Regioselective Suzuki-Miyaura reaction: Application to the microwave-promoted synthesis of 4,7-diarylquinazolines

Article abstract of DOI:10.3390/molecules15052949

New diarylquinazolines displaying pharmaceutical potential were synthesized in high yields from 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline by using microwave-promoted regioselective Suzuki-Miyaura cross-coupling reactions.

Full text of DOI:10.3390/molecules15052949

Molecules 2010, 15, 2949-2961; doi:10.3390/molecules15052949
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Regioselective Suzuki-Miyaura Reaction: Application to the
Microwave-promoted Synthesis of 4,7-Diarylquinazolines
Youssef Kabri, Pierre Verhaeghe, Armand Gellis and Patrice Vanelle *
Laboratoire de Pharmacochimie Radicalaire, Faculté de Pharmacie, Universités d’Aix-Marseille I, II et
III - UMR CNRS 6264 , Laboratoire Chimie Provence, 27 Boulevard Jean Moulin, 13385 Marseille
cedex 05, France; E-Mails: youssef.kabri@univmed.fr (Y.K.); pierre.verhaeghe@univmed.fr (P.V.);
armand.gellis@univmed.fr (A.G.)
* Author to whom correspondence should be addressed; E-Mail: patrice.vanelle@univmed.fr;
Tel.: +33 491 835 580; Fax: +33 491 794 677.
Received: 24 March 2010; in revised form: 8 April 2010 / Accepted: 21 April 2010 /
Published: 27 April 2010
Abstract: New diarylquinazolines displaying pharmaceutical potential were synthesized in
high yields from 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline by using
microwave-promoted regioselective Suzuki-Miyaura cross-coupling reactions.
Keywords: quinazoline; Suzuki-Miyaura reaction; microwaves; SRN1
Introduction
In 1979, Suzuki and Miyaura introduced organoboron reagents into the realm of cross-coupling
chemistry, by demonstrating a palladium-catalyzed reaction of 1-alkenylboranes with aryl and alkynyl
halides [1,2]. Since its discovery, this reaction, which is now referred to as the Suzuki-Miyaura
reaction, has seen significant advancement and has become one of the most powerful carbon-carbon
bond forming methods in organic synthesis [3–6]. The process has important advantages including
functional group compatibility, low toxicity of reagents and intermediates, easy availability of boron
derivatives, high thermal stability and good tolerance toward oxygen and aqueous solvents. Recently,
organic chemists have turned their work to the application of this reaction to the synthesis of more
complex molecules, by using successive Suzuki-Miyaura cross coupling reactions with substrates

Molecules 2010, 15
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containing two or more possible reactive sites. One of the solutions to obtain the desired cross-
coupling products in a selective manner, by assembling such multi-functionalized compounds, is to
favor one of the possible reaction sites [7,8]. Herein, we will describe a regioselective method based
on the modulation of the reaction conditions.
Quinazoline is an important molecular scaffold due to the large variety of pharmacological
properties associated with derivatives based on this heterocyclic system [9]. Especially, their
importance as selective anticancer chemotherapy agents appears unparalleled and attracts the attention
of many pharmaceutical research teams worldwide [10–13]. Focusing on quinazoline substrates, our
group also quite recently described the preparation of new 2-substituted-quinazoline derivatives which
exhibit original antiplasmodial properties [14–16].
In other respects, microwaves, as a non-conventional source of energy, have become a very popular
and useful technology in organic chemistry [17]. The main attraction of using microwaves is the
possibility of achieving short reaction times in cleaner systems [18–20], even under solventless
conditions [21,22]. Microwave irradiation is a simple, rapid and effective method for transferring
energy to a polar reaction medium [23]. Consequently, microwave irradiation has been widely applied
in organic synthesis, including C-C cross-coupling reactions [24,25].
In continuation of the recent Suzuki-Miyaura monocoupling reactions which we presented in the
original 2-(2-methylprop-1-enyl)-6-nitroquinazoline series [26], we investigated the synthesis of a
series of new biarylsubstituted-quinazolines, via a regioselective Suzuki-Miyaura cross coupling
reaction. It was already known in literature [27,28] that the quinazoline C4 position is quite
electrophilic. We therefore investigated the possibility of using 4,7-dichloro-2-(2-methylprop-1-enyl)-
6-nitroquinazoline (5) with various arylboronic acids, aiming at preparing dissymmetric biaryl-
substituted quinazolines, taking into account that chlorinated aromatic carbon atoms, at position  of a
nitro group, also display a high reactivity when involved in palladium-catalyzed coupling
reactions [29].
Results and Discussion
The synthesis of the starting material, 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline (5),
is presented in Scheme 1. The global synthesis strategy was developed in our research group for the
preparation of closely related analogs [30]. Compound 5 was obtained from commercial 2-amino-4-
chlorobenzonitrile in good yield after five steps, under microwave irradiation. The first step is the
condensation between 2-amino-4-chlorobenzonitrile and chloroacetyl chloride, followed by
intramolecular cyclisation, to give product 2 in 67% yield [31]. Then, nitration at the 6 position gave
the expected product 3 (74% yield), followed by a SRN1 reaction with the lithium salt of 2-
nitropropane [32,33] leading to the ethylenic derivative 4 (76% yield). Finally, a microwave-assisted
chlorination reaction using phosphorus oxychloride in the presence of N,N-diethylaniline gave product
5, bearing two chlorine atoms in positions 4 and 7 (87% yield).

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Scheme 1. Synthesis of starting material 5.
O
CN
CN
O
NH
O
i
ii
Cl
+
Cl
Cl
Cl
Cl
N
Cl
N
Cl
NH2
2
H
1
71%
95%
iii
Cl
N
O
N
O
N
O2N
Cl
O2N
Cl
O2N
Cl
N
CH3
iv
NH
v
NH CH3
Cl
CH3
CH3
3
5
4
74%
76%
87%
Reaction conditions: i) MW, 150 W, 50 °C, 5 min; ii) UHP (Urea Hydrogen Peroxide), K2CO3,
H2O/Acetone (1/1), MW, 500 W, 70 °C, 1.5 h; iii) H2SO4, HNO3, r.t, 4 h; iv) 2-nitropropane
lithium salt, methanol, MW, 500 W, 70 °C, 2 h; v) diethylaniline, POCl3, toluene, MW, 500 W,
110 °C, 2 h
The 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline (5) was engaged in a double Suzuki-
Miyaura coupling study with the purpose of identifying reaction conditions which would provide
regioselectivity between the 4 and 7 chlorinated positions of the quinazoline ring (Scheme 2). We
started by using 4 equiv. of 4-methoxyphenylboronic acid, 4 equiv. of Na2CO3 and 2.5 mol % of
Pd(PPh3)4. As suggested by Connolly and co-workers [34], a DME/ethanol (9:1, v/v) mixture was used
as solvent and the reaction was heated with microwave irradiation.
Scheme 2. Regioselective Suzuki-Miyaura reaction.
Cl
Ar
Ar
ArB(OH)2
O2N
Cl
O2N
Cl
O2N
CH3 Ar
Pd(PPh3)4 (2.5 %mol)
N
CH3
CH3
N
CH3
N
CH3
CH3
Na2CO3 (3 equiv)
Ethanol, DME
N
N
N
5
7
6
MW, 300 W, 80 °C, 3 h
6a : Ar = 4-MeO-Ph
6b : Ar = 4-Cl-Ph
6c : Ar = 3-CF3-Ph
7a : Ar = 4-MeO-Ph
7b : Ar = 4-Cl-Ph
7f : Ar = Ph
6d : Ar = 5-CH3-2-thienyl
6e : Ar = 3-NO2-Ph
7g : Ar = 4-F-Ph
7h : Ar = 2-tolyl
Under such conditions, only the double-coupled compound 7a was obtained, in 70% yield, as
presented in Table 1 (Entry 1), showing that both positions were reactive as regards of the Suzuki-
Miyaura reaction.
To minimize double coupling and substitute at the 4-position selectively, we decreased the amount
of arylboronic acid. Using 1.5 equiv. of 4-methoxyphenylboronic acid (Entry 2), some selectivity
appeared, the reaction mixture containing both the monosubstituted product 6a (45% yield) and the
disubstituted product 7a (15% yield). However, a complete selectivity was observed with 1.2 equiv. of

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4-methoxyphenylboronic acid. The monosubstituted product 6a was then obtained in good yield (68%,
Entry 3). This result indicates the possibility of achieving a selective coupling reaction at the C4
position, while preventing the chlorinated C7 position from reacting. The monocoupling at the 4-
position was checked by NOESY spectrum, where a strong correlation between H-5 (8.65 ppm) and
H-2’ (7.77 ppm) was observed.
Table 1. Regioselective Suzuki-Miyaura coupling reaction.
Entry
Arylboronic acid Aryl-
4-MeO-Ph-
Equiv. of Boronic acid Yield % (6/7)
1
2
4.0
1.5
1.2
4.0
2.0
1.5
1.5
2.0
1.5
2.0
1.5
0 / 70
45 / 15
68 / 0
0 / 67
42 / 13
63 / 0
48 / 0
72 / 0
61 / 0
55 / 0
43 / 0
4-MeO-Ph-
3
4-MeO-Ph-
4
4-Cl-Ph-
5
4-Cl-Ph-
6
4-Cl-Ph-
7
3-CF3-Ph-
8
5-CH3-2-thienyl-
5-CH3-2-thienyl-
3-NO2-Ph-
9
10
11
3-NO2-Ph-
Reaction conditions: Pd(PPh3)4 (2.5 mol %), Na2CO3 (3-4 equiv), DME/ethanol (9:1), MW 300 W,
80 °C, 3 h
Starting from this initial encouraging result, the influence of both electron-withdrawing and
electron-donating substituents on arylboronic acids was investigated next. The reactions with 1.5
equiv. of 4-chlorophenylboronic or 3-trifluoromethylphenylboronic acid provided the monosubstituted
products 6b or 6c in 63 and 48% yields, respectively (Entries 6 and 7). The reaction of 5 with 3-nitro-
phenylboronic acid offered lower reactivity in comparison with the reaction of 5 with 4-methoxy-
phenylboronic acid but higher regioselectivity, especially when 2 equiv. of arylboronic acid were used
(Entry 10), leading to the monosubstituted product 6e in 55% yield. A possible explanation for the
lower reactivity and good regioselectivity observed when using 3-nitro or 3-trifluorophenylboronic
acid and 5-methylthiophen-2-ylboronic acid could result from the chelation of the Lewis basic
heteroatoms to the palladium intermediate. Such chelation could be retarding the rate of the reductive
elimination step [35]. By using the preceding best conditions for the double coupling reaction, defined
for the preparation of compounds 7a and 7b, three more symmetric diarylquinazolines 7f-h were
synthesized in good yields (Table 2).
Table 2. Double Suzuki-Miyaura coupling reaction extensions in optimal conditions.
Entry
Aryl-
Ph-
4-F-Ph-
2-Tolyl-
Product
Yield %
1
2
3
85
71
65
7f
7g
7h
Reaction conditions: arylboronic acid (4 equiv.), Pd(PPh3)4 (2.5 mol %), Na2CO3 (4 equiv.),
DME/ethanol (9:1), MW 300 W, 80 °C, 3 h

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In order to achieve the second coupling reaction at the C7 position of monosubstituted product 6a,
and obtain dissymmetric diarylquinazolines, we started by using 2 equiv. of arylboronic acid, 3 equiv.
of Na2CO3, 2.5 mol % of Pd(PPh3)4 and a refluxing mixture of DME/ethanol (9:1, v/v). After 3 h,
under microwave irradiation, starting material 6a and the diarylsubstituted product 8 were obtained in
a 1:1 ratio (27% yield), indicating the lack of reactivity of the C7 quinazoline position under such
reaction conditions, probably due to the insufficient solubility of 6a in the reaction mixture.
We then proceeded to modify the operating procedure. The DME/ethanol solvent mixture was
changed for a DMF/ethanol (9:1) mixture which was refluxed under microwave irradiation (Scheme
3). After 3 h, all the starting material was consumed. A series of dissymmetric diarylquinazolines 8-16
was thus synthesized in good yields via this optimized coupling reaction between 6a or 6b and various
arylboronic acids, as indicated in Table 3.
Scheme 3. Cross coupling reaction at position 7.
Ar1
Ar1
O2N
Ar2
O2N
Cl
N
CH3
CH3
N
CH3
CH3
N
N
6a or b
8-16
Reaction conditions: arylboronic acid (2 equiv.), Pd(PPh3)4 (2.5 mol %), Na2CO3 (3 equiv.),
DMF/ethanol (9 : 1), MW 300 W, 150 °C, 3 h
Table 3. Suzuki-Miyaura reactions between monosubstituted products 6a or 6b and
various arylboronic acids.
Entry
Aryl 1
4-MeO-Ph-
4-MeO-Ph-
4-MeO-Ph-
4-MeO-Ph-
4-MeO-Ph-
4-Cl-Ph-
Aryl 2
4-Cl-Ph-
Ph-
Product
Yield %
1
2
3
4
5
6
7
8
9
8
55
64
43
50
57
54
62
57
58
9
4-F-Ph-
2-Tolyl-
3-CF3-Ph-
4-MeO-Ph-
Ph-
10
11
12
13
14
15
16
4-Cl-Ph-
4-Cl-Ph-
4-F-Ph-
2-Tolyl-
4-Cl-Ph-
Reaction conditions: arylboronic acid (2 equiv.), Pd(PPh3)4 (2.5 mol %), Na2CO3 (3 equiv.),
DMF/ethanol (9 : 1), MW 300 W, 150 °C, 3 h
Experimental
General
Melting points were determined on a Büchi B-540 apparatus and are uncorrected. Elemental
analyses were performed by the Microanalyses Center of the University of Aix-Marseille 3, France.
Both 1H- and 13C-NMR spectra were determined on a Bruker ARX 200 spectrometer. The 1H chemical
shifts are reported as ppm downfield from tetramethylsilane (Me4Si), and the 13C chemical shifts were

Molecules 2010, 15
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referenced to the solvent peak: CDCl3 (76.9 ppm) or DMSO-d6 (39.5 ppm). Solvents were dried by
conventional methods. The following adsorbent was used for column chromatography: silica gel 60
(Merck, particle size 0.063-0.200 mm, 70-230 mesh ASTM). TLC was performed on 5 cm × 10 cm
aluminium plates coated with silica gel 60F-254 (Merck) in an appropriate solvent.
Microwave instrumentation
Multimode reactor: ETHOS Synth Lab station and MicroSYNTH Lab terminal 1024 (Ethos start,
Milestone Inc.). The multimode microwave has a twin magnetron (2 × 800 W, 2.45 GHz) with a
maximum delivered power of 1,000 W in 10 W increments (pulsed irradiation). Built-in magnetic
stirring (Teflon-coated stirring bar) was used in all operations. During experiments, time, temperature
and power were measured with the “easy WAVE” software package. The temperature was measured
throughout the reaction and evaluated by an infrared detector or a optical fiber (ATC-FO 300).
Synthesis
2-Chloro-N-(5-chloro-2-cyanophenyl)acetamide (1) [36] and 7-chloro-2-(chloromethyl)quinazolin-
4(3H)-one (2) [31] were prepared as previously described.
7-Chloro-2-(chloromethyl)-6-nitroquinazolin-4(3H)-one (3)
To a solution of 7-chloro-2-(chloromethyl)quinazolin-4(3H)-one (2, 3 g, 13.1 mmol) in
concentrated sulfuric acid (40 mL), fuming nitric acid (3.26 mL) was added dropwise at 0 °C. The
reaction mixture was stirred at rt for 4 h, poured into crushed ice (100 mL). A precipitate appeared and
was filtered, washed with water (3 × 20 mL) and dried in a vacuum drying oven (dessicator cabinet).
Recrystallization from propan-2-ol gave 2.66 g. of the title compound. Yield 74%; yellow solid, mp
1
13
241 °C. H-NMR (200 MHz, DMSO-d6): 8.69 (1H, s), 8.07 (1H, s), 4.59 (2H, s); C-NMR (50
MHz, DMSO-d6):  = 160.3, 157.0, 151.2, 145.3, 130.9, 130.2, 124.4, 120.7, 43.0; Anal. calcd. for
C9H5Cl2N3O3: C, 39.44; H, 1.84; N, 15.33 %. Found: C, 39.24; H, 1.85; N, 15.26 %.
7-Chloro-2-(2-methylprop-1-enyl)-6-nitroquinazolin-4(3H)-one (4)
7-Chloro-2-(chloromethyl)-6-nitroquinazolin-4(3H)-one (3, 1 g, 3.65 mmol) was added to a
solution of the lithium salt of 2-nitropropane (1.37 g, 14.6 mmol) in methanol (40 mL). The reaction
mixture was irradiated in a microwave oven, at 70 °C, for 2 h at a power of 500 W. After evaporation
of methanol, the residue was dissolved in ethyl acetate (50 mL) and washed with water (3 × 100 mL).
The organic layer was dried over magnesium sulphate and the solvent was removed under vacuum. A
yellow solid was obtained, which was recrystallized from propan-2-ol to give 7-chloro-2-(2-
methylprop-1-enyl)-6-nitro-quinazolin-4(3H)-one (4) (0.78 g, yield 76%); yellow solid, mp 267 °C.
1H-NMR (200 MHz, DMSO-d6):  = 8.61 (1H, s), 7.88 (1H, s), 6.06 (1H, s), 2.34 (3H, s), 1.98 (3H, s);
13C-NMR (50 MHz, DMSO-d6):  = 160.6, 155.9, 155.1, 152.2, 143.9, 130.7, 129.8, 124.5, 119.6,
116.9, 28.3, 21.2; Anal. calcd. for C12H10ClN3O3: C, 51.53; H, 3.60; N, 15.02 %. Found: C, 51.54; H,
3.64; N, 14.92 %.

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4,7-Dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline (5)
7-Chloro-2-(2-methylprop-1-enyl)-6-nitroquinazolin-4(3H)-one (4, 0.5 g, 1.79 mmol) was
dissolved in toluene (40 mL). Diethylaniline (0.86 mL, 5.37 mmol) and phosphorus oxychloride
(0.33 mL, 3.58 mmol) were added. The mixture was heated to 110 °C in the microwave oven
irradiating with 500 W for 2 h. After cooling and hydrolysis with 100 mL of water, the mixture was
extracted with dichloromethane (3 × 50 mL). The combined organic extracts were washed with water
(3 × 100 mL), dried over magnesium sulphate and evaporated. Purification by column chromatography
[silica gel, eluent: dichloromethane/petroleum ether (1/2)] afforded 0.46 g of 4,7-dichloro-2-(2-
methylprop-1-enyl)-6-nitro-quinazoline (5) which recrystallized from propan-2-ol. Yield 87%; brown
solid, mp 105 °C. 1H-NMR (200 MHz, CDCl3):  = 8.69 (1H, s), 8.10 (1H, s), 6.52 (1H, s), 2.42 (3H,
s), 2.09 (3H, s); 13C-NMR (50 MHz, CDCl3):  = 164.3, 162.3, 155.0, 152.2, 146.0, 132.3, 131.3,
123.8, 123.4, 119.1, 28.8, 21.1; Anal. calcd. for C12H9Cl2N3O2: C, 48.34; H, 3.04; N, 14.09 %. Found:
C, 48.42; H, 3.16; N, 13.83 %.
General procedure of the monocoupling and symmetric double coupling Suzuki-Miyaura reaction
4,7-Dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline (5, 0.2 g, 0.67 mmol), and tetrakis(tri-
phenylphosphine) palladium(0) (2.5 mol %) were dissolved in DME (20 mL) under nitrogen and
stirred for 1 h at rt. Arylboronic acid (1.2 to 2 equiv. for monocoupling, 4 equiv. for symmetric double
coupling) in ethanol (2 mL) and sodium carbonate (0.21 g, 2.01 mmol: monocoupling, 0.28 g,
2.68 mmol: symmetric double coupling) were added. The mixture was placed in the microwave oven
irradiating with 300 W, heating to 80 °C for 3 h. After addition of water (50 mL), the solution was
extracted into dichloromethane (3 × 50 mL). The organic layer was washed with water (3 × 100 mL),
dried over sodium sulphate and evaporated. The crude product was purified by column
chromatography [silica gel, eluent: petroleum ether/ethyl acetate (5%)] and recrystallized from propan-
2-ol.
7-Chloro-4-(4-methoxyphenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (6a). Yield 68%; yellow
1
solid, mp 180 °C. H-NMR (200 MHz, CDCl3):  = 8.65 (1H, s), 8.14 (1H, s), 7.77 (2H, d,
13
J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 6.66 (1H, s), 3.93 (3H, s), 2.45 (3H, s), 2.09 (3H, s); C-NMR
(50 MHz, CDCl3):  = 168.6, 164.5, 162.1, 152.6, 145.2, 131.8, 131.2, 130.9, 128.3, 125.7, 124.5,
117.8, 114.7, 55.6, 28.6, 21.0; Anal. calcd. for C19H16ClN3O3: C, 61.71; H, 4.36; N, 11.36 %. Found:
C, 61.49; H, 4.39; N, 11.26 %.
7-Chloro-4-(4-chlorophenyl)-2-(2-methylprop-1-enyl)-6-nitro quinazoline (6b). Yield 63%; yellow
solid, mp 199 °C. 1H-NMR (200 MHz, CDCl3):  = 8.54 (1H, s), 8.22 (1H, s), 7.74 (2H, d, J = 8.5 Hz),
7.60 ( 2H, d, J = 8.5 Hz), 6.69 (1H, s), 2.45 (3H, s), 2.11 (3H, s); 13C-NMR (50 MHz, CDCl3):
 = 168.2, 164.4, 153.9, 152.1, 145.5, 137.7, 134.2, 131.4, 131.2, 129.5, 125.0, 124.1, 117.7, 28.8,
21.2; Anal. calcd. for C18H13Cl2N3O2: C, 57.77; H, 3.50; N, 11.23%. Found: C, 57.54; H, 3.56; N,
11.08 %.

Molecules 2010, 15
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7-Chloro-2-(2-methylprop-1-enyl)-6-nitro-4-(3-(trifluoromethyl) phenyl)quinazoline (6c). Yield 48%;
1
brown solid, mp 151 °C. H-NMR (200 MHz, CDCl3): 8.48 (1H, s), 8.18 (1H, s), 8.07 (1H, s),
13
7.95-7.88 ( 2H, m), 7.79-7.72 (1H, m), 6.66 (1H, s), 2.45 (3H, s), 2.11 (3H, s); C-NMR (50 MHz,
CDCl3):  = 167.6, 164.7, 153.2, 152.7, 145.6, 136.8, 132.9, 131.9, 131.8, 131.3, 129.6, 127.5, 126.7,
124.6, 124.4, 123.6, 117.7, 28.6, 21.0; Anal. calcd. for C19H13ClF3N3O2: C, 55.96; H, 3.21; N, 10.30
%. Found: C, 55.85; H, 3.22; N, 10.14 %.
7-Chloro-2-(2-methylprop-1-enyl)-4-(5-methylthiophen-2-yl)-6-nitro quinazoline (6d). Yield 72%;
1
yellow solid, mp 172 °C. H-NMR (200 MHz, CDCl3):  = 8.99 (1H, s), 8.08 (1H, s), 7.67 (1H, d,
J = 3.9 Hz), 6.97 (1H, d, J = 3.9 Hz), 6.57 (1H, s), 2.62 (3H, s), 2.45 (3H, s), 2.09 (3H, s); 13C NMR
(50 MHz, CDCl3):  = 164.3, 160.9, 152.9, 152.8, 148.2, 145.2, 137.9, 132.8, 131.3, 131.0, 127.7,
124.9, 124.2, 116.5, 28.7, 21.1, 15.8; Anal. calcd. for C17H14ClN3O2S: C, 56.74; H, 3.92; N, 11.68 %.
Found: C, 56.64; H, 4.01; N, 11.48 %.
7-Chloro-2-(2-methylprop-1-enyl)-6-nitro-4-(3-nitrophenyl)quinazoline (6e). Yield 55%; brown solid,
mp 197 °C. 1H-NMR (200 MHz, CDCl3):  =8.68 (1H, s), 8.52-8.47 (2H, m), 8.24 (1H, s), 8.09 (1H,
d, J = 7.6 Hz), 7.87-7.79 (1H, m), 6.70 (1H, s), 2.46 (3H, s), 2.12 (3H, s); 13C-NMR (50 MHz, CDCl3):
 166.7, 164.6, 154.1, 152.5, 148.8, 145.7, 137.6, 135.4, 131.7, 131.6, 130.2, 125.5, 124.8, 124.2,
124.1, 117.5, 28.8, 21.2; Anal. calcd. for C18H13ClN4O4: C, 56.19; H, 3.41; N, 14.56 %. Found: C,
56.16; H, 3.47; N, 14.35 %.
4,7-Bis(4-methoxyphenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (7a). Yield 70%; yellow solid,
mp 175 °C. 1H-NMR (200 MHz, CDCl3):  = 8.58 (1H, s), 8.07 (1H, s), 7.84 (2H, d, J = 8.8 Hz), 7.37
(2H, d, J = 8.9 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.9 Hz), 6.72 (s, 1H), 3.94 (3H, s), 3.87
(3H, s), 2.46 (3H, s), 2.10 (3H, s); 13C-NMR (50 MHz, CDCl3):  = 168.4, 164.0, 161.9, 160.2,
152.4, 147.5, 140.1, 131.8, 131.2, 129.2, 128.8, 128.7, 124.8, 124.1, 118.2, 116.1, 114.6, 114.5, 55.6,
55.4, 28.5, 20.9; Anal. calcd. for C26H23N3O4: C, 70.73; H, 5.25; N, 9.52 %. Found: C, 70.23; H, 5.35;
N, 9.48 %.
4,7-Bis(4-chlorophenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (7b). Yield 67%; yellow solid,
mp 233 °C. 1H-NMR (200 MHz, CDCl3):  = 8.56 (1H, s), 8.08 (1H, s), 7.79 (2H, d, J = 8.4 Hz), 7.62
(2H, d, J = 8.4 Hz), 7.47 (d, 2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 6.72 (1H, s), 2.46 (3H, s),
13
2.11 (3H, s); C-NMR (50 MHz, CDCl3):  = 168.4, 163.7, 153.7, 151.5, 147.2, 140.0, 137.7, 135.4,
134.7, 134.4, 131.3, 129.5, 129.3, 129.2, 124.0, 123.9, 118.3, 28.8, 21.2; Anal. calcd. for
C24H17Cl2N3O2: C, 64.01; H, 3.81; N, 9.33 %. Found: C, 63.57; H, 3.80; N, 9.17 %.
2-(2-Methylprop-1-enyl)-6-nitro-4,7-diphenylquinazoline (7f). Yield 85%; yellow solid, mp 176 °C.
1H-NMR (200 MHz, CDCl3):  = 8.58 (1H, s), 8.08 (1H, s), 7.86-7.81 (2H, m), 7.65-7.61 (3H, m),
13
7.51-7.41 (5H, m), 6.71 (1H, s), 2.46 (3H, s), 2.10 (3H, s); C-NMR (50 MHz, CDCl3):  = 169.2,
164.1, 152.2, 151.7, 147.4, 140.7, 136.5, 136.3, 131.7, 130.8, 130.0, 129.1, 128.9, 127.8, 124.7, 124.1,
118.5, 28.5, 20.9; Anal. calcd. for C24H19N3O2: C, 75.57; H, 5.02; N, 11.02 %. Found: C, 75.36; H,
5.02; N, 10.95 %.

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4,7-Bis(4-fluorophenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (7g). Yield 71%; yellow solid, mp
1
193 °C. H-NMR (200 MHz, CDCl3):  = 8.55 (1H, s), 8.06 (1H, s), 7.89-7.82 (2H, m), 7.44-7.29
(4H, m), 7.22-7.14 (2H, m), 6.70 (1H, s), 2.46 (3H, s), 2.11 (3H, s); 13C-NMR (50 MHz, CDCl3):
 = 168.0, 164.4, 164.1, 163.2, 152.2, 152.1, 147.2, 139.8, 132.4, 132.3, 132.2, 132.0, 131.8, 129.8,
129.6, 124.5, 123.9, 118.3, 116.6, 116.3, 116.1, 115.9, 28.6, 20.9; Anal. calcd. for C24H17F2N3O2: C,
69.06; H, 4.11; N, 10.07 %. Found: C, 68.89; H, 4.33; N 9.90 %.
2-(2-Methylprop-1-enyl)-6-nitro-4,7-bis(2-tolyl)quinazoline (7h). Yield 65%; yellow solid, mp 161 °C.
1H-NMR (200 MHz, CDCl3):  = 8.25 (1H, s), 7.97 (1H, s), 7.53-7.35 (5H, m), 7.33-7.28 (2H, m),
7.24-7.16 (1H, m), 6.70-7.72 (1H, m), 2.44 (3H, m), 2.26 (3H, s), 2.18 (3H, s), 2.08 (3H, m); 13C-NMR
(50 MHz, CDCl3):  = 170.9, 164.2, 152.1, 151.7, 147.3, 141.1, 136.5, 136.2, 135.5, 135.4, 132.1,
131.2, 130.2, 130.0, 129.6, 128.7, 128.3, 126.1, 125.9, 124.7, 123.9, 119.7, 28.6, 20.9, 20.1, 20.0;
Anal. calcd. for C26H23N3O2: C, 76.26; H, 5.66; N, 10.26 %. Found: C, 75.88; H, 5.74; N, 10.12 %.
General procedure of dissymmetric coupling Suzuki-Miyaura reaction of the 7-position
7-Chloro-4-arylquinazoline (6, 0.54 mmol), and tetrakis(triphenylphosphine) palladium(0)
(2.5 mol %) were dissolved in DMF (30 mL) under nitrogen and stirred for 1 h at rt. Arylboronic acid
(2 equiv., 1.08 mmol) in ethanol (2 mL) and sodium carbonate (3 equiv., 1.62 mmol) were added. The
mixture was placed in the microwave oven irradiating with 300 W, heating to 150 °C for 3 h. After
addition of water (50 mL), the solution was extracted into dichloromethane (3 × 50 mL). The organic
layer was washed with water (3 × 100 mL), dried over sodium sulphate and evaporated. The crude
product was purified by column chromatography [silica gel, eluent: petroleum ether/ethyl acetate
(10%)] and recrystallized from propan-2-ol.
7-(4-Chlorophenyl)-4-(4-methoxyphenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (8). Yield 55%;
1
yellow solid, mp 186 °C. H-NMR (200 MHz, CDCl3):  = 8.66 (1H, s), 8.01 (1H, s), 7.83 (2H, d,
J = 8.7 Hz), 7.46 (2H, d, J = 8.5 Hz), 7.36 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.7 Hz), 6.69 (1H, s),
13
3.94 (3H, s), 2.46 (3H, s), 2.10 (3H, s); C-NMR (50 MHz, CDCl3):  = 168.6, 164.1, 162.1, 152.4,
151.9, 146.8, 139.4, 135.1, 131.9, 131.6, 129.2, 128.6, 124.7, 118.5, 114.7, 55.6, 28.6, 21.0; Anal.
calcd. for C25H20ClN3O3: C, 67.34; H, 4.52; N, 9.42 %. Found: C, 67.54; H, 4.67; N, 9.34 %.
4-(4-Methoxyphenyl)-2-(2-methylprop-1-enyl)-6-nitro-7-phenyl quinazoline (9). Yield 64%; yellow
solid, mp 165 °C. 1H-NMR (200 MHz, CDCl3):  = 8.63 (1H, s), 8.02 (1H, s), 7.83 (2H, d, J = 8.9 Hz),
7.49-7.41 (5H, m), 7.13 (2H, d, J = 8.9 Hz), 6.67 (1H, s), 3.93 (3H, s), 2.45 (3H, s), 2.09 (3H, s); 13C-
NMR (50 MHz, CDCl3):  = 168.4, 164.1, 162.0, 152.5, 151.1, 147.2, 140.5, 136.7, 131.8, 131.7,
128.9, 128.8, 128.7, 127.8, 124.9, 124.3, 118.4, 114.6, 55.6, 28.5, 20.9; Anal. calcd. for C25H21N3O3:
C, 72.98; H, 5.14; N, 10.21 %. Found: C, 72.70; H, 5.17; N, 10.06 %.
7-(4-Fluorophenyl)-4-(4-methoxyphenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (10). Yield 43%;
1
yellow solid, mp 180 °C. H-NMR (200 MHz, CDCl3):  = 8.64 (1H, s), 8.03 (1H, s), 7.84 (2H, d,
J = 8.7 Hz), 7.44-7.37 (2H, m), 7.22-7.12 (4H, m), 6.70 (1H, s), 3.94 (3H, s), 2.46 (3H, s), 2.10 (3H,
s); 13C-NMR (50 MHz, CDCl3):  = 168.9, 163.6, 163.2, 162.2, 151.5, 147.2, 139.8, 132.4, 131.9,

Molecules 2010, 15
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130.9, 129.8, 129.6, 128.5, 124.5, 124.0, 118.3, 116.3, 115.8, 114.7, 55.6, 28.7, 21.1; Anal. calcd. for
C25H20FN3O3: C 69.92; H, 4.69; N, 9.78 %. Found: C, 68.63; H, 4.89; N, 9.74 %. HRMS-FAB: m/z [M
+ H]+ calcd. for C25H20FN3O3: 429.1489; Found: 429.1561.
4-(4-Methoxyphenyl)-2-(2-methylprop-1-enyl)-6-nitro-7-o-tolyl quinazoline (11). Yield 50%; yellow
solid, mp 191 °C. 1H-NMR (200 MHz, CDCl3):  = 8.60 (1H, s), 8.02 (1H, s), 7.83 (2H, d, J = 8.8 Hz),
7.35-7.28 (4H, s), 7.13 (2H, d, J = 8.8 Hz), 6.67 (1H, s), 3.93 (3H, s), 2.45 (3H, s), 2.43 (3H, s), 2.09
(3H, s); 13C-NMR (50 MHz, CDCl3):  = 168.3, 164.1, 161.9, 152.6, 150.8, 147.4, 140.5, 138.9, 133.7,
131.8, 131.6, 129.7, 128.9, 127.7, 124.9, 124.2, 118.3, 114.6, 55.6, 28.5, 21.3, 20.8; Anal. calcd. for
C26H23N3O3: C, 73.39; H, 5.45; N, 9.88 %. Found: C, 72.87; H, 5.64; N, 9.65 %.
4-(4-Methoxyphenyl)-2-(2-methylprop-1-enyl)-6-nitro-7-(3-(trifluoro methyl)phenyl)quinazoline (12).
Yield 57%; yellow solid, mp 116 °C. 1H-NMR (200 MHz, CDCl3):  = 8.73 (1H, s), 7.99 (1H, s), 7.84
(2H, d, J = 8.8 Hz), 7.73-7.67 (2H, m), 7.64-7.55 (2H, m), 7.13 (2H, d, J = 8.8 Hz), 6.66-6.67 (1H, m),
3.93 (3H, s), 2.46 (3H, m), 2.08 (3H, m); 13C-NMR (50 MHz, CDCl3):  = 168.5, 164.4, 162.0, 152.7,
151.6, 146.3, 139.0, 137.7, 132.1, 131.8, 131.3, 131.1, 129.2, 128.6, 125.4, 124.9, 124.8, 124.7, 123.8,
118.6, 114.6, 55.5, 28.5, 20.9; Anal. calcd. for C26H20F3N3O3: C, 65.13; H, 4.20; N, 8.76 %. Found: C,
65.00; H, 4.12; N 8.52 %.
4-(4-Chlorophenyl)-7-(4-methoxyphenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (13). Yield 54%;
1
yellow solid, mp 173 °C. H-NMR (200 MHz, CDCl3):  = 8.46 (1H, s), 8.07 (1H, s), 7.78 (2H, d,
J = 8.4 Hz), 7.61 (2H, d, J = 8.4 Hz), 7.37 (2H, d, J = 8.6 Hz), 7.01 (2H, d, J = 8.6 Hz), 6.69 (1H, s),
13
3.87 (3H, s), 2.45 (3H, s), 2.10 (3H, s); C-NMR (50 MHz, CDCl3):  = 169.0, 163.4, 162.7, 160.6,
152.2, 148.1, 141.4, 137.9, 134.4, 131.4, 129.6, 129.5, 129.3, 129.1, 127.9, 123.5, 117.9, 114.6, 55.4,
29.0, 21.4; Anal. calcd. for C25H20ClN3O3: C, 67.34; H, 4.52; N, 9.42 %. Found: C, 66.90; H, 4.58; N,
9.19 %.
4-(4-Chlorophenyl)-2-(2-methylprop-1-enyl)-6-nitro-7-phenyl quinazoline (14). Yield 62%; yellow
solid, mp 204 °C. 1H-NMR (200 MHz, CDCl3):  = 8.53 (1H, s), 8.10 (1H, s), 7.79 (2H, d, J = 8.4 Hz),
13
7.61 (2H, d, J = 8.4 Hz), 7.49-7.41 (5H, m), 6.71 (1H, s), 2.45 (3H, s), 2.11 (3H, s); C-NMR (50
MHz, CDCl3):  = 167.9, 164.1, 152.4, 151.9, 147.5, 140.9, 137.3, 136.4, 134.8, 131.9, 131.3, 129.4,
128.9, 127.8, 124.6, 123.6, 118.2, 28.6, 20.9; Anal. calcd. for C24H18ClN3O2: C, 69.31; H, 4.36; N,
10.10 %. Found: C, 68.91; H, 4.46; N, 9.94 %.
4-(4-Chlorophenyl)-7-(4-fluorophenyl)-2-(2-methylprop-1-enyl)-6-nitro quinazoline (15). Yield 57%;
1
yellow solid, mp 211 °C. H-NMR (200 MHz, CDCl3):  = 8.54 (1H, s), 8.11 (1H, s), 7.79 (2H, d,
J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 7.44-7.37 (2H, m), 7.23-7.14 (2H, m), 6.74 (1H, s), 2.46 (3H,
13
s), 2.12 (3H, s); C-NMR (50 MHz, CDCl3):  = 168.1, 164.1, 163.2, 152.6, 152.1, 147.3, 139.9,
137.5, 134.6, 132.4, 131.7, 131.3, 129.7, 129.6, 129.5, 124.4, 123.8, 118.3, 116.3, 115.9, 28.7, 21.1;
Anal. calcd. for C24H17ClFN3O2: C, 66.44; H, 3.95; N, 9.69 %. Found: C, 66.28; H, 4.11; N, 9.53 %.

Molecules 2010, 15
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4-(4-Chlorophenyl)-2-(2-methylprop-1-enyl)-6-nitro-7-o-tolyl quinazoline (16). Yield 58%; yellow
solid, mp 192 °C. 1H-NMR (200 MHz, CDCl3):  = 8.49 (1H, s), 8.08 (1H, s), 7.79 (2H, d, J = 8.4 Hz),
7.61 (2H, d, J = 8.4 Hz), 7.35-7.28 (4H, m), 6.70 (1H, s), 2.45 (3H, s), 2.43 (3H, s), 2.10 (3H, s); 13C-
NMR (50 MHz, CDCl3):  = 167.7, 164.1, 152.4, 151.5, 147.6, 140.8, 139.0, 137.2, 134.8, 133.4,
131.7, 131.2, 129.7, 129.4, 127.6, 124.7, 123.4, 118.1, 28.5, 21.3, 20.9; Anal. calcd. for C25H20ClN3O2:
C, 69.85; H, 4.69; N, 9.77 %. Found: C, 69.21; H, 4.81; N, 9.52 %.
Conclusions
We have reported herein an efficient and regioselective access to symmetric and dissymmetric 4,7-
diarylquinazolines by using the Suzuki-Miyaura reaction on the 4,7-dichloroquinazoline derivative 5,
under microwave irradiation. The regioselectivity was controlled by modifying both the amount of
arylboronic acid used and the nature of the reaction medium. This method opens the way to a general
synthesis of bis-functionalized quinazolines, skeletons of great interest for designing biologically
active compounds.
Acknowledgments
This work was supported by the CNRS and the University of Aix-Marseille II. The authors thank V.
Remusat for the 1H- and 13C-NMR spectra recording and G. Lanzada for his technical support.
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Sample Availability: Samples of the compounds are available from the authors.
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distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).