Synthesis of Quinazolin-4(3 H)-ones via the Reaction of 2-Halobenzamides with Nitriles

Article abstract of DOI:10.1021/acs.joc.8b01460

This paper describes a convenient method to synthesize quinazolin-4(3H)-ones from simple and readily available 2-halobenzamides and nitriles. The Lewis acid Cu-catalyzed nucleophilic addition of 2-halobenzamide to nitriles followed by S_NAr reaction proceeds smoothly in the presence of ^tBuOK as a base to produce quinazolinone derivatives.

Full text of DOI:10.1021/acs.joc.8b01460

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis of Quinazolin-4(3H)‑ones via the Reaction of
2‑Halobenzamides with Nitriles
Xiaoqiang Yu,† Linqi Gao,† Linan Jia,† Yoshinori Yamamoto,†,‡ and Ming Bao*,†
†State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China
‡WPI-Advanced Institute for Materials Research (WPI-AIMR), Tohoku University, Sendai 980-8577, Japan
S
* Supporting Information
ABSTRACT: This paper describes a convenient method to
synthesize quinazolin-4(3H)-ones from simple and readily
available 2-halobenzamides and nitriles. The Lewis acid
Cu-catalyzed nucleophilic addition of 2-halobenzamide to nitriles
followed by SNAr reaction proceeds smoothly in the presence
t
of BuOK as a base to produce quinazolinone derivatives.
under oxidant- and ligand-free conditions (Scheme 1, eq 4).
Given this finding, systematic studies were conducted to
optimize the conditions for this reaction, and the results are
summarized in Table 1.
INTRODUCTION
■
Quinazolin-4(3H)-one structural motifs are frequently found in
natural products1 and bioactive compounds.2 Compounds of
this class are well-known for their anticancer,3 anti-inflamma-
tory,4 and antimicrobial effects,5 among others.6 Therefore, the
development of convenient and efficient methods to synthesize
quinazolin-4(3H)-ones has attracted considerable attention.
Studies over the past decade have synthesized quinazolin-
4(3H)-one using various methods, including the condensation
of 2-aminobenzamide with aryl aldehyde,7 benzenecarboxylic
acid,8 and aroyl chloride;9 Pd-catalyzed cyclocarbonylation with
aryl halides;10 transition-metal-catalyzed C−H amidation with
benzyl alcohols or condensation with benzyl amine;11
(tBuO)2(DTBP)/TsOH-mediated condensation with methyl-
arenes or methylhetarenes;12 CuCl-catalyzed condensation with
methylhetarenes;13 TFA-catalyzed condensation with ketoal-
kynes;14 and redox condensation between o-substituted nitro-
benzenes with amines in the presence of iron and cobalt
catalysts.15 Recent developments have been reported about the
synthesis of quinazolin-4(3H)-ones via Cu-catalyzed Ullmann-
type coupling reactions.16 Fu and Jiang reported the Cu-catalyzed
cascade reactions of amidine hydrochlorides with substituted
2-halobenzaldehydes, 2-halophenylketones, or methyl 2-haloben-
zoates (Scheme 1, eq 1); Fu et al. developed Cu-catalyzed cascade
reactions of 2-halobenzamides with (aryl)methanamines or amino
acids (Scheme 1, eq 2); Tripathi synthesized quinazolin-4(3H)-
ones via Cu-catalyzed one-pot reaction of 2-bromobenzamides
with aldehydes, alcohols, or methyl arenes, and TMSN3 was used
as a nitrogen source (Scheme 1, eq 3). In these reactions, Cu(I)
salts are used as transition-metal catalysts for the Ullmann-type
C−N coupling reaction, and specific ligands or oxidants are
required for reductive elimination to construct C−N bonds.
In our recent study, we have synthesized isoquinolone,
benzoxazole, and 1-naphthol derivatives through Lewis acid
Cu(OAc)2-catalyzed cyclization reactions under oxidant- and
ligand-free conditions.17−19 In the present work, the Lewis acid
Cu(OAc)2-catalyzed nucleophilic addition of 2-halobenzamides
to nitriles followed by intramolecular SNAr reaction proceeded
RESULTS AND DISCUSSION
■
In our initial studies, the reaction of 2-bromobenzamide (1a)
and benzonitrile (2a) was chosen as a model reaction to
optimize the reaction conditions. When 1a and 2a were treated
t
with BuOK in the absence of copper catalyst at 100 °C, the
desired product 2-phenylquinazolin-4(3H)-one (3a) was
obtained in only 14% yield. The failure in yield improvement
through heating required us to add Lewis acid catalyst. There-
fore, various Lewis acid copper catalysts, such as CuI, CuBr,
CuCl, Cu(OAc)2, and Cu(OTf)2, were assessed (entries 2−6).
Of these, Cu(OAc)2 exhibited the best catalytic activity to give
3a in 80% yield (entry 5). The base was subsequently screened
using Cu(OAc)2 as catalyst. Among the bases tested (NaOH,
K2CO3, Cs2CO3, tBuONa, Et3N, and tBuOK), the highest yield
was obtained by using tBuOK as base (entry 5 vs entries 7−12).
tBuOH, dioxane, toluene, DMF, and CH3OH were then
t
examined as solvents, and BuOH was identified as the most
suitable (entry 5 vs entries 13−16). Therefore, the subsequent
cascade reactions of substrates 1 and 2 were performed using
Cu(OAc)2 as catalyst and tBuOK as base in tBuOH at 100 °C for
16 h.
The reactions of 1a with nitriles 2a−l were performed under
optimized conditions to determine the scope of nitrile sub-
strates. The results are summarized in Table 2. As described in
Table 1, the desired product 3a was obtained in 80% yield (entry 1).
