One-pot solvent-free synthesis of 2, 3- disubstituted 4(3H)- quinazolinones catalyzed by long-chain double SO3H-functionalized Br?nsted acidic ionic liquids under microwave irradiation

Article abstract of DOI:10.1007/s13738-014-0553-0

A solvent-free approach for synthesis of 2, 3-disubstituted 4(3H)-quinazolinones by condensation of anthranilic acid with acyl chlorides and aromatic/aliphatic amines using two long chain double SO₃H-functionalized acdic ionic liquids as catalyst under microwave irradiation was reported. Under optimized conditions, the reactions completed within 4-8 min and gave the target compounds in the yields of 76-94 %. Two ionic liquids could be recovered readily and recycled three times without any significant loss in their catalytic activity.

Full text of DOI:10.1007/s13738-014-0553-0

J IRAN CHEM SOC (2015) 12:897–901
DOI 10.1007/s13738-014-0553-0
ORIGINAL PAPER
One‑pot solvent‑free synthesis of 2, 3‑ disubstituted
4
(3H)‑ quinazolinones catalyzed by long‑chain double
SO H‑functionalized Brønsted acidic ionic liquids
3
under microwave irradiation
Xinzhong Li · Qi Lin · Lefu Wang
Received: 19 July 2014 / Accepted: 28 October 2014 / Published online: 8 November 2014
©
Iranian Chemical Society 2014
Abstract A solvent-free approach for synthesis of 2,
-disubstituted 4(3H)-quinazolinones by condensation of
anthranilic acid with acyl chlorides and aromatic/aliphatic
been developed such as intramolecular aza-Wittig [10],
Niementowski reaction [11], Appel salt transformation
[12], and solid-phase synthesis using aldehydes as C2 unit
[13]. However, these methods also suffered from signifi-
cant limitations, which include multi-step procedure, using
costly and toxic reagents, expensive catalysts and organic
solvents, harsh reaction conditions, low yields, long reac-
tion time, complex experimental processes and work-up,
etc. Considering the importance of this class of molecules,
finding greener alternative procedure appears highly
desirable.
3
amines using two long chain double SO H-functionalized
3
acdic ionic liquids as catalyst under microwave irradiation
was reported. Under optimized conditions, the reactions
completed within 4–8 min and gave the target compounds
in the yields of 76–94 %. Two ionic liquids could be recov-
ered readily and recycled three times without any signifi-
cant loss in their catalytic activity.
Keywords Brønsted acid · Ionic liquids · Multi-
components · Microwave irradiation · 4(3H)-quinazolinone
More recently, acidic ionic liquids as green solvent and
catalysts in organic liquids transformations have attracted
increasing attentions. For example, single sulfonic acid
functionalized Brønsted acidic ionic liquids (SBAILs)
[(CH ) SO HMIM][HSO ] [14], [(CH ) SO HPy][HSO ]
Introduction
2
4
3
4
2 4
3
4
[
14], and Lewis acidic ionic liquids Bi(TFA) -[nbp]FeCl
3 4
2
, 3-Disubstituted 4(3H)-quinazolinones are an impor-
[15], which as green solvents and catalysts had been
successfully applied to the synthesis of 4(3H)-quina-
zolinones. These reports demonstrated the advantages
of reactions carried out in one-pot under solvent-free
conditions with high yields; the products can be isolated
and purified easily and ionic liquids could be recycled.
Unfortunately, these methods are only applicable for
the synthesis of 3-substituted and 2-substituted 4(3H)-
quinazolinones. Herein, we describe a practical, rapid
and simple procedure for synthesis of 2, 3-disubstituted
tant class of fused aromatic heterocycles with a broad
spectrum of biological activities [1–7]. Traditionally,
these compounds were prepared by condensation of isa-
toic anhydride, amines and orthoesters in the presence of
acid catalysts [8]; other commonly used synthetic method
involves the amidation of benzoxazinones with arylamines
[
9]. However, these methods are limited in that only aryl
groups at C-2 or N-3 position are tolerated. In order to
overcome this limitation, novel synthetic approaches have
4
(3H)-quinazolinones via multi-component reactions of
anthranilic acid, acyl chlorides and alkyl- or arylamines
X. Li (*) · Q. Lin
using two long-chain double SO H-functionalized
Department of Chemistry and Chemical Engineering, Minjiang
University, Fuzhou 350108, China
e-mail: lixinzhong99@126.com
3
SBAILs‑1 and 2 as reusable catalysts under microwave
irradiation and solvent-free conditions. This synthetic
strategy combines the merits of ionic liquids and micro-
wave irradiation for the green synthesis of 2, 3-disubsti-
tuted 4(3H)-quinazolinones (Fig. 1).
L. Wang
School of Chemistry and Chemical Engineering, South China
University of Technology, Guangzhou 510640, China
1
3

8
98
J IRAN CHEM SOC (2015) 12:897–901
N
N
SO H
N
SO H
3
3
Me
HSO4
HSO4
(A)
(B)
SO H
3
3
HSO4 H
N
SO H
3
N
N
HO3S
N
N
HO3S
2
HSO4
(
SBAILs -1)
(SBAILs-2)
O
SBAILs-1-2
R1
CO H
2
(
10mol%)
N
1
2
+
R NH
+
R COCl
2
MW
NH2
N
R2
(
4-8 min)
Solvent-free
1
2
3
4(a-i)
1
2
1
2
1
2
a) R =R =C H , b) R =4-MeC H , R =C H , c) R =4-ClC H , R =C H
6
5
6
4
6
5
6
5
6
5
1
2
1
2
1
2
d) R =4-NO C H , R =C H , e) R =4-CNC H , R =C H , f) R =n-C H , R =C H
2
6
4
6
5
6
4
6
5
4
9
6
5
1
2
1
2
1
2
g) R = C H , R =n-C H , h) R = 4-MeC H , R =n-C H , i) R =4-ClC H , R = n-C H
6
5
15 31
6
4
15 31
6
4
15 31
1
2
1
2
j) R =4-NO C H , R =n-C H , k) R =n-C H , R =n-C H
2
6
4
15 31
4
9
15 31
Fig. 1 Synthesis of 2,3-disubstituted 4(3H)-quinazolinones in the presence of long-chain double SO H-functionalized acidic ionic liquids under
3
microwave irradiation
Results and discussion
into diamide via the ring opening reaction [9, 18]. (2)
The excellent solubility of SBAILs‑1 and 2 in water.
The water generated during the cyclization of diamide
could enter into the ionic liquids phase easily from the
organic substrates, which induced a spontaneous phase
separation, this behavior drive the reaction being car-
ried out completely. (3) The microwave irradiation effect
[19]. The reaction of anthranilic acid with benzoyl chlo-
ride and aniline was carried out at 80 °C for 8 h in a
oil bath was investigated, the 2, 3-diphenyl 4(3H)-quina-
zoline was obtained in the yield of 27 %. Thus, micro-
waves have an essential influence on the progress of the
reaction.
With the aim to develop green, efficient, and generality
approaches for synthesis of 2, 3-disubstituted 4(3H)-
quinazolinones, the reaction of anthranilic acid with ben-
zoyl chloride and aniline using SBAILs‑1 and 2 as cata-
lyst under microwave irradiation were chosen as model
reactions. Under the optimum conditions, the results of
reactions are summarized in Table 1. SBAILs‑1 and 2
both exhibited high catalytic activity and led to excellent
yields in 4 min after simple work-up. Based on this suc-
cess, we further expanded the range of substrates, and
the results are listed in Table 1. All reactions proceeded
smoothly and gave the corresponding 2, 3-disubstituted
As shown in Table 1, due to substituent effect, there are
no the corresponding 4(3H)-quinazolines were obtained for
aromatic amines with strong electron-withdrawing groups.
For the purpose of comparison, the reaction of anthranilic
acid with benzoyl chloride and aniline was also carried
4
(3H)-quinazolinones with good to excellent yields.
These good results may be ascribed to the following
facts: (1) The strong polarity of SBAILs‑1 and 2. Which
promote the intermediate benzoxazinone conversion
1
3

J IRAN CHEM SOC (2015) 12:897–901
899
Table 1 Synthesis of 2, 3-disubstituted 4(3H)-quinazolinone in SBAILs‑1 and 2 under microwave irradiation
R2
R1
Time (min)
Yield SBAILs-1/SBAILs-2 (%)
b
M.p. (°C)
References
Compound no.
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
Ph
Ph
4
4
6
6
6
4
4
4
8
8
8
89/86
87/91
83/79
0
156–158 (157–158)
[10]
[11]
[13]
Ph
4-MeC H
177–179 (177–179)
6
4
Ph
4-ClC H
188–190 (190)
6
4
Ph
4-NO C H
4
–
2
6
Ph
4-CNC H
0
–
6
4
Ph
C H
85/82
92/89
94/93
82/76
0
67–70 (68–70)
[9]
4
9
g
h
i
n-C H
Ph
88–90
95–97
50–53
–
1
5
31
31
31
31
31
n-C H
4-MeC H
1
5
6
4
n-C H
4-ClC H
4
1
5
6
j
n-C H
4-NO C H
1
5
2
6
4
k
n-C H
n-C H
9
0
–
1
5
4
Reaction conditions:anthranilic acid:acyl chloride:amine:SBAILs = 1:1.2:1.2:0.1 (mol); microwave power is 300 W
O
O
OH
-HCl
OH
+
RCOCl
O
NH2
N
H
R
(
1)
SO3H
SO H
O
SBAILs
3
O
H
R1
N
O
-
H O
2
1
NH
+
R NH
2
O
N
R
N
HO3S
HO3S
(
3)
(
2)
SBAILs
R
O
N
R1
MW
H O
-
2
R
Fig. 2 The proposed mechanism of synthesis of 2, 3-disubstituted 4(3H)-quinazolinones catalyzed by long-chain double SO H-functionalized
3
Brønsted acidic ionic liquids under microwave irradiation
out in single sulfonic acid functionalized BAILs A and B
Fig. 1). Under the same reaction conditions, the yields of
, 3-diphenyl 4(3H)-quinazoline were 73 and 69 %, respec-
attack of amines in the presence of SBAILs‑1 and 2.
Finally, the expected products were prepared by intermo-
lecular ring-closure of intermediate 3.
(
2
tively; the reason may be ascribed to the lower acidity of
BAILs A and B.
In order to investigate the recyclable of SBAILs‑1 and
2, the reaction of anthranilic acid with benzoyl chloride and
aniline was chosen as model reaction; the reaction results are
listed in Table 2. There are no noticeable decreases in cata-
lyst activity after SBAILs‑1 and 2 have been reused three
times. The slight decrease in yields might be due to the slight
degradation of SBAILs‑1 and 2 during their regeneration.
Based on current experimental results and previous
reports [9,18], a plausible mechanism is proposed in Fig. 2.
First, anthranilic acid reacted with active acyl chloride and
gave intermediate 1, which then converted into key inter-
mediate 3 by intermolecular cyclization and nucleophlic
1
3

