Novel synthesis and biological activity of 2-substituted derivatives of 3-cyano-4-imino-2-methylthio-8-methoxy-4H-pyrimido[2,1-b][1,3]benzothiazole and 3-amino-4-imino-8-methoxy-2H - Pyrazolo[3′,4′:4,5]pyrimido[2,1-b][1, 3]benzothiazole

Article abstract of DOI:10.1002/jhet.559

Figure represented. 2-Amino-6-methoxybenzothiazole 1 on reaction with bis(methylthio)methylene malononitrile 2 in the presence of dimethyl formamide and catalytic amount of anhydrous potassium carbonate afforded 3-cyano-4-imino-8-methoxy-4H-pyrimido[2,1-b][1,3]benzothiazole 3. Under similar experimental conditions, compound 3 on treatment independently with arylamines/heterylamines/phenols/compounds containing active methylene group yielded corresponding 2-substituted derivatives of compound 3 (4_a-d, 5_a-c, 6_a-e, and 7_a-e). Similarly, novel heterocyclic compounds, 3-amino-4-imino-8-methoxy-2H 8_a/aryl 8 _b-c/heteryl 8_d-f/pyrazolo[3′,4′:4, 5]pyrimido[2,1-b][1,3]benzothiazoles, were prepared by heating compound 3 independently with hydrazine hydrate/arylhydrazines/heterylhydrazines, respectively. All these newly synthesized compounds were screened for antimicrobial activity.

Full text of DOI:10.1002/jhet.559

July 2011
Novel Synthesis and Biological Activity of 2-Substituted
Derivatives of 3-Cyano-4-imino-2-methylthio-8-methoxy-4H-
pyrimido[2,1-b][1,3]benzothiazole and 3-Amino-4-imino-8-
methoxy-2H-pyrazolo[30,40:4,5]pyrimido[2,1-b][1,3]benzothiazole
849
S. G. Badne,a D. K. Swamy,b* V. N. Bhosale,c and S. V. Kuberkarc
aDepartment of Chemistry, Shri Shivaji College, Akola, Maharashtra 444001, India
bDepartment of Chemistry, Pratibha Niketan Mahavidyalaya, Nanded, Maharashtra 431602, India
cP.G. Department of Chemistry, Yeshwant Mahavidyalaya, Nanded, Maharashtra 431602, India
*E-mail: swamy_deelip@rediffmail.com
Received February 12, 2010
DOI 10.1002/jhet.559
Published online 14 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
2-Amino-6-methoxybenzothiazole 1 on reaction with bis(methylthio)methylene malononitrile 2 in the
presence of dimethyl formamide and catalytic amount of anhydrous potassium carbonate afforded 3-
cyano-4-imino-8-methoxy-4H-pyrimido[2,1-b][1,3]benzothiazole 3. Under similar experimental condi-
tions, compound 3 on treatment independently with arylamines/heterylamines/phenols/compounds con-
taining active methylene group yielded corresponding 2-substituted derivatives of compound 3 (4a–d
,
5
8
a–c, 6a–e, and 7a–e). Similarly, novel heterocyclic compounds, 3-amino-4-imino-8-methoxy-2H 8a/aryl
b–c/heteryl 8d–f/pyrazolo[30,40:4,5]pyrimido[2,1-b][1,3]benzothiazoles, were prepared by heating com-
pound 3 independently with hydrazine hydrate/arylhydrazines/heterylhydrazines, respectively. All these
newly synthesized compounds were screened for antimicrobial activity.
J. Heterocyclic Chem., 48, 849 (2011).
INTRODUCTION
3-amino-4-imino-8-methoxy-2H-pyrazolo[30,40:4,5]pyrimido
[2,1-b][1,3]benzothiazole 8a and their 2-substituted deriva-
Fused pyrimidobenzothiazoles [1,2] are well known
for their varied biological activities like antiallergic
[3,4], antitumor [5], anti-inflammatory [6], antiparkin-
sonism [7], and phosphodiesterase inhibition [8]. In our
recent publications [9–12], we have outlined convenient
synthesis of new fused heterocyclic systems like oxopyr-
imidobenzothiazoles [9,10], pyrazolopyrimidobenzothia-
zoles [11], and benzothiazolotriazepines [12] and studied
on their biological activities [12]. A literature survey
revealed that very few refs. [13–15] are available on the
synthesis of iminopyrimidobenzothiazoles and iminopyr-
azolopyrimidobenzothiazoles. These observations have
stimulated our considerable interest to explore the syn-
thesis of new fused heterocycles in which iminopyrimi-
dine and pyrazolo iminopyrimidine rings are fused with
another biologically active benzothiazole. In this work,
we report one-pot synthesis of 3-cyano-4-imino-2-meth-
ylthio-8-methoxy-4H-pyrimido[2,1-b][1,3]benzothiazole 3,
tives 4a–d, 5a–c, 6a–e, 7a–e, and 8b–f
.
RESULTS AND DISCUSSION
Compound 3 was prepared from the reaction of bis
(methylthio)methylene malonitrile 2 with 2-amino-6-
methoxy benzothiazole in the presence of N,N0-dimethyl
formamide and a catalytic amount of anhydrous potas-
sium carbonate (Scheme 1). The structure of the com-
pound 3 was assigned on the basis of elemental analysis
and spectral data. IR (potassium bromide): ¼¼NH 3255,
;
CBN 2197 cmꢀ1 1H nuclear magnetic resonance
(NMR; DMSO-d6): d 2.4 (s, 3H, SCH3), 3.7 (s, 3H,
OCH3), 7.1–7.6 (m, 4H, ArAH), 9.2 (s, 1H, ¼¼NH); ms:
m/z 302 (Mþ).
A mechanism for the formation of parent compound 3
can be adduced as shown in Scheme 2.
C
V
2011 HeteroCorporation

850
S. G. Badne, D. K. Swamy, V. N. Bhosale, and S. V. Kuberkar
Vol 48
Scheme 1
Compound 3 possesses a replaceable active methyl-
3-Cyano-4-imino-8-methoxy-2(20-methylphenoxy/40-meth-
ylphenoxy/40-chlorophenoxy/20-nitrophenoxy/40-nitrophe-
noxy)-4H-pyrimido[2,1-b][1,3]benzothiazoles 6a–e were
obtained by the condensation of compound 3 with 2-
methyl phenol/4-methyl phenol/4-chlorophenol/2-nitro-
phenol/4-nitrophenol in N,N0-dimethyl formamide and a
catalytic amount of anhydrous potassium carbonate in-
dependently (Scheme 3). Under similar experimental
conditions, compound 3 reacted independently with
diethyl malonate, ethyl cyanoacetate, ethyl acetoacetate,
acetyl acetone, and malononitrile yielded compounds
that were characterized on the basis of their analytical
and spectral data as 3-cyano-4-imino-8-methoxy-
2(diethylmalonyl/ethylcyanoacetyl/ethylacetoacetyl/ace-
tylacetonyl/malononitrile)-4H-pyrimido[2,1-b][1,3]benzo-
thiazols 7a–e (Scheme 3).
thio group at the 2-position that is activated by the
ring 1-nitrogen atom and the electron withdrawing 3-
cyano group. Compound 3 was reacted with selected
N-, O- and C-nucleophiles like arylamines, heteryl-
amines, substituted phenols, and compounds contain-
ing an active methylene group. These reactions
resulted in the formation of 2-substituted derivatives
of compound 3. According to this method, compound
3 on reaction independently with 4-nitroaniline, 4-
methylaniline, 4-methoxyaniline, and 4-chloroaniline
in the presence of N,N0-dimethyl formamide and a
catalytic amount of anhydrous potassium carbonate
afforded 3-cyano-4-imino-8-methoxy-2-(40-nitroanilino/
40-methylanilino/40-methoxyanilino/40-chloroanilino-4H-
pyrimido[2,1-b][1,3]benzothiazoles 4a-d
,
respectively
(Scheme 3). Under similar experimental conditions,
compound 3 reacted independently with heterylamines
like morpholine, pyrrolidine, and piperidine to
Compounds 4a–d, 5a–c, 6a–e, and 7a–e exhibit absorp-
tion bands in their IR spectra in the range of 3300–3500
and 2180–2230 cmꢀ1 due to ¼¼NH stretching and CN
1
yield
3-cyano-4-imino-8-methoxy-2-(morphilino/pyrroli-
stretching, respectively. H-NMR and mass spectral data
dino/piperidino)-4H-pyrimido[2,1-b][1,3]benzothiazoles 5a-c,
respectively (Scheme 3).
are also in agreement with the structure assigned to
compounds 4a–d, 5a–c, 6a–e, and 7a–e.
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Novel Synthesis and Biological Activity of New Fused Heterocycles
851
Scheme 3
Similarly, novel heterocyclic compounds, 3-amino-4-
the region 3100–3350 cmꢀ1 due to free NH2 and ¼¼NH
1
membered pyrazole ring. The H-NMR spectra of com-
imino-8-methoxy-2(H/phenyl/40-nitrophenyl/20-benzothia-
zolyl/60-chloro-20-benzothiazolyl/60-methyl-20-benzothiazo-
lyl)pyrazolo[30,40:4,5]pyrimido[2,1-b][1,3]benzothiazoles 8a–f
were prepared by heating compound 3 under similar
experimental conditions independently with hydrazine
hydrate/phenyl hydrazine/4-nitrophenylhydrazine/2-hydra-
zinobenzothiazole/6-chloro-2-hydrazinobenzothiazole/6-
methyl-2-hydrazinobenzothiazole, respectively (Scheme 4).
