Synthesis of original 2-substituted 4-arylquinazolines by microwaveirradiated Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1002/ejoc.200900421

Original 2-substituted 4-arylquinazollnes have been synthesized by using a microwave-assisted Suzuki-Miyaura crosscoupling approach, The optimization and generalization of the Suzuki-Miyaura cross-coupling reaction between 2-sub-stituted 4-chloroquinazolines and various boronlc acids are described herein,

Full text of DOI:10.1002/ejoc.200900421

FULL PAPER
DOI: 10.1002/ejoc.200900421
Synthesis of Original 2-Substituted 4-Arylquinazolines by Microwave-
Irradiated Suzuki–Miyaura Cross-Coupling Reactions
Youssef Kabri,[a] Armand Gellis,[a] and Patrice Vanelle*[a]
Keywords: Boron / Microwave chemistry / Cross-coupling / Nitrogen heterocycles
Original 2-substituted 4-arylquinazolines have been synthe-
sized by using a microwave-assisted Suzuki–Miyaura cross-
coupling approach. The optimization and generalization of
the Suzuki–Miyaura cross-coupling reaction between 2-sub-
stituted 4-chloroquinazolines and various boronic acids are
described herein.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
As a continuation of our previous studies[5] directed
towards the preparation of new azaheterocyclic compounds
and the evaluation of their anti-infectious activity, we have
synthesized a series of new quinazoline derivatives substi-
tuted by a variety of groups at the 2-position by a micro-
wave-assisted Suzuki–Miyaura cross-coupling reaction.
Quinazoline derivatives are an important class of com-
pounds and have shown interesting activity as antimalarial
agents (Scheme 1).[6]
Introduction
The palladium-catalysed cross-coupling reactions of aryl-
boronic acids with aryl halides in the presence of a base,
a Suzuki-type reaction, provides a convenient method for
forming carbon–carbon bonds, in particular, in the synthe-
sis of biaryl compounds.[1] In recent years various modifica-
tions to this reaction have been made involving the nature
of catalysts, solvents, bases, reaction conditions and syn-
thetic techniques that have permitted the use of or-
ganoboron compounds that are thermally stable and inert
to water and oxygen.[2] At the same time, microwave heating
has also been used to promote Suzuki reactions.[3] The ben-
eficial effects of microwave irradiation are finding an in-
creased role in process chemistry, especially when conven-
tional methods require forcing conditions or prolonged re-
action times.[4]
Results and Discussion
We have recently developed a microwave-assisted synthe-
sis of 2-(chloromethyl)quinazolin-4(3H)-one (1).[7] This
compound can easily be nitrated by using a HNO3/H2SO4
mixture to give 2-(chloromethyl)-6-nitroquinazolin-4(3H)-
one (2) in 80% yield (Scheme 2). To substitute the 2-posi-
tion of 2, we applied microwave technology in combination
with SRN1 or SN2 reactions.[8] Thus, compound 2 was
treated with the lithium salt of 2-nitropropane (3) to afford
nitroquinazolinone 4. The intermediate C-alkylated product
was not isolated due to very rapid nitrous acid elimination
in alkaline medium because of the acidity of the methylene
protons.
In view of our pharmacomodulation goals, we initially
substituted a methoxy group for the chlorine atom (com-
pound 5), as shown in Scheme 2.
We have previously described a “green chemistry pro-
cedure” that allows the substitution of a chlorine atom by
a sulfone group.[7] This ecofriendly methodology in the
aqueous phase, using microwave technology to ensure re-
spect of the environment, was developed for the preparation
of S-alkylated products 6 and 7 in high yields (Scheme 2).
4-Chloroquinazoline derivatives 8–11 were obtained after
microwave-assisted chlorination of 4–7 by treatment with
Scheme 1.
[a] Laboratoire de Pharmaco-Chimie Radicalaire (LPCR), Faculté
de Pharmacie, Universités dЈAix-Marseille I, II et III – CNRS,
UMR 6264, Laboratoire Chimie Provence,
27 Bd J. Moulin, 13385 Marseille cedex 05, France
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Y. Kabri, A. Gellis, P. Vanelle
FULL PAPER
Scheme 2. Preparation of quinazolines 1–7. Reagents and conditions: (a) MW, 300 W, 50 °C, 5 min; (b) K2CO3, H2O, MW, 500 W, 80 °C,
1 h; (c) H2SO4, HNO3, room temp., 4 h; (d) (CH3)2NO2C– Li+ (3), MW, 500 W, 70 °C, 2 h, CH3OH; (e) CH3OH, NaOH, MW, 500 W,
70 °C, 2 h; (f) p-CH3PhSO2Cl, NaHCO3, Na2SO3, H2O, MW, 300 W, 100 °C, 1 h.
POCl3, as shown in Scheme 3 and Table 1. It appears that
in the presence of a nitro group at the 6-position, the chlori-
nation yield is lower. Deactivation of the quinazoline cycle
most probably accounts for this result.
Scheme 4.
Table 2. Parameters studied for the optimization of the Suzuki–
Miyaura reaction between quinazoline 8 and phenylboronic acid
(12).
Scheme 3.
Conditions[a]
T
[°C]
Boronic acid Yield
Table 1. Results of the chlorination reactions of 2-methylquinaz-
olin-4(3H)-one derivatives 4–7.
Solvent
Time
[h]
[equiv.]
[%]
R1
R2
Yield [%]
DME
DME
DME
Dioxane
DMF
DME
H2O
DME
DME
DME
1.5
2
2
2
2
3
3
24
48
72
MW/150 W
MW/300 W
MW/300 W
MW/300 W
MW/300 W
MW/300 W
MW/300 W
Oil bath
85
85
85
100
150
85
100
85
1.2
1.2
1.5
1.5
1.5
1.9
1.9
1.9
1.9
1.9
50
54
58
46
52
86
Ͻ5
35
49
55
8
NO2
NO2
NO2
H
CH=C(CH3)2
CH2OCH3
CH2SO2Ph(pCH3)
CH2SO2Ph(pCH3)
75
68
74
91
9
10
11
Compounds 8–11, obtained in good yields, present the
Oil bath
Oil bath
85
85
advantage of being functionalizable at the 4-position. We
therefore investigated the possibility of using 4-chloroquin-
azoline derivatives 8–11 as substrates for Suzuki–Miyaura
cross-coupling reactions. To optimize the operating condi-
tions we studied the reaction with compound 8 and phen-
ylboronic acid (12) by using the procedure described by
Guiry and co-workers, but with significant modifications
(Scheme 4).[9]
[a] Microwave instrumentation: the temperature was measured with
an infrared detector and the microwave pulsed power was regulated
by the software of terminal 320 for Ethos start, Milestone Inc.
Catalytic conditions: 3 equiv. Na2CO3 and 2.5 mol-% [Pd(PPh3)4].
time being reduced from 72 to 3 h. The development of
Various reaction parameters were tested and the best water-compatible transition-metal reagents for use in an
conditions were finally defined (Table 2), permitting the aqueous solvent system has been proved to simplify cata-
synthesis of quinazoline 8 in 86% yield in 3 h.
lyst/product separation and to increase catalyst activity.[10]
The best yield of the coupled product was obtained when Therefore we tried to employ water as a solvent in conjunc-
the reaction was stirred at 85 °C with 1.9 equiv. of boronic tion with microwave heating. All the reaction trials realized
acid in a microwave oven (300 W) for 3 h with DME used with water as solvent led to a poor yield of coupling prod-
as solvent. As expected, it was more convenient to carry uct 22, probably due to poor solubility of the starting mate-
out the Suzuki reaction in a microwave reactor, the reaction rial. An alternative method, described by Leadbeater, was
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Arylquinazolines by Microwave-Irradiated Cross-Coupling
to use phase-transfer agent tetrabutylammonium bromide Table 3. Optimal synthetic conditions and corresponding yields of
Suzuki–Miyaura reactions in the three distinct series.
(TBAB) to increase the solvation of the organic sub-
strates.[11]
Based on a number of reports regarding the Suzuki–Mi-
yaura reaction and on our optimization work, reported in
Table 2, we decided to use Na2CO3 as the base (3 equiv.)
and [Pd(PPh3)4] as the catalyst.[12] We first started to work
with the 6-nitrated derivatives. Unfortunately, compound 10
presented poor reactivity towards the Suzuki–Miyaura
cross-coupling reaction. We observed a high percentage of
remaining starting material and significant difficulties in
purification, probably due to a lack of solubility. A mixture
of 4-chloroquinazoline derivative 8, 9 or 11, arylboronic
acid, [Pd(PPh3)4] and Na2CO3 was stirred at 80 °C in a mi-
crowave oven for 3 h (Scheme 5, Table 3). The disappear-
ance of the starting materials was monitored by TLC. By
using the microwave-assisted optimized operating pro-
cedure we prepared a series of 2-substituted 4-arylquinazol-
ines (22–51) by varying the boronic acid (Table 3). The best
result (94%) was obtained by using phenylboronic acid (12)
with substrate 11. The lowest yield (63%) was observed
when treating 5-methylthiophen-2-ylboronic acid (16) with
substrate 9. Generally, the yields obtained seem to be more
influenced by the nature of the boronic acid than by the
nature of the quinazoline substituent at the 2-position.
Scheme 5.
Conclusions
We have described herein an efficient route to original
2-substituted 4-arylquinazolines using a microwave-assisted
Suzuki–Miyaura cross-coupling approach. The microwave-
assisted process, in contrast to conventional heating, gives
the desired compounds in higher overall yields in shorter
reaction times. This work confirms that microwave-irradi-
ated reactions allow easy and rapid access to original aza-
heterocyclic compounds with potential antiplasmodial ac-
tivities. In view of our pharmacomodulation goals, the next
step of our research program involves analysing the anti-
plasmodial activities.
Experimental Section
General: Melting points were determined with a Büchi B-540 appa-
ratus and are uncorrected. Elemental analyses were performed by
the Microanalyses Center of the University of Aix-Marseille 3,
[a] A: R1 = NO2; R2 = CH=C(CH3)2. B: R1 = NO2; R2
CH2OCH3. C: R1 = H; R2 = CH2SO2Ph(pCH3).
=
France. Both 1H and 13C NMR spectra were determined with a
Eur. J. Org. Chem. 2009, 4059–4066
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Y. Kabri, A. Gellis, P. Vanelle
FULL PAPER
Bruker ARX 200 spectrometer. The 1H chemical shifts are reported
as ppm downfield from tetramethylsilane (Me4Si), and the 13C
chemical shifts are referenced to the solvent peak: CDCl3 (δ
=76.9 ppm) or [D6]DMSO (δ =39.5 ppm). Solvents were dried by
conventional methods. The following adsorbent was used for col-
umn chromatography: silica gel 60 (Merck, particle size 0.063–
2-(Tosylmethyl)quinazolin-4(3H)-one (6): 2-(Chloromethyl)quinaz-
olin-4(3H)-one (1; 1 g, 5.14 mmol) was added to a solution of 4-
methylbenzenesulfonyl chloride (1.96 g, 10.28 mmol), NaHCO3
(0.86 g, 10.28 mmol) and Na2SO3 (1.29 g, 10.28 mmol) in water
(30 mL). The reaction mixture was irradiated in a microwave oven
at 100 °C for 1 h at a power of 300 W. The precipitate was filtered,
0.200 mm, 70–230 mesh ASTM). TLC was performed on 5ϫ10 cm washed with water (3ϫ20 mL) and dried in vacuo in a drying oven
aluminium plates coated with silica gel 60F-254 (Merck) in an ap-
propriate solvent.
(desiccator cabinet). The product required was recrystallized from
2-propanol to give 6 (1.42 g, 88%), m.p. 249 °C. 1H NMR
(200 MHz, [D6]DMSO, 22 °C): δ = 2.41 (s, 3 H, CH3), 4.65 (s, 2
H, CH2), 7.41–7.57 (m, 4 H, Ar-H), 7.69–7.84 (m, 3 H, Ar-H), 8.10
Microwave Instrumentation: Multimode reactors: ETHOS Synth
Lab station and MicroSYNTH Lab terminal 1024 (Ethos start,
Milestone Inc.). The multimode microwave has a twin magnetron
(2ϫ800 W, 2.45 GHz) with a maximum delivered power of 1000 W
in 10 W increments (pulsed irradiation). Built-in magnetic stirring
(Teflon-coated stirring bar) was used in all operations. During the
experiments, the time, temperature and power were measured with
the “easy WAVE” software package. The temperature was mea-
sured throughout the reaction and evaluated by an infrared detec-
tor or an optical fibre (ATC-FO 300).
3
(d, JH,H = 7.4 Hz, 1 H, Ar-H) ppm. 13C NMR (50 MHz, [D6]-
DMSO, 22 °C): δ = 21.3 (CH3), 60.7 (CH2), 121.3 (C), 125.9 (CH),
127.2 (CH), 127.4 (CH), 128.4 (2 CH), 129.8 (2 CH), 134.8 (CH),
136.0 (C), 145.0 (C), 146.4 (C), 148.3 (C), 161.4 (C) ppm.
C16H14N2O3S (314.36): calcd. C 61.13, H 4.49, N 8.91; found C
60.78, H 4.58, N 8.79.
6-Nitro-2-(tosylmethyl)quinazolin-4(3H)-one (7): 2-(Chloromethyl)-
6-nitroquinazolin-4(3H)-one (2; 1 g, 4.17 mmol) was added to a
solution of 4-methylbenzenesulfonyl chloride (1.59 g, 8.34 mmol),
NaHCO3 (0.7 g, 8.34 mmol) and Na2SO3 (1.05 g, 8.34 mmol) in
water (30 mL). The reaction mixture was irradiated in a microwave
oven at 100 °C for 1 h at a power of 300 W. The precipitate was
filtered, washed with water (3ϫ20 mL) and dried in vacuo in a
drying oven (desiccator cabinet). The product required was recrys-
To compare the microwave irradiation with conventional heating,
the reactions were performed under similar experimental condi-
tions (amount of reactants and temperature) using a thermostatted
oil bath. The temperature was measured by the insertion of a Quick
digital thermometer into the reaction mixture and the rate of the
temperature rise was adjusted to be the same as measured under
microwave irradiation.
1
tallized from 2-propanol to give 7 (1.39 g, 93%), m.p. 281 °C. H
NMR (200 MHz, [D6]DMSO, 22 °C): δ = 2.42 (s, 3 H, CH3), 4.71
(s, 2 H, CH2), 7.44 (d, 3JH,H = 8.4 Hz, 2 H, 3Ј,5Ј-H), 7.64 (d, 3JH,H
2-(2-Methylprop-1-enyl)-6-nitroquinazolin-4(3H)-one (4): 2-(Chlo-
romethyl)-6-nitroquinazolin-4(3H)-one (2; 0.5 g, 2.08 mmol) was
added to a solution of the lithium salt of the 2-nitropropane anion
(3; 0.8 g, 8.32 mmol) in methanol (20 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 the methanol, the residue was dis-
solved in ethyl acetate and washed with water. The organic layer
was dried with magnesium sulfate and the solvent was removed
under vacuum. A yellow solid was obtained that was recrystallized
from 2-propanol to give 4 (0.38 g, 75%), m.p. 253 °C. 1H NMR
(200 MHz, [D6]DMSO, 22 °C): δ = 1.98 (s, 3 H, CH3), 2.35 (s, 3
3
= 8.7 Hz, 1 H, 8-H), 7.73 (d, JH,H = 8.4 Hz, 2 H, 2Ј,6Ј-H), 8.53
4
3
4
(dd, JH,H = 2.6 Hz, JH,H = 8.7 Hz, 1 H, 7-H), 8.78 (d, JH,H
=
2.6 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, [D6]DMSO, 22 °C): δ
= 21.6 (CH3), 61.3 (CH2), 121.7 (C), 122.4 (CH), 128.8 (2 CH),
129.1 (CH), 129.3 (CH), 130.2 (2 CH), 136.2 (C), 145.5 (C), 145.8
(C), 150.6 (C), 152.6 (C), 161.1 (C) ppm. C16H13N3O5S (359.36):
calcd. C 53.48, H 3.65, N 11.69; found C 53.62, H 3.51, N 11.61.
4-Chloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline (8): 2-(2-Meth-
ylprop-1-enyl)-6-nitroquinazolin-4(3H)-one (0.3 g, 1.22 mmol) was
dissolved in toluene (20 mL). Diethylaniline (0.58 mL, 3.67 mmol)
and phosphorus oxychloride (0.23 mL, 2.44 mmol) were added.
The mixture was heated at 110 °C in the microwave oven irradiating
with 500 W for 2 h. After cooling and hydrolysis with water
(100 mL), the mixture was extracted with dichloromethane. The
combined organic extracts were washed with water (3ϫ60 mL),
dried with magnesium sulfate and the solvents evaporated. Purifi-
cation by column chromatography [silica gel, eluent: dichlorometh-
ane/petroleum ether (1:1)] afforded 0.24 g (75%) of 8 as a brown
solid, m.p. 140 °C. 1H NMR (200 MHz, CDCl3, 22 °C): δ = 2.10
(s, 3 H, CH3), 2.45 (s, 3 H, CH3), 6.58 (s, 1 H, vinylic H), 8.08 (d,
3JH,H = 9.5 Hz, 1 H, 8-H), 8.62 (dd, 4JH,H = 2.3 Hz, 3JH,H = 9.5 Hz,
3
H, CH3), 6.07 (s, 1 H, vinylic H), 7.72 (d, JH,H = 9.0 Hz, 1 H, 9-
4
3
H), 8.46 (dd, JH,H = 2.7 Hz, JH,H = 9.0 Hz, 1 H, 7-H), 8.72 (d,
4JH,H = 2.7 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, [D6]DMSO,
22 °C): δ = 21.5 (CH3), 28.6 (CH3), 117.4 (CH), 120.9 (C), 122.3
(CH), 128.7 (CH), 129.1 (CH), 144.6 (C), 153.7 (C), 154.9 (C),
155.5 (C), 161.6 (C) ppm. C12H11N3O3 (245.23): calcd. C 58.77, H
4.52, N 17.13; found C 58.59, H 4.61, N 17.14.
2-(Methoxymethyl)-6-nitroquinazolin-4(3H)-one (5): A mixture of 2-
(chloromethyl)-6-nitroquinazolin-4(3H)-one (2; 0.5 g, 2.08 mmol)
and sodium hydroxide (0.2 g, 6.24 mmol) dissolved in methanol
(40 mL) was heated at 70 °C for 2 h in the microwave, irradiating
with 500 W. After evaporation of the methanol, water was added
and the solution was neutralized with 2  H2SO4. The aqueous
layer was extracted with chloroform, the combined organic extracts
were dried with magnesium sulfate and the solvents evaporated. A
yellow solid was obtained that was recrystallized from 2-propanol
4
1 H, 7-H), 9.09 (d, JH,H = 2.3 Hz, 1 H, 5-H) ppm. 13C NMR
(50 MHz, CDCl3, 22 °C): δ = 21.1 (CH3), 28.8 (CH3), 120.5 (C),
122.8 (CH), 123.4 (CH), 128.1 (CH), 130.1 (CH), 145.8 (C), 153.6
(C), 154.3 (C), 163.4 (C), 163.7 (C) ppm. C12H10ClN3O2 (263.68):
calcd. C 54.66, H 3.82, N 15.94; found C 54.29, H 3.86, N 15.66.
(0.35 g, 71%), m.p. 229 °C. 1H NMR (200 MHz, [D6]DMSO,
4-Chloro-2-(methoxymethyl)-6-nitroquinazoline
(9):
2-(Meth-
3
22 °C): δ = 3.39 (s, 3 H, OCH3), 4.39 (s, 2 H, CH2), 7.82 (d, JH,H oxymethyl)-6-nitroquinazolin-4(3H)-one (5; 1 g, 4.24 mmol) was
4
3
= 8.9 Hz, 1 H, 8-H), 8.51 (dd, JH,H = 2.7 Hz, JH,H = 8.9 Hz, 1
dissolved in toluene (60 mL). Diethylaniline (2 mL, 12.72 mmol)
H, 7-H), 8.75 (d, JH,H = 2.7 Hz, 1 H, 5-H) ppm. 13C NMR and phosphorus oxychloride (0.8 mL, 8.48 mmol) were added. The
(50 MHz, [D6]DMSO, 22 °C): δ = 59.1 (OCH3), 71.8 (CH2), 122.0 mixture was heated at 110 °C in the microwave oven, irradiating
(C), 122.4 (CH), 128.8 (CH), 129.2 (CH), 145.4 (C), 152.9 (C), with 500 W for 2 h. After cooling and hydrolysis with water
4
158.3 (C), 161.3 (C) ppm. C10H9N3O4 (235.20): calcd. C 51.07, H
3.86, N 17.87; found C 51.24, H 3.93, N 17.67.
(100 mL), the mixture was extracted with dichloromethane. The
combined organic extracts were washed with water (3ϫ100 mL),
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Arylquinazolines by Microwave-Irradiated Cross-Coupling
dried with magnesium sulfate and the solvents evaporated. Purifi-
cation by column chromatography [silica gel, eluent: dichlorometh-
ane/petroleum ether (2:1)] afforded 0.73 g (68%) of 9 as a purple
2-(2-Methylprop-1-enyl)-6-nitro-4-phenylquinazoline (22): Yield:
86% (0.20 g). Yellow solid, m.p. 129 °C. 1H NMR (200 MHz,
CDCl3, 22 °C): δ = 2.10 (s, 3 H, CH3), 2.47 (s, 3 H, CH3), 6.70 (s,
solid, m.p. 119 °C. 1H NMR (200 MHz, CDCl3, 22 °C): δ = 3.62 1 H, vinylic H), 7.62–7.65 (m, 3 H, 3Ј,4Ј,5Ј-H), 7.79–7.84 (m, 2 H,
3
3
4
(s, 3 H, OCH3), 4.85 (s, 2 H, CH2), 8.26 (d, JH,H = 8.9 Hz, 1 H,
2Ј,6Ј-H), 8.11 (d, JH,H = 8.8 Hz, 1 H, 8-H), 8.59 (dd, JH,H =
4
3
4
8-H), 8.69 (dd, JH,H = 2.7 Hz, JH,H = 8.9 Hz, 1 H, 7-H), 9.15 (d,
2.6 Hz, 3JH,H = 8.8 Hz, 1 H, 7-H), 8.98 (d, JH,H = 2.6 Hz, 1 H, 5-
4JH,H = 2.7 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, CDCl3,
H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ = 20.9 (CH3), 28.5
22 °C): δ = 59.5 (OCH3), 74.7 (CH2), 122.0 (C), 122.6 (CH), 128.4 (CH3), 119.2 (C), 124.1 (CH), 124.8 (CH), 126.7 (CH), 129.0 (2
(CH), 130.9 (CH), 146.5 (C), 153.4 (C), 164.6 (C), 165.8 (C) ppm.
C10H8ClN3O3 (253.64): calcd. C 47.35, H 3.18, N 13.98; found C
47.13, H 3.14, N 13.92.
CH), 130.0 (2 CH), 130.3 (CH), 130.7 (CH), 136.3 (C), 145.1 (C),
151.7 (C), 154.1 (C), 164.3 (C), 169.8 (C) ppm. C18H15N3O2
(305.33): calcd. C 70.81, H 4.95, N 13.76; found C 70.63, H 4.98,
N 13.74.
4-Chloro-6-nitro-2-(tosylmethyl)quinazoline (10): 6-Nitro-2-(tosyl-
methyl)quinazolin-4(3H)-one (7; 1 g, 2.65 mmol) was dissolved in
toluene (60 mL). Diethylaniline (1.26 mL, 7.95 mmol) and phos-
phorus oxychloride (0.5 mL, 5.3 mmol) were added. The mixture
was heated at 110 °C in the microwave oven, irradiating with 500 W
for 2 h. After cooling and hydrolysis with water (100 mL), the mix-
ture was extracted with dichloromethane. The combined organic
extracts were washed with water (3ϫ100 mL), dried with magne-
sium sulfate and the solvents evaporated. Purification by column
chromatography [silica gel, eluent: dichloromethane then dichloro-
methane/ethyl acetate (95:5)] afforded 0.78 g (74%) of 10 as a beige
solid, m.p. 228 °C. 1H NMR (200 MHz, CDCl3, 22 °C): δ = 2.47
4-(4-Chlorophenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (23):
Yield: 77% (0.20 g). Yellow solid, m.p. 218 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 2.10 (s, 3 H, CH3), 2.46 (s, 3 H,
3
CH3), 6.69 (s, 1 H, vinylic H), 7.61 (d, JH,H = 8.9 Hz, 2 H, 3Ј,5Ј-
H), 7.77 (d, 3JH,H = 8.9 Hz, 2 H, 2Ј,6Ј-H), 8.11 (d, 3JH,H = 9.7 Hz,
4
3
1 H, 8-H), 8.60 (dd, JH,H = 2.5 Hz, JH,H = 9.7 Hz, 1 H, 7-H),
8.92 (d, JH,H = 2.5 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz,
4
CDCl3, 22 °C): δ = 20.9 (CH3), 28.5 (CH3), 119.0 (C), 123.6 (CH),
124.7 (CH), 126.9 (CH), 129.4 (2 CH), 130.6 (CH), 131.3 (2 CH),
134.7 (C), 137.3 (C), 145.2 (C), 152.1 (C), 154.2 (C), 164.3 (C),
168.6 (C) ppm. C18H14ClN3O2 (339.78): calcd. C 63.63, H 4.15, N
12.37; found C 63.42, H 4.15, N 12.22.
3
(s, 3 H, CH3), 4.86 (s, 2 H, CH2), 7.34 (d, JH,H = 8.6 Hz, 2 H,
3
3
3Ј,5Ј-H), 7.72 (d, JH,H = 8.6 Hz, 2 H, 2Ј,6Ј-H), 8.17 (d, JH,H
=
4-(4-Fluorophenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (24):
Yield: 64% (0.16 g). Yellow solid, m.p. 194 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 2.10 (s, 3 H, CH3), 2.45 (s, 3 H,
CH3), 6.68 (s, 1 H, vinylic H), 7.28–7.36 (m, 2 H, 3Ј,5Ј-H), 7.79–
4
3
8.9 Hz, 1 H, 8-H), 8.72 (dd, JH,H = 2.7 Hz, JH,H = 8.9 Hz, 1 H,
7-H), 9.16 (d, 4JH,H = 2.7 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz,
CDCl3, 22 °C): δ = 21.7 (CH3), 65.6 (CH2), 121.9 (C), 122.6 (CH),
128.6 (3 CH), 129.8 (2 CH), 131.1 (CH), 135.9 (C), 145.4 (C), 147.0
(C), 153.3 (C), 158.1 (C), 164.7 (C) ppm. C16H12ClN3O4S (377.80):
calcd. C 50.87, H 3.20, N 11.12; found C 50.46, H 3.12, N 10.93.
3
7.86 (m, 2 H, 2Ј,6Ј-H), 8.10 (d, JH,H = 9.2 Hz, 1 H, 8-H), 8.58
4
3
4
(dd, JH,H = 2.4 Hz, JH,H = 9.2 Hz, 1 H, 7-H), 8.92 (d, JH,H
=
2.4 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ =
20.9 (CH3), 28.5 (CH3), 116.3 (2 CH), 119.1 (C), 123.8 (CH), 124.8
(CH), 126.9 (CH), 130.5 (CH), 132.1 (2 CH), 132.5 (C), 145.2 (C),
152.0 (C), 154.2 (C), 164.3 (C), 164.4 (C), 168.7 (C) ppm.
C18H14FN3O2 (323.32): calcd. C 66.87, H 4.36, N 13.00; found C
66.52, H 4.40, N 12.81.
4-Chloro-2-(tosylmethyl)quinazoline (11): 2-(Tosylmethyl)quinaz-
olin-4(3H)-one (6; 1 g, 3.18 mmol) was dissolved in toluene
(60 mL). Diethylaniline (1.52 mL, 9.54 mmol) and phosphorus
oxychloride (0.6 mL, 6.36 mmol) were added. The mixture was
heated at 110 °C in the microwave oven, irradiating with 500 W for
2 h. After cooling and hydrolysis with water (100 mL), the mixture
was extracted with dichloromethane. The combined organic ex-
tracts were washed with water (3ϫ100 mL), dried with magnesium
sulfate and the solvents evaporated. Purification by column
chromatography [silica gel, eluent: dichloromethane/petroleum
ether (2:1)] afforded 0.96 g (91%) of 11 as a beige solid, m.p.
153 °C. 1H NMR (200 MHz, CDCl3, 22 °C): δ = 2.45 (s, 3 H, CH3),
2-(2-Methylprop-1-enyl)-6-nitro-4-(o-tolyl)quinazoline (25): Yield:
67% (0.16 g). Brown solid, m.p. 181 °C. 1H NMR (200 MHz,
CDCl3, 22 °C): δ = 2.09 (s, 3 H, CH3), 2.19 (s, 3 H, tolyl CH3),
2.45 (s, 3 H, CH3), 6.70 (s, 1 H, vinylic H), 7.31–7.53 (m, 4 H,
3
3Ј,4Ј,5Ј,6Ј-H), 8.11 (d, JH,H = 9.2 Hz, 1 H, 8-H), 8.51–8.61 (m, 2
H, 5,7-H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ = 19.9
(CH3), 20.9 (CH3), 28.5 (CH3), 120.3 (C), 124.0 (CH), 124.9 (CH),
126.0 (CH), 126.9 (CH), 129.5 (CH), 129.9 (CH), 130.4 (CH), 131.1
(CH), 135.5 (C), 136.1 (C), 145.1 (C), 151.9 (C), 153.6 (C), 164.3
(C), 171.4 (C) ppm. C19H17N3O2 (319.36): calcd. C 71.46, H 5.37,
N 13.16; found C 71.85, H 5.29, N 12.86.
3
4.82 (s, 2 H, CH2), 7.30 (d, JH,H = 8.1 Hz, 2 H, 3Ј,5Ј-H), 7.68–
7.79 (m, 3 H, Ar-H), 7.96–8.00 (m, 2 H, Ar-H), 8.22–8.27 (m, 1 H,
Ar-H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ = 21.6 (CH3),
65.6 (CH2), 122.5 (C), 125.7 (CH), 128.7 (3 CH), 129.5 (CH), 129.6
(2 CH), 135.3 (CH), 136.1 (C), 145.0 (C), 151.2 (C), 154.7 (C),
162.7 (C) ppm. C16H13ClN2O2S (332.80): calcd. C 57.74, H 3.94,
N 8.42; found C 57.53, H 3.92, N 8.24.
2-(2-Methylprop-1-enyl)-4-(5-methylthiophen-2-yl)-6-nitroquinaz-
oline (26): Yield: 78% (0.19 g). Yellow solid, m.p. 172 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 2.09 (s, 3 H, CH3), 2.47 (s, 3 H,
CH3), 2.63 (s, 3 H, thiophenyl CH3), 6.61 (s, 1 H, vinylic H), 6.98–
General Procedure for the Cross-Coupling Reaction: 4-Chloroquin-
azoline derivatives 8–11 (0.76 mmol) and tetrakis(triphenylphos-
phane)palladium(0) (2.5 mol-%) were dissolved in DME (15 mL)
under nitrogen and stirred for 1 h at room temperature. Aryl-
boronic acid (1.9 equiv.) in ethanol (2 mL) and sodium carbonate
(2.28 mmol) were added. The mixture was placed in the microwave
oven irradiating with 300 W, heating at reflux for 3 h. After ad-
dition of water (60 mL), the solution was extracted into dichloro-
methane. The organic layer was washed with water, dried with so-
dium sulfate and the solvents evaporated. The crude product was
purified by column chromatography [silica gel, eluent: dichloro-
methane/petroleum ether (1:4)].
3
7.01 (m, 1 H, 4Ј-H), 7.74 (d, JH,H = 4.1 Hz, 1 H, 3Ј-H), 8.02 (d,
3JH,H = 9.3 Hz, 1 H, 8-H), 8.56 (dd, 4JH,H = 2.5 Hz, 3JH,H = 9.3 Hz,
4
1 H, 7-H), 9.36 (d, JH,H = 2.5 Hz, 1 H, 5-H) ppm. 13C NMR
(50 MHz, CDCl3, 22 °C): δ = 15.5 (CH3), 20.8 (CH3), 28.4 (CH3),
117.6 (C), 123.1 (CH), 124.5 (CH), 126.4 (CH), 127.4 (CH), 130.2
(CH), 132.5 (CH), 138.2 (C), 145.0 (C), 147.4 (C), 151.4 (C), 154.5
(C), 161.3 (C), 163.9 (C) ppm. C17H15N3O2S (325.38): calcd. C
62.75, H 4.65, N 12.91; found C 62.46, H 4.65, N 12.90.
