Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation, DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones

Article abstract of DOI:10.1002/jhet.3385

A series of novel 8-aryl-2-morpholino quinazolines (11a–n, 12a–d, 14a–f, and 15) were synthesized from the precursor 2-thioxo quinazolin-4-ones 8. The 8-aryl-2-morpholino quinazolines compounds were assayed for DNA-PK and PI3K. All compounds showed low DNA-PK % inhibition activity at 10?μM compound concertation, and the most active was 8-(dibenzo[b,d]thiophen-4-yl) 12d with 38% inhibition. Similar pattern of PI3K α, β, γ, and δ isoforms inhibition activity at 10?μM were observed. The most active isoform was PI3K δ of 41% inhibition for 8-(dibenzo[b,d]furan-4-yl) compound 11. Most compounds were less active than expected in spite of the strong structural resemblance to known inhibitors (NU7441, 3, 4, and 6). Loss of activity could be attributed to the tautomerization to the aromatic enol (4-OH), which could specify that the important functional group for the activity is the 4-carbonyl (C=O) group. Alternatively, the aromatization of the pyrimidine heterocyclic ring could alter the conformation, and thus binding site, of the 2-morpholine ring, which could reduce the compound-receptor hydrogen bonding to the morpholine 4-oxygen. Selected compounds displayed appreciable cytotoxicity with 6-chloro-8-(dibenzo[b,d]thiophen-4-yl)-2-morpholinoquinazolin-4(1H)-one 11j exhibiting the greatest activity with an IC₅₀ of 9.95?μM. Therefore, the mechanism of the cytotoxicity of compound 11j were not through DNA-PK or PI3K inhibition activity.

Full text of DOI:10.1002/jhet.3385

Month 2018
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures
Elucidation, DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-
morpholino-quinazolin-4-ones
a
b
b
a
Jacob T. Heppell, Md. Amirul Islam,
Shelli R. McAlpine, and Jasim M. A. Al-Rawi *
a
Department of Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University Bendigo,
P.O. Box 199, Bendigo, Victoria 3550, Australia
b
School of Chemistry, University of New South Wales, Sydney, New South Wales 2052, Australia
*
E-mail: j.al-rawi@latrobe.edu.au
For Part 2, see reference 15.
Received June 5, 2018
DOI 10.1002/jhet.3385
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 8-aryl-2-morpholino quinazolines (11a–n, 12a–d, 14a–f, and 15) were synthesized from
the precursor 2-thioxo quinazolin-4-ones 8. The 8-aryl-2-morpholino quinazolines compounds were assayed
for DNA-PK and PI3K. All compounds showed low DNA-PK % inhibition activity at 10 μM compound
concertation, and the most active was 8-(dibenzo[b,d]thiophen-4-yl) 12d with 38% inhibition. Similar pat-
tern of PI3K α, β, γ, and δ isoforms inhibition activity at 10 μM were observed. The most active isoform
was PI3K δ of 41% inhibition for 8-(dibenzo[b,d]furan-4-yl) compound 11. Most compounds were less ac-
tive than expected in spite of the strong structural resemblance to known inhibitors (NU7441, 3, 4, and 6).
Loss of activity could be attributed to the tautomerization to the aromatic enol (4-OH), which could specify
that the important functional group for the activity is the 4-carbonyl (C=O) group. Alternatively, the aroma-
tization of the pyrimidine heterocyclic ring could alter the conformation, and thus binding site, of the 2-
morpholine ring, which could reduce the compound-receptor hydrogen bonding to the morpholine
4
4
-oxygen. Selected compounds displayed appreciable cytotoxicity with 6-chloro-8-(dibenzo[b,d]thiophen-
-yl)-2-morpholinoquinazolin-4(1H)-one 11j exhibiting the greatest activity with an IC50 of 9.95 μM. There-
fore, the mechanism of the cytotoxicity of compound 11j were not through DNA-PK or PI3K inhibition
activity.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
owing to the low sequence homology of the ATP-binding
domain with other protein kinases [1,2]. Still, off-target
kinase-inhibitory activity associated with currently
available small molecule DNA-PK inhibitors, including
the potent 8-substituted chromen-4-ones 1 (NU7441) and
2 (KU0060648) [2] (Fig. 1), which continue to represent
an obstacle to preclinical development. Therefore, there is
DNA-dependent protein kinase (DNA-PK) inhibitors
have a considerable therapeutic potential as chemo-
potentiating and radio-potentiating agents in cancer
therapy by blocking DNA DSB repair [1–5]. As DNA-
PK, a prominent member of the phosphatidylinositol 3-
kinase-related kinases (PIKK) family of typical serine–
threonine kinases is amenable to the development of
highly kinase-selective ATP-competitive inhibitors,
a
requirement for inhibitors that combine good
pharmaceutical properties with high potency and
selectivity for DNA-PK over other related kinases, most
©
2018 Wiley Periodicals, Inc.

J. T. Heppell, M. A. Islam, S. R. McAlpine, and J. M. A. Al-Rawi
Vol 000
Figure 1. Structures of known, potent, DNA-PK, and/or PI3K inhibitors. DNA-PK IC50 = 42, 38, 13, and 34 nM for compounds 1, 3, 4, and 6,
respectively.
notably members of the PI3-kinase (PI3K) family [2]. 8-
Aryl-2-morpholino-4-yl-chromenones 1 and 2 (Fig. 1)
have been shown to be potent and selective inhibitors of
DNA-PK [3–6]. Structure–activity studies and homology
modeling have shown the importance of the morpholine
oxygen atom and chromenone carbonyl oxygen as
hydrogen bond acceptors to specific groups in the protein
target [6].
Replacing the oxygen-1 of 8-aryl-2-morpholino-
chromenones in compound 1 (NU7441) (DNA-PK
IC50 = 42 nM) [4] with an NH resulted in 8-aryl-2-
morpholino-quinol-4-ones 3 (DNA-PK IC50 = 38 nM)
successfully developed, marketed, and used clinically for
the prevention and treatment of various types of
diseases [10].
Quinazoline inhibitors of the phosphoinositide-3-kinase/
mechanistic target of rapamycin (PI3K/mTOR) pathway
offer viable future treatments for cancer, inflammation,
and autoimmune diseases among others. Additionally,
the development of isoform-specific PI3K inhibitors
offers the potential for safer and more targeted therapy
[11]. For example, compound 5 (Idelalisib) (CAL-101/
GS-1101) (Fig. 1) is a quinazolin-4-one based, PI3Kδ
selective inhibitor that has already been approved for
the treatment of various hematological malignancies
[12,13].
(Fig. 1) [7], which did not significantly affect DNA-PK
activity, indicating that neither the 1-oxygen nor 1-NH
make significant adjustment to the hydrogen bonding
interactions with DNA-PK. This analysis assumes that
the tautomer indicated for the 8-aryl-2-morpholino-
quinol-4-ones 3 is preferred over the alternative 4-
hydroxy enol form [7].
In this work, 8-aryl-2-morpholino quinazolines (11a–n,
12a–d, 14a–f, and 15) were functionalized, synthesized,
structures elucidated, and evaluated for their DNA-PK,
PI3K, and some cytotoxic activity.
Furthermore, replacing the 4a-C of 8-aryl-2-morpholino-
quinol-4-ones 3 with nitrogen gave 9-aryl-2-morpholino-
pyrido[1,2-a]pyrimidin-4-ones 4 (DNA-PK IC50 = 13 nM)
RESULTS AND DISCUSSION
[
7], which showed no significant effect on the DNA-PK
activity.
To probe whether alterations to the heterocyclic core
Synthesis of 8-aryl-2-morpholino-quinazolines (11a–n,
12a–d, 14a–f, and 15).
The commercially available
5-chloro-2-nitrobenzoic acid was reduced according to
the previously reported procedure [14], giving 2-amino-
5-chlorobenzoic acid 7, which was cyclized with freshly
prepared triphenylphosphine thiocyanate to give
compound 8. S-methylation of the 2-thioxo tautomer 8
followed by treatment with morpholine gave 6-chloro-
2-morpholinoquinazolin-4-one (9) according to the
previously reported methods [14,15] (Scheme 1). The
6-chloro atom of compound 9 directed the bromination
with NBS to the 8-position and gave 8-bromo-6-chloro-
2-morpholino quinazolin-4-one (10). Palladium-catalyzed
at positions other than the carbonyl group would be
tolerated. Thus, the 3-CH of in compound 1 (NU7441)
[
6
8] was replaced with nitrogen and gave 1,3-benzoxazine
(LTURM34) which showed comparable DNA-PK
activity (IC50 = 34 nM) [9] to that of the chromenone 1
Fig. 1).
(
Quinazoline have been revealed to possess extensive
potential applications as medicinal drugs. In particular,
a large number of quinazoline-based compounds as
antitumor agents and kinase inhibitors have been
Journal of Heterocyclic Chemistry
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Month 2018
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation,
DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
Scheme 1. Synthesis of 8-aryl-2-morpholino quinazolin-4-ones.
Journal of Heterocyclic Chemistry
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J. T. Heppell, M. A. Islam, S. R. McAlpine, and J. M. A. Al-Rawi
Vol 000
Suzuki coupling with aryl boronic acids subsequently
yields 8-aryl-6-chloro-2-morpholino quinazolin-4-ones
with methyl iodide and benzyl bromide gave 8-bromo-6-
chloro-4-alkyloxy-2-morpholino quinazolines 13a–b,
11a–n. Finally, catalytic hydrogenation with Pd/C of
which subsequently underwent Suzuki coupling to give 8-
some selected compounds (11a, h–j) was successfully
performed to yield the desired 8-aryl-2-morpholino
quinazolin-4-ones 12a–d (Scheme 1). Nevertheless, this
method of hydrogenation failed to de-chlorinate
aryl-6-chloro-4-alkyloxy-2-morpholino quinazolines 14a–f.
De-chlorination of compound 14c (R1
=
CH3,
Ar = dibenzo[b,d]furan-4-yl) with hydrogen and Pd/C gave
the corresponding compound 15 as expected, but compound
14f (R = CH Ph) gave only compound 12c (Scheme 2),
compound 11b (Ar
= 4-methoxyphenyl) and 11c
1
2
(
Ar = 4-(hydroxymethyl)phenyl), as the 8-aryl groups
which occurred as benzyl ether can also be removed under
these conditions. Reducing the temperature and time of the
reaction revealed that the benzyl group is removed at a
faster rate than the 5-chlorine atom.
were electron donating by resonance.
Reagent and reaction condition: (i) PPh (SCN) , 0°C to
3
2
RT, reflux 16–20 h; (ii) 1. NaOH, CH I, 1:1 (v:v) water–
3
methanol, RT, 1.5 h, 2. morpholine, reflux, 8 h; (iii)
NBS, AcOH, RT, 16 h; (iv) arylboronic acid,
PdCl (PPh ) , K CO , 7:3 (v:v) dioxane–water, 50°C,
Moreover, aryl boronic acids that contained sulfur
generally proved to be problematic in Suzuki reaction.
Both 2 and 3-thienylboronic acid failed to yield any
substantial amount of product 11o (Ar = thiophen-2-yl) or
11p (Ar = thiophen-3-yl) as shown initially by TLC and
2
3 2
2
3
24 h; (v) 10% Pd on activated carbon, cyclohexene,
methanol, MW, 160°C, 2 h, P = 60–100 W.
Alkylation 8-bromo-6-chloro-2-morpholino-quinazolin-4-one
1
then by H NMR as the isolated crude product was at
(10). Alkylation of the 4-hydroxy tautomer of 8-bromo-
least 80% starting material (10). Extra boronic acid
6-chloro-2-morpholino-quinazolin-4-one (10) (Scheme 2)
and/or PdCl (PPh ) in the reaction mixture failed to
2
3 2
Scheme 2. Synthesis of 8-aryl-2-morpholino-4-alkyloxy quinazolines.
Journal of Heterocyclic Chemistry
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Month 2018
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation,
DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
Table 1
DNA-PK and PI3K % inhibition of compounds 11a–n, 12a–d, 14a–f, and 15 at 10 μM compound concertation.
No.
Ar
DNA-PK
12
PI3Kα
PI3Kβ
PI3Kγ
PI3Kδ
11a
12
1
25
0
1
1b
11
31
11
0
7
0
25
0
26
12
11c
1
1d
0
0
0
1
0
10
1
11f
11
18
24
11g
11
0
23
0
3
1
1h
12
12
24
12
0
4
19
41
11i
19
14
1
1j
10
2
10
19
37
25
16
0
0
0
11k
11l
1
30
3
0
0
(Continues)
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J. T. Heppell, M. A. Islam, S. R. McAlpine, and J. M. A. Al-Rawi
Vol 000
Table 1
(
Continued)
No.
1m
Ar
DNA-PK
5
PI3Kα
PI3Kβ
PI3Kγ
PI3Kδ
1
21
39
0
0
1
1n
5
18
30
0
32
0
0
0
0
2
0
2
1
2a
2b
20
13
1
8
1
1
2c
14
38
12
15
37
15
0
0
0
0
2d
1
4a
4b
9
7
20
31
30
0
0
1
0
0
1
14c
1
0
12
7
18
1
1
4d
4e
0
8
20
14
28
0
0
0
12
17
(Continues)
Journal of Heterocyclic Chemistry
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Month 2018
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation,
DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
Table 1
(
Continued)
No.
Ar
DNA-PK
1
PI3Kα
PI3Kβ
PI3Kγ
PI3Kδ
14f
0
4
0
28
15
3
13
25
0
7
DNA-PK, DNA-dependent protein kinase; PI3K, phosphatidylinositol 3-kinase.
improve the outcome. In spite of this result, benzo
4-OH/% of the OH to the NH: 12a; 7.89/5; b 8.22/5; c
8.25/8; and d 8.26/15.
[b]-thien-2-yl-boronic acid was successfully employed to
give compound 11m although the crude product did
contain slightly more starting material (10) than all other
Biological activity. DNA-dependent protein kinase
inhibition of 8-aryl-2-morpholinoquinazolin-4(1H)-ones at
10 μM (11a–n, 12a–d, 14a–f, and 15). In the introduction,
it was stated that the 8-(dibenzo[b,d]thiophen-4-yl)-2-
morpholino chromenone 1, quinolin-4-ones 3, and -1,3-
benzoxazine 6 (Fig. 1) are analogues with comparable
DNA-PK IC50 in the nano-molar range of 14 [8], 38 [7],
and 34 nM [9], respectively. In contrast, replacing the
1-O and 3-CH in the chromenone 1 by1-NH and 3N gave
8-aryl products (11a–n). Interestingly, compound 11j
(Ar = dibenzo[b,d]thiophen-4-yl) did not suffer from
these shortcomings and was sufficiently soluble for
purification by flash chromatography.
Reagent and reaction condition: (i) K CO , CH I or
2
3
3
PhCH Br, acetone, reflux, 1.5 h; (ii) arylboronic acid,
2
o
PdCl (PPh ) , K CO , 7:3 (v:v) dioxane–water, 50 C,
2
3 2
2
3
2
4 h; (iii) 10% Pd on activated carbon, cyclohexene,
8
4
-(dibenzo[b,d]thiophen-4-yl)-2-morpholinoquinazolin-
(1H)-one (12d), which only showed 38% DNA-PK
methanol, MW, 160°C, 2 h, P = 60-100 W.
Structure elucidation.
The structures of the new
inhibition at 10 μM (Table 1).
products 11a–n, 12a–d, 14a–f, and 15 were confirmed by
It is worth noting that the homology model [16] of the
catalytic subunit of human DNA-PK was generated based
on the template protein phosphoinositide 3-kinase γ
isoform (PI3K γ) [17], which was used for DNA-PK
homology interaction patterns of chromone analogue
LY294002 [6].
It was found that the morpholine-ring oxygen of
LY294002 was hydrogen-bonded to Val882 (1.5 Å), the
oxygen of the 4-carbonyl group provides hydrogen
bonding with Lys833 (3.2 Å), and the 8-phenyl ring is
stacked between Trp812 (π–π interaction, 3.6 Å) [6].
Consequently, the only structural difference of
compound 12d from compound 1 (Fig. 1) is that nitrogen
1
13
the analysis of their IR, H NMR, and C NMR spectra
1
and C, H, N-microanalysis. The assignment of the H
1
1
NMR spectra of compounds were achieved using H– H
correlation spectroscopy (COSY) while the protonated
13
signals of the C NMR spectra were assigned from the
heteronuclear single quantum coherence spectroscopy
(HSQC) using the assigned proton NMR spectra.
Inspection of the proton NMR spectra of 8-aryl-2-
morpholino-quinazolines 12a–d indicates the 4-OH
formation (heterocyclic ring aromatization) and showed
increasing intensity as the 8-aryl group size increased.
1
ꢀ
The HNMR in DMSO d at 340 K gave δ ppm for
6
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J. T. Heppell, M. A. Islam, S. R. McAlpine, and J. M. A. Al-Rawi
Vol 000
Figure 2. Structures of the keto and enol form of 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-quinazolin-4(1H)-one (11i and 12c). The DNA-PK inhi-
3
bition % at 10 μM 8-(dibenzo[b,d]furan-4-yl)-2-morpholino-quinazolin-4(1H)-one 11i, 12c, and 4-OCH analogues 14c, and 15. The 1-NH and 3-NH
analogues 16 and 17, respectively. [Color figure can be viewed at wileyonlinelibrary.com]
atoms occupy both the 1-position and 3-position (1-NH
and 3-N). This change resulted in a significant loss in
activity. Therefore, the presence of the second nitrogen in
the heterocyclic ring cannot be the single reason for the
drop in the activity as the quinol-4-one 3 (1-NH
analogue) and benzoxazine 6 (LTURM34) were potent
with a similar DNA-PK (Fig. 1).
It is worth noting that DNA-PK activity of the 1-NH and
3-NH analogues 16 and 17, respectively, are much more
potent and in the nM IC50 (Fig. 3).
Moreover, comparing the DNA-PK inhibition activity of
8-(dibenzo[b,d]furan-4-yl)-2-morpholinoquinazolin-4(1H)-
one 11i and 12c with the 4-OCH analogue 8-(dibenzo[b,
3
d]furan-4-yl)-4-methoxyquinazolin-2-yl) morpholine 14c
and 15 showed no appreciable change in the DNA-PK
inhibition (Fig. 3 and Table 1). This result confirm
that compounds 11a–n and 12a–d were interacting
with the DNA-PK in the enol (4-OH) and not the keto-
4-C=O form.
The loss of DNA-PK activity of the 8-aryl-
2
(
-morpholinoquinazolin-4(1H)-one 11a–n and 12a–d
Table 1) could be resulted from the aromatization of the
heterocyclic pyrimidine ring due to the enolization of the
-C=O group (Fig. 3), thus reducing the hydrogen-bond
4
accepting capability of the 4-C=O group (Fig. 2).
Alternatively, the aromatization of the heterocyclic ring
could alter the conformation, and thus binding position,
of the 2-morpholine ring oxygen The importance of
morpholine 4-O in the DNA-PK activity was obvious
from the comparison of DNA-PK of compound 1
Phosphatidylinositol 3-kinase inhibition of 8-aryl-2-morp
holinoquinazolin-4(1H)-ones at 10 μM (11a–n, 12a–d, 14a–f,
and 15). Most compounds in Table 1 displayed some
level of activity against PI3Kα at 10 μM compound
concentration; however, only compounds 11l (X = Cl,
Ar = naphthalene-1-yl), 12a (X = H, Ar = phenyl), and
0
(
NU7441) 2-morpholino-substituent (IC50 = 42 nM) with
14b (X = Cl, R1 = CH3, Ar = [1,1 -biphenyl]-3-yl)
that of NU7742, 2-piperidino-substituent (IC50 > 10 μM)
inhibition were ~30% (Table 1). A similar trend was
with more than 714-fold decrease in DNA-Pk activity
observed for the β isoform as only three compounds 11j
resulted from replacing the morpholine 4-O by CH [18].
(X
=
Cl, Ar
=
dibenzo[b,d]thiophen-4-yl) (37%
2
Alternatively, the loss in the DNA-PK activity of
compound 12d (1,3-dinitrogen structure) resulted from
the N1 replaced the O1 of in structure 6 (Fig. 1)
inhibition), 11m (X = Cl, Ar = benzo [b]thiophen-2-yl)
(39% inhibition), and 12c (X = H, Ar = dibenzo[b,d]
furan-4-yl) inhibited above 30%. In contrast, all
compounds in Table 1 displayed minimal to no activity
against the γ isoform, while the δ isoform was likewise
not appreciably inhibited. However, compound 11i
(DNA-PK IC50 = 34 nM).
Therefore, N1 in compound 12d could push the 8-aryl
group out of the DNA-PK hydrophobic interaction region.
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Month 2018
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation,
DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
Figure 3. Growth inhibition of compounds at 50 μM. Percentage growth inhibition of treated HCT-116 cells was measured using a CCK8 assay. Data
represent results for compounds 11a, 11g, 11j, 12d, 14c, and 14f each at 50 μM concentration. Data are from three separate experiments performed in
quadruplicate, and the error bars are the standard errors of the mean (SEM).
1
13
(
X = Cl, Ar = dibenzo[b,d]furan-4-yl) (41% inhibition)
Spectrometer. H NMR and C NMR spectra were
recorded on a Bruker AC 200 NMR spectrometer with
exhibited a moderate level of activity (Table 1).
Cytotoxicity. As seen in Table 1, DNA-PK and PI3K
activity was significantly lower than expected.
Nevertheless, a selection of compounds was assayed for
cytotoxicity against HCT-116 human colon cancer cells;
results are in Figure 3 and Table 2.
The most potent compound was 6-chloro-8-(dibenzo[b,
d]thiophen-4-yl)-2-morpholinoquinazolin-4(1H)-one 11j
1
Techmag upgrade at 200 MHz for H and 50 MHz for
C, respectively, or a Bruker Avance 300 NMR
spectrometer at 300 MHz for H and 75 MHz for C,
respectively. H COSY and H- C HSQC experiments
were performed only on the Bruker Avance 300 NMR
spectrometer. All H and C NMR spectral results are
recorded as chemical shifts (δ). Chemical shifts recorded
are relative to the internal TMS (0 ppm) for H
spectra and solvent peak (77.0 ppm) for C spectra.
Chemical shifts recorded in DMSO-d are relative to the
solvent peak of 2.5 ppm for H spectra and 39.5 ppm for
C spectra. H NMR multiplicities are expressed as
singlet (s), broad singlet (bs), doublet (d), double doublet
dd), triplet (t), double triplet (dt), triple triplet (tt),
13
1
13
1
1
13
1
13
1
(IC50 = 9.95 μM). Replacing the 6-chloro by hydrogen,
in CDCl
3
13
to give compound 12d, resulted in an appreciable loss of
potency (IC50 = 41.81 μM). Similarly, other aromatic
groups at the 8-position yielded the less potent products
6
1
13
1
1
1g (Ar = 8-(3-aminophenyl)) (IC50 = 34.7 μM) and 11a
(Ar = 8-phenyl), of which was almost inactive at a
compound concentration 50 μM.
(
Cytotoxicity studies revealed a moderate level of
activity against HCT-116 human colon cancer cells.
quartet (q), and multiplet (m). Microanalysis was
performed by Chemical and Microanalytical Services Pty
Ltd in Belmont, Victoria.
2
-Amino-5-chlorobenzoic
acid
(7).
5-Chloro-2-
EXPERIMENTAL
nitrobenzoic acid was reduced with iron and acetic acid
according to previously reported procedure [14] to give 7
as a white solid. Yield = 76%.
6-Chloro-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (8).
Dry crude 2-amino-5-chlorobenzoic acid (7) was reacted
Chemistry. Analytical techniques.
Melting point
determinations were carried out using a Stuart Scientific
SMP3) melting point apparatus, and all melting points
(
are uncorrected. Infrared spectra were recorded on a
Perkin Elmer 1720X or a Bruker Equinox 55 FT-IR
with PPh (SCN)2 according to previously reported
procedure [14] to give 8 as a white solid. Yield = 87%.
3
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Vol 000
Table 2
Growth inhibition of compounds 11a, 11g, 11j, 12d, 14c, and 14f each at 50 μM concentration plus IC50 for those that inhibited above 50% with the
standard errors of the mean (SEM).
%
growth
Substitution
Ar and R
inhibition
± SEM (50 μM)
IC50 (μM)
± SEM
No.
1a
1
15.70 ± 1.53
nd
11g
87.44 ± 2.43
34.7 ± 2.36
1
1j
89.40 ± 2.05
52.89 ± 1.74
22.96 ± 2.71
9.95 ± 1.2
41.81 ± 2.3
nd
1
1
2d
4c
14f
17.33 ± 2.83
-
Percentage growth inhibition of treated HCT-116 cells was measured using a CCK8 assay. Data are from three separate experiments performed in qua-
druplicate and the error bars.
6-Chloro-2-morpholinoquinazolin-4(1H)-one (9).
Crude
8-Bromo-6-chloro-2-morpholinoquinazolin-4(1H)-one
6
-chloro-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
(8)
(10). Crude 6-chloro-2-morpholinoquinazolin-4(1H)-one
(
9) (5.0 mmol) was added to 10 mL acetic acid followed by
(5.0 mmol) 10% (w:w) NaOH (5.5 mmol) were stirred in
the addition of N-bromosuccinimide (NBS) (10.0 mmol) in
three portions each 1 h apart. The reaction was then left to
stir at room temperature overnight before the acetic acid
was evaporated. The resulting solid was washed with
4
0 mL of 1:1 (v:v) methanol–water for 15 min. Methyl
iodide (6.0 mmol) was then added and the solution stirred
for 90 min. The methanol was removed under reduced
pressure, and the resulting solid was collected by
filtration with suction to give the 2-methylthio
intermediate, which was then reacted with morpholine
according to a previously reported procedure [14] with
the modification that the crude oil was triturated with
ethyl acetate to give 9 as a white solid. Yield: 54%.
20 mL of 5% (w:w) NaHCO
before collection by
3
filtration with suction to give 10 as a white solid.
Yield = 89%. Solvent: Nitromethane. mp 325–326°C. IR
3
(KBr): νmax 2976.3 (w, sp C-H st), 1676.8 (m, C=O)
ꢀ
1
1
cm
. H NMR (200 MHz, DMSO-d , T = 340 K):
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation,
DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
δ = 3.70 (s, 8H, H-9, H-10), 7.84 (d, 1H, H-5, J5–7
=
then evaporated under reduced pressure. The resulting oil
or solid was triturated with minimal diethyl ether. The
resulting solid is then collected by filtration with suction
to give the crude product, which was then purified by an
appropriate technique.
2
.2 Hz), 7.95 (d, 1H, H-7, J = 2.2 Hz), 11.53 (bs, 1H,
7–5
13
NH) ppm. C NMR (50 MHz, DMSO-d , T = 340 K):
6
δ = 44.8 (C-9), 65.3 (C-10), 118.4 (C-8), 119.9 (C-4a),
124.4 (C-5), 125.3 (C-6), 136.3 (C-7), 146.6 (C-8a),
1
50.8 (C-2), 161.5 (C-4) ppm. C H N O BrCl
Extraction method 2 (compounds 11a–e, n). The reaction
mixture was poured into a 50 mL round bottom flask, and
the solvent evaporated under reduced pressure; 15 mL of
1
2
11
3
2
(344.59): Calcd C 41.83, H 3.22, N 12.19; found. C
42.07, H 3.41, N 12.20.
4-(8-Bromo-6-chloro-4-methoxyquinazolin-2-yl) morpholine
2
% (w:w) K CO was added, and the resulting solid was
2 3
(13a).
Crude 8-bromo-6-chloro-2-morpholinoquinazolin-
collected by filtration and washed with 2 × 3 mL
tetrahydrofuran to give the crude solid, which was then
purified by an appropriate technique.
4(1H)-one (10) was reacted with K CO and methyl iodide
2
3
according to a previously reported procedure [14] to give
3a as a straw yellow solid. Yield = 94%. R = 0.44
1
f
6
-Chloro-8-aryl-2-morpholino-quinazolin-4-ones (11a–n).
(chloroform). mp 183–184°C. IR (KBr): ν
2901.8 (w,
H NMR
max
ꢀ1
6-Chloro-2-morpholino-8-phenyl-quinazolin-4(1H)-one (11a).
3
1
sp C-H st), 1617.8, 1581.8, 1550.3 cm
.
Crude 8-bromo-6-chloro-2-morpholino-quinazolin-4(1H)-
one 10 was reacted with phenylboronic acid according to
(300 MHz, CDCl , T = 300 K): δ = 3.81 (t, 4H, H-10, J10–9 =
3
4.8 Hz), 3.95 (t, 4H, H-9, J9–10 = 4.8 Hz), 4.09 (s, 3H, OCH ),
3
“General Procedure A: Extraction Method 2” to give 11a
13
7.86 (s, 2H, H-5, H-7) ppm. C NMR (75 MHz, CDCl3,
as a white solid. Yield = 56%. Solvent: Diethyl
T = 300 K): δ = 44.5 (C-9), 54.4 (CH, OCH ), 67.0 (C-10),
3
3
carbonate. mp 316–317°C. IR (KBr): ν
2967.8 (w, sp
max
1
7
12.7 (C-4a), 120.9 (C-8), 122.6 (C-5), 126.3 (C-6), 136.9 (C-
), 149.5 (C-8a), 158.5 (C-2), 167.1 (C-4) ppm.
C H N O BrCl (358.62): Calcd C 43.54, H 3.65, N 11.72;
ꢀ1
1
C-H st), 1671.9 (m, C=O) cm . H NMR (300 MHz,
DMSO-d , T = 360 K): δ = 3.54 (t, 4H, H-9,
6
13 13 3 2
J9–10 = 4.6 Hz), 3.64 (t, 4H, H-10, J10–9 = 4.6 Hz),
found. C 43.67, H 3.68, N 11.82.
7.32–7.45 (m, 3H, H-13, H-14), 7.60 (d, 1H, H-5,
4-(4-(Benzyloxy)-8-bromo-6-chloroquinazolin-2-yl) morpholine
J5–7 = 2.7 Hz), 7.64–7.67 (m, 2H, H-12), 7.89 (d, 1H, H-
(13b).
Crude 8-bromo-6-chloro-2-morpholinoquinazolin-
13
7
, J7–5 = 2.7 Hz), 11.33 (bs, 1H, NH) ppm. C NMR
4(1H)-one (10) was reacted with K CO and benzyl
2
3
(
(
(
75 MHz, DMSO-d , T = 360 K): δ = 44.8 (C-9), 65.1
C-10), 118.6 (C-8), 123.7 (C-5), 125.6 (C-4a), 126.8
C-14), 127.1 (C-12), 129.4 (C-13), 133.5 (C-7), 137.2
6
bromide according to a previously reported procedure [14]
to give 13b as a straw yellow solid. Yield = 95%. R = 0.68
f
(chloroform–petroleum spirit 7:3). mp 139–140°C. IR
3
(C-6/C-11), 137.6 (C-6/C-11), 145.9 (C-8a), 150.0 (C-2),
161.7 (C-4) ppm. C18 Cl.1/2 H O (350.09): Calcd
C 61.70, H 4.86, N 12.00; found. C 61.79, H 4.88, N
1.98 (hemihydrate).
(KBr): ν
2968.3 (w, sp C-H st), 1616.4, 1578.2,
max
ꢀ
1
1
H
16
N
3
O
2
2
1547.3 cm . H NMR (300 MHz, CDCl , T = 300 K):
3
δ = 3.79 (t, 4H, H-10, J10–9 = 4.8 Hz), 3.95 (t, 4H, H-9,
J9–10 = 4.8 Hz), 5.53 (s, 2H, OCH ), 7.33–7.48 (m, 5H,
OBn), 7.87 (d, 1H, H-7, J = 2.4 Hz), 7.89 (d, 1H, H-5,
J5–7 = 2.4 Hz) ppm. C NMR (75 MHz, CDCl3,
T = 300 K): δ = 44.5 (C-9), 66.9 (C-10), 68.9 (CH,
1
2
6
-Chloro-8-(4-methoxyphenyl)-2-morpholino-quinazolin-
7
–5
4
(1H)-one (11b). Crude 8-bromo-6-chloro-2-morpholino-
1
3
quinazolin-4(1H)-one (10) was reacted with 4-
methoxypheny-lboronic acid according to “General
Procedure A: Extraction Method 2” to give 11b as a
OCH ), 112.6 (C-4a), 120.9 (C-8), 122.5 (C-5), 126.3 (C-
2
6
), 128.0 (CH, OBn), 128.4 (CH, OBn), 128.7 (CH,
OBn), 135.9 (C, Obn), 137.0 (C-7), 149.6 (C-8a), 158.3
C-2), 166.4 (C-4) ppm. C H N O BrCl (434.71): Calcd
white solid. Yield = 45%. Solvent: Diethyl carbonate. mp
3
3
1
07–308°C. IR (KBr): νmax 2966.6 (w, sp C-H st),
(
ꢀ1
1
1
9 17 3 2
673.1 (m, C=O), 1593.3 (s, Ar) cm
.
H NMR
C 52.50, H 3.94, N 9.67; found. C 52.63, H 4.09, N 9.81.
General Procedure A: Suzuki Coupling of 6-Chloro-8-
bromo-2-morpholino-quinazolines with Aryl Boronic Acids
(
300 MHz, DMSO-d , T = 340 K): δ = 3.52 (t, 4H, H-9,
6
J9–10 = 4.8 Hz), 3.62 (t, 4H, H-10, J10–9 = 4.8 Hz), 3.78
s, 3H, H-15), 6.93–6.97 (m of ABX, 2H, H-13, H-13a,
(
(10, 13a–b). A 25 mL Schlenk flask was purged with
J13–12 = 9.0 Hz, J13-13a = 2.4 Hz), 7.55 (d, 1H, H-7,
J7–5 = 2.7 Hz), 7.57–7.62 (m of ABX, 2H, H-12, H-12a,
J12–13 = 9.0H z, J12-12a = 2.4 Hz), 7.81 (d, 1H, H-5,
nitrogen for 5 min before the addition of 6-chloro-8-
bromo-2-morpholino-quinazoline (1.0 mmol), aryl
boronic acid (1.25 mmol), K CO (3.0 mmol), Bis
2
3
13
J5–7 = 2.7 Hz), 11.38 (bs, 1H, NH) ppm. C NMR
(
(
triphenylphosphine)
0.05 mmol), and 10 mL of 7:3 (v:v) dioxane–water. The
palladium
(II)
dichloride
(
(
(
75 MHz, DMSO-d , T = 3 40 K): δ = 45.3 (C-9), 55.3
C-15), 65.7 (C-10), 113.4 (C-13), 119.1 (C-8), 123.6
C-5), 126.2 (C-4a), 130.0 (C-6), 131.2 (C-12), 133.8
6
flask was then sealed, and the reaction mixture was
heated with stirring at 50°C for 24 h.
Extraction method 1 (compounds 11f–l, 14a–f).
The
(C-7), 137.8 (C-11), 146.4 (C-8a), 150.5 (C-2), 158.9
(C-14), 162.4 (C-4) ppm. C19 Cl (371.82): Calcd
reaction mixture was poured into a separating funnel with
5 mL of 2% (w:w) K CO . The product was extracted
H N O
18 3 3
1
C 61.38, H 4.88, N 11.30; found. C 61.46, H 5.03, N
11.48.
2
3
with 3 × 30 mL chloroform, dried with MgSO , filtered
4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. T. Heppell, M. A. Islam, S. R. McAlpine, and J. M. A. Al-Rawi
Vol 000
6
-Chloro-8-(4-(hydroxymethyl)phenyl)-2-morpholino-
(75 MHz, DMSO-d , T = 380 K): δ = 45.4 (C-9), 65.7
6
quinazolin-4(1H)-one (11c).
Crude 8-bromo-6-chloro-2-
morpholino-quinazolin-4(1H)-one (10) was reacted with
-(hydroxymethyl) phenylboronic acid according to
General Procedure A: Extraction Method 2” to give 11c
as a white solid. Yield = 55%. Solvent: Diethyl
carbonate. mp 323–324°C. IR (KBr): ν 3449.1 (broad)
(
1
C-10), 119.2 (C-8), 124.6 (C-5), 126.2 (C-4a), 127.7 (C-
3), 131.7 (C-7), 132.4 (C-6), 134.1 (C-12), 136.5 (C-11/
C-14), 136.7 (C-11/C-14), 146.5 (C-8a), 150.7 (C-2),
4
“
1
5
62.2 (C-4) ppm. C H N O Cl (376.24): Calcd C
18 15 3 2 2
7.46, H 4.02, N 11.17; found. C 57.49, H 4.17, N 11.37.
6-Chloro-2-morpholino-8-(pyridine-3-yl)quinazolin-4(1H)-
max
3
one (11f).
Crude 8-bromo-6-chloro-2-morpholino-
(
1
m, OH), 2965.9 (w, sp C-H st), 1671.9 (s, C=O),
591.6 (s, Ar) cm . H NMR (300 MHz, DMSO-d ,
T = 320 K): δ = 3.54 (t, 4H, H-9, J9–10 = 4.2 Hz), 3.64
t, 4H, H-10, J10–9 = 4.2 Hz), 4.56 (d, 2H, H-15, J15-
ꢀ
1
1
quinazolin-4(1H)-one (10) was reacted with 3-Pyridinyl-
boronic acid according to “General Procedure A:
Extraction Method 1” to give 11f as a white solid.
6
(
Yield = 44%. R = 0.26 (chloroform–ethanol 95:5). mp
=
5.0 Hz), 5.12 (t, 1H, OH, JOH-15 = 5.0 Hz), 7.37
f
OH
3
2
1
84–285°C. IR (KBr): νmax 2966.7 (w, sp C-H st),
672.9 (s, C=O), 1594.1 (s, Ar) cm
(
d, 2H, H-12, J12–13 = 8.4 Hz), 7.61 (d, 1H, H-7,
J7–5 = 2.7 Hz), 7.64 (d, 2H, H-13, J13–12 = 8.4 Hz), 7.86
d, 1H, H-5, J5–7 = 2.7 Hz), 11.52 (bs, 1H, NH) ppm.
ꢀ
1
1
.
H NMR
13
(
300 MHz, DMSO-d , T = 3 40 K): δ = 3.54 (t, 4H, H-9,
(
C
6
J9–10 = 4.5 Hz), 3.64 (t, 4H, H-10, J10–9 = 4.5 Hz), 7.44
ddd, 1H, H-14, J14–13 = 4.8 Hz, J14–15 = 8.1 Hz,
J14–12 = 0.6 Hz), 7.71 (d, 1H, H-7, J7–5 = 2.4 Hz), 7.92
d, 1H, H-5, J5–7 = 2.4 Hz), 8.06 (td, 1H, H-15,
NMR (75 MHz, DMSO-d , T = 340 K): δ = 45.3 (C-9),
6
(
62.9 (C-15), 65.7 (C-10), 119.2 (C-8), 124.1 (C-5), 125.9
(
(
(
C-12), 126.2 (C-4a), 129.7 (C-13), 134.1 (C-7), 136.0
C-6), 138.1 (C-11), 141.8 (C-14), 146.5 (C-8a), 150.5
C-2), 162.4 (C-4) ppm. C H N O Cl (371.82): Calcd
(
J15–14 = 8.1 Hz, J15–12 = J15–13 = 1.8 Hz), 8.54 (dd, 1H,
H-13, J13–14 = 4.8 Hz, J13–15 = 1.8 Hz), 8.84 (d, 1H, H-
1
9 18 3 3
C 61.38, H 4.88, N 11.30; found. C 61.19, H 4.93, N 11.53.
13
1
2, J12–15 = 1.8 Hz), 11.47 (bs, 1H, NH) ppm. C NMR
4-(6-Chloro-2-morpholino-4-oxo-1,4-dihydro-quinazolin-8-yl)
(
75 MHz, DMSO-d , T = 340 K): δ = 44.8 (C-9), 65.2
benzamide (11d). Crude 8-bromo-6-chloro-2-morpholino-
quinazolin-4(1H)-one (10) was reacted with 4-
aminocarbonyl-phenylboronic acid according to “General
Procedure A: Extraction Method 2” to give 11d as a
white solid. Yield = 30%. Solvent: Diethylcarbonate. mp
6
(C-10), 118.7 (C-8), 122.4 (C-14), 124.6 (C-5), 125.8 (C-
4
1
2
5
a), 132.8 (C-6), 133.9 (C-7), 134.3 (C-11), 136.8 (C-
5), 146.2 (C-8a), 147.9 (C-13), 149.8 (C-12), 150.4 (C-
), 161.7 (C-4) ppm. C H N O Cl (342.78): Calcd C
19 18
3 3
9.57, H 4.41, N 16.34; found. C 59.53, H 4.53, N 16.53.
8-(3-Aminophenyl)-6-chloro-2-morpholino-quinazolin-
3
35–336°C. IR (KBr): νmax 3419.5 (m, NH), 2955.3 (w,
3
ꢀ1
1
sp C-H st), 1672.6 (s, C=O), 1591.7 (s, Ar) cm . H
4
(1H)-one (11g). Crude 8-bromo-6-chloro-2-morpholino-
NMR (300 MHz, DMSO-d , T = 360 K): 3.56 (t, 4H, H-
6
quinazolin-4(1H)-one (10) was reacted with 3-
aminophenyl-boronic acid according to “General
Procedure A: Extraction Method 1” to give 11 g as an off
9, J9–10 = 4.8 Hz), 3.65 (t, 4H, H-10, J10–9 = 4.8 Hz),
7
.38 (bs, 2H, NH ), 7.66 (d, 1H, H-7, J = 2.4 Hz),
2
7–5
7
.75 (d, 2H, H-12, J12–13 = 8.4 Hz), 7.92–7.95 (m, 3H,
white solid. Yield = 45%. R = 0.32 (ethyl acetate). mp
13
f
H-5, H-13), 11.36 (bs, 1H, NH) ppm.
C NMR
2
2
49–250°C. IR (KBr): ν
3367.0 (broad) (m, NH2),
max
(
(
75 MHz, DMSO-d , T = 340 K): δ = 45.3 (C-9), 65.7
C-10), 119.2 (C-8), 124.7 (C-7), 126.1 (C-4a), 126.9 (C-
3
6
964.2 (w, sp C-H st), 1668.0 (s, C=O), 1587.5 (s, Ar)
ꢀ1
1
cm . H NMR (300 MHz, DMSO-d , T = 3 40 K):
6
1
6
1
5
2), 129.8 (C-13), 133.3 (C-14), 134.3 (C-5), 137.2 (C-
), 140.5 (C-11), 146.6 (C-8a), 150.8 (C-2), 162.4 (C-4),
67.8 (C-15) ppm. C H N O Cl (384.82): Calcd C
δ = 3.57 (t, 4H, H-9, J9–10 = 4.6 Hz), 3.65 (t, 4H, H-10,
J10–9 = 4.6 Hz), 5.24 (bs, 2H, NH ), 6.60 (dd, 1H, H-14,
2
19 17 4 3
J14–15 = 8.1 Hz, J14–16 = J14–12 = 1.6 Hz), 6.83 (td, 1H,
H-16, J16–15 = 7.5 Hz, J16–14 = J16–12 = 1.6 Hz), 6.92 (t,
9.30, H 4.45, N 14.56; found. C 59.57, H 4.62, N 14.68.
6-Chloro-8-(4-chlorophenyl)-2-morpholino-quinazolin-
1
H, H-12, J12–14 = J12–16 = 1.6 Hz), 7.53 (d, 1H, H-7,
4
(1H)-one (11e). Crude 8-bromo-6-chloro-2-morpholino-
13
J7–5 = 2.7 Hz), 7.86 (d, 1H, H-5, J5–7 = 2.7 Hz) ppm.
C
quinazolin-4(1H)-one (10) was reacted with 4-
chlorophenyl-boronic acid according to “General
Procedure A: Extraction Method 2” to give 11e as a
NMR (75 MHz, DMSO-d , T = 340 K): δ = 45.7 (C-9),
6
6
1
1
1
6.1 (C-10), 113.7 (C-14), 116.4 (C-12), 118.5 (C-16),
19.5 (C-8), 124.2 (C-5), 126.4 (C-4a), 128.5 (C-15),
34.3 (C-7), 138.7 (C-6), 139.5 (C-11), 146.9 (C-8a),
48.4 (C-13), 150.7 (C-2), 162.8 (C-4) ppm.
white solid. Yield = 39%. Solvent: Acetic Acid. mp 349–
3
3
1
50°C (decomp.). IR (KBr): ν
2979.1 (w, sp C-H st),
max
ꢀ
1 1
763.8 (s, C=O) cm . H NMR (300 MHz, DMSO-d ,
6
C H N O Cl (356.81): Calcd C 60.59, H 4.80, N
18 17 4 2
T = 380 K): δ = 3.54–3.58 (m, 4H, H-9), 3.64–3.67
m, 4H, H-10), 7.42–7.47 (m of ABX, 2H, H-13,H-13a,
1
5.70; found. C 57.68, H 5.11, N 14.95 (monohydrate).
(
0
8
-([1,1 -biphenyl]-3-yl)-6-chloro-2-morpholino-quinazolin-
J13–12 = 8.7 Hz, J13-13a = 2.1 Hz), 7.61 (d, 1H, H-7,
J7–5 = 2.4 Hz), 7.67–7.71 (m of ABX, 2H, H-12, H-12a,
J12–13 = 8.7 Hz, J12-12a = 2.1 Hz), 7.90 (d, 1H, H-5,
4(1H)-one (11h). Crude 8-bromo-6-chloro-2-morpholino-
quinazolin-4(1H)-one (10) was reacted with biphenyl-3-
boronic acid according to “General Procedure A:
Extraction Method 1” to give 11h as an off white solid.
1
3
J5–7 = 2.4 Hz), 11.26 (bs, 1H, NH) ppm. C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation,
DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
Yield = 33%. R = 0.42 (chloroform–isopropanol 95:5). mp
= 2.7 Hz), 7.90–7.97 (m, 1H, H-16), 8.00 (d, 1H, H-5,
5
f
3
2
46–24 7°C. IR (KBr): 2960.3 (w, sp C-H st), 1671.7 (s,
J5–7 = 2.7 Hz), 8.32–8.38 (m, 2H, H-11, H-19), 11.45
ꢀ
1
1
13
C=O), 1587.3 (s, Ar) cm
.
H NMR (300 MHz,
(bs, 1H, NH) ppm. C NMR (75 MHz, DMSO-d , T = 3
6
DMSO-d , T = 340 K): δ = 3.54–3.60 (m, 8H, H-9, H-
40 K): δ = 44.7 (C-9), 65.1 (C-10), 118.6 (C-8), 120.7
(C-11/C-19), 121.6 (C-11/C-19), 122.3 (C-16), 124.0 (C-
12/C-13), 124.2 (C-17/C-18), 124.8 (C-5), 125.3 (C-4a,
C-6), 126.6 (C-17/C-18), 128.5 (C-12/C-13), 132.7 (C-
11a), 134.0 (C-7), 134.9 (C-14a), 136.4 (C-19a), 138.3
(C-14/C-16a), 138.7 (C-14/C-16a), 146.4 (C-8a), 150.1
(C-2), 161.8 (C-4) ppm. C H N O SCl (447.94): Calcd
6
10), 7.37 (tt, 1H, H-20, J20–19 = 7.2 Hz, J20–18 = 1.5 Hz),
7.44–7.54 (m, 2H, H-15, H-15), 7.62–7.72 (m, H-14, H-
16, H-19), 7.74 (d, 1H, H-7, J7–5 = 2.7 Hz), 7.91 (d, 1H,
H-5, J5–7 = 2.7 Hz), 7.97 (t, 1H, H-12, J
= J12–16 =
12–14
1
3
1.6 Hz), 11.43 (bs, 1H, NH) ppm. C NMR (75 MHz,
DMSO-d , T = 340 K): δ = 44.8 (C-9), 65.2 (C-10),
6
24 18 3 2
1
4
1
18.7 (C-8), 124.0 (C-5), 125.3 (C-14/C-16), 125.8 (C-
a), 126.3 (C-18), 127.0 (C-20), 127.9 (C-15), 128.2 (C-
2), 128.5 (C-19), 128.6 (C-14/C-16), 133.9 (C-7), 137.4
C 64.35, H 4.05, N 9.38; found. C 61.43, H 4.43, N 8.43
(monohydrate).
6-Chloro-2-morpholino-8-(thianthren-1-yl)quinazolin-4(1H)-
(
(
(
C-6), 137.7 (C-13), 139.4 (C-11), 139.9 (C-17), 146.1
C-8a), 150.0 (C-2), 161.9 (C-4) ppm. C H N O Cl
417.89): Calcd C 68.98, H 4.82, N 10.06; found. C
7.49, H 4.95, N 10.36 (monohydrate).
one (11k).
Crude 8-bromo-6-chloro-2-morpholino-
quinazolin-4(1H)-one (10) was reacted with 4-
dibenzothienylboronic acid according to “General
Procedure A: Extraction Method 1” to give 11k as an off
2
4 20 3 2
6
6-Chloro-8-(dibenzo[b,d]furan-4-yl)-2-morpholino-quinazolin-
white solid. Yield = 38%. R = 0.42 (chloroform–
f
4
(1H)-one (11i).
Crude 8-bromo-6-chloro-2-morpholino-
quinazolin-4(1H)-one (10) was reacted with
-(dibenzofuranyl) boronic acid according to “General
isopropanol 95:5). mp 330–331°C. IR (KBr): ν
3175.7
max
3
ꢀ1
(w, sp C-H st), 1666.7 (s, C=O), 1590.2 (s, Ar) cm
.
1
4
H NMR (300 MHz, DMSO-d , T = 330 K): δ = 3.38 (t,
6
Procedure A: Extraction Method 1” to give 11i as an off
4H, H-9, J9–10 = 4.6 Hz), 3.50 (t, 4H, H-10,
white solid. Yield = 16%. R = 0.36 (chloroform–isopropanol
J10–9 = 4.6 Hz), 7.24 (dt, 1H, H-17/H-18, J = 7.5 Hz,
J = 1.5 Hz), 7.28–7.36 (m, 3H, H-12, H-17/H-18, H-16/
H-19), 7.38 (t, 1H, H-13, J13–12 = J13–14 = 7.5 Hz), 7.56
(dd, 1H, H-16/H-19, J = 7.5 Hz, J = 1.5 Hz), 7.56 (d,
1H, H-7, J7–5 = 2.4 Hz), 7.62 (dd, 1H, H-14,
J14–13 = 7.5 Hz, J14–12 = 1.5 Hz), 7.98 (d, 1H, H-5,
f
3
9
5:5). mp 342–343°C. IR (KBr): νmax 3180.7 (w, sp C-H
ꢀ
1
1
st), 1656.6 (s, C=O), 1594.0 (s, Ar) cm . H NMR
(
300 MHz, DMSO-d , T = 340 K): δ = 3.34 (t, 4H, H-9,
6
J9–10 = 4.4 Hz), 3.45 (t, 4H, H-10, J10–9 = 4.4 Hz), 7.40 (dt,
1
1
H, H-18, J18–17 = J18–19 = 7.5 Hz, J18–16 = 1.2 Hz), 7.46 (t,
H, H-12, J12–11 = J12–13 = 7.5 Hz), 7.49 (m, 1H, H-17,
13
J5–7 = 2.4 Hz), 11/50 (bs, 1H, NH) ppm. C NMR
J17–18 = 7.5 Hz, J17–16 = 8.7 Hz, J17–19 = 1.5 Hz), 7.63–7.66
m, 2H, H-13, H-16), 7.84 (d, 1H, H-7, J7–5 = 2.7 Hz), 7.99
d, 1H, H-5, J5–7 = 2.7 Hz), 8.14 (dd, 1H, H-11,
J11–12 = 7.5 Hz, J11–13 = 1.2 Hz), 8.15 (ddd, 1H, H-19,
J19–18 = 7.5 Hz, J = 1.2 Hz, J19–16 = 0.6 Hz), 11.45 (bs,
(75 MHz, DMSO-d , T = 340 K): δ = 44.6 (C-9), 65.2
6
(
(
(C-10), 117.9 (C-8), 124.7 (C-7), 125.2 (C-4a), 127.0 (C-
13), 127.5 (C-17/C-18), 127.6 (C-17/C-18), 127.9 (C-14/
C-16/C-19), 127.9 (C-14/C-16/C-19), 128.4 (C-12), 129.4
(C-16/C-19), 133.9 (C-5), 134.0 (C-11), 135.3 (C-16a/C-
19a), 135.4 (C-16a/C-19a), 135.6 (C-6/C-11a/C-14a),
136.9 (C-6/C-11a/C-14a), 138.3 (C-6/C-11a/C-14a), 147.0
(C-8a), 150.1 (C-2), 161.8 (C-4) ppm. C H N O S Cl
19–17
13
1
H, NH) ppm. C NMR (75 MHz, DMSO-d , T = 340 K):
6
δ = 45.1 (C-9), 65.5 (C-10), 111.6 (C-16), 119.0 (C-11a),
120.5 (C-11), 121.1 (C-19), 122.4 (C-4a), 122.6 (C-12),
123.1 (C-18), 123.8 (C-8, C-19a), 125.0 (C-5), 125.8 (C-6),
127.5 (C-17), 129.5 (C-13), 133.5 (C-14), 135.1 (C-7), 147.2
24 18 3 2 2
(480.00): Calcd C 60.05, H 3.78, N 8.75; found. C
57.85, H 4.02, N 8.88 (monohydrate).
(
C-8a), 150.5 (C-14a), 153.5 (C-2), 155.5 (C-16a), 162.4
6-Chloro-2-morpholino-8-(naphthalene-1-yl)quinazolin-4(1H)-
one (11l). Crude 8-bromo-6-chloro-2-morpholino-quinazolin-
(C-4) ppm. C H N O Cl (431.87): Calcd C 66.75, H 4.20,
24 18 3 3
N 9.73; found. C 63.06, H 4.16, N 8.85 (monohydrate).
4(1H)-one (10) was reacted with 1-naphthaleneboronic acid
according to “General Procedure A: Extraction Method 1” to
6
-Chloro-8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-
quinazolin-4(1H)-one (11j).
Crude 8-bromo-6-chloro-2-
morpholino-quinazolin-4(1H)-one (10) was reacted with
-(dibenzothienyl) boronic acid according to “General
give 11l as an off white solid. Yield = 16%. R = 0.32
f
(chloroform–isopropanol 95:5). mp 295–296°C. IR (KBr):
3
ꢀ1
4
2954.4 (w, sp C-H st), 1663.1 (s, C=O), 1595.3 (s, Ar) cm .
1
Procedure A: Extraction Method 1” to give 11j as an off
H NMR (300 MHz, DMSO-d , T = 360 K): δ = 3.15–3.22
6
white solid. Yield = 21%. R = 0.39 (chloroform–
(m, 4H, H-9), 3.40 (t, 4H, H-10, J10–9 = 4.8 Hz), 7.35–7.51
f
isopropanol 95:5). mp 334–335°C. IR (KBr): ν
2969.0
(m, 4H, H-14, H-15, H-16, H-17), 7.55 (t, 1H, H-13, J13–12 =
J13–14 = 7.5 Hz), 7.60 (d, 1H, H-7, J7–5 = 2.4 Hz), 7.92–7.95
max
3
ꢀ1
(
w, sp C-H st), 1675.4 (m, C=O), 1596.9 (s, Ar) cm
.
1
H NMR (300 MHz, DMSO-d , T = 340 K): δ = 3.38 (t,
(m 2H, H-12, H-18), 8.00 (d, 1H, H-5, J = 2.4 Hz), 11.29
6
5–7
13
4
4
7
H, H-9, J9–10 = 4.8 Hz), 3.49 (t, 4H, H-10, J10–9
.8 Hz), 7.46–7.54 (m of ABX, 2H, H-17, H-18), 7.57–
.62 (m of ABX, 2H, H-12, H-13), 7.79 (d, 1H, H-7, J7–
=
(bs, 1H, NH) ppm. C NMR (75 MHz, DMSO-d6,
T = 340 K): δ = 44.5 (C-9), 65.0 (C-10), 118.3 (C-8), 124.2
(C-5), 124.8 (C-13), 125.1 (C-16/C-17), 125.2 (C-16/C-17),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. T. Heppell, M. A. Islam, S. R. McAlpine, and J. M. A. Al-Rawi
Vol 000
1
1
1
(
25.4 (C-4a), 126.0 (C-14), 127.2 (C-15), 127.5 (C-17/C-18),
27.6 (C-17/C-18), 131.3 (C-6), 132.6 (C-18a), 134.9 (C-7),
35.9 (C-14a), 137.4 (C-11), 147.2 (C-8a), 149.8 (C-2), 161.9
C-4) ppm. C H N O Cl (391.85): Calcd C 67.43, H 4.63,
and sustained for 2 h using a power level of 60–100 W.
After cooling, chloroform (20 mL) was added to the
reaction mixture then filtered to remove the palladium
catalyst. The filtrate was evaporated, and the solid residue
was subject to flash chromatography using an appropriate
solvent to yield the pure product.
22 18 3 2
N 10.74; found. C 64.57, H 4.72, N 9.80.
8-(benzo[b]thiophen-2-yl)-6-chloro-2-morpholino-quinazolin-
4(1H)-one (11m). Crude 8-bromo-6-chloro-2-morpholino-
8
-Aryl-2-morpholino-quinazolin-4-ones
(12a–d).
quinazolin-4(1H)-one (10) was reacted with Benzo [b]
thiophene-2-boronic acid according to “General Procedure
A: Extraction Method 1” gave 11m as a yellow solid.
2
6
(
“
-Morpholino-8-phenyl-quinazolin-4(1H)-one (12a).
Crude
-chloro-2-morpholino-8-phenyl-quinazolin-4(1H)-one
11a) underwent hydro-de-chlorination according to
General Procedure B” to give 12a. Yield = 38%.
R = 0.39 (ethyl acetate–petroleum spirit 3:2). mp 234–
Yield = 26%. Solvent: Acetic acid. mp >350°C. IR
3
(KBr): νmax 2960.4 (w, sp C-H st), 1673.6 (s, C=O),
ꢀ
1
1
f
1586.8 (s, Ar) cm . H NMR (300 MHz, DMSO-d ,
6
3
2
35°C. IR (KBr): νmax 2956.0 (w, sp C-H st), 1673.0 (s,
T = 3 40 K): δ = 3.75–3.82 (m, 8H, H-9, H-10), 7.32–
ꢀ
1
1
C=O), 1591.7 (s, Ar) cm
.
H NMR (300 MHz,
7.41 (m of ABX, 2H, H-15, H-16), 7.85–7.96 (m, 3H, H-
DMSO-d , T = 360 K): δ = 3.54 (t, 4H, H-9, J
=
9–10
6
7, H-14, H-17), 8.14 (s, 1H, H-12), 8.20 (d, 1H, H-5,
4
.5 Hz), 3.65 (t, 4H, H-10, J10–9 = 4.5 Hz), 7.23 (t, 1H,
1
3
J5–7 = 2.4 Hz), 11.57 (bs, 1H, NH) ppm. C NMR
H-6, J6–5 = J6–7 = 7.6 Hz), 7.32 (tt, 1H, H-14, J14–13
=
(
(
(
(
(
(
75 MHz, DMSO-d , T = 340 K): δ = 45.9 (C-9), 65.8
6
7
7
7
.4 Hz, J14–12 = 1.2 Hz), 7.38–7.43 (m, 2H, H-12), 7.63–
C-10), 119.4 (C-8), 122.0 (C-17), 123.1 (C-12), 123.7
C-14), 124.4 (C-17/C-18), 124.5 (C-17/C-18), 124.8
C-7), 126.2 (C-4a), 130.1 (C-18), 132.2 (C-5), 138.2
C-6), 138.7 (C-13), 141.2 (C-11), 145.4 (C-8a), 151.2
C-2), 162.1 (C-4) ppm. C H N O SCl (397.88): Calcd
.67 (m, 3H, H-7, H-13), 7.98 (dd, 1H, H-5, J5–6
=
1
3
.6 Hz, J5–7 = 1.5 Hz), 11.17 (bs, 1H, NH) ppm.
C
NMR (75 MHz, DMSO-d , T = 340 K): δ = 44.9 (C-9),
6
6
5.3 (C-10), 117.6 (C-8), 121.7 (C-6), 125.1 (C-5), 126.3
20 16 3 2
(C-14), 127.1 (C-12), 129.6 (C-13), 134.3 (C-7), 135.5
C 60.37, H 4.05, N 10.56; found. C 60.13, H 4.20, N 10.81.
(C-4a), 138.7 (C-11), 147.0 (C-8a), 149.9 (C-2), 162.8
(
E)-6-Chloro-2-morpholino-8-styryl-quinazolin-4(1H)-one
(
C-4) ppm. C H N O (307.35): Calcd C 70.34, H
(
4
11n).
Crude 8-bromo-6-chloro-2-morpholino-quinazolin-
(1H)-one (10) was reacted with trans-2-phenylvinylboronic
acid according to “General Procedure A: Extraction Method
” to give 11n as a pale-green solid. Yield = 13%. Solvent:
Nitromethane. mp 348–349°C (decomp.). IR (KBr): ν
18 17 3 2
5
.58, N 13.67; found. C 70.18, H 5.58, N 13.51.
0
8-([1,1 -Biphenyl]-3-yl)-2-morpholino-quinazolin-4(1H)-one
0
(
12b).
Crude
8-([1,1 -biphenyl]-3-yl)-6-chloro-2-
2
morpholino-quinazolin-4(1H)-one (11h) underwent hydro-
dechlorination according to “General Procedure B” to give
max
3
2958.8 (w, sp C-H st), 1674.7 (s, C=O), 1591.5 (s, Ar)
ꢀ
1
1
12b. Yield = 57%. R = 0.28 (chloroform–ethyl acetate–
cm . H NMR (300 MHz, DMSO-d , T = 390 K):
δ = 3.70–3.77 (m, 8H, H-9, H-10), 7.28 (tt, 1H, H-16,
J16–15 = 7.2 Hz, J16–14 = 2.1 Hz), 7.40 (t, 2H, H-15,
f
6
nitromethane 5:4:1). mp 289–290°C. IR (KBr): ν
2960.3
max
3
ꢀ1
1
(w, sp C-H st), 1671.7 (s, C=O), 1587.3 (s, Ar) cm . H
NMR (300 MHz, DMSO-d , T = 340 K): δ = 3.50–3.56
J15–14
J12–11 = 16.5 Hz), 7.58–7.60 (m, 2H, H-14), 7.80 (d, 1H, H-
, J7–5 = 2.6 Hz), 7.80 (d, 1H, H-11, J11–12 = 16.5 Hz), 7.92
=
J15–16
=
7.2 Hz), 7.49 (d, 1H, H-12,
6
(m, 8H, H-9, H-10), 7.21 (t, 1H, H-6, J6–5 = J6–7 = 7.5 Hz),
7.33 (tt, 1H, H-20, J20–19 = 7.5 Hz, J20–18 = 1.2 Hz),
7
13
7.41–7.49 (m, 3H, H-15, H-18), 7.56–7.67 (m, 4H, H-14,
(d, 1H, H-5, J5–7 = 2.6 Hz), 11.19 (bs, 1H, NH) ppm.
C
H-16, H-19), 7.72 (dd, 1H, H-7, J 7–6 = 7.5 Hz, J7–5
=
NMR (75 MHz, DMSO-d , T = 360 K): δ = 45.5 (C-9), 65.8
6
1.8 Hz), 7.94 (t, 1H, H-12, J12–14 = J12–16 = 1.8 Hz), 7.97
(
1
(
C-10), 119.1 (C-8), 123.3 (C-11), 123.9 (C-5), 126.5 (C-4a),
26.7 (C-14), 127.9 (C-16), 128.8 (C-15), 130.1 (C-7), 131.1
C-12), 133.9 (C-6), 137.6 (C-13), 146.7 (C-8a), 150.7 (C-2),
(
dd, 1H, H-5, J = 7.5 Hz, J5–7 = 1.8 Hz), 11.25 (bs, 1H,
5–6
13
NH) ppm. C NMR (75 MHz, DMSO-d , T = 340 K):
6
δ = 45.3 (C-9), 65.7 (C-10), 118.1 (C-8), 122.2 (C-6), 125.2
162.2 (C-4) ppm. C H N O Cl (367.83): Calcd C 65.31, H
20 18 3 2
(C-14/C-16), 125.7 (C-5), 126.7 (C-18), 127.3 (C-20), 128.2
4.93, N 11.42; found. C 65.10, H 5.02, N 11.65.
General Procedure B: Hydro-de-chlorination of
(C-15), 128.8 (C-12), 128.9 (C-19), 129.1 (C-14/C-16),
134.9 (C-7), 135.6 (C-4a), 139.6 (C-11, C-13), 140.6 (C-
17), 147.5 (C-8a), 150.3 (C-2), 163.3 (C-4) ppm.
C H N O (383.44): Calcd C 75.18, H 5.52, N 10.96;
6
-chloro-8-aryl-2-morpholino quinazolines (11, 14).
This
method is based on a previously reported procedures for
the hydro-de-chlorination of aryl chlorides [19].
24 21 3 2
The required crude 6-chloro-8-aryl-2-morpholino-
quinazoline (1.0 mmol), 10% palladium on activated
carbon (0.1 mmol), cyclohexene (25.0 mmol) were placed
in a 30 mL quartz tube then suspended in methanol
found. C 75.15, H 5.63, N 11.00.
8
-(Dibenzo[b,d]furan-4-yl)-2-morpholino-quinazolin-4(1H)-
one (12c). Crude 6-chloro-8-(dibenzo[b,d]furan-4-yl)-2-
morpholino-quinazolin-4(1H)-one (11i) underwent hydro-
dechlorination according to a modified version of
“General Procedure B” in which 0.2 mmol of 10% Pd/C
was employed and the reaction was allowed to proceed at
(5 mL). The quartz tube was purged with nitrogen then
placed in a 40 bar sealed housing and heated with stirring
in a Milestone Microwave Lab Station to 160°C at 400 W
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation,
DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
for 3 h to give 12c as a white solid. Yield = 23%. R = 0.20
with phenylboronic acid according to a modified version
of “General Procedure A: Extraction Method 1” in which
0.1 mmol Bis (triphenylphosphine) palladium (II)
dichloride was used to give 14a as an off white solid.
f
(
ethyl acetate–chloroform 1:1). mp 292–293°C. IR (KBr):
3
νmax 2946.3 (w, sp C-H st), 1672.9 (s, C=O), 1602.0 (s,
ꢀ
1 1
Ar) cm . H NMR (300 MHz, DMSO-d , T = 340 K):
6
δ = 3.33 (t, 4H, H-9, J9–10 = 4.6 Hz), 3.45 (t, 4H, H-10,
J10–9 = 4.6 Hz), 7.31 (t, 1H, H-6, J6–5 = J6–7 = 7.5 Hz),
Yield = 34%. R = 0.73 (chloroform–petroleum spirit 7:3).
f
3
mp 168–169°C. IR (KBr): ν
2963.3 (w, sp C-H st),
max
ꢀ
1
1
7.39 (dt, 1H, H-18, J18–17 = J18–19 = 7.5 Hz,
1619.9, 1582.0, 1524.1 cm
.
H NMR (300 MHz,
J18–16 1.2 Hz), 7.45 (t, 1H, H-12,
=
DMSO-d , T = 300 K): δ = 3.65 (t, 4H, H-10,
6
J12–11 = J12–13 = 7.5 Hz), 7.48 (m of ABX, 1H, H-17,
J17–18 = 7.5 Hz, J17–16 = 8.1 Hz, J17–19 = 1.5 Hz), 7.61
J10–9 = 4.8 Hz), 3.73 (t, 4H, H-9, J9–10 = 4.8 Hz), 4.09 (s,
3H, OCH ), 7.34–7.47 (m, 3H, H-13, H-14), 7.66 (d, 1H,
3
(
d, 1H, H-16, J16–17 = 8.1 Hz), 7.62 (dd, 1H, H-13,
H-7, J7–5 = 2.7 Hz), 7.70–7.74 (m, 2H, H-12), 7.83 (d, 1H,
H-5, J5–7 = 2.7 Hz) ppm. C NMR (75 MHz, DMSO-d6,
13
J13–12 = 7.5 Hz, J13–11 = 1.2 Hz), 7.85 (dd, 1H, H-7,
J7–6 = 7.5 Hz, J7–5 = 1.8 Hz), 8.07 (dd, 1H, H-5,
J5–6 = 7.8 Hz, J5–7 = 1.8 Hz), 8.11 (dd, 1H, H-11,
J11–12 = 7.5 Hz, J11–13 = 1.2 Hz), 8.14 (ddd, 1H, H-19,
T = 340 K): δ = 44.4 (C-9), 54.2 (CH, OCH ), 66.1 (C-
3
10), 112.3 (C-4a), 121.6 (C-5), 125.7 (C-6), 127.6 (C-14),
127.7 (C-13), 130.1 (C-12), 133.7 (C-7), 137.5 (C-8/C-
11), 137.9 (C-8/C-11), 149.2 (C-8a), 157.7 (C-2), 166.7
(C-4) ppm. C H N O Cl (445.90): Calcd C 64.13, H
J19–18 = 7.5 Hz, J19–17 = 1.2 Hz, J
= 0.6 Hz), 11.29
19–16
1
3
(bs, 1H, NH) ppm. C NMR (75 MHz, DMSO-d6,
25
20 3 3
T = 340 K): δ = 44.7 (C-9), 65.1 (C-10), 111.1 (C-16),
5.10, N 11.81; found. C 64.13, H 5.15, N 11.82.
4-(8-([1,1 -Biphenyl]-3-yl)-6-chloro-4-methoxyquinazolin-2-
0
1
1
1
17.5 (C-11a), 119.5 (C-11), 120.6 (C-19), 121.5 (C-6),
22.0 (C-12), 122.5 (C-18), 123.2 (C-8/C-19a/C-4a),
23.4 (C-8/C-19a/C-4a), 123.5 (C-8/C-19a/C-4a), 125.7
yl) morpholine (14b).
Crude 4-(8-bromo-6-chloro-4-
methoxyquinazolin-2-yl) morpholine (13a) was reacted
with biphenyl-3-boronic acid according to a modified
version of “General Procedure A: Extraction Method 1”
in which 0.1 mmol Bis (triphenylphosphine) palladium
(II) dichloride was used to give 14b as a white solid.
(
(
(
C-5), 126.9 (C-17), 129.1 (C-13), 130.9 (C-14), 135.2
C-7), 147.8 (C-8a), 149.8 (C-2), 153.2 (C-14a), 155.1
C-16a), 162.8 (C-4) ppm. C H N O (397.43): Calcd
2
4 19 3 3
C 72.53, 4.82, N 10.57; found. C 72.53, H 5.06, N 10.81.
8
-(Dibenzo[b,d]thiophen-4-yl)-2-morpholino-quinazolin-
Yield = 42%. R
3:2). mp 154–155°C. IR (KBr): ν
= 0.51 (chloroform–petroleum spirit
f
3
4
(1H)-one (12d).
Crude 6-chloro-8-(dibenzo[b,d]
2957.6 (w, sp C-H
max
ꢀ
1 1
thiophen-4-yl)-2-morpholino-quinazolin-4(1H)-one (11j)
underwent hydro-dechlorination according to “General
Procedure B” to give 12d as a white solid. Yield = 26%.
R = 0.33 (ethyl acetate–petroleum spirit 3:2). mp 289–
90°C. IR (KBr): νmax 2966.1 (w, sp C-H st), 1673.8 (s,
C=O), 1596.4 (s, Ar) cm
DMSO-d , T = 340 K): δ = 3.38 (t, 4H, H-9, J
.6 Hz), 3.50 (t, 4H, H-10, J10–9 = 4.6 Hz), 7.30 (t, 1H,
H-6, J6–5 = J6–7 = 7.5 Hz), 7.46–7.54 (m of ABX, 2H,
H-17, H-18), 7.56–7.62 (m, 2H, H-12, H-13), 7.81 (dd,
st), 1619.9, 1577.9, 1522.5 cm . H NMR (300 MHz,
DMSO-d , T = 340 K): δ = 3.63 (t, 4H, H-10, J
=
10–9
6
4.8 Hz), 3.76 (t, 4H, H-9, J9–10 = 4.8 Hz), 4.12 (s, 3H,
OCH ), 7.37 (tt, 1H, H-20, J = 7.5 Hz, J20–18
f
3
20–19
=
3
2
1.2 Hz), 7.45–7.50 (m, 2H, H-19), 7.54 (t, 1H, H-15, J15–
= J15–16 = 7.8 Hz), 7.65–7.74 (m, 4H, H-14, H-16, H-
ꢀ
1
1
.
H NMR (300 MHz,
14
=
18), 7.79 (d, 1H, H-7, J7–5 = 2.4 Hz), 7.87 (d, 1H, H-5,
J5–7 2.4 Hz), 8.05 (t, 1H, H-12, J12–14 =
6
9–10
4
=
13
J12–16 = 1.6 Hz) ppm. C NMR (75 MHz, DMSO-d6,
T = 340 K): δ = 44.5 (C-9), 54.2 (CH, OCH ), 66.0 (C-
3
1
1
1
H, H-7, J7–6 = 7.5 Hz, J7–5 = 1.5 Hz), 7.89–7.94 (m,
H, H-16), 8.08 (dd, 1H, H-5, J5–6 = 7.5 Hz, J5–7
.5 Hz), 8.30–8.38 (m, 2H, H-11, H-19), 11.23 (bs, 1H,
10), 112.4 (C-4a), 121.8 (C-5), 125.8 (C-6), 125.9 (C-14/
C-16), 126.7 (C-18), 127.4 (C-20), 128.4 (C-15), 128.8
(C-12), 128.9 (C-19), 129.1 (C-14/C-16), 133.8 (C-7),
137.7 (C-8/C-11), 138.0 (C-8/C-11), 139.9 (C-13), 140.5
(C-17), 149.3 (C-8a), 157.8 (C-2), 166.8 (C-4) ppm.
C H N O Cl (431.91): Calcd C 69.52, H 5.13, N 9.73;
=
13
NH) ppm. C NMR (75 MHz, DMSO-d , T = 340 K):
δ = 44.7 (C-9), 65.2 (C-10), 117.6 (C-8), 120.2 (C-11),
6
1
1
1
1
1
1
21.5 (C-6), 121.6 (C-16), 122.2 (C-19), 124.0 (C-13),
24.1 (C-17), 126.0 (C-5), 126.5 (C-18), 128.5 (C-12),
34.3 (C-4a/C-11a/C-14a/C-19a), 134.3 (C-4a/C-11a/C-
4a/C-19a), 134.4 (C-7), 134.7 (C-4a/C-11a/C-14a/C-
9a), 135.0 (C-4a/C-11a/C-14a/C-19a), 138.4 (C-14),
38.9 (C-16a), 147.4 (C-8a), 149.8 (C-2), 162.7 (C-4)
25 22 3 2
found. C 69.44, H 5.28, N 9.98.
4
-(6-Chloro-8-(dibenzo[b,d]furan-4-yl)-4-methoxyquinazolin-
2-yl) morpholine (14c).
Crude 4-(8-bromo-6-chloro-4-
methoxyquinazolin-2-yl) morpholine (13a) was reacted
with 4-(dibenzofuranyl) boronic acid according to a
modified version of “General Procedure A: Extraction
Method 1” in which 0.1 mmol Bis (triphenylphosphine)
palladium (II) dichloride was used to give 14c as an off
white solid. Yield = 43%. Rf = 0.71 (chloroform–
ppm. C H N O S (413.49): Calcd C 69.71, H 4.63, N
24 19 3 2
10.16; found. C 69.48, H 4.73, N 9.89.
6
-Chloro-8-aryl-2-morpholino-4-methoxy-quinazolin-4-
ones (14a–c). 4-(6-Chloro-4-methoxy-8-phenylquinazolin-2-
yl) morpholine (14a).
Crude 4-(8-bromo-6-chloro-4-
methoxyquinazolin-2-yl) morpholine (13a) was reacted
petroleum spirit 3:2). mp 234–235°C. IR (KBr): ν
2959.3 (w, sp C-H st), 1617.1, 1577.3, 1521.5 cm . H
max
1
3
ꢀ1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. T. Heppell, M. A. Islam, S. R. McAlpine, and J. M. A. Al-Rawi
Vol 000
NMR (300 MHz, DMSO-d , T = 340 K): δ = 3.50 (t, 4H,
J10–9 = 4.8 Hz), 3.82 (t, 4H, H-9, J9–10 = 4.8 Hz), 5.54
6
H-10, J10–9 = 4.8 Hz), 3.57 (t, 4H, H-9, J9–10 = 4.8 Hz),
(s, 2H, OCH ), 7.31–7.52 (m, 9H, OBn, H-15, H-19, H-
2
4.15 (s, 3H, OCH3), 7.40 (dt, 1H, H-18,
20), 7.59–7.71 (m, 5H, H-7, H-14, H-16, H-18), 7.95 (d,
J18–19 = J18–17 = 7.5 Hz, J19–17 = 1.2 Hz), 7.47 (t, 1H,
H-12, J12–11 = J12–13 = 7.5 Hz), 7.49 (m, 1H, H-17,
J17–18 = 7.5 Hz, J17–16 = 8.4 Hz, J17–19 = 1.2 Hz), 7.58
1H, H-5, J5–7 = 2.7 Hz), 8.00 (t, 1H, H-12,
J12–14 = J12–16 = 1.8 Hz) ppm. C NMR (75 MHz,
13
CDCl , T = 300 K): δ = 44.2 (C-9), 66.5 (C-10), 68.1
3
(
bd, 1H, H-16, J16–17 = 8.4 Hz), 7.70 (dd, 1H, H-13,
J13–12 = 7.5 Hz, J13–11 = 1.2 Hz), 7.89 (d, 1H, H-7,
J7–5 = 2.7 Hz), 7.96 (d, 1H, H-5, J = 2.7 Hz), 8.12–
(CH, OCH ), 112.4 (C-4a), 121.9 (C-5), 125.8 (C-14/C-
2
16), 126.4 (C-6), 126.7 (C-18), 126.9 (CH, OBn), 127.7
(C-19), 127.8 (C-20), 127.9 (C-15), 128.3 (CH, OBn),
128.4 (CH, OBn), 128.7 (C-14/C-16), 129.1 (C-12),
134.0 (C-7), 135.9 (C, OBn), 137.5 (C-11/C-13), 137.9
(C-11/C-13), 140.2 (C-8), 140.8 (C-17), 149.2 (C-8a),
157.5 (C-2), 166.1 (C-4) ppm. C H N O Cl (508.01):
5–7
3
1
8
.15 (m, 2H, H-11, H-19) ppm. C NMR (75 MHz,
DMSO-d , T = 340 K): δ = 44.3 (C-9), 54.2 (CH,
OCH ), 65.9 (C-10), 111.5 (C-16), 112.2 (C-11a), 120.5
(
(
6
3
C-11), 121.0 (C-19), 122.3 (C-4a), 122.4 (C-5), 122.6
C-12), 123.0 (C-18), 123.8 (C-8/C-19a), 123.9 (C-8/
31 26 3 2
Calcd C 73.29, H 5.16, N 8.27; found. C 73.35, H 5.23,
C-19a), 125.4 (C-6), 127.5 (C-17), 129.5 (C-13), 133.5
N 8.47.
(
(
(
C-14), 134.7 (C-7), 149.7 (C-8a), 153.6 (C-14a), 155.6
C-16a), 157.7 (C-2), 166.7 (C-4) ppm. C H N O Cl
445.90): Calcd C 67.34, H 4.52, N 9.42; found. C
7.56, H 4.70, N 9.61.
4-(4-(Benzyloxy)-6-chloro-8-(dibenzo[b,d]furan-4-yl)
quinazolin-2-yl)
morpholine
(14f).
Crude 4-(4-
2
5 20 3 3
(benzyloxy)-8-bromo-6-chloroquinazolin-2-yl)
morpholine (13b) was reacted with 4-(dibenzofuranyl)
boronic acid according to a modified version of “General
Procedure A: Extraction Method 1” in which 0.1 mmol
Bis (triphenylphosphine) palladium (II) dichloride was
6
6
-Chloro-8-aryl-2-morpholino-4-bezoloxy-quinazolin-4-ones
14d–f). 4-(4-(Benzyloxy)-6-chloro-8-phenylquinazolin-2-yl)
morpholine (14d).
(
Crude 4-(4-(benzyloxy)-8-bromo-6-
chloroquinazolin-2-yl) morpholine (13b) was reacted with
phenylboronic acid according to a modified version of
used to give 16f as a white solid. Yield = 51%. R = 0.49
f
(chloroform–petroleum spirit 3:2). mp 172–173°C. IR
3
“General Procedure A: Extraction Method 1” in which
(KBr): νmax 2954.9 (w, sp C-H st), 1617.9, 1577.5,
ꢀ
1
1
0.1 mmol Bis (triphenylphosphine) palladium (II)
1518.4, 1448.6 cm
T = 320 K): δ = 3.57 (t, 4H, H-10, J10–9 = 4.6 Hz), 3.63
(t, 4H, H-9, J9–10 = 4.6 Hz), 5.57 (s, 2H, OCH ), 7.33
.
H NMR (300 MHz, CDCl ,
3
dichloride was used to give 14d as an off white solid.
Yield = 40%. R = 0.67 (chloroform–petroleum spirit
2
f
3
3
:2). mp 163–164°C. IR (KBr): νmax 2955.3 (w, sp C-H
st), 1614.8, 1581.0, 1563.3, 1492.5 cm . H NMR
(dt, 1H, H-18, J18–19 = J18–17 = 7.5 Hz, J18–16 = 1.2 Hz),
7.37–7.51 (m, 9H, OBn, H-12, H-16, H-17), 7.69 (dd,
1H, H-13, J13–12 = 7.5 Hz, J13–11 = 1.2 Hz), 7.89 (d, 1H,
H-7, J7–5 = 2.4 Hz), 7.96–7.99 (m, 2H, H-11, H-19), 8.05
ꢀ
1
1
(
300 MHz, CDCl , T = 300 K): δ = 3.73 (t, 4H, H-10,
3
J10–9 = 4.8 Hz), 3.80 (t, 4H, H-9, J9–10 = 4.8 Hz), 5.54
s, 2H, OCH ), 7.34–7.50 (m, 8H, OBn, H-13, H-14),
13
(
(d, 1H, H-5, J5–7 = 2.4 Hz) ppm. C NMR (75 MHz,
CDCl , T = 3 00 K): δ = 44.4 (C-9), 66.8 (C-10), 68.4
(CH, OCH ), 111.6 (C-16), 112.6 (C-11a), 120.0 (C-11),
2
7
.62 (d, 1H, H-7, J7–5 = 2.4 Hz), 7.69–7.73 (m, 2H, H-
3
1
3
12), 7.94 (d, 1H, H-5, J5–7 = 2.4 Hz) ppm. C NMR
2
(
1
75 MHz, CDCl , T = 300 K): δ = 44.5 (C-9), 66.9 (C-
120.6 (C-19), 122.3 (C-12), 122.6 (C-4a, C-18), 122.9
(C-5), 124.2 (C-19a), 124.3 (C-8), 126.5 (C-6), 127.1 (C-
17), 128.0 (CH, OBn), 128.3 (CH, OBn), 128.6 (CH,
OBn), 129.5 (C-13), 133.4 (C-14), 135.4 (C-7), 136.3 (C,
OBn), 149.9 (C-8a), 154.0 (C-14a), 156.0 (C-16a), 157.7
3
0), 68.4 (CH, OCH ), 112.7 (C-4a), 122.1 (C-5), 126.7
2
(
C-6), 127.4 (CH, OBn/C-14), 127.7 (C-13), 128.0 (CH,
OBn), 128.3 (CH, OBn/C-14), 128.6 (CH, OBn), 130.3
C-12), 134.4 (C-7), 136.3 (C, OBn), 137.9 (C-8/C-11),
38.1 (C-8/C-11), 149.6 (C-8a), 157.9 (C-2), 166.4 (C-4)
ppm. C H N O Cl (431.91): Calcd C 69.52, H 5.13, N
(
1
(C-2), 166.4 (C-4) ppm. C31H N O Cl (521.99): Calcd
24 3 3
C 71.33, H 4.63, N 8.05; found. C 71.55, H 4.77, N 7.95.
25 22 3 2
9
.73; found. C 69.52, H 5.27, N 9.97.
4-(8-(Dibenzo[b,d]furan-4-yl)-4-methoxyquinazolin-2-yl)
0
morpholine (15).
Crude 4-(6-chloro-8-(dibenzo[b,d]
4
-(8-([1,1 -Biphenyl]-3-yl)-4-(benzyloxy)-6-chloroquinazolin-
2
6
-yl) morpholine (14e). Crude 4-(4-(benzyloxy)-8-bromo-
-chloroquinazolin-2-yl) morpholine (13b) was reacted
furan-4-yl)-4-methoxyquinazolin-2-yl) morpholine (14c)
underwent hydrodechlorination according to “General
Procedure B” to give 15 as a white solid. Yield = 17%.
with Biphenyl-3-boronic acid according to a modified
version of “General Procedure A: Extraction Method 1”
in which 0.1 mmol Bis (triphenylphosphine) palladium
R
=
0.38 (chloroform–petroleum spirit 3:2). mp
f
3
187–188°C. IR (KBr): νmax 2964.5 (w, sp C-H st), 1621.2,
ꢀ
1
1
(II) dichloride was used to give 14e as a white solid.
1584.7, 1519.2 cm . H NMR (300 MHz, DMSO-d
T = 340 K): δ = 3.45 (t, 4H, H-10, J10–9 = 4.8 Hz), 3.52 (t,
4H, H-9, J9–10 = 4.8 Hz), 4.10 (s, 3H, OCH ), 7.32 (dd,
1H, H-6, J6–7 = 7.2 Hz, J6–5 = 8.1 Hz), 7.36 (dt, 1H, H-18,
18–17 = J18–19 = 7.5 Hz, J18–16 = 0.9 Hz), 7.44 (t, 1H, H-
,
6
Yield = 49%. R = 0.72 (chloroform–petroleum spirit
3
st), 1617.5, 1576.7, 1513.4, 1418.9 cm
f
3
:2). mp 142–143°C. IR (KBr): νmax 2968.4 (w, sp C-H
3
ꢀ
1
1
.
H NMR
(300 MHz, CDCl , T = 300 K): δ = 3.70 (t, 4H, H-10,
J
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation,
DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
1
7
1
2, J12–11 = J12–13 = 7.5 Hz), 7.45 (m, 1H, H-17, J17–18
=
.2 Hz, J17–16 = 8.4 Hz, J17–19 = 1.2 Hz), 7.56 (bd, 1H, H-
6, J16–17 = 8.4 Hz), 7.65 (dd, 1H, H-13, J13–12 = 7.5 Hz,
Sigma Aldrich]. Cells were incubated in the presence of
compound for 72 h at 37°C with 5% CO2.
Proliferation of HCT-116 cells was measured using a
Cell Counting Kit-8 assay (CCK-8; Dojindo Molecular
Technologies, Rockville, Maryland, USA), following the
manufacturer’s instructions. Reduction of the formazan
dye was measured using a ChroMate 4300 microplate
reader (450 nm; Awareness Technology Inc.). The
absorbance values for compound-treated samples were
compared with the DMSO control, and the average
percent growth inhibition was determined for each
compound tested. IC50 values were determined by
plotting the percent growth inhibition versus the
concentration of compound, and analysis was performed
using GraphPad Prism software (GraphPad). Assays were
performed in at least triplicate with each data point
performed in quadruplicates. IC50 value are an average of
three separate experiments performed in quadruplicate,
and the error bars are the standard errors of the mean
J13–11 = 1.2 Hz), 7.89 (dd, 1H, H-7, J7–6 = 7.2 Hz, J7–5
=
1.5 Hz), 7.99 (dd, 1H, H-5, J5–6 = 8.1 Hz, J = 1.5 Hz),
5–7
13
8.08–8.14 (m, 2H, H-11, H-19) ppm. C NMR (75 MHz,
DMSO-d , T = 340 K): δ = 44.2 (C-9), 54.0 (CH, OCH ),
6
3
6
1
1
1
1
1
5
6.0 (C-10), 111.4 (C-11a), 111.5 (C-16), 120.0 (C-11),
21.0 (C-19), 121.6 (C-6), 122.6 (C-12), 122.9 (C-18),
23.6 (C-5), 123.7 (C-4a), 123.8 (C-19a), 123.9 (C-8),
27.4 (C-17), 129.6 (C-13), 131.3 (C-14), 135.1 (C-7),
50.8 (C-8a), 153.8 (C-14a), 155.5 (C-16a), 157.5 (C-2),
67.4 (C-4) ppm. C H N O (411.45): Calcd C 72.98, H
25 21 3 3
.14, N 10.21; found. C 72.73, H 5.27, N 10.42.
BIOLOGICAL EVALUATION
DNA-dependent protein kinase. The DNA-PK assays
(SEM).
were performed by Reaction Biology Corporation, One
Great Valley Parkway, Suite 2 Malvern, PA 19355, USA.
All Compounds were dissolved in DMSO and tested
for their ability to inhibit human DNA-PK. Reactions
were carried out using 20 μM peptide substrate
CONCLUSION
Novel 8-aryl-2-morpholino quinazolines (11a–n, 12a–d,
4a–f, and 15) were synthesized from the precursor 2-
(EPPLSQEAFADLWKK), 10 μg/mL DNA and 10 μM
1
ATP using the HTRF assay format. Compounds were
tested for percentage inhibition of DNA-PK assayed in
a single-dose duplicate mode at a concentration of
thioxo quinazolin-4-ones and characterized.
Some of the newly synthesized compounds were
assayed for inhibitory activity against DNA-PK and PI3K
10 μM.
(Table 1) but were profoundly less active in spite of the
Phosphatidylinositol 3-kinase. The PI3K inhibitors were
strong structural resemblance to potent chromone 1–2,
quinol-4-ones 3, pyrido[1,2-a]pyrimidin-4-ones 4, and
dissolved at 10 mM in dimethyl sulphoxide (DMSO) and
stored at ꢀ20°C until use. PI3K enzyme activity was
determined using a luminescence assay measuring.
ATP consumption is as described previously [20]. PI3K
enzyme activity was determined in 50 μL of 20 mM
HEPES pH 7.5, 5 mM MgCl2 with 180 μM PI and
1
,3-benzoxazine 6 inhibitors. Loss of DNA-PK activity
has been attributed to tautomerization of the quinazolin-
-one core to the aromatic quinazolin-4-ol enol (4-OH)
4
tautomer. The aromatization of the pyrimidine
heterocyclic ring could alter the conformation, and thus
binding site, of the 2-morpholine ring, which could
reduce the compound-receptor hydrogen bonding to the
morpholine 4-oxygen.
Cytotoxicity studies revealed a moderate level of
activity against HCT-116 human colon cancer cells.
Therefore, the tested compounds (Table 2) are likely
targeting other enzymes.
10 μM ATP. After a 60 min incubation at room
temperature, the reaction was stopped by the addition of
50 μL of Kinase-Glo (Promega) followed by a further
1
5 min incubation. Luminescence was then read using a
Fluostar plate reader (BMG Labtech). Compounds were
tested for percentage inhibition of PI3K α, β, γ, and δ
isoforms assayed in a single-dose duplicate mode at a
concentration of 10 μM.
Cytotoxicity assay.
Cytotoxicity of the compounds
against human colon cancer cell line HCT-116 cells was
determined using Cell Counting Kit-8 reduction assay
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[
(
[
[
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. T. Heppell, M. A. Islam, S. R. McAlpine, and J. M. A. Al-Rawi
Vol 000
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[
SUPPORTING INFORMATION
[
Kashishian, A.; Steiner, B.; Johnson, A. J.; Byrd, J. C.; Tyner, J. W.;
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Additional supporting information may be found online
in the Supporting Information section at the end of the
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet