Synthetic approach and functionalization of novel 4-anilinoquinolino-quinazoline heterocyclic scaffolds

Article abstract of DOI:10.1016/j.tet.2016.12.009

An efficient and high yielding protocol is reported for the synthesis of new class of 4-anilinoquinolino-quinazoline hybrids. The target compounds were prepared first by the reaction of 2-aminobenzamide with 2-chloroquinoline-3-carbaldehydes. After oxidation and chlorination, the key 2-quinolyl-4-chloroquinazolines were converted to the corresponding 2-(2-arylaminoquinolyl)-4-arylaminoquinazolines and N-heteroaryl-2-(2-(heteroarylamino)quinolin-3-yl)quinazolin-4-amines.

Full text of DOI:10.1016/j.tet.2016.12.009

Accepted Manuscript
Synthetic approach and functionalization of novel 4-anilinoquinolino-quinazoline
heterocyclic scaffolds
Chamseddine Derabli, Raouf Boulcina, Gilbert Kirsch, Abdelmadjid Debache
PII:
S0040-4020(16)31277-7
10.1016/j.tet.2016.12.009
TET 28301
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 October 2016
Revised Date: 20 November 2016
Accepted Date: 6 December 2016
Please cite this article as: Derabli C, Boulcina R, Kirsch G, Debache A, Synthetic approach and
functionalization of novel 4-anilinoquinolino-quinazoline heterocyclic scaffolds, Tetrahedron (2017), doi:
10.1016/j.tet.2016.12.009.
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Graphical Abstract
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Synthetic approach and functionalization
of novel 4-anilinoquinolino-quinazoline
heterocyclic scaffolds
Chamseddine Derabli, Raouf Boulcina, Gilbert Kirsch, Abdelmadjid Debache

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthetic approach and functionalization of novel 4-anilinoquinolino-quinazoline
heterocyclic scaffolds
Chamseddine Derablia, Raouf Boulcinaa,b,*, Gilbert Kirschc, Abdelmadjid Debachea
a Laboratory of Synthesis of Molecules with Biological Interest, Frères Mentouri-Constantine University, 25000 Constantine, Algeria.
b Faculty of Technology, Batna 2 University, 05000 Batna, Algeria
c SRSMC, Lorraine University, 1 Boulevard Arago, 57070, France.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and high yielding protocol is reported for the synthesis of new class of 4-
anilinoquinolino-quinazoline hybrids. The target compounds were prepared first by the reaction
of 2-aminobenzamide with 2-chloroquinoline-3-carbaldehydes. After oxidation and chlorination,
the key 2-quinolyl-4-chloroquinazolines were converted to the corresponding 2-(2-
arylaminoquinolyl)-4-arylaminoquinazolines and N-heteroaryl-2-(2-(heteroarylamino)quinolin-
3-yl)quinazolin-4-amines.
Available online
Keywords:
Quinazoline derivatives
4-Anilinoquinazolines
Quinolino-quinazoline hybrids
SNAr reaction.
1. Introduction
arylaminoquinolyl)-4-arylaminoquinazolines (6), N- heteroaryl-
2-(2-(heteroarylamino)quinolin-3-yl)quinazolin-4-amines (7) and
its derivatives based on a simple and efficient route.
Over the last decade, the design of six-membered
heterocycles, such as quinazolines has caught the attention of
synthetic chemists due to their immense biological and
pharmacological potency. The quinazoline moiety is present in
natural products and synthetic pharmaceutical compounds.1
Quinazoline derivatives has been extensively studied for their
many pharmacological properties.2 The growing importance of
quinazolines in medicine is highlighted by the huge sales of the
drugs Erlotinib, which is used in the treatment of several types
tumors,3 and Prazosin, an α-adrenergic blocker.4 Likewise, Iressa,
an epidermal growth factor receptor inhibitor, was recently
approved by the U.S. Food and Drug Administration for the
treatment of lung cancer5 (Figure 1). Consequently, the
development of such quinazoline-based drugs has renewed the
interest in developing new and diversified synthetic strategies for
the synthesis of quinazoline derivatives.6
Figure 1. Popular drugs containing the quinazoline scaffold.
As a complement to our previous work on the synthesis of
dihydroquinazolines,7 a safe, efficient, and universal pathway to
synthesize other functionalized class of this heterocycle is highly
demanded. In literature, 4-aminoquinazolines with the quinoline
as substituent have never been described before. To study this
reaction, we decided to construct 4-chloroquinazoline (5), which
could be used as a starting material for this purpose. In this paper,
2. Results and discussion
We wished to synthesize the starting materials 5a-b from
commercially available products. In fact, 2-aminobenzamide
and some quinoline carboxaldehydes were used to obtain
original quinolino-quinazoline heterocycles. We therefore
conducted this reaction by heating at 80-90 °C, a mixture of
we describe for the first time the synthesis of 2-(2-
———
*
Corresponding author. Tel.: +213 559 11 03 29. E-mail address: r.boulcina@univ-batna2.dz (R. Boulcina).

2
Tetrahedron
a yield of 76%. We subsequently applied this method for
2-aminobenzamide 1 with different substituted quinoline
ACCEPTED MANUSCRIPT
compound 4b using the same conditions. The obtained results are
carboxaldehydes 2. Indeed, treatment of this mixture with
K2CO3 in the presence of iodine did not give directly in one
step the oxidized compounds 4a-b. Despite numerous
attempts, we have not been able to isolate these products in
abundant quantities. The reaction of 2-aminobenzamide with
2-chloroquinolin-3-carbaldehydes in the presence of K2CO3
only furnished intermediates 3a-b.
collated in Table 2.
Scheme 3
Table 2. Oxidation and Chlorination of quinazolin-4(3H)-ones 3a-b.a
4a 75%
4b 80%
Scheme 1
We then extended the same method to different quinoline
carboxaldehydes, allowing the synthesis of products 3a-e with
good yields (Table 1).
5b 73%
5a 76%
a Isolated yield.
Functionalization of the quinazoline ring in position 4 with a
chlorine atom makes it easy to achieve aromatic nucleophilic
substitution reactions with various nucleophiles. Among these,
aromatic amines caught our attention because of the very broad
representation of 4-aminoquinazolines in the literature among
molecules of pharmaceutical interest having a quinazoline
pattern. Thus, we studied this reaction with the previously
prepared 4-chloroquinazolines 5a-b.
Scheme 2
Table 1. Reaction of 2-aminobenzamide with different quinoline
carboxaldehydes.a
Compounds 5a-b possess 2-chloro atoms which could possibly
be substituted in nucleophilic substitution reactions. The
literature suggests several procedures that address the aromatic
nucleophilic substitution reaction between 4-chloroquinazoline or
4-chloroquinoline with various primary or secondary amines, and
arylamines.
