Tetrahedron 73 (2017) 351e358

Contents lists available at ScienceDirect

Tetrahedron
journal homepage: www.elsevier.com/locate/tet

Synthetic approach and functionalization of novel 4-anilinoquinolino-

quinazoline heterocyclic scaffolds
Chamseddine Derabli a, Raouf Boulcina a, b, *, Gilbert Kirsch c, Abdelmadjid Debache a
a
Laboratory of Synthesis of Molecules with Biological Interest, Fr
eres 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

a r t i c l e i n f o a b s t r a c t

Article history: An efficient and high yielding protocol is reported for the synthesis of new class of 4-anilinoquinolino-
Received 7 October 2016 quinazoline hybrids. The target compounds were prepared first by the reaction of 2-aminobenzamide
Received in revised form with 2-chloroquinoline-3-carbaldehydes. After oxidation and chlorination, the key 2-quinolyl-4-
20 November 2016
chloroquinazolines were converted to the corresponding 2-(2-arylaminoquinolyl)-4-
Accepted 6 December 2016
Available online 9 December 2016
arylaminoquinazolines and N-heteroaryl-2-(2-(heteroarylamino)quinolin-3-yl)quinazolin-4-amines.
© 2016 Elsevier Ltd. All rights reserved.
Keywords:
Quinazoline derivatives
4-Anilinoquinazolines
Quinolino-quinazoline hybrids
SNAr reaction

1. Introduction as substituent have never been described before. To study this re-
action, we decided to construct 4-chloroquinazoline (5), which
Over the last decade, the design of six-membered heterocycles, could be used as a starting material for this purpose. In this paper,
such as quinazolines has caught the attention of synthetic chemists we describe for the first time the synthesis of 2-(2-
due to their immense biological and pharmacological potency. The arylaminoquinolyl)-4-arylaminoquinazolines (6), N-heteroaryl-2-
quinazoline moiety is present in natural products and synthetic (2-(heteroarylamino)quinolin-3-yl)quinazolin-4-amines (7) and its
pharmaceutical compounds.1 Quinazoline derivatives has been derivatives based on a simple and efficient route.
extensively studied for their many pharmacological properties.2
The growing importance of quinazolines in medicine is high-
2. Results and discussion
lighted by the huge sales of the drugs Erlotinib, which is used in the
treatment of several types tumors,3 and Prazosin, an a-adrenergic
We wished to synthesize the starting materials 5a-b from
blocker.4 Likewise, Iressa, an epidermal growth factor receptor in-
commercially available products. In fact, 2-aminobenzamide and
hibitor, was recently approved by the U.S. Food and Drug Admin-
some quinoline carboxaldehydes were used to obtain original
istration for the treatment of lung cancer5 (Fig. 1). Consequently,
quinolino-quinazoline heterocycles. We therefore conducted this
the development of such quinazoline-based drugs has renewed the
reaction by heating at 80e90
C, a mixture of 2-aminobenzamide 1
interest in developing new and diversified synthetic strategies for
with different substituted quinoline carboxaldehydes 2. Indeed,
the synthesis of quinazoline derivatives.6
treatment of this mixture with K2CO3 in the presence of iodine did
As a complement to our previous work on the synthesis of
not give directly in one step the oxidized compounds 4a-b. Despite
dihydroquinazolines,7 a safe, efficient, and universal pathway to
numerous attempts, we have not been able to isolate these prod-
synthesize other functionalized class of this heterocycle is highly
ucts in abundant quantities. The reaction of 2-aminobenzamide
demanded. In literature, 4-aminoquinazolines with the quinoline
with 2-chloroquinolin-3-carbaldehydes in the presence of K2CO3
only furnished intermediates 3a-b (Scheme 1).
* Corresponding author. Laboratory of Synthesis of Molecules with Biological
We then extended the same method to different quinoline
res Mentouri-Constantine University, 25000 Constantine, Algeria.
Interest, Fre carboxaldehydes, allowing the synthesis of products 3a-e with
E-mail address: r.boulcina@univ-batna2.dz (R. Boulcina). good yields (see Scheme 2 and Table 1).

http://dx.doi.org/10.1016/j.tet.2016.12.009
0040-4020/© 2016 Elsevier Ltd. All rights reserved.
352 C. Derabli et al. / Tetrahedron 73 (2017) 351e358

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 80e90
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 pre-
cursors 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 a
yield of 76%. We subsequently applied this method for compound
4b using the same conditions (Scheme 3). The obtained results are
collated in Table 2.

Fig. 1. Popular drugs containing the quinazoline scaffold.

Scheme 3. Synthesis of 2-(2-Chloroquinolinyl)quinazolin-4(3H)-ones 4a-b and 4-

Chloro-2-(2-chloro-quinolinyl)quinazolines 5a-b.

Functionalization of the quinazoline ring in position 4 with a

Scheme 1. Obtimized conditions
dihydroquinazolin-4(1H)-ones 3a-b.
Scheme 2. Synthesis of 2-(quinolinyl)-2,3-dihydroquinazolin-4(1H)-ones 3a-e.
Table 1
Reaction of 2-aminobenzamide with different quinoline carboxaldehydes.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-
for the synthesis of 2-(quinolinyl)-2,3-
chloroquinazolines 5a-b.
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 ach-
ieve 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

Table 2
Oxidation and chlorination of 2-(quinolinyl)-2,3-dihydro quinazolin-4(1H)-ones 3a-
b.a
 C. Derabli et al. / Tetrahedron 73 (2017) 351e358 353

Table 3
Synthesis of N-(4-heteroaryl)-2-(2-chloroquinolin-3-yl)quinazolin-4-amines.a

Scheme 4. Reaction conditions: (a): i-PrOH, reflux, (b): DMF, 80e90
C.

