Microwave-assisted synthesis in aqueous medium of new quinazoline derivatives as anticancer agent precursors

Article abstract of DOI:10.1039/b816723k

Fast and eco-friendly microwave-irradiated reactions permitting the "green synthesis" of new 2-substituted quinazoline derivatives in aqueous medium via S-alkylation or S_RN1 reaction from 2-chloromethyl-3-methylquinazolin-4(3H)-one derivatives with different benzenesulfinic acids and nitronate anions, are reported herein.

Full text of DOI:10.1039/b816723k

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PAPER
www.rsc.org/greenchem | Green Chemistry
Microwave-assisted synthesis in aqueous medium of new quinazoline
derivatives as anticancer agent precursors
Y. Kabri, A. Gellis and P. Vanelle*
Received 24th September 2008, Accepted 29th October 2008
First published as an Advance Article on the web 19th November 2008
DOI: 10.1039/b816723k
Fast and eco-friendly microwave-irradiated reactions permitting the “green synthesis” of new
2-substituted quinazoline derivatives in aqueous medium via S-alkylation or SRN1 reaction from
2-chloromethyl-3-methylquinazolin-4(3H)-one derivatives with different benzenesulfinic acids and
nitronate anions, are reported herein.
Introduction
Within the last few years, green chemistry has become a major
interest for the chemistry community.1 The investigations and
applications of green chemistry principles have led to the
development of cleaner and more benign chemical processes,
many new technologies being developed each year.2
Scheme 1
In most chemical processes, major adverse effects towards
the environment are due mainly to the consumption of energy
2-subtituted quinazolines, under microwave irradiation, in aque-
for heating. To overcome this problem it is highly desirable to
ous medium. Substituents were selected with different electronic
develop efficient methods that use alternative energy sources
and solubility characteristics, with the aim of investigating the
such as microwave irradiation, to facilitate chemical reactions.
substituent effects at the 2-position.
At the same time, water can undoubtedly be considered as the
cleanest solvent available for chemists.
Results and discussion
Recently, the combination of these two prominent green
chemistry principles, “microwaves” and “water”, has become
very popular and received substantial interest.3
The majority of synthetic routes to 2-substituted quinazolin-
4(3H)-ones is based on Niementowski’s reaction, which involves
the fusion (130–150 ◦C) of anthranilic acid analogues with
amides, proceeding via an o-amidobenzamide intermediate.7 The
reaction yield in such conditions is variable and sometimes, com-
plicated mixtures of carbonaceous compounds and impurities
are formed, requiring a purification step with chromatography
column.
For the above mentioned reasons, we studied extensively
the synthesis of 2-chloromethylquinazolin-4(3H)-one 2 under
microwave irradiation by various methods.
Conventional synthesis of 2 involves two steps, condensation
of 2-aminobenzonitrile with an excess of chloroacetylchloride,
affording 2-chloro-N-(2-cyanophenyl)acetamide 1,8 followed by
Radziszewski’s reaction using UHP (urea hydrogen peroxide)
as a mild, safe and non-hazardous oxidizing agent, leading to
2-chloromethylquinazolin-4(3H)-one 2.9
On the other hand, quinazoline derivatives have shown a
remarkable activity as antitubercular, anti-fungal, antimalarial
and anticancer agents.4 Indeed, quinazoline derivatives have
been shown to be efficient and highly selective inhibitors of
the tyrosine kinase activity of the epidermal growth factor
receptor (EGFR) via a competitive mechanism with the binding
of ATP. These compounds are of potential interest as anticancer
drugs, because EGFR is known to be over-expressed in many
clinical cancers, and its overexpression is associated with poor
prognosis.5
Characterization of molecules which are likely to interact with
the EGFR and to inhibit selectively this tyrosine kinase activity,
R
R
such as gefitinib (Iressaꢀ) or erlofitinib (Tarcevaꢀ), has given rise
to important hopes for both patients and clinitians (Scheme 1).
The growing medicinal importance of these heterocycles
perpetuates to provide strong international effort for the de-
velopment of synthetic methods for their preparation.
We initialy started by conducting the first step in both classical
and microwave-assisted conditions (Scheme 2).
We have recently developed a new microwave-assisted method
for synthesizing compounds in water.6 The biological activity of
the quinazoline derivatives led us to develop the synthesis of new
Laboratoire de Pharmaco-Chimie Radicalaire (LPCR), Faculte´ de
Pharmacie, Universite´s d’Aix-Marseille I, II et III–CNRS,
UMR 6264, Laboratoire Chimie Provence, 27 Bd J. Moulin, 13385,
Marseille cedex 05, France
Scheme 2
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Table 1 Reactions of 2-aminobenzamide with various acid chlorides
In classical conditions, the product 1 is obtained in 54% yield
after 3 h reaction time, whereas under microwave irradiation,
the same product is isolated in 98% yield after only 4 minutes
reaction time. We then compared classical conditions versus
microwave-assisted conditions toward a second reaction step.
In classical conditions (30 h at 84 ◦C), the derivative 2 is
obtained in 55% yie◦ld, and under microwave irradiation (1.5 h
reaction time at 70 C, measured by an infrared detector), the
same product 2 is prepared in 78% yield (Scheme 3).
N◦
Product
Yield
87
2
3
4
81
83
5
72
Scheme 3
Recently in the literature,10 another method described the one
pot solvent-free synthesis of 2, from 2-aminobenzamide and
2-chloroacetic acid, under microwave irradiation (Scheme 4).
This method consists in the fusion of 2-chloroacetic acid with
2-aminobenzamide. After several tests, we could not isolate the
desired compound, using this method.
Scheme 4
From the same 2-aminobenzamide, reacting with an excess of
chloroacetylchloride under microwave irradiation, we formed
the intermediate N-(2-aminophenyl)-2-chloroacetamide. The
crude product was isolated and directly engaged in a cyclization,
with K2CO3 in water, under microwave irradiation, leading to
the expected product 2, as shown in Scheme 5.
Scheme 6
obtained, were appreciably lower than those previously observed
(Scheme 7). However, this method permitted us to confirm
the position of the nitro group on the quinazoline ring, firstly
determined by NMR study.
Scheme 5
This method was generalized with various acid chlorides,
enabling us to obtain compounds 2–5 in good yields (Table 1).
