Mechanistic insights into a catalyst-free method to construct quinazolinones through multiple oxidative cyclization

Article abstract of DOI:10.1016/j.tet.2016.01.027

A novel one-pot benign oxidative cyclization of alcohols with 2-aminobenzamides was successfully developed without catalyst to afford the quinazolinones under O₂. This one-pot protocol involved oxidations and cyclizations to construct the skeleton of quinazolinones through possibly three kinds of distinct reaction mechanisms.

Full text of DOI:10.1016/j.tet.2016.01.027

Accepted Manuscript
Mechanistic insights into a catalyst-free method to construct quinazolinones through
multiple oxidative cyclization
Zhen-zhen Wang, Yu Tang
PII:
S0040-4020(16)30027-8
10.1016/j.tet.2016.01.027
TET 27434
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 October 2015
Revised Date: 14 January 2016
Accepted Date: 15 January 2016
Please cite this article as: Wang Z-z, Tang Y, Mechanistic insights into a catalyst-free method to
construct quinazolinones through multiple oxidative cyclization, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.01.027.
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Zhen-zhen Wanga , Yu Tanga,
aSchool of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery & High-
Efficiency, Tianjin University, Tianjin, 300072 P. R. China.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Mechanistic insights into a catalyst-free method to construct quinazolinones through
multiple oxidative cyclization
Zhen-zhen Wanga , Yu Tanga,
aSchool of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery & High-Efficiency, Tianjin University, Tianjin, 300072 P. R.
China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel one-pot benign oxidative cyclization of alcohols with 2-aminobenzamides was
successfully developed without catalyst to afford the quinazolinones under O2. This one-pot
protocol involved oxidations and cyclizations to construct the skeleton of quinazolinones
through possibly three kinds of distinct reaction mechanisms.
Available online
Keywords:
Mechanistic
2015 Elsevier Ltd. All rights reserved
.
Catalyst-free
Quinazolinones
Oxidative cyclizatio
benzaldehyde under the effect of MnO2,6 I2,7 DDQ,8 PIDA,9
KMnO4,10 Cu(II),11 FeCl3,12 DMSO13 or using 2-aminobenzamide
with benzyl alcohol under the influence of metal catalyst
including zinc,14 iridium,15 ruthenium,16 platnium,17 or
palladium.18
1. Introduction
Quinazolinone and its derivatives widely exist in plants,
animals and microorganisms, showing diverse range of biological
and pharmacological properties. For example, they exhibit
anticancer, anti-inflammatory, anticonvulsant, antimalarial,
antihypertensive, antituberculous and diuretic activities.1
Futhermore, numerous clinical drugs consist of the quinazolinone
core (Fig. 1), including Mecloqualone2 which was famous for its
useful insomnia resistant effect, Nolatrexed3 as a thymidylate
synthase inhibitor for the treatment of cancer and Cloroqualone4
which was used for cancer as well.
Herein, developing green oxidative methods have drawn
extensive and enduring attention in the last few decades. There
are already some reports using O2 for the synthesis of
quinazolinones without catalysts under mild conditions.19 Here
we developed a four-step oxidative cyclization using O2 without
any other additives to generate a series of quinazolinone
compounds from 2-aminobenzamide with benzyl alcohol.
Furthermore, it is amazing for us to find three kinds of possibly
distinct reaction mechanisms from the same substrate.
N
Cl
O
O
S
O
N
N
NH
NH2
Cl
Cl
N
N
N
previous work
Nolatrexed
Mecloqualone
Cloroqualone
DDQ, MnO2, or PIDA
Figure 1. Representative quinazolinones in clinical drugs.
O
O
Iridium or palladium
NH2
OH
NH
+
NH2
N
In view of the significant potential application, there have
been various methods to build the quinazolinone skeleton via
oxidation in the past few years (Fig. 2).5 However, the one-pot
and environment-friendly synthesis of quinazolinone continues to
be one of the major challenges in synthetic organic chemistry. In
previous work, the 4(3H)–quinazolinone could be prepared
O2
our strategy
Figure 2. Methods for the synthesis of Quinazolinones
2. Results and discussion
through
pot reaction from 2-aminobenzamide and
——— one
*Corresponding author. E-mail:yutang@tju.edu.cn, Tel: +86 02227402904, Fax: +86 02227404031

2
Tetrahedron
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In the beginning, 2-aminobenzamide and benzyl alcohol
entry 2). However, when DMF was used as the solvent, the yield
were used as the model reaction to test the possibility of four-step
oxidative cyclization under O2 in DMSO. Not surprisingly, 3a
was detected as the main product after the reaction was complete.
was only 10 %. (Table 1, entry 1) and trace product was obtained
in water. It also gave dissatisfactory results when we used the air
balloon instead of oxygen balloon. No desired product was
detected when the reaction was carried out under N2, which also
demonstrated the importance of O2 in this protocol. Besides, the
attempt to optimize the reaction was unsuccessful by increasing
or decreasing the temperature. Judging by the yield of the desired
product, the entry 4 in table 1 was concluded as the best
condition.
Table 1. Optimization of reaction conditionsa
O
O
NH2
NH2
OH
solvent, time
temperature
NH
+
N
1a
2a
3a
With an optimized procedure in hand, we next investigated the
reactions with various primary alcohols in the presence of O2.
The variation of alcohol derivatives did not affect the efficiency
of this protocol, and the corresponding results were summarized
in Table 2. By treating 2-aminobenzamide 1a with substituted
benzyl alcohol (2a-2k), bearing electron-donating groups, the
desired products 3a-3j were conveniently obtained in moderate to
good yields (entries 2-5). The reactions with substrates of
electron-poor groups were carried out at a much higher
temperature 160 oC, but the yield was relatively low (entry 8).
The halogen substituents such as chloro and bromo groups
afforded the corresponding products in acceptable to good yields
(entries 6, 7and 10). The debrominated product was obtained
when the reaction was run at high temperature (entry 9). This
phenomenon was also observed with the 2-(hydroxymethyl)-
pyridine in 51% yield (entry 11). However, furyl alcohol was not
applicable to this condition with a wide range of temperature
from 100 to 160 oC (entry 12).
Temperature
(oC)
Time Yieldb
Entry
Solvent
Ambient
(h)
(%)
1
2
3
4
5
6
7
8
9
DMF
NMP
140
140
O2
O2
O2
O2
Air
N2
O2
Air
O2
8
8
8
4
4
4
4
4
4
10
77
H2O
Refluxing
140
Trace
82
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
140
72
140
Trace
25
120
160
62
160
80
aReaction condition: 2-aminobenzamide (1a) (0.5mmol), benzyl alcohol
(
2a) (2mmol), solvent (1ml);
bYield of isolated product;
Table 3. Synthesis of 2,4-disubstituted quinazolinones 4a
Table 2. Substrate scope for 2-substituted quinazolinones 3a
O
O
O
O
O
O2, 140 o
DMSO
C
R3
NH2
NH2
R3
R3
NH
R1
O2, 140 o
DMSO
C
N
+
R1
OH
N
N
R2
H
+
R2
OH
R2
+
N
NH2
N
N
1a
2
3
2a
4
1
4'
Entry
R1
Ph (a)
Time (h)
Yield (%)c
Entry
1
R2
H
H
H
H
R3
Time (h)
Yield (%)c
1
4
8
8
8
8
4
6
7
5
8
6
20
82
CH3 (b)
8
67
2
3b
CH2CH3(c)
CH2Ph (d)
Ph (e)
6
68
2
2-Me-C6H4 (b)
4-Me-C6H4 (c)
68
9
13 (37%)d
3
83
4
6
75
4
4-MeO-C6H4 (d)
2-OH-C6H4 (e)
2-Cl-C6H4 (f)
4-Cl-C6H4 (g)
4-NO2-C6H4 (h)
2-Br-C6H4 (i)
4-Br-C6H4 (j)
2-Pyridyl (k)
2-Furyl (l)
65
5
4-NO2
4-F
H
H
(f)
4
29
5
50
6
(g)
10
10
9
80
6b
7b
8b
9b
10
11b
12e
59
7
8b
4-F
CH3(h)
73 (6%)d
40 (18%)d
76
79
4-F
CH2CH3(i)
14
9
5-CH3
5-CH3
5-CH3
H
(j)
6
27 ( 8%)d
10
11b
CH3 (k)
Ph (l)
7
58
67
51
4
15 (39%)d
12
6-Cl
H
(m)
4
70
Nde
aReaction condition: 2-aminobenzamide (1a) (0.5mmol), alcohol (2) (2mmol),
DMSO (1mL);
bThe reaction temperature was 160 oC;
cIsolated yield of product 4;
aReaction condition: 2-aminobenzamide (1a) (0.5mmol), alcohol (
2)
(2mmol), DMSO (1mL);
bThe reaction temperature was 160 oC;
cIsolated yield of product
dIsolated yield of debrominated product 3a
e Temperature was attempted from 100 oC to 160 oC.
3;
dIsolated yield of product 4';
;
To further investigate the substrate scope, a series of 2-
aminobenzamide substrates were used in the reaction (Table
3), including electron-rich (Table 3, entries 1, 2, 7, 8 and 10)
and electron-deficient ones (Table 3, entry 5). They were
useful substrates for this reaction and gave the
corresponding products in low to good yield. However, the
Our initial work focused on optimizing the reaction conditions.
As shown in Table 1, 2-aminobenzamide and benzyl alcohol was
smoothly converted into 2-phenyl-4(3H)-quinazolinone in 82%
yield under O2 in DMSO at 140 oC after 4 h (Table 1, entry 4). A
lower yield was obtained when the solvent was NMP (Table 1,

3
To elucidate the proposed mechanism, a series of back-
substrates with a bulky group such as ethyl, phenyl and
benzyl were more likely to form the byproducts 4’ (Table 3,
entries 3, 8, 11 ) than the ones with a small group such as
ACCEPTED MANUSCRIPT
ground experiments were firstly performed. By treating
benzyl alcohol 2a under the established conditions (160 C,
o
air, DMSO) without the addition of 2-aminobenzamide,
26% of benzaldehyde 2c and 3% of benzyl ether 2d were
formed (Fig. 3, b). Therefore we speculated that
intermediate 5a was probably obtained from reaction of 1a
with benzyl alcohol 2a or benzyl ether 2d. However, 5a was
not detected either under the O2 or under air conditions
when 1a reacted with 2d, which proved that intermediate 5a
was not constructed from benzyl ether 2d. Delightfully, 46%
of 3a was generated when 1a reacted with 2d under the
optimized conditions (Fig. 3, c). Besides, the substrate was
stable when the reaction was carried out under the protection
of nitrogen. Based on the above results, it was concluded
that 2-(benzylamino)benzamide 5a was generated from
reaction of 2-aminobenzamide 1a and benzyl alcohol 2a
through nucleophilic substitution.
methyl (Table 3, entry 7). Notably, DMSO was an efficient
carbon source, which had been reported by Zhao20. Based on
these related research, we hypothesized that nucleophilic
attack and a sequential C–S bond cleavage were involved.
Then the following redox process occurred similarly to those
in Figure 4. The fluorine and chlorine substituted substrates
were also applied to the synthesis of quinazolinones with
good yields (Table 3, entries 6, 12). Moreover, the condition
was tolerated the dual substitution in phenyl group and
nitrogen atom (Table 3, entries 7, 8, 10 and 11).
The intermediate 2-(benzylamino)benzamide 5a (9%) and
the desired product 2-phenyl-4(3H)-quinazolinone 3a (63%)
o
were obtained at 160 C under the air after 2 h (Fig. 3, a).
Moreover, 5a could be transformed into the final product 3a
if the reaction time was prolonged or the reaction was run
under the optimized condition. Since we knew that the
benzyl alcohol could be easily converted to benzaldehyde,
it’s confuseing to find the generation of 5a in the reaction.
These experimental results prompted us to further explore
the mechanism.
Based on the above results, we proposed three kinds of
possibly mechanisms in the reaction (Fig. 4, A, B and C). In
the pathway A, the alcohol was first oxidized under O2 to
form the corresponding aldehyde which reacted with 2-
aminobenzamide to generate the imine. Then the nitrogen
atom of the amine attacked the imine to construct the
dihydrogenated quinazolinone, which was oxidized once
again to build the quinazolinone under the effect of O2 (Fig.
4, A). At the same time, a slight amount of dibenzyl ether
was also obtained and transformed to the imine by treatment
with 2-aminobenzamide (Fig. 4, B). Specifically, the benzyl
ether cation was generated under the effect of O2, which
could be attacked by the amine to form the intermediate.
Elimination of the intermediate gave the imine, which was
converted to the final product on the same theory. We also
detected the intermediate 5a formed through nucleophilic
substitution when the reaction was carried out in the air (Fig.
4, C). Then the 5a was oxidized to construct the imine and
the imine was transformed to the desired product through
two steps. The reason why we could not find the
intermediate 5a in the O2 was that 5a might easily be
converted to the desired product 3a once it was generated.
O
O
O
NH
NH2
OH
160 oC, Air
2h, DMSO
NH2
(a)
+
+
NH2
N
N
H
1a
2a
5a (9%)
3a (63%)
(coversion = 62%)
140 oC, O2
7h, DMSO, 65%
O
O
160 oC, Air
2h, DMSO
H
OH
+
(b)
(c)
2d
(3%)
2a
2c
(26%)
O
O
N
NH2
140 o
4h, DMSO
C
O
NH
+
NH2
2d
1a
3a
O2 46%
N2 0%
Figure 3. The blank and control experiments for the mechanism.
OH
3. Conclusion
OH
H2O
O2
2a
In summary, we have developed a tandem sequence
oxidation and cyclization to construct quinazolinones
skeleton using green oxidant O2 without any other additives.
The method has proved to apply to a broad scope of
substrates and to afford the final 4(3H)-quinazolinones via a
novel one-pot, catalyst-free and environment-friendly
transformation from 2-aminobenzamide and primary alcohol
in satisfactory to good yields.
O
O
C
A
B
O
NH2
NH2
O2
O
H
1a
H2O
O
O
NH2
NH2
NH2
O
N
H
5a
1a
NH2
4. Experimental section
O
O
N
H
O2
NH2
H2O
4.1. General information
NH2
1a
O
N
All reactions were performed under oxygen atmosphere and
stirred magnetically in standard glassware heated at 70 C for 3h
H2
N
o
before use. Reagents and solvents were purchased as reagent
OH
1
grade and without further purification. H and 13C NMR spectra
2a
were recorded on a 600 or 400 MHz BRUKER AVANCE
spectrometer at 25 oC. Chemical shifts values are given in ppm
with TMS as the internal standard. The peak patterns are defined
as follows: s, singlet; d, doublet; t, triplet; q, quartet; qui, quintet;
m, multiplet; dd, doublet of doublets; td, triplet of doublets and
brs, broad singlet. The coupling constants J, are reported in Hertz
O
O
O2
NH
NH
N
H
N
3a
Figure 4. The plausible mechanisms.

4
Tetrahedron
(Hz). Flash column chromatography was performed over silica
δ (ppm): 107.9, 110.1, 118.7, 130.2, 149.5, 150.6, 169.6; mass
ACCEPTED MANUSCRIPT
gel (200–300 mesh) using a mixture of petroleum ether (PE) and
ethyl acetate (EtOAc) or a mixture of petroleum ether and
tetrahydrofuran (THF) as the eluent. TLC plates (Silica gel
GF254) were visualized by exposure to ultraviolet light. Mass
spectrum was obtained on Agilent 6310 Ion Trap and HP5989A
mass spectrometer. High resolution mass spectrometry (HRMS)
was obtained on a Q-TOF micro (BRUKER) spectrometer.
Melting points were determined with a national Micro Melting
point apparatus without corrections. Organic solutions were
concentrated by rotary evaporation below 40 °C in vacuum.
spectrum (ESI): m/e (% relative intensity) 179.8 (100) (M-H)-.
4.2.6 2-amino-4-fluorobenzamide (1g): White solid; mp: 130-133
oC; Rf = 0.38 (40% ethyl acetate in petroleum ether); H NMR
1
(600 MHz, DMSO-d6) δ (ppm): 6.28 (td, 1H, J = 2.6, 8.6 Hz),
6.44 (dd, 1H, J =2.6, 11.9 Hz), 6.90 (s, 2H), 7.08 (brs, 1H), 7.60
(dd, 1H, J = 6.7, 8.8 Hz), 7.73 (brs, 1H); 13C NMR (150 MHz,
DMSO-d6) δ (ppm): 101.3 (dd, J = 5.8, 20.8 Hz), 101.4 (dd, J =
3.3, 19.1 Hz), 110.3, 131.3 (dd, J = 3.2, 11.4 Hz), 152.6 (d, J =
12.6 Hz), 164.46 (d, J = 245.1 Hz), 170.4; 19F NMR (376 MHz,
CDCl3) δ (ppm): -106.9 – -107.0 (m, 1F); mass spectrum (ESI):
m/e (% relative intensity) 177.4 (100) (M+Na)+.
4.2. Synthesis of the N-substituted 2-aminobenzamide 1b-m
To a solution of 2-amino-5-methylbenzamide (1.5 g, 10mmol)
in THF (20 mL) was added triphosgene (0.99g , 3.3mmol)
portionwise about 20 min. The mixture was cooled to r.t. when
the reaction was completed. Through filtration, the crude isatoic
anhydride was got. A stirred solution of isatoic anhydride was
suspending in THF which was heated to 60°C, then the solution
of amine was added dropwise. Progress of the reaction was
monitored using TLC. After completion of the reaction, the
resulting solution was cooled to room temperature and the
solvent was removed under high vacuum to give the crude
product. Then recrystallization from Et2O afforded the pure
product.
4.2.7 2-amino-4-fluoro-N-methylbenzamide (1h): White solid;
mp: 72-74 oC; Rf = 0.46 (40% ethyl acetate in petroleum ether);
1H NMR (600 MHz, DMSO-d6) δ (ppm): 2.72 (d, 3H, J = 4.5
Hz), 6.31 (td, 1H, J = 2.7, 8.6 Hz), 6.46 (dd, 1H, J = 2.6, 11.9
Hz), 6.75 (brs, 2H), 7.51 (dd, 1H, J = 6.8, 8.6 Hz), 8.17 (d, 1H, J
= 3.5 Hz); 13C NMR (150 MHz, DMSO-d6) δ (ppm): 25.9 (d, J =
7.5 Hz), 101.3 (dd, J = 6.2, 22.4 Hz), 101.5 (dd, J = 5.0, 22.6
Hz), 111.4, 130.4(dd, J = 3.0, 11.3 Hz), 152.0 (d, J = 12.6 Hz),
164.3 (d, J = 244.9 Hz), 168.5; 19F NMR (376 MHz, CDCl3) δ
(ppm): -108.3 – -108.4 (m, 1F); mass spectrum (ESI): m/e (%
relative intensity) 191.4 (100) (M+Na)+.
4.2.8 2-amino-4-fluoro-N-ethylbenzamide (1i): White solid; mp:
1
4.2.1 2-amino-N-methylbenzamide (1b): Orange solid; mp: 79-80
78-82 oC; Rf = 0.49 (40% ethyl acetate in petroleum ether); H
1
°C; Rf = 0.22 (40% ethyl acetate in petroleum ether); H NMR
NMR (600 MHz, DMSO-d6) δ (ppm): 1.11 (t, 3H, J = 7.2 Hz),
3.18-3.30 (m, 2H), 6.31 (td, 1H, J = 2.7, 8.6 Hz), 6.46 (dd, 1H, J
= 2.6, 11.9 Hz), 6.75 (brs, 2H), 7.52-7.56 (m, 1H), 8.20 (brs, 1H);
13C NMR (150 MHz, DMSO-d6) δ (ppm): 14.7 (d, J = 2.9 Hz),
33.6, 101.3 (dd, J = 6.4, 20.9 Hz), 101.5 (dd, J = 5.0, 19.2 Hz),
111.6, 130.5 (dd, J = 3.2, 11.1 Hz), 152.0 (d, J = 12.4 Hz), 164.3
(d, J = 245.0 Hz), 167.9; 19F NMR (376 MHz, CDCl3) δ (ppm): -
108.3 – -108.5 (m, 1F); mass spectrum (ESI): m/e (% relative
intensity) 205.6 (100) (M+Na)+.
(600 MHz, CDCl3) δ (ppm): 2.96 (d, 3H, J = 4.8 Hz), 5.50 (brs,
2H), 6.10 (brs, 1H), 6.63 (t, 1H, J = 7.5 Hz), 6.67 (d, 1H, J = 8.2
Hz), 7.19 (t, 1H, J = 7.7 Hz), 7.29 (d, 1H, J = 7.8 Hz); 13C NMR
(150 MHz, CDCl3) δ (ppm): 26.5, 116.3, 116.6, 117.2, 127.3,
132.1, 148.5, 170.1; mass spectrum(ESI): m/e (% relative
intensity) 173.4 (100) (M+Na)+.
4.2.2 2-amino-N-ethylbenzamide (1c): White solid; mp: 97-100
oC; Rf = 0.52 (40% ethyl acetate in petroleum ether); 1H NMR
(600 MHz, CDCl3) δ (ppm): 1.19 (t, 3H, J = 7.3 Hz), 3.35-3.43
(m, 2H), 5.36 (brs, 2H), 6.45 (brs, 1H), 6.60 (t, 1H, J = 7.5 Hz),
6.65 (d, 1H, J = 8.1 Hz), 7.10-7.22 (m, 1H), 7.31 (d, 1H, J = 7.8
Hz); 13C NMR (150 MHz, CDCl3) δ (ppm): 14.8, 34.5, 116.5,
117.2, 127.3, 132.0, 148.5, 169.4; mass spectrum (ESI): m/e (%
relative intensity) 187.7 (100) (M+Na)+.
4.2.9 2-amino-5-methylbenzamide (1j): White solid; mp: 173-175
1
oC; Rf = 0.29 (40% ethyl acetate in petroleum ether); H NMR
(600 MHz, DMSO-d6) δ (ppm): 2.15 (s, 3H), 6.33 (brs, 2H), 6.60
(d, 1H, J = 8.3 Hz), 6.96 (d, 1H, J = 8.1 Hz), 7.02 (brs, 1H), 7.36
(s, 1H), 7.68 (brs, 1H); 13C NMR (150 MHz, DMSO-d6) δ (ppm):
20.0, 113.7, 116.5, 122.7, 128.6, 132.7, 147.8, 171.3; mass
spectrum (ESI): m/e (% relative intensity) 173.4 (100) (M+Na)+.
4.2.3 2-amino-N-benzylbenzamide (1d): Pale yellow solid; mp:
1
123-125 °C; Rf = 0.65 (40% ethyl acetate in petroleum ether); H
4.2.10 2-amino-N, 5-dimethylbenzamide (1k): White solid; mp:
1
NMR (600 MHz, CDCl3) δ (ppm): 4.60 (d, J = 5.6 Hz, 2H), 5.59
(brs, 2H), 6.34 (brs, 1H), 6.62 (t, 1H, J = 7.5 Hz), 6.69 (d, 1H, J
= 8.2 Hz), 7.20 (t, 1H, J = 7.5 Hz), 7.27-7.38 (m, 6H); 13C NMR
(150 MHz, CDCl3) δ (ppm): 43.7, 115.9, 116.6, 117.3, 127.3,
127.5, 127.8, 128.8, 132.4, 138.4, 148.9, 169.3; mass spectrum
(ESI): m/e (% relative intensity) 249.8 (100) (M+Na)+.
122-124oC; Rf = 0.34 (40% ethyl acetate in petroleum ether); H
NMR (600 MHz, DMSO-d6) δ (ppm): 2.15 (s, 3H), 2.71 (d, 3H, J
= 3.8 Hz), 6.17 (brs, 2H), 6.60 (d, 1H, J = 8.1 Hz), 6.95 (d, 1H, J
= 7.8 Hz), 7.27 (s, 1H), 8.12 (brs, 1H); 13C NMR (150 MHz,
DMSO-d6) δ (ppm): 20.0, 25.9, 114.8, 116.4, 122.9, 127.9, 132.3,
147.1, 169.3. mass spectrum (ESI): m/e (% relative intensity)
187.4 (100) (M+Na)+.
4.2.4 2-amino-N-phenylbenzamide (1e): White solid; mp: 130-
1
131 °C; Rf = 0.56 (20% ethyl acetate in petroleum ether); H
4.2.11 2-amino-5-methyl-N-phenylbenzamide (1l): White solid;
mp: 160-162 oC; Rf = 0.74 (20% ethyl acetate in petroleum ether);
1H NMR (600 MHz, DMSO-d6) δ (ppm): 2.22 (s, 3H), 6.11 (brs,
2H), 6.69 (d, 1H, J = 8.2 Hz), 7.03 (d, 1H, J = 8.1 Hz), 7.07 (t,
1H, J = 7.2 Hz) , 7.33 (t, 2H, J = 7.6 Hz), 7.45 (s, 1H), 7.73 (d,
2H, J = 7.9 Hz), 10.0 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ
(ppm): 20.0, 115.4, 116.5, 120.4, 123.1, 123.3, 128.4, 128.5,
132.9, 139.3, 147.4, 167.9. mass spectrum (ESI): m/e (% relative
intensity) 249.8 (100) (M+Na)+.
NMR (600 MHz, CDCl3) δ (ppm): 5.51 (brs, 2H), 6.69-6.72 (m,
2H), 7.14 (t, 1H, J = 7.4 Hz), 7.25(t, 1 H, J = 8.0 Hz), 7.36 (t, 2H,
J = 7.9 Hz), 7.46 (d, 1H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.8 Hz),
7.76 (brs, 1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 116.4,
116.9, 117.6, 120.7, 124.5, 127.3, 129.0, 132.7, 137.9, 148.9,
167.6; mass spectrum (ESI): m/e (% relative intensity) 235.7
(100) (M+Na)+.
4.2.5 2-amino-4-nitrobenzamide (1f): Yellow solid; mp: 218-220
1
oC; Rf = 0.31 (40% ethyl acetate in petroleum ether); H NMR
4.2.12 2-amino-6-chlorobenzamide (1m): White solid; mp: 132-
1
(600 MHz, DMSO-d6) δ (ppm): 7.02 (s, 2H), 7.25 (dd, 1H, J =
2.2, 8.6 Hz), 7.47 (brs, 1H), 7.57 (d, 1H, J = 2.2 Hz) , 7.73 (d,
1H, J = 8.6 Hz), 8.04 (brs, 1H); 13C NMR (150 MHz, DMSO-d6)
134 oC; Rf = 0.28 (40% ethyl acetate in petroleum ether); H
NMR (600 MHz, DMSO-d6) δ (ppm): 5.22 (brs, 2H), 6.57 (d,
1H, J = 7.8 Hz), 6.63 (d, 1H, J = 8.2 Hz), 7.01 (t, 1H, J = 8.0

5
Hz), 7.60 (brs, 1H), 7.82 (brs, 1H); 13C NMR (150 MHz, DMSO-
d6) δ (ppm): 113.6, 116.1, 121.6, 129.8, 130.0, 147.0, 167.6;
mass spectrum (ESI): m/e (% relative intensity) 193.6 (100)
(M+Na)+.
7.5 Hz), 7.55-7.60 (m, 2H), 7.63 (d, 1H, J = 8.0 Hz) , 7.69 (dd,
ACCEPTED MANUSCRIPT
1H, J = 1.4, 7.5 Hz), 7.73 (d, 1H, J = 8.1 Hz), 7.87 (td, 1H, J =
1.6, 7.5 Hz), 8.20 (d, 1H, J = 7.9 Hz), 12.64 (s, 1H); mass
spectrum (ESI): m/e (% relative intensity) 278.8 (100) (M+Na)+.
4.3. Synthesis of 2-substituted-4(3H)-quinazolinones: 3a–k
4.3.7 2-(4-chlorolphenyl)-4(3H)-quinazolinone (3g): Pale-yellow
solid; mp: 295-297 oC; Rf = 0.23 (40% ethyl acetate in petroleum
ether); H NMR (600 MHz, DMSO-d6) δ (ppm): 7.54 (t, 1H, J =
7.5 Hz), 7.63 (d, 2H, J = 8.5 Hz), 7.75 (d, 1H, J = 8.0 Hz), 7.85 (t,
1H, J = 8.2 Hz), 8.16 (d, 1H, J = 7.8 Hz), 8.21 (d, 2H, J = 8.6
Hz), 12.59 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ (ppm):
121.5, 126.3, 127.2, 128.0, 129.1, 130.1, 132.0, 135.1, 136.8,
149.1, 151.8, 162.6; mass spectrum (ESI): m/e (% relative
intensity) 278.8 (100) (M+Na)+.
2-aminobenzamide (1a) (0.5 mmol) and alcohol (2) (2 mmol)
were added to an oven-dried glassware with DMSO (1 mL).
Then the system was degassed and filled with oxygen. The
reaction mixture was stirred and heated to 140 oC. Progress of
the reaction was monitored by TLC. After completion of the
reaction, the resulting solution was cooled to room temperature,
and diluted with dichloromethane, washed with water and brine,
dried over anhydrous Na2SO4 and concentrated with the aid of a
rotary evaporator. The residue was purified by column
1
4.3.8 2-(4-nitrophenyl)-4(3H)-quinazolinone (3h): Pale-yellow
o
chromatography
on
silica
gel
using
petroleum
solid; mp >300 C; Rf = 0.43 (40% ethyl acetate in petroleum
1
ether/tetrahydrofuran (5:1 to 2:1) as eluent to provide the desired
product.
ether); H NMR (600 MHz, DMSO-d6) δ (ppm): 7.59 (t, 1H, J =
7.9 Hz), 7.81 (d, 1H, J = 7.9 Hz), 7.89 (t, 1H, J = 7.6 Hz), 8.19
(d, 1H, J = 8.8 Hz), 8.41 (q, 4H, J = 9.0 Hz), 12.86 (s, 1H); mass
spectrum (ESI): m/e (% relative intensity) 265.7 (100) (M-H)-.
4.3.1 2-phenyl-4(3H)-quinazolinone (3a): White solid; mp: 239-
241oC; Rf = 0.52 (40% ethyl acetate in petroleum ether); 1H NMR
(600 MHz, CDCl3) δ (ppm): 7.52 (dt, 1H, J = 1.2 Hz, 7.8 Hz),
7.57-7.63 (m, 3H), 7.82 (dt, 1H, J = 1.2 Hz, 7.2 Hz), 7.87 (d, 1H,
J = 8.1 Hz), 8.25 (dd, 2H, J = 2.9, 6.7 Hz), 8.33 (dd, 1H, J = 1.2,
7.8 Hz), 11.46 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm):
120.8, 126.4, 126.8, 127.5, 128.0, 129.1, 131.7, 132.7, 134.9,
149.4, 151.8, 163.8; mass spectrum (ESI): m/e (% relative
intensity) 223.4 (100) (M+H)+.
4.3.9 2-(2-bromophenyl)-4(3H)-quinazolinone (3i): White solid;
mp: 148-152 oC; Rf = 0.52 (40% ethyl acetate in petroleum
ether); 1H NMR (600 MHz, CDCl3) δ (ppm): 7.41 (t, 1H, J = 7.4
Hz), 7.49 (t, 1H, J = 7.5 Hz), 7.54 (t, 1H, J = 7.8 Hz), 7.68-7.76
(m, 2H), 7.80-7.88 (m, 2H), 8.27 (d, 1H, J = 8.0 Hz), 10.54 (brs,
1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 121.0, 121.1, 126.5,
127.4, 127.9, 128.0, 131.3, 132.0, 133.8, 134.9, 135.0, 148.9,
152.1, 162.4; mass spectrum (ESI): m/e (% relative intensity)
322.7 (100) [M (79Br) + Na]+, 324.7 (100) [M (81Br) + Na]+.
4.3.2 2-(2-methylphenyl)-4(3H)-quinazolinone (3b): White solid;
mp: 215-217 oC; Rf = 0.56 (40% ethyl acetate in petroleum ether);
1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.40 (s, 3H), 7.30-7.34
(m, 2H), 7.43 (t, 1H, J = 6.8 Hz), 7.49-7.59 (m, 2H), 7.70 (d, 1H,
J = 8.0 Hz), 7.85 (t, 1H, J = 7.6 Hz), 8.19 (d, 1H, J = 7.1 Hz),
12.47 (brs, 1H); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 19.6,
121.0, 125.7, 125.8, 126.6, 127.4, 129.1, 129.9, 130.5, 134.2,
134.5, 136.1, 148.7, 154.4, 161.8; mass spectrum (ESI): m/e (%
relative intensity) 258.8 (100) (M+Na)+.
4.3.10 2-(4-bromophenyl)-4(3H)-quinazolinone (3j): Pale-Yellow
o
solid; mp >300 C; Rf = 0.23 (20% ethyl acetate in petroleum
1
ether); H NMR (600 MHz, DMSO-d6) δ (ppm): 7.54 (t, 1H, J =
7.5 Hz), 7.74-7.77 (m, 3H), 7.85 (dt, 1H, J = 1.3, 7.9 Hz), 8.13
(d, 2H, J = 8.6 Hz), 8.16 (dd, 1H, J = 1.2, 7.9 Hz), 12.60 (s, 1H);
mass spectrum (ESI): m/e (% relative intensity) 322.7 (100) [M
(79Br) + Na]+, 324.7 (100) [M (81Br) + Na]+.
4.3.3 2-(4-methylphenyl)-4(3H)-quinazolinone (3c): White solid;
mp: 236-239 oC; Rf = 0.71 (40% ethyl acetate in petroleum ether);
1H NMR (600 MHz, CDCl3) δ (ppm): 2.46 (s, 3H), 7.38 (d, 2H, J
= 7.9 Hz), 7.50 (t, 1H, J = 7.4 Hz), 7.80 (t, 1H, J = 7.5 Hz), 7.84
(d, 1H, J = 7.9 Hz), 8.16 (d, 2H, J = 8.0 Hz), 8.32 (d, 1H, J = 7.8
Hz), 11.71 (brs, 1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 21.6,
120.7, 126.4, 126.6, 127.4, 127.8, 129.8, 134.9, 142.3, 149.5,
151.9, 163.9; mass spectrum (ESI): m/e (% relative intensity)
236.6 (100) (M+H)+.
4.3.11 2-(2-pyridylphenyl)-4(3H)-quinazolinone (3k): White
solid; mp: 168-165 oC; Rf = 0.37 (40% ethyl acetate in petroleum
ether); H NMR (600 MHz, CDCl3), 7.44-7.48 (m, 1H), 7.51 (t,
1H, J = 7.4 Hz), 7.75-7.84 (m, 2H), 7.90 (t, 1H, J = 7.7 H), 8.35
(d, 1H, J = 7.9 Hz), 8.56 (d, 1H, J = 7.9 Hz), 8.65 (d, 1H, J = 4.3
Hz), 10.95 (s, 1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 122.1,
122.6, 126.3, 126.9, 127.4, 128.1, 134.6, 137.6, 148.6, 148.8,
149.1, 149.2, 161.5; mass spectrum (ESI): m/e (% relative
intensity) 224.4 (100) (M+H)+.
1
4.3.4 2-(4-methoxyphenyl)-4(3H)-quinazolinone (3d): Pale-
4.4. Synthesis of 2,3-disubstituted-4(3H)-quinazolinones: 4b–
m
o
yellow solid; mp: 245-248 C; Rf = 0.36 (40% ethyl acetate in
1
petroleum ether); H NMR (600 MHz, DMSO-d6) δ (ppm): 3.86
4.4.1 3-methyl-2-phenyl-4(3H)-quinazolinone (4b): White solid;
mp: 135-139 oC; Rf = 0.27 (20% ethyl acetate in petroleum ether);
1H NMR (600 MHz, DMSO-d6) δ (ppm): 3.37 (s, 3H), 7.53-5.58
(m, 4H), 7.65-7.71 (m, 3H), 7.84 (t, 1H, J = 7.6 Hz), 8.19 (d, 1H,
J = 7.9 Hz); 13C NMR (150 MHz, DMSO-d6) δ (ppm): 33.8,
120.1, 126.1, 126.8, 127.1, 128.2, 128.4, 129.7, 134.3, 135.4,
147.0, 156.1, 161.6; mass spectrum (ESI): m/e (% relative
intensity) 237.3 (100) (M+H)+.
(s, 3H), 7.09 (d, 2H, J = 8.9 Hz), 7.49 (t, 1H, J = 8.0 Hz), 7.71 (d,
1H, J = 8.0 Hz), 7.82 (t, 1H, J = 7.6 Hz), 8.14 (d, 1H, J = 8.9
Hz), 8.20 (d, 2H, J = 8.9 Hz), 12.39 (s, 1H); mass spectrum
(ESI): m/e (% relative intensity) 274.5 (100) (M+Na)+.
4.3.5 2-(2-hydroxyphenyl)-4(3H)-quinazolinone (3e): White solid;
1
mp > 300oC; Rf = 0.56 (40% ethyl acetate in petroleum ether); H
NMR (600 MHz, DMSO-d6) δ (ppm): 6.97 (t, 1H, J = 7.5 Hz),
7.02 (d, 1H, J = 8.2 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.56 (t, 1H, J =
7.4 Hz,), 7.78 (d, 1H, J = 8.1 Hz), 7.87 (t, 1H, J = 7.6 Hz), 8.17
(d, 1H, J = 7.8 Hz), 8.24 (d, 1H, J = 8.0 Hz), 12.50 (s, 1H), 13.81
(s, 1H); mass spectrum (ESI): m/e (% relative intensity) 261.7
(100) (M+Na)+.
4.4.2 3-ethyl-2-phenyl-4(3H)-quinazolinone (4c): White solid;
mp: 124-127 oC; Rf = 0.74 (40% ethyl acetate in petroleum ether);
1H NMR (600 MHz, CDCl3) δ (ppm): 1.22 (t, 3H, J = 7.0 Hz),
4.05 (q, 2H, J = 7.0 Hz), 7.45-7.60 (m, 6H), 7.70-7.82 (m, 2H),
8.34 (d, 1H, J = 8.2 Hz); 13C NMR (150 MHz, CDCl3) δ (ppm):
14.1, 41.2, 120.9, 126.7, 127.0, 127.4, 127.7, 128.8, 129.8, 134.3,
135.5, 147.1, 156.2, 162.0; mass spectrum (ESI): m/e (% relative
intensity) 273.8 (100) (M+Na)+.
4.3.6 2-(2-chlorolphenyl)-4(3H)-quinazolinone (3f): White solid;
mp: 160-165 oC; Rf = 0.38 (40% ethyl acetate in petroleum
1
ether); H NMR (600 MHz, DMSO-d6) δ (ppm): 7.52 (t, 1H, J =

6
Tetrahedron
4.4.3 3-benzyl-2-phenyl-4(3H)-quinazolinone (4d): White solid;
148.0, 150.4 (d, J = 12.9 Hz), 160.8, 166.2 (d, J = 254.3 Hz); 19
F
NMR (564 MHz, CDCl3) δ (ppm): -103.5 (q, 1F, J = 8.0 Hz);
mass spectrum (ESI): m/e (% relative intensity) 179.4 (100)
(M+H)+.
ACCEPTED MANUSCRIPT
mp: 135-139 oC; Rf = 0.38 (20% ethyl acetate in petroleum ether);
1H NMR (600 MHz, CDCl3) δ (ppm): 5.28 (s, 2H), 6.86-6.99(m,
2H), 7.16-7.23 (m, 3H), 7.35 (d, 2H, J = 7.4 Hz), 7.41 (t, 2H, J =
7.5 Hz), 7.48 (t, 1H, J = 7.4 Hz), 7.54 (t, 1H, J = 7.9 Hz), 7.75-
7.85 (m, 2H), 8.38 (d, 1H, J = 7.9 Hz); 13C NMR (100 MHz,
CDCl3) δ (ppm): 48.8, 120.8, 127.0 , 127.1 , 127.2, 127.4, 127.5,
128.0, 128.5, 128.6, 129.9, 134.6, 135.1, 136.5, 147.1, 156.4,
162.4; mass spectrum (ESI): m/e (% relative intensity) 334.9
(100) (M+Na)+.
4.4.10
7-fluoro-3-ethyl-2-phenyl-4(3H)-quinazolinone
(4i):
White solid; mp: 120-124 oC; Rf = 0.64 (20% ethyl acetate in
1
petroleum ether); H NMR (600 MHz, CDCl3) δ (ppm): 1.22 (t,
3H, J = 7.1 Hz), 4.03 (q, 2H, J = 7.0 Hz), 7.22 (td, 1H, J = 2.5,
8.6 Hz), 7.38 (dd, 1H, J = 2.5, 9.6 Hz), 7.49-7.57 (m, 5H), 8.35
(dd, 1H, J = 6.1, 8.8 Hz); 13C NMR (150 MHz, CDCl3) δ (ppm):
14.1, 41.3, 112.6 (d, J = 21.8 Hz), 115.9 (d, J = 23.6 Hz), 117.7,
127.5, 128.9, 129.5 (d, J = 10.6 Hz), 130.0, 135.2, 149.2 (d, J =
12.9 Hz), 157.5, 161.3, 166.5 (d, J = 254.1 Hz); 19F NMR (376
MHz, CDCl3) δ (ppm): -102.9 (s, 1F); mass spectrum (ESI): m/e
(% relative intensity) 291.3 (100) (M+Na)+; HRMS (ESI) m/z
calcd for C16H13FN2ONa+ 291.0904, found 291.0885.
4.4.4 3-benzyl-4(3H)-quinazolinone (4’d): White solid; mp: 118-
120 oC; Rf = 0.18 (40% ethyl acetate in petroleum ether); H
1
NMR (600 MHz, CDCl3) δ (ppm): 5.21 (s, 2H), 7.28-7.40 (m,
5H), 7.51 (t, 1H, J = 7.3 Hz), 7.71 (d, 1H, J = 8.0 Hz), 7.79-7.73
(t, 1H, J = 7.8 Hz), 8.12 (s, 1H), 8.33 (d, 1H, J = 7.9 Hz); 13
C
NMR (150 MHz, CDCl3) δ (ppm): 49.6, 122.2, 126.9, 127.4,
127.5, 128.0, 128.3, 129.1, 134.4, 135.7, 146.4, 148.0, 161.1;
mass spectrum (ESI): m/e (% relative intensity) 259.7 (100)
(M+Na)+.
4.4.11 7-fluoro-3-ethyl-4(3H)-quinazolinone (4’i): Pale-yellow
solid; mp: 90-93 oC; Rf = 0.14 (20% ethyl acetate in petroleum
ether); 1H NMR (600 MHz, CDCl3) δ (ppm): 1.43 (t, 3H, J = 7.2
Hz), 4.07 (q, 2H, J = 7.2 Hz), 7.22 (td, 1H, J = 2.5, 8.5 Hz), 7.35
(dd, 1H, J = 2.5, 9.5 Hz), 8.06 (s, 1H), 8.33 (dd, 1H, J = 6.1, 8.9
Hz); 13C NMR (150 MHz, CDCl3) δ (ppm): 14.9, 42.2, 112.7 (d, J
= 21.9 Hz), 116.0 (d, J = 23.5 Hz), 118.9 (d, J = 1.9 Hz), 129.4
(d, J = 10.5 Hz), 147.5, 150.3 (d, J = 13.0 Hz), 160.2, 166.3 (d, J
= 254.4 Hz) ; 19F NMR (376 MHz, CDCl3) δ (ppm): -102.5 (s,
1F); mass spectrum (ESI): m/e (% relative intensity) 193.6 (100)
(M+H)+; HRMS (ESI) m/z calcd for C10H9FN2OH+ 193.0772,
found 193.0757.
4.4.5 2,3-diphenyl-4(3H)-quinazolinone (4e): White solid; mp:
150-152oC; Rf = 0.43 (40% ethyl acetate in petroleum ether); H
1
NMR (600 MHz, DMSO-d6) δ (ppm): 7.19-7.28 (m, 4H), 7.28-
7.34 (m, 4H), 7.38 (d, 2H, J = 7.2 Hz), 7.61 (t, 1H, J = 7.2 Hz)
7.78 (d, 1H, J = 8.1 Hz), 7.91 (t, 1H, J = 7.6 Hz), 8.21 (d, 1H, J =
8.0 Hz); 13C NMR (150 MHz, DMSO-d6) δ (ppm): 120.7, 126.4,
127.2, 127.4, 127.5, 128.1, 128.5, 128.8, 128.9, 129.4, 134.8,
135.5, 137.7, 147.2, 155.1, 161.4; mass spectrum (ESI): m/e (%
relative intensity) 299.4 (100) (M+H)+.
4.4.6 7-nitro-2-phenyl-4(3H)-quinazolinone (4f): Yellow solid;
4.4.12 6-methy-2-phenyl-4(3H)-quinazolinone (4j): White solid;
mp: 259-262 oC; Rf = 0.74 (40% ethyl acetate in petroleum ether);
1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.47 (s, 3H), 7.50-7.60
(m, 3H), 7.73-7.70 (m, 2H), 7.96 (s, 1H), 8.18 (d, 2H, J = 7.1
Hz), 12.47 (brs, 1H); 13C NMR (150 MHz, DMSO-d6) δ (ppm):
20.8, 120.6, 125.1, 127.3, 127.5, 128.5, 131.1, 132.7, 135.8,
136.2, 146.6, 151.3, 162.0; mass spectrum (ESI): m/e (% relative
intensity) 258.9 (100) (M+Na)+.
o
mp >300 C; Rf = 0.62 (40% ethyl acetate in petroleum ether); 1H
NMR (600 MHz, DMSO-d6) δ (ppm): 7.59 (t, 2H, J = 7.2 Hz),
7.61-7.67 (m, 1H), 8.18-8.27 (m, 3H), 8.37 (d, 1H, J = 8.6 Hz),
8.44 (s, 1H), 12.93 (brs, 1H); mass spectrum (ESI): m/e (%
relative intensity) 265.7 (100) (M-H)-.
4.4.7 7-fluror-2-phenyl-4(3H)-quinazolinone (4g): White solid;
mp: 120-126 oC; Rf = 0.56 (40% ethyl acetate in petroleum ether);
1H NMR (600 MHz, DMSO-d6) δ (ppm): 7.39 (t, 1H, J = 8.6
Hz), 7.52 (d, 1H, J = 8.6 Hz), 7.57 (t, 2H, J = 7.4 Hz), 7.59-7.64
(m, 1H), 8.14-8.26 (m, 3H), 12.64 (brs, 1H); 13C NMR (150
MHz, DMSO-d6) δ (ppm): 112.4 (d, J = 22.9 Hz), 115.1 (d, J =
23.3 Hz), 118.0, 127.9, 128.6, 128.9 (d, J = 11.2 Hz), 131.6,
132.4, 150.9 (d, J = 13.5 Hz), 153.7, 161.5, 165.8 (d, J =
246.5Hz); 19F NMR (376 MHz, CDCl3) δ(ppm): -102.0 (s, 1F);
mass spectrum (ESI): m/e (% relative intensity) 239.0 (100) (M-
H)-.
4.4.13 3,6-dimethyl-2-phenyl-4(3H)-quinazolinone (4k): White
solid; mp: 135-139 oC; Rf = 0.77 (40% ethyl acetate in petroleum
1
ether); H NMR (600 MHz, CDCl3) δ (ppm): 2.51 (s, 3H) , 3.49
(s, 3H), 7.50-7.54 (m, 3H), 7.55-7.59 (m, 3H), 7.65 (d, 1H, J =
8.3 Hz), 8.12 (s, 1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 21.4,
34.3, 120.2, 126.0, 127.3, 128.0, 128.9, 130.0, 135.4, 135.8,
137.2, 145.3, 155.3, 162.7; mass spectrum (ESI): m/e (% relative
intensity) 273.9 (100) (M+Na)+; HRMS (ESI) m/z calcd for
C17H15NONa+ 273.0998, found 273.0995.
4.4.8 7-fluoro-3-methyl-2-phenyl-4(3H)-quinazolinone (4h):
4.4.14 6-methyl-2,3-diphenyl-4(3H)-quinazolinone (4l): White
White solid; mp: 151-154 oC; Rf = 0.65 (40% ethyl acetate in
solid; mp: 175-179 oC; Rf = 0.54 (20% ethyl acetate in petroleum
1
1
petroleum ether); H NMR (600 MHz, CDCl3) δ (ppm): 3.51 (s,
ether); H NMR (600 MHz, CDCl3) δ (ppm): 2.54 (s, 3H), 7.15
3H), 7.24 (td, 1H, J = 2.5, 8.7 Hz), 7.46 (d, 1H, J = 8.0 Hz), 7.52-
7.62 (m, 5H), 8.35 (dd, 1H, J = 6.1, 8.8 Hz); 13C NMR (150
MHz, CDCl3) δ (ppm):34.3, 112.7 (d, J = 21.9 Hz), 115.9 (d, J =
23.6 Hz), 117.3, 127.9, 128.9, 129.5 (d, J = 10.6 Hz), 130.3,
135.1, 149.5, 157.4, 162.0, 166.5 (d, J = 254.1 Hz); 19F NMR
(376 MHz, CDCl3) δ (ppm): -103.3 (q, 1F, J = 8.6 Hz); mass
spectrum (ESI): m/e (% relative intensity) 277.9 (100) (M+Na)+;
HRMS (ESI) m/z calcd for C15H11FN2ONa+ 277.0748, found
277.0735.
(d, 2H, J = 7.1 Hz), 7.22 (t, 2H, J = 7.3 Hz), 7.23-7.36 (m, 6H),
7.65 (d, 1H, J = 9.6 Hz), 7.83 (d, 1H, J = 5.4 Hz), 8.15 (s, 1H);
mass spectrum (ESI): m/e (% relative intensity) 334.8 (100)
(M+Na)+.
4.4.15 6-methyl-3-phenyl-4(3H)-quinazolinone (4’l): White solid;
mp: 105-109 oC; Rf = 0.23 (20% ethyl acetate in petroleum ether);
1H NMR (600 MHz, CDCl3) δ (ppm): 2.51 (s, 3H), 7.42 (d, 2H, J
= 7.6 Hz), 7.49 (t, 1H, J = 7.3 Hz), 7.55 (t, 2H, J = 7.5 Hz), 7.61
(d, 1H, J = 8.2 Hz), 7.67 (d, 1H, J = 8.3 Hz), 8.08 (s, 1H), 8.15
(s, 1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 21.4, 122.1, 126.6,
127.0, 127.4, 129.1, 129.6, 136.0, 137.6, 138.0, 145.4, 145.8,
160.8; mass spectrum (ESI): m/e (% relative intensity) 237.9
(100) (M+H)+.
4.4.9 7-fluoro-3-methyl-4(3H)-quinazolinone (4’h): White solid;
mp: 127-130 oC; Rf = 0.23 (40% ethyl acetate in petroleum ether);
1H NMR (600 MHz, CDCl3) δ (ppm): 3.60 (s, 3H), 7.22 (t, 1H, J
= 8.1 Hz), 7.34 (d, 1H, J = 9.3 Hz), 8.07 (s, 1H), 8.31 (t, 1H, J =
6.8 Hz); 13C NMR (150 MHz, CDCl3) δ (ppm): 34.1, 112.8 (d, J
= 21.8 Hz), 116.1 (d, J = 23.5 Hz), 118.7, 129.2 (d, J = 10.5 Hz),

7
C. Synthesis 2011
,
1
, 1-22; (c) Wu, X. F.; Oschatz, S.; Sharif, M.;
Beller, M.; Langer, P. Tetrahedron 2014 70, 23-29; (d) He, L.; Li,
H.; Chen, J.; Wu, X. F. RSC Adv. 2014 , 12065-12077; (e) Khan, I.;
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903-917; (g) Baghbanzadeh, M.; Dabiri, M.; Salehi, P. Heterocycles
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4.4.16 5-chloro-2-phenyl-4(3H)-quinazolinone (4m): White
ACCEPTED MANUSCRIPT
solid; mp: 280-282 oC; Rf = 0.71 (40% ethyl acetate in petroleum
ether); 1H NMR (600 MHz, DMSO-d6) δ (ppm): 7.52 (d, 1H, J =
7.4 Hz), 7.56 (t, 2H, J = 7.5 Hz) ,7.61 (t, 1H, J = 7.2 Hz), 7.68 (d,
1H, J = 7.8 Hz), 7.75 (t, 1H, J = 7.9 Hz), 8.18 (d, 2H, J = 7.4
Hz), 12.57 (brs, 1H); 13C NMR (150 MHz, DMSO-d6) δ (ppm):
117.9, 127.0, 127.8, 128.6, 128.9, 131.7, 132.1, 132.5, 134.3,
151.2, 153.0, 160.4; mass spectrum (ESI): m/e (% relative
intensity) 257.5 (100) (M+H)+; HRMS (ESI) m/z calcd for
C15H10ClNOH+ 257.0476, found 257.0463.
,
,
4
,
,
,
,
,
Ghasemi, S.; Habibi, Z.; Faramarzi, M. A. Adv. Synth. Catal. 2014,
356, 1789-1794; (j) Mabkhot, Y. N.; Al-Har, M. S.; Barakat, A.;
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8725-8739; (k) Wu, X. F.; Oschatz, S.; Sharif, M.; Beller, M.;
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CN103588714-A , 2014.
4.4.17 benzyl ether (2b): Rf = 0.50 (5% ethyl acetate in petroleum
1
ether); H NMR (600 MHz, CDCl3) δ (ppm): 4.56 (s, 4H), 7.26-
7.31 (m, 2H), 7.32-7.38 (m, 8H); 13C NMR (150 MHz, CDCl3) δ
(ppm): 72.3, 127.8, 127.9, 128.5, 138.5; mass spectrum (ESI):
m/e (% relative intensity) 220.9 (100) (M+Na)+.
4.4.18 benzylaldehyde (2c): Rf = 0.50 (5% ethyl acetate in
1
petroleum ether); H NMR (600 MHz, CDCl3) δ (ppm): 7.46 (t,
2H, J = 7.8 Hz), 7.53-7.59 (m, 1H), 7.83 (d, 2H, J = 9.0 Hz), 9.97
(s, 1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 128.7, 129.4,
134.1, 136.1, 192.1; mass spectrum (ESI): m/e (% relative
intensity) 128.9 (100) (M+Na)+.
6. (a) Balakumar, C.; Lamba, P.; Kishore, D. P.; Narayana, B. L.; Rao, K.
V.; Rajwinder, K.; Rao, A. R.; Shireesha, B.; Narsaiah, B. Eur. J. Med.
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V. N. S. R.; Kanth, S. R.; Rao, P. S.; Narsaiah, B. J. Fluorine Chem.
2002, 118, 73-79.
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8.
9.
(a) Bakavoli, M.; Shiri, A.; Ebrahimpour, Z.; Rahimizadeh, M. Chin.
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Argade, N. P.; Tetrahedron Lett. 2007, 48, 3243-3246; (c) Bhat, B. A.;
Sahu, D. P.; Synthetic Commun. 2004, 34, 2169-2176.
(a) Mitobe, Y.; Ito, S.; Mizutani, T.; Nagase, T.; Sato, N.; Tokita, S.
Bioorg. Med. Chem. Lett. 2009, 19, 4075-4078; (b) Naleway, J. J.; Fox,
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4.4.19 2-(benzylamino)benzamide (5a): White solid; mp: 165-
167 °C; Rf = 0.33 (40% EtOAc in PE); H NMR (600 MHz,
1
CDCl3) δ (ppm): 4.43 (s, 2H), 5.72 (brs, 2H), 6.60 (t, 1H, J = 7.5
Hz), 6.65 (d, 1H, J = 8.4 Hz), 7.23-7.28 (m, 2H), 7.32 (t, 2H, J =
7.6 Hz), 7.36 (d, 2H, J = 7.3 Hz), 7.40 (dd, 1H, J = 1.3, 7.9 Hz),
8.40 (brs, 1H); mass spectrum(ESI): m/e (% relative intensity)
248.9 (100) (M+Na)+.
Cheng, R.; Guo, T.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Synthesis
2013, 45, 2998-3006.
5. Acknowledgments
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Y.T. thanks National Natural Science Foundation of
China for generous founding [21172169, 21572154]. Open
Fund of Zhejiang Provincial Top Key Discipline of Biology
and the National Basic Research Project (2014CB932201)
for financial support.
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