Good yields similar to that of 3a were obtained when
4-methylbenzonitrile (2b) and 4-methoxybenzonitrile (2c)
were examined under optimized reaction conditions (entries 2
and 3). A relatively low yield (68%) of 3d was obtained when
2-methylbenzonitrile (2d) was treated with 1a (entry 4). This low
Received: June 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01460
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Quinazolin-4(3H)-ones
a
the desired product 3e in only 25% yield (entry 5). Reactions
with arylnitriles 2f−I bearing a halogen atom on the phenyl ring
were also tolerated under the present cascade reaction (entries
6−9). The reaction of picolinonitrile (2j) was founded to be
suitable for the present method to afford 3j in 55% yield (entry
10). Aliphatic nitriles, acetonitrile (2k), and hexanenitrile (2l)
were then used in this reaction. Quinazolinones 3k and 3l were
obtained in 75% and 71% yields, respectively (entries 11 and 12).
We subsequently examined the scope of this reaction with
various 2-halobenzamides under the optimized reaction con-
ditions, and the results are summarized in Table 3. The reactions
of 2-bromo-4-methylbenzamide (1b) with 2a and 2b proceeded
smoothly to produce the corresponding products 3m and 3n in
good yields (entries 1 and 2). A relatively low yield (60%) of 3o
was observed when 2-bromo-5-methoxybenzamide (1c) was
treated with 2a (entry 3). This result indicated that the reactivity
of the arylamide substrate was remarkably influenced by the
electronic properties of the aromatic ring. The reaction of 1c
with 2f produced a low yield of quinazolinone 3p due to the
steric hindrance created by the ortho-halo group on 2f and an
electron-donating group linking on the aromatic ring in 1c
(entry 4). The secondary amides 1d and 1e were also utilized
successfully for the synthesis of 2,3-disubstituted quinazoli-
nones. Products 3q and 3r were obtained in 86% and 80% yields,
respectively (entries 5 and 6). A low yield (35%) of 3s was
obtained when 2a was treated with 3-bromoisonicotinamide
(1f) (entry 7). This low yield was attributed to the ligating
ability of nitrogen atom on pyridine that can lead to catalyst
deactivation. In consideration of the good preliminary results
with 2-bromobenzamides, the present method was then applied
for 2-iodobenzamide (1g). The reactions of 1g with 2a were
carried out under the same conditions, and the desired product
3a was obtained in 85% yield (entry 8). However, no reaction was
observed when 2-cholobenzamide (1h) was examined (entry 9).
On the basis of our experimental outcomes and previous
reports, a plausible mechanism is proposed to account for the
Table 1. Reaction Condition Screening
b
entry
catalyst
none
base
solvent
yield (%)
1
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
none
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
Dioxane
DMF
14
68
2
CuI
3
CuBr
62
4
CuCl
54
5
Cu(OAc)2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
80
6
60
7
NR
39
8
NaOH
K2CO3
Cs2CO3
tBuONa
Et3N
tBuOK
tBuOK
tBuOK
tBuOK
9
NR
NR
31
10
11
12
13
14
15
16
NR
51
22
Toluene
CH3OH
18
23
a
Reaction conditions: 2-Bromobenzamide (1a, 0.5 mmol), benzonitrile
(2a, 0.75 mmol), base (1.5 mmol), and copper catalyst (10 mol %) in
solvent (3.0 mL) at 100 °C for 16 h. Isolated yield was provided.
b
yield was attributed to the steric hindrance created by the ortho-
methyl group in 2d. However, the reaction of substrate 2e
containing an ortho-azyl group on the benzene ring generated
B
DOI: 10.1021/acs.joc.8b01460
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 2. Synthesis of Quinazolin-4(3H)-ones from Various Nitriles
a
Reaction conditions: 2-Bromobenzamide (1a, 0.5 mmol), benzonitrile (2a, 0.75 mmol), base (1.5 mmol), and copper catalyst (10 mol %) in
b
solvent (3.0 mL) at 100 °C for 16 h. Isolated yield was provided.
spectra were recorded on a Bruker Avance II-400 spectrometer
(400 MHz for 1H, 100 MHz for 13C); CDCl3 (or DMSO-d6) and TMS
were used as a solvent and an internal standard, respectively. The
chemical shifts are reported in ppm downfield (δ) from TMS, the
coupling constants (J) are given in Hz. The peak patterns are indicated
as follows: s, singlet; d, doublet; t, triplet; m, multiplet; q, quartet; bs,
broad singlet. TLC was carried out on SiO2 (silica gel 60 F254, Merck),
and the spots were located with UV light. Flash chromatography was
carried out on SiO2 (silica gel 60, 200−300 mesh).
present catalytic cascade reaction (Scheme 2). Initially,
coordination of the cyano group of 1a to Cu(OAc)2 generates
complex I. Then, the nucleophilic addition of 2a to complex I
occurs to produce intermediate II, which subsequently under-
goes intramolecular SNAr reaction to afford intermediate III.
Elimination of intermediate III generates the desired product 3a
with the liberation of Cu(OAc)Br. Finally, ion exchange of
Cu(OAc)Br with KOAc generated in the initial step occurs.
Representative Procedure for the Synthesis of Quinazoli-
nones. A mixture of 2-bromobenzamide (100.0 mg, 0.5 mmol),
benzonitrile (77.3 mg, 0.75 mmol), Cu(OAc)2 (9.1 mg, 0.05 mmol),
CONCLUSION
■
A new method using simple and readily available starting
materials has been developed to synthesize 2-substituted-
4(3H)-quinazolinones. The Lewis acid Cu-catalyzed nucleo-
philic addition of 2-halobenzamides to nitriles and intra-
molecular SNAr reaction proceeded smoothly in the presence
t
tBuOK (168.3 mg, 1.5 mmol), and BuOH (3.0 mL) was stirred at
100 °C under nitrogen atmosphere for 16 h. After cooling to room
temperature, water was added to quench the reaction. The mixture was
then extracted with ethyl acetate (10 mL × 3). The combined organic
layers were dried over anhydrous Na2SO4. After filtration, the solvent
was removed under vacuum. The crude product was purified by column
chromatography (eluent, ethyl acetate: petroleum ether = 1:15) to
afford 2-phenylquinazolin-4(3H)-one as a white solid (88.8 mg, 80%
yield).
Characterization Data of Products. 2-Phenylquinazolin-4(3H)-
one (3a).20 White solid (0.089 g, 80% yield). Mp 233−235 °C (lit.16
233−235 °C). 1H NMR (400 MHz, CDCl3) δ 11.67(bs, 1H), 8.32−8.35
(m, 1H), 8.25−8.28 (m, 2H), 7.78−7.86 (m, 2H), 7.58−7.60 (m, 3H),
7.49−7.53 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 162.7, 152.7,
149.1, 134.9, 133.2, 131.8, 129.0, 128.2, 127.9, 127.0, 126.3, 121.4.
t
of BuOK as a base to produce quinazolinone derivatives. The
affordability of the catalyst, the wide availability of the starting
materials, and the simplicity of the procedure render the present
methodology useful in organic synthesis.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under a
nitrogen atmosphere unless otherwise noted. Solvents were purified by
standard techniques without special instructions. H and 13C NMR
1
C
DOI: 10.1021/acs.joc.8b01460
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 3. Synthesis of Quinazolin-4(3H)-ones from Various 2-Halobenzamides
a
Reaction conditions: 2-Bromobenzamide (1a, 0.5 mmol), benzonitrile (2a, 0.75 mmol), base (1.5 mmol), and copper catalyst (10 mol %) in
b
c
d
solvent (3.0 mL) at 100 °C for 16 h. Isolated yield was provided. Reacted with benzonitrile (2a, 0.75 mmol). Reacted with
4-methoxybenzonitrile (2c, 0.75 mmol). Reacted with 2-chlorobenzonitrile (2f, 0.75 mmol).
e
2-(4-Methylphenyl)quinazolin-4(3H)-one (3b).20 White solid
(0.093 g, 79% yield). Mp 261−264 °C (lit.16 261−263 °C).
1H NMR (400 MHz, DMSO-d6) δ 12.46 (bs, 1H), 8.15 (d, J =
7.9 Hz, 1H), 8.13−8.09 (m, 2H), 7.82−7.80 (m, 1H), 7.72 (m, 1H),
D
DOI: 10.1021/acs.joc.8b01460
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 2. Possible Reaction Mechanism
2
7.52−7.48 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H). 13C NMR
(126 MHz, DMSO-d6) δ 162.2, 152.2, 148.8, 141.4, 134.5, 129.9, 129.2,
127.7, 127.4, 126.4, 125.8, 120.9, 21.0.
3JC−F = 9.0 Hz), 129.2, 127.3, 126.5, 125.7, 120.7, 115.5(d, JC−F
22 Hz).
=
2-(2-Pyridyl)quinazoline-4(3H)-one (3j).24 White solid (0.061 g,
55% yield). Mp 169−171 °C (lit.28 168−170 °C). 1H NMR (400 MHz,
DMSO-d6) δ 11.75 (bs, 1H), 8.73 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H), 8.17
(d, J = 8.0 Hz, 1H), 8.04 (t, J = 7.6 Hz, 1H), 7.84 (t, J = 7.4 Hz, 1H),
7.77 (d, J = 8.0 Hz, 1H), 7.63 (m, 1H), 7.54 (t, J = 7.2 Hz, 1H);
13C NMR (100 MHz, DMSO-d6) δ 160.9, 150.0, 149.0, 148.7, 138.0,
134.7, 127.7, 127.3, 126.6, 126.2, 122.2, 122.0.
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (3c).20 White solid
(0.107 g, 85% yield). Mp 247−248 °C (lit.16 245−246 °C).
1H NMR (400 MHz, DMSO-d6) δ 12.42 (bs, 1H), 8.23−8.16
(m, 2H), 8.13 (d, J = 7.9 Hz, 1H), 7.83−7.79 (m, 1H), 7.70 (d, J =
8.3 Hz, 1H), 7.50−7.48 (m, 1H), 7.08 (d, J = 7.9, 2H), 3.84 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 162.7, 152.7, 149.2, 141.9, 134.9,
130.3, 129.6, 128.1, 127.8, 126.8, 126.3, 121.4, 21.4.
2-Methylquinazolin-4(3H)-one (3k).25 White solid (0.060 g, 75%
2-(o-Tolyl)quinazolin-4(3H)-one (3d).21 White solid (0.072 g, 61%
yield). Mp 238−240 °C (lit.20 235−239 °C). H NMR (400 MHz,
1
yield). Mp 219−221 °C (lit.19 220−222 °C). H NMR (400 MHz,
1
DMSO-d6) δ 12.19 (bs, 1H), 8.06 (dd, J = 1.6, 8.0 Hz, 1H), 7.80−7.72
(m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.46−7.41 (m, 1H), 2.34 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 162.2, 154.7, 149.4, 134.7, 127.0,
126.3, 126.1, 121.1, 21.9.
CDCl3) δ 10.56 (bs, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 3.6 Hz,
2H), 7.58 (m, 1H), 7.53−7.48 (m, 1H), 7.46−7.40 (m, 1H), 7.35
(m, 2H), 2.53 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 161.7, 154.3,
148.7, 136.1, 134.4, 134.2, 130.5, 129.8, 129.1, 127.3, 126.6, 125.7,
125.6, 120.9, 19.5.
2-Butylquinazolin-4(3H)-one (3l).26 White solid (0.077 g, 71%
yield). Mp 107−108 °C (lit.21 108−109 °C). H NMR (400 MHz,
1
2-(2-Aminophenyl)quinazolin-4(3H)-one (3e).22 Brownish solid
(0.030 g, 25% yield). Mp 226−228 °C (lit.18 224−226 °C). 1H NMR
(400 MHz, DMSO-d6) δ 12.12 (bs, 1H), 8.14 (dd, J = 1.6, 7.9 Hz, 1H),
7.84−7.80 (m, 1H), 7.78−7.70 (m, 2H), 7.53−7.45 (m, 1H), 7.26−
7.18 (m, 1H), 7.08 (bs, 2H), 6.84 (d, J = 8.3 Hz, 1H), 6.65−6.57
(m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 162.5, 154.0, 149.9, 148.5,
135.0, 132.3, 129.3, 127.4, 126.7, 126.2, 120.9, 117.1, 115.5, 112.8.
2-(4-Chlorophenyl)quinazolin-4(3H)-one (3f).20 White solid
CDCl3) δ 12.20 (bs, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.79−7.73 (m, 1H),
7.70 (d, J = 8.4 Hz, 1H), 7.50−7.43 (m, 1H), 2.82 (t, J = 8.0 Hz, 2H),
1.93−1.84 (m, 2H), 1.54−1.45 (m, 2H), 1.25 (m, 2H) 1.00 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.6, 157.2, 149.5,
134.7, 127.2, 126.2, 126.2, 120.4, 35.6, 29.7, 22.4, 13.8.
7-Methyl-2-phenylquinazolin-4(3H)-one (3m).20 Light yellow
solid (0.099 g, 84% yield). Mp 240−241 °C (lit.16 240−241 °C).
1H NMR (400 MHz, DMSO-d6) δ 12.44 (bs, 1H), 8.17 (d, J = 7.6 Hz,
2H), 8.03 (d, J = 8.0 Hz, 1H), 7.65−7.48 (m, 4H), 7.33 (d, J = 8.4 Hz,
1H), 2.46 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 162.2, 152.5,
148.9, 145.2, 132.9, 131.9, 128.1, 127.8, 127.2, 125.8, 118.7, 21.4.
2-(4-Methoxyphenyl)-7-methylquinazolin-4(3H)-one (3n).20
Light yellow solid (0.094 g, 75% yield). Mp 248−250 °C (lit.16 246−
248 °C). 1H NMR (400 MHz, DMSO-d6) δ 12.28 (bs, 1H), 8.21−8.14
(m, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.28 (dd, J = 1.6, 8.4 Hz,
1H), 7.11−7.03 (m, 2H), 3.84 (s, 3H), 2.45 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 162.2, 161.9, 152.0, 149.1, 145.1, 129.5, 127.7,
127.0, 125.8, 124.9, 118.4, 114.1, 55.5, 21.4.
(0.079 g, 62% yield). Mp 298−300 °C (lit.16 299−301 °C). H NMR
1
(400 MHz, DMSO-d6) δ 12.46 (bs, 1H), 8.23−8.18 (m, 2H), 8.17−8.13
(dd, J = 0.8, 7.6 Hz, 1H), 7.87−7.83 (m, 1H), 7.75 (d, J = 7.6 Hz, 1H),
7.65−7.60 (m, 2H), 7.54 (m, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 169.2, 166.9, 139.4, 136.1, 133.1, 132.7, 130.6, 129.4, 128.6, 128.3,
127.5, 118.7.
2-(2-Bromophenyl)quinazolin-4(3H)-one (3g).23 Light brown solid
(0.052 g, 35% yield). Mp 175−177 °C (lit.17 175−177 °C). 1H NMR
(400 MHz, DMSO-d6) δ 12.61 (bs, 1H), 8.18 (dd, J = 1.6, 8.0 Hz, 1H),
7.85 (m, 1H), 7.77 (dd, J = 1.2, 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H),
7.65 (dd, J = 1.6, 7.2 Hz, 1H), 7.60−7.46 (m, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 161.5, 153.4, 148.6, 135.9, 134.7, 132.7, 131.7,
130.8, 127.8, 127.5, 127.2, 125.9, 121.3, 121.0.
6-Methoxy-2-phenylquinazolin-4(3H)-one (3o).20 White solid
(0.076 g, 60% yield). Mp 250−252 °C (lit.16 249−251 °C).
1H NMR (400 MHz, DMSO-d6) δ 12.52 (bs, 1H), 8.16 (dd, J =
1.6, 7.6 Hz, 2H), 7.70 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 3.2 Hz, 1H),
7.58−7.50 (m, 3H), 7.44 (dd, J = 3.2, 8.8 Hz, 1H), 3.89 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 162.12, 157.8, 150.2, 143.3, 132.9,
131.1, 129.3, 128.7, 127.6, 124.2, 121.9, 105.9, 55.7.
2-(2-Chlorophenyl)-6-methoxyquinazolin-4(3H)-one (3p). Light
yellow solid (0.058 g, 41% yield). Mp 214−215 °C. IR (KBr) ν 3430,
3066, 1670, 1604, 1491, 1371, 1257, 1088, 1036, 891, 835, 766 cm−1;
1H NMR (400 MHz, DMSO-d6) δ 12.59 (bs, 1H), 7.69−7.64 (m, 2H),
7.63−7.59 (m, 1H), 7.58−7.53 (m, 2H), 7.51−7.43 (m, 2H), 3.90(s,
3H); 13C NMR (100 MHz, DMSO-d6) δ 161.3, 158.2, 150.1, 143.1,
134.0, 131.7, 131.6, 131.1, 129.7, 129.3, 127.3, 124.1, 122.2, 106.0,
2-(2-Chlorophenyl)quinazolin-4(3H)-one (3h).23 White solid
(0.072 g, 57% yield). Mp 172−173 °C (lit.17 172−174 °C). 1H NMR
(400 MHz, DMSO-d6) δ 12.64 (bs, 1H), 8.19 (dd, J = 1.2, 8.0 Hz, 1H),
7.85 (m, 1H), 7.73−7.66 (m, 2H), 7.65−7.53 (m, 3H), 7.49 (m, 1H);
13C NMR (100 MHz, DMSO-d6) δ 161.4, 152.2, 148.6, 134.6, 133.8,
131.6, 131.5, 130.8, 129.6, 127.5, 127.2, 127.1, 125.8, 121.3.
