Synthesis of thieno[2,3-e][1,4]diazepine derivatives

Full text of DOI:10.1134/S1070428014030282

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 3, pp. 449–451. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © N.T. Pokhodylo, O.Ya. Shiika, M.D. Obushak, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 3, pp. 457–459.
SHORT
COMMUNICATIONS
Synthesis of Thieno[2,3-e][1,4]diazepine Derivatives
N. T. Pokhodylo, O. Ya. Shiika, and M. D. Obushak
Ivan Franko Lviv National University, ul. Kirilla i Mefodiya 6, Lviv, 79005 Ukraine
e-mail: obushak@in.lviv.ua
Received November 1, 2013
DOI: 10.1134/S1070428014030282
Strong interest of researchers in 1,4-diazepine
derivatives is determined by broad spectrum of their
biological activity [1–3]. 1,4-Benzodiazepine fragment
is classed with preferred (privileged) structures [4–6];
it is present in more than 40 medicinal agents with
different therapeutic effects [7–9]. Therefore, develop-
ment of methods for the synthesis of new fused hetero-
cyclic systems on the basis of 1,4-diazepines is en-
couraged. For example, bioisosterism of thiophene and
benzene rings [10] was successfully employed in the
synthesis of new 1,4-thieno[1,4]diazepine-containing
drugs, such as Olanzapine, Clotiazepam, and Brotizo-
lam [2, 11]. Taking into account the above stated, new
synthetic approaches to thieno[1,4]diazepines may be
quite promising.
Thus, we have demonstrated the possibility for
convenient transformation of thieno[2,3-d]pyrimidines
into thieno[2,3-e][1,4]diazepines. This novel recycliza-
tion is promising from the viewpoint of synthesis of
biologically active compounds.
Ethyl 2-(2-oxo-1-cyano-2-ethoxyethylidene)-
cyclohexanecarboxylate (II). A mixture of 8 mL
(0.05 mol) of ester I, 6 mL (0.05 mol) of ethyl cyano-
acetate, 0.4 g (0.005 mol) of ammonium acetate, and
0.6 mL (0.01 mol) of acetic acid in 30 mL of benzene
was heated under reflux in a flask equipped with
a Dean–Stark trap until water no longer separated. The
mixture was cooled to room temperature and washed
with a small amount of water, and the organic layer
was separated and evaporated. Yield 11 g (83%). The
properties of the product were consistent with pub-
lished data [15, 16].
In recent time thieno[2,3-e][1,4]diazepines were
successfully synthesized via the Ugi reaction [2, 3]. In
addition, syntheses of these compounds from proline
derivatives and 2-aminobenzenethiols or dithianediol
were reported [12–14].
Diethyl 2-amino-4,5,6,7-tetrahydro-1-benzothio-
phene-3,4-dicarboxylate (III). Compound II, 13.25 g
(0.05 mol), was dissolved in 25 mL of ethanol, 1.6 g
(0.05 mol) of sulfur and 5 mL (0.05 mol) of diethyl-
amine were added, and the mixture was heated for 2–
3 h under reflux with stirring. The mixture was cooled
to room temperature, water was added until crystalliza-
tion started, and the precipitate was filtered off,
washed with ethanol, and dried in air. Yield 11 g
(74%), mp 100–101°C; published data [15]: mp 100.5–
We have developed a procedure for the preparation
of thieno[2,3-e][1,4]diazepines starting from thieno-
[2,3-d]pyrimidine derivatives. This procedure is ex-
pected to extend the range of practically important
1,4-diazepines. As starting compounds we used
2-aminothiophenes prepared via the two-step Gewald
reaction. Knoevenagel condensation of ethyl 2-oxocy-
clohexane-1-carboxylate (I) with ethyl cyanoacetate
gave nitrile II which reacted with molecule sulfur to
produce 2-aminothiophene III. The latter was brought
into reaction with acetonitrile in acid medium, and
thienopyrimidinone IV thus obtained was alkylated
with ethyl bromoacetate. Alkaline hydrolysis of ester V
might be expected to afford carboxylic acid VI which,
however, was not formed under these conditions.
Instead, recyclization of V led to the formation of
thieno[2,3-e][1,4]diazepine system VII.
1
101.5°C. H NMR spectrum, δ, ppm: 1.21 t (3H, CH3,
J = 7.1 Hz), 1.23 t (3H, CH3, J = 7.1 Hz), 1.62–1.76 m
(2H, CH2), 1.84–1.91 m (2H, CH2), 2.47 m (2H, CH2),
3.80 br.s (1H, CH), 3.93–4.21 m (4H, OCH2), 7.14 s
(2H, NH2). Mass spectrum: m/z 298 [M + H]+. Found,
%: C 56.62; H 6.51; N 4.85. C14H19NO4S. Calculated,
%: C 56.55; H 6.44; N 4.71. M 297.37.
Ethyl 2-methyl-4-oxo-3,4,5,6,7,8-hexahydroben-
zo[4,5]thieno[2,3-d]pyrimidine-5-carboxylate (IV).
Compound III, 1.5 g (5 mmol), was dissolved in
449

POKHODYLO et al.
450
O
CN
EtO
O O
O
O
EtO
O
OEt
NH4OAc
AcOH, PhH
S8, Et2NH
EtOH
OEt
+
OEt
OEt
N
NH2
O
S
I
II
III
O
O
O
O
EtO
O
EtO
OEt
Me
NH
BrCH2C(O)OEt
DMF, K2CO3
N
MeCN, HCl
dioxane
Me
N
N
S
S
IV
V
O
O
H
N
O
HO
O
HO
O
OH
Me
N
NaOH, H2O
NaOH, H2O
V
O
N
NH
S
S
VI
VII
25 mL of dioxane saturated with hydrogen chloride,
0.5 mL (10 mmol) of acetonitrile was added, and the
mixture was stirred for 24 h at 40°C. The mixture was
then evaporated under reduced pressure, the residue
was treated with 10 mL of water, and 20% aqueous
sodium hydroxide was added dropwise until pH 7. The
precipitate was filtered off, washed with ethanol, and
4.02–4.09 m (2H, OCH2), 4.20 q (2H, OCH2, J =
7.1 Hz), 4.77 d and 4.87 d (1H each, NCH2, J =
17.7 Hz). Mass spectrum: m/z 379 [M + H]+. Found,
%: C 57.21; H 5.94; N 7.51. C18H22N2O5S. Calculated,
%: C 57.13; H 5.86; N 7.40. M 378.44.
2,5-Dioxo-2,3,4,5,6,7,8,9-octahydro-1H-benzo-
[4,5]thieno[2,3-e][1,4]diazepine-6-carboxylate (VII).
A solution of 1.89 g (5 mmol) of thienopyrimidine V
in 5 mL of ethanol was added to a 20% aqueous solu-
tion of sodium hydroxide (0.4 g, 0.01 mol), and the
mixture was heated to 70°C under stirring and kept for
1 h at room temperature. The mixture was evaporated
and acidified with aqueous HCl, and the precipitate
was filtered off, washed with water, and dried in air.
Yield 0.57 g (41%), mp 182–184°C (from EtOH–
1
dried in air. Yield 1.1 g (75%), mp >250°C. H NMR
spectrum, δ, ppm: 1.21 t (3H, CH3, J = 7.1 Hz), 1.75–
1.94 m (2H, CH2), 2.03 d (2H, CH2, J = 5.2 Hz), 2.33 s
(3H, 2-CH3), 2.67–2.82 m (2H, CH2), 3.98 t (1H, CH,
J = 5.1 Hz), 4.06 q (2H, OCH2, J = 7.1 Hz), 12.15 s
(1H, NH). Mass spectrum: m/z 293 [M + H]+. Found,
%: C 57.60; H 5.69; N 9.70. C14H16N2O3S. Calculated,
%: C 57.52; H 5.52; N 9.58. M 292.36.
Ethyl 3-(2-ethoxy-2-oxoethyl)-2-methyl-4-oxo-
3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrim-
idine-5-carboxylate (V). Thienopyrimidine IV, 1.46 g
(5 mmol), was dissolved in 5 mL of DMF, 2.1 g
(15 mmol) of potassium carbonate and 0.7 mL
(6 mmol) of ethyl bromoacetate were added under
stirring, and the mixture was stirred for 24 h at room
temperature. The mixture was treated with 10 mL of
water, and the organic layer was separated, dried over
Na2SO4, and evaporated. Yield 1.76 g (93%), oily sub-
1
H2O). H NMR spectrum, δ, ppm: 1.63–1.68 m (1H,
CH2), 1.75–1.90 m (1H, CH2), 2.13–2.45 m (4H, CH2),
4.41 s (2H, CH2, diazepine), 4.67 m (1H, CH), 8.71 s
(1H, NH), 9.41 s (1H, NH). Mass spectrum: m/z 281
[M + H]+. Found, %: C 51.50; H 4.39; N 10.08.
C12H12N2O4S. Calculated, %: C 51.42; H 4.32; N 9.99.
M 280.30.
1
The H NMR spectra were recorded on a Varian
Mercury spectrometer at 400 MHz using DMSO-d6 as
solvent and tetramethylsilane as internal reference. The
mass spectra (atmospheric pressure chemical ioniza-
tion) were obtained on an Agilent 1100 LC/MSD
instrument.
1
stance. H NMR spectrum, δ, ppm: 1.19 t (3H, CH3,
J = 7.1 Hz), 1.29 t (3H, CH3, J = 7.1 Hz), 1.81–1.88 m
(2H, CH2), 2.03 d (2H, CH2, J = 4.9 Hz), 2.67–2.85 m
(2H, CH2), 3.05 s (3H, 2-CH3), 3.99 m (1H, CH),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

SYNTHESIS OF THIENO[2,3-e][1,4]DIAZEPINE DERIVATIVES
451
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