Highly enantioselective synthesis of dihydroquinazolinones through Sc(OTf)3-catalyzed intramolecular amidation of imines

Article abstract of DOI:10.1016/j.jfluchem.2014.11.008

A Sc(OTf)₃-catalyzed intramolecular amidation of imines with a novel fluorous bis(oxazolines) as ligand is presented. The corresponding chiral dihydroquinazolinones were obtained in 76-94% yield with enantioselectivities up to 98%. The fluorous ligand can be easily recovered and reused at least three times without significant loss of enantioselectivity.

Full text of DOI:10.1016/j.jfluchem.2014.11.008

Journal of Fluorine Chemistry 169 (2015) 72–77
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Highly enantioselective synthesis of dihydroquinazolinones through
Sc(OTf)3-catalyzed intramolecular amidation of imines
Tao Deng a, Hongjun Wang a, Chun Cai a,b,
*
a Chemical Engineering College, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing, Jiangsu, People’s Republic of China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
People’s Republic of China
A R T I C L E I N F O
A B S T R A C T
Article history:
A Sc(OTf)3-catalyzed intramolecular amidation of imines with a novel fluorous bis(oxazolines) as ligand
is presented. The corresponding chiral dihydroquinazolinones were obtained in 76–94% yield with
enantioselectivities up to 98%. The fluorous ligand can be easily recovered and reused at least three times
without significant loss of enantioselectivity.
Received 17 October 2014
Received in revised form 16 November 2014
Accepted 25 November 2014
Available online 3 December 2014
ß 2014 Published by Elsevier B.V.
Keywords:
Fluorous bis(oxazolines)
Dihydroquinazolinone
Intramolecular amidation
Asymmetric catalysis
1. Introduction
aldehydes/ketones in presence of para-toluene sulfonic acid
as catalyst under reflux conditions [3]. Rostamizadeh et al.
Pharmacologically active heterocycles/intermediates which
possess a chiral center are increasingly being successfully synthe-
sized in a stereoselective route in recent years [1]. Many biological
processes involving these nitrogen containing heterocycles as
markers or messenger molecules and an array of pharmaceuticals
and agrochemicals based on those chemicals have been reported
during the past few decades. 2,3-Dihydroquinazolinone derivatives
including the oxidized form, the quinazolinones, displayed exten-
sive important pharmacological activities, such as antitumor,
analgesic, antifibrillatory, antibiotic, antispermatogenic, and vaso-
observed formation of 2,3-dihydroquinazolin-4(1H)-ones from
isatoic anhydride and aromatic aldehydes under solvent free
conditions using catalytic amounts of iodine in 2008 [4]. Like-
wise, Lewis acid catalysts, such as gallium(III) triflate [5] and
zinc(II) perfluorooctanoate [6] have also been used for catalyz-
ing one-pot reaction for synthesis of quinazolinones. As reported
by Bunce and Nammalwar, various quinazolinone derivatives
can also be synthesized using 2-nitrobenzamides and carbonyl
compounds as the substrates with iron powder as the promoter
[7]. Another synthetic strategy to give different 2-substituted
dihydroquinazolinones from anthranilamide and different alde-
dilatory efficacy [2].
A selection of bio-active quinazolinone
derivatives are shown in Scheme 1. In addition, these compounds
are relevant building blocks in organic synthesis to form more
complex structures such as natural products like luotonin A,
sclerotigenin, fumiquinazoline A or (Æ)-cruciferane (Fig. 1). Conse-
quently, numerous methodologies are described in the literature for
the preparation of these important classes of compounds.
hydes in the presence of b-cyclodextrin water was published by
Ramesh et al. [8]. More recently, Langer and coworkers reported
base mediated synthesis of 2-aryl-2,3-dihydroquinazolin-4(1H)-
ones from 2-aminobenzonitriles and aromatic aldehydes in
water [9].
Regardless of the above methods that are available to synthesize
dihydroquinazolinones as racemates [10], enantioselective synthe-
sis of 2,3-dihydroquinazolinones is not easily achieved since
the aminal stereocenter is sensitive to racemization [11]. Cheng
et al. reported about the asymmetric synthesis of dihydroquina-
zolinones using (S)-TRIP as the catalyst [12]. Singh and coworkers
reported the synthesis of 2,3-dihydroquinazolin-4(1H)-ones from
isatoic anhydride, aldehyde, amine or ammonium acetate in water
Sharma and Kaur developed the synthesis of 2,3-dihydro-
quinazolin-4(1H)-ones from anthranilamide and different
*
Corresponding author at: Chemical Engineering College, Nanjing University of
Science and Technology, 200 Xiao Ling Wei Street, Nanjing, Jiangsu, People’s
Republic of China. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: c.cai@njust.edu.cn (C. Cai).
under microwave in the presence of L-proline [13]. Additionally, in
http://dx.doi.org/10.1016/j.jfluchem.2014.11.008
0022-1139/ß 2014 Published by Elsevier B.V.

T. Deng et al. / Journal of Fluorine Chemistry 169 (2015) 72–77
73
Fig. 1. Selected examples of biologically active quinazolinone derivatives.
2012, Prakash and Kesavan reported the enantioselective synthesis
of 2,3-dihydroquinazolin-4(1H)-ones from 2-aminobenzamides
with aldehydes using Sc(III) as a catalyst (limited to the use
of preformed imines, 54À90% yields, and 83À97% ee’s, À20 8C)
[14]. More recently, in 2013 Lin and co-workers reported the
application of SPINOL-phosphoric acid to this asymmetric conden-
sation [15]. Despite these elegant examples, a general, efficient,
and mild enantioselective protocol has yet to be described and
would be of a great value because of the importance of optically
active 2,3-dihydroquinazolinones.
Our group has great interest in developing different chiral
bis(oxazolines) for asymmetric reactions and has showed their
excellent catalytic reactivity as chiral ligands. These previous
successes led us to envision that recyclable bis(oxazolines)
ligand might be suitable for the asymmetric condensation of 2-
aminobenzamides and different aldehydes. Herein, we present
our preliminary results on this subject. A range of substituted 2,3-
dihydroquinazoline-4(1H)-ones were obtained in high yields
and good enantioselectivities (up to 94% yield, 98% ee).
2. Results and discussion
Initial attempts were made to prove our hypothesis by
screening ligands (Fig. 2, L1–L8) with various Lewis acids such
as Cu(OTf)2, Sc(OTf)3 or Zn(OTf)2. Intramolecular amidation of
imine formed between 2-aminobenzamide (1) and benzaldehyde
(2a) as the model substrates with 1 mol% of Lewis acid and 5 mol%
of ligand in chloroform at room temperature in the presence of
˚
powdered 4 A molecular sieves. A series of chiral bis(oxazolines)
ligands were screened, as shown in Table 1. Although the yields of
the reactions in the presence of ligands L1–L3 were good, the
enantioselectivities of these reactions were frustrating (Table 1,
entries 1–3). In detail, the fluorous bis(oxazolines) L3 almost had
no inducing effect on the enantioselectivity (Table 1, entry 3). Since
Fig. 2. Selected examples of chiral ligands examined.

74
T. Deng et al. / Journal of Fluorine Chemistry 169 (2015) 72–77
Table 1
realize better results than CH2Cl2 did (entries 13–15 vs. 11). Hence,
Optimization of the conditions.a
CH2Cl2 was chosen as the most suitable solvent for further
optimization of the reaction conditions. Lowering the temperature
to 0 8C remarkably lowered the yield but with higher enantios-
electivity (46% yield, 98% ee, Table 1, entry 16). Thus, the optimized
reaction conditions for the model reaction were established.
Furthermore, the scalability of the newly investigated method
was proven with a 1.0 mmol scale experiment (Table 1, entry 17).
The 2,3-dihydroquinazolinone 2a was obtained in 84% yield and
97% ee at room temperature. To illustrate the recycling of the
ligand L6, the recovered ligand in the above reaction was then
reused directly in the next reaction with a 1.0 mmol scale
experiment, and the same procedure was repeated to exhibit
the comparable activity and enantioselectivity (85% yield, 96% ee,
entry 18 vs. 84% yield, 95% ee, entry 19, respectively, Table 1).
With these reaction conditions identified, our attention turned to
extend the scope of our methodology in synthesizing various
optically 2,3-dihydroquinazolinones. The reactions were carried out
using ligand L6 under the optimized conditions, and the results
are summarized in Table 2. To our delight, all reactions proceeded in
generally excellent yields with good to excellent enantioselectiv-
ities. Substituted benzaldehydes bearing either electronically poor,
neutral, or rich group have remarkable differences in enantioselec-
tivities of this reaction although the corresponding products 3a–3k
were obtained in generally high yields and favorable to good
enantioselectivities (76–94% yield, 87–98% ee). In detail, the
presence of an electron-withdrawing group (–Cl, –NO2 or –CF3) in
the para-position of benzaldehyde is well tolerated in synthesizing
substituted 2,3-dihydroquinazolinones 3b–3d (Table 2, entries 2–
4). Among them, p-nitrobenzaldehyde 3d had the highest capability
in enantioselective control with an excellent enantioselectivity of
98% (Table 2, entry 4). When electron-donating groups were
introduced, the reactions ran smoothly, affording the products 3e–
3g in high yields with enantiomeric excess ranging from 92 to 95%
(Table 2, entries 5–7).
Entry
Ligand
Metal
Solvent
Yieldb/%
eec/%
1
2
L1
L2
L3
L4
L5
L6
L7
L8
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Zn(OTf)2
Cu(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CCl4
62
81
70
82
79
78
69
72
13
17
87
59
35
39
42
46
84
85
84
81
19(R)
Racemic
12(R)
30(R)
93(S)
94(S)
Racemic
27(R)
5
3
4
5
6
7
8
9
10
11
12
13
14
15
16d
17e
18f
19g
20h
8
97
62
THF
26
Dioxane
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
45
58
98
97
96
95
92
a
Reactions were carried out using 0.3 mmol of 2 aminobenzamide, 0.36 mmol of
˚
benzaldehyde, 5 mol% of ligand, 1 mol% of metal salt and powdered 4 A molecular
sieves in solvent for 48 h.
b
Isolated yields.
c
The ee value of the compound was checked by chiral HPLC using a Venusil CA
column.
d
At 0 8C for 72 h.
1.0 mmol scale experiment.
e
f
First reuse by F-SPE.
g
Second reuse by F-SPE.
h
Third reuse by F-SPE.
Moreover, the position of electron-withdrawing substituents
appeared to exert some impact on the enantioselectivity. The
these attempts were not successful, we turned our attention to
commercial pybox ligand L4 with Sc(OTf)3 as Lewis acid, these
complexes can be used in different reactions and their catalytic
efficiencies is well demonstrated in the literature [16,17]. We were
delighted to observe that pybox/Sc(OTf)3 catalyzed the intramo-
lecular amidation of imine with great efficiency and with an
enantiomeric excess of 30% (Table 1, entry 4). Encouraged by
this observation, we sought other suitable ligand to enhance the
enantioselectivity of this transformation. The reaction proceeded
to afford the desired optically active 2,3-dihydroquinazolinone 2a
in excellent enantiomeric excess using ligand L5 (Table 1, entry 5).
As we expected, the fluorous bis(oxazolines) L6 revealed similar
enantioselectivity at room temperature to afford 2,3-dihydroqui-
nazolinone 2a in 79% yield with 93% ee (Table 1, entry 6). However,
L7 and L8 failed to improve the enantioselectivity of the reaction
(Table 1, entries 7 and 8).
Scandium(III) triflate was found to be the most suitable metal
partner since reactions catalyzed by other metal triflates such as
Cu(OTf)2 and Zn(OTf)2 in combination with L6 did not improve
either the yield or the enantioselectivity (Table 1, entries 9 and
10). It was observed that 2,3-dihydroquinazolinone 2a was
isolated in very low yields (10–20%) with almost no chiral
induction.
Table 2
Scope of substrates.a
Entry
R
Product
Yieldb/%
eec/%
1
2
C6H5
3a
3b
3c
3d
3e
3f
84
89
94
92
86
83
86
84
91
81
90
82
79
76
85
90
nr
97
98
97
98
92
93
95
88
89
91
92
87
92
94
93
89
–
4-ClC6H4
3
4-CF3C6H4
4-NO2C6H4
4-OMeC6H4
4-Me2NC6H4
4-MeC6H4
3-BrC6H4
4
5
6
7
3g
3h
3i
8
9
2-BrC6H4
10
11
12
13
14
15
16
17
3-NO2C6H4
2-NO2C6H4
2-Pyridinyl
1-Naphthyl
(E)-PhCH5CH
PhCH2CH2
Cyclohexanyl
CH3CH2
3j
3k
3l
3m
3n
3o
3p
–
Then, in the presence of L6, the preliminary evaluation of other
solvents such as CH2Cl2 and CCl4 disclosed that CH2Cl2 was much
superior to CHCl3 and CCl4 with regard to enantioselectivity,
delivering the chiral 2,3-dihydroquinazolinone 2a in 97% ee
(Table 1, entries 11 vs. 5 and 12). However, further screening of
other solvents including THF, toluene and 1,4-dioxane could not
a
Reactions were carried out using 1 mmol of 2-aminobenzamide, 1.2 mmol of
˚
aldehyde, 1 mol% of Sc(OTf)3, 5 mol% of L6 and powdered 4 A molecular sieves at
room temperature in CH2Cl2 for 48 h.
b
Isolated yields.
c
The ee value of the compound was checked by chiral HPLC using a Venusil CA
column and Venusil CO column.

T. Deng et al. / Journal of Fluorine Chemistry 169 (2015) 72–77
75
presence of bromo as well as nitro group on benzaldehyde at either
the ortho or meta position obviously reduced the enantiomeric
excesses of the transformation (Table 2, entries 8–11). The steric
effect of a bromine atom contributed to the diminished enantios-
electivity in the case of o-bromobenzaldehyde (Table 2, entry 9). A
similar steric effect was observed when o-nitrobenzaldehyde
was treated with 2-aminobenzamide to afford 3k with slightly
decreased enantioselectivity (92% ee, Table 2, entry 11).
the seperation of non-fluorous component, pure methanol was
then added onto the fluorous gel column continuously for
obtaining the elutant of fluorous bis(oxazolines). When the bulk
of solvent was removed and the residue was dried in vacuo at 50 8C
for 8 h to give the fluorous bis(oxazolines). The recovered ligand
could be used directly for the next run.
4.4. 2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (3a)
Besides, this protocol could also be applied to heteroaromatic
aldehydes as exemplified by 2-pyridinecarboxaldehyde in 82%
yield and 87% ee (Table 2, entry 12). The 1-naphthyl-bearing
substrate delivered the corresponding product with high enantios-
electivity of 92% albeit with slightly decreased yield (Table 2, entry
Purified by column chromatography eluting with Hexane/
EtOAc 2:1 (84% yield). The ee (97%) was determined by HPLC
analysis, Venusil CA column, Hexane/i-PrOH 85:15, flow
rate = 0.7 mL/min, UV = 254 nm, major enantiomer t1 = 29.1 min,
minor enantiomer t2 = 33.9 min. White solid; 1H NMR (500 MHz,
13). The
a,b-unsaturated aldehyde (cinnamaldehyde) also led to
product 3n in only 76% yield and 94% ee, whereas a saturated
aldehyde (phenylpropyl aldehyde) gave product 3m in 85% yield
and 93% ee (Table 2, entries 14 vs. 15).
DMSO-d6) d 8.26 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.2 Hz,
2H), 7.39–7.33 (m, 3H), 7.24–7.21(m, 1H), 7.09 (s, 1H), 6.73
(d, J = 8.1 Hz, 1H), 6.67–6.64 (m, 1H), 5.73 (s, 1H). 13C NMR
We further expanded the scope of this reaction to aliphatic
(125 MHz, DMSO-d6) d 163.05, 147.32, 141.13, 132.77, 127.91,
aldehydes. When
a
cyclohexyl substituent was introduced,
127.79, 126.82, 126.32, 116.58, 114.43, 113.87, 66.03.
affording the product 3p in 90% yield and 89% ee (Table 2, entry
16) while no desired product was obtained for propionaldehyde
(Table 2, entry 17).
4.5. 2-(4-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (3b)
Purified by column chromatography eluting with Hexane/
EtOAc 2:1 (89% yield). The ee (98%) was determined by HPLC
analysis, Venusil CA column, Hexane/i-PrOH 85:15, flow
rate = 0.7 mL/min, UV = 210 nm, major enantiomer t1 = 18.0 min,
minor enantiomer t2 = 22.6 min. White solid; 1H NMR (500 MHz,
3. Conclusions
In summary, we have presented an efficient protocol for the
synthesis of dihydroquinazolinones through Sc(OTf)3-catalyzed
intramolecular amidation of imines with a fluorous bis(oxazolines)
as ligand. This process was carried out in mild conditions and gave
the corresponding dihydroquinazolinones with moderate to high
yields and good enantiomeric excesses. The reaction expands the
scope of the asymmetric addition with a variety of aldehydes. The
fluorous ligand can be easily recovered and reused at least three
times without significant loss of enantioselectivity. Further
explorations of the chiral bis(oxazolines) type ligands’ applications
in asymmetric catalysis are underway.
DMSO-d6)
d 8.30 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 8.5 Hz,
2H), 7.44 (d, J = 8.4 Hz, 2H), 7.23–7.21 (m, 1H), 7.12 (s, 1H), 6.73
(d, J = 8.1 Hz, 1H), 6.68–6.65 (m, 1H), 5.75 (s, 1H). 13C NMR
(125 MHz, DMSO-d6)
d 164.04, 148.18, 141.26, 133.97, 133.52,
129.29, 128.87, 127.92, 117.85, 115.49, 115.02, 66.30.
4.6. 2-(4-(Trifluoromethyl) phenyl)-2,3-dihydroquinazolin-4(1H)-
one (3c)
Purified by column chromatography eluting with Hexane/
EtOAc 2:1 (94% yield). The ee (97%) was determined by HPLC
analysis, Venusil CA column, Hexane/i-PrOH 85:15, flow
rate = 0.7 mL/min, UV = 210 nm, major enantiomer t1 = 11.9 min,
minor enantiomer t2 = 18.0 min. White solid; 1H NMR (500 MHz,
4. Experimental
4.1. General information
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
purified by column chromatography over silica gel. 1H and 13C
NMR spectra were recorded on a Bruker AMX500 (500 MHz)
spectrometer and tetramethylsilane (TMS) was used as a reference.
All of the products were known compounds and were identified by
comparison of their physical and spectra data with those of
authentic samples. Enantiomeric excesses (ee) were determined
by chiral HPLC using a Venusil CA column and Venusil CO column.
DMSO-d6) d 8.42 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.1 Hz,
2H), 7.59 (d, J = 7.5 Hz, 1H), 7.28–7.18 (m, 2H), 6.74 (d, J = 8.1 Hz,
1H), 6.69–6.66 (m, 1H), 5.84 (s, 1H). 13C NMR (125 MHz, DMSO-d6)
d
163.93, 148.32, 136.28, 133.80, 132.40, 132.19, 129.29, 128.92,
128.69, 128.21, 127.93, 127.20, 117.70, 115.09, 66.33. 19F NMR
(500 MHz, DMSO-d6)
À60.94.
d
4.7. 2-(4-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3d)
Purified by column chromatography eluting with Hexane/EtOAc
2:1 (92% yield). The ee (98%) was determined by HPLC analysis,
Venusil CA column, Hexane/i-PrOH 85:15, flow rate = 0.7 mL/min,
UV = 230 nm, major enantiomer t1 = 21.2 min, minor enantiomer
4.2. General procedure for the enantioselective synthesis of 2,3-
dihydroquinazolinones.
A
mixture of 2-aminobenzamide (1 mmol), aldehyde
t2 = 31.0 min. Yellow solid; 1H NMR (500 MHz, DMSO-d6)
d 8.50
˚
(1.2 mmol), 1 mol% of Sc(OTf)3, 5 mol% of L6 and powdered 4 A
molecular sieves in 1.0 mL anhydrous CH2Cl2 was stirred for 48 h at
room temperature under a nitrogen atmosphere. Completion of
the reaction was ascertained by TLC, and the product was purified
by flash column chromatography to afford desired product.
(s, 1H), 8.24 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.59 (d,
J = 7.3 Hz, 1H), 7.31(s, 1H), 7.26–7.23(m, 1H), 6.75(d, J = 8.1 Hz, 1H),
6.69–6.66 (m, 1H), 5.89 (s, 1H). 13C NMR (125 MHz, DMSO-d6)
d
163.82, 149.89, 147.77, 135.37, 134.14, 129.90, 128.58, 127.97,
126.51, 124.14, 118.05, 115.48, 115.12, 65.85.
4.3. General procedure for recovery of fluorous bis(oxazolines)
4.8. 2-(4-Methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3e)
After the reaction was finished, the mixture was concentrated
and then loaded onto a FluoroFlash1 silica gel for F-SPE. The
residue was eluted by methanol:water (v/v = 80:20) at first for
Purified by column chromatography eluting with Hexane/EtOAc
2:1 (86% yield). The ee (92%) was determined by HPLC analysis,
Venusil CA column, Hexane/i-PrOH 85:15, flow rate = 0.7 mL/min,

76
T. Deng et al. / Journal of Fluorine Chemistry 169 (2015) 72–77
UV = 230 nm, major enantiomer t1 = 17.7 min, minor enantiomer
t2 = 19.2 min. White solid; 1H NMR (500 MHz, DMSO-d6)
8.17
rate = 0.5 mL/min, UV = 230 nm, major enantiomer t1 = 30.9 min,
minor enantiomer t2 = 35.5 min. Yellow solid; 1H NMR (500 MHz,
d
(s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.23–7.20 (m,
1H), 6.99 (s, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.67–
6.64 (m, 1H), 5.69 (s, 1H), 3.73 (s, 3H). 13C NMR (125 MHz, DMSO-d6)
DMSO-d6) d 8.51 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.92
(d, J = 7.6 Hz, 1H), 7.70–7.67 (m, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.33
(s, 1H), 7.27–7.24 (m, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.70–6.67
(m, 1H), 5.92 (s, 1H). 13C NMR (125 MHz, DMSO-d6)
d 163.92,
d
163.18, 147.56, 147.47, 134.15, 132.97, 129.13, 127.66, 1117.56,
114.89, 114.53, 113.11, 65.77, 54.98.
148.28, 147.83, 144.85, 134.16, 133.90, 130.61, 127.97, 123.83,
122.09, 118.11, 115.49, 115.15, 65.72.
4.9. 2-(4-(Dimethylamino) phenyl)-2,3-dihydroquinazolin-4(1H)-
one (3f)
4.14. 2-(2-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3k)
Purified by column chromatography eluting with Hexane/EtOAc
2:1 (83% yield). The ee (93%) was determined by HPLC analysis,
Venusil CA column, Hexane/i-PrOH 85:15, flow rate = 0.7 mL/min,
UV = 210 nm, major enantiomer t1 = 26.2 min, minor enantiomer
Purified by column chromatography eluting with Hexane/
EtOAc 2:1 (90% yield). The ee (92%) was determined by HPLC
analysis, Venusil CA column, Hexane/i-PrOH 80:20, flow
rate = 0.5 mL/min, UV = 210 nm, major enantiomer t1 = 39.5 min,
minor enantiomer t2 = 41.9 min. Yellow solid; 1H NMR (500 MHz,
t2 = 28.4 min. Yellow solid; 1H NMR (500 MHz, DMSO-d6)
d 8.06
(s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.21 (s, 1H),
DMSO-d6) d 8.21 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.5 Hz,
1H), 7.81–7.73 (m, 1H), 7.65–7.59 (m, 2H), 7.29–7.21 (m, 1H), 6.99
(s, 1H), 6.80–6.68 (m, 2H), 6.32 (s, 1H). 13C NMR (125 MHz, DMSO-
6.90 (s, 1H), 6.72–6.65 (m, 4H), 5.62 (s, 1H), 2.86 (s, 6H). 13C NMR
(125 MHz, DMSO-d6)
d 163.32, 150.19, 147.69, 132.62, 128.12,
127.17, 126.82, 116.43, 114.50, 113.87, 111.41, 66.11, 39.63.
d6) d 162.87, 147.15, 146.59, 135.40, 133.38, 133.05, 129.37,
128.39, 126.80, 124.19, 117.18, 114.40, 114.00, 61.67.
4.10. 2-(p-Tolyl)-2,3-dihydroquinazolin-4(1H)-one (3g)
4.15. 2-(Pyridin-2-yl)-2,3-dihydroquinazolin-4(1H)-one (3l)
Purified by column chromatography eluting with Hexane/
EtOAc 2:1 (86% yield). The ee (95%) was determined by HPLC
analysis, Venusil CA column, Hexane/i-PrOH 85:15, flow
rate = 0.7 mL/min, UV = 210 nm, major enantiomer t1 = 26.1 min,
minor enantiomer t2 = 31.4 min. White solid; 1H NMR (500 MHz,
Purified by column chromatography eluting with Hexane/
EtOAc 2:1(82% yield). The ee (87%) was determined by HPLC
analysis, Venusil CA column, Hexane/i-PrOH 85:15, flow
rate = 0.7 mL/min, UV = 230 nm, major enantiomer t1 = 22.9 min,
minor enantiomer t2 = 29.1 min. Yellow solid; 1H NMR (500 MHz,
DMSO-d6)
d 8.21 (s, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 7.9 Hz,
2H), 7.26–7.12 (m, 3H), 7.04 (s, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.66–
6.63 (t, J = 7.4 Hz, 1H), 5.69 (s, 1H), 2.28 (s, 3H). 13C NMR (125 MHz,
DMSO-d6) d 8.55 (d, J = 4.2 Hz, 1H), 8.38 (s, 1H), 7.83–1.80 (m, 1H),
7.61 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.35–7.20 (m, 3H),
6.75 (d, J = 8.1 Hz, 1H), 6.67–6.64 (m, 1H), 5.72 (s, 1H). 13C NMR
DMSO-d6)
d
163.12, 147.38, 138.13, 137.19, 132.73, 128.28,
126.81, 126.26, 116.54, 114.47, 113.88, 65.84, 20.20.
(125 MHz, DMSO-d6) d 164.44, 149.54, 147.70, 138.58, 137.85,
135.50, 134.31, 127.22, 124.16, 120.99, 117.99, 115.10, 67.30.
4.11. 2-(3-Bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (3 h)
4.16. 2-(Naphthalen-1-yl)-2,3-dihydroquinazolin-4(1H)-one (3m)
Purified by column chromatography eluting with Hexane/
EtOAc 2:1 (84% yield). The ee (88%) was determined by HPLC
analysis, Venusil CA column, Hexane/i-PrOH 90:10, flow
rate = 0.7 mL/min, UV = 230 nm, major enantiomer t1 = 37.6 min,
minor enantiomer t2 = 40.7 min. Yellow solid; 1H NMR (500 MHz,
Purified by column chromatography eluting with Hexane/EtOAc
2:1 (79% yield). The ee (92%) was determined by HPLC analysis,
Venusil CA column, Hexane/i-PrOH 85:15, flow rate = 0.7 mL/min,
UV = 273 nm, miajor enantiomer t1 = 18.4 min, minor enantiomer
DMSO-d6)
d
8.37 (s, 1H), 7.65 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.52 (d,
t2 = 22.1 min. White solid; 1H NMR (500 MHz, DMSO-d6)
d 8.57 (d,
J = 7.9 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.35–7.32 (m, 1H), 7.26–7.23
(m, 1H), 7.19 (s, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.68–6.65 (m, 1H), 5.76
J = 7.8 Hz, 1H), 8.30 (s, 1H), 8.01–7.97 (m, 2H), 7.73–7.71 (m, 2H),
7.58–7.52(m, 3H), 7.29–7.26(m, 1H), 7.11(s, 1H), 6.78–6.72(m, 2H),
6.50 (s, 1H). 13C NMR (125 MHz, DMSO-d6)
d163.54, 147.93, 134.65,
(s, 1H). 13C NMR (125 MHz, DMSO-d6)
d
163.99, 148.03, 145.19,
134.06, 131.73, 131.17, 130.18, 127.94, 126.33, 122.16, 117.91,
115.43, 115.04, 66.05.
133.25, 132.76, 130.02, 128.85, 128.08, 127.02, 125.55, 125.30,
124.68, 124.07, 116.75, 114.47, 114.01, 65.41.
4.12. 2-(2-Bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (3i)
4.17. (E)-2-styryl-2,3-dihydroquinazolin-4(1H)-one (3n)
Purified by column chromatography eluting with Hexane/
EtOAc 2:1 (91% yield). The ee (89%) was determined by HPLC
analysis, Venusil CA column, Hexane/i-PrOH 85:15, flow
rate = 0.7 mL/min, UV = 230 nm, major enantiomer t1 = 27.5 min,
minor enantiomer t2 = 33.9 min. Yellow solid; 1H NMR (500 MHz,
Purified by column chromatography eluting with Hexane/
EtOAc 2:1 (76% yield). The ee (94%) was determined by HPLC
analysis, Venusil CA column, Hexane/i-PrOH 85:15, flow
rate = 0.7 mL/min, UV = 230 nm, major enantiomer t1 = 21.0 min,
minor enantiomer t2 = 23.4 min. White solid; 1H NMR (500 MHz,
DMSO-d6)
7.33–7.30 (m, 1H), 7.26–7.23 (m, 1H), 6.98 (s, 1H), 6.80–6.60
(m, 2H), 6.08 (s, 1H). 13C NMR (125 MHz, DMSO-d6)
163.09,
147.16, 138.62, 132.90, 132.27, 130.17, 128.59, 127.54, 126.86,
121.68, 116.99, 114.19, 114.08, 65.86.
d
8.18 (s, 1H), 7.67–7.64 (m, 3H), 7.45–7.42 (m, 1H),
DMSO-d6) d 8.10 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 7.3 Hz,
2H), 7.32 (d, J = 7.7 Hz, 2H), 7.28–7.21 (m, 2H), 6.86 (s, 1H), 6.73
(d, J = 8.0 Hz, 1H), 6.68–6.63 (m, 2H), 6.37–6.34 (m, 1H), 5.28
(d, J = 6.7 Hz, 1H). 13C NMR (125 MHz, DMSO-d6)
d 163.98, 148.22,
148.00, 146.96, 146.54, 134.07, 128.19, 127.95, 125.87, 117.95,
115.46, 115.05, 66.24.
d
4.13. 2-(3-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3j)
4.18. 2-Phenethyl-2,3-dihydroquinazolin-4(1H)-one (3o)
Purified by column chromatography eluting with Hexane/
EtOAc 2:1 (81% yield). The ee (91%) was determined by HPLC
analysis, Venusil CO column, Hexane/i-PrOH 70:30, flow
Purified by column chromatography eluting with Hexane/EtOAc
2:1 (85% yield). The ee (93%) was determined by HPLC analysis,

T. Deng et al. / Journal of Fluorine Chemistry 169 (2015) 72–77
77
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Venusil CA column, Hexane/i-PrOH 85:15, flow rate = 0.7 mL/min,
UV = 280 nm, major enantiomer t1 = 17.2 min, minor enantiomer
t2 = 20.3 min. White solid; 1H NMR (500 MHz, DMSO-d6)
d 8.04
(s, 1H), 7.61–7.59 (m, 1H), 7.28–7.16 (m, 6H), 6.76–6.65 (m, 3H),
4.74–4.72 (m, 1H), 2.74 (d, J = 5.0 Hz, 2H), 1.94–1.90 (m, 2H). 13C
NMR (125 MHz, DMSO-d6) d 163.58, 148.03, 141.07, 132.62, 127.85,
[3] S.D. Sharma, V. Kaur, Synthesis 9 (1989) 677–680.
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4.19. 2-Cyclohexyl-2,3-dihydroquinazolin-4(1H)-one (3p)
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Purified by column chromatography eluting with Hexane/EtOAc
2:1 (90% yield). The ee (89%) was determined by HPLC analysis,
Venusil CA column, Hexane/i-PrOH 85:15, flow rate = 0.7 mL/min,
UV = 254 nm, major enantiomer t1 = 10.9 min, minor enantiomer
t2 = 16.2 min. White solid; 1H NMR (500 MHz, DMSO-d6)
d 7.90
(s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.20–7.18 (m, 1H), 6.74 (d, J = 10.0 Hz,
1H), 6.62–6.59 (m, 1H), 6.55 (s, 1H), 4.44 (s, 1H), 1.69 (d, J = 12.2 Hz,
4H), 1.58(d, J = 30.8 Hz, 2H), 1.11 (s, 5H). 13C NMR (125 MHz, DMSO-
d6)
d 163.20, 147.82, 132.49, 126.70, 115.89, 114.26, 113.55, 68.05,
42.34, 26.47, 26.16, 25.41, 25.09, 25.03.
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2227–2302;
Appendix A. Supplementary data
(b) R. Burai, C. Ramesh, M. Shorty, R. Curpan, C. Bologa, L.A. Sklar, T. Oprea, E.R.
Prossnitz, J.B. Arterburn, Org. Biomol. Chem. 8 (2010) 2252–2255, and references
therein.
Supplementary material related to this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.
2014.11.008.
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