Keactions with 3,6-diaminothieno[2,3-b]-pyridines: Synthesis and characterization of several new fused pyridine heterocycles

Article abstract of DOI:10.1002/hc.20313

6-Aminopyridine-2(1H)thiones 1 reacting with a-halo-compounds 2a-c afforded the alkylthiopyridine derivatives 3a-c which in turn cyclized to the corresponding thieno[2,3-b]pyridine derivatives 4a-c. Several thieno[2,3-b]pyridine derivatives 7, 16, 19, pyr

Full text of DOI:10.1002/hc.20313

Heteroatom Chemistry
Volume 18, Number 4, 2007
Reactions with 3,6-Diaminothieno[2,3-b]-
pyridines: Synthesis and Characterization
of Several New Fused Pyridine Heterocycles
Mohamed A. M. Gad-Elkareem,1 Mohamed A. A. Elneairy,2
and Adel M. Taha2
1Department of Chemistry, Faculty of Science, Al-Azhar University (Assiut branch),
Assiut 71524, A. R. Egypt
2Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt
Received 15 December 2005; revised 12 March 2006
activities and are used as an adenosine receptor
ABSTRACT: 6-Aminopyridine-2(1H)thiones 1 re-
ligand [12,13]. Moreover, thieno[2,3-b]pyridines
acting with α-halo-compounds 2a–c afforded the
possess a wide range of biological activities such
alkylthiopyridine derivatives 3a–c which in turn
as antimicrobial [7,14–16], anti-inflammatory [17],
cyclized to the corresponding thieno[2,3-b]pyridine
ganadotropin releasing hormone antagonizing
derivatives 4a–c. Several thieno[2,3-b]pyridine deri-
[18], antiviral [19,20], and neurotropic activities
vatives 7, 16, 19, pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyri-
[10]. Furthermore, pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]-
midine derivatives 6a,b, 11a–c, 21 and pyrido-
pyrimidines were reported to have antiallergic
[3ꢀ,2ꢀ:4,5]thieno[3,2-c]pyridazine derivatives 13, 17
[21], antiprotozoals [22], antianaphylactic [23,24],
were prepared starting from compounds 4a–c.
and antimicrobial [14,15] activities. The above
ꢁ
C
2007 Wiley Periodicals, Inc. Heteroatom Chem 18:405–
findings stimulated the interest for the synthesis of
additional new numbers of these derivatives that
are required in medicinal chemistry programs.
413, 2007; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20313
INTRODUCTION
RESULTS AND DISCUSSION
It has been found that
Synthesis and characterization of pyridines,
thieno[2,3-b]pyridines, and pyrido[3ꢀ,2ꢀ:4,5]thieno-
[3,2-d]pyrimidines became the main target of this
research group. Several publications demonstrated
this research effort [1–9]. This is because these
derivatives possess diverse biological activities and
are widely used in pharmaceutical and medicinal
preparations. Alkylthiopyridines possess neu-
rotropic [10], cardiovascular [11], antimicrobial [7]
6-amino-4-(4-
methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-
dicarbonitrile (1) [25] reacted with chloroacetoni-
trile (2a) in cold DMF in the presence of potassium
hydroxide to give a reaction product resulting
from equimolecular addition of the reagent to the
reactant with the loss of one molecule of hydrogen
chloride. The IR spectrum of this reaction product
showed among its absorption bands those corre-
sponding to the presence of one NH2 (3380, 3327
cm−1) and CN (2252, 2211 cm−1) functions. Its H
NMR spectrum revealed only signals of OCH3(3.86
ppm), SCH2CN (4.35 ppm), NH2 (8.23 ppm), and
1
Correspondence to: Mohamed A. M. Gad-Elkareem; e-mail:
m65gad@yahoo.com.
c
ꢀ
2007 Wiley Periodicals, Inc.
405

406 Gad-Elkareem, Elneairy, and Taha
aromatic protons. The reaction product could then
be formulated as 2-amino-6-[(cyanomethyl)thio]-4-
(4-methoxyphenyl)pyridine-3,5-dicarbonitrile 3a.
In a similar manner, 1 reacted with chloroace-
tone (2b) and chloroacetamide (2c) to give 2-
amino-4-(4-methoxyphenyl)-6-[(2-oxopropyl)thio]-
pyridine-3,5-dicarbonitrile (3b) and 2-{[6-amino-
3,5-dicyano-4-(4-methoxyphenyl)pyridin-2-yl]thio}-
acetamide (3c) respectively. The structure of 3b,c
was also established based on analytical and spectral
data, which were in a good agreement with the
assigned structure in each case (cf. Scheme 1 and
the Experimental section).
The structure of each of 3a–c was further es-
tablished via their cyclization by boiling their so-
lutions in ethanolic potassium hydroxide to give
the corresponding 3,6-diaminothieno[2,3-b]pyridine
derivatives 4a–c respectively. The IR spectrum of
each of 4a–c showed the presence of additional
bands of a new NH2 group and the disappearance
of the CN band in each case proving that the cy-
clization reaction involved addition to the nitrile
function at position-3 at the pyridine ring of 3a–c
(cf. Scheme 1).
formic acid afforded a reaction product, which
showed the absorption bands of NH2, NH, ring-CO
and CN groups in its IR spectrum. Its 1H NHR
spectrum revealed only the signals of NH2, NH
and a new singlet signal at δ = 7.97 ppm corre-
sponding to the 2H-pyrimidine ring and OCH3
group in addition to the aromatic protons. Conse-
quently, this reaction product could be formulated
as the 7-amino-9-(4-methoxyphenyl)-4-oxo-3,4-
dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carbonitrile (6a) most likely formed via the inter-
mediacy of the carboxamidothieno[2,3-b]pyridine
derivative 5a that on cyclization by loss of the
element of water yielded 6a (cf. Scheme 2).
Under practically the same reaction conditions,
4a reacted with acetic anhydride to give also 7-
amino-9-(4-methoxyphenyl)-2-methyl-4-oxo-3,4-di-
hydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-car-
bonitrile (6b) that is also most likely formed via
first acetylation of the amino group at postion-3 of
the thiophene ring in 4a followed by hydrolysis to
give 5b and cyclization to 6b via loss of water (cf.
Scheme 2).
A solid and conclusive evidence for the structure
of 6a,b came from their independent synthesis via
the reaction of 4c with each of formic acid and acetic
anhydride respectively. Compounds 6a,b prepared
via this route were found to be identical in all aspects
(mp, mixed mp, analytical and spectral data) with
6a,b previously synthesized as described before (cf.
Scheme 2 and the Experimental section).
Compound 4a reacted also with two molecules
of DMF–DMA to give the corresponding bis-3,6-
{[(N,N-dimethylamino)methylene]amino}-2,5-di-
cyanothieno[2,3-b]pyridine derivative 7. The struc-
ture of 7 was established based on elemental
analysis and spectral data studies (cf. the Experi-
mental section).
Moreover, an additional proof for the structure
of 4a–c came from their independent synthesis by
performing the reactions of 1 with each of 2a–c
in boiling sodium methoxide solutions. Compounds
4a–c prepared via this route were found completely
identical in all aspects with 4a–c previously synthe-
sized as described before (cf. Scheme 1 and the Ex-
perimental section).
The
synthesized
3,6-diamino-2,5-dicyano-
thieno[2,3-b]pyridine derivative 4a seemed to be
an excellent candidate for the synthesis of other
desired heterocyclic derivatives through its par-
ticipation in a number of chemical reactions with
different reagents. Thus, the reaction of 4a with
Ar
CN
NC
DMF/KOH
cold
Ar
H2N
N
SCH2R
NC
CN
S
3a-c
KOH/EtOH
reflux
+ ClCH2R
2a-c
Ar
H2N
N
H
NH2
MeONa
reflux
NC
1
H2N
N
S
R
2-4a, R = CN
b, R = COCH3
c, R = CONH2
Ar = C6H4 OCH3-4
4a-c
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

Reactions with 3,6-Diaminothieno[2,3-b]pyridines 407
Ar
Ar
N
Ar
N
NH2
CN
NC
N
R
NHCOR
CONH2
NC
NC
-H2O
HCO2H
or Ac2O
NH
H2N
N
S
H2N
S
H2N
S
O
4a
5a,b
6a, R = H
b, R = CH3
DMF-DMA
2moles
HCO2H
or Ac2O
4c
H
Ar
Ar
NMe2
NMe2
NHR
N
N
NC
N
NC
RNH2 (8a-c)
Me2N
R
Me2N
N
S
CN
N
H
N
N
S
CN
H
7
9a-c
-RN=CHNMe2
-HNMe2
Ar
Ar
N
NC
N
Dimroth
rearrangment
NC
N
N
NR
S
H2N
N
S
H2N
NHR
NH
11a-c
10a-c
8-11a, R = C6 H4-CH3 -4
b, R = C6 H4-Cl-4
c, R = NH2
Ar = C6 H4 OCH3-4
SCHEME 2
The reaction of 7 with aromatic amines and
hydrazine hydrate constituted an easy and logical
route for the synthesis of other heterocyclic deriva-
tives. Thus, 7 reacted with p-toluidine (8a) in glacial
acetic acid to give a reaction product of molecu-
lar formula C24H18N6OS which corresponded to the
addition of the amine to 7 and the loss of one
molecule of N,N-dimethyl-Nꢀ-p-tolylformamidine
and one molecule of dimethylamine. The IR spec-
trum of the reaction product showed the absorp-
tion bands of one NH2, NH (3474, 3356, 3201 cm−1)
In the same manner, the reaction of 7 and
p-chloroaniline (8b) resulted in the formation
of the 7-amino-4-[(4-chlorophenyl)amino]pyrido-
[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carbonitrile de-
rivative 11b while its reaction with hy-
drazine
hydrate
afforded
the
7-amino-4-
hydrazinopyrido[3ꢀ,2ꢀ:4,5]thieno-[3,2-d]pyrimidine-
8-carbonitrile derivative 11c via Dimroth rear-
rangement [27]. The structure assigned for 11b,c
was established on the basis of elemental analysis
and spectral data studies (cf. Scheme 2 and the
Experimental section).
1
and CN (2212 cm−1) functions. Its H NMR spec-
trum revealed the signals of CH3 (δ = 2.30 ppm),
NH2(δ = 7.44–7.60 ppm and Ar H), NH (δ = 9.42
ppm), 2H-pyrimidine at δ = 8.31 ppm, OCH3, and
aromatic protons. Accordingly, and in addition to
analytical data, this compound could be formulated
as the 7-amino-4-[(4-methylphenyl)amino]pyrido-
[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carbonitrile de-
rivative 11a via Dimroth rearrangement [26].
The formation of each of 11a–c is assumed to
proceed via first addition of the aromatic amine or
the hydrazine 8a–c to compound 7 to give the non-
isolable intermediates 9a–c. Each of 9a–c then loses
one molecule of the schiff‘s base and one molecule
of dimethylamine to give the cyclized products 10a–
c which underwent Dimroth rearrangement to yield
the final isolable 11a–c. The above results find a great
Heteroatom Chemistry DOI 10.1002/hc

408 Gad-Elkareem, Elneairy, and Taha
1
support by the previous reports in the recent liter-
ature concerning the same rearrangement reaction
[26,27] (cf. Scheme 2 and the Experimental section).
Compound 4b took its role also in the syn-
thesis of a number of new fused heterocyclic
pyridine derivatives. Thus, 4b reacted with ni-
trous acid to give the corresponding bis-2,6-
diazonium salt intermediate 12 which could be in
situ cyclized via dehydrochlorination involving the
acetyl group and hydrolysis of the 6-diazonium
salt to afford the corresponding 7-hydroxypyrido-
[3ꢀ,2ꢀ:4,5]thieno[3,2-c]pyridazine derivative 13 (or its
tautomer 14). The IR spectrum of the reaction prod-
uct showed the absorption bands of OH at 3404
cm−1, CN at 2230 cm−1, and C O at 1718 cm−1. Its
1H NMR spectrum revealed only the signals of CH2
of pyridazine at δ = 3.78 ppm, OCH3 at δ = 3.85 ppm,
and OH at δ = 5.9 ppm (D2O exchangeable) in ad-
dition to the aromatic protons, thus confirming the
structure of 13 rather than 14 (cf. Scheme 3 and the
Experimental section).
Furthermore, 4b reacted with one molecule of
DMF–DMA to afford a reaction product that could
be formulated as the condensation product on the
amino group of the thiophene ring (15) or the con-
densation product on the amino group of the pyri-
dine ring (16). However, structure 16 was assigned
for this reaction product based on chemical evidence
because the spectral data were of no value in discrim-
inating the two structures (Scheme 3).
sent. Its H NMR revealed the signals of the newly
formed N(CH3)2 and N CH protons at δ = 2.64
and 6.70 ppm and absence of any signals which may
be attributed to the presence of NH2 protons (cf.
Scheme 3 and the Experimental section).
Compound 19 could also be synthesized via the
reaction of 4b with two molecules of DMF–DMA.
Compound 19 prepared via this route was found to
be identical in all aspects (mp, mixed mp, analytical
and spectral data) with 19 previously synthesized as
described before (cf. the Experimental section).
On the other hand, the reaction of 19 with hy-
drazine hydrate gave a reaction product of molec-
ular formula C18H16N6O2S that corresponded to ad-
dition of two molecules of the hydrazine to 19 with
the loss of one molecule of each of dimethylamine
and N,N-dimethylhydrazonoformamide [26]. The IR
spectrum of this reaction product showed the ab-
sorption bands related to the presence of two NH2,
OH and CN functions. Its 1H NMR revealed signals of
CH3 at δ = 1.98 ppm, two NH2 at δ = 5.26, 6.07 ppm
(D2O exchangeable), OH at δ = 7.03 ppm (D2O ex-
changeable) and 2H-pyrimidine at δ = 7.01 ppm, in
addition to the OCH3 and aromatic protons. More-
over, the molecular ion peak of the reaction product
was not observed [28] in its mass spectrum due to
the highly unstable M+. The base beak was found at
m/z = 352 (100%) corresponding to M+ (380)–N2 (28)
(cf. Scheme 3, Fig. 1 and the Experimental section).
Based on the above data the reaction prod-
uct was formulated as 3,7-diamino-4-hydroxy-9-
(4-methoxyphenyl)-4-methyl-3,4-dihydropyrido-
[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carbonitrile (21).
The formation of 21 was assumed to proceed
via addition of two molecules of hydrazine to
19 to give the intermediate adduct 20 which
underwent in situ cyclization to 21 with loss
of one molecule of dimethylamine and N,N-
dimethylhydrazonoformamide [26]. The structure
of compound 21 find a great support by the previous
report in the recent literature concerning the similar
ring system [29].
Thus, 16 reacted with nitrous acid to give the
corresponding diazonium salt that could be in situ
cyclized via dehydrochlorination to afford the cor-
responding pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-c]pyridazine
derivative 17 (or its tautomer 18). The IR spectrum
of the reaction product showed the absorption bands
of CN at 2217 cm−1 and ring-CO at 1705 cm−1 func-
1
tions. Its H NMR spectrum revealed a new singlet
signal at δ = 3.70 ppm which corresponded to the
methylene group at the pyridazine ring, thus con-
firming structure 17 rather than its tautomer 18 to
represent the reaction product (cf. Scheme 3 and the
Experimental section).
It is remarkable to report, here, that an unex-
pected reaction took place on reacting 16 with hy-
drazine hydrate, which gave back the starting 4b and
this could be considered as a further solid evidence
for the structure of both 4b and 16 (cf. Scheme 3).
Compound 16 reacted also with another
molecule of DMF–DMA to give the corresponding
condensation product 19. Structure of 19 was es-
tablished based on elemental analysis and IR spec-
tral data that showed the absorption bands of CN
and (CH3CO ) functions only while the bands re-
lated to the presence of NH2 were entirely ab-
EXPERIMENTAL
Melting points were measured with a Gallenkamp
apparatus and are uncorrected. IR spectra in KBr
discs were recorded on a Bruker Vector 22 FT-IR
spectrophotometer. 1H NMR spectra were deter-
mined in DMSO-d6 and CDCl3 at 300 MHz on a Var-
ian Mercury VX spectrometer using TMS as an inter-
nal standard. Chemical shifts are expressed as δ ppm
and J as Hz units. Mass spectra were recorded on a
GCMS-QP 1000 EX spectrometer at 70 eV. Elemen-
tal analyses were carried out at the Microanalytical
Heteroatom Chemistry DOI 10.1002/hc

Reactions with 3,6-Diaminothieno[2,3-b]pyridines 409
Ar
Ar
N
Ar
N
Cl
H
NC
HO
N
NC
HO
N
O
NC
N
N
O
N
N
N
CH3
N
S
S
S
N
O
14
Cl
13
12
NMe2
Ar
N
N
NC
NaNO2
HCl
H2N
S
COCH3
DMF-DMA
1 mole
15
4b
Ar
NH2
NC
N
DMF-DMA
2 moles
N
COCH3
S
Me2N
N2H4.H2O
16
Ar
N
NMe2
N
NC
HNO2
DMF-DMA
N
S
COCH3
Ar
Me2N
19
NC
N
N
N2H4.H2O
Me2N
N
N
S
O
H
Ar
17
NMe2
H
N
NC
NHNH2
Me2N
Ar
N
N
H
N
S
H
N
H2NHN
NC
N
O
N
20
-(CH3)2NH
-H2NN=CHNMe2
Me2N
S
18
O
Ar
NC
N
Ar = C6 H4 OCH3-4
N
NH2
H2N
N
S
HO
CH3
21
SCHEME 3
Center of Cairo University. Compounds 1 [25] were
prepared according to the literature procedures.
In all the 1H NMR spectra ∗ = Lost after D2O
exchange.
2a–c (0.01 mole). The reaction mixtures were stirred
at room temperature for 2 h, poured onto ice-cold
water, and neutralized with dilute HCl (10%). The
precipitates that formed were collected by filtra-
tion and crystallized from ethanol to yield 3a–c
respectively.
Reactions with Halogen-containing Compounds
in Cold KOH/DMF Solution:General Procedure
6-Amino-2-[(cyanomethyl)thio]-4-(4-methoxy-
phenyl)pyridine-3,5-dicarbonitrile (3a). White crys-
tals from ethanol (69%), mp 232–234◦C; IR (cm−1)
A solution of 1 (0.01 mole) in DMF (20 ml)
containing 0.01 mole of KOH was treated with
Heteroatom Chemistry DOI 10.1002/hc

410 Gad-Elkareem, Elneairy, and Taha
.
.
C6H4OCH3-p
+
C6H4OCH3-p
m/z 353
(20.6%)
+
NC
N
NC
N
- CO
.
NNH2
NNH2
+ H
H2N
N
S
H2N
N
S
O
.
m/z 336
(28.8%)
+
C6H4OCH3-p
NC
H
m/z 364
(1.9%)
N
-CH3CHO
.
-NNH2
H2N
N
S
CH3
HO
m/z 352
(base peak 100%)
- CH4
- N2
+
C6H4OCH3-p
.
C6H4OCH3-p
+
.
NC
B
+
.
NC
N
.
-A
N
-B
CH3CONHNH2
A
NNH2
m/z 74
(1.4%)
H2N
N
S
-NNH2
H2N
N
S
CH3
HO
m/z 380
m/z 306
(5.3%)
+
C6H4OCH3-p
(not observed)
-CH3CHO
NC
N
-HCN
OH
CH3
H2N
N
S
+
m/z 350
(0.7%)
C6H4OCH3-p
C
.
-CHO
NC
.
-CH3
H2N
N
S
+
C6H4OCH3-p
.
+
C6H4OCH3-p
m/z 279
NC
.
NC
N
-N
(6.9%)
.
-C
H2N
N
S
OH
OH
H2N
N
S
.
m/z 321
(32.1%)
+
m/z 335
C6H4OCH3-p
(13.7%)
NC
.
-H
H2N
N
.
+
+
C6H4OCH3-p
C6H4OCH3-p
m/z 223
(2.4%)
.
.
NC
N
NC
D
-D
+2H
m/z 296
(53%)
N
O
H2N
H2N
N
S
N
S
m/z 334
(4.8%)
m/z 294
(4.6%)
FIGURE 1 Fragmentation pattern of compound (21).
ν 3380, 3327 (NH2), 2252, 2211 (two CN), 1607
(N C); H NMR (DMSO-d6) δ 3.86 (s, 3H, OCH3),
6-Amino-2-[(acetylmethyl)thio]-4-(4-methoxy-
phenyl)pyridine-3,5-dicarbonitrile (3b). White
1
4.35 (s, 2H, SCH2), 7.10 (d, J = 8.0 Hz, 2H, Ar H),
crystals from ethanol (70%), mp 210–212◦C; IR
(cm−1) ν 3431, 3334 (NH2), 2211 (CN), 1726 (C O),
1610 (N C); 1H NMR (DMSO-d6) δ 2.35 (s, 3H,
COCH3), 3.86 (s, 3H, OCH3), 4.21 (s, 2H, SCH2),
7.11 (d, J = 8.0 Hz, 2H, Ar H), 7.50 (d, J = 8.0
7.53 (d, J = 8.0 Hz, 2H, Ar H), 8.23 (hump, 2H,
∗
NH2 ). Anal. for C16H11N5OS (321) Calcd: C, 59.80;
H, 3.45; N, 21.79; S, 9.98. Found: C, 59.50; H, 3.70;
N, 22.00; S, 10.20%.
Heteroatom Chemistry DOI 10.1002/hc

Reactions with 3,6-Diaminothieno[2,3-b]pyridines 411
∗
Hz, 2H, Ar H), 7.97 (hump, 2H, NH2 ). Anal. for
3,6-Diamino-5-cyano-4-(4-methoxyphenyl)thieno-
[2,3-b]pyridine-2-carboxamide (4c). Orange crys-
tals from dioxan (68%), mp 280–283◦C; IR (cm−1) ν
3470, 3401, 3363, 3323, 3169 (three NH2), 2217 (CN),
1655 (C O), 1602 (N C). Anal. for C16H13N5O2S
(339) Calcd: C, 56.63; H, 3.86; N, 20.64; S, 9.45.
Found: C, 56.40; H, 4.20; N, 21.00; S, 9.20%.
C17H14N4O2S (338) Calcd: C, 60.34; H, 4.17; N, 16.56;
S, 9.48. Found: C, 60.60; H, 3.90; N, 16.20; S, 9.70%.
6-Amino-2-[(carboxamidomethyl)thio]-4-(4-
methoxyphenyl)pyridine-3,5-dicarbonitrile
(3c).
Yellow crystals from ethanol (63%), mp 225–228◦C;
IR (cm−1) ν 3470, 3401, 3363, 3169 (two NH2),
2213 (CN), 1687 (C O), 1617 (N C). Anal. for
C16H13N5O2S (339) Calcd: C, 56.63; H, 3.86; N, 20.64;
S, 9.45. Found: C, 56.40; H, 4.10; N, 20.90; S, 9.10%.
Reactions of 4a or 4c with Formic Acid and
Acetic Anhydride: General Procedure
A solution of 4a or 4c (0.01 mole) in formic acid or in
acetic anhydride (20 ml) was heated under reflux for
5 h. The solid products obtained after cooling were
filtered off and then crystallized from the proper sol-
vent to yield 6a,b respectively.
Synthesis of 4a–c
Method A (Cyclization of 3a–c). A solution of
3a–c (0.01 mole) in ethanol (30 ml), containing 0.02
mole of potassium hydroxide, was heated under re-
flux for 3 h. The reaction mixture was then cooled,
poured onto ice-cold water, neutralized with dilute
HCl (10%) and the precipitated solid products were
filtered off, washed with water and then crystallized
from dioxan to yield 4a–c.
7-Amino-9-(4-methoxyphenyl)-4-oxo-3,4-dihydro-
pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carboni-
trile (6a). Pale yellow crystals from DMF (58%),
mp >350◦C; IR (cm−1) ν 3457, 3351 (NH2), 3223
(NH), 2218 (CN), 1658 (C O), 1624 (N C); 1H NMR
(DMSO-d6) δ 3.87 (s, 3H, OCH3), 7.03 (d, J = 8.0 Hz,
2H, Ar H), 7.34–7.46 (m, 4H, NH∗2 & Ar H), 7.97 (s,
1H, 2H-pyrimidine), 12.49 (hump, 1H, NH∗). Anal.
for C17H11N5O2S (349) Calcd: C, 55.06; H, 3.19; N,
26.57; S, 5.07. Found: C, 55.30; H, 2.90; N, 26.30; S,
5.40%.
Method B (Reaction of 1 with 2a–c). A solution
of 1 (0.01 mole) in methanolic sodium methoxide
(prepared from 0.02 atom of sodium metal in 30
ml of methanol), was treated with 2a–c (0.01 mole)
and then heated under reflux for 3 h. The reaction
mixture was then cooled, poured onto ice-cold wa-
ter, and neutralized with dilute HCl (10%). The solid
products so formed were filtered off and crystallized
from dioxan to yield 4a–c.
7-Amino-9-(4-methoxyphenyl)-2-methyl-4-oxo-
3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-
8-carbonitrile (6b). Pale yellow crystals from AcOH
(52%), mp 266–267◦C; IR (cm−1) ν 3479, 3372 (NH2),
3218 (NH), 2219 (CN), 1657 (C O), 1610 (N C).
Anal. for C18H13N5O2S (363) Calcd: C, 55.72; H, 3.43;
N, 25.99; S, 4.96. Found: C, 56.00; H, 3.20; N, 26.30;
S, 5.20%.
3,6-Diamino-4(4-methoxyphenyl)thieno[2,3-b]-
pyridine-2,5-dicarbonitrile (4a). Yellow crystals
from dioxan (75%), mp 300–302◦C; IR (cm−1) ν
3454, 3380 3339, 3220 (two NH2), 2215, 2188 (two
CN), 1624 (N C); 1H NMR (DMSO-d6) δ 3.88 (s, 3H,
∗
OCH3), 5.36 (s, 2H, NH2 ), 7.17 (d, J = 8.0 Hz 2H,
Reactions with DMF-DMA in Dry Xylene:
General Procedure
Ar H), 7.45–7.57 (m, 4H, NH∗2 & Ar H). Anal. for
C16H11N5OS (321) Calcd: C, 59.80; H, 3.45; N, 21.79;
S, 9.98. Found: C, 60.00; H, 3.10; N, 22.10; S, 9.70%.
To a solution of the appropriate 4a, 4b, or 16 (0.01
mole) in dry xylene (30 ml), DMF–DMA (0.012 mole)
or (0.024 mole) was added and the reaction mixture
was then heated under reflux for 3–5 h. The solid so
obtained after cooling was collected by filtration and
crystallized from the proper solvent to yield 7, 16, or
19 respectively.
2-Acetyl-3,6-diamino-4(4-methoxyphenyl)thieno-
[2,3-b]pyridine-5-carbonitrile (4b). Orange crystals
from dioxan (72%), mp 268–269◦C; IR (cm−1) ν
3464, 3360 3319, 3213 (two NH2), 2217 (CN), 1630
1
(C O), 1610 (N C); H NMR (DMSO-d6) δ 2.24 (s,
3H, COCH3), 3.42 (s, 1H, NH∗2), 3.87 (s, 3H, OCH3),
7.16 (d, J = 8.0 Hz, 2H, Ar H), 7.44 (d, J = 8.0 Hz,
2H, Ar H), 7.57 (s, 2H, NH∗2); MS: (m/z) 338 (100%),
337 (71.3%), 336 (4.3%), 325 (6.1%), 323 (51.4%),
296 (7.4%), 295 (21.2%). Anal. for C17H14N4O2S
(338) Calcd: C, 60.34; H, 4.17; N, 16.56; S, 9.48.
Found: C, 60.10; H, 4.50; N, 16.30; S, 9.70%.
3,6-Bis{[(N,N-dimethylamino)methylene]amino}-
4-(4-methoxyphenyl)thieno[2,3-b]pyridine-2,5-dicar-
bonitrile (7). Pale yellow crystals from ethanol
(60%), mp 200–202◦C; IR (cm−1) ν 2223, 2196 (two
CN), 1625 (N C); 1H NMR (DMSO-d6) δ 3.04 (s, 6H,
N(CH3)2), 3.15 (s, 6H, N(CH3)2), 3.85 (s, 3H, OCH3),
Heteroatom Chemistry DOI 10.1002/hc

412 Gad-Elkareem, Elneairy, and Taha
7.03 (d, J = 8.0 Hz, 2H, Ar H), 7.27 (d, J = 8.0
Hz, 2H, Ar H), 8.82 (s, 2H, two N CH). Anal. for
C22H21N7OS (431) Calcd: C, 61.23; H, 4.91; N, 22.72;
S, 7.43. Found: C, 61.50; H, 5.20; N, 22.50; S, 7.10%.
for C23H15N6OSCl (458) Calcd: C, 56.49; H, 3.37; N,
25.34; S, 5.81; Cl, 3.21. Found: C, 56.20; H, 3.60; N,
25.10; S, 5.60; Cl, 3.50%.
Reactions with Hydrazine Hydrate: General
Procedure
2-Acetyl-3-amino-6-{[(N,N-dimethylamino)met-
hylene]amino}-4-(4-methoxyphenyl)thieno[2,3-b]-
pyridine-5-carbonitrile (16). Orange crystals from
dioxan (57%), mp 306–307◦C; IR (cm−1) ν 3481, 3330
A solution of the appropriate 7 or 19 (0.01 mole)
in hydrazine hydrate (20 ml) was heated under re-
flux for 6 h and then cooled. The solid so obtained
was collected by filtration and crystallized from the
proper solvent to yield 11c and 21 respectively.
1
(NH2), 2218 (CN), 1622 (C O); H NMR (CDCl3) δ
∗
1.63 (s, 2H, NH2 ), 2.36 (s, 3H, COCH3), 3.22 (s, 6H,
N(CH3)2), 3.89 (s, 3H, OCH3), 7.06 (d, J = 8.0 Hz,
2H, Ar H), 7.36 (d, J = 8.0 Hz, 2H, Ar H), 8.72 (s,
1H, N CH). Anal. for C20H19N5O2S (393) Calcd: C,
61.05; H, 4.87; N, 17.80; S, 8.15. Found: C, 61.30; H,
5.20; N, 17.50; S, 7.90%.
7-Amino-4-hydrazino-9-(4-methoxyphenyl)pyrido-
[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carbonitrile
(11c). Orange crystals from ethanol (52%), mp
135–137◦C; IR (cm−1) ν 3461, 3372, 3331, 3201
(two NH2, NH), 2212 (CN), 1607 (N C).1H NMR
2-Acetyl-3,6-bis{[(N,N-dimethylamino)methylene]-
amino}-4-(4-methoxyphenyl)thieno[2,3-b]pyridine-
5-carbonitrile (19). Orange crystals from dioxan
(54%), mp 220–221◦C; IR (cm−1) ν 2221 (CN), 1653
∗
(DMSO-d6) δ 3.84 (s, 3H, OCH3), 4.39 (s, 2H, NH2 ),
∗
6.28 (s, 2H, NH2 ) 6.90 (d, J = 8.2 Hz, 2H, Ar H),
7.25 (d, J = 8.2 Hz, 2H, Ar H), 7.59 (s, 1H, NH∗),
8.65 (s, 1H, 2H-pyrimidine). Anal. for C17H13N7OS
(363) Calcd: C, 58.66; H, 3.72; N, 25.82; S, 5.91.
Found: C, 58.30; H, 4.00; N, 26.10; S, 5.70%.
1
(C O), 1618 (N C); H NMR (CDCl3) δ 2.37 (s, 3H,
COCH3), 2.64 (s, 6H, N(CH3)2), 3.21 (s, 6H, N(CH3)2),
3.89 (s, 3H, OCH3), 6.70 (s, 1H, N CH), 6.94 (d,
J = 8.0 Hz, 2H, Ar H), 7.22 (d, J = 8.0 Hz, 2H,
Ar H), 8.74 (s, 1H, N CH). Anal. for C23H24N6O2S
(448) Calcd: C, 61.59; H, 5.39; N, 18.74; S, 7.15.
Found: C, 61.40; H, 5.60; N, 19.00; S, 6.90%.
3,7-Diamino-4-hydroxy-9-(4-methoxyphenyl)-4-
methyl-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyri-
midine-8-carbonitrile (21). Orange crystals from
dioxan (55%), mp 270–273◦C; IR (cm−1) ν 3500,
3431, 3358, 3300 (br, OH, two NH2), 2209 (CN),
1607 (N C); 1H NMR (DMSO-d6) δ 1.99 (s, 1H,
Reactions of 7 with Aromatic Amine 8a,b
∗
A solution of 7 (0.01 mole) in glacial acetic acid (20
ml) was treated with 8a,b (0.02 mole). The reaction
mixture was heated under reflux for 4 h. The solid
product so formed after cooling was collected by
filtration and crystallized from acetic acid to yield
11a,b.
CH3), 3.87 (s, 3H, OCH3), 5.26 (s, 2H, NH2 ), 6.07
∗
(s, 2H, NH2 ), 7.01 (s, 1H, 2H-pyrimidine) 7.03–7.46
(m, 5H, OH∗ & Ar H); MS: (m/z) 353 (20.6%), 352
(100%), 350 (0.7%), 336 (28.8%), 335 (13.7%), 334
(4.8%), 321 (32.1%), 306 (5.3%), 296 (53%), 294
(4.6%), 279 (6.9%), 223 (2.4%), 74 (1.4%). Anal. for
C18H16N6O2S (380) Calcd: C, 56.83; H, 4.24; N, 22.09;
S, 8.43. Found: C, 57.10; H, 4.60; N, 22.30; S, 8.20%.
7-Amino-9-(4-methoxyphenyl)-4-[(4-methylphen-
yl)amino]pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carbonitrile (11a). Yellow crystals from AcOH
(63%), mp 330–332◦C; IR (cm−1) ν 3474, 3356
(NH2), 3201 (NH), 2212 (CN), 1616 (N C); 1H NMR
(DMSO-d6) δ 2.30 (s, 3H, CH3), 3.88 (s, 3H, OCH3),
7.05 (d, J = 8.0 Hz, 2H, Ar H), 7.15 (d, J = 8.0 Hz,
2H, Ar H), 7.44–7.60 (m, 6H, NH∗2 & Ar H), 8.31
(s, 1H, 2H-pyrimidine), 9.42 (s, 1H, NH∗). Anal. for
C24H18N6OS (438) Calcd: C, 65.74; H, 4.14; N, 19.17;
S, 7.31. Found: C, 66.00; H, 4.40; N, 19.40; S, 7.10%.
Reactions with Nitrous Acid
A cold solution of the appropriate 4b or 16 (0.01
mole) in concentrated HCl (5 ml) and glacial acetic
acid (5 ml) was treated with a cold saturated solu-
tion of sodium nitrite (0.02 mole) and then stirred in
the ice chest for 30 min. The solid products obtained
were filtered off, washed with water and then crys-
tallized from ethanol to yield 13 and 17 respectively.
7-Amino-4-[(4-chlorophenyl)amino]-9-(4-metho-
xyphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carbonitrile (11b). Yellow crystals from AcOH
(65%), mp 336–338◦C; IR (cm−1) ν 3480, 3372
(NH2), 3208 (NH), 2215 (CN), 1608 (N C). Anal.
7-Hydroxy-9-(4-methoxyphenyl)-4-oxo-3,4-dihydro-
pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-c]pyridazine-8-carbonitrile
(13). Orange crystals from ethanol (45%), mp
145–148◦C; IR (cm−1) ν 3403 (br, OH), 2230 (CN),
1718 (C O), 1607 (N C). 1H NMR (DMSO-d6) δ 3.78
Heteroatom Chemistry DOI 10.1002/hc

Reactions with 3,6-Diaminothieno[2,3-b]pyridines 413
(s, 2H, CH2), 3.85(s, 3H, OCH3), 5.90 (s, 1H, OH∗),
7.09–7.71 (m, 4H, Ar H). Anal. for C17H10N4O3S
(350) Calcd: C, 58.28; H, 2.88; N, 15.99; S, 9.15.
Found: C, 58.00; H, 3.20; N, 15.70; S, 9.40%.
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7-{[(N,N-Dimethylamino)methylene]amino}-9-(4-
methoxyphenyl)-4-oxo-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]-
thieno[3,2-c]pyridazine-8-carbonitrile (17). Orange
crystals from ethanol (43%), mp 135–137◦C; IR
1
(cm−1) ν 2217 (CN), 1705 (C O), 1607 (N C). H
NMR (DMSO-d6) δ 3.31 (s, 6H, N(CH3)2), 3.70 (s,
2H, CH2), 3.87(s, 3H, OCH3), 7.05–7.41 (m, 5H,
Ar H & N CH). Anal. for C20H16N6O2S (404) Calcd:
C, 59.39; H, 3.99; N, 20.78; S, 7.93. Found: C, 59.70;
H, 3.70; N, 21.00; S, 7.60%.
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Heteroatom Chemistry DOI 10.1002/hc