One-Pot Copper(I)-Catalyzed Ligand/Base-Free Tandem Cyclooxidative Synthesis of Quinazolinones

Article abstract of DOI:10.1021/acs.joc.6b00599

A novel and efficient Cu(I)-catalyzed ligand- and base-free multipathway domino strategy has been developed for the synthesis of 2-substituted quinazolinones. The reaction utilizes 2-bromobenzamide and multiform substrates such as aldehydes, alcohols, and methyl arenes for a one-pot protocol, whereas TMSN₃ is used as a nitrogen source. A wide range of substrate scope, functional group tolerance, and operational simplicity are synthetically useful features.

Full text of DOI:10.1021/acs.joc.6b00599

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Article
One Pot Copper(I)-Catalyzed Ligand/Base Free
Tandem Cyclooxidative Synthesis of Quinazolinones
Kapil Upadhyaya, Ravi Kumar Thakur, Sanjeev K. Shukla, and Rama Pati Tripathi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00599 • Publication Date (Web): 25 May 2016
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One Pot Copper(I)-Catalyzed Ligand/Base Free Tandem
Cyclooxidative Synthesis of Quinazolinones
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Kapil Upadhyaya,† Ravi Kumar Thakur,† Sanjeev K. Shukla,║ Rama Pati Tripathi,*†
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║
†Medicinal and Process Chemistry Division, Sophisticated Analytical Instrument Facility,
CSIR-Central Drug Research Institute (CSIR-CDRI), Sector 10, Jankipuram Extension, Sitapur
Road, Lucknow-226031, India.
ABSTRACT
A novel and efficient Cu(I) catalyzed ligand and base free multi pathway domino strategy has
been developed for the synthesis of 2-substituted quinazolinones. Reaction utilizes 2-
bromobenzamide and multiform substrates such as aldehydes, alcohols and methyl arenes for
one pot-protocol whereas TMSN3 used as a nitrogen source. A wide range of substrate scope,
functional group tolerance and operational simplicity are synthetically useful features.
INTRODUCTION
Quinazolin-4-(3H)-one represents a class of annulated six-membered nitrogen heterocycle
(azaheterocycles) and a core structural component in a variety of natural products and
biologically active compounds. Because of their ubiquitous nature and importance as
pharmacophore in drug candidates, they are assigned as privileged structure.1 They are endowed
with numerous pharmacological and biological activities such as anticancer,2 antimalarial,3
antihypertensive,4 anti-inflammatory,5 and anti-tuberculosis activities.6 In view of their
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remarkable significance, enormous efforts have been devoted toward efficient and convenient
strategies for the construction of quinazoline skeleton, especially 2-substituted quinazolines as
summarized in Figure 1.
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Figure 1. Methods for the synthesis of Quinazolin-4-(3H)-one
Conventionally synthesis of quinazolinone involves typical methodologies using
acid/base promoted condensation reaction of carboxylic acid derivatives with 2-aminobenzoic
acid or its derivatives7 and cascade reaction of aldehydes with o-aminobenzamides involving
condensation followed by oxidation of the aminal intermediate.8 However these protocols suffer
from certain disadvantages such as multistep synthesis, use of coupling agents/bases, use of
ligand or additives, harsh reaction conditions, low yields, stoichiometric or large excess amounts
of toxic oxidants and use of highly reactive 2-aminobenzamide. Another drawback associated
with these methodologies is the use of aldehyde which is relatively unstable and synthesized
from readily available alcohols via oxidation with different agents. Guo et al. 9 has reported an
efficient synthesis of quinazolinone from 2-bromobenzamide and aqueous ammonia as a source
of nitrogen. Moreover, while holding merit, the strategy suffers from drawbacks such as use of
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the excess of ammonia as well as ligand during the reaction. Apart from these, other
methodologies have also been used involving the coupling of 2-halobenzoic acid or its
derivatives with ammonia sources which include benzylamines,10 amidines,11 amino acids,12 and
amides13 while all these approaches are efficient but suffered from drawbacks such as a use of
the stoichiometric amounts of bases which lead to the generation of salt wastes. Alternatively, an
interesting palladium catalyzed oxidative CO insertion reacting with 2-aminobenzamide has
reported by Wu and coworkers.14 Recently, condensation of 2-aminobenzamide with aryl methyl
ketones15 and keto alkynes16 was reported. During recent years benzyl alcohols have been used
for the synthesis of quinazolinones using Ir,17 Pt,18 and Pd19 as expensive and heavy metal
catalysts for dehydrogenative oxidative cyclization whereas report on the use of methyl arenes or
heteroarenes for the synthesis of quinazolinone is rare.20 Considering all these facts we have next
focused on the designing of a cascade reaction which uses aldehyde, alcohols and methyl arenes
to access quinazolinones. Herein we report the use of aldehyde, alcohol and methyl
arenes/heteroarenes as coupling partners, which are cost effective and easily available.
Furthermore, the protocol is free from use of ligand and base, uses TMSN3 as nitrogen source
and air/TBHP as oxidant.
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RESULTS AND DISCUSSION
Taking into account on the use of trimethylsilyl azide (TMSN3) as ammonia equivalent in cross
coupling reactions to afford the corresponding primary amine as the sole product,21 we initiated
our investigation on a model reaction of 2-bromobenzamide (1a), benzaldehyde (2a) and TMSN3
to optimize various reaction parameters as represented in Table 1.
Table 1. Optimizing reaction parameters for the condensation of 2-bromobenzamides with
aldehyde.a
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S.No. Azide
equivalent
Base
Catalyst
Solvent
T
(°C)
Yieldb (%)
1.
2.
3.
4.
5.
6.
7.
8.
TMSN3 (2 eq.)
TMSN3 (2 eq.)
TMSN3 (2 eq.)
TMSN3 (2 eq.)
TMSN3 (2 eq.)
TMSN3 (2 eq.)
TMSN3 (2 eq.)
TMSN3 (1.0 Eq.)
TMSN3 (3 Eq.)
NaN3 (2.0 Eq.)
TMSN3 (2 eq.)
TMSN3 (2 eq.)
TMSN3 (2.0 Eq.)
TMSN3 (2.0 Eq.)
TMSN3 (2.0 Eq.)
TMSN3 (2.0 Eq.)
TMSN3 (2.0 Eq.)
TMSN3 (2.0 Eq.)
TMSN3 (2.0 Eq.)
TMSN3 (2.0 Eq.)
TMSN3 (2.0 Eq.)
CuCl
Cu(OAc)2
Cu2O
Cu(OTf)2
CuI
CuBr
FeCl3
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
80°C
66
72
60
65
88
76
NR
60
87
20
42
48
75
64
74
62
68
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.c
21.d
K2CO3
Cs2CO3
PhCl
PEG-400
Dioxane
iPrOH
DMSO
DMSO
DMSO
DMSO
100°C 77
70°C
80°C
80°C
71
85
69
CuI
aUnless otherwise noted, the reactions were carried out with 1a (0.5 mmol), 2a (0.6 mmol), catalyst (0.05 mmol),
b
c
and solvent (1.5 mL) at 80°C in a sealed tube under air atmosphere for 24 h. Isolated yield of 3aa. 20 mol% of
catalyst used. d5 mol% of catalyst used
Subsequent screening of the different copper salts and FeCl3 with DMSO as a solvent at
80°C under air atmosphere was carried out (Table 1, entries 1-7). Among all the metal salts used,
CuI exhibited relatively higher catalytic activity whereas no product was formed with FeCl3. The
amount of TMSN3 used was also investigated. As evident from the results the transformation
was affected when the TMSN3 was reduced from 2 equiv to 1 equiv, resulted in a relatively
lower yield of 3aa (Table 1, entry 8) whereas no appreciable change was observed when loading
of TMSN3 was increased to 3 equiv. (Table 1, entry 9). However changing the azide from
TMSN3 to NaN3 resulted in a poor yield of 3aa (Table 1, entry 10). Addition of base proved to be
detrimental to the reaction as seen from the results while use of K2CO3 afforded only 42% of
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desired product whereas Cs2CO3 did not result in any significant improvement in the yield of the
product (Table 1, entries 11, 12). Screening of solvents revealed that DMSO was the best solvent
among othe solvents (Table 1, entries 13-17). It was also observed that green solvent such as
PEG-400 also afforded a good yield of the product. The effect of temperature on product yield
was also monitored and it was found out that increasing or decreasing the reaction temperature
from 80°C to 100°C and 70°C resulted in relatively less yield i.e. 77% and 71% respectively
(Table 1, entries 18 & 19). No appreciable change in the yield was observed by increasing the
catalyst loading from 10% to 20%. However, a decrease in the catalyst loading to 5% resulted in
only 69% yield of the desired product (Table 1, entries 20 & 21).
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Under the optimum reaction conditions (Table 1, entry 5), the scope and generality of this
CuI-catalyzed domino reaction affording 2-substituted quinazolinones were subsequently
investigated (Scheme 1).
Scheme 1. Scope of the Reaction for Synthesis of Various Quinazolin-4(3H)-ones from
aldehydes.a
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aReaction conditions: 1a (0.5 mmol), aldehyde 2a-v (0.6 mmol), TMSN3 (1.0 mmol), CuI (0.05 mmol), DMSO (1.5
c
mL), 80 °C, air, 24 h. The yields below the structure are isolated yields. bReaction run for 48 hours. 0.75 mmol of
aldehyde used. d2 ml of formaldehyde used.
The reactions with aryl substituted aldehydes bearing electron donating or electron withdrawing
groups proceeded smoothly to provide the desired products 3aa-l in 64-89% yields. It is
noteworthy to mention that fused aryl (e.g., 3am) and heteroaryl (e.g., 3an-aq) aldehydes were
also well tolerated in this reaction producing corresponding products in good yields. To our
delight, both alkenyl- (e.g., 3ar), benzyl- (e.g., 3au) and alkyl-substituted aldehydes (e.g., 3as-t)
were also well tolerated during this transformation to generate the corresponding products in
good to moderate yields. A series of differently substituted 2-bromobenzamides such as methyl
and methoxy were also successfully used in this tandem reaction to afford 2-substituted
quinazolinones (3ba-cb) in yields ranging from 62-84%.
After the successful synthesis of 2-substituted quinazolinones from aldehydes attempts to
extend this methodology to alcohols and methyl arenes as substrates were then investigated.
Encouraged by the previous reports of the oxidant’s use in domino dual oxidative C-N coupling
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reactions,20 a series of oxidants were additionally screened for the above-optimized reaction
condition for the synthesis of quinazolinones as shown in Table 2. Among the various oxidants
(TBHP, DTBP, DDQ and K2S2O8) examined, we observed that two equivalents of TBHP proved
to be the best yielding oxidant to access 2-substituted quinazolinone using alcohol instead of
aldehyde in the three component reaction (Table 2, entries 1-4). While DTBP yielded 71% of the
product, the other two oxidants DDQ and K2S2O8 proved to be inefficient. With two equiv. of
TBHP in the case of methyl arenes the yield of the product 3aa was only 60%, but increasing
TBHP to 3 equiv the yield was improved to 71%. Any further increase in the amount of TBHP
(4.0 eqiv.) reduced the yield to 63% (Table 2, entries 5-7).
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Table 2. Optimization of the Reaction Conditions for the synthesis of 2-substituted
Quinazolin-4(3H)-one using alcohols and methyl arenes.a
S.No. Substrate
Oxidantc
TBHP
DTBP
DDQ
K2S2O8
TBHP
Yieldb (%)
84
71
0
Trace
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7.
4a
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6a
6a
TBHP (3 eq.) 71
TBHP (4 eq.) 63
aUnless otherwise noted, the reactions were carried out with 1a (0.5 mmol), 4a (0.6 mmol), 6a (2 ml) catalyst (0.05
b
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mmol), and solvent (1.5 mL) at 80 °C in a sealed tube under air atmosphere for 24 h. Isolated yield of 3aa. 0.8
mmol of oxidant was used
With the optimized reaction condition for best yield, we explored the scope of the oxidative
tandem reaction to access a series of 2-substituted quinazolinones derived from alcohol or
methyl arenes, as depicted in Schemes 2 & 3.
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Benzyl alcohols bearing electron donating and electron withdrawing groups readily
reacted affording 2-substituted quinazolinone in good to excellent yields (Scheme 2). It is worthy
to note that chloro and bromo substituents survived during the reaction (3ah-i). Naphthyl
alcohol, cinnamyl alcohol and heteroaryl alcohols furnished the desired products in good to
excellent yields. Interestingly alkyl alcohols well reacted under the standard condition to provide
2-substituted quinazolinones in satisfactory yields (5al-m). Differently substituted 2-
bromobenzamides also afforded the good yield of the respective products.
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Scheme 2. Scope of the Reaction for Synthesis of Various Quinazolin-4(3H)-ones from
alcohols.a
aReaction conditions: 1a (0.5 mmol), alcohol 5a-o (0.6 mmol), TMSN3 (1.0 mmol), TBHP (1.0 mmol, 70% aqueous
solution), CuI (0.05 mmol), DMSO (1.5 mL), 80 °C, air, 24 h. The yields below the structure are isolated yields.
b0.75 mmol of alcohol used.
Under the optimized reaction condition when toluene reacted with 2-bromobenzamide
afforded a good yield of the desired product 3aa (scheme 3). With electron donating substituents
such as 4-methylanisole, a drop in yield was observed (3ab). Reaction with substrate having
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more than one benzylic carbon i.e. mesitylene proceeded sluggishly providing a moderate yield
of quinazolinone (7ac). 2-Methyl thiophene also proved to be a good substrate for this
transformation (3ar) in a moderate yield. The reaction of ortho-, para- and meta-xylenes with 2-
bromobenzamide afforded good to moderate yields of the respective quinazolinone without
affecting their other methyl group (7ae-7ag).
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Scheme 3. Scope of the Reaction for Synthesis of Various Quinazolin-4(3H)-ones from
methyl arenes.a
aReaction conditions: 1a (0.5 mmol), methyl arenes 6a-g (2 ml), TMSN3 (1.0 mmol), TBHP (1.5 mmol, 70%
aqueous solution), CuI (0.05 mmol), DMSO (1.5 mL), 80 °C, air, 24 h.
To gain an insight into the cyclooxidative mechanism of quinazolinone formation from
ortho-halobenzamides during this study a series of control experiments were carried out. Under
N2 atmosphere, the reaction of 2-bromobenzamide with benzaldehyde using TMSN3 and CuI as
°
catalyst at 80 C yielded mainly the dihydroquinazolinone intermediate 9 (78 %) along with the
desired 3aa (5 %) (scheme 4, eq 1). The aerial oxidation of 9 with or without CuI resulted in 90
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% and 39 % yield of the desired product 3aa respectively (Scheme 4, eq. 2). This indicates the
CuI and the air are essential for the transformation. However, reaction of 2-bromobenzamide
with TMSN3 using CuI as a catalyst at 80 °C under air atmosphere afforded 2-aminobenzamide
(8) in 4% yield only (scheme 4, eq. 3). This trace amount of reductive product could be
explained due to the lack of proton source in this reductive cleavage.22a
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Scheme 4. Control Experiments and Effect of Radical Inhibitor.
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Inhibition of reaction was observed when TEMPO (2,2,6,6-tetramethylpipridine-N-oxyl),
a radical inhibitor was added to the reaction system, indicating the radical process nature
(Scheme 4, eq. 4). This result shows that the oxidation of benzyl alcohol to benzaldehyde which
is needed in order the reaction to proceed is a radical process during the reaction. The same
negative effect was also observed when methyl arene was used as a substrate for the synthesis of
quinazolinone (Scheme 4, eq. 5). In addition, it was found that amino group played a crucial role
in intermolecular C-N bond formation (Scheme 4, eq. 6). According to literature report, tert-
butoxy intermediate was involved in C-N bond formation.22b Considering this fact, we speculated
that during the reaction tert-butyl benzyl ether generated which undergointermolecular amination
of 1a to give 11. According to our expection, 51% of the desired product was obtained when 1a
was reacted with 10a under standard reaction condition (Scheme 4, eq. 7).
In accordance with the above results and the literature precedents, a possible mechanism
is proposed as shown in Scheme 5. Initially, CuI undergoes oxidative addition with substrate 1a
to give complex A, which undergoes subsequent treatment with TMSN3 to give complex B,
followed by copper catalyzed denitrogenative reaction in presence of trace amount of H2O
present in DMSO provides complex C. The latter readily gets reduced into 2-aminobenzamide
(8) with the aid of moisture present in DMSO during the reaction to complete the catalytic cycle.
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On the other hand benzyl alcohol is oxidized to benzaldehyde via radical pathway with TBHP.
The reaction of benzaldehyde and 2-aminobenzamide afforded an imine (12). CuI assisted
decoposition of TBHP leads to formation of tert-butoxyl and tert-butylperoxy radicals. tert-
butoxyl radical abstracts H• radical from toluene to give benzyl radical. Subsequent coupling of
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t
the kinetically stable tert-butylperoxy radical22c-f and benzyl radical (PhCH2• and OOBu•)
generated intermediate 10b (Path B). This intermediate undergoes intermolecular amination by
reacting with 8 which gets oxidized to imine (12). Moreover, intermediate 11 formation can be
explained by intermolecular C-N bond formation by tert-butylbenzyl ether (10a) which is
generated by the coupling of benzyl radical and tert-butoxy radical (Path A). Subsequently,
imine generated underwent intramolecular cyclization followed by oxidation to furnish the
desired product 3aa.
Scheme 5. Possible mechanism for the CuI catalyzed domino synthesis of 2-aryl
quinazolinone.
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CONCLUSION
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In summary, we have designed and developed a convenient, highly efficient, operationally
simple, ligand and base free one-pot protocol for the synthesis of 2-substituted quinazolinones
from 2-bromobenzamide. It provides a diverse synthetic approach, utilizing inexpensive and
readily available multiform substrates aldehydes, alcohols, methyl arenes and uses TMSN3 as
nitrogen source via multipathway coupled self-sequenced domino reaction involving oxidative
addition, reductive amination, an intermolecular oxidative nitrogenation of benzylic C(sp3)-H
bond, intramolecular cyclization and oxidative dehydrogenation assembled in a single reactor to
afford desired product. Particularly noteworthy, is the broad substrate scope, high yield and
functional group compatibility are significant practical advantages. Even though, our strategy
augurs interesting synthetic methodology, further exploring novel synthetic approach toward the
synthesis of other N-containing heterocycles and understanding a detailed mechanism is
underway in our laboratory.
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EXPERIMENTAL SECTION
General Information. Commercially available reagent grade chemicals were used as
received. All reactions were monitored by TLC on E. Merck Kieselgel 60 F254, with
detection by UV light, spraying draggandorff’s solution. Column chromatography was
performed on Silica Gel (60-120 and 230-400 mesh size). IR spectra were recorded as
thin films or in KBr solution using FTIR (4000–450 cm-1) spectrophotometer. 1H and 13C
NMR spectra were recorded on 400 MHz, 300 MHz, 100 MHz and 75 MHz
spectrophotometer respectively, in CDCl3 and DMSO-d6. Chemical shift values are
reported in ppm relative to TMS (tetramethylsilane) as the internal reference, unless
otherwise stated; s (singlet), d (doublet), t (triplet), dd (double doublet), m (multiplet); J in
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Hertz. The LC-ESI-MS were recorded on a triple-quadrupole (TQD) mass spectrometer, and
HRMS spectra were performed using a mass spectrometer Q-TOF. The 10 µl samples
(dissolve in solvent such as methanol/ acetonitrile/ water) were introduced into the ESI source
through autosampler. The mobile phase 90:10 MeOH/CH3CN: H2O flowed at the rate of 250
µl/min by MS pump. Ion spray voltage was set at 5.3 KV and capillary voltage 34V. The MS
scan run up to 2.5 min and the spectra’s print out are averages of over 10 scan at peak top in TIC.
General Procedure for Preparation of 2-substituted-Quinazolin-4(3H)-ones using
aldehydes.
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To a mixture of 2-bromobenzamide 1a 0.10 g (0.5 mmol), aldehyde 2a-v (0.6 mmol) and CuI
0.01 g (0.05 mmol) in DMSO (1.5 ml) was added TMSN3 0.13 ml (1.0 mmol) in a tube under air
atmosphere. After that tube was sealed, and the reaction mixture was heated at 80 °C for 24 h.
After completion of the reaction, water (20 ml) was added to it. A saturated aq. Na2S2O3 solution
was added till the disappearance of brown color and the reaction mixture was extracted with
ethyl acetate. The combined organic layer was dried on anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure, and the crude product was purified by column ( SiO2,
60-120) chromatography using 15-20% EtOAc : hexane as eluent to get pure quinazolinone
products. Most of the compounds were purified without any column chromatography, where
ethyl acetate was added to the crude product and the resulting suspension was filtered. It was
washed with ethyl acetate 2-3 times to get pure compound. Again filtrate was concentrated and
this process was repeated 2-3 times to get a good yield of the products.
General procedure for the synthesis of 2-substituted-Quinazolin-4(3H)-ones using alcohol
To a mixture of 2-bromobenzamide 1a 0.10 g (0.5 mmol), alcohol 4a-o (0.6 mmol) and CuI 0.01
g (0.05 mmol) in DMSO (1.5 ml) was added TMSN3 0.13 ml (1.0 mmol) and TBHP 0.1 ml (1.0
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mmol, 70% aqueous solution) in a tube under air atmosphere. After that tube was sealed, and the
reaction mixture was heated at 80 °C for 24 h. After completion of the reaction, the same
procedure was followed as reported above.
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General procedure for the synthesis of 2-substituted-Quinazolin-4(3H)-ones using methyl
arenes.
To a mixture of 2-bromobenzamide 1a 0.10 g (0.5 mmol), methyl arenes 6a-g (2 ml) and CuI
0.01 g (0.05 mmol) in DMSO (1.5 ml) was added TMSN3 0.13 ml (1.0 mmol) and TBHP 0.14
ml (1.0 mmol, 70% aqueous solution) in a tube under air atmosphere. After that tube was sealed,
and the reaction mixture was heated at 80 °C for 24 h. After completion of the reaction, the same
procedure was followed as reported above and the crude product was purified by column ( SiO2,
230-400) chromatography using 15-20% EtOAc : hexane as eluent to get pure quinazolinone
products.
2-Phenylquinazolin-4(3H)-one (3aa).10 White solid; Yield: 88% (97 mg); mp 230-232°C (lit.
232−235°C); IR (KBr) cm-1: 3403, 3019, 1670, 1403, 1069; 1H NMR (400 MHz, DMSO-d6):
δ 12.54 (s, 1H), 8.20-8.15 (m, 3H), 7.86-7.82 (m, 1H), 7.76 (d, J = 8.00 Hz, 1H), 7.62-7.51 (m,
4H); 13C NMR (100 MHz, DMSO-d6+CDCl3): δ 162.7, 152.6, 149.2, 134.8, 133.1, 131.6,
128.9, 128.1, 127.9, 126.8, 121.4. HRMS calcd for C14H10N2O[M+H+] 223.0866, found
223.0862.
2-(4-Methoxyphenyl) quinazolin-4 (3H) -one (3ab):20 White solid; Yield: 89% (112 mg); mp
242-247°C (lit. 247−249°C); IR (KBr) cm-1: 3400, 3019, 1676, 1403, 1385, 1069, 758 cm−1;
1H NMR (400 MHz, DMSO-d6): δ 12.41 (br.s, 1H), 8.21-8.18 (dd, J1 = 6.99 Hz, J2 = 2.01 Hz,
2H), 8.14-8.12 (dd, J1 = 7.94 Hz, J2 = 1.15 Hz, 1H), 7.84-7.79 ( m, 1H), 7.71 (d, J = 7.66 Hz,
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1H), 7.50-7.46 (m, 1H), 7.10 (d, J = 9.00 Hz, 2H), 3.85 (s, 3H); C NMR (100 MHz, DMSO-
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d6): δ 162.7, 162.3, 152.3, 149.4, 135.0, 129.9, 127.7, 126.5, 126.2, 125.2, 121.1, 114.4, 55.9.
HRMS calcd for C15H12N2O2[M+H+] 253.0972, found 253.0965.
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2-(2-Methoxyphenyl)quinazolin-4(3H)-one (3ac):23 White solid; Yield: 83% (105 mg); mp 200-
202°C(lit. 198-202°C); IR (KBr) cm-1: 3406, 1676, 1603, 1402, 1217, 1070; 1H NMR (400
MHz, DMSO-d6): δ 12.11 (br.s, 1H), 8.16-8.14 (dd, J1 = 7.89 Hz, J2 = 1.20 Hz, 1H), 7.85-7.81
(m, 1H), 7.72-7.70 (dd, J1 = 7.56 Hz, J2 = 1.82 Hz, 1H), 7.56-7.51 (m, 2H), 7.20 (d, J = 8.23 Hz,
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1H), 7.11-7.07 (m, 1H), 3.86 (s, 3H); C NMR (100 MHz, DMSO-d6): δ 161.6, 157.6, 152.8,
149.5, 134.8, 132.6, 130.9, 127.8, 127.0, 126.2, 123.0, 121.4, 120.9, 112.3, 56.2. HRMS calcd
for C15H12N2O2[M+H+] 253.0972, found 253.0972.
2-(3-Methoxyphenyl)quinazolin-4(3H)-one (3ad):17 White solid; Yield 82% (103 mg); mp 180-
182°C (lit. 181-183°C); IR (KBr) cm-1: 3019, 1672, 1607, 1403, 1070; 1H NMR (400 MHz,
DMSO-d6): δ 12.53 (s, 1H), 8.17 (d, J = 7.25 Hz, 1H), 7.87-7.82 (m, 1H), 7.80 (d, J = 7.79 Hz,
1H), 7.76-7.74 (m, 2H), 7.55-7.51 (t, J = 7.16 Hz, 1H), 7.48-7.44 ( t, J = 7.97 Hz, 1H), 7.17-7.14
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(dd, J1 = 8.16 Hz, J2 = 1.99 Hz, 1H), 3.87 (s, 3H); C NMR (100 MHz, DMSO-d6): δ 162.8,
159.8, 152.6, 148.9, 135.2, 134.4, 130.3, 127.8, 127.2, 126.3, 121.3, 120.5, 118.0, 113.0, 55.8.
HRMS calcd for C15H12N2O2[M+H+] 253.0972, found 253.0964.
2-(4-(Isopropyl)phenyl)quinazolin-4(3H)-one (3ae):24 White solid; Yield 79% (104 mg); mp
271-273°C (lit. 270-273°C); IR (KBr) cm-1: 3019, 1672, 1403, 1215, 1069; 1H NMR (400
MHz, DMSO-d6): δ 12.48 (br.s, 1H), 8.16-8.12 (m, 3H), 7.85-7.81 (m, 1H), 7.74 (d, J =
7.66 Hz, 1H), 7.53-7.49 (m, 1H), 7.43 (d, J = 8.23 Hz, 2H), 3.02-2.95 (m, 1H), 1.25 (s,
3H), 1.24 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 162.7, 152.7, 152.5, 149.3, 135.0,
130.7, 128.2, 127.9, 127.0, 126.8, 126.3, 121.3, 33.8, 24.0 (2C). HRMS calcd for
C17H16N2O[M+H+] 265.1335, found 265.1334.
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2-(3,4,5-Trimethoxyphenyl)quinazolin-4(3H)-one (3af):25 White solid; Yield 74% (115 mg);
mp 257-260°C (lit. 258-260°C); IR (KBr) cm-1: 3401, 3019, 1654, 1403, 1156; 1H NMR (400
MHz, DMSO-d6): δ 12.51 (s, 1H), 8.16 (d, J = 7.64 Hz, 1H), 7.85-7.82 (t, J = 7.25 Hz, 1H), 7.76
(d, J = 8.03 Hz, 1H), 7.57 (s, 2H), 7.53-7.50 (t, J = 7.44 Hz, 1H), 3.91 (s, 6H), 3.75 (s, 3H); 13C
NMR (100 MHz, DMSO-d6): δ 162.5, 158.0, 156.9, 153.8, 145.4, 139.8, 132.8, 132.6, 131.7,
131.0, 126.0, 110.4, 65.3, 61.3. HRMS calcd for C17H16N2O4[M+H+] 313.1183, found
313.1175
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2-(4-Fluorophenyl)quinazolin-4(3H)-one (3ag):20 White solid; Yield: 78% (93 mg); mp 284-
286°C (lit. 284-287°C); IR (KBr) cm-1: 3402, 3019, 2400, 1659, 1403, 1215, 1069; 1H NMR
(400 MHz, DMSO-d6): δ 12.57 (br.s, 1H), 8.27-8.24 (m, 2H), 8.17-8.14 (dd, J1 = 7.89 Hz, J2 =
1.10 Hz, 1H), 7.86−7.82 (m, 1H), 7.75 (d, J = 7.94 Hz, 1H), 7.55-7.51 (m, 1H), 7.42-7.37 (m,
2H); 13C NMR (100 MHz, DMSO-d6): δ 165.7 (d, JC-F = 251.34 Hz), 162.7, 151.9, 149.0, 135.1,
130.8 (d, JC-F = 9.38 Hz), 129.6, 127.9, 127.1, 126.3, 121.2, 116.2 (d, JC-F= 21.96 Hz). HRMS
calcd for C14H9FN2O[M+H+] 241.0772, found 241.0780
2-(4-Chlorophenyl)quinazolin-4(3H)-one (3ah):20 White solid; Yield: 76% (97 mg); mp
>300°C (lit. 298−300°C); IR (KBr) cm-1: 3408, 3308, 3021, 2401, 1672, 1606, 1480, 1409,
1154, 1093; 1H NMR (400 MHz, DMSO-d6): δ 12.59 (br.s, 1H), 8.21 (d, J = 8.30 Hz, 2H), 8.17
(d, J = 7.72 Hz, 1H), 7.86-7.83 (t, J = 7.34 Hz, 1H), 7.75 (d, J = 8.11 Hz, 1H), 7.64 (d, J = 8.40
Hz, 2H), 7.55-7.52 (t, J = 7.34 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 162.6, 151.8, 149.0,
136.7, 135.1, 132.0, 130.0 (2C), 129.1 (2C), 127.9, 127.2, 126.3, 121.4; HRMS calcd for
C14H9ClN2O[M+H+] 257.0476, found 257.0478.
2-(4-Bromophenyl)quinazolin-4(3H)-one (3ai):8d White solid; Yield: 69% (103 mg); mp 292-
294°C (lit. 292−295°C); IR (KBr) cm-1: 3412, 3019, 1650, 1403, 1110, 1065; 1H NMR (400
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MHz, DMSO-d6): δ 12.60 (br.s, 1H), 8.17-8.11 (m, 3H), 7.87-7.83 (m, 1H), 7.78-7.74 (m, 3H),
7.56-7.52 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 162.6, 151.9, 149.0, 135.1, 132.3, 132.1,
130.2, 127.9, 127.3, 126.3, 125.7, 121.4. HRMS calcd for C14H9BrN2O[M+H+] 300.9971,
found 300.9971.
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2-(4-Nitrophenyl)quinazolin-4(3H)-one (3aj):26 Yellow solid; Yield: 64% (85 mg); mp >300°C
(lit. >300°C); IR (KBr) cm-1: 3402, 3019, 2399, 1643, 1522, 1403, 1069; 1H NMR (400
MHz, DMSO-d6): δ 12.82 (br.s, 1H), 8.44-8.37 (m, 4H), 8.20-8.17 (dd, J1 = 7.85 Hz, J2 = 1.15
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Hz, 1H), 7.90-7.86 (m, 1H), 7.81-7.79 (d, J = 8.04 Hz, 1H), 7.60-7.56 ( m, 1H); C NMR (100
MHz, DMSO-d6): δ 162.6, 151.3, 149.4, 148.7, 139.0, 135.3, 129.7 (2C), 128.1, 127.9, 126.4,
124.1 (2C), 121.6. HRMS calcd for C14H9N3O3[M+H+] 268.0717, found 268.0709.
2-(4-(Trifluoromethoxy)phenyl)quinazolin-4(3H)-one (3ak):29 White solid; Yield: 78% (119
mg); mp 267-271°C (lit. 268–271°C); IR (KBr) cm-1: 3401, 2922, 1654, 1403, 1218, 1156,
1069; 1H NMR (400 MHz, DMSO-d6): δ 12.62 (br.s, 1H), 8.32 (d, J = 7.76 Hz, 1H), 7.86-7.83
(t, J = 7.26 Hz, 1H), 7.76 (d, J = 7.97 Hz, 1H), 7.55-7.54 (m, 4H); 13C NMR (100 MHz, DMSO-
d6): δ 162.6, 151.6, 150.8 (d, JC-F = 1.22 Hz), 149.0, 135.1, 132.3, 130.5 (2C), 128.0, 127.2,
126.3, 124.3, 121.7, 121.4, 121.3 (2C), 119.1 (q, JC-F = 256.6 Hz), 116.6; HRMS calcd for
C15H9F3N2O2[M+H+] 307.0689, found 307.0678.
2-(4-(Trifluoromethyl)phenyl)quinazolin-4(3H)-one (3al):29 White solid; Yield: 81% (117 mg);
mp >300°C (lit. 308-310°C); IR (KBr) cm-1: 3400, 3019, 1653, 1403, 1216, 1155, 1067,
669; 1H NMR (400 MHz, DMSO-d6):
δ 12.72 (s, 1H), 8.40 (d, J = 8.03 Hz, 2H), 8.18 (d, J =
7.79 Hz, 1H), 7.91 (d, J = 8.23 Hz, 2H), 7.87-7.83 (t, J = 8.03 Hz, 1H), 7.78 (d, J = 7.93 Hz,
1H), 7.56-7.53 (t, J = 7.50 Hz. 1H); 13C NMR (100 MHz, DMSO-d6)
δ
162.6, 151.6, 148.8,
137.1, 135.1 (2C), 131.5 (q, JC-F = 31.33 Hz), 129.1, 128.4, 128.0, 127.4, 126.3, 125.9 (d, JC-F
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3.43 Hz), 125.7, 123.0 (q, JC-F = 272.7), 121.6; HRMS calcd for C15H10F3N2O [M+H+]
291.0740, found 291.0742.
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2-(Naphthalen-1-yl)quinazolin-4(3H)-one (3am):10 White solid; Yield: 75% (102 mg); mp 297-
299°C (lit. 298-300°C). IR (KBr) cm-1: 3019, 2400, 1675, 1403, 1385, 1069; 1H NMR (400
MHz, DMSO-d6): δ 12.66 (br.s, 1H), 8.23 (d, J = 7.84 Hz, 1H), 8.19 (d, J = 7.64 Hz, 1H),
8.13 (d, J = 8.23 Hz, 1H), 8.06 (d, J = 7.25 Hz, 1H), 7.88-7.85 (t, J = 7.05 Hz, 1H), 7.81
(d, J = 6.86 Hz, 1H), 7.74 (d, J = 7.84 Hz, 1H), 7.67-7.56 (m, 4H); 13C NMR (100 MHz,
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DMSO-d6):
δ 162.5, 154.2, 149.1, 134.9, 133.6, 132.2, 130.8, 130.7, 128.8, 128.1, 127.8, 127.5,
127.2, 126.8, 126.3, 125.6, 125.5, 121.6. HRMS calcd for C18H12N2O [M+H+] 273.1022,
found 273.1025.
2-(Pyridin-3-yl)quinazolin-4(3H)-one (3an):10 White solid; Yield: 65% (72 mg); mp 280-282°C
(lit. 278-281°C); IR (KBr) cm-1: 3400, 3019, 2926, 1677, 1402, 1215, 1108; 1H NMR (400
MHz, DMSO-d6): δ 12.72 (s, 1H), 9.30 ( s, 1H), 8.76 (d, J = 4.08 Hz, 1H), 8.51-8.48 (m, 1H),
8.18-8.16 (dd, J1 = 7.93 Hz, J2 = 1.08 Hz, 1H), 7.88-7.84 (m, 1H), 7.78-7.76 (dd, J1 = 8.14 Hz, J2
= 0.57 Hz, 1H), 7.60-7.53 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 162.6, 152.2, 151.2,
149.2, 148.9, 135.8, 135.1, 129.2, 127.9, 127.4, 126.3, 124.0, 121.5. HRMS calcd for
C13H9N3O [M+H+] 224.0818, found 224.0811.
2-(Quinolin-4-yl)quinazolin-4(3H)-one (3ao): White solid; Yield: 61% (83 mg); mp >300°C;
IR (KBr) cm-1: 3019, 1644, 1403, 1215, 1069; 1H NMR (400 MHz, DMSO-d6): δ 12.83
(br.s, 1H), 9.09 (d, J = 3.73 Hz, 1H), 8.25-8.22 (m, 2H), 8.17 (d, J = 8.59 Hz, 1H), 7.92-7.84 (m,
2H), 7.81 (d, J = 4.29 Hz, 1H), 7.78 (d, J = 8.03 Hz, 1H), 7.70-7.66 (t, J = 7.65 Hz, 1H), 7.64-
7.61 (t, J = 7.47 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 162.1, 152.1, 150.5, 148.8, 148.4,
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139.6, 135.1 (2C), 133.1, 130.3, 129.9, 128.0 (2C), 127.7, 126.3, 126.0, 122.0. HRMS calcd for
C17H11N3O [M+H+] 274.0975, found 274.0975.
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2-(Furan-2-yl)quinazolin-4(3H)-one (3ap):10 White solid.; Yield: 78 % (82 mg); mp 275-
276°C (lit. 274-276°C); IR (KBr) cm-1: 3407, 1660, 1401, 1218, 1069; 1H NMR (400 MHz,
DMSO-d6): δ 12.49 (s, 1H), 8.13 (d, J = 7.51 Hz, 1H), 7.99 (s, 1H), 7.82-7.78 (t, J = 7.28 Hz,
1H), 7.69 (d, J = 8.01 Hz, 1H), 7.63 (d, J = 3.37 Hz, 1H), 7.50-7.46 ( t, J = 7.64 Hz, 1H), 6.75-
6.74 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 162.1, 149.0, 147.0, 146.5, 144.5, 135.0,
127.6, 126.9, 121.5, 114.9, 112.9. HRMS calcd for C12H8N2O2 [M+H+] 213.0659, found
213.0656.
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2-(Thiophene-2-yl)quinazolin-4(3H)-one (3aq):10 White solid ; Yield: 81% (92 mg); mp 221-
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222°C (lit. 220-221°C); IR (KBr) cm-1: 3403, 3019, 1664, 1403, 1215, 1069; H NMR (400
MHz, DMSO-d6): δ 12.65 (br.s 1H), 8.24-8.23 (dd, J1 = 3.77, J2 = 0.87 Hz, 1H), 8.14-8.12 ( dd,
J1 = 7.91 Hz, J2 = 1.17 Hz, 1H), 7.88-7.86 (dd, J1 = 5.02 Hz, J2 = 0.91 Hz, 1H), 7.83-7.79 (m,
1H), 7.67 (d, J = 7.96 Hz, 1H), 7.51-7.47 (m, 1H), 7.25-7.23 (m, 1H); 13C NMR (100 MHz,
DMSO-d6+ CDCl3): δ 162.2, 149.1, 148.3, 137.8, 135.1, 132.6, 129.8, 128.9, 127.4, 126.7,
126.4, 121.3. HRMS calcd for C12H8N2OS [M+H+] 229.0430
, found 229.0441.
(E)-2-Styrylquinazolin-4(3H)-one (3ar):9 Light yellow solid; Yield: 71% (88 mg); mp 226-
228°C (lit. 226-228°C); IR (KBr) cm-1: 3019, 2399, 1669, 1403, 1385, 1215, 1109; 1H NMR
(400 MHz, DMSO-d6):
δ 12.34 (br.s, 1H), 8.12 (d, J = 7.24 Hz, 1H), 7.97 (d, J = 16.25 Hz, 1H),
7.82-7.78 (m, 1H), 7.69-7.66 (m, 3H), 7.49-7.39 (m, 4H), 7.05 (d, J = 16.25 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): δ 162.5, 152.2, 149.5, 138.5, 135.5, 134.8, 130.1, 129.5 (2C), 128.0
(2C), 127.4, 126.5, 126.3, 121.8, 121.5. HRMS calcd for C16H12N2O [M+H+] 249.1022,
found 249.1034.
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2-Ethylquinazolin-4(3H)-one (3as):12 White solid; Yield: 42% (36 mg); mp 228-230°C (lit.
229-231°C); IR (KBr) cm-1: 3399, 3019, 2400, 1672, 1618, 1469, 1403, 1385, 1070; 1H
NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 8.08 (d, J = 7.63 Hz, 1H), 7.77-7.73 (t, J =
7.32 Hz, 1H), 7.60 (d, J = 8.02 Hz, 1H), 7.46-7.42 (t, J = 7.32 Hz, 1H), 2.64-2.59 (quart, J
= 7.40 Hz, 2H), 1.26-1.22 (t, J = 7.40 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 162.2,
158.7, 149.4, 134.6, 127.2, 126.3, 126.1, 121.2, 28.2, 11.7. HRMS calcd for C10H10N2O
[M+H+] 175.0866, found 175.0858.
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2-Pentylquinazolin-4(3H)-one (3at):27 White solid; Yield: 49% (52 mg); mp 152-154°C (lit.
153-154°C); IR (KBr) cm-1: 3019, 1674, 1468, 1215, 929; 1H NMR (400 MHz, DMSO-d6):
δ
12.15 (s, 1H), 8.08 (d, J = 7.20 Hz, 1H), 7.78-7.74 (t, J = 8.03 Hz, 1H), 7.60 (d, J = 8.13
Hz, 1H), 7.46-7.42 (t, J = 7.54 Hz, 1H), 2.60-2.56 (t, J = 7.44 Hz, 2H), 1.73-1.70 (m, 2H),
1.32-1.28 (m, 4H), 0.88-0.84 (t, J = 6.46 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 162.2,
157.9, 149.4, 134.7, 127.2, 126.3, 126.1, 121.2, 34.9, 31.2, 26.9, 22.2, 14.2. HRMS calcd for
C13H16N2O [M+H+] 217.1335, found 217.1327.
2-Benzylquinazolin-4(3H)-one (3au):17 White solid; Yield: 57% (67 mg); mp 248-250°C (lit.
245-247°C); IR (KBr) cm-1: 3401, 3019, 1619, 1403, 1215, 1069; 1H NMR (400 MHz,
DMSO-d6): δ 12.37 (br.s, 1H), 8.09-8.07 (d, J = 7.66 Hz, 1H), 7.79-7.75 (t, J = 7.46 Hz, 1H),
7.62 (d, J = 8.04 Hz, 1H), 7.48-7.45 (t, J = 7.46 Hz, 1H), 7.40 (d, J = 7.18 Hz, 2H), 7.34-7.30 (t,
J = 7.27 Hz, 2H), 7.26-7.22 (t, J = 7.08 Hz, 1H), 3.94 (s, 2H); 13C NMR (100 MHz, DMSO-d6):
δ 162.4, 156.5, 149.3, 137.0, 134.8, 129.3 (2C), 128.9 (2C), 127.2 (2C), 126.6, 126.1, 121.1,
41.2; HRMS calcd for C15H12N2O [M+H+] 237.1022, found 237.1001.
Quinazolin-4(3H)-one (3av):25 White solid ; Yield: 41% (30 mg); mp 211-214°C (lit. 212-
214°C); IR (KBr) cm-1: 3401, 3019, 1667, 1403, 1067; 1H NMR (400 MHz, DMSO-d6): δ
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7.62 (d, J = 7.84 Hz, 1H), 7.53-7.49 (m, 1H); C NMR (100 MHz, DMSO-d6): δ 161.2, 149.1,
145.8, 134.7, 127.6, 127.1, 126.2, 123.1. HRMS calcd for C8H6N2O [M+H+] 147.0553, found
147.0543.
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7-Methyl-2-phenylquinazolin-4(3H)-one (3ba):10 White solid; Yield: 82% (96 mg); mp 238-
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240°C (lit. 240-241°C); IR (KBr) cm-1: 3019, 1666, 1605, 1402, 1069; H NMR (400 MHz,
DMSO-d6): δ 12.44 (s, 1H), 8.18 (d, J = 6.85 Hz, 2H), 8.05 (d, J = 8.05 Hz, 1H), 7.61-7.53 (m,
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4H), 7.36 (d, J = 8.23 Hz, 1H), 2.48 (s, 3H); C NMR (100 MHz, DMSO-d6): δ 162.2, 152.7,
149.3, 145.5, 133.2, 131.7, 129.0 (2C), 128.4, 128.1 (2C), 127.6, 126.1, 119.0, 21.8. HRMS
calcd for C15H12N2O [M+H+] 237.1022, found 237.1012.
7-Methyl-2-(4-Methoxyphenyl)quinazolin-4(3H)-one (3bb):10.Light yellow solid; Yield: 84%
(111 mg); mp 248-250°C (lit. 246-248°C ); IR (KBr) cm-1: 3403, 3019, 1663, 1403, 1069; 1
H
NMR (400 MHz, DMSO-d6): δ 12.32 (br.s, 1H), 8.19 (d, J = 8.69 Hz, 2H), 8.03 (d, J = 8.11 Hz,
1H), 7.52 (s, 1H), 7.32 (d, J = 8.11 Hz, 1H), 7.10 (d, J = 8.69 Hz, 2H), 3.85 (s, 3H), 2.47 (s, 3H);
13C NMR (100 MHz, DMSO-d6): δ 162.6, 162.3, 152.3, 149.5, 149.4, 129.8 (2C), 128.0, 127.4,
126.1, 125.3, 118.7, 114.4 (2C), 55.9, 21.8. HRMS calcd for C16H14N2O2 [M+H+] 267.1128,
found 267.1125.
7-Methyl-2-(Pyridin-3-yl)quinazolin-4(3H)-one (3bn): White solid; Yield: 62% (73 mg); mp
256-260°C; IR (KBr) cm-1: 3681, 3400, 3019, 2399, 1669, 1605, 1522, 1474, 1419, 1024,
669, 626; 1H NMR (400 MHz, DMSO-d6): δ 12.95 (br.s, 1H), 9.29 (s, 1H), 8.75 (s, 1H), 8.49
(d, J = 7.72 Hz, 1H), 8.06 (d, J = 8.05 Hz, 1H), 7.59-7.57 (m, 2H), 7.37 (d, J = 7.89 Hz, 1H),
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2.48 (s, 3H); C NMR (100 MHz, DMSO-d6): δ 162.5, 152.2, 151.2, 149.1, 145.6, 135.7 (2C),
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128.8, 127.6, 126.2, 124.0, 119.1, 21.8. HRMS calcd for C14H11N3O [M+H+] 238.0975,
found 238.0970.
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7-Methyl-2-(Thiophen-2-yl)quinazolin-4(3H)-one (3bq):10 White solid ; Yield: 80% (96 mg);
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mp 290–293°C (lit.291-292°C ); IR (KBr) cm-1: 3401, 3018, 1660, 1403, 1215, 1069; 1
H
NMR (400 MHz, DMSO-d6): δ 12.55 (s, 1H), 8.22 (d, J = 3.33 Hz, 1H), 8.01 (d, J = 8.05 Hz,
1H), 7.86 (d. J = 4.90 Hz, 1H), 7.48 (s, 1H), 7.32 (d, J = 8.00 Hz, 1H), 7.24-7.22 (t, J = 4.24 Hz,
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1H), 2.45 (s, 3H); C NMR (100 MHz, DMSO-d6): δ 162.1, 149.2, 148.3, 145.6, 137.9, 132.5,
129.7, 128.9, 128.2, 127.1, 126.2, 118.9, 21.7. HRMS calcd for C13H10N2OS [M+H+]
243.0587, found 243.0581.
7-Methyl-2-pentylquinazolin-4(3H)-one (3bt): White solid; Yield: 44% (50 mg); mp. 180-
182°C; IR (KBr) cm-1: 3394, 2925, 1675, 1616, 1403, 1217, 1068, 670; 1H NMR (400 MHz,
CDCl3): δ 10.92 (s, 1H), 8.16 (d, J = 8.05 Hz, 1H), 7.49 (s, 1H), 7.29 (d, J = 8.37 Hz, 2H), 2.76-
2.72 (t, J = 7.72 Hz, 2H), 2.50 (s, 3H), 1.89-1.82 (m, 2H), 1.46-1.35 (m, 4H), 0.93-0.90 (t, J =
13
6.91 Hz, 3H); C NMR (100 MHz, CDCl3): δ 163.5, 156.6, 149.4, 145.8, 127.9, 126.9, 126.0,
118.1, 35.9, 31.3, 27.1, 22.3, 21.9, 13.9. HRMS calcd for C14H18N2O [M+H+] 231.1492,
found 231.1495.
6-Methoxy-2-phenylquinazolin-4(3H)-one (3ca):10 Light yellow solid; Yield: 82% (103 mg);
mp 246-247°C (lit. 249-251°C); IR (KBr) cm-1: 3400, 3019, 1664, 1403, 1069; 1H NMR (400
MHz, DMSO-d6):
δ 12.49 (s, 1H), 8.17 (d, J = 6.66 Hz, 2H), 7.71 (d, J = 8.76 Hz, 1H), 7.55-
7.53 (m, 4H), 7.46-7.43 (dd, J1 = 8.81 Hz, J2 = 2.71 Hz, 1H), 3.90 (s, 3H); 13C NMR (100 MHz,
DMSO-d6):
δ 162.5, 158.2, 150.5, 143.6, 133.2, 131.4, 129.6, 129.0 (2C), 127.9 (2C), 124.5,
122.2, 106.3, 56.1. HRMS calcd for C15H12N2O2 [M+H+] 253.0972, found 253.0975.
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6-Methoxy-2-(4-Methoxy)phenyl)quinazolin-4(3H)-one (3cb):28 Light yellow solid; Yield: 80%
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(112 mg); mp 256-258°C (lit.258-259°C); IR (KBr) cm-1: 3397, 1629, 1401, 1068, 770; H
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NMR (400 MHz, DMSO-d6): δ 12.37 (s, 1H), 8.17 (d, J = 8.28 Hz, 2H), 7.67 (d, J = 8.76 Hz,
1H), 7.53 (s, 1H), 7.43 (d, J = 7.05 Hz, 1H), 7.09 (d, J = 8.24 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H);
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13C NMR (100 MHz, DMSO-d6):
δ 162.1, 161.5, 157.4, 149.7, 143.4, 129.1 (2C), 129.0, 124.9,
124.0, 121.4, 113.9 (2C), 105.8, 55.6, 55.4. HRMS calcd for C16H14N2O3 [M+H+] requires
283.1077, found 283.1078.
2-Propylquinazolin-4(3H)-one (5al):12 White solid; Yield: 45% (42 mg); mp 198-200°C (lit.
200–202°C); IR (KBr) cm-1: 3400, 3019, 2400, 1671, 1612, 1466, 1403, 1385, 1069; 1H
NMR (400 MHz, CDCl3):
δ 11.47 (br.s, 1H), 8.30-8.27 (dd, J1 = 7.97 Hz, J2 = 1.08 Hz, 1H),
7.79-7.75 (m, 1H), 2.79-2.75 (t, J = 7.66 Hz, 2H), 1.97-1.87 (sxt, J = 7.46 Hz, 2H), 1.10-1.06 (t,
J = 7.37 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ
164.1, 156.7, 149.6, 135.0, 130.3, 128.6,
127.4, 126.6, 126.4, 120.7, 37.9, 21.1, 13.9. HRMS calcd for C11H12N2O [M+H+] 189.1022,
found 189.1024.
2-Heptylquinazolin-4(3H)-one (5am):27 White solid; Yield: 48% (58 mg); mp 123-126°C (lit.
124-127°C); IR (KBr) cm-1: 2924, 1673, 1612, 1468, 1149; H NMR (400 MHz, CDCl3): δ
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11.30 (s, 1H), 8.29-8.27 (dd, J1 = 8.01 Hz, J2 = 1.07 Hz, 1H), 7.79-7.75 (m, 1H), 7.71-7.69 (dd,
J1 = 8.15 Hz, J2 = 0.58 Hz, 1H), 7.48-7.44 (m, 1H), 2.79-2.75 (t, J = 7.80 Hz, 2H), 1.91-1.83 (m,
2H), 1.49-1.42 (m, 2H), 1.41-1.34 (m, 2H), 1.30-1.25 (m, 4H), 0.89-0.85 (t, J = 6.86 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 63.8, 156.7, 149.4, 134.7, 127.2, 126.3, 126.2, 120.5, 36.0,
31.6, 29.1, 28.9, 27.5, 22.5, 14.0. HRMS calcd for C15H20N2O [M+H+] 245.1648, found
245.1644.
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2-(3,5-Dimethylphenyl)quinazolin-4(3H)-one (7ac):24 White solid; Yield: 44% (55 mg); mp
271-273°C (lit. 273°C); IR (KBr) cm-1: 3402, 3021, 2401, 1665, 1523, 1417, 1027, 928,
670; 1H NMR (400 MHz, DMSO-d6): δ 12.38 (s, 1H), 8.15-8.14 (d, J = 7.54 Hz, 1H), 7.85-
7.81 (m, 3H), 7.75-7.73 (d, J = 8.17 Hz, 1H), 7.53-7.49 (t, J = 7.34 Hz, 1H), 7.22 (s, 1H),
2.37 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ 162.6, 152.9, 149.2, 138.2, 135.0, 133.2,
133.0, 127.9, 126.9, 126.3, 125.9, 121.4, 21.3 (2C). HRMS calcd for C16H14N2O [M+H+]
251.1179, found 251.1178.
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2-(o-Tolyl)quinazolin-4(3H)-one (7ae):20 White solid; Yield: 67% (79 mg); mp 215-218°C (lit.
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216-218°C); IR (KBr) cm-1: 3391, 3019, 2400, 1612, 1403, 1068, 669; H NMR (400 MHz,
DMSO-d6): δ 12.43 (s, 1H), 8.18 (d, J = 7.42 Hz, 1H), 7.85-7.82 (t, J = 6.98 Hz, 1H), 7.70 (d, J
= 8.05 Hz, 1H), 7.56-7.50 (m, 2H), 7.45-7.42 (t, J = 6.98 Hz, 1H), 7.36-7.31 (m, 2H), 2.39 (s,
3H); 13C NMR (100 MHz, DMSO-d6): δ 162.2, 154.8, 149.2, 136.5, 134.9, 134.7, 130.9,
130.3, 129.5, 127.8, 127.0, 126.2, 126.1, 121.4, 20.0. HRMS calcd for C15H12N2O [M+H+]
237.1022, found 237.1018.
2-(p-Tolyl)quinazolin-4(3H)-one (7af):20 White solid; Yield: 65% (76 mg); mp 241–243°C. (lit.
1
239−242°C); IR (KBr) cm-1:3401, 3019, 2400, 1663, 1403, 1156, 1069; H NMR (400 MHz,
DMSO-d6): δ 12.44 (s, 1H), 8.15 (d, J = 7.44 Hz, 1H), 8.10 (d, J = 8.13 Hz, 2H), 7.83-7.79 (t,
1H, J = 7.05 Hz), 7.72 (d, J = 7.84 Hz, 1H), 7.51-7.47 (t, J = 7.44 Hz, 1H), 7.35 (d, J = 7.93 Hz.
2H), 2.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 162.7, 152.6, 149.2, 141.8, 134.9,
130.3, 129.6, 128.1, 127.8, 126.8, 126.2, 21.4. HRMS calcd for C15H12N2O [M+H+]
237.1022, found 237.1016.
2-(m-Tolyl)quinazolin-4(3H)-one (7ag):20 White solid; yield: 59% (69 mg); mp 220-222°C (lit.
221–223°C); IR (KBr) cm-1: 3407, 3019, 1674, 1403, 1216, 1069; 1H NMR (400 MHz,
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DMSO-d6): δ 12.46 (br.s, 1H), 8.17-8.15 (m, 1H), 8.03 (s, 1H), 7.98 (d, J = 7.24 Hz, 1H), 7.86-
7.82 (m, 1H), 7.76 (d, J = 7.89 Hz, 1H), 7.54-7.50 (m, 1H), 7.46-7.39 (m, 2H), 2.41 (s, 3H); 13C
NMR (100 MHz; DMSO-d6): δ 162.6, 152.8, 149.2, 138.3, 135.0, 133.1, 132.4, 128.9,
128.7, 127.9, 126.9, 126.3, 125.3, 121.4, 21.4. HRMS calcd for C15H12N2O [M+H+]
237.1022, found 237.1009.
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2-Aminobenzamide (8):9 To a mixture of 2-bromobenzamide 1a 0.30 g (1.5 mmol) and CuI
0.03 g (0.15 mmol) in DMSO (3.0 ml) was added TMSN3 0.39 ml (3.0 mmol) in a tube under air
atmosphere. After that tube was sealed, and the reaction mixture was heated at 80 °C for 24 h.
After completion of the reaction, water (20 ml) was added to it. A saturated aq. Na2S2O3 solution
was added till the disappearance of brown color and the reaction mixture was extracted with
ethyl acetate. The combined organic layer was dried on anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure and the crude product was purified by column (SiO2, 60-
120) chromatography using 20-25% EtOAc: hexane as eluent to get pure 2-aminobenzamide
products. White solid; Yield: 4% (8 mg); mp 110-112°C (lit. 110°C); IR (KBr) cm-1: 3409,
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3020, 2401, 1659, 1590, 1399, 1316, 1075; H NMR (400 MHz, DMSO-d6): δ 7.71 (br.s, 1H),
7.54 (d, J = 7.84 Hz, 1H), 7.15-7.11 (t, J = 8.00 Hz, 1H), 7.04 (br.s, 1H), 6.69 (d, J = 8.17 Hz,
1H), 6.55 (br.s, 1H), 6.50-6.46 (t, J = 7.15 Hz, 1H); 13C NMR (100 MHz, DMSO-d6,): δ 171.7,
150.6, 132.3, 129.2, 116.8, 114.8, 114.1. HRMS calcd for C7H8N2O [M+H+] 137.0709,
found 137.0713
2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (9):9 To a stirred mixture of 2-bromobenzamide 1a
0.10 g (0.5 mmol), benzaldehyde 0.06 ml (0.6 mmol) and CuI 0.01 g (0.05 mmol) in DMSO (1.5
ml) was added TMSN3 0.13 ml (1.0 mmol) in a tube under nitrogen atmosphere. After that tube
was sealed, and the reaction mixture was heated at 80 °C for 24 h. After completion of the
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reaction, water (20 ml) was added to it. A saturated aq. Na2S2O3 solution was added till the
disappearance of brown color and the reaction mixture was extracted with ethyl acetate. The
combined organic layer was dried on anhydrous sodium sulfate. The combined organic layer was
dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the
crude product was purified by column (SiO2, 60-120) chromatography using 15-20% EtOAc:
hexane as eluent to get the pure dihydroquinazolinone product. White solid; Yield: 87% (0.19 g);
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mp 221-222°C (lit. 220-223°C). IR (KBr) cm-1: 3297, 3019, 1659; H NMR (400 MHz,
DMSO-d6): δ 8.27 (br.s, 1H), 7.62-7.60 (m, 1H), 7.51-7.49 (m, 2H), 7.41-7.33 (m, 3H), 7.26-
7.22 (m, 1H), 7.10 (br.s, 1H), 6.76 (d, J = 8.01 Hz, 1H), 6.69-6.66 (t, J = 7.44 Hz, 1H), 5.75 (s,
1H); 13C NMR (100 MHz, DMSO-d6): δ 164.0, 8.3, 142.1, 133.7, 128.9, 128.7 (2C), 127.8,
127.3 (2C), 117.5, 115.4, 114.8, 67.0. HRMS calcd for C14H12N2O [M+H+] 225.1022,
found 225.1013.
2-(Benzylamino)benzamide (11):10 To a stirred mixture of 2-aminobenzamide (8; 1.0 g, 7.4
mmol), K2CO3 (1.0 g, 7.4 mmol) and NaI (1.1 g, 7.4 mmol) in DMF (10 mL) was added benzyl
chloride (1.2 mL, 10 mmol) and stirred at rt for 1 d. The reaction mixture was cooled and poured
into water. It wasextracted with EtOAc. The organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography
(silica gel, hexanes/EtOAc) to give desired product 11 (1.5 g, 90%) as a pale yellow solid: mp
170−172 °C (lit. 176-177 °C); IR (KBr) (cm−1) 3423, 3205, 1634, 1578, 1512, 1393, 1292,
1
1066, 747; H NMR (400 MHz, DMSO-d6): δ 8.60-8.57 (t, J = 5.39 Hz, 1H), 7.85 (br.s, 1H),
7.63-7.61 (m, 1H), 7.34-7.33 (m, 4H), 7.26-7.18 (m, 3H), 6.63 (d, J = 8.49 Hz, 1H), 6.55-6.51 (t,
13
J = 7.67 Hz, 1H), 4.39 (d, J = 5.71 Hz, 1H); C NMR (100 MHz, DMSO-d6): δ 172.0, 150.0,
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140.1, 132.9, 129.5, 128.9 (2C), 127.5 (2C), 127.2, 114.6, 111.9, 46.4. HRMS calcd for
C14H14N2O [M+H+] 227.1179, found 227.1166.
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Supporting Information. Copies of 1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors *E-mail: rpt.cdri@gmail.com, rp_tripathi@cdri.res.in
Tel: +91 522 2612411. Fax: +91 522 2623405.
NOTES
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
KU and RKT would like to thank UGC, New Delhi for providing fellowship. We thank
SAIF division, CSIR-CDRI for the analytical facilities.
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