Base mediated synthesis of 2-aryl-2,3-dihydroquinazolin-4(1H)-ones from 2-aminobenzonitriles and aromatic aldehydes in water

Article abstract of DOI:10.1039/c3ob42434k

An environmentally friendly and mild procedure to obtain 2,3-dihydroquinazolin-4(1H)-ones from 2-aminobenzonitriles and aromatic aldehydes has been developed. The reactions took place in water with inorganic base (K₃PO₄) as the only promoter. Various desired products have been prepared in moderate to good yields under identical conditions. Further transformation of dihydroquinazolinones to quinazolinones was carried out as well with TBHP as the oxidant.

Full text of DOI:10.1039/c3ob42434k

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Base mediated synthesis of 2-aryl-2,3-
dihydroquinazolin-4(1H)-ones from
2-aminobenzonitriles and aromatic aldehydes
in water†
Cite this: DOI: 10.1039/c3ob42434k
Received 5th December 2013,
Accepted 23rd January 2014
Xiao-Feng Wu,*a,b Stefan Oschatz,b,c Axel Block,b,c Anke Spannenbergb and
DOI: 10.1039/c3ob42434k
www.rsc.org/obc
Peter Langer*b,c
An environmentally friendly and mild procedure to obtain 2,3-
dihydroquinazolin-4(1H)-ones from 2-aminobenzonitriles and
aromatic aldehydes has been developed. The reactions took place
in water with inorganic base (K3PO4) as the only promoter. Various
desired products have been prepared in moderate to good yields
under identical conditions. Further transformation of dihydroquin-
azolinones to quinazolinones was carried out as well with TBHP as
the oxidant.
Since the first synthesis of a heterocyclic compound, pyridine,
by W. Ramsey in 1877,1 numerous synthetic routes have been
developed to obtain these nitrogen-containing structures.2
Many biological processes involve these heterocycles as
markers or messenger molecules and an array of pharmaceuti-
cals and agrochemicals based on those chemicals have been
reported during the past few decades. In this context, 2,3-dihydro-
quinazolinones as well as the oxidized form, the quinazoli-
nones, represent an important class of substances with a wide
range of bioactivities such as thymidylate synthase inhibition,
antihypertensive effects and sedative effects.3 A selection of
bio-active quinazolinone derivatives are shown in Scheme 1.
Notably, these compounds are relevant building blocks in
organic synthesis to form more complex structures such as
natural products like luotonin A, sclerotigenin, fumiquinazo-
line A or ( )-cruciferane.
Scheme 1 Selected examples of biologically active quinazolinone
derivatives.
synthesis of 2,3-dihydroquinazolin-4(1H)-ones from isatoic
anhydride and aromatic aldehydes under solvent free con-
ditions using catalytic amounts of iodine.4 Another synthetic
strategy to give different 2-substituted dihydroquinazolinones
was published by Bunce and co-workers using 2-nitrobenz-
amides and carbonyl compounds as substrates with iron
powder as the promoter.5 More recently, Kesavan and Prakash
reported in 2012 about the enantioselective synthesis of 2,3-
dihydroquinazolin-4(1H)-ones from 2-aminobenzamides with
aldehydes using Sc(III) as a catalyst.6 Likewise, Wang and co-
Based on this wide range of applications of dihydroquin-
azolinones and their analogues, many pathways for the syn-
thesis of this alkaloid like structure have been described. For
example, Rostamizadeh et al. reported in 2008 about the
workers developed
a copper-catalyzed method to yield
2-thioxo-dihydroquinazolinones starting from 2-bromobenz-
amides and isothiocyanates.7 Additionally, Cheng et al. reported
about the asymmetric synthesis of dihydroquinazolinones
using (S)-TRIP as the catalyst.8 Furthermore, Li et al. published
in 2010 about the formation of 2,3-dihydroquinazolin-4(1H)-
ones from 2-aminobenzonitriles and carbonyl compounds
using ZnCl2 as a Lewis acid in refluxing DMF.9 On the other
hand, procedures for quinazolin-4(1H)-ones preparation based
aDepartment of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou,
Zhejiang Province, People’s Republic of China. E-mail: xiao-feng.wu@catalysis.de
bLeibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a,
18059 Rostock, Germany
cUniversität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock,
Germany. E-mail: peter.langer@uni-rostock.de
†Electronic supplementary information (ESI) available: General procedure, NMR
data and spectra, X-ray data. CCDC 975991. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c3ob42434k
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on different catalysts and substrates were developed as
well.10–13
As a part of our contribution to the heterocyclic building
block synthesis, we wish to present herein a convenient and
facile way to obtain 2,3-dihydroquinazoline-4(1H)-ones.
A
Fig. 1 2-Phenyl-1H-benzo[d][1,3]oxazin-4(2H)-imine (1), 2-phenyl-2,3-
dihydroquinazolin-4(1H)-one (2) and p-isopropylphenyl-2,3-dihydroquin-
azolin-4(1H)-one (3).
range of different substituted compounds were obtained from
2-aminobenzonitriles and different aldehydes via a base
mediated tandem imine condensation–cyclization reaction.
Interestingly, the reactions were carried out only with the
addition of a base and using water as a cheap, environmentally
friendly and harmless solvent.14 No additional catalyst was
needed and the desired products were produced in good
yields. Additionally, a two-step-one-pot oxidation to obtain
2-phenyl-quinazolinone was realized without problem.
The model reaction was carried out using simple 2-amino-
benzonitrile and 1.2 equiv. of benzaldehyde in water with
K3PO4 as the base. The desired product was isolated in good
yields. Lowering the temperature below 100 °C resulted in a
decrease of the yield which can be explained by the solubility
of the substrates. The strong base dependency of the activation
of the nitrile group leads to the need for an equimolar amount
of a promoter. Hence, catalytic amounts of the base did not
give any isolatable product at all. Changing the base from
K3PO4 to KOH resulted in a slight increase of the yield
(Table 1, entry 6). The reaction works as well in organic
solvents, such as DMF, DMSO, or toluene, but with lower
conversion and selectivity.
Two similar structures 2-phenyl-1H-benzo[d][1,3]oxazin-
4(2H)-imine (1)15 and 2-phenyl-2,3-dihydroquinazolin-4(H)-one
(2)9 have been reported as the products from the reaction
between 2-aminobenzonitrile and benzaldehyde under similar
reaction conditions respectively (Fig. 1). Regarding the un-
certainty of the structure, we paid special attention to the
structure analysis of the model substance.
Since mass spectroscopic studies as well as 1D-NMR experi-
ments did not give the needed information on the present
structure, we focused on 2D-NMR studies. At first, the coupl-
ings of the two amino-protons with the benzylic hydrogen
atom (pos. 2) are visible in the H–H-COSY spectrum. Addition-
ally, the interaction of these three nuclei can be confirmed by
NOESY experiment. Furthermore, the correlation of the amino-
protons with the hydrogens (Fig. 2) attached to the phenyl ring
(pos. 10 and 14) can be observed. Also, no interaction of the
amino proton (3) with the quinazolinone ring can be detected.
Fig. 2 2D-NMR-coupling pattern of 2, crystal structure and packing
diagram of compound 3, bond length (Å): O(1)–C(2) 1.2448(14), N(1)–
C(1) 1.4542(16), N(2)–C(1) 1.4641(16), N(2)–C(2) 1.3420(15), C(1)–C(9)
1.5123(18), C(2)–C(3) 1.4785(16), C(3)–C(4) 1.3941(17), C(3)–C(8)
1.4044(17), C(4)–C(5) 1.3804(18), C(5)–C(6) 1.390(2), C(6)–C(7)
1.3825(19), C(7)–C(8) 1.4046(18), C(9)–C(10) 1.3780(17), C(9)–C(14)
1.3903(17), C(10)–C(11) 1.3840(18), C(11)–C(12) 1.3857(18), C(12)–C(13)
1.3980(17), C(12)–C(15) 1.5188(18), C(13)–C(14) 1.3859(18), C(15)–C(16)
1.5231(19), C(15)–C(17) 1.534(2).
This indicates that dihydroquinazolinone but not the isomeric
imino benzoxazine is the final product. The structure has also
been confirmed by X-ray analysis (Fig. 2) of the analogue iso-
propyl substituted compound (3). The N(1)–C(1) bond
(1.454 Å) and the C(1)–N(2) bond (1.464 Å) show significant
single bond lengths. Additionally, intermolecular N(1)–
H(1A)⋯O(1) (D–H 0.89(2) Å, H⋯A 2.17(2) Å, D⋯A 2.967(13) Å,
D–H⋯A 149.7(13)) and N(2)–H(2)⋯O(1) (D–H 0.89(2) Å, H⋯A
2.03(2) Å, D⋯A 2.918(13) Å, D–H⋯A 178.8(13)) weak hydrogen
bonds can be observed. Since the significant NH-signals in the
1H-NMR spectra of all isolated compounds follow the same
pattern, it can be assumed that both nitrogen atoms are endo-
cyclic. In addition, gas chromatographic analysis showed the
existence of both enantiomers.
Table 1 Influence of the base concentrationa
Entry
Base
Concentration
Yieldb
1
2
3
4
5
6
K2CO3
CsCO3
K3PO4
K3PO4
KOH
0.2 M
0.2 M
0.002 M
0.2 M
0.002 M
0.2 M
33%
0%
0%
73%
0%
75%
Afterwards, we investigated the limitations and effects of
different substituents on the benzonitrile and the aldehydes,
respectively. The substrates scope is shown in Table 2. Many
different substituted dihydroquinazolinones can be obtained
KOH
a 1 equiv. of 2-aminobenzonitrile, 1.2 equiv. of benzaldehyde, base,
5 mL H2O, 100 °C, 8 h. b Isolated yields.
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Table 2 Synthesis of 2,3-dihydroquinazolin-4(1H)-onesa
Entry
1
Amine
Aldehyde
Product 4
Yieldb (%)
75
2
3
4
58
23
41
5
6
7
8
9
14
0
43
66
43
10
11
64
26
12
13
14
64
0
58
15
22
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Table 2 (Contd.)
Entry
Amine
Aldehyde
Product 4
Yieldb (%)
80
16
17
49
18
19
37
60
20
21
28
0
22
0
a Reaction conditions: 1 equiv. 2-aminobenzonitriles, 1.2 equiv. aldehydes, 1 equiv. K3PO4, 5 mL H2O, 100 °C, 8 h. b Isolated yields.
by this method up to very good yields. Regarding the reaction
mechanism, we believe that the first step is the reaction
between 2-aminobenzonitrile and benzaldehyde to give the
corresponding 2-((hydroxy(phenyl)methyl)amino)benzonitrile.
Scheme 2 Quinazolinone synthesis from benzaldehyde.
This is followed by base assisted nucleophilic attack of OH− to
the nitrile group to give 2-phenyl-1H-benzo[d][1,3]oxazin-4(2H)-
imine as the intermediate which can result in the final
product after rearrangement.
(Table 2, entry 21). No reaction was detected with benzo-
phenone (Table 2, entry 22). Notably, no column purification
was needed for the products isolation. The pure products were
isolated by simple filtration.
Subsequently, we carried out the transformation of
2-phenyl-2,3-dihydroquinazolin-4-(1H)-one to quinazolinone.
By the addition of 4 equiv. of tert-butylhydroperoxide (TBHP)
to the crude reaction mixture from 2-phenyl-1,2-dihydroquina-
zolin-4(1H)-one and heating to 100 °C for 6 hours, 2-phenyl-
quinazolinone was obtained in good yield (Scheme 2). Using
H2O2 or decreasing amounts of oxidant led to less conversion
which was monitored by TLC (hexane–ethylacetate 8 : 2).
Various functional groups are tolerable under these con-
ditions and give the desired products in low to excellent yields.
In general, electron withdrawing groups on the aldehyde or
the 2-aminobenzonitrile, respectively, led to the decrease of
the yields. This can be explained by the reduced solubility of
the substrates. Also, methyl-substituents neighboring the
cyano-group or the aldehyde function did not give the quinazo-
linone due to the steric hindrance. The electronic effect may
be responsible for the results as well, as the ortho-methyl sub-
stituent decreases the activity of the nitrile group. This metho-
dology can also be applied to non-α-protic aldehydes such as
cyclohexane carboxaldehyde and isobutanal (Table 2, entries 9
and 10). For N-methylindole-3-carboxaldehyde, no desired
product could be obtained under these conditions. To our
delight, the related benzothiophene carboxaldehyde succeeded
in giving the dihydroquinazolinone product in 28% yield
Conclusions
In conclusion, an interesting and convenient procedure
for 2,3-dihydroquinazolin-4(1H)-ones synthesis has been
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developed. The desired products were isolated in good yields. General procedure for oxidation of 2,3-dihydroquinazolin-
A cheap inorganic base was applied as a promoter and water 4(1H)-ones to 2-phenyl-quinazolinone
was used as a green solvent for this transformation. One-pot
To the crude reaction mixture of the synthesis of 2,3-dihydro-
synthesis of quinazolinone from 2-aminobenzonitrile and
quinazolinone, 400 µL TBHP-solution (70% in H2O, 4 mmol)
benzaldehyde was realized as well by using TBHP as an
was added. The mixture was heated under stirring to 100 °C
oxidant. Notably, no column purification was needed; all the
for 6 hours. The conversion was monitored by TLC (hexane–
ethylacetate 8 : 2). When no dihydroquinazolinone was found
products were purified by filtration.
in TLC, the precipitate was filtered off and recrystallized from
ethylacetate–hexane, giving 134 mg (60%) 2-phenyl-quinazoli-
none. 1H-NMR (300 MHz, DMSO-d6): δ = 12.55 (s, 1H, NH),
3
3
8.23–8.13 (m, 3H, CH(7 + 10 + 14)), 7.85 (ddd, J = 8.5 Hz, J =
7.0 Hz, 3J = 1.6 Hz, CH(5)), 7.77–7.71 (m, 1H, CH(12)),
7.62–7.49 (m, 4H, CH(4 + 6 + 11 + 13)) ppm; 13C-NMR
Experimental section
General remarks
Distilled water was used as the solvent. All chemicals were (75 MHz, DMSO-d6): δ = 162.3 (CvO(4)), 152.4 (Cquart(2)),
commercially available and were used without further purifi- 148.7 (Cquart(8a)), 134.6 (CH(7)), 132.8 (Cquart(9)), 131.4 (CH-
cation. NMR-data were recorded using Bruker ARX 300 and (12)), 128.6 (CH(10 + 14)), 127.8 (CH(11 + 13)), 127.4 CH(6)),
1
Bruker ARX 400 spectrometers. 13C- and H-spectra were refer- 126.6 (CH(7)), 125.8 (CH(5)), 121.0 (Cquart(4a)) ppm; MS (EI,
enced to deuterated solvent signals. Peaks were characterized 70 eV): m/z (%) = 222 ([M]+, 100), 119 (99), 104 (11), 92 (14), 90
as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), (17), 77 (22), 76 (11), 51 (10).
triplet of triplets (tt), quartet (q) and multiplet (m). Gas-chromato-
graphy-mass-analysis was performed using an Agilent HP-5890
with an Agilent HP-5973 Mass Selective Detector (EI) and an
HP-5-capillary column using helium as a carrier gas. Column-
Acknowledgements
The authors thank the state of Mecklenburg-Vorpommern and
the Bundesministerium für Bildung und Forschung (BMBF)
for financial support. We also thank Drs W. Baumann,
C. Fischer, Ms S. Schareina and Ms S. Buchholz (LIKAT) for
analytical support. We also acknowledge general support from
Prof. Matthias Beller in LIKAT.
chromatography was carried out using Merck 60 Silica-Gel
(0.043–0.06 mm) and distilled solvents were used.
General procedure for the base mediated synthesis of
2,3-dihydroquinazolin-4(1H)-ones from 2-aminobenzonitriles
and aldehydes
A 25 mL pressure tube was charged with 1 mmol (118 mg)
2-aminobenzonitrile, 1.2 mmol benzaldehyde (122 µL, 127 mg),
1 mmol K3PO4 monohydrate (230 mg) and 5 mL water and sub-
sequently sealed. The mixture was heated under stirring at
100 °C for 8 hours. The white precipitate was filtered off under
reduced pressure and washed with water. The crude solid was
dissolved in the minimum amount of boiling ethylacetate and
recrystallized by the addition of n-hexane. Filtering and drying
of the white solid gave 169 mg (75%) 2-phenyl-2,3-dihydroqui-
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nazolin-4(1H)-one. H-NMR (250 MHz, DMSO-d6): δ = 8.28 (s,
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4
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