The structures of compounds 8a–f were confirmed on the ba-
sis of elemental analysis and spectral data.
group indicate that the ring gets cyclized to form five-
pounds 8a–f exhibited singlet in the region d 3–3.5 due
to AOCH3 protons, broad peak in the region d 3.7–5
due to ANH2 proton, and singlet in the region d 7.8–8.5
due to ¼¼NH proton. The mass spectra showed the mo-
lecular ion peaks which correspond to molecular weight
of respective compounds. The mechanism for the forma-
tion of 8a–f can be represented as shown in Scheme 5.
Antimicrobial activity. The synthesized compounds
were tested for their antimicrobial activity by paper disc
diffusion method against S. aureus, B. subtilis, E. coli,
and S. typhi using Norflaxacin as a standard antimicrobial
The IR spectra of compounds 8a–f showed the absence
of CBN stretching absorption band in the range of
2180–2260 cmꢀ1. The presence of absorption bands in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

852
S. G. Badne, D. K. Swamy, V. N. Bhosale, and S. V. Kuberkar
Vol 48
Scheme 4
compound for comparison. The antimicrobial screening
data of the compounds have been incorporated in Table
1. Dimethyl formamide was used as a control solvent.
The compounds 4a, 4d, 6a, 6c, and 6d of the series of 3-
cyano-4-imino-8-methoxy-4H-pyrimido[2,1-b][1,3]benzo-
thiazole and its 2-substituted derivatives were found to
be more active and exhibited zone of inhibition 8–12
mm in diameter against all mentioned species of micro-
organisms. The compound 8a of the series 3-amino-4-im-
ino-8-methoxy-2H-pyrazolo[30,40:4,5]pyrimido[2,3-b][1,3]
benzothiazole is more active and exhibited 8–11 mm
Scheme 5
Table 1
Antimicrobial activity of 3, 4a–d, 5a–c, 6a-e, 7a–e, and 8a–f
.
Diameter in mm of zone of inhibition at
25 lg/disc
Comp. No.
S. aureus
B. subtilis
E. coli
S. typhi
3
4a
4b
4c
4d
5a
5b
5c
6a
6b
6c
6d
6
7
7
NA
10
NA
7
6
8
9
8
11
9
8
NA
8
8
7
8
6
9
12
10
7
NA
8
NA
10
7
NA
NA
9
6
7
6
10
12
9
9
8
12
NA
10
6
8
7
11
9
6e
7a
7b
7c
7d
7e
8a
8b
NA
10
9
NA
NA
NA
NA
NA
NA
10
NA
7
NA
11
6
8
8
9
6
7
9
10
8
7
6
NA
6
7
10
8
NA
NA
7
11
8
9
12
10
9
8c
8d
8e
9
10
7
11
14
NA
8
NA
6
8f
Norflaxacin
NA
24
20
16
NA, no activity.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Novel Synthesis and Biological Activity of New Fused Heterocycles
853
3-Cyano-4-imino-2-(40-nitroanilino)-8-methoxy-4H-pyri-
mido[2,1-b][1,3]benzothiazole (4a) Yield: 0.252 g (64%),
m.p.: 120ꢁC; IR (potassium bromide): ANH 3492, ¼¼NH
zone of inhibition in diameter against all mentioned spe-
cies of microorganisms. The compounds 6b, 7a, and 7b
of the series of 3-cyano-4-imino-8-methoxy-4H-pyri-
mido[2,-1b][1,3] benzothiazole and its 2-substituted
derivatives found to be more active and exhibited 8–12
mm zone of inhibition in diameter against S. aureus and
E. coli, whereas these compounds are less active against
other species B. subtilis and S. typhi. Also the com-
pounds of 8b, 8c, 8d, and 8f of the series 3-amino-4-im-
ino-8-methoxy-2H-pyrazolo[30,40:4,5]pyrimido[2,3-
b][1,3]benzothiazole and its 2-substituted derivatives are
more active against S. aureus and E. coli and exhibited
8–12 mm zone of inhibition in diameter, whereas these
compounds are less active against other species B. subti-
lis and S. typhi. Standard Norflaxacin exhibited 14, 24,
20, and 16 mm zone of inhibition against S. aureus,
B. subtilis, E. coli, and S. typhi, respectively.
3379, CN 2199 cmꢀ1 1H-NMR (DMSO-d6): d 2.2 (s, 1H,
;
NH), 3.2 (s, 3H, OCH3), 7.2–7.9 (m, 7H, ArAH), 9.1 (s, 1H,
¼¼NH); ms: m/z 392 (Mþ) Anal. Calcd. For C18H12N6O3S: C,
55.10; H, 3.06; N, 21.42. Found: C, 55.08; H, 3.02; N,
21.39.
3-Cyano-4-imino-2-(40-methylanilino)-8-methoxy-4H-pyr-
imido[2,1-b][1,3]benzothiazole (4b) Yield: 0.230 g (63%),
m.p.: 227ꢁC; IR (potassium bromide): ANH 3384, ¼¼NH 3280,
1
CN 2215 cmꢀ1; H-NMR (DMSO-d6): d 1.3 (s, 1H, CH3), 2.6
(s, 1H, NH), 3.5 (s, 3H, OCH3), 7.3–8.0 (m, 7H, ArAH), 9.3
(s, 1H, ¼¼NH); ms: m/z 361 (Mþ). Anal. Calcd. for
C19H15N5SO: C, 63.15; H, 4.15; N, 19.39. Found: C, 63.12; H,
4.11; N, 19.36.
3-Cyano-4-imino-2-(40-methoxyanilino)-8-methoxy-4H-
pyrimido[2,1-b][1,3]benzothiazole (4c) Yield: 0.226
g
(62%), m.p.: 116ꢁC; IR (potassium bromide): ANH 3400,
¼¼NH 3375, CN 2200 cmꢀ1
;
1H-NMR (DMSO-d6): d 2.6 (s,
1H, NH), 3.8 (s, 3H, OCH3), 7–7.5 (m, 7H, ArAH), 9.3 (s,
1H, ¼¼NH); ms: m/z 377 (Mþ). Anal. Calcd. for C19H15N5O2S:
C, 60.47; H, 3.97; N, 18.56. Found: C, 60.45; H, 3.95; N,
18.53.
EXPERIMENTAL
Melting points are determined in open capillary tubes and
were uncorrected. All the reactions were monitored by thin
layer chromatography, carried out on 0.2-mm silica gel-G
plates using iodine vapor for detection. Infrared spectra were
recorded in potassium bromide pellets on a Bomen MB 104
FT Infrared spectrophotometer. NMR spectra were obtained on
a Gemini 200 MHz spectrometer with tetramethylsilane as an
internal standard. Mass spectra were recorded on a FT VG-
7070 H mass spectrophotometer using EI technique at 70 eV.
Microanalysis was performed on a Herqeus CHN-O rapid
analyzer.
3-Cyano-4-imino-2-(40-chloroanilino)-8-methoxy-4H-pyri-
mido[2,1-b][1,3]benzothiazole (4d) Yield: 0.224
g (59%),
m.p.: 114ꢁC; IR (potassium bromide): ANH 3380, ¼¼NH 3265,
CN 2190 cmꢀ1 1H-NMR (DMSO-d6): d 2.7 (s, 1H, NH), 3.5
;
(s, 3H, OCH3), 7.2–8.1 (m, 7H, ArAH), 9.2 (s, 1H, ¼¼NH); ms:
m/z 383 (Mþ2), 381 (Mþ). Anal. Calcd. for C18H12N5OSCl: C,
56.69; H, 3.14; N, 18.37. Found: C, 56.65; H, 3.11; N, 18.32.
3-Cyano-4-imino-2-morpholinyl-8-methoxy-4H-pyrimido[2,1-
b][1,3]benzothiazole (5a) Yield: 0.230 g (67%), m.p.: 197ꢁC;
IR (potassium bromide): ¼¼NH 3296, CN 2189 cmꢀ1
;
1H-
NMR (DMSO-d6): d 2.6 (t, 4H, two-NACH2), 3.8 (s, 3H,
AOCH3), 4.0 (t, 4H, AOCH2), 7.0–7.5 (m, 3H, ArAH), 9.2
(s, 1H, ¼¼NH); ms: m/z 341 (Mþ). Anal. Calcd. for
C16H15N5O2S: C, 56.30; H, 4.39; N, 20.52. Found: C, 56.28;
H, 4.35; N, 20.49.
3-Cyano-4-imino-2-methylthio-8-methoxy-4H-pyrimido[2,1-
b][1,3]benzothiaole (3). A mixture of 2-amino-6-methoxy ben-
zothiazole (1.80 g, 0.01 mol) and bis(methylthio)methylene
malononitrile (1.58 g, 0.01 mol) was refluxed in the presence
of 25–30 mL of dimethyl formamide and a pinch of anhydrous
potassium carbonate for 4 h. The reaction mixture was cooled
to room temperature and poured into ice cold water. The sepa-
rated solid product was filtered, washed with water, and
recrystallized from N,N0-dimethyl formamide–ethanol to give
pure 3. Yield: 1.45 g (50%), m.p.: 210ꢁC; IR (potassium bro-
3-Cyano-4-imino-2-pyrrolidinyl-8-methoxy-4H-pyri-
mido[2,1-b][1,3] benzothiazole (5b) Yield: 0.225
g
(69%), m.p.: 145ꢁC; IR (potassium bromide): ¼¼NH 3405, CN
2221 cmꢀ1 1H-NMR (DMSO-d6): d 2.0 (quintet, 4H, two-
;
CH2), 2.5 (t, 4H, two-NCH2), 6.8–7.3 (m, 3H, ArAH), 8.9 (s,
1H, ¼¼NH); ms: m/z 325 (Mþ). Anal. Calcd. for C16H15N5OS;
C, 59.07; H, 4.61; N, 21.53. Found: C, 59.05; H, 4.57; N,
21.49.
3-Cyano-4-imino-2-piperidinyl-8-methoxy-4H-pyrimido[2,1-
b][1,3] benzothiazole (5c) Yield: 0.240 g (71%), m.p.: 155ꢁC;
1
mide): C¼¼NH 3255, CBN 2197 cmꢀ1; H-NMR (DMSO-d6):
d 2.4 (s, 3H, SCH3), 3.7 (s, 3H, OCH3), 7.1–7.6 (m, 3H,
ArAH), 9.2 (S, 1H, ¼¼NH); ms: m/z 302 (Mþ 100%), 255,
228, 202, 164, 138. Anal. Calcd. for C13H10N4S2O: C, 51.65;
H, 3.31; N, 18.54. Found: C, 51.62; H, 3.29; N, 18.52.
IR (potassium bromide): ¼¼NH 3360, CN 2186 cmꢀ1
;
1H-
General procedure for the preparation of 2-substituted
derivatives of 3-cyano-4-imino-2-methylthio-8-methoxy-4H-
pyrimido[2,1-b][1,3]benzothiazole (4a–d, 5a–c, 6a–e, 7a–e). A
mixture of 3 (0.001 mol) and aromatic amines/heterylamines/
phenols/compounds containing active methylene group (0.001
mol) in N,N0-dimethyl formamide (10 mL) and anhydrous po-
tassium carbonate (10 mg) was refluxed independently for 4–6
h. The reaction mixture was cooled to room temperature and
poured into ice cold water. The separated solid product was fil-
tered, washed with water, and recrystallized from N,N0-di-
NMR (DMSO-d6): d 1.5 (quintet, 2H, ACH2), 2.4 (quintet,
4H, two-CH2), 2.8 (t, 4H, two-CH2), 6.8–7.3 (m, 3H, ArAH),
8.9 (s, 1H, ¼¼NH); ms: m/z 339 (Mþ). Anal. Calcd. for
C17H17N5OS: C, 60.17; H, 5.01; N, 20.64. Found: C, 60.14; H,
4.99; N, 20.60.
3-Cyano-4-imino-2-(40-methylphenoxy)-8-methoxy-4H-
pyrimido[2,1-b][1,3]benzothiazole (6a) Yield: 0.180
g
(50%), m.p.: 127ꢁC; IR (potassium bromide): ¼¼NH 3296, CN
2203, CAOAC asymmetric and symmetric stretching 1267,
1227 cmꢀ1 1H-NMR (DMSO-d6): d 2.3 (s, 3H, ACH3), 3.9
;
methyl formamide–ethanol mixture to give pure 4a–c, 5a–c, 6a–e
,
(s, 3H, OCH3), 7–7.9 (m, 8H, ArAH), 9.1 (s, 1H, ¼¼NH); ms:
and 7a–e
.
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S. G. Badne, D. K. Swamy, V. N. Bhosale, and S. V. Kuberkar
Vol 48
m/z 362 (Mþ) Anal. Calcd. for C19H14N4O2S: C, 62.98; H,
3.86; N, 15.46. Found: C, 62.95; H, 3.84; N, 15.42.
3-Cyano-4-imino-2-(20-methylphenoxy)-8-methoxy-4H-
(m, 3H, ArAH), 9.3 (s, 1H, ¼¼NH); ms: m/z 354 (Mþ). Anal.
Calcd. for C17H14N4O3S: C, 57.62; H, 3.95; N, 15.08. Found:
C, 57.58; H, 3.92; N, 15.04.
pyrimido[2,1-b][1,3]benzothiazole (6b) Yield: 0.165
g
3-Cyano-4-imino-2-(a-malononitrile)-8-methoxy-4H-
(46%), m.p.: 130ꢁC; IR (potassium bromide): ¼¼NH 3345, CN
pyrimido[2,1-b][1,3]benzothiazole (7e) Yield: 0.20
g
(65%), m.p.: 195ꢁC; IR (potassium bromide): ¼¼NH 3400, CN
2219, CAOAC asymmetric and symmetric stretching 1250,
1
1220 cmꢀ1; H-NMR (DMSO-d6): d 2.1 (s, 3H, ArACH3), 3.5
2215 cmꢀ1 1H-NMR (deuteriochloroform): d 3.5 (s, 3H,
;
(s, 3H, AOCH3), 7.1–7.9 (m, 7H, ArAH), 9.3 (s, 1H, ¼¼NH);
ms: m/z 362 (Mþ). Anal. Calcd. for C19H14N4O2S: C, 62.98;
H, 3.86; N, 15.46. Found: C, 62.95; H, 3.84; N, 15.42.
OCH3), 4.2 (s, 1H, ACH), 7.1–7.5 (m, 3H); ms: m/z 320
(Mþ). Anal. Calcd. for C15H8N6OS: C, 56.25; H, 2.50; N,
26.25. Found: C, 56.23; H, 2.45; N, 26.22.
3-Cyano-4-imino-2-(40-chlorophenoxy)-8-methoxy-4H-
General procedure for the preparation of 2-substituted-
3-amino-4-imino-8-methoxy-(2H)-pyrazolo[30,40:4,5]
pyrimido[2,1-b][1,3]benzothiazole (6c) Yield: 0.180
g
pyri-
(47%), m.p.: 112ꢁC; IR (potassium bromide): ¼¼NH 3383, CN
mido[2,1-b][1,3]benzothiaoles (8a–f). A mixture of 3 (0.001
mol) and hydrazine hydrate/phenyl hydrazine/4-nitrophenyl-
1
2195 cmꢀ1; H-NMR (DMSO-d6): d 3.6 (s, 3H, AOCH3), 7.2–
7.0 (m, 7H, ArAH), 9.0 (s, 1H, ¼¼NH); ms: m/z 384 (Mþ2),
382 (Mþ). Anal. Calcd. for C18H11N4O2SCl: C, 56.54; H,
2.87; N, 14.65. Found: C, 56.52; H, 2.84; N, 14.61.
hydrazine/2-hydrazine benzothiazole/6-chloro-2-hydrazino
benzothiazole/6-methyl-2-hydrazino benzothiazole (0.002
mol) in N,N-dimethyl formamide (10 mL) and anhydrous
potassium carbonate (10 mg) was refluxed independently
for 4–6 h. The reaction mixture was cooled to room tem-
perature and poured into ice cold water. The separated
solid product was filtered, washed with water, and crystal-
lized from N,N-dimethyl formamide–ethanol mixture to give
3-Cyano-4-imino-2-(20-nitrophenoxy)-8-methoxy-4H-
pyrimido[2,1-b][1,3]benzothiazole (6d) Yield: 0.170
g
(43%), m.p.: 138ꢁC; IR (potassium bromide): ¼¼NH 3373, CN
2188, ArANO2 1529 cmꢀ1 1H-NMR (DMSO-d6): d 3.1 (s,
;
3H, AOCH3), 7–7.8 (m, 7H, ArAH), 8.9 (s, 1H, ¼¼NH); ms:
m/z 393 (Mþ). Anal. Calcd. for C18H11N5O4S: C, 54.96; H,
2.79; N, 17.81. Found: C, 54.92; H, 2.76; N, 17.77.
3-Cyano-4-imino-2-(40-nitrophenoxy)-8-methoxy-4H-
crystalline 8a–f
.
3-Amino-4-imino-8-methoxy-(2H)-pyrazolo[30,40:4,5]pyrimido-
[2,1-b][1,3]benzothiazole (8a) Yield 0.180 g (63%), m.p.: 267ꢁC;
IR (potassium bromide): NH2 asymmetric 3317, NH2 symmetric
pyrimido[2,1-b][1,3]benzothiazole (6e) Yield: 0.160
g
(41%), m.p.: 132ꢁC; IR (potassium bromide): ¼¼NH 3382, CN
3168 cmꢀ1 1H-NMR (DMSO-d6): d 3.4 (broad s, 2H, NH2,
;
2195, ArANO2 1540 cmꢀ1 1H-NMR (DMSO-d6): d 3.3 (s,
;
exchangeable with D2O), 3.7 (s, 3H, OCH3), 6.9–7.7 (m, 3H, ar-
omatic-H), 7.9 (s, 1H, NH, exchangeable with D2O), 8.3 (s, 1H,
¼¼NH exchangeable with D2O); ms: m/z 286 (Mþ,24%), 258,
229, 176, 138. Anal. Calcd. for C12H10N6OS: C, 50.34; H, 3.49;
N, 29.37. Found: C, 50.31; H, 3.46; N, 29.33.
3H, AOCH3), 7.2–7.9 (m, 7H, ArAH), 9.2 (s, 1H, ¼¼NH); ms:
m/z 393 (Mþ). Anal. Calcd. for C18H11N5O4S: C, 54.96; H,
2.79; N, 17.81. Found: C, 54.94; H, 2.75; N, 17.78.
3-Cyano-4-imino-2-(diethylmalonyl)-8-methoxy-4H-
pyrimido[2,1-b][1,3]benzothiazole (7a) Yield: 0.30
g
0
3-Amino-4-imino-8-methoxy-2-phenylpyrazolo[3 ,40:4,5]pyri- mido-
(73%), m.p.: 107ꢁC; IR (potassium bromide): ¼¼NH 3296, CN
[2,1-b][1,3]benzothiazole (8b) Yield: 0.182 g (50%), m.p.: 192ꢁC;
1
2201, C¼¼O of ester 1727, CAO 1274 cmꢀ1; H-NMR (deuter-
IR (potassium bromide): NH2 3353, ¼¼NH, NH2 symmetric
iochloroform): d 1.2 (t, 6H, two-CH3), 3.8 (s, 3H, AOCH3),
4.2 (q, 4H, two-CH2), 6.8–7.3 (m, 3H, ArAH), 9.2 (s, 1H,
¼¼NH); ms: m/z 414 (Mþ). Anal. Calcd. for C19H18N4O2S: C,
55.07; H, 4.34; N, 13.52. Found: C, 55.02; H, 4.31; N, 13.49.
3-Cyano-4-imino-2-(a-ethylcyanoacetyl)-8-methoxy-4H-
pyrimido[2,1-b][1,3]benzothiazole (7b) Yield: 0.20 g (54%),
m.p.: 182ꢁC; IR (potassium bromide): ¼¼NH 3297, CN 2199,
1
3159 cmꢀ1; H-NMR (DMSO-d6): d 3.4 (s, 2H, NH2), 3.9 (s,
3H, OCH3,), 6.9–7.7 (m, 8H, ArAH), 8.5 (s, 1H, ¼¼NH); ms:
m/z 362 (Mþ). Anal. Calcd. for C18H14N6OS: C, 59.66; H,
3.86; N, 23.20. Found: C, 59.64; H, 3.83; N, 23.16.
3-Amino-4-imino-8-methoxy-2-(40-nitrophenyl)pyrazolo[30,40:4,5]
pyrimido-[2,1-b][1,3]benzothiazole (8c) Yield: 0.198 g (48%),
m.p.: 168ꢁC; IR (potassium bromide): NH2 asymmetric and
C¼¼O of ester 1728 cmꢀ1
;
1H-NMR (deuteriochloroform): d
symmetric 3296, 3100, ¼¼NH 3116 cmꢀ1
;
1H-NMR (DMSO-
2.4 (t, 3H, ACH3), 3.8 (s, 3H, AOCH3), 3.9 (q, 2H, AOCH2),
4.2 (s, 1H, ACH), 6.8–7.3 (m, 3H, ArAH), 9.2 (s, 1H, ¼¼NH);
ms: m/z 367 (Mþ). Anal. Calcd. for C17H13N5O3S: C, 55.58;
H, 3.54; N, 19.07. Found: C, 55.54; H, 3.51; N, 19.02.
d6): d 3.1 (broad, 2H, NH2), 3.7 (s, 3H, AOCH3), 7–7.9 (m,
7H, ArAH), 8.2 (s, 1H, ¼¼NH); ms: m/z 407 (Mþ,100%).
Anal. Calcd. for C18H13N7O3S: C, 53.07; H, 3.19; N, 24.07.
Found: C, 53.04; H, 3.15; N, 24.05.
3-Cyano-4-imino-2-(a-ethylacetoacetyl)-8-methoxy-4H-
3-Amino-4-imino-8-methoxy-2-(20-benzothiazolyl)pyrazo-
pyrimido[2,1-b][1,3]benzothiazole (7c) Yield: 0.30
g
lo[30,40:4,5]pyrimido[2,1-b][1,3]benzothiazole
(8d) Yield:
(78%), m.p.: 115ꢁC; IR (potassium bromide): ¼¼NH 3400, CN
0.233 g (59%), m.p.: 165ꢁC; IR (potassium bromide): NH2
1
2226, C¼¼O of ester 1758, CAO 1248 cmꢀ1; H-NMR (DMSO-
asymmetric and symmetric 3481, 3363, ¼¼NH 3240 cmꢀ1; H-
1
d6): d 2.3 (s, 1H, COCH3), 2.8 (t, 3H, CH3), 3.3 (s, 3H,
AOCH3), 4.0 (q, 2H, OCH2), 4.3 (s, 1H, ACH), 7–7.4 (m, 3H,
ArAH), 9.0 (s. 1H, ¼¼NH); ms: m/z 384 (Mþ). Anal. Calcd. for
C17H13N5O3S: C, 56.25; H, 4.16; N, 14.58. Found: C, 56.22; H,
4.11; N, 14.54.
NMR (deuteriochloroform): d 3.2 (broad, 2H, NH2), 3.8 (s,
3H, AOCH3), 7.1–7.9 (m, 7H, ArAH), 8.5 (s, 1H, ¼¼NH); ms:
m/z 419 (Mþ). Anal. Calcd. for C19H13N7OS2: C, 54.41; H,
3.10; N, 23.38. Found: C, 54.38; H, 3.05; N, 23.35.
3-Amino-4-imino-8-methoxy-2-(60-chloro-20-benzothiazolyl)pyr-
azolo[30,40:4,5] pyrimido [2,1-b][1,3]benzothiazole (8e) Yield:
0.196 g (43%), m.p.: 145ꢁC; IR (potassium bromide): NH2
3-Cyano-4-imino-2-(a-acetylacetone)-8-methoxy-4H-pyri-
mido[2,1-b][1,3]benzothiazole (7d) Yield: 0.20
g (56%),
m.p.: 122ꢁC; IR (potassium bromide): ¼¼NH 3402, CN 2210,
1
C¼¼O 1680 cmꢀ1; H-NMR (deuteriochloroform): d 2.6 (s, 6H,
1
3370, 3250, ¼¼NH 3190 cmꢀ1; H-NMR (deuteriochloroform):
two-COCH3), 3.3 (s, 3H, OCH3), 4.0 (s, 1H, ACH), 7.2–7.6
d 3.4 (broad, 2H, NH2), 3.9 (s, 3H, AOCH3), 7–7.7 (m, 6H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Novel Synthesis and Biological Activity of New Fused Heterocycles
855
ArAH), 8.2 (s, 1H, ¼¼NH); ms: m/z 455 (Mþ2, 3%), 453
(Mþ,10%). Anal. Calcd. for C19H12N7S2OCl: C, 50.33; H,
2.64; N, 21.63. Found: C, 50.30; H, 2.61; N, 21.59.
[3] Victor, S. Eur Patent 1981, 2180; Chem Abstr 1981, 94,
2089005.
[4] Dash, B.; Patra, M.; Mohapatra, P. K. J Inst Chem 1980, 52, 92.
[5] Peteri, H. L. US Patent 3,704,303; Chem Abstr 1972, 78,
3-Amino-4-imino-8-methoxy-2-(60-methyl-20-benzothiazolyl)pyr-
azolo [30,40:4,5]pyrimido[2,1-b][1,3]benzothiazole (8f) Yield:
0.208 g (51%), m.p.: 110ꢁC; IR (potassium bromide): NH2
43513 X.
[6] Glennon, R. A.; Gaines, J. J.; Rogers, M. E. J Med Chem
1981, 24, 766.
1
asymmetric and symmetric 3342, 3309, ¼¼NH 3180 cmꢀ1; H-
[7] Wade, J. J.; Toso, C. B.; Matson, C. J.; Stelzer, V. L.
J Med Chem 1983, 26, 608.
NMR (deuteriochloroform): d 2.1 (s, 3H, ArACH3), 3.1
(broad, 2H, NH2), 3.9 (s, 3H, OCH3), 7.2–7.9 (m, 6H, ArAH),
8.4 (s, 1H, ¼¼NH); ms: m/z 433 (Mþ,100%) Anal. Calcd. for
C20H15N7OS2: C, 55.42; H, 3.46; N, 22.63. Found: C, 55.40;
H, 3.43; N, 22.60.
[8] Covington, R. R.; Temple, D. L.; Yevich, J. P. Ger. Pat.
2918085, 1979; Chem Abstr 1979, 94, 163993q.
[9] Baheti, K. G.; Kapratwar, S. B.; Kuberkar, S. V. Syn Com-
mun 2002, 32, 2237.
[10] Baheti, K. G.; Kuberkar, S. V. Indian J Heterocycl Chem
2003, 12, 343.
Acknowledgments. The authors are thankful to Management
and Principal Dr. S.G. Bhadange, Shri. Shivaji College,
Akola (Maharashtra, India) for providing necessary laboratory
facilities and to the Director, I.I.C.T., Hyderabad for provid-
ing spectra.
[11] Baheti, K. G.; Kuberkar, S. V. J Heterocycl Chem USA
2003, 40, 547.
[12] Baheti, K. G.; Kuberkar, S. V. Indian Drugs 2003, 40, 686.
[13] Okamoto, Y.; Kurasawa, Y.; Takagi, K.; Takada, A.; Ueda,
T. Chem Pharm Bull 1974, 22, 243.
[14] Podanyi, B.; Hermeez, I.; Horvath, A. J Org Chem 1986,
51, 2988.
REFERENCES AND NOTES
[1] Gompper, R.; Toepft, W. Chem Ber 1962, 2871.
[2] Alaimo, R. J. J Heterocycl Chem 1973, 10, 769.
[15] Pingle, M. S.; Vartale, S. P.; Bhosle, V. N.; Kuberkar, S.V.
Arkivoc 2006, X, 190.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet