A DMAP-catalyzed mild and efficient synthesis of 1,2-dihydroquinazolines via a one-pot three-component protocol

Article abstract of DOI:10.1016/j.tetlet.2013.10.157

An efficient and simple method for the synthesis of 1,2-dihydroquinazolines catalyzed by 4-(N,N-dimethylamino)pyridine (DMAP) from readily available aromatic or heteroaromatic aldehydes, 2-aminobenzophenone, and ammonium acetate under mild conditions is described. The scope and limitations of the method are discussed.

Full text of DOI:10.1016/j.tetlet.2013.10.157

Tetrahedron Letters 55 (2014) 200–204
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A DMAP-catalyzed mild and efficient synthesis of
1,2-dihydroquinazolines via a one-pot three-component protocol
b
c
a
Chamseddine Derabli a, Raouf Boulcina a, , Gilbert Kirsch , Bertrand Carboni , Abdelmadjid Debache
⇑
a Laboratoire de Synthèse des Molécules d’intérêts Biologiques, Université de Constantine 1, 25000 Constantine, Algeria
b SRSMC site Messin UMR 6575, Université de Lorraine, 57070 Metz, France
c Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and simple method for the synthesis of 1,2-dihydroquinazolines catalyzed by 4-(N,N-dimeth-
ylamino)pyridine (DMAP) from readily available aromatic or heteroaromatic aldehydes, 2-aminobenzo-
phenone, and ammonium acetate under mild conditions is described. The scope and limitations of the
method are discussed.
Received 23 June 2013
Revised 10 October 2013
Accepted 31 October 2013
Available online 8 November 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
1,2-Dihydroquinazolines
DMAP
2-Aminobenzophenone
Six-membered heterocycles, such as quinazolines have been re-
ported to possess diverse biological and therapeutic properties
including anti-inflammatory,1 antibacterial,2 antiplasmodial,3 anti-
tumor,4 antimicrobial, and anti-oxidant.5 They have been also used
as photochemotherapeutic agents,6 DNA-gyrase, JAK2, PDE5, and
EGFR tyrosine kinase inhibitors,7 as well as CB2 receptor agonists.8
In addition, quinazolines are commonly found as building blocks
for a wide variety of natural products such as alkaloids and in var-
ious other microorganisms including Bouchardatia neurococca, Peg-
anum nigellastrum, Bacillus cereus, and Dichroa febrifuga.9 In a
recent report, 3,4-dihydroquinazolines have been found to have
excellent T-type calcium channel blocking activity.10
The development of quinazoline-based drugs has renewed the
interest in developing new synthetic strategies for the synthesis
of quinazolines. Numerous procedures have been reported, such
as copper-catalyzed syntheses,11 photochemical methods,12 the
use of microwave irradiation,13 a maltose-urea-NH4Cl mixture as
a solvent without any catalyst,14 tandem reactions from 2-amino-
benzophenones and benzylic amines,15 and copper-catalyzed
Ullmann N-arylation coupling.16
the generation of 1,2-dihydroquinazolines. Other synthetic ap-
proaches toward 1,2-dihydroquinazolines are based on the reac-
tion of 2-aminobenzonitriles with Grignard reagents, followed by
condensation with an aldehyde.20 The yield of the reaction was
very poor under such conditions due to competitive side reactions.
Moreover, an inert atmosphere and long reaction time were
necessary. Also, 2-carboxylic acid derivatives of 1,2-dihydroqui-
nazoline21 were synthesized from 2-hydroxyglycine and 2-amino-
benzophenones wherein the stabilities of the products were
compromised as they tended to decompose in solution.
The reactions of 2-aminobenzophenones with various alde-
hydes and ammonia have been shown to result in a mixture of qui-
nazoline and dihydroquinazoline derivatives in a variable ratio
depending on the nature of the aldehydes as well as the employed
reaction conditions.22 The reaction apparently suffers from disad-
vantages such as a lack of selectivity often leading to a mixture
of products and a cumbersome work-up procedure. Therefore, im-
proved and environmentally benign approaches that allow for the
rapid, cost-effective syntheses of quinazolines from readily avail-
able precursors are desirable.
However, only a few examples of the preparation of 1,2-
dihydroquinazolines have been reported in the literature. The
reaction of 2-aminobenzamidine with benzaldehyde17 or acetone18
and microwave irradiation of 2-(aminoaryl)alkanone O-phenyl
oximes with carbonyl compounds19 are two such methods for
4-(N,N-Dimethylamino)pyridine (DMAP) has been widely used
in many organic syntheses as a catalyst, for example, in acylation
reactions,23 aldol reactions,24 and Baylis–Hillman reactions.25 It
has been also used in Michael additions26 and esterification reac-
tions in water.27
In the context of our studies on the development of
efficient catalytic organic synthesis,28 we have focused on the
utility of DMAP as a catalyst for the synthesis of a series of
⇑
Corresponding author. Tel./fax: +213 31 81 88 62.
E-mail address: boulcinaraouf@yahoo.fr (R. Boulcina).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.157

C. Derabli et al. / Tetrahedron Letters 55 (2014) 200–204
201
1,2-dihydroquinazolines via reactions between readily available
aldehydes (1), 2-aminobenzophenone (2), and ammonium acetate
(3) in ethanol under mild conditions (Scheme 1).
Initially, a model reaction was conducted, without any catalyst,
between 4-chlorobenzaldehyde (1h) (0.5 mmol), 2-aminobenzo-
phenone (2) (0.5 mmol), and ammonium acetate (3) (1 mmol) in
ethanol at ambient temperature for two hours, which afforded
dihydroquinazoline 4h in moderate yield (Table 1, entry 1). The
O
Ar
O
Ph
NH2
DMAP (20 mol%)
EtOH, 40 °C
N
NH4OAc
H
N
H
Ar
3
1
2
4
Scheme 1. Synthesis of 1,2-dihydroquinazoline derivatives.
Table 1
Optimization of the reaction conditionsa
O
O
Ph
NH2
N
H
NH4OAc
N
H
Cl
3
2
1h
Cl
4h
Entry
Solvent
Time (h)
Catalyst
Catalyst (mol %)
Temperature (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
MeOH
H2O–EtOH
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
2
1
1
1
1
1
2
2
—
—
—
—
—
—
—
—
—
—
—
—
5
10
10
10
10
10
5
15
20
30
20
20
rt
65
78
68
63
—
40
Reflux
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
—
CAN
CAN
PhB(OH)2
SnCl2
17
39
74
71
34
82
82
83
87
85
81
65
9
2
10
11
12
13
14
15
16
17
18
1.5
1.5
1.5
1.5
1
1
1
1.5
1.5
FeCl3Á6H2O
DMAP
DMAP
DMAP
DMAP
DMAP
DABCO
Et3N
a
Reaction conditions: 4-chlorobenzaldehyde (1h) (0.5 mmol), 2-aminobenzophenone (2) (0.5 mmol), NH4OAc (3) (1 mmol), solvent (5 mL).
Isolated yield.
b
Table 2
a
DMAP-catalyzed synthesis of 1,2-dihydroquinazolines
O
Ar
O
Ph
NH2
DMAP (20 mol%)
EtOH, 40 °C
N
N
NH4OAc
H
1
N
H
Ar
3
N
Ar
2
5
4
Entry
Ar
Products
Time (h)
Product ratiob
Yieldc (%)
mp (°C)
Measured
Reported22
1
2
3
4
5
6
7
8
C6H5-
4-Me-C6H4-
2-MeO-C6H4-
4-(Me)2N-C6H4-
C6H5-C6H4-
4-HO-C6H4-
2-Cl-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
3-I-C6H4-
4a:5a
4b:5b
4c:5c
4d:5d
4e:5e
4f:5f
4g:5g
4h:5h
4i:5i
1.5
1
1.5
2
1
2.5
2
1
1.5
1
1.5
1
90:10
90:10
86:14
100:0
84:16
99:trace
100:0
100:0
100:0
75:25
90:10
100:0
84
91
83
76
98
67
78
87
80
86
80
87
94–96
122–124
Gum
95–97
127–129
—
—
—
—
Gum
—
172–174
138–140
200–202
Gum
142–144
178–180
112–114
126–128
134–136
9
—
—
10
11
12
4j:5j
4k:5k
4l:5l
4-F-C6H4-
3-O2N-C6H4-
128–130
—
a
b
c
Reaction conditions: aldehyde (1) (0.5 mmol), 2-aminobenzophenone (2) (0.5 mmol), NH4OAc (3) (1 mmol), DMAP (0.1 mmol), EtOH (5 mL), 40 °C.
