DMF); IR (KBr) nmax/cm-1 3155 (NH), 1651 (C=O), 1616
(C=N); 1H NMR (DMSO-d6) d 3.11 (s, 3H, CH3), 7.22-8.04
(m, 9H, ArH), 8.32 (s, 1H, -CH=N-), 11.85 (br. s, 1H, NH,
D2O-exchangeable); MS m/z (%) 335 (M++1, 88.6%), 334
(M+, 100%), 241 (76.3%), 188 (61.8%), 125 (53.0%), 77
(39.5%). For C18H14N4OS (334.40). Calcd.: C, 64.65; H,
4.22; N, 16.75; S, 9.59%. Found: C, 64.76; H, 4.04; N,
16.98; S, 9.24%.
5-(3-Methylthiazolo[3,2-a]benzimidazol-2-yl)-1,3,4-
oxadiazole-2-thione (8)
To the potassium salt 3 (3.6 g, 10 mmol), a solution of
potassium hydroxide (1.14 g, 20 mmol) in 30 mL water was
added. The reaction mixture was heated under reflux for 2
h, then left to cool and poured into crushed ice and acidified

Heterocycles Pendant to Thiazolo[3,2-a]benzimidazole
J. Chin. Chem. Soc., Vol. 54, No. 6, 2007 1579
with dilute hydrochloric acid. The resulting solid was col-
lected by filtration, washed with water and crystallized
from EtOH/DMF to give compound 8 as a pale brown solid
in 66% yield, mp. 240-242 °C; IR (KBr) nmax/cm-1 3218
appropriate a-haloketones 4a,b (2 mmol) in ethanol (30
mL) was refluxed for 8 h. The formed precipitate was fil-
tered off, washed with ethanol and dried. Recrystallization
from EtOH/DMF gave compounds 10a,b, respectively.
1
(NH), 1616 (C=N); H NMR (DMSO-d6) d 3.07 (s, 3H,
CH3), 7.31-8.07 (m, 4H, ArH), 11.09 (br. s, 1H, NH, D2O-
exchangeable); MS m/z (%) 289 (M++1, 98.4%), 288 (M+,
100%), 242 (75.3%), 187 (49.1%), 151 (44.7%), 118
(62.4%). For C12H8N4OS2 (288.35). Calcd.: C, 49.99; H,
2.80; N, 19.43; S, 22.24%. Found: C, 50.23; H, 2.97; N,
19.68; S, 22.51%.
3-Methyl-2-(6-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazin-3-yl)thiazolo[3,2-a]benzimidazole (10a)
White solid, Yield 57%, mp. >300 °C; IR (KBr)
nmax/cm-1 1582 (C=N); 1H NMR (DMSO-d6) d 3.20 (s, 3H,
CH3), 4.54 (s, 2H, thiadiazine), 7.30-8.14 (m, 9H, ArH);
MS m/z (%) 405 (M++3, 28.3%), 404 (M++2, 33.0%), 403
(M++1, 26.4%), 402 (M+, 19.7%), 354 (72.5%), 303
(45.2%), 254 (66.4%), 189 (100%), 122 (84.6%), 77
(61.4%). For C20H14N6S2 (402.50). Calcd.: C, 59.68; H,
3.51; N, 20.88; S, 15.93%. Found.: C, 59.64; H, 3.34; N,
20.67; S, 15.56%.
4-Amino-5-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-
4H-1,2,4-triazole-3-thione (9)
Method A
To the potassium salt 3 (3.6 g, 10 mmol) in ethanol-
water mixture (1:1, 30 mL) hydrazine hydrate (12 mmol)
was added. The reaction mixture was heated under reflux
for 2 h, then left to cool and poured into crushed ice. The re-
action mixture was acidified with dilute hydrochloric acid.
The resulting solid was collected by filtration, washed with
water and recrystallized from EtOH/DMF to give com-
pound 9.
3-Methyl-2-[6-(4-bromophenyl)-7H-1,2,4-triazolo[3,4-
b]-1,3,4-thiadiazin-3-yl]thiazolo[3,2-a]benzimidazole
(10b)
White solid, Yield 52%, mp. >300 °C; IR (KBr)
nmax/cm-1 1603 (C=N); 1H NMR (DMSO-d6) d 3.08 (s, 3H,
CH3), 4.57 (s, 2H, thiadiazine), 7.29-8.02 (m, 8H, ArH);
MS m/z (%) 485 (M++4, 8.3%), 483 (M++2, 4.0%), 481
(M+, 8.6%), 318 (21.6%), 189 (100%), 77 (43.0%). For
C20H13BrN6S2 (481.40). Calcd.: C, 49.90; H, 2.72; N,
17.46; S, 13.32%. Found: C, 49.68; H, 2.46; N, 17.19; S,
13.29%.
