Synthesis of some novel benzothiazole derivatives

Article abstract of DOI:10.1080/10426500701729653

Novel 1,2,4-triazine, pyridine, and benzopyran derivatives have been synthesized from N-(2-benzothiazolyl)cyanoacetamide via its reaction with some electrophiles. The structure of the synthesized compounds was established by analytical and spectral data. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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Synthesis of Some Novel
Benzothiazole Derivatives
A. M. Hussein a , F. A. Abu-Shanab a , M. A. M. Abdel
Raheim a & M. S. A. El-Gaby a
a Department of Chemistry, Faculty of Science, Al-
Azhar University at Assiut, Assuit, Egypt
Version of record first published: 24 Jun 2008.
To cite this article: A. M. Hussein, F. A. Abu-Shanab, M. A. M. Abdel Raheim & M. S.
A. El-Gaby (2008): Synthesis of Some Novel Benzothiazole Derivatives, Phosphorus,
Sulfur, and Silicon and the Related Elements, 183:7, 1722-1734
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Phosphorus, Sulfur, and Silicon, 183:1722–1734, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701729653
Synthesis of Some Novel Benzothiazole Derivatives
A. M. Hussein, F. A. Abu-Shanab, M. A. M. Abdel Raheim,
and M. S. A. El-Gaby
Department of Chemistry, Faculty of Science, Al-Azhar University at
Assiut, Assuit, Egypt
Novel 1,2,4-triazine, pyridine, and benzopyran derivatives have been synthesized
from N-(2-benzothiazolyl)cyanoacetamide via its reaction with some electrophiles.
The structure of the synthesized compounds was established by analytical and spec-
tral data.
Keywords 1,2,4-triazine; benzothiazole; pyridine, and benzopyran derivatives
INTRODUCTION
The introduction of various heterocyclic moieties at position 2
of the benzothiazole nucleus is beneficial for antimicrobial,1,2
antifungal,3 antimalarial,4 antitumor,5 antiinflammatory,6 histamine
H3 antagonist,7 and diabetes8 activities. Also, benzothiazoles are
commercially important as reactive dyes,9 hair dyes,10 agrochemical
fungicides, insecticides, acaricides,11 herbicides, plant desiccants and
defolicants.12 In continuation of our program directed for the devel-
opment of a new, simple, and efficient procedure for the synthesis
of biologically active heterocyclic compounds utilizing readily obtain-
able intermediates,13−16 we have investigated the reaction of N-(2-
benzothiazolyl)cyanoacetamide (4) with some electrophilic reagents for
the synthesis of some novel 1,2,4-triazine, pyridine and benzopyran
derivatives.
RESULTS AND DISCUSSION
Stetinova et al.17 have reported the synthesis of N-(2-
benzo-thiazolyl)cyanoacetamide (4) by condensation of cyano-
acetohydrazide (1) with acetylacetone to furnish 1-cyanoacetyl-3,
Received 16 March 2007; accepted 1 September 2007.
Address correspondence to M. S. A. El-Gaby, Department of Chemistry, Faculty of Sci-
ence, Al-Azhar University at Assiut, Assuit 71524, Egypt. E-mail: m elgaby@hotmail.com
1722

Novel Benzothiazole Derivatives
1723
5-dimethylpyrazole
(2)
followed
by
treatment
with
2-
aminobenzothiazole (3) in boiling toluene. In our investigation,
cyanoacetamide derivative (4) was synthesized in one step by conden-
sation of ethyl cyanoacetate with 2-aminobenzothiazole (3) in toluene
at reflux temperature in quantitative yield (95%) (Scheme 1).
H3C
CH2(COCH3)2
CH2CONHNH2
N
N
CH3
CN
1
COCH2CN
2
N
S
NH2
NH2NH2
3
toluene/reflux
Ref.17
3
N
CH2COOC2H5
CN
toluene/reflux
S
NHCOCH2CN
4
SCHEME 1
Cyanoacetamide derivative (4) was used as a key intermediate for
the synthesis of hitherto unknown benzothiazole derivatives through
its reaction with some electrophilic reagents. Diazotization of aromatic
amines followed by coupling with active methylene group in compound
(4) in ethanol in the presence of sodium acetate yielded the hydrazone
1
form (6) rather than the azo form (5) based on spectral data. The H
NMR spectrum of compound (6c) recorded in DMSO-d6 revealed a signal
at δ 9.97 ppm, which could be attributed to hydrazone NH group. Cy-
clocondensation of compound (6a) with carbon disulfide in pyridine18 at
reflux temperature furnished the novel 1,2,4-triazinone derivative (7)
in acceptable (74%) yield. The structure of the latter product was es-
tablished based on analytical and spectral data. Its infrared spectrum
was characterized by disappearance of NH group and showed an ab-
sorption band at 2218 cm−1 due to the C N group. The formation of (7)
is assumed to proceed via initial nucleophilic attack of the secondary
amino group of 5 to the thiocarbonyl group of the carbon disulfide fol-
lowed by intramolecular cyclization through elimination of hydrogen
sulfide.18 The 1,2,4-triazinone derivative (8) was obtained by treatment
of compound (6a) with dimethylformamide-dimethylacetal (DMFDMA)
in dry m-xylene under reflux. The molecular structure of compound (8)
was established by analytical and spectral data. The infrared spectrum

