A convenient synthesis of some new indeno[1,2-b]pyridines and indeno[1,2-b] thieno[3,2-e]pyridine derivatives with potential biological activity

Article abstract of DOI:10.1080/10426500601142080

3-Cyano-5-oxo-4(2-thienyl)-indeno[1,2-b]pyridin-2-[1H]thione 3 was prepared from indanone 1 with arylidene cyanoacetamide or from arylideneindanone 2 with cyanoacetamide. S-Alkylation of 3 with halogenated compounds afforded compounds 4a-h. Compounds 4d-h underwent ring closure with sodium ethoxide to produce indenothienopyridines 5a-e, respectively. Treatment of 3 using ethylchoroacetate or chloroacetone gave compounds 6 and 7, respectively. Compounds 5a and 5d were reacted with carbon disulphide in pyridine to give compounds 8a and 8b. Most of the synthesized compounds were screened in vitro for their antimicrobial activities against four species of bacteria and six species of fungi using Chloramphenicol (5%) and Terbinafine (5%) as a standard.

Full text of DOI:10.1080/10426500601142080

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Phosphorus, Sulfur, and Silicon
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A Convenient Synthesis
of Some New Indeno[1,2-
b]Pyridines and Indeno[1,2-
b] Thieno[3,2-e]Pyridine
Derivatives with Potential
Biological Activity
Yasser A. El-Ossaily a
a Chemistry Department, Assiut University, Assiut,
Egypt
Published online: 19 Apr 2007.
To cite this article: Yasser A. El-Ossaily (2007) A Convenient Synthesis of Some New
Indeno[1,2-b]Pyridines and Indeno[1,2-b] Thieno[3,2-e]Pyridine Derivatives with
Potential Biological Activity, Phosphorus, Sulfur, and Silicon and the Related Elements,
182:5, 1109-1117, DOI: 10.1080/10426500601142080
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Phosphorus, Sulfur, and Silicon, 182:1109–1117, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601142080
A Convenient Synthesis of Some New
Indeno[1,2-b]Pyridines and Indeno[1,2-b]
Thieno[3,2-e]Pyridine Derivatives with Potential
Biological Activity
Yasser A. El-Ossaily
Chemistry Department, Assiut University, Assiut, Egypt
3-Cyano-5-oxo-4(2-thienyl)-indeno[1,2-b]pyridin-2-[1H]thione 3 was prepared from
indanone 1 with arylidene cyanoacetamide or from arylideneindanone 2 with
cyanoacetamide. S-Alkylation of 3 with halogenated compounds afforded com-
pounds 4a–h. Compounds 4d–h underwent ring closure with sodium ethoxide
to produce indenothienopyridines 5
, respectively. Treatment of 3 using ethyl-
a–e
choroacetate or chloroacetone gave compounds 6 and 7, respectively. Compounds
5a and 5d were reacted with carbon disulphide in pyridine to give compounds 8a
and 8b.
Most of the synthesized compounds were screened in vitro for their antimicrobial
activities against four species of bacteria and six species of fungi using Chloram-
phenicol (5%) and Terbinafine (5%) as a standard.
Keywords Indenopyridines; indenopyridothie-nopyrimidines; indenothienopyridines
INTRODUCTION
Pyridothienopyrimidines have been the subject of chemical and biolog-
ical studies on account of their interesting pharmacological properties.
Such derivatives have analgesic,1 antipyretic,2 and antiinflammatory3,4
activity. On the other hand, indenopyridines exhibit potent antisper-
matogenic activity and are useful inhibitors of spermatogenesis in
animals.5 Indenopyrimidines show fungicidal activity,6 while indenopy-
ridopyrimidines exhibit moderate antimicrobial activity.7 Also in phar-
macological studies thieno[2,3-d]pyrimidines and thienodipyrimidines
have been shown to posses a variety of pharmacological activities
including antituberculous8 and herpes virus inhibitory9 and anti-
anaphylactic activity.10 Within this context, it seemed of interest herein
Received October 5, 2006; accepted November 1, 2006.
Address correspondence to Yasser A. El-Ossaily, Chemistry Department, Faculty of
Science, Assiut University, Assiut, 71516, Egypt. E-mail: Yasserabdelmoez@Yahoo.com
1109

1110
Y. A. El-Ossaily
to synthesize the title compounds and their eraluation regarding an-
timicrobial activities.
RESULTS AND DISCUSSION
When indan-1,3-dione 1 was heated with arylidene cyanothioacetamide
in refluxed ethanol in the presence of a catalytic amount of piperidine,
3-cyano-5-oxo-4(2-thienyl)indeno[1,2-b]pyridine-2[1H]thione 3 was ob-
tained; compound 3 was also prepared by an alternative route by heat-
ing arylidenoindanone 2 in a methanolic solution of sodium methoxide
with cyanothioacetamide. The product 3, which was produced with the
two routes, was identical in all aspects (m.p., mixed m.p., IR, NMR,
Scheme 1).
SCHEME 1
When mercaptoindenopyridine carbonitrile 3 was refluxed with α-
halogenated compounds in ethanol and in the presence of sodium ac-
etate, the corresponding s-alkylated derivatives 4a–h were obtained
(Scheme 2).
Compounds 4d–h underwent cyclization into indenothienopyridiene
5a–e derivatives, respectively, when heated in ethanolic sodium ethox-
ide solution (Scheme 3). The formation of structures of 4c–h and their
cyclized compounds 5a–e were confirmed on the basis of spectral data.
IR of compounds 4c–h revealed an absorption band at 2220–2200 cm−1
characteristic for the (CN) group, which displaced with band at 3450
and 3350 cm−1 characteristic for (NH2), in cyclized compounds 5a–e.
Also HNMR spectra of compounds 4d–h showed signals at δ 4.2–4.3 as

Indeno and Thieno Pyridines Derivatives
1111
SCHEME 2
SCHEME 3
a singlet characteristic for S CH2 , which displaced with signals at δ
between 5.6 and 6.8 characteristic for NH2 when cyclized to 5a–e.
When 3 was refluxed with ethyl chloroacetate or chloroacetone in
ethanolic sodium ethoxide, compounds 6 and 7 were obtained, respec-
tively (Scheme 4).
On the other hand, indenopyridines 5a and 5d were reacted with
carbon disulphide in pyridine on a steam bath to give monothio and
dithioindenopyridothienopyridines 8a and 8b, respectively (Scheme 5).

1112
Y. A. El-Ossaily
SCHEME 4
SCHEME 5
BIOLOGICAL ACTIVITY
Most of the synthesized compounds (3, 4a, 4b, 4d, 4f, 4g, 4h, 5a, 5d, 7,
8a, 8b) were screened in vitro for their antimicrobial activities against
four species of bacteria (Bacillus cereur, Escherichia coli, Staphylococ-
cus aureus, and Serratia marcescens) and species of fungi (Aspergillus
flavus, Aspergillus niger, Candida albicans, Geotrichum candidum,
Scopulariopsis breuicaulis, and Trichophyton rubrum) using the disc
diffusion method.11,12 Chloramphenicol (5%) and Terbinafine (5%) were
used as a standard, respectively. Samples were dissolved in dimethyl
formamide to a concentration of 5%, and filter paper discs (whatman
no. 3.5 mm in diameter) were impregnated with the solutions. The discs
were placed on the surface of solidified Nutrient agar dishes seeded by
the test bacteria or Czapek’s Dox agar dishes seeded by the test fungi.
The inhibition zones were measured in millimeters by the end of the
incubation period (24 h at 37◦C for bacteria and 28◦C for fungi). The re-
lationship between the structure and the antibacterial activity is quite
clear for the results depicted in Table I. The following generalization in
this aspect may be made: Indenopyridenthione derivative 3 exhibited
a strong to moderate inhibition activity against two species of bacte-
ria, namely B. cereus and S. marcescens. The relatively high antibac-
terial activity of compound 3 may be due to the presence of a cyano
group and sulpher in the molecule. Conversion of the mercapto group

Indeno and Thieno Pyridines Derivatives
1113
TABLE I Results of Biological Screening of
Compounds (3–8): Inhibition Zones in mm
Compound
no.
Bacillus Escherichia Staphylococcus
Serratia
marcescens
cereus
coli
aureus
3
4a
4b
4d
4f
4g
4h
5a
5b
5d
7
8a
15
—
7
10
6
—
—
12
—
6
—
13
13
35
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
6
11
—
—
7
8
8
6
6
9
19
10
11
11
10
15
11
12
12
12
10
11
40
8
12
8
8b
Referenceb 35
37
ainhibition zone around the discs: 26–40 mm: very strong activity;
13–25 mm: strong activity; 7–12 mm: moderate activity; 0–6 mm:
weak activity; dash denotes no activity.
bchloramphenicol (5%, antibacterial activity).
of compounds 3 to 5-alkylated derivatives 4a, 4b, 4d, 4f, 4g, and 4h
through alkylation with different alkylating agents were found to be
more active, especially with serratia marcescens depending on the type
of substituents at C-2 in the pyridine ring.
Built-up fused indenothienopyridines ring systems (5a, 5b, 5d, and
7) exhibited a varied moderate activity depending on the type of sub-
stituents at C-2 in the thiophene ring.
Compounds 8a and 8b showed a strong to moderate activity against
all the tested bacteria species except for E. coli. The relatively high
antibacterial activity may be due to the presence of a fused pyrimidine
ring in the molecule.
ANTIFUNGAL ACTIVITY
The results indicated that all the screened compounds were inactive
against all the tested fungal species.
EXPERIMENTAL
Melting points were determined on a kofler metting point appara-
tus and are uncorrected. IR spectra were recorded on potassium

1114
Y. A. El-Ossaily
bromide disks on a Pye Unicam spectrophotometer using the KBr
1
wafer technique. H NMR spectra were obtained on a Varian 39090
MHZ spectrometer in a suitable deutrated solvent. Chemical shifts
were determined on the δ scale by using tetramethylsilan as the
internal standard. Elemental analyses were obtained on a Perkin
Elmer 240 C microanalyzer. The physical constants and spectral data
of the all new synthesized compounds are listed in Tables I and
II.
3-Cyano-5-oxo-4(2-thienyl)-indeno [1,2-b]pyriden-2[1H]-
thione (3)13
Method A
To a mixture of indandione (1) (0.01 mol), and arylidene cyamoth-
ioacetamide (0.01 mol) in ethanol (30 ml), five drops of piperidine
were added. The mixture was heated under reflux for 6 h and then
allowed to cool. The solid product was collected as orange crystals
(ethanol).
Method B
A mixture of arylideneindandione 2 (0.01 mol), and cyanothioac-
etamide (1 g, 0.01 mol) in methanolic solution of sodium methoxide
(0.01 mol in 20 mL methanol), was heated on a steam bath for 8 h at
50◦C and then allowed to cool, and it acidified with HCl (10%). The
solid product was collected and recrystallized from ethanol as orange
crystals. The physical constants and spectral data of compound 3 are
listed in Tables I and II.
2-Alkylthio-5-oxo- 4 (2-thienyl)-indeno [1,2-b] pyridine-3-
carbonitrile (4a–h): General Procedure
A mixture of compound 3 (0.01 mol), the appropriate halogenated com-
pound (0.01 mol), and sodium acetate (1 g, 0.012 mol) in ethanol (20 mL)
was heated under reflux for 1 h and then allowed to cool. The solid prod-
uct was collected, washed well with water, and recrystallized from the
proper solvent. The physical constants and spectral data of compounds
4a–h are listed in Tables I and II.
3-Amino-2-substituted-4 (2-thienyl)-5-oxoindeno [1,2-b]-
thieno[3,2-e] pyridines (5a–e): General Procedure
A sample of compound 4d–h (0.01 mol) in ethanolic solution of sodium
ethoxide (0.01 mol in 20 mL ethanol) was heated under reflux for

Indeno and Thieno Pyridines Derivatives
1115
TABLE II Physical Constants of compounds (3–8)
Analysis (%) Calcd./Found
Cl
No. Yield (%) M.P. (◦C)
Color
263–365a Red
210–212b Yellow
Molecular Formula
C
H
N
S
3
84
72
79
75
68
82
72
65
84
78
63
80
72
66
63
68
53
70
C17H8N2OS2
(320.39)
C18H19N2OS2
(334.42)
C19H12N2OS2
(348.44)
C24H14N2OS2
(410.51)
63.72 2.51 8.74 20.01
63.50 2.35 8.89 20.13
64.64 3.01 8.37 19.17
64.79 3.22 8.47 19.29
65.49 3.47 8.03 18.40
65.30 3.32 8.17 18.51
70.21 3.43 6.82 15.62
69.98 3.20 6.77 15.40
63.49 2.52 11.69 17.84
63.58 2.40 11.50 17.83
4a
4b
4c
4d
4e
4f
182b
228b
284a
306a
230b
260b
260c
306a
314c
362b
338a
285b
318b
364a
340c
320a
Yellow
Yellow
Orange
Yellow
Yellow
Orange
C19H9N3OS2
(359.43)
C25H14N3O2S2Cl 61.53 2.89 8.61 13.14 7.26
(487.98)
C25H14N2O2S2
(438.53)
C19H11N3O2S2
(377.44)
C26H17N3O3S2
(483.57)
C19H9N3OS2
(359.43)
61.72 3.12 8.42 13.37 7.24
68.47 3.21 6.38 14.62
68.29 3.18 6.46 14.79
60.46 2.93 11.13 16.99
60.53 2.88 11.24 17.19
64.57 3.54 8.68 13.26
64.77 3.44 8.84 13.21
63.49 2.52 11.69 17.84
63.48 2.50 11.70 17.82
4g
4h
5a
5b
5c
5d
5e
6
Canarian
Yellow
Yellow
Orange
Orange
Red
C25H14N3O2S2Cl 61.53 2.89 8.61 13.14 7.26
(487.98)
C25H14N2O2S2
(438.53)
C19H11N3O2S2
(377.44)
C26H17N3O3S2
(483.57)
C21H14N2O3S2
(406.48)
61.63 2.81 8.52 13.24 7.25
68.47 3.21 6.38 14.62
68.40 3.22 6.33 14.82
60.46 2.93 11.13 16.99
60.34 2.82 11.24 16.86
64.57 3.54 8.68 13.26
64.78 3.31 8.89 13.05
62.05 3.47 6.89 15.77
61.93 3.62 7.03 15.96
63.81 3.21 7.44 17.035
63.72 3.41 7.64 16.885
55.15 2.08 9.64 29.44
55.02 2.27 9.44 29.31
57.26 2.16 10.01 22.93
57.43 1.98 10.1 22.84
Orange
Orange
Orange
Yellow
Yellow
7
C20H12N2O2S2
(376.45)
C20H9N3OS4
8a
8b
C20H9N3O2S3
aRecrystallized from ethanol. bRecrystallized from petroleum ether 60–80◦C.
cRecrystallized from methanol.
30 min and then allowed to cool. The solid product was collected
and recrystallized from the proper solvent. The physical constants
and spectral data of compounds 5a–e are listed in Tables I and
II.

1116
Y. A. El-Ossaily
TABLE III Spectral Data of Compounds of (3-8)
No.
IR (KBr) νcm−1
1H NMR δ
3
3150 (NH), 2200 (CN), 1710 (CO)
CF3CO2D: 7.2-8.2 (m, 7H, Ar-H)
4a 2950, 2930 (CH aliph.), 2200 (CN), 1715 CDCl3: 3.2 (s, 3H, SCH3), 7.2-7.9 (m,
(CO) 7H, Ar-H)
4b 3100 (CH arom.), 2920 (CH aiph.), 2200 CDCl3: 1.3 (t, 3H, CH3), 4.3 (q, 2H,
(CN), 1705 (CO) CH2), 7.1-8.0 (m, 7H, Ar-H)
4c 3100 (CH arom.), 2910 (CH aiph.), 2200 CDCl3: 4.1 (s, 2H, CH2), 7.0-8.2 (m, 12H,
(CN), 1700 (CO) Ar-H)
4d 3100 (CH arom.), 2950 (CH aiph.), 2200 DMSO-d6: 4.3 (s, 2H, CH2), 7.1-8.2 (m,
(CN), 1715 (CO) 7H, Ar-H)
4e 3250 (NH), 2200 (CN), 3100 (CH arom.), DMSO-d6: 4.3 (s, 2H, CH2), 7.0-7.9 (m,
2900 (CH aiph.), 1715 (CO), 1650 (CO
amidic.)
11H, Ar-H), 10.6 (s, 1H, NH).
4f 3100 (CH arom.), 2900 (CH aiph.), 2200 CDCl3: 4.2 (s, 2H, CH2), 7.1-7.9 (m, 12H,
(CN), 1710 (CO), 1680 (CO).
4g 3400, 3300 (NH2), 3200 (CH arom.),
2900 (CH aiph.), 2200 (CN), 1700
(CO), 1660 (amidic CO)
Ar-H)
CDCl3: 4.2 (s, 2H, CH2), 5.8 (s, 2H,
NH2), 7.0-8.1 (m, 7H, Ar-H)
4h 3280 (NH), 2920 (CH aiph.), 2200 (CN), DMSO-d6: 3.9 (s, 3H, CH3), 4.2 (s, 2H,
1710 (CO), 1670 (CO amidic)
CH2), 11.2(s, 1H, NH), 7.2-8.1 (m,
11H, Ar-H).
5a 3450, 3350 (NH2), 2200 (CN), 1710 (CO), DMSO-d6: 6.6 (s, 2H, NH2), 7.1-8.0 (m,
1600 (C=N) 7H, Ar-H).
5b 3450, 3350 (NH2), 1715 (CO), 1680 (CO DMSO-d6: 6.8 (s, 2H, NH2), 7.2-8.2 (m,
amidic), 1640 (C=N)
5c 3460, 3400 (NH2), 1700 (CO), 1600
(C=N)
11H, Ar-H), 10.6 (s, 1H, NH).
CDCl3: 6.7 (s, 2H, NH2), 7.1-8.0 (m,
12H, Ar-H)
5d 3450, 3350 (NH2), 1710 (CO), 1645 (CO DMSO-d6: 5.6, 6.7 (2s, 4H, 2NH2),
amidic)
7.2-7.9 (m, 7H, Ar-H).
CDCl3: 3.9 (s, 3H, CH3), 5.8 (S, 2H,
NH2), 7.0-8.2 (m, 11H, Ar-H), 9.2 (s,
1H, NH).
5e 3450, 3350 (NH2), 3320 (NH), 1705
(CO), 1640 (CO amidic), 1590 (C=N)
6
3450, 3350 (NH2), 3100 (CH arom.),
2950 (CH aiph.), 2200 (CN), 1710
(CO), 1650 (CO)
CDCl3: 1.3 (t, 3H, CH3), 4.2 (q, 2H,
CH2), 5.9 (S, 2H, NH2), 7.1-8.0 (m, 7H,
Ar-H)
7
3450, 3380 (NH2), 1705 (CO), 1660 (CO) DMSO-d6: 2.3 (s, 3H, COCH3), 6.1 (S,
2H, NH2), 7.2-7.9 (m, 7H, Ar-H).
8a 3200, 3260 (2NH), 1700 (CO)
8b 3230, 3170 (2NH), 1710, 1680 (2CO)
CF3CO2D: 7.0-8.2 (m, 7H, Ar-H)
CF3CO2D: 7.0-8.1 (m, 7H, Ar-H)
Ethyl 3-Amino-5-oxo-4(2-thienyl)indeno[1,2-b]thieno[3,2-
e]pyridiene-2-carboxylate (6) and 2-Acetyl-3-amino-5-oxo-4-
(2-thienyl)-indeno[1,2-b]thieno[3,2-e]pyridine (7)
A mixture of compound 3 (0.01 mol), ethyl chloroacetate, or chloroace-
tone, and sodium acetate (1 g, 0.012 mol) in ethanol (20 mL) was heated

Indeno and Thieno Pyridines Derivatives
1117
under reflux for 1 h and then allowed to cool. The solid product 6 and 7
was collected, respectively, washed with water, and recrystallized from
the proper solvent. The physical constants and spectral data of com-
pounds 6 and 7 are listed in Tables I and II.
4,11-Dioxo-12-(2-thienyl)-3[H]indeno[1ꢀꢀ,2ꢀꢀ: 2ꢀ,3ꢀ]pyrido
[5ꢀ,6ꢀ:4,5]thieno[3,2,-d]pyrimidin-2(1 H)thione (8a) and 11-oxo-
12-(2-thienyl)indeno[1ꢀꢀ,2ꢀꢀ:2ꢀ,3ꢀ]pyrido[5ꢀ,6ꢀ:4,5]thieno[3,2-d]
pyrimidin-2,4(1 H, 3 H)dithione (8b)
A mixture of compound 5a or 5d (0.005 mol), carbon disulphide (2 mL)
in pyridine (20 mL) was refluxed for 10 h and then allowed to cool. The
solid product was collected and recrystallized from the proper solvent.
The physical constants and spectral data of compound 6a, b are listed
in Tables I and II.
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