Method B
To a solution of 1,3,4-oxadiazole 8 (2.9 g, 10 mmol)
in ethanol (20 mL) hydrazine hydrate (12 mmole) was
added. The reaction mixture was heated under reflux for 2
h, then left to cool and poured into crushed ice. The result-
ing solid was collected by filtration, washed with water and
crystallized from EtOH/DMF to give compound 9 as a
white solid in 62% yield, mp. 291-293 °C; IR (KBr)
nmax/cm-1 3309, 3230, 3129 (NH2, NH), 1613 (C=N); 1H
NMR (DMSO-d6) d 3.07 (s, 3H, CH3), 5.85 (br. s, 2H, NH2,
D2O-exchangeable), 7.27-8.10 (m, 4H, ArH), 8.75 (br. s,
1H, NH, D2O-exchangeable); MS m/z (%) 303 (M++1,
34.7%), 302 (M+, 48.0%), 264 (35.3%), 203 (100%), 188
(64.6%), 58 (18.8%). For C12H10N6S2 (302.38). Calcd.: C,
47.67; H, 3.33; N, 27.79; S, 21.21%. Found: C, 47.93; H,
3.64; N, 27.50; S, 20.86%.
Reaction of 4-amino-5-(3-methylthiazolo[3,2-a]benz-
imidazol-2-yl)-4H-[1,2,4]-triazole-3-thione (9) with
hydrazonyl chlorides 11a,b
General procedure
To a solution of compound 9 (0.60 g, 2 mmol) in etha-
nol (30 mL), the appropriate hydrazonyl chloride 11a,b (2
mmol) was added. The reaction mixture was heated under
reflux for 10 h, then left to cool. The precipitated solid was
filtered, washed with ethanol and dried. Crystallization
from DMF/H2O yielded corresponding compounds 12a,b,
respectively.
Reaction of 4-amino-5-(3-methylthiazolo[3,2-a]benz-
imidazol-2-yl)-4H-[1,2,4]-triazole-3-thione (9) with
a-haloketones 1a,b
3-Methyl-2-(7-phenylhydrazono-6-methyl-7H-1,2,4-tri-
azolo[3,4-b]-1,3,4-thiadiazin-3-yl)thiazolo[3,2-a]benz-
imidazole (12a)
General procedure
A mixture of compound 9 (0.60 g, 2 mmol) and the
Yellow crystals, Yield 58%, mp. >300 °C (DMF/H2O);

1580 J. Chin. Chem. Soc., Vol. 54, No. 6, 2007
Abdel-Aziz et al.
IR (KBr) nmax/cm-1 3414 (NH), 1616 (C=N); H NMR
(DMSO-d6) d 2.56 (s, 3H, CH3), 3.17 (s, 3H, CH3), 7.23-
8.08 (m, 9H, ArH), 11.85 (br. s, 1H, NH, D2O-exchange-
able); MS m/z (%) 446 (M++2, 8.4%), 445 (M++1, 14.1%),
444 (M+, 12.5%), 390 (9.7%), 375 (18.0%), 347 (22.2%),
299 (100%), 189 (15.8%), 106 (19.3%), 77 (42.6%). For
C21H16N8S2 (444.54). Calcd.: C, 56.74; H, 3.63; N, 25.21;
S, 14.43%. Found: C, 56.42; H, 3.29; N, 25.60; S, 14.43%.
5-Amino-1-(3-methylthiazolo[3,2-a]benzimidazol-2-oyl)-
1H-pyrazole-4-carbonitrile (15a)
1
White solid, Yield 72%, mp. 262-264 °C; IR (KBr)
nmax/cm-1 3425, 3283 (NH2), 2226 (CºN), 1675 (C=O),
16248 (C=N); 1H NMR (DMSO-d6) d 2.25 (s, 3H, CH3),
7.31-8.16 (m, 5H, 4ArH and 1H, pyrazole), 8.16 (br. s, 2H,
NH2, D2O-exchangeable); MS m/z (%) 323 (M++1, 16.4%),
322 (M+, 35.0%), 188 (100%), 131 (67.1%), 118 (48.5%),
80 (72.7%). For C15H10N6OS (322.35). Calcd.: C, 55.89; H,
3.13; N, 26.07; S, 9.95%. Found: C, 55.85; H, 3.35; N,
25.86; S, 9.81%.
3-Methyl-2-[7-(4-chlorophenylhydrazono)-6-methyl-
7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazin-3-yl]thiazolo-
[3,2-a]benzimidazole (12b)
Yellow crystals, Yield 62%, mp. >300 °C; IR (KBr)
nmax/cm-1 3179 (NH), 1585 (C=N); 1H NMR (DMSO-d6) d
2.56 (s, 3H, CH3), 3.13 (s, 3H, CH3), 7.23-8.05 (m, 8H,
ArH), 11.68 (br. s, 1H, NH, D2O-exchangeable); MS m/z
(%) 480 (M++2, 11.5%), 479 (M++1, 24.4%), 478 (M+,
12.0%), 347 (36.2%), 262 (100%), 77 (34.3%). For
C21H15ClN8S2 (478.99). Calcd.: C, 52.66; H, 3.16; N,
23.39; S, 13.39%. Found: C, 52.34; H, 2.87; N, 23.05; S,
13.64%.
5-Amino-1-(3-methylthiazolo[3,2-a]benzimidazol-2-oyl)-
1H-pyrazole-4-carboxylic acid ethyl ester (15b)
White solid, Yield 74%, mp. 255-257 °C; IR (KBr)
nmax/cm-1 3412, 3246 (NH2), 1692, 1664 (2C=O), 1608
(C=N); MS m/z (%) 370 (M++1, 37.5%), 369 (M+, 25.1%),
315 (84.4%), 240 (55.5%), 188 (100%), 162 (63.4%), 135
(82.6%), 116 (46.0%). For C17H15N5O3S (369.40). Calcd.:
C, 55.28; H, 4.09; N, 18.96; S, 8.68%. Found: C, 55.53; H,
3.88; N, 18.70; S, 8.75%.
Reaction of hydrazide 2 with acetylacetone, ethoxy-
methylene-malononitrile (14a) and ethoxymethylene-
ethyl cyanoacetate (14b)
1-(3-Methylthiazolo[3,2-a]benzimidazol-2-oyl)-4-phen-
ylthiosemicarbazide (16)
To a mixture of the hydrazide 2 (2.5 g, 10 mmol) in
dry benzene (25 mL), phenyl isothiocyanate (1.35g, 10
mmol) was added, and the reaction mixture was heated un-
der reflux for 5 h, then left to cool. The separated solid was
collected by filtration, washed with ethanol and finally
crystallized from EtOH/DMF to afford thiosemicarbazide
derivative 16 as white crystals in 84% yield, mp. 205-207
°C; IR (KBr) nmax/cm-1 3313, 3224, 3155 (3NH), 1650
(C=O), 1597 (C=N); 1H NMR (DMSO-d6) d 3.11 (s, 3H,
CH3), 7.17-8.09 (m, 9H, ArH), 8.86 (br. s, 1H, NH, D2O-
exchangeable), 9.98 (br. s, 1H, NH, D2O-exchangeable),
10.43 (br. s, 1H, NH, D2O-exchangeable); MS m/z (%) 382
(M++1, 65.9%), 381 (M+, 37.0%), 201 (100%), 189 (34.6%),
142 (27.5%), 64 (55.3%). For C18H15N5OS2 (381.48).
Calcd.: C, 56.67; H, 3.96; N, 18.36; S, 16.81%. Found.: C,
56.66; H, 4.23; N, 18.23; S, 16.96%.
General Procedure
To a solution of hydrazide 2 (0.23 g, 1 mmol) in etha-
nol (20 mL) was added acetylacetone, ethoxymethylene-
malononitrile (14a) or ethoxymethylene-ethyl cyanoace-
tate (14b) (1 mmol). The mixture was refluxed for 4 h, then
allowed to cool. The formed solid was filtered off, washed
with ethanol and recrystallized from EtOH/DMF to afford
the corresponding pyrazole derivatives 13, 15a and 15b,
respectively.
2-(3,5-Dimethyl-pyrazol-1-oyl)-3-methylthiazolo[3,2-a]-
benzimidazole (13)
White solid, Yield 88%, mp. 215-217 °C; IR (KBr)
nmax/cm-1 1683 (C=O), 1541 (C=N); 1H NMR (DMSO-d6)
d 2.28 (s, 3H, CH3), 2.58 (s, 3H, CH3), 3.24 (s, 3H, CH3),
6.31 (s, 1H, pyrazole), 7.30-8.12 (m, 4H, ArH); MS m/z
(%) 311 (M++1, 6.2%), 310 (M+, 11.5%), 265 (100%), 208
(14.0%), 173 (12.1%), 103 (6.4%), 81 (7.2%). For
C16H14N4OS (310.38). Calcd.: C, 61.92; H, 4.55; N, 18.05;
S, 10.33%. Found: C, 62.23; H, 4.29; N, 18.00; S, 10.54%.
2-(3-Methylthiazolo[3,2-a]benzimidazol-2-yl)-5-phenyl-
amino-1,3,4-oxadiazole (17)
Method A
To a mixture of hydrazide 2 (2.5 g, 10 mmol) in DMF

Heterocycles Pendant to Thiazolo[3,2-a]benzimidazole
J. Chin. Chem. Soc., Vol. 54, No. 6, 2007 1581
(20 mL), phenyl isothiocyanate (1.35 g, 10 mmol) was
added, and the reaction mixture was heated under reflux for
8 h, then left to cool, then pour into crushed ice. The sepa-
rated solid was collected by filtration, washed with ethanol
and finally crystallized from EtOH/DMF to give com-
pound 17.
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To a suspension of the thiosemicarbazide 16 (1.9 g, 5
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1589 (C=N); H NMR (DMSO-d6) d 3.12 (s, 3H, CH3),
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white solid in 76% yield, mp. 308-310 °C; IR (KBr) nmax
/
1
cm-1 1616 (C=N); H NMR (DMSO-d6) d 2.89 (s, 3H,
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1582 J. Chin. Chem. Soc., Vol. 54, No. 6, 2007
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