Nitriles in organic synthesis: Synthesis of new benzothiazole derivatives of biological interest

Article abstract of DOI:10.1080/10426500902812498

Cyanobenzothiazole (1) was utilized for the synthesis of several new fused and 2-heterylbenzothiazole derivatives such as pyrimido, pyridino, quinolino, pyrazolopyranyl, pyrimidinopyranyl, and cyclohexanopyranyl benzothiazole derivatives.

Full text of DOI:10.1080/10426500902812498

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Phosphorus, Sulfur, and Silicon and the
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Nitriles in Organic Synthesis: Synthesis
of New Benzothiazole Derivatives of
Biological Interest
A. A. Fadda a , M. Hammouda a , E. M. Afsah a & Ahlam A. Hanash a
a Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt
Version of record first published: 03 Feb 2010.
To cite this article: A. A. Fadda, M. Hammouda, E. M. Afsah & Ahlam A. Hanash (2010): Nitriles in
Organic Synthesis: Synthesis of New Benzothiazole Derivatives of Biological Interest, Phosphorus,
Sulfur, and Silicon and the Related Elements, 185:2, 433-446
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Phosphorus, Sulfur, and Silicon, 185:433–446, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902812498
NITRILES IN ORGANIC SYNTHESIS: SYNTHESIS
OF NEW BENZOTHIAZOLE DERIVATIVES
OF BIOLOGICAL INTEREST
A. A. Fadda, M. Hammouda, E. M. Afsah,
and Ahlam A. Hanash
Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt
Cyanobenzothiazole (1) was utilized for the synthesis of several new fused and 2-
heterylbenzothiazole derivatives such as pyrimido, pyridino, quinolino, pyrazolopyranyl,
pyrimidinopyranyl, and cyclohexanopyranyl benzothiazole derivatives.
Keywords Benzothiazole; 2-cyanomethylbenzothiazole; formaldehyde; pyrazole
INTRODUCTION
Recently there have been broad developments in investigations of both the syn-
thesis and the study of the chemical properties of benzothiazole derivatives, which have
valuable pharmacological activities.1–3 Several lines of evidence support the hypothesis
that 2-cyanomethylbenzothiazole (1) has resulted in their synthesis and chemistry. For the
past decade, we have been exploring the synthetic potential, scope, and limitations of 2-
cyanomethylbenzothiazole and other activated nitriles in heterocyclic synthesis.4–7 Several
new approaches for the synthesis of five-membered and six-membered rings and their fused
heterocyclic derivatives have been developed during our research that has resulted in this
article.
2-Cyanomethylbenzothiazole (1), in the presence of various reagents, undergoes dif-
ferent types of reactions to yield other heterocyclic compounds of biological and industrial
interest.
These advances warrant a review of the chemistry and biological properties of 2-
cyanomethylbenzothiazole and highlight its potential in developing synthetic uses.8
RESULTS AND DISCUSSION
In continuation of our interest in heterocyclic synthesis of compounds with
potential pharmacological value, we decided to study the synthetic potentiality of
Received 18 October 2008; accepted 10 February 2009.
Address correspondence to A. A. Fadda, Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt. E-mail: afadda2@yahoo.com
433

434
A. A. FADDA ET AL.
2-cyanomethylbenzothiazole (1) towards some reagents as a convenient route to some
condensed and substituted benzothiazoles.
The reactivity of 2-cyanomethylbenzothiazole (1a) can be attributed to the con-
tribution of a resonance structure (1b), which is analogous to enamines (Scheme 1). It
has been reported that enamines react with primary amines and 2 mol of formaldehyde
to yield tetrahydropyrimidines.9–11 Thus, it was of interest to study the behavior of 2-
cyanomethylbenzothiazole (1) towards a double Mannich reaction as a route to condensed
pyrimidine systems (Scheme 2).
S
S
CN
CN
N
H
N
1a
1b
Scheme 1
S
S
RNH2
2CH2O
CN
CN
N
H
N
1b
N
R
2
R
a
b
c
-CH2-C6H5
-CH2-(CH2)2CH3
-CH(CH3)2
2a-d
d
-cyclohexyl
Scheme 2
Therefore, when 2-cyanomethylbenzothiazole (1) was treated with primary amines
such as benzylamine, n-butylamine, isopropylamine, or cyclohexylamine and formalin in
a molar ratio of 1:1:2, the pyrimidobenzothiazole derivatives (2a–d), respectively, were
obtained. The analytical and spectral data are consistent with the proposed structures of
compounds (2a–d) (see the Experimental section).
The IR spectra of these products showed stretching frequencies at 2194–2155 cm−1
for CN function group. The mass spectra of (2a–d) showed the molecular ion peak at m/z
305 (M+, 65%), 271 (M+ as base peak), 257 (M+, 43%) and 297 (M+, 9.7%), respectively.
In addition, the 1H NMR spectrum of (2a) exhibited signals at δ 3.0 (d, J = 12.3 Hz, 2H,
CH2 N), δ 3.69 (d, J = 11.5 Hz, 2H, N CH2 N), δ 3.90 (s, 2H, CH2 Ph) and a complex
pattern at δ 7.25–8.01 (9H, aromatic).
Alternatively, treatment of (1) with formalin and secondary amines, such as piperi-
dine, morphline, or dimethylamine in a molar ratio of 1:1:1 under Mannich reaction condi-
tions afforded the methylene bis-compound (3) rather than the expected compound (4). The
structure of 1,3-dicyano-1,3-di[benzothiazol-2-yl]propane (3) was determined by analytical
and spectral data (Scheme 3).
The formation of (3) could be rationalized through a mechanism that involves the
formation of (4) as an intermediate followed by deamination and attack on the enamine (1)
(see Scheme 4).

NITRILES IN ORGANIC SYNTHESIS
435
S
CN
N
H
1
CH2O
R2NH
R2NH= piperidine, morphline or dimethylamine
S
S
S
N
N
H
N
H
NR2
H
CN CN
CN
4
3
Scheme 3
-NHR2
NH
N
CH2
CN
S
NR2
S
CN
4
S
S
S
N
N
N
N
H
CH2
N
H
S
CN
C
CN
N
C
-H, +H
proton transfer
S
S
S
S
N
N
N
N
H
H
CN CN
CN CN
3
Scheme 4
The IR spectrum of compound (3) showed absorption bands around the region
2220 cm−1 attributable to the cyano groups. The 1H NMR spectrum of the reaction product
revealed the CH2 protons and CH protons as multiplet at δ 3.4–3.8 ppm due to vicinal and
geminal coupling and a multiplet at δ 7.1–8.1 ppm due to aromatic protons.
The structure of (3) was further confirmed by an alternative synthesis. Thus, treatment
of (1) with formalin in a molar ratio of 2:1 in refluxing ethanol yielded a product identical
in all respects (mp, mixed mp, IR, and 1H NMR) with (3).7
It has been reported that 6-amino-1,3-dimethyluracil reacts with an equimolar amount
of ketonic Mannich base hydrochloride (5) to give the pyrido[2,3-d]pyrimidin-2,4-diones.12
Also, Troschhutz et al.13 found that the reaction between the nitroketeneaminal and ketonic
Mannich bases hydrochloride (5) gave the pyrido[1,2-a]pyrimidines. Thus, it was of interest
to study the reaction of 2-cyanomethylbenzothiazole (1) with ketonic Mannich bases (5) as
a route to the pyrido[2,1-b][1,3]benzothiazole ring system.

436
A. A. FADDA ET AL.
O
O
slow
Ar
.HCl
N
Ar
, -MeNH2.HCl
5a, b
(A)
5
Ar
a
phenyl
b
2-thienyl
O
S
S
fast
+
CN
CN
Ar
N
H
N
H
1
Ar
O
S
S
-H2O
CN
CN
N
N
6
Ar
HO
Ar
a
b
phenyl
2-thienyl
Ar
6a, b
Scheme 5
We found that compound (1) reacted with the ketobases hydrochloride (5a,b) in a
molar ratio of 1:1 in ethanol in the presence of a catalytic amount of acetic acid to afford
4-cyano-1-aryl-3H-pyrido[2,1-b][1,3]benzothiazoles (6a,b) (see Scheme 5).
The formation of (6a,b) can be explained by a mechanism that involves an initial
deamination of the keto-bases hydrochloride (5a,b) to give the aryl vinyl ketone (A) as an
intermediate. Then the active CH of (1) was added to the vinyl double bond, followed by
cyclization and loss of a water molecule to give the product (6a,b).
In addition, the products (6a,b) were also obtained when (1) was subjected to react
with the diketo-bases hydrochloride (7a,b) in a molar ratio of 2:1 under the same reaction
conditions (see Scheme 6). In this case, the aryl vinyl ketone is formed through two
successive deamination reactions of the diketo-base (7). In this reaction, it is clear that the
substitution pattern at C-1 of the annelated pyridine ring is determined by the structure of
1
the bis-electrophile (aryl vinyl ketone). The H NMR of (6b) showed a doublet at δ 3.51
(J = 6.6 Hz, 2H, C-3), a triplet at δ 3.69 (1H, C-2), a complex pattern at δ 7.53–7.68 (4H,
phenyl), and a multiplet at δ 7.71–8.04 (3H, thienyl). The mass spectrum of (6a) showed
the molecular ion peak at m/z 289 (M++1, 32%).
As an interesting extension of the present research, the synthesis of quinolino[2,1-
b]benzothiazole (9) has been achieved by treating the cyclic keto-base hydrochloride (8b)
or the diketo-base hydrochloride (8a) with (1) (see Scheme 7).
All attempts to dehydrate the hydroxyquinolino[2,1-b]benzothiazole (9) to (10) or
(11) under different reaction conditions such as using glacial acetic, concentrated hy-
drochloric or p-toluensulfonic acid were unsuccessful (see Figure 1).

NITRILES IN ORGANIC SYNTHESIS
437
O
O
O
H
O
Ar
Ar
slow
H
Ar
.HCl
Ar
+
N
NHMe
.HCl
Me
7a, b
, -MeNH2.HCl
O
S
fast
2
6a, b
CN
+
N
2
7
Ar
H
a
phenyl
b
2-thienyl
Scheme 6
R1
O
N
.HCl
R2
S
fast
O
+
N
H
CN
1
8a, R1= R2=
8b, R1= R2= Me
O
S
S
CN
CN
N
H
N
HO
O
9
Scheme 7
S
S
CN
CN
N
N
11
10
Figure 1

438
A. A. FADDA ET AL.
The difficulty of the dehydration of (9) may be due to the instability of the bridged
intermediate carbocation during the E1 process. The IR spectrum of (9) showed strong ab-
sorption bands at 3452 (OH) and 2179 (CN) cm−1. Its mass spectrum exhibited a molecular
ion peak at m/z 284 (M+, 57.5%), 283 (M+ − 1, 100% as base peak) and 282 (M+ − 2,
37.5%).
In addition, it has been reported14 that 1-amino-2,4-dicyano-3-aryl-3H-pyrido[2,1-
b]benzothiazoles (14a–c) were synthesized in (50–70%) yield either by condensation of
2-arylidenecyanomethylbenzothiazoles (12a–c) with malononitrile in THF/N(C2H5)3, or
by condensation of 2-cyanomethylbenzothiazole (1) with arylidenemalononitrile (13a–c)
under the same reaction conditions (see Scheme 8). We report in this article the synthesis
of some new 1-amino-2,4-dicyano-3-aryl-3H-pyrido[2,1-b]benzothiazoles (14a–g) in ex-
cellent yield by a convenient one-pot method from the laboratory available reagents. Thus,
condensation of benzaldehyde derivatives (15a–g), malononitrile, and (1) in a molar ratio of
1:1:1 in ethanolic piperidine afforded the pyrido[2,1-b]benzothiazole (14a–g) in excellent
yield (see Scheme 9).
S
THF
NC
Ar
CN
CN +
Ar
N
S
N(C2H5)3
CN
Ar
12a-c
N
H2N
S
CN
THF
CN
CN +
N
N(C2H5)3
CN
14a-c
14
Ar
1
13a-c
a
b
c
-C6H5
4-OCH3-C6H4
4-Cl-C6H4
Scheme 8
S
S
ethanol
NC
CN
Ar-CHO
+
CN +
CN
N
N
piperidine
15a-g
1
H2N
Ar
CN
14a-g
14, 15
Ar
-C6H5
4-OCH3-C6H4
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4
a
b
c
d
e
f
4-N(CH3)2-C6H4
3,4-O-CH2O-C6H3
g
Scheme 9

NITRILES IN ORGANIC SYNTHESIS
439
Formation of (14) is assumed to proceed by two parallel mechanisms, and that
explains the excellence of the yield. The first mechanism involves initial condensation
of aldehyde with malononitrile, affording the formation of arylidenemalononitriles (13),
followed by Michael addition of 2-cyanomethyl-1,3-benzothiazole (1) to the ylidenic bond
in (13), forming an acyclic intermediate, which, cyclized by nucleophilic attack of the
NH on the cyanocarbon, was followed by tautomerization to the final product (14) (see
Scheme 10). The second mechanism involves initial condensation of aromatic aldehydes
to 2-cyanomethylbenzothiazole, affording the 2-arylidenecyanomethylbenzothiazole (12),
followed by Michael addition of malononitrile (see Scheme 11).
ethanol
CN
CN
Ar
NC
CN
Ar-CHO
+
piperidine
15a-g
13a-c
S
S
CN
CN
Ar
CN
+
CN
Ar
N
N
H
N C
1
13a-g
CN
S
CN
Ar
S
N
CN
Ar
N
H2N
CN
14a-g
HN
CN
Scheme 10
S
S
Ar-CHO
15a-g
+
CN
CN
CN
N
N
HC Ar
1
12a-g
S
S
NC
CN
+
CN
N
N
HC Ar
N C
Ar
12a-g
CN
S
S
S
CN
Ar
CN
Ar
CN
Ar
N
N
N
H
N C
H2N
HN
CN
CN
CN
14a-g
Scheme 11

440
A. A. FADDA ET AL.
In these polyfunctionalized pyrido[2,1-b]benzothiazoles, it is clear that the substi-
tution pattern at C-3 of the annelated pyridine ring is determined by the structure of the
aromatic aldehyde. The analytical, mass spectral, and 1H NMR data are consistent with the
structures proposed for the compounds (14a–g). For example, the mass spectra of (14a–g)
showed the molecular ion peak at m/z 328 (M+, 7.3%), 357 (M+ − 1, 15.2%), 362 (M+,
5.8%), 407 (M+, 14%), 372 (M+ − 1, 23.3%), 371 (M+, 65.2%), and 372 (M+, 60%),
respectively. The IR spectra of these compounds showed the expected bands of CN at
1
2256–2186, NH2 at 3428–3402 and 3361–3324 cm−1. The H NMR spectrum of (14e)
featured signals at δ 4.65 (s, 1H, CH), 6.70 (s, 2H, NH2), and 7.2–8.4 (m, 8H, aromatic).
2-Substituted benzothiazoles constitute an important class of compounds for medici-
nal, agriculture, and organic chemists. The benzothiazole moiety can be found as a common
substructure in a large number of compounds with a wide range of biological activities.15–18
These compounds possess antitumor, antiviral, antimicrobial, and antiglutamate properties.
In view of the synthetic approaches based on unsaturated nitriles as intermediates for
the synthesis of various heterocyclic systems, it appeared that 2-benzylidenecyanomethyl-
1,3-benzothiazole (12a) could conceivably function as precursor to different 2-substituted
benzothiazoles. Thus, 2-benzylidenecyanomethyl-1,3-benzothiazole (12a) was treated with
1-phenyl-3-methyl-2-pyrazolin-5-one (16), barbituric acid (17a), thiobarbituric acid (17b),
and 5,5-dimethyl-1,3-cyclohexanedione (18) to give compounds (19), (20a,b), and (21),
respectively (see Scheme 12).
S
H3C
CN
O
N
N
HC Ar
N
Ph
16
O
12a
O
18
O
O
17a, X= O
17b, X= S
HN NH
S
NH2
O
S
NH2
O
X
N
N
S
NH2
O
Ph
Ph
N
N
Ph
N
O
H3C
Ph
NH
21
19
20
X
O
N
X
H
a
20a, b
O
b
S
Scheme 12
The analytical and spectral data are consistent with the structure proposed for com-
pounds (19), (20a,b), and (21). In general, the IR spectra of these products revealed ad-
sorption bands at 3451–3418 and 3380–3324 cm−1 for NH2 group and disappearance of
absorption bands for CN group. The mass spectra of (19), (20a,b), and (21) showed the
molecular ion peak at m/z 436 (M+, 32%), 392 (M+, 9%), 410 (M++4, 12%), and 404
(M+, 8%), respectively.
The 1H NMR spectrum of (19) displayed signals at δ 2.36 (s, 3H, CH3), 4.84 (s, 1H,
pyran 4-H), and a complex multiplet at δ 7.20–7.41, corresponding to a total of 16 protons
due to aromatic and NH2.

NITRILES IN ORGANIC SYNTHESIS
441
Formation of (19), (20a,b), and (21) could be explained via a mechanism that involves
initial Michael addition of (16), (17a,b), and (18) to the ylidenic bond in (12a) to give an
acyclic intermediate, which, cyclized by the nucleophilic attack of the enolic (OH) on the
cyanocarbon, followed by tautomerization to the final products.
Compound (19) was unambiguously synthesized by an alternative route involv-
ing the condensation of 4-benzylidene-1-phenyl-3-methyl-2-pyrazolin-5-one (22) with 2-
cyanomethylbenzothiazole (1) in refluxing ethanolic piperidine.
Formation of (19) from (1) and (22) or from (12a) and (16) encouraged us to syn-
thesize compound (19) via a one-pot reaction. Thus, condensation of 2-cyanomethyl-
benzothiazole (1), benzaldehyde, and 1-phenyl-3-methyl-2-pyrazolin-5-one (16) in ethano-
lic piperidine afforded (19). Compounds (20a,b) and (21) were also obtained via a one-pot
reaction by condensation of (1), benzaldehyde, and barbituric or thiobarbituric acid and/or
dimedone, respectively.
EXPERIMENTAL
All melting points were recorded on Gallenkamp electric melting point apparatus
and are uncorrected. The IR spectra υ cm−1 (KBr) were recorded on Perkin Elmer Infrared
Spectrophotometer Model 157, Grating. The 1H NMR spectra were obtained on a Varian
Spectrophotometer at 200 MHz using TMS as an internal reference and DMSO-d6 as
solvent. The mass spectra (EI) were recorded on 70 eV with Kratos MS equipment and/or
a Varian MAT 311 A Spectrometer. Elemental analyses (C, H, and N) were carried out at
the Microanalytical Center of Cairo University, Giza, Egypt. The results were found to be
in good agreement ( 0.3%) with the calculated values.
Synthesis of Pyrimidobenzothiazole Derivatives (2a–d):
General Procedure
A mixture of 2-cyanomethyl-1,3-benzothiazole (1) (0.87 g, 0.005 mol), formalin
(1 mL, 0.015 mol), benzylamine (0.54 mL, 0.005 mol) or butylamine (0.5 mL, 0.005
mol) or isopropylamine (0.4 mL, 0.005 mol) or cyclohexylamine (0.57 mL, 0.005 mol) in
ethanol (10 mL), and drops of glacial acetic acid was heated on a steam bath for 30 min.
The reaction mixture was stirred for 3 h at room temperature, then left to stand overnight,
and the separated solids were filtered off and crystallized from ethanol to give compounds
(2a–d), respectively.
Compound (2a): Separated as pale yellow powder in 0.8 g, 53% yield mp 183◦C.
Analysis: Calcd. For C18H15N3S (305.40): C, 70.79%; H, 4.95%; N, 13.76%; S, 10.50;
Found C, 70.58%; H, 4.73%; N, 13.49%; S, 10.38. IR (cm−1) (KBr): 3055, 2930 (CH
aromatic and CH aliphatic), 2155 (CN group), 1603, 1586 (C C aromatic and C C
aliphatic), 1308, 1254 (C N). MS (m/z), rel. inten.: 306 (M++1, 13%), 305 (M+, 65%),
214 (9%), 188 (11%), 187 (44%), 186 (59%), 135 (22%), 108 (11%), 91 (100%). 1H NMR
(CDCl3) δ ppm: 8.01–7.51 (m, 9H, aromatic protons), 3.90 (s, 2H, CH2-Ph), 3.69 (d, J =
11.5 Hz, 2H, N CH2 N) and 3.0 (d, J = 12.3 Hz, 2H, CH2 N).
Compound (2b): Separated as yellow crystals in 0.5 g, 62% yield mp 168–171◦C.
Analysis: Calcd. For C15H17N3S (271.38): C, 66.39%; H, 6.31%; N, 15.48%; S, 11.82;
Found C, 66.82%; H, 6.53%; N, 15.63%; S, 12.01. IR (cm−1) (KBr): 3042, 2975 (CH
aromatic and CH aliphatic), 2168 (CN group), 1621, 1579 (C C aromatic and C C
aliphatic), 1327, 1286 (C N). MS (m/z), rel. inten.: 272 (M++1, 18%), 271 (M+, 100%),

442
A. A. FADDA ET AL.
188 (22%), 187 (62%), 186 (95%), 160 (15%), 136 (19%), 135 (32%), 108 (15%). 1H NMR
(CDCl3) δ ppm: 8.02–7.43 (m, 4H, aromatic protons), 3.67 (d, J = 12.2 Hz, 2H, N CH2 N)
2.97 (d, J = 12.2 Hz, 2H, Ha, CH2 N) 2.72 (t, 2H, N CH2 (CH2)2 CH3), 1.50 (m,
2H, N CH2 CH2 CH2CH3) 1.24 (m, 2H, N CH2 CH2 CH2 CH3) and 0.95 (t, 3H,
CH3).
Compound (2c): Separated as yellow crystals in 1.0 g, 78% yield mp 193◦C. Analy-
sis: Calcd. For C14H15N3S (257.35): C, 65.34%; H, 5.87%; N, 16.33%; S, 12.46; Found C,
65.17%; H, 5.59%; N, 16.43%; S, 12.11. IR (cm−1) (KBr): 3089, 2970 (CH aromatic and
CH aliphatic), 2125 (CN group), 1644, 1619, 1598 (C C aromatic and C C aliphatic),
1487, 1413, 1328 (C N). MS (m/z), rel. inten.: 257 (M+, 43%), 214 (M+ − 1, isopropyl,
4%), 188 (13%), 187 (43%), 186 (100%), 185 (12%), 160 (12%), 159 (17%), 136 (14%),
1
135 (44%), 108 (20%). H NMR (CDCl3) δ ppm: 8.03–7.45 (m, 4H, aromatic protons),
3.63 (d, 2H, Hb, J = 11.5 Hz, N CH2 N) 3.09 (d, 2H, Ha, J = 12.2 Hz, N CH2) 3.17
(m, 1H, CH (CH3)2) and 1.17 (d, 6H, J = 6.15 Hz, 2CH3).
Compound (2d): Separated as yellow crystals in 0.5 g, 34% yield mp 109◦C. Analy-
sis: Calcd. For C17H19N3S (297.42): C, 68.65%; H, 6.44%; N, 14.13%; S, 10.78; Found C,
68.42%; H, 6.17%; N, 14.03%; S, 10.54. IR (cm−1) (KBr): 3070, 2927 (CH aromatic and
CH aliphatic), 2194 (CN group), 1600, 1501 (C C aromatic and C C aliphatic), 1452,
1434, 1314, 1255 (C N). MS (m/z), rel. inten.: 298 (M++1, 3%), 297 (M+, 9.7%), 187
(13%), 186 (21%), 136 (10.6%), 135 (21.5%), 108 (10.56%), 69 (13.7%), 68 (21.1%), 67
(8.3%), 55 (100%). 1H NMR (CDCl3) δ ppm: 8.02–7.45 (m, 4H, aromatic protons), 3.69
(d, 2H, J = 12.25 Hz, N CH2 N) 3.01 (d, 2H, J = 12 Hz, N CH2) 2.73 (m, 1H, CH
(cyclohexyl)), 1.84–1.31 (complex pattern, 10H, cyclohexane).
Synthesis of 2,4-Di(benzothiazol-2(3H)-ylidene)pentanedinitrile (3)
A mixture of 2-cyanomethyl-1,3-benzothiazole (1) (0.87 g, 0.005 mol), formalin
(0.05 mL, 0.006 mol), piperidine (0.5 mL, 0.005 mol) or morphline (0.5 mL, 0.005 mol) in
ethanol (10 mL), and drops of glacial acetic acid was heated on a steam bath for 30 min.
The reaction mixture was stirred for 3 h at room temperature, then the same procedure as
described before was followed. The product obtained was recrystallized from DMF/ethanol
(1:3).
Compound (3): Separated as yellowish crystals in 1.15 g, 64% yield mp 158◦C.
Analysis: Calcd. For C19H12N4S2 (360.46): C, 63.31%; H, 3.36%; N, 15.54%; S, 17.79;
Found C, 63.43%; H, 3.19%; N, 15.24%; S, 17.55. IR (cm−1) (KBr): 3315 (NH), 3020,
2986 (CH aromatic and CH aliphatic), 2228 (CN group), 1421, 1317, 1267 (C N), 1053,
937, 783 and 712 cm−1. MS (m/z), rel. inten.: 360 (M+, 16.21%), 359 (M+ − 1, 27.8%),
358 (M+ − 2, 100%), 225 (23%), 223 (44.4%), 186 (27%), 135 (80.6%), 109 (15.1%), 108
(30.6%), 69 (44.4%). 1H NMR (CDCl3) δ ppm: 9.23 (br. S, 2H, 2NH), 3.62 (s, 2H, CH2),
8.11–7.20 (m, 8H, aromatic protons).
Synthesis of 4-Cyano-1-aryl-3H-pyrido[2,1-b][1,3]benzothiazoles (6a,b)
and Quinolino[2,1-b]benzothiazole (9)
Method A. A mixture of 2-cyanomethyl-1,3-benzothiazole (1) (0.87 g, 0.005
mol) and 3-(dimethylamino)-1-phenylpropane-1-one hydrochloride (5a) (1.0 g, 0.005
mol) or 2-acetylthiophene Mannich base hydrochloride (5b) (1.1 g, 0.005 mol) or

NITRILES IN ORGANIC SYNTHESIS
443
cyclohexanone-2-yl methyl dimethylamine hydrochloride (8b) (0.95 g, 0.005 mol) in
ethanol (15 mL) and glacial acetic acid (3 mL) was heated on a steam bath for 30 min. The
reaction mixture was stirred for 8 h at room temperature (TLC control), then left to stand at
room temperature overnight. The obtained products were filtered off and subjected to col-
umn chromatography on silica gel (pet.ether:ethylacetate 7:3) for (6a), (ether:ethylacetate
9:1) for (6b), and (n-hexane:ether 6:4) for (9).
Method B. A mixture of (1) (0.87 g, 0.005 mol) and bis Mannich bases (7a) (0.83
g, 0.0025 mol) or (7b) (0.86 g, 0.0025 mol) or (8b) (1.43 g, 0.005 mol) in ethanol (15 mL)
and glacial acetic acid (3 mL) was heated and worked up as above to give compounds (6a,
b) and (9), respectively.
Compound (6a): Separated as pale green crystals in 0.6 g, 70% yield mp 98–100◦C.
Analysis: Calcd. For C18H12N2S (288.37): C, 74.97%; H, 4.19%; N, 9.71%; S, 11.12; Found
C, 74.63%; H, 4.38%; N, 9.54%; S, 10.93. IR (cm−1) (KBr): 3061, 2923 (CH aromatic
and CH aliphatic), 2192 (CN group), 1645, 1414 (C C aromatic and C C aliphatic),
1453, 1300 (C N) and 753 cm−1. MS (m/z), rel. inten.: 289 (M++1, 31.9%), 290 (M++2,
1
27.5%), 213 (11.9%), 212 (18.3%), 211 (100%), 210 (23%). H NMR (CDCl3) δ ppm:
7.99–6.62 (m, 9H, aromatic protons), 3.32 (t, 1H, C C H), 3.22 (d, 1H, Ha, J = 8.2 Hz)
and 3.09 (d, 1H, Ha’, J = 8.6 Hz).
Compound (6b): Separated as brown crystals in 0.5 g, 57% yield mp 140–142◦C.
Analysis: Calcd. For C16H10N2S2 (294.39): C, 65.28%; H, 3.42%; N, 9.52%; S, 21.78;
Found C, 65.01%; H, 3.17%; N, 9.26%; S, 21.59. IR (cm−1) (KBr): 3062, 2924 (CH
aromatic and CH aliphatic), 2185 (CN group), 1620, 1578 (C C aromatic and C C
aliphatic), 1433, 1313 (C N), 758 and 728 cm−1. MS (m/z), rel. inten.: 295 (M++1,
6%), 294 (M+, 4.3%), 277 (7.3%), 176 (38.4%), 131 (10.3%), 105 (84.7%), 78 (11%), 77
(100%). 1H NMR (CDCl3) δ ppm: 8.04–7.53 (m, 7H, aromatic and thiophen protons), 3.68
(t, 1H, C C H), 3.53 (d, 1H, Ha, J = 6.6 Hz) and 3.49 (d, 1H, Haꢁ, J = 6.6 Hz).
Compound (9): Separated as pale brown crystals in 0.4 g, 47% yield mp 80–82◦C.
Analysis: Calcd. For C16H16N2OS (284.38): C, 67.58%; H, 5.67%; N, 9.85%; S, 11.28;
Found C, 67.83%; H, 5.39%; N, 9.64%; S, 11.46. IR (cm−1) (KBr): 3452 (OH group), 3064,
2971 (CH aromatic and CH aliphatic), 2179 (CN group), 1598, 1573 (C C aromatic and
C C aliphatic), 1434, 1313 (C N), 1244, 1011, 756 and 726 cm−1. MS (m/z), rel. inten.:
284 (M+, 57.5%), 283 (M+ − 1, 100%), 282 (M+ − 2, 37.5%), 267 (75%), 265 (67.6%).
1H NMR (CDCl3) δ ppm: 8.1 (br. S, 1H, OH), 7.59–7.32 (m, 9H, aromatic protons), 2.07
(dd, 2H, allylic protons), 1.9–1.4 (m, 9H, hexan ring protons).
Synthesis of 1-Amino-2,4-dicyano-3-aryl-3H-pyrido[2,1-b]
benzothiazoles (14a–g)
A mixture of 2-cyanomethyl-1,3-benzothiazole (1) (1.74 g, 0.01 mol), malononitrile
(0.66 g, 0.01 mol), and benzaldehyde (1.06 g, 0.01 mol) or p-anisaldehyde (1.36 g, 0.01
mol) or 4-chlorobenzaldehyde (1.4 g, 0.01 mol) or 4-bromobenzaldehyde (1.85 g, 0.01
mol) or 4-nitrobenzaldehyde (1.5 g, 0.01 mol) or 4-(dimethylamino)benzaldehyde (1.5 g,
0.01 mol) or piperonal (1.5 g, 0.01 mol) in ethanol (15 mL) with triethylamine (3–4 drops)
was refluxed on a water bath for 3 h (TLC control). The reaction mixture was left to stand
at room temperature for 1 h. The obtained products were filtered off and recrystallized from
ethanol to give compounds (14a–g), respectively.
Compound (14a): Separated as yellow crystals in 2.6 g, 79% yield mp 197–198◦C
[lit. 190–191◦C14]. Analysis: Calcd. For C19H12N4S (328.39): C, 69.49%; H, 3.68%; N,

444
A. A. FADDA ET AL.
17.06%; S, 9.76; Found C, 69.71%; H, 3.39%; N, 16.89%; S, 9.49. IR (cm−1) (KBr): 3418,
3324 (NH2 group), 3075, 2892 (CH aromatic and CH aliphatic), 2186 (CN group), 1643,
1616 (C C aromatic and C C aliphatic), 1552, 1451, 1408, 1321 (C N). MS (m/z), rel.
inten.: 329 (M++1, 2.3%), 328 (M+, 7.3%), 327 (M+ − 1, 28.2%), 326 (M+ − 2, 100%),
300 (14.3%), 299 (48.8%). 1H NMR (CDCl3) δ ppm: 7.36–7.25 (m, 11H, aromatic protons
+ 2H, NH2), 4.60 (s, 1H, Ha).
Compound (14b): Separated as greenish yellow crystals in 2.5 g, 70% yield mp
189–191◦C [lit. 193–194◦C14]. Analysis: Calcd. For C20H14N4OS (358.42): C, 67.02%; H,
3.94%; N, 15.63%; S, 8.95; Found C, 67.23%; H, 3.65%; N, 15.41%; S, 8.48. IR (cm−1
)
(KBr): 3418, 3324 (NH2 group), 3056, 2972 (CH aromatic and CH aliphatic), 2221 (CN
group), 1608, 1590 (C C aromatic and C C aliphatic), 1513, 1420, 1319, 1279 (C N),
1181, 1023 (C O). MS (m/z), rel. inten.: 357 (M+ − 1, 15.22%), 356 (14.13%), 332
(39.13%), 331 (26%), 317 (65.2%), 318 (16.3%), 316 (22.83%), 300 (37%), 299 (30%).
1H NMR (CDCl3) δ ppm: 7.74–6.87 (m, 10H, aromatic protons + 2H, NH2), 4.55 (s, 1H,
CH), 3.797 (s, 3H, OMe), 1.699 (br. S, 2H, NH2).
Compound (14c): Separated as yellow crystals in 3 g, 83% yield mp 212–213◦C
[lit. 210–211◦C14]. Analysis: Calcd. For C19H11ClN4S (362.84): C, 62.89%; H, 3.06%; Cl,
9.77%; N, 15.44%; S, 8.84; Found C, 62.57%; H, 3.14%; Cl, 9.52%; N, 15.63%; S, 8.47. IR
(cm−1) (KBr): 3415, 3365 (NH2 group), 3055, 2991 (CH aromatic and CH aliphatic), 2252
(CN group), 1600, 1590 (C C aromatic and C C aliphatic), 1514, 1433, 1383, 1306, 1277
(C N) and 729 (C Cl). MS (m/z), rel. inten.: 362 (M+, 5.8%), 361 (M+ − 1, 3%), 360
(5.57%), 298 (20.4%), 297 (49%), 296 (41.3%), 295 (10%), 270 (16.4%), 261 (11%), 251
(19.7%), 174 (25%), 125 (16%), 107 (12%), 99 (5.3%), 82 (10%), 75 (8.9%), 69 (18.2%),
66 (6.8%), 63 (10.1%).
Compound (14d): Separated as pale yellow crystals in 3.1 g, 76% yield mp 139◦C.
Analysis: Calcd. For C19H11BrN4S (407.29): C, 56.03%; H, 2.72%; Br, 19.62; N, 13.76%;
S, 7.87; Found C, 55.87%; H, 2.62%; Br, 19.43; N, 13.54%; S, 7.61. IR (cm−1) (KBr):
3325 (NH2 group), 3077, 2933, 2850 (CH aromatic and CH aliphatic), 2085 (CN group),
1625, 1583 (C C aromatic and C C aliphatic), 1484, 1338 (C N), 1230, 850, 727, 701
and 650 (C Br) cm−1. MS (m/z), rel. inten.: 408 (M++1, 15.1%), 407 (M+, 14%), 406
(29.7%), 405 (11.5%), 404 (18.8%), 341 (73.8%), 339 (69.3%), 259 (15.7%), 253 (76%),
252 (16.8%), 251 (100%). 1H NMR (CDCl3) δ ppm: 8.19–7.65 (m, 10H, aromatic protons
+ 2H, NH2), 4.64 (s, 1H, Ha).
Compound (14e): Separated as reddish brown crystals in 3.2 g, 86% yield mp 148◦C.
Analysis: Calcd. For C19H11N5O2S (373.39): C, 61.12%; H, 2.97%; N, 18.76%; S, 8.59;
Found C, 61.34%; H, 2.58%; N, 18.61%; S, 8.39. IR (cm−1) (KBr): 3382, 3351 (NH2
group), 3051, 2954 (CH aromatic and CH aliphatic), 2256 (CN group), 1610, 1573, 1451,
1362, 1307 (N O), 1343, 1276, 1240 (C N). MS (m/z), rel. inten.: 373 (M+, 7.6%), 372
(M+ − 1, 23.3%), 371 (M+ − 2, 90.5%), 354 (13.7%), 344 (10%), 324 (26.25%), 307
(54.84%), 306 (100%). 1H NMR (CDCl3) δ ppm: 8.42–7.27 (m, 10H, aromatic protons +
2H, NH2), 4.65 (s, 1H, CH).
Compound (14f): Separated as red crystals in 2.8 g, 76% yield mp 226◦C. Analysis:
Calcd. For C21H17N5S (371.46): C, 67.90%; H, 4.61%; N, 18.85%; S, 8.63; Found C,
67.70%; H, 4.33%; N, 18.61%; S, 8.43. IR (cm−1) (KBr): 3421, 3351 (NH2 group), 3058,
2954, 2923 (CH aromatic and CH aliphatic), 2186 (CN group), 1635, 1602, (C C aro-
matic and C C aliphatic), 1454, 1322, 1301 (C N). MS (m/z), rel. inten.: 371 (M+,
65.2%), 327 (22.52%), 301 (75.1%), 275 (20.62%), 266 (100%), 259 (42.51%), 169
(75.27%), 152 (65.13%), 106 (25.14%), 105 (25.2%), 91 (77.52%), 62 (20.01%). 1H NMR

NITRILES IN ORGANIC SYNTHESIS
445
(CDCl3) δ ppm: 8.15–7.25 (m, 9H, aromatic protons + 2H, NH2), 3.11 (s, 6H, 2Methyl
group).
Compound (14g): Separated as yellow crystals in 2.9 g, 78% yield mp 219◦C.
Analysis: Calcd. For C20H12N4O2S (372.40): C, 64.50%; H, 3.25%; N, 15.04%; S, 8.61;
Found C, 64.81%; H, 3.02%; N, 15.26%; S, 8.43. IR (cm−1) (KBr): 3402, 3366 (NH2 group),
3042, 2961 (CH aromatic and CH aliphatic), 2220 (CN group), 1611, 1596 (C C aromatic
and C C aliphatic), 1502, 1463, 1312, 1277 (C N). MS (m/z), rel. inten.: 372 (M+,
60.02%), 371 (M++1, 20.1%), 320 (20.31%), 306 (77.8%), 305 (100%), 280 (62.51%),
1
247 (75.01%), 246 (27.49%). H NMR (CDCl3) δ ppm: 8.14–7.43 (m, 7H, aromatic
protons), 7.25 (s, 2H, NH2), 6.93 (s, 1H, CH), 6.09 (s, 2H, O CH2 O).
Synthesis of 5-(Benzo[d]thiazol-2-yl)-1,4-dihydro-3-methyl-1,4-
diphenylpyrano[2,3-c]pyrazol-6-amine (19), 7-Amino-6-(benzo[d]thiazol-2-
yl)-2,3-dihydro-5-phenyl-2-oxo-1H-pyrano[2,3-d]pyrimidin-4(5H)-one (20a),
7-Amino-6-(benzo[d]thiazol-2-yl)-2,3-dihydro-5-phenyl-2-thioxo-1H-
pyrano[2,3-d]pyrimidin-4(5H)-one (20b), and 2-Amino-3-(benzo[d]thiazol-2-
yl)-7,8-dihydro-7,7-dimethyl-4-phenyl-4H-chromen-5(6H)-one (21)
Equimolar amounts of 2-benzylidenecyanomethyl-1,3-benzothiazole (12a)14 (1.31
g, 0.005 mol) and 2-pyrazoline-5-one (16) (0.87 g, 0.005 mol), barbituric acid (17a) (0.6
g, 0.005 mol), thiobarbituric acid (17b) (0.7 g, 0.005 mol), or dimedone (18) (0.7 g,
0.005 mol) in ethanol (15 mL) and triethyl amine (3–4 drops) were then added and refluxed
on a steam bath for 3 h (TLC control). The reaction mixture was left to stand at room
temperature overnight, and the obtained products were filtered off and recrystallized from
ethanol to give compounds (19), (20a), (20b), and (21), respectively.
Compound (19): Separated as brown crystals in 2 g, 46% yield mp 190◦C. Analysis:
Calcd. For C26H20N4OS (436.53): C, 71.54%; H, 4.62%; N, 12.83%; S, 7.35; Found C,
71.73%; H, 4.35%; N, 12.66%; S, 7.13. IR (cm−1) (KBr): 3418, 3324 (NH2 group), 3053,
2961 (CH aromatic and CH aliphatic), 1643 (C N), 1616, 1578 (C C aromatic and C C
aliphatic), 1552, 1451, 1408, 1321, 1299 (C N), 1172 (C O). MS (m/z), rel. inten.: 436
(M+, 31.43%), 359 (71.42%), 302 (11.5%), 263 (48.57%), 262 (37.14%), 261 (100%), 174
1
(54.29%), 146 (11.43%), 108 (20.02%), 69 (51.43%), 63 (57%), 51 (25.71%). H NMR
(CDCl3) δ ppm: 7.41–7.20 (m, 16H, aromatic protons + 2H, NH2), 4.84 (s, 1H, CH), 2.36
(s, 3H, CH3).
Compound (20a): Separated as pale brown crystals in 1.8 g, 92% yield mp 205◦C.
Analysis: Calcd. For C20H14N4O3S (390.42): C, 61.53%; H, 3.61%; N, 14.35%; S, 8.21;
Found C, 61.75%; H, 3.36%; N, 14.12%; S, 8.41. IR (cm−1) (KBr): 3444, 3388 (NH2 group),
3027, 2954 (CH aromatic and CH aliphatic), 1689 (CO), 1572 (C N), 1376, 1301 (C N),
1049, 944 (C O). MS (m/z), rel. inten.: 392 (M++2, 9%), 352 (92.3%), 352 (92.31%),
350 (69.23%), 328 (69.23%), 326 (61.54%), 304 (76.92%), 282 (69.23%), 268 (76.92%),
221 (76.92%), 214 (69.23%), 197 (61.54%), 176 (61.54%), 174 (61.54%), 156 (84.62%),
122 (76.92%), 111 (100%), 108 (76.92%), 102 (69.23%), 67 (69.23%), 63 (61.54%), 61
(61.54%).
Compound (20b): Separated as white-brown crystals in 1.8 g, 89% yield mp 277◦C.
Analysis: Calcd. For C20H14N4O2S2 (406.48): C, 59.10%; H, 3.47%; N, 13.78%; S, 15.78;
Found C, 58.95%; H, 3.24%; N, 13.50%; S, 15.53. IR (cm−1) (KBr): 3446, 3407 (NH2),
3070, 2950 (CH aromatic and CH aliphatic), 1720 (CO), 1697 (C S), 1644, 1617, (C C
aromatic and C C aliphatic), 1569 (C N), 1434, 1384, 1349, 1294 (C N), 1240, 1157,

446
A. A. FADDA ET AL.
927 (C O). MS (m/z), rel. inten.: 410 (M++4, 12%), 233 (18.4%), 232 (18.4%), 232
(100%), 231 (85.6%), 174 (5.12%), 172 (25.53%), 146 (8.2%), 145 (7.35%), 144 (71.7%).
Compound (21): Separated as gray crystals in 1.5 g, 75% yield mp 177–178◦C.
Analysis: Calcd. For C24H12N4O2S (402.51): C, 71.62%; H, 5.51%; N, 6.96%; S, 7.97;
Found C, 71.83%; H, 5.72%; N, 6.64%; S, 7.69. IR (cm−1) (KBr): 3421, 3351 (NH2), 3056,
2455 (CH aromatic and CH aliphatic), 1743 (CO), 1662, 1616, (C C aromatic and C C
aliphatic), 1540 (C N), 1479, 1450, 1373, 1284 (C N), 1160, 1124, 933 (C O). MS
(m/z), rel. inten.: 404 (M++2, 3.25%), 403 (M++1, 11.6%), 402 (M+, 8%), 327 (7.5%),
325 (100%). 1H NMR (CDCl3) δ ppm: 7.81–7.03 (m, 11H, aromatic protons + 2H, NH2),
4.84 (s, 1H, CH), 2.49 (s, 2H, CH CO), 2.26 (s, 2H, CH2), 1.14 (s, 3H, Me), 0.97 (s,
3H, Me).
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