Enantioselective synthesis of dihydroquinazolinone derivatives catalyzed by a chiral organocatalyst

Article abstract of DOI:10.1039/c7nj00538e

The asymmetric condensation/amine addition cascade sequence of 2-aminobenzamide and aldehydes, catalyzed by a novel chiral organocatalyst, was realized. The organocatalyst was found to be very effective and highly enantioselective for such cascade reactions at room temperature, affording 2,3-dihydroquinazolinones in excellent yields (up to 99%) with enantiomeric excesses of up to 97%. The best level of stereocontrol was obtained for aromatic/aliphatic aldehydes with ortho, para or meta substituents.

Full text of DOI:10.1039/c7nj00538e

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The role of atropisomers on the photo-reactivity and fatigue of
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Enantioselective Synthesis of Dihydroquinazolinone derivatives Catalyzed by
Chiral Organocatalyst
Ayyanar Siva*, Ponmuthu Kottala Vijaya, Madhappan Mariyappan, Veeramanoharan
Ashokkumar, Velu Sadhasivam, Sankar Balakrishnan, Chithiraikumar Chinnadurai and
Sepperumal Murugesan*
Supramolecular and Organometallic Chemistry Lab, Department of Inorganic Chemistry, School
of Chemistry, Madurai Kamaraj University, Maduraiꢀ625 021, Tamilnadu, India.
Abstract: The asymmetric condensation/amine addition cascade sequence of 2ꢀaminobenzamide
and aldehydes catalyzed by novel chiral organocatalyst were realized. The organocatalyst was
found to be a general, highly enantioselective catalyst for such cascade reactions at room
temperature, affording 2,3ꢀdihydroquinazolinones in an excellent yield (up to 99%) and ee’s (up
to 97%). The best level of stereocontrol was obtained for aromatic/aliphatic aldehydes with an
ortho, para and meta substituents.
Keywords: Dihydroquinazolinone, enantioselective synthesis, organocatalyst, Cinchona
alkaloid, bipyridine.
1. Introduction
The 2,3ꢀdihydroquinazolinone derivatives were exhibited very important in
pharmacological activities, such as antitumor, analgesic, antifibrillatory, antibiotic,
antispermatogenic, and vasodilatory efficacy. In addition, it has been reported that their
enantiomers having different bioacitivities.1,2 Consequently, most of the researchers focused to
develop a new methodology for the asymmetric synthesis of 2,3ꢀdihydroquinazolinone
derivatives. A variety of methods have been developed for the synthesis of dihydroquinazolinone
derivatives, the condensation of 2ꢀaminobenzamide with aldehyde is one of the direct method for
the synthesis of 2,3ꢀdihydroquinazolineꢀ4(1H)ꢀones. Number of acid catalysts, such as pꢀ
TSA/NaHSO3,3 TiCl4/Zn,4 CuCl2,5 ionic liquid–water,6 TFA,7 ammonium chloride,8
heteropolyacid (H3PW12O40),9 silicabonded Nꢀpropylsulfamic acid,10 and celluloseꢀSO3H,11 have
been utilized to accomplish this transformation. Most of the reported synthetic protocols were
1

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associated with the use of expensive reagents, extended reaction times, high reaction
temperatures, and also involve tedious workꢀup procedures.
Regardless of the above methods that are available to synthesize dihydroquinazolinones
as racemates,12 enantioselective synthesis of dihydroquinazolinone is not easily achieved since
the aminal stereocenter is sensitive to racemization.13 Cheng et al., reported about the
asymmetric synthesis of dihydroquinazolinones using (S)ꢀTRIP as a catalyst.14 Singh and
coworkers reported the synthesis of 2,3ꢀdihydroquinazolinꢀ4(1H)ꢀones from isatoic anhydride,
aldehyde, amine or ammonium acetate in water under microwave in the presence of Lꢀproline
catalyst.15 In this context, a few methods have been reported using chiral phosphoric acid as
catalysts. Rueping et al., reported the chiral BINOLꢀphosphoric acid as a catalyst in the
asymmetric synthesis of 2,3ꢀdihydroquinazolinones (limited to aromatic aldehydes without an
ortho substituent, 73−93% yields, and 80−92% ee’s).16 Similarly Tian et al.,developed a new
method for the BINOLꢀphosphoric acidꢀcatalyzed asymmetric synthesis of 2,3ꢀ
dihydroquinazolinones from imines and 2ꢀaminobenzamides with substrate diversity (limited to
the use of preformed imines, 54−90% yields, and 83−97% ee’s, at −20 °C).17 Additionally, in
2012, Kesavan et al., described the Sc(III)ꢀindaꢀpyboxꢀcatalyzed enantioselective version.18
Similarly, Tao Deng and coꢀworkers was reported Sc(OTf)3ꢀcatalyzed intramolecular amidation
of imines with a fluorous bis(oxazolines) as a chiral ligand.19 In 2013 Lin and coꢀworkers
reported the application of SPINOLꢀphosphoric acid to this asymmetric condensation reaction.20
Despite these elegant examples, a general, efficient, and mild enantoselective protocol
has yet to be described and would be of a great value because of the importance of optically
active 2,3ꢀdihydroquinazolinones. The synthesized new organocatalysts 221 (Figure 1) was used
as highly enantioselective catalyst for the asymmetric condensation/amine addition cascade
sequence of 2ꢀaminobenzamides and aldehydes. Herein, we present our preliminary results of
this work. A narrow range of substituted 2,3ꢀdihydroquinazolineꢀ4(1H)ꢀones were obtained in
high yields and good enantioselectivities (up to 99% yield, 97% ee′s).
2

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Figure 1: Singleꢀsite and Multi activeꢀsite containing chiral organocatalysts.
2. Results and Discussion
Table 1: Catalytic asymmetric condensation/amine addition reaction of 2ꢀaminobenzamide 3 and
4ꢀmethylbenzaldehyde 4a with different organocatalysts 1(a-d) and 2 at room temperature
Entry
Organocatalyst
Time (h)a
Yield (%)b
ee’s (%)c
Abs.Conf.d
1
2
3
4
5
12
20
26
36
0.5
87
89
73
65
99
42
50
26
30
96
1a
1b
1c
1d
2
3

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aThe condensation/amine addition reaction of 2ꢀaminobenzamide 3 (0.07 mmol), 4ꢀ
methylbenzaldehyde 4a (0.07 mmol), organocatalysts 1(a-d) and 2, with 1 ml of methanol at
room temperature (30 ºC). bIsolated yield of purified material. cEnantiopurity was determined by
HPLC analysis using a chiral column (Chiralcel ODꢀH) with hexane–IPA as an eluent. (See
supporting information (Figure: S34ꢀS38). dAbsolute configuration was determined by
comparison of the previously reported HPLC retention time.16ꢀ20
The initial studies were carried out using the reaction of 2ꢀaminobenzamide 3 and 4ꢀ
methylbenzaldehyde 4a as the model substrates with 1 mol % of different organocatalyst in
methanol at room temperature (30 ºC). This revealed that 1a-1d are indeed able to act as
catalysts, though their activity and stereoselectivity are insufficient, even with increased their
reaction time from 12 to 36 hrs (entries 1–4 in Table 1). However, our newly synthesized
organocatalyst 2 influenced the reaction rate and we achieved very good yields up to 99% and
ee’s up to 96% (entry 5, Table 1) under the same reaction conditions in less time (only 30 min).
This is due to the multiple active sites are presented in the organocatalysts 2 which can be
increased the number of ion pair interactions between the catalyst and the substrate and also πꢀπ
interaction between the quinoline moiety of the catalyst and aromatic aldehyde substrate.
Further, we believe that the simultaneous cooperative neighboring group of the cinchonium
cation interacts with the substrates.
Then, the asymmetric condensation/amine addition reaction was carried out in different
solvents using organocatalyst 2 at room temperature, with other parameters kept as constant. The
optimization of the condensation/amine addition reaction of 2ꢀaminobenzamide 3 with
4ꢀmethylbenzaldehyde 4a, was carried out under organocatalytic conditions, the obtained results
(Table 2) show that the change of solvent is found to be an important, crucial factor in the
condensation/amine addition reaction due to the polarity of the solvents. The product yields and
ee’s have been found to be poor using aprotic solvents, such as acetone, chloroform and DCM
(entries 1ꢀ3, Table 2), and we found very good yields and ee’s of 5a when using protic polar
solvents, such as methanol and ethanol (entries 4ꢀ5, Table 2). Further, lowering the temperature
to 0 °C remarkably reduced the chemical yield and enantioselectivity (entry 6, Table 2).
Furthermore, the reaction was carried out room temperature condition in presence of polar
aprotic solvents obtained moderate yields and good ee’s (entry 7 and 8, Table 2). From the
observed results of Table 2, using non polar solvents we got better yield and moderate ee’s
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(entry 9 and 10, Table 2). Through extensive screening, the optimized reaction conditions are
found to be 1 mol% of organocatalyst 2, and methanol as solvent at room temperature.
Table 2: Effect of solvent and reaction condition on the asymmetric condensation/amine
addition reaction of 2ꢀaminobenzamide 3 and 4ꢀmethylbenzaldehyde 4a with organocatalyst 2 at
room temperature.
Entry
Solvent
Time (h)a
Yield (%)b
ee’s (%)c
Abs.Conf.d
1
2
Chloroform
Acetone
12
12
12
6
57
52
49
87
99
85
75
80
57
63
36
34
27
64
96
59
84
86
67
60
3
Dichloromethane
Ethanol
4
5
Methanol
Methanole
DMF
0.5
1.0
7
6
7
8
DMSO
7
9
Toluene
10
10
10
Cyclohexane
aThe condensation/amine addition reaction of 2ꢀaminobenzamide
3
(0.07 mmol),
4ꢀmethylbenzaldehyde 4a (0.07 mmol), organocatalyst 2, with 1 ml of methanol at room
b
c
temperature (30 ºC). Isolated yield of purified material. Enantiopurity was determined by
HPLC analysis using a chiral column (Chiralcel ODꢀH) with hexane–IPA as an eluent. (See
supporting information (Figure: S39ꢀS48). dAbsolute configuration was determined by
comparison of the previously reported HPLC retention time.16ꢀ20 e Reaction carried out under
cold condition (0 ºC).
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Table 3: Catalytic asymmetric condensation/amine addition reaction of 2ꢀaminobenzamide 3 and
various substituted aromatic aldehydes 4 (a-o) under optimized conditionsa,b,c,d
O
O
O
organocatalyst 2 (1 mol%)
CH3OH, RT (30οC)
NH2
NH2
NH
H
R
R
H
N
H
3
4 (a-r)
5 (a-r)
R = Ph, 4-CH3Ph, 2-CH3Ph, 4-OCH3Ph, 3,4-OCH3Ph, 4-ClPh, 2-ClPh,
2,4-ClPh, 2-OHPh, 4-FPh, 2,4-FPh, 4-BrPh, 4-NO2Ph, 2-NO2Ph, 4-CNPh,
-cyclohexyl, -CH3, -CH2CH3
99% yield, 96% ee′s
98% yield, 97% ee′s
98% yield, 95% ee′s
99% yield, 91% ee′s
97% yield, 84% ee′s
98% yield, 85% ee′s
97% yield, 95% ee′s
95% yield, 70% ee′s
97% yield, 80% ee′s
98% yield, 75% ee′s
98% yield, 87% ee′s
96% yield, 95% ee′s
98% yield, 83% ee′s
99% yield, 90% ee′s
97% yield, 95% ee′s
94% yield, 90% ee′s
e No reaction
e No reaction
aThe condensation/amine addition reaction of 2ꢀaminobenzamide 3 (0.07 mmol), various
aromatic aldehydes 4 (a-o) (0.07 mmol), organocatalyst 2, with 1 ml of methanol at room
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b
c
temperature (30 ºC). Isolated yield of purified material. Enantiopurity was determined by
HPLC analysis using a chiral column (Chiralcel ODꢀH) with hexane–IPA as an eluent. dAbsolute
configuration was determined by comparison of the HPLC retention time.16ꢀ20 eNo reaction was
observed under optimised reaction condition.
With these optimized reaction conditions identified, our attention turned to an
examination of the scope of catalytic asymmetric condensation/amine addition cascade reaction.
The reactions were carried out using organocatalyst 2 under the optimized conditions, and the
results are summarized in Table 3. All reactions proceeded in generally excellent yields with
good to excellent enantioselectivities. In general, for the first time, a number of different
aromatic aldehydes with electronꢀdonating and ꢀwithdrawing substituents were successfully
applied in the reaction with 2ꢀaminobenzamide. The corresponding (S)ꢀ2,3ꢀ
dihydroquinazolinones 5aꢀ5o were isolated in good yields (up to 99%) and excellent
enantioselectivities (up to 97%, Table 3). Further, the rate of the reaction does not affect in the
presence of electron donating/withdrawing substitution on the aromatic ring of the aldehyde at
various positions. In addition to that the reaction were carried out in the presence of aliphatic
aldehydes such as cyclohexanecarbaldehyde, acetaldehyde, propionaldehyde with
2ꢀ
aminobenzamide. Among these aliphatic aldehyde, cyclohexanecarbaldehyde mediated reaction
gave better yield (94%) and ee’s (90%) than the other two aliphatic aldehydes (Table 3, entry 5pꢀ
5r) under optimised reaction conditions. This may be due to the lack of πꢀ π interaction between
the quinoline moity of the catalyst with the substrate.
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Figure 2: Plausible mechanism for the condensation/amine addition reaction.
Further, we proposed a possible mechanism (Figure 2) for the formation of
dihydroquinazolinone derivatives, the amine is more reactive than the amide, hence amine is
reacted with aldehyde to form imine at the same time hydrogen bonded with the catalyst
(bipyridine, free –OH group containing catalyst) in intermediate III and also strong ion pair
interaction between the enolate anion of the intermediate IV with the quaternary ammonium ion
of the catalyst. Simultaneously π−π interaction is more between the catalyst as well as the
aromatic ring of the substrate in intermediate IV. Further, the intermediate IV loss of one proton
to form intermediate V. Furthermore, the intermediate V consecutively loss of water molecule
and to form an imine derivative VI, then the amide group containing nitrogen lone pair attack the
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imine carbon to form cyclized intermediate VII. After that the proton transfer taking place in
intermediate VII to form intermediate VIII. Finally the 2ꢀ(benzylideneamino)benzamide was
cyclised to form our desired product IX with high yield and ee’s and eliminate the catalyst which
is used for another cycle.
3. Conclusions
In conclusion, we have developed an efficient and practical protocol to synthesize
optically active dihydroquinazolinones derivatives by chiral organocatalyzed asymmetric
condensation/amine addition cascade sequence of 2ꢀaminobenzamide and wide range of
aromatic/aliphatic aldehydes. Following this methodology, a series of 2,3ꢀdihydroquinazolinones
were obtained in excellent yields (up to 99%) with excellent ee’s (up to 97%) at room
temperature. In addition, we found that a different positionꢀsubstituent on the aryl group of
aromatic aldehydes appears to have a remarkable effect on the enantioselectivity. The best level
of stereocontrol was obtained for aromatic aldehydes with an ortho, para and meta substituents.
4. Experimental Methods
4.1. Materials and Methods
All the chemicals and reagents were used in this work as an analytical grade. p-
Tolualdehyde,
veratraldehyde,
4ꢀbromobenzaldehyde,
4ꢀchlorobenzaldehyde,
2ꢀ
chlorobenzaldehyde, 4ꢀnitrobenzaldehyde, 2ꢀnitrobenzaldehyde, 2,4ꢀdichlorobenzaldehyde, 2,4ꢀ
diflurobenzaldehyde, 4ꢀflurobenzaldehyde, and salicylaldehyde, were purchased from Sigma
Aldrich.
2ꢀAminobenzamide, 4ꢀcyanobenzaldehyde, 2ꢀmethylbenzaldehyde and 4ꢀ
methoxybenzaldehyde were purchased from Alfa Aesar and benzaldehyde was obtained from
Merck and all the solvents were obtained from laboratory grade. The melting points were
1
measured in open capillary tubes and are uncorrected. The H and 13C NMR spectra were
recorded on a Bruker (Avance) 300 MHz NMR instrument using TMS as an internal standard,
CDCl3 & DMSO-d6 as a solvent. Standard Bruker software was used throughout. Chemical shifts
are given in parts per million (δꢀscale) and the coupling constants are given in Hertz. Silica gelꢀG
plates (Merck) were used for TLC analysis with a mixture of nꢀhexane and ethyl acetate as an
eluent. The HPLC was recorded in SHIMADZU LCꢀ6AD with a chiral column (Chiralcel ODꢀ
H), using HPLC grade nꢀhexane and isopropanol as solvents.
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4.2. General procedure for the synthesis of enantioselective dihydroquinazolinones
derivatives using chiral organocatalyst (5a-o)
2ꢀAminobenzamide (7 mmol) and aromatic aldehydes (7 mmol) were dissolved in 10 mL
of methanol and 1 mol% of organocatalyst was added and the mixture was stirred at room
temperature, the completion of reaction as indicated by TLC. After completion of the reaction,
the solid was filtered and recrystallized with acetone, to get pure product without column
chromatography.
4.3. Characterization of dihydroquinazolinones derivatives (5)
4.3.1. 2-(p-tolyl)-2,3-dihydroquinazolin-4(1H)-one (5a)
White solid; m.p. 232ꢀ233°C; 99% yield; 96% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 6.26 min, t (minor) = 22.60
min]. [α]D25 = +54.8 (c, 0.98, THF). 1H NMR (300 MHz, DMSOꢀd6) δ 8.26 (s, 1H), 7.58 (d, 1H,
J = 4.92 Hz), 7.34 (d, 2H, J = 3.99 Hz), 7.18 (t, 3H, J = 5.77 Hz), 6.75 (s, 1H), 6.74ꢀ6.63 (m,
2H), 5.69 (s, 1H), 2.27 (s, 3H). 13CNMR (75 MHz, DMSOꢀd6) δ 164.28, 148.40, 139.09, 138.25,
138.83, 129.32, 127.87, 127.25, 117.62, 115.41, 114.93, 66.86, 21.94; ESIꢀMS (m/z) :
C15H14N2O : Calculated : 238.1106, Found : 239.3714.
4.3.2. 2-(o-tolyl)-2,3-dihydroquinazolin-4(1H)-one (5b)
White solid; m.p. 230ꢀ232°C; 99% yield; 91% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 6.27 min, t (minor) = 21.91
min]. [α]D25 = +32.6 (c, 1.05, THF). 1H NMR (300 MHz, DMSOꢀd6) δ 8.27 (s, 1H), 7.60 (d, 2H,
J = 7.68 Hz), 7.36 (d, 2H, J = 7.68 Hz), 7.19 (t, 3H, J = 9.58 Hz), 7.08 (s, 1H), 6.75ꢀ6.64 (m,
2H), 5.70 (s, 1H), 2.28 (s, 3H). 13CNMR (75 MHz, DMSOꢀd6) δ 164.61, 148.74, 139.48, 138.61,
134.20, 129.69, 128.22, 127.61, 117.98, 115.79, 115.29, 67.20, 21.58; ESIꢀMS (m/z) :
C15H14N2O : Calculated: 238.1106, Found : 239.2410.
4.3.3. 2-(4-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (5c)
White solid; m.p. 177ꢀ178°C; 98% yield; 95% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 6.24 min, t (minor) = 22.46
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min]. [α]D25 = +17.7 (c, 1.57, THF). 1H NMR (300 MHz, DMSOꢀd6) δ 8.21 (s, 1H), 7.60 (d, 1H,
J = 7.53 Hz), 7.41 (d, 2H, J = 8.37 Hz), 7.23 (t, 1H, J = 7.51 Hz), 7.02 (s, 1H), 6.93 (d, 2H, J =
8.34 Hz), 6.73 (d, 1H, J = 8.01 Hz), 6.67 (t, 1H, J = 7.42 Hz), 5.70 (s, 1H), 3.73 (s, 3H).
13CNMR (75 MHz, DMSOꢀd6) δ 164.75, 160.70, 148.88, 134.25, 134.22, 129.08, 128.27,
118.06, 115.80, 115.33, 114.50, 67.21, 55.99; ESIꢀMS (m/z) : C15H14N2O2 : Calculated :
254.1055, Found : 255.1434.
4.3.4. 2-(3,4-dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (5d)
White solid; m.p. 211ꢀ213°C; 98% yield; 97% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 3.27 min, t (minor) = 14.29
1
min]. [α]D25 = +27.3 (c, 2.73, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.20 (s, 1H), 7.61 (d, 1H,
J = 7.68 Hz), 7.24 (t, 1H, J = 7.63 Hz), 7.12 (s, 1H), 6.99 (d, 2H, J = 12.81 Hz), 6.93 (d, 1H, J =
8.19 Hz), 6.75 (d, 1H, J = 8.1 Hz), 6.67 (t, 1H, J = 7.39 Hz), 5.69 (s, 1H), 3.74 (s, 3H), 3.73 (s,
13
3H). CNMR (75 MHz, DMSOꢀd6) δ 164.67, 149.45, 148.91, 134.42, 134.13, 128.21, 120.07,
118.05, 115.89, 115.31, 112.11, 111.45, 67.42, 56.41, 56.31; ESIꢀMS (m/z) : C16H16N2O3 :
Calculated : 284.1161, Found (M+) : 284.1410.
4.3.5. 2-phenyl-2,3-dihydroquinazolin-4(1H)-one (5e)
White solid; m.p. 224ꢀ226°C; 97% yield; 95% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 6.37 min, t (minor) = 19.79
1
min]. [α]D25 = +29.2 (c, 1.82, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.31 (s, 1H), 7.59 (d, 1H,
J = 7.71 Hz), 7.47 (d, 2H, J = 7.56 Hz), 7.35 (d, 3H, J = 7.77 Hz), 7.23 (t, 1H, J = 6.94 Hz), 7.12
(s, 1H), 6.74ꢀ6.64 (m, 2H), 5.73 (s, 1H). 13CNMR (75 MHz, DMSOꢀd6) δ 164.59, 148.70,
142.45, 134.27, 129.34, 129.21, 128.25, 127.68, 118.05, 115.75, 115.30, 67.40.
4.3.6. 2-(2-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (5f)
Orange solid; m.p. 220ꢀ221°C; 97% yield; 84% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 3.27 min, t (minor) = 20.53
1
min]. [α]D25 = +35.8 (c, 1.73, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.85 (s, 1H), 7.89 (s, 1H),
7.66 (d, 1H, J = 7.65 Hz), 7.57ꢀ7.49 (m, 3H), 7.39 (d, 1H, J = 7.41 Hz), 7.32 (t, 1H, J = 7.41 Hz),
13
6.96ꢀ6.92 (m, 2H), 6.55 (s, 1H), 5.75 (s, 1H). CNMR (75 MHz, DMSOꢀd6) δ 169.54, 163.55,
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160.52, 146.52, 133.90, 132.69, 132.34, 131.33, 128.84, 126.89, 120.16, 119.54, 119.26, 61.15;
ESIꢀMS (m/z) : C14H12N2O2 : Calculated : 240.0899, Found (M+1) : 241.1124.
4.3.7. 2-(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (5g)
Pale yellow solid; m.p. 197ꢀ198°C; 97% yield; 80% ee, determined by HPLC [Chiralcel
ODꢀH, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 6.32 min, t (minor) =
1
36.83 min]. [α]D25 = +16.4 (c, 1.65, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.83 (s, 1H), 8.27
(t, 1H, J = 7.03 Hz), 8.15 (d, 1H, J = 7.71 Hz), 7.91 (s, 1H), 7.78 (t, 1H, J = 7.56 Hz), 7.66ꢀ7.56
(m, 3H), 7.45 (d, 1H, J = 7.77 Hz), 5.77 (s, 1H). 13CNMR (75 MHz, DMSOꢀd6) δ 168.32,
161.86, 149.94, 137.66, 135.18, 132.80, 131.47, 130.68, 129.98, 128.96, 127.00, 67.42;
C14H11ClN2O : Calculated : 258.0560, Found (M+1) : 259.1007.
4.3.8. 2-(2-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (5h)
Pale yellow solid; m.p. 202ꢀ204°C; 96% yield; 95% ee, determined by HPLC [Chiralcel
ODꢀH, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 3.28 min, t (minor) =
1
78.29 min]. [α]D25 = +15.02 (c, 1.29, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.79 (s, 1H), 8.14
(d, 1H, J = 8.19 Hz), 7.98 (s, 1H), 7.81 (d, 1H, J = 7.68 Hz), 7.63ꢀ7.51 (m, 4H), 7.35 (t, 1H, J =
7.45 Hz), 7.21 (d, 1H, J = 7.71 Hz), 5.75 (s, 1H). 13CNMR (75 MHz, DMSOꢀd6) δ 168.45,
158.74, 150.00, 136.10, 134.23, 133.13, 132.63, 131.56, 131.08, 130.42, 129.71, 128.62, 127.15,
64.87.
4.3.9. 2-(2,4-dichlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (5i)
Pale yellow solid; m.p. 162ꢀ164°C; 95% yield; 70% ee, determined by HPLC [Chiralcel
ODꢀH, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 3.28 min, t (minor) =
1
19.82 min]. [α]D25 = +36.3 (c, 1.35, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.73 (s, 1H), 8.15
(d, 1H, J = 8.49 Hz), 7.89 (s, 1H), 7.79 (t, 1H, J = 8.77 Hz), 7.61 (d, 2H, J = 9.09 Hz), 7.53 (t,
1H, J = 7.75 Hz), 7.35 (t, 1H, J = 7.47 Hz), 7.21 (d, 1H, J = 7.8 Hz), 5.75 (s, 1H). 13CNMR (75
MHz, DMSOꢀd6) δ 164.99, 149.07, 134.86, 131.31, 128.79, 126.05, 118.88, 115.89, 113.04,
112.75, 105.84, 105.50, 105.15, 62.05.
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4.3.10. 2-(4-fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one (5j)
White solid; m.p. 201ꢀ203°C; 98% yield; 85% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 6.28 min, t (minor) = 43.72
min]. [α]D25 = +44.6 (c, 1.29, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.58 (s, 1H), 8.20 (s, 1H),
1
8.02 (t, 2H, J = 6.18 Hz), 7.90 (d, 1H, J = 7.71 Hz), 7.53 (t, 1H, J = 6.75 Hz), 7.41ꢀ7.31 (m, 3H),
7.20 (d, 1H, J = 7.80 Hz), 5.75 (s, 1H). 13CNMR (75 MHz, DMSOꢀd6) δ 167.92, 161.46, 149.54,
137.26, 134.78, 132.37, 131.07, 130.28, 129.58, 128.56, 126.61, 65.08; C14H11FN2O : Calculated
: 242.0855, Found (M+) : 242.1211.
4.3.11. 2-(2,4-difluorophenyl)-2,3-dihydroquinazolin-4(1H)-one (5k)
White solid; m.p. 180ꢀ182°C; 98% yield; 75% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 3.27 min, t (minor) = 44.29
25
1
min]. [α]D = +51.7 (c, 1.21, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.26 (s, 1H), 7.64ꢀ7.57
(m, 2H), 7.29ꢀ7.23(m, 2H), 7.12 (t, 1H, J = 8.49 Hz), 7.05 (s, 1H), 6.74ꢀ6.68 (m, 2H), 6.02 (s,
13
1H). CNMR (75 MHz, DMSOꢀd6) δ 164.04, 148.12, 133.91, 130.43, 127.84, 125.10, 117.93,
114.94, 112.13, 111.80, 104.89, 104.55, 104.21, 61.15; C14H10F2N2O : Calculated : 260.0761,
Found (M+1) : 261.1131.
4.3.12. 2-(4-bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (5l)
Pale yellow solid; m.p. 199ꢀ200°C; 98% yield; 83% ee, determined by HPLC [Chiralcel
ODꢀH, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 8.14 min, t (minor) =
1
20.96 min]. [α]D25 = +73.5 (c, 1.05, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.58 (s, 1H), 7.88
(t, 3H, J = 12.04 Hz), 7.76 (d, 2H, J = 8.28 Hz), 7.64 (s, 1H), 7.53 (t, 1H, J = 7.5 Hz), 7.34 (t,
1H, J = 7.5 Hz), 7.21 (d, 1H, J = 7.83 Hz), 5.75 (s, 1H). 13CNMR (75 MHz, DMSOꢀd6) δ 167.85,
161.67, 149.57, 135.15, 132.52, 132.34, 131.24, 130.25, 128.29, 126.60, 126.25, 64.18;
C14H11BrN2O : Calculated : 302.0055, Found (M+1) : 303.1315.
4.3.13. 2-(4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (5m)
Yellow solid; m.p. 200ꢀ201°C; 99% yield; 90% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 6.29 min, t (minor) = 79.28
1
min]. [α]D25 = +63.7 (c, 1.32, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.72 (s, 1H), 8.37 (d, 2H,
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J = 8.58 Hz), 8.19 (d, 2H, J = 8.61 Hz), 7.82 (d, 1H, J = 7.56 Hz), 7.62 (s, 1H), 7.54 (t, 1H, J =
13
7.11 Hz), 7.34 (t, 1H, J = 7.32 Hz), 7.25 (d, 1H, J = 7.74 Hz), 5.79 (s, 1H). CNMR (75 MHz,
DMSOꢀd6) δ 168.45, 161.19, 149.51, 141.82, 132.55, 131.45, 130.82, 130.44, 129.79, 127.43,
124.88, 66.85.
4.3.14. 2-(2-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (5n)
Yellow solid; m.p. 191ꢀ192°C; 97% yield; 95% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 3.27 min, t (minor) = 90.53
min]. [α]D25 = +27.3 (c, 1.02, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.84 (s, 1H), 8.15 (d, 2H,
1
J = 7.92 Hz), 7.92 (d, 1H, J = 7.23 Hz), 7.84ꢀ7.80 (m, 2H), 7.60 (s, 1H), 7.55 (d, 1H, J = 7.62
Hz), 7.37 (t, 1H, J = 7.5 Hz), 7.19 (d, 1H, J = 7.89 Hz), 5.70 (s, 1H). 13CNMR (75 MHz, DMSOꢀ
d6) δ 168.06, 158.72, 149.64, 149.22, 134.40, 132.76, 132.28, 130.23, 129.99, 129.63, 127.00,
125.07, 64.69; C14H11N3O3 : Calculated : 269.0800, Found (M+) : 269.1132.
4.3.15. 4-(4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)benzonitrile (5o)
Yellow solid; m.p. 250ꢀ252 °C; 98% yield; 87% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 6.25 min, t (minor) = 91.25
25
1
min]. [α]D = +60.1 (c, 1.71, THF). H NMR (300 MHz, DMSOꢀd6) δ 8.68 (s, 1H), 8.14ꢀ8.10
(m, 3H), 8.04 (d, 1H, J = 1.83 Hz), 7.83 (d, 1H, J = 7.68 Hz), 7.61 (s, 1H), 7.54 (t, 1H, J = 7.62
Hz), 7.36 (t, 1H, J = 7.48 Hz), 7.24 (d, 1H, J = 7.83 Hz), 5.75 (s,1H). 13CNMR (75 MHz,
DMSOꢀd6) δ 167.98, 161.30, 149.18, 139.84, 133.34, 132.17, 130.08, 129.93, 129.36, 129.96,
119.67, 118.94, 65.20; C15H11N3O : Calculated : 249.0902, Found (M+) : 249.1511.
4.3.16. 2-cyclohexyl-2,3-dihydroquinazolin-4(1H)-one (5p)
White solid; m.p. 178ꢀ180 °C; 94% yield; 90% ee, determined by HPLC [Chiralcel ODꢀ
H, nꢀhexane /iꢀpropanol = 80/20, 1mL/min, λ = 254 nm, t (major) = 7.24 min, t (minor) = 40.25
25
1
min]. [α]D = +27.4 (c, 1.07, THF). H NMR (300 MHz, DMSOꢀd6) δ 1.12 (s, 5H), 1.54ꢀ1.70
(m, 6H), 4.44 (s, 1H), 6.57 (s, 1H), 6.58ꢀ6.62 (m, 1H), 6.74 (d, 1H, J = 6.39 Hz), 7.17ꢀ7.21 (m,
13
1H), 7.55 (d, 1H, J = 6.36 Hz), 7.89 (s, 1H). CNMR (75 MHz, DMSOꢀd6) δ 164.21, 148.82,
133.49, 127.73, 116.96, 115.48, 114.74, 69.04, 43.35, 27.52, 27.29, 26.41, 26.17, 26.00.
C14H18N2O : Calculated : 230.1419, Found (M+) : 230.1524.
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Acknowledgements
This work was financially supported by the Department of Science and Technology,
SERB, Extramural Major Research Project (Grant No. EMR/2015/000969), Department of
Science and Technology, New Delhi, India (Grant No. SR/F/1584/2012ꢀ13), University Grants
Commission, New Delhi, India (Grant No. UGC No.41ꢀ215/2012 (SR).
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Graphical Abstract
Enantioselective Synthesis of Dihydroquinazolinone derivatives Catalyzed by
Chiral Organocatalyst
Ayyanar Siva*, Ponmuthu Kottala Vijaya, Madhappan Mariyappan, Veeramanoharan
Ashokkumar, Velu Sadhasivam, Sankar Balakrishnan, Chithiraikumar Chinnadurai
Sepperumal Murugesan*
and
The asymmetric condensation/amine addition cascade sequence of 2-aminobenzamide and
aldehydes catalyzed by novel chiral organocatalyst are reported. The organocatalyst is found to
be a good and highly enantioselective catalysts for such cascade reactions at room
temperature, affording 2,3-dihydroquinazolinones in an excellent yield (up to 99%) and ee’s (up
to 97%).
O
O
N
O
organocatalyst 2 (1 mol%)
CH3OH, RT (30 οC)
N
NH2
NH2
NH
HO
H
R
H
N
OH
N
H
R
N
N
N
2 Br
3
4 (a-r)
5 (a-r)
2
18 examples