Facile access to a benzoazepinoquinazolinone via a free radical cyclization

Article abstract of DOI:10.1016/j.tetlet.2014.01.013

An efficient synthetic protocol based on a free-radical cascade reaction via 6-exo-trig and 7-endo-trig cyclization processes is described for a new substituted benzoazepinoquinazolinone system which could in principle be used to form the cyclopropanequinone system found in duocarmycins.

Full text of DOI:10.1016/j.tetlet.2014.01.013

Tetrahedron Letters 55 (2014) 1329–1331
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile access to a benzoazepinoquinazolinone via a free radical
cyclization
Khaled Q. Shawakfeh a, Zakariyya N. Ishtaiwi a, Naim H. Al-Said a,b,
⇑
a Department of Chemistry, Jordan University of Science and Technology, Irbid 22110, Jordan
b College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, Al-Ahsa, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic protocol based on a free-radical cascade reaction via 6-exo-trig and 7-endo-trig
cyclization processes is described for a new substituted benzoazepinoquinazolinone system which could
in principle be used to form the cyclopropanequinone system found in duocarmycins.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 2 August 2013
Revised 4 December 2013
Accepted 6 January 2014
Available online 10 January 2014
Keywords:
Free-radical
Benzoazepinoquinazolinone
Cyclopropanequinone
Quinazolinone
Duocarmycin
O
Cl
O
The incorporation of two pharmacophores, each with different
modes of actions, in a single molecule is one of the techniques
being implemented to treat cancer. Naturally occurring quinazoli-
nones, as well as a large number of synthetic classes of these fused
heterocycles, have been reported to display a diverse range of bio-
logical activities.1,2 Therefore, the core quinazolinone structure has
been exploited extensively as an antibacterial,3 antitubercular,4
antifungal,5 and antitumor6 agent in medicinal chemistry. Duo-
carmycins (1–4) are natural, potent antitumor antibiotics which
bind to DNA in the minor groove and alkylate at N-3 of adenine
in a sequence-selective manner. Extensive biological studies of
these natural products and related synthetic derivatives have
shown that cyclopropylindole (CI), which can be formed by ring
closure of a seco-CI unit, is the minimum potent pharmacophore
and a free phenol is not compulsory for DNA alkylation. Moreover,
from structure–activity relationship studies of these analogues, it
became apparent that the cytotoxicity of the analogues is directly
related to the chemical stability of the molecules in aqueous solu-
tion.7 Several hybrid molecules in which the biologically active
unit in the duocarmycin family is tethered to an organic moiety,
have been designed, synthesized and evaluated for their biological
activity.8
MeO2C
Me
MeO2C
Me
MeO2C
+ HCl
- HCl
R
N
R
N
N
R
N
N
N
H
H
H
O
O
O
O
O
HO
duocarmycin A (2)
duocarmycin C1 (3)
duocarmycin SA (1)
- HCl
R = 5,6,7-trimethoxyindol-2-yl
+ HCl
O
Cl
MeO2C
Me
N
N
R
H
O
HO
duocarmycin C2 (4)
We have been involved in the development of new synthetic
strategies for the preparation of structurally modified stable seco-
CI units.9 In continuation of our studies, we became interested to
design and synthesize hybrid molecules in which the active unit
is coupled to a quinazolinone moiety. Moreover, such a moiety
could enhance the stability as well as improve the bioavailability
upon attaching the active unit to a quinazolinone.
This report describes the first attempt to prepare seco-cyclo-
propaneisoquinolinoquinazolinone (5, seco-CIQQ) and a stable
seco-cyclopropanebenzoazepinoquinazolinone (7, seco-CBAQ),
since both species could in principle form a cyclopropanedienone
fused to a quinoxaline ring system (6, CQQ).
⇑
Corresponding author.
E-mail address: naim@just.edu.jo (N.H. Al-Said).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.013

1330
K. Q. Shawakfeh et al. / Tetrahedron Letters 55 (2014) 1329–1331
impurities was isolated in low yield (20%). The structure of 13
Cl
O
N
O
N
Cl
O
N
was assigned on the basis of its 1H and 13C NMR spectra. It is worth
noting that variation of the concentrations and ratios of the reac-
tants, as well as the way in which the reaction was conducted sig-
nificantly altered the yield and the purity of the products 13 and
14b. The rearranged product 13 was isolated in an acceptable yield
(60%) when a 3:1 mol ratio of (Bu)3SnH and 2-bromo derivative
11a in the presence of AIBN was added to benzene at reflux
temperature.
-HCl
N
N
N
+HCl
-HCl
+HCl
OH
(5, seco-CIQQ)
O
HO
(7, seco-CBAQ)
(6, CQQ)
Following the widely accepted fact that a chlorine atom stabi-
lizes an adjacent radical, we planned to prepare seco-CIqQ CIQQ
5 and seco-CBAQ 7 from quinazolinone derivatives 11a and 11b,
respectively, based on a radical cascade cyclization reaction. Our
approach to quinazolinone derivatives 11a and 11b began with
the condensation of anthranilamide (8) with 5-acetoxy-2-bromo-
benzaldehyde (9b). Initially an iodine-catalyzed aerobic oxidative
cascade coupling of 8 with 9b in refluxing acetonitrile for 72 h,
gave the 2-aryl-substituted quinazolinone derivative 10b10 in
low yield (30–40%), after tedious column chromatographic purifi-
cation. To our surprise, the hydroxyl derivative 10a was also iso-
lated in 15–20% yield.
Various attempts to transform 9b cleanly into the correspond-
ing ester derivative 10b proved unfruitful, leading in all cases to
mixtures of products. Alternatively, we carried out the reaction
using 2-bromo-5-hydroxybenzaldehyde (9a) and anthranilamide
(8) implementing the iodine-aerobic oxidative coupling in ethanol
at reflux for 48 h. To our delight, 10a was isolated in good yield.
The coupling product 10a was efficiently acylated to furnish the re-
quired product 10b in excellent yield.
At this stage, we planned to construct the seco-CI-quinazolinone
conjugates (5 and/or 7) based on the strategy of intramolecular
cyclization of an aryl radical generated at the C-2 position of the
aryl moiety and a radical acceptor attached to N-3 of the quinazoli-
none ring. Thus, the radical acceptor was introduced by N-allyla-
tion of 10b with (E/Z)-1,3-dichloropropene under standard
reaction conditions (acetone, K2CO3). This reaction afforded the ex-
pected product 11a in 80% yield as well as the O-allylated deriva-
tive 12a (Scheme 1).
Furthermore, the structure of 13 was confirmed after conduct-
ing the free radical cyclization of 11b [benzene, 80 °C, (Bu)3SnH,
AIBN], which afforded the benzoazepinoquinazolinone derivative
13 in 40% yield. Moreover, this reaction furnished the expected
product 13 in 60% yield when a 4:1 mol ratio of (Bu)3SnH and 2-
bromo derivative 11b in the presence of AIBN was added to boiling
benzene (Scheme 2). The 1H and 13C NMR spectra of this product
were identical to the compound obtained from 11a.
As indicated in Scheme 3, we propose that the formation of
seco-CBAQ 13 most likely occurs via a 6-exo-trig ring closure of
the generated aryl radical 16 to furnish 17. Instead of immediately
reacting with tributyltin hydride, the radical intermediate 17
undergoes ring expansion to produce the more stable intermediate
18, which has the radical and is further stabilized by conjugation
with the phenyl ring. Subsequent reaction of 18 radical with
tributyltin hydride affords product 13. Similar free radical rear-
rangements have been observed in cyclopropylfurano[e]indoline
systems.12
This mechanism was supported by conducting the cyclization of
11a in the presence of a large excess of (Bu)3SnH (6 equiv) and
AIBN (2 equiv) to trap the free radical intermediate 17 prior to
rearrangement. This reaction afforded 14b via a 6-exo-trig ring clo-
sure of the generated aryl radical 16 to form radical 17. This radical
was trapped by the presence of the large excess (Bu)3SnH to yield
14a which was further dechlorinated in the presence of excess
(Bu)3SnH and AIBN to furnish benzoazepinoquinazolinone 14b.
The acetyl protecting group in compound 13 was removed by
mild hydrolysis in anhydrous methanol containing anhydrous
The minor product 12a could not be fully characterized because
it was contaminated with inseparable impurities. Similarly, allyla-
tion of 10b with 2,3-dichloropropene afforded the required prod-
uct 11b in 55–60% yield as well as the O-allylation derivative 12b.
Suitable reaction conditions to generate the aryl free radical at
the C-2 position were first examined in detail using a 1:1 mol ratio
of Bu3SnH and 2-bromo derivative 11a in the presence of AIBN as a
radical initiator. Conducting the reaction in a dry degassed solution
of 11a in xylene or toluene at reflux temperature furnished more
than three products as indicated by TLC. Fortunately, when the
reaction was carried out in benzene at reflux temperature under
N2, the cyclization occurred smoothly to afford, unexpectedly, the
seco-cyclopropaneazepinoquinazolinone derivative (13)11 as the
major product in reasonable yield (45%) after silica gel column
purification. The expected product 14a was not observed under
these reaction conditions. Furthermore, 14b contaminated with
Cl
O
N
O
N
Y
Cl
O
N
a
N
N
+
N
Br
OAc
(Y = Cl)
(Y = H)
AcO
13
OAc
14a
14b
11a
b
Cl
Cl
O
N
O
N
N
Br
N
a, b
OAc
HO
15
11b
Scheme 2. Reagents and conditions: (a) Bu3SnH (2.0 equiv), AIBN (0.2 equiv),
benzene, (60%); (b) K2CO3, MeOH, (100%).
O
N
OR1
N
N
O
O
R1
Br
H
a
c or d
N
Br
NH2
N
Br
+
+
Br
OHC
NH2
N
OR
OR
OAc
OAc
8
1 = -CH2CH=CHCl)
1 = -CH2CH=CHCl)
12a (
R
11a (
9a
10a
R
(R = H)
(R = H)
b
9b (R = Ac)
10b (R = Ac)
11b (
R
1 = -CH2CCl=CH2)
1 = -CH2CCl=CH2)
12b (
R
Scheme 1. Reagents and conditions: (a) I2 (1.0 equiv), EtOH, reflux 48 h; (b) Et3N (1.3 equiv), Ac2O (1.15 equiv), CH2Cl2, rt, 1 h, (91%); (c) 1,3-dichloropropene (1.25 equiv), KI
(1.25 equiv), K2CO3 (2.0 equiv), acetone, (80%); (d) 2,3-dichloropropene (1.25 equiv), KI (1.25 equiv), K2CO3 (2.0 equiv), acetone, (60%).

K. Q. Shawakfeh et al. / Tetrahedron Letters 55 (2014) 1329–1331
1331
Cl
O
N
O
N
Cl
Cl
O
N
O
N
N
Br
Cl
N
N
AIBN
N
(Bu)4SnH
13
OAc
OAc
17
AcO
OAc
16
11a
18
Scheme 3. Proposed mechanism of the free radical cyclization.
K2CO3 at 0 °C to furnish the target phenolic compound 1513 in
quantitative yield. Isolated 15 was found to be stable for a week
when it was stirred in acetone or methanol containing K2CO3.
However, when the reaction mixture was warmed to 60 °C, the
phenolic compound underwent rearrangement to give a mixture
of inseparable products as indicated by TLC. A similar result was
obtained after stirring phenol 15 with sodium hydride in THF at
room temperature. In contrast, the phenolic derivative was some-
what stable in methanol–water mixture at pH 4–5 on monitoring
by TLC for four days.
In conclusion, an efficient synthetic protocol based on a free-
radical cascade reaction has been described for a new heterocyclic
compound with appropriate substituents which should allow the
formation of cyclopropanequinone system found in duocarmycins.
Furthermore, the new product is stable under mild basic and acidic
conditions. Such a hybrid molecule, which possesses the biologi-
cally active unit at the duocarmycin family fused to quinoxalinone
moiety, may act as a lead molecule for further investigations of no-
vel alkylating agents for the DNA double helix.
Dervan, P.; Beerman, T. Mol. Pharmacol. 2005, 67, 877; (c) Ducry, L.; Stump, B.
Bioconj. Chem. 2010, 21, 5; (d) Tietze, F.; Krewer, B.; von Hof, J.; Frauendorf, H.;
Schuberth, I. Toxins 2009, 1, 134.
9. (a) Al-Said, N.; Shawakfeh, K.; Abdullah, W. Molecules 2005, 10, 1446; (b) Al-
Said, N.; Shawakfeh, K.; Hammad, B. J. Heterocycl. Chem. 2008, 45, 1333.
10. Typical experimental procedure for the synthesis of 10b: I2 (2.54 g, 10 mmol)
was added to
a solution of 2-bromo-5-hydroxy-benzaldehyde 9a (2.01 g,
10 mmol) and o-aminobenzamide 8 (1.36 g, 10 mmol) in EtOH (80 mL). The
mixture was stirred for 15 min then refluxed for 8 h. After the resulting
solution was cooled to room temperature, the solvent was removed using a
rotary evaporator. The residue was dissolved in EtOAc (150 mL), and the
organic layer was washed with water (30 mL). The remaining I2 was removed
by washing with 5% Na2S2O3 solution and then the separated organic layer was
washed with H2O (25 mL), 5% HCl (25 mL), brine (25 mL), and dried over
Na2SO4. The solvent was removed under rotary evaporation to give the crude
product 10a. Without further purification, 10a was suspended in CH2Cl2
(150 mL) and cooled to 0 °C and then Et3N (1.32 g, 13 mmol) was added. A
solution of Ac2O (1.17 g, 11.5 mmol) in CH2Cl2 (10 mL) was added dropwise to
the mixture. The mixture was allowed to warm to room temperature. The
reaction mixture was washed with H2O (50 mL) and the separated organic
layer was dried over Na2SO4. The solvent was removed under rotary
evaporation and the residue purified by column chromatography (20%
EtOAc/hexane) to give 10b (3.27 g, 91%). 1H NMR (CDCl3, 400 MHz): d 10.61
(br s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.85 (br s, 2H), 7.70 (d, J = 8.7 Hz, 1H), 7.55
(m, 2H), 7.17 (dd, J = 8.7 Hz, J = 2.7 Hz, 1H), 2.32 (s, 3H).
11. Typical experimental procedure for the synthesis of 13: A solution of 11a
(1.75 mmol, 0.760 g), Bu3SnH (5.25 mmol, 1.532 g), and AIBN (0.525 mmol,
ꢀ0.1 g) in dry benzene (100 mL) was degased with nitrogen and then refluxed
for 1 h. A solution of AIBN (ꢀ0.1 g) in dry benzene (20 mL) was added and the
mixture was further refluxed for 0.5 h. The mixture was concentrated and
loaded onto a silica gel column, which was run using gradient elution (0–10%
EtOAc/hexane) to give 13 (0.373 g, 60%): 1H NMR (CDCl3, 400 MHz) d 8.33 (d,
J = 7.6 Hz, 1H), d 8.27 (d, J = 2.5 Hz, 1H), 7.76 (m, 2H), 7.50 (m, 1H), 7.41 (d,
J = 8.3 Hz, 1H), 7.28 (dd, J = 8.3 Hz, J = 2.5 Hz, 1H), 5.35 (dd, J = 14.0 Hz,
J = 2.5 Hz, 1H), 3.89 (dd, J = 14.0 Hz, J = 3.9 Hz, 1H), 3.62 (dd, J = 11.0 Hz,
J = 5.3 Hz, 1H), 3.53 (t, J = 10.0 Hz, 1H), 3.47 (m, 1H), 2.36 (s, 3H). 13C NMR
(DEPT-135, CDCl3, 100 MHz) d 133.9, 128.6, 127.0, 126.5, 126.4, 124.9, 120.7,
44.5 (À), 41.0 (À), 40.1, 21.1.
Acknowledgments
We thank the Deanship of Research at Jordan University of Sci-
ence and Technology for financial support.
References and notes
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13. Typical experimental procedure for the synthesis of 15: A solution of 13
(0.035 g, 0.100 mmol) in MeOH (10 mL) was stirred in basic MeOH (prepared
by filtering a solution of K2CO3 (0.50 g) suspended in MeOH (30 mL). The
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consumed (1 h) to give clean spot of 15. The reaction mixture was extracted
with EtOAc (60 mL). The organic layer was washed with H2O (20 mL), dried
over anhydrous Na2SO4 and filtered. The solvent was removed under vacuum.
The residue was dissolved in CDCl3 (1.0 mL) then filtered to remove the
insoluble impurities. 1H NMR (CDCl3, 400 MHz) d 8.34 (d, J = 7.9 Hz, 1H), 7.99
(d, J = 2.1 Hz, 1H), 7.75 (m, 2H), 7.49 (td, J = 13.5 Hz, J = 1.6 Hz, 1H), 7.25 (d,
J = 8.6 Hz, 1H), 7.06 (dd, J = 8.2 Hz, J = 2.5 Hz, 1H), 6.19 (br s, 1H), 5.35 (dd,
J = 13.9 Hz, J = 2.4 Hz, 1H), 3.86 (dd, J = 13.9 Hz, J = 3.8 Hz, 1H), 3.59 (dd,
J = 11.1 Hz, J = 5.2 Hz, 1H), 3.47 (dd, J = 11.1 Hz, 9.8, 1 H), 3.39 (m, 1H). 13C NMR
(DEPT-135, DMSO-d6, 100 MHz) d 134.3, 129.5, 127.2, 126.4, 126.2, 119.5,
113.1, 45.6 (À), 40.7 (À), 37.3.
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