Synthesis of novel benzo[6,7][1,4]oxazepino[4,5-a]quinazolinone derivatives via transition-metal-free intramolecular hydroamination

Article abstract of DOI:10.1055/s-0033-1340310

Novel benzo[6,7][1,4]oxazepino[4,5-a]quinazolinone derivatives were synthesized through an efficient 7-exo-dig hydroamination of 3-substituted-2-[2-(prop-2-yn-1-yloxy)phenyl]-2,3-dihydroquinazolin-4(1H)-ones in the presence of potassium tert-butoxide (KOt-Bu) in DMF at 130 °C. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340310

LETTER
▌385
lSetyternthesis of Novel Benzo[6,7][1,4]oxazepino[4,5-a]quinazolinone Derivatives
via Transition-Metal-Free Intramolecular Hydroamination
Benzo[6,7][1,4]oxazepino[4,5-a]quinazolinone Derivatives
Mohammad Mahdavi,a Niloufar Foroughi,a Mina Saeedi,a Maryam Karimi,a Heshmatollah Alinezhad,b
Alireza Foroumadi,a Abbas Shafiee,a Tahmineh Akbarzadeh*c,d
a
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical
Sciences, Tehran 14176, Iran
b
Faculty of Chemistry, Mazandaran University, Babolsar, Iran
c
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14176, Iran
d
Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
Fax +98(21)66461178; E-mail: akbarzad@tums.ac.ir
Received: 10.10.2013; Accepted after revision: 01.11.2013
cancer,17 and antipsychotic18 activities is well documented
Abstract: Novel benzo[6,7][1,4]oxazepino[4,5-a]quinazolinone
in the literature.
derivatives were synthesized through an efficient 7-exo-dig hy-
droamination of 3-substituted-2-[2-(prop-2-yn-1-yloxy)phenyl]-
2,3-dihydroquinazolin-4(1H)-ones in the presence of potassium
tert-butoxide (KOt-Bu) in DMF at 130 °C.
Furthermore, quinazolinone motifs are one of the most
important frameworks in natural products such as febri-
fugine and isofebrifugine19 and a very significant family
of compounds displaying various biological properties in-
cluding antiulcer,20 anti-inflammatory,21 anticancer,22 hy-
polipidemic,23 and anticonvulsant effects.24 Despite the
fact that benzoxazepine and quinazolinone derivatives
have been frequently synthesized and evaluated for their
bioactivity, there is no report on the synthesis of fused
benzoxazepine-quinazolinone derivatives.
Key words: hydroamination,
2-aminobenzamides,
terminal
alkynes, 7-exo-dig, N-heterocycles
Intramolecular and intermolecular hydroamination reac-
tions constitute a versatile and atom economic synthetic
process for the direct formation of a C–N bond leading to
nitrogen-containing heterocycles.1–3 Various structures
such as complex sulfonamide scaffolds,4 indolizinones,5
indolo[1,2-c]quinazolines,6 azomethine imines,7 tetra-
hydroisoquinoline alkaloids,8 N-heterocyclic carbenes,9
and pyrazoles10 have been successfully prepared by this
approach. The range of reports concerning hydroamina-
tion reactions11–14 confirm hydroamination as a strategy
for the preparation of N-heterocyclic compounds.
In order to obtain the title compounds we concentrated on
3-substituted-2-[2-(prop-2-yn-1-yloxy)phenyl]-2,3-dihy-
droquinazolin-4(1H)-one derivatives 1 (Scheme 1) as a
potential substrate for the intramolecular hydroamination.
In the event, in the presence of strong base, they readily
tolerated 7-exo-dig hydroamination followed by [1,3]-H
shift to afford new benzo[6,7][1,4]oxazepino[4,5-a]quin-
azolinone derivatives 2 (Scheme 1).
As a part of our ongoing studies on the synthesis of het-
erocycles and bioactive compounds,15 we focused on syn-
thetic applications of intramolecular hydroamination to
prepare a novel fused benzoxazepine-quinazolinone scaf-
fold.
Recently, our research group has developed the use of isa-
toic anhydride (3, Scheme 2) as a versatile starting mate-
rial to obtain various heterocyclic compounds.15c,25
Herein, relying on this earlier work, we report the prepa-
ration of novel fused benzoxazepine-quinazolinones 2
starting from 3. Initially, various 2-aminobenzamide de-
rivatives 5 were prepared by the reaction of equimolar
The association of benzoxazepines with various biologi-
cal activities, such as anticonvulsant and hypnotic,16 anti-
O
O
N
O
R1
R1
R1
N
O
KOt-Bu, DMF
[1,3]-H shift
R2
R2
N
N
R2
130 °C, 3–4 h
N
H
N
O
O
R3
R3
R3
2
1
Scheme 1 Synthesis of benzo[6,7][1,4]oxazepino[4,5-a]quinazolinones 2
SYNLETT 2014, 25, 0385–0388
Advanced online publication: 06.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340310; Art ID: ST-2013-D0957-L
© Georg Thieme Verlag Stuttgart · New York

386
M. Mahdavi et al.
LETTER
CHO
O
O
O
O
R2
R3
R1
R1
R1NH2
a
4
6
O
N
N
O
H
R2
b
N
H
O
NH2
N
H
3
5
R3
1
Scheme 2 Synthesis of 3-substituted-2-[2-(prop-2-yn-1-yloxy)phenyl]-2,3-dihydroquinazolin-4(1H)-ones 1a–i. Reagents and conditions: (a)
H2O, r.t., 2–3 h; (b) 2-(prop-2-yn-1-yloxy)benzaldehyde derivatives, K2CO3, DMF, 80 °C, 10–12 h.
amounts of isatoic anhydride (3) and amines 4 in water at band at 1652 cm–1 were observed which could be related
room temperature for 2–3 hours.
to aromatic and aliphatic C–H, C=O, and C=C stretching
frequencies. The MS peak (m/z = 404/402) associated
with the molecular ion was in accordance with the calcu-
Next, these were efficiently reacted with a range of
2-(prop-2-yn-1-yloxy)benzaldehyde derivatives 6 in the
presence of potassium carbonate (K2CO3) in DMF at
80 °C to give 3-substituted 2-[2-(prop-2-yn-1-yloxy)phe-
nyl]-2,3-dihydroquinazolin-4(1H)-ones 1a–i in good
yields (60–75%).
1
lated mass for C24H19ClN2O2. The H NMR spectrum of
2f consisted of two series of signals at high field. A singlet
at δ = 1.98 ppm and two doublets at δ = 4.20 and 5.39 ppm
(J = 16.0 Hz) relating to protons of the CH3 and NCH2
groups, respectively. Two singlets at δ = 6.00 and 6.68
ppm correspond to two CH groups and 12 aromatic pro-
In the next step, we investigated the subsequent intramo-
lecular cyclization reaction of starting material 1 to form
benzo[6,7][1,4]oxazepino[4,5-a]quinazolinones 2. For
our initial optimization studies, we selected 3-(2-chloro-
benzyl)-2-[2-(prop-2-yn-1-yloxy)phenyl]-2,3-dihydro-
quinazolin-4(1H)-one (1f) as a substrate and examined
various conditions for the best performance of hydroami-
nation reaction.
Table 1 Investigation of Various Conditions for the Hydroamination
of 1f to Obtain the Corresponding Product 2f
O
Cl
O
N
Cl
N
O
N
A scrutiny of publications devoted to hydroamination re-
actions revealed that they usually need to be catalyzed by
various metals.2 Therefore, developing an efficient and
easy procedure in the absence of complex and expensive
catalysts would be worthwhile. Recently, Trofimov et
al.26 introduced base/DMSO systems for α-vinylation of
aromatic, aliphatic, and cycloaliphatic ketones with aryl-
acetylenes. Influenced by their results, we investigated
similar systems for the hydroamination reaction in
Scheme 1. Preliminary base and solvent screening was
performed and some results are shown in Table 1. From
these studies we concluded that utilizing KOt-Bu in DMF
led to the formation of the corresponding product 2f in the
best yield.
N
H
O
2f
1f
Entry
Solvent
Base (equiv)
Temp (°C) Yield (%)a
1
2
DMF
KOt-Bu (1)
KOt-Bu (2)
KOt-Bu (2)
KOt-Bu (1)
KOt-Bu (2)
KOt-Bu (3)
KOH (2)
60
80
55
58
60
65
80
80
20
20
35
40
20
20
DMF
3
DMF
100
130
130
130
100
100
60
4
DMF
We also screened for the optimal amount of KOt-Bu and
temperature. We were pleased to observe that when the
model reaction was conducted in the presence of two
equivalents of KOt-Bu in DMF at 130 °C, 2f could be iso-
lated in a promising yield (80%, Table 1, entry 5). Chang-
ing the amount of base to threefold did not result in better
yield (Table 1, entry 6).
5
DMF
6
DMF
7
DMF
8
DMF
NaOH (2)
KOt-Bu (2)
KOt-Bu (2)
KOH (2)
9
DMSO
DMSO
DMSO
DMSO
The structure of 8-(2-chlorobenzyl)-1-methyl-7b,8-di-
hydro-9H-benzo[6,7][1,4]oxazepino[4,5-a]quinazolin-9-
one (2f) was clearly confirmed by mass spectrometry, IR
and NMR spectroscopy. In the IR spectrum of 2f, three
absorption bands at 3053, 2929, and 2850 cm–1, one sharp
absorption band at 1665 cm–1, and one sharp absorption
10
11
12
130
100
130
NaOH (2)
a Isolated yields.
Synlett 2014, 25, 385–388
© Georg Thieme Verlag Stuttgart · New York

LETTER
Benzo[6,7][1,4]oxazepino[4,5-a]quinazolinone Derivatives
387
tons which appeared between δ = 6.78 and 7.81 ppm. As
Supporting Information for this article is available online at
expected, the 13C spectrum showed 24 distinct resonanc-
es.
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
With these results in hand, we prepared various ben-
zo[6,7][1,4]oxazepino[4,5-a]quinazolinone derivatives
2a–i (Table 2).27 Substrates 1 possessing both electron-
rich as well as electron-poor substituents on aromatic
rings underwent 7-exo-dig hydroamination followed by
[1,3]-H shift to give the desired products 2.
References and Notes
(1) Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675.
(2) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada,
M. Chem. Rev. 2008, 108, 3795.
(3) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104.
(4) Gregory, A. W.; Jakubec, P.; Turner, P.; Dixon, D. J. Org.
Lett. 2013, 15, 4330.
(5) Siddiqui, I. R.; Abumhdi, A. A. H.; Shamim, S.; Shireen
Waseem, M. A.; Rahila Srivastava, A.; Srivastava, A. RSC
Adv. 2013, 3, 10173.
(6) Xu, M.; Xu, K.; Wang, S.; Yao, Z.-J. Tetrahedron Lett.
2013, 54, 4675.
Table 2 Synthesis of Benzo[6,7][1,4]oxazepino[4,5-a]quinazoli-
nones 227
O
O
R1
R1
R2
N
O
KOt-Bu, DMF
N
(7) Hunt, A. D.; Dion, I.; Neves, N. D.; Taing, S.; Beauchemin,
A. M. J. Org. Chem. 2013, 78, 8847.
R2
130 °C, 3–4 h
N
H
N
(8) (a) Pouilhès, A.; Baltaze, J.-P.; Kouklovsky, C. Synlett 2013,
24, 1805. (b) Ogata, T.; Kimachi, T.; Yamada, K.-I.;
Yamamoto, Y.; Tomioka, K. Heterocycles 2012, 86, 469.
(9) López-Gómez, M.-J.; Martin, D.; Bertrand, G. Chem.
Commun. 2013, 49, 4483.
O
R3
R3
2
1
(10) Yoshimatsu, M.; Ohta, K.; Takahashi, N. Chem. Eur. J.
2012, 18, 15602.
Entry R1
R2
R3
Product Yield (%)a
(11) Nguyen, T. M.; Nicewicz, D. A. J. Am. Chem. Soc. 2013,
135, 9588.
(12) Roth, T.; Wadepohl, H.; Wright, D. S.; Gade, L. H. Chem.
