N-1-Naphthyl-3-oxobutanamide in heterocyclic synthesis: A facile synthesis of nicotinamide, thieno[2,3-b]pyridine, and Bi- or tricyclic annulated pyridine derivatives containing naphthyl moiety

Article abstract of DOI:10.1080/10426500802453658

N-1-Naphthyl-3-oxobutanamide (1) reacts with arylidinecyanothioacetamide 2a-c in ethanol/piperidine solution under reflux to yield the pyridine-2(1H)-thiones 6a-c. Compound 6a reacts with -haloketones 7a-e to give the 6-thio-N-1-naphthyl-nicotinamides derivatives 8a-e, which cyclized to thieno[2,3-b]pyridine derivatives 9a-e. The reaction of compound 9a with hydrazine hydrate and formamide gives the thieno[2,3-b]pyridine carbohydrazide derivative 10 and pyridothienopyrimidine derivative 11, respectively. Reaction of 9a with benzoyl isothiocyanate gave thiourea derivative 12. Compound 12, upon treatment with alcoholic NaOH, gave pyridothienopyrimidine 13. Saponifications of 9a gave the amino acid 15, which affords 16 when refluxed in Ac2O. Treatment of compound 16 with AcONH₄/AcOH gave 17. Diazotization and self-coupling of 9b gave the pyridothienotriazine 18. Also, diazotization of the ortho-aminohydrazide 10 give the corresponding azide 19, which was subjected to Curtius rearrangement in boiling xylene to give imidazothienopyridine 20. Reaction of 10 with either formic acid or triethylorthoformate and phenyl isothiocyanate gave the corresponding pyridothienotriazepines 22 and 23, respectively. The interaction of 10 with acetylacetone furnished the pyrazolyl derivative 24. The structures of the synthesized compounds were established from their analytical and spectral data.

Full text of DOI:10.1080/10426500802453658

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N-1-Naphthyl-3-oxobutanamide
in Heterocyclic Synthesis:
A Facile Synthesis of
Nicotinamide, Thieno[2,3-
b]pyridine, and Bi- or Tricyclic
Annulated Pyridine Derivatives
Containing Naphthyl Moiety
Abdel Haleem M. Hussein a , Mohamed A. M. Gad-
Elkareem a , Abu-Bakr A. A. M. El-Adasy a & Ismail
M. Othman a
a Department of Chemistry, Faculty of Science, Al-
Azhar University at Assiut, Assiut, Egypt
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To cite this article: Abdel Haleem M. Hussein, Mohamed A. M. Gad-Elkareem, Abu-
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in Heterocyclic Synthesis: A Facile Synthesis of Nicotinamide, Thieno[2,3-b]pyridine,
and Bi- or Tricyclic Annulated Pyridine Derivatives Containing Naphthyl Moiety,
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Phosphorus, Sulfur, and Silicon, 184:2263–2280, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802453658
N-1-Naphthyl-3-oxobutanamide in Heterocyclic
Synthesis: A Facile Synthesis of Nicotinamide,
Thieno[2,3-b]pyridine, and Bi- or Tricyclic Annulated
Pyridine Derivatives Containing Naphthyl Moiety
Abdel Haleem M. Hussein, Mohamed A. M. Gad-Elkareem,
Abu-Bakr A. A. M. El-Adasy, and Ismail M. Othman
Department of Chemistry, Faculty of Science, Al-Azhar University at
Assiut, Assiut, Egypt
N-1-Naphthyl-3-oxobutanamide (1) reacts with arylidinecyanothioacetamide 2a–c
in ethanol/piperidine solution under reflux to yield the pyridine-2(1H)-thiones 6a–
c. Compound 6a reacts with α-haloketones 7a–e to give the 6-thio-N-1-naphthyl-
nicotinamides derivatives 8a–e, which cyclized to thieno[2,3-b]pyridine derivatives
9a–e. The reaction of compound 9a with hydrazine hydrate and formamide gives
the thieno[2,3-b]pyridine carbohydrazide derivative 10 and pyridothienopyrimi-
dine derivative 11, respectively. Reaction of 9a with benzoyl isothiocyanate gave
thiourea derivative 12. Compound 12, upon treatment with alcoholic NaOH, gave
pyridothienopyrimidine 13. Saponifications of 9a gave the amino acid 15, which af-
fords 16 when refluxed in Ac O. Treatment of compound 16 with AcONH /AcOH
2
4
gave 17. Diazotization and self-coupling of 9b gave the pyridothienotriazine 18.
Also, diazotization of the ortho-aminohydrazide 10 give the corresponding azide
19, which was subjected to Curtius rearrangement in boiling xylene to give imida-
zothienopyridine 20. Reaction of 10 with either formic acid or triethylorthoformate
and phenyl isothiocyanate gave the corresponding pyridothienotriazepines 22 and
23, respectively. The interaction of 10 with acetylacetone furnished the pyrazolyl
derivative 24. The structures of the synthesized compounds were established from
their analytical and spectral data.
Keywords N-1-Naphthylnicotinamides; N-1-naphthyl-3-oxobutanamides; pyridine-
2(1H)-thiones; pyridothienopyrididines; pyridothienotriazepines; thieno[2,3-b]pyridines
INTRODUCTION
Polyfunctionally substituted pyridines are among the most inten-
sively studied heterocyclic chemistry. Many of the polyfunctionally
Received 20 May 2008; accepted 5 September 2008.
Address correspondence to Mohamed A. M. Gad-Elkareem, Department of Chem-
istry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt. E-mail:
m65gad@yahoo.com
2263

2264
A. H. M. Hussein et al.
substituted pyridines are biologically active as anti-proliferative,1 car-
diotonic agents,2,3 and antiviral4,5 agents.
The literature contains a number of syntheses of substituted bi-
heterocyclic and triheterocyclic ring systems containing a pyridine
moiety and featuring a variety of pharmacological effects such as
antimicrobial,6,7 antiviral,4,5,8 anti-inflammatory,9 antiallergic,10 anti-
protozoa,11 anti-anaphylactic,12 antitumor,13 and antiparasitic,14 and a
few possess significant hypocholesteromic15 activity.
Recently many chemical structures containing the naphthyl moi-
ety were reported to exhibit diverse biological and pharmaceutical
activities such as anticonvulsant,16 antimicrobial,16,17 anticancer,18,19
antiallergic,20 antiobesity,21 and antidiabetic21 activities. In continua-
tion of our research program for the synthesis of bi- or tricyclic annu-
lated pyridine derivatives,22–31 and in view of the continued interest
in the chemistry of these compounds, we report here the results of
our investigation on the synthesis of new N-1-naphthylnicotinamides,
thieno[2,3-b]pyridines, pyrido-thienopyrididines, and pyridothienotri-
azipenes using pyridine-2(1H)-thiones.
RESULTS AND DISCUSSION
It has been found that N-1-naphthyl-3-oxobutanamides (1) (prepared
by treating 1-naphthylamine with ethyl acetoacetate as described in the
literature32) easily reacted with arylidine cyanothioacetamide 2a–c in
refluxing ethanol and sodium acetate to yield a product that may be ei-
ther pyridine-2(1H)-thiones 6a–c33 or its isomeric thiopyran structure
3. Establishing the exact structure of the reaction product as structure
1
6a–c rather than 3 is based on the spectroscopic data. Thus, the H
NMR spectrum of compound 6b, for example, revealed the presence
of singlet signals at δ = 10.22 and 14.36 ppm assigned to 2NH groups
and no signal assigned for the thiopyrane CH-4. So the pyridine-2(1H)-
thiones 6a–c are considered to be the only reaction products. The for-
mation of compound 6 is assumed to proceed via an initial addition of
the active methylene moiety in 1 to the active double bond in 2, thus
forming the acyclic Michael adduct 4, which then cyclized to 5 by a loss
of water and aromatized by a loss of hydrogen to the final product33
(Scheme 1).
6
The reaction of pyridinethione derivative 6a with α -haloketones 7a–
e in ethanol containing 1.0 g of sodium acetate afforded the S-alkyl-N-
1-naphthylnicotinamide derivatives 8a–e. The structure of compounds
8a–e has been confirmed as the correct one based on its spectral data
and elemental analyses. Thus, the IR spectrum of compound 8a, for

N-1-Naphthyl-3-oxobutanamide in Heterocyclic Synthesis
2265
SCHEME 1
example, exhibited the presence of the absorption band of the CN func-
tional group at υ 2221 cm−1 and a carbonyl ester at υ 1737 cm−1. The 1H
NMR spectrum of compound 8a revealed the appearance of CH3-CH2-
protons at δ = 1.26, 4.25 ppm, SCH2 protons at δ = 5.63 ppm, in addition
to the other protons assigned in compound 6a and the disappearance
of the proton of one NH (δ = 14.50 ppm in compound 6a). Compound
8a underwent cyclization into the thieno[2,3-b]pyridine derivative 9a
upon treatment with ethanolic sodium ethoxide. The IR spectrum of
compound 9a exhibited the disappearance of the absorption band due
to the CN function group and the appearance of absorption bands due to
the NH2 functional group at υ 3450, 3300 cm−1. The 1H NMR spectrum
of compound 9a revealed the disappearance of the protons assigned
to the methylene group at δ = 5.63 ppm and revealed the presence of
two protons as a singlet at δ = 4.02 ppm assignable to the NH2 group
beside the other protons in their proper positions. The structure of 9a
has been confirmed as the correct one by its synthesis via the reaction
of 6a with ethyl chloroacetate (7a) in boiling ethanolic sodium ethoxide
solution. Compound 9a prepared via this route was found to be com-
pletely identical with 9a as prepared by the first route (Scheme 2).

2266
A. H. M. Hussein et al.
SCHEME 2
Similarly, compounds 8b–e underwent reactions into thieno[2,3-b]-
pyridine derivative 9b–e upon treatment with ethanolic sodium ethox-
ide. The structures of 9b–e were established based on spectral data,
elemental analyses, and by their synthesis via the reaction of 6a
with α-haloketones 7b–e in boiling ethanolic sodium ethoxide solution
(Scheme 2).
The reactivity of β-amino ester derivative 9a toward some elec-
trophilic reagents has been studied. Thus, the reaction of 9a with hy-
drazine hydrate afforded 3-aminothieno[2,3-b]pyridine carbohydrazide
derivative 10. The structure of hydrazide 10 was compatible with the
spectroscopic data (IR and 1H NMR). In contrast to this behavior,
when compound 9a was refluxed in formamide solution, it afforded the
expected N-1-naphthyl-4-oxo-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]-
pyrimidine-8-carboxamide derivative 11.
Hard evidence of the structure of 11 came from its synthesis via the
reaction of 9b with triethylorthoformate in acetic anhydride.
Alternatively, the thiourea derivative 12 was obtained by the re-
action of 9a with benzoyl isothiocyanate in anhydrous acetone.34,35
Compound 12, upon alkaline cyclization with alcoholic sodium hydrox-
ide, gave 1,2,3,4-tetrahydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxamide derivative 13 instead of 3-benzoyl-1,2,3,4-tetrahydro-
pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carboxamide derivative 14.
1
The H NMR spectrum of compound 13 revealed the presence of 3NH

N-1-Naphthyl-3-oxobutanamide in Heterocyclic Synthesis
2267
protons and the absence of benzoyl protons. Compound 13 has been
confirmed as the correct one by its synthesis via the reaction of 9b with
carbon disulfide in refluxing dioxane (Scheme 3).
SCHEME 3
Saponification of 9a using alcoholic sodium hydroxide yielded
the sodium salt of the β-amino acid 15, which gave the
pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,3]-oxazine-8-carboxamide derivative 16
when refluxed in acetic anhydride. Structure 16 was established based
on elemental analysis and spectral data. Thus, the IR spectrum of

2268
A. H. M. Hussein et al.
16 showed the absence of any absorption bands that may be at-
tributed to NH2 function group. Moreover, its 1H NMR spectrum
showed two singlet signals at δ = 2.67 and 2.87 ppm assigned to two
CH3. The treatment of 16 with ammonium acetate in boiling acetic
acid led to the formation of pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxamide derivative 17. Compound 17 can also be prepared by heat-
ing compound 9b in acetic anhydride under reflux (Scheme 3).
Treatment of 3-amino-N5-1-naphthylthieno[2,3-b]pyridine-2,5-di-
carboxamide derivative 9b with a cold solution of sodium nitrite
in acetic acid 9b gave N-1-naphthyl-4-oxo-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]-
thieno[3,2-d][1,2,3]triazine-8-carboxamide derivative 18 (Scheme 4).
SCHEME 4
Similarly, diazotization of 3-aminothieno[2,3-b]pyridine carbo-
hydrazide derivative 10 gave the corresponding 3-amino-5-[(1-
naphthylamino)carbonyl]thieno[2,3-b]pyridine-2-carbonyl azide deri-
vative 19, which was subjected to Curtius rearrangement in re-
fluxing xylene25,30 to give N-1-naphthyl-2-oxo-2,3-dihydro-1H-imidazo-
[4ꢀ,5ꢀ:4,5]thieno[2,3-b]pyridine-7-carboxamide derivative 20. Structure
20 was elucidated based on spectral data and elemental analysis (cf.
the Experimental section). Also, the reaction of 10 with formic acid
or triethyl orthoformate in ethanol gave either the N-amino pyrimi-
dine derivative 21 or the triazepine derivative 22. Structure 21 was
1
ruled out based on H NMR, which revealed the absence of N-amino
1
protons. Moreover the H NMR spectrum of the reaction product re-
vealed three protons as singlet signals at δ = 7.14–7.92 with the aro-
matic protons, 10.46 and 11.57 ppm for three NH protons. So the
reaction product was formulated as N-1-naphthyl-5-oxo-4,5-dihydro-
3H-pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-e][1,2,4]triazepine-9-carboxamide deri-
vative 22. Also, the reaction, of 10 with phenyl isothiocyanate in
anhydrous dioxane gave the triazepine derivative 23. The structure
of triazepines 22 and 23 was confirmed by spectral data, elemental
analysis, and reports in the literature.25 The interaction of 10

N-1-Naphthyl-3-oxobutanamide in Heterocyclic Synthesis
2269
SCHEME 5
with acetyl acetone furnished 3-amino-2-[(3,5-dimethyl-1H-pyrazol-
1-yl)carbonyl]-N-1-naphthylthieno[2,3-b]pyridine-5-carboxamide deri-
1
vative 24. The H NMR spectrum of compound 24 showed the pres-
ence of three methyl groups at δ = 2.02, 2.52, and 2.76 ppm (cf. Scheme
5 and the Experimental section).
EXPERIMENTAL
Melting points were measured with a Gallenkamp apparatus and are
uncorrected. IR spectra in KBr discs were recorded on a Bruker Vec-
1
tor 22 FT-IR spectrophotometer. H NMR spectra were determined in
DMSO-d6 and CDCl3 at 300 MHz on Varian Mercury VX spectrometer
using TMS as an internal standard. Chemical shifts are expressed as δ
ppm. Mass spectra were recorded on GCMS-QP 1000 EX spectrometer
at 70 eV. Elemental analyses were carried out at the Microanalytical
Center of Cairo University, Giza, Egypt. Compound 1 was prepared
according to reports in the literature.32

2270
A. H. M. Hussein et al.
Preparation of Compounds 6a–c: General Procedure
A mixture of compound 1 (0.01 mol) and arylidinecyanothioacetamide
2a–c (0.01 mol) in ethanol (30 mL) was treated with piperidine (0.5 mL)
and heated under reflux for 8 h. The reaction mixture was then cooled by
being poured into crushed ice and acidified with HCl. The solid product
was collected and recrystallized from ethanol to give compounds 6a–c.
4-(4-Chlorophenyl)-5-cyano-2-methyl-N-1-naphthyl-6-
thioxo-1,6-dihydropyridine-3-carboxamide (6a)
It was obtained as yellow crystals from ethanol, yield 88%; mp 285◦C;
IR (KBr): υ cm−1 3358, 3200 (2NH ), 3055 (CH-arom.), 2973 (CH-aliph.),
1
2226 (CN) and 1653 (CO). H NMR (DMSO-d6): δ = 2.60 (s, 3H, CH3),
7.15–7.92 (m, 11H, Ar-H), 10.30 (s, 1H, NH) and 14.50 (br, 1H, NH).
MS: m/z = 431 (28%), 426 (80%), 143 (100%). Elemental analysis for
C24H16N3OSCl (429.5): Calcd., C 67.05, H 3.75, N 9.77, S 7.45, Cl 8.26%.
Found, C 67.35, H 3.49, N 9.98, S 7.16, Cl 8.01%.
5-Cyano-2-methyl-4-(4-methylphenyl)-N-1-naphthyl-6-
thioxo-1,6-dihydropyridine-3-carboxamide (6b)
It was obtained as yellow crystals from ethanol, yield 86%; mp 298◦C.
IR (KBr): υ cm−1 3368, 3210 (2NH), 3045 (CH-arom.), 2922 (CH-aliph.),
2209 (CN), 1655(CO).1H NMR (DMSO-d6): δ = 2.35 (s, 3H, CH3), 2.58
(s, 3H, CH3), 7.15–7.89 (m, 11H, Ar-H), 10.22 (s, 1H, NH) and 14.36 (br,
1H, NH). Elemental analysis for C25H19N3OS (409): Calcd. C 73.33, H
4.65, N 10.27, S 7.82%. Found: C 73.60, H 4.43, N 10.55, S 7.60%.
5-Cyano-4-(4-methoxyphenyl)-2-methyl-N-1-naphthyl-
6-thioxo-1,6-dihydropyridine-3-carboxamide (6c)
It was obtained as yellow crystals from ethanol, yield 89%; mp 260◦C.
IR (KBr): υ cm−1 3226, 3174 (2NH), 3051 (CH-arom.), 2933 (CH-aliph.),
2216 (CN) and 1647 (CO). Elemental analysis for C25H19N3O2S(425):
Calcd. C 70.59, H 4.47, N 9.88, S 7.53%. Found: C 70.33, H, 4.70, N
9.62, S 7.31%.
Preparation of Compounds 8a–e: General Procedure
A mixture of compound 6a (0.01 mol), halo compounds 7a–e (0.01 mol),
and sodium acetate (0.5 g) in ethanol (30 mL) was heated under reflux
for 8 h, then cooled, poured into crushed ice, and acidified with HCl. The
precipitates formed were collected and recrystallized from the proper
solvent to give 8a–e.

N-1-Naphthyl-3-oxobutanamide in Heterocyclic Synthesis
2271
Ethyl (4-(4-Chlorophenyl)-3-cyano-6-methyl-5-
[(1-naphthylamino)carbonyl]pyridin-2-ylthio)acetate (8a)
It was obtained as yellow crystals from ethanol, yield 82%; mp 170◦C.
IR (KBr): υ cm−1 3245 (NH), 3054 (CH-arom.), 2982 (CH-aliph.), 2221
(CN), 1737, 1654 (2CO). 1H NMR ( DMSO-d6): δ = 1.26 (t, 3H, CH3), 2.78
(s, 3H, CH3), 4.25 (q, 2H, CH2), 5.63 (s, 2H, S-CH2 ), 7.18–7.91 (m, 11H,
Ar-H) and 10.40 (s, 1H, NH). Elemental analysis for C28H22N3O3SCl
(515.5); Calcd. C 65.18, H 4.27, N 8.15, S 6.21, Cl 6.88%. Found C
665.39, H 4.250, N 8.40, S 60.00, Cl 6.70%.
6-[(2-Amino-2-oxoethyl)thio]-4-(4-chlorophenyl)-5-cyano-
2-methyl-N-1-naphthylnicotinamide (8b)
It was obtained as brown crystals from ethanol, yield 71%; mp 145◦C.
IR (KBr): υ cm−1 3447, 3313 (NH2), 3238 (NH), 3052 (CH-arom.), 2925
1
(CH-aliph.), 2217 (CN), 1671, 1655 (2CO). H NMR (CDCl3): δ = 2.57
(s, 3H, CH3), 2.73 (s, 2H, NH2), 3.99 (s, 2H, S-CH2) and 7.27–7.81
(m, 12H, Ar-H+NH). Elemental analysis for C26H19N4O2SCl (486.5):
Calcd. C 64.13, H 3.90, N 11.51, S 6.58, Cl 7.29%. Found C 64.39, H
3.69, N 11.77, S 6.31, Cl 7.56%.
6-(2-[(3-Acetylphenyl)amino]-2-oxoethylthio)-4-(4-
chlorophenyl)-5-cyano-2-methyl-N-1-naphthylnicotinamide
(8c)
It was obtained as yellow crystals from ethanol, yield 75%; mp
198◦C. IR (KBr): υ cm−1 3474, 3241 (2NH), 3056 (CH-arom), 2920 (CH-
aliph.), 2217 (CN), 1707, 1665 and 1648 (3CO). Elemental analysis
for C34H25N4O3SCl (604.5): Calcd. C 67.49, H 4.14, N 9.26, S 5.29, Cl
5.87%. Found C 67.72, H 4.42, N 9.46, S 5.01, Cl 5.62%.
4-(4-Chlorophenyl)-6-[2-(4-chlorophenyl)-2-oxoethyl]thio-5
-cyano-2-methyl-N-1-naphthylnicotinamide (8d)
It was obtained as yellow crystals from ethanol, yield 68%; mp 186◦C.
IR (KBr): υ cm−1 3471, 3238 (2NH), 3056 (CH-arom), 2926 (CH-aliph.),
2221 (CN), 1702, 1648 (2CO). Elemental analysis for C32H22N4O2SCl2
(597): Calcd. C 64.32, H 3.68, N 9.38, S 5.36, Cl 11.89%. Found C 64.53,
H 3.40, N 9.70, S 5.59, Cl 11.63%.
4-(4-Chlorophenyl)-5-cyano-2-methyl-6-[2-(4-methylphenyl)-
2-oxoethyl]-thio-N-1-naphthylnicotinamide (8e)
It was obtained as yellow crystals from ethanol, yield 70%; mp 195◦C.
IR (KBr): υ cm−1 3445, 3253 (2NH), 3055 (CH-arom), 2923 (CH-aliph.),
2220 (CN), 1716, 1653 (2CO). Elemental analysis for C33H25N4O2SCl

2272
A. H. M. Hussein et al.
(576.5): Calcd. C 68.68, H 4.34, N 9.71, S 5.55, Cl 6.16%. Found C 68.89,
H 4.59, N 9.50, S 5.78, Cl 6.38%.
Preparation of Compounds 9a–e: General Procedure
Method A
A mixture of compound 6a (0.01 mol), halo compounds 7a–e (0.01
mol), and sodium ethoxide (0.01 mol) in ethanol (30 mL) was heated
under reflux for 24 h, then left to stand, poured into cold water, and
acidified with HCl. The product formed was collected by filtration and
recrystallized from the proper solvent to give 9a–e.
Method B
Solutions of each of 8a–e (0.01) in ethanol and sodium ethoxide (0.01
mol Na in 10 mL ethanol) were heated under reflux for 24 h, then left
to stand, poured into cold water, and acidified with HCl. The product
formed was collected by filtration and recrystallized from the proper
solvent to afford 9a–e.
Ethyl 3-Amino-4-(4-chlorophenyl)-6-methyl-5-
[(1-naphthylamino)carbonyl]thieno[2,3-b]pyridine-
2-carboxylate (9a)
It was obtained as pale yellow crystals from ethanol, yield 79%; mp
194◦C. IR (KBr): υ cm−1. 3483, 3398 (NH2), 3157 (NH), 2982 (CH-
aliph.), 1679, 1649 (2CO). 1H NMR (CDCl3): δ = 1.32 (t, 3H, CH3), 2.76
(s, 3H, CH3), 4.02 (s, 2H, NH2), 4.24 (q, 2H, CH2), 6.83-7.83 (m, 12H, Ar-
H + NH). MS: m/z = 517 (2.75%), 515 (9.17%), 115 (100%). Elemental
analysis for C28H22N3O3SCl (515.5): Calcd. C 65.18, H 4.27, N 8.15, S
6.21, Cl 6.88%. Found C 65.00, H 4.01, N 8.39, S 6.50, Cl 6.55%.
3-Amino-4-(4-chlorophenyl)-6-methyl-N5-
1-naphthylthieno[2,3-b]pyridine-2,5-dicarboxamide (9b)
It was obtained as brown crystals from dioxane/ethanol, yield 70%;
mp 250◦C. IR (KBr): υ cm−1 4485, 4432, 3378, 3286 (2NH2), 3185 (NH),
3053 (CH-arom.), 2926 (CH-aliph.), 1665, 1657 (2CO). 1H NMR (DMSO-
d6): δ = 2.49 (s, 3H, CH3), 5.21 (s, 2H, NH2), 7.39-7.88 (m, 13H, Ar-H
+ NH2) and 10.59 (s, 1H, NH). MS: m/z = 488 (5%), 486 (16%), 143
(100%). Elemental analysis for C26H19N4O2SCl (486.5): Calcd. C 64.13,
H 3.90, N 11.51, S 6.58, Cl 7.29%. Found C 64.41, H 3.66, N 11.70, S
6.29, Cl 7.60%.

N-1-Naphthyl-3-oxobutanamide in Heterocyclic Synthesis
2273
N2-(3-Acetylphenyl)-3-amino-4-(4-chlorophenyl)-6-methyl-
N5-1-naphthylthieno[2,3-b]pyridine-2,5-dicarboxamide (9c)
It was obtained as green crystals from dioxane/ethanol, yield 65%;
mp 248◦C. IR (KBr): υ cm−1 3482, 3324 (NH2), 3245, 3200 (2NH), 3053
1
(CH-arom.), 2924 (CH-aliph.), 1705, 1675 and 1648 (3CO). H NMR
(DMSO-d6): δ = 2.49 (s, 3H, CH3), 2.80 (s, 3H, COCH3), 5.89 (s, 2H,
NH2), 7.20-7.92 (m, 14H, Ar-H), 8.27 (s, 1H, Ar-H of acetylphenyl),
9.77 (s, 1H, NH) and 10.41 (s, 1H, NH). Elemental analysis for
C34H25N4O3SCl (604.5): Calcd. C 67.49, H 4.14, N 9.26, S 5.29, Cl
5.87%. Found C 67.70, H 4.46, N 9.56, S 5.60, Cl 5.60%.
3-Amino-4-(4-chlorophenyl)-N2-(4-chlorophenyl)-6-methyl-
N5-1-naphthylthieno[2,3-b]pyridine-2,5-dicarboxamide (9d)
It was obtained as pale yellow crystals from ethanol, yield 62%; mp
230◦C. IR (KBr): υ cm−1 3472, 3321 (NH2), 3252, 3210 (2NH), 3054 (CH-
1
arom.), 2923 (CH-aliph.) 1685 and 1643 (2CO). H NMR (DMSO-d6):
δ = 2.18 (s, 3H, CH3), 7.31–7.76 (m, 17H, Ar-H + NH2), 10.36 (s, 1H,
NH) and 10.53 (s, 1H, NH). Elemental analysis for C32H22N4O2SCl2
(597): Calcd. C 64.32, H 3.68, N 9.38, S 5.36, Cl 11.89%. Found C 64.03,
H 3.90, N 9.60, S 5.62, Cl 11.60%.
3-Amino-4-(4-chlorophenyl)-6-methyl-N2-(4-methylphenyl)-
N5-1-naphthylthieno[2,3-b]pyridine-2,5-dicarboxamide (9e)
It was obtained as pale yellow crystals from ethanol, yield 66%; mp
258◦C. IR (KBr): υ cm−1 3464, 3336 (NH2), 3224, 3215 (2NH), 3055
1
(CH-arom.), 2922 (CH-aliph.) 1683, 1677 (2CO). H NMR (DMSO-d6):
δ = 2.25 (s, 3H, CH3), 2.49 (s, 3H, CH3), 5.89 (s, 2H, NH2), 7.10-7.90 (m,
15H, Ar-H), 9.50 (s, 1H, NH) and 10.37 (s, 1H, NH). Elemental analysis
for C33H25N4O2SCl (576.5): Calcd. C 68.68, H 4.34, N 9.71, S 5.55, Cl
6.16%. Found C 68.39, H 4.09, N 9.98, S 5.71, Cl 6.42%.
3-Amino-4-(4-chlorophenyl)-2-(hydrazinocarbonyl)-6-
methyl-N-1-naphthylthieno[2,3-b]pyridine-5-carboxamide (10)
To a solution of 9a (0.01 mol) in ethanol (30 mL), the hydrazine hydrate
(2 mL) was added. The reaction mixture was heated under reflux for
15 h. The solid product that formed was collected by filtration and re-
crystallized from ethanol to give 10 as deep yellow crystals, yield 66%;
mp 182◦C. IR (KBr): υ cm−1 3480, 3432, 3347, 3285 (2NH2), 3225,
3198 (2NH), 3050 (CH-arom.), 2977 (CH-aliph.), 1651, 1633 (2CO).
1H NMR (CDCLl3): δ = 2.32 (s, 3H, CH3), 5.42 (s, 2H, NH2), 6.95 (s,
2H, NH2), 6.98–7.79 (m, 13H, Ar-H + 2NH). Elemental analysis for

2274
A. H. M. Hussein et al.
C26H20N5O2SCl (501.5): Calcd. C 62.21, H 3.99, N 13.95, S 6.38, Cl
7.08%. Found C 62.44, H 4.31, N 13.71, S 6.15, Cl 7.30%.
9-(4-Chlorophenyl)-7-methyl-4-oxo-N-1-naphthyl-3,
4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-
8-carboxamide (11)
Method A
A solution of compound 9a (0.01 mol) in formamide (10 mL) was
heated under reflux for 5 h, then allowed to cool and poured into cold
water. The solid product was collected and crystallized from ethanol to
give 11.
Method B
To a solution of compound 9b (0.01 mol) in acetic anhydride (30 mL),
triethyl orthoformate (3 mol) was added. The reaction mixture was
refluxed for 8 h, then poured into cold water and left to stand for 12 h.
The solid product that formed was filtered off and recrystallized from
ethanol to give 11 as green crystals, yield 55%; mp > 320◦C. IR (KBr): υ
cm−1 3446, 3326 (2NH), 3057 (CH-arom.), 2986 (CH-aliph.), 1686, 1657
1
(2CO). H NMR (DMSO-d6): δ = 2.78 (s, 3H, CH3), 7.18–7.92 (m, 11H,
Ar-H), 8.09 (s, 1H, CH-pyrimidine), 10.40 (s, 1H, NH), 12.96 (s, 1H,
NH). MS: m/z = 498 (20%), 496 (56%), 115 (100%). Elemental analysis
for C27H17N4O2SCl (496.5): Calcd. C 65.25, H 3.42, N 11.27, S 6.44, Cl
7.15%. Found C 65.353, H 3.76, N 11.55, S, 6.20, Cl 7.38%.
Ethyl 3-[(benzoylamino)carbonothioyl]amino-4-(4-
chlorophenyl)-6-methyl-5-[(N-1-naphthyl)carbonyl]-
thieno[2,3-b]pyridine-2-carboxylate (12)
To a solution of compound 9a (0.01 mol) in anhydrous acetone, benzoyl
isothiocyanate [prepared in situ by heating a mixture of benzoyl chlo-
ride (0.01 mol) and ammonium thiocyanate (0.01 mol) in anhydrous
acetone for 10 min] was added. The reaction mixture was refluxed for
18 h, then poured into cooled water. The precipitate was collected by
filtration, washed with cold water, and recrystallized from ethanol to
give 12 as pale green crystals, yield 56%; mp 180◦C. IR (KBr): υ cm−1
3448, 3378, 3324 (3NH), 3045 (CH-arom.), 2991 (CH-aliph.), 1719, 1682
(2CO).1H NMR (CDCLl3): δ = 1.31 (t, 3H, CH3), 2.75 (s, 3H, CH3), 4.18
( s, 1H, NH), 4.23 (q, 2H, CH2), 6.82 (s, 1H, NH), 7.25–7.82 (m, 12H,
Ar-H + NH). Elemental analysis for C36H27N4O4S2Cl (678.5): Calcd. C

N-1-Naphthyl-3-oxobutanamide in Heterocyclic Synthesis
2275
63.66, H 3.98, N 8.25, S 9.43, Cl 5.23%. Found C 63.98, H 4.22, N 8.45,
S 9.13, Cl 5.50%.
9-(4-Chlorophenyl)-7-methyl-4-oxo-N-1-naphthyl-2-thioxo-
1,2,3,4-tetrahydro-pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]-
pyrimidine-8-carboxamide (13)
Method A
Compound 12 (1 g) was dissolved in ethanol (30 mL) containing 2
mL of 2N NaOH and heated under reflux for 12 h. The reaction mixture
was cooled, poured into ice/water, and acidified with 10% HCl. The solid
that formed was collected by filtration and recrystallized from dioxane
to give 13.
Method B
Compound 9b (0.01 mol) and CS2 (2 mL) in dioxane (20 mL) were
heated under reflux for 15 h. The reaction mixture was cooled, poured
into ice/water and neutralized with HCl. The solid product that formed
was collected by filtration and recrystallized from dioxane to give 13 as
brown crystals, yield 40%; mp 200◦C. IR (KBr): υ cm−1 3448, 3382, 3324
(3NH), 3056 (CH-arom.), 2964 (CH-aliph.), 1688, 1656 (2CO).1H NMR
(DMSO-d6): δ = 2.74 (s, 3H, CH3), 4.07 (s, 1H, NH), 7.81–7.92 (m, 12H,
Ar-H + NH), 10.46 (s, 1H, NH). Elemental analysis for C27H17N4O2S2Cl
(528.5): Calcd. C 61.30, H 3.21, N 10.59, S 12.11, Cl 6.71%. Found C
61.60, H 3.55, N 10.81, S 12.39, Cl 6.46%.
Preparation of Compound 15
The amino ester 9a was heated under reflux for 8 h in ethanolic NaOH
(30 mL 10%). The solid product that was obtained after cooling was
collected by filtration, washed with ethanol, and left to dry to give
compound 15. This compound was used as such in the next procedure.
9-(4-Chlorophenyl)-2,7-dimethyl-4-oxo-N-1-naphthyl-
4H-pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,3]oxazine-8-carboxamide
(16)
The sodium salt 15 (0.5 g) was heated under reflux in acetic anhydride
(30 mL) for 4 h. The reaction mixture was left to stand 12 h. The solid
product that formed was filtered off and recrystallized from dioxane to
give 16 as green crystals, yield 44%; mp 240◦C. IR(KBr): υ cm−1 3423
(NH), 3055 (CH-arom.), 2923 (CH-aliph.), 1722, 1692 (2CO).1H NMR

2276
A. H. M. Hussein et al.
(DMSO-d6): δ = 2.67 (s, 3H, CH3), 2.87 (s, 3H, CH3), 7.17–8.08 (m, 12H,
Ar-H+NH). Elemental analysis for C28H18N3O3SCl (511.5): Calcd. C
65.69, H 3.52, N 8.21, S 6.25, Cl 6.94%. Found: C 65.95, H 3.79, N 8.43,
S 6.53, Cl 6.65%.
9-(4-Chlorophenyl)-2,7-dimethyl-4-oxo-N-1-naphthyl-3,
4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-
8-carboxamide (17)
Method A
A mixture of compound 16 (0.01 mol) and ammonium acetate (0.02
mol) in acetic acid 30 mL was heated under reflux for 12 h. The solid
product that formed after cooling was collected by filtration, washed
with water, and recrystallized from DMF/EtOH to give 17.
Method B
A sample of compound 9b (0.01 mol) in acetic anhydride 30 mL was
heated under reflux for 18 h, then cooled and poured into cold water.
The solid product was collected and recrystallized from DMF/EtOH to
give 17 as green crystals, yield 45%; mp > 300◦C. IR (KBr): υ cm−1 3420,
3382 (2NH), 3056 (CH-arom.), 2966 (CH-aliph.), 1698, 1688 (2CO). 1H
NMR (CDCLl3): δ = 2.67 (s, 3H, CH3), 2.76 (s, 3H, CH3), 7.26–7.92 (m,
12H, Ar-H + NH) and 10.42 (s, 1H, NH). MS: m/z = 512 (8.2%), 510
(24%) and 115 (100%). Elemental analysis for C28H19N4O2SCl (510.5):
Calcd. C 65.81, H 3.72, N 10.97, S 6.17, Cl 6.95%. Found: C 65.55, H
3.93, N 10.68, S 6.50, Cl 6.70%.
9-(4-Chlorophenyl)-7-methyl-4-oxo-N-1-naphthyl-3,
4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,2,3]triazine-
8-carboxamide (18)
To a cold solution of compound 9b (0.01 mol) in acetic acid 30 mL, a cold
solution of sodium nitrite (1 g in 2 mL water) was added dropwise with
stirring for 5 h and left to stand for 2 h. The solid product that formed
was collected by filtration and recrystallized from dioxane to give 18
(60%) as green crystals, mp 220◦C. IR (KBr): υ cm−1 3424, 3486 (2NH),
3057 (CH-arom.), 2968 (CH-aliph.), 1671, 1657 (2CO).1H NMR (DMSO-
d6): δ = 2.74 (s, 3H, CH3), 7.11–7.91 (m, 12H, Ar-H + NH), 10.48 (s, 1H,
NH). Elemental analysis for C26H16N5O2SCl (497.5): Calcd. C 62.71,
H 3.21, N 14.07, S 6.43, Cl 7.13%. Found: C 62.48, H 3.55, N 14.31, S
6.15, Cl 7.38%.

N-1-Naphthyl-3-oxobutanamide in Heterocyclic Synthesis
2277
3-Amino-4-(4-chlorophenyl)-6-methyl-5-
[(1-naphthylamino)carbonyl]thieno[2,3-b]pyridine-2-
carbonyl azide (19)
To a cold solution of 10 (0.01 mol) in acetic acid 20 mL, a cold solu-
tion of sodium nitrite (0.5 g in 2 mL of water ) was added dropwise
with stirring for 6 h and left to stand for 24 h. The precipitate was
collected and recrystallized from ethanol to give 19 (52%) as buff crys-
tals, mp 240◦C. IR (KBr): υ cm−1 3486, 3423 (NH2), 3258 (NH), 3056
(CH-arom.), 2963 (CH-aliph.), 2129 (CON3) and 1656 (CO).1H NMR
(CDCl3) δ = 2.72 (s, 3H, CH3), 7.02–7.80 (m, 14H, Ar-H + NH + NH2).
Elemental analysis for C26H17N6O2SCl (512.5): Calcd. C 60.88, H 3.32,
N 16.39, S 6.24, Cl 6.92%. Found: C 60.57, H 3.53, N 16.67, S 6.49,
Cl 6.70%.
8-(4-Chlorophenyl)-6-methyl-N-1-naphthyl-2-oxo-2,3-dihydro-
1H-imidazo[4ꢀ,5ꢀ:4,5]thieno[2,3-b]pyridine-7-carboxamide
(20)
The carbonyl azide 19 (0.01 mol) was heated under reflux in xylene
(20 mL) for 18 h and allowed to cool. The solid product that formed
was filtered off, then washed with petroleum ether, dried, and recrys-
tallized from dioxane to give 20 (72%) as brown crystals, mp > 300◦C.
IR (KBr): υ cm−1 3443, 3395, 3324 (3NH), 2923 (CH-aliph.), 1720 (CO)
1
and 1648 (CO). H NMR (DMSO-d6): δ = 2.68 (s, 3H, CH3), 7.21–7.87
(m, 13H, Ar-H + 2NH) and 10.29 (s, 1H, NH). Elemental analysis for
C26H17N4O2SCl (484.5): Calcd. C 64.39, H 3.51, N 11.55, S 6.60, Cl
7.32%. Found: C 64.11, H 3.75, N 11.83, S 6.38, Cl 7.55%.
10-(4-Chlorophenyl)-8-methyl-N-1-naphthyl-5-oxo-4,
5-dihydro-3H-pyrido-[3ꢀ,2ꢀ:4,5]thieno[3,2-e][1,2,4]
triazepine-9-carboxamide (22)
Method A
A suspension of 10 (0.01 mol) and triethyl orthoformate (3 mol) in
acetic anhydride 30 mL was heated under reflux for 18 h. The reaction
mixture was poured into cold water and left to stand overnight. The
solid precipitate was filtered off and recrystallized from ethanol to give
22.
Method B
A solution of compound 10 (0.01 mol) in formic acid (30 mL) was
heated under reflux for 24 h. The solid product that formed was col-
lected by filtration and recrystallized from ethanol to give 22 as green

2278
A. H. M. Hussein et al.
crystals, yield 81%; mp 192◦C. IR (KBr): υ cm−1 3391, 3371, 3220 (3NH),
3049 (CH-arom.), 2968 (CH-aliph.), 1670, 1660 (2CO). 1H NMR (DMSO-
d6): δ = 2.60 (s, 3H, CH3), 5.63 (s, 1H, CH-triazepine), 7.14–7.92 (m,
12H, Ar-H + NH), 10.46 (s, 1H, NH) and 11.57 (s, 1H, NH). MS m/z =
517 (41%), 515 (100%). Elemental analysis for C27H18N5O2SCl (511.5):
Calcd. C 63.34, H 3.52, N 13.68, S 6.25, Cl 6.94%. Found: C 63.12, H
3.85, N 13.96, S 6.53, Cl 6.68%.
2-Anilino-10-(4-chlorophenyl)-8-methyl-5-oxo-N-1-naphthyl-
4,5-dihydro-3H-pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-e][1,2,4]-
triazepine-9-carboxamide (23)
To a solution of compound 10 (0.01 mol) in anhydrous dioxane 30
mL, phenyl isothiocyanate (0.01 mol) was added. The mixture was
heated under reflux for 24 h. The solid product that formed after cool-
ing was collected by filtration and recrystallized from dioxane to give
23 (64%) as pale yellow crystals, mp 220◦C. IR (KBr): υ cm−1 3447,
3396, 3380, 3325 (4NH), 3056 (CH-arom.), 2924 (CH-aliph.), 1665, 1656
(2CO).1H NMR (CDCl3): δ = 2.71 (s, 3H, CH3), 7.00 (s, 1H, NH), 7.13
(s, 1H, NH), 7.18–7.84 (m, 18H, Ar-H + 2NH). Elemental analysis for
C33H23N6O2SCl (602.5): Calcd. C 65.72, H 3.81, N 13.94, S 5.31, Cl
5.89%. Found: C 65.97, H 3.58, N 13.68, S 5.60, Cl 5.68%.
3-Amino-4-(4-chlorophenyl)-2-[(3,5-dimethyl-1H-pyrazol-
1-yl)carbonyl]-6-methyl-N-1-naphthylthieno[2,3-b]-
pyridine-5-carboxamide (24)
A mixture of compound 10 (0.01 mol) and acetyl acetone (0.02 mol) in
ethanol (30 mL) was treated with piperidine (0.5 mL). The reaction
mixture was heated under reflux for 6 h. The solid product that formed
after cooling was collected by filtration and recrystallized from ethanol
to give 24 (44%) as green crystals, mp 175◦C. IR (KBr): υ cm−1 3482,
3380 (NH2), 3286 (NH), 3051 (CH-arom.), 2964 (CH-aliph.), 1681, 1648
(2CO). 1H NMR (CDCl3): δ = 2.02 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.76
(s, 3H, CH3), 5.78 (s, CH-pyrazole), 6.93–7.78 (m, 14H, Ar-H + NH +
NH2). Elemental analysis for C31H24N5O2SCl (565.5): Calcd. C 65.78,
H 4.24, N 12.37, S 5.65, Cl 6.27%. Found: C 65.52, H 4.61, N 12.64, S
5.41, Cl 6.55%.
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