Zeolite-catalyzed method for the preparation of 2,3-dihydroquinazolin-4(1H) -ones

Article abstract of DOI:10.1080/00397911.2014.894525

The reaction of isatoic anhydride, amines, and aldehydes in the presence of a microporous zeolite gave 2,3-dihydroquinazolin-4(1H)-one derivatives with good to excellent yield. The yield depends on the structure of the aldehyde and/or amine compound. Copyright

Full text of DOI:10.1080/00397911.2014.894525

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Zeolite Catalysed Method for the Preparation of 2,3-
Dihydroquinazolin-4(1H)-ones
Anna Takács a , Anna Fodor a , János Németh a & Zoltán Hell a
a Department of Organic Chemistry and Technology , Budapest University of Technology and
Economics
Accepted author version posted online: 22 Apr 2014.Published online: 22 Apr 2014.
To cite this article: Anna Takács , Anna Fodor , János Németh & Zoltán Hell (2014): Zeolite Catalysed Method for
the Preparation of 2,3-Dihydroquinazolin-4(1H)-ones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.894525
To link to this article: http://dx.doi.org/10.1080/00397911.2014.894525
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Zeolite Catalysed Method for the Preparation of 2,3-dihydroquinazolin-4(1H)-ones
Anna Takács1, Anna Fodor1, János Németh1, Zoltán Hell1
1Department of Organic Chemistry and Technology, Budapest University of Technology
and Economics
Corresponding author: Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest H-1521, Hungary, Email:
zhell@mail.bme.hu
Abstract
The reaction of isatoic anhydride, amines and aldehydes in the presence of a microporous
zeolite gave 2,3-dihydroquinazolin-4(1H)-one derivatives with good to excellent yield.
The yield depends on the structure of the aldehyde and/or amine compound.
O
O
O
R1
N
E4a
O
R1-NH2
+
+
N
H
N
H
O
R2
R2
3
4
1
2
KEYWORDS: Heterogeneous catalysis, zeolites, quinazolines, multicomponent
reaction, isatoic anhydride.
INTRODUCTION
Nowadays a major challenge for chemists in the synthetic organic chemistry is the
development of environmentally more benign synthetic methods. An important tool in
this work is the elaboration of heterogeneous catalytic processes. Among the catalysts
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developed, natural, artifical or modified mineral-type catalysts have great importance,
since they are generally non-toxic, non-corrosive and often recyclable or even reusable.
In the frame of our work in the field of heterogeneous catalysis, we investigated the
catalytic properties of a zeolite-type small pore size adsorbent, Ersorb-4 (E4) and its more
acidic derivative (E4a). Ersorb-4 (E4) is a clinoptylolite-type zeolite material with high
silicon content (Si/Al ratio 5:1). The original mineral was modified with ionic exchanges
and with other water-phase technologies followed by a thermal treatment yielding a Ca–
K mixed cation-based adsorbent with 4Å pore size. The chemical composition of E4 is
described in Table 1. It has a specific surface area of 40 m2/g (determined by the BET-
method with nitrogen at the temperature of liquid nitrogen). Due to the high Si/Al ratio it
has high acid-proof property; its crystalline structure does not change even after a
longtime treatment in hot 4 N hydrochloric acid. E4 has a slightly surfacial acidic
character (the pH of its aqueous suspension is 4,87). The high silicon content yields high
chemical resistance. It is stable until 500–600 °C. It can adsorb small molecules such as
water, hydrochloric acid, ammonia, methanol or hydrogen sulfide. It has several
advantages, e.g. environmentally-friendly, non-toxic, inexpensive, recoverable and/or
reusable. The small pore size does not allow the adsorption of molecules larger than
methanol in the pores. Based upon this adsorption ability, E4 has been used as large
spectral drying agent (molecular sieve) in both gaseous and liquid phases, suitable for the
dehydration of gaseous hydrochloric acid or even liquid chlorine and sulfur-dioxide.
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E4a is obtained from E4 with ionic exchanges and other treatments. This provides a
change in the surfacial acidity of the material, so that a more acidic (pH 4.35) version of
E4 was achieved. During these treatments the amount of iron and aluminium does not
change significantly but a considerable change in calcium magnesium and potassium
content (Table 1) can be observed. The clinoptylolite-structure does not modify, which
has been proved by the XRD profile of the materials. (Figure 1.).
The acidity of E4 and E4a have been determined by pyridine adsorption method. Thus, in
E4 the amount of Lewis and Brønsted acid sites are 14 and 16 µmol/g, respectively, while
in E4a the corresponding values are 17 and 25 µmol/g, respectively[1].
During our research work with E4 a number of simple methods were elaborated for the
preparation of different heterocycles, e.g. dihydro-[2] and tetrahydroisoquinolines[3], 1,5-
benzodiazepines[4], 1,2-dihydroquinolines[1], etc. E4a was successfully applied in the
synthesis of 3,4-dihydro-pyrimidin-2(1H)-ones in the multicomponent Biginelli
reaction[5]. Continuing this work we investigated the condensation of isatoic anhydride
with amines and aldehydes yielding 2,3-dihydroquinazolin-4(1H)-ones. This reaction was
recently examined using i.a. strontium(II) chloride hexahydrate,[6] Fe3O4 nanoparticles,[7]
citric acid,[8] ZnO nanoparticles,[9] acetic acid,[10] sulfuric acid and silica gel,[11]
montmorillonite K10,[12] L-proline[13] or Amberlyst-15[14] under microwave irradiation, a
Lewis acid-surfactant-combined catalyst, zinc(II) perfluorooctanoate,[15] ionic liquid
[Hmim][NO3],[16] or Bi(NO3)3·5H2O.[17] Some of these catalysts are expensive, not
reusable and/or harmful for the environment.
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RESULTS AND DISCUSSION
First the optimal reaction conditions were examined. The reaction of isatoic anhydride,
butylamine and benzaldehyde was chosen as model reaction (Scheme 1). The results are
summarized in Table 2.
The best results were obtained in ethanol using E4a (Table 2, entry 4); the desired
quinazoline 4a was obtained almost quantitatively. Using these conditions the reaction of
different amines and aldehydes were examined (Scheme 2, Table 3). Good results were
obtained when n-butylamine and aromatic aldehydes were used (Table 3, entries 1-6),
except in case of 2-chlorobenzaldehyde (Table 3, entry 7), probably because of steric
hindrance.
Aniline gave also the expected products in ethanol with variable yield (Table 3, entries 8-
10). In toluene the expected product was obtained with poorer yield (Table 3, entry 8) or
only the appropriate Schiff’s base 5i could be isolated (Table 3, entry 9).
Aralkyl amines (2-phenylethylamine and 3-phenylpropylamine) and benzaldehyde also
gave the appropriate 2,3-dihydroquinazolin-4(1H)-one derivatives (Table 3, entries 11
and 12), in case of 3-phenylpropylamine with excellent yield.
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ortho-Substituted aniline derivatives gave only the appropriate Schiff’s bases (5m, 5n),
probably because of steric hindrance (Table 3, entries 13 and 14), the expected product
was not obtained even after longer heating (Scheme 3).
We also tried to investigate the stereochemical aspects of the reaction. But from the
mixture of (R)-1-phenyl-ethylamine, isatoic anhydride and benzaldehyde (Table 3, entry
15) only 2-amino-N-(1-phenylethyl)benzamide 6o could be isolated after column
chromatography (Scheme 4).
The workup of the reaction mixture was very easy, the catalyst was filtered out and the
solvent was evaporated.
An important factor in the characterization of a heterogeneous catalyst is the recyclability
or reusability. We tested the reusability of E4 in the reaction of isatoic anhydride,
benzaldehyde and n-butylamine. Thus, the catalyst filtered out from the reaction mixture
was washed with acetone, dried at 110 °C for 4 h and reused. The yields obtained in the
2nd and 3rd experiments were 93 and 91%, respectively.
In summary, a heterogeneous catalytic method was developed for the the preparation of
2,3-dihydroquinazolin-4(1H)-one derivatives. This microporous zeolyte catalysed
reaction provides a simple and environmentally benign alternative for the
multicomponent reaction of isatoic anhydride, amines and aldehydes. The experimental
and work-up procedure is simple. Excellent yields have been obtained with n-butylamine
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or aralkyl amines and aromatic aldehydes, varibale results were obtained with aniline
derivatives.
The yields are comparable with the yields obtained with other methods. Some examples
are shown in Table 4.
EXPERIMENTAL
The commercial chemicals were purchased from Merck-Hungary Ltd. except E4 and
E4a, which are the products of Erdőkémia-ker Ltd., Hungary. 1H NMR spectra were
recorded on a BRUKER Avanche-300 instrument using TMS as an internal standard in
CDCl3. GC-MS spectra were made on Shimadzu GC-2010, GC-MS QP2010S
instruments. Thin layer chromatography was carried out using Merck Kieselgel 60 F254
plates with eluents hexane:acetone 4:1 or hexane:acetone 2:1, detection either by UV
light at 254 nm or by heating after spraying with phosphoromolybdic acid solution.
Column chromatography was carried out on Merck Kieselgel 63–200 mesh with hexane-
acetone 4:1 or 2:1 eluents. Melting points are uncorrected and were measured on
Gallenkamp instrument. Elemental analyses data of the new compounds were found to be
in good agreement (±0.3%) with the calculated values.
Pretreatment Of The Catalyst
Before each experiment the sample of E4a was powdered and heated at 100 ˚C for 1h.
A Typical Protocol For The Reaction
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A mixture of 0.82 g (5 mmol) of isatoic anhydride, 5 mmol of the appropriate amine, 5
mmol of the aldehyde and 0.5 g E4a in 10 cm3 ethanol was heated at 80 ˚C for 10-20 h
(as indicated in Table 2). The solid was filtered off, washed with the same solvent, the
filtrate was evaporated. Pure products were obtained by column chromatography
(Kieselgel, hexanes:acetone 4:1).
3-Butyl-2-Phenyl-2,3-Dihydroquinazolin-4(1H)-One (4a)
Yield 95%, white solid, mp 127-130 ˚C (ethanol; lit. 127-128˚C[18]); 1H NMR (300 MHz,
CDCl3[15]) δ (ppm): 0,84 (t, 3H); 1,26-1,29 (m, 2H); 1,52-1,57 (m, 2H); 2,68-2,77 (m,
1H); 3,88-3,98 (m, 1H); 4,45 (s, 1H); 5,71 (s, 1H); 6,48 (d, 1H); 6,80 (t, 1H); 7,20-7,33
(m, 6H); 7,93 (d, 1H); 13C NMR (75 MHz, CDCl3[19]) δ (ppm): 13.9, 20.5, 30.4, 44.7,
72.5, 112.3, 114.6, 115.8, 117.6, 119.4, 119.9, 127.1, 129.6, 133.8, 142.8, 145.1, 161.4;
Anal. Calcd. for C18H20N2O: C 77.14, H 7.14, N 10.00%, found: C 77.23, H 7.19, N
9.74%.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website. Please
make the words "publisher's website" a live DOI link.
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Table 1 Chemical composition of E4 and E4a
Component (w/w%)
E4
E4a
SiO2
73.0
11.2
1.7
76.7
12.2
1.19
2.87
0.34
0.53
0.13
Al2O3
Fe2O3
K2O
5.2
Na2O
CaO
0.38
2.20
0.44
MgO
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Table 2 Determination of the optimal reaction conditions
Entry
Catalyst
Solvent
Reaction time
Yielda (%)
(h)
10
7
1
2
3
4
E4
toluene
30
E4a
E4a
E4a
acetonitrile
toluene
40
10
10
35
ethanol
98 (95b)
aCrude product
bRecrystallized product
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Table 3 Multicomponent reaction of isatoic anhydride with different amines and
aldehydes
Entry R1
R2
Reaction
time/h
10
Product
Yielda/%
1
n-C4H9
H
4a
95
2
n-C4H9
3-OCH3
4-NO2
3-NO2
4-OCH3
4-Cl
2-Cl
H
11
4b
4c
98
3
n-C4H9
11
96
4
n-C4H9
11
4d
4e
97
5
n-C4H9
14
93
6
n-C4H9
10
4f
75
7
n-C4H9
10
4g
50
8
C6H5
10
4h
4i (5i)b
4j
76 (22)b
95 (–)b,c
78
9
C6H5
3-NO2
4-OCH3
H
10
10
11
12
13
14
15
C6H5
14
C6H5-(CH2)2
C6H5-(CH2)3
2-C(CH3)3-C6H4
2-Br-C6H4
(R)-(+)-
17
4k
4l
60
H
15
96
c
H
20
5m
5n
6o
–
b,c
H
15
–
c
H
24
–
CH(CH3)C6H5
aIsolated yield
bIn toluene
cNot determined
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Table 4. Comparison of the yield obtained with referred values
Compound Yield
Referred yield
75[6]
Referred conditions
aq. ethanol, 6 h, reflux
neat, 80 °C, 1 h
1
2
3
4
4a
4d
4h
4j
95
97
76
78
92[17]
80[7]
water, 2 h, reflux, 15
mol% catalyst
88[7]
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Figure 1. XRD profiles of E4 (upper diagram) and E4a (lower diagram)
XRD diffractogram
1200
1000
800
600
400
200
0
5
10
15
20
25
30
35
40
45
50
55
60
2 Θ
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Scheme 1
O
O
O
N
O
+
+
NH2
N
H
N
H
O
4a
1
3a
2a
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Scheme 2
O
O
O
R1
N
E4a
O
R1-NH2
+
+
N
H
N
H
O
R2
R2
3
4
1
2
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Scheme 3
O
R2
E4a
N
R1-NH2
R1
+
R2
3
5
2
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Scheme 4
NH2
O
O
E4a
N
H
O
+
NH2
N
H
O
6o
1
2o
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