Synthesis of a new polycyclic heterocyclic ring system. Part III. Benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-diones

Article abstract of DOI:10.1515/hc-2016-0236

A series of novel tricyclic benzoxazepines with fused imidazolone ring was prepared in five steps starting from the corresponding benzoxazolones 1-3. The key to the reported synthetic approach is transformation of 3-(2-oxopropyl)-2(3H)-benzoxazolones 4-6 to 1-(2-hydroxyphenyl)-4-methyl-1,3-dihydro-2H-imidazol-2-ones 7-12, and their subsequent conversion to the phenoxyacetic acids 19-24, which were finally acylated in polyphosphoric acid to form the oxazepine ring.

Full text of DOI:10.1515/hc-2016-0236

Heterocycl. Commun. 2017; 23(1): 23–27
DSeysisnlatvahVe. Sstainsishoevfa,aManriaenwa S.pGeorolvya acnyd cOglniycanhI.ePetterovr*ocyclic ring
system. Part III. Benzo[b]imidazo[1,5-d][1,4]
oxazepine-1,4(2H,5H)-diones
DOI 10.1515/hc-2016-0236
Received December 23, 2016; accepted December 27, 2016;
previously published online January 31, 2017
been studied as promising anticancer candidates due to
their ability to induce microtubule depolymerization and
apoptosis in numerous cell lines, e.g. human chronic
myeloid leukaemia K562, ovarian carcinoma A2780 and
neuroblastomas SHSY5Y and SK-N-BE(1) [9–12]. Com-
pounds PBOX-6 and PBOX-15 (Figure 1) represent the most
active PBOX members with low micromolar cytotoxicity
[12]. PBOX-6 has shown efficiency in an in vivo mouse
mammary carcinoma model, causing the inhibition of
tumor growth [13].
Abstract: A series of novel tricyclic benzoxazepines with
fused imidazolone ring was prepared in five steps start-
ing from the corresponding benzoxazolones 1–3. The
key to the reported synthetic approach is transforma-
tion of 3-(2-oxopropyl)-2(3H)-benzoxazolones 4–6 to
1-(2-hydroxyphenyl)-4-methyl-1,3-dihydro-2H-imidazol-
2-ones 7–12, and their subsequent conversion to the
phenoxyacetic acids 19–24, which were finally acylated in
polyphosphoric acid to form the oxazepine ring.
In continuation of our previous studies on the syn-
thesis of imidazo[5,1-c][1,4]benzothiazines and benzo[b]
imidazo[1,5-d][1,5]thiazepines [14, 15], herein we present a
Keywords: benzoxazepine; benzoxazole; heterocycle; imi- method for the preparation of benzo[b]imidazo[1,5-d][1,4]
dazole; ring transformation.
oxazepine-1,4(2H,5H)-diones as new heterocyclic systems.
These compounds were inspired by the PBOX compounds
and derived by replacing the fused pyrrole ring of the
PBOX scaffold with an imidazolone.
Introduction
Benzodiazepine and benzoxazepine ring systems are
common pharmacophores, found in numerous structures Results and discussion
with diverse biological activities. Investigations of this
class of compounds started 55 years ago, when Sternbach As part of our research on the design and synthesis
and Reeder published their pioneering work on 1,4-benzo- of novel heterocyclic systems with potential biomedi-
diazepines [1]. The discovery of 1,4-benzodiazepines has cal applications, we developed a convenient five-step
been followed by synthesis of a drug for the treatment of approach to tricyclic benzoxazepines containing a fused
anxiety, sleep disorders and epilepsy [1–3]. Being structur- imidazolone ring. The present method involves the use of
allyrelatedtobenzodiazepines, benzoxazepinederivatives benzoxazolones as easily available starting materials that
have gained significant attention among several research undergo a series of chemical transformations leading to
groups [4, 5]. A number of compounds with benzoxazepine the target molecules.
scaffolds have been described as potent antiviral [6], anti-
AsdepictedinScheme1, benzoxazolonederivatives1–3
convulsant [7] and neuroleptic [8] agents. In recent years, were allowed to react with chloroacetone in N,N-dimeth-
several tricyclic pyrrolo-1,5-benzoxazepines (PBOXs) have ylformamide in the presence of potassium carbonate and
a catalytic amount of benzyltriethylammonium chloride
(TEBA). The milder reaction conditions compared to pre-
viously reported methods [16] led to yields of 82%–89%.
The resulting 3-(2-oxoalkyl)-benzoxazolones are known to
undergoringtransformationto1-(2-hydroxyphenyl)-3,4-dis-
ubstituted-2-imidazolones in the presence of nucleophiles
such as primary amines [17, 18]. Therefore, the reaction of
compounds 4–6 with methylamine or benzylamine under
reflux in n-propanol or 2-methoxyethanol, respectively, led
*Corresponding author: Ognyan I. Petrov, Sofia University
“St. Kliment Ohridski”, Faculty of Chemistry and Pharmacy,
Department of Pharmaceutical and Applied Organic Chemistry,
1 James Bourchier Blvd, 1164 Sofia, Bulgaria,
e-mail: opetrov@chem.uni-sofia.bg
Desislava V. Stanisheva and Mariana S. Gerova: Sofia University
“St. Kliment Ohridski”, Faculty of Chemistry and Pharmacy,
Department of Pharmaceutical and Applied Organic Chemistry,
1 James Bourchier Blvd, 1164 Sofia, Bulgaria
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ꢀD.V. Stanisheva et al.: Benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-diones
fragment at position 5, thus forming the seven-membered
oxazepine ring.
The structure of target tricyclic benzoxazepines with
O
O
O
O
N
O
N
O
N
fused imidazolone ring was confirmed by spectroscopic
techniques.Twocarbonylbandsat1700cmꢀ−ꢀ1 and1650cmꢀ−ꢀ1
are observed in the IR spectra of compounds 25–30, cor-
responding to the CO group in the imidazolone ring and
the carbonyl group of the oxazepine moiety. In the 1H NMR
spectra of compounds 19–24, the methyl doublet appears
at 1.96–2.04 ppm and the corresponding singlet for 25–30
is shifted downfield to 2.44–2.52 ppm. The intramolecular
PBOX-6
PBOX-15
Figure 1ꢁStructures of pyrrolo-1,5-benzoxazepines PBOX-6 and
PBOX-15.
to the formation of imidazolone derivatives 7–12. In the cyclization of 19–24 leading to the formation of a benzox-
next step, compounds 7–12 were treated with ethyl bro- azepine scaffold is confirmed by the disappearance of the
moacetate under basic conditions, yielding esters 13–18 characteristic signal of imidazole-H5 (at 6.45–6.51 ppm in
quantitatively. The corresponding carboxylic acids 19–24 19–24) in the proton spectra of the final products 25–30.
were obtained after alkaline hydrolysis of the ester group. The singlet for the methylene protons of the carboxylic
Intramolecular acylation of these compounds led to target acids is shifted from 4.78–4.81 ppm to 4.58–4.62 ppm in
13
products 25–30. The intramolecular acylation of 19 was the benzoxazepines. The corresponding C NMR signals
tested under various reaction conditions. No product for- are shifted from 64.8–65.3 ppm to 78.9–79.5 ppm. The
mation was observed when conducting the reaction in sul- carbonyl carbon signals can be seen at 169.4–170.0 ppm
furic acid at room temperature or in a mixture of sulfolane/ in the starting acids and at 188.9–189.6 ppm in the final
polyphosphoric acid. The same results were observed compounds.
at higher temperature (80°C). The use of Eaton’s reagent
(P2O5-CH3SO3H) as a reaction medium at 80°C led to the
formation of the desired product at 63% yield after 5 h. Conclusion
The best yield (78%) was achieved in polyphosphoric acid
(PPA) at 120°C for 2 h, and these conditions were chosen Insummary, wedevelopedaconvenientfive-stepapproach
for the acylation of the series of carboxylic acids 19–24. to a new tricyclic ring system containing 1,5-benzoxaze-
Due to the powerful catalytic and dehydrating properties pine fused with an imidazolone. The reported compounds
of the PPA [19], the reaction proceeds via formation of the are structural analogs of the PBOX series, with potentially
mixed anhydride, followed by acylation of the imidazolone interesting biological activities.
R
N
CH3
O
CH3NH2,
n-propanol,
reflux
H
N
R1
R1
R1
N
O
CH3
N
O
ClCH2COCH3
O
O
or
R2
R2
R2
OH
K2CO3, TEBA
DMF, rt
O
C6H5CH2NH2,
2-methoxyethanol,
reflux
1–3
4–6
7–12
BrCH2COOEt
K2CO3, DMF, rt
R
R
R
N
O
N
O
O
N
CH3
O
CH3
N
R1
N
10% aq. NaOH
MeOH, rt
R1
R2
CH3
N
O
R1
PPA, 120°C
R2
OCH2COOEt
R2
OCH2COOH
19–24
25–30
13–18
1, 4: R1 = R2 = H
7, 13, 19, 25: R1 = R2 = H; R = Me
8, 14, 20, 26: R1 = H; R2 = Cl; R = Me
9, 15, 21, 27: R1 = Cl; R2 = H; R = Me
10, 16, 22, 28: R1 = R2 = H; R = Bn
11, 17, 23, 29: R1 = H; R2 = Cl; R = Bn
12, 18, 24, 30: R1 = Cl; R2 = H; R = Bn
2, 5: R1 = H; R2 = Cl
3, 6: R1 = Cl; R2 = H
Scheme 1ꢁSynthesis of benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-diones.
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D.V. Stanisheva et al.: Benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-dionesꢀ
ꢀ25
Jꢀ=ꢀ2.3 Hz), 6.99 (d, 1H, Jꢀ=ꢀ8.6 Hz), 6.89 (dd, 1H, Jꢀ=ꢀ8.6, 2.3 Hz), 6.30 (d,
1H, Jꢀ=ꢀ1.3 Hz), 3.29 (s, 3H), 2.13 (d, 3H Jꢀ=ꢀ1.3 Hz); 13C NMR (125 MHz,
CDCl3): δ 152.1, 151.0, 133.1, 125.2, 123.3, 122.7, 121.1, 120.8, 107.1, 27.8,
10.4. Anal. Calcd for C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74. Found: C,
55.69; H, 4.44; N, 11.95.
Experimental
Melting points were determined on a Böetius hot-stage microscope
and are uncorrected. IR spectra were recorded on a Specord 75 or
Thermo Scientific Nicolet iS10 spectrophotometer. 1H NMR and
13C NMR were obtained on Bruker DRX 300, Bruker DRX 400 and
Bruker DRX 500 spectrometers. Chemical shifts are reported relative
to the solvent peak. Elemental analyses (C, H, N) were carried out on a
Vario III microanalyzer. Thin-layer chromatography (TLC) was carried
out on silica gel plates (Merck 60 F254), using n-heptane/ethyl acetate
(7ꢀ:ꢀ3 v/v), toluene/chloroform/ethyl acetate (3ꢀ:ꢀ1ꢀ:ꢀ1 v/v) or chloro-
form/methanol (9ꢀ:ꢀ1 v/v) as eluent. Column chromatography was per-
formed with a Merck 60 silica gel (0.040–0.063 mm, 230–400 mesh).
1-(5-Chloro-2-hydroxyphenyl)-3,4-dimethyl-1,3-dihydro-2H-
imidazol-2-one (9)ꢁWhite crystals; yield 90%; mp 219–220°С
1
(ethanol); lit mp 214–215°С [17]; H NMR (500 MHz, CDCl3): δ 9.79 (s,
1H), 7.15 (dd, 1H, Jꢀ=ꢀ8.7, 2.6 Hz), 7.07 (d, 1H, Jꢀ=ꢀ2.6 Hz), 7.01 (d, 1H,
Jꢀ=ꢀ8.7 Hz), 6.33 (d, 1H, Jꢀ=ꢀ1.3 Hz), 3.29 (s, 3H), 2.13 (d, 3H, Jꢀ=ꢀ1.3 Hz).
3-Benzyl-1-(2-hydroxyphenyl)-4-methyl-1,3-dihydro-2H-
imidazol-2-one (10)ꢁWhite crystals; yield 96%; mp 58–60°С
1
(ethanol/water 2ꢀ:ꢀ1); lit mp 85–86°С [17]; H NMR (500 MHz, CDCl3):
δ 9.72 (s, 1H), 7.33–7.36 (m, 2H), 7.26–7.30 (m, 3H), 7.22–7.24 (m, 1H),
7.12 (d, 2H, Jꢀ=ꢀ8.3 Hz), 6.93–6.96 (m, 1H), 6.37 (d, 1H, Jꢀ=ꢀ1.2 Hz), 4.94
(s, 2H), 2.04 (d, 3H, Jꢀ=ꢀ1.2 Hz).
Synthesis of 3-(2-oxopropyl)-2(3H)-benzoxazolones 4–6
Powdered K2CO3 (75 mmol), ТЕВА (0.9 mmol) and chloroacetone
(50 mmol) were added to a stirred solution of 2(3H)-benzoxazolone
1–3 (50 mmol) in N,N-dimethylformamide (20 mL). The mixture was
stirred for 2–4 h (TLC) at room temperature and then poured onto
water (100 mL). The resulting precipitate was collected by filtration,
dried and crystallized from ethanol.
3-Benzyl-1-(4-chloro-2-hydroxyphenyl)-4-methyl-1,3-dihydro-
2H-imidazol-2-one (11)ꢁWhite crystals; yield 98%; mp 117–118°С
1
(ethanol); H NMR (500 MHz, CDCl3): δ 10.06 (s, 1H), 7.24–7.37 (m,
5H), 7.12 (d, 1H, Jꢀ=ꢀ2.3 Hz), 7.03 (d, 1H, Jꢀ=ꢀ8.6 Hz), 6.92 (dd, 1H,
Jꢀ=ꢀ8.6, 2.3 Hz), 6.33 (d, 1H, Jꢀ=ꢀ1.4 Hz), 4.93 (s, 2H), 2.04 (d, 3H,
Jꢀ=ꢀ1.3 Hz); 13C NMR (125 MHz, CDCl3): δ 152.3, 151.0, 136.4, 133.2,
129.0, 128.0, 127.2, 125.2, 123.4, 122.7, 121.1, 120.8, 107.7, 45.2, 10.6.
Anal. Calcd for C17H15ClN2O2: C, 64.87; H, 4.80; N, 8.90. Found: C,
65.13; H, 4.53; N, 8.75.
3-(2-Oxopropyl)-2(3H)-benzoxazolone (4)ꢁWhite crystals; yield
82%; mp 119–120°С (ethanol); lit mp 119–120°С [16, 20].
6-Chloro-3-(2-oxopropyl)-2(3H)-benzoxazolone (5)ꢁWhite crys-
1
tals; yield 89%; mp 154–156°С (ethanol); lit mp 155–156°С [16]; H
3-Benzyl-1-(5-chloro-2-hydroxyphenyl)-4-methyl-1,3-dihydro-
2H-imidazol-2-one (12)ꢁWhite crystals; yield 90%; mp 72–73°С
(diisopropyl ether); 1H NMR (500 MHz, CDCl3): δ 9.78 (s, 1H), 7.23–7.37
(m, 5H), 7.17 (dd, 1H, Jꢀ=ꢀ8.7, 2.5 Hz), 7.11 (d, 1H, Jꢀ=ꢀ2.5 Hz), 7.04 (d, 1H,
Jꢀ=ꢀ8.7 Hz), 6.36 (d, 1H, Jꢀ=ꢀ1.1 Hz), 4.93 (s, 2H), 2.04 (d, 3H, Jꢀ=ꢀ1.1 Hz);
13C NMR (125 MHz, CDCl3): δ 152.4, 148.9, 136.4, 129.1, 128.1, 128.0,
127.2, 127.1, 125.3, 122.8, 122.6, 122.2, 107.6, 45.2, 10.6. Anal. Calcd for
C17H15ClN2O2: C, 64.87; H, 4.80; N, 8.90. Found: C, 64.59; H, 4.73; N, 9.21.
NMR (500 MHz, CDCl3): δ 7.26 (d, 1H, Jꢀ=ꢀ1.9 Hz), 7.15 (dd, 1H, Jꢀ=ꢀ8.4,
1.8 Hz), 6.70 (d, 1H, Jꢀ=ꢀ8.4 Hz), 4.59 (s, 2H), 2.29 (s, 3H).
5-Chloro-3-(2-oxopropyl)-2(3H)-benzoxazolone (6)ꢁWhite crys-
1
tals; yield 84%; mp 124–125°С (ethanol); lit mp 125–126°С [16]; H
NMR (500 MHz, CDCl3): δ 7.15 (d, 1H, Jꢀ=ꢀ8.5 Hz), 7.10 (dd, 1H, Jꢀ=ꢀ8.5,
2.0 Hz), 6.79 (d, 1H, Jꢀ=ꢀ2.0 Hz), 4.59 (s, 2H), 2.30 (s, 3H).
Synthesis of 1-(2-hydroxyphenyl)-4-methyl-1,3-dihydro-
2H-imidazol-2-ones 7–12
Synthesis of 2-(2-(4-methyl-2-oxo-2,3-dihydro-1H-
imidazol-1-yl)phenoxy)acetic acids 19–24
Methylamine (40% aqueous solution, 50 mmol) or benzylamine
(50 mmol) was added to a suspension of 3-(2-oxopropyl)-2(3H)-
benzoxazolone 4–6 (25 mmol) in n-propanol (15 mL) or 2-methoxy-
ethanol (15 mL), respectively. The mixture was heated under reflux
for 4–6 h (TLC) and poured onto water (50 mL). After cooling to room
temperature, the solution was acidified with concentrated HCl. The
resulting precipitate was collected by filtration, washed with water,
dried and purified by column chromatography using n-heptane/ethyl
acetate (7ꢀ:ꢀ3 v/v) as eluent.
Powdered K2CO3 (50 mmol) and ethyl bromoacetate (25 mmol) were
added to a solution of the phenol derivative 7–12 (25 mmol) in DMF
(20 mL). The mixture was stirred at room temperature for 2–6 h (TLC)
and then poured onto water (50 mL). The resulting ester 13–18 was
extracted with dichloromethane (3ꢀ×ꢀ15 mL). The extract was washed
with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The ester 13–18 was obtained in a quantitative
yield and hydrolyzed in the next step without further purification. To
a stirred solution of the ester 13–18 in methanol (10 mL), 10% aque-
ous solution of NaOH (10 mL) was added. The mixture was stirred
at room temperature for 1–2 h (TLC) and acidified with concentrated
HCl. The resultant precipitate of carboxylic acid 19–24 was filtered,
washed with water, dried and crystallized.
1-(2-Hydroxyphenyl)-3,4-dimethyl-1,3-dihydro-2H-imidazol-
2-one (7)ꢁWhite crystals; yield 95%; mp 132–133°С (ethanol/water
1
2ꢀ:ꢀ1); lit mp 132–133°С [17]; H NMR (500 MHz, CDCl3): δ 9.72 (s, 1H),
7.17–7.22 (m, 1H), 7.07–7.11 (m, 2H), 6.92 (td, 1H, Jꢀ=ꢀ8.0, 1.4 Hz), 6.35 (d,
1H, Jꢀ=ꢀ1.3 Hz), 3.30 (s, 3H), 2.13 (d, 3H, Jꢀ=ꢀ1.2 Hz).
2-(2-(3,4-Dimethyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenoxy)
acetic acid (19)ꢁWhite crystals; yield 94%; mp 215–217°С (ethanol);
1H NMR (300 MHz, DMSO-d6): δ 13.12 (br s, 1H), 7.36 (dd, 1H, Jꢀ=ꢀ7.8,
1.7 Hz), 7.28 (ddd, 1H, Jꢀ=ꢀ8.5, 7.5, 1.7 Hz), 6.99–7.08 (m, 2H), 6.46 (d,
1-(4-Chloro-2-hydroxyphenyl)-3,4-dimethyl-1,3-dihydro-2H-
imidazol-2-one (8)ꢁWhite crystals; yield 91%; mp 167–169°С (iso-
1
propanol); H NMR (500 MHz, CDCl3): δ 10.05 (s, 1H), 7.09 (d, 1H,
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26ꢀ
1H, Jꢀ=ꢀ1.4 Hz), 4.78 (s, 2H), 3.13 (s, 3H), 2.05 (d, 3H, Jꢀ=ꢀ1.4 Hz); 13C NMR
(75 MHz, DMSO-d6): δ 169.9, 151.8, 128.1, 127.6, 125.7, 121.1, 118.8, 113.1,
Synthesis of 3-methylbenzo[b]imidazo[1,5-d][1,4]
oxazepine-1,4(2H,5H)-diones 25–30
107.8, 64.8, 26.9, 9.8; IR (KBr): 3450, 3140–2500, 1740, 1650, 1620 cmꢀ−ꢀ1
.
Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C, 59.86;
H, 5.35; N, 10.58.
The carboxylic acid 19–24 (20 mmol) was added slowly in small por-
tions to hot (110–120°С) polyphosphoric acid (40 mL). The color of
the mixture changed from pale orange to dark red. The mixture was
stirred at 120°С for 2–4 h (TLC) and poured onto crushed ice (100 g).
The obtained benzoxazepine was isolated by extraction with ethyl
acetate (3ꢀ×ꢀ15 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4 and concentrated under reduced
pressure. Purification of compounds 25–30 was accomplished by col-
umn chromatography using CH2Cl2 as eluent.
2-[5-Chloro-2-(3,4-dimethyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)
phenoxy] acetic acid (20)ꢁWhite crystals; yield 92%; mp 190–192°С
1
(ethanol); H NMR (400 MHz, DMSO-d6): δ 13.16 (s, 1H), 7.40 (d, 1H,
Jꢀ=ꢀ8.5 Hz), 7.21 (d, 1H, Jꢀ=ꢀ2.2 Hz), 7.09 (dd, 1H, Jꢀ=ꢀ8.5, 2.2 Hz), 6.45
(d, 1H, Jꢀ=ꢀ1.4 Hz), 3.12 (s, 3H), 4.85 (s, 2H), 2.04 (d, 3H, Jꢀ=ꢀ1.3 Hz);
13C NMR (100 MHz, DMSO-d6): δ 169.8, 152.5, 151.8, 131.8, 128.7, 124.7,
120.9, 118.9, 113.8, 107.6, 65.1, 26.9, 9.8; IR (nujol): 3140–2500, 1720,
1650, 1620 cmꢀ−ꢀ1. Anal. Calcd for C13H13ClN2O4: C, 52.63; H, 4.42; N, 9.44.
