Palladium-catalyzed one-pot synthesis of quinazolinones via tert-butyl isocyanide insertion

Article abstract of DOI:10.1021/jo500636y

A novel palladium-catalyzed three-component reaction for the synthesis of quinazolin-4(3H)-ones from readily available 2-aminobenzamides and aryl halides via a palladium-catalyzed isocyanide insertion/cyclization sequence has been developed. This methodology efficiently constructs quinazolin-4(3H)-ones in moderate to excellent yields with the advantages of operational simplicity.

Full text of DOI:10.1021/jo500636y

Article
pubs.acs.org/joc
Palladium-Catalyzed One-Pot Synthesis of Quinazolinones via tert-
Butyl Isocyanide Insertion
Xiao Jiang,† Ting Tang,† Jin-Mei Wang,† Zhong Chen,† Yong-Ming Zhu,*,† and Shun-Jun Ji*,‡
†College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
‡College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China
S
* Supporting Information
ABSTRACT: A novel palladium-catalyzed three-component
reaction for the synthesis of quinazolin-4(3H)-ones from
readily available 2-aminobenzamides and aryl halides via a
palladium-catalyzed isocyanide insertion/cyclization sequence
has been developed. This methodology efficiently constructs
quinazolin-4(3H)-ones in moderate to excellent yields with the advantages of operational simplicity.
and their co-workers provided a similar palladium-catalyzed
three-component approach to forming N-containing hetero-
cyclic compounds without further hydrolysis. In a continuation
of our interest in forming potentially bioactive nitrogen
heterocycles, we considered that quinazolin-4(3H)-ones could
be prepared by establishing a C−N bond between easily
accessible anthranilamide20 and aryl halides via palladium-
catalyzed isocyanide insertion under more convenient and mild
conditions (Scheme 2).
INTRODUCTION
■
Quinazolinones, existing in many naturally occurring alkaloids,1
are a significant class of heterocycles. They exhibit various kinds
of biological activities, including antibacterial,2 antifungal,3
antimalarial,4 anticancer,5 antihypertensive,6 antitubercular,7
inhibitors of derived growth factor receptor phosphorylation,8
anticonvulsant,9 selective COX-II inhibitors,10 and other
activities.11 Moreover, they are important building blocks in
the synthesis of natural products12 and bioactive compounds.
As a result, numerous methods for the synthesis of
quinazolinones based on the condensation of 2-aminobenzoic
acids or their derivatives with aldehydes, acid chlorides, or
carboxylic acid derivatives have been developed13 (Scheme 1).
Remarkably, carbon monoxide (CO) used as C1 source can be
introduced to preparing carbonyl-containing compounds. For
instance, the groups of Zhu14a and Beller14b have reported the
construction of quinazolin-4(3H)-ones with moderate yield via
palladium-catalyzed CO insertion (Scheme 1).
RESULTS AND DISCUSSION
■
Initially, anthranilamide and iodobenzene were reacted with
tert-butyl isocyanide in the presence of PdCl2, DPPP, and
Cs2CO3 in toluene, and the reaction conditions were modeled
after the report of Shipman.17s When the reaction was
performed at 120 °C for 8 h, the desired product 2-
phenylquinazolin-4(3H)-one was formed in 27% yield because
of the generation of amide17i (Table 1, entry 1). A slightly
higher yield of 3a was obtained in the presence of CaCl2 as a
dry agent (Table 1, entries 2−4); nevertheless, anthranilamide
could not be converted totally. To our delight, complete
transformation of anthranilamide was achieved (Table 1, entry
5) by increasing the amount of iodobenzene, tert-butyl
isocyanide, and Cs2CO3. Higher temperature gave an even
better yield of 62% (Table 1, entry 6). Further optimization led
to an improved yield of 93% with changing the base to t-
BuONa (Table 1, entries 7 and 8). Solvent screening revealed
that toluene was the optimal solvent (Table 1, entries 9−11). A
lower yield was obtained when other palladium catalysts such as
Pd(OAc)2 and Pd2(dba)3 were employed (Table 1, entries 12
and 13). After many trials with other commercially available
ligands (Table 1, entries 14−18), DPPP gave the best yields of
quinazolinone. Thus, we chose PdCl2 (5%) and DPPP (10%)
as the catalyst system, with t-BuONa (4 equiv) as base, CaCl2
However, the drawbacks of long reaction time, high pressure,
and toxicity limited the applications of CO reactions.
Isocyanides, which are economic and stable kinds of liquid or
solid compounds, are considered as an isoelectronic species of
gaseous CO. Thus, they could be used as an easier handled and
a safer alternative to odorless CO in palladium-catalyzed
carbonylation reactions. Since the initial work of Passerini15 and
Ugi,16 the utility of nucleophilicity and electrophilicity of
isocyanides in multicomponent reactions (MCRs) has been
widely explored. In the past decades, other reactive properties
involving isocyanides, such as isocyanide insertion, have been
attracting more attention. Many applications of isocyanide as a
versatile C1 building block in palladium-catalyzed insertion into
carbon−halogen bonds,17 heteroatom−hydrogen bonds,18a−c
carbon−hydrogen bonds,19 and double carbon−metal bonds in
carbenes18d,e have been reported, which provide a potential for
synthesizing nitrogen-containing fine chemicals. Our group has
successfully constructed the skeleton of isocoumarins,
phthalides,17n and alkynones17q through palladium-catalyzed
isocyanide insertion into C−X bonds. Lang,17j,r Shipman,17s
Received: March 18, 2014
© XXXX American Chemical Society
A
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Scheme 1. Major Methods for Synthesis of Quinazolin-4(3H)-ones
(2 equiv) as an additive, and toluene as solvent to continue our
investigation.
Scheme 2. Strategy to Quinazolin-4(3H)-ones via tert-Butyl
Isocyanide Insertion
Having optimized the reaction conditions, we next explored
the scope of the reaction using anthranilamide and various aryl
halides (Table 2). As indicated in Table 2, most aryl iodides
with electron-donating groups give better results (Table 2,
entries 1−4, 9 and 11) than the substrates with electron-
withdrawing groups (Table 2, entries 6, 8, and 10). Due to a
a
Table 1. Condition Optimizations
b
entry
catalyst
ligand
DPPP
base
solvent
temp (°C)
yield (%)
c
1
2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
Pd2(dba)3
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
AcONa
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DMSO
DMF
120
120
120
120
120
145
145
145
145
145
145
145
145
145
145
145
145
145
27
cd
,
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
PCy3
35
29
28
53
62
ce
,
3
cf
,
4
5
6
7
trace
93
8
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
9
69
10
11
12
13
14
15
16
17
18
61
trace
53
toluene
toluene
toluene
toluene
toluene
toluene
toluene
39
28
DPPB
DPPF
DPEPhos
(R)-BINAP
88
73
51
80
a
Reaction conditions: All reactions were performed with 1a (0.7 mmol), 2a (2.1 mmol), tert-butyl isocyanide (2.1 mmol), catalyst (5 mol %), ligand
(10 mol %), base (4 equiv), and CaCl2 (2 equiv) in 3.0 mL of solvent under nitrogen for 8 h in a round-bottom flask. DPPP = 1,3-
bis(diphenylphosphino)propane, PCy3 = tricyclohexylphosphine, DPPB = 1,4-bis(diphenylphosphino)butane, DPPF = 1,1′-bis(diphenyl-
phosphino)ferrocene, DPEPhos = bis[(2-diphenylphosphino)phenyl]ether, (R)-BINAP = (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.
b
c
Isolated yield. The reaction condtions were 1a (0.7 mmol), 2a (0.84 mmol), tert-butyl isocyanide (0.84 mmol), catalyst (5 mol %), ligand (10
d
e
f
mol %), and base (2 equiv) in 3.0 mL of solvent without CaCl2. Anhydrous CaCl2 (2 equiv). Anhydrous Na2SO4 (2 equiv). Anhydrous MgSO4 (2
equiv).
B
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Table 2. Synthesis of Quinazolin-4(3H)-ones from Various Aryl Halides via Palladium-Catalyzed One-Pot Cyclization
a b
,
Reaction
a
All reactions were performed under nitrogen, using anthranilamide (0.7 mmol), aryl halides (2.1 mmol), tert-butyl isocyanide (2.1 mmol), PdCl2 (5
b
mol %), DPPP (10 mol %), t-BuONa (4 equiv), and CaCl2 (2 equiv) in toluene (3.0 mL) at 145 °C for 8 h. Reaction at 120 °C, 10 h
steric effect, the reaction of 1a with o-methyliodobenzene
(Table 2, entry 3) afforded a lower yield than p-
methyliodobenzene (Table 2, entry 2). m-Methoxyiodobenzene
provided the quinazolin-4(3H)-ones in good yield (Table 2,
entry 4). However, as an electron-donating group, p-phenyl-
iodobenzene gave a poor yield (Table 2, entry 7). As for
electron-poor substituents, such as p-fluoro, p-chloro, and p-
trifluoromethyl groups, the desired products were obtained in
41−86% yield (Table 2, entries 5, 6, and 8). In addition, the
product of dimethyl-substituted aryl iodide was efficiently
generated in 93% yield (Table 2, entry 9), but the substrate
with a relevant 3,5-difluorophenyl group had a low yield (Table
2, entry 10). Heteroaromatic substrates were converted to the
corresponding product in good yield (Table 2, entry 11).
Besides, the yield of bromobenzene (Table 2, entry 12) was a
little lower than that of iodobenzene. Some aryl bromides
C
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screened under our best conditions were transformed to the
desired quinazolinones in moderate to excellent yield (Table 2,
entries 13−15). 1H NMR/13C NMR spectra of 3l revealed that
there was tautomerism between quinazolin-4(3H)-one and
quinazolin-4(1H)-one.
Scheme 3. Plausible Mechanism for the Synthesis of
Quinazolin-4(3H)-ones
To extend the application of this reaction, we then
investigated the reaction of various anthranilamides, and the
results are summarized in Table 3. Both electron-rich (Table 3,
Table 3. Synthesis of Quinazolin-4(3H)-ones from Various
Anthranilamides via Palladium-Catalyzed One-Pot
a
Cyclization Reaction
constructing a C−N bond without further hydrolytic
deaminization offers a rapid and operationally simple route
avoiding the use of toxic carbon monoxide under high pressure
conditions for this class of compounds.
EXPERIMENTAL SECTION
■
General Remarks. Chemicals and reagents were purchased from
commercial suppliers and used without further purification. All
anhydrous solvents used in the reactions were dried and freshly
distilled. TLC was performed on silica HSGF254 plates. Melting
points were determined with a digital melting-point apparatus. 1H and
13C NMR spectra were obtained from a solution in DMSO-d6 with
TMS as internal standard using a 400/101 MHz (1H/13C) or 600/151
MHz (1H/13C) spectrometer. Chemical shifts (δ) are given in ppm
and J in Hz. HRMS or LRMS analyses were carried out on an
electrospray ionization (ESI) apparatus using time-of-flight (TOF)
mass spectrometry.
General Procedure for the Synthesis of Quinazolinones. 1
(0.7 mmol, 1 equiv), 2 (2.1 mmol, 3 equiv), tert-butyl isocyanide (2.1
mmol, 237 μL, 3 equiv), PdCl2 (0.035 mmol, 6 mg, 5 mol %), DPPP
(0.07 mmol, 29 mg, 10 mol %), t-BuONa (2.8 mmol, 269 mg, 4
equiv), anhydrous CaCl2 (1.4 mmol, 156 mg, 2 equiv), and anhydrous
toluene (3.0 mL) were added to a 25 mL round-bottom flask equipped
with a magnetic stirring bar. The flask was purged with nitrogen and
refluxed at 145 °C for 8 h. After completion of the reaction indicated
by TLC, the mixture was filtered and the solvent was removed under
vacuum. Then, the resulting mixture was purified by column
chromatography on silica gel using petroleum ether/EtOAc as eluent
to provide the pure target product.
a
All reactions were performed under nitrogen, using anthranilamides
(0.7 mmol), iodobenzene (2.1 mmol), tert-butyl isocyanide (2.1
mmol), PdCl2 (5 mol %), DPPP (10 mol %), t-BuONa (4 equiv), and
CaCl2 (2 equiv) in toluene (3.0 mL) at 145 °C for 8 h.
entry 4) and electron-poor (Table 3, entries 1−3) substrates
gave good yields, whereas difluoro-substituted anthranilamides
gave an even lower yield (Table 3, entry 3).
2-Phenylquinazolin-4(3H)-one (3a):14b White solid (145 mg,
1
93%); mp 239−240 °C. H NMR (400 MHz, DMSO-d6): δ 12.58
(s, 1H), 8.21 (t, J = 8.8 Hz, 3H), 7.87 (t, J = 7.5 Hz, 1H), 7.78 (d, J =
8.0 Hz, 1H), 7.66−7.51 (m, 4H). 13C NMR (101 MHz, DMSO-d6): δ
162.2, 152.3, 148.8, 134.6, 132.7, 131.4, 128.6, 127.8, 127.5, 126.6,
125.9, 121.0. LRMS (ESI): m/z calcd for C14H10N2O [M + H]+,
223.1; found, 223.0.
A plausible mechanism for this reaction is depicted in
Scheme 3. Oxidative addition of aryl halides to the Pd(0)
catalyst facilitates the formation of palladium complex 2,
followed by tert-butyl isocyanide insertion to get palladium(II)
species 3. Then, under the assistance of t-BuONa, the addition
of 2-aminobenzamide gives the generation of 4, which leads to
the desired 4(3H)-quinazolinones after cyclization with losing
tert-butylamine.
2-p-Tolylquinazolin-4(3H)-one (3b):14a White solid (145 mg,
1
88%). mp 231−234 °C. H NMR (400 MHz, DMSO-d6): δ 12.45
(s, 1H), 8.11 (d, J = 6.8 Hz, 3H), 7.76 (dd, J = 20.5, 9.9 Hz, 2H), 7.49
(s, 1H), 7.32 (s, 2H), 2.36 (s, 3H). 13C NMR (101 MHz, DMSO-d6):
δ 151.8, 148.4, 141.0, 134.1, 129.4, 128.8, 127.3, 127.0, 125.9, 125.4,
120.5, 20.5. LRMS (ESI): m/z calcd for C15H12N2O [M + H]+, 237.1;
found, 237.0.
CONCLUSIONS
■
In summary, we have demonstrated a novel method for the
preparation of quinazolin-4(3H)-ones from anthranilamides
and aryl halides with isocyanide insertion in one step by an
efficient palladium-catalyzed three-component reaction, which
proceeded in reasonable to excellent yields. The strategy of
2-o-Tolylquinazolin-4(3H)-one (3c):14a White solid (121 mg,
1
73%). mp 220−222 °C. H NMR (400 MHz, DMSO-d6): δ 12.45
(s, 1H), 8.18 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.69 (d, J =
7.6 Hz, 1H), 7.51 (d, J = 5.7 Hz, 2H), 7.41 (d, J = 6.6 Hz, 1H), 7.34
(d, J = 7.1 Hz, 2H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6): δ
D
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161.9, 154.4, 148.8, 136.2, 134.5, 134.3, 130.6, 129.9, 129.2, 127.9,
126.7, 125.8, 125.7, 121.0, 19.6. LRMS (ESI): m/z calcd for
C15H12N2O [M + H]+, 237.1; found, 237.1.
MHz, DMSO-d6): δ12.51 (s, 3H), 8.21 (s, 1H, tautomer), 8.11 (m,
8H), 7.85 (d, J = 6.0 Hz, 1H, tautomer), 7.78 (s, 3H), 7.72 (d, J = 6.5
Hz, 2H), 7.63 (s, 1H, tautomer), 7.48 (s, 2H), 7.44−7.33 (m, 6H),
2.92 (d, J = 4.9 Hz, 3H), 1.19 (s, 18H). 13C NMR (101 MHz, DMSO-
d6): δ 162.4, 161.2, 155.5, 152.3, 152.1, 149.3, 148.8, 147.2, 134.7,
134.5, 131.9, 131.2, 130.3, 128.5, 128.3, 127.9, 127.4, 126.6, 126.4,
126.1, 125.9, 122.9, 120.9. LRMS (ESI): m/z calcd for C17H16N2O [M
+ H]+, 265.1; found, 265.0.
2-(3-Methoxyphenyl)quinazolin-4(3H)-one (3d):14a White solid
(143 mg, 81%); mp 181−183 °C. 1H NMR (400 MHz, DMSO-d6): δ
12.55 (s, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.83−7.77 (m, 2H), 7.74 (d, J
= 7.3 Hz, 2H), 7.51 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.13
(d, J = 7.7 Hz, 1H), 3.85 (s, 3H). 13C NMR (101 MHz, DMSO-d6): δ
162.3, 159.4, 152.0, 148.7, 134.6, 134.0, 129.8, 127.6, 126.6, 125.9,
121.1, 120.2, 117.6, 112.5, 55.4. LRMS (ESI): m/z calcd for
C15H12N2O2 [M + H]+, 253.1; found, 253.0.
2-(4-tert-Butylphenyl)quinazolin-4(3H)-one (3m):14b White solid
(173 mg, 89%); mp 151−152 °C. 1H NMR (400 MHz, DMSO-d6): δ
12.46 (s, 1H), 8.13 (d, J = 7.5 Hz, 3H), 7.85−7.79 (m, 1H), 7.72 (d, J
= 7.6 Hz, 1H), 7.58−7.49 (m, 3H), 1.31 (s, 9H). 13C NMR (101
MHz, DMSO-d6): δ 162.3, 154.3, 152.2, 134.6, 130.9, 130.0, 128.4,
127.6, 126.5, 125.9, 125.4, 120.9. LRMS (ESI): m/z calcd for
C16H14N2O [M + H]+, 279.1; found, 279.0.
2-(4-Fluorophenyl)quinazolin-4(3H)-one (3e):13n White solid (140
mg, 83%); mp 293−295 °C. 1H NMR (600 MHz, DMSO-d6): δ 12.53
(s, 1H), 8.23 (s, 2H), 8.14 (d, J = 7.4 Hz, 1H), 7.81 (d, J = 6.9 Hz,
1H), 7.72 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 6.7 Hz, 1H), 7.37 (t, J = 8.0
Hz, 2H). 13C NMR (151 MHz, DMSO-d6): δ 165.3, 163.6, 162.7,
151.8, 149.1, 135.1, 130.8, 130.8, 129.7, 129.7, 127.9, 127.0, 126.3,
121.3, 116.1, 116.0. LRMS (ESI): m/z calcd for C14H9FN2O [M +
H]+, 241.1; found, 241.0.
2-(Naphthalen-2-yl)quinazolin-4(3H)-one (3n):14b White solid
1
(82 mg, 43%); mp 285−287 °C. H NMR (400 MHz, DMSO): δ
12.86 (s, 1H), 8.25 (s, 1H), 8.17−8.01 (m, 3H), 7.99−7.80 (m, 4H),
7.70−7.44 (m, 5H). 13C NMR (101 MHz, DMSO): δ 161.5, 149.7,
147.4, 135.6, 135.0, 134.2, 132.0, 131.5, 130.2, 129.7, 128.7, 128.5,
128.0, 127.4, 126.3, 125.2, 123.0.
2-(4-Chlorophenyl)quinazolin-4(3H)-one (3f):13g White solid (118
mg, 66%); mp 278−279 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.62
(s, 1H), 8.19 (d, J = 8.1 Hz, 2H), 8.15 (d, J = 8.1 Hz, 1H), 7.84 (d, J =
7.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.53 (t,
J = 7.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 162.3, 151.5,
148.7, 136.4, 134.9, 132.9, 131.6, 129.8, 128.8, 127.6, 127.0, 126.0,
121.1. LRMS (ESI): m/z calcd for C14H9ClN2O [M + H]+, 257.0;
found, 256.9.
7-Fluoro-2-phenylquinazolin-4(3H)-one (3o):21 White solid (143
mg, 85%); mp >300 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.62 (s,
1H), 8.36−7.99 (m, 3H), 7.70−7.42 (m, 4H), 7.35 (t, J = 8.6 Hz, 1H).
13C NMR (101 MHz, DMSO-d6): δ 167.1, 164.6, 161.6, 153.7, 151.0,
150.8, 132.4, 131.7, 130.9, 129.0, 128.9, 128.6, 127.9, 118.0, 115.2,
114.9, 112.5, 112.3. LRMS (ESI): m/z calcd for C14H9FN2O [M +
H]+, 241.1; found, 241.0.
2-(Biphenyl-4-yl)quinazolin-4(3H)-one (3g):23 White solid (102
mg, 49%); mp 265−267 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.61
(s, 1H), 8.30 (d, J = 7.9 Hz, 2H), 8.17 (d, J = 7.5 Hz, 1H), 7.85 (d, J =
7.8 Hz, 3H), 7.76 (d, J = 5.9 Hz, 4H), 7.55−7.47 (m, 2H), 7.42 (d, J =
6.7 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ 162.7, 152.4, 149.2,
143.3, 139.4, 135.1, 132.0, 129.5, 128.8, 128.6, 128.0, 127.3, 127.2,
127.0, 126.3, 121.5. LRMS (ESI): m/z calcd for C20H14N2O [M +
H]+, 299.1; found, 299.0.
7-Chloro-2-phenylquinazolin-4(3H)-one (3p):13d White solid (134
mg, 75%); mp >300 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.61 (s,
1H), 8.19 (d, J = 8.0 Hz, 2H), 8.15 (d, J = 7.9 Hz, 1H), 7.88−7.80 (m,
1H), 7.74 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 2H), 7.53 (t, J = 7.1
Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 162.3, 151.4, 148.6,
136.4, 134.8, 134.3, 131.6, 129.7, 128.8, 126.9, 126.0, 121.0. LRMS
(ESI): m/z calcd for C14H9N2O [M + H]+, 257.0; found, 256.9.
6,7-Difluoro-2-phenylquinazolin-4(3H)-one (3q):22 White solid
2-(4-(Trifluoromethyl)phenyl)quinazolin-4(3H)-one (3h):14b
1
1
(74 mg, 41%); mp 249−250 °C. H NMR (400 MHz, DMSO-d6):
White solid (83 mg, 41%); mp 229−230 °C. H NMR (400 MHz,
δ 12.43 (s, 1H), 8.13 (d, J = 6.5 Hz, 2H), 8.05−7.93 (m, 1H), 7.72
(dd, J = 10.7, 6.8 Hz, 1H), 7.62−7.45 (m, 3H). 13C NMR (101 MHz,
DMSO-d6): δ 161.1, 155.3, 155.1, 153.4, 152.7, 152.6, 149.7, 149.6,
147.2, 147.1, 146.8, 146.7, 132.4, 131.6, 128.6, 127.8, 118.3, 118.2,
115.4, 115.2, 113.5, 113.3. LRMS (ESI): m/z calcd for C14H8F2N2O
[M + H]+, 259.1; found, 258.8.
DMSO-d6): δ 12.68 (s, 1H), 8.35 (s, 2H), 8.16 (s, 1H), 8.05−7.62 (m,
4H), 7.54 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 162.2, 161.1,
151.2, 148.5, 148.2, 147.0, 147.0, 137.8, 137.8, 136.6, 136.6, 134.8,
134.8, 131.7, 129.0, 128.7, 128.6, 127.7, 127.7, 127.1, 126.1, 125.9,
125.5, 125.5, 125.3, 125.3, 123.1, 122.6, 121.2. LRMS (ESI): m/z calcd
for C15H9F3N2O [M + H]+, 291.1; found, 290.9.
8-Methyl-2-phenylquinazolin-4(3H)-one (3r):14a White solid (124
mg, 75%); mp 248−249 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.52
(s, 1H), 8.22 (d, J = 6.8 Hz, 2H), 7.98 (d, J = 7.7 Hz, 1H), 7.67 (d, J =
7.0 Hz, 1H), 7.55 (d, J = 7.3 Hz, 3H), 7.38 (t, J = 7.5 Hz, 1H), 2.61 (s,
3H). 13C NMR (151 MHz, DMSO-d6): δ 163.0, 151.5, 147.6, 136.1,
135.3, 133.4, 131.8, 129.1, 128.2, 126.5, 123.9, 121.3, 17.6. LRMS
(ESI): m/z calcd for C15H12N2O [M + H]+, 237.1; found, 237.0.
2-(3,5-Dimethylphenyl)quinazolin-4(3H)-one (3i):24 White solid
(156 mg, 89%); mp 273−273 °C. 1H NMR (400 MHz, DMSO-d6): δ
12.41 (s, 1H), 8.14 (d, J = 7.1 Hz, 1H), 7.81 (s, 3H), 7.73 (d, J = 6.9
Hz, 1H), 7.51 (d, J = 6.3 Hz, 1H), 7.20 (s, 1H), 2.35 (s, 6H). 13C
NMR (101 MHz, DMSO-d6): δ 162.1, 152.4, 148.8, 137.8, 134.6,
132.7, 128.3, 127.4, 126.5, 125.8, 125.5, 121.0. LRMS (ESI): m/z calcd
for C16H14N2O [M + H]+, 251.1; found, 251.0.
2-(3,5-Difluorophenyl)quinazolin-4(3H)-one (3j): White solid (78
mg, 43%); mp 259−260 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.69
(s, 1H), 8.19 (m, 1H), 8.00−7.73 (m, 4H), 7.67 (s, 1H), 7.58−7.31
(m, 1H). 13C NMR (101 MHz, DMSO-d6): δ 164.1, 164.0, 163.6,
163.5, 162.5, 161.7, 161.5, 161.2, 161.1, 150.4, 148.6, 148.4, 147.4,
137.8, 137.8, 137.7, 137.6, 136.7, 136.6, 136.5, 135.3, 129.4, 129.1,
128.2, 127.7, 126.5, 126.4, 123.6, 121.7, 114.8, 114.7, 114.6, 114.5,
111.7, 111.6, 111.5, 111.4, 110.0, 109.8, 109.5, 107.6, 107.3, 107.0. IR
(KBr): ν = 1684, 1594, 1337, 1123, 989, 864, 769, 670 cm−1. HRMS
(ESI): m/z calcd for C14H8F2N2O [M + H]+, 259.0677; found,
259.0691.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H 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: zhuyongming@suda.edu.cn. Fax: (+86)-512-
67166591.
*E-mail: shunjun@suda.edu.cn (S.-J.J.)
■
2-(Thiophen-2-yl)quinazolin-4(3H)-one (3k):14b Yellow solid (104
mg, 65%); mp 278−279 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.67
(s, 1H), 8.23 (s, 1H), 8.12 (d, J = 6.9 Hz, 1H), 7.87 (s, 1H), 7.80 (s,
1H), 7.65 (d, J = 7.3 Hz, 1H), 7.48 (s, 1H), 7.23 (s, 1H). 13C NMR
(151 MHz, DMSO-d6): δ 162.2, 149.1, 148.3, 137.8, 135.1, 132.6,
129.8, 128.9, 127.4, 126.8, 126.4, 121.3. LRMS (ESI): m/z calcd for
C12H8N2OS [M + H]+, 229.0; found, 229.0.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support by PAPD (A
Project Funded by the Priority Academic Program Develop-
■
2-(4-Isopropylphenyl)quinazolin-4(3H)-one (3l):25 Tautomer ratio
1
(2:1), white solid (170 mg, 92%); mp 153−155 °C. H NMR (400
E
dx.doi.org/10.1021/jo500636y | J. Org. Chem. XXXX, XXX, XXX−XXX

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dx.doi.org/10.1021/jo500636y | J. Org. Chem. XXXX, XXX, XXX−XXX