Access to original vinylic chlorides in the quinazoline series via a monoelectronic transfer reaction approach

Article abstract of DOI:10.3390/molecules15042719

A series of new quinazoline derivatives bearing a vinylic chloride group on the 2-position was prepared by using a consecutive SRN1 / ERC1 radical strategy. Copyright

Full text of DOI:10.3390/molecules15042719

Molecules 2010, 15, 2719-2729; doi:10.3390/molecules15042719
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Access to Original Vinylic Chlorides in the Quinazoline Series
via a Monoelectronic Transfer Reaction Approach
Martine Maillard-Boyer, Caroline Castera-Ducros, Pierre Verhaeghe, France Sifredi,
Pascal Rathelot 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: martine.maillard@univmed.fr (M.M.); caroline.ducros@univmed.fr
(C.C.); pierre.verhaeghe@univmed.fr (P.V.); france.sifredi@univmed.fr (F.S.);
pascal.rathelot@univmed.fr (P.R.)
* Author to whom correspondence should be addressed; E-mail: patrice.vanelle@univmed.fr;
Tel.: +33 491 835 528, Fax: +33 491 794 677.
Received: 26 January 2010; in revised form: 21 February 2010 / Accepted: 12 April 2010 /
Published: 13 April 2010
Abstract: A series of new quinazoline derivatives bearing a vinylic chloride group on the
2-position was prepared by using a consecutive SRN1 / ERC1 radical strategy.
Keywords: SRN1; ERC1; quinazoline ring; vinylic chlorides
1. Introduction
The quinazoline ring is of major pharmaceutical interest, considering both that it is the molecular
scaffold of several drug-compounds (Erlotinib, Lapatinib, Prazozin, Alfuzosin…) and, that 4-anilino-
substituted-quinazolines are key structures for the development of new selective anticancer
chemotherapies, as kinase inhibitors. Focusing on the synthesis of new 2,4-bisubstituted-quinazolines,
with a scope of studying their biological properties, our research team also discovered that some
4-anilinoquinazolines have original in vitro antiplasmodial properties [1–2]. Quite recently, we
prepared some 4-anilinoquinazolines, substituted at position 6 with a nitro group and at position 2 with
a vinylic group, one of them exerting in vitro antiplasmodial properties [3]. To explore more precisely
the relations between chemical structure and biological activity, we studied the possibility of
synthesizing new 4-aminated-quinazoline derivatives presenting a vinylic chloride substituent at

Molecules 2010, 15
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position 2. In order to access to such vinylic chloride group, different strategies were developed
among which the one presented by Ryabukhin et al. [4] and the use of trichloromethylated
heterocycles, as substrates for the radical SRN1+ERC1 reaction with nitroalkanes, successful approach
in isoquinoline, imidazole and quinoline series [5–7]. We describe herein, the use of the consecutive
SRN1+ERC1 reaction from 2-trichloromethylquinazoline substrates and nitroalkanes, for the preparation
of these original vinylic chloride derivatives in a rapid and convenient way.
2. Results and Discussion
Since 2009, it is known that 2-chloromethyl-6-nitroquinazoline derivatives can react with
nitroalkanes through a SRN1 mechanism [8]. However, the SRN1 reaction involving a radical anion
intermediate which is generally stabilized with the presence of a nitro group properly located on the
heterocycle, it was not obvious that an aminated quinazoline substrate would react, because of the
electrodonating effect of this group.
First, the key-precursor 1 was prepared from commercial 2-methylquinazolin-4(3H)-one via a
microwave-assisted chlorination procedure using phosphorus pentachloride in phosphorus
oxychloride [9]. Then, after proceeding to a solvent free SNAr reaction with n-propyl- and n-
butylamines, the corresponding intermediates 2 and 3 were nitrated in classical conditions to afford 4
and 5 in good yields (Scheme 1).
Scheme 1. Two step preparation of the radical reaction substrates 4 and 5.
R1
N
R1
N
Cl
N
HN
HN
N
R1NH2 (3 equiv.)
HNO3/H2SO4
RT
O2N
N
Solvent free
RT
CCl3
N
CCl3
CCl3
1 equiv.
