Regioselectivity in 1,5-electrocyclization of N-[as-triazin-3-yl]nitrilimines. Synthesis of s-triazolo[4,3-b]-as-triazin-7(8H)-ones

Article abstract of DOI:10.1016/S0040-4020(02)00946-8

6-Benzyl-3-(arylmethylidenehydrazino)-as-triazin-5(4H)-ones 4 underwent regioselective cyclization upon treatment with either bromine in acetic acid containing sodium acetate or with ferric chloride in refluxing ethanol to give the respective s-triazolo[4,3-b]-as-triazin-7(8H)-ones 7 in overall good yields. The regioselectivity in the studied reactions was elucidated by comparison of ¹³C NMR spectra of 7 and their methyl derivatives with those of their regioisomers prepared by independent methods.

Full text of DOI:10.1016/S0040-4020(02)00946-8

Tetrahedron 58 (2002) 8559–8564
Regioselectivity in 1,5-electrocyclization of
N-[as-triazin-3-yl]nitrilimines.
Synthesis of s-triazolo[4,3-b]-as-triazin-7(8H)-ones
*
Ahmad Sami Shawali and Sobhi M. Gomha
Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
Received 28 May 2002; revised 11 July 2002; accepted 1 August 2002
Abstract—6-Benzyl-3-(arylmethylidenehydrazino)-as-triazin-5(4H)-ones 4 underwent regioselective cyclization upon treatment with either
bromine in acetic acid containing sodium acetate or with ferric chloride in refluxing ethanol to give the respective s-triazolo[4,3-b]-as-triazin-
7(8H)-ones 7 in overall good yields. The regioselectivity in the studied reactions was elucidated by comparison of 13C NMR spectra of 7 and
their methyl derivatives with those of their regioisomers prepared by independent methods. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
s-triazolo[3,4-c]-as-triazin-5(7H)-ones IV or their
tautomers.
Nitrilimines of type I whose N-terminals are bonded to
heterocyclic imino moiety have been reported to undergo
1,5-electrocyclization to give the corresponding fused
s-triazoles (Chart 1). In the course of surveying literature
in this area, we noticed that almost all of nitrilimines of type
I used in such reactions have one site for cyclization.1–3 As
part of our continuing research on the chemistry of
hydrazonoyl halides, which are the major precursors for
nitrilimines,4–6 we felt it would be interesting to study the
1,5-electrocyclization of nitrilimines characterized by
having two different sites for cyclization in an attempt to
shed light on their regiochemistry. We wish to report herein
the results of our study of the cyclization of nitrilimines II
(Chart 1) derived from aldehyde N-(as-triazin-3-yl)hydra-
zones or their respective hydrazonoyl bromides. As shown
in Chart 1, 1,5-electrocyclization of such nitrilimines may
provide s-triazolo[4,3-b]-as-triazin-7(8H)-ones III and/or
2. Results and discussion
The required starting 3-hydrazino-6-benzyl-as-triazin-
5(4H)-one 3 was prepared by reacting 3-methylthio-6-
benzyl-as-triazin-5(4H)-one 2 with hydrazine hydrate as
previously described.7,8 Condensation of equimolar quan-
tities of 3-hydrazino-6-benzyl-5(4H)-as-triazinone 3 with
aldehydes gave the corresponding aldehyde N-[6-benzyl-
5(4H)-as-triazinon-3-yl]hydrazones 4 (Scheme 1). The
elucidation of the structures of compounds 4 was based on
spectral evidence and microanalyses. The mass spectra
showed the molecular ion peaks in high intensity. The IR
spectra of 4 revealed absorption bands in the region 3100–
3400 cm21 due to the NH stretches. Their 1H NMR spectra
showed the presence of the amide (–CONH–) and the
Chart 1.
Keywords: heterocycles; hydrazones; electrocyclization; synthetic methods.
*
Corresponding author; e-mail: haney_sami@mail.com
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00946-8

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intermediate 6 as outlined in Scheme 1. This is remeniscent
of other related oxidative cyclization of aldehyde N-hetero-
aryl hydrazones with iron(III) chloride.9
As pointed out above, there are two directions for 1,5-
electrocyclization of 6 towards the N(2) or N(4) atom, thus
leading to s-triazolo[4,3-b]-as-triazin-7(8H)-ones 7 or
s-triazolo[3,4-c]-as-triazin-5(7H)-ones 8 or a mixture of
both (Scheme 1). TLC analysis of the crude products
isolated from either one of the foregoing dehydrogenative
cyclization methods indicated that only one product was
formed in each case. The mass spectra of the isolated
products showed high intensity molecular ion peaks at the
expected m/z values which are less by two than that of the
corresponding hydrazones 4. Their IR spectra, while
showing the disappearance of the NH group, they revealed
in each case a carbonyl band in the region 1660–
1670 cm21. Also, their 1H NMR spectra lacked the
characteristic signals for the azomethine (–CHvN–) and
the hydrazone (–CvN–NH–) protons present in the
spectra of 4. Such data cannot distinguish, however,
between the two isomeric structures 7 and 8. The definite
structure assignment of the products isolated was, therefore,
made on the basis of the following: (i) chemical evidence,
(ii) comparison of 13C NMR spectra of 7 and their methyl
derivatives with those of their regioisomers (Chart 2)
prepared by independent methods and (iii) chemical
reactions as outlined below.
