Acetoacetanilides in heterocyclic synthesis, Part 1: An expeditious synthesis of thienopyridines and other fused derivatives

Article abstract of DOI:10.1080/10426500600614808

3-Oxo-N-{4-[(pyrimidin-2-ylamino)sulfonyl]phenyl}butanamide 1 reacts with arylidinecyanothioacetamide in refluxing ethanolic TEA to give the pyridinethione 2 rather than thiopyrane 4. Compound 2 reacts with α-haloketones to give the s-alkylated derivative

Full text of DOI:10.1080/10426500600614808

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Acetoacetanilides in
Heterocyclic Synthesis, Part
1: An Expeditious Synthesis
of Thienopyridines and Other
Fused Derivatives
A. A. Harb a , A. M. Hussein b & I. A. Mousa a
a Chemistry Department, South Valley University,
Qena, Egypt
b Chemistry Department, Al-Azhar University, Assiut,
Egypt
Version of record first published: 22 Sep 2006.
To cite this article: A. A. Harb, A. M. Hussein & I. A. Mousa (2006): Acetoacetanilides
in Heterocyclic Synthesis, Part 1: An Expeditious Synthesis of Thienopyridines and
Other Fused Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements,
181:10, 2247-2261
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Phosphorus, Sulfur, and Silicon, 181:2247–2261, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600614808
Acetoacetanilides in Heterocyclic Synthesis, Part 1:
An Expeditious Synthesis of Thienopyridines
and Other Fused Derivatives
A. A. Harb
Chemistry Department, South Valley University, Qena, Egypt
A. M. Hussein
Chemistry Department, Al-Azhar University, Assiut, Egypt
I. A. Mousa
Chemistry Department, South Valley University, Qena, Egypt
3-Oxo-N-{4-[(pyrimidin-2-ylamino)sulfonyl]phenyl}butanamide 1 reacts with ary-
lidinecyanothioacetamide in refluxing ethanolic TEA to give the pyridinethione 2
rather than thiopyrane 4. Compound 2 reacts with α-haloketones to give the s-
alkylated derivatives 7a–e. Compound 7a–e undergoes cyclization into thieno[2,3-
b]pyridine derivatives 8a–e. The saponification of 8a gives the amino acid 9, which
affords 10 when refluxed in Ac2O. The treatment of 10 with NH4OAc/AcOH gives
11. Compound II is also obtained when 8e is refluxed in Ac2O. The reaction of 8a
with hydrazine hydrate gives 12 and with formamide gives 13. Compound 13 also
is obtained from the reaction of 8e with triethylorthoformate. The acetylation of
8a with Ac2O gives the amide derivative 14, which, on treatment with aromatic
amines, affords 15a–c. Compounds 15a–c are cyclized with H2SO4 to 16a–c. Com-
pound 16 is obtained also from the acetylation of compound 8c,d by Ac O. Reac-
2
tions of compound 8e with CS2 in refluxing dioxane afford 17. The diazotization
and self-coupling of 8e give the pyridothienotriazine 18. Finally, the chloronation
of compound 13 with POCl3 affords the chloride derivative 19.
Keywords Pyridinethione; pyridothienooxazine; pyridothienopyrimidine; pyridothieno-
triazine; thieno[2,3-b]pyridines
INTRODUCTION
No doubt that thienopyridine is an interesting class of het-
erocycles, and their chemistry has recently received consider-
able attention, especially because of their potential utility as
antibacterial,1−9 antihypertensive.10 Some fused theinopyridines
Received November 14, 2005; accepted January 4, 2006.
Address correspondence to A. M. Hussein, Al-Azhar University, Chemistry Depart-
ment, Faculty of Science, Assiut 71524, Egypt. E-mail: abdelhaleemmh@yahoo.com
2247

2248
A. A. Harb et al.
such as pyridothienopyrimidine derivatives have applications as
analgesics,11 antipyretics,12 and antiinflammatories.13 Also, the pyri-
dothienotriazine moities are known to exhibit anaphylatic,14 and an-
tiallergic activity. In continuation of our efforts on the chemistry of
pyridinethione and its derivatives,15 we report here a synthesis of
new thieno[2,3-b]pyrimidine and other fused derivatives using acetoac-
etanilide derivative 1 as a starting material.
RESULTS AND DISCUSSION
It has been found that 3-oxo-N-{4-[(pyrimidin-2-ylamino)sulfonyl]
phenyl} butanamide 1 (prepared by treating an aniline derivative with
ethyl acetoacetate as has been described in the literature16) readily
reacts with arylidinecyanothioacetamide in refluxing ethanol contain-
ing a catalytic amount of triethylamine to yield a product that may
be structure 2 or its isomer 4. Establishing the exact structure of the
reaction product as structure 2 rather than 4 based on the spectral
1
data. Thus, the H NMR spectrum revealed the presence of a singlet
signal at δ = 8.4 and 10.6 ppm assigned to 2NH groups and no sig-
nal at range δ = 4–5 ppm assigned for the thiopyrane CH-4. So the
pyridinethione 2 is considered to be only the reaction product. Also, the
mass spectrum of 2 is compatible with the molecular ion peak m/z =
532 (M+1). Compound 2 is assumed to proceed via an initial addition
of the active methylene moiety in 1 to the activated double bond in
3, thus forming the acyclic Michael adduct 5, which then cyclized to
6 by a loss of water and aromatized by a loss of hydrogen to the final
product 2 (Scheme 1).
The pyridinethione 2 reacted with α-haloketones in ethanol contain-
ing a few grams of sodium acetate to afford the S-alkylated derivatives
7a–e. The structure of compounds 7a–e has been confirmed as the cor-
rect one based on its spectral data. Thus, the IR spectrum of compound
7a as an example exhibited the presence of the absorption band of CN
function group at γ 2220 cm−1; the 1H NMR spectrum of compound 7a
revealed the appearance of CH2 protons at δ = 4.0 ppm in addition to
the other protons assigned in compound 2. Also, the mass spectrum of
compound 7a showed the molecular ion peak M+ at m/z = 618 (36%).
Compounds 7a–e underwent cyclization into thienopyridine derivatives
8a–e upon treatment with ethanolic sodium ethoxide. The IR spectra
of compounds 8a–e exhibited the disappearance of the absorption band
due to the CN function group and the appearance of absorption bands
1
due to the NH2 function group at γ 3450–3300 cm−1. The H NMR
spectrum of compound 8a revealed the disappearance of the protons as-
signed to the methylene group at δ = 4.0 ppm and revealed the presence

Acetoacetanilides in Heterocyclic Synthesis, Part 1
2249
SCHEME 1
of a signal of two protons as a singlet at δ = 8.1 ppm assignable to NH2
group, beside the protons in their proper positions. A solid evidence for
the structure of compounds 8a–e. Structure 8a–e has been confirmed as
correct one by its synthesis via a reaction of 2 with α-haloketones in boil-
ing ethanolic sodium ethoxide solution (m.p., m.m.p., TLC) (Scheme 2).
The reactivity of β-amino ester derivative 8a toward some elec-
trophilic reagents has been studied. Thus, the saponification of 8a using
alcoholic sodium hydroxide yielded the sodium salt of the β-amino acid
9, which gave the pyridothienooxazine 10 when refluxed in acetic an-
hydride. The assignment of structure 10 as the reaction product based
on its compatible spectroscopic data. Thus, the IR spectrum showed
the absence of any absorption bands that may by attributed to NH2
function group; its mass spectrum revealed a molecular ion peak at m/z
(40%) = 614 (615M+1) (25%) corresponding to the molecular formula
1
C29H22N6O6S2. Moreover, Its H NMR spectrum showed two singlet
signals at δ1.2 and 1.8 ppm assigned to 2CH3. The treatment of 10
with ammonium acetate in boiling acetic acid led to the formation of

2250
A. A. Harb et al.
SCHEME 2
pyridothienopyrimidine 11. Compound 11 can be prepared by refluxing
compound 8e in acetic anhydride (Scheme 3).
Also, 8a reacted with hydrazine hydrate to afford the hydrazide
derivative 12. The hydrazide 12 was compatible bases on the correct
spectroscopic data (IR and 1H NMR). In contrast to this behavior, when
compound 8a was refluxed in formamide solution afforded the expected
SCHEME 3

Acetoacetanilides in Heterocyclic Synthesis, Part 1
2251
SCHEME 4
pyridothienopyrimidine derivative 13. On the other hand, the acetyla-
tion of 8a with a mixture of acetic anhydride and glacial acetic acid
yielded the acetamide derivative 14, which on treatment with aromatic
amines afforded 15a–c.
Compounds 15a–c when treated with 98% sulfuric acid afforded pyri-
dothienopyrimidines 16a–c. Compounds 16b,c were also obtained by
the direct acetylation of compound 8c,d with acetic anhydride (m.p.,
m.m.p., and TLC) as compounds 16b,c (Scheme 4).
Our investigation extended to include the reactivity of the amino
amide derivative 8e toward some electrophilic reagents. So, the acety-
lation of compound 8e with acetic anhydride gave compound 11, which
was identified by (m.p., m.m.p., TLC, and spectroscopic data). The
treatment of 8e with carbon disulfide in boiling dioxane solution af-
forded the corresponding reaction product 17. This compound was con-
firmed by IR, 1H NMR, and elemental analysis). The diazotization and
self-coupling of the amino amide derivative 8e with sodium nitrite
and HCl gave the pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]triazine derivative 18.
The structure of compound 18 was confirmed by spectral data. The
IR spectrum of 18 showed the absence of any absorption bands that
1
may by attributed to the NH2 function group. Moreover, the H NMR
spectrum of 18 revealed the disappearance of the signal due to NH2

2252
A. A. Harb et al.
SCHEME 5
protons. When compound 8e reacts with triethylorthoformate in glacial
acetic acid afforded 13, which was obtained earlier from the treat-
ment of 8a with formamide. The authentic sample of compound 13 was
identified by m.p., m.m.p., TLC, and spectral data. The chloronation
of compound 13 with phosphorus oxytrichloride afforded the chloride
derivative 19 (Scheme 5).
Conclusion
The importance of the synthesized compounds as an intermediate for
the synthesis of biologically active diaza and folic acid ring systems.
EXPERIMENTAL
All melting points are uncorrected and were determined on a Gal-
lenkamp apparatus; IR spectra were recorded on Schimadzu 470 spec-
trophotometer in potassium bromide discs; 1H NMR spectra were
recorded on a Varian EM-390 (90 Mhz) spectrophotometer using TMS
as internal standard; mass spectrometer MS 30(AEL)at 70ev. analyti-
cal data were obtained from the Microanalytical Data Center at Cairo
University, Giza, Egypt.

Acetoacetanilides in Heterocyclic Synthesis, Part 1
2253
3-Oxo-N-{4-[(pyrimidin-2-ylamino)sulphonayl]phenyl}-
butanamide (1)
Ethylacetoacetate (2.6 mL, 20.0 mmoles) and sulfadiazine (5 g, 20.0
mmoles) were heated in a sand bath without a solvent at 140◦C
for (15 min). The solid product formed was washed with pet. Ether
(40–60), collected by filtration, and then recrystallized from
ethanol/acetic acid as colorless crystals; yield (75%); mp 190◦C; IRν
cm−1 3200(NH); 1700(CO); 1650(CO); MS: m/z = 334; Found: C, 50.28;
H, 4.21; N, 16.75; S, 9.58; calcd. for C14H14N4O4S: C, 50.29; H, 4.22; N,
16.76; S, 9.59 %.
5-Cyano-4-(4-methoxyphenyl)-2-methyl-N-{4-[(pyrimidin-
2-ylamino) sulfonyl]phenyl}-6-thioxo-1,6-dihydropyridine-
3-carboxamide (2)
A mixture of acetoacetanilide (1) (3.34 g, 10.0 mmoles) and p-methoxy
benzylidinecyanothioacetamide (2.18 g, 10.0 mmoles) in ethanol
(50 mL) cotaining a catalytic amount of TEA was heated under reflux
for 2 h. The solid product formed was collected by filtration and recrys-
tallized from ethanol as yellow crystals; yield 60%; mp 220◦C; IRν cm−1
3300 (NH); 2250 (CN); 1650 (CO); MS: m/z = 532; Found: C, 56.36; H;
3.78; N, 15.77; S, 12.03; calcd. for C4H18N6O4S2: C, 56.38; H, 3.79; N,
15.78; S, 12.04%.
2-Substituted-({3-cyano-4-(4-methoxyphenyl)-6-methyl-5-[4-
(pyrimidin-2-ylamino) carbonyl]pyridine-2-yl-}thione (7a–e):
General Procedure
To a solution of pyridinethione 2 (0.1 g, 5.0 mmoles) in ethanol (30 mL)
and sodium acetate (5.0 mmoles), the appropriate halocompound (0.005
mmoles) was added. The reaction mixture was heated under reflux for
1 h. The solid product formed after cooling was collected by filtration,
washed with water several times, and recrystallized from the proper
solvent.
Ethyl({3-Cyano-4-(4-methoxyphenyl)-6-methyl-5-[4-
(pyrimidin-2-ylamino) carbonyl]pyridine-2-
yl})thioacetamide (7a)
Compound (7a) was obtained as colorless crystals from 1,4-dioxane;
yield 42%; mp 190◦C; IRν cm−1 3300 (NH); 3150 (NH); 2250 (CN);
1
1740 (CO); 1650 (CO); H NMR (CDCl3) δ = 1.2 (t, 3H, CH3); 3.6 (s,
3H, OCH3); 4.0 (s, 2H, CH2); 4.2 (q, 2H, CH2); 6.8–8.4 (m, 12H, Ar-H
and NH); 8.6 (s, 1H, NH); MS: m/z = 618 (372 base peak); Found: C,
56.29; H, 4.23; N, 13.57; S, 10.36; calcd. for C29H26N6O6S2: C, 56.30; H,
4.24; N, 13.58; S, 10.37%.

2254
A. A. Harb et al.
6-(Benzoylthio)-5-cyano-4-(4-methoxyphenyl)-2-methyl-N-{4-
[(pyrimidin-2- ylamino)sulfonyl]phenyl}nicotinamide (7b)
Compound (7b) was obtained as white crystals from ethanol; yield 30%;
mp 230◦C; IRν cm−1 3300 (NH); 3100 (NH); 2240 (CN); 1690 (CO); 1660
(CO); MS: m/z = 636; Found: C, 60.90; H, 4.02; N, 12.90; S, 9.85; calcd.
for C33H26N6O5S2: C, 60.91; H, 4.03; N, 12.91; S, 9.86%.
6-({2-[(4-Chlorophenyl)-2-oxoethyl}thio-5-cyano-4-
(4-methoxy-phenyl)-2-methyl-N-{4-[(pyrimidin-2-ylamino)-
sulfonyl]phenyl}nicotinamide (7c)
Compound (7c) was obtained as a white powder from ethanol; yield 20%;
mp 260◦C; IRν cm−1 3400 (NH); 3200 (NH); 2250 (CN); 1700 (CO); 1650
(CO); MS: m/z = 700; Found: C, 56.62; H, 3.74; N, 13.99; S, 9.17; calcd.
for C33H26ClN7O5S2: C, 56.61; H, 3.74; N, 14.00; S, 9.16%.
6-({2-[(4-Tolyl)amino]-2-oxoethyl}thio-5-cyano-4-(4-methoxy-
phenyl)-2-methyl-N-{4-[(pyrimidin-2-ylamino)-
sulfonyl]phenyl}nicotinamide (7d)
Compound (7d) was obtained as yellowish white crystals from 1,4-
dioxane; yield 50%; mp 275◦C; IRν cm−1 3300 (NH); 3150 (NH); 2900–
2970 (CH aliphatic); 2250 (CN); 1670 (CO); 1650 (CO);1H NMR (DMSO-
d6) δ = 2.1 (s, 3H, CH3); 2.6 (s, 3H, CH3); 3.6 (s, 3H, OCH3); 3.8 (s, 2H,
CH2); 7.0–8.5 (m, 17H, Ar-H and NH); 10.3 (s, 1H, NH); 10.8 (s, 1H,
NH); MS: m/z = 679 (680 M+1); Found: C, 60.05; H, 4.29; N, 14.40; S,
9.42; calcd. for C34H29N7O5S2: C, 60.07; H, 4.30; N, 14.42; S, 9.43%.
5-Cyano-4-(4-methoxyphenyl)-2-methyl-3-{4-[(pyrimidin-2-
ylamino)sulfonyl]phenyl}pyridine-6-yl-thio-acetamide (7e)
Compound (7e) was obtained as yellow crystals from ethanol; yield 40%;
mp 290◦C; IRν cm−1 3300 (NH); 3100 (NH); 2260 (CN); 1660 (CO);
MS: m/z = 589; Found: C, 55.02; H, 3.94; N, 16.62; S, 10.87; calcd. for
C27H23N7O5S2: C, 55.00; H, 3.93; N, 16.63; S, 10.88%.
2-Substituted-3-amino-4-(4-methoxyphenyl)-6-methyl-5-[({4-
[(pyrimidin-2-ylamino)sulfonyl]phenyl}amino)carbonyl]thieno
[2,3-b]pyridine (8a–e): General Procedure
To a sample of (7a–e) (1 g) in absolute ethanol (30 mL), a few drops of
sodium ethoxide was added. The reaction mixture was heated under

Acetoacetanilides in Heterocyclic Synthesis, Part 1
2255
reflux for 1 h. The solid product formed after cooling was collected by
filtration and recrystallized from the proper solvent.
Ethyl-3-Amino-4-(4-methoxyphenyl)-6-methyl-5-[({4-
[(pyrimidin-2-ylamino) sulfonyl]phenyl}amino)carbonyl]-
thieno[2,3-b]pyridine-2-carboxylate (8a)
Compound (8a) was obtained as yellow crystals from 1,4-dioxane; yield
32%; mp > 300◦C; IRν cm−1 3400 (NH2); 3200 (NH); 1730 (CO); 1650
(CO); 1H NMR (DMSO-d6) δ = 1.2 (t, 3H, CH3); 2.4 (s, 3H, CH3); 3.8 (s,
3H, OCH3); 4.2 (q, 2H, CH2); 6.4 (s, 2H, NH2); 7.0–7.8 (m, 11H, Ar-H);
8.1 (s, 1H, NH); 10.4 (s, 1H, NH); MS: m/z = 618; Found: C, 56.29; H,
4.23; N, 13.58; S, 10.36; calcd. for C29H26N6O6S2: C, 56.30; H, 4.24; N,
13.58; S, 10.37%.
3-Amino-2-benzoyl-4-(4-methoxyphenyl)-6-methyl-N-{4-
[(pyrimidin-2-ylamino) sulfonyl]phenyl}thieno[2,3-b]pyridine-
5-carboxamide (8b)
Compound (8b) was obtained as colorless crystals from ethanol; yield
30%; mp. >300◦C; IRν cm−1 3450 (NH2); 3200 (NH); 1710 (CO); 1650
(CO); MS: m/z = 650; Found: C, 60.90; H, 4.02; N, 12.90; S, 9.85; calcd.
for C33H26N6O5S2: C, 60.9; H, 4.03; N, 12.91; S, 9.86%.
3-Amino-2-(4-chlorobenzoyl)-4-(4-methoxyphenyl)-6-methyl-
N-{4-[(pyrimidin-2-ylamino)sulfonyl]phenyl}thieno[2,3-b]-
pyridine-5-carboxamide (8c)
Compound (8c) was obtained as white crystals from ethanol; yield 35%;
mp. 290◦C; IRν cm−1 3400 (NH2); 3250 (NH); 3100 (NH); 1690 (CO);
1650 (CO); MS: m/z = 700; Found: C, 56.60; H, 3.73; N, 13.99; S, 9.15;
calcd. for C33H26ClN7O5S2: C, 56.61; H, 3.74; N, 14.00; S, 9.16%.
3-Amino-4-(4-methoxyphenyl)-6-methyl-2-methyl-4-
{4-[(pyrimidin-2-ylamino)sulfonyl]phenyl}thieno[2,3-b]-
pyridine- 5-carboxamide (8d)
Compound (8d) was obtained as colorless crystals from ethanol; yield
25%; mp. >300◦C; IRν cm−1 3400 (NH2); 3200 (NH); 1700 (CO); 1650
(CO); MS: m/z = 679; Found: C, 60.05; H, 4.29; N, 14.40; S, 9.15; calcd.
for C34H29N7O5S2: C, 60.07; H, 4.30; N, 14.42; S, 9.43%.

2256
A. A. Harb et al.
3-Amino-4-(4-methoxyphenyl)-6-methyl-5[({4-[(pyrimidin-2-
ylamino)sulfonyl] phenyl}amino)carbonyl]thieno[2,3-b]-
pyridine-2-amide (8e)
Compound (8e) was obtained as yellowish white crystals from ethanol;
yield 35%; mp 320◦C; IRν cm−1 3450 (NH2); 3200 (NH); 1670 (CO); 1650
(CO);1H NMR (DMSO-d6) δ = 1.5 (s, 3H, CH3); 3.8 (s, 3H, OCH3); 5.6
(s, 2H, NH2); 7.0–7.8 (m, 11H, Ar-H); 8.2 (s, 2H, NH2); 10.8 (s, 1H, NH);
MS: m/z = 589 (590;M+1); Found: C, 55.02; H, 3.94; N, 16.64; S, 10.87;
calcd. for C27H23N7O5S2: C, 55.00; H, 3.93; N, 16.63; S, 10.88%.
3-Amino-4-(4-methoxyphenyl)-6-methyl-5[({4-[(pyrimidin-2-
ylamino)sulfonyl] phenyl}amino)carbonyl]thieno[2,3-b]-
pyridine-2-sodium carboxalate (9)
A suspension of amino ester (8a) (1 g) in ethanolic sodium hydroxide (30
mL, 10%) was refluxed for 3 h. The solid product formed after cooling
was collected by filtration, washed with ethnol, left to dry, and recrys-
tallized from ethanol as wellow crystals; yield 28%; mp 245–248◦C;
IRν cm−1 3450 (NH2); 3300 (NH); 3100 (NH); 1700 (CO); 1660 (CO);
MS: m/z = 612; Found: C, 52.92; H, 3.45; N, 13.71; S, 10.46; calcd. for
C27H21N6NaO6S2: C, 52.94; H, 3.46; N, 13.72; S, 10.47%.
9-(4-Methoxyphenyl)-2,7-dimethyl-N-{4-[(pyrimidin-2-
lamino)sulfonyl]phenyl}-4- oxo-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]-
thieno[3,2-d][1,3]oxazine-8-carboxamide (10)
Compound (9) (0.5 g) was refluxed in acetic anhydride (30 mL) for 3 h.
The reaction mixture was left to stand at r.t. for 5 h. The solid product
formed was collected by filtration and recrystallized from ethanol/acetic
acid as colorless crystals; yield (20%); mp 280–282◦C; IRν cm−1 3300
1
(NH); 3200 (NH); 1710 (CO); 1650 (CO); H NMR (CDCl3) δ = 1.2 (s,
3H, CH3); 1.8 (s, 3H, CH3); 3.6 (s, 3H, OCH3); 7.0–8.2 (m, 12H, Ar-H);
8.4 (s, 1H, NH); 9.0 (s, 1H, NH); MS: m/z = 614; Found: C, 56.65; H,
3.60; N, 13.66; S, 10.42; calcd. for C29H22N6O6S2: C, 56.67; H, 3.61; N,
13.67; S, 10.43%.
9-(4-Methoxyphenyl)-2,7-dimethyl-N-{4-[(pyrimidin-2-
lamino)sulfonyl]phenyl}-4- oxo-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]-
thieno[3,2-d]pyrimidine-8-carboxamide (11)
Method A
A suspension of compound (10) (0.61 g, 1.0 mmoles) in acetic acid
containing ammonium acetate (0.001 mmoles) was refluxed for 3 h.
The solid product formed after cooling was collected by filtration.

Acetoacetanilides in Heterocyclic Synthesis, Part 1
2257
Method B
Compound (8e) (1 g) was refluxed in acetic anhydride (20 mL) for 3
h. The reaction mixture was poured onto ice/water and left to stand for
12 h. The solid product formed was collected by filtration and recrys-
tallized from ethanol as colorless crystals; mp. 180◦C; IRν cm−1 3400
(NH); 3200 (NH); 1710 (CO); 1650 (CO);1H NMR (DMSO-d6) δ = 1.9 (s,
3H, CH3); 2.4 (s, 3H, CH3); .4 (s, 3H, OCH3); 7.0–7.8 (m, 11H, Ar-H); 8.1
(s, 1H, NH); 8.6 (s, 1H, NH); 10.8 (s, 1H, NH); MS: m/z = 613; Found:
C, 56.75; H, 3.77; N, 15.97; S, 10.44; calcd. for C29H23N7O5S2: C, 56.76;
H, 3.78; N, 15.98; S, 10.45%.
3-Amino-2-(hydrazinocarbonyl)-4-(4-methoxyphenyl)-6-
methyl-N-{4-(pyrimidin-2-ylamino)sulfonyl]phenyl}thieno-
[2,3-b]pyridine-5-carboxamide (12)
To a solution of aminoester (8a) (0.61 g, 1.0 mmoles) in ethanol (30 mL),
hydrazine hydrate (0.02 mmoles) was added. The reaction mixture was
refluxed for 3 h. The solid product formed was collected by filtration
and recrystallized from ethanol as yellowish white crystals; yield 24%;
mp 280◦C; IRν cm−1 3500 (NH2); 3400 (NH); 3200 (NH); 1680 (CO);1H
NMR (DMSO-d6) δ = 2.4 (s, 3H, CH3); 3.6 (s, 3H, OCH3); 5.6 (s, 2H,
NH2); 6.4 (s, 1H, NH); 7.0-8.0 (m, 11H, Ar-H); 8.2 (s, 2H, NH2); 10.5
(s, 1H, NH); MS: m/z = 604; Found: C, 53.62; H, 3.99; N, 18.52; S, 10.60;
calcd. for C27H24N8O5S2: C, 53.63; H, 4.00; N, 18.53; S, 10.61%.
9-(4-Methoxyphenyl)-7-methyl-N-{4-[(pyrimidin-2-ylamino)
sulfonyl]phenyl}-4-oxo- 3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-
d]pyrimidine-8-carboxamide (13)
Method A
A suspension of amino ester 8a (0.61 g, 1.0 mmoles) in formamide
(10 mL) was heated under reflux for 3 h, and the reaction mixture
was poured onto ice/water. The solid product formed was collected by
filtration, washed with water several times, and dried.
Method B
To a solution of (8e) (0.59 g, 1.0 mmoles) in acetic acid (30 mL), tri-
ethylorthoformate (3 mL) was added. The reaction mixture was refluxed
for 3 h. The solid product formed was collected by filtration and recrys-
tallized from 1,4-dioxane as colorless crystals; yield 55%; mp > 360◦C;
IRν cm−1 3400 (NH); 3200 (NH); 1710 (CO); 1660 (CO);1H NMR (DMSO-
d6) dδ = 2.4 (s, 3H, CH3); 3.8 (s, 3H, OCH3); 7.0–8.0 (m, 11H, Ar-H); 8.1

2258
A. A. Harb et al.
(s, 1H, pyrimidine-H); 8.4 (s, 1H, NH); 10.7 (s, 1H, NH); MS: m/z = 599;
Found: C, 56.07; H, 3.52; N, 16.34; S, 10.68; calcd. for C28H21N7O5S2:
C, 56.08; H, 3.53; N, 16.35; S, 10.69%.
Ethyl-3-(Acetylamino)-4-(4-methoxyphenyl)-6-methyl-5[{4-
[(pyrimidin-2- ylamino)sulfonyl]phenyl}carbonyl]thieno-
[2,3-b]pyridine-2-carboxalate(14)
A solution of aminoester (8a) (0.61 g, 1.0 mmoles) in acetic acid/acetic
anhydride (30:3 mL), a mixture was heated under reflux for 4 h. The
solid product formed after cooling was collected by filtration and recrys-
tallized from DMF/water as colorless crystals; yield (45%); mp. 285◦C;
IRν cm−1 3450 (NH); 3300 (NH); 3200 (NH); 1700 (CO); 1660 (CO);1H
NMR (DMSO-d6) δ = 1.9 (s, 3H, CH3); 2.2 (s, 3H, CH3); 2.6 (t, 3H, CH3);
3.1 (s, 3H, OCH3); 3.8 (q, 2H, CH2); 5.7 (s, 1H, NH); 7.0–8.0 (m, 12H,
Ar-H); 10.8 (s, 1H, NH); MS: m/z = 660; Found: C, 56.34; H, 4.23; N,
12.70; S, 9.70; calcd. for C31H28N6O7S2: C, 56.35; H, 4.24; N, 12.72; S,
9.71%.
3-(Acetylamino)-4-(4-methoxyphenyl)-6-methyl-N5-{4-
[(pyrimidin-2-ylamino) sulfonyl]phenyl}-N2-arylthieno[2,3-b]-
pyridine-2,5-dicarboxamide (15a–c): General procedure
To a solution of compound (14) (0.66 g, 1.0 mmoles) in ethanol (30 mL),
the appropriate aniline derivative (1.0 mmoles) was added. The reaction
mixture was heated under reflux for 3 h. The solid product formed was
collected by filtration and recrystallized from the proper solvent.
3-(Acetylamino)-4-(4-methoxyphenyl)-6-methyl-N5-{4-
[(pyrimidin-2-ylamino) sulfonyl]phenyl}-N2-phenylthieno-
[2,3-b]pyridine-2,5-dicarboxamide (15a)
Compound 15a was obtained as pale yellow crystals from acetic acid;
yield 42%; mp. 300◦C; IRν cm−1 3450 (NH); 3300 (NH); 1680 (CO); 1660
(CO); 1H NMR (DMSO-d6) δ = 1.6 (s, 3H, CH3); 2.0 (s, 3H, CH3); 3.2 (s,
3H, OCH3); 6.4 (s, 1H, NH); 7.0–8.0 (m, 16H, Ar-H); 8.6 (s, 1H, NH);
10.8 (s, 1H, NH); MS: m/z = 707; Found: C, 59.37; H, 4.12; N, 13.86; S,
9.05; calcd. for C35H29N7O6S2: C, 59.39; H, 4.13; N, 13.85; S, 9.06%.
3-(Acetylamino)-4-(4-methoxyphenyl)-6-methyl-N5{4-
[(pyrimidin-2-ylamino)- sulfonyl]phenyl}-N2-(4-tolyl)thieno
[2,3-b]pyridine-2,5-dicarboxamide (15b)
Compound 15b was obtained as white crystals from ethanol; yield 30%;
mp. 320◦C; IRν cm−1 3300 (NH); 3100 (NH); 1700 (CO); 1650 (CO); MS:

Acetoacetanilides in Heterocyclic Synthesis, Part 1
2259
m/z = 721(722 M+1); Found: C, 59.92; H, 4.34; N, 13.59; S, 8.89; calcd.
for C36H31N7O6S2: C, 59.90; H, 4.33; N, 13.58; S, 8.88%.
3-(Acetylamino)-4-(4-methoxyphenyl)-6-methyl-N5-{4-
[(pyrimidin-2-ylamino)sulfonyl]phenyl}-N2-(4-chlorlphenyl)-
thieno[2,3-b]pyridine-2,5-dicarboxamide (15c)
Compound 15c was obtained as yellow crystals from 1,4-dioxane; yield
25%; mp > 360◦C; IRν cm−1 3400 (NH); 3200 (NH); 1690 (CO); 1650
(CO); MS: m/z = 724; Found: C, 56.63; H, 3.79; N, 13.20; S, 8.62; calcd.
for C35H28ClN7O6S2: C, 56.63; H, 3.80; N, 13.21; S, 8.64%.
9-(4-Methoxyphenyl)-2,7-dimethyl-N-{4-[(pyrimidin-2-
lamino)sulfonyl]phenyl}-4-oxo-3-substituted-3,4-
dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxamide (16a-c): General Procedure
A suspension of compound 15a–c (1g) in 98% sulphuric acid (5 mL) was
stirred for 1 h, and then left at r.t. for 5 days. The solid product formed
after pouring the clear solution on ice water (100 mL) was collected by
filtration, washed with water, dried, and recrystallized from the proper
solvent.
9-(4-Methoxyphenyl)-2,7-dimethyl-N-{4-[(pyrimidin-2-
lamino)sulfonyl]phenyl}-4- oxo-3-phenyl-3,4-dihydropyrido-
[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carboxamide (16a)
Compound 16a was obtained as colorless crystals from 1,4-dioxane;
yield 30%; mp > 360◦C; IRν cm−1 3400 (NH); 3300 (NH); 1700 (CO);
1
1640 (CO); H NMR (DMSO-d6) δ = 2.4 (s, 3H, CH3); 2.8 (s, 3H, CH3);
3.8 (s, 3H, OCH3); 6.8 (s, 1H, NH); 7.0–7.6 (m, 12H, Ar-H); 10.4 (s, 1H,
NH); MS: m/z = 689; Found: C, 60.92; H, 3.94; N, 14.20; S, 9.28; calcd.
for C35H27N7O5S2: C, 60.94; H, 3.95; N, 14.21; S, 9.30%.
9-(4-Methoxyphenyl)-2,7-dimethyl-N-{4-[(pyrimidin-2-
lamino)sulfonyl]phenyl}-4-oxo-3-(4-tolyl)-3,4-dihydropyrido-
[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carboxamide (16b)
Compound 16b was obtained as colorless crystals from ethanol/acetic
acid; yield 20%; mp >360◦C; IRν cm−1 3400 (NH); 3100 (NH); 1710
(CO); 1660 (CO); MS: m/z = 703; Found: C, 61.42; H, 4.14; N, 13.92; S,
9.10; calcd. for C36H29N7O5S2: C, 61.44; H, 4.15; N, 13.93; S, 9.11%.

2260
A. A. Harb et al.
9-(4-Methoxyphenyl)-2,7-dimethyl-N-{4-[(pyrimidin-2-lamino)-
sulfonyl]phenyl}-4-oxo-3-(4-chlorophenyl)-3,4-dihydropyrido-
[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carboxamide (16c)
Compound 16c was obtained as yellow crystals from methanol; yield
25%; mp > 360◦C; IRν cm−1 3300 (NH); 3200 (NH); 1700 (CO); 1650
(CO); MS: m/z = 724; Found: C, 58.05; H, 3.61; N, 13.53; S, 8.87; calcd.
for C35H26ClN7O5S2: C, 58.05; H, 3.62; N, 13.54; S, 8.86%.
9-(4-Methoxyphenyl)-7-methyl-N-{4-[(pyrimidin-2-ylamino)-
sulfonyl]phenyl}-4-oxo-2-thio-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]-
thieno[3,2-d]pyrimidine-8-carboxamide (17)
A suspension of 8e (0.58 g, 1.0 mmoles) and carbon disulfide (2 mL)
in dioxane (20 mL) was heated under reflux for 8 h. The solid product
formed after cooling was collected by filtration and recrystallized from
ethanol as colorless crystals; yield 35%; mp 320◦C; IRν cm−1 3300 (NH);
3100 (NH); 1700 (CO); 1660 (CO); MS: m/z = 631 (632M+1); Found: C,
53.23; H, 3.34; N, 15.51; S, 15.24; calcd. for C28H21N7O5S3: C, 53.24; H,
3.35; N, 15.52; S, 15.23%.
9-(4-Methoxyphenyl)-7-methyl-N-{4-[(pyrimidin-2-ylamino)-
sulfonyl]phenyl}-4-oxo- 3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-
d]triazine-8-carboxamide (18)
To a cold solution of 8e (0.58 g, 10.0 mmoles) in acetic acid (30 mL), a
cold solution of sodium nitrite (1 g in 2 mL of H2O) was added dropwise
with stirring. The stirring was continued for 1 h and left to stand at
r.t. for 1 h. The solid product formed was collected by filtration and
recrystallized from 1,4-dioxane; yield 30%; mp. 280◦C; IRν cm−1 3400
(NH); 3200 (NH); 1690 (CO); 1650 (CO); 1H NMR (DMSO-d6) δ = 2.4 (s,
3H, CH3); 3.6 (s, 3H, OCH3); 7.0–7.8 (m, 11H, Ar-H); 8.4 (s, 1H, NH);
10.8 (s, 1H, NH); MS: m/z = 600; Found: C, 53.97; H, 3.35; N, 18.68; S,
10.67; calcd. for C27H20N8O5S2: C, 53.99; H, 3.36; N, 18.66; S, 10.68%.
4-Chloro-9-(4-methoxyphenyl)-7-methyl-N-{4-[(pyrimidin-2-
ylamino)sulfonyl]
phenyl}-4-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno-
[3,2-d]pyrimidine-8-carboxamide (19)
A suspension of compound 13 (0.59 g, 1.0 mmoles) in POCl3 (10 mL) was
refluxed for 2 h and then left to stand at r.t. The reaction mixture was
poured onto ice/water, and the solid product formed was collected by

Acetoacetanilides in Heterocyclic Synthesis, Part 1
2261
filtration, washed with water several times, dried, and recrystallized
from ethanol/acetic acid as red crystals; yield 35%; mp >360◦C; IRν
cm−1 3300 (NH); 3100 (NH); 1700 (CO); 1650 (CO); MS: m/z = 617;
Found: C, 54.40; H, 3.25; N, 15.85; S, 10.37; calcd. for C28H20ClN7O4S2:
C, 54.41; H, 3.26; N, 15.86; S, 10.38%.
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