Simple and efficient preparation of 3-substituted 6-(4-chlorophenyl)-9- methyl-12H-[1]benzofuro[3,2-e][1,2,4]-triazolo[4,3-b][1,2]diazepines via a silylation-amination reaction

Article abstract of DOI:10.1007/s00706-011-0500-z

A series of new 3-substituted 6-(4-chlorophenyl)- 9-methyl-12H-[1] benzofuro[3,2-e][1,2,4]triazolo- [4,3-b][1,2]diazepines was synthesized from the corresponding bicyclic 1-(4-chlorophenyl)-3,5-dihydro-8- methyl-4H-[1] benzofuro[2,3-d][1,2]diazepin-4-one. The synthesis strategy makes use of silylation-amination as the key step, allowing a wide range of derivatives to be prepared. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0500-z

Monatsh Chem (2011) 142:931–934
DOI 10.1007/s00706-011-0500-z
ORIGINAL PAPER
Simple and efficient preparation of 3-substituted
6-(4-chlorophenyl)-9-methyl-12H-[1]benzofuro[3,2-e][1,2,4]-
triazolo[4,3-b][1,2]diazepines via a silylation–amination reaction
•
Alexander Eresko Valerij Tolkunov
•
Sergej Tolkunov
Received: 10 November 2010 / Accepted: 30 March 2011 / Published online: 4 May 2011
Ó Springer-Verlag 2011
Abstract A series of new 3-substituted 6-(4-chloro-
phenyl)-9-methyl-12H-[1]benzofuro[3,2-e][1,2,4]triazolo-
[4,3-b][1,2]diazepines was synthesized from the corre-
thiones with appropriate hydrazides [3] (Scheme 1).
Because such transformations have not been described for
the [1]benzofuran series, we decided to see if tria-
zolodiazepines can be prepared from derivatives with a
[1]benzofuran fragment according to this route.
sponding
bicyclic
1-(4-chlorophenyl)-3,5-dihydro-8-
methyl-4H-[1]benzofuro[2,3-d][1,2]diazepin-4-one. The
synthesis strategy makes use of silylation–amination as
the key step, allowing a wide range of derivatives to be
prepared.
Results and discussion
Keywords Cyclizations ꢀ Fused diazepines ꢀ
Hexamethyldisilazane ꢀ Silylation–amination
1-(4-Chlorophenyl)-3,5-dihydro-8-methyl-4H-[1]benzofuro
[2,3-d][1,2]diazepine-4-one (1) was transformed into the
corresponding thione 2 by reaction with Lawesson’s
reagent in heated toluene as described elsewhere [6].
Diazepine-4-thione 2 reacts with an appropriate amount of
hydrazides by heating at reflux in n-butanol (‘‘Method A,’’
Scheme 2). New compounds 3a–3e were obtained as stable
solids in good yield.
Introduction
2,3-Benzodiazepines are a class of heterocyclic compounds
that can interact with glutamate receptors and AMPA
(2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic
acid)-type receptors in a noncompetitive manner. These
compounds are of great interest due to their pharmaco-
logical effects against acute and chronic neurodegenerative
diseases such as ischemia and epilepsy [1–5]. Pharmaco-
logical studies have revealed that tricyclic 11H-
[1,2,4]triazolo[4,3-c][2,3]benzodiazepines possess anti-
convulsant activity, which is comparable to that of their
bicyclic precursors [3–5]. Generally, the synthesis of 11H-
[1,2,4]triazolo[4,3-c][2,3]benzodiazepines involves the
condensation of 3,5-dihydro-4H-2,3-benzodiazepin-4-
Much attention has recently been paid to an important
synthetic transformation consisting of the direct conversion
of diazepine-4-one 1 into triazolodiazepines 3a–3e. How-
ever, we found no examples of such methodology being
used to prepare triazolodiazepines. Generally, the direct
conversion of diazepine-4-one 1 to triazolodiazepines 3 can
be accomplished by silylation–amination methods [7–9], in
which 1,1,1,3,3,3-hexamethyldisilazane (HMDS) is the key
reagent. Recently, the silylation–amination reaction was
successfully applied to the preparation of 3-aminobenzof-
uro[2,3-c]pyridines [10]. On the basis of our prior work, we
expected the formation of triazolodiazepines 3a–3e to also
occur under these conditions. In fact, we found that com-
pound 1 reacts readily with hydrazides of benzoic acids and
HMDS in the presence of p-toluenesulfonic acid mono-
hydrate to afford triazolodiazepines 3a–3e (‘‘Method B,’’
Scheme 2). The yields of 3a–3e (from 1 and from 2)
obtained by using both procedures are given in Table 1.
A. Eresko (&) ꢀ V. Tolkunov ꢀ S. Tolkunov
L.M. Litvinenko Institute of Physical Organic and Coal Chemistry,
National Academy of Sciences of Ukraine,
70, R.Luxemburg Str, Donetsk 83114,
Ukraine
e-mail: a_eresko2002@yahoo.com
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A. Eresko et al.
O
Table 1 Synthesis of 3-substituted 6-(4-chlorophenyl)-9-methyl-
12H-[1]benzofuro[3,2-e][1,2,4]triazolo[4,3-b][1,2]diazepines 3a–3e
S
N
N
MeO
MeO
MeO
MeO
R2
NHNH2
NH
N
R2
n-BuOH,
reflux 24-30 h
Compound
R
M.p. (°C) Yield (%)
‘‘Method A’’ ‘‘Method B’’
N
N
R1 = H, Cl, F, NO2
R2 = H, Me, Ph
R1
R1
3a
3b
3c
3d
3e
4-Cl-Ph
238–239
87
90
80
79
78
54
57
51
55
50
4-CH3O-Ph 231–232
4-Pyridinyl 245–246
Scheme 1
2-Thienyl
2-Furanyl
249–250
246–247
A possible mechanism for the silylation–amination
reaction has already been described elsewhere [9]. We
assume the following reaction sequence: HMDS reacts
with a molecule of diazepinone 1 to produce reactive
species A, and intermediate A then interacts with hydrazide
leading to intermediate B. Further cyclization of interme-
diate B results in the formation of the corresponding
triazolodiazepines 3 (Scheme 3).
[2-(4-chlorobenzoyl)-6-methyl-1-benzofuran-3-yl]acetate
and compound 1 were obtained as reported elsewhere [11].
1-(4-Chlorophenyl)-3,5-dihydro-8-methyl-4H-[1]-
benzofuro[2,3-d][1,2]diazepine-4-thione
(2, C18H13ClN2OS)
Lawesson’s reagent (0.5 mmol) was added to a solution of
compound 1 (1 mmol) in 5 cm3 dry toluene. The reaction
mixture was heated at 100 °C for 2 h. The solution was
cooled, and the product crystallized from the reaction
mixture. The precipitate was collected by filtration and
washed with dry toluene to afford compound 2. Yield:
Conclusion
A highly efficient and practical one-pot synthesis of tria-
zolodiazepines has been developed in this work. The
procedure outperforms the existing processes, allowing us
to produce several pharmacologically useful tria-
zolodiazepine derivatives in a clearly shorter synthetic
sequence.
1
85%; m.p.: 204–205 °C; H NMR (400 MHz, DMSO-d6):
d = 2.50 (s, 3H, CH3), 4.09 (s, 2H, CH2), 7.21 (d,
J = 8.0 Hz, 1H, H-7), 7.34 (s, 1H, H-9), 7.46 (d,
J = 8.0 Hz, 2H, H-30, H-50), 7.20 (d, J = 8.0 Hz, 1H,
H-6), 7.80 (d, J = 8.0 Hz, 2H, H-20, H-60), 12.86 (s, 1H,
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 21.50,
37.82, 111.76, 119.70, 121.76, 122.76, 125.09, 128.21,
129.99, 132.98, 135.65, 137.97, 142.75, 149.78, 156.21,
193.31 ppm; MS (EI, 70 eV): m/z = 340 (M?).
Experimental
Melting points were determined in non-sealed capillaries
1
using a Bellstone apparatus. The H NMR and 13C NMR
General procedures for synthesis of 3-substituted 6-(4-
chlorophenyl)-9-methyl-12H-[1]benzofuro[3,2-e]-
[1,2,4]triazolo[4,3-b][1,2]diazepines 3a–3e
spectra were recorded on a Bruker Avance 400 (400 MHz)
using tetramethylsilane (TMS) as an internal standard.
Mass spectra were acquired on a Finnigan MAT INCOS
50, operating in the electron-impact mode (EI) at 70 eV.
The CHNS elemental analysis was performed using a
Fisons AE1108 analyzer, and the results were in good
agreement ( 0.25%) with the calculated values. Methyl
Method A
A solution of diazepine-4-thione 2 (1 mmol) and the
hydrazide of the corresponding acid (1.25 mmol) in 15 cm3
Scheme 2
O
O
Lawesson's
S
N
N
reagent
R
NHNH2
NH
N
NH
N
N
N
R
Toluene,
80 °C, 4 h
n-BuOH,
reflux 20 h
H3C
H3C
H3C
O
O
O
(Method A)
Cl
Cl
Cl
1
2
3
O
3a R = 4-Cl-Ph
3b R = 4-CH3O-Ph
3c R = 4-Pyridinyl
3d R = 2-Thienyl
3e R = 2-Furanyl
R
NHNH2
HMDS, p-TsOH, Py, reflux 20 h
(Method B)
123

Simple and efficient preparation via a silylation–amination reaction
933
Scheme 3
O
H
N N
R
OSi(CH3)3
(H3C)3SiO
H
N
N
NH
N
H3C
H3C
3
1
O
O
A
B
Cl
Cl
120.71, 123.36, 124.95, 125.48, 128.54, 130.40, 131.06,
133.15, 135.89, 139.04, 141.55, 149.71, 152.45, 153.14,
155.29, 160.43 ppm; MS (EI, 70 eV): m/z = 454 (M?).
n-butanol was refluxed for 20 h. The solution was cooled,
and the products 3 crystallized from the reaction mixture.
The precipitate was collected by filtration and washed with
n-butanol to afford compounds 3.
6-(4-Chlorophenyl)-9-methyl-3-(pyridin-4-yl)-12H-[1]-
benzofuro[3,2-e][1,2,4]triazolo[4,3-b][1,2]diazepine
(3c, C24H16ClN5O)
Method B
M.p.: 245–246 °C; 1H NMR (400 MHz, DMSO-d6):
d = 2.46 (s, 3H, CH3), 4.69 (s, 2H, CH2), 7.30 (d,
J = 8.0 Hz, 1H, H-7), 7.50 (s, 1H, H-9), 7.65 (d,
J = 8.0 Hz, 2H, H-30, H-50), 7.79 (d, J = 8.0 Hz, 2H,
H-300, H-500), 7.98 (d, J = 8.0 Hz, 2H, H-20, H-60), 8.02 (d,
J = 8.0 Hz, 1H, H-6), 8.80 (d, J = 8.0 Hz, 2H, H-200,
H-600) ppm; 13C NMR (100 MHz, DMSO-d6): d = 19.68,
21.33, 111.87, 120.81, 122.74, 125.05, 125.61, 128.62,
131.19, 133.01, 133.93, 134.73, 136.31, 139.33, 140.96,
149.83, 150.74, 152.45, 152.94, 155.47 ppm; MS (EI,
70 eV): m/z = 425 (M?).
A solution of diazepine-4-one 1 (1 mmol), the hydrazide
of corresponding acid (1.1 mmol), and HMDS (1.5 mmol)
in 15 cm3 pyridine with a catalytic amount of p-toluene-
sulfonic acid monohydrate (0.1 mmol) was refluxed for
20 h. The solution was then evaporated to dryness, and the
residue was washed with water, dried, and recrystallized
from 2-propanol/dimethylformamide (1:1) to afford com-
pounds 3.
3,6-Bis(4-chlorophenyl)-9-methyl-12H-[1]benzofuro-
[3,2-e][1,2,4]triazolo[4,3-b][1,2]diazepine
(3a, C25H16Cl2N4O)
M.p.: 238–239 °C; 1H NMR (400 MHz, DMSO-d6):
d = 2.50 (s, 3H, CH3), 4.61 (s, 2H, CH2), 7.27 (d,
J = 8.0 Hz, 1H, H-7), 7.38 (s, 1H, H-9), 7.57 (d,
J = 8.0 Hz, 2H, H-30,H-50), 7.60 (d, J = 8.0 Hz, 2H,
H-300, H-500), 7.76 (d, J = 8.0 Hz, 2H, H-20, H-60), 7.95 (d,
J = 8.0 Hz, 1H, H-6), 7.98 (d, J = 8.0 Hz, 2H, H-200,
H-600) ppm; 13C NMR (100 MHz, DMSO-d6): d = 19.73,
21.56, 111.61, 120.71, 123.43, 124.90, 125.39, 128.22,
128.39, 130.26, 130.93, 132.83, 135.00, 136.35, 138.86,
141.40, 149.65, 152.06, 152.65, 155.42 ppm; MS (EI,
70 eV): m/z = 458 (M?).
6-(4-Chlorophenyl)-9-methyl-3-(2-thienyl)-12H-[1]-
benzofuro[3,2-e][1,2,4]triazolo[4,3-b][1,2]diazepine
(3d, C23H15ClN4OS)
M.p.: 249–250 °C; 1H NMR (400 MHz, DMSO-d6):
d = 2.51 (s, 3H, CH3), 4.61 (s, 2H, CH2), 7.22 (t,
J = 4.0 Hz, 1H, H-400), 7.26 (d, J = 8.0 Hz, 1H, H-7),
7.34 (s, 1H, H-9), 7.59 (d, J = 8.0 Hz, 2H, H-30, H-50),
7.70 (d, J = 4.0 Hz, 1H, H-500), 7.90–7.93 (m, 4H, H-6,
H-20, H-60, H-300) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 19.77, 21.54, 111.65, 120.81, 123.43, 124.79, 125.44,
126.88, 127.20, 128.44, 128.59, 129.15, 131.17, 132.97,
136.24, 139.03, 141.41, 148.72, 149.03, 152.77,
155.49 ppm; MS (EI, 70 eV): m/z = 430 (M?).
6-(4-Chlorophenyl)-3-(4-methoxyphenyl)-9-methyl-12H-
[1]benzofuro[3,2-e][1,2,4]triazolo[4,3-b][1,2]diazepine
(3b, C26H19ClN4O2)
6-(4-Chlorophenyl)-3-(2-furanyl)-9-methyl-12H-[1]-
benzofuro[3,2-e][1,2,4]triazolo[4,3-b][1,2]diazepine
(3e, C23H15ClN4O2)
M.p.: 246–247 °C; 1H NMR (400 MHz, DMSO-d6):
d = 2.52 (s, 3H, CH3), 4.60 (s, 2H, CH2), 6.66 (t,
J = 4.0 Hz, 1H, H-400), 7.20 (d, J = 4.0 Hz, 1H, H-500),
7.25 (d, J = 8.0 Hz, 1H, H-7), 7.31 (s, 1H, H-9), 7.56 (d,
J = 8.0 Hz, 2H, H-30, H-50), 7.80 (d, J = 4.0 Hz, 1H,
H-300), 7.83 (d, J = 8.0 Hz, 2H, H-20, H-60), 7.90 (d,
M.p.: 231–232 °C; 1H NMR (400 MHz, DMSO-d6):
d = 2.52 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.57 (s, 2H,
CH2), 7.07 (d, J = 8.0 Hz, 2H, H-300, H-500), 7.26 (d,
J = 8.0 Hz, 1H, H-7), 7.35 (s, 1H, H-9), 7.54 (d,
J = 8.0 Hz, 2H, H-30, H-50), 7.77 (d, J = 8.0 Hz, 2H,
H-20, H-60), 7.89 (d, J = 8.0 Hz, 2H, H-200, H-600), 7.92 (d,
J = 8.0 Hz, 1H, H-6) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 19.64, 21.30, 55.16, 111.82, 113.77, 118.93,
123

934
A. Eresko et al.
J = 8.0 Hz, 1H, H-6) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 19.59, 21.30, 111.73, 111.84, 113.13, 120.83,
123.31, 124.92, 125.54, 128.60, 131.17, 133.06, 136.01,
139.26, 140.75, 141.42, 144.86, 146.16, 149.29, 153.09,
155.42 ppm; MS (EI, 70 eV): m/z = 414 (M?).
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