Synthesis of 2-arylquinazolin-4(3H)-ones by N-aryl benzamidines with aromatic carbonates

Article abstract of DOI:10.1002/jhet.1638

The reaction of N-aryl benzamidines 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1n with diphenyl carbonate 2a or ethyl phenyl carbonate 2b synthesized 2-arylquinazolin-4(3H)-ones 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n in simple and

Full text of DOI:10.1002/jhet.1638

March 2014
Synthesis of 2-Arylquinazolin-4(3H)-ones by N-Aryl Benzamidines with
343
Aromatic Carbonates
Shunichi Aikawa, Chiharu Sekiguchi, Yuko Yamazaki, Mika Hattori, Tatsuya Isaka,
Yasuhiko Yoshida,a,b and Shogo Ihara,b
a
b
b
b
b
*
aBio-Nano Electronics Research Center, Toyo University, Kujirai, Kawagoe, Saitama 350-8585, Japan
bDepartment of Applied Chemistry, Faculty of Science and Engineering, Toyo University,
Kujirai, Kawagoe, Saitama 350-8585, Japan
*
E-mail: s-aikawa@toyo.jp
Received November 8, 2011
DOI 10.1002/jhet.1638
Published online 11 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
The reaction of N-aryl benzamidines 1a–n with diphenyl carbonate 2a or ethyl phenyl carbonate 2b
synthesized 2-arylquinazolin-4(3H)-ones 3a–n in simple and safe process with good yields (71–90%). It
was suggested that different electron-donating substituent in N-aryl benzamidines 1a–n afforded similar
effect to the yields of 2-arylquinazolin-4(3H)-ones 3a–n. In these reactions, N-aryl benzamidines 1a–n
built up intermediate compounds by nucleophilic addition to carbonates 2 to give annulation products
3a–n, following to cyclization involving the elimination of ethanol/phenol.
J. Heterocyclic Chem., 51, 343 (2014).
INTRODUCTION
that the yields of 2-arylquinazolin-4(3H)-ones 3a–n were
remarkably independent on different species of electron-
donating group replaced on N-aryl benzamidines 1. On the
other hand, the yields of the products obtained by N-aryl
benzamidines 1 with ethyl phenyl carbonate 2b were similar
in comparison with those yields as shown in Table 1. The
compounds 3a–n produced in both of the reaction were
characterized by H NMR spectral and elemental analysis
data. Also, products formed isoindolin-1-one ring were not
found in these reactions [7].
In addition, N-aryl benzamidines 1a, 1c, and 1d unreacted
with diethyl carbonate as dialkyl carbonate under the same or
stronger reaction conditions. It seems reasonable to suppose
that this reaction was related to the elimination of alcohol by
means of nucleophilic attack of N-aryl benzamidines 1 to
carbonate. In fact, N-ethoxycarbonyl-N0-(4-methylphenyl)-
4-methylbenzamidine 4e as an intermediate compound
was isolated with the reaction of N-(4-methylphenyl)-4-
methylbenzamidine 1e and ethyl phenyl carbonate 2b at
70ꢀC for 72h with 80.7% yield and then provided 6-
methyl-2-p-tolylquinazolin-4(3H)-one 3e with 88.0% yield
calculated on the basis of its carbamate derivative 4e by
heating at 180ꢀC for 5 h in tetraglyme. These results did
not only provide a relationship between their yields and
elimination of alcohol from carbonate 2 but also a definitive
evidence of mechanism passing through intermediate
compound 4 for these reactions [7].
In 1946, M. M. Endicott et al. [1] first described a synthe-
sis of quinazolin-4(3H)-ones from anthranilic acid with
formamide. Quinazolin-4(3H)-ones, one of the heterocycles,
are applied to intermediate compounds to synthesize
antibacterial and anticancer agents [2], of which synthetic
processes have been developed by many researchers. Y.
Kabri et al. and X. Zhang et al. reported the green chemical
success to provide quinazolin-4(3H)-ones with good yields
by microwave-assisted synthetic process [3]. Additionally,
recent studies of quinazolin-4(3H)-ones developed the novel
catalysts to be achieved with mild reaction and one-pot and/
or solvent-free reaction process [4].
Our earlier studies have certified the reaction to obtain
heterocycles from pyrimidine or oxazine derivatives with
some electrophilic reagents and their reaction mechanism
[5]. Herein, we report the easy and safe one-pot process
synthesizing 2-arylquinazolin-4(3H)-ones 3 by the reaction
of N-aryl benzamidines 1 and aromatic carbonates 2, diphe-
nyl carbonate or ethyl phenyl carbonate, without catalyst, as
shown in Scheme 1.
1
RESULTS AND DISCUSSION
N-aryl benzamidines 1a–n were synthesized and character-
ized with 1H NMR analysis and measurement of melting point
[6]. The reactions of N-aryl benzamidines 1a–n with diphenyl
carbonate 2a at 180ꢀC for 5 h afforded 2-arylquinazolin-
4(3H)-ones 3a–n in good yields (71–90%). It was found
It was concluded that their N-aryl benzamidines 1 reacted
with aromatic carbonates 2 to give 2-arylquinazolin-4-ones
3 within good yield in easy and safe process.
© 2013 HeteroCorporation

344
S. Aikawa, C. Sekiguchi, Y. Yamazaki, M. Hattori, T. Isaka, Y. Yoshida, and S. Ihara
Vol 51
Scheme 1
GeneralprocedureforthesynthesisofN-arylbenzamidines
N-Aryl benzamidines 1a–n were prepared by modifying
Table 1
1.
Yield of 2-arylquinazoline-4(3H)-ones 3 obtained by the reaction of
N-aryl benzamidines 1a–n with aryl carbonates 2.
the literature procedure [6]. A mixture of corresponding 4-
substituted benzonitriles with 4-substituted anilines was heated
at 180–200ꢀC (oil bath) with a mechanical stirring in the
presence of AlCl3 as catalyst. After 20 min, the mixture was
recovered by treatment of diluted HCl solution, neutralized with
diluted NaOH aqueous solution, and then extracted with
sufficient ether. Organic layer was dried with an excess of
Na2SO4 overnight and then evaporated with a rotary evaporator.
