Synthesis of Novel 7-methylene-6,7-dihyrobenzo[f]Benzo[4,5]Imidazo[1,2-d][1,4]Oxazepines via Base-mediated Regioselective Intramolecular Hydroamination

Article abstract of DOI:10.1002/jhet.2833

A versatile and transition metal-free approach for the synthesis of new 7-methylene-6,7-dihyrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepines were developed by an efficient 7-exo-dig regioselective hydroamination of 2-(2-(prop-2-yn-1-yloxy)phenyl)-1H-benzo[d]imidazole in the presence of potassium carbonate in DMF at 90°C.

Full text of DOI:10.1002/jhet.2833

Month 2017
Synthesis of Novel 7-methylene-6,7-dihyrobenzo[f]Benzo[4,5]
Imidazo[1,2-d][1,4]Oxazepines via Base-mediated Regioselective
Intramolecular Hydroamination
a
a
b
Hossein Yavari, Heshmatollah Alinezhad, * and Abbas Shafiee
a
Faculty of Chemistry, University of Mazandaran, Babolsr, Iran
b
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran
University of Medical Sciences, Tehran 14176, Iran
*
E-mail: heshmat@umz.ac.ir
Additional Supporting Information may be found in the online version of this article.
Received May 26, 2016
DOI 10.1002/jhet.2833
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A versatile and transition metal-free approach for the synthesis of new 7-methylene-6,7-dihyrobenzo[f]
benzo[4,5]imidazo[1,2-d][1,4]oxazepines were developed by an efficient 7-exo-dig regioselective
hydroamination of 2-(2-(prop-2-yn-1-yloxy)phenyl)-1H-benzo[d]imidazole in the presence of potassium
carbonate in DMF at 90°C.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
The reaction offers an atom-efficient pathway starting
from readily accessible alkenes and alkynes.
Hydroamination presents an important challenge because
of the repulsion between a nitrogen lone pair and the
olefin/alkyne π system, and it is also difficult to control the
regioselectivity (Markovnikov versus anti-Markovnikov)
of hydroamination [16]. The hydroamination reaction is
usually categorized as acid-catalyzed, base-catalyzed, and
transition metal catalyzed hydroaminations [17–21]. Quite
a few researchers have used this strategy as a key step for
the total synthesis of various natural products and
pharmaceutical agents [22].
Compounds containing “a fused seven-membered
benzoxazepine ring” have been of pivotal interest over
the past few years because of their wide range of
biological activities and pharmacological properties [1–4].
For instance, 5,6-dihydrobenzo[f]imidazo[1,2d] [1,4]
oxazepine scaffolds (Fig. 1) are very promising
therapeutics for various types of cancer treatments. The
connection of benzoxazepines with various biological
activities such as anticonvulsant and hypnotic [5],
anticancer, and antipsychotic activities [6,7] is well
documented in the literature review section. Most
syntheses of 2,3,4,5-tetrahydro-1,4-benzooxazepines can
be prepared by different synthetic methods: (i)
RESULTS AND DISCUSSION
condensation
of
2-aryloxyethylamines
with
2-
formylbenzoic acid to form aminonaphtalides followed
by cyclization; (ii) rearrangement of methyl 2-(8-
methoxy-2,3-dihydro-1,4-benzooxazepine-5-yl) benzoate
using Bischler–Napieralski conditions; and (iii) scandium
or copper triflate-catalyzed acylaminoalkylation of
In continuation of our research program regarding the
synthesis of biologically active nitrogen heterocycles [23–
25] and because of the fact that the synthesis of benzo[f]
imidazo[1,2-d][1,4]oxazepines is quite infrequent, herein,
we developed a new and straightforward approach by the
hydroamination strategy for the synthesis of fused
benzoxazepine-imidazole derivatives 6 in good yields
(Table 1). For this purpose, various ortho-
phenylenediamines 3, 2-(prop-2-yn-1-yloxy)benzaldehydes
4 were heated at 80°C in N,N-dimethylacetamide (DMA)
in the presence of sulfur reagent sodium disulfite
(Scheme 1). The required 2-(prop-2-yn-1-yloxy)
benzaldehyde derivatives 4 were synthesized by the
reaction of various salicylaldehyde derivatives 1 and
propargyl bromide 2 under basic conditions in DMF at
80°C (Scheme 1). We later on examined the reaction
conditions for the intramolecular cyclization of imidazole
α-methoxy-isoindolones
,4-benzoxazepine [8–10].
