BENZOTRIAZINONES

Benzotriazinone is an oxo derivative of benzotriazine, a bicyclic aromatic structure

consists of seven carbon and three nitrogen atoms.
(1)
There are two isomers (1 and 2) of
benzotriazinone that differ in their position of nitrogen atoms.
(2)

NH
N
N
O
1,2,3-benzotriazin-4(3H)-one
N
N
H
N
O
1,2,4-benzotriazin-3(2H)-one


(1) (2)

1,2,3-Benzotriazin-4(3H)-ones represent a class of heterocycles that have a number of
applications. Azinphos methyl (3) is its commercial insecticide.
(19)



N
N
N
O
S
P
O
Z
O
R
1
R
1
C H
3


(3)

Some polymeric benzotriazinone derivatives of formula (4) have proved to be useful for an
imaging medium.
(20)




(4)

NH
N
N
O NO
2
NC
O2N
OH
Diazo compound including benzotriazinones of formula (4) have been tested as a recording
material and it formed a vivid color image ranging from violet to cyan hues to produce good
recording properties. So it can be used for both thermal and pressure-sensitive recording
materials.
(21)


N
N
N
O
SO
2
R
4
R
4
R
1
R
2
R
3


(4)

Matrix metalloproteases can inhibited by the use of some benzotriazinone derivatives (5) to
control inflammatory diseases.
(22)


N
N
N
O
CO
2
H
R
1
O
n


(5)


N-Substituted benzotriazinones (6) have found to useful for the inhibation of histone deacetylase
to treat cell poliferative diseases.
(23)


NHOH
O
N
N
N
O


(6)

Another benzotriazinone (7) derivative has found to be useful for the prevention and treatment of
cerebral insufficiency diseases including schizophrenia and Parkinson s disease by enhancing
glutamatergic synaptic responses.
(24)



N
N
N
O
N
N
+
N
R
1
N
O
O


(7)

1,2,3-benzotriazin-4-one derivatives (8 and 9) have proved as additives to photograpihic plate or
as forming or blowing agents to produce cellular and porous articles based on synthetic,
particularly on thermoplastic resin.
(25)


N
N
N
O
SO2
CH
3

NH
N
N
O R
R1
R2
R
3


(8) (9)

It has been claimed that a series of 3-alkyl, 3-alkylamino, and 3-imino-alkyl derivatives of 6-
sulfamoyl-7-chloro-1,2,3-benzotriazin-4(3)-one shows diuretic activity.
(26, 27)
3-dialkylaminomethyl compounds have researched as an antidepressant.
(28, 29)


Some nuclear halogenated 3-alkyl derivatives of 1,2,3-benzotriazinones have found to be useful
sedatives for the treatment of psychoneurosis.
(30)


Some 1,2,3-benzotriazinone derivatives have shown its antipyretic and sedative activity.
A series of esters of nuclear halogenated 3-carboxy-1,2,3-benzotriazin-4(3H)-one has shown its
depressant activity, while the benzoate ester of substituted 3-(2-hydroxyethyl)-1,2,3-
benzotriazinon-4(3H)-one have reported to function as a coronary dilating agents.
(31)


3-(o-Haloaryl)-1,2,3-benzotriazin-4(3H)-ones are claimed to have antisecretory, anoretic,
anticonvulsants and hypoglycemic activity.
(32)


3-aryl benzotriazinone derivatives have been stated to be use as relaxant, tranquiuzers, sedative,
hypnotic or cramp inhibitors.
(33)


Its 3-alkyl derivatives containing a terminal sulfonamide group have been claimed to act as an
antidiabetics.
(34)


1,2,3-benzotriazinones masked diazonium compounds, so called as Pologenowe dyes. These
were developed in Poland and it is using their since 1959. There are three major advantages
associated with the use of 1,2,3-benzotriazinones as azo-dye equivalents:

Equilibrium exist between the heterocyclic system and the diazonium compound and
preferably goes to the side of the cyclic compound.

Opening of the heterocyclic ring can be easily accomplished thermally, and hence dye
formation can be induced by heat treatment processes.

Most of the benzotriazinones are reasonably water soluble and even their sodium salts are
easily formed which is more water soluble.
(35, 36)




3-hydroxy derivative of 1,2,3-benzotriazinone is used in peptide synthesis as an acylating agent.

(37)


OH
N
N
N
O



Some benzotriazinones has been found to show its contraceptive activity in both male and female
mice, but this observation has not apparently been followed further.
(38, 39)


A number 2-alkyl-1,2,3-benzotriazin-4(3H)ones salts similar to those described earlier have been
used as protective coatings and in the formulation of adhesives.
(40)


3-alkyl-1,2,3-benzotriazin-4(3H)ones have been examined as potential irreversible inhibitors of
chymotrypsin.
(41)


3-(1-adamantyl)-1,2,3-benzotriazinone derivative has proved as a potential virus inhibitor.
(42)


1,2,3-BENZOTRIAZIN-4(3H)-ONES

1,2,3-Benzotriazin-4(3H)-ones are also called as benzazimides, are the most intensively
studied class of 1,2,3-benotriazines. Finger was the first one who designed its synthesis in 1888
by the reaction of anthranilamides with nitrous acid.
(3)


NH
N
N
O
NH
2
NH
2
O
HNO
2


But Zacharias accomplised its synthesis by treating alkyl anthranilates with nitrous acid
and ammonia.
(4)


N
N
N
O
H
O
NH
2
R
O
HNO
2
NH
3


1,2,3-Benzotriazin-4(3H)-ones have its two tautomeric forms (1 and 2). So scientists studied its
structure to determine which tautomer is more stable under neutral conditions.
N
N
N
O
H
N
N
N
O
H
1 2


Infrared spectra of 1,2,3-Benzotriazin-4(3H)-ones showed an intensive band between 1700 and
1667 cm
-1
that confirmed CO-NH group. The PMR spectrum indicated signal for the N-H proton
at -1.00T and a multiplet for the four aromatic protons between 1.90 and 2.40T that proved 1 as a
more stable tautomeric form.
(5,6)
In different publications its mass spectrometry analysis has also
been studied. Whenever it is exposed to mass spectrometer then it mass fragmentation starts with
the loss of nitrogen that is followed by loss of carbon monoxide.
(7, 8)




Karvellas studied whole structure of 1,2,3-Benzotriazin-4(3H)-ones to find its bond lengths
and bond angles.
(9)



RING ATOMS BOND LENGTHS
RING ATOMS BOND
ANGLES(
0
)
C
3
-N
3
-N
3

-
128
N
3
-N
3
-N
3
119
N
3
-N
3
-C
3
120
C
3
-C
3
-N
3
113
N
N
N
O
R
3
X
N
O
R
3
X
-N2
-CO
[XC6H3NR]+
N
N
0
2
N
1
O
H
1
2
3
4
5
6
(A
0
)
N
1
-N
2
1.38
N
2
-N
3
1.27
N
3
-C
4
1.40
C
4
-C
5
1.40
C
5
-C
6
1.46

C
6
-N
1
1.37



Bamberger and Goldberger introduced a new method for the synthesis of benzazimides
that involves the action of oxidizng agents (permagnate, bichromate, persulphate or hydrogen
peroxide) upon 3-aminoindaoles. Reaction mechanism involves hydrolytic opening of indiaole
ring to o-hydrazinobenaimides followed by oxidiation to a diazonium compound which is
cyclized to benzazimides.
(10, 11, 12)


N
N
N
O
H
N
H
N
NH
2
H
2
O
NHNH
2
CONH
2
oxid.


Benzotriazinone can also be synthesized by using isotactic anhydride with amino
Heteroaryl/hexanoic acid derivatives in the presence of triethylamine followed by cyclization in
the presence of nitrous acid.
(13)


N
N
N
O
OH
O
N
H
O
O
O
Et
3
N
NaNO
2
N H
2
OH
O
+
HCl


When N-substituted o-azidobenzamide is reacted with triphenylphosphine or
diphenylmethylphosphine then phosphazides are formed that further treated with isocyanates to
have 1,2,3-benzotriazin-3(4H)one derivatives.
(14)



N3
NH
O
O
CH
3
ArNCO
+
NH
O
O
N
-
N
N
CH
3
PPH
3
N
O
N
N
O
CH
3



REACTIVITY

1,2,3-Benzotriazin-4(3H)-one ring systems are slightly acidic compounds so they are
easily soluble in aqueous or alcoholic bases. But when it is exposed to cold aqueous potassium
hydroxide then it converts to anthranilic acid and in hot aqueous alkali converts to diazoamino
compounds.
(15)


N
N
N
O
R
3
COONa
N
N
NH
R
aqueous or
alcoholic NaOH
OH
NH
2
O
cold
hot
R=H
R=Phenyl


It is also affected by acidic media but ring breakage depends upon the nature and the
concentration of the acids. With hot dilute Sulphuric acid, upon short heating anthranilic acid is
formed but when longer heat is provided then it transformed to salicyclic acid.
(16)


N
N
N
O
R
3
OH
COOH
OH
NH
2
O
long
heating
short term
heating

Most of the reaction of benzotriazinone occurs at third nitrogen which behaves as a
nucleophile to attack at electron deficient center. So alkylation of 1,2,3-benzotriazinones can be
accomplished by using alkyl halides.
(17)


N
NH
N
O
RX
N
N
N
O
R
3


Its acylation reactions are also easy done. Popular insecticide azinphos methyl is also prepared
by formylation of benzotriazinone that is further treated with thionyl chloride and dialkoxy
phosphinodithioic acid.
(18)


N
NH
N
O
N
N
N
O
CH
2
Cl
N
N
N
O
CH
2
OH
N
N
N
O
S
P
R
1
S
R
1
HCHO SOCl
2
RR
1
PS
2
H


APPLICATIONS OF 1,2,3-BENZOTRIAZINONES

1,2,3-Benzotriazinones represent a class of heterocycles that have its number of
applications. Its first use was researched in the field of agriculture as an insecticide, azinphos
methyl.
(19)


N
N
N
O
S
P
O
Z
O
R
1
R
1
C H
3


Some polymeric benzotriazinone derivatives of formula (3) have proved to be useful for an
imaging medium.
(20)



NH
N
N
O NO
2
NC
O2N
OH

(3)

Diazo compound including benzotriazinones of formula (4) have been tested as a recording
material and it formed a vivid color image ranging from violet to cyan hues to produce good
recording properties. So it can be used for both thermal and pressure-sensitive recording
materials.
(21)


N
N
N
O
SO
2
R
4
R
4
R
1
R
2
R
3


(4)

Matrix metalloproteases can inhibited by the use of some benzotriazinone derivatives (5) to
control inflammatory diseases.
(22)


N
N
N
O
CO
2
H
R
1
O
n


(5)


N-Substituted benzotriazinones (6) have found to useful for the inhibation of histone deacetylase
to treat cell poliferative diseases.
(23)


NHOH
O
N
N
N
O


(6)

Another benzotriazinone (7) derivative has found to be useful for the prevention and treatment of
cerebral insufficiency diseases including schizophrenia and Parkinson s disease by enhancing
glutamatergic synaptic responses.
(24)



N
N
N
O
N
N
+
N
R
1
N
O
O


(7)

1,2,3-benzotriazin-4-one derivatives (8 and 9) have proved as additives to photograpihic plate or
as forming or blowing agents to produce cellular and porous articles based on synthetic,
particularly on thermoplastic resin.
(25)


N
N
N
O
SO2
CH
3

NH
N
N
O R
R1
R2
R
3


(8) (9)

It has been claimed that a series of 3-alkyl, 3-alkylamino, and 3-imino-alkyl derivatives of 6-
sulfamoyl-7-chloro-1,2,3-benzotriazin-4(3)-one shows diuretic activity.
(26, 27)
3-dialkylaminomethyl compounds have researched as an antidepressant.
(28, 29)


Some nuclear halogenated 3-alkyl derivatives of 1,2,3-benzotriazinones have found to be useful
sedatives for the treatment of psychoneurosis.
(30)


Some 1,2,3-benzotriazinone derivatives have shown its antipyretic and sedative activity.
A series of esters of nuclear halogenated 3-carboxy-1,2,3-benzotriazin-4(3H)-one has shown its
depressant activity, while the benzoate ester of substituted 3-(2-hydroxyethyl)-1,2,3-
benzotriazinon-4(3H)-one have reported to function as a coronary dilating agents.
(31)


3-(o-Haloaryl)-1,2,3-benzotriazin-4(3H)-ones are claimed to have antisecretory, anoretic,
anticonvulsants and hypoglycemic activity.
(32)


3-aryl benzotriazinone derivatives have been stated to be use as relaxant, tranquiuzers, sedative,
hypnotic or cramp inhibitors.
(33)


Its 3-alkyl derivatives containing a terminal sulfonamide group have been claimed to act as an
antidiabetics.
(34)


1,2,3-benzotriazinones masked diazonium compounds, so called as Pologenowe dyes. These
were developed in Poland and it is using their since 1959. There are three major advantages
associated with the use of 1,2,3-benzotriazinones as azo-dye equivalents:

Equilibrium exist between the heterocyclic system and the diazonium compound and
preferably goes to the side of the cyclic compound.

Opening of the heterocyclic ring can be easily accomplished thermally, and hence dye
formation can be induced by heat treatment processes.

Most of the benzotriazinones are reasonably water soluble and even their sodium salts are
easily formed which is more water soluble.
(35, 36)




3-hydroxy derivative of 1,2,3-benzotriazinone is used in peptide synthesis as an acylating agent.

(37)


OH
N
N
N
O



Some benzotriazinones has been found to show its contraceptive activity in both male and female
mice, but this observation has not apparently been followed further.
(38, 39)


A number 2-alkyl-1,2,3-benzotriazin-4(3H)ones salts similar to those described earlier have been
used as protective coatings and in the formulation of adhesives.
(40)


3-alkyl-1,2,3-benzotriazin-4(3H)ones have been examined as potential irreversible inhibitors of
chymotrypsin.
(41)


3-(1-adamantyl)-1,2,3-benzotriazinone derivative has proved as a potential virus inhibitor.
(42)