Nitriles in heterocyclic synthesis: Reactivity of 2-(benzothiazol-2- ylmethyl)-1,3-thiazol-4(5H)-one towards α,β-unsaturated nitriles

Article abstract of DOI:10.1002/jccs.200300151

The reaction of 2-(benzothiazol-2-ylmethyl)-1,3-thiazol-4(5H)-one 1 with α,β-cinnamonitrile derivatives 2a-n have been reported.

Full text of DOI:10.1002/jccs.200300151

Journal of the Chinese Chemical Society, 2003, 50, 1061-1073
1061
Nitriles in Heterocyclic Synthesis: Reactivity of
2-(Benzothiazol-2-ylmethyl)-1,3-thiazol-4(5H)-one towards
a,b-Unsaturated Nitriles
S. M. Sayed
Chemistry Department, Faculty of Science, South Valley University, Aswan 81528, Egypt
The reaction of 2-(benzothiazol-2-ylmethyl)-1,3-thiazol-4(5H)-one 1 with a,b-cinnamonitrile deriva-
tives 2a-n have been reported.
Keywords: Benzothiazole derivatives; b-Arylacrylonitrile; Alkylidenemalononitrile.
INTRODUCTION
In recent years, there has been increasing interest in
nitrile (2a) in pyridine resulting a product of molecular for-
mula C21H16N4S2O2 (M+ = 420 m/e). The IR spectrum of the
isolated product (5a) revealed the absence of a nitrile absorp-
tion band and the appearances of band for amino function at
3350, 3310 and 3270 cm-1, in addition to one band due to am-
ide carbonyl at 1683 cm-1. Its 1H NMR spectrum revealed two
singlet signals at dH 2.28 and 4.72 ppm corresponding to
methylene and pyran H-4 protons. Also, 1H NMR spectrum
revealed one singlet signal (D2O-exchangeable) at dH 6.73
ppm corresponding to amino protons, in addition to aromatic
protons at dH 7.12-8.1 ppm.
synthesis of heterocyclic compounds that have biological and
commerical importance. Benzothiazole are biologically in-
teresting molecules and their chemistry is receiving consider-
able attention due to their antiviral,1 antibacterial,2 antimicro-
bial,3 and fungicidal activities.4 They are also useful as anti-
allergic,5 anti-inflammatory,6 and anthelmintic7 agents, and
as appetite depressants,8 intermediates for dyes,9 plant pro-
tectants,10 and photographic sensitizers.11 Also, many thi-
azole derivatives have attracted considerable attention be-
cause of their various biological activities.12-15 Moreover, its
frequently present in the tuberculostically active drugs,16 in
addition to their use as mildew-preventing agents.17
Similarly, compound 1 reacted with (2b) to yield the
corresponding thiazolo[4,5-b]pyran derivative (5b). The
structure of 5b was established based on its elemental analy-
sis and spectral data (see experimental). The formation of
5a,b was assumed to proceed via addition of C-5 of thiazole 1
to the b-carbon of 2a,b to yield the non-isolable Michael in-
termediate (3) with subsequent cyclization via addition of the
hydroxyl group on the nitrile function followed by hydrolysis
during working up to yield 5a,b (Scheme I).
Therefore, compounds containing both benzothiazole
and thiazole moities are expected to possess potential biolog-
ical activities. Furthermore, the interesting pharmacological
properties of thiazole derivatives18-24 in relation to the vari-
ous changes in the structures of these compounds is worth
studying to synthesis some less toxic and more potent drugs.
Thus, the introduce of other heterocyclic moities (as the
pyran, pyranopyridine, pyranopyrimidine, and/or pyrano-
triazine ring) should certainly help to fulfill this objective.
In continuation of our previous studies aimed at the
synthesis of functionalized heterocycles,25-29 thus we report
herein the synthesis of heterocyclic compounds containing
the above mentioned rings via the readily available 2-(benzo-
thiazol-2-ylmethyl)-1,3-thiazol-4(5H)-one (1) as starting
material; and its synthetic potential was demonstrated via its
reaction with highly reactive a,b-unsaturated nitrile re-
agents.
In contrast to the behavior of compound 1 toward 2a,b,
compound 1 reacted with furyl and thienyl acrylonitrile de-
rivatives (2c,d) to afford product (6c,d) showing clearly the
1
appearance of nitrile function in its IR spectrums. Its H
NMR spectrum revealed the absence of signal due to pyran
H-4. The formation of 6c,d is assumed to proceed via addi-
tion of C-5 of thiazole 1 to the b-carbon of 2c,d to yield the
non-isolable Michael intermediate (3) which undergoes hy-
drolysis and is subsequently cyclized via loss of ammonia
and finally dehydrogenation during working up under reac-
tion conditions to yield 6c,d (Scheme I).
On the other hand, compound 1 reacted with ethyl ben-
zylidenecyanoacetate (2e) to yield a product of molecular
formula C23H19N3S2O3 (M+ = 449 m/e). The IR spectrum of
Thus, it has been found that 2-(benzothiazol-2-ylmeth-
yl)-1,3-thiazol-4(5H)-one 1 reacts with benzylidenemalono-

1062 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Sayed
Scheme I
CN
X
O
ArCH
C
N
R
a, Ar = C H , X = CN; b, Ar = 4-ClC H , X = CN
2
6
4
5
3
6 4
S
1
c, Ar = C H O, X = CN; d, Ar = C H S, X = CN
4 3
e, Ar = C H , X = CO2Et; f, Ar = 4-ClC H , X = CO2Et
6
5
6 4
g, Ar = C H O, X = CO2Et; h, Ar = C H S, X = CO2Et
4
3
4 3
i, Ar = 4-C H Cl, X = CSNH ; j, Ar = 4-CH OC H , X = CSNH
2
6
4
2
3
6
4
k, Ar = C H , X = CONH ; l, Ar = 4-ClC H , X = CONH
2
6
5
2
6
4
m, Ar = C H O, X = CONH ; n, Ar = C H S, X = CONH
4
3
2
4
3
2
OH
Ar
N
CN
pyridine
1
+
2a,b
R
S
CN
3
OH
..
O
O
O
NH2
NH2
N
CN
N
N
2a,b
2c,d or 2k,l
S
CONH2
S
CN
- NH
S
3
R
R
Ar
Ar
R
Ar
O
5
c, Ar = C H O; d, Ar = C H S
4 3 4 3
6
4
3-6
Ar
N
a
C H
6
4-ClC H
R =
5
b
6 4
S
the isolated product (8a) revealed the absence of absorption
band due to a cyano group and the appearances of one band
due to amino function at 3400, 3330 cm-1, in addition to one
band due to ester carbonyl at 1728 cm-1. Its 1H NMR spectrum
revealed two singlet signals at dH 2.23 and 4.68 ppm due to
methylene and pyran H-4 protons. Also, 1H NMR spectrum
revealed singlet signal (D2O-exchangeable) at dH 6.75 ppm
due to amino protons, in addition to aromatic protons at dH
7.15-8.12 ppm.
Similarly, compound 1 reacted with 2f to yield the cor-
responding thiazolo[4,5-b]pyran derivative (8b). The struc-
ture of 8b was established based on its elemental analysis and
spectral data (see experimental). The formation of 8a,b is as-
sumed to proceed via addition of C-5 of thiazole 1 to the
b-carbon of 2e,f to yield the non-isolable Michael intermedi-
ate (7) with subsequent cyclization via addition of the
hydroxyl group on the nitrile function to yield 8a,b (Scheme
II).
Scheme II

Nitriles in Heterocyclic Synthesis
J. Chin. Chem. Soc., Vol. 50, No. 5, 2003 1063
In contrast to the behavior of 1 toward 2e,f, compound
1 reacted with furyl and/or thienyl acrylonitrile derivatives
(2g,h) to afford products identical with 6c,d in all respects
(mp., mixed mp. and spectral data). The structure of 6c,d was
supported by its independent synthesis from the reaction
furyl and/or thienyl acrylonitrile derivatives (2m,n) with
thiazole 1.
lene, pyran H-4 and NH (D2O-exchangeable) protons, re-
spectively.
Treatment of the triazin-4(3H)-one 11a with electro-
philic reagents such as methyl iodide, 2-chloroacetonitrile
and phenacyl bromide (12a-c) afforded the triazin-4(3H)-one
derivatives (13a-c). The structure of 13a-c was established
based on its elemental analysis and spectral data. For exam-
ple, 1H NMR spectra of 13b showed three singlet signals at dH
2.31, 4.53 and 5.82 due to methylene, pyran H-4 and cyano-
methyl protons, respectively.
The thiocarboxaminocinnamonitrile derivatives (2i,j)
reacted with 1 to yield products corresponding to equi-
molecular addition, cyclization and water elimination afford-
1
ing 10a,b. For example the H NMR of 10a showed disap-
Refluxing of 5a with formic acid afforded 2-(benzothi-
azol-2-ylmethyl)-9-phenyl thiazolo[4¢,5¢:6,5]pyrano[2,3-
d]pyrimidin-8(7H)-one (14). Treatment of 14 with phos-
phours oxychloride gave the 8-chloro derivatives (15) which
exhibited remarkable reactivity of its 8-chloro substituent to-
wards nucleophilic agents such as thiophenol and ethoxide
ion affording the new 2-(benzothiazol-2-ylmethyl)-9-phen-
yl-8-thiophenylthiazolo[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine
(16) and 2-(benzothiazol-2-yl-methyl)-9-phenyl-8-ethoxy-
thiazolo[4¢,5¢:6,5]pyrano[2,3-d]pyrimidines (17), respec-
tively. The structure of 16 and 17 was established based on its
elemental analysis and spectral data. For example, 1H NMR
spectra of 16 showed three singlet signals at dH 2.3, 4.71 and
8.74 due to methylene, pyran H-4 and pyrimidine H-2 pro-
tons, respectively.
pearance of the pyran H-4, in addition to the IR revealed ab-
sorption bands at 3305 and 2223 cm-1 due to NH and cyano
groups, respectively. Based on these findings, these com-
pounds could be formulated as thiazolo[4,5-b]pyridine deriv-
atives 10a,b. Moreover, the reaction products 10a,b were
proved to be stable under conditions that were expected to ef-
fect the opening of the thiopyran ring30 (Scheme III).
Scheme III
H
N
OH
S
N
CSNH2
CN
pyridine
2i,j
N
(i) - H
O
2
1
R
(ii) - H
S
2
S
CN
N
Ar
Ar
R
10
9
Furthermore, treatment of the pyrimidine derivatives
14 with electrophilic reagents 12a-c afforded the pyrimidine
derivatives (18a-c). The structure of 18a-c was established
based on its elemental analysis and spectral data. For exam-
ple, 1H NMR spectra of 18a showed three singlet signals at dH
2.32, 3.62 and 4.69 due to methylene, methyl and pyran H-4
protons, respectively.
9, 10 Ar
a
4-ClC
H
6
4
R =
b
4-CH OC H
3 6 4
S
Also, in contrast to 2i,j, the carboxaminocinnamo-
nitrile derivatives (2k,i) reacted with 1 to yield products cor-
responding to equimolecular addition, cyclization via loss of
ammonia followed by dehydrogenation to yield (6a,b). The
IR of the isolated products 6a,b show absorption bands due to
Aminocarboxamide 5a reacted with urea derivatives to
yield the pyrimidine derivatives (19a,b). The structure of 19b
was supported by its independent synthesis from the reaction
of 5a with carbon disulfide in pyridine yielding a product
identical with 19b in all respects (mp., mixed mp. and spec-
tral data).
1
nitrile function and ring carbonyl groups. Its H NMR re-
vealed the absence of signals due to pyran H-4.
Synthetic approaches to aminocarboxamide derivatives
have been extensively studied, and many syntheses using
aminocarboxamide as starting materials have been re-
ported.31-34 We found that the precursor 5-amino-2-(benzo-
thiazol-2-ylmethyl)-7-phenyl thiazolo[4,5-b]pyran-6-car-
boxamide 5a was nitrosated with sodium nitrite in acetic acid
at 5 °C afforded 7-(benzothiazol-2-ylmethyl)-5-phenylthi-
azolo[4¢,5¢:6,5]pyrano[2,3-d]-1,2,3-triazine-4(3H)-one (11).
The structure of 11 was established based on its elemental
analysis and spectral data. The IR of 11 revealed absorption
bands at 3215 and 1683 cm-1 due to NH function and carbonyl
Similarly aminocarboxamide 5a reacting with phenyl-
isothiocyante gave the anilino pyrimidine derivative (20).
The structure of compounds 19a,b and 20 were consistent
with their elemental analyses and spectral data (see experi-
mental).
Condensation of the b-enaminoester 8a with ethyl
orthoformate gave ethyl 2-(benzotrhiazol-2-ylmethyl)-5-
(ethoxymethylene)amino-7-phenylthiazolo[4,5-b]pyran-6-
carboxylate (21) which was proved to be a key intermediate
for subsequent conversions leading to the related 7-amino-
pyrimidine derivative (22). The structure of 21 was estab-
1
group, respectively. Its H NMR revealed three singlet sig-
nals at dH 2.36, 4.71 and 12.31 ppm corresponding to methy-

1064 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Sayed
Scheme IV
H
N
O
N
O
O
O
N
O
NHPh
X
N
N
N
N
NH
NH
S
R1
S
S
O
R
C6H5
R
C6H5
R
C6H5
20
19a, X = O; b, X = S
a, R = CH b, R = CH CN
18
1
3;
1
2
c, R = CH COC H
1
2
6
5
H2NCXNH2
PhNCS
12a-c
N
CS2/pyridine
O
N
HCO O H
O
NH2
NH2
NH
N
N
NaNO 3 / AcO H
S
O
R
C6H5
S
14
O
R
N
C6H5
PO Cl3/PCl5
5
O
N
O
N
NH
N
S
N
O
N
R
C6H5
11
S
R
C6H5 Cl
15
R1X / KO H
12
NaOEt
C6H5SH
O
N
N
O
N
N
O
N
N
S
R1
N
O
N
R
C6H5
N
S
S
a, R = CH b, R = CH CN
13
1
3;
1
2
R
C6H5 OCH2CH3
R
C6H5 SC6H5
c, R = CH COC H
1
2
6
5
17
16
12
R
1
X
N
a
b
c
CH3
CH3CN
CH2CO Ph Br
I
R =
Cl
S
lished based on its elemental analysis and spectral data. The
1H NMR spectra of 21 showed a characteristic singlet signal
at dH 8.63 due to the N=CH proton. When 21 underwent
ammonolysis in ethanol, it gave the corresponding pyridine
derivatives which were identical in all respects (mp., mixed
mp and spectral data) with compound 14. The structure of the
latter was supported by its independent synthesis via reaction
of 8a with formamide.
to the product obtained by ammonoylsis of 21.
As illustrated in (Scheme VI) 10a was advantageously
used for further cyclizations: Reaction of 10a with electro-
philic reagents 12b,c and subsequent base promoted intra-
molecular ring formation that yielded the 3-aminothieno-
pyridinothiazole (25a,b), respectively. The structure of 24a,b
was established based on its elemental analysis and spectral
data. For example, the IR of 24a revealed two absorption
1
Treatment of 21 with hydrazine hydrate afforded the
corresponding 7-aminopyrimidine derivatives (23) which
could be obtained from 8a by its initial conversion to the cor-
responding hydrazide (22), followed by cyclization with
ethyl orthoformate to give 23. Deamination of 23 was ef-
fected by nitrous acid to afford a product which was identical
bands at 2220 and 2240 cm-1 due to two cyano groups. H
NMR spectra of 24a showed a characteristic singlet signal at
dH 4.36 due to CH2CN proton. Also, the IR of 25a revealed
absorption bands at 3365-3220 and 2205 cm-1 due to amino
and cyano groups, respectively. 1H NMR spectra of 25a ex-
hibit D2O-exchangeable singlet signal at dH 6.13 due to the

Nitriles in Heterocyclic Synthesis
J. Chin. Chem. Soc., Vol. 50, No. 5, 2003 1065
Scheme V
O
N
O
O
NH2
N
CH(O Et)3
N
NH2NH2.H2O
8a
N
NH2
S
S
CONHNH2
CH(OEt)3
R
C6H5
23
R
C6H5
O
22
N
CH OEt
NH2NH2.H2O
N
NaNO 2 / AcO H
S
CO2Et
R
C6H5
conc. NH4O H
21
HCO NH2
14
N
R =
S
NH2 proton. Also, the compound 25b was synthesized di-
rectly by reaction of 10a with 12c in refluxing dioxane con-
taining Et3N or sodium ethoxide (see experimental).
tives 25a with formic acid or formamide furnished 2-(benzo-
thiazol-2-ylmethyl)-10-(4-chlorophenyl) thiazolo[4²,5²:6¢,5¢]-
pyridino[2¢,3¢:5,4]thieno[3,2-d]pyrimidine-6(7H)-one (26)
and 6-amino-2-(benzothiazol-2-ylmethyl)-10-(4-chloro-
phenyl) thiazolo[4²,5²:6¢,5¢]pyridino[2¢,3¢:5,4]thieno[3,2-
d]pyrimidine (27), respectively. The assignment of the latter
structures was based on the elemental analysis and spectral
data of the reaction products. Thus, the IR spectra of 26 re-
Heterocyclic a,b-enaminonirile are versatile synthons
for various cyclization reactions.35,36 The synthetic potential
of the newly synthesized b-enaminonitrile 25a was achieved
by their reaction with different reagents leading to several
new fused-ring heterocycles. Thus, heating the thieno deriva-
Scheme VI
N
S
O
NH
N
R1
12b,c
(CH3)2SO 4
NaO H
/
24c
10a
K2CO 3 / KI
S
CN
O
C H Cl-4
R
6
4
N
N
N
24a, R = CH CN
1
2
b, R = CH COC H
1
2
6 5
S
CN
c, R = CH
1
3
C H Cl-4
R
6
4
28
26
piperidine /
acetone /
THF
O
N
S
N
NH
HCO O H
S
N
N
S
X
N
R
C H Cl-4
6
4
NH2
S
NH2
N
S
R
25a
C H Cl-4
N
N
6 4
HCO NH2
25a, X = CN; b, X = COC H
6
5
S
N
R
C H Cl-4
N
6
4
R =
27
S

1066 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Sayed
vealed the absence of the cyano absorption band and revealed
one band in the region 3310 cm-1 due to stretching NH.
Whereas, the IR of 27 revealed one band in the region 3297-
3156 cm-1 due to the amino group.
on spectral data. It is assumed that acetaldehyde and cyano-
thioacetamide reacts in situ generating (29) which then adds
1 to yield the non-isolable intermediate Michael adduct (30)
which then cyclizes into the final isolable product (31).
Furthermore, the reactivity of 31 toward sulfur and
benzylidenemalononitrile 2a was also examined. Thus, com-
pound 31 readily reacted with elemental sulfur to yield the
thienopyridinothiazole derivative (32). Evidence for the
structure of 32 is provided by spectral data, thus excluding
the existence of the possible isomeric imino form of 32 or the
2-mercaptomethyl derivative of 31 (see experimental). The
formation of 32 from the reaction of 31 with elemental sulfur
is an application of the Gewald38 and Elnagdi synthesis39 to
alkyl heterocyclic carbonitriles. Compound 31 also reacts
with benzylidenemalononitrile 2a to yield the addition prod-
uct (34). The formation of 34, assumed to proceed via the ad-
dition of the methyl anionic center of the conjugate base of 31
to 2a, afforded the non-isolable intermediate (33), which un-
derwent cyclization under the reaction conditions to give the
final product 34. Also, compound 31 reacts with 12c to yield
the thieno[2,3:6,5]pyridino[2,3-d]thiazole (35) (Scheme
For the synthesis of the hitherto substituted amino pyr-
idine derivatives (28), we S-methylated 10a with dimethyl
sulphate in aqueous sodium hydroxide solution to give the
methylthiopyridine derivatives (24c) which are assumed to
undergo substitution reactions. Subsequently 24c were
treated with morpholine which afforded 2-(benzothiazol-2-
ylmethyl)-7-(4-chlorophenyl)-5-(morpholino-4-yl) thiazolo-
[4,5-b]pyridine-6-carbonitrile 28. The structure of 28 was es-
tablished based on its elemental analysis and spectral data.
The IR of 28 revealed an absorption band at 2222 cm-1 due to
a cyano group. The 1H NMR spectra of 28 showed character-
istic two triplet signals at dH 3.93 and 3.71 ppm due to OCH2
and an NCH2 proton, respectively.
Likewise, thiazole 1 reacts with a mixture of acetalde-
hyde and cyanothioacetamide in pyridine at reflux to yield a
product of molecular formula C16H10N4S3 (M+ = 354). This
product was assigned the pyridine thione structure (31) based
Scheme VII
H2
N
O
S
N
CN
R
1
+ H3C CH C
NH2
S
CN
S
CH3
29
30
1) - H O
2) - H
2
2
H
N
S
N
S / Et3N
H
N
NH2
S
S
N
R
N
S
32
S
CN
N
S
COPh
R
CH3
12c
31
S
NH2
2a
R
CH3
35
H
N
H
N
S
S
N
N
NH2
CN
CN
S
S
R
R
CN
CN
34
Ph
Ph
N
33
R =
S

Nitriles in Heterocyclic Synthesis
J. Chin. Chem. Soc., Vol. 50, No. 5, 2003 1067
VII). All compounds 31-35 were established based on their
3.25; N, 12.33; S, 13.98; Cl, 7.81%.
elemental analysis and spectral data (see experimental).
2-(Benzothiazol-2-ylmethyl)-6-cyano-7-phenyl thiazolo-
[4,5-b]pyran-5-one (6a)
EXPERIMENTAL
Yield, 66%; m.p. 289 °C (ethanol); IR (KBr) nmax 2220
(CN), 1733 (CO), 1622 (C=N) cm-1; 1H NMR [DMSO-d6]: d
= 2.27 (s, 2H), 7.12-8.11 (m, 9H); m/z 401 (M+). Calcd. for
C21H11N3S2O2: C, 62.82; H, 2.76; N, 10.47; S, 15.79%.
Found: C, 62.78; H, 2.81; N, 10.41; S, 15.81%.
All melting points are uncorrected. IR spectra were
measured as KBr pellets on a Pye Unicam SP 1000 Spectro-
photometer. 1H NMR spectra were recorded in DMSO-d6 at
200 MHz on a Varian Gemini NMR spectrometer using TMS
as internal reference; the chemical shifts are expressed as d
values (ppm). Mass spectra were obtained on a Shimadzu
GCMS-QP 1000 EX Mass Spectrometer at 70 eV. Elemental
analyses were carried out at the Microanalytical Center of
Cairo University. 2-(benzothiazol-2-ylmethyl)-1,3-thiazol-
4(5H)-one 140 and a,b-cinnamonitrile derivatives 2a-n41,42
were prepared according to literature procedures.
2-(Benzothiazol-2-ylmethyl)-6-cyano-7-(4-chlorophenyl)
thiazolo[4,5-b]pyran-5-one (6b)
Yield, 62%; m.p. 315 °C (ethanol); IR (KBr) nmax 2223
(CN), 1738 (CO), 1632 (C=N) cm-1; 1H NMR [DMSO-d6]: d
= 2.25 (s, 2H), 7.2-8.12 (m, 9H); m/z 436 (M+). Calcd. for
C21H10N3S2O2Cl: C, 57.68; H, 2.32; N, 9.64; S, 14.71; Cl,
8.13%. Found: C, 57.71; H, 2.31; N, 9.63; S, 14.73; Cl,
8.14%.
7-Substituted-2-(benzothiazol-2-ylmethyl)thiazolo[4,5-b]-
pyran derivatives 5a,b; 6a-c; 8a,b and 7-substituted-2-
(benzothiazol-2-ylmethyl)thiazolo[4,5-b]pyridine
derivatives (10a,b) (General Procedure)
2-(Benzothiazol-2-ylmethyl)-6-cyano-7-(2-furyl) thiazolo-
[4,5-b]pyran-5-one (6c)
Yield, 61%; m.p. 264-265 °C (methanol); IR (KBr) nmax
2226 (CN), 1740 (CO), 1635 (C=N) cm-1; 1H NMR [DMSO-
d6]: d = 2.22 (s, 2H), 5.6 (m, 3H), 7.1-7.98 (m, 4H); m/z 391
(M+). Calcd. for C19H9N3S2O3: C, 58.2; H, 2.32; N, 10.74; S,
16.38%. Found: C, 58.11; H, 2.31; N, 10.69; S, 16.42%.
A solution of thaizole 1 (2.48 g, 10 mmol) in pyridine
was treated with the appropriate a,b-cinnamonitrile deriva-
tives 2a-n. The reaction mixture was heated under reflux for
5-7 h. (TLC control). The solvent was removed under re-
duced pressure, and the residue was triturated with ice/water
and neutralized with hydrochloric acid. The solid obtained
was filtered, washed with ice water, dried and recrystallized
from the proper solvent and identified as 5a,b; 6a-c; 8a,b and
10a,b.
2-(Benzothiazol-2-ylmethyl)-6-cyano-7-(2-thienyl)
thiazolo[4,5-b]pyran-5-one (6d)
Yield, 63%; m.p. 264-265 oC (methanol); IR (KBr) nmax
2223 (CN), 1739 (CO), 1635 (C=N) cm-1; 1H NMR [DMSO-
d6]: d = 2.25 (s, 2H), 5.4 (m, 3H), 7.2-8.12 (m, 4H); m/z 408
(M++1). Calcd. for C19H9N3S3O2: C, 55.99; H, 2.23; N, 10.31;
S, 23.60%. Found: C, 55.97; H, 2.20; N, 10.42; S, 23.58%.
5-Amino-2-(benzothiazol-2-ylmethyl)-7-phenyl thiazolo-
[4,5-b]pyran-6-carboxamide (5a)
Yield, 72%; m.p. 254-255 °C (dioxane); IR (KBr) nmax
1
3350, 3310, 3270 (NH2), 1683 (CO), 1635 (C=N) cm-1; H
Ethyl 5-amino-2-(benzothiazol-2-ylmethyl)-7-phenyl
thiazolo[4,5-b]pyran-6-carbo-xylate (8a)
NMR [DMSO-d6]: d = 2.28 (s, 2H), 4.72 (s, 1H), 6.73 (sbr,
2H, D2O-exchangeable), 7.12-8.1 (m, 11H); m/z 420 (M+).
Calcd. for C21H16N4S2O2: C, 59.94; H, 3.84; N, 13.31; S,
15.24%. Found: C, 59.89; H, 3.85; N, 13.33; S, 15.13%.
Yield, 69%; m.p. 258-259 °C (ethanol); IR (KBr) nmax
1
3400, 3330 (NH2), 1728 (CO), 1620 (C=N) cm-1; H NMR
[DMSO-d6]: d = 1.4 (t, 3H), 2.23 (s, 2H), 4.12 (q, 2H), 4.68 (s,
1H), 6.75 (sbr, 2H, D2O-exchangeable), 7.15-8.12 (m, 9H);
m/z 450 (M++1). Calcd. for C23H19N3S2O3: C, 61.44; H, 4.27;
N, 9.35; S, 14.26%. Found: C, 61.40; H, 4.31; N, 9.33; S,
14.24%.
5-Amino-2-(benzothiazol-2-ylmethyl)-7-(4-chlorophenyl)
thiazolo[4,5-b]pyran-6-carboxamide (5b)
Yield, 68%; m.p. 310 °C (dioxane); IR (KBr) nmax 3400,
3320 (NH2), 1680 (CO), 1625 (C=N) cm-1; 1H NMR [DMSO-
d6]: d = 2.25 (s, 2H), 4.71 (s, 1H), 6.62 (sbr, 2H, D2O-ex-
changeable), 7.12 (sbr, 2H, D2O-exchangeable), 7.22-8.05
(m, 8H); m/z 455 (M+). Calcd. for C21H15N4S2O2Cl: C, 55.41;
H, 3.33; N, 12.31; S, 14.09; Cl, 7.79%. Found: C, 55.38; H,
Ethyl 5-amino-2-(benzothiazol-2-ylmethyl)-7-(4-chloro-
phenyl) thiazolo[4,5-b]pyran-6-carboxylate (8b)
Yield, 64%; m.p. 222 °C (ethanol); IR (KBr) nmax 3335,
3305 (NH2), 1735 (CO), 1630 (C=N) cm-1; 1H NMR [DMSO-

1068 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Sayed
d6]: d = 1.38 (t, 3H), 2.27 (s, 2H), 4.31 (q, 2H), 4.71 (s, 1H),
6.24 (sbr, 2H, D2O-exchangeable), 7.21-8.0 (m, 8H); m/z 484
(M+). Calcd. for C23H18N3S2O3Cl: C, 57.07; H, 3.76; N, 8.68;
S, 13.25; Cl, 7.32%. Found: C, 57.1; H, 3.8; N, 8.65; S,
13.24%.
with ice water, dried and recrystallized from the proper sol-
vent to yield 13a-c.
7-(Benzothiazole-2-ylmethyl)-3-methyl-5-phenyl thiazolo-
[4¢,5¢:6,5]pyrano[2,3-d]-1,2,3-triazine-4(3H)-one (13a)
Yield, (55%); m.p. 264-265 °C (DMF); IR (KBr) nmax
1665 (CO), 1620 (C=N) cm-1; 1H NMR [DMSO-d6]: d = 2.29
(s, 2H), 4.12 (s, 3H), 4.7 (s, 1H), 7.14-7.98 (m, 9H); m/z 445
(M+). Calcd. for C22H15N5S2O2: C, 59.29; H, 3.40; N, 15.73;
S, 14.39%. Found: C, 59.27; H, 3.45; N, 15.71; S, 14.37%.
2-(Benzothiazol-2-ylmethyl)-6-cyano-7-(4-chlorophenyl)
thiazolo[4,5-b]pyridine-5(4H)-one (10a)
Yield, 60%; m.p. 169 °C (DMF); IR (KBr) nmax 3305
(NH), 2223 (CN), 1630 (C = N) cm-1; 1H NMR [DMSO-d6]: d
= 2.24 (s, 2H), 7.21-8.11 (m, 8H), 12.9 (s, 1H); m/z 461
(M++1). Calcd. for C21H11N4S3Cl: C, 55.92; H, 2.46; N,
12.43; S, 21.33; Cl, 7.86%. Found: C, 55.86; H, 2.50; N,
12.39; S, 21.32; Cl, 7.88%.
7-(Benzothiazole-2-ylmethyl)-3-cyanomethyl-5-phenyl
thiazolo[4¢,5¢:6,5]pyrano[2,3-d]-1,2,3-triazine-4(3H)-one
(13b)
Yield, (55%); m.p. 264-265 °C (dioxane/ethanol); IR
(KBr) nmax 1680 (CO), 1622 (C=N) cm-1; 1H NMR [DMSO-
d6]: d = 2.3 (s, 2H), 4.7 (s, 1H), 5.63 (s, 2H), 7.21-8.1 (m, 9H);
Calcd. for C23H14N6S2O2: C, 58.7; H, 3.0; N, 17.86; S,
13.63%. Found: C, 58.69; H, 3.02; N, 17.88; S, 13.6%.
2-(Benzothiazol-2-ylmethyl)-6-cyano-7-(4-methoxyphenyl)
thiazolo[4,5-b]pyridine-5(4H)-one (10b)
Yield, 63%; m.p. 264-265 °C (DMF); IR (KBr) nmax
3250 (NH), 2210 (CN), 1635 (C=N) cm-1; 1H NMR [DMSO-
d6]: d = 2.28 (s, 2H), 3.52 (s, 3H), 7.21-8.12 (m, 8H), 13.1 (s,
1H); m/z 446 (M+). Calcd. for C22H14N4S3O: C, 59.17; H,
3.17; N, 12.55; S, 21.54%. Found: C, 59.18; H, 3.22; N,
12.54; S, 21.57.88%.
7-(Benzothiazole-2-ylmethyl)-3-phancyl-5-phenyl thiazolo-
[4¢,5¢:6,5]pyrano[2,3-d]-1,2,3-triazine-4(3H)-one (13c)
Yield, (55%); m.p. 325 °C (DMF/MeOH); IR (KBr)
nmax 1680 (CO), 1628 (C=N) cm-1; 1H NMR [DMSO-d6]: d =
2.28 (s, 2H), 4.72 (s, 1H), 5.82 (s, 2H), 7.15-8.01 (m, 14H);
Calcd. for C23H14N6S2O2: C, 58.7; H, 3.0; N, 17.86; S,
13.63%. Found: C, 58.69; H, 3.02; N, 17.88; S, 13.6%.
7-(Benzothiazole-2-ylmethyl)-5-phenyl thiazolo[4¢,5¢:6,5]-
pyrano[2,3-d]-1,2,3-triazine-4(3H)-one (11)
To an ice/cooled solution of 5-amino-2-(benzothiazol-
2-ylmethyl)-7-phenyl thiazolo[4,5-b]pyran-6-carboxamide
5a (0.42 g, 1 mmol) in acetic acid (10 mL), a solution of so-
dium nitrite (0.14 g, 2 mmol) in sulfuric acid (1 mL) was
added. The reaction mixture was stirred for 24 h. The solution
was poured into water and the solid product was filtered off
and recrystallized from dioxane to give (72%) of 11; m.p. 303
°C; IR (KBr) nmax 3215 (NH), 1683 (CO), 1630 (C=N) cm-1;
1H NMR [DMSO-d6]: d = 2.36 (s, 2H), 4.71 (s, 1H), 7.12-8.11
(m, 9H), 12.31 (s, 1H); m/z 431 (M+). Calcd. for C21H13N5S2O2:
C, 58.45; H, 3.04; N, 16.23; S, 14.86%. Found: C, 58.43; H,
3.11; N, 16.25; S, 14.79%.
2-(Benzothiazole-2-ylmethyl)-9-phenyl thiazolo[4¢,5¢:6,5]-
pyrano[2,3-d]pyrimidine-8(7H)-one (14)
A solution of 5a (0.42 g, 1 mmol) in formic acid (5 mL)
was refluxed for 12 h. The solvent was then removed under
reduced pressure, and water was added to the residue. The
solid product was filtered off and recrystallized from DMF to
yield (68%) of compound 14; m.p. 179 °C; IR (KBr) nmax
3050 (NH), 1685 (CO), 1630 (C=N) cm-1; 1H NMR [DMSO-
d6]: d = 2.26 (s, 2H), 4.69 (s, 1H), 7.11-8.05 (m, 9H), 8.14 (s,
1H,), 12.95 (brs, 1H, D2O-exchangeable). Calcd. for
C22H14N4S2O2: C, 61.37; H, 3.28; N, 13.02; S, 14.89%.
Found: C, 61.35; H, 3.3; N, 13.1; S, 14.86%.
7-(Benzothiazole-2-ylmethyl)-3,5-disubstituted thiazolo-
[4¢,5¢:6,5]pyrano[2,3-d]-1,2,3-triazine-4(3H)-ones (13a-c)
(General Procedure)
2-(Benzothiazole-2-ylmethyl)-8-chloro-9-phenyl thiazolo-
[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine (15)
A solution of 11 (0.43 g, 1 mmol), 15% potassium hy-
droxide (2 mL, 5.3 mmol) and the appropriate electrophilic
reagent 12a-c (2 mmol) in acetone (15 mL) was stirred for 24
h. at room temperature (13a,c) or at reflux temperature (13b).
The solvent was removed under reduced pressure, and the
residue was triturated with ice/water and neutralized with 2N
hydrochloric acid. The solid obtained was filtered, washed
A stirred solution of 14 (0.43 g, 1 mmol) and phospho-
rous pentachloride (0.4 g, 1.9 mmol) in phosphorous oxy-
chloride (10 mL) was refluxed for 10 h. Then, the reaction
mixture was evaporated under reduced pressure, ice was
added, and the solution was neutralized with saturated so-
dium bicarbonate solution. The product obtained was fil-

Nitriles in Heterocyclic Synthesis
J. Chin. Chem. Soc., Vol. 50, No. 5, 2003 1069
tered, washed with water, dried, and recrystallized from the
dioxane/water to yield, (63%) of 15; m.p. 283 °C; IR (KBr)
nmax 1625 (C=N) cm-1; 1H NMR [DMSO-d6]: d = 2.28 (s, 2H),
4.72 (s, 1H), 7.1-8.11 (m, 9H), 8.84 (s, 1H); m/z 450 (M++1).
Calcd. for C22H13N4S2O2Cl: C, 58.85; H, 2.92; N, 12.48; S,
14.28, Cl, 12.66%. Found: C, 58.84; H, 2.91; N, 12.5; S,
14.25, Cl, 12.67%.
2-(Benzothiazole-2-ylmethyl)-7-cyanomethyl-9-phenyl
thiazolo[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine-8(7H)-one
(18b)
Yield, (62%); m.p. 264-265 °C (DMF/H2O); IR (KBr)
nmax 1690 (CO), 1630 (C=N) cm-1; 1H NMR [DMSO-d6]: d =
2.28 (s, 2H), 4.72 (s, 1H), 5.74 (s, 2H), 7.11-8.01 (m, 9H),
8.32 (s,1H). Calcd. for C24H15N5S2O2: C, 61.39; H, 3.23; N,
14.92; S, 13.66%. Found: C, 61.36; H, 3.3; N, 14.89; S,
13.65%.
2-(Benzothiazole-2-ylmethyl)-9-phenyl-8-thiophenyl-
thiazolo[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine (16)
A solution of 15 (0.45 g, 1 mmol) and thiophenol (0.14
g, 1.3 mmol) in EtOH / THF (15 mL, 1:4 v/v) was refluxed for
1 h. The solid was filtered off and recrystallized from
dioxane/ethanol to yield (58%) of compound 16; m.p. 235
°C; IR (KBr) nmax 1635 (C=N) cm-1; 1H NMR [DMSO-d6]: d
= 2.3 (s, 2H), 4.71 (s, 1H), 7.12-8.21 (m, 14H), 8.74 (s, 1H).
Calcd. for C28H18N4S3O: C, 64.34; H, 3.48; N, 10.72; S,
18.4%. Found: C, 64.32; H, 3.49; N, 10.68, S, 18.37%.
2-(Benzothiazole-2-ylmethyl)-7-phenacyl-9-phenyl
thiazolo[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine-8(7H)-one (18c)
Yield, (59%); m.p. 264-265 °C (dioxane); IR (KBr)
nmax 1680 (CO), 1630 (C=N) cm-1; 1H NMR [DMSO-d6]: d =
2.32 (s, 2H), 4.73 (s, 1H), 5.36 (s, 2H), 7.11-8.01 (m, 9H),
8.22 (s, 1H). Calcd. for C30H20N4S2O3: C, 65.67; H, 3.68; N,
10.21; S, 11.69%. Found: C, 65.65; H, 3.71 N, 10.11; S,
11.7%.
2-(Benzothiazole-2-ylmethyl)-8-ethoxy-9-phenyl thiazolo-
[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine (17)
Synthesis of 19a,b (Method A) (General procedure)
A suspension of 5a (0.42 g, 1 mmol) in pyridine (15
mL) was treated with the appropriate reagents (urea or
thiourea) (1 mmol). The reaction mixture was refluxed for
3-5 h., then left to cool, poured onto ice/water and neutralized
with dilute HCl. The solid product formed was collected and
recrystallized from the appropriate solvent.
To a solution of sodium ethoxide (0.05 g of sodium, 2
mmol) in ethanol (25 mL), 15 (0.22 g, 0.5 mmol) was added.
The reaction mixture was refluxed for 5 h. The solid was fil-
tered off and recrystallized from DMF to yield (62%) of com-
pound 17; m.p. 311 °C; IR (KBr) nmax 1630 (C=N) cm-1; 1H
NMR [DMSO-d6]: d = 1.52 (t, 3H), 2.3 (s, 2H), 4.41 (q, 2H),
4.71 (s, 1H), 7.12-7.98 (m, 14H), 8.62 (s, 1H). Calcd. for
C24H18N4S2O2: C, 62.85; H, 3.96; N, 12.22; S, 13.98%.
Found: C, 62.86; H, 3.95; N, 12.3, S, 13.96%.
Synthesis of 19b:- (Method B)
A suspension of 5a (0.42 g, 1 mmol) in pyridine (15
mL) was treated with carbon disulfide (2 mL). The reaction
mixture was refluxed in a water bath until the hydrogen sul-
fide ceased (12 h.). The solid product formed on hot was col-
lected by filtration and recrystallized from DMF, filtered off,
washed with ethanol and dried, to give a compound identical
with 19b in all respects (mp., mixed mp. and spectra data).
2-(Benzothiazole-2-ylmethyl)-7,9-disubstituted thiazolo-
[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine-8(7H)-ones (18a-c)
(General Procedure)
A solution of 14 (0.43 g, 1 mmol), 15% potassium hy-
droxide (2 mL, 5 mmol) and the appropriate electrophilic re-
agents 12a-c (1.5 mmol) in THF (15 mL) was stirred for 48 h.
at room temperature (18a) or at reflux temperature (24 h. for
18b; 12 h. for 18c). The solid obtained was filtered and then
recrystallized from suitable solvent.
2-(Benzothiazole-2-ylmethyl)-5,7-dihydro-6,8-dioxo-9-
phenyl thiazolo[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine (19a)
Yield, (48%); m.p. 289 °C (DMF); IR (KBr) nmax 3400-
3210 (NH), 1660 (CO), 1625 (C=N) cm-1; 1H NMR [DMSO-
d6]: d = 2.29 (s, 2H), 4.72 (s, 1H), 7.13-8.11 (m, 9H), 11.3 (s,
1H), 12.13 (s, 1H). Calcd. for C22H14N4S2O3: C, 59.17; H,
3.17; N, 12.55; S, 14.36%. Found: C, 59.22; H, 3.16; N,
12.54; S, 14.37%.
2-(Benzothiazole-2-ylmethyl)-7-methyl-9-phenyl thiazolo-
[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine-8(7H)-one (18a)
Yield, (57%); m.p. 264-265 °C (dioxane); IR (KBr)
nmax 1660 (CO), 1630 (C=N) cm-1; 1H NMR [DMSO-d6]: d =
2.32 (s, 2H), 3.62 (s, 3H), 4.69 (s, 1H), 7.11-7.97 (m, 9H),
8.12 (s,1H). Calcd. for C23H16N4S2O2: C, 62.14; H, 3.64; N,
12.61; S, 14.42%. Found: C, 62.12; H, 3.65; N, 12.58; S,
14.4%.
2-(Benzothiazole-2-ylmethyl)-5,7-dihydro-8-oxo-9-phenyl
thiazolo[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine-5-thione (19b)
Yield, (56%); m.p. 212 °C (DMF); IR (KBr) nmax 3370-
3200 (NH), 1670 (CO), 1628 (C=N) cm-1; 1H NMR [DMSO-

1070 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Sayed
d6]: d = 2.3 (s, 2H), 4.69 (s, 1H), 7.15-8.13 (m, 9H), 9.1 (s,
1H), 11.23 (s, 1H). Calcd. for C22H14N4S3O2: C, 57.12; H,
3.06; N, 12.12; S, 20.79%. Found: C, 57.1; H, 3.0; N, 12.13;
S, 20.74%.
nol (10 mL) for 1 h., cooled, and the resulting solid collected
and recrystallized from the proper solvent.
Method B: A mixture of 22 (0.44 g, 1 mmol) and ethyl
orthofromate (0.25 g, 1.7 mmol) was heated at 180 °C for 2 h.
The initial melt solidified, triturating with cold methanol and
recrystallized of the solid product from the proper solvent.
23, Yield (68%); m.p. 319-320 °C (DMF); IR (KBr)
6-Anilino-2-(benzothiazole-2-ylmethyl)-9-phenyl thiazolo-
[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine-8-one (20)
1
A suspension of 5a (0.42 g, 1 mmol) in 1,4-dioxane (20
mL) was treated with phenyl isothiocyante (0.15 g, 1 mmol).
The reaction mixture was refluxed for 3-5 h. (TLC control),
then left to cool. The solid product formed was collected by
filtration and recrystallized from dioxane to yield (63%) of
compound 20; m.p. 282 °C; IR (KBr) nmax 3290-3210 (NH),
1665 (CO), 1630 (C=N) cm-1; 1H NMR [DMSO-d6]: d = 2.29
(s, 2H), 4.72 (s, 1H), 7.12-8.05 (m, 14H), 9.54 (s, 1H), 11.62
(s, 1H); m/z 522 (M+). Calcd. for C28H19N5S2O2: C, 64.47; H,
3.68; N, 13.43; S, 12.29%. Found: C, 64.45; H, 3.69; N,
13.42; S, 12.31%.
nmax 3220 (NH2), 1685 (CO), 1635 (C=N) cm-1; H NMR
[DMSO-d6]: d = 2.3 (s, 2H), 4.71 (s, 1H), 6.12 (s, 2H), 7.21-
8.1 (m, 9H), 8.52 (s, 1H). Calcd. for C23H15N5S2O4: C, 60.95;
H, 3.49; N, 16.16; S, 14.79%. Found: C, 60.92; H, 3.45; N,
16.20, S, 14.76%.
Ammonylsis of 21: A mixture of 21 (0.51 g, 1 mmol)
and conc. ammonia (15 mL) was heated under reflux in etha-
nol (15 mL) for 7 h. The reaction mixture was allowed to cool
to room temperature; the crystalline product was filtered off,
washed with ethanol, dried, and recrystallized from the ap-
propriate solvent to give a compound identical with 14 in all
respects (mp., mixed mp. and spectra data).
Ethyl 2-(benzothiazol-2-ylmethyl)-5-((ethoxymethylene)-
amino)-7-phenyl thiazolo[4,5-b]pyran-6-carboxylate (21)
A mixture of 8a (0.45 g, 1 mmol) and ethyl ortho-
formate (0.44 g, 3 mmol) was refluxed for 4-6 h. Excess ethyl
orthoformate was distilled off under vacuum and the residue
was treated with ethanol. The resulting solid product was col-
lected and recrystallized from ethanol to yield (68%) from
compound 21 m.p. 213 °C; IR (KBr) nmax 1705 (CO), 1635
(C=N) cm-1; 1H NMR [DMSO-d6]: d = 1.3-1.5 (m, 6H), 2.3 (s,
2H), 4.32-4.5 (m, 4H), 4.72 (s, 1H), 7.12-8.06 (m, 9H), 8.63
(s, 1H). Calcd. for C26H23N3S2O4: C, 61.76; H, 4.59; N, 8.31;
S, 12.68%. Found: C, 61.75; H, 4.6; N, 8.30, S, 12.63%.
Nitrosation of 23: A suspension of 23 (0.43 g, 1 mmol)
in aqueous acetic acid (15 mL) was warmed to 50 °C and then
treated with sodium nitrite (0.14 g, 2 mmol) in portion. The
reaction mixture was heated until the evolution of nitrogen
dioxide ceased; the resulting solution was cooled and diluted
with water. The solid product was purified by dissolving in
sodium hydroxide solution (10%) and reprecipitating with di-
lute hydrochloric acid followed by recrystallization from the
appropriate solvent to give a compound identical with 14 in
all respects (mp., mixed mp. and spectra data).
5-Substituted-2-(benzothiazol-2-ylmethyl)-7-(4-chloro-
phenyl) thiazolo[4,5-b]pyridine-6-carbonitrile (24a,b)
(General Procedure)
5-Amino-2-(benzothiazol-2-ylmethyl)-7-phenyl thiazolo-
[4,5-b]pyran-6-carboxylic acid hydrazide (22)
A mixture of 10a (0.45 g, 1 mmol), the appropriate
electrophilic reagents 12b,c (1 mmol), potassium carbonate
(0.25 g, 1.7 mmol), and a catalytic amount of potassium io-
dide in acetone (40 mL) was stirred at room temperature for
12 h. The insoluble solid was removed by filtration, washed
with acetone, and combined filtrate and washings were evap-
orated. The residual solid was recrystallized from the appro-
priate solvent.
A mixture of 8a (0.45 g, 1 mmol) and hydrazine hydrate
(1 mL, 80% solution) was refluxed in ethanol (10 mL) for 5
h., cooled, and the colorless resulting solid product collected,
washed with boiling ethanol and recrystallized from dioxane
to yield (68%) from compound 22 m.p. 277-278 °C; IR (KBr)
nmax 3400, 3330, 3190 (NH and NH2), 1673 (CO), 1630
1
(C=N) cm-1; H NMR [DMSO-d6]: d = 2.3 (s, 2H), 4.32 (s,
2H), 4.72 (s, 1H), 5.71 (s, 2H), 7.12-8.05 (m, 9H), 9.35 (s,
1H). Calcd. for C21H17N5S2O4: C, 57.91; H, 3.94; N, 16.08; S,
14.72%. Found: C, 57.92; H, 3.95; N, 16.11, S, 14.70%.
2-(Benzothiazol-2-ylmethyl)-5-cyanomethyl-7-(4-chloro-
phenyl) thiazolo[4,5-b]pyridine-6-carbonitrile (24a)
Yield, 62%; m.p. 283 °C (methanol); IR (KBr) nmax
2220 (CN), 1632 (C=N) cm-1; 1H NMR [DMSO-d6]: d = 2.31
(s, 2H), 4.36 (s, 2H), 7.12-8.11 (m, 8H); m/z 490 (M+). Calcd.
for C23H12N5S3Cl: C, 56.37; H, 2.47; N, 14.29; S, 19.63; Cl,
7.23%. Found: C, 56.34; H, 2.44; N, 14.30; S, 19.65; Cl,
7-Amino-2-(benzothiazol-2-ylmethyl)-9-phenyl thiazolo-
[4¢,5¢:6,5]pyrano[2,3-d]pyrimidine-8(7H)-one (23)
Method A: A mixture of 21 (0.51 g, 1 mmol) and
hydrazine hydrate (1 mL, 80% solution) was refluxed in etha-

Nitriles in Heterocyclic Synthesis
7.24%.
J. Chin. Chem. Soc., Vol. 50, No. 5, 2003 1071
then cooled and treated with ammonia (20%). The precipi-
tated product was filtered off, washed with water, dried and
recrystallized from DMF to yield (68%) of compound 26;
m.p. 323 °C; IR (KBr) nmax 3310 (NH), 1660 (CO), 1630 (C=N)
2-(Benzothiazol-2-ylmethyl)-5-phenacyl-7-(4-chlorophenyl)
thiazolo[4,5-b]pyridine-6-carbonitrile (24b)
1
Yield, 64%; m.p. 298 °C (DMF); IR (KBr) nmax 2222
(CN), 1690 (CO), 1635 (C=N) cm-1; 1H NMR [DMSO-d6]: d
= 2.26 (s, 2H), 4.61 (s, 2H), 7.1-8.12 (m, 13H); m/z 569 (M+).
Calcd. for C29H17N4S3OCl: C, 61.19; H, 3.02; N, 9.85; S,
16.89, Cl; 6.23%. Found: C, 61.21; H, 2.98; N, 9.83; S, 16.91;
Cl, 6.20%.
cm-1; H NMR [DMSO-d6]: d = 2.31 (s, 2H), 8.43 (s, 1H),
7.12-8.05 (m, 8H), 12.83 (s, 1H). Calcd. for C22H12N5S2OCl:
C, 57.19; H, 2.62; N, 15.16; S, 13.88; Cl, 7.67%. Found: C,
57.2; H, 2.59; N, 15.11; S, 13.86; Cl, 7.65%.
6-Amino-2-(benzothiazol-2-ylmethyl)-10-(4-chlorophenyl)
thiazolo[4²,5²:6¢,5¢]pyridino[2¢,3¢:5,4]thieno[3,2-d]pyrimi-
dine (27)
2-Substituted-3-amino-6-(benzothiazol-2-ylmethyl)-4-(4-
chlorophenyl) thieno[4¢,5¢:6,5]pyridino[3,2-b]thiazole
(25a,b)
A mixture of 25a (0.49 g, 1 mmol), formamide (10 mL),
formic acid (5 mL), and DMF (5 mL) were refluxed for 8
hours and then cooled. The precipitated solid was filtered off,
washed with water, dried and recrystallized from dioxane to
yield compound 27; m.p. 294 °C; IR (KBr) nmax 3297, 3156
Method A: A mixture of 24a,b (1 mmol) and piperidine
(0.25 mL) was refluxed in acetone/THF (1:1 v/v, 20 mL) for
5-7 h. The solvent was evaporated at reduced pressure. The
solid product was recrystallized from the suitable solvent.
Method B (for synthesis of 25b): A solution of 10a
(0.45 g, 1 mmol) in 1,4-dioxane (20 mL) containing Et3N
(0.25 mL) or sodium ethoxide solution was treated with
phenacyl bromide (0.199 g, 1 mmol), and the reaction mix-
ture was heated under reflux for 6 h. The solid product ob-
tained after cooling and acidification was filtered off and
recrystallized from the proper solvent.
1
(NH2), 1630 (C=N) cm-1; H NMR [DMSO-d6]: d = 2.3 (s,
2H), 5.36 (s, 2H), 8.43 (s, 1H), 7.12-8.11 (m, 8H). Calcd. for
C22H13N6S2Cl: C, 57.32; H, 2.85; N, 18.24; S, 13.91; Cl,
7.69%. Found: C, 57.29; H, 2.89; N, 18.21; S, 13.88; Cl,
7.68%.
2-(Benzothiazol-2-ylmethyl)-7-(4-chlorophenyl)-5-methyl-
thio thiazolo[4,5-b]pyridine-6-carbonitrile (24c)
Compound 10a (0.9 g, 2 mmol) was suspended in 2N
sodium hydroxide (20 mL). Subsequently, dimethyl sulphate
(0.25 g, 2 mmol) was added dropwise to this suspension. The
obtained solution was stirred for two hours and the precipi-
tate collected by filtration, washed with water, dried and
recrystallized from dioxane to yield (66%) of 24c; m.p. 285
3-Amino-6-(benzothiazol-2-ylmethyl)-4-(4-chlorophenyl)
thieno[4¢,5¢:6,5]pyridino[3,2-b]thiazole (25a)
Yield, 65%; m.p. 235 °C (DMF); IR (KBr) nmax 3365,
3220 (NH2), 2205 (CN), 1635 (C=N) cm-1; 1H NMR [DMSO-
d6]: d = 2.31 (s, 2H), 4.53 (brs, 2H), 7.1-8.12 (m, 8H); m/z 490
(M+). Calcd. for C23H12N5S3Cl: C, 56.37; H, 2.47; N, 14.29;
S, 19.63; Cl, 7.23%. Found: C, 56.39; H, 2.46; N, 14.28; S,
19.61; Cl, 7.25%.
1
°C; IR (KBr) nmax 2225 (CN), 1635 (C=N) cm-1; H NMR
[DMSO-d6]: d = 2.29 (s, 2H), 2.79 (s, 3H), 7.18-8.13 (m, 8H);
m/z 465 (M+). Calcd. for C22H13N4S3Cl: C, 56.82; H, 2.82; N,
12.05; S, 20.68; Cl, 7.62%. Found: C, 56.83; H, 2.80; N,
12.11; S, 20.65; Cl, 7.64%.
3-Amino-6-(benzothiazol-2-ylmethyl)-4-(4-chlorophenyl)
thieno[4¢,5¢:6,5]pyridino[3,2-b]thiazole (25b)
Yield, 66%; m.p. 267 °C (dioxane); IR (KBr) nmax 3380,
3329 (NH2), 1680 (CO), 1630 (C=N) cm-1; 1H NMR [DMSO-
d6]: d = 2.29 (s, 2H), 7.12-8.13 (m, 15H); m/z 569 (M+).
Calcd. for C29H17N4S3OCl: C, 61.19; H, 3.02; N, 9.85; S,
16.89, Cl; 6.23%. Found: C, 61.18; H, 3.10; N, 9.86; S, 16.86;
Cl, 6.24%.
2-(Benzothiazol-2-ylmethyl)-5-(morpholino-4-yl)-7-phenyl
thiazolo[4,5-b]pyridine-6-carbonitrile (28)
A solution of 24c (0.47 g, 1 mmol) in morpholine (10
mL) was refluxed for 2 h. The reaction mixture was then
cooled and treated with water and allowed to stand overnight.
The precipitated product was filtered off, washed with water,
dried and recrystallized from DMF to yield (63%) of com-
pound 28; m.p. > 330 °C; IR (KBr) nmax 2222 (CN), 1635
(C=N) cm-1; 1H NMR [DMSO-d6]: d = 2.29 (s, 2H), 3.71 (t,
4H), 3.93 (t, 4H), 7.12-7.99 (m, 8H); m/z 504 (M+). Calcd. for
C25H18N5S2OCl: C, 59.57; H, 3.61; N, 13.89; S, 12.72; Cl,
7.03%. Found: C, 59.55; H, 3.62; N, 13.86; S, 12.69; Cl,
2-(Benzothiazol-2-ylmethyl)-10-(4-chlorophenyl) thiazolo-
[4²,5²:6¢,5¢]pyridino[2¢,3¢:5,4]thieno[3,2-d]pyrimidine-
6(7H)-one (26)
A solution of 25a (0.49 g, 1 mmol) in formic acid (10
mL, 80%) was refluxed for 8 h. The reaction mixture was

1072 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Sayed
7.1%.
7-Amino-2-(Benzothiazol-2-ylmethyl)-6-benzoyl-8-methyl
thieno[2¢,3¢:6,5]pyridino[2,3-d]thiazole (35)
2-(Benzothiazol-2-ylmethyl)-6-cyano-7-methyl thaizolo-
[4,5-b]pyridine-5(4H)thione (31)
An equimolar amount of 31 (0.35 g, 1 mmol) and
phenacyl bromide 12c (0.19 g, 1 mmol), anhydrous potas-
sium carbonate (0.25 g, 1.6 mmol) in absolute ethanol (25
mL) were heated at reflux for 5-7 h. The reaction mixture was
diluted with water, and the product was collected by filtration
and recrystallized from DMF to yield (57%) of 35; m.p. > 300
°C; IR (KBr) nmax 3425, 3226 (NH2), 1695 (CO), 1630 (C=N)
A solution of acetylidenecyanothioacetamide {(29); 10
mmol; prepared in situ from acetaldehyde and cyanothio-
acetamide} in pyridine (30 mL) was treated with the thiazole
1 (2.48 g, 10 mmol). The reaction mixture was refluxed for
3-5 h., then evaporated in vacuo. The remaining solid was
triturated with ice/water and acidified with conc. HCl. The
solid product, so formed, was collected by filtration, washed
with cold water, dried and finally recrystallized from dioxane
to yield (58%) of 31; m.p. 264-265 °C; IR (KBr) nmax 3200
(NH), 2218 (CN), 1632 (C=N) cm-1; 1H NMR [DMSO-d6]: d
= 2.31 (s, 2H), 2.73 (s, 3H), 7.12-7.01 (m, 4H), 12.98 (s, 1H);
m/z 355 (M++1). Calcd. for C16H10N4S3: C, 54.21; H, 2.85; N,
15.81; S, 27.13%. Found: C, 54.18; H, 2.86; N, 15.8; S,
27.11%.
1
cm-1; H NMR [DMSO-d6]: d = 2.31 (s, 2H), 2.69 (s, 3H),
7.12-8.11 (m, 11H). Calcd. for C24H16N4S3O: C, 60.99; H,
3.42; N, 11.86; S, 20.35%. Found: C, 60.95; H, 3.51; N,
11.84; S, 20.37%.
Received July 29, 2002.
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To a solution of 31 (0.35 g, 1 mmol) in DMF (20 mL),
elemental sulphur (0.032 g, 1 mmol) and a catalytic amount
of triethylamine were added. The reaction mixture was
heated at reflux for 3-5 h., then evaporated in vacuo. The re-
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1
1350 (C=S) cm-1; H NMR [DMSO-d6]: d = 2.29 (s, 2H),
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