2-(4-Fluorophenyl)quinazolin-4(3H)-one (3i).21 White solid
(0.072 g, 60% yield). Mp 292−294 °C (lit.19 293−295 °C). H NMR
1
(500 MHz, DMSO-d6) δ 12.57 (bs, 1H), 8.32−8.21 (m, 2H), 8.16
(dd, J = 8.0, 1.7 Hz, 1H), 7.84 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.52
(m, 1H), 7.43−7.35 (m, 2H).; 13C NMR (100 MHz, DMSO-d6)
1
δ 163.9(d, JC−F = 248.0 Hz), 162.2, 151.3, 148.5, 134.5, 130.2(d,
E
DOI: 10.1021/acs.joc.8b01460
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
55.8; HRMS m/z (ESI, ion trap) calcd for C15H12ClN2O2 (M + H)+
287.0587, found 287.0587.
Advances in the Structural Library of Functionalized Quinazoline and
Quinazolinone Scaffolds: Synthetic Approaches and Multifarious
Applications. Eur. J. Med. Chem. 2014, 76, 193.
3-Benzyl-2-phenylquinazolin-4(3H)-one (3q).27 White solid
(0.134 g, 86% yield). Mp 143−145 °C (lit.22 131−133 °C). H NMR
1
(3) (a) Takase, Y.; Saeki, T.; Watanabe, N.; Adachi, H.; Souda, S.;
Saito, I. Cyclic GMP Phosphodiesterase Inhibitors. 2. Requirement of
6-Substitution of Quinazoline Derivatives for Potent and Selective
Inhibitory Activity. J. Med. Chem. 1994, 37, 2106. (b) Cao, S. L.; Feng,
Y. P.; Jiang, Y. Y.; et al. Synthesis and in Vitro Antitumor Activity of
4(3H)-Quinazolinone Derivatives with Dithiocarbamate Side Chains
Short Communication. Bioorg. Med. Chem. Lett. 2005, 15, 1915.
(c) Chandrika, P. M.; Yakaiah, T.; Rao, A. R. R.; Narsaiah, B.; Reddy, N.
C.; Sridhar, V.; Rao, J. V. Synthesis of Novel 4,6-Disubstituted
Quinazoline Derivatives, their Anti-inflammatory and Anti-cancer
Activity (cytotoxic) Against U937 Leukemia Cell Lines. Eur. J. Med.
Chem. 2008, 43, 846.
(4) Ozaki, K.-i.; Yamada, Y.; Oine, T.; Ishizuka, T.; Iwasawa, Y.
Studies on 4(1H)-Quinazolinones. 5. Synthesis and Antiinflammatory
Activity of 4(1H)-Quinazolinone Derivatives. J. Med. Chem. 1985, 28,
568.
(5) Kuarm, B. S.; Reddy, Y. T.; Madhav, J. V.; Crooks, P. A.; Rajitha, B.
3-[Benzimidazo- and 3-[Benzothiadiazoleimidazo-(1,2-c)quinazolin-5-
yl]-2H-chromene-2-ones as Potent Antimicrobial Agents. Bioorg. Med.
Chem. Lett. 2011, 21, 524.
(400 MHz, CDCl3) δ 8.38 (d, J = 8.0 Hz, 1H), 7.85−7.74 (m, 2H),
7.56−7.50 (m, 1H), 7.49−7.43 (m, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.34
(d, J = 7.6 Hz, 2H), 7.23−7.16 (m, 3H), 6.96−6.89 (m, 2H), 5.27
(s, 2H). 13C NMR (100 MHz, CDCl3) δ 162.5, 156.4, 147.3, 136.6,
135.3, 134.6, 129.9, 128.6, 128.5, 128.0, 127.6, 127.4, 127.2, 127.1,
127.0, 120.9, 48.8.
3-Butyl-2-phenylquinazolin-4(3H)-one (3r).28 White solid
(0.111 g, 80% yield). Mp 112−113 °C (lit.23 115−116 °C). H NMR
1
(400 MHz, CDCl3) δ 8.33 (d, J = 8.0 Hz, 1H), 7.79−7.70 (m, 2H),
7.57−7.46 (m, 6H), 3.98 (t, J = 7.6 Hz, 2H), 1.65−1.55 (m, 2H), 1.20−
1.14 (m, 2H), 0.76 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 162.2, 156.2, 147.2, 135.6, 134.3, 129.8, 128.8, 127.8, 127.4, 126.9,
126.8, 120.9, 45.7, 30.7, 19.9, 13.4.
2-Phenylpyrido[3,4-d]pyrimidin-4(3H)-one (3s).29 White solid
(0.039 g, 35% yield). Mp 264−266 °C (lit.29 266−267 °C). H NMR
1
(400 MHz, DMSO-d6) δ 12.92 (bs, 1H), 9.12 (s, 1H), 8.65 (d, J = 5.2 Hz,
1H), 8.22−8.17 (m, 2H), 7.97 (dd, J = 0.8, 5.2 Hz, 1H), 7.64−7.54
(m, 3H); 13C NMR (100 MHz, DMSO-d6) δ 161.6, 154.5, 150.7, 145.7,
143.6, 132.6, 131.7, 128.6, 127.9, 125.9, 118.0.
(6) (a) Matsuno, K.; Ushiki, J.; Seishi, T.; Ichimura, M.; Giese, N. A.;
Yu, J. C.; Takahashi, S.; Oda, S.; Nomoto, Y. Potent and Selective
Inhibitors of Platelet-Derived Growth Factor Receptor Phosphor-
ylation. 3. Replacement of Quinazoline Moiety and Improvement of
Metabolic Polymorphism of 4-[4-(N-Substituted(thio)carbamoyl)-1-
piperazinyl]-6,7- dimethoxyquinazoline Derivatives. J. Med. Chem.
2003, 46, 4910. (b) Malecki, N.; Carato, P.; Rigo, B.; Goossens, J. F.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01460.
■
S
Characterization for compounds, including copies of
1H and 13C NMR spectra (PDF)
́
Houssin, R.; Bailly, C.; Henichart, J. P. Synthesis of Condensed
Quinolines and Quinazolines as DNA Ligands. Bioorg. Med. Chem.
2004, 12, 641. (c) Kikuchi, H.; Yamamoto, K.; Horoiwa, S.; Hirai, S.;
Kasahara, R.; Hariguchi, N.; Matsumoto, M.; Oshima, Y. Exploration of
a New Type of Antimalarial Compounds Based on Febrifugine. J. Med.
Chem. 2006, 49, 4698.
(7) (a) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Synthesis of Quinazolinones and Quinazolines. Tetrahedron 2005, 61,
10153. (b) Mitobe, Y.; Ito, S.; Mizutani, T.; Nagase, T.; Sato, N.;
Tokita, S. Bioorg. Development of a Selective and Potent Radioactive
Ligand for Histamine H3 Receptors: A Compound Potentially Useful
for Receptor Occupancy Studies. Bioorg. Med. Chem. Lett. 2009, 19,
4075.
(8) Purandare, A. V.; Gao, A.; Wan, H.; Somerville, J.; Burke, C.;
Seachord, C.; Vaccaro, W.; Wityak, J.; Poss, M. A. Bioorg. Identification
of Chemokine Receptor CCR4 Antagonist. Bioorg. Med. Chem. Lett.
2005, 15, 2669.
(9) Potewar, T. M.; Nadaf, R. N.; Daniel, T.; Lahoti, R. J.; Srinivasan,
K. V. A Novel One-Pot Synthesis of 2-Aryl-4(3H)-Quinazolinones
Using Room Temperature Ionic Liquid as Reaction Medium as well as
Promoter. Synth. Commun. 2005, 35, 231.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mingbao@dlut.edu.cn.
ORCID
Xiaoqiang Yu: 0000-0001-9396-3882
Ming Bao: 0000-0002-5179-3499
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation
of China (nos. 21372035 and 21572028) for their financial
support. This work was also supported by Liaoning Natural
Science Foundation of China (201602181) and the Outstanding
Young Scholars Development Growth Plan of universities in the
Liaoning Province (LJQ2015027).
(10) (a) Wu, X. F.; He, L.; Neumann, H.; Beller, M. Palladium-
Catalyzed Carbonylative Synthesis of Quinazolinones from 2-Amino-
benzamide and Aryl Bromides. Chem. - Eur. J. 2013, 19, 12635. (b) Li,
H.; He, L.; Neumann, H.; Beller, M.; Wu, X. F. Cascade Synthesis of
Quinazolinones from 2-Aminobenzonitriles and Aryl Bromides via
Palladium-Catalyzed Carbonylation Reaction. Green Chem. 2014, 16,
1336. (c) Zheng, Z.; Alper, H. Palladium-Catalyzed Cyclocarbonyla-
tion of o-Iodoanilines with Imidoyl Chlorides to Produce Quinazolin-
4(3H)-ones. Org. Lett. 2008, 10, 829. (d) Zeng, F.; Alper, H. Tandem
Palladium-Catalyzed Addition/Cyclocarbonylation: An Efficient Syn-
thesis of 2-Heteroquinazolin-4(3H)-ones. Org. Lett. 2010, 12, 1188.
(e) Zeng, F.; Alper, H. One-Step Synthesis of Quinazolino[3,2-
a]quinazolinones via Palladium-Catalyzed Domino Addition/Carbox-
amidation Reactions. Org. Lett. 2010, 12, 3642. (f) He, L.; Li, H.;
Neumann, H.; Beller, M.; Wu, X. F. Highly Efficient Four-Component
Synthesis of 4(3H)-Quinazolinones: Palladium-Catalyzed Carbon-
ylative Coupling Reactions. Angew. Chem., Int. Ed. 2014, 53, 1420.
(g) Sadig, J. E. R.; Foster, R.; Wakenhut, F.; Willis, M. C. Palladium-
REFERENCES
■
(1) For selected examples, see: (a) Michael, J. P. Quinoline,
Quinazoline and Acridone Alkaloids. Nat. Prod. Rep. 2008, 25, 166.
(b) Michael, J. P. Quinoline, Quinazoline and Acridone Alkaloids. Nat.
Prod. Rep. 2007, 24, 223. (c) Michael, J. P. Quinoline, Quinazoline and
Acridone Alkaloids. Nat. Prod. Rep. 2005, 22, 627. (d) Michael, J. P.
Quinoline, Quinazoline and Acridone Alkaloids. Nat. Prod. Rep. 2004,
21, 650. (e) Michael, J. P. Quinoline, Quinazoline and Acridone
Alkaloids. Nat. Prod. Rep. 2003, 20, 476. (f) Michael, J. P. Quinoline,
Quinazoline and Acridone Alkaloids. Nat. Prod. Rep. 2002, 19, 742.
(g) Taylor, A. P.; Robinson, R. P.; Fobian, Y. M.; Blakemore, D. C.;
Jones, L. H.; Fadeyi, O. Modern Advances in Heterocyclic Chemistry in
Drug Discovery. Org. Biomol. Chem. 2016, 14, 6611.
