Synthesis of polyfunctionally substituted pyrazolonaphthyridine, pentaazanaphthalene, and heptaazaphenanthrene derivatives

Article abstract of DOI:10.1080/10426500600695179

6-Aminopyrazolo[3,4-b]pyridine-5-carbonitrile (2) was used as a precursor for the synthesis of a variety of pyrazolo[3,4-b ][1,8]naphthyridines (3,4) and pentaazacyclopenta[b]naphthalenes (5-10, 13 , 14 ) via the initial addition to either the cyano or am

Full text of DOI:10.1080/10426500600695179

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Synthesis of
Polyfunctionally Substituted
Pyrazolonaphthyridine,
Pentaazanaphthalene, and
Heptaazaphenanthrene
Derivatives
A. A. Aly a
a Chemistry Department, Benha University, Benha,
Egypt
Version of record first published: 22 Sep 2006.
To cite this article: A. A. Aly (2006): Synthesis of Polyfunctionally Substituted
Pyrazolonaphthyridine, Pentaazanaphthalene, and Heptaazaphenanthrene
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 181:10,
2395-2409
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Phosphorus, Sulfur, and Silicon, 181:2395–2409, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600695179
Synthesis of Polyfunctionally Substituted
Pyrazolonaphthyridine, Pentaazanaphthalene,
and Heptaazaphenanthrene Derivatives
A. A. Aly
Chemistry Department, Benha University, Benha, Egypt
6-aminopyrazolo[3,4-b]pyridine-5-carbonitrile (2) was used as a precursor for the
synthesis of a variety of pyrazolo[3,4-b][1,8]naphthyridines (3,4) and pentaaza-
cyclopenta[b]naphthalenes (5–10, 13, 14) via the initial addition to either the
cyano or amino group followed by cyclization. Also, a series of heptaazadi-
cyclopenta[a, g]naphthalenes (15–17) and heptaazacyclopenta[ b]phenanthrenes
(18, 19) were obtained via the interaction of 4-(dibenzothiophen-2-yl)-1,5-dihydro-
5-imino-3-methyl-1-phenyl-1,2,6,8,9-pentaazacyclopenta[ b]naphthalen-6-ylamine
(14) with different reagents. The structures of the synthesized compounds were
established by elemental and spectral analyses.
Keywords Heptaazacyclopenta[b]phenanthrene; pentaazacyclopenta[b]naphthalene;
pyrazolo[3,4-b]pyridine
INTRODUCTION
The pyrido[2,3-d]pyrimidine is a very common feature in many com-
pounds of biological interest. Its employment gave good results in
several fields of medicinal chemistry, such as antitumor, antifolate,
antimycobacterial, and antihistamic chemistry.1−5 They are also ef-
fective as centeral analgesics and as a new drug for the treatment of
insomnia.6−9 In addition, pyrazole has been the focus of high attention
due to its versatile application in agriculture10 and medicine11 as an-
tileukemia and antihypertensive activities.12−14 In view of the aforesaid
versatile benefits and as a continuation of our efforts,15−17 we wish to re-
port on a facile and convenient access to 6-amino-(4-dibenzothiophen-2-
yl)-3-methyl-1-phenyl- 1H-pyrazolo[3,4-b]-pyridine-5-carbonitrile (2),
Received November 25, 2005; accepted February 28, 2006.
The author is grateful to the Botany Department, Faculty of Science, Benha Univer-
sity, Benha, Egypt, for biological screening.
Address correspondence to A. A. Aly, Benha University, Chemistry Department, Fac-
ulty of Science, Benha, Egypt. E-mail: alymaboud@yahoo.com
2395

2396
A. A. Aly
which was required in our laboratory as a key intermediate for the
construction of novel unreported congeners bearing pyrazole and pyri-
dopyrimidine moieties within a single molecular framework likely to
constitute potent antimicrobial agents.
RESULTS AND DISCUSSION
The one-pot reaction of 2,4-dihydro-5-methyl-2-phenylpyrazol-3-one
(1), dibenzothiophene-2-carbaldehyde, and malononitrile in the pres-
ence of ammonium acetate afforded the required starting material, 6-
amino-4-(dibenzothiophen-2-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]
pyridine-5-carbonitrile (2). The structure of 2 was assigned by el-
emental analyses and spectroscopic data; its IR spectrum showed
characteristic bands at 3390, 3260 (νNH2), and 2215 cm−1(νC N). The
1H NMR spectrum (CDCl3) showed signals (3H) at δ2.13 ppm assigned
for methyl protons, at δ5.85 ppm (2H) assigned for NH2, and multiplet
signals (12H) at δ 7.18–8.23 ppm assigned for aromatic protons. Com-
pound 2 was used as a precursor for the synthesis of new heterocyclic
systems because it contains the enaminonitrile moiety, which is well
known as a highly reactive and convenient reagent for the synthesis of
nitrogen heterocycles.18,19 Thus, the reaction of compound 2 with active
methylene compounds20 viz, ethyl cyanoacetate and diethyl malonate
in the presence of ammonium acetate-acetic acid at 190–200◦C fur-
nished pyrazolo[3,4-b][1,8]-naphthyridine derivatives 3a,b (Scheme 1).
The reaction of compound 2 with arylidenemalononitriles viz benzy-
lidene-malononitrile and 4-chlorobenzylidenemalononitrile in refluxing
dioxane21 yielded 5-amino-7-aryl-4-(dibenzothiophen-2-yl)-3-methyl-
1-phenyl-1H-pyrazolo[3,4-b][1,8]-naphthyridine-6-carbonitriles (4a,b).
We have also investigated the possible utility of 2 to develop a
facile and a convenient route to polyfunctionally substituted pyra-
zolopyridopyrimidine that was expected to have a broad spectrum of
biological and physiological potential.22 Thus, the reaction of com-
pound 2 with ammonium thiocyanate in boiling acetic acid afforded
[4-(dibenzothiophen-2-yl)-7,8-dihydro-3-methyl-1-phenyl-7-thioxo-1H-
1,2,6,8,9-pentaazacyclopenta[b]naphthalen-2-yl]-thiourea (5). The ref-
luxing of compound 2 with carbon disulfide in DMF gave the
corresponding
pentaazacyclopenta[b]naphthalene-5,7-dithione
6,
whose IR spectrum showed the absence of bands assignable to amino
and cyano functional groups and displayed the presence of only two
NH functional groups at 3390–3325 cm−1. Similarly, the reaction of
compound 2 with phenyl isocyanate, phenyl isothiocyanate, and formic
acid afforded the expected tricyclic compounds 7a,b and 8, respectively
(Scheme 1).

Pyrazolonaphthyridine, Pentaazanaphthalene
2397
SCHEME 1

2398
A. A. Aly
The enaminonitrile moiety in compound 2 proved to be highly reac-
tive toward other nitrogen nucleophiles. Thus, the reaction of 2 with
formamide, urea, thiourea, and guanidine hydrochloride afforded the
corresponding pyrazolopyrido-pyrimidine derivatives 9 and 10a–c, re-
spectively (Scheme 2).
SCHEME 2
The incorporation of the benzoxazolyl moiety in a pyrazolopy-
ridine system was achieved via the reaction of compound 2 with
o-aminophenol in absolute ethanol containing a few drops of pyridine

Pyrazolonaphthyridine, Pentaazanaphthalene
2399
to afford 5-(benzoxazol-2-yl)-4-(dibenzothiophen-2-yl)-3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridin-6-ylamine (11). The conden-sation
of compound 2 with triethyl orthoformate in refluxing acetic anhydride
yielded the corresponding ethyl pyrazolo[3,4-b]pyridin-6-ylformimidate
12, which underwent further cyclization upon treatment with methyl
amine or benzyl amine and afforded 4-(dibenzothiophen-2-yl)-1,6-
dihydro-3-methyl-6-methyl-/benzyl-1-phenyl-1,2,6,8,9-pentaazacyclo-
penta[b]naphthalen-5-ylideneamine (13a, b). The imidate derivative 12
gave 4-(dibenzothiophen-2-yl)- 1,5-dihydro-5-imino-3-methyl-1-phenyl-
1,2,6,8,9-pentaazacyclopenta[b]naphthalen-6-ylamine (14) upon treat-
ment with hydrazine hydrate at r.t.
Pursuing our interest in the chemistry of pyrazolopyridopyrimidine,
compound 14 was used as a useful intermediate for the preparation of
triazole and triazine systems fused to the pyrimidine ring, which was ex-
pected to possess notable chemical and pharmacological activities.23,24
Thus, the treatment of compound 14 with carbon disulfide afforded
hepaatazadicyclopenta[a, g]naphthalene-2-thione 15 (Scheme 3). The
reaction of compound 14 with carboxylic acids viz formic acid and ace-
tic acid yielded 1,3,4,6,7,8,9-heptaazadicyclopenta[a, g]naphthalenes
16a, b.
Furthermore, the treatment of compound 14 with ethyl cyanoac-
etate in refluxing absolute ethanol gave the expected acetonitrile
derivative 17, whose IR spectrum revealed a characteristic nitrile
absorption band at 2220 cm−1. Our interest in this study was
also focused on the suitability of compound 14 for the construc-
tion of polyfunctionally substituted phenanthrenes. Thus, the reac-
tion of compound 14 with oxalyl chloride in refluxing dry benzene
afforded the phenanthrene-2,3-dione derivative 18. In addition, the
reaction of equimolar amounts of 14 and chloroacetyl chloride in
dry dioxane yielded 12-(dibenzothiophen-2-yl)-2,9-dihydro- 11-methyl-
9-phenyl-1,4,5,7,8,9,10-heptaaza-cyclopenta[b]phenanthren-3-one (19)
(Scheme 3). Structures of the synthesized compounds were confirmed
from their physical and spectral data (cf Experimental Section).
ANTIMICROBIAL ACTIVITY
The antimicrobial activity of some synthesized derivatives was ex-
amined toward various pathogenic bacteria and fungi in vitro using
the hole plate and filter paper disc methods.25 The tested compounds
were dissolved in 10% acetone (v/v) at concentrations of 500, 250, and
125 µg/mL. The results are summarized in Table I.
In summary, the described method is experimentally simple and uses
easily available starting materials and reagents and thus provides a

2400
A. A. Aly
SCHEME 3

Pyrazolonaphthyridine, Pentaazanaphthalene
2401
TABLE I The Antimicrobial Activity of the Tested Compounds
Bacillus Rhodococcus Salmonella Escherichia Aspergillus Penicillium
subtilis equi typhimurium coli niger notatum
Compound
No.
A
MIC MIC MIC
A
MIC
A
MIC
A
A
A
MIC
2
3a
4b
5
6
7b
9
11
14
15
17
19
++ 500 ++
++ 500 ++
++ 250 ++
500
++
250
++ 250
+
125
+
+
500
250
500 + + + 500
++ 500 ++ 250
250
++
125
++ 500 ++ 250 ++ 500
+ + + 250 + + + 125 + + + 250 + + + 250 ++ 500 ++ 250
+ + + 125 + + + 250 + + + 250 + + + 250
+ + + 250 + + + 250 + + + 125 + + + 125 ++ 125
+ + + 125 + + + 125 + + + 250 + + + 125 250 ++ 500
+ + + 250 + + + 250 ++ 500 + + + 250 ++ 250 ++ 250
+ + + 125 + + + 125 + + + 125 ++ 500 125 125
+ + + 500 + + + 125 + + + 250 + + + 125 ++ 250 ++ 250
+ + + 125 + + + 250 + + + 125 + + + 125 500 250
+ + + 250 + + + 125 + + + 125 + + + 250 ++ 500 ++ 500
+
250 ++ 500
+
250
+
+
+
+
+
A = Antimicrobial activity of tested compounds.
MIC = Minimum inhibitory concentration; + >5 mm, slightly active; ++ >7 mm,
moderately active; + + + >9 mm, highly active.
convenient access to new tri- and tetracyclic heterocyclic systems of
biological interest.
EXPERIMENTAL
Melting points are uncorrected. IR spectra in KBr were recorded on a
1
Perkin-Elmer 298 spectrophotometer. H and 13C NMR spectra were
obtained on an Varian Gemini 200 MHz and 50 MHz instrument using
TMS as internal reference with chemical shifts expressed as δ ppm.
Mass spectra were recorded on a Shimadzu GCMS-QP 1000 EX instru-
ment (70 eV El mode). All reactions were monitored by TLC and carried
out on 0.2-mm silica gel 60 F254 (Merck) plates.
6-Amino-4-(dibenzothiophen-2-yl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carbonitrile (2)
A
mixture of 2,4-dihydro-5-methyl-2-phenylpyrazol-3-one (1)
(25 mmol), dibenzothiophene-2-carbaldehyde (25 mmol), malononitrile
(25 mmol), and ammonium acetate (60 mmol) was heated in an oil
bath at 180–190◦C for 12 h. After cooling, the solid formed was washed
with cold water, dried, and recrystallized from n-butanol to give 2.
Yield, 73%, m.p. 213–215◦C; IR: ν = 3390, 3260 (NH2), 2215 (C N),
1
1620–1610 cm−1 (C N); H NMR (CDCl3): δ = 2.13 (s, 3H, CH3), 5.85

2402
A. A. Aly
(br s, 2H, NH2), 7.18–8.23 (m, 12H, ArH); 13C NMR: δ = 14.1 (CH3),
111.4 (C-3a), 119.3 (C-5), 121.4 (CN), 129.2 (C-7a), 141.5 (C-3), 145.2
(C-6), 148.3 (C-4), 113.2, 114.4, 120.3, 121.4, 123.4, 125.2 (C of phenyl
group), 121.3, 124.5, 126.7, 128.2, 129.6, 130.5, 131.5, 133.6, 134.6,
136.7, 137.2, 138.1 (C of dibenzothiophene group); Anal. calcd. for
C26H17N5S (431.51): C, 72.37; H, 3.97; N, 16.23%. Found: C, 72.56; H,
4.13; N, 16.01%.
5-Amino-4-(dibenzothiophen-2-yl)-7,8-dihydro-3-methyl-7-
oxo-1-phenyl-1H-pyrazolo-[3,4-b][1,8]naphthyridine-6-
carbonitrile (3a) and Ethyl 5-Amino-4-(dibenzothiophen-2-yl)-
7,8-dihydro-3-methyl-7-oxo-1-phenyl-1H-pyrazolo-[3,4-b][1,8]
naphthyridine-6-carboxylate (3b)
A mixture of 2 (5 mmol), ethyl cyanoacetate or diethyl malonate
(5 mmol), ammonium acetate (15 mmol), and acetic acid (5 mL) was
heated with stirring at 190–200◦C for 3 h, left to cool, and triturated
with ethanol. The solid product that formed was collected by filtration
and recrystallized from a proper solvent to give 3a and 3b.
3a; Yield, 68% (benzene); m.p. 220–222◦C; IR: ν = 3340, 3290 (NH2),
3170 (NH), 2225 (C N), 1670 cm−1 (CO); 1H NMR (DMSO-d6): δ = 2.11
(s, 3H, CH3), 5.51 (br s, 2H, NH2), 7.15–8.23 (m, 13H, ArH and NH);
Anal. calcd. for C29H18N6OS (498.56): C, 69.86; H, 3.64; N, 16.86%.
Found: C, 69.51; H, 3.42; N, 16.98%.
3b; Yield, 65% (dioxane); m.p. 23–233◦C; IR: ν = 3350, 3280 (NH2),
3190 (NH), 1725, 1670 (2CO), 1610–1605 cm−1 (CN); 1H NMR (DMSO-
d6): δ = 1.35 (t, 3H, CH3), 2.15 (s, 3H, CH3), 4.11 (q, 2H, CH2), 5.62
(br s, 2H, NH2), 7.16–8.35 (m, 13H, ArH and NH); Anal. calcd. for
C31H23N5O3S (545.61): C, 68.24; H, 4.25; N, 12.84%. Found: C, 68.56;
H, 4.53; N, 12.51%.
5-Amino-4-(dibenzothiophen-2-yl)-3-methyl-1,7-diphenyl-1H-
pyrazolo[3,4-b][1,8]-naphthyridine-6-carbonitrile (4a) and
5-Amino-7-(4-chlorophenyl)-4-(dibenzo-thiophen-2-yl)-3-
methyl-1-phenyl-1H-pyrazolo[3,4-b][1,8]naphthyridine-6-
carbonitrile (4b)
A suspension of 2 (5 mmol) and arylidenemalononitrile (5 mmol) in
dioxane (30 mL) containing sodium metal (0.69 g) was heated under
reflux for 3 h. The reaction mixture was poured onto ice-cold water
and then neutralized by diluted HCl. The solid product formed was col-
lected by filtration and recrystallized from a suitable solvent to give 4a
and 4b.

Pyrazolonaphthyridine, Pentaazanaphthalene
2403
4a; Yield, 79% (ethanol); m.p. 196–198◦C; IR: ν = 3390, 3275 (NH2),
22215 cm−1 (C≡N); 1H NMR (CDCl3): δ = 2.11 (s, 3H, CH3), 5.89 (br s,
2H, NH2), 7.19–8.12 (m, 17H, ArH); 13C NMR: δ = 13.95 (CH3), 110.8
(C-3a), 116.7 (C-4a), 123.2 (CN), 130.1 (C-9a), 150.3 (C-4), 155.3 (C-3),
158.7 (C-8a), 163.2 (C-6), 165.3 (C-7), 114.6, 114.9, 124.3, 124.9, 125.3,
125.8 (C phenyl attached to pyrazole ring), 122.4, 125.3, 127.8, 129.1,
130.2, 130.9, 131.9, 132.7, 134.5, 135.8, 136.7, 138.5 (C of dibenzoth-
iophene), 124.3, 126.2, 126.3, 128.3, 128.5, 141.3 (C phenyl attached
to pyridine ring); Anal. calcd. for C35H22N6S (558.66): C, 75.25; H, 3.97;
N, 15.04%. Found: C, 75.53; H, 3.71; N, 15.27%.
4b; Yield, 75% (ethanol); m.p. 201–203◦C; IR: ν = 3380, 3285 (NH2),
2221 (C N), 1620–1610 cm−1 (C N); MS: m/z: 593 (M+); Anal. calcd.
for C35H21ClN6S (593.10): C, 70.88; H, 3.57; N, 14.17%. Found: C, 70.50;
H, 3.42; N, 14.36%.
[4-(Dibenzothiophen-2-yl)-7,8-dihydro-3-methyl-1-phenyl-7-
thioxo-1H-1,2,6,8,9-pentaazacyclopenta[b]naphthalen-5-
yl]thiourea (5)
To a solution of 2 (5 mmol) in acetic acid (20 mL), ammonium thio-
cyanate (15 mmol) was added, and the reaction mixture was refluxed
for 10 h. The solid product that formed after cooling and dilution with
water was filtered off and recrystallized from dioxane to give 5. Yield,
62%; m.p. 246–248◦C; IR: ν = 3390–3180 (multiple bands, NH2, NH),
1260–1250 cm−1 (2CS); MS: m/z: 549 (M+); Anal. calcd. for C28H19N7S3
(549.70): C, 61.18; H, 3.48; N, 17.84%. Found: C, 61.43; H, 3.62; N,
17.60%.
4-(Dibenzothiophen-2-yl)-1,8-dihydro-3-methyl-1-phenyl-
1,2,6,8,9-pentaazacyclo-penta[b]naphthalene-5,7-dithione (6)
To a solution of 2 (6 mmol) in DMF (25 mL), carbon disulfide (9 mmol),
and sodium methoxide (10 mL) (prepared from 0.56 g of sodium metal
in 20 mL of methanol) were added. The reaction mixture was refluxed
for 15 h, and then poured into ice-cold water. A solution of sodium hy-
droxide (10 mL, 1M) was added to it and left overnight. The solution
was filtered off and acidified with dilute acetic acid (10 mL) to give the
solid product, which was collected, washed with dilute acetic acid, dried,
and recrystallized from dioxane to give 6. Yield, 46%; m.p. 247–249◦C;
IR: ν = 3390–3325 (2NH), 1265–1255 cm−1 (2CS); 1H NMR (DMSO-d6):
δ = 2.15 (s, 3H, CH3), 7.12–8.11 (m, 12H, ArH), 8.51, 8.77 (2s, 2H, 2NH,
exchangeable); Anal. calcd. for C27H17N5S3 (507.66): C, 63.88; H, 3.38;
N, 13.80%. Found: C, 63.58; H, 3.14; N, 13.98%.

2404
A. A. Aly
4-(Dibenzothiophen-2-yl)-1,5,6,8-tetrahydro-5-imino-3-methyl-
1,6-diphenyl-1,2,6,8,9-pentaazacyclopenta[b]naphthalen-7-
one (7a) and 4-(Dibenzothiophen-2-yl)-1,5,6,8-tetrahydro-5-
imino-3-methyl-1,6-diphenyl-1,2,6,8,9-pentaazacyclo-
penta[b]naphthalene-7-thione (7b)
A mixture of 2 (5 mmol) and phenyl isocyanate (5 mmol) or phenyl
isothiocyanate (5 mmol) in pyridine (20 mL) was heated under reflux
for 5 h. The reaction mixture was cooled and poured onto ice-cold water
and neutralized with diluted HCl. The solid product so formed was
collected by filtration and recrystallized from a proper solvent to give
7a and 7b.
7a; Yield, 76% (ethanol); m.p. 251–253◦C; IR: ν = 3390, 3320 (2NH),
1
1670 cm−1 (CO); H NMR (CDCl3): δ = 2.18 (s, 3H, CH3), 6.99–8.11
(m, 17H, ArH), 8.34, 9.11 (2H, 2NH, exchangeable); Anal. calcd. for
C33H22N6OS (550.63): C, 71.98; H, 4.03; N, 15.26%. Found: C, 71.62; H,
3.85; N, 15.43%.
7b; Yield, 69% (benzene); m.p. 236–238◦C; IR: ν = 3380, 3230 (2NH),
1255 cm−1 (CS); MS: m/z: 566 (M+); Anal. calcd. for C33H22N6S2
(566.70): C, 69.94; H, 3.91; N, 14.83%. Found: C, 69.62; H, 3.65; N,
14.99%.
4-(Dibenzothiophen-2-yl)-1,6-dihydro-3-methyl-1-phenyl-
1,2,6,8,9-pentaazacyclo-penta[b]naphthalene-5-one (8)
A mixture of 2 (5 mmol) and formic acid (5 mL, 85%) was heated under
reflux for 6 h. The reaction mixture was cooled, and the solid formed
was collected by filtration, dried, and recrystallized from acetic acid to
give 8. Yield, 51%; m.p. 262–264◦C; IR: ν = 3375 (NH), 1675 cm−1 (CO);
1H NMR (CDCl3): δ = 2.13 (s, 3H, CH3), 7.11–8.23 (m, 14H, ArH, 1H
of pyrimidine and NH); Anal. calcd, for C27H17N5OS (459.52): C, 70.57;
H, 3.73; N, 15.24%. Found: C, 70.73; H, 3.85; N, 15.10%.
4-(Dibenzothiophen-2-yl)-3-methyl-1-phenyl-1H-1,2,6,8,9
pentaazacyclopenta[b]naphthalen-5-ylamine (9)
A mixture of 2 (5 mmol) and formamide (10 mL) was heated under
reflux for 10 h. The solid that separated on cooling was filtered off and
recrystallized from n-butanol to give 9. Yield, 73%; m.p. 302–304◦C; IR:
ν = 3405, 3350 (NH2), 1615–1605 cm−1 (CN); 1H NMR (CDCl3): δ = 2.12
(s, 3H, CH3), 5.91 (br s, 2H, NH2), 7.15–8.23 (m, 13H, ArH and 1H of
pyrimidine); Anal. calcd. for C27H18N6S (458.54): C, 70.72; H, 3.96; N,
18.33%. Found: C, 70.52; H, 3.63; N, 18.54%.

Pyrazolonaphthyridine, Pentaazanaphthalene
2405
General Procedure for Preparation of Compounds 10a–c
A mixture of compound 2 (4 mmol) and urea (8 mmol), thiourea
(8 mmol), or guanidine hydrochloride (8 mmol) was heated in an oil
bath at 180◦C for 30 min and then continued for another 2 h at 190◦C.
The molten product was boiled with water, cooled, filtered off, and re-
crystallized from a suitable solvent to give 10a–c.
5-Amino-4-(dibenzothiophen-2-yl)-1,8-dihydro-3-methyl-1-
phenyl-1,2,6,8,9-pentaaza-cyclopenta[b]naphthalen-7-
one (10a)
Yield, 52% (benzene); m.p. 243–245◦C; ν = 3410–3190 (NH2/NH),
1
1670 cm−1 (CO); H NMR (CDCl3): δ = 2.14 (s, 3H, CH3), 5.96 (br s,
2H, NH2), 6.99–8.24 (m, 13H, ArH and NH, exchangeable); Anal. calcd.
for C27H18N6OS (474.54): C, 68.34; H, 3.82; N, 17.71%. Found: C, 68.64;
H, 3.96; N, 17.51%.
5-Amino-4-(dibenzothiophen-2-yl)-1,8-dihydro-3-methyl-1-
phenyl-1,2,6,8,9-pentaaza-cyclopenta[b]naphthalene-7-
thione (10b)
Yield, 53% (dioxane); m.p. 271–273◦C; IR: ν = 3390–3200 (NH2/NH),
1245 cm−1 (CS); Anal. calcd. for C27H18N6S2 (490.60): C, 66.10; H, 3.70;
N, 17.13%. Found: C, 66.36; H, 3.95; N, 17.32%.
4-(Dibenzothiophen-2-yl)-7,8-dihydro-7-imino-3-methyl-1-
phenyl-1H-1,2,6,8,9-pentaazacyclopenta[b]naphthalen-5-
ylamine (10c)
Yield, 56% (DMF-H2O, 3:1); m.p. 256–258◦C; ν = 3420–3210 (NH2/NH),
1610–1600 cm−1 (CN); MS: m/z: 473 (M+); Anal. calcd. for C27H19N7S
(473.55): C, 68.48; H, 4.04; N, 20.70%. Found: C, 68.63; H, 4.25; N,
20.46%.
5-(Benzoxazol-2-yl)-4-(dibenzothiophen-2-yl)-3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]-pyridin-6-ylamine (11)
A mixture of 2 (5 mmol) and o-aminophenol (5 mmol) in absolute ethanol
(25 mL) containing a few drops of pyridine was refluxed for 15 h. The
solid product so obtained after cooling was collected by filtration and
recrystallized from ethanol to give 11. Yield, 73%; m.p. 236–238◦C; IR:
ν = 3410, 3270 (NH2), 1610–1600 cm−1 (CN); 1H NMR (CDCl3): δ = 2.11

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A. A. Aly
(s, 3H, CH3), 5.89 (br s, 2H, NH2), 7.13–8.31 (m, 16H, ArH); 13C NMR:
δ = 13.87 (CH3), 111.3 (C-3a), 120.1 (C-5), 131.8 (C-7a), 150.2 (C-4),
154.3 (C-3), 155.7 (C-6), 164.3 (C-2 of benzoxazole), 120.1, 120.3, 131.1,
131.3, 133.2, 140.3 (C- phenyl attached to pyrazole ring), 118.1, 121.3,
124.8, 126.1, 127.7, 129.3, 130.2, 131.6, 132.7, 134.8, 135.1, 137.2 (C-
dibenzothiophene group), 115.8, 128.4, 130.1, 134.2, 144.1, 153.8 (C of
benzoxazole); Anal. calcd. for C32H21N5OS (523.61): C, 73.40; H, 4.04;
N, 13.38%. Found: C, 73.15; H, 4.34; N, 13.10%.
Ethyl N-[5-cyano-4-(dibenzothiophen-2-yl)-3-methyl-1-phenyl-
1H-pyrazolo[3,4-b]-pyridin-6-yl]formimidate (12)
A mixture of 2 (20 mmol), triethyl orthoformate (10 mL), and acetic
anhydride was heated under reflux for 6 h, cooled, and poured onto
cold water. The formed solid product was collected by filtration and
dried to give 12. Yield, 63%; m.p. 236–238◦C; IR: ν = 2225 (C N), 1615–
1650 cm−1 (CN).
The General Procedure for Preparation the Compounds 13a, b
A mixture of 12 (5 mmol) and the appropriate amine (5 mmol) in abso-
lute ethanol (20 mL) was refluxed for 12 h. The reaction mixture was
poured onto ice-cold water and neutralized with diluted hydrochloric
acid (10 ml). The solid a product was filtered off, dried, and recrystal-
lized from a proper solvent to give 13a, b.
4-(Dibenzothiophen-2-yl)-1,6-dihydro-3,6-dimethyl-1-phenyl-
1,2,6,8,9-pentaaza-cyclopenta[b]naphthalen-5-
ylideneamine (13a)
Yield, 63% (benzene); m.p. 226–228◦C; IR: ν = 3210 (NH), 1610–
1600 cm−1 (CN); Anal. calcd. for C28H20N6S (472.56): C, 71.16; H, 4.27;
N, 17.78%. Found: C, 71.33; H, 4.52; N, 17.53%.
6-Benzyl-4-(dibenzothiophen-2-yl)-1,6-dihydro-3-methyl-1-
phenyl-1,2,6,8,9-pentaazacyclopenta[b]naphthalen-5-
ylideneamine (13b)
Yield, 56% (n-butanol); m.p. 201–203◦C; IR: ν = 3190 (NH), 1615–
1
1610 cm−1 (CN); H NMR (CDCl3): δ = 2.12 (s, 3H, CH3), 4.11 (s, 2H,
CH2), 7.10–8.23 (m, 18H, ArH and 1H of pyrimidine), 8.95 (s, 1H, NH,
exchangeable); Anal. calcd. for C34H24N6S (548.66): C, 74.43; H, 4.41;
N, 15.32%. Found: C, 74.12; H, 4.22; N, 15.60%.

Pyrazolonaphthyridine, Pentaazanaphthalene
2407
4-(Dibenzothiophen-2-yl)-1,5-dihydro-5-imino-3-methyl-1-
phenyl-1,2,6,8,9-pentaazacyclopenta[b]naphthalen-6-
ylamine (14)
To a well-stirred cold solution of compound 12 (20 mmol) in ethanol
(20 mL), hydrazine hydrate (3 mL) was added for 1 h, and then the
reaction mixture was stirred at r.t. for 7 h and left overnight. The solid
that precipitated was filtered off and recrystallized from ethanol to give
14. Yield, 74%; m.p. 252–254◦C; IR: ν = 3375–3210 (NH2/NH), 1610–
1600 cm−1 (CN); 1H NMR (CDCl3): δ = 2.13 (s, 3H, CH3), 5.90 (br s, 2H,
NH2), 7.12–8.13 (m, 13H, ArH and 1H of pyrimidine), 9.12 (s, 1H, NH,
exchangeable); Anal. calcd. for C27H19N7S (473.55): C, 68.48; H, 4.04;
N, 20.70%. Found: C, 68.63; H, 4.26; N, 20.48%.
11-(Dibenzothiophen-2-yl)-10-methyl-8-phenyl-8H-
1,3,4,6,7,8,9-heptaazadicyclo-penta[a,g]naphthalene-2-
thione (15)
To a solution of 14 (5 mmol) in absolute ethanol (25 mL), carbon disul-
fide (3 mL) was added. The reaction mixture was heated on a water
bath for 5 h. The solid formed was collected by filtration, dried, and
recrystallized from DMF-H2O (3:1) to give 15. Yield, 58%; m.p. 201–
203◦C; IR: ν = 3250 (NH), 1245 cm−1 (CS); 1H NMR (CDCl3): δ = 2.11
(s, 3H, CH3), 6.95–8.11 (13H, ArH, and 1H of pyrimidine), 8.96 (s, 1H,
NH, exchangeable); Anal. calcd. for C28H17N7S2 (515.61): C, 65.22; H,
3.32; N, 19.02%. Found: C, 65.10; H, 3.12; N, 19.25%.
The General Procedure for Preparation the Compounds 16a, b
A mixture of 14 (5 mmol) and an excess of the appropriate carboxylic
acids (12 mL) was refluxed for 8 h. The reaction mixture was cooled
and poured onto ice-cold water. The solid product formed was collected
by filtration, dried, and recrystallized from a suitable solvent to give
16a,b.
11-(Dibenzothiophen-2-yl)-10-methyl-8-phenyl-8H-
1,3,4,6,7,8,9-heptaazadicyclo-penta[a,g]naphthalene (16a)
Yield, 55% (dioxane); m.p. 195–197◦C; IR: ν = 1620–1610 cm−1 (CN);
1H NMR (CDCl3): δ = 2.12 (s, 3H, CH3), 7.12–8.11 (m, 14H, ArH, 1H of
pyrimidine and 1H of triazole); Anal. calcd. for C28H17N7S (483.55): C,
69.55; H, 3.54; N, 20.28%. Found: C, 69.30; H, 3.22; N, 20.45%.

2408
A. A. Aly
11-(Dibenzothiophen-2-yl)-2,10-dimethyl-8-phenyl-8H-
1,3,4,6,7,8,9-heptaazadicyclo-penta[a,g]naphthalene (16b)
Yield, 51% (dioxane); m.p. 212–214◦C; IR: ν = 1615–1605 cm−1 (CN);
MS: m/z: 497 (M+); Anal. calcd. for C29H19N7S (497.57): C, 70.00; H,
3.85; N, 19.71%. Found: C, 70.23; H, 3.96; N, 19.48%.
11-[(Dibenzothiophen-2-yl)-10-methyl-8-phenyl-8H-
1,3,4,6,7,8,9-heptaazadicyclo-penta[a,g]naphthalene-2-
yl]acetonitrile (17)
A mixture of 14 (5 mmol) and ethyl cyanoacetate (7 mmol) in absolute
ethanol (40 mL) was refluxed for 8 h. The solid formed after cooling
was filtered off and recrystallized from ethanol to give 17. Yield, 58%;
m.p. 231–233◦C; IR: ν = 2220 (C≡N), 1615–1605 cm−1 (C N); 1H NMR
(CDCl3): δ = 2.13 (s, 3H, CH3), 4.12 (s, 2H, CH2), 7.10–8.15 (m, 13H,
ArH and 1H of pyrimidine); Anal. calcd. for C30H18N8S (522.58): C,
68.95; H, 3.47; N, 21.44%. Found: C, 68.70; H, 3.22; N, 21.65%.
12-(Dibenzothiophen-2-yl)-11-methyl-9-phenyl-9H-
1,4,5,7,8,9,10-heptaazacyclo-penta[b]phenanthrene-2,3-
dione (18)
To a solution of 14 (5 mmol) in dry benzene (25 mL), oxalyl chloride
(4 mL) was added, and the reaction mixture was refluxed for 10 h.
After cooling, the solid product was collected by filtration, dried, and
recrystallized from n-butanol to give 18. Yield, 61%; m.p. 191–193◦C;
IR: ν = 3220 (NH), 1675–1670 cm−1 (2CO); 1H NMR (CDCl3): δ = 2.11
(s, 3H, CH3), 7.12–8.20 (m, 14H, ArH, 1H of pyrimidine and NH); Anal.
calcd. for C29H17N7O2S (527.56): C, 66.02; H, 3.25; N, 18.59%. Found:
C, 66.23; H, 3.42; N, 18.31%.
12-(Dibenzothiophen-2-yl)-2,9-dihydro-11-methyl-9-phenyl-
1,4,5,7,8,9,10-heptaaza-cyclopenta[b]phenanthren-3-one (19)
A mixture of 14 (5 mmol) and chloroacetyl chloride (5 mmol) in dry
dioxane (30 mL) was allowed to stand at r.t. overnight. The formed
precipitate was filtered off and recrystallized from dioxane to give 19.
Yield, 56%; m.p. 213–215◦C; IR: ν = 3210 (NH), 1670 cm−1 (CO); MS:
m/z: 513 (M+); Anal. calcd. for C29H19N7OS (513.57): C, 67.82; H, 3.73;
N, 19.09%. Found: C, 67.51; H, 3.52; N, 19.28%.

Pyrazolonaphthyridine, Pentaazanaphthalene
2409
REFERENCES
[1] A. Gangjee, O. O. Adair, and S. F. Queener, J. Med. Chem., 46, 5074 (2003).
[2] R. J. Perner, Y. Gu, C. Lee, E. K. Bayburt, J. Mckie, K. M. Alexander, K. L. Kohlhaas,
C. T. Wismer, J. Mikusa, M. F. Jarvis, E. A. Kowaluk, and S. S. Bhagwat, J. Med.
Chem., 46, 5249 (2003).
[3] A. Rosowsky, H. Chen, H. Fu, and S. F. Queener, Bioorg. & Med. Chem., 11, 59
(2003).
[4] A. P. Dishington, P. D. Johnson, and J. G. Kettle, Tetrahedron Lett., 45, 3733 (2004).
[5] J. Girardet, E. Gunic, C. Esler, D. Cieslak, Z. Pietrzkowski, and G. Wang, J. Med.
Chem., 43, 3704 (2000).
[6] S. A. El-Assiery, G. H. Sayed, and A. Fouda, Acta Pharm., 54, 143 (2004).
[7] M. N. Nasr and M. M. Gineinah, Arch. Pharm., 335, 289 (2002).
[8] N. Kumar, G. Singh, and A. K. Yadav, Heteroat. Chem., 12, 52 (2001).
[9] C. Mustazza, M. R. D. Guidice, A. Borioni, and F. Gatta, J. Heterocycl. Chem., 38,
1119 (2001).
[10] C. P. Tseng, U.S. Pat. 4838925 (1989); Chem. Abst., 112, 7508 (1990).
[11] B. Zacharie, T. P. Connolly, R. Rej, G. Attardo, and C. L. Penney, Tetrahedron, 52,
2271 (1996).
[12] A. Gomtsyan, S. Didomenico, C. Lee, A. O. Stewart, S. S. Bhagwat, E. A. Kowalulk,
and M. F. Jarvis, Bioorg. & Med. Chem. Lett., 14, 4165 (2004).
[13] M. A. Berghot and E. B. Moawad, Eur. J. Pharm. Sci., 20, 173 (2003).
[14] C. R. Cardoso, F. C. De Brito, K. C. Dasilva, A. L. De Miranda, and C. A. Fraga,
Bioorg. Med. Chem. Lett., 12, 9 (2002).
[15] Y. A. Issac and A. A. Aly, Z. Naturforsch, 58b, 1227 (2003).
[16] A. A. Aly and S. A. Nassar, Heteroat. Chem., 15, 2 (2004).
[17] A. A. Aly and A. A. F. Wasfy, Ind. J. of Chem., 43B, 629 (2004).
[18] M. T. Cocco, C. Congiu, A. Maccioni, and V. Onnis, J. Heterocycl., 30, 253 (1993).
[19] A. Z. A. Hassanien, I. S. Abdel Hafiz, and M. H. Elnagdi, J. Chem. Research (S), 8
(1999).
[20] F. Al-Omran, M. M. Abdel Khalik, H. Al-Awadhi, and M. H. Elnagdi, Tetrahedron,
52, 11915 (1996).
[21] M. A. Sofan, F. N. A. El-Taweel, T. M. Abu El-Maati, and A. A. El-Agamey, Pharmazie,
49, 482 (1994).
[22] J. Contreras, Y. Rival, S. Chayer, J. Bourguignon, and C. Wermuth, J. Med. Chem.,
42, 730 (1999).
[23] A. Krutosikova, S. Mastik, M. Dandarova, and A. Lycka, Collect. Czech. Chem. Com-
mun., 62, 1612 (1997).
[24] M. Benckova, A. Krutosikova, and M. Dandarova, Chem. Papers, 51, 398 (1997).
[25] C. Leiferet, S. Chidbouree, S. Hampson, S. Workman, D. Sigee, H. A. Epton, and
A. Harbour, J. Appl. Bacteriol, 78, 97 (1995).