As a first attempt to elucidate the actual structure of the
isolated products, an authentic sample of 3-phenyl-6-
benzyl-s-triazolo[4,3-b]-as-triazin-7(8H)-one 7a was pre-
pared and compared with the product isolated from the
studied dehydrogenative cyclization of 4a. Thus, reaction of
6-benzyl-3-hydrazino-as-triazin-5(4H)-one 3 with benzoyl
chloride in pyridine at reflux gave a crystalline compound,
which proved to be identical in all respects with that
obtained from dehydrogenative cyclization of 4a (Scheme
1). As reactions of 3-hydrazino-6-substituted-as-triazin-
5(4H)-ones with carboxylic acids or acyl chlorides at reflux
were reported to give the respective 3,6-disubstituted
s-triazolo[4,3-b]-as-triazin-7(8H)-ones,10 – 13 it is not
unreasonable to conclude therefore that oxidative cycliza-
tion of hydrazones 4 proceeds via participation of N(2) of
as-triazine moiety and exclusively affords 7. This con-
clusion is in agreement with literature reports which
indicate that in as-triazin-5(4H)-ones the presence of N(1)
atom increases the basicity of N(2) in relation to N(4) which
is situated between two electron-deficient carbon atoms, and
thus the N(2) is more nucleophilic than N(4).14–16
Scheme 1.
hydrazone (–CvN–NH–) protons as two singlets at d 11.6
and 12.8, respectively. The latter two signals disappeared
upon exchange with deuterium oxide. In addition, they
showed, in each case, a singlet at d 3.86–4.02 due to the
benzylic (Ph–CH2–) protons and a multiplet signal at d
7.06–8.83 due to the aromatic and azomethine (–CHvN–)
protons.
Next, the oxidative cyclization of the hydrazone derivatives
4 by two alternative methods was examined. In the first
method, compounds 4 were treated with bromine in acetic
acid in the presence of sodium acetate at room temperature.
In our hands, such treatment yielded the respective
triazolotriazines directly (Scheme 1). Attempts to isolate
the intermediate hydrazonoyl bromides 5 failed, however.
This result indicates that the latter intermediates underwent
in situ tandem dehydrobromination, to give the correspond-
ing nitrilimines 6, and 1,5-electrocyclization as soon as they
are formed under the reaction conditions employed to yield
the respective triazolotriazines as the end products (Scheme
1). Alternatively, treatment of the hydrazones 4 with
iron(III) chloride in ethanol yielded products that proved
to be identical in all respects with those obtained above
(Scheme 1). This finding suggests that the latter oxidative
cyclization of 4 proceeds via the same nitrilimine
The assignment of structure 7 and its tautomeric form 7A
was further confirmed by comparison of the methylation
product of 7a with authentic samples of two isomers namely
6-benzyl-8-methyl-3-phenyl-s-triazolo[4,3-b]-as-triazin-
7(8H)-one and 6-benzyl-1-methyl-3-phenyl-s-triazolo[4,3-
b]-as-triazin-7(1H)-one 13a and 15a, respectively (Scheme
2). Both isomers 13a and 15a have been unreported hitherto
and thus they were prepared unambiguously as outlined in
Scheme 2.
The synthetic strategy for 13a was based on oxidation of the
hydrazone precursor 12a. The latter was prepared by

A. S. Shawali, S. M. Gomha / Tetrahedron 58 (2002) 8559–8564
8561
Chart 2.
treatment of 10 with hydrazine hydrate to give the novel
hydrazino derivative 11, and reaction of the latter with
benzaldehyde to yield the hydrazone 12a. Treatment of
the latter hydrazone derivative with FeCl3 in EtOH gave
6-benzyl-8-methyl-3-phenyl-s-triazolo[4,3-b]-as-triazin-
7(8H)-one 13a (Scheme 2).
