Temperature-controlled synthesis of N-acyl anthranilamides and quinazoline-4ones via Pd-catalysed cascade consisting of isocyanide insertion

Article abstract of DOI:10.24820/ark.5550190.p010.868

A one step synthesis of functionlized N-acyl anthranilamide via Pd-catalyzed carboxamidation of o-halo substituted N-phenylamide consisting of isocyanide insertion followed by oxidation of the imine intermediate has been achived successfully. Furthermore,

Full text of DOI:10.24820/ark.5550190.p010.868

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Temperature-controlled synthesis of N-acyl anthranilamides and quinazoline-4-
ones via Pd-catalysed cascade consisting of isocyanide insertion
Irfan Khan,a Jaybir Singh,b Imran Khan,c Sunil Dutt,c Shahnawaz Khan,*d and Vikas Tyagi*c
aCoordination Chemistry Laboratory, Department of Chemistry, Mohan Lal Sukhadia University, Udaipur,
Rajasthan, India
bDepartment of Pharmacy, Dr. B. R. Ambedkar University, Agra-282002, India
cSchool of Chemistry and Biochemistry, Thapar Institute of Engineering and Technology, Patiala-147004,
Punjab, India
dDepartment of Chemistry, Bhupal Nobles University, Udaipur, Rajasthan, India
Email: vikas.tyagi@thapar.edu vtyagi1985@gmail.com
Received 01-02-2019
Accepted 05-20-2019
Published on line 05-24-2019
Abstract
A one step synthesis of functionlized N-acyl anthranilamide via Pd-catalyzed carboxamidation of o-halo
substituted N-phenylamide consisting of isocyanide insertion followed by oxidation of the imine intermediate
has been achived successfully. Furthermore, at elevated temprature (160oC) the Pd-catalyzed tandem reaction
afforded functionlized quinazolin-4-one in a single step without the isolation of N-acyl anthranilamide and
proceed through carboxamidation/de-t-butylation/cyclodehydration cascade. This work extends the
application of isocyanide insertion chemistry for synthesizing diverse N-heterocycles by transition metal
catalysed sequential reactions in a single step.
Keywords: N-acyl anthranilamide, quinazoline-4-one, isocyanide, palladium, cascade reactions
DOI: https://doi.org/10.24820/ark.5550190.p010.868
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Introduction
Transition metal catalysed sequential reactions (tandem) for the syntheses of functionalized heterocycles are
on high demand due to the presence of less purification and separation steps and production of fewer
numbers of toxic substances throughout the synthesis.1-4
Figure. 1. Some biologically active molecules and natural products containing N-acyl anthranilamide and
quinazolin-4-one motifs.
Despite the progress in this area,5-7 we are lagging behind in the development of new one step
methods proceeds through a sequence of reactions for the synthesis of nitrogen-containing heterocycles,
those are ubiquitous and integral pharmacophoric units prevalent in a diverse variety of bioactive natural
products, synthetic drugs, pharmaceutical and agrochemicals.8-9 Among these nitrogen-containing
heterocycles N-acyl anthranilamide and quinazolin-4-one cores and their derivatives constitute an imperative
class of compounds with a diverse therapeutic and pharmacological properties such as antimicrobial,
anticonvulsant, anticancer, antimalarial, antihypertensive, anti-inflammatory, anti-diabetic, antitumor, anti-
cholinesterase, dihydrofolate reductase inhibition, cellular phosphorylation inhibition, and kinase inhibitory
activities, also, they are part of a number of natural products (Figure 1).10-18 Due to the exhibition of a number
of biological activities and part of a number of natural products, the development of new methods for the
synthesis of N-acyl anthranilamide and quinazoline-4-one skeleton have grabbed lot of attention in recent
years.19-20 In general, we use anthranilic acids for synthesizing corresponding anthranilamide, although, this
process is inherently restricted by the limited range of commercially available anthranilic acids.21 Additionally,
various methods have been reported for the synthesis of N-acyl anthranilamide and quinazoline-4-one
skeleton in recent years (Scheme 1).22-25 However, mostly of them have certain drawbacks such as multistep,
longer reaction time, the limited selection of commercially available starting materials and lower yields.19-20, 22-
24
This prompted us to develop a single step synthesis of N-acyl anthranilamide and the quinazoline-4-one
skeleton using isocyanide-insertion chemistry.
There are many reports about Pd-metal catalyzed aminocarbonylation for the synthesis of amides from
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aryl halides,26-30 however; the use and handling of toxic carbon monoxide limited the scope of this kind of
reaction. In last few years, isocyanides which are isoelectronic with carbon monoxide have been used as
synthetic surrogates of CO in Pd-catalysed tandem reactions for synthesizing a broad range of nitrogen-
containing heterocyles.31-32 Previously, we have been also engaged in exploring the applications of isocyanide
as precursors and developed new methodologies for the synthesis of highly diverse nitrogen-containing
heterocycles.33-34 In continuation of these studies, herein, we reported a synthetic protocol, enabled to furnish
functionalized N-acyl anthranilamide and quinazoline-4-one skeleton starting with o-halo substituted N-
phenylamide via a temperature dependent Pd-catalyzed cascade consisting of carboxamidation or
carboxamidation/de-tertbutylation/cyclodehydration cascade.
Scheme 1. Recent approaches for the synthesis of N-acyl anthranilamide and quinazolin-4-one.
Results and Discussion
We initiated the study by using amide 1a and tert-butyl isocyanide 2a as a model substrates for the
optimization of palladium-catalyzed carboxamidation reaction. The investigation was carried out using
different catalysts, base and solvents (Table 1). The reaction did not proceed in the absence of the Pd catalyst
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(Table 1, entry 1). Among the three Pd-catalysts used (PdCl2, Pd(PPh)3 and Pd(OAc)2), Pd(OAc)2 was found to
o
be the best and provided the product 3a in 72% yield in DMF/H2O as a solvent at 120 C (Table 1, entry 4).
Furthermore, PdCl2 and Pd(PPh)3 furnished inferior yields of product 3a (Table 1, entry 2 and 3). We next
tested the coupling reaction using various bases such as Cs2CO3, K2CO3, Na2CO3, K3PO4 and KOtBu in DMF/H2O
o
at 120 C, with Pd(OAc)2 as a catalyst, among these bases Cs2CO3 was found to be the most effective base
(Table 1, entry 4). Using Pd(OAc)2 as catalyst and Cs2CO3 as base in DMSO/H2O provided slightly poor yield of
3a (Table 1, entry 9), while using toluene and CH3CN under the same conditions furnished 3a in only poor
yields (Table1, entry 10 and 11). The procedure was unfavourable when base was omitted from the reaction
(Table 1, entry 12). Further optimization revealed that PPh3 was essential in this reaction as well. Without
PPh3, the yield decreased to 49%.When tested the carboxamidation reaction in dry DMF as solvent, the
efficacy of carboxamidation reaction was affected and gave product only in trace amount (Table 1, entry 13).
Table 1. Optimization of conditions for N-acyl anthranilamide synthesis.
Entry
catalyst
base
ligand
yield %
b
1
2
3
4
5
6
7
8
-
Cs2CO3
Cs2CO3
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
0c
33
59
72
59
41
32
53
PdCl2
Pd(PPh3)4 Cs2CO3
Pd(OAc)2 Cs2CO3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
K3PO4
KOtBu
Pd(OAc)2 Na2CO3
9
Pd(OAc)2 Cs2CO3
Pd(OAc)2 Cs2CO3 Toluene/ H2O
Pd(OAc)2 Cs2CO3 CH3CN/H2O
DMSO/H2O
41
19
31
0d
10
11
12
13
Pd(OAc)2
-
DMF/H2O
DMF
Pd(OAc)2 Cs2CO3
trace
aReaction conditions: All reactions were performed either in microwave tube or 10 mL round bottom flask
using N-(2-bromophenyl)benzamide 1a (1.0 equiv.), t-butyl isocyanide 2a (1.1 equiv.), Pd-catalyst (5 mol %),
PPh3(5 mol %) and base (1.2 equiv.), solvent (0.5 mL of H2O in 1.5 mL of solvent) at 120oC for 15-20 min in MW
b
or 4-5 hrs at conventional heating. isolated yield.
It is interesting to note that at room temprature there was no conversion but the reaction was
o
completed within 15-20 min under MW conditions at 120 C,while in the absence of MW irradiations it took 4-
5 h to reach the completion. After having optimized reaction conditions for the carboxamidation of N-(2-
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bromophenyl)benzamide 1a with tert-butyl isocyanide 2a, we further explore the reaction scope for other
substituted N-phenylamide with a range of isocyanides (Table 2). In addition to t-butyl isocyanide, the
carboxamidation of 1a with tert-octyl and cyclohexyl isocyanide substrates provided N-acyl anthranilamide
products 3b and 3c in good yields (63 and 74%, respectively) when employing 5 mol % of Pd(OAc)2 in
DMF/H2Ounder microwave irraditation for 20 min. Next, we investigated the scope of substituted N-phenyl
amide (Table 2). To our delight, many substituents at different positions on the phenyl group are compatible
with the reaction conditions, producing the corresponding products in good yields (Table 2, entries 3d-3i). For
electron-donating group such as 3,4,5-trimethoxy, 4-methoxy or 2, 4-methyl substituted phenyl amide with
tert-butyl or cyclohexyl isocyanides reactions work nicely and gave 58%, 55%, 59% and 61% yield respectively
(Table 2, entry 3d-3g). Also, m-Cl and p-F on phenyl group were tolerated well and gave 61% and 59% yield
respectively.
Table 2. Substrate scope of Pd-catalyzed cascade for the synthesis of diverse N-acyl anthranilamide
derivativea.
3b 63%
3e 55%
3a 72%
3d 58%
3c 74%
3f 59%
3g 61%
3j 54%
3i 59%
3h 61%
3k 32%
aReaction conditions: Pd(OAc)2 (5 mol %), Cs2CO3 (1.2 equiv.), DMF/H2O (2 mL), MW, 120 οC, reaction time 20
b
min. Yields refer to isolated products.
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(Table 2, entry 3h &3i). Moreover, we investigated N-phenylamide bearing an alkyl group such as t-butyl and
n-propyl instead of phenyl group and the reaction gave corrosponding products in decent yield (Table 2, entry
3j-3n), however slightly lower yield obtained compared to phenyl group.
There are few methods available for synthesizing quinazolin-4-one by the cyclodehydration reaction of N-acyl
anthranilamides. Although, we envisaged that by conducting the Pd-catalyzed reaction at elevated
temperature, both the carboxamidation and cyclodehydration sequence could be accomplished in a single
step. To synthesize quinazolin-4-one selectively, we did temperature variations under previously optimized
conditions (Table 3). Increasing the temperature of the reaction between 1a and 2a under the optimized
1
catalyst conditions to 140oC and monitoring the reaction by H NMR, N-acyl anthranilamide product 3a was
formed in 42% yield along with the quinazoline-4-one (4a) in 21% yield (Table 3, entry 3). When we elevated
the temprature upto 160oC, quinazoline-4-one was formed selectively (Table 3, entry 5). Also, we found that in
the absence of Pd-catalyst, heating the isolated N-acyl anthranilamide 3a gave quinazoline-4-one 4a only in
trace amount. This result suggested to us that cyclodehydration of 3a to 4a is assisted by the Pd- catalyst
rather than being solely thermally induced.
Table 3. Optimization of condition for quinazolinone synthesisa.
Entry
Variation from the
‘‘standard conditions’’
yield% yield%
a
3a
4a
1.
2.
3.
4.
5.
None
Without Pd(OAc)2
At 140oC
72%
trace
42%
trace
trace
0%
n. r.
21%
n. r.
62%
Without H2O
At 160oC
aReaction conditions: reactions were performed in a microwave vial using N-(2-bromophenyl)benzamide 1a
(1.0 equiv.), t-butylisocyanide 2a (1.1 equiv.),Pd-catalyst (5 mol %), PPh3 (5 mol %) and CS2CO3 (1.2 equiv.),
solvent (0.5 mL of H2O in 1.5 mL DMF) at different temperatures for 15-20 min in MW, yields refer to isolated
products.
After optimizing the reaction conditions for the selective synthesis of quinazoline-4-one by the reaction
of 1a with 2a, we investigated the scope of one step cascade reaction for a broad range of N-phenylamides. A
number of substituents at different positions on the phenyl group such alkyl, methoxy and phenyl compatible
with the optimized reaction conditions, gave the corresponding products 4a-4i in good yields (Table 4, entries
4a-4i). Furthermore, when we tested cyclohexyl isocyanide in place of t-butyl isocyanide, no quinazoline-4-one
formed, N-acyl anthranilamide was the product. Also, this experiment indirectly supports de-tert-butylation
(step viii, scheme 2) during the synthesis of quinazoline-4-one.
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Table 4. Substrate scope of Pd-catalyzed cascade for synthesis of diverse quinazolinone derivativesa.
4a 62%
4d 45%
4b 63%
4e 51%
4c 54%
4f 61%
4g 47%
4i 43%
4h 53%
aReaction conditions: Pd(OAc)2 (5 mol %), Cs2CO3 (1.2 equiv.), DMF/H2O (1.7 mL), MW, 160 οC, reaction time
20 min. Yields refer to isolated products.
A plausible mechanism for anthranilamide and quinazolinone synthesis is proposed in Scheme 2. Thus,
oxidative insertion of Pd(0) into the o-halo substituted N-phenylamide (i) leads to the intermediate (ii) which
on insertion of t-butyl isocyanide (2a) leads to Pd(II) species (iii), Intermediate (iii) via fast ligand exchange
with water gives intermediate (iv), which can react through two differnet pathways which depend on reaction
temperature. At lower temperature (120oC) pathway A is followed, reductive elimination and subsequent
tautomerization, to give N-acyl anthranilamide as product and Pd(0) for another catalytic cycle. At higher
temperature (160oC) reaction follows path B, which goes through de-tertbutylation and subsequent
cyclodehydration in the persence of Pd-catalyst to furnish quinazoline product.
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Scheme 2. Plausible mechanism for anthranilamide and quinazolinone synthesis.
Conclusions
In summary, we have reported the first synthesis of N-acyl anthranilamide and quinazolin-4-one
derivatives via Pd-catalyzed cascade reaction consisting of isocyanide insertion into diverse o-halo
substituted N-phenylamides. This cascade reaction allows the synthesis of N-acyl anthranilamide at
120oC by use of easily available and less expensive starting materials, while at elevated temperature
(160oC) provides quinazolin-4-one as the only detectable product. Additionally, a broad range of
substrates are tolerated in this protocol which provides a diverse library of N-acyl anthranilamide and
quinazolin-4-one derivatives for combinatorial and medicinal chemistry use. Moreover, reported work
here contributes to expand the growing number of transition metal catalysed sequential reactions in
one-pot for the synthesis of functionalized nitrogen-containing heterocycles.
Experimental Section
General. All reagents and solvents were purchased from commercial sources and used without purification.
NMR spectra were recorded on a Bruker spectrometer at 300 (400) and 75 (100) MHz, respectively in
deuterated solvents with TMS as internal reference (chemical shifts δ in ppm, coupling constant J in Hz.).
Multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), multiplet (m), and broad singlet (brs).
Mass spectra and HRMS were taken in the ESI positive ion mode. The reaction progress was monitored by thin
layer chromatography (TLC) on pre-coated silica gel plates. Column chromatography was performed over
Merck silica gel (230-400 flash). All compounds were characterized by TLC, 1H NMR and 13C NMR and HRMS.
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General procedure for the synthesis of substituted N-acyl anthranilamides(3a-3k). Substituted N-
phenylamide 1 (1 equiv.), isocyanide 2 (1.1 equiv.), Pd(OAc)2 (5 mol %), Cs2CO3 (1.2 equiv.), PPh3(5 mol %) and
DMF:H2O (3:1) as a solvent were added in a 10 mL microwave vial containing a stirring bar, the vial was sealed
tightly with a Teflon cap and placed in microwave cavity for 15-20 min at a pre-selected temperature of 120
°C. After completion of the reaction as indicated by TLC, the resulting mixture was filtered through a pad of
celite, and the celite was rinsed with EtOAc. The solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography on silica gel (eluent: hexane/ EtOAc) affording the
corresponding coupling product 3a-3kin 74-32% yields.
General procedure for the synthesis of substituted quinazoline-4-one (4a-4i). Substituted N-phenylamide 1 (1
equiv.), isocyanide 2 (1.1 equiv.), Pd(OAc)2 (5 mol %), Cs2CO3 (1.2 equiv.), PPh3(5 mol %) and DMF:H2O (3:1) as
a solvent were added in a 10 mL microwave vial containing a stirring bar, the vial was sealed tightly with a
Teflon cap and placed in a microwave cavity for 15-20 min at a pre-selected temperature of 160 °C. After
completion of the reaction as indicated by TLC, the resulting mixture was filtered through a pad of celite, and
the celite was rinsed with EtOAc. The solvent was evaporated under reduced pressure and the residue was
purified by flash column chromatography on silica gel (eluent: hexane/ EtOAc) affording the corresponding
coupling products 4a-4i in 63-43% yields.
0
2-Benzamido-N-tert-butylbenzamide (3a). Solid, Yield 72%,mp 143-146 C, FT-IR (KBr)  (cm-1): 3425, 2946,
2324, 1627, 1106, 759,1H NMR (400 MHz, CDCl3): δ 11.95 (brs, 1H), 8.77 (d, J 8.4 Hz, 1H), 8.06-8.04 (m, 2H),
13
7.58-7.44 (m, 5H), 7.09 (t, J 7.2 Hz, 1H), 6.16 (br s, 1H), 1.52 (s, 9H) ppm, C NMR (100 MHz, CDCl3): 169.0,
165.5, 139.5, 134.8, 132.2, 131.7, 128.7, 127.4, 126.4, 122.7, 122.3, 121.6, 52.2, 28.7 ppm, HRMS (ESI) Calcd.
for C18H20N2O2 [M+H]+ 297.1525 Found 297.1595.
1
2-Benzamido-N-(2,4,4-trimethylpentan-2-yl)benzamide (3b). Solid, Yield 63%, H NMR (400 MHz, CDCl3): δ
11.9 (brs, 1H), 8.76 (d, J 8.0 Hz, 1H), 8.05 (d, J 6.8 Hz, 2H), 7.58-7.42 (m, 5H), 7.08 (t, J 7.2 Hz, 1H), 6.20 (brs,
13
1H), 1.92 (s, 2H), 1.57 (s, 6H), 1.07 (s, 9H) ppm, C NMR (100 MHz, CDCl3): 168.8, 165.4, 139.3, 134.8, 132.0,
131.7, 128.7, 127.3, 126.3, 122.8, 122.7, 121.7, 56.1, 51.5, 31.7, 31.5, 29.1 ppm, HRMS (ESI) Calcd. for
C22H28N2O2 [M+H]+ 353.2151 Found 353.2221.
2-Benzamido-N-cyclohexylbenzamide (3c). Solid, Yield 74%, H NMR (300 MHz, CDCl3): δ 12.0 (brs, 1H), 8.77
1
(d, J 8.1 Hz, 1H), 8.05 (d, J 5.7 Hz, 2H), 7.55-7.49 (m, 5H), 7.05 (t, J 7.2 Hz, 1H), 6.43 (brs, 1H), 4.00-3.97 (m, 1H),
13
2.07-2.04 (m, 2H), 1.81-1.67 (m, 3H), 1.51-1.21 (m, 5H) ppm, C NMR (75 MHz, CDCl3): 168.3, 165.5, 139.7,
134.8, 132.4, 131.8, 128.7, 127.3, 126.6, 122.7, 121.5, 121.0, 48.8, 33.0, 25.4, 24.9 ppm, HRMS (ESI) Calcd. for
C20H22N2O2 [M+H]+ 323.1681 Found 323.1751
N-(2-(tert-Butylcarbamoyl)phenyl)-3,4,5-trimethoxybenzamide (3d). Solid, Yield 58%, H NMR (400 MHz,
1
CDCl3): δ 12.1 (brs, 1H), 8.79 (d, J 8.4, 1H), 7.51-7.43 (m, 2H), 7.32 (s, 2H), 7.08 (t, J 7.6 Hz, 1H), 6.13 (brs, 1H),
13
3.97 (s, 6H), 3.92 (s, 3H), 1.49 (s, 9H) ppm, C NMR (100 MHz, CDCl3): 169.3, 165.2, 153.3, 141.2, 140.1, 132.6,
130.4, 126.6, 122.8, 121.7, 121.4, 104.8, 61.1, 56.3, 52.4, 28.9 ppm, HRMS (ESI) Calcd. for C21H26N2O5 [M+H]+
387.1842 Found 387.1917.
1
N-(2-(Cyclohexylcarbamoyl)phenyl)-3,4,5-trimethoxybenzamide (3e). Solid, Yield 55%, H NMR (300 MHz,
CDCl3): δ 12.1 (brs, 1H), 8.88-8.47 (m, 1H), 7.54-7.48 (m, 2H), 7.30 (s, 2H), 7.11 (t, J 9.6 Hz, 1H), 6.28 (brs, 1H),
3.98 (s, 6H), 3.93 (s, 3H), 3.98-3.93 (m, 1H), 2.05-2.02 (m, 2H), 1.80-1.66 (m, 3H), 1.49-1.20 (m, 5H) ppm, 13C
NMR (75 MHz, CDCl3): 168.3, 165.2, 153.2, 141.0, 139.8, 132.5, 130.3, 126.4, 122.7, 121.3, 120.9, 104.7, 60.9,
56.2, 48.8, 32.9, 25.4, 24.8 ppm, HRMS (ESI) Calcd. for C23H28N2O5 [M+H]+ 413.1998 Found 413.2073.
1
N-tert-Butyl-2-(4-methoxybenzamido)benzamide (3f). Solid, Yield 59%, H NMR (400 MHz, CDCl3): δ 11.78
(brs, 1H), 8.69 (d, J 8.4 Hz, 1H), 7.98 (d, J 8.8 Hz, 2H), 7.44-7.39 (m, 2H), 7.00-6.94 (m, 3H), 6.29 (brs, 1H), 3.86
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(s, 3H), 1.50 (s, 9H) ppm, 13C NMR (100 MHz, CDCl3): 169.3, 165.2, 162.6, 139.7, 132.2, 129.4, 127.4, 126.8,
122.6, 122.4, 121.6, 114.1, 55.6, 52.3, 28.7 ppm, HRMS (ESI) Calcd. for C19H22N2O3 [M+H]+ 327.1630 Found
327.1705.
1
2-Benzamido-N-tert-butyl-3,5-dimethylbenzamide (3g). Solid, Yield 61%, H NMR (400 MHz, CDCl3): δ 9.88
(brs, 1H), 8.16 (d, J 7.5 Hz, 2H), 7.58-7.46 ( m, 3H), 7.00 (s, 1H), 6.95 (s, 1H), 6.50 (brs, 1H), 2.25 (s, 3H), 2.19 (s,
13
3H), 1.25 (s, 9H) ppm, C NMR (100 MHz, CDCl3): 169.2, 167.4, 136.6, 136.5, 135.4, 133.8, 132.6, 131.7, 130.3,
128.4, 127.8, 125.3, 51.6, 28.4, 20.8, 18.4 ppm, HRMS (ESI) Calcd. for C20H24N2O2 [M+H]+ 325.1838 Found
325.1912.
1
N-tert-Butyl-2-(3-chlorobenzamido)benzamide (3h). Solid, Yield 61%, H NMR (400 MHz, CDCl3): δ 12.0 (s,
1H), 8.69 (s, J 8.4 Hz, 1H), 8.03 (s, 1H), 7.87 (d, J 7.6 Hz, 1H), 7.53-7.42 (m, 4H), 7.04 (t, J 7.6 Hz, 1H), 6.33 (br s,
1H), 1.53 (s, 9H) ppm, 13C NMR (100 MHz, CDCl3): 169.2, 164.3, 139.3, 136.9, 135.1, 132.3, 131.9, 130.2,
128.3, 126.8, 125.2, 123.2, 122.4, 121.7, 52.4, 28.9 ppm, HRMS (ESI) Calcd. for C18H19ClN2O2 [M+H]+ 331.1135
Found 331.1212.
1
N-tert-Butyl-2-(4-fluorobenzamido)benzamide (3i). Solid, Yield 59%, H NMR (400 MHz, CDCl3): δ 11.9 (brs,
1H), 8.72 (d, J 8.4, 1H), 8.05-8.02 (m, 2H), 7.49-7.42 (m, 2H), 7.20 (t, J 8.4 Hz, 2H), 7.06 (t, J 7.6 Hz, 1H), 6.19
13
(brs, 1H), 1.50 (s, 9H) ppm, C NMR (100 MHz, CDCl3): 169.2, 164.5, 139.7, 132.4, 131.3, 131.2, 130.0, 129.9,
126.7, 123.0, 122.2, 121.7, 116.0, 115.8, 52.4, 28.9 ppm, HRMS (ESI) Calcd. for C18H19FN2O2 [M+H]+ 315.1431
Found 315.1506.
N-tert-Butyl-2-butyramidobenzamide (3k). Solid, Yield 54%, 1H NMR (400 MHz, CDCl3): 10.8 (brs, 1H), 8.4 (s,
1H), 7.39 (t, J 5.4 Hz, 2H), 7.00 (s, J 5.4 Hz, 1H), 6.16 (brs, 1H), 2.35 (t, J 7.2 Hz, 2H), 1.76 (t, J 7.2 Hz, 2H), 1.45
(s, 9H), 1.02-0.96 (m, 3H) ppm, 13C NMR (75 MHz, CDCl3): 172.1, 169.0, 139.2, 132.1, 126.7, 122.6, 122.4,
121.7, 52.2, 40.5, 28.9, 19.2, 13.9 ppm, HRMS (ESI) Calcd. for C15H22N2O2 [M+H]+ 263.1681 Found 263.1757.
1
N-tert-Butyl-2-pentanamidobenzamide (3j). Solid, Yield = 78%, H NMR (400 MHz, CDCl3): 10.8 (brs, 1H), 8.52
(d, J 8.4 Hz, 1H), 7.51-7.36 (m, 2H), 7.03 (t, J 7.6 Hz, 1H), 6.16 (brs, 1H), 2.40 (t, J 7.6 Hz, 2H), 1.76-1.64 (m, 2H),
1.48 (s, 9H), 1.45-1.36 (m, 2H), 0.97 (t, J 7.6 Hz, 3H) ppm, 13C NMR (75 MHz, CDCl3): 172.1, 168.8, 139.1, 131.9,
126.4, 122.4, 122.2, 121.5, 52.0, 38.1, 28.7, 27.6, 22.3, 13.7 ppm, HRMS (ESI) Calcd. for C16H24N2O2 [M+H]+
277.1838 Found 277.1904.
2-Phenylquinazolin-4(3H)-one (4a). Solid, Yield = 62%, mp 176-178 0C FT-IR (KBr)  (cm-1): 3425, 2943, 2354,
1
1637, 1123, 761, H NMR (400 MHz, DMSO-d6): 12.5 (brs, 1H), 8.20 (t, J 8.4 Hz, 3H), 7.86 (t, J 7.6 Hz, 1H), 7.76
(d, J 8.0 Hz, 1H), 7.59-7.50 (m, 4H) ppm, 13C NMR (100 MHz, DMSO-d6): 162.7, 152.7, 149.2, 135.0, 133.1,
131.8, 129.0, 128.2, 127.9, 127.0, 126.3, 121.4 ppm, HRMS (ESI) Calcd. for C14H10N2O [M+H]+ 223.0793 Found
223.0864.
2-(4-Ethylphenyl)quinazolin-4(3H)-one(4b). Solid, Yield 63%, 1H NMR (300 MHz, CDCl3): δ 11.5 (brs, 1H), 8.36
(d, J= 5.8 Hz, 1H), 8.21 (d, J 6.0 Hz, 2H), 7.86-7.79 (m, 2H), 7.53-7.51 (t, J 5.1 Hz, 1H), 7.50 (d, J 6.0 Hz, 2H), 2.81
13
(q, J 5.7 Hz, 2H), 1.35 (t,J 5.7 Hz, 3H) ppm, C NMR (75 MHz, CDCl3): δ 163.7, 151.7, 149.6, 148.4, 134.8, 130.2,
128.6, 127.9, 127.4, 126.5, 126.4, 28.8, 15.3 ppm.
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (4c). Solid, Yield 54%, H NMR (400 MHz, DMSO-d6): δ 12.4 (brs,
1
1H), 8.21-8.13 (m, 3H), 7.84 (t, J=8.4 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H),
3.88 (s, 3H) ppm, 13C NMR (100 MHz, DMSO-d6): δ 162.3, 161.8, 151.8, 148.9, 134.5, 129.4, 127.3, 126.1,
125.7, 124.7, 120.7, 113.9, 55.4 ppm, HRMS (ESI) Calcd. for C15H12N2O2 [M+H]+ 253.0899 Found 253.0970.
2-(3,4,5-Trimethoxyphenyl)quinazolin-4(3H)-one (4d). Solid, Yield 45%, 1H NMR (400 MHz, DMSO-d6): 8.58 (d,
J 8.4 Hz, 1H), 8.37 (brs, 1H), 7.64-7.62 (m, 2H), 7.26-7.22 (m, 1H), 7.16 (s, 2H), 3.95 (s, 6H), 3.93 (s, 3H) ppm,
13C NMR (100 MHz, DMSO-d6): 165.3, 153.7, 142.1, 140.9, 134.5, 132.2, 129.2, 124.4, 121.1, 116.7, 104.7,
102.3, 61.1, 56.5 ppm, HRMS (ESI) Calcd. for C17H16N2O4 [M+H]+ 313.1110 Found 313.1185.
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2‐(3,4‐Dimethoxyphenyl)‐3,4‐dihydroquinazolin‐4‐one (4e). Solid, Yield 51%, H NMR (400 MHz, CDCl3): δ
7.96 (d, J=6.4 Hz, 1H), 7.38-7.34 (m, 1H), 7.23 (brs, 1H), 7.08-7.05 (m, 1H), 6.94-6.88 (m, 2H), 6.71 (d, J=7.6 Hz,
1H), 3.93 (s, 6H) ppm, 13C NMR (100 MHz, CDCl3): δ 164.8, 150.4, 149.6, 147.3, 134.0, 130.9, 128.7, 120.1,
119.7, 114.5, 110.9, 109.8, 69.0, 56.0 ppm.
2‐(4‐Propylphenyl)‐3,4‐dihydroquinazolin‐4‐one (4f). Solid, Yield 61%, 1H NMR (400 MHz, CDCl3): δ 11.26 (brs,
1H), 8.36 (d, J 7.6 Hz, 1H), 8.17 (d, J 8.0 Hz, 2H), 7.86-7.79 (m, 2H), 7.53 (d, J 6.8 Hz, 1H), 7.42 (d, J 8.4 Hz, 2H),
2.74-2.70 (m, 2H), 1.78-1.69 (m, 2H), 1.02 (m, 3H) ppm, 13C NMR (100 MHz, CDCl3): δ 163.5, 151.7, 149.6,
146.9, 134.8, 130.2, 129.2, 127.9, 127.1, 126.6, 126.4, 37.9, 24.3, 13.7 ppm.
1
2‐(4‐tert‐Butylphenyl)‐3,4‐dihydroquinazolin‐4‐one (4g). Solid, Yield 47%, H NMR (400 MHz, CDCl3): δ11.3
(brs, 1H), 8.37 (d, J=7.2 Hz, 1H), 8.20 (d, J 7.2 Hz, 2H), 7.87-7.80 (m, 2H), 7.63 (d, J 8.4 Hz, 2H), 7.54-7.50 (m,
1H), 1.41 (s, 9H)ppm, 13C NMR (100 MHz, CDCl3): δ 163.8, 155.2, 151.7, 149.6, 134.8, 129.9, 127.9, 127.1,
126.5, 126.3, 126.0, 35.0, 31.2 ppm.
1
2‐(2,4,5‐Trimethylphenyl)‐3,4‐dihydroquinazolin‐4‐one (4h). Solid, Yield 53%, H NMR (400 MHz, CDCl3): δ
9.94 ( brs, 1H), 8.31 (d, J 8.0 Hz, 1H), 7.81 (d, J 3.6 Hz, 2H), 7.53-7.49 (m, 1H), 7.36 (s, 1H), 7.12 (s, 1H), 2.48 (s,
3H), 2.31 (s, 6H) ppm, 13C NMR (100 MHz, CDCl3): δ 162.8, 153.6, 149.2, 139.4, 134.7, 134.5, 133.9, 132.8,
130.9, 129.8, 127.8, 126.7, 126.3, 120.6, 19.6, 19.1, 1.02 ppm.
2‐(3‐Phenoxyphenyl)‐3,4‐dihydroquinazolin‐4‐one (4i). Solid, Yield = 43%, 1H NMR (400 MHz, CDCl3): δ 11.38
13
(brs, 1H), 8.26 (s, 1H), 7.99-7.95 (m, 2H), 7.82-7.81 (m, 2H), 7.58-7.10 (m, 8H) ppm, C NMR (100 MHz, CDCl3):
δ 163.6, 157.8, 156.9, 151.0, 149.2, 134.9, 134.7, 130.4, 129.9, 128.0, 126.9, 126.4, 123.6, 122.2, 122.1, 118.9,
118.0 ppm.
Acknowledgements
We acknowledge the financial support from Department of Science and Technology, India
(DST/INSPIRE/04/2017/000095).
Supplementary Material
The copies of 1H NMR and 13C NMR spectra of all synthesized compounds presented in the
Supplementary Material.
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