1724
A. M. Hussein et al.
of compound (8) indicated the absence of the NH group and its 1H NMR
spectrum recorded in DMSO-d6 exhibited a signal characteristic for
N, N-dimethyl protons. The formation of the latter product is assumed
to proceed through addition of the secondary amino group in compound
(6a) to the electrophilic carbon atom in DMFDMA with elimination of
methanol followed by intramolecular cyclization by loss of methanol to
give (8) (Scheme 2).
SCHEME 2
Cyclocondensation of compound (4) with ketene dithioacetal (9) in re-
fluxing ethanol as solvent and catalytic amounts of piperidine yielded
the pyridinone derivative (11) in good yield (88%). The structure of
compound (11) was confirmed based on its analytical and spectral data.

Novel Benzothiazole Derivatives
1725
SCHEME 3
1
Thus, the H NMR spectrum showed the presence of a singlet for the
protons of the thiomethyl group at δ 1.78 ppm in addition to the signals
of the amino and aromatic protons. The formation of (11) is assumed to
proceed via Michael addition of the active methylene function in (4) to
ketene (9) and elimination of methyl mercaptan to form non-isolable
intermediate (10) followed by intra-molecular cyclization19 and tau-
tomerization to furnish (11), Scheme 3. Treatment of compound (4) with
3-aminocrotononitrile (12) in ethanol in the presence of triethylamine
under reflux furnished the pyridinone derivative (14). The molecular
structure of (14) was established based on its elemental analysis and
spectral data. Its infrared spectrum showed absorption bands at 3269,
3114 cm−1 due to NH2 group in addition to the two absorption bands at
2203 and 1666 cm−1, which can be assigned to C N and C O, respec-
tively. In addition, its 1H NMR spectrum in DMSO-d6 displayed signals
characteristic for amino, pyridine, methyl, and aromatic protons. The
formation of (14) was assumed to be processed via the intermediate (13)
followed by intramolecular cyclization20 through nucleophilic addition
of the secondary amino group to the cyano group and tautomerization
(Scheme 3).
The reaction of (4) with α,β-unsaturated ketones (15a, b) in the
presence of catalytic amount of piperidine led to the formation of
pyridinone derivatives (17a, b). The formation of (17) is assumed

1726
A. M. Hussein et al.
SCHEME 4

Novel Benzothiazole Derivatives
1727
to proceed via Michael addition of the active methylene function in
(4) to the activated double bond in (15) followed by intramolecu-
lar cyclization to furnish pyran (16) which was subjected to Dim-
roth rearrangement20 (Scheme 4). Benzylidene derivative (18) was
obtained by treatment of (4) with 4-methyl benzaldehyde in refluxing
acetic acid in the presence of potassium acetate.17 Reaction of ben-
zylidene derivative (18) with cyanothioacetamide (19a) under reflux
in ethanol in the presence of catalytic amount of triethylamine af-
forded the pyridinethione derivative (20) in quantitative yield. The
formation of (20) is assumed to proceed via Michael addition of
the active methylene function in (4) to the double bond in (18) fol-
lowed by intramolecular cyclization and autoxidation,19 under the
reaction conditions. In a similar manner, cyclization of benzylidene
derivative (18) with cyanoacetic acid hydrazide (19b) in ethanol at
reflux temperature in the presence of piperidine produced the N-
aminopyridinone derivative (21). 4,6-Dimethyl-2-oxo-1-(benzothiazol-
2-yl)-1,2-dihydro-pyridine-3-carbonitrile (23) was achieved by the re-
action of (4) with acetylacetone at 200◦C in the absence of solvent,
via intermediate formation (22) followed by elimination of water,
Scheme 4.
Some benzopyran derivatives possessing a carboxamide moiety are
found to have antibacterial,21 diuretic, analgesic, myorelaxant,22 and
antifungal23 activities. Thus, 3-(2-benzothiazolyl) carboxamide-2H-1-
benzopyran-2-imine (24) was synthesized by the cyclocondensation
of compound (4) with salicylaldehyde in ethanol in the presence of
ammonium acetate. The product was identified by spectroscopy and
elemental analysis. Its infrared spectrum revealed the absence of the
C N group. On the other hand, the reaction of (4) with salicylalde-
hyde in acetic anhydride in the presence of fused sodium acetate fur-
nished benzopyran derivative (25). The structure of compound (25)
was established based on its elemental analysis, spectral data and
an independent synthesis through conversion of imino group in com-
pound (24) to a carbonyl group with hydrochloric acid at room tem-
perature. Treatment of compound (4) with hydrazine hydrate fur-
nished amino pyrazole derivative (27), via intermediate formation (26)
followed by intramolecular cyclization through elimination of water,
Scheme 5.
CONCLUSION
In conclusion, we have found a facile method for the synthesis of N-(2-
benzothiazolyl)cyanoacetamide 4. Also, the reaction of cyanoacetamide
derivative 4 with some electrophilic reagents was investigated.

1728
A. M. Hussein et al.
SCHEME 5
EXPERIMENTAL
Melting points are uncorrected. IR spectra were recorded (KBr) on a
Perkin Elmer 1650 spectrophotometer. 1H NMR spectra were recorded
on a Varian Gemini spectrometer 200 (200 MHz), using DMSO-d6 as
a solvent and TMS as internal standard. Chemical shifts are given in
δ ppm. Microanalytical data were obtained from the Microanalytical
Unit at Cairo University. Found: C, H, N for all compounds were within
0.4% from theoretical value. Physical data for the synthesized com-
pounds are given in Table I. Also, the spectral data are collected in
Table II.
N-(2-Benzothiazolyl)cyanoacetamide (4)
A mixture of ethyl cyanoacetate (0.01 mol) and 2-aminobenzothiazole
3 (0.01 mol) in toluene (20 mL) was refluxed for 5 h, the solid product

Novel Benzothiazole Derivatives
1729
TABLE I Physical and Analytical Data of the Synthesized
Compounds
Elemental
analysis
Molecular
formula
(%)
MP
Solvent
cryst.
Yield
Color
(◦C)
(mol. wt)
C% H% N%
6a 238–239 D/E
6b 242–244 D/E
6c 240–241 D/E
Yellow
86
82
76
74
62
88
77
77
70
88
74
86
87
82
70
C16H10ClN5OS 54.01 2.83 19.68
(355.81) 54.10 2.80 19.70
C16H10BrN5OS 48.01 2.52 17.50
Yellow
Yellow
Brown
Brown
(400.26)
17H13N5OS
(335.39)
48.30 2.50 17.50
60.88 3.91 20.88
60.80 3.90 20.80
C
7
8
252–253
E
C
17H8ClN5OS2 51.32 2.03 17.60
(397.87) 51.30 2.00 17.60
C19H15ClN6OS 55.54 3.68 20.45
268–269 D/E
(410.89)
15H9N5OS2
(339.40)
14H10N4OS
(282.33)
55.50 3.60 20.40
53.08 2.67 20.63
53.10 2.60 20.60
59.56 3.57 19.84
59.50 3.50 19.80
11
>300 DMF/E Brown
C
C
14 298–299 DMF/E Brown
17a 200–202 D/E
Yellow
C
26H19N3O3S 68.86 4.22 9.27
(453.52) 68.80 4.20 9.20
25H16ClN3O2S 65.57 3.52 9.18
(457.94) 65.50 3.50 9.10
C21H15N5OS2 60.41 3.62 16.77
(417.51) 60.40 3.60 16.70
21H16N6O2S 60.57 3.87 20.18
17b >300
D
E
Brown
C
20 140–141
Pale yellow
Yellow
21 330–332 D/E
C
(416.46)
15H11N3OS
(281.34)
60.50 3.80 20.10
64.04 3.94 14.94
64.10 3.90 14.90
23 232–233
24 170–171
25 206–207
E
E
E
E
Brown
C
Pale yellow
Brown
C
17H11N3O2S 63.54 3.45 13.08
(321.36) 63.50 3.40 13.10
C17H10N2O3S 63.35 3.13 8.69
(322.34)
63.30 3.10 8.70
51.93 3.92 30.28
51.90 3.90 30.20
27
90–91
Brown
C
10H9N5S
(231.28)
Where E = Ethanol; D = Dioxane; and DMF = Dimethylformamide.
produced on heating was collected and recrystallized from acetic acid
to give 4 as colorless crystals, m.p. 246◦C (Lit.17 m.p. 246–248◦C).
N-(2-Benzothiazolyl)-2-arylhydrazono-2-cyanoacetamides
(6a–c)—General Procedure
Aromatic amine (0.01 mol) was dissolved in a mixture of concentrated
HCl (3 mL) and water (6 mL) and cool to 0◦C in an ice bath. A cold

1730
A. M. Hussein et al.
TABLE II Spectral Data of the Synthesized Compounds
IR/νmax(cm−1
)
1H NMR (DMSO-d6) (δ/ppm)
6a
6b
6c
3448, 3292 (NH), 2221
(C N), 1689 (C O;
amide).
3442, 3292 (NH), 2262
(C N), 1689 (C O;
amide).
3420, 3270 (NH), 2170
(C N), 1634 (C O;
amide).
2218 (C N), 1676 (C O).
2195 (C N), 1696 (C O).
4.12 (s, 1H, NH), 7.28–7.46 (m, 4H,
Ar H), 7.72, 7.98 (2d, 4H, Ar H),
7.81 (1H, NH).
2.29 (s, 3H, CH3), 7.19–7.47 (m, 4H,
Ar H), 7.65, 7.91 (2d, 4H, Ar H),
7.77 (1H, NH), 9.97 (s, 1H, NH).
7.29–7.99 (m, 8H, Ar H).
3.23 (s, 6H, 2CH3), 7.24–8.24 (m, 8H,
Ar H), 8.87 (s, 1H, triazine-H).
1.78 (s, 3H, SCH3), 3.90 (2H, NH2),
7.34–7.99 (m, 4H, Ar H).
7
8
11
3323, 3198 (NH2), 2935,
2855 (CH-aliph), 2204
(C N), 1630 (C O).
3269, 3114 (NH2), 2926
(CH-aliph), 2203 (C N),
1666 (C O).
14
2.51 (s, 2, 3H, CH3), 6.21 (s, 2H, NH2),
7.22–7.91 (m, 4H, Ar H), 10.01 (s,
1H, H-pyridine).
17a
17b
20
3394, 3296 (NH), 2951
(CH-aliph), 1652 (C O).
3398 (NH), 1686 (C O).
—
7.30–8.00 (m, 14H, Ar H), 8.32, 8.36
(2s, 2H, 2NH).
1.27 (s, 2H, NH2), 2.34 (s, 3H, CH3),
7.13–7.40 (m, 9H, Ar H + NH), 7.80
(1H, NH).
3335, 3205 (NH2), 2940
(CH-aliph), 2214 (C N),
1633 (C O).
21
23
3324, 3300 (NH2), 2945
(CH-aliph), 2204 (C N),
1643 (C O).
3075 (CH-arom), 2219
(C N), 1675 (C O).
2.34 (s, 3H, CH3), 3.65 (4H, NH2),
7.16–7.37 (m, 8H, Ar H), 9.93 (s,
1H, NH).
2.24, 2.48 (2s, 6H, CH3), 6.19 (s, 1H,
pyridine-H), 7.49–8.09 (m, 4H,
Ar H).
24
25
3259, 3192 (NH), 3060
(CH-arom), 1705 (C O).
3421 (NH), 3062 (CH-arom),
1764 (C O; lactone), 1678
(C O; amide).
7.0–7.9 (m, 9H, Ar H), 8.01, 8.70 (2H,
2NH).
7.20–7.60 (m, 10H, Ar H + NH).
27
3378, 3299 (NH2), 3063
(CH-arom), 1612 (C N).
5.46 (s, 2H, NH2), 6.40–7.14 (m, 7H,
Ar H + NH).
aqueous solution of sodium nitrite (0.01 mol) was then added. The
diazonium salt thus obtained was filtered into a cold mixture of sodium
acetate (2 g) and 4 (0.01 mol) in ethanol (30 mL). The resulting solid
was washed with water and recrystallized from the proper solvent to
give 6.