mixture of 2 compounds: mono and disubstituted derivatives (6a

and 7a respectively) after 60 min. An attempt in DMF at 80e90
C
gave the same result (Scheme 4).
However, when the reaction was run in DMF at room temper-
ature during 24 h, 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.
The use of these catalysts led to completely different results.
Indeed, a catalytic amount of HCl (1N) resulted in the total con-
sumption of the starting material and formation of the desired
product 6a after 3 h at room temperature. However, the use of an
equivalent of K2CO3 has no effect on this transformation even after
24 h by giving almost similar results to those obtained without the
use of catalyst. Under these conditions, we synthesized a series of
quinolino-quinazolines 6a-l with yields ranging from 48 to 75%
(Table 3).
On the other hand, the reaction was carried out with 2 equiva-
lents 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.
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 ob-
tained in the majority of cases with good yields.
The structures of all compounds were easily established with 1H
and 13C NMR data. The exact structure of compound 7h was
determined according to both HSQC and HMBC 2D NMR
experiments.

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-(hetero-
arylamino)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.

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-
354 C. Derabli et al. / Tetrahedron 73 (2017) 351e358

Table 4 CDCl3 or DMSO-d6. Chemical shifts (d) are given in part per million
Synthesis of N- heteroaryl-2-(2-(heteroarylamino)quinolin-3-yl)quinazolin-4- downfield from TMS as an internal standard and J values in Hz. The
amines.a
chemicals were used as obtained commercially. High Resolution
Mass spectra were recorded with a MicroTof-Q 98. Elemental ana-
lyses were carried out on a Microanalyzer Flash EA1112 CHNS/O
Thermo Electron.

4.2. General procedure I for the preparation of compounds (3a-e)

In a 100 mL flask were introduced 5 mmol (0.68 g) of 2-

aminobenzamide and 5 mmol of the corresponding quinoline car-
boxaldehyde derivative with 5 mmol (0.69 g) of K2CO3 in 20 mL
DMF. The reaction medium was heated at 80
C for 3 h (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.

4.2.1. 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) n 3410, 3198, 2932,
2854, 2152, 1652, 1608, 1497, 1385, 1122, 1034, 972, 740 cm1. 1H
NMR (400 MHz, DMSO-d6) d 8.59 (s, 1H), 8.20 (br s, 1H), 8.04 (td,
J ¼ 7.6, 1.2 Hz, 1H), 8.00 (d, J ¼ 1.2 Hz, 1H), 7.70 (d, J ¼ 7.6, 1H), 7.60
(d, J ¼ 8.4 Hz, 1H), 7.42 (td, J ¼ 7.6, 1.2 Hz, 1H), 7.21 (td, J ¼ 7.6, 1.2 Hz,
1H), 6.90 (s, 1H), 6.76 (d, J ¼ 8.4 Hz, 1H), 6.70 (t, J ¼ 7.2 Hz, 1H), 6.24
(br s, 1H).13C NMR (100 MHz, DMSO-d6) d 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, 63.8. HRMS (ESIþ) m/z 350.0431 [MþK]þ, calcd for
C17H3712ClKN3O: 350.0276.

4.2.2. 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) n 3415, 3194, 2933,
2857, 2150, 1655, 1605, 1493, 1384, 1120, 1036, 975, 745 cm1. 1H
NMR (250 MHz, DMSO-d6) d 8.39 (s, 1H), 7.96 (br s, 1H), 7.75e7.71
(m, 1H), 7.65 (d, J ¼ 8.0 Hz, 1H), 7.55 (d, J ¼ 7.0 Hz, 1H), 7.41 (t,
J ¼ 8.0 Hz, 1H), 7.20 (td, J ¼ 7.0, 1.5 Hz, 1H), 6.81e6.67 (m, 2H), 6.60
(s, 1H), 6.25 (br s, 1H), 2.66 (s, 3H, CH3); 13C NMR (62.5 MHz, DMSO-
d6) d 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.

4.2.3. 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) n 3422, 3184,
2938, 2860, 2155, 1657, 1618, 1487, 1390, 1123, 1039, 972, 737 cm1.
NMR (400 MHz, DMSO-d6) d 8.55 (s, 1H), 8.34 (br s, 1H), 7,89 (d,
J ¼ 9.2 Hz, 1H), 7.70 (dd, J ¼ 7.6, 1.6 Hz, 1H), 7.57 (d, J ¼ 2.8 Hz,
1H),7.48 (dd, J ¼ 9.2, 2.8 Hz, 1H), 7.29 (td, J ¼ 7.6, 1.6 Hz, 1H), 7.16 (s,
1H), 6.79 (d, J ¼ 8.0 Hz, 1H), 6.76 (td, J ¼ 8.0, 1.6 Hz, 1H), 6.22 (br s,
1H), 3.89 (s, 3H, OCH3).13C NMR (100 MHz, DMSO-d6) d 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 (ESIþ) m/z 362.0629 [MþNa]þ, calcd
for C18H35
14 ClN3NaO2: 362.0672.

4.2.4. 2-(2,7-Dichloroquinolin-3-yl)-2,3-dihydroquinazolin-4(1H)-
one (3d)
IR 8201 spectrometer, only significant absorption band frequencies
Following general procedure I, compound 3d was obtained as a
are cited. 1H and 13C NMR spectra were recorded on a Bruker
white solid (1.46 g, 85%). M.p.:>260
C. IR (KBr) n 3435, 3194, 2942,
Avance 400 instrument at 400 and 100 MHz respectively and
2863, 2162, 1665, 1609, 1492, 1391, 1124, 1043, 974, 739, 605 cm1.
Brüker advance DPX 250 (250 MHz for the 1H, 62.5 for the 13C), in
NMR (250 MHz, DMSO-d6) d 8.39 (s, 1H), 8.23 (d, J ¼ 8.8 Hz, 1H), 8.11
 C. Derabli et al. / Tetrahedron 73 (2017) 351e358
(d, J ¼ 1.9 Hz, 1H), 7.76e7.70 (m, 2H), 7.32 (td, J ¼ 8.5, 1.5 Hz, 1H),
7.20 (s, 1H), 6.83e6.75 (m, 2H), 6.27 (s, 1H). 13C NMR (62.5 MHz,
DMSO-d6) d 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 (ESIþ) m/z
366.0155 [MþNa]þ, calcd for C17H35 11 Cl2N3NaO: 366.0177.
4.2.5. 2-(Quinolin-4-yl)-2,3-dihydroquinazolin-4(1H)-one (3e)
Following general procedure I, compound 3e was obtained as a
white solid (1.07 g, 78%). M.p.:>260
C. IR (KBr) n 3437, 3196, 2939,
2853, 2156, 1655, 1604, 1487, 1389, 1125, 1035, 979 cm1. 1H NMR
(400 MHz, DMSO-d6) d 8.94 (d, J ¼ 4.4 Hz, 1H), 8.54 (d, J ¼ 8.0 Hz,
1H), 8.42 (br s, 1H), 8.10 (dd, J ¼ 8.0, 0.8 Hz, 1H) 7.81 (td, J ¼ 8.0,
1.6 Hz, 1H), 7.72e766 (m, 2H), 7.63 (d, J ¼ 4.4 Hz, 1H), 7.28 (td,
J ¼ 8.0, 1.6 Hz, 1H), 7.21 (s, 1H), 6.77e6.73 (m, 2H), 6.59 (br s, 1H). 13C
NMR (100 MHz, DMSO-d6) d 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 (ESIþ) m/z 276.1114 [MþH]þ, calcd for C17H14N3O: 276.1137.
4.3. General procedure II for the preparation of compounds (4a-b)
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 80e90
C for 6 h
(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 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.
4.3.1. 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) n 3437, 3024, 2353,
1670, 1605, 1473, 1392, 1342, 1242, 1119, 1010, 883, 759, 675,
613 cm1. 1H NMR (400 MHz, DMSO-d6) d 12.68 (br s, 1H), 8.83 (s,
1H), 8.23 (dd, J ¼ 8.0, 0.8 Hz, 1H), 8.16 (d, J ¼ 8.0, 1H), 8.08 (d,
J ¼ 8.4 Hz, 1H), 7.95 (td, J ¼ 8.4, 1.2 Hz, 1H), 7.29 (td, J ¼ 8.4, 1.6 Hz,
1H), 7.77 (t, J ¼ 8.0 Hz, 2H), 7.61 (td, J ¼ 8.0, 0.8 Hz, 1H).13C NMR
(100 MHz, DMSO-d6) d 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 (ESIþ) m/z 308.0598 [MþH]þ, calcd for C17H35 11 ClN3O:
308.0591.
4.3.2. 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) n 3438, 3166, 3028,
2358, 1675, 1607, 1477, 1396, 1349, 1246, 1125, 1016, 889, 764,
679 cm1. 1H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1H), 8.78 (s,
1H), 8.21 (dd, J ¼ 8.0, 1.2 Hz, 1H), 7.98 (d, J ¼ 8.4, 1H), 7.87 (td, J ¼ 8.4,
1.6 Hz, 1H), 7.80 (d, J ¼ 7.6 Hz, 1H), 7.75 (d, J ¼ 7.6 Hz, 1H), 7.64 (t,
J ¼ 8.0 Hz, 1H), 7.59 (td, J ¼ 8.0, 1.2 Hz, 1H), 2.73 (s, 3H, CH3).13C NMR
(100 MHz, DMSO-d6) d 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 (ESIþ) m/z 322.0744 [MþH]þ, calcd for C18H35 13 ClN3O:
322.0747.
4.4. General procedure III for the preparation of compounds (5a-b)
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 ammo-
nium hydroxide. The obtained precipitate was isolated by vacuum
filtration, rinsed twice with 50 mL of water. The solid was dried at
355
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.
4.4.1. 4-Chloro-2-(2-chloroquinolin-3-yl)quinazoline (5a)
Following general procedure III, compound 5a was obtained as a
pale yellow solid (2.47 g, 76%); m.p.: 172e174
C; IR (KBr) n 3448,
3066, 2927, 2357, 1608, 1562, 1477, 1396, 1380, 1319, 1126, 999, 845,
760 cm1. 1H NMR (400 MHz, CDCl3) d 8.66 (s, 1H), 8.29 (dd, J ¼ 8.4,
0.8 Hz, 1H), 8.11 (d, J ¼ 8.4, 1H), 8.03 (d, J ¼ 8.4 Hz, 1H), 7.97 (td,
J ¼ 8.4, 1.2 Hz, 1H), 7.87 (d, J ¼ 8.0 Hz, 1H), 7.74 (m, 2H), 7.55 (td,
J ¼ 8.0, 0.8 Hz, 1H).13C NMR (100 MHz, CDCl3) d 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 (ESIþ) m/z 326.0257 [MþH]þ, calcd for
C17H3510 Cl2N3: 326.0252.
4.4.2. 4-Chloro-2-(2-chloro-8-methylquinolin-3-yl)quinazoline
(5b)
Following general procedure III, compound 5b was obtained as a
pale yellow solid (2.47 g, 73%); m.p.: 132e134
C; IR (KBr) n 3450,
3068, 2929, 2520, 2367, 1611, 1564, 1479, 1396, 1382, 1319, 1131,
1005, 849, 756 cm1. 1H NMR (400 MHz, CDCl3) d 8.61 (s, 1H), 8.29
(dd, J ¼ 8.0, 0.8 Hz, 1H), 8.11 (d, J ¼ 8.4, 1H), 7.96 (d, J ¼ 8.4, 1.2 Hz,
1H), 7.79e7.69 (m, 2H), 7.57 (d, J ¼ 7.6 Hz, 1H), 7.42 (t, J ¼ 7.6 Hz, 1H),
2.74 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) d 162.4, 159.4, 151.4,
147.3, 146.9, 141.2, 136.7, 135.3, 131.6, 130.5, 129.3, 129.1, 127.2, 126.1,
125.9, 122.4, 17.8. HRMS (ESIþ) m/z 340.0418 [MþH]þ, calcd for
C18H35
12 Cl2N3: 340.0408.
4.5. General procedure IV for the preparation of compounds (6a-l)
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 dis-
solved 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 h 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).
4.5.1. 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.: 242e244
C. IR (KBr) n 3435, 2934,
2859, 2057, 1623, 1556, 1506, 1369, 1294, 1142, 1030, 745 cm1. 1H
NMR (400 MHz, CDCl3) d 8.39 (s, 1H), 7.98e7.81 (s, 4H), 7.77 (d,
J ¼ 7.2 Hz, 1H), 7.72 (d, J ¼ 8.4, 1H), 7.62 (d, J ¼ 7.6 Hz, 1H), 7.50 (t,
J ¼ 8.0 Hz, 3H), 7.31 (t, J ¼ 8.0 Hz, 2H), 7.15 (d, J ¼ 7.2 Hz, 1H), 7.06 (t,
J ¼ 7.2 Hz, 1H).13C NMR (400 MHz, CDCl3) d 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 (ESIþ) m/z 383.1055[MþH]þ, calcd for
C23H3516 ClN4: 383.1063.
4.5.2. 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.: 192e194
C. IR (KBr) n 3433, 2924,
2854, 2052, 1627, 1566, 1516, 1365, 1292, 1149, 1029, 744 cm1. 1H
NMR (400 MHz, CDCl3) d 8.59 (s, 1H), 8.25 (d, J ¼ 8.0 Hz, 1H), 8.07 (t,
J ¼ 7.2 Hz, 1H), 7.96 (d, J ¼ 8.4 Hz, 1H), 7.92e7.86 (m, 2H), 7.77 (td,
J ¼ 8.4, 1.2 Hz, 1H), 7.66 (td, J ¼ 8.0, 1.2 Hz, 1H), 7.60 (td, J ¼ 8.0,
1.2 Hz, 1H), 7.48 (m, 1H), 7.32e7.27 (m, 2H), 7.15 (td, J ¼ 8.4, 1.2 Hz,
356 C. Derabli et al. / Tetrahedron 73 (2017) 351e358
1H) 2.45 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) d 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 (ESIþ)
m/z 397.1220 [MþH]þ, calcd for C24H35 18 ClN4: 397.1220.
4.5.3. N-(4-Chloro-2-methylphenyl)-2-(2-chloroquinolin-3-yl)
quinazolin-4-amine (6c)
Following general procedure IV, compound 6c was obtained as a
white solid (142 mg, 66%). M.p.: 224e226
C; IR (KBr) n 3456, 3045,
2932, 2342, 1607, 1565, 1526, 1345, 1252, 1149, 1039, 740, 659 cm1.
1
H NMR (400 MHz, CDCl3) d 8.59 (s, 1H), 8.20 (d, J ¼ 9.2 Hz, 1H), 8.09
(d, J ¼ 8.0 Hz, 1H), 8.07 (d, J ¼ 8.0 Hz, 1H), 7.96 (d, J ¼ 8.0, Hz, 1H),
7.94e7.89 (m, 2H), 7.79 (td, J ¼ 8.4, 1.2 Hz, 1H),7.68 (td, J ¼ 8.0,
1.2 Hz, 1H), 7.60 (td, J ¼ 8.0, 1.2 Hz, 1H), 7.39 (s, 1H), 7.28e7.26 (m,
3H), 2.43 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) d 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 (ESIþ) m/z
431.0841 [MþH]þ, calcd for C24H35 17 Cl2N4: 431.0830.
4.5.4. 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) n 3454, 3036,
2925, 2855, 2329, 1604, 1552, 1521, 1438, 1327, 943, 850, 741, 659,
601 cm1. 1H NMR (400 MHz, CDCl3) d 8.63 (s, 1H), 8.11 (d,
J ¼ 8.0 Hz, 1H), 8.07 (d, J ¼ 8.4 Hz, 1H), 7.99 (d, J ¼ 8.0 Hz, 1H),
7.93e7.89 (m, 2H), 7.83 (dd, J ¼ 8.8, 2.8 Hz, 2H), 7.80 (td, J ¼ 8.4,
1.2 Hz, 1H), 7.67 (td, J ¼ 8.0, 1.2 Hz, 1H), 7.65 (s, 1H), 7.61 (td, J ¼ 8.0,
1.2 Hz, 1H), 7.52 (dd, J ¼ 8.8, 2.8 Hz, 2H).13C NMR (100 MHz, CDCl3)
d 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
(ESIþ) m/z 463.0159 [MþH]þ, calcd for C23H81 35
15 Br ClN4 or
C23H79
15 Br37
ClN4 : 463.0148.
4.5.5. N-(4-Bromo-2-fluorophenyl)-2-(2-chloroquinolin-3-yl)
quinazolin-4-amine (6e)
Following general procedure IV, compound 6e was obtained as a
white solid (160 mg, 67%). M.p.: 226e228
C; IR (KBr) n 3441, 3066,
2924, 2858, 2357, 1624, 1562, 1523, 1408, 1327, 1122, 1022, 933, 860,
748, 663 cm1. 1H NMR (400 MHz, CDCl3) d 8.89 (t, J ¼ 8.4 Hz, 1H),
8.66 (s, 1H), 8.12 (d, J ¼ 8.4 Hz, 1H), 8.09 (d, J ¼ 8.0 Hz, 1H), 8.00 (d,
J ¼ 8.0 Hz, 1H), 7.96e7.89 (s, 2H), 7.84e7.80 (s, 2H), 7.71 (td, J ¼ 8.0,
1.2 Hz, 1H), 7.63 (td, J ¼ 8.0, 1.2 Hz, 1H), 7.39e7.34 (m, 2H).13C NMR
(100 MHz, CDCl3) d 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 (ESIþ) m/z 502.9890
[MþNa]þ, calcd for C23H81 35 79 37
13 Br ClFNaN4 or C23H13 Br ClFNaN4:
502.9873.
4.5.6. 2-(2-Chloroquinolin-3-yl)-N-(3,5-dichlorophenyl)
quinazolin-4-amine (6f)
Following general procedure IV, compound 6f was obtained as a
white solid (119 mg, 53%). M.p.:>250
C. IR (KBr) n 3443, 2944,
2545, 2355, 1604, 1571, 1525, 1435, 1392, 1315, 1117, 1018, 925, 825,
767 cm1. 1H NMR (400 MHz, DMSO-d6) d 10.18 (s, 1H), 8.86 (s, 1H),
8.63 (d, J ¼ 8.0 Hz, 1H), 8.21 (d, J ¼ 3.2 Hz, 2H), 8.17 (d, J ¼ 7.6 Hz,
1H), 8.06 (d, J ¼ 7.6 Hz, 1H), 8.00e7.96 (m, 2H), 7.91 (td, J ¼ 7.6,
1.2 Hz, 1H), 7.78 (td, J ¼ 8.4, 2.4 Hz, 1H), 7.73 (td, J ¼ 8.0, 1.2 Hz, 1H),
7.30 (t, J ¼ 2.0 Hz, 1H).13C NMR (100 MHz, DMSO-d6) d 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 (ESIþ) m/z
451.0302 [MþH]þ, calcd for C23H35 14 Cl3N4: 451.0284.
4.5.7. 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.: 222e224
C. IR (KBr) n 3431, 2924,
2858, 2067, 1613, 1565, 1526, 1343, 1246, 1145, 1045, 752 cm1. 1H
NMR (400 MHz, CDCl3) d 8.59 (s, 1H), 8.06 (d, J ¼ 8.0 Hz, 1H), 7.99 (d,
J ¼ 8.0, 1H), 7.94 (d, J ¼ 7.6 Hz, 2H), 7.90 (td, J ¼ 8.0, 0.8 Hz, 1H), 7.74
(t, J ¼ 8.0 Hz, 1H), 7.68e7.62 (m, 3H), 7.48 (t, J ¼ 7.6 Hz, 1H), 7.42 (t,
J ¼ 8.0 Hz, 2H), 7.17 (t, J ¼ 7.6 Hz, 1H), 2.85 (s, 3H, CH3).13C NMR
(400 MHz, CDCl3) d 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 (ESIþ) m/z 397.1235 [MþH]þ, calcd for C24H35 18 ClN4: 397.1220.
4.5.8. 2-(2-Chloro-8-methylquinolin-3-yl)-N-(o-tolyl)quinazolin-4-
amine (6h)
Following general procedure IV, compound 6h was obtained as a
white solid (148 mg, 72%). M.p.: 210e212
C. IR (KBr) n 3460, 3035,
2927, 2854, 2329, 1604, 1562, 1524, 1458, 1365, 1245, 1149, 1041,
941, 741, 659 cm1.1H NMR (400 MHz, CDCl3) d 8.56 (s, 1H), 8.26 (d,
J ¼ 7.6 Hz, 1H), 8.07 (d, J ¼ 8.4 Hz, 1H), 7.95 (d, J ¼ 8.4 Hz, 1H), 7.90
(td, J ¼ 8.4, 1.2 Hz, 2H), 7.72 (d, J ¼ 8.0 Hz, 1H), 7.65 (td, J ¼ 8.0,
0.8 Hz, 1H), 7.65 (d, J ¼ 6.8 Hz, 1H), 7.47 (t, J ¼ 8.0 Hz, 2H), 7.33e7.27
(m, 2H), 7.15 (t, J ¼ 8.4, 0.8 Hz, 2H), 2.83 (s, 3H, CH3), 2.46 (s, 3H,
CH3).13C NMR (100 MHz, CDCl3) d 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 (ESIþ) m/z 411.1471
[MþH]þ, calcd for C25H35 20ClN4: 411.1376.
4.5.9. N-(4-Chloro-2-methylphenyl)-2-(2-chloro-8-
methylquinolin-3-yl)quinazolin-4-amine (6i)
Following general procedure IV, compound 6i was obtained as a
white solid (142 mg, 64%). M.p.: 234e236
C. IR (KBr) n 3446, 3042,
2935, 2352, 1609, 1558, 1521, 1334, 1265, 1152, 1040, 747, 659 cm1.
1
H NMR (400 MHz, CDCl3) d 8.55 (s, 1H,) 8.21 (d, J ¼ 8.4 Hz, 1H), 8.08
(d, J ¼ 8.0 Hz, 1H), 7.95 (d, J ¼ 8.0 Hz, 1H), 7.91 (t, J ¼ 8.0, Hz, 1H), 7.72
(d, J ¼ 8.0 Hz, 1H), 7.67 (td, J ¼ 8.0, 0.8 Hz, 1H), 7.65 (d, J ¼ 6.8 Hz,
1H), 7.48 (t, J ¼ 7.6 Hz, 1H), 7.38 (d, J ¼ 7.6 Hz, 1H), 7.28e7.26 (m,
2H,) 2.83 (s, 3H, CH3), 2.42 (s, 3H, CH3).13C NMR (100 MHz, CDCl3)
d 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 (ESIþ) m/z 445.1067 [MþH]þ, calcd for
C25H3519 Cl2N4: 445.0987.
4.5.10. N-(4-Bromophenyl)-2-(2-chloro-8-methylquinolin-3-yl)
quinazolin-4-amine (6j)
Following general procedure IV, compound 6j was obtained as a
white solid (170 mg, 72%). M.p.: 230e232
C. IR (KBr) n 3414, 3027,
2945, 2845, 2369, 1601, 1548, 1519, 1433, 1322, 936, 854, 749, 657,
608 cm1. 1H NMR (400 MHz, CDCl3) d 8.59 (s, 1H), 8.07 (d,
J ¼ 7.6 Hz, 1H), 7.98 (d, J ¼ 8.0 Hz, 1H), 7.91 (td, J ¼ 8.4, 1.2 Hz, 1H),
7.85 (dd, J ¼ 8.0, 2.8 Hz, 2H), 7.74 (d, J ¼ 8.0 Hz, 1H),7.68 (d, J ¼ 8.0,
1.2 Hz, 1H), 7.43 (d, J ¼ 8.0, 1.2 Hz, 1H), 7.59 (s, 1H) 7.53 (dd, J ¼ 8.0,
2.8 Hz, 2H), 7.48 (d, J ¼ 7.2 Hz, 1H).13C NMR (100 MHz, CDCl3)
d 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 (ESIþ) m/z 477.0389 [MþH]þ, calcd for C24H81 35
17 Br ClN4
or C24H79 37
17 Br ClN4: 477.0305.
4.5.11. 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.: 240e242
C. IR (KBr) n 3461, 3036,
2928, 2855, 2327, 1611, 1565, 1524, 1418, 1330, 1142, 1032, 943, 852,
741, 653, 602 cm1. 1H NMR (400 MHz, CDCl3) d 8.93 (t, J ¼ 8.8 Hz,
1H), 8.62 (s, 1H), 8.10 (d, J ¼ 8.4 Hz, 1H), 8.00 (d, J ¼ 8.0 Hz, 1H), 7.94
 C. Derabli et al. / Tetrahedron 73 (2017) 351e358
(td, J ¼ 8.0, 1.2 Hz, 2H), 7.82 (s, 1H), 7.77 (d, J ¼ 8.0 Hz, 1H), 7.71 (td,
J ¼ 8.0, 1.2 Hz, 1H), 7.65 (d, J ¼ 7.2 Hz, 1H), 7.51 (t, J ¼ 7.6 Hz, 1H),
7.40e7.36 (m, 2H), 2.87 (s, 3H, CH3).13C NMR (100 MHz, CDCl3)
d 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 (ESIþ) m/z 495.0275 [MþH]þ, calcd for
C24H1681 35
Br ClFN4 or C24H79 37
16 Br ClFN4: 495.0210.
4.5.12. 2-(2-Chloro-8-methylquinolin-3-yl)-N-(3,5-dichlorophenyl)
quinazolin-4-amine (6l)
Following general procedure IV, compound 6l was obtained as a
white solid (111 mg, 48%). M.p.: 224e226
C. IR (KBr) n 3383, 2939,
2357, 1624, 1581, 1520, 1431, 1389, 1311, 1107, 1014, 921, 768 cm1. 1H
NMR (400 MHz, CDCl3) d 8.58 (s, 1H), 8.00 (d, J ¼ 8.0 Hz, 1H),
7.88e7.82 (m, 4H), 7.67 (d, J ¼ 8.0 Hz, 1H), 7.60 (td, J ¼ 8.0, 1.2 Hz,
1H), 7.54 (dd, J ¼ 7.2, 1.2 Hz, 1H), 7.49 (s, 1H), 7.40 (t, J ¼ 8.0 Hz, 1H),
7.65 (t, J ¼ 2.0 Hz, 1H), 2.76 (s, 3H, CH3).13C NMR (100 MHz, CDCl3)
d 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,
17.8. HRMS (ESIþ) m/z 465.0354 [MþH]þ, calcd for C24H35 16 Cl3N4:
465.0441.
4.6. General procedure V for the preparation of compounds (7a-h)
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 dis-
solved 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).
4.6.1. N-Phenyl-2-(2-(phenylamino)quinolin-3-yl)quinazolin-4-
amine (7a)
Following general procedure V, compound 7a was obtained as a
yellow solid (184 mg, 84%). M.p.:>260
C. IR (KBr) n 3435, 2927,
2858, 2359, 1609, 1552, 1527, 1481, 1421, 1351, 1246, 1151, 949, 896,
754, 677, 605 cm1. 1H NMR (400 MHz, CDCl3) d 12.75 (s, 1H), 9.22
(s, 1H), 7.95 (d, J ¼ 8.4 Hz, 2H), 7.90 (d, J ¼ 8.4 Hz, 1H), 7.80 (d, J ¼ 8.0,
1H), 7.77e7.74 (m, 4H), 7.60 (d, J ¼ 8.0 Hz, 1H), 7.54 (t, J ¼ 8.0 Hz,
1H), 7.46 (t, J ¼ 8.0 Hz, 1H), 7.44e7.40 (m, 3H), 7.30 (t, J ¼ 8.0 Hz,
2H), 7.21e7.18 (m, 2H), 6.96 (t, J ¼ 7.2 Hz, 1H).13C NMR (100 MHz,
CDCl3) d 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 (ESIþ) m/z 440.1924
[MþH]þ, calcd for C29H22N5: 440.1875.
4.6.2. N-(o-Tolyl)-2-(2-(o-tolylamino)quinolin-3-yl)quinazolin-4-
amine (7b)
Following general procedure V, compound 7b was obtained as a
yellow solid (198 mg, 85%). M.p.: 202e204
C. IR (KBr) n 3432, 3047,
2359, 1577, 1513, 1446, 1403, 1335, 1250, 1153, 1047, 944, 892,
792 cm1. 1H NMR (400 MHz, CDCl3) d 12.10 (s, 1H), 9.23 (s, 1H),
8.62 (d, J ¼ 8.4 Hz, 1H), 8.03 (d, J ¼ 8.0 Hz, 2H), 7.94 (d, J ¼ 8.0, 1H),
7.88 (td, J ¼ 8.0, 1.2 Hz, 1H), 7.77 (d, J ¼ 8.4 Hz, 1H), 7.63 (t, J ¼ 8.4 Hz,
2H), 7.88 (td, J ¼ 8.4, 1.6 Hz, 1H), 7.42e7.23 (m, 6H), 7.05 (t,
J ¼ 7.2 Hz, 1H), 2.63 (s, 3H, CH3), 2.45 (s, 3H, CH3).13C NMR
(100 MHz, CDCl3) d 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,
357
119.2, 19.6, 18.2. HRMS (ESIþ) m/z 468.2176 [MþH]þ, calcd for
C31H26N5: 468.2188.
4.6.3. N-(2-Methoxyphenyl)-2-(2-((2-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.: 209e210
C. IR (KBr) n 3414, 2943,
1682, 1535, 1458, 1408, 1331, 1238, 1176, 1114, 1029, 945, 856, 790,
736, 660, 590 cm1. 1H NMR (400 MHz, CDCl3) d 12.90 (s, 1H), 9.41
(s, 1H), 9.32 (s, 1H), 8.96 (dd, J ¼ 7.2, 2.0 Hz, 1H), 8.41 (s, 1H), 8.13 (d,
J ¼ 8.4 Hz, 1H), 7.97 (d, J ¼ 8.4, 1H), 7.92e7.87 (m, 2H), 7.78 (d,
J ¼ 8.4 Hz, 1H), 7.67e7.62 (m, 2H), 7.31 (t, J ¼ 7.6 Hz, 1H), 7.22e7.12
(m, 3H), 7.07e7.03 (m, 3H), 4.07 (s, 3H, OCH3), 4.05 (s, 3H, OCH3).13C
NMR (100 MHz, CDCl3) d 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.
HRMS (ESIþ) m/z 500.2131 [MþH]þ, calcd for C31H26N5O2:
500.2087.
4.6.4. N-(p-Tolyl)-2-(2-(p-tolylamino)quinolin-3-yl)quinazolin-4-
amine (7d)
Following general procedure V, compound 7d was obtained as a
yellow solid (203 mg, 87%). M.p.:>260
C. IR (KBr) n 3437, 2947,
2355, 1607, 1563, 1486, 1412, 1345, 1249, 1142, 947, 899, 752 cm1.
1
H NMR (400 MHz, CDCl3) d 12.80 (s, 1H), 10.12 (s, 1H), 9.26 (s, 1H),
8.62 (d, J ¼ 8.0 Hz, 1H), 8.05 (d, J ¼ 8.0 Hz, 1H), 7.97 (t, J ¼ 7.6, 1H),
7.84e7.77 (m, 5H), 7.73e7.63 (m, 3H), 7.34 (d, J ¼ 8.0 Hz, 3H), 7.34
(d, J ¼ 8.4 Hz, 2H), 2.38 (s, 3H, CH3), 2.31 (s, 3H, CH3).13C NMR
(100 MHz, CDCl3) d 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 (ESIþ) m/z
468.2192 [MþH]þ, calcd for C31H26N5: 468.2188.
4.6.5. N-(4-Chloro-2-methylphenyl)-2-(2-((4-chloro-2-
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) n 3437, 3043,
2356, 1577, 1523, 1450, 1407, 1334, 1249, 1153, 1045, 941, 852, 790,
748, 659, 532 cm1. 1H NMR (400 MHz, CDCl3) d 12.05 (s, 1H), 9.18
(s, 1H), 8.59 (d, J ¼ 8.4 Hz, 1H), 8.01 (d, J ¼ 8.4 Hz, 1H), 7.92 (d,
J ¼ 8.0 Hz, 2H), 7.89 (td, J ¼ 8.4, 1.2 Hz, 1H), 7.77 (d, J ¼ 8.0 Hz, 1H),
7.67 (d, J ¼ 8.0 Hz, 1H), 7.65e7.59 (m, 2H), 7.36e7.26 (m, 6H), 2.58 (s,
3H, CH3), 2.41 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) d 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 (ESIþ) m/z 536.1473 [MþH]þ,
calcd for C31H24Cl2N5: 536.1409.
4.6.6. 2-(8-Methyl-2-(phenylamino)quinolin-3-yl)-N-
phenylquinazolin-4-amine (7f)
Following general procedure V, compound 7f was obtained as a
yellow solid (186 mg, 82%). M.p.: 226e228
C. IR (KBr) n 3433, 2923,
2356, 1604, 1562, 1523, 1488, 1411, 1342, 1245, 1149, 948, 894, 752,
675, 602 cm1. 1H NMR (400 MHz, CDCl3) d 12.93 (s, 1H), 9.42 (s,
1H), 8.14 (d, J ¼ 8.0 Hz, 2H), 8.05 (t, J ¼ 8.4 Hz, 1H), 7.91 (td, J ¼ 8.0,
1.2, 2H), 7.86 (d, J ¼ 8.0 Hz, 2H), 7.61 (td, J ¼ 8.0, 1.2 Hz, 2H),
7.55e7.52 (m, 4H), 7.42 (t, J ¼ 8.4 Hz, 2H), 7.31 (d, J ¼ 7.6 Hz, 1H),
7.21 (t, J ¼ 7.6 Hz, 1H), 7.05 (t, J ¼ 7.6 Hz, 1H), 2.81 (s, 3H, CH3).13C
NMR (100 MHz, CDCl3) d 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 (ESIþ)
m/z 454.2087 [MþH]þ, calcd for C30H24N5: 454.2032.
358 C. Derabli et al. / Tetrahedron 73 (2017) 351e358
4.6.7. 2-(8-Methyl-2-(o-tolylamino)quinolin-3-yl)-N-(o-tolyl)
quinazolin-4-amine (7g)
Following general procedure V, compound 7g was obtained as a
yellow solid (207 mg, 86%); M.p.: 194e196
C. IR (KBr) n 3423, 2937,
2858, 2357, 1610, 1568, 1528, 1490, 1415, 1347, 1255, 1142, 950, 895,
756, 672 cm1. 1H NMR (400 MHz, CDCl3) d 12.11 (s, 1H), 9.21 (s, 1H),
9.00 (d, J ¼ 7.6 Hz, 1H), 8.05 (t, J ¼ 7.6 Hz, 2H), 7.93 (d, J ¼ 7.6, 1H),
7.87 (dd, J ¼ 8.0, 1.2 Hz, 1H), 7.60 (dd, J ¼ 8.0, 1.2 Hz, 1H), 7.51e7.47
(m, 2H), 7.43e7.25 (m, 6H), 7.17 (t, J ¼ 7.2 Hz, 1H), 7.03 (t, J ¼ 7.2 Hz,
1H), 2.72 (s, 3H, CH3), 2.68 (s, 3H, CH3), 2.45 (s, 3H, CH3).13C NMR
(100 MHz, CDCl3) d 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 (ESIþ) m/z 482.2405 [MþH]þ,
calcd for C32H28N5: 482.2345.
4.6.8. N-(2-Methoxyphenyl)-2-(2-((2-methoxyphenyl)amino)-8-
methylquinolin-3-yl)quinazolin-4-amine (7h)
Following general procedure V, compound 7h was obtained as a
yellow solid (226 mg, 88%). M.p.: 192e194
C. IR (KBr) n 3413, 2945,
1681, 1538, 1462, 1407, 1330, 1292, 1234, 1174, 1117, 1030, 952, 858,
792, 739, 659, 592 cm1. 1H NMR (400 MHz, CDCl3) d 12.82 (s, 1H),
9.37 (d, J ¼ 7.6, 1.2 Hz, 1H), 9.19 (s, 1H), 8.81 (dd, J ¼ 7.2, 2.0 Hz, 1H),
8.17 (s, 1H), 7.93 (t, J ¼ 8.0 Hz, 1H), 7.70 (d, J ¼ 7.6, 1H), 7.67 (dd,
J ¼ 8.0, 1.2 Hz, 1H), 7.48 (d, J ¼ 7.6 Hz, 1H), 7.37 (m, 2H),7.10 (t,
J ¼ 7.6 Hz, 1H), 7.06e6.88 (m, 5H), 7.10 (dd, J ¼ 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) d 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 (ESIþ) m/z 514.2314 [MþH]þ, calcd for
C32H28N5O2: 514.2243.
Acknowledgments
We thank MESRS, Algeria, for financial support.
References
1. (a) Foster A, Coffrey HA, Morin MJ, Rastinejad F. Science. 1999;286:2507;
(b) Gundla R, Kazemi R, Sanam R, et al. J Med Chem. 2008;51:3367;
(c) Luth A, Lowe W. Eur J Med Chem. 2008;43:1478.
2. Khan I. Bioorg Med Chem. 2016;24:2361.
3. Seo HN, Choi JY, Choe YJ, et al. Bioorg Med Chem Lett. 2007;17:5740.
4. Gundla R, Kazemi R, Sanam R, et al. J Med Chem. 2008;51:3367.
5. (a) Mendes da Silva JF, Walters M, Al-Damluji S, Ganellin CR. Bioorg Med Chem.
2008;16:7254;
(b) Rewcastle GW, Palmer BD, Bridges AJ, Hollis Showalter HD, Sun L, Nelson J,
McMichael A, Kraker AJ, Fry DW, Denny WA. J Med Chem. 1996;39:918;
(c) Luth A, Lowe W. Eur J Med Chem. 2008;43:1478.
6. (a) Connolly DJ, Cusack D, O'Sullivan TP, Guiry PJ. Tetrahedron. 2005;61:10153;
(b) Besson T, Chosson E. Comb Chem High Throughput Screen. 2007;10:903;
(c) Michael JP. Nat Prod Rep. 2003;20:476;
(d) Undheim K, Benneche T. In Comprehensive Heterocyclic Chemistryvol. 6. Ox-
ford: Pergamon; 1998.
7. Derabli C, Boulcina R, Kirsch G, Carboni B, Debache A. Tetrahedron Lett. 2014;55:
200.
8. Juvale K, Wiese M. Bioorg Med Chem Lett. 2012;22:6766.
9. Fares M, Eldehna WM, Abou-Seri SM, Abdel-Aziz HA, Aly MH, Tolba MF. Arch
Pharm Chem Life Sci. 2015;348:144.