9
00
J IRAN CHEM SOC (2015) 12:897–901
Yield (%) (SBAILs-1/SBAILs-2
Table 2 Recycling of SBAILs‑1‑2 in reaction of anthranilic acid with benzoyl chloride and aniline
Run
Molar ratio of acid/chloride/amine/ILs (mol)
MW power (W)
Time (min)
1
2
3
1:1.2:1.2:0.1
1:1.2:1.2:0.1
1:1.2:1.2:0.1
300
300
300
4
4
4
88/85
87/84
87/84
Experimental
400 MHz) δ(ppm): 8.36 (d, J = 7.8, 1H), 7.84 (m, 2H), 7.02–
.62 (m, 10H), 2.50 (s, 3H, –CH ); Anal. Calcd. for C H N O:
7
3
21 16 2
Materials and methods
C, 80.78; H, 5.12; N, 8.97. Found: C, 80.75; H, 5.14; N, 9.02.
‑Phenyl‑3‑(4‑chlorophenyl) 4(3H)‑quinazolinone(4c)
White crystal, m.p. 188–190 °C;IR (KBr): 3,058, 1,655,
2
IR spectra were recorded on a Perkin-Elmer FT-IR 240-c
spectrophotometer using KBr optics. H NMR (400 MHz)
spectra were recorded on Bruker spectrometer in D O with
1
2
−1
1
1
,596, 1,578, 1,519, 1,491, 824, 691 cm ; H NMR
DSS as internal standard. The microwave devices were CEM
Discover system (Model No. DUS107 manufactured by
CEM Company in USA). N-Methylimidazole was purified
by distillation before use, and the other chemicals were of
commercial grade and used as received without further puri-
fication unless otherwise stated. Brønsted acidic ionic liquids
SBAILs‑1 and 2 [16] and A and B [17] were synthesized
according to the methods reported in the literature cited.
(
3
7
CDCl , 400 MHz) δ(ppm): 8.35 (d, J = 7.8, 1H), 7.86 (m,
3
H), 7.12–7.62 (m, 9H); Anal. Calcd. for C H N ClO: C,
20 13 2
2.18; H, 3.91; N, 8.42. Found: C, 72.13; H, 3.95; N, 8.39.
2
‑Phenyl‑3‑butyl 4(3H)‑quinazolinone(4f)
White crystal, m.p. 67–70 °C; IR (KBr): 3,057, 2,957, 1,670,
−
,607, 1,587, 1,567, 701 cm ; H NMR (CDCl , 400 MHz)
3
1 1
1
δ(ppm): 8.34 (d, J = 7.8, 1H), 7.70–7.80 (m, 2H), 7.51–7.62
General procedure for the synthesis of 2, 3-disubstituted
(
m, 2H), 4.02 (t, N–CH , 2H), 1.60 (m, 2H), 1.20 (m, 2H),
4
(3H)-quinazolinones(4a‑4j)
2
0
.81 (t, 3H); Anal. Calcd. for C H N O: C, 77.70; H, 6.48;
18 18 2
N, 10.07. Found: C, 77.68; H, 6.43; N, 10.02.
‑Pentadecyl‑3‑phenyl 4(3H)‑quinazolinone(4 g)
White crystal, m.p. 88–90 °C;IR (KBr): 3,062, 2,918, 1,684,
A mixture of anthranilic acid (3.6 mmol), acyl chloride
4.3 mmol) and amine (4.3 mmol) was added SBAILs‑1 or
(
2
SBAILs‑2 (0.36 mmol). After stirring at room temperature
for 15 min, the mixture was subjected to microwave irradi-
ation at 300 W for a specified time (Table 2). The progress
of the reaction was monitored by TLC (silica gel 60 F 254
TLC plates, ethyl acetate: cyclohexane, 1:1 v/v). On com-
pletion, the mixture was washed with water (3 × 30 mL),
−
,608, 1,589, 1,572, 693 cm ; H NMR (CDCl , 400 MHz)
3
1 1
1
δ(ppm) 8.27 (d, J = 7.8, 1H), 7.78 (m, 1H), 7.12-7.64 (m,
7
0
8
H), 2.52 (t, J = 7.4, N–CH , 2H), 1.02–1.73 (m, 26H),
2
.91 (t, J = 7.2, –CH , 3H); Anal. Calcd. for C H N O: C,
saturated NaHCO solution (3 × 30 mL) and 5 % HCl
3
29 40
2
3
0.57; H, 9.25; N, 6.78. Found: C, 80.55; H, 9.24; N, 6.74.
aqueous (3 × 30 mL), respectively, The rude product was
collected and recrystallized in hot ethanol; the target com-
pounds were obtained as crystalline solids.
2
‑Pentadecyl‑3‑(4‑methylphenyl) 4(3H)‑quinazolinone(4 h)
Characterization data for target compounds
White crystal, m.p. 95–97 °C; IR (KBr): 3,062, 2,918,
1
−
,661, 1,595, 1,571, 1,530, 772 cm ; H NMR (CDCl ,
3
1 1
2
, 3‑Diphenyl 4(3H)‑quinazolinone (4a)
400 MHz) δ(ppm): 8.28 (d, J = 7.2, 1H), 7.78 (m, 1H),
7
.50-7.70 (m, 2H), 7.12–7.40 (m, 4H), 2.50 (t, J = 7.6,
White crystal, m.p. 156–158 °C; IR (KBr): 1,683, 1,599,
N–CH2, 2H), 1.02–1.70 (m, 26H), 0.91 (t, J = 7.2, –CH3,
3H); Anal. Calcd. for C30H42N2O: C, 80.73; H, 9.41;
N,6.27. Found: C, 80.75; H, 9.39; N, 6.24.
−
1 1
1
4
7
,584, 1,555, 1,532, 1,489, 690 cm ; H NMR (CDCl ,
3
00 MHz) δ(ppm): 8.36 (d, J = 7.2 Hz, 1H), 7.86 (m, 3H),
.13–7.60 (m, 9H); Anal. Calcd. for C H N O: C, 80.55;
2
0
14
2
H, 4.69; N, 9.39. Found: C, 80.58; H, 4.72; N, 9.41.
‑Phenyl‑3‑(4‑methylphenyl) 4(3H)‑quinazolinone (4b)
White crystal, m.p. 177–179 °C; IR (KBr): 3,033, 1,678,
2‑Pentadecyl‑3‑(4‑chlorophenyl) 4(3H)‑quinazolinone(4i)
2
White crystal, m.p. 50–53 °C; IR (KBr): 3,063, 2,917,
−
1 1
1
,682, 1,607, 1,589, 1,571, 1,490, 831, 696 cm ; H NMR
(CDCl , 400 MHz) δ(ppm) 8.26 (d, J = 7.8, 1H), 7.78
3
−1 1
1
,604, 1,587, 1,562, 1,510, 808, 768 cm ; H NMR (CDCl ,
(d, J = 7.2, 1H), 7.51–7.72 (m, 2H), 7.11–7.40 (m, 4H),
3
1
3

J IRAN CHEM SOC (2015) 12:897–901
901
2
2
7
.42 (t, J = 7.4, N–CH , 2H), 1.70 (m, 2H), 1.20–1.42 (m,
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3
29 39
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5
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After reaction, the aqueous phase that contained the
SBAILs‑1 or SBAILs‑2 was collected and washed thor-
oughly with ethyl ether (3 × 7.5 mL) and dried at 105 °C
for 8 h under high vacuum, then reused for the next run.
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both ionic liquids and microwave irradiation and provides a
rapid, simple, high efficient and eco-friendly approach for
the synthesis 2,3-disubstituted 4(3H)-quinazolinone.
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Acknowledgments We are grateful to the Natural Science Founda-
tion of Fujian Province (2013J01053), the Research Project of Fujian
Province Education Department (JA13252), and the Research Project
of Fuzhou City (2012-G-138) for financial supports.
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