Synthesis of S-triazolo[3,4-a]phthalazine and related polynuclear heterocyclic systems

Article abstract of DOI:10.1080/104265090902769

The applicability and synthetic potency of the novel reagent 1-hydrazinophthalazine 1 to develop an expeditious convenient synthetic route via the annelation reactions with appropriate reagents for polyfunctionally substituted triazoles, pyrazoles, tetrazoles, and polycyclic condensed systems are reported. Chemical and spectroscopic study for the structures of the newly synthesized compounds are investigated. The prepared compounds were tested in vitro for their antimicrobial activity. Copyright Taylor & Francis Inc.

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Synthesis of S-triazolo[3,
4a] phthalazine and Related
Polynuclear Heterocyclic
Systems
A. A. Aly a & I. A. Gad El-Karim a
a Chemistry Department , Benha University , Benha,
Egypt
Published online: 19 Aug 2006.
To cite this article: A. A. Aly & I. A. Gad El-Karim (2005) Synthesis of S-triazolo[3, 4a]
phthalazine and Related Polynuclear Heterocyclic Systems, Phosphorus, Sulfur, and
Silicon and the Related Elements, 180:9, 1997-2011, DOI: 10.1080/104265090902769
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Phosphorus, Sulfur, and Silicon, 180:1997–2011, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090902769
Synthesis of S-triazolo[3,4-a]phthalazine and Related
Polynuclear Heterocyclic Systems
A. A. Aly
I. A. Gad El-Karim
Chemistry Department, Benha University, Benha, Egypt
The applicability and synthetic potency of the novel reagent 1-hydrazinophthalazine
1 to develop an expeditious convenient synthetic route via the annelation reac-
tions with appropriate reagents for polyfunctionally substituted triazoles, pyrazoles,
tetrazoles, and polycyclic condensed systems are reported. Chemical and spectro-
scopic study for the structures of the newly synthesized compounds are investigated.
The prepared compounds were tested in vitro for their antimicrobial activity.
Keywords 1-Hydrazinophthalazine; annelation reactions; s-triazolo[3,4-a]phthalazine;
tricyclic heterocycles
INTRODUCTION
The discovery of the pronounced antitumor, bactericidal, and other bio-
logical activities1−5 of phthalazine derivatives has stimulated consider-
able research in this field. Phenoxathiin derivatives also demonstrate
a great importance due to their significant potential bioresponses.6,7
In view of the aforementioned facts, we continue our medicinal chem-
istry program8,9 directed towards the development of novel heterocyclic
systems. Here we report a facile and convenient access to 1-hydrazino-
4-phenoxathiin-2-yl-phthalazine (1) required in our laboratory as a syn-
thon for the construction of polycyclic condensed systems for biological
evaluation.
RESULTS AND DISCUSSION
The key precursor 1-hydrazino-4-phenoxathiin-2-yl-phthalazine (1)
was prepared in high yield upon refluxing equimolar amounts of
Received May 21, 2004; accepted September 16, 2004.
All strains were kindly supplied from the Botany Department, Faculty of Science,
Benha University, Benha, Egypt.
Address correspondence to A. A. Aly, Benha University, Chemistry Department, Fac-
ulty of Science, Benha, Egypt. E-mail: alymaboud@hotmail.com
1997

1998
A. A. Aly and I. A. G. El-Karim
1-chloro-4-phenoxathiin-2-yl-phthalazine10 and hydrazine hydrate in
ethanol.
The structure of the reaction product 1 was assigned on the ba-
sis of elemental analysis and compatible spectroscopic data. Thus, its
mass spectrum revealed a molecular ion peak at m/z (%) = 358 (20.1)
corresponding to the molecular formula C20H14N4OS. The IR spec-
trum showed absorption peaks at 3395–3150 (νNHNH2) and 1621 cm−1
(νC N). The 1H NMR spectrum (DMSO-d6) showed a broad signal (2H)
at δ 6.24 ppm assigned for the NH2 protons, a multiplet signal (11H) at
(6.98–7.41 ppm) assigned for the aromatic protons, and a broad signal
at 9.25 ppm assigned for NH, which disappeared upon addition on of
D2O to the NMR sample.
Reaction of 1 with aliphatic acids (viz formic acid and acetic acid)
afforded 6-phenoxathiin-2-yl-[1,2,4]triazolo[3,4-a]phthalazine (2a) and
3-methyl-6-phenoxathiin-2-yl-[1,2,4]triazolo[3,4-a]-phthalazine (2b),
respectively, in a comparable cyclization mechanism as recorded
before11,12 (Scheme 1), but in low yield. Since orthoesters are the
reagents of choice in the preparation of fused s-triazoles, the compound
1 reacts with orthoesters (viz triethyl orthoformate and triethyl
orthoacetate) to reproduce 2a and b, albeit in a better yield.
An alternative route to obtain (2b) as well as the phenyl deriva-
tive 4 involved the reaction of compound 1 with an equivalent amount
of acid, chloride (viz acetyl chloride and benzoyl chloride) in dry
pyridine at 0◦C. This reaction furnished the phthalazine derivatives
3a and 3b, which were cyclized by action of phosphorous oxychlo-
ride to afford 2b and 4, respectively. Compound 4 also was obtained
via the direct fusion of benzoic acid with compound 1 at 200◦C
for 5 h. The reactants converted smoothly into the desired prod-
uct; a slight decomposition was encountered but no hydrazide in-
termediate was isolated. This one-step procedure provided a higher
yield (87%) of 4 than that obtained via the two steps procedure
(51%, Scheme 1). Fusion of compound 1 with urea gave 6-phenoxa-
thiin-2-yl-2H-[1,2,4]triazolo[3,4-a]-phthalazin-3-one (5a) in good yield
(81%).
Spectral data of compound 5a indicated that it exists predominantly
in the keto-form (νCO at 1670 cm−1) and revealed only minor OH
stretching absorption (νOH at 3400 cm−1). 6-phenoxathiin-2-yl-2H-
[1,2,4]triazolo[3,4-a]phthalazin-3-thione (5b) was obtained via treat-
ment of compound 1 with carbon disulfide. To reach the optimum con-
ditions for the reaction, it was conducted under two different conditions.
Thus, the refluxing of 1 with carbon disulfide in alcoholic potassium hy-
droxide was found to proceed much faster than performing the reflux in
chloroform.13,14 The readiness by which the former reaction proceeded

Synthesis of Heterocyclic Systems
1999
SCHEME 1 Reagents: i, RCOOH; ii, RC(COOEt)3; iii, PhCOOH; iv, RCOCl;
v, POCl3, vi, H2NCONH2; vii, CS2; and viii, CH3I.
was attributed to feasible aggregation under these conditions. The thiol
derivative 5b, on treatment with methyl iodide in aqueous base, was
converted to 3-methylsulfanyl-6-phenoxathiin-2-yl-[1,2,4]-triazolo[3,4-
a]-phthalazine (6).

2000
A. A. Aly and I. A. G. El-Karim
In view of the known antifungal and antiviral characteristics15,16 in-
herent in substituted thiosemicarbazide derivatives, the synthesis of
new compounds incorporating such a group was enhanced. Thus, the
condensation of 1 with benzyl isothiocyanate in boiling ethanol afforded
the corresponding thiosemicarbazide derivative 7. The cyclodesulfur-
ization of 7 with HgO in boiling dioxane gave benzyl-(6-phenoxathiin-
2-yl-[1,2,4]-triazolo[3,4-a]phthalazin-3-yl)amine (8), while its cycliza-
tion with phenacyl bromide afforded thiazolylphthalazine derivative 9
(Scheme 2).
SCHEME 2 Reagents: ix, PhCH2NCS; x, HgO; and xi, PhCOCH2Br.
For this study, our interest also was directed towards the synthe-
sis of pyrazolylphthalazine derivatives as possible potential antihy-
pertensive agents.17 Thus, compound 1 was subjected to react with
active methylene compounds (viz ethyl acetoacetate, ethyl cyanoac-
etate and diethyl malonate) to afford the pyrazolyl-phthalazine deriva-
tives 10–12, respectively. Also, condensation of 1 with acrylonitrile
in boiling pyridine gave the propionitrile derivative 13, which un-
derwent acid hydrolysis to give pyrazolylphthalazine derivative 14
(Scheme 3).
The scope of this investigation was further extended towards the
synthesis of tetrazolophthalazine and phenanthrene derivatives. Thus,
thermal cyclization18 of 15 (150◦C) obtained by diazotization of 1 af-
forded tetrazolophthalazine derivative 16.
On the other hand, a tetraazaphenantherene derivative was ob-
tained via the reaction of 1 with ethyl chloroacetate and/or chloroacetyl
chloride. Although two isomeric products 9-phenoxathiin-2-yl-3H-3,4,

Synthesis of Heterocyclic Systems
2001
SCHEME 3 Reagents: xii, CH3COCH2COOEt; xiii, CNCH2COOEt; xiv,
CH2(COOEt)2; xv, CH2 CHCN; and xvi, NaOH.

2002
A. A. Aly and I. A. G. El-Karim
10,10a-tetraazaphenanthren-2-one (17a) and 9-phenoxathiin-2-yl-3H-
3,4,10,10a-tetraazaphenanthren-1-one (17b) were expected, only one
product was isolated and successfully identified by spectral data as
(17a). Further tetraazaphenanthrene derivatives were obtained by
the reaction of 1 with bromomalonitrile in the presence of potassium
carbonate, and by refluxing of compound 1 with α-haloketones (viz
chloroacetone and phenacyl bromide in dry xylene). In both reactions
more than one cyclization product was anticipated. However, the former
reaction afforded a tetraazaphenanthrene derivative (18a) rather than
a mixture of (18a and b), while the latter furnished 1-methyl- and 1-
phenyl-9-phenoxathiin-2-yl-3H-3,4,10,10a-tetraazaphenanthrene (19a
and b) rather than a mixture of (19a and b) and (20a and b; Scheme 4).
The structures of all of the synthesized compounds were confirmed by
spectroscopic methods and elemental analysis data (see the experimen-
tal section).
ANTIMICROBIAL ACTIVITY
The antimicrobial activity of some synthesized compounds was deter-
mined in vitro using the hole plate and filter paper method.19 All com-
pounds were tested for activity against gram positive and gram neg-
ative bacteria and selected fungi. A qualitative screen was performed
on all compounds while quantitative assays were done only on active
compounds. The results are listed in Table I.
In conclusion, the readily available 1-hydrazinophthalazine pro-
vides an easy and convenient route to various inaccessible phthalazine
derivatives of biological interest.
EXPERIMENTAL
Melting points were taken in open capillary tubes and were uncorrected.
IR spectra in KBr are recorded on a Shimadzu 470 spectrophotometer.
1H NMR spectra in DMSO-d6 were recorded on Varian Gemini and
200 MHz (chemical shifts are expressed as δ, ppm) and the mass spectra
were obtained on a Shimadzu GCMS QP 1000 Ex-mass spectrometer
(70 eV EI mode).
1-Hydrazino-4-phenoxathiin-2-yl-phthalazine (1)
A mixture of 1-chloro-4-phenoxathiin-2-ylphthalazine10 (20 mmol) and
hydrazine hydrate (20 mmol) in (30 mL) ethanol was refluxed for
6 h. The reaction mixture was cooled, filtered, and recrystallized from
ethanol to give 1. Yield, 72%; mp 252–4◦C. IR: ν = 3395–3150 (NHNH2),

Synthesis of Heterocyclic Systems
2003
SCHEME 4 Reagents: xvii, NaNO2/H2O; xviii, DMF; xix, ClCH2COOEt; xx,
ClCH2COCl; xxi, BrCH(CN)2; xxii, ClCH2COCH3; and xxiii, PhCOCH2Br.
1621 cm−1 (C N); 1H NMR: δ = 6.24 (br s, 2H, NH2), 6.98–7.41 (m, 11H,
ArH), 9.25 (br s, 1H, NH, exchangeable with D2O); MS: m/z: 358 (M+);
Anal. Calcd. for C20H14N4OS: C, 67.02; H, 3.94; N, 15.63%; Found: C,
67.15; H, 3.81; N, 15.75%.

2004
A. A. Aly and I. A. G. El-Karim
TABLE I Activity (A) and Minimum Inhibitory Concentration (MIC)
Calculated as µg/mL for Compounds 3–19
Penicillium
Bacillus Subtilis
Bacillus Cereus
Escherichia Coli
Chrysogenium
Compound
A
MIC
A
MIC
A
MIC
A
MIC
3b
5b
8
11
14
17
18
19b
++
++
++
++
++
−
500
250
500
250
500
−
+
++
+
250
500
250
500
250
250
250
250
+
+
250
250
250
250
250
250
500
125
−
+
+
−
+
−
+
−
—
500
250
—
250
—
++
+
+
++
++
+
+
++
+
++
+
500
500
250
—
+
+
Antimicrobial activity (A): + + +, highly active; ++, moderately active; +, slightly
active, and inactive.
Preparation of Triazolophthalazine Derivatives 2a,b
Method A
A mixture of 1-hydrazinophthalazine 1 (10 mmol) and aliphatic acids
(21 mmol), namely formic acid, and/or acetic acid, was heated under re-
flux for 7 h. The excess acid was removed under reduced pressure on a
steam bath and the residual viscous oil was basified with a 30% NaOH
solution. The alkaline solution was extracted with CHCl3 (3 50-mL por-
tions) and the combined extracts were dried (Na2SO4). After removal
of chloroform, the solid product was crystallized from a suitable solvent
to afford 2a,b. Yield for 2a, 59%; 2b, 62%.
Method B
A mixture of 1-hydrazinophthalazine 1 (15 mmol) and orthoesters
(31 mmol), namely triethyl orthoformate and/or triethyl orthoacetate,
was refluxed for 4 h. The excess ortho ester and alcohol were removed
on a steam bath under reduced pressure. The crude product was crys-
tallized to give a product, which was identified by its mp and mmp
determination as 2a,b. Yield for 2a, 79%; 2b, 80%.
Independent Synthesis of 2b
Phosphorous oxychloride (15 mL) was added slowly to 3a (15 mmol), and
the mixture was refluxed for 6 h. After removal of the excess of phospho-
rous oxychloride under reduced pressure, the residue was cautiously
made alkaline with a cold sodium hydroxide solution. This solution

Synthesis of Heterocyclic Systems
2005
was extracted with chloroform (3 40-mL portions), and the combined
extracts were dried (Na2SO4). After removal of chloroform, the residue
crystallized to give a solid product, which was identified as 2b by mp
and mmp determination. Yield, 51%.
6-Phenoxathiin-2-yl-[1,2,4]triazolo[3,4-a]phthalazine (2a)
Mp, 273–5◦C (benzene), IR: ν = 3050 (Ar H), 1610 cm−1 (C N); MS
m/z: 368 (M+), Anal. Calcd. for C21H12N4OS: C, 68.46; H, 3.28; N,
15.21%; Found: C, 68.59; H, 3.16; N, 15.37%.
3-Methyl-6-phenoxathiin-2-yl-[1,2,4]triazolo[3,4-a]phthalazine
(2b)
Mp, 296–8◦C (benzene), IR: ν = 3060 (Ar H), 1618 cm−1 (C N);
1H NMR: δ = 3.19 (s, 3H, CH3), 7.11–8.25 (m, 11H, ArH); Anal. Calcd.
for C22H14N4OS: C, 69.09; H, 3.69; N, 14.65%; Found: C, 69.20; H, 3.55;
N, 14.79%.
2-Acetyl- and 2-benzoyl-1-[4-(phenoxathiin-2-yl)phthalazin-
1-yl]-hydrazine (3a,b)
Hydrazinophthalazine 1 (20 mmol) in dry pyridine (25 mL), the acid
chlorides (20 mmol), namely, and acetyl chloride and/or benzoyl chlo-
ride were added dropwise. The reaction mixture was stirred at room
temperature for 45 min and then heated for 2 h on a steam bath. The
reaction mixture was poured on crushed ice (40 g). The solid products
were crystallized from an appropriate solvent to give 3a,b.
3a, Yield, 80%; mp 276–8◦C (ethanol); IR: ν = 3360–3190 (NH), 1675
(CO), 1615 cm−1 (C N); 1H NMR: δ = 2.31 (s, 3H, CH3), 7.13–8.11 (m,
11H, ArH); 9.51–10.43 (br s, 2H, 2NH, exchangeable); Anal. Calcd. for
C22H16N4O2S: C, 65.98; H, 4.03; N, 13.99%; Found: C, 65.83; H, 4.19; N,
13.82%.
3b, Yield, 86%; mp 266–8◦C (ethanol); IR: ν = 3340–3180 (NH), 1670
(CO), 1618 cm−1 (C N); Anal. Calcd. for C27H18N4O2S: C, 70.11; H, 3.92;
N, 12.11%; Found: C, 70.25; H, 3.80; N, 12.27%.
6-Phenoxathiin-2-yl-3-phenyl-[1,2,4]triazolo[3,4-a]
phthalazine (4)
Method A
A mixture of 3b (10 mmol) and phosphorous oxychloride (15 mL) in
toluene (30 mL) was heated under reflux for 6 h. The excess solvent was

2006
A. A. Aly and I. A. G. El-Karim
removed under reduced pressure and the residue was basified carefully
with ice and a 30% NaOH solution. The solid product was crystallized
from ethanol to give 4. Yield, 51%, mp 303–5◦C, IR: ν = 3100 (Ar H),
1610 cm−1 (C N); 1H NMR: δ = 7.14–8.26 (m, 16H, ArH); Anal. Calcd.
for C27H16N4OS: C, 72.95; H, 3.63; N, 12.60%; Found: C, 72.81; H, 3.75;
N, 12.79%.
Method B
A mixture of 1 (10 mmol) and benzoic acid (10 mmol) was heated at
200◦C for 5 h. After cooling to room temperature, the reaction mixture
was dissolved in aqueous ethanol and the solution was made alkaline
with a dilute sodium hydroxide solution. The solid product was crystal-
lized and was identified as 4 by its mp and mmp determination. Yield,
87%.
6-Phenoxathiin-2-yl-2H-[1,2,4]triazolo[3,4-a]phthalazin-
3-one (5a)
A mixture of 1 (10 mmol) and urea (13 mmol) was heated at 180–
190◦C for 6 h. The reaction mixture was cooled and added to a so-
lution of sodium hydroxide (5%, 20 mL), filtered, and the filterate
was acidified with dil. HCl. The solid product was crystallized from
ethanol to give 5a. Yield, 81%; mp 290–2◦C, IR: ν = 3400 (OH), 3260
(NH), 1670 (CO), 1619 cm−1 (C N); MS m/z: 384 (M+); Anal. Calcd. for
C21H12N4O2S: C, 65.61; H, 3.15; N, 14.57%; Found: C, 65.50; H, 3.27; N,
14.69%.
6-Phenoxathiin-2-yl-2H-[1,2,4]triazolo[3,4-a]phthalazin-3-
thione (5b)
Method A
To a suspension solution of 1 (15 mmol) in ethanol (30 mL), carbon
disulfide (30 mmol) and potassium hydroxide (50 mmol) were added
and the reaction mixture was refluxed for 4 h, then filtered while hot.
The filterate was acidified with hydrochloric acid and the precipitate
was crystallized from ethanol to give 5b. Yield, 81%; mp 312–4◦C; IR:
ν = 3205 (NH), 1615 (C N), 1240 cm−1 (CS); MS m/z: 400 (M+); Anal.
Calcd. for C21H12N4OS2: C, 62.98; H, 3.02; N, 13.99%; Found: C, 62.83;
H, 3.17; N, 13.81%.
Method B
A mixture of 1 (10 mmol), chloroform (50 mL) and carbon disulfide
(4 mL) were heated under reflux until the evolution of hydrogen sulfide

Synthesis of Heterocyclic Systems
2007
ceased (30 h). Upon cooling, the product, which separated from the
reaction mixture, was crystallized and identified as 5b by mp and mmp
determination. Yield, 95%.
3-Methylsulfanyl-6-phenoxathiin-2-yl-[1,2,4]triazolo[3,4-a]-
phthalazine (6)
A solution of thiol 5b (10 mmol) in sodium hydroxide (20 mL, 1.5 N
solution) and methyl iodide (30 mmol) was stirred at room temperature
for 1 h. The reaction mixture was extracted with chloroform, dried over
Na2SO4, and evapourated to give a solid product which crystallized
from dioxane to give 6. Yield, 78%; mp 230–2◦C; IR: ν = 3090 (Ar H),
1
2950 (alkyl-H), 1618 cm−1 (C N); H NMR: δ = 2.85 (s, 3H, SCH3),
7.09–8.11 (m, 11H, ArH); Anal. Calcd. for C22H14N4OS2: C, 63.75; H,
3.40; N, 13.52%; Found: C, 63.86; H, 3.29; N, 13.39%.
4-Benzyl-1-[(4-phenoxathiin-2-yl)phthalazin-
1-yl]thiosemicarbazide (7)
To a solution of 1 (20 mmol) in ethanol (30 mL), benzyl isothiocyanate
(20 mmol) was added. The reaction mixture was left to stand at room
temperature for 1 h, whereupon a yellow crystalline product precipi-
tated. The reaction mixture was left overnight, filtered, and crystallized
from ethanol to give 7. Yield, 78%; mp 211–3◦C; IR: ν = 3320–3215
1
(NH), 1620 (C N), 1250 cm−1 (CS); H NMR: δ = 4.10 (s, 2H, CH2),
7.03–8.11 (m, 16H, ArH), 9.12, 10.22, 10.75 (3s, 3H, 3NH, exchange-
able); Anal. Calcd. for C28H21N5OS2: C, 66.25; H, 4.17; N, 13.80%;
Found: C, 66.10; H, 4.29; N, 13.68%.
Benzyl-(6-phenoxathiin-2-yl-[1,2,4]triazolo[3,4-a]phthalazin-
3-yl)-amine (8)
To a solution of 7 (10 mmol) in dry dioxane (25 mL), freshly prepared
yellow HgO (10 mmol) was added and the reaction mixture was heated
under reflux for 8 h, and then filtered while hot. The filtrate was evap-
orated under reduced pressure and the obtained product was crystal-
lized from benzene-petroleum ether (60–80◦C) to give 8. Yield, 73%;
1
mp 197–9◦C; IR: ν = 3240 (NH), 1620 cm−1 (C N); H NMR: δ = 4.25
(s, 2H, CH2), 7.06–8.13 (m, 16H, ArH), 10.11 (s, 1H, NH, exchangeable);
Anal. Calcd. for C28H19N5OS: C, 71.02; H, 4.04; N, 14.79%; Found: C,
71.16; H, 4.17; N, 14.63%.

2008
A. A. Aly and I. A. G. El-Karim
N-(3-benzyl-4-phenyl-3H-thiazol-2-ylidene)-Nꢀ-
(4-phenoxathiin-2-ylphthalazin-1-yl)hydrazine (9)
A suspension solution of 7 (10 mmol) and phenacyl bromide (13 mmol)
in absolute ethanol (25 mL) was heated under reflux for 3 h, then
(13 mmol) of anhydrous sodium acetate was added. The reaction mix-
ture was heated for an additional 1 h, then cooled and poured into
ice-cold water. The solid product was crystallized from ethanol to afford
9. Yield, 81%; mp 186–8◦C; IR: ν = 3260 (NH), 1621–1610 cm−1 (C N);
MS, m/z: 607 (M+); Anal. Calcd. for C36H25N5OS2: C, 71.15; H, 4.15; N,
11.52%; Found: C, 71.28; H, 4.33; N, 11.40%.
Preparation of Pyrazolylphthalazine Derivatives 10–12
A solution of 1 (10 mmol) and active methylene compounds,
namely ethyl acetoacetate, ethyl cyanoacetate, and/or diethylmalonate
(12 mmol), in ethanol (25 mL) containing catalytic amount of piperidine
(1 mL) was refluxed for 4 h. The solid compound obtained after cooling
was crystallized from a suitable solvent to give the compounds 10–12.
5-Methyl-2-(4-phenoxathiin-2-ylphthalazin-1-yl)-
2,4-dihydro-pyrazol-3-one (10)
Yield, 71%; mp 270–2◦C (benzene); IR: ν = 1675 (CO), 1612 cm−1 (C N);
1H NMR: δ = 2.61 (s, 3H, CH3), 3.83 (s, 2H, CH2), 6.98–7.89 (m, 11H,
ArH); Anal. Calcd. for C24H16N4O2S: C, 67.91; H, 3.80; N, 13.20%;
Found: C, 67.80; H, 3.94; N, 13.33%.
5-Amino-2-(4-phenoxathiin-2-yl-phthalazin-1-yl)-
2,4-dihydro-pyrazol-3-one (11)
Yield, 68%; mp 223–5◦C (ethanol); IR: ν = 3300–3220 (NH), 1670 (CO),
1615 cm−1 (C N); MS m/z: 425 (M+); Anal. Calcd. for C23H15N5O2S: C,
64.93; H, 3.55; N, 16.46%; Found: C, 64.80; H, 3.68; N, 16.32%.
1-(4-Phenoxathiin-2-yl-phthalazin-1-yl)pyrazolidine-3,5-
dione (12)
Yield, 71%; mp 236–8◦C (ethanol); IR: ν = 3320 (NH), 1675–1665 (2CO),
1
1618 cm−1 (CN); H NMR: δ = 3.79 (s, 2H, CH2), 6.97–7.89 (m, 11H,
ArH), 9.87 (s, 1H, NH, exchangeable); Anal. Calcd. for C23H14N4O3S:
C, 64.78; H, 3.31; N, 13.14%; Found: C, 64.62; H, 3.46; N, 13.25%.

Synthesis of Heterocyclic Systems
2009
3-[Nꢀ-(4-Phenoxathiin-2-yl-phthalazin-1-yl)-
hydrazino]propionitrile (13)
A solution of 1 (10 mmol) and acrylonitrile (10 mmol) was refluxed
in pyridine (25 mL) for 4 h. After cooling, the reaction mixture was
poured onto ice and HCl and the solid formed was crystallized from
benzene to give 13. Yield, 65%; mp 281–3◦C; IR: ν = 3300–3200 (NH),
2230 (C N), 1616 cm−1 (C N); MS m/z: 411 (M+); Anal. Calcd. for
C23H17N5OS: C, 67.13; H, 4.16; N, 17.02%; Found: C, 67.25; H, 4.28; N,
17.15%.
1-(4-Phenoxathiin-2-yl-phthalazin-1-yl)-2,3-dihydro-
1H-pyrazol-5-ylamine (14)
A solution of 13 (10 mmol) in ethanol (25 mL) and sodium hydroxide
(15 mL, 20%) was refluxed for 8 h. The reaction mixture was cooled
to room temperature and acidified with hydrochloric acid to give a
solid product which was crystallized to give 14. Yield, 51%; mp 207–
9◦C (benzene); IR: ν = 3380–3150 (NH and NH2), 3080 (Ar H), 1612
cm−1 (C N); 1H NMR: δ = 4.10 (s, 2H, CH2), 4.55 (s, 1H, methine pro-
ton), 6.23 (br s, 2H, NH2), 7.01–8.03 (m, 11H, ArH), 9.92 (s, 1H, NH, ex-
changeable); Anal. Calcd. for C23H17N5OS: C, 67.13; H, 4.16; N, 17.02%;
Found: C, 67.27; H, 4.05; N, 17.18%.
1-Azido-4-phenoxathiin-2-yl-phthalazine (15)
To a well-stirred mixture of 1 (5 mmol) and sodium nitrite (15 mmol) in
H2O (15 mL), conc HCl (1 mL) was added (1 mL) at 0–3◦C. The reaction
mixture was stirred for additional 1 h at the same temperature. The
precipitate thus obtained was filtered and crystallized from benzene
to give 15. Yield, 60%; mp 170–3◦C (with decomposition); IR: ν = 2235
(N3), 1615 cm−1 (C N).
6-Phenoxathiin-2-yl-tetrazolo[5,1-a]phthalazine (16)
A mixture of 15 (10 mmol) and DMF (10 mL) was heated at 150◦C
for 15 min. The reaction mixture was evaporated to dryness in
vacuo and the residue was recrystallized from ethanol to yield 16.
Yield, 49%; mp 156–8◦C; IR: ν = 1620 (C N), 1090–1040 cm−1 (tetra-
1
zole ring20); H NMR: δ = 7.01–8.15 (m, 11H, ArH); Anal. Calcd. for
C20H11N5OS: C, 65.03; H, 3.00; N, 18.96%; Found: C, 65.18; H, 3.17; N,
18.82%.

2010
A. A. Aly and I. A. G. El-Karim
9-Phenoxathiin-2-yl-3H-3,4,10,10a-tetraazaphenanthren-
2-one (17a)
Method A
A mixture of 1 (10 mmol) and ethyl chloroacetate (10 mmol) in abso-
lute ethanol (35 mL) was refluxed for 8 h. The solid separated on cooling
and was filtered off and recrystallized from benzene to give 17a. Yield,
56%; mp 321–3◦C; IR: ν = 3320 (NH), 1670 (CO), 1620 cm−1 (C N);
1H NMR: δ = 4.11 (s, 2H, CH2), 7.12–8.15 (m, 11H, ArH), 9.13 (s, 1H,
NH, exchangeable); Anal. Calcd. for C22H14N4O2S: C, 66.32; H, 3.54; N,
14.06%; Found: C, 66.45; H, 3.41; N, 14.19%.
Method B
A mixture of 1 (10 mmol) and chloroacetyl chloride (10 mmol) in dry
dioxane (30 mL) stood at room temperature overnight. The precipitated
solid was filtered off and crystallized to give 17a, which identified by
mp and mmp. Yield, 60%.
2-Amino-9-phenoxathiin-2-yl-3H-3,4,10,10a-
tetraazaphenanthrene-1-carbonitrile (18a)
To a solution of anhydrous potassium carbonate (10 mmol) in ethanol
(30 mL) were added equimolar amounts of compound 1 (10 mmol) and
bromomalononitrile (10 mmol). The reaction mixture was heated under
reflux for 5 h. The reaction mixture was allowed to cool to room tem-
perature, then the formed solid was filtered off and recrystallized from
dioxane to produce 18a. Yield, 65%; mp 322–4◦C; IR: ν = 3360–3160
1
(NH and NH2), 2240 (C N), 1615 cm−1 (C N); H NMR: δ = 6.01 (br
s, 2H, NH2), 7.09–8.11 (m, 11H, ArH), 9.85 (s, 1H, NH, exchangeable);
Anal. Calcd. for C23H14N6OS: C, 65.39; H, 3.34; N, 19.89%; Found: C,
65.23; H, 3.48; N, 19.72%.
1-Methyl- or 1-phenyl-9-phenoxathiin-2-yl-3H-3,4,10,10a-
tetraazaphenanthrenes (19a,b)
A mixture of 1 (10 mmol) and α-haloketones namely chloroacetone
and/or phenacyl bromide in dry xylene (30 mL) was heated under reflux
for 6 h. The solid precipitate, which separated upon cooling was filtered
off and crystallized from a proper solvent to give 19a, b.
19a, Yield, 57%; mp 290–2◦C (dioxane); IR: ν = 3290 (NH), 1617 cm−1
(C N); MS m/z: 396 (M+); Anal. Calcd. for C23H16N4OS: C, 69.68; H,
4.07; N, 14.13%. Found: C, 69.54; H, 4.19; N, 14.28%.

Synthesis of Heterocyclic Systems
2011
19b, Yield, 55%; mp 272–4◦C (dioxane); IR: ν = 3275 (NH), 1620 cm−1
1
(C N); H NMR: δ = 7.12–8.11 (m, 17H, ArH and triazine H-2), 9.81
(s, 1H, NH, exchangeable); Anal. Calcd. for C28H18N4OS: C, 73.34; H,
3.96; N, 12.22%; Found: C, 73.49; H, 3.83; N, 12.36%.
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