A new DMAP-catalyzed and microwave-assisted approach for introducing heteroarylamino substituents at position-4 of the quinazoline ring

Article abstract of DOI:10.1016/j.tet.2014.09.024

We report herein a new methodology for synthesizing quinazoline derivatives bearing a heteroarylamino moiety at position-4 of the quinazoline ring. As an alternative to the Buchwald-Hartwig cross-coupling reaction, which appears, until now, as the only efficient way to react 4-chloroquinazolines with numerous amino nitrogen-containing heterocycles displaying poor nucleophilicity, we developed a DMAP-catalyzed reaction involving microwave irradiation. Optimization of the reaction conditions led to the use of 30 mol % of DMAP in toluene, using a monomode microwave reactor and sealed vials. Moreover, the S_NAr reaction intermediate salt was isolated and fully characterized. Finally, the procedure was extended to two different 2-substituted-quinazoline series and also to various anilines, demonstrating that this approach was a general efficient way to access to such 4-substituted quinazoline scaffolds of high pharmaceutical interest.

Full text of DOI:10.1016/j.tet.2014.09.024

Tetrahedron 70 (2014) 8257e8266
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new DMAP-catalyzed and microwave-assisted approach for
introducing heteroarylamino substituents at position-4 of the
quinazoline ring
Armand Gellis a, Charline Kieffer a, Nicolas Primas a, Gilles Lanzada a, Michel Giorgi b,
,
Pierre Verhaeghe c, Patrice Vanelle a
*
a
ꢀ
ꢀ
Aix-Marseille Universite, CNRS, ICR, UMR 7273, Laboratoire de Pharmacochimie Radicalaire, Faculte de Pharmacie, 27 Bd Jean MoulindCS30064,
13385 Marseille cedex 05, France
b
ꢀ
Aix-Marseille Universite, CNRS, Spectropole FR 1739, 13397 Marseille cedex 20, France
c
ꢀ
ꢀ
Universite Paul Sabatier, Faculte des Sciences Pharmaceutiques, Laboratoire de Chimie de Coordination UPR 8241 CNRS, 205 Route de Narbonne, 31400
Toulouse, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2014
Accepted 8 September 2014
Available online 16 September 2014
We report herein a new methodology for synthesizing quinazoline derivatives bearing a heteroarylamino
moiety at position-4 of the quinazoline ring. As an alternative to the BuchwaldeHartwig cross-coupling
reaction, which appears, until now, as the only efficient way to react 4-chloroquinazolines with nu-
merous amino nitrogen-containing heterocycles displaying poor nucleophilicity, we developed a DMAP-
catalyzed reaction involving microwave irradiation. Optimization of the reaction conditions led to the use
of 30 mol % of DMAP in toluene, using a monomode microwave reactor and sealed vials. Moreover, the
SNAr reaction intermediate salt was isolated and fully characterized. Finally, the procedure was extended
to two different 2-substituted-quinazoline series and also to various anilines, demonstrating that this
approach was a general efficient way to access to such 4-substituted quinazoline scaffolds of high
pharmaceutical interest.
Keywords:
Quinazoline ring
Pharmaceutical chemistry
Heteroaryl moiety
DMAP
Microwave
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
phenoxy-,7 thiophenoxy-,8 or sulfonamide substituents9 at posi-
tion-4 of the quinazoline ring. Through all studied series, the lead-
Quinazoline is the core ring of numerous drug compounds,
which scaffold always includes an amino or anilino substituent at
position-4 of the quinazoline ring. Thus, prazosine, alfusozine,
terazosine and doxazosine form a homogeneous group of a1-re-
ceptor blockers used in the treatment of both benign prostatic
hyperplasia and hypertension while erlotinib, gefitinib, lapatinib
and vandetanib constitute a major subfamily of kinase inhibitor
anti-cancer agents (Fig. 1).
compound belonged to the 4-anilinosubstituted one, presenting an
inhibitory concentration 50% (IC50) value of 0.4 M on the W2
multi-resistant Plasmodium falciparum strain, a cytotoxic concen-
m
tration 50% (CC50) of 16 mM on the human HepG2 cell line and thus,
a corresponding selectivity index (SI) of 40 (Fig. 3).6
Taking into account that the antiplasmodial mechanism of ac-
tion of our lead-quinazoline could involve the inhibition of one of
the parasite kinases, we decided to investigate the synthesis of new
Concerning the research for new kinase inhibitors, it was re-
ported that quinazolines bearing a heteroarylamino moiety at po-
sition-4 were promising ALK5 (Activin A receptor type 2-Like
Kinase) inhibitors (Fig. 2).1
Among of our research activities centred on the synthesis of
original molecules with anti-infective properties,2e4 we developed
various series of new quinazolines bearing an aryl-,5 anilino-,6
* Corresponding author. Tel.: þ33 4 9183 5580; fax: þ33 4 9179 4677; e-mail
Fig. 1. Typical structures of the quinazoline-containing drug compounds erlotinib and
prazosine.
address: patrice.vanelle@univ-amu.fr (P. Vanelle).
http://dx.doi.org/10.1016/j.tet.2014.09.024
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

8258
A. Gellis et al. / Tetrahedron 70 (2014) 8257e8266
Fig. 2. Structure of an ALK5 quinazoline inhibitor bearing an aminoheteroaryl moiety
at position-4.
Scheme 2. Study of SNAr reaction between substrate 1 and 2-aminobenzothiazole
following previously described procedures.
Indeed, when substrate
1
was reacted with 2-
aminobenzothiazole in a reaction medium containing methanol,
the reaction product that we obtained resulted from the sub-
stitution of the chlorine atom by methanol. This result illustrates
well the poor nucleophilicity of aminated nitrogen-containing
heterocycles, in comparison with other amines including anilines,
which easily undergo SNAr reactions with 4-chloroquinazolines3,6
(Scheme 3).
Fig. 3. Antiplasmodial lead-compound in 4-substituted-2-CCl3-quinazoline series.
close structural analogues bearing a heteroarylamino moiety at
position-4, in a view to identify more potent and selective anti-
plasmodial derivatives.
2. Results and discussion
Scheme 3. Reaction of substrate 1 with 2-aminobenzothiazole in a mixture of di-
chloromethane and methanol.
To access to the target 4-heteroarylaminoquinazolines in a fast
and efficient way, the synthesis pathway, which was chosen con-
sisted in an SNAr reaction between 4-chloroquinazolines and di-
verse heterocyclic amines. Effectively, 4-chloroquinazolines and
especially molecules such as compound 1, bearing a strong electro-
attracting group at position-2, display a good reactivity at position-
4 toward most of nucleophilic reactants, including some carban-
ions.10 For that purpose, quinazoline substrates 1 and 2 were pre-
pared (Scheme 1) by using a microwave-assisted methodology,
which we previously reported.11
Then, we made a bibliographical search (ScifinderÒ substructure
search May 27th 2014) concerning the reported reactions between
4-chloroquinazolines and heteroarylamines. Very few references
were reported, all concerning the Pd-catalyzed BuchwaldeHartwig
reaction. Thus, Gellibert et al., described a reaction with 4-
aminopyridine and Pd2(dba)3 as catalyst, leading to coupled
product in moderate yields (Scheme 4).1 The same methodology
and catalyst were also used in an analogous reaction reported in
a patent by Suzuki et al., leading to a limited 25% yield.19
Scheme 4. Example of BuchwaldeHartwig cross-coupling reactions from 4-
chloroquinazoline derivatives.
Scheme 1. Preparation of 4-chloroquinazoline substrates 1 and 2.
The use of microwave energy to heat and drive chemical re-
actions is growing at a rapid rate, with new and innovative appli-
cations in organic synthesis, continuously being reported in the
literature. In many instances, microwave heating has been shown
to dramatically reduce processing times, increase product yields
and to enhance product purities or material properties compared to
conventionally processed experiments.12e17 Although a variety of
different microwave reactors and processing options are available
today,18 the overwhelming majority of all currently published mi-
crowave synthesis protocols describe the use of this non-classical
heating principle in conjunction with sealed reactors.12,13
The BuchwaldeHartwig reaction is a rather expensive Pd-ligand
requiring reaction. Moreover, the few examples reported in the
literature show mild reaction yields for the coupling between 4-
chloroquinazolines and heteroarylamines. Indeed, substrate 1 in-
cludes a trichloromethyl group at position-2 of the quinazoline
ring, which can lead to competitive side-reactions when using Pd-
catalyzed synthetic approaches. Effectively, probably because of the
oxidant character of the trichloromethyl group, Pd-catalyzed re-
actions such as the Sonogashira reaction involving substrate 1 can
lead to undesirable homodimeric quinazoline by-products, drasti-
cally decreasing the coupling reaction yield.20
Thus, substrate
1
was reacted with an excess of 2-
In such a context, we decided to investigate another synthetic
option to reach the target molecules in good yields and short re-
action times: the use of 4-(dimethylamino)pyridine (DMAP). DMAP
is known as an important and quite useful catalyst reagent in or-
ganic synthesis.21 DMAP and its analogues have been widely used
in many organic synthesis reactions, among which nucleophilic
aminobenzothiazole in various reaction conditions,3 including
microwave-assisted and solvent-free ones,6 in both sealed reactors
and open flasks. These trials appeared unsuccessful and did not
allow any LC/MS detection of the expected product in the reaction
media, while many resins were formed (Scheme 2).

A. Gellis et al. / Tetrahedron 70 (2014) 8257e8266
8259
substitutions. Indeed, DMAP is an efficient catalyst for some nu-
cleophilic aromatic substitution reactions, in particular to prepare
4-phenoxyquinolines from 4-haloquinolines and phenols.22
The reaction of substrate 1 with 2-aminobenzothiazole (2 equiv)
was then carried out in a sealed tube, under microwave irradiation,
using 10 mol % of DMAP in toluene at 130 ꢀC. For the first time, the
awaited reaction did proceed and afforded the expected product in
37% yield, after 1.5 h (Scheme 5).
the reaction to proceed. The amount of catalyst was then evaluated.
With 20 mol % of DMAP, compound 4 was obtained in better yield,
but initial product remained. A better reaction yield (75%) was
obtained when using 30 mol % of DMAP, but the reaction was not
complete after 1.5 h. When increasing to 40 mol % of DMAP, we
obtained an analogous result, indicating that the optimal amount of
DMAP was 30 mol %, leading to a 75% reaction yield. This last result
was slightly improved by increasing the reaction time to 2 h,
leading to an optimal reaction yield of 83%. Heating the reaction
mixture to 110 ꢀC or 150 ꢀC instead of optimal 130 ꢀC (in a sealed
reactor) leads to a significant decrease of the reaction yield. Curi-
ously, when transposing the optimal reaction conditions used in
entry 9 (monomode reactor) to a multimode microwave oven
(entry 13) the reaction yield was drastically reduced. The expla-
nation of this last result could come from the type of flask used:
sealed vial in the monomode oven versus traditional open flask in
the multimode oven, impacting on the reaction medium temper-
ature, which can be reached. Note that, in classical conditions
(conventional heating), the reaction yield did not exceed 78% after
a long 36 h reaction time (entry 14). Finally, the number of equiv-
alents of 2-aminobenzothiazole was also studied, considering that
some of heteroarylamines are expensive reagents. Optimal amount
of the heterocyclic amine appeared to be 2 equiv (entries 15e17).
After optimizing the reaction conditions, we investigated its
extension to a broad spectrum of heteroarylamines, according to
the general reaction presented in Scheme 6. We then synthesized
a series of 22 new quinazolines (4e25), in moderate to good yields
(31e83%) and short reaction time (2 h), under microwave irradia-
tion. All assays were done in 5 mL sealed reactors and the evolution
of the reactions was monitored by LC/MS. The results are presented
in Table 3.
Scheme 5. Reaction of 4-chloro-2-trichloromethylquinazoline
1
and 2-
aminobenzothiazole in presence of DMAP.
This experimental result prompted us to compare the efficacy of
DMAP with other tertiary amine catalysts.23,24 The use of 10 mol %
of
DABCO
(1,4-diazabicyclo(2.2.2)octane),
DBU
(1,8-
diazabicyclo(5.4.0)undec-7-ene) or TEA (triethylamine) was not
successful (Table 1). Consequently, DMAP was kept as the reaction
catalyst, and the optimization of the reaction was carried out.
Table 1
Reaction between substrate 1 and 2-aminobenzothiazole, depending on the tertiary
amine catalyst used
Entry
Catalyst
Yield (%)
1
2
3
4
5
d
0
37
0
0
0
DMAP
DBU
DABCO
TEA
All parameters of the DMAP-catalyzed reaction between qui-
nazoline 1 and 2-aminobenzothiazole were investigated. The re-
sults are presented in Table 2. Concerning the solvent, THF, DMF,
DMSO and toluene were studied. Quinazoline 4 was obtained in
very low 8 and 7% yields with DMSO and DMF, respectively, at
150 ꢀC for 1.5 h while only traces of 4 were detected with THF at
80 ꢀC, showing that toluene was, by far, the best tested solvent for
Scheme 6. General reaction for the synthesis of 4-heteroarylamino-2-
trichloromethylquinazolines 4e25.
It should be noted that the reaction between 4-chloro-2-
trichloromethylquinazoline 1 and 3-amino-1,2,4-triazole afforded
two different products 18 and 19, in respective 41 and 39% yields
(Scheme 7).
Table 2
Studied parameters for the DMAP-catalyzed reaction of 1 with 2-aminobenzothiazole, leading to 4
Entry
DMAP (mol %)
Reaction conditions
Amine (equiv)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
10
10
10
10
20
20
30
40
30
40
30
40
40
40
30
30
30
1.5 h, 130 ꢀC/Monomode MW
1.5 h, 150 ꢀC/Monomode MW
1.5 h, 150 ꢀC/Monomode MW
1.5 h, 80 ꢀC/Monomode MW
1.5 h, 130 ꢀC/Monomode MW
2 h, 130 ꢀC/Monomode MW
1.5 h, 130 ꢀC/Monomode MW
1.5 h, 130 ꢀC/Monomode MW
2 h, 130 ꢀC/Monomode MW
2 h, 130 ꢀC/Monomode MW
3 h, 110 ꢀC/Monomode MW
0.5 h, 150 ꢀC/Monomode MW
2 h, 800 W, 110 ꢀC/Multimode MW
36 h, 110 ꢀC/Classical conditions
2 h, 130 ꢀC/Monomode MW
2 h, 130 ꢀC/Monomode MW
2 h, 130 ꢀC/Monomode MW
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
1.2
1.5
Toluene
DMSO
DMF
37
8
7
THF
Traces (LC/MS)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
61
65
75
75
83
80
62
52a
39
78
82
51
62
9
10
11
12
13
14
15
16
17
The monomode microwave oven used was a Biotage Initiator. The multimode microwave oven used was a Milestone Synth Lab Station.
a
Formation of resins.

8260
A. Gellis et al. / Tetrahedron 70 (2014) 8257e8266
Table 3
DMAP-catalyzed
SNAr
for
the
formation
of
4-heteroarylamino-2-
trichloromethylquinazolines 4e25
Nꢀ
Yield (%)
Nꢀ
Yield (%)
N
N
Het
Het
HN
HN
HN
N
S
Scheme 8. General reaction for the synthesis of 4-heteroarylamino-2-
trichloromethylquinazolines 26e32.
4
5
83
77
15
16
38
51
N
HN
HN
Cl
H
Table 4
N
N
Reaction yields in DMAP-catalyzed SNAr reactions between quinazoline substrate 2
and various 4-heteroarylamines
HN
HN
S
Nꢀ
Yield (%)
N
CH
CH
Het
N
HN
6
7
68
71
17
18
63
S
S
N
S
26
27
87
81
H
HN
HN
N
N
N
N
Cl
41*
HN
HN
HN
HN
HN
Cl
N
N
S
NO
8
9
49
76
19
20
39*
30
S
S
S
CH
CH
N
N
N
28
29
65
72
OCH
HN
HN
HN
HN
S
S
S
N
N
N
N
F
10
11
65
61
21
22
45
60
Cl
N
Cl
CH
NO
30
31
49
83
HN
HN
N
S
HN
HN
S
Cl
N
N
N
12
13
14
75
63
52
23
24
25
47
41
35
N
N
HN
HN
HN
O
CH
N
Cl
32
78
N
HN
N
CH
HN
O
N
N
HN
HN
N
H
O
all cases, the DMAP-catalyzed procedure (method A) lead to a sig-
nificant improvement in reaction yields.
Scheme 7. Reaction between 1 and 3-amino-1,2,4-triazole.
Scheme 9. General reaction for the synthesis of 4-arylamino-2-substituted quinazo-
lines 33e48 DMAP-catalyzed.
To demonstrate that this reaction could be generalized to other
quinazoline substrates in which the reactivity of position-4 is not
influenced by the presence of a trichloromethyl group at position-2,
we carried out the same SNAr reaction from substrate 2 (Scheme 8).
The reaction yields, varying from medium to good, are presented in
Table 4 and show that the reaction was not substrate-dependant in
quinazoline series.
Moreover, we extended the reaction procedure to anilines
(Scheme 9) in order to compare its efficiency with the one of the
solvent-free procedure (method B), which we previously reported
in 2-trichloromethylquinazoline series.6 As presented in Table 5, in
The probable mechanism for the SNAr reaction catalyzed by
DMAP is shown in Scheme 10. First, the nitrogen atom of the pyr-
idine ring of DMAP (I) attacks the carbon at position-4 of quina-
zoline ring, to form the cationic quinazoline intermediate (II). Next,
the heteroarylamine reacts with the intermediate (II) to afford the
corresponding 4-heteroarylaminoquinazoline, and DMAP is
regenerated to participate in
(Scheme 10).
a subsequent catalytic cycle
To support this mechanistic hypothesis, the quinazoline salt
intermediate (II) was formed by reacting equimolar quantities of
DMAP and substrate 1 in toluene. Chloride 49 was obtained with

A. Gellis et al. / Tetrahedron 70 (2014) 8257e8266
8261
Table 5
DMAP-catalyzed SNAr for the formation of 4-arylaminoquinazolines
Nꢀ
Yield (%) R1¼CCl3
Nꢀ
Yield (%) R1¼CH3
R
method A/B
method A
HN
33
34
90/62
85/66
41
42
91
92
HN
HN
Cl
Scheme 11. Reaction to isolate the intermediate coupling compound 49.
CH
NO
35
36
89/71
96/77
43
44
87
97
HN
HN
37
38
39
98/90
97/90
91/86
45
46
47
95
97
98
HN
HN
HN
OCH
Cl
CF
Cl
40
82/75
48
96
Fig. 4. X-ray structure of intermediate salt 49 (crystal structure including one aceto-
nitrile molecule from the crystallizing medium used).
HN
Cl
bibliographical references as providing moderate yields, we de-
veloped an efficient alternative synthetic procedure. After con-
ducting a large study, focussing on each reaction parameter, the use
of the DMAP catalyst, toluene as a solvent and microwave irradia-
tion in a sealed vial, the reaction could be performed easily and
rapidly. Moreover, the SNAr reaction intermediate was isolated and
fully characterized. Such a synthetic approach was extended to
various quinazoline substrates and aniline derivatives, demon-
strating its large interest for the preparation of molecules display-
ing pharmaceutical potential.
Method A: MW, DMAP 30 mol %, 2 equiv of aniline reagent, toluene, 2 h, 130 ꢀC.
Method B: 3 equiv of aniline reagent, solvent-free, 15 min, 140 ꢀC.
Cl
N
N
N
CCl3
Cl-
N
N
HN
N
S
H3C
N
N
CH3
I
4. Experimental section
4.1. General
CCl3
N
N
N
CCl3
€
Melting points were determined on a Kofler melting point ap-
Cl-
N
N
N
II
paratus and are uncorrected. Elemental analyses and X-ray dif-
fraction analysis were carried out at the Spectropole, Faculte des
Sciences de Saint-Jerome (Marseille) with a Thermo Finnigan
EA1112 analyzer and a Brucker Nonius diffractometer. HRMS anal-
ꢀ
N
^
S
H2N
N
ꢀ
yses were carried out at the Faculte de Pharmacie of Marseille on
N
S
CCl3
NH2
a QStar Elite (Applied Biosystems SCIEX) spectrometer or Electro-
spray MicrOTOF Q (Bruker, Daltonic), using PEG as the matrix. The
experimental exact mass was given for the ion with the maximum
isotopic abundance. Analysis of fragments was performed with
Scheme 10. Probable mechanism for the SNAr reaction catalyzed by DMAP.
ꢀ
a triple quadrupole LCMS-8030 Shimadzu at the Faculte de Phar-
a quantitative yield (Scheme 11). This intermediate compound was
isolated, NMR-characterized and its structure was also confirmed
by X-ray diffraction analysis (Fig. 4).
macie of Marseille. NMR spectra were recorded on a Bruker ARX
ꢀ
200 spectrometer at the Faculte de Pharmacie of Marseille
(200 MHz 1H NMR: reference CHCl3
d
¼7.26, and 50 MHz 13C: ref-
erence CHCl3
d
¼76.9). The following adsorbent was used for col-
3. Conclusion
umn chromatography: silica gel 60 (Merck, particle size
0.063e0.200 mm, 70e230 mesh ASTM). TLC was performed on
5 cmꢁ10 cm aluminium plates coated with silica gel 60F-254
(Merck) in an appropriate eluent. Visualization was performed with
ultraviolet light (234 nm). Purity of synthesized compounds was
Until now, the introduction of weakly nucleophilic heretoaryl-
amines at position-4 of the 4-chloroquinazoline was carried out by
using the BuchwaldeHartwig cross-coupling reaction. Because this
particular reaction is rather expensive and also reported in a few
ꢀ
checked by LC/MS analyses, which were realized at the Faculte de

8262
A. Gellis et al. / Tetrahedron 70 (2014) 8257e8266
Pharmacie of Marseille with a Thermo Scientific Accela High Speed
LC SystemÒ coupled using a single quadrupole mass spectrometer
Thermo MSQ PlusÒ. The RP-HPLC column is a Thermo Hypersil
GoldÒ 50ꢁ2.1 mm (C18 bounded), with particles of a diameter of
4.4.1. N-(2-(Trichloromethyl)quinazolin-4-yl)benzo[d]thiazol-2-
amine (4). MW: 395.69 g/mol. Yellow solid (83%). Mp
229 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
d 6.50 (br s, 1H),
1.9 mm. The volume of sample injected on the column is 1
mL.
7.27e7.34 (m, 1H), 7.42e7.50 (m, 1H), 7.64e7.68 (m, 1H), 7.75e7.83
Chromatographic analysis, total duration of 8 min, is on the gra-
dient of the following solvents: t¼0 min, water/methanol 50:50;
0<t<4 min, linear increase in the proportion of water to a water/
methanol ratio of 95:5; 4<t<6 min, water/methanol 95:5;
6<t<7 min, linear decrease in the proportion of water to return to
a water/methanol ratio of 50:50; 6<t<7 min, water/methanol
(m, 1H), 7.95e8.07 (m, 3H), 8.71e8.75 (m, 1H). 13C NMR (DMSO-d6,
50 MHz):
d 97.9 (C), 117.1 (C), 122.6 (CH), 124.0 (2CH), 124.8 (CH),
127.2 (CH), 128.8 (CH), 129.2 (CH), 129.3 (C), 130.7 (C), 135.1 (CH),
149.5 (C), 159.7 (C), 162.1 (C), 167.4 (C). LC/MS (ESIþ) tR 5.15 min, m/z
[MþH]þ 394.91/396.94/398.74. Anal. Calcd for C16H9Cl3N4S: C,
48.57; H, 2.29; N, 14.16. Found: C, 48.95; H, 2.49; N, 13.94 .
50:50. The water used was buffered with ammonium acetate 5 mM.
The retention times (tR) of the molecules analyzed are indicated in
minutes. The microwave reactions were performed using multi-
mode reactors: ETHOS Synth Lab station and MicroSYNTHÒ Lab
terminal 1024 (Ethos start, Milestone Inc.); or monomode reactors:
BiotageÒ Initiator classic in sealed vials.
4.4.2. 4-Chloro-N-(2-(trichloromethyl)quinazolin-4-yl)benzo[d]thia-
zol-2-amine (5). MW: 430.14 g/mol. Yellow solid (77%). Mp
255e256 ꢀC (isopropanol). Eluent (column chromatography)
CH2Cl2/AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
d
6.42 (br s, 1H),
7.28e7.35 (m, 1H), 7.53e7.57 (m, 1H), 7.82e7.88 (m, 1H), 7.95e8.05
(m, 3H), 8.99e9.02 (m, 1H). 13C NMR (DMSO-d6, 50 MHz):
97.4 (C),
d
4.2. Crystal-structure analysis
120.8 (C), 120.9 (CH), 122.0 (C), 123.1 (CH), 123.3 (CH), 126.6 (CH),
127.0 (CH), 128.8 (CH), 130.9 (C), 136.1 (CH), 142.7 (C), 146.2 (C),
148.3 (C), 160.2 (C), 168.6 (C). LC/MS (ESIþ) tR 5.74 min, m/z [MþH]þ
428.86/430.80/432.84. Anal. Calcd for C16H8Cl4N4S: C, 44.68; H,
1.87; N, 13.03. Found: C, 44.93; H, 1.81; N, 13.15.
The X-ray diffraction measurements were carried out on
a Bruker-Nonius KappaCCD diffractometer at 223 K. Structures
were solved using SIR92 and refinements calculations based on F2
were performed using SHELXL-97. Compound 49 was crystallized
in acetonitrile solution at 5 ꢀC to provide desired single crystals.
2-Methyl-4(3H)-quinazolinone was purchased from Sigma
Aldrich.
4.4.3. 5,6-Dimethyl-N-(2-(trichloromethyl)quinazolin-4-yl)benzo[d]
thiazol-2-amine (6). MW: 423.75 g/mol. Pale yellow solid (68%). Mp
250 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d
2.24 (s, 3H), 2.32 (s, 3H),
6.23 (br s, 1H), 7.24e7.27 (m, 1H), 7.43e7.50 (m, 1H), 7.56e7.62 (m,
1H), 7.79e7.86 (m, 1H), 8.03e8.07 (m, 1H), 8.17e8.23 (m, 1H). 13
NMR (CDCl3, 50 MHz): 19.9 (CH3), 20.2 (CH3), 97.5 (C), 119.8 (C),
4.3. Molecules prepared according to previously described
procedures
C
d
4-Chloro-2-trichloromethylquinazoline
1
and 4-chloro-2-
122.6 (CH), 122.0 (C), 124.8 (CH), 128.7 (CH), 129.1 (CH), 132.3 (CH),
130.9 (C), 134.5 (C), 134.9 (CH), 136.0 (C), 143.4 (C), 149.5 (C), 159.8
(C), 166.3 (C). LC/MS (ESIþ) tR 5.67 min, m/z [MþH]þ 422.93/424.90/
426.85. Anal. Calcd for C18H13Cl3N4S: C, 51.02; H, 3.09; N, 13.22.
Found: C, 51.39; H, 2.91; N, 13.09.
methylquinazoline
2
were prepared as described in the
literature.6,11,16,20
4.3.1. 4-Chloro-2-trichloromethylquinazoline (1). C9H4Cl4N2. MW:
282.18 g/mol. White solid (82%). Mp 127 ꢀC (lit. 127 ꢀC).16 1H NMR
(CDCl3, 200 MHz):
8.20e8.24 (m, 1H), 8.33e8.38 (m, 1H).
d
7.82e7.90 (m, 1H), 8.03e8.12 (m, 1H),
4.4.4. 6-Chloro-N-(2-(trichloromethyl)quinazolin-4-yl)benzo[d]thia-
zol-2-amine (7). MW: 430.14 g/mol. Yellow solid (71%). Mp
212 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
4.3.2. 4-Chloro-2-methylquinazoline (2). C9H7ClN2. MW: 178.62 g/
mol. White solid (73%). Mp 86 ꢀC (lit. 81.5e83 ꢀC).23 1H NMR (CDCl3,
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d
5.87 (br s, 1H), 7.32e7.36
(m, 1H), 7.51e7.66 (m, 2H), 7.89e7.97 (m, 2H), 8.12e8.16 (m, 1H),
8.23e8.27 (m, 1H). 13C NMR (CDCl3, 50 MHz):
97.2 (C), 113.9 (C),
200 MHz):
d
2.75 (s, 3H), 7.48e7.56 (m, 1H), 7.75e7.86 (m, 2H),
d
8.05e8.09 (m, 1H).
120.5 (CH), 121.4 (CH), 121.6 (CH), 127.3 (CH), 129.3 (CH), 129.7 (C),
130.0 (CH), 133.9 (C), 134.8 (CH), 144.7 (C), 149.7 (C), 155.9 (C), 160.1
(C), 168.4 (C). LC/MS (ESIþ) tR 5.70 min, m/z [MþH]þ 428.78/430.90/
432.74. Anal. Calcd for C16H8Cl4N4S: C, 44.68; H, 1.87; N, 13.03.
Found: C, 44.29; H, 1.95; N, 13.28.
4.3.3. 4-Methoxy-2-(trichloromethyl)quinazoline (3). MW: 277.53 g/
mol. White solid (32%). Mp 83 ꢀC (isopropanol). Eluent (column
chromatography) CH2Cl2/petroleum ether 5:5. 1H NMR (CDCl3,
200 MHz): d 4.28 (s, 3H), 7.63e7.70 (m, 1H), 7.87e7.95 (m, 1H), 8.08
(d, J¼8.2 Hz, 1H), 8.21 (d, J¼8.2 Hz, 1H). 13C NMR (CDCl3, 50 MHz):
4.4.5. 6-Nitro-N-(2-(trichloromethyl)quinazolin-4-yl)benzo[d]thia-
zol-2-amine (8). MW: 440.69 g/mol. Yellow solid (49%). Mp
260 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
d
54.9 (CH3), 97.1 (C), 123.5 (CH), 128.5 (CH), 128.7 (CH), 134.3 (CH),
146.6 (C),150.2 (C),160.2 (C),168.1 (C). LC/MS (ESIþ) tR 4.45 min, m/z
[MþH]þ 277.05/279.06/281.05. Anal. Calcd for C10H7Cl3N2O: C,
43.28; H, 2.54; N, 10.09. Found: C, 43.67; H, 2.83; N, 10.38.
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d
4.1 (br s, 1H), 7.76e7.82 (m,
2H), 7.87e7.90 (m, 1H), 8.01 (t, J¼8.5 Hz, 1H), 8.17e8.21 (m, 1H),
8.29e8.41 (m, 2H). 13C NMR (CDCl3, 50 MHz):
92.9 (C), 117.3 (C),
d
4.4. General procedure for the preparation of compounds
4e25
120.1 (CH),121.5 (CH),123.4 (CH),126.6 (CH),128.8 (CH),129.5 (CH),
131.4 (C), 135.8 (CH), 136.6 (C), 143.9 (C), 146.3 (C), 150.9 (C), 162.4
(C), 168.2 (C). LC/MS (ESIþ) tR 4.56 min, m/z [MþH]þ 439.86/441.87/
443.87. Anal. Calcd for C16H8Cl3N5O2S: C, 43.61; H, 1.83; N, 15.89.
Found: C, 43.26; H, 2.01; N, 15.48.
A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g,
0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate
heteroarylamine (1.41 mmol, 2 equiv) in toluene (3 mL) was in-
troduced in miniaturized sealed reactor (5 mL). The reaction mix-
ture was irradiated in a monomode microwave oven, for 2 h at
130 ꢀC. After removal of the toluene under reduced pressure, the
residue was purified by silica gel column chromatography and
recrystallized from appropriate solvent.
4.4.6. 6-Methoxy-N-(2-(trichloromethyl)quinazolin-4-yl)benzo[d]
thiazol-2-amine (9). MW: 425.72 g/mol. Pale yellow solid (76%). Mp
188 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
d
3.56 (br s, 1H), 3.82 (s,
3H), 7.04 (dd, J¼8.8 Hz, J¼2.5 Hz, 1H), 7.56e7.61 (m, 2H), 7.74e7.82

A. Gellis et al. / Tetrahedron 70 (2014) 8257e8266
8263
(m, 1H), 7.98e7.99 (m, 2H), 8.73e8.77 (m, 1H). 13C NMR (DMSO-d6,
50 MHz): 56.2 (CH3), 97.9 (C), 105.6 (C), 115.9 (2CH), 124.6 (CH),
[MþH]þ 378.02/379.97/382.11. Anal. Calcd for C16H10Cl3N5: C,
d
50.75; H, 2.66; N, 18.50. Found: C, 50.61; H, 2.70; N, 18.63.
128.6 (CH), 128.8 (CH), 129.2 (CH), 129.8 (C), 135.1 (CH), 141.3 (C),
149.4 (C), 156.6 (C), 156.8 (C), 159.6 (C), 168.7 (C). LC/MS (ESIþ) tR
4.86 min, m/z [MþH]þ 424.95/426.92/428.94. Anal. Calcd for
4.4.12. N-(Quinolin-2-yl)-2-(trichloromethyl)quinazolin-4-amine
(15). MW:
205 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
389.67
g/mol.
Yellow
solid
(38%).
Mp
C
17H11Cl3N4OS: C, 47.96; H, 2.60; N, 13.16. Found: C, 48.31; H, 2.49;
N, 13.32.
d
7.54 (t, J¼7.5 Hz, 1H),
7.72e7.81 (m, 2H), 7.90e8.01 (m, 4H), 8.41e8.45 (m, 1H), 8.58e8.62
4.4.7. 6-Fluoro-N-(2-(trichloromethyl)quinazolin-4-yl)benzo[d]thia-
zol-2-amine (10). MW: 413.68 g/mol. Beige solid (65%). Mp
249 ꢀC (isopropanol). Eluent(column chromatography) CH2Cl2/AcOEt
(m, 1H), 8.86e8.90 (m, 1H), 11.26 (br s, 1H). 13C NMR (DMSO-d6,
50 MHz):
d 98.1 (C), 115.2 (C), 117.7 (CH), 124.6 (CH), 124.7 (CH),
126.2 (CH), 128.5 (CH), 128.8 (C), 129.1 (CH), 129.3 (CH), 131.2 (CH),
135.3 (CH), 136.3 (C), 139.3 (CH), 149.6 (C), 152.3 (C), 159.7 (C), 159.8
(C). LC/MS (ESIþ) tR 5.20 min, m/z [MþH]þ 388.97/391.03/393.05.
Anal. Calcd for C18H11Cl3N4: C, 55.48; H, 2.85; N, 14.38. Found: C,
55.86; H, 2.74; N, 14.17.
9:1. 1H NMR (DMSO-d6, 200 MHz):
d
5.74 (br s,1H), 7.12e7.18 (m,1H),
7.55e7.65 (m, 3H), 7.89e7.96 (m, 1H), 8.11e8.15 (m, 1H), 8.24e8.28
(m, 1H). 13C NMR (DMSO-d6, 50 MHz):
d
97.7 (C), 109.1 (d, J¼26.5 Hz,
CH),115.0 (d, J¼23.1 Hz, CH),116.0 (C),124.6 (CH),125.8 (C),128.7 (C),
128.9(CH),129.3(CH),129.4(CH),135.4(CH),136.7(C),149.4(C),156.7
(C), 159.5 (C), 163.3 (d, J¼240.0 Hz, C). LC/MS (ESIþ) tR 4.95 min, m/z
[MþH]þ 412.98/414.85/416.81. Anal. Calcd for C16H8Cl3FN4S: C, 46.45;
H, 1.95; N, 13.54. Found: C, 46.08; H, 2.04; N, 13.59.
4.4.13. N-(1H-Indol-5-yl)-2-(trichloromethyl)quinazolin-4-amine
(16). MW:
Mp>350 ꢀC (isopropanol). Eluent (column chromatography)
CH2Cl2/AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
6.42 (m, 1H),
377.66
g/mol.
Pale
yellow
solid
(51%).
d
4.4.8. 6-Methyl-N-(2-(trichloromethyl)quinazolin-4-yl)benzo[d]thia-
zol-2-amine (11). MW: 409.72 g/mol. Pale yellow solid (61%). Mp
248 ꢀC (isopropanol). Eluent(column chromatography) CH2Cl2/AcOEt
7.33e7.48 (m, 2H), 7.58e7.76 (m, 2H), 7.85e7.92 (m, 2H), 8.20e8.22
(m, 1H), 8.73 (d, J¼8.2 Hz, 1H), 10.23 (br s, 1H), 11.16 (br s, 1H). 13
C
NMR (DMSO-d6, 50 MHz):
d 98.7 (C), 101.8 (CH), 111.4 (CH), 113.9
9:1. 1H NMR (DMSO-d6, 200 MHz):
d
2.40 (s, 3H), 4.88 (br s, 1H), 7.28
(C), 114.4 (CH), 117.8 (CH), 118.9 (CH), 123.9 (CH), 126.5 (CH), 128.3
(CH), 128.8 (CH), 130.7 (C), 133.7 (C), 139.3 (C), 149.2 (C), 158.9 (C),
161.3 (C). LC/MS (ESIþ) tR 3.64 min, m/z [MþH]þ 377.02/379.00/
381.11. Anal. Calcd for C17H11Cl3N4: C, 54.07; H, 2.94; N, 14.84.
Found: C, 54.46; H,2.89; N, 14.69.
(d, J¼8.0 Hz, 1H), 7.55 (d, J¼¼10.0 Hz, 1H), 7.75e7.83 (m, 2H),
7.96e8.05 (m, 2H), 8.73 (d, J¼8.0 Hz, 1H). 13C NMR (DMSO-d6,
50 MHz): d 21.39 (CH3), 97.9 (C),116.8 (C),122.3 (CH),124.8 (CH),128.4
(CH),128.8 (CH),129.1 (CH),129.5 (CH),132.0 (C),133.6 (C),135.8 (CH),
146.3 (C), 149.5 (C), 159.7 (C), 162.4 (C), 167.4 (C). LC/MS (ESIþ) tR
5.58 min, m/z [MþH]þ 408.96/411.08/413.06. Anal. Calcd for
4.4.14. N-(1H-Indazol-6-yl)-2-(trichloromethyl)quinazolin-4-amine
(17). MW: 378.64 g/mol. Pale yellow solid (63%). Mp
230 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
C17H11Cl3N4S: C, 49.83; H, 2.71; N, 13.67. Found: C, 50.17; H, 2.63; N,
13.89.
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
d 5.20 (br s, 1H),
4.4.9. 5-Chloro-N-(2-(trichloromethyl)quinazolin-4-yl)benzo[d]ox-
azol-2-amine (12). MW: 411.95 g/mol. Beige solid (75%). Mp
264 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
d 5.07 (br s, 1H), 7.23e7.28
(m, 1H), 7.37e7.47 (m, 2H), 7.66e7.74 (m, 1H), 7.87e8.05 (m, 2H),
7.60e7.82 (m, 3H), 7.91e8.01 (m, 3H), 8.60e8.62 (m, 1H), 8.80 (d,
J¼8.2 Hz, 1H), 10.39 (br s, 1H). 13C NMR (DMSO-d6, 50 MHz):
d 98.5
(C), 102.8 (CH), 114.6 (C), 117.0 (CH), 120.01 (C), 120.5 (CH), 124.3
(CH), 128.5 (CH), 129.0 (CH), 133.6 (CH), 134.6 (CH), 137.4 (C), 140.7
(C), 149.5 (C), 158.9 (C), 160.7 (C). LC/MS (ESIþ) tR 3.68 min, m/z
[MþH]þ 378.04/380.06/382.06. Anal. Calcd for C16H10Cl3N5: C,
50.75; H, 2.66; N, 18.50. Found: C, 50.98; H, 2.57; N, 18.46.
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
8.73 (dd, J¼1.0 Hz, J¼8.1 Hz, 1H). 13C NMR (CDCl3, 50 MHz):
d 95.4
(C), 111.2 (CH), 114.7 (CH), 120.6 (C), 124.3 (CH), 125.9 (CH), 128.7
(CH), 129.1 (CH), 130.4 (C), 134.9 (CH), 135.7 (C), 144.1 (C), 148.2 (C),
154.1 (C), 159.7 (C), 162.4 (C). LC/MS (ESIþ) tR 5.33 min, m/z [MþH]þ
412.95/414.88/416.84. Anal. Calcd for C16H8Cl4N4O: C, 46.41; H,
1.95; N, 13.53. Found: C, 46.53; H, 1.92; N, 13.67 .
4.4.15. N-(1H-1,2,4-Triazol-3-yl)-2-(trichloromethyl)quinazolin-4-
amine (18). MW: 329.57 g/mol. Beige solid (41%). Mp
217 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d 4.58 (br s, 1H), 7.75e7.83
4.4.10. . N-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2-(trichloromethyl)
quinazolin-4-amine (13). MW: 392.67 g/mol. Yellow solid (63%).
Mp 244 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
d 3.84 (s, 3H), 4.90 (br s,
1H), 7.28e7.33 (m, 2H), 7.55e7.70 (m, 3H), 7.82e7.88 (m, 2H), 8.63
(m, 1H), 7.98e8.06 (m, 1H), 8.19 (d, J¼8.3 Hz, 1H), 9.28 (s, 1H), 9.58
(d, J¼8.3 Hz, 1H). 13C NMR (CDCl3, 50 MHz):
d 96.4 (C), 114.6 (C),
127.6 (CH), 129.5 (2CH), 129.9 (CH), 135.6 (CH), 144.7 (CH), 153.2 (C),
153.6 (C), 159.5 (C). LC/MS (ESIþ) tR 3.80 min, m/z [MþH]þ 328.99/
330.93/333.05. Anal. Calcd for C11H7Cl3N6: C, 40.09; H, 2.14; N,
25.50. Found: C, 40.37; H, 2.08; N, 25.32.
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
(d, J¼8.5 Hz, 1H). 13C NMR (DMSO-d6, 50 MHz):
d 28.5 (CH3), 98.6
(C), 109.0 (CH), 111.2 (CH), 120.6 (C), 123.2 (CH), 123.3 (CH), 125.6
(CH), 127.3 (CH), 128.1 (CH), 128.5 (C), 130.5 (C), 133.3 (CH), 149.8
(C), 151.8 (C), 159.9 (C), 165.0 (C). LC/MS (ESIþ) tR 5.55 min, m/z
[MþH]þ 392.01/393.94/396.04. Anal. Calcd for C17H12Cl3N5: C,
52.00; H, 3.08; N, 17.84. Found: C, 52.39; H, 3.01; N, 18.13.
4.4.16. 1-(2-(Trichloromethyl)quinazolin-4-yl)-1H-1,2,4-triazol-3-
amine (19). MW: 329.57 g/mol. Yellow solid (39%). Mp
257 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d 7.83e7.92 (m, 1H), 8.02 (s,
1H), 8.06e8.14 (m, 1H), 8.26 (d, J¼8.3 Hz, 1H), 8.40 (br s, 2H), 9.63
4.4.11. N-(1H-Benzo[d]imidazol-2-yl)-2-(trichloromethyl)quinazolin-
4-amine (14). MW: 378.64 g/mol. Pale yellow solid (52%). Mp
231 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
(d, J¼8.3 Hz, 1H). 13C NMR (CDCl3, 50 MHz):
d 96.2 (C), 115.0 (C),
128.3 (CH), 130.0 (CH), 130.5 (CH), 136.0 (CH), 145.7 (CH), 152.8 (C),
155.6 (C), 155.5 (C), 158.1 (C). LC/MS (ESIþ) tR 4.26 min, m/z [MþH]þ
328.94/330.94/332.94. Anal. Calcd for C11H7Cl3N6: C, 40.09; H, 2.14;
N, 25.50. Found: C, 39.91; H, 2.10; N, 25.67.
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d 2.11 (br s, 1H), 5.99 (br s,
1H), 6.91e7.09 (m, 1H), 7.23e7.31 (m, 3H), 7.51e7.57 (m, 1H),
7.73e7.81 (m, 1H), 8.09e8.38 (m, 2H). 13C NMR (CDCl3, 50 MHz):
d
96.8 (C), 110.5 (CH), 114.8 (CH), 120.2 (C), 121.4 (CH), 124.0 (CH),
4.4.17. N-(2-(Trichloromethyl)quinazolin-4-yl)thiazol-2-amine
125.9 (CH), 129.7 (CH), 131.4 (CH), 132.2 (C), 137.5 (CH), 138.9 (C),
(20). MW:
345.63
g/mol.
Beige
solid
(30%).
Mp
152.5 (C),153.0 (C),157.0 (C),160.1 (C). LC/MS (ESIþ) tR 4.20 min, m/z
175 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/

8264
A. Gellis et al. / Tetrahedron 70 (2014) 8257e8266
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d
6.08 (br s, 1H), 7.20 (d,
128.6 (CH), 128.8 (CH), 134.7 (CH), 136.9 (CH), 139.6 (C), 142.0 (C),
149.6 (C),150.1 (C),159.1 (C),160.5 (C). LC/MS (ESIþ) tR 3.93 min, m/z
[MþH]þ 444.92/446.84/448.75. Anal. Calcd for C21H15Cl3N4O: C,
56.59; H, 3.39; N, 12.57. Found: C, 56.20; H, 3.49; N, 12.89.
J¼4.1 Hz, 1H), 7.57 (d, J¼4.1 Hz, 1H), 7.78e7.89 (m, 1H), 7.96e8.04
(m, 1H), 8.14e8.18 (m, 1H), 8.71 (d, J¼8.5 Hz, 1H). 13C NMR (CDCl3,
50 MHz):
d 98.0 (C), 107.4 (CH), 114.7 (C), 124.6 (CH), 128.8 (CH),
128.9 (CH), 134.8 (CH), 139.5 (CH), 149.2 (C), 158.8 (C), 163.5 (C),
169.3 (C). LC/MS (ESIþ) tR 4.32 min, m/z [MþH]þ 344.98/346.98/
348.98. Anal. Calcd for C12H7Cl3N4S: C, 41.70; H, 2.04; N, 16.21.
Found: C, 41.58; H, 2.17; N, 16.06 .
4.5. General procedure for the preparation of compounds
26e48
A mixture of 4-chloro-2-methylquinazoline 2 (0.2 g, 1.12 mmol),
DMAP (41 mg, 0.34 mmol, 0.3 equiv) and adequate aromatic amine
reagent (2.24 mmol, 2 equiv) in toluene (3 mL) was introduced in
miniaturized sealed reactor (5 mL). The reaction mixture was ir-
radiated in a monomode microwave oven, for 2 h at 130 ꢀC. After
removal of the toluene under reduced pressure, the residue was
purified by silica gel column chromatography, and recrystallized.
4.4.18. N-(Pyridin-2-yl)-2-(trichloromethyl)quinazolin-4-amine
(21). MW:
154 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
6.06 (br s,1H), 7.05e7.11 (m,
339.61
g/mol.
Yellow
solid
(45%).
Mp
d
1H), 7.61e7.70 (m, 1H), 7.80e7.92 (m, 2H), 8.05e8.14 (m, 2H),
8.30e8.33 (m, 1H), 8.90e8.95 (m, 1H). 13C NMR (CDCl3, 50 MHz):
d
97.6 (C), 114.1 (C), 116.1 (CH), 119.5 (CH), 121.6 (CH), 128.8 (CH),
129.7 (CH), 134.2 (CH), 139.9 (CH), 145.9 (CH), 149.7 (C), 151.5 (C),
157.4 (C), 160.2 (C). LC/MS (ESIþ) tR 4.27 min, m/z [MþH]þ 339.06/
340.99/343.04. Anal. Calcd for C14H9Cl3N4: C, 49.51; H, 2.67; N,
16.50. Found: C, 49.42; H, 2.61; N, 16.59.
4.5.1. N-(2-Methylquinazolin-4-yl)benzo[d]thiazol-2-amine
(26). MW:
268 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
2.68 (s, 3H), 7.29e7.33 (m,
1H), 7.39e7.54 (m, 2H), 7.64e7.82 (m, 4H), 8.53e8.57 (d, J¼8.1 Hz,
1H). 13C NMR (CDCl3, 50 MHz):
22.8 (CH3), 120.0 (C), 120.6 (CH),
292.36
g/mol.
Yellow
solid
(87%).
Mp
d
4.4.19. N-(5-Chloropyridin-2-yl)-2-(trichloromethyl)quinazolin-4-
amine (22). MW: 374.05 g/mol. Yellow solid (60%). Mp
196 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
d
121.4 (2CH), 123.8 (CH), 125.8 (CH), 126.3 (CH), 127.0 (CH), 132.2 (C),
134.2 (CH), 147.9 (C), 150.7 (C), 151.1 (C), 151.8 (C), 173.4 (C). LC/MS
(ESIþ) tR 4.17 min, m/z [MþH]þ 293.18. Anal. Calcd for C16H12N4S: C,
65.73; H, 4.14; N, 19.16. Found: C, 65.51; H, 4.09; N, 19.31.
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d 7.68e7.97 (m, 3H),
8.04e8.13 (m, 2H), 8.30 (d, J¼2.5 Hz, 1H), 8.58 (br s, 1H), 8.94 (d,
J¼8.9 Hz, 1H). 13C NMR (CDCl3, 50 MHz):
d 97.3 (C), 113.9 (C), 116.6
(CH), 121.3 (CH), 126.7 (C), 129.1 (CH), 130.1 (CH), 134.5 (CH), 139.9
(CH), 144.6 (CH), 149.7 (C), 149.8 (C), 156.9 (C), 159.9 (C). LC/MS
(ESIþ) tR 5.05 min, m/z [MþH]þ 372.98/374.94/376.95. Anal. Calcd
for C14H8Cl4N4: C, 44.95; H, 2.16; N, 14.98. Found: C, 45.12; H, 2.19;
N, 14.79.
4.5.2. 4-Chloro-N-(2-methylquinazolin-4-yl)benzo[d]thiazol-2-
amine (27). MW: 326.80 g/mol. Yellow solid (81%). Mp
266 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d 2.70 (s, 3H), 7.26 (t,
J¼7.9 Hz, 1H), 7.48e7.95 (m, 6H), 8.76 (br s, 1H). 13C NMR (CDCl3,
50 MHz):
d 24.8 (CH3), 119.8 (C), 120.9 (CH), 121.0 (CH), 124.4 (CH),
4.4.20. N-(Pyridin-3-yl)-2-(trichloromethyl)quinazolin-4-amine
124.5 (CH), 126.5 (CH), 127.1 (CH), 129.1 (C), 132.1 (C), 134.7 (CH),
135.1 (C), 145.9 (C), 156.0 (C), 158.2 (C), 167.4 (C). LC/MS (ESIþ) tR
5.12 min, m/z [MþH]þ327.01/328.98/331.22. Anal. Calcd for
(23). MW:
222 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
339.61
g/mol.
Yellow
solid
(47%).
Mp
d
7.48 (dd, J¼8.3 Hz,
C16H11ClN4S: C, 58.80; H, 3.39; N, 17.14. Found: C, 58.59; H, 3.44; N,
J¼4.8 Hz, 1H), 7.76e7.84 (m, 1H), 7.93e8.04 (m, 2H), 8.36 (d,
J¼3.9 Hz, 1H), 8.44e8.48 (m, 1H), 8.66e8.70 (d, J¼8.3 Hz, 1H), 9.19
(d, J¼2.1 Hz, 1H), 10.38 (br s, 1H). 13C NMR (DMSO-d6, 50 MHz):
17.32.
4.5.3. 5,6-Dimethyl-N-(2-methylquinazolin-4-yl)benzo[d]thiazol-2-
amine (28). MW: 320.41 g/mol. Yellow solid (65%). Mp
212 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
d
98.2 (C), 114.6 (C), 123.9 (CH), 124.1 (CH), 128.9 (CH), 129.2 (CH),
129.8 (CH), 135.0 (CH), 136.3 (C), 143.1 (CH), 144.7 (CH), 149.4 (C),
159.1 (C), 160.3 (C). LC/MS (ESIþ) tR 3.85 min, m/z [MþH]þ 339.02/
341.01/342.91. Anal. Calcd for C14H9Cl3N4: C, 49.51; H, 2.67; N,
16.50. Found: C, 49.69; H, 2.70; N, 16.44.
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
d
2.37 (s, 3H), 2.38 (s, 3H),
2.86 (s, 3H), 7.46e7.77 (m, 5H), 8.50e8.54 (d, J¼7.9 Hz, 1H), 14.58
(br s, 1H). 13C NMR (DMSO-d6, 50 MHz):
20.1 (CH3), 20.2 (CH3),
d
22.8 (CH3), 120.1 (C), 121.1 (CH), 121.5 (2CH), 125.7 (CH), 126.9 (CH),
129.5 (C), 133.1 (C), 134.1 (CH), 135.1 (C), 147.8 (C), 149.3 (C), 151.2
(C), 151.4 (C), 173.4 (C). LC/MS (ESIþ) tR 4.80 min, m/z [MþH]þ
321.18. Anal. Calcd for C18H16N4S: C, 67.47; H, 5.03; N, 17.49. Found:
C, 67.19; H, 5.13; N, 17.65.
4.4.21. N-(Pyridin-4-yl)-2-(trichloromethyl)quinazolin-4-amine
(24). MW:
254 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
7.80e7.88 (m, 1H),
339.61
g/mol.
Yellow
solid
(41%).
Mp
d
7.97e8.07 (m, 2H), 8.12e8.15 and 8.54e8.56 (2d, A2B2 Syst, 4H),
8.73 (d, J¼8.2 Hz, 1H), 10.47 (br s, 1H). 13C NMR (DMSO-d6, 50 MHz):
4.5.4. 6-Chloro-N-(2-methylquinazolin-4-yl)benzo[d]thiazol-2-
amine (29). MW: 326.8 g/mol. Yellow solid (72%). Mp
211 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
d
97.9 (C), 114.9 (C), 115.8 (2CH), 124.3 (CH), 129.3 (CH), 129.4 (CH),
135.5 (CH), 147.7 (2CH), 149.0 (C), 149.7 (C), 159.1 (C), 159.9 (C). LC/
MS (ESIþ) tR 4.01 min, m/z [MþH]þ 339.08/341.07/343.07. Anal.
Calcd for C14H9Cl3N4: C, 49.51; H, 2.67; N, 16.50. Found: C, 49.73; H,
2.62; N, 16.39.
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
d 2.69 (s, 3H), 7.41e7.91
(m, 5H), 8.09 (d, J¼2.1 Hz, 1H), 8.62 (d, J¼7.8 Hz, 1H). 13C NMR
(DMSO-d6, 50 MHz):
d 24.9 (CH3), 119.7 (C), 121.0 (CH), 121.7 (CH),
124.5 (CH), 126.9 (CH), 127.0 (CH), 127.8 (CH), 129.4 (C), 132.0 (C),
134.5 (CH), 135.3 (C), 146.2 (C), 156.4 (C), 158.6 (C), 167.2 (C). LC/MS
(ESIþ) tR 4.60 min, m/z [MþH]þ 327.13/329.23/330.68. Anal. Calcd
for C16H11ClN4S: C, 58.80; H, 3.39; N, 17.14. Found: C, 59.11; H, 3.41;
N, 16.95.
4.4.22. N-(3-(Benzyloxy)pyridin-2-yl)-2-(trichloromethyl)quinazo-
lin-4-amine (25). MW: 445.73 g/mol. Yellow solid (35%). Mp
130 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
d 5.07 (s, 2H), 6.93e6.98
(m, 2H), 7.06e7.10 (m, 2H), 7.35e7.41 (m, 1H), 7.59e7.82 (m, 3H),
7.91e7.95 (m, 2H), 8.07e8.10 (m, 1H), 8.55 (d, J¼8.1 Hz, 1H). 13C
4.5.5. N-(2-Methylquinazolin-4-yl)-6-nitrobenzo[d]thiazol-2-amine
NMR (DMSO-d6, 50 MHz):
d
69.8 (CH2), 98.3 (C), 114.1 (C), 121.1
(30). MW:
337.36
g/mol.
Yellow
solid
(49%).
Mp
(CH), 123.7 (CH), 124.1 (CH), 127.1 (2CH), 128.1 (CH), 128.5 (2CH),
263 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/

A. Gellis et al. / Tetrahedron 70 (2014) 8257e8266
8265
AcOEt 9:1. 1H NMR (DMSO-d6, 200 MHz):
1H), 7.60e7.90 (m, 4H), 8.22e8.26 (m, 1H), 8.60e8.63 (m, 1H),
8.93e8.94 (m, 1H). 13C NMR (DMSO-d6, 50 MHz):
24.6 (CH3), 119.6
d
2.72 (s, 3H), 5.73 (br s,
1H NMR (200 MHz, CDCl3)
7.82e7.96 (m, 1H), 8.00e8.13 (m, 4H), 8.53 (br s, 1H).
d
: 7.41e7.58 (m, 2H), 7.66e7.74 (m, 1H),
d
(C), 119.0 (CH), 119.5 (CH), 119.8 (C), 122.2 (CH), 125.1 (CH), 127.1
(CH), 127.3 (CH), 133.9 (C), 134.8 (CH), 135.3 (C), 145.9 (C), 156.9 (C),
160.8 (C), 168.0 (C). LC/MS (ESIþ) tR 3.84 min, m/z [MþH]þ 338.14.
Anal. Calcd for C16H11N5O2S: C, 56.96; H, 3.29; N, 20.76. Found: C,
57.21; H, 3.25; N, 20.64.
4.5.15. N-(2,4-Dichlorophenyl)-2-(trichloromethyl)quinazolin-4-
amine (40).6 MW: 407.51 g/mol. White solid (82%). Mp 204 ꢀC. 1H
NMR (200 MHz, CDCl3)
d
: 7.40 (dd, J¼2.4 and 9.0 Hz, 1H), 7.48 (d,
J¼2.4 Hz, 1H), 7.69e7.77 (m, 1H), 7.89e7.98 (m, 2H), 8.07e8.14 (m,
1H), 8.35 (br s, 1H), 9.10 (d, J¼9.0 Hz, 1H).
4.5.6. 2-Methyl-N-(1-methyl-1H-benzo[d]imidazol-2-yl)quinazolin-
4-amine (31). MW: 289.33 g/mol. Pale yellow solid (83%). Mp
178 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
4.5.16. 2-Methyl-N-phenylquinazolin-4-amine
235.28 g/mol. Beige solid (91%). Mp 166 ꢀC (lit. 163e165 ꢀC).25 1H
NMR (200 MHz, CDCl3) : 2.65 (s, 3H), 7.32 (m, 1H), 7.49 (m, 2H),
7.77 (m, 4H), 8.15 (m, 1H), 8.59 (dd, J¼7.5 Hz, 1H).
(41).25 MW:
d
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d
2.71 (s, 3H), 3.89 (s, 3H),
7.23e7.28 (m, 3H), 7.44e7.73 (m, 4H), 8.56 (d, J¼7.9 Hz, 1H), 14.56
(br s, 1H). 13C NMR (CDCl3, 50 MHz):
23.3 (CH3), 28.7 (CH3), 108.8
d
4.5.17. N-(4-Chlorophenyl)-2-methylquinazolin-4-amine
(CH), 116.4 (CH), 120.5 (C), 122.0 (CH), 122.2 (CH), 125.3 (2CH), 126.5
(CH), 133.0 (C), 133.7 (CH), 135.6 (C), 147.7 (C), 153.4 (C), 154.2 (C),
154.9 (C). LC/MS (ESIþESIþ) tR 4.18 min, m/z [MþH]þ 290.14. Anal.
Calcd for C17H15N5: C, 70.57; H, 5.23; N, 24.21. Found: C, 70.50; H,
5.27; N, 24.32.
(42).26 MW: 269.73 g/mol. Pale beige solid (92%). Mp 204 ꢀC (lit.
203e205 ꢀC).26 1H NMR (200 MHz, CDCl3)
d: 2.73 (s, 3H), 7.47 (d,
J¼8.8 Hz, 2H), 7.78 (d, J¼8.8 Hz, 2H), 7.83 (m, 2H), 8.09 (t, J¼7.8 Hz,
1H), 8.61 (d, J¼8.3 Hz, 1H).
4.5.18. 2-Methyl-N-p-tolylquinazolin-4-amine
249.31 g/mol. White solid (87%). Mp 270 ꢀC (lit. 265e268 ꢀC).26 1H
NMR (200 MHz, CDCl3)
(43).26 MW:
4.5.7. 5-Chloro-N-(2-methylquinazolin-4-yl)benzo[d]oxazol-2-
amine (32). MW: 310.74 g/mol. Beige solid (78%). Mp
218 ꢀC (isopropanol). Eluent (column chromatography) CH2Cl2/
d
: 2.41 (s, 3H), 2.66 (s, 3H), 7.28 (d, J¼8.2 Hz,
2H), 7.62 (d, J¼8.2 Hz, 2H), 7.77 (m, 2H), 8.02 (m, 1H), 8.54 (m, 1H).
AcOEt 9:1. 1H NMR (CDCl3, 200 MHz):
d 2.75 (s, 3H), 7.18e7.40 (m,
2H), 7.50e7.58 (m, 2H), 7.72e7.86 (m, 2H), 8.57 (d, J¼7.5 Hz,1H). 13
C
4.5.19. 2-Methyl-N-(4-nitrophenyl)quinazolin-4-amine (44).26 MW:
280.28 g/mol. Pale yellow solid (97%). Mp 141 ꢀC (lit. 138e141 ꢀC).26
NMR (CDCl3, 50 MHz): d 22.7 (CH3), 110.7 (CH), 117.7 (CH), 119.7 (C),
123.8 (CH), 125.8 (2CH), 126.7 (C), 127.5 (CH), 129.6 (C), 135.05 (CH),
141.6 (C), 145.9 (C), 147.4 (C), 151.3 (C), 155.1 (C), 165.2 (C). LC/MS
(ESIþ) tR 4.38 min, m/z [MþH]þ 311.20/313.14. Anal. Calcd for
1H NMR (200 MHz, CDCl3)
8.36 (m, 2H), 8.60 (m, 1H).
d: 2.74 (s, 3H), 7.84 (m, 2H), 8.15 (m, 3H),
C
16H11ClN4O: C, 61.84; H, 3.57; N, 18.03. Found: C, 61.97; H, 3.49; N,
4.5.20. N-(3-Methoxyphenyl)-2-methylquinazolin-4-amine
17.89.
(45).26 MW: 265.31 g/mol. Pale beige solid (95%). Mp 218 ꢀC (lit.
220e221 ꢀC).26 1H NMR (200 MHz, CDCl3)
d: 2.72 (s, 3H), 3.85 (s,
4.5.8. N-Phenyl-2-trichloromethylquinazolin-4-amine (33).6 MW:
3H), 6.30 (m, 1H), 7.40 (m, 3H), 7.82 (m, 2H), 8.09 (t, J¼7.5 Hz, 1H),
338.62 g/mol. Beige solid (90%). Mp 150 ꢀC. 1H NMR (200 MHz,
8.60 (d, J¼8.3 Hz, 1H).
CDCl3) d: 7.15e7.23 (m, 1H), 7.40e7.48 (m, 2H), 7.62e7.71 (m, 2H),
7.84e7.88 (m, 1H), 7.93e7.99 (m, 3H), 8.07e8.11 (m, 1H).
4.5.21. N-(3-Chlorophenyl)-2-methylquinazolin-4-amine
(46).6 MW: 269.73 g/mol. Beige solid (97%). Mp 171 ꢀC. 1H NMR
4.5.9. N-(4-Chlorophenyl)-2-(trichloromethyl)quinazolin-4-amine
(200 MHz, CDCl3)
d
: 2.72 (s, 3H), 7.11 (dd, J¼0.9 and 8.0 Hz, 1H), 7.32
(34).6 MW: 373.06 g/mol. Yellow solid (85%). Mp 208 ꢀC. 1H NMR
(dd, J¼8.0 and 8.2 Hz, 1H), 7.50 (dd, J¼0.9 and 8.0 Hz, 1H), 7.64e7.88
(200 MHz, CDCl3)
d: 7.36e7.43 (m, 2H), 7.64e7.71 (m, 2H),
(m, 5H), 8.01 (br s, 1H).
7.85e7.95 (m, 4H), 8.07e8.11 (m, 1H).
4.5.22. 2-Methyl-N-(3-(trifluoromethyl)phenyl)quinazolin-4-amine
(47).7 MW: 303.28 g/mol. Beige solid (98%). Mp 178 ꢀC. 1H NMR
4.5.10. N-(p-Tolyl)-2-(trichloromethyl)quinazolin-4-amine
(35).6 MW: 352.65 g/mol. Yellow solid (89%). Mp 146 ꢀC. 1H NMR
(200 MHz, CDCl3)
d: 2.72 (s, 3H), 7.40 (d, J¼7.7 Hz, 1H), 7.52 (dd,
(200 MHz, CDCl3)
d
: 2.23 (s, 3H), 7.03e7.07 (m, 2H), 7.43e7.52 (m,
J¼7.3 and 7.7 Hz, 2H), 7.74e8.06 (m, 5H), 8.23 (br s, 1H).
1H), 7.69e7.83 (m, 5H), 7.91e7.95 (m, 1H).
4.5.23. N-(2,4-Dichlorophenyl)-2-methylquinazolin-4-amine
4.5.11. N-(4-Nitrophenyl)-2-(trichloromethyl)quinazolin-4-amine
(48).6 MW: 304.17 g/mol. Beige solid (98%). Mp 154 ꢀC. 1H NMR
(200 MHz, CDCl3) d: 2.75 (s, 3H), 7.32e7.38 (m, 1H), 7.45e7.46 (m,
(36).6 MW: 383.62 g/mol. Yellow solid (96%). Mp 294 ꢀC. 1H NMR
(200 MHz, DMSO-d6)
8.27e8.39 (m, 4H), 8.74 (d, J¼8.3 Hz, 1H), 10.65 (s, 1H).
d
: 7.81e7.89 (m, 1H), 8.00e8.08 (m, 2H),
1H), 7.52e7.60 (m, 1H), 7.77e7.85 (m, 1H), 7.90e7.94 (m, 2H), 8.19
(br s, 1H), 8.88 (d, J¼8.3 Hz, 1H).
4.5.12. N-(3-Methoxyphenyl)-2-(trichloromethyl)quinazolin-4-
4.6. Procedure for the preparation of N-methyl-N-(1-(2-(tri-
chloromethyl)quinazolin-4-yl)pyridine-4(1H)-ylidene)meth-
anaminium chloride (49)
amine (37).6 MW: 368.64 g/mol. Yellow solid (98%). Mp 142 ꢀC. 1H
NMR (200 MHz, CDCl3) d: 3.89 (s, 3H), 6.71e6.76 (m, 1H), 7.14e7.33
(m, 2H), 7.66e7.70 (m, 2H), 7.84e7.93 (m, 2H), 8.05e8.12 (m, 2H).
A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g,
0.71 mmol) and 1.0 equiv of DMAP (87 mg, 0.78 mmol) in toluene
(3 mL) was introduced in miniaturized sealed reactor (5 mL). The
reaction mixture was irradiated in a monomode microwave oven,
for 30 min at 130 ꢀC. After removal of the toluene under reduced
pressure, the residue was purified by silica gel column chroma-
tography, using dichloromethane/ethyl acetate (7:3), afforded
0.28 g of compound 49. White solid (100%), MW: 404.12 g/mol. Mp
4.5.13. N-(3-Chlorophenyl)-2-(trichloromethyl)quinazolin-4-amine
(38).6 MW: 373.06 g/mol. Beige solid (97%). Mp 174 ꢀC. 1H NMR
(200 MHz, CDCl3)
d: 7.11e7.17 (m, 1H), 7.25e7.37 (m, 1H),
7.63e7.75 (m, 3H), 7.85e7.95 (m, 2H), 8.06e8.11 (m, 1H),
8.21e8.23 (m, 1H).
4.5.14. 2-(Trichloromethyl)-N-(3-(trifluoromethyl)phenyl)quinazo-
lin-4-amine (39).6 MW: 406.62 g/mol. Beige solid (91%). Mp 139 ꢀC.
199 ꢀC (dec). 1H NMR (200 MHz, CDCl3)
d: 3.55 (s, 6H), 7.64e7.68 (d,

8266
A. Gellis et al. / Tetrahedron 70 (2014) 8257e8266
ꢂ
6. Verhaeghe, P.; Azas, N.; Hutter, S.; Castera-Ducros, C.; Laget, M.; Dumetre, A.;
Gasquet, M.; Reboul, J.-P.; Rault, S.; Rathelot, P.; Vanelle, P. Bioorg. Med. Chem.
2009, 17, 4313e4322.
J¼7.8 Hz, 2H), 7.99e8.07 (m, 1H), 8.15e8.23 (m, 1H), 8.31e8.39 (m,
2H), 8.83 (d, J¼7.8 Hz, 2H). 13C NMR (CDCl3, 50 MHz):
d 41.4 (2CH3),
95.4 (C), 109.5 (2CH), 115.9 (C), 123.6 (CH), 130.1 (CH), 132.0 (CH),
136.8 (CH), 140.7 (2CH), 152.6 (C), 157.5 (C), 158.6 (C), 159.5 (C). LC/
MS (ESIþ) tR 3.24 min, m/z [MþH]þ 367.04/369.10/371.12. HRMS
(ESIþ) m/z 367.0281 [MþH]þ, calcd for C16H14Cl3N4: 367.0278.
ꢂ
7. Castera-Ducros, C.; Azas, N.; Verhaeghe, P.; Hutter, S.; Garrigue, P.; Dumetre, A.;
Mbatchi, L.; Laget, M.; Remusat, V.; Sifredi, F.; Rault, S.; Rathelot, P.; Vanelle, P.
Eur. J. Med. Chem. 2011, 46, 4184e4191.
ꢂ
8. Verhaeghe, P.; Dumetre, A.; Castera-Ducros, C.; Hutter, S.; Laget, M.; Fersing, C.;
Prieri, M.; Yzombard, J.; Sifredi, S.; Rault, S.; Rathelot, P.; Vanelle, P.; Azas, N.
Bioorg. Med. Chem. Lett. 2011, 21, 6003e6006.
ꢂ
9. Primas, N.; Verhaeghe, P.; Cohen, A.; Kieffer, C.; Dumetre, A.; Hutter, S.; Rault,
4.6.1. Crystal data for compound 49. C18H17Cl4N5, M¼445.17, tri-
S.; Rathelot, P.; Azas, N.; Vanelle, P. Molecules 2012, 17, 8105e8117.
10. Since, M.; Khoumeri, O.; Verhaeghe, P.; Maillard-Boyer, M.; Terme, T.; Vanelle, P.
Tetrahedron Lett. 2011, 52, 3810e3813.
11. Verhaeghe, P.; Rathelot, P.; Gellis, A.; Rault, S.; Vanelle, P. Tetrahedron 2006, 62,
8173e8176.
ꢁ
ꢁ
ꢁ
a
ꢁ
clinic, a¼9.0976 (3) A, b¼10.2471 (3) A, c¼12.0374 (4) A, ¼96.152
3
(3)ꢀ,
b
¼111.436 (3)ꢀ,
g
¼97.826 (2) , V¼1019.73 (6) A , T¼223 K,
ꢀ
space group P-1, Z¼2.
12. Kappe, C. O.; Dallinger, D. Mol. Divers. 2009, 13, 71e193.
13. Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325e3355.
14. Kabri, Y.; Verhaeghe, P.; Gellis, A.; Vanelle, P. Molecules 2010, 15, 2949e2961.
15. Gellis, A.; Njoya, Y.; Crozet, M. P.; Vanelle, P. Synth. Commun. 2001, 31,
1257e1262.
16. Djekou, S.; Gellis, A.; El-Kashef, H.; Vanelle, P. J. Heterocyclic Chem. 2006, 43,
1225e1229.
17. Kabri, Y.; Gellis, A.; Vanelle, P. Eur. J. Org. Chem. 2009, 4059e4066.
18. Kappe, C. O.; Dallinger, D.; Murphree, S. S. Practical Microwave Synthesis for
Organic Chemists: Strategies Instruments and Protocols; Wiley-VCH: Weinheim,
Germany, 2009.
Acknowledgements
This work was supported by the Centre National de la Recherche
Scientifique (CNRS) and Aix-Marseille Universite (AMU). C.K.
thanks the Assistance Publique-Hopitaux de Marseille (AP-HM) for
ꢀ
^
hospital appointment. The authors warmly thank Vincent Remusat
for the 1H and 13C NMR spectra recording.
19. Suzuki, M.; Kondo, K.; Kurimura, M.; Valluru, K. -R.; Takahashi, A.; Kuroda, T.;
Takahashi, H.; Fukushima, T.; Miyamura, S.; Ghosh, I.; Dogra, A.; Harriman, G.;
Elder, A.; Shimizu, S.; Hodgetts, K.; Newcom, J. Quinazolines as therapeutic
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