The 2-chloromethylquinazolin-4(3H)-one 2 can be methy-
lated by using dimethylsulfate (DMS) in a water/THF (1:1)
mixture and then, nitrated using the HNO3–H2SO4 mixture,
leading to 2-chloromethyl-3-methyl-6-nitroquinazolin-4(3H)-
one 7 in 63% global yield (Scheme 6).
Aiming at avoiding the last nitration step, we investigated an-
other synthetic procedure for the preparation of 2-chloromethyl-
3-methyl-6-nitroquinazolin-4(3H)-one 7, starting from the
2-amino-5-nitrobenzonitrile. Unfortunately, the yields we
Scheme 7
Recently, we described a “green chemistry procedure” allow-
ing the substitution of a chloride atom by a sulfone group.6 This
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ecofriendly methodology in aqueous phase using microwave
technology to ensure respect of the environment, was developed
for the preparation of new 2-substituted quinazolines (Table 2).
Experimentaly, a simple addition of both 2-chloromethyl-3-
methylquinazolin-4(3H)-one derivatives 6, 7 and the sodium
salt of benzenesulfinic acid 10a–j in an aqueous solution gave
the corresponding S-alkylated product 11a–j and 12a–j in high
yields (Scheme 8).
Table 2 Reactions of 2-chloromethyl-3-methyl quinazolin-4(3H)-one
derivatives 6, 7 with benzenesulfinic acid anions 10a–ja
Yield Yield
R1 = H R1 = NO2
Anion
Product
68
71
66
67
67
60
—
95
91
71
67
69
63
75
Scheme 8
When the same reaction was carried out under classical
conditions (24 h, 100 ◦C), 2-chloromethyl-3-methyl quinazolin-
4(3H)-one 6 reacted with the benzenesulfonyl chloride, leading
to the same product 11a, with a lower yield (70%).
The above results show the activation of the S-alkylation
reaction by microwave heating.
In order to extend the chemical variability in position 2,
we applied the microwave technology to the SRN1 reaction in
the quinazoline series. Thus, compound 7 was treated with 2-
nitropropane anion 13a to afford the ethylenic derivative 15a as
shown in Scheme 9.
Scheme 9
—
57
54
59
—
—
The C-alkylated product 14a was not isolated because the
nitrous acid elimination is very rapid in basic medium, due to
the acidity of the methylene protons.
The best reaction yield (98%) of 15a was obtained when the
reaction was carried out under 500 W microwave power, during
15 minutes, in methanol using 3 equivalents of 2-nitropropane
anion 13a. The electron transfer mechanism was confirmed by
complete inhibition studies.11
From these interesting results, we sought to generalize this
SRN1 reaction in the quinazoline series to various nitronate
anions 13b–d (Table 3).
It was described that the thermal effects and specific effects
induced by the microwave field can be observed for polar
mechanisms when the polarity is increased during the reaction,
from the ground state (GS) towards the transition state (TS).12
We recently observed that the TS for S-alkylation reaction
(SN2 mechanism) involves loose ion pairs as a charge delocalised
a Microwave instrumentation: the temperature was measured by an
infrared detector, and the microwave pulsed power was regulated by
the software of terminal 320 for Ethos start, Milestone Inc. Reaction
conditions: 1 h, microwave power 300 W, 100 ◦C.
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Table 3 Reactions of 2-chloromethyl-3-methylquinazolin-4(3H)-one
derivatives 7 with several nitronate anions 13a–da
properly substituted in position 4, as potential inhibitors of the
EGFR.
Anion
Product
Yield
98
Experimental
General experimental
Melting points were determined on a Bu¨chi B-540 and are
uncorrected. Elemental analyses were performed by the Micro-
analyses center of the University of Aix-Marseille 3, France.
97
95
1
Both H and 13C NMR spectra were determined on a Bruker
1
ARX 200 spectrometer. The H chemical shifts are reported
as ppm downfield from tetramethylsilane (Me4Si), and the 13C
chemical shifts were 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 were performed
on 5 cm ¥ 10 cm aluminium plates coated with silica gel 60F-254
(Merck) in an appropriate solvent.
93
Microwave instrumentation
Multimode reactors. ETHOS Synth Lab station and Mi-
croSYNTH 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 1000 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 an optical fiber (ATC-FO 300).
In order to compare microwave irradiation with conventional
heating, the reactions were performed under similar experimen-
tal conditions (amount of reactants and temperature) using
a thermostated 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.
a Microwave instrumentation: the temperature was measured by an
infrared detector, and the microwave pulsed power was regulated by
the software of terminal 320 for Ethos start, Milestone Inc. Reaction
conditions: 15 min, microwave power 500 W, 65 ◦C.
(soft) anion,6 whereas the GS involves a neutral electrophile
and tighter ion pair. During the course of the reaction, ionic
dissociation is increased and that way, polarity is enhanced from
GS to TS. Thus, a favourable microwave effect can be observed.
It is the same for the SRN1 reactions using charged species such
as the nitroalkane lithium salts and radicals or radical anions
derived from 7.
All the quinazoline derivatives obtained are to be screened for
their antitumor activity. Their cytotoxicity is under evaluation in
triplicate on colon adenocarcinoma cell line (HT29 and SW620)
and vulvar epidermoid carcinoma cell line (A431), in order to
evaluate the activity of the prepared 2-substituted quinazolines
on the EGFR signaling.
Experimental procedure
2-Chloro-N-(2-cyanophenyl)acetamide 1
Classical method.8
Conclusion
Microwave method. To a solution of 2-aminobenzonitrile
(5 g, 42.2 mmol) in pyridine (10.2 mL, 126.7 mmol),
chloroacetylchloride (5.7 mL, 71.8 mmol) diluted in DMF
(48 mL) was added dropwise at 0 ◦C. The reaction mixture
was irradiated in a microwave oven at 40 ◦C, for 4 min. at a
power of 150 W. After cooling, 100 mL of water were added.
A precipitate appeared and was filtered, washed with water (3 ¥
20 mL) and dried in a vacuum drying oven (dessicator cabinet).
Recrystallization from 2-propanol gave 8.05 g (98%) of white
In the present study, we have investigated the preparation
of new anticancer agent precursors in a quinazoline series.
Using dedicated microwave irradiation in aqueous medium, the
Niementowski reaction could be easily and rapidly performed,
affording the intermediate 2-chloromethyl-6-nitroquinazolin-
4(3H)-one 9 in very good yield. This compound served as a
substrate for the synthesis of several new quinazolines, bearing
various substituents in position 2. The present synthetic method
is a simple, efficient, inexpensive and green approach for the
preparation of 2-substituted quinazolines via S-alkylation or
SRN1 reactions in aqueous medium.
◦
solid, mp 116 C (Lit.8 115–116 ◦C). dH (200 MHz; CDCl3)
4.26 (s, 2H, CH2Cl), 7.21–7.28 (m, 1H, H ar), 7.59–7.67 (m, 2H,
H ar), 8.38 (d, J = 8.8 Hz, 1H, H ar), 8.86 (bs, 1H, NH). dC
(50 MHz; CDCl3) 42.9, 102.9, 115.8, 121.1, 125.1, 132.4, 134.2,
139.3, 164.3.
These new quinazoline derivatives could be employed as
intermediates in the synthesis of more complex quinazolines,
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2-Chloromethylquinazolin-4(3H)-one 2
2-Chloromethyl-3-methylquinazolin-4(3H)-one 6
To a mixture of 1 (5.76 g, 29.6 mmol) and acetone/H2O (v/v
1:1, 160 mL) was added K2CO3 (0.8 g, 5.8 mmol) and UHP
(5.6 g, 59.2 mmol). The reaction mixture was irradiated in a
2-Chloromethylquinazolin-4(3H)-one 2 (1.56 g, 8.02 mmol),
dimethyl sulfate (1.52 ml, 16.04 mmol) and potassium hydroxide
(0.78 g, 13.9 mmol) were intimately mixed in a solution
THF/H2O (v/v 1:1, 40 mL). The reaction mixture was irradiated
in a microwave oven, at 60 ◦C, for 30 min. at a power of
500 W. After cooling, 60 mL of water were added. A precipitate
appeared and was filtered, washed with water (3 ¥ 20 mL) and
dried in a vacuum drying oven (dessicator cabinet). The product
was recrystallized from 2-propanol gave 1.43 g (85%) of yellow
◦
microwave oven at 70 C, for 1.5 h at a power of 500 W. After
cooling, 100 mL of water were added. A precipitate appeared
and was filtered, washed with water (3 ¥ 20 mL) and dried
in a vacuum drying oven (dessicator cabinet). Recrystallization
from 2-propanol gave 4.49 g (78%) of white solid, mp 249–
◦
250 C (Lit.9 247–248 ◦C). dH (200 MHz; DMSO-d6) 4.55 (s,
◦
2H, CH2Cl), 7,51–7.58 (m, 1H, H ar), 7.68 (d, J = 8.1 Hz, 1H,
H ar), 7.80–7.87 (m, 1H, H ar), 8.12 (d, J = 8.1 Hz, 1H, H ar).
dC (50 MHz; DMSO-d6) 43.4, 121.4, 126.0, 127.4, 134.8, 148.4,
152.5, 161.7.
solid, mp 185 C (Lit.15 182 ◦C), dH (200 MHz; CDCl3) 3.77
(s, 3H, N-CH3), 4.65 (s, 2H, CH2Cl), 7,48–7.56 (m, 1H, H ar),
7.66–7.81 (m, 2H, H ar), 8.29 (dd, J = 2.4 Hz, J = 8.2 Hz, 1H, H
ar). dC (50 MHz; CDCl3) 30.7, 44.4, 120.8, 126.9, 127.4, 134.4,
146.6, 151.6, 162.1.
The same method was used to prepare compound 7 from 9,
by methylation.
General procedure for the synthesis of 2-chloromethylquinazolin-
4(3H)-one 2–5, from 2-aminobenzamide, via the corresponding
2-amidobenzamide derivatives
2-Chloromethyl-3-methyl-6-nitroquinazolin-4(3H)-one 7
First step: a mixture of 2-aminobenzamide (1 g, 7.40 mmol) and
corresponding acid chloride derivative (6 eq) was irradiated in a
microwave oven at 50 ◦C, for 5 min. at a power of 300 W. After
cooling, 50 mL of water were added. A precipitate appeared
and was filtered, washed with water (3 ¥ 20 mL) and dried in
a vacuum drying oven (dessicator cabinet). A white solid was
obtained and directly engaged in the second step.
Second step: a mixture of the corresponding intermediate
compound and K2CO3 (0.5 eq) in water (40 mL), was irradiated
in a microwave oven at 80 ◦C for 1 h at a power of 500 W. After
cooling, 60 mL of water were added. A precipitate appeared
and was filtered, washed with water (3 ¥ 20 mL) and dried in a
vacuum drying oven (dessicator cabinet). Recrystallization from
2-propanol gave the expected compound 2–5.
To a solution of 2-chloromethyl-3-methylquinazolin-4(3H)-one
6 (1.18 g, 5.65 mmol) in concentrated sulfuric acid (12.7 mL),
fuming nitric acid (1.3 mL) was added dropwise at 0 ◦C. The
reaction mixture was stirred at the room temperature 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 fr◦om
2-propanol gave 1.22 g (85%) of yellow solid, mp 178–179 C,
(Found: C, 47.05; H, 3.24; N, 16.90. C10H8ClN3O3 requires C,
47.35; H, 3.18; N, 16.57%). dH (200 MHz; CDCl3) 3.80 (s, 3H,
N-CH3), 4.66 (s, 2H, CH2Cl), 7,82 (d, J = 9.1 Hz, 1H, H ar),
8.55 (dd, J = 2.5, J = 9.1 Hz, 1H, H ar), 9.15 (d, J = 2.5 Hz, 1H,
H ar). dC (50 MHz; DMSO-d6) 31.1, 44.1, 121.0, 123.6, 128.5,
129.2, 146.3, 150.6, 154.8, 161.1.
2-Chloro-N-(2-cyano-4-nitrophenyl)acetamide 8
2-Methylquinazolin-4(3H)-one 3
A mixture of 2-amino-5-nitrobenzonitrile (1 g, 6.13 mmol) and
corresponding acid chloride (6 eq) was irradiated in a microwave
Light yellow solid, mp 230–231 C, (Lit.13 229–230 ◦C). dH
◦
◦
(200 MHz; CDCl3) 2.26 (s, 3H, CH3), 7.43–7.62 (m, 2H, H ar),
7.66–7.82 (m, 1H, H ar) 8.24 (d, J = 8.1 Hz, 1H, H ar), 11.09 (bs,
1H, NH). dC (50 MHz; CDCl3) 24.1,126.9, 128.9, 130.0, 131.9,
135.0, 147.8, 154.5, 163.2.
oven at 50 C, for 5 min. at a power of 300 W. After cooling,
50 mL of water were added. A precipitate appeared and was
filtered, washed with water (3 ¥ 20 mL) and dried in vacuum
drying oven (dessicator cabinet). A brown solid was obtained◦in
47% yield and directly engaged in the second step, mp 159 C
(Lit.16 157–159 ◦C).
2-(2-Nitrophenyl)quinazolin-4(3H)-one 4
Light yellow solid, mp 212 ◦C, (Lit.14 210–212 ◦C). dH (200 MHz;
DMSO-d6) 7.49–7.61 (m, 2H, H ar), 7.65 (d, J = 8.4 Hz, 1H,
H ar) 7.81–7.95 (m, 4H, H ar), 8.21 (t, J = 8.1 Hz, 1H, H ar).
dC (50 MHz; DMSO-d6) 121.1, 124.4, 125.9, 127.0, 127.2, 129.2,
131.3, 131.7, 134.1, 134.7, 147.5, 148.5, 151.6, 161.5.
2-Chloromethyl-6-nitroquinazolin-4(3H)-one 9
To a mixture of 2-chloro-N-(2-cyano-4-nitrophenyl)acetamide 8
(0.5 g, 2.08 mmol) and acetone/H2O (v/v 1:1, 20 mL) was added
K2CO3 (0.06 g, 0.42 mmol) and UHP (0.4 g, 4.16 mmol). The
◦
reaction mixture was irradiated in a microwave oven at 70 C,
for 1.5 h at a power of 500 W. After cooling, 50 mL of water
were added. A precipitate appeared and was filtered, washed
with water (3 ¥ 20 mL) and dried in a vacuum drying oven
(dessicator cabinet). The product required was recrystallized
from 2-propanol gave 0.25 g (51%) of yellow solid, mp 235 ◦C,
(Found: C, 44.81; H, 2.61; N, 17.64. C9H6ClN3O3 requires C,
45.11; H, 2.52; N, 17.54%). dH (200 MHz; DMSO-d6) 4.61 (s,
2H, CH2Cl), 7.89 (d, J = 8.9 Hz, 1H, H ar), 8.57 (dd, J = 2.7,
2-Phenylquinazolin-4(3H)-one 5
Light yellow solid, mp 241 ◦C, (Lit.13 241–242 ◦C). dH (200 MHz;
CDCl3) 7.48–7.60 (m, 4H, H ar), 7.78–7.91 (m, 2H, H ar), 8.24–
8.35 (m, 3H, H ar). dC (50 MHz; CDCl3) 120.8, 126.4, 126.8,
127.5, 127.5, 127.9, 129.0, 129.0, 131.7, 132.7, 134.9, 149.4,
151.8, 163.8.
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J = 8.9 Hz, 1H, H ar), 8.81 (d, J = 2.7 Hz, 1H, H ar) dC (50 MHz;
DMSO-d6) 43.4, 121.9, 122.4, 129.0, 129.5, 145.8, 152.9, 156.5,
161.3.
2-[(4-Fluorophenylsulfonyl)methyl]-3-methylquinazolin-4(3H)-
one 11d
White solid, mp 184 ◦C, (Found: C, 57.88; H, 3.96; N, 8.43.
C16H13FN2O3S requires C, 57.82; H, 3.94; N, 8.43%). dH
(200 MHz; CDCl3) 3.84 (s, 3H, CH3), 4.67 (s, 2H, CH2), 7.12–
7.21 (m, 2H, H ar), 7.28 (d, J = 8.9 Hz, 1H, H ar), 7.45–7.53 (m,
1H, H ar), 7.64–7.72 (m, 1H, H ar), 7.76–7.84 (m, 2H, H ar),
8.26 (dd, J = 2.1 Hz, J = 8.9 Hz, 1H, H ar). dC (50 MHz; CDCl3)
32.0, 62.0, 116.6, 120.6, 120.7, 126.9, 127.0, 127.9, 131.7, 131.9,
133.9, 134.5, 146.1, 146.3, 161.9, 163.7, 166.3.
General procedure for the synthesis of the sulfonylmethyl-
quinazolin-4(3H)-one derivatives (11a–j and 12a–j)
The sodium salts were commercially available or prepared as
previously described.17
Conventional conditions. To a solution of benzenesulfonyl
chloride (2 eq), NaHCO3 (0.34 g, 1.92 mmol), Na2SO3 (2 eq)
in water (30 mL) at 100 ◦C, was added 2-chloromethyl-3-
methylquinazolin-4(3H)-one 6 (0.2 g, 0.96 mmol). The reaction
mixture was heated at 100 ◦C for 24 h and filtered. The precipitate
was filtered, washed with 3 ¥ 20 mL of water and dried in
a low pressure drying oven. The product required 11a was
recrystallized from 2-propanol.
2-[(4-Bromophenylsulfonyl)methyl]-3-methylquinazolin-4(3H)-
one 11e
White solid, mp 217 ◦C, (Found: C, 48.46; H, 3.28; N, 6.83.
C16H13BrN2O3S requires C, 48.87; H, 3.33; N, 7.12%). dH
(200 MHz; CDCl3) 3.84 (s, 3H, CH3), 4.66 (s, 2H, CH2), 7.29
(d, J = 8.2 Hz, 1H, H ar), 7.46–7.55 (m, 1H, H ar), 7.64–7.74
(m, 5H, H ar), 8.26 (dd, J = 2.9 Hz, J = 8.2 Hz, 1H, H ar). dC
(50 MHz; CDCl3) 32.0, 62.0, 120.7, 126.9, 128.0, 129.9, 130.3,
132.4, 134.5, 135.3, 137.0, 146.1, 146.2, 162.0.
Microwave irradiation conditions. To a solution of substi-
tuted sulfonyl chloride (2 eq), NaHCO3 (2 eq), Na2SO3 (2 eq) in
water (30 mL) was added 2-chloromethyl-3-methylquinazolin-
4(3H)-one 6 (0.2 g, 0.96 mmol) or 2-chloromethyl-3-methyl-6-
nitroquinazolin-4(3H)-one 7 (0.2 g, 0.79 mmol). 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 (3 ¥ 20 mL) and dried in a vacuum drying oven
(dessicator cabinet). The product required was recrystallized
from 2-propanol.
3-Methyl-2-[(4-nitrophenylsulfonyl)methyl]quinazolin-4(3H)-
one 11f
White solid, mp 273 ◦C, (Found: C, 53.54; H, 3.61; N,
11.32. C16H13N3O5S requires C, 53.48; H, 3.65; N, 11.69%). dH
(200 MHz; DMSO-d6) 3.68 (s, 3H, CH3), 5.32 (s, 2H, CH2), 7.32
(d, J = 8.5 Hz, 1H, H ar), 7.49–7.56 (m, 1H, H ar), 7.72–7.80
(m, 1H, H ar), 8.11 (d, J = 8.5 Hz, 1H, H ar), 8.19 (d, J =
9.1 Hz, 2H, H ar), 8.41 (d, J = 9.1 Hz, 2H, H ar). dC (50 MHz;
DMSO-d6) 31.8, 60.2, 120.6, 124.7, 126.8, 127.2, 128.1, 131.0,
135.1, 144.7, 146.5, 147.7, 151.2, 161.6.
3-Methyl-2-(phenylsulfonylmethyl)quinazolin-4(3H)-one 11a
White solid, mp 186 ◦C, (Found: C, 61.19; H, 4.47; N,
8.93. C16H14N2O3S requires C, 61.13; H, 4.49; N, 8.91%). dH
(200 MHz; CDCl3) 3.85 (s, 3H, CH3), 4.72 (s, 2H, CH2), 7.34 (d,
J = 8.3 Hz, 1H, H ar), 7.45–7.56 (m, 3H, H ar), 7.64–7.73 (m,
2H, H ar), 7.84 (m, 2H, H ar), 8.26 (dd, J = 2.3 Hz, J = 8.3 Hz,
1H, H ar). dC (50 MHz; CDCl3) 32.0, 62.1, 120.7, 127.0, 127.1,
127.7, 128.7, 129.2, 134.2, 134.3, 138.0, 146.2, 146.3, 162.0.
3-Methyl-2-[(3-nitrophenylsulfonyl)methyl]quinazolin-4(3H)-
one 11i
White solid, mp 233 ◦C, (Found: C, 53.52; H, 3.65; N,
11.58. C16H13N3O5S requires C, 53.48; H, 3.65; N, 11.69%). dH
(200 MHz; CDCl3) 3.86 (s, 3H, CH3), 4.74 (s, 2H, CH2), 7.18
(d, J = 8.7 Hz, 1H, H ar), 7.46–7.54 (m, 1H, H ar), 7.62–7.75
(m, 2H, H ar), 8.06–8.15 (m, 1H, H ar), 8.27 (dd, J = 2.3 Hz,
J = 8.7 Hz, 1H, H ar), 8.50–8.55 (m, 1H, H ar), 8.71 (m, 1H, H
ar). dC (50 MHz; CDCl3) 31.9, 61.6, 120.7, 124.5, 126.7, 127.2,
128.1, 128.7, 130.3, 134.4, 134.6, 140.0, 145.8, 146.0, 148.3,
161.7.
3-Methyl-2-(tosylmethyl)quinazolin-4(3H)-one 11b
White solid, mp 178 ◦C, (Found: C, 62.15; H, 5.00; N,
8.54. C17H16N2O3S requires C, 62.18; H, 4.91; N, 8.53%). dH
(200 MHz; CDCl3) 2.44 (s, 3H, CH3), 3.83 (s, 3H, CH3), 4.69 (s,
2H, CH2), 7.30 (d, J = 8.5 Hz, 2H, H ar), 7.38 (d, J = 8.5 Hz,
1H, H ar), 7.44–7.54 (m, 1H, H ar), 7.65–7.74 (m, 3H, H ar),
8.27 (dd, J = 2.4 Hz, J = 8.5 Hz, 1H, H ar). dC (50 MHz; CDCl3)
21.3, 32.1, 62.0, 120.6, 126.8, 127.0, 127.8, 128.8, 129.8, 134.4,
135.2, 145.6, 146.0, 146.6, 161.8.
2-[(4-Chlorophenylsulfonyl)methyl]-3-methylquinazolin-4(3H)-
3-Methyl-2-[(thiophen-2-ylsulfonyl)methyl]quinazolin-4(3H)-
one 11c
one 11j
White solid, mp 207 ◦C, (Found: C, 55.03; H, 3.72; N, 7.98.
C16H13ClN2O3S requires C, 55.09; H, 3.76; N, 8.03%). dH
(200 MHz; CDCl3) 3.84 (s, 3H, CH3), 4.67 (s, 2H, CH2), 7.29
(d, J = 8.4 Hz, 1H, H ar), 7.44–7.54 (m, 3H, H ar), 7.65–7.75
(m, 3H, H ar), 8.26 (dd, J = 2.2 Hz, J = 8.4 Hz, 1H, H ar). dC
(50 MHz; CDCl3) 32.0, 61.9, 120.6, 126.8, 127.0, 127.9, 129.4,
130.3, 134.5, 136.4, 141.3, 146.0, 146.2, 161.8.
White solid, mp 189 ◦C, (Found: C, 52.55; H, 3.86; N,
8.70. C14H12N2O3S2 requires C, 52.48; H, 3.78; N, 8.74%). dH
(200 MHz; CDCl3) 3.84 (s, 3H, CH3), 4.83 (s, 2H, CH2), 7.12–
7.16 (m, 1H, H ar), 7.43–7.55 (m, 2H, H ar), 7.66–7.76 (m, 3H,
H ar), 8.28 (d, J = 8.6 Hz, 1H, H ar). dC (50 MHz; CDCl3) 32.0,
63.0, 120.6, 127.0, 127.8, 128.0, 134.4, 135.4, 135.8, 138.4, 146.2,
146.3, 161.8.
206 | Green Chem., 2009, 11, 201–208
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3-Methyl-6-nitro-2-(phenylsulfonylmethyl)quinazolin-4(3H)-
3-Methyl-6-nitro-2-[(4-nitrophenylsulfonyl)methyl]
one 12a
quinazolin-4(3H)-one 12f
Yellow solid, mp 202 ◦C, (Found: C, 53.17; H, 3.71; N,
11.70. C16H13N3O5S requires C, 53.48; H, 3.65; N, 11.69%). dH
(200 MHz; CDCl3) 3.87 (s, 3H, CH3), 4.71 (s, 2H, CH2), 7.41 (d,
J = 8.9 Hz, 1H, H ar), 7.51–7.58 (m, 2H, H ar), 7.67–7.74 (m,
1H, H ar), 7.82–7.86 (m, 2H, H ar), 8.44 (dd, J = 2.1 Hz, J =
8.9 Hz, 1H, H ar), 9.10 (d, J = 2.1 Hz, 1H, H ar). dC (50 MHz;
CDCl3) 32.4, 62.2, 120.8, 123.7, 128.4, 128.7, 129.3, 134.6, 137.9,
146.1, 149.8, 150.1, 154.2, 160.8.
Yellow solid, mp 244 ◦C, (Found: C, 47.26; H, 2.91; N,
13.47. C16H12N4O7S requires C, 47.53; H, 2.99; N, 13.86%). dH
(200 MHz; DMSO-d6) 3.70 (s, 3H, CH3), 5.46 (s, 2H, CH2), 7.52
(d, J = 8.6 Hz, 1H, H ar), 8.22 (d, J = 8.9 Hz, 2H, H ar), 8.42
(d, J = 8.9 Hz, 2H, H ar), 8.47 (dd, J = 2.5 Hz, J = 8.6 Hz, 1H,
H ar), 8.77 (d, J = 2.5 Hz, 1H, H ar). dC (50 MHz; DMSO-d6)
32.3, 60.2, 120.7, 123.0, 124.7, 129.1, 129.3, 131.1, 144.5, 146.1,
150.3, 151.3, 151.5, 161.0.
2-[(4-methoxyphenylsulfonyl)methyl]-3-methyl-6-nitro
quinazolin-4(3H)-one 12g
3-Methyl-6-nitro-2-(tosylmethyl)quinazolin-4(3H)-one 12b
Yellow solid, mp 241 ◦C, (Found: C, 54.51; H, 4.07; N,
11.28. C17H15N3O5S requires C, 54.68; H, 4.05; N, 11.25%). dH
(200 MHz; DMSO-d6) 2.46 (s, 3H, CH3), 3.87 (s, 3H, CH3),
4.72 (s, 2H, CH2), 7.34 (d, J = 8.9 Hz, 2H, H ar), 7.53 (d, J =
9.3 Hz, 1H, H ar), 7.73 (d, J = 8.9 Hz, 2H, H ar), 8.48 (dd,
1H, J = 2.3 Hz, J = 9.3 Hz, 1H, H ar), 9.11 (d, J = 2.3 Hz,
1H, H ar). dC (50 MHz; DMSO-d6) 21.6, 32.3, 61.2, 120.5,
122.9, 128.9, 129.1, 130.1, 136.2, 145.5, 145.9, 150.5, 151.6,
161.0.
Yellow solid, mp 217 ◦C, (Found: C, 52.38; H, 3.94; N,
10.46 C17H15N3O6S requires C, 52.44; H, 3.88; N, 10.79%). dH
(200 MHz; DMSO-d6) 3.68 (s, 3H, CH3), 3.85 (s, 3H, CH3) 5.15
(s, 2H, CH2), 7.11 (d, J = 8.7 Hz, 2H, H ar), 7.58 (d, J = 8.9 Hz,
1H, H ar), 7.80 (d, J = 8.7 Hz, 2H, H ar), 8.51 (dd, J = 2.6 Hz,
J = 8.9 Hz, 1H, H ar), 8.79 (d, J = 2.6 Hz, 1H, H ar). dC
(50 MHz; DMSO-d6) 32.0, 56.0, 61.1, 114.5, 120.2, 122.7, 128.6,
128.8, 130.1, 131.0, 145.6, 150.2, 151.5, 160.7, 163.9.
3-Methyl-6-nitro-2-[(2-nitrophenylsulfonyl)methyl]
quinazolin-4(3H)-one 12h
2-[(4-Chlorophenylsulfonyl)methyl]-3-methyl-6-nitro
quinazolin-4(3H)-one 12c
Yellow solid, mp 232 ◦C, (Found: C, 47.79; H, 2.96; N,
13.46. C16H12N4O7S requires C, 47.53; H, 2.99; N, 13.86%). dH
(200 MHz; DMSO-d6) 3.72 (s, 3H, CH3), 5.50 (s, 2H, CH2), 7.47
(d, J = 9.2 Hz, 1H, H ar), 7.85–7.92 (m, 1H, H ar), 7.98–8.11
(m, 3H, H ar), 8.48 (dd, J = 2.6 Hz, J = 9.2 Hz, 1H, H ar),
8.80 (d, J = 2.6 Hz, 1H, H ar). dC (50 MHz; DMSO-d6) 32.1,
61.4, 120.4, 122.6, 125.1, 128.7, 130.7, 132.7, 133.1, 136.5, 145.7,
148.8, 150.1, 150.9, 155.0, 160.7.
◦
Yellow solid, mp 260 C, (Found: C, 48.49; H, 3.07; N, 10.52.
C16H12ClN3O5S requires C, 48.80; H, 3.07; N, 10.67%). dH
(200 MHz; DMSO-d6) 3.71 (s, 3H, CH3), 5.29 (s, 2H, CH2),
7.56 (d, J = 9.4 Hz, 1H, H ar), 7.70 (d, J = 8.3 Hz, 2H, H
ar), 7.93 (d, J = 8.3 Hz, 2H, H ar), 8.52 (dd, J = 2.8 Hz, J =
9.4 Hz, 1H, H ar), 8.80 (d, J = 2.8 Hz, 1H, H ar). dC (50 MHz;
DMSO-d6) 32.3, 60.7, 120.6, 122.7, 129.0, 129.7, 131.1, 137.8,
139.9, 146.0, 150.4, 151.6, 161.0.
General procedure for the synthesis of the
6-nitroquinazolin-4(3H)-one derivatives (15a–d)
2-[(4-Fluorophenylsulfonyl)methyl]-3-methyl-6-nitro
quinazolin-4(3H)-one 12d
The lithium salts were prepared as previously described.18
◦
Yellow solid, mp 234 C, (Found: C, 50.69; H, 3.26; N, 10.91.
Classical conditions. To a solution of lithium salt of ni-
tronate anion 13a (3 eq) in methanol (20 mL) was added
2-chloromethyl-3-methyl-6-nitroquinazolin-4(3H)-one 7 (0.2 g,
0.79 mmol). The reaction mixture was heated (oil bath), to
C16H12FN3O5S requires C, 50.93; H, 3.21; N, 11.14%). dH
(200 MHz; DMSO-d6) 3.69 (s, 3H, CH3), 5.24 (s, 2H, CH2),
7.42 (d, J = 9.1 Hz, 1H, H ar), 7.52 (d, J = 9.6 Hz, 2H, H ar),
7.95 (m, 2H, H ar), 8.49 (dd, J = 2.4 Hz, J = 9.1 Hz, 1H, H ar),
8.77 (d, J = 2.4 Hz, 1H, H ar). dC (50 MHz; DMSO-d6) 31.9,
60.5, 116.5, 120.2, 122.6, 128.7, 132.1, 134.9, 145.6, 150.1, 151.3,
160.7, 165.5.
◦
65 C, for 3 h. After evaporation of methanol, the residue was
dissolved in ethyl acetate and washed with water (3 ¥ 30 mL).
The organic layer was dried over magnesium sulfate and the
solvent was removed under vacuum. Then, the product 15a was
recrystallized from 2-propanol and dried in a vacuum drying
oven (dessicator cabinet).
2-[(4-Bromophenylsulfonyl)methyl]-3-methyl-6-nitro
quinazolin-4(3H)-one 12e
Microwave conditions. To a solution of lithium salt of
nitronate anion 13a–d (3 eq) in methanol (20 mL) was added
2-chloromethyl-3-methyl-6-nitroquinazolin-4(3H)-one 7 (0.2 g,
0.79 mmol). The reaction mixture was irradiated in a microwave
oven, at 65 ◦C, for 15 min. at a power of 500 W. After evaporation
of methanol, the residue was dissolved in ethyl acetate and
washed with water (3 ¥ 30 mL). The organic layer was dried over
magnesium sulfate and the solvent was removed under vacuum.
Then, the corresponding product 15a–d was recrystallized from
Yellow solid, mp 247 ◦C, (Found: C, 43.65; H, 2.69; N, 9.27.
C16H12BrN3O5S requires C, 43.85; H, 2.76; N, 9.59%). dH
(200 MHz; DMSO-d6) 3.71 (s, 3H, CH3), 5.28 (s, 2H, CH2),
7.57 (d, J = 9.1 Hz, 1H, H ar), 7.85 (m, 4H, H ar), 8.53
(dd, J = 3.0 Hz, J = 9.1 Hz, 1H, H ar), 8.80 (d, J =
3.0 Hz, 1H, H ar). dC (50 MHz; DMSO-d6) 32.3, 60.7, 120.6,
122.9, 129.0, 131.1, 132.7, 137.3, 139.9, 146.0, 150.4, 151.6,
161.0.
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1
2-propanol and dried in a vacuum drying oven (dessicator
cabinet).
for their cooperation, V. Remusat for the H and 13C NMR
spectra recording and are thankful to G. Lanzada for his
technical support.
3-Methyl-2-(2-methylprop-1-enyl)-6-nitroquinazolin-4(3H)-
one 15a
References
Yellow solid, mp 145 ◦C, (Found: C, 60.13; H, 5.01; N,
16.17. C13H13N3O3 requires C, 60.22; H, 5.05; N, 16.21%). dH
(200 MHz; CDCl3) 2.06 (s, 3H, CH3), 2.10 (s, 3H, CH3), 3.63 (s,
3H, CH3), 6.18 (s, 1H, CH), 7.76 (d, J = 8.8 Hz, 1H, H ar), 8.48
(dd, J = 2.8 Hz, J = 8.8 Hz, 1H, H ar), 9.13 (d, J = 2.8 Hz, 1H,
Har). dC (50 MHz; CDCl3) 20.7, 27.1, 31.7, 117.4, 120.1, 123.6,
128.1, 128.5, 145.4, 150.7, 151.3, 156.2, 161.4.
1 (a) P. T. Anastas, and J. C. Warner, Green Chemistry: Theory and
PracticeOxford University Press: New York, 1988; (b) A. S. Matlack,
Introduction to Green Chemistry, Marcel Dekker Inc.: New York,
2001; (c) M. Lancester, Green Chemistry: An Introductory Text, Royal
Society of Chemistry: Cambridge, 2002; (d) J. H. Clark, and D.
Macquarrie, Handbook of Green Chemistry & Technology, Blackwell
Publishers: Oxford, 2002.
2 (a) L. Bai, J. X. Wang and Y. Zhang, Green Chem., 2003, 5, 615; (b) V.
Pironti and S. Colonna, Green Chem., 2005, 7, 43; (c) M. Nu¨chter,
B. Ondruschka, W. Bonrath and A. Gum, Green Chem., 2004, 6,
128.
2-(Cyclopentylidenemethyl)-3-methyl-6-nitroquinazolin-4(3H)-
one 15b
3 (a) D. Dallinger and C. O. Kappe, Chem. Rev, 2007, 107, 2563;
(b) M. A. Herrero, J. M. Kremsner and C. O. Kappe, J. Org. Chem.,
2008, 73, 36.
Yellow solid, mp 175 ◦C, (Found: C, 62.98; H, 5.35; N,
14.68. C15H15N3O3 requires C, 63.15; H, 5.30; N, 14.73%). dH
(200 MHz; CDCl3) 1.80 (m, 4H, 2CH2), 2.63 (t, J = 7.4 Hz,
2H, CH2), 2.94 (t, J = 7.4 Hz, 2H, CH2), 3.66 (s, 3H, CH3),
6.40 (s, 1H, CH), 7.73 (d, J = 9.1 Hz, 1H, H ar), 8.46 (dd, J =
2.8 Hz, J = 9.1 Hz, 1H, H ar), 9.12 (d, J = 2.8 Hz, 1H, H ar).
dC (50 MHz; CDCl3) 25.5, 26.5, 31.1, 33.5, 36.9, 111.8, 119.7,
123.7, 128.0, 128.4, 145.0, 151.6, 156.0, 161.5, 167.3.
4 (a) C. S. Genther and C. C. Smith, J. Med. Chem., 1977, 20, 237;
(b) J. Guan, Q. Zhang, M. O’Neil, N. Obaldia III, A. Ager, L. Gerena
and A. J. Lin, Antimicrob. Agents Chemother., 1985, 27, 525; (c) M.
Guetschow, E. Tonew and S. Leistner, Pharmazie, 1995, 50, 672; (d) J.
Kunes, J. Bazant, M. Pour, K. Waisser, M. Slosarek and J. Janota, Il
Farmaco, 2000, 55, 725; (e) R. B. Lichtner, A. Menrad, A. Sommer,
U. Klar and M. R. Schneider, Cancer Res., 2001, 61, 5790; (f) A.
Dandia, R. Singh and P. Sarawgi, J. Fluor. Chem., 2005, 126, 307;
(g) A. Abdel-Maboud, J. Chem. Res., 2006, 7, 461; (h) H. Kikuchi,
K. Yamamoto, S. Horoiwa, S. Hirai, R. Kasahara, N. Hariguchi,
M. Matsumoto and Y. Oshima, J. Med. Chem., 2006, 49, 4698; (i) P.
Verhaeghe, N. Azas, M. Gasquet, S. Hutter, C. Ducros, M. Laget, S.
Rault, P. Rathelot and P. Vanelle, Bioorg. Med. Chem. Lett., 2008,
18, 396.
2-(Cyclohexylidenemethyl)-3-methyl-6-nitroquinazolin-4(3H)-
one 15c
Yellow solid, mp 154 ◦C, (Found: C, 63.92; H, 5.79; N,
14.03. C16H17N3O3 requires C, 64.20; H, 5.72; N, 14.04%). dH
(200 MHz; CDCl3) 1.67 (m, 6H, 3CH2), 2.39 (t, J = 6.3 Hz,
2H, CH2), 2.59 (t, J = 6.3 Hz, 2H, CH2), 3.64 (s, 3H, CH3),
6.10 (s, 1H, CH), 7.77 (d, J = 9.5 Hz, 1H, H ar), 8.48 (dd, J =
2.6 Hz, J = 9.5 Hz, 1H, H ar), 9.14 (d, J = 2.6 Hz, 1H, H ar).
dC (50 MHz; CDCl3) 26.1, 26.5, 31.1, 33.5, 36.9, 111.8, 119.7,
123.7, 128.0, 128.4, 145.0, 151.6, 156.0, 161.5, 167.3.
5 (a) F. Ciardiello and G. Tortora, Clin. Cancer Res., 2001, 7, 2958;
(b) T. Furuta, T. Sakai, T. Senga, T. Osawa, K. Kubo, T. Shimizu,
R. Suzuki, T. Yoshino, M. Endo and A. Miwa, J. Med. Chem., 2006,
49, 2186; (c) Y. Kitano, T. Suzuki, E. Kawahara and T. Yamazaki,
Bioorg. Med. Chem., 2007, 17, 5863; (d) A. Wissner, H. Fraser, C. L.
Ingalls, R. G. Dushin, M. B. Floyd, K. Cheung, T. Nittoli, M. R.
Ravi, X. Tan and F. Loganzo, Bioorg. Med. Chem., 2007, 15, 3635;
(e) Z. Rachid, F. Brahimi, Q. Qiu, C. Williams, J. M. Hartley, J. A.
Hartley and B. J. Jean-Claude, J. Med. Chem., 2007, 50, 2605.
6 A. Gellis, N. Boufatah and P. Vanelle, Green Chem., 2006, 8,
483.
7 S. J. von Niementowski, J. Prakt. Chem., 1895, 51, 564.
8 K. Gewald, H. Schafer, P. Bellmann and H. Muller, Chem. Ber., 1991,
124, 1237.
2-(Cyclododecylidenemethyl)-3-methyl-6-nitroquinazolin-4(3H)-
one 15d
9 V. Bavetsias, Synth. Commun., 1998, 28, 4547.
Yellow solid, mp 130 ◦C, (Found: C, 68.56; H, 7.76; N,
10.83. C22H29N3O3 requires C, 68.90; H, 7.62; N, 10.96%). dH
(200 MHz; CDCl3) 1.35 (m, 14H, 7CH2), 1.57 (m, 2H, CH2),
1.73 (m, 2H, CH2), 2.38 (t, J = 6.3 Hz, 2H, CH2), 2.56 (t, J =
6.3 Hz, 2H, CH2), 3.64 (s, 3H, CH3), 6.26 (s, 1H, CH), 7.75 (d,
J = 8.4 Hz, 1H, H ar), 8.49 (dd, J = 2.5 Hz, J = 8.4 Hz, 1H, H ar),
9.14 (d, J = 2.5 Hz, 1H, H ar). dC (50 MHz; CDCl3) 22.5, 23.2,
23.9, 24.1, 24.4, 24.5, 24.6, 24.7, 24.9, 29.9, 31.9, 33.2, 117.9,
120.2, 123.6, 128.1, 128.7, 145.3, 151.5, 156.5, 156.8, 161.5.
10 M. Rahimizadeh, Z. Tavallai and M. Bakavoli, Indian J. Chem. Sec
B, 2004, 43B, 679.
11 M. Chanon and M. L. Tobe, Angew. Chem. Int. Ed. Engl., 1982,
21, 1.
12 (a) L. Perreux and A. Loupy, Tetrahedron, 2001, 57, 9199; (b) A.
Loupy, C. R. Chim., 2004, 7, 103.
13 D. J. Connolly, J. Org. Chem., 2004, 69, 6572.
14 A. D. Roy, A. Subramanian and R. Roy, J. Org. Chem., 2006, 71,
382.
15 P. S. N. Reddy, T. Vasantha and C. Naga Raju, Indian J. Chem. Sec
B, 1999, 38B, 40.
16 K. Gewald, H. Schaefer, P. Bellmann and H. Mueller, Chem. Ber.,
1991, 124, 1237.
17 L. K. Liu, Y. Chi and K.-Y. Jen, J. Org. Chem., 1980, 45, 406.
18 (a) S. Djekou, A. Gellis, J. Maldonado, M. P. Crozet and P. Vanelle,
Heterocycles, 2001, 55, 535; (b) Y. Njoya, N. Boufatah, A. Gellis, P.
Rathelot, M. P. Crozet and P. Vanelle, Heterocycles, 2002, 57, 1423.
Acknowledgements
This work was supported by the CNRS and the University of
Aix-Marseille II. The authors thank T. Terme and P. Verhaeghe
208 | Green Chem., 2009, 11, 201–208
This journal is
The Royal Society of Chemistry 2009
©