The other isomeric compound namely 6-benzyl-1-methyl-3-
phenyl-s-triazolo[4,3-b]-as-triazin-7(1H)-one 15a was
prepared by reaction of benzoyl chloride with 3-(1-
methylhydrazino)-6-benzyl-as-triazin-5(4H)-one 14 in
refluxing pyridine (Scheme 2). The precursor 14 was
prepared by reaction of 2 with methylhydrazine. Reactions
of methylhydrazine with other 6-substituted-3-methylthio-
as-triazin-5(4H)-ones were reported to give the respective
3-(1-methylhydrazino)-as-triazine derivatives.17 Both 13a
and 15a proved to have different physical constants as
depicted in Section 3.
Treatment of 7a with methyl iodide in ethanol in the
presence of sodium hydroxide yielded a product that proved
1
to be identical in all respects (mp, mixed mp, IR and H
NMR) with 13a (Scheme 2). This finding indicates that the
products isolated from oxidative cyclization of the hydra-
zone derivatives 4 have structure 7 and exist predominantly
in the tautomeric form 7A. The predominance of the latter
form is compatible with Clar’s rule which is used to
interpret the relative stability of fused heterocyclic iso-
mers.18,19 The form 7A, having one Clar’s circle more than
the other form 7B (Scheme 1) is expected to be more stable
as it has higher degree of aromatic stability. This same rule
can also account for our finding that methylation of 7a led to
the formation of 13a in preference of 15a as the former is
expected to be more stable than the latter as it has one Clar’s
circle more than 15a.
The assigned structure 13a and in turn structure 7 was
further confirmed by its comparison with an authetic sample
of its isomer namely 6-benzyl-8-methyl-3-phenyl-s-tria-
zolo[3,4-c]-as-triazin-5(8H)-one 18 which was prepared
unequivocally by the method depicted in Scheme 3. Thus,
treatment of 9 with hydrazine hydrate gave the hydrazino
derivative 16. Reaction of the latter with benzaldehyde
Scheme 2.

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A. S. Shawali, S. M. Gomha / Tetrahedron 58 (2002) 8559–8564
were secured by mixed mps and superimposable IR spectra.
6-Benzyl-3-methylthio-5(4H)-as-triazinone 2,7 6-benzyl-3-
hydrazino-as-triazin-5(4H)-one 3,8 6-benzyl-2-methyl-3-
methylthio-as-triazin-5(2H)-one 920 (dC (DMSO-d6)
164.2, 139.4, 130.0, 128.7, 128.5, 127.2, 126.9, 39.5, 38.9,
36.5) and 6-benzyl-4-methyl-3-methylthio-5(4H)-as-triazi-
none 1021 (dC (DMSO-d6) 156.8, 151.3, 136.9, 132.8, 129.1,
128.2, 126.4, 38.6, 36.6, 35.7) were prepared by literature
methods.
3.1.1. 6-Benzyl-3-hydrazino-4-methyl-as-triazin-5(4H)-
one (11) and 6-benzyl-3-hydrazino-2-methyl-as-triazin-
5(2H)-one (16). General method. To 6-benzyl-4-methyl-3-
methylthio-as-triazin-5(4H)-one 10 (1 g, 4 mmol) in 2-pro-
panol (10 ml) was added hydrazine hydrate (80% in
hydrazine, 2 ml). The reaction mixture was refluxed for
10 h, then cooled. The solid that precipitated was filtered off
and crystallized from DMF to give 11 (0.64 g, 69%) as pale
yellow needles, mp 271–2728C; (Found: C, 57.2; H, 5.4; N,
30.3. C11H13N5O (231.3) requires: C, 57.19; H, 5.62; N,
30.30%); nmax (KBr) 3402, 3055, 1674 cm21; dH (CDCl3)
3.39 (s, 3H, NCH3), 3.79 (s, 2H, CH2Ph), 4.90 (s, 2H, NH2),
7.17–7.29 (m, 5H, Ph), 12.12 (s, 1H, NH); dC (DMSO-d6)
156.9, 147.6, 138.6, 132.8, 129.5, 128.8, 126.7, 38.9, 36.5;
MS m/z (%) 231 (100), 185 (40), 114 (32), 91 (42), 77 (17).
Scheme 3.
afforded the hydrazone derivative 17. Treatment of the latter
with ferric chloride in ethanol or with bromine in acetic acid
in presence of sodium acetate yielded 18. The latter product
proved different in all respects (mp, IR and 1H NMR
spectra) from 13a (see Section 3).
In addition to the foregoing chemical evidence, the
tautomeric structure 7A was further confirmed by compari-
son of 13C NMR spectra of the isolated products with those
of some triazinones 9–11 and 16 and the triazolotriazinones
13 and 15 (Chart 2). This is because literature reports14–16
indicate that the chemical shift of the carbonyl carbon in as-
triazin-5(4H)-ones and their annelated analogs is markedly
affected by the nature of the adjacent nitrogen, i.e. N(4),
pyridine type or pyrrole type, being larger downfield for the
former type (Chart 2). The 13C NMR spectrua of 7 revealed
the signal for the carbonyl carbon resonance at d 154.9. This
chemical shift value suggests that N(4) atom is sp3-
hybridized nitrogen atom i.e. pyrrole type as it is similar
to that found for the triazinones 10 (d 156.8) and 11 (d
156.9) and different from those of 9 (d 164.2), and 15 (d
166.6) and 16 (d 166.6) (Chart 2).
When the above procedure was repeated using 6-benzyl-2-
methyl-3-methylthio-as-triazin-5(4H)-one 9 in lieu of 10,
the hydrazine derivative 16 was obtained as pale yellow
needles (0.62 g, 68%); mp 262–2648C; (Found: C, 57.3; H,
5.4; N, 30.2, C11H13N5O (231.3) requires: C, 57.19; H, 5.62;
N, 30.30%); nmax (KBr) 3394, 3030, 1681 cm21; dH
(CDCl3) 3.36 (s, 3H, NCH3), 3.76 (s, 2H, CH2Ph), 7.18–
7.23 (m, 5H, Ph), 8.54 (s, 2H, NH2), 12.11 (s, 1H, NH); dC
(DMSO-d6) 166.6, 149.1, 138.1, 132.8, 129.7, 128.6, 126.8,
37.3, 36.5; MS m/z (%) 232 (70), 217 (45), 171 (42), 118
(35), 93 (100), 77 (20).
3.1.2. Synthesis of 6-benzyl-3-(1-methylhydrazino)-as-
triazin-5(4H)-one 14. To a well-stirred solution of 2 (2.2 g,
0.013 mol) in isopropanol (30 ml) was added methylhydra-
zine (6 g, 0.13 mol). The reaction mixture was refluxed
while being stirred for 6 h, then cooled. The solid product
that separated was filtered off and crystallized from
i-propanol to give the hydrazine 14 as colorless needles
(1.8 g, 61%), mp 238–2398C; (Found: C, 57.4; H, 5.5; N,
30.1. C11H13N5O (231.3) requires: C, 57.19; H, 5.62; N,
30.30%); nmax (KBr) 3286, 3170, 1674 cm21; dH (CDCl3)
3.11 (s, 3H, NCH3), 3.77 (s, 2H, CH2Ph), 7.11–7.29 (m, 5H,
Ph), 9.90 (s, 2H, NH2), 12.12 (s, 1H, NH); MS m/z (%) 231
(42), 93 (100), 77 (33).
In conclusion, all evidence presented in this work points to
the fact that cyclization of 6-benzyl-3-(3-arylmethylidene-
hydrazino)-as-triazin-5(4H)-ones 4 is regioselective and
leads to s-triazolo[4,3-b]-as-triazin-7(8H)-ones 7 in overall
good yields and that the latter products exist predominantly
in the tautomeric form 7A (Scheme 1).
3. Experimental
3.1. General
3.2. Preparation of hydrazones 4, 12 and 17
All melting points were determined in open capillary tubes
and are uncorrected. The IR spectra were recorded in a Pye-
Unicam SP300 instrument in potassium bromide disks. The
1H and 13C NMR spectra were recorded in a Varian Mercury
General procedure. A mixture of the hydrazine 3 (0.01 mol)
and the appropriate aldehyde (0.01 mol) in acetic acid
(30 ml) was heated under reflux for 30 min, then cooled.
The mixture was diluted with water and the solid produced
filtered off, washed with water, dried and crystallized from
the proper solvent to give the respective hydrazone 4.
1
VXR-300 spectrometer (300 MHz for H and 75 MHz for
13C) in CDCl3 or DMSO-d6 and the chemical shifts were
related to that of the solvent. Mass spectra were obtained in
a GCMS-Q1000-EX spectrometer, the ionizing voltage was
70 eV. Elemental analyses were carried out by the
Microanalytical Center of Cairo University, Giza, Egypt.
The identification of compounds from different experiments
Repetition of the above procedure using 11 and 16 each in
place of 3 afforded the hydrazone derivatives 12 and 17,

A. S. Shawali, S. M. Gomha / Tetrahedron 58 (2002) 8559–8564
8563
respectively. The physical constants of the hydrazones 4a–
f, 12a, b and 17 are listed below.
N, 21.01%); nmax (KBr) 3190, 1680 cm21; dH (CDCl3) 2.39
(s, 3H, CH3Ph), 3.17 (s, 3H, NCH3), 3.93 (s, 2H, CH2Ph),
6.3–8.36 (m, 10H, ArH), 12.3 (s, 1H, NH).
3.2.1. 6-Benzyl-3-[(phenylmethylene)hydrazino]-as-tria-
zin-5(4H)-one (4a). (2.4 g, 80%) as yellowish needles, mp
2588C (AcOH); (Found: C, 66.7; H, 4.9; N, 22.9.
C17H15N5O (305.3) requires: C, 66.87; H, 4.95; N, 22.94);
3.2.9. 6-Benzyl-2-methyl-3-[(phenylmethylene)hydra-
zino]-as-triazin-5(2H)-one (17). (2.2 g, 70%) as yellow
solid, mp 2358C; (Found: C, 67.5; H, 5.4; N, 22.1.
C18H17N5O (319.3) requires: C, 67.70; H, 5.37; N,
21.90%); nmax (KBr) 3209, 1681 cm21; dH (CDCl3) 3.41
(s, 3H, NCH3), 3.95 (s, 2H, CH2Ph), 7.02–7.60 (m, 11H,
ArH, vCH), 11.0 (s, 1H, NH).
n
max (KBr) 3200, 3150, 1660 cm21; dH (CDCl3) 4.01 (s, 2H,
CH2Ph), 7.2–7.8 (m, 11H, 2Ph, vCH), 8.72 (s, 1H, NH),
12.06 (s, 1H, NH).
3.2.2. 6-Benzyl-3-[(4-methylphenylmethylene)hydra-
zino]-as-triazin-5(4H)-one (4b). (2.6 g, 82%) as white
plates, mp 2968C (AcOH); (Found: C, 67.5; H, 5.4; N, 21.8.
C18H17N5O (319.3) requires: C, 67.70; H, 5.37; N, 21.93%);
3.3. Synthesis of s-triazolo[4,3-b]-as-triazin-7(8H)-ones
(7a–f and 13a, b) and s-triazolo[3,4-c]-as-triazin-5(8H)-
one (18)
n
max (KBr) 3210, 3100, 1643 cm21; dH (CDCl3) 2.34 (s, 3H,
CH3Ph), 3.87 (s, 2H, CH2Ph), 7.2–7.8 (m, 9H, ArH), 8.0 (s,
1H, vCH), 11.6 (s, 1H, NH), 12.77 (s, 1H, NH).
Method A. Bromine (0.44 g, 5.5 mmol) in acetic acid (5 ml)
was added dropwise to a stirred mixture of the appropriate
hydrazone 4 (5 mmol) and sodium acetate (1.2 g, 15 mmol)
in acetic acid (30 ml). The reaction mixture was stirred for
12 h at room temperature. The mixture was then poured
onto ice-cold water (250 ml). The solid that precipitated was
filtered off, washed with 5% sodium bicarbonate solution
and then with water, dried and crystallized from the
appropriate solvent to give the respective triazolotriazines 7.
3.2.3. 6-Benzyl-3-[(4-chlorophenylmethylene)hydra-
zino]-as-triazin-5(4H)-one (4c). (2.9 g, 85%) as yellowish
needles, mp 3128C (AcOH); (Found: C, 60.3; H, 4.1; N,
20.5. C17H14ClN5O (339.8); requires: C, 60.09; H, 4.15; N,
20.61%); nmax (KBr) 3200, 3095, 1641 cm21; dH (CDCl3)
3.87 (s, 2H, CH2Ph), 7.29–8.05 (m, 10H, ArH, vCH), 11.8
(s, 1H, NH), 12.82 (s, 1H, NH).
Method B. To the appropriate hydrazone 4 (14 mmol) in
ethanol (40 ml), a solution of ferric chloride (2 M, 5 ml) was
added. The mixture was refluxed for 20 min, then left
overnight at room temperature. The excess solvent was
distilled under reduced pressure, and solid residue left was
washed with water several times, dried and finally crystal-
lized from the appropriate solvent to give the respective
triazolotriazines 7.
3.2.4. 6-Benzyl-3-[(4-bromophenylmethylene)hydra-
zino]-as-triazin-5(4H)-one (4d). (3.2 g, 85%) as yellowish
needles, mp 2828C (AcOH); (Found: C, 53.2; H, 3.7; N,
18.1.C17H14BrN5O (384.2) requires: C, 53.14; H, 3.67; N,
18.22%); nmax (KBr) 3210, 3100, 1641 cm21; dH (CDCl3)
3.86 (s, 2H, CH2Ph), 7.17–8.64 (m, 10H, ArH, vCH), 11.7
(s, 1H, NH), 12.80 (s, 1H, NH).
3.2.5. 6-Benzyl-3-[(2-furanylmethylene)hydrazino]-as-
triazin-5(4H)-one (4e). (2.3 g, 80%) as white solid, mp
2488C (AcOH–H2O); (Found: C, 61.2; H, 4.6; N, 23.6.
C15H13N5O2 (295.3) requires: C, 61.01; H, 4.44; N,
23.72%); nmax (KBr) 3336, 3100, 1650 cm21; dH (CDCl3)
3.97 (s, 2H, CH2Ph), 6.48–7.50 (m, 8H, ArH, Het-H), 8.34
(s, 1H, vCH), 12.0 (s, 1H, NH), 12.15 (s, 1H, NH).
Repetition of the foregoing procedure using 12 and 17 each
in lieu of 4 yielded the corresponding triazolotriazines 13
and 18, respectively. The physical constants of the
triazolotriazines 7a–f, 13a, b and 18 are given below.
3.4. Alternate synthesis of 7a
To a solution of the hydrazine 3 (2.2 g, 0.01 mol) in dry
pyridine (20 ml) was added benzoyl chloride (2.1 g,
0.015 mol) and the resulting mixture was refluxed for 1 h,
then cooled. The resulting mixture was triturated with
ethanol (10 ml) and the solid precipitated filtered off and
crystallized from ethanol to give 7a which proved to be
identical in all respects with 7a prepared above.
3.2.6. 6-Benzyl-3-[(2-thienylmethylene)hydrazino]-as-
triazin-5(4H)-one (4f). (2.4 g, 80%) as pale brown needles,
mp 2438C (AcOH–H2O); (Found: C, 57.7; H, 4.2; N, 22.3.
C15H13N5OS (311.3) requires: C, 57.86; H, 4.21; N,
22.49%); nmax (KBr) 3400, 3100, 1640 cm21; dH (CDCl3)
4.02 (s, 2H, CH2Ph), 7.06–7.47 (m, 8H, ArH, Het-H), 8.83
(s, 1H, vCH), 11.49 (s, 1H, NH), 11.54 (s, 1H, NH).
3.4.1. 6-Benzyl-3-phenyl-s-triazolo[4,3-b]-as-triazin-
7(8H)-one (7a). (1.06 g, 70%) as white solid, mp 2878C
(EtOH); (Found: C, 67.2; H,4.3; N, 22.9. C17H13N5O
(303.3) requires C, 67.32; H, 4.32; N, 23.09%); nmax (KBr)
3456, 1689 cm21; dH (CDCl3) 4.05 (s, 2H, CH2Ph), 7.23–
8.08 (m, 10H, ArH), 13.92 (s, 1H, NH); dC (DMSO-d6)
154.9, 136.2, 131.6, 129.5, 129.4, 128.9, 128.3, 127.9,
127.4, 126.6, 123.7, 120.6, 37.1.
3.2.7. 6-Benzyl-4-methyl-3-[(phenylmethylene)hydra-
zino]-as-triazin-5(4H)-one (12a). (2.8 g, 88%) as pale
brown solid, mp 2048C (AcOH); (Found: C, 67.5; H, 5.3; N,
21.7. C18H17N5O (319.3) requires: C, 67.70; H, 5.37; N,
21.90%); nmax (KBr) 3195, 1690 cm21; dH (CDCl3) 3.19 (s,
3H, NCH3), 3.82 (s, 2H, CH2Ph), 7.25–7.94 (m, 11H, ArH,
vCH), 12.7 (s, 1H, NH).
3.2.8. 6-Benzyl-4-methyl-3-[(4-methylphenylmethylene)-
hydrazino]-as-triazin-5(4H)-one (12b). (2.5 g, 76%) as
pale yellow solid, mp 2218C (EtOH); (Found: C, 68.3; H,
5.6; N, 21.2. C19H19N5O (333.4) requires: C, 68.45; H, 5.74;
3.4.2. 6-Benzyl-3-(4-methylphenyl)-s-triazolo[4,3-b]-as-
triazin-7(8H)-one (7b). (1.18 g, 75%) as white solid, mp
3188C (AcOH–EtOH); (Found: C, 68.3; H, 4.4; N, 21.9.
C18H15N5O (317.3) requires C, 68.13; H, 4.76; N, 22.07%);

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A. S. Shawali, S. M. Gomha / Tetrahedron 58 (2002) 8559–8564
nmax (KBr) 3448, 1659 cm21; dH (CDCl3) 2.40 (s, 3H,
CH3Ph), 4.09 (s, 2H, CH2Ph), 7.31–8.06 (m, 9H, ArH),
14.50 (s, 1H, NH).
methanol (10 ml). To the the resulting mixture was added
methyl iodide (1.47 g, 0.01 mol). The reaction mixture was
left overnight at room temperature while being stirred. The
solid that precipitated was filtered off and crystallized from
acetic acid to give 13a (2.1 g, 65%) as white solid, mp
1728C; (Found: C, 68.3; H, 4.4; N, 22.1. C18H15N5O (317.3)
requires: C, 68.13; H, 4.70; N, 22.07%).The latter product
proved identical in all respects with 13a obtained from
oxidative cyclization of 12a.
3.4.3. 6-Benzyl-3-(4-chlorophenyl)-s-triazolo[4,3-b]-as-
triazin-7(8H)-one (7c). (1.28 g, 76%) as pale brown plates,
mp 3008C (EtOH); (Found: C, 60.2; H, 3.7; N, 20.9.
C17H12ClN5O (337.8) requires C, 60.45; H, 3.58; N,
20.73%); nmax (KBr) 3440, 1665 cm21; dH (CDCl3) 3.33
(s, 2H, CH2Ph), 7.48–7.86 (m, 9H, ArH), 13.03 (s, 1H, NH).
3.5.1. Synthesis of 6-benzyl-1-methyl-3-phenyl-s-tria-
zolo[4,3-b]-as-triazin-7(1H)-one (15a). To a solution of
the hydrazine 14 (2.2 g, 0.01 mol) in dry pyridine (20 ml)
was added benzoyl chloride (2.1 g, 0.015 mol) and the
resulting mixture was refluxed for 2 h, then cooled. The
resulting mixture was triturated with ethanol (10 ml) and the
solid that precipitated was filtered off and crystallized from
acetic acid to give 15a (2.3 g, 75%) as white needles, mp
2288C; (Found: C, 68.1; H, 4.6; N, 22.0. C18H15N5O (317.3)
requires C, 68.13; H, 4.76; N, 22.07%); nmax (KBr)
1697 cm21; dH (CDCl3) 3.48 (s, 3H, NCH3), 3.87 (s, 2H,
CH2Ph), 7.19–8.08 (m, 10H, ArH); dC (DMSO-d6) 166.6,
162.8, 156.7, 149.1, 138.0, 132.8, 132.5, 129.7, 128.9,
128.8, 128.6, 126.8, 37.3, 36.5.
3.4.4. 6-Benzyl-3-(4-bromophenyl)-s-triazolo[4,3-b]-as-
triazin-7(8H)-one (7d). (1.47 g, 77%) as brown plates,
mp 2988C (AcOH); (Found: C, 53.3; H, 3.3; N, 18.2.
C17H12BrN5O (382.2) requires C, 53.42; H, 3.16; N,
18.32%); nmax (KBr) 3210, 3100, 1661 cm21; dH (CDCl3)
3.9 (s, 2H, CH2Ph), 7.2–8.4 (m, 9H, ArH), 11.99 (s, 1H, NH).
3.4.5. 6-Benzyl-3-(2-furanyl)-s-triazolo[4,3-b]-as-triazin-
7(8H)-one (7e). (1.0 g, 68%) as yellow solid, mp 2868C
(AcOH); (Found: C, 61.5; H, 3.6; N, 23.6. C15H11N5O2
(293.3) requires C, 61.43; H, 3.78; N, 23.88%); nmax (KBr)
3386, 1665 cm21; dH (CDCl3) 3.82 (s, 2H, CH2Ph), 7.0–8.0
(m, 8H, ArH, Het-H), 12.10 (s, 1H, NH).
3.4.6. 6-Benzyl-3-(2-thienyl)-s-triazolo[4,3-b]-as-triazin-
7(8H)-one (7f). (1.08 g, 70%) as yellow needles, mp 2388C
(EtOH); (Found: C, 58.1; H, 3.7; N, 22.3. C15H11N5OS
(309.3) requires: C, 58.24; H, 3.58; N, 22.64%); nmax (KBr)
3456, 1650 cm21; dH (CDCl3) 3.83 (s, 2H, CH2Ph), 7.1–8.3
(m, 8H, ArH, Het-H), 12.6 (s, 1H, NH).
References
1. Shawali, A. S.; Abdallah, M. A. Adv. Heterocycl. Chem. 1995,
63, 277.
2. Huisgen, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 947.
3. Taylor, E. C.; Turchi, I. J. Chem. Rev. 1979, 79, 181.
4. Shawali, A. S. Chem. Rev. 1993, 93, 2731.
5. Shawali, A. S. Heterocycles 1983, 20, 2239.
6. Shawali, A. S.; Parkanyi, C. J. Heterocycl. Chem. 1980, 17, 833.
7. (a) Watanabe, S.; Ueda, T. Chem. Pharm. Bull. 1963, 11,
1551. (b) Eid, M. M.; Hassan, R. H.; Kadry, A. M. Pharmazie
1988, 43, 166.
3.4.7. 6-Benzyl-8-methyl-3-phenyl-s-triazolo[4,3-b]-as-
triazin-7(8H)-one (13a). (1.1 g, 70%) as white solid, mp
1728C (AcOH); (Found: C, 68.1; H, 4.6; N, 22.2.
C18H15N5O (317.3) requires: C, 68.13; H, 4.76; N,
22.07%); nmax (KBr) 1675; dH (CDCl3) 3.17 (s, 3H,
NCH3), 3.79 (s, 2H, CH2Ph), 7.25–7.92 (m, 10H, ArH);
dC (DMSO-d6) 161.9, 153.1, 149.5, 144.5, 137.1, 133.6,
129.5, 128.8, 128.2, 127.8, 127.1, 125.8, 38.5, 35.8.
8. Kalfus, K. Collect. Czech. Chem. Commun. 1968, 33, 2513.
9. (a) Gruttadauria, M.; Buccheri, F.; Cusmano, G.; Meo, P. L.;
Noto, R.; Werber, G. J. Heterocycl. Chem. 1993, 30, 765.
(b) Butler, R. N. Chem. Rev. 1984, 84, 249.
3.4.8. 6-Benzyl-8-methyl-3-(4-methylphenyl)-s-tria-
zolo[4,3-b]-as-triazin-7(8H)-one (13b). (1.1 g, 67% yield)
as white solid, mp 2168C (AcOH); (Found: C, 68.6; H, 5.2;
N, 21.2. C19H17N5O (331.3) requires: C, 68.87; H, 5.17; N,
21.13%). nmax (KBr) 1670; dH (CDCl3) 2.17 (s, 3H, CH3Ph),
3.11 (s, 3H, NCH3), 3.95 (s, 2H, CH2Ph), 7.2–8.13 (m, 9H,
ArH).
10. Eid, M. M.; Badawy, M. A.; Ibrahim, Y. A. J. Heterocycl.
Chem. 1983, 20, 1255.
11. Youssef, M. S. K.; Hassan, Kh. M.; Atta, F. M.; Abbady, M. S.
J. Heterocycl. Chem. 1984, 21, 1565.
12. Ilford Ltd. Belg. 642,615, 1964; Chem. Abstr. 1965, 65,
18127b.
3.4.9. 6-Benzyl-8-methyl-3-phenyl-s-triazolo[3,4-c]-as-
triazin-5(8H)-one (18). (1.0 g, 68%) as white solid, mp
2478C (EtOH); (Found: C, 68.1; H, 4.8; N, 21.9. C18H15N5O
(317.3) requires: C, 68.13; H, 4.76; N, 22.07%); nmax (KBr)
1689; dH (CDCl3) 3.39 (s, 3H, NCH3), 4.0 (s, 2H, CH2Ph),
7.2–8.1 (m, 10H, ArH); dC (DMSO-d6) 162.3, 156.8, 149.6,
138.1, 132.8, 132.5, 129.8, 129.2, 128.9, 128.8, 128.6,
126.9, 36.6, 35.8.
13. Ilford Ltd. Fr. 1,379,480, 1964; Chem. Abstr. 1964, 65,
11838b.
14. Shawali, A. S.; Gomha, S. M. J. Prakt. Chem. 2000, 342, 599.
15. Giannola, L. I.; Giammona, G.; Plazzo, S.; Lamartina, L.
J. Chem. Soc., Perkin Trans. 1 1984, 2707.
16. Daunis, J.; Follet, M.; Marzin, C. Org. Magn. Resn. 1980, 13,
330.
17. Daunis, J.; Follet, M. Bull. Soc. Chim. Fr. 1976, 1178.
18. Hajos, G.; Messmer, A.; Neszmely, A.; Parkanyi, L. J. Org.
Chem. 1984, 49, 3199.
3.5. Alternate synthesis of 13a
19. Moussad, A.; Abdelhamid, H. A.; Elnemr, A.; El-Ashry, E. H.
Bull. Chem. Soc. Jpn 1992, 65, 546.
Compound 7a (3.1 g, 0.01 mol) was added to a stirred
methanolic sodium methoxide solution, prepared by dis-
solving sodium metal (0.23 g, 0.01 mol) in absolute
20. Cattelain, E. Bull. Soc. Chim. Fr. 1945, 12, 39.
21. Cattelain, E. Bull. Soc. Chim. Fr. 1944, 11, 249.