First SNAr reaction using TDAE-initiated carbanions in quinazoline series

Article abstract of DOI:10.1016/j.tetlet.2011.05.060

We report herein the first example of a S_NAr reaction using TDAE-initiated carbanions in quinazoline series. The o-nitrobenzyl carbanion, formed by the action of TDAE on o-nitrobenzyl chloride, reacts with 4-chloro-2-trihalomethylquinazolines 4

Full text of DOI:10.1016/j.tetlet.2011.05.060

Tetrahedron Letters 52 (2011) 3810–3813
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Tetrahedron Letters
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First SNAr reaction using TDAE-initiated carbanions in quinazoline series
⇑
Marc Since, Omar Khoumeri, Pierre Verhaeghe, Martine Maillard-Boyer, Thierry Terme, Patrice Vanelle
Laboratoire Chimie Provence LCP, UMR CNRS 6264, Universités d’Aix-Marseille I, II et III, Équipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean
Moulin, 13385 Marseille Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein the first example of a SNAr reaction using TDAE-initiated carbanions in quinazoline
series. The o-nitrobenzyl carbanion, formed by the action of TDAE on o-nitrobenzyl chloride, reacts with
4-chloro-2-trihalomethylquinazolines 4 and 5 via a SNAr mechanism. This enabled a new series of 4-
benzyl-2-trihaloquinazoline derivatives to be synthesized in good yields under mild reaction conditions
offering promising prospects for pharmacomodulation.
Received 11 April 2011
Revised 10 May 2011
Accepted 13 May 2011
Available online 19 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
TDAE
4-Chloroquinazolines
o-Nitrobenzyl chloride
SNAr
o-Nitrobenzyl carbanion
Since 2001, the 2-trihalomethylquinazoline scaffold has been
intensively studied by medicinal chemists due to its large spec-
trum of biological activities, including anticancer properties.1 Re-
cently, our research team examined the anti-infectious potential
of the 2-trichloromethylquinazoline scaffold. For the first time,
several 4-substituted-2-trichloromethyl-quinazolines showed an
activity against the W2 multi-resistant Plasmodium falciparum
strain, combined with a safe toxicological profile (Fig. 1).2 Some
of these derivatives were obtained via an aromatic nucleophilic
substitution on 4-chloro-2-trichloromethylquinazoline. With the
aim of expanding the molecular diversity at position 4 of the qui-
nazoline ring, we decided to replace the aniline moiety by a benzyl
group for pharmacomodulation purposes.
tivity of magnesium with the trichloromethyl group9 prohibits
their use in our study. Therefore, developing a selective methodol-
ogy under milder conditions to perform SNAr reactions on 4-chlo-
roquinazoline substrates with a wide range of benzylcarbanions
could well be a new strategic option in the functionalization of
the 4 position of the quinazoline ring.
Tetrakis(dimethylamino)ethylene (TDAE) is an organic reducing
agent,10 which reacts with haloalkyl derivatives to generate a carb-
anion under mild conditions.11 Using this strategy, we have devel-
oped several reactions between nitrobenzylic substrates and
various electrophilic species: firstly via nucleophilic addition with
activated-carbonyl reagents,12 and more recently, via nucleophilic
substitution in a
-halocarbonyl series.13
With respect to 4-chloroquinazolines, the literature involving
these substrates in SNAr reactions with various nucleophilic spe-
cies such as thiolates,3 ethanolates,4 phenates4 and amines5
abounds, due to the highly electrophilic nature of position 4. How-
ever, very few examples of SNAr reactions between 4-chloroqui-
nazolines and carbanions have been reported. These carbanions
were generated from organomagnesian6 species or from substrates
with an activated methyl group and a strong base such as NaH,
NaOEt or NaNH2.7 Because of the drastic conditions used in these
methods, 4-benzylquinazolines are usually formed by cyclization
of N-(2-(2-phenylacetyl)phenyl)acetamide.8 To our knowledge,
only one example of SNAr using benzylmagnesium bromide on 4-
chloroquinazoline has been reported.6 However, the potential reac-
As part of ongoing research programme directed towards the
development of original synthetic methods in medicinal chemis-
try,14 we report herein the reactivity of various 4-chloro-2-triha-
lomethylquinazoline derivatives with nitrobenzylic carbanions
formed in situ using the TDAE strategy.
NO2
NO2
O
N
N
NH
N
CCl3
N
CCl3
W2 P. fa l c IC50= 5 µM
W2 P. fa l c IC50= 3 µM
⇑
Corresponding author. Tel.: +33 49183 5580, fax: +33 49179 4677.
E-mail addresses: patrice.vanelle@univmed.fr, patrice.vanelle@pharmacie.univ-
Figure 1. Structure of some 2-trichloromethylquinazolines displaying antiplasmo-
mrs.fr (P. Vanelle).
dial activity.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.060

M. Since et al. / Tetrahedron Letters 52 (2011) 3810–3813
3811
Table 1
Reaction of nitrobenzyl chlorides 1–3 with 4-chloroquinazolines 4–5 via the TDAE strategy
NO2
Cl
R1
NO2
TDAE (1 equiv.), DMF, N2,
-20 °C 1h, then, 50 °C 0.5 h
N
R1
+
Cl
N
N
N
R2
1 equiv.
1-3
2 equiv.
R2
4-5
6-11
Entrya
Nitrobenzyl chloride
R1
H
4-Chloroquinazoline
R2
Product
Yieldb (%)
1
2
3
4
5
6
1
2
3
1
2
3
4
4
4
5
5
5
CCl3
CCl3
CCl3
CF3
CF3
CF3
6
7
8
9
10
11
83
80
65
90
87
45
5-CH3
4,5-(OCH3)2
H
5-CH3
4,5-(OCH3)2
a
Two equiv of quinazoline 4 or 5, 1 equiv of o-nitrobenzyl chloride derivatives 1-3 and TDAE in anhydrous DMF stirred at À20 °C for 1 h and then heated to 50 °C for
30 min.
b
% All yields refer to chromatographically isolated pure products and are relative to o-nitrobenzylchloride 1–3.
o-Nitrobenzyl chloride derivatives (1–3) were added to 1 equiv
of TDAE and 2 equiv of 4-chloro-2-trichloromethylquinazoline 415
(Table 1) providing 4-(2-nitrobenzyl)-2-(trichloromethyl)quinazo-
line derivatives (6–8).16 Reaction conditions (DMF, À20 °C for 1 h
then heated to 50 °C for 0.5 h) were similar to previous conditions
used in nucleophilic substitution between o-nitrobenzylic carba-
chloroquinazoline compounds with 5-(chloromethyl)-6-nitro-
benzo[d][1,3]dioxole 12 as the TDAE substrate (Table 2). These
new quinazoline derivatives are either commercially available or
prepared as previously described.15,17
From quinazolines
4 and 5, the 5-(chloromethyl)-6-nitro-
benzo[d][1,3]dioxole 12 furnished the corresponding substitution
products 13 and 14 in, respectively, 72 and 95% yield (Table 2, en-
tries 7 and 8).16 However, this methodology could not be general-
ized to 4-chloro-2-methylquinazoline 15, 4-chloroquinazoline 16.
The 5-(chloromethyl)-6-nitrobenzo[d][1,3]dioxole 12 was reduced
as 5-methyl-6-nitrobenzo[d][1,3]dioxole 20 in 55% (entry 9) to 76%
(entry 10) yields. Only traces of the substitution products were iso-
lated from ethyl 4-chloroquinazoline-2-carboxylate 17 (Table 2,
entry 11). Finally, quinazoline 18 (R2 = CCl3) provided the substitu-
tion product 19 in 23% yield and 71% yield of the 5-(chloromethyl)-
6-nitrobenzo[d][1,3]dioxole 12 was recovered unchanged.18 This
nions and
a
-halocarbonyl derivatives.13 This methodology was
then successfully extended to the synthesis of 4-(2-nitrobenzyl)-
2-(trifluoromethyl)quinazoline (9–11)16 from the commercially
available 4-chloro-2-trifluoromethylquinazoline 5. In both cases,
yields were high and slightly better in trifluoromethyl series (65–
83%/45–90%) except for the 1-(chloromethyl)-4,5-dimethoxy-2-
nitrobenzene 3. These experiments thus abundantly yielded the
expected substitution products (6–11) in high yields.
In order to determine the scope and the limits of our
methodology, we attempted to extend this reaction to various 4-
Table 2
Reaction of nitrobenzyl chloride 12 with 4-chloroquinazolines 4–5, 15–18
NO2
O
O
Cl
NO2
TDAE (1 equiv.), DMF, N2,
-20 °C 1h, then, 50 °C 0.5h
O
O
N
+
R1
Cl
N
N
R1
N
R2
1 equiv.
12
2 equiv.
R2
4-5, 15-18
13-14, 19
Entrya
Quinazoline
R1
R2
Product
Yieldb (%)
7
8
9
10
11
12
4
5
15
16
17
18
H
H
H
H
H
6-Cl
CCl3
CF3
CH3
H
COOEt
CCl3
13
14
—
—
—
72
95
0c
0c
Tracesc
23d
19
a
b
c
Two equiv of quinazoline 4–5, 15–18, 1 equiv of o-nitrobenzyl chloride 12 and TDAE in anhydrous DMF stirred at À20 °C for 1 h and then warmed up to 50 °C for 30 min.
% All yields refer to chromatographically isolated pure products and are relative to o-nitrobenzyl chloride 12.
Reduction product 20 is observed.
d
Accompanied by the unchanged 5-(chloromethyl)-6-nitrobenzo[d][1,3]dioxole 12.

3812
M. Since et al. / Tetrahedron Letters 52 (2011) 3810–3813
Cl
1/ TDAE (1 equiv.), DMF,
N2, -20°C 1 h, then rt 3 h
+
N
Cl
N
2/ H2O
N
N
CCl3
O
O
1 equiv.
3 equiv.
Cl
22 (40 %)
20
21
Scheme 1. TDAE-initiated reaction of 2-trichloromethyl-quinazoline 20 with 4-chlorobenzaldehyde 21.
Cl
Cl
Cl
N
1/ TDAE (1 equiv.), DMF, N 2,
-20°C 1 h, 50 °C 0.5 h
N
Cl
N
+
N
2/ H2O
CCl3
O
Cl
O
3 equiv.
21
1 equiv.
23 (27 %)
4
Scheme 2. TDAE-initiated reaction of 2-trichloromethyl-quinazoline 4 with 4-chlorobenzaldehyde 21.
uncompleted reduction of TDAE substrate 12 combined with
numerous by-products could be explained by competition with
the reducible nature of quinazoline 18. We can note that in the
reactions of quinazolines 15–18, the quinazoline substrates are
not recovered totally (20%) but associated with TDAE adducts.
The absence of reaction observed with quinazolines 15–17 led
us to consider this reaction as electron withdrawing group-depen-
dent. The substitution reaction seems to be correlated with the
electropositive nature of the quinazoline 4-position (–CF3 > –
CCl3 > –COOEt). Moreover, the carbanion formed via the TDAE
methodology (stabilized by TDAE++ counterion) was less reactive
than a carbanion formed by an organometallic strategy.19 The for-
mation of reduction product 20 could be explained by the TDAE-
initiated carbanion which was unable to give the substitution on
the 4-chloro position, and was then reduced as derivative 20. All
these experimental data support a SNAr mechanism of an o-nitro-
benzyl carbanion, formed via the action of the TDAE, on 4-
chloro-2-trihalomethyl-quinazolines 4 and 5.
preliminary study reveals some drawbacks to this reaction it re-
mains an easy, original and selective method to create a carbon–
carbon bond despite the presence of a CCl3 group. This work con-
stitutes a good starting point towards the generalization of the
SNAr reaction using TDAE-initiated carbanions in other series. Anti-
plasmodial evaluation of these new 4-(2-nitrobenzyl)-2-(trichloro-
methyl)quinazoline derivatives is currently underway.
Acknowledgements
This work is supported by the Centre National de la Recherche
Scientifique. We express our thanks to V. Remusat for 1H and 13C
NMR spectra recording.
References and notes
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Concerning the competitive reaction observed with trichloro-
methyl groups in TDAE strategy, we have previously demonstrated
that a trichloromethyl group can react with the TDAE and aldehyde
to form
ity of 4-chloro-2-trichloromethylquinazoline
a
-chloroketone derivatives.20 To reveal the chemoselectiv-
4
under TDAE
conditions, we first examined the ability of TDAE to reduce the
2-trichloromethyl group in quinazoline series. Thus, we subjected
the 2-trichloromethylquinazoline 202a to 1 equiv of TDAE and
3 equiv of 4-chlorobenzaldehyde 21 at À20 °C for 1 h, followed
by 2 h at rt which produced the expected
40% yield (Scheme 1).21
a-chloroketone 22 in
The same reaction was observed by reacting 4-chloro-2-trichlo-
romethylquinazoline 4 with aldehyde 21 under SNAr conditions
providing
a-chloroketone 23 in 27% yield (Scheme 2). This con-
firmed the TDAE reactivity of the 2-trichloromethyl group of 4 un-
der these conditions20 and may explain the competition observed
with the TDAE reactivity between o-nitrobenzyl chloride 12 and
4-chloroquinazoline 18 (Table 2, entry 12).
In conclusion, we reported here the first example of a SNAr
reaction using TDAE-initiated o-nitrobenzyl carbanions in 4-
chloro-2-trihalomethylquinazolines series. Thus, a new series of
4-benzyl-2-trihalomethylquinazoline derivatives was synthesized
in good yields under mild reaction conditions. Such an approach
constitutes an original synthetic tool for conducting the functional-
ization of the 4 position of quinazoline scaffold. While this

M. Since et al. / Tetrahedron Letters 52 (2011) 3810–3813
3813
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8.09 (m, 2H, 2ÂCH); 8.18–8.30 (m, 2H, 2ÂCH). 13C NMR (50 MHz, CDCl3) d 21.4
(CH3); 38.6 (CH2); 119.7 (q, J = 275.6 Hz, CF3); 123.8 (C); 124.5 (CH); 125.4
(CH); 129.0 (CH); 129.9 (CH); 130.0 (CH); 131.4 (C); 133.7 (CH); 134.8 (CH);
144.7 (C); 146.8 (C); 149.5 (C); 151.9 (q, J = 36.2 Hz, C); 169.8 (C). Anal. Calcd
for C17H12F3N3O2: C, 58.79; H, 3.48; N, 12.10. Found: C, 59.49; H, 3.52; N, 12.07.
4-(4,5-Dimethoxy-2-nitrobenzyl)-2-trifluoromethylquinazoline (11). Yellow solid,
mp 170 °C. 1H NMR (200 MHz, CDCl3) d 3.92 (s, 3H, CH3); 3.97 (s, 3H, CH3); 5.09
(s, 2H, CH2); 6.92 (s, 1H, CH); 7.73 (s, 1H, CH); 7.78–7.86 (m, 1H, CH); 7.98–8.06
(m, 1H, CH); 8.17–8.22 (m, 1H, CH); 8.32–8.36 (m, 1H, CH). 13C NMR (50 MHz,
12. (a) Nadji-Boukrouche, A. R.; Khoumeri, O.; Terme, T.; Liacha, M.; Vanelle, P.
ARKIVOC 2010, 10, 358–370; (b) Juspin, T.; Giuglio-Tonolo, G.; Terme, T.;
Vanelle, P. Synthesis 2010, 844–848; (c) Juspin, T.; Terme, T.; Vanelle, P. Synlett
2009, 1485–1489; (d) Khoumeri, O.; Crozet, M. D.; Terme, T.; Vanelle, P.
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T.; Vanelle, P. Tetrahedron 2008, 64, 11237–11242; (f) Amiri-Attou, O.; Terme,
T.; Vanelle, P. Synlett 2005, 3047–3050; (g) Giuglio-Tonolo, G.; Terme, T.;
Vanelle, P. Synlett 2005, 251–254; (h) Giuglio-Tonolo, G.; Terme, T.;
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Tonolo, G.; Terme, T.; Médebielle, M.; Vanelle, P. Tetrahedron Lett. 2003, 44,
6433–6435.
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CDCl3)
d
38.0 (CH2); 56.3 (2ÂCH3); 108.3 (CH); 114.7 (CH); 119.8 (q,
J = 275.6 Hz, C); 123.9 (C); 124.6 (CH); 126.2 (C); 129.9 (2ÂCH); 134.9 (CH);
141.2 (C); 148.0 (C); 149.5 (C); 151.9 (q, J = 36.6 Hz, C); 153.1 (C); 170.1
(C). Anal. Calcd for C18H14F3N3O4: C, 54.97; H, 3.59; N, 10.68. Found: C, 55.80;
H, 3.64; N, 10.60. 4-((6-Nitrobenzo[d][1,3]dioxol-5-yl)methyl)-2-
trichloromethylquinazoline (13). Yellow solid, mp 193 °C. 1H NMR (200 MHz,
CDCl3) d 5.08 (s, 2H, CH2); 6.14 (s, 2H, CH2); 6.82 (s, 1H, CH); 7.70 (s, 1H, CH);
7.74–7.83 (m, 1H, CH); 7.96–8.04 (m, 1H, CH); 8.18–8.27 (m, 2H, 2ÂCH). 13C
NMR (50 MHz, CDCl3) d 39.9 (CH2); 97.0 (C); 103.0 (CH2); 106.0 (CH); 111.7
(CH); 122.4 (C); 124.2 (CH); 128.8 (C); 129.5 (CH); 130.0 (CH); 134.7 (CH);
143.0 (C); 147.2 (C); 149.3 (C); 151.9 (C); 160.3 (C); 169.5 (C). Anal. Calcd for
C17H10Cl3N3O4: C, 47.86; H, 2.36; N, 9.85. Found: C, 47.90; H, 2.34; N, 9.79.
4-((6-Nitrobenzo[d][1,3]dioxol-5-yl)methyl)-2-trifluoromethylquinazoline (14).
Yellow solid, mp 208 °C. 1H NMR (200 MHz, CDCl3) d 5.04 (s, 2H, CH2); 6.13
(s, 2H, CH2); 6.76 (s, H, CH); 7.67 (s, H, CH); 7.77–7.85 (m, 1H, CH); 7.98–8.06
(m, 1H, CH); 8.19–8.29 (m, 2H, 2ÂCH). 13C NMR (50 MHz, CDCl3) d 38.8 (CH2);
103.1 (CH2); 106.1 (CH); 111.8 (CH); 119.8 (q, J = 275.9 Hz, C); 123.8 (C); 124.5
(CH); 128.5 (C); 129.9 (CH); 130.0 (CH); 134.9 (CH); 142.9 (C); 147.4 (C); 149.5
(C); 152.0 (C); 152.1 (q, J = 36.6 Hz, C); 169.8 (C). Anal. Calcd for C17H10F3N3O4:
C, 54.12; H, 2.67; N, 11.14. Found: C, 54.58; H, 2.65, N, 11.04.
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8173–8176.
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16. General procedure for the reaction of o-nitrobenzyl derivatives 1–3, 12 and
4-chloro-2-trihalomethylquinazoline derivatives 4–5 using TDAE. Into a two-
necked flask equipped with a nitrogen inlet were added, under nitrogen at
À20 °C, 6 mL of anhydrous DMF solution of o-nitrobenzyl chloride derivatives
(1 mmol, 1 equiv) and corresponding 2-trihalomethyl-4-chloroquinazoline
derivatives. The solution was stirred and maintained at this temperature for
15 min and then the TDAE (1 equiv) was added dropwise via a syringe. A green
to purple colour immediately developed with the formation of a white fine
precipitate. The solution was vigorously stirred for 1 h and heated to 50 °C for
0.5 h. After this time, the crude was extracted with dichloromethane (50 mL),
washed with water (3 Â 100 mL) and dried with Na2SO4. Evaporation of the
solvent left an orange to brown viscous liquid as the crude product. Purification
was by silica gel chromatography (CH2Cl2/petroleum ether (8:2)).
4-(2-Nitrobenzyl)-2-trichloromethylquinazoline (6). White solid, mp 168 °C, 1H
NMR (200 MHz, CDCl3) d 5.16 (s, 2H, CH2); 7.39–7.65 (m, 3H, 3ÂCH); 7.75–7.83
(m, 1H, CH); 7.96–8.04 (m, 1H, CH); 8.16–8.29 (m, 3H, 3ÂCH). 13C NMR
(50 MHz, CDCl3) d 38.6 (CH2); 97.0 (C); 122.5 (C); 124.3 (CH); 125.2 (CH); 128.3
(CH); 129.5 (CH); 130.1 (CH); 131.8 (C); 133.2 (CH); 133.4 (CH); 134.7 (CH);
149.2 (C); 149.3 (C); 160.3 (C); 169.4 (C). Anal. Calcd for C16H10Cl3N3O2: C,
50.22; H, 2.63; N, 10.98. Found: C, 49.69; H, 2.69; N, 10.80. 4-(5-Methyl-
2-nitrobenzyl)-2-trichloromethylquinazoline (7). Yellow solid, mp 161 °C. 1H
NMR (200 MHz, CDCl3) d 2.40 (s, 3H, CH3); 5.13 (s, 2H, CH2); 7.22–7.28 (m, 2H,
2ÂCH); 7.74–7.82 (m, 1H, CH); 7.95–8.03 (m, 1H, CH); 8.07–8.29 (m, 3H,
3ÂCH). 13C NMR (50 MHz, CDCl3) d 21.4 (CH3); 38.6 (CH2); 97.0 (C); 122.5 (C);
124.3 (CH); 125.4 (CH); 128.8 (CH); 129.5 (CH); 130.0 (CH); 131.7 (C); 133.8
(CH); 134.6 (CH); 144.6 (C); 146.9 (C); 149.3 (C); 160.2 (C); 169.6 (C). Anal.
Calcd for C17H12Cl3N3O2: C, 51.48; H, 3.05; N, 10.59. Found: C, 50.83; H, 3.05; N,
10,59. 4-(4,5-Dimethoxy-2-nitrobenzyl)-2-trichloromethylquinazoline (8). Yellow
solid, mp 180 °C. 1H NMR (200 MHz, CDCl3) d 3.89 (s, 3H, CH3); 3.95 (s, 3H,
CH3); 5.10 (s, 2H, CH2); 6.92 (s, 1H, CH); 7.73–7.79 (m, 2H, 2ÂCH); 7.92–8.01
(m, 1H, CH); 8.13–817 (m, 1H, CH); 8.25–8.29 (m, 1H, 1CH). 13C NMR (50 MHz,
CDCl3) d 38.1 (CH2); 56.2 (CH3); 56.3 (CH3); 97.1 (C); 108.2 (CH); 114.5 (CH);
122.4 (C); 124.3 (CH); 126.5 (C); 129.5 (CH); 129.9 (CH); 134.6 (CH); 141.3 (C);
147.8 (C); 149.2 (C); 153.0 (C); 160.1 (C); 169.8 (C). Anal. Calcd for
18. 4,6-Dichloro-2-trichloromethylquinazoline (18) White solid, mp 172 °C. 1H NMR
(200 MHz, CDCl3) d 8.00 (dd, J = 9,0 Hz, J = 2.2 Hz, 1H, CH); 8.17 (d, J = 9.0 Hz,
1H, CH); 9.33 (d, J = 2.2 Hz, 1H, CH). 13C NMR (50 MHz, CDCl3) d 95.6 (C); 123.5
(C); 124.9 (CH); 131.3 (CH); 136.9 (C); 137.0 (CH); 148.6 (C); 160.1 (C); 163.0
(C). Anal. Calcd for C9H3Cl5N2: C, 34.16; H, 0.96; N, 8.85. Found: C, 34.15; H,
0.94; N, 8.57. 6-Chloro-4-((6-nitrobenzo[d][1,3]dioxol-5-yl)methyl)-2-
trichloromethylquinazoline (19). White solid, mp 206 °C. 1H NMR (200 MHz,
CDCl3) d 5.02 (s, 2H, CH2); 6.16 (s, 2H, CH2); 6.83 (s, 1H, CH); 7.73 (s, 1H, CH);
7.91–7.97 (m, 1H, CH); 8.13–8.17 (m, 1H, CH); 8.24–8.25 (m, 1H, CH). 13C NMR
(50 MHz, CDCl3) d 39.3 (CH2); 96.7 (C); 103.1 (CH2); 106.2 (CH); 111.9 (CH);
123.0 (C); 123.4 (CH); 128.3 (C); 131.6 (CH); 135.5 (C); 135.7 (CH); 143.0 (C);
147.4 (C); 147.8 (C); 152.1 (C); 160.5 (C); 168.9 (C). Anal. Calcd for
C17H9Cl4N3O4: C, 44.28; H, 1.97; N, 9.11. Found: C, 43.75; H, 1.87; N, 8.91.
19. (a) Peng, W.; He, P.; Zhu, S.; Li, Z. Tetrahedron Lett. 2004, 45, 3677–3680; (b)
Peng, W.; Zhao, J.; Zhu, S. J. Fluorine Chem. 2006, 127, 360–366.
20. Montana, M.; Terme, T.; Vanelle, P. Tetrahedron Lett. 2006, 47, 6573–6576.
21. Procedure for the reaction of 4-chloro- or 4-phenyl-2-trichloro methylquinazoline
and 4-chlorobenzaldehyde using TDAE. Into a two-necked flask equipped with a
nitrogen inlet were added, under nitrogen at À20 °C, 6 mL of anhydrous DMF
solution of 2-trihalomethyl-4-chloroquinazoline (1 mmol, 1 equiv) and 4-
chlorobenzaldehyde (3 mmol, 3 equiv). The solution was stirred and
maintained at this temperature for 15 min and then the TDAE (1 equiv) was
added dropwise via a syringe. An orange colour immediately developed with
the formation of a white fine precipitate. The solution was vigorously stirred
for 1 h and heated slowly to rt over 3 h or 50 °C over 0.5 h. After this time, the
crude was extracted with dichloromethane (50 mL), washed with water
(3 Â 100 mL) and dried with Na2SO4. Evaporation of the solvent left an
orange to brown viscous liquid as the crude product. Purification was by
silica gel chromatography (CHCl3). 2-Chloro-2-(4-chlorophenyl)-1-(4-
phenylquinazolin-2-yl)ethanone (22). Yellow solid, mp 89 °C. 1H NMR
(200 MHz, CDCl3) d 7.22 (s, 1H, CH); 7.27–7.31 (m, 2H, 2ÂCH); 7.54–7.61 (m,
5H, 5ÂCH); 7.70–7.79 (m, 3H, 3ÂCH); 7,95–8.04 (m, 1H, CH); 8.20–8.16 (m, 1H,
CH); 8.25–8.29 (m, 1H, CH). 13C NMR (50 MHz, CDCl3) d. 61.3 (CH); 123.3 (C);
127.2 (CH); 128.7 (2ÂCH); 129.0 (2ÂCH); 130.2 (3ÂCH); 130.3 (CH); 130.6
(2ÂCH); 134.2 (C); 134.5 (CH); 135.0 (C); 136.4 (C); 151.0 (C); 154.0 (C); 169.4
(C); 190.4 (C). RMS (EI): calcd for C22H14Cl2N2O [M]+: 392.0; found, 392.0. 2-
Chloro-2-(4-chlorophenyl)-1-(4-chloroquinazolin-2-yl)ethanone (23). Beige solid,
mp 171 °C. 1H NMR (200 MHz, CDCl3) d 7.08 (s, 1H, CH); 7.31 (d, J = 8.5 Hz, 2H,
2ÂCH); 7.55 (d, J = 8.5 Hz, 2H, 2ÂCH); 7.84–7.93 (m, 1H, CH); 8.04–8.12 (m, 1H,
CH); 8.21–8.26 (m, 1H, CH); 8.32–8.36 (m, 1H, CH). 13C NMR (50 MHz, CDCl3) d
60.9 (CH); 124.3 (C); 126.1 (CH); 129.2 (2ÂCH); 130.0 (CH); 130.6 (2ÂCH);
131.6 (CH); 133.6 (C); 135.3 (C); 135.9 (CH); 150.5 (C); 153.3 (C); 164.0 (C);
188.9 (CO). HR-MS calcd for C16H9Cl3N2O [M+H]+: 350.9853, found: 350.9850.
C
18H14Cl3N3O4: C, 48.84; H, 3.19; N, 9.49. Found: C, 48.75; H, 3.25; N, 9.42.
4-(2-Nitrobenzyl)-2-trifluoromethylquinazoline (9). White solid, mp 155 °C. 1H
NMR (200 MHz, CDCl3) d 5.12 (s, 2H, CH2); 7.35–7.39 (m, 1H, CH); 7.45–7.64
(m, 2H, 2ÂCH); 7.78–7.86 (m, 1H, CH); 7.98–8.07 (m, 1H, CH); 8.12–8.30 (m,
3H, 3ÂCH). 13C NMR (50 MHz, CDCl3) d 38.5 (CH2); 120.7 (q, J = 275.6 Hz, CF3);
123.8 (C); 124.4 (CH); 125.2 (CH); 128.4 (CH); 129.9 (2ÂCH); 131.6 (C); 133.1
(CH); 134.4 (CH); 134.9 (C); 149.2 (C); 149.5 (C); 151.9 (q, J = 36.2 Hz, C); 169.6
(C). Anal. Calcd for C16H10F3N3O2: C, 57.66; H, 3.02; N, 12.61. Found: C, 58.23;
H, 2.97, N, 12.42. 4-(5-Methyl-2-nitrobenzyl)-2-trifluoromethyl-quinazoline (10).
White solid, mp 147 °C. 1H NMR (200 MHz, CDCl3) d 2.40 (s, 3H, CH3); 5.10 (s,
2H, CH2); 7.16 (s, 1H, CH); 7.24–7.29 (d, 1H, CH); 7.77–7.85 (m, 1H, CH); 7.98–