Pentafluorophenylammonium triflate as a suitable and effective metal-free catalyst for the synthesis of quinazoline derivatives via one-pot multicomponent method

Article abstract of DOI:10.1007/s11164-013-1483-7

A simple and facile synthesis of highly functionalized quinazoline derivatives has been successfully developed by treatment of aldehydes, ammonium acetate, and 2-aminoaryl ketones or isatoic anhydride under reflux conditions in the presence of a pentafluorophenylammonium triflate (PFPAT) organocatalyst. These catalytic condensation reactions represent green chemical processes, while the PFPAT organocatalyst is air-stable, cost-effective, easy to handle, and easily removed from the reaction mixtures.

Full text of DOI:10.1007/s11164-013-1483-7

Res Chem Intermed
DOI 10.1007/s11164-013-1483-7
Pentafluorophenylammonium triflate as a suitable
and effective metal-free catalyst for the synthesis
of quinazoline derivatives via one-pot multicomponent
method
•
Samad Khaksar Milad Gholami
Received: 9 September 2013 / Accepted: 12 November 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract A simple and facile synthesis of highly functionalized quinazoline
derivatives has been successfully developed by treatment of aldehydes, ammonium
acetate, and 2-aminoaryl ketones or isatoic anhydride under reflux conditions in the
presence of a pentafluorophenylammonium triflate (PFPAT) organocatalyst. These
catalytic condensation reactions represent green chemical processes, while the
PFPAT organocatalyst is air-stable, cost-effective, easy to handle, and easily
removed from the reaction mixtures.
Keywords Organocatalyst Á Metal-free Á Quinazoline Á PFPAT
Introduction
The term ‘organocatalysis’ describes the acceleration of chemical reactions through
the addition of a substoichiometric quantity of an organic compound [1, 2]. The
operational simplicity, ready availability of catalysts, environmental compatibility
and low toxicity associated with organocatalysis makes it an attractive method to
synthesize complex structures. They can also be applied in less demanding reaction
conditions, such as rigorously anhydrous or anaerobic conditions. A lot of catalysts
have been designed and applied in this area [3–8]. However, the design and
development of new, effective, and easily accessible organic catalysts continues to
be a major challenge.
Quinazolines are the important structural motifs that are widely present in
numerous natural products, synthetic pharmaceuticals, and functional materials.
Since many of these heterocyclic systems exhibit biological activities, such as
antitumor, antibiotic, antidefibrillatory, antipyretic, analgesic, antihypertonic,
S. Khaksar (&) Á M. Gholami
Chemistry Department, Islamic Azad University, Ayatollah Amoli Branch, Amol, Iran
e-mail: S.khaksar@iauamol.ac.ir
123

S. Khaksar, M. Gholami
diuretic, antihistamine, antidepressant, and as vasodilating agents, these derivatives
have become an integral part of pharmacologically important heterocyclic
compounds [9–11]. These derivatives also act as selective JAK2, PDE5, and
epidermal growth factor receptor (EGFR) inhibitors of tyrosine kinase activity [12–
14]. Furthermore, the quinazoline ring is a core structure of several drug molecules
such as gefitinib (Iressa), erlotinib (Tarceva) and actinomycin [15–18]. Considering
the above reports, the development of new synthetic methodologies for the
construction of quinazoline scaffolds will be a beneficial and interesting challenge.
In accordance with the significance of quinazoline, several synthetic methods have
been developed for the construction of this kind of fused heterocycles from suitable
precursors [19–35]. Very recently, Panja et al. [36] reported I2 catalyzed reaction
between 2-aminobenzophenone, aromatic aldehyde, and ammonium acetate for the
preparation of quinazoline derivatives in a one-pot synthesis. Zhang et al. [37]
developed a novel catalyst-free synthesis of quinazoline derivatives using a low
melting sugar–urea–salt mixture as a solvent. However, some of these procedures
have certain limitations such as the use of hazardous organic solvents, strongly
acidic conditions, expensive moisture-sensitive catalysts, or tedious work-up
conditions, and low yields. In view of these drawbacks, the synthetic protocols
utilizing new catalysts devoid of metals are becoming more important due to the
growing concern for sustainable chemistry. In recent years, pentafluorophenylam-
monium triflate (PFPAT) has proved to be very useful as a Brønsted acid catalyst in
carrying out various organic transformations [38–44]. PFPAT has received
extensive recognitions in organic synthesis due to its unique properties of being
readily affordable, water stability, recyclability, operational simplicity, strong
tolerance to oxygen, and nitrogen-containing substrates and functional groups, and
it can often be used in catalytic amounts. In a continuation of our interest in
developing more efficient and environmentally benign methodologies [45–48], we
report a new, convenient, mild, and efficient procedure for the synthesis of
quinazoline derivatives, which are obtained through a one-pot three-component
condensation reaction of aldehydes, ammonium acetate, and 2-aminoaryl ketones,
as well as condensation of aldehydes, ammonium acetate, and isatoic anhydride
under reflux conditions using PFPAT as an efficient organocatalyst (Scheme 1).
Experimental
Apparatus and analysis
NMR spectra were determined on an FT-NMR Bruker AV-400 spectrometer in
CDCl3 or DMSO-d6 and are expressed in d values relative to tetramethylsilane;
coupling constants (J) are measured in hertz. Melting points were determined on an
Electrothermal 9100 apparatus. Infrared spectra were recorded on a Rayleigh WQF-
510 Fourier transform instrument. Commercially available reagents were used
throughout without further purification.
123

PFPAT as a suitable and effective metal-free catalyst
O
Ph
N
R1
R1
Ph
PFPAT (10 mol %)
Toluene, reflux, 4 h
R2
N
+
CHO
O
+
NH4OAc
NH2
O
R2
2
1
3
4a-o
O
R3
NH4OAc
or
O
PFPAT (10 mol %)
Toluene, reflux, 3 h
N
+
+
R2
H
R3
N
O
NH2
R2
N
H
H
6
5
7
8a-q
Scheme 1 Synthesis of quinazoline derivatives
General procedure for the synthesis of quinazoline derivatives
A mixture of 2-aminoaryl ketone (1 mmol), an aromatic aldehyde (1 mmol), and
ammonium acetate (1.2 mmol) dissolved in 3 mL toluene, and PFPAT (10 mol%)
was stirred for 4 h at 110 °C. The reaction was monitored by TLC. The reaction
mixture, after being cooled to room temperature, was poured onto crushed ice and
stirred for 5–10 min. The crystalline product was collected by filtration under
suction (water aspirator), washed with ice-cold water (40 mL), and then recrystal-
lized from hot ethanol to afford pure products.
General procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
A mixture of isatoic anhydride (1 mmol), an aromatic aldehyde (1 mmol) and
ammonium acetate (1.2 mmol) dissolved in 3 mL toluene, and PFPAT (10 mol%)
was stirred for 3 h at 110 °C. The reaction was monitored by TLC. The reaction
mixture, after being cooled to room temperature was poured onto crushed ice and
stirred for 5–10 min. The crystalline product was collected by filtration under
suction (water aspirator), washed with ice-cold water (40 mL) and then recrystal-
lized from hot ethanol to afford pure products.
Spectroscopic data for selected examples follow:
2-(4-Methylphenyl)-4-phenylquinazoline (4b) mp: 165–167 °C; IR (KBr, cm-1):
1
1,075, 1,540, 1,602; H NMR (400 MHz, CDCl3): d = 2.45 (s, 3 H), 7.32 (d,
J = 8.0 Hz, 2H), 7.50–7.60 (m, 4H), 7.86–7.90 (m, 3H), 8.14 (t, J = 7.7, 2H), 8.58
(d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = 21.2, 121.2, 126.3, 126.5,
127.8, 128.2, 129.2, 129.4, 129.9, 130.2, 130.3, 133.8, 135.2, 137.2, 140.3, 151.6,
159.8, 167.6.
2-(4-Chloro-phenyl)-4-phenylquinazoline (4e) mp: 188–190 °C; IR (KBr; cm-1):
1
845, 1,335, 1,520, 1,570; H NMR (400 MHz, CDCl3): d = 7.51–7.65 (m, 6 H),
7.86–7.91 (m, 3 H), 8.11–8.14 (m, 2H), 8.65 (d, J = 8.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d = 121.5, 126.86, 127.2, 128.1, 128.5, 128.7, 129.1, 129.7,
130.4, 133.7, 137.4, 151.5, 159.2, 168.2.
123

S. Khaksar, M. Gholami
6-Chloro-4-phenyl-2-(p-tolyl)-quinazoline (4i) mp: 213–215 °C; IR (KBr,
1
cm-1): 780, 1,340, 1,568, 1,610; H NMR (400 MHz, CDCl3): d = 2.45 (s, 1H),
7.32 (d, J = 8.0 Hz, 2H), 7.61–7.63 (m, 3H), 7.78–7.87 (m, 3H), 8.07–8.09 (m,
2H), 8.56 (d, J = 9.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = 21.4, 121.8,
125.6, 128.1, 128.5, 129.8, 130.1, 130.3, 130.8, 132.3, 134.3, 135.8, 136.9, 141.1,
150.5, 160.4, 167.3.
6-Chloro-2-(4-nitrophenyl)-4-phenylquinazoline (4j) mp: 221–223 °C; IR (KBr,
cm-1): 780, 1,350, 1,560, 1,610; 1H NMR (400 MHz, CDCl3): d = 7.65 (t,
J = 2.8 Hz, 3H), 7.83–7.88 (m, 3H), 8.12 (t, J = 4 Hz, 3H), 8.36 (d, J = 9.0 Hz,
2H), 8.85 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = 122.5, 123.8,
126.1, 128.9, 129.4, 130.5, 130.6, 131.1,133.9, 135.1, 136.8, 143.6, 149.2, 150.3,
158.1, 168.0.
6-Nitro-2-(2-nitro-phenyl)-4-phenyl-quinazoline (4m) mp: 233–235 °C; IR (KBr,
cm-1): 1,537, 1,345, 1,095, 695; 1H NMR (400 MHz, CDCl3): d = 7.50 (d,
J = 8.7 Hz, 2H), 7.65 (t, J = 2.2 Hz, 3H), 7.86–8.22 (m, 3H), 8.60–8.68 (m, 3H),
9.05 (s, J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 121.5, 124.3, 128.1,
129.1, 129.4, 130.3, 130.8, 131.2, 131.4, 135.6, 136.3, 138.2, 145.8, 154.5, 162.1.
6-Nitro-2-(4-methylphenyl)-4-phenylquinazoline (4n) mp: 218–220 °C; IR (KBr,
1
cm-1): 775, 1,540, 1,600, 1,655; H NMR (400 MHz, CDCl3): d = 2.45 (s, 3H),
7.35 (d, J = 7.8 Hz, 2H), 7.65–7.88 (m, 5H), 8.24 (d, J = 9.0 Hz, 1H), 8.62 (d,
J = 7.8 Hz, 3H), 9.05 (d, J = 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d = 21.5, 120.2, 124.1, 126.8, 129.1, 129.3, 129.5, 130.4, 130.8, 131.1, 134.3,
136.5, 142.2, 145.8, 154.5, 163.5, 169.3.
2,3-Dihydro-2-phenylquinazolin-4(1H)-one (8a) mp: 225–227 °C; IR (KBr,
1
cm-1): 1,508, 1,610, 1,653, 3,062, 3,302; H NMR (400 MHz, CDCl3): d = 5.76
(s, 1H), 6.68 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 8.09 Hz, 1H), 7.10 (br s, NH), 7.25 (t,
J = 7.3 Hz, 1H), 7.33–7.41 (m, 3H), 7.50 (d, J = 7.44 Hz, 2H), 7.62 (d,
J = 7.7 Hz, 1H), 8.28 (br s, NH); 13C NMR (100 MHz, CDCl3): d = 67.4,
115.2, 115.8, 117.9, 127.7, 128.2, 129.1, 129.3, 134.1, 142.5, 148.7, 164.4.
2-(4-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (8b) mp: 201–203 °C; IR
(KBr, cm-1): 1,292, 1,483, 1,650, 1,667, 3,025, 3,307; 1H NMR (400 MHz,
CDCl3): d = 5.77 (s, 1H), 6.70 (t, J = 8.1 Hz, 1H), 6.95 (d, J = 6.4 Hz, 1H), 7.15
(br s, 1H, NH), 7.22–7.47 (m, 3H), 7.51 (d, J = 8.8 Hz, 2H), 7.61 (dd, J1 = 7.8 Hz,
J2 = 1.3 Hz, 1H), 8.34 (br s, NH); 13C NMR (100 MHz, CDCl3): d = 65.8, 114.4,
115.1, 117.27, 127.3, 128.3, 128.7, 132.9, 133.3, 140.7, 147.7, 163.4.
2,4-Dichloro-2,3-dihydroquinazolin-4(1H)-one (8d) mp: 182–184 °C; IR (KBr,
1
cm-1): 1,661, 3,025, 3,179, 3,337; H NMR (400 MHz, CDCl3): d = 6.1 (s, 1 H),
6.71(t, J = 8.1 Hz, 1H), 6.93(d, J = 6.4 Hz, 1H), 7.04 (br s, 1H, NH), 7.24–7.29 (t,
J = 7.5 Hz, 1 H), 7.47–7.50 (m, 1 H), 7.65–7.68 (m, 3 H), 8.25 (br s, NH); 13C
NMR (100 MHz, CDCl3): d = 63.3, 114.6, 114.7, 117.6, 127.4, 128.6, 128.9,
130.9, 132.9, 133.5, 133.9, 136.9, 147.5, 163.6.
2-(4-Bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (8g) mp: 201–203 °C; IR
1
(KBr, cm-1): 1,430, 1,480, 1,651, 1,665, 3,025, 3,188, 3,307; H NMR (400 MHz,
CDCl3): d = 5.76 (s, 1H), 6.67–6.77 (m, 2H), 7.15 (s, 1H, NH), 7.25 (dt,
J1 = 7.7 Hz, J2 = 1.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.58–7.62 (m, 3H), 8.35
123

PFPAT as a suitable and effective metal-free catalyst
(br s, NH); 13C NMR (100 MHz, CDCl3): d = 65.8, 114.4, 114.9, 117.3, 121.5,
127.3, 129.1, 131.2, 133.4, 141.1, 147.6, 163.5.
2-(4-Methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (8j) mp: 179–180 °C; IR
1
(KBr, cm-1): 1,240, 1,386, 1,482, 1,608, 1,650, 3,174, 3,296; H NMR (400 MHz,
CDCl3): d = 3.83 (s, 3H), 5.79 (s, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.83(d,
J = 7.6 Hz, 1H), 7.04 (dt, J1 = 8.6 Hz, J2 = 2.0 Hz, 2H), 7.10 (br s, NH),
7.30–7.35 (m, 1H), 7.51–771 (m, 3H), 8.28 (br s, 1H, NH); 13C NMR (100 MHz,
CDCl3): d = 55.2, 66.3, 113.6, 114.4, 115.1, 117.07, 127.3, 128.2, 133.2, 133.4,
148.0, 159.5, 163.6.
2,3-Dihydro-3-phenyl-2-(4-chlorophenyl)quinazolin-4(1H)-one (8n) m.p: 216–218 °C;
IR (KBr, cm-1): 1,088, 1,385, 1,486, 1,613, 1,631, 3,025, 3,294. 1H NMR
(400 MHz, CDCl3): d = 6.33 (d, J = 2.7 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.77
(d, J = 7.8 Hz, 1H), 7.18–7.22 (m, 1H), 7.25–7.29 (m, 3H), 7.31–7.42 (m, 6H),
7.67–7.73 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 72.1, 114.8, 115.3, 117.7,
126.1, 126.2, 128.1, 128.4, 128.5, 128.6, 132.9, 133.8, 139.6, 140.5, 146.4, 162.1.
Result and discussion
In preliminary experiments, the model reaction of 2-aminobenzophenone
(1.0 mmol), benzaldehyde (1.0 mmol), and ammonium acetate (1.2 mmol) cata-
lyzed by PFPAT was conducted to screen the optimal reaction conditions, and the
results were listed in Table 1. It is noteworthy that, in the absence of a catalyst, the
reaction failed to give the desired product, even after long reaction time (24 h;
Table 1, entry 1).
Then, the effect of temperature, the amount of catalyst, and the reaction time on
the yield of the product were examined. Reaction at 110 °C in toluene in the
presence of 10 mol% PFPAT afforded the product 4a in 88 % yield (Table 1, entry
4). Increasing either the amount of catalyst and/or prolonging the reaction time did
not improve the yield (Table 1, entry 10), while reducing these factors led to a
reduction in product yield (Table 1, entry 3). Building upon this result, further
studies were conducted and it was found that 10 mol% of PFPAT was optimum for
this reaction and gave a product of 88 % yield in just 4 h (Table 1, entry 4). The
reaction was also examined in solvents such as H2O, THF, CH2Cl2, ethanol, and
diethyl ether. In the presence of solvents, the reaction was sluggish and the
formation of byproducts was observed (Table 1, entries 5–9). Moreover, when the
reaction was carried out in toluene medium, in most cases a solid product was
separated at the end of the reaction.
To establish the scope and generality of this three-component reaction, we
extended our studies with a wide range of substrate combinations, and the desired
substituted quinazolines were obtained in excellent yields (Table 2).
This protocol well tolerates aromatic aldehydes containing both electron-
donating and electron-withdrawing substituents. The electronic effect seemed to
have a slight influence on the reaction since either the electron-withdrawing or the
electron-donating groups on the different aromatic ring resulted in the scarcely
discriminated yields from the reaction, as evidenced by benzaldehydes with either
123

S. Khaksar, M. Gholami
Table 1 Effect of different
PFPAT and solvent on
formation of 4
Entries
PFPAT amount
(mol%)
Condition/solvent
Time (h)/
yield
1
2
0
10
5
RT/toluene
24/0
RT/toluene
24/30
8/70
3
110 °C/toluene
110 °C/toluene
RT/CH2Cl2
RT/THF
4
10
10
10
10
10
10
15
4/88
5
24/15
24/10
24/10
24/0
6
7
RT/ethanol
8
RT/H2O
9
RT/diethyl ether
110 °C/toluene
24/0
10
4/88
RT Room temperature
Table 2 PFPAT-catalyzed synthesis of functionalized quinazolines
Entries
R1
R2
Product
Yield (%)
mp (°C)
References
1
H
C6H5
4a
4b
4c
4d
4e
4f
88
92
90
90
95
92
95
88
95
90
90
85
90
92
Trace
120–122
165–166
155–157
185–186
189–190
141–143
193–194
99–100
213–214
221–223
169–171
224–225
233–234
216–218
–
[36]
[37]
[36]
[37]
[37]
[36]
[37]
[37]
[37]
[36]
[37]
[37]
[37]
[37]
2
H
4-Me-C6H4
4-OMe-C6H4
4-OH-C6H4
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4
2-Cl-C6H4
4-Me-C6H4
4-NO2-C6H4
3-Pyridyl
3
H
4
H
5
H
6
H
7
H
4g
4h
4i
8
Cl
Cl
Cl
Cl
Cl
NO2
NO2
Me
9
10
11
12
13
14
15
4j
4k
4l
2-Thienyl
4-Cl-C6H4
4-Me-C6H4
C6H5
4m
4n
4o
an o- or a p-Cl substituent (Table 2, entries 5, 8), which resulted in the
corresponding products (95–92 %). Both 4-methoxybenzaldehyde (Table 2, entry
3) and 4-nitrobenzaldehyde (Table 2, entry 7) were suitable substrates in this
reaction. The experimental procedure is very efficient, convenient, and rapid, and
has the ability to tolerate a variety of other functional groups, such as alkyl,
methoxyl, nitro, and halides under these reaction conditions. Furthermore, acid
sensitive aldehydes [49, 50] worked well without any decomposition or polymer-
ization under these reaction conditions (entries 11, 12). However aliphatic
aldehydes did not undergo condensation under this reaction condition.
123

PFPAT as a suitable and effective metal-free catalyst
Ph
Ph
N
R1
R1
O
PFPAT (10 mol %)
N
NH2
NH4OAc
Ph
Toluene, reflux, 4 h
R2
aromatization
Ph
Ph
R1
R2
R1
R1
CHO
NH
N
NH
Cyclization
NH2
R2
N
H
R2
N
I
II
Scheme 2 Proposed mechanism for quinazoline synthesis
The effect of substituent on 2-aminobenzophenone derivatives on the yield and
reaction time has also been studied (Table 2, entries 9–15). It was found that the
performance of this three-component reaction strongly depends on the electronic
property of the substituents on the aniline ring of 2-aminobenzophenone. In general,
electron-withdrawing groups worked well, affording good-to-excellent yields in all
cases (Table 2, entries 9–14).
Lastly, the very simple reaction workup furnished products of satisfactory purity
in most cases without chromatographic purification. The structure of the products
(4a–o) was established from their IR spectral data and comparison of their melting
points with those of authentic samples [36, 37]. Also, the structure of some products
was confirmed by 1H NMR and 13C NMR spectral data. A plausible mechanism for
the formation of quinazoline is shown in Scheme 2 [36].
In this process, PFPAT acts as Brønsted acid and plays a significant role in
increasing the electrophilic character of the electrophiles (Scheme 2). First, the keto
group of benzophenone moiety is activated by PFPAT followed by the N-
nucleophilic amine attacks on the carbonyl to form intermediate I. Subsequently, the
reaction of activated aldehyde with I proceeds to afford intermediate II that is
converted to product 4 via an intramolecular cyclization. The highly hydrophobic
pentafluorophenyl moiety effectively repels H2O produced by the dehydration steps.
The present protocol was extended using isatoic anhydride, and the reaction of
benzaldehyde, ammonium acetate, and isatoic anhydride was carried out under
similar reaction conditions. The desired product 8a was obtained in 90 % yield. The
reaction of other aromatic aldehydes substituted with Cl, Br, F, Me, NO2, and MeO
was also performed with isatoic anhydride and ammonium acetate, and the desired
products 8b–j were isolated in good yields (Table 2, entries 2–10). To expand the
scope of amine substrates, ammonium acetate and primary aromatic amines
including aniline, p-toluidine, and 4-chloroaniline were applied to this protocol. In
all cases, the desired reactions took place successfully to afford a series of 2,3-
dihydroquinazolin-4(1H)-one (8m–q) in good yields (Table 3).
123

S. Khaksar, M. Gholami
Table 3 PFPAT catalyzed synthesis of 2,3-dihydroquinazolin-4(1H)-ones
Entries
2
Aldehyde
Amine
Product
Yield
90
mp (°C)
References
[31]
NH4OAc
8a
224–225
CHO
CHO
2
3
NH4OAc
NH4OAc
8b
8c
95
80
200–202
229–230
[32]
[32]
Cl
CHO
Cl
Cl
Cl
4
5
NH4OAc
NH4OAc
8d
8e
85
90
142–184
300–301
[32]
[32]
CHO
Cl
CHO
O2N
O2N
6
7
NH4OAc
NH4OAc
8f
80
90
180–181
200–202
[31]
[32]
CHO
CHO
8g
Br
F
8
NH4OAc
NH4OAc
NH4OAc
8h
8i
95
90
80
236–238
227–229
179–180
[31]
[32]
[31]
CHO
CHO
CHO
9
Me
10
8j
MeO
O
11
12
NH4OAc
NH4OAc
8k
8l
90
80
182–185
218–220
[31]
[32]
CHO
CHO
N
H
13
8m
85
202–204
[33]
CHO
NH2
123

PFPAT as a suitable and effective metal-free catalyst
Table 3 continued
Entries
14
Aldehyde
Amine
Product
Yield
90
mp (°C)
References
[33]
8n
216–218
CHO
CHO
NH2
NH2
Cl
15
16
17
8o
8p
8q
80
85
90
216–217
219–220
195–196
[33]
[33]
[33]
Me
CHO
Cl
NH2
CHO
Me
NH2
The superiority of PFPAT to other arylammonium triflates is ascribed to the
lower basicity of the C6F5NH2 counter-amine compared to ArylNH2. The use of
C6F5NH2 raised the acidity of catalyst and the highly hydrophobic pentafluorophe-
nyl moiety effectively repels H2O produced by the dehydration steps. In addition,
C6F5NH2 easily separated from the reaction mixture after workup with distillation
under reduced pressure (C6F5NH2: bp 153 °C at 760 mmHg).
Conclusion
In conclusion, we have developed an efficient synthesis of quinazoline derivatives
via the one-pot three-component coupling reaction of aldehydes, ammonium
acetate, and 2-aminoaryl ketones or isatoic anhydride under reflux conditions using
PFPAT as an efficient organocatalyst. In contrast to the existing methods using
potentially hazardous catalysts/additives, the present method offers the following
competitive advantages: (1) PFPAT is easy to prepare from commercially available
pentafluoroaniline and triflic acid, (2) short reaction time, (3) ease of product
isolation/purification by non-aqueous work-up, (4) no side reaction, (5) low costs
and simplicity in process and handling, and (6) quinazolines are produced by an
environmentally benign process.
Acknowledgment This research is supported by the Islamic Azad University, Ayatollah Amoli Branch.
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