Eco-friendly H2O2 oxidation of 1,2-dihydroquinazoline-3-oxides to quinazoline-3-oxides

Article abstract of DOI:10.1080/00397911.2021.1934876

2-Aminobenzaldehyde, 1-(2-aminophenyl)ethanone, and 2-aminophenyl phenyl methanone oximes 1 were reacted with aromatic aldehydes to give the corresponding 1,2-dihydroquinazoline-3-oxides 2. The latter were converted in high yields to a series of quinazoli

Full text of DOI:10.1080/00397911.2021.1934876

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Eco-friendly H2O2 oxidation of 1,2-
dihydroquinazoline-3-oxides to quinazoline-3-
oxides
Rashinikumar Samandram, Meliha Çetin Korukçu & Necdet Coşkun
To cite this article: Rashinikumar Samandram, Meliha Çetin Korukçu & Necdet Coşkun (2021)
Eco-friendly H2O2 oxidation of 1,2-dihydroquinazoline-3-oxides to quinazoline-3-oxides, Synthetic
Communications, 51:15, 2349-2356, DOI: 10.1080/00397911.2021.1934876
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SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 15, 2349–2356
https://doi.org/10.1080/00397911.2021.1934876
Eco-friendly H2O2 oxidation of 1,2-dihydroquinazoline-3-
oxides to quinazoline-3-oxides
Rashinikumar Samandram , Meliha C¸etin Korukc¸u , and Necdet Cos¸kun
ꢀ
Departmentof Chemistry, Bursa Uludag University, Bursa, Turkey
ABSTRACT
ARTICLE HISTORY
Received 25 March 2021
2-Aminobenzaldehyde, 1-(2-aminophenyl)ethanone, and 2-amino-
phenyl phenyl methanone oximes 1 were reacted with aromatic
aldehydes to give the corresponding 1,2-dihydroquinazoline-3-oxides
2. The latter were converted in high yields to a series of quinazoline-
3-oxides 3 using an environmentally benign H2O2-tungstate oxidant
system at room temperature. A high yielding one-pot procedure was
also developed for the synthesis of compounds 3.
KEYWORDS
1,2-dihydroquinazoline-3-
oxide; H2O2 oxidation;
N-oxides; quinazoline;
quinazoline-3-oxide
GRAPHICAL ABSTRACT
CONTACT Necdet Cos¸kun
Uludag University, Bursa 16059 Nilufer, Turkey.
coskun@uludag.edu.tr
Department of Chemistry, Faculty of Arts and Sciences, Bursa
ꢀ
€
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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R. SAMANDRAM ET AL.
Introduction
The quinazoline ring system is an important structural unit frequently encountered in
medicinal chemistry as well as in organic synthesis.[1–3] Many alkaloids containing qui-
nazoline skeletons are known.[4–6] They constitute an important class of compounds
with anticonvulsant, antibacterial, antidiabetic, and anticancer activities.[1,7–10] Many
methods for the synthesis of quinazoline derivatives are known.[11–15] In an earlier
study, we have reported the synthesis of quinazoline-1-ols and their ring expansion
upon carbamoylation with aryl isocyanates.[16] Later on, 2-substituted-1,2,3,4-tetrahy-
droquinazolines were oxidized using the H2O2-tungstate system to give regioselectively
the corresponding quinazoline-1-oxides.[17] In the same report, the photochemical and
thermal behavior of the latter was discussed in detail. Afterward, a significant number
of studies on the synthesis of quinazoline-3-oxides have appeared in the literature.[18–21]
According to one approach,[18] 1,2-dihydroquinazoline-3-oxides were converted
to 4-methyl-2-substituted quinazolines by visible light irradiation. It was assumed a
light-induced water elimination from the dihydroquinazoline-3-oxide to give the
corresponding quinazoline. The water elimination in the case of 4-methyl-2-(4-nitro-
phenyl)-1,2-dihydroquinazoline-3-oxide was reported to be unsuccessful. A series of 2,4-
disubstituted quinazoline-3-oxides were synthesized by oxidation of the corresponding
1,2-dihydroquinazoline-3-oxides using activated MnO2.[22] This novel approach is sim-
ple and convenient and provides a series of 2,4-disubstituted quinazoline-3-oxides.
Hydrogen peroxide is a widely used green oxidant for many transformations.[23]
Oxidations of various organic compounds with aqueous H2O2 in the presence of cata-
lytic amounts of pharmacologically harmless tungstates are described in the
literature.[24]
In this work, the synthesis of 1,2-dihydroquinazoline-3-oxides and their eco-friendly
transformation into quinazoline-3-oxides using H2O2-tungstate oxidant system is
reported (Scheme 1).
Results and discussion
As a continuation of our investigations on the reactions of cyclic nitrones like 3,4-dihy-
droisoquinoline-2-oxides[25]
and
2,5-dihydro-1H-imidazole-3-oxides[26,27]
and
photochemical conversions of quinazoline-1-oxides[17] we needed a series of 4-unsubsti-
tuted-quinazoline-3-oxides 3a–j to investigate their photochemical as well as thermal
behaviors. To begin with, we have prepared first compounds 2a–j from the reaction of
amino oximes 1 with the corresponding aldehydes[18,28] (Scheme 1). The optimization
Scheme 1. The synthesis of 1,2-dihydroquinazoline- and quinazoline-3-oxides.

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Table 1. Optimization of the reaction conditions for the synthesis of compounds 2.
Entrya
Solvent (cat)
Yield (%)
1
2
3
4
5
6
7
CH2Cl2 (AgOTf)
CH2Cl2
94
96
96
93
94
91
97
CHCl3
Benzene
Toluene
MeOH/H2Ob
EtOH
aAll reactions were performed in 20 mL of solvent using equivalent amounts of oxime 1 (1 mmol) and the correspond-
ing aldehyde. The reaction mixtures were stirred at room temperature for 24 h. In the case of entry 1, 0.02 mol%
AgOTf was used as a catalyst. bThe solvent ratio is 1/1.
(Table 1) of the reaction conditions was conducted in the case of aminobenzaldehyde
oxime and p-nitrobenzaldehyde.
The reaction was first performed in CH2Cl2 at room temperature using AgOTf as a
catalyst and the corresponding 2a was obtained in 94% yield. The yield of the reaction
in the same solvent was 96% when it was performed in the absence of the catalyst.
Chloroform, benzene, and toluene were also good media for the conversion of 1 into
2a. However, ethanol proved to be the best solvent for the reaction at room
temperature.
Equimolar amounts of amino oxime 1 and aromatic aldehydes were dissolved in
ethanol and stirred at room temperature for ca 24 h. In all cases, except 2f the products
are precipitating and easily isolated by filtration. The precipitates were washed several
times with warm hexane then dried under vacuum. The structures and the yields of
compounds 2a–m are presented in Table 2.
Compounds 2k–l and 3k–l are known,[18,22] however to the best of our knowledge a
method for the synthesis and characterization data for 2a–j and 3a–j are not available
in the literature. Therefore, we propose a simple high yielding procedure for the synthe-
sis of compounds 2a–m and their oxidation with H2O2-tungstate in THF to the synthet-
ically important quinazoline-3-oxides 3a–m. The newly prepared compounds were
characterized by spectral as well as analytical methods.
Compound 2a was subjected to oxidation with AgOTf, MnO2, and KMnO4 (Table
3, entries 1–3) in DMSO, and the reaction product 3a was formed only in the cases
of entries 2–3 in low yields. No product formation was observed in the case of
AgOTf (Table 3, entry 1). The use of MnO2 and KMnO4 without solvent did not
produce the expected 3a (Table 3, entries 4–5). The use of KMnO4/MnO2 mixtures
in DMSO and DMF or without solvent produced the quinazoline-3-oxide in moder-
ate yields (Table 3, entries 6–8). The oxidation of 2a with the H2O2-Na2WO4 in
THF-H2O and THF provided the formation of product 3a in high yields at room

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R. SAMANDRAM ET AL.
Table 2. Structures and yieldsa,b of 1,2-dihydroquinazoline-3-oxides 2a–m.
aIsolated yields: bReaction conditions: amino oxime 1 and aldehyde each 1 mmol, dissolved in EtOH (20 mL) were stirred
at room temperature for 24 h (for compounds 2k–m, 47 h).
temperature (Table 3, entries 9–10). The use of dry THF proved to be the better
choice as a reaction solvent.
Compounds 2a–m were subjected to oxidation under the optimized conditions to
give compounds 3a–m in good to high yields (Table 4). The structures of compounds 3
were elucidated by elemental analysis, 1H and 13C NMR data. 4-Methyl-2-(4-nitro-
phenyl)-1,2-dihydroquinazoline-3-oxide 2k was identical with the one obtained by
irradiation of 1k in acetonitrile in the presence of Ru(bpy)3Cl2.[18] The first 4-unsubsti-
tuted quinazoline-3-oxide 3b was obtained in our lab as a by-product from the oxida-
tion of the corresponding tetrahydroquinazoline.[17] The physical and spectral data for
3b obtained by oxidation of 2b with H2O2-tungstate were the same as for our previ-
ously reported one.

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Table 3. Optimization of the reaction conditions for the synthesis of compounds 3.
Entry
Solvent
Oxidizing agent
AgOTfc
Time (h)
Temp (ꢀC)
Yield (%)a
1
2
3
4
5
6
7
8
DMSOb
DMSOb
DMSOb
8
90
130
130
rt
c
MnO2
23
22
8
52
43
c
KMnO4
c
MnO2
c
KMnO4
5
rt
DMSOb
DMFb
KMnO4/MnO2d
23
20
21
24
24
100
100
rt
rt
rt
49
47
52
74
92
d
KMnO4/MnO2d
KMnO4/MnO2e
H2O2-Na2WO4e
H2O2-Na2WO4
9
10
THF/H2Of
THFb
aIsolated yields; bThe reactions were performed in 4 mL of solvent with 1 mmol of 2a; c1 mmol of the oxidizer was
e
f
used; dThe ratio is 0.3/0.7; 4/0.05; 4 mL (1/1).
Scheme 2. One-pot synthesis of compounds 3b,c,e–g,i.
One-pot procedure involving the short time stirring of the amino oxime and alde-
hyde mixture in THF and addition of the oxidizing system provided compounds
3b,c,e–g,i with improved overall yields (Scheme 2, Table 4).
Experimental section
Materials and methods
Melting points were recorded on an Electrothermal Digital melting point apparatus. IR
1
spectra were obtained using a JASCO FT-IR 6800 spectrophotometer. H and 13C NMR
spectra were recorded on a Bruker at 600, Jeol 500, and Agilent 400 MHz spectrometers.
The elemental analyses were performed on TruSpec and EuroEA 3000 CHNS analyzers.
The compounds prepared were dried in a vacuum oven at room temperature.
Column chromatography was performed by using 70–230 mesh (0.063–0.200 mm) sil-
ica gel and preparative TLC with silica gel 60 HF254 (90% <45 mm) by using technical

2354
R. SAMANDRAM ET AL.
Table 4. Oxidation of 1,2-dihydroquinazoline-3-oxidesa,b 2a–m with H2O2-Na2WO4 in THF at rt.
aIsolated yields; The yields in the parenthesis are according to the one-pot procedure. bReaction conditions: To the solu-
tion of compound 2 (1 mmol) in THF (4 mL), H2O2 (4 mmol, 35%, 0.389 g) and Na2WO4.2H2O (0.05 mmol, 0.017 g)
were added and the mixture was stirred at room temperature (for compounds 3a–j 20–24 h). For the compounds
3k–m the reaction was performed at 60 ꢀC (47 h).
grade solvents. All of the reagents used in this work were purchased from commercial
suppliers and used without any further purifications.
General procedure for the preparation of compounds 2a–m
To a solution of amino oxime (1 mmol) in EtOH (20 mL) aldehyde (1 mmol) was added
at room temperature and stirred for 24 h (for compounds 2k–m, 47 h). The precipitat-
ing product was isolated by filtration through a sintered glass funnel and washed with
warm hexane. In the case of 2f the solvent was evaporated and the crude was treated
with warm hexane. Recrystallization from acetonitrile provided yellow-colored crystals.

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General procedure for the preparation of compounds 3a–m
To a solution of substrate 2a–m (1 mmol) in THF (4 mL), H2O2 (4 mmol, 35%, 0.389 g)
and Na2WO4Á2H2O (0.05 mmol, 0.017 g) were added and the mixture was stirred at
room temperature for compounds 3a–j (20–24 h). For the compounds 3k–m the reac-
tion was performed at 60 ꢀC (47 h). After evaporation of the solvent, water was added
(15 mL) and the mixture was basified with 10% NaOH. The mixture was extracted with
chloroform (3 Â 15 mL) and the combined extracts were dried over anhydrous Na2SO4,
filtered. The residue after evaporation of the solvent was subjected to flash column
chromatography using silica gel as an adsorbent and ethyl acetate-petroleum ether
(gradually increasing the amount of ethyl acetate) as eluent mixture. The isolated prod-
ucts were recrystallized from acetonitrile.
One-pot procedure for the preparation of compounds 3a–m
To a solution of amino oxime 1 (1 mmol) in THF (4 mL) aldehyde (1 mmol) was added
at room temperature and after an hour H2O2 (4 mmol, 35%, 0.389 g) and
Na2WO4Á2H2O (0.05 mmol, 0.017 g) were added and the mixture was stirred for 24 h.
The isolation procedure is the same for compounds 3 obtained according to the general
procedure starting from isolated 2.
Conclusion
Thus the developed methods provide the synthesis of 1,2-dihydroquinazoline, 2a–m and
quinazoline-3-oxides, 3a–m in high yields at room temperature. The method for the
synthesis of compound 2 involves the none photochemical, expensive metal complexes
free condensation of compound 1 with the corresponding aldehydes. The ease of the
product isolation, simply filtering the formed precipitate, is another advantage worth
mentioning. Compounds 3 were prepared by oxidation of isolated 2 in high yields at
room temperature using H2O2-tungstate system. Compounds 3 can also be obtained in
improved overall yields and for shorter reaction times when the mixture of 1 and the
aromatic aldehyde in THF is treated with the aforementioned oxidizing system.
Full experimental detail and 1H and 13C NMR spectra can be found via the
“Supplementary Content” section of this article’s webpage.’
Funding
ꢀ
The present work was financially supported by Bursa Uludag University Research Fund (Project
No: DDP(F)-2020/6).
ORCID
Rashinikumar Samandram
Meliha C¸etin Korukc¸u
http://orcid.org/0000-0002-0808-9738
http://orcid.org/0000-0003-1283-8006
Necdet Co¸skun
http://orcid.org/0000-0002-8464-9768

2356
R. SAMANDRAM ET AL.
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