(2) For selected examples, see: (a) Demeunynck, M.; Baussanne, I.
Survey of Recent Literature Related to the Biologically Active 4(3H)-
Quinazolinones Containing Fused Heterocycles. Curr. Med. Chem.
2013, 20, 794. (b) Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Recent
F
DOI: 10.1021/acs.joc.8b01460
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Catalyzed Synthesis of Benzimidazoles and Quinazolinones from
Common Precursors. J. Org. Chem. 2012, 77, 9473. (h) Shen, Y.; Han,
C.; Cai, S.; Lu, P.; Wang, Y. One-Pot Synthesis of 4(3H)-
Quinazolinones from Azides, Alkynes, Anilines, and Carbon Monoxide.
Tetrahedron Lett. 2012, 53, 5671.
Aldehydes and Aqueous Ammonia: Application to the Synthesis of the
Alkaloid Tryptanthrin. RSC Adv. 2014, 4, 59289. (i) Xu, W.; Zhu, X. R.;
Qian, P. C.; Zhang, X. G.; Deng, C. L. Copper-Catalyzed Tandem
Reaction of 2-Aminobenzamides with Tertiary Amines for the
Synthesis of Quinazolinone Derivatives. Synlett 2016, 27, 2851.
(j) Upadhyaya, K.; Thakur, R. K.; Shukla, S. K.; Tripathi, R. P. One-
Pot Copper(I)-Catalyzed Ligand/Base-Free Tandem Cyclooxidative
Synthesis of Quinazolinones. J. Org. Chem. 2016, 81, 5046.
(17) Mayo, M. S.; Yu, X.; Feng, X.; Yamamoto, Y.; Bao, M.
Isoquinolone Synthesis through SNAr Reaction of 2-Halobenzonitriles
with Ketones Followed by Cyclization. J. Org. Chem. 2015, 80, 3998.
(18) Mayo, M. S.; Yu, X.; Zhou, X.; Feng, X.; Yamamoto, Y.; Bao, M.
Synthesis of Benzoxazoles from 2-Aminophenols and β-Diketones
Using a Combined Catalyst of Brønsted Acid and Copper Iodide. J. Org.
Chem. 2014, 79, 6310.
(19) Yu, X.; Zhu, P.; Bao, M.; Yamamoto, Y.; et al. 1-Naphthol
Synthesis through Base-Promoted SNAr Reactions of ortho-Haloace-
tophenones Followed by Lewis-Acid-Catalyzed Cyclization. Asian J.
Org. Chem. 2016, 5, 699.
(20) Xu, W.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Copper-Catalyzed
Domino Synthesis of Quinazolinones via Ullmann-Type Coupling and
Aerobic Oxidative C−H Amidation. Org. Lett. 2011, 13, 1274.
(21) Jiang, X.; Tang, T.; Wang, J. M.; Chen, Z.; Zhu, Y. M.; Ji, S. J.
Palladium-Catalyzed One-Pot Synthesis of Quinazolinones via tert-
Butyl Isocyanide Insertion. J. Org. Chem. 2014, 79, 5082.
(22) Yuan, A.; Zheng, C.; Zhang, Z.; Yang, L.; Liu, C.; Wang, H. A
Novel Quinazolinone Derivative as Fluorescence Quenching Off-On
Sensor for High Selectivity of Fe3+. J. Fluoresc. 2014, 24, 557.
(23) Laha, J. K.; Tummalapalli, K. S. S.; Jethava, K. P. Implications of
Dynamic Imine Chemistry for the Sustainable Synthesis of Nitrogen
Heterocycles via Transimination followed by Intramolecular Cyclisa-
tion. Org. Biomol. Chem. 2016, 14, 2473.
(24) Mekala, R.; Akula, R.; Kamaraju, R.; Bannoth, C.; Regati, S.;
Sarva, J. An Efficient Synthesis of 2-Substituted Quinazolin-4(3H)-ones
Catalyzed by Iron(III) Chloride. Synlett 2014, 25, 821−826.
(25) Chen, X.; Chen, T.; Zhou, Y.; Han, D.; Han, L.; Yin, S. Metal-
Free Aerobic Oxidative C−N Bond Cleavage of Tertiary Amines for the
Synthesis of N-Heterocycles with High Atom Efficiency. Org. Biomol.
Chem. 2014, 12, 3802.
(26) Chen, H.; Chiba, S. Copper-Catalyzed Redox-Neutral C−H
Amination with Amidoximes. Org. Biomol. Chem. 2014, 12, 42−46.
(27) Parua, S.; Das, S.; Sikari, R.; Sinha, S.; Paul, N. D. One-Pot
Cascade Synthesis of Quinazolin-4(3H)-ones via Nickel-Catalyzed
Dehydrogenative Coupling of o-Aminobenzamides with Alcohols. J.
Org. Chem. 2017, 82, 7165−7175.
(28) Sadig, J. E. R.; Foster, R.; Wakenhut, F.; Willis, M. C. Palladium-
Catalyzed Synthesis of Benzimidazoles and Quinazolinones from
Common Precursors. J. Org. Chem. 2012, 77, 9473.
(11) (a) Hikawa, H.; Ino, Y.; Suzuki, H.; Yokoyama, Y. Pd-Catalyzed
Benzylic C−H Amidation with Benzyl Alcohols in Water: A Strategy to
Construct Quinazolinones. J. Org. Chem. 2012, 77, 7046. (b) Zhou, J.;
Fang, J. One-Pot Synthesis of Quinazolinones via Iridium-Catalyzed
Hydrogen Transfers. J. Org. Chem. 2011, 76, 7730. (c) Sharif, M.;
Opalach, J.; Langer, P.; Beller, M.; Wu, X. F. Oxidative Synthesis of
Quinazolinones and Benzothiadiazine 1,1-Dioxides from 2-Amino-
benzamide and 2-Aminobenzenesulfonamide with Benzyl Alcohols and
Aldehydes. RSC Adv. 2014, 4, 8. (d) Ge, W.; Zhu, X.; Wei, Y. Oxidative
Synthesis of Quinazolinones and Benzothiadiazine 1,1-Dioxides from
2-Aminobenzamide and 2-Aminobenzenesulfonamide with Benzyl
Alcohols and Aldehydes. RSC Adv. 2013, 3, 10817. (e) Nguyen, T.
B.; Ermolenko, L.; Al-Mourabit, A. Selective Autoxidation of Benzyl-
amines: Application to the Synthesis of Some Nitrogen Heterocycles.
Green Chem. 2013, 15, 2713. (f) Watson, A. J. A.; Maxwell, A. C.;
Williams, J. M. Ruthenium-Catalysed Oxidative Synthesis of Hetero-
cycles from Alcohols. Org. Biomol. Chem. 2012, 10, 240. (g) Hisano, T.;
Ichikawa, M.; Nakagawa, A.; Tsuji, M. Studies on Organosulfur
Compounds. XII. Syntheses and Pharmacological Activities of 2-
Heterocyclic Substituted 4(3H)-Quinazolinones. Chem. Pharm. Bull.
1975, 23, 1910. (h) Abdel-Jalil, R. J.; Aldoqum, H. M.; Ayoub, M. T.;
Voelter, W. Synthesis and Antitumor Activity of 2-Aryl-7-fluoro-6-(4-
methyl-1-piperazinyl)-4(3H)-quinazolinones. Heterocycles 2005, 65,
2061. (i) Bakavoli, M.; Shiri, A.; Ebrahimpour, Z.; Rahimizadeh, M.
Clean Heterocyclic Synthesis in Water: I2/KI Catalyzed One-Pot
Synthesis of Quinazolin-4(3H)-ones. Chin. Chem. Lett. 2008, 19, 1403.
(j) Balakumar, C.; Lamba, P.; Kishore, D. P.; Narayana, B. L.; Rao, K.
V.; Rajwinder, K.; Rao, A. R.; Shireesha, B.; Narsaiah, B. Synthesis, Anti-
Inflammatory Evaluation and Docking Studies of Some New
Fluorinated Fused Quinazolines. Eur. J. Med. Chem. 2010, 45, 4904.
(12) Zhao, D.; Wang, T.; Li, J. X. Metal-Free Oxidative Synthesis of
Quinazolinones via Dual Amination of sp3 C−H Bonds. Chem.
Commun. 2014, 50, 6471.
(13) Li, Q.; Huang, Y.; Chen, T.; Zhou, Y.; Xu, Q.; Yin, S. F.; Han, L.
B. Copper-Catalyzed Aerobic Oxidative Amination of sp3C−H Bonds:
Efficient Synthesis of 2-Hetarylquinazolin-4(3H)-ones. Org. Lett. 2014,
16, 3672.
(14) Yang, X.; Cheng, G.; Shen, J.; Kuai, C.; Cui, X. Cleavage of the
C−C Triple Bond of Ketoalkynes: Synthesis of 4(3H)-Quinazolinones.
Org. Chem. Front. 2015, 2, 366.
(15) Nguyen, T. B.; Le Bescont, J.; Ermolenko, L.; Al-Mourabit, A.
Cobalt- and Iron-Catalyzed Redox Condensation of o-Substituted
Nitrobenzenes with Alkylamines: a Step- and Redox-Economical
Synthesis of Diazaheterocycles. Org. Lett. 2013, 15, 6218.
(16) (a) Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Highly Efficient
Copper-Catalyzed Cascade Synthesis of Quinazoline and Quinazoli-
none Derivatives. Chem. Commun. 2008, 47, 6333. (b) Liu, X.; Fu, H.;
Jiang, Y.; Zhao, Y. A Simple and Efficient Approach to Quinazolinones
under Mild Copper-Catalyzed Conditions. Angew. Chem., Int. Ed. 2009,
48, 348. (c) Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y.
Environmentally Friendly Iron-Catalyzed Cascade Synthesis of 1,2,4-
Benzothiadiazine 1,1-Dioxide and Quinazolinone Derivatives. J. Comb.
Chem. 2009, 11, 653. (d) Xu, W.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H.
Copper-Catalyzed Domino Synthesis of Quinazolinones via Ullmann-
Type Coupling and Aerobic Oxidative C−H Amidation. Org. Lett.
2011, 13, 1274. (e) Xu, W.; Fu, H. Amino Acids as the Nitrogen-
Containing Motifs in Copper-Catalyzed Domino Synthesis of N-
Heterocycles. J. Org. Chem. 2011, 76, 3846. (f) Xu, L.; Jiang, Y.; Ma, D.
Synthesis of 3-Substituted and 2,3-Disubstituted Quinazolinones via
Cu-Catalyzed Aryl Amidation. Org. Lett. 2012, 14, 1150. (g) Chen, H.;
Chiba, S. Copper-Catalyzed Redox-Neutral C−H Amination with
Amidoximes. Org. Biomol. Chem. 2014, 12, 42. (h) Guo, S.; Li, Y.; Tao,
L.; Zhang, W.; Fan, X. Rapid Assembly of Quinazolinone Scaffold via
Copper-Catalyzed Tandem Reaction of 2-Bromobenzamides with
(29) Gelling, I. R.; Wibberley, D. G. Pyridopyrimidines. Part V.l
Syntheses and Properties of Pyrido[3,4-d]-pyrimidin-4(3H)-ones and
-pyrimidine-2,4-(1H,3H)-diones. J. Chem. Soc. C 1969, 0, 931.
G
DOI: 10.1021/acs.joc.8b01460
J. Org. Chem. XXXX, XXX, XXX−XXX