Eur. J. 2013, 19, 13823.
1
2
3
4
5
6
7
8
9
Bu
Bu
Bn
H
H
H
H
Br
H
H
Br
H
H
2a
2b
2c
2d
2e
2f
68
70
80
74
85
80
82
71
70
OMe
H
(13) Strom, A. E.; Hartwig, J. F. J. Org. Chem. 2013, 78, 8909.
(14) Wang, Y.; Rapakousiou, A.; Latouche, C.; Daran, J.-C.;
Singh, A.; Ledoux-Rak, I.; Ruiz, J.; Saillard, J.-Y.; Astruc,
D. Chem. Commun. 2013, 49, 5862.
(15) (a) Akbarzadeh, T.; Rafinejad, A.; Mollaghasem, J. M.;
Safavi, M.; Fallah-Tafti, A.; Pordeli, M.; Ardestani, S. K.;
Shafiee, A.; Foroumadi, A. Arch. Pharm. Chem. Life Sci.
2012, 345, 386. (b) Akbarzadeh, T.; Tabatabai, S. A.;
Khoshnoud, M. J.; Shafaghani, B.; Shafiee, A. Bioorg. Med.
Chem. 2012, 11, 769. (c) Mahdavi, M.; Asadi, M.; Saeedi,
M.; Rezaei, Z.; Moghbel, H.; Foroumadi, A.; Shafiee, A.
Synlett 2012, 23, 2521.
4-FC6H4CH2
4-FC6H4CH2
2-ClC6H4CH2
4-MeC6H4CH2
Ph
H
H
H
H
2g
2h
2i
H
O
OMe
H2C
(16) Deng, X.-Q.; Song, M.-X.; Wei, C.-X.; Sun, Z.-G.; Quan,
Z.-S. Med. Chem. Res. 2011, 20, 996.
a Isolated yields.
(17) Banerji, B.; Pramanik, S. K.; Sanphui, P.; Nikhar, S.;
Biswas, S. C. Chem. Biol. Drug Des. 2013, 82, 401.
(18) Liégeois, J. F.; Deville, M.; Dilly, S.; Lamy, C.; Mangin, F.;
Résimont, M.; Tarazi, F. I. J. Med. Chem. 2012, 55, 1572.
(19) (a) Koepfli, J. B.; Mead, J. F.; Brockman, J. A. Jr. J. Am.
Chem. Soc. 1947, 69, 1837. (b) Kobayashi, S.; Ueno, M.;
Suzuki, R.; Ishitani, H. Tetrahedron Lett. 1999, 40, 2175.
(20) Terashima, K.; Shimamura, H.; Kawase, A.; Tanaka, Y.;
Tanimura, T.; Kamisaki, T.; Ishizuka, Y.; Sato, M. Chem.
Pharm. Bull. 1995, 43, 2021.
The structures of all products 2a–i were elucidated from
their spectroscopic analyses as described herein for 2f.
In summary, a convenient and applicable protocol for the
intramolecular hydroamination reaction of 3-substituted
2-[2-(prop-2-yn-1-yloxy)phenyl]-2,3-dihydroquinazolin-
4(1H)-ones has been developed in the absence of transi-
tion-metal catalysts.
(21) Rather, B. A.; Raj, T.; Reddy, A.; Ishar, M. P. S.; Sivakumar,
S.; Paneerselvam, P. Arch. Pharm. Chem. Life Sci. 2010,
343, 108.
The corresponding benzo[6,7][1,4]oxazepino[4,5-a]quin-
azolinone derivatives were readily obtained using two
equivalents of KOt-Bu in DMF at 130 °C in good yields.
We believe that this method could be applicable in the
drug discovery area.
(22) Cao, S. L.; Feng, Y. P.; Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.;
Li, R. T. Bioorg. Med. Chem. Lett. 2005, 15, 1915.
(23) Kurogi, Y.; Inoue, Y.; Tsutsumi, K.; Nakamura, S.; Nagao,
K.; Yohsitsugu, H.; Tsuda, Y. J. Med. Chem. 1996, 39, 1433.
(24) Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.;
Greenwood, T. D. J. Med. Chem. 1990, 33, 161.
(25) (a) Asadi, M.; Ebrahimi, M.; Mahdavi, M.; Saeedi, M.;
Ranjbar, P. R.; Yazdani, F.; Shafiee, A.; Foroumadi, A.
Synth. Commun. 2013, 43, 2385. (b) Shafii, B.; Saeedi, M.;
Mahdavi, M.; Foroumadi, A.; Shafiee, A. Synth. Commun.
2014, 44, 215. (c) Farzipour, S.; Mahdavi, M.; Saeedi, M.;
Acknowledgement
This research was supported by grants from the research council of
Tehran University of Medical Sciences and Iran National Science
Foundation (INSF).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 385–388

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M. Mahdavi et al.
LETTER
Yavari, H.; Mirzahekmati, M.; Ghaemi, N.; Foroumadi, A.;
Shafiee, A. Synth. Commun. 2013, in press .
Yield 0.23 g (68%); yellow oil. IR (KBr): 3060, 2957, 2850,
1659 (C=O), 1614, 1482 cm–1. 1H NMR (400 MHz, DMSO-
d6): δ = 0.87 (t, J = 7.2 Hz, 3 H, NCH2CH2CH2CH3), 1.27–
1.33 (m, 2 H, NCH2CH2CH2CH3), 1.54–1.63 (m, 2 H,
NCH2CH2CH2CH3), 2.02 (s, 3 H, CH3), 2.84–2.91 (m, 1 H,
NCH2aCH2CH2CH3), 4.04 (m, 1 H, NCH2bCH2CH2CH3),
5.76 (s, 1 H, CH, H2), 6.67 (s, 1 H, CH), 6.72 (d, J = 7.6 Hz,
1 H, H13), 6.82 (t, J = 7.6 Hz, 1 H, H11), 6.88 (d, J = 7.0 Hz,
1 H, H4), 6.99 (t, J = 7.0 Hz, 1 H, H6), 7.05 (d, J = 7.0 Hz, 1
H, H7), 7.24 (dt, J = 7.0, 1.2 Hz, 1 H, H5), 7.29 (dt, J = 7.6,
(26) (a) Trofimov, B. A.; Schmidt, E. Yu.; Ushakov, I. A.;
Zorina, N. V.; Skital’tseva, E. V.; Protsuk, N. I.; Mikhaleva,
A. I. Chem. Eur. J. 2010, 16, 8516. (b) Trofimov, B. A.;
Schmidt, E. Y.; Zorina, N. V.; Ivanova, E. V.; Ushakov, I. A.
J. Org. Chem. 2012, 77, 6880.
(27) Synthesis of Benzo[6,7][1,4]oxazepino[4,5-
a]quinazolinone Derivatives 2 – General Procedure
A mixture of 3-substituted 2-[2-(prop-2-yn-1-
yloxy)phenyl]-2,3-dihydroquinazolin-4(1H)-one 1 (1
mmol) and KOt-Bu (2 mmol) in DMF (5 mL) was stirred at
130 °C for 3–4 h. Upon completion of reaction, checked by
TLC, the reaction mixture was poured into cold H2O, the
precipitate was filtered off, and the residue was purified
using plate chromatography eluting with PE–EtOAc (4:1).
8-Butyl-1-methyl-7b,8-dihydro-9H-benzo[6,7][1,4]-
oxazepino[4,5-a]quinazolin-9-one (2a)
1.2 Hz, 1 H, H12), 7.77 (dd, J = 7.6, 1.2 Hz, 1 H, H10). 13
NMR (100 MHz, DMSO-d6): δ = 14.1, 20.0, 20.3, 30.3,
C
45.3, 70.6, 107.1, 113.7, 115.9, 119.4, 121.2, 123.9, 124.9,
128.3, 130.5, 131.2, 134.1, 143.5, 143.7, 155.1, 162.0. Anal.
Calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C,
75.28; H, 6.78; N, 8.19.
Data for compounds 2b–i are given in the Supporting
Information.
Synlett 2014, 25, 385–388
© Georg Thieme Verlag Stuttgart · New York