Two-step syntheses of 3-methyl and 3-phenyl-1,2,4-benzotriazines

Article abstract of DOI:10.1002/hc.20200

3-Methyl-1,2,4-benzotriazine and some of its derivatives were prepared in moderate yields (50-70%) via a reductive cyclization by a PtO ₂-catalyzed hydrogenation of the corresponding 2- nitrophenylhydrazones of the pyruvic acid. The latter comp

Full text of DOI:10.1002/hc.20200

Heteroatom Chemistry
Volume 17, Number 2, 2006
Two-Step Syntheses of 3-Methyl and
3-Phenyl-1,2,4-Benzotriazines
Mohamed Khodja,1 Saad Moulay,1 Hocine Boutoumi,1
and Horst Wilde2
1Laboratoire des Mate´riaux Organiques, De´partement de Chimie Industrielle, Faculte´ des Sciences
de L’Inge´nieur, Universite´ Saaˆd Dahlab de Blida, B. P. 270, Route de Soumaˆa, 09000, Blida, Algeria
2Institut fu¨ r Organische Chemie der Universita¨t Leipzig, Johannisallee 29,
D-04103 Leipzig, Germany
Received 8 July 2005; revised 14 November 2005
Several pathways for the synthesis of 1,2,4-
ABSTRACT: 3-Methyl-1,2,4-benzotriazine and some
benzotriazines have been reported [6–12]. For
of its derivatives were prepared in moderate yields
example, 3-amino-1,2,4-benzotriazine was prepared
(50–70%) via a reductive cyclization by a PtO2-
in 57% yield by the reduction of 3-amino-1,2,4-
catalyzed hydrogenation of the corresponding 2-
benzotriazine 1-oxide with sodium dithionite, the
nitrophenylhydrazones of the pyruvic acid. The lat-
latter oxide was obtained in 39% yield by reacting
ter compounds were obtained in yields higher than
nitroaniline with cyanamide [13]. Various pathways
90% by reacting 2-nitrophenylhydrazines with sodium
for the synthesis of 3-phenyl-1,2,4-benzotriazine
pyruvate salt. Three 3-phenyl-1,2,4-benzotriazine com-
have been described [9,12,14–19]. It is enlightening
pounds were also produced via a reductive cy-
to recall that the oxidized of 1,2,4,benzotriazines
clization by a Pt/C-catalyzed hydrogenation of their
have been of special interest because of their
corresponding 2-nitrophenylhydrazono-ethers in high
potential antitumor activity [20,21]. Indeed, the
ꢀ
C
yields (>70%).
2006 Wiley Periodicals, Inc. Het-
synthesis of 3-amino-1,2,4-benzotriazine-1,4-oxide,
also known as tirapazamine, is nowadays a central
occupation for many workers [22–24]. Accordingly,
1,2,4-benzotriazines are valuable precursors to very
promising cancer therapeutic molecules.
eroatom Chem 17:166–172, 2006; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20200
In continuation of our work on heterocyclic syn-
thesis [5], we developed short pathways to produce
3-methyl and 3-phenyl-1,2,4-benzotriazines from
phenylhydrazones and phenylhydrazono-ethers, re-
spectively. The hydrazones have been used largely
as starting materials in the Fischer’ indole synthesis
[25].
INTRODUCTION
The reductive cyclization of nitrophenylhydrazones
has been widely used to afford nitrogen-based
heterocyclic molecules. To name but a few, there are
4H-pyrazolo-[1,5-a]benzimidazoles [1], ethyl-(1,2,4-
benzotriazine-3-yl)acetate and its derivatives [2],
benzo[1,2-b:5,4-bꢁ]bis(1H)-imidazo[1,2-b]pyrazoles
[3], 1,2-dihydro-1,2,5-benzotriazepines [4], and
3,4-dihydropyridazino[1,6-a]benzoimidazoles [5].
EXPERIMENTAL
Apart from the starting material for the synthesis
of 1a and 3a, which was purchased from Aldrich,
the remaining phenylhydrazines were synthesized
Correspondence to: Mohamed Khodja; e-mail: saadmoul@
yahoo.com.
2006 Wiley Periodicals, Inc.
c
ꢀ
166

Two-Step Syntheses of 3-Methyl and 3-Phenyl-1,2,4-Benzotriazines 167
according to the method described in the literature
[26]. Benzonitrile, sodium pyruvate, perchloric acid,
ethanol, PtO2, Pt/C, methanol, and chloroform CDCl3
were purchased from Aldrich. The iminoester used
in Eq. (3) was prepared from benzonitrile using the
Pinner reaction.
alyst was removed by filtration and the solvent was
distilled off. The remaining yellow crystals were re-
crystallized; 2a, 2b, 2d, and 2e were recrystallized
from petroleum ether and, 2c and 2f from ethanol
and methanol, respectively.
Melting points were recorded with a Boetus mi-
crohotstage. Elemental analyses were performed on
a HERAEUS CHN-O-RAPID analyzer. Infrared and
UV–Vis spectra were measured with a Specord M80
Carl Zeiss Jena spectrophotometer and a Beckmann
DU 650 spectrophotometer, respectively. 1H NMR
spectra were recorded using a Varian Gemini 200
spectrometer; chemical shifts for NMR signals are
reported in ppm from TMS (tetramethylsilane) used
as an internal standard.
General Procedure for Synthesis of 4a–c
The corresponding nitrophenylhydrazine (0.01 mol)
and 0.01 mol of the imino-ester (1.49 g) were dis-
solved in 25 mL of ethanol and the mixture was
stirred at room temperature for 1 h. The obtained
yellow crystals (3a–c) were filtered and dried. The
latter substance was dissolved in 25 mL of ethanol
and subjected to reduction by hydrogen in the pres-
ence of Pt/C at room temperature. Afterwards, the
catalyst was removed by filtration and the solvent
was distilled off. The obtained crystals (4a–c) were
purified by recrystallization from petroleum ether.
General Procedure for Synthesis of 1a–f
Sodium pyruvate (1.1 g, 0.01 mol) and the corre-
sponding 2-nitrophenylhydrazine (0.01 mol) were
dissolved in 10 mL of ethanol and the mixture was
stirred in the presence of 10 mL of a 35% ethano-
lic solution of perchloric acid. Immediately, a yellow
crystal precipitated and was sequentially filtered,
washed with water until neutral pH, and dried. Fi-
nally, the product was purified by recrystallization;
compounds 1a and 1b–f were recrystallized from
toluene and ethanol, respectively.
RESULTS AND DISCUSSION
Synthesis of 3-Methyl-1,2,4-benzotriazines 2a–f
The different 2-nitrophenylhydrazones of pyruvic
acid 1a–f shown in Table 1 were obtained accord-
ing to the method of Schwesinger et al. [4]. At
room temperature, the nitrophenylhydrazines re-
acted readily with sodium pyruvate in the presence of
a 35% ethanolic solution of perchloric acid (Eq. (1)).
The corresponding phenylhydrazones were instan-
taneously precipitated as yellow crystals. The yields
of the corresponding phenylhydrazones were quan-
titative and generally higher than 90%. With the ex-
ception of 1a, they all recrystallized from ethanol
and their melting points were found to be in the
range of 200–230◦C. It is interesting that the reaction
General Procedure for Synthesis of 2a–f
The corresponding 2-nitrophenylhydrazone of pyru-
vic acid (3 mmol) dissolved in 50 mL of ethanol was
hydrogenated in the presence of PtO2 at room tem-
perature; about 202 mL of hydrogen was absorbed
before the end of the reaction. Afterwards, the cat-
TABLE 1 Characteristic Results of 2-Nitrophenylhydrazones of Pyruvic Acid 1a–fa
Elemental Analysis
Found (Calculated)
R1
H
R2
H
Yield (%)
mp ( ◦C)
227–228
228–229
225–229
236–237
232–233
201–202
Molecular Formula
C9H9N3O4 (232.2)
C9H8ClN3O4 (257.6)
C9H8ClN3O4 (257.6)
C9H8BrN3O4 (302.1)
C9H8BrN3O4 (302.1)
C9H7ClN4O6 (268.2)
C (%)
H (%)
N (%)
1a
1b
1c
1d
1e
1f
95
92
95
95
95
90
48.39
(48.43
42.03
(41.96
41.97
(41.96
35.92
(35.78
35.59
(35.78
35.85
(37.72
4.25
4.06
3.21
3.13
3.17
3.13
2.55
2.67
2.85
2.67
2.37
2.33
18.76
18.83)
16.45
16.31)
16.20
16.31)
14.07
13.91)
14.08
13.91)
18.60
18.52)
Cl
H
H
Cl
H
Br
H
Br
Cl
NO2
aAll compounds decomposed beyond their melting points.

168 Khodja et al.
TABLE 2 Spectral Data of 2-Nitrophenylhydrazones of Pyruvic Acid 1a–f
IR (ν, cm−1) (KBr)
1H NMR (δ, ppm) (DMSO-d6)
UV---Vis (EtOH)
λmax (log ε)
NH, CO
CH3
H-Ar
NH
1a
223 (4.03)
281 (4.10)
303 (4.17)
416 (3.82)
207 (4.11)
308 (4.20)
422 (3.79)
224 (3.85)
287 (4.15)
301 (4.13)
407 (3.68)
211 (4.15)
307 (4.25)
422 (3.84)
222 (3.73)
288 (4.00)
300 (3.99)
404 (3.86)
207 (4.17)
277 (4.13)
346 (4.11)
3295; 1670
2.34 (s, 3H)
7.24 (t, 1H)
7.91 (t, 1H)
8.20 (dd, 1H)
8.33 (dd, 1H)
7.92 (dd, 1H)
8.18 (d, 1H)
8.29 (d, 1H)
7.25 (dd, 1H)
8.19 (d, 1H)
8.30 (d, 1H)
10.79 (s, 1H)
1b
1c
3320; 1720
3305; 1675
2.33 (s, 3H)
2.38 (s, 3H)
10.68 (s, 1H)
10.75 (s, 1H)
1d
1e
3315; 1710
3305; 1690
2.31 (s, 3H)
2.37 (s, 3H)
8.10 (d, 2H)
8.43 (d, 1H)
10.70 (s, 1H)
10.69 (s, 1H)
7.37 (dd, 1H)
8.23 (d, 1H)
8.40 (d, 1H)
1f
3305; 1695
2.41 (s, 3H)
8.47 (s, 1H)
9.09 (s, 1H)
10.83 (s, 1H)
was diastereoselective, that is, the isomer (Z) was
exclusively formed as revealed by H NMR analysis
appreciable amount of HCl or HClO4, only the (E)
isomer was detected. The high melting points of
1a–f also suggest the (Z) conformation as reported
[27]. Also, in this line, Zeghough et al. [28] outlined
the synthesis of 3,3ꢁ-dichloro-4,4ꢁ-diphenylene dihy-
drazone ethyl pyruvate and obtained a yellow crystal
which melted at 215–218◦C.
Elemental analysis results also supported the
success of the reaction providing the expected prod-
ucts. Infrared spectroscopy showed two distinct
bands fluctuating between 3295–3320 and 1670–
1720 cm−1 attributed to the absorptions of NH and
C O of the carboxylic group, respectively. The broad
bands at around 3295–3320 cm−1, which appeared in
the IR spectra, suggest the formation of a hydrogen
bonding mentioned above.
1
(Table 2); a single downfield peak was observed at
δ 10.68–10.88 ppm, and was assigned to the proton
affixed to the nitrogen atom. The exclusive forma-
tion of the (Z) isomer is probably due to the cre-
ated hydrogen bonding forming two six-membered
heterocyclic moieties as illustrated in A. Moreover,
thin layer chromatography analysis using different
eluting systems revealed one spot, indicating the
presence of a single compound. The formation of
only the (Z) isomer was also observed in a simi-
lar work [27]. It should be noted that in neutral or
slightly acidic media, the synthesis of the methyl and
ethyl pyruvate of nitrophenylhydrazones gave a mix-
ture of (E) and (Z); whereas, in the presence of an
(1)

Two-Step Syntheses of 3-Methyl and 3-Phenyl-1,2,4-Benzotriazines 169
TABLE 3 Characteristic Results of 3-Methyl-1,2,4-benzotriazines 2a–f
Elemental Analysis
Found (Calculated)
R1
H
R2
H
Yield (%)
mp ( ◦C)
94–95
Molecular Formula
C8H7N3 (145.2)
C (%)
H (%)
N (%)
2a
2b
2c
2d
2e
2f
69
57
52
52
53
63
65.80
(66.19
53.37
(53.50
53.72
(53.50
43.01
(42.88
42.76
(42.88
49.52
(49.37
4.86
4.86
3.41
3.37
3.31
3.37
2.68
2.70
2.71
2.70
3.58
3.63
28.88
28.95)
23.32
23.40)
23.18
23.40)
18.67
18.75)
18.88
18.75)
28.61
28.79)
Cl
H
112–114
136–137
117–118
127–128
233–234
C8H6ClN3 (179.6)
C8H6ClN3 (179.6)
C8H6BrN3 (224.1)
C8H6BrN3 (224.1)
C8H7ClN4 (194.6)
H
Cl
H
Br
H
Br
Cl
NO2
Under atmospheric pressure and at room tem-
parent isomers 2c and 2e, and this was not the case
for the phenylhydrazones. The elemental analysis re-
sults indicate the authenticity of the products. The
latter were also characterized by UV–Vis, IR, and
1H NMR spectra, and the results are compiled in
Table 4. The IR spectra revealed the disappearance
of the bands at 3295–3320 and 1670–1720 cm−1 of
the secondary amine and the carbonyl, respectively.
Moreover, the singlet peak at δ 10.68–10.88 ppm was
perature, the hydrogenation of different phenylhy-
drazones 1a–f was conducted in ethanol and in the
presence of PtO2 as a catalyst (Eq. (2)). The nitro
group is first reduced to the amino group followed by
a cyclization (in the case of 1f, the two nitro groups
are, obviously, both reduced leading to the corre-
sponding 2f). The intramolecular cyclization [9] is
promoted by the nucleophilic attack of the nitrogen
lone electron pair on the adjacent amino group upon
the carbon of the C N bond. This attack is followed
by a concomitant decarboxylation and an air oxida-
tion affording the desired products 2a–f. In Eq. (2),
1
absent in the H NMR spectra, suggesting that cy-
1
clization had occurred. The H NMR results shown
in Table 4 are in a good agreement with the molecu-
lar structures of the products 2a–f.
(2)
the intermediate products are illustrated in order to
provide an insight into the occurrence of the final
products. These products (2a–f) were obtained in
moderate yields as can be seen in Table 3. The prod-
uct 2a was formed in 69% yield, which is the high-
est. It is interesting to note that the melting points
depend on the nature of the substituents and their
positions on the phenyl ring. For example, the melt-
ing points of 2b and 2d are lower than those of their
It is worth mentioning that attempts were
made to use a number of other reducing agents
to convert the nitro group of the phenylhydra-
zones into the amino functionality and either they
failed or the yields were not satisfactory. Both sys-
tems, such as metals in acidic media (Zn/HCl,
Zn/AcOH, Sn/AcOH) and sodium bisulfite (or
sodium borohydride), were inefficient. However,
sodium dithionite and the Fe/aq. NaCl system were

170 Khodja et al.
TABLE 4 Spectral Data of 3-Methyl-1,2,4-benzotriazines
2a–f
successful but afforded yields of only 30 and 10%,
respectively.
UV---Vis (EtOH)
λmax (log ε)
Solvent
1H NMR (δ, ppm)
Synthesis of 3-Phenyl-1,2,4-benzotriazines 4a–c
2a
2b
2c
2d
2e
2f
234 (4.03)
303 (3.38)
332 (3.20)
446 (2.48)
237 (4.30)
317 (3.74)
443 (2.43)
CDCl3
3.10 (s, 3H)
7.60–8.50 (m, 4H)
First, the reaction of the corresponding 2-nitro-
phenylhydrazines with benzoimino-ester afforded
the 2-nitrophenylhydrazono-ethers 3a–c (Eq. (3)).
Some other 2-nitrophenylhydrazono-ethers that re-
sulted from the reaction of imino-esters and 2-
nitrophenylhydrazines were reported earlier, and
served as precursors for the synthesis of the cor-
responding 1,2,4-benzotriazines [2]. In the present
work, the used imino-ester was made using the Pin-
ner reaction starting with benzonitrile. The forma-
tion of hydrazono-ethers 3a–c was not as instanta-
neous as that of hydrazones 1a–f, hinting probably at
the effect of the two six-membered heterocyclic moi-
eties shown in A. The precipitation of 3a–c indeed
occurred only after 1 h of reaction, but the products
were obtained in a high purity. Second, these highly
pure hydrazono-ethers were hydrogenated at room
temperature in the presence of Pt/C as a catalyst (Eq.
(4)). The reaction took place via a tetrahydro inter-
mediate, as for 3-methyl-1,2,4-benzotriazines, which
CDCl3
CDCl3
3.06 (s, 3H)
7.69 (dd, 1H)
7.90 (d, 1H)
8.38 (d, 1H)
3.13 (s, 3H)
7.83 (d, 2H)
8.40 (d, 1H)
237 (4.49)
294 (3.41)
345 (3.46)
454 (2.46)
242 (4.30)
322 (3.83)
448 (2.47)
CDCl3
3.07 (s, 3H)
7.80 (dd, 1H)
8.09 (d, 1H)
8.29 (d, 1H)
3.08 (s, 3H)
7.76 (d, 1H)
7.95 (dd, 1H)
8.61 (d, 1H)
2.74 (s, 3H)
6.83 (s, 1H)
7.09 (s, 2H)
8.26 (s, 1H)
239 (4.44)
292 (3.48)
344 (3.49)
447 (2.34)
224 (4.34)
270 (4.34)
402 (3.90)
CDCl3
DMSO-d6
TABLE 5 Characteristic Results of 3-Phenyl-1,2,4-benzotriazines 4a–c
Elemental Analysis
Found (Calculated)
R1
H
R2
H
Yield (%)
mp ( ◦C)
126–127
169–170
136–138
Molecular Formula
C (%)
H (%)
N (%)
4a
4b
4c
75
72
84
C13H9N3 (207.2)
75.34
(75.12
64.60
(64.48
54.56
(54.39
4.38
4.29
3.34
3.17
2.82
2.98
20.27
20.45)
17.39
17.25)
14.69
14.51)
H
Cl
H
C
13H8ClN3 (241.7)
13H8BrN3 (286.1)
Br
C
TABLE 6 Spectral Data of 3-Phenyl-1,2,4-benzotriazines 4a–c
UV---Vis (EtOH)
λmax (log ε)
IR (ν, cm−1) (KBr)
1H NMR (δ, ppm) (CDCl3)
4a
4b
214 (4.09)
263 (4.31)
356 (2.47)
1500
1450
1325
7.42–7.58 (m, 3H)
7.65–8.02 (m, 3H)
8.33–8.50 (m, 1H)
8.60–8.75 (m, 2H)
7.37–7.62 (m,3H)
7.76 (q, 1H)
216 (4.13)
263 (4.36)
370 (3.59)
463 (2.45)
1495
1405
1310
7.96 (d, 1H)
8.41 (d, 1H)
8.56–8.75 (m, 1H)
7.37–7.63 (m, 3H)
7.79 (dd, 1H)
8.16 (d, 1H)
8.29 (d, 1H)
4c
217 (4.17)
270 (4.34)
354 (3.14)
454 (2.45)
1495
1410
1310
8.50–8.75 (m, 2H)

Two-Step Syntheses of 3-Methyl and 3-Phenyl-1,2,4-Benzotriazines 171
led to the products 4a–c upon evaporation of ethanol
and subsequent oxidation by air. Interestingly, the
overall yields of 4a–c were higher than 72%. Elemen-
tal analyses and spectral data shown in Tables 5 and
6, respectively, confirmed the products structures. 1H
NMR results for all products showed peaks at 7.37–
8.75 ppm pertaining to the protons of the two phenyl
rings. The UV–Vis spectra revealed bands in the UV
region (214–270 nm) and two to three bands in the
visible region (354–463 nm). All products decom-
posed beyond their melting points which are higher
than those of their methyl-1,2,4-benzotriazine ana-
logues (2a, 2c, 2d).
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