A general literature review of nucleophilic substitution reactions
on 4-chloroquinazolines, allowed us to note that some reaction
parameters are found in a vast majority of publications. Among
these, the use of isopropanol (i-PrOH) as solvent at reflux. To
achieve the first reaction test, we kept these two parameters.8,9
A first try to substitute on the 4-chloroquinazoline 5a was run in
i-PrOH at 80 °C. The reaction with one equivalent of aniline gave
a mixture of 2 compounds: mono and disubstituted derivatives
(6a and 7a respectively) after 60 min. An attempt in DMF at 80-
90 °C gave the same result (Scheme 4).
3a 95%
3c 89%
3b 93%
3d 85%
NH
Cl
3e 76%
NH
N
N
a Isolated yields.
a or b
N
N
N
NH2
N
HN
N
Cl
5a
N
Subsequently, we selected 2,3-dihydroquinazolin-4(1H)-one 3a-b
to study the oxidation reaction using iodine or KMnO4. Without
isolation from the reaction medium, compounds 3a-b were
directly treated by I2 in DMF at 80-90 °C. This led to the
formation of compounds 4a-b in yields of 75 and 80%
respectively.
We were then interested in the synthesis of chlorinated precursors
in position 4. Product 5a was isolated after reflux in POCl3
overnight. In addition, we observed the residual presence of some
resins. Indeed, we conducted a recrystallization in ethanol to
eliminate these resins. Product 5a was isolated in pure form with
Cl
6a
N
1 équiv.
7a
Scheme 4 Reaction conditions: (a): i-PrOH, reflux, (b): DMF, 80-90 °C.
However, when the reaction was run in DMF at room
temperature during 24 hours, formation of 6a reached 70% with
complete disappearance of 7a. In addition, we tested the reaction
with two different catalysts with acid or basic character: HCl
(1N), and K2CO3.

3
Table 3. Synthesis of N-(4-heteroaryl)-2-(2-chloroquinolin-3-yl)quinazolin-
synthesized a series of quinolino-quinazolines 6a-l with yields
ranging from 48 to 75% (Table 3).
ACCEPTED MANUSCRIPT
4-aminesa
On the other hand, the reaction was carried out with 2 equivalents
of aniline or its derivatives in isopropanol at reflux. The results
showed that the starting material 5a-b had been consumed (TLC)
after 60 min. The resulting suspensions were cooled and the
solids were collected by filtration and recrystallized if necessary
from EtOH. If no precipitates were formed the mixtures were
extracted with ethyl acetate and purified by column
chromatography.
Table 4. Synthesis of N- heteroaryl-2-(2-( heteroarylamino)quinolin-3-
yl)quinazolin-4-aminesa
6a 71%
6b 75%
6d 70%
6c 66%
6e 67%
6f 53%
6h 72%
6j 72%
7a 84%
7b 85%
6g 68%
7c 90%
7d 83%
6i 64%
7f 82%
7e 79%
6k 63%
6l 48%
a Isolated yields.
The use of these catalysts led to completely different results.
Indeed, a catalytic amount of HCl (1N) resulted in the total
consumption of the starting material and formation of the desired
product 6a after 3 hours at room temperature. However, the use
of an equivalent of K2CO3 has no effect on this transformation
even after 24 hours by giving almost similar results to those
obtained without the use of catalyst. Under these conditions, we
7g 86%
7h 88%
a Isolated yields.

4
Tetrahedron
63.8. HRMS (ESI+) m/z 350.0431 [M+K]+, calcd for
ACCEPTED MANUSCRIPT
C17H1237ClKN3O: 350.0276.
To demonstrate the efficiency and the scope of the present
method, we performed SNAr reaction using substrates with
different electron-withdrawing or electron-donating groups. As
shown in Table 4, the bi-substituted compounds 7a-h were
obtained in the majority of cases with good yields.
2-(2-Chloro-8-methylquinolin-3-yl)-2,3-dihydroquinazolin-
4(1H)-one (3b)
Following general procedure I, compound 3b was obtained as a
white solid (1.50 g, 93%). M.p.:>260 °C; IR (KBr) ν 3415, 3194,
2933, 2857, 2150, 1655, 1605, 1493, 1384, 1120, 1036, 975, 745
1
The structures of all compounds were easily established with H
and 13C NMR data. The exact structure of compound 7h was
determined according to both HSQC and HMBC 2D NMR
experiments.
cm-1. H NMR (250 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.96 (br
1
s,1H), 7.75-7.71 (m, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.0
Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.20 (td, J=7.0, 1.5 Hz, 1H),
6.81-6.67 (m, 2H), 6.60 (s,1H), 6.25 (br s, 1H), 2.66 (s, 3H,
CH3); 13C NMR (62.5 MHz, DMSO-d6) δ 163.5, 146.1, 145.4,
136.6, 134.9, 132.8, 130.6, 130.1, 126.8, 126.3, 125.9, 125.0,
117.3, 114.0, 63.0, 44.1. Anal. Calcd for C18H14ClN3O: C, 66.77;
H, 4.36; N, 12.98. Found: C, 66.47; H, 4.30; N, 12.77.
3. Conclusion
In conclusion, we have adapted a series of reactions between 4-
chloro-2-(2-chloroquinolin-3-yl)quinazolines 5a-b with diverse
arylamines to get 20 new N-(4-heteroaryl)-2-(2-chloroquinolin-3-
yl)quinazolin-4-amines
6a-l
and
N-
heteroaryl-2-(2-(
heteroarylamino)quinolin-3-yl)quinazolin-4-amines 7a-h with
good yields. After many attempts, focusing of each reaction
parameter, the SNAr reaction products were isolated and fully
characterized. This method allowed us to access easily and
quickly a variety of new heterocyclic analogues of chloroquine.
The preliminary results of the biological studies showed that
these compounds have good antiplasmodial activity.
2-(2-Chloro-6-methoxyquinolin-3-yl)-2,3-dihydroquinazolin-
4(1H)-one (3c)
Following general procedure I, compound 3c was obtained as a
white solid (302 mg, 89%). M.p.:>260 °C. IR (KBr) ν 3422,
3184, 2938, 2860, 2155, 1657, 1618, 1487, 1390, 1123, 1039,
972, 737 cm-1. NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.34
(br s,1H), 7,89 (d, J=9.2 Hz, 1H), 7.70 (dd, J=7.6, 1.6 Hz, 1H),
7.57 (d, J=2.8 Hz, 1H),7.48 (dd, J=9.2, 2.8 Hz, 1H), 7.29 (td,
J=7.6, 1.6 Hz, 1H), 7.16 (s, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.76 (td,
J=8.0, 1.6 Hz, 1H), 6.22 (br s, 1H), 3.89 (s, 3H, OCH3).13C NMR
(100 MHz, DMSO-d6) δ 158.0, 147.3, 145.8, 142.7, 136.6, 133.5,
132.0, 128.9, 128.1, 127.5, 123.7, 117.7, 115.7, 114.8, 106.3,
63.9, 55.7. HRMS (ESI+) m/z 362.0629 [M+Na]+, calcd for
C18H1435ClN3NaO2: 362.0672.
4. Experimental section
4.1. General remarks
Melting points were determined on an Electrothermal capillary
fine control apparatu. IR spectra were recorded on a Shimadzu
FT-IR 8201 spectrometer, only significant absorption band
frequencies are cited. 1H and 13C NMR spectra were recorded on
a Bruker Avance 400 instrument at 400 and 100 MHz
respectively and Brüker advance DPX 250 (250 MHz for the 1H,
62.5 for the 13C), in CDCl3 or DMSO-d6. Chemical shifts (δ) are
given in part per million downfield from TMS as an internal
standard and J values in Hz. The chemicals were used as
obtained commercially. High Resolution Mass spectra were
recorded with a MicroTof-Q 98. Elemental analyses were carried
out on a Microanalyzer Flash EA1112 CHNS/O Thermo
Electron.
2-(2,7-Dichloroquinolin-3-yl)-2,3-dihydroquinazolin-4(1H)-
one (3d)
Following general procedure I, compound 3d was obtained as a
white solid (1.46 g, 85%). M.p.:>260 °C. IR (KBr) ν 3435, 3194,
2942, 2863, 2162, 1665, 1609, 1492, 1391, 1124, 1043, 974, 739,
605 cm-1. NMR (250 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.23 (d,
J=8.8 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 7.76-7.70 (m, 2H), 7.32
(td, J=8.5, 1.5 Hz, 1H), 7.20 (s, 1H), 6.83-6.75 (m, 2H), 6.27 (s,
1H). 13C NMR (62.5 MHz, DMSO-d6) δ 161.0, 146.3, 145.6,
142.9, 137.7, 133.5, 132.1, 130.7, 128.5, 126.1, 121.1, 116.2,
116.0, 113.4, 113.2, 60.5. HRMS (ESI+) m/z 366.0155 [M+Na]+,
calcd for C17H1135Cl2N3NaO: 366.0177.
4.2. General Procedure
compounds (3a-e)
I
for the preparation of
In a 100 mL flask were introduced 5 mmol (0.68 g) of 2-
aminobenzamide and 5 mmol of the corresponding quinoline
carboxaldehyde derivative with 5 mmol (0.69 g) of K2CO3 in 20
mL DMF. The reaction medium was heated at 80 °C for 3 hours
(the progress of the reaction was monitored by TLC). Then the
mixture was decomposed onto 100 mL of water. The precipitate
obtained was filtered on Buchner, washed with water (3 × 50
mL) and dried. The resulting solid was recrystallized from
ethanol.
2-(Quinolin-4-yl)-2,3-dihydroquinazolin-4(1H)-one (3e)
Following general procedure I, compound 3d was obtained as a
white solid (1.07 g, 78%). M.p.:>260 °C. IR (KBr) ν 3437, 3196,
2939, 2853, 2156, 1655, 1604, 1487, 1389, 1125, 1035, 979 cm-1.
1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J=4.4 Hz, 1H), 8.54
(d, J=8.0 Hz, 1H), 8.42 (br s, 1H), 8.10 (dd, J=8.0, 0.8 Hz, 1H)
7.81 (td, J=8.0, 1.6 Hz, 1H), 7.72-766 (m, 2H), 7.63 (d, J=4.4 Hz,
1H), 7.28 (td, J=8.0, 1.6 Hz, 1H), 7.21 (s, 1H), 6.77-6.73 (m,
2H), 6.59 (br s, 1H). 13C NMR (100 MHz, DMSO-d6) δ 163.6,
150.3, 148.3, 147.8, 144.6, 133.4, 129.6, 129.3, 127.5, 126.6,
125.3, 124.6, 119.7, 117.5, 114.9, 114.6, 63.9. HRMS (ESI+) m/z
276.1114 [M+H]+, calcd for C17H14N3O: 276.1137.
2-(2-Chloroquinolin-3-yl)-2,3-dihydroquinazolin-4(1H)-one
(3a)
Following general procedure I, compound 3a was obtained as a
white solid (1.47 g, 95%). M.p.:>260 °C. IR (KBr) ν 3410, 3198,
2932, 2854, 2152, 1652, 1608, 1497, 1385, 1122, 1034, 972, 740
4.3. General Procedure II for the preparation of
compounds (4a-b)
1
cm-1. H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.20 (br s,
1H), 8.04 (td, J=7.6, 1.2 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.70 (d,
J=7.6, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.42 (td, J=7.6, 1.2 Hz, 1H),
7.21 (td, J=7.6, 1.2 Hz, 1H), 6.90 (s, 1H), 6.76 (d, J=8.4 Hz, 1H),
6.70 (t, J=7.2 Hz, 1H), 6.24 (br s, 1H).13C NMR (100 MHz,
DMSO-d6) δ 163.8, 149.9, 147.7, 147.1, 137.5, 133.2, 131.2,
130.6, 130.5, 127.4, 123.8, 117.7, 117.4, 114.7, 111.4, 111.2,
In a 250 mL flask fitted with a condenser, compounds 3a-b (20
mmol) were dissolved in 100 mL of DMF, then 25 mmol (3.17 g)
of iodine was added and the mixture was heated at 80-90 °C for 6
hours (The progress of the reaction was monitored by TLC).
After cooling, the mixture was poured onto 500 mL of water. The
precipitate formed was filtered on frit, washed with water (3 × 50

5
mL) then with 100 mL of a 20% solution of sodium thiosulfate to
remove traces of iodine, followed by washing with water. The
obtained solid was recrystallized from EtOH.
130.5, 129.3, 129.1, 127.2, 126.1, 125.9, 122.4, 17.8. HRMS
ACCEPTED MANUSCRIPT
(ESI+) m/z 340.0418 [M+H]+, calcd for C18H1235Cl2N3: 340.0408.
4.5. General Procedure IV for the preparation of
compounds (6a-l)
2-(2-Chloroquinolin-3-yl)quinazolin-4(3H)-one (4a)
Following general procedure II, compound 4a was obtained as a
white solid (4.60 g, 75%). M.p.:>260 °C. IR (KBr) ν 3437, 3024,
2353, 1670, 1605, 1473, 1392, 1342, 1242, 1119, 1010, 883, 759,
675, 613 cm-1. 1H NMR (400 MHz, DMSO-d6) δ 12.68 (br s, 1H),
8.83 (s, 1H), 8.23 (dd, J=8.0, 0.8 Hz, 1H), 8.16 (d, J=8.0, 1H),
8.08 (d, J=8.4 Hz, 1H), 7.95 (td, J=8.4, 1.2 Hz, 1H), 7.29 (td,
J=8.4, 1.6 Hz, 1H), 7.77 (t, J=8.0 Hz, 2H), 7.61 (td, J=8.0, 0.8
Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 161.5, 151.2, 148.5,
147.0, 146.8, 140.4, 134.7, 132.2, 128.6, 128.1, 128.0, 127.7,
127.4, 127.3, 126.0, 125.9, 121.3. HRMS (ESI+) m/z 308.0598
[M+H]+, calcd for C17H1135ClN3O: 308.0591.
In a 100 mL flask equipped with a condenser, 0.5 mmol (1 eq.) of
4-chloro-2-(2-chloroquinolin-3-yl)quinazolines
5a-b
were
dissolved in 10 mL of DMF. 0.5 mmol (1 eq.) of the aromatic
amine dissolved in 5 mL of DMF was then added with a few
drops of HCl (1N). After 3 hours of stirring at room temperature
(the progress of the reaction was followed by TLC), water was
added in sufficient quantity to dissolve the salts, if a precipitate
was formed, it was filtered under vacuum. The product was dried
and recrystallized in ethanol. If no precipitate was obtained, the
mixture was extracted twice with ethyl acetate. The organic
phases were dried over magnesium sulphate, filtered and
evaporated. The product was purified by silica gel column eluted
with EtOAc / cyclohexane (1/9).
2-(2-Chloro-8-methylquinolin-3-yl)quinazolin-4(3H)-one (4b)
Following general procedure II, compound 4b was obtained as a
white solid (5.14 g, 80%). M.p.:>260 °C. IR (KBr) ν 3438, 3166,
3028, 2358, 1675, 1607, 1477, 1396, 1349, 1246, 1125, 1016,
889, 764, 679 cm-1. 1H NMR (400 MHz, DMSO-d6) δ 12.75 (br s,
1H), 8.78 (s, 1H), 8.21 (dd, J=8.0, 1.2 Hz, 1H), 7.98 (d, J=8.4,
1H), 7.87 (td, J=8.4, 1.6 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.75 (d,
J=7.6 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.59 (td, J=8.0, 1.2 Hz,
1H), 2.73 (s, 3H, CH3).13C NMR (100 MHz, DMSO-d6) δ 162.1,
151.0, 148.7, 146.1, 146.0, 140.6, 135.6, 134.4, 131.9, 128.3,
127.7, 127.3, 127.0, 126.4, 126.1, 125.9, 121.3, 17.3. HRMS
(ESI+) m/z 322.0744 [M+H]+, calcd for C18H1335ClN3O:
322.0747.
2-(2-Chloroquinolin-3-yl)-N-phenylquinazolin-4-amine (6a)
Following general procedure IV, compound 6a was obtained as a
white solid (136 mg, 71%). M.p.: 242-244 °C. IR (KBr) ν 3435,
2934, 2859, 2057, 1623, 1556, 1506, 1369, 1294, 1142, 1030,
1
745 cm-1. H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.98-7.81
(s, 4H), 7.77 (d, J=7.2 Hz, 1H), 7.72 (d, J=8.4, 1H), 7.62 (d,
J=7.6 Hz, 1H), 7.50 (t, J=8.0 Hz, 3H), 7.31 (t, J=8.0 Hz, 2H),
7.15 (d, J=7.2 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H).13C NMR (400
MHz, CDCl3) δ 163.0, 158.0, 157.1, 151.1, 147.6, 141.1, 138.8,
133.1, 130.1, 129.1, 128.0, 126.4, 124.9, 123.9, 123.8, 122.5,
120.3, 113.3. HRMS (ESI+) m/z 383.1055[M+H]+, calcd for
C23H1635ClN4: 383.1063.
4.4. General Procedure III for the preparation of
compounds (5a-b)
2-(2-Chloroquinolin-3-yl)-N-(o-tolyl)quinazolin-4-amine (6b)
Following general procedure IV, compound 6b was obtained as a
white solid (148 mg, 75%). M.p.: 192-194 °C. IR (KBr) ν 3433,
2924, 2854, 2052, 1627, 1566, 1516, 1365, 1292, 1149, 1029,
In a 250 mL flask fitted with a condenser, 10 mmol of
quinazolin-4(3H)-ones 4a-b was dissolved in 30 mL of POCl3.
The mixture was refluxed for l8 hours. After removal of solvent,
the residue was decomposed on 100 mL of ice water and
neutralized with ammonium hydroxide. The obtained precipitate
was isolated by vacuum filtration, rinsed twice with 50 mL of
water. The solid was dried at room temperature to constant
weight. A small sample of the product was recrystallized from
ethanol. The crude product was used without further purification
for further reactions.
1
744 cm-1. H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.25 (d,
J=8.0 Hz, 1H), 8.07 (t, J=7.2 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H),
7.92-7.86 (m, 2H), 7.77 (td, J=8.4, 1.2 Hz, 1H), 7.66 (td, J=8.0,
1.2 Hz, 1H), 7.60 (td, J=8.0, 1.2 Hz, 1H), 7.48 (m, 1H), 7.32-7.27
(m, 2H), 7.15 (td, J=8.4, 1.2 Hz, 1H) 2.45 (s, 3H, CH3).13C NMR
(100 MHz, CDCl3) δ 160.4, 157.7, 150.6, 148.9, 147.4, 140.1,
136.3, 133.3, 130.8, 130.6, 129.9, 129.4, 128.3, 128.1, 127.1,
126.9, 126.0, 125.4, 124.1, 120.4, 113.8, 18.1. HRMS (ESI+) m/z
397.1220 [M+H]+, calcd for C24H1835ClN4: 397.1220.
4-Chloro-2-(2-chloroquinolin-3-yl)quinazoline (5a)
Following general procedure III, compound 5a as a pale yellow
°
solid (2.47 g, 76%); m.p.: 172-174 C; IR (KBr) ν 3448, 3066,
N-(4-Chloro-2-methylphenyl)-2-(2-chloroquinolin-3-
yl)quinazolin-4-amine (6c)
2927, 2357, 1608, 1562, 1477, 1396, 1380, 1319, 1126, 999, 845,
760 cm-1 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.29 (dd,
J=8.4, 0.8 Hz, 1H), 8.11 (d, J=8.4, 1H), 8.03 (d, J=8.4 Hz, 1H),
7.97 (td, J=8.4, 1.2 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.74 (m,
2H), 7.55 (td, J=8.0, 0.8 Hz, 1H).13C NMR (100 MHz, CDCl3) δ
159.1, 151.4, 148.5, 147.7, 141.0, 135.4, 131.6, 131.1, 129.5,
129.0, 128.5, 128.2, 127.5, 126.7, 125.9, 122.4. HRMS (ESI+)
m/z 326.0257 [M+H]+, calcd for C17H1035Cl2N3: 326.0252.
Following general procedure IV, compound 6c was obtained as a
white solid (142 mg, 66%). M.p.: 224-226 °C; IR (KBr) ν 3456,
3045, 2932, 2342, 1607, 1565, 1526, 1345, 1252, 1149, 1039,
1
740, 659 cm-1. H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.20
(d, J=9.2 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.0 Hz,
1H), 7.96 (d, J=8.0, Hz, 1H), 7.94-7.89 (m, 2H), 7.79 (td, J=8.4,
1.2 Hz, 1H),7.68 (td, J=8.0, 1.2 Hz, 1H), 7.60 (td, J=8.0, 1.2 Hz,
1H),7.39 (s, 1H), 7.28-7.26 (m, 3H), 2.43 (s, 3H, CH3).13C NMR
(100 MHz, CDCl3) δ 160.3, 157.6, 150.7, 148.7, 147.4, 140.1,
134.8, 133.4, 133.1, 131.8, 130.9, 130.4, 129.4, 128.3, 128.0,
127.2, 126.9, 125.5, 120.2, 113.7, 17.9. HRMS (ESI+) m/z
431.0841 [M+H]+, calcd for C24H1735Cl2N4: 431.0830.
4-Chloro-2-(2-chloro-8-methylquinolin-3-yl)quinazoline (5b)
Following general procedure III, compound 5b as a pale yellow
°
solid (2.47 g, 73%); m.p.: 132-134 C; IR (KBr) ν 3450, 3068,
2929, 2520, 2367, 1611, 1564, 1479, 1396, 1382, 1319, 1131,
1005, 849, 756 cm-1 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H),
8.29 (dd, J=8.0, 0.8 Hz, 1H), 8.11 (d, J=8.4, 1H), 7.96 (d, J=8.4,
1.2 Hz, 1H), 7.79-7.69 (m, 2H), 7.57 (d, J=7.6 Hz, 1H), 7.42 (t,
J=7.6 Hz, 1H), 2.74 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ
162.4, 159.4, 151.4, 147.3, 146.9, 141.2, 136.7, 135.3, 131.6,
N-(4-Bromophenyl)-2-(2-chloroquinolin-3-yl)quinazolin-4-
amine (6d)
Following general procedure IV, compound 6d was obtained as a
white solid (161 mg, 70%). M.p.:>250 °C. IR (KBr) ν 3454,
3036, 2925, 2855, 2329, 1604, 1552, 1521, 1438, 1327, 943, 850,

6
Tetrahedron
CCEPTED MANUSCRIPT
741, 659, 601 cm-1. 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H),
2H), 2.83 (s, 3H, CH3), 2.46 (s, 3H, CH3).13C NMR (100 MHz,
A
8.11 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.0
Hz, 1H), 7.93-7.89 (m, 2H), 7.83 (dd, J=8.8, 2.8 Hz, 2H),7.80
(td, J=8.4, 1.2 Hz, 1H), 7.67 (td, J=8.0, 1.2 Hz, 1H), 7.65 (s, 1H),
7.61 (td, J=8.0, 1.2 Hz, 1H), 7.52 (dd, J=8.8, 2.8 Hz, 2H).13C
NMR (100 MHz, CDCl3) δ 160.1, 156.9, 150.5, 148.7, 147.5,
140.2, 137.2, 133.5, 133.0, 132.0, 131.1, 129.4, 128.4, 128.0,
127.3, 126.9, 122.9, 120.2, 117.1, 113.6. HRMS (ESI+) m/z
CDCl3) δ 157.6, 146.7, 140.4, 136.5, 134.8, 133.4, 131.1, 130.6,
130.4, 129.6, 127.2, 126.9, 126.8, 126.7, 126.0, 125.6, 120.3,
113.6, 19.6, 17.9, 17.8. HRMS (ESI+) m/z 411.1471 [M+H]+,
calcd for C25H2035ClN4: 411.1376.
N-(4-Chloro-2-methylphenyl)-2-(2-chloro-8-methylquinolin-
3-yl)quinazolin-4-amine (6i)
463.0159
[M+H]+,
calcd
for
C23H1581Br35ClN4
or
Following general procedure IV, compound 6i was obtained as a
white solid (142 mg, 64%). M.p.: 234-236°C. IR (KBr) ν 3446,
3042, 2935, 2352, 1609, 1558, 1521, 1334, 1265, 1152, 1040,
C23H1579Br37ClN4 : 463.0148.
1
N-(4-Bromo-2-fluorophenyl)-2-(2-chloroquinolin-3-
yl)quinazolin-4-amine (6e)
747, 659 cm-1. H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H,) 8.21
(d, J=8.4 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz,
1H), 7.91 (t, J=8.0, Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.67 (td,
J=8.0, 0.8 Hz, 1H), 7.65 (d, J=6.8 Hz, 1H), 7.48 (t, J=7.6 Hz,
1H), 7.38 (d, J=7.6 Hz, 1H),7.28-7.26 (m, 2H,) 2.83 (s, 3H, CH3),
2.42 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) δ 160.5, 157.5,
147.5, 146.7, 141.4, 140.4, 136.5, 134.9, 133.4, 131.8, 131.0,
130.6, 130.3, 129.4, 127.2, 126.9, 126.7, 125.9, 125.5, 122.6,
120.2, 113.6, 18.0, 17.8. HRMS (ESI+) m/z 445.1067 [M+H]+,
calcd for C25H1935Cl2N4: 445.0987.
Following general procedure IV, compound 6e was obtained as a
white solid (160 mg, 67%). M.p.: 226-228 °C; IR (KBr) ν 3441,
3066, 2924, 2858, 2357, 1624, 1562, 1523, 1408, 1327, 1122,
1022, 933, 860, 748, 663 cm-1. H NMR (400 MHz, CDCl3) δ
1
8.89 (t, J=8.4 Hz, 1H), 8.66 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 8.09
(d, J=8.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.96-7.89 (s, 2H),
7.84-7.80 (s, 2H), 7.71 (td, J=8.0, 1.2 Hz, 1H), 7.63 (td, J=8.0,
1.2 Hz, 1H), 7.39-7.34 (m, 2H).13C NMR (100 MHz, CDCl3) δ
159.9, 156.5, 150.6, 148.6, 140.3, 133.6, 133.0, 129.5, 128.4,
128.1, 127.9, 127.6, 127.3, 126.9, 126.2, 126.1, 123.8, 120.2,
118.4, 118.2, 115.4, 113.8. HRMS (ESI+) m/z 502.9890
N-(4-Bromophenyl)-2-(2-chloro-8-methylquinolin-3-
yl)quinazolin-4-amine (6j)
[M+Na]+,
C23H1379Br37ClFNaN4: 502.9873.
calcd
for
C23H1381Br35ClFNaN4
or
Following general procedure IV, compound 6j was obtained as a
white solid (170 mg, 72%). M.p.: 230-232 °C. IR (KBr) ν 3414,
3027, 2945, 2845, 2369, 1601, 1548, 1519, 1433, 1322, 936, 854,
1
2-(2-Chloroquinolin-3-yl)-N-(3,5-dichlorophenyl)quinazolin-
4-amine (6f)
749, 657, 608 cm-1. H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H),
8.07 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.91 (td, J=8.4,
1.2 Hz, 1H), 7.85 (dd, J=8.0, 2.8 Hz, 2H), 7.74 (d, J=8.0 Hz,
1H),7.68 (d, J=8.0, 1.2 Hz, 1H), 7.43 (d, J=8.0, 1.2 Hz, 1H), 7.59
(s, 1H) 7.53 (dd, J=8.0, 2.8 Hz, 2H), 7.48 (d, J=7.2 Hz, 1H).13C
NMR (100 MHz, CDCl3) δ 160.3, 156.9, 150.5, 147.5, 146.7,
140.5, 137.2, 136.5, 133.4, 132.7, 132.0, 131.1, 129.3, 127.2,
127.0, 126.9, 126.0, 122.8, 120.2, 117.0, 113.5, 17.9. HRMS
(ESI+) m/z 477.0389 [M+H]+, calcd for C24H1781Br35ClN4 or
C24H1779Br37ClN4: 477.0305.
Following general procedure IV, compound 6f was obtained as a
white solid (119 mg, 53%). M.p.:>250 °C. IR (KBr) ν 3443,
2944, 2545, 2355, 1604, 1571, 1525, 1435, 1392, 1315, 1117,
1018, 925, 825, 767 cm-1. H NMR (400 MHz, DMSO-d6) δ
1
10.18 (s, 1H), 8.86 (s, 1H), 8.63 (d, J=8.0 Hz, 1H), 8.21 (d, J=3.2
Hz, 2H), 8.17 (d, J=7.6 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 8.00-
7.96 (m, 2H), 7.91 (td, J=7.6, 1.2 Hz, 1H), 7.78 (td, J=8.4, 2.4
Hz, 1H), 7.73 (td, J=8.0, 1.2 Hz, 1H), 7.30 (t, J=2.0 Hz, 1H).13C
NMR (100 MHz, DMSO-d6) δ 164.2, 162.5, 155.5, 152.7, 151.9,
146.7, 145.9, 139.1, 139.0, 137.8, 136.9, 133.7, 133.5, 133.0,
132.8, 132.5, 131.8, 128.2, 127.8, 125.1, 118.9. HRMS (ESI+)
m/z 451.0302 [M+H]+, calcd for C23H1435Cl3N4: 451.0284.
N-(4-Bromo-2-fluorophenyl)-2-(2-chloro-8-methylquinolin-3-
yl)quinazolin-4-amine (6k)
Following general procedure IV, compound 6k was obtained as a
white solid (155 mg, 63%). M.p.: 240-242 °C. IR (KBr) ν 3461,
3036, 2928, 2855, 2327, 1611, 1565, 1524, 1418, 1330, 1142,
1032, 943, 852, 741, 653, 602 cm-1. 1H NMR (400 MHz, CDCl3)
δ 8.93 (t, J=8.8 Hz, 1H), 8.62 (s, 1H), 8.10 (d, J=8.4 Hz, 1H),
8.00 (d, J=8.0 Hz, 1H), 7.94 (td, J=8.0, 1.2 Hz, 2H), 7.82 (s, 1H),
7.77 (d, J=8.0 Hz, 1H), 7.71 (td, J=8.0, 1.2 Hz, 1H), 7.65 (d,
J=7.2 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.40-7.36 (m, 2H), 2.87 (s,
3H, CH3).13C NMR (100 MHz, CDCl3) δ 160.1, 156.5, 147.4,
146.7, 140.6, 136.5, 133.6, 131.2, 129.4, 128.0, 127.9, 127.6,
127.1, 127.0, 126.3, 126.2, 126.0, 123.9, 120.1, 118.4, 118.2,
115.5, 113.8, 17.8. HRMS (ESI+) m/z 495.0275 [M+H]+, calcd
for C24H1681Br35ClFN4 or C24H1679Br37ClFN4: 495.0210.
2-(2-Chloro-8-methylquinolin-3-yl)-N-phenylquinazolin-4-
amine (6g)
Following general procedure IV, compound 6g was obtained as a
white solid (135 mg, 68%). M.p.: 222-224 °C. IR (KBr) ν 3431,
2924, 2858, 2067, 1613, 1565, 1526, 1343, 1246, 1145, 1045,
752 cm-1. H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.06 (d,
1
J=8.0 Hz, 1H), 7.99 (d, J=8.0, 1H), 7.94 (d, J=7.6 Hz, 2H), 7.90
(td, J=8.0, 0.8 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.68-7.62 (m,
3H), 7.48 (t, J=7.6 Hz, 1H), 7.42 (t, J=8.0 Hz, 2H), 7.17 (t, J=7.6
Hz, 1H), 2.85 (s, 3H, CH3).13C NMR (400 MHz, CDCl3) δ 163.0,
158.0, 157.1, 151.1, 147.6, 141.1, 138.8, 133.1, 130.1, 129.1,
128.0, 126.4, 124.9, 123.9, 123.8, 122.5, 120.3, 113.3. HRMS
(ESI+) m/z 397.1235 [M+H]+, calcd for C24H1835ClN4: 397.1220.
2-(2-Chloro-8-methylquinolin-3-yl)-N-(3,5-
dichlorophenyl)quinazolin-4-amine (6l)
2-(2-Chloro-8-methylquinolin-3-yl)-N-(o-tolyl)quinazolin-4-
amine (6h)
Following general procedure IV, compound 6k was obtained as a
white solid (111 mg, 48%). M.p.: 224-226 °C. IR (KBr) ν 3383,
2939, 2357, 1624, 1581, 1520, 1431, 1389, 1311, 1107, 1014,
Following general procedure IV, compound 6h was obtained as a
white solid (148 mg, 72%). M.p.: 210-212 °C. IR (KBr) ν 3460,
3035, 2927, 2854, 2329, 1604, 1562, 1524, 1458, 1365, 1245,
1149, 1041, 941, 741, 659 cm-1.1H NMR (400 MHz, CDCl3) δ
8.56 (s, 1H), 8.26 (d, J=7.6 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.95
(d, J=8.4 Hz, 1H), 7.90 (td, J=8.4, 1.2 Hz, 2H), 7.72 (d, J=8.0
Hz, 1H), 7.65 (td, J=8.0, 0.8 Hz, 1H), 7.65 (d, J=6.8 Hz, 1H),
7.47 (t, J=8.0 Hz, 2H), 7.33-7.27 (m, 2H), 7.15 (t, J=8.4, 0.8 Hz,
1
921, 768 cm-1. H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.00
(d, J=8.0 Hz, 1H), 7.88-7.82 (m, 4H), 7.67 (d, J=8.0 Hz, 1H),
7.60 (td, J=8.0, 1.2 Hz, 1H), 7.54 (dd, J=7.2, 1.2 Hz, 1H), 7.49
(s, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.65 (t, J=2.0 Hz, 1H), 2.76 (s,
3H, CH3).13C NMR (100 MHz, CDCl3) δ 160.1, 156.7, 150.8,
147.4, 146.8, 141.0, 140.0, 136.6, 135.3, 133.6, 132.3, 131.2,
129.6, 127.5, 127.0, 126.9, 126.0, 124.1, 120.0, 119.4, 113.5,

7
17.8. HRMS (ESI+) m/z 465.0354 [M+H]+, calcd for
HRMS (ESI+) m/z 500.2131 [M+H]+, calcd for C31H26N5O2:
500.2087.
ACCEPTED MANUSCRIPT
C24H1635Cl3N4: 465.0441.
4.6. General Procedure
compounds (7a-h)
V
for the preparation of
N-(p-Tolyl)-2-(2-(p-tolylamino)quinolin-3-yl)quinazolin-4-
amine (7d)
In a 100 mL flask equipped with a condenser, 0.5 mmol (1 eq.) of
4-chloro-2-(2-chloroquinolin-3-yl)quinazolines 5a-b were
Following general procedure V, compound 7d was obtained as a
yellow solid (203 mg, 87%). M.p.:>260 °C. IR (KBr) ν 3437,
2947, 2355, 1607, 1563, 1486, 1412, 1345, 1249, 1142, 947, 899,
752 cm-1. 1H NMR (400 MHz, CDCl3) δ 12.80 (s, 1H), 10.12 (s,
1H), 9.26 (s, 1H), 8.62 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H),
7.97 (t, J=7.6, 1H), 7.84-7.77 (m, 5H), 7.73-7.63 (m, 3H), 7.34
(d, J=8.0 Hz, 3H), 7.34 (d, J=8.4 Hz, 2H), 2.38 (s, 3H, CH3),
2.31 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) δ 158.4, 157.5,
152.5, 148.5, 147.5, 139.7, 138.3, 136.0, 133.8, 131.0, 130.2,
129.1, 129.0, 128.7, 127.5, 126.7, 125.7, 123.2, 122.8, 122.7,
119.3, 118.5, 113.7, 26.3, 20.6. HRMS (ESI+) m/z 468.2192
[M+H]+, calcd for C31H26N5: 468.2188.
dissolved in 10 mL of isopropanol. Then 1 mmol (2 eq.) of the
aromatic amine dissolved in 5 mL of isopropanol was added.
After 60 min of stirring at reflux (the progress of the reaction was
followed by TLC), water was added in sufficient quantity to
dissolve the salts, if a precipitate was formed, it was filtered
under vacuum. The product was dried and recrystallized from
ethanol. If no precipitate was formed, the mixture was extracted
twice with ethyl acetate. The organic layers were dried over
magnesium sulphate, filtered and evaporated. The product was
purified by silica gel column eluted with EtOAc / cyclohexane
(1/9).
N-(4-Chloro-2-methylphenyl)-2-(2-((4-chloro-2-
N-Phenyl-2-(2-(phenylamino)quinolin-3-yl)quinazolin-4-
amine (7a)
methylphenyl)amino)quinolin-3-yl)quinazolin-4-amine (7e)
Following general procedure V, compound 7e was obtained as a
yellow solid (211 mg, 79%). M.p.:>260 °C. IR (KBr) ν 3437,
3043, 2356, 1577, 1523, 1450, 1407, 1334, 1249, 1153, 1045,
941, 852, 790, 748, 659, 532 cm-1. 1H NMR (400 MHz, CDCl3) δ
12.05 (s, 1H,), 9.18 (s, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.01 (d,
J=8.4 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.89 (td, J=8.4, 1.2 Hz,
1H), 7.77 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.65-7.59
(m, 2H), 7.36-7.26 (m, 6H), 2.58 (s, 3H, CH3), 2.41 (s, 3H,
CH3).13C NMR (100 MHz, CDCl3) δ 159.4, 157.2, 153.1, 149.4,
141.1, 137.9, 133.8, 133.4, 131.1, 131.0, 130.7, 130.5, 129.8,
128.6, 128.3, 126.9, 126.7, 126.3, 126.2, 126.1, 123.4, 123.2,
122.8, 120.5, 119.0, 113.5, 19.4, 18.1. HRMS (ESI+) m/z
536.1473 [M+H]+, calcd for C31H24Cl2N5: 536.1409.
Following general procedure V, compound 7a was obtained as a
yellow solid (184 mg, 84%). M.p.:>260 °C. IR (KBr) ν 3435,
2927, 2858, 2359, 1609, 1552, 1527, 1481, 1421, 1351, 1246,
1151, 949, 896, 754, 677, 605 cm-1. 1H NMR (400 MHz, CDCl3)
δ 12.75 (s, 1H), 9.22 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.90 (d,
J=8.4 Hz, 1H), 7.80 (d, J=8.0, 1H), 7.77-7.74 (m, 4H), 7.60 (d,
J=8.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H),
7.44-7.40 (m, 3H), 7.30 (t, J=8.0 Hz, 2H), 7.21-7.18 (m, 2H),
6.96 (t, J=7.2 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 159.3,
156.7, 153.1, 149.1, 148.3, 141.3, 140.8, 138.0, 133.4, 130.8,
129.1, 128.8, 128.7, 128.6, 126.8, 126.4, 124.9, 123.3, 122.6,
122.1, 121.6, 120.4, 119.7, 118.7, 113.5. HRMS (ESI+) m/z
440.1924 [M+H]+, calcd for C29H22N5: 440.1875.
2-(8-Methyl-2-(phenylamino)quinolin-3-yl)-N-
N-(o-Tolyl)-2-(2-(o-tolylamino)quinolin-3-yl)quinazolin-4-
amine (7b)
phenylquinazolin-4-amine (7f)
Following general procedure V, compound 7f was obtained as a
yellow solid (186 mg, 82%). M.p.: 226-228 °C. IR (KBr) ν 3433,
2923, 2356, 1604, 1562, 1523, 1488, 1411, 1342, 1245, 1149,
Following general procedure V, compound 7b was obtained as a
yellow solid (198 mg, 85%). M.p.: 202-204 °C. IR (KBr) ν 3432,
3047, 2359, 1577, 1513, 1446, 1403, 1335, 1250, 1153, 1047,
948, 894, 752, 675, 602 cm-1. H NMR (400 MHz, CDCl3) δ
1
1
944, 892, 792 cm-1. H NMR (400 MHz, CDCl3) δ 12.10 (s, 1H),
12.93 (s, 1H), 9.42 (s, 1H), 8.14 (d, J=8.0 Hz, 2H), 8.05 (t, J=8.4
Hz, 1H), 7.91 (td, J=8.0, 1.2, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.61
(td, J=8.0, 1.2 Hz, 2H), 7.55-7.52 (m, 4H), 7.42 (t, J=8.4 Hz,
2H), 7.31 (d, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.05 (t, J=7.6
Hz, 1H), 2.81 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) δ 159.4,
156.7, 152.2, 149.2, 141.6, 141.0, 138.1, 134.3, 133.4, 131.0,
131.2, 129.1, 128.7, 128.6, 126.7,126.6, 124.9, 123.1, 122.3,
122.1, 121.2, 120.4, 119.4, 118.3, 113.5, 106.0, 26.9. HRMS
(ESI+) m/z 454.2087 [M+H]+, calcd for C30H24N5: 454.2032.
9.23 (s, 1H), 8.62 (d, J=8.4 Hz, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.94
(d, J=8.0, 1H), 7.88 (td, J=8.0, 1.2 Hz, 1H), 7.77 (d, J=8.4 Hz,
1H), 7.63(t, J=8.4 Hz, 2H), 7.88 (td, J=8.4, 1.6 Hz, 1H), 7.42-
7.23 (m, 6H), 7.05 (t, J=7.2 Hz, 1H), 2.63 (s, 3H, CH3), 2.45 (s,
3H, CH3).13C NMR (100 MHz, CDCl3) δ 159.6, 157.3, 153.4,
149.4, 141.1, 139.4, 136.3, 133.4, 133.4, 131.5, 130.9, 130.7,
130.2, 128.8, 128.6, 128.3, 126.7, 126.6, 126.4, 126.2, 126.0,
124.9, 123.4, 122.5, 122.4, 122.2, 120.6, 119.2, 19.6, 18.2.
HRMS (ESI+) m/z 468.2176 [M+H]+, calcd for C31H26N5:
468.2188.
2-(8-Methyl-2-(o-tolylamino)quinolin-3-yl)-N-(o-
tolyl)quinazolin-4-amine (7g)
N-(2-Methoxyphenyl)-2-(2-((2-
Following general procedure V, compound 7g was obtained as a
yellow solid (207 mg, 86%); M.p.: 194-196 °C. IR (KBr) ν 3423,
2937, 2858, 2357, 1610, 1568, 1528, 1490, 1415, 1347, 1255,
methoxyphenyl)amino)quinolin-3-yl)quinazolin-4-amine (7c)
Following general procedure V, compound 7c was obtained as a
yellow solid (225 mg, 90%). M.p.: 209-210 °C. IR (KBr) ν 3414,
2943, 1682, 1535, 1458, 1408, 1331, 1238, 1176, 1114, 1029,
945, 856, 790, 736, 660, 590 cm-1. 1H NMR (400 MHz, CDCl3) δ
12.90 (s, 1H), 9.41 (s, 1H), 9.32 (s, 1H), 8.96 (dd, J=7.2, 2.0 Hz,
1H), 8.41 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.4, 1H),
7.92-7.87 (m, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.67-7.62 (m, 2H),
7.31 (t, J=7.6 Hz, 1H), 7.22-7.12 (m, 3H), 7.07-7.03 (m, 3H),
4.07 (s, 3H, OCH3), 4.05 (s, 3H, OCH3).13C NMR (100 MHz,
CDCl3) δ 159.5, 156.4, 153.0, 149.4, 149.3, 148.8, 140.5, 133.0,
130.7, 128.6, 128.5, 128.1, 126.7, 123.6, 123.3, 122.6, 121.2,
121.0, 120.9, 120.6, 120.1, 120.0, 114.3, 110.6, 110.2, 56.1, 56.0.
1
1142, 950, 895, 756, 672 cm-1. H NMR (400 MHz, CDCl3) δ
12.11 (s, 1H), 9.21(s, 1H), 9.00 (d, J=7.6 Hz, 1H), 8.05 (t, J=7.6
Hz, 2H), 7.93 (d, J=7.6, 1H), 7.87 (dd, J=8.0, 1.2 Hz, 1H), 7.60
(dd, J=8.0, 1.2 Hz, 1H), 7.51-7.47 (m, 2H), 7.43-7.25 (m, 6H),
7.17 (t, J=7.2 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 2.72 (s, 3H, CH3),
2.68 (s, 3H, CH3), 2.45 (s, 3H, CH3).13C NMR (100 MHz,
CDCl3) δ 159.8, 157.1, 152.3, 149.5, 147.3, 141.4,139.8, 136.4,
134.4, 133.3, 131.2, 130.8, 130.0, 128.2, 127.8, 126.7, 126.5,
126.4, 126.0, 125.8, 124.7, 123.2, 122.2, 121.8, 121.4, 120.5,
118.8, 113.7, 106.0, 19.9, 18.2, 18.1. HRMS (ESI+) m/z 482.2405
[M+H]+, calcd for C32H28N5: 482.2345.

8
Tetrahedron
ACCEPTED MANUSCRIPT
N-(2-Methoxyphenyl)-2-(2-((2-methoxyphenyl)amino)-8-
methylquinolin-3-yl)quinazolin-4-amine (7h)
Following general procedure V, compound 7h as a yellow solid
(226 mg, 88%). M.p.: 192-194 °C. IR (KBr) ν 3413, 2945, 1681,
1538, 1462, 1407, 1330, 1292, 1234, 1174, 1117, 1030, 952, 858,
792, 739, 659, 592 cm-1. 1H NMR (400 MHz, CDCl3) δ 12.82 (s,
1H), 9.37 (d, J=7.6, 1.2 Hz, 1H), 9.19 (s, 1H), 8.81 (dd, J=7.2,
2.0 Hz, 1H), 8.17 (s, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.70 (d, J=7.6,
1H), 7.67 (dd, J=8.0, 1.2 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.37
(m, 2H),7.10 (t, J=7.6 Hz, 1H), 7.06-6.88 (m, 5H), 7.10 (dd,
J=7.2, 2.0 Hz, 1H), 3.92 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 2.71
(s, 3H, CH3).13C NMR (100 MHz, CDCl3) δ 159.5, 156.1, 152.1,
149.2, 148.7, 147.3, 140.7, 134.4, 132.7, 131.6, 130.7, 130.7,
128.5, 127.1, 126.5, 126.4, 123.4, 123.0, 122.2, 121.0, 120.9,
120.7, 120.6, 120.4, 119.9, 119.4, 114.2, 110.4, 110.0, 56.0, 55.9,
18.7. HRMS (ESI+) m/z 514.2314 [M+H]+, calcd for C32H28N5O2:
514.2243.
Acknowledgments
We thank MESRS (Ministry of Superior Education and Scientific
Research), Algeria, for financial support.
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