4-(Furan-2-yl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline (27):
Yield: 89 % (0.20 g). Yellow solid, m.p. 169 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 2.10 (s, 3 H, CH3), 2.46 (s, 3 H,
Eur. J. Org. Chem. 2009, 4059–4066
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4063

Y. Kabri, A. Gellis, P. Vanelle
FULL PAPER
4
3
CH3), 6.62 (s, 1 H, vinylic H), 6.71–6.73 (m, 1 H, 4Ј-H), 7.66 (d, 9.2 Hz, 1 H, 8-H), 8.65 (dd, JH,H = 2.4 Hz, JH,H = 9.2 Hz, 1 H,
3JH,H = 8.6 Hz, 1 H, 3Ј-H), 7.90 (m, 1 H, 5Ј-H), 8.01 (d, JH,H
9.3 Hz, 1 H, 8-H), 8.56 (dd, JH,H = 2.4 Hz, JH,H = 9.3 Hz, 1 H,
=
7-H), 9.05 (d, 4JH,H = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz,
CDCl3, 22 °C): δ = 59.5 (OCH3), 75.5 (CH2), 120.8 (C), 124.1
3
4
3
7-H), 9.87 (d, 4JH,H = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, (CH), 127.1 (CH), 129.1 (2 CH), 130.0 (2 CH), 130.9 (CH), 131.0
CDCl3, 22 °C): δ = 20.8 (CH3), 28.5 (CH3), 112.8 (CH), 116.9 (C),
(CH), 135.7 (C), 145.9 (C), 153.7 (C), 165.9 (C), 170.9 (C) ppm.
117.3 (CH), 124.3 (CH), 124.8 (CH), 126.7 (CH), 130.2 (CH), 145.2 C16H13N3O3 (295.29): calcd. C 65.08, H 4.44, N 14.23; found C
(C), 147.0 (CH), 151.1 (C), 153.3 (C), 154.8 (C), 156.3 (C), 164.3
(C) ppm. C16H13N3O3 (295.29): calcd. C 65.08, H 4.44, N 14.23;
found C 65.06, H 4.43, N 14.20.
65.05, H 4.34, N 14.34.
4-(4-Chlorophenyl)-2-(methoxymethyl)-6-nitroquinazoline (33):
Yield: 75% (0.18 g). Grey solid, m.p. 209 °C. 1H NMR (200 MHz,
CDCl3, 22 °C): δ = 3.67 (s, 3 H, OCH3), 4.98 (s, 2 H, CH2), 7.64
2-(2-Methylprop-1-enyl)-6-nitro-4-(3-nitrophenyl)quinazoline (28):
Yield: 75 % (0.20 g). Yellow solid, m.p. 217 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 2.12 (s, 3 H, CH3), 2.47 (s, 3 H,
3
3
(d, JH,H = 8.3 Hz, 2 H, 3Ј,5Ј-H), 7.77 (d, JH,H = 8.3 Hz, 2 H,
3
4
2Ј,6Ј-H), 8.38 (d, JH,H = 9.4 Hz, 1 H, 8-H), 8.68 (dd, JH,H
=
2.4 Hz, 3JH,H = 9.4 Hz, 1 H, 7-H), 9.01 (d, JH,H = 2.4 Hz, 1 H, 5-
H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ = 59.5 (OCH3),
75.5 (CH2), 120.6 (C), 123.6 (CH), 127.3 (CH), 129.5 (2 CH), 131.1
(CH), 131.4 (2 CH), 134.1 (C), 137.7 (C), 146.0 (C), 153.8 (C),
165.9 (C), 169.7 (C) ppm. C16H12ClN3O3 (329.74): calcd. C 58.28,
H 3.67, N 12.74; found C 58.58, H 3.72, N 12.63.
4
CH3), 6.71 (s, 1 H, vinylic H), 7.80–7.88 (m, 1 H, Ar-H), 8.11–8.19
4
(m, 2 H, 8-H, Ar-H), 8.49–8.53 (m, 1 H, Ar-H), 8.64 (dd, JH,H
=
3
2.4 Hz, JH,H = 9.4 Hz, 1 H, 7-H), 8.70–8.72 (m, 1 H, Ar-H), 8.85
(d, JH,H = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, CDCl3,
4
22 °C): δ = 21.0 (CH3), 28.6 (CH3), 118.8 (C), 122.9 (CH), 124.5
(CH), 124.9 (CH), 125.3 (CH), 127.3 (CH), 130.1 (CH), 130.9
(CH), 135.5 (CH), 138.0 (C), 145.4 (C), 148.8 (C), 152.9 (C), 154.2
(C), 164.3 (C), 167.3 (C) ppm. C18H14N4O4 (350.33): calcd. C
61.71, H 4.03, N 15.99; found C 61.53, H 4.03, N 15.94.
4-(4-Fluorophenyl)-2-(methoxymethyl)-6-nitroquinazoline (34):
Yield: 76% (0.18 g). Grey solid, m.p. 208 °C. 1H NMR (200 MHz,
CDCl3, 22 °C): δ = 3.67 (s, 3 H, OCH3), 4.97 (s, 2 H, CH2), 7.30–
4-(4-Methoxyphenyl)-2-(2-methylprop-1-enyl)-6-nitroquinazoline
(29): Yield: 64 % (0.16 g). Yellow solid, m.p. 175 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 2.09 (s, 3 H, CH3), 2.46 (s, 3 H,
3
7.39 (m, 2 H, 3Ј,5Ј-H), 7.80–7.89 (m, 2 H, 2Ј,6Ј-H), 8.34 (d, JH,H
= 8.6 Hz, 1 H, 8-H), 8.68 (dd, 4JH,H = 2.4 Hz, 3JH,H = 8.6 Hz, 1 H,
7-H), 9.01 (d, 4JH,H = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz,
CDCl3, 22 °C): δ = 59.5 (OCH3), 75.5 (CH2), 116.4 (2 CH), 120.7
(C), 123.8 (CH), 127.3 (CH), 131.0 (CH), 131.9 (C), 132.3 (2 CH),
146.0 (C), 153.8 (C), 164.6 (C), 165.9 (C), 169.7 (C) ppm.
C16H12FN3O3 (313.28): calcd. C 61.34, H 3.86, N 13.41; found C
61.32, H 3.95, N 13.47.
3
CH3), 3.94 (s, 3 H, OCH3), 6.68 (s, 1 H, vinylic H), 7.14 (d, JH,H
= 8.8 Hz, 2 H, 3Ј,5Ј-H), 7.81 (d, 3JH,H = 8.8 Hz, 2 H, 2Ј,6Ј-H), 8.08
3
4
3
(d, JH,H = 9.3 Hz, 1 H, 8-H), 8.56 (dd, JH,H = 2.7 Hz, JH,H
=
9.3 Hz, 1 H, 7-H), 9.01 (d, JH,H = 2.7 Hz, 1 H, 5-H) ppm. 13C
NMR (50 MHz, CDCl3, 22 °C): δ = 20.9 (CH3), 28.5 (CH3), 55.6
(OCH3), 114.6 (2 CH), 119.1 (C), 124.3 (CH), 124.8 (CH), 126.7
(CH), 128.8 (C), 130.2 (CH), 131.9 (2 CH), 145.0 (C), 151.7 (C),
154.2 (C), 162.0 (C), 164.2 (C), 169.3 (C) ppm. C19H17N3O3
(335.36): calcd. C 68.05, H 5.11, N 12.53; found C 67.61, H 5.17,
N 12.42.
4
2-(Methoxymethyl)-6-nitro-4-(o-tolyl)quinazoline (35): Yield: 82%
(0.19 g). Rose solid, m.p. 104 °C. 1H NMR (200 MHz, CDCl3,
22 °C): δ = 2.17 (s, 3 H, CH3), 3.67 (s, 3 H, OCH3), 4.98 (s, 2 H,
3
CH2), 7.31–7.53 (m, 4 H, 3Ј,4Ј,5Ј,6Ј-H), 8.33 (d, JH,H = 9.2 Hz, 1
4
4
H, 8-H), 8.59 (d, JH,H = 2.3 Hz, 1 H, 5-H), 8.66 (dd, JH,H
=
2-(2-Methylprop-1-enyl)-6-nitro-4-[3-(trifluoromethyl)phenyl]quinaz-
oline (30): Yield: 76% (0.22 g). Yellow solid, m.p. 152 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 2.11 (s, 3 H, CH3), 2.47 (s, 3 H,
CH3), 6.71 (s, 1 H, vinylic H), 7.73–7.81 (m, 1 H, Ar-H), 7.89–8.00
3
2.3 Hz, JH,H = 9.2 Hz, 1 H, 7-H) ppm. 13C NMR (50 MHz,
CDCl3, 22 °C): δ = 19.9 (CH3), 59.5 (OCH3), 75.5 (CH2), 121.9
(C), 124.0 (CH), 126.2 (CH), 127.4 (CH), 129.5 (CH), 130.3 (CH),
130.9 (CH), 131.3 (CH), 134.9 (C), 136.2 (C), 145.9 (C), 153.2 (C),
166.0 (C), 172.5 (C) ppm. C17H15N3O3 (309.32): calcd. C 66.01, H
4.89, N 13.58; found C 65.99, H 4.97, N 13.68.
3
(m, 2 H, Ar-H), 8.11 (s, 1 H, Ar-H), 8.15 (d, JH,H = 9.3 Hz, 1 H,
4
3
8-H), 8.62 (dd, JH,H = 2.2 Hz, JH,H = 9.3 Hz, 1 H, 7-H), 8.88 (d,
4JH,H = 2.2 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, CDCl3,
22 °C): δ = 20.9 (CH3), 28.6 (CH3), 119.0 (CH), 123.3 (CH), 124.6
(CH), 126.9 (CH), 127.1 (CH), 127.4 (CH), 129.1 (C), 129.5 (CH),
130.7 (CH), 131.9 (C), 133.1 (C), 137.2 (C), 145.3 (C), 152.5 (C),
154.2 (C), 164.3 (C), 168.3 (C) ppm. C19H14F3N3O2 (373.33): calcd.
C 61.13, H 3.78, N 11.26; found C 61.10, H 3.79, N 11.28.
2-(Methoxymethyl)-4-(5-methylthiophen-2-yl)-6-nitroquinazoline
(36): Yield: 63 % (0.15 g). Yellow solid, m.p. 181 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 2.64 (s, 3 H, thiophenyl CH3), 3.66
3
(s, 3 H, OCH3), 4.90 (s, 2 H, CH2), 7.01 (d, JH,H = 3.6 Hz, 1 H,
4Ј-H), 7.78 (d, 3JH,H = 3.6 Hz, 1 H, 3Ј-H), 8.25 (d, 3JH,H = 9.3 Hz,
4
3
1 H, 8-H), 8.64 (dd, JH,H = 2.1 Hz, JH,H = 9.3 Hz, 1 H, 7-H),
2-(2-Methylprop-1-enyl)-6-nitro-4-(3,4,5-trimethoxyphenyl)quinaz-
4
9.43 (d, JH,H = 2.1 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz,
1
oline (31): Yield: 66% (0.2 g). Yellow solid, m.p. 191 °C. H NMR
CDCl3, 22 °C): δ = 15.7 (CH3), 59.4 (OCH3), 75.3 (CH2), 119.4
(C), 123.4 (CH), 126.9 (CH), 127.7 (CH), 130.9 (CH), 133.3 (CH),
137.4 (C), 146.0 (C), 148.4 (C), 154.2 (C), 162.5 (C), 165.8 (C) ppm.
C15H13N3O3S (315.35): calcd. C 57.13, H 4.16, N 13.33; found C
57.10, H 4.16, N 13.30.
(200 MHz, CDCl3, 22 °C): δ = 2.11 (s, 3 H, CH3), 2.48 (s, 3 H,
CH3), 3.95 (s, 6 H, OCH3), 3.99 (s, 3 H, OCH3), 6.70 (s, 1 H, vinylic
3
H), 7.05 (s, 2 H, 2Ј,6Ј-H), 8.11 (d, JH,H = 9.5 Hz, 1 H, 8-H), 8.59
4
3
4
(dd, JH,H = 2.5 Hz, JH,H = 9.5 Hz, 1 H, 7-H), 9.11 (d, JH,H
=
2.5 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ =
20.9 (CH3), 28.5 (CH3), 56.4 (2 OCH3), 61.1 (OCH3), 107.6 (2 CH),
119.1 (C), 124.1 (CH), 124.9 (CH), 126.7 (CH), 130.4 (CH), 131.5
(C), 140.6 (C), 145.1 (C), 151.7 (C), 153.7 (2 C), 154.3 (C), 164.2
(C), 169.3 (C) ppm. C21H21N3O5 (395.41): calcd. C 63.79, H 5.35,
N 10.63; found C 63.41, H 5.29, N 10.22
4-(Furan-2-yl)-2-(methoxymethyl)-6-nitroquinazoline (37): Yield:
80 % (0.17 g). Yellow solid, m.p. 152 °C. 1H NMR (200 MHz,
CDCl3, 22 °C): δ = 3.66 (s, 3 H, OCH3), 4.90 (s, 2 H, CH2), 6.73–
3
6.75 (m, 1 H, 4Ј-H), 7.75 (d, JH,H = 3.5 Hz, 1 H, 3Ј-H), 7.92 (m,
3
4
1 H, 5Ј-H), 8.22 (d, JH,H = 9.1 Hz, 1 H, 8-H), 8.63 (dd, JH,H
=
2-(Methoxymethyl)-6-nitro-4-phenylquinazoline (32): Yield: 88% 2.1 Hz, 3JH,H = 9.1 Hz, 1 H, 7-H), 9.91 (d, JH,H = 2.1 Hz, 1 H, 5-
4
(0.19 g). Rose solid, m.p. 164 °C. 1H NMR (200 MHz, CDCl3,
H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ = 59.4 (OCH3),
75.4 (CH2), 113.0 (CH), 118.3 (CH), 118.4 (C), 124.3 (CH), 127.0
(CH), 130.7 (CH), 145.9 (C), 147.5 (CH), 152.7 (C), 154.4 (C),
22 °C): δ = 3.67 (s, 3 H, OCH3), 4.98 (s, 2 H, CH2), 7.63–7.66 (m,
3
3 H, 3Ј,4Ј,5Ј-H), 7.78–7.83 (m, 2 H, 2Ј,6Ј-H), 8.33 (d, JH,H
=
4064
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4059–4066

Arylquinazolines by Microwave-Irradiated Cross-Coupling
157.0 (C), 165.9 (C) ppm. C14H11N3O4 (285.25): calcd. C 58.95, H 4-(4-Chlorophenyl)-2-(p-tosylmethyl)quinazoline (43): Yield: 91%
3.89, N 14.73; found C 58.75, H 3.97, N 14.67.
(0.28 g). Yellow solid, m.p. 160 °C. 1H NMR (200 MHz, CDCl3,
22 °C): δ = 2.43 (s, 3 H, tosyl CH3), 4.93 (s, 2 H, CH2), 7.25 (d,
3JH,H = 8.2 Hz, 2 H, tosyl 3,5-H), 7.50 (br. s, 4 H, Ar-H), 7.60–
7.70 (m, 3 H, Ar-H), 7.89–7.96 (m, 1 H, Ar-H), 8.05–8.09 (m, 2 H,
Ar-H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ = 21.6 (CH3),
66.0 (CH2), 121.3 (C), 126.5 (CH), 128.5 (CH), 128.7 (2 CH), 128.8
(2 CH), 128.9 (CH), 129.5 (2 CH), 131.4 (2 CH), 134.3 (CH), 134.9
(C), 136.4 (C), 136.8 (C), 144.7 (C), 151.4 (C), 155.2 (C), 167.5
(C) ppm. C22H17ClN2O2S (408.90): calcd. C 64.62, H 4.19, N 6.85;
found C 64.37, H 4.46, N 6.57.
2-(Methoxymethyl)-6-nitro-4-(3-nitrophenyl)quinazoline (38): Yield:
67% (0.17 g). Rose solid, m.p. 171 °C. 1H NMR (200 MHz, CDCl3,
22 °C): δ = 3.67 (s, 3 H, OCH3), 4.98 (s, 2 H, CH2), 7.82–7.90 (m,
3
1 H, Ar-H), 8.11–8.15 (m, 1 H, Ar-H), 8.37 (d, JH,H = 8.9 Hz, 1
H, 8-H), 8.49–8.54 (m, 1 H, Ar-H), 8.69–8.74 (m, 2 H, 7-H, Ar-
4
H), 8.91 (d, JH,H = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz,
CDCl3, 22 °C): δ = 59.5 (OCH3), 75.4 (CH2), 120.4 (C), 122.9
(CH), 125.0 (CH), 125.6 (CH), 127.7 (CH), 130.3 (CH), 131.4
(CH), 135.6 (CH), 137.4 (C), 146.2 (C), 148.8 (C), 153.8 (C), 166.1
(C), 168.3 (C) ppm. C16H12N4O5 (340.29): calcd. C 56.47, H 3.55,
N 16.46; found C 56.21, H 3.53, N 16.43.
4-(4-Fluorophenyl)-2-(p-tosylmethyl)quinazoline (44): Yield: 79%
(0.24 g). Yellow solid, m.p. 150 °C. 1H NMR (200 MHz, CDCl3,
22 °C): δ = 2.43 (s, 3 H, tosyl CH3), 4.94 (s, 2 H, CH2), 7.17–7.28
(m, 4 H, Ar-H), 7.55–7.65 (m, 3 H, Ar-H), 7.67–7.71 (m, 2 H, Ar-
H), 7.89–7.97 (m, 1 H, Ar-H), 8.06–8.10 (m, 2 H, Ar-H) ppm. 13C
NMR (50 MHz, CDCl3, 22 °C): δ = 21.6 (CH3), 65.8 (CH2), 115.5
(CH), 116.0 (CH), 121.4 (C), 126.7 (CH), 128.5 (CH), 128.6 (CH),
128.8 (2 CH), 129.6 (2 CH), 132.3 (2 CH), 132.5 (C), 134.4 (CH),
136.4 (C), 144.7 (C), 151.1 (C), 155.0 (C), 164.2 (C), 167.8 (C) ppm.
C22H17FN2O2S (392.45): calcd. C 67.33, H 4.37, N 7.14; found C
66.96, H 4.48, N 7.07.
2-(Methoxymethyl)-4-(4-methoxyphenyl)-6-nitroquinazoline (39):
Yield: 87 % (0.21 g). Brown solid, m.p. 148 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 3.66 (s, 3 H, OCH3), 3.94 (s, 3 H,
3
OCH3), 4.96 (s, 2 H, CH2), 7.15 (d, JH,H = 8.8 Hz, 2 H, 3Ј,5Ј-H),
3
3
7.81 (d, JH,H = 8.8 Hz, 2 H, 2Ј,6Ј-H), 8.28 (d, JH,H = 9.3 Hz, 1
4
3
H, 8-H), 8.64 (dd, JH,H = 3.4 Hz, JH,H = 9.3 Hz, 1 H, 7-H), 9.09
(d, JH,H = 3.4 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, CDCl3,
4
22 °C): δ = 55.6 (OCH3), 59.5 (OCH3), 75.6 (CH2), 114.7 (2 CH),
120.7 (C), 124.3 (CH), 126.9 (CH), 128.2 (C), 130.8 (CH), 132.0 (2
CH), 145.8 (C), 154.0 (C), 162.2 (C), 165.9 (C), 170.2 (C) ppm.
C17H15N3O4 (325.32): calcd. C 62.76, H 4.65, N 12.92; found C
62.39, H 4.64, N 13.01.
4-(o-Tolyl)-2-(p-tosylmethyl)quinazoline (45): Yield: 70% (0.21 g).
1
Yellow solid, m.p. 122 °C. H NMR (200 MHz, CDCl3, 22 °C): δ
= 2.03 (s, 3 H, tolyl CH3), 2.38 (s, 3 H, tosyl CH3), 4.94 (s, 2 H,
CH2), 7.10–7.44 (m, 6 H, Ar-H), 7.50–7.70 (m, 4 H, Ar-H), 7.87–
3
7.92 (m, 1 H, Ar-H), 8.05 (d, JH,H = 8.2 Hz, 1 H, Ar-H) ppm. 13
C
2-(Methoxymethyl)-6-nitro-4-[3-(trifluoromethyl)phenyl]quinazoline
(40): Yield: 83 % (0.22 g). Rose solid, m.p. 105 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 3.68 (s, 3 H, OCH3), 4.99 (s, 2 H,
CH2), 7.75–7.83 (m, 1 H, Ar-H), 7.91–8.00 (m, 2 H, Ar-H), 8.10
NMR (50 MHz, CDCl3, 22 °C): δ = 19.6 (CH3), 21.5 (CH3), 66.1
(CH2), 122.4 (C), 125.5 (CH), 126.9 (CH), 128.1 (CH), 128.5 (2
CH), 128.6 (CH), 129.2 (CH), 129.3 (CH), 129.4 (2 CH), 130.6
(CH), 134.1 (CH), 135.8 (C), 136.1 (C), 136.3 (C), 144.5 (C), 150.9
(C), 155.1 (C), 170.3 (C) ppm. C23H20N2O2S (388.48): calcd. C
71.11, H 5.19, N 7.21; found C 70.88, H 5.32, N 6.95.
3
(br. s, 1 H, Ar-H), 8.36 (d, JH,H = 9.4 Hz, 1 H, 8-H), 8.70 (dd,
4JH,H = 2.4 Hz, 3JH,H = 9.4 Hz, 1 H, 7-H), 8.94 (d, 4JH,H = 2.4 Hz,
1 H, 5-H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ = 59.5
(OCH3), 75.5 (CH2), 120.6 (C), 123.4 (CH), 126.9 (CH), 127.5
(CH), 127.7 (CH), 129.1 (C), 129.6 (CH), 131.3 (CH), 131.9 (C),
133.2 (CH), 136.5 (C), 146.1 (C), 153.8 (C), 166.0 (C), 169.3
(C) ppm. C17H12F3N3O3 (363.29): calcd. C 56.20, H 3.33, N 11.57;
found C 56.06, H 3.39, N 11.42.
4-(5-Methylthiophen-2-yl)-2-(p-tosylmethyl)quinazoline (46): Yield:
78% (0.27 g). Yellow solid, m.p. 135 °C. 1H NMR (200 MHz,
CDCl3, 22 °C): δ = 2.38 (s, 3 H, tosyl CH3), 2.55 (s, 3 H, thiophenyl
CH3), 4.85 (s, 2 H, CH2), 6.86 (m, 1 H, 4Ј-H), 7.20–7.26 (m, 2 H,
tosyl 3,5-H), 7.53–7.67 (m, 4 H, Ar-H), 7.81–7.89 (m, 1 H, Ar-H),
3
3
7.97 (d, JH,H = 8.1 Hz, 1 H, Ar-H), 8.42 (d, JH,H = 8.1 Hz, 1 H,
Ar-H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ = 15.5 (CH3),
21.5 (CH3), 65.9 (CH2), 120.1 (C), 125.9 (CH), 126.8 (CH), 128.2
(CH), 128.6 (2 CH), 128.9 (CH), 129.5 (2 CH), 132.2 (CH), 133.7
(CH), 136.1 (C), 137.9 (C), 144.4 (C), 146.6 (C), 151.7 (C), 154.9
(C), 160.5 (C) ppm. C21H18N2O2S2 (394.51): calcd. C 63.93, H 4.60,
N 7.10; found C 63.58, H 4.60, N 6.97.
2-(Methoxymethyl)-6-nitro-4-(3,4,5-trimethoxyphenyl)quinazoline
(41): Yield: 80% (0.23 g). Rose solid, m.p. 173 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 3.68 (s, 3 H, OCH3), 3.95 (s, 6 H,
OCH3), 3.98 (s, 3 H, OCH3), 4.98 (s, 2 H, CH2), 7.02 (s, 2 H, 2Ј,6Ј-
H), 8.33 (d, JH,H = 9.1 Hz, 1 H, 8-H), 8.67 (dd, JH,H = 2.8 Hz,
3JH,H = 9.1 Hz, 1 H, 7-H), 9.16 (d, 4JH,H = 2.8 Hz, 1 H, 5-H) ppm.
13C NMR (50 MHz, CDCl3, 22 °C): δ = 56.5 (2 OCH3), 59.5
(OCH3), 61.1 (OCH3), 75.5 (CH2), 107.7 (2 CH), 108.1 (C), 120.7
(C), 124.2 (CH), 127.2 (CH), 130.8 (C), 131.0 (CH), 132.1 (C),
145.9 (C), 153.8 (C), 153.9 (C), 165.9 (C), 170.5 (C) ppm.
C19H19N3O6 (385.37): calcd. C 59.22, H 4.97, N 10.90; found C
59.08, H 5.04, N 10.82.
3
4
4-(Furan-2-yl)-2-(p-tosylmethyl)quinazoline (47): Yield: 91%
(0.22 g). Yellow solid, m.p. 149 °C. 1H NMR (200 MHz, CDCl3,
22 °C): δ = 2.40 (s, 3 H, tosyl CH3), 4.87 (s, 2 H, CH2), 6.59–6.61
3
3
(m, 1 H, 4Ј-H), 7.15 (d, JH,H = 3.6 Hz, 1 H, 3Ј-H), 7.24 (d, JH,H
= 7.2 Hz, 2 H, tosyl 3,5-H), 7.61–7.97 (m, 6 H, Ar-H), 8.88 (d,
3JH,H = 8.6 Hz, 1 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3,
22 °C): δ = 21.5 (CH3), 66.0 (CH2), 112.3 (CH), 116.8 (CH), 119.3
(C), 126.6 (CH), 128.4 (CH), 128.8 (3 CH), 129.4 (2 CH), 133.9
(CH), 136.3 (C), 144.4 (C), 146.2 (CH), 152.2 (C), 153.2 (C), 155.2
(2 C) ppm. C20H16N2O3S (364.42): calcd. C 65.92, H 4.43, N 7.69;
found C 65.59, H 4.58, N 7.42.
4-Phenyl-2-(p-tosylmethyl)quinazoline (42): Yield: 94% (0.27 g).
1
Yellow solid, m.p. 156 °C. H NMR (200 MHz, CDCl3, 22 °C): δ
3
= 2.43 (s, 3 H, tosyl CH3), 4.96 (s, 2 H, CH2), 7.26 (d, JH,H
=
8.4 Hz, 2 H, tosyl 3,5-H), 7.53 (br. s, 5 H, 2Ј,3Ј,4Ј,5Ј,6Ј-H), 7.59–
3
7.63 (m, 1 H, Ar-H), 7.69 (d, JH,H = 8.4 Hz, 2 H, tosyl 2,6-H),
7.89–7.96 (m, 1 H, Ar-H), 8.06–8.13 (m, 2 H, Ar-H) ppm. 13C
NMR (50 MHz, CDCl3, 22 °C): δ = 21.6 (CH3), 66.1 (CH2), 121.5 4-(3-Nitrophenyl)-2-(p-tosylmethyl)quinazoline (48): Yield: 72%
(C), 127.0 (CH), 128.3 (CH), 128.5 (2 CH), 128.8 (3 CH), 129.5 (2 (0.23 g). Yellow solid, m.p. 132 °C. 1H NMR (200 MHz, CDCl3,
CH), 130.1 (2 CH), 130.3 (CH), 134.1 (CH), 136.4 (C), 136.5 (C),
144.6 (C), 151.4 (C), 155.2 (C), 168.8 (C) ppm. C22H18N2O2S
(374.46): calcd. C 70.57, H 4.85, N 7.48; found C 70.21, H 4.76, N
7.39.
22 °C): δ = 2.41 (s, 3 H, tosyl CH3), 4.95 (s, 2 H, CH2), 7.28 (d,
3JH,H = 7.2 Hz, 2 H, tosyl 3,5-H), 7.65–7.76 (m, 4 H, Ar-H), 7.92–
3
8.02 (m, 3 H, Ar-H), 8.12 (d, JH,H = 8.4 Hz, 1 H, Ar-H), 8.37–
8.41 (m, 2 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ =
Eur. J. Org. Chem. 2009, 4059–4066
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4065

Y. Kabri, A. Gellis, P. Vanelle
FULL PAPER
21.6 (CH3), 66.1 (CH2), 121.1 (C), 124.8 (CH), 124.9 (CH), 125.9
(CH), 128.7 (2 CH), 129.1 (CH), 129.4 (CH), 129.6 (2 CH), 129.7
(CH), 134.6 (CH), 136.0 (CH), 136.3 (C), 138.2 (C), 145.1 (C),
148.4 (C), 151.8 (C), 155.4 (C), 165.9 (C) ppm. C22H17N3O4S
(419.45): calcd. C 63.00, H 4.09, N 10.02; found C 62.68, H 4.32,
N 9.59.
recording the 1H and 13C NMR spectra and G. Lanzada for his
technical support.
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4-(4-Methoxyphenyl)-2-(p-tosylmethyl)quinazoline (49): Yield: 67%
(0.21 g). Yellow solid, m.p. 171 °C. 1H NMR (200 MHz, CDCl3,
22 °C): δ = 2.41 (s, 3 H, tosyl CH3), 3.89 (s, 3 H, OCH3), 4.92 (s,
3
3
2 H, CH2), 7.01 (d, JH,H = 9.2 Hz, 2 H, 3Ј,5Ј-H), 7.24 (d, JH,H
=
3
8.4 Hz, 2 H, tosyl 3,5-H), 7.52 (d, JH,H = 9.2 Hz, 2 H, 2Ј,6Ј-H),
7.56–7.60 (m, 1 H, Ar-H), 7.66 (d, JH,H = 8.4 Hz, 2 H, tosyl 2,6-
H), 7.84–7.92 (m, 1 H, Ar-H), 8.02 (d, JH,H = 8.1 Hz, 1 H, Ar-
3
3
H), 8.13 (d, 3JH,H = 8.1 Hz, 1 H, Ar-H) ppm. 13C NMR (50 MHz,
CDCl3, 22 °C): δ = 21.5 (CH3), 55.4 (OCH3), 66.1 (CH2), 113.9 (2
CH), 121.4 (C), 126.9 (CH), 127.9 (CH), 128.7 (2 CH), 128.8 (CH),
128.9 (C), 129.4 (2 CH), 131.8 (2 CH), 133.8 (CH), 136.4 (C), 144.5
(C), 151.6 (C), 155.1 (C), 161.4 (C), 168.0 (C) ppm. C23H20N2O3S
(404.48): calcd. C 68.30, H 4.98, N 6.93; found C 67.96, H 4.92, N
6.79.
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2-(p-Tosylmethyl)-4-[3-(trifluoromethyl)phenyl]quinazoline
(50):
Yield: 74% (0.24 g). Yellow solid, m.p. 105 °C. 1H NMR
(200 MHz, CDCl3, 22 °C): δ = 2.41 (s, 3 H, tosyl CH3), 4.96 (s, 2
3
H, CH2), 7.26 (d, JH,H = 7.9 Hz, 2 H, tosyl 3,5-H), 7.67–7.83 (m,
3
7 H, Ar-H), 7.92–8.03 (m, 2 H, Ar-H), 8.13 (d, JH,H = 8.5 Hz, 1
H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3, 22 °C): δ = 21.5
(CH3), 66.0 (CH2), 121.3 (C), 123.8 (C), 126.2 (CH), 126.6 (CH),
126.8 (CH), 128.7 (2 CH), 128.8 (CH), 129.0 (CH), 129.1 (CH),
129.5 (2 CH), 131.2 (C), 133.4 (CH), 134.4 (CH), 136.3 (C), 137.3
(C), 144.9 (C), 151.6 (C), 155.3 (C), 167.1 (C) ppm.
C23H17F3N2O2S (442.45): calcd. C 62.44, H 3.87, N 6.33; found C
61.99, H 4.11, N 6.18.
2-(p-Tosylmethyl)-4-(3,4,5-trimethoxyphenyl)quinazoline (51): Yield:
70% (0.25 g). Yellow solid, m.p. 148 °C. 1H NMR (200 MHz,
CDCl3, 22 °C): δ = 2.41 (s, 3 H, tosyl CH3), 3.90 (s, 6 H, OCH3),
3.94 (s, 3 H, OCH3), 4.95 (s, 2 H, CH2), 6.88 (s, 2 H, 2Ј,6Ј-H),
7.24–7.28 (m, 2 H, tosyl 3,5-H), 7.61–7.73 (m, 3 H, Ar-H), 7.89–
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3
7.96 (m, 1 H, Ar-H), 8.05 (d, JH,H = 8.1 Hz, 1 H, Ar-H), 8.18 (d,
3JH,H = 8.1 Hz, 1 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3,
22 °C): δ = 21.6 (CH3), 56.5 (2 OCH3), 61.0 (OCH3), 66.0 (CH2),
107.8 (2 CH), 121.5 (C), 126.9 (CH), 128.2 (CH), 128.7 (2 CH),
128.8 (CH), 129.5 (2 CH), 131.8 (C), 134.1 (CH), 136.6 (C), 140.2
(C), 144.6 (C), 151.4 (C), 153.4 (2 C), 155.1 (C), 168.6 (C) ppm.
C25H24N2O5S (464.53): calcd. C 64.64, H 5.21, N 6.03; found C
64.41, H 5.36, N 6.11.
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Acknowledgments
This work was supported by the Centre Nacional de la Recherche
Scientifique (CNRS) and the University of Aix-Marseille II. The
authors thank P. Verhaeghe for his cooperation, V. Remusat for
Received: April 16, 2009
Published Online: July 8, 2009
4066
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4059–4066