Novel Benzothiazole Derivatives
1731
4-(2-Benzothiazolyl)-2-(4-chlorophenyl)-5-oxo-3-thioxo-2,3,4,5-
tetrahydro-1,2,4-triazine-6-carbonitrile (7)
A mixture of compound 6a (0.01 mol) and carbon disulfide (0.012 mol) in
pyridine (10 mL) was refluxed for 2 h, then allowed to cool, and poured
into cold water (30 mL) and acidified with HCl. The solid product was
collected and recrystallized from the proper solvent to give 7.
4-(2-Benzothiazolyl)-2-(4-chlorophenyl)-3-(N,N-
dimethylamino)-5-oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-
carbonitrile (8)
A mixture of compound 6a (0.01 mol) and dimethylformamide-
dimethylacetal (0.01 mol) in m-xylene (30 mL) was refluxed for 1 h,
then allowed to cool and poured into ether (50 mL). The solid product
was collected and recrystallized from the proper solvent to give 8.
6-Amino-1-(2-benzothiazolyl)-4-methylsulfanyl-2-oxo-1,2-
dihydro-pyridine-3,5-dicarbonitrile (11)
A mixture of compound 4 (0.01 mol), ketene dithioacetal 9 (0.01 mol)
and piperidine (0.01 mol) in ethanol (30 mL) was heated under reflux
until the evolution of methyl mercaptan had stopped. After cooling, the
reaction mixture was poured into cold water (40 mL) and acidified with
HCl. The product was collected by filtration and recrystallized from the
proper solvent to give 11.
6-Amino-1-(2-benzothiazolyl)-4-methyl-2-oxo-1,2-dihydro-
pyridine-3-carbonitrile (14)
A mixture of compound 4 (0.01 mol), 3-aminocrotononitrile 12 (0.01
mol) and triethylamine (0.01 mol) in ethanol (30 mL) was heated under
reflux for 0.5 h, then allowed to cool and poured into cold water (50
mL). The solid product was collected and recrystallized from the proper
solvent to give 14.
3-(2-Benzothiazolyl)carboxamide-6-phenyl-4-(4-substituted
phenyl)-2-oxo-1,2-dihydropyridines (17a,b)—General
Procedure
A mixture of compound 4 (0.01 mol), α,β-unsaturated ketone 15 (0.01
mol) and piperidine (0.05 mol) in ethanol (30 mL) was heated under

1732
A. M. Hussein et al.
reflux for 12 h, the solid product produced on heating was collected and
recrystallized from the proper solvent to give 17.
6-Amino-5-(2-benzothiazolyl)carboxamide-4-(4-methylphenyl)
-2-thioxo-1,2-dihydropyridine-3-carbonitrile (20)
A mixture of compound 18 (0.01 mol), cyanothioacetamide 19a (0.01
mol) and triethylamine (0.01 mol) in ethanol (30 mL) was heated under
reflux for 1 h, the solid product produced on heating was collected and
recrystallized from the proper solvent to give 20.
1,6-Diamino-5-(2-benzothiazolyl)carboxamide-4-(4-methyl-
phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (21)
A mixture of compound 18 (0.01 mol), cyanoacetic acid hydrazide 19b
(0.01 mol) and piperidine (0.01 mol) in ethanol (30 mL) was heated un-
der reflux for 0.5 h, the solid product produced on heating was collected
and recrystallized for the proper solvent to give 21.
4,6-Dimethyl-1-(2-benzothiazolyl)-2-oxo-1,2-dihydro-pyridine-
3-carbonitrile (23)
A mixture of compound 4 (0.01 mol) and acetylacetone (0.01 mol) was
heated at 200◦C for ten minutes. The reaction mixture was left to cool,
then triturated with ethanol. The solid product so formed was collected
by filtration and recrystallized from the proper solvent to give 23.
3-(2-Benzothiazolyl)carboxamide-2H-1-benzopyran-2-imine
(24)
A mixture of compound 4 (0.01 mol), salicylaldehyde (0.01 mol) and
ammonium acetate (0.02 mol) in ethanol (30 mL) was refluxed for 1 h,
then allowed to cool. The solid product was collected and recrystallized
from the proper solvent to give 24.
3-(2-Benzothiazolyl)carboxamide-2-oxo-2H-1-benzopyran (25)
Method A
A mixture of compound 4 (0.01 mol), salicylaldehyde (0.01 mol) and
sodium acetate (2 g) in acetic anhydride (10 mL) was refluxed for 1 h,
then allowed to cool. The solid product was collected and recrystallized
from the proper solvent to give 25.

Novel Benzothiazole Derivatives
1733
Method B
To a solution of compound 24 (0.01 mol) in boiling ethanol (30 mL),
conc. HCl (3 mL) was added. The reaction mixture was allowed to cool
down to ambient temperature overnight. The product was collected,
washed with cold water and recrystallized from the proper solvent to
give 25.
3-Amino-5-(2-benzothiazolyl)amino-1H-pyrazole (27)
A mixture of compound 4 (0.01 mol) and hydrazine hydrate (0.02 mol)
was heated at 180◦C for 30 minutes. The reaction mixture was left to
cool, then triturated with ethanol. The solid product, so formed, was
collected by filtration and recrystallized from the proper solvent to give
27.
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