2 : R1 = C3H7 95%
3 : R1 = C4H9 73%
4 : R1 = C3H7 85%
5 : R1 = C4H9 75%
1
Then, compound 4, which is prepared in higher global yield, was chosen as a substrate for studying
the SRN1+ERC1 reaction with 2-nitropropane. The first reaction assay, at room temperature (RT)
under N2 atmosphere and light irradiation, enabled us to isolate both vinylic chloride 6 and the dimer
of 2-nitropropane 7 (Scheme 2).
Scheme 2. General presentation of the SRN1+ERC1 reaction of substrate 4 with 2-nitropropane.
CH3
CH3
HN
HN
N
H3C
CH3
NO2
CH3
N2, hν, RT
NO2
CH3
O2N
O2N
H3C
O2N
+
+
M
N
N
CH3
CH3
Solvent
N
CCl3
CH3
Cl
7
6
4

Molecules 2010, 15
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In order to optimize the reaction, several experimental conditions were studied, especially the ones
described by Kornblum et al. [10] (lithium salt of 2-nitropropane in DMSO or DMF) and Norris et al. [11]
(phase transfer conditions using TBAOH and 2-nitropropane). The results showed that the phase
transfer conditions of Norris gave the best reaction yield. The amount of 2-nitropropane required was
also studied, indicating that the reaction yield is globally optimal (82%) when using 5 equiv. (Table 1,
entries 1–6). Reaction progress was monitored by TLC, and appeared to be complete after 4 hours.
The formation of dimer 7 clearly suggested a consecutive SRN1+ERC1 reaction mechanism. To
validate this hypothesis, we studied the influence of several radical reaction inhibitors (Table 1 entries
7–10). The results showed that the reaction obeys to a radical pathway, in particular when comparing
run 3 with runs 8 or 9. The synthesis of vinylic chloride 6 in low yield, when using 1 equiv. of
p-dinitrobenzene (assay 10), may be due to the insufficient difference in reduction potential between
p-dinitrobenzene and substrate 4, partially permitting the monoelectronic reduction of this last by the
2-nitropropane anion, followed by the formation of product 6, through complete SRN1+ERC1
reaction sequence.
Table 1. Reactivity of substrate 4 with 2-nitropropane.
2-Nitropropane
Run*
M+
Solvent
Inhibitor
Yield of 6 (%)
(equiv.)
1
2
NBu4
NBu4
NBu4
NBu4
Li
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
DMF
2
4
5
6
5
5
5
5
5
5
-
60
75
82
83
53
70
25
0
-
3
-
4
-
5
-
6
Li
DMSO
-
7
Li
DMSO
CuCl2 (1 equiv.)
TEMPO (1 equiv.)
O2 bubbling
p-dinitrobenzene
8
NBu4
NBu4
NBu4
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
9
0
10
35
*Reaction conditions: N2 atmosphere, 60W white light irradiation, RT. Reactions were monitored
by TLC.
From the optimal reaction conditions previously presented, we then extended the reaction to other
nitroalkanes, in order to prepare several vinylic chlorides in quinazoline series (Scheme 3). So the
same radical reaction was conducted with two other secondary nitroalkanes (nitrocycloalkanes) and
three primary nitroalkanes. In the reactions using secondary nitroalkanes, the corresponding vinylic
chlorides were obtained in identical yields (60–82%) as with nitroalkane dimers, whereas in the
reactions involving primary nitroalkanes, only the corresponding vinylic chlorides were obtained, in
significantly lower yields (50–56%), as presented in Table 2. Concerning the vinylic chlorides
prepared from primary nitroalkanes, the analysis of 2D Noesy NMR spectra revealed a Z configuration
for the vinylic double bond.
Such results appeared identical to the ones obtained with the SRN1+ERC1 reaction operated in 2-
trichloromethylquinoline series [7], but demonstrate that this reaction can be compatible with the
presence of an electrodonating group on the heterocyclic scaffold.

Molecules 2010, 15
Scheme 3. Optimal reaction conditions for the synthesis of vinylic chloride derivatives from 4.
2722
CH3
CH3
HN
N
HN
N
R2
R3
TBAOH 40% (5 equiv.)
O2N
O2N
H
NO2
N
+
N
R2
CH2Cl2
N2, hν, RT, 4 h
CCl3
R3
1 equiv.
5 equiv.
Cl
50-82%
4
Table 2. Series of vinylic chloride derivatives prepared from 4, using optimal reaction conditions.
Nitroalkane
Vinylic chloride
Dimer
Yield of vinylic chloride (%)
CH3
NO
2 CH3
CH3
NO2
CH3
HN
H3C
O2N
H
NO2
CH3
N
CH3
CH3
82
H3C
7
N
Cl
6
CH3
O2N
HN
O2N
O2N
O2N
NO2
NO2
60
66
N
NO2
N
9
Cl
8
CH3
O2N
HN
NO2
N
N
11
Cl
10
CH3
HN
NO2
Not isolated
Not isolated
Not isolated
56
50
52
N
H
H3C
N
CH3
Cl
12
CH3
HN
NO2
O2N
N
H
H3C
CH3
N
Cl
13
CH3
HN
NO2
O2N
N
H
H3C
N
CH3
Cl
14

Molecules 2010, 15
2723
To enlarge the reaction spectrum, we involved two other aminated substrates in the same reaction
with 2-nitropropane, using the previously optimal reaction conditions. Substrate 5, containing an other
primary amine substituent, was prepared in parallel with 4 and afforded vinylic chloride 15 in 57 %
yield (Scheme 4).
Scheme 4. Extension of the reaction with substrate 5.
HN
N
CH3
+
HN
N
CH3
CH3
CH3
CH3
NO2
CH3
TBAOH 40% (5 equiv.)
O2N
O2N
H
N
N
CH2Cl2
CCl3
N2, hν, RT
1 equiv.
5 equiv.
Cl
15 57%
5
Aiming at preparing a vinylic chloride product bearing an anilino substituent at position 4 of
quinazoline, we had to prepare an appropriate substrate candidate for the SRN1+ERC1 reaction. Thus,
since the nitration reaction could not be done after the introduction of the aniline onto the quinazoline
ring, the synthetic strategy from 2-methylquinazolin-4(3H)-one was modified, starting by a nitration
step, under classical conditions. After successive chlorination and solvent free SNAr reactions, 18 was
obtained (Scheme 5).
Scheme 5. Three step preparation of substrate 18.
CF3
O
N
O
Cl
N
HN
N
CF3
HNO3
O2N
PCl5 O2N
POCl3
O2N
3 equiv.
NH2
NH
CH3
NH
CH3
N
N
H2SO4
N
CCl3
CCl3
80%
17 70%
16
18 74%
So we applied the optimal reaction conditions defined previously to the reaction of 18 with
2-nitropropane and obtained the expected vinylic chloride 19 in 45% yield (Scheme 6).
Scheme 6. SRN1+ERC1 reaction of 18 with 2-nitropropane.
HN
N
CF3
+
HN
N
CF3
CH3
CH3
CH3
NO2
O2N
O2N
TBAOH 40% (5 equiv.)
N
N
CH2Cl2
N2, hν, RT, 4 h
CH3
CCl3
1 equiv.
5 equiv.
Cl
18
19 45%

Molecules 2010, 15
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When 2-methylquinazolin-4(3H)-one is first chlorinated and then nitrated, compound 20 is formed
in 72% global yield (Scheme 7).
Scheme 7. Two step preparation of substrate 20.
O
N
Cl
O
N
O2N
HNO3
PCl5 / POCl3
MW, 15 min
NH
CH3
N
NH
CCl3
H2SO4
N
CCl3
1 75%
20 96%
Finally, because of its trichloromethyl group, we thought that such nitrated lactam ring 20 could be
an interesting substrate for the SRN1+ERC1 reaction. Unfortunately, its low solubility in
dichloromethane did not allow the use of the optimal phase transfer reaction conditions that we
already presented. So we reacted 20 with the lithium salt of 2-nitropropane in DMSO (Kornblum
conditions [10]) during 2 hours and formed the vinylic chloride product 21 in 67 % yield, in addition
to the dimer of 2-nitropropane 7, in similar yield (Scheme 8).
Scheme 8. SRN1+ERC1 reaction of 20 with the lithium salt of 2-nitropropane.
O
O
H3C
CH3
NO2
DMSO
NO2
CH3
O2N
O2N
+
H3C
+
Li
NH
CCl3
NH CH3
CH3
N2, hν, RT, 2h
CH3
O2N
N
N
CH3
5 equiv.
1 equiv.
Cl
21 67%
7
20
3. Experimental
3.1. General
1
Melting points were determined with a B-540 Büchi melting point apparatus. 200 MHz H-NMR
and 50 MHz 13C-NMR spectra were recorded on a Brüker ARX 200 spectrometer in CDCl3 or DMSO-
d6 at the Faculté de Pharmacie de Marseille. 1H- and 13C-NMR chemical shifts (δ) are reported in ppm
with respect to CDCl3 7.26 ppm (1H), 77.2 ppm (13C) or DMSO-d6 2.50 ppm (1H), 39.5 (13C). 2D
NOESY NMR spectra and elemental analyses were carried out at the Spectropole, Faculté des
Sciences et Techniques de Saint-Jérôme. Silica gel 60 (Merck, particular size 0.063–0.200 mm,
70–230 mesh ASTM) was used for column chromatography. TLC was performed on 5 cm × 10 cm
aluminium plates coated with silica gel 60F-254 (Merck) in appropriate solvent. The following
substrates or subproducts were prepared and described previously: 4-chloro-2-trichloromethyl-
quinazoline (1) [9,12], N-butyl-2-trichloromethylquinazolin-4-amine (3) [13], 2,3-dimethyl-2,3-
dinitrobutane (7) [14], 1-nitro-1-(1-nitrocyclopentyl)cyclopentane (9) [15], 1-nitro-1-(1-nitrocyclo-

Molecules 2010, 15
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hexyl)cyclohexane (11) [16], 2-methyl-6-nitroquinazolin-4(3H)one (16) [17], 4-chloro-6-nitro-2-
trichloromethylquinazoline (17) [18], and 6-nitro-2-trichloromethylquinazolin-4(3H)-one (20) [18].
3.2. Preparation of N-propyl-2-trichloromethylquinazolin-4-amine (2)
Three equiv. of propylamine were added onto 1 equiv. of 4-chloro-2-trichloromethylquinazoline
(1). The solvent-free reaction mixture was stirred at 30 °C for 1 min. The mixture was poured into a
solution of NaOH (5%) and extracted with dichloromethane. The organic layer was washed with water
three times, dried over anhydrous Na2SO4, concentrated in vacuo and recrystalized from cyclohexane
1
to afford 2 in 95% yield.Beige solid; yield 95%, mp 136 °C. H-NMR (CDCl3) δ 1.03 (3H, t,
J = 7.3 Hz), 1.69–1.87 (2H, m), 3.66–3.76 (2H, m), 6.06 (1H, br s), 7.49–7.57 (1H, m), 7.73–7.81 (2H,
m), 7.97 (1H, d, J = 8.3 Hz). 13C-NMR (50 MHz; CDCl3) δ 11.6 (CH3), 22.5 (CH2), 43.4 (CH2), 98.4
(C), 113.8 (C), 121.2 (CH), 127.4 (CH), 129.0 (CH), 133.2 (CH), 149.1 (C), 160.7 (C), 161.5 (C).
Anal. calcd for C12H12Cl3N3: C, 47.32; H, 3.97; N, 13.80. Found: C, 47.90; H, 4.24; N, 13.85.
3.3. General Procedure for the Preparation of Compounds 4 and 5
To concentrated sulfuric acid (25 mL), 1 equiv. of N-alkyl-2-trichloromethylquinazolin-4-amine (2)
or 3 was added at 0 °C. Then, 5 equiv. of concentrated nitric acid were added slowly. The reaction
mixture was stirred for 5 h at rt. The reaction mixture was then slowly poured into a water-ice mixture
and alkalinized with sodium carbonate, making the desired products precipitate. The suspension was
filtered and the precipitate was dried under reduced pressure. After purification by chromatography on
a silica gel column, eluting with dichloromethane, products 4 or 5 were recrystallized from ethyl
acetate and obtained, respectively, in 85 and 75% yields.
1
6-Nitro-N-propyl-2-trichloromethylquinazolin-4-amine (4): Yellow solid; yield 85%, mp 151 °C. H-
NMR (CDCl3) δ 1.07 (3H, t, J = 7.3 Hz), 1.76-1.94 (2H, m), 3.74–3.84 (2H, m), 6.58 (1H, br s), 8.07 (1H,
d, J = 9.1 Hz), 8.54 (1H, dd, J = 9.1 Hz and J = 2.4 Hz), 8.83 (1H, d, J = 2.4 Hz). 13C-NMR (CDCl3) δ
11.7 (CH3), 22,5 (CH2), 44.2 (CH2), 97.3 (C), 113.1 (C), 118.5 (CH), 127,2 (CH), 130.8 (CH), 145.7
(C), 152.7 (C), 161.6 (C), 164.4 (C). Anal. Calcd for C12H11Cl3N4O2: C, 41.23; H, 3.17; N, 16.03.
Found: C, 41.74; H, 3.05; N, 16.45.
1
N-Butyl-6-nitro-2-trichloromethylquinazolin-4-amine (5): Yellow solid; yield 75%, mp 168 °C. H-
NMR (CDCl3) δ 1.01 (3H, t, J = 7.3 Hz), 1.40–1.59 (2H, m), 1.75–1.87 (2H, m), 3.82 (2H, q, J = 12.7
Hz), 6.75 (1H, br s), 8.07 (1H, d, J = 9.2 Hz), 8.55 (1H, dd, J = 9.2 and 2.3 Hz), 8.83 (1H, d, J = 2.3
Hz). 13C-NMR (CDCl3) δ 13.8 (CH3), 20.1 (CH2), 31.1 (CH2), 41.9 (CH2), 97.3 (C), 112.9 (C), 118.0
(CH), 126.9 (CH), 131.1 (CH), 145.5 (C), 153.0 (C), 161.3 (C), 164.5 (C). Anal. Calcd for
C13H13Cl3N4O2: C, 42.94; H, 3.60; N, 15.41. Found: C, 43.01; H, 3.63; N, 15.25.
3.4. General Procedure for the Synthesis of Vinylic Chlorides 6, 8, 10, 12, 13, 14, 15 and 19
Five equiv. each of both nitroalkane and 40% TBAOH were stirred at room temperature for 30 min
under nitrogen atmosphere. Then, 1 equiv. of 4-substituted-6-nitro-2-trichloromethylquinazoline
substrate 4, 5 or 18, solubilized in dichloromethane, was added. The mixture was rapidly stirred at rt

Molecules 2010, 15
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under nitrogen atmosphere with white light irradiation (60 W) for 4 h. After disappearance of substrate
(monitored by TLC), the reaction was stopped with addition of water and the product was extracted
with dichloromethane. The organic layer, washed with water several times, was finally dried over
anhydrous sodium sulphate and evaporated. The product was purified by chromatography on a silica
gel, eluting with appropriate solvent, to give the corresponding vinylic chloride products.
2-(1-Chloro-2-methylprop-1-enyl)-6-nitro-N-propylquinazolin-4-amine (6): The eluent was petroleum
1
ether-ethyl acetate 50:50. Yellow solid; yield 82%, mp 145 °C. H-NMR (CDCl3) δ 1.06 (3H, t,
J = 7.3 Hz), 1.73–1.86 (2H, m), 2.05 (3H, s), 2.09 (3H, s), 3.66–3.76 (2H, m), 6.29 (1H, br s), 7.94
(1H, d, J = 9.2 Hz), 8.48 (1H, dd, J = 9.2 Hz and 2.4 Hz), 8.76 (1H, d, J = 2.4 Hz). 13C-NMR (CDCl3)
δ 11.7 (CH3), 22.4 (CH3), 22.7 (CH2), 23.3 (CH3), 43.7 (CH2), 112.5 (C), 118.4 (CH), 124.5 (C), 126.6
(CH), 130.1 (CH), 137.7 (C), 144.7 (C), 153.4 (C), 160.7 (C), 164.2 (C). Anal. Calcd for
C15H17ClN4O2: C, 56.16; H, 5.34; N, 17.47. Found: C, 56.75; H, 5.69; N, 17.05.
2-[Chloro(cyclopentylidene)methyl]-6-nitro-N-propylquinazolin-4-amine (8): The eluent was
dichloromethane-ethyl acetate 98:2. Orange solid; yield 60%, mp 160 °C. 1H-NMR (DMSO-d6) δ 0.95
(3H, t, J = 7.3 Hz), 1.59–1.80 (6H, m), 2.59–2.65 (2H, m), 2.92–2.98 (2H, m), 3.49–3.51 (2H, m), 7.76
(1H, d, J = 9.2 Hz), 8.42 (1H, dd, J = 9.2 Hz and 2.3 Hz), 8.98–9.00 (1H, m), 9.31 (1H, d, J = 2.3 Hz).
13C-NMR (DMSO-d6) δ 11.7 (CH3), 21.8 (CH2), 25.1 (CH2), 27.8 (CH2), 35.2 (CH2), 36.6 (CH2), 43.0
(CH2), 112.3 (C), 120.6 (CH), 122.4 (C), 126.5 (CH), 129.2 (CH), 144.0 (C), 153.4 (C), 154.2 (C),
160.2 (C), 161.9 (C). HR MS (+ESI): m/z 347.1269 (M+H+). Calcd for C17H19ClN4O2: 346.1197.
2-[Chloro(cyclohexylidene)methyl]-6-nitro-N-propylquinazolin-4-amine (10): The eluent was
1
petroleum ether-ethyl acetate 50:50. Yellow solid; yield 66%, mp 170 °C. H-NMR (CDCl3) δ 1.05
(3H, t, J = 7.3 Hz), 1.61–1.85 (10H, m), 2.57–2.62 (2H, m), 3.66–3.76 (2H, m), 6.37 (1H, br s), 7.93
(1H, d, J = 9.2 Hz), 8.46 (1H, dd, J = 9.2 Hz and 2.4 Hz), 8.77 (1H, d, J = 2.4 Hz). 13C-NMR
(CDCl3) δ 11.7 (CH3), 22.7 (CH2), 26.4 (CH2), 27.3 (CH2), 27.9 (CH2), 30.0 (CH2), 32.4 (CH2), 43.7
(CH2), 112.4 (C), 118.4 (CH), 121.5 (C), 126.6 (CH), 130.2 (CH), 143.8 (C), 144.7 (C), 153.6 (C),
160.8 (C), 164.3 (C). HR MS (+ESI): m/z 361.1426 (M+H+). Calcd for C18H21ClN4O2: 360.1353.
(Z)-2-(1-Chloroprop-1-enyl)-6-nitro-N-propylquinazolin-4-amine (12): The eluent was dichloro-
1
methane. Green solid; yield 56%, mp 176 °C. H-NMR (CDCl3) δ 1.03–1.10 (3H, m), 1.72–1.90 (2H,
m), 2.08 (3H, d, J = 7.0 Hz ), 3.67–3.77 (2H, m), 6.43 (1H, br s), 7.63 (1H, q,
J = 7.0 Hz), 7.92–7.98 (1H, m), 8.44 (1H, dd, J = 9.2 Hz and 2.4 Hz)), 8.78 (1H, d, J = 2.4 Hz). 13C-
NMR (CDCl3) δ 11.8 (CH3), 15.8 (CH3), 22.5 (CH2), 43.9 (CH2), 112.9 (C), 118.9 (CH), 126.9 (CH),
129.4 (CH), 132.4 (C), 134.5 (CH), 144.6 (C), 152.5 (C), 160.0 (C), 160.5 (C). HR MS (+ESI): m/z
307.0956 (M+H+). Calcd for C14H15ClN4O2: 306.0884.
(Z)-2-(1-Chlorobut-1-enyl)-6-nitro-N-propylquinazolin-4-amine (13): The eluent was dichloro-
methane. Yellow solid; yield 50%, mp 163 °C. 1H-NMR (CDCl3) δ 0.98–1.23 (6H, m), 1.77–1.88 (2H,
m), 2.46–2.61 (2H, m), 3.68–3.78 (2H, m), 6.40 (1H, br s), 7.55 (1H, t, J = 9.3 Hz), 7.97 (1H, d,
J = 9.2 Hz), 8.45 (1H, dd, J = 9.2 Hz and 2.4 Hz), 8.78 (1H, d, J = 2.4 Hz). 13C-NMR
(CDCl3) δ 11.2 (CH3), 12.2 (CH3), 22.0 (CH2), 22.9 (CH2), 43.1 (CH2), 112.3 (C), 118.0 (CH), 126.1

Molecules 2010, 15
2727
(CH), 129.3 (CH), 130.8 (C), 139.8 (CH), 143.8 (C), 152.6 (C), 159.4 (C), 160.3 (C). Anal. Calcd for
C15H17ClN4O2: C, 56.16; H, 5.34; N, 17.47. Found: C, 55.82; H, 5.75; N, 17.01.
(Z)-2-(1-Chloropent-1-enyl)-6-nitro-N-propylquinazolin-4-amine
(14):
The
eluent
was
1
dichloromethane-ethyl acetate 99:1. Yellow solid; yield 52%, mp 156 °C. H-NMR (DMSO-d6) δ
0.92–0.99 (6H, m), 1.49–1.76 (4H, m), 2.36–2.44 (2H, m), 3.50–3.60 (2H, m), 7.46–7.53 (1H, m),
7.81 (1H, d, J = 9.1 Hz), 8.43 (1H, dd, J = 9.1 Hz and 2.0 Hz), 9.01 (1H, br s), 9.33 (1H, d,
J = 2.0 Hz). 13C-NMR (DMSO-d6) δ 12.1 (CH3), 14.2 (CH3), 21.6 (CH2), 21.9 (CH2), 31.7 (CH2), 43.2
(CH2), 113.5 (C), 120.9 (CH), 126.9 (CH), 129.7 (CH), 132.6 (C), 137.1 (CH), 144.3 (C), 153.8 (C),
160.2 (C), 160.4 (C). HR MS (+ESI): m/z 335.1269 (M+H+). Calcd for C16H19ClN4O2: 334.1197.
N-Butyl-2-(1-chloro-2-methylprop-1-enyl)-6-nitroquinazolin-4-amine (15): The eluent was petroleum
1
ether-ethyl acetate 50:50. Beige solid; yield 57%, mp 135 °C. H-NMR (CDCl3) δ 1.00 (3H, t,
J = 7.2 Hz), 1.40–1.58 (2H, m), 1.72–1.84 (2H, m), 2.05 (3H, s), 2.09 (3H, s), 3.75 (2H, m), 6.42 (1H,
br s), 7.96 (1H, d, J = 9.2 Hz), 8.49 (1H, dd, J = 9.2 and 2.3 Hz), 8.73 (1H, d, J = 2.3 Hz). 13C-NMR
(CDCl3) δ 13.8 (CH3), 20.2 (CH2), 22.2 (CH3), 23.1 (CH3), 31.3 (CH2), 41.6 (CH2), 112.3 (C), 118.2
(CH), 124.4 (C), 126.4 (CH), 130.0 (CH), 137.4 (C), 144.5 (C), 153.3 (C), 160.5 (C), 164.0 (C). Anal.
Calcd for C16H19ClN4O2: C, 57.40; H, 5.72; N, 16.73. Found: C, 57.02; H, 5.94; N, 16.43.
2-(1-Chloro-2-methylprop-1-enyl)-6-nitro-N-[3-(trifluoromethyl)]-phenylquinazolin-4-amine
(19):
The eluent was dichloromethane. Yellow solid, yield 45%, mp 201 °C. 1H-NMR (CDCl3) δ 2.13 (6H, s),
7.45-7.60 (2H, m), 7.98–8.11 (3H, m), 8.40 (1H, br s), 8.58 (1H, dd, J = 9.1 Hz and 2.2 Hz), 9.07 (1H,
13
d, J = 1.7 Hz). C-NMR (CDCl3) δ 22.5 (CH3), 23.7 (CH3), 112.3 (C), 118.0 (CH), 118.8 (CH, q,
J = 4.0 Hz), 121.6 (CH, q, J = 4.0 Hz), 123.8 (C, q, J = 272.6 Hz), 124.1 (C), 124.7 (CH), 127.0 (CH),
129.7 (CH), 130.6 (CH), 131.6 (C, q, J = 32.6 Hz), 138.0 (C), 140.1 (C), 145.2 (C), 153.3 (C), 158.2
(C), 163.1 (C). Anal. calcd for C19H14ClF3N4O2: C, 53.98; H, 3.34; N, 13.25. Found: C, 54.4; H, 3.52;
N, 12.95.
3.5. Preparation of 6-nitro-2-trichloromethyl-N-[(3-trifluoromethyl)]phenylquinazolin-4-amine (18)
Three equiv. of 3-trifluoromethylaniline were added onto 1 equiv. (500 mg) of 4-chloro-6-nitro-2-
trichloromethylquinazoline (17). The solvent-free reaction mixture was stirred at 120 °C for 15 min.
The mixture was poured into a saturated solution of sodium carbonate and extracted with
dichloromethane. The organic layer was washed with water three times, dried over anhydrous Na2SO4
and concentrated in vacuo. After purification by chromatography (silica gel, eluent: dichloromethane)
1
the product was obtained in 74% yield. Yellow solid; yield 74%, mp 234 °C. H-NMR (DMSO-d6) δ
7.56 (1H, d, J = 7.7 Hz), 7.67–7.75 (1H, m), 8.14 (1H, d, J = 9.2 Hz), 8.22 (1H, d, J = 8.3 Hz),
8.65–8.71 (2H, m), 9.80 (1H, d, J = 2.4 Hz), 11.05 (1H, br s). 13C-NMR (DMSO-d6) δ 97.2 (C), 113.7
(C), 118.7 (CH, q, J = 4.0 Hz), 120.8 (CH), 120.9 (CH), 124.1 (CF3, q, J = 272.7 Hz), 125.5 (CH),
127.8 (CH), 129.3 (C, q, J = 31.9 Hz), 129.8 (CH), 130.4 (CH), 138.9 (C), 146.0 (C), 152.5 (C), 159.5
(C), 162.7 (C). Anal. calcd for C16H8Cl3F3N4O2: C, 42.55; H, 1.79; N, 12.41. Found: C, 42.50; H,
1.91; N, 11.97.

Molecules 2010, 15
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3.6. Preparation of 2-(1-chloro-2-methylprop-1-enyl)-6-nitroquinazolin-4(3H)-one (21)
To a DMSO solution (15 mL) of the lithium salt of 2-nitropropane (0.76 g, 8.1 mmol, 5 equiv.), a
DMSO solution (15 mL) containing 0.5 g (1.6 mmol, 1 equiv.) of 20 was added rapidly. The mixture
was stirred at rt for 2 h under N2 atmosphere and light irradiation (60W). After the disappearance of 20
(monitored by TLC), the mixture was poured into cold water, filtered, and extracted with
dichloromethane. The combined organic layer were dried over anhydrous Na2SO4 and evaporated. The
solid product was washed with petroleum ether and dried under reduced pressure to give 21 in 67%
yield. Yellow solid; yield 67%, mp 248 °C. 1H-NMR (CDCl3) δ 2.17 (3H, s), 2.30 (3H, s), 7.84 (1H, d,
J = 9.0 Hz), 8.56 (1H, dd, J = 9.0 Hz and 2.4 Hz), 8.76 (1H, d, J = 2.4 Hz), 9.74 (1H, br s). 13C-NMR
(CDCl3) δ 23.2 (CH3), 24.3 (CH3), 117.0 (C), 121.3 (C), 123.1 (CH), 128.9 (CH), 129.4 (CH), 146.2
(C), 151.7 (C), 152.3 (C), 160.4 (C), (C-NO2) was not observed in these experimental conditions.
Anal. Calcd for C12H10ClN3O3: C, 51.53; H, 3.60; N, 15.02. Found: C, 50.99; H, 3.53; N, 14.94.
4. Conclusions
Quinazoline derivatives are molecules with a high pharmaceutical potential, particularly when
targeting kinases. Using the consecutive SRN1+ERC1 radical reaction strategy, a series of original
4-propylaminoquinazolines, bearing a vinylic chloride group at position 2, was prepared in a simple
and convenient way from corresponding trichloromethylated substrates. The reaction parameters were
studied and optimized by using a phase-transfer procedure involving 5 equiv. of both TBAOH and
2-nitropropane, and the radical mechanism was investigated by employing radical reaction inhibitors
such as TEMPO. Finally, the reaction was extended in 4-butylaminoquinazoline, 4-anilinoquinazoline
and quinazoline-4(3H)-one series, demonstrating that the SRN1+ERC1 reaction operated onto nitrated
quinazolines is compatible with the presence of an alkylamino electrodonating group, so as with a
lactam function.
Acknowledgements
This work was supported by the CNRS and the Université de la Méditerranée. The authors thank V.
Remusat for recording NMR spectra.
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Sample Availability: Samples of the compounds are available from the authors.
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