Efficient access to 2,6,8-trisubstituted 4-aminoquinazolines through microwave-assisted one-pot chemoselective Tris-Suzuki-Miyaura or SNAr/bis-Suzuki-Miyaura reactions in water

Article abstract of DOI:10.1002/ejoc.201500162

An efficient, sequential, one-pot strategy for synthesizing polyfunctionalized quinazoline derivatives is presented. After selective amination of 6,8-dibromo-2,4-dichloroquinazoline at the C-4 position, 2,6,8-trisubstituted 4-aminoquinazoline derivatives

Full text of DOI:10.1002/ejoc.201500162

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FULL PAPER
DOI: 10.1002/ejoc.201500162
Efficient Access to 2,6,8-Trisubstituted 4-Aminoquinazolines through
Microwave-Assisted One-Pot Chemoselective Tris-Suzuki–Miyaura or
SNAr/Bis-Suzuki–Miyaura Reactions in Water
Youssef Kabri,[a] Maxime D. Crozet,[a] Thierry Terme,[a] and Patrice Vanelle*[a]
Keywords: Synthetic methods / Microwave chemistry / Cross-coupling / Chemoselectivity / Regioselectivity / Palladium /
Nitrogen heterocycles
An efficient, sequential, one-pot strategy for synthesizing
polyfunctionalized quinazoline derivatives is presented.
After selective amination of 6,8-dibromo-2,4-dichloroquinaz-
Miyaura reactions under microwave irradiation in an aque-
ous medium. This approach, used with a variety of boronic
acids, affords polysubstituted quinazoline derivatives in good
oline at the C-4 position, 2,6,8-trisubstituted 4-aminoquinaz- to excellent yields in only a few steps and in the environmen-
oline derivatives were prepared through one-pot chemose- tally benign solvent water.
lective sequential tris-Suzuki–Miyaura or SNAr/bis-Suzuki–
ceva)[11] are known to act as selective inhibitors of the tyros-
Introduction
ine-kinase activity of the epidermal growth factor receptor
The Suzuki–Miyaura coupling reaction has proven to be
(EGFR). Taking our previous study of sequential polyfunc-
tionalization of 6,8-dibromo-2,4-dichloroquinazoline (4)[12]
one of the most reliable routes for C–C bond construction
since its discovery in 1979.[1] It has been applied widely in
a step further, we selectively introduced an amino group at
the synthesis of bioactive complex molecules thanks to its
the C-4 position of 4, keeping chloride at C-2, bromide at
mild reaction conditions and its compatibility with a broad
C-6, and C-8 as supplementary reactive centers for further
range of functional groups such as ester, nitrile, and
study. Herein, we report efficient access to 2,6,8-trisubsti-
amide.[2] In recent years, organic reactions using water[3] as
tuted 4-aminoquinazolines through microwave-assisted
a inexpensive, nontoxic, nonvolatile solvent, together with
consecutive one-pot chemoselective tris-Suzuki–Miyaura or
multistep sequences carried out in a single flask, such as
SNAr/bis-Suzuki–Miyaura cross-coupling reactions in
tandem, cascade, or sequential reactions, have received con-
water.
siderable attention in organic chemistry.[4] In this context
and in connection with our research program on the design
and synthesis of original molecules with pharmacological
properties,[5] the SNAr reaction was combined with the Su-
zuki–Miyaura cross-coupling reaction to perform one-pot
sequential polyfunctionalization of the quinazoline ring.
The quinazoline ring is a privileged motif that is present
in a wide range of natural products and bioactive molecules.
As a result, this versatile scaffold has been widely exploited
in medicinal chemistry, affording many highly substituted
quinazolines with a broad spectrum of biological proper-
ties, including antibacterial,[6] antiviral,[7] antitubercular,[8]
and anticancer[9] agents. Additionally, 4-aminoquinazoline
derivatives such as gefitinib (Iressa)[10] and erlotinib (Tar-
Results and Discussion
As described in our previous work,[12] the synthesis of 4
was achieved in 30% overall yield in four steps by using 2-
aminobenzonitrile as starting material, as shown in
Scheme 1. Bromination of 2-aminobenzonitrile with N-
[a] Aix-Marseille Université, Institut de Chimie Radicalaire ICR,
UMR CNRS 7273, Laboratoire de Pharmaco-Chimie
Radicalaire, Faculté de Pharmacie,
27 Boulevard Jean Moulin – CS 30064, 13385 Marseille Cedex
05, France
E-mail: patrice.vanelle@univ-amu.fr
http://icr-amu.cnrs.fr/spip.php?rubrique19
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500162.
Scheme 1. Synthesis of 6,8-dibromo-2,4-dichloroquinazoline (4).
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Y. Kabri, M. D. Crozet, T. Terme, P. Vanelle
FULL PAPER
bromosuccinimide (NBS) led to 2-amino-3,5-dibromo- cross-coupling Suzuki–Miyaura reaction and palladium-
benzonitrile 1 in 77% yield. Then, using an aqueous solu- catalyzed reduction of aromatic bromide (analyzed by LC-
tion of NaOH, the nitrile group was hydrolyzed to an acid MS). This result revealed that the reactivity of C-6-Br and
group, leading to compound 2 in 81% yield. Anthranilic C-8-Br bonds under Suzuki–Miyaura conditions is, respec-
acid 2 was converted into 6,8-dibromoquinazolin-2,4- tively, similar and superior to that of the C-2-Cl bond.
(1H,3H)-dione (3) in good yield (76%) by using urea and Decreasing the temperature to 90 °C allowed 7a to be ob-
cesium carbonate in N,N-dimethylformamide (DMF). In tained in somewhat higher yield (77%) and limited the for-
the last step, intermediate 3 was chlorinated in the presence mation of 8 and 9 (Table 1, entry 2). Varying the solvent,
of phosphorus oxychloride and diisopropylethylamine, for instance using dioxane/EtOH (9:1) and DMF/EtOH
leading to substrate 4 in 63% yield.
(9:1) did not improve the product yield of 7a (Table 2, en-
Our study began with the SNAr regio- and chemoselec- tries 3–4). Interestingly, the use of an H2O/EtOH mixture
tive reaction between 4 and 3-chloroaniline (1.1 equiv.) in a (9:1) as solvent in the presence of tetra-N-butylammonium
mixture of CH2Cl2/EtOH (2:1) at room temperature bromide (TBAB) as phase-transfer reagent at 90 °C for
(Table 1, entry 1). These conditions were previously found 1.5 h afforded 7a in 82% isolated yield and no traces of
to be effective in the SNAr reaction with 4-chloroquinaz- mixture 9. Trials with different catalysts revealed that bis-
oline derivatives.[13] Complete conversion of the reaction (triphenylphosphine) palladium(II) dichloride performed
(monitoring by LC-MS) was achieved within 1 h, and the best in our reaction conditions (Table 2, entries 6–11). Note
expected 4-aminoquinazoline derivative 5a was isolated in that with Pd(OAc)2/PPh3 and Pd(dba)2, the reaction was
70% yield. In addition to the desired compound, the disub- not complete and starting material was observed (entries 10
stituted quinazoline derivative 6 was obtained in 20% yield and 11); there was no reaction with Pd(PPh3)4 in water, and
(Scheme 2). Decreasing the temperature to 0 °C limited the only starting material was recovered (entry 7).
formation of 6 (Table 1, entry 2); however, using potassium
The scope and limitations of this bis-Suzuki–Miyaura
acetate (1.3 equiv.) in a mixture of tetrahydrofuran (THF) chemoselective reaction were then investigated by using the
and water (2:1) at room temperature[14] gave compound 5a optimized procedure; namely PdCl2(PPh3)2 (5 mol-%),
in excellent yield and complete selectivity for the C-4 posi- TBAB (1 equiv.), K2CO3 (6 equiv.) in H2O/EtOH (9:1) un-
tion (entry 3). The same result was obtained with dieth- der microwave irradiation at 90 °C for 1.5 h using (hetero)-
ylamine but the reaction took longer (entry 4).
arylboronic acids (Table 3).
To overcome the problem of solubility, we decided to use
As first observations, good to high yields of 6,8-disubsti-
5b as starting material for our study. Our investigation be- tuted 4-aminoquinazoline derivatives were obtained with a
gan with the bis-Suzuki–Miyaura chemoselective reaction wide range of aryl and heteroarylboronic acids bearing an
at the C-6 and C-8 positions between 5b and (4-meth- electron-donating or an electron-withdrawing group (entries
oxyphenyl)boronic acid under similar experimental condi- 1–8). However, with heteroarylboronic acid and boronic
tions to those described recently.[12] When the reaction was acids bearing an electron-withdrawing group, the reactions
performed in the presence of 4-methoxyphenyl boronic acid were achieved, respectively, after 1.5 h at 105 °C (entry 8)
(2.05 equiv.), K2CO3, and PdCl2(PPh3)2 in a 1,2-dimethoxy- and 2 h at 95 °C (entries 6 and 7).
ethane (DME)/EtOH mixture (9:1) at 100 °C under micro-
After optimization of the bis-Suzuki–Miyaura chemose-
wave irradiation (Table 2, entry 1), we obtained 61% yield lective reaction, we then investigated the one-pot, chemose-
of dicoupled product 7a, 10% yield of tricoupled product lective tris-Suzuki–Miyaura reaction of 6,8-dibromo-2-
8, and 19% yield of mixture 9 as a result of both the mono chloro-N,N-diethylquinazolin-4-amine (5b). One-pot, multi-
Table 1. Study of the SNAr regio- and chemoselective reaction at the 4-position of 4.
Entry
Condition
Amine
Yield 5 (%)
Yield 6 (%)
1
2
3
4
CH2Cl2/EtOH (2:1), r.t., 1 h
CH2Cl2/EtOH (2:1), 0 °C, 8 h
THF/H2O (2:1), CH3COOK (1.3 equiv.), r.t., 4 h
THF/H2O (2:1), CH3COOK (1.3 equiv.), r.t., 24 h
3-chloroaniline
3-chloroaniline
3-chloroaniline
diethylamine
5a (70)
5a (82)
5a (93)
5b (91)
20
10
0
0
Scheme 2. SNAr regio- and chemoselective reaction at the 4-position of 4.
2
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2,6,8-Trisubstituted 4-Aminoquinazolines
Table 2. Optimization of bis-Suzuki–Miyaura chemoselective reaction of 5b with (4-methoxyphenyl)boronic acid.
Entry
Catalyst
Solvent
V (9:1)
Temp.
[°C]
Time
[h]
Yield (%)
7a/8/9
1
2
3
4
5
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
DME/EtOH
DME/EtOH
dioxane/EtOH
DMF/EtOH
H2O/EtOH
100
90
90
100
100
1
1
1
1
1
61:10:19
77:5:10
68:10:15
49:5:36
71:19:0
TBAB
6
7
PdCl2(PPh3)2
Pd(PPh3)4
H2O/EtOH
TBAB (1 equiv.)
H2O/EtOH
TBAB (1 equiv.)
DME/EtOH
H2O/EtOH
90
1.5
1
82:5:0
0:0:0
100
8
9
Pd(PPh3)4
PdCl2(dppf)2
100
100
1
1
63:12:10
70:10:0
TBAB (1 equiv.)
H2O/EtOH
TBAB (1 equiv.)
H2O/EtOH
10
11
Pd(OAc)2,
PPh3
Pd(dba)2
100
100
1
1
20:0:0
55/trace:
trace
TBAB (1 equiv.)
step processes are economically advantageous in terms of diation, allowing the synthesis of 2,6,8-trisubstituted 4-ami-
the outlay for catalyst, solvent, purification materials, and noquinazoline derivatives. First, (4-methoxyphenyl)boronic
time.
acid can be expected to react selectively at the C-6 and C-8
The sequential, one-pot, two-step, tris-Suzuki–Miyaura positions, with subsequent addition of phenylboronic acid
reactions of 5b were studied by using (4-methoxyphenyl)- leading to reaction at the C-2 position of 5b (Scheme 3). In
boronic acid and phenylboronic acid under microwave irra- the first step, we treated 5b according to our typical bis-
Scheme 3. One-pot chemoselective tris-Suzuki–Miyaura reaction.
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Table 3. Scope of bis-Suzuki–Miyaura chemoselective reaction of
Table 4. Scope of the one-pot, chemoselective tris-Suzuki–Miyaura
5b with boronic acids.[a]
reaction of 5b with boronic acids.[a]
[a] Reaction conditions, Step 1: (4-methoxyphenyl)boronic acid
(2.05 equiv.), PdCl2(PPh3)2 (5 mol-%), K2CO3 (6 equiv.), TBAB
(1 equiv.), H2O/EtOH (9:1), MW, 90 °C, 1.5 h; Step 2: boronic acid
(1.2 equiv.), PdCl2(PPh3)2 (5 mol-%), K2CO3 (3 equiv.), MW, 100 °C, 1 h.
[a] Reaction conditions: boronic acid (2.05 equiv.), PdCl2(PPh3)2
(5 mol-%), K2CO3 (6 equiv.), TBAB (1 equiv.), H2O/EtOH (9:1),
MW, 90 °C, 1 h 30. [b] MW, 95 °C, 2 h. [c] MW, 105 °C, 1 h 30.
4
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2,6,8-Trisubstituted 4-Aminoquinazolines
Suzuki–Miyaura conditions: (4-methoxyphenyl)boronic Table 5. Scope of the one-pot, chemoselective SNAr/bis-Suzuki–Mi-
yaura reaction of 5b with 3-chloroaniline and boronic acids.[a]
acid (2.05 equiv.), PdCl2(PPh3)2 (5 mol-%), TBAB
(1 equiv.), K2CO3 (6 equiv.) in H2O/EtOH (9:1) under mi-
crowave irradiation at 90 °C for 1.5 h. In the second step,
phenylboronic acid (1.2 equiv.), PdCl2(PPh3)2 (5 mol-%),
and K2CO3 (3 equiv.) were added and the mixture was
heated again under microwave irradiation for 1 h at 100 °C
to give the isolated trisubstituted 4-aminoquinazoline
derivative 9a in good yield (86%) and the tricoupled com-
pound 8 in 9% yield. Note that, without adding fresh Pd
and base, the conversion of intermediate 7a into compound
9a was not complete (monitoring by LC-MS). Microwave
heating the mixture at 90 °C for 1.5 h in this second step
resulted in incomplete conversion of the intermediate from
the first step to compound 9a, according to LC-MS analy-
sis.
The scope and generality of this one-pot chemoselective
tris-Suzuki–Miyaura reaction was next assessed by using
various boronic acids. We chose (4-methoxyphenyl)boronic
acid for the first step and different boronic acids for the
second step (Table 4).
High yields of 2,6,8-trisubstituted 4-aminoquinazoline
derivatives 9a–j were obtained under the reaction condi-
tions previously described with a broad range of (hetero)-
arylboronic acids bearing an electron-donating or electron-
withdrawing group (Table 4, entries 1–10).
Finally, we turned our attention to the sequential, one-
pot chemoselective SNAr/bis-Suzuki–Miyaura reaction of
5b. As in our previous study,[12] the chemoselective reaction
of an excess of 3-chloroaniline with 4 led to the 2,4-disubsti-
tuted quinazoline derivative, and no reactivity of C-6-Br
and C-8-Br bonds toward SNAr was observed.
With the optimized reaction conditions in hand, we per-
formed the sequential, one-pot synthesis of 2,6,8-trisubsti-
tuted 4-aminoquiazoline derivative 10a from 3-chloroanil-
ine and (4-methoxyphenyl)boronic acid (Scheme 4). In the
first step, we reacted 3-chloroaniline (2 equiv.) with 5b in
EtOH (2.5 mL) under microwave irradiation at 110 °C for
1 h. After cooling to room temperature, (4-methoxyphenyl)-
boronic acid (2.2 equiv.), PdCl2(PPh3)2 (5 mol-%), TBAB
(1 equiv.), K2CO3 (6 equiv.), and H2O (2.5 mL) were added
and the mixture was heated under microwave irradiation at
100 °C for 1 h. SNAr reaction occurred exclusively at the
C-2 position and bis-Suzuki–Miyaura at the C-6 and C-8
positions, and the corresponding product 10a was isolated
in high yield (88%). When the reaction mixture was heated
at 100 °C for 1 h in the first step, a mixture of the starting
material and the aminated product in C-2 position was ob-
served by LC-MS analysis. For the second step, to decrease
the reaction time and guided by the results of the previous
bis-Suzuki–Miyaura chemoselective study, the reaction was
carried out at 100 °C.
To ascertain the scope of the one-pot, chemoselective
SNAr/bis-Suzuki–Miyaura reaction, we prepared a new
series of 2,6,8-trisubstituted 4-aminoquinazoline derivatives
[a] Reaction conditions, Step 1: 3-chloroaniline (2 equiv.), EtOH,
by using our optimized reaction conditions. In the first step,
MW, 110 °C, 1 h; Step 2: boronic acid (2.2 equiv.), PdCl2(PPh3)2
we used 3-chloroaniline and in the second step various bo-
ronic acids (Table 5). The reaction conditions showed a
(5 mol-%), K2CO3 (6 equiv.), TBAB (1 equiv.), H2O/EtOH (1:1),
MW, 100 °C, 1 h.
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Y. Kabri, M. D. Crozet, T. Terme, P. Vanelle
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Scheme 4. One-pot chemoselective SNAr/bis-Suzuki–Miyaura reaction.
with a Thermo MSQ Plus simple quadrupole. A Thermo Hypersil
Gold 50ϫ2.1 mm chromatographic column was used (SiO2 C18)
with 1.9 μm diameter particles. Analysis was 8 min running, with
an MeOH/H2O eluent gradient from 50:50 to 95:05.
broad tolerance for the presence of a wide range of (hetero)-
arylboronic acids bearing an electron-donating or -with-
drawing group. Good to excellent yields of 2,6,8-trisubsti-
tuted 4-aminoquinazoline derivatives were obtained
(Table 5, entries 1–9).
2-Amino-3,5-dibromobenzonitrile (1): A mixture of 2-aminobenzo-
nitrile (5 g, 42.3 mmol) and NBS (16.57 g, 93.1 mmol, 2.2 equiv.)
was heated to reflux in MeCN (80 mL) for 3 h. After cooling, a
precipitate appeared and was filtered, washed with water (3ϫ
60 mL) and dried in a vacuum drying oven (desiccator cabinet).
Recrystallization from propan-2-ol gave 1 (8.90 g, 77%) as a brown
solid; m.p. 158 °C (Lit.[15] 156 °C). 1H NMR (CDCl3, 200 MHz,
Conclusions
In summary, an original one-pot, chemoselective tris-Su-
zuki–Miyaura reaction and one-pot, chemoselective SNAr/
bis-Suzuki–Miyaura reaction were developed by using 5b,
allowing the chemoselective functionalization of the C-2,
C-6, and C-8 positions of this quinazoline scaffold. This
sequential, one-pot approach affords easy access to 2,6,8-
trisubstituted 4-aminoquinazoline derivatives in good to ex-
cellent yields in water under microwave irradiation. In ad-
dition, this environmentally friendly procedure tolerates a
wide range of boronic acids and represents a promising
green route for the synthesis of these important pharmaceu-
tical heterocyclic compounds.
4
24 °C): δ = 4.91 (s, 2 H, NH2), 7.47 (d, JH,H = 2.1 Hz, 1 H, Ar-
4
H), 7.71 (d, JH,H = 2.1 Hz, 1 H, Ar-H) ppm. 13C NMR (CDCl3,
50 MHz, 24 °C): δ = 97.9 (CCN), 108.2 (CAr), 109.7 (CAr), 115.6
(CAr), 133.6 (CHAr), 139.4 (CHAr), 146.2 (CAr) ppm.
2-Amino-3,5-dibromobenzoic Acid (2): To a solution of 1 (8 g,
29.0 mmol) in water (100 mL), NaOH (1.16 g, 1 equiv.) was added.
The reaction mixture was heated at 100 °C for 8 h. After cooling,
a precipitate appeared and was filtered, washed with water (3ϫ
60 mL) and dried in a vacuum drying oven (desiccator cabinet).
Recrystallization from propan-2-ol gave 2 (6.58 g, 81%) as yellow
solid; m.p. 223 °C (Lit.[16] 226–228 °C). 1H NMR ([D6]DMSO,
4
200 MHz, 24 °C): δ = 6.80 (s, 2 H, NH2), 7.72 (d, JH,H = 1.9 Hz,
4
1 H, Ar-H), 7.78 (d, JH,H = 1.9 Hz, 1 H, Ar-H), 8.05 (s, 1 H,
COOH) ppm. 13C NMR ([D6]DMSO, 50 MHz, 24 °C): δ = 105.1
(CAr), 110.6 (CAr), 117.0 (CAr), 130.9 (CHAr), 136.8 (CHAr), 146.2
(CAr), 169.4 (CCOOH) ppm.
Experimental Section
6,8-Dibromoquinazoline-2,4-(1H,3H)-dione (3): A mixture of 2 (5 g,
16.95 mmol), urea (5.09 g, 84.75 mmol, 5 equiv.), and Cs2CO3
(0.55 g, 1.69 mmol, 0.1 equiv.) was heated to reflux in DMF
(80 mL) for 24 h. After cooling, a precipitate appeared that was
filtered, washed with water (3ϫ 60 mL) and dried in a vacuum
drying oven (desiccator cabinet). Recrystallization from propan-2-
ol gave 3 (4.14 g, 76%) as a brown solid; m.p. 289 °C (Lit.[17] 291–
292 °C). 1H NMR ([D6]DMSO, 200 MHz, 24 °C): δ = 7.84 (d,
General: Melting points were determined with Büchi B-540 and are
uncorrected. Elemental and HRMS analyses were carried out at
the Spectropole, Faculté des Sciences et Techniques de Saint-
1
Jérôme, Marseille, France. 200 or 250 MHz H NMR spectra (ref-
erence CDCl3 δ = 7.26, [D6]DMSO δ = 2.50 ppm) and 50 or
62.5 MHz 13C NMR spectra (reference CDCl3 δ = 77.0, [D6]-
DMSO δ = 39.7 ppm) were recorded with a Bruker ARX 200 spec-
trometer in CDCl3 and [D6]DMSO solvents at the Faculté de Phar-
macie de Marseille. Solvents were dried by conventional methods.
The following adsorbent was used for column chromatography: sil-
ica gel 60 (Merck, particle size 0.063–0.200 mm, 70–230 mesh
ASTM). TLC was performed on 5 cmϫ10 cm aluminum plates
coated with silica gel 60F-254 (Merck) in an appropriate eluent.
HRMS spectra were recorded with a QStar Elite (Applied Biosys-
tems SCIEX) spectrometer; PEG was used as matrix for HRMS.
4
4JH,H = 2.2 Hz, 1 H, Ar-H), 7.94 (d, JH,H = 2.2 Hz, 1 H, Ar-H),
10.76 (s, 2 H, 2 NH) ppm. 13C NMR ([D6]DMSO, 50 MHz, 24 °C):
δ = 110.4 (CAr), 114.0 (CAr), 118.0 (CAr), 128.5 (CHAr), 138.8
(CHAr), 145.1 (CAr), 153.4 (CCO), 162.7 (CCO) ppm.
6,8-Dibromo-2,4-dichloroquinazoline (4): A solution of 3 (4 g,
12.5 mmol), POCl3 (11.4 mL, 10 equiv.), and diisopropyl ethyl-
amine (4.4 mL, 25.0 mmol, 2 equiv.) was heated to reflux for 6 h.
Following this, the reaction mixture was poured with care over
crushed ice and stirred vigorously. This aqueous mixture was ex-
tracted with CH2Cl2, and the combined organic layers were washed
with brine, dried with Na2SO4, and evaporated under reduced pres-
sure. Flash chromatography (silica gel; CH2Cl2/petroleum ether,
2:1) provided, after recrystallization from propan-2-ol, 4 (2.81 g,
Microwave reactions were performed with a Biotage Initiator Mi-
crowave oven using 2–5 mL sealed vials; temperatures were mea-
sured with an IR-sensor and reaction times are given as hold times.
LC/MS analyses were performed at the Faculté de Pharmacie de
Marseille with an Accela High System chain U-HPLC coupled
6
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2,6,8-Trisubstituted 4-Aminoquinazolines
63%) as a yellow solid; m.p. 145 °C (Lit.[18] 148–149 °C). 1H NMR
0.05 equiv.), K2CO3 (0.32 g, 2.29 mmol, 6 equiv.), and TBAB
4
(CDCl3, 200 MHz, 24 °C): δ = 8.37 (d, JH,H = 2.0 Hz, 1 H, Ar- (0.12 g, 1 equiv., 0.38 mmol) in a H2O/EtOH mixture (9:1, 5 mL)
4
H), 8.39 (d, JH,H = 2.0 Hz, 1 H, Ar-H) ppm. 13C NMR (CDCl3, was heated at 90 °C under microwave irradiation for 1.5 h. After
50 MHz, 24 °C): δ = 122.7 (CAr), 124.1 (CAr), 124.2 (CAr), 127.7 cooling, water (80 mL) was added and the solution was extracted
(CHAr), 142.3 (CHAr), 149.0 (CAr), 156.3 (CAr), 163.3 (CAr) ppm.
with dichloromethane (3ϫ 60 mL). The organic layer was washed
with water (3ϫ 100 mL), dried with Na2SO4 and the solvents evap-
orated. The crude product was purified by column chromatography
[silica gel; petroleum ether/ethyl acetate (5%), (15% for 7g), (100%
for 7h)] and recrystallized from propan-2-ol.
6,8-Dibromo-2-chloro-N-(3-chlorophenyl)quinazolin-4-amine (5a):
To a solution of 4 (1 g, 2.23 mmol) in a THF/H2O mixture (2:1,
12 mL) were added 3-chloroaniline (0.3 mL, 1.1 equiv., 2.45 mmol)
and potassium acetate (0.36 g, 1.3 equiv., 2.9 mmol). The reaction
mixture was stirred at room temperature for 4 h. At the end of this
time, a precipitate appeared that was filtered, washed with water
2-Chloro-N,N-diethyl-6,8-bis(4-methoxyphenyl)quinazolin-4-amine
(7a): Yield 140 mg (82 %); yellow solid; m.p. 155 °C. 1H NMR
(3ϫ 10 mL) and dried in a vacuum drying oven (desiccator cabi- (CDCl3, 250 MHz, 24 °C): δ = 1.45 (t, 3JH,H = 7.0 Hz, 6 H, 2 CH3),
net). Recrystallization from propan-2-ol gave 5a (1.15 g, 92%) as a
yellow solid; m.p. 235 °C. 1H NMR ([D6]DMSO, 200 MHz, 24 °C):
δ = 7.26–7.46 (m, 2 H, 2 Ar-H), 7.76–7.93 (m, 2 H, 2 Ar-H), 8.38
3
3.80 (q, JH,H = 7.1 Hz, 4 H, 2 CH2), 3.88 (s, 6 H, 2 OCH3), 7.03
3
3
(d, JH,H = 8.5 Hz, 4 H, 4 Ar-H), 7.58 (d, JH,H = 8.7 Hz, 2 H, 2
3
4
Ar-H), 7.68 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.93 (d, JH,H
=
(s, 1 H, Ar-H), 8.83 (s, 1 H, Ar-H), 10.32 (s, 1 H, NH) ppm. 13C 1.7 Hz, 1 H, Ar-H), 7.98 (d, JH,H = 1.7 Hz, 1 H, Ar-H) ppm. 13C
NMR ([D6]DMSO, 50 MHz, 24 °C): δ = 116.4 (CAr), 119.0 (CAr), NMR (CDCl3, 62.5 MHz, 24 °C): δ = 13.1 (2 CH3), 45.5 (2 CH2),
121.2 (CHAr), 122.3 (CHAr), 123.0 (CAr), 124.8 (CHAr), 125.8 55.3 (OCH3), 55.4 (OCH3), 113.6 (2 CHAr), 114.6 (2 CHAr), 115.5
(CHAr), 130.5 (CHAr), 133.0 (CAr), 139.5 (CAr), 139.5 (CHAr), 147.6 (CAr), 121.0 (CHAr), 128.1 (2 CHAr), 131.0 (CAr), 131.7 (2 CHAr),
4
(CAr), 157.4 (CAr), 158.7 (CAr) ppm. C14H7Br2Cl2N3 (447.94):
calcd. C 37.54, H 1.58, N 9.38; found C 37.42, H 1.49, N 9.22.
132.3 (CHAr), 132.8 (CAr), 136.6 (CAr), 139.1 (CAr), 150.0 (CAr),
155.8 (CA r ), 159.3 (CA r), 159.5 (CAr ), 164.5 (CA r) ppm.
C26H26ClN3O2 (447.96): calcd. C 69.71, H 5.85, N 9.38; found C
69.54, H 5.88, N 9.58.
6,8-Dibromo-2-chloro-N,N-diethylquinazolin-4-amine (5b): To
a
solution of 4 (1 g, 2.23 mmol) in a THF/H2O mixture (2:1, 12 mL)
were added diethyamine (0.23 mL, 1.1 equiv., 2.45 mmol) and po-
tassium acetate (0.36 g, 1.3 equiv., 2.9 mmol). The reaction mixture
2-Chloro-N,N-diethyl-6,8-diphenylquinazolin-4-amine (7b): Yield
118 mg (80 %); yellow solid; m.p. 150 °C. 1H NMR (CDCl3,
3
was stirred at room temperature for 24 h. At the end of this time, 250 MHz, 24 °C): δ = 1.47 (t, JH,H = 7.0 Hz, 6 H, 2 CH3), 3.81
water was added (10 mL), the solution was extracted with CH2Cl2, (q, 3JH,H = 7.0 Hz, 4 H, 2 CH2), 7.37–7.55 (m, 6 H, 6 Ar-H), 7.65–
4
and the combined organic layers were dried with Na2SO4 and evap-
orated under reduced pressure. Flash chromatography (silica gel,
CH2Cl2/petroleum ether, 1:1) provided, after recrystallization from
7.76 (m, 4 H, 4 Ar-H), 8.01 (d, JH,H = 2.0 Hz, 1 H, Ar-H), 8.08
(d, 4JH,H = 2.0 Hz, 1 H, Ar-H) ppm. 13C NMR (CDCl3, 62.5 MHz,
24 °C): δ = 13.0 (2 CH3), 45.5 (2 CH2), 115.4 (CAr), 122.2 (CHAr),
127.0 (2 CHAr), 127.6 (CHAr), 127.8 (CHAr), 128.0 (2 CHAr), 129.2
propan-2-ol, 5b (1.00 g, 91%) as a yellow solid; m.p. 128 °C. 1H
3
NMR (CDCl3, 200 MHz, 24 °C): δ = 1.40 (t, JH,H = 7.0 Hz, 6 H, (2 CHAr), 130.6 (2 CHAr), 132.9 (CHAr), 136.8 (CAr), 138.5 (CAr),
3
4
2 CH3), 3.73 (q, JH,H = 7.0 Hz, 4 H, 2 CH2), 7.95 (d, JH,H
=
139.6 (CAr), 140.2 (CAr), 150.4 (CAr), 156.2 (CAr), 164.4 (CAr) ppm.
C24H22ClN3 (387.90): calcd. C 74.31, H 5.72, N 10.83; found C
74.41, H 5.74, N 10.78.
2.0 Hz, 1 H, Ar-H), 8.07 (d, JH,H = 2.0 Hz, 1 H, Ar-H) ppm. 13C
NMR (CDCl3, 50 MHz, 24 °C): δ = 12.7 (2 CH3), 45.7 (2 CH2),
116.2 (CAr), 116.7 (CAr), 123.6 (CAr), 126.8 (CHAr), 138.8 (CHAr),
150.0 (CAr), 157.7 (CAr), 162.4 (CAr) ppm. C12H12Br2ClN3 (393.50):
calcd. C 36.63, H 3.07, N 10.68; found C 36.86, H 2.95, N 10.72.
4
2-Chloro-N,N-diethyl-6,8-di-p-tolylquinazolin-4-amine (7c): Yield
95 mg (76 %); yellow solid; m.p. 213 °C. 1H NMR (CDCl3,
3
250 MHz, 24 C°): δ = 1.45 (t, JH,H = 7.0 Hz, 6 H, 2 CH3), 2.43
6,8-Dibromo-N2,N4-bis(3-chlorophenyl)quinazoline-2,4-diamine (6): (s, 6 H, 2 CH3), 3.80 (q, JH,H = 6.8 Hz, 4 H, 2 CH2), 7.27–7.32
3
3
To a solution of 4 (1 g, 2.23 mmol) in a CH2Cl2/EtOH mixture
(m, 4 H, 4 Ar-H), 7.55 (d, JH,H = 7.9 Hz, 2 H, 2 Ar-H), 7.62 (d,
(2:1, 12 mL) was added 3-chloroaniline (0.3 mL, 1.1 equiv., 3JH,H = 7.7 Hz, 2 H, 2 Ar-H), 7.98 (d, JH,H = 1.3 Hz, 1 H, Ar-
4
4
2.45 mmol). The reaction mixture was stirred at room temperature
H), 8.03 (d, JH,H = 1.3 Hz, 1 H, Ar-H) ppm. 13C NMR (CDCl3,
for 1 h. At the end of this time, a precipitate appeared that was 62.5 MHz, 24 °C): δ = 13.1 (2 CH3), 21.1 (CH3), 21.3 (CH3), 45.5
filtered, washed with water (3ϫ 10 mL), and dried in a vacuum (2 CH2), 115.4 (CAr), 121.6 (CHAr), 126.9 (2 CHAr), 128.8 (2
drying oven (dessicator cabinet). Flash chromatography (silica gel; CHAr), 129.9 (2 CHAr), 130.4 (2 CHAr), 132.6 (CHAr), 135.6 (CAr),
CH2Cl2/petroleum ether, 1:2) provided, after recrystallization from
136.8 (CAr), 137.3 (CAr), 137.4 (CAr), 137.7 (CAr), 139.6 (CAr),
150.3 (CAr), 156.0 (CAr), 164.5 (CAr) ppm. HRMS: calcd. for
C26H26ClN3 [M + H+] 416.1888; found 416.1888.
propan-2-ol, 6 (0.23 g, 20%) as a yellow solid; m.p. 222 °C. 1H
3
NMR ([D6]DMSO, 200 MHz, 24 °C): δ = 7.01 (d, JH,H = 6.3 Hz,
3
1 H, Ar-H), 7.19–7.34 (m, 2 H, 2 Ar-H), 7.43 (t, JH,H = 7.7 Hz, 1
2-Chloro-N,N-diethyl-6,8-bis(4-fluorophenyl)quinazolin-4-amine
(7d): Yield 131 mg (81 %); yellow solid; m.p. 186 °C. 1H NMR
(CDCl3, 250 MHz, 24 °C): δ = 1.46 (t, 3JH,H = 7.1 Hz, 6 H, 2 CH3),
3
H, Ar-H), 7.81 (d, JH,H = 8.2 Hz, 1 H, Ar-H), 7.93 (s, 1 H, Ar-
3
H), 8.02 (d, JH,H = 8.2 Hz, 1 H, Ar-H), 8.23 (s, 1 H, Ar-H), 8.48
(s, 1 H, Ar-H), 8.75 (s, 1 H, Ar-H), 9.81 (s, 1 H, NH), 9.93 (s, 1 H,
NH) ppm. 13C NMR ([D6]DMSO, 50 MHz, 24 °C): δ = 114.1
(CAr), 114.4 (CAr), 117.7 (CHAr), 118.9 (CHAr), 121.0 (CHAr), 121.3
(CHAr), 121.9 (CHAr), 124.0 (CHAr), 125.6 (CHAr), 130.1 (CHAr),
130.4 (CHAr), 133.1 (CAr), 133.3 (2 CAr), 138.5 (CHAr), 140.5 (CAr),
142.0 (CAr), 147.4 (CAr), 156.1 (CAr), 157.7 (CAr) ppm. HRMS
(ESI): m/z [M + H]+ calcd. for C20H12Br2Cl2N4 538.8857; found
538.8858.
3
3.81 (q, JH,H = 6.6 Hz, 4 H, 2 CH2), 7.13–7.23 (m, 4 H, 4 Ar-H),
7.57–7.63 (m, 2 H, 2 Ar-H), 7.66–7.71 (m, 2 H, 2 Ar-H), 7.90 (s, 1
H, Ar-H), 8.01 (s, 1 H, Ar-H) ppm. 13C NMR (CDCl3, 62.5 MHz,
3
24 °C): δ = 13.0 (2 CH3), 45.6 (2 CH2), 115.0 (d, JC,F = 21.6 Hz,
3
2 CHAr), 115.4 (CAr), 116.1 (d, JC,F = 21.6 Hz, 2 CHAr), 122.2
(CHAr), 128.6 (d, 4JC,F = 8.3 Hz, 2 CHAr), 132.2 (d, 4JC,F = 8.3 Hz,
2 CHAr), 132.5 (CHAr), 134.3 (d, 5JC,F = 2.8 Hz, CAr), 135.9 (CAr),
136.2 (d, 5JC,F = 3.7 Hz, CAr), 138.7 (CAr), 150.3 (CAr), 156.3 (CAr),
2
2
One-Pot, Chemoselective Bis-Suzuki–Miyaura Coupling Reaction; 162.6 (d, JC,F = 246.8 Hz, CAr), 162.7 (d, JC,F = 247.7 Hz, CAr),
General Procedure: A solution of 5b (0.15 g, 0.38 mmol), boronic 164.3 (CAr) ppm. C24H20ClF2N3 (423.89): calcd. C 68.00, H 4.76,
acid (0.78 mmol, 2.05 equiv.), PdCl2(PPh3)2 (13 mg, 0.019 mmol, N 9.91; found C 68.19, H 4.54, N 10.52.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O50162
/KAP1
Date: 04-05-15 13:31:12
Pages: 13
Y. Kabri, M. D. Crozet, T. Terme, P. Vanelle
FULL PAPER
2-Chloro-6,8-bis(4-chlorophenyl)-N,N-diethylquinazolin-4-amine
(7e): Yield 134 mg (77 %); yellow solid; m.p. 208 °C. 1H NMR
H) ppm. NMR (CDCl3, 62.5 MHz, 24 °C): δ = 13.2 (2 CH3), 45.3
(2 CH2), 55.3 (OCH3), 55.4 (2 OCH3), 113.2 (2 CHAr), 113.5 (2
(CDCl3, 250 MHz, 24 °C): δ = 1.46 (t, 3JH,H = 7.0 Hz, 6 H, 2 CH3), CHAr), 114.5 (2 CHAr), 115.9 (CAr), 121.0 (CHAr), 128.1 (2 CHAr),
3
3.81 (q, JH,H = 7.1 Hz, 4 H, 2 CH2), 7.42–7.49 (m, 4 H, 4 Ar-H), 129.9 (2 CHAr), 131.2 (CHAr), 132.0 (CAr), 132.1 (2 CHAr), 133.4
3
3
7.56 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.65 (d, JH,H = 8.5 Hz, 2
(CAr), 135.5 (CAr), 139.5 (CAr), 143.5 (CAr), 149.5 (CAr), 157.9
(CAr), 158.9 (CAr), 159.2 (CAr), 161.1 (CAr), 164.0 (CAr) ppm.
HRMS: calcd. for C33H33N3O3 [M + H+] 520.2595; found
4
4
H, 2 Ar-H), 7.89 (d, JH,H = 1.9 Hz, 1 H, Ar-H), 8.02 (d, JH,H
=
1.9 Hz, 1 H, Ar-H) ppm. 13C NMR (CDCl3, 62.5 MHz, 24 °C): δ
= 13.0 (2 CH3), 45.6 (2 CH2), 115.3 (CAr), 122.5 (CHAr), 128.2 (2 520.2594.
CHAr), 128.3 (2 CHAr), 129.4 (2 CHAr), 131.8 (2 CHAr), 132.3
One-pot, Chemoselective Tris-Suzuki–Miyaura Coupling Reaction;
(CHAr), 133.8 (CAr), 134.1 (CAr), 135.7 (CAr), 136.7 (CAr), 138.5
(CAr), 138.6 (CAr), 150.4 (CAr), 156.5 (CAr), 164.2 (CAr) ppm.
C24H20Cl3N3 (456.79): calcd. C 63.10, H 4.41, N 9.20; found C
63.19, H 4.33, N 9.19.
General Procedure: A solution of 5b (0.2 g, 0.508 mmol), (4-meth-
oxyphenyl)boronic acid (0.16 g, 1.04 mmol, 2.05 equiv.),
PdCl2(PPh3)2 (18 mg, 0.025 mmol, 0.05 equiv.), K2CO3 (0.42 g,
3.05 mmol, 6 equiv.), and TBAB (0.16 g, 1 equiv., 0.508 mmol) in
a H2O/EtOH mixture (9:1, 5 mL) under argon was heated at 90 °C
under microwave irradiation for 1.5 h. After cooling, boronic acid
2-Chloro-N,N-diethyl-6,8-bis[4-(trifluoromethyl)phenyl]quinazolin-4-
amine (7f): Yield 129 mg (65 %); yellow solid; m.p. 215 °C. 1H
3
NMR (CDCl3, 250 MHz, 24 °C): δ = 1.48 (t, JH,H = 6.9 Hz, 6 H, (0.70 mmol, 1.2 equiv.), PdCl2(PPh3)2 (18 mg, 0.025 mmol,
2 CH3), 3.82 (q, JH,H = 7.0 Hz, 4 H, 2 CH2), 7.72–7.76 (m, 6 H, 0.05 equiv.), and K2CO3 (0.21 g, 1.525 mmol, 3 equiv.) were intro-
3
3
6 Ar-H), 7.82 (d, JH,H = 8.2 Hz, 2 H, 2 Ar-H), 7.96 (s, 1 H, Ar-
duced under argon. The mixture was heated at 100 °C for 1 h under
H), 8.13 (s, 1 H, Ar-H) ppm. 13C NMR (CDCl3, 62.5 MHz, 24 °C): microwave irradiation. After cooling, water (80 mL) was added and
δ = 13.1 (2 CH3), 45.7 (2 CH2), 115.4 (CAr), 123.6 (CHAr), 124.0 the solution was extracted with dichloromethane (3ϫ 60 mL). The
2
2
(q, JC,F = 272.6 Hz, CF3), 124.3 (q, JC,F = 272.6 Hz, CF3), 125.0
organic layer was washed with water (3 ϫ 100 mL), dried with
4
4
(q, JC,F = 3.7 Hz, 2 CHAr), 126.2 (q, JC,F = 3.7 Hz, 2 CHAr), Na2SO4, and the solvents evaporated. The crude product was puri-
3
3
127.4 (2 CHAr), 129.7 (q, JC,F = 32.2 Hz, CAr), 130.1 (q, JC,F
=
fied by column chromatography [silica gel; petroleum ether/ethyl
32.6 Hz, CAr), 130.9 (2 CHAr), 132.7 (CHAr), 135.4 (CAr), 138.6 acetate (5%) (10% for 9g; 30% for 9h)] and recrystallized from
(CAr), 141.9 (CAr), 143.5 (CAr), 150.8 (CAr), 157.0 (CAr), 164.1
(CAr) ppm. C26H20ClF6N3 (523.90): calcd. C 59.61, H 3.85, N 8.02;
found C 59.70, H 3.35, N 8.21.
propan-2-ol.
N,N-Diethyl-6,8-bis(4-methoxyphenyl)-2-phenylquinazolin-4-amine
(9a): Yield 214 mg (86 %); yellow solid; m.p. 170 °C. 1H NMR
(CDCl3, 200 MHz, 24 °C): δ = 1.50 (t, 3JH,H = 7.0 Hz, 6 H, 2 CH3),
2-Chloro-N,N-diethyl-6,8-bis(3-nitrophenyl)quinazolin-4-amine (7g):
1
3
Yield 111 mg (61%); yellow solid; m.p. 221 °C. H NMR (CDCl3,
3.85 (q, JH,H = 7.2 Hz, 4 H, 2 CH2), 3.89 (s, 3 H, OCH3), 3.94 (s,
3
3
3
250 MHz, 24 °C): δ = 1.50 (t, JH,H = 7.0 Hz, 6 H, 2 CH3), 3.85
3 H, OCH3), 7.05 (d, JH,H = 8.6 Hz, 2 H, 2 Ar-H), 7.10 (d, JH,H
3
3
(q, JH,H = 7.0 Hz, 4 H, 2 CH2), 7.66 (t, JH,H = 8.1 Hz, 1 H, Ar-
= 8.7 Hz, 2 H, 2 Ar-H), 7.40–7.49 (m, 3 H, 3 Ar-H), 7.64 (d, 3JH,H
H), 7.71 (t, JH,H = 81 Hz, 1 H, Ar-H), 7.99 (d, JH,H = 8.1 Hz, 1 = 8.6 Hz, 2 H, 2 Ar-H), 7.86 (d, 3JH,H = 8.6 Hz, 2 H, 2 Ar-H), 7.99
3
3
H, Ar-H), 8.01 (s, 1 H, Ar-H), 8.08 (d, JH,H = 7.4 Hz, 1 H, Ar- (d, 4JH,H = 1.7 Hz, 1 H, Ar-H), 8.05 (d, 4JH,H = 1.8 Hz, 1 H, Ar-H),
3
H), 8.18 (s, 1 H, Ar-H), 8.28 (d, 3JH,H = 8.1 Hz, 2 H, 2 Ar-H), 8.51
8.51–8.53 (m, 2 H, 2 Ar-H) ppm. NMR (CDCl3, 50 MHz, 24 °C): δ
(s, 1 H, Ar-H), 8.55 (s, 1 H, Ar-H) ppm. NMR (CDCl3, 62.5 MHz, = 13.2 (2 CH3), 45.3 (2 CH2), 55.3 (OCH3), 55.4 (OCH3), 113.3 (2
24 °C): δ = 13.0 (2 CH3), 45.7 (2 CH2), 115.3 (CAr), 121.8 (CHAr), CHAr), 114.5 (2 CHAr), 116.0 (CAr), 121.0 (CHAr), 128.1 (2 CHAr),
122.7 (2 CHAr), 123.9 (CHAr), 125.3 (CHAr), 128.9 (CHAr), 130.3 128.2 (2 CHAr), 128.4 (2 CHAr), 129.8 (CHAr), 131.4 (CHAr), 131.7
(CHAr), 132.2 (CHAr), 132.8 (CHAr), 134.2 (CAr), 136.9 (CHAr), (CAr), 132.0 (2 CHAr), 133.2 (CAr), 136.0 (CAr), 138.8 (CAr) 138.9
137.7 (CAr), 139.6 (CAr), 141.4 (CAr), 148.2 (CAr), 149.0 (CAr),
(CAr), 139.6 (CAr), 157.8 (CAr), 159.1 (CAr), 159.3 (CAr), 164.0
150.9 (CAr), 157.3 (CAr), 163.9 (CAr) ppm. HRMS: calcd. for (CAr) ppm. C32H31N3O2 (489.91): calcd. C 78.50, H 6.38, N 8.58;
C24H20ClN5O4 [M + H+] 478.1277; found 478.1277.
found C 78.25, H 6.37, N 8.69.
2-Chloro-N,N-diethyl-6,8-di(pyridin-3-yl)quinazolin-4-amine (7h):
N,N-Diethyl-6,8-bis(4-methoxyphenyl)-2-p-tolylquinazolin-4-amine
(9b): Yield 230 mg (90 %); yellow solid; m.p. 167 °C. 1H NMR
Yield 95 mg (64%); yellow solid; m.p. 176 °C. 1H NMR (CDCl3,
3
250 MHz, 24 °C): δ = 1.47 (t, JH,H = 6.8 Hz, 6 H, 2 CH3), 3.82
(CDCl3, 200 MHz, 24 °C): δ = 1.49 (t, 3JH,H = 7.0 Hz, 6 H, 2 CH3),
3
3
(q, JH,H = 7.0 Hz, 4 H, 2 CH2), 7.41–7.47 (m, 2 H, 2 Ar-H), 7.95 2.41 (s, 3 H, CH3), 3.85 (q, JH,H = 7.2 Hz, 4 H, 2 CH2), 3.88 (s, 3
3
3
(s, 2 H, 2 Ar-H), 8.12 (s, 2 H, 2 Ar-H), 8.66 (t, JH,H = 4.4 Hz, 2 H, OCH3), 3.94 (s, 3 H, OCH3), 7.05 (d, JH,H = 8.9 Hz, 2 H, 2
3
3
H, 2 Ar-H), 8.90–8.91 (m, 2 H, 2 Ar-H) ppm. NMR (CDCl3, Ar-H), 7.09 (d, JH,H = 8.9 Hz, 2 H, 2 Ar-H), 7.25 (d, JH,H
=
3
62.5 MHz, 24 °C): δ = 13.0 (2 CH3), 45.6 (2 CH2), 115.4 (CAr),
8.0 Hz, 2 H, 2 Ar-H), 7.64 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.85
122.9 (CHAr), 123.3 (CHAr), 123.9 (CHAr), 132.3 (CHAr), 133.5 (d, 3JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.97 (d, 4JH,H = 2.0 Hz, 1 H, Ar-
4
3
(CAr), 134.0 (CAr), 134.3 (CHAr), 135.5 (CAr), 136.6 (CAr), 138.3 H), 8.03 (d, JH,H = 2.0 Hz, 1 H, Ar-H), 8.39 (d, JH,H = 8.0 Hz,
(CHAr), 148.1 (CHAr), 148.7 (CHAr), 149.1 (CHAr), 150.4 (CHAr), 2 H, 2 Ar-H) ppm. 13C NMR (CDCl3, 50 MHz, 24 °C): δ = 13.2
150.8 (CAr), 157.0 (CAr), 163.9 (CAr) ppm. HRMS: calcd. for (2 CH3), 21.5 (CH3), 45.4 (2 CH2), 55.3 (OCH3), 55.4 (OCH3),
C22H20ClN5 [M + H+] 390.1480; found 390.1484.
113.3 (2 CHAr), 114.5 (2 CHAr), 115.9 (CAr), 121.0 (CHAr), 128.1
(2 CHAr), 128.4 (2 CHAr), 129.0 (2 CHAr), 131.5 (CHAr), 131.5
(CAr), 132.0 (2 CHAr), 133.2 (CAr), 136.0 (CAr), 139.3 (CAr), 140.1
(CAr), 140.2 (CAr), 157.7 (CAr), 157.9 (CAr), 159.1 (CAr), 159.3
(CAr), 163.9 (CAr) ppm. C33H33N3O2 (503.63): calcd. C 78.70, H
6.60, N 8.34; found C 79.02, H 6.71, N 8.66.
N,N-Diethyl-2,6,8-tris(4-methoxyphenyl)quinazolin-4-amine (8):
Yield 37 mg (19%); yellow solid; m.p. 173 °C. 1H NMR (CDCl3,
3
250 MHz, 24 °C): δ = 1.48 (t, JH,H = 7.0 Hz, 6 H, 2 CH3), 3.83
3
(q, JH,H = 7.1 Hz, 4 H, 2 CH2), 3.87 (s, 3 H, OCH3), 3.88 (s, 3 H,
3
OCH3), 3.93 (s, 3 H, OCH3), 6.96 (d, JH,H = 8.9 Hz, 2 H, 2 Ar-
3
3
H), 7.04 (d, JH,H = 8.8 Hz, 2 H, 2 Ar-H), 7.08 (d, JH,H = 8.7 Hz,
N,N-Diethyl-6,8-bis(4-methoxyphenyl)-2-o-tolylquinazolin-4-amine
(9c): Yield 169 mg (66 %); yellow solid; m.p. 151 °C. 1H NMR
2 H, 2 Ar-H), 7.63 (d, JH,H = 8.5 Hz, 2 H, 2 Ar-H), 7.84 (d, 3JH,H
3
= 8.5 Hz, 2 H, 2 Ar-H), 7.96 (d, JH,H = 1.9 Hz, 1 H, Ar-H), 8.02 (CDCl3, 200 MHz, 24 °C): δ = 1.46 (t, 3JH,H = 6.9 Hz, 6 H, 2 CH3),
4
(d, 4JH,H = 1.9 Hz, 1 H, Ar-H), 8.45 (d, 3JH,H = 8.9 Hz, 2 H, 2 Ar-
2.62 (s, 3 H, CH3), 3.83 (q, JH,H = 7.1 Hz, 4 H, 2 CH2), 3.89 (s, 6
3
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50162
/KAP1
Date: 04-05-15 13:31:12
Pages: 13
2,6,8-Trisubstituted 4-Aminoquinazolines
3
3
H, 2 OCH3), 7.03 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.05 (d, JH,H (CAr), 148.5 (CAr), 156.5 (CAr), 159.3 (CAr), 159.6 (CAr), 163.9
= 8.7 Hz, 2 H, 2 Ar-H), 7.20–7.30 (m, 3 H, 3 Ar-H), 7.66 (d, 3JH,H (CAr) ppm. HRMS: calcd. for C33H30F3N3O2 [M + H+] 558.2363;
= 8.7 Hz, 2 H, 2 Ar-H), 7.75 (d, 3JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.98 found 558.2366.
3
(d, JH,H = 2.0 Hz, 1 H, Ar-H), 8.04–8.10 (m, 2 H, 2 Ar-H) ppm.
N,N-Diethyl-6,8-bis(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-
13C NMR (CDCl3, 50 MHz, 24 °C): δ = 13.4 (2 CH3), 22.2 (CH3),
quinazolin-4-amine (9g): Yield 247 mg (84 %); yellow solid; m.p.
45.5 (2 CH2), 55.3 (OCH3), 55.4 (OCH3), 113.5 (2 CHAr), 114.6 (2
1
3
189 °C. H NMR (CDCl3, 200 MHz, 24 °C): δ = 1.50 (t, JH,H
=
CHAr), 115.2 (CAr), 121.1 (CHAr), 125.6 (CHAr), 128.1 (2 CHAr),
129.0 (CHAr), 130.9 (CHAr), 131.3 (CHAr), 131.8 (3 CHAr), 133.0
(CAr), 136.5 (CAr), 137.9 (2 CAr), 138.3 (CAr), 139.3 (CAr), 159.2
(CAr), 159.5 (2 CAr), 160.5 (CAr), 163.8 (CAr) ppm. C33H33N3O2
(503.63): calcd. C 78.70, H 6.60, N 8.34; found C 78.44, H 6.60, N
8.25.
3
7.0 Hz, 6 H, 2 CH3), 3.86 (q, JH,H = 7.0 Hz, 4 H, 2 CH2), 3.88 (s,
6 H, 2 OCH3), 3.91 (s, 3 H, OCH3), 3.96 (s, 6 H, 2 OCH3), 7.04
3
3
(d, JH,H = 8.7 Hz, 4 H, 4 Ar-H), 7.63 (d, JH,H = 8.7 Hz, 2 H, 2
3
Ar-H), 7.86 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.87 (s, 2 H, 2 Ar-
4
4
H), 7.99 (d, JH,H = 1.8 Hz, 1 H, Ar-H), 8.03 (d, JH,H = 1.8 Hz,
1 H, Ar-H) ppm. 13C NMR (CDCl3, 50 MHz, 24 °C): δ = 13.1 (2
CH3), 45.4 (2 CH2), 55.3 (OCH3), 55.4 (OCH3), 55.9 (2 OCH3),
60.9 (OCH3), 105.5 (CHAr), 113.1 (2 CHAr), 114.5 (3 CHAr), 115.7
(CAr), 121.0 (CHAr), 128.1 (3 CHAr), 131.4 (CAr), 131.5 (CAr), 132.1
(2 CHAr), 133.1 (CAr), 136.2 (CAr), 139.2 (CAr), 139.9 (CAr), 152.9
(3 CAr), 157.0 (CAr), 159.2 (CAr), 159.4 (CAr), 163.8 (CAr) ppm.
N,N-Diethyl-2-(4-fluorophenyl)-6,8-bis(4-methoxyphenyl)quinazolin-
4-amine (9d): Yield 219 mg (85%); yellow solid; m.p. 128 °C. 1H
3
NMR (CDCl3, 200 MHz, 24 °C): δ = 1.49 (t, JH,H = 6.9 Hz, 6 H,
2 CH3), 3.85 (q, 3JH,H = 7.1 Hz, 4 H, 2 CH2), 3.89 (s, 3 H, OCH3),
3
3.94 (s, 3 H, OCH3), 7.05 (d, JH,H = 9.5 Hz, 2 H, 2 Ar-H), 7.10
3
3
C
35H37N3O5 (579.69): calcd. C 72.52, H 6.43, N 7.25; found C
(d, JH,H = 9.3 Hz, 2 H, 2 Ar-H), 7.15 (d, JH,H = 9.2 Hz, 2 H, 2
3
3
72.02, H 6.33, N 7.21.
Ar-H), 7.64 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.83 (d, JH,H
=
8.7 Hz, 2 H, 2 Ar-H), 7.98 (d, 4JH,H = 1.8 Hz, 1 H, Ar-H), 8.03 (d,
4JH,H = 1.8 Hz, 1 H, Ar-H), 8.46–8.53 (m, 2 H, 2 Ar-H) ppm. 13C
NMR (CDCl3, 50 MHz, 24 °C): δ = 13.2 (2 CH3), 45.3 (2 CH2),
55.3 (OCH3), 55.4 (OCH3), 113.3 (2 CHAr), 114.5 (2 CHAr), 115.0
N,N-Diethyl-6,8-bis(4-methoxyphenyl)-2-(pyridin-3-yl)quinazolin-4-
amine (9h): Yield 177 mg (71 %); yellow solid; m.p. 204 °C. 1H
3
NMR (CDCl3, 200 MHz, 24 °C): δ = 1.49 (t, JH,H = 7.0 Hz, 6 H,
2 CH3), 3.86 (q, 3JH,H = 7.0 Hz, 4 H, 2 CH2), 3.88 (s, 3 H, OCH3),
3
(d, JC,F = 21.2 Hz, 2 CHAr), 115.9 (CAr), 121.0 (CHAr), 128.1 (2
3
3.93 (s, 3 H, OCH3), 7.04 (d, JH,H = 8.9 Hz, 2 H, 2 Ar-H), 7.08
4
CHAr), 130.3 (d, JC,F = 8.4 Hz, 2 CHAr), 131.5 (CAr), 131.7
3
(d, JH,H = 8.9 Hz, 2 H, 2 Ar-H), 7.39–7.46 (m, 1 H, Ar-H), 7.63
(CHAr), 132.0 (2 CHAr), 133.1 (CAr), 135.1 (CAr), 136.0 (CAr), 139.6
3
3
(d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.79 (d, JH,H = 8.7 Hz, 2 H, 2
Ar-H), 7.99 (d, 4JH,H = 2.0 Hz, 1 H, Ar-H), 8.04 (d, 4JH,H = 2.0 Hz,
1 H, Ar-H), 8.63–8.65 (m, 1 H, Ar-H), 8.75–8.79 (m, 1 H, Ar-H),
9.68 (s, 1 H, Ar-H) ppm. 13C NMR (CDCl3, 50 MHz, 24 °C): δ =
13.2 (2 CH3), 45.3 (2 CH2), 55.3 (OCH3), 55.4 (OCH3), 113.3 (2
CHAr), 114.6 (2 CHAr), 116.2 (CAr), 121.0 (CHAr), 123.5 (CHAr),
128.1 (2 CHAr), 131.6 (2 CHAr), 132.0 (2 CHAr), 133.0 (CAr), 135.3
(CAr), 136.6 (CAr), 136.7 (CHAr), 140.0 (CAr), 148.8 (CAr), 148.9
(CHAr), 149.2 (CAr), 155.6 (CAr), 159.1 (CAr), 159.5 (CAr), 163.8
(CAr) ppm. HRMS: calcd. for C31H30N4O2 [M + H+] 491.2442;
found 491.2441.
(CAr), 149.0 (d, 5JC,F = 4.0 Hz, CAr), 157.0 (CAr), 159.1 (CAr), 159.4
2
(CAr), 163.9 (CAr), 164.2 (d, JC,F = 248.5 Hz, CAr) ppm.
C32H30FN3O2 (507.60): calcd. C 75.72, H 5.96, N 8.28; found C
75.86, H 5.71, N 8.33.
2-(4-Chlorophenyl)-N,N-diethyl-6,8-bis(4-methoxyphenyl)quin-
azolin-4-amine (9e): Yield 190 mg (71%); yellow solid; m.p. 158 °C.
3
1H NMR (CDCl3, 200 MHz, 24 °C): δ = 1.49 (t, JH,H = 6.9 Hz, 6
3
H, 2 CH3), 3.84 (q, JH,H = 7.1 Hz, 4 H, 2 CH2), 3.88 (s, 3 H,
3
OCH3), 3.94 (s, 3 H, OCH3), 7.04 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-
3
3
H), 7.09 (d, JH,H = 8.6 Hz, 2 H, 2 Ar-H), 7.40 (d, JH,H = 8.5 Hz,
2 H, 2 Ar-H), 7.63 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.82 (d, 3JH,H
= 8.6 Hz, 2 H, 2 Ar-H), 7.98 (d, JH,H = 1.8 Hz, 1 H, Ar-H), 8.03
3
N,N-Diethyl-6,8-bis(4-methoxyphenyl)-2-(5-methylthiophen-2-yl)-
quinazolin-4-amine (9i): Yield 69 % (179 mg); yellow solid; m.p.
3
(d, 3JH,H = 1.8 Hz, 1 H, Ar-H), 8.43 (d, 3JH,H = 8.5 Hz, 2 H, 2 Ar-
H) ppm. 13C NMR (CDCl3, 50 MHz, 24 °C): δ = 13.2 (2 CH3),
45.4 (2 CH2), 55.3 (OCH3), 55.4 (OCH3), 113.3 (2 CHAr), 114.5 (2
CHAr), 116.0 (CAr), 121.0 (CHAr), 128.1 (2 CHAr), 128.3 (2 CHAr),
129.7 (2 CHAr), 131.5 (CHAr), 131.6 (CAr), 132.0 (2 CHAr), 133.1
(CAr), 135.9 (CAr), 136.3 (CAr), 137.4 (CAr), 137.5 (CAr), 139.6
(CAr), 156.9 (CAr), 159.1 (CAr), 159.4 (CAr), 163.9 (CAr) ppm.
C32H30ClN3O2 (524.05): calcd. C 73.34, H 5.77, N 8.02; found C
73.17, H 5.68, N 8.01.
1
3
139 °C. H NMR (CDCl3, 200 MHz, 24 °C): δ = 1.47 (t, JH,H
=
3
6.9 Hz, 6 H, 2 CH3), 2.53 (s, 3 H, CH3), 3.80 (q, JH,H = 6.9 Hz, 4
H, 2 CH2), 3.88 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), 6.76 (d, 4JH,H
3
= 2.9 Hz, 1 H, Ar-H), 7.03 (d, JH,H = 8.6 Hz, 2 H, 2 Ar-H), 7.07
3
3
(d, JH,H = 8.6 Hz, 2 H, 2 Ar-H), 7.60 (d, JH,H = 8.6 Hz, 2 H, 2
Ar-H), 7.74 (d, 3JH,H = 3.5 Hz, 1 H, Ar-H), 7.83 (d, 3JH,H = 8.6 Hz,
4
4
2 H, 2 Ar-H), 7.94 (d, JH,H = 1.8 Hz, 1 H, Ar-H), 7.98 (d, JH,H
= 1.8 Hz, 1 H, Ar-H) ppm. 13C NMR (CDCl3, 50 MHz, 24 °C): δ
= 13.2 (2 CH3), 15.9 (CH3), 45.4 (2 CH2), 55.3 (OCH3), 55.4
(OCH3), 113.3 (2 CHAr), 114.6 (2 CHAr), 115.7 (CAr), 121.0
(CHAr), 126.4 (CHAr), 128.0 (2 CHAr), 128.5 (CHAr), 128.6 (CAr),
131.4 (CAr), 131.7 (CHAr), 132.1 (2 CHAr), 133.2 (CAr), 135.7 (CAr),
138.8 (CAr), 142.4 (CAr), 144.2 (CAr), 154.9 (CAr), 159.2 (CAr),
159.4 (CAr), 163.7 (CAr) ppm. C31H31N3O2S (509.66): calcd. C
73.05, H 6.13, N 8.24; found C 73.09, H 6.26, N 8.26.
N,N-Diethyl-6,8-bis(4-methoxyphenyl)-2-[4-(trifluoromethyl)phen-
yl]quinazolin-4-amine (9f): Yield 232 mg (82%); yellow solid; m.p.
1
3
143 °C. H NMR (CDCl3, 200 MHz, 24 °C): δ = 1.50 (t, JH,H
=
3
6.9 Hz, 6 H, 2 CH3), 3.87 (q, JH,H = 6.8 Hz, 4 H, 2 CH2), 3.89 (s,
3 H, OCH3), 3.94 (s, 3 H, OCH3), 7.05 (d, JH,H = 8.8 Hz, 2 H, 2
Ar-H), 7.09 (d, JH,H = 8.8 Hz, 2 H, 2 Ar-H), 7.64 (d, JH,H
3
3
3
=
3
8.8 Hz, 2 H, 2 Ar-H), 7.70 (d, JH,H = 8.2 Hz, 2 H, 2 Ar-H), 7.82
N,N-Diethyl-6,8-bis(4-methoxyphenyl)-2-(naphthalen-2-yl)quin-
azolin-4-amine (9j): Yield 244 mg (89%); yellow solid; m.p. 178 °C.
(d, 3JH,H = 8.8 Hz, 2 H, 2 Ar-H), 8.00 (d, 4JH,H = 1.8 Hz, 1 H, Ar-
4
3
3
H), 8.05 (d, JH,H = 1.8 Hz, 1 H, Ar-H), 8.57 (d, JH,H = 8.2 Hz,
2 H, 2 Ar-H) ppm. 13C NMR (CDCl3, 50 MHz, 24 °C): δ = 13.2
1H NMR (CDCl3, 200 MHz, 24 °C): δ = 1.53 (t, JH,H = 6.9 Hz, 6
3
H, 2 CH3), 3.90 (q, JH,H = 7.0 Hz, 4 H, 2 CH2), 3.89 (s, 3 H,
3
(2 CH3), 45.5 (2 CH2), 55.3 (OCH3), 55.4 (OCH3), 113.4 (2 CHAr),
OCH3), 3.97 (s, 3 H, OCH3), 7.05 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-
2
3
114.6 (2 CHAr), 116.0 (CAr), 121.0 (CHAr), 124.3 (q, JC,F
=
H), 7.14 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.46–7.52 (m, 2 H, 2
4
3
272.3 Hz, CF3), 125.1 (q, JC,F = 4.0 Hz, 2 CHAr), 128.2 (2 CHAr), Ar-H), 7.66 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.85–7.99 (m, 5 H,
3
4
4
128.7 (2 CHAr), 131.3 (q, JC,F = 31.8 Hz, CAr), 131.4 (CAr), 131.8 5 Ar-H), 8.01 (d, JH,H = 1.9 Hz, 1 H, Ar-H), 8.06 (d, JH,H
=
(CHAr), 132.0 (2 CHAr), 133.0 (CAr), 136.8 (CAr), 139.7 (CAr), 142.1 1.9 Hz, 1 H, Ar-H), 8.63 (dd, 3JH,H = 8.6, 4JH,H = 1.3 Hz, 1 H, Ar-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O50162
/KAP1
Date: 04-05-15 13:31:12
Pages: 13
Y. Kabri, M. D. Crozet, T. Terme, P. Vanelle
FULL PAPER
H), 9.04 (s, 1 H, Ar-H) ppm. 13C NMR (CDCl3, 50 MHz, 24 °C):
δ = 13.3 (2 CH3), 45.4 (2 CH2), 55.4 (2 OCH3), 113.3 (2 CHAr),
7.64–7.78 (m, 5 H, 5 Ar-H), 7.91 (s, 1 H, Ar-H), 8.03 (s, 2 H, 2
Ar-H), 9.26 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 62.5 MHz,
114.5 (2 CHAr), 116.1 (CAr), 121.1 (CHAr), 125.7 (CHAr), 125.8 24 °C): δ = 13.2 (2 CH3), 45.0 (2 CH2), 113.5 (CAr), 117.0 (CHAr),
(CHAr), 126.5 (CHAr), 127.6 (CHAr), 127.8 (CHAr), 128.1 (2 CHAr), 117.6 (CHAr), 120.2 (CHAr), 122.4 (CHAr), 126.8 (2 CHAr), 127.1
128.4 (CHAr), 129.2 (CHAr), 131.5 (CHAr), 131.7 (CAr), 132.1 (2 (CHAr), 127.4 (CHAr), 128.2 (2 CHAr), 129.3 (2 CHAr), 129.7
CHAr), 133.2 (CAr), 133.3 (CAr), 134.4 (CAr), 136.1 (CAr), 136.4 (CHAr), 130.3 (2 CHAr), 131.8 (CHAr), 132.7 (CAr), 133.1 (CAr),
(CAr), 139.6 (CAr), 148.9 (CAr), 157.8 (CAr), 159.2 (CAr), 159.4
138.1 (CAr), 139.8 (CAr), 140.0 (CAr), 142.9 (CAr), 150.6 (CAr),
(CAr), 164.0 (CAr) ppm. C36H33N3O2 (539.67): calcd. C 80.12, H 155.4 (CAr), 163.9 (CAr) ppm. C30H27ClN4 (479.02): calcd. C 75.22,
6.16, N 7.79; found C 79.36, H 6.12, N 7.70.
H 5.68, N 11.70; found C 75.19, H 5.59, N 11.34.
N2-(3-Chlorophenyl)-N4,N4-diethyl-6,8-bis(4-fluorophenyl)quin-
azoline-2,4-diamine (10d): Yield 120 mg (92%); yellow solid; m.p.
157 °C. 1H NMR ([D6]DMSO, 250 MHz, 24 °C): δ = 1.38 (t, 3JH,H
One-pot, Chemoselective SNAr/Bis-Suzuki–Miyaura Coupling Reac-
tion; General Procedure: A solution of 5b (0.1 g, 0.25 mmol) and 3-
chloroaniline (0.05 mL, 0.51 mmol, 2 equiv.) in EtOH (2.5 mL) was
heated at 110 °C under microwave irradiation for 1 h. After cool-
ing, boronic acid (0.56 mmol, 2.2 equiv.), PdCl2(PPh3)2 (9 mg,
0.013 mmol, 0.05 equiv.), K2CO3 (0.21 g, 1.53 mmol, 6 equiv.),
TBAB (0.08 g, 1 equiv., 0.25 mmol), and water (2.5 mL) were
added under argon. The mixture was heated at 100 °C for 1 h under
microwave irradiation. After cooling, water (80 mL) was added and
the solution was extracted with dichloromethane (3ϫ 60 mL). The
organic layer was washed with water (3 ϫ 100 mL), dried with
Na2SO4, and the solvents evaporated. The crude product was puri-
fied by column chromatography [silica gel, petroleum ether/ethyl
acetate (10%) (30% for 10e; 50% for 10h)] and recrystallized from
propan-2-ol.
3
= 6.8 Hz, 6 H, 2 CH3), 3.75 (q, JH,H = 6.8 Hz, 4 H, 2 CH2), 6.86
3
3
(d, JH,H = 7.9 Hz, 1 H, Ar-H), 7.13 (t, JH,H = 8.2 Hz, 1 H, Ar-
3
H), 7.26–7.35 (m, 4 H, 4 Ar-H), 7.55 (d, JH,H = 8.2 Hz, 1 H, Ar-
H), 7.73 (d, JH,H = 8.5 Hz, 1 H, Ar-H), 7.76 (d, JH,H = 8.7 Hz,
1 H, Ar-H), 7.81 (d, JH,H = 8.7 Hz, 1 H, Ar-H), 7.83 (d, JH,H
8.5 Hz, 1 H, Ar-H), 7.88 (d, JH,H = 1.7 Hz, 1 H, Ar-H), 7.98 (d,
4JH,H = 1.7 Hz, 1 H, Ar-H), 8.08 (s, 1 H, Ar-H), 9.28 (s, 1 H,
NH) ppm. 13C NMR ([D6]DMSO, 62.5 MHz, 24 °C): δ = 13.2 (2
CH3), 44.9 (2 CH2), 113.5 (CAr), 115.0 (d, 3JC,F = 21.1 Hz, 2 CHAr),
116.1 (d, JC,F = 21.1 Hz, 2 CHAr), 117.0 (CHAr), 117.5 (CHAr),
120.3 (CHAr), 122.5 (CHAr), 128.8 (d, JC,F = 8.3 Hz, 2 CHAr),
3
3
3
3
=
4
3
4
4
129.7 (CHAr), 131.6 (CAr), 131.7 (CHAr), 132.1 (d, JC,F = 8.3 Hz,
2 CHAr), 133.1 (CAr), 136.0 (d, 5JC,F = 3.2 Hz, CAr), 136.5 (d, 5JC,F
N2-(3-Chlorophenyl)-N4,N4-diethyl-6,8-bis(4-methoxyphenyl)quinaz-
oline-2,4-diamine (10a): Yield 120 mg (88 %); yellow solid; m.p.
= 3.2 Hz, CAr), 137.0 (CAr), 142.8 (CAr), 150.5 (CAr), 155.37 (CAr),
2
2
161.8 (d, JC,F = 243.6 Hz, CAr), 162.0 (d, JC,F = 244.5 Hz, CAr),
163.5 (CAr) ppm. C30H25ClF2N4 (515.00): calcd. C 69.97, H 4.89,
N 10.88; found C 69.98, H 4.49, N 10.58.
1
3
167 °C. H NMR (CDCl3, 250 MHz, 24 °C): δ = 1.44 (t, JH,H
=
3
7.0 Hz, 6 H, 2 CH3), 3.75 (q, JH,H = 7.0 Hz, 4 H, 2 CH2), 3.88 (s,
3 H, OCH3), 3.91 (s, 3 H, OCH3), 6.88 (d, JH,H = 7.9 Hz, 1 H,
Ar-H), 7.01–7.14 (m, 6 H, 6 Ar-H), 7.27 (d, JH,H = 7.9 Hz, 1 H,
Ar-H), 7.60 (d, JH,H = 8.7 Hz, 2 H, 2 Ar-H), 7.71 (d, JH,H
3
3
N2-(3-Chlorophenyl)-N4,N4-diethyl-6,8-bis(3,4,5-trimethoxyphen-
yl)quinazoline-2,4-diamine (10e): Yield 149 mg (89%); yellow solid;
3
3
=
8.6 Hz, 2 H, 2 Ar-H), 7.86 (d, 4JH,H = 2.0 Hz, 1 H, Ar-H), 7.95 (d,
4JH,H = 2.0 Hz, 1 H, Ar-H), 8.03 (s, 1 H, NH) ppm. 13C NMR
(CDCl3, 62.5 MHz, 24 °C): δ = 13.2 (2 CH3), 45.3 (2 CH2), 55.3
(OCH3), 55.4 (OCH3), 113.6 (2 CHAr), 114.1 (CAr), 114.5 (2 CHAr),
116.1 (CHAr), 117.9 (CHAr), 120.9 (CHAr), 121.5 (CHAr), 127.8 (2
CHAr), 129.3 (CHAr), 131.4 (2 CHAr), 131.7 (CHAr), 132.2 (CAr),
133.3 (CAr), 133.4 (CAr), 134.4 (CAr), 138.2 (CAr), 141.8 (CAr),
150.6 (CAr), 155.0 (CAr), 158.9 (CAr), 159.1 (CAr), 164.8 (CAr) ppm.
C32H31ClN4O2 (536.07): calcd. C 71.30, H 5.80, N 10.39; found C
71.18, H 5.64, N 10.28.
1
m.p. 198 °C. H NMR ([D6]DMSO, 250 MHz, 24 °C): δ = 1.43 (t,
3
3JH,H = 6.8 Hz, 6 H, 2 CH3), 3.71 (s, 3 H, OCH3), 3.73 (q, JH,H
= 6.5 Hz, 4 H, 2 CH2), 3.75 (s, 3 H, OCH3), 3.78 (s, 6 H, 2 OCH3),
3
3.89 (s, 6 H, 2 OCH3), 6.86 (d, JH,H = 7.9 Hz, 1 H, Ar-H), 6.99
3
(s, 2 H, 2 Ar-H), 7.02 (s, 2 H, 2 Ar-H), 7.10 (t, JH,H = 8.2 Hz, 1
3
H, Ar-H), 7.72 (d, JH,H = 8.4 Hz, 1 H, Ar-H), 7.99 (s, 1 H, Ar-
H), 8.00 (s, 1 H, Ar-H), 8.16 (s, 1 H, Ar-H), 9.29 (s, 1 H, NH) ppm.
13C NMR ([D6]DMSO, 62.5 MHz, 24 °C): δ = 13.2 (2 CH3), 44.9
(2 CH2), 55.9 (2 OCH3), 56.2 (2 OCH3), 60.1 (OCH3), 60.3
(OCH3), 104.3 (2 CHAr), 107.8 (2 CHAr), 113.3 (CAr), 116.8
(CHAr), 117.6 (CHAr), 120.1 (CHAr), 122.3 (CHAr), 129.6 (CHAr),
131.8 (CHAr), 132.8 (CAr), 133.2 (CAr), 135.5 (CAr), 135.9 (CAr),
136.8 (CAr), 137.2 (CAr), 138.1 (CAr), 142.9 (CAr), 150.4 (CAr),
152.6 (2 CAr), 153.6 (2 CAr), 155.3 (CAr), 163.9 (CAr) ppm.
C36H39ClN4O6 (659.17): calcd. C 65.60, H 5.96, N 8.50; found C
65.71, H 5.85, N 8.34.
N2-(3-Chlorophenyl)-N4,N4-diethyl-6,8-bis(p-tolylphenyl)quin-
azoline-2,4-diamine (10b): Yield 110 mg (85%); yellow solid; m.p.
149 °C. 1H NMR ([D6]DMSO, 250 MHz, 24 °C): δ = 1.38 (t, 3JH,H
= 6.6 Hz, 6 H, 2 CH3), 2.35 (s, 3 H, CH3), 2.39 (s, 3 H, CH3), 3.73
3
3
(q, JH,H = 6.5 Hz, 4 H, 2 CH2), 6.84 (d, JH,H = 7.1 Hz, 1 H, Ar-
3
3
H), 7.12 (t, JH,H = 7.7 Hz, 1 H, Ar-H), 7.29 (d, JH,H = 7.9 Hz, 4
3
3
H, 4 Ar-H), 7.58 (d, JH,H = 7.9 Hz, 2 H, 2 Ar-H), 7.66 (d, JH,H
= 8.1 Hz, 3 H, 3 Ar-H), 7.85 (s, 1 H, Ar-H), 7.96 (s, 1 H, Ar-H),
8.08 (s, 1 H, Ar-H), 9.23 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
62.5 MHz, 24 °C): δ = 13.2 (2 CH3), 20.8 (CH3), 21.1 (CH3), 44.9 (2
CH2), 113.5 (CAr), 117.0 (CHAr), 117.5 (CAr), 120.2 (CHAr), 121.8
(CHAr), 126.6 (3 CHAr), 128.8 (CHAr), 129.7 (CAr), 129.9 (4 CHAr),
130.1 (2 CHAr), 131.3 (CHAr), 132.7 (CAr), 133.2 (CAr), 136.2 (CAr),
136.7 (CAr), 137.2 (CAr), 138.1 (CAr), 142.9 (CAr), 155.2 (CAr),
163.9 (CAr) ppm. C32H31ClN4 (507.07): calcd. C 75.80, H 6.16, N
11.05; found C 75.93, H 6.14, N 10.86.
N2-(3-Chlorophenyl)-N4,N4-diethyl-6,8-bis[4-(trifluoromethyl)-
phenyl]quinazoline-2,4-diamine (10f): Yield 130 mg (83%); yellow
solid; m.p. 161 °C. 1H NMR ([D6]DMSO, 250 MHz, 24 °C): δ =
3
3
1.39 (t, JH,H = 6.5 Hz, 6 H, 2 CH3), 3.76 (d, JH,H = 6.8 Hz, 4 H,
2 CH2), 6.84 (d, 3JH,H = 8.1 Hz, 1 H, Ar-H), 7.10 (t, 3JH,H = 7.9 Hz,
3
3
1 H, Ar-H), 7.46 (d, JH,H = 7.7 Hz, 1 H, Ar-H), 7.82 (d, JH,H
=
3
8.7 Hz, 4 H, 4 Ar-H), 7.93 (d, JH,H = 8.4 Hz, 2 H, 2 Ar-H), 8.00
3
(d, JH,H = 7.5 Hz, 3 H, 3 Ar-H), 8.11 (s, 2 H, 2 Ar-H), 9.36 (s, 1
H, NH) ppm. 13C NMR ([D6]DMSO, 62.5 MHz, 24 °C): δ = 13.2
(2 CH3), 45.0 (2 CH2), 113.5 (CAr), 117.0 (CHAr), 117.6 (CHAr),
120.5 (CHAr), 124.0 (CHAr), 124.6 (q, 2JC,F = 272.1 Hz, CF3), 124.8
N2-(3-Chlorophenyl)-N4,N4-diethyl-6,8-diphenylquinazoline-2,4-di-
amine (10c): Yield 101 mg (83%); yellow solid; m.p. 153 °C. 1H (q, 2JC,F = 272.1 Hz, CF3), 125.1 (q, 4JC,F = 3.2 Hz, 2 CHAr), 126.1
4
3
NMR ([D6]DMSO, 250 MHz, 24 °C): δ = 1.40 (br. s, 6 H, 2 CH3), (q, JC,F = 3.2 Hz, 2 CHAr), 127.6 (2 CHAr), 128.7 (q, JC,F
=
3
3
3.75–3.77 (br. s, 4 H, 2 CH2), 6.84 (d, JH,H = 7.4 Hz, 1 H, Ar-H),
30.1 Hz, CAr), 128.8 (q, JC,F = 32.7 Hz, CAr), 129.7 (CHAr), 130.9
3
7.11 (t, JH,H = 7.4 Hz, 1 H, Ar-H), 7.38–7.50 (m, 6 H, 6 Ar-H),
(CAr), 131.0 (2 CHAr), 131.8 (CAr), 131.9 (CHAr), 133.2 (CAr), 136.7
10
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Pages: 13
2,6,8-Trisubstituted 4-Aminoquinazolines
(CAr), 142.6 (CAr), 143.9 (CAr), 151.1 (CAr), 155.8 (CAr), 163.5
(CAr) ppm. C32H25ClF6N4 (615.01): calcd. C 62.49, H 4.10, N 9.11;
found C 62.33, H 3.93, N 8.91.
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N2-(3-Chlorophenyl)-N4,N4-diethyl-6,8-bis(3-nitrophenyl)quin-
azoline-2,4-diamine (10g): Yield 130 mg (90%); yellow solid; m.p.
192 °C. 1H NMR ([D6]DMSO, 250 MHz, 24 °C): δ = 1.41 (t, 3JH,H
3
= 6.3 Hz, 6 H, 2 CH3), 3.77 (q, JH,H = 6.7 Hz, 4 H, 2 CH2), 6.82
3
3
(d, JH,H = 7.6 Hz, 1 H, Ar-H), 7.08 (t, JH,H = 7.9 Hz, 1 H, Ar-
[2]
[3]
3
H), 7.46 (d, JH,H = 8.1 Hz, 1 H, Ar-H), 7.73–7.83 (m, 2 H, 2 Ar-
H), 8.05 (s, 1 H, Ar-H), 8.12 (s, 2 H, 2 Ar-H), 8.19 (d, JH,H
3
=
3
7.7 Hz, 2 H, 2 Ar-H), 8.28 (t, JH,H = 7.7 Hz, 2 H, 2 Ar-H), 8.56
(s, 1 H, Ar-H), 8.63 (s, 1 H, Ar-H), 9.38 (s, 1 H, NH) ppm. 13C
NMR ([D6]DMSO, 62.5 MHz, 24 °C): δ = 13.1 (2 CH3), 45.0 (2
CH2), 113.5 (CAr), 117.1 (CHAr), 117.5 (CHAr), 120.5 (CHAr),
121.2 (CHAr), 122.1 (CHAr), 122.2 (CHAr), 124.2 (CHAr), 125.4
(CHAr), 129.6 (CHAr), 129.9 (CHAr), 130.1 (CAr), 130.7 (CHAr),
131.8 (CHAr), 133.1 (CAr), 133.3 (CHAr), 135.5 (CAr), 136.9 (CHAr),
141.0 (CAr), 141.3 (CAr), 142.5 (CAr), 147.7 (CAr), 148.7 (CAr),
151.0 (CAr), 155.8 (CAr), 163.5 (CAr) ppm. C30H25ClN6O4 (569.01):
calcd. C 63.32, H 4.43, N 14.77; found C 62.79, H 4.29, N 14.34.
[4]
[5]
N2-(3-Chlorophenyl)-N4,N4-diethyl-6,8-di(pyridin-3-yl)quinazoline-
2,4-diamine (10h): Yield 101 mg (83%); yellow solid; m.p. 183 °C.
3
1H NMR ([D6]DMSO, 250 MHz, 24 °C): δ = 1.40 (t, JH,H
=
3
7.0 Hz, 6 H, 2 CH3), 3.78 (q, JH,H = 7.1 Hz, 4 H, 2 CH2), 6.86
3
4
3
(dd, JH,H = 7.7, JH,H = 1.1 Hz, 1 H, Ar-H), 7.13 (t, JH,H
=
8.1 Hz, 1 H, Ar-H), 7.50–7.60 (m, 3 H, 3 Ar-H), 7.98 (s, 1 H, Ar-
3
4
H), 8.08 (dd, JH,H = 9.3, JH,H = 1.7 Hz, 2 H, 2 Ar-H), 8.16–8.24
(m, 2 H, 2 Ar-H), 8.58–8.62 (m, 2 H, 2 Ar-H), 8.90 (s, 1 H, Ar-H),
9.04 (s, 1 H, Ar-H), 9.33 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
62.5 MHz, 24 °C): δ = 13.2 (2 CH3), 45.0 (2 CH2), 113.4 (CAr),
117.1 (CAr), 117.7 (CAr), 120.4 (CAr), 123.2 (CHAr),123.6 (CHAr),
124.2 (CHAr), 129.5 (CHAr), 129.8 (CHAr), 131.8 (CHAr), 133.1
(CAr), 134.3 (CHAr), 134.8 (CAr), 135.2 (CAr), 135.4 (CHAr), 137.8
(CHAr), 142.7 (CHAr), 147.9 (CHAr), 148.2 (CHAr), 148.5 (CHAr),
150.5 (CAr), 151.1 (CHAr), 155.7 (CAr), 163.5 (CAr) ppm.
C28H25ClN6 (480.99): calcd. C 69.92, H 5.24, N 17.47; found C
69.60, H 5.16, N 17.20.
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a) P.-P. Kung, M. D. Casper, K. L. Cook, L. Wilson-Lingardo,
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622.
N2-(3-Chlorophenyl)-N4,N4-diethyl-6,8-bis(5-methylthiophen-2-yl)-
quinazoline-2,4-diamine (10i): Yield 91 mg (69%); yellow solid; m.p.
168 °C. 1H NMR ([D6]DMSO, 250 MHz, 24 °C): δ = 1.40 (t, 3JH,H
= 6.8 Hz, 6 H, 2 CH3), 2.48 (s, 3 H, CH3), 2.49 (s, 3 H, CH3), 3.69
3
(q, JH,H = 7.0 Hz, 4 H, 2 CH2), 6.84–6.86 (m, 2 H, 2 Ar-H), 6.95
3
4
3
(dd, JH,H = 7.9, JH,H = 1.3 Hz, 1 H, Ar-H), 7.25 (t, JH,H
=
3
8.1 Hz, 1 H, Ar-H), 7.39 (d, JH,H = 3.5 Hz, 1 H, Ar-H), 7.57 (d,
3JH,H = 8.2 Hz, 1 H, Ar-H), 7.63 (d, JH,H = 3.5 Hz, 1 H, Ar-H),
3
4
4
7.79 (d, JH,H = 1.5 Hz, 1 H, Ar-H), 8.12 (d, JH,H = 1.5 Hz, 1 H,
Ar-H), 8.35 (s, 1 H, Ar-H), 9.30 (s, 1 H, NH) ppm. 13C NMR ([D6]-
DMSO, 62.5 MHz, 24 °C): δ = 13.2 (2 CH3), 15.2 (CH3), 15.3
(CH3), 45.0 (2 CH2), 113.3 (CAr), 117.7 (CHAr), 118.6 (CHAr),
119.8 (CHAr), 120.7 (CHAr), 123.7 (CHAr), 125.3 (CHAr), 126.6
(CHAr), 126.7 (CAr), 127.2 (CHAr), 127.3 (CHAr), 129.9 (CHAr),
130.4 (CAr), 133.2 (CAr), 137.0 (CAr), 139.1 (CAr), 140.8 (CAr),
141.3 (CAr), 142.4 (CAr), 149.1 (CAr), 155.2 (CAr), 163.6 (CAr) ppm.
HRMS: m/z calcd. for C28H27ClN4S2 [M + H+] 519.1438; found
519.1437.
[10]
[11]
[12]
[13]
Acknowledgments
This work was supported by the Centre National de la Recherche
Scientifique (CNRS) and Aix-Marseille Université. The authors
thank V. Remusat for NMR spectra recording and the Spectropole
team for various analytical measurements.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11

Job/Unit: O50162
/KAP1
Date: 04-05-15 13:31:12
Pages: 13
Y. Kabri, M. D. Crozet, T. Terme, P. Vanelle
FULL PAPER
[16] A. Zabeer, A. Bhagat, O. P. Gupta, G. D. Singh, M. S. Yous-
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G. P. Zhikhareva, V. A. Bondarenko, S. D. Yuzhakov, O. V.
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Zh. 1987, 21, 802–807.
Received: February 2, 2015
Published Online: ᭿
12
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Job/Unit: O50162
/KAP1
Date: 04-05-15 13:31:12
Pages: 13
2,6,8-Trisubstituted 4-Aminoquinazolines
Nitrogen Heterocycles
Y. Kabri, M. D. Crozet, T. Terme,
P. Vanelle* ...................................... 1–13
Efficient Access to 2,6,8-Trisubstituted 4-
Aminoquinazolines through Microwave-
Assisted One-Pot Chemoselective Tris-
Suzuki–Miyaura or SNAr/Bis-Suzuki–
Miyaura Reactions in Water
Keywords: Synthetic methods / Microwave
chemistry / Cross-coupling / Chemoselec-
tivity / Regioselectivity / Palladium / Nitro-
gen heterocycles
A sequential, one-pot strategy for syn-
thesizing polyfunctionalized quinazoline
derivatives in good to excellent yields in
only a few steps and in the environmentally
benign solvent water is presented. The ap-
proach uses
a chemoselective Suzuki–
Miyaura reaction.
Eur. J. Org. Chem. 0000, 0–0
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13