N-aryl benzamidines were recystallized from a solution mixed
benzene and n-hexane and dried in vacuo.
Diphenyl carbonate
Ethyl phenyl
carbonate 2b %
3
R1
R2
2a %
a
b
c
d
e
f
g
h
i
j
k
l
m
n
H
H
H
Me
Me
Me
OME
OME
OMe
H
H
81.2
84.2
81.7
83.2
89.8
70.4
83.7
85.6
82.6
84.2
71.3
80.0
89.0
81.5
77.5
85.3
82.1
73.0
84.1
78.5
85.7
85.1
84.7
73.5
59.8
63.2
85.5
83.2
Me
OMe
H
Me
OMe
H
Me
OMe
Br
CI
CI
Me
H
N-Phenyl benzamidine (1a) [6]. The product was collected
as colorless powder, synthesized by the reaction of benzonitrile
(50 mmol), aniline (50 mmol), and AlCl3 (50 mmol); 72.8%
1
yield; mp 117–118ꢀC; H NMR d 4.83 (2H, brs, NH ꢁ 2), 7.00
H
Me
CI
(2H, d, J = 8.3 Hz, Ar-H), 7.07 (1H, t, J = 7.6 Hz, Ar-H), 7.35
(2H, d, J = 7.6 Hz, Ar-H), 7.43–7.49 (3H, m, Ar-H), 7.89 (2H,
d, J = 8.3 Hz, Ar-H).
CI
N-(4-Methylphenyl) benzamidine (1b).
The product was
collected as colorless powder, synthesized by the reaction of
benzonitrile (30 mmol), p-toluidine (24 mmol), and AlCl3
1
(23 mmol); 77.3% yield; mp 99–101ꢀC; H NMR d 2.33 (3H, s,
CH3), 4.83 (2H, brs, NH ꢁ 2), 6.89 (2H, d, J = 8.3 Hz, Ar-H),
7.16 (1H, d, J = 7.6 Hz, Ar-H), 7.42–7.49 (3H, m, Ar-H), 7.88
(2H, d, J = 8.3 Hz, Ar-H).
EXPERIMENTAL
All melting points were provided with uncorrected
measurement. H NMR data were obtained using a JEOL JNM-
1
N-(4-Methoxylphenyl) benzamidine (1c). The product was
collected as pale pink powder, synthesized by the reaction of
benzonitrile (21 mmol), p-anisidine (21 mmol), and AlCl3
ECX500M (500 MHz) spectrometer in CDCl3 or DMSO-d6 with
tetramethylsilane (0.03%) as an internal standard. Elemental
analyses of 2-arylquinazolin-4(3H)-ones 3 and the intermediate
compound 4e were performed using a Perkin-Elmer 2400 II
CHN analyzer.
1
(20 mmol); 30.7% yield; mp 112–113ꢀC; H NMR d 3.80 (3H,
s, OCH3), 4.85 (2H, brs, NH ꢁ 2), 6.91 (4H, brs, Ar-H),
7.42–7.49 (3H, m, Ar-H), 7.87 (2H, d, J = 6.9 Hz, Ar-H).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Synthesis of 2-Arylquinazolin-4(3H)-ones by N-Aryl
345
Benzamidines with Aromatic Carbonates
N-Phenyl 4-methylbenzamidine (1d).
collected as colorless powder, synthesized by the reaction of
The product was
CH3), 4.81 (2H, brs, NH ꢁ 2), 6.87 (2H, d, J= 8.0 Hz, Ar-H), 7.17
(2H, d, J= 8.0 Hz, Ar-H), 7.41 (2H, d, J= 8.6 Hz, Ar-H), 7.82 (2H,
d, J= 8.6 Hz, Ar-H).
p-tolylnitrile (20 mmol), aniline (20 mmol), and AlCl3
1
(20 mmol); 48.0% yield; mp 151–153ꢀC; H NMR d 3.80 (3H,
N-(4-Chlorophenyl) benzamidine (1n).
The product was
s, OCH3), 4.85 (2H, brs, NH ꢁ 2), 6.91 (4H, brs, Ar-H), 7.42–
collected as light brown powder, synthesized by the reaction of
4-chlorobenzonitrile (40 mmol), aniline (40 mmol), and AlCl3
(40 mmol); 49.6% yield; mp 143–144ꢀC; 1H NMR d 4.81 (2H, brs,
NH ꢁ 2), 6.97 (2H, d, J= 7.5 Hz, Ar-H), 7.07 (1H, t, J=7.5Hz, Ar-
H), 7.36 (2H, t, J=7.5Hz, Ar-H), 7.42 (2H, d, J= 8.5 Hz, Ar-H),
7.83 (2H, d, J= 8.5 Hz, Ar-H).
7.49 (3H, m, Ar-H), 7.87 (2H, d, J = 6.9 Hz, Ar-H).
N-(4-Methylphenyl) 4-methylbenzamidine (1e).
The product
was collected as light gray powder, synthesized by the reaction
of p-tolylnitrile (20 mmol), p-toluidine (20 mmol), and AlCl3
1
(20 mmol); 45.0% yield; mp 116–117ꢀC; H NMR d 2.33 (3H, s,
CH3), 2.40 (3H, s, CH3), 4.79 (2H, brs, NH ꢁ 2), 6.88 (2H, d,
J= 8.0 Hz, Ar-H), 7.16 (2H, d, J= 8.0 Hz, Ar-H), 7.23 (2H, d,
J= 8.0 Hz, Ar-H), 7.76 (2H, d, J= 8.0 Hz, Ar-H).
Ethyl phenyl carbonate (2b).
Ethyl phenyl carbonate was
prepared by modifying the literature procedure [8]. Toluene solution
containing phenol (0.39 mol) and pyridine (0.26 mol) was added
into ethyl chloroformate (0.26 mol) and dissolved with toluene
at room temperature. After heating at 100ꢀC for 1 h, a reaction
mixture was washed with benzene and diluted HCl aqueous
solution, neutralized with diluted NaOH aqueous solution, and
washed with plenty of ion-exchanged water twice. Organic layer
was dried with Na2SO4 overnight, and then evaporated. The residue
was purified by distilling under reduced pressure to afford the
N-(4-Methoxyphenyl) 4-methylbenzamidine (1f). The product
was collected as pink powder, synthesized by the reaction of p-
tolylnitrile (30 mmol), p-anisidine (30 mmol), and AlCl3 (30 mmol);
1
15.7% yield; mp 139–140ꢀC; H NMR d 2.40 (3H, s, CH3), 3.80
(3H, s, OCH3), 4.81 (2H, brs, NH ꢁ 2), 6.92 (4H, brs, Ar-H), 7.24
(2H, d, J=8.0Hz, Ar-H), 7.77 (2H, d, J= 8.0 Hz, Ar-H).
N-Phenyl 4-methoxybenzamidine (1g).
The product was
1
collected as pale pink powder, synthesized by the reaction of
product as colorless liquid; 65.2% yield; bp 125ꢀC/10 mmHg; H
p-anisonitrile (19 mmol), aniline (19 mmol), and AlCl3
NMR d 1.39 (3H, t, J=7.0Hz, CH3), 4.32 (2H, q, J=7.0Hz, CH2),
7.18 (2H, d, J= 8.0 Hz, Ar-H), 7.24 (1H, t, J= 8.0 Hz, Ar-H), 7.38
(2H, t, J= 8.0 Hz, Ar-H).
1
(19 mmol); 23.0% yield; mp 146–148ꢀC; H NMR d 3.89 (3H,
s, OCH3), 4.76 (2H, brs, NH ꢁ 2), 6.95 (2H, d, J = 8.9 Hz, Ar-
H), 6.98 (2H, d, J = 7.4 Hz, Ar-H), 7.05 (1H, t, J = 7.4 Hz, Ar-
H), 7.35 (2H, t, J = 7.4 Hz, Ar-H), 7.84 (2H, d, J = 8.9 Hz, Ar-H).
General procedure for the synthesis of 2-arylquinazolin-4(3H)-
ones 3 by reaction of N-aryl benzamidines 1 and diphenyl
carbonate 2a. A mixture of N-aryl benzamidines 1 and diphenyl
carbonate 2a in triglyme was heated at 180ꢀC for 5 h with stirring.
After the reaction mixture was cooled to room temperature, the
precipitated material was collected by filtration, washed with mixed
solution of benzene and n-hexane, and dried in high vacuum.
Samples for analysis were recrystallized from ethyl acetate.
N-(4-Methylphenyl) 4-methoxybenzamidine (1h).
The
product was collected as pink powder, synthesized by the
reaction of p-anisonitrile (20 mmol), p-toluidine (20 mmol), and
AlCl3 (20 mmol); 12.6% yield; mp 125–127ꢀC; 1H NMR d
2.33 (3H, s, CH3), 3.86 (3H, s, OCH3), 4.76 (2H, brs, NH ꢁ 2),
6.88 (2H, d, J = 8.0 Hz, Ar-H), 6.95 (2H, d, J = 8.5 Hz, Ar-H),
7.16 (2H, d, J = 8.0 Hz, Ar-H), 7.84 (2H, d, J = 8.5 Hz, Ar-H).
2-Phenylquinazolin-4(3H)-one (3a) [7].
The product
N-(4-Methoxyphenyl) 4-methoxybenzamidine (1i).
The
was obtained as colorless powder, synthesized by the reaction of
product was collected as pink powder, synthesized by the reaction
N-phenyl benzamidine 1a (20 mmol) and diphenyl carbonate 2
1
of p-anisonitrile (20 mmol), p-anisidine (20 mmol), and AlCl3
(20 mmol) in triglyme (40 mL); 81.2% yield; mp 236–237ꢀC; H
1
(20 mmol); 9.7% yield; mp 151–153ꢀC; H NMR d 3.81 (3H, s,
NMR: d 7.51–7.62 (4H, m, Ar-H), 7.75 (1H, d, J=7.9Hz, Ar-H),
7.85 (1H, t, J= 7.9 Hz, Ar-H), 8.16 (1H, d, J= 7.9 Hz, Ar-H), 8.19
(2H, d, J= 7.9 Hz, Ar-H), 12.5 (1H, brs, NH); Anal. Calcd for
C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.65; H, 4.63;
N, 12.64.
OCH3), 3.86 (3H, s, OCH3), 4.77 (2H, brs, NH ꢁ 2), 6.92 (4H, brs,
Ar-H), 6.95 (2H, d, J= 8.6 Hz, Ar-H), 7.83 (2H, d, J=8.6Hz, Ar-H).
N-Phenyl 4-bromobenzamidine (1j).
The product was
collected as pale purple powder, synthesized by the reaction of
benzonitrile (14 mmol), 4-bromobenzenamine (14 mmol), and AlCl3
(14 mmol); 70.5% yield; mp 122–124ꢀC; 1H NMR d 4.84 (2H, brs,
NH ꢁ 2), 6.88 (2H, d, J= 8.6 Hz, Ar-H), 7.43–7.51 (5H, m, Ar-H),
7.86 (2H, d, J= 8.4 Hz, Ar-H).
6-Methyl-2-phenylquinazolin-4(3H)-one (3b).
The product
was obtained as colorless powder, synthesized by the reaction of
N-(4-methylphenyl) benzamidine 1b (20 mmol) and diphenyl
carbonate 2 (20 mmol) in triglyme (40 mL); 84.2% yield; mp 255–
1
N-Phenyl 4-chlorobenzamidine (1k).
The product was
256ꢀC; H NMR: d 2.46 (3H, s, CH3), 7.53–7.60 (3H, m, Ar-H),
collected as colorless powder, synthesized by the reaction of
benzonitrile (30 mmol), 4-chlorobenzenamine (30 mmol), and AlCl3
(30 mmol); 71.7% yield; mp 118–120ꢀC; 1H NMR d 4.84 (2H, brs,
NH ꢁ 2), 6.93 (2H, d, J= 8.6 Hz, Ar-H), 7.32 (2H, d, J=8.6Hz,
Ar-H), 7.44–7.51 (3H, m, Ar-H), 7.86 (2H, d, J= 8.3 Hz, Ar-H).
7.65 (1H, d, J= 8.6 Hz, Ar-H), 7.67 (1H, dd, J= 8.6 Hz, 2.0 Hz, Ar-
H), 7.96 (1H, d, J= 2.0 Hz, Ar-H), 8.17 (2H, d, J= 7.7 Hz, Ar-H),
12.5 (1H, brs, NH); Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12;
N, 11.86. Found: C, 76.01; H, 4.86; N, 11.80.
6-Methoxy-2-phenylquinazolin-4(3H)-one (3c).
The product
N-(4-Chlorophenyl) 4-methylbenzamidine (1l).
was collected as colorless powder, synthesized by the reaction of
The product
was obtained as colorless powder, synthesized by the reaction of
N-(4-methoxylphenyl) benzamidine 1c (15 mmol) and diphenyl
carbonate 2a (15 mmol) in triglyme (30 mL); 81.7% yield; mp 260–
261ꢀC; 1H NMR: d 3.90 (3H, s, OCH3), 7.52–7.59 (4H, m, Ar-H),
7.45 (1H, dd, J=8.9Hz, 3.2Hz, Ar-H), 7.70 (1H, d, J=8.9Hz,
Ar-H), 8.16 (2H, d, J=7.7Hz, Ar-H), 12.5 (1H, brs, NH); Anal.
Calcd for C15H12N2O2 : C, 71.42; H, 4.79 N, 11.10. Found: C,
71.70; H, 4.86; N, 11.14.
p-tolylnitrile (20 mmol), 4-chlorobenzenamine (20 mmol), and
1
AlCl3 (20 mmol); 90.6% yield; mp 142–144ꢀC; H NMR d 2.41
(3H, s, CH3), 4.81 (2H, brs, NH ꢁ 2), 6.92 (2H, d, J=8.6Hz, Ar-
H), 7.25 (2H, d, J= 8.3 Hz, Ar-H), 7.31 (2H, d, J= 8.6 Hz, Ar-H),
7.75 (2H, d, J= 8.3 Hz, Ar-H).
N-(4-Methylphenyl) 4-chlorobenzamidine (1m). The product
was collected as colorless powder, synthesized by the reaction of
4-chlorobenzonitrile (18 mmol), p-toluidine (18 mmol), and AlCl3
2-p-Tolylquinazolin-4(3H)-one (3d) [7].
The product was
obtained as pale yellow powder, synthesized by the reaction of
N-phenyl-4-methylbenzamidine 1d (20 mmol) and diphenyl
1
(18 mmol); 63.1% yield; mp 140–142ꢀC; H NMR d 2.33 (3H, s,
Journal of Heterocyclic Chemistry
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S. Aikawa, C. Sekiguchi, Y. Yamazaki, M. Hattori, T. Isaka, Y. Yoshida, and S. Ihara
Vol 51
carbonate 2a (20 mmol) in triglyme (40 mL); 83.2% yield; mp 236–
237ꢀC; 1H NMR: d 2.50 (3H, s, CH3), 7.36 (2H, d, J=8.3Hz, Ar-
H), 7.50 (1H, t, J= 7.7 Hz, Ar-H), 7.73 (1H, d, J= 7.7 Hz, Ar-H),
7.83 (1H, t, J= 7.7 Hz, Ar-H), 8.10 (2H, d, J= 8.3 Hz, Ar-H), 8.14
(1H, d, J= 7.7 Hz, Ar-H), 12.4 (1H, brs, NH); Anal. Calcd for
C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C, 76.48; H, 5.23;
N, 11.80.
6-Methyl-2-p-tolylquinazolin-4(3H)-one (3e) [7]. The product
was obtained as pale yellow powder, synthesized by the reaction
of N-(4-methylphenyl)-4-methylbenzamidine 1e (20 mmol) and
diphenyl carbonate 2a (20 mmol) in triglyme (40 mL); 89.8% yield;
mp 272–273ꢀC; 1H NMR: d 2.39 (3H, s, CH3), 2.46 (3H, s, CH3),
7.35 (2H, d, J= 8.3 Hz, Ar-H), 7.63 (1H, d, J= 8.3 Hz, Ar-H), 7.65
(1H, dd, J=8.3Hz, J= 2.0Hz, Ar-H), 7.94 (1H, d, J=2.0Hz,
Ar-H), 8.08 (2H, d, J= 8.3 Hz, Ar-H), 12.4 (1H, brs, NH); Anal.
Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C,
76.86; H, 5.69; N, 11.29.
(1H, t, J = 7.5 Hz, Ar-H), 7.70 (1H, d, J = 8.6 Hz, Ar-H), 7.99
(1H, dd, J = 8.6 Hz, 2.3 Hz, Ar-H), 8.18 (2H, d, J = 7.5 Hz, Ar-
H), 8.24 (1H, d, J = 2.3 Hz, Ar-H), 12.7 (1H, brs, NH); Anal.
Calcd for C14H9BrN2O: C, 55.84; H, 3.01; N, 9.30. Found: C,
55.83; H, 2.88; N, 9.34.
6-Chloro-2-phenylquinazolin-4(3H)-one (3k). The product
was obtained as colorless powder, synthesized by the reaction of
N-phenyl-4-chlorobenzamidine 1k (20 mmol) and diphenyl
carbonate 2a (20 mmol) in triglyme (40 mL); 71.3% yield; mp
290–291ꢀC; 1H NMR: d 7.56 (2H, t, J = 7.4 Hz, Ar-H), 7.61
(1H, t, J = 7.4 Hz, Ar-H), 7.77 (1H, d, J = 8.6 Hz, Ar-H), 7.87
(1H, dd, J = 8.6 Hz, 2.3 Hz, Ar-H), 8.10 (1H, d, J = 2.3 Hz, Ar-
H), 8.18 (2H, d, J = 7.4 Hz, Ar-H), 12.7 (1H, brs, NH); Anal.
Calcd for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91. Found: C,
65.51; H, 3.50; N, 10.89.
6-Chloro-2-p-tolylquinazolin-4(3H)-one (3l) [7]. The product
was obtained as colorless powder, synthesized by the reaction of N-
(4-chlorophenyl)-4-methylbenzamidine 1l (20 mmol) and diphenyl
carbonate 2a (20 mmol) in triglyme (40 mL); 80.0% yield; mp 292–
293ꢀC; 1H NMR: d 2.40 (3H, s, CH3), 7.36 (2H, d, J=8.3Hz, Ar-
H), 7.75 (1H, d, J= 8.5 Hz, Ar-H), 7.85 (1H, dd, J= 8.5 Hz, 2.6 Hz,
Ar-H), 8.08 (1H, d, J= 2.6 Hz, Ar-H), 8.09 (2H, d, J=8.3Hz, Ar-
H), 12.5 (1H, brs, NH); C15H11ClN2O: C, 66.55; H, 4.10; N, 10.35.
Found: C, 66.61; H, 3.85; N, 10.41.
2-(4-Chlorophenyl)-6-methylquinazolin-4(3H)-one (3m). The
product was obtained as colorless powder, synthesized by the
reaction of N-(4-methylphenyl)-4-chlorobenzamidine 1m (20 mmol)
and diphenyl carbonate 2a (20 mmol) in triglyme (40 mL); 89.0%
yield; mp 306–307ꢀC; 1H NMR: d 2.47 (3H, s, CH3), 7.62 (2H, d,
J=8.6Hz, Ar-H), 7.65 (1H, d, J= 8.3 Hz, Ar-H), 7.67 (1H, dd,
J=8.3Hz, 2.0Hz, Ar-H), 7.96 (1H, d, J= 2.0 Hz, Ar-H), 8.19 (2H,
d, J= 8.6 Hz, Ar-H), 12.6 (1H, brs, NH); Anal. Calcd for
C15H11ClN2O: C, 66.55; H, 4.10; N, 10.35. Found: C, 66.85; H,
4.01; N, 10.21.
6-Methoxy-2-p-tolylquinazolin-4(3H)-one (3f).
The product
was obtained as pale yellow powder, synthesized by the reaction
of N-(4-methoxyphenyl)-4-methylbenzamidine 1f (20 mmol) and
diphenyl carbonate 2a (20 mmol) in triglyme (40 mL); 70.4%
yield; mp 231–233ꢀC; 1H NMR: d 2.45 (3H, s, CH3), 3.89
(3H, s, OCH3), 7.34 (2H, d, J= 8.3 Hz, Ar-H), 7.44 (1H, dd,
J=8.9Hz, 3.2Hz, Ar-H), 7.54 (1H, d, J= 3.2 Hz, Ar-H), 7.68 (1H,
d, J= 8.9 Hz, Ar-H), 8.08 (2H, d, J= 8.3 Hz, Ar-H), 12.4 (1H, brs,
NH); Anal. Calcd for C16H14N2O2 : C, 72.16; H, 5.30; N, 10.52.
Found: C, 72.35; H, 5.22; N, 10.46.
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (3g) [8,9]. The
product was obtained as colorless powder, synthesized by the
reaction of N-phenyl-4-methoxybenzamidine 1g (10 mmol) and
diphenyl carbonate 2a (10 mmol) in triglyme (20 mL); 83.7%
yield; mp 240–242ꢀC; 1H NMR: d 3.85 (3H, s, OCH3), 7.09
(2H, d, J = 8.9 Hz, Ar-H), 7.48 (1H, t, J = 7.6 Hz, Ar-H), 7.70
(1H, d, J = 7.6 Hz, Ar-H), 7.81 (1H, t, J = 7.6 Hz, Ar-H), 8.13
(1H, d, J = 7.6 Hz, Ar-H), 8.19 (2H, d, J = 8.9 Hz, Ar-H), 12.4
(1H, brs, NH); Anal. Calcd for C15H12N2O2 : C, 71.42; H, 4.79;
N, 11.10. Found: C, 71.64; H, 5.01; N, 11.25.
2-(4-Chlorophenyl)quinazolin-4(3H)-one (3n).
The product
was obtained as colorless powder, synthesized by the reaction of
N-(4-chlorophenyl) benzamidine 1n (20 mmol) and diphenyl
carbonate 2a (20 mmol) in triglyme (40 mL); 81.5% yield; mp 305–
2-(4-Methoxyphenyl)-6-methylquinazolin-4(3H)-one (3h) [7].
The product was obtained as pale yellow powder, synthesized
by the reaction of N-(4-methylphenyl)-4-methoxybenzamidine
1h (10 mmol) and diphenyl carbonate 2a (10 mmol) in triglyme
(20 mL); 85.6% yield; mp 256–257ꢀC; 1H NMR: d 2.37 (3H,
s, CH3), 3.85 (3H, s, OCH3), 7.08 (2H, d, J = 8.9 Hz, Ar-H),
7.61 (1H, d, J = 8.3 Hz, Ar-H), 7.64 (1H, dd, J = 8.3 Hz, 2.1 Hz,
Ar-H), 7.93 (1H, d, J = 2.1 Hz, Ar-H), 8.18 (2H, d, J = 8.9Hz,
Ar-H), 12.3 (1H, brs, NH); Anal. Calcd for C16H14N2O2 : C,
72.16; H, 5.30; N, 10.52. Found: C, 72.44; H, 5.55; N, 10.66.
6-Methoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one (3i). The
product was obtained as pale yellow powder, synthesized by the
reaction of N-(4-methoxyphenyl)-4-methoxybenzamidine 1i
(10 mmol) and diphenyl carbonate 2a (10 mmol) in triglyme
306ꢀC; 1H NMR:
d 7.63 (2H, d, J= 8.6 Hz, Ar-H), 7.54
(1H, t, J= 7.5 Hz, Ar-H), 7.75 (1H, d, J= 7.5 Hz, Ar-H), 7.85 (1H, t,
J= 7.5 Hz, Ar-H), 8.16 (1H, d, J= 7.5 Hz, Ar-H), 8.21 (2H, d,
J= 8.6 Hz, Ar-H), 12.6 (1H, brs, NH); Anal. Calcd for C14H9ClN2O:
C, 65.51; H, 3.53; N, 10.91. Found: C, 65.50; H, 3.50; N, 10.86.
General procedure for the synthesis of 2-arylquinazolin-4
(3H)-ones 3 by reaction of N-aryl benzamidines 1 and ethyl
phenyl carbonate 2b.
A mixture of N-aryl benzamidines 1
and ethyl phenyl carbonate 2b in tetraglyme was heated at
180ꢀC for 5 h with stirring. After the reaction mixture was
cooled to room temperature, the precipitated material was
collected by filtration and washed with ethyl acetate. Samples
for analysis were recrystallized from ethyl acetate.
1
(20 mL); 82.6% yield; mp 264–266ꢀC; H NMR: d 3.85 (3H, s,
2-Phenylquinazolin-4(3H)-one (3a) [7].
The product was
obtained as colorless powder, synthesized by the reaction of N-
phenyl benzamidine 1a (20 mmol) and ethyl phenyl carbonate
2b (25 mmol) in tetraglyme (25 mL); 77.5% yield; mp 236–
237ꢀC; 1H NMR: d 7.51–7.62 (4H, m, Ar-H), 7.75 (1H, d,
J = 7.9 Hz, Ar-H), 7.85 (1H, t, J = 7.9 Hz, Ar-H), 8.16 (1H, d,
J = 7.9 Hz, Ar-H), 8.19 (2H, d, J = 7.9 Hz, Ar-H), 12.5 (1H, brs,
NH); Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60.
Found: C, 75.76; H, 4.80; N, 12.78.
OCH3), 3.89 (3H, s, OCH3), 7.09 (2H, d, J= 8.9 Hz, Ar-H), 7.43
(1H, dd, J= 8.9 Hz, 2.9 Hz, Ar-H), 7.53 (1H, d, J= 2.9 Hz, Ar-H),
7.67 (1H, d, J= 8.9 Hz, Ar-H), 8.17 (2H, d, J= 8.9 Hz, Ar-H), 12.4
(1H, brs, NH); Anal. Calcd for C16H14N2O3 : C, 68.07; H, 5.00; N,
9.92. Found: C, 68.23; H, 5.23; N, 9.98.
6-Bromo-2-phenylquinazolin-4(3H)-one (3j). The product
was obtained as colorless powder, synthesized by the reaction
of N-phenyl-4-bromobenzamidine 1j (20 mmol) and diphenyl
carbonate 2a (20 mmol) in triglyme (40 mL); 84.2% yield; mp
296–297ꢀC; 1H NMR: d 7.56 (2H, t, J = 7.5 Hz, Ar-H), 7.61
6-Methyl-2-phenylquinazolin-4(3H)-one (3b).
The product
was obtained as colorless powder, synthesized by the reaction of N-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Synthesis of 2-Arylquinazolin-4(3H)-ones by N-Aryl
347
Benzamidines with Aromatic Carbonates
(4-methylphenyl) benzamidine 1b (20 mmol) and ethyl phenyl
carbonate 2b (26 mmol) in tetraglyme (40 mL); 85.3% yield; mp
255–256ꢀC; 1H NMR: d 2.46 (3H, s, CH3), 7.53–7.60 (3H, m, Ar-
H), 7.65 (1H, d, J= 8.6 Hz, Ar-H), 7.67 (1H, dd, J= 8.6 Hz, 2.0 Hz,
Ar-H), 7.96 (1H, d, J= 2.0 Hz, Ar-H), 8.17 (2H, d, J=7.7Hz, Ar-
H), 12.5 (1H, brs, NH); Anal. Calcd for C15H12N2O: C, 76.25; H,
5.12; N, 11.86. Found: C, 76.10; H, 5.35; N, 11.93.
(1H, d, J = 8.3 Hz, Ar-H), 7.64 (1H, dd, J = 8.3 Hz, 2.1 Hz, Ar-
H), 7.93 (1H, d, J = 2.1 Hz, Ar-H), 8.18 (2H, d, J = 8.9 Hz, Ar-
H), 12.3 (1H, brs, NH); Anal. Calcd for C16H14N2O2 : C, 72.16;
H, 5.30; N, 10.52. Found: C, 71.92; H, 5.55; N, 10.58.
6-Methoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one
(3i). The product was obtained as pale yellow powder, synthesized
by the reaction of N-(4-methoxyphenyl)-4-methoxybenzamidine 1i
(10 mmol) and ethyl phenyl carbonate 2b (13 mmol) in tetraglyme
6-Methoxy-2-phenylquinazolin-4(3H)-one (3c).
The product
1
was obtained as colorless powder, synthesized by the reaction of
N-(4-methoxylphenyl) benzamidine 1c (20 mmol) and ethyl phenyl
carbonate 2b (27 mmol) in tetraglyme (40 mL); 82.1% yield; mp
(20 mL); 84.7% yield; mp 264–266ꢀC; H NMR: d 3.85 (3H, s,
OCH3), 3.89 (3H, s, OCH3), 7.09 (2H, d, J= 8.9 Hz, Ar-H), 7.43
(1H, dd, J= 8.9 Hz, 2.9 Hz, Ar-H), 7.53 (1H, d, J= 2.9 Hz, Ar-H),
7.67 (1H, d, J=8.9Hz, Ar-H), 8.17 (2H, d, J= 8.9 Hz, Ar-H), 12.4
(1H, brs, NH); Anal. Calcd for C16H14N2O3: C, 68.07; H, 5.00; N,
9.92. Found: C, 68.17; H, 5.28; N, 10.06.
260–261ꢀC; 1H NMR:
d 3.90 (3H, s, OCH3), 7.52–7.59
(4H, m, Ar-H), 7.45 (1H, dd, J= 8.9 Hz, 3.2 Hz, Ar-H), 7.70 (1H, d,
J=8.9Hz, Ar-H), 8.16 (2H, d, J= 7.7 Hz, Ar-H), 12.5 (1H, brs,
NH); Anal. Calcd for C15H12N2O2 : C, 71.42; H, 4.79 N, 11.10.
Found: C, 71.60; H, 5.06; N, 11.01.
6-Bromo-2-phenylquinazolin-4(3H)-one (3j).
The product
was obtained as pale yellow powder, synthesized by the
reaction of N-phenyl-4-bromobenzamidine 1j (15 mmol)
and ethyl phenyl carbonate 2b (20 mmol) in tetraglyme
(30 mL); 73.5% yield; mp 296–297ꢀC; 1H NMR: d 7.56
(2H, t, J = 7.5 Hz, Ar-H), 7.61 (1H, t, J = 7.5 Hz, Ar-H),
7.70 (1H, d, J = 8.6 Hz, Ar-H), 7.99 (1H, dd, J = 8.6 Hz,
2.3 Hz, Ar-H), 8.18 (2H, d, J = 7.5 Hz, Ar-H), 8.24 (1H, d,
J = 2.3 Hz, Ar-H), 12.7 (1H, brs, NH); Anal. Calcd for
C14H9BrN2O: C, 55.84; H, 3.01; N, 9.30. Found: C,
55.86; H, 3.15; N, 9.15.
2-p-Tolylquinazolin-4(3H)-one (3d) [7].
The product was
obtained as pale yellow powder, synthesized by the reaction of
N-phenyl-4-methylbenzamidine 1d (20 mmol) and ethyl phenyl
carbonate 2b (25mmol) in tetraglyme (40 mL); 73.0% yield; mp
236–237ꢀC; 1H NMR: d 2.50 (3H, s, CH3), 7.36 (2H, d,
J = 8.3 Hz, Ar-H), 7.50 (1H, t, J = 7.7Hz, Ar-H), 7.73 (1H, d,
J = 7.7 Hz, Ar-H), 7.83 (1H, t, J = 7.7Hz, Ar-H), 8.10 (2H, d,
J = 8.3 Hz, Ar-H), 8.14 (1H, d, J = 7.7 Hz, Ar-H), 12.4 (1H, brs,
NH); Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86.
Found: C, 76.46; H, 5.34; N, 11.88.
6-Chloro-2-phenylquinazolin-4(3H)-one (3k).
The product
6-Methyl-2-p-tolylquinazolin-4(3H)-one (3e) [7]. The product
was obtained as pale yellow powder, synthesized by the reaction of
N-(4-methylphenyl)-4-methylbenzamidine 1e (20 mmol) and ethyl
phenyl carbonate 2b (25 mmol) in tetraglyme (40 mL); 84.1% yield;
mp 272–273ꢀC; 1H NMR: d 2.39 (3H, s, CH3), 2.46 (3H, s, CH3),
7.35 (2H, d, J= 8.3 Hz, Ar-H), 7.63 (1H, d, J= 8.3 Hz, Ar-H), 7.65
(1H, dd, J=8.3Hz, J= 2.0 Hz, Ar-H), 7.94 (1H, d, J=2.0Hz, Ar-
H), 8.08 (2H, d, J= 8.3 Hz, Ar-H), 12.4 (1H, brs, NH); Anal. Calcd
for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.83; H,
5.92; N, 11.32.
6-Methoxy-2-p-tolylquinazolin-4(3H)-one (3f). The product
was obtained as pale yellow powder, synthesized by the reaction
of N-(4-methoxyphenyl)-4-methylbenzamidine 1f (20 mmol) and
ethyl phenyl carbonate 2b (25mmol) in tetraglyme (40mL);
78.5% yield; mp 231–233ꢀC; 1H NMR: d 2.45 (3H, s, CH3),
3.89 (3H, s, OCH3), 7.34 (2H, d, J = 8.3Hz, Ar-H), 7.44 (1H, dd,
J = 8.9Hz, 3.2Hz, Ar-H), 7.54 (1H, d, J = 3.2 Hz, Ar-H), 7.68
(1H, d, J = 8.9Hz, Ar-H), 8.08 (2H, d, J = 8.3 Hz, Ar-H), 12.4
(1H, brs, NH); Anal. Calcd for C16H14N2O2 : C, 72.16; H, 5.30;
N, 10.52. Found: C, 72.29; H, 5.17; N, 10.44.
was obtained as colorless powder, synthesized by the reaction of
N-phenyl-4-chlorobenzamidine 1k (20 mmol) and ethyl phenyl
carbonate 2b (26 mmol) in tetraglyme (40 mL); 59.8% yield; mp
290–291ꢀC; 1H NMR: d 7.56 (2H, t, J=7.4Hz, Ar-H), 7.61 (1H, t,
J= 7.4 Hz, Ar-H), 7.77 (1H, d, J= 8.6 Hz, Ar-H), 7.87 (1H, dd,
J=8.6Hz, 2.3Hz, Ar-H), 8.10 (1H, d, J= 2.3 Hz, Ar-H), 8.18 (2H, d,
J= 7.4 Hz, Ar-H), 12.7 (1H, brs, NH); Anal. Calcd for C14H9ClN2O:
C, 65.51; H, 3.53; N, 10.91. Found: C, 65.41; H, 3.51; N, 10.84.
6-Chloro-2-p-tolylquinazolin-4(3H)-one (3l) [7]. The product
was obtained as colorless powder, synthesized by the reaction of
N-(4-chlorophenyl)-4-methylbenzamidine 1l (20 mmol) and ethyl
phenyl carbonate 2b (27 mmol) in tetraglyme (40 mL); 63.2% yield;
mp 292–293ꢀC; 1H NMR: d 2.40 (3H, s, CH3), 7.36 (2H, d,
J=8.3Hz, Ar-H), 7.75 (1H, d, J= 8.5 Hz, Ar-H), 7.85 (1H, dd,
J=8.5Hz, 2.6Hz, Ar-H), 8.08 (1H, d, J= 2.6 Hz, Ar-H), 8.09
(2H, d, J= 8.3 Hz, Ar-H), 12.5 (1H, brs, NH); C15H11ClN2O: C,
66.55; H, 4.10; N, 10.35. Found: C, 66.68; H, 4.21; N, 10.35.
2-(4-Chlorophenyl)-6-methylquinazolin-4(3H)-one (3m). The
product was obtained as colorless powder, synthesized by the
reaction of N-(4-methylphenyl)-4-chlorobenzamidine 1m (20 mmol)
and ethyl phenyl carbonate 2b (27 mmol) in tetraglyme (40 mL);
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (3g) [8,9].
The
1
product was obtained as colorless powder, synthesized by the
reaction of N-phenyl-4-methoxybenzamidine 1g (10 mmol) and
ethyl phenyl carbonate 2b (13 mmol) in tetraglyme (20 mL); 85.7%
yield; mp 240–242ꢀC; 1H NMR: d 3.85 (3H, s, OCH3), 7.09
(2H, d, J=8.9Hz, Ar-H), 7.48 (1H, t, J= 7.6 Hz, Ar-H), 7.70
(1H, d, J= 7.6 Hz, Ar-H), 7.81 (1H, t, J= 7.6 Hz, Ar-H), 8.13 (1H,
d, J= 7.6 Hz, Ar-H), 8.19 (2H, d, J= 8.9 Hz, Ar-H), 12.4 (1H, brs,
NH); Anal. Calcd for C15H12N2O2 : C, 71.42; H, 4.79; N, 11.10.
Found: C, 71.44; H, 5.17; N, 11.29.
85.5% yield; mp 306–307ꢀC; H NMR: d 2.47 (3H, s CH3), 7.62
(2H, d, J= 8.6 Hz, Ar-H), 7.65 (1H, d, J= 8.3 Hz, Ar-H), 7.67 (1H, dd,
J= 8.3 Hz, 2.0 Hz, Ar-H), 7.96 (1H, d, J= 2.0 Hz, Ar-H), 8.19 (2H, d,
J= 8.6 Hz, Ar-H), 12.6 (1H, brs, NH); Anal. Calcd for C15H11ClN2O:
C, 66.55; H, 4.10; N, 10.35. Found: C, 66.35; H, 4.19; N, 10.32.
2-(4-Chlorophenyl)quinazolin-4(3H)-one (3n).
The product
was obtained as colorless powder, synthesized by the reaction of
N-(4-chlorophenyl) benzamidine 1n (20 mmol) and ethyl phenyl
carbonate 2b (26 mmol) in tetraglyme (40 mL); 83.2% yield; mp
305–306ꢀC; 1H NMR: d 7.63 (2H, d, J= 8.6 Hz, Ar-H), 7.54
(1H, t, J=7.5Hz, Ar-H), 7.75 (1H, d, J= 7.5 Hz, Ar-H), 7.85
(1H, t, J=7.5Hz, Ar-H), 8.16 (1H, d, J= 7.5 Hz, Ar-H), 8.21
(2H, d, J= 8.6 Hz, Ar-H), 12.6 (1H, brs, NH); Anal. Calcd for
C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91. Found: C, 65.66; H,
3.62; N, 10.87.
2-(4-Methoxyphenyl)-6-methylquinazolin-4(3H)-one (3h) [7].
The product was obtained as pale yellow powder, synthesized by
the reaction of N-(4-methylphenyl)-4-methoxybenzamidine 1h
(20 mmol) and ethyl phenyl carbonate 2 (25 mmol) in tetraglyme
1
(40 mL); 85.1% yield; mp 256–257ꢀC; H NMR: d 2.37 (3H, s,
CH3), 3.85 (3H, s, OCH3), 7.08 (2H, d, J = 8.9 Hz, Ar-H), 7.61
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

348
S. Aikawa, C. Sekiguchi, Y. Yamazaki, M. Hattori, T. Isaka, Y. Yoshida, and S. Ihara
Vol 51
[2] Chandrinka, L. M.; Yakaiah, T.; Narsaiah, B.; Sridhar, V.;
Venugopal, G.; Rao, J. V.; Kumar, K. P.; Murthy, S. N. U.; Rao, A. R.
R. Indian J Chem 2009, 48B, 840.
[3] a) Kabri, Y.; Gellis, A.; Vanelle, P. Green Chem 2009, 11, 201;
b) Zhang, X.; Ye, D.; Sun, H.; Guo, D.; Wang, J.; Huang, H.; Zhang, X.;
Jiang, H.; Liu, H. Green Chem 2009, 11, 1881.
[4] a) Raid, J. A.-J.; Wolfgang, V.; Muhammad, S. Tetrahedron
Lett 2004, 45, 3475; b) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew Chem
Int 2009, 48, 348; c) Roopan, S. M.; Maiyalagan, T.; Khan, F. N. Can J
Chem 2008, 86, 1019; d) Adib, M.; Ansari, S.; Mohammadi, A.;
Bijanzadeh, R. H. Tetrahedron Lett 2010, 51, 30.
[5] a) Ihara, S.; Soma, T.; Yano, D.; Aikawa, S.; Yoshida, Y. Synth
Commun 2011, 41, 3600; b) Ihara, S.; Soma, T.; Yano, D.; Aikawa, S.;
Yoshida, Y., J Heterocyclic Chem 2011, 48, 577.
Intermediate compound 4
N-Ethoxycarbonyl-N0-(4-methylphenyl)-4-methylbenzamidine (4e).
The product was obtained as colorless powder, synthesized by
the reaction of N-(4-methylphenyl)-4-methylbenzamidine 1e
(10 mmol) and ethyl phenyl carbonate 2b (10 mmol) at 70ꢀC
for 72 h in diglyme (20 mL); 80.7% yield; 1H NMR: d 0.99
(3H, t, J = 7.2Hz, CH3), 2.27 (3H, s, CH3), 2.36 (3H, s, CH3),
3.85 (2H, q, J = 7.2 Hz, CH2), 7.13 (2H, d, J = 8.0Hz, Ar-H), 7.29
(2H, d, J = 8.0Hz, Ar-H), 7.37 (2H, d, J = 8.0 Hz, Ar-H), 7.55
(2H, d, J = 8.0 Hz, Ar-H), 9.69 (1H, brs, NH); Anal. Calcd for
C14H9ClN2O: C, 72.95; H, 6.80; N, 9.45. Found: C, 73.15; H,
7.08; N, 9.49.
[6] Cooper, C. F.; Partridge, W. M. Org Synth 1956, 36, 64.
[7] Dean, D. W.; Papadopoulos, P. E. J Heterocyclic Chem 1982,
19, 171.
REFERENCES AND NOTES
[8] Nassar, N. M.; Agha, J. B.; Digenis, A. G. Journal of
Labelled compounds and radiopharmanceuticals 1986, XXIII, 667.
[9] Chatterjee, A.; Raychauhuri, R. J Indian Chem Soc 1969, 46, 103.
[1] Endicott, M. M.; Wick, E.; Mercury, L. M.; Sherrill, L. M. J Am
Chem Soc 1946, 68, 1299.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet