4-aryl-1-hydrazino-5H-2,3-benzodiazepine and 1-aryl-4-hydrazino-5H-2,3- benzodiazepine in the synthesis of condensed [1,2]diazepines

Article abstract of DOI:10.1007/s10593-013-1249-6

A method has been developed for the cyclization of 4-aryl-1-hydrazino-5H-2, 3-benzodiazepine and 1-aryl-4-hydrazino-5H-2,3-benzodiazepine into 3-R-6-aryl-7H-[1,2,4]triazolo[3,4-a]- and 3-R-6-aryl-7H-[1,2,4]triazolo[4,3-c] benzodiazepine derivatives with various substituents in the triazole ring.

Full text of DOI:10.1007/s10593-013-1249-6

Chemistry of Heterocyclic Compounds, Vol. 49, No. 2, May, 2013 (Russian Original Vol. 49, No. 2, February, 2013)
4-ARYL-1-HYDRAZINO-5H-2,3-BENZODIAZEPINE AND
1-ARYL-4-HYDRAZINO-5H-2,3-BENZODIAZEPINE IN THE
SYNTHESIS OF CONDENSED [1,2]DIAZEPINES
O. I. Kharaneko1*, V. Yu. Popov1, and S. L. Bogza1
A method has been developed for the cyclization of 4-aryl-1-hydrazino-5H-2,3-benzodiazepine and
1-aryl-4-hydrazino-5H-2,3-benzodiazepine into 3-R-6-aryl-7H-[1,2,4]triazolo[3,4-a]- and 3-R-6-aryl-
7H-[1,2,4]triazolo[4,3-c]benzodiazepine derivatives with various substituents in the triazole ring.
Keywords: [1,2,4]triazolo[3,4-a][2,3]benzodiazepine, [1,2,4]triazolo[4,3-c][2,3]benzodiazepine, cyclization.
2,3-Benzodiazepine derivatives have shown themselves to be promising ligands of AMPA glutamate
receptors [1]. Annelation of an imidazole ring at the edge c of the benzodiazepine system preserves the high
level of neurotropic activity, and emphasizes the anticonvulsant and neuroprotective components in the
pharmacological profile [2, 3]. The spectrum of the biological activity of 2,3-benzodiazepines annelated with
azoles raises the hope that other similar structural modifications will be of value in medicinal chemistry.
In a previous study [4], we described a synthetic method for a new heterocyclic system –
[1,2,4]triazolo[3,4-a][2,3]benzodiazepine 2 – by the cyclization of 1-hydrazino-4-(4-methoxyphenyl)-5H-2,3-benzo-
diazepine (1) with carboxylic acids in the presence of catalytic quantities of hydrochloric acid.
OMe
OMe
7
RCOOH
H+
6
N
N
N
11b
N
N
HN
R
3
N
2
NH2
1
R = Me, Et, (MeO)2C6H3CH2
It was noted that under these conditions benzoic acid gave different products, the structure of which we
could not establish.
_______
*To whom correspondence should be addressed, e-mail: kharaneko@ukr.net, o_kharaneko@mail.ru.
1L. M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, National Academy of Sciences
of Ukraine, 70 R. Luxemburg St., Donetsk 83114, Ukraine.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 2, pp. 343-350, February, 2013. Original
article submitted May 14, 2012.
0009-3122/13/4902-0317©2013 Springer Science+Business Media New York
317

We established that 4-(4-methoxyphenyl)-2,5-dihydro-1H-2,3-benzodiazepin-1-one (3) on refluxing in
water for 1-2 min with a twofold excess of hydrochloric acid was converted quantitatively into 2-amino-3-(4-meth-
oxyphenyl)isoquinolin-1(2H)-one hydrochloride (4).
OMe
OMe
HCl
H2O, 
N
N
NH
2 · HCl
N
O
H
O
4
3
At the same time, 1-hydrazino-4-(4-methoxyphenyl)-5H-2,3-benzodiazepine (1) remained unchanged
on refluxing in water for 30 min with a twofold excess of hydrochloric acid.
We have established in the present work that 6-(4-methoxyphenyl)-3-phenyl-7H-[1,2,4]triazolo[3,4-a]-
[2,3]benzodiazepine hydrochloride (5a) was formed on refluxing hydrazine 1 with benzoyl chloride for 1 h in
absolute dioxane. In a similar way we also obtained the triazolobenzodiazepines 5b,c. In addition, we achieved
the cyclization of compound 1 with the acyl chloride of succinic acid monoester to give compound 6, and with
N-phthalimido-substituted carboxylic acids we obtained compounds 7a-c.
ArCOCl
OMe
1
Dioxane
N
· HCl
N
N

N
Ar
5a–c
OMe
1) MeOOCCH CH COCl,
dioxane, 
2
2
N
2) NaOH, H2O, 
N
N
N
COOH
6
OMe
O
N
O
(CH2)n
N
N
OMe
O
N
Cl
NaOH, N2H4
N
N
(CH2)n
N
N
Dioxane
2-PrOH, 
O

N
N
(CH2)n
O
H2N
8a–c
7a–c
5 a Ar = Ph, b Ar = 2-2-furyl, с Ar = 1,3-dimethyl-1H-pyrazol-5-yl; 7, 8 a n = 1, b n = 2, c n = 3
We obtained 3-aminoalkyl-substituted derivatives 8a-c by hydrazinolysis of the phthaloyl group of
triazolobenzazepines 7a-c.
318

Cyclization of 4-hydrazino-7,8-dimethoxy-1-phenyl-5H-2,3-benzodiazepine (9a) and 1-(2-chloro-
phenyl)-4-hydrazino-7,8-dimethoxy-5H-2,3-benzodiazepine (9b) [5] with acyl chlorides derived from
heterocyclic and functionally substituted acids proceeded under the same conditions as the cyclization of
compound 1. This enabled us to obtain triazolobenzodiazepines 10a,b and 11 by a significantly simpler method
than that proposed earlier [6].
H
N
N
NH2
N
MeO
MeO
MeO
MeO
N
1) MeOOCCH2CH2COCl,
N
dioxane, 
N
N
2) NaOH, H2O, 
O
R
R
HO
9a,b
10a,b
O
N
N
MeO
MeO
Me
Cl
(from 9a)
N
N
N
N
Me
Me
N
Me
N
· 2HCl
11
9, 10 a R = H, b R = Cl
The principal characteristics of the obtained compounds are given in Table 1. The structures of the
synthesized compounds were confirmed by 1H and 13C NMR, as well as IR spectra (Table 2).
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Yield,
%
Mp, °С
C
H
Cl
N
C16H14N2O2·HCl
C23H18N4O·HCl
C21H16N4O2·HCl
C22H20N6O·2HCl
C20H18N4O3
63.51
63.47
68.55
68.57
64.23
64.21
57.81
57.78
66.25
66.29
64.29
64.27
64.89
64.87
65.41
65.43
5.01
4.99
4.81
4.75
4.41
4.36
4.82
4.85
5.02
5.01
4.13
4.15
4.41
4.44
4.72
4.71
11.70
11.71
8.81
8.80
9.00
9.02
15.52
15.50
9.22
9.25
13.79
13.91
14.30
14.26
18.42
18.37
15.53
15.46
14.42
14.41
14.00
14.01
13.62
13.63
107-108
182-183
214-216
178-179
227-229
197-199
206-208
190-192
74-76
98
99
99
89
54
92
94
94
91
94
92
4
5а
5b
5с
6
—
C26H19N5O3·HCl
C27H21N5O3·HCl
C28H23N5O3·HCl
C18H17N5O
7.13
7.30
7.11
7.09
7.01
6.90
—
7a
7b
7c
8a
8b
8c
67.72
67.70
68.48
68.45
57.11
57.15
5.39
5.37
5.73
5.74
5.50
5.52
21.92
21.93
21.03
21.01
16.68
16.66
C19H19N5O
—
65-67
C20H21N5O·2HCl
16.89
16.87
—
159-163
C21H20N4O4
64.32
64.28
59.11
59.09
56.70
56.68
5.22
5.14
4.52
4.49
5.99
4.96
14.31
14.28
13.19
13.13
17.25
17.24
117-120
110-112
184-186
72
57
32
10a
10b
11
C21H19ClN4O4
C23H22ClN6O2·2HCl
8.33
8.31
14.53
14.55
319

In the 1H NMR spectra of compounds 5a-c, 6, 7a-c, 8a-c, 10a,b, and 11, there was a singlet at 4.08-4.32
ppm, assigned to the diazepine ring CH2 group (according to the data of [6], similar compounds had this
1H NMR signal at 3.8-3.9 ppm). In the 13C NMR spectra of compounds 5a, 6, and 8a-c, there were signals
belonging to the triazole ring C-3 carbon atom at 147-148 ppm, which matched the published spectra of
analogous compounds [7], and a signal for the C-11b atom at 150-154 ppm. The diazepine ring C-7 atom (CH2
group) gave a signal at 53-54 ppm.
1
A two-dimensional H–13C HMBC spectrum was recorded for the compound 5a. Key interactions
confirming the structure of compound 5a are given in Figure 1.
Fig. 1. Two-dimensional 1H–13C HMBC spectrum of compound 5a.
Our investigations have thus enabled a convenient synthesis of isomeric triazolo-condensed
2,3-benzodiazepines with many options for their functionalization. The method developed by us for the
annelation of a triazole ring to 2,3-benzodiazepines has advantages when compared to known methods, not only
in convenience and high yields of the final products, but also in the possibility of obtaining 3-carboxyalkyl- and
3-aminoalkyl-substituted triazolobenzodiazepines with a variable length of linker, which provides attractive
opportunities in the search for lead structures in medicinal chemistry.
320

EXPERIMENTAL
The IR spectra were recorded on an IR-75 instrument in KBr pellets. The 1H and 13C NMR spectra were
recorded on a Bruker Avance II instrument (400 and 100 MHz, respectively) in DMSO-d6, internal standard was
TMS. Elemental analysis was carried out using an Elementar vario El cube analyzer. Melting points were
determined with a Boetius type hot stage apparatus and were not corrected.
2-Amino-3-(4-methoxyphenyl)isoquinolin-1(2H)-one Hydrochloride (4). Conc. HCl (0.3 ml,
4 mmol) was added to a suspension of 4-(4-methoxyphenyl)-2,5-dihydro-1H-2,3-benzodiazepin-1-one (3)
(1.0 g, 3.76 mmol) in boiling water (10 ml). The mixture was boiled for 5 min. The starting compound 3
dissolved completely in the first minute, and after its dissolution the product 4 immediately began to separate.
The mixture was cooled, the colorless crystalline solid was filtered off, washed with water, and air-dried.
6-(4-Methoxyphenyl)-3-phenyl-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepine Hydrochloride (5a).
1-Hydrazino-4-(4-methoxyphenyl)-5H-2,3-benzodiazepine (1) (1.0 g, 3.6 mmol) and abs. dioxane (5 ml) were
placed in a 20-ml round bottom flask. The mixture was heated until complete dissolution of the solid, and then
benzoyl chloride (0.5 ml, 4.3 mmol) was added to the solution. The mixture was heated in the flask under reflux
for 1 h. The solid precipitated at the beginning of the addition gradually dissolved, and then precipitation of the
final product began. At the end of refluxing, the solution was cooled to room temperature, the solid was filtered
off, washed with a small volume of abs. dioxane, and air-dried.
3-(2-Furyl)-6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepine hydrochloride (5b)
was obtained analogously using furan-2-carboxylic acid chloride.
6-(4-Methoxyphenyl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiaze-
pine Dihydrochloride (5c). Hydrazine 1 (1.0 g, 3.6 mmol) and abs. dioxane (5 ml) were placed in a 20-ml
round bottom flask. The mixture was heated until full dissolution, then 1,3-dimethylpyrazole-5-carboxylic acid
chloride (0.7 g, 4.4 mmol) was added to the solution with stirring. The mixture was heated under reflux for 1 h.
The solid that initially precipitated was gradually dissolved. At the end of refluxing, the solution was cooled to
room temperature and poured into hot water (30 ml) containing conc. HCl (2 ml). The precipitated oil
crystallized on trituration. After cooling, the solid was filtered off, washed with water, and air-dried.
3-[6-(4-Methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepin-3-yl]propionic Acid (6).
Hydrazine 1 (1.0 g, 3.6 mmol) and abs. dioxane (5 ml) were placed in a 30-ml round bottom flask. The mixture
was heated to full dissolution, and the acyl chloride derived from succinic acid monomethyl ester (0.6 g, 4.0
mmol) was added with stirring. The mixture heated under reflux for 1 h, and aqueous NaOH solution (10 ml)
was added to a strongly alkaline reaction to litmus, then refluxed for a further 2 h. The dioxane was removed by
distillation in vacuum, and AcOH was added to the residue to give a weakly acidic medium. The precipitated
solid was filtered off, washed with water, and air-dried.
2-{[6-(4-Methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepin-3-yl]methyl}-1H-isoindolo-
1,3(2H)-dione Hydrochloride (7a). Hydrazine 1 (1.0 g, 3.6 mmol) and abs. dioxane (5 ml) were placed in a 20-
ml round bottom flask. The mixture was heated to complete dissolution of the solid, and phthaloylglycyl
chloride (1.6 g, 7.2 mmol) was added to the solution with stirring. The mixture in the flask was heated under
reflux for 1 h, cooled to room temperature, the solid was filtered off, and washed with a small quantity of abs.
dioxane.
2-{2-[6-(4-Methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepin-3-yl]ethyl}-1H-isoindolo-
1,3(2H)-dione hydrochloride (7b) was obtained analogously to compound 7a from hydrazine 1 and
β-phthalimidopropionic acid chloride.
2-{3-[6-(4-Methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepin-3-yl]propyl}-1H-isoindolo-
1,3(2H)-dione hydrochloride (7c) was obtained analogously to compound 7a from hydrazine 1 and
γ-phthalimidobutyryl chloride.
321

322

323

1-[6-(4-Methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepin-3-yl]methylamine
(8a).
Compound 7a (1.500 g, 3.1 mmol) was placed in a 30-ml round bottom flask, NaOH (0.124 g, 3.1 mmol),
2-PrOH (10 ml), and hydrazine hydrate (0.3 ml, 6.2 mmol) were added. The mixture was refluxed for 4 h, then
2-PrOH was distilled off under reduced pressure, water (5 ml) was added, the mixture was acidified with HCl to
a strongly acidic reaction to litmus, and the solution was brought to boiling. After slowly cooling the solution,
the precipitated solid was filtered off, washed on the filter with water (2 ml), and solid NaOH was added to the
filtrate to a strongly alkaline reaction. The separated oily residue of compound 8a crystallized with time. It was
filtered off, washed on the filter with water, and air-dried.
2-[6-(4-Methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepin-3-yl]ethylamine (8b) was
obtained analogously to compound 8a from compound 7b.
{3-[6-(4-Methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepin-3-yl]propyl}amine dihydrochlo-
ride (8c) was obtained analogously to compound 8a from compound 7c. The oil, which separated after making
the filtrate alkaline, was extracted with CH2Cl2 (25 ml). The extracts were combined, and the CH2Cl2
evaporated. The residue was dissolved in dioxane (5 ml), and a solution of HCl in ether was added to give a
strongly acidic reaction. The precipitated oil crystallized on trituration, the solid was filtered off, washed with
dioxane, and air-dried.
3-(8,9-Dimethoxy-6-phenyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepin-3-yl)propionic acid (10a)
was obtained analogously to compound 6 from 4-hydrazino-7,8-dimethoxy-1-phenyl-5H-2,3-benzodiazepine
(9a).
3-[6-(2-Chlorophenyl)-8,9-dimethoxy-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepin-3-yl]propionic
acid (10b) was obtained analogously to compound 6 from 1-(2-chlorophenyl)-4-hydrazino-7,8-dimethoxy-
5H-2,3-benzodiazepine (9b).
3-(1,3-Dimethyl-1H-pyrazol-5-yl)-6-phenyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine dihydro-
chloride (11) was obtained analogously to compound 5c from 4-hydrazino-7,8-dimethoxy-1-phenyl-5H-2,3-benzo-
diazepine (9a) and 1,3-dimethylpyrazole-5-carboxylic acid chloride.
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