Ratios were determined from the 1H NMR spectra of the mixtures.
Isolated yield of pure 1,2-dihydroquinazoline.

202
C. Derabli et al. / Tetrahedron Letters 55 (2014) 200–204
Table 3
DMAP-catalyzed synthesis of 1,2-dihydroquinazolines from heterocyclic aldehydes or diketonesa
Entry
ArCHO or diketone
Products
Time (h)
Product ratiob
Yieldc (%)
mp (°C)
Measured
Reported21
1
2
3
4
Ar = 2-thienyl
Ar = 4-quinolyl
Ar = 2-(Cl)-8-(Me)-3-quinolyl
Ar = 2-(Cl)-6-(OMe)-3-quinolyl
4m:5m
4n:5n
4o:5o
4p:5p
2.5
2
2
85:15
90:10
100:0
82:18
68
94
85
98
Gum
Gum
—
—
218–220
182–184
Gum
1.5
—
O
O
5
4q:5q
4
99:trace
78
144–146
142–145
N
H
a
b
c
Reaction conditions: aldehyde or diketone (0.5 mmol), 2-aminobenzophenone (2) (0.5 mmol), NH4OAc (3) (1 mmol), DMAP (0.1 mmol), EtOH (5 mL), 40 °C.
Ratios were determined from the 1H NMR spectra of the mixtures.
Isolated yield of pure 1,2-dihydroquinazoline.
N
N
O
O
H
N
Ph
O
Ar
path b
Ph
NH4OAc
+
+
3
Ar
H
NH2
2
1
H2N
2
D
path a
Ph
N
HO
O
N
Ph
+ H2O
Ar
N
N
H
Ar
H
N
E
A
- H2O
NH4OAc - H2O
3
N
Ph
N
Ph
Ph
N
Ph
N
N
H
N
N
N
N
Air
N
N
N
H
Ar
N
B
Ar
N
Ar
Ar
H
C
5
4
Scheme 2. Proposed mechanisms for the synthesis of 1,2-dihydroquinazolines 4.
same condensation was then conducted at different temperatures.
Compared with the reaction at room temperature, both the yield
and reaction rate were improved considerably at 40 °C (entry 2);
reflux temperature was found to be less effective and the desired
product was obtained in a lower yield (68%) after one hour.
We then evaluated the effect of the solvent on this reaction.
Protic solvents proved to be crucial for the reaction. The reaction
carried out in pure methanol afforded the adduct 4h in 63% yield
after one hour (Table 1, entry 4). However, no reaction was
observed when other organic solvents were used. By conducting
the reaction in 50% aqueous ethanol or in CH3CN, the desired
dihydroquinazoline 4h was not formed at all, and the starting
substrates were recovered (Table 1, entries 5 and 6). Among the
solvent systems examined, we found that ethanol was the solvent
of choice.
Various Lewis acid catalysts such as CAN, PhB(OH)2, SnCl2, and
FeCl3.6H2O were utilized but with limited success. Among the
examined catalysts, phenylboronic acid and SnCl2 exhibited rela-
tively good catalytic activity (Table 1, entries 9 and 10). These re-
sults prompted us to examine the reaction with other catalysts
such as Lewis bases. In the case of DMAP, the reaction proceeded
more effectively; it was able to catalyze the reaction affording
product 4h in higher yields (entries 12–16). The use of DMAP
(20 mol %) gave the corresponding product in 87% yield without
any side-products being detected (entry 15). The use of DABCO
or triethylamine as other Brønsted base catalysts gave similar re-
sults (entries 17 and 18), but with diminished yields.
Thus, under the optimized conditions, the generality of the
reaction was investigated by employing several aromatic
aldehydes. The results are summarized in Table 2. In general, the
reactions were rapid at 40 °C and the corresponding dihydroqui-
nazolines were formed in 67–98% yields. The electronic nature of
the substituents on the benzene ring had no significant influence
on the reactivity. An unsubstituted phenyl group (Table 2, entry
1) or aryl groups with electron-donating substituents (entries 2
and 3) afforded high yields, as did those with electron-withdraw-
ing groups. However, the presence of 2-chloro-, 4-N,N-dimethyl-
amino-, or 4-hydroxy- groups on the aromatic ring gave slightly
diminished yields.
Next, we were interested in applying this protocol to other
starting materials. Therefore, a variety of heterocyclic aldehydes
were reacted in a similar manner with 2-aminobenzophenone
and ammonium acetate. As
a result, differently substituted
dihydroquinazolines were obtained in moderate to good yields

C. Derabli et al. / Tetrahedron Letters 55 (2014) 200–204
203
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ranging from 68% to 98% (Table 3, entries 1–4). The use of isatin
also gave the corresponding product in good yield (entry 5).
In order to evaluate further the efficiency of this protocol, 2-
aminoacetophenone was subjected to the reaction with benzalde-
hyde and NH4OAc in the presence of 20 mol % of DMAP under the
same conditions described above. Unfortunately, the reaction pro-
vided a mixture of products accompanied by unreacted starting
materials, and we were not able to isolate the desired 1,2-
dihydroquinazoline.
In all cases, we obtained 1,2-dihydroquinazolines in high yields
as the major product with only a small amount of the oxidized
form. The quantity of this minor product was increased by allowing
the dihydroquinazolines to stand in air for a few hours. To prevent
aromatization, it was necessary to store the products under an in-
ert atmosphere. The other product ratios are listed in Tables 2 and
3.
Based on the above observations, we propose two plausible
mechanistic pathways for the present protocol in which we believe
that DMAP acts as a base.29 The first reaction mechanism (path a) is
proposed to proceed via the condensation of the aldehyde (1) with
2-aminobenzophenone (2) to furnish the corresponding aldimine
A. Further condensation of this intermediate with ammonium ace-
tate gives diimine B which was isolated and identified by 1H NMR
spectroscopy. Deprotonation of B with the catalyst produces carb-
anion intermediate C, which undergoes intramolecular cyclization
to form the target 1,2-dihydroquinazoline 4, which can be aroma-
tized by air to give the corresponding quinazoline 5 as a minor
product.
In another possible mechanism (path b), the condensation of
aldehyde (1) with NH4OAc results in the formation of aldimine D,
the further reaction of which with 2-aminobenzophenone (2)
leads, after dehydration, to the desired product 4. The proposed
mechanisms are shown in Scheme 2.
It is important to note that with the exception of compounds 4c,
4g, 4m, and 4p, which were isolated by pouring the reaction mix-
tures onto cold water, followed by extraction with ethyl acetate,
evaporation and then flash column chromatography on silica gel
using EtOAc/hexane (1:3) as the eluent, all the other dihydroqui-
nazolines were recrystallized to provide the desired products in
pure form.30
21. Hoefnagel, A. J.; van Koningsveld, H.; van Meurs, F.; Peters, J. A.; Sinnema, A.;
van Bekkum, H. Tetrahedron 1993, 49, 6899.
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DMAP is more soluble in water than in organic solvents and it
could be recovered almost quantitatively from the aqueous layer.
The structures of the products were confirmed by FT-IR, 1H, 13
NMR, HRMS, and elemental analysis.
C
In summary, we have succeeded in developing an efficient,
general, and one-pot procedure for the synthesis of 1,2-dihydro-
quinazoline derivatives through the DMAP-catalyzed reaction of
2-aminobenzophenone with aromatic or heteroaromatic aldehydes
and ammonium acetate. This method offers several advantages
such as high selectivity, mild reaction conditions, and easily
accessible starting materials.
27. Sakakura, A.; Kawajiri, K.; Ohkubo, T.; Kosugi, Y.; Ishihara, K. J. Am. Chem. Soc.
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30. General procedure for the synthesis of 2-aryl-4-phenyl-1,2-dihydroquinazolines
(4): A mixture of an aldehyde (1) (1.0 equiv), 2-aminobenzophenone (2) (1.0
equiv), NH4OAc (3) (2.0 equiv), and DMAP (0.2 equiv.) in absolute EtOH (5 ml)
was stirred at 40 °C for the stipulated period of time (see Tables 2 and 3). After
completion of the reaction, as monitored by TLC, the mixture was poured into
ice-cold H2O and the solid product was filtered, washed with H2O (3-5 mL) and
dried. The crude product was recrystallized from EtOAc to give pure
dihydroquinazolines. For compounds 4c, 4g, 4m, and 4p, after cooling, H2O
was added and the product was extracted with EtOAc (3 Â 15 mL). The
combined organic extract was washed with H2O, dried (anhyd Na2SO4) and the
solvent removed followed by flash column chromatography over silica gel (60–
120 mesh) to furnish the desired product.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.157.
References and notes
1. (a) Balakumar, C.; Lamba, P.; Kishore, D. P.; Narayana, B. L.; Rao, K. V.;
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4904; (b) Alafeefy, A. M.; Kadi, A. A.; Al-Deeb, O. A.; El-Tahir, K. E. H.; Al-Jaber,
N. A. Eur. J. Med. Chem. 2010, 45, 4947.
2. Tiwari, R.; Chhabra, G. Asian J. Chem. 2010, 22, 5981.
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Selected spectroscopic data: 2-(4-Chlorophenyl)-4-phenyl-1,2-dihydroquinazoline
(4h). Yellow solid; mp 142–144 °C; IR (KBr)
m
3320, 2364 1620, 1537, 1486,
;
1321, 1263, 1155, 1015, 964, 805, 741, 697 cmÀ1
1H NMR (CDCl3, 400 MHz) d
7.72–7.61 (m, 5H, arom.), 7.49–7.36 (m, 4H, arom.), 7.32–7.21 (m, 2H, arom.),
6.77 (td, J = 8.0,1.0 Hz, 1H, arom.), 6.72 (d, J = 8.0 Hz, 1H), 6.02 (s, 1H, CH), 4.38
(s, 1H, NH); 13C NMR (CDCl3, 100 MHz) d 165.8, 146.9, 141.5, 141.4, 140.9,

204
C. Derabli et al. / Tetrahedron Letters 55 (2014) 200–204
138.1, 132.9, 130.2, 129.4, 129.3, 129.1, 128.1, 127.8, 127.5, 127.3, 127.2, 118.3,
(m, 8H, arom.), 7.34–7.26 (m, 2H, arom.), 6.83–6.74 (m, 2H, arom.), 6.48 (s, 1H,
CH), 4.79 (s, 1H, NH), 2.81 (s, 3H, CH3); 13C NMR (CDCl3, 62.5 MHz) d 167.4,
148.2, 146.8, 146.6, 139.3, 138.0, 136.4, 133.2, 132.6, 130.9, 129.9, 129.3, 123.0,
128.4, 127.5, 127.1, 126.1, 120.4, 118.9, 117.9, 114.8, 68.8, 18.0. Anal. calcd for
117.9, 114.3, 72.4. Anal. calcd for C20H15N2Cl: C, 75.35; H, 4.74; N, 8.79; Found:
C, 75.42; H, 5.05; N, 9.03. HRMS calcd for C20H16N2Cl (MH+) 319.0924; found
319.0863. 2-(2-Chloro-8-methylquinolin-3-yl)-4-phenyl-1,2-dihydroquinazoline
(4o). Yellow solid; mp 182–184 °C; IR (KBr)
m
3329, 1605, 1551, 1470, 1315,
C
24H18N3Cl: C, 75.09; H, 4.73; N, 10.95; Found: C, 75.18; H, 4.94; N, 11.37.
1080, 756, 698 cmÀ1 1H NMR (CDCl3, 250 MHz) d 8.52 (s, 1H, arom.), 7.74–7.41
;
HRMS calcd for C24H19N3Cl (MH+) 384.1189; found 384.1162.