Regardless of the fact that the derivatives of
with
the
formation
of
1
benzoxazepine and imidazole have been frequently
synthesized and evaluated for their bioactivity, the related
literature is in need for the adequate reports about the
synthesis of fused benzoxazepine-imidazole derivatives. In
recent years, intramolecular and intermolecular
hydroamination reactions, the addition of an amine to an
unsaturated carbon–carbon multiple bond, are the widely
explored reactions for the direct formation of the C―N
bond in the synthesis of nitrogen heterocycles [10–15].
©
2017 Wiley Periodicals, Inc.

H. Yavari, H. Alinezhad, and A. Shafiee
Vol 000
Table 2
Investigation of various conditions for the hydroamination of 5a to obtain
the corresponding product 6a.
Figure 1. Benzo[f]imidazo [1, 2-d][1,4]oxazepine-5(6H)-one derivatives.
a
Table 1
Temperature
(°C)
Yield of
Entry
Solvent
Base (equiv)
6a(%)
Synthesis of 7-methylene-6,7-dihyrobenzo[f]benzo[4,5]imidazo[1,2-d]
[
1,4]oxazepines 6.
1
2
3
4
5
6
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMA
K
K
K
K
K
K
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
(3)
(3)
(3)
(1)
(1.5)
(2)
90
70
60
90
90
90
90
90
90
90
92
56
29
70
79
83
61
36
84
50
0
a
Entry
R
R
Product
Yield (%)
1
2
3
4
5
6
7
8
H
7-Me
H
7-Me
H
7-Me
H
H
H
10-Br
10-Br
8-OMe
8-OMe
6a
6b
6c
6d
6e
6f
70
75
65
64
61
56
58
60
t-BuOK (1.5)
KOH (3)
1
1
0
1
K
2
3
CO (3)
t-BuOK (1.5)
C
C
6
H
H
5
6g
6h
7-Me
6
5
a
Isolated yields.
a
Isolated yields.
oxazepines in good yields [23–26]. To our delight, the
Scheme 1. Synthetic rout for the preparation of 2-(2-(prop-2-yn-1-yloxy)
phenyl)-1H–benzo[d]imidazole 5. [Color figure can be viewed at
wileyonlinelibrary.com]
results revealed that replacing KOt-Bu by K CO3 can
2
lead to the formation of 7-exo-dig hydroamination, which
did not undergo 1,3 hydrogen shift to afford 7 (Scheme 2).
CONCLUSIONS
In summary, a new synthetic strategy for the synthesis of
7
-methylene-6,7-dihyrobenzo[f]benzo[4,5]imidazo[1,2-d]
[1,4]oxazepine derivatives through regioselective base-
mediated 7-exo-dig hydroamination of 2-(prop-2-yn-1-
yloxy)benzaldehyde derivatives is described which
affords exclusively exo product rather than endo product
because of the use of potassium carbonate base. It also
offers an efficient access to a large variety of substituted
imidazo oxazepine derivatives from readily available
ortho-phenylenediamines.
derivative 5 to form 7-methylene-6,7-dihyrobenzo[f]benzo
[
4,5] imidazo[1,2-d][1,4]oxazepines in moderate to good
yields (64-92%). The effect of protic and aprotic solvents
such as THF, CH OH, EtOH, DMA, and DMF was also
3
tested. Various bases such as alkali metals, alkoxides, and
carbonates were then examined, and it was found that the
combination of three equivalents of K CO in DMF at
EXPERIMENTAL
Melting points were taken on a Kofler hot stage
2
3
1
13
9
0°C was merely effective and led to the formation of the
apparatus (England) and are uncorrected. H- and C-
NMR spectra were recorded on Bruker FT-500
(Germany) using tetramethylsilane as an internal standard.
IR spectra were obtained on a Nicolet Magna FTIR 550
spectrophotometer (KBr disks). The elemental analysis
was performed with an Elmentar Analysensysteme GmbH
VarioEL CHNS mode (Germany). Mass spectra were re-
corded on an Agilent Technology (HP, Santa Clara, CA)
mass spectrometer operating at an ionization potential of
70 eV.
corresponding product 6a in good yield (92%). Increasing
the amount of K CO accompanied by the temperature
2
3
did not lead to an augment in yields (Table 2). Based on
these studies, we started to synthesize the various
derivatives of 7-methylene-6,7-dihyrobenzo[f]benzo [4,5]
imidazo[1,2-d] [1,4] oxazepines.
In our previous work, we took advantage of
hydroamination in the presence of KOt-Bu in DMF
providing the corresponding benzo[f]imidazo[1,2-d][1,4]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Imidazo[1,2-d][1,4]Oxazepines by Intramolecular Hydroamination
Scheme 2. Synthetic of 7-methylene-6,7 dihyrobenzo[f]benzo[4,5]imidazo[1,2d][1,4]oxazepine derivatives.
General procedure for the synthesis of 2-(2-(prop-2-yn-1-
yloxy)phenyl)-1H–benzo[d]imidazole (5).
7.31–7.34(m, 2H of Ph), 7.70–7.74 (m, 2H of Ph), 8.13
13
Mixture of
ortho-phenylenediamines (3; 1 mmol) and 2-(prop-2-yn-
-yloxy) benzaldehydes (4; 1 mmol) was heated at 80°C
(d, J = 2.3 Hz, H-C(6)). C NMR: 71.7; 110.6; 117.4;
19.6; 122.8; 123.3; 123.4; 123.7; 123.8; 124.3; 132.9;
1
+
1
137.4; 141.9; 147.7; 155.4. MS: m/z (%) = 326[m] (100),
328[m + 2] (91), 290(22), 247(30), 219(41), 191(8).
+
for 16 h in DMA in the presence of sulfur reagent
sodium disulfite (1 mmol). Upon completion of reaction,
checked by TLC, the reaction mixture was poured into
ice water with stirring. The precipitated products were
recrystallized from ethanol to give pure samples (5)
Anal. Calcd for C H BrN O (326.01): C 58.74, H 3.39,
16
11
2
N 8.56. Found: C 59.64, H 4.04, N,7.98.
2-Bromo-9-methyl-7-methylene-6,7-dihyrobenzo[f]benzo[4,5]
imidazo[1,2-d][1,4]oxazepines (6d).
Cream solid; yield
1
(64%); m.p. 375–377. IR: 1651, 1250, 1112. H–NMR:
General procedure for the synthesis of 7-methylene-6,7-
dihyrobenzo[f]benzo[4,5]imidazo[1,2d][1,4]oxazepine derivatives
2.47 (s, 3H of CH ); 4.90 (s, 2H of CH ); 5.74 (d,
3
2
(
6). A mixture of 2-(2-(prop-2-yn-1-yloxy)phenyl)-1H–
J = 12.0 Hz, CH); 5.82 (d, J = 12.0 Hz, CH); 7.09 (d,
J = 8.2 Hz, 1H–C(8)); 7.17 (d, J = 8.2 Hz, H-C(9));
7.59–7.55 (m, 2H of Ph); 7.63 (t, J = 8.0 Hz, H-C(5));
benzo[d]imidazole (5; 1 mmol) and potassium carbonate
in DMF was stirred at 90°C for 24 h. Upon completion
of reaction, checked by TLC, the reaction mixture was
poured into cold water, and the precipitate filtered. The
residue was purified using column chromatography,
eluting with petroleum ether/ethyl acetate (9:1).
13
8.7 (dd, J = 6.6 Hz, 2.3 Hz, H-C(6)). C–NMR: 21.5;
71.7; 113.8; 118.8; 119.1; 119.2; 122.9; 125.2; 132.5;
132.8; 133.9; 134.0; 137.5; 142.9; 147.2; 155.4. MS: m/z
+.
+
(%) = 340 [m] (100), 342[m + 2] (91), 325(14), 261(44),
7
-Methylene-6,7-dihyrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]
2
33(50), 210(19). Anal. Calcd for C H BrN O (340.02):
17
13
2
oxazepine (6a). Cream solid; yield: (92%); m.p. 289–291°C.
C 59.84, H 3.84, N 8.21. Found: C 59.64, H 4.04, N 7.98.
1
IR: 1618, 1258, 1029. H NMR: 4.91 (s, 2H of CH ); 5.74
2
4
-Methoxy 7-methylene-6,7-dihyrobenzo[f]benzo[4,5]imidazo
(
(
(
s, CH); 5.81 (s, CH); 7.09 (d, J = 8.2 Hz, H-C(8)); 7.20
t, J = 8.2 Hz, H-C(10)); 7.32–7.34 (m, 2H of Ph); 7.45
t, J = 7.1 Hz, H-C(9)); 7.73–7.77(m, 2H of Ph); 8.69 (d,
[
2
1,2-d][1,4]oxazepine (6e). Cream solid; yield (75%) m.p.
97–301°. IR: 1620, 1215, 1035. H NMR: 3.88 (s, 3H
1
of OCH ); 4.69 (s, CH); 4.77 (s, CH); 5.09 (s, 2H of
3
J = 10 Hz, H-C(11)). Anal. Calcd for C H N O
16
12
2
CH ); 7.25–7.33 (m, 4H of Ph), 7.53–57 (m, 1H of Ph),
2
(248.09): C 77.40, H 4.87, N 11.28. Found: C 77.11, H
13
7
.73 (d, J = 8.0, H-C(7)); 7.85 (d, J = 6.4, H-C(11)).
C
4
.14, N 11.92.
NMR: 56.1; 80.60; 93.3; 110.1; 114.7; 119.3; 121.4;
9-Methyl 7-methylene-6,7-dihyrobenzo[f]benzo[4,5]imidazo[1,2-
1
1
5
22.2; 122.5; 124.7; 134.3; 141.4; 142.9; 149.8; 151.3;
d][1,4]oxazepine (6b).
Cream solid; yield (75%); m.p.
57.5. Anal. Calcd for C H N O (278.11): C 73.37, H
1
17 14 2 2
2
95–299°. IR: 1608, 1210, 1045. H–NMR: 2.43 (s, 3H
.07, N 10.07, Found: C 73.91, H 5.04, N 10.58.
of CH ); 4.91 (d, J = 4.8 Hz, 2H of CH ); 5.64 (d, J = 19,
3
2
CH); 5.22 (d, J = 19,CH); 7.05–7.18 (m, 2H of Ph); 7.16
(
(
t, J = 8, H-C(10)); 7.40 (t, J = 7.2, H-C(9)); 7.48–7.51
m, 2H of Ph), 7.61 (d, J = 8.1, H-C(6)); 8.69 (t, J = 7, H-
Acknowledgments. This research was supported by grants from
the University of Mazandaran and the research council of
Tehran University of Medical Sciences.
13
C(11)). C-NMR: 21.5; 71.8, 110.3; 118.9; 119.1; 120.3;
1
1
20.4; 122.3; 124.6; 124.7; 131.3; 131.4; 132.9; 137.9;
43.1; 148.6; 156.0. Anal. Calcd for C H N O (262.11):
1
7 14 2
C 77.84, H 5.38, N 10.68; Found: C 77.91, H 5.04, N 10.98.
REFERENCES AND NOTES
2
-Bromo7-methylene-6,7-dihyrobenzo[f]benzo[4,5]imidazo
[
3
2
1,2-d][1,4]oxazepine (6c). Cream solid; yield (65%); m.p.
70–372°. IR: 1651, 1112, 1250 cm . H NMR: 4.90 (s,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet