Synthesis of quinazoin-4-ones through an acid ion exchange resin mediated cascade reaction

Article abstract of DOI:10.1039/d0ob00881h

An interesting cascade reaction of N-(2-(4,5-dihydrooxazol-2-yl)phenyl)benzamide in the presence of an acid ion exchange resin is described. In this reaction, a range of substrates bearing various substituent groups are well compatible. This work provides a green and atom-economical alternative approach for the synthesis of quinazolin-4-ones in good yields.

Full text of DOI:10.1039/d0ob00881h

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DOI: 10.1039/D0OB00881H
Journal Name
PAPER
Synthesis of quinazoin-4-ones through acid ion exchange resin
mediated cascade reaction†
Huiyong Yang,‡ Jun Xu,‡ Yilan Zhang, Lei He, Pengfei Zhang, and Wanmei Li*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An interesting cascade reaction of N-(2-(4,5-dihydrooxazol-2-
yl)phenyl)benzamide in the presence of acid ion exchange resin is
described. In this reaction, a range of substrates bearing various
substituent groups are well compatible. This work provides a
green and atom-economic alternative approach for the synthesis
of quinazolin-4-ones in good yields.
Previous works:
a) Transition-metal-catalyzed ortho C-H functionalization of arenes
O
FG
O
Transiton-Metal Catalyst
N
N
H
H
Ortho C-H Functionalization
N
O
N
N
O
O
FG = I, CF3, SO2Ar
b) Transition-metal-catalyzed para C-H nitration of aryloxazolines
NO2
O
O
Transiton-Metal Catalyst
Introduction
N
H
N
H
Para C-H Nitration
N
O
The development of simple and efficient methods for the synthesis
of quinazolin-4-one and its derivatives has been attracted great
attention because they have been found important applications in
natural products, synthetic drugs and agrochemicals (Figure 1).1 The
traditional methods to synthesize these compounds involve the
condensation transformations of aldehydes, carboxylic acids or
esters with amides under harsh reaction conditions.2 A relatively
moderate method has been developed in recent years by the
Minisci reaction from the radical couplings using quinazolin-4-(3H)-
ones as building blocks.3,4 However, this new method still suffers
from some instinctive drawbacks such as the utilities of expensive
and toxic metal catalysts, large amount of strong oxidants and
functionalized alkyl substrates, resulting in a costly and challenging
This work:
Unexpected
O
N
O
OH
Acid ion exchange resin
N
N
H
N
O
Scheme 1 The transformations of aryloxazolines
In this way, the uses of transition-metal catalysts and functionalized
alkyl substrates could be efficiently avoided. Nevertheless, there is
still a substantial interest in developing alternative approaches for
the synthesis of such organic molecules.
As one of efficient directing groups, 2-(2-oxazolyl)aniline is
commonly used in the transition-metal catalyzed C-H
functionalization reaction for the construction and late-stage
diversification of functional molecules.8 For instance, Yu and Dai
accomplished ortho C-H functionalization of aromatic carboxylic
acid assisted by such readily removable directing group through
oxidation addition-reduction elimination mechanism (Scheme
O
O
OH
O
N
N
N
N
N
N
OH
N
Cl
N
OH
N
N
F
F
Albaconazole
Diproqualone
Luotonin A
O
N
N
O
O
1a).8a-f In addition, Guo et al. reported
regioselective C-H bond mono- and bis-nitration of aryloxazolines
through a single-electron-transfer process, demonstrating other
uses for this directing group (Scheme 1b).9
a nickel-catalyzed
H
N
H2NO2S
N
O
N
N
N
N
HO
Metolazone
Febrifugine
Piriqualone
Figure 1 Biologically active molecules containing a quinazolin-4-
In recent years, an increasing number of organic reactions
performed in the presence of ion exchange resin have been
gradually reported because of the good recoverability and
recyclability of such substrates.10 In continuation of our interests in
developing new, green and atom-economic methods for the
synthesis of N-containing heterocycles,11 herein, we reported other
uses of 2-(2-oxazolyl)aniline to prepare quinazolin-4-one derivatives
by an acid ion exchange resin mediated cascade reaction of N-(2-
(4,5-dihydrooxazol-2-yl)phenyl)benzamide for the first time.
one moiety
task to prepare the substrates and remove the trace amounts of
metal catalysts from the final products.5 Alternatively, the cross-
dehydrogenative coupling (CDC) reactions provide another
approach for the synthesis of quinazolin-4-(3H)-ones derivatives.6,7
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 311121, China.
E-mail: liwanmei@hznu.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/xxxxxx.
‡ These authors contributed equally to this work.
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Table 2 Substrate scopea,b
Table 1 Optimization of reaction conditionsa,b
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DOI: 10.1039/D0OB00881H
O
O
N
R2
O
O
Dowex 50WX2
OH
R1
N
OH
N
Dowex 50WX2
N
N
R2
H
H2O/Acetone, 100 o
C
H
solvent, temp.
N
O
N
R1
N
O
1
2
1a
2a
O
2b
2c
2d
2e
2f
2h
2i
2j
, R = 2-Me, 77%
, R = 2-Cl, 65%
, R = 2-F, 69%
, R = 3-Me, 80%
, R = 3-CF3, 73%
, R = 4-Me, 84%
, R = 4-OMe, 86%
, R = 4-Cl, 87%
, R = 4-Br, 84%
, R = 4-F, 82%
OH
R
Entry
1
2
3
4
Solvent (v/v = 9:1)
Temp./oC
100
100
100
100
100
100
100
100
100
100
100
80
Yield [%]b
N
2k
2l
H2O
H2O/MeCN
H2O/EtOH
H2O/THF
H2O/Acetone
H2O/DCE
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/Acetone
H2O/Acetone
35
57
32
47
75
45
50
65
83
82
0
N
O
, R = 4-CF3, 77%
2g
2m
, R = 2,4-Cl2, 62%
O
O
OH
OH
OH
OH
N
N
N
O
N
S
N
5
N
6
2n
2o
2p
, 71%
, 81%
, 83%
7c
O
O
O
8d
OH
OH
OH
N
N
N
N
N
9e
N
10f
11g
12e
13e
14e,h
15e,i
2q
2r
2s
, 80%
80%
, 84%
O
O
O
53
80
36
81
OH
OH
OH
Ph
N
N
N
N
120
100
100
Ph
N
N
2t
2u
2v
, 85%
O
, 79%
, 86%
O
N
a
Reaction conditions: 1a (0.3 mmol), dowex 50WX2 (100 mg),
OH
2w
2x
2y
, n = 2, 86%
, n = 7, 84%
, n = 13, 77%
N
solvent (5.0 mL), 100 oC, 6 h, air. Isolated yields. Dowex
b
c
N
N
2z
, trace
d
e
50WX2 (25 mg). Dowex 50WX2 (50 mg). Dowex 50WX2 (150
CnH2n+1
mg). f Dowex 50WX2 (200 mg). g Without dowex 50WX2. The
h
F
O
O
O
i
reaction was performed for 3 hours. The reaction was
performed for 12 hours.
OH
O
OH
OH
OH
N
N
N
N
N
N
Results and discussion
2aa
2ab
2ac
, 82%
, 80%
, 85%
O
O
F
O
We initially use N-(2-(4,5-dihydrooxazol-2-yl)phenyl)benzamide
(1a) as substrate and Fe(NO3)3 as nitration reagent in the presence
of 10 mol% of CuCl2 to develop a transition-metal catalyzed ortho C-
H nitration of arenes using 2-(2-oxazolyl)aniline as the directing
group. However, the unexpected product (2a) was isolated in 49%
yield, whose structure was confirmed by NMR and X-ray
crystallographic analysis (CCDC NO. 1959603) (see Supporting
Information). As far as we know, the synthesis of quinazoin-4-ones
from N-(2-(4,5-dihydrooxazol-2-yl)phenyl)benzamide (1a) has not
been reported yet. In this case, we tried to explore this interesting
transformation. After a preliminary study, we found that the
product (2a) could be obtained in 35% yield in water12 in the
presence of dowex 50WX2 (Table 1, entry 1). The dowex 50WX2
was chosed in this experiment because it could be recovered and
reused. To improve the yield, some mixed solvents (v/v = 3:1)
including H2O/MeCN, H2O/EtOH, H2O/THF, H2O/Acetone and
H2O/DCE then were screened (Table 1, entries 2-6). To our delight,
the yield was improved to 75% when H2O/Acetone was used as
solvent (Table 1, entry 5). The amount of dowex 50WX2 had a very
important role on the reaction yield. The yield could be enhanced to
83% when the amount of dowex 50WX2 was increased from 25 to
150 mg (Table 1, entries 7-9), however, no significant change was
observed when the dosage was further increased (Table 1, entry 10).
Expectedly, no product was obtained in the absence of dowex
50WX2 (Table 1, entry 11). The reaction yield could not be further
improved no matter changing the reaction temperature or time
(Table 1, entries 12-15).
OH
OH
N
N
N
N
Cl
N
N
F
2ad
2ae
2af
, 79%
, 78%
, 76%
O
O
O
OH
OH
OH
N
N
N
O
S
N
Cl
N
Cl
N
2ag
2ah
2ai
, 73%
, 81%
, 70%
a
Reaction conditions: 1 (0.3 mmol), dowex 50WX2 (150 mg),
H2O/Acetone (5.0 mL, v/v = 9:1), 100 oC, 6 h, air. b Isolated yields.
With the optimized reaction condition in hand, we next start to
explore the substrate scope of the cascade reaction (Table 2). Firstly,
a wide range of substituted benzamides prepared through the
amidation of 2-(2-oxazolyl)aniline with substituted benzoic acid
were tested under the optimized condition, which provided the
desired products (2b-m) in 62-87% yields. From table 2, it can be
seen that the substituted position and electron effect of
benzamides had great impacts on this reaction. The substitutions at
the para- position (2g-l) or with an electron-donating (2b, 2e, 2g, 2h)
group were more favorable for the reaction. In addition to
benzamides, some other carboxamides such as aromatic amides
(2n-p), aliphatic amides (2r-y) and even the unstable olefin (2q)
were all amenable under the standard condition to yield the
corresponding products in high yields. Although the relatively small
substitutions can go smooth in this reaction, the adamantyl group
could not be converted into the corresponding product (2z) due to
the large steric hindrance. The influence of functional groups on the
2 | J. Name., 2012, 00, 1-3
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O
O
OH
According to the results of mechanism studies VaienwdArtpicrleevOinoliunes
works, we proposed a possible mechanismDfoOrI:t1h0e.1c0a3s9c/aDd0eOBre0a0c8t8io1Hn
(Scheme 5). Initially, substrate 1a accepted a proton to form
intermediate A. Then, the oxygen atom of H2O molecule attacked
intermediate A to generate intermediate C through a nucleophilic
Dowex 50WX2
N
N
(a)
(b)
H
H2O/Acetone, 100 o
C
N
N
O
1a
2a
, 76% (1.01 g)
(5 mmol)
O
O
addition process. Intermediate
C
further transformed to
Dowex 50WX2
OH
N
N
intermediate D via an intramolecular hydrogen transfer process.
The elimination process of intermediate D led to the dissociation of
C-O bond to give intermediate E. The second intramolecular
H
H2O/Acetone, 100 o
C
N
O
N
Antibiotic activity
2aj
1aj
(5 mmol)
, 82% (0.84 g)
hydrogen transfer process converted intermediate
E
to
Scheme 2 Gram-scale synthesis and application
intermediate F. After the generation of intermediate H via an
intramolecular addition-elimination process of intermediate F, the
target product 2a was obtained through a deprotonation process.
benzene ring of the 2-(2-oxazolyl)aniline was also investigated.
Pleasingly, the substrates bearing an electron-donating group (2ab,
2ac, 2ag) or an electron-withdrawing group (2aa, 2ad-af, 2ah, 2ai)
could undergo the reaction smoothly, providing the corresponding
quinazolin-4-ones in 70-85% yields.
To display the application value of this methodology, a gram-
scale synthesis of 3-(2-hydroxyethyl)-2-phenylquinazolin-4(3H)-one
(2a) was carried out under the standard condition, giving the
desired product in good yield (76%, 1.01 g) (Scheme 2a).
Furthermore, antibiotic active substance (2aj) could easily be
obtained in high yield and large scale by simply one-step reaction
(Scheme 2b).13
1a
3a
H+
O
O
H
OH
N
N
H
HN
O
H2O
N
H2O
A
H
O
O
H
OH
N
OH
N
H
N
HOH
O
H
HN
G
B
PT = proton transfer
Finally, a recycling experiment of dowex 50WX2 was carried out
because we tried to develop a green and atom-economic method
for the synthesis of quinazolin-4-one derivatives (Scheme 3). When
the reaction was completed, dowex 50WX2 was retrieved by an
easy filtration process, and then reutilized in the next round. Even
after six-times rounds, the activity of dowex 50WX2 could still
remain stable, affording the desired product at less 75% yield.
O
OH
H
N
O
OH
N
N
H
OH2
H
F
HN
O
PT
C
O
PT
O
N
H
N
OH
OH
OH
OH
H
HN
E
HN
D
Detected by HRMS
[M+H]+ 285.1234, Found 285.1243
Scheme 5 Plausible Mechanism
Conclusions
In conclusion, we reported an interesting cascade transformation
of N-(2-(4,5-dihydrooxazol-2-yl)phenyl)benzamide. The substrates
with various functional groups were well compatible, giving the
corresponding products in good to excellent yields. This method
provided an alternative access for the synthesis of quinazolin-4-
ones.
Scheme 3 Recycling experiment
To understand the mechanism of such transformation, the radical
inhibition experiment was carried out (Scheme 4). Target product
(2a) could be also generated in 82% yield when two equivalents of
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was added as radical
inhibitor, indicating that the radical pathway was not involved in
this reaction.
Experimental section
General Information
All the chemicals were obtained commercially and used without any
prior purification. All products were isolated by short
chromatography on a silica gel (200-300 mesh) column using
petroleum ether (60-90°C) and ethyl acetate. 1H and 13C NMR
spectra were recorded on a Bruker Advance 500 spectrometer at
ambient temperature with CDCl3 as solvent and tetramethylsilane
(TMS) as the internal standard. Melting points were determined on
an X-5 Data microscopic melting point apparatus. Analytical thin
layer chromatography (TLC) was performed on Merk precoated TLC
(silica gel 60 F254) plates. Compounds for HRMS were analyzed by
O
O
TEMPO (2.0 equiv)
OH
Dowex 50WX2
N
N
H
H2O/Acetone, 100 o
C
N
N
O
1a
2a
, 82%
Scheme 4 Control experiments
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positive mode electrospray ionization (ESI) using Agilent 6530 QTOF NMR (500 MHz, CDCl3) δ 8.34 (d, J = 7.8 Hz, 1H), 7.83-7.76 (m, 2H),
View Article Online
mass spectrometer.
7.50 (ddt, J = 17.8, 14.8, 7.0 Hz, 5H), 4.48-D4O.4I:210(.m10,391/HD)0, O3B.8040-838.81H8
(m, 1H), 3.81-3.75 (m, 1H), 3.74-3.67 (m, 1H), 2.20 (s, 1H).13C NMR
(126 MHz, CDCl3) δ 163.20, 153.51, 147.08, 134.78, 134.14, 132.33,
General procedure for the synthesis of products 2
To a mixture of dowex 50WX2 (150 mg) and H2O (1.5 mL), was 131.37, 130.37, 129.89, 127.62, 127.55, 127.46, 126.84, 120.93,
added N-(2-(4,5-dihydrooxazol-2-yl)phenyl)benzamide (1) (0.3 61.23, 48.29. HRMS (ESI+): Calculated for C16H13ClN2O2H: [M+H]+
o
mmol) in acetone (0.5 mL). The mixture was stirred at 100 C for 6 301.0739, Found 301.0740.
hours. After the completion (as indicated by TLC), the dowex 2-(2-Fluorophenyl)-3-(2-hydroxyethyl)quinazolin-4(3H)-one (2d).
o
50WX2 was recycled through filtration, and the filtrate was Obtained as a white solid (59 mg, 69% yield); M.p. 142-143 C; 1H
extracted with EtOAc and the collected organic layer was washed NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.6 Hz,
with brine, dried with MgSO4. The solvent was removed under 1H), 7.74 (Hz, d, J = 8.0 1H), 7.58 -7.49 (m, 3H), 7.32 (t, J = 7.5 Hz,
reduced pressure, and the obtained residue was further purified by 1H), 7.21 (t, J = 9.0 Hz, 1H), 4.42-4.34 (m, 1H), 3.98 -3.89 (m, 1H),
silica gel column chromatography (200-300 mesh silica gel, PE/EA = 3.78-3.84 (m, 1H), 3.68-3.74 (m, 5.4 Hz, 1H), 2.89 (s, 1H). 13C NMR
3:1).
(126 MHz, CDCl3) δ 163.12, 158.94 (d, J = 248.2 Hz), 151.62, 147.09,
134.80, 132.3 (d, J = 7.6 Hz), 130.58 (d, J = 2.5 Hz), 127.64, 127.52,
126.80, 125.03 (d, J = 2.5 Hz), 123.25 (d, J = 16.4 Hz), 120.80, 116.18
General procedure for gram-scale synthesis of product 2a
To a mixture of dowex 50WX2 (2.5 g) and H2O (25 mL), was added (d, J = 21.4 Hz), 60.99, 48.63. 19F NMR (471 MHz, CDCl3) δ -113.81.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)benzamide (1a) (5.0 mmol) in HRMS (ESI+): Calculated for C16H13FN2O2H: [M+H]+ 285.1034, Found
acetone (8 mL). The mixture was stirred at 100 oC for 6 hours. After 285.1037.
the completion (as indicated by TLC), the dowex 50WX2 was 3-(2-Hydroxyethyl)-2-(m-tolyl)quinazolin-4(3H)-one (2e). Obtained
o
recycled through filtration, and the filtrate was extracted with as a white solid (67 mg, 80% yield); M.p. 143-144 C; 1H NMR (500
EtOAc and the collected organic layer was washed with brine, dried MHz, CDCl3) δ 8.26 (d, J = 7.9 Hz, 1H), 7.73 (dt, J = 13.6, 7.0 Hz, 2H),
with MgSO4. The solvent was removed under reduced pressure, and 7.49 (t, J = 7.4 Hz, 1H), 7.40 – 7.35 (m, 1H), 7.33 (s, 1H), 7.30 (d, J =
the obtained residue was further purified by silica gel column 8.0 Hz, 2H), 4.17 (t, J = 5.5 Hz, 2H), 3.77 (t, J = 5.5 Hz, 2H), 3.35 (s,
chromatography (200-300 mesh silica gel, PE/EA = 3:1).
1H), 2.41 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.57, 156.47,
147.15, 138.90, 135.10, 134.70, 130.73, 128.75, 128.68, 127.43,
127.18, 126.67, 125.10, 120.51, 61.19, 48.72, 21.48. HRMS (ESI+):
Calculated for C17H16N2O2H: [M+H]+ 281.1285, Found 281.1286.
General procedure for large-scale synthesis of antibiotic active
substance 2aj
To a mixture of dowex 50WX2 (2.5 g) and H2O (25 mL), was added 3-(2-Hydroxyethyl)-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)acetamide (1aj) (5.0 mmol) in one (2f). Obtained as a white solid (73 mg, 73% yield); M.p. 163-
o
acetone (8 mL). The mixture was stirred at 100 oC for 6 hours. After 164 C; 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 8.0 Hz, 1H), 7.88 (s,
the completion (as indicated by TLC), the dowex 50WX2 was 1H), 7.83-7.76 (m, 3H), 7.74 (d, J = 8.1 Hz, 1H), 7.67 (t, J = 7.6 Hz,
recycled through filtration, and the filtrate was extracted with 1H), 7.54 (t, J = 7.5 Hz, 1H), 4.16 (t, J = 4.9 Hz, 2H), 3.85 (t, J = 4.9 Hz,
EtOAc and the collected organic layer was washed with brine, dried 2H), 2.82 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 163.15, 154.93,
with MgSO4. The solvent was removed under reduced pressure, 146.77, 135.83, 134.99, 131.81, 131.40 (q, J = 32.8 Hz), 129.53,
and the obtained residue was further purified by silica gel column 127.71, 127.42, 126.85 (q, J = 2.5 Hz), 126.78, 125.60 (q, J = 3.8 Hz),
chromatography (200-300 mesh silica gel, PE/EA = 3:1).
123.58 (q, J = 237.4 Hz), 120.61, 60.80, 48.69. 19F NMR (471 MHz,
CDCl3) δ -62.70. HRMS (ESI+): Calculated for C17H13F3N2O2H: [M+H]+
335.1002, Found 335.1004.
3-(2-Hydroxyethyl)-2-phenylquinazolin-4(3H)-one (2a). Obtained
o
1
as a white solid (66 mg, 83% yield); M.p. 155-156 C; H NMR (500
MHz, CDCl3) δ 8.26 (d, J = 7.9 Hz, 1H), 7.72 (dd, J = 16.3, 7.6 Hz, 2H),
7.49-7.52 (m, J = 7.6 Hz, 6H), 4.16 (t, J = 5.3 Hz, 2H), 3.77 (t, J = 5.3
Hz, 2H), 3.07 (s, 1H).13C NMR (126 MHz, CDCl3) δ 163.52, 156.31,
147.11, 135.20, 134.72, 129.99, 128.90, 128.18, 127.42, 127.25,
126.69, 120.55, 61.15, 48.73. HRMS (ESI+): Calculated for
C16H14N2O2H: [M+H]+ 267.1128, Found 267.1129.
3-(2-Hydroxyethyl)-2-(p-tolyl)quinazolin-4(3H)-one (2g). Obtained
o
as a white solid (71 mg, 84% yield); M.p. 156-157 C; 1H NMR (500
MHz, CDCl3) δ 8.28 (d, J = 7.8 Hz, 1H), 7.79 – 7.72 (m, 2H), 7.50 (t, J =
7.2 Hz, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 4.21 (t, J
= 5.2 Hz, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.10 (s, 1H), 2.43 (s, 3H). 13
C
NMR (126 MHz, CDCl3) δ 163.75, 156.43, 147.15, 140.21, 134.69,
132.27, 129.54, 128.08, 127.42, 127.16, 126.69, 120.49, 61.56,
48.89, 21.43. HRMS (ESI+): Calculated for C17H16N2O2H: [M+H]+
281.1285, Found 281.1284.
3-(2-Hydroxyethyl)-2-(o-tolyl)quinazolin-4(3H)-one (2b). Obtained
o
1
as a white solid (65 mg, 77% yield); M.p. 145-146 C; H NMR (500
MHz, CDCl3) δ 8.30 (d, J = 8.0 Hz, 1H), 7.82 -7.71 (m, 2H), 7.52 (t, J =
7.4 Hz, 1H), 7.38 (dd, J = 17.4, 8.7 Hz, 2H), 7.31 (t, J = 6.2 Hz, 2H),
4.29-4.34 (m, 1H), 3.77-3.82 (m, 1H), 3.67-3.73 (m, 2H), 3.17 (s, 1H),
2.23 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.43, 155.88, 147.15,
135.46, 134.77, 134.47, 130.74, 130.02, 128.11, 127.42, 127.33,
126.72, 126.34, 120.63, 60.88, 47.96, 19.30. HRMS (ESI+):
Calculated for C17H16N2O2H: [M+H]+ 281.1285, Found 281.1285.
2-(2-Chlorophenyl)-3-(2-hydroxyethyl)quinazolin-4(3H)-one (2c).
Obtained as a white solid (59 mg, 65% yield); M.p. 90-91 oC; 1H
3-(2-Hydroxyethyl)-2-(4-methoxyphenyl)quinazolin-4(3H)-one (2h).
o
1
Obtained as a white solid (76 mg, 86% yield); M.p. 155-156 C; H
NMR (500 MHz, CDCl3) δ 8.27 (d, J = 7.9 Hz, 1H), 7.78- 7.70 (m, 2H),
7.52- 7.46 (m, 3H), 7.01 (d, J = 8.6 Hz, 2H), 4.22 (t, J = 5.3 Hz, 2H),
3.86 (s, 3H), 3.82 (t, J = 5.3 Hz, 2H), 3.08 (s, 1H). 13C NMR (126 MHz,
CDCl3) δ 162.77, 159.78, 155.20, 146.14, 133.64, 128.81, 126.48,
126.34, 126.06, 125.64, 119.39, 113.24, 60.43, 54.44, 47.93. HRMS
(ESI+): Calculated for C17H16N2O3H: [M+H]+ 297.1234, Found
297.1235.
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
Journal Name
COMMUNICATION
2-(4-Chlorophenyl)-3-(2-hydroxyethyl)quinazolin-4(3H)-one
(2i). 7.7 Hz, 2H), 7.63 (s, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.23V(idew, JAr=tic3le.O3nHlinze,
Obtained as a white solid (78 mg, 87% yield); M.p. 160-161 C; 1H 1H), 6.61 (d, J = 1.7 Hz, 1H), 4.46 (t, J = 5.2 Hz, 2H), 4.07 (t, J = 5.2 Hz,
NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 6.9 Hz, 2H), 3.29 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 163.97, 147.38,
1H), 7.65 (d, J = 7.9 Hz, 1H), 7.54-7.42 (m, 5H), 4.12 (t, J = 5.4 Hz, 147.27, 146.19, 144.92, 134.86, 127.50, 127.45, 126.80, 120.27,
2H), 3.76 (t, J = 5.4 Hz, 2H), 3.23 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 116.31, 112.14, 62.28, 48.86. HRMS (ESI+): Calculated for
163.18, 155.36, 146.95, 136.21, 134.76, 133.63, 129.87, 129.12, C14H12N2O3H: [M+H]+ 257.0921, Found 257.0922.
o
DOI: 10.1039/D0OB00881H
127.40, 127.38, 126.65, 120.52, 60.59, 48.59.HRMS (ESI+): 3-(2-Hydroxyethyl)-2-(thiophen-2-yl)quinazolin-4(3H)-one
(2p).
o
Calculated for C16H13ClN2O2H: [M+H]+ 301.0739, Found 301.0738.
Obtained as a white solid (68 mg, 83% yield); M.p. 101-102 C; 1H
2-(4-Bromophenyl)-3-(2-hydroxyethyl)quinazolin-4(3H)-one
(2j). NMR (500 MHz, CDCl3) δ 8.14 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.6 Hz,
Obtained as a white solid (87 mg, 84% yield); M.p. 164-165 C; 1H 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 5.1
NMR (500 MHz, CDCl3) δ 8.25 (d, J = 7.7 Hz, 1H), 7.83-7.59 (m, 4H), Hz, 1H), 7.45-7.39 (m, 1H), 7.14-7.05 (m, 1H), 4.36 (t, J = 5.3 Hz, 2H),
7.57-7.35 (m, 3H), 4.15 (s, 2H), 3.80 (s, 2H), 3.00 (s, 1H). 13C NMR 3.96 (t, J = 4.7 Hz, 2H), 3.60 (s, 1H).13C NMR (126 MHz, CDCl3) δ
(126 MHz, CDCl3) δ 163.29, 155.35, 147.02, 134.81, 134.13, 132.12, 163.48, 150.31, 146.97, 136.29, 134.72, 130.34, 129.30, 127.49,
130.07, 127.46, 127.45, 126.72, 124.49, 120.58, 60.89, 48.68. HRMS 127.34, 127.31, 126.61, 120.09, 61.11, 48.90. HRMS (ESI+):
(ESI+): Calculated for C16H13BrN2O2H: [M+H]+ 345.0233, Found Calculated for C14H12N2O2SH: [M+H]+ 273.0692, Found 273.0691.
o
345.0232.
(E)-3-(2-hydroxyethyl)-2-(prop-1-en-1-yl)quinazolin-4(3H)-one (2q).
o
1
2-(4-Fluorophenyl)-3-(2-hydroxyethyl)quinazolin-4(3H)-one (2k). Obtained as a white solid (56 mg, 80% yield); M.p. 138-139 C; H
Obtained as a white solid (70 mg, 82% yield); M.p. 158-159 C; 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.7 Hz,
o
NMR (500 MHz, CDCl3) δ 8.23 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 5.27 (dd, J = 15.5,
1H), 7.68 (d, J = 8.1 Hz, 1H), 7.57 (dd, J = 7.9, 5.5 Hz, 2H), 7.48 (t, J = 5.2 Hz, 1H), 4.23 (dd, J = 13.5, 5.1 Hz, 1H), 3.85 (dt, J = 15.9, 7.9 Hz,
7.5 Hz, 1H), 7.20 (t, J = 8.4 Hz, 2H), 4.15 (t, J = 5.3 Hz, 2H), 3.79 (t, J = 2H), 3.60 (dd, J = 13.5, 9.2 Hz, 1H), 3.26 (dd, J = 15.1, 9.0 Hz, 1H),
5.3 Hz, 2H), 3.25 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 163.45 (d, J = 3.10 (d, J = 15.1 Hz, 1H), 1.38 (d, J = 6.3 Hz, 3H). 13C NMR (126 MHz,
252.0 Hz), 163.29, 155.47, 146.95, 134.75, 131.36 (d, J = 3.8 Hz), CDCl3) δ 161.63, 156.90, 147.27, 134.43, 127.09, 126.92, 126.84,
130.58 (d, J = 8.8 Hz), 127.35, 126.65, 120.50, 116.03 (d, J = 21.4 Hz), 120.02, 73.13, 69.06, 47.40, 44.96, 22.74. HRMS (ESI+): Calculated
60.70, 48.63. 19F NMR (471 MHz, CDCl3) δ -109.74 HRMS (ESI+): for C13H14N2O2H: [M+H]+ 231.1128, Found 231.1131.
Calculated for C16H13FN2O2H: [M+H]+ 285.1034, Found 285.1036.
3-(2-Hydroxyethyl)-2-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-
2-Cyclohexyl-3-(2-hydroxyethyl)quinazolin-4(3H)-one
Obtained as a white solid (69 mg, 84% yield); M.p. 130-131 C; H
(2r).
o
1
one (2l). Obtained as a white solid (77 mg, 77% yield); M.p. 155- NMR (500 MHz, CDCl3) δ 8.17 (d, J = 7.9 Hz, 1H), 7.69 (t, J = 7.6 Hz,
156 oC; 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.9 Hz, 1H), 7.78 (dd, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 4.32 (t, J = 5.6 Hz,
J = 12.5, 4.6 Hz, 3H), 7.71 (d, J = 8.1 Hz, 3H), 7.52 (dd, J = 11.1, 3.9 2H), 3.95 (t, J = 5.4 Hz, 2H), 3.18 (s, 1H), 2.94 (t, J = 11.4 Hz, 1H),
Hz, 1H), 4.16 (t, J = 5.3 Hz, 2H), 3.84 (t, J = 5.3 Hz, 2H), 2.68 (s, 1H). 1.89 (t, J = 11.7 Hz, 4H), 1.82 – 1.70 (m, 3H), 1.38 (d, J = 8.5 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 163.12, 154.98, 146.94, 138.67, 134.88, 13C NMR (126 MHz, CDCl3) δ 163.62, 160.58, 147.50, 134.26, 127.06,
132.05 (q, J = 34.0 Hz), 128.99, 127.62, 127.51, 126.75, 125.92 (q, J 126.51, 126.32, 120.08, 61.38, 45.48, 41.92, 31.43, 26.11, 25.75.
= 3.8 Hz), 123.65 (q, J = 273.4 Hz), 120.67, 60.79, 48.58. 19F NMR HRMS (ESI+): Calculated for C16H20N2O2H: [M+H]+ 273.1598, Found
(471 MHz, CDCl3)
δ -62.95. HRMS (ESI+): Calculated for 273.1599.
C17H13F3N2O2H: [M+H]+ 335.1002, Found 335.1004.
2-Cyclobutyl-3-(2-hydroxyethyl)quinazolin-4(3H)-one
Obtained as a white solid (59 mg, 80% yield); M.p. 120-122 C; 1H
(2s).
o
2-(2,4-Dichlorophenyl)-3-(2-hydroxyethyl)quinazolin-4(3H)-one
(2m). Obtained as a white solid (62 mg, 62% yield); M.p. 189-190 oC; NMR (500 MHz, CDCl3) δ 8.11 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 7.4 Hz,
1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 7.2 Hz, 1H), 7.82-7.70 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 4.13 (t, J = 5.5 Hz,
2H), 7.57-7.49 (m, 3H), 7.43 (d, J = 6.6 Hz, 1H), 4.48-4.40 (m, 1H), 2H), 3.90 (t, J = 5.4 Hz, 2H), 3.85 (dd, J = 17.0, 8.5 Hz, 1H), 3.62 (s,
3.87 (s, 1H), 3.72 (d, J = 14.7 Hz, 2H), 2.86 (s, 1H). 13C NMR (126 MHz, 1H), 2.65 – 2.53 (m, 2H), 2.34 (dd, J = 17.6, 8.7 Hz, 2H), 2.10 – 2.01
CDCl3) δ 162.81, 152.83, 146.86, 136.86, 134.84, 133.23, 132.76, (m, 1H), 1.91 (d, J = 10.3 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ
131.52, 129.70, 127.89, 127.79, 127.49, 126.85, 120.88, 60.69, 163.46, 158.58, 147.35, 134.24, 127.08, 126.43, 126.40, 120.02,
48.18. HRMS (ESI+): Calculated for C16H12Cl2N2O2H: [M+H]+ 60.96, 46.05, 38.45, 26.51, 17.56. HRMS (ESI+): Calculated for
335.0349, Found 335.0350.
3-(2-Hydroxyethyl)-2-(naphthalen-2-yl)quinazolin-4(3H)-one (2n).
C14H16N2O2H: [M+H]+ 245.1285, Found 245.1285.
2-Cyclopropyl-3-(2-hydroxyethyl)quinazolin-4(3H)-one
(2t).
o
1
Obtained as a white solid (59 mg, 85% yield); M.p. 96-97 oC; 1H
NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 8.0, 1.0 Hz, 1H), 7.65 – 7.60
(m, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.35 – 7.29 (m, 1H), 4.47 (t, J = 5.5
Hz, 2H), 4.05 (t, J = 5.5 Hz, 2H), 3.97 (s, 1H), 2.33 (ddd, J = 8.2, 4.8,
3.2 Hz, 1H), 1.22 (dd, J = 4.9, 2.4 Hz, 2H), 1.06 (dd, J = 8.1, 2.6 Hz,
2H). 13C NMR (126 MHz, CDCl3) δ 162.98, 158.00, 147.10, 134.24,
126.54, 126.44, 126.17, 119.93, 60.81, 46.29, 14.55, 8.43. HRMS
(ESI+): Calculated for C13H14N2O2H: [M+H]+ 231.1128, Found
231.1129.
Obtained as a white solid (67 mg, 71% yield); M.p. 174-175 C; H
NMR (500 MHz, CDCl3) δ 8.33 (d, J = 7.7 Hz, 1H), 8.05 (s, 1H), 7.97 (d,
J = 8.4 Hz, 1H), 7.90 (t, J = 5.1 Hz, 2H), 7.82-7.75 (m, 2H), 7.63-7.50
(m, 4H), 4.23 (t, J = 5.3 Hz, 2H), 3.81 (t, J = 5.3 Hz, 2H), 2.98 (s, 1H).
13C NMR (126 MHz, CDCl3) δ 163.74, 156.27, 147.24, 134.82, 133.56,
132.82, 132.44, 128.85, 128.52, 128.28, 127.89, 127.57, 127.54,
127.34, 127.16, 126.79, 124.84, 120.62, 61.55, 48.95. HRMS (ESI+):
Calculated for C20H16N2O2H: [M+H]+ 317.1285, Found 317.1286.
2-(Furan-2-yl)-3-(2-hydroxyethyl)quinazolin-4(3H)-one
(2o).
2-Benzyl-3-(2-hydroxyethyl)quinazolin-4(3H)-one (2u). Obtained as
a white solid (68 mg, 79% yield); M.p. 93-94 C; H NMR (500 MHz,
o
Obtained as a white solid (62 mg, 81% yield); M.p. 151-152 C; 1H
o
1
NMR (500 MHz, CDCl3) δ 8.25 (d, J = 7.9 Hz, 1H), 7.74 (dt, J = 15.1,
CDCl3) δ 8.05 (d, J = 6.8 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.58 (d, J =
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COMMUNICATION
Journal Name
8.1 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.24 (t, J = NMR (500 MHz, CDCl3) δ 7.71 – 7.66 (m, 2H), 7.52 (s,V5ieHw)A,r7tic.3le8O(ndlinde,
4.9 Hz, 1H), 7.20 (d, J = 7.1 Hz, 2H), 4.41 (s, 2H), 4.12 (t, J = 5.2 Hz, J = 8.9, 3.0 Hz, 1H), 4.23 (t, J = 5.3 Hz, 2H),D3O.9I:510(.s1,0339H/)D, 03O.8B400(t8,8J1H=
2H), 3.85 (t, J = 5.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 162.92, 5.2 Hz, 2H), 2.87 (s, 1H) 13C NMR (126 MHz, CDCl3) δ 163.75,
156.20, 146.80, 135.27, 134.46, 129.07, 128.23, 127.34, 126.85, 158.80, 153.87, 142.05, 135.34, 129.88, 129.23, 128.93, 128.25,
126.72, 126.58, 120.25, 60.52, 46.94, 42.36. HRMS (ESI+): 125.21, 121.37, 105.89, 61.95, 55.89, 49.01.HRMS (ESI+): Calculated
Calculated for C17H16N2O2H: [M+H]+ 281.1285, Found 281.1285.
for C17H16N2O3H: [M+H]+ 297.1234, Found 297.1236.
3-(2-Hydroxyethyl)-2-phenethylquinazolin-4(3H)-one
(2v). 3-(2-Hydroxyethyl)-7-methyl-2-phenylquinazolin-4(3H)-one (2ac).
Obtained as a white solid (76 mg, 86% yield); M.p. 137-138 C; 1H Obtained as a white solid (69 mg, 82% yield); M.p. 184-185 C; 1H
NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 6.9 Hz, NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.2 Hz, 1H), 7.47-7.53 (m, 6H),
1H), 7.58 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.30- 7.23 (m, 7.32 (d, J = 8.2 Hz, 1H), 4.17 (t, J = 5.2 Hz, 2H), 3.79 (t, J = 5.2 Hz, 2H),
4H), 7.20 (t, J = 7.0 Hz, 1H), 4.17 (t, J = 5.4 Hz, 2H), 3.90 (t, J = 5.3 Hz, 3.33-3.08 (m, 1H), 2.49 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.59,
2H), 3.46 (s, 1H), 3.25- 3.18 (m, 2H), 3.17 -3.12 (m, 2H). 13C NMR 156.31, 147.24, 145.83, 135.30, 129.93, 128.88, 128.16, 127.14,
(126 MHz, CDCl3) δ 162.96, 156.55, 147.11, 140.62, 134.35, 128.62, 126.50, 118.14, 61.47, 48.78, 21.99. HRMS (ESI+): Calculated for
128.50, 126.78, 126.54, 126.53, 126.42, 120.16, 60.68, 46.14, 36.81, C17H16N2O2H: [M+H]+ 281.1285, Found 281.1286.
o
o
33.15. HRMS (ESI+): Calculated for C18H18N2O2H: [M+H]+ 295.1441, 7-Chloro-3-(2-hydroxyethyl)-2-phenylquinazolin-4(3H)-one (2ad).
Found 295.1439.
Obtained as a white solid (70 mg, 78% yield); M.p. 187-188 oC; 1H
NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 1.9 Hz,
1H), 7.51 (s, 5H), 7.44 (dd, J = 8.6, 2.0 Hz, 1H), 4.17 (t, J = 5.4 Hz, 2H),
3.78 (s, 2H), 2.91 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 162.97,
157.56, 148.12, 140.93, 134.98, 130.19, 128.96, 128.18, 128.10,
127.88, 127.06, 119.02, 61.09, 48.74. HRMS (ESI+): Calculated for
C16H13ClN2O2H: [M+H]+ 301.0739, Found 301.0742.
7-Fluoro-3-(2-hydroxyethyl)-2-phenylquinazolin-4(3H)-one (2ae).
Obtained as a white solid (65 mg, 76% yield); M.p. 190-191 oC; 1H
NMR (500 MHz, CDCl3) δ 7.64-7.68 (m, 1H), 7.59-7.44 (m, 6H), 7.16-
7.08 (m, 1H), 4.16 (t, J = 5.4 Hz, 2H), 3.79 (t, J = 5.4 Hz, 2H), 2.84 (s,
1H). 13C NMR (126 MHz, CDCl3) δ 166.73 (d, J = 255.8 Hz), 163.00,
157.54, 149.39 (d, J = 12.6 Hz), 135.03, 130.18, 129.57 (d, J = 11.3
Hz), 129.00, 128.04, 117.36, 116.18 (d, J = 23.9 Hz), 112.83 (d, J =
22.7 Hz), 61.49, 48.79. 19F NMR (471 MHz, CDCl3) δ -111.89.HRMS
(ESI+): Calculated for C16H13FN2O2H: [M+H]+ 285.1034, Found
285.1037.
2-Cyclohexyl-5-fluoro-3-(2-hydroxyethyl)quinazolin-4(3H)-one (2af).
Obtained as a white solid (69 mg, 79% yield); M.p. 161-162 oC; 1H
NMR (500 MHz, CDCl3) δ 7.59 (td, J = 8.2, 5.5 Hz, 1H), 7.39 (d, J =
8.2 Hz, 1H), 7.04- 6.98 (m, 1H), 4.30 (t, J = 5.7 Hz, 2H), 3.95 (d, J =
2.0 Hz, 2H), 3.15 (s, 1H), 2.99- 2.92 (m, 1H), 1.92-1.87 (m, 4H), 1.79-
1.70 (m, 3H), 1.45-1.30 (m, 3H). 13C NMR (126 MHz, CDCl3) δ
161.78, 161.00 (d, J=265.9 Hz), 160.62 (d, J= 3.8 Hz), 149.62, 134.38
(d, J = 10.1 Hz), 123.05 (d, J = 5.0 Hz), 112.56 (d, J = 21.4 Hz), 109.90
(d, J = 6.3 Hz), 60.96, 45.22, 41.96, 31.33, 26.02, 25.74. 19F NMR
2-Ethyl-3-(2-hydroxyethyl)quinazolin-4(3H)-one (2w). Obtained as
a white solid (56 mg, 86% yield); M.p. 140-141 oC; 1H NMR (500
MHz, CDCl3) δ 8.10 (d, J = 7.9 Hz, 1H), 7.71 – 7.65 (m, 1H), 7.57 (d, J
= 8.1 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 4.28 (t, J = 5.3 Hz, 2H), 3.99 (t, J
= 5.3 Hz, 2H), 3.51 (s, 1H), 2.97 (q, J = 7.4 Hz, 2H), 1.36 (t, J = 7.4 Hz,
3H). 13C NMR (126 MHz, CDCl3) δ 163.05, 158.47, 147.01, 134.36,
126.60, 126.53, 126.48, 120.06, 60.89, 46.25, 28.54, 11.51. HRMS
(ESI+): Calculated for C12H14N2O2H: [M+H]+ 219.1128, Found
219.1127.
2-Heptyl-3-(2-hydroxyethyl)quinazolin-4(3H)-one (2x). Obtained as
o
1
a white solid (73 mg, 84% yield); M.p. 93-94 C; H NMR (500 MHz,
CDCl3) δ 8.09 – 8.02 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 8.1
Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 4.26 (t, J = 5.3 Hz, 2H), 3.99 (t, J = 5.3
Hz, 2H), 3.76 (s, 1H), 2.94- 2.88 (m, 2H), 1.77 (dt, J = 15.5, 7.7 Hz,
2H), 1.44 (dt, J = 14.6, 6.8 Hz, 2H), 1.38-1.26 (m, 6H), 0.89 (t, J = 6.8
Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 163.02, 157.83, 147.08, 134.28,
126.58, 126.49, 126.37, 120.04, 60.80, 46.43, 35.44, 31.69, 29.36,
29.05, 27.45, 22.58, 14.05. HRMS (ESI+): Calculated for C17H24N2O2H:
[M+H]+ 289.1911, Found 289.1911.
3-(2-Hydroxyethyl)-2-tridecylquinazolin-4(3H)-one (2y). Obtained
as a white solid (87 mg, 77% yield); M.p. 102-103 oC; 1H NMR (500
MHz, CDCl3) δ 8.07 (dd, J = 7.9, 0.7 Hz, 1H), 7.71-7.61 (m, 1H), 7.54
(d, J = 8.1 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 4.27 (t, J = 5.3 Hz, 2H),
3.99 (t, J = 5.3 Hz, 2H), 3.62 (s, 1H), 2.95 – 2.87 (m, 2H), 1.77 (dt, J =
15.5, 7.7 Hz, 2H), 1.49-1.40 (m, 2H), 1.34 (dd, J = 13.3, 5.4 Hz, 2H),
1.26-1.21 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 163.07, 157.78, 147.11, 134.28, 126.61, 126.51, 126.37,
120.06, 60.89, 46.44, 35.44, 31.91, 29.67, 29.64, 29.60, 29.51, 29.41,
29.35, 27.45, 22.68, 14.11. HRMS (ESI+): Calculated for C23H36N2O2H:
[M+H]+ 373.2850, Found 373.2848.
5-Fluoro-3-(2-hydroxyethyl)-2-phenylquinazolin-4(3H)-one (2aa).
Obtained as a white solid (68 mg, 80% yield); M.p. 188-189 oC; 1H
NMR (500 MHz, CDCl3) δ 7.64-7.68 (m, 1H), 7.59-7.44 (m, 6H), 7.16
– 7.08 (m, 1H), 4.16 (t, J = 5.4 Hz, 2H), 3.79 (t, J = 5.4 Hz, 2H), 2.84 (s,
1H). 13C NMR (126 MHz, CDCl3) δ 161.04 (d, J = 267.1 Hz), 160.56,
157.39, 149.03, 135.03 (d, J = 10.1 Hz), 134.88, 130.17, 128.94,
128.13, 123.41 (d, J = 3.8 Hz), 113.67 (d, J = 24.4 Hz), 110.34 (d, J =
6.3 Hz), 60.86, 48.56. 19F NMR (471 MHz, CDCl3) δ -110.62.HRMS
(ESI+): Calculated for C16H13FN2O2H: [M+H]+ 285.1034, Found
285.1036.
(471 MHz, CDCl3)
δ -111.36. HRMS (ESI+): Calculated for
C16H19FN2O2H: [M+H]+ 291.1504, Found 291.1500.
2-Cyclohexyl-3-(2-hydroxyethyl)-7-methylquinazolin-4(3H)-one
(2ag). Obtained as a white solid (70 mg, 81% yield); M.p. 132-133
oC; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 8.1 Hz, 1H), 7.44 (s, 1H),
7.22 (dd, J = 8.1, 1.0 Hz, 1H), 4.32 (t, J = 5.6 Hz, 2H), 3.95 (d, J = 4.7
Hz, 2H), 2.98 (s, 1H), 2.92-2.85 (m, 1H), 2.47 (s, 3H), 1.91-1.85 (m,
4H), 1.83-1.73 (m, 4H), 1.40-1.34 (m, 2H). 13C NMR (126 MHz, CDCl3)
δ 163.71, 160.52, 147.67, 145.24, 127.95, 126.82, 126.37, 117.73,
61.71, 45.44, 41.92, 31.49, 26.12, 25.77, 21.85. HRMS (ESI+):
Calculated for C17H22N2O2H: [M+H]+ 287.1754, Found 287.1761.
7-Chloro-2-(furan-2-yl)-3-(2-hydroxyethyl)quinazolin-4(3H)-one
(2ah). Obtained as a white solid (62 mg, 70% yield); M.p. 128-129
1
oC; H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.6 Hz, 1H), 7.73 (d, J =
1.9 Hz, 1H), 7.65 (dd, J = 1.6, 0.7 Hz, 1H), 7.43 (dd, J = 8.6, 2.0 Hz,
1H), 7.28 (d, J = 3.5 Hz, 1H), 6.63 (dd, J = 3.5, 1.8 Hz, 1H), 4.50 (t, J =
3-(2-Hydroxyethyl)-6-methoxy-2-phenylquinazolin-4(3H)-one (2ab)
Obtained as a white solid (76 mg, 85% yield); M.p. 204-205 oC; 1H
6 | J. Name., 2012, 00, 1-3
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COMMUNICATION
5.4 Hz, 2H), 4.08 (t, J = 5.4 Hz, 2H), 2.95 (s, 1H). 13C NMR (126 MHz,
CDCl3) δ 163.39, 148.38, 147.41, 147.15, 145.08, 141.00, 128.30,
127.90, 127.01, 118.73, 116.90, 112.25, 62.23, 48.67. HRMS (ESI+):
Calculated for C14H11ClN2O3H: [M+H]+ 291.0531, Found 291.0537.
7-Chloro-3-(2-hydroxyethyl)-2-(thiophen-2-yl)quinazolin-4(3H)-one
(2ai). Obtained as a white solid (67 mg, 73% yield); M.p. 132-133 oC;
1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.57
(d, J = 4.0 Hz, 2H), 7.42 (d, J = 8.6, 2.0 Hz, 1H), 7.17- 7.13 (m, 1H),
4.44 (t, J = 5.4 Hz, 2H), 4.02 (t, J = 5.4 Hz, 2H), 3.05 (s, 1H). 13C NMR
(126 MHz, CDCl3) δ 163.18, 151.42, 148.06, 141.02, 136.22, 130.37,
129.77, 128.18, 127.94, 127.60, 127.01, 118.58, 61.47, 49.02. HRMS
(ESI+): Calculated for C14H11ClN2O2SH: [M+H]+ 307.0303, Found
307.0309.
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3-(2-Hydroxyethyl)-2-methylquinazolin-4(3H)-one (2aj). Obtained
o
1
as a white solid (0.84 g, 82% yield); M.p. 157-158 C; H NMR (500
MHz, CDCl3) δ 8.12 (d, J = 9.1 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.57 (d,
J = 8.1 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 4.29 (t, J = 5.2 Hz, 2H), 4.03 (t,
J = 5.2 Hz, 2H), 3.13 (s, 1H), 2.72 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
162.65, 155.19, 146.67, 134.53, 126.65, 126.18, 123.53, 120.12,
60.84, 47.18, 23.56. HRMS (ESI+): Calculated for C11H12N2O2H:
[M+H]+ 205.0972, Found 205.0978.
Acknowledgements
We thank the National Natural Science Foundation of China
(21871071), the Key Research and Development Project of Zhejiang
(2019C01081), and the General Scientific Research Projects of
Zhejiang Education Department (Y201840022) for financial support.
Notes and references
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DOI: 10.1039/D0OB00881H
R2
O
N
O
OH
Acid ion exchange resin
R2
N
R1
N
H
R1
N
O
(+) Acid ion exchange resin can be reused
(+) H2O/Acetone as green solvent
(+) 35 examples with good yields
We report other use of 2-(2-oxazolyl)aniline to prepare quinazolin-4-one derivatives by acid ion exchange
resin mediated cascade reaction of N-(2-(4,5-dihydrooxazol-2-yl)phenyl)benzamide for the first time. It is
noted that the acid ion exchange resin can be reused for six times without significant loss of activation.