Studies with 2-benzothiazolylacetonitrile: Synthesis of new 2-thienylbenzothiazoles and N-thienyl maleimide derivatives

Article abstract of DOI:10.1080/10426500210233

The synthesis of new 2-thienylbenzothiazoles and N-thienyl maleimide derivatives utilizing 2-benzothiazolyl acetonitrile 1 as starting component.

Full text of DOI:10.1080/10426500210233

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Phosphorus, Sulfur, and Silicon and the Related
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Studies With 2-Benzothiazolylacetonitrile: Synthesis of
New 2-Thienylbenzothiazoles and N-Thienyl maleimide
Derivatives
Yehya Mahmmoud Elkholy a
a Chemistry Department, Faculty of Science, Helwan University, Ain-Helwan, Cairo, Egypt
Version of record first published: 27 Oct 2010.
To cite this article: Yehya Mahmmoud Elkholy (2002): Studies With 2-Benzothiazolylacetonitrile: Synthesis of New 2-
Thienylbenzothiazoles and N-Thienyl maleimide Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:1,
115-122
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Phosphorus, Sulfur and Silicon, 2002, 177:115–122
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STUDIES WITH 2-BENZOTHIAZOLYLACETONITRILE:
SYNTHESIS OF NEW 2-THIENYLBENZOTHIAZOLES
AND N-THIENYL MALEIMIDE DERIVATIVES
Yehya Mahmmoud Elkholy
Chemistry Department, Faculty of Science, Helwan University,
Ain-Helwan, Cairo, Egypt
(Received April 19 2001.)
The synthesis of new 2-thienylbenzothiazoles and N-thienyl maleimide
derivatives utilizing 2-benzothiazolyl acetonitrile 1 as starting compo-
nent.
Keywords: 2-benzothiazolylacetonitrile; maleic anhydride; thiophene
Azolyl acetonitriles are readily obtainable compounds that have been
3
extensively utilized as intermediates in heterocyclic synthesis1
which are of potential biological activity.4,5 Thiazole and its derivatives
are long known for their antibacterial6 activity and their use as
hypoglycemic,7 fungicidal8 and herbicidal9 agents. In conjunction with
our previous work10,11 we report here the results of our further work
exploring the synthetic potential of 2-benzothiazolylacetonitrile 1.
Thus, it has been found that 1 reacts with acetone in the presence of
sulfur and triethylamine in boiling ethanol solution to yield a product
that is assigned the structure 3a based on analytical and spectral
data. The IR spectrum of this product revealed the absence of the CN
signal and the appearance of the NH2 signal as required by structure
3. The formation of 3 is assumed to proceed via the nonisolated
intermediate mercapto derivative 2 that cyclizes and then aromatized
readily under the reaction condition to give 3. Similarly, compound 1
reacts with cyclohexanone to yield the thienyl benzothiazole derivative
3b. Furthermore, a mixture of malononitrile and sulfur reacted with
compound 1 to yield either 5a or 7a. The formation of 7a is assumed
to proceed via addition of CH2 group of the malononitrile to the CN
Address correspondence to Yehya Mahmmoud Elkholy, Chemistry Department, Fac-
ulty of Science, Helwan University, Ain-Helwan, Cairo, Egypt. E-mail: Y elkholy@
yahoo.com
115

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Y. M. Elkholy
function in 1 followed by reaction with sulfur to yield 6a which was
cyclized into 7a. Alternatively CH2 of 1 may added to the CN function
of malononitrile and then reacted with sulfur to give the intermediate
4, which was cyclized to 5. Structure 7a is preferred over possible 5a
1
based on the IR spectrum which showed a CN signal at 2250 cm
.
Alternative 5a is expected to show a CN signal at a lower frequency.12
Similar to malononitrile, ethyl cyanoacetate yields 7b (cf. Scheme 1).
SCHEME 1
In other trials to prepare thienylbenzothiazole derivative with di-
amino substituent as a good dyestuff, compound 1 reacted with ben-
zoylisothiocyanate to yield a 1:1 adduct which may be formulated as 8.
Structure 8 was established for the reaction product based on 1H NMR
which revealed the absence of the CH2 function and the presence of NH
as well as SH function. Compound 8 reacted with phenacyl bromide
to yield a product which was formulated as 10 rather than isomeric
11.13 Compound 11 was established based on the IR spectrum, which
showed signals for two NH2 groups and disappearance of cyano group.
Compound 11 is believed to be formed via the nonisolated intermediate
9, which undergoes cyclization under the reaction condition to give the
final isolated product. (cf. Scheme 2).
Furthermore, compound 1 reacts with methyldine derivative 12
and sulfur in the presence of ethanolic triethylamine to give

Thienylbenzothiazoles
117
SCHEME 2
SCHEME 3
theinyl derivatives 15a–d through the nonisolated intermediate 13
and 14.
Compounds 3a, 7a, and 7b reacted with maleic anhydride to give
the thienylamidomaleic acid derivatives 16a–c, which readily cyclized

118
Y. M. Elkholy
to give N-thienylmaleimide derivatives 17a–c via elimination of H2O
when heated in acetic anhydride (cf. Scheme 4).
SCHEME 4
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were obtained on
1
a Shimadzu 408 spectrophotometer. The H NMR were measured in
DMSO[d6] on a Varian EM-390 MHz spectrometer using TMS as inter-
nal reference and chemical shifts are expressed as ppm. Analytical
data were obtained from the Analytical Data Unit at Cairo University,
Egypt.
General Procedure for the Synthesis of
2-Thienylbenzothiazole Derivatives ( 3a,b and 7a,b)
A solution of 1 (0.01 mol) in ethanol (30 ml) was treated with the ap-
propriate amount of active methylene reagents (0.01 mol) and sulfur
(0.01 mol) with catalytic amount of triethylamine (2 ml). The reaction
mixture was heated under reflux for 5 h. The solvent was removed un-
der reduced pressure and the residue was triturated with water and
neutralized with conc. HCl. The solid product so formed was collected
by filtration and recrystallized from DMF.

Thienylbenzothiazoles
119
2-[3-(2-amino-4-methyl)thienyl]benzothiazole (3a)
Compound 3a was obtained as yellow crystals (65%) from DMF; m.p.
1
127 C; IR: 3400–3100 (br. NH2), 2990 (CH3), 1600 (C N) cm
.
1H
NMR: 2.2 (s, 3H, CH3), 6.9–8.2 (m, 7H, aromatic and NH2) ppm. Anal.
requires for C12H10N2S2 (246.34): C, 58.5; H, 4.08, N, 11.37; S, 26.01.
Found: C, 58.8; H, 4.1; N, 11.5; S, 26.2.
2-[3-(2-aminocyclohexa[b]thienyl)]benzothiazole (3b)
Compound 3b was obtained as yellow crystals (68%) from DMF; m.p.
142 C; IR: 3400–3150 (br. NH2), 1620(C N) cm 1. 1H NMR: 2.6 (t, 4H,
2CH2); 3.6 (m, 4H, 2CH2); 6.9–8.3 (m, 6H, aromatic and NH2). Anal.
requires for C15H14N2S2 (286.40): C 62.90: H, 4.92, N, 9.78; S, 22.39.
Found: C, 63.0; H, 4.4; N, 9.91; S, 22.7.
2-[2-(3,5-diamino-4-cyanothienyl]benzothiazole (7a)
Compound 7a was obtained as yellow crystals (60%) from DMF;
m.p. 146 C; IR: 3400–3150 (br. NH2), 2250 (CN), 1620 (C N) cm 1. 1H
NMR: 7.2–7.9 (m, 8H, aromatic and NH2 protons). Anal. requires for
C12H8N4S2 (272.34): 52.92; H, 2.95; N, 20.57; S, 23.54. Found: C 53.2;
H, 3.3; N, 20.8; S, 23.8.
2-[2-(3,5-diamino-4-ethoxycarbonyl)]benzothiazole (7b)
Compound 7b was obtained as yellow crystals (70%) from DMF;
m.p. 162 C; IR: 3450–3150 (br. NH2), 1700–1680 (CO) cm 1-1H NMR:
1.3 (t, 3H, CH3); 4.2(q, 2H, CH2); 7.1–7.5 (m, 8H, aromatic and NH2
protons). Anal. requires for C14H13N3O2S2 (319.3) C, 52.66; H, 4.07; N,
13.16; S, 20.06. Found: C 52.9; H, 4.1; N, 13.5; S, 20.3.
Reaction of Compound 1 with Benzoylisothiocyonate
A solution of benzoylisothiocyonate (0.01 mol) in acetone (30 ml) was
treated with compound 1 (0.01 mol). The reaction mixture was heated
under reflux for 3 h. The solvent was removed under reduced pressure
and the residue was triturated with water. The solid product formed
was collected by filtration and recrystallized from ethanol.
2-benzamido-1-benzothiazolyl-1-cyano-2-mercaptoethene
(8)
Compound 8 was obtained as brown crystals (65%) from ethanol; m.p.
175 C; IR: 3150 (NH); 2200 (CN), 1680 (C O); 1600 (C N) cm 1-1H
NMR: 7.3–8.3 (m, 10H, aromatic and NH protons); 10.6 (s, 1H, SH)
Anal. requires for C17H11N3OS2 (337.39) C, 60.51; H, 3.28; N, 12.45; S,
19.0. Found: C, 60.8; H, 3.5; N, 12.7; S, 19.4.

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Y. M. Elkholy
Synthesis of Diaminothiophene Derivative (11)
A solution of compound 8 (0.01 mol) in dioxane (40 ml) was treated with
phenacyl bromide (0.01 mol) and triethylamine (2 ml). The reaction mix-
ture was heated under reflux for 4 h. The solvent was then evaporated
under reduced pressure and the residue was triturated with water. The
solid product formed was collected by filtration and recrystallized from
DMF.
2-[3-(2,4-Diamino-5-benzoyl)thienyl]benzothiazole (11)
Compound 11 was obtained as yellow crystals (58%) from DMF; m.p.
210 C; IR: 3300 (br. 2NH2); 1680 (CO), 1600 (C N) cm 1-1H NMR:
7.3–7.9 (m, 9H, aromatic protons); 8.2 (br, 4H, 2NH2). Anal. requires
for C18H13N3OS2 (351.4): C, 61.52; H, 3.72; N, 11.95; S, 18.2 Found: C,
61.8; H, 3.5; N, 11.6; S, 17.9.
General Procedure for the Synthesis of Thienyl
Derivatives (15a--d)
A solution of the appropriate methyldine derivatives 12a–d (0.01 mol)
[prepared in situ from the reaction of the corresponding aldehyde and
active methylene in ethanol in the presence of a catalytic amount of
triethylamine] and sulfur element (0.01 mol) were added to compound
1 (0.01 mol). The reaction mixture was heated under reflux for 4 h. The
solid product so formed was collected by filtration and recrystallized
from DMF.
2-[3-(2-amino-5-thiamido)thienyl]benzothiazole (15a)
Compound 15a was obtained as brown crystals (67%) from DMF;
m.p. 276 C; IR: 3400–3100 (NH2)cm 1-1H NMR: 5.4 (br, 2H, NH2);
7.1–8.3 ppm (m, 7H, aromatic, thiophene-H and NH2 protons). Anal.
requires for C12H9N3S3 (291.38): C 49.46; H, 3.10; N, 14.41; S, 33.02.
Found: C, 49.6; H, 3.2; N, 14.8; S, 33.4.
2-[3-(2-amino-5-ethoxycarbonyl)thienyl]benzothiazole
(15b)
Compound 15b was obtained as brown crystals (71%) from DMF;
m.p. 291 C; IR: 3350 (NH2), 1700 (ester CO cm 1-1H NMR:
1.3
(t, 3H, CH3); 4.2 (q, 2H, CH2); 7.1–8.2 (m, 7H, aromatic, thiophene-
H and NH2 protons). Anal. requires for C14H12N2O2S2 (304.34): C,
55.25; H, 3.96, N, 9.20; S, 21.06. Found: C, 55.6; H, 3.6; N, 9.5; S,
21.3.

Thienylbenzothiazoles
121
2-[3-(2-amino-5-cyano-4-methyl)thienyl]benzothiazole
(15c)
Compound 15c was obtained as yellow crystals (68%) from DMF;
m.p. 298 C; IR: 3200–3100 (NH2), 2210 (CN) cm 1-1H NMR: 1.7 (s,
3H, CH3); 7.1–8.2 (m, 6H, aromatic and NH2 protons). Anal. requires
for C13H9N3S2 (271.33): C 57.54; H, 3.33; N, 15.48; S, 23.63. Found: C,
57.6; H, 3.6; N, 15.8; S, 23.7.
2-[3-(2-amino-4-methyl-5-thiamido)thienyl]benzothiazole
(15d)
Compound 15d was obtained as yellow crystals (65%) from DMF;
m.p. 283 C; IR: 3400–3100 (NH2) cm 1-1H NMR: 1.7 (s, 3H, CH3),
4.2 (br., 2H, NH2), 7.1–8.2 (m, 6H, aromatic and NH2). Anal. requires
for C13H11N3S3 (305.4): C, 51.12; H, 3.62; N, 13.75; S, 31.49. Found:
C, 51.4; H, 3.8; N, 13.9; S, 31.6.
Reaction of 3a, 7a, and 7b with Maleic Anhydride
A solution of compounds 3a, 7a, and 7b (0.01 mol) in DMF (40 ml)
was treated with maleic anhydride (0.01 mol) and the reaction mixture
was heated under reflux for 5 h. The solvent was then evaporated in
vacuo and the residue was treated with ice and water; the solid product
formed on standing was collected by filtration and recrystallized from
DMF.
Compound 16a was obtained as yellow crystals (61%) from DMF;
m.p. 243 C; IR: 3380–3350 (NH, OH), 1730, 1670 (2CO) cm 1.1H NMR:
5.4, 5.6 (2d, 2H, 2CH), 1.7 (s, 3H, CH3), 7.1–8.2 (m, 4H, aromatic
protons) 10.12 (s, 1H, OH), 13.2 (br, 1H, NH). Anal. requires for
C16H12N2O3S2 (344.35): C, 55.80; H, 3.50; N, 8.13; S, 18.62. Found: C,
55.6; H, 3.6; N, 8.4; S, 18.7.
Compound 16b was obtained as yellow crystals (68%) from DMF;
m.p. 233 C; IR: 3400–3350 (OH, NH), 2210 (CN), 1740, 1665 (CO)
cm 1.1H NMR: 5.4, 5.6 (2d, 2H, 2CH), 7.1–8.1 (m, 6H, aromatic-
protons and NH2); 10.10 (s, 1H, OH); 13.10 (br, 1H, NH). Anal. requires
for C16H10N4O3S2 (370.35): C, 51.88; H, 2.71; N, 15.12; S, 17.31. Found:
C, 51.4; H, 2.6; N, 15.6; S, 17.7.
Compound 16c was obtained as yellow crystals (68%) from DMF; m.p.
213 C; IR: 3400–3100 (OH, NH), 1740–1670 (CO), 1735 (CO) cm 1. 1H
NMR: 1.3 (t, 3H, CH3); 4.2 (q, 2H, CH2); 8.2 (br, 4H, 2NH2), 7.1–7.6
(m, 4H, aromatic protons), 10.0 (s, 1H, OH); 13.10 (br, 1H, NH). Anal.
requires for C18H15N3O5S2 (417.37): C, 51.79; H, 3.61; N, 10.06; S, 15.36.
Found: C, 51.6; H, 3.4; N, 10.4; S, 15.4.

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Y. M. Elkholy
Synthesis of N-thienylmaleimide Derivatives (17a--c)
A solution of 16a–c (0.01 mol) in acetic anhydride (30 ml) was heated
under reflux for 2 h. The reaction mixture was treated with ice and
water; the solid product formed on standing was collected by filtration
and recrystallized from absolute ethanol.
Compound 17a was obtained as yellow crystals (50%) from EtOH;
1
m.p. 280 C; IR: 1680 (CO) cm 1. H NMR: 1.7 (s, 3H, CH3), 6.4, 6.8
(2d, 2H, 2CH), 7.1–8.2 (m, 4H, aromatic protons). Anal. requires for
C16H10N2O2S2 (326.35): C, 58.88; H, 3.08; N, 8.58; S, 19.64. Found: C,
58.6; H, 3.2; N, 8.4; S, 19.7.
Compound 17b was obtained as yellow crystals (48%) from EtOH;
m.p. 250 C; IR: 3400–3100 (NH2), 2210 (CN), 1680 (CO) cm 1. 1H NMR:
6.4, 6.8 (2d, 2H, 2CH), 7.1–8.1 (m, 6H, aromatic-protons, and NH2).
Anal. requires for C16H8N4O2S2 (352.35): C, 54.53; H, 2.28; N, 15.89; S,
18.19. Found: C, 54.4; H, 2.6; N, 15.6; S, 18.4.
Compound 17c was obtained as yellow crystals (45%) from EtOH;
m.p. 220 C; IR: 3400–3100 (NH2), 1675 (CO), 1735 (CO) cm 1. 1H NMR:
1.3 (t, 3H, CH3); 4.2 (q, 2H, CH2); 7.1–8.1 (m, 6H, aromatic protons,
and NH2). Anal. requires for C18H13N3O4S2 (399.37): C, 54.13; H, 3.27;
N, 10.51; S, 16.05. Found: C, 54.4; H, 3.4; N, 10.4; S, 16.4
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