Found: C, 52.45; H, 4.48; N, 9.47.
2,3-Dimethylbenzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-
1
dione (25)ꢁWhite crystals; yield 71%; mp 165–167°С (ethanol); H
NMR (300 MHz, CDCl3): δ 7.99–8.02 (m, 1H), 7.18–7.28 (m, 3H), 4.59 (s,
2H), 3.38 (s, 3H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 189.4, 151.5,
150.9, 134.1, 130.9, 127.9, 125.8, 124.9, 122.2, 119.4, 79.4, 27.7, 10.8; IR
(nujol): 1690, 1650 cmꢀ−ꢀ1. Anal. Calcd for C13H12N2O3: C, 63.93; H, 4.95;
N, 11.47. Found: C, 63.62; H, 4.88; N, 11.49.
2-[4-Chloro-2-(3,4-dimethyl-2-oxo-2,3-dihydro-1Н-imidazol-1-yl)
phenoxy] acetic acid (21)ꢁWhite crystals; yield 90%; mp 225–227°С
1
(ethanol); H NMR (300 MHz, DMSO-d6): δ 13.12 (br s, 1H), 7.48 (d,
1H, Jꢀ=ꢀ2.7 Hz), 7.32 (dd, 1H, Jꢀ=ꢀ8.9, 2.7 Hz), 7.11 (d, 1H, Jꢀ=ꢀ8.9 Hz), 6.52
(d, 1H, Jꢀ=ꢀ1.4 Hz), 4.80 (s, 2H), 3.13 (s, 3H), 2.05 (d, 3H, Jꢀ=ꢀ1.3 Hz);
13C NMR (75 MHz, DMSO-d6): δ 169.8, 151.7, 150.6, 127.3, 126.9, 126.7,
124.3, 119.0, 114.8, 107.5, 65.0, 26.9, 9.8; IR (nujol): 3120–2400, 1720,
1650, 1620 cmꢀ−ꢀ1. Anal. Calcd for C13H13ClN2O4: C, 52.63; H, 4.42; N, 9.44.
Found: C, 52.38; H, 4.44; N, 9.52.
8-Chloro-2,3-dimethylbenzo[b]imidazo[1,5-d][1,4]oxazepine-
1,4(2H,5H)-dione (26)ꢁWhite crystals; yield 68%; mp 220–221°С
(isopropanol); 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 1H, Jꢀ=ꢀ8.7 Hz), 7.24
(dd, 1H, Jꢀ=ꢀ8.7, 2.4 Hz), 7.21 (d, 1H, Jꢀ=ꢀ2.3 Hz), 4.58 (s, 2H), 3.36 (s,
3H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 188.7, 151.8, 150.7, 134.5,
132.3, 129.6, 126.0, 125.7, 122.7, 119.1, 79.3, 27.8, 10.8; IR (nujol): 1700,
1650 cmꢀ−ꢀ1. Anal. Calcd for C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05.
Found: C, 56.23; H, 3.92; N, 10.14.
2-[2-(3-Benzyl-4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)
phenoxy]acetic acid (22)ꢁWhite crystals; yield 85%; mp 145–146°С
(toluene); 1H NMR (500 МHz, DMSO-d6): δ 13.09 (s, 1H), 7.43 (dd, 1H,
Jꢀ=ꢀ7.8, 1.7 Hz), 7.36 (t, 2H, Jꢀ=ꢀ7.5 Hz), 7.25–7.32 (m, 4H), 7.09 (dd, 1H,
Jꢀ=ꢀ8.4, 0.9 Hz), 7.04 (td, 1H, Jꢀ=ꢀ7.7, 1.1 Hz), 6.51 (d, 1H, Jꢀ=ꢀ1.4 Hz), 4.79
(s, 2H), 4.85 (s, 2H), 1.95 (d, 3H, Jꢀ=ꢀ1.3 Hz); 13C NMR (125 МHz, DMSO-
d6): δ 169.9, 152.1, 151.9, 138.1,128.7, 128.2, 127.8, 127.2, 126.8, 125.7, 121.1,
118.4, 113.3, 108.6, 64.9, 43.6, 10.0; IR (nujol): 3160–2500, 1720, 1650,
1620 cmꢀ−ꢀ1. Anal. Calcd for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28. Found:
C, 67.28; H, 5.46; N, 8.44.
9-Chloro-2,3-dimethylbenzo[b]imidazo[1,5-d][1,4]oxazepine-
1,4(2H,5H)-dione (27)ꢁWhite crystals; yield 62%; mp 202–203°С
1
(ethanol); H NMR (500 MHz, CDCl3): δ 8.01 (d, 1H, Jꢀ=ꢀ2.5 Hz), 7.18
(dd, 1H, Jꢀ=ꢀ8.6, 2.5 Hz), 7.10 (d, 1H, Jꢀ=ꢀ8.6 Hz), 4.53 (s, 2H), 3.34 (s,
3H), 2.49 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 188.7, 150.6, 149.9, 134.6,
131.7, 130.8, 127.8, 124.8, 123.2, 119.0, 79.2, 27.8, 10.8; IR (nujol): 1700,
1650 cmꢀ−ꢀ1. Anal. Calcd for C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05.
Found: C, 56.35; H, 3.99; N, 10.19.
2-[2-(3-Benzyl-4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-
5-chlorophenoxy]-acetic acid (23)ꢁWhite crystals; yield 97%; mp
168–169°С (ethanol); 1H NMR (500 МHz, DMSO-d6): δ 13.14 (s, 1H), 7.47
(d, 1H, Jꢀ=ꢀ8.5 Hz), 7.36 (t, 2H, Jꢀ=ꢀ7.5 Hz), 7.25–7.29 (m, 3H), 7.23 (d, 1H,
Jꢀ=ꢀ2.2 Hz), 7.11 (dd, 1H, Jꢀ=ꢀ8.5, 2.2 Hz), 6.51 (d, 1H, Jꢀ=ꢀ1.4 Hz), 4.86 (s,
2H), 4.84 (s, 2H), 1.94 (d, 3H, Jꢀ=ꢀ1.3 Hz); 13C NMR (125 МHz, DMSO-d6):
δ 169.8, 152.7, 152.1, 138.0, 131.9, 128.9, 128.7, 127.3, 126.9, 124.7, 121.1,
118.7, 113.9, 108.4, 65.2, 43.7, 10.0; IR (KBr): 3450, 3150–2400, 1740,
1680, 1620 cmꢀ−ꢀ1. Anal. Calcd for C19H17ClN2O4: C, 61.21; H, 4.60; N, 7.51.
Found: C, 61.48; H, 4.73; N, 7.22.
2-Benzyl-3-methylbenzo[b]imidazo[1,5-d][1,4]oxazepine-
1,4(2H,5H)-dione (28)ꢁWhite crystals; yield 44%; mp 167–169°С
1
(ethanol); H NMR (500 МHz, CDCl3): δ 8.11 (dd, 1H, Jꢀ=ꢀ7.3, 2.3 Hz),
7.38–7.41 (m, 2H), 7.28–7.36 (m, 5H), 7.24–7.26 (m, 1H), 5.06 (s, 2H), 4.63
(s, 2H), 2.48 (s, 3H); 13C NMR (125 МHz, CDCl3): δ 189.7, 151.5, 151.1,
135.8, 133.9, 130.9, 129.2, 128.3, 128.0, 127.5, 125.8, 125.0, 122.2, 119.7,
79.5, 45.1, 11.0; IR (nujol): 1690, 1650 cmꢀ−ꢀ1. Anal. Calcd for C19H16N2O3:
C, 71.24; H, 5.03; N, 8.74. Found: C, 71.48; H, 5.23; N, 8.68.
2-[2-(3-Benzyl-4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-
4-chlorophenoxy]-acetic acid (24)ꢁWhite crystals; yield 90%; 2-Benzyl-8-chloro-3-methylbenzo[b]imidazo[1,5-d][1,4]oxa-
mp 176–178°С (ethanol); 1H NMR (500 МHz, DMSO-d6): δ 13.13 (s, 1H), zepine-1,4(2H,5H)-dione (29)ꢁWhite crystals; yield 63%; mp 130–
7.55 (d, 1H, Jꢀ=ꢀ2.7 Hz), 7.34–7.38 (m, 3H), 7.29 (d, 1H, Jꢀ=ꢀ7.3 Hz), 7.26 (d, 132°С (ethanol); 1H NMR (500 MHz, CDCl3): δ 8.04 (d, 1H, Jꢀ=ꢀ8.8 Hz),
2H, Jꢀ=ꢀ7.2 Hz), 7.14 (d, 1H, Jꢀ=ꢀ8.9 Hz), 6.58 (d, 1H, Jꢀ=ꢀ1.4 Hz), 4.84 (s, 7.28–7.38 (m, 5H), 7.26 (dd, 1H, Jꢀ=ꢀ8.8, 2.4 Hz), 7.23 (d, 1H, Jꢀ=ꢀ2.4 Hz),
2H), 4.81 (s, 2H), 1.94 (d, 3H, Jꢀ=ꢀ1.2 Hz); 13C NMR (125 МHz, DMSO-d6): 5.01 (s, 2H), 4.59 (s, 2H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
δ 169.9, 152.1, 150.8, 138.0, 128.8, 127.7, 127.4, 127.1, 126.9, 126.7, 124.4, 188.9, 151.9, 150.9, 135.6, 134.3, 132.5, 129.6, 129.2, 128.3, 127.5, 126.8,
118.8, 115.1, 108.4, 65.3, 43.7, 10.1; IR (KBr): 3450, 3150–2600, 1740, 126.0, 122.7, 119.3, 79.3, 45.1, 11.0; IR (nujol): 1700, 1650 cmꢀ−ꢀ1. Anal.
1650, 1620 cmꢀ−ꢀ1. Anal. Calcd for C19H17ClN2O4: C, 61.21; H, 4.60; N, 7.51. Calcd for C19H15ClN2O3: C, 64.32; H, 4.26; N, 7.90. Found: C, 64.60; H,
Found: C, 61.48; H, 4.59; N, 7.82.
4.24; N, 7.93.
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ꢂꢁꢁꢁ
D.V. Stanisheva et al.: Benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-dionesꢀ
ꢀ27
2-Benzyl-9-chloro-3-methylbenzo[b]imidazo[1,5-d][1,4]oxa-
zepine-1,4(2H,5H)-dione (30)ꢁWhite crystals; yield 66%; mp 175–
Zisterer, D. M. Identification of tubulin as the molecular target
of proapoptotic pyrrolo-1,5-benzoxazepines. Mol. Pharmacol.
2006, 70, 60–70.
1
176°С (ethanol); H NMR (500 МHz, CDCl3): δ 8.13 (d, 1H, Jꢀ=ꢀ2.5 Hz),
7.30–7.38 (m, 5H), 7.22 (dd, 1H, Jꢀ=ꢀ8.6, 2.5 Hz), 7.14 (d, 1H, Jꢀ=ꢀ8.6 Hz), [10] Bright, S.; Campiani, G.; Deininger, M.; Lawler, M.; Williams,
5.02 (s, 2H), 4.57 (s, 2H), 2.45 (s, 3H); 13C NMR (125 МHz, CDCl3): δ
189.0, 150.9, 150.0, 135.6, 134.4, 131.7, 130.9, 129.2, 128.4, 127.9, 127.5,
124.9, 123.3, 119.4, 79.3, 45.2, 11.1; IR (nujol): 1700, 1650 cmꢀ−ꢀ1. Anal.
Calcd for C19H15ClN2O3: C, 64.32; H, 4.26; N, 7.90. Found: C, 64.58; H,
4.33; N, 7.88.
D.; Zisterer, D. Sequential treatment with flavopiridol synergis-
tically enhances pyrrolo-1,5-benzoxazepine-inducen apoptosis
in human chronic myeloid leukemia cells including those
resistant to imatinib treatment. Biochem. Pharmacol. 2010, 80,
31–38.
[11] Nathwani, S.-M.; Butler, S.; Fayne, D.; McGovern, N.; Sarkadi,
B.; Meegan, M.; Loyd, D.; Campaini, G.; Lawler, M.; Williams,
D.; Zisterer, D. Dual targeting of tumour cells and host endothe-
lial cells by novel microtubule-targeting agents, pyrrolo-
1,5-benzoxazepines. Cancer Chemother. Pharmacol. 2010, 65,
289–300.
Acknowledgments: The authors are thankful to the Sofia
University Scientific Research Fund (grant 116/2016) for
financial support.
[12] Lennon, J.; Bright, S.; Carroll, E.; Butini, S.; Campiani, G.;
O’Merara, A.; Williams, D.; Zisterer, D. The novel pyrrolo-
1,5-benzoxazepin, PBOX-6, synergistically enhance the apoptotic
effects of carboplatin in drug selective and multidrug resistant
neuroblastoma cells. Biochem. Pharmacol. 2014, 87, 611–624.
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D.C.; Zisterer, D.M. The pyrrolo-1,5-benzoxazepine, PBOX-6,
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